JPH04288086A - New cephem compound - Google Patents

Abstract

PURPOSE:To obtain a new cephem compound, having high antimicrobial activity and useful as an antimicrobial agent due its inhibition to growth of a wide range of pathogenic germs. CONSTITUTION:A compound expressed by formula I [R<1> is (protected) amino; Z is N or CH; -W- us formula II or III (R<3> is H or organic group); R<2> is (protected) carboxy or group COO<->; A is lower alkylene or lower alkenylene in which oxo can be contained; R<6> is H, lower alkyl, etc.; Y is N or N<+>-R<4> (R<4> is lower alkyl or lower alkoxy-lower alkyl), provided that R us other than COO when Y is N and R<2> is COO<-> when Y is N<+>-R<4>] and its salt, e.g. 7beta-[2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydropyraz olo[1,5- a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid. The aforementioned compound is obtained by reacting, e.g. a compound expressed by formula IV (X<1> is acid residue) with a compound expressed by formula V in a solvent, preferably in the presence of a base such as pyridine.

Description

[Detailed description of the invention]

0001

FIELD OF INDUSTRIAL APPLICATION This invention relates to a novel cephem compound having high antibacterial activity, and is used in the medical field.

0002

BACKGROUND OF THE INVENTION Although many cephem compounds are known, the cephem compound represented by the following general formula (I) of the present invention is not known.

0003

[Problems to be Solved by the Invention] Many cephem compounds that have antibacterial activity and are useful as pharmaceuticals are known.
This invention was made with the intention of developing even better medicines.

0004

SUMMARY OF THE INVENTION The present invention relates to novel cephem compounds and salts thereof. The target cephem compound and its salt are novel and can be represented by the following general formula (I). [wherein R1 is amino or protected amino, Z is N
or CH, (wherein R3 means hydrogen or an organic group), R2 is carboxy, protected carboxy or COO-, A
is lower alkylene or lower alkenylene which may have oxo, R6 is hydrogen, lower alkyl or lower alkoxycarbonyl, Y is N or N+-R4 (in the formula R
4 means lower alkyl or lower alkoxy (lower) alkyl), provided that (i) when Y is N, R2 is carboxy or protected carboxy, and (ii) when Y is N+-R4 , R2 is COO-. ]

The target compound (I) can be produced according to the following process. Process (1)

Process (2)

Process (3)

Process (4)

Process (5) In each of the above formulas, R1, R2, R4, R6, A, Y, Z, W
are as defined above, and X1 represents an acid residue.

The starting compound (II) is new and can be produced by the following method. Process A

0
011 Process (B)

Process (C)

Process (D)

Process (E)

Process (F)

Process (G) R7 is lower alkoxy, X represents an acid residue.

[0017] Compounds (I), (Ia) to (Ig)
, (III) and (IX) shall include syn isomers, anti isomers and mixtures thereof. Regarding the target compound (I), for example, syn isomer means a geometric isomer having a partial structure of the following formula (wherein R1, R3, and Z are each as defined above), and anti-isomer and means a geometric isomer having a partial structure of the following formula (wherein R1, R3, and Z are each as defined above), and all of these geometric isomers and mixtures thereof are within the scope of the present invention. included. In this specification, these geometric isomers and mixtures thereof are represented using the following partial structural formulas for convenience. (In the formula, R1, R3, and Z are each as defined above)

Suitable examples of pharmaceutically acceptable salts of the target compound (I) include conventional non-toxic salts, such as salts with inorganic bases, such as alkali metal salts (eg, sodium salts, potassium salts, etc.). ), alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.), ammonium salts; salts with organic bases, e.g. organic amine salts (e.g. triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.); addition salts with inorganic acids (e.g. hydrochlorides, hydrobromides, sulfates, phosphates, etc.); organic carboxylic acid or sulfonic acid addition salts ( e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); basic or acidic amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.) ) or acid addition salts, such as salts with bases and acid addition salts.

[0019] In the above and below descriptions of this specification, preferred examples and illustrations of the various definitions encompassed within the scope of the present invention will now be described in detail. "Lower" means, unless otherwise specified, a group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Suitable examples of the "lower alkyl moiety" in "lower alkyl" and "lower alkoxy (lower) alkyl" include straight chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl,
Examples include butyl, tertiary butyl, pentyl, hexyl, etc., and among them, C1-C4 alkyl is more preferred. Suitable examples of the "lower alkylene moiety" in the "lower alkylene which may have oxo" include linear or branched alkylene, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene. , ethyl ethylene, propylene, etc., and among them, C1-C4 alkylene is more preferred. Suitable examples of "lower alkenylene" include straight chain or branched alkenylene, such as vinylene, 1- or 2-propenylene,
Examples thereof include 1, 2, or 3-butenylene, 1, 2, 3, or 4-pentenylene, and among them, C1-C4 alkenylene is more preferred.

[0020] Suitable examples of the "acid residue" include halogen (eg, chlorine, bromine, iodine, etc.). Preferred examples of "protected amino" include acylamino or al(lower) which may have suitable substituents.
Mention may be made of amino groups substituted with conventional protecting groups such as alkyl (eg benzyl, trityl, etc.). Suitable "acyl moieties" in "acylamino" include carbamoyl, aliphatic acyl groups, and acyl groups containing aromatic rings or heterocycles. Suitable examples of the acyl include lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.); , 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butane) arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); al(lower) alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); and lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.). Suitable examples of "organic groups" include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl,
hexyl, etc.), mono (or di or tri) halo(lower) alkyl (e.g. fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl), lower alkenyl (e.g. vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3
or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl), lower alkynyl (such as ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), aryl (e.g. phenyl, naphthyl, etc.), ar(lower) alkyl, e.g. phenyl(lower) alkyl (e.g. benzyl, phenethyl, phenylpropyl, etc.) , Carboxy (lower) alkyl, the lower alkyl moiety can include those listed above, the lower alkyl moiety includes those listed above, and the protected carboxy moiety includes those listed below. Examples include protected carboxy (lower) alkyl and hydroxy protecting groups that can be used.

[0021] Suitable examples of "protected carboxy" include esterified carboxy. Further, preferable examples of the ester moiety include lower alkyl esters (for example, 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.)
, lower alkenyl esters (e.g. vinyl esters,
lower alkynyl esters (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxyalkyl esters (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.) ; lower alkylthioalkyl esters (e.g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(or di- or tri)halo(lower) alkyl esters (e.g. 2-iodoethyl ester, 2-iodoethyl ester, etc.); , 2,2-trichloroethyl ester, etc.); lower alkanoyloxy (lower)
Alkyl esters (e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester) ); lower alkanesulfonyl (lower) alkyl esters (e.g., mesyl methyl ester, 2-mesylethyl ester, etc.); al (lower) alkyl esters, e.g.
Phenyl (lower) alkyl ester, which may have more than ,4-
Dimethoxybenzyl ester, 4-hydroxy-3,5
aryl esters which may have one or more suitable substituents, such as substituted or unsubstituted phenyl esters (such as phenyl esters, tolyl esters, t-butyl phenyl esters, etc.); (xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower) alkylsilyl ester; lower alkylthioester (for example, methylthioester, ethylthioester, etc.).

Suitable examples of "lower alkoxy" and the "lower alkoxy moiety" in "lower alkoxy (lower) alkyl" and "lower alkoxycarbonyl" include straight chain or branched alkoxy, such as methoxy,
Examples include ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy, and more preferred among them are C1-C4
It is alkoxy. Suitable examples of "hydroxy protecting groups" include acyl and the like. Suitable examples of "acyl" include those exemplified above.

The method for producing the target compound and raw material compound of the present invention will be explained in detail below. Process (1) Compound (I) or a salt thereof is a compound (II) or a reactive derivative thereof at an amino group or a salt thereof.
I) or a reactive derivative at its carboxy group or a salt thereof. Suitable examples of reactive derivatives at the amino group of compound (II) include Schiff base-type imino compounds or their enamine-type tautomers formed by reacting compound (II) with carbonyl compounds such as aldehydes and ketones. ;
A silyl derivative formed by reacting compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl)acetamide], bis(trimethylsilyl)urea; Examples include derivatives formed by reaction with phosphorus trichloride or phosgene. Suitable examples of reactive derivatives at the carboxy group of compound (III) include those commonly used in the field of β-lactam chemistry, acid halides, acid anhydrides, active amides, active esters, and the like. Suitable examples of reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids (such as dialkyl phosphoric acids, phenyl phosphoric acids, diphenyl phosphoric acids, dibenzyl phosphoric acids, halogenated phosphoric acids, etc.), dialkyl phosphorous acids, sulfurous acids,
Thiosulfuric acid, sulfuric acid, sulfonic acid (such as methanesulfonic acid), aliphatic carboxylic acid (such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or mixed acid anhydrides with acids such as aromatic carboxylic acids (e.g. benzoic acid); symmetric acid anhydrides; imidazole, 4-substituted imidazole, 1-hydroxy-1H-benzotriazole, dimethylpyrazole, triazole or tetrazole. activated amides; or active esters (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester) , phenylthioester, p
-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-hydroxy compounds (
Examples include esters with N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.). . These reactive derivatives are
It can be appropriately selected depending on the type of compound (III) used. The reaction usually involves water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N
- common solvents such as dimethylformamide, pyridine,
It is carried out in an organic solvent that does not adversely affect the reaction. These customary solvents can also be used as a mixture with water. In this reaction, when compound (III) is used in the form of the free acid or its salt, the reaction is carried out using conventional 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'-carbonyl-
Bis(2-methylimidazole);Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N
-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride;
Oxalyl chloride; lower alkyl haloformate (e.g. ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-
sulfophenyl) isoxazolium inner salt; 1-(
p-chlorobenzenesulfonyloxy)-6-chloro-
It is preferable to carry out the reaction in the presence of a so-called Vilsmeier reagent prepared by reacting 1H-benzotriazole; N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, or the like. The reaction may 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,N-di(lower)alkylbenzylamine, etc. You can also do it. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Process (2) Compound (Ib) or a salt thereof can be produced by introducing a carboxy protecting group into compound (Ia) or a salt thereof. As the carboxy-protecting group-introducing agent used in this reaction, conventional esterifying agents such as alcohols or reactive derivatives thereof (eg, halides, sulfonates, sulfates, diazo compounds, etc.) can be mentioned. This reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal carbonates, tri(lower)alkylamines, pyridine, and the like. The reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. When alcohol is used as the carboxy-protecting group-introducing agent, the reaction is carried out in the presence of a condensing agent as exemplified in process (1).

