CA1057739A - Pyridinylthiomethyl derivatives of cyanomethylthioacetyl cephalosporins - Google Patents
Pyridinylthiomethyl derivatives of cyanomethylthioacetyl cephalosporinsInfo
- Publication number
- CA1057739A CA1057739A CA229,637A CA229637A CA1057739A CA 1057739 A CA1057739 A CA 1057739A CA 229637 A CA229637 A CA 229637A CA 1057739 A CA1057739 A CA 1057739A
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- formula
- acid
- lower alkyl
- salt
- compound
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—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, cefaclor, or cephalexine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- 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
New pyridinylthiomethyl derivatives of cyano-methylthioacetylcephalosporins of the following general formula, and their salts wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion or the group -CH2-O-?-R4; R1, R] and R3 each is hydrogen or lower alkyl; and R4 is lower alkyl, phenyl or phenyl-lower alkyl;
are useful as antibacterial agents.
New pyridinylthiomethyl derivatives of cyano-methylthioacetylcephalosporins of the following general formula, and their salts wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion or the group -CH2-O-?-R4; R1, R] and R3 each is hydrogen or lower alkyl; and R4 is lower alkyl, phenyl or phenyl-lower alkyl;
are useful as antibacterial agents.
Description
l.os7739 This invention relates to new antibacterial pyridinylthiomethyl derivatives of cyanomethylthioacetyl-cephalosporins which have the formula (I) 11 / \
CH C NH . CHCH CH2 Rl-C-CN C N ~ 2 N
CH C NH . CHCH CH2 Rl-C-CN C N ~ 2 N
2 i O
COOR
R represents hydrogen, lower alkyl, phenyl-lower alkyl, tri(low&r alkyl)silyl, a salt forming ion or the group -CH2-O-C-R~; Rl, R2 and R3, which may be the same or different, each represents hydrogen or lower alkyl; and R4 represents lower alkyl, phenyl or phenyl-lower alkyl.
The preferred members within each group are as follows: R is hydrogen, or a salt forming ion, especially an alkali metal like sodium or potassium, or an amine salt, especially dicyclohexylamine; and Rl, R and R3 each is hydrogen.
_I' ~
105773~
The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having one to seven carbons in the chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.
The salt forming ions are 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, e.g., a cycloalkylamine like dicyclohexylamine or a lower alkylamine like methylamine, triethylamine, etc.
The products of formula I can be prepared by two alternate methods. According to one method, a compound of formula (II) ~ ~ CH
COOR
wherein R has the meaning above defined, but preferably is alkali metal or hydrogen, is made to react with a compound of the formula (III) Rl 3 NC C - S _ CH - C - X
wherein X is a halogen, preferably chlorine or bromine, ~o57739 especially the first, e.g., in the presence of an amine salt like triethylamine in an inert organic solvent like acetone, preferably at a reduced temperature, e.g., about 0 to 5 C. If R is hydrogen, the free acid is converted to the salt form by reaction with a compound having the desired salt ion in the appropriate solvent. Conversely, if R is a salt ion, the salt can be converted to the free acid by a conventional technique like neutralization.
An alternative, preferred method comprises reacting a compound of the formula (IV) Rl 3 NC--C -- S-- CH--C --NH~
I / ~ N - CH2-lower alkanoyloxy R O
wherein R has the meaning defined previously, but preferably is a salt forming ion, especially an alkali metal like potassium, the lower alkanoyloxy group is preferably acetoxy and the other symbols have the meanings previously defined, with 2-pyridinethiol,l-oxide or a salt thereof, preferably an alkali metal salt like the potassium or sodium salt.
This reaction is effected by bringing together the reactants in an aqueous solvent, preferably at a slightly alkaline pH
with heating.
The starting material of formula II is produced by reacting 7-aminocephalosporanic acid with 2-pyridinethiol l-oxide or salt thereof in the same manner as described above.
~.o5773~
The starting material of formula IV is produced as described in U.S. patent 3,855,212 issued December 17, 1974, e.g., by acylating a compound of the formula (V) H2N~
N ~ CH2-lower alkanoyloxy COOR
wherein R has the meaning defined above, with a reactive derivative of an acid of the formula (VI) S-CH COOH
Rl-C-CN
I
wherein Rl, R2 and R3 have the meaning defined above.
