KR800001672B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Title compds. (I; R1 = H, alkyl; X = O,S, NR2 ; R2 = H, alkyl; R3 = heterocyclic radical including nitrogen) were prepd. by reaction of compd. II and III. Thus, 0.678 g 7-(4-thiocyano-3-oxobutyrylamide)-3-acetoxymethyl-3-cephem-4 carb-oxylate, 0.116 g sodium hydrogencarbonate were circulated in phosphoric acid buffer soln., and added 0.6185 g l-methyl-tetrazol-5-thiol to give 7-2-(2-oxo-4-thiazolin-4-yl)-acet-amide-3-(l-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxy-late.

Description

Method for preparing cephalosporin derivative

The present invention provides novel antimicrobial agents, general formulas, which are valuable as therapeutic agents for diseases of animals, including livestock and humans, particularly infectious diseases caused by gram positive and negative bacteria.

(Wherein R ¹ represents a hydrogen atom, an alkyl group, X represents an oxygen atom, a sulfur atom or NR ² (R ² represents a hydrogen atom, an alkyl group, and a double alkyl group may combine with R ¹ to form a ring.) A group represented by R ³ represents a nitrogen-containing heterocyclic group.) Preparation of 7- [2- (2-exosubstituted-4-thiazolin-4-yl) acetamide]-cephalosporin derivative represented by It is about a method.

The present inventors, first, general formula

(Wherein R is an organic residue derived from a sulfur-containing nucleus reagent, and others are the same as described above), and the like 7- (4-substituted thio-3-oxobutyryl) Inventing a process for preparing amide) -cephalosporin derivatives, these compounds have a strong antibacterial action, in particular Escherichia, Escherichia Coli and Clavsciella. It has been found that Klebsiella pnoumoniae has excellent characteristics of exhibiting stronger antimicrobial activity than known cephalosporins (Japanese Patent Application No. 49-1521).

Based on this research, the inventors of the present invention conducted the research again and found that the general formula

The compound represented by (symbol in a formula is the same as the above), and a general formula

When the compound represented by (the symbol in the formula is the same as the above) is reacted, it is found that the compound is converted into the new cephalosporin represented by the general formula (I), and 7- [2- (2- obtained in this manner. Exosubstituted-4-thiazolin-4-yl) acetamide] -cephalosporin derivative (I) has a strong and broad antimicrobial spectrum as a result of the antimicrobial test, in particular Escherichia, a Gram-negative bacterium. Collie, Klebsiella. To pneumoniae, proteus. Brutearis (Proteus vulgaris) and Proteus. The present invention was found to have a stronger antimicrobial activity than known cephalosporins and to be a preferred cephalosporin agent against Morphogni (Proteus morganii).

In said formula, R <^1> represents alkyl groups, such as a hydrogen atom, methyl, ethyl, and a propyl. X represents a group represented by a carbon atom, a sulfur atom or NR ² , wherein R ² represents a hydrogen atom or an alkyl group as described above, and is bonded to R ¹ with an alkyl group such as methyl, ethyl or propyl to form a ring. You may form. R ³ may contain one or more nitrogen atoms which may be oxidized, or may have a substituent on its nucleus as a nitrogen-containing heterocyclic group which may contain atoms other than nitrogen, for example, oxygen and sulfur. As such a nitrogen-containing heterocyclic group, for example, pyridyl, N-oxide pyridyl, pyrimidyl, pyridinyl, N-oxide pyridadidinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3- Thiadiazoline, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl-1,2,4- Oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazole, 1,2,4-ryltriazolyl, 1H-tetrazolyl, 2H- Tetrazolyl etc. are used a lot. Substituents on these nitrogen-containing heterocyclic groups include, for example, hydroxyl group, mercapto group, amino group, carboxyl group, carbamoyl group and lower alkyl group (e.g. methyl, ethyl, trilomethyl, propyl, isopropyl, butyl). Monovalent or lower alkyl such as isobutyl), lower alkoxy groups (e.g., methoxy, ethoxy, protoxy, isopropoxy, butoxy), halogen atoms (e.g. chlorine, cancellation, etc.) The thing which has various substituents through multiple devices, such as a benzene group and -S-, -N- group, is used. When the polyvalent group is a lower alkylene group, the substitution may be a hydroxyl group, a mercapto group, an amino group, a morpholino group, a carboxyl group, a sulfo group, a carbamoyl group, an alkoxycarbonyl group, a lower alkylbacamoyl group, an alkoxy group or an alkyl group. A thio group, an alkylsulfonyl group, an acyloxy group, a morpholinocarbonyl group, etc. may be sufficient.

기일 경우에는, 치환분은 저급알킬기 및 상기 치환분을 가지는 저급알킬렌기등이라도 좋다. 다가기가

일 경우에는, 다시 카복실기, 알콕시카보닐기, 아실기, 카바모일기, 저급알킬카바모일기등의 치환분이 직결되어 있어도 좋다. 구체적으로는, 예를들면 카복시메틸, 카바모일메틸, N-저급알킬카바모일메틸(예를들면, N, N-디메틸카바모일메틸), 하이드록시 저급알킬(예를들면 하이드록시메틸, 2-하이드록시에틸), 아실옥시저급알킬(예를들면 아세톡시메틸, 2-아세톡시에틸), 알콕시카보닐메틸(예를들면 메톡시카보닐메틸, 핵실옥시카보닐메틸, 옥틸옥시카보닐메틸), 메틸티오메틸, 메틸설포닐메틸, N-저급알킬아미노 저급알킬(예를들면 N, N-디메틸아미노메틸, N, N-디메틸아미노에틸, N, N, N-트리메틸암모늄에틸), 모르폴리노메틸등의 치환알킬기, 저급알킬아미노(예를들면 메틸아미노), 설포저급 알킬아미노(예를들면 2-설포에틸아미노), 하이드록시저급알킬아미노(예를들면 하이드록시에틸아미노), 저급알킬아미노(예를들면 2-디메틸 아미노에틸아미노, 2-트리메틸 암모늄 에틸아미노), 아실아미노(예를들면 아세틸아미노), 2-디메틸아미노 아세틸아미노, 2-트리메틸 암모늄 아세틸아미노, 저급알콕시 카보닐아미노(예를들면 메톡시카보닐 아미노)등의 치환 아미노기, 메틸티오, 2-하이드록시 에틸티오, 2-아실옥시에틸티오(예를들면 2-아세톡시에틸티오, 2-페닐 아세톡시에틸티오, 2-카프로일옥시에틸티오), 카복시메틸티오, 알콕시 카보닐 메틸티오(예를들면 메톡시 카보닐 메틸티오, 핵실옥시 카보닐 메틸 티오), 카바모일 메틸티오, N-저급알킬 카바모일메틸티오(예를들면 N, N-디메틸 카바모일메틸티오), 아세틸 메틸티오, N-저급알킬아미노 저급알킬티오(예를들면 2-N, N-디메틸 아미노 에틸티오, 2-N, N N-트리메틸 암모늄 에틸티오), 모르폴리노카보닐메틸티오, 2-설포에틸티오 등의 치환티오기를 들수 있다.To approach -S-,

In the case of a group, the substitution may be a lower alkyl group, a lower alkylene group having the above substitution, or the like. Approaching

