Note: Descriptions are shown in the official language in which they were submitted.
GG211/194
10577~0
This invention relates to new 3-heterothio[alkoxycarbonyl
and alkoxythiocarbonyl)thioacetyl]cephalosporin derivatives which
have the formula
(I) IRl S
R2-O-C-S-CH - CO - NH ~ (
Z ~ CH 2 - S - R4
COOR3
Rl is hydrogen, lower alkyl, phenyl, thienyl or
furyl.
R2 is lower alkyl or phenyl-lower alkyl.
R3 is hydrogen, lower alkyl, tri(lower alkyl)silyl,
tri(lower alkyl)stannyl, phenyl-lower alkyl, a salt forming
ion, or -CH2-O-C-R wherein R is lower alkyl, phenyl, or
phenyl-lower alkyl.
Z is O or S.
R4 is a nitrogen and/or sulfur or oxvaen-containing
heterocyclic rin~ system selected from the arou~ consistinq
of oxadiazole, thiazole, tetrazole and thiadiazole and in
addition, when Z is O, i~oxazole, isothiazole and l-oxo-
pyridine and wnen Z i8 S, triazole and thiatriazole, and
lower alkyl substituted analogs of said heterocyclic rings;
are useful as antibacterial agents.
'q~
GG211/194
105774V
The various groups represented by the symbols have
the meanings defined below and these definitions are retained
throughout this specification.
The lower alkyl groups are straight or branched chain
hydrocarbon groups containing 1 to 8 carbon atoms, preferably
1 to 4 carbons. Examples of the type of these groups are
methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
isopentyl, etc. The phenyl-lower alkyl groups include
one or two phenyl radicals attached to such lower alkyl groups,
e.g., benzyl, phenethyl, benzhydryl, etc.
The salt forming ions represented by R3 are metal
ions, e.g., alkali metal ions such as sodium or potassium;
alkaline earth metal ions such as calcium or magnesium, or
an amine salt ion, of which a number are known for this
purpose, for example, especially lower alkylamines like
methylamine or triethylamine, and phenyl-lower alkylamines
like dibenzylamine.
The nitrogen containing heterocyclics are particularly
1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, tetrazole,
1,2,3-triazole, 1,2,3,4-thiatriazole and their lower alkyl
derivatives, especially the radicals 3-lower alkyl-1,2,4-
thiadiazol-5-yl, 5-lower alkyl-1,3,4-thiadiazole-2-yl,
2-lower alkyl-1,3,4-oxadiazole-5-yl and l-lower alkyl-1,2,3,4-
tetrazol-5-yl. The preferred lower alkyl group is methyl.
Preferred embodiments of this invention are as
follows:
R1 is hydrogen, lower alkyl of 1 to 4 carbons, phenyl,
furyl, thienyl, especially hydrogen,phenyl or thienyl.
GG21yl94
~05'7740
R2 is lower alkyl of 1 to 4 carbons, especially
methyl or ethyl.
oR3 is hydrogen, alkali metal, diphenylmethyl or
-CH2-O-C-R, especially hydrogen, pivaloyloxymethyl, sodium
or potassium. R is lower alkyl, especially t-butyl.
R4 is thiadiazole, tetrazole and their methyl
substituted analogs, especially, 1,3,4-thiadiazole, 5-methyl-
1,3,4-thiadiazole, tetrazole and most especially l-methyl-lH-
tetrazole.
The new derivatives of alkoxycarbonyl and alkoxvthio-
carbonyl)thioacetyl]cephalosporins of this invention are produced
by reacting 7-aminocephalosporanic acid (7-ACA) (or derivative
wherein R3 is other than hydrogen) with a mercaptan HS-R4 at a
pH of about 8-8.5 to obtain the derivative of the formula
(II) S
2 ~
~ I CH 2 - S- R4
COOR3
The product of formula II is then acylated on the amino
group with a thioacetic acid of the formula
(III) IRl
R2-0-C-S-CH-COOH
z
or activated derivatives thereof. The symbols have the meanings
already defined.
The activated derivatives referred to include, for
example, the reaction product with an anhydride forming
reagent ~uch as ethylchloroformate, benzoyl chloride,
1~57 74~ GG211/194
pivaloyl chloride, etc., or with bisimidazolecarbonyl, dicyclo-
hexylcarbodiimide, p-nitrophenol or the like.
