CA1207752A - PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM AND DERIVATIVES SO PRODUCED - Google Patents
PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM AND DERIVATIVES SO PRODUCEDInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel derivatives, e.g. salts of a compound of the Formula I
I
in which X stands for a halo, e.g. chlorine, bromine, or iodine, and prefer-ably is a bromine, with a .beta. -lactam antibiotic or a pro-drug thereof con-taining a basic group are provided herein. They are prepared by reacting a solution of potassium 6 .beta. -halopenicillanate, where halo is chloro, bromo, or iodo, with a solution of the antibiotic or a pro-drug thereof, or by treating an organic solvent solution of a 6 .beta. -halopenicillanic acid, wherein halo is chloro, bromo, or iodo, with an organic solvent solution of the antibiotic.
Examples of such .beta. -lactam antibiotics include penicillins, cephalosporins, substituted 6 .beta. -amidinopenicillanic acids, ampicillin, amoxycillin, cepha-lexin, cefaclor, and mecillinam, and pro-drugs thereof e.g., pivmecillinam, bacmecillinam, penethamate, pivampicillin, and bacampicillin. Processes for the preparation of such derivatives are also provided which involve interrac-tion of solutions, e.g. organic solvent solutions, of the reactants. The .beta. -halopenicillanic acids of formula I are potent inhibitors of .beta. -lactamases from a variety of gram-positive and gram-negative bacteria, making the above-described derivatives of .beta. -halopenicillanic acids valuable in human and veterinary medicine.
Novel derivatives, e.g. salts of a compound of the Formula I
I
in which X stands for a halo, e.g. chlorine, bromine, or iodine, and prefer-ably is a bromine, with a .beta. -lactam antibiotic or a pro-drug thereof con-taining a basic group are provided herein. They are prepared by reacting a solution of potassium 6 .beta. -halopenicillanate, where halo is chloro, bromo, or iodo, with a solution of the antibiotic or a pro-drug thereof, or by treating an organic solvent solution of a 6 .beta. -halopenicillanic acid, wherein halo is chloro, bromo, or iodo, with an organic solvent solution of the antibiotic.
Examples of such .beta. -lactam antibiotics include penicillins, cephalosporins, substituted 6 .beta. -amidinopenicillanic acids, ampicillin, amoxycillin, cepha-lexin, cefaclor, and mecillinam, and pro-drugs thereof e.g., pivmecillinam, bacmecillinam, penethamate, pivampicillin, and bacampicillin. Processes for the preparation of such derivatives are also provided which involve interrac-tion of solutions, e.g. organic solvent solutions, of the reactants. The .beta. -halopenicillanic acids of formula I are potent inhibitors of .beta. -lactamases from a variety of gram-positive and gram-negative bacteria, making the above-described derivatives of .beta. -halopenicillanic acids valuable in human and veterinary medicine.
Description
This application is a division of application Serial No. 352,237 filed May 20, 19~0.
This invention relates to the preparation of derivatives, e.g. salts, of the Formula I
X H ~
~a `COO H
in which X stands for chlorine, bromine or iodine, with a ~ -lactam anti-biotic or a pro-drug thereof, containing a basic group, and to the derivatives so producedO
In the treatment of bacterial infections, it is a serious problem that ~ -lactamase producing bacteria occur with increasing frequency. These enzymes inactivate a variety of ~ -lactam antibiotics, and it is well recog-nized that ~ -lactarnases from both gram-positive and gram-negative bacteria contribute significantly to the resistance of bacteria to ~ -lactam anti-biotics.
It has now been found that the 6 ~ -halopenicillanic acids of Formula I are potent inhibitors of ~ -lactamases from a variety of gram-positive and gram-negative bacteria. This property makes the derivatives, e.g., salts, of 6 ~ -halopenicillanic acids with the ~ -lactam antibiotics valuable in human and veterinary medicine because they can protect ~ -lactam antibiotics against inactivation when co-administered with these.
In addition to the inhibitory activity against ~ -lactamases, ~4Q !
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the 6 3 -halopenicillanic acids have antibacterial properties (cf. Table I) and are particularly active against Neisseria species.
Apart from impure 6 7 -bromopenicillanic acid, which has been ' - la -~Z~775i2 mentioned in the literature, the derivatives of aspects of this invention are new~ and none of them, including ~ -bromopenicillanic acid, have hitherto been obtained in a pure state.
It has been reported (J. Org. Chem. Vol. 43, pp. 3611-3613, 1978;
Proc. Natl. Acad. Sci. USA, Vol. 75, pp. 4145-4149, 1978; U.S. Patent No.
4,180,506 (Dec. 25, 1979); Biochem. J., Vol. 177, pp. 365-367, 1979) that mix~tures of 6 ~ - and 6c~ -bromopenicillanic acids are obtained either on epimerization of the latter or by selective hydrogenation of 6,6-dibromo-penicillanic acid, the 6 ~ -bromo epimer being present in the reaction mix-tures in estimated amounts of from 5 to 15%. The same literature has reported that such epimeric mixtures act as inhibitors of ~ -lactamases, and since pure 6 ~ -bromopenicillanic acid has no effect on these enzymes, the inhibitory activity has been attributed to the 6 ~ -bromo isomer. It has also been reported (Tetrahedron Letters No 48, pp. 4631-4634, Nov. 1970) that selective reduction of trimethylsilyl 6,6-dibromopenicillanate with tri-n-butyltin hydride followed by hydrolysis and salt formation afforded a 30 per cent yield of sodium 6 ~ -bromopenicillanate containing less than 5 per cent of the 6~ -bromo epimer, but that the major side reaction was over-reduction ~o penicillanic acid. The same literature also describes a similar reduction of the corresponding 6-chloro-6-iodopenicillanate providing a 39 per cent yield of a mixture of 6 ~ -and 6c~ -chloropenicillanic acids con-taining 25 per cent of the 6 ~ -epimer. However, neither 6 ~ -bromo and 6 ~ -chloropenicillanic acid nor salts and easily hydrolyzable esters of these compounds have so far been isolated in a pure crystalline state. 6 ~ -Iodopenicillanic acid or its salts and esters have not been reported previously in the literature.
Thus, it is an object of one aspect of the present invention -,~
,~ ,.
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to provide derlvatives of 6 ~ -halopenicillanic acids of the Formula I with -lactam antibiotics in a form suitable for medical use, these derivatives exhibiting strong ~ -lactamase inhibitory activity, increasing in the order Cl~ Br~ I and also showing antibacterial activity, in particular against Neisseria species.
An object of another aspect of the present invention is ~o provide processes for the preparation of such derivatives of the acids of Formula I.
By one broad aspect of this invention, a process is provided for preparing a derivative of a compound of the Formula I
X H H
' H C~OH
in which X stands for a halo, e.g. chloro, bromo or iodo, with a ~ -lactam antibiotic or a pro-drug thereof containing a basic group, which process comprises reacting a solution of potassium 6 ~ -halopenicillanate, wherein halo is chloro, bromo or iodo, with a solution of such antibiotic or such pro-drug thereof.
The above derivative may be a salt, in which case the process may either comprise reacting an aqueous solution of potassium 6 ~ -halopenicil-lanate with an aqueous solution of the antibiotic, or may comprise treating an organic solvent solution of a 6~ -halopenicillanic acid, wherein halo is chloro, bromo, or iodo, with an organic solution of the antibiotic.
Whether the derivative is the acid of the salt, the ~ -lactam antibiotic may be selected from the group consisting of penicillins, cephalos-porins and substituted 6 g -amidinopenicillanic acids, and pro-drugs thereof;
or it may be selected from the group consisting of ampicillin, amoxycillin, ~'~
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mecillinam, cephlexinl and cefaclor, and pivarnpicillin~ bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof; or it may be selected from the group consisting of benzylpenicillin, phenoxy-methylpenicillin, carbenicillin, methicillin, propicillin, epicephalexin, cephacetrile cephamandole, cephapirin, cephradine, and cephaloglycine. The other pro-drugs of the ~ -lactam antibiotic may be selected from the group consisting of hetacillin; metampicillin; the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl ~C -esters of carbenicillin, or of ticarcillin; 6 ~ -amidinopenicillanic acid derivatives; and 7 ~ -amidinocephalosporanic acid derivatives.
In an especially advantageous embodiment of the above processes, the halo is bromo.
: Other specific embodiments of this process provide the following processes:
(a) the preparation of the pivampicillin salt of 6 ~ -iodopenicillanic acid by reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 B -ioeopenicillanate;
(b) the preparation of the pivampicillin salt of 6 ~ -bromopenicillanic acid by reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 ~ -bromopenicillanate;
(c) the preparation of the bacampicillin salt of 6 ~ -iodopenicillanic acid by reacting an aqueous solution of bacampicillin hydrochloride ~L~Q~7~
with an aqueous solution of potassium 6 ~ -iodopeniciLlanate;
(d) the preparation of the bacampicillin salt of 6 ~ -bromopenicillanic acid by reacting an aqueous solution of bacampicillin hydrochloride with an aqueous solution of potassium 6 0 -bromopenicillanate.
(e) the preparation of the pivmecillinam salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an organic solvent solution of pivmecillinam;
(f) the preparation of the pivmecillinam salt of 6 ~ -bromopenicillanic acid by treating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of pivmecillinam;
(g) the preparation of the bacmecillinam salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an : organic solvent solution of bacmecillinam;
(h) the preparation of the bacmecillinam salt of 6 ~ -bromopenicillanic acid by ~reating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of bacmecillinam;
~i) the preparation of the penethamate salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an organic solvent solution of penethamate; and (j) the preparation of the penethamate salt of 6~ -bromopenicillanic acid by treating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of penethamate.
Thus, according to the process of one aspect of the invention dis-closed and claimed in the above-identified parent application Serial ~o.
252,237, mixtures of epimeric 6-halopenicillanic acids are produced by aqueous equilibration of a salt of a 6 ~ -halopenicillanic acid at 30 - 40C. and a moderately basic pH-value (8 - 10) for 6 - 48 hours, preferably at 30 - 32C.
and pll 9.0 - 9.1 for 20 - 24 hours, the pll ,~ - 5 -~2~7~
in the reaction mixture preferably being held constant by the addition of dilute aqueous base via an automatic titrator. The amount of 6 ~ -halo epimer present in the resulting mixtures decreases in the order of I~ Br~ Cl, but the yields of the ~ -epimers are at least twice as high as those described in the literature for the epimerization of 6 ~ -bromopenicillanic acid or by using the heretofore described method for the epimerization of the corres-ponding 6c~ -chloro and 6 ~ -iodo acidsO
As disclosed and claimed in the above-identified parent application Serial No. 352,237, the epimeric mixtures of 6-chloro, 6-bromo, or 6-iodo-penicillanic acids thus obtained can be separated by column chromatographyon silica gel using as developing solvent an appropriate mixture of organic solvents, e.g., ether-petroleum ether, ethyl acetate-petroleum ether, chloro-form-benzene or ethyl acetate-cyclohexane, these solvent mixtures prefer-ably containing a low percentage (0.1 - 0.5%~ of a carboxylic acid, e.g., formic acid or acetic acid. A highly efficient developing solvent for the separation of the epimeric mixtures referred to above by dry column chroma-tography on silica gel is, e.g., ether-petroleum ether-formic acid, 70:30:0:1.
Hereby the more polar 6 ~ -halopenicillanic acids are completely separated from their less polar 6c~ -epimers and, following a usual work-up procedure of the eluates, obtained in a pure crystalline state, either in the form of the free acids or as the corresponding potassium or sodium salts. The purity c)f the crystalline 6~ -halopenicillanic acids thus obtained as well as ~he respective potassium and sodium salts is at least 99 per cent, as determined by thin-layer and gas-liquid chromatography.
In another embodiment of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, 6,6-dihalopenicillanic acids or salts thereof can be selectively reduced by trea~ment with alkali 7~
me~al or tetraalkylammonium boranates, e.g., sodium borohydride, potassium borohydride, sodium cyanoborohydride, tetrabutylammonium boranate, or cetyl trimethylammonium boranate to afford favourably high yields (~ 50%) of the free 6 ~ -halopenicillanic acids of Formula I. The reactions are performed in an appropriate organic solvent, e.g., dimethyl sulphoxide, dimethylforma-mide, ethyl acetate or methylene chloride, and at temperatures between 0 and C., preferably at room temperature. The 6 ~ -halopenicillanic acids of Formula I can be separated from the corresponding 6c~ -halo- and/or 6,6-dihalopenicillanic acids present in the crude reaction mixtures by column chromatography as referred to above or by fractionate crystalliæation known to the man skilled in the art.
According to a further variant of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, the new esters of the 6 ~ -halo acids of Formula I can be prepared by epimeri~ation of the corresponding 6 ~ -halopenicillanic acid esters in an appropriate organic solvent, e.g., methylene chloride, chloroform or dimethylformamide, in the presence of an organic base, e.g., 1,5-diazabicycloL4.3.0]non-5~ene or tri-ethylamine, and at temperatures between -10C. and room temperature. The epimeric mixtures of the corresponding 6-halopenicillanic acid esters thus obtained are separated by column chromatography under similar conditions as mentioned above to afford the pure 6 ~ -halo isomers.
In a further embodiment of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, the esters can be obtained by selective reduction of 6,6-dihalopenicillanic acid esters with alkali metal or tetraalkylammonium boranates, similar to the procedure referred to before. The 6 ~ -halo esters thus obtained are separated from minor amounts of the corresponding 6,7~-eipmers and/or unreacted starting materials by column chromatography as described above.
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As disclosed and claimed in the above-identified parent application Serial No. 352,237, the ~ -halopenicillanic acids of Formula I or their salts can be converted into the corresponding esters by well-known esterifi-; cation processes, and vice versa such esters can be cleaved chemically or enzymatically to give the corresponding free acids of Formula I or salts thereof under conditions which do not result in any appreciable destruction of the remaining part of the molecule.
By another aspect of the inventioo disclosed and claimed in theabove-identified parent application Serial No. 352,237, an essentially pure, preferably crystalline compound of the Formula I is provided in which X
stands for chlorine, bromine or iodine, salts and easily hydrolyzable esters thereof, and salts of such esters.
As disclosed and claimed in the above-identified parent application i Serial No. 352,237, species of such compound include 6 ~ -iodopenicillanic acid, 6 ~ -bromopenicillanic acid, and 6 ~ -chloropenicillanic acid.
As disclosed and claimed in the above-identified parent application Serial No. 352,237, the salt may be an alkali metal salt, for example, a potassium salt, e.g., potassium 6~ -bromopenicillanate, potassium 6 ~ -chloro-penicillanate or potassium 6J~ -iodopenicillanate, or sodium salt, e.g., sodium 6~A -bro~openicillanate, sodium 6~ -chloropenicillanate or sodium 6 ~ -iodopenicillanate.
Another variant disclosed and claimed in the above-identified parent application Serial No. 352,237, provides the alkanolyoxyalkyl or alkoxycar-bonyloxyalkyl ester, preferably pivaloyloxymethyl 6 ~ -bromopenicillanate and pivaloyloxymethyl 6 ~ -iodopenicillanate.
Now, however, according to another aspect of the invention provided by the present divisional application, the salt may be an alkaline earth salt, or a salt with a pharmaceutically acceptable, non-toxic amine, for example, a 7S~
salt with a ~ -lactam antibiotic or a pro-drug thereof containing a basic group, preferably of 6 ~ ~iodopenicillanic acid or of 6 ~ -bromopenicillanic acid or of ~ -chloropenicillanic acid. Preferred species of such salts include the pivampicillin salt of 6~ -iodopenicillanic acid, the pivampicillin salt of 6~ -bromopenicillanic acid, the bacampicillin salt of 6 ~ -iodopenicillanic acid, the bacampicillin salt of 6~ -bromopenicillanic acid, the pivmecillinam salt of 6 ~ -iodopenicillanic acid, the pivmecillinam salt of 6 ~ -bromopeni-cillanic acid, the bacmecillinam salt of 6 ~ -iodopenicillanic acid, the bacmecillinam salt of 6~ -bromopenicillanic acid, the penethamate salt of 6 ~ -iodopenicillanic acid, and the penethamate salt of 6 ~ -bromopenicillanic acid.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, the salts of the 6 ~ -halopenicillanic acids are salts with pharmaceutically acceptable, non-toxic bases, and among the suitable salts mention may be made of alkali metal salts and alkaline earth metal salts, e.g., lithiumS sodium, potassium, magnesium, and calcium salts, as well as salts with ammonia and suitable non-toxic amines, e.g., lower alkylamines, e.g., triethylamine, lower alkanolamines, e.g., diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g.~ dicyclohexylamine, benzylamines, e.g., N-methylbenzylamine, N-ethylbenzylamine, N-benzyl- ~ -phenylethylamine, N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines, e.g., morpholine~ N-ethylpiperidine or the like. Now, however, according to another aspect of the invention provided by the present divisional application, salts formed with, e.g., ~ -lactam antibiotics or pro-drugs thereof containing a basic group, e.g., pivampicillin, pivmecillinam, bacampicillin, bacmecillinam, penethamate, ampicillin or amoxycillin, are provided. In some instances, it is preferred to use salts which are readily soluble in water, whereas for other purposes, it may be appropriate to use an only slightly soluble salt, e.g., in _ 9 _ ~, .
, . ...
~;~a77~
order to obtain a prolonged effect or for preparation of aqueous suspensions.
The above list, however, is only to be considered illustrative for, and not to be limiting of, the present invention.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, the esters of the 6 ~ -halopenicillanic acids are esters which are readily hydrolyzed in vivo or in vitro. Such esters include acyloxy-alkyl, alkoxycarbonyloxyalkyl or aminocycloxyalkyl esters of the Formula II
~ ~H ''''COO-c-o-e-R2 in which X has the same meaning as in Formula I, Rl is hydrogen, methyl, or ethyl, and R2 i5 a straight or branched alkyl or alkoxy with from 1 to 6 carbon atoms, or an aryl or aryloxy radical, or R2 is a strai~ht or branched amino-alkyl with from 1 to 6 carbon atoms, the alkyl moiety optionally being sub-stituted by one or more additional groups~ e.g., hydroxy, mercapto9 alkoxy, alkylthio, carbalkoxy, carboxamido, phenyl or hydroxyphenyl. The asterisk in the ester moiety indicates the possibility of an asymmetric carbon atom.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, among the above esters the following are preferred:
alkanoyloxymethyl with from 3 to 8 carbon atoms, l-(alkanoyloxy)ethyl with from 4 to 9 carbon atoms, alkoxycarbonyloxymethyl with from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl with from 4 to 7 carbon atoms, and ~ -amino-alkanoyloxymethyl with from 2 to 6 carbon atoms. Other preferred esters are ~ - 10 -~2U~7S;2 lactonyl esters, e.g., 3-phthalidyl, 4-crotonolactonyl or ~ -butyrolacton-4-yl esters. Also within the scope of such esters are methoxymethyl, cyanomethyl, or mono- or dialkyl substituted aminoalkyl esters, e.g., 2-dimethylaminoethyl,
This invention relates to the preparation of derivatives, e.g. salts, of the Formula I
X H ~
~a `COO H
in which X stands for chlorine, bromine or iodine, with a ~ -lactam anti-biotic or a pro-drug thereof, containing a basic group, and to the derivatives so producedO
In the treatment of bacterial infections, it is a serious problem that ~ -lactamase producing bacteria occur with increasing frequency. These enzymes inactivate a variety of ~ -lactam antibiotics, and it is well recog-nized that ~ -lactarnases from both gram-positive and gram-negative bacteria contribute significantly to the resistance of bacteria to ~ -lactam anti-biotics.
It has now been found that the 6 ~ -halopenicillanic acids of Formula I are potent inhibitors of ~ -lactamases from a variety of gram-positive and gram-negative bacteria. This property makes the derivatives, e.g., salts, of 6 ~ -halopenicillanic acids with the ~ -lactam antibiotics valuable in human and veterinary medicine because they can protect ~ -lactam antibiotics against inactivation when co-administered with these.
In addition to the inhibitory activity against ~ -lactamases, ~4Q !
.
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the 6 3 -halopenicillanic acids have antibacterial properties (cf. Table I) and are particularly active against Neisseria species.
Apart from impure 6 7 -bromopenicillanic acid, which has been ' - la -~Z~775i2 mentioned in the literature, the derivatives of aspects of this invention are new~ and none of them, including ~ -bromopenicillanic acid, have hitherto been obtained in a pure state.
It has been reported (J. Org. Chem. Vol. 43, pp. 3611-3613, 1978;
Proc. Natl. Acad. Sci. USA, Vol. 75, pp. 4145-4149, 1978; U.S. Patent No.
4,180,506 (Dec. 25, 1979); Biochem. J., Vol. 177, pp. 365-367, 1979) that mix~tures of 6 ~ - and 6c~ -bromopenicillanic acids are obtained either on epimerization of the latter or by selective hydrogenation of 6,6-dibromo-penicillanic acid, the 6 ~ -bromo epimer being present in the reaction mix-tures in estimated amounts of from 5 to 15%. The same literature has reported that such epimeric mixtures act as inhibitors of ~ -lactamases, and since pure 6 ~ -bromopenicillanic acid has no effect on these enzymes, the inhibitory activity has been attributed to the 6 ~ -bromo isomer. It has also been reported (Tetrahedron Letters No 48, pp. 4631-4634, Nov. 1970) that selective reduction of trimethylsilyl 6,6-dibromopenicillanate with tri-n-butyltin hydride followed by hydrolysis and salt formation afforded a 30 per cent yield of sodium 6 ~ -bromopenicillanate containing less than 5 per cent of the 6~ -bromo epimer, but that the major side reaction was over-reduction ~o penicillanic acid. The same literature also describes a similar reduction of the corresponding 6-chloro-6-iodopenicillanate providing a 39 per cent yield of a mixture of 6 ~ -and 6c~ -chloropenicillanic acids con-taining 25 per cent of the 6 ~ -epimer. However, neither 6 ~ -bromo and 6 ~ -chloropenicillanic acid nor salts and easily hydrolyzable esters of these compounds have so far been isolated in a pure crystalline state. 6 ~ -Iodopenicillanic acid or its salts and esters have not been reported previously in the literature.
Thus, it is an object of one aspect of the present invention -,~
,~ ,.
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to provide derlvatives of 6 ~ -halopenicillanic acids of the Formula I with -lactam antibiotics in a form suitable for medical use, these derivatives exhibiting strong ~ -lactamase inhibitory activity, increasing in the order Cl~ Br~ I and also showing antibacterial activity, in particular against Neisseria species.
