CA1088517A - 3-heterothiomethyl ureido cephalosporins - Google Patents
3-heterothiomethyl ureido cephalosporinsInfo
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- CA1088517A CA1088517A CA271,818A CA271818A CA1088517A CA 1088517 A CA1088517 A CA 1088517A CA 271818 A CA271818 A CA 271818A CA 1088517 A CA1088517 A CA 1088517A
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- amino
- methyl
- lower alkyl
- phenyl
- thio
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
L-Isomer compounds of the formula
L-Isomer compounds of the formula
Description
~,~.192b This invention relates to the optically active L-isomer form of the cephalosporins of the formula : (I) Rl-~H-~- ,S ~
C=O ~ I CH2 S R4 t COOR3 wherein Rl is phenyl, thienyl, or furyl; R4 represents certain heterocyclic group; 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 qroup -CH2-O-I~-R wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl and phenyl-lower alkyl.
The various groups represented by the symbols have the meaning defined below and these definitions are retained -throughout this specification.
!~
~ 1 GG192b The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, 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 such lower alkyl groups attached to a phenyl, e.g., benzyl, phenethyl, diphenylmethyl, etc.
The substituted phenyl and substituted phenyl-lower alkyl groups include one or two (preferably only one) simple substituents selected from halogen (preferably chlorine or bromine), lower alkyl and lower alkoxy, e.g. 2-, 3- or 4-chloro-phenyl, 2-, 3-, or 4-bromophenyl, 3,4-dichlorophenyl, 2-methyl-phenyl, 4-ethoxyphenyl, 2-, 3-, or 4-chlorobenzyl, 2-, 3-, or 4-ethylphenethyl, etc.
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 methylamine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine.
The heterocyclic groups represented by R4 are N - N ~ - N N N N I R5 N - N
~N ~ -~S)--- R5 ~ -~o~ R5 ~ ~ S' ' ~ S~
iS~'~
~ 5 , -~,N 5 , and ~N`3 wherein R5 is hydrogen or alkyl of 1 to 4 carbons.
The preferred embodiments of this invention are the compounds of formula I wherein:
R3 is hydrogen, sodium or potassium.
s N--N r --N ~--N N ~ CH
4 -~N,N - ~S ~ CH3 _ `O CH3 , ~ S N
especially 5-methyl-1,3,4-thiadiazol-2-yl and l-methyl-lH-tetrazol-5-yl.
The L-isomer compounds of formula I are preferably prepared by reacting an a-amino compound of the formula (II) Rl- IH_3_N~
NH2 H o,~ N~ CH2-S-R4 COOH
preferably in the form of its trifluoroacetic acid salt with an alkali or alkaline earth cyanate such as potassium cyanate in solution at a pH of from about 7 to about 8.
The compounds of formula II can be prepared by acylating a 3-heterothiomethyl-7-aminocephalosporin of the formula (III) H2N ~ S~
wherein R3 is preferably diphenylmethyl or t-butyl or other ester protecting groups with an acid chloride of the formula ( IV ) C~H 1l Rl- I -C-Cl NH2 HCl or an a-(substituted)amino acid of the formula i517 (V) Rl-CH-COOH
NH-Y ~
wherein Y is a protecting group such as ~ CH2-O-C- or H3CO ~ CH2-O-l- or (CH3)3-C-O-C-. The protecting group is removed, for example, by treatment with trifluoroacetic acid and anisole to yield the trifluoroacetate salt of the compound of formula II.
The L-isomer compounds of formula I can also be pre-1~ pared by reacting an -ureido compound of the formula (VI) L
R~ -COOH
HN-~-NH2 O
with the 3-heterothiomethyl-7-aminocephalosporin of formula III.
This reaction is carried out by converting the -ureido compound of formula VI 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 chloroformate, or an acyl halide, at reduced temperature of from about 0C to about -20C.
Alternatively, the ~-ureido compound of formula VI 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 L-isomers of formula I can also be prepared by reacting the compound of formula VI with 7-ACA preferably in the presence of dicyclohexylcarbodiimide to yield the ~ Si 7 ~.~.192b compound of formula VII (as disclosed in Pat. No. 3,833,568) (VII) Rl- !CH-N~ 1 N-H ~ N ~ CH2 0 C CH3 followed by treatment with the compound of the formula ~, (VIII) R4-S-H
in solution at a pH of from about 7.8 to about 8Ø
Similarly, the L-isomers 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 (IIX), preferably trifluoro-acetic acid in the presence of anisole, to yield the salt of formula O
(IX) Rl-~H-~-NH I l~S~
NH2 0~ ~H2-0-C-CH3 ~ HX COOR3 The salt of formula IXis then treated with an alkali or alkaline earth cyanate followed by treatment with the compound of formula VIII to yield the desired compounds.
The compounds of formula I wherein R3 is lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, or the acyloxymethyl group -CH2-O-C-R may be obtained by reacting the 3-heterothiomethyl-7-amino-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 ~ ~X~ halo-R3 or (XI) R ~N+-N- `
:~: 30 wherein halo is preferably chlorine or bromine in an inert ~ ' S
iO~517 r,~l92b solvent such as dimethylformamide, acetone, dioxane, benzene, or the like at about or below ambient temperature.
Similarly, the compounds of formula I wherein R3 is tri(lower alkyl)stannyl or tri(lower alkyl)silyl are obtained by introducing such groups onto the 3-heterothiomethyl cephalosporanic acid moiety either before or after the acylation reaction.
The carboxylate salts of the compounds of formula I are formed by reacting the carboxyl group of the cePhalosporanic acid moiety, i.e. R3 is hydrogen, with any of the salt forming ions described above.
The L-isomer 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, Klebsiella pneumoniae, Proteus rettgeri, Escherichia coli, etc. In particular, it has been found that these L-isomers are considerably more active than the corresponding D-isomer or D,L-isomeric mixture against beta-lactamase producing organisms such as Enterobacter, indole-positive Proteus, resistant Escherichia coli, and Serratia.
The compounds of formula I can be used as antibacterial agents 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 100 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.
~ G~,192b 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 according to conventional pharmaceutical practice.
Illustrative process details are provided in the examples for the various reactions. All temperatures are on the centigrade scale.
