KR910008374B1 - Process for preparation of cephalosporin - Google Patents

Abstract

Cephalosporin derivs. of formula (I), their pharmaceutically acceptable non-toxic salts and their physiologically hydrolyzable esters and solvates are new. (I) are prepd. by reacting a cpd. of formula (II) with a cpd. of formula (III) in the presence of a solvent. In the formulas, R1 = C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl or C(Ra)(Rb)COOH; Ra and Rb each = H or C1-4 alkyl; or CRaRb = C3-7 cycloalkyl; R2 = C1-4 alkyl, C3-4 alkenyl or C3-7 cycloalkyl; n = 0 or 1; R3 = H or amino-protecting gp.; R4 = H or carboxyl-protecting gp. (I) exhibit antibacterial activity against Gram-positive and -negative bacteria. (I) have good stability to beta-lactamase.

Description

New cephalosporin antibiotics and preparation method thereof

The present invention relates to cephalosporin compounds useful as antibiotics, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates.

Cephalosporin antibiotics are widely used to treat diseases of pathogenic bacteria in humans and animals, and are particularly useful for the treatment of diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and for treating penicillin-sensitive patients. In many cases, it is desirable to use antibiotics that are active against both Gram-positive and Gram-responsive microorganisms and, therefore, considerable research has been made on the development of various types of cephalosporin antibiotics.

For example, British Patent No. 1,399,086 describes a broad and comprehensive description of cephalosporin derivatives represented by the following general formula (A).

이며, P는 유기그룹이다.Wherein R is hydrogen or an organic group, R ^a is an etherified monovalent organic group that is linked to oxygen through a carbon atom,

And P is an organic group.

On the other hand, Tsudomuderachi et al. Described in US Patent No. 4,390,534 with respect to the cefem and cefem compound of the following general formula (b).

임을 조건으로 하며; …선은 단일결합 또는 이중결합임을 표시한다. 그러나, 위의 영국특허 제1,399,086호의 P그룹이나 미합중국 특허 제4,390,534호의 R⁴그룹은 각각 유기그룹 또는 임의로 치환된 헤테로시클릭티오알킬 그룹으로 광범위하게 나타내고 있을 뿐, 본 발명의 핵심인 3위치에 (1-치환기-4,6-디아미노피리미디니움-2-일)티오메틸 그룹을 포함할 수 있다는 언급이나 제시가 전혀 없다.In the above formula, R ¹ is an amino or protective amino group; R ² is hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, O- or S-containing 5-membered heterocyclic substituted with optionally substituted cycloalkyl, cycloalkenyl or oxo group; R ³ is hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyridiniumalkyl, optionally substituted heterocyclicthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazoliumalkyl; R ⁴ is carboxy or protected carboxy; R ⁵ is COO when R ⁴ is optionally substituted pyridinium alkyl or optionally substituted thiazolium alkyl

Is conditional; … Lines indicate single bonds or double bonds. However, the P group of British Patent No. 1,399,086 or the R ⁴ group of U.S. Patent No. 4,390,534 are each broadly represented as an organic group or an optionally substituted heterocyclicthioalkyl group, and at the core 3 of the present invention ( There is no mention or suggestion that it may include a 1-substituent-4,6-diaminopyrimidinium-2-yl) thiomethyl group.

In addition, European Patent Application No. 62,321 describes cefem compounds of the general formula (C) and pharmaceutically acceptable salts thereof.

그리고 그룹은 하나이상의 질소원자를 함유하는 임의로 치환된 헤테로시클릭 양이온 기이다. 또한 다음 일반식 (다')로 표시되는 중간체가 기재되어 있다.Wherein R ¹ is amino or protected amino, R ² is an optionally substituted lower aliphatic hydrocarbon group, or cycloalkenyl,

And groups are optionally substituted heterocyclic cation groups containing one or more nitrogen atoms. In addition, intermediates represented by the following general formula (D ′) are described.

는 상기엣 정의한 바와 같으며, R⁴는 보호카르복실 그룹이며, X

는 산잔기이다.Wherein R ¹ , R ² and

Is as defined above, R ⁴ is a protective carboxyl group, X

Is a mountain residue.

European Patent Application No. 74,653 describes cefem compounds or salts of the following general formula (d).

Wherein R ¹ is an amino or protective amino group; R ² is an optionally substituted lower aliphatic hydrocarbon group, cyclo (lower) alkyl or cyclo (lower) alkenyl; R ³ is (lower) alkylamino, N-protected (lower) alkylamino, di (lower) alkylamino, sulfo (lower) alkylamino, hydroxy (lower) alkylamino, N-protected hydroxy (lower) alkylamino , Acyloxy (lower) alkyl, (lower) alkoxy (lower) alkoxy (lower) alkyl, di (lower) alkylamino (lower) alkyl, (lower) alkyldio (lower) alkyl, (lower) alkylthio, (lower) Alkoxy (lower) alkoxy, (lower) alkoxy, hydroxy (lower) alkoxy, acyl (lower) alkyl, hydroxy (lower) alkylthio, di (lower) alkylamino (lower) alkylthio, N-containing unsaturated 5 -A membered heterocyclic group, an N-containing unsaturated 5-membered heterocyclic thio, or an N-containing unsaturated 5 or 6-membered heterocyclic (lower) alkyl which may be substituted with a suitable substituent; R ⁴ is hydrogen or (lower) alky.

