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WO2000042041A1 - Composes a base d'esters de carbapenem - Google Patents

Composes a base d'esters de carbapenem Download PDF

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Publication number
WO2000042041A1
WO2000042041A1 PCT/JP2000/000115 JP0000115W WO0042041A1 WO 2000042041 A1 WO2000042041 A1 WO 2000042041A1 JP 0000115 W JP0000115 W JP 0000115W WO 0042041 A1 WO0042041 A1 WO 0042041A1
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WO
WIPO (PCT)
Prior art keywords
oxo
group
methyl
pyrr
compound according
Prior art date
Application number
PCT/JP2000/000115
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English (en)
Japanese (ja)
Inventor
Isao Kawamoto
Yasuo Shimoji
Osamu Kanno
Akihiko Nakagawa
Toshio Terao
Original Assignee
Sankyo Company, Limited
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Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU20030/00A priority Critical patent/AU2003000A/en
Publication of WO2000042041A1 publication Critical patent/WO2000042041A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a potent rubanem ester compound having excellent antibacterial activity, a pharmacologically acceptable derivative thereof, a pharmaceutical composition containing them as an active ingredient for preventing or treating bacterial infections, and preventing bacterial infections.
  • the present invention also relates to a method for preventing or treating bacterial infections, and a method for producing the same, which comprises administering a medicament for the treatment, using a pharmacologically effective amount thereof to a warm-blooded animal.
  • Chenameycin derivatives which are potent antibacterial antibiotics, have excellent antibacterial activity, but their chemical and biological stability is low, so they are enzymes that exist in the human body. It is easily degraded by putidinase I and loses its activity, resulting in low urine recovery. Furthermore, some animal species may be toxic to the kidneys. Therefore, the chenamycin derivative imidenem is combined with dehydrobeptidase I inhibitor cilastatin, and panidenem is combined with the organic anion transport inhibitor betamibron. Was developed. Subsequently, it was found that the introduction of a methyl group at the 1-position of the carbane skeleton improved the chemical stability and the stability to dehydrobeptidase-I.
  • Potassium derivatives that can be used as agents have also been developed. However, these are all injections, not oral or suppositories. Therefore, there is a demand for the development of a potent Lumbanem derivative that, when administered to a living body, is efficiently absorbed and then hydrolyzed to exhibit antibacterial activity.
  • Japanese Patent Application Laid-Open No. Hei 2-499783 Japanese Patent Application Laid-Open No. Hei 7-165 759, Japanese Patent Laid-open No. Hei 2-2-235787, Japanese Patent Laid-Open No. Hei 4-2797988 , Japanese Unexamined Patent Publication No.
  • the 3-position carboxyl group of the carboxylic acid skeleton is like an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, or a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group.
  • Specific examples of such an in vivo hydrolyzed ester residue-protected potubanenum ester derivative are disclosed.
  • ester residues such as an alkyl group
  • specific synthesis is required for use as an effective antibacterial agent for oral administration. There are no cases in which absorption was examined.
  • the present inventors have studied various carbanem derivatives having ester residues that have not been specifically disclosed up to now.
  • the carbane ester compound of the present invention having an ester residue such as alkyl represented by the general formula (I) is more stable and lower in production cost than the ester derivatives known so far. It was found to be excellent in absorption from the digestive tract.
  • the compound (I) of the present invention has low toxicity and has been found to be effective as an antibacterial agent for treating or preventing (especially treating) bacterial infections, thereby completing the present invention.
  • the present invention provides a compound represented by the general formula (I)
  • R 3 represents a hydrogen atom or a C 1 -C 4 alkyl group
  • R 2 is, CI- C 2 0 alkyl group, C 3- C 7 cycloalkyl or C 3- C 7 cycloalkyl - shows the C 1 one C 6 alkyl group.
  • a pharmacologically acceptable derivative thereof a pharmaceutical composition containing them as an active ingredient for preventing or treating bacterial infections, and a medicament for preventing or treating bacterial infections.
  • the “C 1 -C 4 alkyl group” for R 3 is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl And ethyl, n-propynole, isopropyl, n-butyl and t-butyl groups, preferably a methyl or ethyl group, more preferably a methyl group.
  • R 3 is preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.
  • the 2-oxopyrrolidinyl group is preferably substituted at the 4-position.
  • the group represented by formula (IIa) for R 1 is preferably 2-oxo-14-pyrrolidinyl or 1-methyl-12-oxo-14-pyrrolidinyl group, most preferably 2-oxo-14-pyrrolidinyl group.
