Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The present invention relates to mixtures ofamidino-
penicillanie acids and penicillins obtainable from penicillin
esters and pharmaceutieally acceptable salts thereof.
Canadian application No, 267,544 filed December 9, 1976
Canadian Patent No. 1,020,158 there are disclosed and claimed
penicillin esters have the general formula I:
~ R ~ ~C- - C / \ ~ 3
.': O=C ~ C~
C-~
~3co~ ~ S C1~3 O
Cll ~ C~2
O~ C~-l C-/
, O ,.
;,
in which Rl and R2 represent an alkyl radical having from 1 to 6
carbon atoms, a eycloalkyl or cycloalkylalkyl radical the cyclo-
:
alkyl part having from 3 to 10 earbon atoms, or Rl and R2 to-
` gether with the nitorgen atom represent a heterocyclic ring with
from 4 to 8 carbon atoms. In particular, Rl and R2 which may be
the same or different represent e.g. a methyl, ethyl, propyl,
isopropyl, n-butyl, see.butyl, tert.butyl, one of the isomerie
pentyl or hexyl radieal, a eyelopentyl, cyelohexyl, 1 adamantyl,
l-bicyclo (2.2 2)-
.
~ -
:
:
2 -
octyl, cyclopentenyl and cyclohexenyl, cyclopentylrrlethyl,
cycLohexylmethyl, cyclopentenylethyl~ cyclohexenylmethyl
etc., or ~1 and R2 when taken together with the nitrogen
atom represent heterocyclic radicals having flom 4 to ~
carbon atoms and optionally containing other hetero atoms
in the ring, such as S, 0 or N, forming more or less
hydrogenatecl ring systems e.g. piperidyl, morpholinvl,
hexahydro-lH-azepin-l-yl; or hexahydro-1(2H~-azocinnyl.
The radlcals Rl and R2 may be further substituted with
halogen atoms, an alkyl, hydroxy3 alkoxy, alkylthio group,
an acyl group, a carboxy, carbalkoxy, carbamyl, carbamido,
cyano or sulfonyl group, an amino- or substituted amino
. .
; group.
; R~ represents radicals known from natural, biosynthetic
: .
and semisynthetic penicillins. Such radicals are e.g.
benzyl, phenoxymethyl, 2,6 dimethoxyphenyl, a-azidoheIIzyl~
;
a-aminobenzyl, -carboxybenzyl, ~-phenoxyethylg a-phenoxy-
propyl, 3-phenyl-5-methyl-4-isoxazolyl, 3-(2-chlorophenyl)-
- 5-methyl-4-isoxazolyl, 3-(2,6-dichlorophenyl)-5-^methyl-
4-isoxazolyl, 3-(2-chloro-6-fluorophenyl)-5-methyl-
4-isoxazolyl, 2-ethoxy-1-naphtyl, 2-thienylmethyl,
3-thienylmethyl and ~-(3-guanyl-1-ureido)-ben~yl.
:,
.:
~ 2a
'
. .
-
The salts of the new compounds are salts with inorganic
or organic pharmaceutically acceptable acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric
acid, citric acid, fumaric acid, maleic acid, p-(N,N-dipropyl-
sulfamyl)-benzoic acid and the like acids.
~ he~ Rl, R2 or R3 contain asy~metric carbon atoms the
compounds of the lnvention will exist in different diastereoiso-
meric forms and the invention comprises all of these forms as well
:
as mixtures thereof. The form in which the compounds are obtain
depends on which enantiomer of the starting materials and which
method is used to make the compounds. The mixtures of the
diastereoisomers may be separated by fractional crystallization
or other known methods.
In contrast to the amidinopenicillanic acids and some
of the free penicillins which form therein the compounds of the
invention are efficiently absorbed from the gastro-intestinal tract
and after the absorption they are rapidly transformed into the
corresponding free penicillins and amidinopenicillanic acids,
either spontaneously or under the influence of enzymes present
in the body. Thus, the esters of the present invention have the
advantage over admixtures of the compounds forming the esters
; which mixtures as hereinafter stated have a synergistic antibiotic
effect in the body in being more rapidly and efficiently absorbed
by the body.
,
By oral administration the esters of the invention of .
. the co-pending application give rise to high concentrations of
, the corresponding free penicillins and amidinopenicillanic acids
; in blood and tissues due to efficient a~sorption comhined with
- rapid hydrolysis in the organism, whereby a broad-spectrum
infection can be combated, ~ue to the fact that the amidino-
~; penicillins possess strong antibacterial effect especially on
:, gramnegative bacteria.
.
; It has also been found 'hat by the simultaneous high
concentrations of these two types of antibiotics a .synergistic
:" .
~ effect is obtained (for instance by administration of the com-
..,.,:. ~
~,~ pound of formula I in which RlR2N- stands for a hexamethylene-
~`~ imine radical and R3 is benzyl).
