CA1074298A - 3-heterothio-7-ureido cephalosporins - Google Patents
3-heterothio-7-ureido cephalosporinsInfo
- Publication number
- CA1074298A CA1074298A CA234,462A CA234462A CA1074298A CA 1074298 A CA1074298 A CA 1074298A CA 234462 A CA234462 A CA 234462A CA 1074298 A CA1074298 A CA 1074298A
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- Prior art keywords
- methyl
- amino
- ene
- oxo
- thia
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
ABSTRACT
Compounds of the formula wherein R1 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl substituted phenyl and phenyl-lower alkyl and certain heterocyclic groups; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)stannyl, tri(lower alkyl)silyl, a salt forming ion, or the group
Compounds of the formula wherein R1 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl substituted phenyl and phenyl-lower alkyl and certain heterocyclic groups; R2 is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)stannyl, tri(lower alkyl)silyl, a salt forming ion, or the group
Description
10~7~
Cephalosporins having in the 7-position certain -ureido and alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl and heteroacetyl groups are disclosed in U.S.
Patent No. 3,673,183 and 3,833,S68. Cephalosporins substituted in the 3-position with -CH2-S-hpetero groups and in the 7-position with -~ -phenyl groups and -C-CH-hetero groups are disclosed as possessing antibacterial activity in U.S. Patent Nos. 3,641,021;
3,759,904; 3,813,388; 3,821,207; and 3,796,801 (method of treating Enterobacter infections). Also disclosed as useful intermediates are cephalospoxins substituted in the 3-posiOion with -CH2-S-hetero groups and in the 7-position with a -C-(CH2)3-CH-COOH
group, U.S. Patent No. 3,819,621. cHo Thi~ invention relates to new cephalosporins of the formula Rl-CH-C-NH ~ ~ ~
o~ ~C~2-S-R4 Rl is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cyclo-alkadienyl, phenyl, phenyl-lower alkyl or substituted phenyl and phenyl-lower alkyl and certain heterocyclic groups; R2 represents hydrogen or lower alkyl, and R3 represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, substituted phenyl-lower alkyl, tri(lower alkyl)stannyl, tri~lower alkyl)silyl, a salt forming ion, or the group -CH2-O-~-R wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl and phenyl-lower alkyl; and R4 represents certain heterocyclic groups.
I_ ~
-- ~07429~ ~
The various groups represented by the symbols have the meaning defined below and these definitions are retained throu~hout this specficiation.
The lower alkyl groups referred to throughout this specif-ication include straight or branched chain hyarocarbon groups containing 1 to 8 carbon atom~, preferably 1 to 4 carbons.
Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. The lower alkoxy groups include such lower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy, propoxy, etc. The phenyl-lower alkyl and diphenyl-lower alkyl groups include ~uch lower alkyl groups attached to a phenyl, e.g., benzyl, phenethyl, diphenylmethyl, etc.
Cycloalkyl refers to groups having 3 to 7 carbons in the ring, l.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The terms cycloalkenyl and cycloalkadienyl atSo represent rings having 3 to 7 carbons with one or two double bonds, i.e., cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, etc. The double bond or bonds may be located at Yarious positions, i.e., 1,4-cyclo-hexadienyl, etc.
The substituted phenyl and subst~tuted phenyl-lower alkyl groups xepresenting Rl, R3, or R include one or more (pre-ferably only one) simple substituents selected fro~ halogen (preferably chlorine or brimine), lower alkyl and lower alkoxy, e.g., 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl, 2-, 3-, or 4-chlorobenzyl, 2-, 3- or 4-ethylphenethyl, etc. Also, in the case of Rl, the phenyl substituent can be hydroxyl group.
07429t5/
The salt forming ions represented by R3 may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, phenyl-lower alkylamines such as dibenzylamine, N,N-dibenzylethylenediamine, lower alkylamines such as methyl-amine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine.
The heterocyclics represented by Rl are thienyl, furyl, pyrryl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, ànd tetrazolyl. They are attached at any available position as for example 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrryl, 2-, 3- or 4-pyridyl, 2- or 5-thiazolyl, 3- or 5-isothia-zolyl, 2- or 5-oxazolyl, 3- or 5-isoxazolyl, 3- or 5-(1,2,4-thia-diazolyl), etc. Alqo included within the meaning of Rl are such heterocyclic~ havinga halogen ~preferably Cl or Br) or a lower alkyl ~preferably methyl or ethyl) substituent, i.e. 5-~1-methyl-tetrazolyl), 2-(5-chlorothienyl), 2-~4-chloropyrryl), etc.
The heterocyclic groups represented by R4 are N - N N N N N N~ R
~N , ~ S 1 R , ~ 0 ~ R5 ~ ~ S ~N
~ ~ ~ R5 ~ R5 wherein R5 is hydrogen or alkyl of 1 to 4 carbons.
Preferred embodiments of this invention are as followss Rl is phenyl, benzyl, phenethyl, substituted phenyl, benzyl and phenethyl, cycloalkyl, cycloalkenyl and cycloalkadienyl of 5 to 7 carbons, thieny~ furyl, pyrryl and pyridyl.
- -~0742~1 R2 is hydrogen or lower alkyl of 1 to 4 carbons.
R3 is hydrogen, lower alkyl of 1 to 4 carbons, benzyl, phenethyl, diphenylmethyl, trimethylsilyl, trimethylstannOyl, aluminum, alkaline earth metal, alkali metal, or -CH2-O-C-R.
R is lo~er alkyl of 1 to 4 carbons, phenyl, benzyl, or phenethyl, The most preferred embodiments are:
Rl is phenyl 1,4-cyclohexadien-1-yl, thienyl or pyridyl, especially phenyl, 2-thienyl, 3-thienyl or 3-pyridyl.
0 R2 i5 hydrogen or methyl, especially hydrogen.
R3 i8 hydrogen, diphenyl-methyl or potassium, especially hydrogen.
~ , S ~ CH3, ~ ~ H3, ~ 5,N
especially 5-methyl-1,3,4-thiadiazol-2-yl and l-methyl-lH-tetrazol-5-yl.
Compounds of formula I are obtained by reacting an ~-ureido compound of the formula (II) Rl-CIH-COOH
NH-~-N-R2 O H
with a 3-heterothio-7-amino substituted cephalosporin of the formula (III) HzN I ¦ ~
N ~ CH2-S-R4 wherein R3 is preferably diphenyl-methyl or t-butyl or other ester protecting groups~
107429~
This reaction is carried out by converting the -ureido compound of formula II to a mixed carbonic or other anhydride by treating a solution of the a-ureido compound in an organic solvent containing a tri(lower alkyl)amine with an anhydride forming agent, i.e. a lower alkyl chloroformate, an aryl chloro-formate, or an acyl halide, at reduced temperatures of from about 0C to about -20C.
Alternatively, the a-ureido compound of formula II can be converted to an activated ester by reacting with a carboxyl group activating agent such as dicyclohexylcarbodiimide or bisimidazole carbonyl. In some cases the carboxyl group may be activated by conversion to an acid halide, e.g., the chloride, or to an azide.
The methoas of preparing the a-ureido compounds of formula II
are known to those skilled in the art and a number of such methods are discussed in U.S. 3,833,568 referred to above.
The compounds of formula I can also be prepared by acylating the compound of formula III with an acid chloride of formula 0 (IV) Rl-fH-C-Cl
Cephalosporins having in the 7-position certain -ureido and alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl and heteroacetyl groups are disclosed in U.S.
Patent No. 3,673,183 and 3,833,S68. Cephalosporins substituted in the 3-position with -CH2-S-hpetero groups and in the 7-position with -~ -phenyl groups and -C-CH-hetero groups are disclosed as possessing antibacterial activity in U.S. Patent Nos. 3,641,021;
3,759,904; 3,813,388; 3,821,207; and 3,796,801 (method of treating Enterobacter infections). Also disclosed as useful intermediates are cephalospoxins substituted in the 3-posiOion with -CH2-S-hetero groups and in the 7-position with a -C-(CH2)3-CH-COOH
group, U.S. Patent No. 3,819,621. cHo Thi~ invention relates to new cephalosporins of the formula Rl-CH-C-NH ~ ~ ~
o~ ~C~2-S-R4 Rl is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cyclo-alkadienyl, phenyl, phenyl-lower alkyl or substituted phenyl and phenyl-lower alkyl and certain heterocyclic groups; R2 represents hydrogen or lower alkyl, and R3 represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, substituted phenyl-lower alkyl, tri(lower alkyl)stannyl, tri~lower alkyl)silyl, a salt forming ion, or the group -CH2-O-~-R wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl and phenyl-lower alkyl; and R4 represents certain heterocyclic groups.
I_ ~
-- ~07429~ ~
The various groups represented by the symbols have the meaning defined below and these definitions are retained throu~hout this specficiation.
The lower alkyl groups referred to throughout this specif-ication include straight or branched chain hyarocarbon groups containing 1 to 8 carbon atom~, preferably 1 to 4 carbons.
Examples of the type of groups contemplated are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. The lower alkoxy groups include such lower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy, propoxy, etc. The phenyl-lower alkyl and diphenyl-lower alkyl groups include ~uch lower alkyl groups attached to a phenyl, e.g., benzyl, phenethyl, diphenylmethyl, etc.
Cycloalkyl refers to groups having 3 to 7 carbons in the ring, l.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The terms cycloalkenyl and cycloalkadienyl atSo represent rings having 3 to 7 carbons with one or two double bonds, i.e., cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, etc. The double bond or bonds may be located at Yarious positions, i.e., 1,4-cyclo-hexadienyl, etc.
The substituted phenyl and subst~tuted phenyl-lower alkyl groups xepresenting Rl, R3, or R include one or more (pre-ferably only one) simple substituents selected fro~ halogen (preferably chlorine or brimine), lower alkyl and lower alkoxy, e.g., 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl, 2-, 3-, or 4-chlorobenzyl, 2-, 3- or 4-ethylphenethyl, etc. Also, in the case of Rl, the phenyl substituent can be hydroxyl group.
07429t5/
The salt forming ions represented by R3 may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, phenyl-lower alkylamines such as dibenzylamine, N,N-dibenzylethylenediamine, lower alkylamines such as methyl-amine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine.
The heterocyclics represented by Rl are thienyl, furyl, pyrryl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, ànd tetrazolyl. They are attached at any available position as for example 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrryl, 2-, 3- or 4-pyridyl, 2- or 5-thiazolyl, 3- or 5-isothia-zolyl, 2- or 5-oxazolyl, 3- or 5-isoxazolyl, 3- or 5-(1,2,4-thia-diazolyl), etc. Alqo included within the meaning of Rl are such heterocyclic~ havinga halogen ~preferably Cl or Br) or a lower alkyl ~preferably methyl or ethyl) substituent, i.e. 5-~1-methyl-tetrazolyl), 2-(5-chlorothienyl), 2-~4-chloropyrryl), etc.
The heterocyclic groups represented by R4 are N - N N N N N N~ R
~N , ~ S 1 R , ~ 0 ~ R5 ~ ~ S ~N
~ ~ ~ R5 ~ R5 wherein R5 is hydrogen or alkyl of 1 to 4 carbons.
Preferred embodiments of this invention are as followss Rl is phenyl, benzyl, phenethyl, substituted phenyl, benzyl and phenethyl, cycloalkyl, cycloalkenyl and cycloalkadienyl of 5 to 7 carbons, thieny~ furyl, pyrryl and pyridyl.
- -~0742~1 R2 is hydrogen or lower alkyl of 1 to 4 carbons.
R3 is hydrogen, lower alkyl of 1 to 4 carbons, benzyl, phenethyl, diphenylmethyl, trimethylsilyl, trimethylstannOyl, aluminum, alkaline earth metal, alkali metal, or -CH2-O-C-R.
R is lo~er alkyl of 1 to 4 carbons, phenyl, benzyl, or phenethyl, The most preferred embodiments are:
Rl is phenyl 1,4-cyclohexadien-1-yl, thienyl or pyridyl, especially phenyl, 2-thienyl, 3-thienyl or 3-pyridyl.
0 R2 i5 hydrogen or methyl, especially hydrogen.
R3 i8 hydrogen, diphenyl-methyl or potassium, especially hydrogen.
~ , S ~ CH3, ~ ~ H3, ~ 5,N
especially 5-methyl-1,3,4-thiadiazol-2-yl and l-methyl-lH-tetrazol-5-yl.
Compounds of formula I are obtained by reacting an ~-ureido compound of the formula (II) Rl-CIH-COOH
NH-~-N-R2 O H
with a 3-heterothio-7-amino substituted cephalosporin of the formula (III) HzN I ¦ ~
N ~ CH2-S-R4 wherein R3 is preferably diphenyl-methyl or t-butyl or other ester protecting groups~
107429~
This reaction is carried out by converting the -ureido compound of formula II to a mixed carbonic or other anhydride by treating a solution of the a-ureido compound in an organic solvent containing a tri(lower alkyl)amine with an anhydride forming agent, i.e. a lower alkyl chloroformate, an aryl chloro-formate, or an acyl halide, at reduced temperatures of from about 0C to about -20C.
Alternatively, the a-ureido compound of formula II can be converted to an activated ester by reacting with a carboxyl group activating agent such as dicyclohexylcarbodiimide or bisimidazole carbonyl. In some cases the carboxyl group may be activated by conversion to an acid halide, e.g., the chloride, or to an azide.
The methoas of preparing the a-ureido compounds of formula II
are known to those skilled in the art and a number of such methods are discussed in U.S. 3,833,568 referred to above.
The compounds of formula I can also be prepared by acylating the compound of formula III with an acid chloride of formula 0 (IV) Rl-fH-C-Cl
2 0 NH 2 ' HCl or an a-(substituted)amino acid of the formula (V) Rl-CH-COOH
NH-Y o wherein Y is a leaving group such as ~ CH2-0-C- or H3C0 ~ CH2-0-C- or ~CH3 ) 3-C-O-C- to yield the intermediate of formula .
(VI ) Rl- I H-C-NH ~S~
2 ~N~CH2-S-R4
NH-Y o wherein Y is a leaving group such as ~ CH2-0-C- or H3C0 ~ CH2-0-C- or ~CH3 ) 3-C-O-C- to yield the intermediate of formula .
(VI ) Rl- I H-C-NH ~S~
2 ~N~CH2-S-R4
3 COOH
~074291~
Various intermediates of formula VI where Rl is phenyl are disclosed in U.,S. Pat. Nos. 3,821,207; 3,813,388; 3,641,021;
_ 3,759,904_ ,an,d 3,796,801.
The intermediates of formula VI are converted to the final products of formula I by treatment with an isocyanate of the formula ~ VII) R2-N=C=~
or when ~2 is hydrogen an alkali or alkaline earth cyanate such ag potassium cyanate in solution at a pH of from about 7 to abo,ut 8.
--- 10 The final products of formula I can also be prepared by reacting the compound of formula II with 7-ACA preferably in the presence of dicyclohexylcarbodiimide to yield the compound of formula VIII (a~ disclosed in 3,673;183) ~ VIII) C-O oFr~L CH2-0-~-C~3 ~-R2 COOR3 followed by treatment with the compound of the formula IX) R4-S-H
in solution at a pH of from about 7.8 to about 8Ø
Similarly, the final products of formula I can be prepared by reacting the compounds of formula IV or V with an ester of 7-ACA preferably in the presence of dicyclohexylcarbodiimide followed by treatment with an acid (HX), preferably trifluoro-acetic acid in the presence of anisole, to yield the salt of formula ~074298 . GGl92-193 (x) R
Rl-lH-c-N~
HX ~ . ~ CH2-0-~-CH3 The salt of formula X is treated with the isocyanate of formula VII (or the alkali or alkaline earth cyanate where R2 is hydrogen) followed by treatment with the compound of formula IX to yield the final product of formula 1.
