LU79774A1 - PROCESS FOR THE PREPARATION OF PENICILLANIC ACID 1,1-DIOXIDES AND ITS ESTERS USEFUL AS B-LACTAMASE INHIBITORS - Google Patents

Description

OC 40.799

-Z J_ GfîAND-DUCHÉ DE LUXEMBOURG

/ —...... Î7â ...... 7 7 4 from ........ 6 ...... June ..... 197.8 ......... ... Œg Mr. Minister ,,,. , the National Economy and the Middle Classes

Title issued: ........................................ 3¾¾ j Industrial Property Service

'' LUXEMBOURG

'y // W

/. Patent Application / u-M _................................

* I. Request ........ The ..... company ... d.ite: ..... PF LS ER..INC .., ...... 235 ... East ..... 42M .... S.treet. / ...... to ........................... ..... (1, * ........ JSEM-YQßK., ..... E.ta.t ... de ..... New-Yo.rk.f .. ... E.fca.tS "Onis ...... d .. ^ ÂJïïérigue. / ...... r.eprés.en · -.........

......... fcéé. ,, par .... MQ.ns.le.ur ...... Ja.cgues .... da .. „^ ....... ................ ® ......... ds .... authorized .................. .................................................. .................................................. .................................................. ..................................................

deposit ........ this ..... SlX ..... June ..... 19.QQ ..... SQ.ixanfce. ~ d.iXr.huifc ..... .................................................. ........ (3) at ............. 15 ......... .. hours, at the Ministry of National Economy and the Middle Classes , in Luxembourg: 1. the present request for obtaining a patent for an invention concerning: ........ "Process of ..... prepa.ration ... âG .... .l.rlrd.ioxvdes de ..... lVacide .... pGniçil -..... (4) .............. lanique et de ..... ses will be ..... useful as ..... inhibitors ..........................

........... ^. “Lactamasa" .................................. .................................................. .................................................. .................................................. ...................................

declares, assuming responsibility for this declaration, that the inventor (s) is (are): ......... Kaÿne ..... Ern! âs: L_.BSR3ÎH.,. .... 4Q .... MD.ntiG.ello ..... Driv.e .., ...... âJB & SUiQfflU .................. .............. (5) ......... C.Qrat.é ..... de .... Iï.ew ... Lo.ndQn ./......E.ta.t....de....c;Qnn.e.çtiGut./......EM.fes-nais Vacation..â!.Mé. r.içDae 2. the delegation of power, dated ....... NM'i “YORK .......................... .. le ..... 2.4 .... abri.l ..... l9.78 _______ 3. description in language ......... fXclïlÇcviSG .......... ......................... of the invention in two copies; 4 ........ /. / ............... ... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on __________CL. June ..... 19.78 ........................................... .................................................. .................................................. .................................................. ............................

claims priority for the above patent application Aid (s) request (s) of (6) ....................... patent ... ........................................... filed® s <r / ( 7) .......... in .... States. “Un.is ..... dimérique ...........

on ...... 7 ..... June ..... 19.7.7 .......... (No, ...... 8o4.32o) and, on February 21 1978 ................................................. (8) ............... (Er ...... 8.79 ..,. 381) ................. .................................................. .........................

in the name of ......... X .. 'lî «æ; ntfôMr ............................. .................................................. .................................................. ................................................ .. .. (9) elect domicile for him / her and, if designated, for their proxy, in Luxembourg ........................... ............

.......... 3.5, ..... bld. Royal................................................. .................................................. .................................................. ............................................. ao> request delivery a patent for the invention for the subject described and represented in the appendices y ”above. - with postponement of this issue to ............... 13 ....................... month.

II. Deposit Minutes

The aforementioned patent application has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, dated: ’_ June 6, 1578! ! - Pr. The Minister 1 to 3 p.m. - / of the National Economy and the Middle Classes,

: (0 'B ................................ U' M% tT

i >> V - The I./V ^ hf! I Λ KS> nfi7 \ 1 ^ '· ....... c: r-à ·. $ / Y y D. 4o.799

CLAIMING PRIORITY

'· Of the patent application / çfi / _............

i £ pi IN THE UNITED STATES OF AMERICA

I JUNE 7, 1977 ".

FEBRUARY 21, 1978 ΝΜΝΜΜΜΜΜ · ΜΜΜ ·· "Μ · ΜΜΜΙ ·· ΐη ·· Μ ·· ΜΗ · ΗΗ ·· Μ · * Brief Description j] filed in support of a request for

PATENT

at

Luxembourg; i | on behalf of: PFIZER INC.

j j i | I for: "Process for the preparation of 1,1-dioxides of penicillanic acid and of its esters useful as inhibitors of ^ -lactamase".

i! *] i! ^ | * i i "***. . 1

The present invention relates to 1,1-dioxides of penicillanic acid and its esters useful as inhibitors of β-lactamase.

One of the best known and most commonly used categories of antibacterial agents is β-lactam antibiotics. These compounds are characterized by the presence of a nucleus consisting of a jf 2-azetidinone (β-lactam) ring condensed either to a thiazolidine ring. either to a dihydro-1,3-thiazine cycle. When the nucleus contains a thiazolidine ring, the compounds are penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are cephalosporins. As typical examples of penicillins commonly used in clinical practice, benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalotin, cephalexin and cefazolin.

However, despite the common use of β-lactam antibiotics as useful chemotherapeutic agents, some of them have the serious disadvantage of not being active against certain microorganisms. It appears that in many cases this resistance of particular microorganisms to a given β-lactam antibiotic is due to the production of β-lactamase by the microorganism. Ss-lactamases are enzymes that cleave the ß-lactam cycle of penicillins and cephalosporins to form products that are devoid of antibacterial activity. However, some substances are capable of inhibiting ß-lactamase and h when using a β-lactamase inhibitor in combination with penicillin or cephalosporin, the antibacterial activity of penicillin can be increased or cephalosporin against certain microorganisms. The increase in antibacterial efficacy of a combination of a β-lactamase-inhibiting substance and a β-lactam antibiotic is believed to be significantly greater than the sum of the antibacterial activities of the individual components.

The invention relates to new chemical compounds i 2 j τ- belonging to penicillins which are useful as antibacterial agents. More particularly, these compounds are 1,1-dioxides of fishericillanic acid and its esters which are easily hydrolyzable in vivo.

5 In addition, the 1,1-dioxides of fishericillanic acid and its esters which are easily hydrolyzable in vivo are powerful inhibitors of microbial lactamases. The use of 1,1-dioxide of pnicillanic acid and some of its readily hydrolyzable esters makes it possible to increase the efficacy of β-lactam antibiotics.

The invention also relates to derivatives of 1,1-dioxide of fishericillanic acid comprising a group protecting the carboxy radical, these compounds being useful as chemical intermediates in the synthesis of 1,1-dioxide of fisheryillic acid .

The invention also relates to 1-oxides of fishericillanic acid and of some of its esters useful as chemical intermediates in the synthesis of 1,1-dioxide of fishericillanic acid.

The 1,1-dioxides of benzylpenicillin, phenoxymethylpenicillin and some of their esters have been described in U.S. Patent Nos. 3,197,466 and 3,536,698 and in an article by Guddal et al. . in Tetrahedron Letters No. 9, 38l (1962). Harrison et al.

25 in Journal of the Chemical Society (London), Perkin I, 1772 (1976) described various 1,1-dioxides and 1-oxides of penicillin including methyl phthalimidopenicillanate 1,1-dioxide, 1,1- methyl 6,6-dibromopenicillanate dioxide, methyl penicillanate ία-oxide, methyl penicil-30 lf5-oxide, 6,6-dibromopenicil-lanic acid Ια-oxide and lß- 6,6-dibromopenicillanic acid oxide.

The invention therefore relates to new compounds corresponding to the formula:

0 0 CH

^ 3 H, v / 'rjJT3. ~ '(I)' 'COOR1 i s •. 3 τ- (where R "1" represents a hydrogen atom or an ester-generating residue which is easily hydrolyzable in vivo or a conventional protecting group for the carboxy radical of penicillin), and their salts formed with a base suitable for use in pharmacy.

5 The term "ester-generating residue which is easily hydrolyzable in vivo" means non-toxic ester residues which are rapidly cleaved in the blood or the tissues of γ mammals to release the corresponding free acid (i.e. the compound of formula I, where R1 represents a hydrogen atom).

10 Typical examples of such easily hydrolysable ester-generating residues that R1 can represent are an alkanoyloxymethyl radical containing 3 to 8 carbon atoms / 1- (alkanoyloxy) ethyl comprising 4 to 9 · carbon atoms, 1-methyl 1- (alkanoyloxy) ethyl having 5 to 10 15 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, l-methyl-l- (alkoxycarbonyloxy) ethyl | having 5 to 8 carbon atoms, 3-phthalidyl, 4-crotono- i lactonyl and y-butyrolactone-4-yl.

The compounds of formula (I) or R1 represents a hydrogen atom or an easily hydrolyzable ester-generating residue in vivo are useful as antibacterial agents and for enhancing the antibacterial activity of β-lactam antibiotics. The compounds of formula I, where R1 represents a protecting group for the carboxy radical of penicillin, are useful as chemical intermediates for the synthesis of compounds of formula (I) where R1 represents a hydrogen atom or an easily ester-generating residue hydrolyzable In vivo. Typical protecting groups for the carboxy radical are * 30 benzyl and substituted benzyl groups such as 4 ~ nitrobenzyl.

The invention also relates to the new compounds of formula: “î • · 4 I w ο AA“ 3 JAJA -wi) o '% 1

COOR

and · 1 \ \ l> Œ3!

'P CH3 --- Cm) J

0 ^ N% 1

COOR

(or R1 has the same definition as above) and their salts - These compounds of formulas II and III are intermediates in the preparation of the compounds of formula I.

The invention will now be described in detail.

The invention relates to new compounds of formulas I, II and III which are called in the present description derived from penicillanic acid which is represented! felt by the developed formula: j \ s Λ.

HfJ'CK - {VI))

o / -N ~ \ J

COOH 1

In Formula IV / discontinuous bonding of a bicyclic ring substituent indicates that the substituent is% below the plane of the bicyclic ring. It is said that such a substituent is in the α configuration. Conversely, a continuous line bond of a substituent to the bicyclic nucleus indicates that the substituent is fixed above the plane of the nucleus. This configuration is called configuration 0.

Also, there are cited in the present description certain derivatives of cephalosporanic acid which has the formula: \ 5 '.....

i · - dd) 2 \

Q 7 N Y XCH2-Q-G-CH3 --- (V) J

COOH

* f In formula V, the hydrogen atom on carbon 6 is below the plane of the bicyclic nucleus.

The terms deacetoxycephalosporanic acid and 3-deacetoxymethylcephalosporanic acid respectively designate the compounds of formulas VI and VII:

'·? 'H

j — Γ Ί i — X- ^ \

) -N vYY 0-N

o Y ch3 0 Y.

