KR950008321B1 - Cephem derivatives - Google Patents

Abstract

This 3-ammonium cephem derivative of formula (I) is new and used as antibiotics and its intermediate for an injection. In formula R1 is H or heteroaralkanoyl gp. of formula (A). The manufacuring method comprises the steps of: a) hydrolysing 3-acetate ligand of 7-amino cephalosphorinic acid with sodium hydroxide; b) protecting 7-amino gp. of (a) product with salicylaldehyde; c) protecting 4-carboxylic acid of (b) product with diphenyl methyl ester; d) chlorinating 3-hydroxymethylcephalosphorin with pentachlorophosphin and pyridine, and producing the intermediate containing 3-ammonium of formula (5); e)reacting (5) with NaI and amine; f) deprotecting 7- and 4-protecting gp. of (e) product; and g) condensating (f) product. This cephem compd. has good antibacterial activity.

Description

Cefem derivatives

The present invention relates to a cefem derivative, and more particularly to a novel 3-ammonium cefem derivative represented by the following general formula (I) useful as an antibiotic for injection and its intermediate.

[Formula 1]

In the above formula, R ₁ is hydrogen or a heteroaryl alkanoyl group represented by the following general formula (A),

[Formula 2]

(Where R ₃ is R ₄ is -CH ₃ , -CH ₂ COOH, -C (CH ₃ ) COOH.

R ₂ is to be.

Cephalosporins (also known as "cefem") antibiotics of 3-ammonium derivatives have already been developed a lot, for example Blister Mayer U.S. Patent No. 4,943,631 which is represented by the following general formula "BMY A cephalosporin antibiotic called -28142 "has been introduced.

[Formula 3]

Hoechst's German Patent No. 390,956 introduces a cephalosporin antibiotic called cefprirome (aka HR-810) represented by the following general formula.

[Formula 4]

In addition, US Pat. No. 4,098,888 introduces a cephalosporin antibiotic called cefotaxime represented by the following general formula, and is said to be useful for the treatment of diseases caused by general pathogens.

[Formula 5]

Where R is to be.

As such, cephalosporins are easily soluble and have been developed as antibiotics for injection. They are also well known for their absorption into the body and are widely known as antibiotics having a wide range of good antimicrobial activities, not only Gram-negative bacteria but also Gram-positive bacteria.

It is an object of the present invention to provide a cefe derivative represented by the general formula (I) having a superior antimicrobial activity than an existing injectable antibiotic by introducing a new substituent.

Hereinafter, the present invention will be described in detail.

The present invention is a 3-ammonium cefem derivative represented by the general group (I) having a substituent on the 10 position.

Hereinafter, the present invention will be described in more detail.

The method for synthesizing cephalosporin of the cefem derivative having a substituent at the 10-position represented by the general formula (I) of the present invention, that is, 3-ammonium derivative, is as follows.

That is, the 7-amino cephalosporinic acid represented by the following general formula (1) is hydrolyzed to the acetate group in 3-position by using sodium hydroxide to form a hydroxymethyl group in 3-position. Obtain the compound of 2).

[Formula 6]

[Formula 7]

The amino group at the 7-position of the compound of formula (2) is then protected using salicylic aldehyde to obtain the compound of formula (3). Subsequently, the carboxylic acid which exists in the 4-position of the compound of following General formula (3) is protected by diphenyl methyl ester, and the compound represented by following General formula (4) is obtained.

[Formula 8]

[Formula 9]

The cephalosporin 9 or less 3-cefem of the hydroxymethyl group in the 3-position of the general formula (4) thus obtained is cloned with the pentachlorophosphine and the pyridine to the hydroxy group to be the cephm of the chloromethyl group. The compound represented by General formula (5) is obtained.

The cefem compound represented by the following general formula (5) having the 3-chloromethyl group obtained in the above manner is a very important intermediate for synthesizing the cefem compound having the 3-ammonium derivative according to the present invention. By the amine reagent reacting with the cefe compound having a group, it is possible to obtain various compounds by changing various substituents at the 10-position.

