JPS6361954B2 - - Google Patents

Description

[Detailed description of the invention]

This invention describes the general formula useful as an antibacterial substance. (wherein R ¹ is amino or protected amino,
R ² is lower alkenyl, lower alkynyl, cyclo(lower) alkyl, lower alkylthio(lower) alkyl or carboxy(lower) alkyl, R ³
3,7-di-substituted-3-cephem-4- represented by: carboxy or protected carboxy, R ⁴ means tetrazolyl having a lower alkenyl, respectively)
Carboxylic acid compounds, their salts, their production methods, and methods for preventing bacterial infections using them as active ingredients.
It relates to therapeutic agents. The target substance () of the present invention is novel and can be produced by the following methods 1 to 4. Method 1 Method 2 Method 3 Method 4 [In the formula, R ¹ , R ² , R ³ and R ⁴ each have the same meaning as before, R ^1a is protected amino, R ^2a is protected carboxy(lower) alkyl, R ^2b is carboxy(lower) alkyl , X is the formula R ⁴ -S- (where R ⁴
means a group that can be substituted by a group represented by (the same meaning as above)] Among the starting materials, some of the compounds () are new and can be produced by the method shown in the following scheme. (In the formula, R ¹ , R ^1a and R ^2a each have the same meaning as before,
Z means protected carboxy and Y means halogen.) Other starting materials () can be produced by the following method. (In the formula, R ³ and R ⁴ each have the same meaning as before.) Target substances represented by formulas (), (b) and (d) and formulas (a), (), (a), (
a'), (b), (), (), () ~ (XII),
(
) and () are to be understood to include their tautomers based on the thiazole group. That is, in the target material and starting material, the formula

[Formula] (in the formula, R ¹ has the same meaning as before) is a group represented by the formula

[Formula] (in the formula, R ¹ has the same meaning as before), the formula

[Formula] is its tautomeric structure

[Formula] (wherein R ^1b is imino or protected imino). That is, each of the above groups (A)
and (B) are in a so-called tautomeric relationship as shown by the equilibrium equation below. (In the formula, R ¹ and R ^1b have the same meanings as before.) The tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds as described above is widely known in the literature, and the above isomers are in equilibrium. It is obvious to those skilled in the art that they are related and that they can be easily interchanged. Therefore, they should be recognized as belonging to the same category as the compounds themselves. Therefore, both the starting material and the target material, these tautomers are clearly included within the scope of the present invention. In the description herein and in the examples, starting materials and target materials containing such tautomers are referred to as one of these for convenience, i.e.

Represented by [Formula]. Furthermore, target substances (), (b), (d) and starting materials (a), (), (a), (a′), (b
),
() ~ (), () ~ (), (), (
)
includes syn-isomers, anti-isomers and mixtures thereof. For example, regarding the target substance (), the syn isomer has a partial structure in its molecule. The corresponding anti-isomer has a partial structure in the molecule. In the description of the present invention, when the syn isomer and the anti isomer are conveniently explained using one expression, a partial structure. It is expressed by. The syn isomer and anti isomer of the other above-mentioned raw materials and target substances are the same as the geometric isomers described for compound (). The salts of 3,7-disubstituted-3-cephem-4-carboxylic acid compound () include commonly used non-toxic salts, including metal salts [e.g. alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth salts, metal salts (e.g. calcium salts, magnesium salts, etc.)],
Inorganic salts such as ammonium salts, organic amine salts (e.g. trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), organic acid salts (e.g. acetate, maleate,
Organic salts such as tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate,
Inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acids (e.g. arginine,
Examples include salts with aspartic acid, glutamic acid, etc. In the description given above and below by the present specification, examples of various groups included within the scope of the present invention will be explained as follows. The term "lower" means having 1 to 6 carbon atoms unless otherwise specified. Examples of suitable protected amino groups include acylamino, or amino substituted with conventional protecting groups other than acyl, such as aryl(lower)alkyl (eg, benzyl, trityl, etc.). Suitable protected iminos include acyliminos or iminos substituted with conventional protecting groups other than acyl, such as aryl(lower)alkyl (eg, benzyl, trityl, etc.). Suitable acyl moieties in the terms "acylamino", "acylimino" and "acyloxy" include carbamoyl, aliphatic acyl, acyl containing aromatic or heterocyclic groups. Suitable examples of the above acyl include lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably having 1 to 4 carbon atoms, more preferably having 1 to 4 carbon atoms. 2; lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (such as mesyl,
ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.); aryl (lower) alkanoyl (e.g. enylacetyl, phenylpropionyl, etc.); aryl (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.); and the like. The above acyl moieties may contain one to three suitable substituents, such as halogen (e.g. chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy,
isopropoxy, etc.), lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (eg, vinyl, allyl, etc.), aryl (eg, phenyl, tolyl, etc.), and the like. Preferred examples of acylamino include lower alkanoylamino or halo(lower)alkanoylamino [more preferably trihalo(lower)alkanoylamino], and preferred examples of acyloxy include lower alkanoyloxy. Suitable “lower alkylthio(lower)alkyl”,
The lower alkyl moiety in "carboxy(lower) alkyl" includes branched ones, such as methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, tertiary butyl, pentyl,
Examples include hexyl. Suitable cyclo(lower) alkyl has 3 or more carbon atoms.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable lower alkenyl includes those having 2 to 6 carbon atoms, such as vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl, and preferably those having 2 to 4 carbon atoms. Illustrated. Suitable lower alkynyl includes those having 2 to 6 carbon atoms, such as ethynyl, 2-propynyl,
Examples include 2-butynyl, 3-pentynyl, 3-hexynyl, etc., preferably those having 2 to 4 carbon atoms, and more preferably those having 2 to 3 carbon atoms. Suitable protected carboxy and protected carboxy moieties in "protected carboxy (lower) alkyl" include esterified carboxy, where the ester moiety includes lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,
Tertiary butyl ester, pentyl ester, tertiary
pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.), where the lower alkyl moiety preferably has 1 to 4 carbons; 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 esters (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy (lower) alkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxy methyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl (lower) alkyl ester (e.g. mesylmethyl ester, 2-propionyloxyethyl ester, etc.);
- mesylethyl ester, etc.); aryl (lower)
Alkyl esters [e.g. phenyl (lower) alkyl esters, which may have one or more suitable substituents (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-hydroxy-3,5-ditertiary butylbenzyl ester);
Aryl esters (e.g. phenyl esters,
tolyl ester, tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.). Suitable examples of protected carboxy include lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxy carbonyl, etc.), preferably 2 carbon atoms
