KR930010628B1 - Cephalosporin antibiotics - Google Patents

Abstract

Cephalosporin derivatives of formula (I), their pharmaceutically acceptable non-toxic salts and their physiologically hydrolyzable esters and solvates are new. In (I), R1=C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl or -C(Ra)(Rb)COOH; Ra and Rb = H or C1-4 alkyl; or CRaRb=C3-7 cycloalkyl; R2=C1-4 alkyl, C3-4 alkenyl, C3-7 cycloalkyl or amino; Q=CH or N. Also claimed is the prepn. of (I) which comprises reacting a compound of formula (II) with 2,6-diamino-4-thio-1-methyl pyrimidine in water or a mixed solvent of H2O and acetonitrile or acetone at 40-100 deg.C and pH 5-8.

Description

New cephalosporin antibiotics and preparation method thereof

The present invention relates to novel cephalosporin compounds of formula (I) useful as antibiotics, pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates, and methods for their preparation.

Wherein R ¹ is a C _1-4 alkyl group (preferably methyl, ethyl group) or C _3-4 alkenyl group (preferably allyl group) or C _3-4 alkynyl (preferably propanyl group) or C (R ^a ) (R ^b ) COOH. Here, 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 represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached . When R ^a and R ^b are different, the carbon atom to which they are attached becomes the asymmetric center. Such compounds are diastereo isomers and the present invention includes diastereo isomers and mixtures thereof of each of these compounds.

R ² represents a C _1-4 alkyl group (preferably methyl, ethyl group) or a C _3-4 alkenyl group (preferably allyl group), a C _3-7 cycloalkyl group or an imino group. Q is CH or N.

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, and are particularly useful for treating 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-negative microorganisms and, therefore, considerable research has been made on the development of various forms 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).

Wherein R is hydrogen or an organic group, R ^a is an etherified monovalent organic group which is linked to oxygen through a carbon atom, B is S or S → 0, and P is an organic group.

British Patent No. 1,522,140 describes cephalosporin antibiotics of the general formula (I), wherein the compound is a syn isomer or is present as a mixture of syn and anti isomers containing at least 90% or more syn isomers. .

Wherein R 'is a furyl or thienyl group, R''is a C _1-4 alkyl group, C _3-7 cycloalkyl group, furylmethyl or thienylmethyl group, and R''is hydrogen or carbamoyl, carboxymethyl, sulf Ponyyl or methyl group.

These compounds show high antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, and are very stable against β-lactamase produced by various Gram-negative bacteria as well as in vivo. In an attempt to find antibiotics with enhanced broad spectrum antimicrobial potency and strong activity against Gram-negative bacteria, other compounds with similar structures have been developed. This development led to various changes such as introducing a specific group at the 3-position of the 7-β acyl amido group and the cephalosporin derivative of the general formula (B).

For example, Belgian Kingdom Patent No. 852,427 discloses that R in general formula (A) is substituted with various other organic groups including 2-iminothiazol-4-yl and that the oxygen atom of the oxyimino group is attached to an aliphatic hydrocarbon group. Cephalosporin antibiotic compounds are described in which the hydrogenated group itself can be substituted with a carboxyl group.

In such compounds, the substituent at the C-3 position is acyloxymethyl, hydroxymethyl, formyl or an optionally substituted heterocyclic thiomethyl group.

However, the P group of British Patent No. 1,399,086 above is broadly represented as an organic group or an optionally substituted heterocyclylthioalkyl group, and is located at the 3-position (1-substituent-2, 6- There is no mention or suggestion that it may include diimino-pyrimidinium-4-yl) thiomethyl groups.

European Patent Application No. 47,977 describes cefem compounds of the general formula (C) and salts thereof.

In which n is 0 or 1; Am is an optionally substituted imino; T is a thiadiazolyl component (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 thiozolium, 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-substituted (Lower) alkenyl, (lower) alkylthio or carboxy-substituted (lower) alkylthio, imino or monosubstituted imino [substituents are (lower) alkyl, (lower) alkanoyl or iminobenzenesulfonyl] , Di (lower) alkylimino, substituted carbamoyl [substituents are (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy, hydroxy or cyanoim], di (lower) -alkyl carbamoyl, thio Carbamoyl, 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 cefem derivatives having an (substituted) iminothiadiazole ring at the 7-position, one of the greatest features of the present invention is the (1-substituent-2, 6-diimino pyrimidinium- 4-yl) thiomethyl group has no explanation or presentation.

