KR20050099094A - New cephem compounds, preparation method thereof and composition containing the same - Google Patents

Abstract

The present invention provides a novel cefem compound in which a 1,8-naphthyridine derivative is substituted at the C-3 position of the cefe nucleus, and an aminothiazole derivative is acylated at the C-7 position of the cefe nucleus, and a method for preparing the compound; It relates to an antimicrobial composition containing.

Description

New cefem compound, preparation method thereof, and antimicrobial composition containing same {NEW CEPHEM COMPOUNDS, PREPARATION METHOD THEREOF AND COMPOSITION CONTAINING THE SAME}

The present invention relates to a novel cephalosporin compound and derivatives thereof, and more particularly, to a quaternary ammonium salt by substituting a 1,8-naphthyridine derivative at the C-3 position of the cefe nucleus, and at the C-7 position. Novel cephalosporin compounds, pharmacologically / pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, hydrates, solvates, or isomers thereof, wherein the aminothiazole derivatives are acylated.

The present invention also relates to a method for producing the novel cephalosporin compound and an antimicrobial composition containing the same.

The cephalosporin-based antimicrobial agent can not completely exclude the possibility of cross-reactivity with penicillins, but is known as a relatively non-toxic drug other than this hypersensitivity reaction, and is currently considered as the most preferred antimicrobial agent.

The early development of the cephalosporin-based antimicrobial agent having this advantage, that is, the first generation cephalosporin-based antimicrobial was characterized by a strong antimicrobial effect against Gram-positive bacteria, but the number of generations, especially Gram-negative bacteria and / or Gram-negative bacteria Increasing the antimicrobial effect on negative bacilli, aerobic Gram-negative bacteria and so on. In other words, cephalosporin-based antimicrobial agents have been developed to extend the antimicrobial spectrum to be effective for both Gram-negative bacteria and Gram-positive bacteria as the number of generations of development increases, and also for ease of administration or patient compliance. Drugs that can be administered or have long half-lives have been preferred.

It is well known that the activity or pharmacokinetics of cephalosporin antibiotics are affected by the type of substituents at the C-3 or C-7 position. Based on this fact, the present invention is excellent in antimicrobial activity and in particular Pseudomonas, while maintaining appropriate fat solubility that affects absorption and half-life by controlling the substituents introduced at this C-3 or C-7 position. To provide an antibacterial agent with a strong antimicrobial structure in the stomach.

The present inventors have made efforts to develop an antimicrobial agent having excellent antimicrobial activity and having a particularly strong antimicrobial activity in Pseudomonas, while maintaining proper fat solubility as described above. The present invention has been accomplished by discovering that a compound in which a naphthyridine derivative is substituted and an acylated aminothiazole derivative at the C-7 position meets this purpose.

Accordingly, it is an object of the present invention to provide novel cephalosporin compounds represented by the following general formula (I), pharmacologically / pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, hydrates, solvates, or their To give isomers.

  It is another object of the present invention to provide a new method for preparing the compound of the following general formula (I).

  Another object of the present invention is a compound of the general formula (I), a pharmacologically / pharmaceutically acceptable salt thereof, a physiologically hydrolyzable ester thereof, as an active ingredient, together with a pharmaceutically acceptable carrier, It is to provide an antimicrobial composition containing a hydrate, solvate, or an isomer thereof.

The present invention relates to novel cephalosporin compounds represented by the following general formula (I), pharmacologically / pharmaceutically acceptable salts thereof, physiologically hydrolysable esters thereof, hydrates, solvates, and isomers thereof. .

(Ⅰ)

Wherein, R ₁ represents a lower alkyl group substituted by hydrogen, lower alkyl, a lower alkyl group substituted with fluorine, a lower alkyl group substituted with a carboxyl group or its inorganic cationic salt, or a protected carboxyl group; R ₂ represents hydrogen, a hydroxy group, an amino group or a lower alkyl group; R ₃ represents hydrogen, a nitrile group, an ester group, an amide group, a carboxyl group or a carboxylic acid hydrazide group, provided that in formula (I), R ₁ is a methyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid. Compounds and R ₁ is a carboxypropyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid are excluded from the present invention).

It is preferable that lower alkyl of R < ₁ > is C1-C6 linear or branched alkyl or C3-C6 cycloalkyl. Examples of linear or branched alkyl of 1 to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, tert -butyl, butyl, pentyl, hexyl, and cyclopropyl, cyclobutyl, Cyclopentyl and cyclohexyl can be mentioned.

