JPH0491092A - New cephem compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) amino; R<2> is lower alkyl; R<3> is COO<-> or (protected) carboxy; R<4> is lower alkyl; R<5> is lower alkylamino, (protected) carboxy-lower alkylamino or ureido; X<-> is anion; (n) is 0 or 1; (n) is 0 when R<3> is COO<->, and (n) is 1 when R<3> is (protected) carboxy]. EXAMPLE:7beta-[2-(2-Formylaminothiazol-4-yl)-2-methoxyiminoacetamido]- 3-[3-(N- methoxycarbonylmethyl)amino-2-methyl-1-pyrazolio]-methyl-3-cephem-4- carboxylate. USE:Antibacterial agent against Gram-positive bacteria and Gramnegative bacteria. PREPARATION:A compound of formula II (or its reactive derivative) is made to react with a compound of formula III (or its reactive derivative).

Description

[Detailed description of the invention]

"Industrial Application Field" This invention relates to novel cephem compounds and salts thereof. More specifically, the present invention relates to novel cephem compounds and salts thereof having antibacterial activity. Therefore, this invention is useful in the pharmaceutical field. “Structure of the Invention” The target cephem compound is new, and the following - Arson [
1]. [1 Co] [In the formula, R' is an ami7 group or a protected ami7 group, R1 is a lower alkyl group, R3 is a -cooe group, a carboxy group or a protected carboxyne group, R4 is a lower alkyl group, and Rb is a 7 lower alkylamino groups, carboxy (lower) alkylamino group, protected carboxy (lower) alkylamino group or ureido group, XO is an anion, n means O or 1, respectively. However, R3 is -co
When R5 is an oO group, n is 0; when R5 is a carboxy group or a protected carboxyne group, n is 1. ] Regarding the target compound Nl, it is necessary to pay attention to the following points. That is, the target compound [1]+m (i
Includes anti-isomers, anti-isomers and mixtures thereof. An anti-isomer means one geometric isomer having a partial structure of the formula: (wherein R1 and Rz have the same meanings as before), and an anti-isomer means a geometric isomer having a partial structure of the formula: (wherein R1 and R' have the same meanings as before), and all such geometric isomers and mixtures thereof are included within the scope of this invention. In this specification, the partial structures of these geometric isomers and mixtures thereof will be shown by the following formulas for convenience. -R2 (wherein R1 and R' have the same meanings as before). Another point to note is that the virazolio moiety of the compound [H can exist in tautomeric forms and such tautomeric equilibrium can be represented by the formula below. 1 (in the formula, R' and Rs each have the same meaning as before). Although all of the above tautomerisms are included within the scope of the present invention, in this specification, the target compound [1] will be expressed by one expression of the virazosoo group of formula (A) for convenience. The cephem compound [1] of the present invention can be produced by the production method shown by the following reaction formula.

[Left below]

[11] or a reactive derivative thereof at an amino group or a salt thereof + -R2 [I11] or a reactive derivative thereof at a carboxyne group or a salt thereof [+] or a salt thereof In formula 1, R'R'R''R' R ',XC
) and n each have the same meaning as before]. The raw material compound can be produced by a known method, a method described in the production example below, or a method analogous thereto. In the foregoing and following description of this specification, preferred examples and explanations of various definitions falling within the scope of this invention are set forth in detail below. The term lower is used to include groups having from ] to 6 carbon atoms, unless otherwise specified. Suitable "lower alkyl groups", as well as [lower alkylamino groups], "calhoki/(lower) alkylamino groups" and "'protected carboxy(lower) alkylamino groups"
Preferred "lower alkyl moieties" of "groups" include methyl,
Mention may be made of straight-chain or branched-chain alkyls such as ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, hexyl, etc., among which preferred are C1-C4 alkyl groups. . Suitable "amino-protecting groups" for the "protected amine group" include acyl groups described below, such as substituted or unsubstituted alkylidene groups such as benzylidene and hydroxybenzylidene, such as benzyl, phenethyl, benzhydryl, trityl, etc. an al(lower)alkyl group, such as a mono- or di- or triphenyl(lower)alkyl group,
