WO1996007655A1 - Nouveau derive de carbapenem - Google Patents

Nouveau derive de carbapenem Download PDF

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Publication number
WO1996007655A1
WO1996007655A1 PCT/JP1995/001756 JP9501756W WO9607655A1 WO 1996007655 A1 WO1996007655 A1 WO 1996007655A1 JP 9501756 W JP9501756 W JP 9501756W WO 9607655 A1 WO9607655 A1 WO 9607655A1
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Prior art keywords
group
hydrogen atom
lower alkyl
compound
alkyl group
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PCT/JP1995/001756
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English (en)
Japanese (ja)
Inventor
Susumu Nakagawa
Hiroshi Fukatsu
Yoshiaki Kato
Yuichi Sato
Tomoyasu Kanesaka
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU45960/96A priority Critical patent/AU4596096A/en
Publication of WO1996007655A1 publication Critical patent/WO1996007655A1/fr

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    • 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

Definitions

  • the present invention relates to a novel compound (7-oxo-1-azabicyclo [3.2.0] hepta-2-en-2-carboxylic acid) compound, a pharmaceutically acceptable salt or non-toxic ester thereof,
  • the present invention relates to an antibacterial agent containing a compound or a pharmaceutically acceptable salt or a nontoxic ester thereof as an active ingredient, and a method for producing the compound.
  • Potassium derivatives represented by chenamycin have broad and strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and are resistant to the production of S-lactamase, an enzyme that degrades c-lactam. It also has efficacy against bacteria. However, it is degraded by dehydrobeptidase I (hereinafter abbreviated as DHP-I) present in the human body, and has the drawbacks that its antibacterial activity is reduced and its urinary recovery rate is reduced.
  • DHP-I dehydrobeptidase I
  • the substituent R ′ of the substituent is defined as the following groups substituted with a carbamoyloxy group or a rubamoyl group, a lower alkynole group, a cycloalkyl group, an aralkyl group, an arylene group. , A heteroaryl group, a heteroaralkyl group, or an alkylheteroaralkyl group; or Base
  • R 2 is a hydrogen atom, a lower alkyl group with or without a substituent or an alkanoyl group
  • R 4 is a hydrogen atom, a formyl group or an optionally substituted lower alkyl group, a lower alkanol group or a lower alkylsulfonyl group, and R 5 , R 6 and R 7 are the same or different and are different from each other. Or a thioxo group], but no disclosure or suggestion that the compound has significant antibacterial activity.
  • R 4 is a hydrogen atom, a formyl group, or an optionally substituted lower alkyl group, a lower alkanoyl group or a lower alkylsulfonyl group
  • R 5 , R 6 and R 7 are the same or different
  • the compound of the present invention having a substitution group represented by the following formula: is a novel compound not described in the literature, and is useful for gram-positive bacteria and gram-negative bacteria containing MRSA. Strong antibacterial power It has been found that the compound has excellent stability to DHP-I, has low toxicity to the central nervous system, and has good oral absorbability in its ester form. That is, the present invention relates to the general formula
  • R ′ is a hydrogen atom or a lower alkyl group
  • R 2 is a hydrogen atom, an ester residue or an alkali metal
  • R 3 is
  • R 4 is a hydrogen atom, a formyl group or an optionally substituted lower alkyl group, lower alkanoyl group or lower alkylsulfonyl group, R 5 , R 6 and R 7 are the same or different Or a thioxo group)]], a process for its production and its use as an antibacterial agent.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cycloalkyl group.
  • the lower alkynyl group means a linear or branched alkanol group having 2 to 7 carbon atoms or a cyclic alkanol group having 4 to 7 carbon atoms, such as an acetyl group, a propionyl group, and a cyclopropanol group.
  • a lower alkylsulfonyl group means that the above lower alkyl group is a sulfonyl group.
  • cyclopropanesulfonyl group butanesulfonyl group, sec-butanesulfonyl group, t-butanesulfonyl group, cyclobutanesulfonyl group, pentanesulfonyl group, cyclopentanesulfonyl group, hexanesulfonyl group, cyclohexanesulfonyl group, etc.
  • a methanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group and the like are preferable.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among them, a fluorine atom and a chlorine atom are preferable.
  • a lower alkoxy group refers to a straight-chain or branched C 1 -C 6 or C 3 -C 6 cyclic alkoxide having an oxygen atom substituted by the above-mentioned lower alkyl group, such as a methoxy group.
  • Ethoxyquin, propoxy isopropoxy, cyclopropoxy, butoxy, sec-butoxy, t-butoxy, cyclobutoxy, pentoxy, cyclopentoxy, hexoxy, cyclohexyloxy
  • methoxy group, ethoxy group, isopropoxy group, t-butoxy group, cyclohexyloxy group and the like are preferable.
  • An optionally substituted lower alkyl group, lower alkanoyl group or lower alkylsulfonyl group means a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanol group or a substituted or unsubstituted lower alkyl group.
  • the substituents that can be substituted include, for example, a halogen atom, a cyano group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, an N-lower alkyl labamoyl group, N-di-lower alkylcarbamoyl groups and the like are preferable, and among them, for example, hydroxyl group, carbamoyl group, N-lower alkyl rubamoyl group, ⁇ , ⁇ -di-lower alkyl rubamoyl group and the like are preferable.
  • the lower alkyl group which may be substituted includes, for example, the above-mentioned lower alkyl group, halo lower alkyl group, cyano lower alkyl group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, carboxy lower alkyl group, Lower alkoxycarbonyl lower alkyl group, lower alkyl group of N-lower alkyl group, N-lower alkyl lower alkyl group of lower alkyl group, ⁇ , ⁇ -di-lower alkylcarbamoyl lower alkyl group, etc., among which hydroxy lower alkyl group, carbamoyl Lower alkyl groups, ⁇ -lower alkyl rubamoyl lower alkyl groups, ⁇ , ⁇ -di lower alkyl rubamoyl lower alkyl groups, and the like are preferred.