COOH COOH î / /

VI VII

The 4-crotonolactonyl and γ-butyrolactone-4-yl radicals correspond to formulas VIII and IX respectively.

The wavy lines correspond to the two epimers and their mixtures. % 0 Y

0.

o

7111 'IX

"10 When R1 is an easily generator hydrolyzable ester residue in vivo in a compound of formula I, it consists * of a group theoretically derived from an alcohol of formula R ^ -OH and therefore the COOR fragment of such compound of formula I represents an ester group. In addition, the nature of R1 is such that the COOR1 group is easily cleaved in vivo to release a free carboxy group (COOH). Therefore, Rx is a group such that when a mammalian tissue or blood is brought into contact with a compound of formula I where R1 is a residue i (- ester generator easily hydrolyzed in vivo, we obtain easily the compound of formula I where R1 represents a hydrogen atom. The R "* - groups are well known in penicillin chemistry. In most cases, they improve the absorption characteristics of the penicillinic compound. moreover, the nature of R1 must be such that the compound of formula (I) has properties suitable for pharmacy and that it liberates by cleavage in vivo of the fragments suitable for pharmacy, e As previously indicated the groups R1 are well known and easily identified by penicillin specialists. In this regard, see DOS patent application No. 2,517,316 filed in the Federal Republic of Germany. Typical groups represented by R "* · are 3-phthalidyl radicals, 4-crotonolactonyle, y — buu-yro-15 lacton e-4-yle and those of formulas: R3 -Q R3 0 I "5 I n c - C-O-C-R3“ C-O-C-O-R3 \: * i · j X XI ...

3 4 where R and R each represent a hydrogen atom and an alkyl radical having 1 or 2 carbon atoms and R ^ represents an alkyl radical having 1 to 6 carbon atoms. However, it is preferred that R1 represents an alkanoyloxymethyl radical 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 , 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 -crotonolactonyle and Y ~ butyrolactone-4-yle.

The compounds of formula I can be prepared, where has the definition previously indicated by oxidation of. 30 compounds of formula II or III, where R has the same definition as above. A wide variety of oxidants known in the art of oxidizing the 7 sulfoxides to sulfones can be used in this process. Particularly suitable reducing agents are, however, metal permanganates such as alkaline permanganates and alkaline earth permanganates as well as organic peroxyacids such as peroxycarboxylic organic acids. Mention may in particular be made, as reducing agents, of sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

When oxidizing a compound of formula II or III, where R1 has the definition indicated above (in the corresponding compound of formula I with a metal permanganate, the compound of formula II or III is generally treated with approximately 0.5 to approximately 5 molar equivalents of permanganate and preferably about 1 molar equivalent of permanganate 15 in a suitable solvent system A suitable solvent system is a solvent system which does not exhibit undesirable interaction with the starting materials or the product and is commonly used. If desired, a co-solvent miscible with water but not interacting with permanganate, such as tetrahydrofuran, can be added. The reaction is normally carried out at a temperature within the range from about -20 to about 50 ° C., preferably about 0 ° C. At about 0 ° C., the reaction is normally completed rapidly, for example within an hour. Although the reaction can be carried out by condition neutral, basic or acid, it is preferable to operate under practically neutral conditions to avoid decomposition of the cyclic system (3-lactam of the compound of formula I. In practice it is often advantageous to buffer the pH of the reaction medium in the vicinity of neutrality. The product is collected according to conventional techniques. Generally, any excess permanganate is decomposed with sodium bisulfite and, if the product precipitates, it is collected by filtration. It is separated from manganese dioxide by extraction in an organic solvent and then the solvent is removed by evaporation. Otherwise, if the product does not precipitate in the solution at the end of the reaction, it is isolated according to a = usual solvent extraction treatment.

When a compound of formula II or III is oxidized, where R "* - has the definition indicated above, into the corresponding compound: 8 ji .j formula I with an organic peroxyacid, for example a peroxycarboxylic acid, generally one treats the compound of 1 formula II or III with approximately 1 to approximately 4 molar equivalents, preferably approximately 1.2 molar equivalent of: j 5 the oxidant in an organic solvent inert to the reaction, ij Mention may be made, as examples of solvents Typical are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as ethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out. a temperature of about -20 to about 50 ° C., preferably about 25 ° C. In the vicinity of 25 ° C., reaction times of about 2 to about 16 hours are generally used Normally, to isolate the product, the solvent is removed by evaporation under empty. We can purify | The product according to conventional methods well known in the art.

j When oxidizing a compound of formula (II) or (III) i] to a compound of formula (I) with an organic peroxyacid, | it is sometimes advantageous to add a catalyst such as a | Manganese salt, for example manganic acetylacetonate.

One can also obtain the compound of formula (I) (where R · * - represents a hydrogen atom) by elimination j of the protective group R from a compound of formula (I) where R

] represents a protecting group for the carboxypenicillinic radical. In the present context, R can be any protective group 3j] tor any carboxy radicals commonly used in penicillin chemistry to protect a carboxy radical in position 3. The nature of the protective group of the carboxy radical t has not of particular limitation. The only conditions that i 30 must fulfill the protecting group R ^ of the carboxy radical are | that: (1) it must be stable during the oxidation of the compound i _ of formula (II) or (III) and (2), it must be able to be removed from the i compound of formula (I) under such conditions that the 3 ~] lactam remains practically intact.

|! "35 Typical examples of protective groups that may be mentioned include the tetrahydropyranyl group, the benzyl group, the substituted benzyl groups (e.g. 4-nitrobenzyl), the benzhydryl group, the 2,2,2-trichloroethyl group, the group ii i; •. 9 tert-butyl and the phenacyl group * One can also consult in this regard: the patents of the United States of America n ° 3,632,850 and n ° 3,197,466? the British patent n ° 1,041,985 ; Woodward et al. Journal of the American Chemical Society, 5 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 HE Flynn, Academie Press, Inc., 1972. The protecting group for the penicillin carboxy radical is removed in the usual way, taking into account the lability of the ß-lactam ring system.

Similarly, the compounds of formula (I) can be prepared in which R ^ - has the same definition as above, by oxidation of a compound of formula: ch3.

H / ch_ T 1 3 i 0 \ 1

COOR

15 where R1 has the same definition as above. The procedure is exactly as previously described for the oxidation of a compound of formula (II) or (III) except that generally two times more oxidant is used.

It is possible to prepare directly by esterification of a compound of formula (I) in which X represents a hydrogen atom the compounds of formula (I) in which represents an ester-generating residue which is easily hydrolysable in vivo. The particular method chosen depends on the precise structure of the ester generating residue, but those skilled in the art can easily choose an appropriate method. In the case where R ^ represents a 3-phthalidyl, 4-crotonolactonyl, y-butyrolactone-4-yl or 3 4 5 radical, those of formulas (X) and (XI) where R, R and R have the definition indicated above, the compound of formula (I) can be alkylated where R1 represents a hydrogen atom with a halide of. . 30 3-phthalidyl, a 4-crotonolactonyl halide, a halide of Y ~ butyrolactone-4-yl or a compound of formulas: 10 3 3 0 RJ Ο I »5. i "5

Q-C-O-C-R and Q-C-O-C-O-R

U U

R R

XII XIII

3 4 5 where Q represents a halo radical and R, R and R have the definitions indicated above. The terms "halide" and "halo" apply to chlorine, bromine and iodine derivatives. To carry out the reaction in a practical manner, a salt 5 of a compound of formula (I) in which R1 represents a hydrogen atom, is dissolved in a suitable polar organic solvent such as Ν, Ν-dimethylformamide, then about 1 molar equivalent of the halide is added. When the reaction is practically complete, the is isolated. produced according to conventional techniques.

It suffices simply to dilute the reaction mixture with an excess of water and then to extract the product in an organic solvent immiscible with water, then to evaporate the solvent to recover the product. The commonly used starting compound salts are alkali metal salts such as a sodium or potassium salt or tertiary amine salts such as triethylamine, N-ethylpiperidine, N, N- dimethylaniline and N-methylmorpholine. The reaction is carried out at a temperature in the range of about 0 to 100 ° C, generally about 25 ° C. The time required for the completion of the reaction will vary depending on various factors such as the concentration and reactivity of the reactants. Thus, in the case of halo-type compounds, iodide reacts faster than bromide which itself reacts faster * than chloride. In practice, it is often advantageous, when using a chloro compound, to add up to one molar equivalent of an alkali metal iodide. This accelerates the reaction. Taking into account the above factors, reaction times of about 1 to about 24 hours are generally used.

•. 11

One can prepare the ία-oxide of penicillinic acid which is the compound of formula (II) where R ^ represents a hydrogen atom by debromination of the ία-oxide of 6,6-dibromopenicillanic acid. Debromination can be carried out according to a conventional hydrogenolysis technique. A solution of 6,6-dibromopenicillanic acid ία-oxide is stirred under an atmosphere of hydrogen or of a mixture of hydrogen and an i. inert diluent such as nitrogen or argon in the presence of a catalytic amount of a catalyst consisting of palladium calcium carbonate 10 -. Solvents suitable for this debroma-tion are lower alkanols such as methanol; ethers such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; the water ; and mixtures of these sol-vants. Usually, however, conditions are chosen such that the dibromo compound is soluble. Hydrogenolysis is generally carried out at ordinary temperature and under a pressure between the vicinity of atmospheric pressure and about 3.5 bars. The catalyst is generally present in an amount between about 10% of the weight of the dibromo compound and the weight of the latter, although larger amounts can be used. The reaction generally requires about 1 hour, after which the compound of formula (II) is collected, where R1 represents a hydrogen atom, by simple filtration, then removal of the solvent in vacuo.

To prepare the 6,6-dibromo-penicillanic acid Ια-oxide, 6,6-dibromopenicillanic acid is oxidized with 1 equivalent of 3-chloroperbenzoic acid in tetra-30 hydrofuran between 0 and 25 ° C for about 1 hour, according to the procedure described by Harrison et al "in Journal of the Chemical Society, (London) Perkin I, 1772 (1976). 6,6-Dibromopenicillanic acid is prepared according to the method of Clayton, Journal of the Chemical Society (London), (C) 2123 35 (1969).

The penicillinic acid β-oxide which is the compound of formula (III), where R "*" represents a hydrogen atom, can be prepared by controlled oxidation of penicillinic acid. 12 picnic. This requires treating penicillanic acid with 1 molar equivalent of 3-chloroperbenzoic acid in an inert solvent, at around 0 ° C for about 1 hour. Typical solvents that can be used are chlorinated hydrocarbons such as chloroform and dichloromethane; ethers such as ethyl ether and tetrahydrofuran; and low molecular weight esters such as ethyl acetate and butyl acetate. The product is collected according to conventional techniques.