etc. Suitable "acyl groups" include, for example, lower alkanoyl groups such as formyl, acetyl, propionyl, hexanoyl, bi(loyl), mono(or di- or tri)halo(lower) alkanoyl such as chloroacetyl, trifluoroacetyl, etc. groups, such as lower alkoxycarbonyl groups such as methquinecarbonyl, ethoxycarbonyl, secondary butquinecarbonyl, tertiary pentyluoquine carbonyl, hequineluoquinecarbonyl, carbamoyl groups, such as aroyl groups such as benzoyl, toluoyl, naphthoyl, For example, an alkanoyl group such as phenylacetyl and phenylpropionyl, an arylokydicarbonyl group such as fenoquinecarbonyl and naphthyloquine sulfonyl, an arylokyne(lower) alkanoyl group such as phenoxyacetyl and phenoxyprobionyl, For example, arylglyoxyloyl groups such as phenylglyoxyloyl, naphthylglyoxyloyl, naphthylglyoxyloyl, al(lower) alkoxy which may have a suitable substituent such as benzyloxycarbonyl, P-nitrobenzyloxycarbonyl, etc. Carbonyl group, etc. Suitable [protected carboxyl group] includes esterified carboxyne group, and specific examples of the ester moiety of the esterified carboxyne group include a suitable substituent. For example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-7 chloro Lower alkyl esters such as vinyl esters, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, imbutyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxy ethyl ester, ]-7' robionyl oquin ethyl ester,
Lower alkyl esters such as 2-propionyloxyethyl ester, hexanoyloxyethyl ester, lower alkyl esters such as 2-propionyloxyethyl ester, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, or e.g. 2-iodoethyl ester, 2,2.
2-) Mono(or di- or tri)halo(lower) alkyl esters such as dichloromethane ethyl esters; lower alkenyl esters such as vinyl esters, allyl esters; lower alkenyl esters such as t+f ethynyl esters, propynyl esters, etc. esters such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(3-methoxyphenyl)methyl ester, 314-dimethoxybenzyl ester, 4-hydroxy-3,5 - Al (lower) alkyl esters optionally having suitable substituents such as ditertiary butyl benzyl esters; e.g. phenyl esters,
Examples include aryl esters which may have appropriate substituents, such as 4-chlorophenyl ester, tolyl ester, 4-tertiary-butylphenyl ester, xylyl ester, mesityl ester, and cumenyl ester. Suitable anions include formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, chloride bromide, iosite, sulfate, bosphate, and the like. Suitable salts of the target compound N] include pharmaceutically acceptable salts, especially the commonly used non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, and alkali metal salts such as calcium salts, magnesium salts, etc. Metal salts such as earth metal salts, ammonium salts such as triethylamine salts, pyridine salts, picoline salts, synchhexylamine salts, N. Yoiki salts such as N'-dibenzylethylenediamine salts, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, such as formates, acetates, trifluoroacetates,
Examples include organic acid salts such as maleate, tartrate, methanesulfonate, benzenesulfonate, and P-toluenesulfonate, and salts with amino acids such as arginine salt, asharagate, and glutamate. The method for producing the target compound "1" will be explained in detail below. Production method 1 The target compound [1] or a salt thereof is obtained by converting the compound [■] or its reactive derivative or salt thereof in the amine 7 group to the compound [Dll] Alternatively, it can be produced by reacting the carboxyne group with its reactive derivative or its salt. Suitable reactive derivatives of the amino group of compound [11] include compound [ll] and aldehydes, ketones, etc. Ship's basic imino or its enamine tautomer produced by reaction with a carbonyl compound: Compound [11] and bis(trimethylsilyl)acetamide,
For example, N-(trimethylsilyl)acetamide, mono(
Examples include silyl derivatives produced by a reaction with a silyl compound such as trimethylsilyl)urea and the like: derivatives produced by a reaction between compound [11] and phosphorus trichloride or phosgene. For suitable salts of compound [n] and its reactive derivatives, refer to those exemplified for compound H]. Suitable reactive derivatives of the carboxyne group of compound [I[1] include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples of reactive derivatives include acid chlorides: acid azides: such as dialkyl phosphates, phenyl phosphates, diphenyl (
[substituted sialyl phosphorous acids such as dibenzyl phosphoric acid, halogenated phosphoric acids, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid , mixed acid anhydrides with acids such as aliphatic carboxylic acids such as pentanoic acid, isopentanoic acid, 2-ditylbutyric acid, trichloroacetic acid, or aromatic carboxylic acids such as e.g. benzoic acid: Symmetric acid anhydrides: imidazole, 4 -activated amides with substituted imidazoles, dimethylpyrazoles, triazoles, or tetrazoles: or e.g. Noah/methyl esters, metquin methyl esters, dimethyliminomethyl esters, vinyl esters, propargyl esters, p-nitrophenyl esters, 2.4- Dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, menulfenyl ester, phenylazophenyl ester, phenylthioester, p-=trophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester , 8-quinolylthioester, or activated esters such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,