Process (3) Compound (Id) or a salt thereof can be produced by subjecting compound (Ic) or a salt thereof to an amino-protecting group elimination reaction. This reaction is carried out by conventional methods such as hydrolysis and reduction. Hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid. Suitable bases include alkali metals (e.g. sodium, potassium, etc.), alkaline earth metals (e.g. magnesium, calcium, etc.), their hydroxides or carbonates or bicarbonates, trialkylamines (e.g. trimethylamine, triethylamine, etc.). etc.), picoline, 1,
5-diazabicyclo[4.3.0]non-5-ene, 1
,4-diazabicyclo[2.2.2]octane, 1,8
Mention may be made of inorganic and organic bases such as -diazabicyclo[5.4.0]undec-7-ene. Suitable acids include organic acids (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.) . Desorption using a Lewis acid such as trihaloacetic acid (such as trichloroacetic acid, trifluoroacetic acid, etc.) is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.). The reaction is usually carried out in a solvent such as water, alcohol (eg, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, a mixture thereof, or any other solvent that does not adversely affect the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. Reduction methods used in the elimination reaction include chemical reduction and catalytic reduction. Suitable reducing agents for use in chemical reduction include metals (e.g. tin, zinc, iron, etc.) or metal compounds (e.g. chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g. formic acid, acetic acid, propionic acid, etc.).
trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts for use in catalytic reduction include platinum catalysts (e.g., platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., palladium sponges, palladium black, palladium oxide, palladium on charcoal, etc.). ,
colloidal palladium, palladium barium sulfate, palladium barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.) , copper catalysts (eg reduced copper, Raney copper, Ullmann copper, etc.). The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide, mixtures thereof, and the like. Furthermore, when the acid used for chemical reduction is liquid, it can also be used as a solvent, and suitable solvents for use in catalytic reduction include diethyl ether, dioxane, tetrahydrofuran, etc., in addition to the solvents mentioned above. Mention may be made of the customary solvents or mixtures thereof. The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.

Process (4) Compound (If) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to an elimination reaction of the hydroxy protecting group. This reaction is the process (3) above.
Therefore, the description of process (3) can be referred to for the reagents to be used and reaction conditions such as solvent and reaction temperature.

Process (5) Compound (Ig) or a salt thereof can be produced by reacting compound (IX) or a salt thereof with compound (X) or a salt thereof. The reaction is carried out in solvents such as water, phosphate buffer, acetone, chloroform, acetonitrile, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide. However, the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. Hydrophilic solvents in the solvent may be used as a mixture with water. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling, room temperature, or heating. The reaction can also be performed using alkalis such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, sodium 2-ethylhexanoate, etc. Preferably, it is carried out in the presence of an inorganic or organic base such as a metal alkanoate.

Process (A) Compound (VI) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. This reaction can be carried out using solvents such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, etc. It can be carried out in an organic solvent that does not have an adverse effect on the The reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate, or an organic base such as a trialkylamine. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. This reaction is preferably carried out in the presence of an alkali metal halide (eg, sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (eg, sodium thiocyanate, potassium thiocyanate), or the like.

Process (B) Compound (VIII) or its salt is compound (VIa)
Alternatively, it can be produced by reacting a salt thereof with compound (VII). The reaction typically involves water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane,
Chloroform, methylene chloride, dimethylacetamide,
The reaction is carried out in a conventional solvent such as N,N-dimethylformamide or any other organic solvent that does not adversely affect the reaction. Among these solvents, hydrophilic solvents can be used as a mixture with water. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Process (C) Compound (IIa) or a salt thereof can be produced by subjecting compound (VIb) or a salt thereof to an amino-protecting group elimination reaction. This reaction is carried out in the process (3) described above.
), therefore, the description of process (3) can be referred to for the reagents to be used and reaction conditions such as solvent and reaction temperature. Also included within the scope of the present invention.

It can be manufactured by process (D). This reaction can be carried out in the same manner as in process (3) above, so the reagents used and reaction conditions (e.g. solvent, reaction temperature, etc.)
As for the process (3), those explained in the process (3) can be cited as they are.

Process (E) Compound (VIa) or a salt thereof can be produced by subjecting compound (VIc) or a salt thereof to a reduction reaction. This reaction can be carried out in the same manner as in Production Example 9 below.

Process (F) Compound (XII) or a salt thereof can be produced by reacting compound (IVa) or a salt thereof with compound (XI) or a salt thereof. This reaction can be carried out similarly to process (A).

Process (G) Compound (VId) or a salt thereof can be produced by subjecting compound (XII) or a salt thereof to a reduction reaction. This reaction can be carried out in the same manner as in Production Example 12-(1) below.

Processes (A) to (G) and (1) to (
Suitable salts of the target compound and the starting compound and their reactive derivatives in 5) include the same salts as exemplified for compound (I).

The target compound (I) and its pharmaceutically acceptable salts are novel and have high antibacterial activity, inhibiting the growth of a wide range of pathogenic bacteria including gram-positive and gram-negative bacteria, and are useful as antibacterial agents. It is. In order to demonstrate the usefulness of the target compound (I), minimum inhibitory concentration (MIC) test data for representative compounds belonging to the compound (I) are shown below. Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. Each test strain was cultured overnight in tryptocase-soy broth, and one loopful (108 viable bacteria/ml) was inoculated onto heart infusion agar (HI-agar) containing a representative test compound at each concentration level. After incubation at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was expressed in μg/ml. Test compound (1) 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(4,5
,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) Test results

When the object compound (I) of the present invention and its pharmaceutically acceptable salts are used for therapeutic purposes, the compound is used as an active ingredient in an organic or inorganic solid form suitable for oral administration, parenteral administration or external use. Alternatively, it may be administered as a conventional formulation with a pharmaceutically acceptable carrier such as a liquid excipient. These formulations may be solid dosage forms such as tablets, granules, powders, capsules, etc., or liquid dosage forms such as solutions, suspension syrups, emulsions, lemonades, etc. If necessary, the above formulations may contain various auxiliaries, stabilizers, wetting agents, and other commonly used additives, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, china clay, sucrose, corn starch, and talc. , gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. can be added. The dosage of compound (I) varies depending on the patient's age and other conditions, the type of disease, the type of compound used, etc., but in general, 1 dose for each patient.
From about 1 mg to about 4,000 mg or more can be administered per day. For the treatment of infectious diseases caused by pathogenic bacteria, the target compound (I) should be administered at an average dose of about 5 ml per dose.
0mg, 100mg, 250mg, 500mg, 100
0mg or 2000mg can be administered.