. ,
According to the present invention therefore there is
provided a composition having synergistic physiological activity
which comprises a compound of the formula
H H
~ O : ,
r . R - C-NH ~ S
. \ "CH3
.~, 20 O~ , ~ CH3
~ - COOH
- in which R3 represents radicals from known penicillins, and a
.^` compound of the formula
.' H H
.~ R ~
N~H =N ~ CH3
COOH
in which each of Rl and R2 is an alkyl group or Rl and R2
together with the nitrogen atom represent a heterocyclic ring with
: from 5 to 7 carbon atoms in the ring.
~he present invention also provides a method of preparing
. .
. -- 4
:: -
- ~ .
. .
h~ s~l~'J~:3
.-~ a composition having synergistic phy~iolo~ical activity which
comprises mixin~ a compound of the ~ormula
H
O
R3-C-NH ~ C~3
O ~ C~3
COOH
in which R3 represents radicals from known penicillins, and a
compound of the formula
H H
10,,_~N-CH=N ~
'~. O
. - COOH
in which each of Rl- and R2 is an alkyl group or Rl and R2
together with the nitrogen a~om represent a heterocyclic ring
with from S to 7 carbon atoms in the ring.
According to a preferred embodiment of the present
invention there is provided a composition having synergistic
physiological activity which comprises a compound of the formula
O H
. 11 1 1
COOH
in which R3 represents a radical selected from the group consisting
of benzyl~phenoxymethyl ana 3-~-chlorphenyl)-~-methyl-4-iso~a-
zolyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-S isoxazolyl,
D(-)- ~-azidobenzyl and Vl~ aminobenzyl and a compound of the
formula
;
.
- 4a -
.
` Rl H H
\ N - CH = N ~ ~ CH3
N ~ CH3
-. COOH
~- in which each of Rl and R2 is an alkyl group or Rl and R2 to-
.~ gether with the nitrogen atom represent a heterocyclic ring with
,-` from 5 to 7 carbon atoms in the ring.
; According to another embodiment of the present invention
.. 10 there is provided a composition having synergistic physiological
. ,.
activity which comprises a compound of the formula
R3-C-NH~ < 3
o C~3
.
~:' COOH
, in which R3 represents a radical selected from the group con-
sisting of benzyl, phenoxymethyl and 3-t0-chlorophenyl)-S-
:' methyl-4-isoxazolyl, and a compound of the formula
: 20 R H H
:" 1 , j ~
CH = N~CH3
. , COOH
in which each of Rl and R2 is an alkyl group or Rl and R2 to-
gether with the nitrogen atom represents a heterocyclic ring with
from ~ to 7 carbon atoms in the ~ing.
~ ccording to a further embodiment of the pr~sent invention
there is provided a composition ha~ing synergistic physiological
.
activity which comprises a compound of the formula
." ' .
.~, .
: . . - 4~ -
:
.: .
s~
CO-NH _ ~ S CH3
CH3
- N
~ O COOH
:~ in which R3 represents a radical selected from the group consisting
~- of benzyl, phenoxymethyl, 3-(2'-chloro-6'-fluorophenyl)-5-
methyl-4-isoxazOlylr D(-)- a-azidoben~yl, D(~ aminobenzyl and
3-(0-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the
. 10 formula
1 H H
N-CH=N ~ CH3
O COOH
in which each of Rl and R2 is a straight or branched alkyl radical
having from 1 to 4 carbon atoms, or Rl and R2 togehter with the
nitrogen atom represent a heterocyclic ring with from 4 to 8
carbon atoms in the ring.
The compounds of formula (I) are well tolerated com-
pounds which are administered in clinical practice either as such
or, preferably, in the form of one of their salts mixed with
carriers and/or auxiliary agents and in any suitable form of
. pharmaceutical presentation for oral use, such as tablets, pills
or dragees, or can be filled in medical containers such as
capsules, or as far as suspensions are concerned, filled into
bottles. Pharmaceutical organic or inorganic, solid or liquid
:~ carriers suitable for oral administration can
.~'''' , .
,
.;~ ,
: . - 4c.-
,''' ' ' , .
'` ~
be used ~o make up the composi.tion~ Gclatine,
lactoce, c,tarc1~ agnesium stc~aL~t~ t~lc, vege
table and anirncll fats and oils, gum, polyalkyl.elle
;~' glycol 9 or other Icno~l carricrs for medicaments are
,:.-,~
all suitable as carriers~ The preferred salt of the
~ esters is the hydrochloride, but salts wit1-1 other
: inorganic or organic acids may b~ used as mentionecl
...
above. ~urthermore, the compositions may contain
~: other pharmaceutically active components which can
appropria~ely be administered together with the est~r
, in the treatment of infectious diseases.
'': In the first method according to the inventlon a salt of
penicillin of the general ~ormula II is reacted with
` ;~ a compound of the general formul~ III
,, .
ONH~H C/ S \c/C~l3
`CH3 t- YCH2Cl
O=C N CH
``~ COO:~
II III
.::
.:: in ~Ihich o~nulae R3 is as defined above, ~ is a cation
.~ ,,
: .
such as a potassi~1m, sodi~lm, amn)on3uln or triallcyl-
.; . ammonilllt1 ion ancl Y represents a bromine atom; an iodine''' .
