Note: Descriptions are shown in the official language in which they were submitted.
~0662~9
-- FIELD OF THE INVENTION .
- This inv2n.tion relates to novel derivati~s of sub
, ' . ~ ' . , ! . , , ' , '
: s~ttu~ed(4~vxo-~-pyridînyl)acety~amino~peni~illin and - .
cephalosporins, to their methods o~ prepar~tion, and to
.. ~h~ir ~seFulnes~ as an~;bacterial a~ents, . -
- -. BACKGROUND OF_THE INVENTION - : . .
This i~vsn~ion relates to new synthetlc compounds o~ .
- the pen;clliin ànd cephalosporin classes which are u5~ful : -
.as-ant;bac~er;al ag~nts.. These compounds po$sess ~ hi`~h ~ ~
., , .,. , I
degree o~ activi~y against a large number of mic~oorga-
- nisms. The seph~losporin derivatives.of thts Inven~ion are
~51 ~ . - . . . .
1 particularly:useful against penicillinase-producing micro-
,. . . . .
or~an;sms~ As antibacterial agents the compounds of this
invention are therapeutTcally ef~ect7ve in the treatment
. . . .
of in~ectious diseases due to gram-posit;ve and gram- :
negative bacter.ia in poultry and animals~ including man,
In addition, the compounds of this invention are useFul as
. animal ~eed supplements and as the a~tive ingredient in
- germlcidal preparations employed as surFace disin~ectants~
. .
. . .
,
.
,: . . , .. ,, . , , , :
.' .: ., , ' ~ ,.
M-781-1
1066'~69
PRIOR ART
The cleavage of penicillins to 6-aminopenicillanic
acid in 1959 and the chemical cleavage of cephalosporin to
give the corresponding 7-aminocephalosporanic acid made
possible the synthesis of new synthetic penicillins and
cephalosporins not previously available vja fermentation
procedures. Acylation of the amino group has produced
derivatives containing a heterocyclic ring in the 6-posi-
tion side chain, as in the case of the penicillin series,
or in the corresponding 7-position side chain, as in the
case o~ the cephalosporin series. Such heterocycles
include the thiophene ring, as for example, U.S. Patent
Nos. 3,218,318, 3,449,338 and 3,49~,979 (cephaloridine
and cephalothin); picoline, U.S. Patent 3,553,203; hydantoin3
U.S. Patent 3,227,712; and various other nitrogen contain- ~;
ing heterocycles including pyrrolidine and nicotinic acid, '
U.S. Patent 3,308,120.
In each instance the heterocyclic moity is attached
~o a side chain, generally that of an acetyl radical, via
one of the ring carbon atoms. The present invention is
concerned with 4-oxo-1-pyridinyl derivatives which are
linked directly to the acetyl radical through the hetero
atom. Examples known to applicants contain7ng this type
of linkage, and in this regard representing the closest
prior art, are the tetrazole ring in U.S. Patent 3,516,997
(cefazolin) and certain quinazolinyl derivatives of peni-
cillanic acid, U.S. Patent :3,652,547.
, . ' '.' ' '., .'
.. , - , ., , . ., . ' ~
,. . .
~066~9 M-781~
SUMMARY OF THE INVENTION
This invention relates to novel 4-oxo-1-pyridinyl
penicillin and cephalosporin derivatives. More particu-
larly, this invention relates to substituted(4-oxo-1-
pyridinyl)acetylamino _penicillin and cephalosporin deri-
vatives which are useful as antibacterial agents and which
may be represented by the general formula:
- O
R l ~, R3 '
R2 N ~ R4
~8
C H--CI--NH tr~
R5 O ~ N--Rff
O
;' (l) ~,
'
wherein .:
Rl7 Rz~ R3 and R4 are each selected from the group
consisting of hydrogen~ halogen, hydroxyl, lower
alkyl, trifluoromethyl, nitro, amino, cyano, carboxy,
carbomethoxy, carbethoxy and when R1 is taken in
combination with Rz forms the cyclic radical
-CH2CH2CH2CH2- and -CH--CH-CH=CH-;
Rs is selected from the group consisting of hydrogen,
methyl, carboxy, carbomethoxy and carbethoxy;
R6 is selected from the group
~ ~CH3
: / IC ~CH and fH2 ~ ~
--CH f--C H2X
C OOR7 ~
COOR7
M-781-1
. ,
~66Z6g
X is selected from the group consisting of hydrogen,
hydroxy, acetoxy, N-pyridinium, 5-methyl-1,3,4-
thiadiazol-2-ylthio and 1-methyl-1,2J3,4-tetrazol-
5-ylthio;
R7 is selected from the group consisting of hydrogenJ
alkanoyloxymethylJ alkanoylaminomethyl, alkoxy-
carbonylaminomethyl and D-(alkanoyloxy)benzyl in
; ~ which the alkanoyl or alkoxy group contains from
-~ 1 to 5 carbon atoms; ~ -
~ .
lO ~ R8 is hydrogen or methoxy; and ~ -
the pharmaceutically acceptable salts thereof. ~ .
The compounds of the present invention are prepared : ~ :
by the condensation of a 6-aminopenicillanic acid or a
7-aminocephalosporanic acid with a (substituted)4-oxo-1- ;
. pyridinylacettc acid as illustrated in the following
reaction scheme. .
;.. , . :
, : ~. O
R1 ~ R3 HzN ~ ~ :
Rz N R4 ~~ N -R6
~H-D-OH o .
(111) : ~
:','. (Il)
';''.;
'' O
.: R1 ~ R9
.. ~ 11 11 .
~ HaO ~ ~H-~-NH ~ S
", ( I)
:
. ' ~
' .~
.
.': ' , .... . . .
M-781-1
: `
~IL066269
DETAILED DESCRIPTION OF THE INVENTION
All of the compounds of the present invention contain
a 4-oxo-1-pyridinyl radical or a 4-pyridone moiety at the
terminal position of the acetylamino side chain, as indi-
cated in general Formula (I) above. In the case of the ~-
penicillin series, the acetylamino side chain is enumerated
as the 6-position, whereas in the cephalosporin series of
compounds the 7-position is enumerated. The numbering
system for these two series of compounds is illustrated for
10 , the intermediates 6-aminopenicillanic acid (IV) and
7-aminocephalosporanic acid (V) below:
CH3
NH2 ~ S~ ~C NH2 ~ S
/~_NL__~ H3 ~ N ~ CH20C-CH3
O ( ;OOH
COOH
(IV) (V)
The 4-pyridone moiety attached to the acetylamino
side chain may be substituted or unsubstituted. These
substituents are present in either the 2-, 3-, 5- or
6-positions of the pyridine nucleus and include the
following radicals: halogen~, hydroxyl, lower alkyl, tri-
fluoromethyl, nitro, amino, cyano, carboxyl and the
methyl and ethyl esters of the carboxyl radical. The
term halogen includes the fluoro, chloro, bromo and
iodo radicals. The term lower alkyl as used herein
includes both straight and branched chair, aliphatic
M-78~-1
- ~066Z6~
hydrocarbon radicals having from 1 to ~ carbon atoms.
Specifically included are such members as methyl, ethyl,
propyl, isopropyl, bu~yl, isobutyl, and the t-butyl
radicals.
In addition to the various substituents described ; ;
above, the 4-pyridone moiety can be considered as substi-
tuted with an adjacent saturated or unsaturated six-
membered ring. Thus, the symbol R1 when taken in combina-
tion with the adjacent symbol R2 can be viewed as forming
an attached 6-membered alicyclic or aromatic derivative at -
the 2J3-position of the pyridine ring. These derivatives ~ -
are more properly termed 2-[substituted(4-oxo-1-tetrahydro-
quinolinyl)]acetylamino and 2-[substituted(4-oxo-1-
quinolinyl)]acetylamino derivatives of penicillins and ~;
cephalosporins. Due to the symmetry of the pyridine
molecule only one pair of adjacent symbols need be so
defined. The present invention is not intended to include
; the tricyclic heterocyclic dibenzo-pyridine or acridine
; ring systems.
In addition to the mandatory substitution of the 2-
methyl group of the acetylamino or acetamido portion of the
molecule with 4-oxo-1-pyridinyl radical, the 2-methyl
group may contain additional substitution in the form of a
methyl radical or a carboxyl radical as represented by the
symbol R5. When R5 is methyl, the compounds are more
properly termed as propionyl derivatives of 6-aminopeni-
cillanic acid or of 7-aminocephalosporanic acid. However, -
for the sake of uniformity in nomenclature, they are
termed as 2-(substituted)acetylamino derivat7ves herein.
'
. . ... , " , " . ~ ........... . .......... . ... . .... ..
.
~ M-781-1
~0~269
Thus, for example, in the case of a cephalosporanic acid
derivative in which R5 is methyl and the 4-pyridone remains
unsubstituted, the compound is designated as 7-[2-(4-oxo-
1-pyridyl)-2-methylacetylamino]cephalosporanic acid. In
addition to the carboxyl radical at R5 the methyl and
ethyl esters or carbomethoxy and carbethoxy radicals are
also contemplated to be within the scope of the present
inventionO
This invention is essentially concerned with the pre-
paration and description of 2-(4-oxo-1-pyridinyl)ace-tyl-
amino side-chain derivatives of the ~-lactam antibiotics.
These derivatives are prepared by condensation with the
readily available 6-amino penicillanic acid or any of the
available 7-aminocephalosporin intermediates. Thus, where
R6 is the radical
~ C/cH3 , `,
/ I ~CH3 ~-
- CH
COOR
derivatives of the penicillin series are delineated,
whereas when R6 is the radical ;
CH
I 2
~C-CH2X
-f
COOR7
derivatives of the cephalosporin series are described.
