KR910001007B1 - Penicillanic acid and cephalosporin derivatives - Google Patents

Abstract

Penicillanic acid or cephalosporic acid derivs. of formula (I) are prepd. by reacting an acid halide cpd. of R1CH(NH2)COOH with a cpd. of formula (II) in an inert solvent at -20-30 deg.C to produce a cpd. of formula (III), activating (III) with 1- hydroxybenzotriazole and dicyclohexylcarbodimide in dimethylformamide solvent, and reacting the activated cpd. with a cpd. of formula (IV). In the formulas, R1= C1-6 cyclic cpd., phenyl, substd. phenyl, thienyl or halophenyl; R2= a gp. of formula (V); X= H, amino, nitro or halogen; R3= H, alkali metal cation or ester forming gp.; and R4= -CH3, -CH2COOH or - C(CH3)2COOH. (I) have a strong antibacterial activity.

Description

Peniclanic Acid and Cephalosporinic Acid Derivatives

The present invention relates to peniclanic acid and cephalosporin derivatives represented by the following structural formula (I).

형태의 그룹이고(이때, X는 수소, 아미노기, 니트로기, 할로겐이며, R₄는 메틸,

이다), Y는 3개의 탄소원자로된

형태의 그룹이거나, 치환된 3개의 탄소원자로된

형태의 그룹이고, [이때 R₅은 수소, 아세톡시, 또는

형태의 그룹이다(여기서, R₆, R₇, R₈, R₉는 수소, 1-4개의 탄소원자를 갖는 저급알킬, 페닐, 할로페닐 또는 하이드록시페닐이다)]. R₃는 수소, 알칼리금속 양이온 또는 에스테르를 형성하는 그룹을 나타낸다.In the above formula, R ₁ is a cyclic compound consisting of 1-6 carbon atoms or phenyl, substituted phenyl, thienyl, halophenyl, R ₂ is

Is a group of the form wherein X is hydrogen, amino, nitro, halogen, R ₄ is methyl,

Y is three carbon atoms

Form groups, or substituted three carbon atoms

Is a group of the form wherein R ₅ is hydrogen, acetoxy, or

Group, wherein R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, lower alkyl having 1-4 carbon atoms, phenyl, halophenyl or hydroxyphenyl. R ₃ represents a group forming hydrogen, an alkali metal cation or an ester.

로 표시된 것과 같은 구조의 신이성체를 나타낸다.In the penicilanic acid and cephalosporin derivatives of the present invention, the molecular structure of R ₂ is

Represents an isomer of a structure as indicated by

Conventionally, the α-amino group of ampicillin and amoxicillin or the α-amino group of acylated cephalosporin, 4-hydroxy-1,5-naphthyridine-3-carboxylic acid and 2-oxane-1-imidazolidinyl When a group such as carboxylic acid, 4-ethyl-2,3-dioxo-1-piperazinyl carboxylic acid, 4-hydroxy-2-methylpyridine-5-carboxylic acid, etc. is introduced as a new acylating agent, the antibacterial spectrum is broadened. USP studies show strong antibacterial activity against Pseudomonas aeruginosa 3,933,759, U.S.P. 3,761,512, C.A.31313b (1975), C.A.87, 6002V (1977) and the like.

In the present invention, (Z) -2- (2-aminothiazol-4-yl) -2-alkoxyiminoacetic acid exhibiting strong antimicrobial activity against Gram-negative bacteria, Pseudomonas aeruginosa, Cerecia, etc. The group and its analogs were introduced into α-amino groups such as ampicillin and cephalosporin-based antibiotics, thereby inventing an antibiotic such as the above-described structural formula (I).

The compound of formula (I) according to the present invention may be prepared by the following process. First, when the compound of formula (I) is a penicilanic acid derivative (I ′), the compound is prepared by the following method.

That is, the following compound of formula (IV) was prepared by reacting an acid halide of the compound of formula (II) with a compound of formula (III) at a temperature of -20 ° C to 30 ° C in an inert solvent, followed by 1-hydroxy benzo When triazole and dicyclohexyl carbodiimide are activated in a dimethylformamide solution, and then reacting the compound of formula (V) with the compound of formula (VI), the compound of formula (I ') Obtained.

