ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDS

ESTERS D'ACIDES AMIDINOPENICILLANIQUES SUBSTITUEES EN .alpha.

English Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to new penicillanic acid
derivatives which are effective in treatment of infectious diseases caused
by bacterial microorganisms and to methods for their preparation. More
precisely this invention relates to new esters of amidinopenicillanic acids
of the formula:
<IMG>
I
and therapeutically acceptable salts thereof, wherein R1 and R2, which are
the same or different, are alkyl groups containing from 1 to 10 carbon atoms
R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring
system; R3 is selected from the group consisting of
<IMG> <IMG>
and
in which radicals R4 is selected from the group consisting of alkyl groups
containing from 1 to 8 carbon atoms, or phenyl, R5 is selected from the group
consisting of hydrogen, methyl and ethyl, with the proviso that when R1 and
R2 together with the adjacent nitrogen atom form a hexahydro-1H-azepine ring
R3 is <IMG> and R5 is methyl R4 is not ethyl. The compounds of this
invention are of value in the treatment of infectious diseases in man or
animals caused by bacterial organisms. They are prepared according to known
methods for the preparation of penicillin derivatives.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
<IMG>
and pharmaceutically acceptable salts thereof, wherein R1 and R2 which are
the same or different, are alkyl groups containing from 1 to 10 carbon atoms,
or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic
ring system, R3 is selected from the group consisting of
<IMG> and <IMG>
in which R4 is selected from the group consisting of alkyl groups containing
from 1 to 8 carbon atoms and phenyl and R5 is selected from the group consist-
ing of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 to-
gether with the adjacent nitrogen atom form a hexahydro-1H-azepine ring, R3 is
<IMG>
and R5 is methyl R4 is not ethyl, which process comprises (a) reacting a
reactive derivative of a compound of the formula III
<IMG> III
wherein R1 and R2 have the meanings specified above and R6 is oxygen or sul-
phur, with a compound or a salt of a compound of formula IV
<IMG> IV
wherein R3 has the meaning specified above, or (b) reacting a reactive deriva-
tive of a compound of formula VI
19

<IMG> VI
with a compound of formula VII
<IMG> VII
wherein R1, R2 and R3 have the meanings specified above, or (c) reacting a
compound or a salt of a compound of formula II
<IMG> II
with a compound of formula
R3Y
wherein R1, R2 and R3 have the meanings specified above to obtain the compound
of formula I or a salt thereof and, if required, converting the compound of
formula I into a pharmaceutically acceptable salt.
2. A process according to claim 1(a) wherein the reactive deriva-
tive of the compound of formula III is an acid amide halogenide, a dialkyl
sulphate complex of an acid amide or an acid amide acetal.
3. A process according to claim 1(a) wherein the reactive deriva-
tive of the compound of formula III is a compound of formula V
<IMG>
wherein R1 and R2 are as specified in claim 1 and R7 is an alkyl group.
4. A process according to claim 1(b) wherein the reactive deriva-
tive of the compound of formula VI is the product of reaction between the
compound of formula IV and a dihalogendimethyl ether in the presence of a
tertiary organic base.

5. A process according to claim 1 wherein R1 and R2 together
with the adjacent nitrogen atom form a heterocyclic ring containing from 3
to 7 carbon atoms and R3 is of the formula
<IMG>
wherein R4 is an alkyl group containing from 1 to 8 carbon atoms and R5 is
hydrogen, methyl or ethyl.
6. A process according to claim 5 wherein the heterocyclic ring
contains 6 or 7 carbon atoms.
7. A process according to claim 1 wherein a compound of the
formula I with one or more asymmetrical centers is resolved in its optical
antipodes.
8. A compound conforming to the structural formula
<IMG>
or a pharmaceutically acceptable salt thereof, in which formula R1 and R2
which are the same or different, are either alkyl groups containing from 1
to 10 carbon atoms, or R1 and R2 together with the adjacent nitrogen atom
form a heterocyclic ring system; R3 is selected from the group consisting of
<IMG> and <IMG>
in which radicals R4 is selected from the group consisting of alkyl groups
containing from 1 to 8 carbon atoms, and phenyl, R5 is selected from the
group consisting of hydrogen, methyl and ethyl, with the proviso that when
R1 and R2 together with the adjacent nitrogen atom form a hexahydro-1H-azepine
ring R3 is R5 and R5 is methyl, R4 is not ethyl whenever prepared
<IMG>
by the process of claim 1 or by an obvious chemical equivalent thereof.
21