The ~-lactam nucleus can remain unsubstituted or it
can be substituted with a methoxy substutuent as indicated
by the symbol R8. Such substitution occurs at the 6-
M-781-1 ;~
~6~z69 ' ~. .
position of the penicillin series and at the 7-position of
the cephalosporin series of compoundsO -
Both the 3-position oF the penicillin and the 2- -~
position of the cephalosporin series of compounds are
substituted by a carboxylic acid or a carboxylic acid ester
as represented by the partial structure -COOR7. When R
is hydrogen, the corresponding penicillanic acids or
cephalosporanic acids are obtained. Additionally, the
symbol R7 can represent the following radicals: alkanoyloxy- ; ~ -
methyl, alkanoylaminomethyl, alkoxycarbonylaminomethyl and
p-(alkanoyloxy)benzyl. These esters confer excellent
properties of absorption upon the molecule and at the same
time are physiologically labile. Thus, these esters are
readily absorbed from the gastro-intestinal tract and `
enzymatically hydrolyzed to the corresponding penicillanic ;
or cephalosporanic acids thereby, providing excellent oral
activity.
Certain specific variations within the cephalosporin
series are further indicated by the symbol X. Thus~
where X is hydrogen the desacetoxycephalosporanic acids are
delineated; and where the symbol X is hydroxyl, the
desacetylcephalosporanic acids are indicated. Where the
symbol X represents an acetoxy radical the ~-lactam nucleus
is that of cephalosporanic acid. Additional substituents at
the 3-position of decephalosporanic acid which are included
within the purview of the present invention and represented
by the symbol X are the 3-pyridinium, the 5-methyl-1,3,4-
thiadiazol-2-ylthio and the 1-methyl-1,2,3,4-tetrazol-5-
ylthio radicals.
-8-
,. .. . . . . .
M-781-1
- ~ 69
The pharmaceutically acceptable salts of the compounds -
of Formula (I) above include the non-toxic, carboxylic
acid salts formed with any suitable inorganic or organic
bases. Illustratively, these salts include those of
alkali metals, as for example, sodium and potassium;
alkaline earth metals, such as calcium and magnesium; light
metals of Group IIIA including aluminum; and organic pri-
mary, secondary and tertiary amines, as for example, tri-
alkylamines, including triethylamine, procaine, dibenzyl-
amine, 1-ethenamine~ N,N~-dibenzylethylenediamine, dihydro-
abietylamine, N-(lower)al~kylpiperidine, and additional
amines which have been used to form non-toxic salts with
benzylpenicillin. These salts can be prepared using con-
ventional means such as contacting and neutralizing a solu-
tion of the carboxylic acid in a polar solvent with a
stoichiometric quantity of a base.
Also included as pharmaceutically acceptable acid
addition salts are the non-toxic organic or inorganic acid
addition salts of the base compounds of Formula (I) above.
Illustrative inorganic acids which form suitable salts
include hydrochloric, hydrobromic, sulfuric and phosphoric
acids as well as acid metal salts such as sodium mono-
hydrogen orthophosphate and potassium hydrogen sulfate.
Illustrative organic acids which form suitable salts include
mono, di and tricarboxylic acids, as for example, acetic,
glycolic, lactic, pyruvic, malonic, succinic, glutaric,
fumaric, malic, tartaric, citric, ascorbic, maleic,
hydroxymaleic, benzoic, p-hydroxybenzoic~ phenylacetic,
cinnamic, salicylic, 2-phenoxybenzoic and sulfonic acids
such as methane sulfonic acid and 2-hydroxyethane sulfonic
g_
~- ~ M - 781~
~ 0~6;~69
acid. Such salts can exist in either a hydrated or a
substantially anhydrous form. -~
In addition to the non-toxic, carboxylic acid salts
and the non-toxic acid addition salts of the base compounds~
the term pharmaceutically acceptable salts is taken to -~ -
include internal salts or zwitter-ions of those compounds
of Formula (I) above which are amphoteric in nature.
Thus, compounds such as 7-[2-(4-oxo-1-pyridinium)acetyl-
amino]cephalosporanate, 7-[2-(4-oxo-1-pyridinium)acetyl-
amino]-3-[(5-methyl-1,~,4-thiadiazole-2-ylthio)methyl]-
decephalosporanate or 7-[2-(4-oxo-1-pyridinyl)acetylamino]-
(pyridiniummethyl)decephalosporanate, can exist as a
- dipolar ion, particularly when they are in solution.
Illustrative specIfic base compounds which are encom- 1
passed by Formula (I) a~ove include:
6-[2-(4-oxo-1-pyridinyljacetylamino]penicillanic acid,
6-[2-(2-hydroxy-4-oxo-1-pyridinyl)acetylamino]pencillanic
acid, - -
6-[2-(~-trifluoromethyl-4-oxo-1-pyridinyl)-2-methylacetyl-
amino]penicillanic acid, ;
6-[2-(2,3,5-trichloro-4-oxo-1-pyridinyl)acetylamino]
penicillanic acid,
6-[2-(3-cyano-4-oxo-1-pyridinyl)acetylamino]penicillanic
acid,
6-[2-(2-ethyl-5-methyl-4-oxo-1-pyridinyl)-2-carbethoxy-
acetylamino]penicillanic acid,
6-[2-(2-amino-4-oxo-1-quinolinyl)acetylamino]penicillanic
acid, ~
-10- :'
~: ' : ','' "'
- ,',
,
.. . .. ..
, ,........ , . . ~ . ., . .
: :
~ M-781-1
~066Z69
acetoxymethyl 6-[2-(4-oxo-1-pyridinyl)acetylamino]-
penicillanate,
N-acetylaminomethyl 6-[2-(3-chloro-4-oxo-1-pyridinyl)
acetylamino]penicillànate, :
(N-ethoxycarbonyl-N-methyl)aminomethyl 6-[2-(2-chloro-4- ~. .
oxo-1-quinolinyl)acetylamino]penicillanate, :
7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalosporanic acid,
7-[2-(2-nitro-4-oxo-1-pyridinyl)acetylamino]cephalosporanic :` .
acid
7-[2-(2,5-dicarboxy-4-oxo-1-pyridinyl)-2-carboxyacetyl-
amino]cephalosporanic acid,
7-[2-(2-chloro-3-hydroxy-4-oxo-1-tetrahydroquinolinyl)- ~
acetylamino]cephalosporanic acid, ~:
7-[2-(2,3,5j6-tetramethyl-4-oxo-1-pyridinyl)-2-methylacetyl-
amino]cephalosporanic acid,
7-[2-(2,5-dicarbethoxy-4-oxo-1-pyridinyl)-2-carbethoxy-
acetylamino]cephalosporanic acid,
pivaloyloxymethyl 7-[2-(4-oxo-1-pyridinyl)acetylamino]-
cephalosporanate,
p-acetyloxybenzyl 7-[2-(3,5-dicyano-4-oxo-1-pyridinyl)
acetylamino]cephalosporanate/
(N-propionyl-N-methyl)aminomethyl 7-[2--(3-amino-4-oxo-1-
pyridinyl)-2-carbethoxyacetylamino]cephalosporanate,
7-[2-(3,5-dimethyl-4-oxo-1-pyridinyl)-2-methylacetyl-
amino]desacetoxycephalosporanic acid,
7-[2-(2-cyano-4-oxo-1-quinolinyl)acetylamino]desacetoxy-
cephalosporanic acid,
7-[2-(2,3,5,6-tetraiodo-4-oxo-1-pyridinyl)acetylamino]-
desacetoxycephalosporanic acid,
~ -11-
~- M-781
6ZG9
7-[2-(2,6-dihydroxy-4-oxo-1-pyridinyl)-2-carbomethoxy-
acetylamino]desacetoxycephalosporanic acid,
7-~2-(2,6-dinitro-4-oxo-1-pyridinyl)acetylamino]desacetoxy- ~ ~:
cephalosporanic acidJ
7 [2-(4-oxo-1-pyridinyl)acetylamino]desacetylcephalo~
sporanic acid,
7-[2-(2-carboxy-5-methyl-4-oxo-1-pyridinyl)-2-carboxyacetyl~
amino]desacetylcephalosporanic acid, . - .
7-[2-(3-amino-5-bromo-4-oxo-1-pyridinyl)acetylamino]- :
: ~:lQ desacetylcephalosporanic acid, ~ - :
: 7-[2-(3-carbomethoxy-4-oxo-1-tetrahydroquinolinyl)-2- - ~ :
. methylacetylamino]desacetylcephalosporanic acid,
~: : 7-[2~ trifluoromethyl-4-oxo-1-pyridinyl)acetylamino]- -; ..
desacetylcephalosporanic acid,
: 7~[2-(5-chloro-2-cyano-4-oxo-1-pyridinyl)acetylamino3-
.
: ~ desacetylcephalosporanic acid3
: : : p-propionyloxybenzyl 7-[2-(3~5-dichloro-4-oxo-1-pyridiny
-carbomethoxyacetylamino]desacetylcephalosporanate,
isopropoxymethyl 7 [2-(5-nitro-4-oxo-1-quinolinyl)acetyl-
2~ amino]desacetylcephalosporanatej
pivaloyloxymethyl 7-[2-(4-oxo-1-tetrahydroquinolInyl)-
acetylamino]desacetoxycephalosporanate,
7-[2-(4-oxo-1-pyridinyl)acetylamino]-3~(pyridiniummethyl)- -~
decephalosporanate,
7-[2-(2-hydroxy-3,5-dibromo-l~-oxo-1-pyridinyl)acetyl-
amino~-3-(pyridiniummethyl)decephalosporanate,
7-[2-(2,6-dicyano-4-oxo-1-pyridinyl)acetylamino]-3- .
(pyridiniummethyl)decephalosporanate,
7-[2-(2-carbomethoxy-4-oxo-1-pyridinyl)-2-carbethoxy- ;::
acetylamino]-3-(pyridiniummethyl)decephalosporanate
-12-
:.
.: . ., , ., . , . :... ' '
.. . .
.. . . . . . .