The lower alkyl group substituted with the protected carboxyl group of R ₁ is a lower substituted with a carboxyl group esterified with a commonly used group such as tert -butyl, diphenylmethyl, 4-methoxy benzyl, 4-nitro benzyl, benzyl and the like. It means an alkyl group.

Salts used for lower alkyl substituted with the inorganic cation salt of the carboxyl group of R ₁ include inorganic cationic salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and hydrochloric acid, hydrobromic acid and hydroiodic acid. Inorganic acid salts such as sulfate, carbonate, and bicarbonate; organic acid salts such as maleate, lactate, tartarate, organic sulfonates such as benzenesulfonate, methanesulfonate, paratoluenesulfonate, and arginine And amino acid salts such as lysine and glycine, and amine salts such as ammonia, trimethylamine, triethylamine, pyridine, procaine, and picoline.

  The compound of formula (I) and pharmaceutically useful salts thereof can be obtained by substitution reaction of the cefem compound of formula (II) with the compound of formula (III).

(Ⅱ)

(Ⅲ)

Wherein X is a silylated 3-iodomethyl group and R ₁ , R ₂ , R ₃ are as defined above.

 The cefem compound of the general formula (II) can be obtained by reacting the compound of the general formula (IV) with iodine trimethylsilane (TMSI), which method is described in U.S. Patent No. 4,266,049 (filed May 5, 1981). And US Pat. No. 4,748,172, filed May 31, 1988.

(Ⅳ)

X is a halogen atom such as chlorine, bromine or iodine or acetoxy.

1,8-naphthyridine derivatives of general formula (III) are Org. React ., 28 , 38 (1982), J. Org. Chem. , 39 , 721 (1974), J. Med. Chem. , 20 , 126 (1977), J. Chem. Soc. ( C ), 318 (1966), and J. Chem. Soc. ( C ), 1566 (1967) and the like can be prepared according to the method introduced in the literature.

The desired compound of formula (I) can be obtained by reacting a cefe compound of formula (II) with a 1,8-naphthyridine derivative of formula (III) in anhydrous aprotic organic solvent and hydrolyzing.

The reaction is carried out at -30 ℃ to 50 ℃, it is preferable to use anhydrous organic solvent as the reaction solvent. Such organic solvents include lower nitro solvents such as acetonitrile and propionitrile, halogenated alkyl solvents such as chloroform, carbon tetrachloride and dichloromethane, ether solvents such as tetrahydrofuran and dioxane, and N, N -dimethylformamide. Amide solvents such as amide solvents, ester solvents such as ethyl acetate and methyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, sulfoxide solvents such as dimethyl sulfoxide, aromatic hydrocarbons such as benzene and toluene It is preferable to use a solvent or a mixed solvent thereof.

As the amine group of the general formulas (II) and (III) and the protecting group of the carboxyl group and the alcohol, a group which does not participate in the substitution reaction is used. As the protecting group of an amine group, for example, formyl group, acetyl group, chloracetyl group, dichloracetyl group, tert -butoxycarbonyl group, benzyloxycarbonyl group, triphenyl group, 4-methoxybenzyl group, diphenylmethyl group, etc. Examples of the protecting group for the carboxyl 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. Examples of the protecting group for the alcohol include an acetoxy group, methoxymethyl group, tetrahydrofuranyl group, tert -butyl group and the like. Also preferred as protecting groups for amine groups, carboxyl groups and alcohol groups are bis (trimethylsilyl) acetamide, N, O -bistrimethylsilyltrifluoroacetamide, N -methyl- N- (trimethylsilyl) acetamide, N -methyl -Silylated reagents such as N -trimethylsilyltrifluoroacetamide, and the like, which is advantageous because it can protect amine groups and carboxyl groups simultaneously.

The compound of formula (I) can be obtained by a crystallization method or the like.

Antimicrobial agents based on the compound of formula (I) and pharmacological / pharmaceutical useful salts thereof are formulated together with a carrier which is commonly used pharmaceutically, for injections (intravenous injections, intramuscular injections), capsules, tablets, powders Oral and rectal dosage forms, oil-based suppositories, water-soluble suppositories, and the like. The compounds of formula (I) and salts thereof of the present invention are preferably formulated into an injection such as intravenous or intramuscular injection.

These various preparations can be prepared using commonly used excipients, extenders, binders, wetting agents, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, preservatives, copulation agents, analgesics, and the like. .