~ 517 f.G192b Example 1 7B-[[[(Aminocarbonyl)amino](L-2-thienyl)acetyl]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 a) L-~-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-thio-pheneacetic acid 14.2 g. of L-(2-thienyl)glycine (prepared by the method of Nishimura et al., Nippon Kagaku Zasshi, Vol. 82, p. 1688-91 (1961); Chem. Abst., Vol. 58, p. 11464f) are suspended in 142 ml. of water and brought into solution by the addition of 37.9 ml. of triethylamine. A solution of 20.6 g. of (~-methoxyphenyl)methoxycarbonylazide in 142 ml. of dioxane is added with stirring. The mixture which is turbid at first becomes clear after 30 minutes. This is stirred for an addi-tional hour at room temperature. The dioxane is then evaporated in vacuum. Flakes form in the aqueous phase which are extracted by shaking with ether. The aqueous phase is cooled to 0, layered over with ethyl acetate and acidified with 2N hydrochloric acid to pH 2.5. The aqueous phase is extracted twice more with ethyl acetate, the combined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuum to 23.5 g.
of L--[[[(4-methoxyphenyl)methoxy]carbonyl]amino~-2-thiophene-acetic acid; m.p. 100-102; [~]20 = +68.3 (c=l, tetrahydrofuran).
b) 7~-[[[[[(4-Methoxyphenyl)methoxy]carbonyl]amino](L-2-thienYl)-acetyl]amino]-3-[[(l-met_y~ -tetrazol-5-yl)thio]methyll-8 oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 14.9 g. of 3-[(1-methyl-lH-tetrazol-5-yl)thio]-7-amino-cephalosporanic acid, diphenylmcthyl ester are dissolved in 30 300 ml. of methylene chloride and 300 ml. of anhydrous tctra-1(~517 (;.;I 92~) hydrofuran are added. Then 11.62 g. of L--[[[(4-methoxyphenyl)-methoxy]carbonyl]amino]-2-thiopheneacetic acid from part (a) are added, the mixture is cooled to 0, and a solution of 6.79 g. of dicyclohexylcarbodiimide in 100 ml. of anhydrous tetrahydrofuran is added dropwise with stirring over 30 minutes.
The reaction mixture is stirred for 90 minutes at 0-5 and 90 minutes at room temperature. The precipitated dicyclo-hexylurea is then filtered off and the filtrate is concentratcd in vacuum. The residue is taken up with ethyl acetate, ~iltered, washed with sodium bicarbonate solution and with water. The ethyl acetate solution is dried with magnesium sulfate, treated with activated charcoal, filtered and concentrated in vacuum to a small volume. On stirring in excess petroleum ether, 24 g. of 7a-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-(L-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-S-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 110; are obtained as a precipitate.
c) ?B-[[(-Amino-L-2-thienyl)acetyl]amino]-3-[[(1-methYl-l~-tetraQol-5-yl~thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 24 g. of the diphenylmethyl ester product from part (b) are stirred in 100 ml. of anisole and 300 ml. of trifluoroacetic acid are added dropwise at 0. After 10 minutes, this mixture is evaporated under vacuum. The residue is treated with ether and filtered to yield 17.8 g. of 7B-[[(~-amino-L-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, trifluoroacetic acid salt.
~,(;l'l,?l) d) 7B-[[[(Aminocarbonyl)amino](L-2-thienyl)acetvl]amino]-3-[[(l-methyl-l~-tetrazol-S-yl)thio~methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 12 g. of the trifluoroacetic acid salt product from part (c) are added to a solution of 3.4 g. of potassium cyanate in 85 ml. of water and stirred for 3 hours at room temperature. This mixture is filtered and the filtrate is acidified to pH 1.5 with 2N hydrochloric acid while cooling.
The precipitate is isolated and yields 6.8 g. of 7B-[[[(amino-carbonyl]amino](L-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. 14g-153 (dec.).
An aqueous equimolar solution of this acid and sodium bicarbonate is lyophilized to yield 7~-[[[(aminocarbonyl)amino]-(L-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid, sodium salt; m.p. 187-188 (dec.). In a similar manner, one can obtain the potassium salt.
Example 2 7B-~[[(Aminocarbonyl]amino](L-3-thienyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyc_o[4.2.01oct-2-ene-2-carboxylic acid a) L-~-[1[(4-Methoxyphenyl)methoxylcarbonyl]amino]-3-thio-pheneacetic acid 18 g. of L-(3-thienyl)glycine ~prepared by the method of Nishimura et al., supra) are suspended in 300 ml. of water with 10 g. of magnesium oxide. 32 g. of (~-methoxyphenyl)-methoxycarbonylazide in 250 ml. of dioxane are added dropwise.
30 The mixture is stirred for 24 hours at room temperature, then --10--.
~ b'S~7 ~;~192~
the dioxane is distilled off. The residue is filtered and the filtrate is extracted by shaking with ether. The aqueous phase is layered with ethyl acetate and acidified to pH 2.5 with 2N
hydrochloric acid with cooling. The ethyl acetate is washed with water, dried over sodium sulfate and evaporated. The residual oil is dissolved in toluene, cyclohexane is added, and the mix-ture is refrigerated. Crystallization begins and 20.8 g.
of white crystalline L-~-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]-3-thiopheneacetic acid are obtained; m.p. 95-97:
[a]n25 = +76.8 (0.1~ in methanol).
b) 7~-1[[[[(4-Methoxyphenyl)methoxy]carbonyllamino](L-3-thienYl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabic c1O[4 2.0]oct-2-ene-2-carboxylic acid, Y
diphenylmethyl ester 10 g. of the L-~-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]-3-thiopheneacetic acid from part (a) are dissolved in 150 ml. of tetrahydrofuran and stirred for 15 minutes at 0 with 6.5 g. of dicyclohexylcarbodiimide. Then 14 g.
of 3-[(1-methyl-lH-tetrazol-5-yl)thio]-7-aminocephalosporanic acid, diphenylmethyl ester dissolved in 100 ml. of tetrahydro-furan are added. After 12 hours, the reaction mixture is filtered, the filtrate is treated with charcoal and evaporated in vacuum. The residual brown oil is dissolved in 20 ml.
of methylene chloride and added dropwise to a mixture of ether and petroleum ether. 20 g. of light yellow 7B-1[[[[(4-methoxyphenyl)methoxy]carbonyl]amino](L-3-thienyl)-acetyl]amino]-3-~[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-aæabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained; m.p. 95.
10~i51'~
GGl~
c) 7B-[[(-Amino-L-3-thienyl)acetyl]amino]-3-[[(1-methYl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 13 g. of the diphenylmethyl ester product from part (b) are dissolved in 200 ml. of anisole-trifluoroacetic acid tl:4) at 5. After 10 minutes stirring, the mixture is evaporated under vacuum. The residue is treated with a mixture of ether and petroleum ether and filtered to yield 8.4 g. of solid yellow 7B-[[(~-amino-L-3-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyll-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p. 125 (dec.).
d) 7~-[[[(Aminocarbonyl)amino](L-3-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 7.9 g. of the trifluoroacetic acid salt product from part (c) are dissolved in 50 ml. of water and the pll is adjusted to 7.2 with 2N sodium hydroxide. After the addition of 1.5 g.
of potassium cyanate, the mixture is stirred for 3 hours at constant pH. The reaction mixture is cooled, adjusted to pH 1.5 with 2N hydrochloric acid, the precipitate is filtered off and dissolved in methanol, then treated with charcoal.
Concentrating the methanolic solution crystallizes 4.2 g. of 7~-[[~(aminocarbonyl)amino](L-3-thienyl)acetyl]amino~-3-[~ methyl-lH-tetrazol-5-yl)thio]methyll-8-oxo-s-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; m.p. 157 (dec.).