~ he compounds of formula I wherein R3 iS lower alkyl, phenyl-lower alkyl, substituted phenyl-lower al~yl, diphenyl-lower alkyl, or the acyloxymethyl group -CH2-O- -R may be obtained by reacting the 3-heterothio-7-amino substituted cephalosporin of formula III or the 7-ACA either before or after the acylation of the 7-amino substituent with one or two moles of a compound of the formula (XI) halo-R3 or ~XII) R3-N -N
whereln halo is preferably chlorine or bromine in an inert solvent such as dimethylformamide, acetone, dioxane, benzene, or the like at about ambient temperature or below.
Simi~arly, the compounds of formula I wherein R3 is tri~lower alkyl) stannyl or tri(lower alkyl)silyl are obtained by in~roducing such groups onto the 3-heterothio cephalosporanic acld moiety either before or after the acylation reaction.
The carboxylate salts of the compound of formula I are formed by reacting the carboxyl group of the cephalosporanic acid moiety, i.e. R3 i~ hydrogen, with any of the salt forming ions described above.
It will be appreciated that the compounds of formula I
are optically active due to the presence of an asymmetric .. .
_7-1074Z9~ GG192-193 carbon atom in the 7-position side chain. By selection of the appropriate starting material it is possible to obtain the compounds of formula I as a mixture of optically active isomers or isolated as a single isomer. The various isomers as well as their mixtures are within the scope of this invention.
Where possible, it is generally preferred to obtain the D-isomer since that is the one which exhibits greater biological activity.
Illustrative process details are provided in the examples for the various reactions.
--- The compounds of formula I have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as StaphYlococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or as surface disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a - compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to lO0 mg./Xg., daily, orally or parenterally, in slngle or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.
Up to about 600 mg; of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared accordin~ to conventional pharmaceutical practice.
They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy e~uipment, at a concentration of about 0.2 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying.
They are also useful as nutritional supplements in animal feeds.
The following examples are illustrative of the invention.
A11 temperatures are on the centigrade scale.
. .
_g_ 1~742g~
Example 1 7~-~[[(Aminocarbonyl)amino]~D-phenyl)acetyl]amino]-3-~[(1-meth~l-lH-tetrazol-5-yl)thio]methvl]-8-oxo- -thia-1-az ~
~4.?. 0] oct-2-ene-2-carboxylic acid -a) Ethyl acetate adduct of 7-amino-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi~yc~o[4.2.01oct-2-ene-2-carboxYlic acid, 4-methylbenzenesulfonic acid salt 32.8 g. of 7-amino-3-[[~1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (produced from 7-aminocephalosporanic acid by treatment ,, with l-methyl-tetrazole-5-thiol at 60C at a pB of 7.5-8.0 in water/acetone) are finely pulverized and suspended in a mixture of 700 ml. of anhydrous dioxane and 575 ml. of anhydrous methanol.
20.6 g. of 4-methylbenzenesulfonic acid monohydrate are added to the suspension with vigorous stirring. After 30 minutes a clear solution results, which is then concentrated on a rotary evapora-tor. In order to completely remove water from the residue, 200 ml. of anhydrous dioxane are added and the solution again concen~rated. This procedure is repeated twice more. The oily residue crystallizes upon trituration with ethyl acetate.
61.2 g. of the ethyl acetate adduct of 7-amino-3-~ methyl-lH-,tetrazol-5-yl)thiolmethyll-8-oxo-5-thia-l-azabicyclo[4.2.0l-oct-2-ene-2-carboxylic acid, 4-methylbenzenesulfonic acid salt are obtained.
b) 7-Amino-3-~[(l-methyl-l~-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-l-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenYl-methyl ester The product from part (a) is suspended in a mixture of 700 ml. dioxane and 300 ml. of ethyl acetate. To this mixture is added dropwise at 10-15 with vigorous stirring a solution 107 4 Z9 ~ GG19~193 of diphenyldiazomethane ~produced from 40 g. of benzophenone hydrazone and 43.7 g. of mercuric oxide by stirring vigorously for 6 hours with 220 ml. of petro'eum ether (b.p. 40 to 60), filtering and concentrating] in 2~0 ml. of anhydrous dioxane.
After stirring for 3 hours at room temperature a clear, wine red solution results, which is treated with 75 ml. of methanol to remove excess diphenyldiazomethane. After the wine red color disappears, the yellow brown solution is concentrated, the residue is dissolved in 800 ml. of methylene chloride and the solution is washed with a solution of 40 g. of dibasic potassium phosphate - in 80~ ml. of water and then with400 ml.Of water, dried with magnesi~m sulfate and concentrated. The viscous residue is triturated with petroleum ether. 47.7 g. of 7-amino-3-[1~1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.01oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained. The crude product is purified by stirring for 1 hour with 50 ml. of ice cold ethyl acetate and filtered under suction, to yield 28.5 g. of purified product, m.p. 153-156 (dec.).
The product is recrystallized from methylene chloride/petroleum ether, m.p. 166-168 (dec.).
c) D--[~[~4-Methoxyphen~)methoxvlcarbonyl~amino]-2-~henvlacetic acid D-(2-phenyl)glycine and magnesium oxide are suspended in water. To this suspension is added a solution of (p-methoxy-phenyl)methoxycarbonylazide in dioxane. The mixture i~s~stirred at room temperature, filtered, and the filtrate is-extracted with ether. The aqueous phase is layered over with ethyl acetate, washed with water, dried, and concentrated to obtain D-~-t[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-phenylacetic acid.
GGl92-193 d) 7B-[[[[[(4-Methoxyphenyl)methoxy]carbonYl]amino](D-phenyl)-acetyl]amino3-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
~074291~
Various intermediates of formula VI where Rl is phenyl are disclosed in U.,S. Pat. Nos. 3,821,207; 3,813,388; 3,641,021;
_ 3,759,904_ ,an,d 3,796,801.
The intermediates of formula VI are converted to the final products of formula I by treatment with an isocyanate of the formula ~ VII) R2-N=C=~
or when ~2 is hydrogen an alkali or alkaline earth cyanate such ag potassium cyanate in solution at a pH of from about 7 to abo,ut 8.
--- 10 The final products of formula I can also be prepared by reacting the compound of formula II with 7-ACA preferably in the presence of dicyclohexylcarbodiimide to yield the compound of formula VIII (a~ disclosed in 3,673;183) ~ VIII) C-O oFr~L CH2-0-~-C~3 ~-R2 COOR3 followed by treatment with the compound of the formula IX) R4-S-H
in solution at a pH of from about 7.8 to about 8Ø
Similarly, the final products of formula I can be prepared by reacting the compounds of formula IV or V with an ester of 7-ACA preferably in the presence of dicyclohexylcarbodiimide followed by treatment with an acid (HX), preferably trifluoro-acetic acid in the presence of anisole, to yield the salt of formula ~074298 . GGl92-193 (x) R
Rl-lH-c-N~
HX ~ . ~ CH2-0-~-CH3 The salt of formula X is treated with the isocyanate of formula VII (or the alkali or alkaline earth cyanate where R2 is hydrogen) followed by treatment with the compound of formula IX to yield the final product of formula 1.
~ he compounds of formula I wherein R3 iS lower alkyl, phenyl-lower alkyl, substituted phenyl-lower al~yl, diphenyl-lower alkyl, or the acyloxymethyl group -CH2-O- -R may be obtained by reacting the 3-heterothio-7-amino substituted cephalosporin of formula III or the 7-ACA either before or after the acylation of the 7-amino substituent with one or two moles of a compound of the formula (XI) halo-R3 or ~XII) R3-N -N
whereln halo is preferably chlorine or bromine in an inert solvent such as dimethylformamide, acetone, dioxane, benzene, or the like at about ambient temperature or below.
Simi~arly, the compounds of formula I wherein R3 is tri~lower alkyl) stannyl or tri(lower alkyl)silyl are obtained by in~roducing such groups onto the 3-heterothio cephalosporanic acld moiety either before or after the acylation reaction.
The carboxylate salts of the compound of formula I are formed by reacting the carboxyl group of the cephalosporanic acid moiety, i.e. R3 i~ hydrogen, with any of the salt forming ions described above.
It will be appreciated that the compounds of formula I
are optically active due to the presence of an asymmetric .. .
_7-1074Z9~ GG192-193 carbon atom in the 7-position side chain. By selection of the appropriate starting material it is possible to obtain the compounds of formula I as a mixture of optically active isomers or isolated as a single isomer. The various isomers as well as their mixtures are within the scope of this invention.
Where possible, it is generally preferred to obtain the D-isomer since that is the one which exhibits greater biological activity.
Illustrative process details are provided in the examples for the various reactions.
--- The compounds of formula I have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as StaphYlococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or as surface disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a - compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to lO0 mg./Xg., daily, orally or parenterally, in slngle or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.
Up to about 600 mg; of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared accordin~ to conventional pharmaceutical practice.
They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy e~uipment, at a concentration of about 0.2 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying.
They are also useful as nutritional supplements in animal feeds.
The following examples are illustrative of the invention.
A11 temperatures are on the centigrade scale.
. .
_g_ 1~742g~
Example 1 7~-~[[(Aminocarbonyl)amino]~D-phenyl)acetyl]amino]-3-~[(1-meth~l-lH-tetrazol-5-yl)thio]methvl]-8-oxo- -thia-1-az ~
~4.?. 0] oct-2-ene-2-carboxylic acid -a) Ethyl acetate adduct of 7-amino-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi~yc~o[4.2.01oct-2-ene-2-carboxYlic acid, 4-methylbenzenesulfonic acid salt 32.8 g. of 7-amino-3-[[~1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (produced from 7-aminocephalosporanic acid by treatment ,, with l-methyl-tetrazole-5-thiol at 60C at a pB of 7.5-8.0 in water/acetone) are finely pulverized and suspended in a mixture of 700 ml. of anhydrous dioxane and 575 ml. of anhydrous methanol.
20.6 g. of 4-methylbenzenesulfonic acid monohydrate are added to the suspension with vigorous stirring. After 30 minutes a clear solution results, which is then concentrated on a rotary evapora-tor. In order to completely remove water from the residue, 200 ml. of anhydrous dioxane are added and the solution again concen~rated. This procedure is repeated twice more. The oily residue crystallizes upon trituration with ethyl acetate.
61.2 g. of the ethyl acetate adduct of 7-amino-3-~ methyl-lH-,tetrazol-5-yl)thiolmethyll-8-oxo-5-thia-l-azabicyclo[4.2.0l-oct-2-ene-2-carboxylic acid, 4-methylbenzenesulfonic acid salt are obtained.
b) 7-Amino-3-~[(l-methyl-l~-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-l-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenYl-methyl ester The product from part (a) is suspended in a mixture of 700 ml. dioxane and 300 ml. of ethyl acetate. To this mixture is added dropwise at 10-15 with vigorous stirring a solution 107 4 Z9 ~ GG19~193 of diphenyldiazomethane ~produced from 40 g. of benzophenone hydrazone and 43.7 g. of mercuric oxide by stirring vigorously for 6 hours with 220 ml. of petro'eum ether (b.p. 40 to 60), filtering and concentrating] in 2~0 ml. of anhydrous dioxane.
After stirring for 3 hours at room temperature a clear, wine red solution results, which is treated with 75 ml. of methanol to remove excess diphenyldiazomethane. After the wine red color disappears, the yellow brown solution is concentrated, the residue is dissolved in 800 ml. of methylene chloride and the solution is washed with a solution of 40 g. of dibasic potassium phosphate - in 80~ ml. of water and then with400 ml.Of water, dried with magnesi~m sulfate and concentrated. The viscous residue is triturated with petroleum ether. 47.7 g. of 7-amino-3-[1~1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.01oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained. The crude product is purified by stirring for 1 hour with 50 ml. of ice cold ethyl acetate and filtered under suction, to yield 28.5 g. of purified product, m.p. 153-156 (dec.).
The product is recrystallized from methylene chloride/petroleum ether, m.p. 166-168 (dec.).
c) D--[~[~4-Methoxyphen~)methoxvlcarbonyl~amino]-2-~henvlacetic acid D-(2-phenyl)glycine and magnesium oxide are suspended in water. To this suspension is added a solution of (p-methoxy-phenyl)methoxycarbonylazide in dioxane. The mixture i~s~stirred at room temperature, filtered, and the filtrate is-extracted with ether. The aqueous phase is layered over with ethyl acetate, washed with water, dried, and concentrated to obtain D-~-t[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-phenylacetic acid.
GGl92-193 d) 7B-[[[[[(4-Methoxyphenyl)methoxy]carbonYl]amino](D-phenyl)-acetyl]amino3-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
4.95 g. (0.01 mol.) of 7-amino-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.03-oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (b) and 3.78 g. (0.012 mol.) of D--[[[(4-methoxyphenyl)methoxy]-carbonyl]amino]-2-phenylacetic acid from part (c) are suspended in a mixture of lO0 ml. of tetrahydrofuran and 50 ml. of methylene chloride. ~o this suspension are added dropwise at 0-5C over a period of 1 hour 2.27 g. (0.011 mol.) of dicyclo-hexylcarbodiimide dissolved in 40 ml. of absolute tetrahydrofuran.
This mixture is stirred for 90 minutes at 0-5C (the solution becomes almost clear after about 30 minutes, then it again becomes turbid as the dicyclohexylurea precipitates) and 90 minutes at room temperature. The dicyclohexylurea i5 filtered off and the filtrate is concentrated. The residue is dissolved in 800 ml. of ethyl acetate and the solution is shaken twice with lN sodium bicarbonate solution and twice with water. The solution is then treated with activated carbon, dried with magnesium sulfate, filtered and concentrated to a volume of approximately lO0 ml. 5.5 g. of 7B-l[l~[(4-methoxyphenyl)-methoxy]carbonyllaminol(D-phenyl)acetyl]amino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thla-1-azabicyclo~4.2.0]-oct-2-ene-2-carbo~ylic acid, diphenylmethyl ester crystallize, the compound begins to decompose at 143C.
~074Z9~3 e) 73-[[(~-Amino-D-phenyl)acetyl?amino]-3-[[(1-methyl-1~-te~razol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicvclo[4.2.0]-_ oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 3.8 g. of 7~-1[[[[(4-methoxyphenyl)methoxy]carbonyl]-- amino](D-phenyl)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, diphenylmethyl ester from part ~d) are added at 0-5C to a mixture of 76 ml. of trifluoroacetic acid and 22.8 mI. of anisole. After 10 minutes, the solvent is evaporated under vacuum. The residue, upon trituration with ether, ~ solidifies to yield 2.85 g. of 7B-[t(~-amino-D-phenyl)acetyl]-amino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, trifluoro-acetic acid salt, which decomposes above 126C.
f) 7B-l[~AminocarbonYl)amino](D-Phenyl)acetyl]amino-l-3-[~( methyl-l_,tetrazol-5-Yl)thio]methYll-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxvlic acid O.25 g. (O.003 mol.) of potas~ium cyanate are dissolved in 6 ml. of water and to the solution are added 0.86 g. ~0.0015 _ ~0 mol.) of 7B-~ -amino-D-phenyl)acetyllamino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio~methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid ~alt from part (e).
This mixtuxe is stirred at room temperature and after about lS minutes, the solution becomes practically clear. The solution i8 stirred at room temperature for a total of about.three hours, filtered, and the filtrate is acidified to pH 1.5 with 2N hydro-chloric acid. The resulting precipitate is filtered under suction and washed with water, to yield 0.6 g. of 7~ [(amino-carbOnyl)amino]~D-phenyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-30 5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-107429~
carboxylic acid, m.p. 163-165C (dec.).
Example 2 7B-[[[(Aminocarbo ~ -phenyl)acetyl~amino]-3-[[(1-methyl-lH-tetrazol-5-yl)t ~ oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxYlic acid, Potassium salt ._ . An equimolar aqueous solution of the final product from example 1 and potassium bicarbonate is freeze-dried to yield as a powder 7~-[[~aminocarbonyl)amino](D-phenyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl]-8-oxo-5-10 thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt.
Example 3 7B-[[[(Aminocarbon~l)amino ] (D-1,4-cyclohexadien-1-yl)acetyl]-aminol -3-~ methYl-lH-tetrazol-5-Yl)thio]methvl]-8-oxo-5-thia-_ l-azabicYclo[4.2.0]oct-2-ene-2-carboxvlic acid ' Following the procedure of example 1 but substituting D-2-(1,4-cyclohexadien-1-yl)glycine for the D-(2-phenyl)-glycine in part ~c) one obtains the titled product.
