JPS61165394A - Novel cephem compound and preparation thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is (protected) amino; R<2> is lower alkyl; R<3> is (protected) carboxy]. EXAMPLE:7-[ 2-Ethoxyimino-2-( 2-aminothiazol-4-yl )acetamido ]-3-( 1,2,4-thiadiazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (synisomer). USE:An antibacterial agent. PREPARATION:The compound of formula II, its reactive derivative or its salt is made to react with the compound of formula III, its reactive derivative or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Field of Application" The cephem compounds of the present invention represented by the following general formula (I) and salts thereof exhibit antibacterial activity and are useful as medicines.

"Prior Art" Many cephem compounds are known, but they have the following general formula (
Cephem compounds represented by I) are completely unknown.

"Problems to be Solved by the Invention" Many cephem compounds that have antibacterial effects and are useful as medicines are known, but this invention was made with the intention of developing even better medicines.

rMeans to solve the problem j 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 and its salt are novel;
It can be represented by the following general formula (I): (wherein R1 is an amine or a protected amine group, R is a lower alkino group, and R3 is a carboxy or protected carboxy group).

According to this invention, the target compound <1) can be produced by the following production method.

(I[) or a reactive derivative at its amino group or at its carboxylic group or a reactive derivative at its carboxylic group or a salt thereof
Derivative or salt thereof or salt thereof 1. Ashiyu (V) or salt thereof
or a salt thereof or a salt thereof (in the above formula, R1, R2, R3 are each as defined above, and Y is an acid residue). shall include the syn isomer, the anti isomer and mixtures thereof.

For example, for compound (I), the syn isomer means one geometric isomer having a partial structure represented by the following formula: (wherein R and R2 are each as defined above),
The anti-isomer is defined by the following formula: (wherein R1 and R2
means another geometric isomer having the partial structure shown in (each has the same meaning as above).

Suitable salts of the target compound (1) are conventional non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, etc.; Ammonium salts, such as trimethylamine salt, triethylamine salt, pyridine salt,
Organic base salts such as pilin salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, such as acetate, maleate, tartrate, methanesulfonate,
Organic acid salts such as benzenesulfonate, formate, toluenesulfonate, such as hydrochloride, hydrobromide, sulfate,
Examples include inorganic acid salts such as phosphates, and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

In the foregoing and subsequent description of this specification, pertinent illustrations of the various definitions that fall within the scope of this invention are described in detail below.

"Lower" means 1 to 1 carbon atom, unless otherwise specified.
It means 6 pieces.

Suitable mono-protected amino groups include, for example, those substituted with conventional protecting groups such as alkyl, which may have at least one substituent such as benzyl, trityl, etc. Mention may be made of amino groups or acylamino groups.

Suitable acyl moieties for "acylamino" herein include aliphatic acyl groups and acyl groups containing aromatic rings or heterocycles. Suitable examples of such acyls include formyl, acetyl, propionyl,
Lower alkanoyl such as butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, Lower alphkydicarbonyl such as hexyloxycarbonyl, lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, arenesulfonyl such as benzenesulfonyl, tosyl, etc., such as benzoyl, toluoyl, xyloyl, Aroyl such as naphthoyl, phthaloyl, indancarbonyl, alkanoyl (lower) alkanoyl such as phenylacetyl, phenylpropionyl, al(lower) alkanoyl such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.
(lower) alkoxycarbonyl and the like.

The acyl moiety may have at least one substituent such as a halogen such as chlorine, bromine, fluorine, or iodine.

Suitable "lower alkyl" may include, for example, straight-chain or branched types such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., but having 1 to 4 carbon atoms. It is preferable to have the following.

Suitable "1-protected carboxy" includes esterified carboxy and the like.