An equimolar solution of this acid and potassium ; bicarbonate is lyophilized to obtain as a yellow powder 7~-[[[(aminocarbonyl)amino](L-3-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, potassium salt;
~ S17 (.~.192~
m.p. 174~ (dec.). In a similar manner, by employing sodium bicarbonate, one obtains the sodium salt.
Example 3 7B-[[[(Aminocarbonyl)amino](L-phenYl)acetyl]amino]-3-[[(1-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid a) L--[[[(4-Methoxyphenyl)methoxy]carbonyllamino]phenylacetic acid L-Phenylglycine (obtained from D,L-phenylglycine by the method of Nishimura et al., supra) and magnesium oxide are suspended in water and reacted with a solution of (p-methoxy-phenyl)methoxycarbonylazide in dioxane according to the pro-cedure of example l(a) to yield L-a-[[[(4-methoxyphenyl)methoxy~-carbonyl]amino]phenylacetic acid.
b) 7~-[[[[[(4-Methoxyphenyl)me~hoxy]carbonyl~amino](L-phenyl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 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, diphenylmethyl ester and L-a-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]phenylacetic acid from part (a) are reacted in the presence of dicyclohexylcarbodiimide according to the procedure of example l(b) to yield 7B-[[[[[(4-methoxyphenyl)methoxy]-carbonyl]aminol(L-phenyl)acetyl]amino]-3-[[(l-methyl-lE~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01-oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 117 (dec.).
--1~--(;~;l97.~, c~ 7~-[l(n-~mino-L-phenyl)acetyllamino]-3-ll(l-methyl-lu-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicYclo acid, trifluoroacetic acid salt The diphenylmethyl ester product from part (b) is treated with trifluoroacetic acid and anisole according to the procedure of example l(c) to yield 7B-[[(~-amino-L-phenyl)-acetyl]amino]-3-[[~1-methyl-lH-tetrazol-5-yl)thiolmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt.
d) 7B-[[[(Aminocarbonyl)amino~(L-Phenyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The trifluoroacetic acid salt product from part (c) is reacted with potassium cyanate according to the procedure of example l(d) to yield 7~-[[[(aminocarbonyl)amino](L-phenyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo[4.2.0]oct-2-ene-2-carboxylic acid;
m.p. 156 (dec.).
An aqueous equimolar solution of this acid and potassium 2G bicarbonate is freeze-dried to yield 7B-[[[(aminocarbonyl)-amino](L-phenyl3acetyl]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, potassium salt; m.p. 174 (dec.).
Similarly, by substituting sodium bicarbonate for the potassium bicarbonate one obtains the corresponding sodium salt.
~ 517 ~;~.l92b Example 4 7B-[~l(Aminocarbonyl)amino](L-2-furyl)acetyl]aminol-3-~methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azahicyclo-~4.2.0]oct-2-ene-2-carboxylic acid a) L-~ (4-Methoxyphenyl)methoxylcarbonyl]amino]-2-furanacetic acid 40 g. of L-(2-furyl)glycine tobtained from D,L-(2-furyl)-glycine by the method of Nishimura et al., supra) are stirred into 455 ml. of water and brought into solution by the addition of 122 ml. of triethylamine. A solution of 66 g. of (p-methoxyphenyl)-methoxycarbonylazide in 455 ml. of diox~ne is add~d with stirring.
The turbid mixture becomes clear after 30 minutes reaction time and the dioxane is evaporated in vacuo. The aqueous phase is washed with ether, cooled to 0, layered over with ethyl acetate and acidified to pH 2.5 with 2N hydrochloric acid.
This mixture is extracted twice with ethyl acetate, the com-bined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuo. The oily residue solidifies upon trituration with Petroleum to yield 74 g. of L-~-1[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-furanacetic acid;
m.p. 91-95 (dec.).
b) 7~-~[[[[(4-M_thoxyphenyl)methoxy]carbonyl]aminol(L-2-furvl)-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 36.4 g. (0.074 moles) of 3-[(1-methyl-lH-tetrazol-5-yl)-thio]-7-aminocephalosPoranic acid, diphenylmethyl ester are dissolved in 370 ml. of methylene chloride. Then a solution of 27 g. (O.Q88 moles) of L-~-[[[(4-methoxyphenyl)methoxy]-carbonyl]amino]-2-furanacetic acid, from part (a), in 450 ml.
~ S 1 ~ G~.192b of tetrahydrofuran is added, the mixture is cooled to 0, and a solution of 16.73 g. (0.081 moles) of dicyclohexylcarbodiimide in 150 ml. of tetrahydrofuran is added dropwise. The mixture is stirred for 90 minutes at 0 and 90 minutes at room temperature.
The precipitated dicyclohexylurea is filtered off under suction and the filtrate is concentrated. The residue is taken up in ethyl acetate, washed three times with sodium bicarbonate solution and three times with water, dried and concentrated.
The concentrated residue solidifies upon trituration with ether. This material is filtered under suction and stirred in 250 ml. of ethyl acetate. The mixture is stirred for
C=O ~ I CH2 S R4 t COOR3 wherein Rl is phenyl, thienyl, or furyl; R4 represents certain heterocyclic group; 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 qroup -CH2-O-I~-R wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted phenyl and phenyl-lower alkyl.
The various groups represented by the symbols have the meaning defined below and these definitions are retained -throughout this specification.
!~
~ 1 GG192b The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms, 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 such lower alkyl groups attached to a phenyl, e.g., benzyl, phenethyl, diphenylmethyl, etc.
The substituted phenyl and substituted phenyl-lower alkyl groups include one or two (preferably only one) simple substituents selected from halogen (preferably chlorine or bromine), lower alkyl and lower alkoxy, e.g. 2-, 3- or 4-chloro-phenyl, 2-, 3-, or 4-bromophenyl, 3,4-dichlorophenyl, 2-methyl-phenyl, 4-ethoxyphenyl, 2-, 3-, or 4-chlorobenzyl, 2-, 3-, or 4-ethylphenethyl, etc.
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 methylamine, triethylamine, and N-lower alkylpiperidines such as N-ethylpiperidine.
The heterocyclic groups represented by R4 are N - N ~ - N N N N I R5 N - N
~N ~ -~S)--- R5 ~ -~o~ R5 ~ ~ S' ' ~ S~
iS~'~
~ 5 , -~,N 5 , and ~N`3 wherein R5 is hydrogen or alkyl of 1 to 4 carbons.
The preferred embodiments of this invention are the compounds of formula I wherein:
R3 is hydrogen, sodium or potassium.
s N--N r --N ~--N N ~ CH
4 -~N,N - ~S ~ CH3 _ `O CH3 , ~ S N
especially 5-methyl-1,3,4-thiadiazol-2-yl and l-methyl-lH-tetrazol-5-yl.
The L-isomer compounds of formula I are preferably prepared by reacting an a-amino compound of the formula (II) Rl- IH_3_N~
NH2 H o,~ N~ CH2-S-R4 COOH
preferably in the form of its trifluoroacetic acid salt with an alkali or alkaline earth cyanate such as potassium cyanate in solution at a pH of from about 7 to about 8.
