Note: Descriptions are shown in the official language in which they were submitted.
77S2
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 !
.
~775~
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
-,~
,~ ,.
~77~Z
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,
- 3 -
~'~
~77SZ
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
1 0 X
~ ~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
-- 11 --
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
- 16 -
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.
- 19 -
~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
- 20 -
~ 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.
- 25 -
~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-
- 26 -
~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.
27 -
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.
- 29 -
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.
- 33 -
~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%.
- 36 -
~ 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
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
- 38 -
?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
- 47 -
~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.
- 57 -
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 -
5Z
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).