In one case, substitutions such as a carboxyl group, an alkoxycarbonyl group, an acyl group, a carbamoyl group, and a lower alkyl carbamoyl group may be directly connected. Specifically, for example, carboxymethyl, carbamoylmethyl, N-lower alkylcarbamoylmethyl (eg, N, N-dimethylcarbamoylmethyl), hydroxy loweralkyl (eg hydroxymethyl, 2- Hydroxyethyl), acyloxy lower alkyl (e.g. acetoxymethyl, 2-acetoxyethyl), alkoxycarbonylmethyl (e.g. methoxycarbonylmethyl, nucleosiloxycarbonylmethyl, octyloxycarbonylmethyl) , Methylthiomethyl, methylsulfonylmethyl, N-lower alkylamino lower alkyl (e.g. N, N-dimethylaminomethyl, N, N-dimethylaminoethyl, N, N, N-trimethylammoniumethyl), morpholi Substituted alkyl groups, such as nomethyl, lower alkylamino (for example, methylamino), sulfo lower alkylamino (for example, 2-sulfoethylamino), hydroxy lower alkylamino (for example, hydroxyethylamino), lower alkyl Amino (eg 2-dimethyl aminoethylamino, 2-trimethyl ammonium ethylamime ), Substituted amino groups such as acylamino (eg acetylamino), 2-dimethylamino acetylamino, 2-trimethyl ammonium acetylamino, lower alkoxy carbonylamino (eg methoxycarbonyl amino), methylthio, 2 -Hydroxy ethylthio, 2-acyloxyethylthio (eg 2-acetoxyethylthio, 2-phenyl acetoxyethylthio, 2-caproyloxyethylthio), carboxymethylthio, alkoxy carbonyl methylthio ( For example methoxy carbonyl methylthio, nucleosiloxy carbonyl methyl thio), carbamoyl methylthio, N-lower alkyl carbamoylmethylthio (eg N, N-dimethyl carbamoylmethylthio), acetyl methylthio, N-lower alkylamino lower alkylthio (e.g. 2-N, N-dimethyl amino ethylthio, 2-N, N N-trimethyl ammonium ethylthio), morpholinocarbonylmethylthio, 2-sulfoethylthio, etc. Substituted thio group is mentioned.

In the method of the present invention, (C) provided as a raw material is itself a novel cephalosporin, for example, a general formula

(The symbol in the formula is the same as the above.)

Compound represented by the general formula

Wherein X ¹ represents an oxygen atom, a sulfur atom, or a group represented by HR ⁴ (R ⁴ represents a hydrogen atom or an alkyl group), or a general formula

(Wherein W represents a halogen atom) and a general formula

The symbol in the formula is the same as described above.

Compound represented by and general formula

X ″ may be prepared by reacting a compound represented by an oxygen atom, a sulfur atom or a protected amino group, and others as described above, and removing the protecting group if necessary. In addition, the general formulas (III), (IV) and (iii) in the compounds are themselves novel cephalosporins, for example, prepared according to the following scheme.

(Wherein Z is

M represents potassium or sodium. Other symbols are the same as above.)

That is, 7-amino-cephalosporin derivative (XI) is known per se, using 4-halogeno-3-oxobutyrylhalogenide (XIV) obtained by reacting a molar molecular weight of halogen with deketene. When acylated by the method (XII) is obtained, (III) is formed by the reaction of (XII) and thiol compound (XIII) again, and (IV) is reacted by the reaction of (i) and rodan salt (XV). Obtained.

Among the compounds (i), as the halogen atom represented by W, a chlorine atom, a cancel atom and the like are often used. Moreover, as a specific example of a thiol compound (III), thionosodium, an alkyl or acylated thioniosodium, N, N'-methyl thionosodium, ammonium dithiocarbamate, ammonium thiocarbate, etc. are conveniently used. In the reactions of (i) and (iii), the former is usually freed, the latter is usually freed, or a salt with an alkali metal such as lithium, sodium or potassium in a thiol group, or It is provided to the reaction as an ammonium salt. The reaction is usually carried out by mixing three moieties of both equimolar amounts and 1 to 2 equivalents of base in a solvent. Suitable solvents for such reactions include water, methanol, ethanol, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide or other non-reactions in general. Organic solvents; and the like. The double hydrophilic solvent may be used in admixture with water. Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal carbonates such as sodium hydrogen carbonate, organic tertiary amines such as trimethylamine, triethylamine and pyridine And other bases. Since the base is for neutralizing the carboxyl group of cephalosporin and the halogenated hydrochloric acid which is released by the reaction, about 2 equivalents are used when the substituted thiol is used as a glass, and about 1 equivalents is used when the alkali metal salt is used. Good to do. Although reaction temperature is not specifically limited, Usually, it is good to carry out under cooling. The reaction generally proceeds quickly and completes in less than 10 minutes, but in some cases it may require more than 30 minutes. The obtained (III) and (IV) can be purified immediately by known means such as solvent extraction, liquid conversion, conversion, distillation, crystallization, recrystallization, chromatography, You may perform a dehydration ring reaction or reaction with a compound (V).

The dehydration ring closure reaction of 7- (4-substituted thio-3-oxobutyrylamide) cephalosporin derivative (III) proceeds easily in a solvent. As the solvent, water, alcohol, acetone, acetonitrile, dioxane, dimethylformamide, dimethyl sulfoxide or a suitable mixed solvent thereof is usually used. This reaction is accelerated by the presence of an acid or a base. As the acid, a pH acidic phosphate buffer solution, hydrochloric acid, phosphoric acid, sulfuric acid, or an acidic alkali metal salt thereof, or other inorganic or organic acids may be used. As the base, inorganic or organic bases such as pH-based phosphate buffer solution, alkali metal hydroxide metal hydroxide, alkali metal hydrogen carbonate salt, triethylamine, pyridine, ammonia and N, N-dimethylaniline are used. In addition, compound (III) is the reaction liquid of the above-mentioned raw material synthesis | combination as it is, or, when isolated, as a free acid, as alkali metal salts, such as sodium and potassium, or trimethyl silester, methoxymethyl ester, 2-methylsulfur It is provided to reaction as ester of the property which is easy to decompose | disassemble, such as a polyethyl ester, P-nitrobenzyl ester, 2,2, 2- trichloroethyl ester, and a trityl ester. The reaction usually proceeds sufficiently to room temperature, and may be heated or cooled as necessary. When the reaction is left for several hours to several tens of hours, a lung recycled product is produced. In addition, when a buffer solution is selected as a solvent, since it already contains the above-mentioned acid or base as a component, the conversion to (IX) may sufficiently proceed only by dissolving only (III) therein and allowing it to stand. . Whether acid (or acid) is appropriate or basic (or basic) is appropriate for this reaction. For example, compound (III) and (iii) can be easily distinguished using a thin layer chromatogram. By observing the situation where (Ⅸ) is produced by thin layer chromatography in contact with the above-described acid or base, it is possible to accurately screen the reaction conditions of the acid and the base and other reactions.

In addition, some of the compounds (III) are very likely to be closed, and may be closed by the reaction conditions applied to the above-described production step itself. In such a case, (III) is not isolated, and (iii) is generated only by the synthesis conditions. The obtained 7- [2- (2-isosubstituted-4-thiazolin-4-yl) acetamide] cephalosporin derivative may be a known means, for example, solvent extraction, liquid conversion, conversion, distillation, Isolation and purification can be carried out by crystallization, recrystallization, chromatography, de-esterification, and the like. In addition, 7- (4-thio-dicyano-3-oxo-butyryl amide) - cephalosporin derivatives (Ⅳ) has the general formula H ₂ X '(X' represented by the water are the same as above) (Ⅴ) What is necessary is just to react with hydrogen sulfide or an amine. The mode of presence of (IV), the type of solvent, acid and base, the method of selecting the reaction conditions, the reaction conditions, and the method of isolating the product are all based on the conversion from (III) to (iii).

