KR810001351B1 - Process for preparing 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compound - Google Patents

Abstract

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Description

Process for preparing 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compound

The present invention relates to novel 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compounds and their pharmaceutically acceptable salts.

More specifically, pharmaceutically acceptable salts thereof having antibiotics with the novel 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compounds and methods for their preparation, pharmaceutical compositions And therapeutically used for the treatment of infectious diseases in humans and animals.

It is therefore an object of the present invention to provide 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compounds which are active against pathogenic microorganisms and their pharmaceutically acceptable salts.

Another object of the present invention is to provide a process for preparing these salts with a 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compound.

A further object of the present invention is a pharmaceutical composition comprising, as active ingredients, the mentioned 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compounds and their pharmaceutically acceptable salts thereof. To provide.

A further object of the present invention is a pharmaceutical composition comprising, as an active ingredient, the aforementioned 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compounds and their pharmaceutically acceptable salts. Provide a red composition.

A further object of the present invention is to provide a method for the treatment of an infectious disease caused by pathogenic bacteria in humans and animals.

The desired 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compound is novel and can be represented by the following general formula (I).

In the above structural formula,

R ¹ is lower alkyl,

R ² is a carboxy or protected carboxy group,

R ³ is an amino or protected amino group,

R ⁴ is hydrogen or lower alkyl.

According to the present invention, 2-lower alkyl-7-substituted-2 or 3-cefe-4-carboxylic acid compound (I) can be prepared by various processes described by the following table.

In the above structural formula,

R ¹ , R ² , R ³ and R ⁴ are each as defined above,

R ^2a is a protected carboxy group,

R ^3a is a protected amino group,

R ^4a is lower alkyl,

R ⁵ is the ester moiety of the esterified carboxy group represented by the formula: -COOR ⁵ ,

Y is an interstitial acid.

Starting compounds (V) in the present invention are novel compounds and can be prepared by conventional processes as illustrated by the following table.

Wherein R ¹ , R ² , R ^4a and Y are as defined above.

(R³는 상기 정의한 것)의 그룹의 경우에서 언급한 목적과 출발 화합물의 분자에서 포함될 게이며, 구조식의 언급한 그룹은 호변구조식 :With respect to the target compound (I), it will be understood to include tautomers, i.e., structural formulas

(R ³ is as defined above) in the case of the group mentioned above and in the molecule of the starting compound, and the mentioned group of the structural formula:

(R³'는 이미노 또는 보호된 이미노그룹)에 의해 차례대로 나타낼 수 있다.

(R ³ ′ may be indicated in turn by imino or protected imino group).

That is, two of the groups mentioned are each in equilibrium and some tautomers can be represented by the following equilibrium.

Wherein R ³ and R ³ ′ are the definitions above.

These forms of tautomerism between aano compounds and the corresponding imino-compounds as described above are well known in the literature and those skilled in the art can easily convert both of the tautomers and fall within the same category of the compound itself. You will know.

Therefore, the tautomeric form of the target compound (I) is expressly included in the form of the present invention.

에 의해 나타난다.In the present specification and claims, the objectives and starting compounds comprising such groups of isomers are represented by

Indicated by

Furthermore, with regard to the target compound (I) and the starting compound (V), it is understood that the stated purpose and starting compound include the new isomers, anti-isomers and mixtures thereof. In other words, the stated purpose and starting compound can be optionally obtained as neoisomers or antiisomers or mixtures thereof.

에 의해 나타나는 부분적 구조를 갖는 하나의 기하학적 이성체를 의미하고 안티이성체는 다음 구조식 :

에 의해 나타나는 부분적 구조를 갖는 다른 기하학적 이성체를 의미한다.Thus, in this specification, neoisomers have the following structural formula:

Means one geometric isomer having a partial structure represented by the anti-isomer is the following structural formula:

By other geometric isomers having a partial structure represented by.

In which R ⁴ is as mentioned above.

Suitable pharmaceutically acceptable salts of the desired compound (I) are conventionally non-toxic salts, metal salts such as alkali metal salts (ie sodium salts, potassium salts) and alkaline earth metal salts (ie calcium salts, magnesium salts, etc.), Ammonium salts, inorganic base salts (i.e., trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, etc.), organic acid salts (i.e. acetate, Maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like. , Glutamic acid, and the like).

In the foregoing and in the continuation of the specification, the description of suitable embodiments and various definitions of the invention is included in the scope of the invention described in detail below.

The term "lower" means carbon atoms 1 to 6 unless otherwise stated.

