Note: Descriptions are shown in the official language in which they were submitted.
1~56815 GG187-190
This invention relates to new thxee-thio derivatives of thio-
alkoxycarbonyl-and carbamoyl-substituted thioacetylcephalo-
sporins of the formula
/S
Rl ~ CH CO - NH - CH CH CH2
S-C- R2
(I) O ~ . N C C 2 3
1 '
C-OR
wherein R represents hydrogen, lower alkyl, phenyl-lower alkyl,
tri(lowgr alkyl)silyl, a salt forming ion or the group
-CH2-O-~-R4; and in addition, tri(lower alkyl)stannyl and
phenyl when R2 is lower alkylthi.o; Rl represents hydrogen,
lower alkyl, phenyl, thienyl, furyl or pyridyl; R2 represents
lower alkylthio lower alkyl amino or phenyl-lower alkylamino;
: R3 represents lower alkyl or a five membered heterocyclic ring
20 system including thiadiazolyl, (lower alkyl)thiadiazolyl, . ::
triazolyl, tetrazolyl or (lower alkyl)tetrazolyl when R2 is
lower alkylthio~ and when R2 is lower alkylamino or phenyl-
lower alkylamino, R3 represents a five or six-membered hetero-
cycle including thiadiaæol~, oxadiazole, isoxazole, isothiazole,
tetrazole, pyridine-N-oxide and their lower alkyl substituted
analogs; R~ represents lower alkyl, phenyl or phenyl-lower
alkyl.
-d ~
' .
, . , , ' : . . '.': . . ~ .:
1~5~5 GG187 190
Encompassed within th~ general formula I are:
(a) 3-alkylthio~ and 3-heterothio derivatives of
[(thioalkoxycarbonyl3thioacetyl3cephalosporins having the formula
/ S \
Rl CH - CO - NH CH - CH CH2
(Ia) S-C-R~
O C -N C-CH -S-R
C
C-OR
11 ' .
o
wherein R represents hydrogen, lower alkyl, phenyl-lower ~:
alkyl, tri(lower alkyl)stannyl, tri(lgwer alkyll-silyl, a
salt forming ion or the group -CH2-O-C-R4; R1 represents
: hydrogen, lower alkyl, phenyl, pyridyl, thienyl or furyl;
R3 represents lower alkyl or a five membered heterocyclic
ring:system including thiadiazolyl, ~lower alkyl)thiadia-
zolyl, triazolyl, tetrazolyl or (lower alkyl)tetrazolyl;
R2 represents lower alkyl; and R4 represents lower alkyl, : .
phenyl or phenyl-lower alkyl.
T~e preferred m~mbers within each group are as
follows: R is hydrogen, lower alkyl, alkali metal, tri-
O
methylsilyl, benzhydryl, or -CH2-O~C-R4, e~pecially hydrogen,
methyl, pivaloyloxymethyl, s~dium~or potassium; Rl is
hydrogen, lowex alkyl or phenyl, especially hydrogen or phenyl; :~ :
R2 is lower alkyl, especially methyl ox ethyl; R3 is lower
alkyl, especially methyl, (lower alkyl)thiadiazolyl or :
(lower alkyl)tetrazolyl; and R4 is methyl or t-butyl , and
-2-
: . . , : , ,
.: .
:. , , ,:: , ,
1~56815 GG187-19Q
(b) 3-heterothio(carbamoylthioacetyl?caphalosporin
derivatives of the formula
Rl CH Co - NH - CH - CH CH2
(Ib) S F-R~
O C ~ C-CH -S-R
C-OR
' 11
O
wherein R represents hydrogen, lower alkyl, phenyl-lower
alkyl, tri~lower alkyl)silyl, a salt forming ion or the
group -CH2-O-C-R4; Rl represents hydrogen, lower alkyl,
ph nyl, thi nyl~ or pyridyl; R2 represents lower alkyl or ~ -
: : phenyl-lower alkyl; R3 represents a five or six-membered .~ -~
heterocycle including thiadiazole, oxadiazole, isoxazole,
:~ isothiazole, tetrazole, pyridine-N-oxide and their lower ~-
alkyl substituted analogs; R4 represents lower alkyl, phenyl
or phenyl-lower alkyl.
The preferred members within each group as as
~follows: R is hydrogen, alkali metal, trimethysilyl,
diphenylmethyl or -CH2-O-Q-R4, especially hydrogen,
pivaloyloxymethyl, sodium or potassium; Rl is hydrogen, phenyl
or thienyl, especially hydrogen or phenyl; R2 is lower alkyl,
especially methyl or ethyl; R3 is preferably (lower alkyl)-
tetrazole or (lower alkyl)thiadiazole, especially wherein the
lower alkyl ~roup is methyl; R4 is methyl or t-butyl. : .
. ',, ', , , , , : : '
~ 8~ GG187-190
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 the straight and
branched chain hydrocarbon groups in the series from methyl
to heptyl, the Cl to C4 members and especially methyl and
ethyl being pref~rred.
~ he phenyl-lower alkyl radicals include a phenyl
ring attached to a lower alkyl group of the kind described
above as well as those containing two phenyl groups such
as diphenylmethyl.
The salt forming ions represented by R are metal
ions, e.g., ~lkali metal ions such as sodium or potassium,
alkaline earth metal ions such as calcium or magnesium, or
an amine salt ion, e.g., a ~lower alkyl)amine like methylamine
or triethylamine.
- The heterocyclic groups represented by R3 when R2 is
lower alkylthio are the five membered nitrogen heterocyclics
thiadiazole, triazole, tetrazole and their lower alkyl substituted
~0 analog~ including 1,2,4-thiadiazol-5-yl, 1,2,4~thiadiazol-3-yl,
1,3,4-thiadiazol 2-yl, 1,2,4-triazol 3-yl, 1,2,3-triazol-4-yl,
tetrazolyl as well as these radicals bearing a lower alkyl group,
e~pecially methyl.