According to a preferred modification, the 7-amino-
cephalosporanic acid derivative of formula II, preferably
in the form of its diphenylmethyl ester, in an organic solvent
like tetrahydrofuran is added to a mixture containing the acid
of formula III and dicyclohexylcarbodiimide in an organic
solvent like the one mentioned above at a reduced temperature
of about 0 C. The dicyclohexylurea formed during the
reaction is removed and the product is recovered from the
filtrate. When the preferred diphenylmethyl ester is used,
the ester group is removed by treatment with trifluoroacetic
acid and anisole.
The acids of formula III wherein Z is O are formed
by reacting a mercaptoacetic acid of the formula
-(IV)
Rl-CH-COOH
SFi
with a chloroformic acid ester of the formula
(V) Cl--C-O-R2
in the presence of an inorganic or organic base, e.g.,
an alkali metal hydroxide such as potassium hydroxide or
triethylamine or dimethylaniline.
GG211/194
~0S~'~40
The acids of formula III wherein Z is S are produced
by the method of Bonner, J. Org. Chem. 33, 1831(1968) as
described in U.S. 3,880,845 issued April 29, 1975.
When R3 is the acyloxymethyl group -CH2-O-CO-R, this
group can be introduced onto the 7-ACA moiety prior to the
reaction with the acid of formula III by treatment with one
to two moles of a halomethyl ester of the formula
(VI) hal -CH2OCOR
wherein hal is halogen, preferably chlorine or bromine, in
an inert organic solvent such as dimethylformamide, acetone,
dioxane, benzene or the like at about ambient temperature or
below.
Further process details are also provided in the
illustrative examples.
Certain of the compounds of this invention may exist
in different optically active forms. The various stereo-
isomeric forms as well as racemic mixtures are within the
scope of the invention.
The compounds of this invention have antibacterial
activity against both gram positive and gram negative
organisms such as Staphylococcus aureus, Proteus rettgeri,
and E. hafniae. They may be used as antibacterial agents
in a prophylactic manner or to combat infections caused by
organisms such as those named above, and in general can be
utilized in a manner similar to cephradine and other cephalo-
sporins. For example, a compound of formula I or a
physiologically acceptable salt thereof can be used in
various animal species in an amount of about 1 to 50 mg/kg
daily, orally or parenterally, in single or two to four
lOS7740 GG211/194
divided doses to treat infections of bacterial origin, e.g.,
5.0 mg/kg has been found useful in mice.
Up to about 600 mg. of a compound of formula I
or a physiologically acceptable salt thereof can be incorporated
in an oral dosage form such as tablets, capsules or elixirs
or in an injectable form in a sterile aqueous vehicle compounded
according to conventional pharmaceutical practice.
The following examples are preferred embodiments
which are illustrative of the invention and serve a models
for the preparation of other compounds of this invention.
Additional variations are produced in the same manner by
appropriate substitution in the starting materiaI. All
temperatures are in degrees celsius.
Example 1
DL-2[[(EthoxYcarbonyl)thio]phenyl]acetic acid
3.4 gms. (20 mM) of a-mercaptophenylacetic acid
are dissolved with 2.2 gms. (40 mM) of potassium hydroxide
in 50 ml. of water. 25 ml. of chloroform are added and,
at a temperature of 5, 2.2 gms. (25 mM) of ethyl chloro-
20 formate are added dropwise with intensive stirring. After14 hours, the chloroform phase is separated, the water
phase is acidified with 2N hydrochloric acid and extracted
with ether. After drying and evaporating the solvent,
2.6 gms. of white crystalline DL-2-[[(ethoxycarbonyl)thio]-
phenyl]acetic acid are obtained, m.p. 108-110.
-6-
GG211/194
iO5'7'740
Example 2
DL-2-[[(Methoxycarbonyl)thioJphenyl]acetic acid
By substituting methyl chloroformate for the
ethyl chloroformate in the procedure of Example 1, white
crystalline DL-2-[(methoxycarbonyl)thio~phenylacetic acid
is obtained, m.p. 58.
Example 3
DL-2-[(Methoxycarbonyl)thio]-2-phenylacetic acid chloride
2.8 gms. (15 mM) of the acid obtained in Example 2
are heated with 15 ml. of thionyl chloride and 15 ml. of
absolute ether for 24 hours under reflux with the exclusion
of water vapor. After evaporating the solvent and excess
thionyl chloride, crude DL-2-[(methoxycarbonyl)thio~-2-
phenylacetic acid chloride is obtained which is used in
the next step without further purification.
