JPH01279894A - Novel cephem compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents (protected) amino; R<2> represents lower alkyl or (protected) carboxy lower alkyl; R<3> represents lower alkyl; R<4> represents H or (protected) amino; Z represents N or CH] or salt thereof. EXAMPLE:7beta-[2-(5-Amino-1, 2, 4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino) acetamide]-3-(1-methyl-3-amino-4,5-dihydro-1-pirazolio) methyl-3-cephem-4- carboxylate (syn isomer). USE:An antibacterial agent against Gram-positive and Gram-negative bacteria. PREPARATION:A compound expressed by formula II (Y represents leaving group) or salt thereof is reacted with a compound expressed by formula II or salt thereof.

Description

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

1. Prior Art Although many cephem compounds are known, the cephem compound represented by the following general formula (1) of the present invention is not known.

"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 developed with the intention of developing even better medicines.

``Means for solving problems'' 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 new and has the following general formula (
1).

[In the formula, R1 is an amino group or a protected amine group, R2 is a lower alkyl group, a carboxy(lower) alkyl group, or a protected carboxy(lower) alkyl group, R3 is a lower alkyl group, R4 is hydrogen or an amine group or a protected amine group, Z means N or CH.

Regarding the target compound (I), the following points should be pointed out.

That is, the target compound (I) includes a syn isomer, an anti isomer, and a mixture thereof. The syn isomer has the following formula: (wherein R1, R2 and Z each have the same meaning as before)
An anti-isomer means one geometric isomer having a partial structure represented by the following formula: (wherein R1, R2 and Z each have the same meanings as before) Isomers are meant, 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 are conveniently expressed by the following formula: (wherein R1,
R2 and Z each have the same meaning as before).

The cephem compound (1) of the present invention can be produced by the production method shown by the following reaction formula.

or a salt thereof (I[[) or a salt thereof or a salt thereof manufacturing method 2 (Ia) or a salt thereof (Ib) or a salt thereof (wherein R1, R2, R3, R4 and z are respectively the preceding and have the same meaning, Y means a leaving group, and R1 means a protected amine group).

Preferred examples of the various definitions in the above and below descriptions of this specification will be explained in detail below.

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

A suitable "protecting group" for "unprotected amine 7 group" is
Acyl groups mentioned below, such as substituted or unsubstituted alkylidene groups such as benzylidene and hydroxybenzylidene, mono- or di- or triphenyl groups such as benzyl, phenethyl, benzhydryl, trityl, etc.
(lower) alkyl groups such as lower) alkyl groups, and the like.

Suitable mono-acyl groups include, for example, formyl, acetyl, propionyl, hexanoyl, pivaloyl-terminated lower alkanoyl groups, such as mono(or di- or tri)halo(lower) such as chloroacetyl, trifluoroacetyl, etc.
Alkanoyl groups, such as methoxycarbonyl, lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, carbamoyl groups, such as aroyl groups such as benzoyl, toluoyl, naphthoyl, etc., such as phenylacetyl, phenylpropionyl, etc. an aryloxy(lower)alkanoyl group such as phenoxycarbonyllphenoxyacetyl, phenoxypropylene, arylglyoxyloyl group such as phenylglyoxyloyl, naphthylglyoxyloyl, e.g. benzyl Examples thereof include al (lower) alkyl dicarbonyl groups which may have appropriate substituents such as oxycarbonyl, phenethyloxycarbonyl, and p-nitrobenzyloxycarbonyl.

Suitable lower alkyl groups and lower alkyl moieties of rcarboxy(lower)alkyl groups and protected carboxy(lower)alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Mention may be made of straight or branched alkyl groups such as tertiary butyl, pentyl, hexyl and the like.

Examples of the "preferable 1-protected carboxy moiety of the protected carboxy (lower) alkyl group" include esterified carboxy groups, and specific examples of the ester moiety of the esterified carboxy group include: , lower alkyl esters which may have appropriate substituents, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, etc. For example, acetoxymethyl ester, propionyloxymethyl ester,
Butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxyethyl ester Lower alkanoyloxy (lower) alkyl esters such as esters, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, or mono(or di- or tri)halo(lower) alkyl esters; e.g. vinyl esters;
Lower alkenyl esters such as allyl ester; lower alkynyl esters such as ethynyl ester and propynyl ester; such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, triple ester, benzhydryl ester, bis(methoxyphenyl ) methyl ester, 3.
4-dimethoxybenzyl ester, 4-hydroxy-3
.