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

The compounds of formulas (II) and (III) can be prepared, in which represents an ester-generating residue which is easily hydrolysable in vivo directly from the compound of formula (II) or (III), in which R represents a d atom. by esterification using conventional techniques.

'1

In the case where R represents a 3-phthalidyl, 4-croto-nolactonyl, y-butyrolactone-4-yl radical or a radical of formulas ^ 3 4 5 (X) and (XI) or R, R and R have the definitions previously indicated, the appropriate compound of formula (II) or (III) can be alkylated, where R "^ represents a hydrogen atom, with a 3-phthalidyl halide, a 4-crotonolactonyl halide, a halide of y-butyrolactone-4-yl or a compound of formula (XII) or (XIII).

The reaction is carried out exactly as previously described for the esterification of 1,1-dioxide of penicillanic acid with a 3-phthalidyl halide, a 4-crotonolactonyl halide, a γ-butyrolac-tone-4 halide -yle or a compound of formula (XII) or (XIII).

Alternatively, the compounds of formula (II) y can be prepared in which R "* - represents an easily ester-generating ester residue, hydrolyzable in vivo, by oxidation of the appropriate ester of 6,6-dibromopenicillanic acid and then debromination Esters of 6,6-dibromopenicillanic acid are prepared from 6,6-dibromopenicillanic acid according to conventional methods, for example the oxidation can be carried out with a molar equivalent of 3 ~ chloroperbenzoic acid as previously described for the oxidation of 6,6-dibromopenicillanic acid to the • 13 oxide of 6,6-dibromopenicillanic acid; and carry out the debromination as previously described for the debromination of the acid ία-oxide 6,6-dibromopenicillanic.

Similarly, it is possible to prepare the compounds of formula (III) in which R * represents an ester-generating residue which is easily hydrolysable in vivo, to oxidize the appropriate ester of * '' "penicillanic acid. The latter are easily prepared compounds by esterification of penicillanic acid according to conventional methods, for example, one oxidizes with an equivalent molar of 3-chloroperbenzoic acid as previously described for the oxidation of penicillanic acid into lß-oxide penicillanic acid.

The compounds of formula (II) can be obtained in two different ways where Rx represents a group protecting the carboxy radical. They can be obtained in a simple manner by attachment of a protecting group of the carboxy radical to the la-oxide of penicillanic acid. Otherwise, it is possible (a) to attach a protecting group from the carboxy radical to 6,6-dibromopenicillanic acid; (b) oxidizing the protected 6,6-dibromopenicillanic acid to a protected 6,6-dibromopenicillanic acid Ια-oxide with a molar equivalent of 3-chloroperbenzoic acid; and (c) debrominating the hydroxide from 6,6-dibromopenicillanic acid protected by hydrogenolysis.

The compounds of formula (III) où in which R 1 represents a protecting group for the carboxy radical can be obtained in a simple manner by attachment of a protecting group to the penicillanic acid β-oxide. Otherwise, it is possible to (a) attach a protecting group from the carboxy radical to penicillanic acid; and (b) oxidizing the protected penicillanic acid with a molar equivalent of 3-chloroperbenzoic acid as previously described.

The compounds of formulas (ï), (ll) and- (ïll) where.R represents a hydrogen atom are acidic and form salts with basic agents. These salts can be prepared according to conventional techniques such as contacting the acid component and component, basic, generally in a molar ratio of 1: 1, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then collected by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent. or, in the case of aqueous changes, by lyophilization, as appropriate. Basic agents.

14 which can be used to form a salt are organic or mineral in nature and mention may be made, for example, of ammonia, organic amines, hydroxides, carbonates, bicarbonates, hydrides and alcoholates of aicanns metals and hydroxides, 5 carbonates , alkaline earth metal hydrides and alcoholates.

Examples of such bases which may be mentioned are primary amines * such as n-propylamine, n-butylamine, * aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-even; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; Alcoholates such as sodium ethylate and potassium ethylate; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; 20 and alkali metal salts of fatty acids ·., À. long chain such as sodium 2-ethylhexanoate.

! The preferred salts of the compounds of formulas (I), (II) and (III) are the sodium, potassium and triethylamine salts.

As previously indicated, the compounds of formula (I) in which R · * "represents a hydrogen atom or an ester-generating residue which is easily hydrolysable in vivo are anti-bacterial agents of moderate activity. highlight the in vitro activity of the compound of formula (I) where R1 represents a hydrogen atom, measure its minimum inhibitory concentrations (CMl) expressed in yg / ml vis-à-vis various microorganisms. procedures recommended by the "International Collaborative Study on Antibiotic Sensitivity Testing" (Ericcson and Sherris, Acta.

35 Pathologica and Microbiologia Scandinav, Supp. 217, Sections A and B: 1-90 [1970.1), in which a brain infusion and heart infusion agar and a repeated inoculation device are used. Culture tubes are diluted overnight to 100th and standard inocula (20,000-15,000 10,000 in approximately 0.002 ml are placed on the surface of a dish containing 20 ml of brain infusion agar and infusion of the heart). Twelve dilutions of 2 of the test compound are used, the initial concentration being 200 pg / 5 ml. When the dishes are read after 18 hours at 37 ° C., the single colonies are not taken into account. It is considered that the “CCMI sensitivity” of the microorganism studied is the minimum concentration of the compound capable of causing complete inhibition of development evaluated with the naked eye. The MICs of 1,1-dioxvde 10 of penicillanic acid against various microorganisms are shown in Table I.

TABLE I

Antibacterial activity in vitro of 1,1-dioxide '_ penicillanic acid_ microorganisms___ qmI · (ng./iai.)

Staphylococcus aureus 100 '

Streptococcus faecalis> 200 i

Streptococcus pyogenes' 100 d

Escherichia coli50 days

Pseudomonas aeruginosa 200 ι

. I

Klebsiella pneumoniae 50

Proteus mirabilis 100

Proteus Morgani 100

Salmonella typhimurium 50 {

Pasteurella multocida 50 I

i

Serratia marcescens 100 '‘i

Enterobacter aarogenes 25 d

Enterobacter clocae 100 |

Citrobacter freundii 50 d i

, Providencia 100 J

Staphylococcus epidermis 200 I

»Pseudomonas putida> 200 d

Henophilus influenzae> 50 d

Neisseria gonorrhoeae. 0.312 d

The compounds of formula (I) where represents a hydrogen atom or an ester-generating residue which is easily hydrolyzable in vivo are active in vivo as anti-bacterial agents. To determine this activity, acute experimental infections are created in mice by intraperitoneal inoculation of a standardized culture of the microorganism to be studied in suspension in 5% porcine gastric mucin. The severity of the infection is standardized so that the mice receive one to ten times the amount of the microorganism (the DLj-q is the minimum inoculum of the microorganism necessary to regularly kill 100% of the untreated infected control mice. ). The test compound is administered to infected mice in multiple doses. At the end of the test, to evaluate the activity of a compound, the number of survivors among the animals treated is counted and the activity of the compound is expressed by the percentage of surviving animals.

The in vitro antibacterial activity of the compound of formula (I) where R1 represents a hydrogen atom makes it useful as an industrial antimicrobial, for example for water treatment, sludge control, conservation of paints and woods as well as for local application as a disinfectant. In the case of local application of this compound, it is often practical to mix the active ingredient with a non-toxic support such as a vegetable or mineral oil or an emollient cream. Likewise, it can be dissolved or dispersed in diluents or liquid solvents such as water, alkanols, glycols or their mixtures. In most cases, concentrations of an active ingredient in the range of from about 0.1% to about 10% by weight based on the entire composition can be used.

The in vivo activity of the compounds of formula (I) where R represents a hydrogen atom or a generating residue. 30 ester easily hydrolyzable in vivo makes them useful for the fight against bacterial infections in mammals including humans, by oral and parenteral administration.

These compounds are useful for combating infections caused by sensitive bacteria in humans, in particular infections caused by strains of Neisseria gonorrhoeae.

For the therapeutic use of a compound of formula (I) or of a salt thereof in a mammal, in particular in humans, the compound can be administered alone or in! 17 mix with carriers or diluents suitable in pharmacies. Oral or parenteral, i.e. intramuscular, subcutaneous or intraperitoneal administration can be carried out. The support or the diluent is chosen according to the mode of administration provided. For example, for oral administration, an antibacterial petanic compound can be used in the form of tablets, capsules, lozenges, cachets, powders, syrups, elixirs, aqueous solutions and suspensions and the like depending on the practice. usual pharma-1Û ceutique. The ratio of the active ingredient to the support varies according to the chemical nature, the solubility and the stability of the active ingredients as well as the dosage envisaged. Generally, pharmaceutical compositions containing an antibacterial agent of formula (I) may contain between about 20% and about 95% of the active ingredient. In the case of tablets for oral administration / carriers which are commonly used are lactose, sodium citrate and salts of phosphoric acid. Various disintegrating tablets such as starch and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. For oral administration in capsule form, diluents such as lactose and high molecular weight polyethylene glycols can be used. In the case of aqueous suspensions for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweeteners and / or flavorings can be added. For parenteral administration by the intramuscular, intraperitoneal, subcutaneous or intravenous route, sterile solutions of an active ingredient are generally prepared, the pH of which is adjusted and buffered appropriately. For intravenous administration, the total concentration of dissolved matter should be such that the preparation is isotonic. As previously indicated, the antibacterial agents of the invention are used to combat sensitive microorganisms in humans. The prescribing physician will, as a last resort, determine the appropriate dosage for a human subject taking into account the patient's age, weight and response 18 as well as the nature and severity of the symptoms. The compounds of the invention are normally used orally at daily doses in the range of about 10 to about 200 mg per kilogram of body weight and parenterally at daily doses in the range of about 10 to about 400 mg per kilogram of body weight. These values are only illustrative and in some cases it may be necessary to use dosages outside the limits indicated.

However, as previously indicated, the compounds of formula (I) in which represents a hydrogen atom or an ester-generating residue which is easily hydrolysable in vivo, are potent inhibitors of microbial β-lactamases and they increase the antibacterial efficacy of ß-lactam antibiotics (penicillins and cephalosporins) against many microorganisms, particularly those that produce β-lactamase. To evaluate the increase in the efficacy of a β-lactam antibiotic caused by these compounds of formula (I), experiments are carried out in which: the MIC of a given antibiotic alone and a compound of formula (I) alone. These MICs are compared to the MICs obtained with a combination of the antibiotic and the compound of formula (I). When the antibacterial activity of the combination is significantly higher than that suggested by the activities of the individual compounds, the activity is considered to be! increased. To measure the MICs of the combinations, we operate according to; the method described by Barry and Sabath in "Manual of Clinical; Microbiology", edited by Lenette, Spaulding and Truant, 2nd edition, 1974, American Society for Microbiology.

The experimental results show that 1,1- [penicillanic acid dioxide increases the activity of am-

; _ picillin as indicated in table II. Table II

i: shows that against 19 strains resistant to ampicillin I of Staphylococcus aureus, the MIC type of ampicillin and i 35 of 1,1-dioxide of penicillanic acid and of 200 μg / ml.