Although the present invention will be described in more detail with reference to the following examples, the following examples are illustrative of the present invention, and the scope of the present invention is not limited by the following examples.

Example

Preparation Example 1. Preparation of 2-aminonicotinaldehyde

37.39 g of nicotinamide and 52.40 g of ammonium sulfamate were heated to 150 ° C., and the mixture was completely dissolved, and then the temperature was gradually raised to 200 ° C. and maintained at this temperature for 6 hours. Once the material inside the reactor was completely solidified, water was added to collect the deposits and washed with ether to remove nicotinonitrile. 2N hydrochloric acid was added to the obtained solid to reflux for 4 hours, and then the product was made alkaline and extracted with ether. The obtained ether solution was dried using potassium carbonate, and the ether was evaporated to obtain the target compound.

Melting point; 98 ~ 99 ℃

IR (KBr, cm-1); 3413 (NH2), 1666, 1558 (C = O)

1H NMR (DMSO- d 6, ppm ); 9.85 (s, 1 H, CHO), 8.23 (d, 1 H, J α-β = 4 Hz),

7.99 (d, 1H, J β-γ = 8 Hz), 7.55 (bs, 2H, NH 2), 6.74 (dd, 1H)

Preparation Example 2. Preparation of 2-amino-1,8-naphthyridine-3-carboxyamide

After adding 5 ml of ethanol to 3.66 g of 2-aminonicotinaldehyde, 5.1 g of cyanoacetamide and 0.65 g of piperidine obtained in Preparation Example 1 and refluxing for 1 hour, the resulting material was filtered and evaporated, and then dimethylform Recrystallization using an amide gave the target compound.

Melting point; 280 ℃

IR (KBr, cm-1); 3350, 3199 (N-H), 1668 (amide), 1558 (amide)

1H NMR (DMSO- d 6, ppm ); 8.78 (d, 5-H, 1H, J 5-6 = 8 Hz), 8.51 (s, carboxamide 2H),

                     8.28 (s, 7-H, 1H), 8.10 (d, 4-H, 1H), 7.57 (s, 1-NH2, 2H),

                     7.22 (q, 6-H, 1H)

Preparation Example 3. Preparation of 2-amino-1,8-naphthyridine-3-carboxylic acid

To 0.66 g of 2-amino-1,8-naphthyridine-3-carboxyamide obtained in Preparation Example 2, 10 ml of water and 0.28 g of caustic soda were refluxed for 2.5 hours, and the material in the reactor was refluxed for about 1 hour. The solution was cooled when dissolved in a clear solution. Acidified with 1N hydrochloric acid to precipitate a solid, which was filtered and dried to obtain the target compound.

Melting point; 336 ~ 337 ℃

IR (KBr, cm-1); 3408, 3161 (N-H), 2700 (acid OH), 1701 (acid C = O),

1H NMR (DMSO- d 6, ppm ); 8.331 (s, acid-H, 1H), 8.340 (d, 7-H, 1H),

                        7.979 (s, 5-H, 1H), 7.288 (q, 6-H, 1H)

Preparation Example 4. Preparation of Methyl-2-hydroxy-1,8-naphthyridine-3-carboxylate

0.37 g of 2-aminonicotinaldehyde obtained in Production Example 1. 0.81 g of dimethylmalonate and 0.07 g of piperidine were refluxed under 50 ml of ethanol for 24 hours. After the reflux, the resulting material was filtered and evaporated, and then recrystallized with methanol to obtain the target compound.

Melting Point: 138 ℃

IR (KBr, cm-1) 3392 (N-H), 1704 (ester C = O), 1677 (ring C = O)

1H NMR (DMSO- d 6, ppm ); 8.61 (d, 7-H, 1H, J 6-7 = 4 Hz),

8.53 (d, 5-H, 1H, J 5-6 = 8 Hz), 8.23 (d, 4-H, 1H),

                        7.30 (q, 6-H, 1H), 4.29 (q, OCH3, 3H), 3.35 (s, OH, 1H)

Preparation Example 5. Preparation of 2-hydroxy-1,8-naphthyridine-3-carboxylic acid hydrazide

0.41 g of methyl-2-hydroxy-1,8-naphthyridine-3-carboxylate and 0.102 g of hydrazine monohydrate obtained in Preparation Example 4 were refluxed under 10 ml of methanol for 1 hour. After reflux, the precipitate was separated and recrystallized from ethanol to obtain the target compound.

