WO2001057041A1 - Composes 1-methylcarbapedem - Google Patents

Composes 1-methylcarbapedem Download PDF

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Publication number
WO2001057041A1
WO2001057041A1 PCT/JP2001/000664 JP0100664W WO0157041A1 WO 2001057041 A1 WO2001057041 A1 WO 2001057041A1 JP 0100664 W JP0100664 W JP 0100664W WO 0157041 A1 WO0157041 A1 WO 0157041A1
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group
compound
pharmacologically acceptable
methyl
acceptable salt
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PCT/JP2001/000664
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English (en)
Japanese (ja)
Inventor
Isao Kawamoto
Yasuo Shimoji
Satoshi Ohya
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Sankyo Company, Limited
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Priority to AU2001230550A priority Critical patent/AU2001230550A1/en
Publication of WO2001057041A1 publication Critical patent/WO2001057041A1/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
    • 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 1-methylcarbazanem compound having excellent antibacterial activity, a pharmacologically acceptable prodrug thereof, a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient (particularly an antibacterial agent). ), Compositions containing them for treating or preventing bacterial infections, their use for producing medicaments for treating or preventing bacterial infections, and methods for treating bacterial infections thereby; [Background] on prevention methods
  • the problem to be solved by the present invention is to have a more potent and balanced antibacterial activity against a wide range of bacteria including Pseudomonas aeruginosa showing such resistance, to have excellent pharmacokinetics, and
  • An object of the present invention is to provide a safe lenvanem derivative having low nephrotoxicity.
  • the inventors of the present invention have conducted various studies on 1-methylcarbapenem compounds over many years, and as a result, it has been found that compound (I) of the present invention having a strong basic group at the terminal is resistant to conventional anti-bacterial antifungal agents It has been found that it exhibits excellent antibacterial activity against a wide range of bacteria including these. Furthermore, the compound (I) of the present invention exhibits excellent pharmacokinetics such as a long half-life in blood and has low toxicity including nephrotoxicity, and thus is an antibacterial agent for treating and preventing (particularly treating) bacterial infections. The present inventors have found that they are effective as agents and completed the present invention.
  • the present invention has the general formula
  • R 1 represents a hydrogen atom or a _ 6 alkyl group
  • 13 ⁇ 4 2 and 1? 3 are independently a hydrogen atom or a ( ⁇ _ 6 alkyl group
  • R 4 represents a hydrogen atom or a _ 6 alkyl group
  • n 0, 1 or 2
  • A represents a ds alkylene group (the alkylene group may be via an oxygen atom or a sulfur atom, and may be substituted with an amino group, a hydroxyl group, or a phenyl group).
  • ⁇ ( ⁇ Alkyl group) '' in the definition of RR 2 , R 3 , R 4 , R 6 , R 7 and R 8 represents a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl Sohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl
  • Examples of the “group represented by the formula —NR 7 R 8 ” in the definition of R 6 include, for example, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino and dimethylamino. And getylamino groups, and preferably an amino or methylamino group.
  • the “ 8 alkylene group” in the definition of A represents a linear, branched or cyclic divalent saturated hydrocarbon group having 1 to 8 carbon atoms, for example, methylene (—CH 2 —), ethylene (— CH 2 CH 2- ), trimethylene (-CH 2 C3 ⁇ 4CH 2- ), tetramethylene (-CH 2 CH 2 C CH 2- ), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2- ), methyl methylene (- CH (C3 ⁇ 4) -) , propylene (-CH (CH 3) CH 2 -) and 1,4 - can be exemplified hexylene group, etc. cyclohexylene.
  • _ 8 alkylene group which may be through an oxygen atom or a sulfur atom, for example, the formula - CH 2 OCH 2 CH 2 - , -CH 2 CH 2 OCH 2 C -, - CH (CH 3) 0CH 2 CH 2 —, —CH 2 SCH 2 CH 2 —, —C C3 ⁇ 4SCH 2 CH 2 —, —CH (CH 3 ) SC CH 2 — and the like.
  • Cu alkylene group may be replaced by an amino group, a hydroxyl group or a phenyl group, and may be, for example, a group represented by the formula —CH 2 CH (OH) CH 2 —, —C3 ⁇ 4CH (NH 2 ) CH 2 — , -CH 2 CH (C Ph) CH 2- and the like.