Tsudomuterachi et al. Describe US cefe and cefe compounds of the general formula (D) in US Pat. No. 4,390,534.

Wherein R ¹ is an imino or a protected imino group; R ² is hydrogen or acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, oxygen or sulfur containing 5-membered hetero rings substituted with optionally substituted cycloalkyl, cycloalkenyl or oxo groups; R ³ is hydrogen or an alkyl group; R ⁴ is hydrogen, acyloxyalkyl, alkylthioalkyl, optionally substituted pyridiniumalkyl, optionally substituted heterocyclicthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolium alkyl; R ⁵ is carboxy or protected carboxy; Provided that R ⁵ is COO- when R ⁴ is optionally substituted pyridiniumalkyl or optionally substituted thiazoliniumalkyl; The --- line indicates a single bond or a double bond.

However, the R ⁴ group in US Pat. No. 4,390,534 above shows a broad range of optionally substituted heterocyclylthioalkyl groups, but only at the 3-position of the core of the present invention (1-substituent-2, 6-diiminopyrimidinium). There is no mention or suggestion that it may contain a -4-yl) thiomethyl group.

Thus, the inventors have conducted studies and have cephalo having 1-substituted-2 and 6-diiminopyrimidinium-4-yl thiomethyl groups at the C-3 position, and at the same time having several groups specific at the 7-β-position. It has been found that the sporin compounds show potent activity against a wide range of pathogens.

The compounds according to the invention also include geometric isomers, mixtures of syn and anti-isomers containing at least 90% of syn-isomers or syn-isomers.

In addition, solvates (including hydrates) of the compound of general formula (I) are also included in the scope of the present invention. Moreover, since the iminothiazole group can form an iminothiazoline group and tautomer in General Formula (I) compound, such tautomer is also included in the scope of the present invention.

2-iminothiazol-4-yl 2-iminothiazolin-4-yl

Furthermore, since the compound of general formula (I) may have a resonance structure such as general formula (I ′) or general formula (I ′), such a resonance structure is also included in the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, hydroxyl acid, succinic acid, benzo Organic carboxylic acids such as phosphoric acid, tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid and other acids known and used in the art of penicillin and cephalosporin And salts of; These acid addition salts are prepared by conventional techniques. Or compounds of formula (I) may also form non-toxic salts with bases. Bases used herein include alkali metal hydroxides (e.g. caustic soda, caustic), alkaline earth metal hydroxides (e.g. calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate) Inorganic bases, such as these, and organic bases, such as imino acid, 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 the art of penicillin and cephalosporin. Such esters are prepared by known methods.

Formula (I) compound has high antimicrobial activity against various Gram-positive and Gram-negative bacteria and is used for the prevention and treatment of bacterial infection in animals including humans. Formula (I) compounds are formulated by known methods using known pharmaceutical carriers and excipients and are in unit dosage forms or in multidose containers. The compositions are in the form of solutions, suspensions or emulsions in oil or aqueous media and may contain conventional dispersing agents, suspending agents or stabilizers. In addition, the composition may be in the form of a dry powder which is dissolved before use, for example, in sterile, pyrogen-free water. The compounds of formula (I) may also be formulated as suppositories using conventional suppository bases such as cocoa butter or other glycerides. If desired, the compounds of the present invention may be administered in combination with other antibacterial agents such as penicillin or cephalosporin.

When forming the composition in the unit dosage form, it is preferable to contain about 50 to 1,500 mg of the active ingredient of the compound of formula (I). The dosage of the compound of general formula (I) is according to the doctor's prescription depending on factors such as the patient's weight and age and the particular nature and severity of the disease. However, dosages required for adult treatment typically range from about 500 to 5,000 mg per day, depending on the frequency and route of administration. The total dosage of about 150 to 3,000 mg per day will be sufficient, usually in single doses for intramuscular or intravenous administration to adults, but a higher daily dosage is preferred for some strains of infection.