  • a carboxyl-protecting group is, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group; for example, a 2,2,2-trichloroethyl group, a 2,2,2- Halo-substituted lower alkyl groups such as trifluoroethyl group; for example, acetoxmethyl group, propionyloxymethyl group, isopropionyloxymethyl group, bivaloyoxymethyl group, cyclohexanoyloxymethyl group, 1- ⁇ Lower alkynyl groups such as cetoxyshetyl group, 1-propionyloxyxethyl group, 1-isopropionyloxyxethyl group, 1-bivaloyloxethyl group, 1-cyclohexyloxyxyl group, etc. Roxyalkyl group; for example, a lower alkyl group such as
  • the hydroxyl-protecting group is, for example, a lower alkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group: for example, a methoxymethyl group or a 2-methoxyethoxy group.
  • a lower alkoxymethyl group such as a xymethyl group; for example, a tetrahydroviranyl group; for example, a benzyl group, a p-methoxybenzyl group, a 2,4-dimethyloxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzyl
  • An aralkyl group such as a trityl group; an acyl group such as a formyl group or an acetyl group; an tert-butoxycarbonyl group, a 2-ethoxyethoxycarbonyl group, a 2,2,2-trichloromouth ethoxycarbonyl group, etc.
  • Lower alkoxycarbonyl group for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2--2-propenyloxycarbonyl group, 2-methyl-2 —Alkenyloxycarbonyl groups such as —propenyloxycarbonyl, 2-butenyloxycarbonyl, cinnamyloxycarbonyl, etc.
  • an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, a P-methoxybenzyloxycarbonyl group, an o-nitrobenzoyloxycarbonyl group, a p-nitrobenzoyloxycarbonyl group, and the like,
  • a 2-propenyloxycarbonyl group, a p-nitrobenzoyloxycarbonyl group, a t-butyldimethylsilyl group and the like are preferable.
  • the non-toxic ester of the general formula [I] means a conventional pharmaceutically acceptable carboxy group at the 3-position of the carbane skeleton, such as an acetoxmethyl group, a propionyloxymethyl group, Isopropionyloxymethylinole, butyryloxymethyl, isoptyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl, bivaloyloxymethyl, cyclopentylcarponyloxymethyl, Lower alkanoyloxyalkyl groups such as cyclohexylcarboxyloxymethyl group, 1-methyl-1-cyclohexylcarbonyloxymethyl group: for example, methoxycarbonyloxymethyl group, ethoxycarbonyldioxymethyl group, propoxylcarbonylyl group Xymethyl group, isopropoxycarbonyloxymethyl group , T-butoxycarboxyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, cyclohexyloxycarbonyloxymethyl group
  • No Larkyr Luka Rubonyloxyalkylalkyl groups for example, aralkyloxycarbonyloxyalkyl groups such as benzyloxycarbonyloxymethyl group, phenethyloxycarbonyloxymethyl group, and naphthylmethyloxycarbonyl group; An aralkyloxycarbonylalkyl group such as a benzyloxycarbonylmethyl group, a phenyloxycarbonylmethyl group, a naphthylmethyloxycarbonylmethyl group; a phthalidyl group; (5-methyl-2-oxo-1,3 — Dioxol-41-yl) methyl group and other (5-substituted-2-oxo-l, 3-dioxol-41-yl) methyl groups, among which lower alkanolylalkyl groups and lower alkoxy groups. Dioxyalkyl group, (5-substituted 2-oxo-1,3-dioxolen-4
  • R 1 represents a hydrogen atom or a lower alkyl group, preferably a methyl group. Suitable.
  • R 2 represents a hydrogen atom, a nontoxic ester residue or an alkali metal.
  • R 4 represents a hydrogen atom, a formyl group or an optionally substituted lower alkyl group, a lower alkanoyl group or a lower alkylsulfonyl group, among which a hydrogen atom or an optionally substituted lower alkyl group or a lower alkyl group; Alkanoyl groups are preferred.
  • the optionally substituted lower alkyl group, lower alkyl group or lower alkylsulfonyl group is as described above, but among them, hydroquin lower alkyl group, lower alkyl group of carbamoyl, and N-lower alkylcarbamoyl are preferred.
  • Lower alkyl group, ⁇ , ⁇ -di-lower alkyl group rubamoyl lower alkyl group, hydroquine lower alkanoyl group, carbamoyl lower alkanoyl group, ⁇ -lower alkyl group rubamoyl lower alkanol group, ⁇ , ⁇ dialkyl lower alkylcarbamoyl lower group Alkinyl groups and the like are preferred.
  • R 4 include, for example, a hydrogen atom, a formyl group, a methyl group, an ethyl group, a t-butyl group, a fluoromethyl group, a hydroxymethyl group, a 2-hydroxyshethyl group, and a 3-hydroquinpropyl group.
  • ⁇ -dimethylcarbamoylethyl group 11 ⁇ , ⁇ -dimethylcarbamoyl-1-methylethyl group, acetyl group, propionyl group, butyryl group, isoptyryl group, valeryl group, isovalerinole group, vivaloneole group, Hydroxyacetizole group, 1-hydroxypropionyl group, 2-hydroxypropionyl group, rubamoyl methylcarbonyl group, 1 rubamoylethyl carbonyl group, 2 rubamoylethyl carbonyl group, 1 1-methylcarbamoylethylcarbonyl group, 2-methylcarbamoylmethylcarbonyl group, 2-methylcarbamoylmethylcarbonyl group, 2-ethylcarbamoylmethylcarbonyl group, 2-dimethylcarbamoylethylcarbonyl group, 2-dimethylcarbamoylethylcarbonyl group, ⁇ methylcarbamo
  • R 5 , R 6 and R 7 are the same or different and represent an oxo group or a thioxo group.
  • the salt of the general formula [I] means a conventional pharmaceutically acceptable salt, and the carboxyl group at the 3-position of the carbanem skeleton (when R 2 is a hydrogen atom) or R 4 is a hydrogen atom And the salts in the above case.
  • Examples of the basic addition salt at the carboxyl group at the 3-position include other metal salts such as sodium salt and potassium salt wherein R 2 is an alkali metal; Alkaline earth metal salts such as salts and magnesium salts; for example, ammonium salts: for example, trimethylamine salts, triethylamine salts: dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, etc.
  • other metal salts such as sodium salt and potassium salt wherein R 2 is an alkali metal
  • Alkaline earth metal salts such as salts and magnesium salts
  • ammonium salts for example, trimethylamine salts, triethylamine salts: dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, etc.