  • R 1 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a methyl group.
  • R 2 and R 3 are preferably independently a hydrogen atom, a methyl group or an ethyl group, more preferably independently a hydrogen atom or a methyl group, and most preferably both are hydrogen atoms.
  • R 4 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.
  • R 5 is preferably a formimidoyl, an acetimidoyl or an amidino group, and more preferably an amidino group.
  • n is preferably 1 or 2.
  • A is preferably methylene (- (3 ⁇ 4-), methylmethylene (-CH (CH 3) -) , ethylene (- CH 2 CH 2 -) , trimethylene (-CH 2 CH 2 C -) or 2-arsenide Dorokishi Doo Rimechiren (- CH 2 CH (0H) CH 2 -) a group, more preferably methylene (-CH 2 -), methylmethylene (- CH (CH 3) - ) or ethylene (- CH 2 CH 2 -) group, and most methylene (- Oh in) group - CH 2.
  • “Pharmaceutically acceptable prodrug” of compound (I) means that the original compound or its salt is produced by cleavage in a human or animal body by a chemical or biological method such as hydrolysis. Esters and amide derivatives in which the carboxy, hydroxyl, and amino groups of compound (I) are protected by a group that forms (a group that forms a so-called prodrug). Such a derivative can be determined by orally or intravenously administering to an experimental animal such as a rat mouse, and then examining the body fluid of the animal to detect the original compound or its salt. More can be determined.
  • Examples of such a carboxyl group, hydroxyl group and amino group-protecting group include groups known in the field of medicinal chemistry, for example, an acyloxy C w alkyl group, a ( ⁇ 6 alkoxycarbonyloxy C 4 alkyl group, and phthalidyl. group, 5-methylcarbamoyl Lou 2 Okiso -1, 3-Jiokisoren - 4 Irumechiru group, Ashiru group, d_ 6 Arukokishikaru Boniru group, may be mentioned Amino d_ 6 Ashiru group.
  • alkoxycarbonyl d_ 4 alkyl group examples include, for example, t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (Isopropoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (cyclohexyloxycarbonyloxy) ethyl, and 1- (cyclopentyloxycarbonyloxy) ethyl group.
  • acyl group examples include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanol, hexadecanyl, octadecanol, and alkanol groups such as 20 alkanol, benzoyl and benzoyl.
  • alkanol groups such as 20 alkanol, benzoyl and benzoyl.
  • a 5- or 6-membered heterocarbonyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms such as C 6 _ 1 () arylcarbonyl group, pyridylcarbonyl and phenylcarbonyl.
  • Examples of the “d- 6 alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, octadecyl And a carbonyl group.
  • Examples of the "amino ( 6 acyl group)” include, for example, amino acid groups such as glycyl, alanyl, ⁇ -ryanyl, leucyl, isoleucyl, fenylalanil, histidyl, asparagyl, prolyl, and lysyl.
  • More preferred protecting groups among the above are 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetooxymethyl, pivaloyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl And 1- (isopropoxycarbonyloxy) ethyl or 1- (cyclohexyloxycarbonyloxy) ethyl group, which are preferably used as a protecting group for a carboxy group to form an ester derivative.
  • the compound (I) of the present invention and a pharmacologically acceptable prodrug thereof can form a "pharmacologically acceptable salt" as required.
  • “Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonic acid, ethanesulfonic acid Sulphonates such as, benzene sulphonic acid, ⁇ -toluene sulphonic acid; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbic acid Acid addition salts such as organic acids such as salts, lactates, gluconates and malates; amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, and aspartate; lithium salts Inorganic salts such as sodium, potassium, calcium, and magnesium salts; and ammonium, triethylamine, and diisopropylamine salts; Examples thereof include salts with an
  • the compound (1) of the present invention can be prepared by leaving in the air, freeze-drying from an aqueous solution, or recrystallization.
  • hydrates that may absorb water and become adsorbed water or form hydrates are also included in the present invention.
  • the compound (I) of the present invention absorbs certain other solvents and may form a solvate. Such solvates are also included in the present invention.
  • the compound of the present invention has an asymmetric carbon, various isomers exist. Each of them, or mixtures thereof in any proportion, are encompassed by the present invention.