The heterocyclic groups represented by R3 when R2 is
lower alkylamino or phenyl-lower alkylamino are thiadiazole,
oxadiazole, isoxazole, i~othiazole, tetrazole, pyridine-N-oxide
and their lower alkyl substituked analogs, especially 1,3,4-thia-
diazole, 1,2,4~thiadiazole, tetrazole, 5~methyl-1,3,4-thiadiazol-
2-yl, 3-methyl-1,2,4-thiadiazol-5-yl, tetrazole and l-methyl-
tetrazol-5-yl.
-4-
~S~8~5 GG187-190
The new cephalosporin derivatives of this invention
are produced by several methods. Accordiny to one method,
a 7-aminocephalosporanic acid (7-ACA) deriva-tive of the
formula
~II)
H2N - CH CH \ CH2
~ C N ~-CH2-S-R3
C-OR
O
is reacted with a thioacetic acid of ~he formula
(III)
Rl-CH-COOH
S - C-R2
11
or an activated derivative thereof~
- The activated derivatives referred to include, for
example, the reaction product with an anhydride forming
reagent such as ethylchloroformate, benzoyl chloride,
pivaloyl chloride, etc., an acid chloride or an activated
ester like the benzhydryl ester, t-butyl ester, trimethyl-
silyl ester or trimethylstannyl ester or triethylamine salt.
Dicyclohexylcarbodiimide can also be used to effect thereaction.
One preferred synthesis comprises reacting ~he acid
of formula III with the diphenylmethyl ester of the 7-ACA
derivative of formula II and then hydrolyzing the ester ~ith
trifluoroacetic acid and anisole to obtain the free carboxyl
group in the 4-position.
-5-
' ' ' , . ~ . ..
~S~BlS
GG187-190
The reaction between the 7~-aminocephalosporanic
acid compound and the thioacetic acid can be carried
out, for example, by dissolving or suspending the acid in
an inert organic solvent such as chloroform, tetrahydro~uran,
methylene chloride, dioxane, benzene or the like, and
adding, at a reduced temperature of about 0-5C, about an
equimolar amount of the 7-ACA ~ompound in the
presence of an activating compound such as dicyclohexyl-
carbodiimide. The product of the reaction is then isolated
1 by conventional procedures, e.y., by concentration or evapora-
tion of the solvent. If a derivative of the 7-aminocephalo-
sporanic acid compound, such as the diphenylmethyl ester
is used, the free acid is obtained by hydrolysis, e.g., with
trifluoroacetic acid or the like. Salts can then be derived
from the free acid.
The 7-ACA derivative of formula II is produced by
reacting 7-ACA or its derivative (wherein R has the other
meanings described above) with a mercaptan HS-R3 at a pH of
about 8 - 8.5. This reaction can al~o be effected after
acylation of 7-ACA with the thioacetic acid of formula III as
~hown below.
According to another preferred embodiment an
acid o formula III i5 reacted with a compound of the formula
(IV~
' / S\
H2N - CH _ CH CH2
C -N ~ C-CH2~ C 3
C OR
O
''
,
, . . . : . . ;
~ 5 GGl87-lgo
preferably where.in R is diphenylmethyl. When R is the
preferred diphenylmethyl group, it is converted to the
free acid with trifluoroacetic acid and anisole. The
product of the formula
(V)
/s\ : ~
Rl CH--CO--NH--CH ~ CH CH2
S~C-R2 l l
C_ N~C-cH2c CH3
C-OH
i5 then.reacted with a th~.ol of the formula
(VI )
R3~SH
in basic solution, e.g., at a pH of about 7.8, to obtain
the product of formula I.
O . .
Il .
When R is..the ac~loxymethyl group CH~-O-C-R4
this group can be introduced into the 7-aminocephalosporanic
acid moiety prior to the reaction with the carbamoylthioacetic
acid or the activated derivative by treatment with one to
two moles of a halomethyl ester of the formula
(VII)
hal CH2OCOR4
wherein hal is halogen, preferably chlorine or bromine, in
an inert organic solvent suoh as dimethylformamide, acetone,
dioxane, benzene or the like, at about ambient temperature
or below.
.. . .
..
, : : . .
10~ 5 GG187-190
The [(thiocarbonyl)thio]acetic acid of formula III
twhen R2 is alkylthio) is produced by reacting a mercaptoacetic
acid of the formula
~V) Rl-CH-COOH
SH
with a diazomethane like diphenyldiazomethane to obtain
its ester like the benzhydryl ester. This is then made to
react with a chloroformic acid thioester of the formula
(VI)
ClC-SR2
and the ester group is then removed, e.g., by hydrolysis,
such as treatment with trifluoroacetic acid. This is then
used for the acylation of the 7-aminocephalosporanic acid
compound of ~ormula II.
The carbamoylacetic acid of formula III (when R2
is lower alkylamino~ or phenyl lower alkylamino is produced
by reacting a mercaptoa~e~ic acid of the formula
R -CH-COOH
(VIII) 1 1
SH
.
with a base, e.g., an alkylamlne like triethylamine, and with
an isocyanate R2N=C=O, in an inert solvent like tetrahydro-
furan, then acidifying, e.g., with hydrochloric acid or the
like.
-8~
,. ' '
GG187 190
~Q~&~
Alternatively the acid of formula V is converted to
an ester like the diphenylmethyl or t-butyl ester by reaction
with a diphenyldiazomethane Or isobutylene, followed by
reaction with the isocyanate and treatment with trifluoro-
acetic acid/anisole. ;
Further process details are also provided in theillustrative examples.
Certain of the compounds of this invention may
exist in diffarent optically active forms. The various
stereoisomeric forms as well as the racemic mixtures are
within the scope of the invention.