Next, the present invention will be explained in more detail with reference to production examples and examples. Production Example 1 (1) Sodium iodide (2.63 g) and 7β-tertiary butoxycarbonylamino-3-chloromethyl-3
-cephem-4-carboxylic acid benzhydryl (9.03
g) in N,N-dimethylformamide (27 ml) was added 4,5,6,7-tetrahydropyrazolo[1,5
-a] Add pyrimidine (5.4 g) under ice cooling. The mixture is stirred at room temperature for 1 hour and then poured into a mixture of water and ethyl acetate. The separated organic layer is washed with water and brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7β-tert-butoxycarbonylamino-3-(4,
Benzhydryl 5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylate (2.83 g) is obtained. IR (Nujol): 3150, 1775, 1710,
1560 cm-1 NMR (DMSO-d6, δ):
1.41 (9H, s), 1.92-1.98 (2H, m
), 2.79-2.96 (2H, m), 3.41 (2H
, br s), 3.85-3.91 (2H, m), 3
．． 97 (2H, br s), 5.14 (1H, d, J
= 5Hz), 5.31 (1H, d, J = 3Hz), 5.
55 (1H, dd, J = 8Hz, 5Hz), 6.95 (
1H, s), 7.05 (1H, d, J=3Hz), 7.
27-7.47 (10H, m), 8.05 (1H, d,
J=8Hz) The following compound is obtained in the same manner as in Production Example 1-(1). (2) 7β-tertiary butoxycarbonylamino-3
-(2,3-dihydro-1H-imidazo[1,2-b]
Pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid benzhydryl IR (Nujol): 3180, 1770, 1720,
1695, 1620 cm-1 NMR (DMSO-d6, δ): 1.45 (9H, s)
, 3.45-3.67 (4H, m), 3.75-4.1
4 (4H, m), 5.17 (1H, d, J=5Hz),
5.26 (1H, br s), 5.52 (1H, dd
, J=8Hz, 5Hz), 6.91 (1H, s), 7.
08-7.47 (10H, m), 7.08 (1H, br
s), 7.96 (1H, d, J=8Hz)

003
9] Production Example 2 (1) Anisole (2.7 ml) and 7β-tert-butoxycarbonylamino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl ) Trifluoroacetic acid (5.4 ml) is added to a solution of benzhydryl methyl-3-cephem-4-carboxylate (2.7 g) in dichloromethane (8.1 ml) under ice cooling. The mixture is stirred at room temperature for 1.5 hours and then poured into diisopropyl ether. The obtained precipitate was collected by filtration and 7β-amino-
3-(4,5,6,7-tetrahydropyrazolo[1,5
-a]pyrimidin-4-yl)methyl-3-cephem-
4-carboxylic acid ditrifluoroacetate (2.93g)
get. IR (Nujol): 3130, 1780, 1670,
1610 cm-1 NMR (DMSO-d6, δ):
1.92-2.28 (2H, m), 3.01-3.28
(2H, m), 3.57 (2H, br s), 3.8
9-4.10 (2H, m), 4.22 (2H, br
s), 5.18 (2H, br s), 5.73 (1H
, d, J=3Hz), 7.46(1H, d, J=3Hz
) The following compound is obtained in the same manner as in Production Example 2-(1). (2) 7β-amino-3-(2,3-dihydro-1
H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid ditrifluoroacetate IR (Nujol): 3130, 1780, 1655,
1590 cm-1 NMR (DMSO-d6, δ):
3.48-3.88 (4H, m), 3.89-4.28
(4H, m), 5.16 (1H, d, J=5Hz), 5
．． 25 (1H, d, J = 5Hz), 5.39 (1H, b
r s), 7.25 (1H, brs)

Production Example 3 (1) 7β-tertiary butoxycarbonylamino-3
-(4,5,6,7-tetrahydropyrazolo[1,5-
a] pyrimidin-4-yl)methyl-3-cephem-4
- Methyl iodide (
6 ml) at room temperature. The mixture was stirred at the same temperature for 8 hours and then poured into diisopropyl ether. The resulting precipitate was collected by filtration to give 7β-tert-butoxycarbonylamino-3-
(1-Methyl-4,5,6,7-tetrahydro-4-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylic acid benzhydryl iodide (8.1
5g) is obtained. IR (Nujol): 3250.1780, 1710,
1680, 1600 cm-1 NMR (DMSO-d6, δ): 1.46 (9H, s)
, 1.95-2.22 (2H, m), 3.32-3.6
8 (4H, m), 3.83 (3H, s), 3.97-4
．． 26 (4H, m), 5.15 (1H, d, J = 5Hz
), 5.56 (1H, dd, J=8Hz, 5Hz), 6
．． 06 (1H, d, J = 3Hz), 6.93 (1H, s
), 7.21-7.52 (10H, m), 7.95 (1
H, d, J = 8Hz), 8.01 (1H, d, J = 3H
z) The following compound is obtained in the same manner as in Production Example 3-(1). (2) 7β-tertiary butoxycarbonylamino-3
-[2,3-dihydro-5-methyl-1-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylic acid benzhydryl iodide IR (Nujol): 3250, 1770, 1700, 1655,
1580cm-1 NMR (DMSO-d6, δ): 1.48 (9H, s)
, 3.51-4.48 (8H, m), 3.84 (3H,
s), 5.21 (1H, d, J = 5Hz), 5.67 (
1H, dd, J=8Hz, 5Hz), 5.88 (1H,
d, J=3Hz), 6.93 (1H, s), 7.21-
7.52 (10H, m), 7.95 (1H, d, J=5
Hz), 8.08 (1H, d, J = 3Hz)

0041
] Production Example 4 7β-tertiary butoxycarbonylamino-3-(2,3
-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid benzhydryl (9.9 g) in formic acid (39.6 ml) and concentrated hydrochloric acid (2.97 ml). ) at room temperature. The mixture was stirred at the same temperature for 2 hours, and then poured into a mixture of acetone (300 ml) and ethyl acetate (600 ml) under ice cooling. The resulting precipitate was collected by filtration to give 7β-amino-3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid. The dihydrochloride (6.31 g) is obtained. IR (Nujol): 3120, 1780, 1710,
1590cm-1 NMR (D2O, δ): 3.57
and 3.81 (2H, ABq, J=18Hz), 3.
88-4.51 (6H, m), 5.18 (1H, d, J
= 5Hz), 5.19 (1H, d, J = 3Hz), 5.
34 (1H, d, J = 5Hz), 7.88 (1H, br
s)

Production Example 5 (1) 7β-tertiary butoxycarbonylamino-3
-(1-methyl-4,5,6,7-tetrahydro-4-
Pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-3-carboxylic acid benzhydryl iodide (8.
1 g) and anisole (8.1 ml) in dichloromethane (
24.3 ml) solution and trifluoroacetic acid (16.2 ml).
) under ice-cooling. The mixture is stirred at room temperature for 2 hours and then poured into diisopropyl ether. The resulting precipitate was collected by filtration to give 7β-amino-3-(1-methyl-4,5,6,7
-tetrahydro-4-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate.
Ditrifluoroacetate (4.78 g) is obtained. IR (Nujol): 3130, 1780, 1660,
1600cm-1 NMR (DMSO-d6, δ):
2.06-2.38 (2H, m), 3.15-3.41
(2H, m), 3.55 (2H, br s), 3.8
7 (3H, s), 4.07-4.28 (2H, m), 4
．． 40 (2H, br s), 5.20 (2H, br s)
s), 6.22 (1H, d, J=3Hz), 8.08
(1H, d, J=3Hz) The following compound is obtained in the same manner as in Production Example 5-(1). (2) 7β-amino-3-[2,3-dihydro-5
-Methyl-1-(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate ditrifluoroacetate IR (Nujol): 3370, 1770, 1660,
1590 cm-1 NMR (DMSO-d6, δ):
3.50 and 3.75 (2H, ABq, J=18Hz
), 3.72-4.52 (6H, m), 3.85 (3H
, s), 5.09 (1H, d, J=5Hz), 5.20
(1H, d, J=5Hz), 6.03 (1H, d, J=
3Hz), 8.12 (1H, d, J=3Hz)

004
3] Example 1 (1) N-(trimethylsilyl)acetamide (3
．． 14g) and 7β-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid ditrifluoroacetate (1.35 g) of dichloromethane (20 m
l) Add 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid methanesulfonic anhydride (syn isomer) (1 .01 g) at 10°C. After stirring for 1 hour at room temperature, the mixture is poured into diisopropyl ether. The resulting precipitate is collected by filtration and suspended in water. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and diluted with Diaion HP-
20 (trademark: Mitsubishi Kasei) and eluted with water. Fractions containing the target compound are collected and adjusted to pH 2 with 1N hydrochloric acid. The resulting precipitate was collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-
methylethoxyimino)acetamide]-3-(4,5
, 6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) (532 mg) is obtained. IR (Nujol): 3270, 1765, 1710,
1610 cm-1 NMR (DMSO-d6, δ):
1.43 (6H, s), 1.92-2.18 (2H, m
), 2.88-3.15 (2H, m), 3.44 (2H
, br s), 3.81-4.18 (4H, m), 5
．． 12 (1H, d, J = 5Hz), 5.38 (1H, b
r s), 5.76 (1H, dd, J=8Hz, 5H
z), 7.02 (1H, br s), 8.09 (2H
, br s), 9.35 (1H, d, J=8Hz) The following compound is obtained in the same manner as in Example 1-(1). (2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1
-methylethoxyimino)acetamide]-3-(1-
Methyl-4,5,6,7-tetrahydro-4-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-
4-carboxylate (syn isomer) IR (Nujol): 3290, 3140, 1770,
1670, 1605 cm-1 NMR (D2O+NaHCO3, δ): 1.53 (6H
, s), 2.06-2.37 (2H, m), 3.15-
3.48 (4H, m), 3.78 (3H, s), 3.9
8-4.22 (4H, m), 5.19 (1H, d, J=
5Hz), 5.78 (1H, d, J=5Hz), 5.9
2 (1H, d, J = 3Hz), 7.64 (1H, d, J
=3Hz)

