JPH0243726B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antibacterial activity enhancer for β-lactam antibiotics and an antibacterial composition containing the same. The most well-known and widely used antibiotics in the medical field at present, particularly in the treatment of infectious diseases, are the beta-lactam antibiotics, namely the natural and semi-synthetic penicillins and cephalosporins. These β-lactam antibiotics exhibit a cell wall synthesis inhibitory effect against various pathogenic microorganisms and are highly useful, but in recent years, cases have been observed in which their antibacterial activity decreases or disappears. However, it has been pointed out that the drug does not have the expected clinical effects. This reduction or disappearance of antibacterial activity is caused by the β-lactam degrading enzyme (β-lactamase) produced by the target microorganism.
It is recognized that this is caused by the cleavage and decomposition of the lactam ring, and there is a demand for research and development of antibiotics that can effectively act on such β-lactamase producing bacteria (β-lactam antibiotic resistant bacteria). The present inventors have conducted various studies from the viewpoint of providing a substance capable of inhibiting the activity of β-lactamase produced by resistant bacteria in order to meet the above-mentioned needs. As a result, the compound represented by the following general formula () has the desired β-lactamase activity inhibitory effect, and when used in combination with known β-lactam antibiotics, it synergistically enhances the antibacterial activity of these. It has been found that this has the effect of The present invention was completed based on this new knowledge. That is, the present invention is based on the general formula [In the formula, R represents a hydrogen atom or an ester-forming residue that can be hydrolyzed in vivo] An antibacterial activity enhancer for a β-lactam antibiotic containing a compound represented by the following or a pharmaceutically acceptable salt thereof, and the above compound and a β-lactam antibiotic. The compound represented by the above general formula () used as the active ingredient of the antibacterial activity enhancer of the present invention not only has a strong β-lactamase activity inhibitory effect, but also has a synergistic effect on the antibacterial activity of known β-lactam antibiotics. It is characterized in that it has an effect of improving (enhancing effect). Therefore, when used in combination with a β-lactam antibiotic, it not only significantly improves the antibacterial activity of the antibiotic, but also exhibits excellent antibacterial activity against pathogenic bacteria that are resistant to the antibiotic. The present invention also provides an antibacterial composition having such previously unprecedented antibacterial activity. The compound represented by the above general formula () is β-
It is known as an intermediate in the synthesis of lactam antibiotics. In addition, the compound () has antibacterial activity against penicillin G-resistant Staphylococcus aureus, but does not have sufficient antibacterial activity against Gram-negative bacteria such as Escherichia coli. It is also known [(J.Med.Chem., 18, 10, 986-991 (1975)]).
However, when this compound () is used as an antibacterial agent in combination with a β-lactam antibiotic, β-
It is completely unknown that the antibacterial activity of lactam antibiotics can be synergistically improved. The ester-forming residues that can be hydrolyzed in vivo, represented by R in the above general formula (), include various well-known ester-forming residues that can be easily hydrolyzed in the blood or tissues of normal mammals. Any of the groups may be used. The above groups are typically, for example, an alkanoyloxymethyl group having 3 to 8 carbon atoms, a 1-(alkanoyloxy)ethyl group having 4 to 9 carbon atoms, and a 1-methyl-(alkanoyloxy) group having 5 to 10 carbon atoms. Ethyl group, alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, 1- having 4 to 7 carbon atoms
(Alkoxycarbonyloxy)ethyl group, 1-methyl-(alkoxycarbonyloxy)ethyl group having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl group having 3 to 9 carbon atoms, 4 to 10 carbon atoms
Examples include 1-[N-(alkoxycarbonyl)amino]ethyl group, 3-phthalidyl group, 4-crotonolactonyl group, and γ-butyrolactone-4-yl group. The antibacterial activity enhancer of the present invention has the above general formula ()
The compound represented by or a pharmaceutically acceptable salt thereof, such as an alkali metal salt such as a sodium salt or a potassium salt, can be prepared into a dosage form for oral or parenteral administration using a conventional pharmaceutical carrier as an active ingredient. . By administering it together with a conventional β-lactam antibiotic preparation, it can exhibit the β-lactamase activity inhibiting action and the antibacterial action enhancing action of antibiotics as desired in the present invention. In addition, the above-mentioned active ingredient compound can be mixed alone into a conventional β-lactam antibiotic preparation to prepare a single antibiotic preparation; in this case, by administering such an antibiotic preparation, It can exhibit the desired antibacterial activity enhancing effect. In the above, examples of antibiotics that can be used in combination with the enhancer of the present invention or its active ingredient compound include common penicillins such as ampicillin, amoxicillin, hetacillin, cyclacillin, mecillinum, carbenicillin, sulbenicillin, ticarcillin, piperacillin, apalcillin, mesolocillin, etc. and cephalosporins such as cephalolidine, cephalothin, cefapirin, cefacetril, cefazolin, cephalexin, cephaladine, etc., and salts thereof. can. Among these, antibiotics sensitive to β-lactamase, which are hydrolyzed and inactivated by β-lactamase, are preferable because the effects of the above-mentioned combination are extremely noticeable. The combined ratio of the above antibiotic and the enhancer of the present invention varies depending on the type of antibiotic and is not constant, but usually about 0.1 to 10 moles of the active ingredient compound of the enhancer of the present invention is preferably about 0.5 mole to 1 mole of the antibiotic. It is preferable to set the amount to 5 mol. The dosage unit form of the antibiotic preparation prepared by blending the enhancer of the present invention or its active ingredient compound is a conventional oral dosage form such as a tablet, capsule, granule, powder, syrup, troche, or oral liquid. , suspensions, etc., and preparations for parenteral administration, such as aqueous or suspension injections such as intravenous, intramuscular, and subcutaneous injections;
It may be an injection that is dissolved before use. Such preparations can be manufactured according to conventional methods using common carriers commonly used in this field. The daily dosage of the above preparation can be determined as appropriate and is not limited, but usually in oral administration, the total amount of the active ingredient compound of the enhancer of the present invention and the antibiotic is about 10 to 200 mg/Kg, For parenteral administration, it is preferable to aim for an amount of about 1 to 100 mg/Kg. Thus, when used in combination with a β-lactam antibiotic, the antibacterial activity enhancer of the present invention can synergistically increase the antibacterial action of the antibiotic. Similarly, the antibacterial composition of the present invention containing the active ingredient compound of the enhancer and a β-lactam antibiotic can also significantly improve the antibacterial action of the combined β-lactam antibiotic. Therefore, the antibacterial composition of the present invention can be used to treat various infections caused by various pathogenic microorganisms in which the antibiotics contained therein have been used in the past, and can exhibit even more excellent effects.
Excellent therapeutic effects can also be achieved for diseases that are caused by microorganisms that are resistant to the above antibiotics and cannot be cured by administering the antibiotics alone. The pathogenic microorganisms to which the composition of the present invention can be applied include various Gram-positive microorganisms belonging to the genus Bacillus, Streptococcus, Klebscilla, Haemophilus, Staphylococcus, Salmonella, Escherichia, Pseudomonas, etc. Examples include bacteria and gram-negative bacteria. Experimental examples will be given below to explain the present invention in more detail. Experimental Example 1 The inhibitory activity of the compound represented by the following formula, which is the active ingredient of the antibacterial activity enhancer of the present invention, against penicillinase (β-lactamase) derived from the genus Bacillus was determined using the PH stat method [Journal Pharmaceutical Co., Ltd.] using penicillin G as a substrate. Science, No. 61
Vol. 10, pp. 1954-1958, 1972]. The results are shown in Table 1 below. <Test compound> Compound 1