The compounds of this invention have a broad
spectrum of antibacterial activity agalinst both gram positive
and gram negative organisms such as Staphylococcus aureus,
Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus
vulgaris,Escherichia coli and Streptococcus pyogenes. They
are useful as antibacterial agents, e.g., to combat infections
due to organisms such as those named above, and in general
they can be utilized in a manner similar to cephradine and -~
~0 ~ other cephalosporins. For example, a compound of formula I ~
:'.
,,. .:.: - :.
_9_ ~
~`6~ GG187-190
or a physiologically acceptable salt -thereof can be used in
various animal species affected by infections of such
bacterial origin in an amount of about 1 to 75 mg/kg daily,
orally or parenterally, in single or two to four divided
doses.
Up to about 500 mg. of a compound of formula I
or a physiologically acceptable salt thereof is administered
by incorporating in an oral dosage form such as tablets,
capsules or elixirs or in an injectable form in a sterile
aqueous vehicle prepared according to conventional pharmaceu-
tical practice~
The following examples are illustrative of the
invention. All temperatures are in degrees celsius. Additional
variations are produced in the same manner by appropriate
substitution ln the starting material.
Example 1
DL-[[(Meth~amino)carbonyl]thio]phenylace-tic acid
10.08 g. (60 mM) cf a-mercaptophenylacetic acid
and 6.~ g. (60 mM) of triethylamine are dissolved in 50 ml. of
tetrahydrofuran and 3.42 g. (60 mM) of methylisocyanate
dissolved in 20 ml. of tetrahydrofuran ar~ added dropwise
with stirring. After stirring for 2 hours, the solvent is
drawn off-in a vacuum and the oily residue is dissolved in
water. The mixture is then acidified with 2N hydrochloric
acid and extracted three times each with 20 ml. of ether.
After drying off the ether, 10.5 g. of white crystalline
DL-[[(methylamino)carbonyl]thio]phenylacetic acid are obtained,
which is recrystallized from ether/petroleum ether,
m.p. 12~-129~.
--10--
~5~5 GG187-190
Example 2
DL-[[(~thYlamino)carbonyl]th~o]phenylacetic acid
By substituting ethylisocyanate for the methyliso-
cyanate in the procedure of Example 1, white crystalline
DL-[[(ethylamino)carbonyl]thio]phenylacetic acid is obtained
and recrystallized from cyclohexane, m.p. 115-117 (dec.).
Example 3
DL-3-[(Acetyloxy)methyl]-7~-[[[[(methylamino)carbonyl]thio]-
phenylacetyl]amino]-8-oxo-5-thia-1-azabi~yclo[4.2.0]oct-2-
ene-carboxylic acid, diphenylmethyl ester
1 g. (5 mM) o~ dicyclohexylcarbodiimide is added
to 1.1 g. (5 mM) of DL-[[(methylamino)carbonyl]thio]phenyl
acetic acid in 50 ml. of tetrahydrofuran and stirred for
1 hour at -5. 2.1 g. (5 mM) of 7-aminocephalosporanic
acid, benzhydryl ester in 15 ml. of tetrahydrofuran are then
added and the mixture is stirred for 5 hours at 0 and for
1 hour at room temperature. The precipitate of dicyclohexyl- ;
urea is fiItered off and the filtrate is evaporated. The oily
residue is dissolved in 20 ml. of methylene chloride. Filtra-
, 20 tion over charcoal and precipitation with petroleum ether
produces 1.3 g. o~ white DL-3-[(acetyloxy)methyl-7~-[[[[(methyl-
amino)carbonyl]thio]phenyl]acetyl]amino]~8-oxo-5-thia~
azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl
ester which is reprecipitated from methylene chloride/carbon ~:
tetrachloride, m.p. 73 (dec.).
'
.. ., . . . :.. ~.
. , , , . " .~ , , : . '. . '
, . . . .
GG187-190
Example 4_
phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
3 g. of the product of Example 3 are dissolved at
o in 25 ml. of trif}uoroacetic acid/anisole and stirred for
15 minutes. After drawing off the trifluoroacetic acid in
vacuum, an oily residue remains which is washed repeatedly
with absolute ether until it becomes quite firm. The residue
is dissolved in sodium bicarbonate solution, filtered and
acidified with hydrochloric acid, with cooling, to a pH of 2.5.
The solution is extracted three times each with 20 ml. of
ethyl acetate. The organic phase is dried and evaporated.
0.9 g. of DL-3-[(acetyloxy)methyl]-7~-[[[[~methylamino)carbonyl]-
thio]phenylacetyl]amino]-8-oxo-~5-thia--1-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid is obtained as a light yellow powder -~
m.p. 121 (dec.) after reprecipitation from methylene chloride/
petroleum ether.
Example 5
Alternate method for producin~ the product of Example 4
4.5 g. ~20 mM) of DL-[[(methylamino)carbonyl]thio]-
phenylacetic acid are dissolved in 50 ml. of tetrah~drofuran.
2 q. (20 mM) of triethylamine are added and while stirring
at a temperature of 0 2.5 q. (20 mM) of ethyl chloroformate
are added dropwise. After one hour, a solution of 5.4 g. (20 ~)
of 7-aminocephalosporanic acid, triethylamine salt in 200 ml.
ofmethylene chloxide are added and the whole mixture is stirred
for 14 hours at 5. After filtering and drawing off the solvent,
the oily residue is treated with water, The aqueous solution
is extraated with ethyl acetate, filtered and acidified to pH 2.5.
, - - ~ :
~5~815 GG187-190
Repeated extraction with ethyl acetate and evaporation of the
ethyl acetate solution in vacuum yields after recrystallization
from methylene chloride/petroleum ether, DL-3-[(acetoxy)-
methyl]-7~-[[[[(methyl~mino)carbonyl]thio]phenyl]amino]-8-
oxo-5-thia-1-azabicyclo[4.2.0]-oct-2 ene-carboxylic acid as
a light yellow powder, 2.5 g., m.p. 61. The product
produced by this method is only 67% pure.