Suitable examples of the ester moiety in the esterified carboxy include, for example, acetoxymethyl ester,
Propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2)-acetoxypropyl ester, 1(
or 2 or 3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyloxyethyl ester, 1 (or 2 or 3)-probionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester , 1 (or 2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyloxyethyl ester, 1 (or 2)-hexanoyloxyethyl ester, imbutyryloxymethyl ester, 2-
Lower alkanoyloxy (lower) alkyl esters such as ethylbutyryloxymethyl ester, 3゜3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl ester, lower alkanes such as 2-mesylethyl ester, etc. Sulfonyl (lower) alkyl esters, such as 2-iodoethyl ester, 2,
2. Mono (or di or tri)-halo (lower) alkyl esters such as 2-trichloroethyl ester, such as methoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1- Lower alkyl dicarbonyloxy (lower) alkyl esters such as isopropoxycarbonyloxyethyl ester, phthalidylidene (lower) alkyl esters or e.g. (5-methyl-
2=oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1.

3-・oxol-4-yl) methyl ester, (5
-Propyl-2-xo-1,3-dioxo-4-
(5-lower furkyl-2-xo-1,3-dioxo-4-yl)(lower) alkyl esters such as ethyl esters, etc. Lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester; lower such as vinyl ester, allyl ester, etc. Alkenyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters; such as benzyl esters;
4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, triple ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3.4-dimethoxybenzyl ester, 4-
Al (lower) hydroxy-3,5-di may have at least one suitable substituent such as monobutyl benzyl ester, for example mono (or di or tri) phenyl (lower) alkyl ester Alkyl ester; e.g. phenyl ester, 4-chlorophenyl ester,
Examples include aryl esters which may have at least one appropriate substituent, such as tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc. .

Suitable "acid residues" include acyloxy, such as halogens such as fluorine, chlorine, bromine, and iodine. can be mentioned.

Preferred embodiments of the target compound (I) are shown below.

A preferred embodiment of R1 is amine, R2 is lower alkyl, and R3 is carboxy.

The method for producing the object compound of this invention will be explained in detail below.

The single target compound (I) or a salt thereof is a compound (I[) or a reactive derivative at its amino group or a salt thereof,
It can be produced by reacting with compound (III) or a reactive derivative at its carboxy group or a salt thereof.

Suitable reactive derivatives at the amino group of compound (I[) include ship base type imino or hepta-tautomeric enamine type produced by reacting compound (If) with carbonyl compounds such as aldehydes, ketones, etc. isomers, silyl derivatives produced by reacting compound (II) with silyl compounds such as N,O-bis(trimedelsilyl)acetamide, N-trimethylsilylacetamide, etc.; reacting compound (I) with phosphorus trichloride or phosgene; Examples include derivatives produced by oxidation.

Suitable salts of compounds (I[) and (II) include those exemplified for compound (I).

Suitable reactive derivatives of the carboxy group of compound (I[) include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples include acid chlorides; acid azides; e.g. dialkyl phosphoric acids,
Substituted phosphoric acids such as phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acids, sulfites, thiosulfuric acids, alkanesulfonic acids such as methanesulfonic acid and ethanesulfonic acid, sulfuric acid, alkyl carbonates, Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric 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 for example cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl [(CH2)-=cH-1 esters, vinyl esters, propargyl esters, p-nitrophenyl esters , 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-talesylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester , piperidyl ester, 8-quinolylthioester, or active esters such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy- Examples include esters with N-hydroxy compounds such as 6-chloro-IH-benzotriazole. These reactive derivatives can be appropriately selected depending on the type of compound (II[) used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other solvent that does not adversely affect the reaction. It is carried out in an organic solvent. These conventional solvents may be used in combination with water.

When compound (III) is used in free or salt form,
The reaction involves N,N'-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexylrubodiimide, N.N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide N-ethyl-N'- (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, triphenylphosphine, 2-ethyl-7-
Hydroxybenzisoxazolium salt, 2-ethyl-5
-(m-sulfophenyl)inxazolium hydroxide inner salt, 1-(p-chlorobenzenesulfonylokidi)-6-chloro-IH-benzotriazole, N,N
- It is preferred to carry out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent, which is prepared by reacting dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.

The reaction is performed using an alkali metal bicarbonate, a tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N. It may be carried out in the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine and the like. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature.

Production 1: Target compound (1) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof.

Suitable salts for compound (KV>) include those exemplified for compound (I>).

Suitable salts of the compound (Vl) include, for example, alkali metal salts such as sodium salts and potassium salts, metal salts such as silver salts, etc.