9. A compound according to claim 8, which contains one or more
asymmetrical centers, in the form of a pure stereoisomer whenever prepared
by the process of claim 7 or by an obvious chemical equivalent thereof.
10. A process according to claim 1 in which R1 and R2 together form a
hexamethylene group and R3 is 1-acetoxyethyl.
11. A process according to claim 1 in which 1'-acetoxyethyl 6-
(hexahydro-1H-azepin-1-yl)methyleneamino penicillanate is prepared by
reacting 1'-acetoxy-ethyl 6-aminopenicillanate with 1-hexamethyleneimino-
carboxaldehyde-dimethyl-acetate.
12. 1'-Acetoxyethyl 6-(hexahydro-1H-azepin-1-yl)methyleneamino
penicillanate whenever prepared by the process of claim 11 or by an obvious
chemical equivalent thereof.
13. A process according to claim 1 in which R1 and R2 together form a
hexamethylene group and R3 is ethoxycarbonyloxymethyl.
14. A process according to claim 1 in which ethoxycarbonyloxy methyl-
6-(hexahydro-1H-azepin-1-yl)-methyleneamino penicillanate is prepared by
reacting ethoxycarbonyloxymethyl-6-amino-penicillanate with 1-hexamethy-
leneaminacarboxaldehyde-dimethylacetal.
15. A process according to claim 1 in which ethoxycarbonyloxymethyl
6-(hexahydro-1H-azepin-1-yl)-methyleneaminopenicilllanate is prepared by
reacting ethoxycarbonyloxymethyl-6-amino-penicillanate with hexahydro-1H-
azepin-1-yl-chloroformiminium chloride.
16. A process according to claim 15 in which the ethoxycarbonyloxy-
methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-
6-phenylacetamide penicillanate with phosphorus penta chloride in the
22

presence of quinoline, followed by addition of methanol, to remove the
phenylacetyl side chain in the 6-position.
17. Ethoxycarbonyloxymethyl 6-(hexahydro-1H(azepin-1-yl)-methylene-
amino-penicillanate whenever prepared by the process of claim 14, 15 or 16
or by an obvious chemical equivalent thereof.
18. A process according to claim 1 in which R1 and R2 together form a
pentamethylene group and R3 is 1-ethoxycarbonyloxyethyl.
19. A process according to claim 1 in which 1'-ethoxycarbonyloxy-
ethyl 6-(piperidyl-1-)-methyleneaminopenicillanate is prepared by reacting
1'-ethoxycarbonyloxyethyl-6-amino penicillanate with N-piperidylchloroformi-
minium chloride.
20. A process according to claim 19 in which the ethoxycarbonyloxy-
methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-
6-phenylacetamido-penicillanate with phosphorus penta chloride in the
presence of quinoline, followed by addition of methanol, to remove the
phenylacetyl side chain in the 6-position.
21. 1'-Ethoxycarbonyloxyethyl 6-(piperidyl-1-)-methyleneamino-
penicillanate whenever prepared by the process of claim 19 or 20 or by an
obvious chemical equivalent thereof.
22. A process according to claim 1 in which R1 and R2 together forms
pentamethylene groups and R3 is 1-acetoxyethyl.
23. A process according to claim 1 in which 1'-acetoxyethyl-6-
(piperidyl-1)-methyleneaminopenicillanate is prepared by reacting 1'-
acetoxyethyl-6-amino penicillanate with N-piperidylchloroformiminiumchloride.
24. A process according to claim 23 in which the ethoxycarbonyloxy-
23

methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-
6-phenylacetamide penicillanate with phosphorus penta, chloride in the
presence of quinoline, followed by addition of methanol, to remove the
phenylacetyl side chain in the 6-position.
25. l'-Acetoxyethyl 6-(piperidyl-1)-methyleneaminopenicillanate when-
ever prepared by the process of claim 23 or 24 or by an obvious chemical
equivalent thereof.
24

Description

~,oS~20
The present invention relates to new penicillanic acid
derivatives which are effective in treatment of infectious diseases caused
by bacterial microorganisms and to methods for their preparation.
More precisely this invention relates to new esters of amidino-
penicillanic acids of the formula
Rl N-CH=N - CH - CH / \ C / 3
H R2 / ¦ ~ ¦ \ CH3
CO - N CH -COOR
and pharmaceutically acceptable salts thereof, wherein Rl and R2, which are
the same or different, are alkyl groups containing from 1 to 10 carbon atoms,
Rl and R2 together with the adjacent nitrogen atom form a heterocyclic ring
system; R3 is selected from the group consisting of
CH3 R5
_1~_0_CO_R4 and -CH-o-Coo-R4
in which radicals R4 is selected from the group consisting of alkyl groups
containing from 1 to 8 carbon atoms, and phenyl; R5 is selected from the
group consisting of hydrogen, methyl and ethyl, with the proviso that when
Rl and R2 together with the adjacent nitrogen atom form a hexahydro-lH-azepine
ring, R3 is -CH-o-CooR4 and R5 is methyl, R4 is not ethyl.
The compound in which Rl and R2 together with the adjacent
nitrogen atom form a hexahydro-lH-azepine ring, R3 is
R5
-CH-o-CooR4, R5 is methyl and R4 is ethyl, i.e. 1'-ethoxycarbonyloxy-ethyl-6-
~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanate of formula
N-CH=N-CH-CH C
H3 CH3 O
CO-N CH - COO-CH-O-C-O-C2H5
vis;~n~JQ
is the subject of~pplication ~4~-ial Mo. divided out of this
application.
'. ~

14~20
Illustrative examples of radicals included in the above definitions
are: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
hexyl, heptyl, octyl, 2-ethyl-hexyl -NRl, R2 forming a ring system:
/ 2 \ / CH2 - CH2 / CH2 - CH2 \
-N CH2 -H ¦ -N / CH2
CH2 CH2 - CH2 CH2 - CH2
CH2 - CH2 - CH2\
-N / 2
\ CH2 - 2
.:
i~
ij
.~:
:~ .
i :
i _ la
'(
. .