  • Aliphatic amine salts aralkylamine salts such as ⁇ , ⁇ '-dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts and isoquinoline salts: eg tetramethyl Ammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethyl Anmoniumu salts, benzyltri Petit Ruan monitor ⁇ unsalted, methyl trioctyl ammonium Niu arm salts, quaternary Anmoniumu salts such as tetrabutyl Anmoniumu salt: arginine salts, basic amino acid salts such as lysine salts.
  • Examples of acid addition salts in bases include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, and perchlorate; for example, acetate, propionate, lactate, and the like.
  • Organic acid salts such as maleate, fumarate, tartrate, malate, citrate, ascorbate; methanesulfonate, isethionate, benzenesulfonate, ⁇ -toluenesulfonic acid Sulfonates such as salts: Examples thereof include acid aminates such as aspartate and glutamate.
  • R 30 represents a hydrogen atom or a hydroxyl-protecting group
  • R ′ represents a hydrogen atom or a lower alkyl group
  • R 2 ° represents a hydrogen atom or a carboxyl group-protecting group
  • inert organic solvent used in the above reaction examples include getyl ether, tetrahydrofuran, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, acetone, Ethyl acetate, acetonitrile, N, N-dimethylformamide, hexamethylphosphate triamide or a mixture of the above-mentioned solvents can be mentioned.
  • acetonitrile and ⁇ , ⁇ -dimethylformamide are preferable.
  • Bases used in the reaction include, for example, secondary aliphatic amines such as ⁇ , ⁇ -diisopropylamine, for example, trimethylamine, triethylamine, ⁇ . ⁇ -diisopropylethylamine, ⁇ -methylmorpholine, ⁇ -methyl Pyrrolidine, ⁇ -methylbiperidine, ⁇ , ⁇ -dimethylaniline, 1,8-diazabicyclo [5.
  • secondary aliphatic amines such as ⁇ , ⁇ -diisopropylamine, for example, trimethylamine, triethylamine, ⁇ . ⁇ -diisopropylethylamine, ⁇ -methylmorpholine, ⁇ -methyl Pyrrolidine, ⁇ -methylbiperidine, ⁇ , ⁇ -dimethylaniline, 1,8-diazabicyclo [5.
  • DBU pendant 7-ene
  • DBN 1,5-diazabicyclo [4.3.0] nona 5-ene Tertiary aliphatic amines
  • pyridine 4-dimethylamino
  • aromatic amines such as pyridine, picoline, lutidine, quinoline, and isoquinoline, and N, N-diisopropylethylamine and triethylamine are particularly preferable.
  • Examples of the activating reagent used in the reaction include acid anhydrides such as trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and p-toluenesulfonic anhydride; And acid chlorides such as p-toluenesulfonyl chloride and diphenyl chloride phosphate. Diphenyl chlorophosphate is particularly preferred.
  • the group L in the general formula [ ⁇ '] represents a leaving group, for example, a halogen atom, trifluoroacetoxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, diphenyl Examples thereof include a phosphoryloxy group, and a diphenylphosphoryloxy group is particularly preferable.
  • the reaction is quantitatively completed in a temperature range of -40 to 50 ° C, preferably -20 to 20 ° C, usually for 0.5 to 3 hours.
  • reaction is carried out according to a conventional method to quantitatively obtain the reactive derivative [ ⁇ ] of the general formula [ ⁇ ].
  • R 4 ° represents a hydrogen atom, a protecting group for an imino group, a formyl group or an optionally substituted lower alkyl group, a lower alkanoyl group or a lower alkylsulfonyl group, R 5 , R 6 and R 7 represent Which is the same or different and represents an oxo group or a thioxo group] is carried out using the above-mentioned inert organic solvent and a base group,
  • the reaction is carried out in such a manner that 1 to 2 moles, preferably 1 to 1.5 moles, of the reactive derivative [ ⁇ '] and 1.2 to 1 mole of the compound 1 of the general formula [Ilia], [Illb] or [IIIc] are used. is used, - 40 ⁇ 50 ° C, preferably carried out in a temperature range one 20 to 20 e C, completed in the usual 0.5 to 3 hours.
  • the compound of the general formula [IVa:], [IVb] or [IVc] can also be produced in one step from the compound of the general formula [ ⁇ ]. That is, a compound of the general formula [Ilia]. [Illb] or [IIIc] is reacted in the same reaction system without isolating the reactive derivative [ ⁇ '] derived from the compound of the general formula [ ⁇ ].
  • the compound of the general formula [IVa] or [IVb] can be produced efficiently.
  • the base is used in an amount of 2 to 4 mol, preferably 2.5 to 3.5 mol, per 1 mol of the compound of the general formula [ ⁇ ].
  • the protecting group for the hydroxyl group and the amino group or the imino group is, for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group.
  • the carboxyl group-protecting group is, for example, an aralkyl group such as a benzyl group, a p-nitrobenzyl group or a benzhydryl group, for example, a platinum catalyst such as platinum oxide, platinum wire, platinum black, etc.
  • the protective group can be removed by catalytic hydrogenation using a palladium catalyst such as palladium black, palladium oxide, palladium monocarbon, palladium hydroxide-carbon.
  • Examples of the solvent used for the catalytic hydrogenation reaction include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid and the like, or a mixed solvent of these organic solvents and a buffer such as water or phosphate.
  • the reaction is completed in 0.5 to 4 hours in a temperature range of 0 to 50 ° C under a hydrogen gas stream of 1 to 4 atm.
  • the protecting group for the hydroxyl group and the amino group or the amino group or the imino group is, for example, an aryloxycarbonyl group
  • the protecting group for the carboxyl group is, for example, an aryl group
  • the protective group can be removed by reacting an organic soluble palladium complex catalyst in an inert organic solvent containing a group scavenger [W. McCombie et al., The Journal of Organic Chemistry (J Chem.), Vol. 47, pp. 587-590 (1982), and the method of F. Guibe (Guib6), and the same literature, Vol. 52, pp. 4984-4993 (1987)].
  • Examples of the solvent used for the reaction include water, acetone, getyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride, chloroform and the like, or a mixed solvent thereof.
  • Suitable palladium compound complexes used in this reaction include, for example, para Palladium hydroxide-carbon, palladium hydroxide-carbon, palladium chloride (11), palladium acetate (11), tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenoxyphosphine) no, radium (0) , Tetrakis (triethoxyphosphine) palladium (0), bis [ethylenebis (diphenylphosphine)] palladium (0), tetrakis [tri (2-furyl) phosphine] palladium (0), bis (triphenyl) Phosphine) palladium (II) chloride, bis (triphenylphosphine) palladium (II) acetate, and the like.