:'
~ 5
' ''"
:
;.-
atom, an alkylsul.phonyl.oxy ~roup or an arylsulphonyloxy group,
.~ preferably in an inert or~anic solvent, e.g. dimeth~lformamide
`,t` or acetone, and at room temperature or at slightly el.evated
temperatures, whereby a compound of the general $ormula IV,
:1 in which R3 is as defined abo~e, is obtainea:
H H
R3-CON~C C ~ C< CH3
O=~ _ N _ CH IV
`-COOCH2Cl
~. The compounds of formula IV are then reacted with a salt
-. 10 of a compound of the general formula V:
H H
Rl N-CH=N~------C~ ~ 3 V
- C~H
'. "COOX
in which Rl, R2 and X are as defined above, at room temperature
or at slightl~ elevated temperatues, whereby a compound of formula
.I is obtained.
The compounds of formula V are disclosed in our Canadian
Patent No. 914,165 issued Nov. 7, 1972.
In a second method a compound of formula V is reacted
20 with a compoundofformula III - under conditions like those
. described for the reaction between II and III - to yield a new
:~ compound of the general formula VI:
- ,~
;"
'':
:.
.,.,~ - .
: - 6 -
.: , ,;j
~. . .~ .
~':
:
;~
R ~ H
~ CEl'-L~ ~ ~,S < C113 VI
; , O-=C~ CH
,................... `"COOC~2Cl
. .
~' in which ~1 and R2 are as deined above, 'rhese
compo~mds are new a~d being interestll~g int,erme-
'.' diates in the preparation o~ the cornpoul-ds of this
' invention~ they a7so consti~ute part of th~ inven-
~:' t,ion.
, , .
Reaction between a compound o~ orlnula II and a
compound of formula VI - under conditlons like those
' described above for the r~action between IV and V
. yields ~ compound of ~ormula I.
In a third me~hod a compound of orrnula VII:
: H H
"" ~4-~H ~ C / S \C<c~3
Cli3 VII
` 0-~ N C~
' " ~CO~)X
:-
: . .
~' in wllich X is as defined above and R4 represent,s a
,.,., hydrogen atom or a protect.ing group sucll as t,-rityl,
carbol)enzoxy or the like, is re~-lC~ed t~ith a compoun~
:
~ of ~he above formula IV ~o yi.eld a compo~nd of ti~e
.,.,- general formula VIII:
:
~ 7
.
, .
t3
.
:,
` R Ell~ ' ~S ~CH 3
O-C--N CH
--C-O VIII
H E~ O
~ CH
R CONH~, ' ,/S~ / 3 CH,
3 f--cl 3
O:C--N --CH
1~
O
in which R3 and R4 are as defined above. The reaction conditions
are similar to those described for the reaction between compounds
of formula IV and V. The compounds of formula VIII are described
in our Belgium Patent No. 764,699.
rn the case where R4 represents a hydrogen atom the
intermediates of formula VIII can be used directly in the next
step, and if R4 represents a protective group this is first re-
moved, e.g. by hydrogenation or hydrolysis.
In a next step the compounds of formula VIII (R4=H)
are reacted with a reactive derivative of an amide or a thioamide
of the general formula IX:
> N-CH=R5 IX
~':
,.~,
;"
-- 8 --
:
i.n ~.7l1iC~ <lnCi 1'2 hav~ thc~ e.l~L~ L~.~s ~t?l~inecl be:Eo-,-e, and
:. 1?~5 stands ~or O or S t:o yield ~ co~pou~ o~ ~or~ lLl I7
.~
Tl~e star~ materi.~1ls o.~ ~or;nula I~ c~Lrt~ knol~irl or
~- can l~e prepaL-e(l by 1net.hods Itnown ~rom gel~eral3~ xe~l
. tr~ bookSs.
~ The ami.des c.f forlllul.a XX can by wellw1cnowLL methods
be tr~rls~t~rt~d intt- reclctive der:ivatlves such as ~.?.cid
a~i(~e hali~1es, acid ami.tic~ cli.alkyl sulp~Late complc~es
or acid alllit~e acetals. The acid amide llalides used
are preferabl~?7 the chlorides or bromides~ and they
can be prcp.~red by t-ieating the amides with haloc,en~
ating a~ents. It is preferred to use halo~,enating
agents ~hich throughout the reaction form ~7aseous
: by~prod~cts, such as phocgene~ O~C~L1Y1 halides, or
: thionyl halides, but a1.so otllers may be ust-~d. Tlle rc~-
.' action can be performcd in ine7-t-.7 dry, oL-gani.c solvents7,
, .
e.g. ether or toluene, in which the amlcle halicle ilL
.' most cases wi].l be insoluble and frc?m wl-ich it can be
:.' i.sola~ed l)y fi1.t~rat:ion afte~r the reactioll is completed.