1~51`~'~0
The above illustrative examples illustrate, where applicable,
all the radicals Rl-R4 to the extent of the definition given to each radical
and within the boundaries with regard to number of carbon atoms which may be
prescribed for each radical.
The invention relates in a further aspect to such chemical
intermediates which are new and useful in the preparation of the compounds of
the formula I.
The compounds of the invention are of value in the treatment
of infectious diseases in man or animal caused by bacterial organisms. They
may be isolated and used as such but also, depending on the presence of basic
groups in the molecule, in the form of salts with pharmaceutically acceptable
organic or inorganic acids. Examples of suitable acids are hydrochloric acid,
hydrobromic acid~ sulphuric acid, phosphoric acid, acetic acid, tartaric acid,
citric acid, and fumaric acid.
The side chain of the structure in formula I may contain an
asymmetric center. Depending on the configuration around this center the
compound will occur in different diastereoisomeric forms which are all biologi-
cally active. Likewise the ester groups may contain asymmetric atoms, e.g.
; when R5-CH3 or C2H5, giving rise to different diastereoisomeric forms which
also all are biologically active. It is to be understood that the invention
comprises the pure diastereoisomers as well as mixtures of them.
Penicillanic acid derivatives of the general fo~la 11
-- 2 --

~5~
`\ N-CH=N-CH - CH / \ C ~ 3
R2 / l l ¦ CH3
CO - N CH - COOH
are known to have strong antibacterial activity especially against gramnega-
tive organisms ~Canadian Patent No. 914,165). They are, however, not well
absorbed by the oral route and have to be given by injection. It is one pur-
pose of the present invention to provide esters of compounds of formula II,
which are well absorbed orally and hydrolysed within the body to give blood
and organ levels of the compounds of formula II that are adequate for the
treatment of infectious diseases caused by bacteria sensitive to penicillanic
acids of the general formula II. To achieve the full antibacterial activity
of the penicillanic acids II it is necessary to choose such ester groups that
are rapidly hydrolyzed in vivo. It is an essential feature of the present
invention to provide such ester groups that are rapidly hydroly2ed in the body
after oral absorption.
The compounds of the invention with the formula I are well tolerated,
give a low frequency of side-effects and may readily be used in pharmaceutical
preparations, either as such or in the form of their salts, and they can be
intermixed with solid carriers or adjuuants.or both. In such preparations
the ratio between the therapeutic substance and the carriers and adjuvants
may vary between 1 % and 95 %. The preparation may either be processed to
for instance tablets, pills or dragees or can be supplied to medical contain-
brs, such as capsules or as regards mixtures they can be filled on bottles.
Pharmaceutically acceptable, organic oriinoganic, solid or liquid carriers
may be used, suitably for oral or enteral administration or for topical
application, in manufacturing the preparations. Gelatine, lactose, starch,
magnesium stearate, talc, vegetabilic and animalic fats and oils, vegetabilic
rubber and polyalkylene glycol and other kno~n carriers for pharmaceuticals
are all suitable or manufacturing preparations of said compounds. Moreover,
the preparation may contain other pharmaceutical active~components, being
- 3 -

1~5~ .0
suitably adminstratable together with the compounds of the invention when
treating infectious diseases. For instance other suitable antibiotical sub-
stances, e.g. gentamycin and polymyxin.
In the treatment of bacterial infections in man, the compounds of
invention are for example administered in amounts corresponding to 5 to 20
mg/kg/day, preferably in the range of 10 to 100 mg/kg/day in divided dosages,
e.g. two, three or four times a day. They are administered in dosage~units
containing e.g. 175, 350, 500 and 1000 mg of the compounds.
Examples of preferred compounds of the invention are given in Tables
10 1-5. The designations Me and Et in the tables mean methyl and ethyl,
respectively.
Table I
Rl R2 R3
ethyl ethyl CH~Me)OCOMe
propyl propyl "-
ethyl isopropyl "-
isopropyl isopropyl "-
methyl n.butyl "-
ethyl t.butyl "-
n.heptyl n!heptyl "-
methyl methyl "-
RlR2N- R3
pyrrolidyl-l CH~Me)OCOMe
2-methylpiperidyl-1 "-
3-methylpiperidyl-1 "-
4-methylpiperidyl-1 "-
2, 6-dimethylp,iperidyl - l "-
hexahydro-lH-azepin-l-yl "-
hexahydro-lH-azepin-l-yl "-
hexahydro-lC2H~-azocinyl CH(Me)OCOMe
1,2,3,4-tetrahydroisoquinolyl-2 "-
4-methylpiperazinyl~
morfolinyl~4 "-
~Table 2 _ _ 3
Rl R2 R
- 4 -