The compounds of formula II can be prepared by acylating a 3-heterothiomethyl-7-aminocephalosporin of the formula (III) H2N ~ S~
wherein R3 is preferably diphenylmethyl or t-butyl or other ester protecting groups with an acid chloride of the formula ( IV ) C~H 1l Rl- I -C-Cl NH2 HCl or an a-(substituted)amino acid of the formula i517 (V) Rl-CH-COOH
NH-Y ~
wherein Y is a protecting group such as ~ CH2-O-C- or H3CO ~ CH2-O-l- or (CH3)3-C-O-C-. The protecting group is removed, for example, by treatment with trifluoroacetic acid and anisole to yield the trifluoroacetate salt of the compound of formula II.
The L-isomer compounds of formula I can also be pre-1~ pared by reacting an -ureido compound of the formula (VI) L
R~ -COOH
HN-~-NH2 O
with the 3-heterothiomethyl-7-aminocephalosporin of formula III.
This reaction is carried out by converting the -ureido compound of formula VI 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 chloroformate, or an acyl halide, at reduced temperature of from about 0C to about -20C.
Alternatively, the ~-ureido compound of formula VI 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 L-isomers of formula I can also be prepared by reacting the compound of formula VI with 7-ACA preferably in the presence of dicyclohexylcarbodiimide to yield the ~ Si 7 ~.~.192b compound of formula VII (as disclosed in Pat. No. 3,833,568) (VII) Rl- !CH-N~ 1 N-H ~ N ~ CH2 0 C CH3 followed by treatment with the compound of the formula ~, (VIII) R4-S-H
in solution at a pH of from about 7.8 to about 8Ø
Similarly, the L-isomers 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 (IIX), preferably trifluoro-acetic acid in the presence of anisole, to yield the salt of formula O
(IX) Rl-~H-~-NH I l~S~
NH2 0~ ~H2-0-C-CH3 ~ HX COOR3 The salt of formula IXis then treated with an alkali or alkaline earth cyanate followed by treatment with the compound of formula VIII to yield the desired compounds.
The compounds of formula I wherein R3 is lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, or the acyloxymethyl group -CH2-O-C-R may be obtained by reacting the 3-heterothiomethyl-7-amino-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 ~ ~X~ halo-R3 or (XI) R ~N+-N- `
:~: 30 wherein halo is preferably chlorine or bromine in an inert ~ ' S
iO~517 r,~l92b solvent such as dimethylformamide, acetone, dioxane, benzene, or the like at about or below ambient temperature.
Similarly, the compounds of formula I wherein R3 is tri(lower alkyl)stannyl or tri(lower alkyl)silyl are obtained by introducing such groups onto the 3-heterothiomethyl cephalosporanic acid moiety either before or after the acylation reaction.
The carboxylate salts of the compounds of formula I are formed by reacting the carboxyl group of the cePhalosporanic acid moiety, i.e. R3 is hydrogen, with any of the salt forming ions described above.
The L-isomer 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, Klebsiella pneumoniae, Proteus rettgeri, Escherichia coli, etc. In particular, it has been found that these L-isomers are considerably more active than the corresponding D-isomer or D,L-isomeric mixture against beta-lactamase producing organisms such as Enterobacter, indole-positive Proteus, resistant Escherichia coli, and Serratia.
The compounds of formula I can be used as antibacterial agents 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 100 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.
~ G~,192b 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 according to conventional pharmaceutical practice.
Illustrative process details are provided in the examples for the various reactions. All temperatures are on the centigrade scale.
~ 517 f.G192b Example 1 7B-[[[(Aminocarbonyl)amino](L-2-thienyl)acetyl]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 a) L-~-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-thio-pheneacetic acid 14.2 g. of L-(2-thienyl)glycine (prepared by the method of Nishimura et al., Nippon Kagaku Zasshi, Vol. 82, p. 1688-91 (1961); Chem. Abst., Vol. 58, p. 11464f) are suspended in 142 ml. of water and brought into solution by the addition of 37.9 ml. of triethylamine. A solution of 20.6 g. of (~-methoxyphenyl)methoxycarbonylazide in 142 ml. of dioxane is added with stirring. The mixture which is turbid at first becomes clear after 30 minutes. This is stirred for an addi-tional hour at room temperature. The dioxane is then evaporated in vacuum. Flakes form in the aqueous phase which are extracted by shaking with ether. The aqueous phase is cooled to 0, layered over with ethyl acetate and acidified with 2N hydrochloric acid to pH 2.5. The aqueous phase is extracted twice more with ethyl acetate, the combined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuum to 23.5 g.
of L--[[[(4-methoxyphenyl)methoxy]carbonyl]amino~-2-thiophene-acetic acid; m.p. 100-102; [~]20 = +68.3 (c=l, tetrahydrofuran).
b) 7~-[[[[[(4-Methoxyphenyl)methoxy]carbonyl]amino](L-2-thienYl)-acetyl]amino]-3-[[(l-met_y~ -tetrazol-5-yl)thio]methyll-8 oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 14.9 g. of 3-[(1-methyl-lH-tetrazol-5-yl)thio]-7-amino-cephalosporanic acid, diphenylmcthyl ester are dissolved in 30 300 ml. of methylene chloride and 300 ml. of anhydrous tctra-1(~517 (;.;I 92~) hydrofuran are added. Then 11.62 g. of L--[[[(4-methoxyphenyl)-methoxy]carbonyl]amino]-2-thiopheneacetic acid from part (a) are added, the mixture is cooled to 0, and a solution of 6.79 g. of dicyclohexylcarbodiimide in 100 ml. of anhydrous tetrahydrofuran is added dropwise with stirring over 30 minutes.
The reaction mixture is stirred for 90 minutes at 0-5 and 90 minutes at room temperature. The precipitated dicyclo-hexylurea is then filtered off and the filtrate is concentratcd in vacuum. The residue is taken up with ethyl acetate, ~iltered, washed with sodium bicarbonate solution and with water. The ethyl acetate solution is dried with magnesium sulfate, treated with activated charcoal, filtered and concentrated in vacuum to a small volume. On stirring in excess petroleum ether, 24 g. of 7a-[[[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-(L-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-S-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 110; are obtained as a precipitate.
c) ?B-[[(-Amino-L-2-thienyl)acetyl]amino]-3-[[(1-methYl-l~-tetraQol-5-yl~thio]methyl]-8-oxo-5-thia-1-azabicyclol4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 24 g. of the diphenylmethyl ester product from part (b) are stirred in 100 ml. of anisole and 300 ml. of trifluoroacetic acid are added dropwise at 0. After 10 minutes, this mixture is evaporated under vacuum. The residue is treated with ether and filtered to yield 17.8 g. of 7B-[[(~-amino-L-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, trifluoroacetic acid salt.
~,(;l'l,?l) d) 7B-[[[(Aminocarbonyl)amino](L-2-thienyl)acetvl]amino]-3-[[(l-methyl-l~-tetrazol-S-yl)thio~methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 12 g. of the trifluoroacetic acid salt product from part (c) are added to a solution of 3.4 g. of potassium cyanate in 85 ml. of water and stirred for 3 hours at room temperature. This mixture is filtered and the filtrate is acidified to pH 1.5 with 2N hydrochloric acid while cooling.