In the above scheme, R ₁ , R ₂ , R ₃ and R ₄ and X are as described above.

On the other hand, when the compound of formula (I) is a cephalosporinic derivative (I "), except that the following compound of formula (VII) is prepared using the following compound of formula (VI) instead of the compound of formula (III). What is necessary is just to implement in the same way as when manufacturing a penicilanic acid derivative, and this is shown as a following reaction formula.

In the above scheme, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ and X are as described above.

On the other hand, in the present invention, in order to prepare the compounds of the structural formula (IV) and (iii) which is a reaction intermediate, Chem. Ber., 106, 3626 (1973), J. Am. chem. Soc., 77, 1067 (1955), J. Am. chem. Soc., 90, 1650 (1968), chem. pharm. Bull, 25, Noll 3115 (1977), U.S.P., 4,098,888 (1976), J. Am. chem. Soc., 73, 3547 (1952), J. Am. Azides used in semisynthetic methods such as many types of peniclanic acid and cephalosporinic acid, as described in chem. Soc., 74, 5304 (1952), chem. Ber., 94, 1972 (1961), and the like. Azide method for activating and reacting in the form, acid chloride method for reacting carboxylic acid with thionyl chloride pentachloride, phosphorus oxychloride and phosgene to make an acid chloride, alkylchlorocarbonate, dialkylchlorophosphate, and diphenylketene with carboxylic acid Mixed acid anhydride method, nitrophenyl ester, 2-pyridine thioester, 2-benzothiazole ester, 1-hydroxybenzotriazole, 1-hydroxybenzothiazole ester to react to prepare an acid anhydride Active ester method, also dicyclo hexylcarbodiimide, 1-ethoxycarbonyl-2-epoxy-1,2-dihydroxyquinoline, 1-isobutyloxycarbonyl-2-isobutyl jade Solid peptide peptideoquinoline, 1-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline, etc. can be used using -1,2-dihydroquinoline, etc., etc. have.

The process of preparing the compounds of formulas (IV) and (iii) proceeds at a reaction temperature of -20 ° C to 30 ° C in an inert solvent, where it is reacted with a basic reagent or silylating agent or without them.

Representative inert solvents that can be used in the present invention include acetone, tetrahydrofuran, dimethylacetamide, dimethylformamide, dioxane, dichloromethane, chloroform, benzene, toluene, ethylacetate or mixtures thereof, and the like as typical basic reagents. For example, Alkali hydrates, such as sodium hydroxide and potassium hydroxide; Alkali hydrogen carbonate (alkali carbonate), such as sodium hydrogen carbonate and potassium hydrogen carbonate: triamine amine, pyridine, diethylamine, pyridine, diethylamine, diethylaniline, N-methylmorpholine, and the like. And typical silylating agents include N, O-bis (trimethylsilyl) acetamide, hexamethyldisilazane, trimethylsilylacetamide, trimethylsilyl chloride and the like.

In addition, the acid halide of the compound of formula (II) used as a starting material in the present invention is prepared by reacting the compound of formula (II) with a halogenating agent such as phosphate pentachloride and thionyl chloride.

On the other hand, in carrying out the present invention, a number of reaction intermediates are used, among which known compounds are U.S.P 2,985,648, U.S.P. 3,192,198, J. Med.chem. 12,310 (1969), Brit. P. 1,017,624, U.S.P. 3,816,253, U.S.P. 3,641,021, U.S.P. 3,855,213 or the like can be prepared.

Subsequently, when the compound of formula (IV) or (iii) prepared as described above is reacted with the compound of formula (V), a compound of formula (I ') or (II "), which is the target compound of the present invention, is prepared. The compound of formula (V) is activated by reacting 1-hydroxybenzotriazole with dicyclohexylcarbodiimide in a dimethylformamide solution, followed by reaction with the compound of formula (IV) or (iii). The compound of formula (V) can be prepared according to US Pat. No. 4,098,888, Ger. P. 2,921,316 or the like.