Al (lower) alkyl esters which may have suitable substituents such as 5-ditertiary butylbenzyl ester; for example, phenyl esters, 4-chlorophenyl esters,
tolyl ester, 4-Ea butylphenyl ester,
Examples include aryl esters which may have appropriate substituents, such as xylyl esters, mesityl esters, and cumenyl esters.

Suitable r-leaving groups include, for example, halogens such as chlorine, bromine, and iodine, sulfonyloxy groups such as benzenesulfonyloxy, tosyloxy, and mesyloxy, and lower alkanoyloxy groups such as acetyloxy and propionyloxy. It will be done.

Suitable salts of the target compound (1) are commonly used non-toxic salts,
Metal salts such as alkali metal salts such as sodium salts, potassium salts and alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N. Organic base salts such as N'-dibenzylethylenediamine salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates,
Examples include organic acid salts such as toluene sulfonate, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with amino acids such as arginine salt, aspartate, and glutamate. It will be done.

Preferred embodiments of the target compound (1) are as follows.

A preferred embodiment of R1 is an amino group or an acylamino group (more preferably a lower alkanoylamino group), and a preferred embodiment of R2 is a lower alkyl group [more preferably a (C1-C4) alkyl group] or a carboxy (
(lower) alkyl group [more preferably carboxy (C1
-C4) alkyl group, a preferred embodiment of R3 is a lower alkyl group [preferably a (C1-C4) alkyl group], a preferred embodiment of R4 is hydrogen or an amino group, a preferred embodiment of Z is N or CI It is.

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

Production method 1 Compound (1) or a salt thereof can be produced by reacting compound (I[) or a salt thereof with compound (I[[) or a salt thereof.

For suitable salts of compound (II), refer to the salts exemplified for compound (I).

For suitable salts of compound (Ift), compound (I)
Reference may be made to the acid addition salts exemplified for.

This reaction can be 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 may be carried out in any other organic solvent as long as it does not adversely affect the reaction. Among the solvents, hydrophilic solvents may be used as a mixture with water.
If [[) is a liquid, it can also be used as a solvent.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling, room temperature, or heating.

1 Compound (Ib) or a salt thereof can be produced by subjecting Compound (Ia) or a salt thereof to an elimination reaction of the amine protecting group.

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

Hydrolysis is preferably carried out in the presence of a base or # (including Lewis acids).

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, trialkylamines such as trimethylamine, triethylamine, etc. Picoline, 1,5-diazabicyclo[4,3,0conon-5-ene, 1,4-
Examples include diazabicycloC2,2,2-cooctane, 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.

Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid, trifluoroacetic acid, etc. is preferably carried out in the presence of a cation scavenger such as anisole, phenol, etc.

The reaction is usually carried out in water, an alcohol such as ethanol, methylene chloride, a solvent such as tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent as long as it does not adversely affect the reaction. It can be performed. Liquid bases or acids can also be used as solvents.

Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.

Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents that can be 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 formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction include platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, such as palladium sponges, palladium black, palladium oxide, palladium-carbon, colloidal palladium, Palladium catalysts such as palladium-barium sulfate and palladium-barium carbonate; nickel catalysts such as reduced nickel, nickel oxide, and Raney nickel; cobalt catalysts such as reduced cobalt and Raney cobalt; reduced iron;
Commonly used catalysts include iron catalysts such as Raney iron, copper catalysts such as reduced steel, Raney copper, Ullmann steel, and the like.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. If the acids used in the chemical reduction are liquids, they can also be used as solvents. Suitable solvents for use in the catalytic reduction include, in addition to the above-mentioned solvents, conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

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

The target compound (I) and its salts are novel, exhibit strong antibacterial activity, inhibit the growth of a wide range of pathogenic bacteria including Durum-positive bacteria and Durum-negative bacteria, and are useful as antibacterial agents.

In order to demonstrate the usefulness of the target compound (I), the results of Test M regarding the MIC (minimum inhibitory concentration) of the representative compound of this invention are shown below.

Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below.

The test bacterial strain was cultured overnight in trypto-case soy broth, and one platinum loop (106 viable bacteria/Kai) was added to Heart Infusion Agar (2018) containing the test compound at each concentration level.
After inoculating on I agar) and culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was expressed as < / mQ.

Test compound 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-(1-methyl-3
-amino-4,5-dihydro-1-pyrazolio)methyl-3-cephem-4-carboxilade (syn isomer)
(hereinafter abbreviated as compound A).

The object compound (1) of this invention and its salts for the treatment of K. aureus can be prepared in a pharmaceutically acceptable form such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral and topical administration. The compound is used in the form of a conventional pharmaceutical preparation containing the compound as an active ingredient in admixture with a carrier.

Pharmaceutical preparations may be in solid form such as tablets, granules, powders, or capsules, or may be solutions, suspensions, syrups, emulsions,
It may be in liquid form such as lemonade.

If necessary, auxiliaries, stabilizers, wetting agents, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil, olive oil,
Other commonly used additives such as cocoa butter, ethylene glyfur, etc. may also be included.

The dose of compound (H) depends on the patient's age, condition, type of disease,
It varies depending on the type of compound (I) to be applied. In general, an amount between 1 mg and about 4000 mg or more may be administered to a patient per day, and for the treatment of pathogenic bacterial infections, an average of about 50
mg, 100mg, 250mg, 500mg, 100
It may be used in dosages of 0 mg and 2000 nng.

Hereinafter, the present invention will be explained in detail according to examples.

7β-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-chloromethyl-3
1-Methyl-3-amino-
4,5-dihydropyrazole (0.79 g) is added under water cooling. The mixture is stirred for 1 hour at 0° C. and 30 minutes at room temperature. 6. The reaction mixture is poured into ethyl acetate (200 mQ), the precipitate is filtered and dried over Ti phosphorous oxide under reduced pressure. Dissolve the dried powder in water and adjust to pH 3 with IN hydrochloric acid! do. The solution is passed through a column of 1 Diaion HP-20J (trademark, manufactured by Mitsubishi Kasei Corporation) and eluted with isopropyl alcohol. Both parts containing the target compound were combined, the isopropyl alcohol was distilled off, and lyophilized to give 7β-[2-(
5-amino-1,2,4-thiadiazol-3-yl)
-2-(1-carboxy-1-methylethoxyimino)
Acetamitoc-3-(1-methyl-3-amino-4,
5-dihydro-1-pyrazolio)methyl-3-cephem-4-carboxilade (syn isomer) (0,28 g)
get.

IR: 3300. 1760.
1590-1630°1510 am-1 NMR (D20.δ) = 1.60 (6H, s), 3
．． 19.3.28 (Total 3H1 each s), 3.1
0-4.50 (88゜), 5.30.5.32
(Total IH, each d.

J=5Hz), 5.84 (LH, d, J:5Hz)
β-C2-C2-formamidothiazol-4-yl)-2-ethoxyiminoacetamitoco-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer)
2g) of N,N-dimethylformamide (30mQ)
Add 1-methyl-4゜5-dihydropyrazole (1
, 78 g) was added under water cooling. The mixture was stirred at room temperature for 1 hour. 1. The reaction mixture was poured into ethyl acetate (300 ml). The precipitate was collected by filtration, washed with ethyl acetate, and incubated under reduced pressure with Ti.
Dry with phosphorous oxide to give 7β-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-4,5-dihydro-1-pyrazolio)methyl-3 -cephem-4-carboxilade (syn isomer) (1,80 g) is obtained.

dog farm 1 The following compounds are obtained in the same manner as in Examples 1 and 2.

7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-(1-methyl-4
,5-dihydro-1-pyrazolio)methyl-3-cephem-4-carboxilade (syn isomer).

IR (Streak 9-L): 3300. 1790.
1690. 1630 am-'NMR(D O"
NaHCO3,S)' 1.53 (6H1s),
2.90 (3H, s), 3.03-4.35 (8
H, m), 5.28 (IH, d.

