JPS621954B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a novel antibacterial compound and a method for producing the same. According to this invention, the novel antibacterial compound has the general formula: (In the formula, -COOR is a carboxyl group or a lower alkoxycarbonyl group, and X is a halogen atom, an azide group, or a lower alkoxy group.) and pharmaceutically acceptable and non-toxic salts thereof. The compound () is useful as a treatment for mastitis in domestic animals and in the treatment of infectious diseases in animals, including poultry and humans, especially those caused by Gram-positive and Gram-negative bacteria, and as a nutritional fortifier for animal foods. be. Pharmaceutically acceptable non-toxic salts include ammonium salts and substituted ammonium salts (e.g. benzylamine salts, N-benzyl-β-phenethylamine salts,
N,N-dibenzylethylenediamine salt, dehydroabiethylamine salt, etc.), metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt, and basic amino acid salts (such as arginine salt, lysine salt, ornithine salt, Histidine salt). Other non-toxic salts known in the penicillin art are included. The compound () of this invention has the general formula, for example: Amino-penicillanic acid represented by or
Derivatives or salts thereof whose carboxyl and/or amino groups are protected and the general formula: (wherein R and can. Preferred examples of the esterified carboxy group -COOR of general formulas () and () include ethoxycarbonyl group, n- and isopropoxycarbonyl group, n-, iso- and t-butoxycarbonyl group, and 2-methylpropoxycarbonyl group. group, 2,2-dimethylpropoxycarbonyl group,
Lower alkoxycarbonyl groups such as 1-ethylpropoxycarbonyl group, trichloroethoxycarbonyl group and diacetylmethoxycarbonyl group, phenoxycarbonyl group, methylphenoxycarbonyl group, chlorophenoxycarbonyl group and indaniloxycarbonyl group aralkoxycarbonyl groups such as aryloxycarbonyl groups, nitrobenzyloxycarbonyl groups, methoxybenzyloxycarbonyl groups and diphenylmethoxycarbonyl groups,

【formula】

[Formula] or

Heterocyclic carbonyl groups and groups containing oxygen atoms such as [Formula]

