GB2031413A - 3,7-Disubstituted-3-cephem-4- carboxylic Acid Compounds and Processes for the Preparation Thereof - Google Patents

3,7-Disubstituted-3-cephem-4- carboxylic Acid Compounds and Processes for the Preparation Thereof Download PDF

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GB2031413A
GB2031413A GB7930513A GB7930513A GB2031413A GB 2031413 A GB2031413 A GB 2031413A GB 7930513 A GB7930513 A GB 7930513A GB 7930513 A GB7930513 A GB 7930513A GB 2031413 A GB2031413 A GB 2031413A
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alkyl
compound
cephem
syn isomer
carboxy
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Fujisawa Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon 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, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom

Abstract

3,7-Disubstituted-3-cephem-4- carboxylic acid compounds of the formula: <IMAGE> wherein R<1> is amino or a protected amino, R<2> is a substituted aliphatic hydrocarbon group, R<3> is carboxy or protected carboxy, and R<4> is hydrogen, acyloxy or a heterocyclicthio group which may be substituted by C1-6 alkyl, with the proviso that R<2> is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R<4> is acetoxy and that R<2> is not benzyl when R<4> is tetrazolylthio having a methyl, and pharmaceutically acceptable salts thereof have antibacterial activity.

Description

SPECIFICATION 3,7-Disubstituted-3-cephem-4-carboxylic Acid Compounds and Processes for the Preparation Thereof The present invention relates to new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new 3,7-disubstituted-3cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof which have antibacterial activities and to processes for the preparation thereof, to pharmaceutical composition comprising the-same, and to a method of using the same therapeutically in the treatment of infectious diseases in human beings and animals.
Accordingly, it is one object of the present invention to provide 3,7-disubstituted-3-cephem-4- carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic bacteria.
Another object of the present invention is to provide processes for the preparation of 3,7 disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide pharmaceutical composition comprising as active ingredients, said 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.
Still further object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in human beings and animals.
The object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds are novel and can be represented by the following formula (I):
wherein R1 is amino or a protected amino, R2 is an aliphatic hydrocarbon group having suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is hydrogen, acyloxy or a heterocyclicthio group which may have lower alkyl, with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl.
The object compounds of the present invention (I) are novel compounds and can be prepared by the Process 1 to 4 as mentioned below.
Process 1
or its reactive deri- or its reactive derivative vative at the amino at the carboxy group or a group or a salt salt thereof thereof
or a salt thereof Process 2
Efimination of the amino protective group
or a sait there of
or a salt thereof Process 3
Elimination of the a carboxy protective group
or a salt thereof
or a salt thereof Process 4
(Ie) (XVIII) or a salt thereof or its reactive derivative at the mercapto group
or a salt thereof wherein R1, R2, R3 and R4 are each as defined above, Ra is a protected amino, R2a is a protected carboxy(lower)alkyl, R2b is a carboxy(lower)alkyl, X' is a group which can be substituted with a group of the formula: R4wS wherein R4' is a heterocyclic group which may have a lower alkyl, R4' is as defined above, R46 is hydrogen, carbamoyloxy or a heterocyclicthio group which may have lower alkyl, with proviso that R2 is not benzyl when R4' is tetrazolyl having a methyl.
Among the starting compounds, the compound III) is novel and can be prepared by the processes which are illustrated by the following scheme.
wherein R1, R1a and R2 are each as defined above, Z is a protected carboxy and Y is halogen.
Some of the other starting compound (II) is also novel and can be prepared by the processes as illustrated below.
or a salt thereoF
or a Salt thereof wherein R3 is as defined above, Y' is an acid residue, R5 is lower alkyl, R6 is a group which can be substituted with a group of the formula:
and X is an alkali metal.
Regarding the object compounds of the formulae (I), (Ib), (Id), and (If), and the starting compounds of the formulae (la), (Ic), (le), (III), (Illa), (Illa'), (Illb), (VII), (VIII) and (X)-(XlI), it is to be understood that said object and starting compounds include tautomeric isomers relating to their thiazole groups. That is, in case that the group represented by the formula:
(wherein R1 is as defined above) in the formula of said object and starting compounds take the formula:
(R1 is as defined above), said group of the formula:
can also be alternatively represented by its tautomeric formula:
(wherein Rlb is imino or a protected imino).That is, both of the said groups (A) and (B) are in the state of equilibrium as so-called tautomeric forms which can be represented by the following equilibrium:
(wherein R1 and Rib are each as defined above).
These types of tautomerism between 2-amino-thiazole compounds and 2-iminothiazoline compounds as stated above have been well known in the literature, and it is obvious to a person skilled in the art that both of the tautomeric isomers are equilibrated and easily convertible reciprocally, and accordingly it is to be understood that such isomers are included within the same category of the compound per Se. Accordingly, the both of the tautomeric forms of the object compounds and the starting compounds are clearly included within the scope of the present invention. In the present specification and examples, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula:
only for the convenient sake.
Furthermore, regarding the object compounds (I), (Ib), (Id) and (If), and the starting compounds (la), (Ic), (le), (lil), (illa), (Illa'), (Illb), (lV)- (VII) and (X)-(XIl) it is to be understood that said object and starting compounds include syn-isomer, anti-isomer and a mixture thereof. For example regarding the object compound (I), said syn-isomer can be represented by the partial structure of the formula:
in its molecule, while the corresponding anti-isomer is represented by the partial structure of the formula:
in its molecule, and in case that it is convenient for the explanation of this invention to express both of the syn-isomer and anti-isomer by one general formula, it is represented by the partial structure of the formula
Regarding the other object compounds and starting compounds as mentioned above, the syn isomer and the anti-isomer can also be referred to the same geometrical isomers as illustrated for the compound (I).
Suitable pharmaceutically acceptable salt of the object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), ammonium salt etc., an organic salt, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) etc., an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.) or a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), and the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intend to include within the scope thereof are explained in details as follows.
The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise provided.
Suitable protected amino may include an acyl-amino and amino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g., benzyl, trityl, etc.) or the like.
Suitable protected amino may include an acylimino and imino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g. benzyl, trityl, etc.) and the like.
Suitable acyl moiety in the terms "acylamino", "acylimino" and "acyloxy" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, hexanoyl, etc.), preferably one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s): lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyi, t-pentyloxycarbonyl, hexyloxy-carbonyl, etc.); lower alkanesulfonyl (e.g. mesyl), ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, napthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.); and the like.
The acyl moiety as stated above may have 1 to 3 suitable substituent(s) such as halogen (e.g.
chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g. vinyl, allyl, etc.), aryl (e.g. phenyl, tolyl, etc.) or the like.
Preferable example of acylamino may be lower alkanoylamino or mono-, di- or trihalo(lower)alkanoyl-amino and preferable example of acyloxy may be lower alkanoyloxy or carbamoyloxy.
Aliphatic hydrocarbon group is intended to mean straight, branched or cyclic aliphatic hydrocarbon having 1 to 6 carbon atom(s) and may include lower alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkynyl and the like. And said aliphatic hydrocarbon group has 1 to 2 suitable substituent(s) such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, a heterocyclic group or the like.
Suitable lower alkyl and lower alkyl moiety in the terms "lower alkylthio", "carboxy(l-ower)alkyl" and "protected carboxy(lower)alkyl" may include one which may be branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, wherein lower alkyl may preferably be one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).
Suitable cyclo(lower)alkyl is one having 3 to 6 carbon atoms and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Suitable lower alkenyl is one having 2 to 6 carbon atoms and may include, for example, vinyl, alyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like.
Suitable lower alkynyl is one having 2 to 6 carbon atoms and may include ethynyl, 2-propynyl, 2butynyl, 3-pentynyl, 3-hexynyl and the like.
Suitable protected carboxy and protected carboxy moiety in the term "protected carboxy(lower)alkyl" may include esterified carboxy in which said ester moiety may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.), wherein lower alkyl moiety may preferably be one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);; lower alkanoyloxy(lower)alkyl ester (e.g. acetoxy-methyl ester, propionyloxymethyl ester, butyryloxy-methyl ester, valeryloxymethyl ester, pivaloyloxy-methyl ester, hexanoyloxymethyl ester, 2acetoxy-ethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g. mesyl-methyl ester, 2-mesylethyl ester, etc); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy3,5-ditertiarybutylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) (e.g. phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.), and the like.
Preferable example of protected carboxy may be lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2 to 7 carbon atoms, preferably one having 2 to 5 carbon atoms.
Suitable aryl and aryl moiety, in the terms "arylthio" and "aryloxy" may include phenyl, tolyl, xylyl, mesityl, cumenyl, napthyl and the like, wherein said aryl group may have 1 to 3 suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine, or fluorine), hydroxy amino(lower)alkyl (e.g. aminomethyl, aminoethyl, aminopropyl, aminobutyl, etc.), protected amino(lower)alkyl wherein protected amino is as defined above, preferably lower alkoxycarbonylamino(lower)alkyl (e.g.
methoxycarbonylaminonjethyl, ethoxycarbonyl-aminomethyl, t-butoxycarbonylaminomethyl, etc.), or the like.
Suitable lower alkoxy may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).
Suitable heterocyclic group and heterocyclic moiety in the term "a heterocyclicthio group which may have lower alkyl" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl; pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl etc.), tetrazolyl (e.g. 1 H-tetrazolyl or2H-tetrazolyl), etc.; saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.;; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isqquinolyl, indazolyl, benzotriazolyl, tetrazolopyradazinyl, etc; unsaturated 3- to 8-membered (preferably 5 to 6 membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.
1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, etc.) etc.; saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiadiazolyl (e.g. 1,2,4 thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, etc.), etc.; saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; ; unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like; wherein said hetercyclic group may have 1 to 2 lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.) substituent(s).
Suitable halogen may include chlorine, bromine, fluorine and iodine.
Suitable acid residue may include aforesaid halogen, lower alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy, etc.), arenesulfonyloxy (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like.
Suitable group which can be substituted with a group of the formula:
may include azido, aforesaid halogen, acyloxy and the like.
Suitable alkali metal may include sodium, potassium and the like.
Suitable X' may include azido, aforesaid halogen, acyloxy and the like.
Among the suitable examples of each of the groups of the object compounds as explained and illustrated above, the preferred examples thereof are illustrated as follows: Preferable example of R' may be amino or acylamino (more preferably lower alkanoylamino or halo(lower)alkanoylamino); Preferable example of R2 may be lower alkylthio(lower)alkyl, lower alkoxy(lower)alkyl, ar(lower)alkyl [more preferably phenyl(lower)alkyl]which may have halogen, hydroxy, amino(lower)alkyl or acylamino(lower)alkyl, ar(lower)alkenyl[more preferably phenyl(lower)alkenyl]. acyloxy(lower)alkyl [more preferably lower alkanoyloxy(lower)alkyl], carboxy(lower)alkyl, protected carboxy(lower)alkyl [more preferably lower alkoxycarbonyl(lower)alkyl] or isoxazolyl(lower)alkyl; Preferable example of R3 may be carboxy; and preferable example of R4 may be hydrogen, acyloxy (more preferably carbamoyloxy or lower alkanoyloxy), tetrazolylthio which may have lower alkyl, thiadiazolylthio or tetrazolopyradazinylthio, with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl.
The processes for preparing the object compounds of the present invention are explained in details in the following.
Process 1: The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as acetoacetic acid or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as trimethyl-silylacetamide, bis(trimethylsilyl)acetamide or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene, and the like.
