WO1993008196A1 - Ester de penicilline g - Google Patents

Ester de penicilline g Download PDF

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Publication number
WO1993008196A1
WO1993008196A1 PCT/JP1992/001327 JP9201327W WO9308196A1 WO 1993008196 A1 WO1993008196 A1 WO 1993008196A1 JP 9201327 W JP9201327 W JP 9201327W WO 9308196 A1 WO9308196 A1 WO 9308196A1
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Prior art keywords
group
ohz
penicillin
ester
same manner
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PCT/JP1992/001327
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English (en)
Japanese (ja)
Inventor
Satoru Takahashi
Atsushi Yamamura
Hisashi Hayashida
Hirofumi Takagi
Shigeo Kaneda
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Fujisawa Pharmaceutical Co., Ltd.
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Publication of WO1993008196A1 publication Critical patent/WO1993008196A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to a novel penicillin G ester for fisheries. More specifically, the present invention has improved absorption to fish bodies as compared to penicillin G calcium salt, and as a result, improved the effect of preventing and treating fish diseases (especially streptococcal disease).
  • the present invention relates to a novel penicillin G ester, a method for producing the same, and a composition comprising the same for the prevention and treatment of fish disease. Background art
  • erythromycin has been used as a therapeutic agent for streptococcal disease in fish, but there is a problem that resistant bacteria are increasing.
  • the penicillin G ester of the present invention is a novel compound and is represented by the following general formula (I).
  • A is one, X is N or CH, and R 1 is
  • One (CH) n one (C 1 C 0) alkyl group (wherein R ′ is a hydrogen or lower alkyl group, n is an integer of 0 to 3, and the alkanoyl moiety is a hydroxyl group, a cyano group, a halogen, It may be substituted with a group selected from a lower alkanoyloxy group and a lower alkoxyl group), a lower alkenoyl group, a cyclopropylcarbonyloxymethyl group, a cyclohexylcarbonyloxymethyl group, a benzoyloxy group Group, benzoyloxymethyl group, formula
  • Y— (CH 2 CH 2 ) m OR 6 (where Y is —Q— or one COO—, R 5 is hydrogen, ethoxymethyl or lower alkyl group, R 6 is lower alkyl group or lower alkanoyl group, m Is an integer of 1 to 8),
  • Formula 1 Z—CO OR 7 (where Z is one, one CH 2 —, one CH 2 CH 2 — or one CH—CH—, R 7 is a lower alkyl group, provided that Z In the formula, R 7 is not an ethyl group, or CH 2 W (where W is hydrogen, a hydroxyl group, a lower alkoxy group or a cyano group, but when W is hydrogen, X is not CH), or
  • R 2 is hydrogen, a lower alkoxy group or a lower alkoxy group, Does R 3 each represent hydrogen;
  • A is one CH 2 C-,
  • X is N or CH, R 'is 4-position C ⁇ OCH 3 , R 2 and R 3 each represent hydrogen;
  • A is the formula CH 2 M— (where M is 0 or S), X is N or CH, R or halogen, lower alkyl group, lower alkoxy group, lower alkanoyl group, lower alkoxy carbonyl group, lower Alkoxycarbonyl lower alkyl group, lower alkanoyloxy lower alkyl group, lower alkanoyloxy group, hydroxy lower alkyl group, or formula 10 (CH 2 CH 20 ) k R 8 (where R 8 is a lower alkyl group , K represents an integer of 1 to 3), R 2 represents hydrogen or a lower alkanoyloxy group, and R 3 represents hydrogen or a lower alkyl group, respectively; or
  • A is one, X is N or CH, R 1 is at position 4 one CH 2 NH 2 , one CH 2 NHCH 3 ,
  • a penicillin G ester and a salt thereof A penicillin G ester and a salt thereof.