An object of another aspect of the present invention is ~o provide processes for the preparation of such derivatives of the acids of Formula I.
By one broad aspect of this invention, a process is provided for preparing a derivative of a compound of the Formula I
X H H
' H C~OH
in which X stands for a halo, e.g. chloro, bromo or iodo, with a ~ -lactam antibiotic or a pro-drug thereof containing a basic group, which process comprises reacting a solution of potassium 6 ~ -halopenicillanate, wherein halo is chloro, bromo or iodo, with a solution of such antibiotic or such pro-drug thereof.
The above derivative may be a salt, in which case the process may either comprise reacting an aqueous solution of potassium 6 ~ -halopenicil-lanate with an aqueous solution of the antibiotic, or may comprise treating an organic solvent solution of a 6~ -halopenicillanic acid, wherein halo is chloro, bromo, or iodo, with an organic solution of the antibiotic.
Whether the derivative is the acid of the salt, the ~ -lactam antibiotic may be selected from the group consisting of penicillins, cephalos-porins and substituted 6 g -amidinopenicillanic acids, and pro-drugs thereof;
or it may be selected from the group consisting of ampicillin, amoxycillin, ~'~
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mecillinam, cephlexinl and cefaclor, and pivarnpicillin~ bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof; or it may be selected from the group consisting of benzylpenicillin, phenoxy-methylpenicillin, carbenicillin, methicillin, propicillin, epicephalexin, cephacetrile cephamandole, cephapirin, cephradine, and cephaloglycine. The other pro-drugs of the ~ -lactam antibiotic may be selected from the group consisting of hetacillin; metampicillin; the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonylethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl ~C -esters of carbenicillin, or of ticarcillin; 6 ~ -amidinopenicillanic acid derivatives; and 7 ~ -amidinocephalosporanic acid derivatives.
In an especially advantageous embodiment of the above processes, the halo is bromo.
: Other specific embodiments of this process provide the following processes:
(a) the preparation of the pivampicillin salt of 6 ~ -iodopenicillanic acid by reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 B -ioeopenicillanate;
(b) the preparation of the pivampicillin salt of 6 ~ -bromopenicillanic acid by reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 ~ -bromopenicillanate;
(c) the preparation of the bacampicillin salt of 6 ~ -iodopenicillanic acid by reacting an aqueous solution of bacampicillin hydrochloride ~L~Q~7~
with an aqueous solution of potassium 6 ~ -iodopeniciLlanate;
(d) the preparation of the bacampicillin salt of 6 ~ -bromopenicillanic acid by reacting an aqueous solution of bacampicillin hydrochloride with an aqueous solution of potassium 6 0 -bromopenicillanate.
(e) the preparation of the pivmecillinam salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an organic solvent solution of pivmecillinam;
(f) the preparation of the pivmecillinam salt of 6 ~ -bromopenicillanic acid by treating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of pivmecillinam;
(g) the preparation of the bacmecillinam salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an : organic solvent solution of bacmecillinam;
(h) the preparation of the bacmecillinam salt of 6 ~ -bromopenicillanic acid by ~reating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of bacmecillinam;
~i) the preparation of the penethamate salt of 6 ~ -iodopenicillanic acid by treating an organic solvent solution of 6 ~ -iodopenicillanic acid with an organic solvent solution of penethamate; and (j) the preparation of the penethamate salt of 6~ -bromopenicillanic acid by treating an organic solvent solution of 6 ~ -bromopenicillanic acid with an organic solvent solution of penethamate.
Thus, according to the process of one aspect of the invention dis-closed and claimed in the above-identified parent application Serial ~o.
252,237, mixtures of epimeric 6-halopenicillanic acids are produced by aqueous equilibration of a salt of a 6 ~ -halopenicillanic acid at 30 - 40C. and a moderately basic pH-value (8 - 10) for 6 - 48 hours, preferably at 30 - 32C.
and pll 9.0 - 9.1 for 20 - 24 hours, the pll ,~ - 5 -~2~7~
in the reaction mixture preferably being held constant by the addition of dilute aqueous base via an automatic titrator. The amount of 6 ~ -halo epimer present in the resulting mixtures decreases in the order of I~ Br~ Cl, but the yields of the ~ -epimers are at least twice as high as those described in the literature for the epimerization of 6 ~ -bromopenicillanic acid or by using the heretofore described method for the epimerization of the corres-ponding 6c~ -chloro and 6 ~ -iodo acidsO
As disclosed and claimed in the above-identified parent application Serial No. 352,237, the epimeric mixtures of 6-chloro, 6-bromo, or 6-iodo-penicillanic acids thus obtained can be separated by column chromatographyon silica gel using as developing solvent an appropriate mixture of organic solvents, e.g., ether-petroleum ether, ethyl acetate-petroleum ether, chloro-form-benzene or ethyl acetate-cyclohexane, these solvent mixtures prefer-ably containing a low percentage (0.1 - 0.5%~ of a carboxylic acid, e.g., formic acid or acetic acid. A highly efficient developing solvent for the separation of the epimeric mixtures referred to above by dry column chroma-tography on silica gel is, e.g., ether-petroleum ether-formic acid, 70:30:0:1.
Hereby the more polar 6 ~ -halopenicillanic acids are completely separated from their less polar 6c~ -epimers and, following a usual work-up procedure of the eluates, obtained in a pure crystalline state, either in the form of the free acids or as the corresponding potassium or sodium salts. The purity c)f the crystalline 6~ -halopenicillanic acids thus obtained as well as ~he respective potassium and sodium salts is at least 99 per cent, as determined by thin-layer and gas-liquid chromatography.
In another embodiment of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, 6,6-dihalopenicillanic acids or salts thereof can be selectively reduced by trea~ment with alkali 7~
me~al or tetraalkylammonium boranates, e.g., sodium borohydride, potassium borohydride, sodium cyanoborohydride, tetrabutylammonium boranate, or cetyl trimethylammonium boranate to afford favourably high yields (~ 50%) of the free 6 ~ -halopenicillanic acids of Formula I. The reactions are performed in an appropriate organic solvent, e.g., dimethyl sulphoxide, dimethylforma-mide, ethyl acetate or methylene chloride, and at temperatures between 0 and C., preferably at room temperature. The 6 ~ -halopenicillanic acids of Formula I can be separated from the corresponding 6c~ -halo- and/or 6,6-dihalopenicillanic acids present in the crude reaction mixtures by column chromatography as referred to above or by fractionate crystalliæation known to the man skilled in the art.
According to a further variant of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, the new esters of the 6 ~ -halo acids of Formula I can be prepared by epimeri~ation of the corresponding 6 ~ -halopenicillanic acid esters in an appropriate organic solvent, e.g., methylene chloride, chloroform or dimethylformamide, in the presence of an organic base, e.g., 1,5-diazabicycloL4.3.0]non-5~ene or tri-ethylamine, and at temperatures between -10C. and room temperature. The epimeric mixtures of the corresponding 6-halopenicillanic acid esters thus obtained are separated by column chromatography under similar conditions as mentioned above to afford the pure 6 ~ -halo isomers.
In a further embodiment of the process disclosed and claimed in the above-identified parent application Serial No. 352,237, the esters can be obtained by selective reduction of 6,6-dihalopenicillanic acid esters with alkali metal or tetraalkylammonium boranates, similar to the procedure referred to before. The 6 ~ -halo esters thus obtained are separated from minor amounts of the corresponding 6,7~-eipmers and/or unreacted starting materials by column chromatography as described above.
~077S~
As disclosed and claimed in the above-identified parent application Serial No. 352,237, the ~ -halopenicillanic acids of Formula I or their salts can be converted into the corresponding esters by well-known esterifi-; cation processes, and vice versa such esters can be cleaved chemically or enzymatically to give the corresponding free acids of Formula I or salts thereof under conditions which do not result in any appreciable destruction of the remaining part of the molecule.
By another aspect of the inventioo disclosed and claimed in theabove-identified parent application Serial No. 352,237, an essentially pure, preferably crystalline compound of the Formula I is provided in which X
stands for chlorine, bromine or iodine, salts and easily hydrolyzable esters thereof, and salts of such esters.
As disclosed and claimed in the above-identified parent application i Serial No. 352,237, species of such compound include 6 ~ -iodopenicillanic acid, 6 ~ -bromopenicillanic acid, and 6 ~ -chloropenicillanic acid.
As disclosed and claimed in the above-identified parent application Serial No. 352,237, the salt may be an alkali metal salt, for example, a potassium salt, e.g., potassium 6~ -bromopenicillanate, potassium 6 ~ -chloro-penicillanate or potassium 6J~ -iodopenicillanate, or sodium salt, e.g., sodium 6~A -bro~openicillanate, sodium 6~ -chloropenicillanate or sodium 6 ~ -iodopenicillanate.
Another variant disclosed and claimed in the above-identified parent application Serial No. 352,237, provides the alkanolyoxyalkyl or alkoxycar-bonyloxyalkyl ester, preferably pivaloyloxymethyl 6 ~ -bromopenicillanate and pivaloyloxymethyl 6 ~ -iodopenicillanate.
Now, however, according to another aspect of the invention provided by the present divisional application, the salt may be an alkaline earth salt, or a salt with a pharmaceutically acceptable, non-toxic amine, for example, a 7S~
salt with a ~ -lactam antibiotic or a pro-drug thereof containing a basic group, preferably of 6 ~ ~iodopenicillanic acid or of 6 ~ -bromopenicillanic acid or of ~ -chloropenicillanic acid. Preferred species of such salts include the pivampicillin salt of 6~ -iodopenicillanic acid, the pivampicillin salt of 6~ -bromopenicillanic acid, the bacampicillin salt of 6 ~ -iodopenicillanic acid, the bacampicillin salt of 6~ -bromopenicillanic acid, the pivmecillinam salt of 6 ~ -iodopenicillanic acid, the pivmecillinam salt of 6 ~ -bromopeni-cillanic acid, the bacmecillinam salt of 6 ~ -iodopenicillanic acid, the bacmecillinam salt of 6~ -bromopenicillanic acid, the penethamate salt of 6 ~ -iodopenicillanic acid, and the penethamate salt of 6 ~ -bromopenicillanic acid.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, the salts of the 6 ~ -halopenicillanic acids are salts with pharmaceutically acceptable, non-toxic bases, and among the suitable salts mention may be made of alkali metal salts and alkaline earth metal salts, e.g., lithiumS sodium, potassium, magnesium, and calcium salts, as well as salts with ammonia and suitable non-toxic amines, e.g., lower alkylamines, e.g., triethylamine, lower alkanolamines, e.g., diethanolamine or triethanolamine, procaine, cycloalkylamines, e.g.~ dicyclohexylamine, benzylamines, e.g., N-methylbenzylamine, N-ethylbenzylamine, N-benzyl- ~ -phenylethylamine, N,N'-dibenzylethylenediamine or dibenzylamine, and heterocyclic amines, e.g., morpholine~ N-ethylpiperidine or the like. Now, however, according to another aspect of the invention provided by the present divisional application, salts formed with, e.g., ~ -lactam antibiotics or pro-drugs thereof containing a basic group, e.g., pivampicillin, pivmecillinam, bacampicillin, bacmecillinam, penethamate, ampicillin or amoxycillin, are provided. In some instances, it is preferred to use salts which are readily soluble in water, whereas for other purposes, it may be appropriate to use an only slightly soluble salt, e.g., in _ 9 _ ~, .
, . ...
~;~a77~
order to obtain a prolonged effect or for preparation of aqueous suspensions.
The above list, however, is only to be considered illustrative for, and not to be limiting of, the present invention.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, the esters of the 6 ~ -halopenicillanic acids are esters which are readily hydrolyzed in vivo or in vitro. Such esters include acyloxy-alkyl, alkoxycarbonyloxyalkyl or aminocycloxyalkyl esters of the Formula II
~ ~H ''''COO-c-o-e-R2 in which X has the same meaning as in Formula I, Rl is hydrogen, methyl, or ethyl, and R2 i5 a straight or branched alkyl or alkoxy with from 1 to 6 carbon atoms, or an aryl or aryloxy radical, or R2 is a strai~ht or branched amino-alkyl with from 1 to 6 carbon atoms, the alkyl moiety optionally being sub-stituted by one or more additional groups~ e.g., hydroxy, mercapto9 alkoxy, alkylthio, carbalkoxy, carboxamido, phenyl or hydroxyphenyl. The asterisk in the ester moiety indicates the possibility of an asymmetric carbon atom.
As disclosed and claimed in the above-identified parent application, Serial No. 352,237, among the above esters the following are preferred:
alkanoyloxymethyl with from 3 to 8 carbon atoms, l-(alkanoyloxy)ethyl with from 4 to 9 carbon atoms, alkoxycarbonyloxymethyl with from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl with from 4 to 7 carbon atoms, and ~ -amino-alkanoyloxymethyl with from 2 to 6 carbon atoms. Other preferred esters are ~ - 10 -~2U~7S;2 lactonyl esters, e.g., 3-phthalidyl, 4-crotonolactonyl or ~ -butyrolacton-4-yl esters. Also within the scope of such esters are methoxymethyl, cyanomethyl, or mono- or dialkyl substituted aminoalkyl esters, e.g., 2-dimethylaminoethyl,
2-diethylaminoethyl, or 3-dimethylaminopropyl esters.
In particular, as disclosed and claimed in the above-identified parent application~ Serial No. 352,237, the esters which are preferred are those which are well-absorbed upon oral administration and during or after the absorption are hydrolyzed to the free acids of Formula I.
As disclosed and claimed in the above-identified parent applica~ion, Serial No. 352,237, esters which contain an amino group in the ester moiety can be prepared and used in the form of their salts with pharmaceutically acceptable, non-toxic inorganic or organic acids. Examples of suitable inorganic and organic acids include, but are not limited to, the following: hydrohalide acids, e.g., hydrochloric, hy~drobromic and hydriodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, pamoic acid, p-(dipropylsulfamyl)-benzoic acid (probenecid), and phenoxy-methylpenicillin or other acidic ~ -lactam antibiotics. As mentioned above, easily soluble or only slightly soluble salts may be preferred for different purposes.
It has also been discovered that the compounds of aspects of the invention disclosed and claimed in the above-identified parent application, Serial No. 352,237, may be present in a synergistic composition together with a /-" -lactam antibiotic.
By another aspect of this invention provided by the present divisional application, a derivative is provided of a compound of Formula I
x ~ LZ07~S2 ~L .~
0 H "~()01~
; wherein X is a halo, e.g. chloro, bromo or iodo with a ~ -lactarn antibiotic or a pro-drug thereof containing a basic group.
The derivative is preferably a 6 ~ -halopenicillanic acid salt of a -lactam antibiotic or a pro-drug thereof containing a basic group, more preferably a ~ -bromopenicillanic acid salt of a ~ -lactam antibiotic or a pro-drug thereof containing a basic group.
The derivative may be one wherein the ~ -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins and substituted 6 ~ -~amidinopenicilanic acids and pro-drugs thereof; or wherein the ~ -lactam antibiotic i~ selected from the group consisting of ampicillin, amoxycillin, cephalexin, cefaclor and mecillinam, and pivampicillin, bacampicillin, pivmecil-linam, bacmecillinam and penethamate and other pro-drugs thereof; or wherein the ~ lactam antibiotic is selected from the group consisting of benzylpeni-cillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, epicillin, tricarcillin, cyclacillin, cephaloridine, cephalothin? cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine, and cephalogly-cine; or where the other pro-drug of the ~ -lactam antibiotic is selected from the group consisting of hetacillin, metampicillin; the acetoxymethyl, pivaloyl-oxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl or indanyl ` c~ -esters of carbenicillin, or of ticarcillin; 6 ~ -amidinopenicillanic acid derivatives; and 7 ~ -amidinocephalosporanic acid derivatives.
By specific embodiments of these concepts, the following compounds ~7~S~
are provided, namely: the pivampicillin salt of 6 ~ -iodopenicillanic acid;
the pivampicillin salt of 6 ~ -bromopenicillanic acid; the bacampicillin salt of 6 ~ -iodopenicillanic acid; the bacampicillin salt of 6 ~ -bromopenicillanic acid; the pivmecillinam salt of 6 ~ -iodopenicillanic acid; the pivmecillinam ~; salt of 6 ~ -bromopenicillanic acid; the bacmecillinam salt of 6 ~ -iodopenicil-lanic acid; the bacmecillinam salt of 6 ~ -bromopenicillanic acid; the pene-thamate salt of 6 ~ -iodopenicillanic acid; and the penethamate salt of 6~ -bromopenicillanic acid.
As taught herein, the compositions disclosed herein may be used in the treatment of bovine mastitis, and then the ~ -lactam antibiotic is selected from the group consisting of benzylpenicillin, ampicillinS amoxycillin, car-benicillin, cloxacillin, flucloxacillin, ticarcillin, nafcillin, dicloxacillin, oxacillin, methicillin, carfecillin, mecillinam, cephaloridine, cephalexin, cephacetrile, a mixture of ampicillin/cloxacillin, a mixture of amoxycillin/
cloxacillin, a mixture of ampicillin/flucloxacillin and a mixture of ampicillin/
mecillinam.
Suitable~ -lactam antibiotics for such compositions include not only those known to be highly susceptible to ~ -lactamases, but also those which have a good degree of intrinsic resistance to ~ -lactamases. Thus, as described hereinabove, ~ -lactam antibiotics for such compositions include benæyl-penicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefaæolin, cephalexin, cefaclor, cephacetrile, cephamandole, cephapirin, cephradine, cephaloglycine, mecillinam, and other well known penicillins, , i .~, ~?C V.i s `~
i'77~;~
cephalosporins or amidinopenicillanic acids or pro-drugs thcrcoE, e.g., hetacillin, metampicillin, the acetoxymcthyl, pivaloxyloxymethyl, ethoxy-carbonyloxyethyl, or phthalidyl esters of ben~ylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; or che phenyl, tolyl and indanyl -esters of carbenicillin, ticarcillin or the like, or 6 ~ -amidino-penicillanic acid pro-drugs, e.g., pivmecillinam or bacmecillinam; or a similar 7~ -amidinocephalosporanic acid derivative.
When present in a synergistic pharmaceutical cornpostion as taught herein together with another ~-lactam antibiotic, the ratio of the compounds of a;pects of this invention to the other ~ -lactam antibiotic(s) is from 10:1 and 1:10 and advantageously may be from 3:1 to 1:3, calculated as the free acids. The range however9 is not to be considered limiting the invention.
When present in a synergistic pharmaceutical composition as taught herein together with another ~ -lactam a~tibiotic, the ratio of the compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 to the other ~ -lactam antibiotic(s) is from 10:1 to 1:10, and advantageously may be from 3:1 ; to 1:3, calculated as the free acids. The range however, is not to be considered limiting the invention.
,~s disclosed and claimed in the above-identified parent application, the 6 ~ -halopenicillanic acids are potentiators oE ~ -lactamase sensitive antibiotics and may by thcmsclvcs bc uscEul in combatting somc spcciEic bacterial intcctions.
7t~ ~ ~
More specifically, the antibacterial spectra of the pure 6~ -halopenicillanic acids will appear from Table I below.
/
~ /
/
2~7~S2 Table I
Antibacterial spectra a)of 6~-bromopenicillanic acid (A), 6~_ chloropenicillanic acid (B) and 6~-iodopenicillanic acid (C) . ICso Cug/ml) . .
: Organism A ¦ B ¦ C
_ Staph.aureus CJ9 32 4 63 Dipl . pneumoni ae EA1 . 6 5 . O 5 ~ o S trep . pyo gen e ~3 EC 6 . 3 6 ~ 3 5 o Strep.~aecalis EI3 ~100 ~100 ~100 Cor~neb.xerosis FF 5~0 5.0 16 Bacillus subt. KA2 5.0 7-9 13 Ps eud . aeruginos a ~3A2 ~100 ~ 0 ~100 Alcaligenes faecalis GA 2.0 ~.5 10 Escherichia coli HA2 50 50 ~100 " " HA58(RTEM~ 100 ~100 `100 Kleb. pneumoniae HE 63 63 ~100 Enterobact.aerogene~ HC7A 63 63 ~10~
Pr~teus ~ulg. HJ 40 40 100 Salm. typhimurium HL2 100 100 ~100 Shigella dysenteriae HR 50 40 ,100 Neisseria gonorrhoeae DAZ 0.25 0.20 oO79 n meningitidis DB 0~79 o.63 1.6 aemophllus infl~enzae IX3 32 20 >100 )Determined by serial dilutions in fluid medium, inoculum 10 CFU ) (gram-positive organism) or 10 CFU (gram-negative organism) )CFU = colony forming units In Table II is shown the in vitro activity against ~-lactamase producing bacterial strains of selected ~-lac~
tam antibiotics in 1:1 com~inationswith the 6~-halopeni-cillanic acids of formula I. These data indicate that, in com-bination with the 6~-halopenicillanic acids, benzylpenicillin and ampicillin are highly active against otherwise resistant strains of Staphylococcus aureus. A ~similar synergistic effect against strains of Klebsiella pneumoniae, Proteus mirabilis, and Escherichia coli is shown by combinations of ampicillin as well as mecillinam with the 6~-halo acids of the invention, disclosed and clai~ned in the above-identified parent appli~
cation Serial No. 352,237.
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~7~752 As disclosed and claimed in the above-identified parent appli-cation Serial No. 352,237, pharmaceutical compositions are provided for use in the treatment of infectious diseases, the compositions con~aining, as an active ingredient, at least one of the compounds of the invention disclosed and claim~d in the above-identified parent application Seriàl No. 352,237. The compositions include forms adapted for enteral9 paren-teral~ intramammal or topical use and may be used for the treatment of infections in mammals including humans.
The free 6 ~ -halopenicillanic acids of formula I or their salts may be used for enteral, parenteral and topical administration. However, for oral use it may be in some instances be advantageous to use an easily hydrolyzable ester or a salt thereof.
In~ectable or infusable compositions of the 6~-halopenicillanic acids of formula I or their sa~ts are suitable, when high tissue levels of the 6~ -h~lopenicillanic acids are rapidly desired, or when used in combination with a parenterally administered ~ -lactam antibiotic9 as described below.
For intramammal use it is preferred to use an ester of the 6 ~-halopenicillanic acids which provides an adequate local concentration, e.g., a dialkylaminoalkyl ester or a salt thereof.
The active ingredLent of formula I can be used as such or can be mixed up with carriers and/or auxiliary agents.