The precipitate is isolated and yields 6.8 g. of 7B-[[[(amino-carbonyl]amino](L-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. 14g-153 (dec.).
An aqueous equimolar solution of this acid and sodium bicarbonate is lyophilized to yield 7~-[[[(aminocarbonyl)amino]-(L-2-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid, sodium salt; m.p. 187-188 (dec.). In a similar manner, one can obtain the potassium salt.
Example 2 7B-~[[(Aminocarbonyl]amino](L-3-thienyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyc_o[4.2.01oct-2-ene-2-carboxylic acid a) L-~-[1[(4-Methoxyphenyl)methoxylcarbonyl]amino]-3-thio-pheneacetic acid 18 g. of L-(3-thienyl)glycine ~prepared by the method of Nishimura et al., supra) are suspended in 300 ml. of water with 10 g. of magnesium oxide. 32 g. of (~-methoxyphenyl)-methoxycarbonylazide in 250 ml. of dioxane are added dropwise.
30 The mixture is stirred for 24 hours at room temperature, then --10--.
~ b'S~7 ~;~192~
the dioxane is distilled off. The residue is filtered and the filtrate is extracted by shaking with ether. The aqueous phase is layered with ethyl acetate and acidified to pH 2.5 with 2N
hydrochloric acid with cooling. The ethyl acetate is washed with water, dried over sodium sulfate and evaporated. The residual oil is dissolved in toluene, cyclohexane is added, and the mix-ture is refrigerated. Crystallization begins and 20.8 g.
of white crystalline L-~-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]-3-thiopheneacetic acid are obtained; m.p. 95-97:
[a]n25 = +76.8 (0.1~ in methanol).
b) 7~-1[[[[(4-Methoxyphenyl)methoxy]carbonyllamino](L-3-thienYl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabic c1O[4 2.0]oct-2-ene-2-carboxylic acid, Y
diphenylmethyl ester 10 g. of the L-~-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]-3-thiopheneacetic acid from part (a) are dissolved in 150 ml. of tetrahydrofuran and stirred for 15 minutes at 0 with 6.5 g. of dicyclohexylcarbodiimide. Then 14 g.
of 3-[(1-methyl-lH-tetrazol-5-yl)thio]-7-aminocephalosporanic acid, diphenylmethyl ester dissolved in 100 ml. of tetrahydro-furan are added. After 12 hours, the reaction mixture is filtered, the filtrate is treated with charcoal and evaporated in vacuum. The residual brown oil is dissolved in 20 ml.
of methylene chloride and added dropwise to a mixture of ether and petroleum ether. 20 g. of light yellow 7B-1[[[[(4-methoxyphenyl)methoxy]carbonyl]amino](L-3-thienyl)-acetyl]amino]-3-~[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-aæabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained; m.p. 95.
10~i51'~
GGl~
c) 7B-[[(-Amino-L-3-thienyl)acetyl]amino]-3-[[(1-methYl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 13 g. of the diphenylmethyl ester product from part (b) are dissolved in 200 ml. of anisole-trifluoroacetic acid tl:4) at 5. After 10 minutes stirring, the mixture is evaporated under vacuum. The residue is treated with a mixture of ether and petroleum ether and filtered to yield 8.4 g. of solid yellow 7B-[[(~-amino-L-3-thienyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyll-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p. 125 (dec.).
d) 7~-[[[(Aminocarbonyl)amino](L-3-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 7.9 g. of the trifluoroacetic acid salt product from part (c) are dissolved in 50 ml. of water and the pll is adjusted to 7.2 with 2N sodium hydroxide. After the addition of 1.5 g.
of potassium cyanate, the mixture is stirred for 3 hours at constant pH. The reaction mixture is cooled, adjusted to pH 1.5 with 2N hydrochloric acid, the precipitate is filtered off and dissolved in methanol, then treated with charcoal.
Concentrating the methanolic solution crystallizes 4.2 g. of 7~-[[~(aminocarbonyl)amino](L-3-thienyl)acetyl]amino~-3-[~ methyl-lH-tetrazol-5-yl)thio]methyll-8-oxo-s-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; m.p. 157 (dec.).
An equimolar solution of this acid and potassium ; bicarbonate is lyophilized to obtain as a yellow powder 7~-[[[(aminocarbonyl)amino](L-3-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, potassium salt;
~ S17 (.~.192~
m.p. 174~ (dec.). In a similar manner, by employing sodium bicarbonate, one obtains the sodium salt.
Example 3 7B-[[[(Aminocarbonyl)amino](L-phenYl)acetyl]amino]-3-[[(1-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid a) L--[[[(4-Methoxyphenyl)methoxy]carbonyllamino]phenylacetic acid L-Phenylglycine (obtained from D,L-phenylglycine by the method of Nishimura et al., supra) and magnesium oxide are suspended in water and reacted with a solution of (p-methoxy-phenyl)methoxycarbonylazide in dioxane according to the pro-cedure of example l(a) to yield L-a-[[[(4-methoxyphenyl)methoxy~-carbonyl]amino]phenylacetic acid.
b) 7~-[[[[[(4-Methoxyphenyl)me~hoxy]carbonyl~amino](L-phenyl)-acetyl]amino]-3-[[(1-methyl-1~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 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, diphenylmethyl ester and L-a-[[[(4-methoxyphenyl)methoxy]carbonyl]-amino]phenylacetic acid from part (a) are reacted in the presence of dicyclohexylcarbodiimide according to the procedure of example l(b) to yield 7B-[[[[[(4-methoxyphenyl)methoxy]-carbonyl]aminol(L-phenyl)acetyl]amino]-3-[[(l-methyl-lE~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01-oct-2-ene-2-carboxylic acid, diphenylmethyl ester; m.p. 117 (dec.).
--1~--(;~;l97.~, c~ 7~-[l(n-~mino-L-phenyl)acetyllamino]-3-ll(l-methyl-lu-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicYclo acid, trifluoroacetic acid salt The diphenylmethyl ester product from part (b) is treated with trifluoroacetic acid and anisole according to the procedure of example l(c) to yield 7B-[[(~-amino-L-phenyl)-acetyl]amino]-3-[[~1-methyl-lH-tetrazol-5-yl)thiolmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt.
d) 7B-[[[(Aminocarbonyl)amino~(L-Phenyl)acetyl]amino]-3-[[(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid The trifluoroacetic acid salt product from part (c) is reacted with potassium cyanate according to the procedure of example l(d) to yield 7~-[[[(aminocarbonyl)amino](L-phenyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo[4.2.0]oct-2-ene-2-carboxylic acid;
m.p. 156 (dec.).
An aqueous equimolar solution of this acid and potassium 2G bicarbonate is freeze-dried to yield 7B-[[[(aminocarbonyl)-amino](L-phenyl3acetyl]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, potassium salt; m.p. 174 (dec.).
