JPH0246037B2 - SEFUEMUJUDOTAI - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cefem derivative represented by the following general formula (). (wherein R ₁ is hydrogen or an amino protecting group, R ₂ is carboxyC ₁ -C ₄ alkyl; R ₃ is hydrogen or a physiologically acceptable salt; R ₄ is hydrogen, and Y is a substituted pyridinium group, and the _-OR2 group is in the syn-position.) If _R1 is an amino protecting group, optionally
The protecting group may be removed to convert it into a free amino group. As the amino protecting group, amino protecting groups known in peptide chemistry (see, for example, Houben-Weyl, Vol. ZV/1, p. 46 (1974)) can be used. Alkyloxycarbonyl having 1 to 4 alkyl carbon atoms, substituted in particular by halogen or cyano, such as methoxycarbonyl, tert-butyloxycarbonyl, trichloroethoxycarbonyl, cyan-tert-butyloxycarbonyl, or
Arylalkyloxycarbonyl having ~4 alkyl carbon atoms, especially phenylalkyloxycarbonyl, in which the aryl residue may also be further substituted, for example by nitro or lower alkyloxy, especially benzyloxycarbonyl, p- Nitro- or p-methoxy-benzyloxycarboxy, 3,5-dimethoxybenzyloxycarbonyl, 2-biphenyl-(4)-isopropyl-oxycarbonyl, or trialkylsilyl in which the alkyl has 1 to 4 carbon atoms, such as trimethylsilyl , tert-butyldimethylsilyl, etc. can be used. In addition to these, benzyl, benzhydryl, chloroacetyl, trichloroacetin, triphenylmethyl, and the like can be used similarly. 1 to 1 in carboxy C ₁ to C ₄ alkyl of R ₂
Alkyl having 4 carbon atoms is, for example, methyl, ethyl, propyl and butyl. In addition, if R ₃ is a physiologically acceptable salt, it can be converted into a free carboxylic acid if necessary, or conversely, if R ₃ is a hydrogen atom, it can be converted into a free carboxylic acid if desired. It can also be converted into an acceptable salt. "Physiologically acceptable salts" include, for example, alkali or alkaline earth ions, especially sodium, potassium, aluminum or magnesium ions, ammonium ions and organic ammonium ions, in particular optionally substituted alkylated ammonium ions, such as triethylammonium ions. ion or diethanolammonium ion, as well as morpholine ammonium ion, benzylammonium ion, procaine ammonium ion, L-arginine ammonium ion and L-lysine ammonium ion. The compound of the formula () of the present invention has the general formula () (wherein R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned meanings, and B represents a group that can be exchanged by a nucleophilic group) consisting of unsubstituted pyridine. It can be produced by reacting a nucleophilic compound with a base in the presence of a base. In the formula, B can in particular represent an acyloxy having 1 to 4 carbon atoms, especially acetoxy, a halogen, especially chlorine or bromine, an azido group, a carbamoyloxy group or a 2-mercapto-pyridine-N-oxide residue. The use of said pyridine compounds as exchangeable groups is described in Tetrahedron Letters, Vol. 23 (1972), No. 2345.