  • Such a stereoisomer may be obtained by using a stereospecific raw material compound, or by synthesizing the compound according to the present invention using asymmetric synthesis or asymmetric induction, or by synthesizing the compound according to the present invention. If desired, it can be obtained by division using a conventional optical division method or separation method.
  • the isomer represented by the following formula (la) is most preferred.
  • A is methylene (-CH 2 -), methylmethylene (- CH (CH 3) - ) or ethylene A compound which is a (-CH 2 CH 2- ) group,
  • A is methylene (- CH 2 -) compound is a group.
  • R 1 force represents a hydrogen atom or a methyl group
  • R 2 and R 3 forces? Independently represents a hydrogen atom or a methyl group
  • R 4 represents a hydrogen atom or a methyl group
  • A is methylene (- CH 2 -), methylmethylene (- CH (CH 3) - ) or ethylene (- CH 2 CH 2 -) compound of the proximal.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 and R 3 independently represent a hydrogen atom or a methyl group
  • n Indicates force 1 or 2
  • a force, methylene (- CH 2 -) compound of the proximal A force, methylene (- CH 2 -) compound of the proximal.
  • R 1 represents a methyl group
  • R 2 and R 3 forces independently represent a hydrogen atom or a methyl group
  • R 5 represents an amidino group
  • n 1 or 2
  • A is a compound in which A represents a methylene (-CH 2- ) group.
  • the compound (I) of the present invention can be specifically exemplified in Table 1.
  • the compound (I) of the present invention is not limited to these exemplified compounds.
  • the 1-methylcarbanemine derivative having the general formula (I) of the present invention can be produced by the following method .
  • the 2-position side chain of the compound represented by the general formula (I) The substituent of the sulfur atom is represented by R, and the general formula (I) is abbreviated as follows.
  • the compound having the general formula (I) of the present invention can be produced according to the following method.
  • Method A is a method for producing a 1-methylcarbazanem derivative having the general formula (I) by condensing the compound of the general formula (II) and the compound of the general formula (III) and removing a protecting group as necessary. Is the law.
  • R 1Q represents a carboxyl protecting group
  • L represents a leaving group
  • Rp represents R which may have a protecting group
  • the "protective group for carboxy group" of R 10 for example methyl, Echiru, t - _ 4 alkyl group such as butyl; benzyl, 4-main Tokishibenjiru, 4 two Torobenjiru, 2-two preparative port base Njiru
  • a benzyl group optionally having such a substituent; a benzhydryl group; an aryl group optionally having a substituent at the 2-position such as aryl, 2-chloroaryl, and 2-methylaryl; 2,2,2-trichloro Halogenoethyl groups such as ethyl, 2,2-dibromoethyl and 2,2,2-tribromoethyl; and 2-trimethylsilylethyl groups
  • a “leaving group” is a group having the formula —OR 11 or —S (O) R 12, for example.
  • R 11 is methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, prono, Sulphonyl, isoprono, Alkanesulfonyl groups such as phenylsulfonyl and butanesulfonyl groups; phenylsulfonyl, tolylsulfonyl and naphthylsulfonyl.
  • R 12 is a methyl-, ethyl-, propyl-, isopropyl-like ( 4- alkyl group; fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl, difluoromethyl, difluoroethyl, dichloroethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, etc.
  • the substituent may be a halogen atom such as fluorine, chlorine, or bromine; a ( 4 alkyl group such as methyl, ethyl, propyl, or isopropyl; methoxy, ethoxy, or propoxy).
  • (C! _ 4 alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl ; Carbamoyl, mono- or di- (Ci- 4 alkyl) carbamoyl group; nitro group; hydroxyl group and cyano group. ).
  • the protecting group which Rp may have is a protecting group for a hydroxyl group, an amino group or an imino group.
  • the “protecting group for the hydroxyl group” contained in Rp includes, for example, tri-( ⁇ _ 4 alkylsilyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl; benzyloxycarbonyl, 4-nitrobenzyl) Optionally substituted benzyloxycarbonyl groups such as methoxycarbonyl, 4-chlorobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl (the substituent is nitro, methyl, chlorine or methyl) An aryloxycarbonyl group which may be substituted at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl.