Examples thereof include esters with N-hydroxy compounds such as 1-hydrocytyl-IH-benzotriazole. These reactive derivatives can be arbitrarily selected from them depending on the type of compound [I11] to be used. For suitable salts of compound [I11] and its reactive derivatives, refer to those exemplified for compound [1]. The reaction is usually carried out using water, an alcohol such as methanol or ethanol, gamma setone, dioxane, acetonitrile,
Chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N. The reaction is carried out in a commonly used solvent such as N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used in mixtures with water. When the compound [■] is used in the free form or its salt form in this reaction, N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N°-morpholinoethylcarbodiimide: N-cyclohexyl -N'
-(4-diethylaminonechlorohexyl)carbodiimide, N,N'diethylcarbodiimide, N,N'
-diisopropylcarbodiimide; N-ethyl-N'
-(3゜dimethylaminopropyl)carbodiimide;
N. N'-carbonylbis-(2-methylimidazole),
Pentamethyleneketene-N-cyclohexylimine: diphenylketene-N-cyclohexylimine, ethoxy/
Acetylene, 1-alkoxy 1-chloroethylene: trialkyl phosphite; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride): phosphorus trichloride: thionyl chloride; oxalyl chloride, halogens such as ethyl chloroformate, isopropyl chloroformate, etc. Acid lower alkyl; triphenylphosphine: 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)
Inoxazolium hydroxide/doφ inner salt: ] −
(] p-Chlorobenzenesulfonyluoquine-6-chloro-IH-benzotriazole: So-called Bylsma produced by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.) Preferably, the reaction is carried out in the presence of a conventional condensing agent such as Ear's reagent, etc. The reaction is also carried out in the presence of alkal metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N - The reaction may be carried out in the presence of an inorganic or organic base such as di(lower) alkylbenzylamine, etc. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. Removal of the protecting group from the product can be carried out by the method described in the Examples below or a method analogous thereto. It is a compound that exhibits strong antibacterial activity and inhibits the growth of a wide range of pathogenic bacteria, including Durham-positive and Durham-negative bacteria, and is useful as an antibacterial agent.For treatment, the compound according to the present invention can be administered orally or parenterally. The compounds may be used in the form of conventional pharmaceutical preparations containing them as active ingredients in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for administration or topical administration. The pharmaceutical formulation may be in solid form, such as a capsule, tablet, dragee, ointment, or skewer, or in liquid form, such as a solution, suspension, or emulsion. Auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers, and other lactose, fumaric acid, citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, terra alba, sucrose. , cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil,
Commonly used additives such as cocoa butter, ethylene glycol, etc. may also be included. Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds according to this invention have an average single dose of about 10.
, 50g, 100. ．． 250K, 500. and 100
0. The administration of this drug was found to be effective in treating pathogenic bacterial infections. In general, 1 mg/individual and about 6000 ■/day
It is sufficient to administer an amount between the same amount as that of the individual or a larger amount. Example J This invention will be explained below according to Production Examples and Examples. Production Example 1 A solution of 5-formylamino-1-methylpyrazole (5 g) in N,N-dimethylformamide (50 μl) was hydrogenated. Sodium (1.6 g) is added in portions under water cooling. Methyl iodide (2.5 sr) is then added to the mixture under the same conditions. The mixture is stirred for ] hours under water cooling. Ethyl acetate (500 mf) is added to the reaction mixture. Add a mixture of water and water (<100ml). Separate the organic layer and dilute the aqueous layer with ethyl acetate.