Example 2 (1) 7β-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid・Dissolve ditrifluoroacetate (1.35 g) in a mixture of water (10 ml) and tetrahydrofuran (20 ml), and add 1-[2-(2-aminothiazol-4-yl)-2-
A solvate of methoxyiminoacetyl]benzotriazole-3-oxide (syn isomer) and N,N-dimethylformamide (1.41 g) is added at room temperature and the mixture is adjusted to pH 7 with aqueous sodium bicarbonate. The mixture is kept at pH 7 with aqueous sodium bicarbonate solution for 6 hours, then adjusted to pH 2 with 1N hydrochloric acid and washed three times with ethyl acetate. The aqueous layer was subjected to column chromatography using Diaion HP-20 and eluted with 20% isopropyl alcohol. Fractions containing the target compound were collected and lyophilized to obtain 7β-[
2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3 -cephem-4-carboxylic acid (syn isomer) (321 mg) is obtained. IR (Nujol): 3270, 1765, 1660,
1600cm-1 NMR (D2O, δ): 2.01
-2.31 (2H, m), 3.09-3.31 (2H,
m), 3.26 and 3.58 (2H, ABq, J=1
8Hz), 3.88-4.19 (4H, m), 3.77
(3H, s), 5.16 (1H, d, J=5Hz), 5
．． 71 (1H, br s), 5.74 (1H, d, J
=5Hz), 6.96 (1H, s), 7.48 (1H,
br s) The following compound is obtained in the same manner as in Example 2-(1). (2) 7β-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(1
-Methyl-4,5,6,7-tetrahydro-4-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) IR (Nujol): 3200, 1755, 1670 ，
1605cm-1 NMR (D2O, δ): 2.04
-2.38 (2H, m), 3.12-3.48 (4H,
m), 3.77 (3H, s), 3.98 (3H, s),
4.01-4.26 (4H, m), 5.18 (1H, d
, J=5Hz), 5.72 (1H, d, J=5Hz),
5.92 (1H, d, J = 3Hz), 6.92 (1H,
s), 7.62 (1H, d, J=3Hz)

[0045]
Example 3 Phosphorus oxychloride (690 ml) in tetrahydrofuran (6 ml)
2-(2-formylaminothiazol-4-yl)-2-oxoacetic acid (600 m
g) is added at -10°C and the mixture is stirred at 0°C for 1 hour. 7β-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid ditrifluoroacetate (1. 348 g), N-(trimethylsilyl)acetamide (2.76 g) was added to dichloromethane (14
ml). The activated acid solution obtained above is added to this solution at -10°C, and the mixture is stirred at 5°C for 4 hours and at room temperature for 14 hours. The precipitate was collected by filtration and diluted with ethyl acetate (1
0 ml) and vacuum dry. The resulting powder was suspended in methanol (6 ml), and concentrated hydrochloric acid (2 ml) was added thereto. The resulting solution is stirred at room temperature for 3.6 hours and then added dropwise into ethyl acetate (200 ml). Add oily compound to water (
15 ml) and adjust the pH to 1.8 by adding saturated aqueous sodium hydrogen carbonate solution. Diaion HP solution
-20 (40 ml) column chromatography and eluted with 20% isopropyl alcohol aqueous solution. The eluate was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-oxoacetamide]-3-
[4,5,6,7-tetrahydropyrazolo[1,5-a
]pyrimidin-4-yl)methyl-3-cephem-4-
Carboxylic acid (519 mg) is obtained. IR (Nujol): 3320, 1775, 1665,
1620, 1520 cm-1 NMR (DMSO-d6, δ): 3.0-4.1 (10
H, m), 5.21 (1H, d, J = 4.8Hz), 5
．． 34 (1H, d, J = 1.8Hz), 5.75 (1H
, dd, J=8.3Hz, 4.8Hz), 7.19(1
H, d, J = 1.8 Hz), 7.40 (2H, br
s), 7.82 (1H, s), 9.79 (1H, d, J
=8.3Hz)

Example 4 (1) 7β-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid - Add N-(trimethylsilyl)acetamide (2.756 g) to ditrifluoroacetate (1.348 g) and dissolve in dichloromethane (14 ml). To this solution was added 2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetyl chloride hydrochloride (syn isomer) (965 mg) at -10°C, and the mixture was stirred at 0°C for 5 hours. The mixture was poured into cold water (50 ml) and the aqueous layer was diluted with ethyl acetate (20 ml).
ml). The pH of the aqueous layer was adjusted to 2.2, and the mixture was subjected to column chromatography using Diaion HP-20 (100 ml), eluted with a 20% aqueous isopropyl alcohol solution, and the eluate was concentrated under vacuum to 50 ml. The resulting residue was adjusted to pH by adding saturated aqueous sodium hydrogen carbonate solution.
8 and stir at room temperature for 2.2 hours. The reaction mixture was adjusted to pH 2.5 by adding 6N hydrochloric acid, and insoluble matter was filtered off. The filtrate was evaporated under vacuum, and the residue was subjected to column chromatography on Diaion HP-20 (50 ml), eluting with 20% aqueous isopropyl alcohol. The eluate was lyophilized to yield 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(4,5,6,7-tetrahydropyrazolo[1,5- a] pyrimidin-4-yl)methyl-3-
Cephem-4-carboxylic acid (syn isomer) (785 mg
). IR (Nujol): 1765, 1655, 1560c
m-1 NMR (DMSO-d6, δ): 3.2-4
．． 1 (10H, m), 5.19 (1H, d, J = 4.8
Hz), 5.34 (1H, d, J=1.8Hz), 5.
79 (1H, dd, J=8.1 and 4.8Hz), 6
．． 66 (1H, s), 7.12 (2H, br s),
7.19 (1H, d, J = 1.8Hz), 9.48 (1
H, d, J = 8.1Hz), 11.30 (1H, br
s) The following compound is obtained in the same manner as in Example 4-(1). (2) 7β-[2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-(
2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3150, 1760, 1660c
m-1 NMR (DMSO-d6, δ): 3.45-
4.38 (8H, m), 5.16 (1H, d, J=5H
z), 5.31 (1H, d, J = 3Hz), 5.76 (
1H, dd, J = 8Hz, 5Hz), 6.63 (1H,
s), 7.03 (2H, br s), 7.16 (1H
, d, J=3Hz), 9.38(1H, d, J=8Hz
), 11.26 (1H, br s)

Example 5 (1) N-(trimethylsilyl)acetamide (3
．． 41g) of 7β-amino-3-(1-methyl-4,5
,6,7-tetrahydro-4-pyrazolo[1,5-a]
pyrimidinio)methyl-3-cephem-4-carboxylate ditrifluoroacetate (1.5 g) in dichloromethane (30 ml).
-thiadiazol-3-yl)-2-methoxyiminoacetyl chloride hydrochloride (syn isomer) (0.8 g) is added under ice cooling. The mixture was stirred at the same temperature for 1 hour and then poured into ethyl acetate. The resulting precipitate is collected by filtration and dissolved in water, and the solution is adjusted to pH 4 with saturated aqueous sodium bicarbonate solution. The aqueous solution was subjected to column chromatography using Diaion HP-20 and eluted with 10% isopropyl alcohol. The fraction containing the target compound was lyophilized to obtain 7β
-[2-(5-amino-1,2,4-thiadiazole-
3-yl)-2-methoxyiminoacetamide]-3-
(1-Methyl-4,5,6,7-tetrahydro-4-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) (127m
g) is obtained. IR (Nujol): 3300, 1755, 1670,
1605 cm-1 NMR (D2O, δ): 2.15
-2.41 (2H, m), 3.18-3.52 (4H,
m), 3.81 (3H, s), 4.01-4.28 (4
H, m), 4.10 (3H, s), 5.22 (1H, d
, J=5Hz), 5.83 (1H, d, J=5Hz),
5.96 (1H, d, J = 3Hz), 7.68 (1H,
d, J=3Hz) The following compound is obtained in the same manner as in Example 5-(1). (2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(2,3-dihydro-1H-imidazo[
1,2-b]pyrazol-1-yl) methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3300, 1755, 1660, 1590 cm-1
NMR (DO, δ): 3.37 and 3.67 (
2H, ABq, J=18Hz), 3.68-4.28(
6H, m), 4.07 (3H, s), 5.21 (1H,
d, J=5Hz), 5.48 (1H, d, J=3Hz)
, 5.79 (1H, d, J = 5Hz), 7.37 (1H
,br s) (3) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-[2,3-dihydro-5-methyl- 1-
(1H-imidazo[1,2-b]pyrazolio)]methyl-3-cephem-4-carboxylate (syn isomer)
IR (Nujol): 3250, 1755, 1665,
1590cm-1 NMR (D2O, δ): 3.33
and 3.67 (2H, ABq, J=18Hz), 3.
78 (3H, s), 3.88-4.48 (6H, m),
4.08 (3H, s), 5.22 (1H, d, J=5H
z), 5.78 (1H, d, J = 5Hz), 5.79 (
1H, d, J = 3Hz), 7.72 (1H, d, J = 3
Hz)