ExamPle 4
7-[[DL-2-[(Methoxycarbonyl)thio]-2-phenylacetyl]amino~-3-
(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-ene-
carboxylic acid, 3-acetate
A solution of 1.9 gms. (10 mM) of the product
of Example 3 in a little chloroform is added dropwise at
a temperature of -20 to a solution of 2.7 gms. (10 mM)
of 7-ACA and 2 gms. of triethylamine in chloroform, with
stirring. The mixture is stirred for 20 minutes at -20
and 18 hours at room temperature. The solution cools to
0, 30 ml. of 2N hydrochloric acid are added and the solution
shaken well. The chloroform is separated and washed twice
each with 50 ml. of water. It is then dried over sodium
sulfate and after evaporating the solvent, the 7-[[DL-2-
[(methoxycarbonyl)thio~-2-phenylacetyl~amino]-3-(hydroxy-
~o57740 GG211/194
methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic
acid, 3-acetate is obtained in the form of a sticky mass which,
after the addition of chloroform, solidifies. After
recrystallization from methylene chloride/carbon tetrachloride,
the pure product forms as light beige crystals, m.p.
74-75 (dec.).
The potassium salt is obtained by the freeze
drying of a solution containing one equivalent each of the
acid and potassium bicarbonate, m.p. 175 (dec.).
Example 5
7-1[DL-2-[(Ethoxycarbonyl)thio]-2-Phenylacetyl]amino]-3-
(hydroxYmethY1)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid, 3-acetate
By substituting DL-2-[[(ethoxycarbonyl)thio]phenyl]-
acetic acid for the DL-2-[[(methoxycarbonyl)thio]phenyl]acetic
acid in the procedure of Bxample 3 and then following the
procedure of Example 4 with the product, 7-[[DL-2-[(ethoxy-
carbonyl)thio]-2-phenylacetyl]amino]-3-(hydroxymethyl)-8-oxo-
5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,
3-acetate is obtained m.p. 112.
The potassium salt is obtained by the procedure
of Example 4, m.p. 167.
The following additional products are similarly
obtained:
7-[[DL-2-(ethoxycarbonyl)thio]acetyl]amino]-3-
(hydroxymethyl3-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene
carboxylic acid 3-acetate
7-l[DL-2-[(n-butoxycarbonyl)thio]acetyl]amino-3-
(hydroxymethyl)-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene
carboxylic acid-3-acetate
7740 GG211/194
7-[[DL-2-[(benzyloxycarbonyl)thio]-2-phenyl-
acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid-3-acetate
7-[[DL-2-[(Benzyloxycarbonyl)thio]acetyl]amino]-
3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid-3-acetate.
Example 6
3-[[(5-Methyl-1,3,4-thiadiazol-2-Yl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox lic acid
y
A mixture of 13.6 g. (0.5 M) of 7-aminocephalo-
sFor~nic acid (7-ACA) in 100 ml. of water and 50 ml. of
acetone are brought to pH 8 with sodium hydroxide while
stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-
5-thiol are added and the mixture is heated at 80 for four
hours. After cooling to 5, this is acidified to pH 3.5
with dilute hydrochloric acid and stirred for 15 minutes.
The precipitated solid is filtered under suction and washed
with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio~-
methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid is purified by dissolving in sodium bicarbonate
solution and reprecipitating with 2N hydrochloric acid; yield
12.7 g., m.p. 206.
Example 7
3-[[(3-MethYl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid
By substituting 3-methyl-1,2,4-thiadiazole-5-
thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the
procedure of Example 6, 11.6-g. of 3-[[(3-methyl-1,2,4-
thiadiazol-5-yl)thiolmethyl]-7-amino-8-oxo-5-thia-1-
azabicyclol4.2.01oct-2-ene-2-carboxylic acid, m.p. 186
_g_
1057740 GG211/194
(dec.) are obtained.
Example 8
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methYl]-7-amino-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
By substituting 0.57 M of l-methyl-lH-tetrazol-5-
thiol for the 2-methyl-1,3,4-thiadiazol 5-thiol in the pro-
cedure of Example 7, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]-
methyl]-7-amino-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid is obtained.