In such compositions9 the proportion of therapeutically active material of formula I to carriers and auxiliary agents can vary between 1%
and 95%. The compositions can be worked up to pharmaceutical forms of presentation, e.g., tablets, capsules, powders, syrups, suspensions, solu-tions, including forms suitable for injection or infusion.
~7~7~i~
The carriers and/or auxiliary agents are pharmace~tically acceptable materials, e.g., gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene, glycol, or other known carriers for medicaments, and diluents, binders, buffers, preservatives, disintegrants, coating materials, and the likz in accordance with pharmaceutical practice in the manner well understood by those skilled in the art, in order to provide appropriate forms of pharmaceutical presentation, including sustained release preparations, double tablets containing the therapeutically active ingredients separated from each other, and enteric coated tablets, etc.
The compositions including the compounds of the invention dis-closed and claimed in the above-identified parent application Serial No.
/ 352,237 are conveniently administered 1~ sage units containin~ a total amount of from 0.025 g to 2.5 g, and preferably from 0.1 ~, to 1.0 g, of the an ib.-cterial agents, calculated as the free acids. The expression "ancibacterial agents" shall here and in the following mean one or more compounds of th~ invention disclosed and claimed in the above-identified parent application 9erial No. 352,237, alone or ~ z~ 5~
combined with one or more known ,~ -lactam antibiotics, salts or pro-drugs thereof. When used in veterinary practice, the dosage units may contain up to 25 g of the antibacterial agents.
By the term ~Idosage unit" is meant a unitary, e.g., a single dose capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically stable unit comprising either the active materials as such or a mixture thereof with a pharmaceutical carrier.
Similarly, for infusion, the aforesaid compositions are given in dosage units containing up to 10 g of the antibacterial agents in aqueous solution.
For parenteral use, e.g., injections, the aforesaid composi-tions are given, e.g., in an aqueous solution or suspension as a dosage unit containing from 0~1 g to 1 g of the antibacterial agents, calculated as the free acids, to be dissolved or suspended immediately before ~Ise~ or ready for use together with a pharmaceutically acceptable vehicle.
In the form of a dosage unit the compounds may be administered oDce or more times a day at appropriate intervals, always depending~
however, on the condition of the patient.
Thus, a daily dose will am~unt to from 0.1 g to 30 g (corres-ponding to 1 - 425 mg/kg body weight/day), preferably from 0.2 g to 6 g of the antibacterial agents, calculated as the free acids.
The aforesaid compositions may be used in the treatment of lnfections of inter alia tne respiratory tract, the urinary tract, and soft tissues in humans and mav also be use~ to treat infections in animals e.g. mastitis in cattle.
~ 20a -~ Z~ S2 In co~pounded synergistic comyositions containing other ~ -lactam antibiotics, the latter will normally be present in approximately ~he same amoun~s as convent;onally used when such ~ -lactam antibiotics are the sole therapeutic agents, but under certain circu~stancesjit may be appropriate to reduce the amounts thereof.
Particularly favoured compounded synergistic compositions will contain from 50 - 1000 mg of the ~ -lactam antibiotic, a salt or a pro-drug thereof, and the 6~ -halopenicillanic acid9 a salt or a pro-d}ug thereof, in an amoun~ within the aforementioned ratios, and more suitably from 200 - 500 mg of the ~ -lactam antibiotic~ a salt or a pro-drug thereof9 and from 25 - 250 mg of the 6~-halopenicillanic acid, a salt o~ a pro-dr~g-thereof.~
The compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 may be admlnistered in the fPrm of their pharmaceutically acceptable, non-toxic esters~ The term "non toxic" for such esters means that they are thera-peutically acceptable for their intended form of administration. In general, the esters of the compounds of aspects of the invention disclosed and claimed in the abo~e-identified parent applcation Serial No. 352,237 are used in oral administration, but their use in parenteral administration is also within the scope of aspects of the invention disclosed and claimed f in the above-identified parent application Serial No. 352,237.
The method of using the compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 may consist in administering compositions or compounded syner-gistic compositions of aspects of the invention now provided by this divisional application, or in administering such compositions containing the compounds of aspects of the invention disclosed and claimed in the - 20 b -above-identified parent application Serial No. 352,237 alone or together with compositions containing other ~ -lactam antibiotics as now provided by the present divisional application. In the latter case, the two types of compositions may be administered simultaneously or at intervals and with varying proportions between the 6 ~-halopenicillanic acid and the -lactam antibiotic.
According to the present teachin~s between 0.1 and 30 g of .
the antibacterial agents will be administered each day of the treatment, but more often between 500 and 6000 mg of the antibacterial agents will be administered per day.
It shall be expressly understood that the above ranges of doses indicate the total amount of antibacterial agents, i.e., one or more compounds of the invention disclosed and claimed in the above-identi-fied parent application Serial No. 352,237 administered either alone, combined with, or given at intervals with other ~ -lactam antibiotics as above.
The invention in its v~rious aspects will be further described in the following Examples which are not to be construed as limiting the invention.
- 20 c -s~
Example 1 Potassium 6~-bromopenicillanate .
~ solution of potassium 6~-bromopenicillanate (7.64 g, 24 mmol~ in 0~04 M aqueous disodium hydrogen phosphate ~800 ml) was incubated for 72 hours at 30 C. According to an NMR-spectrum (D20) of a freeze-dried 5 ml ~ample~the epimeric mixture contained 10-12~ of the 6~-bromo compound.
After addition of sodium chloride (160 g), the mixture was stirred at 0 C under a layer of ether (250 ml), and the pH of the aqu~ous phase was adj~sted to 3 with 4 N
aqueous hydrochloride. The organic layer was separated, the aqueous phase was re-extracted with ether (100 ml3, and the combined ethereal extracts were washed with satu-rated aqueous sodium chloride (10 ml), dried, and concen-trated to 40 ml at reduced pressure~ The concentrated solution was subjected to dry column chromatography on silica gel (Silîca Woelm TSC, Woelm Pharma, Eschwege, W~stern Germany). The column (~ 5.6 cm, length 46 cm) was developed with ether-petroleum ether-formic acid, 70:~0:0.1 ~1200 ml), fractions a 2 cm ~ere scraped out, suspended in ethyl acetate ~10 ml/fraction~ a and samples of the supernatants were examined by thin-layer chroma-tography using the above mentioned solvent system. Fractions containing the pure, more polar 6~-bromopenicillanic acid were combined and eluted with ethyl acetate. The resulting 12~75;~
ethyl acetate eluate wa~ concentrated to 50 ml at reduced pressure and washed thoroughly with water (6 x 5 ml) to remove the~majo~ amount of formic acid~
To the organic layer was added water (40 ml)~ and the apparent pH of the mixture was adjusted to 7.2 by addition of 005 M aqueous potassium bicarbonate. The aqueous layer was separated and freeze-dried t~ afford 0.54 ~ of pure potassium 6~-bromopenicillanate as a colourless amorphous powder which crystallized from n-butanol 9 [ J~ ~240~ (c=0.2, H20~-/ In the ac~ompanying dr~wings~
/ Figure 1 is a detailed FT proton NMR spectrographof a product of an aspect of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237.
The det~lled Fr proton NMR-spectrum (fig. 1) sho~ed signals at ~ = 1.47 (s, 3H; CH3-2~) 7 1.59 (s, 3Hy C~3-2~) 7 4.27 (59 lH; CH-3), 5.52 and 5.58 (doublets, J-4 Hz~ 2H;
CH-5a and CH-6ay confer fig. la) ppm.
Instrument JEOL FX 100. Concentration 50 mg per ml.
All data converted to tetramethylsilane as 0.00 ppm ~-scale.
_ 23 ~ 775~
xam~le 2 A solution of potassium 6~-chloropenicillanate (13~14 g, 48 mmol) in 0.04 M aqueous disodium hydrogen phosphate (1600 ml) was incubated for 96 hours at 30C to yield~ as revealed by an NMR-spectrum (D20) of a freeze-dried 5 ml sample of the reaction mixture, 5-60/o of 6~-chloro-penicillanic acid in admixture with the starting material.
To the reaction mixture was added sodium chloride (320 g) and ether (400 ml)~ and the pH of the aqueo~s phase was adjusted to 3 by addition of 4 N aqueous hydrochloric acid at 0C with stirring. The organic phase was separated, the aqueous layer was re-extracted with ether (200 ml)~
and the combined ethereal extracts were washed with saturated aqueous sodium chloride (20 ml), dried, and concentrated to 50 ml at reduced pressure. The concentrate was subjeGted to dry column chromatography on silica gel (as described in Example 1 for the sepa-ration of the corresponding 6-epimeric bromopenicillanic acids). Fractions containing the pure 6~-chloropenicil-lanic acid were eluted with ethyl acetate, and the resulting solution was worked up in a similar manner as described in Example 1 to afford o.68 g of potassium _ 24 -~ 2~
6~-chloropenicillanate as an amorphous powder which cry-stallized from n-butanol.
The NMR-spectrum (D20) showed signals at ~ = 1.48 (s~ 3H; CH3-2a)~ 1.58 ~s~ 3H; CH3-2~), 4-27 (s~ lH~ CH-3), 5,43 and 5.63 (2d, J=4 Hz, 2H; CH-5a and CH-6~) ppm.
Tetramethylsilane was used as external reference.
Exam~le 3 Potassium 6~-iodopenicillanate By following the procedure of Example 1, but substitu-ting potassium 6a-iodopenicillanate for the potassium 6-bromopenicilla~ate, the desired compound was obtained as an amorphous product which crystallized from n-butanol.
Example 4 Potassium 6~-bromopenicillanate A solution Or potassium 6~-bromopenicillanate ~15.28 g, 48 mmol) in water (320 ml) was adjusted to pH 9.0 with 1 N
aqueous sodium hydroxide and stirred for 24 hours at 30C.
During the reaction a pH of 9.0 was maintained in the solution by addition of 1 N aqueous sodiu~ hydroxide via an automatic titrator. An NMR spectrum (D~O) obtained from a freeze-dried 1 ml sample of the solution indicated the presence of approx-imately 25% of the 6~-bromo compound in the epimeric mixture formed.
~2~ i2 The mixture was worked up and purified by column chromatography as described in Example 1 to yield crystal-line potassium 6~ bromopenicillanate identical with the product prepared in Example l; []DO +253 (c=0.55 1 M
phosphate buffer, pH 7 ) .
Calculated for C8H9BrKN03S: C~ 30.19; H~ 2.85; BrJ
25.11; N~ 4.40; S, 10.08%. Found: C9 30.16; Hg 2.95;
Br9 25.28; N, 4~33, S9 10.07%.
Example 5 Potassium 6~-chloropenicillanate By following the procedure of Example 4, but substi-tuting potassium 6~-chloropenicillanate for the potassium 6-bromopenicillanate, an epimeric mixture containing about 15~ of the 6~-chloro compound was obtained7 as revealed by a~ NMR spectrum (D20) of a freeze-dried sample of ~he reaction mixture~
: The crystalline title compound was obtained using a similar work~up and chromatography method as described in Example l; [~]D +243 (c=0.5, 1 M phosphate buffer pH 7)~
Example 6 Potassium 6~ iodopenicillanate A. cetoxvmethyl 6-diazopenicillanate To a stirred solution of acet~xymethyl 6~-aminopenicilla-~Z~
nate (5.77 g, 20 mmol) and sodium nitrite (2.76 g, 40 mmol)in a mixture of dichlorome-thane (120 ml) and water (120 ml) was added dropwise ~t 0-3C 4N aqueous sulphuric acid (7 ml).
After stirring at the low temperature for a further 30 minutes, the organic phase was separated, dried (Na2S04), and concentrated to approximately 30 ml at reduced pressure.
This concentrate was used immediately in the following step.
B. Acetoxymethyl 6~-iodopen_cillanate The co~centrated solution o* acetoxymeth.yl 6-diazopeni-cillanate from step A above was diluted with icecold acetone ~180 ml), and to the stirred mixture was added dropwise at 0-3C a solution of sodium iodide.(9.0 g, 60 mmol) and 57%
; hydroiodic acid ~7.4 ml~ in water (15 ml). After stirring at 0-3 C for a further 25 minutes, the mixture was treated with solid sodium bicarbonate (10 g) and filtered. The filtrate was diluted with ethyl acetate (150 ml) 7 acetone was removed at reduced pressure, and the remaining organic layer was separated, washed with 0.5 M aqueous sodium thiosulphate (2 x 100 ml), dried (Na2S04), and concentrated to about 10 ml at reduced pres.sure~
Thi~ concentrated solution was subjected to dry col~mn chromatography on silica gel (ether-petroleum ether, 4:6~ to yield pure acetoxymethyl 6a-iodopeni'cillanate as a sli~ltly yellowish oil.
Z
The NMR spectrum (CDC13) showed signals at ~ = l.48 (5~ 3H; CH3-2a), 1~63 (5~ 3H; CH3-2~), 2.11 (S9 3H; COCH3), 4-56 ~s~ lH; CH-3)~ 4.99 (d, J=1l5 HZ9 lH; CH-6) 7 5.45 (d, J=1.5 Hz~ lH~ CH-5), an`d 5.79 (ABq, J=5.5 HZs 2H; OCH20) ppm-Tetramethylsilane was used as internal reference.
C. Potassium 6a-iodo~enicillanate __ _ To a s~lution o~ acetoxymethyl 6a~iodopenicillanate (2.0 g~ 5 mmol) in 70% aqueous methanol (50 ml~ was added 4 N aqueous hydrochloric acid (1.5 ml), and, after protection from light, the mixture was stirred at room temperature for
In particular, as disclosed and claimed in the above-identified parent application~ Serial No. 352,237, the esters which are preferred are those which are well-absorbed upon oral administration and during or after the absorption are hydrolyzed to the free acids of Formula I.
As disclosed and claimed in the above-identified parent applica~ion, Serial No. 352,237, esters which contain an amino group in the ester moiety can be prepared and used in the form of their salts with pharmaceutically acceptable, non-toxic inorganic or organic acids. Examples of suitable inorganic and organic acids include, but are not limited to, the following: hydrohalide acids, e.g., hydrochloric, hy~drobromic and hydriodic acid, phosphoric acid, sulphuric acid, nitric acid, p-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, pamoic acid, p-(dipropylsulfamyl)-benzoic acid (probenecid), and phenoxy-methylpenicillin or other acidic ~ -lactam antibiotics. As mentioned above, easily soluble or only slightly soluble salts may be preferred for different purposes.
It has also been discovered that the compounds of aspects of the invention disclosed and claimed in the above-identified parent application, Serial No. 352,237, may be present in a synergistic composition together with a /-" -lactam antibiotic.
By another aspect of this invention provided by the present divisional application, a derivative is provided of a compound of Formula I
x ~ LZ07~S2 ~L .~
0 H "~()01~
; wherein X is a halo, e.g. chloro, bromo or iodo with a ~ -lactarn antibiotic or a pro-drug thereof containing a basic group.
The derivative is preferably a 6 ~ -halopenicillanic acid salt of a -lactam antibiotic or a pro-drug thereof containing a basic group, more preferably a ~ -bromopenicillanic acid salt of a ~ -lactam antibiotic or a pro-drug thereof containing a basic group.
The derivative may be one wherein the ~ -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins and substituted 6 ~ -~amidinopenicilanic acids and pro-drugs thereof; or wherein the ~ -lactam antibiotic i~ selected from the group consisting of ampicillin, amoxycillin, cephalexin, cefaclor and mecillinam, and pivampicillin, bacampicillin, pivmecil-linam, bacmecillinam and penethamate and other pro-drugs thereof; or wherein the ~ lactam antibiotic is selected from the group consisting of benzylpeni-cillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, epicillin, tricarcillin, cyclacillin, cephaloridine, cephalothin? cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine, and cephalogly-cine; or where the other pro-drug of the ~ -lactam antibiotic is selected from the group consisting of hetacillin, metampicillin; the acetoxymethyl, pivaloyl-oxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl or indanyl ` c~ -esters of carbenicillin, or of ticarcillin; 6 ~ -amidinopenicillanic acid derivatives; and 7 ~ -amidinocephalosporanic acid derivatives.
By specific embodiments of these concepts, the following compounds ~7~S~
are provided, namely: the pivampicillin salt of 6 ~ -iodopenicillanic acid;
the pivampicillin salt of 6 ~ -bromopenicillanic acid; the bacampicillin salt of 6 ~ -iodopenicillanic acid; the bacampicillin salt of 6 ~ -bromopenicillanic acid; the pivmecillinam salt of 6 ~ -iodopenicillanic acid; the pivmecillinam ~; salt of 6 ~ -bromopenicillanic acid; the bacmecillinam salt of 6 ~ -iodopenicil-lanic acid; the bacmecillinam salt of 6 ~ -bromopenicillanic acid; the pene-thamate salt of 6 ~ -iodopenicillanic acid; and the penethamate salt of 6~ -bromopenicillanic acid.
As taught herein, the compositions disclosed herein may be used in the treatment of bovine mastitis, and then the ~ -lactam antibiotic is selected from the group consisting of benzylpenicillin, ampicillinS amoxycillin, car-benicillin, cloxacillin, flucloxacillin, ticarcillin, nafcillin, dicloxacillin, oxacillin, methicillin, carfecillin, mecillinam, cephaloridine, cephalexin, cephacetrile, a mixture of ampicillin/cloxacillin, a mixture of amoxycillin/
cloxacillin, a mixture of ampicillin/flucloxacillin and a mixture of ampicillin/
mecillinam.
Suitable~ -lactam antibiotics for such compositions include not only those known to be highly susceptible to ~ -lactamases, but also those which have a good degree of intrinsic resistance to ~ -lactamases. Thus, as described hereinabove, ~ -lactam antibiotics for such compositions include benæyl-penicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefaæolin, cephalexin, cefaclor, cephacetrile, cephamandole, cephapirin, cephradine, cephaloglycine, mecillinam, and other well known penicillins, , i .~, ~?C V.i s `~
i'77~;~
cephalosporins or amidinopenicillanic acids or pro-drugs thcrcoE, e.g., hetacillin, metampicillin, the acetoxymcthyl, pivaloxyloxymethyl, ethoxy-carbonyloxyethyl, or phthalidyl esters of ben~ylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; or che phenyl, tolyl and indanyl -esters of carbenicillin, ticarcillin or the like, or 6 ~ -amidino-penicillanic acid pro-drugs, e.g., pivmecillinam or bacmecillinam; or a similar 7~ -amidinocephalosporanic acid derivative.
When present in a synergistic pharmaceutical cornpostion as taught herein together with another ~-lactam antibiotic, the ratio of the compounds of a;pects of this invention to the other ~ -lactam antibiotic(s) is from 10:1 and 1:10 and advantageously may be from 3:1 to 1:3, calculated as the free acids. The range however9 is not to be considered limiting the invention.
When present in a synergistic pharmaceutical composition as taught herein together with another ~ -lactam a~tibiotic, the ratio of the compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 to the other ~ -lactam antibiotic(s) is from 10:1 to 1:10, and advantageously may be from 3:1 ; to 1:3, calculated as the free acids. The range however, is not to be considered limiting the invention.
,~s disclosed and claimed in the above-identified parent application, the 6 ~ -halopenicillanic acids are potentiators oE ~ -lactamase sensitive antibiotics and may by thcmsclvcs bc uscEul in combatting somc spcciEic bacterial intcctions.
7t~ ~ ~
More specifically, the antibacterial spectra of the pure 6~ -halopenicillanic acids will appear from Table I below.
/
~ /
/
2~7~S2 Table I
Antibacterial spectra a)of 6~-bromopenicillanic acid (A), 6~_ chloropenicillanic acid (B) and 6~-iodopenicillanic acid (C) . ICso Cug/ml) . .
: Organism A ¦ B ¦ C
_ Staph.aureus CJ9 32 4 63 Dipl . pneumoni ae EA1 . 6 5 . O 5 ~ o S trep . pyo gen e ~3 EC 6 . 3 6 ~ 3 5 o Strep.~aecalis EI3 ~100 ~100 ~100 Cor~neb.xerosis FF 5~0 5.0 16 Bacillus subt. KA2 5.0 7-9 13 Ps eud . aeruginos a ~3A2 ~100 ~ 0 ~100 Alcaligenes faecalis GA 2.0 ~.5 10 Escherichia coli HA2 50 50 ~100 " " HA58(RTEM~ 100 ~100 `100 Kleb. pneumoniae HE 63 63 ~100 Enterobact.aerogene~ HC7A 63 63 ~10~
Pr~teus ~ulg. HJ 40 40 100 Salm. typhimurium HL2 100 100 ~100 Shigella dysenteriae HR 50 40 ,100 Neisseria gonorrhoeae DAZ 0.25 0.20 oO79 n meningitidis DB 0~79 o.63 1.6 aemophllus infl~enzae IX3 32 20 >100 )Determined by serial dilutions in fluid medium, inoculum 10 CFU ) (gram-positive organism) or 10 CFU (gram-negative organism) )CFU = colony forming units In Table II is shown the in vitro activity against ~-lactamase producing bacterial strains of selected ~-lac~
tam antibiotics in 1:1 com~inationswith the 6~-halopeni-cillanic acids of formula I. These data indicate that, in com-bination with the 6~-halopenicillanic acids, benzylpenicillin and ampicillin are highly active against otherwise resistant strains of Staphylococcus aureus. A ~similar synergistic effect against strains of Klebsiella pneumoniae, Proteus mirabilis, and Escherichia coli is shown by combinations of ampicillin as well as mecillinam with the 6~-halo acids of the invention, disclosed and clai~ned in the above-identified parent appli~
cation Serial No. 352,237.
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~7~752 As disclosed and claimed in the above-identified parent appli-cation Serial No. 352,237, pharmaceutical compositions are provided for use in the treatment of infectious diseases, the compositions con~aining, as an active ingredient, at least one of the compounds of the invention disclosed and claim~d in the above-identified parent application Seriàl No. 352,237. The compositions include forms adapted for enteral9 paren-teral~ intramammal or topical use and may be used for the treatment of infections in mammals including humans.
The free 6 ~ -halopenicillanic acids of formula I or their salts may be used for enteral, parenteral and topical administration. However, for oral use it may be in some instances be advantageous to use an easily hydrolyzable ester or a salt thereof.
In~ectable or infusable compositions of the 6~-halopenicillanic acids of formula I or their sa~ts are suitable, when high tissue levels of the 6~ -h~lopenicillanic acids are rapidly desired, or when used in combination with a parenterally administered ~ -lactam antibiotic9 as described below.
