KR940000198B1 - Pyridine compounds - Google Patents

Abstract

Cephem derivs. of formula (I) and their pharmaceutically acceptable salts are new. 4 (Or 3)-(4-ethyl-2,3-dioxo-1-piperazinyl carboxyamido) pyridine compounds (II) substituted at C-3 of cephem derivs. (I) are prepared by reacting 4-ethyl-2,3-dioxo-1-piperazinyl carbonyl chloride with 4 (or 3)-aminopyridine in the presence of triethylamine. (II) are useful as a material for the prepn. of antibacterial cephem compounds.

Description

Pyridine compounds

The present invention relates to a novel cephal compound and a compound used for the preparation of a pharmacologically useful novel cefem compound represented by the following general formula (I), which exhibits broad antibacterial activity against Gram-positive bacteria and Gram-negative bacteria and also shows strong antibacterial activity against various resistant bacteria. .

R in formula (I) is hydrogen, lower alkyl, lower alkyl substituted with carboxy (or inorganic cation salt thereof) or lower alkyl substituted with protected carboxy. Substituents are bonded at positions 3 and 4 of the pyridine ring. Lower alkyl in the present invention means alkyl having a straight or branched chain having 1 to 5 carbon atoms and cycloalkyl having 3 to 6 carbon atoms unless otherwise specified. Preferred lower alkyl substituted with carboxy is methyl, ethyl. And propyl, isopropyl, tert-butyl, butyl, pentyl, hexyl and the like having from 1 to 6 carbon atoms, more preferably from 1 to 4 carbohydrates.

By protecting group is meant carboxyl esterified with commonly used groups such as tert-butyl, diphenylmethyl, 4-methoxybenzyl, benzyl, 4-nitrobelzyl and the like.

Pharmacologically useful salts in formula (I) include inorganic metal salts such as sodium and potassium, inorganic cationic salts such as alkaline metals such as calcium and magnesium, and hydrochloric acid, hydrobromide, hydroiodide, sulfate, carbonate and bicarbonate. Organic salts such as inorganic acid salts, maleates, lactates, tartrates, organic sulfonates such as benzene sulfonate, methane sulfonate, 4-toluene sulfonate and amino acid salts such as arginine, lysine, glycine and trimethylamine, ammonia, triethylamine Amine salts such as pyridine, procaine, picoline, and the like.

Specific examples of the substituent at position 3 in the present invention include the following, but are not limited thereto.

4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine,

3- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine.

Compounds of formula (I) and their pharmacologically useful salts can be obtained by reactions of the following formulas (II) and (III).

In said Formula (II), X is a halogen atom or an acetoxy group, a halogen atom means an iodine, a bromine, and a chlorine atom, and especially bromine or iodine is preferable. The reaction is carried out at a temperature of -30 ℃ to 50 ℃ and anhydrous solvent is preferred as the reaction solvent. Suitable organic solvents include lower nitrile solvents such as acetonitrile, propionitrile, chloroform, carbon tetrachloride, halogenated alkyls such as dichloromethane, ethers such as tetrahydrofuran, dioxane, amides such as N, N-dimethylformamide, esters such as ethyl acetate, Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, aromatic hydrocarbons such as benzene, toluene and mixed solvents thereof are possible. The protecting group of the amine group and carboxyl group of general formula (II) is group which does not participate in a substitution reaction.

Examples of the protecting group for the amine group include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, triphenyl group, 4-methoxybenzyl group, diphenylmethyl group and the like. Examples of the protecting group include 4-methoxybenzyl group, 4-nitrobenzyl group, tert-butyl group, diphenylmethyl group, methyl group, 2,2,2-trichloroethyl group, pivaloyloxymethyl group and the like.

In addition, as a protecting group for amine groups and carboxyl groups, silylation reagents include bis (trimethylsilyl) acetamide and N-methyl- (trimethylsilyl) trifluoroacetamide, which have the advantage of protecting amine and carboxyl groups simultaneously. have. Pharmacologically useful salts of formulas (II) and (III) are the same as those mentioned for formula (I).