Melting Point:> 300 ℃

IR (KBr, cm-1); 3280.6 and 3213.1 (N-H), 1645 (C = O), 1635 (ring C = O)

1H NMR (DMSO- d 6, ppm ): 11.481 (s, CO-NH-, 1H), 8.861 (d, 5-H, 1H, J 5-6 = 8Hz),

                       8.415 (d, 4-H, 1H), 7.357 (q, 6-H, 1H), 3.821 (s, OH, 1H)

Preparation Example 6 Preparation of 3-cyano-2-hydroxy-1,8-naphthyridine

0.37 g of 2-aminonicotinaldehyde, 0.06 g of methyl cyanoacetate and 0.07 g of piperidine obtained in Preparation Example 1 were refluxed for 30 minutes under 50 ml of ethanol. After refluxing the product was filtered and evaporated, and then recrystallized with N, N- dimethylformamide to obtain the target compound.

mp〉 300 ℃

IR (KBr, cm-1); 2233 (CN), 1674 (ring C = O)

1H NMR (DMSO- d 6, ppm ); 8.81 (s, 7-H, 1H), 8.68 (d, 5-H, 1H, J 5-6 = 8 Hz), 8.22 (d, 4H, 1H), 7.36 (t, 6-H, 1H), 3.34 (s, OH, 1H)

Preparation Example 7 Preparation of 2-hydroxy-1,8-naphthyridine-3-carboxyamide

0.37 g of 2-aminonicotinaldehyde, 0.63 g of methylmalonamide and 0.07 g of piperidine obtained in Preparation Example 1 were refluxed under 50 ml of ethanol for 30 minutes. After reflux, the product was filtered and evaporated, and then recrystallized with N, N -dimethylformamide to obtain the target compound.

mp〉 300 ℃

IR (KBr, cm-1); 3338 and 3176 (N-H), 1666 and 1558 (amide and ring C = O)

1H NMR (DMSO- d 6, ppm ); 8.93 (s, 5-H, 1H, J 5-6 = 8 Hz), 8.82 (s, NH2, 2H), 8.63 (d, 7-H, 1H, J 6-7 = 4 Hz), 8.35 (d , 4-H, 1H),

                    7.36 (q, 6-H, 1 H), 3.38 (s, OH, 1 H)

Preparation Example 8. Preparation of 3-amino-2-hydroxy-1,8-naphthyridine

2.04 g of hydrazide, 10 ml of concentrated hydrochloric acid and 20 ml of water were stirred with cooling. A solution of 3 ml of water and 0.76 g of sodium nitrite was slowly added thereto for 30 minutes, and the internal temperature was maintained at 5 ° C or lower. The solution was stirred under cooling for 2 hours, then again at room temperature for 2 hours, and finally heated under steam bath for 5 hours. The mixture was quenched and neutralized with potassium carbonate, the precipitates were collected, washed with water and dried to afford the desired compound.

Melting Point: 283 ℃

IR (KBr, cm-1); 3350 (N-H), 1700 (ring C = O)

1H NMR (DMSO- d 6, ppm ): 8.985 (s, NH2, 2H), 8.791 (d, 5-H, 1H, J 5-6 = 8 Hz),

                        8.274 (s, 7-H, 1H), 8.142 (d, 4-H, 1H),

                        7.476 (q, 6-H, 1H)

Preparation Example 9. Preparation of 2,3-dihydroxy-1,8-naphthyridine

1.61 g of 3-amino-2-hydroxy-1,8-naphthyridine and 25 ml of 10% caustic soda obtained in Preparation Example 8 were heated under a steam bath for 7 hours. After adding acetic acid to this solution to acidify, the resulting white crystals were collected by filtration and recrystallized with N, N -dimethylformamide to obtain the target compound.

Melting Point:> 300 ℃

IR (KBr, cm-1); 3380 (N-H), 1665 (ring C = O)

1H NMR (DMSO- d 6, ppm ): 8.791 (d, 5-H, 1H, J 5-6 = 8Hz), 8.274 (s, 7-H, 1H),

                        8.142 (d, 4-H, 1H), 7.476 (q, 6-H, 1H)

Example 1. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (2-amino-3- Preparation of Carboxylic Acid) -1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was added to a dispersion solution of 0.19 g of 2-amino-1,8-naphthyridine-3-carboxylic acid and 10 ml of acetonitrile obtained in Preparation Example 3, thereby completely. Melted.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this was added 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide also in a nitrogen atmosphere, stirred at room temperature for one hour for silylation, ice-cooled and 0.75 ml of iodotrimethylsilane under nitrogen atmosphere. It was added and stirred for 30 minutes at room temperature. The solution was concentrated by evaporation under reduced pressure, a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. The silylated 2-amino-1,8-naphthyridine-3-carboxylic acid prepared above was added thereto, stirred at room temperature for 3 hours, and then ice-cooled to prepare a mixed solution of 1 ml of methanol and 2 ml of acetonitrile. Added and stirred for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium bicarbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 430 mg of the target compound.