  • scavengers for the aryl group examples include dimedone, formic acid, acetic acid, ammonium formate, sodium formate, sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, pyrrolidine, piperidine, Tributyltin hydride and the like can be mentioned.
  • the reaction is performed using 0.01 to p.5 mol of the catalyst and 1 to 6 mol of the nucleophile per 1 mol of the compound of the general formula [IVa], [IVb] or [IVc], and is 10 to 50. It is carried out in a temperature range of C, preferably in a temperature range of 0 to 30 e C, and is usually completed in 0.5 to 3 hours.
  • the protecting group for the hydroxyl group and the Z or imino group is 0-nitrobenzyloxycarbonyl group
  • the protecting group for the carboxyl group is o-nitrobenzyl group.
  • the protecting group can be removed by a photoreaction (Amit, etc.), The Journal of Organic Chemistry (J. Org. Chem.), 39, pp. 192-196 (1974)].
  • the compound of the general formula [I] is subjected to a usual treatment method, for example, column chromatography using silica gel or an adsorption resin, or lyophilization or crystallization.
  • a usual treatment method for example, column chromatography using silica gel or an adsorption resin, or lyophilization or crystallization.
  • the compound can be isolated.
  • the protecting group for the carboxyl group at the 3-position of the compound represented by the general formula [IVa], [IVb] or [IVc] may be a lower alkanoyloxyalkyl group such as an acetoxymethyl group or a bivaloyloxymethyl group; When it is a lower alkoxycarbonyloxyalkyl group such as 1- (isopropoxycarbonyloxy) ethyl group or 11- (cyclohexyloxycarbonyloxy) ethyl group, for example, methoxymethyl group, indanyl group, phthalidyl group, etc. Since such esters are physiologically hydrolyzed in vivo, they can be directly converted into human or Can be administered to animals.
  • the compound of the general formula [I] can be converted into a pharmaceutically acceptable salt or ester by a conventional method.
  • R 1 is a hydrogen atom
  • the starting material represented by the general formula [ ⁇ ] can be obtained by the method of Salzmann et al. [J. Am. Chem. Soc. Vol. 102, pp. 6161-6163 (1981)]; when R 'is a methyl group, the method of Shih et al. [Heterocycles. Vol. 21, pp. 29-40 (1984) Year)] or a method equivalent thereto.
  • R ′ represents a hydrogen atom or a lower alkyl group
  • R 30 represents a hydrogen atom or a hydroxyl-protecting group
  • R 2 ° represents a hydrogen atom or a carboxyl-protecting group.
  • R 4 ° represents a hydrogen atom, a protecting group for an imino group, a formyl group or an optionally substituted lower alkyl group, a lower alkanoyl group or a lower alkylsulfonyl group, and R 6 and R 7 are the same or different.
  • M is 0 or 1]
  • R 1 , R 20 .R 30 .R 4 °, R 6 and R m have the above-mentioned meanings].
  • the reaction is carried out in a temperature range of -40 to 50 ° C, preferably -20 to 20 ° C, and is usually quantitatively completed in 0.5 to 36 hours.
  • R 1 is a hydrogen atom or a lower alkyl group
  • R 2 is a hydrogen atom, an ester residue or an alkali metal
  • R 4 is a hydrogen atom, a formyl group or an optionally substituted lower alkyl group, a lower alkyl group.
  • An alkanoyl group or a lower alkylsulfonyl group, R 6 and R 7 are the same or different and each represents an oxo group or a thioxo group, and m represents 0 or 1.].
  • the compounds of the present invention have strong antibacterial activity against various gram-positive and gram-negative bacteria.
  • the in vitro antibacterial activity against bacteria was measured by the following agar plate dilution method [The standard method of the Japan Society for Chemotherapy: Chemotherapy, Vol. 29, 76-79 (1981)].
  • One platinum loop (each inoculum: 10 e CFUZml) of each test strain cultured overnight in Mueller Hinton broth was inoculated into Muller Hinton broth (MH agar).
  • This medium contained the compound of the present invention at each concentration. After culturing at 37 ° C for 16 hours, the minimum growth inhibitory concentration (MIC: g / ml) was measured.
  • Example 11 As a comparative compound, Example 11 in which R 1 of S—R 1 is a pyrrolidinyl group, as disclosed in Japanese Patent Application Laid-Open No. 2-49783, cited in the above prior art, is described. And the compound of Example 10 was synthesized and measured as the compounds of Reference Example 1 and Reference Example 2, respectively.
  • the compounds of the present invention exhibited better antibacterial activity than the compounds described in Reference Examples.
  • the compound of the present invention exhibits excellent antibacterial activity because of the structural feature of the compound of the present invention, that is, the substituent at the 2-position of the kar 'and' venem skeletons. It is completely unexpected and was first clarified by the present invention.
  • the compound of the present invention is a compound in which central nervous symptoms and nephrotoxicity are remarkably improved as compared with imidenem.
  • the compounds of the present invention are extremely stable with respect to DHP-I, and have excellent physicochemical stability and solubility in water, although they differ depending on each compound.
  • Escherichia coli ML4707 was cultured at 37 ° C. for 18 hours, suspended in saline, and inoculated intraperitoneally into mice [1.0 ⁇ 10 7 cells / mouse (25LDso)].
  • the compound of the present invention and cefaclor as a control compound were each suspended in a 0.5% strength ruboxymethylcellulose solution, and 1 hour after inoculation of the bacteria.
  • 20 mg / kg and 2 mgZkg were orally administered to ICR mice (4 weeks old, male, body weight 20 g, 10 mice per group), respectively, and the number of surviving mice after 5 days was observed.
  • the compound of the present invention showed an excellent infection control effect by oral administration as compared with the control compound.
  • the compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration and external administration.
  • a pharmaceutical preparation suitable for parenteral administration, oral administration and external administration.
  • the pharmaceutical preparation include liquid preparations such as injections, syrups and emulsions; solid preparations such as tablets, capsules and granules; and external preparations such as ointments and suppositories.
  • These preparations may optionally contain commonly used additives such as bases, auxiliaries, stabilizers, wetting agents, emulsifiers, absorption enhancers, surfactants and the like.
  • additives examples include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn flour, magnesium stearate, and talc.