Example 6 7β-amino-3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-
Cephem-4-carboxylic acid ditrifluoroacetate (2
g) and N-(trimethylsilyl)acetamide (5.0
2-(2-
Aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride (syn isomer) (1.19g)
Add under ice-cooling. The mixture is stirred at room temperature for 1 hour and then poured into isopropyl ether. The resulting precipitate is collected by filtration. The precipitate was dissolved in water and the pH was adjusted to 5.5 with saturated aqueous sodium bicarbonate solution. Add the solution to Diaion HP-20
column chromatography. target compound 2
Elution was carried out with 0% isopropyl alcohol, and the eluate was lyophilized to yield 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2,
3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) (530 mg) is obtained. IR (Nujol): 3300, 3150, 1770,
1665, 1615 cm-1 NMR (D2O, δ): 3.38 and 3.67 (2H
, ABq, J=18Hz), 3.68-4.28 (6H
, m), 3.99 (3H, s), 5.22 (1H, d,
J=3Hz), 5.48 (1H, d, J=3Hz), 5
．． 77 (1H, d, J = 5Hz), 6.97 (1H, s
), 7.38 (1H, br s)

Example 7 7β-[2-(2-aminothiazol-4-yl)-2
-Hydroxyiminoacetamide]-3-(4,5,6
,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid (
Potassium carbonate (62 mg) and iodomethyl pivalate (236 mg) were added to a solution of (410 mg) in N,N-dimethylformamide (3 ml) at 5°C, and the mixture was stirred at the same temperature for 1.8 hours. The mixture is poured into a cold mixture of ethyl acetate and water and adjusted to pH 6 by adding saturated aqueous sodium bicarbonate solution. The organic layer is washed with water and brine and dried over magnesium sulfate. After filtration, the filtrate is subjected to evaporation under vacuum. The residue was triturated with isopropyl ether to give 7β-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(4
,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) (283
mg). IR (Nujol): 3280, 3160, 1785,
1745, 1665, 1610, 1560, 1520c
m-1 NMR (DMSO-d6, δ): 1.12 (9H, s)
, 3.5-4.2 (10H, m), 5.23 (1H, d
, J=4.8Hz), 5.33(1H, d, J=1.8
Hz), 5.81 (1H, dd, J=8.1 and 4.
8Hz), 5.81 and 5.88 (2H, A
Bq, J=6.0Hz), 6.66 (1H, s), 7.
13 (2H, br s), 7.19 (1H, d, J=
1.8Hz), 9.49 (1H, d, J=8.1Hz)
,11.30(1H,s)

Production Example 6 1H-imidazo[1,2-b]pyrazole (7g) with N
, N-dimethylformamide solution (14 ml) was added with methyl iodide (12.21 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with tetrahydrofuran (100 ml),
Ethyl acetate (200 ml) and isopropyl ether (2
5-methyl-1H-
Imidazo[1,2-b]pyrazolium iodide is obtained. NMR (DMSO-d6, δ): 4.08 (3H, s)
, 6.53 (1H, d, J = 3.4Hz), 7.78 (
1H, dd, J=2.1Hz, 1.1Hz), 8.2-
8.3 (2H, m), 12.89 (1H, br s)

Production Example 7 Ion exchange resin (3 g, Diaion SA10A (
(Trademark: Mitsubishi Kasei)) and stirred at room temperature for 1 hour. The ion exchange resin was filtered off, and the filtrate was concentrated under reduced pressure to give 5-methyl-5H-imidazo[1,2-b]pyrazole (0.
5g) is obtained. IR (NEET): 3100, 1540, 1500, 14
60,1240,1140,1080,930,740
cm-1 NMR (DMSO-d6, δ): 3.70 (3H, s)
, 6.08 (1H, d, J = 3.5Hz), 7.10 (
1H, s), 7.57 (1H, d, J=3.5Hz),
7.62 (1H, s)

Production Example 8 1H-imidazo[1,2-b]pyrazole (3g) and N
, 2 in a suspension of N-dimethylformamide (10 ml).
Sodium iodide (8.4 g) is added under stirring at 0°C. Add chloromethyl methyl ether (4.5 m
1) was slowly added at 5° C. and the mixture was stirred for 40 minutes. Diisopropyl ether (75 m
After addition of l), the diisopropyl ether is decanted. Dissolve the remaining oily substance in water and add Diaion SA-1.
Adjust pH to 10.5 with 0A (60 ml). The resin is filtered off and the filtrate is concentrated under reduced pressure. The remaining oil was subjected to column chromatography on silica gel (30 g) and eluted with a mixture of methanol and dichloromethane (1:4). Fractions containing the target compound were collected and evaporated under vacuum to give 5-methoxymethyl-5H-imidazo[1,2-b
] Pyrazole (4 g) is obtained. NMR (DMSO-d6, δ): 3.20 (3H, s)
, 5.48 (2H, s), 6.27 (1H, d, J=3
Hz), 7.21 (1H, d, J=2Hz), 7.77
(1H, d, J=2Hz), 7.90 (1H, d, J=
3Hz)

Production Example 9 7β-tertiary butoxycarbonylamino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5
-a]pyrimidin-4-yl)methyl-3-cephem-
4-Carboxylic acid benzhydryl ester 1-oxide (
20g) in N,N-dimethylformamide (200ml
) and cooled to -20°C. Phosphorus trichloride (4.1 ml) was added dropwise to the solution and stirred at -10 to -20°C for 1 hour. The reaction solution was poured into a mixture of ice water (1 liter) and ethyl acetate (500 ml) and adjusted to pH 7.0 with saturated sodium bicarbonate solution. The organic layer is separated, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was dissolved in methylene chloride (30 ml) and subjected to column chromatography using silica gel (200 g), eluting with a mixed solvent of methylene chloride and ethyl acetate (3:1). The fraction containing the target product is concentrated under reduced pressure. Powderize the residue with diisopropyl ether, collect by filtration,
After washing with diisopropyl ether and drying with phosphorus pentoxide, 7β-tert-butoxycarbonylamino-3-(5
-oxo-4,5,6,7-tetrahydropyrazolo[1
,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid benzhydryl ester (5 g) was obtained. NMR (DMSO-d6, δ): 1.39 (9H, s)
, 2.85-2.93 (2H, m), 3.13-3.2
5 (2H, m), 4.10-4.80 (2H, m), 4
．． 68 and 4.76 (2H, ABq, J=1
6Hz), 5.08 (1H, d, J=5Hz), 5.5
2 (1H, d, J=3Hz), 5.55 (1H, dd,
J=5Hz, 8Hz), 6.96 (1H, s), 7.1
0-7.20 (10H, m), 8.05 (1H, d, J
=8Hz)

Production Example 10 The following compound was obtained in the same manner as in Production Examples 2-(1) and 4. (1) 7β-amino-3-(5-oxo-4,5,
6,7-tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid dihydrochloride (2) 7β-amino-3-(7-methyl-2, 3-
dihydro-1H-imidazo[1,2-b]pyrazole-
1-yl)methyl-3-cephem-4-carboxylic acid dihydrochloride NMR (D2O, δ): 2.08 (3H, s), 3.6
3 and 3.81 (2H, ABq, J=17.8Hz)
, 3.91-4.09 (2H, m), 4.19-4.3
8 (2H, m), 4.39 and 4.50 (2H, AB
q, J = 15.6Hz), 5.19 (1H, d, J = 4
．． 9Hz), 5.34 (1H, d, J=4.9Hz),
7.02(1H,s) (3) 7β-amino-3-(7-ethoxycarbonyl-2,3-dihydro-1H-imidazo[1,2-b]
Pyrazol-1-yl) methyl-3-cephem-4-carboxylic acid dihydrochloride IR (Nujol): 3350, 1780, 1700,
1580 cm-1 NMR (D2O, δ): 1.32 (3H, t, J=7.
1Hz), 3.36 and 3.56 (2H, ABq, J
=17.7Hz), 3.61-4.23(6H, m),
4.42 and 4.63 (2H, ABq, J=14.8
Hz), 5.11 (1H, d, J=4.5Hz), 5.
47 (1H, d, J = 4.5Hz), 7.67 (1H,
s)