Suitable lower alkyls may include such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl.

Suitably protected carboxys may include such as esterified carboxys and suitable examples of ester moieties in the esterified carboxys mentioned include suitable substituents such as lower alkanoyloxy (lower) alkylesters (i.e. acetoxy Methyl ester, propionyloxy methyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxy ethyl ester, 2-propionyloxyethyl ester, etc.), lower alkanesulfonyl ( Lower) alkyl esters (i.e. 2-methylethyl ester, etc.) or mono (or di or tri) halo (lower) alkyl esters (i.e. 2-iodethyl ester, 2,2,2-trichloroethyl ester, etc.), At least one of lower alkenyl esters (ie, vinyl esters, allyl esters, etc.) and lower alkynyl esters (ie, ethynyl esters, propylyl esters, etc.) Lower alkyl esters that may have (ie methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, pentyl esters, hexyl esters, 1-cyclopropylethyl esters, etc.): suitable substituents (ie benzyl Ester, 4-methoxybenzyl ester, 4-nitro benzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxy benzyl ester, 4-hydroxy Ar (lower) alkyl esters which may have at least one of -3,5-ditherbutyl butylbenzyl ester, etc.

May be one such as an aryl ester which may have at least one suitable substituent (ie, phenylester, 4-chlorophenylester, tolylester, tertarybutylphenyl ester, xylyl ester, mezzyl ester, cumenyl ester, etc.) have.

Suitably protected amino are ar (lower) which may have at least one of acyl, suitable substituents (ie benzyl, 4-methoxybenzyl, phenethyl, trityl, 3,4-dimethoxybenzyl, etc.) as mentioned below Amino groups substituted by conventional protecting groups such as alkyl may be included.

Suitable acyls may include carbamoyl, aliphatic acyl groups and acyl groups including aromatic or heterocyclic rings.

Suitable examples of acyls mentioned are lower alkanoyls (ie formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, fivaroyl, etc.), lower alkoxycarbonyl (Ie methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxy carbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl, Hexyloxycarbonyl, etc.): lower alkanesulfonyl (ie, mesyl, methanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.): arnesulfonyl (ie, benzenesulfonyl, soil, etc.): Aroyl (ie benzoyl, toluoyl, naphthoyl, phthaloyl, intancarbonyl, etc.), ar (lower) alkanoyl (ie phenylacetyl, phenylpropionyl, etc.): ar (lower) alkoxycarbonyl (ie , Benzyloxycarbonyl and the like).

Acyl moieties as mentioned above include halogens (ie chlorine, bromine, iodine or fluorine), cyano, lower alkyl (ie methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (ie vinyl, Or at least one suitable substituent, such as allyl).

Suitable examples of this may be mono (or di or tri) halo (lower) alkanoyl (ie trifluoro acetyl, etc.).

Suitable ester moieties of esterified carboxy may include esters exemplified for the protected carboxy.

Suitable residues of acids may include such as halogens (ie chlorine, bromine, urethra or fluorine).

Various processes for preparing the target compounds of the present invention are described in detail below.

Process 1

The target compound (I) or salts thereof can be prepared by reacting compound (V) or salts thereof with compound (VI).

Suitable salts of compound (V) may be mentioned as one exemplified for compound (I).

The reaction is usually carried out in solvents such as water, alcohols (ie methanol, etc.), benzene, dimethylformamide, tetrahydrofuran or any dry solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at ambient temperature to heating.

Process 2

The desired compound (Ia) or salts thereof may be prepared by removing compound (Ib) or salts thereof by removing an amino protecting group.

Suitable salts of compound (Ib) may be mentioned with metal salts, ammonium salts and organic amine salts exemplified for compound (I).

The removal reaction is carried out in accordance with conventional methods such as hydrolysis and reduction. Hydrolysis may also include methods using acids or bases or hydrazines.

These methods may be chosen depending on the type of protection group removed.

Of these methods, hydrolysis using acids is the most common and substituted or unsubstituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted or unsubstituted aralkoxy carbonyl, aralkyl (ie trisyl), It is a preferred method for removing protective groups such as substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylene.

Suitable acids include organic or inorganic acids such as poromic acid, trifluoroacetic acid, benzenesulphonic acid, P-toluenesulphonic acid, hydrochloric acid and the most suitable acids can be easily removed from the reaction mixture by conventional methods such as distillation under reduced pressure. Acids for example are formic acid, trifluoroacetic acid and the like.

Acids may be selected depending on the type of protection group removed.

