JPS6121203B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel antibacterial compositions. More specifically, this invention uses the formula (): (In the formula, R ¹ is a hydrogen atom, hydroxy group, lower alkoxycarbonyloxy group, or acyloxy group, R ² is a hydrogen atom, halogen atom, or nitro group, R ³ is a lower alkyl group, and R ⁴ is an acetoxy group or a heterocyclic thio group. , n means 1 or 2, respectively) and an aminoglycoside antibiotic or a pharmaceutically acceptable salt thereof. It provides: Generally, cephalosporin antibiotics have low toxicity and many exhibit excellent antibacterial activity. However, very few drugs are known to be effective against Pseudomonas aeruginosa. On the other hand, so-called aminoglycoside antibiotics are known to exhibit strong antibacterial activity against Pseudomonas aeruginosa, but they have side effects such as hearing loss and nephrotoxicity, so it would be preferable if the desired effect could be achieved with lower doses. That's why. It is known that the combination of an aminoglycoside antibiotic, such as gentamicin or tobramycin, and a penicillin antibiotic, carbenicillin, has a synergistic effect against Pseudomonas aeruginosa (for example, the
Japanese Journal of Antibiotics March 1977
209 pages). The inventors of this invention previously discovered that a group of cephalosporin compounds belonging to the general formula () have excellent antibacterial activity against Pseudomonas aeruginosa and have broad antibacterial activity against other Gram-negative and Gram-positive bacteria. It was found that the spectrum showed good blood concentration and concentration distribution in organs. Furthermore, as a result of studying these cephalosporin compounds, they found that they have a strong synergistic effect, especially against Pseudomonas aeruginosa, when used in combination with aminoglycoside antibiotics, leading to the completion of this invention. Due to the strong synergistic effect of the antibacterial composition of this invention, the desired effect can be obtained with a smaller amount than when using either a cephalosporin compound or an aminoglycoside antibiotic alone, and in particular, side effects when using an aminoglycoside antibiotic are reduced. It has the feature of being It is also believed that the antibacterial spectrum of each compound is complemented and resistance acquisition is slowed down. The cephalosporin compound of formula () used in this invention is preferably of the D(-) type.
A part of it is known, for example, from Japanese Patent Application Laid-Open No. 52-87189. However, most of them are new substances. Regarding their manufacturing method and properties, reference is made to the description in Japanese Patent Application No. 111125/1982. An example of a method for producing a cephalosporin compound of formula () is as follows: (In the formula, R ⁴ is the same as defined in the formula ().) 7-Aminocephalosporanic acids having the formula (): (In the formula, R ¹ , R ² , R ³ and n are the same as defined in the formula ().) A reactive derivative of a carboxylic acid having the following formula may be reacted by a conventional method. The compound of formula () is added to the amino group of substituted phenylglycine by a conventional method.