~ M~781-1
~066Z69
7-[2-(4-oxo-1-quinolinyl)acetylamino]-3-(pyridiniummethyl)~
decephalosporanate,
7-~2-(3-chloro-2,6-dimethyl-4-oxo-1-pyridinyl)-2-methyl-
acetylamino]-3-(pyridiniummethyl)decephalosporanate,
7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(5-methyl-1,3,4-
thiadiazol-2-ylthio)methyl]decephalosporanic acid,
7-[2-(2-bromo-3S5-dichloro-4-oxo-1-pyridinyl)acetylamino]-
3-[(5-methyl 1,3,4-thiadiazol-2-ylthio)methyl]
decephalosporanic acid,
7-[2-(4;oxo-1-tetrahydroquinolinyl)-2-carboxyacetyl-
amino]-3-~(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]-
. decephalosporanic acid,
7-L2-(3-cyano-4-oxo-1-pyridinyl)-2-methylacetylamino]-3-
(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo- ,
. ~ .
sporanic acid,
7-~2-(3,5-dihydroxy-4-oxo-1-pyridinyl)acetylamino]-3- ~: -
[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo-
sporanic acid,
pivaloxymethyl 7-[2-(4-oxo-1-pyrid7nyl)acetylamino]-3
[(5-methyl-1,3,l~-thiadiazol-2-ylthio)methyl]decephalo-
sporanate,
(N-ethoxycarbonyl-N~methyl)aminomethyl 7-[2-(5-chloro-4-
oxo-1~tetrahydroquinol7nyl)-2 methylacetylamino]-3-
[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo-
sporanate,
(N-acetyl-N-methyl)aminomethyl 7-[2-(3-cyano-4-oxo-1-
pyridinyl)acetylamino]-3-[(5-methyl-1,3,4-thiadiazol-
2-ylthio)methyl]decephalosporanate,
7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(1-methyl-1,2,3,4-
tetrazol-5-ylthio)methyl]decephalosporanic acid,
-13-
M-781-1
3LID6~26~
7-[2-(5-methyl-2-propyl-4-oxo-1-pyridinyl)-2-methylacetyl-
amino]-3-~(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyi]- ~
decephalosporanic acid, :
7-[2-(3-trifluoromethyl-4-oxo-1-pyridinyl)acetylamino]-
3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]-
decephalosporanic acid,
7-[2-(4-oxo-1-quinolinyl)-2-carboxyacetylamino]-3-[(1-
methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalo-
sporanic acid,
7-[2-(2-chloro-5,6-difluoro-4-oxo-1-pyridinyl)acetyl-
amino]-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]- . .
decephalosporanic acid,
aceto~ymethyl 7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(1-
methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalo-
sporanate,
(N-methoxycarbonyl-N-methyl)aminomethyl 7-[2-(2J6-dihydroxy- :~
4-oxo-1-pyridinyl)-2-carbethoxyacetylamino]-3-[(1- . .
,. ~
methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalo-
sporanate,
p-pivaloyloxybenzyl 7-[2-(5-trifluoromethyl-4-oxo-1- .
quinolinyl)acetylamino]-3-[(1-methyl-1,2,3,4- :
tetrazol-5-ylthio)methyl]decephalosporanate,
7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalo-
sporanic acid,
7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(5- :
methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo- ~ ~ :
sporanic acid,
6-methoxy-6-[2-(4-oxo-1-pyridinyl)acetylamino]penicillanic
acid, : . .
-14-
~ ~ M-781-1
~06626~
7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]decephalo-
sporanic acid,
6-methoxy-6-~2-(3,5-dicyano-4-oxo-1-pyridinyl)acetylamino]-
penicillanic acid,
6-methoxy-6-~2-(5-nitro-4-oxo-1-quinolinyl)-2-carbethoxy-
acetylamino]per,icillanic acid,
pivaloyloxymethyl 6-methoxy-6-[2-(4-oxo-1-pyridinyl)-
acetylamino]penicillanate, .
7-methoxy-7-[2-(5-ch10ro-4-oxo-1-quinolinyl)-2-methyl-
acetylamino]cephalosporanic acid, ;-
' 7-methoxy-7-[2-(2-hydroxy-4-oxo-1-pyridinyl)-2-carbo-
methoxyacetylamino]cephalosporanic acid,
acetoxymethyl 7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetyl-
: amino]cephalosporanate,
N-acetylaminomethyl 7-methoxy-7-[2-(2,6-dimethyl-4-oxo-
1-pyridinyl)-2-carbethoxyacetylamino]cephalosporanate,
7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]desacetyl- :
cephalosporanic acid,
p-acetoxybenzyl 7-methoxy-7-[2-(5-tri~luoromethyl-4-oxo-1-
quinolinyl)-2-ethylacetylamino]desacetoxycephalo-
sporanate,
acetoxymethyl 7-methoxy-7-[2-(4-oxo-1~pyridinyl)acetyl-
amino]-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)-
methyl]decephalosporanate,
(N-ethoxycarbonyl-N-methyl)aminomethyl 7-methoxy-7-[2-(4-
oxo-1-pyridinyl)acetylamino]-3-[(1-methyl-1,2,3,4-
` tetrazol-5-ylthio)methyl]decephalosporanate,
7-methoxy-7-[2-(4-oxo-1~pyridinyl)acetylamino]-3-[(1-
methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalo-
30 sporanate. :
-15- :~
.
..
, , . . : , ' . .
M- 781- 1
" ~1066'~69
The products of the present invention are prepared by
reacting a ~-lactam 6-aminopenicillanic acid or 7-amino- : -
cephalosporanic acid, or derivative thereof, having the
formula
: -.
H2N trS .: :
N - R
( I I 1)
with a 4-oxo-1-pyridinylacetic acid having the formula .
.'".
O ::
R1 ~ R3 . :
R2 I R~
CH-C-OH ~:
( I 1)
wherein the symbols R1, R2, R3, R4, R5, R6 and R8 have the
values previously assigned. :
10The ~-lactam starting materials (Ill) are all known
compounds. The compoundJ 6-aminopenicillanic acid, having .~
the formula ~.
S ~H
H2N ~- ~' ~ \
~L~~ . CH3
COOH `
(Vl)
-16-
... .
. . ' : . ' ' ` ' `:. .
M-781-1
~L066Z6~
can be prepared using biological methods and can also be
prepared by the hydrolysis of various penicillins as
described in U.S. Patent 3,499J909.
Hydrolysis of the antibiotic cephalosporin C results
in the formation of 7-aminocephalosporanic acid, Loder et
al., Biochem. J. 79, 408-416 (1961), having the formula
:
H2N r~S ~ O
N ~--CH2OCCH3
COOH
( V)
The compound 7-aminodesacetoxycephalosporanic acid
having the formula
HzN 1~ S ~
~ N ~CH3
O
COOH
(Vl)
is prepared by the catalytic reduction of cephalosporin C,
followed by the hydrolytic removal of the 5-aminoadipoyl
side chain as described in U.S. Patent ~,129,224,
Those compounds of the ~-lactam starting material (Ill)
above wherein the symbol R8 represents a methoxy group have
been previously described in U.S. Patent 3,778,4~2.
Treatment of cephalosporin C with an acetyl esterase
prepared from orange peel, Jeffery et al., Biochem. J., 81,
-17
,'.'' ' ' '' '' ' ' ' :. ,. ', ' ' ':
. ~ . . . . . . , ~
. .
. ~ :
.-. M-781-1
~366Z69
591 (1961) results in the -formation of 3-hydroxymethyl- :
7-aminodecephalosporanic acid or 7-aminodesacetylcephalo-
sporanic acid having the formula
H2N ~ S ~ .
o ~ N~L C H2 0H ~ "
COOH .~ :
( V I I ) ,.
Treatment of cephalosporin C with pyridine followed
by an acid hydrolysis produces the compound, 7-amino-3- .
(pyridiniummethyl)decephalosporanic acid having the formula ~. ~
shown below The preparation of this compound is known in : -
the art and described, for example, in U.S. Patent :
3,117,126 and British patents 932,644, 957,570 and 959,054. -
~ ~ CH2 ~
(VIII) :: . .
The 3-thiolated 7-aminocephalosporanic acids can be
obtained by reacting 7-aminocephalosporanic acid with the
appropriate thiol as described in U.S. Patent 3,516,997.
Thus when 5-methyl-1,3,4-thiadiazole 2-thiol is employed
the compound 7-amino-3-[(5-methyl-1~3,4-thiadiazol-2-
ylthio)methyl]decephalosporanic acid is obtained, which
has the formula
2 r~ ' CH -S ~ ~ CH
COOH .
(IX)
-18-
.
.. . .
, ~
' ' ' , , .' ' . , :, ' .
M-781-1
~ 066Z69
When the compound 1-methyl-1,2,3,4-tetrazole-5-thiol is
employed the compound 7-amino-3-[(1-methyl-1,2,~,4-tetra-
zol-5~ylthio)methyl]decephalosporanic acid is obtained
having the ~ormula
H2N I - ~S ~ N --N
o~L N ~ CH2-S ~
COOH CH3
(X)
The 4-oxo-1-pyridinyl-(substituted)-acetic acids (Il)
used as starting materials are for the most part known com-
pounds which can be synthesized in either one or two steps
via the condensation of an alkali metal salt oF an hydroxy-
pyridine (Xl) with ethylbromoacetate or a substitutedethylbromoacetate (Xll). Generally the potassium salt of
hydroxypyridine is preferred to effect condensation, and
.
the resulting ester hydrolyzed to the desired 4-oxo-1-
pyridinyl-(substituted)-acetic acid (Il) with an aqueous :
base as illustrated in the following reaction scheme:
OH R3 ~
KOH ~ Rl ~ R3 + BrCH-~-OC2H
R2 R4R2 N R~ . R5
(Xl)K ~3 (Xll)
O O
R~~R3 Hydrolysis R~ I R3
R2 ~ ~ l R4 OH ~3 R2 ~ R~ :
CH-COOH ICH-lCl-OC2Hs
R5 Rs O , .
(Il) (Xlll) ~ :
~ 9 .,,: '
.. . .
.. . .
' ~ '
:- , - ., . . '' . . : .
. . -. ~ . , , - " ... . .
... . . .. . . . . . . . .
~ M-781-1
.~66:~69
.
Alternatively, the 4-oxo-1-pyridinyl-(substituted)- -
acetic acids (il) are directly prepared by reaction of a ~ .