Example 9
3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicyclol4.2.0]oct-2~ene-2-carboxylic acid,
diphenylmethyl ester
18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-
S-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70% perchloric acid are added dropwise. After 30
minutes, a slightly turbid solution forms. This solution is
filtered and to the filtrate is added dropwise with stirring
12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters
of absolute ether. The solid, light brown precipitate,
which is the perchloric acid salt of the desired product,
is dried over Kieselgel in a dessiccator. To obtain the base,
the perchloric acid salt is dissolved in water and treated
with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase i5 treated with activated carbon and
sodium sulfate to obtain the 10 g. of the product, 7-amino-3-
[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-
--10--
GG211/194
1057740
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl
ester, as a light brown powder, m.p. 157-159. The product
is recrystallized from tetrahydrofuran/petroleum ether. The
isomeric thiadiazolyl derivative is similarly obtained from the
product of Example 7.
Example 10
3-[[(1-Methyl-lH-tetrazol-5-Yl)thio]methyl]-7-amino-8-oxo-5-
thia-l-azabicvclo[4.2.0]oct-2-ene-carboxylic acid, diPhenYl-
methyl ester
The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-
yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.),
is obtained by the procedure of Example 9 utilizing as
starting material 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)-
thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
Example 11
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-
carbonYl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester
1.1 g. (5 mM) of the product of Example 2 is
dissolved in 25 ml. of tetrahydrofuran and added at 0 to
1.0 g. of dicyclohexylcarbodiimide in 5 ml. of tetrahydrofuran.
After 30 minutes, 2.48 gm. of 3-[[(1-methyl-lH-tetrazol-5-
yl]thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
2-ene-2-carboxylic acid diphenylmethyl ester dissol~ed in
15 ml. of tetrahydrofuran is added. After stirring for
12 hours, the dicyclohexylurea which has formed is filtered
~ff. The filtrate is treated with activated carbon and the
solvent is drawn off leaving 3-[[(1-methyl-lH-tetrazol-5-
--11-- ,
1057740 GG211/194
yl)thio]methyl]-7~-[[[(methoxycarbonyl)thio]phenylacetyl]-
amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid diphenylmethyl ester as a light brown powder, yield
2.7 g., m.p. 92-94 (dec.).
Example 12
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methyl-
carbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabi-
cyclo[4.2.0]oct-2-ene-2-carboxylic acid
2 g. of the product of Example 11 is stirred
in a mixture of 15 ml. of trifluoroacetic acid and 3 ml.
of anisole at 0 for 15 minutes. After the solvent is
drawn off and the residue is treated with ether/petroleum
ether (1:1), the solid brown residue is taken up in sodium
bicarbonate solution, filtered and the filtrate is extracted
with ethyl acetate and then acidified to pH 2.5 with 2N
hydrochloric acid while cooling with ice. This is extracted
with ethyl acetate. The organic phase is treated with
activated carbon and the solvent is drawn off to obtain
the product 3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7~-
[[[(methoxycarbonyl)thio]phenylacetyl]amino]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The product
is recrystallized from tetrahydrofuran/petroleum ether as a
light brown powder, yield 0.5 g., m.p. 128 (dec.).
Example 13
3-1[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[(methoxy-
carbonYl)thio]phenylacetyl]amino-8-oxo-5-thia-l-azabi
[4.2.0]oct-2-ene-2-carboxylic acid! potassium salt
The potassium salt of the product of Example 12 is
obtained by freeze drying an equimolar aqueous solution of
the acid of that example and potassium bicarbonate,
-12-
105~40 GG 211/194
m.p. 153-154 (dec.).