! However, the MICs for ampicillin and penicillanic acid 1,1-dioxide in combination are 1.56 and 3.12 yg / ml, respectively. In other words, while ampicillin alone •. 19 has a typical CMX of 200 yg / ml vis-à-vis the 19 strains of Staphylococcus aureus, its standard MIC is reduced to 1.56 yg / ml in the presence of 3.12 μg / ml of 1,1-dioxide penicillanic acid. The increase in the antibacterial efficacy of ampicillin against 26 strains of ampicillin-resistant Haemophilus influenzae, 18 strains of ampicillin-resistant Klebsiella pneumoniae and 15 is also shown in Table II. strains of the anaerobic germ Bacteroides fragilis. Tables III, IV and V show the increase in the antibacterial activity of benzylpenicillin (penicillin G), carbenicillin (α-carboxybenzylpenicillin) and cefazolin against the strains of S. aureus, H influenzae, K. pneumoniae and Bacteroides fragilis.

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The compounds of formula (I), in which R1 represents a hydrogen atom or an ester-generating residue which is easily hydrolysable in vivo, increases the in vivo antibacterial efficacy of ß-lactam antibiotics. They lower the amount of antibiotic necessary to protect the mice from an inoculum which would otherwise be fatal from certain β-lactamase producing bacteria.

. The ability of the compounds of formula (I ^ where R1 represents a hydrogen atom or a generative residue of ester easily hydrolyzable in vivo ^ to * increase the effectiveness of an antibiotic type ß-lactam vis β-lactamase producing bacteria makes them particularly useful for co-administration with β-lactam antibiotics in the treatment of bacterial infections of mammals and in particular humans. bacterial infection / the compound of formula (I) can be mixed with the ß-lactam antibiotic and the two therapeutic agents administered simultaneously, or the compound of formula (I) can be administered as a separate agent of treatment with a β-lactam antibiotic In some cases it may be advantageous to administer the compound of formula (I) to the subject before starting treatment with a β-lactam antibiotic.

When administering 1,1-dioxide of Pancillinic Acid or one of its esters which are readily hydrolyzable in vivo to enhance the efficacy of a 3-lactam antibiotic, it is preferably administered in compositions containing conventional pharmaceutical carriers or diluents.

The preparation methods previously indicated can be used for the use of a 1,1-dioxide of picnicillanic acid or of one of its esters which are easily hydrolyzable in vivo as a single antibacterial agent for co-administration with another ß-lactam antibiotic. A pharmaceutical composition consisting of a pharmacy-suitable carrier of a β-lactam antibiotic and 1,1-dioxide of Pancillanic acid or one of its readily hydrolyzable esters normally contains about 5 to about 80% by weight of the support suitable in pharmacies.

When 1,1-dioxide of penicillinic acid or one of its easily hydrolyzable esters in vivo is used in combination with another β-lactam antibiotic, the sulfone can be administered orally or parenteral ^ that is to say intramuscular, subcutaneous or intraperitoneal.

5 Although the prescribing physician ultimately decides on the dosage to be used in a human subject, the ratio of the daily doses of penicillanic acid 1,1-dioxide or one of its esters and the antibiotic type ß-lactam a is normally in the ranges of about 1: 3 to 3: 1.

In addition, when penicillanic acid 1,1-dioxide or one of its esters which are readily hydrolyzable in vivo in combination with another β-lactam antibiotic is used, the daily administration dose the oral dose of each component is normally in the range of about 10 to about 200 mg per kg of body weight and the daily parenteral dose of each component is normally in the range of about 10 to about 400 mg per kg of body weight. These values are purely illustrative and / in some cases it may be necessary to use doses outside the limits indicated.

Typical β-lactam antibiotics with which penicillanic acid 1,1-dioxide and its easily hydrolyzable esters can be co-administered in vivo are: penicillanic 6- (2-phenylacetamido) acid, 6- (2-phenoxyacetamido) penicillanic acid, 6- (2-phenylpropionamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid, 6- (D- 2-arnino ~ 2- [4-hydroxyphenyl] acetamido) penicillanic acid 6- (D-2-amino-2- [1,4-cyclohexadienyl] acetamido) »penicillanic acid 6- (1-aminocyclohexanecarboxamido ) penicillanic acid 6- (2-carboxy-2-phenylacetamido) penicillanic acid 6- (2-carboxy-2- [3-thienylJacetamido) penicillanic acid 6- (D-2- [ 4-ethylpiperazine-2,3-dione-l-carboxamido] -2-phenylacetamido) penicillanic acid 6 ~ (D-2- [4-hydroxy-l, 5-naphthyridine-3 ~ carboxamido] ~ 2-phenylacetamido ) -penicillanic, ¥ 26 6- (D-2-sulfo-2-phenylacetamido) penicillanic acid, 6- (D-2-sulfamin.o-2-phenylacetamido) penic acid llanic, 6- (D-2- [imidazolidine-2-one-l-carboxamido] -2 ~ phenylacetamido) penicillanic acid, 5 6- (D- [3-methylsulfonylimidazolidine-2-one-l-) acid carboxami-do] -2-phenylacetaraido) -penicillanic acid 6 - ([hexahydro-1H-azepine-1-yl] methylene-amino) penicillanic, 6- (2-phenylacetamido) acetoxymethyl penicillanate, 10 acetoxymethyl penicillanate 6- (D-2-amino-2-phenylacetarido), acetoxymethyl 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) penicillanate, 6- (2-phenylacetamido ) pivaloyloxymethyl penicillanate, 6- (D-2-amino-2-phenylacetamido) pivaloyloxy-15 methyl penicillanate, 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) pivaloyloxymethyl penicillanate - (2-Phenylacetamido) penicillanate from 1- (ethoxycarbonyloxy) ethyl, 20 6- (D “2-amino-2-phenylacetamido) penicillanate from 1- (ethoxycarbonyloxy) ethyl, 6- (D-2-amino-2 1- (ethoxycarbonyloxy) ethyl - [4-hydroxyphenyl] acetamido) -penicillanate, 3-phthalidyl penicillanate 6- (2-phenylacetamido), 25 3- (phthalidyl) penicillanate 6- (D-2-amino-2-phenylacetamido), 3- (D-2-amino-2- [4-hydroxyphenyl] acetamido) 3-phthalidyl penicillanate, 6- (2-phenoxycarbonyl-2-phenylacetamido) penicillanic, 11 6- (2-tolyloxycarbonyl-2-phenylacetamido) penicillanic acid, 30 6- (2- [5-indanyloxycarbonyl] -2-phenylacetamido) penicillanic acid 6- (2-phenoxycarbonyl-2- [3-thienyl] acetamido) penicillinic acid 6- (2-tolyloxycarbonyl-2- [3-thienyl] acetamido) penicillinic acid 6- ( 2- [5-indanyloxycarbonyl] -2- [3-thienyl] acetamido) penicillanic acid 6- (2,2-dimethyl-5 ~ oxo-4 ~ phenyl-l-imidazolidinyl) penicillanic, ΐ •. 27 7- (2- [2-thienyl] acetamido) cephalosporanic acid, 7- (2- [l-tetrazolyl] acetamido-3- (2- [5-methyl-1,3,4-thia) acid -diazolyl] thiomethyl) -3-deacetoxymethylcephalosporanic, 7- (D-2-amino-2-phenylacetamido acid) deacetoxycephalosporo-5 ranic acid, 7-a-methoxy-7- (2- [2-thienyl] acetamido) -3-carbamoyloxy- * methyl-3-deacetoxymethyl cephalosporanic, 7- (2-cyanacetamido) cephalosporanic acid, * 7- (D “2-hydroxy-2-phenylacetamido) acid -3- (5- [ 1-methyltetra- 10 zolyl] thiomethyl) -3-deacetoxymethyl cephalosporanic acid 7- (2- [4-pyridylthio] acetamido) cephalosporanic acid 7 ~ (D-2 - amino-2 “· [1, 4-cyclohexadienyl] acetamido) cephalosporanic acid 1 ~ (D-2-amino-2-phenylacetamido) cephalosporanic, and their salts suitable in pharmacy.

As is obvious to those skilled in the art, some of the β-lactam compounds are effective when administered orally or parenterally while others are only effective when administered orally. parenteral. When 1,1-dioxide of penicillanic acid or ion of its esters is readily hydrolyzable in vivo simultaneously (that is to say as a mixture) with a ß-lactam antibiotic effective only by administration parenteral, a combination suitable for parenteral administration should be used. When 1,1-dioxide of penicillanic acid or one of its esters is used simultaneously (as a mixture) with a ß-lactam antibiotic which is effective orally or parenterally, suitable combinations can be prepared for oral or parenteral administration.

* In addition, preparations of penicillanic acid 1,1-dioxide or its esters can be administered orally and at the same time administered parenterally by another B-lactam antibiotic; preparations of penicillanic acid 1,1-dioxide or one of its esters may also be administered parenterally by the administration of another β-lactam antibiotic orally at the same time.

•. The invention is illustrated by the following nonlimiting examples. The infrared (IR) spectra are determined with potassium bromide pellets (KBr) or in dispersion in Nujol and the absorption bands c “1 o useful for the diagnosis are expressed in number of waves (cm).

The nuclear magnetic resonance (NMR) spectra at 60 MHz are measured from solutions in deuterochloroform j (CDCl 4) / perdeuterodimetyl sulfoxide (DMSO-dg) or deuterium oxide (D20) and the positions of the peaks are expressed. in 10 (ppm) relative to tettramethylsilane or sodium 2,2-dimethyl-2-sila-pentane-5-sulphonate. The following abbreviations are used to characterize the peaks: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet.

EXAMPLE 1 Penicillanic acid 1,1-dioxide To a solution of 6.51 g (41 mmol) of potassium permanganate in 130 ml of water and 4.95 ml of glacial acetic acid cooled to about 5 ° C, on. add a cold solution (about 5 ° C) of 4.58 g (21 mmol) of the sodium salt of penicillanic acid in 50 ml of water, stir the mixture at about 5 ° C for 20 minutes, then the cooling bath is removed. Solid sodium bisulfite is added until the color of potassium permanganate has disappeared and the mixture is filtered. Half the volume of a saturated sodium chloride solution is added to the aqueous filtrate, then the pH is adjusted to 1.7. The acid solution is extracted with ethyl acetate. The extracts are dried and then evaporated under vacuum to obtain 3.47 g of the desired product. The aqueous mother liquor is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is dried and evaporated in vacuo to obtain 0.28 g of additional product. The total yield is therefore 3.75 g (78% yield). The NMR spectrum (DMSO-dg) of the product shows absorptions at 1.40 (s, 3H), 1.50 (s, 3H), 35 3.13 (dd, 1H, J = 16 Hz, J2 = 2Hz ), 3.63 (dd, 1H, = 16Hz, H J2 = 4 Hz), 4.22 (s, 1H) and 5.03 (dd, 1H, J = 4 Hz, J2 = 2Hz)! ppm.