Example 6
DL-3-[(Acetyloxy)methyl]-7~-[[[[(ethylamino)carbonyl]thio]
phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene 2-carboxylic acid,_d_phenylmethyl ester
4.8 g. (20 mM) of DL-[[(ethylamino)carbonyl]thio]-
phenylacetic acid are dissolved in 150 ml. of tetrahydrofuran
and stirred with 8.4 g. (20 mM) of 7-ACA benzhydryl ester
and 4.05 g. (20 mM) of dicyclohexylcarbodiimide for
8 hours at 0. By evaporating the filtered solution, 9 g.
of DL-3-~(acetyloxy)methyl]-7~-[[[[(ethylamino)carbonyl]thio]-
phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- i
ene-2-carboxylic acid, diphenylmethyl ester are obtained as
a yellow powder, m.p. 75 (dec.).
Exam~le 7
3-[[(5-methyl-1,3,4-thiadiaz _-2-yl)thio]methyl]-7-amino-8-
:
oxo-5-thla-1-a_a cyclo[4.2.0]oct-2-ene-2-carbox~lic acid
A mixture of 13.6 g. (0.5 M) of 7-aminocephalo-
sporanic 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
-13-
,
,, . ., ~
.
GG187-190
~5~8~S
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
biearbonate solution and reprecipitating with 2N hydroehlorie
acid; yield 12.7 g., m.p. 206.
Example 8
3-[[(3-Methyl~1,2,4-thiadiazol-5-yl)thiolmethyl]-7-amino-
8-oxo-5-thia-1-azab eyclo[4.2.0]oct-2-ene-2-carboxylic acid
By substituting 3-methyl-1,2,4-thiadiazole-5-
thiol for the 2-methyl-],3,4-thiadiazole-5-thiol in the
procedure of Example 7, 11.6 gO of 3 [[(3-methyl-1,2,4-
thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-
azabicyelo[4.2.0]oxo-2-ene-2-earboxylie acid, m.p. 186
~dee.) are ob~ained.
Example 9
3-l[(l-Methyl-lH-tetrazol-S yl)thio]methyl]-7-amino-8-oxo-
5- hla-1-azabieyelo[4.2.0]oet-2-ene-2-earboxylie aeid
By substituting 0.57 M of l-methyl-lH-tetrazole-5-
thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the pro-
Qedure of Example 7, 3-[[(1-methyl-lH-tetrazol-5-yl)thio]-
methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
earboxylie aeid is obtained.
Example 10
7-Amino-3-L[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-
8-oxo-5-thia-1-azabieyelo[4.2.0]oet-2-ene-2-earboxylie aeid,
diphenylmethyl ester
18 g. of 7-amino-3~[[(5-methyl-1,3,4-thiadiazol-5-
yl)thio]methyl]-8-oxo-5-thia-1-azabieyelo[4.2.0]oet-2-ene-2-
earboxylie aeid are suspended in 350 ml. of tetrahydrofuran.
-14-
' ' '; ' ' ' . :
105~815 GG187~190
4.1 ml. of 70~ perchloric acid are add~d dropwise. After
30 minutes, a slightly turbid solution forms. This solution
is filtered and to the filtrate is added dropwise with stirring
12 q. 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 desiccator. 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 the 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 rom tetrahydrofuran/petroleum ether.
Example 11
7-Amino-3-~[(1-methYl-lH-tetrazol-5-yl)thio]methYl]-8-oxo-5-
thia-l-azablc~clo[4.200]oct-2-ene-carboxylic acid, diphen~l-
methY1 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 10 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-carboxyllc
acid.
-15
'
.. . , : , ~ :"" . . ::
... . , . . :, .. ;. .~ . , :
. .
1056815 GG187-190
Example 12
7~-[[[[(Methylamino)carbonyl]thio]phenylacetyl]amino]-3-
[[~l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,diphenylmethyl
ester
1.15 g. of DL-[[(methylamino)carbonyl]thio]phenyl-
acetic acid and 1 g. ( 5 mol.) of dicyclohexylcarbodiimide are
stirred in 50 ml. of tetrahydrofuran at a temperature of
0-5. After 10 minutes a solution of 2.5 g. ( 5 mol.) of
3-[[(1-methyl-lH-tetrazol-5~yl)thio]methyl]-7-amino-8-oxo-5-
thia-l-azabicyclo[4O2.0]oct-2-ene-2-car~oxylic acid diphenyl-
methyl ester is added dropwise. The whole is stirred for
12 hours, filtered from the dieyclohexylurea formed and after
drawing off the solvent, 2.8 a. of the product, 7~-[[[[(methyl-
amino)carbonyI]thio]phenylaeetyl]amino]-3-l[(l-methyl-lH-
tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo[4.2.0]-
oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained.
Recrystallization from chloroform/earbon tetrachloride yields
a beige powder, m.p. 122-124 (dec.).
Example_13
7~-[[[[(Methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-
methyl-lH-tetr ~ y~ methyl]-8-oxo-5-thia-1-azabieyelo-
[4.2.0]oct-2-ene-2-earboxylic acid
2 g. of the product of Example 1 are stirred for -
10 minutes at 5 in a mixture of 20 ml. of trifluoroacetie
aeid and 5 ml. of anisole. After drawing off the trifluor-
aeetie aeid, the mixture is washed with ether/petroleum ether
~ and the brown powder obtained is added to a solution of
sodium biearbonate. The whole is filtered, treated with
eharcoal, eooled at 5 and aeidified with 2N hydroehloric
-15-
: . , , ., ~ , . , . , , :
GG187-190
acid at pH 2.5. After extrac-tion with ethyl acetate and
drawing off of the solve~t, the free acid, 7~-[[[[(methyl-
amino)carbonyl]thio]phenylacetyl]ami~o]-3-[[(1-methyl-lH-tetrazol-
5-yl)thio~methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid, in the form oE a beige po~der, is obtained
from the organic phase, mOp. 139 (dec.). The product is
recrystallized from tetrahydrofuran/petroleum ether.