  • R represents - (CH 2) £ - 0 - in - (C ⁇ 0 C n) Arukanoiru group (wherein, ⁇ Is an integer of 1 to 3, and the alkanoyl moiety may be substituted with a cyano group, -halogen, lower alkanoyloxy group, lower alkoxycarbonyl group), lower alkenoyl group, cyclopropylcarboxyloxymethyl group, cycloalkyl Hexylcarbonyloxymethyl group, benzoyloxy group, benzoyloxymethyl group,
  • R one (CH) n - 0 - ( C ⁇ - C] 0) Arukanoiru group (wherein, R 4 is hydrogen or a lower alkyl group, n is an integer of 0-3 Arukanoi Le moiety arsenide Dorokishi group Has been replaced),
  • R and R are each hydrogen, a (0 ⁇ — C ⁇ 0) alkanoyl group,
  • R 8 is hydrogen or a methyl group
  • Y is halogen
  • Suitable pharmaceutically acceptable salts of the target compound (I) are conventional non-toxic salts and include acid addition salts. More specifically, inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic sulfonic acid addition salts or organic sulfonic acid addition salts (eg, formate, acetic acid) Salt, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), acidic amino acids (Eg, aspartic acid, glutamic acid, etc.).
  • inorganic acid addition salts eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • organic sulfonic acid addition salts or organic sulfonic acid addition salts eg, formate, acetic acid) Salt, trifluoroacetate, maleate, tartrate
  • “Lower” shall mean from 1 to 6 (preferably 1 to 4) carbon atoms unless otherwise indicated.
  • Suitable "halogens" include fluorine, chlorine, bromine and iodine.
  • alkyl group Preferable lower of "lower alkyl group”, “lower alkoxy lower alkyl group”, “lower alkoxycarbonyl lower alkyl group”, “lower alkanoyloxy lower alkyl group” and “hydroxy lower alkyl group”
  • the alkyl moiety may be a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, and hexyl. Or a branched chain alkyl group.
  • the lower alkyl group may be substituted with a suitable substituent such as a cyano group.
  • alkanoyl groups may be substituted with a hydroxyl group, a cyano group, a halogen, a lower alkanoyloxy group or a lower alkoxycarbonyl group.
  • Suitable “lower alkanoyl groups” include, for example, formyl, acetyl, Alkanoyl groups such as propionyl, butyryl, isobutyryl, para'relyl, isopa'relinole, and pivaloyl; and those which may be substituted with a hydroxyl group, a cyano group, a halogen, a lower alkoxy group, or a lower alkoxycarbonyl group;
  • Examples of the alkanoyl group include cyanoacetyl, chloroacetyl, cyclopropyl zolevonyl, acetooxyacetyl, or ethoxycarbonylpropionyl.
  • Suitable "lower alkanoyloxy groups” include, for example, lower alkanoyloxy groups such as formyloxy, acetooxy, propionyloxy, butyryloxy, isoptyryloxy, norreloxy, isovalerizoleoxy, and vivaloyloxy groups. Is mentioned.
  • lower alkenoyl groups include groups such as 2-butenyl.
  • Suitable lower alkoxy moieties for the preferred "lower alkoxy group J," “lower alkoxycarbonyl group” and “lower alkoxycarbonyl lower alkyl group J" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Examples include groups such as isobutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy.
  • acid halide_1 examples include cyanoacetyl chloride, chloroacetyl chloride, cyclopropylcasolebonyl chloride, acetoxyacetyl chloride, ethoxycarbonylpropionyl chloride and the like.
  • Suitable “acid anhydrides” include alkyl anhydrides, for example, acetic anhydride, argenic anhydride, for example, 2-butenoic anhydride and the like.
  • Compound (la) can be produced by reacting compound (IV) or a salt thereof with compound (Ilia).
  • This reaction is usually carried out with carpoimides such as dicyclohexyl carpoimidide, triazoles such as benzotriazole and benzotriazole, and iodide 2-chloro-1-methylpyridinium.
  • carpoimides such as dicyclohexyl carpoimidide
  • triazoles such as benzotriazole and benzotriazole
  • iodide 2-chloro-1-methylpyridinium is usually carried out with carpoimides such as dicyclohexyl carpoimidide
  • a general condensing agent such as a halo pyridinichem salt
  • a conventional esterification method such as a mixed acid anhydride method.
  • Suitable salts of compound (IV) include alkali metal salts (eg, sodium salt, potassium salt, cesium salt, etc.) and alkaline earth metal salts (eg, potassium salt, magnesium salt) And the like).
  • alkali metal salts eg, sodium salt, potassium salt, cesium salt, etc.
  • alkaline earth metal salts eg, potassium salt, magnesium salt
  • This reaction is usually performed in the presence of a base such as trialkylamine, such as trimethylamine or triethylamine.
  • a base such as trialkylamine, such as trimethylamine or triethylamine.
