JPS59161388A - Novel cephem compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) amino; R<2> is lower alkyl, (protected) carboxy(lower)alkyl or cycloalkyl; R<3> is (protected) carboxy] and its salt. EXAMPLE:7-[2-( 5-Amino-1,2,4-thiadiazol-3-yl )-2-carboxymethoxyimino-acetamido]- 3-[(4-carboxy-3-hydroxyisothiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid sodium salt (syn-isomer). USE:An antibacterial agent. PREPARATION:The compound of formula II or its reactive derivative at the amino group or their salt is made to react with the compound of formula III or its reactive derivative at carboxyl group or their salt.

Description

DETAILED DESCRIPTION OF THE INVENTION 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, and methods for producing them.

The target cephem compound is a new compound and can be represented by the following general formula.

[In the formula, R1 is an amine group or a protected amine group, R2 is a lower alkyl group, a carboxy(lower) alkyl group, a protected carboxy(lower) alkyl group or a cycloalkylρ group, and R3 is a carboxy group or a protected Decoct each carboxy group].

According to this invention, the novel cephem compound (I) can be produced by the production method shown by the following reaction formula.

Production method 1 0OH (n) (In)- or its amino group or reactive derivative at its carboxy group or its salt
or its salts (I) or its salts production method 2 (Ia) or its salts 0OH (Ib) or its salts [In the formula, R1, R2 and R3 each have the same meaning as before, and RK is a protected carboxy (lower) alkyl group, R2
b means a carboxy (lower) alkyl group].

In this invention, the target compound (I) and (I”O)
, and starting compounds (1) and (Ia), all of these compounds include syn isomers, anti-isomers, and mixtures thereof.

To explain the target compound (I), its syn isomer means one geometric isomer having a group represented by the following formula: means another geometrical variant having a group of the formula: in which R1 and R2 each have the same meaning as before.

Furthermore, for other compounds, their syn isomers and anti-isomers are also each shown in the same geometrical configuration as the target compound (I).

Suitable salts of the target compound (I) are customary non-toxic salts, including inorganic salts, such as IJum salts,
Alkali metal salts such as potassium salts and metal salts such as alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts etc.; organic salts such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts; , picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamine)methane salt, phenylethylbenzylamine salt, 7't- is a sulfonic acid salt; for example, an inorganic acid salt such as a hydrochloride, a hydrobromide, a sulfate, a phosphate; an example is a salt with a basic or acidic amino acid such as arginine, aspartic acid, glutamic acid, or lysine.

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.

"Lower", unless otherwise specified, shall mean groups having 1 to 6 carbon atoms.

Suitable protected amine groups include acylamino groups and a/I/(lower) groups such as benzyl, trityl, etc.
7/L/(lower) of an alkyl group, such as benzylidene, etc.
Alkylidene groups, such as J-ethoxycarboni/L'-
An amine group substituted with a conventional protecting group other than an acyl group such as a lower alkylidene group substituted with 2-glopylidene, dimethylaminomethylene, etc. Can be mentioned.

Suitable acyl moieties of the "acylamino group" include carbamoyl groups, aliphatic acyl groups, and acyl groups containing aromatic rings or heterocycles. Suitable examples of these acyl groups include lower alkanoyl groups such as formi, acetyl, propionyl, butyryl, imbutyryl, valeryl, invaleryl, oxalyl, succinyl, and pivaloyl, preferably those having 1 to 4 carbon atoms. , more preferably those having 1 to 2 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propanesulfonyl, l-cyclopropylethoxycarbonyl, impropoxycarbonyl, ctoxycarbonyl, tertiary butoxycarbonyl, pentyl oxycarbonyl,
Lower alkoxycarbonyl groups having 2 to 7 carbon atoms, preferably those having 3 to 6 carbon atoms, such as tertiary benzyloxycarbonyl, hexyloxycarbonyl/v; examples, t td mesyl, ethanesulfonyl, Lower alkanesulfonyl/L/ groups such as propanesulfonyl, isopropanesulfonyl, butanesulfonyl; for example, arenesulfonyl groups such as benzenesulfonyl, tosi/I/; examples, aroyl groups of benzoyl, toluoyl phthaloyl, indancarbonyl) v4 ; e.g. evaphenylacetyl, phenylgropionyl, etc. a)
V (lower) alkanoyl group.