Suitable salt of the compounds (II) and (III) may include an acid addition salt such as an organic acid salt (e.g. acetate, maleate, tartrate, benzene-sulfonate, toluensulfonate, etc.) or an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metal salt (e.g. sodium salt, potassium salt, calcium salt, magnesium salt, etc.); ammonium salt; an organic amine salt (e.g.
triethylamine salt, dicyclohexylamine salt, etc.), and the like.
Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkyl-phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride, an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole;; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl + [(CH3)2-N=CH-j ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, tri chlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc), or an ester with a N-hydroxy compound (e.g. N,Ndimethylhydroxylamine, 1-hydroxy-2-(1 H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1hydroxy-6-chloro-1 H-benzotriazole, etc.), and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture thereof.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethyl-carbodiimide; N-cyclohexyl-N'-(4-diethylam inocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -alkoxy-1 -chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine;; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecu lar salt; 1 -(p-chlorobenzenesu lfonyloxy)-6-chloro- 1 H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,Ndi(tower)alkylbenzylamine, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.
In the present reaction, a syn isomer of the object compound (I) can be obtained preferably by conducting the present reaction of the compound (II) with the corresponding syn isomer of the starting compound (III), for example, in the presence of a Vilsmeier reagent as mentioned above etc. and under around neutral condition.
Process 2: The object compound (Ib) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to elimination reaction of the amino protective group.
Suitable salt of the compound (la) may include a metal salt, ammonium salt, an organic amine salt and the like as aforementioned.
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction; a method by reacting the compound (la) wherein the productive group is acyl group with iminohalogenating agent and then with iminoetherifying agent, and, if necessary, subjecting the resulting compound to hydrolysis; or the like.
The hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliminated.
Among these methods, hydrolysis using an acid is one of the common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl (e.g. tbutoxycarbonyl, t-pentyloxycarbonyl, etc.), a Ikanoyl (e.g., formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.), substituted phenylthio, substituted aralkylidine, substituted alkylidene, substituted cycloalkylidene, or the like.Suitable acid may include an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and preferable acid is an acid which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvent may include an organic solvent, water or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction may preferably be carried out in the presence of anisole.
The hydrolysis using hydrazine is commonly applied for eliminating the protective group, for example, succinyl or phthaloyl.
The hydrolysis with a base is preferably applied for eliminating acyl group, for example, haloalkanoyl (e.g. trifluoroacetyl, etc.) etc. Suitable base may include an inorganic base or an organic base. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof. Preferable base may be alkali metal acetate.
Among the protective groups, the acyl group can generally be eliminated by hydrolysis as mentioned above or by the other conventional hydrolysis. In case that the acyl group is halogen, substituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminated by treating with a heavy metal such as copper, zinc or the like.
The reduction elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxy-carbonyl, etc.) 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.) and the like.
Among the protective groups, the acyl group can be eliminated by treating with an iminohalogenating agent (e.g. phosphorus oxychloride, phosphorus pentachloride, etc.) and an iminoetherifying agent such as lower alkanol (e.g. methanol, ethanol, etc.) if necessary, followed by hydrolysis.
The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly elevated temperature.
The present invention includes, within its scope, the cases that the protected carboxy is transformed into the free carboxy group and protected amino(lower)alkyl being the substituent on ar(lower)alkyl for R2 is transformed into amino(lower)alkyl accorading to reaction conditions in the course of the reaction or in post-treatment.
Process 3: The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the carboxy protective group.
Suitable salt of the compound (Ic) can be referred to the ones exemplified for the compound (la).
The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis or the like. The hydrolysis may include a method using an acid or base and the like. These methods may be selected depending dn kind of the protective groups to be eliminated.
The hydrolysis using an acid is one of the most common and preferable methods for eliminating the protective groups such as phenyl(lower)alkyl, substituted phenyl(lower)alkyl, lower alkyl, substituted lower alkyl, or the like. Suitable acids may include inorganic or organic acid, for-example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. The present reaction may be carried out in the presence of anisole. The acid suitable for the reaction can be selected according to the protective group to be eliminated and other factors. The hydrolysis using an acid may be carried out in the presence of a solvent, such as an organic solvent, water or a mixed solvent thereof.
The reaction temperature is not critical and may suitably be selected in accordance with the kind of the protective group and the elimination method, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly warming.
The present invention includes, within its scope, the cases that the protected carboxy group for R3 is transformed into the free carboxy group; that the protected amino group is transformed into the free amino group during the reaction or post-treating in the present reaction.
Process 4 The object compound (If) or a salt thereof can be prepared by reacting the compound (le) or a salt thereof with the compound (XVIII) or its reactive derivative at the mercapto group.
Suitable salt of the compound (le) can be referred to the ones exemplified for the compound (or).
Suitable reactive derivative at the mercapto group of the compound (XVIII) may include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) or the like.
The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in around neutral medium. When the compound (le) or the compound (XVIII) is used in a free form, the reaction is preferably, conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine, and the like.The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under slightly heating.
The present reaction includes within its scope the case that protected amino for R' is transformed to free amino according to the kind of protective group and/or reaction conditions.
The reaction of the compound (VIII) with compound (IX) is usually carried out in a solvent such as water, alcohol, mixture thereof or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The processes for preparing the starting compound (ill) are explained in details as follows.
1. The compound (XIII) or its salt can be prepared by reacting hexylamine with carbon disulfide in the presence of a strong base.
Suitable strong base may include an inorganic base or an organic base, for example, alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium methoxide, etc.), alkali metal hydride (e.g. sodium hydride, etc.) or the like.
The present reaction is usually carried out in a solvent such as water or any other solvent which does not adversely affect the reaction, and usually carried out under cooling or at ambient temperature.
2. The compound (XV) can be prepared by reacting the compound (XIII) or its salt with the compound (XIV).
The present reaction is usually carried out in a solvent such as water or any other solvent which does not adversely affect the reaction, and usually carried out under cooling or at ambient temperature.
3. 1-Hexyl-1 H-tetrazole-5-thiol or a salt thereof can be prepared by reacting the compound (XV) with the compound (XVI).
The present reaction is usually carried out in a solvent such as an alcohol (e.g. methanol, ethanol, etc.), an aqueous alcohol or any other solvent which does not adversely affect the reaction, and preferably carried out under warming or heating.
4. The compound (ill) or a salt thereof can be prepared by reacting 1 -hexyl-1 H-tetrazole-5-thiol or a salt thereof with the compound (XVII) or a salt thereof.
Suitable salt of the compound (XVII) can be referred to the ones exemplified for the compound (la).
The suitable salt of 1-hexyl-1 H-tetrazole-5-thiol may include a metal salt such as alkali metal salts (e.g. sodium salt, potassium salt, etc.) or the like.
The present reaction may be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, buffer solution or any other solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in weakly basic or around neutral condition. When the compound (XVII) and/or 1 -hexyl-1 H-tetrazole-5-thiol is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine, pyridine, and the like.The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming. The reaction product can be isolated from the reaction mixture by conventional methods.
In the aforementioned reactions and/or the post-treating of the reactions of the present invention, the aforementioned tautomeric isomers may occasionally be transformed into the other tautomeric isomers and such case is also included in the scope of the present invention.
In case that the object compound (I) is obtained in a form of the free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable salt as aforementioned by a conventional method.
The object compound (I) and pharmaceutically acceptable salt thereof of the present invention are all novel compounds which exhibit high antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as anti-bacterial agents.
Now, in order to show the utility of the object compound (I), with regard to some representative compounds of this invention, there are shown the test data on the in vitro anti-bacterial activity in the following.
Test Compounds ( 1 ) 7-[2-Methylthiomethoxyimino-2-(2-amino-thiazol-4-yl)acetamido}-3-( 1 ,3,4-thiadiazol-2-yl)- thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2) 7-[2-Benzyloxyimino-2(2-aminothiazol-4-yl)acetamido]-3-( 1 ,3,4-thiadiazol-2-yI)thio-methyl- 3-cephem-4-carboxylic acid (syn isomer) (3) 7-[2-(4-Aminomethylbenzyloxyimino)-2-(2-aminothiazol-4-yI)aceta mido]-3-( 1 ,3,4-thiadiazol 2-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer) In Vitro Antibacterial Activity: Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described beiow.
One loopful of an overnight culture of each test strain in Trypticase-soy broth (10B viabie cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentration of test compounds, and the minimal inhibitory concentration (MIC) was expressed in terms of Mg/ml after incubation at 370C for 20 hours.
Test Results
MIC (bg/ml) TestBacteria TestCompounds (1) (2) ' (3) Staph.aureus 6 1.56 0.78 0.78 Staph.aureus 32 1.56 0.78 1.56 For therapeutic administration, the object compound (I) or pharmaceutically acceptable salts thereof of the present invention is used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.The pharmaceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid form for injection such as solution, suspension, or emulsion. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.
While the dosage of the compounds may vary from and also depend upon the age, conditions of the patient. a kind of disease, a kind of the compound (I) to be applied, etc., an average single dose of about 10 mg, 50 mg., 100 mg., 250 mg, 500 mg and 1,000 mg. of the object compound (I) of the present invention has proved to be effective in treating diseases infected by pathogenic bacteria.
In general, daily dose between 1 mg/body and about 6,000 mg/body or even more may be administered to a patient.
The following preparations and examples are given for the purpose of illustrating the present invention: Preparation 1 (1) Water (500 ml) was added to hexylamine (490.0 g) and a solution of sodium hydroxide (193.6 g) in water (700 ml) was added thereto under ice-cooling and stirring. Carbon disulfide (367.8 g) was added dropwise thereto over 2 hours at 2 to 1 O0C and then methyl iodide (687.3 g) was added dropwise thereto over 1 hour at O to 50C. The resulting mixture was stirred for 30 minutes at the same temperature and for 2 hours at ambient temperature.The reaction mixture was extracted with diethyl ether (1.5 I). The extract was washed with a saturated aqueous solution of sodium chloride (300 ml), dried over magnesium sulfate and concentrated to give an oil of methyl Nhexyldithiocarbamate (825.5 g).
I.R. (Film): 3225, 2960, 2935, 2860 cam~' N.M.R. (CDCl3, ops): 0.86 (3H, t, J=5.0 Hz), 1.1 01 .90 (8H, m) 2.58 (3H, s), 3.72 (2H, m) (2) Sodium azide (155.9 g) and water (0.8 t) were added under stirring to a solution of methyl Nhexyldithiocarbamate (430 g) in ethanol (1.7 I) and the resulting mixture was refluxed for 3.5 hours at 900C. Ethanol was distilled off from the reaction mixture and the residue was washed with diethyl ether (1 I), adjusted to pH 2.0 with conc. hydrochloric acid and extracted with diethyl ether (1 I). The extract was washed with water, dried over magnesium sulfate and concentrated to give an oil of 1 hexyl-1H-tetrazole-5-thiol (431.3 g).
I.R. (Film: 3110,2960,2930,2860 cm-l N.M.R. (CDCI3, ): 0.91 (3H, t, J=5.0 Hz), 1.10-1.65 (6H, m), 1.97 (2H, m), 4.33 (2H, t, J=7.0 Hz) (3) To 7-aminocephalosporanic acid (150.0 g) was added 0.2 M phosphate buffer solution (3 i), which was prepared by dissolving sodium bisphosphate dihydrate (62.1 g) and disodium hydrogen phosphate (25.5 g) in water (3 1), and the resulting mixture was adjusted to pH 6.5 with 2N aqueous solution of sodium carbonate. To the mixture was added 1 -hexyl-1 H-tetrazole-5-thiol (154.6 g) and the resulting mixture was stirred for 2 hours at 60 to 650C and at pH 6.0 to 6.5 with bubbling of nitrogen gas.The reaction mixture was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling.