The compounds according to the invention exhibit a wide range of antimicrobial activities, which are generally highly active against gram negative and positive bacteria, and this activity also applies to many gram negative bacteria producing β-lactam.

Examples of preferred compounds having high antimicrobial activity among the compounds according to the present invention are compounds of formula (I) wherein R ¹ is ethyl, R ² is methyl or ethyl and Q is N, ie the following formulas (Ia) and (Ib) Compound and its non-toxic salts.

The compounds of the general formulas (I-a) and (I-b) remarkably exhibit the antimicrobial activity of the compounds of the general formula (I), and particularly exhibit excellent antimicrobial activity against Pseudomonas strains.

Other examples of preferred compounds according to the invention are summarized in Table 1 below.

TABLE 1

According to the present invention, the compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, a physiologically hydrolysable ester, hydrate or solvate thereof is prepared by the compound of formula (II) in the presence of a solvent It can be prepared by reacting with the compound of (III), removing the imino protecting group or acid protecting group before or after the reaction if necessary or reducing the S-oxide [S → (0) n].

Wherein R ¹ , R ² and Q are as defined above; n is 0 or 1; R ³ is hydrogen or an imino protecting group; R ⁴ represents hydrogen or a carboxyl protecting group; R ⁵ is a C _1-4 alkyl group, C _3-4 alkenyl group or C _3-4 alkynyl group or a —C (R ^a ) (R ^b ) —COO (R ^c ) group. 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 represent a C _3-7 cycloalkyl group together with the carbon atom to which they are attached, R ^c represents hydrogen or a carboxyl protecting group.

Wherein R ^{3, which} is an iminoprotective group, is an acyl, substituted or unsubstituted ar (lower) alkyl group (eg benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), bowo (lower) alkyl (eg Trichloromethyl, trichloroethyl, etc.), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like. Acyls suitable as iminoprotecting 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.), lower alkanesul Ponyyl (eg methanesulfonyl, ethanesulfonyl, etc.), or ar (lower) alkoxycarbonyl (eg 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 silane, boron, phosphorus compound and imino group may also be an imino protecting group.

The carboxyl protecting group of R ⁴ is generally suitable as long as it can be easily removed under mild conditions, and examples thereof include (lower) alkyl esters (eg methyl esters, t-butyl esters, etc.) and (lower) alkenyl esters (eg. Vinyl esters, allyl esters, etc.), (lower) alkoxy (lower) alkyl esters (e.g. methoxymethyl esters, etc.), (lower) alkylthio (lower) alkyl esters (e.g. methylthiomethyl esters, etc.), halo (lower) ) Alkyl esters (eg 2,2,2-trichloroethyl ester, etc.), substituted or unsubstituted aralkyl esters (eg benzyl esters, P-nitrobenzyl esters, etc.) or silyl esters. The imino protecting group and the carboxyl protecting group can be easily removed under mild reaction conditions such as hydrolysis or reduction to form a free imino group or a carboxyl group. The imino protecting group or carboxyl protecting group is appropriately selected and used depending on the chemical property of the general formula (I) compound.

L is a leaving group, for example, a halogen such as chlorine or fluorine, a (lower) alkanoyloxy group such as acetoxy, or a (lower) alkanesulfonyloxy such as metal sulfonyloxy, or a paratoluenesulfonyloxy. Nesulfonyloxy or alkoxy carbonyloxy and the like.

In the structure of the compound of the general formula (II), the dotted line represents the general formula (II-a) compound, or the general formula (II-b) compound as the general formula (II) compound alone, or a) a compound and a mixture of the general formula (II-b) compound.

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

The compound of general formula (II) which is a starting material of the present invention can be prepared according to the following reaction scheme as a known compound. That is, it can be prepared by activating a compound of formula (IV) or a salt thereof with an acylating agent and reacting with a compound of formula (V).