Examples 4-27 Similarly, following the procedure of example 1 but substituting for the D-(2-phenyl)glycine in part (c) the compound in Col. A one obtains the product in Col. B.
10742~8 GGl 9 2-193 Col. A Col. B
NN2 NN ~L 2 I~N~N
Ex. Rl . CH3 ._ 10 6 C2H5 7 t-C4 Hg n-CSHll ~2 H
.... 20 10H2C ClH--H2C 2 ..
112 1 C~c--~074Z9& GG192-193 Ex.
12 2 \ / H
13 H C~ ~Cli2 10 ~ 14 C~
C}
17 <~
1 8 ~ CH2-10~4298 GGl 9 2-193 Ex.
19 ~ (CH2) 2-- - 10 zo ~ (CH2)3-.... . .
2 2 ` H3 C
23 HO~
. 30 -- 1074Z~8 GGl9_ 193 Ex. R
.. 10 25 H3CO ~ CH2-~ ......... . .
26 . HO~ CH2 _ 20 .. H5C2 2 7 ~CH2 ) 2 _ 30 Ex. Rl 28 Cl ~ CH2 ~ (CH2)2 Exam~le 30 7B-[[[~Aminocarbonyl)amino](D-phenvl)acetyl]amino]-3-[[( methyl-1,3,4-thiadiazol-2-yl)thio]methYl]-8-oxo-5-thia-1-azabic~clo[4.2.0]oct-2-ene-2-carboxylic acid a) 7-Amino-3-[[~5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0~oc~-2-ene-2-carboxylic acid, diphenylmethyl ester la g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)-thlo]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70~ perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is flltered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture i5 poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the p~rchloric 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 bica~bonate. The aqueous solution obtained is extracted with chloroform. The chloro-1074Z9~3 . GG192-193 Corm phase is treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 15.7-159. The product is recrystallized from tetrahydrofuran/petroleum ether.
b) 7B-[[[(Aminocarbonyl)amino](D-phenyl)acetyl]amino]-3-[[(5 -.methyl-1,3,4-thiadiazol-2-vl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~.2.0]oct-2-ene-2-carboxylic acid 10Following the procedure of example 1, part (d), (e), _ . and (f) I.-ut employing the 7-amino-3-[[(5-methyl-1,3,4-thia-diazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01-oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (a) ~n example l(d) one obtains the titled product.
Examples 31-80 Following the procedure of example 1 but employing the 7-aminocephalosporanic acid derivatives shown in Col. A
the products shown in Col. B are obtained Col. A Col. B
H2N I ~ S~ ~ CH-C-NH ~ S~
N. ~ CH2-S-R4 C-O ~ ~ CH2-S-R4 Ex. R3 R4 N---N .
H
32 H ~ Ig ._ 30 C2H5 ~07429~3 GG192-lg3 Ex. R3 R4 33 . H
~1~
C H
34 H ~
4Hg CN~) C2HS
3 6 t-C 4 H g N _N
N
~ 20 CH3 ; Cl 38 -CN2~ iN~
39 -ca ~ ~ N--N
1~)74Z9~3 -Ex. R3 R4 41 -CH2-0-C-CH2 ~ i - N
H
-10 42 ~ S ~ H
43 H ~ ~ C2H5 44 CH ~ ~ 5 ~ C~
CH2 ~ OCH3 ~ ~ CH3 Il N-------N
46 -CH2-0-C-C2H5 ~ S ~ CH3 )74Z9~3 -Ex. R3 R4 47 -CH2-0-C~ ~3~ C~3 ~ CN
H N~--N
o CH3 51 H r~
, C2H5 _.
CH2 0 C~BrJ~ ,!!L CH3 O
OCH3 ..
53 -CN2-0-C-CH2~ ~o,L CN3 . ~
1~)7'~298 Ex. _ R4 54 -CH~
-CH~ N~c!~3 __ 56 H J~CH3 S~
57 -CH2-0-~Y-CH3 ~C2H5 58 -CH ~ --IN
2 0 [~ S~N
~S~ .
..
t-C4Hg ~H
1117~29~8 -GGl 9 2-19 3 Ex. R3 R4 61 H H~CH3 ' 62 H H3C~ H
.__' 63 H ~C3H7 64 -C ~ N~ l!
6 5 H H ~r CH3 ~
. _ .
66 H H3~;--H
67 H 5C2~ H
~07429~3 .
Ex.... R3R4 69 H ~3 ~ .
O
_ ,,, N N
Si (CH3 ) Nl N~
71 Sn(CH3) 3 J~8J C~3 72 Si ~C2H5) 3 ~
: ,...
N ---_N
73 S n~C2H5) 3 , .
N N
74 Ca/2 ~ ~,N
.
10742~8 GG19~193 Ex. R3 4 : ~.
Mg/2 ~ S J CH3 76 Na N - ~
,.,, 10 ~~~ 77 Na ~ - N
. ~ N
N N
78 Al/3 ~ NJ
79 [CH3NH3]~3 ._ . .
~(c6H5cH2)2NH21 ~ ~
, By also substituting the D-2-(1,4-cyclohexadi-en-1-yl)-glycine from example 3 or the compounds of Col. A from examples 4 to 29 , for the D-2-(phenyl)glycine in example 1 other compounds within the scope of this invention are obtained.
. 30 :
GGl92-193 Examples 81-88 Following the procedure o~ example l but substituting for the potassium cyanate in part (f) one of the following:
methylisocyanate ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate i-butylisocyanate t-butylisocyanate ,_ .. . pentylisocyanate one obtains:
7B-~[[(methylaminocarbonyl)amino]~D-phenyl)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 acid7 7~-tlt(ethylaminocarbonyl)amino](D-2-phenyl)acetyl]amino]
3-[t(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-i-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[l(propylaminocarbonyl)amino]~D-2-phenyl)acetyl]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;
73-~t[~i-propylaminocarbonyl)amino](D-2-phenyl)acet amino]-3-~[(1-methyl-lH-tetrazol-5-yl)thio]methyl)-8-oxo-5-.
thia-l-azabicyclot4.2.0~oct-2-ene-2-carboxylic acid;
7~-[l[(butylaminocarbonyl)amino~(D-2-phenyl)acetyl]-amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl],8-oxo-5-thia-l-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(i-butylaminocarbonyl)amino](D-2-phenyl)acetyl]-amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
-~ 1079L29~
7~-[[[(t-butylaminocarbonyl)amino3(D-2-phenyl)acetyl]-amino]-3-[1(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
and 7B-[~[(pentylaminocarbonyl)amino](D-2-phenyl)acetyl]-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 respectively.
Similarly, these alkylisocyanates can be employed in the procedures of examples 3 to 80 to obtain other compounds within the scope of this invention.
.... _ .
1~7429~
7~-~[l(t-butylaminocarbsnyl)amino][D-2-phenyl)acetyl]-amino]-3- 1 E (l-methyl-lH-tetraæol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.01oct-2-ene-2-carboxylic acid;
and 7~-[1[(pentylaminocarbonyl)amino](D-2-phenyl)acetyl]-amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio~methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid respectively.
Similarly, these alkylisocyanates can be employed in the pro-cedures of examples 3 to 80 to obtain other compounds within the cope of this invention.
Example 89 7~-[[~Aminocarbonyl)amino]~D~-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 a) D~-a-ureido-2-thiopheneacetic acid 15.8 g (0.1 mol) of DL-2-thienylglycine are heated together with 8.2 g (0.1 mol~ o~ potassium cyanate in 100 ml of water.
After 30 mlnutes, the mixture i~ cooled and acidified with dilute hydrochlorlc acld. The precipitated product, DL-a-ureido-2-thio-pheneacetlc acid, is filtered, washed with ice water and a small amount of ethanol. Recrystallization from methanol yields 17 g of .. _ .. . . .. _ . . . . _ .. . .. _ . .
white crystals, of D~-~-ureid~2-thiopheneacetic acid;m.p. 183-185.
b) 3-1(AcetyloxY)methyl~-7B-[~[~aminocarbonyl)aminol(D~-2-thienYl)-acetyl~amino~-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxyllc acid 9.2 g (50 mmol) of D~-~-ureido-2-thiopheneacetic acid from part (a) are dissolved in 40 ml of absolute dimethylformamide.
10.3 g (50 mmol) of dicyclohexylcarbodiimide dissolved in 10 ml of methylene chloride are added dropwise at 0. After stirring for 1/2 hour, a solution of 13.5 g (50 mmol) of 7-aminocephalosporanic acid and 10 g (100 mmol) of triethylamine is added. This mixture 1~)7429~
is stirred for 24 hours at 5. After filtering, the filtrate is concentrated under vacuum, the oily residue is taken up in water, --filtered and after treating with activated carbon at 5 it is layered over with ethyl acetate and acidified with 2N hydrochloric acid. ~he ethyl acetate solution is washed with water, dried and concentrated. 8.1 g of a viscid residue are obtained. The pro-duct, 3-~(acetyloxy)methyl~-7B-~ E [ (aminocarbonyl)-amino3(D~-2-thienyl~acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is recrystallized twice from isopropanol; yield 2.1 g. The intermediate of part (b) can also be obtained by the following synthesis:
c) D~-~ r 1~1, l-Dimethyiethoxy~carbonyy amino]thien-2-yUacetic acid 3.8 g ~25 mmol) of DL-2-thienylglycine and 2 g ~50 mmol) of magnQsium oxide in 50 ml of water/dioxane (1:1) are stlrred for one hour at room temperature. 4.25 g (28 mmol) of t-butyloxycar-bonylazlde di~olved in 15 ml of dioxane are added dropwise and the reaction mixture ls stirred for 24 hours at 50. After fil-tering, the fil~rate is concentrated under vacuum, the oily re~idue i8 treated with ethyl acetate and then taken up with water.
This i5 then acidified with citric acid while cooling with ice and the aqueous acid ~olution is extracted with ethyl acetate. The solvent is drawn off from the ethyl acetate solution to obtain 4 g of white product, DL-l[[l,l-dimethylethoxy)carbonyllaminolthien-2-yl]acetic acidt m.p. 70-72.
d) 3-[(Acetyloxy)methyl]-7B-[[[[(l,l-dlmethylethoxy)carbonYll-amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-~4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
This mixture is stirred for 90 minutes at 0-5C (the solution becomes almost clear after about 30 minutes, then it again becomes turbid as the dicyclohexylurea precipitates) and 90 minutes at room temperature. The dicyclohexylurea i5 filtered off and the filtrate is concentrated. The residue is dissolved in 800 ml. of ethyl acetate and the solution is shaken twice with lN sodium bicarbonate solution and twice with water. The solution is then treated with activated carbon, dried with magnesium sulfate, filtered and concentrated to a volume of approximately lO0 ml. 5.5 g. of 7B-l[l~[(4-methoxyphenyl)-methoxy]carbonyllaminol(D-phenyl)acetyl]amino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thla-1-azabicyclo~4.2.0]-oct-2-ene-2-carbo~ylic acid, diphenylmethyl ester crystallize, the compound begins to decompose at 143C.
~074Z9~3 e) 73-[[(~-Amino-D-phenyl)acetyl?amino]-3-[[(1-methyl-1~-te~razol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicvclo[4.2.0]-_ oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 3.8 g. of 7~-1[[[[(4-methoxyphenyl)methoxy]carbonyl]-- amino](D-phenyl)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, diphenylmethyl ester from part ~d) are added at 0-5C to a mixture of 76 ml. of trifluoroacetic acid and 22.8 mI. of anisole. After 10 minutes, the solvent is evaporated under vacuum. The residue, upon trituration with ether, ~ solidifies to yield 2.85 g. of 7B-[t(~-amino-D-phenyl)acetyl]-amino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, trifluoro-acetic acid salt, which decomposes above 126C.
f) 7B-l[~AminocarbonYl)amino](D-Phenyl)acetyl]amino-l-3-[~( methyl-l_,tetrazol-5-Yl)thio]methYll-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxvlic acid O.25 g. (O.003 mol.) of potas~ium cyanate are dissolved in 6 ml. of water and to the solution are added 0.86 g. ~0.0015 _ ~0 mol.) of 7B-~ -amino-D-phenyl)acetyllamino]-3-[~(1-methyl-lH-tetrazol-5-yl)thio~methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid ~alt from part (e).
This mixtuxe is stirred at room temperature and after about lS minutes, the solution becomes practically clear. The solution i8 stirred at room temperature for a total of about.three hours, filtered, and the filtrate is acidified to pH 1.5 with 2N hydro-chloric acid. The resulting precipitate is filtered under suction and washed with water, to yield 0.6 g. of 7~ [(amino-carbOnyl)amino]~D-phenyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-30 5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-107429~
carboxylic acid, m.p. 163-165C (dec.).
Example 2 7B-[[[(Aminocarbo ~ -phenyl)acetyl~amino]-3-[[(1-methyl-lH-tetrazol-5-yl)t ~ oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxYlic acid, Potassium salt ._ . An equimolar aqueous solution of the final product from example 1 and potassium bicarbonate is freeze-dried to yield as a powder 7~-[[~aminocarbonyl)amino](D-phenyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl]-8-oxo-5-10 thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt.
Example 3 7B-[[[(Aminocarbon~l)amino ] (D-1,4-cyclohexadien-1-yl)acetyl]-aminol -3-~ methYl-lH-tetrazol-5-Yl)thio]methvl]-8-oxo-5-thia-_ l-azabicYclo[4.2.0]oct-2-ene-2-carboxvlic acid ' Following the procedure of example 1 but substituting D-2-(1,4-cyclohexadien-1-yl)glycine for the D-(2-phenyl)-glycine in part ~c) one obtains the titled product.
Examples 4-27 Similarly, following the procedure of example 1 but substituting for the D-(2-phenyl)glycine in part (c) the compound in Col. A one obtains the product in Col. B.
10742~8 GGl 9 2-193 Col. A Col. B
NN2 NN ~L 2 I~N~N
Ex. Rl . CH3 ._ 10 6 C2H5 7 t-C4 Hg n-CSHll ~2 H
.... 20 10H2C ClH--H2C 2 ..
112 1 C~c--~074Z9& GG192-193 Ex.
12 2 \ / H
13 H C~ ~Cli2 10 ~ 14 C~
C}
17 <~
1 8 ~ CH2-10~4298 GGl 9 2-193 Ex.
19 ~ (CH2) 2-- - 10 zo ~ (CH2)3-.... . .
2 2 ` H3 C
23 HO~
. 30 -- 1074Z~8 GGl9_ 193 Ex. R
.. 10 25 H3CO ~ CH2-~ ......... . .
26 . HO~ CH2 _ 20 .. H5C2 2 7 ~CH2 ) 2 _ 30 Ex. Rl 28 Cl ~ CH2 ~ (CH2)2 Exam~le 30 7B-[[[~Aminocarbonyl)amino](D-phenvl)acetyl]amino]-3-[[( methyl-1,3,4-thiadiazol-2-yl)thio]methYl]-8-oxo-5-thia-1-azabic~clo[4.2.0]oct-2-ene-2-carboxylic acid a) 7-Amino-3-[[~5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0~oc~-2-ene-2-carboxylic acid, diphenylmethyl ester la g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)-thlo]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
4.1 ml. of 70~ perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is flltered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture i5 poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the p~rchloric 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 bica~bonate. The aqueous solution obtained is extracted with chloroform. The chloro-1074Z9~3 . GG192-193 Corm phase is treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-~[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 15.7-159. The product is recrystallized from tetrahydrofuran/petroleum ether.
b) 7B-[[[(Aminocarbonyl)amino](D-phenyl)acetyl]amino]-3-[[(5 -.methyl-1,3,4-thiadiazol-2-vl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~.2.0]oct-2-ene-2-carboxylic acid 10Following the procedure of example 1, part (d), (e), _ . and (f) I.-ut employing the 7-amino-3-[[(5-methyl-1,3,4-thia-diazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01-oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (a) ~n example l(d) one obtains the titled product.