For intramammal use it is preferred to use an ester of the 6 ~-halopenicillanic acids which provides an adequate local concentration, e.g., a dialkylaminoalkyl ester or a salt thereof.
The active ingredLent of formula I can be used as such or can be mixed up with carriers and/or auxiliary agents.
In such compositions9 the proportion of therapeutically active material of formula I to carriers and auxiliary agents can vary between 1%
and 95%. The compositions can be worked up to pharmaceutical forms of presentation, e.g., tablets, capsules, powders, syrups, suspensions, solu-tions, including forms suitable for injection or infusion.
~7~7~i~
The carriers and/or auxiliary agents are pharmace~tically acceptable materials, e.g., gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene, glycol, or other known carriers for medicaments, and diluents, binders, buffers, preservatives, disintegrants, coating materials, and the likz in accordance with pharmaceutical practice in the manner well understood by those skilled in the art, in order to provide appropriate forms of pharmaceutical presentation, including sustained release preparations, double tablets containing the therapeutically active ingredients separated from each other, and enteric coated tablets, etc.
The compositions including the compounds of the invention dis-closed and claimed in the above-identified parent application Serial No.
/ 352,237 are conveniently administered 1~ sage units containin~ a total amount of from 0.025 g to 2.5 g, and preferably from 0.1 ~, to 1.0 g, of the an ib.-cterial agents, calculated as the free acids. The expression "ancibacterial agents" shall here and in the following mean one or more compounds of th~ invention disclosed and claimed in the above-identified parent application 9erial No. 352,237, alone or ~ z~ 5~
combined with one or more known ,~ -lactam antibiotics, salts or pro-drugs thereof. When used in veterinary practice, the dosage units may contain up to 25 g of the antibacterial agents.
By the term ~Idosage unit" is meant a unitary, e.g., a single dose capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically stable unit comprising either the active materials as such or a mixture thereof with a pharmaceutical carrier.
Similarly, for infusion, the aforesaid compositions are given in dosage units containing up to 10 g of the antibacterial agents in aqueous solution.
For parenteral use, e.g., injections, the aforesaid composi-tions are given, e.g., in an aqueous solution or suspension as a dosage unit containing from 0~1 g to 1 g of the antibacterial agents, calculated as the free acids, to be dissolved or suspended immediately before ~Ise~ or ready for use together with a pharmaceutically acceptable vehicle.
In the form of a dosage unit the compounds may be administered oDce or more times a day at appropriate intervals, always depending~
however, on the condition of the patient.
Thus, a daily dose will am~unt to from 0.1 g to 30 g (corres-ponding to 1 - 425 mg/kg body weight/day), preferably from 0.2 g to 6 g of the antibacterial agents, calculated as the free acids.
The aforesaid compositions may be used in the treatment of lnfections of inter alia tne respiratory tract, the urinary tract, and soft tissues in humans and mav also be use~ to treat infections in animals e.g. mastitis in cattle.
~ 20a -~ Z~ S2 In co~pounded synergistic comyositions containing other ~ -lactam antibiotics, the latter will normally be present in approximately ~he same amoun~s as convent;onally used when such ~ -lactam antibiotics are the sole therapeutic agents, but under certain circu~stancesjit may be appropriate to reduce the amounts thereof.
Particularly favoured compounded synergistic compositions will contain from 50 - 1000 mg of the ~ -lactam antibiotic, a salt or a pro-drug thereof, and the 6~ -halopenicillanic acid9 a salt or a pro-d}ug thereof, in an amoun~ within the aforementioned ratios, and more suitably from 200 - 500 mg of the ~ -lactam antibiotic~ a salt or a pro-drug thereof9 and from 25 - 250 mg of the 6~-halopenicillanic acid, a salt o~ a pro-dr~g-thereof.~
The compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 may be admlnistered in the fPrm of their pharmaceutically acceptable, non-toxic esters~ The term "non toxic" for such esters means that they are thera-peutically acceptable for their intended form of administration. In general, the esters of the compounds of aspects of the invention disclosed and claimed in the abo~e-identified parent applcation Serial No. 352,237 are used in oral administration, but their use in parenteral administration is also within the scope of aspects of the invention disclosed and claimed f in the above-identified parent application Serial No. 352,237.
The method of using the compounds of aspects of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237 may consist in administering compositions or compounded syner-gistic compositions of aspects of the invention now provided by this divisional application, or in administering such compositions containing the compounds of aspects of the invention disclosed and claimed in the - 20 b -above-identified parent application Serial No. 352,237 alone or together with compositions containing other ~ -lactam antibiotics as now provided by the present divisional application. In the latter case, the two types of compositions may be administered simultaneously or at intervals and with varying proportions between the 6 ~-halopenicillanic acid and the -lactam antibiotic.
According to the present teachin~s between 0.1 and 30 g of .
the antibacterial agents will be administered each day of the treatment, but more often between 500 and 6000 mg of the antibacterial agents will be administered per day.
It shall be expressly understood that the above ranges of doses indicate the total amount of antibacterial agents, i.e., one or more compounds of the invention disclosed and claimed in the above-identi-fied parent application Serial No. 352,237 administered either alone, combined with, or given at intervals with other ~ -lactam antibiotics as above.
The invention in its v~rious aspects will be further described in the following Examples which are not to be construed as limiting the invention.
- 20 c -s~
Example 1 Potassium 6~-bromopenicillanate .
~ solution of potassium 6~-bromopenicillanate (7.64 g, 24 mmol~ in 0~04 M aqueous disodium hydrogen phosphate ~800 ml) was incubated for 72 hours at 30 C. According to an NMR-spectrum (D20) of a freeze-dried 5 ml ~ample~the epimeric mixture contained 10-12~ of the 6~-bromo compound.
After addition of sodium chloride (160 g), the mixture was stirred at 0 C under a layer of ether (250 ml), and the pH of the aqu~ous phase was adj~sted to 3 with 4 N
aqueous hydrochloride. The organic layer was separated, the aqueous phase was re-extracted with ether (100 ml3, and the combined ethereal extracts were washed with satu-rated aqueous sodium chloride (10 ml), dried, and concen-trated to 40 ml at reduced pressure~ The concentrated solution was subjected to dry column chromatography on silica gel (Silîca Woelm TSC, Woelm Pharma, Eschwege, W~stern Germany). The column (~ 5.6 cm, length 46 cm) was developed with ether-petroleum ether-formic acid, 70:~0:0.1 ~1200 ml), fractions a 2 cm ~ere scraped out, suspended in ethyl acetate ~10 ml/fraction~ a and samples of the supernatants were examined by thin-layer chroma-tography using the above mentioned solvent system. Fractions containing the pure, more polar 6~-bromopenicillanic acid were combined and eluted with ethyl acetate. The resulting 12~75;~
ethyl acetate eluate wa~ concentrated to 50 ml at reduced pressure and washed thoroughly with water (6 x 5 ml) to remove the~majo~ amount of formic acid~
To the organic layer was added water (40 ml)~ and the apparent pH of the mixture was adjusted to 7.2 by addition of 005 M aqueous potassium bicarbonate. The aqueous layer was separated and freeze-dried t~ afford 0.54 ~ of pure potassium 6~-bromopenicillanate as a colourless amorphous powder which crystallized from n-butanol 9 [ J~ ~240~ (c=0.2, H20~-/ In the ac~ompanying dr~wings~
/ Figure 1 is a detailed FT proton NMR spectrographof a product of an aspect of the invention disclosed and claimed in the above-identified parent application Serial No. 352,237.
The det~lled Fr proton NMR-spectrum (fig. 1) sho~ed signals at ~ = 1.47 (s, 3H; CH3-2~) 7 1.59 (s, 3Hy C~3-2~) 7 4.27 (59 lH; CH-3), 5.52 and 5.58 (doublets, J-4 Hz~ 2H;
CH-5a and CH-6ay confer fig. la) ppm.
Instrument JEOL FX 100. Concentration 50 mg per ml.
All data converted to tetramethylsilane as 0.00 ppm ~-scale.
_ 23 ~ 775~
xam~le 2 A solution of potassium 6~-chloropenicillanate (13~14 g, 48 mmol) in 0.04 M aqueous disodium hydrogen phosphate (1600 ml) was incubated for 96 hours at 30C to yield~ as revealed by an NMR-spectrum (D20) of a freeze-dried 5 ml sample of the reaction mixture, 5-60/o of 6~-chloro-penicillanic acid in admixture with the starting material.
To the reaction mixture was added sodium chloride (320 g) and ether (400 ml)~ and the pH of the aqueo~s phase was adjusted to 3 by addition of 4 N aqueous hydrochloric acid at 0C with stirring. The organic phase was separated, the aqueous layer was re-extracted with ether (200 ml)~
and the combined ethereal extracts were washed with saturated aqueous sodium chloride (20 ml), dried, and concentrated to 50 ml at reduced pressure. The concentrate was subjeGted to dry column chromatography on silica gel (as described in Example 1 for the sepa-ration of the corresponding 6-epimeric bromopenicillanic acids). Fractions containing the pure 6~-chloropenicil-lanic acid were eluted with ethyl acetate, and the resulting solution was worked up in a similar manner as described in Example 1 to afford o.68 g of potassium _ 24 -~ 2~
6~-chloropenicillanate as an amorphous powder which cry-stallized from n-butanol.
The NMR-spectrum (D20) showed signals at ~ = 1.48 (s~ 3H; CH3-2a)~ 1.58 ~s~ 3H; CH3-2~), 4-27 (s~ lH~ CH-3), 5,43 and 5.63 (2d, J=4 Hz, 2H; CH-5a and CH-6~) ppm.
Tetramethylsilane was used as external reference.
Exam~le 3 Potassium 6~-iodopenicillanate By following the procedure of Example 1, but substitu-ting potassium 6a-iodopenicillanate for the potassium 6-bromopenicilla~ate, the desired compound was obtained as an amorphous product which crystallized from n-butanol.
Example 4 Potassium 6~-bromopenicillanate A solution Or potassium 6~-bromopenicillanate ~15.28 g, 48 mmol) in water (320 ml) was adjusted to pH 9.0 with 1 N
aqueous sodium hydroxide and stirred for 24 hours at 30C.
During the reaction a pH of 9.0 was maintained in the solution by addition of 1 N aqueous sodiu~ hydroxide via an automatic titrator. An NMR spectrum (D~O) obtained from a freeze-dried 1 ml sample of the solution indicated the presence of approx-imately 25% of the 6~-bromo compound in the epimeric mixture formed.
~2~ i2 The mixture was worked up and purified by column chromatography as described in Example 1 to yield crystal-line potassium 6~ bromopenicillanate identical with the product prepared in Example l; []DO +253 (c=0.55 1 M
phosphate buffer, pH 7 ) .
Calculated for C8H9BrKN03S: C~ 30.19; H~ 2.85; BrJ
25.11; N~ 4.40; S, 10.08%. Found: C9 30.16; Hg 2.95;
Br9 25.28; N, 4~33, S9 10.07%.
Example 5 Potassium 6~-chloropenicillanate By following the procedure of Example 4, but substi-tuting potassium 6~-chloropenicillanate for the potassium 6-bromopenicillanate, an epimeric mixture containing about 15~ of the 6~-chloro compound was obtained7 as revealed by a~ NMR spectrum (D20) of a freeze-dried sample of ~he reaction mixture~
: The crystalline title compound was obtained using a similar work~up and chromatography method as described in Example l; [~]D +243 (c=0.5, 1 M phosphate buffer pH 7)~
Example 6 Potassium 6~ iodopenicillanate A. cetoxvmethyl 6-diazopenicillanate To a stirred solution of acet~xymethyl 6~-aminopenicilla-~Z~
nate (5.77 g, 20 mmol) and sodium nitrite (2.76 g, 40 mmol)in a mixture of dichlorome-thane (120 ml) and water (120 ml) was added dropwise ~t 0-3C 4N aqueous sulphuric acid (7 ml).
After stirring at the low temperature for a further 30 minutes, the organic phase was separated, dried (Na2S04), and concentrated to approximately 30 ml at reduced pressure.
This concentrate was used immediately in the following step.
B. Acetoxymethyl 6~-iodopen_cillanate The co~centrated solution o* acetoxymeth.yl 6-diazopeni-cillanate from step A above was diluted with icecold acetone ~180 ml), and to the stirred mixture was added dropwise at 0-3C a solution of sodium iodide.(9.0 g, 60 mmol) and 57%
; hydroiodic acid ~7.4 ml~ in water (15 ml). After stirring at 0-3 C for a further 25 minutes, the mixture was treated with solid sodium bicarbonate (10 g) and filtered. The filtrate was diluted with ethyl acetate (150 ml) 7 acetone was removed at reduced pressure, and the remaining organic layer was separated, washed with 0.5 M aqueous sodium thiosulphate (2 x 100 ml), dried (Na2S04), and concentrated to about 10 ml at reduced pres.sure~
Thi~ concentrated solution was subjected to dry col~mn chromatography on silica gel (ether-petroleum ether, 4:6~ to yield pure acetoxymethyl 6a-iodopeni'cillanate as a sli~ltly yellowish oil.
Z
The NMR spectrum (CDC13) showed signals at ~ = l.48 (5~ 3H; CH3-2a), 1~63 (5~ 3H; CH3-2~), 2.11 (S9 3H; COCH3), 4-56 ~s~ lH; CH-3)~ 4.99 (d, J=1l5 HZ9 lH; CH-6) 7 5.45 (d, J=1.5 Hz~ lH~ CH-5), an`d 5.79 (ABq, J=5.5 HZs 2H; OCH20) ppm-Tetramethylsilane was used as internal reference.
C. Potassium 6a-iodo~enicillanate __ _ To a s~lution o~ acetoxymethyl 6a~iodopenicillanate (2.0 g~ 5 mmol) in 70% aqueous methanol (50 ml~ was added 4 N aqueous hydrochloric acid (1.5 ml), and, after protection from light, the mixture was stirred at room temperature for
3 days. The mixture was poured into water (150 ml), extracted twice with ether (lO0 ml), and the combined ethereal extr~cts were washed with water (2 x 25 ml)0 To the organic layer was added fresh water (40 ml)g and the pH in the aq~eous phase was adjusted to 6.8 by addition of 1 M potas~ium bicarbonate with s*irring. The aqueous phase was separated and freeze--dried to give potassium 6a-iodopenicillanate as an amorphous powd~r, which crystallized from acetone.
The NMR-spectrum (D20) showed signals at ~ = 1.46 (s, 3H;
CH3-2a~ 57 (S9 3H; C~3-2~)~ 4.30 (5, lH; CH-3), 5.24 (d, J=1.5 Hz, lH; CH-6), and 5.46 (d, J=1.5 Hz, lH; CH-5~ ppm.
D. Potassium 6~-iodo~enicillanate A solution of potassium 6a-iodopenicillanate (3.65 g, 10 mmol) in water (200 ml) was stirred at 30 C for 20 hours, _ 28 -~ 775i2 a constant pH of 9.0 being maintained in the reaction MiX -t~re by additions of 0.1 N sodium hydroxide via an autornatic titrator. According to the NMR spectrum (D20) of a freeze--dried 1 ml-sample, the epimeric mixture of 6-iodopenicilla-nates thus fo~med contained approximately 30% o~ the 6~-iodo compound.
To the mixture was added ether (150 ml), and the pH of the aqlleOUS phase was adjusted to 3.0 by addition of 4 N
hydrochloric acid with stirringO Thé organic phase ~ias sepa-rated, the aqueous p~ase re-extracted with ethe~ ~50 ml) 9 and the combi~ed ethereal extracts were washed with saturated aqueous ~odium chloride (2 x 20 ml), dried (MgS0~), and con-centra*ed t~ about 6_8 ml at reduced pressure. The concentrate thus obtained was subjected to dry column chromatography on silica gel (ether-petroleum ether-formic acid, 70:30:0.1), and~ analogously to the procedure described in Exampie 1 for tha sepa~ation and isolation of the corresponding 6~- and 6a-bromo compounds, potas~ium 6~-iodopenicillanate was ob-tai~ed in a crystalline state; [a]D +260 (c=0.5, 1 M
phosphate buffer pH 7).
The NMR spectrum (~2~ showed sig~als at ~ = 1.49 (s, 3H;
CH3-2~), 1.65 ~s, 3H; CH3-2~), 4.~9 (s, lH; CH-3), 5.42 and 5.80 (2d, J=3.5 Hz, 2H; CH-5, and CH-6) ppm.
Calculated for C8H9IKN03S: C, 26.31; H, 2.48, I, 34.75 N, 3.84; S, 8.78C/o. ~ound: C, 26.51; ~, 2.58; I, 34.91;
N, 3.75; S, 8.800/o.
75;2 Example 7 Pivalo~loxymethyl 6~-bromopenicillanate To ~ solution of potassium 6~-bromopenicillanate (o.64 g, 2 mmol) in dimethylformamide (15 ml) was added chloromethyl pivalate (0.27 ml~ 2.5 mmol)~ and the mixture was stirred for 16 hours at room temperature. After dilution with ethyl acetate (45 ml), the ~ixture was washed with water ( 4 Y 10 ml), dried (MgSo43, and evaporated in vacuo. The residual oil crystallized from diisopropyl ether to give the title compound, meltin~
point: 67 - 68C.
The NMR spectrum (CDC13~ showed signals at ~ = 1.23 (s~ 9H; C(CH3)3)~ 1-51 (s~ 3H; CH3-2~ 6B (s~ 3~;
CH3-2~), 4.54 (s~ lH; CH-3), 5032 and 5.57 (2 d7 J=4 Hz, 2H; CH-5 and CH-6), and 5.82 (ABq, J=5.5 Hz, 2H; OCH~O) ppm.
Tetrame$hyl~ilane was used as internal reference.
.
Example 8 Pivaloyloxymethyl 6~-chloropenicillanate By substituting potassium 6~-chloropenicillanate for the potassium 6~-bromopenicillanat~ in the procedure of Example 7, pivaloyloxymethyl 6~-chloropenicillanate was ob*ained as colourless crystals~ melting point: 68 - 69 C.
The NMR spectrum (CDC13) showed signals at ~ - 1.2~
-~ ~ 3 ~
~7~5~
(s, 9H; C(CH3)3), 1-51 (s, 3H; CH3-2a)~ 1-66 (s; 3H;
CH3~?~), 4.53 (s, lH; CH-3), 5.22 and 5.60 (2d, J=4 Hz, 2H; CH-5 and CH-6), and 5.82 (ABq, J=5.5 Hz, 2H; oCH2oj ppm.
Tetramethylsilane was used as internal reference.
Example 9 PivaloyloxYmethyl 6,B-iodopenicillanate A. Pivaloyloxymethyl 6-diazopenicillanate A stirred mixture of pivaloyloxymethyl 6~-amino-penicillanate (3.30 g~ 10 mmol) and sodium nitrite ~1~38 g, 20 mmol) in methylene chloride (120 ml) and water (120 ml) was cooled to 0 C and tr~ated with 2 N aqueous sulphuric acid (7.5 ml) ~or 40 minutes. The organic phase was separated, dried (Na2SOL~), and concentrated at reduced pressure to 30 ml. The concentrate was used imme-diately for the subsequent transformation.
B. Pi~aloyloxymethY1 6~-iodopenicillanate The concentrate of pi~aloyloxyme$hyl 6-diazopeni-cillanate from step A abo~e was diluted with acetone (120 ml), cooled to 0 C~ and to the stirred mixture was added a cold solution of 670~o aqueous hydroiodic acid (3.5 ml) and sodium iodide (4.5 g) in water ~20 ml).
After stirring for a further 20 minutes at the low tempe-rature, the mixture was treated wi$h solid sodium bi-3~ _ ~2~775~
carbonateg filtered, and evaporated. The résidue obtainedwas taken up in ethyl acetate (100 ml) and washed wi~h 5% aqueous sodium thiosulphate (2 x 75 ml). The organic phase was separated, dried ~MgS04), a~d evaporated in vacuo. The residual oil was purified by column chroma-tography on silica gel using ether-petroleum ether, 30:70, as the eluant to yield pure pivaloyloxymethyl 6a-iodopenicillanate as colourless crystals from diiso-propyl ether~ melting point: 63 - 64 C.
C. Pivaloyloxymethvl 6~-iodopenicillanat;e To a stirred solution of pivaloyloxymethyl 6a-iodo-penicillanate (0.88 g, 2 ~rnol~ in dry methylene chloride (20 ml) was added at -5 C a 1 M solution of 1,5-diaza-bicyclo[4.3.0~non-5-ene (DBN~ in dry methylen~ chloride (2 ml). The mi~ture was stirred at 0 C ~or 20 minutes, shaken with 1 N aqueous ace$ic acid (2 ml)~ diluted with methylene chloride (20 ml), washed with ~ater (2 x 10 ml~ 9 dried (Na2S04~ and evaporated ln vacuo to a dark oil. The residue was purified by colomn chroma-tography on silica gel using ether-petroleum ether, 30:70, as the el~ant to afford pivaloyloxymethyl 6~-iodo~
penicillanate as a slightly yellowish oil which crystallized from diisopropyl ether, melting point: 78-79 C.
~ _ 32 ~775i~
The NMR spectrum (CDC13) showed signals at S - 1.23 (s, 9H; C(CH3)3)~ 1-49 (s, 3H; CH3-2a), l jO (s, 3~I;
; CH3,~ 4-55 (s~ lH; CH-3)~ 5038 and 5.62 (2d~ J=4 Hz~
i 2H; CH-5 and CH-6), and 5.81 (ABq9 J=5.5 Hz, 2H; OCH20) ppm.
Tetramethylsilane was used as internal reference.
Exam~le 10 Acetoxymethyl 6~_bromopenicillanate Chloromethyl acetate (0.11 ml~ 1~2 mmol~ was added to a solution of potassium 6~-bromopenicillanate (0.32 g~ 1 mmol) in dimet~ylformamide (5 ml), and the mixture was stirred for 16 hours at room temperature in a dark room. After dilution ~ith ether (20 ml), the mixt~re was washed ~ith water ~4 x 5 ml), dried (MgSOI~), and evaporated in vacuo to yield the title com-pound as a yellowish oil.
The NMR spectrum (CDC13) showed signals at ~ - 1.49 ~s~ 3H; C_3-2~ 68 (s, 3H; CH3-2~)7 2.11 (s~ 3H; COCH3),
The NMR-spectrum (D20) showed signals at ~ = 1.46 (s, 3H;
CH3-2a~ 57 (S9 3H; C~3-2~)~ 4.30 (5, lH; CH-3), 5.24 (d, J=1.5 Hz, lH; CH-6), and 5.46 (d, J=1.5 Hz, lH; CH-5~ ppm.