It can be created by introducing [Formula]. Note that the compound in which R ¹ is a lower alkoxycarbonyloxy group or an acyloxy group in formula () can also be produced after a compound in formula () in which R ¹ is a hydroxy group is once produced. Of course, in formula () R ⁴
A compound in which R is a heterocyclic thio group can be derived from a compound of formula () in which R ⁴ is an acetoxy group. When the D(-) form is used as the carboxylic acid of formula (), the desired D(-) form of the cephalosporin compound can be obtained. In the formula (), the term "lower" in the terms "lower alkoxycarbonyl group" and "lower alkyl group" means 1 to 4 carbon atoms. Preferred examples of the "acyloxy group" include an acetoxy group, a lower aliphatic acyloxy group such as a propionyloxy group, an aromatic acyloxy group such as a benzoyloxy group, and an acetoacetoxy group. A preferred example of a "halogen atom" is a chloro atom. A preferred example of the “heterocyclic thio group” is 1,3,4-thiadiazol-2-yl-
Thio group, 5-methyl (or ethyl)-1,3,
There are 4-thiadiazol-2-yl-thio group and 1-methyl-(1,2,3,4-tetrazole)-5-yl-thio group. Preferred specific examples of the cephalosporin compound of formula () are as follows. a 7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yne-carbonylamino)-p-
Ethoxycarbonyloxy (or propoxycarbonyloxy or 1-butoxycarbonyloxy)-phenylacetamide]-3-(5-
Methyl (or hydrogen)-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, b 7-[D(-)-α(4-methyl (or ethyl or propyl) -2,3-dioxo-piperazin-1-yl-carbonylamino)-p-
Acetoxy (or propionyloxy)-phenylacetamide]-3-(5-methyl (or hydrogen)-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, c 7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yne-carbonylamino)-p-
Acetoacetoxyphenylacetamide]-3-
(5-methyl (or hydrogen)-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, d 7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yne-carbonylamino)-p-
hydroxyphenylacetamide]-3-(5-methyl (or hydrogen)-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-carboxylic acid, e 7-[D(-)- α(4-Methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yl-carbonylamino)-m-
Chloro-p-ethoxycarbonyloxy (or propoxycarbonyloxy or i-butoxycarbonyloxy)-phenylacetamide]-3-(5-methyl (or hydrogen)-1,
3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, f7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazine) -1-yl-carbonylamino)-m-
Chloro-p-acetoxy (or propionyloxy)-phenylacetamide]-3-(5-methyl (or hydrogen)-1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4- Carboxylic acid, g 7-[D(-)-α-4-methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yl-carbonylamino)-m-
Chloro-p-acetoacetoxyphenylacetamide]-3-(5-methyl (or hydrogen)-1,
3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid, h7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazine) -1-yne-carbonylamino)-m-
Chloro-p-hydroxyphenylacetamide]
-3-(5-methyl (or hydrogen)-1,3,4
-thiadiazol-2-yl-thiomethyl)-
3-Cefem-4-carboxylic acid, i7-[D(-)-α(4-methyl (or ethyl or propyl)-2,3-dioxo-piperazin-1-yl-carbonylamino)-m-
Chloro (or hydrogen) phenylacetamide] -
3-(5-methyl (or hydrogen)-1,3,4-
Thiadiazol-2-yl-thiomethyl)-3
- cefem-4-carboxylic acid, j and a "2-oxoimidazolidine" compound in place of the above "2,3-dioxopiperazine". Aminoglycoside antibiotics include kanamycin, deoxykanamycin B, verdomycin,
Sisomicin, cerdomycin, destomycin,
Examples include dihydropectinomycin, amikacin, tobramycin, nebramycin, mutamicin, canendomycin, gentamicin, and similar substances thereof. Pharmaceutically acceptable salts of aminoglycoside antibiotics and pharmaceutically acceptable salts of cephalosporin compounds of formula () include those known in the respective technical fields. The active ingredients used in this invention are generally suitable for parenteral administration, and it is therefore generally preferred that the compositions of this invention be formulated for parenteral administration. As carriers for parenteral administration, those known in the art can be used. For example, physiological saline and Ringer's solution may be used. The blending ratio (weight ratio) of the cephalosporin compound and the aminoglycoside antibiotic in formula () is:
An example is 200:1~1:2, more commonly 100:1~
It may be 1:1, with 50:1 to 30:1 being advantageous. Usually 20 mg or more of the composition of this invention per day for adults.
6000mg, more commonly 100mg to 3000mg will be administered. However, higher doses may be used for systemic infections or infections caused by stubborn microorganisms. Next, among the new cephalosporin substances used in this invention, a representative compound is the formula (): Compound represented by [However, all are D(-) forms]
The physical properties of are shown in Table 1.

【table】

[Table] Also, formula (): Compounds represented by [However, all are D(-) forms]
The physical properties of are shown in Table 2.