Examples 31-80 Following the procedure of example 1 but employing the 7-aminocephalosporanic acid derivatives shown in Col. A
the products shown in Col. B are obtained Col. A Col. B
H2N I ~ S~ ~ CH-C-NH ~ S~
N. ~ CH2-S-R4 C-O ~ ~ CH2-S-R4 Ex. R3 R4 N---N .
H
32 H ~ Ig ._ 30 C2H5 ~07429~3 GG192-lg3 Ex. R3 R4 33 . H
~1~
C H
34 H ~
4Hg CN~) C2HS
3 6 t-C 4 H g N _N
N
~ 20 CH3 ; Cl 38 -CN2~ iN~
39 -ca ~ ~ N--N
1~)74Z9~3 -Ex. R3 R4 41 -CH2-0-C-CH2 ~ i - N
H
-10 42 ~ S ~ H
43 H ~ ~ C2H5 44 CH ~ ~ 5 ~ C~
CH2 ~ OCH3 ~ ~ CH3 Il N-------N
46 -CH2-0-C-C2H5 ~ S ~ CH3 )74Z9~3 -Ex. R3 R4 47 -CH2-0-C~ ~3~ C~3 ~ CN
H N~--N
o CH3 51 H r~
, C2H5 _.
CH2 0 C~BrJ~ ,!!L CH3 O
OCH3 ..
53 -CN2-0-C-CH2~ ~o,L CN3 . ~
1~)7'~298 Ex. _ R4 54 -CH~
-CH~ N~c!~3 __ 56 H J~CH3 S~
57 -CH2-0-~Y-CH3 ~C2H5 58 -CH ~ --IN
2 0 [~ S~N
~S~ .
..
t-C4Hg ~H
1117~29~8 -GGl 9 2-19 3 Ex. R3 R4 61 H H~CH3 ' 62 H H3C~ H
.__' 63 H ~C3H7 64 -C ~ N~ l!
6 5 H H ~r CH3 ~
. _ .
66 H H3~;--H
67 H 5C2~ H
~07429~3 .
Ex.... R3R4 69 H ~3 ~ .
O
_ ,,, N N
Si (CH3 ) Nl N~
71 Sn(CH3) 3 J~8J C~3 72 Si ~C2H5) 3 ~
: ,...
N ---_N
73 S n~C2H5) 3 , .
N N
74 Ca/2 ~ ~,N
.
10742~8 GG19~193 Ex. R3 4 : ~.
Mg/2 ~ S J CH3 76 Na N - ~
,.,, 10 ~~~ 77 Na ~ - N
. ~ N
N N
78 Al/3 ~ NJ
79 [CH3NH3]~3 ._ . .
~(c6H5cH2)2NH21 ~ ~
, By also substituting the D-2-(1,4-cyclohexadi-en-1-yl)-glycine from example 3 or the compounds of Col. A from examples 4 to 29 , for the D-2-(phenyl)glycine in example 1 other compounds within the scope of this invention are obtained.
. 30 :
GGl92-193 Examples 81-88 Following the procedure o~ example l but substituting for the potassium cyanate in part (f) one of the following:
methylisocyanate ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate i-butylisocyanate t-butylisocyanate ,_ .. . pentylisocyanate one obtains:
7B-~[[(methylaminocarbonyl)amino]~D-phenyl)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 acid7 7~-tlt(ethylaminocarbonyl)amino](D-2-phenyl)acetyl]amino]
3-[t(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-i-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[l(propylaminocarbonyl)amino]~D-2-phenyl)acetyl]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;
73-~t[~i-propylaminocarbonyl)amino](D-2-phenyl)acet amino]-3-~[(1-methyl-lH-tetrazol-5-yl)thio]methyl)-8-oxo-5-.
thia-l-azabicyclot4.2.0~oct-2-ene-2-carboxylic acid;
7~-[l[(butylaminocarbonyl)amino~(D-2-phenyl)acetyl]-amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl],8-oxo-5-thia-l-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(i-butylaminocarbonyl)amino](D-2-phenyl)acetyl]-amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
-~ 1079L29~
7~-[[[(t-butylaminocarbonyl)amino3(D-2-phenyl)acetyl]-amino]-3-[1(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
and 7B-[~[(pentylaminocarbonyl)amino](D-2-phenyl)acetyl]-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 respectively.
Similarly, these alkylisocyanates can be employed in the procedures of examples 3 to 80 to obtain other compounds within the scope of this invention.
.... _ .
1~7429~
7~-~[l(t-butylaminocarbsnyl)amino][D-2-phenyl)acetyl]-amino]-3- 1 E (l-methyl-lH-tetraæol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.01oct-2-ene-2-carboxylic acid;
and 7~-[1[(pentylaminocarbonyl)amino](D-2-phenyl)acetyl]-amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio~methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid respectively.
Similarly, these alkylisocyanates can be employed in the pro-cedures of examples 3 to 80 to obtain other compounds within the cope of this invention.
Example 89 7~-[[~Aminocarbonyl)amino]~D~-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 a) D~-a-ureido-2-thiopheneacetic acid 15.8 g (0.1 mol) of DL-2-thienylglycine are heated together with 8.2 g (0.1 mol~ o~ potassium cyanate in 100 ml of water.
After 30 mlnutes, the mixture i~ cooled and acidified with dilute hydrochlorlc acld. The precipitated product, DL-a-ureido-2-thio-pheneacetlc acid, is filtered, washed with ice water and a small amount of ethanol. Recrystallization from methanol yields 17 g of .. _ .. . . .. _ . . . . _ .. . .. _ . .
white crystals, of D~-~-ureid~2-thiopheneacetic acid;m.p. 183-185.
b) 3-1(AcetyloxY)methyl~-7B-[~[~aminocarbonyl)aminol(D~-2-thienYl)-acetyl~amino~-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxyllc acid 9.2 g (50 mmol) of D~-~-ureido-2-thiopheneacetic acid from part (a) are dissolved in 40 ml of absolute dimethylformamide.
10.3 g (50 mmol) of dicyclohexylcarbodiimide dissolved in 10 ml of methylene chloride are added dropwise at 0. After stirring for 1/2 hour, a solution of 13.5 g (50 mmol) of 7-aminocephalosporanic acid and 10 g (100 mmol) of triethylamine is added. This mixture 1~)7429~
is stirred for 24 hours at 5. After filtering, the filtrate is concentrated under vacuum, the oily residue is taken up in water, --filtered and after treating with activated carbon at 5 it is layered over with ethyl acetate and acidified with 2N hydrochloric acid. ~he ethyl acetate solution is washed with water, dried and concentrated. 8.1 g of a viscid residue are obtained. The pro-duct, 3-~(acetyloxy)methyl~-7B-~ E [ (aminocarbonyl)-amino3(D~-2-thienyl~acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is recrystallized twice from isopropanol; yield 2.1 g. The intermediate of part (b) can also be obtained by the following synthesis:
c) D~-~ r 1~1, l-Dimethyiethoxy~carbonyy amino]thien-2-yUacetic acid 3.8 g ~25 mmol) of DL-2-thienylglycine and 2 g ~50 mmol) of magnQsium oxide in 50 ml of water/dioxane (1:1) are stlrred for one hour at room temperature. 4.25 g (28 mmol) of t-butyloxycar-bonylazlde di~olved in 15 ml of dioxane are added dropwise and the reaction mixture ls stirred for 24 hours at 50. After fil-tering, the fil~rate is concentrated under vacuum, the oily re~idue i8 treated with ethyl acetate and then taken up with water.
This i5 then acidified with citric acid while cooling with ice and the aqueous acid ~olution is extracted with ethyl acetate. The solvent is drawn off from the ethyl acetate solution to obtain 4 g of white product, DL-l[[l,l-dimethylethoxy)carbonyllaminolthien-2-yl]acetic acidt m.p. 70-72.
d) 3-[(Acetyloxy)methyl]-7B-[[[[(l,l-dlmethylethoxy)carbonYll-amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-~4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
5.4 g (20 mmol) of DL-[[[~ dimethylethoxy)carbonyl]-aminol-thien-2-yl]acetic acid from part (c) are dissolved in 50 ml of tetrahydrofuran and 4.05 g (20 mmol) of dicyclohexylcarbodiimide 107429~3 are added at 0. After stirring for 30 minutes, 8.8 g (20 mmol) of 7-aminocephalosporanic acid, diphenylmethyl ester are added dropwise. After 24 hours, the precipitated dicyclohexylurea is filtered off. After drawing off the solvent and recrystallizing the beige residue from methylene chloride/potassium ether 10.5 g of the product, 3-[(acetyloxy)-methyl-7B-~[l[(l,l-dimethylethoxy)-carbonyllamino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabi-cyclol4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, are obtained a~ a light beige powder; m.p. 78 (dec.).
e) 3-[~Acetyloxy)methyl~-7B-ltl(aminocarbonyl)amino~(D1-2-thienyl)acetyl~amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5 g of 3-[~acetyloxy)methyll-7B-[~[[(l,l-dimethylethoxy)-carbonyl]aminol(DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabi-cyclo[4.2>0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester ~rom part ~d) are stirred for 15 minutes in a mixture of 20 ml of tri~luoroacetic acid and 3 ml of anisole at 5. After ev~porating the trl~luoroacetic acid under vacuum and wa~htng the ~e-~idue with ether, 2.3 g of 3-[(acetyloxy)-methyl]-7~-[t( -amino-DL-2-thienyl)-acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-car_ boxylic acid, trifluoroacetic acid salt are obtained. This pro-duct is dissolved in water and the colution i~ ad~usted to pH 8 with sodium hydroxide. It i9 then quickly heated to 80 and 0.4 g of pot~ssium cyanate di~solved in 2 ml of water are added.
After stirring for l minute, the reaction mixture i9 quic~ly cooled, layered over with ethyl acetate and acidified to pH 3.5 with 2N hydrochloric acid. This i9 extracted with 5 X 100 ml of ethyl acetate. The combined ethyl acetate extracts are dried, concentrated to about l/3 the volume,treated with activated carbon and the product, 3-[(acetyloxy)methyl~-7~-l[[(aminocarbonyl)-1~429~ _ GGi92-193 .., ., , . _ ~
amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, is precipitated with petroleum ether. The product is crystallized from isopropanol as light beige crystals; m.p. 145 (dec.).
f) 7B-[[[(Aminocarbon~_amino]~DL-2-thienYl)acetyl]amino]-3-[~(l_methyl_lH_tetrazol-5-yl)thio]methYl?-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2.27 g. of the 3-[(acetyloxy)methyl]-7B-[[[(amino-' _ carbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-S-thia-l---- 10 azabicyclot4.2.0]oct-2-ene-2-carboxylic acid from part (b) or (e) are dissolved in a mixture of acetone/water (1:1) with the aid of SN sodium hydroxide. ~he pH is adjusted to 7.6-8.0 and S mmol. of l-methyl-lH-tetrazole-5-thiol is added. The pH
i8 maintained at 7.8 by the addition of 5N sodium hydroxide.
The reaction mixture is heated for 3 hours at 50-60. After cooling and distilling off the acetone, the mixture is acidified to pH 2.5 with 2~ hydrochloric acid while cooling with ice and the precipitate is extracted with ethyl acetate to yield the titled product.
. .
Example90 73- ~ l)amino]~DL-2-thienyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-S-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclot4.2.0]oct-2-ene-2-carboxYlic acid a) DL-~-l[[(4-Methoxyphenyl)methoxylcar-bo~l]amino]-2-thi pheneacetic acid 1.9 g. (12.5 mmol.) of DL-2-thienylglycine and 1 g.
of magneqium oxide are suspended in S0 mmol. of water. After stirring for 1/2 hour, 3 g. tl5 mmol.) of (p-methoxybenzyloxy-carbonyl)azide in 25 ml. of dioxane are added. After stirring for 48 hours at room temperature, the mixture is filtered.
1074Z9t~
The filtrate is extracted with 200 ml. of ether. The aq~eous phase is layered over with an equal volume of ethyl acetate and vigorously stirred with 20 g. of ion exchange resin (Dowex 50, acid form) for 2 hours. The éthyl acetate is separated, washed with 100 ml. of water, dried and concen-trated. A light oil remains as residue which crystallizes on trituration with petroleum ether. The DL-c~-[[[(4-methoxy-phenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid obtained melts at 153-156.
10~ b) DL-~-t[[(4-Methoxyphenvl)methoxY]carbonYltamino]-2-thio-~2heneacetic acid, 2,5-dioxo-1-~vrrolidinyl ester
e) 3-[~Acetyloxy)methyl~-7B-ltl(aminocarbonyl)amino~(D1-2-thienyl)acetyl~amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5 g of 3-[~acetyloxy)methyll-7B-[~[[(l,l-dimethylethoxy)-carbonyl]aminol(DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-l-azabi-cyclo[4.2>0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester ~rom part ~d) are stirred for 15 minutes in a mixture of 20 ml of tri~luoroacetic acid and 3 ml of anisole at 5. After ev~porating the trl~luoroacetic acid under vacuum and wa~htng the ~e-~idue with ether, 2.3 g of 3-[(acetyloxy)-methyl]-7~-[t( -amino-DL-2-thienyl)-acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-car_ boxylic acid, trifluoroacetic acid salt are obtained. This pro-duct is dissolved in water and the colution i~ ad~usted to pH 8 with sodium hydroxide. It i9 then quickly heated to 80 and 0.4 g of pot~ssium cyanate di~solved in 2 ml of water are added.
After stirring for l minute, the reaction mixture i9 quic~ly cooled, layered over with ethyl acetate and acidified to pH 3.5 with 2N hydrochloric acid. This i9 extracted with 5 X 100 ml of ethyl acetate. The combined ethyl acetate extracts are dried, concentrated to about l/3 the volume,treated with activated carbon and the product, 3-[(acetyloxy)methyl~-7~-l[[(aminocarbonyl)-1~429~ _ GGi92-193 .., ., , . _ ~
amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid, is precipitated with petroleum ether. The product is crystallized from isopropanol as light beige crystals; m.p. 145 (dec.).
f) 7B-[[[(Aminocarbon~_amino]~DL-2-thienYl)acetyl]amino]-3-[~(l_methyl_lH_tetrazol-5-yl)thio]methYl?-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2.27 g. of the 3-[(acetyloxy)methyl]-7B-[[[(amino-' _ carbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-S-thia-l---- 10 azabicyclot4.2.0]oct-2-ene-2-carboxylic acid from part (b) or (e) are dissolved in a mixture of acetone/water (1:1) with the aid of SN sodium hydroxide. ~he pH is adjusted to 7.6-8.0 and S mmol. of l-methyl-lH-tetrazole-5-thiol is added. The pH
i8 maintained at 7.8 by the addition of 5N sodium hydroxide.
The reaction mixture is heated for 3 hours at 50-60. After cooling and distilling off the acetone, the mixture is acidified to pH 2.5 with 2~ hydrochloric acid while cooling with ice and the precipitate is extracted with ethyl acetate to yield the titled product.
. .
Example90 73- ~ l)amino]~DL-2-thienyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-S-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclot4.2.0]oct-2-ene-2-carboxYlic acid a) DL-~-l[[(4-Methoxyphenyl)methoxylcar-bo~l]amino]-2-thi pheneacetic acid 1.9 g. (12.5 mmol.) of DL-2-thienylglycine and 1 g.
of magneqium oxide are suspended in S0 mmol. of water. After stirring for 1/2 hour, 3 g. tl5 mmol.) of (p-methoxybenzyloxy-carbonyl)azide in 25 ml. of dioxane are added. After stirring for 48 hours at room temperature, the mixture is filtered.
1074Z9t~
The filtrate is extracted with 200 ml. of ether. The aq~eous phase is layered over with an equal volume of ethyl acetate and vigorously stirred with 20 g. of ion exchange resin (Dowex 50, acid form) for 2 hours. The éthyl acetate is separated, washed with 100 ml. of water, dried and concen-trated. A light oil remains as residue which crystallizes on trituration with petroleum ether. The DL-c~-[[[(4-methoxy-phenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid obtained melts at 153-156.