That is, the reaction of sodium iodide and an amine compound to a cefe compound having a 3-chloromethyl group represented by the following general formula (5) yields a 3-ammonium cefe compound represented by the following general formula (7).

[Formula 10]

[Formula 11]

In the above formula, R ₂ is as defined above.

On the other hand, the amine compound used above is represented by the following general formula (6), it is synthesized according to the Lucard reaction as shown in the following scheme.

Scheme 1

In the above formula, R ₂ is as defined above.

The compound of the general formula (7) synthesized by the above process is subsequently removed with the formic acid and hydrochloric acid to remove the protecting groups at the 7-position and 4-position, and the 7-amino represented by the following general formula (8) -3-ammonium cefem compound is obtained.

[Formula 12]

R ₂ in the above formula is as defined above.

Here, the 7-amino-3-ammonium cefe compound represented by the general formula (8) is an important intermediate, and various types of 3-ammonium cefem derivatives can be synthesized by introducing various substituents at the 7-position. For example, when the compound of formula (A), which is a derivative of aminothiazole, is condensed with the compound of formula (8), the compound of formula (9) is obtained, and finally, in the present invention The cefem derivatives of the general formula (I), useful as novel antibiotics with the desired 3-ammonium derivatives, are synthesized.

[Formula 13]

In the above formula, R ₂ , R ₃ and R ₄ are as defined above.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

Preparation of Diphenylmethyl 7β- (hydroxy) benzilideneamino-3-hydroxymethyl-3-cepem-4-carboxylate

Scheme 2

At room temperature, 50.00 g (0.18 mol) of 7-aminocephalosporinic acid was suspended in 320 ml of water and 320 ml of methanol mixed solution, 15.40 g (0.38 mol) of NaOH was dissolved in 50 ml of water and added dropwise at -20 ° C. After stirring at -20 ~ 110 ℃ for 1 hour. The pH was adjusted to 7.5 with c-HCL, and 29.15 g (0.25 mol) of salylsalaldehyde was added at 15 ° C. and stirred at the same temperature for 1 hour. The reaction mixture was adjusted to pH = 4.0 ~ 4.5 with 1N-HCl, and the ethyl acetate solution of diphenyl diazomethane was added dropwise. After stirring for 3 hours, ethyl acetate was added to the reaction mixture, which was then washed with brine and water. The organic solvent was distilled off under reduced pressure, and the resulting residue was subjected to 78.0 g (yield: 85%) of the target substance using ethyl acetate n-hexane.

¹ H-NMR (DMSO-d ₆ ) δ: 3.70 (s, 2H), 4.30 (s, 2H), 5.15 (t, 1H), 5.40 (d, 1H), 5.75 (d, 1H-, 6.95 (s , H), 7.20-7.70 (m, 14H), 8.80 (s, 1H).

Example 2

Preparation of Diphenylmethyl 7β- (hydroxy) benzylideneamino-3-chloromethyl-3-chloromethyl-3-cepem-4-carboxylate

Scheme 3

28.0 G (0.13 mol) of PCl ₅ was suspended in 600 ml of CH ₂ Cl ₂ , followed by 60.0 g (0.12 mol) of diphenylmethyl7β- (hydroxy) benzylideneamino- obtained at Example 1 at −30 ° C. 3-hydroxymethyl-3-cepem-4-carboxylate was added slowly and stirred for 30 minutes. 10.8 ml (0.13 mol) of pyridine was added dropwise to the reaction mixture, followed by stirring at -30 to -20 ° C for 2 hours. After cooling water is added to the reaction mixture, the organic layer is separated. The organic layer was washed with brine, and then the solvent was removed under reduced pressure, and then purified by chromatography. Thus, 25.0 g of the target product (yield: 40%) was obtained.

¹ H-NMR (CDCL ₃ ) δ: 3.60 (ABq, 2H), 4.40 (ABq, 2H), 5.15 (d, 1H), 5.35 (d, 1H), 7.05 (s, 1H), 7.2-7.6 (m , 14H), 8.65 (s, 1H).