Precipitates were collected by filtration and washed with water, and methanol (4 1) and conc.
hydrochloric acid (400 ml) were added thereto. The mixture was stirred for 2 hours and an insoluble material was filtered off. The filtrate was treated with an activated charcoal and adjusted to pH 3.5 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, in turn washed with water, acetone and diethyl ether and dried to give powder of 7-amino-3-(1 -hexyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (116.38 g).
I.R. (Nujol): 1803, 1620, 1350 cam~' N.M.R. (d6-DMSO 8): 0.95 (3H, t, J=6.5 Hz), 1.26 (6H, m), 1.80 (2H, m), 3.65 (2H, ABq, J=1 8 Hz), 4.00-4.50 (4H, m),- 4.79 (1 H, d, J=6.0 Hz), 4.95 (1 H, d, J=6.0 Hz) Preparation 2 (1) Sodium bicarbonate (0.84 g) was added to a suspension of 2-(2-formamidothiazol-4yl)glyoxylic acid (2 g) in water (120 ml) to prepare a solution. Ethyl 2-aminooxyacetate hydrochloride (4.56 g) was added to the solution and stirred at ambient temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times.The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-ethoxy-carbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.44 g), mp. 112 0C (dec.).
I.R.(Nujol): 3150, 1'740, 1670, 1550 cm-l N.M.R. (DMSO-d6, our): 1.23 (3H, t, J=7 Hz), 4.16 (2H, q, J=7 Hz), 4.77 (2H, s), 7.56 (1 H, s), 8.54 (1H,s) (2) A mixture of 2-ethoxycarbonylmethoxyimino-2-(2-forma midothiazol-4-yI)acetic acid (syn isomer) (7.2 g), conc. hydrochloric acid (10 ml), ethanol (70 ml) and tetrahydrofuran (20 ml) was stirred for 2 hours at ambient temperature. After removing the solvent from the reaction mixture in vacuo, water was added thereto and the mixture was adjusted to pH 3.3 with an aqueous solution of sodium bicarbonate under ice-cooling.Precipitates were collected by filtration and dried to give 2ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) 4.6 g).
I.R. (Nujol): 3170, 1 720, 1 660, 1620 cm-' N.M.R. (d8-DMSO, b): 1.27 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 4.77 2H, s), 6.96 (1 H, s) Preparation 3 Sodium bicarbonate (4.2 g) was added to a suspension of 2-(2-formamidothiazol-4-yl)glyoxylic acid (10 g) in water (500 ml) to prepare a solution. t-Butyl 2-aminooxyacetate hydrochloride (8.1 g) was added to the solution and stirred at ambient temperature for 3 hours while adjusting to pH 6 with sodium bicarbonate. The resultant solution was adjusted to pH 1.5 with hydrochloric acid, salted out and extracted with ethyl acetate three times.The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 2-t-butoxy-carbonylmethoxyimino-2-(2-formamidothiazol-4-yI)- acetic acid (syn isomer) (11.3 g), mp. 11 70C (dec).
I.R. (Nujol): 3180, 3140, 1750, 1690, 1630 cm-l N.M.R. (DMSO-d6, S): 1.46 (9H, s), 4.66 (2H, s) 7.56 (1 H, d, 8.56 (1 H, s), 12.67 (1 H, broad s) Preparation 4 (1) 2-Bromoethyl benzoate (27.5 g) was added dropwise to a stirred mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (15.7 g), potassium carbonate (20.7 g) and N,N-dimethylformamide (25 ml) under ice cooling over 10 minutes, and stirred at ambient temperature for 4 hours. The resultant mixture was filtered and washed with acetone. The filtrate and washings were combined and concentrated in vacuo. After adding water (100 ml) to the residue, the solution was extracted with methylene chloride three times.The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g).
(2) A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer) (28 g), sulfuryl chloride (13.5 g) and acetic acid (30 ml) was stirred at 400C for 10 minutes and at room temperature for 5.5 hours. After adding water (200 ml) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro3-oxobutyrate (syn isomer) (29 g).
(3) A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer) (29 g), thiourea (7.76 g), sodium acetate (8.37 g), water (75 ml) and ethanol (75 ml) was stirred at 400C for an hour. The resultant solution was concentrated in vacuo and the residue was extracted twice with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. After adding diethyl ether (200 ml) to the oily residue, the soluble substance was separated by decantation and the solution was concentrated in vacuo. The residue was crystallized with diisopropyl ether and the precipitates were collected by filtration to give ethyl 2-(2-benzoyloxyethoxyimino)-2-(2-am inothiazol-4-yl)acetate(syn isomer) (9 g).
N.M.R. (DMSO-d6, S): 1.28 (3H, t, J=7 Hz), 4.34 (2H, q, J=7 Hz), 4.56 (4H, m), 6.44 (2H, broad s), 6.68 (1 H, s), 7.68-7.34 (3H, m), 8.06 (2H, d,d, J=8 Hz, 2Hz) (4) A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-2- (2-aminothiazol-4-yl)acetate (syn isomer) (8.5 g), 1 N aqueous sodium hydroxide (35 ml), methanol (40 ml) and tetrahydrofuran (40 ml) was stirred at 35 to 400C for 9 hours and at ambient temperature for 12 hours. After adjusting the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial.The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-hydroxyethoxyimino)-2-(2-amino-thiazol-4yl)acetic acid (syn isomer) (3.3 g).
I.R. (Nujol): 3350, 3075, 1680, 1620 cm-l N.M.R. (DMSO-d6, S): 3.64 (2H, t, J=5 Hz), 4.10 (2H, t, J=5 Hz), 6.84 (1 H, s), 7.16(2H, m).
(5) A solution of formic acid (1.6 g) and acetic anhydride (3.6 g) was stirred at 500C for an hour.
After cooling,2-(2-hydroxyethoxyimino)-2-(2-aminothiazol-4-yi)acetic acid (syn isomer) (1 g) was added to the solution and stirred at ambient temperature for 3 hours. Diisopropyl ether was added to the resultant solution, and the precipitates were filtered off. The filtrate was concentrated in vacuo, and the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration to give 2-(2-formyloxyethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (0.7 g).
I.R. (Nujol): 3200, 1710, 1690 cm- N.M.R. (DMSO-d6, S): 4.38 (4H, s), 7.58 (1 H, s), 8.26 (1 H, s), 8.54 (1 H,s) Preparation 5 (1) Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)-acetate (syn isomer) (126.4 g), formic acid (81.3 g) and acetic anhydride (1 80 g) were treated in a similar manner to that of Preparation 4-(5) to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)-acetate (syn isomer) (109.6 g).
I.R. (Nujol): 3320, 3140, 3050, 1710, 1555 cm- N.M.R. (d6-DMSO, S): 1.30 (3H, t, J=7 Hz), 4.33 (2H, q, J=7 Hz), 7.54 (1 H, s), 8.54 (1 H, s), 11.98 (1H, s), 12.58 (1H, s) (2) A mixture of chloromethylthiomethane (7.97 g), powdered potassium iodide (15.1 g) and acetone (79 ml) was stirred at ambient temperature for an hour, the resulting mixture was filtered and washed with a small amount of acetone. The washings and the filtrate were combined and added to a stirred suspension of ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (17.5 g) and powdered potassium carbonate (15.5 g) in acetone (300 ml).The mixture was stirred at ambient temperature for 3 hours, filtered and washed with acetone. The washings and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform to give ethyl 2-methylthiomethoxyimino-2-(2-forma midothiazol-4-yl)acetate (syn isomer) (2.4g),mp. 130to 1310C.
I.R. (Nujol): 3160, 3125, 3050, 1740, 1695 cm- N.M.R. (d6-DMSO, S): 1.32 (3H, t, J=7 Hz), 2.22 (3H, s), 4.38 (2H, q, J=7 Hz), 5.33 (2H, s), 7.67 (1H,s),8.56 (1H,s) (3) A mixture of ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yI)acetate (syn isomer) (2.4 g), 1 N aqueous sodium hydroxide (23.8 ml) and methanol (19.8 ml) was stirred at 300C for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate three times.The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yI)acetic acid (syn isomer) (1.13 g), mp. 157 C (dec.).
I.R. (Nujol): 3210, 3160, 3075, 1700, 1555 cm- N.M.R. (d6-DMSO, S):2.24 (3H, s), 5.31 (2H, s), 7.61(1H, s),8.57 (1H, s), 12.73 (1H, s) Preparation 6 The following compounds were obtained according to similar manners to those of Preparations 2 to 5.
(1) 2-Benzyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol): 3330, 3200,3100, 1660, 1590 cm-l (2) 2-(3-Isoxazolyl)methoxyimino-2(2-formamido-thiazol-4-yI)acetic acid (syn isomer), mp.
1100C(dec.).
I.R. (Nujol): 3270, 3130, 1680, 1540 cm-l (3) 2-(2-Ethoxyethoxy)imino-2-(2-formamidothiazol-4-yI)acetic acid (syn isomer).
I.R. (Nujol): 3350, 3140, 1740, 1700 cm-' Preparation 7 The solution of 4-bromo-3-hydroxybenzyloxyamine phosphate (17.4 g) in water (200 ml) and ethanol (200 ml) was stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 2 (2-Formamidothiazol-4-yl)glyoxylic acid (10.0 g) was added to the solution and the resulting suspension was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours ethanol was removed from the resultant solution in vacuo. Ethyl acetate was added to aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate.The solution was concentrated in vacuo to give 2-(2 formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetic acid (syn isomer, 14.8 g).
I. R. pNUajXol: 3350, 3150, 1720, 1680, 1570 cm-' N.M.R. 8 (DMSO-d6, ppm): 5.13 (2H, m), 6.8 (1 H, dd, J=8 Hz, 2 Hz), 7.02 (1 H, d, J=2 Hz), 7.5 (1H, d, 5=8 Hz), 7.58 (1H, s), 8.58 (1H, s), 10.35(1H, broad s), 12.7 (1H, broad s).
Preparation 8 (1) A mixture of 1,4-bis(chloromethyl)benzene (25 g), N-hydroxyphthalimide (23.4 g) and triethylamine (14.5 g) in acetonitrile (200 ml) was heated under reflux for 1.5 hours. The reaction mixture was poured into ice-water (1 I) and the precipitates were washed with ethanol and dried to give N(4-chloromethylbenzyloxy)phthalimide (25.5 g).
I.R. v max Nujol: 1780, 1760, 1740, 1720, 1610 cm- N.M.R. # (DMSO-d6, ppm): 4.8 (2H,s), 5.23 (2H, s), 7.22 (4H, s), 7.9 (4H, s).
(2) A mixture of N-(4-chloromethylbenzyloxy)phthalimide (18.5 g) and potassium phthalimide (15.4 g) in N,N-dimethylformamide (180 ml) was stirred at 600C for 5 hours. The mixture was poured into ice-water and the precipitates were collected by filtration. The precipitates were washed with water and acetone in turn to give N-(4-phthalimidomethylbenzyloxy)phthalimide (21.0 g).