D. Potassium 6~-iodo~enicillanate A solution of potassium 6a-iodopenicillanate (3.65 g, 10 mmol) in water (200 ml) was stirred at 30 C for 20 hours, _ 28 -~ 775i2 a constant pH of 9.0 being maintained in the reaction MiX -t~re by additions of 0.1 N sodium hydroxide via an autornatic titrator. According to the NMR spectrum (D20) of a freeze--dried 1 ml-sample, the epimeric mixture of 6-iodopenicilla-nates thus fo~med contained approximately 30% o~ the 6~-iodo compound.
To the mixture was added ether (150 ml), and the pH of the aqlleOUS phase was adjusted to 3.0 by addition of 4 N
hydrochloric acid with stirringO Thé organic phase ~ias sepa-rated, the aqueous p~ase re-extracted with ethe~ ~50 ml) 9 and the combi~ed ethereal extracts were washed with saturated aqueous ~odium chloride (2 x 20 ml), dried (MgS0~), and con-centra*ed t~ about 6_8 ml at reduced pressure. The concentrate thus obtained was subjected to dry column chromatography on silica gel (ether-petroleum ether-formic acid, 70:30:0.1), and~ analogously to the procedure described in Exampie 1 for tha sepa~ation and isolation of the corresponding 6~- and 6a-bromo compounds, potas~ium 6~-iodopenicillanate was ob-tai~ed in a crystalline state; [a]D +260 (c=0.5, 1 M
phosphate buffer pH 7).
The NMR spectrum (~2~ showed sig~als at ~ = 1.49 (s, 3H;
CH3-2~), 1.65 ~s, 3H; CH3-2~), 4.~9 (s, lH; CH-3), 5.42 and 5.80 (2d, J=3.5 Hz, 2H; CH-5, and CH-6) ppm.
Calculated for C8H9IKN03S: C, 26.31; H, 2.48, I, 34.75 N, 3.84; S, 8.78C/o. ~ound: C, 26.51; ~, 2.58; I, 34.91;
N, 3.75; S, 8.800/o.
75;2 Example 7 Pivalo~loxymethyl 6~-bromopenicillanate To ~ solution of potassium 6~-bromopenicillanate (o.64 g, 2 mmol) in dimethylformamide (15 ml) was added chloromethyl pivalate (0.27 ml~ 2.5 mmol)~ and the mixture was stirred for 16 hours at room temperature. After dilution with ethyl acetate (45 ml), the ~ixture was washed with water ( 4 Y 10 ml), dried (MgSo43, and evaporated in vacuo. The residual oil crystallized from diisopropyl ether to give the title compound, meltin~
point: 67 - 68C.
The NMR spectrum (CDC13~ showed signals at ~ = 1.23 (s~ 9H; C(CH3)3)~ 1-51 (s~ 3H; CH3-2~ 6B (s~ 3~;
CH3-2~), 4.54 (s~ lH; CH-3), 5032 and 5.57 (2 d7 J=4 Hz, 2H; CH-5 and CH-6), and 5.82 (ABq, J=5.5 Hz, 2H; OCH~O) ppm.
Tetrame$hyl~ilane was used as internal reference.
.
Example 8 Pivaloyloxymethyl 6~-chloropenicillanate By substituting potassium 6~-chloropenicillanate for the potassium 6~-bromopenicillanat~ in the procedure of Example 7, pivaloyloxymethyl 6~-chloropenicillanate was ob*ained as colourless crystals~ melting point: 68 - 69 C.
The NMR spectrum (CDC13) showed signals at ~ - 1.2~
-~ ~ 3 ~
~7~5~
(s, 9H; C(CH3)3), 1-51 (s, 3H; CH3-2a)~ 1-66 (s; 3H;
CH3~?~), 4.53 (s, lH; CH-3), 5.22 and 5.60 (2d, J=4 Hz, 2H; CH-5 and CH-6), and 5.82 (ABq, J=5.5 Hz, 2H; oCH2oj ppm.
Tetramethylsilane was used as internal reference.
Example 9 PivaloyloxYmethyl 6,B-iodopenicillanate A. Pivaloyloxymethyl 6-diazopenicillanate A stirred mixture of pivaloyloxymethyl 6~-amino-penicillanate (3.30 g~ 10 mmol) and sodium nitrite ~1~38 g, 20 mmol) in methylene chloride (120 ml) and water (120 ml) was cooled to 0 C and tr~ated with 2 N aqueous sulphuric acid (7.5 ml) ~or 40 minutes. The organic phase was separated, dried (Na2SOL~), and concentrated at reduced pressure to 30 ml. The concentrate was used imme-diately for the subsequent transformation.
B. Pi~aloyloxymethY1 6~-iodopenicillanate The concentrate of pi~aloyloxyme$hyl 6-diazopeni-cillanate from step A abo~e was diluted with acetone (120 ml), cooled to 0 C~ and to the stirred mixture was added a cold solution of 670~o aqueous hydroiodic acid (3.5 ml) and sodium iodide (4.5 g) in water ~20 ml).
After stirring for a further 20 minutes at the low tempe-rature, the mixture was treated wi$h solid sodium bi-3~ _ ~2~775~
carbonateg filtered, and evaporated. The résidue obtainedwas taken up in ethyl acetate (100 ml) and washed wi~h 5% aqueous sodium thiosulphate (2 x 75 ml). The organic phase was separated, dried ~MgS04), a~d evaporated in vacuo. The residual oil was purified by column chroma-tography on silica gel using ether-petroleum ether, 30:70, as the eluant to yield pure pivaloyloxymethyl 6a-iodopenicillanate as colourless crystals from diiso-propyl ether~ melting point: 63 - 64 C.
C. Pivaloyloxymethvl 6~-iodopenicillanat;e To a stirred solution of pivaloyloxymethyl 6a-iodo-penicillanate (0.88 g, 2 ~rnol~ in dry methylene chloride (20 ml) was added at -5 C a 1 M solution of 1,5-diaza-bicyclo[4.3.0~non-5-ene (DBN~ in dry methylen~ chloride (2 ml). The mi~ture was stirred at 0 C ~or 20 minutes, shaken with 1 N aqueous ace$ic acid (2 ml)~ diluted with methylene chloride (20 ml), washed with ~ater (2 x 10 ml~ 9 dried (Na2S04~ and evaporated ln vacuo to a dark oil. The residue was purified by colomn chroma-tography on silica gel using ether-petroleum ether, 30:70, as the el~ant to afford pivaloyloxymethyl 6~-iodo~
penicillanate as a slightly yellowish oil which crystallized from diisopropyl ether, melting point: 78-79 C.
~ _ 32 ~775i~
The NMR spectrum (CDC13) showed signals at S - 1.23 (s, 9H; C(CH3)3)~ 1-49 (s, 3H; CH3-2a), l jO (s, 3~I;
; CH3,~ 4-55 (s~ lH; CH-3)~ 5038 and 5.62 (2d~ J=4 Hz~
i 2H; CH-5 and CH-6), and 5.81 (ABq9 J=5.5 Hz, 2H; OCH20) ppm.
Tetramethylsilane was used as internal reference.
Exam~le 10 Acetoxymethyl 6~_bromopenicillanate Chloromethyl acetate (0.11 ml~ 1~2 mmol~ was added to a solution of potassium 6~-bromopenicillanate (0.32 g~ 1 mmol) in dimet~ylformamide (5 ml), and the mixture was stirred for 16 hours at room temperature in a dark room. After dilution ~ith ether (20 ml), the mixt~re was washed ~ith water ~4 x 5 ml), dried (MgSOI~), and evaporated in vacuo to yield the title com-pound as a yellowish oil.
The NMR spectrum (CDC13) showed signals at ~ - 1.49 ~s~ 3H; C_3-2~ 68 (s, 3H; CH3-2~)7 2.11 (s~ 3H; COCH3),
4.54 (s, lH; CH-3) 9 5.33 and 5.59 (2d~ J=4 Hz, 2H; CH-5a and CH-6a), and 5.82 (ABq~ J=5.5 Hz, 2H; OCH20) ppm. Tetramethyl-silane was used as internal reference.
Example 11 Acetoxymethyl 6~-iodopenicillanate Following the procedure of Example 10, but substituting potassium 6~-iodopenicillanate for the potassium 6~-bromo-penicillanate~ the title compound was obtained as a yellowish oil.
~2~7~5;2 The NMR spectrum (CDC13) showed signal~ at S = 1.50 (s, 3H; CH3-~j, 1.70 (s, 3~; CH3-2~), 2.12 (s, 3H; COCH3), 4.55 (s~ 1~; CH-3)~ 5.39 and 5.63 (2d, J=3.5 Hz, 2H; CH-5a and CH-6a), and 5.83 (ABq, J=505 Hz~ 2H; oCH203 ppmO Tetra-methylsilane was used as internal reference.
Examples 12-14 6~-Halopenicillanic acids The crystalline 6~-halopenicillanic acids listed in Table III below could be obtained as follows:
a) By concentrations at reduced pressure of the ethyl acetate solutions containing the pure 6~-halo compounds obtained after separation from the correspondi~g 6-epimers by dry column chro~atography on silica gel (as described in Example 1).
b) By liberation from aqueous solutions of the corresponding potassium salts under a layer of ether or ethyl acetate at pH 3 followed by separation of the organic phase~ drying~
and crystallizatio~ from ether-diisopropylether or ethyl acetate-hexane.
Table III:
See next page X H H
/ ~ N
~ `
~2~775~
[a3 lH-NMR data (~/ppm; CD3CN) Example X D
(c=0.5~ CHCl ) CH-5 and CH-6 12 Br~272 5.48 and 5.54, 2d, J=4 9 0 HZ
13 Cl~264 5.38 and 5.58, 2d~ J=4.0 Hz ~ 276 5~35 and 5.74, 2d, J=4,0 Hz .
The above acids decompose at 80-100 C, therefore a well-defined melting point cannot be determined.
Sodium -6~-bromopenicillanate A. Tetrabutylammonium 6~6-dibromopenicillanate : To a solution of tetrabutylammonium hydrogen sulphate (34 g, 0.1 mol3 in water (50 ml) 9 methylene chloride (100 ml) was added, followed by 2N sodium hydroxide (50 ml). To the stirred mixture was added 6,6-dibromopenicillanic acid ~36 g, o.l mol3 and the pH adjusted to 700 with 2N sodium hydroxide.
The organic layer was separated, and the aqueous phase was re-extracted with methylene chloride (50 ml). After drying of the combined organic phases, ethyl acetate (500 m].) was added, and the soluti.on was concentrated to . 300 ml in vacuo.
B Sodium ~ -bromopenicillanate To the above solution of tetrabutylammonium 6,6-di-bromopenicillanate, tetrabutylammonium boranate (24.9 g9 - 35 ~
~ 2~7~
0.1 mol) was added in one portion with stirring~ After ~ ~ 30 minutes, the temperature in the mixture had raised to 45-50C, whereafter it slowly decreased. After standing for 1 hour, the solution was diluted with ether (300 ml)~
water (300 ml) was added, and the pH was adjus-ted to 3 with hydrochloric acid. The organic phase was separated and washed with water. Fresh ~ater (50 ml) was added to the organic phase, and the pH was adjusted to 6.8 with aqueous potassium bicarbonate. The aqueous layer was sepa-rated7 and water was remo~ed azeotropically with n-butanol in vacuo to yield a crystalline mixture of the potassium salts of 6~-bromo-~ 6~-bromo-, and 6,6-dibromopenicillanic acid in an approximate ratio of 65:25:10.
From an aqueous solution of the above salts, the free acids were liberated at pH 3 (dilute hydrochloric acid) under a layer of ether~ and the resulting mixture was separated by colu~n chromato~raphy in a similar way as described in Example 1 to yield, after salt formation with 0.5 M sodium bicarbonate and remo~al of water by azeotropic distillation with n-butanol, crystalline sodium 6~-bromo-penicillanate; [~3D +266 (c=0~5, 1 M phosphate buffer pH 7) Calculated for C8HgBrNNaO3S C~ 31.80; H, 3.00; Br~
26.45; N~ 4.64; 5~ 10.61%. Found: C, 31.85; H, 3.04; Br~
26.53; N9 4.56, S, 10.72%.
~ 7 Example 16 6~ ~romopenicillanic acid To a stirred suspension of potassium 6~6-dibromo-penicillanate (11.91 g, 30 mmol) in dimethylformamide (30 ml) was added sodium borohydride (1.14 g, 30 mmol). In -the course of approximately 30 minutes~ the temperature in the reaction mixture rose to 50 C~ whereafter it slowly decreased to normal. After stirring at room tempe-rature for 20 hours~ water (100 ml) and ether (100 ml) were added, and the pH of the mixture was adjusted to 3 with dilute hydrochloric acid. The organic layer was sepa-rated, the aqueous layer was extracted with ether (25 ml), and the combined organic extracts were washed with water (25 ml). To the organic phase was added fresh water (25 ml) 9 and the pH of the aqueous phase was adjusted to 7 by addi-tion of 1 M potassium bicarbonate with stirring. The aqueous layer was separated9 and the water removed azeotropically by distillation with n-butanol in vacuo to give a crystalline mixture of the potassium salts of 6~_ and 6a-bromopeni_ cillanic acid in an appro~imate ratio of 55:45, a~s indicated by NMR spectroscopy.
The above potassium salts were dissolved in water (5 ml/g salt), and the pH of the aqueous phase was adjusted to 3 with 4 N hydrochloric acid under a layer of ethyl acetate
Example 11 Acetoxymethyl 6~-iodopenicillanate Following the procedure of Example 10, but substituting potassium 6~-iodopenicillanate for the potassium 6~-bromo-penicillanate~ the title compound was obtained as a yellowish oil.
~2~7~5;2 The NMR spectrum (CDC13) showed signal~ at S = 1.50 (s, 3H; CH3-~j, 1.70 (s, 3~; CH3-2~), 2.12 (s, 3H; COCH3), 4.55 (s~ 1~; CH-3)~ 5.39 and 5.63 (2d, J=3.5 Hz, 2H; CH-5a and CH-6a), and 5.83 (ABq, J=505 Hz~ 2H; oCH203 ppmO Tetra-methylsilane was used as internal reference.
Examples 12-14 6~-Halopenicillanic acids The crystalline 6~-halopenicillanic acids listed in Table III below could be obtained as follows:
a) By concentrations at reduced pressure of the ethyl acetate solutions containing the pure 6~-halo compounds obtained after separation from the correspondi~g 6-epimers by dry column chro~atography on silica gel (as described in Example 1).
b) By liberation from aqueous solutions of the corresponding potassium salts under a layer of ether or ethyl acetate at pH 3 followed by separation of the organic phase~ drying~
and crystallizatio~ from ether-diisopropylether or ethyl acetate-hexane.
Table III:
See next page X H H
/ ~ N
~ `
~2~775~
[a3 lH-NMR data (~/ppm; CD3CN) Example X D
(c=0.5~ CHCl ) CH-5 and CH-6 12 Br~272 5.48 and 5.54, 2d, J=4 9 0 HZ
13 Cl~264 5.38 and 5.58, 2d~ J=4.0 Hz ~ 276 5~35 and 5.74, 2d, J=4,0 Hz .
The above acids decompose at 80-100 C, therefore a well-defined melting point cannot be determined.
Sodium -6~-bromopenicillanate A. Tetrabutylammonium 6~6-dibromopenicillanate : To a solution of tetrabutylammonium hydrogen sulphate (34 g, 0.1 mol3 in water (50 ml) 9 methylene chloride (100 ml) was added, followed by 2N sodium hydroxide (50 ml). To the stirred mixture was added 6,6-dibromopenicillanic acid ~36 g, o.l mol3 and the pH adjusted to 700 with 2N sodium hydroxide.
The organic layer was separated, and the aqueous phase was re-extracted with methylene chloride (50 ml). After drying of the combined organic phases, ethyl acetate (500 m].) was added, and the soluti.on was concentrated to . 300 ml in vacuo.
B Sodium ~ -bromopenicillanate To the above solution of tetrabutylammonium 6,6-di-bromopenicillanate, tetrabutylammonium boranate (24.9 g9 - 35 ~
~ 2~7~
0.1 mol) was added in one portion with stirring~ After ~ ~ 30 minutes, the temperature in the mixture had raised to 45-50C, whereafter it slowly decreased. After standing for 1 hour, the solution was diluted with ether (300 ml)~
water (300 ml) was added, and the pH was adjus-ted to 3 with hydrochloric acid. The organic phase was separated and washed with water. Fresh ~ater (50 ml) was added to the organic phase, and the pH was adjusted to 6.8 with aqueous potassium bicarbonate. The aqueous layer was sepa-rated7 and water was remo~ed azeotropically with n-butanol in vacuo to yield a crystalline mixture of the potassium salts of 6~-bromo-~ 6~-bromo-, and 6,6-dibromopenicillanic acid in an approximate ratio of 65:25:10.
From an aqueous solution of the above salts, the free acids were liberated at pH 3 (dilute hydrochloric acid) under a layer of ether~ and the resulting mixture was separated by colu~n chromato~raphy in a similar way as described in Example 1 to yield, after salt formation with 0.5 M sodium bicarbonate and remo~al of water by azeotropic distillation with n-butanol, crystalline sodium 6~-bromo-penicillanate; [~3D +266 (c=0~5, 1 M phosphate buffer pH 7) Calculated for C8HgBrNNaO3S C~ 31.80; H, 3.00; Br~
26.45; N~ 4.64; 5~ 10.61%. Found: C, 31.85; H, 3.04; Br~
26.53; N9 4.56, S, 10.72%.
~ 7 Example 16 6~ ~romopenicillanic acid To a stirred suspension of potassium 6~6-dibromo-penicillanate (11.91 g, 30 mmol) in dimethylformamide (30 ml) was added sodium borohydride (1.14 g, 30 mmol). In -the course of approximately 30 minutes~ the temperature in the reaction mixture rose to 50 C~ whereafter it slowly decreased to normal. After stirring at room tempe-rature for 20 hours~ water (100 ml) and ether (100 ml) were added, and the pH of the mixture was adjusted to 3 with dilute hydrochloric acid. The organic layer was sepa-rated, the aqueous layer was extracted with ether (25 ml), and the combined organic extracts were washed with water (25 ml). To the organic phase was added fresh water (25 ml) 9 and the pH of the aqueous phase was adjusted to 7 by addi-tion of 1 M potassium bicarbonate with stirring. The aqueous layer was separated9 and the water removed azeotropically by distillation with n-butanol in vacuo to give a crystalline mixture of the potassium salts of 6~_ and 6a-bromopeni_ cillanic acid in an appro~imate ratio of 55:45, a~s indicated by NMR spectroscopy.
The above potassium salts were dissolved in water (5 ml/g salt), and the pH of the aqueous phase was adjusted to 3 with 4 N hydrochloric acid under a layer of ethyl acetate
5 ml/g salt). The organic phase was separated, washed with ~ 37 -~1177SZ
water9 dried~ and diluted with an equal volume of hexaneq Seeding of the resulting solution followed by concentration at reduced pressure to about half the volume afforded crystalline 6~-bromopenicillanic acid which was filtered off~ washed with ethyl acetate-hexane (1:1), and dried.
Recrystallization from ether-diisopropyl ether gave the analytical sample, [a]D +268 (c-0.59 CHC13).
Caleul2ted for C8HlO~rN03S: C, 34.30; H, 3.60~ Br~
28053; N9 5.00; Sg 11.45~ Found: C, 34.479 H, 3.81;
Br, 28.66; N, 4.99; S, 11.43~.
Example 17
water9 dried~ and diluted with an equal volume of hexaneq Seeding of the resulting solution followed by concentration at reduced pressure to about half the volume afforded crystalline 6~-bromopenicillanic acid which was filtered off~ washed with ethyl acetate-hexane (1:1), and dried.
Recrystallization from ether-diisopropyl ether gave the analytical sample, [a]D +268 (c-0.59 CHC13).
Caleul2ted for C8HlO~rN03S: C, 34.30; H, 3.60~ Br~
28053; N9 5.00; Sg 11.45~ Found: C, 34.479 H, 3.81;
Br, 28.66; N, 4.99; S, 11.43~.
Example 17
6~-Bromopenicillanic acid A. Dicyclohexylammonium ~-bromopenicillanate To a solution of 6,6-dibromopenicillanic acid (10.8 g, 30 mmol) in dimethylsulphoxide (75 ml) was added sodium cyanoborohydride (2.1 g; 90/0 pure)~ and the mixturo was stirred until a clear solution was obtained (30 minutes). After standing for 72 hours, the mixture ~as di-luted with water (75 ml) to precipitate unreacted starting material as dimethylsulphoxide,solvate (C8HgBr2N03S, C2H60S)o The crystals were filtered off, washed with water and dried.
The filtrate was extracted with methylene chloride (4 x 25 ml), and the combined extracts were washed with water (50 ml~, dried (Na2S04), and concentrated at reduced pressure to ?7~S;~
about half the volume. After addition of dicyclohexyl-amine (2.5 ml) and acetone (50 ml), the mixture was further concentrated to - 25 ml. Crystallization was induced by scratching~ and~ after standing for l hour at room temperature~ the pure dicyclohexylammoniu~ 6~-bromopeni-cillanat0 was filtered off, washed with acetone 9 and dried.
The compound exhibited no well-defined melting point 9 after darkening at about 170 C, it decomposed at 280-290 C.
B. 6~-Bromo~nicillanic acid_ A stirred suspension of dicyclohexylammonium 6~-bromo-penicillanate in ethylacetate-water (l:l) (20 ml/g salt) was adjusted to pH 3 with 4 N hydrochloric acid. Precipi-tated dicyclohexylammonium chloride was filtered off~ and the organic layer was separated, washed twice with water, and dried. Addition of an equal volume of hexane ~ollowed by concentration of the solution at reduced pressure yielded pure, crystalline 6~-bromopenicillanic acid, identical with the compound described in Examples 12 and 16.
Example 18 Sodium 6~-iodopenicillanate A. 6,6-Diiodopenicillanic acid morpholine_salt To a stirred solution of 6-aminopenicillanic acid (110 g, ~0.5 mol) in a mixture of 5 ~ sulphuric acid (400 ml) and methylene chloride (1.5 liter~ were added ~ 3 9 --- ~2~77~;i2 dropwise and simultaneously at 0C 2.5 M aqueous sodi~m nitrite (340 ml) and 0.5 M methanolic iodine (1 liter).
