CA1056815A - Alkyl and heterothio derivatives of alkyl o or s carbonyl thioacetyl cephalosporins - Google Patents
Alkyl and heterothio derivatives of alkyl o or s carbonyl thioacetyl cephalosporinsInfo
- Publication number
- CA1056815A CA1056815A CA223,673A CA223673A CA1056815A CA 1056815 A CA1056815 A CA 1056815A CA 223673 A CA223673 A CA 223673A CA 1056815 A CA1056815 A CA 1056815A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- thio
- oxo
- amino
- ene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Abstract
ABSTRACT
This invention relates to new three-thio derivatives of thio-alkoxycarbonyl-and carbamoyl-substituted thioacetylcephalo-sporins of the formula
This invention relates to new three-thio derivatives of thio-alkoxycarbonyl-and carbamoyl-substituted thioacetylcephalo-sporins of the formula
Description
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 (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
Rl ~ CH CO - NH - CH CH CH2 (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.
~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
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.
' ' ' , . ~ . ..
~S~BlS
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~
,. ' ' ~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~.
~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.).
' .. ., . . . :.. ~.
. , , , . " .~ , , : . '. . ' , . . . .
Example 4_ phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
:. , , ,:: , , 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.
~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
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.
' ' ' , . ~ . ..
~S~BlS
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~
,. ' ' ~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~.
~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.).
' .. ., . . . :.. ~.
. , , , . " .~ , , : . '. . ' , . . . .
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
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~
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 , ,, . ., ~
.
~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.
' ' '; ' ' ' . :
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.
' .. . , : , ~ :"" . . ::
... . , . . :, .. ;. .~ . , :
. .
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 : . , , ., ~ , . , . , , :
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):
,: . .
.
" .
, . '.
, ' ' .
'. ~ .
, , . ., . , . ', , , . ":
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]-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]-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 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 '~ .
,, .
''' ~ , ... . .. .. ..
.: :
~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 .
.. ~ , , .
~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.
.
: ,. ':, ': , ~ 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 . ' ' :. :' ,, , .. , . :. .
, : .. . . ; . . ~ : .
,, , , . : ,' ' . ,~ ~. ' . ~ .' '' '.' . : . .
. - .. : , . :~.
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)-' : .
,' ' .
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
.
~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.
' ' '; ' ' ' . :
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.
' .. . , : , ~ :"" . . ::
... . , . . :, .. ;. .~ . , :
. .
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 : . , , ., ~ , . , . , , :
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):
,: . .
.
" .
, . '.
, ' ' .
'. ~ .
, , . ., . , . ', , , . ":
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]-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]-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 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 '~ .
,, .
''' ~ , ... . .. .. ..
.: :
~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 .
.. ~ , , .
~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.
.
: ,. ':, ': , ~ 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 . ' ' :. :' ,, , .. , . :. .
, : .. . . ; . . ~ : .
,, , , . : ,' ' . ,~ ~. ' . ~ .' '' '.' . : . .
. - .. : , . :~.
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)-' : .
,' ' .
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, : ' "., ,- , ' .
~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]-
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, : ' "., ,- , ' .
~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-:
,.' ' ' . ' ~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]-
,.' ' ' . ' ~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~-,~
., . : . . , . ~ , .. .
: . : . .
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-- . . , . , . . ............. , ' ' . ,, .: : . . ;
/ 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.
" ' ' .
~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.
; 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~-,~
., . : . . , . ~ , .. .
: . : . .
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-- . . , . , . . ............. , ' ' . ,, .: : . . ;
/ 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.
" ' ' .
~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.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R? is lower alkylamlno or lower alkylthio; R3 is lower alkyl substituted tetrazolyl and R is hydrogen or a salt forming ion, characterized by reacting a compound of the formula with a thioacetic acid of the formula or a reactive derivative thereof.
2. A process as in claim 1 wherein R? is lower alkylthio.
3. A process as in claim 1 wherein R? is lower alkylamino.
4. A process as in claim 1 wherein R3 is 1-lower alkyl-1H-tetrazol-5-yl.
5. A process as in claim 1 wherein R? is methylamino and R3 is 1-methyl-1H-tetrazol-5 yl.
6. A process as in claim 1 wherein R? is methylthio and R3 is 1-methyl-1H-tetrazol-5-yl.
7. A compound of the formula wherein R? is lower alkylamino or lower alkylthio; R3 is loweralkyl substituted tetrazolyl and R is hydrogen or a salt forming ion, whenever prepared by the process of claim 1.
8. A compound as in claim 7 wherein R? is lower alkylthio, whenever prepared by the process of claim 2.
9. A compound as in claim 7 wherein R? is lower alkylamino, whenever prepared by the process of claim 3.
10. A compound as in claim 7 wherein R3 is 1-lower alkyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 4.
11. A compound as in claim 7 wherein R? is methylamino and R3 is 1-methyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 5.
12. A compound as in claim 7 wherein R? is methylthio and R3 is 1-methyl-1H-tetrazol-5-yl, whenever prepared by the process of claim 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US468727A US3929776A (en) | 1974-05-10 | 1974-05-10 | 3-Heterothio derivatives of {8 (thioalkoxycarbonyl)thioacetyl{9 cephalosporins |
| US05/501,902 US3931170A (en) | 1974-08-30 | 1974-08-30 | 3-Heterothio derivatives of (carbamoylthioacetyl)cephalosporins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1056815A true CA1056815A (en) | 1979-06-19 |
Family
ID=27042510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,673A Expired CA1056815A (en) | 1974-05-10 | 1975-04-02 | Alkyl and heterothio derivatives of alkyl o or s carbonyl thioacetyl cephalosporins |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS50154285A (en) |
| CA (1) | CA1056815A (en) |
| DE (1) | DE2520829A1 (en) |
| FR (1) | FR2269955B1 (en) |
| GB (1) | GB1500582A (en) |
-
1975
- 1975-04-02 CA CA223,673A patent/CA1056815A/en not_active Expired
- 1975-04-08 GB GB1439875A patent/GB1500582A/en not_active Expired
- 1975-05-06 FR FR7514147A patent/FR2269955B1/fr not_active Expired
- 1975-05-09 DE DE19752520829 patent/DE2520829A1/en not_active Withdrawn
- 1975-05-10 JP JP5589875A patent/JPS50154285A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB1500582A (en) | 1978-02-08 |
| FR2269955B1 (en) | 1978-07-28 |
| DE2520829A1 (en) | 1975-11-20 |
| FR2269955A1 (en) | 1975-12-05 |
| JPS50154285A (en) | 1975-12-12 |
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