  • the reaction is usually carried out in a solvent such as dichloromethan, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, provided that the solvent does not adversely affect the reaction.
  • a solvent such as dichloromethan, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, provided that the solvent does not adversely affect the reaction.
  • the reaction can be carried out in any other solvent.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.
  • Compound (lb) can be produced by subjecting compound (Ie) to an acylation reaction.
  • acylating agent used in this reaction examples include conventional ones capable of introducing an acyl group into a hydroxyl group, preferably lower alkanoic carboxylic acids, these acid anhydrides, such as acetic anhydride and the like. ) Acid halides and the like.
  • the reaction is usually carried out in the presence of a conventional condensing agent such as a carbodiimide compound or a triazole pyridium. It is.
  • This reaction is usually carried out by alkyl lithium such as n-butyllithium, sodium hydrogen hydride, aluminum hydride such as hydrogen hydride, trimethylamine, trimethylamine, etc. It is preferable to carry out the reaction in the presence of a salt group such as a tri (lower) amin, pyridine, picolin, lutidine, or a pyridine derivative such as 4-dimethylaminopyridine.
  • a solvent such as dichloromethan, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, provided that the solvent does not adversely affect the reaction.
  • the reaction can be carried out in any other solvent.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.
  • Compound (I c) can be produced by subjecting compound 00 to an elimination reaction.
  • This reaction can be performed, for example, by solvolysis, reduction, or the like.
  • Suitable acids used in the solvolysis reaction include, for example, organic acids such as acetic acid, glacial acetic acid, propionic acid and trichloroacetic acid.
  • Chemical reduction and catalytic reduction can be used as the reduction method applicable to this reaction.
  • the reducing agent used for the reduction may be a chemical reducing agent such as a metal such as tin, zinc or iron or a metal compound such as gromium chloride or chromium acetate, for example, formic acid, acetic acid, propionic acid or trifluorene.
  • a chemical reducing agent such as a metal such as tin, zinc or iron or a metal compound such as gromium chloride or chromium acetate, for example, formic acid, acetic acid, propionic acid or trifluorene.
  • Acetic acid, p Combination with organic or inorganic acids such as toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sodium borohydride, sodium borohydride and trifluoroacetic acid or pyridine Combination of sodium borohydride and phosphoryl chloride, borane-methyl sulfide complex, catalyst for catalytic reduction
  • organic or inorganic acids such as toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sodium borohydride, sodium borohydride and trifluoroacetic acid or pyridine
  • platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., for example, palladium sponge.
  • Palladium catalysts such as radium black, palladium oxide, palladium oxide 0, palladium oxide, palladium oxide, palladium oxide 0, palladium oxide 0 , potassium radium monocarbonate, etc.
  • nickel catalysts such as reduced Nigel, nickel oxide, Raney nickel
  • conventional catalysts such as cobalt catalysts such as reduced cobalt and Raney cobalt, iron catalysts such as reduced iron and Raney iron, and copper catalysts such as reduced copper, Raney copper and Ullman copper.
  • the reaction is usually carried out in water, for example, an alcohol such as methanol or ethanol, a solvent such as chloride methylene, tetrahydrofuran, dioxane, NN-dimethylformamide or ethylene glycol dimethyl ether.
  • an alcohol such as methanol or ethanol
  • a solvent such as chloride methylene, tetrahydrofuran, dioxane, NN-dimethylformamide or ethylene glycol dimethyl ether.
  • the reaction is performed in a mixture thereof, but the reaction can be performed with any other solvent that does not adversely influence the reaction.
  • Liquid bases or acids can also be used as solvents.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating. .
  • Compound (Id) can be produced by reacting compound (IV) or a salt thereof with compound (IIb).
  • This reaction is usually carried out with carpoimides such as dicyclohexyl carpoimidide, triazoles such as benzotriazole, and halogeno such as ethyl chloroformate and isopropyl chloroformate.
  • carpoimides such as dicyclohexyl carpoimidide
  • triazoles such as benzotriazole
  • halogeno such as ethyl chloroformate and isopropyl chloroformate.
  • Lower alkyls, iodide 2 chloro 1 —methylpyridinium, etc., and the like.
  • Compounds ( ⁇ ⁇ ) in the absence of a common condensing agent Using a method such as the use of a halide such as methyl 4- (bromoacetyl) benzoate, or a conventional esterification method such as the mixed acid anhydride method. It is.