2-pyridone with chloroacetic acid or a substituted chloro- :
acetic acid (XIV) in the presence of a strong aqueous base
as indicated in the following reaction scheme:
O ''.:
R1 3
~ + ClCIH-COOH
R2 ~N~R4 R5
H (XIV) -
(XI) o OH
. - R1 Il R3
HCl + ~ :: . ..
R2 N R4
CH-COOH ~ .
R5
, , : ( l l) :`
A preferred method involves the prior silylation of a (sub-
: ~stituted)-4-hydroxypyridine (XI) in the presence of an
: organic base, such as triethylamine, with a tri-(lower
alkyl) substituted halosilane, as for example, chlorotri-
methylsilane. This method enables purification of the
silylated intermed7ate which, in turn, results in the pre-
paration of (substituted)-4-oxo-1-pyridinylacetic acids
(II) having fewer contaminants and in an increased yield.
The (substituted)-4-oxo-1-pyridinyl acetic acids of
Formula (II) wherein R5 is hydrogen can also be prepared
by treating pyrone or by treating a substituted pyrone -.
with glycine in the presence of a base. In this nucleo-
philic reaction the pyrone ring is opened, water eliminated
and the ring reclosed with the amino nitrogen atom now con-
-20-
~ " ' '
.. , . . . : ' , : :
:' ., , , ;~ . . . , .. ~ . ,
M-781-1
~06GZ6~
tained in the pyridine ring. This reaction, which is gen-
erally conducted at elevated temperatures for an extended
period of time, can be illustrated as -follows using 2,6-
dimethyl-4-pyrone (XV)to prepare 2,6-dimethyl-4-pyridone-
1-acetic acid (XVI).
Il :'
~ + H2~CH2COOH
CH3 -~
(XV) base
.`
~ '
:.
~ :',
H20 + ~
CH3 I CH3 < _
CH2COOH
~i
( XV I ) `, "
In general the 6-aminopenicillanic or 7-aminocephalo-
sporanic acid derivatives of the present invention çan be
prepared by the condensation of a 4-oxo-1-pyridinylacetic
acid (Il) and an amino-~-lactam (Ill) as previously indi- ~:
cated. The coupling reaction is generally conducted in
solution in the presence of a suitable solvent. Suitable -
solvents include acetone, dioxane, acetonitrile, chloro-
form, ethylene chloride, tetrahydrofuran or other inert ~
and readily available solvents. The coupling reaction is ~;
further generally conducted in the presence o-f a base,
-21-
" ,-: ~ . ,', . ;" '." ' '~
. . . , . .. , . :. . . .
M-781-1 :
~G6ZG9
. . ,
such as an alkali metal carbonate or an alkali metal acid
carbonate, trialkylamine, in which the alkyl group has
from 1 to 5 carbon atoms or pyridine. The temperature of
the coupling reaction can vary from -20C. to 100C. with
the preferred temperature at room temperature or slightly
below room temperature. The reaction time can vary any-
where from 15 minutes to as long as 36 hours, depending,
oF course, upon the temperature of the reaction mixture
and the reactivity of the particular reactants employed. --
Preferably a period of from 1 to 8 hours is employed.
Following the condensation reaction, the reaction products
are isolated and recovered using conventional extraction
and crystallization procedures which are well known to
those skilled in the art. `
In order to provide a suitable driving force for the
coupling reaction a coupling agent is employed. One type
of coupling agent acts essentially as a dehydration agent,
promoting the acylation and removing the water formed dur-
ing the reaction. Such dehydrative coupling agents or
dehydration agents, as termed hereinj include the compounds: ;
dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholino-
methylcarbodiimide, pentamethylketone-N-cyclohexylimine,
N-ethyl-5-phenylisoxazolium-3-sulfonate and phosphorous
trichloride. The compound dicyclohexylcarbodiimide
represents a preferred dehydration agent particularly in
the preparation of the cephalosporin series of compounds.
A second class of coupling agents can be viewed as
interacting with the various 4-oxo-1-pyridinyl acetic acids
employed in such a manner as to activate the carbonyl
radical of the acetic acid portion of the molecule,
-22-
.
. . .. . .
M-781-1
~066;~69
thereby forming a reactive intermediate. This reactive
intermediate, in turn, acylates the amino-~-lactarn. Thus~
the corresponding acid halides, acid azides~ mixed acid
anhydrides with alkylphosphoric acid or alkylcarbonic acid,
acid amides with imidazole or a 4-substituted imidazole,
acid cyanomethyl esters and acid p-nitrophenyl esters are
all suitable reactive equivalents which may be successfully
employed.
The preparation of a reactive intermediate represents
a preferred process for the preparation of the compounds
of this invention, and in particular, for the preparation
of the cephalosporin derivatives herein described. Suitable
coupling agen-ts include carbonyldiimidazole~ alkylchloro-
formate in which the alkyl group has from 1 to 5 carbon
atoms, thionyl chloride, chloroacetonitrile, and bis-p-
nitrophenyl carbonate. The preferred coupling agent is
carbonyldiimidazole which, in general, is added to a
solution of the 4-oxo-1-pyridinylacetic acid at a tempera- ;
ture below room -temperature. The reaction mixture is per- -
mitted to reach room temperature and the reaction mixture
.
~ subjected to reduced pressure in order to remove the ;~
~..... .
carbon dioxide evolved during the formation of the
imidazolide. The solution containing the reactive imid-
azolide intermediate is again chilled and now coupled with
the appropriate ~actam. Coupling is generally conducted at
a temperature of from 0C. to 150C, for a period of
1-12 hours, whereupon the desired product is recovered
using isolation techniques which are well known to those
skilled in the art.
-23- -
- '
:~. , ' '' ' ;
--- M-781-~
~66~69~ ~:
. :
As an alternative to the direct coupling of the amino-
~-lactam acid, the appropriate 6-aminopenicillanic acid or
7-aminocephalosporanic acid can be coupled as a neutral
salt or in the form of an ester. Suitable salts include
the trialkylammonium salts wherein the alkyl group has -
from 1 to 5 carbon atoms. Illustrative of such salts are
those formed with trimethylamine or triethylamine. Esters
represented by Formula (111) above are those in which the
Free carboxyl group of the amino-~-lactam has been
~ suitabl~ esterified. In those cases in which the ester
..
group is subsequently removed in order to obtain the free
acid, a preference is shown for those ester groups which ~
are readily removed. ~ -
Both the silyl and stannyl esters are among those
esters readily converted to the corresponding free acid
under relatively mild conditions. Thus, for example, the
esterS may be subjected to hydrolysisJ solvolys is or a
nucleophilic exchange, without alteration of the remaining
portion of the molecule. Suitable silylating agents
include the alkyldisilazanes, as for example, tetramethyl-
disilazane and hexamethyldisilazane, or bis-trimethylsilyl-
acetamide Suitable stannylating agents include, for
example, a bis-(tri-lower alkyl-tin)oxide such as b7s-
(tri-n-butyl-tin)oxide; a tri-lower alkyl-tin-hydroxide
such as triethyl-tin-hydroxide; a tri-lower alkoxy tin
compound such as triethoxy-tin-hydroxide; and a tri-lower
alkyl-tin-halide such as tri-n-butyl-tin-chloride. The
resulting silylated or stannylated carboxyl group can be
regenerated to the desired free carboxylic acid by treat-
ment with a neutral hydrogen-donating agent. Water or a ;
~24-
M-781~1
~I:i 66~69
lower alkanol/ as for example~ ethanol, is preferably
used as the hydrogen-donating agent. :~
An alternative method for the preparation of the
compounds of the present invention involves the treatment
of a 6~-haloacetamidopenicillin or a 7~-haloacetamido-
cephalosporin derivative with a silylated 4-hydroxypyridine
as illustrated in the following reaction sçheme:
.. . .
~ + ¦ ~ N - R ~ ~ ~
O
~ (~VII) (XVIII)
~ ''''~''"
R~R~
FH_C_NHtTSI < ,, _ '.: :, '
// N R
( l) , '
wherein R1, R2, R3, R4, Rs, R~ and R8 have the values
previously assigned; Rg is lower alkyl having from 1 to 5
carbon atoms; and Y is bromo or chloro. .
The a-haloacetamido-~-lactam starting materials are
known compounds which have been previously described in
J, Med. Chem,16, 1413 (1973), Be1gium Patent 758J587~ and
-25-
'''' . '
'.'" : . . ' ' . . ' ........................... ': ' ' . '':
,
M~781-l
~ 066ZG9
U.S. Patents 2,941,995 and 3,516,997. Preparation of the
silylated 4-hydroxypyridines takes place with a suitable
silylating agent as previously described. Suitable silyla-
ting agents include: diloweralkyl chlorosilane, tri-
loweralkyl chlorosilane, diloweralkyl bromo5ilane and
triloweralkyl bromosilane in which the loweralkyl group
contains from 1 to 5 carbon atoms, tetramethyldisilazane,
hexamethyldisilazane and bis-trimethylsilylacetamide.
The condensation reaction is generally conducted in
an inert solvent such as chloroform, acetone, methylene ;
chloride, dimethylformamide dioxane or acetonitrile The
temperature of the reaction can vary from -20c. to 100C.
with a temperature of 20~C. preferred. Usually the
reaction takes place in an inert atmosphere such as nitrogen,
argon or helium. The reaction is generally conducted for
a period of from 15 minutes to 36 hours, depending upon the
nature of the reactants and the temperature at ~hich the
reaction is conducted. The reaction is usually complete
in from 1 to 24 hours at the preferred temperature range.
In general, one equivalent of the silylated 4-hydroxy-
pyridine derivative is reacted with one equivalent of the
a-haloacetamido-~-lactam derivative. The ~-lactam deriva-
tive can also be employed in the form of a salt, such as
sodium, triethylamine, N,N diethylaniline or diisopropyl-
ethylamine. Alternatively, the ~-lactam may be in the
form of an ester. Esters include those which can be readily
removed to regenerate the free acid under mild conditions
and which do not alter the remainder of the molecule.
Specifically, such esters include: t-bu-tyl, trialkylsilyl
and trialkylstannyl wherein the alkyl group has from 1 to 5
-26-
, M-781-1
~6~Z69
carbon atoms or benzyl esters, with the preferred esters ~:
being of the trialkylsilyl type. Such esters can be
readily hydrolyzed to the free acid by treatment with a
neutral hydrogen donating agent such as an alcohol.