Melting point; 210 ° C (dec.)

IR (KBr, cm-1); 3421.5 (N-H), 2945.1 (acid OH), 1772.5 (β-lactam C = O),

                1683 (acid C = O), 1652.9 (amide C = O)

1H NMR (DMSO- d 6, ppm ); 9.595 (d, CONH, 1 H), 9.206 (s, naphthyridine acid-H, 1 H),

6.657 (s, thiazole-H, 1 H), 5.747 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                       5.31 and 5.01 (ABq, 3'-CH2, 2H), 3.571 (s, OCH3, 3H),

                       3.442 (d, 2-CH2, 2H)

Example 2. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (methyl-2-hydroxy-3-car Preparation of Cyclate) -1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was added to a dispersion solution of 0.20 g of methyl-2-hydroxy-1,8-naphthyridine-3-carboxylate and 10 ml of acetonitrile obtained in Preparation Example 4. Completely dissolved.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.58 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this, 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide was also added in a nitrogen atmosphere, stirred at room temperature for 1 hour, silylated, ice-cooled, and 0.94 ml of iodotrimethylsilane was added under a nitrogen atmosphere. Stirred at room temperature for 30 minutes. The solution was concentrated by evaporation under reduced pressure, and then a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. To this, silylated methyl-2-hydroxy-1,8-naphthyridine-3-carboxylate prepared above was added and stirred at room temperature for 3 hours, followed by ice cooling and 1 ml of methanol and 2 ml of acetonitrile. A mixed solution was added and stirred for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 290 mg of the target compound.

Melting point; 210 ~ 214 ℃ (dec.)

IR (KBr, cm-1); 3380 (N-H), 2940 (acid OH), 1775 (β-lactam C = O),

                1735 (acid C = O),

1H NMR (DMSO- d 6, ppm ); 9.667 (d, CONH, 1H), 8.268 (s, 1H),

6.747 (s, thiazole-H, 1 H), 5.833 (q, 7-H, 1 H, J 7-NH = 8 Hz),

5.35 and 5.15 (ABq, 3′-CH 2, 2H), 5.801 (d, 6H, 1H, J 6-7 = 4.5 Hz),

                4.278 (s, 3 H)

Example 3. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (3-cyano-2-hydroxy- ) -1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

To a dispersion solution of 0.18 g of 3-cyano-2-hydroxy-1,8-naphthyridine and 10 ml of acetonitrile obtained in Preparation Example 6, 1.05 ml of N, O -bis (trimethylsilyl) acetamide was added and dissolved completely. .

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this was added 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide also in a nitrogen atmosphere, stirred at room temperature for one hour to silylate and ice-cooled, and then 0.75 ml of iodotrimethylsilane was added under a nitrogen atmosphere. It was added and stirred for 30 minutes at room temperature. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. The silylated 3-cyano-2-hydroxy-1,8-naphthyridine prepared above was added thereto, stirred at room temperature for 3 hours, cooled with ice, and a mixed solution of 1 ml of methanol and 2 ml of acetonitrile was added thereto. Added and stirred for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 370 mg of the target compound.

Melting point; 195 ~ 196 ℃ (dec.)

IR (KBr, cm-1); 3350 (N-H), 2945 (acid OH), 2230 (CN), 1760 (β-lactam C = O),

                1690 (acid C = O)

1H NMR (DMSO- d 6, ppm ); 9.721 (d, CONH, 1H), 8.692 (s, 1H),

6.805 (s, thiazole-H, 1 H), 5.852 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                        5.228 and 5.061 (ABq, 3'-CH2, 2H), 3.409 (d, 2-CH2, 2H)

Example 4. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (2-amino-3-carboxyamide)- Preparation of 1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was added and dissolved completely in a dispersion solution of 0.2 g of 2-amino-1,8-naphthyridine-3-carboxyamide and 10 ml of acetonitrile obtained in Preparation Example 2.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this was added 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide also in a nitrogen atmosphere, stirred at room temperature for one hour to silylate and ice-cooled, and then 0.75 ml of iodotrimethylsilane was added under a nitrogen atmosphere. It was added and stirred for 30 minutes at room temperature. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. The silylated 2-amino-1,8-naphthyridine-3-carboxyamide prepared above was added thereto, stirred at room temperature for 3 hours, cooled with ice, and a mixed solution of 1 ml of methanol and 2 ml of acetonitrile was added thereto. Stir for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then crystallized at pH 3 with 1N hydrochloric acid to obtain 380 mg of the target compound.