  • the “C 1 -C 20 alkyl group” for R 2 is a linear or branched alkyl group having 1 to 20 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutynole, t-butynole, 3-methylbutynole, pentyl, 2-pentynole, 3-pentynole, 3-methylpentyl, hexynole, 2-methynolepentinole, heptinole, 2-heptyl, 3-heptyl, 4-heptyl, octyl , Noninole, Decyl, Pen Examples include decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and nonadecyl groups.
  • Methyl, ethyl, propyl, isopropynole, butyl, isobutynole, pentinole, 3-pentynole, and 3-methylbutyl are preferred.
  • C 1 -C 10 alkyl such as hexyl, heptyl, octynole or nonyl; more preferably ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 3-pentyl, 3-methylbutyl or hexyl
  • a C 2 -C 6 alkyl group such as a group, most preferably an ethyl, propyl, butyl, isobutyl, 3-methylbutyl or pentyl group.
  • the “C 3 -C 7 cycloalkyl group” for R 2 is a saturated cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutynole, cyclopentyl, cyclohexyl or cycloheptyl. It is preferably a C4-C6 cycloalkyl group such as a cyclobutyl, a cyclopentyl or a cyclohexyl group, and most preferably a cyclohexyl group.
  • the “C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl group” for R 2 is an alkyl group having 1 to 6 carbon atoms substituted with a saturated cyclic alkyl having 3 to 7 carbon atoms,
  • a “pharmacologically acceptable derivative” of compound (I) is a compound that undergoes degradation by hydrolysis or the like when administered to a living body, and the ester portion of compound (I) or compound (I) undergoes hydrolysis. It is a derivative capable of producing a carboxylic acid compound produced by the above.
  • Examples of the group forming such a derivative include a C 10 -C 10 aryloxy group, a C 1 -C 10 anorecoxy-carbonyl group, a C 6 -C 10 aryl-carbonyl group, and a 5- (C 1 -C 4 alkyl) 12 -oxo-11, 3 -dioxolen 14 -ylmethyl group may be mentioned, and preferably C 11 -C 10 alkyl group.
  • C 1 _C 10 alkenyl group is an alkynyl group having 1 to 10 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, norrelinole, isonoklerinole, vivaloyl Octanoyl, nonanoyl, decanoinole, etc., preferably C 2 -C 5 alkanoyl, more preferably acetyl, propionyl, butyryl or isobutyryl, particularly preferably acetyl, propionyl or isobutyryl.
  • a butyryl group most preferably an acetyl group.
  • the “C 1 -C 10 alkanoyl group” may have a substituent, and examples thereof include substituents such as amino, methylamino, dimethylamino, hydroxyl, and fuunyl.
  • the “C 1 -C 10 alkanoyl group having a substituent” is preferably a C 2 -C 6 alkanoyl group having a substituent (the substituent is an amino, methylamino, dimethylamino, hydroxyl or fuzyl group) And more preferably an ⁇ or
  • a “C 1 -C 10 alkoxy-carbonyl group” is an alcohol having 1 to 10 carbon atoms.
  • a carbonyl group substituted by a xy group for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butoxyloxycarbonyl, pentinoleoxycarbonyl, hexyloxycanoleponyl, heptyloxycarbonyl, Examples thereof include octyloxycarbonyl, nonyloxycarbonyl and decyloxycarbonyl groups, preferably a C 1 -C 4 alkoxycarbonyl group, and more preferably a methoxycarbonyl or ethoxycarbonyl group. Most preferably, it is an ethoxycarbonyl group.
  • the “C 6 -C 10 aryl-1 carbonyl group” includes, for example, a benzoyl, 11-naphthyl or 2-naphthoyl group, and is preferably a benzoyl group.
  • “5- (C 1 -C 4 alkyl) -12-oxo-1,3-dioxolen-4-ylmethyl group” is, for example, 5-methyl-2-oxo-1, 3-dioxolen-4-ylmethyl, 5 — Ethyl 1-2-oxo-1,3 -dioxolen 4-inolemethyl, 5-propyl-12 -oxo-1,3 -dioxolen-1,4-inolemethinole or 5-butyl-2-oxo-1,3 -dioxolen-1,4-methylmethyl
  • Examples of the group include a 5-methyl-12-oxo_1,3-dioxolen-14-ylmethyl group.