In the above scheme, n, R ³ , R ⁴ , R ⁵ , L and Q are as described above, and the dotted line in the compound of formula (V) is represented by the following formula (Va) Or a compound of the formula (Va) and a compound of the formula (Vb).

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

In preparing the compounds of formula (II), the active acylated derivatives of formula (IV) are acid chlorides, acid anhydrides, mixed acid anhydrides (preferably methylchloroformate, mesitylenesulfonyl chloride, p-toluene Acid anhydrides formed with sulfonyl chloride or chlorophosphate) or activated esters (preferably those formed in the reaction with N-hydroxy benzotriazole in the presence of a condensing agent such as dicyclo hexyl carbodiimide). . The acylation reaction may also proceed with the free acid of formula (IV) in the presence of a condensing agent such as dicyclo hexyl carbodiamide, carbonyl diimidazole. On the other hand, the acylation reaction usually proceeds well in the presence of organic bases such as tertiary amines (preferably triethylamine, dimethylaniline, pyridine), inorganic bases such as sodium bicarbonate, sodium carbonate, and the like and are used as methylene chloride and chloroform. Solvents of the same kind, such as halogenated carbon, terahydrofuran, acetonitrile, dimethyl formamide or dimethyl acetamide and the like. Also mixed solvents of the above solvents may be used and may be used in the form of an aqueous solution.

The temperature of the acylation reaction is about -50 degreeC-50 degreeC (preferably -30 degreeC-20 degreeC), and the acylating agent of the compound of general formula (IV) is a conventional method if the compound of general formula (V) is needed. The imino protecting group or carboxyl protecting group can be removed. That is, the protecting group can be removed by a hydrolysis or reduction method, and in the case where the protecting group contains an imino group, it is preferable to hydrolyze via imino halogenation and imino etherification. Acid hydrolysis is useful for the removal of tri (di) phenyl methyl or alkoxycarbonyl groups and also proceeds with organic or inorganic acids such as formic acid, trifluoroacetic acid, p-toluene sulfonic acid, hydrochloric acid.

The compound of general formula (III) used in the present invention is a novel substance The compound of general formula (III) used in the present invention is a novel substance thereof is described in detail in the preparation examples below.

Meanwhile, in the present invention, in preparing the compound of the general formula (I) by substituting the compound of the general formula (III) at the C-3 position of the compound of the general formula (II), the solvent used may be mixed with water or water. A mixed aqueous solution with a water miscible solvent such as acetonitrile or acetone is used, and the pH of the reaction solution is in the range of 5 to 8 (preferably 6 to 7.5), and the reaction temperature is 40 to 100 ° C (preferably). The reaction proceeds well in the range of about 60 ° C to 80 ° C. Compounds of formula (III) may use equivalents or excess (1-2 equivalents) to compound of formula (II), while sodium iodide (potassium), bromosodium (potassium) is used to stabilize reaction intermediates and products. ) Or salts such as potassium thiocyanate.

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

The compound of general formula (I) of the present invention and its nontoxic salts (preferably have high antibacterial activity against alkali metal salts, alkaline earth metal salts, inorganic acid salts and organic acid salts or imino acids), The usefulness was evaluated by obtaining the minimum Inhibitory Concenration for a standard strain using the known compound Cefotaxime as a control agent. After dilution by dilution method, the cells were dispersed in Muller-Hinton agar medium, and then, 2 µl of the standard test strain having 10 CFU per ml was inoculated and incubated at 37 ° C. for 20 hours. 2 is shown.

Main compound of the present invention

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

Ib: 7-[(Z) -2- (5-imino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- (2,6 -Diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Ic: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- (2,6-diimino- 1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Id: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- (2,6-diimino- 1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Ie: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] -3- (2,6-diimino -1-iminopyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

If: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] -3- (2,6-diimino -1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Ig: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (propene-1-oxyimino) acetamido] -3- (2,6-diimino-1 -Methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Ih: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (2,6-diimino-1-methylpyri Midinium-4-yl) thiomethyl-3-cepem-4-carboxylate

Ii: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (2,6-diimino-1-methylpyri Midinium-4-yl) thiomethyl-3-cepem-4-carboxylate