This reaction consists of water, phosphate buffer, acetone, chloroform, nitrobenzene, ethylene chloride, ethylene chloride, acetonitrile, N. It may be carried out in a solvent such as N-dimethylformamide, methanol, ethanol, nityl, tetrahydrofuran, dimethyl sulfoxide or any other solvent that does not adversely affect the reaction, preferably a strongly polar solvent. Among these solvents, hydrophilic solvents may be used in combination with water. It is preferable to carry out the reaction in a nearly neutral solvent. When compound (V) is used in free form, the reaction is carried out in the presence of a base, such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, an organic base such as a trialkylamine, etc. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling, room temperature, heating, or slightly heating.

The object compound (1) of the present invention and its salts are novel compounds that exhibit high antibacterial activity and inhibit the growth of a wide variety of pathogenic bacteria, including gram-positive and gram-negative bacteria, and are useful as antibacterial agents.

For drug therapy, the compounds of this invention may be mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. It can be used in the form of pharmaceutical preparations containing it as an active ingredient. Pharmaceutical formulations may be capsules, tablets, dragees, ointments or suppositories, solutions, suspensions, emulsions, and the like. If desired, the above formulation may contain auxiliaries, stabilizers, m.p. Contains W4 agents or emulsifiers, buffers and other commonly used additives. It's okay to be rare.

Although the dosage of the compound varies depending on the age and condition of the patient, the compound of this invention has an average single dose of about 10 m
g, 50mg, 100mg, 250mg, 50
It is effective in treating infections caused by pathogenic bacteria at 0mg and 1000mg. Generally 1 mg to 60 mg per day
Amounts of 00 mg or more may be administered.

In order to demonstrate the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below.

[1] Trial test stand Nia-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamitoco-3-(1.2.4-thiadiazol-5-yl)thiomethyl-3- Cephem
4-Carboxylic acid (syn isomer) [hereinafter referred to as compound (1)] [2] Test method: In vitro antibacterial activity was measured by the following agar plate multiple dilution method.

The test bacterial strain was cultured overnight in tryptopase soy broth, and one platinum loop (108 viable bacteria/wit) was transferred to heart infusion agar containing the test compound at each concentration level.
After inoculating on HI agar) and culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was expressed as (/relative).

[3] Test results: MIc (</ all ) The present invention will be described below according to Production Examples and Examples.

1 produced aminocephalosporanic acid (21.2g),
Potassium L, 2,4-thiadiazole-5-thiolate (10,6 g) was added to a solution of trifluoroacetic acid (370 acetic acid) and the mixture was stirred for 2.3 minutes until clear, and the boron trifluoride ether ring was added. was added to this and the mixture was stirred at room temperature for 7 h. The reaction mixture was evaporated under reduced pressure and the residue was brought to pH 3.0 with 3% aqueous ammonium hydroxide solution.
Do t. The precipitate is collected by filtration, washed with acetone and diethyl ether, and dried to obtain the crude target compound (28.5 g). This crude target compound (25.0 g) was mixed with concentrated hydrochloric acid (23.0 g).
011111) and the mixture is stirred at room temperature for 30 minutes. Insoluble matters were removed by filtration, and the filtered solution was adjusted to pH 3.0 with a 28% aqueous ammonium hydroxide solution under water cooling. The resulting precipitate was collected by filtration, washed with cold water, acetone and diisopropyl ether, and dried to give 7-amino-3-(
1,2,4-thiadiazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (15.8 g) is obtained.

LR (x Dial): 3150. 1790.
1610. 1530 cm-'NMR (CF3C
OOH, δ): 3.87 (2H, s), 4.6
3.4.97 (2H, ABq, J=14Hz>, 5
．． 43 (2H, m), 8.93 (IH, s) 2-ethoxyimino-2-(2-aminothiazole-4
-yl) acetic acid (syn isomer) (0,215g) N,N
- Diisopropylethylamine (0,258 g) and mesyl chloride (
0.229 g) was added at -30° C. and the mixture was stirred at the same temperature for 1 hour to obtain an activated acid solution. 7-amino-3-(1,2,4-thiadiazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid (0,39
The activated acid solution obtained above was added to a mixture of 6g), water (6g), and tetrahydrofuran (611) under cooling in an ice bath, and the mixture was diluted with an aqueous sodium bicarbonate solution at -7g.
, and then adjust the pH value to 7 with sodium bicarbonate.
．． Stir for 1.5 hours while keeping the temperature between 0 and 8.0 while cooling. The solution was adjusted to pH 3.0 with 6N hydrochloric acid, saturated with sodium chloride and diluted with tetrahydrofuran (101 nll').
) and ethyl acetate (100111).