~s~o
ethyl ethyl ~HCEt)OCOMe
propyl propyl "-
ethyl isopropyl "-
isopropyl isopropyl "-
methyl n.butyl "-
ethyl t.butyl "-
n.heptyl n.heptyl "-
methyl methyl "-
RlR2N- - ~ R3
pyrrolidyl-l CH(Et)OCOMe
2-methylpiperidyl-1 "-
3-methylpiperidyl-1 "-
4-methylpiperidyl-1 "-
2,6-dimethylpiperidyl-1 "-
hexahydro-lH-azepin-l-yl "-
hexahydro-lH-azepin-l-yl "-
hexahydro-lC2H)-azocinyl "-
1,2,3,4-tetrahydroisoquinolyl-2 "-
4-methylpiperizinyl-1 "-
morfolinyl-4 "-
Table 3 2 3
Rl R R
ethyl ethyl~ CH20C0OEt
propyl propyl "-
ethyl isopropyl "-
isopropyl isopropyl "-
methyl n.butyl "-
ethyl t.butyl "-
n.heptyl n.heptyl "-
methyl methyl "-
RlR N- R3-
~ CH OCOOEt
pyrrolldyl-l 2
2-methylpiperidyl^l ''-
3-methylpiperidyl-1
4-methylpiperidyl-1 "_
2,6-di~ethylpipe~idyl-1 "-
hex~hydro-IH~azepin-l-yl "-
hexahydro-lH-azepin-l-yl "-
hexahydro-1(2H)-azocinyl "-
- 5 ~
r

~.~s~ o
1,2,3,4-tetrahydrosioquinolyl-2 "-
4-methylpiperazinyl-1 "-
morfolinyl-4 "-
Table 4 - 3
Rl R2 R
ethyl ethyl CH(Me)OCOOEt
propyl propyl "-
ethyl isopropyl "-
isopropyl isopropyl "-
methyl n.butyl "-
ethyl t.butyl CH ~le)OCOOEt
n,heptyl n.heptyl "-
methyl methyl ~-
R R N- R
pyrrolidyl-l CH~Me)OCOOEt
2`methylpiperidyl-1 "-
3-methylpiperidyl-1 "-
4-methylpiperidyl-1 "-
G 2,6-dimethylpiperidyl-1 "-
llv~lly~lru-lH-~
l.vxal.~ v~
hexahydro-1(2H)-azocinyl "-
1,2,3,4-tetrahydroisoquinolyl-2 "-
4-methylpiperazinyl-1 "-
morfolinyl-4 "-
Table 5
R2 R3
ethyl ethyl CH20COOpropyl
propyl propyl "-
ethyl isopropyl "-
isopropyl isopropyl CH(Me)OCOO-propyl
methyl n.butyl "-
ethyl t.butyl "
- 6 -

~ ~5~?,0
n.heptyl n.heptyl CH~Me)OCOOn-hexyl
methyl methyl CHtMe)OCOOCH2CH2NH2
RlR2~1 R3
._ - - - -
pyrrolidyl-l CH(Me)OCOCH2CH2NHMe
2-met:hylpiperidyl-1 " ~
3-methylpiperidyl-1 " ~
4-methylpiperidyl-1 CH2OCOOCH2CH2NEt2
2,6-dimethylpiperidyl-1 " ~
hexahydro-lH-azepin-l-yl "~ ;~
hexahydro-lH-azepin-l-yl CH2OCOOCH2CH2NH2
hexahydro-1~2H)-azocinyl " ~
1,2,3,4-tetrahydroisoquinolyl-2 CH2OCOOCH2CH2NHMe
4-methylpiperazinyl-1 "~
morfolinyl-4 "~
The compounds of the invention are prepared by different methods ~ --
such as by reacting a reactive derivative of an amide OT thioamide of the
formula III
Rl
N - CH = R6 III
R2~
where Rl and R2 are as defined above and R6 is O or S, with an ester of 6-
aminopenicillanic acid with the formula IV
S \ / CH3
H N-CH - CH C IV
2 1 ¦ ¦ \ CH3 3
CO - N CH - COOR
where R3 is as defined above.
The reactive derivatives of the amides or thioamides of
formula III are acid amide halogenides or dialkylsulphate complexes of acid
b~;n~
amides or acid amide acetals. The former two reagents may be 4~usiuuul accord-
ing to known methods by treatment of compounds of the formula III with halo-
genating agents like phosgeneJ oxalyldichloride, thionyl chloride or thionyl
omide or with a dialkylsulphate like dimethyl sulphate. The reactions with
. ~ _ 7 _

i(~S14~0
the halogenating agents are performed in inert dry organic solvents like
diethylether, toluene, benzene, chloroform or carbon tetrachloride. The
halogenides are usuall~ obtained as
! :
i~ '
.1~
~ - 7a -
:
~`i ~. ., . ' '' ' '
.: .. ': . -: .: . :. . . . . ' .