In all of the aforementioned coupling reactions, -,~ .
compounds of the present invention having reactive func~
tional groups which can interfere with the coupling -.
reaction are protected using suitable blocking groups. Thus, .:; .
carboxyl groups located on the 4-pyridone portion of the
: 10 molecule or on the acetic acid portion of the molecule ~:
may be silylated or etherified with other labile esters :
as previously described. Similarly, amino and hydroxyl ;~
groups located on the 4-pyridone portion of the molecule
can be suitably protected as labile derivatives. Such
derivatives include silyl ethers, benzyl ethers and . .~ :
carbonate esters for hydroxyl groups, carbobenzyloxy) : :
carbo-t-butyloxy and triphenylmethyl derivatives for amino ~ .
groups.
An alternative route to the cephalosporin derivatives ~ .
of Formula (I), wherein the symbol X represents 5-methyl ~
1~3,4-thiadiazol-2-ylthio or 1-methyl-1,2,3,4-tetrazol-5- . .
ylthio, consists of the displacement of the acetoxy group ~.
from the methyl group at the 3-position of the substituted ..
(4-oxo-1-pyridinylacetyl)aminocephalosporanic acids (XIX).
This is illustrated in the following two reaction
schemes: . .
''''~ ' "' '
-27- ...
"'.'~ :.' "".
~. .
. .
i6Z169
o '-~,
R l ~ R3 ,
fH Cl-NH ~ O HS ~ ~H3~ ~ :
Rs O N ~ ~ CH20-C-CH3 (XX)
COOH : :
(XIX)
: .
R, ~ ~
Rz 1 4 R8
H-IC-NH ~ S ~ N - N < :- .
o ~y--C H2--S~ S J--C H3 ~ "
C 00~1 '. .
( XX I )
and
(XIX) HS --~N~ l ~ r .
Rl ~ R3 CH3 ~
Rz IN R4 R8 S .;
ICH-C-NH ~ ~ N~
Rs O ~ ~ CHz-S ~ ~7,N
COOH CH3
-28-
' ' ' .
M~781-1
.
106626~
wherein the symbols R1) R2, R3, R~, R5 and R8 have the
values previously assigned.
The cephalosporanic acids of Formula (XIX) are ~ -
dissolved with the 2-mercapto-5-methyl-1,3,4-thiadiazole
(XX) or a metallic salt thereof in an inert solvent. `
PreFerably an alkali metal salt of the cephalosporanic acid ~;
(XIX) is employed. These salts can be prepared, for
example, by the treatment of the cephalosporanic acid with
.~. .
an alkali metal bicarbonate. The reaction is conducted ~ ~
;
in water or an aqueous organic solvent such as aqueous
acetone, aqueous tetrahydrofuran or aqueous dimethyl~
formamide. If desired, the pH of the reaction mixture
can be controiled by the addition of aqueous buffers. If
the free cephalosporanic acids are employed as starting
. . .
materials, the reaction can be conducted in the presence
.. .
of a base, such as sodium bicarbonate, triethylamlne, or
potassium bicarbonate.
The reaction can be conducted over a temperature
range of from 25C. to 110C. Preferably a temperature
range of from 50C. to 100C. is employed. If desired,
the reaction may be conducted in the presence of an inert
gas such as nitrogen or argon. The reaction time may vary
from 15 minutes to 24 hours, with a reaction time of from
15 minutes to 6 hours preferably employed.
In certain instances the displacement of the acetoxy
group from the methyl group at the 3-position results in
the migration of the double bond to the 2-position of the
~-lactam nucleus. Under those circumstances the position `-
of the double bond can be re-established by the oxidation
of the ring sulfur to the sulfoxide with such oxidizing
-29-
. , , . . , .: i ,
', ' :: . . . . , '
. .
M-781-1
'' ` ~06~6Z69 , "
agents as hydrogen peroxide, sodium metaperiodate or an
organic peracid. Subsequent reduction of the sulfoxide
by means of catalytic hydrogenation or sodium dithionite
provides the desired cephalosporin derivatives which are ;;
unsaturated in the 3-position of the ~-lactam nucleus.
The novel compounds of the present invention are
biologically active and have been found to possess good
antibacterial activity. Thus, they are useful antimicrobial
agents having a broad-spectrum of antimicrobial activity
in vitro against standard laboratory microorganisms which
are used to screen activity against pathogenic bacteria.
The antibacterial spectrum oF typical compounds of the -
present invention is determined in a standard manner by
the agar-dilution streakplate technique commonly used for `
.
the testing of new antibiotics.
:. ;
The presence of the 7-methoxy substituent in the
cephalosporin series has a beneficial effect in increasing
or enhancing the spectrum of antimicrobial activity against
certain gram-negative type microorganisms. More particu-
20larly, compounds containing the 7-methoxy substituent are
active against certain gram-negative microorganisms -that
are resistant to compounds which do not contain the 7-
methoxy substituent, as -for example, Enterobacter aerogenes
Enterobacter cloacae, Serratia marcescens and the indole-
positive species of Proteus.
. . . _ .
The high In vitro antibacterial activity of the
novel compounds of this invention not only rnakes them
useful as pharmacological agents ~ se, but makes them
useful as additives for animal feeds, as well as additives
30for materials which are subject to microbial deterioration,
-30-
M-781-1
1066Z69
such as cu-tting oils and fuel oils. These compounds
are also useful for their antibac-terial effect in soaps,
shampoos and in topical compositions for the treatment
of wounds and burns. ~;~
The invention described herein is more particularly
illustrated in conjunction with the following sp~cific
examples.
: ~ .
EXAMPLE 1
4-Pyridone 1-acetic acid
, ~''
A suspension of 4-hydroxypyridine (19.0 g., 0.2 mole),
triethylamine (22.2 g., 0.22 mole) and toluene (300 ml.) is
heated to its reflux temperature and chlorotrimethylsilane
(23 g , 0.2 mole) is added dropwise. The mixture is heated -~
with stirring at its reflux temperature for 18 hours and
filtered. The filtrate is evaporated and the residue is
distilled at reduced pressure to yield 10.4 g. of silylated
4-hydroxypyridine, b.p 15 102-104C.
The silylated 4-hydroxypyridine (9 g., 0.054 mole)
is mixed with ethylbromoacetate (25 ml.) and the mixture
is stirred until the exothermic reaction subsides.
The solidified mixture is triturated with ether and
filtered. The solid is recrystallized from isopropyl ;~
alcohol to give 8 g. oF 4-pyridone-1-acetic acid, ethyl
ester, hydrobromide salt, having a m.p. of 195C.
The ester, hydrobromide salt (8 g., 0.03 mole) prepared
~'''''.
','.
-31-
.,. .. . , . .. . :
, . . . . . . . . ..
M--781-1 ~
~ 06~
in this manner is added to a 1 N sodium hydroxide solution
(80 ml) and the mixture is s-tirred for 5 hours, acidified
and evaporated to 20 ml. The solution is chilled and
filtered to yield 3.7 9 of 4-pyridone-1-acetic acid having
a m.p. 265-6C.
Following essentially the same procedure but substi-
tuting 3-methyl-4-pyridinol, 2,5-dimethyl-4-pyridinol, 3-
nitro-4-pyridinol for the 4-hydroxypyridine above, there
is obtained ~-methyl-4-pyridone-1-acetic acid, 2,5-dimethyl-
4-pyridone-1-acetic acid and 3-nitro-4-pyridone-1-acetic
acid, respectively.
EXAMPLE 2
4-Quinolone 1-acetic acid
4-Hydroxyquinoline trihydrate (20 9., 0.2 mole) is dis-
solved in a 50~ aqueous potassium hydroxide solution and
chloroacetic acid (20 g., 0.2 mole) is incrementally added.
The resulting solution is heated at its reflux temperature
for 18 hours, chilled, acidified and filtered to give 7 g
of 4-quinolone-1-acetic acid having a m.p. 278-279C.
Following essentially the same procedure but substi-
tuting 3-cyano-2,6-dimethyl-4-pyridinol, 5-chloro~2-ethoxy-
4-pyridinol or 3-trifluoromethyl-4-pyridinol for the 4-
hydroxyquinoline trihydrate above,results in the prepara-
tion of 3-cyano-2,6-dimethyl-4-pyridone-1-acetic acid, 5-
chloro-2-ethoxy-4-pyridone-1-acètic acid and 3-trifluoro-
methyl-4-pyridone-1-acetic acid, respectively.
EXAMPLE 3
2,6-Dimethyl-4-pyridone-1-acetic ac id
-32~
M-781-1
~066Z69
2,6-Dimethyl-4-pyrone (12 4 g.,0.1 mole) is added
to a solution of triethylamine (20 g.,0.2 mole) and
glycine (7.5 g., 0.1 mole) in ethanol (100 ml)/water (10
ml). The mixture is heated to its reflux temperature
for 4 days, chilled, acidified and filtered to yield 4 g ~ `
of 2,6-dimethyl-4-pyridone-1-acetic acid, having a m.p.
of 243C.
~ ollowing essentially the same procedure but substi-
tuting 3-methoxy-2-methyl-4-pyrone~ 3-hydroxy-4-pyrone,
10 ~ and 2,6-dicarbethoxy-4-pyrone for the 2,6-dimethyl-4~
pyrone above, results in the formation of 3-methoxy-2-
methyl-4-pyridone-1-acetic acid, 3-hydroxy-4-pyridone-1-
acetic acid and 2,6-dicarbethoxy-4-pyridone-1-acetic
acid, respectively. -`
..., .. . i . ..
EXAMPLE 4
:
7-~2-(4 ~ l)acetylaminol-
ceehalosporanic acid, sodlum salt ~ -
The compound 4-pyridone-1-acetic acid (3.06 g ,
0.02 mole) is dissolved in dimethylformamide (50 ml) and
the solution is chilled to 0C. Carbonyldiimidazole (3.2
g" 0.02 mole) is added and the mixture is stirred under
nitrogen at 0C. ~or 30 minutes and then warmed to room
temperature. The reaction flask is evacuated ~or 30 min- -~
utes to remove the carbon dioxide and chilled to -20C.