~5 things are listed. Suitable examples of groups that can be substituted with the group represented by the formula R ⁴ -S- include acid residues such as azide, halogen or acyloxy, of which halogen and acyloxy are as exemplified above. . Preferred halogens are chlorine, bromine, fluorine and iodine. Among the preferred examples of each group in the target substance explained and exemplified above, the following are particularly preferred. A preferred example of R ¹ is amino or acylamino [more preferably lower alkanoylamino or halo(lower)alkanoylamino (even more preferably trihalo(lower)alkanoylamino)],
A preferred example of R ³ is carboxy. The method for producing the target substance of this invention will be described in detail below. Method 1 The target substance () or its salts can be obtained by reacting the compound () or its reactive derivatives at its amino group or their salts with the compound () or its reactive derivatives at its carboxyl group or their salts. can be manufactured. Reactive derivatives at the amino group of compound () include Schiff base-type imino obtained by reacting compound () with a carbonyl compound such as acetoacetic acid, or an enamine-type compound that is a tautomer thereof; Silyl compounds obtained by reacting silyl compounds such as trimethylsilylacetamide and bis(trimethylsilyl)acetamide; derivatives obtained by reacting the compound () with phosphorus trichloride, phosgene, etc. are included. Suitable salts of compounds () and () include acid addition salts, such as organic acid salts (e.g. acetate,
maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or inorganic acid salts (e.g. hydrochloride, bromate, sulfate, phosphate, etc.); metal salts (e.g. sodium salt, potassium salt, (calcium salt, magnesium salt, etc.); ammonium salt; organic amine salt (for example, triethylamine salt, dicyclohexylamine salt, etc.), and the like. Suitable examples of reactive derivatives at the carboxy group of compound () include acid halides, acid anhydrides,
Active amides and active esters are included, such as acid chloride; acid azide; substituted phosphoric acid (such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid,
Acids such as sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.) mixed acid anhydride; symmetrical acid anhydride; imidazole, 4
- activated amides with substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles, etc.; or activated esters (e.g. cyanomethyl esters,
Methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ =CH−] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,
Trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester , 8-quinolylthioester, etc.)
or N-hydroxy compounds (e.g. N,N-
dimethylhydroxylamine, 1-hydroxy-
Examples include esters with 2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.). These reactive derivatives are arbitrarily selected depending on the type of compound () used. The reaction can be carried out using conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, or other organic solvents that do not adversely affect the progress of the reaction. It is generally carried out in the presence of , and these can also be used in combination. When the compound () is reacted in the form of the free acid or its salts, the reaction is carried out using common condensing agents, such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-
diethylaminocyclohexyl)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; polyethyl phosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxane Zolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide inner salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-
It is preferable to carry out the reaction in the presence of 1H-benzotriazole; the so-called Vilsmeier reagent obtained by the reaction of dimethylformamide with thionyl chloride, phosgene, or phosphorus oxychloride; and the like. The reaction can also be carried out using organic or inorganic bases such as alkali metal hydrogen carbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N
-It can also be carried out in the presence of di(lower)alkylbenzylamine or the like. The reaction temperature is not limited;
Usually, the process proceeds to cooling or room temperature. In this reaction, preferably, the compound () is reacted with the syn isomer of the starting material () in the presence of the above-mentioned Vilsmeier reagent in the vicinity of neutrality. Isomers can be produced. Method 2 Target substance (b) or its salts can be obtained by subjecting compound (a) or its salts to an amino-protecting group elimination reaction. Examples of the salt of compound (a) include the metal salts, ammonium salts, and organic amine salts mentioned above. This elimination reaction is carried out according to a conventional method, for example, by hydrolysis; when the ring group is acyl, the compound (a) is reacted with an iminohalogenating agent, and then reacted with an iminoetherifying agent. ,
If necessary, a method of further hydrolysis may be employed. Hydrolysis includes a method using either an acid, a base, or hydrazine, and these methods are appropriately selected depending on the type of protecting group to be removed. Among these methods, the method using an acid is the most common one, for example, substituted or unsubstituted alkoxycarbonyl (e.g., tertiary pentyloxycarbonyl, etc.), alkanoyl (e.g., formyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, etc. This is a preferred method for removing protecting groups such as substituted aralkoxycarbonyl (eg, benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene, and the like. Preferred acids include organic or inorganic acids such as dilic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid.
Particularly preferred are those which can be easily removed from the reaction system by conventional methods such as distillation under reduced pressure, such as acidic acid, trifluoroacetic acid, and hydrochloric acid. The acid used in the reaction is appropriately selected depending on the type of protecting group to be removed. When performing an elimination reaction using an acid,
This can be carried out in the presence or absence of a solvent, and preferred solvents include organic solvents, water, and mixed solvents thereof. When using trifluoroacetic acid, it is preferable to carry out the elimination reaction in the presence of anisole. Hydrolysis using hydrazine is applied to the elimination reaction of protecting groups such as succinyl or phthaloyl. Elimination reactions using bases can be performed on acyl, e.g. haloalkanoyl (e.g. trifluoroacetyl etc.)
Recommended for removal. Preferred bases include inorganic and organic bases, and hydrolysis using a base is carried out in water, a hydrophilic organic solvent, or a mixture thereof. Preferred bases include alkali metal acetates. Among the protecting groups, acyl can be removed by the hydrolysis described above or other common hydrolysis.
When the acyl is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it can be eliminated by treatment with a heavy metal such as copper or zinc. Reductive elimination is the elimination of protective groups such as haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. applied to. Suitable reduction methods include reduction with an alkali metal borohydride (eg, sodium borohydride, etc.). Among the protecting groups, acyl is treated with an iminohalogenating agent (e.g., phosphorous oxychloride, phosphorus pentachloride, etc.), followed by an iminoetherifying agent such as a lower alkanol (e.g., methanol, ethanol, etc.), and further hydrolyzed if necessary. It can also be removed by The reaction temperature is not limited and can be appropriately selected depending on the type of amino protecting group and the type of the above-mentioned elimination reaction, but this reaction is carried out under mild conditions.