  • position 2 such as trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl Is a tri-Cw alkylsilyl or chlorine-substituted ethyloxycarbonyl group, and is preferably a 4-dihydroxybenzyl or a 4-dibenzyloxycarbonyl group.
  • the “protecting group for amino or amino group” contained in Rp includes, for example, 2-substituted substituents such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, and 2-methylaryloxycarbonyl.
  • Aryloxycarbonyl group (the substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-cyclobenzyloxy
  • An optionally substituted benzyloxycarbonyl group such as carbonyl or 4-dihydroxybenzyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro) is mentioned.
  • it is an aryloxycarbonyl group or a 4-to-2 opening benzyloxycarbonyl group, more preferably a 4-to-2 opening benzyloxycarbonyl group. Is a group.
  • Method A comprises reacting a compound having the formula (II) with a compound having the formula (III) in the presence of a base to produce a compound having the formula (IV) (Step A1), and then removing the protecting group.
  • This is a method for producing a compound (I) by subjecting it to a reaction (Step A2). Further, the obtained compound (I) Can be converted as necessary into a pharmacologically acceptable salt or derivative by a method obvious to those skilled in the art.
  • each step will be described.
  • Step A1 is a step of producing a compound having the general formula (IV), in which the compound (II) is reacted with a mercaptan derivative having the general formula (III) in an inert solvent in the presence of a base.
  • L has the formula -. Is a group represented by OR 11, the compounds of formula (II) as the departure material, DH Shih et al., Produced by the method described in Heterocycles 21, 29 (1984) You. L has the formula - if S (0) Ru Oh a group represented by R 12, the starting compound ([pi) is prepared according to the process disclosed in JP 62- 30781 JP.
  • the mercaptan derivative having the general formula (III), which is a synthetic intermediate, can be produced by Method B described below.
  • L force ' is a group of the formula one OR 11
  • the solvent used is not particularly limited as long as it does not inhibit the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; and solvents such as acetonitrile.
  • Trils; amides such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide; esters such as ethyl acetate and methyl acetate; ethers such as getyl ether, tetrahydrofuran, and dioxane Preferred are acetonitrile, ⁇ , ⁇ -dimethylformamide and tetrahydrofuran, and more preferred is acetonitrile.
  • the base used in this step is not particularly limited as long as it is generally used in organic synthesis.
  • organic amines such as triethylamine and diisopropylethylamine; and lithium carbonate and carbonate
  • An inorganic base such as sodium can be mentioned, and preferred is diisopropylethylethylamine.
  • reaction temperature is not particularly limited, the reaction is usually carried out at ⁇ 20 ° C. to 40 ° C. (preferably ⁇ 10 ° C. to 20 ° C.).
  • the reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
  • tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfo Oxide, water and a mixed solvent thereof can be mentioned, and preferred is acetonitrile.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, particularly the -lactam ring.
  • Examples include diisopropylethylamine, triethylamine, N-methylpiperidine, and 4-dimethylamine.
  • Organic bases such as minopyridine; and inorganic bases such as potassium carbonate and sodium bicarbonate can be mentioned, and preferred is diisopropylpropylethylamine.
  • the reaction temperature is not particularly limited, but it is preferable to carry out the reaction at a relatively low temperature in order to suppress a side reaction, usually from 120 ° C to 40 ° C (preferably from 10 ° C to 20 ° C).
  • the reaction time mainly on the reaction temperature, the force depends on the type of reaction reagent?, It is usually for 15 minutes to 7 5 hours (preferably 3 0 minutes to 1 8 hours).
  • the target compound (IV) of this step is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography. Further, if desired, the target compound (IV) can be subjected to the next step without isolation.
  • Step A2 is a step of converting compound (IV) to compound (I) and is achieved by removing the protecting group of the compound.
  • the removal of the protecting group depends on the type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley & Sons, Inc.) 0
  • Protecting group R 10 A benzyl group or a benzhydryl group which may have a substituent such as benzyl or 4-nitrobenzyl, and a hydroxyl group, an amino group and an imino group contained in Rp.
  • the protecting group of the group may have a substituent such as benzyl or 4-nitrobenzyl, or may have a substituent such as benzyloxycarbonyl or 4-dibenzobenzyloxycarbonyl.