I.R V Nujul: 1780, 1760, 1740, 1720, 1610 cm- N.M.R. # (DMSO-d6, ppm): 4.78 (2H, S0, 5.13 (2H, s), 7.38 (4H, m), 7.83 (8H, m).
(3) 100 % Hydrazine hydrate (4.2 g) was added to a suspension of N-(4phthalimidomethylbenzyloxy)-phthalimide (16.4 g) in ethanol (160 ml) at 600C and stirred at the same temperature for an hour. Conc. hydrochloric acid (12 ml) and water (120 ml) were added to the resultant mixture under ice-cooling. After filtration of the insoluble substance, the filtrate was concentrated in vacuo. The residue was adjusted to pH 7.0 with 10% sodium hydroxide solution and washed with ethyl acetate. To the aqueous solution containing 4-aminomethylbenzyloxyamine were added 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.3 g) and ethanol (150 ml), and the solution was stirred at pH 4.0 to 4.5 for 2.5 hours. The precipitates were collected by filtration and washed with water. The precipitates containing 2-(2-formamidothiazol-4-yl)-2-(4aminomethylbenzyloxyimino)acetic acid (syn isomer) were added to a mixture of water (100 ml) and dioxane (100 ml) and adjusted to pH 8.0 with 10% sodium hydroxide. Triethylamine (3.2 g) and 2-tertbutoxycarbonyloxyimino-2-phenylacetonitrile'(4.7 g) were added to the mixture and stirred at room temperature for 6 hours.
Dioxane was removed in vacuo, and the aqueous residue was washed with diethyl ether. Diethyl ether was added to the aqueous solution and adjusted to pH 3.0 with 10% hydrochloric acid. After removing diethyl ether from the mixture, the residue was washed with a sodium chloride saturated solution, dried over magnesium sulfate and evaporated in vacuo to give 2-(2-formamidothiazol-4-yl)-2 (4-tertbutoxycarbonylaminomethylbenzyloxyimino)acetic acid (syn isomer, 3.8 9).
I.R. # Nujol: 3300, 3150, 1710, 1690, 1620, 1560 cm- N.M.R.# (DMSO-d6, ppm): 1.38 (9H s), 4.15 (2H, d, J=6 Hz), 5.22 (2H, (s), 7.6 (1 H, s),7.68 (4H, s), 8.62 (1 H, s), 12.8 (1 H, broad s).
Preparation 9 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40.0 g), 4-fluorobenzyl chloride (43.6 9), N,N-dimethylformamide (60.0 ml), potassium carbonate (52.0 g) and ethyl acetate (60.0 ml) were treated in a conventional manner to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.4 9).
I.R. (Film): 3000,2940, 1730, 1690, 1600 cm- N.M.R. (DMSO-d6, S): 1.21 (3H, t, J=7.0 Hz), 2.34 (3H, s), 4.26 (2H, q, J=7.0 Hz), 5.32 (2H, s), 6.97-7.73 (4H, m).
(2) Ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.0 9) and sulfuryl chloride (35.6 9) and acetic acid (70.0 ml) were treated in a similar manner to that of Preparation 4-(2) to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 29.55 9).
I.R. (Film): 1720, 1600 cm- N.M.R. (DMSO-D6, #): 1.20 (3H, t, J=7.0 Hz), 4.28 (2H, q, J=7.0 Hz), 4.87 (2H,s), 5.36 (2H, s), 7.00-7.75 (4H, m).
(3) Ethyl 2-(4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 29.0 9), thiourea (8.8 9), sodium acetate (7.9 g), water (72.5 ml), tetrahydrofuran (60 ml) and ethanol (72.5 ml) were treated in a similar manner to that of Preparation 4-(3) to give ethyl 2-(4-fluorobenzyloxyimino)-2-(2aminothiazol-4-yl)acetate (syn isomer, 28.0 9).
I.R. (Nujol): 3450, 3150, 3100, 1710, 1620 cm- N.M.R. (DMSO-d6, s): 1.23 (3H, t, J=7.0 Hz), 4.30 (2H, q, J=7 Hz), 5.15 (2H, s), 6.90 (1 H, s), 6.95-7.60 (4H, m) (4) Ethyl 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer, 25.5 9), 1- methylimidazole (1.3 9), 1N sodium hydroxide solution (118.3 ml), methanol (250 ml) and tetrahydrofuran (200 ml) were treated in a similar manner to that of Preparation 4-(4) to give 2-(4fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer, 22.11 9).
I.R. (Nujol): 3650, 3450, 3300, 3150, 1630 cm- N.M.R. (DMSO-d6, as): 5.16 (2H, s), 6.88 (1 H, s). 7.04-7.66 (4H, m) (5) 2-(4-Fiuorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer, 23.4 9), bis (trimethylsilyl)acetamide (32.2 g), 2,2,2-trifluoroacetic anhydride (49.9 9) and dry ethyl acetate (234 ml) were treated in a similar manner to that of Preparation 4-(5) to give 2-(4-fluorobenzyloxyimino)-2 [2-(2.2.2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer, 18.9 9), mp. 180 to 1 820C.
I.R. (Nujol): 3200,3150, 1730 cm- N.M.R. (DMSO-d6, #): 5.25 (2H, s), 7.02-7.60 (4H, m), 7.72 (1 H, s).
Preparation 10 (1) The following compound was obtained by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) with 3,4-dichlorobenzyl chloride in a conventional manner.
Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer), oil I.R. (Film): 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080, 1010 cm- N.M.R. (CCI4, ): 1.30 (3H, t, J=6 Hz), 2.30 (3H, s),4.30 (2H, q, J=6 Hz), 4.47 (2H, s), 7.00- 7.53 (3H, m) (2) The following compound was obtained according to a similar manner to that of Preparation 4 (2).
Ethyl 2-(3,4dichlorobenzyloxyimino)-3Oxo-4-chlorobutyrate (syn isomer), oil.
I.R. (Film): 1740,1710,1590,1470, 1400,1370,1320,1260, 1200,1130, 1O1Ocm1 N.M.R. (CCI4, S): 1.37 (3H, t, J=6 Hz), 4.23 (2H, q, J=6 Hz), 4.43 (2H, s),5.27 (2H, s). 7.10- 7.60 (3H, m) (3) The following compound was obtained according to a similar manner to that of Preparation 4 (3).
Ethyl 2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yI)acetate (syn isomer).
I.R. (Nujol): 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010, 880, 810, cm-' N.M.R. (DMSO-d6, S): 1.25 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 5.17 (2H, s), 6.93 (1 H, s), 7.27-7.73 (3H, m) (4) The following compound was obtained according to a similar manner to that of Preparation 4 (4).
2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer).
I.R. (Nujol): 3430, 1660, 1590, 1400, 1010 cm-l N.M.R. (DMSO-d6, ): 5.23 (2H, s), 6.93 (1 H, s), 7.30-7.77 (3H, m) (5) The following compound was obtained according to a similar manner to that of Preparation 4 (5).
2-(3,4-Dichiorobenzyloxyimino)-2-[2-(2,2,2-trifluoroaceta mido)thiazol-4-yl]acetic acid (syn isomer).
I.R. (Nujol): 1720, 1580, 1300, 1260, 1200, 1160, 1150 cm-l N.M.R. (DMSO-d6, b): 5.40 (2H, s), 7.47-7.93 (4H, m) Preparation 11 To a suspension of N-(cinnamyloxy)phthalimide (21.0 g) in ethanol (200 ml) was added hydrazine hydrate (8.3 g) at 60 C and the mixture was stirred for 1.5 hours at the same temperature. To the mixture were added conc. hydrochloric acid (22 ml) and water (220 ml) and the resulting mixture was filtered. The filtrate was concentrated to give precipitates, which were filtered off. The filtrate was adjusted to pH 7.0 and to the solution containing 0-cinnamyl hydroxylamine were added ethanol (300 ml) and 2-(2-formamidothiazol-4-yl)glyoxylic acid (10.0 g). The mixture was stirred for 2 hours at pH 4.0 to 4.5.The reaction mixture was concentrated and adjusted to pH 2.0 after addition of ethyl acetate.
The organic layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-cinna myloxyimino-2-(2-formamidothiazol-4-yI)-acetic acid (syn isomer) (8.6 g).
I.R. (Nujol): 3400-3100, 1700, 1 550 cm- N.M.R. (DMSO-d6, 8): 4.85 (2H, d, J=5 Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H, m), 7.6 (1 H, s), 8.57 (1H,s), 12.7 (1H, broad s).
Example 1 The Vilsmeier reagent was prepared from dry dimethylformamide (0.139 g), phosphorus oxychloride (0.290 g) and dry tetrahydrofuran (1.0 ml) by the conventional method. Dry tetrahydrofuran (3.0 ml) was added thereto and then 2-methyithiomethoxyimino-2-(2- formamidothiazol-4-yI)acetic acid (syn isomer) (0.4 g) was added thereto at-5 to OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was dropwise added at -5 to 0 C to a stirred solution of 7-amino-3-(1,3,4-thiadiazol-Z-yl)thlomethyl-3-cephem-4-carboxylic acid (0.725 g) in a mixture of water (7 ml) and acetone (7 ml) keeping the pH at 7.5 to 8.5 by triethylamine and the mixture was stirred for 30 minutes at the same temperature at pH 7.5 to 8.5. Acetone was removed from the reaction mixture.To the residue were added ethyl acetate and water and the mixture was adjusted to pH 2.0 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether to give 7-[2-methyl-thiomethoxyimino-2-(2forma midothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thlomethyl-3-cephem-4-ca rboxylic acid (syn isomer) (0.64 g).
I.R. (Nujol): 3230, 1780, 1680, 1550 cm-' N.M.R. (d6-DMSO, 2.22 (3H, s), 3.72 (2H, ABq J=1 8 Hz), 4.44 (2H, ABq, J=1 4 Hz), 5.18 (1 H, d, J=5 Hz), 5.23 (2H, s), 5.84 (1 H, d,d, J=5 and 9 Hz), 7.46 (1 H, s), 8.52 (1 H, s), 9.54 (1 H, s), 9.74 (1 H, d, J=9 Hz), 12.64 (1 H, broad s).
Example 2 Phosphorus oxychloride (2.3 g) was added at a time to a suspension of 2-benzyloxyimino-2-(2aminothiazol-4-yl)acetic acid (syn isomer) (3.4 g) in dry tetrahydrofuran (30 ml) at -30C and the mixture was stirred for 20 minutes at the same temperature. Trimethylsilylacetamide (2.4 g) and tetrahydrofuran (5 ml) were added dropwise thereto and the resulting mixture was stirred for 20 minutes at the same temperature. Phosphorus oxychloride (2.3 g) was added thereto and the mixture was stirred for 30 minutes at 0 to 30C. Dry dimethylformamide (1.1 g) was added thereto at a time at O to 30C and the mixture was stirred for 1 hour at the same temperature to give a clear solution.On the other hand, trimethylsilyacetamide (12.7 g) was added to a stirred suspension of 7-amino-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.0 g) in dry ethyl acetate (60 ml) and the solution was stirred for 1 hour at ambient temperature. To this stirred solution was added the aboveobtained tetrahydrofuran solution at a time at -200C, and the resulting mixture was stirred for 2 hours at-5 to -1 50C. To the reaction mixture was added a saturated aqueous solution of sodium chloride (50 ml). An organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.0). The extract was washed with ethyl acetate, treated with an activated charcoal and adjusted to pH 4.5 with 10% hydrochloric acid.Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.03 g).