Example 14
7~-[[[[(Methylamino)caxbonyl]thio]phenylacetyl]amino]-3-
; 10 [[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-
azabicyclo[4~2.0]oct-2-ene-2-carboxylic acid, potassium salt
ihe potassium salt is obtained by freeze drying a
molecularly equivalent aqueous solution of the acid obtained
in Example 2 and potassium bicarbonate as a light colored -
powder, m.p. 164 (dec.).
Exam les 15 49
- P ---
The products below are obtained by the procedure
of Example 12 by reacting the acid
Rl-CH-COOH
; S-C- NH-R
~ 1l 2 - -
, O
with the diphenylmethyl ester of one of the following
(prepared as in Example 10) and then proceeding according to
Example 13 (also Example 14 to obtain a salt):
,: . .
.
" .
-17-
, . '.
, ' ' .
'. ~ .
, , . ., . , . ', , , . ":
1 ~ 5 ~ ~ 5 GG187-190
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-tetxazol-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-isoxazolyl)thio]methyl]-7-ACA
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-S-yl)thio]methyl]-
7-ACA
3-[[(1,2,4~thiadiazol-5-yl)thio]methyl-7 ACA
3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl-7-ACA
3-[[(3-methyl-1,2,4~thiadiazol-5-yl)thio]methyl-7-ACA
3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl~7-ACA
~ 3-[[(1-oxo-2-pyridyl)thio]methyl-7-ACA : :
. :
-18~
~5~5 GG187-190 ~ -
Example
7~-[[[2-(methylamino)carbonyl]thio]-2-(2-pyridyl)-
acetyl]amino]-3-[[(1,3,4-thiazol-2-yl)thio]methyl]-
8-oxo-5-thia-1-azabieyclo[4.2.0]oct-2-ene-2-
carboxylic acid
16 7~-[[[2-(n-butylamino)carbonyl]thio]-2-phenylaeetyl]-
amino]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0Joet-2-ene~2-carboxylie
acid
17 7~-[[~2~(ethylamino)earbonyl]thio]-2-propionyl]- -
amino]-3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oet-2-
ene-2-earboxylic aeid
18 7~-[[[2-(benzylamino)carbonyl]thio]acetyl]amino-3-
[[(3-methyl-5-isothiazolyl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.200]oct-2-ene-2-carboxylic aeid
19 7~-[[[(2-phenethyl)amino]earbonyl]thio]-2-(2-thienyl)-
acetyl]amino]-3-[[(3-isothiazolyl)thio]methyl]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylie acid
7~-[[[[2-(methylamino)carbonyl]thio]-2-phenylacetyl~-
amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-5-
thia-l-azabicyelo[4.2.0]oct-2-ene-2-earboxylie aeid
21 7~-1[[2-(methylamino)earbonyl]thio]-2-phenylaeetyl]-
amino]-3-[[(5-methyl-3-isoxazolyl)thio]methyl]-8-
oxo-5-thia-1-azabieyclo[4.2.0]oet-2-ene-2-earboxylie
acid
22 7~-[[[2-(propylamino)carbonyllthio]-2-phenylacetyl]-
amino]-3-[[~1l2,4-thiadiazol-5-yl)thio]methyl]-8~oxo-
5-thia-1-azabicyclo[4.2.0]oct~2-ene-2-carboxylic aeid
.~ .
--19-- ~
iB~5
GG187-190
xample
.
23 7~-[[[2-(methylamino)earbonyl]thio]acetyl]amino]-
3-[~(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-
thia-l-azabieyclo[4.2.0]oet-2-ene 2-carboxylie acid
24 7~-[[[2-(ethylamino)earbonyl]thio]-2-phenylaeetyl]-
amino]-3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oet-2-ene-
2-earboxylie acid
7~-[[2-(methylamino)carbonyl]thio]butyramido]-3-
[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-
l-azabicyelo[4.2.0]oet-2-ene-2-earboxylic aeid
26 7~-[[(2-methylamino)earbonyl]thio]propionamido]-3-
[[(5-methyl~3-isothiazolyl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oet-2-ene-2-earboxylie aeid
27 7~-~[[2 ~ethylamino)earbonyl]thio~-2-phenylaeetyl]-
amino]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-5-thia-
1-azabieyelo[4.3.0]oet-2~ene-2-earboxylie aeid
28 7~-[[[2-(butylamino)earbonyl]thio]aeetyl]amino-3-
[[(3-methyl-4-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-
azabieyelo[4.2.0]oct-2-ene-2-earboxylie aeid
7~-[~[2-(methylamino)earbonyl]thio]-2-phenylaeetyl]-
amino]-3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-
8-oxo-5-thia-1-azabieyelo[4.2.0]oet-2-ene-2-earboxylie
aeid
7~-[[[2-tmethylamino)carbonyl~thio]aeetyl]amino]-3-
[[(l-eth~l-lH-tetrazol-S-yl)thio]methyl]-l-azabi-
eyelo[4.2.0]oet-2-ene-2-earboxylie acid
31 7~-[[[2-(methoxy)earbonyl]thio]`-2-(2-pyridyl)aeetyl]-
amino]-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]~8-
oxo-5-thia-1-azabieyclo[4.2.0]oct-2-ene-2-earboxylie aeid
'~ .
-20-
,, .
''' ~ ,
... . .. .. ..