In addition, a cephalosporin derivative (VIII) is manufactured by reaction of a 7-amino- cephalosporin derivative (XI) with a carboxylic acid compound (XII). This reaction can proceed chemically or enzymatically. In the reaction, the amino compound (XI) has a carboxyl group on the fourth position, for example, a salt such as alkali, alkaline earth, organic amine, such as sodium, potassium, magnesium, calcium, aluminum, triethylamine, or 2-methyl, for example. Alkali, acid and enzyme treatment of sulfonylethyl, trimethylsilyl, dimethylsilenyl, benzhydryl, 2,2,2-trichloroethyl, phenacyl, P-methoxybenzyl, P-nitrobenzyl and methoxymethyl It also includes the case where it can be induced easily by free carboxyl group by reduction etc., or it is an ester etc. which show activity in a living body as it is. Carbonic acid (XII) is used as a free phosphor or as a reactive derivative thereof. That is, it is provided to an acylation reaction as a free acid or a salt with sodium, potassium, calcium, trimethylamine, pyridine or the like, or as a derivative of an acid halide, an acid anhydride, a mixed acid anhydride, an active amide, an ester or the like. As the activating ester, for example, P-nitrophenylaceter, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinoimide ester or N-hydroxyphthalimide ester is used. As the mixed acid anhydride, a mixed anhydride with carbonate monoesters such as monomethyl carbonate and monoisobutyl carbonate, and a lower anhydride which may be substituted with halogen such as pivalic acid or trichloroacetic acid are used.

When carbonic acid (XII) is used in the form of a free acid or salt, a suitable condensing agent is used, and as the condensing agent, for example, N, N'-disubstituted carbodiimide such as NN'-dicyclohexyl carbodiimide Azolite compounds such as Drew, N, N'-carbonylimidazole, N, N'-thionylimidazole, N-ethoxycarbonyl-2-ethoxy-1,2, -dihydrokinolin And dehydrating agents such as phosphorus oxychloride and alkoxyacetylene are used. When these condensing agents are used, it is thought that reaction proceeds through the reactive derivative of carboxylic acid.

This reaction can usually be carried out freely and smoothly in a solvent. Examples of the solvent include water, acetone, diisobutyl ketone, tetrahydrofuran, ethyl acetate, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, pyridine, dimethylaniline, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. General solvents or mixtures thereof are used as long as the reaction of the present invention is not inhibited. The reaction temperature is not particularly limited but is usually carried out under cooling to room temperature. When the reaction proceeds deoxidatively, base is coexisted as necessary. Bases used here include aliphatic, aromatic or heterocyclic nitrogen bases or carbonic acid or bicarbonate alkali metal salts such as triethylamine, N, N-dimethylaniline, N-ethylmorpholine, pyridine, collidine, 2,6-ruti Dean, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate are often used. When the acylation reaction 3 mainly uses dehydration reaction, it goes without saying that water is preferably removed from the solvent. In some cases, moisture may be avoided and organized in an inert gas such as nitrogen.

The cephalosporin derivative obtained is subjected to its own known deprotecting group operation if necessary, and then isolated and purified by known means such as solvent extraction, liquid conversion, distillation, distillation, crystallization, recrystallization, and chromatography. When the imino group in the starting compound (XII) is protected in the form of protonated with an acid, the free imino body in (i) is easily obtained in the purification process or only by controlling the liquid. When the imino group is protected with an acyl group, known deacylation treatments suitable for the acyl group, for example, formyl, amyloxycarbonyl, and t-butoxycarbonyl groups are acid treated, 2,2,2. Trichloro ethoxycarbonyl, benzyloxycarbonyl and paranitrobenzyl oxycarbonyl groups are subjected to reduction treatment and 2-methylsulfonylethoxy carbonyl groups are subjected to alkali treatment, respectively. The furnace body is obtained. The amino compound (XI) and carboxylic acid (XII) can be carried out using an enzyme which produces microorganisms such as microorganisms, cultures thereof, or processed products thereof. In this case, for example, the method of Belken Patent No. 781,562 It can be carried out according to.

The target compound (I) is a 7- [2- (2-exosubstituted-4-thiazolin-4-yl) acetamide] -3-acetoxymethyl- cephalosporin derivative (III) and a nitrogen-containing disulfide thiol ( It is prepared by reacting iii). In this reaction, the compound (i) may be used in the form of glass, or may be a salt with a base, for example, an organic amine salt with sodium, potassium or the like. Nitrogen-containing heterocyclic thiols are, for example, (1) heterocycles. Chapter 5 of Chemistry (AR Katrik and JM Gorosquiser, John Willie & Sons, 1960) or Organic Chemistry (Kodai Munio Supervision, Asagura Bookstore), vol. 15, etc. It manufactures according to the method well-known by itself, or (2) It manufactures by chemical conversion by the well-known method of the disulfide ring thiol obtained by the known document or the method of said (1). The nitrogen-containing bicyclic ring thiol to be used is provided to reaction as a salt with alkali metals, such as lithium, sodium, or potassium in a free or thiol group. This reaction is usually carried out by heating from about 40 ° C to about 80 ° C near neutral. The reaction is carried out in a solvent, and an aqueous solvent such as a mixed solvent of water or a polar solvent which does not participate in the reaction of water and acetone, tetrahydrofuran, dimethylformamide, methanol, ethanol or dimethyl sulfoxide, etc. Well used When (iii) is used in a glass state, it is sometimes desirable to add a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate to the reaction system to correct the liquidity to neutrality. Moreover, you may use a buffer solution as needed.

The reaction time and other reaction conditions may be appropriately determined depending on the raw material solvent and temperature to be used. The obtained 7- [2- (2-exosubstituted-4-thiazolin-4-yl) acetamide] -cephalosporin derivative (I) can be isolated and purified by using the above known means.

In addition, Compound (I) produced by the method of the present invention, when R ₁ is a hydrogen atom, are two kinds of mutant isomers by isomerization (automerization) as shown in the following formulas, respectively. ) Structure (automatic. Foam).

를 표시한다 다른 기호는 상기와 동일하다)(Wherein Z is

Other symbols are the same as above)

Which form of this type of compound is present depends on its structure, the present conditions, and the like. In the literature, any compound in which X is an oxygen atom or a sulfur atom is known as thiazolin. Foams (R. Dahlboom, S. Gronoowitz and B. Mathiasson, Acta Chem. Scand. 17,2479 (1963) and B. Ellis and PJF Griffiths, Spectrochimica Acta, 222, 2005 (1966), while Examples of compounds in which X is an amino group take thiazolinfoam (GJ Kruger and G. Gafner Acta Cryst B27,326 (1971) and JM Vandndendbelt and Vandenbelt 66, 1633 (1944) also take thiazole.foam). Examples (LM werbel, Chen SInd 1966, 1634) can also be found.

However, the compound (I) of the present invention when R ¹ is a hydrogen atom is as shown in the following formula.

(Symbols in the formula are the same as above)

Since the thiazolin foam is stabilized by the contribution of hydrogen bonds, it is not only the case where X is an oxygen atom or a sulfur atom, but also the imino group, even if it is hard, even if it is hard, It seems to catch. However, this equilibrium relationship is greatly changed depending on the re-state in which compound (I) is placed, for example, the liquidity of the solvent, the polarity of the solvent, the temperature, the type of the substituent, and the like, and may sometimes be reversed. Therefore, the compound (I) may be named by any foam. In abstract, thiazolin is the name of the compound when X is an oxygen atom or a sulfur atom. Since the compound of the case where X is an imino group is named thiazoline and a foam, the compound I of this invention is named based on this.

The cephalosporin derivative (I) obtained by the method of the present invention may be used as a free carboxyl group, but non-toxic cations such as sodium and potassium, arginine, ornithine, ridine, histidine, and the like. You may use it, forming salt with polyhydroxyalkylamine, such as basic amino acid, N-methylglucamine, diethanolamine, triethanolamine, and trishydroxymethylamino methane. Moreover, these carboxyl groups of the 4th position can be esterified, for example, can be converted into biologically active ester derivatives which have the effect of increasing blood concentration and extending the effective time. As an effective ester group in that case, For example, alpha-alkoxy-, such as alkoxymethyl, such as methoxymethyl, ethoxymethyl, isopropoxymethyl, (alpha)-methoxyethyl, and (alpha)-ethoxyethyl, and (alpha) -alkoxyethyl- Alkylthiomethyl groups, such as (alpha)-substituted methyl group, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, acyloxymethyl groups, such as pivaloyloxymethyl and (alpha)-acetoxybutyl, or (alpha)-acyloxy- (alpha)-substituted methyl group Etc. are used.