When the removal reaction is conducted to the acid, it can be carried out with or without solvent. Suitable solvents include water, conventional organic solvents or mixtures thereof. Hydrolysis using hydrazine is commonly used to remove phthaloyl form amino-protecting groups. Reductive elimination may be carried out by protecting groups such as haloalkoxy carbonyl (ie trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (ie benzyloxycarbonyl, etc.), 2-pyridylmeth It is generally used for the removal of oxycarbonyl and the like.

Suitable reductions are, for example, reduction with alkali metal borohydrides (eg, sodium borohydrides, etc.), metal salt compounds (ie chromose chloride, chromose acetate, etc.) and organic or inorganic acids (ie acetic acid). , Propionic acid, hydrochloric acid), in other words by mixing with other metals (ie, tin, zinc, iron, etc.) or the metals mentioned, or catalytic reduction. Suitable catalysts include one of the prior art, such as raneybukel, platinum oxide, palladium on charcoal.

Among the protecting groups, acyl groups can generally be removed by hydrolysis. In particular, trifluoroacetyl groups can be easily removed by treatment with water at intermediate conditions and halogen-substituted-alkoxy carbonyl and 8-quinolyloxycarbonyl groups are usually removed by treatment with heavy metals such as copper and zinc. Among the protecting groups, acyl groups are treated with an imino halogenating agent (i.e., phosphorus oxychloride, etc.) and an amino esterifying agent, i.e., lower alkanols (i.e., methanol, ethanol, etc.), if necessary, by hydrolysis. Can be removed.

The reaction temperature is not critical and can be appropriately selected depending on the kind of protecting group for the amino group and the removal method as mentioned above, and the reaction is preferably performed under mild conditions such as cooling or slightly elevated temperature.

The present invention includes the case where the protected carboxy is converted to the free carboxy group during the reaction or the workup step of the present process.

Process 3

The desired compound (If) or salts thereof may be prepared by reacting compound (Ig) or salts thereof with an alkylating agent.

Suitable salts of compound (Ig) may be mentioned as one of those exemplified for compound (III).

Suitable alkylating agents used in this reaction include di (lower) alkylsulfates (i.e. dimethylsulfate, diethylsulfate, etc.) diazo (lower) alkanes (i.e. diazomethane, diazoethane, etc.), lower alkyl halides (i.e. Methyl iodide, ethyl iodide, ethyl bromide, etc.), lower alkylsulfonates (ie, methyl P-toluenesulfonate, etc.) may be included.

Reactions with diazo- (lower) alkanes are commonly carried out in solvents such as diethyl ether, dioxane or other solvents that do not adversely affect the reaction under cooling or ambient temperature.

The reaction with other alkylating agents is usually carried out in solvents such as water, acetone, ethanol, diethyl ether, dimethylformamide or any other solvent which does not adversely affect the reaction under cooling or heating and the reaction is carried out with inorganic bases or already mentioned. It is preferably carried out in the presence of an organic base as shown.

Process 4

The target compound (In) or salts thereof can be prepared by combining compound (Ii) or salts thereof by removing a carboxy protecting group.

Suitable salts of compound (Ii) may be referred to as acid addition salts exemplified for compound (I).

In this removal reaction, all conventional methods are used in the removal reaction of carboxy protecting groups. For example, hydrolysis and reduction can be used. When the carboxy 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 may include inorganic bases and organic bases as mentioned in Process 2.

Suitable acids may include organic acids (ie, formic acid, acetic acid, propionic acid, etc.) and inorganic acids (ie, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

In other words, it can be used for the removal of protecting groups such as 2-iodoethyl ester and 2,2,2-trichloroethyl ester. Reductions that may be used in the present invention include metals (i.e. zinc, zinc amalgam, etc.) or chromium salt compounds (i.e., chromus chloride, chromus acetate, etc.) and organic or inorganic acids (i.e. acetic acid, propionic acid, Reduction using a combination of hydrochloric acid, etc.) and reduction in the presence of a metallic catalyst. Metallic catalysts for catalytic reduction include, for example, platinum catalysts (ie, platinum wires, sponge platinum, platinum black, platinum claroids, etc.), palladium catalysts (ie, palladium sponges, palladium black, palladium oxides, and varieties). Such as palladium on oxalate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium claroid, etc. Include.

The reaction temperature is not critical and can be selected depending on the type of carboxy protecting group and the removal method.