•. EXAMPLE 2 Benzyl penicillanate 1,1-dioxide To an agitated solution of 6.85 g (24 mmol) of benzyl penicillanate in 75 ml of chloroform devoid of ethanol, the following is added under nitrogen to an ice-water bath, in two portions, several minutes apart, 4.78 g of 85% pure 3-chloroperbenzoic acid. Stirring is continued for 30 minutes in an ice-water bath and then for 45 minutes without cooling from the outside. The reaction mixture is washed with aqueous alkali (pH 8.5) and then saturated sodium chloride and dried and evaporated in vacuo to give 7.05 g of residue. Examination of this residue shows that it consists of a mixture of 5.5: 1. benzyl penicillanate oxide and benzyl penicillanate 1,1-dioxide.

To a stirred solution of 4.85 g of the mixture of 5.5: 1 of sulfoxide - sulfone above in 50 ml of chloroform devoid of ethanol, 3.2 g of acid are added under nitrogen at ordinary temperature. 85% pure 3-chloroperbenzoic acid. The reaction mixture is stirred for 2.5 hours and then diluted with ethyl acetate. The mixture obtained is added to water at pH 8.0 and then two layers are separated. The organic phase is washed with water at pH 8.0 and then saturated sodium chloride and dried over sodium sulfate. The solvent is evaporated under vacuum to obtain 3.59 g of the desired compound.

The NMR spectrum of the product (in CDCl 4) shows absorptions at 1.28 (s, 3H), 1.58 (s, 3H), 3.42 (m, 2H), 4.37 (s, 1H), 4.55 (m, 1H), 5.18 (q, 2H, J = 12 Hz) and 7.35 (s, 5H) ppm.

EXAMPLE 3 Penicillanic Acid 1,1-Dioxide "To a stirred solution of 8.27 g of benzyl penicillanate 1,1-dioxide in a mixture of 40 ml of methanol and 10 ml of ethyl acetate , 10 ml of water are slowly added, followed by 12 g of 5% palladium on calcium carbonate. The mixture is stirred under a hydrogen atmosphere at 3.6 bar for 40 minutes and filtered through a supercel (diatomaceous earth). The filtrate cake is washed with methanol and then aqueous methanol and the washing liquids are added to the filtrate. The combined solution is evaporated in vacuo to remove most of the organic solvents and then the residue is partitioned into ethyl acetate and water at a pH of 2.8. The ethyl acetate phase is separated and the aqueous phase is subjected to further extraction with ethyl acetate. The combined ethyl acetate solutions are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is suspended in a 1: 2 mixture of ethyl acetate and ether to obtain 2.37 g of the desired product having a melting point of 148-51 ° C. The mixture of ethyl acetate and ether is evaporated to obtain 2.17 g of additional product.

EXAMPLE 4 pivaloyloxymethyl penicillanate 1,1-dioxide A 0,615 g (2,4l mmoles) of penicillanic acid 1,1-dioxide in 2 ml of Ν, Ν-dimethylformamide, 0.215 g (2.50) is added mmol) of diisopropylethylamine then 0.365 ml of chloromethyl pivalate. The reaction mixture is stirred at room temperature for 24 hours and then diluted with ethyl acetate and water. The ethyl acetate phase is separated and washed three times with water and once with a saturated sodium chloride solution. The ethyl acetate solution is dried with anhydrous sodium sulfate and evaporated in vacuo to obtain 0.700 g of the desired product as a solid, m.p. 103-4 ° C. The spectrum of R.M.N. of the product (in CDCl ^) has absorptions at 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 The procedure of Example 4 is repeated, since pivaloyloxymethyl chloride is replaced by an equimolar amount of acetoxymethyl chloride, propionyloxymethyl chloride or hexanoyloxy-methyl chloride for obtain respectively acetoxymethyl penicillanate 1,1-dioxide, propionyloxymethyl penicillanate 1,1-dioxide and hexanoyloxymethyl penicillanate 1,1-dioxide.

•. 31 EXAMPLE 6 3-phthalidyl penicillanate dioxide-0,783 g (3.36 rnmoles) of penicillanic acid 1,1-dioxide in 5 ml of Ν, Ν-dimethylformamide, 0.47 ml is added of triethylamine, then 0.715 g of 3-bromophthalide.

The reaction mixture is stirred for 2 hours at room temperature and then diluted with ethyl acetate ‘and water. The pH of the aqueous phase is brought to 7.0 and the phases are separated. The ethyl acetate phase is washed successively with water and a saturated solution of 1 10 sodium chloride and dried over sodium sulfate.

J

| The ethyl acetate solution is evaporated in vacuo to obtain the desired product in the form of a white foam.

The NMR spectrum of the product (in CDCl 4) shows absorptions S 1/47 (s, 6H), 3.43 (m, 1H), 4.45 (s, 1H), 4.62 (m, 1H), 7.40 and 7.47 (2 s, 1H) and 7.73 (m, 4H) ppm.

When we resume the above procedure, replacing 3-bromophthalide by 4-bromocrotonolactone and 4-bromo-y-butyrolactone, we obtain 4-crotonolactonyl penicillanate dioxide 1.1 and 20 respectively, 1-penicillanate y-butyrolactone-4-yl dioxide.

EXAMPLE 7 1.1- 1- (Ethoxycarbonyloxy) ethyl penicillanate dioxide

A mixture of 0.654 g of penicillinic acid 1,1-dioxide, 0.42 ml of triethylamine, 0.412 g of 1-chloroethyl ethyl ethyl carbonate is stirred at ordinary temperature for 6 days. 0.300 g of sodium bromide and 3 ml of Ν, Ν-dimethylformamide. It is then diluted with ethyl acetate and water and then the pH is adjusted to 8.5.

The ethyl acetate phase is separated, washed three times with water and once with saturated sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate is removed by evaporation under vacuum to obtain 0.390 g of the desired product in the form of an oil.

The above product is combined with an approximately equal amount of the same material obtained in a similar experiment. The combined product is dissolved in chloroform and 1 ml of pyridine is added. The mixture is stirred at room temperature overnight and the chloroform is removed by evaporation in vacuo. The residue is subjected to a partition between ethyl acetate and water at pH 8. The separated ethyl acetate phase is evaporated under vacuum and dried to obtain 150 mg of the desired product (yield 5 approximately 7 %). The IR spectrum (film) of the product has absorptions at 1805 and 1763 cm 1. The spectrum of R.M.N. (CDC13) has absorptions at: 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.

10 EXAMPLE 8

The procedure of Example 7 is repeated, except that the 1-chloroethyl ethyl carbonate is replaced by an equimolar amount of 1-chloroalkyl and alkyl carbonate, of 1 chloride. - (alkanoyloxy) 115 ethyl or 1-methyl1-1- (alkanoyloxy) ethyl chloride suitable for obtaining the following compounds: 1,1-methoxycarbonyloxymethyl penicillanate dioxide, 1,1-ethoxycarbonyloxymethyl penicillanate dioxide, 1 , Isobutoxycarbonyloxymethyl penicillanate 1-dioxide, 1- (methoxycarbonyloxy) ethyl penicillanate 1,1-ethyl (1,1-butoxycarbonyloxy) penicillanate 1,1, 1-penicillanate dioxide - (acetoxy) ethyl, 1- (butyryloxy) ethyl penicillanate 1,1, 1- (pivaloyloxy) ethyl penicillanate 1,1, 1- (hexanoyloxy) penicillanate 1,1-dioxide ethyl, 1-methyl-l-^ (acetoxy) ethyl penicillanate 1,1, and 1,-methyl-l- (isobutyryloxy) ethyl penicillanate 1,1-dioxide.

EXAMPLE 9 The procedure of Example 4 is repeated, except that the chloromethyl pivalate is replaced by an equimolar amount of benzyl bromide or 4-nitrobenzyl bromide in order to obtain 1.1 respectively. benzyl penicillanate dioxide and 4-nitrobenzyl penicillanate 1,1-dioxide.

1 EXAMPLE 10 ία-oxide of penicillanic acid To 1.4 g of 5% palladium on calcium carbonate previously hydrogenated in 50 ml of water, a solution is added! . ’! tion of 1.39 g of 1,6-dibromo-benzyl penicillanate 1α-oxide in 50 ml of tetrahydrofuran.

The mixture is stirred under a nitrogen atmosphere at a pressure of about 3.1 bars at 25 ° C for 1 hour and then filtered.

5 The filtrate is evaporated in vacuo to remove most of the tetrahydrofuran and then the aqueous phase is extracted with ether. The ethereal extracts are evaporated under vacuum to obtain 0.5 g of a product which appears to consist essentially of Ια-benzyl penicillanate oxide.

The above benzyl penicillanate oxide is combined with an additional 2.0 g of benzyl 6,6-dibromo-penicillanate oxide and dissolved in 50 ml of tetrahydrofuran. The solution is added to 4.0 g of 5% palladium on calcium carbonate in 50 ml of water and the resulting mixture is stirred under a hydrogen atmosphere at about 3.1 bar and 25 ° C overnight . The mixture is filtered and the filtrate is extracted with ether. The extracts are evaporated in vacuo and the residue is purified by chromatography on silica gel, eluting with chloroform. 0.50 g of material are obtained.

This material is hydrogenated at approximately 3.1 bars at 25 ° C in a 1: 1 mixture of water and methanol with 0.50 g of 5% palladium on calcium carbonate for 2 hours. An additional 0.50 g of 5% palladium on calcium carbonate is then added and the hydrogenation is continued at 3.1 bars and at 25 ° C. overnight. The reaction mixture is filtered, extracted with ether and the extracts are discarded. The pH of the residual aqueous phase is adjusted to 1.5 and then extracted with ethyl acetate. The extracts are dried in ethyl acetate over sodium sulfate, then evaporated in vacuo to obtain 0.14 g of icα-oxide of penicillanic acid. The spectrum of R.M.N. (CDCl ^ / DMSO-dg) has absorptions at 1.4 (s, 3H), 1.64 (s, 3H), 3.60 (m, 2H), 4.3 (s, 1H) and 4, 54 (m, 1H) ppm. The infrared spectrum of the product (35 KBr disc) shows absorptions at 1795 and 1745 cm EXAMPLE 11 l-penicillanic acid oxide 1.0 g of 5% palladium on calcium carbonate, i '34 i' · previously hydrogenated in 30 ml of water, a solution of 1.0 g of 6,6-dibromopenicillic acid ία-oxide is added. The mixture is stirred under a hydrogen atmosphere at approximately 3.1 bars and at 25 ° C for 1 hour. The reaction mixture is filtered and the filtrate is concentrated under vacuum to remove the methanol. The residual aqueous phase is diluted with an equal volume of water, it is 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 extracts are dried in ethyl acetate over sodium sulfate and evaporated in vacuo to obtain the Ια-oxide of penicillanic acid.

