JPH03255087A - Novel cephem compound and its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula l [R<1> is (protected) amino; R<2> is (protected) lower carboxyalkyl; R<3> is lower hydroxyalkyl; R<4> is lower alkanoylamino or carbamoylamino; R<5> is H or lower alkyl]. EXAMPLE:7beta-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1methyle thoxyimino) acetamido]-3-[3-carbamoylamino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3 -cephem-4- carboxylate. USE:An antibacterial agent. PREPARATION:A compound of formula II (or its salt) is made to react with a compound of formula III (or its salt) usually in an organic solvent in the presence of a condensation agent (e.g. Vilsmeier reagent).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel cefete compound having high antibacterial activity, and is used in medical fields.

"Prior Art" Many cephem compounds are known, but the cephem compound represented by the following formula [1] of the present invention is not known.

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

[Means for Solving the Problems] The target cephem compound and its salts are novel and can be represented by the following general formula [1].

"In the formula, R1 is an amine group or a protected amino group, R2 is a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, R3 is a hydroxy (lower) alkyl group, (, R4 is a lower Alkanoylamino 7 group or carbamoylamino 2.r, R5 means hydrogen or a lower alkyl group, respectively.] Regarding target compound N], it is necessary to keep in mind the following points: Namely, target compound [1] includes syn isomers, anti isomers and mixtures thereof. Syn isomers are all of the formula: are included within the scope of this invention.

In this specification, the partial structures of these geometric isomers and mixtures thereof are conveniently represented by the following formula (wherein R1
and R2 each have the same meaning as before).

Another point to note is that the pyrazolio moiety of compound [1] can exist in a tautomeric form, and such tautomeric equilibrium is represented by the following formula, where RI and One geometric isomer having a partial structure represented as Geometric isomers and such geometric isomers and mixtures thereof (wherein R3R4
and R' each have the same meaning as before).

Although any of the tautomerisms mentioned above are included within the scope of the present invention, in this specification, the target compound "I" will be represented by one expression of the virazolio group of formula (A) for convenience.

The cephem compound [+] of this invention can be produced by the production method shown by the following reaction formula.

or its salts [■] or its salts [■ or its salts ↓ Nb] or its salts [wherein, R'R'R3R' and R5 each have the same meaning as before, and RA is a protected carboxy ( lower) alkyl group, RH
each represents a carboxy(lower)alkyl group] In the above and following descriptions of this specification, preferred examples and explanations of various definitions included within the scope of this invention will be explained in detail below.

The term lower is used, unless otherwise specified, to include groups having 1 to 6 carbon atoms.

Suitable "protecting groups" for "protected amino groups" include:
Lower alkanoyl groups such as formyl, acetyl, propionyl, pivaloyl, hexanoyl, mono(or di or tri)halo(lower)alkanoyl groups such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, e.g. methoxycarbonyl, ethoxy Lower alkoxycarbonyl groups such as carbonyl, propoxycarbonyl 1, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, carbamoyl groups, such as aroyl groups such as benzoyl, toluoyl, naphthoyl, etc., such as phenylacetyl, phenylpropionyl, etc. Al(lower)alkanoyl groups such as phenoxycarbonyl, aryloxycarbonyl groups such as naphthyloxycarbonyl, aryloxy(lower)alkanoyl groups such as fenoquinacetyl, 75noquinepropionyl, such as phenylglyoxyloyl, naphthylglyoxy arylglyochineloyl groups such as loyl, for example benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, a(lower) alkoxycarbonyl group optionally having a suitable substituent, for example benzylidene; Substituted or unsubstituted al(lower)alkylidene groups such as hydroxybenzylidene, mono(ma- or di- or tri)phenyl(lower)alkyl groups such as benzyl, phenethyl, benzhydryl, trityl, etc.
(lower) alkyl groups, etc., and among them, preferred are lower alkameyl groups or carbamoyl groups, and more preferred are C1-C4 alkanoyl groups or carbamoyl groups.