In the present invention, the hetero compound substituted at position 3 of the cefe is synthesized as in Example as a novel substance which forms an amide bond between an aminopyridine derivative and 4-ethyl-2,3-dioxo-1-piperazine derivative. . Compound of formula (I) was isolated and purified by organic solvent extraction, crystallization and column chromatography. These compounds include Gram-positive bacteria such as Streptococcus, Staphylococcus, Corynebacterium, and Bacillus, Gram-negative bacteria, Escherichia coli, Krebs. It exhibits broad antimicrobial activity against.

To demonstrate the antimicrobial activity, compounds of formula (I) were tested by in vitro antimicrobial activity assay, and cytotaxic (CTX) was used as a comparative material. In vitro antimicrobial activity measurement test indicates the minimum inhibitory concentration (MIC) in μg / m1 according to the following method.

MIC values of these compounds were determined according to the Agar-dilution method. That is, 1.5 ml of 2-fold diluted test compound is dispensed into a test tube, and 13.5 ml of Muller-Hinton Agar is added. After mixing, pour into sterile Petri dishes and coagulate. Inoculate the test suspension suspension dilution (about 10 cfu / ml) on the mixed agar plate using an inoculator.

After 18 hours of incubation at 37 ° C, the concentration of the test compound in which the growth of the test bacteria is inhibited is determined as MIC.

Table 1 shows the MIC of the test compounds.

TABLE 1

Antimicrobial agents based on the compound of formula (1) or salts thereof are mainly used in various formulations such as oral preparations such as injections (intravenous injections, intramuscular injections), capsules, tablets, powders, and rectal dosage forms, oil-based suppositories, and water-soluble suppositories. do.

These various preparations can be prepared using commonly used excipients, weighting agents, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, fusion aids, preservatives, copulation agents, analgesics, etc. have.

Hereinafter, the scope of the present invention is not limited by these examples, which will be described in detail for the present invention by way of examples.

Example 1

4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine

4-ethyl 2,3-dioxo-1-piperazinylcarbonyl chloride (1.04 g) is dissolved in acetonitrile (30 ml) and cooled to 0 ° C. After adding triethylamine (0.7 ml) at 0 ° C. and adding 4-aminopyridine (0.5 g), a white solid is produced within 5 minutes. After 2 hours filtration gives a solid. This solid was poured into 100 ml of methanol, stirred for 20 minutes, and filtered to obtain the title compound.

m.p. : 215 ~ 220 ℃

NMR (CDCl ₃ ): 1.3 (3H, t), 4.1 (2H, d), 7.5 (2H, 2-d), 8.5 (2H, 2-d), 11.3 (1H, s)

Example 2

3- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine

4-ethyl-2,3-dioxo-1-piperazinylcarbonyl chloride (1.04 g) is dissolved in acetonitrile (30 ml) and cooled to 0 ° C. Trimethylamine (0.7 ml) was added to 0 ° C. in the same manner as in Example 1, and 3-aminopyridine (0.5 g) was added to give a white solid, which was filtered after 2 hours to obtain a solid. Methanol (100ml) was added to the solid, and the mixture was stirred for 20 minutes and filtered to obtain the target compound.

m.p. : 219 ~ 220 ℃

NMR (CDCl ₃ ): 1.3 (3H, t), 4.0 (2H, d), 7.4 (2H, m), 8.3 (2H, m)

Reference Example 1

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (4-ethyl-2,3-dioxo -1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid ( 920 mg) was suspended in dried dichloromethane (10 ml) and N-methyl-N- (trimethylsilyl) -trifluoroacetamide (1.