The 7- [2- (2-exosubstituted-4-thiazolin-4-yl) acetamide] -cephalosporin derivative (I) thus obtained has a broad and strong antimicrobial spectrum against Gram-negative bacteria and Gram-positive bacteria, in particular Gram-negative bacteria Escherichia. collie. Klebsiela. To pneumoniae, proteus. Brugaris and Proteus. The bacterium of Morganium and the like has stronger antibacterial activity than known cephalosporins, so it is used for the treatment of infections caused by these bacteria in humans and animals and shows excellent therapeutic effect. In addition, among the heterocyclic substituents described above in the object (I) of the present invention, a substituent having a strong electron-absorbing property in general has a high fat solubility in an antibacterial activity, and a group which is easily hydrolyzed in vivo can be obtained by oral administration. In the absorption, the carboxyl group which is basic and the cephmyl ring fourth position, and the substituent which makes intramolecular ion pair reduce the pain at the time of parenteral administration, and the high hydrophilic substituent brings about a desirable characteristic in metabolic efficiency, respectively. Therefore, compared with known cephalosporins, the objective (I) of this invention which introduce | transduced these substituents has the outstanding characteristic in terms of antibacterial activity, body absorption rate, local action (pain, etc.), and low toxicity, respectively. The object (I) of the present invention can be administered as a solution or suspension together with a known cephalosporin agent, for example, by administration of powder or with a carrier or excipient which can be used physiologically according to a conventional method. Specifically, for example, in the treatment of the above-described bacterial infectious diseases, purulent diseases, respiratory infections, biliary tract infections, intestinal infections, urinary tract infections and obstetrics and gynecological infections in humans, 7- [2- (2 -Aminothiazol-4-yl) acetamide] -3- [2- (2-hydroxy itylthio) -1,3,4-thiadiazol-5-yl] thiomethyl-3-cepem-4- Sodium carbonate, 7- [2- (2-aminothiazol-4-yl) acetamide) -3- [2- (N, N-dimethylcarbamoylmethyl) -1,3,4-thiadiazole- 5-yl] thiomethyl-3-cepem-4-carboxylate, 7- [2- (2-aminothiazol-4-yl) acetamide] -3- [2- (2-acetoxyethylthio) -1,3,4-thiadiazol-5-yl] thiomethyl-3-cepem-4-carboxylic acid sodium, 7- [2- (2-aminothiazol-4-yl) acetamide] -3- (2-carboxymethylthio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-dicarboxylate, 7- [2- (2-aminothiazol-4-yl) Acetadad] -3- (2-carbamoylmethyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cepem- 4-sodium carboxylate, 7- [2- (2-aminothiazol-4-yl) acetamide] -3- (1-carbamoylmethyl-1H-tetrazol-5-yl) thiomethyl-3-cepem Sodium 4-carboxylate and 7- [2- (2-aminothiazol-4-yl) acetamide-3- (4-carboxymethylthiazol-2-yl) thiomethyl-3-cepem-4-carbon It is good to administer about 5-20mg of sodium disodium 3 times divided into 3-4 times a day.

Next, the present invention will be described by way of examples.

In addition, the NAR spectrum is measured by Varian HA100 type (100 MHz) or T60 type (60 MHz), and the δ value is expressed in ppm based on tetramethylsilane.

Where s is the singlet, d is the doublet, t is the triplet, f is the quadruple, m is the multiplet, and j is the coupling constant.

Reference Example 1

Preparation of 2-methylsulfonylmethyl-1,3,4-thiadiazole-5-thiol:

(1) A 30 ml solution of 4.9 g of potassium hydroxide methanol was ice-cooled and stirred, and 12.5 g of methylsulfonylacetylhydrazide and 5.3 ml of carbon disulfide were added thereto, followed by stirring for 30 minutes at room temperature under cooling. Methanol was distilled off under reduced pressure, and ethanol was added to the residue to disintegrate to obtain a crystalline powder, which was filtered and dried to obtain 20.39 g of potassium 3- (methylsulfonylacetyl) dithiocarbate.

(2) A mixture obtained by dissolving 8.0 g of 3- (methylsulfonylacetyl) dithiocarbamate in 40 ml of ice-cold concentrated sulfuric acid was stirred for 10 minutes under ice-cooling, poured into 150 g of ice, and the crystals precipitated. The crystals were filtered off, washed with cold water and dried to obtain the title compound.

Yield 2.29 g.

Condensation 204-206 ° C (decomposition)

IR (cm ^-1 chinuzol) 1315, 1139.

NMR (100 MHz, in d ₆ -DMSO) ε3.08 (S, CH ₃ ), 4.56 (Broad, s, SH), 4,89 (s, CH ₂ ).

Elemental Analysis: For C ₄ H ₆ N ₂ O ₂ S ₃

Theoretical C, 22.84 H, 2.88 N, 13.32

Found C, 22.97 H, 2.85 N, 13.18

Reference Example 2

In the same manner as in Reference Example 1 above, for example, the following 2-substituted-1,3,4-thiadiazole-5-thiol was prepared from the corresponding 2-substituted acetylhydrazide.

(1) 2-methylthiomethyl-1,3,4-thiadiazole-5-thiol.

Dew point 105-107 ° C. (recrystallized from ethyl acetate).

MNR (in 60 MAz, CDC / 3) δ 2.14 (S, CH ₃ ), 4.01 (S, cH ₂ ).

(2) 2-carbamoylmethyl-1,3,4-thiadiazole-5-thiol.

Condensation point 179-182 ° C (decomposition) (recrystallized from ethanol)

NMR (60 MHz), in d ₆ -DMSO, δ 3.72 (s, CH ₂ ), 7.14 and 7.64 (s, ConH ₂ ), 14.22 (broad s, NHN).

(3) 2methoxycarbonylmethyl-1,3,4-thiadiazole-5-thiol.

Melting point 79-80 ° C. (crystallized from benzene).

NMR (60 MHz), in d ₆ -DMSO, δ 3.67 (S, CH ₂ ), 3.36 and 14.35 (S, dog 1H, SH each).

(4) 2-carboxymethyl-1,3,4-thiadiazole-5-thiol.

Dew point 166-168 ° C. (decomposition) (recrystallized from ethyl benzene).

NMR (60 MHz in d ₆ -DMSO) δ 3.90 (S, CH ₂ ), 6.32 (broad, s, SH and CO ₂ H).

(5) 2-borolinomethyl-1,3,4-thiadiazole-5-thiol.

NMR (at 60 MHz, CDC / 3) δ 2.5-2.7 (CH ₂ NCH ₂ ), 3.72 (s, CH ₂ -morpholino), 3.7-3.9 (CH ₂ OCH ₂ ), 11.6 (Broad s, HN— N =).

(6) 2-N, N-dimethylcarbamoylmethyl-1,3,4-thiadiazole-5-thiol

IR (cm ^-1 inch KBr); 1633.

NMR (60 MHz in c ₆ -DMSO); δ 2.85 and 3.01 (each s, 2 × CH ₃ ), 4.05 (s, CH ₂ ).

Reference Example 3

Preparation of 2- (2-hydroxyethylamino) -1,3,4-thiadiazole-5-thiol:

(1) A 25 ml solution of 12.2 g of dithiocarbadic acid ester and 18.3 g of 2-aminoethanol was heated to 95 ° C. for 5 hours. After cooling, 10 ml of acetic acid was added to the reaction solution, and crystals precipitated when left overnight in the refrigerator. When this was filtered and dried, 2.85 g of 4- (2-hydroxyethyl) thiosemicarbazide was obtained.

(2) A mixture of 1.35 g of 4- (2-hydroxyethyl) thiosemicarbazide, 2.14 g of carbon disulfide and 20 ml of pyridine was heated to reflux for 5 hours with stirring.