Examples include cyclo(lower)alkyl)v(lower)alkanoyl groups such as evacyclohexylacetyl and cyclopentylacete)V; Examples include a)v(lower)alkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl.

Preferred lower alkyl (lower) alkyl groups and protected carboxy (
Suitable lower alkyl moieties of "lower alkyl group" include methyl, ethyl, propyl, inflovir, gutyl,
Inbutyl, secondary butyl, tertiary butyl, pentyl,
ml@-4. with 1 to 6 carbon atoms such as tertiary pentyl, hexyl, etc. or branched alkyl groups, preferably those having 1 to 4 carbon atoms.

Suitable cycloalkyl p groups include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cyclohexyl, etc.
Preferably, those having 4 to 7 carbon atoms are mentioned.

Suitable protected carboxy groups and suitable protected carboxyl moieties of "protected carboxy (lower) alkyl groups" include esterified carbomodi groups; Examples of the ester moiety include methyl ester, ethyl ester,
Lower alkyl esters such as probyl ester, imbutyl ester, butyl ester, imbutyl ester, tertiary butyl ester, pen f / L / ester, tertiary pentyl ester, hexyl ester, Eusik tetrapropylethyl ester, Those in which the lower alkyl moiety preferably has 1 to 4 carbon atoms: lower alkenyl esters such as ehabinylestenopearyl ester; lower alkynyl esters such as glopinyl ester; 2,2.2-
1) Mono(or tri)-halo(lower) alkyl esters such as chloroethyl ester/I/; Examples: acetoxymethyl ester, propionyloxyethyl ester, 1-acetoxyethyl ester, hali/I
) /L/Lower alkanoyloxy (lower) alkyl esters such as oxymethyl ester, pivaloyloxymethyl ester teropionyloxyethyl ester lyloxyether ester; for example, mesyl methyl ester, 2-mesylethyl ester lower alkanesulfonyl ester ;a) V (lower) alkyl ester, Example Ud pen 9) v varnish 7'/l', 4-methoxybenzyl ester netyl ester thyl ester l', 3.4-dimethoxybenzyl ester, 4-hydroxy -3,5-ditertiary butyl pencil ester. Good phenyl (lower) alkyl esters, such as methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, lower alkoxycarbonyloxy (lower) alkyl esters that may be substituted with and, such as ethoxycarbonyloxymethyl ester; heterocyclic esters , preferably penzotetonhydrotetrafurinone ester which may be substituted with an oxo group, more preferably phthalidyl ester /I/: for example, 70yloxy C low P alkyl ester of benzoyloxymethyl ester ester, e.g. phenyl ester, butyl tolyl ester Examples include aryl esters which may have one or more substituents, such as phenyl ester, xylyl ester, methyl ester, and cumenyl ester.

Preferred embodiments of the target compound CI) are as follows.

A preferred embodiment of R1 is an amino group; a preferred embodiment of R2 is a lower alkyl group, a carboxy (lower) alkyl group, a protected carboxy (lower) alkyl group [more preferably an esterified carboxy (lower) alkyl group] group, most preferably lower alkoxycarboni)V
A preferred embodiment of (lower)argyl R3 is a carboxy group.

The method for producing the target compound (1) will be explained in detail below.

Production method 1 Target compound (I) or its salts can be obtained by reacting compound (n) or its reactive derivative with an amine group or its salts with compound (■) or its reactive derivative with its carboxyl group or its salts. can be manufactured.

Suitable salts of compounds (II) and (Iif) include those exemplified for compound CI).

Suitable reactive derivatives at the amine group of compound (II) include reactive derivatives for @ used in amidation;
For example, Schiff's base type imino or its enamine type tautomer is produced by the reaction of compound (II) with a carbonyl compound; by the reaction of compound (■) with bis(trimetersi-nor)acetamide or trimethylsilylacetamide. Generated IJ/Silicon conductor: Examples include derivatives generated by the reaction of compound (II) with phosphorus trichloride or phosgene.