EXAMPLE 12 i - “j lg-oxide of penicillanic acid I 15 To a stirred solution of 2.65 g (12.7 mmol) of penicillanic acid in chloroform at 0 ° C., 2.58 are added. g 85% pure 3-chloroperbenzoic acid. After 1 hour, the reaction mixture is filtered and the filtrate is evaporated under vacuum. The residue is dissolved in a small amount of | 20 chloroform. The solution is slowly concentrated until a precipitate begins to appear. At this point, the evaporation is stopped and the mixture is diluted with ether. The precipitate is separated by filtration, washed with ether and dried to obtain 0.615 g of lg-oxide of penicillanic acid from P.F.

25 140-3 ° C. The IR spectrum of the product (solution in CHC1.-.) _1 ^ shows absorptions at 1775 and 1720 cm. The NMR spectrum (CDCl 4 / DMSO-dg) shows absorptions at 1.35 (s, 3H), 1.76 (s, 3H), 3.36 (m, 2H), 4.50 (s, 1H ) and 5.05 (m, 1H) ppm.

The spectrum of R.M.N. shows that the product is approximately 30 to 90% pure.

Examination of the mother liquor, consisting of chloroform and ether, shows that it contains an additional quantity of penicillanic acid lg-oxide and also a certain quantity of penicillanic acid ία-oxide.

35 EXAMPLE 13

The Ια-oxide of penicillanic acid or the 1 ß-oxide of penicillanic acid is esterified with the appropriate alkanoyloxy chloride, according to Example 5, to obtain the following compounds: i * •. 35; Ια-acetoxymethyl penicillanate oxide, j ία-propionyloxymethyl penicillanate oxide, Ια-pivaloyloxymethyl penicillanate oxide j lß-acetoxymethyl penetillinyl oxide and propionyl ethyl acetate pivaloyloxymethyl.

j EXAMPLE 14

Penicillanic acid Ια-oxide or penicillanic acid l-oxide is reacted with 3-bromophthalide, 4-bromo-crotonolactone or 4-bromo-y-butyrolactone to obtain the compounds following: Ια-3-phthalidyl penicillanate oxide, Ια-4-crotonolactonyl penicillanate oxide, Ια-y-butyrolactone-4 ~ yl penicillanate oxide, 25 1ß ~ 3-pbtalidyl penicillanate oxide, 1ß-oxide of 4-crotonolactonyl penicillanate, and β-yyrolactone-4-yl penicillanate oxide.

EXAMPLE 15

The penicillanic acid Ια-oxide or penicillanic acid l-oxide is reacted with 1-chloroalkyl and alkyl carbonate or the appropriate 1- (alkanoyloxy) ethyl chloride according to the procedure of Example 7, - to obtain the following compounds: Ια-1- (ethoxycarbonyloxy) ethyl penicillanate oxide, Ια-methoxycarbonyloxymethyl penicillanate oxide, i! î 25 Ια-ethoxycarbonyloxymethyl penicillanate oxide, j Ια-isobutoxycarbonyloxymethyl penicillanate oxide, 1 1-α-1- (methoxycarbonyloxy) ethyl penicillanate oxide, Ια-penicillanate 1-α-ethyl acetatecarbonyl 1- (acetoxy) ethyl penicillanate oxide, Ια-1- (butyryloxy) ethyl penicillanate oxide,; 1- (pivaloyloxy) ethyl penicillanate oxide, i. 1- (Ethoxycarbonyloxy) ethyl penicillanate oxide, methyl methylcarbonyloxy penicillanate oxide, ethoxycarbonyloxymethyl penicillanate oxide,! 35 Isobutoxycarbonyloxymethyl penicillanate iß-oxyEe, j: 1- (methoxycarbonyloxy) ethyl penicillanate oxide, j1 1- (butoxycarbonyloxy) ethyl penicillanate oxide,! 1- (acetoxy) ethyl penicillanate oxide, i ". ‘36 1 *; 1- (Butyryloxy) ethyl penicillanate lß and | 1- (pivaloyloxy) ethyl penicillanate oxide.

I EXAMPLE 16 "1 1" ---

The ία-oxide of penicillanic acid 5 and the l-oxide of penicillanic acid are reacted with bromide! benzyl according to the procedure of Example 4 and i * is obtained | respectively benzyl penicillanate Ια-oxide and; , benzyl penicillanate oxide.

j In a similar manner / the Ια-oxide of j 10 penicillanic acid and the l-oxide of penicillanic acid are reacted with 4-nitrobenzyl bromide according to the procedure of Example 4 to obtain respectively respectivementα -penicil oxide- | 4-nitrobenzylanate and 4-nitrobenzylpenicillanate lß-oxide.

I 15 EXAMPLE 17} 1,1-dioxide of penicillanic acid 1 To 2.17 g (10 mmol) of Ια-oxide of penicillanic acid in 30 ml of chloroform without ethanol (about 0 ° C.) 1 , 73 g (10 mmol) of 3-chloroperbenzoic acid. The mixture is stirred for 1 hour at about 0 ° C and then for another 24 hours at 25 ° C. The reaction mixture I is evaporated, filtered under vacuum to obtain the penicillanic acid 1,1-dioxide.

! EXAMPLE 18 Ü 25 The procedure of Example 17 is repeated, except that the Ια-oxide of penicillanic acid I is replaced by: | penicillanic acid lß-oxide, I acetoxymethyl penicillanate ία-oxide, | , 30 propionyloxymethyl penicillanate ία-oxide, l it pivaloyloxymethyl penicillanate ία-oxide, 5. acetoxymethyl penicillanate lß-oxide, propionyloxymethyl penicillanate lß-oxide, pivaloyloxymethyl penicillanate lß-oxide, | 35 3-phthalidyl penicillanate ία-oxide, | 3-phthalidyl penicillanate lß-oxide, | 1- (ethoxycarbonyloxy) ethyl penicillanate ία-oxide, \ methoxycarbonyloxymethyl penicillanate ία-oxide, ΐ 1 * i j! ·. ji ethoxycarbonyloxymethyl penicillanate ία-oxide, isobutoxycarbonyloxymethyl ëα-penicillanate oxide, 1- (methoxycarbonyloxy) ethyl penicillanate ία-oxide, icα-penicillanoxycarbonyl 1- 1- (acetoxy) ethyl penicillanate lot-1- (butyryloxy) ethyl penicillanate lot, 1- (pivaloyloxy) ethyl penicillanate lot-1, penicillanate ß (1-oxyethoxycarbonyloxy) ethyl, methoxycarbonyloxymethyl penicillanate 1 ß-oxide, ethoxycarbonyloxymethyl 13-penicillanate oxide, isobutoxycarbonyloxymethyl 1-oxyethylcarbonyloxycarbonyloxycarboxylate , 1- (butoxycarbonyloxy) ethyl penicillanate 1ß-oxide, 1- (acetoxy) ethyl penicillanate 1ß, 1- (butyryloxy) ethyl penicillanate 1ß-oxide, and 1β-ethyl oxide 1- (pivaloyloxy) ethyl penicillanate.

! The following are obtained respectively: penicillanic acid 1,1-dioxide, acetoxymethyl penicillanate 1,1-dioxide, propionyloxymethyl penicillanate 1,1-dioxide, pivaloyloxymethyl penicillanate 1,1-dioxide , acetoxymethyl penicillanate 1,1-dioxide, propionyloxymethyl penicillanate 1,1-dioxide, pivaloyloxymethyl 1,1-penicillanate dioxide, 3-phthalidyl penicillanate 1,1-dioxide 3-phthalidyl penicillanate 1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl penicillanate 1,1-dioxide, methoxycarbonyloxymethyl penicillanate dioxide, 1,1-ethoxycarbonylethyl penicillanate dioxide , Isobutoxycarbonyloxymethyl penicillanate 1,1-dioxide, 1- (methoxycarbonyloxy) ethyl penicillanate 1,1, 1- (butoxycarbonyloxy) ethyl penicillanate 1,1 1- (acetoxy) ethyl penicillanate dioxide, 1- (butyryloxy) ethyl penicillanate dioxide, 1,1-di 1- (pivaloyloxy) ethyl penicillanate oxide, 1- (ethoxycarbonyloxy) ethyl penicillanate 1,1-dioxide, methoxycarbonyloxymethyl 1,1-penicillanate dioxide, 1,1-ethoxycarbonyloxymethyl penicillanate dioxide, 38 isobutoxycarbonyloxymethyl penicillanate 1,1-dioxide, 1- (methoxycarbonyloxy) ethyl penicillanate 1,1-penicillanate 1- (butoxycarbonyloxy) ethyl 1,1-dioxide 1- (acetoxy) ethyl penicillanate dioxide,; 5 1- (Butyryloxy) ethyl penicillanate 1,1-dioxide and 1- (Pivaloyloxy) ethyl penicillanate 1,1-dioxide.

EXAMPLE 19

The benzyl penicillanate oroxide and the benzyl penicillanate 1β-oxide are oxidized with 3-10 chloroperbenzoic acid according to the procedure of Example 17, and in both cases the 1,1-dioxide dioxide is obtained. benzyl pernilla.

Similarly, 4-nitrobenzyl penicillanate Ια-oxide and 4-nitrobenzyl penicillanate 15-oxide are oxidized with 3-chloroperbenzoic acid according to the procedure of Example 17 and 1 is obtained, 4-nitrobenzyl penicillanate 1-dioxide.

EXAMPLE 20 1.1- Penicillanic Acid Dioxide The hydrogenolysis of 4-nitrobenzyl penicillanate 1,1-dioxide according to the procedure of Example 3 produces penicillanic acid 1,1-dioxide.

EXAMPLE 21

J

1.1- sodium penicillanate dioxide in a stirred solution of 32.75 g (0.14 mole) of penicillanic acid 1,1-dioxide in 450 ml of acetate! of ethyl, a solution of 25.7 g (0.155 mol) of sodium 2-ethylhexanoate in 200 ml of ethyl acetate is added.

The resulting solution is stirred for 1 h and then a 10% excess of sodium 2-ethylhexanoate is added in a small volume of ethyl acetate. The product immediately begins to precipitate. Stirring is continued for 30 minutes and then the precipitate is separated by filtration. The precipitate is washed successively with ethyl acetate, with a 1: 1 mixture of ethyl acetate and ether and ether. The solid is then dried over phosphorus pentoxide at about 0.1 mm / Hg; ’For 16 hours at 25 ° C to obtain 36.8 g of the desired sodium salt contaminated with a small amount of ethyl acetate.