It is written on the page. The above production is carried out by reacting 1 mol of the compound of general formula () with 1 mol of the nucleophilic compound in a solvent that does not interfere with the reaction. Using an excess amount of nucleophilic compound has a favorable effect on the yield. If the corresponding anti-compounds appear in trace amounts, these can be removed by customary methods, for example by recrystallization. Examples of solvents that do not interfere with the reaction are water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or any other solvent that does not adversely affect the reaction. . Strong polar solvents, especially water, are advantageous. Among the solvents, hydrophilic solvents, inter alia acetone, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, can also be used in mixtures with water. The reaction is carried out in the PH range 5-8, especially at neutral PH values. If the compound ( ) (R ₃ = hydrogen) is used in free form, the reaction is preferably carried out with a base such as an alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, such as sodium or potassium bicarbonate. The reaction is carried out in the presence of an organic base such as an inorganic base, a trialkylamine or a tertiary ammonium base. The compounds of formula () can also be used directly in the form of their salts, especially the sodium or potassium salts. The reaction temperature may vary within a wide range. The reaction is usually carried out at room temperature or at elevated temperatures up to the reflux temperature of the solvent or solvent mixture used, but for all purposes at temperatures not exceeding approximately 80°C. Isolation of the compound of formula () from the reaction medium can be carried out by known methods depending on the solubility of the compound obtained. Thus, for example, the reaction product can be taken up in water, if appropriate after evaporation of the organic solvent, and the clarified reaction mixture can be expediently treated after a corresponding purification operation, such as filtration or centrifugation. Addition of mineral acids in approximately stoichiometric amounts precipitates in the form of free carboxylic acids (R ₃ =H). Dilute acids such as dilute hydrochloric acid or sulfuric acid are particularly suitable as mineral acids. Strong organic acids of low molecular weight, such as formic acid or trifluoroacetic acid, or also arylsulfonic acids, such as toluenesulfonic acid or naphthalenesulfonic acid, have also found use. Sometimes also lyophilization of the solution is suitable. Amidocefemic acids of the formula () are usually precipitated as amorphous solid substances or in crystalline form. This is optionally separated as the free acid by extraction at pH 2-1. Various water-immiscible organic solvents can be used as extractants. For example, halogenated hydrocarbons such as methylene chloride or esters such as ethyl acetate or n-butyl acetate, or ketones such as methyl isobutyl ketone. By evaporating the solvent, for example, from the extract and trituring with, for example, ether, the resulting amidocefemic acid of the formula is obtained. If desired, protecting groups added for temporary protection of amino groups can be removed by methods known in the literature, such as those described in peptide chemistry. For example, when R ₁ represents a triphenylmethyl group, the cleavage is carried out in an acidic medium. Mixtures of formic acid and water, particularly water and formic acid in a ratio of 1:1 to 4:1, have proven advantageous. Isolation of compounds of formula () having free amino as well as carboxyl groups can be carried out by known laboratory methods. For example, when triphenylmethyl groups are removed as triphenylcarbinol, the triphenylcarbinol can be removed by suction and then the solution is concentrated. The resulting acid with formula () can be converted into its physiologically acceptable salt. In particular, it can be converted into an alkali salt, such as the sodium salt, or into a salt with an organic base, especially a tertiary amine, such as the procaine salt. Conversion to a salt is performed using the general formula () using a method known per se.
by reacting the carboxylic acid with the desired base such as sodium bicarbonate or the sodium salt of an organic carboxylic acid such as sodium acetate, sodium propionate, sodium hexanoate, sodium 2-ethyl-hexanoate or potassium acetate. It can be done. It is also possible to isolate the salt directly from the reaction solution, for example by precipitation using a suitable organic solvent or by freeze-drying. The nucleophilic compounds used in the present invention are known compounds and can be produced by methods described in the literature. Compounds of general formula () used as starting materials are of general formula () (In the formula, B, R ₃ and R ₄ are the same as above.) A lactam represented by the general formula () (wherein R ₁ and R ₂ are the same as above). Cefem compounds having the general formula are known in the literature or are described in the literature, e.g.
“Cephalosporin and
Penicillins, Chemistry and Biology, 1972 edition. Anti-position in said publication

Distinguished from [formula] and completely opposite

It should be noted that in order to obtain a compound of the formula with an R ₂ O- group in the syn position shown as [formula], a starting material with the general formula already exists as a syn compound. Therefore, if the mild reaction conditions customary for the reaction with syn compounds are maintained, final products of the syn type are usually obtained. Nevertheless, it may happen that small amounts of the corresponding anti-compound appear as contaminants in the final product, which can be done, if desired, by methods known in the laboratory, such as recrystallization. can be separated. Carboxylic acids having the general formula used for acylation are prepared by various methods. Thus, for example, a compound of formula where R ₁ is hydrogen is called thiourea. and subsequent saponification of the ester group, the reaction expediently being carried out with stoichiometric amounts of thiourea at room temperature in a hydrous solvent such as acetone; It should be carried out in no more than 2-3 hours (eg up to about 2-3 hours). Compounds of the formula in which the amino group is substituted by R ₁ are α of 2-aminothiazole-4-glyoxyl-alkyl or aralkyl esters.
It is also possible to react the -carbonyl group with a hydroxylamine compound having the general formula H ₂ N--OR ₂ and subsequently saponify the ester obtained in a manner known per se. The method for producing the aminothiazole-glyoxyester used in this reaction is disclosed in German patent application No. P2710.