In a separate ~lask, 7-aminocephalosporanic acid is
silylated by heating a suspension o~ 7-aminocephalosporanic
acid (5.4 g" 0.02 mole) and hexamethyldisilazane (8 ml) in
chloro~orm (50 ml) at re~lux for 30 minutes. This solu-
.
-33-
."'," ' ,
.
'.' ' ,, ` ,' , ' ': ' :~,. '
:` .' ,' ' ~. .
M-781-1
~L061626~
tion is evaporated to dryness to remove the liberated
ammonia. A solution of the residue in chloroform (50ml)
is chilled to -20C. and added to the imidazolide. The
reaction mixture is stirred at 0C. for 1 hour, warmed to
room temperature and stirred overnight.
The solution is treated with 2 ml of methanol and the
precipitated 7-aminocephalosporanic acid is removed by
filtration. A solution of sodium 2-ethylhexanoate in
n-butanol (10 ml of a 2 N solution) is added, and the mix-
ture is diluted with ether to an approximate volume of 1
liter in order to precipitate the product. After repre-
cipitation from methanol with ether, a yield oF 2.? g.
of 7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalosporanic
acid is obtained as a white solid having a m.p. of 180C.
(dec). Iodine titration indicated a purity of 72.7~.
~ Repeating es~entially the same procedure but substi-
tuting 6-aminopenicillanic acid, 7-aminodesacetylcephalo-
sporanic acid, 7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-
ylthio)methyl]decephalosporanic acid, 7-amino-3-[(1-methyl-
1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanic acid and
7-amino-7-methoxycephalosporanic acid for the 7-aminocephalo-
sporanic acid above, results in the formation of the sodium
salt of 6-~2-(4-oxo-1-pyridinyl)acetylamino]penicillanic
acid, 7-[2-(4-oxo-1-pyridinyl)acetylamino]desacetylcephalo-
sporanic acid, 7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(5-
methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic
acid, 7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(1-methyl-
1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanic acid,
and 7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]-
cephalosporanic acid, respectively.
-3~-
M-781-1 .
10662~
EXAMPLE 5
6-~2-(4-Oxo-1-quinolinyl)acetylaminol-
penicillanic acid, sodium salt
A solution of 4-quinolone-1-acetic acid (4.1 g., 0.02
mole) in 50 ml of dimethylformamide is placed under an
atmosphere of nitrogen, chilled to 10~C. and carbonyldi-
imidazole (~.2 g., 0.02 mole) ts added in one portion. Aftçr
the mixture has warmed to room temperature the flask is
evacuated for 15 minutes to remove the carbon dioxide -
evolved in formation of the imidazolide. The solution is
chilled to 10C. and a solution of 6-aminopenicillanic
acid (4.4 g., 0.02 mole) and triethylamine (5 g.,20~ excess)
in chloroform (50 ml) is added. The reaction mixture is
stirred at 10C. for 1 hour, warmed to room temperature
and stirring is continued for an additional 3 hours.
Ten ml of a 2 N solution of sodium 2-ethylhexanoate in -
butanol is added and the product is precipitated by
the addition of ether (700 ml). The 6-[2-(4-oxo~
quinolinyl)acetylamino]penicillanic acid is filtered~ repre-
cipitated from methanol with ether and vacuum dried to
yield 4.8 g of a white solid, m.p. 204C. (dec). Iodine `
titration indicates 86.4~ purity.
Repeating essentially the same procedure, but substi- ~ :
tuting 2,5-dimethyl-4-pyridone-1-acetic acid, 3-nitro-4-
pyridone-1-acetic acid, 3-hydroxy-4-pyridone-1-acetic
acid and 3,5-diiodo-4-pyridone-1-acetic acid for the 4-
quinolone-1-acetic acid above, results in the preparation
of the sodium salt of 6-[2-(2,5-dimethyl-4-oxo-1-pyridinyl)-
acetylamino]penicillanic acid, 6-[2-(3-nitro-4-oxo-1-
-35-
, ''` ' ' ', ,
` M-781-1 -
~066;26!~
pyridinyl)acetylamino]penicillanic acid, 6-[2-(3-hydroxy-
4-oxo-1-pyridinyl)acetylamino]penicillanic acid and
6-[2-(3J5-diiodo-4-oxo-1-pyridinyl)acetylamino]penicillanic
acid, respectively.
Substituting 7-amino--7-methoxycephalosporanic acid
for the 6-amino penicillanic acid above results in the
formation of the sodium salts of
6-~2-(4-Qxo-1-quinolinyl)acetylamino]-7-methoxycephalo-
sporanic acid,
6 [2-(2,5-dimethyl-4-oxo-1-pyridinyl)acetylamino]-7-methoxy-
cephalosporanic acid,
6-[2-(3-nitro-4-oxo-1-pyridinyl)acetylamino]-7-methoxy-
cephalosporanic acid,
6-[2-(3-hydroxy-4-oxo-1-pyridinyl)acetylamino]-7-methoxy-
cephalosporanic acid, and
- 6-[2~-(3l5-diiodo-4-oxo-1-pyridinyl)acetylamino]-7-methoxy-
cephalosporanic acid.
EXAMPLE 6
_ _
7-[2-(?~6-Dimethyl-~:a~eyridinyl~acetylamin
cephalosporanic acid~ sodium_salt
2,6-Dimethyl-4~pyridone-1-acetic acid (3.6 g., 0.02
mole) is dissolved in dimethylformamide (50 ml.) and the
solution is chilled to 0C. Carbonyldiimidazole (3.2 9.,
0.02 mole) is added and the mixture is stirred under
nitrogen at 0C. for 30 minutes and permitted to warn to
room temperature. The reaction flask is evacuated for 30
minutes to remove the evolved carbon dioxide. The result-
ing solution is chilled to -20C. and a chloroform solu-
-36-
M-781-1
6269
tion (50 ml.) of trimethylsilyl-7-aminocephalosporanic
acid (0.02 mole) prepared as in Example 4 above, is added
thereto. The reaction mixture is stirred at 0C. for 1
hour, warmed to room temperature and stirred overnight.
The reaction mixture is treated with 2 ml. of methanol
and the precipitated 7-aminocephalosporanic acid is removed - -
by filtratration. A 2 N solution of sodium 2-ethylhexanoate
in n-butanol (10 ml.) is added to the reaction mixture,
which is diluted to 1 liter with ether and filtered. The
7-[2-(2,6-dimethyl-4-oxo-1-pyridinyl)acetylamino]cephalo-
sporanic acid so obtained is reprecipitated from methanol
using ether and vacuum dried to yield 5.0 g. of a white
powder having a m.p. of 240C.
Following essentially the same procedure but substi-
tuting 3-methyl-4-pyridone-1-acetic acid, 5,6,7,8-tetra-
hydro-4-quinolone-1-acetic acid, 5-chloro~2-ethoxy-4-
pyridone-1-acetic acid, 3-trifluoromethyl-4-pyridone-1-
acetic acid and 3-hydroxy-4-pyridone-1-acetic acid for the
2,6-dimethyl~4-pyridone-1-acetic acid above results in the -
preparation of the sodium salts of 7-[2-(3-methyl-4-oxo-1-
pyridinyl)acetylamino]cephalosporanic acid, 7-[2-(5,6,7,8-
.
tetrahydro-4-oxo-1-quinolinyl)acetylamino]cephalosporanic
acid, 7-[2-(5-chloro-2-ethoxy-4-oxo-1-pyridinyl)acetyl-
amino]cephalosporanic acid, 7-[2-(3-trifluoromethyl-4-oxo-
1-pyridinyl)acetylamino]cephalosporanic acid and 7-[2-(3-
hydroxy-4-oxo-1-pyridinyl)acetylamino]cephalosporanic acid,
respectively.
-37-
. .
. .
M-781-1
~LOG6Z69
Substituting trimethylsilyl-6-amino-6-methoxy-
penicillanic acid for the trimethylsilyl-7-aminocephalo-
sporanic acid above results in the formation of the
sodium salts of
6-[2-(2,6-dimethyl-4-oxo-1-pyridinyl)acetylamino]-6-methoxy-
penicillanic acid,
6-[2-(3-methyl-4-oxo-1-pyridinyl)acetylamino]-6-methoxy-
penicillanic acid,
6-[2-(5,6,7,8-tetrahydro-4-oxo-1-quinolinyl)acetylamino]-6-
methoxypenicillanic acid,
6~[2-(5-chloro-2-ethoxy-4 oxo-1-pyridinyl)acetylamino]-6-
methoxypenicillanic acid,
6-[2-(3-trifluoromethyl-2-oxo-1-pyridinyl)acety1amino]-6-
methoxypenicillanic acid, and
6-[2-(3-hydroxy-4-oxo-1-pyridinyl)acetylamino]-6-methoxy-
penicillanic acid.
EXAMPLE 7
7-~2-(4-Oxo-1-pyridinyl)acetylamino-~-
(pyridiniummethyl)decephalosporanic acid
7-[2-(4-Oxo-1-pyridinyl)acetylamino]cephalosporanic ~
acid, sodium salt, is dissolved in water and reacted with ~ -
pyridine in the presence of potassium thiocyanate at 60C.
for 6 hours. Work-up is conducted according -to J.L. Spencer,
et al., J. Org. Chem. 32, 500 (1967) and results in the
preparation of 7-[2-(4-oxo-1-pyridinyl)acetylamino~ 3-
(pyridiniummethyl)decephalosporanic acid as the zwitterion.
-38-
.
-'- . ~,. . . . . .. .
,.... , . . , : . .: , - : , , :
. . . . . . . . . . . . . . .
, , , , : ', ,, , ' ,.,. .' ' ',, ,
M-781-1 ~
6;~69
.