  • “Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate, ethanesulfonate Salts, benzenesulfonates, p-sulfonates such as toluenesulfonates; oxalates, tartrates, citrates, maleates, succinates, acetates, benzoates, mandelates, Acid addition salts such as organic acid salts such as ascorbate, lactate, dalconate, malate, amino acid salts such as glycine, lysine, arginine, olnitine, glutamate, and aspartate Hydrochloride, hydrobromide, phosphate, sulfate, methanesulfone Acid salt, p-toluenesulfonate, oxalate, tart
  • the compound (I) of the present invention absorbs water by being left in the air, freeze-dried from an aqueous solution, or recrystallized to form adsorbed water or form a hydrate. In some cases, a solvate may be formed by handling with an organic solvent, and such salts are also included in the present invention.
  • the compound (I) of the present invention has an asymmetric carbon in the molecule, and there are various optical isomers based on its configuration.
  • the present invention includes individual isomers and a mixture of isomers. You. Among these isomers, preferred are those in which the 1-position of the carbane skeleton is in the R-configuration and the 5- and 6-positions are in the same configuration as chenamycin (5S, 6S). Further, there may be mentioned compounds in which the configuration of single carbon having a hydroxyl group at the 6-position substituent is the R configuration.
  • the compounds of the present invention represented by the general formula (I) the following compounds are preferred.
  • a compound in which the substitution position of the group represented by the formula (IIa) in R 1 is the 4-position.
  • R 1 is a 2-oxo-14-pyrrolidinyl or 1-methyl-12-oxo-14-pyrrolidinyl group.
  • R 2 is a compound which is a C 1 one C 2 0 alkyl group.
  • R 2 is a C 2 —C 6 alkyl group.
  • R 2 is an ethyl, propyl, butyl, isobutyl, 3-methylbutyl or pentyl group.
  • R 1 is a 2-oxo-14-pyrrolidinyl group or a 1-methyl-2-oxo-4-pyrrolidinyl group
  • R 2 is a C 1 -C 10 alkyl group
  • R 1 is a 2-oxo-4-pyrrolidinyl group and R 2 is a C 2 -C 6 alkyl group.
  • R 1 is a 2-oxo-14-pyrrolidinyl group and R 2 is an ethyl or propyl group.
  • Table 1 specifically shows compounds having the general formula (I) or compounds suitable as pharmaceutically acceptable derivatives thereof.
  • Ethyl 6 (1-Hydroxitytyl) -1 1-Methyl-2— (1-Acetinole 2-oxo-1 41-Pyrrolidininolethio) 1-1-Canolebapene 1- 2-Emu 3-Carboxylate Compound No. 5 9: Ethyl 6— (1-acetoxityl) —1-Methyl-2- (1-acetinolate 2-oxo-14-pyrrolidinylthio) -1—1-Lubapen-1 2-Em-1—3-Roleboxylate ⁇ Compound No.
  • Ethyl 6 (1-Hydroxityl) — 1-Methyl-1 2— (1 —Methyl-2-oxo-4 4-Pyrrolidininolethio) 1 1—Canolebapene 1 2 —Em-1 3—Norevoxylate Compound No. 1 1 4: Ethyl 6— (1-Acetokishetyl) 1 1-Methinole 2-(1-Methylinole 2 —Oxo 1 4 —Pyrrolidininorecho) 1 1—Canolebapen 1 2 —Em 1 3 —Power Silate.
  • the most preferred compounds are the following compounds.
  • the compound of formula (I) according to the present invention can be produced by introducing a group represented by R 2 into the carboxyl group at the 3-position of the carbane compound represented by formula (III). (Method A).
  • R 1 and R 2 are the same as described above.
  • the compound represented by the formula (III), which is a starting material, is disclosed in JP-A-2-49783, JP-A-7-165759, JP-A-2-223358 No. 7, JP-A-4-127995, JP-A-8-53453, The Journal of Antibiotics 50 (5), 429-439 (1997) and the like or It can be manufactured by an equivalent method. Hereinafter, the above manufacturing method will be described in detail.
  • the first step is accomplished by reacting compound (III) with a compound represented by R 2 L in a solvent in the presence of a base.
  • Examples of the compound represented by R 2 L given the click hole Li de R 2, Buromi de, methanesulfonate halide or R 2 as Yodai de, triflumizole Ruo b methanesulfonyl Honeto, the sulfonates such as toluene sulfonate And preferably a halide of R 2 .
  • the halides the reactivity of iodide is high, which is suitable. Chloride or promide can be used in the presence of sodium iodide.