Suitable "lower alkyl group" and "carboxy (lower) alkyl group j1 "protected carboxy (lower)
Preferred "lower alkyl moieties" of alkyl groups and "hydroxy (lower) alkyl groups" include straight chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc. Branched chain alkyl groups are mentioned, and preferred among them are C1-C4 alkyl groups.

Suitable "protected carboxy groups" of "protected carboxy (lower) alkyl groups" include esterified carboxy groups, and specific examples of the ester moieties of the esterified carboxy groups include: 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- which may have an appropriate substituent. Lower alkyl esters such as cyclopropyl esters, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, imbutyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1 -Lower alkanoyl ookine (lower) alkyl esters such as acetoxyethyl ester, 1-propionyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester, etc. lower) alkyl esters, or mono(or di- or tos)halo(lower) alkyl esters, such as e.g. 2-iodoethyl ester, 2,2.21-lichloroethyl ester; lower alkenyls, e.g. vinyl esters, allyl esters, etc. Esters; for example, lower alkynyl esters such as ethynyl ester and propynyl ester; for example, benzyl ester, 4-methoxybenzyl ester, 42l-lovenzyl ester,
Phenethyl ester, trityl ester, benzhydryl ester, bis(3-methoxyphenyl)methyl ester, 3゜4-
Dimethoxybenzyl ester, 4-hydroxy-3,5
- Al (lower) alkyl esters which may have suitable substituents such as di-tertiary butyl benzyl ester; e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tertiary butyl benzyl ester, bovine silyl Examples include aryl esters which may have appropriate substituents such as esters, mesityl esters, and cumenyl esters.

Suitable salts of the target compound [1] include pharmaceutically acceptable salts, especially commonly used non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, and calcium salts and magnesium salts. Metal salts such as alkaline earth metal salts, ammonium salts such as triethylamine salts, pyridine salts, bifrin salts, dicyclohexylamine salts, organic salts such as N,N'-dibenzylethylenediamine salts, such as hydrochlorides, bromide salts, etc. Inorganic acid salts such as hydroxides, sulfates, phosphates, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, Hensensulfonates, 1) -) Examples include organic acid salts such as luenesulfonate, salts with amino acids such as arginine salt, aspartate, and glutamate.

Preferred embodiments of the target compound [1] are as follows.

A preferred embodiment of R1 is an ami7 group, and a preferred embodiment of R2 is a carboxyl (lower) alkyl group [more preferably a carboxy (C) group.

~C4) an alkyl group, most preferably a carboxymethyl group or a 1-carboxy-1-methylethyl group] or an esterified carboxy(lower)alkyl group, more preferably a lower alkoxycarbonyl(lower)alkyl group, most preferably a Lower alkoxycarbonyl (01
~C4) alkyl group] A preferred embodiment of R3 is a hydroxy (C, ~C4) alkyl group, more preferably a hydroxyethyl group], a preferred embodiment of R4 is a lower alkanoylamino group or carbamoylamino 21 (a preferred embodiment of R') Embodiments include hydrogen or a (C, to C4) alkyl group, more preferably a methyl group.

The method for producing the target compound [1] will be explained in detail below.

Production method 1 The target compound [+] or its salts can be produced by reacting the compound [■] or its salts with the compound [IrI] or its salts.

Suitable salts for compounds [11] and [III] include those exemplified for compound [1].

The reaction is usually carried out in conventional solvents such as water, alcohols such as methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, NlN-dimethylformamide, pyridine, etc. 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 []Tl] is used in the free form or its salt form in this reaction, N,N'-dicyclohexylcarbodiimide/N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-7chlorohexyl-N "-(4-diethylaminocyclohexyl)carbodiimide; N, N"diethylcarbodiimide N, N"
-diisopropylcarbodiimide; N-ethyl-N'-
(3dimethylaminopropyl)carbodiimide; NlN
゛ -Carbonylbis-(2-methylimidazole);
Pentamethyleneketene-N-cyclohexylimine ° diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-Alkoxyl-1-chloroethylene; Trialkyl phosphite; Isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride: Chloride thionyl; oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate, isoproyl chloroformate; l-diphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m sulfophenyl)inoxacillium hydroxide inner salt; I-(p-chlorobenzenesulfonyloxy)-6-chloro-] ]H-
Ben7'l-lyazole; prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, etc. in the presence of a conventional condensing agent such as the so-called Vilsmeier's reagent, etc. It is preferable to carry out the reaction.