I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm- N.M.R. (d6-DMSO, S): 3.59 (2H, ABq, J=1 8.0 Hz), 4.47 (2H, ABg' J= 12.0 Hz), 5.09 (1 H, d, J=4.0 Hz), 5,15 (2H, s), 5.73 (1H, d,d, J=4.0 and 8.0 Hz), 6,74 (1H, s), 7.36 (5H, m), 9.56 (1 H, s), 9.69 (1 H, d, J=8.0 Hz) Example 3 The Vilsmeier reagent was prepared from dry dimethylformamide (0.667 g), phosphorus oxychloride (1.40 g) and dry ethyl acetate (4 ml) by the conventional method.Dry ethyl acetate (16 ml) was added thereto and then 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer) (2 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added dropwise at-15 C to a stirred solution of 7-amino-3 (1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.01 g) and trimethylsilylacetamide (9.6 g) in dry ethyl acetate (30 ml), and the mixture was stirred for 50 minutes at 5 to -50C. To the reaction mixture was added water (50 ml). An insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate.The extracts were washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverised with diethyl ether and the powder was collected by filtration and dried to give 7-[2-t butoxycarbonylmethoxyimino-2-(2-forma midothiazol-4-yl)acetamido]-3-( 1 ,3,4-thiadiazol-2-yl)- thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.67 g).
I.R. (Nujol): 3225, 1780, 1725, 1685, 1550 cm-' N.M.R. (d6-DMSO,S): 1.38 (9H, s),3.64 (2H, ABq, J=1 7 Hz), 4.38 (2H, ABq, J=14 4 Hz), 4.56 (2H, s), 5.12 (1H, d, J=5 Hz), 5.77 (1H, d,d,J=5 and 9 Hz), 7.38 (1H,s), 8.47 (1H, s), 9.49 (1H, s), 9.54 (1H, d, J=9 Hz), 12.57 (1H, broad s) Example 4 The following compounds were obtained according to similar manners to those of Examples 1 to 3.
(1) 7-[2-Methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R (Nujol): 3250, 1780, 1675, 1550 cm- N.M.R. (d6-DMSO, S): 2.22 (3H, s), 3.72 (2H, ABq J=1 9 Hz), 3.96 (3H, s), 4.33 (2H, ABq, J=1 4 Hz), 5.17 (1 H, d, J=5 Hz), 5.26 (2H, s), 5.85 (1 H, d,d, J=5 and 8 Hz), 7.48 (1 H, s), 8.54 (1 H, s), 9.78 (1 H, d, J=8 Hz), 12.64 (1 H, s) (2) 7-[2-(2-Ethoxyethyoxy)imino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R.(Nujol): 3500, 3200, 1780, 1720, 1680 cm- N.M.R. (ds-DMSO, #): 1.13 (3H, t, J=7 Hz), 3.2#4.0 (6H,m), 4.30 (2H, t, J=4 Hz), 4.50 (2H, ABg, J=1 3 Hz), 5.23 (1H, d, J=5 Hz), 5.87 (1H, d,d, J=5 and 8 Hz), 7.48 (1 H, s), 8.58 (1H, s), 9.60 (1H, s), 9.70 (1H, d, J=8 Hz).
(3) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3carbamoyloxymethyl-3-cephem-4-ca rboxylic acid (syn isomer).
I.R. (Nujol): 1770, 1710, 1670 cm- N.M.R. (d6-DMSO, S): 3.50 (2H, m), 4.10-4.60 (4H, m), 4.79 (2H, m), 5.16 (1 H, d, J=5.0 Hz), 5.81(1K, d,d, J=5.0 and 8.0 Hz), 6.58 (2H, broad s), 7.47 (1H, s), 8.28 (1H, s), 8.55 (1H, s) (4) 7-[2(2-Formyloxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetamido]-3-methyl-3-cephem4-carboxylic acid (syn isomer).
I.R. (Nujol): 3150, 1765, 1675 cm- N.M.R. (d6-DMSO, #): 2.03 (3H, s), 3.45 (2H, ABq, J=18 Hz), 4.36 (4H, m), 5.11 (1H, d, J=5 Hz), 5.75 (1H, d.d. J=5 and 8 Hz), 7.46 (1H, s), 8.24 (1H, s), 8.53 (1H, s), 9.63 (1H, d, J=8 Hz) (5) 7-[2-(2-Formyloxysthoxy)imino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1-methyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R.(Nujol): 3160, 1775,1710, 1670 cm- N.M.R. (ds-DMSO, #): 3.71 (2H, ABg, J=18.0 Hz), 3.96 (3H, s), 4.00#4.54 (6H, m), 5.16 (1H, d, J=4.5 Hz), 5.84 (1H, d,d, J=4.5 and 9.0 Hz), 7.45 (1H,s), 8.24 (1H,s), 8.53 (1H, s). 8.53 (1H. s). 9.70 (1 H, d, J=9.0 Hz) (6) 7-[2-(2-Formyloxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4,-thiadiazol2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3180, 1775, 1673 cm- N.M.R. (d8-DMSO, #): 3.75 (2H, m). 4.25#4.65 (6H, m), 5.22 (1H, d, J=5.0 Hz). 5.88 (1 H, d,d, J=5.0 and 9.0 Hz), 7.49 (1H, s), 8.26 (1H, s), 8.57 (1H, s), 9.59 (1H, s), 9.71 (1H, d. J=9.0 Hz) (7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3250. 1775, 1720, 1680, 1540 cm- N.M.R. (d8-DMSO, #): 1.22 (3H, t, J=7 Hz), 3.74 (2H, s),4.20 (2H, q, J=7 Hz), 4.77 (2H, s), 5.22 (1H, d, J=5 Hz), 5.88 (1H, d,d, J=5 and 8 Hz), 7.51 (1H, s), 8.58 (1H, s), 9.63 (1H, s), 963 (1H, s), 9.70 (1 H, d, J=8 Hz). 12.68 (1H, broad s) (8) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(t-methyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3250, 1780, 1725, 1680, 1540 cm-' N.M.R. (d6-DMSO, #): 1.22 (3H, t, J=7 Hz), 3.73 (2H, s), 3.97 (3H,s), 4.18 (2H, q. J=7 Hz), 4.35 (2H, ABq, J=14 Hz), 4,76 (2H, s), 5.18 (1K, d, J=5 Hz), 5.86 (1H, d,d, J=5 and 9 Hz), 7.48 (1H, s). 8.56 (1H,s). 9.67 (1H, d, J=9 Hz), 12.69 (1H, broad s) (9) 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(t-methyl1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3180, 1785, 1725, 1690, 1550 cm- N.M.R. (d8-DMSO, #): 1.45 (9H, s), 3.72 (2H, ABq, J=1 7 Hz), 3.96 (3H, s), 4.33 (2H, ABq, J=1 4 Hz), 4.64 (2H, s), 5.17 (1H, d, J=5 Hz), 5.84 (1H, d,d, J=5 and 9 Hz), 7.46 (1H, s), 8,52 (1H, s), 9.62 (1H, d, J=9 Hz), 12.61 (1H broad s) (10) 7-[2-Benzyloxylmino-2-(2-aminothlazol-4-yl)-acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm-' N.M.R. (d6-DMSO, #): 0.86 (3H, m), 0.97#1.53 (6H, m), 1.53#2.10 (2H, m), 3.70 (2H, m), 4.10#4.77 (4H, m), 5.00#5.50 (3H,m), 5.85 (1H, d,d, J=5.0 and 8.0 Hz), 6.80 (1H, s), 6.98#7.63 (7H, m), 9.71 (1H, d, J=8.0 Hz).
(11) 7-[2-(3-lsoxazolyl)methyoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1775, 1675, 1540 cm-' N.M.R. (d6-DMSO, #]: 3.72 (2H, s), 4.45 (2H, ABq, J=1 3 Hz), 5.18 (1 H, d, J=5 Hz), 5.30 (2H, s), 5.96 (1H, d,d, J=5 and 8 Hz), 6.67 (1 H, d, J=2 Hz), 7.50 (1H, s), 8.55 (1 H, s), 8.90 (1H, d, J=2 Hz), 9.58 (1H, s). 9.79 (1H, d, J=8 Hz), 12.69 (1H, s) (12) 7-[2-Methylthiomethoxylmlno-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1670 cm-1 @@@@@@@@@ 5-yl)thio-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1770, 1670, 1530 cm- (14) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yi)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm- (15) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl) acetamido]-3-(1-methyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3220, 1780, 1680, 1630 cm-' (16) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol 2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm- (17) 7-[2-t-Butoxcarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm-1 (18) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm-1 (19) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230 3110, 1775, 1675 cm- (20) 7-[2-Carboxymethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm- (21) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm-1 (22) 7-[2-(4-t-Butoxycarbonylaminomethylbenzyloxyimino)-2-(2-formamidothiazol-4yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300-3150, 1790, 1690, 1550 cm- N.M.R. (DMSO-d6 S): 1.33 (9H, s), 3.6 (2H, m), 4.08 (2H, d, J=5 Hz), 4.4 (2H, ABq, J=14 Hz), 5.11 (1H, d, J=5 Hz), 5.13 (2H, m), 5.78 (1H, dd, J=5 and 8 Hz), 7.25 (4H, m), 7.33 (1 H, s), 8.47 (1H, s), 9.5 (1H, s), 9.68 (1H, d, J=8 Hz), 12.5 (1H, broad s) (23) 7-[2-(t-Butoxycarbonylmethoxylmino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1H tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3170, 1770, 1720, 1670 cm- N.M.R. (DMSO-d6, S): 1.44 (9H, s), 3.68 (2H, m), 4.33 (2H, ABq, J=12.0 Hz), 4.63 (2H, s), 5.16 (1 H, d, J=5.0 Hz), 5.82 (1 H, dd, J=5.0 and 8.0 Hz), 7.43 (1H, s). 8.51 (1H, 5), 9.56 (1 H, d, J=8.0 Hz).
(24) 7-[2-(4-Fluorobenzyloxyimino)-2-[2-(2,2,2-trlfluoroacetamido)thiazol-4-yl]acetamido]-3-(1 methyl H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3370, 3180, 1760, 1710, 1680, 1650 cm- N.M.R. (DMSO-d6, S): 3.68 (2H, m), 3.92 (3H, s), 4.32 (2H, m), 5.03-5.35 (3H, m), 5.83 (1 H, dd, J=5 and 8 Hz), 6.99-7.70 (4H, m), 7.54 (1H, s), 9.87 (1H, d, J=8 Hz) (25) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-( 1 H-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 112 to 125 C (dec.).
I.R. (Nujol): 3250, 1770, 1730, 1680 cm-1 N.M.R. (DMSO-d6 #): 1.20 (3H, t, J=8 Hz), 3.71 (2H, m), 4.07 (2H, q. J=8 Hz), 4.36 (2H,m), 4.77 (2H, m), 5.20 (1H, d, J=5 Hz), 5.88 (1H, dd, J=5 and 8 Hz), 7.50 (1H, s), 8.57 (1H,s), 9.67 (1H, d, J=8 Hz), 12.38 (1H, broad s) (26) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-( 1 H-tetrazol-5-yl)thiomethyl-3cephem-4-carboxylic acid (syn isomer), mp 172 to 1 740C (dec).