【table】

[Table] Next, production examples of the compounds of this invention are listed. Production example 7-[D-(-)-α(4-ethyl-2,3-dioxo-piperazin-2-yl-carbonylamino)-p-ethoxycarbonyloxy-phenylacetamide]-3-(1 ,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-
Preparation of carboxylic acid, compound No. 5 in Table 1: 7-[D-(-)-α-t-butoxycarbonylamino-p-ethoxycarbonyloxy-phenylacetamide]-3-(1, 3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4
-7-[D-(-)-α-amino-p] obtained by a conventional method from carboxylic acid [mp 156-157°C (decomposition)]
-Ethoxycarbonyloxy-phenylacetamide]-3-(1,3,4-thiadiazol-2-yl-thiomethyl)-3-cephem-4-carboxylic acid was used as a raw material. This was reacted with 4-ethyl-2,3-dioxo-piperazin-1-yl-carbonyl chloride in a conventional manner to obtain the title compound. Yield: 91% mp158~162℃ (decomposition) IR (KBr): 1780 (β-lactam), 1720~
1650cm ^-1 UVλmax: 264nm (methanol) Next, the present invention will be explained with reference to test examples. Test Example Pseudomonas aeruginosa KM338 derived from ATCC17653 strain (the MICs of penicillin G and carbenicillin against this bacterium are 30,000 μg/ml and 125 μg/ml, respectively) was used as a bacterial strain. Using a microtiter plate, compound No. 2, compound No. 13, and
Each of compound No. 5 and deoxykanamycin B
(DKB), amikacin (AMK) at various concentrations, and trypticase soy broth (Trypticase soy broth) containing each concentration of the drug.
50μ of test bacteria cultured for 18 hours (approximately 2×10 ⁶ cells/ml) was added to 50μ of soy broth (final bacterial concentration).
10 ⁵ cells/ml) and statically cultured at 37°C for 24 hours. The presence or absence of bacterial growth was determined visually and measured by the minimum inhibitory concentration (MIC) of each concomitant drug. The results are shown in Figures 1a-3b. In these figures, the horizontal axis indicates compounds No. 2 and No. 2, which are compounds according to the present invention.
13, the concentration (μg/ml) of each compound No. 5,
The DKB or AMK concentration was plotted on the vertical axis, and the MIC of the concomitant drug was plotted, and each point was connected to form a curve. In this figure, the area surrounded by the curve, the vertical axis, and the horizontal axis is the area that indicates the combined concentration of the concomitant drug that does not inhibit the growth of bacteria, and that the combined concentration in the area excluding this area can inhibit the growth of bacteria. It represents. In other words, it depends on where this plot falls on the inside, outside, or on the line of the area surrounded by the line connecting the two points obtained in the case of single-acting use of each drug, the vertical axis, and the horizontal axis. Therefore, when the two drugs are used together, the effects are different; if a curve is concave inward, there is a synergistic effect, if the curve is bulging outward, there is an antagonistic effect, and if the curve is on a straight line, there is an antagonistic effect. This indicates that there is an additive effect. From Figures 1a to 3b, No. 1 of Table 1 according to the present invention.
It is understood that compounds No. 2, No. 13, and No. 5 all give curves concave to the inside of the straight line, and exhibit excellent synergistic effects when used in combination with deoxykanamycin B and amikacin. Compounds No. 2, 5, and 13 shown in Table 1 were intramuscularly injected into rats, and their acute toxicity was
It was over 2000mg/Kg.

[Brief explanation of the drawing]

Figures 1a to 3b show representative compound No. of the present invention.
2, No. 13, No. 5 and an aminoglycoside antibiotic against Pseudomonas bacteria.

Claims (1)

[Claims] 1 Formula (): (In the formula, R ¹ is a hydroxy group or a lower alkoxycarbonyloxy group, R ² is a hydrogen atom, R ³ is a lower alkyl group, R ⁴ is a 1,3,4-thiadiazol-2-ylthio group, and n is 2. 1. An antibacterial composition comprising a D(-)cephalosporin compound or a pharmaceutically acceptable salt thereof having the following: and an aminoglycoside antibiotic or a pharmaceutically acceptable salt thereof. 2. The composition according to claim 1, wherein the weight ratio of the cephalosporin compound of formula () or its salt to the aminoglycoside antibiotic or its salt is 200:1 to 1:2. 3. Claim 1, wherein the aminoglycoside antibiotic is kanamycin, deoxykanamycin B, amikacin, tobramycin, nebramycin, mutamicin, verdomycin, sisomicin, cerdomycin, destomycin, dihydrospectinomycin, canendomycin, or gentamicin. Or the composition according to item 2. 4 Claim 1 adapted for injection administration
The composition according to any one of Items 1 to 3.