Examples 14 - 44
The products below are obtained by reacting
the acid ll
R2-O-C-S-CH-COOH
O
with the diphenylmethyl ester of one of the following
according to the procedure of Example 11 and then following
with the procedure of Example 12. Salts are produced by
continuing with the procedure of Example 14.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-
methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylic acid
3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-
7-ACA
3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-
7-ACA
3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-5-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isothiazolyl)thio]methyl]-7-ACA
3-[[(3-isoxazolyl)thio]methyl]-7-ACA
3-[[(5-methyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-
7-ACA
3-[[(5-ethyl-3-isoxazolyl)thio]methyl]-7-ACA
3-[[(3-methyl-4-i~oxazolyl)thio]methyll-7-ACA
-13-
1057740 GG211/194
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-
7-ACA
3-[[(5-ethyl-3-isothiazolyl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-
7-ACA
3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-1[(2-pyridinyl-N-oxide)thio]methyl]-7-ACA
Example
14 7~-[[[[2-(methoxycarbonyl]thio]-2-(2-pyridyl)-
acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
7~-[[[[2-(n-butoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyll-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid
16 7~-1[[[2-ethoxy)carbonyl]thio]-2-(2-pyridyl)acetyl]-
amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-
2-carboxylic acid
17 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-
[[(3-methyl-5-isothiazolyl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
18 7~-[[[[(2-ethoxy)carbonyl]thio]-2-(2-thienyl)ace.tyl]-
amino]-3-[[(3-isothiazolyl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
19 7~-[[[[2-(benzyloxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-S-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
-14-
105 ~74~ GG211/194
Example
7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(5-methyl-3-isoxazolyl)thio]methyl]-8-
oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
21 7~-[[[[2-(propoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
22 7~-[[[[2-(phenethoxy)carbonyl]thio]acetyl]amino]-3-
[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
23 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid
24 7~-[[[2-(methoxy)carbonyl]thio]butyramido]-3-
[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
7~-[[[(2-benzyloxy)carbonyl]thio]propionamido]-3-
[[(S-methyl-3-isothiazolyl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
26 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]amino]-
3-[[3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylic acid
27 7B-[[[[2-(butoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(3-methyl-4-isoxazolyl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
-15-
lOS7740 GG 211/194
Example
28 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
29 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-
[[l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid
7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-
8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-carboxylic
acid
31 7~-[[[[2-(ethoxy)carbonyl]thio]-2-phenylacetyl]amino]-
3-[[3-thiazolyl]thio]methyll-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid
32 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(2-methyl-1,3,4-thiadiazol-5-yl]thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
33 7~-[[[[2-(ethoxy)carbonyl]thio]-2-(2-furyl)acetyl]-
amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio)-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid and potassium salt
34 7B-[[[[2-(propoxy)carbonyl]thio]-2-(2-thienyl)acetyl]-
amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
and sodium salt
7~-[1[[(2-ethoxy)carbonyl]thio]acetyl]amino]-3-
1[(5-ethyl-1,3,4-oxadiazol-2-yl)thiolmethyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid
-16-
GG211/194
1057740
Example
36 7~-~[[[2-(n-butoxy)carbonyl]thio]acetyl]amino]-
3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
37 7~-[[[[2-(methoxy)carbonyl]thio]-2-(2-thienyl)acetyl]-
amino]-3-[[(2-methylthiazol-5-yl)thio]methyl-8~oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid triethylamine salt
38 7~-1[[[2-(benzyloxy)carbonyl]thio]-2-(3-furyl)acetyl]-
amino]-3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
pivaloyloxymethyl ester
39 7~-[[[[2-(methoxy)carbonyl]thio]-2-(3-pyridyl)]acetyl]-
amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
trimethylsilyl ester
7~-[[[[2-(methoxy)carbonyl]thio]-2-(2-thienyl)-
acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid phenylmethyl ester
41 7~[[[[2-(ethoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(2-pyridinyl-N-oxide)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4..2.0]oct-2-ene-2-
carboxylic acid
42 7~-[[[[2-(benzyloxy)carbonyl]thio-2-phenylacetyl]-
amino]-3-[[(2-pyridinyl-N-oxide)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid pivaloyloxymethyl ester
G~ 211/194
10577~0
Example
43 7~-[[[[2-(methoxy)carbonyl]thio]acetyl]amino]-3-
[[(2-pyridinyl-N-oxide)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and
potassium salt.
44 7~-[[[[2-(methoxy)carbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid and sodium salt.
Example 45
3-[[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicyclo[4.2 O]oct-2-ene-2-carboxylic acid
A mixture of 13.6 g. (0.5 M) of 7-am~nocephalosporanic
acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are
brought to pH 8 with sodium hydroxide while stirring.
9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol
are added and the mixture is heated at 80 for four hours.
After cooling to 5 , this is acidified to pH 3.5 with dilute
hydrochloric acid and stirred for 15 minutes. The precipi-
tated solid is filtered under suction and washed with acetone.
This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is
purified by dissolving in sodium bicarbonate solution and
reprecipitating with 2N hydrochloric acid; yield 12.7 g.,
m.p. 206.
GG211/194
1057 740
Example 46
.