Example 3

Preparation of Diphenylmethyl 7β- (hydroxy) benzylideneamino-3- [4- (2-pyridyl) -1-methylpiperaziniummethyl] -3-cefe-4-carboxylate iodide

Scheme 4

After dissolving 5.00 g (9.63 mmol) of diphenylmethyl 7β- (hydroxy) benzylideneamino-3-chloromethyl-3-cepem-4-carboxylic acid obtained in Example 2 in 100 ml of CCl ₄ , the solution was dried at 0 ° C. 10 ml of acetone solution was added dropwise to 1.75 g (11.67 mmol) of Nal, and stirred for 1 hour at room temperature. The reaction mixture was filtered through celite, and the filtrate was washed with a saturated Na ₂ S ₂ O ₃ aqueous solution and brine, and the water was removed from the solution, which was then cooled to 1.85 g (10.44 mmol) of 1-methyl-4- (2-pyridyl). ) A solution of piperazine dissolved in 15 ml of CCl ₄ was added dropwise at 0 ° C. and stirred for 1 hour. The resulting precipitate was filtered and washed with CCl ₄ to obtain 4.8 g (yield: 63%) of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (ABq, 2H), 3.04-4.60 (m, 8H), 5.40 (d, H), 6.70-7.90 (m, 16H), 8.20 (m, 2H) , 8.85 (s, 1 H).

Example 4

Preparation of Diphenylmethyl 7β- (hydroxy) benzylideneamino-3- [4- (2-pyrimidyl) -1-methylpiperaziniummethyl] -3-cepm-4-carboxylate iodide

Scheme 5

The method described in Practical Example 3 except for using 1.78 g (10.44 mol) of 1-methyl-4- (2-pyrimidyl) piperazine in place of 1-methyl-4- (2-pyridyl) piperazine The same procedure was followed. As a result, 4.58 g (yield: 58%) of the target product was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 3.05 (s, 3H), 3.10 (ABq, 2H), 3.50-4.60 (m, 10H), 5.35 (d, 1H), 5.85 (d, 1H), 6.70 -7.50 (m, 14H), 8.35 (d, 2H), 8.50 (s, 1H).

Example 5

Preparation of 7-amino-3- [4- (2-pyridyl) -1-methylpiperaziniummethyl] -3-cefe-4-carboxylate hydrochloride

Scheme 6

Diphenylmethyl7β- (hydroxy) benzylideneamino-3- [4- (2-pyridyl) -1-methylpiperaziniummethyl] -3-cepem-4-carboxylate obtained in Example 3 above 5.00 g (6.33 mmol) of iodide was added to a mixed solution of 20 ml of 98% formic acid and 6 ml of c-HCl, stirred at room temperature for 1 hour, and then added to 500 ml of acetone. The solid was filtered and dissolved in a small amount of water. Was added to acetone. The resulting solid was filtered and dried to obtain 1.1 g (yield 35%) of the title compound.

¹ H-NMR (D ₂ O) δ: 3.20 (s, 3H), 3.50-4.40 (m, 12H), 5.20 (d, 1H), 5.40 (d, 1H), 7.15 (t, 1H), 3.75 ( m, 1H), 7.95 (t, 1H), 8.15 (d, 1H).

Example 6

Preparation of 7-amino-3- [4- (2-pyrimidyl) -1-methylpiperaziniummethyl] -3-cefe-4-carboxylate hydrochloride

Scheme 7

Except for using the compound 5.00g (6.34mmol) obtained in Example 4 was carried out in the same manner as in Example 5. As a result, 1.3 g (yield: 48%) of the target product was obtained by the preparation.

¹ H-NMR (D ₂ O) δ: 3.05 (s, 3H), 3.10 (ABq, 2H), 3.30-4.80 (m, 10H), 5.05 (d, 1H), 6.9 (t, 1H), 840 ( d, 2H).