European Patent Application No. 47,977 describes cefem compounds of the general formula (e) and their salts:

Wherein n is 0 or 1 and Am is optionally substituted amino; T is thiazozolyl (attached to another group by its two carbon atoms); R ₂ is hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; R ₁ is optionally substituted thiazolium, optionally substituted pyrazolium, tri (lower) alkyl ammonium or a pyridinium group of the formula

Wherein R ^a is substituted (lower) alkyl [substituent is cycloalkyl, methyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfonyl], (lower) alkenyl or carboxy (Lower) alkylthio, amino or monosubstituted amino substituted with (lower) alkenyl, (lower) alkalthio or carboxy [substituents are (lower) alkyl, (lower) alkanoyl or aminobenzenesulfonyl], di ( Lower) alkylamino, substituted carbamoyl [substituents are (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy, hydroxy or cyanoim], di (lower) alkylcarbamoyl, thiocarbamoyl , Cycloalkyl, phenyl, hydroxy, (lower) alkoxy, halogen, (lower) alkoxycarbonyl, (lower) alkanoyloxy, (lower) alkanoyl, carboxyl, sulfocyano, nitro or hydroxy sulfo (lower) Alkyl; R ^b has the same meaning as hydrogen or carbamoyl, or R ^a ; R ^c has the same meaning as hydrogen or R ^a . Although there are many known cefe derivatives having a (substituted) aminothiadiazole ring at the 7-position, [(1-substituent-4,6-diaminopyrimidin-2-) at the 3-position which is the most characteristic feature of the present invention. There is no explanation or presentation of the 1) thio] methyl group.

Accordingly, the present inventors have conducted studies, and the cephalosporin compound having a heterocyclic thiomethyl group optionally substituted at the C-3 position and several groups specific at the 7-β-position shows strong activity against a wide range of pathogens. Found the facts.

The present invention relates to cephalosporin compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates.

In the above general formula, R ¹ is a C _1-4 alkyl group (preferably methyl, ethyl), C _3-4 alkynyl group (preferably allyl group), C _3-4 alkylyl group (preferably propazyl group) or —C (R ^a ) (R ^b ) CO ₂ H, wherein when R ¹ is —C (R ^a ) (R ^b ) CO ₂ H, R ^a , R ^b may be the same or different and each hydrogen Or C _1-4 alkyl group, or R ^a and R ^b represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, and R ² is a C _1-4 alkyl group (preferably a straight alkyl group, , Methyl, ethyl, n-propyl, or n-butyl group) or C _3-4 alkenyl group (preferably allyl group) or C _3-7 cycloalkyl group.

The compounds according to the invention are geometric isomers, including syn-isomers or mixtures of syn- and anti-isomers containing at least 90% of syn-isomers. In addition, when R ¹ is represented by -C (R ^a ) (R ^b ) CO ₂ H in formula (I), when R ^a and R ^b are different, the carbon atoms to which they are attached become asymmetric centers. Such compounds are diastereo isomers and the present invention includes diastereo isomers and mixtures thereof of each of these compounds. In addition, within the scope of the present invention, the solvate (including hydrate) of the compound of formula (I) is water, and the thiadiazol group of the compound of formula (I) forms a tautomer with thiadiazolinyl groups as follows. Because it can be a 5-amino-1,2,4-thiadiazol-2-yn-3-yl type or a 5-amino-1,2,4-thiadiazol-3-yn-3-yl type Included as tautomers.

Pharmaceutically acceptable non-toxic salts of the compounds of general formula (I) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoro acetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, succinic acid, benzo Known in the art of salts with organic carboxylic acids or sulfonic acids such as phosphoric acid, tartaric acid, fumaric acid, manderic acid, ascorbic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid and penicilis and cephalosrins And salts with other acids that have been used. These acid addition salts are prepared by conventional techniques. Compounds of general formula (I) may also form non-toxic salts with bases, depending on the R ¹ group. (R ¹ is as defined above). Bases used herein include inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. calcium hydroxide), sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate and amino acids. Organic bases are included.

Examples of physiological hydrolysable esters of the compound of general formula (I) include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2 Oxo-1,3-dioxoren-4-yl methyl and other physiologically hydrolysable esters known and used in penicillin and cephalosporin techniques. Such esters are prepared by known methods.

The general formula (Ⅰ) compound exhibits high antimicrobial activity against various Gram-positive and Gram-negative bacteria and is used for prevention and treatment of infections of animals including humans. Formula (I) compounds are formulated by known methods using known pharmaceutical carriers and excipients, and are in unit dosage form or in multi-dose containers. The composition is in the form of a solution, suspension or emulsion in oil or aqueous medium and may contain conventional dispersions, suspensions or stabilizers. In addition, the composition may be in the form of a dry powder that is reconstituted before use, for example, with sterile, pyrogen-free water. The compounds of formula (I) may also be formulated as suppositories using conventional suppository gases such as cocoa butter or other glycerides. If desired, the compounds of the present invention can be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

The composition preferably contains about 50 to 1,500 mg of the active ingredient of the compound of formula (I) when formed in unit dosage form. The dosage of the compound of general formula (I) depends on the doctor's prescription depending on factors such as the patient's weight and age and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 500 to 5,000 mg per day, depending on the frequency and route of administration. A total daily dosage of about 150 to 3,000 mg per day would be sufficient, separated into a single dose for intramuscular or intravenous administration to an adult, but a higher daily dosage is preferred for some strains of infection.

-락타마제를 생성하는 그람음성균에도 적용된다. 특히, 본 발명에 따른 화합물은 슈도모나스 균주에 대하여 매우 높은 활성을 나타낸다.The compounds according to the present invention exhibit a wide range of antimicrobial activities, generally having high activity against gram-negative bacteria,

It also applies to gram-negative bacteria that produce lactamase. In particular, the compounds according to the invention show very high activity against Pseudomonas strains.

Examples of preferred compounds having high antimicrobial activity among the compounds according to the present invention include compounds of formula (I) wherein R ¹ is -C (CH ₃ ) ₂ CO ₂ H and R ² is methyl or ethyl, i.e. Compounds of I-a) and (I-b) and non-toxic salts thereof.

Compounds of formulas (I-a) and (I-b) show significant antibacterial activity among the compounds of formula (I), and in particular exhibit excellent antimicrobial activity against Gram-positive strains.