  • the dosage depends on the patient's condition, body weight, age, sex, dosage form, number of administrations, etc., but the preferred daily dose for adults is usually about 5 to 50 mg / kg of the active ingredient, and the preferred daily dose for children is It is preferably in the range of about 5 to 25 mg Zkg, administered once or several times a day.
  • the compound of the present invention may optionally contain cilastatin [(Z) -7- (L-amino-2-carboxyethylthio) -12- (2,2-dimethylcyclopropanecarboxamide) -12-sodium heptenoate [JP-A-56-81518, Europe No. 28,778, Journal of the Medicinal Chemistry, CI. Med. Chem.), 30, 3074 (1987)] and the like, and can be administered in combination with a DHP-I inhibitor.
  • the NMR spectrum is determined by using tetramethylsilane (TMS) as the internal standard when measuring with heavy dimethyl sulfoxide or heavy chloroform solution, and using 2,2 as the internal standard when measuring with heavy aqueous solution.
  • TMS tetramethylsilane
  • DSS 2-Dimethyl-2-silapentane-1-sulfonate
  • CDsOD heavy methanol
  • Step 1 In a stream of nitrogen, under ice-cooling, to 30 ml of a methanol solution of 248 mg (1.43 mmol) of 5-acetylthio-1-piberidinone obtained in Reference Example 3 was added 1.44 ml of a 1N aqueous sodium hydroxide solution. Stirred for minutes. After 1.56 ml of 1N hydrochloric acid was added to the reaction solution at room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in chloroform. The chloroform solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of 5-mercapto-12-piperidinone.
  • Step 2 530 mg (ll mmol) of the above compound was dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of 0.5M 4-morpholinepropanesulfonic acid buffer (pH 7), and 320 mg of 10% palladium-carbon catalyst was added to the reaction solution. Hydrogenation was performed at room temperature under normal pressure for 2 hours. After removing the catalyst and concentrating the filtrate under reduced pressure, the obtained residue is purified by reversed-phase ram chromatography (LC-SORB TM SP-B-ODS; water to 10% methanol).
  • LC-SORB TM SP-B-ODS reversed-phase ram chromatography
  • Step 1 p-Nitrobenzinole (1R5R, 6S) — 2-Diphenylphosphoryloxy 6 — [(1R) 1-1H-Droxityl] -1 Monomethyl 1 1—Canolebapene 2—Emu 3—Caprolboxylate 552mg (0.929 mmol) in 18 ml of dry acetonitrile in a nitrogen stream under ice cooling under ice cooling with 0.39 ml (2.24 mmol) of ⁇ , ⁇ -dipropylpropylethylamine obtained in Reference Example 4. 364 mg (1.23 mmol) of 2-thiopiperidinone trifluoromethanesulfonate was added, and the reaction solution was stirred at the same temperature overnight.
  • Step 2 306 mg (0.622 mmol) of the above compound was dissolved in a mixture of 9 ml of tetrahydrofuran and 9 ml of 0.5M 4-morpholinepropanesulfonic acid buffer (pH 7), and 184 mg of 10% palladium-carbon catalyst was added to the reaction solution. Hydrogenation was performed at room temperature under normal pressure for 2 hours. The catalyst was removed by filtration, and the residue was concentrated under reduced pressure.
  • Step 1 In the same manner as in Step 1 of Example 2, 70 mg (0.53 arm ol) of (5R) -5-mercapto-1-piperidinone obtained in Reference Example 5 was used to obtain p-nitrobenzyl (1R, 5S, 6S) — 6— [(1R) 1-1-hydroxyethyl] 1-1-methyl-2 -— [(3R) 16-year-old pipepiperidine 1-3-ylthio] 1-11 A rate of 180 mg (yield: 70.9%) was obtained.
  • Step 2 In the same manner as in Step 1 of Example 1, 96.0 mg (yield: 70.0%) of the title compound was obtained using 180 mg (0.38 mmol) of the above compound.
  • the results of HPLC analysis, IR, NMR, and UV spectrum of this compound were consistent with those of the diastereomer A of the title compound of Example 1 (highly polar compound).
  • Step 1 In the same manner as in Step 1 of Example 2, 80 mg (0.54 mmol) of (5R) -5-mercapto-12-tipopiberidinone obtained in Reference Example 6 was used to prepare p-nitropentenyl (1R, 5S, 6S) —6— [(1R) -1-Hydroxyethyl] —1-Methyl-2 — [(3R) -1-6-Toxopiperidine-1-3-ylthio] -11-Luba pen—2— Thus, 250 mg (yield: 93.6%) of pale yellow oily substance of m-3-carboxylate was obtained.
  • Step 1 In the same manner as in Step 1 of Example 2, 320 mg (2.23 mmol) of 4-mercapto 2-piberidinone obtained in Reference Example 7 was used to prepare p-nitrobenzyl (1R5S.6S) (1R) -1-Hydroxityl] -1-methyl-2- (2-oxopiperidine-1-4-ylthio) 1-1-l-rubapene-2-emum 3-carboxylate diastereomer a pale yellow oil 400 mg (yield: 37.8) %) And 157 mg (yield: 14.9%) of white powder of diastereomer b.
  • Step 2 In the same manner as in Step 2 of Example 1, using 380 mg (0.80 mmol) of diastereomer a of the above compound, 175 mg (yield: 60.5%) of diastereomer A of the title compound (highly polar compound) was obtained.
  • 380 mg (0.80 mmol) of diastereomer a of the above compound 175 mg (yield: 60.5%) of diastereomer A of the title compound (highly polar compound) was obtained.
  • Step 3 In the same manner as in Step 2 of Example 1, 156 mg (0.33 mmol) of diastereomer b of the above compound was used to obtain 86.8 mg (yield: 73.0%) of diastereomer B of the title compound (low-polar compound). .
  • Step 1 In the same manner as in Step 1 of Example 2, 290 mg (1.76 marol) of 4-mercapto-2-thiopiperidinone obtained in Reference Example 8 was used to obtain p-nitrobenzene (1R.5S.6S ) —6— [(1R)-1—Hydroxityl] — 1-Methyl-1- (2-Thioxopiperidine—4-ylthio) 1—1 Lubapen—2-Emu 3—Carboxylate Diastereomer a (Low polarity compound) ) Was obtained, and 370 mg (yield: 42.8%) of a pale yellow oil of diastereomer b (a highly polar compound) was obtained.