EXAMPLE 8
7-~2-(4-Oxo-l-pyridinyl)acetylamino
desacetylcephalosporanic acid
7-[2-(4-Oxo-1-pyridinyl)acetylamino]cephalosporanic
acid, sodium salt, is treated with an acetyl esterase
isolated from orange peel according to J. D~A. Je~fery~ ~ -
et al., Biochem. J., 81, 591 (1961) to yield 7-[2-(4-oxo-
1-pyridinyl)acetylamino]desace~ylcephalosporanic acid~
sodium salt.
EXAMPLE ~ ~-
4-Trimethylsilyloxypyridine
. ~, .
- ~ To 500 g. of crude 4-hydroxypyridine is added 5.5 l.
. o-F toluene. The mixture is heated with stirring and
approximately 700 ml. oF toluene is distilled in order to
remove any water present. The reaction mixture is main-
tained at its reFulx temperature and trimethylsilylchloride
(543 g.) is slowly added thereto. The reaction mixture is
reFluxed For approximately ~ hours, cooled and filtered.
The Filtrate is evaporated under reduced pressure to
remove the toluene and the residue distilled at 18-20 mm.
yielding 620 g. oF 4-trimethylsilyloxypyridine having
a b.p. oF 95-6C.
EXAMPLE 10
~-L2-(4-Oxo-1-pyridinyl)acetylaminol-
cephalosporanic acid, sodium_salt
39-
:.
'' ~ ' .. ', ,' - .. . , . ~ . , :
.. . . . .
3L~66~
To 20.0 g. of 7-(2-bromoacetamido)cephalosporanic
acid, prepared in accordance with U.S. Patent 3,647,789, is
added 135 ml. of chloroform and 20 ml. of N,O-bis-
(trimethylsilyl)acetamide. The mixture is stirred for about
1 hour under an atmosphere of dry nitrogen gas, 9.4 ml. of
4-trimethylsilyloxypyridine added, and the resulting mixture
stirred at room temperature for approximately 15 hours while
maintaining an atmosphere of dry nitrogen gas. Methyl
alcohol (80 ml.) is added to the reaction mixture with stirring
until all of the precipitate which initially forms is
dissolved. The mixture is poured into approximately 1 liter
of anhydrous ether with stirring, the solvent removed by
decantation, and the sticky precipitate which remains is
dissolved in an additional 400 ml. of methyl alcohol. A
solution of 2 N sodium-2-ethylhexanoate (65 ml.) in n-butanol
is added to the solution containing the dissolved precipitate,
and the resulting mixture is treated with charcoal and filtered
through a bed of diatomaceous earth. Isopropyl alcohol
(900 ml.) is slowly added to the filtrate. The precipitate
which forms is removed by filtration, washed with ether
and dried in vacuo to yield 17.2 gms. of 7-[2-(4-oxo-1-
pyridinyl)acetylamino]-cephalosporanic acid, sodium salt.
Following essentially the same procedure and
substituting 7-[2-chloroacetamido]-7-methoxycephalosporanic
acid, 7-[2-chloro-2-methylacetamido]desacetylcephalosporanic
acid, 7-[2-bromo-2-carbethoxyacetamido]desacetoxycephalo-
sporanic acid, 6-[2-chloro-2-methylacetamido]penicillanic
acid, 6-[2-bromoacetamido]-6-methoxypenicillanic acid, and
6-[2-bromo-2-carbethoxyacetamido]penicillanic acid for
the 7-(2-bromoacetamido)cephalosporanic acid above, ~
' . ' ' . ' .
:~ . .
-40-
-~ "~,,,.~" ' '
10ti6'~6~
results in the preparation of 7-[2-(4-oxo-1-pyridinyl)-
acetylamino]-7-methoxycephalosporanic acid, 7-[2-(4-oxo-
l-pyridinyl)-2-methylacetylamino]desacetylcephalosporanic
acid, 7-[2-(4-oxo-1-pyridinyl)-2-carbethoxyacetylamino]-
desacetoxycephalosporanic acid, 6-[2-(4-oxo-1-pyridinyl)-
2-methylacetylamino]penicillanic acid, 6-[2-(4-oxo-1-pyridinyl)-
acetylamino]-6-methoxypenicillanic acid, and 6-[2-(4-oxo-1-
pyridinyl)-2-carbethoxyacetylamino]penicillanic acid.
. .
Substituting 2,6-dimethyl-4-trimethylsilyloxy- ~;
pyridine, 2,6-bis(carbotrimethylsilyloxy)-4-trimethyl- ~-
silyloxypyridine and 3-chloro-4-trimethylsilyloxypyridine -
for the 4-trimethylsilyloxypyridine above results in the
formation of the corresponding 2-(2,6-dimethyl-4-oxo-1- ~ -~
pyridinyl), 2-(2,6-dicarboxy-4-oxo-1-pyridinyl), and
2-(3-chloro-4-oxo-1-pyridinyl) derivatives of the various
cephalosporanic and penicillanic acids shown.
EXAMPLE 11
7-(~-sromoacetylamino)-3-[(5-methyl-l~3~4-thiadia
2-ylthio)methyl]decephalosporanic acid
To 1.4 g. of 7-amino-3-[(5-methyl~1,3,4-thiadiazol-
2-ylthio)methyl]decephalosporanic acid, prepared as described
in U.S. Patent 3,516,997, and contained in a stirred mixture
of 25 ml. of water and 25 ml. of acetone is added 3 g. of
sodium bicarbonate. The mixture is chilled to -10C. and 2.2 g.
of bromoacetyl bromide in one ml. of acetone is slowly
added to the stirred mixture over a period of 10 minutes.
The mixture is stirred for an additional hour at -10C. and
permitted to come to room temperature. The reaction
mixture is extracted with ethyl
,
-41-
/~
"'J ~:~r~ ~
" '', ' ' '" '" ' ~ ' ' ,' .'',', ' ; '',',
.. . . . .
M-781-1
~0616Z69
acetate and the organic phase is d7scarded. Th~ aqueous
phase is layered with 100 ml. of ethyl acetate and the
aqueous phase adjusted to a pH of 2 with a 40~ solution
of phosphoric acid. The organic phase is separated, dried
over sodium sulfate and decolorized with charcoal. The
solution is filtered, evaporated and ~he residue is tri-
turated with ether. The residue is dried in vacuo to
yield 0.7 g. of 7-(~-bromoacetylamino)-3 [(5-methyl-1,3,4-
thiadiazol-2-ylthio)methyl]decephalosporanic acid.
Following essentially the same procedure and substi-
tuting 7-amino-7-methoxy-3-~(5-methyl-1,3,4-thiadiazol~2-
ylthio)methyl]decephalosporanic acid, 7-amino-3~[(1-
methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanic
acid and 7-amino-7-methoxy-3-[(1-methyl-1,2,3,4-tetrazol-
5-ylthio)methyl]decephalosporanic acid for the 7-amino-3-
[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic
acid above results in the formation of 7-(~-bromoacetyl-
amino)-7-methoxy-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]-
decephalosporanic acid, 7-(~-bromoacetylamino)-3-[(1-methyl-
1,2,3,4-tetrazol-5-ylthto)methyl~decephalosporanic acid, and
7-(~-bromoacetylamino)-7-methoxy-3-[(1-methyl-1,2J3,4-tetra.
zol-5-ylthio)methyl]decephalosporanic acid, r~spec-tively.
, -
EX~MPLE 12 ;;
7~~?-(4-Oxo-1-pyrj~j ~
[(5-methyl-1,3,4-thiadiazol-2-Ylthio)methyll ;
decephalosporanic acid sodium_salt ~
:
To 4.65 g. of 7-(a-bromoacetylamino)-3 [(5-methyl-
1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic, as ~
- .
-42-
. .
.: . :
,. , , ~ , , , ~. , ~ .
,, .. , .. . : .
, . .. . .
~ ~ M - 7~1-1
~1~6~;26~
prepared in Example 11, is added 50 ml. of chloroform and
5 ml. of N,0-bis(trimethylsilyl)acetamide. The mixture is
stirred'under an atmosphere of nitrogen until a clear solu- -'
- tion is obtained, 4-trimethylsilyloxypyridine (1.6 9.) is
added and the mixture stirred for 18 hours under nitrogen.
Methyl alcohol (5 ml.) is added and the solid precipitate '
which forms is collected via filtration. The precipitate ~'~
is dissolved in 100 ml. of methyl alcohol, 5 ml. of a 2 N
sodium 2-ethylhexanoate solution in n-butanol is added, '
followed by 200 ml. of ether. The precipitate wnich forms
is collected via filtration and dried under vacuum to yield
the sodium salt oF 7-[2-(4-oxo-1-pyridinyl)acetylamino~
' [(5-me-thyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo-
' sporanic acid.
Following essentially the same procedure but substi- '
tuting 7-(a-bromoacetylamino)-7-methoxy-3-[(5~methyl-173,~
thiadiazo7-2-ylthio)methyl]decephalosporanic acid, 7-(~--
~romoacetylamino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthioj-
methyl]decephalosporanic acid or 7-(~-bromoacetylamino)-7- ''
methoxy-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl~-
' ~ decephalosporanic acid for the 7-(a-bromoacetylamino)-3-[(5
- methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic
acid above results in the formation of the sodium salts of
7-methoxy-7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(5-methyl- '
1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic acid,
7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-[(1-methyl-1,2,3,4-
tetrazol-2-ylthio)methyl]decephalosporanic acid, and 7-
methoxy-7-[2-(4'-oxo-1-pyridinyl)acetylamino]-3-C(1-methyl-
1,2,3,4-tetrazol-2-ylthio)methyl]decephalosporanic acid~ '
respectively. '
-43-
,
.,~ . .' ' ' "` "' .
. . '. .' " ' ' ' ' ' '
. - . , , :
.
.. . . . . . .