902.0 specification. The hydroxylamine derivatives necessary for the reaction are mostly known or can be easily prepared from literature descriptions. The reaction of both components is carried out under conditions described in the literature for the reaction of glyoxylic acid derivatives with carbonyl reagents. If in the general formula the residue R ₁ represents a protecting group that can be easily removed again, its introduction into the amino group is carried out by methods known from peptide chemistry for amino protecting groups [in detail Schröder
See Lu¨bke et al., The Peptides, Volume 1, Section 3 (1965)]. If such a radical represents, for example, triphenylmethyl, its introduction is carried out using triphenylchloromethane, the reaction expediently being carried out in the presence of a base in an organic solvent, such as, for example, a halogenated hydrocarbon. . Chloroform and methylene chloride have proven advantageous as halogenated hydrocarbons for this purpose. As bases there may be mentioned in particular tertiary amines such as, for example, triethylamine or N-methylmorpholine. basis

In order to avoid the syn-type oxime group from changing to the anti-type for any reason, not only in the production of a starting material containing [Formula] in the syn-type, but also in all other reactions. and, as known in the literature to a specialist in reactions with syn compounds, such as no elevated temperature, no prolonged reaction time, absence of a substantial excess of acidic reaction components, etc. It is expedient to use reaction conditions that are as mild and cautious as possible. General formula with amide-forming ability used in acylation reactions with compounds of formula The reactive derivatives of carboxylic acids having the formula are obtained from the carboxylic acids by methods known in the literature. Examples of reactive derivatives include activated esters such as P-nitrophenyl ester, trichlorophenyl ester, azide or anhydride. A preferred method of activation of the carboxyl group consists in converting it into a symmetrical anhydride. The method for preparing symmetrical anhydrides corresponds to methods known in the literature and commonly used in peptide chemistry. For example, an internal anhydride is obtained from a carboxylic acid of the general formula using a condensing agent such as an N,N-disubstituted carbodiimide, e.g. dicyclohexylcarbodiimide, which is subsequently reacted with an aminocefem carboxylic acid of the formula in an organic solvent. . The preparation of compounds of general formula by acylation of compounds of formula with carboxylic acids of formula may be carried out under various experimental conditions, for example using various solvents. Suitable solvents are, for example, organic solvents such as halogenated hydrocarbons, such as methylene chloride or chloroform, but also water or mixtures of water with water-miscible organic solvents. For good reaction progress, it is expedient for the aminolactam derivative of the formula to be in solution. When using aminocefem carboxylic acids with the general formula (R ₃ =hydrogen), the compound must be brought into solution in the presence of a base. Suitable bases for dissolving 7-ACS and many 7-amino-Δ ⁸ -cephem-4-carboxylic acids include inorganic or organic bases. Therefore, for preparing solutions in organic solvents, in particular tertiary amines such as triethylamine, N,N-dimethylaniline or N-methylmorpholine are used, and for preparing aqueous solutions, especially sodium bicarbonate or potassium bicarbonate. Alkali bicarbonates such as, as well as tertiary amines have been found to be good. Bases are generally added in at least stoichiometric amounts based on the desired reaction. For example, about 0.1 to 2 molar excess of base, especially about 0.2 to 0.8 molar excess, may be advantageous. For compounds with formulas that are sensitive to bases, the base can be added continuously according to the progress of the reaction.
Keep the pH constant at about 4-8, especially 6-7. The dissolution of aminolactam derivatives having the formula can be carried out over a wide temperature range. However, for all purposes it should not exceed about 40°C. For base-sensitive derivatives, a temperature range of about 0 to 15°C is preferably selected. An activated derivative of a carboxylic acid having the general formula is added to an aminocephem derivative of the formula present in solution or optionally in suspension. The reaction is carried out in a manner known per se. When water or a mixture of water and an organic solvent is used as the reaction medium, it is preferred to maintain the temperature between about -5°C and +10°C. When using organic solvents, the acylation can also be carried out at up to about 65° C., especially at room temperature. For better performance of the reaction, the activated carboxylic acid derivative of the formula is added in diluted form in a solvent that does not interfere with the reaction. If the acylation is carried out in an aqueous medium, anhydrous ketones, such as, for example, acetone or methyl ethyl ketone, or, under vigorous stirring, ethers, such as, for example, diethyl ether or diisopropyl ether, can be used as solvents for the activated carboxylic acid derivatives. If the acylation is carried out in a non-aqueous medium, it is preferred that the same solvent used for the acylation is used for diluting the acid derivative. The activated acid derivatives having the formula are used in at least stoichiometric amounts to achieve high yields. Approximately 5