Suitable reactive derivatives at the carboxy group of compound (IIf) include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples thereof include acid chlorides; acid azides; e.g.
, Jf dialkyldi) v phosphoric acid, dibenzo/L/IF acid, substituted sulfuric acids such as halogenated phosphoric acid, sialygyl substomatous acid, sulfurous acid, alkanesulfonic acid such as methanesulfonic acid, ethanesulfonic acid, thiosulfuric acid, sulfuric acid , alkyl carbonates, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, impentanoic acid, 2-ethyl)V-butyric acid, acetic acid or trichloroacetic acid or acids such as aromatic carboxylic acids such as benzoic acid. Mixed acid anhydrides; also known as acid anhydrides: with imidazole, dimethylpyrazole, triazole or tetrazole; curved amides; or activated esters such as cyanogen methyl ester, methoxymethyl ester, dimethetyliminomethyl C (CH3) 2N=CH”:
J ester, vinyl ester, proha/L/gyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, Pyranyl ester, pyridyl ester, piperidyl ester, 8-
Quinolylthioester, or N,l'J-dimethylhydroxylamine, nihydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or nihydroxy-6-chloro-1
Examples include esters with H-benzyl lyazole. These reactive derivatives are the compounds to be used (Hl)
Depending on the type, you can arbitrarily select one from among them.

The reaction is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N.

] The reaction is carried out in a conventional solvent such as liginoterformamide, pyridine, etc., but it can be carried out in any other solvent as long as it does not adversely affect the reaction. Among these solvents, hydrophilic solvents may be used in combination with water.

Compound <Hi)k When used in the reaction in the form of the free acid or in the form of its salts, N,N-dicyclohexylcarbodiimide: N-7 clohexy Jz - N-morpholinoethercarbodiimide yv - N'-' (4- Diethylaminocyclo, xy, di]cacarbodiimide; N,N-diethylcarbosiimide, N,N-diisopropylcarbosiimide-11-ethyl-N-(3-dimetelaminopropylene)carbodiimide; N,N-carbonylbis(2-
methylimidazole], pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate,
Polyphosphoric acid inpropylene) v: Diethyl phosphorochloricate: oxychloride; phosphorus trichloride; phosphorus pentachloride; thionyl chloride, oxalyl chloride; triphenylphosphine: N-technical f
) Ly - '7-Hytroxybenzisoxazolium fluoroborate &4iN-ethyl) v-5-phenylinoxacillium-3'-sulfonate il-CI)
-10robenzenesulfonyloxy) 6-chloro, o
-IH-hensitriazole: a compound formed by the reaction of dimethylformamide with thionyl chloride or phosgene (chloromethylene)dimethylammonium chloride, a compound formed by the reaction of dimethylformamide with phosphorus, etc., such as the so-called Vilsmeier reagent, etc. Preferably, the reaction is carried out in the presence of a condensing agent.

This reaction also applies to alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, tri(lower)alkylamines, pyridine, N-(
The reaction may be carried out in the presence of an inorganic or organic base such as lower) argylmorpholine, N.N-cy(low M)alkylbenzylamine, N,N-cy(lower)alkylaniline, and the like. If the base or condensing agent is liquid, they can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature.

Production method 2 The target compound (Ib) or its salts is a compound (:1
．． a) t or its salts can be produced by subjecting it to an elimination reaction of the cal number (xy 1α4j1 (group) in R2a.

Suitable salts of compounds (Ia) and (It)) include those exemplified for compound (I).

This reaction can be carried out by conventional methods such as hydrolysis, reduction, etc.

When the protecting group is an ester, it can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides, carbonates or bicarbonates of these metals, trialkylamines such as trimethylamine, triethylamine, etc. 0] Non-5-dyne, 1,4-diazabicyclo[2.

2,2] octane, 1,8-diazabicyclo(5,
4. 0] Undecene-7, and other inorganic bases and organic bases. Suitable acids include, for example, git
, organic acids such as acetic acid, propionic acid, trifluoroacetic acid,
Examples include inorganic acids such as hydrochloric acid, bromic acid, and sulfuric acid. Acidic hydrolysis using trifluoroacetic acid is usually accelerated by the addition of anisole.

The reaction is usually carried out in a solvent such as water, methylene chloride, an alcohol such as methanol, ethanol, etc., or a mixture thereof, or in any other solvent which does not adversely affect the reaction. can be done. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of cooling to heating.

Reduced B'nitrobennyl, 2-ethyl iodide, 2,
2.2-) It is preferably applied to the removal of holding groups such as lichloroethyl/l/.

Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and organic acids or inorganic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrogen bromide, etc. It is a combination with acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. are conventional catalysts such as copper catalysts such as reduced copper, Raney copper, Ullmann copper, etc.

The reduction is usually carried out in water, alcohols such as methanol, ethanol, etc.), v,N,N-dimethylformamide, tetrahydrofuran, or mixtures thereof, but any solvent that does not adversely affect the reaction may be used. , or any other solvent.