  • Benzyloxycarbonyl group which may be In the case of, the protecting group can be removed by reacting with hydrogen and a reducing agent using a catalytic reduction catalyst or metal sulfide.
  • Reducing agents include, for example, hydrogen and catalytic reduction catalysts such as palladium-carbon; and alkali metal sulfides such as sodium sulfide or lithium sulfide, preferably hydrogen and / or It is a carbon catalyst.
  • the solvent used is not particularly limited as long as it does not participate in the reaction, especially but not exclusively a force 5 ', preferably alcohols such as methanol, ethanol; as tetrahydrofuran, ethers such as di-O-hexane; or of It is a mixed solvent of an organic solvent and water.
  • the reaction temperature is usually from 0 ° C to 50 ° C (preferably from 10 ° C to 40 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent, usually from 5 minutes to 12 hours. Time (preferably 30 minutes to 4 hours).
  • the protecting group R 10 is Ariru, 2-chloroallyl, 2 - if a 2-position may Ariru group optionally substituted as Mechiruariru, and hydroxyl group contained in Rp, the amino group and I amino group
  • the protecting group is a substituted or unsubstituted aryloxycarbonyl group such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylaryloxycarbonyl, bis (triphenyl) Phosphine) palladium oxide-tributyltin hydride, tetrakis (triphenylphosphine), Palladiums such as radium-tributyltin hydride-trialkyltin hydrides or tetrakis (triphenylphosphine) palladium-2-ethylhexanoic acid or sodium 2-ethylhexanoate
  • the protective group can be removed by reacting with a deprotecting agent such as a
  • the deprotecting agent is preferably bis (triphenylphosphine) norradium chloride-tributyltin hydride or tetrakis (triphenylphosphine) no, “radium-2-ethylhexanoate”. It is.
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
  • examples thereof include halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and ethyl acetate.
  • reaction temperature is not particularly limited, it is generally carried out at a temperature of from 120 ° C to 100 ° C (preferably from 0 ° C to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours (preferably). 30 minutes to 12 hours.
  • the protecting group R 10 is a halogenoethyl group such as 2,2-dibromoethyl and 2,2,2-trichloroethyl
  • a metal such as zinc and an acid such as acetic acid or hydrochloric acid are used.
  • the protective group can be removed by reacting with a reducing agent. Suitable reducing agents are zinc and acetic acid.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and fatty acids such as acetic acid. And a mixed solvent of these organic solvents and water.
  • the reaction temperature is usually 0 ° C to 4 0 ° C (preferably 1 0 a to 3 0 ° to 0, while during the reaction depends on the type of the starting compound and the reducing agent forces?, Usually 5 minutes to 1 2 Time (preferably 30 minutes to 4 hours).
  • the target compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles from the reaction mixture and then distilling off the solvent.
  • the target compound (I) thus obtained can be purified, if necessary, by a conventional method such as a recrystallization method, preparative thin-layer chromatography, column chromatography and the like.
  • the 1-methylcarbapanem compound having the general formula (I) thus obtained can be used, if necessary, according to methods or techniques known in the field of medicinal chemistry, in particular, / 3-lactam antibiotics. It can be converted into a derivative such as an ester that undergoes hydrolysis in vivo as a pharmacologically acceptable prodrug, and can be purified as a pharmacologically acceptable salt. In addition, a pharmacologically acceptable prodrug is used in place of the carboxyl-protecting R 1 Q group as the starting material ( ⁇ ).
  • Compound (IV) can also be obtained using a compound protected with a desired protecting group (for example, a bivaloyloxymethyl group and the like).
  • a mercaptan derivative having the general formula (III), which is a synthetic intermediate, can be produced by the following Method B.
  • R 2 , R 3 , R 4 , n and A have the same meaning as described above.
  • R 5 p represents an optionally R 5 may have a protecting group
  • R 1 3 represents a protecting group of a mercapto group
  • R 1 is a protecting group
  • the protecting group for R 5 p has the same meaning as the protecting group for imino or amino which is the protecting group for Rp.
  • Protecting group of the mercapto group of R 1 3 represents a protecting group can be selectively removed while maintaining the protective group of R 5 p and R 1 p.