Melting point; 215 ~ 220 ℃ (dec.)

IR (KBr, cm-1); 3385 (N-H), 2940 (acid OH), 1768 (β-lactam C = O),

                1690 (acid C = O), 1645 (amide C = O)

1H NMR (DMSO- d 6, ppm ); 9.54 (d, CONH, 1 H), 8.560 (s, naphthyridine amide-H, 1H),

6.713 (s, thiazole-H, 1 H), 5.657 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                        5.239 and 5.023 (ABq, 3'-CH2, 2H), 3.80 (s, OCH3, 3H),

                        3.382 (d, 2-CH2, 2H)

Example 5. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (2,3-dihydroxy) -1 Preparation of, 8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was completely dissolved in 0.162 g of 2,3-dihydroxy-1,8-naphthyridine obtained in Preparation Example 9 and 10 ml of acetonitrile.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this was added 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide also under a nitrogen atmosphere, followed by stirring at room temperature for one hour to be silylated, ice-cooled, and then 0.75 ml of iodotrimethylsilane in a nitrogen atmosphere. It was added under and stirred for 30 minutes at room temperature. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe and stirred for 5 minutes to completely dissolve the oily substance. To this was added silylated 2,3-dihydroxy-1,8-naphthyridine prepared above, stirred at room temperature for 3 hours, ice-cooled, and a mixed solution of 1 ml of methanol and 2 ml of acetonitrile was added thereto for 30 minutes. Was stirred. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 390 mg of the target compound.

Melting point; 212 ℃ (dec.)

IR (KBr, cm-1); 3380.9 (O-H), 2948.9 (acid OH), 1787.9 (β-lactam C = O),

                1743.5 (acid C = O), 1652.8 (amide C = O)

1H NMR (DMSO- d 6, ppm ); 9.684 (d, CONH, 1 H), 8.927 (s, naphthyridine 5H, 1H),

6.818 (s, thiazole-H, 1 H), 5.831 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                        5.348 and 5.117 (ABq, 3′-CH 2, 2H), 3.445 (s, OH, 2H),

                        3.291 (d, 2-CH2, 2H)

Example 6. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (2-hydroxy-3-carboxylic acid Preparation of Hydrazide) -1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was added to a dispersion solution of 0.2 g of 2-hydroxy-1,8-naphthyridine-3-carboxylic acid hydrazide prepared in Preparation Example 5 and 10 ml of acetonitrile. In addition, it dissolved completely.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere, and 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide was also added in a nitrogen atmosphere, followed by stirring at room temperature for 1 hour to be silylated, followed by ice cooling. 0.75 ml of iodotrimethylsilane was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. The silylated 2-hydroxy-1,8-naphthyridine-3-carboxylic acid hydrazide prepared above was added thereto, stirred at room temperature for 3 hours, and then ice-cooled to obtain 1 ml of methanol and 2 ml of acetonitrile. A mixed solution was added and stirred for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 340 mg of the target compound.

Melting point; 211 ℃ (dec.)

IR (KBr, cm-1); 3404.1 (O-H), 3386.7 (N-H), 2879.5 (acid OH), 1778.3 (β-lactam C = O),

                1693.4 (acid C = O), 1666 (amide C = O)

1H NMR (DMSO- d 6, ppm ); 10.721 (s, naphthyridine CONH), 9.82 (d, CONH, 1H),

                 7.339 (s, naphthyridine NH2, 2H), 6.858 (s, thiazole-H, 1H),

5.843 (q, 7-H, 1H, J 7-NH = 8 Hz), 5.23 and 5.098 (ABq, 3'-CH2,2H),

                 3.887 (s, 3H), 3.291 (d, 2-CH2, 2H)

Example 7. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (3-amino-2-hydroxy)- Preparation of 1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