Furthermore, when the acids used in the chemical reduction are liquids, they can also be used as solvents.

The skin temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.

Compound (I) and its salts, which are the objects of this invention, are novel compounds that exhibit high in-pile activity and inhibit the growth of a wide range of pathogenic bacteria, including crumb-positive bacteria and crumb-negative bacteria, and are useful as antibacterial agents. For therapeutic use, the compounds of this invention may be used in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or external administration, containing said compounds as active ingredients. It can be used in the form of conventional pharmaceutical preparations.

The pharmaceutical formulation may be in solid form, such as capsule tablets, dragees, diluted tablets, or liquid forms, such as bath solutions, liquid tablets, or emulsions.

Optionally in the above formulations, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and others, lactose, fumaric acid, citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, malic acid, magnesium stearate, Commonly used additives such as clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. may be included.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds of this invention can be administered once on average.
n;), 50m9.10C11i? , 25QT19.5
001119. A drug that has been found to be effective in treating pathogenic bacterial infections at 1000mg. In general, l Tnli per day
~60001119 liters or more may be administered.

In order to demonstrate the usefulness of N-type compound (I), the results of in vitro antibacterial tests on representative compounds of this invention are shown below.

Test compound 7-(2-(5-amino-1:2,4-thiasiacy)
v-3-i/V) -2-carboxymethoxyiminoacetamide]-3-((4-carboxy-3-hydroxyisotheacy/L'-5-yl)thiomethyl]-3
- Sodium cephem-4-carboxylate (syn isomer) Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below.

Each test strain was cultured in Otryptocase Soypros overnight and one platinum loop (108 viable bacteria/ml) was added to heart infusion agar containing the test compound at each concentration level (
After inoculating onto H-technical agar] and culturing at 1.37°C for 20 hours,
The minimum degree of inhibition (1v1C) was expressed as μ7/solution.

Test results MIC (μfl　/rnl) This invention will be explained below with reference to production examples and examples.

Production Example 1 2-(5-formamidoyu, 2,4-theadiazo/L
'-3-yl]-2-hydroxyiminoacetic acid (syn isomer) (9,60f) and potassium tertiary poly-1-oxide (14,!l) in dimethyl sulfoxide (100ηt(
3) Add dimethyl sulfoxide (10 ml) of tert-butyl 2-bromo-2-methylbutyrate (14,1) to the medium temperature mixture.
The solution is added under stirring below 25° C. and stirred at room temperature for 31E1. The reaction mixture was mixed with concentrated hydrochloric acid (7,4 ml) and cold water (5 ml).
ml) (2007 nl) and the mixture is adjusted to pH 6.5 with aqueous sodium bicarbonate solution. Separate the aqueous layer, add diethyl ether to it, and adjust the mixture to pH 20 with 6N hydrochloric acid.
Adjust to. The organic layer is separated and the aqueous layer is extracted with diethyl ether. The organic layer and extract are combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. Remaining m
Recrystallize from K-diethyl ether, dry and give 2-
(5-formamide-1,2,4-thiadiazole-3
-2-(U'-tertiary poxyl-1)
-methylpropoxyimino)acetic acid (syn isomer) (2
，'? 6? ). The same compound is also obtained from the 7p solution.

Melting point 128-131°C (decomposition) R (nujo/L'): 3550. 3150.
3020. 1730°16'70. 1540.
1250. 1140. 11UOcmNMLR(DM
S○-cl, +D20, δ): 0.88 (3H, t
, J=7Hz).

138 (3H, S), 1.43 (9H, S), 1.86
(2H.

q, J=7Hz), 8. a2(IH,s) Production Example 2 2-(5-formamide-1,2,4-theasis/
A 1N aqueous solution of sodium hydroxide (22.4 iJ) of -2-(ni-tert-butoxycarbonyl-syn isomer) (3.5i) was stirred at room temperature for 24 hours. Add ethyl acetate (30 ml) to the solution. The mixture was adjusted to pH 2.0 with 1 q hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the organic layer and extract and add water
Then, dry with magnesium sulfate and concentrate to obtain
g+f; f<tdiisopropyl ether 2-(5-
Aminoyu, 2,4-thiadiazole)v-3-i/L'
) − 2 = − (1-tert-butoxycarbonyl-1-methylgloboximino)acetic acid (syn isomer)
We obtain (2.21).