The reactive derivatives of the acids of formula VI
include, for example, acid halides, acid anhydrides, mixed anhydrides of the acid with carbonic acid monoesters, trimethylacetic acid or benzoic acid, acid azides, active esters like cyanomethyl ester, p-nitrophenyl ester or 2,4-dinitrophenyl ester, or active amides like acylamidazoles.
An acid of formula VI can also be reacted with a compound of formulas V or II in the presence of a carbodi-imide, for example, N,N-dicyclohexylcarbodiimide, an isoxazolium salt, for example, N-ethyl-5-phenylisoxazolium-3-sulfonate or 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ester.
105~3~ GG196 The acids of formula VI and their ester of formula IX below are new compounds which are produced from the corresponding derivatives of haloacetonitriles having the formula (VII) R
I
NC - C - X
I
wherein Rl and R2 have the meaning defined above and X is halogen, especially chlorine, by reaction with a thioacetic acid ester of the formula (VIII) wherein R3 has the meaning defined above and R6 is lower alkyl, especially methyl or ethyl, in the presence of an acid binding agent. The ester formed by this reaction has the formula (IX) 13 S CH COOR
I
Rl-C-CN
I
and this is converted at the conclusion of that reaction, to the free acid of formula V by conventional saponification.
Alternatively, acids of formula VI can be produced directly by reacting a haloacetonitrile of formula VII with a thioacetic acid of formula VIII wherein R6 is hydrogen instead of lower alkyl, in the presence of a base, e.g., an alkylamine like triethylamine.
An alternate process for the production of a compound of formula VI is by the reaction of a thioacetonitrile of the formula (X) IRl NC - C SH
with a haloacetic acid of the formula 10 (XI) IR3 X - CH COOH
wherein X is halogen, preferably chlorine, in the presence of an acid binding agent. . O
When R is the acyloxymethyl group -CH2-0-C-R4, this group.may be introduced onto the 7-aminocephalosporanic acid moiety either prior to or subsequent to the reaction with the acylating agent by treatment with one or two moles of a halomethyl ester of the formula (XII) wherein X is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like at about ambient temperature or below.
The products of this invention form salts which are also part of the invention. Basic salts form with the acid moiety when the symbol R is hydrogen as discussed above.
It will be appreciated that certain of the compounds of this invention exist in various states of solvation as well as in different isomeric or optically active forms. The lQ57739 various forms as well as their mixtures are within the scope of this invention.
Further process details are provided in examples.
The compounds of this invention have antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureuS, Salmonella schottmuelleri, Proteus vulgaris, Escherichia coli, Streptococcus pyogenes, Proteus rettgeri and Enterobacter hafniae. They may be used as antibacterial agents to combat infections due to organisms such as those named above, and in general can be utilized in a manner similar to cephradine and other cephalosporins. For example, a compound of the formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 50 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g.,
COOR
R represents hydrogen, lower alkyl, phenyl-lower alkyl, tri(low&r alkyl)silyl, a salt forming ion or the group -CH2-O-C-R~; Rl, R2 and R3, which may be the same or different, each represents hydrogen or lower alkyl; and R4 represents lower alkyl, phenyl or phenyl-lower alkyl.
The preferred members within each group are as follows: R is hydrogen, or a salt forming ion, especially an alkali metal like sodium or potassium, or an amine salt, especially dicyclohexylamine; and Rl, R and R3 each is hydrogen.
_I' ~
105773~
The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.
The lower alkyl groups are straight or branched chain hydrocarbon radicals having one to seven carbons in the chain, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.
The salt forming ions are 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, e.g., a cycloalkylamine like dicyclohexylamine or a lower alkylamine like methylamine, triethylamine, etc.
The products of formula I can be prepared by two alternate methods. According to one method, a compound of formula (II) ~ ~ CH
COOR
wherein R has the meaning above defined, but preferably is alkali metal or hydrogen, is made to react with a compound of the formula (III) Rl 3 NC C - S _ CH - C - X
wherein X is a halogen, preferably chlorine or bromine, ~o57739 especially the first, e.g., in the presence of an amine salt like triethylamine in an inert organic solvent like acetone, preferably at a reduced temperature, e.g., about 0 to 5 C. If R is hydrogen, the free acid is converted to the salt form by reaction with a compound having the desired salt ion in the appropriate solvent. Conversely, if R is a salt ion, the salt can be converted to the free acid by a conventional technique like neutralization.