The mixed solution was solid under reduced pressure, and water was added to the residue to precipitate crystals.

This crystal was filtered to give the titled compound.

Quantity 1.35 g

NMR (in 60 MHz, d ₆ -DMSO) δ 3.19 (t, CH ₂ ), 3.46 (t, CH ₂ ), 7.33 (broad s, CH).

Reference Example 4

In the same manner as in Reference Example 3, for example, the following 2-substituted alkylamino-1,3,4-thiadiazole-5-thiol was prepared from the corresponding substituted alkylamine.

(1) 2- (2-dimethylaminoethylamido) -1,3,4-thiadiazole-5-thiol.

NMR (in 60 MHz, d ₆ -DMSO) δ 2.90 (s, 2XCH ₃ ), 3.40 (t, CH ₂ ), 4.28 (t, CH ₂ ).

(2) 2- (2-sulfoethylamino) -1,3,4-thiadiazole-5-thiol.

IR (cm ^-1 inch KBr) 1210, 1170, 1050.

NMR (60 MHz in heavy water) δ 3.17 (t, CH ₂ ), 3.78 (t, CH ₂ ).

Reference Example 5

Preparation of 2- (2-hydroxyethylthio) -1,3,4-thiadiazole-5-thiol:

3.0 g of 1,3,4-thiadiazole-2,5-dithiol was ice-cooled stirred in a 22 ml solution of 1N sodium hydroxide, and 2.5 g of ethylene bromhydrin was added dropwise. The mixed solution was allowed to stand at room temperature overnight to precipitate pale yellow needles. The resultant was filtered off and dried to obtain the title compound.

Quantity 3.0g.

Melting point 112-113 ℃

IR (cm ^-1 inch KBr) 1500, 1280, 1055.

NMR (in 60 MHz, NaHCO ₃ -D ₂ O); δ 3.50 (t, CH ₂ ), 4.60

Reference Example 6

In the same manner as in Reference Example 5, by the reaction of the corresponding substituted alkyl halogenide and 1,3,4-thiadiazole-2,5-dithiol, for example, the following disubstituted alkylthio- 1,3,4-VII; adiazole-5-thiol was prepared.

(1) 2- (2-sulfoethylthio) -1,3,4-thiadiazole-5-thiol

IR (cm ^-1 inch KBr) 1190, 1040.

NMR (60 MHz in heavy water); δ 3.45 (S, ₂ × CH ₂ ).

(2) 2-carbamoylmethylthio-1,3,4-thiadiazole-5-thiol

IR (cm ^-1 inch KBr) 1685.

NMR (60 MHz in d6-DMSO); δ3.83 (S, CH ₂ ), 7.14 and 7.50 (each Broad S, CONH ₂ ).

(3) 2-acetylmethylthio-1,3,4-thiadiazole-5-thiol

NMR (in 60 MHz, d5-DMOS); δ 2.20 (S, CH ₃ ), 4.20 (S, CH ₂ ).

(4) 2- (2-acetoxyethylthio) -1,3,4-thiadiazole-5-thiol

IR (cm <^-1> KBr) 1702.

NMR (in 60 MHz, d 6 -DMSO); δ 2.00 (S, CH ₃ ), 3.38 (t, CH ₂ ), 4.24 (t, CH ₂ ).

(5) 2-ethoxycarbonylmethylthio-1,3,4-thiadiazole-5-thiol

IR (cm ^-1 inch KBr) 1705.

NMR (in 60 MHz, NaCHO ₃ -D ₂ O); δ 1.21 (t, CH ₃ ), 4.10 (q, CH ₂ D).

(6) 2- (2-dimethylaminoethylthio) -1,3,4-thiadiazole-5-thiol

NMR (60 MHz in heavy water); δ 2.27 (S, 2XCH ₃ ), 2.68 (t, CH ₂ ), 3.26 (t, CH ₂ ).

(7) 2- (2-benzoyloxyethylthio) -1,3,4-thiadiazole-5-thiol

NMR (in 60 MHz, CCCl ₃ ); δ 3.47 (t, CH ₂ ), 4.59 (t, CH ₂ ), 7.45 and 7.88-8.00 (m, C ₆ H ₅ ).

Reference Example 7

Preparation of 7- [2- (2-oxo-4-thiazolin-4-yl) acetamide] -3-acetoxymethyl-3- cefe-4-carboxylic acid:

(1) A 10 ml solution of 4.4 g of methylene chloride of diketene was cooled to −35 ° C., and 3.92 g of chlorine was introduced thereto, followed by stirring for 15 minutes. Separately, 10.9 g of 7-aminocephalosporinic acid and 8.1 g of triethylamine were dissolved in 100 ml of methylene chloride, cooled to -30 ° C, and the reaction solution was added thereto while cooling and stirring not to exceed -30 ° C. . After 1 hour, the liquid temperature was gradually raised to room temperature, the solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the residue, which was mixed with 100 ml of 10% aqueous phosphate solution. The aqueous layer was taken, saturated with salt, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried, concentrated to 20 ml under reduced pressure, and left to cool. Crystals precipitated and were filtered. 7- (4-chloro-3-oxobutyrylamide)- 3-acetoxymethyl-3-cepem-4-carboxylic acid was obtained.

Quantity 6.3g

Melting Point 135-140 ° C (Decomposition)

IR (cm ^-1 inch KBr) 1790, 1750, 1650

NMR (in 100 MHz, d ₆ -DMSO); δ 2.00 (S, COCH ₃ ), 3.41 and 3.64 (ABq, J18 Hz, 2-CH ₂ ), 3.56 (S, COCH ₂ CO), 4.50 (S, ClCH ₂ ), 4.67 and 5.00 (ABq, J 13 Hz, 3-CH ₂ ), 5.07 (d, J 4.5 Hz, 6-H), 5.66 (dd, J 4.5 and 8 Hz, 7-H), 9.04 (d, J 8 Hz, CONH).

Elemental Analysis: for C ₁₄ H ₁₅ ClN ₂ O ₂ S

Theory C, 43.03; H, 3.87; N, 7.17.

Found: C, 43.01; H, 3.89; N, 7.18.

(2) 0.39 g (1 mmol) of 7- (4-chloro-3-oxobutyrylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid and rhodan potassium (1.5 mmol) in 10 ml of acetonitrile It dissolved and stirred for 16 hours at room temperature. The solvent was distilled off under reduced pressure, 10 ml of saturated brine was added to the residue, which was acidified with 50% phosphoric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried and depressurized to distill the solvent, and ether was added to the residue to disintegrate the residue. The powder was filtered off, resulting in 7- (4-thiocyano-3-oxobutyrylamide) -3. Acetoxymethyl-3-cepem-4-carboxylic acid was obtained.

Quantity 0.39 g

IR (cm ^-1 inches KB ₆ ) 2350 (CN), 1785, 1730.

NMR (in 100 MHz, d ₆ -DMSO); δ2.01 (S, COCH ₃ ), 3.42 and 3.66 (ABg, J 18 Hz, 2-CH ₂ ), 3.62 (S, COCH ₂ CO), 4.37 (S, SH ₂ CD), 4.68 and 5.00 (ABq, J 12 Hz, 3-CH ₂ ), 5.09 (d, J 4.5 Hz, 6-H), 5.67 (dd, J 4.5 and 8 Hz, 7H), 9.06 (d, J 8 Hz, CONH).

For _{C 15 H 15 N 3 O 7} S 2 · 0.5 (CH 5) 2 O: Elemental Analysis

Theory C, 43,11; H, 3.5 2; N, 9.50.

Found: C, 42.98; H, 3. 74; N, 9.44.