Aftsr the addition was finished, the cooling bath was removed, and stirring of the mixture was continued for 1 hour. The organic layer was separated~ and the aqueous phase was extracted with methylene chloride (200 ml). The combined organic extracts were washed with 1 M aqueous sodium thiosulphate (600 ml~ and dried (Na~S04). After addition of morpholine (32.6 ml~ 0.375 mol), the resulting solution was concentrated at reduced pressure to about 200-250 ml to afford, after cooling7 the title compound as colourless crystals which were collected, washed with acetone, and dried~ Yield: 162.6 g; melting point: 152-154 C
(decomposition).
; Calculated for C12H18I2N204S: C, 26.68; H~ 3.36; I, 46.99; N, 5.19; S, 5.940/o. Found: C, 27.019 H, 3.44; I, 46.70;
N~ 5.18; S~ 5.64%.
B. Sodi~m 6~-iodopenicillanate A stirred solution of 6~6-diiodopenicillanic acid morpholine salt (54 g, 0.1 mol) in methylene chloride (500 ml~
was protected from light, and cetyl trimethylammonium boranate (36 g, 0.12 m~l) was added. After stirring for 15 minutes at room temperature~ the mixture was evaporated in vacuo.
The residue was triturated with acetone' (250 ml), insoluble ., ' - 4 ~ ~77~2 salt was remo~ed by filtration and the filtrate evaporated to dryness~ The residual oil was dissol~ed in ethy]. acetate (200 ml), water (200 ml) was added, and the pH in the ~.
aqueous pha~e,was adjusted to 7 by addition of 2 N sodium hydro~ide with stirring. The aqueous layer was separated~
the organic phase washed with water (50 ml), and the pH
of the combined aqueous phases was adjusted to 3 with dilute hydrochloric acid under a layer of ether (200 ml). The organic phase was separated~ the aqueous phase was re-extracted with ether, and the combined ethereal extracts were dried and concentrated at reduced pressure to about 80-100 ml.
The concentrate contained a mixture of 6~- and 6-iodopeni-cillanic acids as well as minor amounts of penicillanic acid (approximate ratio 50:40:10) which were separated by dry column chromatography using a similar procedure as described in Example 1~ The pure 6~-iodo acid thus obtained gave, after salt formation with 0.5 M aqueous sodium bi-carbonate and removal of water by azeotropic distillation with n-butanol~ crystalline sodium 6~-iodopenicillanate;
[~]D +274 (c=0.5y 1 M phosphate buffer pH 7).
Calculated for C8H9INNaO3S: C, 27.52; H, 2.60; I, 36.35;
N~ 4.01; S, 9.i80/o. Found: C, 27.31; H, 2,64; I, 36012;
N9 3.92; S, 9. 340,h.
Example 19 6 Iodo enicillanic acid ~~ P
~L2~ 7S~
_ 41 -A. 6,6-Diiodopenicillanic acid dimeth~lsulphoxide solvate To a cooled solution of 6,6-diiodopenicillanic acid morpholine salt (10.8 gj 20 mmol) in dimethylsulphoxide (~0 ml) was added 1 N hydrochloric acid (20 ml), and crys-tallization was induced by scratching. After further addition of water (20 ml)~ the crystals were filtered off, washed with water? and dried to give an almost quantitative yield of the title compound which showed an ill-defined melting point with slow decomposition above 120-125 C.
Calculated for C8~9I2N03S~ C2~6 I, 47.78, N, 2.64; S, 12.07%. Found: C, 22.96~ H9 2.81;
I, 47.64~ N, 2.74, S, 12.14%~
B Dic clohex lammonium 6~ iodo enicillanate Y _ Y
To a solution of 6,6-diiodopenicillanic acid dimethyl-sulphoxide solvate (5.31 g, 10 mmol) in dimet~ylsulphoxide (25 ml3 was added sodium cyanoborohydride (0.7 g; 90% pure), and the mixture was stirred until a clear solution was obtained (about 30 minutes~. After standing for 40 hours at room temperature, water (50 ml) was added, and the mixture was cooled to 5 C to,precipitate unreacted starting material which was collected9 washed with water, and dried.
The filtrate was extracted with methylene chioride ~3 x 25 ml)~
and the combined extracts were washed with water (2 x 10 ml), dried (Na2S04), and carefully evaporated in vacuo The residual oil was dissolved in acetone (25 ml), an equi~alent ~ 2 - ~2~7~
amount of dicyclohexylamine wasadded, and crystal.lization was induced by scIatching. After standing for 1 hour, the pure dicyclohexylammonium 6~-iodopenicillana*e was filtered off, washed with acetone, and dried. The compound showe~
no well-defined melting point~ after darkening at 150C~ it decomposed slowly above this temperature.
: C. 6~-Iodopenicillanic acid By substituting dicyclohexylarnmonium 6~-iodopenicil-lanate for the corresponding 6~-bromopenicillanate in the procedure of Example 17 B, 6~ iodopenicillanic acid was obtained as colourless crystals. Recrystallization from ether-diiospropyl ether afforded the analytical sample, [a]D +278 (c=0~S~ CHCl3)o Calculated for C8HloIN03S: C, 29~37; H~ 3.08; Ig 38.79j N~ 4,28; S9 ~.80%. Found: C, 29.46; H, 3.13; I~ 38.96;
N~ 4027; S9 9~81C/o, Example 20 Pivaloyloxymethy~ 6~-bromopenicillanate A. Pivaloylox~methyl 6,6-dibromoDenicillanate : To a solution of potassium 6,6-dibromopenicillanate (5.96 g, 15 mmol) in dimethylformamide ~30 ml) was added chloromethyl pivalate (2.22 ml, 15 mmol), and the mixture was stirred for 16 hours at room temperature. After dilution with ethyl acetate (120 ml), the mixture was washed with - 43~ 7~5~2 water (4 x 30 ml), dried, decolollrized by stirring with charc,oal (0.5 g; 1 hour~ 9 and evaporated to dryness to give the desired compound as a yellow oil which crystallized from ether-hexane; melting poînt: 101-102 C.
B. Pi~aloyloxymethy~ 6~-bromopenicillanate To a solution of pivaloyloxymethyl 6~6-dibromopenicil-lanate (~.68 g, 12 mmol) in dimethylsulphoxide (25 ml) was added sodium cyanoborohydride (o.84 gj 90/0 pure) 9 and the ~ixture was stirred for 24 hours at room temperature in a dark room. After addition of water (7~ ml), the mixture was extracted with ether (3 x 25 ml~, and the combined ethereal extracts were washed with water ~3 x 10 ml)/ dried, and concentrated at reduced pressure to about 20 ml. The concentrate was subjected to column chromatography on silica gel similar to the procedure described in Example 9 C. Hereby) the 6~-bromo compound was separated from unreacted starting material. Fractions containing *he more polar 6~-bromo ester were combined and evaporated in vacuo.
The residual oil was crystalli~ed from ether-diisopropyl ether to give pivaloyloxymethyl 6~-bromopenicillanate, melting point: 66-68 C, identical with the compound de-scribed in Example 9 C.
- `
~2~77S~
Example 21 6~-Bromo~nicillanic acid pivampicillin salt To a stirred solution of pivampicillin hydrochloride (2.50 , 5 mmol) in water (100 ml) was added dropwise Ool M
aqueous potassium 6~bromopenicillanate (50 ml). The colour-less precipitate thus obtained was filtered off, washed with water (3 x 10 ml), and dried in vacuo to give the pure title compound as colourless crystals which began to decompose at 120-130 C without melting.
The l:R-spectrum (KBr) showed bands at 3030, 2970 2935" 2870, 1790, 1770, 1680, 1600, an~l 627 cm 1.
The NMR-spectrum (CDC13) showed signals atSS= 1~20 (s~ 9H; C~CH333), 1-36 (s, 3H; CE~3-2) 7 1.44 (s, 3H; CH3-2) 1-52 (s~ 3H; CH3--2), 1~54 ~s; 3H; CH3--Z),4-26 (s, lH;
CH--3) 9 4,40 (s, lH; CH--3~ ~ 5011 (s~ lH; CHCO) ~ 5.23, 5.36, 5.43~ and ~ 5.76 (4 doublets~ J=3.8-4.2 Hz9 4H; CH--5 and CH--S) ~ 5079 (ABq, J=5.5 Hz, 2H; OCH20) 9 7.40 (s, 5H; arom.
CH), and 7.82 ~d, J=8.2 Hz, lH; CONH) ppm. Tetramethyl-silane wa~ used as internal reference.
:Example 22 6~-Iodopenicillanic acid bacampicillin salt A solution of potassium o~-iodopenicillanate (0. 73 g, 2 mmol) in water (20 ml) was added dropwise to a stirred solution of bacampicillin hydrochloride (1.0 g, Z mmol) in water (40 ml). The resulting crystalline precipitate ~ ~ 45 -~77~;Z
was filtered off, washed with water, and dried to afford the pure title compound which decomposed at 110-120 without melting.
The IR-spectrum (~B~) showed bands at 3030~ ~980, 2870~ 1780~ 1765, 1695, 1625 9 and 618 cm 1~
The NMR~spectrum (CDC13) showed signals at ~ = 1.31 (t, J=7 Hz, 3H; OCH2CH3), la38 (s, 3H; CH3-2~ 1.49 (s~
3H; CH3-2~, 1.54 (s~ 3H; CH3 2) 9 1~59 (s, 3H7 C~3-2)~ 4.25 (m, 4H; OCH2CH3 and CH-3), 4.99 (s, lH; CHCO), 5.12 (bs, NH3+), 5.21, 5.45, 5.54, and 5.64 (4 doublets, J=3.8-4.2 Hz, 4H;-CH-5 and CH-6~ 6~76 (ABq, J=5.$ Hz, lH; CHCH3) 9
The filtrate was extracted with methylene chloride (4 x 25 ml), and the combined extracts were washed with water (50 ml~, dried (Na2S04), and concentrated at reduced pressure to ?7~S;~
about half the volume. After addition of dicyclohexyl-amine (2.5 ml) and acetone (50 ml), the mixture was further concentrated to - 25 ml. Crystallization was induced by scratching~ and~ after standing for l hour at room temperature~ the pure dicyclohexylammoniu~ 6~-bromopeni-cillanat0 was filtered off, washed with acetone 9 and dried.
The compound exhibited no well-defined melting point 9 after darkening at about 170 C, it decomposed at 280-290 C.
B. 6~-Bromo~nicillanic acid_ A stirred suspension of dicyclohexylammonium 6~-bromo-penicillanate in ethylacetate-water (l:l) (20 ml/g salt) was adjusted to pH 3 with 4 N hydrochloric acid. Precipi-tated dicyclohexylammonium chloride was filtered off~ and the organic layer was separated, washed twice with water, and dried. Addition of an equal volume of hexane ~ollowed by concentration of the solution at reduced pressure yielded pure, crystalline 6~-bromopenicillanic acid, identical with the compound described in Examples 12 and 16.
Example 18 Sodium 6~-iodopenicillanate A. 6,6-Diiodopenicillanic acid morpholine_salt To a stirred solution of 6-aminopenicillanic acid (110 g, ~0.5 mol) in a mixture of 5 ~ sulphuric acid (400 ml) and methylene chloride (1.5 liter~ were added ~ 3 9 --- ~2~77~;i2 dropwise and simultaneously at 0C 2.5 M aqueous sodi~m nitrite (340 ml) and 0.5 M methanolic iodine (1 liter).
Aftsr the addition was finished, the cooling bath was removed, and stirring of the mixture was continued for 1 hour. The organic layer was separated~ and the aqueous phase was extracted with methylene chloride (200 ml). The combined organic extracts were washed with 1 M aqueous sodium thiosulphate (600 ml~ and dried (Na~S04). After addition of morpholine (32.6 ml~ 0.375 mol), the resulting solution was concentrated at reduced pressure to about 200-250 ml to afford, after cooling7 the title compound as colourless crystals which were collected, washed with acetone, and dried~ Yield: 162.6 g; melting point: 152-154 C
(decomposition).
; Calculated for C12H18I2N204S: C, 26.68; H~ 3.36; I, 46.99; N, 5.19; S, 5.940/o. Found: C, 27.019 H, 3.44; I, 46.70;
N~ 5.18; S~ 5.64%.
B. Sodi~m 6~-iodopenicillanate A stirred solution of 6~6-diiodopenicillanic acid morpholine salt (54 g, 0.1 mol) in methylene chloride (500 ml~
was protected from light, and cetyl trimethylammonium boranate (36 g, 0.12 m~l) was added. After stirring for 15 minutes at room temperature~ the mixture was evaporated in vacuo.
The residue was triturated with acetone' (250 ml), insoluble ., ' - 4 ~ ~77~2 salt was remo~ed by filtration and the filtrate evaporated to dryness~ The residual oil was dissol~ed in ethy]. acetate (200 ml), water (200 ml) was added, and the pH in the ~.
aqueous pha~e,was adjusted to 7 by addition of 2 N sodium hydro~ide with stirring. The aqueous layer was separated~
the organic phase washed with water (50 ml), and the pH
of the combined aqueous phases was adjusted to 3 with dilute hydrochloric acid under a layer of ether (200 ml). The organic phase was separated~ the aqueous phase was re-extracted with ether, and the combined ethereal extracts were dried and concentrated at reduced pressure to about 80-100 ml.
The concentrate contained a mixture of 6~- and 6-iodopeni-cillanic acids as well as minor amounts of penicillanic acid (approximate ratio 50:40:10) which were separated by dry column chromatography using a similar procedure as described in Example 1~ The pure 6~-iodo acid thus obtained gave, after salt formation with 0.5 M aqueous sodium bi-carbonate and removal of water by azeotropic distillation with n-butanol~ crystalline sodium 6~-iodopenicillanate;
[~]D +274 (c=0.5y 1 M phosphate buffer pH 7).
Calculated for C8H9INNaO3S: C, 27.52; H, 2.60; I, 36.35;
N~ 4.01; S, 9.i80/o. Found: C, 27.31; H, 2,64; I, 36012;
N9 3.92; S, 9. 340,h.
Example 19 6 Iodo enicillanic acid ~~ P
~L2~ 7S~
_ 41 -A. 6,6-Diiodopenicillanic acid dimeth~lsulphoxide solvate To a cooled solution of 6,6-diiodopenicillanic acid morpholine salt (10.8 gj 20 mmol) in dimethylsulphoxide (~0 ml) was added 1 N hydrochloric acid (20 ml), and crys-tallization was induced by scratching. After further addition of water (20 ml)~ the crystals were filtered off, washed with water? and dried to give an almost quantitative yield of the title compound which showed an ill-defined melting point with slow decomposition above 120-125 C.
Calculated for C8~9I2N03S~ C2~6 I, 47.78, N, 2.64; S, 12.07%. Found: C, 22.96~ H9 2.81;
I, 47.64~ N, 2.74, S, 12.14%~
B Dic clohex lammonium 6~ iodo enicillanate Y _ Y
To a solution of 6,6-diiodopenicillanic acid dimethyl-sulphoxide solvate (5.31 g, 10 mmol) in dimet~ylsulphoxide (25 ml3 was added sodium cyanoborohydride (0.7 g; 90% pure), and the mixture was stirred until a clear solution was obtained (about 30 minutes~. After standing for 40 hours at room temperature, water (50 ml) was added, and the mixture was cooled to 5 C to,precipitate unreacted starting material which was collected9 washed with water, and dried.
The filtrate was extracted with methylene chioride ~3 x 25 ml)~
and the combined extracts were washed with water (2 x 10 ml), dried (Na2S04), and carefully evaporated in vacuo The residual oil was dissolved in acetone (25 ml), an equi~alent ~ 2 - ~2~7~
amount of dicyclohexylamine wasadded, and crystal.lization was induced by scIatching. After standing for 1 hour, the pure dicyclohexylammonium 6~-iodopenicillana*e was filtered off, washed with acetone, and dried. The compound showe~
no well-defined melting point~ after darkening at 150C~ it decomposed slowly above this temperature.
: C. 6~-Iodopenicillanic acid By substituting dicyclohexylarnmonium 6~-iodopenicil-lanate for the corresponding 6~-bromopenicillanate in the procedure of Example 17 B, 6~ iodopenicillanic acid was obtained as colourless crystals. Recrystallization from ether-diiospropyl ether afforded the analytical sample, [a]D +278 (c=0~S~ CHCl3)o Calculated for C8HloIN03S: C, 29~37; H~ 3.08; Ig 38.79j N~ 4,28; S9 ~.80%. Found: C, 29.46; H, 3.13; I~ 38.96;
N~ 4027; S9 9~81C/o, Example 20 Pivaloyloxymethy~ 6~-bromopenicillanate A. Pivaloylox~methyl 6,6-dibromoDenicillanate : To a solution of potassium 6,6-dibromopenicillanate (5.96 g, 15 mmol) in dimethylformamide ~30 ml) was added chloromethyl pivalate (2.22 ml, 15 mmol), and the mixture was stirred for 16 hours at room temperature. After dilution with ethyl acetate (120 ml), the mixture was washed with - 43~ 7~5~2 water (4 x 30 ml), dried, decolollrized by stirring with charc,oal (0.5 g; 1 hour~ 9 and evaporated to dryness to give the desired compound as a yellow oil which crystallized from ether-hexane; melting poînt: 101-102 C.
B. Pi~aloyloxymethy~ 6~-bromopenicillanate To a solution of pivaloyloxymethyl 6~6-dibromopenicil-lanate (~.68 g, 12 mmol) in dimethylsulphoxide (25 ml) was added sodium cyanoborohydride (o.84 gj 90/0 pure) 9 and the ~ixture was stirred for 24 hours at room temperature in a dark room. After addition of water (7~ ml), the mixture was extracted with ether (3 x 25 ml~, and the combined ethereal extracts were washed with water ~3 x 10 ml)/ dried, and concentrated at reduced pressure to about 20 ml. The concentrate was subjected to column chromatography on silica gel similar to the procedure described in Example 9 C. Hereby) the 6~-bromo compound was separated from unreacted starting material. Fractions containing *he more polar 6~-bromo ester were combined and evaporated in vacuo.
The residual oil was crystalli~ed from ether-diisopropyl ether to give pivaloyloxymethyl 6~-bromopenicillanate, melting point: 66-68 C, identical with the compound de-scribed in Example 9 C.
- `
~2~77S~
Example 21 6~-Bromo~nicillanic acid pivampicillin salt To a stirred solution of pivampicillin hydrochloride (2.50 , 5 mmol) in water (100 ml) was added dropwise Ool M
aqueous potassium 6~bromopenicillanate (50 ml). The colour-less precipitate thus obtained was filtered off, washed with water (3 x 10 ml), and dried in vacuo to give the pure title compound as colourless crystals which began to decompose at 120-130 C without melting.
The l:R-spectrum (KBr) showed bands at 3030, 2970 2935" 2870, 1790, 1770, 1680, 1600, an~l 627 cm 1.
The NMR-spectrum (CDC13) showed signals atSS= 1~20 (s~ 9H; C~CH333), 1-36 (s, 3H; CE~3-2) 7 1.44 (s, 3H; CH3-2) 1-52 (s~ 3H; CH3--2), 1~54 ~s; 3H; CH3--Z),4-26 (s, lH;
CH--3) 9 4,40 (s, lH; CH--3~ ~ 5011 (s~ lH; CHCO) ~ 5.23, 5.36, 5.43~ and ~ 5.76 (4 doublets~ J=3.8-4.2 Hz9 4H; CH--5 and CH--S) ~ 5079 (ABq, J=5.5 Hz, 2H; OCH20) 9 7.40 (s, 5H; arom.
CH), and 7.82 ~d, J=8.2 Hz, lH; CONH) ppm. Tetramethyl-silane wa~ used as internal reference.
:Example 22 6~-Iodopenicillanic acid bacampicillin salt A solution of potassium o~-iodopenicillanate (0. 73 g, 2 mmol) in water (20 ml) was added dropwise to a stirred solution of bacampicillin hydrochloride (1.0 g, Z mmol) in water (40 ml). The resulting crystalline precipitate ~ ~ 45 -~77~;Z
was filtered off, washed with water, and dried to afford the pure title compound which decomposed at 110-120 without melting.
The IR-spectrum (~B~) showed bands at 3030~ ~980, 2870~ 1780~ 1765, 1695, 1625 9 and 618 cm 1~
The NMR~spectrum (CDC13) showed signals at ~ = 1.31 (t, J=7 Hz, 3H; OCH2CH3), la38 (s, 3H; CH3-2~ 1.49 (s~
3H; CH3-2~, 1.54 (s~ 3H; CH3 2) 9 1~59 (s, 3H7 C~3-2)~ 4.25 (m, 4H; OCH2CH3 and CH-3), 4.99 (s, lH; CHCO), 5.12 (bs, NH3+), 5.21, 5.45, 5.54, and 5.64 (4 doublets, J=3.8-4.2 Hz, 4H;-CH-5 and CH-6~ 6~76 (ABq, J=5.$ Hz, lH; CHCH3) 9
7.39 (s, 5H; arom. CH), and 7~ 72 (d7 J=805 Hz, lH; CONH) ppm.
~etramethylsilane was used as internal reference.
Examples 23-25 Further salts of 6~-halo~enicillanic acids with inorganic bases Treatment of an ethereal solution of the 6~-halopeni cillanic acid with an equi~alent amount of aqueous base followed by separation of the aqueous phase and fr0eze-drying afforded the salts listed in Table IV as colourless powders.
_ Table IV X H H Z
page /~ N ~ ~ ~ In _ 46 -~2~?7~S2 Example X n Z
23a Cl 1 Na~
23b Cl 2~ Ca++
24a Br 1 Li~
24b Br 2 Ca 25a I 1 Li+
25b I 2 Ca~+
--~ -- . e _ Examples 26 28 Further salts of ~-halopenicillanic acids with organic bases By treatment of a solution of the 6~-halopenicillanic acid in a suitable organic solvent, e.g. acetone, ethyl acetat0 or ether, with an equivalent amount of the organic base (preferably dissolved in the same solvent), the desired salt was obtained as a crystalline precipitate which was ; filtered off and dried in vacuo. The salts obtained by this method are listed in Table V below.