Ij: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxyl-1-oxyimino) acetamido] -3- (2,6- Diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Ik: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxy--1-oxyimino) acetamido] -3- (2,6- Diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

Il: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (2,6-diimino-1-methylpyrimidy Nium-4-yl) thiomethyl-3-cepem-4-carboxylate

Im: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (2,6-diimino-1-methylpyrimidy Nium-4-yl) thiomethyl-3-cepem-4-carboxylate

In: 7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-2oxyimino) acetamido] -3- (2,6-diimino -1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate

TABLE 2

[Production Example 1]

Synthesis of 2,6-diimino-4-chloro-1-methyl-1-pyrimidinium iodide

2,6-Diimino-4-chloro-1,3-pyrimidine (14.45 g) is dissolved in tetrahydrofuran (100 ml), and methyl iodide (70 g) is mixed and refluxed for 10 hours. The reaction solution is cooled to 0 ° C., the resulting solid is filtered, washed with tetrahydrofuran and dried to give the title compound (25.6 g).

NMR: (δ, DMSO-d ₆ ) 7.2 (d, 4H), 6.90 (s, 1H), 4.12 (s, 3H)

[Production Example 2]

Synthesis of 2,6-diimino-4-chloro-1-ethyl-1-pyrimidinium iodide

2,6-Diimino-4-chloro-1,3-pyrimidine (14.45 g) is dissolved in tetrahydrofuran (100 ml), then ethyl iodide (70 g) is mixed and refluxed for 8 hours. The reaction solution is cooled to 0 ° C., the resulting solid is filtered, washed with tetrahydrofuran and dried to give the title compound (25 g).

NMR: (δ, DMSO-d ₆ ) 7.3 (d, 4H), 6.91 (s, 1H), 4.20 (q, 2H), 1.42 (t, 3H)

[Manufacture example 3]

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

Compound (28.6 g) and sodium hydrosulfide hydrate (28 g) produced in Preparation Example 1 were mixed with methyl alcohol (150 ml) and refluxed for 1 hour. Quickly remove the insolubles, remove the solvent and chromatograph the dichloromethane: methanol (5: 1) with eluent to afford the title compound (8.2 g).

Melting Point: Decomposes above 210 ℃

NMR: (δ, DMSO-d ₆ ) 7.05 (s, 2H), 6.42 (s, 2H), 5.96 (s, 1H), 3.69 (s, 3H)

[Production Example 4]

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

Compound (30.04g) and sodium hydrosulfide hydrate (28g) produced in Preparation Example 2 were mixed with methyl alcohol (150ml) and carried out in the same manner as Preparation Example 3 to obtain the title compound (8.6g).

Melting Point: Decomposes above 206 ℃

NMR: (δ, DMSO-d ₆ ) 7.06 (s, 2H), 6.50 (s, 2H), 5.94 (s, 1H), 4.19 (q, 2H), 1.42 (t, 3H)

Example 1

(6R, 7R) -7-[(Z) -2- (5-imino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- Synthesis of (2,6-diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ia)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (5-imino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acet Amido] -3-cef-4-carboxylic acid (500 mg) was added to the solution prepared in Preparation Example 3 (300 mg) and potassium iodide (800 mg) in a solution suspended in distilled water (5 ml) and pH 7.1 in aqueous sodium bicarbonate solution. Heat to 70 ° C. while adjusting to ˜7.2. The reaction solution was stirred for 4 hours, cooled to room temperature, adjusted to pH 3.0-3.5 with 2N hydrochloric acid aqueous solution, and the resulting precipitate was filtered and washed with distilled water (5 ml). The filtered solid is dissolved, and the title compound (300 mg) is obtained by chromatography on silica gel using acetonitrile: distilled water (5: 1) mixed solvent as an eluent.