10~ b) DL-~-t[[(4-Methoxyphenvl)methoxY]carbonYltamino]-2-thio-~2heneacetic acid, 2,5-dioxo-1-~vrrolidinyl ester
6.7 g. ~20 mmol.) of the DL-~-[[[(4-methoxyphenyl)-methoxy]carbonyllamino]-2-thiopheneacetic acid from part (a) are dis~olved in 150 ml. of tetrahydrofuran. 2.3 g. of N
hydroxysuccinnamide and 4.1 g. (20 mmol.) of dicyclohexyl-carbodiimide in tetrahydrofuran are added dropwise at 0. After stirring for 24 hours, the mixture i8 filtered and the filtrate is concentrated. ~he oily residue crystallizes on rubbing.
Upon recrystallization from benzene/cyclohexane, 7.5 g. of 20 light beige crystalline DL-~-[[[(4-methoxyphenyl)methoxy~ -carbonyllamino]-2-thiopheneacetic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 140-142, are obtained.
c) ~b~nvl)methoxy]carbonvl]amino] ~DL-2-thienyl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclo ~4.2.0~oct-2-ene-2-carbcxylic acid and ~074Z98
hydroxysuccinnamide and 4.1 g. (20 mmol.) of dicyclohexyl-carbodiimide in tetrahydrofuran are added dropwise at 0. After stirring for 24 hours, the mixture i8 filtered and the filtrate is concentrated. ~he oily residue crystallizes on rubbing.
Upon recrystallization from benzene/cyclohexane, 7.5 g. of 20 light beige crystalline DL-~-[[[(4-methoxyphenyl)methoxy~ -carbonyllamino]-2-thiopheneacetic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 140-142, are obtained.
c) ~b~nvl)methoxy]carbonvl]amino] ~DL-2-thienyl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclo ~4.2.0~oct-2-ene-2-carbcxylic acid and ~074Z98
7~-[[[[[(4-Methoxyphenyl)methoxy]carbonyl]amino](DL-2-thienyl)-acetvl]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, diphenylmethyl ester 3.2 g. (10 mmol.) of 3-[(1-methyl-lH-tetrazol-5-yl)thio~-7-aminocephalosporanic acid are dissolved in 20 ml. of dimethyl-formamide by the addition of 2.02 g. (20 mmol.) of triethyl-amine. 4.18 g. (10 mmol.) of DL-~-[[[(4-methoxyphenyl)methoxy]-carbonyl]amino]-2-thiopheneacetic acid, 2,5-dioxo-1-pyrrolidinyl ester from part (b) are added dropwise at room temperature.
_ After three hours, the solvent is distilled off under oil vacuum. There remains a brown viscid residue which is com-pletely soluble in water with the aid of a little sodium carbonate. The aqueous solution is shaXen with ethyl acetate, the aqueous phase is treated with activated carbon, layered over with ethyl acetate and acidified with 2N hydrochloric acid. The solvent is drawn off from the ethyl acetate ex-tract and the residue is recrystallized from methylene chloride/
petroleum ether to obtain 2.5 g. of 7B-[[1[[(4-methoxyphenyl)-methoxy]carbonyl]amino](D~-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; m.p. 63 (dec.).
Similarly, by employing an equivalent amount of the diphenylmethyl ester of 3-[(1-methyl-lH-tetrazol-5-yl)thio~-7-aminocephalosporanic acid, m.p. 168-169 ~dec.)., in the above procedure one obta~ns as a beige po~der 7B-11[11(4-methoxyphe..yl)methoxy]carbonyl]amino](DL-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 98-100 ~dec.).
10742g~
d) 7B-[[[(Aminocarbonyl)amino](DL-2-thienyl)ace~y~_amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxYlic acid 1.2 g. (2.5 mmol.) of the 7B-1[[[[(4-methoxyphenyl)-methoxy]carbonyl]amino](DL-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thiolmethyl]-8-oxo-5-thia-l-azabicyclo[4.2.03-oct-2-ene-2-carboxylic acid from part (c) or an equivalent amount of the diphenylmethyl ester are treated at 5 with a mixture of trifluoroacetic acid and 1.5 ml. of anisole. The solvent is drawn off and the solid residue is washed with ether to obtain 0.7 g. of 7B-t[~-amino-DL-2-thienyl)acetyl]-amino]-3-[[(1-methyl-lH- tetrazol-5-yl)thio]methyll-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoro-acetic acid salt. This crude salt is converted with potassium cyanate .to the ureido compound by the procedure of example l(e).
The ureido compound is crystailized from isopropanol and recrystallized once from tetrahydrofuran/petroleum ether.
The product, 7~-[[~(aminocarbonyl)amino](DL-2-thienyl)acetyl]-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 as a beige powder; m.p. 165-167 (dec.).
.
Example 91 7~-[1[(Aminocarbonyl)amino](DL-2-thienvl)acetxl?amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methYl]-8-oxo-5-thia-1-azabicyclol4.2.0~oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from either examp'le~89~~or 90~~and~~potassium~bicarbonate~~s'~~freez'ë- ~~~'' dried to yield as a light powder 7~-[[l(aminocarbonyl)amino]-(DL-2-thienyl)acetyl]amino]-3-~ -methyl-lH-tetrazol-s-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt; m.p. 183-186.
. .
1~742~
Example 92 .
7~-[[[(Aminocarbonyl)amino](DL-2-thienyl)acetyl]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-carboxvlic acid a) 7-Amino-3-1[(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, diphenyl-methyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)-thio]methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
- ; 10 4.1 ml. of 70~ perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Xieselgel 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 chloro-form phase i5 treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-[1~5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl~-8-oxo-S-thia-l-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157-159. The product is recrystallized from tetrahydrofuran/petroleum ether.
1o74Z9~il b) 7~-[~f~[(4-Methoxxphenyl)methoxy]carbonyl]amino](DL-2-thieny ~ l]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]_ethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
_ After three hours, the solvent is distilled off under oil vacuum. There remains a brown viscid residue which is com-pletely soluble in water with the aid of a little sodium carbonate. The aqueous solution is shaXen with ethyl acetate, the aqueous phase is treated with activated carbon, layered over with ethyl acetate and acidified with 2N hydrochloric acid. The solvent is drawn off from the ethyl acetate ex-tract and the residue is recrystallized from methylene chloride/
petroleum ether to obtain 2.5 g. of 7B-[[1[[(4-methoxyphenyl)-methoxy]carbonyl]amino](D~-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; m.p. 63 (dec.).
Similarly, by employing an equivalent amount of the diphenylmethyl ester of 3-[(1-methyl-lH-tetrazol-5-yl)thio~-7-aminocephalosporanic acid, m.p. 168-169 ~dec.)., in the above procedure one obta~ns as a beige po~der 7B-11[11(4-methoxyphe..yl)methoxy]carbonyl]amino](DL-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 98-100 ~dec.).
10742g~
d) 7B-[[[(Aminocarbonyl)amino](DL-2-thienyl)ace~y~_amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methvl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxYlic acid 1.2 g. (2.5 mmol.) of the 7B-1[[[[(4-methoxyphenyl)-methoxy]carbonyl]amino](DL-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thiolmethyl]-8-oxo-5-thia-l-azabicyclo[4.2.03-oct-2-ene-2-carboxylic acid from part (c) or an equivalent amount of the diphenylmethyl ester are treated at 5 with a mixture of trifluoroacetic acid and 1.5 ml. of anisole. The solvent is drawn off and the solid residue is washed with ether to obtain 0.7 g. of 7B-t[~-amino-DL-2-thienyl)acetyl]-amino]-3-[[(1-methyl-lH- tetrazol-5-yl)thio]methyll-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoro-acetic acid salt. This crude salt is converted with potassium cyanate .to the ureido compound by the procedure of example l(e).
The ureido compound is crystailized from isopropanol and recrystallized once from tetrahydrofuran/petroleum ether.
The product, 7~-[[~(aminocarbonyl)amino](DL-2-thienyl)acetyl]-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 as a beige powder; m.p. 165-167 (dec.).
.
Example 91 7~-[1[(Aminocarbonyl)amino](DL-2-thienvl)acetxl?amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methYl]-8-oxo-5-thia-1-azabicyclol4.2.0~oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from either examp'le~89~~or 90~~and~~potassium~bicarbonate~~s'~~freez'ë- ~~~'' dried to yield as a light powder 7~-[[l(aminocarbonyl)amino]-(DL-2-thienyl)acetyl]amino]-3-~ -methyl-lH-tetrazol-s-yl) thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt; m.p. 183-186.
. .
1~742~
Example 92 .
7~-[[[(Aminocarbonyl)amino](DL-2-thienyl)acetyl]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-carboxvlic acid a) 7-Amino-3-1[(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, diphenyl-methyl ester 18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)-thio]methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran.
- ; 10 4.1 ml. of 70~ perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran.
After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Xieselgel 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 chloro-form phase i5 treated with activated carbon and sodium sulfate to obtain 10 g. of the product, 7-amino-3-[1~5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl~-8-oxo-S-thia-l-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157-159. The product is recrystallized from tetrahydrofuran/petroleum ether.
1o74Z9~il b) 7~-[~f~[(4-Methoxxphenyl)methoxy]carbonyl]amino](DL-2-thieny ~ l]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]_ethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester
8.8 g. of the diphenylmethyl ester from part (a), 5.77 g. of DL-a-1[[~4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid from example 2(a) and 3.55 g. of dicyclo-hexylcarbodiimide in 80 ml. of tetrahydrofuran are stirred for 24 hours at 0. The t~trahydrofuran is drawn off under vacuum and the product is obtained from the filtrate by recrystalliza-~~- tion from tetrahydrofuran/petroleum ether. Beige crystals of 7~-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino](DL-2-thienyl)-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, diphenylmethyl ester; m.p. 104-106, are obtained.
c) 73-~[~(Aminocarbonyl)amino](DL-2-thienvl)acetyl]amino]-3-[[(5-methYl-1,3,4-thiadiazol-2-yl1thio]methvl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxYlic acid The product from part (b) is treated with trifluoro-acetic acid and anisole at 0C followed by treatment at 80with potassium cyanate at~pH 7.8 accordlng to tne-procedure of example l(e). The 73-[tl(aminocarbonyl)amino]~D~-2-thienyl) acetyl]aminol-3-1[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid obtained is recrystallized from tetrahydrofuran/petxoleum ether as a beige powder, m.p. 155-157 (dec.).
Example 93 7B-[[[(Aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from example 92 and potassium bicarbonate is freeze-dried to yield as a beige powder 7~-[[[~aminocarbonyl)amino](DL-2-thienyl)-acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid, potassium salt; m.p.-194-196 (dec.).
Example 94 7B-[~[(Aminocarbonyl)amino](DL-3-thienyl)acetyl]amino]-3-[l(l-methyl~ tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-?-carboxvlic acid a) DL-a-Bromo-3-thiopheneacetic acid 2-thienylbromide is treated with butyl lithium and chloral to obtain 2-[(1-hydroxy-2-trichloro)ethyl]thiaphene which is then treated with sodium methoxide to obtain a-methoxy-3-thienylacetic acid lGronowitz et al., Ark. Chemi., 17, 561 (1961)].
150 ml. of 30% hydrogen bromide in acetic acid is added to a solution of 16 g. (100 mmol.) of (a-methoxy-3-thienyl)acetic acid in 50 ml. of glacial acetic acid. The mixture i5 left to stand at room temperature for 24 hours and then poured into ice water. The solution i5 extracted three times with 60 ml. of ether. The ether phase-is washed with water, dried over magnesium sulfate and evaporated.
The residue, 18 g. of crude DL-a-bromo-3-thiopheneacetic acid are recrystallized from cyclohexane; yield 14 g.; m.p.
80-82.
~74~ GG192-1933 b) DL-a-Azido-3-thiopheneacetic acid 4 g. (62 mmol.) of sodium azide and 3.5 g. (33 mmol.) of sodium carbonate are added to a solution of 12 g. (54 mmol.) of DL-~-bromo-3-thiopheneacetic acid in 75 ml. of acetone (96%).
The mixture is stirred at room temperature for 12 hours in darkness and after this time the solvent is evaporated and the resldue is di~solved in 75 ml. of water. 50 ml. of ether i8 added, the water phase is acidified with 2N sulfuric acid and extracted quickly twice more with 50 ml. of ether. After washing with water and drying over sodium sulfate, the com-_ bined ether phases are evaporated. Crystallization of the residue from cyclohexane yields 7.4 g. of white crystalline DL-~-azido-3-thiopheneacetic acid; m.p. 58-59.
c) DL-a-Amino-3-thiopheneacetic acid 0.3 g. of palladium/barium sulfate catalyst are added to a solution of 6 g. of DL-~-azido-3-thiopheneacetic acid in 40 ml. of ethanol and 40 ml. of 0.5N hydrochloric acid.
~ydrogenation takes place at about 60 psig. after 2 hours.
After filtration, the volume is concentrated to about 30 ml.
When the pH is brought to 6.5 with ammonia, the amino acid separates as a white powder. After washing with ethanol/
water and drylng, 3.5 g. of the product, DL--amino-3-thiopheneacetic acid, are obtained; m.p. 283-285.
d) DL--~[t~4-MethoxyphenYl)methoxYlcarbonyl]amino]-3-thio-pheneacetic acid 1.9 g. (12.5 mmol.) of DL-~-amino-3-thiophe~eacetic acid and 1 g. of magnesium oxide are stirred in 25 ml. of water and 25 ml. of dioxane. After stirring for 1 hour, 3.0 g.
~15 mmol) of l(p-methoxybenzyl)oxy]carbonylaz~de are added.
Stirring is continued for 24 hours. The mixture is filtered and . . . ':
-~0~7429;~
extracted with 20 ml of ether. 50 ml of ethyl acetate and 20 g of Dowex 50 (~+ form) are added to the filtrate and the mixture is stirred well or two hours. They ethyl acetate phase is separated, washed with 50 ml of water, dried over sodium sulfate and evaporated. The oily residue crystallizes after the addition of pentane to yield 3.4 g of white crystalline DL-~-[[[(4-methoxy-phenyl)methox~carbonyllamino]-3-thiopheneaceticacid; m.p; 118(dec).
e) 3-~Acetyloxy)methyl]-7B-[[1[(4-methoxyphenyl)methoxy]-carbonyllaminol~DL-3-thienYl)acetyl]amino]-8-oxo-5-thia-1-azabi-cyclo~4.2.0~oct-2-ene-2-carboxylic acid S g of the product from part ~d), 1.5 g of triethylamine and 1-8 g of chloroformicacid ethyl e5ter in 50 ml of tetrahydrofuran are converted to the mixed anhydride. The mixed anhydride is reacted with a solution of 4 g of 7-aminocephalosporanic acid and 2.5 g of tristhylamine in methylene chloride for 12 hour~. The ~olvent i9 then xemoved from the solution and the partially solid r-sidue is di~solved with water and a small amount of sodlum car-bonate And extr~cted with 50 ml of ethyl acetate. The aqueous pha~e i5 cooled, acldified to p~ 2.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase i9 treated with activated carbon and concentrated to obtain 3.7 g of llght beige product, 3-l(acetyloxy)methyl~-7~-[[[[~4-methoxyphenyl)methoxy]-carbonyllamino]~D~-3-thlenyl)acetyl]amino~-8-oxo-5-thia-1-azabl-cyclo~4.2.0]oct-2-ene-2-carboxylic acidtm.p. 113~(dec.), which is recrystallized from methylene chloride/petroleum ether.
f) 3-[(Acetyloxy~methyl]-7B-[[[(aminocarbonyl)amino](DL-3-thienyl)-acetyl~amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-boxylic acid The product from Example 6, part ~e) is stirred with 15 ml of triflùoroacet~c acid and worked up as in Example 89, and after ~ ~0>'.74Z5~
reaction with potassium cyanate as in Example 89, the title compound is obtained.
g) 7~-[1~(Aminocarbonyl)amino~(DL-3-thienyl)acetyl]amino~-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxYlic acid The 3-l(acetyloxy)methyl]-7~[[[(aminocarbonyl)amino](DL-3-thienyl)acetyl]amino~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from part (f) is treated with l-methyl-lH-tetra-zole-5-thiol according to the procedure of Example 89 (f) to yield the titled compound.