For example, it is desirable to carry out cooling, at room temperature, or under slight heating. Depending on the reaction conditions, protected carboxy may be converted to free carboxy during the course of the reaction or during post-treatment, and such cases are also included within the scope of the present invention. Method 3 Target substance (d) or its salts can be obtained by subjecting compound () or its salts to an elimination reaction of the carboxy protecting group. Salts of compound () include compound (
The salts exemplified for a) are exemplified as they are. This elimination reaction is carried out according to a conventional method such as hydrolysis, and the hydrolysis is carried out using an acid, a base, or the like. These methods are selected depending on the type of protecting group to be removed. Hydrolysis using an acid is a very common method and is suitable for removing protecting groups such as phenyl (lower) alkyl, substituted phenyl (lower) alkyl, lower alkyl, substituted lower alkyl, and the like. Suitable acids include organic or inorganic acids such as dinic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. The reaction can also be carried out in the presence of anisole. The suitable acid for the reaction is selected according to the protecting group to be removed and other factors. Hydrolysis using acids can be carried out using organic solvents,
It can be carried out in a solvent such as water or a mixed solvent thereof. The reaction temperature is not limited and is appropriately selected depending on the protecting group and the type of elimination reaction, but it is preferably carried out under mild conditions such as cooling, room temperature or slight heating. During the course of the reaction or post-treatment, the protected carboxy represented by R ³ may change to free carboxy, and the protected amino may change to free amino, but these cases are also within the scope of the present invention. contained within. Method 4 The target substance () or its salts is a compound (
) or its salts with the compound ( ) or a reactive derivative at its mercapto group. Suitable salts for compound () include those exemplified for compound (). Preferred examples of reactive derivatives of the mercapto group of compound () include metal salts of alkali metal salts (eg, sodium salts, potassium salts, etc.). This reaction can be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or Particularly strongly polar solvents are used which do not have an adverse effect on this reaction. Among these solvents, hydrophilic solvents may be used in combination with water, and the reaction is preferably carried out near neutrality. When compound () or compound () is used in a free state, inorganic salts such as alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, etc.
Alternatively, the reaction is preferably carried out in the presence of a base such as an organic base such as a trialkylamine. The reaction temperature is not limited, and the reaction can be carried out at room temperature, with heating, or with slight heating. Depending on the type of protecting group and/or reaction conditions
The protected amino represented by R ¹ may be converted to a free amino, and such cases are also within the scope of the present invention. The method for producing the starting material () is detailed below. 1 Compound () or its salts are ()
Alternatively, it can be obtained by reacting a salt thereof with a compound ( ) or a reactive derivative of its mercapto group. Suitable salts of compound () include those exemplified as salts of compound (a). Suitable reactive derivatives of the mercapto group of the compound () include metal salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.). This reaction can be carried out in a solvent, such as water, acetone, phosphate buffer, chloroform, nitrobenzene, methylene chloride,
Ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or a particularly strongly polar solvent that does not adversely affect this reaction is used. Among these solvents, hydrophilic solvents may be used in combination with water. The reaction is preferably carried out under weak basic or neutral conditions. Compound(
) and/or thiol compound () in the free state, in the presence of an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, or an organic base such as a trialkylamine or pyridine. It is preferable to do so. Although the reaction temperature is not limited, it is usually carried out at room temperature or under heating. The reaction products are separated from the reaction mixture according to conventional methods. 2 Compound () or its salts are compound () or salts thereof.
) or a salt thereof to an elimination reaction of 5-amino-5-carboxyvaleryl group. This elimination reaction is carried out by (i) acting on the compound () or its salts with a silylating agent, (ii) acting on the product with an iminohalogenating agent, and (iii) acting on the product with an iminoetherifying agent. It can be obtained by letting Suitable salts of compound () include those exemplified for compound (a). Suitable examples of the silylating agent include mono- or bistrialkylsilylacetamide [eg, trimethylsilylacetamide, bis(trimethylsilyl)acetamide, etc.], trimethylchlorosilane, dimethyldichlorosilane, hexamethyldisilazane, and the like. Compound()
The reaction between the silylating agent and the silylating agent is carried out by heating or heating in the presence of a base. Suitable examples of iminohalogenating agents include 3
Examples include phosphorus chloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, and phosgene. Although the reaction temperature is not limited, it is usually carried out at room temperature or under cooling. Suitable examples of the iminoetherifying agent to be reacted with the product thus obtained include alcohol,
Metal alkoxides, etc. are shown. Suitable alcohols include alkanols (methanol,
ethanol, propanol, isopropanol, butanol, tertiary butanol, etc.), which may be substituted with alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). Suitable examples of metal alkoxides include alkali metal alkoxides (eg, sodium alkoxide, potassium alkoxide, etc.), alkaline earth metal alkoxides (eg, calcium alkoxide, barium alkoxide, etc.), and the like. Although the reaction temperature is not limited, the reaction is usually carried out with cooling or at room temperature. The product thus obtained is subjected to hydrolysis if necessary. Hydrolysis can be easily carried out by simply pouring the reaction mixture obtained above into water. etc.) or an acid (for example, dilute hydrochloric acid, acetic acid, etc.) may be added. During the above reaction and/or post-treatment, the above tautomer may be converted into other tautomers, and such cases are also included within the scope of the present invention. When the target substance () is obtained in the form of a free acid at the 4-position and/or when the target substance has a free amino group, it can be converted into the above-mentioned salts by conventional methods. The target substance () and its salts of the present invention are all new compounds, inhibit the growth of a wide range of pathogenic microorganisms including Gram-positive bacteria and Gram-negative bacteria, exhibit high antibacterial activity, and are useful as antibacterial agents. Next, in order to demonstrate the usefulness of the target substance (), we will show the in vitro antibacterial activity of representative compounds. Test compound (1) 7-[2-cyclopentyloxyimino-2
-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer) (2) 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamide]-
3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3) 7-[2-(2-propynyl)oximino-
2-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer) (4) 7-[2-methylthiomethoxyimino-2-
(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer) In vitro antibacterial activity test method In vitro antibacterial activity was determined by the agar plate dilution method described below. Trypticase soy broth (bacteria count 10 ⁸
One platinum loop of the test strain cultured overnight in heart infusion agar (HI-agar)
was inoculated. This medium contained antibacterial agents at various concentrations, and the minimum inhibitory concentration (MIC) was measured after culturing at 37°C for 20 hours. (Unit: Kg/ml) Test results

[Table] When administering the target compound of the present invention () or its salts for the purpose of prevention or treatment,
They are administered in the form of conventional preparations containing the substance as the active ingredient and a pharmaceutically acceptable vehicle, such as an organic or inorganic, solid or liquid vehicle for oral, parenteral or topical use. Such preparations include solid preparations such as capsules, tablets, granules, ointments, and suppositories, and liquid preparations such as solutions, suspensions, and emulsions. Furthermore, if necessary, stabilizers, wetting agents or emulsifiers may be added as adjuvants in the formulation.