Melting Point: Decomposes above 158 ℃

NMR: (δ, D ₂ O) 6.21 (s, 1H), 5.83 (d, 1H), 5.19 (d, 1H), 4.34 (q, 2H), 3.6 ~ 4.1 (dd, 2H), 3.45 ~ 4.85 ( dd, 2H), 3.64 (s, 3H), 1.31 (t, 3H)

IR (KBr, cm ^-1 ): 1768 (β-lactam), 1676

Example 2

(6R, 7R) -7-[(Z) -2- (5-imino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acetamido] -3- Synthesis of (2,6-diimino-1-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ib)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (5-imino-1,2,4-thiadiazol-3-yl) -2- (ethoxyimino) acet Amido] -3-cefe-4-carboxylic acid (500 mg) was added to the solution prepared in Preparation Example 4 (320 mg) and potassium iodide (800 mg) in a solution suspended in distilled water (5 ml). In the same manner as the title compound (280 mg) is obtained.

Melting Point: Decomposes above 161 ℃

NMR: (δ, D ₂ O) 6.13 (s, 1H), 5.82 (d, 1H), 5.20 (d, 1H), 4.35 (q, 2H), 4.10 (q, 2H), 3.6 ~ 4.1 (dd, 2H), 3.4-4.8 (dd, 2H), 1.36 (m, 6H)

IR (KBr, cm ^-1 ): 1769 (β-lactam), 1680,1590

Example 3

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- (2,6 Synthesis of -Diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ic)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido]- To a solution of 3-cefem-4-carboxylic acid (500 mg) suspended in distilled water (5 ml), the compound (200 mg) prepared in Preparation Example 3 and potassium iodide (800 mg) were added thereto, and the same procedure as in Example 1 was carried out. To give the title compound (330 mg) as a solid.

Melting Point: Decomposes above 175 ℃

NMR: (δ, D ₂ O) 6.99 (s, 1H), 6.19 (s, 1H), 5.78 (d, 1H), 5.20 (d, 1H), 3.6 ~ 4.3 (dd, 2H), 3.4 ~ 4.0 ( dd, 2H), 3.61 (s, 3H), 1.49 (s, 6H)

IR (KBr, cm ^-1 ): 1766 (β-lactam), 1669,1615,1558

Example 4

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido] -3- (2,6 Synthesis of -diimino-1-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Id)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxyprop-2-oxyimino) acetamido]- To a solution of 3-cefe-4-carboxylic acid (500 mg) suspended in distilled water (5 ml), the compound (210 mg) prepared in Preparation Example 4 and potassium iodide (800 mg) were added thereto, and the same procedure as in Example 1 was carried out. To give the title compound (300 mg).

Melting Point: Decomposes above 163 ℃

NMR: (δ, D ₂ O) 6.99 (s, 1H), 6.20 (s, 1H), 5.78 (d, 1H), 5.20 (d, 1H), 3.7 ~ 4.3 (dd, 1H), 3.41 ~ 4.05 ( dd, 1H), 3.61 (q, 2H), 1.52 (s, 6H), 1.21 (t, 3H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1680,1590

Example 5

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] -3- (2, Synthesis of 6-diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ie)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] To the solution of 3-Cefe-4-carboxylic acid (500 mg) suspended in distilled water (5 ml) was added the compound (300 mg) prepared in Preparation Example 3 and potassium iodide (800 mg) in the same manner as in Example 1. The title compound (280 mg) is obtained.

Melting Point: Decomposes above 167 ℃

NMR: (δ, D ₂ O) 7.01 (s, 1H), 6.24 (s, 1H), 5.80 (d, 1H), 5.20 (d, 1H), 4.81 (s, 2H), 3.8 ~ 4.4 (dd, 1H), 3.3-4.18 (dd, 2H), 3.62 (s, 3H), 3.08 (s, 1H)

IR (KBr, cm ^-1 ): 1770 (β-lactam), 1680,1588

Example 6

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] -3- (2, Synthesis of 6-diimino-1-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (If)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propyn-1-oxyimino) acetamido] To a solution of -3-cefe-4-carboxylic acid (500 mg) suspended in distilled water (5 ml) was added the compound (310 mg) prepared in Preparation Example 4 and potassium iodide (800 mg) in the same manner as in Example 1. The title compound (270 mg) is obtained.