The 7~-[t~amlnocarbonyl)amino](DL-3-thienyl)acetyl~amino]-3-[[~l-methyl-lH-tetrazol-5-yl)thio]methyl~-8-oxo-5-thia-1-azabi-cyclol4.2.0]oct-2-ene-2-carboxylic acid can also be obtained ~y following the procedure of Example 2 but substituting DL-3-thienyl-glycine for the D~-2-thienylglycine in part (a) of Example 90.
Example 95 7~-11[(Aminocarbonyl~amino](D-2-thlenyl)acetyllamino]-3-[t~l-mothyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thla-1-azabicyclo-[4.2.01Oct-2-ene-2-carboxyllc acid a) D-~-[[t~4-MethoxY~henYl)methoxY~carbonYl]amino-2-thiophene acetlc acid 15.7 g of D-~2-thienyl)glycine (m.p.)218-21~,produced from the racemate with D-camphor-10-sulfonic acid) and 8 g of magnesium oxido are suspended in 200 ml of water. To this suspen5ion is added a solution of 22.8 g of ~p-methoxyphenyl)methoxycarbonyl-a2ide in 200 ml of dioxane and this mixture is stirred for 3 days at room temperature. The mixture is filtered, the filtrate is extracted once with ether, the aqueous phase is layered over with ethyl acetate, cooled to about 10 and acidified to pH 2 30~ with dilute hydrochloric acid. The aqueous phase is once more :
.
~07429~
extracted with ethyl acetate, the combined extracts are washed once with water, dried with magnesium sulfate and concentrated.
The residue crystallizes upon trituration with petroleum ether.
The crude product, D-a-[[[(4-methoxyphenyl)methoxy~carbonyl]-amino]-2-thiopheneacetic acid, is recrystallizea from ethyl acetate/petroleum ether, yield 25.2 g, m.p. 65-67.
D) 3-[(AcetYloxv)methvl]-7B-[[[[[(4-methoxvphenyl)methoxy]-carbonyl]amino](D-2-thienyl)acetYl]amino]-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid 3.2 g. (0.01 mol.) of the product from part (a) is brought into solution in 40 ml. of methylene chloride with 1.1 ml. of N-methylmorpholine. The solution is cooled to -15, 1.39 ml. of isobutylchloroformate are added, and the mixture is sSirred for 10 minutes. To this is added a solution of 3.26 g. (0.1012 mol.) of 7-aminocephalosporanic acid and 3.1 ml. of triethylamine in 40 ml. of methylene chloride. The mixture is stirred for 1 hour at -5 and 1 hour at 5. This mixture is then evaporated to dryness in a rotary evaporator.
The solid residue is triturated with ether and filtered under suction. The substance is then dissolved in ice water, layered over with ethyl acetate and acidified to pH 2.5. The layers are separated, the a~ueous layer is extracted once more with ethyl acetate, the combined ethyl acetate extracts are washed with water, dried with magnesium sulfate and con-centrated. The residue ~4.9 g.) is dissolved in 200 ml. of ethyl acetate and the solution is treated with activated ~074Z~8 carbon. After filtration 2 g. of 3-[(acetyloxy)methyl]-7~-t[~[~(4-methoxyphenyl)methoxy]carbonyl]amino](D-2-thienyl)-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, crystallize; m.p. 142-143 (dec.).
c) 3-[(Acety~oxy)methyl]-7B-[[(-amino-D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid 2.0 g. of the product from part (b) are added at -5 to a mixture of 10 ml. of trifluoroacetic acid and 4 ml. of anisole. The mixture is stirred for 10 minutes and is then con-centrated in a rotary evaporator. The residue is treatedwith ether and filtered under suction. The crude 3-[(acetyloxy)-methyl~-7~-[[~-amino-D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt i8 dissolved in 50 ml. of water and 20 ml. of a solution of the acetate form of the ion exchange resin Amb~rlite LA 1 in isobutylmethyltetone are added. The mixture i8 stirred for 2 hours at room temperature. The layers are separated, the aqueous phase is washed several times with ether and freeze-dried to yield 1 g. of 3-[~acetyloxy)methyl]-7B-[[~-amino-D-2-thienyl)acetyl]amino~-8-oxo-5-thia-1-azabicyclo-14.2.0]oct-2-ene-2-carboxylic acid.
d) 3-[(Acetyloxy)methyl]-7B-~ aminocarbonyl)amino](D-2-thienyl) acetyl]amino]-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid A mixture of 1 g. of the product from part (c) and 0.194 g. of potassium cyanate in 7.5 ml. of water are quickly heated in a preheated bath at 80. The mixture is then immediately cooled to room temperature and permitted to stand overnight. The reaction mixture is concentrated to 1074Z9~
G~lY~-193 about 4 ml. and the pH is adjusted to 1.5 with 2N hydrochloric acid. The precipitate is filtered under suction to obtain 0.5 g. of 3-[(acetyloxy)methyl]-73-[l[(aminocarbonyl)amino-(D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-aæabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid; m.p. 155-160 (dec.).
e) 7B-[[[(Aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-3-l[(1-methyl-1~-tetrazol-5-yl)thio]methyll-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid 0.01 mol. of the product from part (d) and 0.011 mol. of 1-methyl-lH-tetrazole-5-thiol are heated in an aqueous acetone solution at pH 7 according to the procedure of example l(f) to yield the 7~-l[~(aminocarbonyl)amino](D-2-thienyl)acetyl]-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.
Example 96 7B-[[[(Methylaminocarbonvl)amino](D-2-thienyl)acetyl~amino]-3 [[(l-methyl-1~-tetrazol-5-yl)thio]methvl~-8-oxo-5-~ia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) 3-[(Acetyloxy)methyl]-7~-l[[(methvlaminocarbonyl)amino]-(D-2-thienyl)acetyllamino]-8-oxo-5-thia-1-azabicvclo[4.2.0]-oct-2-ene-2-carboxylic acid 1.5 g. of 3-~(acetyloxy)m~thyl]-7B-[[(-amino-D-2-; thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt from example 7(c) and 1.01 ml. of triethylamine are dissolved at 0-5 in 20 ml.
of anhydrous methylene chloride. To the clear sol~tion is added 2.49 g. of a 10~ solution of methylisocyanate in methylene chloride. This mixture is stirred for 2 hours at 0-5 and then concentrated. The residue is taken up in a little water, shaken with ether, filtered and acidified with 2N hydrochloric acid.
1074~9~ ,G192-lg3 0.8 g. of 3-~(acetyloxy)methyl~-7B-[[[(methylaminocarbonyl)-amino](D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid are obtained; m.p. 178-180 (dec.).
b) 7B-~[[(Methylaminocarbonyl)amino](D-2-thienyl)acetyl]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 0.01 mol. of the product from part (a) and 0.011 mol.
of l-methyl-lH-tetrazole-5-thiol are reacted according to the procedure of example l(f) to yield the 7B-l[[(methylamino-carbonyl)amino](D-2-thienyl)acetyllamino]-3-[[(1-methyl-lH--~ tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid.
Example 97 7B-~ Amlnocarbonyl)amino](DL-3-pYridYl)acetYl]amino]-3-[~(l-methyl-l~-tetrazol-5-Yl)thio]methyl]-8-oxo-5-thia-1-a bicyclo~4.2.0loct-2-ene-2-carboxYlic acid a) DL-~ (4-Methoxyp-henyl)methoxy~carbonyl]amino~-3-~Yridin-e acetic acid DL-2-(3-Pyridyl)glycine ~prepared from pyridine-3-aldehyde by the Strecker synthesis) is reacted with (p-methoxybenzyloxycarbonyl)azide according to the procedure set forth in Example 2(a) to yield D~--~t~(4-methoxyphenyl)-methoxy]carbonyl]amino]-3-pyridineacetic acid; m.p. 155-156 (dec.).
b) 3-~(Acetyloxy)methyl]-7B-~[~ 4-methoxvphenyl)methoxY]-carbonyl]aminol~DL-3-pyridyl)acetyl]amino]-8-oxo-5-thia-1-_zabic~yclo~4.2.0]oct-2-ene-2-carboxvlic acid The product from part (a) is reacted with isobutyl-chloroformate in the presence of N-methylmorpholine followed by reaction with 7-aminocephalosporanic acid according to the procedure of examplegs~b) to yield the 3-~(acetyloxy)methyl]--46~
1 07 4 2~ 8 GG192-193 _, _ . , . _ 7B-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino](DL-3-pyridyl) acetyl]amino]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2--carboxylic acid. - --c) 3-[(Acetvloxy)methyl]-7~-[[(~-amino-DL-3-pyridvl)acetyl]-amino]-8-oxo-5-thia-1-azabicYclo[4.2.0]oci-2-ene-2-carboxylic _cid, trifluoroacetic acid salt . -- .. .... .
4 g. of the product from part (b) are added at -5 to a mixture of 50 ml. of trifluoroacetic acid and 20 ml. of anisole. After 10 minutes, the trifluoroacetic acid is evaporated ~ 10 under vacuum. The residue is treated with ether and filtered to yield the 3-[(acetyloxy)methyl]-73-[[(~-amino-DL-3-pyridyl)-acetyl]amino]-B-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p. 138-140 (dec.).
d) 3-[(Acetyloxy)methyl]-7B-[[l(aminocarbonyl)aminol(DL-3-pyridyl)acetxl]amino]-8-oxo-5-thia-1-azabicYclo[4.2.0]oct-2-ene-2-carboxylic_acid 3.5 g. of the product from part (c) and 1.09 g. of pota~sium isocyanate are stirred o~ernight in 50 ml. of water at room temperature. The reaction mixture i5 filtered and the filtrate is freeze-dried to yield the 3-~(acetyloxy)methyl]-7B-~(aminocarbonyl)amino](DL-3-pyridyl)acetyl]amino]-8-oxo-5-thla-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
e) 7~-~[~(Aminocarbonyl)amino](DL-3-pyr-id-y~)acetvl]amino]-3-[[(l-methyl-l~tetrazol-5-Yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The product from part (d) and l-methyl-lH-tetrazole-5-thiol are reacted according to the procedure of example99 (f) to yield the 7~-[[[(aminocarbonyl)aminol(DL-3-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.
~7429~
. Exam~les 98-117 Following the procedures of any of examples 91, 94, or 97 but substituting for the DL-2-thienylglycine, DL-3-thienyl-glycine, and DL-3-pyridylglycine one of the following:
DL-2-fùrylglycine DL-3-furylglycine DL-2-pyrrylglycine DL-3-pyrrylglycine DL-2-pyridylglycine DL-4-pyridylglycine -- 10 DL-2-thiazolylglycine DL-5-thiazolylglycine DL-3-isothiazolylglycine D~-5-isothiazolylglycine D~-2-oxazolylglycine DL-S-oxazolylglycine DL-3-isoxazolylglycine DL-S-isoxazolylglycine DL-3-~1,2,4-thiadiazolyl)glycine DL-5-~1,2,4-thiadiazolyl)glycine ., DL-5-(1-methyltetrazolyl)glycine DL-2-(S-chlorothienyl)glycine DL-3-(4-methylthienyl)glycine DL-2-(4-chloropyrryl)glycine one obtains ..
7~-ttl(aminocarbonyl)amino](DL-2-furyl)acetyl]amino]-3 ~t~l-methyi-lH-tetrazol-5-ylJthio]methyl]-8-oxo-s-thia azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-3-f~ryl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
_ - - - . .. . . ~ . ~ . .
107~Z98 GG1~2-193 7~-[[[(aminocarbonyl)amino](DL-2-pyrryl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-~ aminocarbonyl)amino](DL-3-pyrryl)acetyl~amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]méthyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-[[[(aminocarbonyl)amino](DL-2-pyridyl)acetyl]amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino]~DL-4-pyridyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-2-thiazolyl)acetyl]amino]-3-~[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
73-[[[(aminocarbonyl)amino](DL-5-thiazolyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-3-isotlliazolyl)acetyl]amino]-3-tt(l-methyl-lH-tetrazol-5-yl)thio]methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
73-~(aminocarbonyl)amino](DL-5-isothiazolyl)acetyl]amino]-3-~t(l-methyl-lH-tetrazol-s-yl)thiolmethyl]-8-oxo-5-thia azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7~-t[t(aminocarbonyl)amino](DL-2-oxazolyl)acetyl]amino]-3 t~tl-me.thyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-~hia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7~-~tt~aminocarbonyl)amino](DL-5-oxazolyl)acetyl]amino]-3-[l(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
74Z9~
GGi92-193 73-[[~(aminocarbonyl)amino](DL-3-isoxazolyl)acetyl]-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;
7B-[[[(aminocarbonyl)amino](DL-5-isoxazolyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-3-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-~(aminocarbonyl)amino][DL-3-(1,2,4-thiadiazolyl) acetyl~amino]-3-~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acidS
7B-~l(aminocarbonyl)amino]lDL-S-(1,2,4-thiadiazolyl)]-_. 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;
7B-[~(aminocarbonyl)amino][D~-5-~1-methyltetrazolyl)]-acetyl]amino]-3-~ methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-[~[~aminocarbonyl)amino]~DL-2-(5-chlorothienyl)]-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;
7B-~(aminocarbonyl)amino][DL-3-(4-methylthienyl)]-acetyl]amlno]-3-1[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
and 7B-l~[(aminocarbonyl)amino][DL-2-(4-chloropyrryl)]-acetyl]amino]-3.-~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
r~spectively.
._ .
~ 1.074Zg~
_ GG192-193 Examples 118-124 .
Following the procedure of example 96but substituting for the methylisocyanate one of the following:
ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate i-butylisocyanate t-butyllsocyanate pentylisocyanate _...... one obtains:
7B-~[l(ethylaminocarbonyl)amino](D-2-thienyl~acetyl]aminol-3-lt(l-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-1-aza~cyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-l~l~propylaminocarbonyl)amino](D- 2- thienyl)acetyl]amino]-3-[1(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-llt(i-propylaminocarbonyl)amino](D-2-thienyl)acetyl]
amino]-3-[[(1-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-20 thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-lll~butylaminocarbonyl)amino]~D-2-thienyl)acetyl]-amino]-3-~L(l-methyl-lH-tetrazol-s-yl)thiolmethyl]-8 thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-~ i-butylaminocarbonyl)amino](D-2-thienyl)acetyl]-amino]-3-[1(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7B~ t-butylaminocarbonyl)amino](D-2-thienyl)acetyl]
amino]-3-[1(l-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
GG1~2-193 and 7~-[[[(pentylaminocarbonyl)amino](D-2-thienyl)acetyl]-- aminoJ-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid respectively.
Similarly by employing the methylisocyanate from example 8 or the alkylisocyanates of examples 30-36 in place of the potassium cyanate in examples 1, 4, and 9 to 29 other compounds within the scope of tbis invention are obtained.
Examples 125-174 Following the procedures of examples90 or 92 but em-ploying the substituted 7-aminocephalosporanic acid deriva-tives shown in Col. A the products shown in Col. B are obtained.
Col. A Col. 3 CN S R ~ NH ~ N ~ C~2-S-R4 Ex. R3 R4 ~ 125 ~ ~ ~
1i6 r ,N
N
GGl 9 2--193 1~7425~8 F;x. R3 R4 N N
128 H ~ 4 N
C4Hg N__N
29 C~
[~1 C H
. .13 0 t-C4 Hg ~,N
'' 10 N
131 -CH2 ~ ~ IN
Cl CH3 i3 2 -CH2 ~ ~rl~
~ N N
133 -CH2~>--CH3 ~N,N
.. _ C2H5 R N
135 -CH2-0-C-CH2~ ~ N
N
H
13 6 ~5~ H
107429~ GG192-193 EX. R3 R4 137 . H
~ C2H5 '-' _ 138 CH~ ~SJLC3H7 13 9 2 ~ 3 N--N
~io -CH2-0-C-C2H5 ~
CH2-0-C~ ~ CH3 _........ S
li2 H ~o,~.~ H
143 ~ L CH;
E:x . R3 R4 144 H ~
145 . H
C H
1l 46 _cH2_o_c~Br --~ iCH3 fl ,OCH3 47 -CH2-0-C-C}~2~ N--N
48 ~ i~
14 9 -CH ~) N 1.- CH3 (~ . 9~ N
. .