I.R. (Nujol): 3250, 3150, 1770, 1620 cm-1 N.M.R. (DMSO-d8, S): 3.67 (2H, m), 4.33 (2H, m). 5.08-5.36 (3H, m), 5.83 (1H, dd, J=4 and 8 Hz), 6.88 (1K, s), 7.39 (5H, s), 9.73 ( 1 H, d, J=8 Hz) (27) 7-[2-(4-Fluorobenzyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetamido]-3 (1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, j 770, 1720, 1650 cm-1 N.M.R. (DMSO-d6, #): 3.73 (2H, ABq, J=1 8 Hz), 4.49 (2H, ABq, J=14 Hz), 5.03-5.46 (3H, m), 5.88 (1H, dd, J=4 and 8 Hz), 7.03-7.84 (4H, m), 7.59 1H, s), 9.60 (1K, s), 9.88 (1H, d, J=8 Hz) (28) 7-[2-Cinnamyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm- N.M.R. (DMSO-d6, #): 3.67 (2H, m), 4.45 (2H, ABq, J=1 4 Hz), 4.83 (2H, d, J=5 Hz), 5.18 (1H, d, J=5 Hz), 5.87 (1 H, dd, J=5 and 8 Hz), 6.65 (1H, s), 6.12-7.0 (2H, m), 7.1-7.7 (5H, m), 8.53 (1H, s), 9.57 (1H,s), 9.73 (1H, d, J=8 Hz), 12.6 (1H, broad s) (29) 7-[2-(4-Fluorobenzyloxyimino)-2-I2- (2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3 (1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1730, 1660 cm- (30) 7-[2-(4-Fluorobenzyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetamido]cephalosporanic acid (syn isomer).
I.R. (Nujol): 3250, 1780, 1730, 1660, 1630 cm- N.M.R. (DMSO-d6, #): 2.07 (3H, s), 3.59 (2H, m), 4.90 (2H, ABq, J=14 Hz), 5.13-5.46 (3H, m), 5.90 (1H, dd, J=5 and 8 Hz), 7.30-7.77 (4H, m), 7.58 (1H, s), 9.68 (1H, d, J=4.0 Hz) (31) 7-[2-(3,4-Dichlorobenzyloxyimino)-2- {(2,2,2-trifluoroacetamido)thiazol-4-yl]acetamido]cephalosporanic acid (syn isomer).
I.R. (Nujol): 1780, 1730, 1650 cm-1 N.M.R. (DMSO-d6, #): 2.03 (3H, s), 3.57 (2H, m), 4.87 (2H, ABq, J=12 Hz), 5.17-5.23 (3H, m), 5.87 (1H, dd, J=6 and 8 Hz), 7.33-7.73 (4H,m), 9.87 (1H, d, J=8 Hz (32) 7-[2-(3-hydroxy-4-bromobenzyloxyimino)-2-(2-forma midothiazol-4-yl)acetamido]-3-( 1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm- N.M.R. (DMSO-d6, #): 3.7 (2H, broad s), 4.45 (2H, A8'q, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.18 (2K, s), 5.82 (1H, dd, J=5 and 8 Hz), 6.97 (1H, d, J=2 Hz), 7.4 (1 H, s), 7.45 (1H, d, J=8 Hz), 8.5 (1H, s), 9.68 (1H, d, J=8 Hz), 12.6(1H, broad s) (33) 7-[2-(4-Aminomethylbenzyloxyimino)-2-(2-aminothiazol -4-yl)acetamido]-3-( 1,3,4- thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer).
I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm- (34) 7-[2-(t-Butoxycarbonylmethoxylmino)-2-(2-amlnothlazol-4-yl)acetamldo]-3(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm- @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ 5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm- (36) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),mp 168 to 185 C (dec).
I.R. (Nujol): 3250, 1765, 1670, 1625 cm-' (37) 7-[2-(4-Fluorobenzyloxylmlno)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 1490C (dec).
I.R. (Nujol): 3250, 1765, 1650 cm-' (38) 7-[2-Cinnamyloxyimino-2-(2-a minothiazol-4-yl)-acetamido]-3-( 1 ,3,4-thiadiazol-2- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350--3100, 1760, 1650, 1620, 1520 cm-l (39) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3- (1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm- (40) 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (syn isomer), mp 185 to 192 C (dec).
I.R. (Nujol): 3380, 3250, 1780, 1700, 1650 cm- (41) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalospuranic acid (syn isomer), mp 200 to 2050C (dec).
I.R. (Nujol): 1730, 1640, 1600, 1230, 1020 cm-1 (42) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm- (43) 7-[2-Caboxymethoxyimino-2-(2-aminothiazol-4yl)acetamido]-3-(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 1 78 to 1 8O0C (dec).
I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm-' (44) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3 [tetrazolo[1,5-b]pyradazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3150, 1780, 1720, 1670 cm- N.M.R. (DMSO-d6, S): 1.42 (9H, s), 3.73 (2H, m), 4.25-4.85 (4H, m), 5.17 (1 H, d, J=4 Hz), 5.84 (1H, dd, J=4 and 8 Hz), 7.43 (1H,s), 7.72 (1H, d, J=10 Hz), 8.50 (1H, s), 8.56 (1H, d, J=10 Hz), 9.56 (1 H, d, J=8 Hz) (45) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[tetrazolo[1,5b]-pyridazin-6yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1770, 1670, 1620 cm-1 (46) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[tetrazolo[1,5-b] pyridazin-6-yl]-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm- Example 5 A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)aceta midoj-3-( 1,3,4- thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g), conc. hydrochloric acid (0.405 g), methanol (8.7 ml) and tetrahydrofuran (5 ml) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7#8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes.Precipitates were collected by filtration, washed with water and dried to give 7 [2-methylthiomethoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer) (0.4 g).
IR. (Nujol): 3340, 3200, 1775, 1670 cm-1 N.M.R. (d5-DMSO, b): 2.23 (3H, s), 3.74 (2H, s),4.48 (2H, ABq, J=13 Hz), 5.20 (1H, d, J-5 Hz), 5.24 (2H, s), 5.83 (1 H, d,d, J=5 and 9 Hz), 6.83 (1H, s),7.28 (2H, broad s), 9.62 (1 H, s), 9.68 (1H,d,J=9 Hz) Example 6 A mixture of 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3- (1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g), conc. hydrochloric acid (3.74 g) and methanol (35 ml) was stirred for 2 hours and 40 minutes at ambient temperature.
The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7-8). The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-t-butoxy-carbonylmethoxyimino-2-(2aminothiazol-4yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g).
I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm-' N.M.R. (d5-DMSO, 8)1.46 (9H, s), 3.67 (2H, s),4.42 (2H, ABg J=1 4 Hz), 4.55 (2H, 5), 5.16 (1 H, d, J=5 Hz), 5.78 (1H, d,d, J=5 and 9 Hz), 6.77 (1H, s), 7.21 (2H, s), 9.43 (1 H, d, J=9 Hz), 9.52 (1H,s) Example 7 To a stirred solution of sodium acetate (2.7 g) in water (46 ml) was added 7-[2-(4fluorobenzyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-actamido]-3-(1,3,4-thiadiazol-2yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 g) and the mixture was stirred for 20.5 hours at ambient temperature.The reaction mixture was adjusted to pH 5.0 with 10% hydrochloric acid after addition of ethyl acetate and the resulting mixture was shaken. The aqueous layer was separated, washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid.
Precipitates were collected by filtration, washed with water and dried to give 7-[2-(4 fluorobenzyloxyimino)-2-(2-a minothiazol-4-yl)aceta mido]3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3- cephem-4-carboxylic acid (syn isomer) (1.82 g), mp 145 to 1490C (dec).
I.R. (Nujol): 3250, 1765, 1650 cm- N.M.R. (DMSO-d6, 8):3.73 (2H, ABq, J=1 8 Hz), 4.48 (2H, ABq, J=14 Hz), 5.01-5.39 (3H, m), 5.85 (1H, dd, J=4 and 8 Hz), 6.83 (1 H, s), 7.02-7.75 (4H, m). 9.63 (1 H, s), 9.75 (1H, d, J=8 Hz) Example 8 The following compounds were obtained according to similar manners to those of Examples 5 to 7.
(1) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl 3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm- (2) 7-[2-Benzyluxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-hexyl-1H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm- (3) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl- 1H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1770, 1670, 1530 cm- N.M.R. (d6-DMSO, 8)2.20 (3H, s),3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s), 5.17 (1 H, d, J=5 Hz), 5.22 (2H, s), 5.82 (1H, d,d, J=5 and 8 Hz), 6.82 (1H, s), 7.28 (2H, broad s),9.60 (1 H, d, J=8 Hz) (4) 7-[2-(2-Ethoxyethoxy)imino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm- N.M.R. (d6-DMSO, b): 1.08 (3H, t, J=7 Hz), 3.45 (2H, q, J=7 Hz), 3.5#3.90 (4H, m), 4.20 (2H, t, J=4 Hz), 4.47 (2H, ABq, J=13 Hz), 5.17 (1 H, d, J=5 Hz), 5.80 (1H, d,d, J=5 and 8 Hz), 6.77 (1H, s), 9.55 (1H, s), 9.55 (1H, d, 5=8 Hz) (5) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4 carboxylic acid (syn isomer).
IR. (Nujol): 3350, 3220, 1780, 1680, 1630 cm-1 N.M.R. (d6-DMSO, #): 1.23 (3H, t, J=7 Hz), 3.70 (2H, s), 3.97 (3H, s), 4.16 (2H, q, J=7 Hz), 4.35 (2H, s), 4.69 (2H, s), 5.15 (1H, d, J=5 Hz), 5.80 (1H, d,d, J=5 and 9 Hz), 6.81 (1H, s), 7.24 (2H, broad s), 9.54 (1 H, d, J=9 Hz) (6) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothlazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm- N.M.R. (d6-DMSO, #): 1.21 (3H, t, J=7 Hz), 3.72 (2H, ABg, J=18 Hz), 4.18 (2H, q, J=7 Hz), 4.70 (2H, s), 5.20 (1 H, d, J=5 Hz), 5.84 (1 H, d,d, J=5 and 8 Hz), 6.84 (1 H, s), 7.26 (2H, broad s), 9.56 (1H, d, J=8 Hz), 9.60 (1H, s) (7) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamidol3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm- N.M.R. (d6-DMSO, #): 3.68 (2H, s), 3.94 (3H, s), 4.32 (2H, ABg, J=14 Hz), 4.70(2H, s), 5.14 (1H, d, J=5 Hz), 5.78 (1H, d,d, J=5 and 9 Hz), 6.81 (1H, s), s), 7.1 (2H, broad s), 9.59 (1H, d, J=9 Hz).
(8) 7-[2-(3-Isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm- N.M.R. (d6-DMSO, #):3.71 (2H, ABq, J=18 Hz), 4.46 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=5 Hz), 5.27 (2H, s), 5.82 (1H, d,d, J=5 and 8 Hz), 6.66 (1H, s), 6.83 (1H, s), 7.30 (2H, broad s), 8.87 (1H, s), 9.57 (1H, s), 9.75 (1H, d, 5=8 Hz) (9) 7-[2-Carboxymjethoxylmino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,34-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm- (10) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-( 1 H-tetrazol-5-yl)thiomethyl-3cephem-4-carboxylic acid (syn isomer), mp 172 to 1 740C (dec).
I.R. (Nujol): 3250, 3150, 1770, 1620 cm- (11) 7-[2-(4-Aminomethylbenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer).