The acid aLIlidc ha].ide~s are hygroscopic and ratl-ler un-
' s~ablt-~ and are the~re~ore pre~'crably usecl i.n the n~xt
' ste~p withollt purification.
': The aci.c~ amide dial1cyl sulp11a~e complexts can ~e
:..................... prep~lred by tl-t-~ating tl-1e amic1es ~;t11 di.alkyl su7pllatc,
'.' preferab1.y dillltthy] sulphclte, unclcr ~i~e].l- kLlC.?~L~ condi~
tions. 13y trt-at..in~ t:hc~ acid anlidc ~-1i.al1cyl snlpll-lt:e
~ ~S~ 3
_ comp3cS~es ~it~ sodium lc~ er alcoi~:lat~s~ e,~,. sodium
metho~:Lcle, acicl alni~le c~cete,l.s of tlle general ~ormul.a
l~a:
:~ > N-C~I(OR6~2 IXa
~' < .
in ~7hich r~ and R~ have the meanin~s definecl a~ove
and ~6 is a lol~er alk~l group~ are forrned, l~hlch
acetals may also be usecl in the nex'. step.
I~n acid thioamide~ are usccl as starti.ng mate
- ri.als a reactive clerivative in form of an ~cid thio~
amide a]kyl hL~lide complex can l~e ~orm~d by treatmerli~
with allcyl. halides, e.g. 10l.7er~allcy]. iodi.deL~ This
reaction is wellkno~n frolrl the chernical literature.
The reaction conditions for the reciction bet~een
the anli.de deri.vative and thc cvmpound o:~ for~ula VIII
depend on the reaction component-s llse~ in t:he process,
.
~en acid ami.de acetals are used in the react.ion
with the compoul-lds of ~ormula VIII~ the reclction
. temperature dcpcrlds on the reaction componen~s. The
. reaction is performed in iner~ organic solvents~ for
instance cther.
en ~cid amide halides~ diC~Llkyl sulpl-c~te com-
p].e~es, or thioamlde al.kyl halide comple~.es ~re used,
- 10 -
.~
the re~.c~ion is also per~o-n-ed in iner~ or~anic s~L-
~e~ts, ~ich are dry and ~rcle f~o~ tr~ces a~ alcoh~ls,
pre~era~ly chloro~o~ , in ~ ich ~he r~c~ion CO!llpO~
nents are solul~le, but solvents ln ~hich the s~rting
; materials are insoluble, e.g. ether, may be used as
~ell. The reaction is perfor~ned under cooling and in
the presence of at least one equivalent Qf a tertiary
amine, for example trimethylamine, triethylamine, N,N
~; -diisopropylethylamine or N metl1ylmorpholine. In the
; case where one equivalent of the tert~amine is used,
the reaction product ~7ill be obtained as a salt ~1hen
an acid amide halide is used9 and as the ~ee esters
o ormula I ~^~hen the diallc~l sulphate complexes and
thioamlcle alkyl halide complexes are used.
The reaction time depends on the reactants, the
temperature and the solvents used in the process.
In another embodiment of the mcthod a compound o~
the above formula VI is reactecl with a compound of the. ,~.
above formula VII under the same conditions as de-
scribed above for the reaction between the colnpo~lnds
of formula IV and forrnula VII to yield a compound of
formula ~:
~l\ H H
R2 N CH N~; / S\ ~C1~3
O-C- --N--- -CH
. C,---O X
I~41-lN~ / \c/C'~
O C~ N~ CII
,()
C- O
in t.?l-ich Rl, ~2 ~nd P~L~ ave ~he above de~i.ned
meanings. In th~ cas~ hen I~4 is different fror,)
hydrogen t-his proteeting gJ10l~p h3s to be spl:it oLf
~hel-eater the re2.ction product of form~lla ~, (X~
is ac~rlated witl~ a ~eacti~e derjvative of an zci.d
R3 COOi~ in ~hich R3 is as above defined ~o yield
the compounds of the invention. This acylation
process i.s well Icno~n from the preparation of other
semi-s~nthet.ic penici].lins.
The invention will be further described in the
~ollowing Exam~3.es w}~ich are no~ to be construed as
l.imiting the inventionO
'~
, . . .
.'' ~
~ '
,
: . .
~..
'';
.
~' ~
E_r~ 1
- ~L(~Ie~;ahydro-~?~ azep~ y-L~-tnet~enearninol_pen~ n
. o~ ~e~:hyl ~ ?Y~
:
To a suspension of sodi-um ~(hexahydro-1~t-a7~epin
~ yl)~methyleneam.ino]-penicillanate (3.5 g.) in di
-~ methylrormamide (50 ml . ) was added chloromethyl ben7.yl
penici11ina~e ~3.8 ~,~ ). Ater stir~in~, a~ roor; ten~pe~-
.. ature for 6S hours the mixture was diluted with ethyl
acetate ~ ~00 ml . ) and washed with w~ter ( 3 x 25 ral . ) .
, .