Another example of a preferred compound according to the present invention is a compound in which R ¹ and R ² in Formula (I) are shown in Table 1 below.

TABLE 1

(O)_n]를 환원함을 특징으로 하여 제조된다.Compounds of formula (I) according to the present invention, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof are prepared by the following formula (II) in the presence of a solvent React with the compound of III) and, if necessary, remove or protect the amino protecting group before or after the reaction, or

(O) _n ], characterized by reducing.

Was above formula, R ^1, R ² are the same as described above, n is 0 or 1, R ⁵ is C _{1 ~ 4} alkyl group, C _{3 ~ 4} alkenyl group, C _{3 ~ 4} alkynyl group or -C (R ^a ) (R ^b ) CO ₂ (R ^c ) groups, where R ^a and R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a R ^b is attached to C _3-7 cycloalkyl group together with a carbon atom present, R ^c is hydrogen or carboxyl protecting group], R ³ is hydrogen or amino protecting group, R ⁴ is hydrogen or carboxyl protecting group.

Wherein the aminoprotecting group is acyl, substituted or unsubstituted ar (lower) alkyl (e.g. benzene, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (e.g. trichloromethyl, Trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like. Acyls suitable as aminoprotecting groups may be aliphatic acyl groups and acyl groups having aromatic or heterocycles. Examples of such acyl groups include lower alkanoyl having 1 to 6 carbon atoms (e.g., formyl, acetyl, etc.), alkoxycarbonyl having 2 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, etc.) and lower alkanes. Sulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), arenesulfonyl (e.g., benzenesulfonyl, paratoluenesulfonyl, etc.), ar (lower) alkanoyl (e.g., phenylacetyl, etc.) or ar (lower) Alkoxycarbonyl (for example, benzyloxycarbonyl etc.) etc. are mentioned. The above-mentioned acyl may have 1 to 3 suitable substituents such as halogen, hydroxy, cyano, nitro and the like. In addition, the reaction product of the silane, boron, phosphorus compound and amino group may be an amino protecting group. R⁵R^cI R⁴The carboxyl protecting group is suitable as long as it can be easily removed under moderately relaxed conditions. Examples include (lower) alkyl esters (eg, methyl esters, t-butyl esters, etc.) and (lower) alkenyl esters (eg, vinyl esters). , Allyl ester, etc.), (lower) alkoxy (lower) alkyl esters (e.g., methoxymethyl esters, etc.), (lower) alkylthio (lower) alkyl esters (e.g., methylthiomethyl esters, etc.), halo (lower) alkyls Esters (eg, 2,2,2-trichloroethyl ester, etc.), substituted or unsubstituted aralkyl esters (eg, benzyl esters, P-nitrobenzyl esters, etc.), or silyl esters. The amino protecting group and the carboxyl protecting group can be easily removed under mild reaction conditions such as hydrolysis or reduction to form a free amino group or a carboxyl group. The amino protecting group or carboxyl protecting group can be appropriately selected and used depending on the chemical properties of the general formula (I) compound. L is a leaving group, for example, halogen such as chlorine, fluorine, (lower) alkanoyloxy groups such as acetoxy, (lower) alkane sulfonyloxy such as methanesulfonyloxy, paratoluene sulfonyloxy, etc. A nesulfonyloxy group or an alkoxy carbonyloxy.

The meaning of the dotted line in the structure of the compound of Formula (II) means that the compound of Formula (II) alone represents the following Formula (II-a), or each of Formula (II-b), It means a mixture of a general formula (II-a) compound and a general formula (II-b) compound.

Wherein n, R ³ , R ⁴ , R ⁵ and L are the same as described above.

Compounds of the general formula (II) which are the starting materials of the present invention are known compounds and are prepared according to the following schemes. That is, it is prepared by activating the compound of the following general formula (IV) or a salt thereof with an acylating agent and reacting with the compound of the general formula (V).

[Scheme]

In the above scheme, n, R ³ , R ⁴ , R ⁵ and L are as described above, and the meaning represented by the dotted line in the compound of formula (V) means that the compound of formula (V) alone is -a) a compound or a compound of general formula (V-b), or a mixture of a compound of general formula (V-a) and a compound of general formula (V-b).

Wherein n, R ⁴ and L are as described above.

In preparing compounds of formula (II), the active acylated derivatives of formula (IV) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloro formate, mesitylene sulfonyl chloride, P-toluene sulfide). Acid anhydrides formed with polyvinyl chloride or chlorophosphate) or activated esters (preferably those formed in the reaction with N-hydroxy benzo triazole in the presence of a condensing agent such as dicyclohexyl carbodiimide). The acylation reaction may also proceed with the free acid of general formula (IV) in the presence of a condensing agent such as dicyclohexyl carbodiimide, carbonyl diimidazole. On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary amines (preferably triethylamine, dimethyl aniline, pyridine), sodium bicarbonate, and sodium carbonate inorganic bases. Solvents such as halogenated carbon, tetrahydrofuran, acetonitrile, dimethyl formamide or dimethyl acetamide and the like. It can also be used as a mixed solvent of the above solvents, can also be used as a water-soluble.

The temperature of the acylation reaction is about -50 ° C to 50 ° C (preferably -30 ° C to 20 ° C), and the acylating agent of the compound of formula (IV) is equivalent to or slightly excess ( 1.05 to 1.2 equivalents).

If necessary, the compound of the general formula (II) may remove the amino protecting group or the carboxyl protecting group by conventional methods. That is, the protecting group can be removed by a hydrolysis or reduction method, and when including an amido group as the protecting group, it is preferable to hydrolyze via amino halogenation and amino etherification. Acid hydrolysis is useful for removing tri (di) phenyl methyl or alkoxycarbonyl groups and proceeds with organic or inorganic acids such as formic acid, trifluoroacetic acid, P-toluene-sulfonic acid, hydrochloric acid.