Process 5

The target compound (Ij) or salts thereof can be prepared by matching the compound (In) or salts thereof by an esterification reaction. Suitable salts of compound (Ih) may be mentioned as one illustrated for compound (I).

The esterifying agent used in the present reaction may be a compound of the following structural formula.

XR ⁵ (XI)

Wherein R ⁵ is as defined above and X is hydroxy or a reactive derivative thereof.

Suitable examples of reactive derivatives of hydroxy may include residues of acids as already mentioned.

The reaction is usually carried out in solvents such as dimethylformamide, pyridine, hexamethyl phosphortriamide, dioxane or other solvents that do not adversely affect the reaction.

In the case where compound (Ih) is used in the form of a free acid, the reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as mentioned in Step 2. The reaction temperature is not critical and the reaction is preferably carried out at cooling, ambient or warm.

In the reactions already mentioned or in the post-treatment steps of the process of the invention, the tautomers already mentioned are optionally changed to other tautomers and such cases are included within the form of the invention.

In the reactions already mentioned or in the post-treatment steps of the process of the invention, the mentioned syn or anti-isomers are modified, in part or in whole, into other isomers and such cases are included within the invention form.

When the desired compound (I) is obtained in free acid form at the 4 position or when the desired compound (I) is a free amino group, it can be modified by the conventional method into a pharmaceutically acceptable salt as already mentioned. have.

The preparation of starting compounds is described in detail below.

Compound (X) may be prepared by reacting a reactive derivative thereof or a salt thereof at the compound (II) or an amino group with a reactive derivative thereof at the compound (IX) or carboxy group.

This acylation reaction is carried out by conventional methods.

Starting compounds (Va) can be prepared by reacting compound (X) with a nitrogenating agent.

Suitable nitrosizing agents may include nitro acid, alkali metal nitrates (ie, sodium nitrate, etc.), lower alkylnitrites (ie, amylrite, etc.).

The reaction is usually carried out in solvents such as water, acetic acid, benzene, methanol, ethanol or other solvents that do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at cooling or ambient temperature.

Starting compound (Vb) can be prepared by reacting compound (Va) with an alkylating agent.

The reaction is carried out in a similar manner as described for the reaction in process 3.

The compound (I) of the present invention and its pharmaceutically acceptable salts exhibit high antibiotic activity and inhibit the growth of microorganisms, including pic-positive and gram-negative bacteria. In particular, the neoisomers of the target compound (I) and their pharmaceutically acceptable salts generally exhibit higher antibiotic activity than the target compound (I) and their corresponding anti-isomers which are pharmaceutically acceptable. Indicates. For therapeutic purposes, the compounds according to the invention are pharmaceutical preparations comprising the compounds mentioned in admixture as pharmaceutically acceptable carriers and mixtures, such as organic or inorganic solids or liquid excipients which are suitable for oral, subcutaneous or external administration as active ingredients. It can be used in the form of a formulation. The pharmaceutical preparation may be such as a capsule, tablet, dragee, ointment or suppository, solution, suspension, emulsion. If desired, auxiliary, stabilizer, wetting or emulsifying agents, buffers and other commonly used additives may be included in the formulation.

The dosage of the compound is converted according to age and the condition of the patient, while the average single dose of 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound according to the invention is used for the treatment of infectious diseases caused by pathogenic bacteria. It proved to be effective.

To demonstrate the usefulness of the target compound, the antibiotic activity of the representative compounds of the present invention on test strains of pathogenic bacteria is shown below the minimum inhibitory concentration.

Test Methods

In vitro antibiotic activity is determined by a double agar plate dilution method as described below.

In tripeptase-soybean juice, one ring (10 ⁸ live cells per ml) of the overnight culture of each test strain was cultured on HI-agar medium containing graded concentrations of representative test compounds and the minimum inhibitory concentration [MIC] was 37 ° C. After 20 hours incubation in μg / ml.

Test compound

(1) 2-Methyl-7- [2-methoxy imino-2- (2-aminothiazol-4-yl) acetamido] -3-cepam-4-carboxylic acid (neoisomer) [test Compound (1)]

(2) pivaloyloxymethyl 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cepam-4-carboxylate (neoisomer) [Test Compound (2)]

Claims (1)

A process for preparing a compound of formula (I) and salts thereof by reacting a compound of formula (II) or a salt thereof with a compound of formula (III).

In the above structural formula, R ¹ is lower alkyl, R ² is a carboxy or protected carboxy group, R ³ is an amino or protected amino group, R ⁴ is hydrogen or lower alkyl, Y is the residue of the acid.