Melting point: 8'7~189℃ (decomposition: 9°C): 3420
+3320. 3220+1750.

1720, 1635, 1535, 1420
, 1240, 1 Yu 40.

1020 cm NMIR (DMS○-d6, δ): 0.85 (3H
, t, J=7Hz).

■． 4o(ah,S), 1.43(9H,S), 1.8
6 (2H.

q, J=7Hz), s, 21 (2H, broad S)
Example 7] 7-amino-3-((4-carboxy-3-hydroxyinthiazol-5-yl)thionothyl-3-cephem-4-carboxylic acid (1.0'?) and sodium hydrogen carbonate (648 m9 ), e Dissolve in 50% acetone aqueous solution (26 ml), and add 2-(5-
Amine-1. 2. Mixed acid anhydride (syn isomer) of 4-thiadiazonon-3-yl)-2-canonboxymethoxyiminoacetic acid and methanesulfonic acid (832 mg
) was added at 10°C with stirring, and stirred for 30 minutes while adjusting the pH to 7 with an aqueous sodium bicarbonate solution at 10-15°C.

Ethyl acetate (2 oml) is added to the reaction mixture and the mixture is adjusted to pH 1.5 with 6N hydrochloric acid. After removing the insoluble matter,
The organic layer is separated and evaporated to dryness. The residue is triturated in 7setonitrile to obtain a powder (650 mg).

The powder is dissolved in methanol (20 ml) and to this is added a solution of sodium acetate (82 ml) in methanol (2 ml). The formed precipitate is removed, and the r solution is concentrated to 5 ml. Separate the precipitate, wash with ethanol and dry,
-(2-(5-amino-1, 2.4-thiasiacy)v-3-yl)-2-carboxymethoxyiminoacetamide)-3-((4-carboxy-3-hydroxyisothiazole-thea)thiomethyl] -3-Cephem-
Sodium 4-carboxylate (syn isomer) (23o
m9) is obtained.

Melting point 205-210℃ (decomposition) Engineering R (Nugeot/V): 3300, 176
0, 1680, 1600.

1520, 1240, 1050. 1020
cm”NMR (D,,0,δ): 3.53
and 3.77 (2H, ABcl.

J=18Hz), 4.02 and 4,43
．． (2H, ABq.

, J'=Ya-Hz), 4. '78 (2H,S),
5.23 (IH, cl.

Example 2 In fact, in the same manner as fluid 1, 7-amino-3-[(4-carboxy-3-hydroxythiazole-5- ia 1
z) Thiomethyl]-3-cephem-4-carboxylic acid, 2-(5-amino-1, 2.4-theasiacy/
L'-3-i/v)-2-ethoxyiminoacetyl chloride hydrochloride (reacted with the syn isomer to obtain the following compound.

7-(z-(5-amino-1,2.4-thiadiazol-3-yl)-2-ethoxyiminoacetamide)
-3-1: (4-carboxy-3-hydroxyisotheazol-5-yl]thionotyl]-3-cephem-4-
Carboxylic acid (Syn J. substance).

Melting point 180-185℃ (decomposition) Engineering R (nujo-/V): 3400,
3250, 3200, F'70.

1'700, 1670, 1620. 154
0 (Hn 1NMR (D20 +NaHCO3, δ
): 5.88 (H, d, J = 4Hz).

5, 25 (IH, d, J = 4Hz), 4.40 (2H,
(1, J=7Hz), 4.36 and 3.93 (2H
, ABq, J=14Hz).

3, 80 and 3.53 (2H, ABO., J
-,,l 8Hz), 1.3 7(3H,t+J
=7Hz. ) Example 3 In the same manner as in Example 1, 7-amino-3-[(4-carboxy-3-hydroxyinthiazol-5-yl]thiomethyl]-3-cephem-4-carleboxylic acid 2-
The following compound is obtained by reacting with (s-amine-122,4-theasiacy/V-3-yl)-2-cyclobentyloxyiminoacetel chloride hydrochloride (syn isomer).

7-(z-(5-amine-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide)-3-((4-carboxy-3-hydroxyisothiazol-5-yl)thiomethyl ]-3-cephem-4-carboxylic acid (syn isomer).

Melting point 182-187℃ (decomposition) Engineering R (Nujol): 3300. 3200. 1
7'70. Nooo.

1680, Yu 6 Yu 0. Yu520. 1400.
1240°1000 cm NMR (DMS, 0-cl6. δ): 9.4'?
(LH, cl, J=sHz).