To the dispersion solution of 0.157 g of 3-amino-2-hydroxy-1,8-naphthyridine and 10 ml of acetonitrile obtained in Preparation Example 8, 1.05 ml of N, O -bis (trimethylsilyl) acetamide was added and completely dissolved.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere. To this, 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide was also added in a nitrogen atmosphere, stirred at room temperature for 1 hour, silylated, ice-cooled, and 0.75 ml of iodotrimethylsilane was added under a nitrogen atmosphere. Stirred at room temperature for 30 minutes. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe, and stirred for 5 minutes to completely dissolve the oily substance. To this, silylated 3-amino-2-hydroxy-1,8-naphthyridine prepared above was added, stirred at room temperature for 3 hours, ice-cooled and a mixed solution of 1 ml of methanol and 2 ml of acetonitrile was added thereto. Stir for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 390 mg of the target compound.

Melting point; 205 ℃ (dec.)

IR (KBr, cm-1); 3409 (O-H), 3384.8 (N-H), 2872.8 (acid OH), 1733.9 (β-lactam C = O),

                 1654.8 (Acid C = O)

1H NMR (DMSO- d 6, ppm ); 9.658 (d, CONH, 1H), 7.923 (s, naphthyridine NH2, 1H),

6.771 (s, thiazole-H, 1 H), 5.742 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                       5.281 and 5.041 (ABq, 3'-CH2, 2H), 3.478 (s, OH, 1H),

                       3.437 (d, 2-CH2, 2H)

Example 8. 7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [8- (2-hydroxy-3-carboxyamide) Preparation of -1,8-naphthyridiniummethyl] -3-cepem-4-carboxylate

1.05 ml of N, O -bis (trimethylsilyl) acetamide was added completely to a dispersion solution of 0.2 g of 2-hydroxy-1,8-naphthyridine-3-carboxyamide and 10 ml of acetonitrile obtained in Preparation Example 7. Melted.

7-β-[( Z ) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid 0.5 g was dispersed in 10 ml of dichloromethane under nitrogen atmosphere, and 0.8 ml of N -methyl- N- (trimethylsilyl) trifluoroacetamide was also added in a nitrogen atmosphere, followed by silylation by stirring at room temperature for one hour, After ice-cooling, 0.75 ml of iodotrimethylsilane was added under a nitrogen atmosphere, followed by stirring at room temperature for 30 minutes. The solution was concentrated by evaporation under reduced pressure, and a mixed solution of 10 ml of acetonitrile and 2 ml of tetrahydrofuran was injected using a syringe and stirred for 5 minutes to completely dissolve the oily substance. The silylated 2-hydroxy-1,8-naphthyridine-3-carboxyamide prepared above was added thereto, stirred at room temperature for 3 hours, cooled with ice, and a mixed solution of 1 ml of methanol and 2 ml of acetonitrile. Was added and stirred for 30 minutes. The precipitated solid was collected by filtration, 10 ml of water was added thereto, dissolved with saturated sodium hydrogen carbonate, and then precipitated with crystals at pH 3 using 1N hydrochloric acid to obtain 390 mg of the target compound.

Melting point; 208 ℃ (dec.)

IR (KBr, cm-1); 3396.4 (O-H), 3365.5 (N-H), 2883 (acid OH),

1770.5 ( β -lactam C = O), 1703 (acid C = O), 1674 (amide C = O)

1H NMR (DMSO- d 6, ppm ); 9.705 (d, CONH, 1H), 9.552 (s, naphthyridine CONH, 2H),

6.836 (s, thiazole-H, 1 H), 5.833 (q, 7-H, 1 H, J 7-NH = 8 Hz),

                      5.164 and 5.061 (ABq, 3'-CH2, H), 3.851 (s, 3H),

                      3.271 (d, 2-CH2, 2H)

Antibacterial test

Each of Examples 1 to 8 prepared as described above was tested for in vitro antimicrobial activity by measuring minimum growth inhibitory concentration (MIC: Minimum um Inhibitory Concentration, unit ㎍ / ml) according to the following method.

 [Test strain]

  Gram-positive bacteria

: Bacillus subtilis ATCC6633,

Staphylococcus aureus KCTC1928,

Staphylococcus aureus subsp. ATCC6538P

Micrococcus luteus ATCC9341,

Streptococcus pyrogens ATCC21059

  Gram-negative bacteria

Salmonella typhomurium KCTC1925

Escherichia coli ATCC9637

Escherichia coli KCTC1923

Pseudomonas aeruginosa ATCC15692

Pseudomonas aeruginosa ATCC27853

Alcaligenes faecalis ATCC8750

Klepsiella oxytoca ATCC8724

 [badge]

Muller Hinton Agar Medium was used to prepare test strain cultures and assay plates.