Melting Point: Decomposes above 158 ℃

NMR: (δ, D ₂ O) 7.00 (s, 1H), 6.31 (s, 1H), 5.85 (d, 1H), 5.24 (d, 1H), 4.82 (s, 2H), 3.8 ~ 4.4 (dd, 2H), 3.3 ~ 4.2 (dd, 2H), 4.18 (q, 2H), 3.09 (s, 1H), 1.41 (t, 3H)

IR (KBr, cm ^-1 ): 1760 (β-lactam), 1670

Example 7

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propene-1-oxyimino) acetamido] -3- (2, Synthesis of 6-diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ig)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (2-propene-1-oxyimino) acetamido] To a solution of 3-Cefe-4-carboxylic acid (400 mg) suspended in distilled water (10 ml) was added the compound (200 mg) prepared in Preparation Example 4 and potassium iodide (800 mg) in the same manner as in Example 1. The title compound (180 mg) is obtained.

Melting Point: Decomposes above 168 ℃

NMR: (δ, D ₂ O) 6.96 (s, 1H), 5.11 ~ 6.25 (m, 5H), 6.32 (s, 1H), 5.84 (d, 1H), 5.18 (d, 1H), 4.40 (ABq, 2H), 3.61 (ABq, 2H), 3.65 (s, 3H)

IR (KBr, cm ^-1 ): 1769 (β-lactam), 1671,1619

Example 8

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (2,6-diimino- Synthesis of 1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ih)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3-cepem- 4-carboxylic acid (400 mg) was suspended in distilled water (5 ml), followed by mixing the compound (200 mg) prepared in Preparation Example 3 with potassium iodide (800 mg) in the same manner as in Example 1, followed by the title compound ( 200 mg).

Melting Point: Decomposes above 158 ℃

NMR: (δ, D ₂ O) 7.01 (s, 1H), 6.28 (s, 1H), 5.79 (d, 1H), 5.22 (d, 1H), 4.55 (s, 2H), 4.20 (ABq), 3.52 (ABq), 3.58 (s, 3H)

IR (KBr, cm ^-1 ): 1766 (β-lactam), 1675,1610

Example 9

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (2,6-diimino- Synthesis of 1-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ii)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3-cepem- 4-carboxylic acid (400 mg) was suspended in distilled water (5 ml), followed by mixing the compound (250 mg) prepared in Preparation Example 3 with potassium iodide (800 mg) in the same manner as in Example 1, followed by the title compound ( 185 mg).

Melting Point: Decomposes above 165 ℃

NMR: (δ, D ₂ O) 7.00 (s, 1H), 6.28 (s, 1H), 5.80 (d, 1H), 5.21 (d, 1H), 4.56 (s, 2H), 4.20 (ABq), 3.52 (ABq), 4.12 (q, 2H), 1.42 (t, 3H)

IR (KBr, cm ^-1 ): 1762 (β-lactam), 1668,1610

Example 10

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxyl-1-oxyimino) acetamido] -3- ( Synthesis of 2,6-diimino-1-methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ij)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxy-1--1-iminomino) acetami Fig. 3] Suspension of 4-cefe-4-carboxylic acid (500 mg) in distilled water (5 ml) and then the compound (200 mg) prepared in Preparation Example 3 and potassium iodide (800 mg) was mixed in the same manner as in Example 1 In the same manner, the title compound (310 mg) is obtained.

Melting Point: Decomposes above 163 ℃

NMR: (δ, D ₂ O) 7.01 (s, 1H), 6.29 (s, 1H), 5.80 (d, 1H), 5.23 (d, 1H), 4.23 (ABq, 2H), 3.55 (ABq, 2H) , 3.75 (s, 3H), 1.43 (d, 3H)

IR (KBr, cm ^-1 ): 1760 (β-lactam), 1669,1612

Example 11

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxyl-1-oxyimino) acetamido] -3- ( Synthesis of 2,6-diimino-1-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Ik)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (R, S-carboxy-1--1-iminomino) acetami Fig. 3] Suspension of 4-cefe-4-carboxylic acid (500 mg) in distilled water (5 ml) and then the compound (300 mg) prepared in Preparation Example 4 and potassium iodide (800 mg) was mixed in the same manner as in Example 1 In the same manner, the title compound (290 mg) is obtained.