The compound of formula (III) used in the present invention is a novel substance, the preparation method thereof is described in detail in the preparation examples below. Meanwhile, in the present invention, in preparing the compound of formula (I) by substituting the compound of formula (III) at the C-3 position of the compound of formula (II), the solvent used may be mixed with water or water. It can also be used as a mixed aqueous solution, such as acetonitrile or acetone, and the pH of the reaction solvent is in the range of 5 to 8 (preferably 6 to 7.5), and the reaction temperature is 40 ° C to 100 ° C (preferably 60 ° C to The reaction proceeds well in the range of about 80 ° C). Compounds of formula (III) can be used in the equivalent or excess (1-2 equivalents) to compound (II), while sodium iodide (potassium) and bromo sodium (potassium) are used to stabilize reaction intermediates and products. ) Or salts such as potassium thiocyanate.

The desired compound of formula (I) can be separated or purified from the reaction product of the reaction by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

Compounds of the general formula (I) of the present invention and nontoxic salts thereof (preferably alkali metal salts, alkaline earth metal salts, organic salts, salts with inorganic and organic acid salts or amino acids) are a wide variety of pathogenic bacteria including various Gram-positive and negative bacteria. It has a high antimicrobial activity against, and is useful for the treatment of bacterial infections in animals including humans. The usefulness was evaluated by determining the minimum inhibitory concentration (Minimun Inhibitory Concentration) for the standard strain using the known compound Ceftazidime as a control agent. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Mueller-Hinton agar medium, and then inoculating 2 μl of the test strain having 10 ⁷ CFU / ml at 37 ° C. Incubation was performed for 20 hours, and the results are shown in Table 1.

Compound of the Invention

Ia: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- (4,6- Diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ib: 7-[(Z) -2- (5-amino-1,2,4-thiodiazol-3-yl) -2- (ethoxyimino) acetamido] -3- (4,6- Diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ic: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- (4,6- Diamino-1-propylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Id: 3- (1-allyl-4,6-diaminopyrimidinium-2-yl) -7-[(Z) -2- (5-amino-1,2,4-thiadiazole-3- Yl) -2- (ethoxyimino) acetamido] -3-cepem-4-carboxylate

Ie: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- (4,6- Diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

If: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- (4,6- Diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ig: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acetamido]- 3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ih: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acetamido]- 3- (4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ii: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyamino) acetamido]- 3- (4,6-diamino-1-propylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Ij: 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyamino) acetamido]- 3- (1-butyl-4.6-diaminopyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate

Control Compound: Ceftazidime

TABLE 2

Antimicrobial Activity of Compounds of the Invention (MIC, μg / ml)

As shown in Table 2, the compounds Ia and IIb of the present invention show comparable antimicrobial activity against most standard strains, as compared to the control agent ceftazidime, which is widely known as a broad spectrum antibiotic. Gram-positive bacteria, which have been pointed out as a weak point, are showing 2 ~ 4 times better results.

This suggests that the antimicrobial range of the compounds Ia and Ib of the present invention is broader and useful than ceftazidime used as a control agent.

In the following Examples, the method for preparing Compound (I) of the present invention will be described in detail.

[Production Example 1]

Synthesis of 4,6-diamino-1-methyl-2 (1H) -pyrimidinethione.

Metal sodium (4.6 g) was added to the dried ethyl alcohol (100 ml), and the mixture was heated to reflux for 1 hour, followed by N-methylthiourea (9 g) and malononitrile (6.6 g). The reaction solution was heated to reflux for 24 hours, cooled to room temperature, neutralized with concentrated hydrochloric acid, and the resulting precipitate was filtered, washed with water (20 ml) and ethyl alcohol (50 ml), and dried to give a pale yellow solid. (8.1 g) is obtained. (Melting point: decomposes at 185 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 3.80 (s, 3H), 5.39 (s, 1H)

[Production Example 2]

Synthesis of 4,6-diamino-1-ethyl-2 (1H) -pyrimidinethione.

Metal sodium (4.6 g) was added to the dried ethyl alcohol (100 ml), and the mixture was heated to reflux for 1 hour, followed by addition of N-ethylthiourea (10.4 g) and malononitrile (6.6 g). The reaction solution was heated to reflux for 48 hours, cooled to room temperature, neutralized with concentrated hydrochloric acid, and the resulting precipitate was filtered and washed with ethyl alcohol (50 ml). The filtrate is concentrated under reduced pressure and chromatographed on silica gel to give the yellow solid title compound (6.2 g). (Melting point: decomposes at 197 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 3.80 (s, 3H), 5.39 (s, 1H)

[Manufacture example 3]

Synthesis of 4,6-diamino-1-propyl-2 (1H) -pyrimidinethione.

To the dried ethyl alcohol (100 ml) was added sodium metal (4.6 g), and refluxed for 1 hour, followed by N-propylthiourea (11.8 g) and malononitrile (6.6 g). The reaction solution was heated to reflux for 72 hours, then cooled to room temperature, neutralized with concentrated hydrochloric acid, and the resulting precipitate was filtered and washed with ethyl alcohol (50 ml). The filtrate is concentrated under reduced pressure and chromatographed on silica gel to give a tan solid title compound (5.7 g). (Melting point: decomposes at 195 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 0.96 (t, 3H), 1.81 (m, 2H), 4.51 (t, 2H), 5.46 (s, 1H)

[Production Example 4]

Synthesis of 1-butyl-4,6-diamino-2 (1H) -pyrimidinethione.

To the dried ethyl alcohol (100 ml) was added sodium metal (4.6 g), and refluxed for 1 hour, followed by N-butylthiourea (13.2 g) and malononitrile (6.6 g). The reaction solution was heated to reflux for 72 hours, then cooled to room temperature, neutralized with concentrated hydrochloric acid, and the resulting precipitate was filtered and washed with ethyl alcohol (50 ml). The filtrate is concentrated under reduced pressure and chromatographed on silica gel to give the brown solid title compound (4.6 g). (Melting point: decomposition above 195 ° C).