The orga~ic phase ~i~as extracted w~th dilute hydrochlol ic.,
acid (p~l c 2.5). T~lè aqueous phase was separa~ed and
~:~ m~de alkaline by addi.ng sodium bicarbonate. The oil
which separatecl was t~ken up in ethyl acetate and Lhe
solution was dried and evapi~ratecl to clryness in vacuo
to yield the clesired compound as an amorphous powder,
."
The NI~-spectrum (CDC13) showed pealcs at ~ -- 1.47 (s),
1.65 (s), 1.58 (m), 3.37 (m), 3.63 ~s), 4.38 (s), 4040
, . (s), 5.08 Idd)l 5.4 - 5.8 (m~9 5,i37 (s), 6.20 (d)9 7.32
(s) and 7.5~ (d~ ppm. TMS was used as internal reference.
The I~-spectrum ~CHC13) sho-~ed st-f~ng ~ands at 1773,
1673 and 1.63C) cm l.
~ he starting material s used in the ~ove example
are prepar~d in the follo~ing rnanner:
- 13
.
.
6~~ f~ c~ ~f~ ?--rr~ rlc~mi~lc3l
- ~C~ i. c i. ~ c ~l ~f~ c~ ~r.~ t; ~ .
rl~ ri,f~-~t ~lellf~,,in~ rt~
~' was preparecl frorn tl~e ~ orlnylllf~amet1lyleneimine~dime~llyl
^ , sulfate complex ~y reaction Witll sodi Ulll Ir~etho~cide ac-
;,~ cvrc1in~ to t~e method of BredeLec1c et a3~ (Chc~m. 13er.
. ...
,-'~ lOl, 4l (l968)). The boiling point was ~3-.,4 C./12 min 1-1~,~
,.~ .
"~'
~- 6 I(~ YC O- a~ r~ r~ neamLnol
c~,]~anic a _ i,h~drate. A solution of the abo~e
mentioned acid amide acetal (4.l g.) in dry ether (`100
ml.) was slol~7ly added to a solu~ion of trirrlethylsi]yl
6-aminopenicillanate (6.8 g~) in ether (500 ml.) at
-30C. wit1-1 stirring. Tne terrlperature was raised to
0 within half an hour. Water (300 ml.) ~.7as adc1ed.
The stirring was continued for ten minutes ~7hereaIter
the aqueous phase was separated~ extracted with ether
and freczedried. The solid produc~ as crystalli~ed
from methanol-acetone. It meltcd with decompositi,on
f-rom 135 to 142C..
,
Sodium 6 I~he~a'n~vdro~ a~er)i~ vl)-lTeth~lene~rllin
~.el1l ci. ~- ]. c~tll~ ~-.e -
To a solution of 6~[(hexahyd-~o lh7 a~epin-l-yl)~inethyl-
en~amir.o~ Llicil,Jalllc acid dihydrate ~]3.3 ~.) Ir1 cli~
: .
:
~ '!4
s~
: '
Inethylfo~-rna~ni(le (L20 ml.) t~7as ac~decl socllum carbonate
: (3 7 g.). ~.~ter st7' rrin~ at rooln tempe~^ature or 1.()
: m:inu~es ~he c3esi~^ed compouncl crystalli.zed. The crys
tals ~iTere fil~ercd off and (re.Ltecl wi~h abs. ethanc~l
(110 ml. ) . Inor&clIlic mat~rial ~as separated by fll-
tra~ion and e~her (110 ml.) was added to the filtr~te
.- whereupon tlle de~ired sodium salt crystalli.~ed. The
~ crys~als ~ere ilterecl o~ ~ncl used in the next step
... without furtller purification.
.~
,hlo~^omethyl. ~_n 3._113 a te
.i,
To a suspension oE triethylammonium benzylpeni
cillin.7.te (~ ) ;.n d~methylfo~L~.Iir~ide (400 ~ a.s
added chLoroiodomethane (40 ml).
~fter st::irring o~rernighc the mixture was diluted
.. with ethyl acetate (].200 ml) ancl extracted ti7Lth water
(2 x 400 lnl), 2% aqueous sodium bicarbonat~ (1()0 nll)
and fin~lly v~ater (2 ~ 200 ml).
The organic phase was dried and evaporated ~n v~cu.
.~ to yield chlorornethyl benzyl.penicillinate as a darlc,
viscous oil, ~.7~icll could be used in the ne~;t step
without furtl-er purificativn.
.~ A s;lrnple of the crude ester t~as puri~ied by clry
columri cllron~atograp}ly on silic~ ~el (~luent : cycloi-exane-
. eth)~]. ~ce.ate 7:3) ancl the pure chlcromethyl ben ylp2ni-
~-: cilli.nate thus obta-ncd crystallize~ fJ:on) ether :
:
~-: petroLeu-,n el:her to yield cololI~less cr~stals ~it-h mOp.
92. - 93 C~
20. ~17g.8 (c - 1, C~C13)
: ,
The IR-spec~rum (ICBr) sho~ed stron bands at: 17$5
1770, 1655 1547, 1303, 1139, 111& ancl 712 cm 1.