3-[[(3-Methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
By substituting 3-methyl-1,2,4-thiadiazole-5-
thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the
procedure of Example 45,11.6 g. of 3-[.[t3-methyl-1,2,4-
thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid, m.p. 186 (dec.), are
obtained.
Example 47
3-[[~1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
By substituting 0.57 M of l-methyl-lH-tetrazol-5-
thiol for the 2-methyl-1,3,4-thiadiazol-5-thiol in the
procedure of Example 45~3-[[(1-methyl-lH-tetrazol-5-yl)thiol-
methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid is obtained.
Example 48
3-~[(5-methYl-1,3,4-thiadiazol-2-vl)thio]methyl]-7-amino-
8-oxo-5-thia-1-azabicYclo[4.2.0]oct-2-ene-2-carboxylic acid,
diphenylmethyl ester
18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-
2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70% perchloric acid are added dropwise. After 30
minutes, a slightly turbid solution forms. This solution is
filtered and to the filtrate is added dropwise with stirring
lZ g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters
of ahsolute ether. The solid, light brown precipitate,
--19--
1057740 GG21l/194
which is the perchloric acid salt of the desired product,
is dried over Kieselgel in a dessiccator. To obtain the
base, the perchloric acid salt is dissolved in water and
treated with the calculated equivalent of potassium bicarbonate.
The aqueous solution obtained is extracted with chloroform.
The chloroform phase is treated with activated carbon and
sodium sulfate to obtain 10 g. of the product, 7-amino-3-
~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid,diphenylmethyl
ester, as a light brown powder, m.p. 157-159 . The product
is recrystallized from tetrahydrofuran/petroleum ether. The
isomeric thiadiazolyl derivative is similarly obtained from
the product of Example 2.
Example4g
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenyl-
methyl ester
The product, 7-amino-3-[[(1-methyl-lH-tetrazol-5-
yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
carboxylic acid, diphenylmethyl ester, m.p. 168-169 (dec.),
is obtained by the procedure of Example 48utilizing as starting
material 7-amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Example 50
3-[l(l-Methvl-lH-tetrazol-5-yl?thio]methyl]-7~-[[[[(methoxy)-
thiocarbonyl]thiolphenylacetyl]amino]-8-oxo-5-thia-l-aza-
bic~clol4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
At a temperature of 0 , ].2 g. (5 mM) of DL-[(methoxy-
thiocarbonyl)thio]phenylclcetic acid (produced by the method
o~ J Org. ~hern , supra) toyether ~ith 1 g. (5 mM) of
-20-
1057740 GG2~ 94
dicyclohexylcarbodiimide in 50 ml. of tetrahydrofuran are
stirred for 15 minutes. A solution of 2.5 g. (5 mM) of 3-
[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-7-aminocephalosporanic
acid, diphenylmethyl ester in 20 ml. of tetrahydrofuran is
added dropwise. After 24 hours of stirring, the mixture is
filtered from the dicyclohexylurea whi,ch forms. After
drawing off the solvent, a solid residue is obtained from
the filtrate which, after being treated with charcoal and
recrystallized several times, produces 3.1 g. of 3-[[(1-
methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-
carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicYClo-
[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester,
in the form of a beige powder, m.p. 105 (dec.).
Example 51
3-[[(1-MethYl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)-
thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid
3 g. of the product obtained in Example 6 are
stirred for 15 minutes at 0 in 30 ml. of trifluoroacetic
acid/anisole (4:1). After drawing off the trifluoroacetic
acid/anisole mixture in vacuum, the oily residue is solidified
with ether/petroleum ether. The solid brown mass is stirred
for 5 minutes in 50 ml. of saturated sodium bicarbonate
solution and after filtration, the filtrate is cooled to
and acidified with 2N hydrochloric acid to pH 3. The
precipitate which forms is collected and dissolved in
tetrahydrofuran/ethyl acetate. The solution is then treated
with charcoal. After ether is added to the filtrate,
3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyll-7B-[[[[(methoxy)-
thiocarbonyllthio3phenylacetyllamino]-8-oxo-5-thia-1-
~ azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of
-21-
lOS7 740 GG211/194
a beige powder. After recrystallization from ethyl acetate/petroleum ether, 1.2 g. are obtained, m.p. 115 (dec.).