In the present invention, the pharmacologically acceptable salts of the compound of formula (I) include alkali metal salts such as natrium salts and carium salts, alkaline earth metal salts such as calium and magnesium salts, dicyclohexylamine salts, Organic amine salts such as N, N'-benzyl ethylenediamine salt and diethanolamine salt, organic carbonates such as formate, acetate, maleate, tartarate salt and toluene sulfonate salt or sulfonate salt, and the like. Lower alkyl esters such as methyl esters, ethyl esters, furophyll esters, isopropyl esters, butyl esters, isobutyl esters, tertiary butyl esters, benzyl esters, hexyl esters and 1-cyclofurophil esters, vinyl esters and aryls; Lower alkenyl esters such as esters, and lower alcohol cyalkynyl esters such as methoxymethyl ester, ethoxymethyl ester, and 1-methoxyethyl ester, and methylthio And lower alkyl thioesters such as methyl ester and ethyl thiomethyl ester.

Hereinafter, the present invention will be described in more detail as examples. It is to be understood, however, that the invention is not limited to these embodiments, but may be modified within the scope of the claims.

Reference Example 1

[Production of (Z) -2-methoxyimino-2- (aminothiazol-4-yl) acetic acid benzotriazole ester.]

2.79 g of 2- (2-aminothiazol-4-yl) methoxyiminoacetic acid was dissolved in 25 ml of NN'-dimethylformamide, followed by 1.87 g of 1-hydroxy benzotriazole and 2.86 g of dicyclohexylcarbodiimide. After the addition of the mixture, the mixture was reacted for 3 hours at 23 ° C., filtered, and 35 ml of distilled water was added to the filtrate for 1 hour to give pale yellow crystals. This was filtered and dried to obtain 3.82 g of the target product.

Reference Example 2

[Preparation of (Z) -2- (t-butoxycarbonylfurop-2-oxyimino) -2- (2-aminothiazol-4-yl) acetic acid benzotriazole ester.]

25 g of (Z) -2- (2-t-butoxycarbonylfurop-2-oxyamino) -2- (2-aminothiazol-4-yl) acetic acid was dissolved in 25 ml of NN'-dimethylformamide. The same experiment as in Reference Example 1 was repeated to obtain 31.0 g of the target compound.

Example 1

Preparation of [6- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] phenylacetamido] pheniclanic acid. ]

50 ml of NN'-dimethylformamide and 4.03 g of ampicillin were mixed and stirred, and 2.8 ml of triethylamine was added thereto at 5 ° C. for 5 minutes to form a clear solution, followed by (Z) -2- 3.82 g of methoxyimino-2- (2-aminothiazol-4-yl) acetic acid benzotriazole ester is added and reacted at room temperature for 5 hours.

Subsequently, 200 ml of isopropanol was added at a temperature of 10 ° C., 5 ml of sodium-2-ethylhexanoic acid was added for 20 minutes, and the precipitated crystals were filtered and dissolved in 100 ml of ice-cold water, and then the pH of the solution was adjusted to 2.8 with 1N hydrochloric acid. If it is adjusted to, white crystals are precipitated. This was filtered and dried to obtain 4.2 g of the target product.

Example 2

[6- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyimino) -2- (2-aminothiazol-4-yl) acetamido ] Phenylacetamido] Phenylalanic Acid.]

5.35 g of the material prepared in Reference Example 2, i.e., (Z) -2 (t-butoxycarbonylfurov-2-oxyimino) -2- (2-aminothiazol-4-yl) acetic acid benzotriazole ester Was processed in the same manner as in Example 1 to obtain 4.82 g of the target product.

Example 3

[6- [D (-)-alpha- (Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-(4-hydroxyphenyl) acetamido] Preparation of Penicylanic Acid.]

4.2 g of amoxicillin was added to 50 ml of NN'-dimethylformamide, followed by stirring in the same manner as in Example 1 using the compound prepared in Reference Example 1 to obtain 5.04 g of the target substance.

Example 4

[6- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyimino) -2- (2-aminothiazol-4-yl) acetamido ]-(4-hydroxyphenyl) acetamido] phenic silane acid.]

6.04 g of the target product was obtained by treating in the same manner as in Example 3 using the compound prepared in Reference Example 2.