[Formula] etc. are included. The substitution position of the substituent ROOC- is preferably at the meta-position or the rose-position of the phenylacetic acid (). Preferred examples of the esterified carboxy group -COOR of general formula () include lower alkoxycarbonyl groups such as t-butoxycarbonyl group and trichloroethoxycarbonyl group and aralkoxycarbonyl group as defined above and an oxygen atom. Includes heterocyclic carbonyl groups. Examples of X in general formula () are hydrogen atoms, halogen atoms such as chlorine atoms and bromine atoms, azide groups, lower alkoxy groups such as methoxy groups and ethoxy groups,
These include lower alkylthio groups such as methylthio and ethylthio groups, lower alkanoyloxy groups such as acetoxy and pivaloyloxy groups, or 2-methylpropionyloxy groups, and formyloxy groups. Trimethylchlorosilane, trimethoxychlorosilane, methyldimethoxychlorosilane, methoxydimethylchlorosilane, dimethyldichlorosilane, methylmethoxydichlorosilane, dimethoxydichlorosilane, hexamethyldisilazane, N,
Silyl compounds such as O-bis-trimethylsilyl-trifluoroacetamide, N,O-bis-trimethylsilylacetamide, and 2-chloro-1,
3,2-dioxaphosphorane, 2-chloro-5-
A phosphorus compound such as methyl-1,3,5-dioxaphosphorane is used as a protecting agent for the amino group and/or carboxy group of the compound (). Examples of salts of compound () are alkali metal salts and trialkylamine salts. Reactive derivatives of substituted phenylacetic acids () are acid halides, mixed acid anhydrides, active amides, active esters and similar reactive derivatives. Reagents used to form such reactive derivatives include, for example, methoxycarbonyl chloride, ethoxycarbonyl chloride, propoxycarbonyl chloride, butoxycarbonyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, pivaloyl chloride, and benzene. These include sulfonyl chloride, toluenesulfonyl chloride, sulfuryl chloride, thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, N-halosaccharide and N-halosuccinimide. The reaction of acylating amino-penicillanic acid () with a reactive derivative of substituted phenyl acetic acid () is
Triethylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine or It is carried out in the presence of an acid acceptor such as N-ethylpiperidine. However, when a salt of compound () is used, the reaction is carried out in an aqueous solvent such as water or a mixture of water and a water-miscible organic solvent such as methanol, ethanol, acetone, dioxane, acetonyl, dimethylformamide. If desired, a compound () having an esterified carboxyl group such as a benzyloxycarbonyl group, a methoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group or a t-butoxycarbonyl group is heated in an inert solvent at -20 to 30°C. By treatment with trifluoroacetic acid or hydrogen bromide at a temperature of , it can be converted to a compound with the corresponding free carboxy group. Compounds with esterified carboxy groups, such as trichloroethoxy- or nitrobenzyloxy-carbonyl groups, can be converted to compounds with free carboxy groups by reductive decomposition using zinc and inorganic or organic acids. Additionally, groups such as benzyloxycarbonyl, diphenylmethoxycarbonyl or di(methoxyphenyl)-methoxycarbonyl can be converted to free carboxy groups by catalytic reduction using a palladium or platinum catalyst and hydrogen. The compounds of this invention have asymmetric carbon atoms in their side chains, and as a result, each compound has two types of optically active isomers. In this invention, DL−
It is to be understood that both epimeric forms as well as mixtures are included. According to one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of general formula () as described above. Such compositions also contain a pharmaceutically acceptable carrier. The compositions of this invention are generally used for administration to humans and other mammals in the usual manner, for example, for the treatment of diseases of the urinary tract system, respiratory system, and soft tissues, otitis media, and mastitis. It will be done. Suitable formulation forms for the compositions of this invention include tablets,
They include capsules, creams, syrups, suspensions, aqueous solutions, preformed powders, and may be used in sterile forms suitable for injection or infusion. Such compositions may contain conventional pharmaceutically acceptable substances such as diluents, binders, coloring agents, flavoring agents, preservatives, disintegrants and the like in accordance with conventional pharmaceutical practice. The total dose of antibiotics of this invention is generally 50
~1500mg, commonly used is 100~
It is 1000mg. However, the injection or infusion may contain an amount of anti-antibiotic, for example 4 g or more, if desired. Generally 50~ of this invention
An amount of between 6000 mg will be administered per day, and more usually between 500 and 3000 mg per day. The following examples illustrate the invention. Example 1 A solution of 1 mmol (0.21 g) of DL-α-chloro-p-carboxyphenylacetic acid and 1 mmol (0.10 g) of N-methylmorpholine in 5 ml of anhydrous tetrahydrofuran was heated to -40 over 5 minutes. ℃
Then 1 ml of anhydrous tetrahydrofuran solution containing 1 mmol (0.11 g) of ethyl chloroformate was added. The reaction mixture was then stirred at -15 to -10°C for 1 hour. 3 ml of anhydrous methylene chloride solution containing 1 mmol (0.316 g) of the triethylamine salt of 6-aminopenicillanic acid was added to the above mixed acid anhydride solution, and the mixture was heated at -30 °C for 30 minutes and at -30 to -10 °C.
Stirred at ℃ for 1 hour. The temperature was then raised to 0°C. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate.
The mixture was adjusted to pH 6 by adding 10 ml and 10 ml of ice water and stirred for 10 minutes. The aqueous layer was separated, adjusted to pH 2.5 with a 20% aqueous phosphoric acid solution, and completely extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution,
After drying, it was concentrated under reduced pressure. The residue was mixed with diisopropyl ether to obtain 0.22 g of fine white powder of 6-(DL-α-chloro-4-carboxyphenylacetamide)-penicillanic acid. Yield 54% IR: 1785, 1700, 1680 cm ^-1 MIC: E. coli, 25γ/ml Examples 2 to 6 The following DL-α-chloro-p-carboxyphenylacetic acid used in Example 1 was used instead of DL-α-chloro-p-carboxyphenylacetic acid. I used something. 2 DL-α-azido-p-carboxyphenylacetic acid 3 DL-α-methoxy-p-carboxyphenylacetic acid 4 DL-α-chloro-p-ethoxycarbonylphenylacetic acid 5 DL-α-promo-p-ethoxy Carbonylphenylacetic acid 6 DL-α-methoxy-p-ethoxycarbonylphenylacetic acid The following product was obtained. 2 6-(DL-α-azido-4-carboxyphenylacetamide)-penicillanic acid: Yield 58% IR: 1785 cm ^-1 MIC: E. coli, 25γ/ml 3 6-(DL-α-methoxy -4-carboxyphenylacetamide)-penicillanic acid: Yield 47% IR: 1780, 1700 cm ^-1 MIC: E. cory, 25γ/ml 4 6-(DL-α-chloro-4-ethoxycarbonylphenylacetamide) cetamide)-penicillanic acid: Yield 68% IR: 1785 cm ^-1 MIC: E. Colli, 25γ/ml 5 6-(DL-α-bromo-4-ethoxycarbonylphenylacetamide)-penicillanic acid: Yield Rate 68% IR: 1790 cm ^-1 MIC: E. coli, 25γ/ml 6 6-(DL-α-methoxy-4-ethoxycarbonylphenylacetamide)-penicillanic acid:
Yield: 68% IR: 1790 cm ^-1 MIC: E. coli, 25γ/ml All of the compounds of Examples 1 to 6 above did not kill the mice at doses below 500 mg/Kg when administered intraperitoneally to mice. Ta.

Claims (1)

[Claims] 1 General formula (): (In the formula, -COOR is a carboxy group or a lower alkoxycarbonyl group, and X is a halogen atom, an azido group, or a lower alkoxy group.) and pharmaceutically acceptable non-toxic salts thereof. 2. The compound according to claim 1, wherein -COOR in the general formula () is a carboxy group. 3. The compound according to claim 2, wherein in the general formula (), X is a chlorine atom, a bromine atom, an azide group, or a methoxy group. 4 General formula: (In the formula, -COOR is a carboxy group or a lower alkoxycarbonyl group, and X is a halogen atom, an azide group, or a lower alkoxy group.) A compound represented by the formula or a pharmaceutically acceptable non-toxic salt thereof and an excipient. An antibacterial agent consisting of.