The N~ spectrum (CDC13) showed signal.s at ~- 1..51
(s), 3.64- (s), 4.41 (s~, ~53 (d, Jc5), 5.68 (dd, J -. 5,
J = ~)~ S.69 (d, J - 6), 5.85 (d, J = 6), 6.2 (d, J C ~-9)~
~ and 7.35 (s) ppm. TMS was used as internal re-~crence.
:: -''''~~ ' '
;' '
Example 2
~ex~dro ~ a7~e~ l~me~,~ inol-l~C'lliC llarl-
etl~T1 benzy ~ cillinclte,. ~ ~r~ loric~.e.
. ~ solution of 6-~(heS~ahydro~ Aazepin-i yl)-methylene
aminoJ- penicillanoyloxyrnethyl benzy1penicillinate in
ethyl. acetate was extracted wi.th dilute hycIroclll.ori.c
acid (pH - 2.5). 'rI-Ie aqucous phase ~ s sc~-~arated
''''
~ lG
,;' -
'`."
;
ancl ree~e-dried to af~ord the desired compound as a
coloulles,s amorphous po~der,
~ pJe 3
ex~ o~ T,^clz( pI t~ met l~Tl~tlc~ i.no~nic~ n-
me ~ oY~r~net.. ~ L ~ e I
`
This compound was obtained as clescribed i.n l.xample 1
by using chloromethyl phenoxylr.etllylpenicillinate instead
of chloromet~yl ben~lpenic:il.li.nate.
: Tl-le l~r~ spectrum (CDC13) sho~ed peaks atJ- 1.51 (s),
1.53 (s), 1.60 (s), 1.$7 (s), 1.6 (m), 3.38 (m), 4~41 (s)s
;~ 4.50 (s~, 4.5S (s), 5.11(dd), 5.3 - 5.~ (r,l), 5.90 (s),
6.8 - 7.~ (m) and 7.~5 (d) ppm. T~S was used as internal
re~'erence .
Thc ll~-spectrurn (C~C13) showed strong bands at
17GS, 1.6~5 and 1625 cm L.
reparatiorl of tlle starting lriat:e~-i.al: ;
Chlrln~ Y~ ~Yrnc~ T~ .C`i l ] il~e
To a solution o~ pheno~ymethyl..penici.llin (70 g)
and tri.etllylalT~ e (29~4 ml ) in clilnetllyl~orl,l3~.licle (250 ml)
w~s added chloroioclolllethane (S0 ml), and t:he mixTttlre
: was stirr~cl ~or 3.5 hc)urs at roolTIT~emper~ltllre~ 1eTI
17 -
'
ihe mixt:~lrP~ as cliluied ~ hyl aCet-a~e (50C,7 ml) ~nd
et7.1er (5~)0 ml)~ ~iliered, and the ~i.lt~rate ~aslled ~ h
water (3 ~; 250 ml), 0.5 Al ~queous sodium bIcarbonc~te
(100 ml), and water (2 x 100 rnl~. The or~anic phase
~7as dricd a~cl ~vaporated i.n ~ac.uo to ~ield the crude
ester as a brownish gum, which could be used ~or the
next step t~ithout furtller puri.~ication. ..
Ex~e 4
lex~hyclro~ azeLin l-yl)-me~ ne~n_inol Denici -~7a
oylo~nlei-'nyl pheno~meihyl~qnicl _ina P h~-~ocllloricle.
A soluti.on of 6-[(hexahydro~ azepirl l-yl)-methylene-
amino]-penicillanoyloxymethyl phenoxymethylpenici.llinate
in ethyl ~cetate was extracted with dilute hydroc:l)loric
acid (pl-l - 2.5). The aqucous phase ~.as freeze-dricd to
af~ord the desi.recl compound as an amorpllous pol~der.
, . . .
-
., .
~ Examl)le 5
.' .':
~ .
;~"
_hloromot~h~l 6 r (he~a~ o .I-I-azeE~.n~l~ etl~ le_ ranll.nO ~~
penicill.]nate
_~.. . _
. ., ' .
. To a suspension of sociium 6~[(he~;ahyciro~ a~epin-].-y].J~
-~. metlly.l.eneamino~ penicillana~e (0.5 ~.) in dimcth~].form~rni(l~
....
: I
~ '
~ 4~9
(5 ml) ~as adc'lccl clllo70ioclor,~ethane ~1 ml.). A~te~
st~rrirls7 ~t roorn ~:emperatu-rc for 3.5 llours tl~e mlxtur~
w~s di3uted Wi~ll eth~l ac~atc (25 ml~ ~nd .a~hed ~ith
water (3 x 5 ml)~
The orgarlic phase was ~xtracted wi~h dilute hyclro-
clllol-ic acid (pl~2.5). The aqueous pll~se ~as sepc?rated
and made allcal:;ne by adding sodiun~ bicar~onate~ The oi
which separa~ccl r~7as taken up in ethyl acc~tate and t}~e
solution was dried and eva~oratecl to (Iryne~s in vacuo
to yield the desired compo~ln(l c'-l5 a ycllo~7 oil,
The Nl~ spcctrum (CDCl3) sho~7ed peaks at~ - 1.55(5~,
3..68 (i), 1.62 (m), 3.45 (rn), 4~42 (s), 5.20 (dcl),
5.52 ~c~), 5.Jo (d), 5.87 (d) and 7~66 (d) ppm~ T~S
was usecl as internal refe-rence.