Buffers and other general-purpose additives can also be included. The dosage of the compound is determined depending on the age, patient condition, type of disease, and type of compound administered, but generally it is administered between 1 mg and 6000 mg at least once a day, and the average 10 per time
Administered in amounts of mg, 50mg, 100mg, 250mg, 500mg and 1000mg. Next, production examples of the raw materials of the present invention and examples for obtaining target compounds will be shown. Production example of raw materials 1 (1) Sodium hydrogen carbonate (10.6g) in water (220ml)
1-allyl-1H-tetrazole-5-thiol (21.3 g) was added to the solution at 76-78°C over 15 minutes to form the sodium salt of 7-(5-amino-5-carboxyvaleramido)cephalosporanic acid. After adding (54.9g), the mixture was heated to 76-78℃.
The mixture was stirred for 80 minutes. The reaction mixture was heated to 6N under ice-cooling.
After adjusting the pH to 3.0 with hydrochloric acid, it was filtered. The filtrate is treated with nonionic adsorption resin “Diaion HP-20”.
(Trademark: Mitsubishi Chemical Industries, Ltd.) column chromatography and eluted with 30% aqueous isopropyl alcohol. The eluate was adjusted to pH 6.5 with a 28% ammonia aqueous solution, concentrated and lyophilized to give 7-(5-amino-5-carboxyvaleramide)-3-(1-allyl-1H-tetrazol-5-yl). ) Ammonium salt of thiomethyl-3-cephem-4-carboxylic acid (21.7
g) was obtained. IR (nujiol): 3175, 1760, 1590 cm ^-1 NMR (d ₆ -DMSO, δ): 1.23-2.42 (6H, m),
3.12-3.97 (3H, m), 4.37 (2H, broads), 4.80-5.15 (3H, m), 5.15-5.51
(2H, m), 5.51−6.25 (2H, m), 8.77
(1H, d, J=8Hz) (2) 7-(5-amino-5-carboxyvaleramide)-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
N,N-dimethylaniline (18.2 ml) was added to a mixture of ammonium salt of carboxylic acid (10.0 g), trimethylsilyl chloride (20.9 g) and methylene chloride (75 ml), and the mixture was stirred under reflux for 2.5 hours. After adding phosphorus pentachloride (5.83 g) at -30 to 35°C, the mixture was stirred at the same temperature for 2 hours. 2 at the same temperature
-Ethoxyethanol (38 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Water (80 ml) was added over 10 minutes at -5 to -10°C, and the mixture was stirred at the same temperature for 5 minutes. Separate the aqueous layer and PH with 28% ammonia aqueous solution.
4.2, the precipitate was filtered, washed with 70% aqueous acetone (40 ml) and methanol (40 ml), and dried to give 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl- 3-cephem-4-carboxylic acid (4.1 g) was obtained. IR (nujiol): 3150, 1800, 1610, 1530 cm ^-1 NMR (d ₆ -DMSO, δ): 3.65 (2H, ABq, J
= 18Hz), 4.33 (2H, ABq, J = 13Hz),
6.38-4.70 (7H, m) Production Example 2 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) in the presence of potassium carbonate (72.3 g) and N,N-dimethylformamide (280 ml) 56.7 g) and 2-propynyl bromide (43
g) was reacted to obtain ethyl 2-(2-propynyloxyimino)-3-oxobutyrate (syn isomer) (71.2 g). IR (liquid film): 3280, 3220, 2120, 1735, 1670 cm ^-1 (2) Ethyl 2-(2-propynyloxyimino)-3-oxobutyrate (syn isomer) (71.2 g) and sulfuryl chloride (50.2 g) ) in acetic acid (80 ml) to give 2-(2-propynyloxyimino)
Ethyl -3-oxo-4-chlorobutyrate (syn isomer) (61.6 g) was obtained. IR (liquid film): 3300, 2130, 1745, 1720, 1675 cm ^-1 (3) Ethyl 2-(2-propynyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer)
(61 g) and thiourea (20 g) were reacted in the presence of sodium acetate trihydrate (35.8 g), water (150 ml) and ethanol (180 ml).
Ethyl (2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer) (35.6 g) was obtained. IR (Nudiyol): 3290, 2220, 1729 cm ^-1 (4) 2-(2-propynyloxyimino)-2-
(2-Aminothiazol-4-yl)ethyl acetate (syn isomer) (2.8 g), 1N aqueous sodium hydroxide solution (22.17 ml), methanol (23 ml)
and hydrolyzed in the presence of tetrahydrofuran (20 ml) to give 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl).
Acetic acid (syn isomer) (1.924 g) was obtained. IR (Nujiol): 2190, 1740 cm ^-1 Production Example 3 To acetic anhydride (239 g) was added sulfuric acid (107 g) under ice cooling, and the mixture was stirred at 50°C for 1 hour and then cooled to 20°C.
2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl) was added to the resulting mixture.
Acetic acid (syn isomer) (135 g) was added, and the mixture was stirred at room temperature for 3 hours. Diisopropyl ether (400 ml) was added to this mixture, and the precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried.
(2-Propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (118.4 g) was obtained. IR (Nujiyor): 3250, 2130, 1685, 1600,
1560cm ^-1 NMR (d ₆ -DMSO, δ): 3.53 (1H, m) 4.87
(2H, d, J=2Hz), 7.63 (1H, s),
8.61 (1H, s), 12.7 (1H, broad s) Production example 4 2-(2-formamidothiazol-4-yl)
Allyloxyamine hydrochloride (19.8 g) was added to an aqueous solution of glyoxylic acid (30 g) and sodium hydrogen carbonate (12.6 g), and the mixture was stirred at room temperature and pH 6 for 7 hours. After adding ethyl acetate (500 ml) to the reaction mixture, the pH was adjusted to 1.9 with 10% hydrochloric acid, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off. The product was triturated in diisopropyl ether, filtered and dried to give 2-allyl-
Oximino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (25.3 g) was obtained. IR (nujiol): 3110, 1730, 1660, 1540 cm ^-1 NMR (d ₆ , DMSO, δ): 4.70 (2H, m), 5.13
−5.60 (2H, m), 5.73−6.27 (1H, m),
7.57 (1H, s), 8.35 (1H, s) Reference example (1) Add chloride to a solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) (48.9 g) in acetic acid (49 ml) at room temperature with stirring. Sulfuryl (35.2 g) was added at once and stirred at the same temperature for 1 hour. Water (200 ml) was added to the resulting solution and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous sodium bicarbonate solution, and washed with water. This solution was dried over magnesium sulfate and then concentrated under reduced pressure to obtain ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (53.8 g) as a pale yellow oil. (2) Ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (38.4g), thiourea (13.2g), sodium acetate (14.3g), methanol (95ml) and water (95ml) mixture at 48℃
After stirring for 40 minutes, the pH was adjusted to 6.5 with an aqueous sodium hydrogen carbonate solution. The generated precipitate is collected by filtration,
After washing with diisopropyl ether, 2-ethoxyimino-2-(2-aminothiazole-4-
Ethyl acetate (syn isomer) (14.7 g) was obtained. mp130~131℃ IR (Nujiyor): 3450, 3275, 3125, 1715,
1620cm ^-1 (3) Add 2-ethoxyimino to a mixture of 1N sodium hydroxide (45.9ml) and ethanol (30ml).