  • Step 3 In the same manner as in Step 2 of Example 1, using diastereomer b of the above compound (highly polar compound) 360 mg (0.73 mmol), diastereomer B of the title compound (low polar compound) 74.1 mg (yield: 26.7 mg) %).
  • Step 1 In the same manner as in Step 1 of Example 2, using 290 mg (2.21 mmol) of 3-merbutyrate-2-piberidinone obtained in Reference Example 9, p-nitrobenzil (1R.5S.6S) -6- [(1R) -1-Hydroxityl] — 1-Methyl-2- (2-oxopiperidine-1-3-ylthio) -11-Lubapen-1-2-Em—3-Carboxylate diastereomer a (high 480 mg (yield: 39.0%) of a pale yellow oily substance (polar compound) and 200 mg (yield: 16.3%) of diastereomer b (low polar compound) as a white powder.
  • Step 2 In the same manner as in Step 2 of Example 1, 460 mg (0.97 mmol) of diastereomer a (highly polar compound) of the above compound was used, and 261 mg (yield: 74.6%) of diastereomer A of the title compound (highly polar compound) ).
  • Step 3 In the same manner as in Step 2 of Example 1, diastereomer B of the title compound (low-polar compound) was used in an amount of 91.4 mg (yield: 66.6) using 180 mg (0.38 mmol) of diastereomer b of the above compound (low-polar compound). %).
  • Step 1 In the same manner as in Step 1 of Example 2, p-nitrobenzil (580 mg (1.95 mmol) of 3-mercapto-2-thiopiberidinone 'trifluoromethanesulfonate obtained in Reference Example 10 was used to obtain p-nitrobenzil ( 1R.5S.6S) — 6— [(1R) — 1-Hydroxitytil] 1-methyl-2--1 (2-Toxopiperidine 1-3-ylchio) 1—1-Lubapen 1—2-emu 3—Carboxylate diastereomer As a result, 580 mg (yield: 47.1%) of a pale yellow oily substance (a highly polar compound) and 390 mg (yield: 31.7%) of a pale yellow oily substance of diastereomer b (a low polar compound) were obtained.
  • Step 2 In the same manner as in Step 2 of Example 1, 550 mg (1.12 mmol) of diastereomer a (highly polar compound) of the above compound was used, and 87.2 mg (yield: 20.6 mg) of diastereomer A of the title compound (highly polar compound) %) And 123 mg of diastereomer B (low-polarity compound) (yield: 29.1%).
  • Step 3 In the same manner as in Step 2 of Example 1, 370 mg (0.75 mmol) of the diastereomer b (low-polarity compound) of the above compound was used to obtain 42.7 mg (yield) of diastereomer A of the title compound (highly polar compound). : 15.0%) and 74.5 mg (yield: 26.4%) of diastereomer B (low-polarity compound).
  • Step 1 To an acetone solution (2.5 ml) of 83.2 mg (0.55 mmol) of bivaloyloxymethyl chloride was added 91.1 mg (0.61 mmol) of sodium iodide. In a nitrogen gas stream, 60 after heating for 30 minutes at e C, the reaction solution was ether residue obtained by concentration under reduced pressure was added to and concentration of the insoluble matter was ⁇ , the ⁇ under reduced pressure Bibaroiruo Obtained xymethylazide.
  • the reaction solution was diluted with ethyl acetate, and the organic layer was washed successively with water, saturated sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the resulting residue was subjected to silica gel column chromatography (Wakogel TM C-300 black form-methanol) to obtain 67.5 mg (yield: 53.6%) of diastereomer a of the title compound as a white powder.
  • Step 2 In the same manner as in the previous step, using 0 mg (0.22 mmol) of diastereomer B (low-polarity compound) as the starting material, 41.7 mg (yield: 41.5%) of a colorless oil of diastereomer b of the title compound was obtained. .
  • Step 1 In the same manner as in Example 9, the sodium (1R, 5S, 6S) 16-[(1R) -11-hydroxyethyl] -11-methyl-2- (2-thio) obtained in Example 6 was obtained.
  • Step 2 In the same manner as in Example 9, 70 mg (0.19 mmol) of diastereomer B (low polar compound) as the starting material was used, and 43.2 mg (yield: 49.5%) of pale yellow oil of diastereomer b of the title compound I got
  • Step 1 In the same manner as in Example 9, the sodium (1R, 5S, 6S) 16-[(1R) -11-hydroxyethyl] -11-methyl-2- (2-oxo) obtained in Example 7 was obtained. Sopiperidine-l-ylthiol) l-l-lappene-l- 2-emu 3-carboxylate diastereomer A (highly polar compound) lOOmg (0.28mmol) 61.1 mg (yield: 48.7%) of white powder of diastereomer a of the title compound was obtained.
  • Step 2 In the same manner as in Example 9, 91.6 mg (yield: 72.8%) of diastereomer b of the title compound was obtained using lOOmg (0.28 mmol) of diastereomer B (low polar compound) as the starting material.
  • lOOmg (0.28 mmol
  • diastereomer B low polar compound
  • Step 1 In the same manner as in Step 1 of Example 2, using 506 mg (1.71 mmol) of (5R) —1-methyl-5-mercapto-1-2-piperidinone trifluoromethanesulfonate obtained in Reference Example 11 , ⁇ -Nitrobenzil (1R, 5S, 6S) — 6 — [(1R) -1-hydroxyethyl) 1-1-methyl-2-[(3R) —1-methyl-6-year-old oxopiperidine-1-3-ylthio] L.Og (79.7% yield) was obtained as a pale yellow oily substance.
  • Step 2 In the same manner as in Step 2 of Example 1, 460 mg (yield 59.8%) of the title compound was obtained using the above compound l.Og (2.04 mmol).
  • Example 9 sodium (1R, 5S, 6S) -6-[(1R) -11-hydroxyxethyl] -1-methyl-1-2-((3R) -11-methyl) obtained in Example 14 was obtained. 10-mg (yield: 82.0%) of the title compound was obtained as a white powder by using l-lmg (0.27 mmol) of 6-year-old oxopiperidine-l-3-ylthiol-l-lappen-l-l-emu 3-l-lupoxylate.