  • Suitable salts of compound (IV) include alkali metal salts (eg, sodium salt, potassium salt, cesium salt, etc.) and alkaline earth metal salts (eg, potassium salt, magnesium salt) Etc.).
  • alkali metal salts eg, sodium salt, potassium salt, cesium salt, etc.
  • alkaline earth metal salts eg, potassium salt, magnesium salt
  • Etc. alkali metal salts
  • a base such as trialkylamine such as trimethylamine, triethylamine, or tri-n-butylamine.
  • the reaction is usually carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, provided that the solvent does not adversely affect the reaction.
  • a solvent such as methylene chloride, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, provided that the solvent does not adversely affect the reaction.
  • the reaction can be performed in any other solvent.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.
  • Compound (Ie) can be produced by subjecting compound (VI) to a reduction reaction.
  • Reduction methods applicable to this reaction include chemical reduction and catalytic reduction.
  • the reducing agent used for the reduction may be a chemical reducing agent such as a metal such as tin, zinc or iron or a metal compound such as chromium chloride or potassium acetate, and a chemical compound such as formic acid, acetic acid, propionic acid or tricarboxylic acid.
  • a chemical reducing agent such as a metal such as tin, zinc or iron or a metal compound such as chromium chloride or potassium acetate, and a chemical compound such as formic acid, acetic acid, propionic acid or tricarboxylic acid.
  • Combination with organic or inorganic acids such as fluorosulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and hydrobromic acid, sodium borohydride, sodium cyanoborohydride, hydrogen borohydride
  • a combination of sodium hydrogen hydride and acetic acid or pyridin, a combination of sodium borohydride and phosphoryl chloride, a borane-methyl sulfide complex, and a catalyst for catalytic reduction include, for example, Platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum catalyst such as platinum wire, for example, palladium Palladium catalysts such as aluminum sponge, palladium black, palladium oxide, palladium monocarbon, colloid palladium, barium radium monosulfate, barium radium monocarbonate, such as reduced nickel, nickel oxide, and Raney Ni Nickel catalysts such as gels, for example, cobalt catalysts such as reduced cobalt and Raney cobalt, iron catalyst
  • the reaction is usually carried out in or on a solvent such as, for example, alcohols such as methanol, ethanol, etc., methylene chloride, tetrahydrofuran, dioxane, NN-dimethylformamide.
  • a solvent such as, for example, alcohols such as methanol, ethanol, etc., methylene chloride, tetrahydrofuran, dioxane, NN-dimethylformamide.
  • the reaction is performed in a mixture, but the reaction can be performed with any other solvent that does not adversely affect the reaction.
  • Liquid acids can also be used as solvents.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.
  • Compound (If) is produced by reacting compound (XI), which is synthesized in two steps from compound (VIII) and compound (IX), with compound ( ⁇ or a salt thereof). Can be done.
  • the intermediate compound (X) or (XI) is reacted without purification in the three-step reaction to obtain the desired compound (If).
  • the intermediate compound (X) or (X I) is available as a reagent, it may be used.
  • the compound (IV) or the salt is mixed with the compound (XI) in an appropriate solvent, if necessary, in the presence of a base, and the reaction is carried out under cooling or heating.
  • Suitable salts of the compound (IV) are the same as described above.
  • Solvents usually include methylene chloride, tetrahydrofuran, dioxane,
  • the reaction can be carried out in a solvent such as N, N-dimethylformamide or a mixture thereof, or in any other solvent that does not adversely influence the reaction.
  • organic bases such as trimethylamine, triethylamine, and pyridine are preferable.
  • Compound (Ig) can be produced by reacting compound (XII) with compound (XII) synthesized with paraformaldehyde in the presence of concentrated hydrochloric acid and compound (IV) or a salt thereof.
  • This production method is a two-step reaction in which compound (XIII) is synthesized in the first step, and compound (XIII) is purified without purification by compound (IV) or a salt thereof and a base, if necessary, in a suitable solvent.
  • the compound (Ig) is synthesized by mixing below. At this time, it is preferable to activate the reaction by halogen exchange by adding a salt such as sodium iodide, sodium iodide, or sodium bromide.
  • Suitable solvents are usually in a solvent such as methylene chloride, tetrahydrofuran, dioxane, N, N-dimethylformamide or a mixture thereof, or do not adversely affect the reaction.
  • the reaction can be carried out in any other solvent as long as the solvent is used.