1 ml) was added, followed by stirring for 1 hour, followed by silylation, iodine trimethylsilane (0.47 ml) was added in ice cooling, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, 4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxyimido) pyridine (200 mg) was dissolved in acetonitrile (10 ml) and tetrahydrofuran (1 ml). Was reacted with N, O-bistrimethylsilylacetamide (1.4 ml) for 2 hours at room temperature in an acetonitrile (10 ml) solvent, and then silylated pyridine derivative was added for 3 hours, followed by methanol (0.6 ml). And acetonitrile (2 ml) mixture was added to deprotect, stirred for 10 minutes and filtered. The resulting solid was suspended in water (10 ml), maintained at pH 7 with sodium bicarbonate, concentrated, and passed through a silica gel column with a 30% ethanol aqueous solution as a developing solvent, followed by freeze drying to obtain the target compound (50 mg).

m.p. : 219 ° C (dec)

IR (KBr, Cm ^-1 ): 1780

NMR (DMSO-d6): 1.5 (1H, t), 3.8 (3H, s), 4.0 (4H, m), 4.3 (2H, d), 5.1 (1H, d), 5.8 (1H, d), 6.8 (1H, s), 7.1 (2H, s), 8.1 (2H, m), 9.0 (2H, m), 9.5 (1H, d), 11.5 (1H, s)

Reference Example 2

7-β [(Z) -2- (2-aminothiazol-4-yl) -2- (propazyloxyimino) acetamido] -3- [4- (4-ethyl-2,3-di Oxo-1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (propazyloxyimino) acetamido] -3-acetoxymethyl-3-cepem-4-carboxyl The acid (920 mg) was suspended in dried dichloromethane (10 ml), and N-methyl-N- (trimethylsilyl) -trifluoroacetamide (2 ml) and iodine trimethylsilane (0.9 ml) were used in the same manner as in Reference Example 1. After concentration, the solution was dissolved in acetonitrile (10 ml) and tetrahydrofuran (4 ml) and 4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine (2.5 ml) was added to the solution. The reaction mixture was added to the silylated pyridine derivative, reacted for 3 hours, methanol (1 ml) was added, deprotected, and filtered to obtain the target compound (300 mg).

m.p. : 225 ° C (dec.)

IR (KBr, Cm ^-1 ): 1775

NMR (DMSO-d6): 1.8 (3H, t), 3.8 (3H, s), 4.0 (4H, m), 4.3 (2H, d), 4.6 (1H, d), 5.2 (1H, d), 5.8 (1H, dd), 6.8 (1H, s), 7.2 (2H, s), 7.4 (1H, m), 8.2 (2H, q), 8.9 (2H, m), 9.5 (1H, d), 11.6 ( 1H, s)

Reference Example 3

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3- [3- (4- Ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3-acetoxymethyl-3- Sepem-4-carboxylic acid (520 mg) was dried dichloromethane (8 ml)

) And reacted with N-methyl-N- (trimethylsilyl) -trifluoroacetamide (1.4 ml) and iodine trimethylsilane (0.6 ml) in the same manner as in Reference Example 1, and concentrated with acetonitrile (7 ml). To a solution dissolved in tetrahydrofuran (1 ml), 4- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine (200 mg) was added to N, O- in acetonitrile (5 ml) solvent. The silylated pyridine derivative produced by reacting with bistrimethylsilylacetamide (1.7 ml) was added thereto, followed by reaction for 3 hours, methanol (0.5 ml) was added to deprotection, filtered and purified to obtain the target compound (100 mg).

m.p. : 213 ° C (dec.)

IR (KBr, Cm ^-1 ): 1768, 1685

NMR (DMSO-d6): 1.8 (3H, t), 4.0 (4H, m), 4.6 (2H, s), 5.1 (1H, d), 5.8 (1H, dd), 6.8 (1H, s), 7.2 (2H, s), 8.2 (2H, m), 9.2 (2H, m), 9.5 (1H, d), 11.3 (1H, s)

Reference Example 4

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (4-ethyl-2,3-dioxo -1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate.

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid ( 500 mg) was suspended in dried dichloromethane (10 ml) and N-methyl-N- (trimethylsilyl) -trifluoroacetamide (

1.2 ml) was added, followed by reaction with iodine trimethylsilane (0.47 ml), concentration, and acetonitrile (1).