The extract was dried over magnesium sulfate and then evaporated, and the residue was triturated in diethyl ether to give 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1, 2,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0,110 g) is obtained.

Melting point: 210℃ (decomposition) LR (striped tool)! 3300. 1780.
1670. 1630°1530 cm-' NMR (DMSO-ds, 6)' 1-22 (3
H, t, J=6Hz), 3.74 (2H, m), 4
．． 12 (2H, q, J=6Hz), 4.30.4.
64 (2H, ABq, J=14Hz), 5.18 (
IH, d, J = 5Hz).

5.76 (IH, dd, J near Hz, 5Hz), 6
．． 78 (18, s).

8.71 (IH, s), 9.57 (IH, d, J
=7Hz>1 cliff ■1 According to the method of Example 1, the following compound is obtained.

7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamitoco-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-
4-Carboxylic acid (syn isomer) Melting point 205°C (decomposition) IR (Xdi1-L)' 1780. 1670.
At 1630 cm-1, Iris Ni-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]cephalosborane # (synisomer) (4.55 g), potassium 1.2.4
-thiadiazole-5-thiolate (1,36 g), sodium bicarbonate (0,84 g) and phosphate buffer (
pH 6.86, LQOml) mixture at 65°C for 5.
Stir for 5 hours, cool and adjust to pH 3.0 with 6N hydrochloric acid v4.
! ! do. The resulting precipitate is collected by filtration and dissolved in an aqueous sodium hydrogen carbonate solution, and 6N hydrochloric acid is further added to this solution to obtain a precipitate. After filtering the precipitate and dissolving it in an aqueous sodium bicarbonate solution, the aqueous solution was mixed with a nonionic adsorption resin 1 Diaion HP-20J' (trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) (1
00111) is subjected to column chromatography.

After washing the column with water, it is eluted with a 10% aqueous isopropyl alcohol solution. The eluted fractions containing the target compound are collected, saturated with sodium chloride, and extracted with tetrahydrofuran. The extract was dried over magnesium sulfate and then evaporated, and the residue was triturated in diethyl ether to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamitoco-3-(1,2 ,4-thiadiazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid (
Syn isomer) (0.75 g) is obtained.

Melting point 205°C (decomposition) IR (Xdi*-h): 1780. 1670.
1630 cm-1HMR (DMSO-d6.8
): 3.53.3.79 (2H, ABq.

J=181(z), 3.86 (3H,s), 4.
30.4.60 (2H.

ABq, J=14Hz>, 5.13 (LH, d, J
=5Hz), 5.74(IH, dd, J=7Hz, 5
Hz>, 6.76 (IH, s), 8.68 (LH
,s), 9.58 (IH,d,,C7Hz>Example 4 According to the method of Example 3, the following compound is obtained.

7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-
4-Carboxylic acid (synisomer) Melting point: 210°C (decomposition) IR (Sujiwor): 3300. 1780.
1670. 1630°1530 cm-1

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is amino or a protected amino group, R
^2 is lower alkyl, R^3 is carboxy or a protected carboxy group) and salts thereof. 2. Formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is carboxy or a protected carboxy group) Compound or its reactive derivative at the amino group or its salt , formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is amino or a protected amino group, R
^2 is lower alkyl) or its reactive derivative at the carboxy group or its salt to form a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where R^1, R^ 2, R^3 have the same meanings as above) or a salt thereof, or formula (2): ▲There are numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^ 2, R^3 have the same meanings as above, Y is an acid residue) or a salt thereof, and a compound or a salt thereof represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ By reacting, a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1, R^2, and R^3 each have the same meaning as above) or a salt thereof is obtained. Featured formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3 each have the same meanings as above) A method for producing a novel cephem compound or its salt .