  • Step 1 In the same manner as in Step 1 of Example 2, 1.5 g of the crude product containing (5R) -1-carbamoylmethyl-5-mercapto-1-piperidinone * trifluoromethanesulfonate obtained in Reference Example 12 was used. Using p-Nitrobenzil (1R.5S, 6S)-2-[(3R) 1 1 1 force rubamoylmethyl-6-oxopiperidine-1 3 -ylthio]-6-[(1R) —1 1-Methyl-1-carbapene 2-emmu-3-carboquinate 480 mg (yield 32.3%) as yellow oil Obtained as material.
  • Step 2 In the same manner as in Step 1 of Example 1, 460 mg (2.04 mmol) of the above compound was used to obtain 264.5 mg (yield: 73.0%) of the title compound.
  • Example 9 sodium (1R.5S.6S) -2-([3R) -l-lumbamoylmethyl-6-year-old oxopiperidine-13-ylthio] obtained in Example 16 was obtained. 6-[(1R) -1-1-hydroxyethyl] -1-methyl-l-lappen-l-heme-3-carboxylate Using lOlmg (0.24mmol), 57.8 mg (yield 47.1%) of the title compound was white. Obtained as a powder.
  • Step 1 In the same manner as in Step 1 of Example 2, (5R) -1- (2-hydroxyethyl) -15-mercapto-12-piperidinone obtained in Reference Example 13. Trifluoromethan sulfonate 480 mg (1.48 mmol) Using p-Nitrobenzil (1R5S, 6S) -1 6-[(1R) -1-hydroxyethyl] 1-2-[(3R) -1- (2-Hydroxyshetyl) 1-6-oxo 540 mg (yield 64.7%) of piperidine-l-ylthio] -l-methyl-l-l-lappene-l- 2-emu-3-carboxylate was obtained as a yellow oily substance.
  • Step 2 of Example 1 310.9 mg (yield: 73.6%) of the title compound was obtained using 540 mg (1.04 mmol) of the above compound.
  • Example 9 sodium (1R.5S.6S) -6-[(1R) -1-hydroxyethyl) -12-[(3R) -1- (2-hydroxyethyl) obtained in Example 18 was obtained.
  • Step 1 Under a nitrogen atmosphere, 4.3 ml (60.0 mmol) of acetyl chloride was added to a solution of 3.4 g (20.0 mmol) of 3-acetylthiosuccinimide obtained in Reference Example 14 in 50 ml of dry ethanol, followed by heating under reflux for 2 hours.
  • Step 2 To a solution of 2.1 g (4.42 mmol) of the above compound in 60 ml of tetrahydrofuran and 60 ml of distilled water, 560 mg (6.63 mmol) of sodium hydrogen carbonate and 700 mg of 10% palladium-carbon catalyst were added, and the mixture was stirred at room temperature under a normal pressure hydrogen stream. The mixture was stirred for 2 hours. After removing the catalyst, the solvent was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase column chromatography (Chemco LC-SORB TM SP—B-ODS.7) and lyophilized. Thus, 206 mg (13% yield) of a 1: 2 mixture of diastereomer A (highly polar compound) and diastereomer B (lowly polar compound) of the title compound was obtained.
  • Step 2 Using 1.5 g of the compound, 232 mg (yield 20%) of a 4: 1 mixture of diastereomer A (highly polar compound) and diastereomer B (lowly polar compound) of the title compound in the same manner as in Step 2 of Example 20 ).
  • Step 1 37 ml of trifluoroacetic acid was added to a solution of 1.96 g (7.4 mmol) of 2,6-dioxo-3- (p-methoxybenzyl) thiopiperidine obtained in Reference Example 16 in 4.0 ml of anisol at room temperature, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure at 60 eC .
  • Step 2 In the same manner as in Step 2 of Example 20 using 1.6 g (3.27 mmol) of the above compound, diastereomer A of the title compound (highly polar compound) 6.97 mg (yield 5.7%) and diastereomer B (lowly polar compound) 456.7 mg (37% yield).
  • diastereomer A of the title compound (highly polar compound) 6.97 mg (yield 5.7%) and diastereomer B (lowly polar compound) 456.7 mg (37% yield).
  • Step 1 Using 740 mg (2.65 mmol) of 2,6-dioxo-3- (p-methoxybenzyl) thio-1-methylbiperidine obtained in Reference Example 17, P was used in the same manner as in Step 1 of Example 23.
  • Step 2 An approximately 2: 3 mixture of diastereomer A (highly polar compound) and diastereomer B (lowly polar compound) of the title compound in the same manner as in Step 2 of Example 20 using the compound l.Og (2.00 mmol) 4690 ( Yield 60%).
  • Step 1 The same method as in Step 1 of Example 23 using 770 mg (2.61 mmol) of 3- (p-methoxybenzyl) thio-1-methyl-2-oxo-1-6-thiopipiperidine obtained in Reference Example 18 And p-Nitrobenzil (1R, 5S, 6S) -6-[(1R) —1-hydroxyethyl] -1-methyl-2- (1-methyl-2-oxo-6-thioxopiperidine-1 3 960 mg (yield 71%) of thio-l-l-l-bapene-2-em-3-carboxylate were obtained.
  • Step 2 An approximately 4: 3 mixture of diastereomer A (highly polar compound) and diastereomer B (lowly polar compound) of the title compound was obtained in the same manner as in Step 2 of Example 20 using 960 mg (1.85 mmol) of the above compound. Rate of 8.7%).
  • Example 20 Sodium (1R, 5S, 6S) obtained in Example 20 in the same manner as in Example 9 2- (2,5-di, oxopyrrolidine-1-yl) thio 6-[(1R) -1-hydroxyethyl ]-Title using 80 mg (0.22 mmol) of a 1: 2 mixture of diastereomer A (highly polar compound) and diastereomer B (low polar compound) of 1-methyl-1 monolubapen-2-hem-3-carboxylate Compound 28. Img (yield 28 ° / o) was obtained.
  • Example 23 Sodium (1R.5S.6S) obtained in Example 23 in the same manner as in Example 9; 2- (2,6-dioxopiperidine-13-yl) thio-6-[(1R) -11-hydroxy)
  • the title compound (54.0 mg, yield 54%) was obtained using 80 mg (0.21 mmol) of diastereomer B (a low-polar compound) of 1-methyl-1-1-l-lappen-12-em-3-carboxylate. Obtained.
  • Example 9 the sodium (1R, 5S, 6S) -2- (2,6-dioxo-1-methylbiperidine-13-yl) thio 6- [1] obtained in Example 24 was obtained.