(3) 0.413 g of 7- (4-thiocyano-3-oxobutyrylamide) -3-acetoxymethyl-3-cepem-carboxylic acid and 0.084 g of sodium bicarbonate were dissolved in 5 ml of a phosphate buffer solution of PH 6.4, It was left for 2 days at room temperature. Aqueous solution of 50% phosphoric acid was added to the mixture to make 3.0. The mixture was saturated with sodium chloride and extracted with ethyl acetate (3x10). The ethyl acetate solution was washed with brine, dried, concentrated and ether. The resultant was filtered off with suction to obtain a compound of the title.

Quantity 0.18.

Melting Point 180 ℃

IR (cm ^-1 inches KBr) 1775, 1775, 1715, 1665.

UVλ max (ε value in 1% NaHCO ₃ water) 248 nm (1.14 × 10 ₄ ).

NMR (in 100 MHz, d ₆ -DMSO); δ2.01 (S, CH ₃ CO), 3.33 (S, CH ₂ CO ₂ ), 3.43 and 3.66 (ABq, J 18 Hz, 2-CH ₂ ), 4.69 and 5.00 (ABq, J 13 Hz, 3-CH ₂ ), 5.08 (d, J 4.5 Hz, 6-H), 5.69 (dd, J 4.5 and 8.0 Hz, 7-H), 6.00 (s, thiazolin 5- H), 8.96 (d, 8.0 Hz, CONH).

Elemental Analysis: For C ₁₅ H ₁₅ N ₃ O ₇ S ₂

Theory C, 43.58; H, 3. 66; N, 10.16.

Found: C, 43.37; H, 3. 48; N, 9.77.

Reference Example 8

Preparation of 7- [2- (2-aminothiazol-4-yl) acetamide-3-acetoxymethyl-3-cepem-4-carbonate sodium:

(1) A 10 g solution of 3.4 g of methylene chloride of diketene was cooled to -30 deg. C, and a dropwise 6.4 g of 10 ml solution of methylene chloride was added dropwise thereto. Separately, 10.9 g of 7-aminocephalosporinic acid and 8.1 g of triethylamine were dissolved in 100 ml of methylene chloride, and cooled to -30 ° C. The reaction solution was added thereto while cooling and stirring not to exceed -30 ° C. . After 1 hour, the liquid temperature was gradually raised to room temperature, the solvent was distilled off under reduced pressure, and 100 ml of ethyl acetate was added to the residue, which was vigorously shaken with 100 ml of 10% aqueous phosphate solution. The aqueous layer was taken, saturated with salt and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried, treated with activated charcoal, dried under reduced pressure, and left to stand by adding ether to the residue, which crystallized. The resultant was filtered off with suction and obtained 7- (4-bromo-3- Oxobutyrylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid was obtained.

Quantity 8g

IR (cm ^-1 inch KBr) 1780, 1735, 1650

NMR (in 100 MHz, d ₆ -DMSO); δ 2.01 (S, CH ₃ CO), 3.54 (m, 2-CH ₂ ), 3.62 (S, COCH ₂ ), 4.37 (S, BrCH ₂ Co), 4.67 And 5.01 (ABq, J 14 Hz, 3-CH ₂ ), 5.08 (d, J 4 Hz, 6-H), 5.66 (dd, J 4 and 8 Hz, 7-H), 9.04 (d, J 8 Hz , CONH).

Elemental analysis: for C ₁₄ H ₁₅ BrN ₂ O ₇ S · 4/1 C ₄ H ₈ O ₂

Theory C, 39.40; H, 3.75; N, 6.13.

Found: C, 39.20; H, 3.63; N, 6.09.

(2) 0.442 g of thiouroxo and 0.88 g of sodium bicarbonate were dissolved in a mixture of 53 ml of water and 26.4 ml of tetrahydrofuran, and 7- (4-bromo-3-oxobutyrylamide) -3-acetoxy was added thereto. 2.3 g of methyl-3-cepem-4-carboxylic acid was slowly added to dissolve and stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, the tetrahydrofuran was distilled off, and the whole amount was further concentrated to 20 ml. The residue was loaded with column chromatography of polystyrene resin (Anbarite XAD-2) and water.

Fractions containing the desired product were collected and freeze-dried to obtain the title compound.

Quantity 1.305 g (52.6% of yield)

IR (cm ^-1 inch KBr) 1767.

UV ² max (ε value in water) 256 nm (1.35 × 10 ⁴ ).

NMR (100 MHz, Underwater); δ 2.15 (S, CH ₃ CO), 3.39 and 3.69 (ABq, J 18 Hz, 2-CH ₂ ), 3.62 (S, CH ₂ CO), 4.75 and 4.94 (ABq, J 13 Hz, 3-CH ₂ ), 5.15 (d, J 5 Hz, 6-H), 7.71 (d, J 5 Hz, 7H), 5.52 (S, thiazole 5-H).

Elemental Analysis: For C ₁₅ H ₁₅ N ₄ O ₆ S ₂ Na · 2H ₂ O

Theory C, 38.29; H, 4.07; N, 11.91.

Found: C, 38.41; H, 3. 90; N, 11.72.

Reference Example 9

Preparation of 7- [2- (2-aminothiazol-4-yl) acetamide-3-acetoxymethyl-3-cepem-4-carboxylic acid:

0.602 g of thioxo and 0.664 g of sodium bicarbonate were dissolved in a mixture of 80 ml of water and 40 ml of tetrahydrofuran, and 7- (4-chloro-3-oxobutylamide) -3-acetoxymethyl-3-cefem- was added thereto. 3.085 g of 4-carboxylic acids were slowly added to dissolve and stirred at room temperature for 1 hour. Tetrahydrofuran was distilled off under latent pressure, and the crystal | crystallization precipitated when the residue was left to stand at room temperature. The crystals were filtered off, and the filtrate was concentrated and left again to precipitate crystals. This crystal was filtered off and combined with the previous crystal to obtain 2.703 g (yield 83%) of the title compound.

IR (cm <^-1> KBr) 1776.

UVλ max (ε value in water) 256 nm (1.35 × 10 ₄ ).

NMR (in 100 MHz, d ₆ -DMSO); δ2.01 (S, CH ₃ CO), 3.38 (S, CH ₂ CO), 3.40 and 3.63 (ABq, J 18 Hz, 2-CH ₂ ), 4.68 and 4.98 (ABq, J 13 Hz, 3-CH ₂ ), 5.06 (d, J 5 Hz, 6-H), 5.68 (dd, J 5 and 8 Hz, 7-H), 6.23 (S, thiazole 5-H ), 6,90 (broad S, NH ₂ ), 8.82 (d, J 8 Hz, CONH), 9.20 (broad S, COOH).

Example 1

Preparation of 7- [2- (2-exosubstituted-4-thiazolin-4-yl) acetamide] -3-nitrogen-containing heterocyclic thiomethyl-3-cepem-4-carboxylic acid [I] or salts thereof:

The typical physical properties produced by the method of the following Production Method 1-4 are shown in Tables 1-8.

[Preparation 1]

0.824 g of 7- [2- (2-aminothiazol-4-yl) acetamide] -3-acetoxymethyl-3-cepem-4-carboxylic acid (reference example 9,2 mmol), nitrogen-containing monocyclic thiol (2.2 mmol) and 0.336 g (4 mmol) of sodium hydrogen carbonate are dissolved in 8 ml of water. If it is not a homogeneous solution, 4 ml of tetrahydrofuran is added thereto, and the mixture is heated to 60-65 ° C. to 6-8. Stirred for time. After cooling, tetrahydrofuran was distilled off under reduced pressure, and the residue was added to column chromatography of polystyrene resin (Anbarite XAD-2), and continuous elution from water to 40% methanol was performed. The indicated compound, 7- [2- (2-aminothiazol-4-yl) acetamide] -3-nitrogen heterocyclic thiomethyl-3-cefem- Sodium 4-carbonate was obtained.