  • organic bases such as trimethylamine, triethylamine, pyridine and the like are preferable.
  • Compound (Ig) can be produced by reacting compound (XIII) derived from compound (XIV) with compound (IV) or a salt thereof.
  • compound (XIII) is synthesized in the first step in a two-step reaction, and compound (XIII) ′ is synthesized with compound (IV) or a salt thereof without purification.
  • the reaction is performed to obtain a compound (Ig).
  • This production method is carried out by a method according to Production method 7.
  • Compound (Ih) can be produced by subjecting compound (Ii) to an elimination reaction of a hydroxy protecting group.
  • Suitable methods for this elimination reaction include conventional methods such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably performed in the presence of a base.
  • a phenyl ester which is active toward a base is present in compound (Ii)
  • deprotection must be performed selectively under milder conditions than usual.
  • Suitable bases include, for example, hydroxides or carbonates or bicarbonates of alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium and calcium, for example trimethyla.
  • the reaction is usually carried out in or in water, for example in alcohols such as methanol, ethanol, etc., in solvents such as methylene chloride, tetrahydrofuran, N, N-dimethylformamide.
  • the reaction is performed in a mixture, but the reaction can be performed in any other solvent that does not adversely influence the reaction.
  • the reaction temperature is not particularly limited, the reaction is usually performed under cooling or heating.
  • the reducing agent used for the reduction is, for example, a metal such as tin, zinc or iron or a metal compound such as chromium chloride or chromium acetate, and a metal compound such as chromium chloride or acetic acid. Combinations with organic acids, such as pionic acid, are preferred.
  • the reaction is usually carried out in a solvent such as water, for example, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, or a mixture thereof.
  • a solvent such as water, for example, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, or a mixture thereof.
  • the reaction can be carried out in any other solvent that does not adversely affect the reaction.
  • the reaction temperature is not particularly limited, the reaction is usually performed under cooling or heating.
  • the compounds obtained by Production Methods 1 to 9 are separated or purified by a conventional method such as extraction, precipitation, fractional crystallization, recrystallization, or chromatography.
  • the starting material compound used in the present invention is prepared by the method described in JP-A-56-75463, the method described in 62, the method described in CA79 (3) 18773g, and the production examples described later. Can be produced by the method disclosed in US Pat.
  • the object compound (I) of the present invention is novel and has improved oral absorption in fish as compared with known penicillin G esters, and is useful as an agent for preventing and treating fish diseases.
  • Streptococcal disease Streptococcus ′
  • Streptococcal disease such as hamachi (puri), rainbow trout, bu, horse mackerel, tilapia, flounder, etc. Sp.
  • Puri amberjack
  • horse mackerel nodular disease Pasulella 'Picisida
  • penguin flounder
  • Thai edziera infection Edziera tarda
  • the prophylactic and / or therapeutic agent for this fish disease is compound (I) in solid, semi-solid or liquid carrier, diluent or not, powder, powder, fine granule, granule Add compound (I) directly or as a mixture of the above various forms to fish feeds, including mixed feed, fine granules, tablets, liquids, pellets, syrups, or mixed feed. And can be adjusted.
  • the carrier include raw foods such as fish mince (for example, mackerel, sardine, locust, hornago, saury, walleye pollack, squid mince, etc.), fish meal, soybean meal, yeast, flour, vitamin And other commonly used feeds such as lactose, sucrose, glucose, starch, talc, acid clay, etc.
  • fish mince for example, mackerel, sardine, locust, hornago, saury, walleye pollack, squid mince, etc.
  • fish meal soybean meal
  • yeast flour
  • vitamin And other commonly used feeds such as lactose, sucrose, glucose, starch, talc, acid clay, etc.
  • an emulsifier, a dispersant, a gelling agent, an adhesive, and the like may be appropriately added.
  • Drugs containing compound (I) as described above are useful for the prevention and treatment of fish diseases such as hamachi (puri), horse mackerel, horse mackerel, koi, Thailand, penguin, flounder, rainbow trout, tilapia, flounder, etc.
  • fish diseases such as hamachi (puri), horse mackerel, horse mackerel, koi, Thailand, penguin, flounder, rainbow trout, tilapia, flounder, etc.
  • compound (I) is stable in live feed such as fish mince, and Powder or fine granules premixed with the above carrier are added to raw feed alone or a mixture of raw feed such as fish mince and blended feed, and mixed and used as it is or as pellets.
