CA1112569A - Methods for preparation of new penicillin esters - Google Patents
Methods for preparation of new penicillin estersInfo
- Publication number
- CA1112569A CA1112569A CA140,652A CA140652A CA1112569A CA 1112569 A CA1112569 A CA 1112569A CA 140652 A CA140652 A CA 140652A CA 1112569 A CA1112569 A CA 1112569A
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- Canada
- Prior art keywords
- compound
- formula
- methyl
- ring
- carbon atoms
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides a composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula
The invention provides a composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula
Description
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)-.
~ -:
:
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,
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 - 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 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
~':
,.~, ;"
:
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, .~
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:
.
.
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
' 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 . .
, . , .'' ;
:~ `
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 .
. .
:, .:
~ 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 - 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 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
~':
,.~, ;"
:
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, .~
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:
.
.
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
' 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 . .
, . , .'' ;
:~ `
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 .
. .
Claims (3)
1. A method of preparing a composition having synergistic physiological activity which comprises concurrently providing a compound of the formula in which R3 represents a radical selected from the group consist-ing of benzyl, phenoxymethyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolyl, D(-)-.alpha.-azidobenzyl, D(-)-.alpha.-aminobenzyl and 3-(o-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is a straight or branched alkyl radical having from 1 to 4 carbon atoms, or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 4 to 8 carbon atoms in the ring.
2. A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents a radical selected from the group consist-ing of benzyl, phenoxymethyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolyl, D(-)-.alpha.-azidobenzyl, D(-)-.alpha.-aminobenzyl and
3-(o-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is a straight or branched alkyl radical having from 1 to 4 carbon atoms, or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 4 to 8 carbon atoms in the ring.
(3) A method of preparing a composition having synergistic physiological activity which comprises mixing a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(4) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represents a heteroeyelic ring with from 5 to 7 carbon atoms in the ring.
(5) A method of preparing a composition having syner-gistic physiological activity which comprises mixing a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxa-zolyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolyl, D(-)-.alpha.
-azido-benzyl and D(-)-.alpha.-aminobenzyl and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(6) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxa-zolyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-5-isoxazolyl, D(-)-.alpha.
-azidobenzyl and D(-)-.alpha.-aminobenzyl and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(7) A method of preparing a composition having syner-gistic physiological activity which comprises mixing a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(8) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(3) A method of preparing a composition having synergistic physiological activity which comprises mixing a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(4) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxazolyl, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represents a heteroeyelic ring with from 5 to 7 carbon atoms in the ring.
(5) A method of preparing a composition having syner-gistic physiological activity which comprises mixing a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxa-zolyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolyl, D(-)-.alpha.
-azido-benzyl and D(-)-.alpha.-aminobenzyl and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(6) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents a radical selected from the group consisting of benzyl, phenoxymethyl and 3-(0-chlorophenyl)-5-methyl-4-isoxa-zolyl, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-5-isoxazolyl, D(-)-.alpha.