0.824 g of 7- [2- (2-aminothiazol-4-yl) acetamide] -3-acetoxymethyl-3-cepem-4-carboxylic acid (reference example 9,2 mmol), nitrogen-containing monocyclic thiol (2.2 mmol) and 0.336 g (4 mmol) of sodium hydrogen carbonate were dissolved in 40 ml of a phosphate buffer solution at pH 6.4, which was warmed to 60-65 ° C. and stirred for 7-8 hours. The reaction solution was concentrated to about 20 ml under reduced pressure, which was poured into column chromatography of polystyrene resin (Anbarite XAD-2) and developed sequentially with water, 5% ethanol and 10% ethanol. The resultant compound, 7- [2- (2-aminothiazol-4-yl) acetamide] -3-nitrogen heterocyclic thiomethyl-3-cepem-4, was collected by lyophilization of the fractions containing the desired product. Sodium carbonate was obtained.

[Process 3]

0.824 g of 7- [2- (2-aminothiazol-4-yl) acetamide] -3-acetoxymethyl-3-cepem-4-carboxylic acid (reference example 9,2 mmol), 2- (2- A mixture of 0.596 g (2 mmol) of benzoyloxyethylthio) -1,2,4-thiadiazole-5-thiol, 0.336 g (4 mmol) of sodium bicarbonate, 5 ml of tetrahydrofuran and 10 ml of water was heated to 65 ° C. Warmed for 5 hours. It was dried under reduced pressure, and the solution obtained by dissolving the residue in 4 ml of acetonitrile was poured into silica gel column chromatography and developed with 5% aqueous acetonitrile and then 15% aqueous acetonitrile. Crystals precipitated when the fractions containing the desired product were collected and concentrated. The compound of interest, which was filtered off with suction, 7- [2- (2-aminothiazol-4-yl) acetamide] -3-2- (2-benzoyloxyethylthio) -1,3,4-thiadia Sol-5-yl] 0.43 g of thiomethyl-3-cepem-4-carboxylic acid was obtained.

[Process 4]

0.974 g of 7- [2- (2-oxo-4-thiazolin-4-yl) acetamide] -3-acetoxymethyl-3-cepem-4-carboxylic acid (reference example 7,2 mmol), nitrogen-containing The mixed solution obtained by dissolving a cyclic ring thiol (1.1 mmol) and 0.336 g (4 mmol) of sodium bicarbonate in 8 ml of water and 4 ml of tetrahydrofuran was heated to 60-65 ° C. and stirred for 6-8 hours. After cooling, the reaction solution was adjusted to pH 3.0 with phosphoric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, concentrated to dryness under reduced pressure, and the residue was decomposed with ether, 7- [2- (2-oxo-4-thiazolin-4-yl) acetamide]- 3-Nitrogen heterocyclic thiomethyl-3-cepem-4-carboxylic acid was obtained as a powder.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

Regarding the cephalosporin derivatives prepared according to the present invention, the results of the measurement of the lowest growth inhibition concentration of various bacteria and the measurement of preliminary treatment effects on infected mice are as follows.

(a) Determination of minimum growth inhibition concentration (Table 9)

[Table 9]

(b) Determination of preliminary treatment effects on infected mice

(Table 10-12)

Test animal: 5 identical male ICR / SLC reagents / group

Infection method: Intraperitoneal Escherichia coli 0-111

Reagent: 1 dose immediately after infection: Observation period: 7 days

[Table 10]

[Table 11]

[Table 12]

EXAMPLE

Preparation of 7-2- (2-oxo-4-thiazolin-4-yl) acetamide-3- (1-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid:

0.678 of 7- (4-thiocyano-3-oxobutythylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid and 0.116 g of sodium bicarbonate were dissolved in 27 ml of phosphate buffer solution at pH6.4, It was left one night. 0.1685 of 1-methyltetrazole-5-thiol was added to this mixed solution, and it heated at 56-59 degreeC and stirred for 8 hours. After cooling, an aqueous 50% phosphoric acid solution was added to make acid, and extracted with ethyl acetate (3 x 20 ml). The ethyl acetate extract was washed with water, dried, concentrated and left to crystallize. This crystal was filtered to give the titled compound. This product contains 1 molecule of ethyl acetate as a crystalline solvent.

Quantity 0.25g

Melting Point 107 ° C (Decomposition)

IR (cm ⁻¹ KBr) 1785, 1730, 1660.UVλ max (ε value in ethanol) 244 nm (1.22 × 10 ⁴ )

NMR (δ value in d ₆ -DMSO) 3.34 (S, CH ₂ CO), 3.70 (m, 2-CH ₂ ), 3.92 (S, tetrazole-CH ₃ ), 4.30 (m, 3-H ₂ ), 5.07 (b, J 5 Hz, 6-H), 5.68 (dd, J 5 8 Hz, 7-H), 6.01 (S, thiazolin 5-H), 8.98 (d, J 8 Hz, CONH).

Elemental Analysis: for C ₁₅ H ₁₅ N ₇ O ₅ S ₃ , CH ₃ COOC ₂ H ₅

Theoretical: C, 40.92; H, 4.16; N, 17.57

Found: C, 40.51; H, 4.00; N, 16.61

Antibacterial Spectrum (mcg / ml, Agar Dilution Method)

Example 3

Of 7-2- (2-oxo-4-thiazolin-4-yl) acetamide-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid Produce :

0.487 g of 7- (4-thiocyano-3-oxobutyrylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid and 0.084 g of sodium bicarbonate were mixed with 20 ml of phosphate buffer solution of pH6.4 and tetrahydro It was dissolved in a mixture of furan 2.5ml and left overnight. 0.13 g of 1,3,4-thiadiazole-2-thiol and 0.084 g of sodium bicarbonate were added to the mixed solution, and the mixture was heated to 58 ° C and stirred for 16 hours. After cooling, a 50% aqueous solution of phosphoric acid was added to make acid, and the mixture was extracted with activated carbon and extracted with ethyl acetate (2 x 20 ml). The ethyl acetate extract was washed with water, dried, concentrated under reduced pressure and left to crystallize. The resultant was filtered off with suction to obtain the compound shown. This product contains 1 molecule of ethyl acetate and 1 water each as a crystalline solvent.

Quantity 0.1g

Melting Point 122-140 ° C (Decomposition)

IR (cm ^-1 inch KBr) 1780, 1650, 1535.

NMR (δ value in d ₆ -DMSO) 3.33 (S, CH ₂ CO), 3.69 (m, 2-CH ₂ ), 4.29 and 4.5 (ABq, J14 Hz, 3-CH ₂ ), 5.07 (d, J4.5 Hz , 6-H), 5.68 (dd, J4.5 and 8 Hz, 7-H), 8.98 (d, J8 Hz, CONH), 9.50 (S, thiadiazole 5-H).

Elemental Analysis: For C ₁₅ H ₁₃ N ₅ O ₅ S ₄ .CH ₃ COOC ₂ H ₅ · H ₂ O

This launch: C, 39.50; H, 4.01; N, 12.12

Found: C, 39.25; H, 3.15; N, 11.74

Antibacterial Spectrum (mcf / ml, Agar Dilution Method)

Example 4

7-2- (2-oxo-4-thiazolin-4-yl) acetamide-3- (5-methyl-1,3,4-oxathiazol-2-yl) thiomethyl-3-cepem-4 Preparation of carbonic acid:

0.487 g of 7- (4-thiocyano-3-oxobutyrylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid and 0.084 g of sodium bicarbonate were mixed with 20 ml of phosphate buffer solution of pH 6.4 and tetrahydrofuran. It was dissolved in 2.5 ml of the mixed solution and left for 1 night. 0.13 g of 5-methyl-1,3,4-oxadiazole-2-thiol and 0.084 g of sodium hydrogen carbonate were added to the mixed solution, and the mixture was heated to 58 ° C and stirred for 7 hours. After cooling, an aqueous 50% phosphoric acid solution was added to make acid, and extracted with ethyl acetate (2 x 20 ml). The ethyl acetate extract was washed with water, dried, concentrated under reduced pressure, and left to crystallize. The resultant was filtered off with suction to obtain a compound of the title. This product contains ethyl acetate and water / molecule each as a crystalline solvent.