8.10 (2I (, blow 1' S), 5.80 (L
H, dd.

J=8Hz, 4f(Z), 5.1'? (Engineering H
, (1, J=4Hz).

4.8-4.6 (LH) 4.27 and 4, O'
7 (2H, ABa-.

J=14 top (Z), 3.6'? (2H, 7-1111
1-1'S), 2.0-1.3 (8H) Example 4 The following compound was obtained in the same manner as in Example 1.

7-(z-(5-amino-1,2,4-thiadiazol-3-yl)-2-(u-carboxy-1-methylpropoxyimino)acetamide]-3-((4-carboxy-3- Hydroxythiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn-A form).

Melting point 20'7~2°C (decomposition) R (nujol): 3300. 3200
．．工'i"70. l'i'30-16'70
．． Engineering 620. 1520. 1240. ．． 116C
1,1140゜1 1000 Example 5 2-(5-aminoyl, 2,4-thiadiazole-
3-yl)-2-(1-tert-butoxycarbonyl-methylpropoxyimino)! Acid (syn isomer) (2,
lof? ) was added at -15°C with stirring, and -20 to -12
Stir for 40 min at °C'''C. The reaction mixture is
methylene chloride (26 ml) of carbonic acid (2,61F) and trinotylsilylacetamite (page 13.59)
Add to the solution at -20°C with stirring, and add to the solution at -20 to -10°C for 40 min.
Stir for a minute. Reaction mixture total sodium bicarbonate (3,
Pour into a solution of 87) in water (80 yd), separate the entire aqueous layer, and wash with ethyl acetate.

Add ethyl acetate/I/ to the aqueous solution and pipize the mixture i with 6N hydrochloric acid.
Adjust to EI 1.5. The organic layer is separated, and the aqueous layer is further extracted with ethyl acetate. The organic layer and extract are combined, washed with water, dried over magnesium sulfate, and concentrated to a specific weight. The resulting precipitate was collected and dried to give 7-(2-(5-amine-1,2,4-thiadiazol-3-yl)-2-(1-tertiary gutoxycarbony/L/-1-methyl). propoxyimino)acetamide)-3-(4-carboxy-3-hydroxyisotheacy1V-5-i)V)naomethyl")-s-senem-4-carboxylic acid (synthelic triad) (1,9' 7g)
get.

Melting point from 203 to 20°C (decomposition) (Nushor): 3300. 3200.
l'780. 1'720°1680, 1615.
1515. Engineering 250. L140CmNi Note (
DMSO-d6 +D20. δ'): 0.88 (3H
, t, J='7H'Z), 1.40(12H,S), 1
．． 95(2H,q,J-,,7Hz), 3.50 and 3.8'7 (2I(,ABq, J=18E(Z)
, 3.9-4.5 (2E(,m), 5.18 (
IH.

σ, J=5Hz), 5.85 (LH,d,
J=5Hz) Example 6 '7-(2-(5-amino-l, 2.4-theacyacy/l/-3-yl)-2-(1-tertiary poxycarbonino v-1- methylpropoxyimino)acetamido)-3-C(4-carboxy-3-hydroxyinthiazol-5-ylthiomethyl]-3-cephem-4-
A warm mixture of carboxylic acid (syn isomer) (1,90 g) and anisole (2d) in trifluoroacetic acid (10 M) is stirred under cooling in a water bath for 1 hour. The reaction mixture is diluted with cold diisopropyl ether (6 oml). Pour into the tank and remove the precipitate that forms.

The precipitate was dissolved in bicarbonate of I-lium (892 m9) of water (4 o
ml] solution, washed with ethyl acetate, and added ethyl acetate (25 mg) and tetrahydrofuran (25 mg) to this solution.
Add the mixture. The pH of the mixture was adjusted to 4.5 with 6N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was adjusted to pH 3 with 6N hydrochloric acid, and a mixed solvent of ethyl acetate and tetrahydrofuran (
Extract with 1:l). The extract is washed with brine, dried over magnesium sulfate, and concentrated to a small volume. The resulting precipitate was collected and diluted with diethyl ether 5-amino-1,2. 4-thiadiazol-3-yl)-2-(1-carboxy-1-methylpropoxyimino]acetamide)-3-1c(4-carphogycin
-Hydroxyisotheacy/l/=5-yl]thiomethy/V) -3-cephem-4-carboxylic acid (syn isomer) (1,031) is obtained.