Melting Point: Decomposes above 168 ℃

NMR: (δ, D ₂ O) 7.00 (s, 1H), 6.28 (s, 1H), 5.81 (d, 1H), 5.22 (d, 1H), 4.21 (ABq, 2H), 3.56 (ABq, 2H) , 4.21 (q, 2H), 1.51 (d, 3H), 1.40 (t, 3H)

IR (KBr, cm ^-1 ): 1765 (β-lactam), 1670,1615

Example 12

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (2,6-diimino-1 Synthesis of -methylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Il)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-cepem-4 -Suspended carboxylic acid (500mg) in distilled water (10ml), and then mixed the compound (200mg) and potassium iodide (800mg) prepared in Preparation Example 3 and carried out in the same manner as in Example 1 to the title compound (350mg Get)

Melting Point: Decomposes above 158 ℃

NMR: (δ, D ₂ O) 7.02 (s, 1H), 6.29 (s, 1H), 5.82 (d, 1H), 5.22 (d, 1H), 4.30 (ABq, 2H), 3.80 (s, 1H) , 3.45 (ABq, 2H), 3.58 (s, 3H)

IR (KBr, cm ^-1 ): 1762 (β-lactam), 1620

Example 13

(6R, 7R) -7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (2,6-diimino-1 Synthesis of -Ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate (Im)

(6R, 7R) -3-acetoxymethyl-7-[(Z) -2- (2-iminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-cepem-4 -Suspended carboxylic acid (500 mg) in distilled water (10 ml), and then the compound (300 mg) prepared in Preparation Example 4 and potassium iodide (800 mg) was mixed and then carried out in the same manner as in Example 1 to give the title compound (260 mg) Get)

Melting Point: Decomposes above 161 ℃

NMR: (δ, D ₂ O) 7.00 (s, 1H), 6.29 (s, 1H), 5.83 (d, 1H), 5.23 (d, 1H), 4.31 (ABq, 2H), 4.25 (q, 2H) , 3.47 (ABq, 2H), 3.80 (s, 3H), 1.42 (t, 3H)

Claims (8)

The cephalosporin compound represented by the following general formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiologically hydrolysable esters thereof, hydrates, solvates and isomers thereof.

Wherein R ^1-a represents methoxy, ethoxy, 2-propyn-1-oxy, 2-propene-1-oxy or —OC (R ^a ) (R ^b ) COOH, wherein R ^a , R ^b may be the same or different and each represents hydrogen or methyl, R ² is methyl or ethyl and Q is CH or N. A compound of formula (I), a pharmaceutically acceptable non-toxic salt thereof, physiologically characterized by reacting with a compound of formula (III) in the presence of a compound of formula (II), a solvent and a stabilizer: A process for preparing hydrolyzable esters, hydrates or solvates thereof.

Wherein R ^1-a represents methoxy, ethoxy, 2-propyn-1-oxy, 2-propene-1-oxy or —OC (R ^a ) (R ^b ) COOH, wherein R ^a R ^b may be the same or different and each represents hydrogen or methyl, R ² represents methyl or ethyl, R ³ represents hydrogen or iminoprotecting group, R ⁴ represents hydrogen or carboxyl protecting group, and R ^{1- b} represents methoxy, ethoxy, 2-propyn-1-oxy, 2-propene-1-oxy or -OC (R ^a ) (R ^b ) COO (R ^c ), wherein R ^a , R ^b may be the same or different and each represents hydrogen or methyl, R ^c represents hydrogen or a carboxyl protecting group, Q is CH or N and L is a leaving group. The method of claim 2 wherein the solvent used is water or a mixed aqueous solution of water and a water miscible solvent. The method of claim 3 wherein the water miscible solvent is acetonitrile. The method according to claim 2, 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 2, wherein the reaction solvent has a pH of 5-8. The method of claim 2 wherein the stabilizer is potassium iodide. The method according to claim 2, wherein the imino protecting group or acid protecting group is removed or the S-oxide is reduced before or after reacting the compound of formula (II) with the compound of formula (III).