Quantity 0.1g

Melting Point 122-140 ° C (Decomposition)

IR (cm ^-1 inch KBr) 1784.

NMR (δ value in d ₆ -DMSO) 2.44 (S, oxadiazole-CH ₃ ), 3.32 (S, CH ₂ CO), 3.54 and 3.78 (ABq, J18 Hz, 2-CH ₂ ), 4.13 | 4.36 (ABq, I14 Hz, 3-CH ₂ ), 5.06 (d, J4.5 Hz, 6-H), 5.66 (m, 7-H), 6.00 (S, thiazolin 5-H), 8.98 (d, J9 Hz , CONH).

Elemental Analysis: For C ₄ H ₁₅ N ₅ O ₆ S ₃ , CH ₃ COOC ₂ H ₅ , H ₂ O

This theory: C, 41.72; H, 4.38; N, 12.17.

Found: C, 41.40; H, 3.71; N, 12.04.

Example 5

7-2- (2-oxo-4-thiazolin-4-yl) acetamide-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4 Preparation of carbonic acid:

0.417 g of 7- (4-thiocyano-3-oxobutyrylamide) -3-acetoxymethyl-3-cepem-4-carboxylic acid and 0.084 g of sodium hydrogencarbonate were dissolved in 20 ml of phosphate buffer solution at pH 6.4 and 1 I left it.

0.145 g of 5-methyl-1,3,4-thiadiazole-2-thiol and 0.084 g of sodium bicarbonate were added to the mixed solution, and the mixture was heated to 60 ° C and stirred for 6.5 hours. After cooling, an aqueous 50% phosphoric acid solution was added to make acidic, saturated with salt, and the reaction solution was extracted with a mixture of ethyl acetate and tetrahydrofuran (2: 1) (3 x 20 ml). The extract was washed with saturated brine, dried and concentrated to allow crystals to precipitate. Filtration of this gave 0232 g (yield 49%) of the title compound.

IR (cm ^-1 inch KBr) 1786, 1655.

NMR (δ in d ₆ -DMSO) 2.63 (S, thiadiazole 5-CH), 3.30 (S, CH ₂ CO), 3.53 and 3.77 (ABq, J 18.0 Hz, 2-CH ₂ ), 4.18 and 4.49 (ABq, J14.0 Hz, 3-CH ₂ ), 5.04 (d, J5.0 Hz, 6-H), 5.65 (dd, J5.0 and 8.0 Hz, 7-H), 5.98 (S, thiazolin 5- H), 8.94 (d, J8.0 Hz, CONH).

Example 6

Preparation of 7-2- (2-aminothiazol-4-yl) acetamide-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepem-4-carbonate

0.47 g of 7-2- (2-aminothiazol-4-yl) acetamide-3-acetoxymethyl-3-cepem-4-carboxylic acid and 0.14 1,3,4-thiadiazole-2-thiol g was dissolved in 20 ml of a phosphate buffer solution of pH 6.4, which was warmed to 55-60 ° C. and stirred for 15 hours. After cooling, 0.084 g of sodium hydrogen carbonate was added to the reaction solution, which was then poured into column chromatography of polystyrene resin (Anbarite XAD-2) and developed with water. The fractions containing the desired product were collected and freeze-dried to obtain the title compound.

Quantity 0.096 g.

IR (cm ^-1 inch KBr) 1763.

UVλ max (ε value in water) 262 nm (1.57 × 10 ⁴ ).

NMR (medium value δ) 3.41 and 3.77 (ABq, J18 Hz, 2-CH ₂ ), 3.60 (S, CH ₂ CO), 4.09 and 4.54 (ABq, J13 Hz, 3-CH ₂ ), 5.08 (d, J5 Hz, 6-H), 5.65 (d, J 5 Hz, 7-H), 6.48 (S, thiazole 5-H).

Elemental Analysis: For C ₁₅ H ₁₃ N ₆ O ₄ S ₄ Na.3.5H ₂ O

This theory: C, 32.43; H, 3.63; N, 15.13.

Found: C, 32.32; H, 3.05; N, 14.36.

Antibacterial Spectrum (mcg / ml, Agar Dilution Method)

Example 7

Preparation of 7-2- (2-aminothiazol-4-yl) acetamide-3- (1-methyltetrazol-5-yl) thiomethyl-3-cefe-4-carboxylic acid sodium:

0.47 g of 7-2- (2-aminothiazol-4-yl) acetamide-3-acetoxymethyl-3-cepem-4-carbonate, 0.138 g of 1-methyltetrazol-5-thiol and hydrogen carbonate 0.084 g of sodium was dissolved in a pH 6.4 buffer solution, which was warmed to 50-55 ° C. and stirred for 16 hours. After cooling, the reaction solution was poured into column chromatography of polystyrene resin (Anbarite XAD-2) and developed with water. The fractions containing the desired product were collected and freeze-dried to obtain the title compound.

Quantity 0.173 g.

IR (cm ^-1 inch KBr) 1763.

UVλ max (ε value in water) 260 nm (1.48 × 10 ⁴ ).

NMR (medium value δ) 3.48 and 3.81 (ABq, J17 Hz, 2-CH ₂ ), 3.63 (S, CH ₂ CO), 5.06 (S, tetrazol 1-CH ₃ ), 4.09 and 4.37 (d, J14 Hz, 3-CH ₂ ), 5.13, d, J 5 Hz, 6-H), 5.68 (b, J 5 Hz, 7-H), 6.52 (S, thiazole 5-H).

For _{C 15 H 15 N 8 O 4} S 3 · 2.5H 2 O: Elemental Analysis

This theory: C, 33.64; H, 3. 76; N, 20.92.

Found: C, 33.80; H, 3.33; N, 19.86.

Antibacterial Spectrum (mcg / ml, Agar Dilution Method)

Example 8

7-2- (2-aminothiazol-4-yl) acetamide-2- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cepem-4-carbon Preparation of Sodium Acid:

7-2- (2-aminothiazol-4-yl) acetamide-3-acetoxymethyl-3-cepem-4-carbonate sodium 0.47 g, 5-methyl-1,3,4-thiadiazole- A mixture of 0.157 g of 2-thiol and 0.084 g of sodium hydrogen carbonate dissolved in 20 ml of a phosphate buffer solution having a pH of 6.4 was heated to about 55 ° C and stirred for 15 hours. After cooling, the reaction solution was poured into column chromatography of polystyrene resin (Anbarite XAD-2) and developed with water. The fractions containing the desired product were collected and freeze-dried to obtain the title compound.

Quantity 0.118 g

IR (cm ^-1 inch KBr) 1763.

NMR (median δ value) 2.76 (S, thiadiazole 5-CH ₃ ), 3.42 and 3.79 (ABq, J18 Hz, 2-CH ₂ ), 3.62 (S, CH ₂ CO), 4.02 and 4.51 (ABq, J14 Hz ), 3-CH ₂ ), 5.11 (b, J 5 Hz, 6-H), 5.68 (b, J 5 Hz, 7-H), 6.50 (S, thiazole 5-H).

Elemental Analysis: For C ₁₆ H ₁₅ N ₆ O ⁴ S ⁵ Na.2.5H ₁ O

This theory: C, 34.84; H, 3.65; N, 15.23.

Found: C, 34.87; H, 3. 47; N, 14.82.

Claims (1)

A method for preparing a cephalosporin derivative compound of general formula (I) by reacting the following general formula compound with a general formula compound.

Wherein R ¹ is a hydrogen atom, an alkyl group, X is an oxygen atom, a sulfur atom or NR ² (R ² is a hydrogen atom, an alkyl group, or a double alkyl group may combine with R ¹ to form a ring), and R ³ is It is a nitrogen heterocyclic group.