Ethyl 2-(2-aminothiazol-4-yl)acetate (syn isomer) (5 g) was added, and the mixture was stirred at room temperature for 5 hours. After distilling off ethanol from the product solution under reduced pressure, the residue was dissolved in water (60 ml),
The pH was adjusted to 2.0 with 10% hydrochloric acid. The resulting solution was salted out, the precipitate was collected by filtration, and dried to give 2-ethoxyimino-2-(2-aminothiazole-4-
yl) acetic acid (syn isomer) (2.9 g) was obtained. IR (Nujiyor): 3625, 3225 (Shoulder),
3100, 1650, 1615 cm ^-1 NMR (d ₆ -DMSO, δ): 1.20 (3H, t, J=
7Hz), 4.09 (2H, q, J = 7Hz), 6.82
(1H, s), 7.24 (2H, broad s) (4) 2-ethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (100
g), acidic acid (85.5g) and acetic anhydride (190.1g)
was treated in the same manner as in Production Example 3 to obtain 2-ethoxyimino-2-(2-formamidothiazole-4-
yl) acetic acid (syn isomer) (99.1 g) was obtained. IR (nujiol): 3200, 3140, 3050, 1700 cm ^-1 NMR (d ₆ -DMSO, δ): 1.18 (3H, t, J =
6Hz), 4.22 (2H, q, J = 6Hz), 7.56
(1H, s), 8.56 (1H, s), 12.62 (1H, broad s) Production example 5 (1) Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (126.4 g), diic acid (81.3 g) and acetic anhydride (180 g) were treated in the same manner as in Production Example 3, and 2-hydroxyimino-2-(2-formamidothiazol-4-yl)ethyl acetate (syn isomer )
(109.6g) was obtained. IR (Nujiyor): 3320, 3140, 3050, 1710,
1555cm ^-1 NMR (d ₆ -DMSO, δ): 1.30 (3H, t, J=
7Hz), 4.33 (2H, q, J = 7Hz), 7.54
(1H, s), 8.54 (1H, s), 11.98 (1H,
s), 12.58 (1H, s) (2) Chloromethylthiomethane (7.97g), potassium iodide powder (15.1g) and acetone (79ml)
The mixture was stirred at room temperature for 1 hour and the product was filtered and washed with a small amount of acetone. The washing solution and filtrate were combined to give 2-hydroxyimino-2-(2-
Add to a suspension of ethyl formamidothiazol-4-yl) acetate (syn isomer) (17.5 g) and potassium carbonate powder (15.5 g) in acetone (300 ml), stir at room temperature for 3 hours, then filter and wash with acetone. did. The washing liquid and filtrate were combined and concentrated under reduced pressure. The product was dissolved in ethyl acetate, washed with twice the amount of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue was developed on silica gel column chromatography and eluted with chloroform to obtain 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)ethyl acetate (syn isomer) (2.4 g). Ta. mp.130~130℃. IR (Nujiyor): 3160, 3125, 3050, 1740,
1695cm ^-1 NMR (d ₆ -DMSO, δ): 1.32 (3H, t, J=
7Hz), 2.22 (3H, s), 4.38 (2H, q, J
=7Hz), 5.33 (2H, s), 7.67 (1H, s),
8.56(1H,s) (3) 2-methylthiomethoxyimino-2-(2-
Ethyl formamidothiazol-4-yl) acetate (syn isomer) (2.4 g), 1N aqueous sodium hydroxide solution (23.8 ml) and methanol (19.8 ml)
The mixture was stirred at 30°C for 2.5 hours. The generated liquid
After adjusting the pH to 7 with 10% hydrochloric acid, methanol was distilled off under reduced pressure. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling, and extracted three times with ethyl acetate.
The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to obtain 2-methylthiomethoxyimino-2-(2
-formamidothiazol-4-yl)acetic acid (syn isomer) (1.13 g) was obtained. mp.157℃ (decomposition) IR (nujiol): 3210, 3160, 3075, 1700,
1555cm ^-1 NMR (d ₆ -DMSO, δ): 2.24 (3H, s), 5.31
(2H, s), 7.61 (1H, s), 8.57 (1H,
s), 12.73 (1H, s) Production Example 6 The following compound was obtained in the same manner as Production Examples 2 to 5. 2-tertiary butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)
Acetic acid (syn isomer). mp.117℃ (decomposition) IR (nujiol): 3180, 3140, 1750, 1690,
1630 cm ^-1 Production Example 7 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) was reacted with cyclopentyl bromide in a conventional manner to obtain the following compound. (i) Ethyl 2-cyclopentyloxyimino-3-oxobutyrate (syn isomer). Oily substance. IR (liquid film): 1740, 1670, 1495, 1430 cm ^-1 NMR (CCl ₄ , δ): 1.32 (3H, t, J = 7Hz),
1.4−2.2 (8H, m), 2.33 (3H, s), 4.27
(2H, q, J=7Hz), 4.87 (1H, m) (2) The following compound was obtained in the same manner as in Reference Example-(1). (i) Ethyl 2-cyclopentyloxyimino-3-oxo-4-chlorobutyrate (syn isomer).