  • Solvents used include those that dissolve the starting materials to some extent and do not participate in the reaction. Is not particularly limited, for example, aliphatic saturated hydrocarbons such as n-pentane, n-hexane, n_heptane, and n-octane; aromatic hydrocarbons such as benzene, toluene, and xylene Ethers such as getyl ether, tetrahydrofuran, and dioxane; esters such as ethyl formate, methyl acetate, and ethyl acetate; nitriles such as acetonitrile; methylene chloride; —Ndrogenide hydrocarbons such as dichloroethane, chlorophonolem, chlorobenzene, and dichlorobenzene; N, N-dimethylformamide, N, N-dimethylacetamide, and N-methyl-1-pyrrolidone Such amides can be mentioned.
  • a mixed solvent in which these are appropriately combined can also be used.
  • preferred solvents are esters, nitriles or amides, more preferably amides (especially N, N-dimethylformamide or N, N-dimethylacetamide). It is.
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction.
  • Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, and potassium carbonate.
  • Inorganic bases such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylbiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) )
  • Organic bases such as pyridine, quinoline, 2,6-di (t-butyl) -14-methylpyridine, N, N-dimethylaniline and N, N-getylaniline can be mentioned.
  • inorganic bases such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate or organic bases such as triethylamine, diisopropylethylamine and dicyclohexylamine are preferred
  • the reaction temperature is usually from ⁇ 10 to 50 degrees, preferably from 0 to 30 degrees.
  • the reaction time varies depending on the solvent, base, reaction temperature and the like used, but is usually from 10 minutes to 10 hours, preferably from 0.5 to 3 hours.
  • the desired product can be obtained by appropriately combining the methods.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • An immiscible organic solvent such as water and ethyl acetate is added.
  • the organic layer containing the target compound is added.
  • the solvent is distilled off.
  • the target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds, such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.
  • the compound (I) can also be obtained by dissolving a salt of the compound (III) prepared and isolated in advance in a solvent and reacting the resultant with a compound represented by R 2 L.
  • a pharmacologically acceptable derivative of compound (I) can be produced by the following method.
  • Method B is a method for producing a compound (I) of 6 Kuraihi Dorokishechiru hydroxyl in derivatives obtained by introducing a group R 4 Ru earthenware pots are degraded in vivo group (IV).
  • R 4 is an alkanoyl, substituted alkanoyl, or arylcarbonyl group
  • examples of the reactive derivative of R 4 include acid halides, acid anhydrides, mixed acid anhydrides, and acid imidazole compounds. Is an acid anhydride.
  • examples of R 4 include anorecoxycarbonyl halides and dialkyl carbonates.
  • alkoxycarbonylhalo is used. It is a genid.
  • R 4 is a 5- (C 1 -C 4 alkyl) —2-oxo-1,3-dioxolen-4-ylmethyl group, a halide is preferred.
  • the solvent used is not particularly limited as long as it dissolves the starting material to some extent and does not participate in the reaction.
  • fats such as n-pentane, n-hexane, n-heptane, and n-octane
  • Aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, tetrahydrofuran, and dioxane
  • ethers such as ethyl formate, methyl acetate, and ethyl acetate
  • Nitrile hydrocarbons such as methylene chloride, 1,2-dichlorobenzene, chlorophonolem, chlorobenzene, and dichlorobenzene
  • N, N-dimethylform Examples include amides such as amides, N, N-dimethylacetamide, and N-methyl-12-pyrrolidone. Further, a mixed solvent in which these are appropriately combined can also be
  • the base to be used is not particularly limited as long as it is used as a base in a usual reaction.
  • Organic bases such as N, N-dimethylaniline and N, N-getylaniline can be mentioned.
  • pyridine 4- (N, N-dimethylamino) pyridine or a combination thereof.
  • Bases to the reactive derivative of the R 4, usually 1 to 1. 1 molar equivalent is used, but it is also possible to use a large excess as a solvent.
  • a catalytic amount of 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in combination with other bases.
  • the reaction temperature is usually from ⁇ 10 to 50 degrees, preferably from 0 to 30 degrees.
  • the reaction time varies depending on the solvent, base, reaction temperature and the like used, but is usually from 10 minutes to 10 hours, preferably from 0.5 to 3 hours.
  • the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
  • the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off.
  • the target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds, such as treatment with activated carbon, recrystallization, reprecipitation, and column chromatography.
  • Process C is a process for preparing a compound R 1 Ami de nitrogen residues to derivatives of the radicals R 5, which may be broken down and input electrically in vivo of (I) (VII).
  • R 1 and R 2 have the same meanings as described above, and R 6 represents a hydroxyl-protecting group.