I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm- N.M.R. (DMSO-d6- 8): 3.68 (2H, broad s), 3.97 (2H, d, J=6 Hz), 4.43 (2H, ABq, J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.12 (2H, s), 5.72 (1H, dd, J=5 and 7 Hz), 6.88 (1H, s), 7.43 (4H, s), 9.5 (1H, s), 9.8 (1H, d, J=7 Hz) (12) 7-[2-(t-Butxycarbonylmethoxylmino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm-' (13) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm- N.M.R. (DMSO-d6, #): 3.67 (2H,m), 3.94 (3H, s), 4.32 (2H, m), 4.98-5.36 (3H, m), 5.78 (1H, dd, J=5 and 8 Hz), 6.72 (1H,s), 6.95-7.65 (4H, m), 9.65 (1H, d, J=8 Hz) (14) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-amlnothiazol-4-yl)acetamido]-3-(1H-tetrasol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 168 to 185 C (dec).
I.R. (Nujol): 3250, 1765, 1670, 1625 cm-' N.M.R. (DMSO-d6, #): 1.21 (3H, t, J=7 Hz). 3.70 (2H, broad s), 4.18 (2H, q, J=7 Hz), 4.31 (2H, m), 4.72 (2H, broad s), 5.17 (1H, d, J=4 Hz), 5.82 (1H, dd, J=4 and 7 Hz), 6.83 (1H, s), 7.17 (2H, broad s), 9.57 (1H, d, J=7 Hz) (15) 7-[2-(4-Fluorobenzyloxylmino)-2-(2-aminothiazol-4-yl)acetamido]3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 1490C (dec).
I.R. (Nujol): 3250, 1765, 1650 cm- (16) 7-[2-Clnnamyloxyimino-2-(2-ainothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm- N.M.R. (DMSO-d6, #): 3.47-3.97 (2H, m), 4.47 92H, ABq, J=14 Hz), 4,8 (2H, d.J=5 Hz), 5,18 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz), 6,83 (1H, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m), 9.6 (1H, s), 9.72 (1H, d, J=8 Hz) (17) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)thomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm-' N.M.R. (DMSO-d6, #): 3.69 (2H, ABq, J=18 Hz), 4.35 (2H, ABq, J=15 Hz), 4.93-5.43 (3H, m), 5.81 (1H, dd, J=5 and 8 Hz), 6.80 (1H, s), 6.96-7.70 (4H, m), 9.73 (1H, d, J=8 Hz) (18) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (syn isomer), mp 185 to192 C (dec).
I.R. (Nujol): 3380, 3250, 1780, 1700, 1650 cm- N.M.R. (DMSO-d6, #): 2.02 (3H, s), 3.53 (2H, m), 4.84 (2H, ABq, J=13 Hz), 5.13 (2H, s). 5,40 (1H, d, J=4 Hz), 5.79 (1H, dd, J=4 and 8 Hz), 6.73 (1H, s), 6.96-7.63 (4H, m), 9.62 (1H, d, J=8 Hz) (19) 7-[2-(3,4-Dichlorobenzyloxyimino)-2-(2-amlnothiazol-4-yl)acetamidolcephalosporanic acid (syn isomer), mp 200 to 205 C (dec).
I.R. (Nujol): 1730, 1640, 1600, 1230, 1020 cm-' N.M.R. (DMSO-dss, S): 2.00 (3H, s), 3.30 (2H, ABq, J=18 Hz), 4.68-5.12 (5H, m), 5.60 (1H, dd, J=6 and 8 Hz), 6.72 (1 H, s). 7.32-7.64 (3H, m), 9.60 (1 H, d, J=8 Hz) (20) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400--3100, 1760, 1660, 1620, 1520 cm-' N.M.R. (DMSO-d6, #): 3.72 (2H, broad s), 4.47 (2H, ABq, J=14 Hz), 5.1 (1H, d, J=5 Hz), 5.22 (2H, s), 5.83 (1H, dd, J=5 and 8 Hz), 6.85 (1H, s), 6.87 (1H, dd, J=2 and 8 Hz), 7.08 (1H, d, J=2 Hz), 7.52 (1H, d, J=8 Hz), 9.67 (1H, s), 9.77 (1H, d, J=8 Hz) (21) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 178 to 180 C (dec).
I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm-' (22) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[tetrazolo[1,5blpyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1770, 1670, 1620 cm-' N.M.R. (DMSO-d6, #): 1.41 (9H, s), 3.72 (2H, m), 4.42 (2H, ABq, J=14 Hz), 4,55 (2H, s), 5.16 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 6.79 (1H, s). 7.74 (1H, d, J=10 Hz), 8.57 (1H, d, J=10 Hz), 9.48 (1H, d, J=8 Hz) @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ 6yl]thio-methyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm-' Example 9 Trifluoroacetic acid (4 ml) was added under ice-cooling to a stirred suspension of 7-[2-tbutoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]3-( 1 ,3,4- thiadiazoiyl-2-yl)thiomethyl-3cephem-4-carboxylic acid (syn isomer) (1.0 g) in anisol (1 ml), and the resultant mixture was stirred for 70 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried, suspended in water (10 ml) and then dissolved in a 10% aqueous solution of sodium hydroxide (pH 7-7.5). The solution was adjusted to pH 3.0 with 10% hydrochloric acid under icecooling and stirring and stirred for 30 minutes under ice-cooling.Precipitates were collected by filtration, washed with water and dried to give 7-[2-carboxymethoxyimino-2-(2-ami nothiazol-4-yl)- acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.75 g).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm- N.M.R. (d6-DMSO, #): 3.68 (2H, s), 4.46 (2H, ABq, J=15 Hz), 4.61 (2H, s), 5.17 (1H, d, J=5 Hz), 5.82 (1 H, d,d, J=5 and 9 Hz), 6.83 (1 H, s), 7.23 (2H, broad s), 9.50 (1 H, d, J=9 Hz), 9.53 (1H, s) Example 10 The following compounds were obtained according to a similar manner to that of Example 9.
(1) 7-[2-Carboxymethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-@ methyl 1 H-tetrazol5-yl )thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm-' N.M.R. (d5-DMSO, S): 3.72 (2H, AB9' J=1 6 Hz),3.96 (3H, s), 4.33 (2H, ABq, J=14 Hz), 4.67 (2K, s), 5.17 (1H, d, J=5 Hz), 5.86 (1H, d,d, J= 5 and 9 Hz), 7.47 (1 H, s), 8.52 (1H, s), 9.64(1K, d, J=9 Hz). 12.64 (1H, broad s) (2) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( methyl 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm- (3) 7-[2-Carboxymethoxyimino-2-(2-a minothiazol-4-yl)-aceta mido]-3-( 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 178 to 180 C (dec).
I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm- N.M.R. (DMSO-d6, #): 3.69 (2H, m), 4.32 (2H, ABq, J=14 Hz), 4.60 (2H, m), 5.14 (1 H, d, J=5 Hz), 5.79 (1H, dd, J=5 and 8 Hz), 6.79 (1H, s), 9.47 (1H, d, J=8 Hz) (4) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-[tetrazolo[1,5-b]pyradazin 6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm- N.M.R. (DMSO-d6, S): 3.77 (2H, ABq, J=1 8 Hz), 4.45 (2H, ABq, J=1 4 Hz), 4.63 (2H, s), 5.20 (1H, d, J=4 Hz), 5.86 (1H, dd, J=4 and 8 Hz), 6.84 (1H, s), 7.78 (1H, d, J=10 Hz), 8.61 (1H, d, J=10 Hz), 9.54 (1 H, d, J=8 Hz) Example 11 7-[2-(4-Fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamidolcephalosporanic acid (syn isomer) (1.1 g) and 1,3,4-thiadiazole-2-thiol (0.23 9) were added to a stirred solution of sodium bicarbonate (0.34 g) in pH 6.8 phosphate buffer (30 ml) and the mixture was stirred for 3 hours at 60 to 650C. The reaction mixture was cooled and adjusted to pH 3 with 10% hydrochloric acid.
Precipitates were collected by filtration, washed with water and dried to give 7-[2-(4fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadazol-2-yl)thiomethyl-3 cephem-4-carboxylic acid (syn isomer) (0.45 g) mp 145 to 1490C (dec).
I.R. (Nujol): 3250, 1765, 1650 cm- N.M.R. (DMSO-d6, #): 3.73 (2H, ABq, J=1 8 Hz), 4.48 (2H, ABq, J=14 Hz), 5.01-5.39 (3H, m), 5.85 (1H, dd, J=4 and 8 Hz), 6.83 (1 H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H, d, J=8 Hz) Example 12 The following compounds were obtained according to a similar manner to that of Example 11.
(1) 7-[2-Methylthiomethoxylmino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2ul)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3230, 1780, 1680, 1550 cm- (2) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-aceta mido]3-( 1 ,3,4-th iadiazol-2-yl)thiomethyl- 3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3320, 3200, 1770, 1670, 1610 cm-' (3) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamido-thlazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3225, 1780, 1725, 1685, 1550 cm-' (4) 7-[2-Methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2- methyl 1 H tetrazol-5yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn isomer).
I.R. (Nujol): 3250, 1780, 1675, 1550 cm-' (5) 7-[2-(2-Ethoxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetamido]yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3500, 3200, 1780, 1720, 1680 cm-' (6) 7-[2-Ethoxycarbonylmethoxylmino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3250, 1775, 1720, 1680, 1 540 cm- (7) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-( methyl 1 Htetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3250, 1 780, 1725, 1 680, 1 540 cm-l (8) 7-[2-t-Butoxycarbonylmethoxyimino-2-(2-formamido-thlazol-4-yl)acetamido]-3-(1-methyl1H-tetrazol-5-yl)thlomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol):3180, 1785, 1725, 1690, 1550 cm-' (9) 7-[2-Benzyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3250, 1780, 1680, 1633 cm-' (10) 7-[2-(3-(soxazolyl)methoxyimino-2-(2-formamido-thiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1 775, 1675, 1 540 cm- (11) 7-[2-Methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1670 cm~1 (12) 7-[2-Methylthiomethoxyimino-2-[2-aminothiazol-4-yllaceta mido]-3-( 1 -methyl-l H-tetrazol- 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300. 1770, 1670, 1530 cm-' (13) 7-[2-(2-Ethoxyethoxy)imino-2-(2-a minothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3160, 3100, 1780, 1670, 1630 cm- @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ tetrazol-5-yI)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3220, 1780, 1680, 1630 cm-' 47-[2-Ethoxycarbnylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm-' (1 6) 7~[2-t-ButoxycarbonyImethoxyimino-2-(2-a minothiazol-4-yl)acetamido]-3-( 1 ,3,4-thiadiazol- 2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1775, 1730, 1675, 1630 cm-' (17) 7-2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1 methyl 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3340, 3200, 1775, 1675, 1630 cm-' (18) 7-[2-(3-(soxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350, 3230, 3110, 1775, 1675 cm-' (19) 7-[2-Carboxymethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3200, 1780, 1720, 1680, 1545 cm- (20) 7-[2-Carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm- (21) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1Htetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3170, 1770, 1720, 1670 cm- (22) 7 [2-Ethoxycarbonylmethoxyimino-2-(2-formamido-thiazol-4-yI)aceta midoj-3-( 1 H-tetrazol 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 112 to 1250C (dec).
I.R. (Nujol): 3250, 1770, 1730, 1680 cm-' (23) 7-[2-Benzyloxyimino-2-(2-a minothiazol-4-yl)-aceta mido]-3-( 1 H-tetrazol-5-yl )thiomethyl-3cephem-4-carboxylic acid (syn isomer), mp 172 to 1 740C (dec).