NMR (δ, D ₂ O + acetone d-6): 0.88 (t, 3H), 1.36 (m, 2H), 1.69 (m, 2H), 4.59 (t, 2H), 5.41 (s, 1H)

Production Example 5

Synthesis of 1-allyl-4,6-diamino-2 (1H) -pyrimidinethione.

To the dried ethyl alcohol (100 ml) was added sodium metal (4.6 g), and refluxed for 1 hour, followed by N-allylthiourea (11.6 g) and malononitrile (6.6 g). The reaction solution was heated to reflux for 72 hours, then cooled to room temperature, neutralized with concentrated hydrochloric acid, and the resulting precipitate was filtered and washed with ethyl alcohol (50 ml). The filtrate is concentrated under reduced pressure and chromatographed on silica gel to give a tan solid title compound (6.2 g). (Melting point: decomposes at 193 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 5.42 (s, 1H), 5.16 (d, 1H), 6.11 (m, 5H)

[Manufacture example 6]

Synthesis of 2- (hydroxyimino) malononitrile.

Malonnitrile (66.1 g) is dissolved in water (50 ml) and acetic acid (50 ml), and a reaction solution in which sodium nitrite (69 g) is dissolved in water at 4 ° C is added dropwise and stirred at that temperature for 3 hours. Extract three times with ethyl acetate (500 ml, 250 ml, 250 ml, respectively), dry over anhydrous magnesium sulfate, and concentrate. The residue was triturated with ethyl ether to give the title compound (92.5 g) as a white solid.

[Manufacture example 7]

Synthesis of 2- (methoxyimino) malononitrile.

2- (hydroxyimino) malononitrile (95 g) is dissolved in diethylsulfoxide (200 ml), calcium carbonate (140 g) and dimethylsulfate (126.1 g) are added and stirred at room temperature for 1 hour. Ethyl ether (700 ml) was added to the reaction solution, and washed five times with distilled water (1 liter). The organic layer was dehydrated and concentrated under reduced pressure to obtain the title compound (90 g) as a slightly yellow liquid.

Boiling Point: 60 ~ 65 ℃ / 20mmHg

NMR (δ, CDCl ₃ ): 3.90 (s, 3H)

[Manufacture example 8]

Synthesis of 2- (ethoxyimino) malononitrile.

The title compound is obtained by reacting 2- (hydroxyimino) malononitrile and diethylsulfate in the same manner as in Preparation Example 7.

Boiling Point: 65 ~ 67 ℃ / 13mmHg

NMR (δ, CDCl ₃ ): 1.20 (t, 3H), 4.20 (q, 2H)

[Manufacture example 9]

Synthesis of 2- (tert-butoxycarbonylprop-2-oxyimino) malenonitrile.

2- (hydroxyimino) malononitrile and tert-butyl-2-bromo-2-methylpropionate were reacted in the same manner as in Preparation Example 8 to obtain the title compound.

Boiling Point: 115 ~ 120 ℃ / 13mmHg

NMR (δ, CDCl ₃ ): 1.48 (s, 9H), 1.63 (s, 6H)

[Production Example 10]

Synthesis of 2-cyano-2- (methoxyimino) acetamidinium acetate.

To ammonium chloride (14.2 g) and concentrated aqueous ammonium hydroxide solution (178 ml) in ethanol (90 ml) was added 2- (methoxyimino) malononitrile (29 g) at -5 to 0 ° C and stirred at this temperature for 10 hours. do. Extracted three times with methylene chloride (450ml, 100ml, 100ml, respectively), dehydrated, filtered and concentrated. The residue is taken up in ethyl acetate and crystallized with acetic acid to give the title compound (20.5 g) as light brown.

NMR (δ, DMSO-d6): 1.90 (s, 3H), 1.90 (s, 3H), 4.18 (s, 3H), 7.88 (s, 4H)

[Production Example 11]

2-cyano-2- (ethoxyimino) acetamidinium acetate synthesis.

2- (ethoxyimino) malononitrile was treated in the same manner as in Preparation Example 10 to obtain the title compound (22.4 g).

NMR (δ, DMSO-d6): 1.20 (t, 3H), 1.90 (s, 3H) 4.10 (q, 2H), 7.90 (s, 4H)

[Manufacture example 12]

Synthesis of 2- (tert-butoxycarbonylprop-2-oxyimino) -2-cyano acetamidinium acetate.

To a solution of ammonium acetate (18.5 g) in methanol (100 ml) was added 2- (tert-butoxycarbonylprop-2-oxyimino) malononitrile (19 g), stirred for 2 hours, and then at room temperature overnight. Let it stand. The reaction is concentrated, water is added and extracted with ethyl acetate. Dehydrate, filter, concentrate and add ethyl ether to the residue and stir for 30 minutes. The resulting precipitate was filtered to give the title compound (15 g) as pale yellow.

NMR (δ, DMSO-d6): 1.40 (s, 9H), 1.60 (s, 6H), 1.98 (s, 3H), 7.38 (bs, 3H)

[Production Example 13]

Synthesis of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetonitrile.

2-Cyano-2- (methoxyimino) acetamidinium acetate (12.5 g) is dissolved in methanol (100 ml) and triethylamine (23.4 ml) is added. Bromine (12.9 g) is added at -15 ° C. Add dropwise and stir for 5 minutes at -15-10 C. A solution of potassium thiocyanate (3.7 g) dissolved in methanol (55 ml) at −10 to −5 ° C. is added dropwise and stirred at 0 ° C. for 2 hours. The reaction solution is poured into ice water (1.2 liters), stirred for 30 minutes, and the resulting precipitate is filtered and dried to give a light brown title compound (12.2 g).

NMR (δ, DMSO-d6): 3.90 (s, 3H), 8.37 (s, 2H)

Production Example 14

Synthesis of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetonitrile.