  • Such protecting groups include, for example, an optionally substituted benzyl group such as 4-methoxybenzyl; and an optionally substituted alkenyl group such as formyl, acetyl, chloroacetyl and trichloroacetyl. And is preferably 4-methoxybenzyl or acetyl.c
  • the protecting group for the amino group in Rip has the same meaning as the protecting group for the amino group which is the protecting group for Rp.
  • a compound having the formula (V) is produced by condensing a compound having the formula (VI) with a compound having the formula (VII) (Step B1), and then the protecting group for the mercapto group is removed.
  • This is a method for producing a compound having the general formula (III) by selective removal (Step B2).
  • each step will be described.
  • Step B1 is a step for producing a compound having the formula (V), in which the compound (VI) is reacted with the general formula (VII) with a condensing agent in an inert solvent, preferably in the presence of a base.
  • the compound (VI) can be produced by the method described in Isao Kawamoto, Synlett, pp. 575-577 (1995) or JP-A-2-3687, or a method analogous to the method described.
  • Compound (VII) can be produced by Method C described below.
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction.
  • halogenated hydrocarbons such as dichloromethane and dichloroethane
  • ketones such as acetone and 2-propanone
  • dimethyl sulfoxide and the like Sulfoxides amides such as N, N-dimethylformamide
  • nitriles such as acetonitrile
  • ethers such as ethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane.
  • sulfoxides or nitriles and more preferably dimethyl sulfoxide or acetonitrile.
  • the condensing agent to be used is not particularly limited as long as it is used for forming an amide bond in organic synthesis.
  • dicyclohexyl carbodiimide, diisopropyl pillcarbodiimide, N-ethyl- ⁇ '- Examples thereof include (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, and bivaloyl chloride, and preferably carbodiimidazole or pivaloyl chloride.
  • Examples of the base used include organic amines such as triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4- (dimethylamino) pyridine, diazabicycloundecene, and diazabicyclononene. And preferably with triethylamine or diisopropylethylamine.
  • the reaction temperature is usually from 0 ° C to 40 ° C (preferably from 10 ° C to 30 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent. 2 hours (preferably 30 minutes to 4 hours).
  • compound (V) is collected from the reaction mixture according to a conventional method.
  • it can be obtained by distilling off the solvent under reduced pressure, adding a water-immiscible solvent such as ethyl acetate to the residue and washing with water, and then distilling off the solvent.
  • the desired compound (V) thus obtained can be used, if necessary, in a conventional manner such as a recrystallization method, preparative thin-layer chromatography, It can be purified by, for example, column chromatography.
  • Step B1 is a step of producing compound (III), which is achieved by selectively removing a mercapto group-protecting group by reacting a deprotecting reagent in an inert solvent. .
  • the removal of the protecting group varies depending on the type, but is generally performed by a method used in the field of synthetic organic chemistry (Greene & Wuts, Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley). & Sons, ⁇ nc.).
  • protecting group R 1 3 force In the case of a benzyl group which may have a substituent such as 1,4-methoxybenzyl, the protecting group can be removed with an acid in an inert solvent.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction. Examples thereof include hydrocarbons such as benzene, toluene, and anisol; and halogenated hydrocarbons such as dichloromethane and dichloroethane. it can.
  • Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic acids such as P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid; carboxylic acids such as trifluoroacetic acid; A mixed acid can be mentioned, and a mixed acid of trifluoromethanesulfonic acid and trifluoroacetic acid is preferable.
  • mineral acids such as hydrochloric acid and sulfuric acid
  • sulfonic acids such as P-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid
  • carboxylic acids such as trifluoroacetic acid
  • a mixed acid can be mentioned, and a mixed acid of trifluoromethanesulfonic acid and trifluoroacetic acid is preferable.
  • the reaction temperature is usually 0 ° C to 50 ° C (preferably 0 ° C to room temperature), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 30 minutes to 12 hours (preferably 30 minutes to 4 hours).
  • the protecting group is an alkanoyl group such as R 13 -acetyl
  • the protecting group can be removed with a salt or base of a hydrazine compound in an inert solvent.
  • a salt of the hydrazine compound for example, hydrazine-acetic acid, N, N-dimethylhydrazine'acetic acid can be used, and hydrazine.acetic acid is preferable.