I.R. (Nujol): 3250, 3150, 1770, 1620 cm-' (24) 7-[2-Cinnamyloximino-2-(2-formamidothiazol-4-yl)acetamido]-3-( 1 ,3,4-thiadiazol-2- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm- @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1780, 1680, 1540 cm-' (26) 7-[2-(4-Aminomethylbenzyloxylmino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid dihydrochloride (syn isomer).
I.R. (Nujol): 3400-3100, 1770, 1660, 1620, 1540 cm- (27) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3280, 3200, 1770, 1670, 1630 cm-' (28) 7-[2-(4-Fluorobenzyloxyimino)-2-(2-a mi nothiazol-4-yl)aceta mido]-3-( 1-methyl- 1 H-tetrazol5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm-' (29) 7-[2-Ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 168 to 1 850C (dec.).
I.R. (Nujol): 3250, 1765, 1670, 1625 cm-l (30) 7-[2-Cinnamyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm- @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm- (32) 7-[2-(3-Hydroxy-4-bromobenzyloxylmino)-2-(2-aminothiazol-4-yl)acetamido]-3(1,3,4thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm- (33) 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 178 to 1 8O0C (dec).
I.R. (Nujol): 3300, 3280, 1770, 1670, 1630 cm- (34) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3- tetrazolo[1,5-b]-pyridazin-6-yl]-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3150, 1780, 1720, 1670 cm- (35) 7-[2-(t-Butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-[tetrazolo[1.5b]-pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3300, 1770, 1670, 1620 cm-1 (36) 7-[2-Carboxymethoxyimino-2-(2-a minothiazol-4-yl)acetamido]-3-[tetrazolo 1 ,5-b]pyridazin- 6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
I.R. (Nujol): 3270, 3170, 1765, 1670, 1620 cm-

Claims (42)

  1. Claims 1. 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds of the formula:
    wherein R' is amino or a protected amino, R2 is an aliphatic hydrocarbon group having suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is hydrogen, acyloxy or a heterocylicthio group which may have lower alkyl, with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl, and pharmaceutically acceptable salts thereof.
  2. 2. Syn isomer of a compound of claim 1, wherein
    group is
  3. 3. A compound of claim 2, wherein R2 is lower alkylthio(lower)alkyi, lower alkoxy(lower)alkyl, ar(lower)alkenyl, aceloxy(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, isoxazolyl(lower)alkyl, or ar(lower)alkyl which may have halogen, hydroxy, amino(lower)alkyl or acylamino(lower)alkyl, R3 is carboxy and R4 is hydrogen, lower alkanoyloxy, carbamoyloxy, thiadiazolylthio, tetrazolopyridazidinylthio or tetrazolylthio which may have a lower alkyl, with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl.
  4. 4. A compound of claim 3 wherein R1 is lower alkanoylamino, R2 is lower alkanoyloxy(lower)alkyl and R4 is hydrogen or carbamoyloxy.
  5. 5. A compound of claim 3, wherein R2 is ar(lower)alkyl having 1 to 2 halogen and R4 is lower alkanoyloxy.
  6. 6. A compound of claim 5, wherein R1 is amino or halo(lower)alkanoylamino, R2 is phenyl(lower)alkyl having 1 to 2 halogen.
  7. 7. A compound of claim 6, wherein R1 is amino or trihalo(lower)alkanoylamino, R2 is benzyl having 1 to 2 chlorine or fluorine and R4 is acetoxy.
  8. 8. A compound of claim 7, wherein R' is amino or 2,2,2-trifluoroacetamido and R2 is 4-fluorobenzyl or 3,4-dichlorobenzyl.
  9. 9. A compound of claim 3, wherein R' is amino, lower alkanoylamino or halo(lower)alkanoylamino, R2 is lower alkylthio(lower)alkyl, lower alkoxy(lower)alkyl, ar(lower)alkenyl, lower alkanoyloxy(lower)a Ikyl, carboxy(lower)aikyl, lower alkoxycarbonyl(lower)alkyl, isoxazolyl(lower)alkyl, or ar(lower)alkyl which may have 1 to 2 halogen, hydroxy, amino(lower)alkyl or lower alkoxycarbonylamino(lower)alkyl and R4 is thiadiazolylthio.
  10. 10. A compound of claim 9, wherein R' is amino, lower alkanoylamino or trihalo(lower)alkanoylamino and R2 is lower alkylthio(lower)alkyl, lower alkoxy(lower)alkyl, phenyl(lower)alkenyl, lower alkanoyloxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, isoxazolyl(lower)alkyl, or phenyi(lower)alkyl which may have 1 to 2 halogen, hydroxy, amino(lower)alkyl or lower alkoxycarbonylamino(lower)alkyl.
  11. 11. A compound of claim 10, wherein R1 is amino, formamido or 2,2,2-trifluoroacetamido and R2 is methylthiomethyl, ethoxyethyl, cinnamyl, formyloxyethyl, carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, isoxazolylmethyl, or benzyl which may have 1 to 2 fluorine, bromine, hydroxy, aminomethyl or t-butoxycarbonylaminomethyl.
  12. 12. A compound of claim 11, which is 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4 yl)acetamido]-3-(l ,3,4-thiadiazol-2-yl)thiomethyl -3-cephem-4-carboxylic acid (syn isomer).
  13. 1 3. A compound of claim 11, which is 7-[2-cinnamyloxyimino-2-(2-aminothiazol-4 yl)acetamido]-3-(l ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  14. 14. A compound of claim 11, which is 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  15. 1 5. A compound of claim 1, which is 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-4- yI)aceta mido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  16. 1 6. A compound of claim 11, which is 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  17. 1 7. A compound of claim 11, which is 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yI)- acetamido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  18. 18. A compound of claim 11, which is 7-[2-(3-hydroxy-4-bromobenzyloxyimino)-2-(2 aminothiazol-4-yl)acetamido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  19. 1 9. A compound of claim 11, which is 7-[2-(4-aminomethylbenzyloxyimino)-2-(2-aminothiazol- 4-yI)acetamido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) and its dihydrochloride.
  20. 20. A compound of claim 3, wherein R1 is amino or lower alkanoylamino, R2 is carboxy(lower)alkyl or lower alkoxycarbonyl(lower)alkyl and R4 is tetrazolopyridazinylthio.
  21. 21. A compound of claim 20, wherein R1 is amino orformamido and R2 is carboxymethyl or t-butoxycarbonylmethyl.
  22. 22. A compound of claim 21, which is 7-L2-carboxymethoxyimino-2-(2-aminothiazol-4- yl)acetamido]-3-[tetrazolo[ 1 ,5-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  23. 23. A compound of claim 3, wherein R1 is amino, lower alkanoylamino or halo(lower)alkanoylamino, R2 is lower alkylthio(lower)alkyl, lower alkanoyloxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, or phenyl(lower)alkyl which may have a halogen and R4 is tetrazolylthio which may have a lower alkyl, with proviso that R2 is not benzyl when R4 is tetrazolylthio having a methyl.
  24. 24. A compound of claim 23, wherein R2 is carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, or phenyl(lowerXalkyl which may have a halogen and R4 is tetrazolylthio which may have a hexyl.
  25. 25. A compound of claim 24, wherein R' is amino, formamido or 2,2,2-trifluoroacetamido, R2 is carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, or benzyl which may have a fluorine.
  26. 26. A compound of claim 25, which is 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-( 1 -hexyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  27. 27. A compound of claim 25, which is 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamidoj- 3-(1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  28. 28. A compound of claim 25, which is 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yI)- aceta midoj-3-( 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  29. 29. A compound of claim 23, wherein R2 is lower alkylthio(lower)alkyl, lower alkanoyloxy(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, or phenyl(lower)alkyl having a halogen and R4 is tetrazolylthio having a methyl.
  30. 30. A compound of claim 29, wherein R1 is amino, formamido or 2,2,2-trifluoroacetamido and R2 is methylthiomethyl, formyloxyethyl, carboxymethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, or benzyl having a fluorine.
  31. 31. A compound of claim 30, which is 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4 yl)aceta mido]-3-( 1 -m ethyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn isomer).
  32. 32. A compound of claim 30, which is 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4 yl)acetamido]-3-(1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  33. 33. A compound of claim 30, which is 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4 yl)acetamido]3-(l methyl 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
  34. 34. A process for preparing 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula:
    wherein R1 is amino or a protected amino, R2 is an aliphatic hydrocarbon group having suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 iS hydrogen, acyloxy or a heterocyciicthio group which may have lower alkyl, with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl, or pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula:
    wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the formula::
    wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof.
  35. 35. A process for preparing a compound of the formula:
    wherein R2 is an aliphatic hydrocarbon group having suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is hydrogen, acyloxy or a heterocyclic thio group which may have lower alkyl with proviso that R2 is not carboxy(lower)alkyl, protected carboxy(lower)alkyl or benzyl when R4 is acetoxy and that R2 is not benzyl when R4 is tetrazolylthio having a methyl, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:
    wherein R2, R3 and R4 are each as defined above and R15 is a protected amino, or a salt thereof, to elimination reaction of the amino protective group.
  36. 36. A process for preparing a compound of the formula:
    wherein R' is amino or a protected amino, R2b is a carboxy(lower)alkyl, R3 is carboxy or a protected carboxy, and fl4n is hydrogen, carbamoyloxy or a heterocyclicthio group which may have lower alkyl, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:
    wherein R1, R3 and R48 are each as defined above and R2a is a protected carboxy(lower)alkyl, or a salt thereof, to eliminate reaction of the carboxy protective group.
  37. 31. A process for preparing a compound of the formula:
    wherein R' is amino or a protected amino, R2 is an aliphatic hydrocarbon group having suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is a heterocyclic group which may have lower alkyl, with proviso that R is not benzyl when R4 is tetrazolyl having a methyl, or pharmaceutlcally acceptable salts thereof, which comprises reacting a compound of the formula:
    wherein R. R and R are each as defined above and X' is a group which can be substituted with a group of the formula: R4' -S- wherein R4' is as defined above, or a salt thereof, with a compound of the formula: R4,-SH wherein R4' is as defined above or its reactive derivative at the mercapto group.
  38. 38. A compound of the formula:
    wherein R' is amino or a protected amino and R2 is ar(lower)alkenyl, and a salt thereof.
  39. 39. Syn isomer of a compound of claim 38, wherein R2 is cinnamyl.
  40. 40. A process for preparing a compound of the formula:
    wherein R' is amino or a protected amino and R2 is ar(lower)alkenyl, or a salt thereof, which comprises reacting a compound of the formula:
    wherein R' is as defined above, with a compound of the formula: R2-ONK2 wherein R2 is as defined above or a salt thereof.
  41. 41. A pharmaceutical antibacterial composition comprising a compound of claim 1 in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
  42. 42. A method for producing a pharmaceutical antibacterial composition which comprises mixing a compound of claim 1 as an active ingredient with an Inert carrier.
GB7930513A 1978-09-04 1979-09-03 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for their preparation thereof Expired GB2031413B (en)

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GB7835435 1978-09-04
GB7930513A GB2031413B (en) 1978-09-04 1979-09-03 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for their preparation thereof

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GB2031413B GB2031413B (en) 1983-07-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043334A (en) * 1984-11-02 1991-08-27 Glaxo Group Limited Cephalosporin antibiotics

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043334A (en) * 1984-11-02 1991-08-27 Glaxo Group Limited Cephalosporin antibiotics

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