Example 52
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-[[[[(methoxy)thio-
carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabic~clo-
[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt, monohydrate
3-[[(1-Methyl-lH-tetrazol-5-yl)thio]methyl]-7~-
[[[[(methoxy)thiocarbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, potassium salt,
monohydrate is obtained by freeze drying an equimolar aqueous
solution of the acid obtained in Example 51 and potassium
bicarbonate. A yellow powder is obtained, m.p. 123 (dec.).
Examples 53-83
The additional products below are obtained by
reacting the acid
IRl
R -O-C-S-CH-COOH
2 1l
with the diphenylmethyl ester of one of the following
according to the procedure of Example 50 and then following
with the procedure of Example 51. Salts are produced by
continuing with the procedure of Example 52.
3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-
methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylic acid
3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-7-ACA
3-11(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[~5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA
3~ 3-1[(l-ethyl~ tetrazol-5-yl)thio]methyl]-7-ACA
-22- i
105~40 GG21yl94
3-[[~1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA
3-[[(1,2,3-triazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-7-ACA
3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-7-ACA
3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-7-ACA
3-[[(1,2,4-thiadiazol-S-yl)thio]methyl-7-ACA
Example
53 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-(2-furyl)-
acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
54 7B-[[[[2-(n-butoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)-
acetyl]amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid.
56 7B-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-
[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
57 7B-[[[[(2-ethoxy)thiocarbonyl]thio]-2-(2-thienyl)acetyl]
amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
58 7B-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-1[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
59 7B-[11[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-
-23-
GG211/194
1057740
Example
amino]-3-[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
61 7B-[[[[2-(phenethoxy)thiocarbonyl]thio]acetyl]amino]-3-
[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
62 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thiomethyl]-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
63 7B-[[[2-(methoxy)thiocarbonyl]thio]but~ramido]-3_
[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
64 7B-[[[(2-benzyloxy)thiocarbonyl]thio]propionamido]-
3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
7B-1[~[2-(methoxy)thiocarbonyl]thio]-(2-furyl)acetyl]-
amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
66 7B-[[[[2-(butoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
67 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(3-methyl-1,2,4-oxadiazol-S-yl)thio]-
methyl~-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-
-24-
GG211/194
~057740
Example
2-carboxylic acid.
68 7~-[[1[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-
[[(l-ethyl-lH-tetrazol-5-yl)thio]methyl]-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid.
69 7B-[[[[2-(methoxy)thiocarbonyl,]thio]-2-phenylacetyl]-
amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]aminol-
3-[[(1,2,3-triazol-5-yl)thio]methyl -8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
71 7B-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]
amino]-3-[[5-methyl-1,3,4-thiadiazol-2-yl]thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
72 7B-[[[[2-(ethoxy)thiocarbonyl]thio]-2-(2-furyl)acetyl]-
amino]-3-[[(5-methyl-1,3,4-thiadiaaol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2
carboxylic acid and potassium salt.
73 7B-[[[[2-(propoxy)thiocarbonyl]thio]-2-(2-thienyl)-
acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid.
74 7B-[[[[(2-ethoxy)thiocarbonyl]thio]acetyl]amino]-3-
[1(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7B-[1[[2-(n-butoxyjthiocarbonyl]thio]acetyl]amino]-3-
[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
-25-
-
GG211/194
1057740
Example
76 7~-[~[[2-(methoxy)thiocarbonyl]thio]-2-(2-thienyl)-
acetyl]amino~-3-[[(5-ethyl-1,3,4-oxadiazol-5-yl)thiol-
methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
77 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-(3-furyl)-
acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid pivaloyloxymethyl ester.
78 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-(3-thienyl)]-
acetyl]amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
79 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-~2-thienylj-
acetyl]amino]-3-[[(1,3,4-oxadiazol-2-yl)thio~methyl]-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid phenylmethyl ester.
7~-[[[[2-(ethoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid triethylamine salt.
31 7~-[[[[2-(benzyloxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-[[(1,2,3-triazol-5-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
pivaloyloxymethyl ester.
~2 7~-[[[[2-(methoxy)thiocarbonyl]thio]acetyl]amino]-3-
[[(1,2,3,4-thiatriazol-5-yl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
and potassium salt.
3~
-26-
GG2~ 194
~057740
Example
83 7~-[[[[2-(methoxy)thiocarbonyl]thio]-2-phenylacetyl]-
amino]-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid and sodium salt.
-27-