Example 5

[7- [D (-)-alpha-[(Z) -2- (t-methoxyimino-2 (2-aminothiazol-4-yl) acetamido] phenylacetamido] -cephalospo Preparation of Lansan.]

4.05 g of cephalos glycine is added to 100 ml of dichloromethane and dissolved by adding 2.8 ml of triethylamine for 5 minutes while maintaining the temperature of the solution at 0 ° C.

To this, a solution obtained by dissolving 3.82 g of the compound prepared in Reference Example 1 in 100 ml of tetrahydrofuran was added and reacted at room temperature for 5 hours. The reaction solution was concentrated and dissolved by adding 100 ml of water, and then the pH of the reaction solution with 2N hydrochloric acid. Is adjusted to 3.2 to precipitate crystals. This was filtered and dried to obtain 4.25 g of the target product.

Example 6

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acetamido ] Phenylacetamido] Cepalosporonic Acid.]

4.21 g of cephalolysine was added to 50 ml of dimethylformamide, and 2.8 ml of triethylamine was added thereto. Then, 5.35 g of the compound prepared in Reference Example 2 was added thereto, and the resultant was treated as in Example 5 to obtain 5.80 g of the target substance.

Example 7

[7- [D (-)-alpha (Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-(4-hydroxyphenyl) acetamido] ce Preparation of Palosporranic Acid.]

4.21 g of 7- [D (-)-alpha- (4-hydroxyphenyl) acetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid was added to 50 ml of NN'-dimethylformamide, 2.8 ml of triethylamine was added and dissolved at 0 ° C., and 3.82 g of the compound prepared in Reference Example 1 was added thereto, and the resultant was treated in the same manner as in Example 5 to obtain 4.21 g of the target compound.

Example 8

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyimino) -2- (2-aminothiazol-4-yl) acetamido )-(4-hydroxyphenyl) acetamido] cephalosporonic acid.]

5.35 g of the target product was obtained by treating in the same manner as in Example 7 using 5.35 g of the compound prepared in Reference Example 2.

Example 9

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [1-methyl-1H-tetra Sol-5-yl) -thiomethyl] -3-cepem-4-carboxylic acid.]

4.78 g of 7- [D (-)-alpha-aminophenyl acetamido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid and Reference Example 3.82 g of the target product was obtained by treating in the same manner as in Example 5 using 3.82 g of the material prepared in (1).

Example 10

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyimino) -2- (2-aminothiazol-4-yl) acetamido ] Phenylacetamido] -3- [methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefe-4-carboxylic acid.]

5.35 g of the target product was obtained by treating in the same manner as in Example 9 using 5.35 g of the material prepared in Reference Example 2.

Example 11

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -4- (hydroxyphenyl) acetamido ] -3- [1-Methyl-1H-tetrazol-5-yl) -3-cepem-carboxylic acid.]

3.82 g of the material prepared in Reference Example 1 was used in the same manner as in Example 5 to obtain 5.01 g of the target substance.

Example 12

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -3- [1-methyl-1H-tetrazol-5-yl) Preparation of Thiomethyl] -3-cepem-4-carboxylic acid.]

5.35 g of the material prepared in Reference Example 2 was treated in the same manner as in Example 11 to obtain 6.57 g of the target substance.

Example 13

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] phenylacetamido] -3- [1, Preparation of 2,3-triazol-4-yl) thiomethyl] -3-cefe-4-carboxylic acid.]

4.48 g of 7- [D (-)-alpha-aminophenyl acetamido- (1,2,3-triazol-4-yl) thiomethyl] -3-cef-4-carboxylic acid and in Reference Example 1 4.18 g of the target product was obtained by treating the prepared material in the same manner as in Example 5.

Example 14

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acetamido ] Phenylacetamido] -3- [1,2,3-triazol--4-yl] -3-cefe-4-carboxylic acid.]

5.35 g of the target product was obtained by treating in the same manner as in Example 13 using 5.35 g of the material prepared in Reference Example 2.

Example 15

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-(4-hydroxyphenyl) acetamido ] -3-[(1,2,3-triazol-4-yl) thiomethyl] -3-cepem-4-carboxylic acid.]