An alternative, preferred method comprises reacting a compound of the formula (IV) Rl 3 NC--C -- S-- CH--C --NH~
I / ~ N - CH2-lower alkanoyloxy R O
wherein R has the meaning defined previously, but preferably is a salt forming ion, especially an alkali metal like potassium, the lower alkanoyloxy group is preferably acetoxy and the other symbols have the meanings previously defined, with 2-pyridinethiol,l-oxide or a salt thereof, preferably an alkali metal salt like the potassium or sodium salt.
This reaction is effected by bringing together the reactants in an aqueous solvent, preferably at a slightly alkaline pH
with heating.
The starting material of formula II is produced by reacting 7-aminocephalosporanic acid with 2-pyridinethiol l-oxide or salt thereof in the same manner as described above.
~.o5773~
The starting material of formula IV is produced as described in U.S. patent 3,855,212 issued December 17, 1974, e.g., by acylating a compound of the formula (V) H2N~
N ~ CH2-lower alkanoyloxy COOR
wherein R has the meaning defined above, with a reactive derivative of an acid of the formula (VI) S-CH COOH
Rl-C-CN
I
wherein Rl, R2 and R3 have the meaning defined above.
The reactive derivatives of the acids of formula VI
include, for example, acid halides, acid anhydrides, mixed anhydrides of the acid with carbonic acid monoesters, trimethylacetic acid or benzoic acid, acid azides, active esters like cyanomethyl ester, p-nitrophenyl ester or 2,4-dinitrophenyl ester, or active amides like acylamidazoles.
An acid of formula VI can also be reacted with a compound of formulas V or II in the presence of a carbodi-imide, for example, N,N-dicyclohexylcarbodiimide, an isoxazolium salt, for example, N-ethyl-5-phenylisoxazolium-3-sulfonate or 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ester.
105~3~ GG196 The acids of formula VI and their ester of formula IX below are new compounds which are produced from the corresponding derivatives of haloacetonitriles having the formula (VII) R
I
NC - C - X
I
wherein Rl and R2 have the meaning defined above and X is halogen, especially chlorine, by reaction with a thioacetic acid ester of the formula (VIII) wherein R3 has the meaning defined above and R6 is lower alkyl, especially methyl or ethyl, in the presence of an acid binding agent. The ester formed by this reaction has the formula (IX) 13 S CH COOR
I
Rl-C-CN
I
and this is converted at the conclusion of that reaction, to the free acid of formula V by conventional saponification.
Alternatively, acids of formula VI can be produced directly by reacting a haloacetonitrile of formula VII with a thioacetic acid of formula VIII wherein R6 is hydrogen instead of lower alkyl, in the presence of a base, e.g., an alkylamine like triethylamine.
An alternate process for the production of a compound of formula VI is by the reaction of a thioacetonitrile of the formula (X) IRl NC - C SH
with a haloacetic acid of the formula 10 (XI) IR3 X - CH COOH
wherein X is halogen, preferably chlorine, in the presence of an acid binding agent. . O
When R is the acyloxymethyl group -CH2-0-C-R4, this group.may be introduced onto the 7-aminocephalosporanic acid moiety either prior to or subsequent to the reaction with the acylating agent by treatment with one or two moles of a halomethyl ester of the formula (XII) wherein X is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like at about ambient temperature or below.
The products of this invention form salts which are also part of the invention. Basic salts form with the acid moiety when the symbol R is hydrogen as discussed above.
It will be appreciated that certain of the compounds of this invention exist in various states of solvation as well as in different isomeric or optically active forms. The lQ57739 various forms as well as their mixtures are within the scope of this invention.
Further process details are provided in examples.
The compounds of this invention have antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureuS, Salmonella schottmuelleri, Proteus vulgaris, Escherichia coli, Streptococcus pyogenes, Proteus rettgeri and Enterobacter hafniae. They may be used as antibacterial agents to combat infections due to organisms such as those named above, and in general can be utilized in a manner similar to cephradine and other cephalosporins. For example, a compound of the formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 50 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g.,
3.0 mg./kg. in mice.
Up to about 600 mg of a compound of formula I
or a physiologically acceptable salt thereof is 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.
The following examples are illustrative of the invention. All temperatures are on the centigrade scale.