Oily substance. IR (liquid film): 1750, 1735, 1465, 1435 cm ^-1 NMR (CCl ₄ , δ): 1.33 (3H, t, J = 7Hz),
1.3−2.4 (8H, m), 4.28 (2H, q, J=7
Hz), 4.46 (2H, s), 4.86 (1H, m) (3) The following compound was obtained in the same manner as in Reference Example-(2). (i) 2-cyclopentyloxyimino-2-
(2-aminothiazol-4-yl)ethyl acetate (syn isomer). mp.134-136℃. IR (Nujiyor): 3490, 3450, 3250, 3120,
1735, 1540, 1460 cm ^-1 NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J=
7Hz), 1.62 (8H, broad s), 4.27 (2H,
q, J=7Hz), 4.70 (1H, m), 6.85 (1H,
s), 7.20 (2H, s) (4) The following compound was obtained in the same manner as in Reference Example-(3). (i) 2-cyclopentyloxyimino-2-
(2-aminothiazol-4-yl)acetic acid (syn isomer). mp.186℃ (decomposition) IR (Nujiol): 3330, 3120, 1635, 1450cm ^-1 NMR (DMSO-d ₆ , δ): 1.1-2.2 (8H, m),
4.68 (1H, m), 6.81 (1H, s) 7.18 (2H,
Broad S) (5) The following compound was obtained in the same manner as in Production Example 3. (i) 2-cyclopentyloxyimino-2-
[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer). IR (Nujiyor): 3200, 3130, 1720, 1590,
1580cm ^-1 NMR (DMSO-d ₆ , δ): 1.34-2.22 (8H, m),
4.81 (1H, m), 7.71 (1H, s) Production Example 8 The following compounds were obtained in the same manner as in Examples 1 to 4 described below. 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazole-4
-yl)acetamide]-3-(1-allyl-1H
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3250, 1780, 1720, 1680,
1540cm ^-1 NMR ( _d6 -DMSO, δ): 1.44 (9H, s), 3.71
(2H, ABq, J=18Hz), 4.37 (2H, ABq,
J = 14Hz), 4.62 (2H, s), 4.8-5.4 (5H,
m), 5.5-6.4 (2H, m), 7.46 (1H, s),
8.52 (1H, s), 9.58 (1H, d, J=8Hz),
12.60 (1H, broad s) Production Example 9 The following compound was obtained in the same manner as in Examples 6 to 9 described below. 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)
acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer). IR (Nujiyor): 3330, 1780, 1730, 1680,
1630 cm ^-1 Production Example of Target Substance 1 In dry ethyl acetate (0.75 ml), dry dimethylformamide (0.25 g) and phosphorus oxychloride (0.528
2-allyloxyimino-2-(2-formamidothiazole-4
-yl)acetic acid (syn isomer) (0.80 g) and dry ethyl acetate (10 ml) were added, and the mixture was stirred at the same temperature for 30 minutes to obtain a yellow solution. This solution was added to 7-amino-3
-(1-allyl-1H-tetrazol-5-yl)
The mixture was added to a solution of thiomethyl-3-cephem-4-carboxylic acid (1.11 g) and trimethylsilylacetamide (2.96 g) in dry ethyl acetate (15 ml) at -10°C with stirring, and the mixture was stirred at the same temperature for 1.5 hours.
After adding water (15 ml) to this reaction mixture, the ethyl acetate layer was separated and an aqueous sodium bicarbonate solution (30 ml) was added to the reaction mixture.
ml). PH the aqueous extract with 10% hydrochloric acid
After adjusting to 2.0, extraction was performed with ethyl acetate (150 ml), and the extract was washed with water, dried, and concentrated. The residue was triturated in diisopropyl ether to give 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamide] as a colorless powder.
-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g) was obtained. IR (nujiol): 3180, 1775, 1665 cm ^-1 NMR (d ₆ -DMSO, δ): 9.68 (1H, d, J =
8Hz), 8.51 (1H, s), 7.40 (1H, s),
5.60-6.33 (3H, m), 4.85-5.57 (7H,
m), 4.27-4.77 (4H, m), 3.70 (2H,
ABq, J = 18 Hz) Example 2 Vilsmeier reagent was prepared from dry dimethylformamide (2.6 g), phosphorus oxychloride (5.4 g) and dry ethyl acetate (10.4 ml), and to this was added dry ethyl acetate (100 ml). ) was added, and then 2-cyclopentyloxyimino-2-[2-
(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (10.4g)
added. This mixture was stirred at the same temperature for 30 minutes. The resulting product mixture was converted into 7-amino-3-
(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (9.6
g) and trimethylsilylacetamide (24.8g)
The mixture was added to a solution of dry ethyl acetate (192 ml) at -10°C with stirring, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the ethyl acetate layer was separated and extracted with an aqueous sodium hydrogen carbonate solution (PH7.5). The aqueous layer was washed with twice the amount of ethyl acetate, and after adding ethyl acetate and tetrahydrofuran, it was washed with 10% hydrochloric acid.
Adjusted to PH2.0. The oil layer was separated, washed with water, dried over magnesium sulfate, treated with activated carbon, and evaporated to dryness. The residue was triturated in diethyl ether, the powder was filtered off and washed with diethyl ether.
7-[2-cyclopentyloxyimino-2-{2
-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamide]-3-(1-
Allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (18.18 g) was obtained. NMR (DMSO-d ₆ , δ): 1.28-2.26 (8H, m)
3.73 (2H, m), 4.39 (2H, ABq, J=14
Hz), 4.77 (1H, m), 4.88-5.47 (5H,
m), 5.70-6.52 (2H, m), 7.50 (1H,
s), 9.67 (1H, d, J = 8.0Hz) Example 3 Vilsmeier reagent was prepared from dry dimethylformamide (0.5g), phosphorus oxychloride (1.3g) and dry ethyl acetate (2.0ml) by a conventional method. . Dry tetrahydrofuran (18 ml) was added to this, and 2-(2-propynyl)oxyimino-2 was further heated at 0°C.
-2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.6 g) was added, and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was converted into 7-amino-3-
(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0
g) trimethylsilylacetamide (5.1g)
The mixture was added to dry ethyl acetate (40 ml) at -10°C with stirring, and stirred at -10°C to -20°C for 1 hour. Water (30 ml) was added to the reaction mixture, and the oil layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate. After adjusting the aqueous layer to pH 2.2 with concentrated hydrochloric acid, the precipitate was collected by filtration, washed with water, and dried to form a colorless powder of 7-[2-(2-propynyl).
Oximino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer)
(2.40g) was obtained. IR (nujiol): 3310, 2170, 1780, 1680 cm ^-1 NMR (d ₆ -DMSO, δ): 3.49 (1H, m) 3.72
(2H, m), 4.38 (2H, ABq, J=14Hz),
4.57-5.52 (7H, m), 5.69-6.40 (2H,
m), 7.46 (1H, s), 8.55 (1H, s), 9.75
(1H, d, J=8Hz) Example 4 Dry dimethylformamide (0.209g), phosphorus oxychloride (0.434g) and dry ethyl acetate (0.75ml)
A Vilsmeier reagent was prepared from the following by a conventional method. Dry tetrahydrofuran (6.5 ml) was added to this, and 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl) was further heated at 0°C.