  • the most preferred method is to administer a moist pellet to hamachi.
  • the dosage and administration period of the prophylactic and therapeutic agent for fish disease of the present invention will vary depending on conditions such as the type of fish, age, water temperature, and the degree of illness. Usually, 1 to 500 mg of compound (I) may be orally administered per day with a fish weight of 1 kg.
  • a control drug penicillin G potassium salt
  • the penicillin G ester of the present invention were used in an absorption and excretion test in rainbow trout and in juvenile yellowtail. A test for the protective effect against experimental streptococcal disease was conducted.
  • a commercial blended feed (pellet) was crushed, and a drug was added and mixed so that a predetermined amount was contained in a feed of 1.5% of the fish body weight. After 50% water was added to the drug-added feed and kneaded sufficiently, a 4 mm-diameter pellet was adjusted, and the specified amount was freely fed once.
  • Two, three rainbow trout were taken from each section at 3, 6, and 24 hours after the end of the administration, and blood was collected from the heart using a heparin-treated syringe. The obtained blood was stored at ⁇ 20 until it was used for analysis.
  • Test compound Blood titer ( ⁇ g / m £) (Example number) No.
  • Test compound Blood concentration (IX g / m &) (Example number) No.
  • Test compound Blood concentration ( ⁇ g / m £) (Example number) No.
  • Example 2 1 0.95 1.30 1.34
  • Example 2 1 2 0.73 2.19 1.40 Average 0.84 1.75 1.37
  • Test compound Blood concentration (g / ra ⁇ 0) (Example number) No.
  • Puri fry with an average body weight of about 50 g to which no antibacterial substance was provided for 4 weeks or more was used. The fish were reared for one week on a commercial formula diet containing no antimicrobial substances.
  • 11 fish were accommodated in a circulation tank made of 100 L of polycarbonate having a diameter of 48 cm and a depth of 80 cm.
  • pellet A commercial blended feed (pellet) was confused, and the drug was added and mixed so that a predetermined amount was contained in a feed of 4.0% of the fish body weight. After adding 40% water to this drug-added feed and thoroughly kneading, a pellet was prepared and allowed to feed freely for 2 days before infection, 1 day before infection, 1 day after infection, and 2 days after infection for a total of 5 days. Was.
  • the surviving fish bacteria isolation rate is the percentage of whether the inoculated bacteria were present from the kidneys and brain of the test fish that survived 10 days later.
  • Test fish Hamachi (weight about 50 g)
  • Test fish Hamachi (body weight: about 75 g)
  • Infectious bacterium Hamachi-derived streptococcus (HY89038 8)
  • the obtained residue was purified by silica gel chromochromataraphy using a mixed solvent of n-hexane and ethyl acetate (7: 3) as the eluent, and the 3-forminolephenyl ester of penicillin G was purified. (1.12 g) as an amorphous powder.
  • Poly (ethylene glycol) methyl ether 14-hydroxyl ether (average molecular weight 433).
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate (2: 1) as a developing solvent, and the 3-acetoximetylphenol of penicillin G was purified.
  • the ester (870 mg) is obtained as an oil.
  • Penicillin G 2 acetoximetinolphenyl ester
  • Penicillin G 3 (1-acetoxy) ethyl phenyl ester IR (film): 3420, 1784, 1742, 1730, 1681cm -1
  • Example 1 3-Hydroxymethylphenyl ester of 8-penicillin G (0-44 g) is dissolved in methylene chloride (20 ml) and cooled to 5 ° C. To the solution are sequentially added pinoroinole chloride (133 mg), triethylamine (llO mg) and 4-dimethylaminopyridine (1 O mg), and the mixture is stirred for 30 minutes. The reaction solution is concentrated under reduced pressure, water (20 ml) is added, and the mixture is extracted with ethyl acetate (30 ml ⁇ 2). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate (2 : 1) as a developing solvent, and the 3—bivaloyloxymethyl phenyl ester of penicillin G (3 70 mg).