N , CH;
174298 GGl92--193 Ex. R3 R4 131-CH2 -O-C -C~3 ~ C 2 35 152 -CH~
S
153 H rllN
8~N
154 t-C4Hg S
155 ~ 11 CH3 ~ . .. .
156 H H3C~H
157 ~rr 3 7 '' . : - . - .
4~9~ -Ex. R3 R4 158 -C ~ N~ ll 15 9 H H~ CH
160 H H3C ~
161 H5C2~b H
162 ~ '?
. 163 H ~3 ~1~
- i64 Si (CH3) 3 ~;~
~074~$~B
_GG192-193 Ex. R3 R4 165 sn (CH3)3 N 2~
~ ,~ CH3 166 SL (C2H5) 3 ~ ~CE13 l6? (C2H5~ 3 N N
N
168 Ca/2 . N N
N,N
2 0 169 Mg/2 r~ c~3 i70 Na N_N
J~S~L CH3 171 Na ~
N,N
423~
_GGlg2-193 EX. - R3 R4 _l?2 A1/3 73 ~CH3NH3 ]~ JN
, ~ N N
174 1 (C6HSCH2) 2NH2] ~ CH3 These same compounds can also be prepared according to the procedures of examples 89 and 94 to 97 ~y ~ubstitutlng- ---for the l-methyl-l~tetrazole-5-thiol the compound R4-S-H
wherein R4 is as set forth above in Col. B.
59_
c) 73-~[~(Aminocarbonyl)amino](DL-2-thienvl)acetyl]amino]-3-[[(5-methYl-1,3,4-thiadiazol-2-yl1thio]methvl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxYlic acid The product from part (b) is treated with trifluoro-acetic acid and anisole at 0C followed by treatment at 80with potassium cyanate at~pH 7.8 accordlng to tne-procedure of example l(e). The 73-[tl(aminocarbonyl)amino]~D~-2-thienyl) acetyl]aminol-3-1[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid obtained is recrystallized from tetrahydrofuran/petxoleum ether as a beige powder, m.p. 155-157 (dec.).
Example 93 7B-[[[(Aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid, potassium salt An equimolar aqueous solution of the final product from example 92 and potassium bicarbonate is freeze-dried to yield as a beige powder 7~-[[[~aminocarbonyl)amino](DL-2-thienyl)-acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo14.2.0]oct-2-ene-2-carboxylic acid, potassium salt; m.p.-194-196 (dec.).
Example 94 7B-[~[(Aminocarbonyl)amino](DL-3-thienyl)acetyl]amino]-3-[l(l-methyl~ tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-?-carboxvlic acid a) DL-a-Bromo-3-thiopheneacetic acid 2-thienylbromide is treated with butyl lithium and chloral to obtain 2-[(1-hydroxy-2-trichloro)ethyl]thiaphene which is then treated with sodium methoxide to obtain a-methoxy-3-thienylacetic acid lGronowitz et al., Ark. Chemi., 17, 561 (1961)].
150 ml. of 30% hydrogen bromide in acetic acid is added to a solution of 16 g. (100 mmol.) of (a-methoxy-3-thienyl)acetic acid in 50 ml. of glacial acetic acid. The mixture i5 left to stand at room temperature for 24 hours and then poured into ice water. The solution i5 extracted three times with 60 ml. of ether. The ether phase-is washed with water, dried over magnesium sulfate and evaporated.
The residue, 18 g. of crude DL-a-bromo-3-thiopheneacetic acid are recrystallized from cyclohexane; yield 14 g.; m.p.
80-82.
~74~ GG192-1933 b) DL-a-Azido-3-thiopheneacetic acid 4 g. (62 mmol.) of sodium azide and 3.5 g. (33 mmol.) of sodium carbonate are added to a solution of 12 g. (54 mmol.) of DL-~-bromo-3-thiopheneacetic acid in 75 ml. of acetone (96%).
The mixture is stirred at room temperature for 12 hours in darkness and after this time the solvent is evaporated and the resldue is di~solved in 75 ml. of water. 50 ml. of ether i8 added, the water phase is acidified with 2N sulfuric acid and extracted quickly twice more with 50 ml. of ether. After washing with water and drying over sodium sulfate, the com-_ bined ether phases are evaporated. Crystallization of the residue from cyclohexane yields 7.4 g. of white crystalline DL-~-azido-3-thiopheneacetic acid; m.p. 58-59.
c) DL-a-Amino-3-thiopheneacetic acid 0.3 g. of palladium/barium sulfate catalyst are added to a solution of 6 g. of DL-~-azido-3-thiopheneacetic acid in 40 ml. of ethanol and 40 ml. of 0.5N hydrochloric acid.
~ydrogenation takes place at about 60 psig. after 2 hours.
After filtration, the volume is concentrated to about 30 ml.
When the pH is brought to 6.5 with ammonia, the amino acid separates as a white powder. After washing with ethanol/
water and drylng, 3.5 g. of the product, DL--amino-3-thiopheneacetic acid, are obtained; m.p. 283-285.
d) DL--~[t~4-MethoxyphenYl)methoxYlcarbonyl]amino]-3-thio-pheneacetic acid 1.9 g. (12.5 mmol.) of DL-~-amino-3-thiophe~eacetic acid and 1 g. of magnesium oxide are stirred in 25 ml. of water and 25 ml. of dioxane. After stirring for 1 hour, 3.0 g.
~15 mmol) of l(p-methoxybenzyl)oxy]carbonylaz~de are added.
Stirring is continued for 24 hours. The mixture is filtered and . . . ':
-~0~7429;~
extracted with 20 ml of ether. 50 ml of ethyl acetate and 20 g of Dowex 50 (~+ form) are added to the filtrate and the mixture is stirred well or two hours. They ethyl acetate phase is separated, washed with 50 ml of water, dried over sodium sulfate and evaporated. The oily residue crystallizes after the addition of pentane to yield 3.4 g of white crystalline DL-~-[[[(4-methoxy-phenyl)methox~carbonyllamino]-3-thiopheneaceticacid; m.p; 118(dec).
e) 3-~Acetyloxy)methyl]-7B-[[1[(4-methoxyphenyl)methoxy]-carbonyllaminol~DL-3-thienYl)acetyl]amino]-8-oxo-5-thia-1-azabi-cyclo~4.2.0~oct-2-ene-2-carboxylic acid S g of the product from part ~d), 1.5 g of triethylamine and 1-8 g of chloroformicacid ethyl e5ter in 50 ml of tetrahydrofuran are converted to the mixed anhydride. The mixed anhydride is reacted with a solution of 4 g of 7-aminocephalosporanic acid and 2.5 g of tristhylamine in methylene chloride for 12 hour~. The ~olvent i9 then xemoved from the solution and the partially solid r-sidue is di~solved with water and a small amount of sodlum car-bonate And extr~cted with 50 ml of ethyl acetate. The aqueous pha~e i5 cooled, acldified to p~ 2.5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase i9 treated with activated carbon and concentrated to obtain 3.7 g of llght beige product, 3-l(acetyloxy)methyl~-7~-[[[[~4-methoxyphenyl)methoxy]-carbonyllamino]~D~-3-thlenyl)acetyl]amino~-8-oxo-5-thia-1-azabl-cyclo~4.2.0]oct-2-ene-2-carboxylic acidtm.p. 113~(dec.), which is recrystallized from methylene chloride/petroleum ether.
f) 3-[(Acetyloxy~methyl]-7B-[[[(aminocarbonyl)amino](DL-3-thienyl)-acetyl~amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-car-boxylic acid The product from Example 6, part ~e) is stirred with 15 ml of triflùoroacet~c acid and worked up as in Example 89, and after ~ ~0>'.74Z5~
reaction with potassium cyanate as in Example 89, the title compound is obtained.
g) 7~-[1~(Aminocarbonyl)amino~(DL-3-thienyl)acetyl]amino~-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxYlic acid The 3-l(acetyloxy)methyl]-7~[[[(aminocarbonyl)amino](DL-3-thienyl)acetyl]amino~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from part (f) is treated with l-methyl-lH-tetra-zole-5-thiol according to the procedure of Example 89 (f) to yield the titled compound.
The 7~-[t~amlnocarbonyl)amino](DL-3-thienyl)acetyl~amino]-3-[[~l-methyl-lH-tetrazol-5-yl)thio]methyl~-8-oxo-5-thia-1-azabi-cyclol4.2.0]oct-2-ene-2-carboxylic acid can also be obtained ~y following the procedure of Example 2 but substituting DL-3-thienyl-glycine for the D~-2-thienylglycine in part (a) of Example 90.
Example 95 7~-11[(Aminocarbonyl~amino](D-2-thlenyl)acetyllamino]-3-[t~l-mothyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thla-1-azabicyclo-[4.2.01Oct-2-ene-2-carboxyllc acid a) D-~-[[t~4-MethoxY~henYl)methoxY~carbonYl]amino-2-thiophene acetlc acid 15.7 g of D-~2-thienyl)glycine (m.p.)218-21~,produced from the racemate with D-camphor-10-sulfonic acid) and 8 g of magnesium oxido are suspended in 200 ml of water. To this suspen5ion is added a solution of 22.8 g of ~p-methoxyphenyl)methoxycarbonyl-a2ide in 200 ml of dioxane and this mixture is stirred for 3 days at room temperature. The mixture is filtered, the filtrate is extracted once with ether, the aqueous phase is layered over with ethyl acetate, cooled to about 10 and acidified to pH 2 30~ with dilute hydrochloric acid. The aqueous phase is once more :
.
~07429~
extracted with ethyl acetate, the combined extracts are washed once with water, dried with magnesium sulfate and concentrated.
The residue crystallizes upon trituration with petroleum ether.
The crude product, D-a-[[[(4-methoxyphenyl)methoxy~carbonyl]-amino]-2-thiopheneacetic acid, is recrystallizea from ethyl acetate/petroleum ether, yield 25.2 g, m.p. 65-67.
D) 3-[(AcetYloxv)methvl]-7B-[[[[[(4-methoxvphenyl)methoxy]-carbonyl]amino](D-2-thienyl)acetYl]amino]-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid 3.2 g. (0.01 mol.) of the product from part (a) is brought into solution in 40 ml. of methylene chloride with 1.1 ml. of N-methylmorpholine. The solution is cooled to -15, 1.39 ml. of isobutylchloroformate are added, and the mixture is sSirred for 10 minutes. To this is added a solution of 3.26 g. (0.1012 mol.) of 7-aminocephalosporanic acid and 3.1 ml. of triethylamine in 40 ml. of methylene chloride. The mixture is stirred for 1 hour at -5 and 1 hour at 5. This mixture is then evaporated to dryness in a rotary evaporator.
The solid residue is triturated with ether and filtered under suction. The substance is then dissolved in ice water, layered over with ethyl acetate and acidified to pH 2.5. The layers are separated, the a~ueous layer is extracted once more with ethyl acetate, the combined ethyl acetate extracts are washed with water, dried with magnesium sulfate and con-centrated. The residue ~4.9 g.) is dissolved in 200 ml. of ethyl acetate and the solution is treated with activated ~074Z~8 carbon. After filtration 2 g. of 3-[(acetyloxy)methyl]-7~-t[~[~(4-methoxyphenyl)methoxy]carbonyl]amino](D-2-thienyl)-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, crystallize; m.p. 142-143 (dec.).
c) 3-[(Acety~oxy)methyl]-7B-[[(-amino-D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid 2.0 g. of the product from part (b) are added at -5 to a mixture of 10 ml. of trifluoroacetic acid and 4 ml. of anisole. The mixture is stirred for 10 minutes and is then con-centrated in a rotary evaporator. The residue is treatedwith ether and filtered under suction. The crude 3-[(acetyloxy)-methyl~-7~-[[~-amino-D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt i8 dissolved in 50 ml. of water and 20 ml. of a solution of the acetate form of the ion exchange resin Amb~rlite LA 1 in isobutylmethyltetone are added. The mixture i8 stirred for 2 hours at room temperature. The layers are separated, the aqueous phase is washed several times with ether and freeze-dried to yield 1 g. of 3-[~acetyloxy)methyl]-7B-[[~-amino-D-2-thienyl)acetyl]amino~-8-oxo-5-thia-1-azabicyclo-14.2.0]oct-2-ene-2-carboxylic acid.
d) 3-[(Acetyloxy)methyl]-7B-~ aminocarbonyl)amino](D-2-thienyl) acetyl]amino]-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid A mixture of 1 g. of the product from part (c) and 0.194 g. of potassium cyanate in 7.5 ml. of water are quickly heated in a preheated bath at 80. The mixture is then immediately cooled to room temperature and permitted to stand overnight. The reaction mixture is concentrated to 1074Z9~
G~lY~-193 about 4 ml. and the pH is adjusted to 1.5 with 2N hydrochloric acid. The precipitate is filtered under suction to obtain 0.5 g. of 3-[(acetyloxy)methyl]-73-[l[(aminocarbonyl)amino-(D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-aæabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid; m.p. 155-160 (dec.).
e) 7B-[[[(Aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-3-l[(1-methyl-1~-tetrazol-5-yl)thio]methyll-8-oxo-5-thia-1-azabicvclo[4.2.0]oct-2-ene-2-carboxylic acid 0.01 mol. of the product from part (d) and 0.011 mol. of 1-methyl-lH-tetrazole-5-thiol are heated in an aqueous acetone solution at pH 7 according to the procedure of example l(f) to yield the 7~-l[~(aminocarbonyl)amino](D-2-thienyl)acetyl]-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.
Example 96 7B-[[[(Methylaminocarbonvl)amino](D-2-thienyl)acetyl~amino]-3 [[(l-methyl-1~-tetrazol-5-yl)thio]methvl~-8-oxo-5-~ia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) 3-[(Acetyloxy)methyl]-7~-l[[(methvlaminocarbonyl)amino]-(D-2-thienyl)acetyllamino]-8-oxo-5-thia-1-azabicvclo[4.2.0]-oct-2-ene-2-carboxylic acid 1.5 g. of 3-~(acetyloxy)m~thyl]-7B-[[(-amino-D-2-; thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt from example 7(c) and 1.01 ml. of triethylamine are dissolved at 0-5 in 20 ml.
of anhydrous methylene chloride. To the clear sol~tion is added 2.49 g. of a 10~ solution of methylisocyanate in methylene chloride. This mixture is stirred for 2 hours at 0-5 and then concentrated. The residue is taken up in a little water, shaken with ether, filtered and acidified with 2N hydrochloric acid.
1074~9~ ,G192-lg3 0.8 g. of 3-~(acetyloxy)methyl~-7B-[[[(methylaminocarbonyl)-amino](D-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid are obtained; m.p. 178-180 (dec.).
b) 7B-~[[(Methylaminocarbonyl)amino](D-2-thienyl)acetyl]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 0.01 mol. of the product from part (a) and 0.011 mol.
of l-methyl-lH-tetrazole-5-thiol are reacted according to the procedure of example l(f) to yield the 7B-l[[(methylamino-carbonyl)amino](D-2-thienyl)acetyllamino]-3-[[(1-methyl-lH--~ tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid.