Additional variations may be produced in the same manner by appropriate substitution in the starting material.
Example 1 31.8 g. ~0.3 mol.) of thioacetic acid methyl ester are added to 150 ml. (0.03 mol.) of 2N sodium methylate solution.
22.6 g. (0.3 mol.) of chloroacetonitrile dissolved in 30 ml.
of methanol are added dropwise while cooling and stirring.
It is stirred overnight then refluxed for 30 minutes. The reaction mixture is cooled and the solvent is evaporated.
100 ml. of water are added to the residue and the aqueous solution is extracted twice with ether. The combined ether extracts are decolorized with activated carbon and dried with magnesium sulfate. The ether is distilled off and the residue is distilled under vacuum. 30.5 g. of 2-[(cyanomethyl)thio]acetic acid methyl ester are obtained b.P.lo 132-134.
Example 2 14.5 g. (0.1 mol.) of 2-~(cyanomethyl)thio]acetic acid methyl ester are dissolved in ethanol and a solution of 6.7 g. (0.12 mol.) of potassium hydroxide in 40 ml. of ethanol is added dropwise while cooling. This is stirred
Up to about 600 mg of a compound of formula I
or a physiologically acceptable salt thereof is 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.
The following examples are illustrative of the invention. All temperatures are on the centigrade scale.
Additional variations may be produced in the same manner by appropriate substitution in the starting material.
Example 1 31.8 g. ~0.3 mol.) of thioacetic acid methyl ester are added to 150 ml. (0.03 mol.) of 2N sodium methylate solution.
22.6 g. (0.3 mol.) of chloroacetonitrile dissolved in 30 ml.
of methanol are added dropwise while cooling and stirring.
It is stirred overnight then refluxed for 30 minutes. The reaction mixture is cooled and the solvent is evaporated.
100 ml. of water are added to the residue and the aqueous solution is extracted twice with ether. The combined ether extracts are decolorized with activated carbon and dried with magnesium sulfate. The ether is distilled off and the residue is distilled under vacuum. 30.5 g. of 2-[(cyanomethyl)thio]acetic acid methyl ester are obtained b.P.lo 132-134.
Example 2 14.5 g. (0.1 mol.) of 2-~(cyanomethyl)thio]acetic acid methyl ester are dissolved in ethanol and a solution of 6.7 g. (0.12 mol.) of potassium hydroxide in 40 ml. of ethanol is added dropwise while cooling. This is stirred
4 hours at room temperature and 1 hour at 0. The resulting precipitate is filtered under suction, washed with ethanol and ether and dried. 15.4 g. of 2-[(cyanomethyl)thio]acetic acid, potassium salt, m.p. 203-205 (dec.) are obtained. The free acid is obtained by dissolving the potassium salt in water and treating with an equivalent amount of aqueous sulfuric acid. The ether solution is dried and concentrated to obtain the free acid.
Example 3 30 g. of 2-[(cyanomethyl)thio]acetic acid potassium salt are suspended in benzene, 5 drops of pyridine are added and the mixture is cooled to 10. At this temperature 76.7 g.
of oxalyl chloride in 150 ml. of benzene are slowly dropped in with stirring. After the vigorous evolution of gas has stopped, the reaction mixture is stirred for 1 hour at room temperature. This is then filtered and the filtrate is concentrated at room temperature. The residue is distilled under vacuum to obtain 19.8 g. of 2-1(cyanomethyl)thio]acetyl chloride~ b P O.lmm Example 4 2.72 g. (0.01 mol.) of 7-amipocephalosporanic acid are suspended in 50 ml. of water at room temperature.
1.4 ml. of triethylamine are added and this is stirred until a clear solution is obtained. 50 ml. of acetone are added and the solution if cooled to 0-5. Simultaneously a solution of 1.65 g. (0.01 mol.) of 2-[(cyanomethyl)thio]acetyl chloride in 15 ml. of acetone and a solution of 1.4 ml. of triethyl-amine in 15 ml. of acetone are added dropwise while stirring with care that the pH stays in the range 7.5 - 8. This is stirred for an additional 30 minutes at 5. Then 50 ml. of ethyl acetate are added, cooled to 0 and acidified with 2N
hydrochloric acid to pH 1.5. The mixture is filtered, the layers are separated, the organic phase is washed three times with water, dried with magnesium sulfate and the solvent is evaporated in a rotary evaporator to obtain 3-[(acetyloxy)-methyl]-7B-[[[(cyanomethyl)thio]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The crude product is dissolved in methanol, filtered and 5 ml. of a 2N solution of potassium ethylhexanoate in n-butanol are added.