Similarly, by substituting sodium bicarbonate for the potassium bicarbonate one obtains the corresponding sodium salt.
~ 517 ~;~.l92b Example 4 7B-[~l(Aminocarbonyl)amino](L-2-furyl)acetyl]aminol-3-~methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azahicyclo-~4.2.0]oct-2-ene-2-carboxylic acid a) L-~ (4-Methoxyphenyl)methoxylcarbonyl]amino]-2-furanacetic acid 40 g. of L-(2-furyl)glycine tobtained from D,L-(2-furyl)-glycine by the method of Nishimura et al., supra) are stirred into 455 ml. of water and brought into solution by the addition of 122 ml. of triethylamine. A solution of 66 g. of (p-methoxyphenyl)-methoxycarbonylazide in 455 ml. of diox~ne is add~d with stirring.
The turbid mixture becomes clear after 30 minutes reaction time and the dioxane is evaporated in vacuo. The aqueous phase is washed with ether, cooled to 0, layered over with ethyl acetate and acidified to pH 2.5 with 2N hydrochloric acid.
This mixture is extracted twice with ethyl acetate, the com-bined ethyl acetate extracts are dried with magnesium sulfate and concentrated in vacuo. The oily residue solidifies upon trituration with Petroleum to yield 74 g. of L-~-1[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-furanacetic acid;
m.p. 91-95 (dec.).
b) 7~-~[[[[(4-M_thoxyphenyl)methoxy]carbonyl]aminol(L-2-furvl)-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 36.4 g. (0.074 moles) of 3-[(1-methyl-lH-tetrazol-5-yl)-thio]-7-aminocephalosPoranic acid, diphenylmethyl ester are dissolved in 370 ml. of methylene chloride. Then a solution of 27 g. (O.Q88 moles) of L-~-[[[(4-methoxyphenyl)methoxy]-carbonyl]amino]-2-furanacetic acid, from part (a), in 450 ml.
~ S 1 ~ G~.192b of tetrahydrofuran is added, the mixture is cooled to 0, and a solution of 16.73 g. (0.081 moles) of dicyclohexylcarbodiimide in 150 ml. of tetrahydrofuran is added dropwise. The mixture is stirred for 90 minutes at 0 and 90 minutes at room temperature.
The precipitated dicyclohexylurea is filtered off under suction and the filtrate is concentrated. The residue is taken up in ethyl acetate, washed three times with sodium bicarbonate solution and three times with water, dried and concentrated.
The concentrated residue solidifies upon trituration with ether. This material is filtered under suction and stirred in 250 ml. of ethyl acetate. The mixture is stirred for
2 hours at 0 and filtered under suction to yield 30.4 g. of 7~-[[[[[(4-methoxyphenyl)methoxy~carbonyl~amino~(L-2-furyl)-acetyl~amino~-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0~oct-2-ene-2-carboxylic acid, diphenylmethyl ester, m.p. 149-152.
c) 7~-[[(-Amino-L-2-furyl)acetyl~amino~-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 30 g. of the diphenylmethyl ester product from part (b) are treated with 120 ml. of anisole and 390 ml. of trifluoro-acetic acid according to the ~rocedure of example l(c) to yield 21.9 g. of 7~-[[(~-amino-L-2-furyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0~-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p.
133-135 (dec.).
~ 517 .~.192~.
d) 7B-[[[(Aminocarbonyl)amino](L-2-furyl)acetYllaminol-3-ll(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.01oct-2-ene-2-carboxylic acid 28.2 g. of the trifluoroacetic acid salt product from part (c) are suspended in 290 ml. of water at room temperature.
8.15 g. of Potassium cyanate are added and the mixture is stirred for three hours at room temperature. The almost clear solution is cooled to 0-5 and acidified to PH 3.5. A flocculent pre-cipitate is filtered off. The clear filtrate is acidificd to pH 1.5 and allowed to stand in the refrigerator at about 0-5 to yield 19.8 g. of 7~-[[[(aminocarbonyl)amino]tL-2-furyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid; -m.p. 142-145 (dec.).
An aqueous equimolar solution of this acid and sodium bicarbonate is lyophilized to yield 7B-[[[(aminocarbonyl)aminol-(L-2-furyl)acetyl]amino]-3-l[(l-methyl-lH-tetrazol-5-yl)thio]-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt; m.p. 170-174 (dec.). In a similar manner by employing po~assium bicarbonate one obtains the potassium salt.
; Example 5 7~-[[[(Aminocarbonyl)amino]tL-3-furYl)acetyl]amino]-3-[[(1-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid Following the procedure of example 4 but substituting L-(3-furyl)glycine (obtained from D,L-(3-furyl)glycine by the method of Nishimura et al., supra) for the L-(2-furyl)-glycine in part (a), one obtains 7~-[[[(aminocarbonyl)amino]-l()~b~517 ~,~.19 2b tL-3-furyl)acetyl~amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio)-methyl]-8-oxo-S-thia-l-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid and its sodium and potassium salts.
Examples 6-55 Following the procedure of example 1 but employing the substituted 7-aminocephalosporanic acid derivatives shown in Col. A the products shown in Col. B are obtained.
Col. A Col. B
~ 0 H2N I ~ ~ ~CH-I-NH ~ ~S~
N ~ -CH2-S-R4 pH ~ N ~ CH2 S R4 Ex. R3 R4 Nl I--~
H ~N,N
7 H ~ - N
N - N
: 8 H ~ IN
. .
~ .
i517 Ex. R3 R4 N N
g H
N' -CH{O~ N N
11 t--C4Hg N~ N
N
C~33 N---N
12 -CH2~) _1~ ~N
Cl C~3 13 --CH2~) ~ N__ N
14 -CH2 ~--C1~3 --1I N
R N_N
` ~ :; 15 -CH2-0-C-CH3 ~
I
16 -CH2-0-~-CH2~ 1~ ,N
N
,~ 1' .
~ ~ 17 H
~, :
1~ 517 G-; l ')2b Ex. R3 R4 18 H ~ _~
J_ C2H5 N ---N
19 - CH ~ ---I``S Jl_ C3 7 [~J
-CH2~OCH3 N---N
21 -C112-0-C-C2115 r~
2 2 -CH2-O-C~ C113 S
.
N - -N
23 1~
~ O
~ ~` -CH - Ccj~ C113 O
lO~ ;1 92 Ex. R3 R4 H N---N
Il .!L C1l3 26 H N. _.N
27 _CH2_o_C~r ~ C113 l OCH3 23 -CH -O-C--CH2~ L-CH3 29 -CH~3 S
c) 7~-[[(-Amino-L-2-furyl)acetyl~amino~-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt 30 g. of the diphenylmethyl ester product from part (b) are treated with 120 ml. of anisole and 390 ml. of trifluoro-acetic acid according to the ~rocedure of example l(c) to yield 21.9 g. of 7~-[[(~-amino-L-2-furyl)acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio~methyl~-8-oxo-5-thia-1-azabicyclo[4.2.0~-oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt; m.p.
133-135 (dec.).