.: :
~5~5 GG187-190
Example
32 7~-[~[2-(ethylamino)carbonyl]thio]-2-(2-pyridyl)-
acetyl]amino~-3-[[3-thiazolyl]thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid
33 7~-[[[2-(benzylamino)carbonyl]thio]-2-(2-furyl)-
acetyl]amino]-3-[[2-(2-methyl-1,3!4-thiadia~ol-5-
yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylic acid
34 7~-[[[2-(ethylamino)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
7~- E [ [2-(propylamino)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
36 7~-[[[(2-phenylethyl)carbonyl]thio]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 -~
37 7~-[[[2-(n-butylamino)carbonyl]thio]-2-(2-pyridyl)-
acetyl]amino-3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl~-
8-oxo-5-thia-1-azabicyclo[4.2O0]oct-2-ene-2-carboxylic
acid
38 7~-[[[2-(methylamino)carbonyl]thio]-2-(3-thienyl)-
acetyl]amino] 3-[[(2-methylthiazol-5-yl)thio]methyl-
- 8-oxo-S-thia-L-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid triethylamine salt
39 7~-[[[[2-(ethylamino)carbonyl]thio]-2 (3-furyl)acetyl]-
amino]-3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-
... .
~5~5 GG187-190
Example
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid pivaloyloxymethyl ester
7~-[[[[2-(methylamino)carbonyl]thio]-2-t3-pyridyl]-
aoetyl]amino]-3-[[(3 isoxazolyl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo14.2.0]oct-2-ene-2-carboxylic
acid trimethylsilyl ester
41 7~-[[[[2-(methylamino)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
42 7~-[[~2-(ethylamino)carbonyl]thio]-2-(2-pyridyl)-
acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl~-
thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.Q]oct-2-
ene-2-carboxylic acid diphenylmethyl ester
43 7~-[[[2-(benzylamino)carbonyL]thio]-2-(2-thienyl)acetyl]-
amino]-3-[[(3-methyl-1,2,4~thiadiazol-5-yl)thio]methyl]-
:
8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic
acld
44 7~-[[[2-(ethylamino)carbonyl]thio]-2-phenylacetyl]amino]-
- 3-[~ methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
7~-[[[2-(benzylamino)carbonyl]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
46 7~-[[[2-(methylamino)carbonyl]]thio]-2-(2-pyridyl)-
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
-22-
.
.. ~ , , .
~a~s~8~5 GG187-190
E xample
47 7~-[[[2-(benzylamino)carbonyl]thio]-2~(2-furyl)-
acetyl]amino]-3-[[(1-methyl-lH-tetrazol-S-yl)thio]-
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid
48 7~-[[[2-(methylamino)carbonyl]thio]phenylacetyl]amino]-
3-[[(1-oxo-2-pyridyl)thio]methyl]-8-oxo-5-thia-1-
azabicyclo[4.~.0]oct-2-ene-2-carboxylic acid
49 7~-[[~[(methylamino)carbonyl]thio]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 potassium salt
Example 50
DI. Mercaptophenylacetic acid, benzhydryl ester
9.0 gms. (50 mM) of DL-a-mercaptophenylacetic acid
are dissolved in 25 ml. of absolut~ dioxane. A solution of
11 gms. (55 mM) of diphenyldiazomethane and 20 ml. of dioxane
.
are added dropwise, with stirring. The reaction is exothermic.
The mixture is stirred for an additional 30 minutes and the
solvent is evaporated in vacuum. The residual yellow oil
is washed with ether and left to crystallize. Racrystallization
from cyclohexane yields 12 gms. of light yellow crystals,
DL-a-mercaptophenylacetlc acid, benzhydryl ester, m.p. 86-87.
23-
.
: ,. ':,
': ,
~ 5 GG187-190
Example 51
DL~2-[[(Methylthio)carbonyl]thio]phenylacetic acid, benzhydryl
ester
3.34 gms. (10 mM) of DL~a-mercaptophenylacetic acid,
benzhydryl ester are dissolved together with 1.01 gm. (10 mM)
of triethylamine in 25 ml. of chloroform and, while cooling,
1.1 gm. (10 mM) of chloroformic acid thiomethyl ester are
added. After stirring for 1 hour, 25 ml. of water are added
and the mixture is shaken well. The chloroform phase is
dried over sodium sulfate and after evaporating the solvent
in vacuum, the DL-2-[(methylthiocarbonyl)thio]phenylacetic
acid, benzhydryl ester forms as a light oil which
crystallizes after trituration. Recrystallization from
cyclohexane yields 301 gms. of white crystals, m.p. 108-110.
Example52
DL-2-[[(Methylthio)carbonyl]thio]phenylacetic acid
2.04 g. (5 mM) of DL-2-[(methylthiocarbonyl)thio]phenyl-
acetic acid, benzhydryl ester are stirred for 10 minutes in a mix-
ture of 15 ml. of trifluoroacetic acid and 1 ml. of anisole at
io 0-5. This is then evaporated to dryness and the residue
is dissolved in ether. The ether solution is shaken
3 times with dilute aqueous sodium bicarbonate solution. The
vater phase is -idified with 2N hydro_hloric acid and extracted
. ' '
-24-
:. :' ,, , .. , . :. .
, : .. . . ; . . ~ : .
,, , , . : ,' ' . ,~ ~. ' . ~ .' '' '.' . : . .
. - .. : , . :~.
1 ~5 S~ ~ S GG187-190
twice, each with 20 ml. of ether. After drying over sodium
sulfate and evaporating the ether in vacuum, DL-2-[(methyl-
thiocarbonyl)thio]phenylacetic acid forms as a colorless oil
which, after trituration with petroleum ether,crystallizes.
Recrystallization from cyclohexane/benzene yields 0.9 gms.
of white crystals, m.p. 101-102.