2-Cyano-2- (ethoxyimino) acetamidinium acetate was treated in the same manner as in Preparation Example 13 to obtain the title compound.

NMR (δ, DMSO-d6): 1.37 (t, 3H), 4.50 (q, 2H), 8.37 (s, 2H)

[Production Example 15]

Synthesis of 2- (5-amino-1,2,4-thiadiazol-5-yl) -2- (tert-butoxycarbonylprop-2-oxyimino) acetonitrile.

2- (tert-butoxycarbonylprop-2-oxyimino) -2-cyanoacetamidinium acetate was treated in the same manner as in Production Example 13 to obtain the title compound.

NMR (δ, DMSO-d6): 1.40 (s, 9H), 1.58 (s, 6H), 8.43 (s, 2H)

[Production Example 16]

Synthesis of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetic acid.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetonitrile (12.2 g) was added to 4-N aqueous sodium hydroxide solution (250 ml), and 50 to Stir at 55 ° C. for 5 hours. The reaction mixture is cooled, the pH is adjusted to 1 with phosphoric acid, and then extracted with a mixed solvent of ethyl acetate and tetrahydrofuran (3: 1). Dry filtration is concentrated, and the residue is triturated with ethyl ether to give a light brown title compound (11.2 g).

NMR (δ, DMSO-d6): 3.91 (s, 3H), 8.20 (s, 2H)

[Production Example 17]

Synthesis of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetic acid.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetonitrile was treated in the same manner as in Production Example 16 to obtain the title compound.

NMR (δ, DMSO-d6): 1.20 (t, 3H), 4.20 (q, 2H), 8.21 (s, 2H)

[Production Example 18]

Synthesis of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acetic acid.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-butoxycarbonylprop-2-oxyimino) acetonitrile was treated in the same manner as in Preparation Example 16 To obtain the title compound.

NMR (δ, DMSO-d6): 1.42 (s, 6H), 8.22 (s, 2H)

[Production Example 19]

(6R, 7R) -3-acetoxymethyl-7 [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido ] -3-Sefem-4-carboxylic acid synthesis.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetic acid (2.0 g) was dissolved in dried dimethylacetamide (20 ml) and stored at -10 ° C. Cool. Triethylamine (1.5 ml) and mesitylenesulfonyl chloride (2.3 g) are added and stirred at -10 ° C for 1 hour. 7-Amino-cephalosporinic acid (3.26 g) and triethylamine (3 ml) are added and stirred at room temperature for 2 hours. Water (100 ml) is poured into the reaction solution, the pH is adjusted to 1 with phosphoric acid, and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran (3: 1). Dry, filter, concentrate and triturate the residue with isopropyl ether to afford the title compound (3.05 g) as a light brown solid.

NMR (δ, DMSO-d6): 2.05 (s, 3H), 3.2 ~ 3.6 (ABq, 2H), 3.95 (s, 3H), 4.42 ~ 5.05 (ABq, 2H), 5.18 (d, 1H), 5.80 ( q, 1H), 8.20 (s, 2H)

[Production Example 20]

(6R, 7R) -3-acetoxymethyl-7 [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido ] -3-Sefem-4-carboxylic acid synthesis.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetic acid was treated in the same manner as in Production Example 19 to obtain the title compound.

NMR (δ, DMSO-d6): 1.25 (t, 3H), 2.05 (s, 3H), 3.40 ~ 3.80 (ABq, 2H), 4.22 (q, 2H), 4.60 ~ 5.18 (q, 1H), 8.28 ( s, 2H)

[Production Example 21]

(6R, 7R) -3-acetoxymethyl-7 [(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2 -Oxyimino) acetamido] -3-cepem-4-carboxylic acid.

2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acetic acid was treated in the same manner as in Production Example 19 to obtain the title compound. Get

NMR (δ, D ₂ O): 1.58 (s, 6H), 2.05 (s, 3H), 3.10-3.72 (ABq, 2H), 4.60-4.95 (ABq, 2H), 5.14 (d, 1H), 5.70 ( d, 1H)

Example 1

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of 4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate.

To a solution obtained by suspending the compound (500 mg) obtained in Production Example 19 in distilled water (5 ml), 4,6-diamino-1-methyl-2 (1H) -pyrimidinethione (200 mg) and potassium iodide (800 mg) were added thereto. It heats at 70 degreeC, adjusting to pH 7.1-7.2 with sodium bicarbonate aqueous solution. The reaction solution was stirred for 4 hours, cooled to room temperature, adjusted to pH 3 ~ 3.5 with 2N hydrochloric acid aqueous solution, and the resulting precipitate was filtered, and chromatographed on silica gel using distilled water (5: 1) as a eluent. To obtain the title compound (300 mg) as a white or white solid. (Melting point: decomposes at 161 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 3.62 (s, 3H), 3.66 (ABq, 2H), 4.05 (s, 3H), 4.45 (ABq, 2H), 5.15 (d, 1H), 5.81 ( d, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1680, 1630, 1570

Example 2

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamino] -3- (4 Synthesis of, 6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate.

The compound synthesized in Preparation Example 19 and 4,6-diamino-1-ethyl-2 (1H) -pyramidinethione were treated in the same manner as in Example 1 to obtain the title compound. (Melting point: decomposes at 169 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 3.60 (q, 2H), 3.60 (ABq, 2H), 4.05 (s, 3H), 4.55 (ABq, 2H), 5.11 (d, 1H), 5.82 ( d, 1 H), 5.68 (s, 1 H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1690, 1630, 1580

Example 3

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of 4,6-diamino-1-propylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate.