  • R 6 represents a "hydroxyl protecting group" in R 6, may be used those suitable from those commonly used in the field of organic synthetic chemistry, trimethylsilyl, triethyl Chirushirinore, t - butyl dimethicone Honoré Siri Honoré Trial CI—C 4 The most preferred is a triethylsilyl group.
  • the compound represented by formula (V) starting material is obtained by a protecting group R 6 in a conventional manner a hydroxy group of the compound of the aforementioned (I).
  • the C one 1 step, in a solvent a compound (V), the presence of a base, to produce compound (VI) by reaction with a reactive derivative of R 5.
  • R 5 is an alkanoyl group
  • examples of the reactive derivative of R 5 include an acid halide, an acid anhydride, a mixed acid anhydride, and an acid imidazole compound. is there.
  • examples of R 5 include an alkoxycarbonyl group, examples thereof include an alkoxycarbonyl halide, a dialkyl carbonate and the like, and preferably an alkoxycarbonyl halide.
  • R 5 is alkyl or 5- (C 1 -C 4 alkyl) -12-oxo-1,3-dioxolen-14-ylmethyl, halides are preferred.
  • the solvent used is not particularly limited as long as it dissolves the starting material to some extent and does not participate in the reaction.
  • fats such as n-pentane, n-hexane, n-heptane, and n-octane
  • Aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as getyl ether, tetrahydrofuran, and dioxane
  • esters such as ethyl formate, methyl acetate, and ethyl acetate Nitriles such as acetonitrile
  • nodroyl hydrocarbons such as methylene chloride, 1,2-dichlorobenzene, chlorophonolem, chlorobenzene, and dichlorobenzene
  • N. N-dimethylformamide
  • amides such as N, N, N-dimethylacetamide and N-methyl-2-pyrrolidone.
  • the base to be preferably used is not particularly limited as long as it is used as a base in a usual reaction.
  • organic bases such as N, N-dimethinorealinen and N, N-jetinorealineline. Among them, preferred is 41- (N, N-dimethylamino) pyridine.
  • Bases to the reactive derivative of R 5, usually 1 to 1. 1 molar equivalent is used, but it is also possible to use a large excess as a solvent. Note that 4- (N, N-dimethylamino) pyridine or 4-pyrrolidinopyridine can be used in a catalytic amount in combination with another base.
  • the reaction temperature is usually from ⁇ 10 to 50 degrees, preferably from 0 to 30 degrees.
  • the reaction time varies depending on the solvent, base, reaction temperature and the like used, but is usually from 10 minutes to 10 hours, preferably from 0.5 to 3 hours.
  • the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off.
  • the target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds, such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.
  • Step C-12 is a step of removing a protecting group for a hydroxyl group of compound (V I) to obtain compound (V I I).
  • the protecting group is a tri-C 1 -C 4 alkylsilyl group
  • a compound which forms a fluorine anion such as tetrabutylammonium fluoride or potassium fluoride (preferably tetrabutylammonium fluoride) is used. ).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction temperature and reaction time are not particularly limited, but are usually 6 hours to 3 days at room temperature (preferably (Appropriately 10 to 18 hours).
  • the desired product can be obtained by a conventional method, for example, by appropriately combining techniques such as concentration, extraction, activated carbon treatment, and crystallization.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added. And the solvent is distilled off.
  • the target compound can be purified, if necessary, by a method commonly used for separation and purification of organic compounds, such as activated carbon treatment, recrystallization, reprecipitation, and column chromatography.
  • Method D is a method for producing a derivative (VIII) in which the groups R 4 and R 5 that can be degraded in vivo are introduced into the hydroxyl group of the 6-hydroxyl group of compound (I) and the amide nitrogen residue of R 1, respectively. is there.
  • the D-1 step in a solvent to the compound (VII), in the presence of a base is accomplished by reacting a reactive derivative of R 4. This step can be achieved in the same manner as described in Method B described above.
  • the thus-obtained compound of general formula (I) and its pharmacologically acceptable derivatives (IV), (VII) and (VIII) may be optionally used in medicinal chemistry, According to methods or techniques known in the field of 3-lactam antibiotics, they can be purified as pharmacologically acceptable salts.
  • the compound (I) and its pharmacologically acceptable derivative are used as a medicine (especially an antibacterial agent), the compound (I) itself or an appropriate pharmacologically acceptable excipient, diluent or the like is used. They can be mixed and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injections.
  • These preparations may contain excipients (e.g., lactose, sucrose, dextrose, saccharides such as mannite, sorbitol; corn starch, potato starch, hi-starch, dextrin, carboxymethyl starch).