0 ml) and 3- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine (220 mg) in a solution dissolved in tetrahydrofuran (2 ml) in acetonitrile (10 ml) solvent, N, The silylated pyridine derivative produced by reacting with O-bistrimethylsilylacetamide (1.5 ml) was added thereto, followed by reaction for 3 hours, and methanol (0.7 ml) was added to deprotection, followed by filtration and purification to obtain the target compound (60 mg).

m.p. : 215 ° C (dec.)

IR (KBr, Cm ^-1 ): 1770, 1690

NMR (DMSO-d6): 1.8 (3H, t), 4.8 (3H, s), 4.0 (4H, m), 5.1 (1H, d), 5.8 (1H, dd), 6.8 (1H, s), 7.8 (3H, m), 8.8 (1H, d), 9.5 (1H, d), 11.5 (1H, s)

Reference Example 5

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (propazyloxyamino) acetamido] -3- [3- (4-ethyl-2,3- Dioxo-1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (propazyloxyamino) acetamido] -3-acetoxymethyl-3-cepem-4-carboxyl The acid (690 mg) was suspended in dried dichloromethane (8 ml), and N-methyl-N (trimethylsilyl) -trifluoroacetamide (1.5 ml) was added in the same manner as in Reference Example 1, followed by iodine trimethylsilane (0.8 ml). ), And concentrated to a solution of acetonitrile (10 ml) and tetrahydrofuran (3 ml) in 3- (4-ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridine (300 mg). The reaction was carried out for 3 hours by adding the silylated pyridine derivative formed by reacting with N, O-bistyrimethylsilyl acetamide (2.0 ml) in acetonitrile (10 ml) solvent, deprotection by addition of methanol (0.7 ml), filtration, Purification gave the target compound (180 mg).

m.p. : 227 ° C (dec.)

IR (KBr, Cm ^-1 ): 1773, 1690

NMR (DMSO-d6): 1.7 (3H, t), 3.6 (3H, s), 4.0 (4H, m), 4.2 (2H, d), 4.7 (2H, m), 5.2 (1H, d), 5.6 (1H, d), 6.7 (1H, s), 7.2 (2H, s), 7.4 (1H, d), 8.2 (2H, q), 8.9 (2H, m), 9.5 (1H, d), 11.6 ( 1H, s)

Reference Example 6

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3- [3- (4- Ethyl-2,3-dioxo-1-piperazinylcarboxamido) pyridiniummethyl] -3-cepem-4-carboxylate

7-β-[(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -3-acetoxymethyl-3- Cefem-4-carboxylic acid (500 mg) was dried dichloromethane (7

ml), and N-methyl-N- (trimethylsilyl) -trifluoroacetamide (1.4 ml) was reacted with iodine trimethylsilane (0.6 ml) in the same manner as in Reference Example 1, followed by concentration with acetonitrile (8 ml). ) And 3- (4-ethyl-2,3-dioxo in a solution dissolved in tetrahydrofuran (1 ml).

-1-piperazinylcarboxamido) pyridine (190 mg) was reacted with N, O-bistrimethylsilylacetamide (1.0 ml) in an acetonitrile (6 ml) solvent and then added to the silylated pyridine derivative for 3 hours. After the reaction, methanol (0.5 ml) was added to deprotect and filtered to obtain the target compound (80 mg).

m.p. : 221 ° C (dec.)

IR (KBr, Cm ^-1 ): 1771, 1693

NMR (DMSO-d6): 1.5 (3H, t), 4.5 (3H, s), 3.9 (4H, m), 5.2 (1H, d), 5.6 (2H, m), 6.8 (1H, s), 7.7 (3H, m), .8 (1H, d), 9.4 (1H, d), 11.4 (1H, s)

Claims (1)

Compound represented by the following structural formula (III) and its pharmacologically useful salt.