Example 53
3-[[(5-MethYl-1,3,4-thiadiazol-2-yl)thioJmethyl]-7-amino-8- ~
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ~ -
A mixture of 13.6 g. ( .05 M) of 7-aminocephalosporanic
acid 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 3-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
By substituting 3-methyl-1,2,4-thiadiazole-5-thiol
or the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure
of Example 5~,11.6 g. of 3 [[(3-methyl-1,2,4-thiadiazol-5-yl)-
'
: .
- 30
25-
,' ' .
GG187-190
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 55
sy substituting l-methyl-lH-tetrazole-5-thiol for the
2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of
Example 53 r 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 is obtained.
Example 56
DL-7~-[[[[(Methylthio)carbonyl]thio]phenylacetyl]amino]-
3-[~(1-methyl-lH-t_trazol-5-yl)thio]methyl]-8-oxo-5-thia-
l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
6.4 gms. (20 mM) of the product of Example 6 are
suspended in 20 ml. of water/acetone ~1:1) and 4.5 gms.
of sodium bicarbonate are added. The mixture is stirred
until a clear solution results. 4.2 cJms. (21 mM) of
DL-2-1[(methylthio)carbonyl]thio]phenylacetic acid chloride
(obtained by stirring the acid for 6 hours in thionyl
chloride and then distilling the excess thionyl chloxide off
in vacuum) dissolved in 20 ml. of acetone are added during
cooling. After the addition of the solution, the mixtur~
is stirred for 1 hour at room temperature. The insoluble products
are then filtered off and the acetonë is evaporated in a
rotary evaporator. The aqueous solution is then adjusted to p~ 2
with 2 N hydrochloric acid while cooling with ice and extracted
twice with S0 ml. portions of ethyl acetate. The ethyl
acetate phase is treated with charcal, filtered and dried
over sodium sulfate. After evaporating the solvent, a firm
light yellow foam is obtained which weighs 2.8 gms. After
recrystalliz,ation with methylene chloride/ether/petroleum ether,
-26-
: ' "., ,- , ' .
GG187-190
~S~
. the pure product DL-7~-[[[[(methylthio)carbonyl]thio]phenylacetyl]- -
amino]-3-[[~1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is
obtained, yield: 1.1 gm., m.p. 89-90.
Example 57
DL-7~-[[[[(Methylthio)carbonyl]thio]phenylacetyl]amino 3-
[[(l-methyl-lH-tetrazol~5-yl)thio]methyl3 8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt
The potassium salt of the product of Example56 i~
obtained by dissolving the acid in a molecular equivalent
amount of aqueous potassium bicarbonate solution and freeze
drying.
The following additional examples are obtained by -
the procedure of Examples53 and 56,by substituting for
the 2-methyl-1,3,4-thiadiazole-5-thiol in Example 53,the
thiol indieated by the 3-substituent, and for the DL-2-
[[(methylthio)earbonyl]thio]phenylacetic acid chloride in
Example 56,the acid ehloride indieated by the 7-substituent:
Example
58 DL-3-[[(1,3,4-thiadiazol-2-yl)thio]methyl-7~-[2-
[[[~methylthio)carbonyl] thio]phenylacetyl]amino]-
-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
earboxylic acid~
59 DL-3-[[(1,3,4-thiadiazol-2-yl~thio]methyl] 7~-
[2-[~[(ethylthio~earbonyl3thio]phenylacetyl]amino]-
8-oxo-5-thia-1-azabieyelo[4.2.0]oet-2-ene-2-
eaxboxylic aeid.
6b DL-3-1[(5-ethyl-1,3,4-thiadiazol-2-yl)thio]methyl]-
7~-[2-[[[(n-butylthio)carbonyl]thio]phenylacetyl]_
amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
-27-
:
,.' ' ' . '
GG187-190
~5~ 5
Example
-2-carboxylic acid and sodium salt.
61 DL-3-1[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-
7~-[[[(methylthio~carbonyl]thio]acetylamino]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
acid and potassium salt.
6~ DL-3-[[(1,2,4-triazol-3-yl)thio]methyl]-7~-
[2 [[(methylthio)carbonyl]thio]phenylacetyl]amino]-
8-oxo 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
~ 10 carboxylic acid.
; 63 DL-3-[[(5-methyl-1,2,4-triazol-3-yl)thio]methyl]-
7~-[2-[[(methylthio)carbonyl]thio]phenylacetyl]-
amino]-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-
ene-2-carboxylic acid. ~-
64 DL-3-[[(1,2,3 triazol-5-yl)thio]methyl]-7~-[2-
[[(ethylthio)carbonyl]thio]-2-(2-thienyl3acetyl]-
; amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid.
`~ 65 3-[[(1-methyl-1,2,3-triazol-S-yl)thio~methyl-7~-
[2-[[(methylthio)carbonyl]thio]acetyl]amino~-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
. .
carboxylic acid.
~6 DL-3-[[(lH~tetrazol-5-yl)thio]methyl]-7~-~[1[(methyl-
thio)carbonyl]thio]phenylacetyl]amino]-8-oxo-5-
thia-l-aza~:cyclo[4.2.0]oct-2-ene-2-carboxylic
;~- acid.
- 67 DL-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methyl]-7~-
` I[[[(methylthio)carbonyl]thio]acetyl]amino]-8-oxo-
5-thia-1-azabicyclo[4.3.0]oct-2-ene-2-carboxylic
- 30 acid, trimethylsilyl ester.
2~-
,~
., . : . . , . ~ , .. .
: . : . .
GG187-190
Example
58 DL-3-[[(1,2,4-tr azol-3~yl)thio]methyl]-7~-
[2 [[(methylthio)carbonyl3khio]-2-(2-furyl)acetyl]-
amino]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-
2-carboxylic acid.