Add acetic acid (syn isomer) (0.65g) and stir at the same temperature.
Stir for 30 minutes. On the other hand, 7-amino-3-(1-
Allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.25g)
and water adjusted to pH 7.5 with triethylamine (10
ml) and acetone (10 ml) in a solvent, stir, and add the previously obtained mixture to this at -5 to 0°C.
The mixture was added at pH 7.5 and stirred at the same temperature for 30 minutes.
Ethyl acetate (60 ml) was added to this reaction mixture, the pH was adjusted to 2.5 with 10% hydrochloric acid, insoluble matter was filtered off, and the filtrate was extracted with twice the amount of ethyl acetate.
The extracts were combined, washed with twice the amount of saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.
The solvent was evaporated and the residue was triturated in diethyl ether to give a yellowish powder of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-(1- Allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(1.03g) was obtained. IR (Nujiyor): 3250, 3200, 1780, 1670,
1540cm ^-1 NMR (d ₆ -DMSO, δ): 2.23 (3H, s) 3.72
(2H, s), 4.38 (2H, ABq, J=14Hz),
4.8-5.6 (7H, m), 5.7-6.4 (2H, m),
7.48 (1H, s), 8.55 (1H, s), 9.75 (1H,
d,, J=8Hz), 12.69 (1H, broad s) Example 5 The following compound was obtained in the same manner as Examples 1 to 4. (1) 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamide]-
3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 3350, 3210, 1778, 1675cm ^-1 (2) 7-[2-(2-propynyl)oxyimino-
2-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer). IR (Nujiyor): 3330, 2170, 1780, 1683,
1630cm ^-1 (3) 7-[2-methylthiomethoxyimino-2-
(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (nujiol): 3270, 1760, 1650, 1520 ^{cm -1} (4) 7-[2-carboxymethoxyimino-2-
(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (Nudiyol): 3360, 1780, 1680, 1630cm ^-1 (5) 7-[2-Cyclopentyloxyimino-2
-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer). mp.140~145℃
(Disassembly). IR (Nudiyol): 3300, 1770, 1660, 1620 cm ^-1 Example 6 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamide]
-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.30 g) in methanol (13 ml) was added with concentrated hydrochloric acid (0.33 g). and stirred at room temperature for 4.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate (25 ml). After washing this aqueous solution with ethyl acetate (25 ml),
% of hydrochloric acid, the resulting precipitate was collected by filtration, washed with water, and dried to obtain a colorless powder of 7-[2-allyloxyimino-2-(2-aminothiazole-4).
-yl)acetamide]-3-(1-allyl-1H
-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95g)
I got it. IR (nujiol): 3350, 3210, 1778, 1675 cm ^-1 NMR (d ₆ -DMSO, δ): 3.68 (2H, ABq, J
= 18Hz), 4.40-4.71 (4H, m), 4.80-5.45
(7H, m), 5.64-6.24 (3H, m), 6.74
(1H, s), 7.35 (2H, broad s), 9.62
(1H, d, J=8Hz) Example 7 7-[2-cyclopentyloxyimino-2-
{2-(2,2,2-trifluoroacetamide)
thiazol-4-yl}acetamide]-3-(1
-Allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (18.0 g) and tetrahydrofuran (36 ml)
was added to a solution of sodium acetate trihydrate (35.6 g) in water (360 ml), and after stirring at room temperature for 18 hours,
Tetrahydrofuran was distilled off from the reaction mixture.
The residual liquid was adjusted to PH3.0 with 15% hydrochloric acid, and the resulting precipitate was washed with water and dried to obtain crude 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamide]. -3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
(20g) was obtained. This crude product was subjected to column chromatography using aluminum oxide (60 ml) for 3 to 5
% sodium acetate aqueous solution as eluent,
The pure target substance (8.31 g) was obtained. mp.140~145
°C (decomposition). IR (nujiol): 3300, 1770, 1660, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.16-2.26 (8H, m),
3.73, (2H, m), 4.41 (2H, ABq, J=14
Hz), 4.68 (1H, m), 4.89-5.52 (5H,
m), 5.62-6.43 (2H, m), 6.73 (1H,
s), 9.51 (1H, d, J=8Hz) Example 8 7-[2-(2-propynyl)oxyimino-2
-(2-formamidothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
Concentrated hydrochloric acid (0.3 g) was added to a solution of -carboxylic acid (syn isomer) (2.0 g) in methanol (14 ml), and the mixture was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate.
After washing this aqueous solution with ethyl acetate, the pH was adjusted using concentrated hydrochloric acid.
Adjusted to 2.8. The generated precipitate was collected by filtration, washed with water, and dried to give 7-[2-(2-propynyl)oximino-2-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazole). -5-yl)thiomethyl-3-cephem-4
-carboxylic acid (syn isomer) (1.43 g) was obtained. IR (Nujiyor): 3330, 2170, 1780, 1680,
1630cm ^-1 NMR (d ₆ -DMSO, δ): 3.46 (1H, m) 3.70
(2H, m), 4.37 (2H, ABq, J=13.5Hz
s), 4.57-5.47 (7H, m), 5.60-6.49
(2H, m), 6.77 (1H, s), 7.25 (2H, broad s), 9.64 (1H, d, J = 8.0Hz) Example 9 7-[2-methylthiomethoxyimino-2-(2
-formamidothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95g) Concentrated hydrochloric acid (0.324g)
g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours.