1~51~'~0
hygroscopic precipitates.
~reatment of the acid amide dialkylsulphate complexes with strong
bases, e.g. sodium methoxide, convert them into acid amide acetals of the
formula (V)
2,",N - CH(OR )2 V
where R7 is a lower alkyl group originating from the dialkylsulphate, which
also can be reacted with the esters of 6-aminopenicillanic acid with the
formula IV to give the compounds of the invention.
The esters of 6-aminopenicillanic acid with the general structure
IV may be prepared by treatment of 6-APA with compounds R3-Y , where R3 has
the same meaning as above and Y is halogen or a functionally equivalent
group capable of reacting with a carboxy group under formation of an ester
linkage, such as an organic sulphonic acid residue. The reaction is pref-
erably performed in organic solvents like dimethylformamide, dimethyl-
~ulphoxide or hexamethylphosphoramide.
Alternatively 6-acylaminopenicillanic acid~ with acyl groups that
can be removed without destruction of the penicillin ring system are treated
with R3-Y wherein R3 and Y have the meaning specified above, to give esters
1 of the 6-acylamino penicillanic acids from which the acyl groups then are re-
t 20 moved to give the esters of 6-aminopenicillanic acid of the formula III. A
I ~ preferred method consists of reacting a salt, e.g. the sodium, potassium or
tetraalkylammonium salt of 6-phenylacetamido penicillanic acid(benzyl-
penicillin) with R3-Y in an organic solvent like chloroform, methylene-
I :~
chloride, acetone, dimethylformamide, dimethylsulphoxide or hexamethyl-
ph4sphoramide or in a mixture of an organic solvent and water, e.g. aqueous
acetone or dioxane to give the corresponding ester of benzylpenicillin. The
phenylacetyl side chain is then removed according to the method described
1:
in United States patent No. 3,697,515 or South African Patent publication
67/2g27 by treatment with phosphorous pentachloride in presence of a
tertiary oreanic base to give an imino chloride which is reacted with an
.
~ - 8 -
.'~

~Si~O
alcohol like propanol to give the corresponding imino ether which is hydrolyzed
by add:it.ion of water or alcoholized by addition of alcohol, to give the ester
III. Alternatively the phenylacetyl side chain may be removed by enzymatic
hydrolysis using an E.coli acylase according to the method described in
;
- 8a -
r~;,.
. .

105~ 0
French Patent 1 576 027
In still another method N-protected 6-aminopenicillanic acids are
reacted with R3-Yl to give the corresponding ester from which the protecting
groups are removed to give the compounds of the general formula IV.
Examples of protecting groups which can be used are the benzyloxycarbonyl
group which is removed by catalytic hydrogenation, the 0-nitro-phenyl-
sulphenyl group which can be removed by treatment with nucleophilic agents
at acid pH (Jap. Pat. 505 176), and the trityl group which can be removed
by mild acid hydrolysis.
lD Alternative methods can be used for the preparation of the
compounds of the invention. 6-formamidopenicillanic acid may be converted
into esters of the formula (VI)
/ \ / 3
HCONHCH - CR ¦ \ CH3 VI
CO - N CH - COOR
where R3 is as defined above by reaction with R3Y under the conditions
previously indicated. Treatment of an ester of 6-aminopenicillanic acid,
i.e. a compound of formula IV,with an l,l-dihalogendimethyl ether, e.g.
l-dichlorodimethyl ether, in presence of a tertiary organic base, gives
a reactive derivative of the compound of formula VI which reactive
derivative reacts with an amine of the formula (VII):
1. ~ 1
R ~ NH VII
R2 "'
where R and R are as defined a~ove, to give the compound of formula I.
~ A third method consists of reacting compounds of formula II,
1 suitable in form of a salt, e~gO a sodium, potassium, calcium,
triethylammoni~m or tetraalkylammonium salt, with a compound R3 ~ wherein
R and Y have the meaning specified above to give the compounds of the
~ _ 9 _
;
.. . . .

~C~514'~
invention with the general formula I. The reaction s suitably performed
in organic solvents like chloroform, methylenechloride, acetone,
dimethylformamide~ dimethylsulphoxide or hexamethylphosphoramide or in
aqueous organic solvents like aqueous dioxane.
H - 9a -