An excess of ~25% may prove advisable. Alternatively, the compounds of the present invention may have, in the third position,
It can also be produced by reacting a lactam of general formula () having an unsubstituted pyridinium group with a carboxylic acid-reactive derivative of general formula (). The compounds of general formula () according to the invention are valuable chemotherapeutic agents, having surprisingly strong antibacterial activity against Gram-positive and Gram-negative bacteria and unexpectedly good efficacy against penicillinase-forming staphylococci. It also exhibits some bacteriostatic activity. Compounds having the general formula () are distinguished by remarkable antimicrobial activity against a series of bacteria for which known cephalosvorins have little efficacy. The compounds of formula () furthermore exhibit favorable toxicological and pharmacological properties, so that they represent a valuable antimicrobial action for the treatment of infectious diseases. The products according to the invention can also be used in combination with other active ingredients such as penicillins, aminoglycosides, cephalosporins, the aminoglycoside series or compounds that influence the course of bacterial infections, such as antipyretics, analgesics or anti-inflammatory agents. Compounds of general formula () may be administered orally, intramuscularly or intravenously. Pharmaceutical preparations containing one or more compounds of general formula () as an active ingredient may contain one or more compounds of general formula () in one or more pharmacologically acceptable carrier substances or diluents. , for example mixed with fillers, emulsifiers, lubricants, taste correctors, coloring substances or buffer substances, in suitable galenic formulations such as tablets, dragees, capsules or in solutions or suspensions suitable for parenteral administration. It can be prepared by eggplant. Carriers or diluents include, for example, tragacanth, lactose, talc, agar, polyglycols, ethanol and water. Parenteral administration includes, inter alia, suspensions or solutions. It is also possible to administer the active substances neat, without carriers or diluents, in a suitable form, for example in a capsule. A suitable dose of the compound of general formula is approximately 60
Approximately 0.4-20 g, especially 0.5-4 g per kg adult per day. It may be administered in a single dose or generally in several doses, a single dose containing an amount of approximately 50 to 1000 mg, in particular 100 to 500 mg, of active substance. Hereinafter, the production of the compound of formula () of the present invention will be explained in more detail with reference to Examples. Example 1 7-[α-syn-carboxymethoxyimino]
α-(2-amino-thiazol-4-yl)-
Acetamide]-3-pyridinium methyl-3
-Production of cefem-4-carboxylate monosodium salt 7-β-[α-syn-carboxymethoxyimino-α-(2-amino-thiazol-4-yl)
- Acetamide] - A mixture of 100 mg of cephalosporanic acid disodium salt and 500 mg of NaJ was added to pyridine.
Heat to 60° C. for 3 hours in 0.15 ml and 0.15 ml water.
The reaction mixture was diluted with 5 ml of water and 3 ml of ethyl acetate was added.
Extract 4 times with ml. Traces of ethyl acetate in the aqueous phase are removed in vacuo at 20°C. Then the aqueous phase
Purify on 20g of HP20. After washing off the inorganic salts with water, the organic substances are eluted with a 4:1 mixture of water and isopropanol. After removing the isopropanol in vacuo at 20° C., lyophilization of the solution gives 35 mg of a mixture of the title compound and the starting cephalosporin. The above mixture is chromatographed on a Sephadex G-25 column using 0.02M sodium acetate as eluent. Fractions containing the desired product were purified with HP20 as described above.
Desalt with 20g of and freeze-dry. Title compound 25
mg is obtained. NMR (D20): δ = 3.6ppm (AB, C-2-CH ₂ ) δ = 4.6ppm (s, 2H, OCH ₂ ) δ = 5.1ppm (d, 1H, C-6-H) δ = 5.45ppm (d, 2H, CH ₂ -N) δ = 5.8ppm (q, 1H, C-7-H) δ = 7.05ppm (s, 1H, thiazole-H) δ = 8.05ppm (m, 5H, pyridine) δ = 8.5ppm (m, 5H, pyridine) δ = 8.9ppm (d, 5H, pyridine) IR (KBr): 3450cm ^-1 , 1750cm ^-1 (β-lactam), 1620cm ^-1 (carboxylate)

Claims (1)

[Claims] 1. A cefem derivative represented by the following general formula (). (wherein R ₁ is hydrogen or an amino protecting group; R ₂ is carboxyC ₁ -C ₄ alkyl; R ₃ is hydrogen or a physiologically acceptable salt; R ₄ is hydrogen; Y is an unsubstituted pyridinium group; and the _-OR2 group is in the syn-position.