Table V X H H
See next ~ S ~", Z
page ~ ~ N ~ ~", o H 'COOH
i _ n ~L2~7~5;2 ~ . Exa~ple X n Z
-- ~ _ 26a Cl 1 dicyclohexylamine 26b Cl 2 N7N~-dibenzylethylenediamine 27a Br 1 morpholine 27b Br 2 N,N' dibenzylethylenediamine 27c Br 1 N-ethylpiperidine 27d Br 1 procaine 28a I 1 dibenzylamine 28b I 2 NJN~-dibenzylethylenediamine 28c I 1 N-methylbenzylamine 28d 1 1 procaine Examples 2~-30 Salts of 6~-halopenicillanic acids with ~-l.actam an*ibiotics and pro-dru~s thereof containing a basic group ; The salts listed in Table VI below were prepared by procedures simila~ to those described in the preceeding Examples 21-22 (A), 23 25 (B), or 26-28 (C).
_ 48~
r~- 3rZ~7~7 75i;~
.__ (~ O
~ ol oD ~ 00 ~ O O O
O O O O ~ O O
~ o o co 0 ~ ~ r~
O O O O O
cr~ ~ ~ o r~ ) o ~~
E ~ o o t~ u~ O u~ o ~ O O
~_ I`
b~ I~ O ~ O O ~ U~
I o~
~ r~
H --I --I ~I N N--I ~I N
~) r~ O ~ O O U~U~
. ~ ~ ~D ~ ~ ~D
~ cr~
IJ N N ~ N N N ~ ~1 o ~ U~ O ~ ~ O 0 O ~ ~ N 11~ l` ~ t~ r l 1S~
~ 0~ O C`l ~ C~l N ~ ~D
(3~
O O O O ~ O O O O O
O ~ t~ ~ - It~ l~. ;~t~ t~ ~) t~
~ O O~ ~ ~ ~ O CS~
\~i~ . _ `~
h ~"~ ,_~Z; ~:1 I 0 ~ v ~ m t-. ~ h f:: E E ~ E E
rl ~ E ~1 , E O ~ ~ O ~ E~
t~ E E a~ ~1 X ~d E E o r~ X
o ~ P, o ~ o E E rl,I t~ G) . E E
m P~ ¢ c P~ c h h h h h h X a~ Q ~ t~ m m H ~ H 1-1 H H
H O
r-l ,~ E
,~ ~a ~ ~ c) o a~ 4~ ~ ,o ~ ~ tD ~
t~ X I~ O O O O O O
_ N N N N N ~I t~
/~g ~i7752 Example ~1 Tablets Component Per tablet 6~-Iodopenicillanic acid sodium salt 250 mg Microcrystalline cellulose1].0 mg Hydroxypropyl cellulose 5 mg Alginic acid 10 mg Talc 23 mg Magnesium stearate 2 m~
400 mg The active component of formula I is blended with the microcrys-talline cellulose, granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through 1 mm sieves. Alginic acid~ talc~
and magnesium stearate are added, and the mixture is compressed into tablets each weighing 400 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose~
_ - 50 ~
7~2 Example Tablets Component Per tablet 6~-Bromopenicillanic acid sodium salt 250 mg Microcrystalline cellulose110 mg Hydroxypropyl cellulose 5 mg Alginic acid 10 mg Talc 23 mg Ma~nesiu~ stearate 2 m~
: 400 mg :
By the same procedure as described in Example 31, the tablets containing 6~-bromopenicillanic acid sodium salt are obtained.
.
Example Parenteral ~o~mulation Component Per vial 6~-Iodopenicillanic acid sodium salt 125 mg The sterile crystalline component is filled into sterile vials which are aseptically sealed. For parenteral admini-stration, 2 ml of sterile ph~siological saline is added to the content of the ~ial.
775~
Example ~4 Parenteral formulation Component Per vial 6~-Bromopenicillanic- acid sodium salt 125 mg _ _ _ _ .
The above formulation i5 obtained by the same procedure as described in Example 33.
Example_~
Capsules Component Per capsule 6~-Iodo~enicillanic acid potassium salt lZ5 mg Hydroxypropyl cellulose 3 mg Talc 6 mg Magnesium stearate _ mg 135 mg The active ingredient of formula I is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through l mm sieves~ Talc and magnesium stearate are added~ the components are well mixed to obtain a uniform blend, and 135 mg of the blend is filled in a No. 3 hard gelatine capsule.
_ 52 -Example ~6 C~_ules - Component Per capsule 6~-~romopenicillanic acid pivampi~
cillin salt 250 mg Hydroxypropyl cellulose 5 mg Talc 23 mg Magnesium stearate 2 mg 280 mg The active compound of formula I is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through 1 mm sieves. The diluents are added9 and the:mixture is carefully blended, 280 mg of the blend being :: filled in No. 2 gelatine capsules.
Example Tablets .
Cornponent Per tablet 6~-Iodopenicillanic acid sodium salt 125 mg Ampici.llin 250 mg Corn starch 75 mg Hydroxypropyl cellulose10 mg Alginic acid 10 mg TaIc 20 mg Magnesium stearate 5 i~
~ 495 mg - 53- ~LZ~ 52 In the above composition, the ac~ive components, i.e., of formula I and the other antibiotics are blended with corn sta~ch,granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, a~d screened through 1 mm screens. Alginic acid, talc, and magnesium stearate are added, and the mixture is com~
pressed into tablets each weighing 495 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose.
Example Tablets .
Component Per tablet 6~-Bromopenicillanic acid potassium salt 125 mg Ampicillin 250 mg Corn starch 75 mg Hydroxypropyl celluloselO mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 m~
495 mg __ _ _ ~
By the same procedure as described in Example 37, the tablets cvntaining 6~-bromopenicillanic acid potassium salt and ampicillin are obtained.
- 5~ h~
Example ~9 Tablets Component Per tablet 6~-Iodopenicillanic acid potassium salt 200 mg Pivampicillîn free ba~e 250 mg Corn starch 100 mg Hydroxypropyl cellulose 5 mg Methyl cellulose 5 mg Alginic acid 15 mg .Talc 20 mg Magnesium ~tearate 5 m~
600 mg In the above composition, 6~-iodopenicillanic acid potassium salt and half the amount of corn starch are blended 7 granulated wlth a 10% solution o~ hydroxypropyl cellulose in is~propanol, dried at 40 C and screened through 1 mm screensO The balance of corn starch is blended with piv-ampicillin, granulated with paste ~f methyl cellulose and water9 dried at 50 C, and screened through 0.7 mm screens.
The granulates are blended with alginic acid, talc, and magnesium stearate, and the mixture is compressed into tablets each ~eighing 600 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose.
- ~ 55 ~
~2~7 Example 40 Tablets Component Per tablet 6~-Bromopenicillanic acid sodium salt 150 mg ~ Pivampicillin free base250 mg : Corn starch 100 mg Hydroxypropyl cellulose 5 mg Methyl cellulose 5 mg Alginic acid 15 ~g . Talc 20 mg Magnesium stearate 5 m~
550 mg The tablets containing 6~-bromopenicillanic acid sodium salt and pivampicillin free base are obtained by the same pro~edure as described in Example 39.
Example 41 Tablets Component Per tablet 6~-Iodopenicillanic acid sodium salt 125 mg Amoxycillin 250 mg Corn starch 80 mg Hydroxypropyl cellulose , 10 mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 m~
500 mg , ~ 56 -~77~iZ
The active ingredients, i.e., the compound of forMula I and the other antibictics are blended with the corn starch, granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40C, and screened through 1 mm screensO After addition of alginic acid9 talc~ and magnesium stearate~ the mixture is compressed into tablets each weighing 500 mg. The tablets are covered with a ~ilm-eoating of hydroxypropyl methyl cellulose.
Example 42 Tablets Component Per tablet 6~-Bromopenicillanic acid potassium salt 125 mg Amoxycillin 250 mg Corn 5tarch 80 mg Hydroxypropyl cellulose10 mg " Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 mg 5O mg By the sameprocedureas described in Example 419 the tablets containing 6~-bromopenicillanic acid potassium salt and amoxycillin are obtained.
Example_4 Tablet s Component Per tablet ~ . _ _ ...... . ... ., . . . . _ . _ 6~Iodopenicillanic acid pivampicillin salt 500 mg Hydroxypropyl cellulose lO mg Microcrystalline cellulose 200 mg Magnesium stearate lO m~
710 mg ~ . . . . __ . ...... .. . __. .
The active component of formula I is granulated with a 15% solution of hydroxypropyl cellulose and isopropanol, dried at 40 C, and screened through 1 mm sieves. MicrocrystalliDe cellulose and magnesium stearate are added, and the mixture is com-pressed into tablets each weighing 710 mg.
Exam~le 44 Tablets Component Per tablet 6~-Bromopenicillanic acid pivmecillinam salt 350 mg Hydroxypropyl cellulose lO mg Microcrystalline cellulose 130 mg Magnesium stearate 10 m~
~ 500 mg -- . .. . . _ f. _ 58 -~2~S~
The tablets containing the pivmecillinam salt of 6~-bromopenicillanic acid are obtained by the same procedure as described in Example 43.
Example 4 , ~
Tablets Component Per tablet 6~-Iodopenicillanic acid potassium salt 125 mg CEPHALEXIN 250 mg Corn starch 80 mg ; Hydro~ypropyl cellulose lO mg Alginic acid 10 mg Talc 20 mg ; Magnesium stearate 5 mg 5O mg The tablets containing 6~-iodopenicillanic acid potassium salt and CEPH~EXIN are obtained by the same procedure as described in Example 41.
~ 59 ~ ~Z~775 Example 46 Tablets Component Per ta~let 6~-Bromopenicillanic acid sodium salt 125 mg CEFACLOR 250 mg Corn starch 80 mg Hydroxypropyl cellulose10 mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 mF
5 ~g By the same procedure as described in Example 41, the tablets containing 6~-bromopenicillanic acid sodium salt a~d CEFACLOR are obtainedO
Exampie 47 6~-Iodopenicillanic acid sodium saltLPivmecillinam HCl Two-layer tablets Granulate I
Component Per tablet 6~-Iodopenicillanic acid sodium salt 100 mg Hydroxypropyl cellulose2 mg Dicalcium phosphate dihydrate 86 mg Sodium starch glycolate10 mg Magnesium stearate 2 mg _ 60 -~Z~7~
The 6~-iodopenicillanic acid sodium salt is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40C 7 and screened through 0075 mm screens. The granules are blended with dicalcium phosphate dihydrate, sodium starch glycolate and magnesium stearateO
&ranulate II
Component Per tablet Pivmecillinam hydrochloride 100 rng Hydroxypropyl cellulose 2 mg Microcrystalline cellulose . 50 mg Magnesium stearate 1.5 mg Tal 3.5 mg Pivmecillinam hydrochloride is granulated with a solution of hydroxypropyl cellulose, dried at 40C, and screened through 0.75 mm~screens~ The granules are blended with microcrystal-line cellulose, magnesium stearate9 and talc.
The granulates are compressed into two-layer tablets containing 200 mg of granulate I as the bottom layer and 157 mg of granulate II as the top layer.
The tablets are film-coated with hydroxypropylmethyl cellulose dissolved in ethanol-water (1:1). .
.
~21~7~5;~
Example 48 6~-Bromopenicillanic acid sodium salt/Pivampicillin base Two-layer tablets Granulate I
, ,,, .~
Component Per tablet . . . ~
6~-Bromopenicillanic acid sodium salt lOO mg Polyvinyl pyrrolidone 5 mg Dicalcium phosphate dihydrate85 mg Sodium starch glycolate 8 mg Magnesium stearate 2 mg The 6~-bromopenicillanic acid sodium salt is granulated with a solution of polyvinyl pyrrolidone in isopropanol~
dried at 40 C, screened through 0.75 mm screens, and blended . with dicalcium phosphate dihydrate, starch, and magnesium stearate.
Granulate II
Component Per tablet Pivampicillin base 125 mg Starch 30 mg Hydroxypropyl cellulose 3.5 mg Magnesium stearate , 1.5 mg The pivampicillin base and 10 mg of the starch are blended and granulated with a solution of hydroxypropyl cellulose in de-ionized water, dried at 50C, and screened - ~Z~77r-- 62 - ~
through 0,75 mm screens. The granules are blended with the rest of the starch and magnesium stearate.
The granulates are compressed into tablets containing 200 mg of granulate I as~`the bottom layer and 160 mg of granulate II as the top layer, The tablets are film~coated with hydroxypropylmethyl cellulose dissolved in de-ionized water~ethanol (1:1).
Example 49 6~-Bromo~enicillanic acid sodium salt/AmoxYcillin Two-layer tablets Granulate I
Component Per tablet 6~-Bromopenicillanic acid sodium salt 100 mg Polyvinyl pyrrolidGne 7 mg Lactose 50 mg Silicon dioxide 1.5 mg Magnesium stearate 1.5 mg .
The 6~-bromopenicillanic acid sodium salt is granulated with a solution of polyvinyl pyrrolidone in isopropanol, dried at 40 C, and screened through 0~75 mm screens, The granules are blended wi*h lactose, silicon dioxide and magnesium stearate.
~_ - 63 -Granulate II
Component Per tablet , ~
Amoxycillin 200 mg Starch 30 mg Polyvinyl pyrrolidonè 6 mg Silicon dioxide 2 mg Magnesium stearate 2 mg Amoxycillin is blended with starch~ granulated with a solut on of polyvinyl pyrrolidonein de~ionized water, dried a* 50 C, and screened through 0.75 mm screens. The granules are blended with silicon dioxide and magnesium.
The granulates are compressed into tablets contain-ing 240 mg of granulate II as the bottom layer and 160 mg of granulate I as th~ top layer.
Example ~o 6~-Iodopeni~illanic acid sodium _salt!Pivmecillinam HCl/pivo ampicillin Three-layer tablets ~ranulate I
Component Per tablet 6~-Iodopenicillanic acid sodium salt100 mg Hydroxypropyl cellulose 2 mg Microcrystalline cellulose 50 mg Sodium starch glycolate 6 mg Magnesium stearate 2 mg _ ~4 -6~-Iodopenicillanic acid sodium salt is granulated with a solution of hydroxyprop~l cellulose in isopropanol, dried at 40 C, and screened through 0.75 mm screens 7 whereafter '~ microcrystalline cellulos~g sodiu~ starch glycolate~ and magnesium stearate are added.
Granulate II
Component Per tablet _ _ Pivmecillinam hydrochloride lOO mg Hydroxypropyl cellulose2 mg Microcrystalline cellulose 50 mg Magnesiuln stearate1.5 mg Pivmecillinam hydrochloride is granulated with a solution of h,vdroxypropyl cellulose in isopropanol, dried at 40 C7 and screened through 0.75 mm screens. The granules are blended with microcrystalline cellulose and magnesium stearate.
Granulate III
Component Per tablet .
Pivampicillin base 125 mg Starch 24 mg Hydroxypropyl cellulose3.5 mg Sodium starch glycolate7 ng Magnesium stearate 1.5 mg The pivampicillin base and lO mg starch are blended - 65 _ ~ 7~5~
and granulated with a solution of hydroxypropyl cellulose dissolved in de-ionized water, the granulated mass being dri0d at 50~C t and screened through 0~75 mm screans. There-after sodium starch glycolate, the rest of the starch~ and magnesium stearate are added.
The granulates are compressed into tablets containing 160 mg of granulata I as the bottom layer, 153.5 mg of granulate II as the intermediate layer, and 161 mg of granu-late III as the top layer~ The tablets are co~ered with a film-coating of hydroxypropylmethyl cellulose dissolved in de-ionized water ethanol (l:l).
~etramethylsilane was used as internal reference.
Examples 23-25 Further salts of 6~-halo~enicillanic acids with inorganic bases Treatment of an ethereal solution of the 6~-halopeni cillanic acid with an equi~alent amount of aqueous base followed by separation of the aqueous phase and fr0eze-drying afforded the salts listed in Table IV as colourless powders.
_ Table IV X H H Z
page /~ N ~ ~ ~ In _ 46 -~2~?7~S2 Example X n Z
23a Cl 1 Na~
23b Cl 2~ Ca++
24a Br 1 Li~
24b Br 2 Ca 25a I 1 Li+
25b I 2 Ca~+
--~ -- . e _ Examples 26 28 Further salts of ~-halopenicillanic acids with organic bases By treatment of a solution of the 6~-halopenicillanic acid in a suitable organic solvent, e.g. acetone, ethyl acetat0 or ether, with an equivalent amount of the organic base (preferably dissolved in the same solvent), the desired salt was obtained as a crystalline precipitate which was ; filtered off and dried in vacuo. The salts obtained by this method are listed in Table V below.
Table V X H H
See next ~ S ~", Z
page ~ ~ N ~ ~", o H 'COOH
i _ n ~L2~7~5;2 ~ . Exa~ple X n Z
-- ~ _ 26a Cl 1 dicyclohexylamine 26b Cl 2 N7N~-dibenzylethylenediamine 27a Br 1 morpholine 27b Br 2 N,N' dibenzylethylenediamine 27c Br 1 N-ethylpiperidine 27d Br 1 procaine 28a I 1 dibenzylamine 28b I 2 NJN~-dibenzylethylenediamine 28c I 1 N-methylbenzylamine 28d 1 1 procaine Examples 2~-30 Salts of 6~-halopenicillanic acids with ~-l.actam an*ibiotics and pro-dru~s thereof containing a basic group ; The salts listed in Table VI below were prepared by procedures simila~ to those described in the preceeding Examples 21-22 (A), 23 25 (B), or 26-28 (C).
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/~g ~i7752 Example ~1 Tablets Component Per tablet 6~-Iodopenicillanic acid sodium salt 250 mg Microcrystalline cellulose1].0 mg Hydroxypropyl cellulose 5 mg Alginic acid 10 mg Talc 23 mg Magnesium stearate 2 m~
400 mg The active component of formula I is blended with the microcrys-talline cellulose, granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through 1 mm sieves. Alginic acid~ talc~
and magnesium stearate are added, and the mixture is compressed into tablets each weighing 400 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose~
_ - 50 ~
7~2 Example Tablets Component Per tablet 6~-Bromopenicillanic acid sodium salt 250 mg Microcrystalline cellulose110 mg Hydroxypropyl cellulose 5 mg Alginic acid 10 mg Talc 23 mg Ma~nesiu~ stearate 2 m~
: 400 mg :
By the same procedure as described in Example 31, the tablets containing 6~-bromopenicillanic acid sodium salt are obtained.
.
Example Parenteral ~o~mulation Component Per vial 6~-Iodopenicillanic acid sodium salt 125 mg The sterile crystalline component is filled into sterile vials which are aseptically sealed. For parenteral admini-stration, 2 ml of sterile ph~siological saline is added to the content of the ~ial.
775~
Example ~4 Parenteral formulation Component Per vial 6~-Bromopenicillanic- acid sodium salt 125 mg _ _ _ _ .
The above formulation i5 obtained by the same procedure as described in Example 33.
Example_~
Capsules Component Per capsule 6~-Iodo~enicillanic acid potassium salt lZ5 mg Hydroxypropyl cellulose 3 mg Talc 6 mg Magnesium stearate _ mg 135 mg The active ingredient of formula I is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through l mm sieves~ Talc and magnesium stearate are added~ the components are well mixed to obtain a uniform blend, and 135 mg of the blend is filled in a No. 3 hard gelatine capsule.
_ 52 -Example ~6 C~_ules - Component Per capsule 6~-~romopenicillanic acid pivampi~
cillin salt 250 mg Hydroxypropyl cellulose 5 mg Talc 23 mg Magnesium stearate 2 mg 280 mg The active compound of formula I is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, and screened through 1 mm sieves. The diluents are added9 and the:mixture is carefully blended, 280 mg of the blend being :: filled in No. 2 gelatine capsules.
Example Tablets .
Cornponent Per tablet 6~-Iodopenicillanic acid sodium salt 125 mg Ampici.llin 250 mg Corn starch 75 mg Hydroxypropyl cellulose10 mg Alginic acid 10 mg TaIc 20 mg Magnesium stearate 5 i~
~ 495 mg - 53- ~LZ~ 52 In the above composition, the ac~ive components, i.e., of formula I and the other antibiotics are blended with corn sta~ch,granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40 C, a~d screened through 1 mm screens. Alginic acid, talc, and magnesium stearate are added, and the mixture is com~
pressed into tablets each weighing 495 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose.
Example Tablets .
Component Per tablet 6~-Bromopenicillanic acid potassium salt 125 mg Ampicillin 250 mg Corn starch 75 mg Hydroxypropyl celluloselO mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 m~
495 mg __ _ _ ~
By the same procedure as described in Example 37, the tablets cvntaining 6~-bromopenicillanic acid potassium salt and ampicillin are obtained.
- 5~ h~
Example ~9 Tablets Component Per tablet 6~-Iodopenicillanic acid potassium salt 200 mg Pivampicillîn free ba~e 250 mg Corn starch 100 mg Hydroxypropyl cellulose 5 mg Methyl cellulose 5 mg Alginic acid 15 mg .Talc 20 mg Magnesium ~tearate 5 m~
600 mg In the above composition, 6~-iodopenicillanic acid potassium salt and half the amount of corn starch are blended 7 granulated wlth a 10% solution o~ hydroxypropyl cellulose in is~propanol, dried at 40 C and screened through 1 mm screensO The balance of corn starch is blended with piv-ampicillin, granulated with paste ~f methyl cellulose and water9 dried at 50 C, and screened through 0.7 mm screens.
The granulates are blended with alginic acid, talc, and magnesium stearate, and the mixture is compressed into tablets each ~eighing 600 mg. The tablets are covered with a film-coating of hydroxypropyl methyl cellulose.
- ~ 55 ~
~2~7 Example 40 Tablets Component Per tablet 6~-Bromopenicillanic acid sodium salt 150 mg ~ Pivampicillin free base250 mg : Corn starch 100 mg Hydroxypropyl cellulose 5 mg Methyl cellulose 5 mg Alginic acid 15 ~g . Talc 20 mg Magnesium stearate 5 m~
550 mg The tablets containing 6~-bromopenicillanic acid sodium salt and pivampicillin free base are obtained by the same pro~edure as described in Example 39.
Example 41 Tablets Component Per tablet 6~-Iodopenicillanic acid sodium salt 125 mg Amoxycillin 250 mg Corn starch 80 mg Hydroxypropyl cellulose , 10 mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 m~
500 mg , ~ 56 -~77~iZ
The active ingredients, i.e., the compound of forMula I and the other antibictics are blended with the corn starch, granulated with a 10% solution of hydroxypropyl cellulose in isopropanol, dried at 40C, and screened through 1 mm screensO After addition of alginic acid9 talc~ and magnesium stearate~ the mixture is compressed into tablets each weighing 500 mg. The tablets are covered with a ~ilm-eoating of hydroxypropyl methyl cellulose.