1(~51~'~0
As described above the starting material may be in the form of
a salt, for instance a sodium, potassium, calcium or trialkylammonium salt,
in some of the ways for the preparation of the compounds of the invention.
In addition, tetraalkylammonium salts and other analogues salts
such as salts where the cation has the formula
AlA2A3A4N 1~)
in which formula A is selected from the group consisting of straight
and branched alkyl groups containing from 3 to 6 carbon atoms, substituted
and unsubstituted aryl, and substituted and unsubstituted aralkyl, and
wherein A , A3 and A , which are the same or different, are selected from
the group consisting of straight and branched alkyl groups containing from
1 to 6 carbon atoms, provided that A , A3 and A are alkyl with 3-6 carbon
atoms when A is alkyl, may be used.
Illustrative examples of suitable combinations of A , A , A3
and A in the quaternary ammonium ion A1A2A3A4N ~ are given below:
Table I. Examples of suitable combinations of the radicals
A -A4 in the AlA2A3A4N ~ ion
A1 A2 A3 A4
n-propyl n-propyl n-propyl n-propyl
i-propyl i-propyl i-propyl i-propyl
n-butyl n-butyl n-butyl n-butyl
i-butyl i-butyl i-butyl i-butyl
n-pentyl n-pentyl n-pentyl n-pentyl
n-hexyl n-hexyl n-hexyl n-hexyl
phenyl methyl methyl methyl
phenyl ethyl ethyl ethyl
p-tolyl ethyl ethyl ethyl
p-chlorophenyl ethyl ethyl ethyl
When the radicals A -A all are different the resulting ion
:
contains an asymmetric centre and may occur in two enantiomeric
forms. Epimeric forms can occur if A , A , A3 andtor A contain one
or more asymmetric carbon atoms.
-- 10 --
i , . . . . .
.. ..

~5~1~ZO
Examples of quaternary ammonium ions containing an asymmetric
centre are given in Table II below:
Table II - Examples of quaternary ammonium ion AlA2A3A4N ~3
containing an asymmetric centre
Al A2 A3 A4
benzyl n-propyl i-propyl n-butyl
benzyl n-propyl i-propyl sec.butyl
benzyl n-propyl n-butyl sec.butyl
n-propyl n-propyl n butyl sec.butyl
n-propyl n-propyl n-propyl sec.butyl
n-propyl n-propyl n-propyl sec.pentyl
n-propyl n-propyl n-propyl sec.hexyl
n-propyl n-propyl n.butyl sec.hexyl
-
The use as describéd above of a quaternary salt form of the start-
ing material for the preparation of the compounds of this inyention is not
previously described in the literature pertaining to this technical field. In
this method the preferred cation is the tetraalkylammonium ion, particularly
the tetrabutylammonium ion. The preferred solvents are chloroform, methylene-
chloride and acetone.
The quaternary ammonium salt form of the above described starting
material may be prepared by reacting the starting material in question with a
quaternary ammonium salt of the formula
AlA2A3A4N ~ B Q
wherein Al, A2, A3 and A4 have the meanings specified above and B is a suitable
anion such as HS04 ~ , CL ~ or CH3COO Q to the formation of a quaternary salt
of the starting material.
The salts of the formula above which contains B as the anion may
be prepared in known manner analogous as described in for instance Belgian
patent 751,791. The anion B ~3 is in the preferred embodiment HS04 ~3 .
The following examples will further illustrate the invention.
- 11 -

1~51'~0
Example 1 illustrates the preparation of l'-ethoxycarbonyloxy
ethyl-6-(hexahydro-lH-azepin-l-yl)methyleneamino penicillanate which is not
within the claims of this application but is the subject of the divisional
application mentioned above. It will readily be inferred that compounds with-
in the claims of this application can be made by the procedures illustrated
in Example 1. Likewise in Example 8 formulations (b), (g) and (i) contain
the compound of the divisional application but it will be appreciated that
compounds within the claims of this application could be substituted for that
compound in the formulations shown.
- lla -
P~.
. , .

1~514~0
Example 1. l-Ethoxycarbonyloxy-ethyl 6-(hexahydro-lH-azepin-l-yl)-methylene-
amino penicillanate
,~ef~
l-Hexamethyleneiminocarboxaldehyde-dimcth~ t~G (3.1 g) in
chloroform ~50 ml) was added dropwise at -30C to a solution of l-ethoxycar-
bonyloxy-ethyl 6-amino-penicillanate (5 g) and triethylamine Cl.9 ml) in
chloroform (150 ml) during 15 minutes. Then the temperature is allowed to
rise to 0 during 30 minutes and the mixture is stirred at O for another 60
minutes. Water (120 ml) is added and stirring is continued for 10 minutes.
The water phase is separated and the organic layer is washed with water and
stripped. The residue (5 g) showed a strong IR-absorption band at 1775 cm 1
(~-lactam ring).
Incubation of the product with human serum at 37C was found to
cause a rapid formation of 6-(hexahydro-lH-azepin-l-yl)-methyleneamino pen-
icillanic acid.
The l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate was prepared
as described in Canadian Patent No. 960,211.
Example 2
By substituting the l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate
in example 1 with l-acetoxy-ethyl 6-aminopenicillanate and ethoxycarbonyloxy-
methyl 6-amino-penicillanate, ~-acetoxy-ethyl and ethoxycarbonyloxymethyl
6-~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanates respectively were
', obtained. The compounds showed strong ~-lactam absorption in IR at 1775 cm 1
and were rapdily hydroly~ed by human serum to the corresponding penicillanic
acids.
Example 3 l-Ethoxycarbonyloxyet,hyl 6-,~piperidyl-1-)-methyleneaminopenicillanate
To phosphorus pentachloride ~1.7 g, 0.008 mole) and quinoline (1.8
g, 0.016 mole~ in dry methylene chloride (50 ml~ l-ethoxycarbonyloxyethyl ben-
~ylpenicillanate C3.2 g, 0.007 mole) was added with stirring and chilling to
-40C, the reaction was kept in dry iner~ gas Cargon~. After 1 hour dry me-
thanol C2.24 g) was added dropwise and the temperature was adjustsd to -30.
~ - 12 -

~Si4'20
After 1 hour brine ClS ml) was dropped to the solution while the temperature
was allowed to rise to 0. After 15 min. the organic phase was dried and
evaporated in vacuo, the residue was triturated with petroleum
- 12a -
~, .