Example 7

7-β [(Z) -2- (2-amino-4-thiazol) -2- (methoxyimino) acetamino] -3- [4- (2-pyridyl) 1-methylpiperazinium Preparation of Methyl] -3-cepem-4-carboxylate

Scheme 8

Under anhydrous conditions, 90 mg (0.45 mmol) of 2-2 (amino-4-thiazol) -2- (methoxyimino) -acetic acid was dissolved in 4 ml of DMF and 50 gm (0.48 mmol) of tree at -5 to 0 ° C. Ethylamine was added dropwise and stirred at the same temperature for 30 minutes, then 148 mg (0.52 mmol) of FMS (1-methane sulfooxy-6-trifluoro methyl benzotriazole) was added dropwise in 2 ml DMF, and then added for 1 hour. Stirred. 200 mg (0.37 mmol) of 7-amino-3- [4- (2-pyridyl) -1-methylpyreraziniummethyl] -3-cefe-4-carboxylate hydrochloride obtained in Example 5 was added thereto. Stirred for 3 hours. Acetone was added to the reaction mixture, and the solid produced was filtered, and the acetone was washed and dried to obtain 220 mg of the target product (yield: 82%).

¹ H-NMR (D ₂ O) δ: 3.15 (s, 3H), 3.55 (ABq, 2H), 3.90 (S, 3H0, 3.40-3.90 (m, 8H), 4.00 (ABq, 2H), 5.35 (d , 1H), 5.80 (d, 1H), 6.85 (s, 1H), 6.90 (m, 2H), 7.70 (m, 1H), 8.15 (m, 1H)

Example 8

7-β-[(Z) -2- (2-amino-4-thiazol) -2- (methoxyimino) acetamino] -3- [4- (2-pyrimidyl) -1-methylpipera Preparation of Genium Methyl] -3-cepem-4-carboxylate

Scheme 9

200 mg (0.47 mmol) of 7-amino-3- [4- (2-pyrimidyl) -1-methylpiperaziniummethyl] -3-cef-4-carboxylate hydrochloride obtained in Example 6 was used. Except for the above, the same procedure as in Example 7 was carried out to obtain 200 mg (yield: 74%) of the title compound.

¹ H-NMR (D ₂ O) δ: 3.05 (s, 3H), 3.40 (ABq, 2H), 3.80 (s, 3H0, 3.45-4.45 (m, 10H), 5.20 (d, 1H), 6.70 (t , 1H), 6.90 (s, 1H), 8.25 (d, 2H).

Example 9

7-β-[(Z) -2- (2-amino-4-thiazol) -2- (t-butoxycarbonylmethoxyimino) acetamino] -3- [4- (2-pyridyl)- Preparation of 1-Methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 10

136 mg (0.45 mmol) of 2- (2-amino-thiazol) -2- (t-butoxycarbonylmethoxyamino) acetic acid in 5 ml of DMF-enzyme under anhydrous conditions and 50 mg (0.49 mmol) at -5 to 0 ° C Triethylamine was added dropwise, stirred at the same temperature for 30 minutes, and then 148 mg (0.52 mmol) of FMS (1-methanesulfooxy-6-trifluoromethylbenzotriazole) was added dropwise in 3 ml DMF. Stir for 1 hour. 158 mg (0.37 mmol) of 7-amino-3- [4- (2-pyridyl) -1-methylpiperaziniummethyl] -3-cef-4-carboxylate hydrochloride obtained in Example 5 were added thereto, followed by room temperature. Stirred for 3 hours. Acetone was added to the reaction mixture, and the solid produced was filtered, washed with acetone, and dried to obtain 210 ml (yield: 84%) of the title compound.