This solution is poured into 300 ml. of ether. The precipi-tate is filtered under suction and washed with ether to obtain the potassium salt, m.p. 168-170.
105~3~ GG196 Example 5 4.23 g. (0.01 mol.). of 3-[(acetyloxy)methyl]-7~-[[[(cyanomethyl)thio]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxyIic acid, potassium salt are dissolved in 50 ml. of water and 1.49 g. of 2-pyridinethiol l-oxide, sodium salt are added. The clear solu,tion is heated for 6 hours at 60. The solution is diluted with 150 ml. of water, layered over with 300 ml. of ethyl acetate and the sodium salt solution is acidified to pH5 with 2N hydro-chloric acid with cooling. A precipitate forms which isfiltered under suction to obtain 2 g. of 7B-[[[(cyanomethyl)thio]-acetyl]amino]-8-oxo-3-[(2-pyridinylthio)methyl]-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid N-oxide. The layers are separated, the ethyl acetate layer is dried with magnesium sulfate, concentrated to small volume and let stand in the refrigerator overnight. An additional 0.3 g. of the product are thus obtained, m.p. 136-138 (dec.).
The following additional products are obtained according to the procedure of Example 5. By substituting ~ for the3-[(acetyloxy)methyl]-7-[[[(cyanomethyl)thio]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt, the analogous substance having the appropriate Rl, R2 or R3 substituent, the end product having the same substituent or substituents is obtained.
lOS7739 .
<~ ~ ~ o u~
N U 31~ Ul C ) = O
\~C / ' .
O--Z
I -U\\o . .
Z
I~ U~
co~ ~ ~
~ ~ I ~
O ~U~
o_O o =o Ul ~ ~
~: ~
o e~ _~
lOS7739 ~ ~ ~ m ~,, ~ r . N
~ I ~
~; O ~gO=U
~ ~
~ U~
:~
t~ ~ U
~.~, .
2 0 ~-1 :~ ~ $"' ~:
:I: u~D
o 3 ~ o=O
~; ~ z 1~:
,~
~. o
Example 3 30 g. of 2-[(cyanomethyl)thio]acetic acid potassium salt are suspended in benzene, 5 drops of pyridine are added and the mixture is cooled to 10. At this temperature 76.7 g.
of oxalyl chloride in 150 ml. of benzene are slowly dropped in with stirring. After the vigorous evolution of gas has stopped, the reaction mixture is stirred for 1 hour at room temperature. This is then filtered and the filtrate is concentrated at room temperature. The residue is distilled under vacuum to obtain 19.8 g. of 2-1(cyanomethyl)thio]acetyl chloride~ b P O.lmm Example 4 2.72 g. (0.01 mol.) of 7-amipocephalosporanic acid are suspended in 50 ml. of water at room temperature.
1.4 ml. of triethylamine are added and this is stirred until a clear solution is obtained. 50 ml. of acetone are added and the solution if cooled to 0-5. Simultaneously a solution of 1.65 g. (0.01 mol.) of 2-[(cyanomethyl)thio]acetyl chloride in 15 ml. of acetone and a solution of 1.4 ml. of triethyl-amine in 15 ml. of acetone are added dropwise while stirring with care that the pH stays in the range 7.5 - 8. This is stirred for an additional 30 minutes at 5. Then 50 ml. of ethyl acetate are added, cooled to 0 and acidified with 2N
hydrochloric acid to pH 1.5. The mixture is filtered, the layers are separated, the organic phase is washed three times with water, dried with magnesium sulfate and the solvent is evaporated in a rotary evaporator to obtain 3-[(acetyloxy)-methyl]-7B-[[[(cyanomethyl)thio]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The crude product is dissolved in methanol, filtered and 5 ml. of a 2N solution of potassium ethylhexanoate in n-butanol are added.
This solution is poured into 300 ml. of ether. The precipi-tate is filtered under suction and washed with ether to obtain the potassium salt, m.p. 168-170.