1(~51'~'~0
ether and dried yielding a crystalline mass (2.8 g, 100%), IR 1790 cm 1 (~_
lactam). To a solution of this material (2.8 g, 0.007 mole) and triethyl-
amine (o.84 ml, o.oo6 mole) in chloroform (50 ml) at -50 - -60 N-
piperidylchloroformiminiumchloride (1.1 g, o.oo6 mole) in chloroform (20 ml)
was added dropwise. The mixture was kept under dry argon for 1.5 h during
which time the temperature rose to 0 . The solvent was removed in vacuo at
40 and the residue was slurried with dry acetone (100 ml) and filtered.
The flltrate was concentrated in vacuo and the remaining oil was triturated
with petroleum ether until crystallisation, yield 1.2 g, IR-absorption 1760
cm (~-lactam), NMR: ringlet at 480 cps (methyleneimino), multiplet at 320
cps (5- and 6`position of penicillin nucleus).
Example 4
l'-Acetoxyethyl 6-(piperidyl-1)-meth~leneamino~enicillanate was
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
prepared as described in Example 3 from l'-acetoxyethyl benzylpenicillinate
(2.94 g, 0.007 mole) and N-piperidylchloroformiminiumchloride (1.1 g, o.oo6
mole) yielding a half crystalline mass. IR-absorption at 1760 cm 1 (~-lactam).
Example 5
Ethoxy_a b_n~loxymethyl 6-(hexahyd_o_lH-_z~p_n-l-yl)_methylene_
amin_E~I c.LIanate was prepared as described in Example 3 from ethoxy-
carbonyloxymethyl benzylpenicillinate (3. g, mole) and hexahydro-lH-azepin-l-
ylchloroformiminium chloride (1.15 g, o,oo6 mole) yielding an oil; IR-
absorption 1760 cm (~-lactam).
ExamPle 6
Phenox~carbonylo~ymethyl 6-(ethy_-isop_o~yl)-met~ylene~m_n~p_n_c_l-
la_ate was prepared as described in Example 3 from phenoxycarbonyloxymethyl
benzylpenicillinate (3.4 g, 0,007 mole) and N-ethyl-N-isopropylchloroformim-
inium chloride (1.02 g, o.oo6 mole) yielding an oily product; IR-absorption
1775 cm 1 (~-lactam).
Example 7
_h_n_xycarbonyloxyme_hyl_ 6-(N,N-di - e_hyl_-methyleneaminopenicil-
_anate was prepared as described in Example 3 from phenoxycarbonyloxymethyl
benzylpenicillinate (3.4 g, 0.007 mole) and N,N-dimethylchloroformiminium
chloride (0.77 g, o.oo6 mole) yielding a half crystalline mass; IR-absorption
1775 cm 1 (~-la-ctam).
- 13 -

' ' lQs~ o
Example 8. Pharmaceutical formulations
For preparation of tablets the following compositions were
made:
a) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)-
-methyleneamino penicillanate 325 mg
Starch 100 mg
Magnesium stearate lO mg
b) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-
-azepin-l-(yl)-methyleneamino penicillanate 350 mg
Starch 100 mg
Magnesium stearate 10 mg
c) Ethoxycarbonyloxymethyl 6-hexahydro-lH-
azepin-l-(yl)-methyleneamino penicillanate 350 mg
Calcium carbonate 100 mg
Magnesium stearate lO mg
d) 1'-Ethoxycarbonyloxyethyl 6-(piperidyl-1)-
-methyleneamino-penicillanate 350 mg
Lactose lO0 mg
Magnesium stearate 10 mg
~ ~ ~20 e) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene-
: amino-penicillanate 300 mg
!~ Calcium carbonate lO0 mg
~:: Lactose lO0 mg
Magnesium stearate 10 mg
: For filling in capsules the following formulations were made:
f) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)-
methyleneamino penicillanate 350 mg
Magnesium stearate 5 mg
gj l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-azepin-l-
:30 -(yl)-methyleneamino penicillanate350 mg
Lactose 40 mg
Magnesium stearate 5 mg
~;~ - 14 -
'
,
.. . . .. , , - -