The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. A reaction may also be carried out.

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

Production method 2 Target compound [1b] or its salt is compound [1a]
or its salts can be produced by subjecting it to an elimination reaction of the carboxy covalent group at R4 and R5.

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

Hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as thorium and potassium; alkaline earth metals such as magnesium and calcium; hydroxides or carbonates or bicarbonates thereof; , picoline, 1°5-diazabicyclo[4,3,0]non-5
Inorganic and organic bases such as -ene, I,4-diazabicyclo[2,2,2]octane, 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 I.lichloroacetic acid and J.lifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.

For example, 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 a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. It can be carried out. 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 that can be applied to this elimination reaction include 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 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 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 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 iron catalysts such as Raney iron, copper catalysts such as reduced copper, Raney copper, Ullmann copper, 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.

Furthermore, if the acids used in the chemical reduction are in solution 7 = 18 they can also be used as solvents. Further, suitable solvents used in the catalytic reduction include, in addition to the above-mentioned solvents, conventional solvents such as diethyl ether, diokigan, 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.

To be administered for therapeutic purposes, the object compound [1] of the present invention and its salts may be prepared in pharmaceutically acceptable organic or inorganic solid or liquid excipients suitable for oral, parenteral and topical administration. mixed with a carrier to be
The compounds can be used in the form of customary pharmaceutical preparations containing them as active ingredients.

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

If necessary, auxiliary agents, stabilizers, wetting agents and other commonly used lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose,
Cornstarch, talc, gelatin, agar, pectin,
Additives such as droplets, olive Ab, cocoa butter, ethylene glycol, etc. may be included.

The dosage of compound "1" varies depending on the patient's age, condition, type of disease, type of compound to be applied, etc. Generally, the dose of compound "1" is administered to the patient in an amount of I mg to about 4000 μg per day or more. The object compound N of the present invention is administered at an average dose of about 50 mg for the treatment of pathogenic bacterial infections.
0mg250mg, 500mg, 1000mg, 20
00 mg may be used.

The present invention will be described in more detail below with reference to Examples.

Example 1 7β-amino-3-[3-carbamoylamino-2-(
2-Hydroxyethyl)-1-virazowaokomethyl-3
-cephem-4-carboxilade dihydrochloride (0,6
g) and N-trimethylsilylacetamide (1,73 g
) in methylene chloride (12+nf) while stirring under water cooling, add 2-(5-amino-1,2,4thiadiazol-3-yl)-2-(+-carboxy-1-methylethoxyimino)acetic acid. Add methanesulfonic anhydride (syn isomer) (0,557 g). After stirring for 2 hours at room temperature, the reaction mixture is poured into diethyl ether (240d). The precipitate formed is filtered and dried. The obtained powder was dissolved in water (30+d) and adjusted to pH 2 with IN hydrochloric acid.
Adjust to O. This solution is subjected to column chromatography using a nonionic adsorption resin "Diaion HP2O" (trade name, manufactured by Mitsubishi Kasei Co., Ltd.) and eluted with a 10% aqueous isopropyl alcohol solution. Collect fractions containing the target product,
The isopropyl alcohol was distilled off under reduced pressure and then lyophilized to give 7β-[2-(5-amino-]).

2.4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-
3-'3-carbamoylamino-2-(2-hydroxyethyl)-1-bilagliocomethyl-3cephem-4-
Carboxilad (syn isomer) (0, IQ8rr,
).

IR (nudicol i-'): 1770,15
7ON M R (D, O, δ): 1.60 (s,
611), 3. l0and3.50(ABq, 2
11J=+81k), 3.90(t, 211.J
=61k), 4.50-4.70 (m, 2H).