  • Penicillin G 3 Propionyloxymethyl phenyl ester IR (Nushi, yl): 3350, 1780, 1734, 1679cm -1
  • Penicillin G 3_ (1-oxo-1-2-dichloroacetoxy) propyloxymethyl phenyl ester (100 mg) in tetrahydrofuran (5 ml), ethanol (5 ml) and water (2 ml). To the solution was added a saturated solution of sodium hydrogen carbonate (0.5 ml), And stir for 30 minutes. The reaction mixture is concentrated under reduced pressure, added with water (1 ⁇ 1), neutralized with dilute hydrochloric acid, and extracted with ethyl acetate (10 ml ⁇ 2). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel gel chromatography using a mixed solvent of n-hexane and ethyl acetate (1: 1) as a developing solvent, and the 3- (1-oxo) of penicillin G was purified.
  • 1-Hydroxypropyl) oxymethylphenyl ester 50 mg is obtained.
  • Penicillin G 4-one [2 — (2-ethoxy) ethoxy] ethoxyphenine.
  • Esters of penicillin G and poly (ethylene glycol) methyl ether 14-hydroxy phenol (average molecular weight 433).
  • esters of penicillin G with poly (ethylene glycol) methyl ether 4- 4-hydroxyphenyl ether (average molecular weight 477)
  • Penicillin G 3- [2- (2-ethoxy) ethoxy] ethoxyphenol ester.
  • Penicillin G and poly (ethylene glycol) monomethyl ether 4 -Ester with hydroxybenzoate average content: 802).
  • Example 4 5 "
  • Example 4 9-The following compounds are obtained in the same manner as in Example 1.
  • Penicillin G 3 cyanomethyl phenyl ester.
  • Penicillin G 4- [N- (2,2,2-triethoxy) ethoxycarbonylaminomethyl] phenyl ester (5.0 g) in dioxane (12 Oml), acetic acid (30 ml) Dissolve in a mixed solvent of water and water (15 ml). Reduce the temperature of the solution to 17 ° C and add zinc powder (5.0 g). — Stir at 7 ° C for 90 minutes and filter with suction. The filtrate is concentrated under reduced pressure at room temperature. Ethyl acetate (5 Oml) is added to the residue, and the precipitated white crystals are filtered off. Add water (150 ml) to the filtrate and extract three times with ethyl acetate (150 ml). The crystals precipitated from the extract are collected by filtration to obtain 4-aminomethylphenyl ester of penicillin G (1.5 G) as white crystals.
  • Penicillin G 3 Hydroximetyl phenyl ester
  • the target penicillium was obtained from lithium salt (1.58 g).
  • 4- [2- (2-ethoxy) ethoxy] ethoxyphenyloxymethyl ester (1.16 g).
  • Example 78-4-Hydroxymethylphenyloxymethyl ester of penicillin G (270 mg) is dissolved in pyridine (5 ml). Acetic anhydride (117 mg) was added while stirring at an internal temperature of 0-5 ° C, and the internal temperature was raised to room temperature, followed by stirring at 1 ⁇ room temperature. Methanol was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. Ethyl acetate (100 ml) was added, and the mixture was added twice with a 2N aqueous hydrochloric acid solution (50 ml) and twice with a saturated aqueous sodium hydrogen carbonate solution (50 ml). Wash with saturated saline (50 ml).
  • Paraformaldehyde (196 mg) is added to benzene (2 ml), and concentrated hydrochloric acid (2.5 ml) is added dropwise with stirring at room temperature. After stirring at room temperature for 10 minutes, raise the internal temperature to 40 ° C, and add o-toluenethiol (621 mg). The internal temperature is further raised to 50 ° C, stirred for 2 hours, and then cooled to room temperature. Add benzene (50 ml) to the reaction mixture, wash twice with 7 (30 ml) at 0-5 ° C, dry over magnesium sulfate, and concentrate under reduced pressure.
  • Example 81 In the same manner as in Example 79, the desired 4-methylphenylthiomethyl ester of penicillin G (I.OOg) is obtained from p-toluenethiol (621 mg) and a potassium salt of penicillin G (1.86 g). .
  • ⁇ , ⁇ -Dimethylformamide (DMF) (5 ml) was added to the residue to dissolve it, and while stirring at room temperature, sodium salt of penicillin G (2.45 g) and sodium iodide (986 mg) were added. Add. After stirring at room temperature for 5 hours, add ethyl acetate (100 ml) and wash three times with water (50 ml). The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product.