-azidobenzyl and D(-)-.alpha.-aminobenzyl and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(7) A method of preparing a composition having syner-gistic physiological activity which comprises mixing a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
(8) A composition having synergistic physiological activity which comprises a compound of the formula in which R3 represents radicals from known penicillins, and a compound of the formula in which each of R1 and R2 is an alkyl group or R1 and R2 together with the nitrogen atom represent a heterocyclic ring with from 5 to 7 carbon atoms in the ring.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA267,544A CA1020158A (en) | 1971-05-05 | 1976-12-09 | Methods for preparation of new penicillin esters |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1335871 | 1971-05-05 | ||
GB13358/1971 | 1971-05-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1112569A true CA1112569A (en) | 1981-11-17 |
Family
ID=10021514
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA140,652A Expired CA1112569A (en) | 1971-05-05 | 1972-04-26 | Methods for preparation of new penicillin esters |
Country Status (10)
Country | Link |
---|---|
US (1) | US3869449A (en) |
JP (1) | JPS5541240B1 (en) |
CA (1) | CA1112569A (en) |
DE (1) | DE2221912A1 (en) |
DK (1) | DK140481B (en) |
FR (1) | FR2135339B1 (en) |
GB (1) | GB1335718A (en) |
NL (1) | NL7205957A (en) |
SE (1) | SE417098B (en) |
ZA (1) | ZA722545B (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1579931A (en) * | 1976-04-15 | 1980-11-26 | Leo Pharm Prod Ltd | Bis-penicillanoyl-oxy-alkanes |
US4345071A (en) * | 1976-06-29 | 1982-08-17 | Leo Pharmaceutical Products, Ltd. A/S | Derivatives of penicillanic acid |
LU77362A1 (en) * | 1977-05-17 | 1979-01-19 | ||
US4407751A (en) * | 1979-02-13 | 1983-10-04 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Processes for preparing β-lactams |
IE49881B1 (en) * | 1979-02-13 | 1986-01-08 | Leo Pharm Prod Ltd | B-lactam intermediates |
IE49371B1 (en) * | 1979-02-13 | 1985-09-18 | Leo Pharm Prod Ltd | 6-(azacycloalkyl-or azabicycloalkyl-methyl imino)penicillanic acid esters |
US4244951A (en) * | 1979-05-16 | 1981-01-13 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4377524A (en) * | 1979-05-16 | 1983-03-22 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4309347A (en) * | 1979-05-16 | 1982-01-05 | Pfizer Inc. | Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide |
DE3051044C2 (en) * | 1979-06-19 | 1989-03-30 | Leo Pharmaceutical Products Ltd. A/S (Loevens Kemiske Fabrik Produktionsaktieselskab), Ballerup, Dk | |
US4340539A (en) * | 1980-01-21 | 1982-07-20 | Bristol-Myers Company | Derivatives of 6-bromo penicillanic acid |
US4488994A (en) * | 1980-09-08 | 1984-12-18 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4432903A (en) * | 1980-09-08 | 1984-02-21 | Pfizer Inc. | Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide |
US4323499A (en) * | 1981-01-05 | 1982-04-06 | Pfizer Inc. | 6-(2-Aryl-2-(1,1-dioxopenicillanoyloxy-methoxycarbonyl)acetamido penicillanic acids |
US4540687A (en) * | 1981-09-09 | 1985-09-10 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
US4582829A (en) * | 1981-09-09 | 1986-04-15 | Pfizer Inc. | Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds |
KR100694685B1 (en) * | 1999-07-30 | 2007-03-13 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3669978A (en) * | 1970-05-28 | 1972-06-13 | American Home Prod | Process for the production of semi-synthetic penicillin intermediate |
US3704290A (en) * | 1970-12-09 | 1972-11-28 | American Home Prod | 6-(1 - substituted aminocycloalkane-carboxamido)-penicillanic acid and salts |
US3770722A (en) * | 1971-10-04 | 1973-11-06 | Pfizer | 6 - (alpha - (aryl substituted)acylamino-acylamino)penicillanic acidsand derivatives thereof |
-
1971
- 1971-04-20 GB GB1335871A patent/GB1335718A/en not_active Expired
-
1972
- 1972-04-13 US US243855A patent/US3869449A/en not_active Expired - Lifetime
- 1972-04-17 ZA ZA722545A patent/ZA722545B/en unknown
- 1972-04-20 DK DK193172A patent/DK140481B/en unknown
- 1972-04-26 CA CA140,652A patent/CA1112569A/en not_active Expired
- 1972-05-02 JP JP4337972A patent/JPS5541240B1/ja active Pending
- 1972-05-03 NL NL7205957A patent/NL7205957A/xx not_active Application Discontinuation
- 1972-05-04 DE DE19722221912 patent/DE2221912A1/en not_active Withdrawn
- 1972-05-04 SE SE7205896A patent/SE417098B/en unknown
- 1972-05-05 FR FR7216200A patent/FR2135339B1/fr not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1335718A (en) | 1973-10-31 |
SE417098B (en) | 1981-02-23 |
DK140481B (en) | 1979-09-10 |
FR2135339A1 (en) | 1972-12-15 |
FR2135339B1 (en) | 1975-06-20 |
DE2221912A1 (en) | 1972-11-16 |
NL7205957A (en) | 1972-11-07 |
JPS5541240B1 (en) | 1980-10-22 |
US3869449A (en) | 1975-03-04 |
ZA722545B (en) | 1973-01-31 |
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