The solvent was distilled off under reduced pressure, the residue was dissolved in a saturated aqueous solution of sodium hydrogen carbonate, and this aqueous solution was washed with ethyl acetate (25 ml), and then adjusted to pH 1.5 with 10% hydrochloric acid. The generated precipitate was collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2
-aminothiazol-4-yl)acetamide]
-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.78 g) was obtained. IR (nujiol): 3270, 1760, 1650, 1520 cm ^-1 NMR (d ₆ -DMSO, δ): 2.21 (3H, s), 3.72
(2H, s), 4.38 (2H, ABq, J=14Hz),
4.8-5.6 (7H, m), 5.7-6.4 (2H, m),
6.80 (1H, s), 7.26 (2H, broad s),
9.66 (1H, d, J=8Hz) Example 10 The following compound was obtained in the same manner as in Examples 6-9. (1) 7-[2-carboxymethoxyimino-2-
(2-aminothiazol-4-yl)acetamido-3-(1-allyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 3360, 1780, 1680, 1630 cm ^-1 Example 11 7-[2-tertiary butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)
acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
To a suspension of 4-carboxylic acid (syn isomer) (2.05 g) in anisole (2 ml) was added trifluoroacetic acid (20 ml) while stirring under ice cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the resulting precipitate was collected by filtration, washed with diethyl ether, dried, and dissolved in an aqueous sodium hydrogen carbonate solution. After filtering off insoluble matter, the filtrate was adjusted to pH 3.2 with concentrated hydrochloric acid, and the formed precipitate was collected by filtration, washed with water, and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazole-4- )
acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer) (0.8 g) was obtained. IR (nujiol): 3360, 1780, 1680, 1630 cm ^-1 NMR (d ₆ -DMSO, δ): 3.68 (2H, ABq, J
= 19Hz), 4.36 (2H, ABq, J = 14Hz),
4.60 (2H, s), 4.60-6.2 (7H, m), 6.80
(1H, s), 7.24 (2H, broad s), 9.51
(1H, d, J = 9 Hz) Example 12 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (4.8 g) was added at pH 6. Four
1- in phosphate buffer (100 ml)
Allyl-1H-tetrazole-5-thiol (2.1
g) was added and stirred at 55-60°C for 2 hours. After cooling the reaction mixture, adjust the pH to 3.0 with 10% hydrochloric acid.
The generated precipitate was collected by filtration, washed with water and dried to give 7-[2-
Allyloxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer)
(2.0g) was obtained. IR (nujiol): 3350, 3210, 1778, 1675 cm ^-1 NMR (DMSO-d ₆ , δ): 3.68 (2H, ABq, J
= 18Hz), 4.40-4.71 (4H, m), 4.80-5.45
(7H, m), 5.64-6.24 (3H, m), 6.74
(1H, s), 7.35 (2H, broad s), 9.62
(1H, d, J=8Hz) Example 13 The following compound was obtained in the same manner as in Example 12. (1) 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 3180, 1775, 1665 cm ^-1 (2) 7-[2-(2-propynyl)oximino-
2-(2-formamidothiazol-4-yl)
acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nudiyol): 3310, 2170, 1780, 1680 ^{cm -1} (3) 7-[2-methylthiomethoxyimino-2-
(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). IR (Nujiyor): 3250, 3200, 1780, 1670,
1540cm ^-1 (4) 7-[2-(2-propynyl)oxyimino-
2-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer). IR (Nujiyor): 3330, 2170, 1780, 1683,
1630cm ^-1 (5) 7-[2-methylthiomethoxyimino-2-
(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (nujiol): 3270, 1760, 1650, 1520 ^{cm -1} (6) 7-[2-carboxymethoxyimino-2-
(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). IR (Nudiyol): 3360, 1780, 1680, 1630cm ^-1 (7) 7-[2-cyclopentyloxyimino-2
-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4
-Carboxylic acid (syn isomer). mp.140~145℃
(Disassembly). IR (nujiyor): 3300, 1770, 1660, 1620cm
^-1 .

Claims (1)

[Claims] 1. General formula (wherein R ¹ is amino or protected amino,
R ² is lower alkenyl, lower alkynyl, cyclo(lower) alkyl, lower alkylthio(lower) alkyl or carboxy(lower) alkyl, R ³
3,7-di-substituted-3-cephem-4- represented by: carboxy or protected carboxy, R ⁴ means tetrazolyl having a lower alkenyl, respectively)
Carboxylic acid compounds and their salts. 2. A syn isomer of the compound according to claim 1, wherein [Formula] is [Formula]. 3 R ¹ is amino or lower alkanoylamino,
Claim 2 in which R ² is lower alkenyl
Compounds described in Section. 4 R ¹ is amino or formamide, R ² is allyl,
4. The compound according to claim 3, wherein R ⁴ is allyl-containing tetrazolyl. 5 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamide]-3
-(1-allyl-1H-tetrazol-5-yl)
The compound according to claim 4, which is thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 6 R ¹ is amino or lower alkanoylamino,
Claim 2 in which R ² is lower alkynyl
Compounds described in Section. 7. The compound according to claim 6, wherein R ¹ is amino or formamide, R ² is 2-propynyl, and R ⁴ is allyl-containing tetrazolyl. 8 7-[2-(2-propynyl)oxyimino-
2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) A compound according to scope item 7. 9. The compound according to claim 2, wherein R ¹ is amino or halo (lower) alkanoylamino, and R ² is cyclo (lower) alkyl. 10. The compound according to claim 9, wherein R ¹ is amino or trifluoroacetamide, R ² is cyclopentyl, and R ⁴ is allyl-containing tetrazolyl. 11 7-[2-cyclopentyloxyimino-
2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) A compound according to Range 10. 12. The compound according to claim 2, wherein R ¹ is amino, lower alkanoylamino or halo (lower) alkanoylamino, and R ² is lower alkylthio (lower) alkyl or carboxy (lower) alkyl. 13. The compound according to claim 12, wherein R ¹ is amino, formamide or trifluoroacetamide, R ² is carboxymethyl or methylthiomethyl, and R ⁴ is allyl-bearing tetrazolyl. 14 7-[2-carboxymethoxyimino-2
-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazole-
Claim 1 which is 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
Compound according to item 3. 15 7-[2-methylthiomethoxyimino-2
-(2-aminothiazol-4-yl)acetamide]-3-(1-allyl-1H-tetrazole-
Claim 1 which is 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
Compound according to item 3. 16 General formula (wherein R ¹ is amino or protected amino,
R ² is lower alkenyl, lower alkynyl, cyclo(lower) alkyl, lower alkylthio(lower) alkyl or carboxy(lower) alkyl, R ³
3,7-di-substituted-3-cephem-4- represented by: carboxy or protected carboxy, R ⁴ means tetrazolyl having a lower alkenyl, respectively)
When producing carboxylic acid compounds or their salts, the general formula (wherein R ³ and R ⁴ have the same meanings as above) or a reactive derivative thereof at the amino group or a salt thereof, the general formula (wherein R ¹ and R ² have the same meanings as above) or a reactive derivative thereof at the carboxy group or a salt thereof is applied to the 3,7-disubstituted-3-cepheme- 4-
A method for producing a carboxylic acid compound or its salts.