E~am~_c G
_ (~ a~ dro-3l-~c~ pir~ Tl)-r~etl~1 eneamino_ ~ni ll~
~ _o~;ymetll~Tl b~n~ ~ ,c~ ateO
.'''
~;A solution ol chloromethyl G-[(hc~a~lydro~ azcpin l-yl)
methy1encamino J -~enicillanate (Q~l g) in climc~hylfor~amic~e
(2 ml) 7c~s stirrecl ~t room tcmp~r~t-lre ~Jitll potassi:~lm
ben~)~lpcnicillinate (0.1 g) ~or 65 hours. The mixture
w~s dil-l~ed ~7i~h etl~yl ac~t~te (8 ml.) clnd ~shc~ 7itll
water (3 x 2 m:L~ Ihe OrgalliC ~ .l5~ lS driecl and e~a-
.. . .
- ' . .
.
' '
:
;...................... porated ~o d~ ness i.n ~7~. 10 t~o ~ield an ,~morpllous; powcler. By ~llin l~ r cl~roma~o~,l^apll~r oll~silica gel
erck l3~25~) in the ollowir2~ 50~ent SYStCI'lS the
product had ~he ~ollowing R~_~Ta1UeS:
I n-but~anol-acetic acid ~ water (4:1:1) Rf - 0,~5
lI n~butanol acet-ic acid - water (4:1:5)(upper layer)
Rf -- 0.~'~2
III n-~utyl acetate~n-butanol~acetic acid-
', methanol- l/lS~I phosphate buffer solu
~ion (p~i = 5.8)(80:15:~0:5:24) Rf - Q.27
. .
-. These P~f~values were ident~ical t-o those of an authentic
' sarnple.
': .
; Example 7
`,' '
''~'' ~. 6-~mi~o~ ~c ~ ~l ben;.~ nlci~.l.in tc~
', '
To a suspension o~ potassiurl 6-amino penicillanaLe
~ 2 g) in dimethylormanlide (20 ml ) l~7as added chloro-
,' rnethyl benzylpenicillinate (1.8 g)0 Af~er stir~-in~ at
'' roorn temperature for 4~ hours the mi~ture was cliluted
i~h e~ l aceta~e (~0 ml) and ~ashed ~ith 7.~7at-e. (3
. .
10 n-l). Th2 organic phase was ex~ractecl with c~ilute
h~drochloric acid (pl~ = 20 5) 0 The a{iueous pllase was
:: mczde alkal:ine by adclin& sod.i~ n bicarbonat,e. Tlle oil
ich separatecl was t:alen up i1-l eti~y:l. ace~cli:e. Tlle ~,ol
.
~ 20 ~
ti.on w~ls drj-r:c~ an(l evapora~ecl to clryness in V'?C~10 ~0
ield ~h~ dc~tired COml~OUI?C? a~ an al1lorpl10us po~cle1~.
Th~ Nl~ spectr~,? (Cl)C13) sho~ed l~eaks at ~ 5
(.) 1.50 (s)~ l~G3 ( '7) ~ 2.2S (hs)g 3~63 (s), 4.42 (s),
.~ 4.~t', (d), 5.~ - 5.8 (m)3 5.t37 (s) and 7~33 (s) ppm.
T~S ~.~as used as internal rcfer~nce.
B. 6-l7(1~e~ql~r(1ro-lHwn.~,e~in-l y.1~ metl1~lenecmil?oll~?~e
~,, --e t lyl ber.? ~ c i 'l l .i ~I t- e
.
o N-~ormylh~st~methylel?eimine (1.3 g.) i.n dry
ether (25 ml.) at 0 5 was s3Owly aclcled oxalyl chlo.
. ride (0.85 ml.. ) in dry ether (5 n?l~) Witil stirring.
The mi~ture ~as stirred fvr 2 1/2 hours at 0-5. The
amide cllloricle formecl~as filtered off and ~ashed
with dry ether. It was kept in an clesicca~oL.
- The c~de an?ide chloride (1~0 mg) in dry chl.oroform
~3 ml) ~as slo~ly adcled to a solutioll of 6-aminopeni-
cil].anoyloxymethyl ben~ylpenicilli.nate (560 mg.) and
triethylamine (0.2~ ml.) in dry chloroforrn (3 ml.~ at
- 40 with stirring. The yellow solution was stirred
for half an hour at 20 whereupol-l the temperature was
rai.sed to 0 ~ithin 15 minutes. 'l`h~ solvent was rell-oved
]n vacuo and the resiclue trituratecl~ h acetone (5 ml~)~
~fter filtr2tion ~nd evaporation in Va~t10 the oily
rcsidue ~as taken tlp in ether (25 ml.) and extrac~c?d ~ith
clilute hy~ll-och]oric acid (3.25 1113.~ pl-~ ~..5). 'I`he ~oj~le()~ls
.,
- 2~ ~
f~' ~
~hase was filtered and made allcaline (pll~ 7.5). The
s~lid fo~m~d wa~ ~iltered of and washcd wi~h water.