The title compound was obtained by treating the compound synthesized in Preparation Example 19 and 4,6-diamino-1-propyl-2 (1H) -pyramidinethione in the same manner as in Example 1. (Melting point: decomposes at 167 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 1.05 (t, 3H), 1.80 (m, 2H), 3.52 (ABq, 2H), 3.80 (q, 2H), 4.05 (s, 3H), 4.55 ( ABq, 2H), 5.16 (d, 1H), 5.65 (s, 1H), 5.84 (d, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1695, 1640, 1580

Example 4

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( Synthesis of 1-allyl-4,6-diaminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate.

The title compound was obtained by treating the compound synthesized in Preparation Example 19 and 1-allyl-4,6-diamino-2 (1H) -pyramidinethione in the same manner as in Example 1. (Melting point: decomposes at 158 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 3.56 (ABq, 2H), 4.05 (s, 3H), 4.42 (ABq, 2H), 5.16 (d, 1H), 5.70 (s, 1H), 5.85 ( d, 1H), 5.05-6.51 (m, 5H)

IR (KBr, cm ^-1 ): 1760 (β-lactam), 1700, 1650, 1590

EXAMPLES 5-8

The compound synthesized in Production Example 20, 4,6-diamino-1-methyl-2 (1H) -pyrimidinethione, 4,6-diamino-1-ethyl-2 (1H) -pyrimidinethione, 4, 6-Diminomino-1-propyl-2 (1H) -pyrimidinethione and 1-allyl-4,6-diamino-2 (1H) -pyrimidinethione were reacted in the same manner as in Example 1 to obtain the title compound. Get

Example 5

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Synthesis of 4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-carboxylate (melting point: decomposed at 163 DEG C or higher).

NMR (δ, D ₂ O + acetone d-6): 1.30 (t, 3H), 3.60 (s, 3H), 3.56 (ABq, 2H), 4.30 (q, 2H), 4.40 (ABq, 2H), 5.13 ( d, 1H), 5.62 (s, 1H), 5.84 (d, 1H)

IR (KBr, cm ^-1 ): 1788 (β-lactam), 1690, 1630, 1580

Example 6

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Synthesis of 4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate. (Melting point: decomposes at 165 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 1.18 (t, 3H), 1.30 (t, 3H), 3.60 (q, 2H), 3.58 (ABq, 2H), 4.30 (q, 2H), 4.40 ( ABq, 2H), 5.18 (d, 1H), 5.71 (s, 1H), 5.84 (d, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1695, 1630, 1570

Example 7

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Synthesis of 4,6-diamino-1-propylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate. (Melting point: decomposes at 158 ℃ or higher)

NMR (δ, D ₂ O-acetone d-6): 1.05 (t, 3H), 1.30 (t, 3H), 1.80 (m, 2H), 3.54 (ABq, 2H), 4.0 (q, 2H), 4.32 (q, 2H), 4.58 (ABq, 2H), 5.18 (d, 1H), 5.69 (s, 1H), 5.84 (d, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1690, 1640, 1580

Example 8

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( Synthesis of 1-aryl-4,6-diaminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate. (Melting point: decomposes at 159 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 1.31 (t, 3H), 3.60 (ABq, 2H), 4.32 (q, 2H), 4.42 (ABq, 2H), 5.16 (d, 1H), 5.68 ( s, 1H), 5.82 (d, 1H), 5.05 to 6.51 (m, 5H)

IR (KBr, cm ^-1 ): 1769 (β-lactam), 1695, 1630, 1570

Example 9

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate.

The compound (500 mg) obtained in Production Example 21 was dissolved in distilled water (10 ml), and 4,6-diamino-1-methyl-2 (1H) -pyrimidinethione (200 mg) and potassium iodide (1.2 g) were added thereto. The reaction solution was adjusted to aqueous solution pH 7.3 to 7.5 with sodium bicarbonate, stirred at 70 ° C. for 4 hours, and then cooled to room temperature to remove insoluble matters. The filtrate was adjusted to pH 4 and concentrated under reduced pressure on silica gel. Chromatography with acetonitrile-distilled water (4: 1) mixed solvent as eluent yields the title compound (200 mg) as a white or white solid. (Melting point: decomposes at 154 ℃ or higher)

NMR (δ, D ₂ O + acetone d-6): 1.52 (s, 6H), 3.51 (s, 3H), 3.58 (ABq, 2H), 4.40 (ABq, 2H), 5.18 (d, 1H), 5.60 ( s, 1H), 5,81 (d, 1H)

IR (KBr, cm ^-1 ): 1769 (β-lactam), 1700, 1650, 1590

[Examples 10-13]

The compound synthesized in Production Example 21, 4,6-diamino-1-ethyl-2 (1H) -pyrimidinethione, 4,6-diamino-1-propyl-2 (1H) -pyrimidinethione, 1- Butyl-4,6-diamino-2 (1H) -pyrimidinethione and 1-allyl-4,6-diamino-2 (1H) -pyrimidinethione were reacted in the same manner as in Example 9 to Obtain the title compound.

Example 10

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (carboxyprop-2-oxyimino) acetamido ] -3- (4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate (melting point: decomposition | decomposition above 161 degreeC).

NMR (δ, D ₂ O + acetone d-6): 1.32 (t, 3H), 1.58 (s, 6H), 3.56 (ABq, 2H), 4.02 (q, 2H), 4.43 (ABq, 2H), 5.18 ( d, 1H), 5.58 (s, 1H), 5.81 (d, 1H)

IR (KBr, cm ^-1 ): 1767 (β-lactam), 1695, 1640, 1580

Example 11

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxysisprop-2-oxyimino) acet Amido] -3- (4,6-diamino-1-propylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate (melting point: decomposed at 159 占 폚 or higher).

NMR (δ, D ₂ O + acetone d-6): 1.02 (t, 3H), 1.52 (s, 6H), 1.53 (m, 2H), 3.60 (ABq, 2H), 3.98 (t, 2H), 4.45 ( ABq, 2H), 5.18 (d, 1H), 5.58 (s, 1H), 5.81 (d, 1H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1690, 1630, 1570

Example 12

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (1-butyl-4,6-diaminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate (melting point: decomposition above 163 ° C).

