JP2002154971A - Anti-mrsa agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an anti-MRSA(methicillin-resistant Staphylococcus aureus) agent on the basis of the findings that a tylosin derivative showing a certain level of sensitivity to macrolide antibiotics manifests sensitivity to MRSA, too. SOLUTION: The objective anti-MRSA agent includes, as an active ingredient, a 4"-substituted tylosin derivative represented by formula (I) (wherein R1 is H or hydroxy group and R2 is methoxy, methylthio, methylsulfonyl or benzoyl group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antibacterial agent against methicillin-resistant Staphylococcus aureus (hereinafter, abbreviated as MRSA).

[0002]

2. Description of the Related Art Staphylococcus aureu
Since s ) is highly pathogenic, it has been studied diversified as a causative agent of infectious disease, and various chemotherapeutic agents have been developed for the infectious disease. However, various problems have arisen since the bacteria easily acquire resistance to chemotherapeutic agents. Typical examples of this problem include hospital-acquired infections and community-acquired infections by the methicillin-resistant bacteria of the bacteria.

At present, vancomycin is often used as the ultimate chemotherapeutic agent for MRSA infection, but resistant bacteria to vancomycin have also appeared (Ito et al., Journal of the Japanese Society of Chemotherapy, Vol. 48, 7-2
0,2000). In addition, since vancomycin is liable to cause side effects such as hearing and kidney damage, it may be necessary to monitor the blood concentration at the time of administration.

[0004] On the other hand, macrolide antibiotics such as erythromycin and spiramycin are mainly gram-positive because they have a moderate antibacterial range, but are highly medically reliable and have excellent transferability to the lung. Fungi, especially
It has been widely used to treat S. aureus infections. Therefore, a large number of Staphylococcus aureus resistant to macrolide antibiotics have appeared, and furthermore, 8 out of MRSA
It has also been confirmed that more than 5% of the strains were resistant to macrolide antibiotics (Nakamura et al., The Japanese Journal)
of Antibiotics, Vol. 51, No. 7, pp. 494-50
0, 1998).

[0005]

As mentioned above, although vancomycin has certain disadvantages, it still has an MR.
It is useful as a therapeutic agent for SA infection. However, given the properties of Staphylococcus aureus, such as the ease of acquiring resistance, it would be desirable to provide an anti-MRSA agent with a class of drugs that are structurally distinct from vancomycin. Therefore, an object of the present invention is to meet such a demand.

[0006]

In order to achieve the above object, the present inventors have determined that most of MRSA are simultaneously macrolide antibiotic-resistant bacteria (see Nakamura et al., Supra). In general, a search has been made to find a macrolide antibiotic that has anti-MRSA activity from among macrolide antibiotics that are generally considered to be medically reliable.

As a result, a tylosin derivative showing a certain sensitivity to certain macrolide antibiotic-resistant Staphylococcus aureus (Japanese Patent Publication No. 5-10356, Japanese Patent Application Laid-Open No. 4-1640)
No. 93) was also found to be sensitive to MRSA. The present invention is based on such findings.

Therefore, according to the present invention, formula (I)

[0009]

Embedded image

(Wherein, R ¹ represents a hydrogen atom or a hydroxyl group, and R ² represents a methoxy group, a methylthio group, a methylsulfonyl group, or a benzoyl group). Anti-MRS
Agent A is provided.

[0011]

DETAILED DESCRIPTION OF THE INVENTION The anti-MRSA agent of the present invention can be used in vivo or in vitro in humans and other mammals and, where appropriate, other animals, regardless of the dosage form. Includes formulations that can be sterilized, bacteriostatic, or sterilized, but are particularly contemplated for medical use.

[0012] The active ingredient used in the present invention, as shown by the formula (I), is added to 4 "-O of tylosin by p-
It is characterized by having a substituent group that can be classified as substituted phenylacetyl. These tylosin derivatives (or compounds) are disclosed in the above-mentioned Japanese Patent Publication No. 5-10356 and Japanese Patent Laid-Open Publication No. 4-140909. These individual compounds are equivalent to the anti-MRSA activity of a compound (hereinafter, referred to as TS-D1) in which R ¹ in the formula (I) is a hydrogen atom and R ² is a methoxy group (hereinafter, referred to as TS-D1). 1 for certain MRSA, or with some difference in antibacterial activity and spectrum
It has an MIC (minimum inhibitory concentration) activity of 2.5 μg / ml or less.

The specific examples of the compound represented by the formula (I) are summarized for the combinations of the substituents R ¹ and R ² , as shown in Table 1 below.

[0014]

[Table 1]

^R and ^S have the configuration (R) and (S) on the carbon atom to which R ¹ is attached, and * is a mixture thereof.