~ 517 .~.192~.
d) 7B-[[[(Aminocarbonyl)amino](L-2-furyl)acetYllaminol-3-ll(l-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.01oct-2-ene-2-carboxylic acid 28.2 g. of the trifluoroacetic acid salt product from part (c) are suspended in 290 ml. of water at room temperature.
8.15 g. of Potassium cyanate are added and the mixture is stirred for three hours at room temperature. The almost clear solution is cooled to 0-5 and acidified to PH 3.5. A flocculent pre-cipitate is filtered off. The clear filtrate is acidificd to pH 1.5 and allowed to stand in the refrigerator at about 0-5 to yield 19.8 g. of 7~-[[[(aminocarbonyl)amino]tL-2-furyl)-acetyl]amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid; -m.p. 142-145 (dec.).
An aqueous equimolar solution of this acid and sodium bicarbonate is lyophilized to yield 7B-[[[(aminocarbonyl)aminol-(L-2-furyl)acetyl]amino]-3-l[(l-methyl-lH-tetrazol-5-yl)thio]-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt; m.p. 170-174 (dec.). In a similar manner by employing po~assium bicarbonate one obtains the potassium salt.
; Example 5 7~-[[[(Aminocarbonyl)amino]tL-3-furYl)acetyl]amino]-3-[[(1-methyl-l~-tetrazol-5-yl)thio]methyl]-8-oxo-S-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid Following the procedure of example 4 but substituting L-(3-furyl)glycine (obtained from D,L-(3-furyl)glycine by the method of Nishimura et al., supra) for the L-(2-furyl)-glycine in part (a), one obtains 7~-[[[(aminocarbonyl)amino]-l()~b~517 ~,~.19 2b tL-3-furyl)acetyl~amino]-3-[[(1-methyl-lH-tetrazol-5-yl)thio)-methyl]-8-oxo-S-thia-l-azabicyclo[4.2.01oct-2-ene-2-carboxylic acid and its sodium and potassium salts.
Examples 6-55 Following the procedure of example 1 but employing the substituted 7-aminocephalosporanic acid derivatives shown in Col. A the products shown in Col. B are obtained.
Col. A Col. B
~ 0 H2N I ~ ~ ~CH-I-NH ~ ~S~
N ~ -CH2-S-R4 pH ~ N ~ CH2 S R4 Ex. R3 R4 Nl I--~
H ~N,N
7 H ~ - N
N - N
: 8 H ~ IN
. .
~ .
i517 Ex. R3 R4 N N
g H
N' -CH{O~ N N
11 t--C4Hg N~ N
N
C~33 N---N
12 -CH2~) _1~ ~N
Cl C~3 13 --CH2~) ~ N__ N
14 -CH2 ~--C1~3 --1I N
R N_N
` ~ :; 15 -CH2-0-C-CH3 ~
I
16 -CH2-0-~-CH2~ 1~ ,N
N
,~ 1' .
~ ~ 17 H
~, :
1~ 517 G-; l ')2b Ex. R3 R4 18 H ~ _~
J_ C2H5 N ---N
19 - CH ~ ---I``S Jl_ C3 7 [~J
-CH2~OCH3 N---N
21 -C112-0-C-C2115 r~
2 2 -CH2-O-C~ C113 S
.
N - -N
23 1~
~ O
~ ~` -CH - Ccj~ C113 O
lO~ ;1 92 Ex. R3 R4 H N---N
Il .!L C1l3 26 H N. _.N
27 _CH2_o_C~r ~ C113 l OCH3 23 -CH -O-C--CH2~ L-CH3 29 -CH~3 S
3 0 -CH ~ I~ S~ N
-: N -~CH3 ~: 31 H --~ S,N
l( ~W51~ G(; 1 '32 b Ex. R3 R4 32 -CH2-0-C-CH3 5 C2il5 3 3 -CH ~ N--N
S
---`..,S,,N
t-C4Hg ~ ,N
, ~
~1 C~
36 H il11 3 S N
37 H H3C~ H
38 H H ~C3H7 (;~ 2b Ex. R3 R4 3 9 -CH ~> H l~ H
H i{~ C 3
-: N -~CH3 ~: 31 H --~ S,N
l( ~W51~ G(; 1 '32 b Ex. R3 R4 32 -CH2-0-C-CH3 5 C2il5 3 3 -CH ~ N--N
S
---`..,S,,N
t-C4Hg ~ ,N
, ~
~1 C~
36 H il11 3 S N
37 H H3C~ H
38 H H ~C3H7 (;~ 2b Ex. R3 R4 3 9 -CH ~> H l~ H
H i{~ C 3
4 1 ~
4 2 H 5,C 2 ~ H
' 43 -CH~
--~ 3 O
;: 45 Si (C~3 ) 3 (;(; 1 `~;2 ~, Ex. R
46 Sn (CH3)3 N tl C"3 47 Si (C2H5) 3 ~S J - CH3 48 ( 2 5) 3 N N
N
(:113 N N
4 9 Ca/2 ~
N' N ~
C~13 Mg/2 11 N
1.
S
51 Na N ---N
~ !I CH
52 Na ~ Ir IN' _;~4_~
(;~;1 92b Ex. R3 R4 53 Al/3
4 2 H 5,C 2 ~ H
' 43 -CH~
--~ 3 O
;: 45 Si (C~3 ) 3 (;(; 1 `~;2 ~, Ex. R
46 Sn (CH3)3 N tl C"3 47 Si (C2H5) 3 ~S J - CH3 48 ( 2 5) 3 N N
N
(:113 N N
4 9 Ca/2 ~
N' N ~
C~13 Mg/2 11 N
1.
S
51 Na N ---N
~ !I CH
52 Na ~ Ir IN' _;~4_~
(;~;1 92b Ex. R3 R4 53 Al/3
5 4 [ CH 3 NH 3 ~ ~N~X
55 [ (C6H5CH2) 2NH21 ~ J
Similarly, by employing the 7-aminocephalosporanic acid of Col. A within the procedures of examples 2 to 5, other com-pounds within the scope of the invention are obtained.
i'i -.
i:l !~
,~
:
:1`~', . ~, .
'~'
55 [ (C6H5CH2) 2NH21 ~ J
Similarly, by employing the 7-aminocephalosporanic acid of Col. A within the procedures of examples 2 to 5, other com-pounds within the scope of the invention are obtained.
i'i -.
i:l !~
,~
:
:1`~', . ~, .
'~'
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing an L-isomer compound of the formula wherein R1 is phenyl, thienyl or furyl; R3 is selected from the group consisting of hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)-stannyl, a salt forming ion, substituted phenyl-lower alkyl and the group -CH2-O-?-R wherein R is selected from the group consisting of lower alkyl, phenyl, phenyl-lower alkyl and substituted phenyl and phenyl-lower alkyl and wherein said phenyl substituent is selected from the group consisting of halogen, lower alkyl and lower alkoxy; and R4 is selected from the group consisting of , , , , , , and wherein R5 is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbons, characterized by reacting a compound of the formula with an alkali or alkaline earth metal cyanate.