Example 42 Tablets Component Per tablet 6~-Bromopenicillanic acid potassium salt 125 mg Amoxycillin 250 mg Corn 5tarch 80 mg Hydroxypropyl cellulose10 mg " Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 mg 5O mg By the sameprocedureas described in Example 419 the tablets containing 6~-bromopenicillanic acid potassium salt and amoxycillin are obtained.
Example_4 Tablet s Component Per tablet ~ . _ _ ...... . ... ., . . . . _ . _ 6~Iodopenicillanic acid pivampicillin salt 500 mg Hydroxypropyl cellulose lO mg Microcrystalline cellulose 200 mg Magnesium stearate lO m~
710 mg ~ . . . . __ . ...... .. . __. .
The active component of formula I is granulated with a 15% solution of hydroxypropyl cellulose and isopropanol, dried at 40 C, and screened through 1 mm sieves. MicrocrystalliDe cellulose and magnesium stearate are added, and the mixture is com-pressed into tablets each weighing 710 mg.
Exam~le 44 Tablets Component Per tablet 6~-Bromopenicillanic acid pivmecillinam salt 350 mg Hydroxypropyl cellulose lO mg Microcrystalline cellulose 130 mg Magnesium stearate 10 m~
~ 500 mg -- . .. . . _ f. _ 58 -~2~S~
The tablets containing the pivmecillinam salt of 6~-bromopenicillanic acid are obtained by the same procedure as described in Example 43.
Example 4 , ~
Tablets Component Per tablet 6~-Iodopenicillanic acid potassium salt 125 mg CEPHALEXIN 250 mg Corn starch 80 mg ; Hydro~ypropyl cellulose lO mg Alginic acid 10 mg Talc 20 mg ; Magnesium stearate 5 mg 5O mg The tablets containing 6~-iodopenicillanic acid potassium salt and CEPH~EXIN are obtained by the same procedure as described in Example 41.
~ 59 ~ ~Z~775 Example 46 Tablets Component Per ta~let 6~-Bromopenicillanic acid sodium salt 125 mg CEFACLOR 250 mg Corn starch 80 mg Hydroxypropyl cellulose10 mg Alginic acid 10 mg Talc 20 mg Magnesium stearate 5 mF
5 ~g By the same procedure as described in Example 41, the tablets containing 6~-bromopenicillanic acid sodium salt a~d CEFACLOR are obtainedO
Exampie 47 6~-Iodopenicillanic acid sodium saltLPivmecillinam HCl Two-layer tablets Granulate I
Component Per tablet 6~-Iodopenicillanic acid sodium salt 100 mg Hydroxypropyl cellulose2 mg Dicalcium phosphate dihydrate 86 mg Sodium starch glycolate10 mg Magnesium stearate 2 mg _ 60 -~Z~7~
The 6~-iodopenicillanic acid sodium salt is granulated with a solution of hydroxypropyl cellulose in isopropanol, dried at 40C 7 and screened through 0075 mm screens. The granules are blended with dicalcium phosphate dihydrate, sodium starch glycolate and magnesium stearateO
&ranulate II
Component Per tablet Pivmecillinam hydrochloride 100 rng Hydroxypropyl cellulose 2 mg Microcrystalline cellulose . 50 mg Magnesium stearate 1.5 mg Tal 3.5 mg Pivmecillinam hydrochloride is granulated with a solution of hydroxypropyl cellulose, dried at 40C, and screened through 0.75 mm~screens~ The granules are blended with microcrystal-line cellulose, magnesium stearate9 and talc.
The granulates are compressed into two-layer tablets containing 200 mg of granulate I as the bottom layer and 157 mg of granulate II as the top layer.
The tablets are film-coated with hydroxypropylmethyl cellulose dissolved in ethanol-water (1:1). .
.
~21~7~5;~
Example 48 6~-Bromopenicillanic acid sodium salt/Pivampicillin base Two-layer tablets Granulate I
, ,,, .~
Component Per tablet . . . ~
6~-Bromopenicillanic acid sodium salt lOO mg Polyvinyl pyrrolidone 5 mg Dicalcium phosphate dihydrate85 mg Sodium starch glycolate 8 mg Magnesium stearate 2 mg The 6~-bromopenicillanic acid sodium salt is granulated with a solution of polyvinyl pyrrolidone in isopropanol~
dried at 40 C, screened through 0.75 mm screens, and blended . with dicalcium phosphate dihydrate, starch, and magnesium stearate.
Granulate II
Component Per tablet Pivampicillin base 125 mg Starch 30 mg Hydroxypropyl cellulose 3.5 mg Magnesium stearate , 1.5 mg The pivampicillin base and 10 mg of the starch are blended and granulated with a solution of hydroxypropyl cellulose in de-ionized water, dried at 50C, and screened - ~Z~77r-- 62 - ~
through 0,75 mm screens. The granules are blended with the rest of the starch and magnesium stearate.
The granulates are compressed into tablets containing 200 mg of granulate I as~`the bottom layer and 160 mg of granulate II as the top layer, The tablets are film~coated with hydroxypropylmethyl cellulose dissolved in de-ionized water~ethanol (1:1).
Example 49 6~-Bromo~enicillanic acid sodium salt/AmoxYcillin Two-layer tablets Granulate I
Component Per tablet 6~-Bromopenicillanic acid sodium salt 100 mg Polyvinyl pyrrolidGne 7 mg Lactose 50 mg Silicon dioxide 1.5 mg Magnesium stearate 1.5 mg .
The 6~-bromopenicillanic acid sodium salt is granulated with a solution of polyvinyl pyrrolidone in isopropanol, dried at 40 C, and screened through 0~75 mm screens, The granules are blended wi*h lactose, silicon dioxide and magnesium stearate.
~_ - 63 -Granulate II
Component Per tablet , ~
Amoxycillin 200 mg Starch 30 mg Polyvinyl pyrrolidonè 6 mg Silicon dioxide 2 mg Magnesium stearate 2 mg Amoxycillin is blended with starch~ granulated with a solut on of polyvinyl pyrrolidonein de~ionized water, dried a* 50 C, and screened through 0.75 mm screens. The granules are blended with silicon dioxide and magnesium.
The granulates are compressed into tablets contain-ing 240 mg of granulate II as the bottom layer and 160 mg of granulate I as th~ top layer.
Example ~o 6~-Iodopeni~illanic acid sodium _salt!Pivmecillinam HCl/pivo ampicillin Three-layer tablets ~ranulate I
Component Per tablet 6~-Iodopenicillanic acid sodium salt100 mg Hydroxypropyl cellulose 2 mg Microcrystalline cellulose 50 mg Sodium starch glycolate 6 mg Magnesium stearate 2 mg _ ~4 -6~-Iodopenicillanic acid sodium salt is granulated with a solution of hydroxyprop~l cellulose in isopropanol, dried at 40 C, and screened through 0.75 mm screens 7 whereafter '~ microcrystalline cellulos~g sodiu~ starch glycolate~ and magnesium stearate are added.
Granulate II
Component Per tablet _ _ Pivmecillinam hydrochloride lOO mg Hydroxypropyl cellulose2 mg Microcrystalline cellulose 50 mg Magnesiuln stearate1.5 mg Pivmecillinam hydrochloride is granulated with a solution of h,vdroxypropyl cellulose in isopropanol, dried at 40 C7 and screened through 0.75 mm screens. The granules are blended with microcrystalline cellulose and magnesium stearate.
Granulate III
Component Per tablet .
Pivampicillin base 125 mg Starch 24 mg Hydroxypropyl cellulose3.5 mg Sodium starch glycolate7 ng Magnesium stearate 1.5 mg The pivampicillin base and lO mg starch are blended - 65 _ ~ 7~5~
and granulated with a solution of hydroxypropyl cellulose dissolved in de-ionized water, the granulated mass being dri0d at 50~C t and screened through 0~75 mm screans. There-after sodium starch glycolate, the rest of the starch~ and magnesium stearate are added.
The granulates are compressed into tablets containing 160 mg of granulata I as the bottom layer, 153.5 mg of granulate II as the intermediate layer, and 161 mg of granu-late III as the top layer~ The tablets are co~ered with a film-coating of hydroxypropylmethyl cellulose dissolved in de-ionized water ethanol (l:l).
Claims (60)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a derivative of a compound of the Formula I
in which X stands for halo selected fromm the group consisting of chloro, bromo and iodo with a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, which process comprises: reacting a solution of potassium 6 .beta. -halo-penicillanate, where halo is chloro, bromo or iodo, with a solution of said antibiotic or said pro-drug thereof.
in which X stands for halo selected fromm the group consisting of chloro, bromo and iodo with a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, which process comprises: reacting a solution of potassium 6 .beta. -halo-penicillanate, where halo is chloro, bromo or iodo, with a solution of said antibiotic or said pro-drug thereof.
2. The process of claim 1 wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and sub-stituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof.
3. The process of claim 2 wherein said halo is bromo.
4. The process of claim 1 wherein said .beta. -lactam antibiotic is selected from the group consisting of ampicillin, amoxycillin, cephalexin, mecillinam, and cefaclor, and pivampicillin, bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof.
5. The process of claim 4 wherein said halo is bromo.
6. The process of claim 3 wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine, and cephaloglycine.
7. The process of claim 6 wherein said halo is bromo.
8. The process of claim 1 wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metampicillin;
the acetoxymethyl, pivaloxyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine, the phenyl, tolyl, or indanyl ? -esters of carbenicillin, or of ticarcillin;
6 .beta. -amidinopenicillanic acid derivatives; and 7 .beta. -amidinocephalosporanic acid derivatives.
the acetoxymethyl, pivaloxyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine, the phenyl, tolyl, or indanyl ? -esters of carbenicillin, or of ticarcillin;
6 .beta. -amidinopenicillanic acid derivatives; and 7 .beta. -amidinocephalosporanic acid derivatives.
9. The process of claim 8 wherein said halo is bromo.
10. A process according to claim 1 wherein said derivative is a salt, and wherein said process comprises: reacting an aqueous solution of potassium 6 .beta. -halopenicillanate, wherein halo is chloro, bromo, or iodo, with an aqueous solution of said antibiotic.
11. The process of claim 10 wherein halo is bromo.
12. The process of claim 10 wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and sub-substituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof.
13. The process of claim 12 wherein said halo is bromo.
14. The process of claim 10 wherein said .beta. -lactam antibiotic is selected from the group consisting of ampicillin, amoxycillin, mecillinam, cephalexin, and cefaclor; and pivampicillin, bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof.
15. The process of claim 14 wherein halo is bromo.
16. The process of claim 10 wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine, and cephaloglycine.
17. The process of claim 16 wherein halo is bromo.
18. The process of claim 10 wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metampicillin;
the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxymethyl, or phthlidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine;
the phenyl, tolyl, or indanyl .alpha. -esters of carbenicillin, or of ticarcillin;
6 .beta. -amidino penicillanic acid derivatives; and 7 .beta. -amidinocephalosporanic acid derivatives.
the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxymethyl, or phthlidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine;
the phenyl, tolyl, or indanyl .alpha. -esters of carbenicillin, or of ticarcillin;
6 .beta. -amidino penicillanic acid derivatives; and 7 .beta. -amidinocephalosporanic acid derivatives.
19. The process of claim 11 wherein said halo is bromo.
20. A process according to claim 10 for the preparation of the pivampicillin salt of 6 .beta. -iodopenicillanic acid, which process comprises reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 .beta. -iodopenicillanate.
21. A process according to claim 10 for the preparation of the pivampicillin salt of 6 .beta. -bromopenicillanic acid, which process comprises reacting an aqueous solution of pivampicillin hydrochloride with an aqueous solution of potassium 6 .beta. -bromopenicillanate.
22. A process according to claim 10 for the preparation of the bacampicillin salt of 6 .beta. -iodopenicillanic acid, which process comprises reacting an aqueous solution of bacampicillin hydrochloride with an aqueous solution of potassium 6 .beta. -iodopenicillanate.
23. A process according to claim 10 for the preparation of the bacampicillin salt of 6 .beta. -bromopenicillanic acid, which process comprises reacting an aqueous solution of bacampicillin hydrochloride with an aqueous solution of potassium 6 .beta. -bromopenicillanate.
24. A process according to claim 1 wherein said derivative is a salt and wherein said process comprises treating an organic solvent solution of a 6 .beta. -halopenicillanic acid, wherein halo is chloro, bromo, or iodo, with an organic solvent solution of said antibiotic.
25. A process according to claim 24 for the preparation of the pivmecillinam salt of 6 .beta. -iodopenicillanic acid, which process comprises treat-ing an organic solvent solution of 6 .beta. -iodopenicillanic acid with an organic solvent solution of pivmecillinam.
26. A process according to claim 24 for the preparation of the pivmecillinam salt of 6 .beta. -bromopenicillanic acid, which process comprises treating an organic solvent solution of 6 .beta. -bromopenicillanic acid with an organic solvent solution of pivmecillinam.
27. A process according to claim 24 for the preparation of the bacmecillinam salt of 6 .beta. -iodopenicillanic acid, which process comprises treating an organic solvent solution of 6 .beta. -iodopenicillanic acid with an organic solvent solution of bacmecillinam.
28. A process according to claim 24 for the preparation of the bacmecillinam salt of 6 .beta. -bromopenicillanic acid, which process comprises treating an organic solvent solution of 6 .beta. -bromopenicillanic acid with an organic solvent solution of bacmecillinam.
29. A process according to claim 24 for the preparation of the penethamate salt of 6 .beta. -iodopeniciilanic acid, which process comprises treat-ing an organic solvent solution of 6 .beta. -iodopenicillanic acid with an organic solvent solution of penethamate.
30. A process according to claimm 24 for the preparation of the penethamate salt of 6 .beta. -bromopenicillanic acid, which process comprises treat-ing an organic solvent solution of 6 .beta. -bromopenicillanic acid with an organic solvent solution of penethamate.
31. A derivative of a compound of the Formula I
wherein X is halo selected from the group consisting of chloro, bromo and iodo with a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, whenever prepared by the process of claim 1, or by its obvious chemical equiva-lent.
wherein X is halo selected from the group consisting of chloro, bromo and iodo with a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, whenever prepared by the process of claim 1, or by its obvious chemical equiva-lent.
32. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and sub-stituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof, whenever pre-pared by the process of claim 2 or by its obvious chemical equivalent.
33. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and sub-stituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof, and wherein said halo is bromo, whenever prepared by the process of claim 3 or by its obvious chemical equivalent.
34. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected from the group consisting of ampicillin, amoxycillin mecillinam, cephalexin, and cefaclor; and pivampicillin, bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof, whenever prepared by the process of claim 4, or by its obvious chemical equivalent.
35. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected fromm the group consisting of ampicillin, amoxycillin, mecillinam, cephalexin, and cefaclor; and pivampicillin, bacampicillin, pivmecillinam, bacmecillinam and penethamate and other pro-drugs thereof, wherein said halo is bromo, whenever prepared by the process of claim 5 or by its obvious chemical equivalent.
36. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpeni-cillin, carbenicillin, methicillin, propicillin, epicillin, ticarcillin, cycla-cillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole1 cephapirin, cephridine, and cephaloglycine, whenever prepared by the process of claim 6 or by its obvious chemical equivalent.
37. The derivative of claim 31 wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpeni-cillin , carbenicillin, methicillin, propicillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephridine, and cephaloglycine, and wherein said halo is bromo, whenever prepared by the process of claim 7 or by its obvious chemical equivalent.
38. The derivative of claim 31 wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metampi-cillin, the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl .alpha. -esters of carbenicillin, or of ticarcillin; 6 .beta. -amidopenicillanic acid derivatives; and 7 .beta. -amidino-cephalosporanic acid derivatives, whenever prepared by the process of claim 8, or by its obvious chemical equivalent.
39. The derivative of claim 31 wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metampi-cillin; the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl ?-esters of carbenicillin, or of ticarcillin; 6.beta. -amidinopenicillanic acid derivatives; and 7 .beta. -amidinocepha-losporanic acid derivatives, and wherein said halo is bromo, whenever prepared by the process of claim 9 or by its obvious chemical equivalent.
40. As a derivative of claim 31, a 6 .beta. -halopenicillanic acid salt of a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, wherein halo is chloro, bromo or iodo, whenever prepared by the process of claim 10, or by its obvious chemical equivalent.
41. As a derivative of claim 31, a 6 .beta. -bromopenicillanic acid salt of a .beta. -lactam antibiotic or a pro-drug thereof containing a basic group, wherein said halo is bromo, whenever prepared by the process of claim 11, or by its obvious chemical equivalent.
42. As a derivative of claim 31, a 6 .beta. -halopenicillanic acid salt of a .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and substituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof, whenever prepared by the process of claim 12, or by its obvious chemical equivalent.
43. As a derivative of claim 31, a 6 .beta. -bromopenicillanic acid salt of a .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of penicillins, cephalosporins, and substituted 6 .beta. -amidinopenicillanic acids, and pro-drugs thereof, and wherein said halo is bromo, whenever prepared by the process of claim 13 or by its obvious chemical equivalent.
44. As a derivative of claim 31, a 6 .beta. -halopenicillanic acid salt of .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of ampicillin, amoxycillin, mecillinam, cephalexin, and cefaclor; and pivampicillin, bacampicillin, pivmecillinam, bacmecillan and penethamate, and other pro-drugs thereof, whenever prepared by the process of claim 14 or by its obvious chemical equivalent.
45. As a derivative of claim 31, a 6 .beta. -bromopenicillanic acid salt of a .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of ampicillin, amoxycillin, mecillinam, cephalexin, and cefaclor; and pivampicillin, bacampicillin, pivemcillinam, bacmecillinam and penethamate and other pro-drugs thereof, whenever prepared by the process of claim 15 or by its obvious chemical equivalent.
46. As a derivative of claim 31, 6 .beta. -halopenicillanic acid salt of a .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, epicillin, ticarcillin, cyclacillin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine, and cephaloglycine, whenever prepared by the process of claim 16 or by its obvious chemical equivalent.
47. As a derivative of claim 31, a 6.beta. -bromopenicillanic acid salt of a .beta. -lactam antibiotic, wherein said .beta. -lactam antibiotic is selected from the group consisting of benzylpenicillin, phenoxymethylpenicillin, carbenicil-lin, methicillin, propicillin, epicillin, ticarcillin, cyclacillin, cephalori-dine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cepha-pirin, cephradine, cephloglycine, and wherein said halo is bromo, whenever prepared by the proces of claim 17 or by its obvious chemical equivalent.
48. As a derivative of claim 31, a 6 .beta. -halopenicillanic acid salt of a pro-drug of a .beta. -lactam antibiotic, wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metam-picillin; the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl .alpha. -esters of carbenicillin, or of ticarcillin; 6 .beta. -amidinopenicillanic acid derivatives; and 7 .beta. -amidino-cephalosporanic acid derivatives, whenever prepared by the process of claim 18 or by its obvious chemical equivalent.
49. As a derivative of claim 31, a 6 .beta. -bromopenicillanic acid salt of a pro-drug of a .beta. -lactam antibiotic, wherein said pro-drug of said .beta. -lactam antibiotic is selected from the group consisting of hetacillin; metampi-cillin; the acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl, or phthalidyl esters of benzylpenicillin, of ampicillin, of amoxycillin, or of cephaloglycine; the phenyl, tolyl, or indanyl .alpha. -esters of carbenicillin, or of ticarcillin; 6 .beta. -amidinopenicillanic acid derivatives; and 7 .beta. -amidino-cephalosporanic acid derivatives, wherein said halo is bromo, whenever pre-pared by the process of claim 19 or by its obvious chemical equivalent.
50. The pivampicillin salt of 6 .beta. -iodopenicillanic acid, whenever prepared by the proces of claim 20 or by its obvious chemical equivalent.
51. The pivampicillin salt of 6 .beta. -bromopenicillanic acid, whenever prepared by the process of claim 21, or by its obvious chemical equivalent.
52. The bacampicillin salt of 6 .beta. -iodopenicillanic acid, whenever prepared by the process of claim 22, or by its obvious chemical equivalent.
53. The bacampicillin salt of 6 .beta. -bromopenicillanic acid whenever prepared by the process of claim 23, or by its obvious chemical equivalent.
54. As a derivative of claim 31, a h .beta. -halopenicillanic acid salt of a .beta. -lacam antibiotic or a pro-drug thereof containing a basic group, whenever prepared by the process of claim 24 or by its obvious chemical equiva-lent.
55. The pivmecillinam salt of 6 .beta. -iodopenicillanic acid, whenever prepared by the process of claim 25, or by its obvious chemical equivalent.
56. The pivmecillinam salt of 6 .beta. -bromopenicillanic acid, when-ever prepared by the process of claim 26, or by its obvious chemical equiva-lent.
57. The bacmecillinam salt of 6 .beta. -iodopenicillanic acid, whenever prepared by the process of claim 27, or by its obvious chemical equivalent.
58. The bacmecillinam salt of 6 .beta. -bromopenicillanic acid, when-ever prepared by the process of claim 28, or by its obvious chemical equiva-lent.
59. The penethamate salt of 6 .beta. -iodopenicillanic acid, when-ever prepared by the process of claim 29, or by its obvious chemical equiva-lent.
60. The penethamate salt of 6 .beta. -bromopenicillanic acid, whenever prepared by the process of claim 30, or by its obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000411636A CA1207752A (en) | 1979-05-21 | 1982-09-16 | PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM AND DERIVATIVES SO PRODUCED |
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7917665 | 1979-05-21 | ||
| GB7917665 | 1979-05-21 | ||
| GB7930819 | 1979-09-05 | ||
| GB7930819 | 1979-09-05 | ||
| GB7941252 | 1979-11-29 | ||
| GB7941252 | 1979-11-29 | ||
| GB8006681 | 1980-02-27 | ||
| GB8006681 | 1980-02-27 | ||
| CA000352237A CA1265787A (en) | 1979-05-21 | 1980-05-20 | Method for producing chemical compounds |
| CA000411636A CA1207752A (en) | 1979-05-21 | 1982-09-16 | PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM AND DERIVATIVES SO PRODUCED |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1207752A true CA1207752A (en) | 1986-07-15 |
Family
ID=27508170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000411636A Expired CA1207752A (en) | 1979-05-21 | 1982-09-16 | PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM AND DERIVATIVES SO PRODUCED |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1207752A (en) |
-
1982
- 1982-09-16 CA CA000411636A patent/CA1207752A/en not_active Expired
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