  • excipients e.g., lactose, sucrose, dextrose, saccharides such as mannite, sorbitol; corn starch, potato starch, hi-starch, dextrin, carboxymethyl starch.
  • Starch derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethyl cenorellose, carboxymethylcellulose, phenolic methylcellulose calcium carbonate, phenolic cellulose such as internally cross-linked carboxymethylcellulose sodium
  • arabia gum dextran; pullulan; silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; calcium carbonate Carbonate induction Conductors; sulfate derivatives such as calcium sulfate; binders (eg, the above-mentioned excipients; gelatin; poly (vinylpyrrolidone); macrogol, etc.); disintegrants (eg, the above-mentioned excipients; Mouth Scarmellose sodium, carboxymethyl starch sodium, chemically modified starch such as cross-linked polyvinylpyrrolidone, starch, cellulose derivatives,
  • Sodium salt sulfuric acids such as sodium sulfate Leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium peryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, methyl paraben, Paraoxybenzoic acid esters such as propylparaben; phenolic alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; Merosal; acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour flavors, flavors, etc.), suspending agents (eg, polysorbate 80, carboxymethylcellulose sodium, etc.) It is manufactured by a known method using additives such as a diluent, a formulation solvent (eg,
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 50 mg) per dose and the upper limit is 200 mg (preferably 100 mg). mg), in the case of intravenous administration, the lower limit is 1 Omg (preferably 10 Omg) per dose; the upper limit is 300 Omg (preferably 200 Omg) for adults, 1 to 10 mg / day. It is desirable to administer 6 times according to symptoms.
  • Example 7 of the present invention and the compound 14 described in The Journal of Antibiotics 50 (5), 429-439 (1997), which is one of the closest prior art documents, were each orally administered to dogs.
  • the concentration of the active substance in the plasma was measured by high performance liquid chromatography and the absolute bioavailability (BA) was compared.
  • the measured plasma concentration was plotted against the time after administration of the sample, and the area under the one-hour curve (AUC) in the plasma concentration was determined.
  • AUC area under the one-hour curve
  • the absolute bioavailability ratio (BA) was calculated using, and is shown in Table 2, together with the separately calculated pharmacological parameters.
  • the powder of the above formulation is mixed, wet-granulated using corn starch paste, and dried.
  • the mixture is tableted with a tableting machine to give tablets of 20 O mg. These tablets can be sugar-coated if necessary.
  • the compound of the present invention having the above general formula (I) or a pharmaceutically acceptable derivative thereof exhibits excellent absorption and long-lasting body kinetics when administered to a living body. Therefore, the compound having the general formula (I) or a pharmacologically acceptable salt thereof according to the present invention is useful for a medicament (particularly an antibacterial agent) for treating or preventing (preferably treating) bacterial infections caused by various pathogenic bacteria. Useful as an ingredient.

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  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Problème: trouver des composés à base de carbapenem manifestant d'excellentes activité antimicrobienne et absorbabilité perorale. Solution du problème: composés à base d'esters de carbapenem correspondant à la formule générale (I) dans laquelle R2 est alkyle C¿1?-C20, cycloalkyle C3-C7 ou cycloalkyle (C3-C7)alkyle(C1-C6) et R?3¿ est hydrogène ou alkyle C¿1?-C4.
PCT/JP2000/000115 1999-01-13 2000-01-12 Composes a base d'esters de carbapenem WO2000042041A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20030/00A AU2003000A (en) 1999-01-13 2000-01-12 Carbapenem ester compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP634399 1999-01-13
JP11/6343 1999-01-13

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WO2000042041A1 true WO2000042041A1 (fr) 2000-07-20

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337637A1 (fr) * 1988-04-01 1989-10-18 Sankyo Company Limited Dérivés de 2-(hétérocyclylthio)carbapénème, leur préparation et leur application comme antibiotiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337637A1 (fr) * 1988-04-01 1989-10-18 Sankyo Company Limited Dérivés de 2-(hétérocyclylthio)carbapénème, leur préparation et leur application comme antibiotiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASAO MIYAUCHI, ROKURO ENDO, MASAFUMI HISAOKA, HIROSHI YASUDA, ISAO KAWAMOTO: "Synthesis and Structure-activity Relationships of a Novel Oral Carbapenem, CS-834", THE JOURNAL OF ANTIBIOTICS, vol. 50, no. 5, 1997, pages 429 - 439, XP002922224 *

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