Production Example 11 The following compound was obtained in the same manner as in Production Example 1-(1). (1) 7β-tertiary butoxycarbonylamino-3
-[1-(2,2-diethoxyethyl)pyrazole-5
-yl]aminomethyl-3-cephem-4-carboxylic acid benzhydryl IR (Nujol): 3330, 3150, 1775,
1715, 1695 cm-1 NMR (DMSO-d6, δ): 0.97-1.05 (
6H, m), 1.40 (9H, s), 3.35 (2H,
m), 3.40-3.61 (4H, m), 3.90-4
．． 04 (4H, m), 4.71 (1H, t, J = 5.4
Hz), 5.04 (1H, m), 5.07 (1H, d,
J=4.8Hz), 5.50(1H, dd, J=4.8
Hz, 9.1Hz), 5.66 (1H, m), 6.94
(1H, s), 7.03 (1H, m), 7.26-7.
51 (10H, m), 8.02 (1H, d, J = 9.1
Hz) (2) 7β-tertiary butoxycarbonylamino-3
-[1-(2,2-diethoxyethyl)-3-methylpyrazol-5-yl]aminomethyl-3-cephem-4
-Carboxylic acid benzhydryl IR (Nujol): 3320, 1775, 1710,
1685 cm-1 NMR (DMSO-d6, δ):
1.03 (6H, m), 1.41 (9H, s), 1.9
2 (3H, s), 3.40 (2H, m), 3.53-3
．． 61 (4H, m), 3.81-3.93 (4H, m)
, 4.68 (1H, m), 4.89 (1H, s), 5.
07 (1H, d, J = 4.8Hz), 5.56 (2H,
m), 6.95 (1H, s), 7.30-7.51 (1
0H, m), 8.02 (1H, d, J = 8.9Hz) (3) 7β-tertiary butoxycarbonylamino-3
-(7-ethoxycarbonyl-2,3-dihydro-1H
-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid benzhydryl NM
R (DMSO-d6, δ): 1.21 (3H, t, J=
7.1Hz), 1.41 (9H, s), 3.37-3.
81 (4H, m), 3.98-4.19 (4H, m),
4.56 (2H, m), 5.16 (1H, d, J=4.
8Hz), 5.57 (1H, dd, J=8,9Hz),
6.93 (1H, s), 7.27-7.50 (10H,
m), 7.54 (1H, s), 8.06 (1H, t, J
=8.9Hz) (4) 7β-tertiary butoxycarbonylamino-3
-(7-methyl-2,3-dihydro-1H-imidazo[
1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid benzhydryl IR (Nujol): 1770, 1705, 1590 cm-1 NMR (DMSO-d6, δ): 1.41 (9H, s)
, 1.84 (3H, s), 3.49-3.68 (4H,
m), 3.74-4.04 (4H, m), 5.16 (1
H, d, J = 4.8Hz), 5.57 (1H, dd, J
=8.9Hz, 4.8Hz), 6.93(1H, s),
7.01 (1H, s), 7.23-7.46 (10H,
m), 8.07 (1H, d, J = 8.9Hz)

005
6] Production Example 12 (1) 7β-tertiary butoxycarbonylamino-3
-[1-(2,2-diethoxyethyl)pyrazole-5
-yl]aminomethyl-3-cephem-4-carboxylic acid benzhydryl (0.5g) in acetonitrile (5m
l) Add p-toluenesulfonic acid monohydrate (0.2
8g) at room temperature. After stirring for 5 hours at room temperature, the mixture is poured into ethyl acetate. The resulting precipitate was collected by filtration and 7β
-Amino-3-(1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid tripe-toluenesulfonate (412 mg) is obtained. IR (Nujol): 1780, 1710cm-1NM
R (DMSO-d6, δ): 2.29 (9H, s), 3
．． 40 and 3.59 (2H, ABq, J = 17.8H
z), 5.00 and 5.12 (2H, ABq, J=1
5.0Hz), 5.24 (2H, br s), 6.0
8 (1H, d, J = 2.7Hz), 7.12 (6H, d
, J=7.8Hz), 7.47 (1H, m), 7.49
(6H, d, J=7.8Hz), 7.83 (1H, m)
, 7.88 (1H, m) The following compound is obtained in the same manner as in Production Example 12-(1). (2) 7β-amino-3-(6-methyl-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-
3-Cephem-4-carboxylic acid tripe-toluenesulfonate IR (Nujol): 1775, 1700cm-1NM
R (DMSO-d6, δ): 2.08 (3H, s), 2
．． 29 (9H, s), 3.41 and 3.61 (2H,
ABq, J=18.0Hz), 5.01 and 5.12
(2H, ABq, J=15.0Hz), 5.24 (2H
, br s), 6.09 (1H, s), 7.12 (6
H, d, J=8Hz), 7.27 (1H, m), 7.4
9 (6H, d, J=8Hz), 7.91 (1H, m)

Production Example 13 5-oxo-4,5,6,7-tetrahydropyrazolo[
1,5-a]pyrimidine (17.6 g) was dissolved in N,N-dimethylformamide (180 ml) and tetrahydrofuran (180 ml) and cooled to -20°C. A 1.6 mol n-butyllithium 15% hexane solution (80.7 ml) was added dropwise to the solution, and the mixture was stirred at -20°C for 30 minutes. Add 7β-tert-butoxycarbonylamino-3-iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester 1-oxide (40 g) to the reaction solution.
, N-dimethylformamide (400 ml) was added dropwise. After the dropwise addition was completed, the bath was replaced with an ice water bath and the reaction was carried out at 5° C. or lower for 1.5 hours. After the reaction, 1N-hydrochloric acid (200ml)
) and poured into ice water (400 ml) and ethyl acetate (800 ml). The pH at that time was 3.0. The pH was adjusted to 6.5 with saturated sodium bicarbonate solution, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was powdered with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried over phosphorus pentoxide to give 7β-tert-butoxycarbonylamino-3-(5-oxo-4,5,6,7 -Tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)methyl-3-cephem-4-carboxylic acid benzhydryl ester 1-oxide (20.5 g) was obtained. NMR (DMSO-d6, δ): 1.43 (9H, s)
,2.65-3.20(2H+2H,m),3.20-
4.10 (2H, m), 4.6-4.8 (2H, m),
4.95 (1H, d, J = 5Hz), 5.55 (1H,
d, J=3Hz), 5.30-5.59 (1H, m),
7.00 (1H, s), 7.10 (1H, d, J=3H
z), 7.10-7.80 (10H, m)

[0058]
Example 8 The following compound is obtained in the same manner as in Examples 1-(1), 2-(1), 5-(1) and 6. (1) 7β-[2-(2-aminothiazole-4-
yl)-2-ethoxyiminoacetamide]-3-(2
,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3300,17
65, 1660, 1620 cm-1 NMR (DMS
O-d6, δ): 1.27 (3H, t, J=7Hz),
3.51-4.22 (10H, m), 5.18 (1H,
d, J=5Hz), 5.31 (1H, br s), 5
．． 78 (1H, dd, J=8Hz, 5Hz), 6.70
(1H, s), 7.14 (3H, br s), 9.5
0(1H, d, J=8Hz) (2) 7β-[2-(2-aminothiazole-4-
yl)-2-ethoxyimino)acetamide]-3-(
4,5,6,7-tetrahydropyrazolo[1,5-a]
pyrimidin-4-yl) methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3300, 1775, 1675c
m-1 NMR (DMSO-d6, δ): 1.24 (3H, t,
J=7Hz), 1.88-2.21 (2H, m), 2.
90-3.18 (2H, m), 3.47 (2H, br
s), 3.75-4.68 (6H, m), 5.14 (
1H, d, J = 5Hz), 5.41 (1H, br s
), 5.75 (1H, dd, J=5Hz, 8Hz), 6
．． 69 (1H, s), 7.06 (1H, br s),
7.12 (2H, br s), 9.48 (1H, d,
J=8Hz) (3) 7β-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(7
-ethoxycarbonyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3
-Cephem-4-carboxylic acid (syn isomer) IR (Nujol): 1770,1695cm-1NMR (DMS
O-d6, δ): 1.26 (3H, t, J=7Hz),
3.25-4.27 (8H, m), 3.83 (3H, s
), 4.63 (2H, br s), 5.06 (1H,
d, J=5Hz), 5.61(1H, dd, J=8Hz
, 5Hz), 6.71 (1H, s), 7.16 (2H,
br s), 7.49 (1H, s), 9.47 (1H
, d, J=8Hz) (4) 7β-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(7
-Methyl-2,3-dihydro-1H-imidazo[1,2
-b]pyrazol-1-yl)methyl-3-cephem-
4-Carboxylic acid (syn isomer) IR (Nujol): 3200, 1755, 1650c
m-1 NMR (DMSO-d6, δ): 1.92 (3H, s)
, 3.50-3.74 (4H, m), 3.84 (3H,
s), 3.87-4.14 (4H, m), 5.18 (1
H, d, J = 4.7Hz), 5.78 (1H, dd, J
=8.1Hz, 4.7Hz), 6.75(1H,s),
7.04 (1H, s), 7.23 (2H, br s)
,9.63(1H,d,J=8.1Hz)(5) 7
β-[2-(2-aminothiazol-4-yl)-2-
ethoxyiminoacetamide]-3-(6-methyl-1
H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3200, 1765, 1655c
m-1 NMR (DMSO-d6, δ): 1.20 (3H, t,
J = 7.0Hz), 2.20 (3H, s), 3.25 and 3.42 (2H, ABq, J = 18.0Hz), 4
．． 07 (2H, q, J = 7.0Hz), 4.86 (2H
,br s),5.15(1H,d,J=4.8Hz
), 5.46 (1H, m), 5.80 (1H, dd, J
=8.3Hz, 4.8Hz), 6.70 (1H, s),
7.08 (1H, d, J = 2.3Hz), 7.22 (2
H, br s), 7.43 (1H, d, J = 2.3H
z), 9.58 (1H, d, J=8.3Hz) (6)
7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]
-3-(1H-imidazo[1,2-b]pyrazole-1
-yl) Methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3200, 1760, 1660c
m-1 NMR (DMSO-d6, δ): 3.22 and 3.4
5 (2H, ABq, J=18.0Hz), 3.88 (3
H, s), 4.90 (2H, br s), 5.14 (
1H, d, J = 4.9Hz), 5.68 (1H, d, J
= 2.2Hz), 5.82 (1H, dd, J = 4.9H
z, 8.5Hz), 7.19 (1H, m), 7.47 (
1H, m), 7.57 (1H, d, J=4.9Hz),
8.13 (2H, br s), 9.60 (1H, d,
J=8.5Hz) (7) 7β-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(1
H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) I
R (nujol): 3300, 1770, 1660cm
-1 NMR (DMSO-d6, δ): 3.24 and 3.4
5 (2H, ABq, J = 18.0Hz), 3.81 (3
H, s), 4.98 (2H, br s), 5.15 (
1H, d, J = 4.8Hz), 5.67 (1H, d, J
= 2.1Hz), 5.79 (1H, dd, J = 8.2H
z, 4.8Hz), 6.72 (1H, s), 7.20 (
3H, br s), 7.48 (1H, m), 7.57
(1H, d, J=2.1Hz), 9.62 (1H, d,
J=8.2Hz) (8) 7β-[2-(2-aminothiazole-4-
yl)-2-ethoxyiminoacetamide]-3-(1
H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (syn isomer) I
R (nujol): 3200, 1770, 1660cm
-1 NMR (DMSO-d6, δ): 1.19 (3H, t,
J = 7.0Hz), 3.25 and 3.45 (2H, A
Bq, J = 17.9Hz), 4.07 (2H, q, J =
7.0Hz), 4.91 (2H, br s), 5.1
6 (1H, d, J = 4.9Hz), 5.67 (1H, d
, J=2.0Hz), 5.81 (1H, dd, J=4.
9Hz, 8.3Hz), 6.70 (1H, s), 7.2
0 (1H, m), 7.23 (2H, br s), 7.
47 (1H, m), 7.57 (1H, d, J = 2.0H
z), 9.60 (1H, d, J=8.3Hz) (9)
7β-[2-difluoromethoxyimino-2-(2-
tritylaminothiazol-4-yl)acetamide]
-3-(1H-imidazo[1,2-b]pyrazole-1
-yl) Methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 1770, 1655 cm-1NM
R (DMSO-d6, δ): 3.33-3.57 (2H
, m), 5.12 (2H, br s), 5.17 (1
H, d, J = 4.9Hz), 5.75 (1H, m), 5
．． 76 (1H, dd, J=4.9Hz, 7.9Hz),
6.97 (1H, s), 7.09-7.98 (19H,
m), 9.64 (1H, d, J = 7.9Hz) (10) 7β-[2-(2-aminothiazole-4
-yl)-2-allyloxyiminoacetamide]-3
-(2,3-dihydro-1H-imidazo[1,2-b]
Pyrazol-1-yl) methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 1770, 1690, 1670,
1590 cm NMR (DMSO-d6, δ): 3.36 and 3.5
6 (2H, ABq, J=18Hz), 3.50-4.1
8 (6H, m), 4.56 (2H, m), 5.08 (1
H, d, J=5Hz), 5.10-5.50 (1H+1
H, m), 5.38 (1H, d, d, J = 5Hz, 8H
z), 5.55-6.10 (1H, m), 6.70 (1
H, s), 7.13 (1H, d, J=3Hz), 7.0
-7.30 (2H, bs), 9.55 (1H, d, J=
8Hz) (11) 7β-[2-(2-aminothiazole-4
-yl)-2-methoxyiminoacetamide]-3-(
5-oxo-4,5,6,7-tetrahydropyrazolo[
1,5-a]pyrimidin-4-yl) methyl-3-cephem-4-carboxylic acid (syn isomer) IR (nujol): 1760, 1665, 1610 cm-1 NMR (DMSO-d6, δ): 2. 75-3.08(
2H, m), 3.10-3.50 (2H, m), 3.8
3 (3H, s), 3.90-4.20 (2H, m), 4
．． 75 (2H, br s), 4.97 (1H, d, J
= 5Hz), 5.58 (1H, d, d, J = 5Hz, 8
Hz), 6.20 (1H, bs), 6.69 (1H, s
), 7.15 (2H, bs), 7.25 (1H, bs)
,9.43(1H,d,J=8Hz)