J=5Hz), 5.86 (IH, d, J=5Hz)
, 8.16 (LH,s) Tue] d1± 7β-[2-(2-formamidodeazol-4-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carvone # (Syn isomer) (
Ig) of N,N-dimethylformamide (15fflQ
) 1-Methyl-3-amino-4,5-dihydropyrazole (0,628 g) is added to the solution under water cooling. The mixture is stirred at room temperature for 2 hours.The reaction mixture is poured into ethyl acetate (15011111).The powder is filtered and vacuum T
i Dry over phosphorous oxide to obtain a yellow powder. A methanol (10fflQ) solution of the above powder was added with concentrated hydrochloric acid (0.7mlQ).
) at room temperature. Stir the mixture under the same conditions for 3 hours.
The reaction mixture is adjusted to pH 7 with saturated aqueous sodium bicarbonate solution and washed with ethyl acetate. pH the water syrup with 6N hydrochloric acid
2, pass through a column of 1 Diaion HP-20J, and elute with 5% isopropyl alcohol. Both fractions containing the target compound were combined, the isopropyl alcohol was distilled off, and lyophilized to give 7β-[2-(2-aminodeazol-4-yl)-2-ethoxyiminoacetamide]-3-(1- Methyl-3-amino-4,5-dihydro-1-pyrazolio)methyl-3-cephem-4-carboxilade (syn isomer) (0,32 g) is obtained.

IR: 3150-3400.
1770. 1590-1670 cm-' NMR (D20.8): 1.40 (3H1t,
J=6Hz), 3-23.3-33 (total IH, each s), 2.98-3.70 (4H.

m), 3.55.3.90 (2H, ABq, J=1
8Hz), 3.70-4.50 (2H, m), 5
．． 33.5.36 (LH, d, J=5Hz).

5.85 (18, d, J=5Hz>, 7.00 (
LH, s) 1 encounter 1 7β-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamide]-3-(1-methyl-4,5-dihydro-1-pyrazolio)methyl- 3
-cephem-4-carboxilade (syn isomer) (1
, 7g) in methanol (17+IIQ) is added concentrated hydrochloric acid (Q, 9mM). The mixture is stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 4.5 with a saturated aqueous solution of sodium hydrogen suboxide, and methanol was distilled off. The residue was adjusted to pH 2.5 with IN hydrochloric acid, and then diluted with 'Diaion HP-
20" column and eluted with 5% isopropyl alcohol. The fractions containing the target compound were combined, the isopropyl alcohol was distilled off, and lyophilized to give 7β-[2
-(2-aminodeazol-4-yl)-2-ethoxyiminoacetamitoco-3-(1-methyl-4,5-dihydro-1-virazolio)methyl-3-cephem-4-
Carboxilad (syn isomer) (0.5 g) is obtained.

IR (striped seal): 3350. 1770.
1650. 1610°1530 cm' NMR (D20.l; )' 1.28 (3H1t
, J=6Hz>, 2-87(3H,s), 2.95-
4.00 (8H, m), 4.24 (2H, q.

6Hz), 5.23 (LH, d, J: 5Hz),
5.81 (IH, d.

Claims (3)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an amino group or a protected amino group, and R^2 is a lower alkyl group, a carboxy (lower) alkyl group, or a protected amino group. a carboxy (lower) alkyl group, R^3 is a lower alkyl group, R^4 is hydrogen, an amino group or a protected amino group, and Z means N or CH] and salts thereof. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is an amino group or a protected amino group, and R^2 is a lower alkyl group, a carboxy (lower) alkyl group, or a protected amino group. a carboxy (lower) alkyl group, Z is N or CH, Y is a leaving group], or its salt is represented by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R ^3 means a lower alkyl group, R^4 means hydrogen, an amino group or a protected amino group) or a salt thereof,
General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^3, R^4 and Z each have the same meaning as before) A new cephem compound or its salt A method for producing a novel cephem compound, characterized in that it obtains. (3) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1_a is a protected amino group, R^2 is a lower alkyl group, a carboxy (lower) alkyl group, or a protected (lower) alkyl group, R^3 is a lower alkyl group, R^4 is hydrogen, an amino group or a protected amino group, Z means N or CH] or a salt thereof, by removing the amino-protecting group. For the separation reaction, a new cephem compound represented by the general formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^2, R^3, R^4 and Z each have the same meaning as before) A method for producing a novel cephem compound, characterized by obtaining a cephem compound or a salt thereof.