The anti-MRSA agent of the present invention may be in any dosage form as long as it is suitable for the purpose of use. In general, when used in humans, it is prepared into, but not limited to, oral preparations, suppositories, topical preparations and injections. These formulations contain commonly used fillers, extenders,
It is prepared by a conventional method using a diluent or excipient such as a binder, a disintegrant, a surfactant and a lubricant. Representative from the viewpoint of dosage form, tablets, pills, suppositories, injections,
Ointments, gels, gel creams, solutions, powders, granules, capsules, syrups and the like can be mentioned. Hereinafter, typical preparations will be further described.

In the case of tableting, carriers conventionally known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica, and the like. Excipients such as acid, water, ethanol, propanol, syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder , Laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc., disintegrators such as sucrose, cocoa butter, hydrogenated oil, etc. 4 Ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, humectants, such as starch, starch, lactose, kaolin, bentonite,
Adsorbents such as colloidal silicic acid, lubricating agents such as purified talc, stearates, powdered boric acid, and polyethylene glycol can be exemplified. Further, the tablet can be a tablet coated with a usual coating as required, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet or a multilayer tablet.

When the suppository is formed into a suppository, the suppository base may be selected from conventionally known suppository bases, specifically, lipophilic bases, water-soluble bases and emulsion bases. It is appropriately selected and used. Suppository bases include, for example, synthetic oleaginous bases such as cacao butter, hydrogenated peanut oil and hydrogenated coconut oil, and water-soluble bases such as polyethylene glycols, tweenlen, and pluronic.

When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into the form of solutions, emulsions and suspensions, any diluent known in the art can be widely used. For example, water, lactic acid aqueous solution, ethyl alcohol,
Examples include propylene glycol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents and the like may be added. May be.

The base of the ointment used in preparing the ointment includes, for example, higher fatty acids or their esters, waxes, surfactants, higher alcohols, silicone oil, water,
Mention may also be made of per se commonly used in the art, such as absorption promoters and humectants.

As a base material for preparing a liquid or a gel,
Usually, a lower alkanol, a combination of water and a surfactant, or a water-soluble polymer is used. Surfactants that can be used in the preparation of the present invention, including such liquid preparations, are preferably nonionic surfactants, and specific examples thereof include polyoxyethylene sorbitan acyl ester-based polysorbate 80, polysorbate 60, Polysorbate 20, dimethylsiloxane / methyl (POE) siloxane copolymer of silicone polyether copolymer, etc .: polyoxyethylene acyl ester based polyoxyl 40, polyoxyethylene lauryl ether, etc .; polyoxyethylene alcohol ether based lauromacorgome Glycerin monostearate glyceryl monostearate and decaglycerin monolaurate; sorbitan fatty acid ester span 60 monostearate; sorbitan acyl ester sesquiole Sorbitan phosphate, and the like; HCO-60 of polyoxy hydrogenated castor oil, HCO-50, etc.; can be exemplified Pluronic F68, etc. polyoxyethylene propylene glycol mono fatty acid esters. These nonionic surfactants may be used alone or in combination of two or more at an appropriate ratio.

As the water-soluble polymer compound, a natural or synthetic polymer compound is used. Examples of the natural high molecular compound include soluble polysaccharides such as acacia gum, xanthan gum, pectin, carrageenan, sodium alginate, etc., soluble polypeptides such as gelatin, chitins such as chitin and chitosan. Further, as the synthetic high molecular compound, a natural high molecular compound is partially chemically processed, for example, sodium carboxymethyl cellulose which is a soluble polysaccharide,
Hydroxypropylcellulose and the like can be mentioned, and pure synthetic polymer compounds include polyvinyl alcohol-based compounds such as polyvinyl alcohol and derivatives thereof, and polyvinyl pyrrolidone-based compounds such as polyvinyl pyrrolidone and derivatives thereof.

In the preparation of the present invention prepared as described above, the content of the active ingredient is appropriately adjusted depending on the dosage form, and is blended. The dosage should be determined by a physician in consideration of the administration route and the condition of the patient (symptoms, age, etc.).
200 to 400 mg of the active ingredient at a time, three times a day,
600-1200 mg can be administered per day.

[0024]

EXPERIMENTAL EXAMPLES The effects of the present invention can be confirmed by the following experiments. Above, Nakamura et al., The Japanese Journ
al of Antibiotics, Vol. 51, No. 7, pp. 494-5
The method for determining the minimum inhibitory concentration of a drug on bacteria was determined by the Japanese Society of Chemotherapy (see Chemotherapy 29; 76, 1981) using the clinically isolated MRSA strain in accordance with the method described in US Pat. The measured results are shown in Table 2 below.

[0025]

[Table 2]

B99001 to B99037 represent MRSA clinical isolates isolated from 37 patients one by one.
The patient's bronchial sputum (1-2) and sputum (3,
28-32), catheter urine (4-6, 24, 26-2)
7), pressure sores (7-8, 12, 14-21, 23, 34)
-36), natural urine (9-11, 25, 37), open pus (13), IVH and others (22, 33).