69 DL-3-[1(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-
7 ~~ [ 1 L (methylthio)carbonyl]thio]-2-(2-pyridyl)-
acetyl]amino]-8-oxo-5-thia l-azabicyclo[4.2.0]-
oct-2-ene-2-carboxyllc acid.
DL-3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-7~-
[[l[(n propylthio)carbonyl]thio]acetyl]amino~-
3-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid, trimethylsilyl ester.
71 DL-3-[[(1,2,4~thiadiazol-3-yl)thio]methyl]-7~-
[[[[(methylthio)carbonyl]thio]phenylacetyllamino]-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid.
72 DL-3-[[(5-b~ltyl-1,2,4-thladiazol-3-yl)thio]methyl]-
7~-[[[[(methylthio)carbonyl]thio]acetyl]amino]-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic
~ acid.
73 DL-3-[(methylthio)methyl~-7~-[DL-2-[[(methylthio)-
carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-~
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid methyl ~-
ester.
74 DL-3-l~ethylthio~methyl]-7~-[[(methylthio)carbonyl]- -~
thio]phenylacetyl]amino]-8-oxo-5-thia-1-a~abicyclo-
14.2.0]oct-2-ene-2-carboxylic acid.
DL 3-l(methylthio)methyl]-7~-[[[[(methylthio)-
carbonyl]thiolacetyl]amino] 8-oxo-5-thia-1-
29-
- . . , . , . . ............. , ' '
. ,, .: : . . ;
/ GG187-l9o
3L~5~ 5
Example
azabicyclo[4.2.0~oct-2 ene-2-carboxylic acid
and sodium salt.
76 DL-3-~(ethylthio)methyl]-7~-~[[[~ethyl~io)c~rb~nyl]-
thio]acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylic acid and triethylamine salt.
77 DL-3-[(methylthio)methyl]-7~-[[[(methylthio)carbonyl3-
thio]-2-(2-thienyl)acetyl]amino]-8-oxo-5-thia-l-
azabicyclo[4.2.0]oct-2 ene-2-carboxylic acid,
benzhydryl ester.
7~ DL 3-[(ethylthio)methyl]-7~-[[l(methylthio)carbonyl]-
thio]-2-(3-furyl)acetyl]amino]-8-oxo-5-thia-l-
aza~icyclo[4.2.0]oct-2-ene-2-carboxylic acid.
79 DL-3-[(methylthio)methyl3-7~-[[[(methylthio)carbonyl]-
thio]-2-(2-pyridyl)acetyl]amino]-8-oxo-5-thia-1-
azabicyclo[4.2.0joet-2-ene-2-carboxylic acid.
DL-3-[(propylthio)methyl]-7~-[[[(methylthio)carbonyl]-
thio]phenylaeetyl]amino]~8 oxo-5-thia-l-azabicyclo-
[4.2~0]oct-2-ene-2-carboxylic acid.
81 DL-3-[[(l-ethyl-lH-tetrazol-5-yl)thio]methyl]-
7~-[[[(ethylthio)carbonyl]thio]-2-(2-pyridyl)-acetyl]-
amino]-8-oxo-5-thia-1-azabicyclo[4.2.03Oct-2-ene-2-
carboxylie acid and potassium salt.
~2 D~-3-[[~lH-tetrazol-5-yl)thio]methyl]-7~-~ E ~methyl-
thio)caxbonyl]thio]acetyl~amino]-8-oxo-5-thia-1-
azabieyelo[4.2.0]oct-2-ene-2-carboxylie acid.
~3 DL-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-
7~-[l[(ethylthio)carbonyl3thio]-2-(2-furyl)acetyl]
amino]-8-oxo-5-thia~l-azabicyclo[4.2.0]oct-2-
ene-2-carboxylie acid and potassium salt.
" ' ' .
-30-
~5 ~ ~5 GG187-190
Example
84 DL-3 ~[(l~methyl-lH-tetrazol-5-yl)thio]methyl]-7~-
[2-~[(methylthio)earbonyl]thio]-2-(3-thienyl)acetyl]-
amino]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2- ene-
2-earboxylie aeid pivaloyloxymethyl ester.
DL-3-[[(1-ethyl-lH-tetrazol-5-yl)thio]methl-7~-
[[(ethylthio)earbonyl]thio]aeetyl]amino]-8-oxo-
5~thia-1-azabicyelo14.2.0]oct-2-ene-2-carboxylic acid.
86 DL-3-[[(lH-tetrazol-5-yl)thio]methyl]-7~-[2-
[n-butylthio)earbonyl3thio]aeetyl]amino3-8-oxo-
5-thia-1-azabieyelo[4.2.0]oet-2-ene-2-carboxylie
aeid.
87 DL-3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl3-
7~-[~[[(methylthio~earbonyl~thio]phenylaeetyl]amino]- -
; 8-oxo-5-thia-1-azabieyclo[4.2.0loet-2-ene-2-
earboxylie aeid.
88 DL-3~[[(1,2,4-thiadiazol-3-yl)thio]methyl-7~-
[[[2-[(methylthio?earbonyl]thi3propionyl3amino]-
8-oxo-5-thia-1-azabieyclol4.2.0]oet-2-ene~2-
earboxylie aeid pivalo~loxymethyl ester.
89 DL-3-[[(lH-tetrazol-5-yl)thio3methyl]-7~-[[[2-[(eth
thio)earbonyl]thio]propionyl]amino]-8-oxo-5-thia- ~;
l-azabieyleo[4.2.0]oet-2-ene-2-earboxylic aeid.
DL-3-[[(1-methyl lH-tetrazol-5-yl)thio]methyl]-
7~-[~[2-[[(methylthio)earbonyl]thio]butyryl]amino~-
8-oxo-5-thia~l-azabieyelo[4.2.0~oet-2-ene-2-
earboxylie aeid and potassium salt.
31-