Melting point 20'i'~2JO℃ (decomposition) Engineering R (Nushor): 3300. 3200.
l'70. Near 30-1+570. 1620
．． 1520. 1240. 1160°1140,
1000 cyn NMR (D20+NaHC○3.δ): 0.92(
3H, t, J=7Hz).

1.53 (3H, S), 1.95 (2H, C1, J two shouts).

3.45 and 3.90 (2H,, A-E(1, J=
18Hz).

3.90 and 4.40 (2 kings (, ABq, J=14
E(Z).

5.24 (IH, Ij, J=5Hz), 5.8'?
(IH, d, J=5Hz) Example 7 The following compound was obtained in the same manner as in Example 6.

'7-(2-(5-amino-1,2,4-thiadiazol-3-ylk-2-carboxymethoxyiminoacetamide, l]-34(4-carboxy-3-hydroxyisothiazol-5-yl)thiomethino v ]-3-cephem-4-carboxylic acid sodium (syn isomer).

Melting point: 205-210C (decomposition)

Claims (1)

[Claims] 1) General formula: [In the formula, R1 is an amino group or a protected amine group, R
2 is a lower alkyl group, a carboxy (lower) alkyl group,
A novel cephem compound represented by a protected carboxy (lower) alkyl/L' group or a cycloalkyl group, R3 means a carboxy group or a protected carboxy group, respectively, and salts thereof. 2) R1 is an amino group or an acylamino group, and R2
is a lower alkyl group, a carboxy (lower) alkyl group, an esterified carboxy (lower) alkyl group, or a cycloalkyl group, and is an R3 carboxy group or an esterified carboxy group. compound. 3) Syn isomer of the compound according to claim 2. 4) Claims in which R1 is an amine group, R2 is a lower alkyl group, carboxy (lower) argyl group, lower alkoxycarboni/L/(lower) alkyl group, or cycloalkyl group, and R3 is a carboxy group Compound according to item 3. 5) '7-C2-(5-amino-1,2
．． 4-thiadiazol-3-yl)-2-carbogysimethoxyiminoacetamide)-3-((4-carboxy-3-hydroxyinteacy)v-5-i/I/)
thionof) -] 3-cephemu 4-carboxylic acid sodium isomer), 7-C2-(5-amino-1,2.4-thiadiazole)V-3-i)v)-2-ethoxyiminoacetamide )-3-C(4-carboxy-3-hydroxydithiazoa-/l/-5-i/1./)thiomethylcou-3-cephem-4-carvone e (syn isomer),
'2-(2-(5-aminoyl, 2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamide]-3~[(4-carboxy-3-hydroxyisothiazol-5-yl]thiomethy) v) -3-
Cephem-4-carboxylic acid (syn isomer), 'i'-(2-(!15-amino-1.2.4-thiadiazol-3-yl)-2-(1-tertiary gluponyl-l) - 7 metherproboximine acetamide)
-3-(a,-carboxy-3-hydroxyinthiazo)V-5-i)v)thiomethyl]-3-cephem-
4-carboxylic acid (syn-11-mer), and 7-(z-(δ-amine-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1=methylpropoxyimino)acetamide )-3-[(4-carboxy-3-hydroxyinthiazo-/v-5-yl]
[Thiomethyl]-3-cephem-4-carboxylic acid (Syn M
4. The compound according to claim 4, which is selected from the group consisting of: 6) (1) General formula: (wherein, R3 means all carboxy groups or protected carboxy groups) or the reactive derivative heavy tobacco salts in its amine group, the general formula: [Formula where R1 is an amino group or a protected amine group; R1 is an amino group or a protected amine group;
2 is a lower alkyl group, a carboxy (lower) alkyl group,
By reacting with a protected carboxy(lower)alkyl group or cycloalkyl compound or a reactive derivative at its carboxy group or a salt thereof, the compound has the general formula: ) or a salt thereof, or (2) general formula: [wherein R1 and R3 have the same meanings as above, and R- means a protected carboxy(lower) alkyl group ] or a salt thereof is subjected to the elimination reaction of the carboxy protecting group in step 7 to form the general formula: [wherein R1 and R3 are the same radicals as before, and R'b is A process for producing a compound represented by the general formula: (wherein R1, R2 and R3 each have the same meanings as before) or a salt thereof, which is characterized by obtaining a compound represented by a carboxy group or a salt thereof.