5, 25 (d, 1.H, J=51k), 5.34 (
brs, 2)1), 5.86(d, 1.!LJ・
s+h), s, a5(d, u+, , +-a+b
), s, 15(d, III, J.3) Example 2 7β-amino-3-[3-acetamido-2-(2-acetoxyethyl,)-1-virazolio]methyl 3-cephem-4- Carboxilade di(trifluoroacetic acid)
Salt <1.0g> and N-trimethylsilylacetamide <
2-(5-amino-1,2,4-thiadiazol-3-yl)-2-<1-carboxy-
Add 1-methylethoxyimino)acetic acid methanesulfonic anhydride (syn isomer) (0.85 g). After stirring at room temperature for 2 hours, the reaction mixture was diluted with diethyl ether (240
mg). The precipitate formed is filtered and dried. The powder obtained is dissolved in water (30 mj2). The pH was adjusted to 1-22-13 with IN aqueous sodium hydroxide solution and stirred for 2 hours under water cooling. This solution is
The pH was adjusted to 2 with N-hydrochloric acid, and the mixture was subjected to column chromatography using a nonionic adsorption resin "Diaion IP-20J (trade name, manufactured by Mitsubishi Kasei Corporation)" and eluted with a 10% aqueous isopropyl alcohol solution.

Fractions containing the target product were collected, the isopropyl alcohol was distilled off under reduced pressure, and then lyophilized to give 7β[2-(5-amino-1,2,4-thiadiazol-3yl)-2-(
1-carboxy-I-methylethoxyimino)acetamide]-1[3-acetylamino-2-(2-hydroxyethyl)-1-virazolio]methyl-3-cephem-4-carboxilade (syn isomer) (0, 15g)
get.

IR (nujigor a-'): 1770.156O
NMR, (D20.δ): 1.53(s, 6H
), 2.26(s, 311), 3.13and3
, 50 (ABQ, 2H, 18ru), 3.86 (t,
2+1. J=61k), 4.50~4,70(m
, 2B), 5.20-5.50 (m, 2H),
5.25(d, [1°J=!J), 5.84(d,
1)1. J=5le), 6.92(d, IIL
J=31k).

8, 16 (d, III, J=3k) Example 3 7β-amino 3-[3-formamido-4-methyl-
Di(trifluoroacetic acid) salt of 1(2-formyluochynethyl)-1-virazolio]methyl-3-cephem-4-carboxilade (1,0 g) and N-trimethylnrylacetamide (2,06 g) in methylene chloride (20
+n1) solution under water cooling, add 2-(5 amino-1,2,4
-Thiadiazol-3-yl)2-(1-carboxy-1-methylethoxyimino)acetic acid methanesulfonic anhydride (syn isomer) (0°66 g) is added. After stirring for 1 hour at room temperature, the reaction compound was dissolved in diethyl ether (200 mf
f) Pour into the container and filter the precipitated powder. This powder is poured into water (2On+N), and the solution is adjusted to pH 12 with an IN aqueous solution of sodium hydroxide under water cooling, stirred for 10 minutes at the same temperature, and then adjusted to r) H7 with IN hydrochloric acid. This solution was added to the nonionic adsorption resin “Diaion HP-20J”.
The resultant mixture was subjected to column chromatography using commercial ti + manufactured by Mitsubishi Kasei Co., Ltd., and eluted with water. Fractions containing the target product were collected, adjusted to p1]2 with IN hydrochloric acid, and subjected to column chromatography using a nonionic adsorption resin "Diaion HP-20J (trademark: manufactured by Mitsubishi Chemical Corporation). After washing with (300 m&), it was eluted with a 7.5% isopropyl alcohol aqueous solution, the fractions containing the target product were collected, the inpropyl alcohol was distilled off under reduced pressure, and then lyophilized. -amino-12,4-thiadiazol-3-yl) -2-(1-carboxy-I-methylethoxyimino)acetamide]-:(-[3-formylamino-4-methyl-2(2-hydroxyethyl) −
1-virazolio]methyl-3-cephem-4-carboxilade (syn isomer) (o, 2g, 8g) is obtained.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is an amino group or a protected amino group,
R^2 is a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, R^3 is a hydroxy (lower) alkyl group, R^4 is a lower alkanoylamino group or carbamoylamino group, R^5 is hydrogen or a lower alkyl group, respectively. ] A novel cephem compound and its salts.