2. The process of claim 1 wherein R1 is 2-thienyl or 3-thienyl and R3 is hydrogen, sodium or potassium.
3. The process of claim 1 wherein 7.beta.-[(.alpha.-amino-L-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)aminol(L-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.
4. The process of claim 1 wherein 7.beta.-[[.alpha.-amino-L-3-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](L-3-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.
tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid.
5. The process of claim 1 wherein R1 is 2-furyl or 3-furyl and R3 is hydrogen, sodium or potassium.
6. The process of claim 1 wherein 7.beta.-[[.alpha.-amino-L-2-furyl)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](L-2-furyl)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.
7. The process of claim 1 wherein 7.beta.-[[.alpha.-amino-L-3-furyl)-acetyl]amino]-3-1[(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.-[[[(aminocarbonyl)-amino](L-3-furyl)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. The process of claim 1 wherein R1 is phenyl and R3 is hydrogen, sodium or potassium.
9. The process of claim 1 wherein R4 is , or
10. The process of claim 1 wherein 7.beta.-[[.alpha.-amino-L-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 is reacted with potassium cyanate to form 7.beta.[[[(aminocarbonyl)-amino](L-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.
11. A compound of the formula wherein R1 is phenyl, thienyl or furyl; R3 is selected from the group consisting of hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, tri(lower alkyl)-stannyl, a salt forming ion, substituted phenyl-lower alkyl and the group wherein R is selected from the group consisting of lower alkyl, phenyl, phenyl-lower alkyl and substituted phenyl and phenyl-lower alkyl and wherein said phenyl substituent is selected from the group consisting of halogen, lower alkyl and lower alkoxy; and R4 is selected from the group consisting of , , , , , , and wherein R5 is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbons, whenever prepared by the process of claim 1.
12. The compound of claim 11 wherein R1 is 2-thienyl or 3-thienyl and R3 is hydrogen, sodium or potassium, whenever prepared by the process of claim 2.
13. The compound of claim 11 wherein the product is 7.beta.-[[[(aminocarbonyl)amino](L-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, whenever prepared by the process of claim 3.
14. The compound of claim 11 wherein the product is 7.beta.-[[[(aminocarbonyl)amino](L-3-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, whenever prepared by the process of claim 4.
15. The compound of claim 11 wherein R1 is 2-furyl or 3-furyl and R3 is hydrogen, sodium or potassium, whenever prepared by the process of claim 5.
16. The compound of claim 11 wherein the product is 7.beta.-[[[(aminocarbonyl)amino](L-2-furyl)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, whenever prepared by the process of claim 6.
17. The compound of claim 11 wherein the product is 7.beta.-[[[(aminocarbonyl)amino](L-3-furyl)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, whenever prepared by the process of claim 7.
18. The compound of claim 11 wherein R1 is phenyl and R3 is hydrogen, sodium or potassium, whenever prepared by the process of claim 8.
19. The compound of claim 11 wherein R4 is , , or whenever prepared by the process of claim 9.
20. The compound of claim 11 wherein the product is 7.beta.-[[[(aminocarbonyl)amino](L-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, whenever prepared by the process of claim 10.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/664,795 US4088815A (en) | 1974-09-20 | 1976-03-08 | 3-Heterothio-7-ureido cephalosporins |
| US664,795 | 1976-03-08 | ||
| US664,796 | 1976-03-08 | ||
| US05/664,796 US4088816A (en) | 1974-09-20 | 1976-03-08 | 3-Heterothio substituted 7-(ureido-heteroacetyl) cephalosporins |
| US764,134 | 1977-02-02 | ||
| US05/764,134 US4127716A (en) | 1976-03-08 | 1977-02-02 | 3-heterothiomethyl ureido cephalosporins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088517A true CA1088517A (en) | 1980-10-28 |
Family
ID=27418117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA271,818A Expired CA1088517A (en) | 1976-03-08 | 1977-02-15 | 3-heterothiomethyl ureido cephalosporins |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS52108996A (en) |
| AT (1) | AT352876B (en) |
| AU (1) | AU2236777A (en) |
| CA (1) | CA1088517A (en) |
| CS (1) | CS191190B2 (en) |
| DD (1) | DD129793A5 (en) |
| DE (1) | DE2707812A1 (en) |
| DK (1) | DK97077A (en) |
| ES (1) | ES456591A1 (en) |
| FR (1) | FR2343745A2 (en) |
| GB (1) | GB1573786A (en) |
| NL (1) | NL7702405A (en) |
| NZ (1) | NZ183332A (en) |
| PL (1) | PL196501A1 (en) |
| PT (1) | PT66272B (en) |
| SE (1) | SE7702558L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2927534A1 (en) * | 1979-07-07 | 1981-01-08 | Bayer Ag | OPTICALLY PURE HETEROCYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
-
1977
- 1977-02-14 NZ NZ183332A patent/NZ183332A/en unknown
- 1977-02-15 CA CA271,818A patent/CA1088517A/en not_active Expired
- 1977-02-17 AU AU22367/77A patent/AU2236777A/en not_active Expired
- 1977-02-23 DE DE19772707812 patent/DE2707812A1/en not_active Ceased
- 1977-03-04 DK DK97077A patent/DK97077A/en not_active Application Discontinuation
- 1977-03-04 CS CS771474A patent/CS191190B2/en unknown
- 1977-03-07 NL NL7702405A patent/NL7702405A/en not_active Application Discontinuation
- 1977-03-07 ES ES456591A patent/ES456591A1/en not_active Expired
- 1977-03-07 GB GB9511/77A patent/GB1573786A/en not_active Expired
- 1977-03-07 PT PT66272A patent/PT66272B/en unknown
- 1977-03-07 SE SE7702558A patent/SE7702558L/en not_active Application Discontinuation
- 1977-03-08 FR FR7706808A patent/FR2343745A2/en active Pending
- 1977-03-08 DD DD7700197733A patent/DD129793A5/en unknown
- 1977-03-08 PL PL19650177A patent/PL196501A1/en unknown
- 1977-03-08 AT AT155177A patent/AT352876B/en not_active IP Right Cessation
- 1977-03-08 JP JP2583677A patent/JPS52108996A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52108996A (en) | 1977-09-12 |
| CS191190B2 (en) | 1979-06-29 |
| AU2236777A (en) | 1978-08-24 |
| ES456591A1 (en) | 1978-02-16 |
| DE2707812A1 (en) | 1977-09-15 |
| DK97077A (en) | 1977-09-09 |
| NL7702405A (en) | 1977-09-12 |
| ATA155177A (en) | 1979-03-15 |
| PL196501A1 (en) | 1978-02-13 |
| PT66272A (en) | 1977-03-31 |
| AT352876B (en) | 1979-10-10 |
| FR2343745A2 (en) | 1977-10-07 |
| SE7702558L (en) | 1977-09-09 |
| PT66272B (en) | 1978-08-08 |
| NZ183332A (en) | 1979-10-25 |
| DD129793A5 (en) | 1978-02-08 |
| GB1573786A (en) | 1980-08-28 |
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