¹ H-NMR (D ₂ O) δ: 1.30 (s, 9H), 3.15 (s, 3H), 3.60 (ABq, 2H), 3.65-3.90 (m, 8H), 4.00 (ABq, 2H), 4.85 ( s, 2H), 5.40 (d, 1H), 5.85 (d, 1H), 6.90 (m, 2H), 7.75 (m, 1H), 8.00 (m, 1H)

Example 10

7-β-[(Z) -2- (2-amino-4-thiazol) -2-{(1-carboxy) methoxyimino} acetamino-3- [4- (2-pyridyl) -1 -Methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 11

Dissolve 70 mg (0.1 mmol) of the compound obtained in Example 9 in 10 ml of water, add 1 ml of concentrated hydrochloric acid, stir for 1 hour, neutralize with 5% aqueous sodium hydrogen carbonate solution, filter the solid produced by adding acetone, and filter the acetone. Washing to dryness gave 45 mg (yield: 70%) of the title compound.

¹ H-NMR (D ₂ O) δ: 3.20 (s, 3H), 3.55 (s, 3H), 4.05 (ABq, 2H), 3.65-3.90 (m, 8H), 4.90 (s, 2H), 5.45 ( d, 1H), 5.90 (d, 1H), 6.85 (m, 2H), 6.95 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H)

Example 11

7-β-[(Z) -2- (2-amino-4-thiazol) -2- (t-butoxycarbonylmethoxyimino) acetamino] -3- [4- (2-pyrimidyl)- Preparation of 1-Methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 12

210 mg (yield: 69%) of the target compound was obtained in the same manner as in Example 9, except that 192 mg (0.45 mmol) of the compound obtained in Example 6 was used.

¹ H-NMR (D ₂ O) δ: 1.35 (s, 9H), 3.10 (s, 3H), 3.55 (ABq, 2H), 3.65-3.90 (m, 8H), 4.05 (ABq, 2H), 4.90 ( s, 2H), 5.40 (d, 1H), 5.80 (d, 1H), 6.75 (t, 2H), 6.80 (s, 1H), 8.30 (d, 2H)

Example 12

7-β [(Z) -2- (2-amino-4-thiazol) -2-{(1-carboxy) -methoxyimino} acetamino] -3- [4- (2-pyrimidyl)- Preparation of 1-Methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 13

50 mg (yield: 54%) of the title compound was obtained in the same manner as in Example 10, except that 100 mg (0.15 mmol;) of the compound obtained in Example 11 was used.

¹ H-NMR (D ₂ O) δ: 3.15 (s, 3H), 3.55 (ABq, 2H), 3.60-3.90 (m, 8H), 4.10 (ABq, 2H), 5.00 (s, 2H), 5.35 ( d, 1H), 5.75 (d, 1H), 6.70 (t, 2H), 6.85 (s, 1H), 8.25 (d, 2H)

Example 13

7-β [(Z) -2- (2-amino-4-thiazol) -2-{(1-t-butoxycarbonyl-1-methyl) -ethoxyimino} acetamino] -3- [ Preparation of 4- (2-pyridyl) -1-methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 14

5 ml of 148 mg (0.45 mmol) of 2- (2-amino-4-thiazol) -2- (1-t-butoxycarbonyl-1-methyl) ethoxyiminoacetic acid was dissolved in DMF under unconditional conditions. 50 mg (0.49 mmol) of triethylamine was added dropwise at ˜0 ° C., stirred for 30 minutes at the same temperature, and then 148 mg (0.52 mmol) of FMS (1-methanesulfooxy-6-trifluoromethylbenzotriazole) was added to 2 ml DMF. It was dissolved in and added dropwise, and stirred for 1 hour. Acetone was added to the reaction mixture, and the solid produced was filtered, washed with acetone, and dried to obtain 180 mg of the target product (yield 69%).

¹ H-NMR (D ₂ O) δ: 1.30 (s, 9H), 1.55 (s, 5H), 3.20 (ABq, 2H), 3.65-3.90 (m, 8H), 4.05 (ABq, 2H), 5.50 ( s, 2H), 5.90 (d, 1H), 6.85 (d, 1H), 6.95 (m, 2H), 7.80 (m, 1H), 8.05 (m, 1H).