Example 9 The following compound was obtained in the same manner as in Example 4-(1). (1) 7β-[2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-(
7-Methyl-2,3-dihydro-1H-imidazo[1,
2-b] Pyrazol-1-yl) methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3200, 1760, 1650c
m-1 NMR (DMSO-d6, δ): 1.92 (3H, s)
, 3.49-3.70 (4H, m), 3.77-4.1
4 (4H, m), 5.17 (1H, d, J = 4.8Hz
), 5.78 (1H, dt, J=8.1Hz, 4.8H
z), 6.66 (1H, s), 7.03 (1H, s),
7.12 (2H, br s), 9.48 (1H, d,
J = 8.1Hz), 11.30 (1H, br s) (2) 7β-[2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-(
1H-imidazo[1,2-b]pyrazol-1-yl)
Methyl-3-cephem-4-carboxylic acid (syn isomer)
IR (Nujol): 1760, 1650cm-1NM
R(DMSO-d6, δ): 3.23 and 3.48 (
2H,ABq,J=10.9Hz) 4.88 and 4.
98 (2H, ABq, J = 15.1Hz), 5.18 (
1H, d, J = 4.8Hz), 5.74 (1H, d, J
= 2.2Hz), 5.80 (1H, dd, J = 7.9H
z, 4.8Hz), 6.77 (1H, s), 7.24 (
1H, m), 7.53 (1H, m), 7.61 (1H,
d, J=2.2Hz), 9.65 (1H, d, J=7.
9Hz), 11.93 (1H, br s)

0060
] Example 10 (1) N,N-dimethylformamide (0.379
ml) and phosphorus oxychloride (
0.457 ml) is stirred under cooling for 30 minutes. Add 2-(2-tritylaminothiazole-4-
yl)-2-difluoromethoxyiminoacetic acid (syn isomer) (1.96 g) is added with stirring under cooling and the mixture is stirred at 3-5° C. for 30 minutes to prepare an activated acid solution. On the other hand, dichloromethane ( 46.98 ml) of N-trimethylsilylacetamide (6.43 g). The activated acid solution obtained above is added to this solution under cooling, and the mixture is stirred for 1.5 hours. The reaction mixture was diluted with diethyl ether (800 m
Powder with l). The precipitate is filtered and dried under reduced pressure. Methanol (28.5ml) and concentrated hydrochloric acid (4.28ml)
Add the obtained powder to the mixture of ) and stir at room temperature for 3 hours. The reaction mixture is triturated with ethyl acetate (500 ml). The precipitate is filtered and dried under reduced pressure. Add the powder to water and adjust the pH to 5 with saturated sodium bicarbonate solution. The solution was subjected to column chromatography using HP-20 (100 ml) and eluted with 40% isopropyl alcohol solution. Fractions containing the target product are collected and concentrated under reduced pressure to remove isopropyl alcohol. The residue was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamide]-
3-(4,5,6,7-tetrahydropyrazolo[1,5
-a]pyrimidin-4-yl)methyl-3-cephem-
4-carboxylic acid (syn isomer) (0.60 g) is obtained. IR (Nujol): 3300, 1765, 1680,
1580 cm-1 NMR (DMSO-d6, δ): 1.9-2.2 (2H
, m), 2.8-3.2 (2H, m), 3.2-3.5
(2H, m), 3.8-4.1 (4H, m), 5.06
(1H, d, J=5Hz), 5.41 (1H, br
s), 5.65 (1H, dd, J=8Hz, 5Hz),
6.93 (1H, s), 7.03 (1H, br s)
, 7.03 (1H, t, J = 72Hz), 7.25 (2
H, br s), 9.80 (1H, d, J=8Hz)
The following compound is obtained in the same manner as in Example 10-(1). (2) 7β-[2-(2-aminothiazole-4-
yl)-2-difluoromethoxyiminoacetamide]
-3-(2,3-dihydro-1H-imidazo[1,2-
b] pyrazol-1-yl)methyl-3-cephem-4
-Carboxylic acid (syn isomer) IR (Nujol): 3300, 1760, 1665,
1600 cm-1 NMR (DMSO-d6, δ): 3.2-3.5 (2H
, m), 3.7-4.2 (6H, m), 5.05 (1H
, d, J=5Hz), 5.31(1H, d, J=2Hz
), 5.59 (1H, dd, J=8Hz, 5Hz), 6
．． 93 (1H, s), 7.04 (1H, t, J=72H
z), 7.12 (1H, d, J = 2Hz), 7.26 (
2H, br s), 9.80 (1H, d, J=8Hz
) (3) 7β-[2-(2-aminothiazole-4-
yl)-2-difluoromethoxyiminoacetamide]
-3-(1H-imidazo[1,2-b]pyrazole-1
-yl) Methyl-3-cephem-4-carboxylic acid (syn isomer) IR (Nujol): 3200, 1760, 1660c
m-1 NMR (DMSO-d6, δ): 3.23 and 3.4
6 (2H, ABq, J = 17.9Hz), 4.92 (2
H, br s), 5.18 (1H, d, J = 4.8H
z), 5.68 (1H, d, J=2.1Hz), 5.8
1 (1H, dd, J=4.8Hz, 7.9Hz), 6.
97 (1H, s), 7.10 (1H, t, J = 71.0
Hz), 7.21 (1H, m), 7.35 (2H, br
s), 7.46 (1H, d, J=2.1Hz), 7
．． 56 (1H, d, J = 2.1Hz), 9.96 (1H
, d, J=7.91Hz)