105~3~ GG196 Example 5 4.23 g. (0.01 mol.). of 3-[(acetyloxy)methyl]-7~-[[[(cyanomethyl)thio]acetyl]amino]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxyIic acid, potassium salt are dissolved in 50 ml. of water and 1.49 g. of 2-pyridinethiol l-oxide, sodium salt are added. The clear solu,tion is heated for 6 hours at 60. The solution is diluted with 150 ml. of water, layered over with 300 ml. of ethyl acetate and the sodium salt solution is acidified to pH5 with 2N hydro-chloric acid with cooling. A precipitate forms which isfiltered under suction to obtain 2 g. of 7B-[[[(cyanomethyl)thio]-acetyl]amino]-8-oxo-3-[(2-pyridinylthio)methyl]-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid N-oxide. The layers are separated, the ethyl acetate layer is dried with magnesium sulfate, concentrated to small volume and let stand in the refrigerator overnight. An additional 0.3 g. of the product are thus obtained, m.p. 136-138 (dec.).
The following additional products are obtained according to the procedure of Example 5. By substituting ~ for the3-[(acetyloxy)methyl]-7-[[[(cyanomethyl)thio]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt, the analogous substance having the appropriate Rl, R2 or R3 substituent, the end product having the same substituent or substituents is obtained.
lOS7739 .
<~ ~ ~ o u~
N U 31~ Ul C ) = O
\~C / ' .
O--Z
I -U\\o . .
Z
I~ U~
co~ ~ ~
~ ~ I ~
O ~U~
o_O o =o Ul ~ ~
~: ~
o e~ _~
lOS7739 ~ ~ ~ m ~,, ~ r . N
~ I ~
~; O ~gO=U
~ ~
~ U~
:~
t~ ~ U
~.~, .
2 0 ~-1 :~ ~ $"' ~:
:I: u~D
o 3 ~ o=O
~; ~ z 1~:
,~
~. o
Claims (2)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R is hydrogen, an alkali metal or alkaline earth metal, characterized by acylating a compound of the formula (II) with a reactive derivative of an acid of the formula (IV) or by reacting a compound of the formula (IV) with a 2-pyridinethiol, 1-oxide or a salt thereof.
2. A compound of the formula wherein R is hydrogen, an alkali metal or an alkaline earth metal, whenever prepared by the process of claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49935474A | 1974-08-21 | 1974-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1057739A true CA1057739A (en) | 1979-07-03 |
Family
ID=23984947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA229,637A Expired CA1057739A (en) | 1974-08-21 | 1975-06-18 | Pyridinylthiomethyl derivatives of cyanomethylthioacetyl cephalosporins |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5143795A (en) |
| AU (1) | AU497282B2 (en) |
| BE (1) | BE832615A (en) |
| CA (1) | CA1057739A (en) |
| CH (1) | CH608240A5 (en) |
| DE (1) | DE2537280A1 (en) |
| FR (1) | FR2282274A1 (en) |
| GB (1) | GB1507925A (en) |
| NL (1) | NL7508109A (en) |
-
1975
- 1975-05-19 GB GB2125475A patent/GB1507925A/en not_active Expired
- 1975-06-16 AU AU82257/75A patent/AU497282B2/en not_active Expired
- 1975-06-18 CA CA229,637A patent/CA1057739A/en not_active Expired
- 1975-07-08 NL NL7508109A patent/NL7508109A/en not_active Application Discontinuation
- 1975-08-07 CH CH1032075A patent/CH608240A5/en not_active IP Right Cessation
- 1975-08-19 FR FR7525670A patent/FR2282274A1/en not_active Withdrawn
- 1975-08-21 DE DE19752537280 patent/DE2537280A1/en not_active Withdrawn
- 1975-08-21 BE BE159353A patent/BE832615A/en unknown
- 1975-08-21 JP JP10198075A patent/JPS5143795A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE2537280A1 (en) | 1976-03-04 |
| AU8225775A (en) | 1976-12-23 |
| NL7508109A (en) | 1976-02-24 |
| CH608240A5 (en) | 1978-12-29 |
| GB1507925A (en) | 1978-04-19 |
| JPS5143795A (en) | 1976-04-14 |
| AU497282B2 (en) | 1978-12-07 |
| FR2282274A1 (en) | 1976-03-19 |
| BE832615A (en) | 1975-12-16 |
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