- P,y thin laycr chromatography in the solvent
-`-` systems described in E~ample 6 the produc~ showed.:
.~ Rf-~ralues identieal to those of an authentic sample.
"~
E~ ~ 8
,.,; . .
:',
- By fc)~lowing ~he procedure described in E~.ample
~;
1 and by replacing the chloromethyl benzylpenicilliate
with the chloromethyl est~rs of ~ chloro-~6-1uoro
phenyl~-5-methyl-4-iso~azolylpenicillin and D(-) c~
aæidobenzylpenicillin5 respeetivelyl the ollowing
compounds were prepared:6~[(hexahydro~LI-I~azep:Ln-7-yl)-
methyleneamino~-penicil]anoyloxymethyl 3~(2-chloro-6
fluorophenyl)-5-methyl-4-iso~a~.olylpenicil~.ina~e and
6 C(hexahydro~lH-azepin~l~yl)-nlethyleneamino~peTIlcilla-
. . .
noylGxymethyl D ~ a azidobenzylpenicillinate~ Thecompounds were isolated as amorphQus powders, the Ir~
~ and N~ spectra of which were as exp2cted~
Preparation of the starting materials:
The chlororneth~l esters were prepared as described
in E~ample 1 for chloromei-hyl ~enzylpen:icilllna~e~
'''`'
,
:
., ;' .
.- .F,xample 9
(~Ie~;a ~V~T~ n = r~ ~i n ~
cillanoy~ erlici.ll.i.nate,
dihydrochloride.
A solution of 6-[(hexahydro-lH-a~epin-l-yl)-~lethy
leneflmino]~penicillanoyloxymethyl ~ azidoben~yl-
penicillinate (5.1 g) in ethyl acetate (100 ml) was
placed in a three-necked 500 ml flask equipped with a
gas inlet - outlet tube, a glass-calomel combination
electrode, a burette and a magnetic stirrer. Water
`. ~00 ml) was added and the system was 1ushed with ni.trogcn~10% palladium-on-carbon catalyst (3 g) was added and a
s~ream of hydrogen was bubbled through the suspension
while stirring, a p~-value o 2.5 being maintained in the
mixture by adding l.0 N hydrochloric acid. When the con
sumption of acid had ceased, the catalyst was ~iltered o~.
The aqueous phase was separated and freeze-dried to afford
the desired ~ompound as a colourless amorpho~ls product
The IR and NMR-spectra of this product confi.rmed that
. the reaction had taken place as e~pected~
.
E m~
6~L~ ~ n~ n~
~y~ t..hyL ~ tl~ i c~o ~ y~-
; peni.ci~.l.;~natel
. .
23 -
,
. ,
.''
;
:~ `
Following tlle procedure descrîbed in E~armple 1 the
above compound was prepared from sodi.~m 6~[(i~-ethyl i~-
isopropyl~mino)-metilyl.enearnino¦-pellicillanate and ch3.oro-
me~hyl 3-(o-chlorophenyl)-5-methyl-~-isoxazolylpenicllli~
`. nate. The compound was iso].ated as an amorphous po~der.
:. Preparation of the starting materials~
:.. .
Sodi~un 6~ ethyl-~-isopropylamino~-methyLeneamino~
; penicillanate was prepared in analogy wi~h sodi~Lm 6
[(hexahydro-lH azepin~l-yl)~methyleneamino¦-peniclllanate
~vide Example 1).
Chloromethyl 3-(o-chlorophenyl) ~-methy3.~4-i.so~azclyl.
penicil:LirLate was prepared in analogy with chlc~romethyl
. ,;
:~ benzylpenicillinate (cfr. Exarnple 1). The compouncl was
isolated as an amorplous powder~
.:' .
Exa~le 11
__._ _ __
6-~ 1e~all~ ~ ~en~.cil.lan-
: ~ ~ n~ er,ici.llirlat~.
~ This compound was prepared from sodium 6-C~he~tah~dro-
- 1~(2H)-azocinnyl~-Tnethyleneamino] penicillanate and chloro
methyl ben~ylpenicillinate followLng ~he procedure desc~i.bec
~: in E~ample 1, It was obtained as an amorphous po~der.
Prep~ation of the start:in~ mate-ri.als:
Sodium 5 [(nexahydrool-(2H)-azoci.nnvl)-methyleneam.inol-
...
'
~ 4
~ "'
penicillanate ~as prepared in anal.ogy wit:h sodium
:~ . 6 ~(hexahydro l.H- azepin-l-yl)~mæthylenearnino]-peni
-~ cillanat~e (see Example 1).
.,
:,..
'', '
. ~, . .
,5
.
. .