39

The ethyl acetate content is reduced by heating at 100 ° C for 3 hours under vacuum. The IR spectrum of the final product (KBr disc) shows absorptions at 1786 and 1608 cm \

The spectrum of R.M.N. (D20) has absorptions at 1.48 (s, 5 3H), 1.62 (s, 3H), 3.35 (dd, s, 1H, ^ = 16Hz, J2 = 2Hz), i 3.70 ( dd, 1H, J = 16Hz, J2 = 4Hz), 4.25 (s, 1H) and 5.03 (dd, 1H, s, J1 = 4Hz, J2 = 2Hz) ppm.

i. It is also possible to prepare the desired sodium salt j i -i by replacing the ethyl acetate with acetone.

10 EXAMPLE 22! Penicillanic acid 1,1-dioxide i To a mixture of 7600 ml of water and 289 ml of acid | crystalline acetic acid, add 379 ”5ê of permanganate in portions! potassium. This mixture was stirred for 15 minutes and cooled to 0 ° C. Then adding with stirring a mixture that; 270 g of penicillanic acid, 260 ml of 4N sodium hydroxide and 2400 ml of water (pH 7.2) were prepared and which were prepared | cooled to 8 ° C. The temperature rises to 15 ° C during this last addition. The temperature of the mixture obtained is lowered to 4 ° C. to 5 ° C. and stirring is continued for 30 minutes. 142.1 g of sodium bisulfite are then added to the reaction mixture in portions over 10 minutes. The mixture is stirred for | 10 minutes at 10 ° C. then 100 g of supercel (diatomaceous earth) are added. After another 5 minutes of stirring, the mixture is filtered. 4.0 liters of ethyl acetate I are added to the filtrate, then the pH of the aqueous phase is reduced to 1.55 with I 6N hydrochloric acid. The ethyl acetate phase is separated

And combine it with several subsequent acetate extracts

ethyl. The combined organic phase is washed with water, dried over MgSO 4 and evaporated to near dryness in vacuo. On | * stir the suspension thus obtained with 700 ml of ether at 10 ° C

j for 20 minutes then the solid is collected by filtration, j 82.6 g (yield 26%) of the desired compound are obtained, having a melting point of 154-155.5 ° C (decomposition).

j.35 EXAMPLE 23 pivaloyloxymethyl penicillanate 1,1-dioxide To a solution of 1.25 g of pivaloyl-oxymethyl penicillanate in 40 ml of chloroform, cooled to about -15 ° C., 0.8 g of 3-chloroperbenzoic acid. We shake the •. 40 mix at about -15 ° C for 20 minutes and allow to warm to room temperature. Analysis of the solution obtained by R.M.N. indicates that it contains both 1a- and 18-oxide.

The chloroform solution is concentrated to approximately 20 ml and 0.8 g of 3-chloroperbenzoic acid is added. The mixture is stirred overnight at room temperature and then all of the solvent is removed by evaporation in vacuo. The residue is dissolved 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 removed by evaporation under vacuum. The residue is partitioned between ethyl acetate and water at pH 6.0 and sodium bisulfite is added until the search for peroxides is negative. The pH of the aqueous phase is brought to 8.0 and the phases are separated. The organic phase is washed with salt water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in ether and reprecipitated by addition of hexane. The solid is recrystallized from ether to obtain 0.357 g of the desired compound.

The spectrum of R.M.N. of the product (CDCl ^) has absorptions at: 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 24 3-phthalidyl penicillanate 1,1-dioxide To a solution of 713 mg of 3-phthalidyl penicillanate in 3 ml of chloroform, 0.430 g of 3-chloroperbenzoic acid is added at approximately 10 ° C. The mixture is stirred for 30 minutes and then 0.513 g of 3-30 chloroperbenzoic acid is added. The mixture is stirred for 4 hours at room temperature, then the solvent is removed by evaporation in vacuo. The residue is partitioned between ethyl acetate and water at pH 6.0 and sodium bisulfite is added to decompose the remaining peracid. The pH of the aqueous phase is brought to 8.8. The phases are separated and the organic phase is evaporated under vacuum. The desired compound is obtained in the form of a foam. The spectrum of R.M.N.

(CDCl ^) has absorptions at: 1.62 (m, 6H), 3.3 (m, 2H), 4.52 (p, 1H), 5.23 (m, 1H) and 7.63 (m , 5H) ppm.

ί 41 EXAMPLE 25 1> 1, 2,2,2-trichloroethyl penicillanate dioxide j To 100 mg of 2,2,2-trichlorethyl penicillanate i in a small volume of chloroform, 50 mg of acid is added 5 3 -chloroperbenzoic acid and the mixture is stirred for 30 minutes. The example of the reaction product then shows that it consists essentially of sulfoxide (the NMR spectrum in CDCl 4, exhibits absorptions at 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. Add 100 mg of 3-chloroperbenzoic acid and stir the mixing overnight The solvent is then removed by evaporation in vacuo and the residue is partitioned between ethyl acetate and water at pH 6.0 and sufficient sodium bisulfite is added to decompose excess of peracid 15 and the pH is brought to 8.5 The organic phase is separated, washed with salt water and dried, evaporated under vacuum to obtain 65 mg of the desired product. NMR spectrum (CDCl3) has absorptions at 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 26 4-nitrobenzyl penicillanate 1,1-dioxide A solution of 4r-nitrobenzyl penicillanate in chloroform is cooled to about 15 ° C and an equivalent of 3-chloroperbenzoic acid is added. The reaction mixture is stirred for 20 minutes. Examination of the reaction mixture, by spectrometry of R.M.N ^ shows that it contains 4-nitrobenzyl penicillanate 1-oxide. One equivalent of 3-chloroperbenzoic acid is added and the reaction mixture is stirred for 4 hours. A new equivalent of 3-chloroperbenzoic acid is then added and the reaction mixture is stirred overnight. The solvent is removed by evaporation and the residue is partitioned between ethyl acetate and water at pH 8.5. The ethyl acetate phase is separated, washed with water, dried and evaporated to obtain the crude product. The crude product is purified by chromatography on silica gel, eluting with a 1: 4 mixture of ethyl acetate and chloroform.

The spectrum of R.M.N. product (CDCl ^) present; '· 42 t' of absorption at: 1.35 (s, 3H), 1.58 (s, 3H), 3.45 (m, 2H), 4.42 (s, 1H), 4.58 (m , 1H), 5.30 (s, 2H) and 7.83 (α, 4H) ppm.

EXAMPLE 27 1.1- lucerne dioxide penicillanic 5 To 0.54 g of penicillanate 1,1-dioxide 4-! nitrobenzyl in 30 ml of methanol and 10 ml of ethyl acetate, * 0.54 g of 10% palladium on carbon is added. The mixture is stirred under a hydrogen atmosphere at a pressure of approximately 3.5 bar until the hydrogen fixation ceases. The reaction mixture is filtered and the solvent is removed by evaporation.

The residue is partitioned between ethyl acetate and water at pH 8.5 and the aqueous phase is removed. Fresh ethyl acetate is added and the pH is adjusted to 1.5. The ethyl acetate phase is removed, washed with water and dried and then evaporated in vacuo. 0.168 g of the desired compound is obtained; as a crystalline solid.

'EXAMPLE 28 1.1- penicillanic acid dioxide

A stirred solution of 512 mg of 4-nitrobenzylpenicillanate dioxide is cooled to 0 ° C. in a mixture of 5 ml of acetonitrile and 5 ml of water, then it is added in portions over several minutes, a solution of 484 mg 'I of sodium dithionite in 1.4 ml of 1.0N sodium hydroxide. The reaction mixture is stirred for a further 5 minutes and then diluted with ethyl acetate and water at pH 8.5. The ethyl acetate phase is separated and evaporated in vacuo to obtain 300 mg of the starting material. Fresh ethyl acetate is added to the aqueous phase and the pH is adjusted to 1.5. The ethyl acetate is separated, dried and evaporated in vacuo to obtain 50 mg of the desired compound.

EXAMPLE 29 1.1- 1-methyl- __- 1- (acetoxy) ethyl penicillanate dioxide To 2.33 g of penicillanic acid 1,1-dioxide 35 in 5 ml of Ν, Ν-dimethylformamide, 1.9 ml are added of ethyl-diisopropylamine and then 1.37 g of 1-methyl-1- (acetoxy) ethyl chloride are added dropwise at approximately 20 ° C. The mixture is stirred at room temperature for about 16 hours. The mixture is then diluted with ethyl acetate and water. The phases are separated and the ethyl acetate phase is washed with pH 9 water. The ethyl acetate solution is then dried over sodium sulfate and evaporated in vacuo to give 1 / 65 g of crude product in the form of an oil. The oil solidifies by standing in the refrigerator and 4 is recrystallized from a mixture of chloroform and ether to obtain a product having a melting point of 90-92 ° C.

I The spectrum of R.M.N. of the crude product (CDCl ^) 10 has absorptions at: 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 30

The procedure of Example 29 is repeated, except that the 1-methyl-1- (acetoxy) ethyl chloride is replaced by the 1-methyl-1- (alkanoyloxy) ethyl chloride. suitable for obtaining the following compounds: 1.1- 1-methyl-l- (propionyloxy) ethyl penicillanate dioxide, 1.1- 1-methyl-l- (pivaloyloxy) ethyl penicillanate dioxide, 20 and 1.1- 1-penicillanate dioxide -methyl-1- (hexanoyloxy) ethyl.

EXAMPLE 31 1.1 Penicillanic Acid Dioxide To a stirred solution of 1.78 g of penicillinic acid in water at pH 7.5, 1.46 ml of 40% peracetic acid are added, then add 2.94 ml of 40% peracetic acid 30 minutes - later. The reaction mixture is stirred for 3 days at room temperature and diluted with ethyl acetate and water. Solid sodium bisulfite is added to decompose the excess peracid and then the pH is adjusted to 1.5. The ethyl acetate phase is separated, dried over sodium sulfate and evaporated in vacuo. The residue consists of a 3: 2 mixture of penicillanic acid 1,1-dioxide and penicillanic acid l-oxide.

EXAMPLE 32 1.1- pivaloyloxymethyl penicillanate dioxide An agitated solution of

I I

; 44.595 mg of pivaloyloxymethyl penicillanate 1-oxide in 5 ml of ethyl acetate and 5 mg of manganic acetylacetonate are added. 0.89 ml of 40% peracetic acid is added in several minutes to the dark brown mixture obtained in small quantities. After 40 minutes, the cooling bath is removed and the mixture is stirred at room temperature for 3 days.

The mixture is diluted with ethyl acetate and water at pH 8.5 and the ethyl acetate phase is separated, dried and evaporated in vacuo. 178 mg of product are obtained as R.M.N. watch consisting of a mixture of pivaloyloxymethyl penicillanate 1,1-dioxide and pivaloyloxymethyl penicillanate 1-oxide.

The above product is redissolved in ethyl acetate and again oxidized with 0.9 ml of peracetic acid and 5 mg of manganic acetylacetonate as previously described for 16 hours. The reaction mixture is treated as previously described. 186 mg of pivaloyloxymethyl penicil-lanate 1,1-dioxide are obtained.