Extract times. Combine the organic layers and dry with magnesium sulfate. The solvent was distilled off, the residue was subjected to column chromatography using silica gel, and extracted with a mixture of ethyl acetate and diimpropyl ether (3:]). Fractions containing the target compound were collected and the solvent was distilled off under reduced pressure to obtain 5-(N-formyl-N-methylamino)-1-methylpyrazole (
2.5 g) are obtained as crystals. IR (medium 1-l): 1660-1f+
80. 1550 1320 c-10R (DiI
SO-d,, D; 3.07 (3H, s), 3.
67(3)1. s), 6.28 (1B, d, J
=2Hz), 7.44(IH,d, J=211z
), 8.20(IH,s) Production Example 2 The following compound is obtained in the same manner as in Production Example]. 5-(N-formyl-'N-methoxycarbonylmethyl)ami7-1-methylpyrazole (10,6 g). NMR (CDC1,, J): 3.68 (3H, s),
3.77 (3H, s), 4.26 (2R, s),
6.46 (IH, d, no 3Hz), 7.39 (
JR, d, J = 3Hz). 8, 15 (IB, ε) &l Carp J 7β-Tertiary butoxylponylamino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (]Og) and sodium iodide (2,91g)
5-ureido-1-methylpyrazole (6.8 g
) at room temperature. After stirring at the same temperature, the mixture is poured into a mixture of ethyl acetate, tetrahydrofuran and water. The organic layer is separated, washed with brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 7β-tertiary butoxaldicarbonylamino-3-(3-ureido-2-methyl-
1-Virazolio)methyl-3-cephem-4-carboxylic acid benzhydryl ester iodide (12, Ig) is obtained. IR (streak z-k): 3250. 17
80. 1705 cm-'mouth R (DMSO-d,,
δ): 1.43 (9H, s), 3.39 (2H, b
rs), 3°67 (3B, s), 5.18 (IH,
d, J=5)1z), 5.38(2)1. brg)5
．． 68 (II, dd, J5HzAyod8Hz),
6.88 (1B, d, J=3Hz). 7.00 (IH, s), '/, 1B-7.68 (10
H,m), 8.01CIH,d. J=8Hz), 8.22 (1H, d, J=3Hz) Production Example 4 The following compound was obtained in the same manner as Production Example 3. 76-tertiary butquine carbonyl amide/-3-[3-(
N-formyl-N-methyl)amino-2-methyl-1-
Virazolio] methyl-3-cephem-4-carboxylic acid benzhydryl ester iodide. NMR (DMSO-d, δ): 1.38 (9H,
s), 3.29 (3H, s), 3.68 (3) 1.
s), 3. (17-3, 77 (2B, m), 5.1
8 (IH, d, J=511z). 5.35-5.75 (3H, s), 6.90 (IH,
s), 7.01 (IH, d, J・2) 1z), 7.
08-7.60 (101 (, Maro), 8.02 ([, r
3. J=8Hz). 8,35(IH,s), 8.43(IH,d, J=
2Hz) V road side 5 The following compound is obtained in the same manner as in Production Example 3. 7β-tertiary butoxycarbonylamino-3-f3-
(N-formyl-N-methoxycarbonylmethyl)ami/-2-methyl-1-virazolio]methyl-3-cephem-4-carboxylic acid benzhydryl ester iodide. IR (Nujigor): 3300. 17
80. 1620 cm-'1 River 7β-tertiary butoxylponylamino-3-(3-ureido-2-methyl-1-virazolio)methyl-3-cephem-4-carboxylic acid benzhydryl ester iodide (12.0 g ) to a mixed solution of methylene chloride (36 ml) and anisole (12 m7) was added trifluoroacetic acid (
24■ Add I) under water cooling. After stirring at the same temperature for 1 hour, the mixture was poured into diisopropyl ether (700 sF) and 7β-amino-3-(3-ureido-2-methyl-1
-Pyrazolio)methyl-3-cephem-4-carboquinrad di(trifluoroacetic acid) salt (9.20 g) is obtained. NMR (DMSO-da, J): 3.53 (2H, b
rs), 3.90 (3H, s), 5°33 (20,
s), 5.68 (2111,brs), 6.9
8 (ltl, d, J=3rlz). 8,33 (In, d, J=311z) Production Example 7 The following compound was obtained in the same manner as in Production Example 6. 7β-amino-3-[3-(N-formyl-N=esteramino-2-methyl-1-pyrazolio]methyl-3-
Di(trifluoroacetic acid) salt of cephem-4-carboquinrad. NMR (D, O, δ): 3.46 (31, s),
3.87 and 4.00 (total 31°7al
ag), 3.13-3.77 (2B, m), 5
．． 05-5.47 (4H, @6.89 (II (, d,
J=2Hz), 8.32(In, d, J=2Hz),
8.36 (IH, s) 0μ The following compound is obtained in the same manner as in Production Example 6. Di(trifluoroacetic acid) salt of 7β-amino-3-[3-(N-formyl-Nmethoxycarbonylmethyl)amino-2-methyl-1-virazolio]methyl-3-cephem-4-carboxilade. IR (Medi1-L): 3300. 17
80. 1610 cm" Production Example 9 7β-amino-3-'[3-(N-formyl-N-methyl)amino-2-methyl-1-virazoliocomethyl-3-