M-781-1
~O~i EiZ691
EXAMPLE 13
7-~2-(3-cyano-4-oxo- ~ dinyl)acetylaminol-3-
[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl
decePhalosPoranic acid, sodium salt
To a chloroform solution of 7-(~-bromoacetylamino)-3-[(5-
methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic
acid and N,N-diethylaniline is added one equivalent of 3-
cyano-4-trimethylsilyloxypyridine. The mixture is stirred
for approximately 15 hours at room temperature under an
atmosphere of nitrogen. Methyl alcohol is added followed
by the addition of anhydrous ether. The precipitate which
forms is removed by filtration, dissolved in methyl alcohol
and an equivalent amount of a solution of 2 N-sodium
2-ethylhexanoate in butanol added thereto. An equal
~ . . .
volume of ether is added and the precipitate which forms
is removed by filtration and dried under vacuum to yield ;
7-[2-(3-cyano-4-oxo-1-pyridinyl)acetylamino]-3-[(5-methyl-
1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic acid ;
as the sodium salt.
:
EXAMPLE 14
7-Methoxy-7-~2-(4-oxo-1 ~uinolinyl~acetylaminol-
3-~ k~l-1,2J3~4-tetrazol-5-ylthio~m~thyl]
d..~eh~ anic acid, sodium salt
A mixture of sodium 7-methoxy-7-[2-(4-oxo-1-quinolinyl)-
acetylamino]cephalosporanate (3.5 g.), sodium bicarbonate
(2.5 g.), 1-methyl-5~mercapto-1,2,3J4-tetrazole (2.6 g.),
and 60 ml. of water is heated at about 70~C. under an
atmosphere of nitrogen for about 4 hours. The reaction
4~
~'"''' .
. , . . . i . . . . . . .. .
':, . '' , , .. ' . ~ . ,
~_ M - 781-1
1~66Z~
, .
mixture is cooled and evaporated under reduced pressure.
The residue which remains is triturated with acetone, -
dissolved in methanol and filtered. Isopropyl alcohol is
- added to the filtrate to form a precipitate, which is
collected by filtration and vacuum dried to yield a pre-
cipitate of 7-methoxy-7-[2-(4-oxo-1-quinolinyl)acetyl-
amino]-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]
decephalosporanic acid as the sodium salt.
Following essentially the same procedure but sub-
stituting 7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalo-
sporanic acid or 7-[2-methyl-2-(2,6-dimethyl-4-oxo-1-
pyridinyl)acetylamino]cephalosporanic acid results in
the formation of 7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-
[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalo-
sporanic acid and 7-[2-methyl-2-(2,6-dimethyl-4-oxo-1- -~
,. .
pyridinyl)acetylamino]-3-[(1-methyl-1,2,3,4-tetrazol-5-
ylthio)methyl]decephalosporanic aci~ as their sodium salts,
respectively.
. :' " '
EXAMPLE 15
7-~2-~4-oxo-1-p~idinyl)acetylamino1-3-~(5-methyl- ~ ;
4-thiadiazol-2-ylthio ~ethylldecephalosporanic
acid,_sodium salt
To a solution of (5 g.) of sodium 7-[2-(4-oxo-1-
pyridinyl)acetylamino]cephalosporanate in 500 ml. of water
is added (0.95 g.) of sodium bicarbonate and (2.9~ g.) of
2-mercapto-5-methyl-1,3,4-thiadiazole. The mixture is
heated under a nitrogen atmosphere at 70C. for 3 hours
and evaporated under reduced pressure. The residue is
dissolved in 50 ml. of rnethanol and treated with an excess
- -~5-
M-781-1
~06626~
of acetonitrile. The white precipitate which forms is
removed by filtration, washed with acetonitrile and dried
under vacuum to yield (4.3 g.) 7-[2-(4-oxo-1-pyridinyl)
acetylamino]-3-~(5-methyl-1,3,4-thiadiazol-2-ylthio)
methyl]decephalosporanic acid as the sodium salt.
Following essentially the same procedure but substi-
tuting the sodium salts of 7-methoxy-7-[2-(4-oxo-1-
quinolinyl)acetylamino]cephalosporanic acid, 7-methoxy-7-
[2-(4-oxo-1-pyridinyl)acetylamino]cephalosporanic acid
or 7-[2-methyl-2-(2,6-dimethyl-4-oxo-1-pyridinyl)-
acetylamino]cephalosporanic acid results in the formation
of 7-methoxy-7-~2-(4-oxo-1-quinolinyl)acetylamino]-3-[(5- -
methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanic ;
acid, 7-methoxy-7-[2-(l~-oxo-1-pyridinyl)acetylamino]-
3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalo- -
` sporanic acid or 7-[2-methyl-2-(2,6-dimethyl-4-oxo-1-
pyridinyl)acetylamino]-3-[(5-methyl-1,3,4-thiadiazol-2- ~ -
ylthio)methyl]decephalosporanic acid as their sodium ~ -
salts, respectively. ;~
EXAMPLE 16
' , ,: - , . :
Pivaloyloxymethyl 7-r2-~4-oxo-1-pyridinyl~ ~ ;
acetylaminolcepha_~rora ate
To (4.5 g.) of sodium 7-[2-(4-oxo-1-pyridinyl)~ ;
acetylamino]cephalosporanate dissolved in 40 ml. of
dimethylformamide and chilled to 0C. is added (2.6 g.) of
pivaloyloxymethyliodide and the solution stirred for
approximately 25 minutes. The mixture is diluted with
ethyl acetate (170 ml.), washed well with water and then
washed with a dilute solution of sodium bicarbonate. The
-46-
- . . . . .. . .
. .
-, :. .. : , . . . . . . ..
:,. , :
M-7~
.,.~
~06~:;Z69
organic phase is dried over anhydrous sodium sulfate,
~iltered and evaporated to dryness to yield pivaloyloxy-
methyl 7-[2-~4-oxo-1-pyridinyl)acetylamino]cephalosporanate.
Following essentially the same procedure but substi-
tuting acetoxymethyliodide, N-chloromethyl-N-methyl-
urethane, or p-acetoxybenzylbromide for the pivaloyloxy-
methyliodide above results in the formation of acetoxymethyl
7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalosporanate, -
N-ethoxycarbonyl-N-methylaminoethyl 7-[2-(4-oxo-1-
pyridinyl)acetylamino]cephalosporanate and p-acetyloxy- : -
benzyl 7-[2-(4-oxo-1-pyridinyl)acetylamino]cephalospora- :
nate, respectively.
Substituting the sodium salts of 7-methoxy-7-[2-(4- :
oxo-l-pyridinyl)acetylamino]-3-[(1-methyl-lJ2,3,4-tetrazol- ~ .
5-ylthio)methy1]decephalosporanic acid, 6-methoxy-6-
[2-(3-cyano-4-oxo-1-pyridinyl)acetylamino]penicillanic
acid or 6-[2-(4-oxo-1-quinolinyl)-2-methylacetylamino]-
penicillanic acid for the 7-[2-(4-oxo-1-pyr;dinyl)acetyl-
amino]cephalosporanic acid above results in the formation
of pivaloyloxymethyl 7-methoxy-7-[2-~4-oxo-1-pyridinyl)-
acetylamino]-3-~(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]- ~
decephalosporanate, pivaloyloxymethyl 6-methoxy-6-[2-(3- .
cyano-4-oxo-1-pyridinyl)acetylamino]penicillanate and
pivaloyloxymethyl 6-[2-(4-oxo-1-quinolinyl)-2-methyl- ..
acetylamino]penicillanate, respectively. .-.
" ''
'.~ "
-47-
M-781-1
~ 6Z 6~
EXAMPLE 17
. .
N-Ethoxycarbon~l-N-methylamino 7-~2_(4-oxo-
1-pyridinyl)acetylaminol-~- ~5-m~ hyl-1~3,4-
thiadiazol-2-yl ~
To a slurry o-F sodium 7-[2-(4~oxo-1-pyridinyl)- -
acetylamino]-3-~(5-methyl-1,3,4-thiadiazol-2-ylthio)-
methyl]decephalosporanate (0.01 mole) contained in 20 ml.
of dimethylformamide and maintained at a temperature of
0-5~C. is added a sol.ution of N-chloromethyl-N-methyl- .
: 10urethane (0.01 mole) contained in 5 ml. of dimethyl- J,:
formamide The mixture is stirred for about one hour and
poured into water. The precipitate which.forms is dissolved :.-
in ethyl acetate~ washed with water followed by a dilute
solution of sodium bicarbonate and dried over magnesium 1
sulfate. The solution is evaporated under reduced . ~
pressure to yield the desired N-ethoxycarbonyl-N-methyl- :.
amino 7-[2-(4-oxo-1-pyridinyl)acetylamino]-3-~(5-methyl- : :
1,~,4-thiadiazol-2-ylthio)methyl]decephalosporanate~
. .
EXAMPLE 18
Specific nutrient agar plates are completely innocu- ..
lated with the various test organisms. Filter paper discs
are placed on the surface of the agar and wetted with 0.1 ml.
of a solution containing 10, 100 and 1/000 micrograms of
the test compound. Zones of inhibition of microbial growth
are used to indicate the antibacterial activity of the test
compound against the various test organisms employed
..
~48-
.
' :, -.....
.. ... . ...
: . , ... . :
M-781 ~
`` :
~L696GZ69
.
The following table summarizes the in vitr_ activity
of the following representative compounds: 6-[2-(4-oxo-
1-pyr7dinyl)acetylamino]penicillanic acid, sodium salt :~
(1), 7-[2-(4-oxo-1-pyridinyl)acetylamino]desacetoxycephalo-
sporanic acid (2), 6-~2-(3,5-diiodo-4~oxo-1-pyridinyl)- ~ ~ .
acetylamino]penicillanic acid, sodium salt (3), 7-[2-(2,6- .
dimethyl-4-oxo-1-pyridinyl)acetylamino]desacetoxycephalo- ~.
sporanic acid, sodium salt (4), 7-[2-(4-oxo-1-pyridinyl)-
acetylamino]cephalosporanic acid, sodium salt (5) and
6-[2-(4-oxo-1 quinolinyl)acetylamino]penicillanic acid, ~ :
sodium salt (6). ~
.
` . .''
' ~'` "' '
''.: ' ~
.. .. .. .
,~
.: .
-49-
M-781-1
.
~66Z69
a)
o
"
U~
a) ,,:
(V U~ :.
In ~
~ ~ ., ..
- C o U) o o o o o
_. ~, , o o o o o
_ ., o ~ o o o o o
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