[Table] From the above, it can be seen that the active ingredient compound of the present invention has a penicillinase activity inhibiting effect. The concentration of the above compound that inhibited 0.6 units of penicillinase by 50% was 2×10 ⁻⁴ M. Experimental Example 2 The same Compound 1 used in Experimental Example 1 above and the minimum inhibitory concentration (MIC) of ampicillin against various bacteria, as well as the above Compound 1
The MIC of ampicillin against various bacteria when used in combination with 0.625 μg/ml of ampicillin was measured according to the standard method of the Japanese Society of Chemotherapy. Trypto soya broth (Nitsui) was used as the culture medium for bacterial enrichment, and Heart Infusion Agar (Nitsui) was used as the culture medium for sensitivity measurement. The results are shown in Table 2 below.

[Table] From Table 2 above, it can be seen that a remarkable synergistic effect is observed when Compound 1 and ampicillin are used in combination. Experimental Example 3 The same compound 1 used in Experimental Example 1 above, the respective MICs of cephaloridine, and the MIC of cephaloridine when 20 μg/ml of the above compound 1 was used together.
The MIC was measured for each of the eight types of clinically isolated E. coli in the same manner as in Experimental Example 2 above. As a result, the MIC against the above 8 types of E. coli when compound 1 was administered alone
were all >50 μg/ml, and cephaloridine alone was 12.5 μg/ml, but when compound 1 was used in combination with 20 μg/ml, cephaloridine
The MIC was 1.56 μg/ml, confirming the synergistic effect of the combined use of Compound 1 and cephaloridine.

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom or an ester-forming residue that can be hydrolyzed in vivo.] An antibacterial activity enhancer for a β-lactam antibiotic containing a compound represented by the following or a pharmaceutically acceptable salt thereof. 2. The antibacterial activity enhancer according to claim 1, wherein the β-lactam antibiotics are ampicillin, amoxicillin, and cephaloridine. 3 β-lactam antibiotics and general formula [In the formula, R represents a hydrogen atom or an ester-forming residue that can be hydrolyzed in vivo] An antibacterial composition containing a compound represented by the following or a pharmaceutically acceptable salt thereof. 4. The antibacterial composition according to claim 3, wherein the β-lactam antibiotics are ampicillin, amoxicillin and cephaloridine.