In methanol (26 sJ) solution of di(trifluoroacetic acid) salt (5.3 g) of cephem-4-carboxilade,
Add concentrated hydrochloric acid (2.6 ml). The mixture is stirred at room temperature for 2 hours. The reaction mixture was added dropwise into ethyl acetate (260 s), and the resulting powder was collected by filtration, washed with diisopropyl ether, dried under reduced pressure over phosphorus pentoxide, and 7β-amino-3-(3-methylamino/- 2-Methyl-1-virazolio)methyl-3-cephem-4-carboquinlade dihydrochloride (2,45 g) is obtained. NMR (DzO-Nat (CO,, J): 2.93 (
3H, s), 3.25-3.38 (2H. m), 3.63 (3H, s), 5.07-5.33
(4H, m), 5.97 (Ind, J=21(z),
7.89(II(,d,J=2Hz) Production Example 10 The following compound is obtained in the same manner as Production Example 9. 7β-Amino-3-[3-(N-methoxycarbonylmethyl)amino-2-methyl- 1-virazolio]methyl-3-cephem-4-carboxilade dihydrochloride. IR (Nuji x-k): 3200-33
50. 1780. 1610 am-' Example I N,N-dimethylformamide (0,13d). Ethyl acetate (0,37a&) and phosphorus oxychloride (01
The mixture of 56d) is stirred for 30 minutes under water cooling. Add tetrahydrofuran (3-) to the mixture. And 2-(
2-Formylaminothiazol-4-yl)-2-methoxyiminoacetic acid (N-isomer) (0,327y) was added under water cooling, and the mixture was stirred at 3-5°C for 1 hour to produce an activated acid solution. do. On the other hand, 7β-ami/-3-[3-(N
-methquincarbonylmethyl)amino-2-methyl-1
- Virazoliocomethyl-3-cephem-4-carboxilade dihydrochloride (0.7 g) is dissolved in a solution of N-(trimethylsilyl)acetamide (1,87y) in tetrahydrofuran (14d>). The acid solution is added at -20°C, the mixture is stirred at -10°C to 0°C for 2 hours, the mixture is poured into ethyl acetate (140aff) and the resulting powder is filtered off. The powder is washed with diisopropyl ether. and dried over phosphorous pentoxide under reduced pressure to give 7l-E2(2-formylaminothiazol-4-yl)2-methoxyiminoacetamide]
-3-[3-(N-methoxycarbonylmethyl)amino-2-methyl-1-virazoliocomethyl-3-cephem-4-carboxilade (syn isomer') (1,
399). (This compound was used in the next experiment without being purified.) Example 2 The following compound was obtained in the same manner as in Example. 7β-[2-(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(3-
Methylamino-2-methyl-1-virazolio)methyl-
3-cephem-4-carboxilade (syn isomer). (This compound was used in the next experiment without being purified) Example 3 The following compound was obtained in the same manner as in Example 1. 7β-[2(2-formylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(3-ureido-2-methyl-1-virazolio)methyl-3-cephem-4-carboxilade tri Fluoroacetate (
syn isomer). IR (meth1-ru) = 17f (1,1660
, e-1 HMR (DMSO-d,, δ): 3.4
1 (2H, brs), 3.90 (3H, s), 39
7 (3H, s), 5.22 (IH, d, J=5Hz
), 5.48 (2H, brs) 5.91 (1111,
dd, J=51]z and 8Hz), 6.88(
IH, d, J = 3Hz) 7, 44 (I) I, s),
8.320FI, d, J=3Hz), 8.50(
1B, s). 9, 75 (II, d, J = 8 Hz) Tomusami 1 7β-[2-(2-formylaminothiazol-4-yl)-2-methquiniminoacetamide]-3-(3-
(N-Methoxycarbonylmethyl)amino-2-methyl-1-virazolio]methyl-3-cephem-4-carboquinlade (syn isomer) (1,4 g) in methanol (
8d) Add concentrated hydrochloric acid (0.4d) to the solution at room temperature. The mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into ethyl acetate (80-) and the resulting powder is collected by filtration. The powder is dissolved in cold water under water cooling and adjusted to pH 13 with IN aqueous sodium hydroxide solution. After stirring for 20 minutes under the same conditions, the solution was adjusted to pH 2.5 with 3N hydrochloric acid, and subjected to column chromatography using Diaion HP-20J (Korouko Mitsubishi Kasei Co., Ltd. 12) and 5% inpropyl alcohol. Extract with an aqueous solution. Both fractions containing the target compound are collected, and the solvent is distilled off under reduced pressure.