PREPARATION A

20 ία-6,6-dibromopenicillanic acid

This compound is prepared by oxidation of 6,6-dibromopenicillanic acid with an equivalent of 3-chloro-perbenzoic acid in tetrahydrofuran between 0 and 25 ° C for about 1 hour according to the procedure described by Harrison and 125 coll. in Journal of the Chemical Society (London) Perkin, I, 1772 (1976).

PREPARATION B

Benzyl 6,6-dibromopenicillanate acid To a solution of 54 g (0.165 mole) of 6.6-30 dibromopenicillanic acid in 350 ml of Ν, Ν-dimethylacetamide, 22.9 ml (0.165 mole) of triethylamine are ♦ added and the solution is stirred for 40 minutes. 19.6 ml (0.165 mole) of benzyl bromide is added and the mixture is stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide is filtered off and the filtrate is added to 1500 ml of ice water, the pH of which has been adjusted to 2. The mixture is extracted with ether and the extracts are washed successively with sodium bicarbonate. saturated, water and water * · 45 * ”. salted. The dried ethereal solution is evaporated under vacuum over magnesium sulphate to obtain a whitish solid which is recrystallized from isopropanol. 70.0 g (yield | 95%) of the desired compound are obtained at m.p. 75-76 ° C. The infrared spectrum (KBr disc) shows absorptions at 1795 and I 1740 cm 1. The spectrum of R.M.N. (CDC13) has absorptions; * at 1.53 (s, 3H), 1.58 (s, 3H), 4.50 (s, 1H), 5.13 (s, 2H), d ^ 5.72 (s, 1H) and 7 , 37 (s, 5H) ppm.

| PREPARATION C

I 10 Benzyl 6,6-dibromopenicillanate ί-oxide To a stirred solution of 13.4 g (0.03 mole) of benzyl 6.6-dibromopenicillanate in 200 ml of dichloromethane, a solution of 6.12 is added g (0.03 mole) of 3-chloroperbenzoic acid in approximately 100 ml of dichloromethane

15 0 ° C. Stirring is continued for 1.5 hours at approximately 0 ° C

and the reaction mixture is filtered. The filtrate is washed successively with 5% sodium bicarbonate and water and then dried over sodium sulfate. The solvent is removed by evaporation in vacuo to obtain 12.5 g of the desired product as an oil. The oil is solidified by trituration: in ether. Filtered to obtain 10.5 g of Ια-oxide of benzyl 6.6-dibromopenicillanate in the form of a solid.

The IR spectrum (CHCl 4) shows absorptions at 1800 and 1750 J cm. The spectrum of R.M.N. of the product (CDCl 4) exhibits absorptions at: 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 D

4-nitrobenzyl penicillanate The triethylamine salt of penicillanic acid is reacted with 4-nitrobenzyl bromide according to the procedure described in Preparation B to obtain 4-nitrobenzyl penicillanate.

| PREPARATION E

] 2,2,2-Trichlorethyl Penicillanate 35 To 403 mg of penicillanic acid in 10 ml of dichloromethane, 25 mg of diisopropylcarbodiimide are added, then 0.19 ml of 2,2,2-trichloroethanol. The mixture is stirred for approximately 16 hours and then the solvent is removed by evaporation t 46! + under vacuum. The crude product is purified by column chromatography with silica gel as adsorbent and chloroform as eluent.

! PREPARATION F

5 3-phthalidyl penicillanate To a solution of 506 mg of penicillanic acid in 2 ml of Ν, Ν-dimethylformamide, 0.476 ml of diisopropylethylamine is added, then 536 mg of 3-phthalidyl bromide.

The mixture is stirred for about 16 hours and then diluted with ethyl acetate and water. The pH is adjusted to 3.0 and the phases are separated. The organic phase is washed with water, then water at pH -8.0 and dried with anhydrous sodium sulfate. The dried ethyl acetate solution is evaporated in vacuo to obtain 713 mg of the desired ester as an oil. The spectrum of R.M.N. (CDCl ^) has adsorptions at 1.62 (m, 6H), 3.3 (m, 2H), 4.52 (s, 1H), 5.23 (m, 1H) and 7.63 (m, 5H).

PREPARATION G

Pivaloyloxymethyl penicillanate 20 To 3.588 g of 6,6-dibromopenicillanic acid in 10 ml of Ν, Ν-dimethylformamide, 1.8 ml of diisopropylethylamine and then 1.40 ml of chloromethyl pivalate are added. The mixture is stirred for about 16 hours and then diluted with ethyl acetate and water. The organic phase is separated and washed successively at pH 3.0 and water at pH 8.0. The solution is dried with ethyl acetate over sodium sulfate and evaporated in vacuo to obtain pivaloyloxymethyl 6,6-dibromopenicillanate in the form of an amber oil (3.1 g) which slowly crystallizes.

The above ester is dissolved in 100 ml of methanol and then 3.1 g of 10% palladium on carbon and 1.31 g of potassium bicarbonate are added in 20 ml of water. The mixture is stirred under hydrogen at atmospheric pressure until there is no longer any fixation of hydrogen. The reaction mixture is filtered and the methanol is removed by evaporation in vacuo. The residue is subjected to a partition between water and ethyl acetate at pH 8 and then the organic phase is separated. The organic phase is dried over sodium sulfate and evaporated under vacuum at 47! to obtain 1.25 g of the desired compound. The spectrum of R.M.N. (CDCl ^) has absorptions at 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.

5 PREPARATION H

4-nitrobenzyl penicillanate * To a stirred solution of 2.14 g of penicilanic acid and 2.01 ml of ethyldiisopropylamine in 10 ml of Ν, Ν-dimethylformamide, 2.36 g are added dropwise of 4-nitrobenzyl bromide at about 20 ° C. The mixture was stirred at room temperature for about 16 hours, then diluted with ethyl acetate and water. The phases are separated and the ethyl acetate phase is washed with water at pH 12.5, then with water at pH 8.5. The ethyl acetate solution is then dried over sodium sulfate and evaporated in vacuo to give 3.36 g of the desired compound.

The spectrum of R.M.N. of the product (in CDCl ^) has absorptions at 1.45 (s, 3H), 1.68 (s, 3H), 3.32 (m, 2H), 4.50 (s, 1H), 5, 23 (m, 1H), 5.25 (s, 2H) and 7.85 (q, 20 4H) ppm.

Of course, the invention is in no way limited to the exemplary embodiments which have just been described, it is on the contrary liable to variants and modifications which will appear to those skilled in the art.

* j

Claims (17)

1. Process for the preparation of a compound with pharmaceutical activity of formula: IH% P Λ j — rs ^ cn3 - - N - \, * 0 COOR6 * or one of its pharmaceutically acceptable salts, formula in which R represents a hydrogen atom or an easily hydrolyzable ester radical in vivo, characterized in that it consists in oxidizing a compound of formula:? 0 P13 H: kCH H! 0 0 ^ "w m3 or j N —-l 3 o '' 1 1 COOR where R1 is a hydrogen atom, an easily ester-forming hydrolyzable ester-forming radical ® in vivo or a classic carboxy radical protecting group penicillins and then, if necessary, remove the protecting group from the carboxy radical. 2. Method according to claim 1, characterized in that the starting material corresponds to the formula: \ \ / rf3 \ Î Vs Y "0” 3 rVYf ~ CH3!. Or • · 'C0 ° *' '0' ' 'COOR1' iJ ù ; ^ 3. The method of claim 1, charac-; terized in that the starting material corresponds to the formula:] CH. \ J VS vi-CHa \ i .. Ci; . O- '““ "W 4. Method according to any one of the res-! · Dications 2 and 3j characterized in that R1 is a hydrogen atom or a radical-forming ester that is easily hydrolyzable in vivo. 5. Method according to claim 4 * character-; laughed at in that the oxidation is carried out using a reagent chosen from metal permanganates and peroxy-carboxylic organic acids · 6. Method according to claim 5, characterized in that the oxidation is carried out using a metal permanganate in a solvent inert with respect to the reaction at a temperature ranging from about -20 to about 50 ° C. 7 * Process according to claim 6, characterized in that the metal permanganate is potassium permanganate. 8. Method according to claim 7, characterized in that R is a hydrogen atom. 9. Method according to claim 7> characterized in that R represents the pivaloyloxy-methyl group. 10. The method of claim 5 * character- | This is accomplished by the oxidation using an organic peroxycarboxylic acid in a solvent inert to the reaction at a temperature in the range of about -20 to about 50 ° C. 11. The method of claim 10, charac- ii 'terized in that the peroxycarboxylic acid is peracetic acid. I · * 12. The method of claim 11, charac-: 'terxse in that one performs the oxidation in the presence of a salt! . manganese. 13. The method of claim 11, characterized in that R ^ is a hydrogen atom. 14. The method of claim 11, charac-: terized in that R represents the pivaloyloxymethyl group. 15. Process for the preparation of an active compound | quickly pharmaceutical formula: I "Λ, /.-¾ I Ί] ch3 J? -N - '/,! 0 'COOR7 i i i j i 7! in which R represents a 3-phthalidyl group, a 4 ~ ci'otonolactonyl group, an X -butyrolacton-4-yl group and the groups corresponding to the formulas: R3 0 R3 O! lî tr, î I! c -C-O-C-R0 and -C-O-C-O-R0 R4 where R3 and R ^ each represent a hydrogen atom or a group * ce alkyl containing 1 or 2 carbon atoms and R represents a group! j, alkyl containing 1 to 6 carbon atoms, characterized in that it i consists in reacting a salt of 1,1-dioxide of penicilla- acid! nique with 3-phtaüdyle chloride, 3-phthalidyl bromide,] 4-crotonolacton-4 ~ yl chloride, 4-crotonolacton-4-yl bromide, Y-butyrolacton chloride ~ 4 ~ yle, Y-butyro lacton-4-yl bromide or a compound of formula: R3 0 R3 Ο 1 it tr i II r Ô-COC-R0 or ß-COCO-R5 Â4 R4 where. Ö represents a chlorine or bromine atom, in a solvent inert to the reaction, at a temperature lying in! the range from 0 to 100 ° C. | * 16. The method of claim 15, charac-; n] i terized in that R4 is an alkanoyloxymethyl group containing 3 to 4; 8 carbon atoms, I A λ · f ; -17 · A method according to claim lo, charac- terized in that R represents the pïvaloyloxyméthyl group. l8. Process for the preparation of a pharmaceutical composition, characterized in that it consists in mixing a diluent or a pharmaceutically acceptable carrier and a compound of formula: Λ Λ CH 0, 0 '3 V "<o' -1 / Xi- CH 3 yn - \ ° _ '' 'C00R · 1 or a salt thereof formed with a pharmaceutically acceptable base formula in which R is a hydrogen atom or an ester-forming radical which is easily hydrolysable in vivo. T 4 i 7 J