11~5~4;~0
For oral suspensions the following formulations were prepared:
h) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene~mino
penicillanate 35 mg
Aluminium monostearate 50 mg
Tween - 80 ~ 1.2 mg
Peanut oil ad 1000 mg
i) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-
azepin-l-(yl)-methyleneamino penicillanate 36 g
Sodium benzoate o.48 g
Sodium chloride 0-75 g
Flavouring agents 4.7 g
Aerosil ~ 0.3 g
Antifoam ~ o.o375 g
Alkali salts of polysaccharide sulphates 4.0 g
Sodium saccharinate 0.4 g
Sorbitol ad 100 g

l(~S14~0
SUPPLEMENTARY DISCLOSURE
Example 9 Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~j(hexahydro-lH-azepin-
l-yl)-methyleneaminopenicillanate hydrochloride
A. Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~-amino~enicillanate
hydrochloride used as starting material
A solution of l'(S)-ethoxycarbonyloxyethyl 6-phenylacetamido peni-
cillanate (7.4 g, 0.016 mole) in 10 ml dry ethanol-free chloroform was added
to a stirred mixture of phosphorus pentachloride (3.8 g, 0.018 mole) and
quinoline (4.8 g, 0.037 mole) in 25 ml dry ethanol-free chloroform at -20C
under dry nitrogen. After stirring at this temperature for l h, the solution
was cooled to -30C and dry propanol (12 ml) was added during 20 mins. The
temperature was allowed to rise to -15C during 30 mins, then cold brine
(25 ml) was added with vigorous stirring while the temperature rose to -50C.
The reaction mixture was poured into 50 ~1 ice-cold ligroin and stirred for
15 mins, then a further 55 ml ice-cold ligroin were added and the mixture
stirred for a further 10 mins. The mixture was then allowed to separate and
the oil-water phase collected and extracted with 30 ml chloroform. The chloro-
form phase was dried at 0C over sodium sulphate. lR (CHC13) showed ~-lactam
(1790 cm~l) and ester (1790 cm~l). NMR (CDCl3): C(6)H, lH, d at 5.68 ppm
(J=4.0 Hz); C(s)H, lH, d at 5.20 ppm (J=4.0 Hz).
B. l~(S)-Ethoxycarbonyloxyethyl 6~-(hexahydro-lH-azepin-l-yl)-methyl-
ideneaminopenicillanate hydrochloride
To the above-described chloroform solution of l'(S)-ethoxycarbonyl-
~;~ oxyethyl 6~-aminopenicillanate hydrochloride cooled to 10C, triethylamine
(5.80 ml, 0.042 mole) was added with stirring. The temperature was allowed
to rise to -25C and then a solution of hexahydro-lH-azepin-l-ylchloroform-
iminium chloride (3.79 g, 0.021 mole) in 10 ml dry ethanol-free chloroform
was added dropwise. The mixture was then stirred at 0C for 30 mins. After
removal of the solvent u~der reduced pressure the resulting residue was
~30 slurried with dry acetone (50 ml) and filtered. The filtrate was stripped
:~ F~
-- /6 --

1~514~0
of solvent and leached with petroleum ether and the syrupy residue dissolved
by stirring with 10 ml 2-pentanon. The solution was kept at ~5C overnight
whereupon the crude product crystallized and was collected by filtration.
i The,crude product was dissolved in methylene chloride (12 ml) and washed with
cold saturated brine (2xlS ml). After drying the organic phase over sodium
sulphate, the solvent was removed under reduced pressure and the resulting
residue slurried with dry acetone (S ml) affording the analytically pure
crystalline product, m.p. 147-149C (decomposition). [~]D = +163.5 (c=l;
96 % ethanol). lR (KBr): 1795 cm~l (~)-lactam car~onyl); 1760 cm~l (ester
' 10 carbonyl); 1675 cm~l (-CH=NH-). ''
¦ A proton NMR spectrum of the product showed only one signal for
,~ the C-3 proton indicating the presence of only one stereoisomer. This was
confirmed by a carbon-13 NMR spectrum in CDC13 since only one signal was seen
for the 2~.-methyl carbon at 29.44 ppm (from TMS) whereas a mixture of the two
, stereoisomers gave signals for this carbon at 29.51 and 30.50 ppm.
,, Found: C 50.21; H 6.62; C1 7.55; N 8.89; S 6.56; Calc. for
' C20~32C1N3C69~ CSC.25; ~ 6,75; ol 7.42; N 5.79; S 6.71.
t
1 ~
'
'j
F :`
~ C -/7-
( ~
,
!, ~ ` ` `

1(~514;~0
MMR (D20): -CH2CH3 3 H t at 1.27 ppm (J=7.O HZ)
-OCHO-
CH3
C(2)(CH3)217 H m at 1.4-2.1 ppm
/CH2 CH2
~H2'CH2
- c~
N 4 H m at 3.4-3.9 ppm
,CH2
_OCH2CH3 2 H q at 4.25 ppm (J=7.0 Hz)
C(3)H 1 H s at 4.65 ppm
C(5)H 1 H d at 5.56 ppm 1J=4.0 Hz)
.
C(6)H 1 H d at 5.64 ppm (J=4.0 Hz)
-OCH- 1 H q at 6.79 ppm (J=5.5 Hz)
CH3
i: +
N-CH=N- 1 H s, at 8.05 ppm
~ H broad
.~
,~ -
1 ~ :
f ~
F
'~'!,``~ G - J~~
,. ~
~ . ~
..