 Measurement of Antimicrobial Activity

Each compound prepared in the above example was dissolved in a small amount of DMSO, and sterile distilled water was added so that the concentration of the final DMSO was 10% by volume. 0.5 ml of each sample prepared in this way was diluted 14 times in a two-step dilution method and the concentration of each compound in the final medium when mixed with 14.5 ml of Muller Hinton agar medium was 40, 20, 10, 5, 2.5, 1.25, respectively. , 0.625, 0.3125, 0.156, 0.075, 0.039, 0.0195, 0.00975, 0.004875 (μg / ml).

As a control medium, 0.5 ml of 10% by volume of DMSO solution was mixed with 14.5 ml of Muller Hinton agar medium.

[Judgement of Antibacterial Activity]

Each test strain was inoculated into the assay medium, incubated for 18 hours at 37 ° C, and visually observed to confirm the minimum inhibitory concentration (MIC) of the antimicrobial agent that inhibits the growth of the test strains. Is shown in Table 1.

Table 1 . Minimum growth inhibitory concentration for each strain (MIC. (Μl / ml))

According to the present invention, by establishing a new cefem compound and a method for producing the same, an antimicrobial agent having a structure having excellent antimicrobial activity against Gram-negative bacteria as well as Gram-negative bacteria and having a strong antimicrobial activity, in particular, can be prepared.

Claims (3)

The cephalosporin compound and pharmacology represented by the following general formula (I), wherein the 1,8-naphthyridine derivative is substituted at the C-3 position of the cefe nucleus and the aminothiazole derivative is acylated at the C-7 position. Pharmaceutically acceptable salts thereof, physiologically hydrolysable esters, hydrates, solvates or isomers thereof: (Ⅰ) In formula (I), R ₁ is hydrogen, lower alkyl group, lower alkyl group substituted with fluorine, lower alkyl group substituted with carboxyl group or inorganic cation salt thereof, or lower alkyl group substituted with protected carboxyl group; R ₂ is hydrogen, a hydroxy group, an amino group or a lower alkyl group; R ₃ is hydrogen, a nitrile group, an ester group, an amide group, a carboxyl group or a carboxylic acid hydrazide group, provided that in formula (I), R ₁ is a methyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid. And a compound wherein R ₁ is a carboxypropyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid). A method for producing a cefe compound of general formula (I), wherein the compound represented by the following general formula (I) is prepared by substitution reaction of a cefe compound of general formula (II) with a compound of general formula (III): (Ⅰ) In formula (I), R ₁ is hydrogen, lower alkyl group, lower alkyl group substituted with fluorine, lower alkyl group substituted with carboxyl group or inorganic cation salt thereof, or lower alkyl group substituted with protected carboxyl group; R ₂ is hydrogen, a hydroxy group, an amino group or a lower alkyl group; R ₃ is hydrogen, a nitrile group, an ester group, an amide group, a carboxyl group or a carboxylic acid hydrazide group, provided that in formula (I), R ₁ is a methyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid. The compound and R ₁ are a carboxypropyl group, R ₂ is a hydroxy group, and a compound in which R ₃ is a carboxylic acid is excluded. (Ⅱ) (Ⅲ) In the general formulas (II) and (III), X is a silylated 3-iodinemethyl group, and R ₁ , R ₂ and R ₃ are as defined in the general formula (I).   As an active ingredient, a compound represented by the following general formula (I), a pharmacologically / pharmaceutically acceptable salt thereof, a physiologically hydrolysable ester thereof, a hydrate, a solvate, or an isomer thereof Antimicrobial composition. (Ⅰ) In formula (I), R ₁ is hydrogen, lower alkyl group, lower alkyl group substituted with fluorine, lower alkyl group substituted with carboxyl group or inorganic cation salt thereof, or lower alkyl group substituted with protected carboxyl group; R ₂ is hydrogen, a hydroxy group, an amino group or a lower alkyl group; R ₃ is hydrogen, a nitrile group, an ester group, an amide group, a carboxyl group and a carboxylic acid hydrazide group, provided that in formula (I), R ₁ is a methyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid. And a compound wherein R ₁ is a carboxypropyl group, R ₂ is a hydroxy group, and R ₃ is a carboxylic acid).