  • DMF ⁇ , ⁇ -Dimethylformamide
  • the target penicillin G was obtained from 3-methyl-5- (methylthio) salicylic alcohol acetate (400 mg) and penicillin G potassium salt (555 mg). Acetoxy 3-acetoxymethyl-5-methylphenylthiomethyl ester (330 mg) is obtained.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un composé représenté par la formule générale (I) et à un agent préventif ou curatif pour le traitement des maladies chez les poissons, qui contient un tel composé comme ingrédient actif. Dans la formule (I), A représente un liaison simple et R1 représente (a), alcénoyle inférieur, cyclopropylcarbonyloxyméthyle, cyclohexylcarbonyloxyméthyle, benzoyloxy, benzoyloxyméthyle, (b) (où Y représente -O- ou -COO-), -Z-COOR7 (où Z représente une liaison simple, -CH¿2?-, -CH2CH2- ou -CH=CH-), -CH2W (où W représente hydrogène, hydroxy, alcoxy inférieur ou cyano), -CH2NH2, -CH2NHCH3, (c), -CH2N(C2H5)2, (d), (e), (f) ou (g) placé en position 3; ou, dans une variante, A représente (h) et R?1¿ représente -COOCH¿3? placé en position 4; ou, dans une autre variante, A représente -CH2M- (où M représente O ou S) et R?1¿ représente halogène, alkyle inférieur, alcoxy inférieur, alcanoyle inférieur, alcoxycarbonyle inférieur, alcoxycarbonyle inférieur-alkyle inférieur, alcanoyloxy inférieur-alkyle inférieur, alcanoyloxy inférieur, alkyle inférieur hydroxylé, ou -O(CH¿2?CH2O)kR?8 (où R8¿ représente alkyle inférieur et k représente un nombre entier compris entre 1 et 3); R2 représente hydrogène, alcoxy inférieur ou alcanoyloxy inférieur; R3 représente hydrogène; et X représente N ou CH.
PCT/JP1992/001327 1991-10-15 1992-10-12 Ester de penicilline g WO1993008196A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP3/332994 1991-10-15
JP33299491 1991-10-15
JP4/119989 1992-04-13
JP11998992 1992-04-13
JP11999092 1992-04-13
JP4/119990 1992-04-13
JP15440192 1992-05-20
JP4/154401 1992-05-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000259A1 (fr) * 1995-06-14 1997-01-03 Fujisawa Pharmaceutical Co., Ltd. Procede ameliore de production de phenyl-ester de penicilline g
JP2007508244A (ja) * 2003-08-01 2007-04-05 バイオコン・リミテッド 加水分解可能なプロドラッグのためのアリールカルバメートオリゴマーおよびこれを含むプロドラッグ

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49125387A (fr) * 1973-04-05 1974-11-30
JPS5234638B2 (fr) * 1972-03-03 1977-09-05

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5234638B2 (fr) * 1972-03-03 1977-09-05
JPS49125387A (fr) * 1973-04-05 1974-11-30

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 62, Abstract No. 13018h; & J. CHEM. SOC., 1965 (March), 1595-1605. *
CHEMICAL ABSTRACTS, Vol. 84, No. 11, Abstract No. 74168S; & YAMANOUCHI SEIYAKU KENKYU HOKOKU, 2, 95-108, (1974). *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000259A1 (fr) * 1995-06-14 1997-01-03 Fujisawa Pharmaceutical Co., Ltd. Procede ameliore de production de phenyl-ester de penicilline g
CN1092661C (zh) * 1995-06-14 2002-10-16 武田雪林格·布朗动物保健株式会社 青毒素g苯酯的改进制备方法
JP2007508244A (ja) * 2003-08-01 2007-04-05 バイオコン・リミテッド 加水分解可能なプロドラッグのためのアリールカルバメートオリゴマーおよびこれを含むプロドラッグ
US7335751B2 (en) * 2003-08-01 2008-02-26 Biocon Limited Aryl carbamate oligomers for hydrolyzable prodrugs and prodrugs comprising same
US7625995B2 (en) 2003-08-01 2009-12-01 Biocon Limited Aryl carbamate oligomers for hydrolyzable prodrugs and prodrugs comprising same
AU2004264818B2 (en) * 2003-08-01 2011-09-29 Biocon, Ltd Aryl carbamate oligomers for hydrolyzable prodrugs and prodrugs comprising same
US8143366B2 (en) 2003-08-01 2012-03-27 Biocon Limited Aryl carbamate oligomers for hydrolyzable prodrugs and prodrugs comprising same

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