4.62 g of the target compound was obtained by treating in the same manner as Example 5 using 4.62 g of Sephatrizin and 3.82 g of the material prepared in Reference Example 1.

Example 16

[7- [D (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acetamido ]-(4hydroxyphenyl) acetamido] -3- [1,2,3-triazol-4-yl) thiomethyl] -3-cepem-4-carboxylic acid.]

5.35 g of the material prepared in Reference Example 2 was used in the same manner as in Example 15 to obtain 6.3 g of the target substance.

Example 17

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido) phenylacetamido] -3- (1, Preparation of 2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid.]

7 [(D (-)-alpha-aminophenylacetamido] -3-[(1,2,4,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-tri 4.88 g of the target product was obtained by treating in the same manner as in Example 5 using 4.88 g of azin-3-yl) thiomethyl] -3-cef-4-carboxylic acid and 3.82 g of the material prepared in Reference Example 1.

Example 18

[7-[(D) (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acet Amido) phenylacetamido] -3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thiomethyl ] -3-Cemfe-carboxylic Acid Preparation.]

5.65 g of the target substance was obtained in the same manner as in Example 17, using 5.35 g of the material prepared in Reference Example 2.

Example 19

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido)-(4-hydroxyphenyl) acetamido ] -3- (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4- Preparation of Carboxylic Acids.]

7 [(D (-)-alpha-amino- (4-hydroxy phenylacetamido) -3-[(1,2,4,6-tetrahydro-2-methyl-5,6-dioxo-1 5.05 g of 2,4-triazin-3-yl) thiomethyl] -3-cef-4-carboxylic acid and 3.82 g of the material prepared in Reference Example 1 were treated in the same manner as in Example 5 3.80 g was obtained.

Example 20

[7-[(D) (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acet Amido)-(4-hydroxyphenyl) acetamido] -3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazine 3-yl) thiomethyl] -3-cefem-carboxylic acid.]

5.25 g of the target product was obtained by treating in the same manner as in Example 19 using 5.35 g of the material prepared in Reference Example 2.

Example 21

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] phenylacetamido] desacetoxy cephalospo Preparation of Lansan.]

3.65 g of Separexin and 3.82 g of the compound prepared in Reference Example 1 were treated in the same manner as in Example 1 to obtain 4.07 g of the target compound.

Example 22

[7-[(D) (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acet Amido) phenylacetamido] desacecetoxy cephalosporan acid.]

5.35 g of the compound prepared in Reference Example 2 was used in the same manner as in Example 21 to obtain 4.64 g of the target compound.

Example 23

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-(4-hydroxyphenyl) acetamido [Production of desacetoxy cephalosporonic acid.]

3.82 g of Sepadoxyl and 3.82 g of the compound prepared in Reference Example 1 were treated in the same manner as in Example 1 to obtain 3.74 g of the target substance.

Example 24

[7-[(D) (-)-alpha-[(Z) -2- (t-butoxycarbonylfurov-2-oxyamino) -2- (2-aminothiazol-4-yl) acet Amido)-(4-hydroxyphenyl) acetamido] Deacecetoxy cephalosporan acid.]

5.35 g of the material prepared in Reference Example 2 was treated in the same manner as in Example 23 to obtain 4,59 g of the target substance.

Example 25

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] phenylacetamido] cephalosporic acid sodium Preparation of salts.]

5.0 g of the compound prepared in Example 5 was added to 100 ml of isopropanol, and 2.0 ml of triethylamine was added dropwise while maintaining the temperature of the solution at 0 ° C for 5 minutes. To this was added 5 ml of sodium 2-ethylhexanoic acid and stirred at 0 ° C. for 30 minutes to precipitate white crystals. This was filtered and dried to obtain 4.8 g of the desired product.

Example 26

[7- [D (-)-alpha-[(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-(4-hydroxyphenyl) acetamido ] -3- [1-Methyl-1H-tetrazol-5-yl) -3-cefem-4-carboxylic acid sodium salt.]

5.0 g of the material prepared in Example 11 was used to treat the same method as in Example 25 to obtain 4.2 g of the target substance.