In addition, as comparative examples, 14-membered ring macrolide antibiotics such as oleandomycin, erythromycin and roxithromycin, and 16-membered ring macrolide antibiotics such as leucomycin, josamycin and spiramycin are also shown in the table. Like Tylosin, it was insensitive to the clinically isolated material. Example 1 Production Example of Capsule (1) 100% of 4 ″ -O- (4-methoxyphenylacetyl) tyrosine, 100 mg of lactose, and 1 mg of magnesium stearate (all in a capsule) were uniformly mixed. The resulting mixture is added to about 200 capsules per capsule.
mg, packed in a No. 3 hard gelatin capsule. Example 2 Production Example of Capsule (2) 100% of 4 ″ -O- (4-methoxymanderoyl) tylosin, 100 mg of lactose, and 1 mg of magnesium stearate (all in a capsule) were uniformly mixed. Approximately 200 m per capsule was obtained.
g. Fill into a No. 3 hard gelatin capsule. Example 3 Production Example of Tablet (1) 70 mg of 4 ″ -O- (4-methoxyphenylacetyl) tylosin, 60 mg of lactose, corn starch 57
mg (each tablet). Mix 1
The mixture is granulated by mixing with 0% starch paste solution, and corn starch (60 mg) and magnesium stearate (3 mg per tablet) are added and mixed well to form tablets having a diameter of 8 mm and a weight of about 250 mg. Example 4 Production Example of Tablet (2) 70 mg of 4 ″ -O- (4-methoxymanderoyl) tylosin, 60 mg of lactose, 57 mg of corn starch
(All tablets per tablet). 10% mixture
Mix with starch paste solution and granulate, then add corn starch 6
0 mg and magnesium stearate 3 mg (all 1
Per tablet) and mix well, 8mm in diameter, weight about 25
Form into 0 mg tablets. Example 5 Production Example of Suspended Syrup Preparation (1) 200 mg of 4 ″ -O- (4-methoxyphenylacetyl) tylosin, 100 mg of sodium carboxymethylcellulose, 14 mg of methyl parahydroxybenzoate, 6 mg of ethyl paraoxybenzoate, 40 ml of simple syrup,
10 ml of purified water (both per bottle) is mixed well, suspended, and put into a dosage bottle. Example 6 Production Example of Suspended Syrup (2) 200 mg of 4 ″ -O- (4-methoxymanderoyl) tylosin, sodium carboxymethylcellulose 1
00 mg, methyl paraoxybenzoate 14 mg, ethyl paraoxybenzoate 6 mg, single syrup 40 ml, purified water 10 ml (each bottle) are mixed well, suspended, and put into a prescription bottle. Example 7 Production Example of Ointment (1) 3 g of stearyl alcohol, 8 g of beeswax and 84 g of white petrolatum were dissolved by heating on a water bath, 3 g of cholesterol was added with stirring, and the mixture was stirred until completely dissolved to prepare an ointment base. I do. Then put 4 ″ -O- in the mortar
2 g of (4-methoxyphenylacetyl) tyrosine is added, the ointment base is added little by little and mixed, and the mixture is allowed to cool naturally to prepare 100 g of ointment. Example 8 Production Example of Ointment (2) 3 g of stearyl alcohol, 8 g of beeswax and 84 g of white petrolatum were dissolved by heating on a water bath, 3 g of cholesterol was added with stirring, and the mixture was stirred until completely dissolved to prepare an ointment base. I do. Then put 4 ″ -O- in the mortar
(4-Methoxymanderoyl) 2 g of tylosin,
Ointment base was added little by little and mixed, allowed to cool naturally and ointment 1
Prepare 00g.

[0028]

Until now, erythromycin, roxithromycin, clarithromycin, acetylspiramycin, josamycin and the like have been used in large quantities in Japan. From these facts, it is inferred that the MRSA strains in Table 2 show a wide range of cross-resistance to various 14-membered macrolides and 16-membered macrolide antibiotics. Nevertheless, according to Table 2 above, certain tylosin derivatives were found to be present in these MRSA clinical isolates in 3.12 to 12.5.
It is noteworthy (unexpected) that it exerts antibacterial activity at concentrations as low as μg / ml. Note that vancomycin (control) exerts an antibacterial activity at a lower concentration than the tylosin derivative according to the present invention. However, in view of the fact that vancomycin has significantly higher side effects than macrocytic antibiotics as described above, the present invention which can provide an anti-MRSA agent other than vancomycin is extremely useful.

Claims (2)

[Claims] (1) Formula (1) (Wherein R ¹ represents a hydrogen atom or a hydroxyl group, and R ² represents a methoxy group, a methylthio group, a methylsulfonyl group or a benzoyl group). Methicillin-resistant Staphylococcus aureus agent. 2. The anti-methicillin-resistant Staphylococcus aureus agent according to claim 1, wherein in the 4 ″ -substituted tylosin derivative, R ² in the formula (I) is a methoxy group.