Example 11 The following compound was obtained in the same manner as in Example 7. (1) 7β-[2-(2-aminothiazole-4-
yl)-2-difluoromethoxyiminoacetamide]
-3-(1H-imidazo[1,2-b]pyrazole-1
-yl)methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) IR (Nujol): 1770, 1740, 1670c
m-1 NMR (DMSO-d6, δ): 1.15 (9H, s)
, 3.30 and 3.43 (2H, ABq, J=18.
1Hz), 4.85 and 4.95 (2H, ABq, J
= 15.3Hz), 5.23 (1H, d, J = 4.9H
z), 5.64 (1H, d, J=1.6Hz), 5.8
9 (1H, dd, J=4.9Hz, 7.9Hz), 5.
90 and 5.97 (2H, ABq, J=6.0Hz)
, 6.98 (1H, s), 7.10 (1H, t, J=7
1.0Hz), 7.19 (1H, m), 7.40 (2H
, br s), 7.47 (1H, m), 7.59 (1
H, d, J = 1.6Hz), 9.97 (1H, d, J =
7.9Hz) (2) 7β-[2-(2-aminothiazole-4-
yl)-2-hydroxyiminoacetamide]-3-(
2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) IR (Nujol): 3350,1780 ,1750,1670,
1600cm-1 NMR (DMSO-d6, δ): 1.12 (9H, s)
, 3.52-3.74 (4H, m), 3.92-4.0
5 (4H, m), 5.23 (1H, d, J = 4.8Hz
), 5.33 (1H, d, J = 1.8Hz), 5.81
(1H, dd, J=8.1Hz, 4.8Hz), 5.8
3 and 5.88 (2H, ABq, J=6.0Hz),
6.66 (1H, s), 7.12 (2H, br s)
,7.19(1H,d,J=1.8Hz),9.49(
1H, d, J = 8.1Hz), 11.30 (1H, br
s) (3) 7β-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-(2
,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid pivaloyloxymethyl (syn isomer) IR (Nujol): 1780,1750, 1670cm-1 NMR (DMSO-d6, δ): 1.17 (9H, s)
, 3.51-4.12 (8H, m), 3.82 (3H,
s), 5.22 (1H, d, J = 5Hz), 5.31 (
1H, d, J = 2Hz), 5.69-5.91 (3H,
m), 6.71 (1H, s), 7.15 (1H, br
s), 7.17 (2H, br s), 9.55 (1
H, d, J=8Hz)

Example 12 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-
N,N of 3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (2.6 g)
-5-methoxymethyl-5H-imidazo[1,2-b]pyrazole (
3.9 g) was added while stirring at 20°C, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into ethyl acetate (200 ml), and the resulting precipitate was collected by filtration. The precipitate was washed with water (20
ml) and pH 3.0 with sodium bicarbonate solution.
Adjust to. The resulting solution was subjected to HP-20 column chromatography using a 5% isopropyl alcohol solution as the eluent, and the desired fraction was lyophilized to give 7
β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3
-[5-methoxymethyl-1-(1H-imidazo[1,
2-b]pyrazolio)]methyl-3-cephem-4-carboxylate (syn isomer) (150 ml) is obtained. IR (Nujol): 1780, 1760, 1660,
1600, 1520 cm-1 NMR (DMSO-d6, δ): 3.28 (3H, s)
, 3.86 (3H, s), 4.83 (1H, d, J=5
Hz), 4.90-5.28 (2H, m), 5.63 (
1H, dd, J=5Hz, 8Hz), 5.74 (2H,
bs), 6.90 (1H, d, J=3Hz), 7.98
(1H, bs), 8.12 (2H, bs), 8.21 (
1H, d, J = 2Hz), 8.42 (1H, d, J = 3
Hz), 9.41 (1H, d, J = 8Hz)

0063
Example 13 7β-[2-(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer)
(2.53 g) in N,N-dimethylformamide solution (
5-methyl-5H-imidazo[1,2-b
] Pyrazole (2 g) was added and stirred at room temperature for 2.5 hours. The reaction mixture was triturated with a mixture of ethyl acetate (225ml) and isopropyl ether (225ml). The powder was collected by filtration and dried under reduced pressure. Methanol (15m
Add the powder to a mixture of 1) and concentrated hydrochloric acid (1.5 ml) and stir at room temperature for 3 hours. The reaction mixture is triturated with ethyl acetate. The powder is filtered and dried under reduced pressure. Add the powder to water and adjust the pH to 2 with 1N hydrochloric acid. The aqueous solution was subjected to HP-20 column chromatography.
Elute with % isopropyl alcohol solution. Collect fractions containing the target product and concentrate under reduced pressure to remove isopropyl alcohol. The residue was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-[5-methyl-1-(1H-imidazo[1,2-b]pyrazolio). )] Methyl-3-cephem-
4-carboxylate (syn isomer) (0.53 g) is obtained. IR (Nujol): 3300, 3130, 1760,
1600, 1530, 1030cm-1NMR (DMS
O-d6, δ): 2.97 and 3.41 (2H, AB
qJ=17.3Hz), 3.80 (3H, s), 4.0
2 (3H, s), 4.96 and 5.14 (2H, AB
q, J = 13.9Hz), 4.99 (1H, d, J = 4
．． 8Hz), 5.59 (1H, dd, J=9.5Hz,
4.8Hz), 6.70 (1H, s), 6.78 (1H
, d, J=3.4Hz), 7.23(2H, brs),
7.97 (1H, s), 8.15-8.21 (2H, m
), 9.54 (1H, d, J = 9.5Hz)

Example 14 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-
N of 3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (1.08 g),
5-Methyl-5H-imidazo[1,2-b]pyrazole (0.5%) was added to N-dimethylformamide solution (2.2ml).
48 g) and stirred at room temperature for 3 hours. The reaction mixture is triturated with ethyl acetate (10 ml). The powder is filtered and dried over diphosphorous pentoxide under reduced pressure. Add the powder to water and adjust the pH to 2 with 1N hydrochloric acid. The aqueous solution is HP-2
0 (30 ml) column chromatography, 1
Elute with 0% isopropyl alcohol aqueous solution. Fractions containing the target product are collected and concentrated under reduced pressure to remove isopropyl alcohol. The residue was lyophilized to give 7β-[2-(
5-amino-1,2,4-thiadiazol-3-yl)
-2-methoxyiminoacetamide]-3-[5-methyl-1-(1H-imidazo[1,2-b]pyrazolio)
] Methyl-3-cephem-4-carboxylate (syn isomer) (0.05 g) is obtained. IR (Nujol): 3250, 1760, 1600,
1040 cm NMR (DMSO-d6, δ): 2.94 and 3.4
0 (2H, ABq, J=17Hz), 3.86 (3H,
s), 4.02 (3H, s) 4.96 and 5.13 (
ABq, J = 14Hz), 4.96 (1H, d, J = 4
．． 9Hz), 5.61 (1H, dd, J=9.5Hz,
4.9Hz), 6.78 (1H, d, J=3.4Hz)
, 7.98 (1H, br s), 8.1-8.2 (4
H, m), 9.49 (1H, d, J = 9.5Hz)

0
7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2,
3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3-cephem-4-carboxylic acid (synisomer) (2.1 g) in ethanol (14.7 m
A 2M sulfuric acid solution (2.1 ml) is added to a mixture solution of 1) and water (2.1 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, and the resulting precipitate was collected by filtration to give 7β-[2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-3
-Cephem-4-carboxylic acid sulfate (syn isomer) (
1.94 g) is obtained. IR (Nujol): 3210, 1765, 1710,
1660, 1610 cm-1 NMR (DMSO-d6, δ): 3.46-4.14 (
8H, m), 3.89 (3H, m), 5.18 (1H,
d, J=5Hz), 5.40 (1H, br s), 5
．． 76 (1H, dd, J=8Hz, 5Hz), 6.79
(1H, s), 7.27 (1H, br s), 9.6
2 (1H, d, J=8Hz)

Claims (2)

[Claims] Claim 1 General formula: [wherein R1 is amino or protected amino, Z is N
or CH, (wherein R3 means hydrogen or an organic group), R2 is carboxy, protected carboxy or COO-, A
is lower alkylene or lower alkenylene which may have oxo, R6 is hydrogen, lower alkyl or lower alkoxycarbonyl, Y is N or N+-R4 (in the formula R
4 means lower alkyl or lower alkoxy (lower) alkyl), provided that (i) when Y is N, R2 is carboxy or protected carboxy, and (ii) when Y is N+-R4 , R2 is COO-. ] A novel cephem compound and its salt. [Claim 2] General formula: [wherein R2 is carboxy, protected carboxy or COO-, A is lower alkylene or lower alkenylene which may have oxo, R6 is hydrogen, lower alkyl or lower alkoxycarbonyl , Y is N or N+
-R4 (wherein R4 means lower alkyl or lower alkoxy(lower) alkyl), provided that (
i) When Y is N, R2 is carboxy or protected carboxy; (ii) When Y is N+-R4, R2 is COO-. ] A novel cephem compound and its salt.