[Antibacterial Test]

The minimum inhibitory concentration for the growth of each compound prepared by the method of Examples 1 to 26 was measured using "Microtite Burose Dilution Method".

end. Use strain: Staphylococcus aureus (A. 25923)

Staphylococcus epididis (A., 12228)

Sarshinarutea (A. 9341)

Bacillus subtilis (A. 6633)

Pseudomonas aureginosa (N. 10490)

Sarsinariquipeencis (N. 27592)

this. Coli (A. 9637)

Alcaligenes pecalis (A. 1311)

I. Control Antibiotic: Amoxicillin

Sephatrigin

Sepadroxil

All. Medium: Muller-Hinton Agar (PH 7.4 ± 0.2)

la. Test Method: The strain was pre-cultivated in a solid medium, and the culture was suspended in Muller-Hinton Bruce, a medium for transplantation of test cells, and a hop intensity of about 0.3 was obtained at 625 mm using a spectrophotometer.

Subsequently, a constant concentration of sample solution was added to the Muller-Hinton Bruce, and 200 ml were dispensed into the test tube. At this time, the concentration range of the compound was set to 0.005-50 μg / ml.

After 5 ml each of the test medium suspension liquid medium was added to the dispensed test tube and incubated at 35 ° C. for 18 hours, the minimum concentration of the compound inhibited by the naked eye was measured. The results are as shown in Table 1 below.

TABLE 1

As can be seen in Table 1, the peniclanic acid and cephalosporin derivatives of the formula (I) and salt compounds thereof according to the present invention have a broad and strong spectrum with respect to Gram-negative bacteria and Gram-positive bacteria. It is a compound with stronger antimicrobial activity than conventional antibiotics.

Claims (3)

Peniclanic acid and cephalosporin derivatives represented by the following structural formula (I).

In the above formula, R ₁ is a cyclic compound consisting of 1-6 carbon atoms or phenyl, substituted phenyl, thienyl, halophenyl, R ₂ is

Is a group of the form wherein X is hydrogen, amino, nitro, halogen, R ₄ is methyl,

Y is three carbon atoms

Form groups, or substituted three carbon atoms

Is a group of the form wherein R ₅ is hydrogen, acetoxy, or

Group, wherein R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, lower alkyl having 1-4 carbon atoms, phenyl, halophenyl or hydroxyphenyl. R ₃ represents a group forming hydrogen, an alkali metal cation or an ester. In an inert solvent, an acid halide of the following compound of formula (II) and a compound of formula (III) were reacted at a temperature of -20 ° C to 30 ° C to prepare the following compound of formula (IV), followed by 1-hydroxy benzotriazole And dicyclohexyl carbodiimide in the dimethylformamide solution, and then reacting the compound of formula (V) with the compound of formula (IV).

In the above formula, R ₁ is a cyclic compound consisting of 1-6 carbon atoms or phenyl, substituted phenyl, thienyl, halophenyl, R ₂ is

Is a group of the form wherein X is hydrogen, amino, nitro, halogen, R ₄ is methyl,

to be). R ₃ represents a group forming hydrogen, an alkali metal cation or an ester. The acid halide of the following compound of formula (II) and the following compound of formula (VI) were reacted at a temperature of -20 ° C to 30 ° C in an inert solvent to prepare the following compound of formula (VII), followed by 1-hydroxy benzotriazole And dicyclohexyl carbodiimide to activate in a dimethylformamide solution, and then reacting the compound of formula (V) with the compound of formula (I).

In the above formula, R ₁ is a cyclic compound consisting of 1-6 carbon atoms or phenyl, substituted phenyl, thienyl, halophenyl, R ₂ is

Is a group of the form wherein X is hydrogen, amino, nitro, halogen, R ₄ is methyl,

to be), R ₃ represents a group forming hydrogen, an alkali metal cation or an ester, and R ₅ represents hydrogen, acetoxy or

In the form (wherein R ₆ , R ₇ , R ₈ , R ₉ are hydrogen, lower alkyl having 1-4 carbon atoms, phenyl, halophenyl or hydroxyphenyl).