  • Approx. 2 3 mixture of diastereomer A (highly polar compound) and diastereomer B (low polar compound) of carboxylate 8011 ⁇ (0.20 mmol) to give 71.2 mg (yield 72%) of the title compound.
  • Example 9 sodium obtained in Example 25 (1R.5S.6S)-6- [(1R) 1-1-Hydroxyethyl] —1-Methyl-2- (1-Methyl-2-oxo-6-Toxopiperidin-1-3-yl) Thio 1-Lubapen-1 2-Emu 3-Carboxyle Using 81.0 mg (0.20 mmol) of a 4: 3 mixture of diastereomer A (highly polar compound) and diastereomer B (lowly polar compound), 37.8 mg (yield 38%) of the title compound was obtained.
  • the reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 248 mg (yield: 33.0%) of the title compound.
  • reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • the obtained residue is subjected to silica gel column chromatography (Wakoge C-300 Then, 680 mg (yield: 64,4%) of (5R) -1-methyl-5- (p-methoxybenzylthio) -2-piberidinone was obtained as a yellow oily substance.
  • reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • the resulting residue was subjected to gel chromatography on silica gel (Wakogel TM C-300, form-methanol in black mouth) to give (5R) — 1 rubamoyl methyl 5-— (p-methoxybenzyl) thio 2 — 810 mg (yield: 44.9%) of piberidinone was obtained.
  • reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography (Wakogel TM C-300 chromatoform-methanol) to give (5R) -111 [2- (2-tetrahydroviranyl) oxexetil] —5— (p— Methoxybenzyl) thio-2-piperidinone (990 mg, yield: 66.2%) was obtained as a yellow oily substance.
  • the compound of the present invention is a novel compound that has not been described in the literature, and is sensitive and has a particularly high antibacterial activity against resistant Gram-positive bacteria and Gram-negative bacteria including MRSA, excellent stability against / 3-lactamase and DHP-I, and Since it has safety to the central nervous system, it is useful as an antibacterial agent, and its ester form can be absorbed orally, and is expected to make a great contribution to the treatment of infectious diseases.

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Abstract

La présente invention concerne un nouveau composé représenté par la formule générale (I), un procédé de production de ce composé, et l'utilisation de ce composé comme agent antibactérien. Dans cette formule générale (I), R1 représente un hydrogène ou alkyle inférieur, R2 représente un hydrogène, un radical ester ou un métal alcalin, et R3 est un groupe représenté par l'une quelconque des formules générales (a), (b) ou (c) dans lesquelles R4 est un hydrogène, formyle, un alkyle inférieur éventuellement substitué, un alcanoyle inférieur éventuellement substitué ou alkylsulfonyle inférieur éventuellement substitué, R?5, R6 et R7¿ représentent chacun un oxo ou thioxo. Ce composé constitue avantageusement un agent antibactérien car il fait preuve d'une puissante activité antibactérienne contre les bactéries gram-positives et gram-négatives à MRSA et présente une très bonne résistance contre les β-lactamases et le DHD-1, ainsi qu'une bonne innocuité vis-à-vis du système nerveux central. Ses dérivés esters, qui sont administrables par voie perorale, devraient grandement contribuer au traitement des maladies infectieuses.
PCT/JP1995/001756 1994-09-06 1995-09-04 Nouveau derive de carbapenem WO1996007655A1 (fr)

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EP0826687A1 (fr) * 1996-08-16 1998-03-04 Suntory Limited Dérivés de carbapenem et agents antimicrobiens les contenant
WO2004035539A1 (fr) * 2002-10-18 2004-04-29 Meiji Seika Kaisha, Ltd. Procede destine a la fabrication de carbapenem et intermediaire utilise dans sa fabrication
US7662872B2 (en) 2005-10-11 2010-02-16 The Yokohama Rubber Co., Ltd. Salt of carboxylic acid containing N-substituted succinimide thio group and unvulcanized rubber composition containing the same
EP3737675A4 (fr) * 2018-01-12 2022-01-05 Kymera Therapeutics, Inc. Ligands crbn et leurs utilisations
US11679109B2 (en) 2019-12-23 2023-06-20 Kymera Therapeutics, Inc. SMARCA degraders and uses thereof
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
US11807636B2 (en) 2018-11-30 2023-11-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11897882B2 (en) 2018-07-06 2024-02-13 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
US11932624B2 (en) 2020-03-19 2024-03-19 Kymera Therapeutics, Inc. MDM2 degraders and uses thereof
US12077555B2 (en) 2019-04-05 2024-09-03 Kymera Therapeutics, Inc. STAT degraders and uses thereof
US12091411B2 (en) 2022-01-31 2024-09-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
US12150995B2 (en) 2020-12-30 2024-11-26 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12168057B2 (en) 2017-12-26 2024-12-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12171768B2 (en) 2021-02-15 2024-12-24 Kymera Therapeutics, Inc. IRAK4 degraders and uses thereof
US12187744B2 (en) 2021-10-29 2025-01-07 Kymera Therapeutics, Inc. IRAK4 degraders and synthesis thereof

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Publication number Priority date Publication date Assignee Title
EP0826687A1 (fr) * 1996-08-16 1998-03-04 Suntory Limited Dérivés de carbapenem et agents antimicrobiens les contenant
WO2004035539A1 (fr) * 2002-10-18 2004-04-29 Meiji Seika Kaisha, Ltd. Procede destine a la fabrication de carbapenem et intermediaire utilise dans sa fabrication
US7662872B2 (en) 2005-10-11 2010-02-16 The Yokohama Rubber Co., Ltd. Salt of carboxylic acid containing N-substituted succinimide thio group and unvulcanized rubber composition containing the same
US12168057B2 (en) 2017-12-26 2024-12-17 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
EP3737675A4 (fr) * 2018-01-12 2022-01-05 Kymera Therapeutics, Inc. Ligands crbn et leurs utilisations
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11932635B2 (en) 2018-01-12 2024-03-19 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US11897882B2 (en) 2018-07-06 2024-02-13 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
US11807636B2 (en) 2018-11-30 2023-11-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12258341B2 (en) 2018-11-30 2025-03-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US12077555B2 (en) 2019-04-05 2024-09-03 Kymera Therapeutics, Inc. STAT degraders and uses thereof
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