NMR (δ, D ₂ O + acetone d-6): 0.98 (t, 3H), 1.50 (m, 4H), 1.54 (s, 6H), 3.60 (ABq, 2H), 3.95 (t, 2H), 4.46 ( ABq, 2H), 5.18 (d, 1H), 5.58 (s, 1H), 5.81 (d, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1690, 1620, 1550

Example 13

(6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (1-allyl-4,6-diaminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate (melting point: decomposed at 156 占 폚 or higher).

NMR (δ, D ₂ O + acetone d-6): 1.58 (s, 6H), 3.60 (ABq, 2H), 3.71 (d, 2H), 4.45 (ABq, 2H), 5.18 (d, 1H), 5.60 ( s, 1H), 5.81 (d, 1H), 5.01 to 6.51 (m, 3H)

IR (KBr, cm ^-1 ): 1760 (β-lactam), 1680, 1620, 1570

Claims (19)

A cephalosporin compound represented by the following general formula (I), a pharmaceutically acceptable nontoxic salt thereof, a physiologically hydrolysable ester thereof, a hydrate or a solvate thereof

Wherein, R ¹ is C _{1 ~ 4} alkyl group, C _{3 ~ 4} alkenyl group, C _{3 ~ 4} alkynyl group or ^{-C (R a) (R b} ) a CO ₂ H, [herein, R ¹ is -C When represented by (R ^a ) (R ^b ) CO ₂ H, R ^a , R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b are attached to C _3-7 cycloalkyl group together with a carbon atom present in the formula 2] represents a C _1-4 alkyl group, a C _3-4 alkenyl group or a C _3-7 cycloalkyl group. The composition of claim 1, wherein (6R, 7R) -7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetami Fig.]-3- (4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolyzable A compound of formula (I) which is a decomposable ester, hydrate or solvate thereof. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester thereof, hydrate or A compound of formula (I) that is a solvate. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- ( 4,6-diamino-1-propylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable nontoxic salt, physiologically hydrolysable ester thereof, hydrate or A compound of formula (I) that is a solvate. The compound of claim 1, wherein 3- (1-allyl-4,6-diaminopyrimidin-2-yl) -7-[(Z) -2- (5-amino-1,2,4-thiadia Zol-3-yl) -2- (ethoxyimino) acetamido] -3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester, hydrate or solvate thereof Phosphorus compound of general formula (I). The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 4,6-diamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester, hydrate or A compound of formula (I) that is a solvate. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3- ( 4,6-diamino-1-ethylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically hydrolysable ester thereof, hydrate or A compound of formula (I) that is a solvate. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (4,6-diamino-1-methylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically water-soluble A compound of formula (I) which is a decomposable ester, hydrate or solvate thereof. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (4,6-diamino-1-ethylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically water-soluble A compound of formula (I) which is a decomposable ester, hydrate or solvate thereof. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (4,6-diamino-1-propylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically water-soluble A compound of formula (I) which is a decomposable ester, hydrate or solvate thereof. The compound of claim 1, wherein 7-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (2-carboxyprop-2-oxyimino) acet Amido] -3- (1-butyl-4,6-diaminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate, pharmaceutically acceptable non-toxic salt, physiologically water-soluble A compound of formula (I) which is a decomposable ester, hydrate or solvate thereof. A compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable, characterized by reacting a compound of formula (II) with a compound of formula (II) in the presence of a solvent Process for preparing esters, hydrates or solvates thereof.

Wherein, R ¹ is C _{1 ~ 4} alkyl group, C _{3 ~ 4} alkenyl group, C _{3 ~ 4} alkynyl group or ^{-C (R a) (R b} ) CO 2 H [ where, R ¹ is -C (R ^a ) When represented by (R ^b ) CO ₂ H, R ^a , R ^b may be the same or different and each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b are the carbons to which they are attached a C _{3 ~ 7} represents a cycloalkyl group; with the atom, R ² is R ¹ is C _{1 ~ 4} alkyl group, C _{3 ~ 4} alkenyl or C _{3 ~} represents a ₇ cycloalkyl group, n is 0 or 1, R ⁵ are the same C _{1 ~ 4} alkyl group, C _{3 ~ 4} alkenyl group, C _{3 ~ 4} alkynyl group or ^{-C (R a) (R b} ) CO 2 (R c) group [herein, R ^a, R ^b is Or may be different and each represent hydrogen or a C _1-4 alkyl group, or R ^a and R ^b represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached; R ^c is a hydrogen or a carboxyl protecting group], R ³ is a hydrogen or an amide protecting group, R ⁴ is a hydrogen or a carboxyl protecting group, and L is a leaving group such as halogen, such as chlorine, fluorine, or lower acetoxy. Or a lowerene alkanesulfonyloxy group such as an alkanoyloxy group, methanesulfonyloxy, an arenesulfonyloxy group or an alkoxycarbonyloxy group such as paratoluenesulfonyloxy. The method of claim 12, wherein the solvent used is water or a mixed aqueous solution of water and a water miscible solvent. The method of claim 13, wherein the water miscible solvent is acetonitrile, acetone. 13. The method according to claim 12, wherein the amount of the compound of formula (III) is 1 to 2 equivalents based on the compound of formula (II). The method of claim 12, wherein the pH of the reaction solvent is characterized in that 5-8. The method of claim 12, wherein the reaction is carried out in the presence of a stabilizer. 18. The method of claim 17, wherein the stabilizing agent is one or more selected from sodium iodide, potassium iodide, bromosodium, bromopotassium or potassium thiocyanate. The method according to claim 12, wherein the amino protecting group or acid protecting group is removed before or after reacting the compound of formula (II) with the compound of formula (III), or the S-oxide is reduced.