Freeze-dry to give 7β-[2-(2-aminothiazole-
4-yl)-2-methoxyiminoacetamide] -3
-E3- (N-carbo-cow dimethyl)amino-2-methyl-1-virazolio]methyl-3-cephem-4-carboquinlade (syn isomer) (0,259) is obtained. IR (medium 1-l): 3350. 17
70. 1660 1610 cmNMR (DyO-
NaHCO−, δ): 3.1] and σ 3.38(
2B, 8BQ, J=1111Hz), 3.69(
3H,s), 3.99(3H,s), 4.9
9 and 5.28 (2H18BQ, J=14Hz
), 5.17 (II, d, J=5Hz), 5.77
(IH, d, J=5Hz), 5.86 (IH, d, J
=3Hz), 7.00(IH,s). 7,85 (IH, d, J・3Hz) Example 5 The following compound was obtained in the same manner as in Example 4. 7β-[2-(2-aminothiazol-4-yl)-2
-methquiniminoacetamidoco-3-(3-methylamino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboquinlade (non-isomer). IR (Nuji Lun): 3200-330
0. 1770. 1670. 1620°1530
c■ Violet NMR (DyO, J): 2.90 (3H, s),
3.08 (1B, d, J bow 8Hz), 3°34 (
IH, d, J=18Hz), 3.60 (3H, s),
3.97 (3B, s) 5.03 (IH, d, J12H
z), 5.18 (1B, d, J=5Hz), 5.2
7 (IH, d, J12Hz), 5.79 (IH, d
, J□5Hz), 5.91 (IH. d, J=3Hz), 6.96 (]) I, s), 7.
86 (II, d, J=3Hz) Example 6 The following compound is obtained in the same manner as in Example 4. 7β-[2-(2-aminothiazol-4-yl)-2
-Methoxyiminoacetamide] -3-(3-ureido-2-methyl-1-virazolio)methyl-3-cephem-4-carboxilade (non-isomer). 1R (1 dil): 1765. 1
700 1660 c-1) IMR (DMSO-d
,,J): 3.29 (2B, brs), 3.8
3 (3H, s), 3°85 (3H, s), 5.
08 ([, d, J=5Hz), 5.33 (28, b
rs). 5.67 ([, dd, J=5Hzj yo IJ8Hz),
6.18 CIH, d, J=3Hz). 7.16 (2E, brs), 8.18 (IH, d,
J=3flz), 9.54 (IH, d. J・8Hz) Patent applicant Fujisawa Pharmaceutical Co., Ltd. Agent Patent attorney Toshio Yoshikawa

Claims (1)

[Claims] Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an amino group or a protected amino group, R^2 is a lower alkyl group, and R^3 is -COO^ ■ group, carboxy group or protected carboxy group, R^4 is a lower alkyl group, R^5 is a lower alkylamino group, carboxy (lower) alkylamino group, protected carboxy (lower) alkylamino group or ureido group , X^■ Anion n means 0 or 1, respectively. However, R^3 is -C
When it is an OO^■ group, n is 0, and when R^2 is a carboxy group or a protected carboxy group, n is
is 1. ] A novel cephem compound and its salt.