Example 97 7B-~ Amlnocarbonyl)amino](DL-3-pYridYl)acetYl]amino]-3-[~(l-methyl-l~-tetrazol-5-Yl)thio]methyl]-8-oxo-5-thia-1-a bicyclo~4.2.0loct-2-ene-2-carboxYlic acid a) DL-~ (4-Methoxyp-henyl)methoxy~carbonyl]amino~-3-~Yridin-e acetic acid DL-2-(3-Pyridyl)glycine ~prepared from pyridine-3-aldehyde by the Strecker synthesis) is reacted with (p-methoxybenzyloxycarbonyl)azide according to the procedure set forth in Example 2(a) to yield D~--~t~(4-methoxyphenyl)-methoxy]carbonyl]amino]-3-pyridineacetic acid; m.p. 155-156 (dec.).
b) 3-~(Acetyloxy)methyl]-7B-~[~ 4-methoxvphenyl)methoxY]-carbonyl]aminol~DL-3-pyridyl)acetyl]amino]-8-oxo-5-thia-1-_zabic~yclo~4.2.0]oct-2-ene-2-carboxvlic acid The product from part (a) is reacted with isobutyl-chloroformate in the presence of N-methylmorpholine followed by reaction with 7-aminocephalosporanic acid according to the procedure of examplegs~b) to yield the 3-~(acetyloxy)methyl]--46~
1 07 4 2~ 8 GG192-193 _, _ . , . _ 7B-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino](DL-3-pyridyl) acetyl]amino]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2--carboxylic acid. - --c) 3-[(Acetvloxy)methyl]-7~-[[(~-amino-DL-3-pyridvl)acetyl]-amino]-8-oxo-5-thia-1-azabicYclo[4.2.0]oci-2-ene-2-carboxylic _cid, trifluoroacetic acid salt . -- .. .... .
4 g. of the product from part (b) are added at -5 to a mixture of 50 ml. of trifluoroacetic acid and 20 ml. of anisole. After 10 minutes, the trifluoroacetic acid is evaporated ~ 10 under vacuum. The residue is treated with ether and filtered to yield the 3-[(acetyloxy)methyl]-73-[[(~-amino-DL-3-pyridyl)-acetyl]amino]-B-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p. 138-140 (dec.).
d) 3-[(Acetyloxy)methyl]-7B-[[l(aminocarbonyl)aminol(DL-3-pyridyl)acetxl]amino]-8-oxo-5-thia-1-azabicYclo[4.2.0]oct-2-ene-2-carboxylic_acid 3.5 g. of the product from part (c) and 1.09 g. of pota~sium isocyanate are stirred o~ernight in 50 ml. of water at room temperature. The reaction mixture i5 filtered and the filtrate is freeze-dried to yield the 3-~(acetyloxy)methyl]-7B-~(aminocarbonyl)amino](DL-3-pyridyl)acetyl]amino]-8-oxo-5-thla-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
e) 7~-~[~(Aminocarbonyl)amino](DL-3-pyr-id-y~)acetvl]amino]-3-[[(l-methyl-l~tetrazol-5-Yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The product from part (d) and l-methyl-lH-tetrazole-5-thiol are reacted according to the procedure of example99 (f) to yield the 7~-[[[(aminocarbonyl)aminol(DL-3-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.
~7429~
. Exam~les 98-117 Following the procedures of any of examples 91, 94, or 97 but substituting for the DL-2-thienylglycine, DL-3-thienyl-glycine, and DL-3-pyridylglycine one of the following:
DL-2-fùrylglycine DL-3-furylglycine DL-2-pyrrylglycine DL-3-pyrrylglycine DL-2-pyridylglycine DL-4-pyridylglycine -- 10 DL-2-thiazolylglycine DL-5-thiazolylglycine DL-3-isothiazolylglycine D~-5-isothiazolylglycine D~-2-oxazolylglycine DL-S-oxazolylglycine DL-3-isoxazolylglycine DL-S-isoxazolylglycine DL-3-~1,2,4-thiadiazolyl)glycine DL-5-~1,2,4-thiadiazolyl)glycine ., DL-5-(1-methyltetrazolyl)glycine DL-2-(S-chlorothienyl)glycine DL-3-(4-methylthienyl)glycine DL-2-(4-chloropyrryl)glycine one obtains ..
7~-ttl(aminocarbonyl)amino](DL-2-furyl)acetyl]amino]-3 ~t~l-methyi-lH-tetrazol-5-ylJthio]methyl]-8-oxo-s-thia azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-3-f~ryl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
_ - - - . .. . . ~ . ~ . .
107~Z98 GG1~2-193 7~-[[[(aminocarbonyl)amino](DL-2-pyrryl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-~ aminocarbonyl)amino](DL-3-pyrryl)acetyl~amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]méthyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-[[[(aminocarbonyl)amino](DL-2-pyridyl)acetyl]amino-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino]~DL-4-pyridyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-2-thiazolyl)acetyl]amino]-3-~[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
73-[[[(aminocarbonyl)amino](DL-5-thiazolyl)acetyl]amino]-3-[[(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7~-[[[(aminocarbonyl)amino](DL-3-isotlliazolyl)acetyl]amino]-3-tt(l-methyl-lH-tetrazol-5-yl)thio]methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
73-~(aminocarbonyl)amino](DL-5-isothiazolyl)acetyl]amino]-3-~t(l-methyl-lH-tetrazol-s-yl)thiolmethyl]-8-oxo-5-thia azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7~-t[t(aminocarbonyl)amino](DL-2-oxazolyl)acetyl]amino]-3 t~tl-me.thyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-~hia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7~-~tt~aminocarbonyl)amino](DL-5-oxazolyl)acetyl]amino]-3-[l(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
74Z9~
GGi92-193 73-[[~(aminocarbonyl)amino](DL-3-isoxazolyl)acetyl]-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;
7B-[[[(aminocarbonyl)amino](DL-5-isoxazolyl)acetyl]-amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-3-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-~(aminocarbonyl)amino][DL-3-(1,2,4-thiadiazolyl) acetyl~amino]-3-~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]oct-2-ene-2-carboxylic acidS
7B-~l(aminocarbonyl)amino]lDL-S-(1,2,4-thiadiazolyl)]-_. 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;
7B-[~(aminocarbonyl)amino][D~-5-~1-methyltetrazolyl)]-acetyl]amino]-3-~ methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-[~[~aminocarbonyl)amino]~DL-2-(5-chlorothienyl)]-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;
7B-~(aminocarbonyl)amino][DL-3-(4-methylthienyl)]-acetyl]amlno]-3-1[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
and 7B-l~[(aminocarbonyl)amino][DL-2-(4-chloropyrryl)]-acetyl]amino]-3.-~(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
r~spectively.
._ .
~ 1.074Zg~
_ GG192-193 Examples 118-124 .
Following the procedure of example 96but substituting for the methylisocyanate one of the following:
ethylisocyanate propylisocyanate i-propylisocyanate butylisocyanate i-butylisocyanate t-butyllsocyanate pentylisocyanate _...... one obtains:
7B-~[l(ethylaminocarbonyl)amino](D-2-thienyl~acetyl]aminol-3-lt(l-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-1-aza~cyclo[4.2.0]oct-2-ene-2-carboxylic acid;
7B-l~l~propylaminocarbonyl)amino](D- 2- thienyl)acetyl]amino]-3-[1(l-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-llt(i-propylaminocarbonyl)amino](D-2-thienyl)acetyl]
amino]-3-[[(1-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-20 thia-1-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-lll~butylaminocarbonyl)amino]~D-2-thienyl)acetyl]-amino]-3-~L(l-methyl-lH-tetrazol-s-yl)thiolmethyl]-8 thia-l-azabicyclo~4.2.0]oct-2-ene-2-carboxylic acid;
7B-~ i-butylaminocarbonyl)amino](D-2-thienyl)acetyl]-amino]-3-[1(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclol4.2.0]oct-2-ene-2-carboxylic acid;
7B~ t-butylaminocarbonyl)amino](D-2-thienyl)acetyl]
amino]-3-[1(l-methyl-lH-tetrazol-S-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
GG1~2-193 and 7~-[[[(pentylaminocarbonyl)amino](D-2-thienyl)acetyl]-- aminoJ-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid respectively.
Similarly by employing the methylisocyanate from example 8 or the alkylisocyanates of examples 30-36 in place of the potassium cyanate in examples 1, 4, and 9 to 29 other compounds within the scope of tbis invention are obtained.
Examples 125-174 Following the procedures of examples90 or 92 but em-ploying the substituted 7-aminocephalosporanic acid deriva-tives shown in Col. A the products shown in Col. B are obtained.
Col. A Col. 3 CN S R ~ NH ~ N ~ C~2-S-R4 Ex. R3 R4 ~ 125 ~ ~ ~
1i6 r ,N
N
GGl 9 2--193 1~7425~8 F;x. R3 R4 N N
128 H ~ 4 N
C4Hg N__N
29 C~
[~1 C H
. .13 0 t-C4 Hg ~,N
'' 10 N
131 -CH2 ~ ~ IN
Cl CH3 i3 2 -CH2 ~ ~rl~
~ N N
133 -CH2~>--CH3 ~N,N
.. _ C2H5 R N
135 -CH2-0-C-CH2~ ~ N
N
H
13 6 ~5~ H
107429~ GG192-193 EX. R3 R4 137 . H
~ C2H5 '-' _ 138 CH~ ~SJLC3H7 13 9 2 ~ 3 N--N
~io -CH2-0-C-C2H5 ~
CH2-0-C~ ~ CH3 _........ S
li2 H ~o,~.~ H
143 ~ L CH;
E:x . R3 R4 144 H ~
145 . H
C H
1l 46 _cH2_o_c~Br --~ iCH3 fl ,OCH3 47 -CH2-0-C-C}~2~ N--N
48 ~ i~
14 9 -CH ~) N 1.- CH3 (~ . 9~ N
. .
N , CH;
174298 GGl92--193 Ex. R3 R4 131-CH2 -O-C -C~3 ~ C 2 35 152 -CH~
S
153 H rllN
8~N
154 t-C4Hg S
155 ~ 11 CH3 ~ . .. .
156 H H3C~H
157 ~rr 3 7 '' . : - . - .
4~9~ -Ex. R3 R4 158 -C ~ N~ ll 15 9 H H~ CH
160 H H3C ~
161 H5C2~b H
162 ~ '?
. 163 H ~3 ~1~
- i64 Si (CH3) 3 ~;~
~074~$~B
_GG192-193 Ex. R3 R4 165 sn (CH3)3 N 2~
~ ,~ CH3 166 SL (C2H5) 3 ~ ~CE13 l6? (C2H5~ 3 N N
N
168 Ca/2 . N N
N,N
2 0 169 Mg/2 r~ c~3 i70 Na N_N
J~S~L CH3 171 Na ~
N,N
423~
_GGlg2-193 EX. - R3 R4 _l?2 A1/3 73 ~CH3NH3 ]~ JN
, ~ N N
174 1 (C6HSCH2) 2NH2] ~ CH3 These same compounds can also be prepared according to the procedures of examples 89 and 94 to 97 ~y ~ubstitutlng- ---for the l-methyl-l~tetrazole-5-thiol the compound R4-S-H
wherein R4 is as set forth above in Col. B.
59_
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R1 is phenyl or 2-thienyl; R3 is hydrogen, diphenyl-lower alkyl or a salt forming ion; and R4 is 1-methyl-1H-tetrazole-5-yl or 5-methyl-1,3,4-thiadiazol-2-yl, characterized by reacting a compound of the formula wherein the symbols are as previously defined, with an alkali or alkaline earth cyanate.
2. A process according to claim 1 wherein the cyanate reactant is potassium cyanate.
3. A process according to claim 1 wherein R1 is phenyl.
4. A process according to claim 1 wherein R1 is 2-thienyl.
5. A process according to claim 1 wherein R4 is 1-methyl-1H-tetrazole-5-yl.
6. A process according to claim 1 wherein R4 is 5-methyl-1,3,4-thiadiazol-2-yl.
7. A process according to claim 1 wherein 7.beta.-[[(.alpha.-amino-phenyl)acetyl]amino]-3-[[1-methyl-1H-tetrazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxxylic acid is reacted with potassium cyanate to form 7.beta.-[[[(aminocarbonyl)-amino](phenyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
8. A process according to claim 1 wherein 7.beta.-[[(.alpha.-amino-2-thienyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is reacted with potassium cyanate to form 7.beta.-[[[(amino-carbonyl)amino](2-thienyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
9. A process according to claim 1 wherein 7.beta.-[[(.alpha.-amino-2-thienyl)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 is reacted with potassium cyanate to form 7.beta.-[[[(aminocarbonyl)amino](2-thienyl)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.
10. A compound of the formula wherein R1 is phenyl or 2-thienyl; R3 is hydrogen, diphenyl-lower alkyl or a salt forming ion; and R4 is 1-methyl-1H-tetrazole-5-yl or 5-methyl-1,3,4-thiadiazol-2-yl, whenever prepared by the process of claim 1.
11. A compound according to claim 10, whenever prepared by the process of claim 2.
12. A compound according to claim 10 wherein R1 is phenyl, whenever prepared by the process of claim 3.
13. A compound according to claim 10 wherein R1 is 2-thienyl, whenever prepared by the process of claim 4.
14. A compound according to claim 10 wherein R4 is 1-methyl-1H-tetrazole-5-yl, whenever prepared by the process of claim 5.
15. A compound according to claim 10 whenever R4 is 5-methyl-1,3,4-thiadiazol-2-yl, whenever prepared by the process of claim 6.
16. A compound according to claim 10 wherein R1 is phenyl, R3 is hydrogen and R4 is 1-methyl-1H-tetrazole-5-yl, whenever prepared by the process of claim 7.
17. A compound according to claim 10 wherein R1 is 2-thienyl, R3 is hydrogen and R4 is 1-methyl-1H-tetrazole-5-yl, whenever prepared by the process of claim 8.
18. A compound according to claim 10 wherein Rl is 2-thienyl, R3 is hydrogen and R4 is 5-methyl-1,3,4-thiadiazol-2-yl, whenever prepared by the process of claim 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50790074A | 1974-09-20 | 1974-09-20 | |
| US50790674A | 1974-09-20 | 1974-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1074298A true CA1074298A (en) | 1980-03-25 |
Family
ID=27056025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,462A Expired CA1074298A (en) | 1974-09-20 | 1975-08-29 | 3-heterothio-7-ureido cephalosporins |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5156494A (en) |
| AU (1) | AU8451975A (en) |
| CA (1) | CA1074298A (en) |
| DE (1) | DE2540804A1 (en) |
| FR (1) | FR2285135A1 (en) |
| GB (1) | GB1522164A (en) |
| HU (1) | HU171053B (en) |
| IE (1) | IE43538B1 (en) |
| NL (1) | NL7511147A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1075679A (en) * | 1975-07-30 | 1980-04-15 | E.R. Squibb And Sons | 3-heterothio-7-thioureido cephalosporins |
| JPS54117494A (en) * | 1978-03-03 | 1979-09-12 | Takeda Chem Ind Ltd | Cephalosporin compound and its preparation |
| GR78166B (en) * | 1981-05-04 | 1984-09-26 | Chinoin Gyogyszer Es Vegyeszet | |
| FR2977239B1 (en) | 2011-07-01 | 2015-10-23 | Air Liquide | CRYOGENIC FLUID RESERVOIR AND USE THEREOF |
-
1975
- 1975-08-29 CA CA234,462A patent/CA1074298A/en not_active Expired
- 1975-09-01 IE IE191275A patent/IE43538B1/en unknown
- 1975-09-03 AU AU84519/75A patent/AU8451975A/en not_active Expired
- 1975-09-03 GB GB3631375A patent/GB1522164A/en not_active Expired
- 1975-09-12 DE DE19752540804 patent/DE2540804A1/en not_active Withdrawn
- 1975-09-15 HU HU75SU00000902A patent/HU171053B/en unknown
- 1975-09-19 FR FR7528832A patent/FR2285135A1/en active Granted
- 1975-09-20 JP JP11423375A patent/JPS5156494A/en active Pending
- 1975-09-22 NL NL7511147A patent/NL7511147A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| GB1522164A (en) | 1978-08-23 |
| HU171053B (en) | 1977-10-28 |
| FR2285135A1 (en) | 1976-04-16 |
| AU8451975A (en) | 1977-03-10 |
| FR2285135B1 (en) | 1980-05-30 |
| DE2540804A1 (en) | 1976-04-15 |
| JPS5156494A (en) | 1976-05-18 |
| IE43538L (en) | 1976-03-20 |
| NL7511147A (en) | 1976-03-23 |
| IE43538B1 (en) | 1981-03-25 |
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