Example 14

7-β [(Z) -2- (2-amino-4-thiazol) -2-{(1-carboxy-1-methyl) ethoxyimino} acetamino] -3- [4- (2-pyri Preparation of Dyl) -1-Methylpiperaziniummethyl-3-cepem-4-carboxylate

Scheme 15

Dissolve 70 mg (0.1 mmol) of the compound obtained in Example 13 in 10 ml of water, add 1 ml of concentrated hydrochloric acid, stir for 1 hour, neutralize with 5% aqueous sodium hydrogen carbonate solution, and then filter acetone by adding acetone. Continued washing and drying to give 40 mg (yield: 63%) of the title compound.

¹ H-NMR (D ₂ O) δ: 1.60 (s, 6H), 3.25 (s, 3H), 3.55 (ABq, 2H), 3.65-3.95 (m, 8H), 4.10 (ABq, 2H), 5.50 ( s, 2H), 5.85 (d, 1H), 6.90 (m, 2H), 7.85 (m, 1H), 8.15 (m, 1H)

Example 15

7-β [(Z) -2- (2-amino-4-thiazol) -2-{(1-t-butoxycarbonyl-1-methyl) ethoxyimino} acetamino] -3- [4 Preparation of-(2-pyrimidyl) -1-methylpiperaziniummethyl] -3-cepem-4-carboxylate

Scheme 16

Except for using 192 mg (0.45 mmol) of the compound obtained in Example 6, 230 mg (yield: 73%) of the title compound was obtained by the same method as in Example 13.

¹ H-NMR (D ₂ O) δ: 1.30 (s, 9H), 3.15 (s, 3H), 3.60 (ABq, 2H), 3.65-3.90 (m, 8H), 4.00 (ABq, 2H), 4.85 ( s, 2H), 5.40 (d, 1H), 5.85 (d, 1H), 6.90 (m, 2H), 7.75 (m, 1H), 8.00 (m, 1H)

Example 16

7-β [(Z) -2- (2-amino-4-thiazol) -2-{(1-carboxy-1-methyl) ethoxyimino} acetamino] -3- [4- (2-pyri Preparation of midyl) -1-methylpiperaziniummethyl] -3-cef-4-carboxylate

Scheme 17

Except for using 150 mg (0.2 mmol) of the compound obtained in Example 15, the same procedure as in Example 14 was carried out to obtain 855 mg (yield 62%) of the title compound.

¹ H-NMR (D ₂ O) δ: 1.55 (s, 6H), 3.20 (s, 3H), 3.45 (ABq, 2H), 3.65-4.00 (m, 8H), 4.00 (ABq, 2H), 5.50 ( d, 1H), 5.95 (d, 1H), 6.85 (t, 2H), 6.85 (s, 1H), 8.30 (d, 2H).

In order to investigate the usefulness of the compounds of the present invention as described above using the compounds obtained in Examples 7 and 8 of the present invention and the well-known compound cetaxtaxe (cefortaxime) as a control agent was evaluated by obtaining a minimum inhibitory concentration (MIC) . The minimum inhibitory concentration was investigated by in vitro antibacterial action by agar dilution method. That is, the test compound was diluted by a 2-fold dilution method, dispersed in Müller-Hinton agar medium, and then inoculated with the test strain having 10 ⁷ cfu per ml and incubated at 37 ° C. for 20 hours. The results are shown in the following table.

TABLE 1

As is evident from the results of the table, the compounds according to the invention, for example the 3-ammonium cefem derivatives obtained in Examples 7 and 8 are equal or much superior to Cytaxime, a conventional representative antibiotic, particularly for Pseudomonas aeruginosa. It was found that it has a broad antibacterial activity.

Claims (1)

3-cefem derivative in which the ammonium substituent is fired at the 10-position represented by the following general formula (I). In the above formula, R ₁ is hydrogen or a heteroaryl alkanoyl group represented by the following general formula (A), (Where R ₃ is R ₄ is -CH ₃ , -CH ₂ COOH, -C (CH ₃ ) COOH. R ₂ is to be.