  • the solvent used in this case is not particularly limited as long as it does not inhibit the reaction.
  • halogenated hydrocarbons such as dichloromethane and dichloroethane
  • sulfoxides such as dimethyl sulfoxide
  • N, N-dimethyl Amides such as formamide and N, N-dimethylacetamide
  • amides are preferred.
  • the reaction temperature is not particularly limited, but is usually from o ° C to room temperature (preferably room temperature).
  • the reaction time varies depending on the solvent, the reaction temperature and the type of the reaction reagent, but is usually from 30 minutes to 24 hours. Time (preferably 1 to 8 hours).
  • the base used examples include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, and calcium hydroxide; and alkali metal alcoholates such as sodium methoxide. And preferably sodium methoxide.
  • the solvent used includes alcohols such as methanol and ethanol, and is preferably methanol.
  • reaction temperature is not particularly limited, it is generally ⁇ 10 ° C. to room temperature (preferably 0 ° C.).
  • the reaction time varies depending on the solvent, the reaction temperature and the type of the reaction reagent, but is usually 30 minutes. To 24 hours (preferably 1 to 8 hours).
  • the mercaptopyrrolidine compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure. The obtained compound can be purified, if necessary, by a conventional method such as a recrystallization method or column chromatography.
  • the mercaptopyrrolidine compound (III) obtained by this method can be used as a raw material in the above-mentioned Step A1 without isolation from the reaction solution.
  • R 2 , R 3 > RR 5 p, n and A have the same meaning as described above.
  • R 1 4 and R 1 5 represents a protecting group of the Amino group, L 1 represents a leaving group.
  • R 14 is a protecting group for an amino group and is a protecting group which can be selectively removed while maintaining R which is a protecting group for a secondary amino group.
  • a protecting group include an aryloxycarbonyl group which may be substituted at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl ( The substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, And an optionally substituted benzyloxycarbonyl group such as benzyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro).
  • R 15 is a protecting group for a secondary amino group in the ring, and is a protecting group that can be selectively removed while maintaining the protecting group for R 5 p.
  • protecting groups include, for example, 2,2,2, -trichloroethyloxycarbonyl, diphenylmethyloxycarbonyl, an optionally substituted alkyloxycarbonyl group such as t-butyloxycarbonyl (the substituent is a halogen atom or a phenyl group), and preferably t-butyloxycarbonyl .
  • Leaving group in L 1 is mainly not particularly limited as long as it varies depending on the type in R 5 R 6 used Oite usually organic synthetic chemistry, for example pyrazole, methyl Chio, main butoxy, amino, etc. And preferably pyrazole or methylthio.
  • the compound (X) is produced by condensing the compound (VIII) with the compound (IX) (Step C1), and the compound is selectively removed by removing the protecting group of the terminal amino group.
  • Preparation of (XI) (Step C2), reaction of compound (XI) with compound (XII) to prepare compound (XIII) (Step C3), and then protection of the secondary amino group in the ring This is a method for producing a compound (VII) by selectively removing a group (Step C4).
  • each step will be described.
  • Step C1 is a step of producing compound (X), and is accomplished by condensing compound (VIII) and compound (IX) in an inert solvent using a condensing agent.
  • Compound (VIII) can be commercially available or can be produced by a method obvious to those skilled in the art.
  • a precursor of compound (VIII), which is an amino acid having no protecting group can be obtained by the Gabriel synthesis method (see JWLOTO et al., J. Org. Chem., 47, pp. 2027-2033 (1982)).
  • compound (VIII) is obtained by introducing R 1 4 is a protecting group to Amino group by methods obvious to those skilled in the art (H.Kruse et, J.Org.Chem., 50, pp2792-2794 ( 1985 year )), An alkyl group can be introduced as R 4 if necessary by a method obvious to those skilled in the art.
  • Compound (IX) can also be commercially available or can be produced by a method obvious to those skilled in the art. For example, a cyclic dimine compound obtained by condensing an alkylenediamine derivative and an alkyldione compound is reduced (see D. Giardina et al., J. Med.
  • the inert solvent used is not particularly limited as long as it does not inhibit the reaction, but is preferably a dry solvent, for example, nitriles such as acetonitrile; hydrocarbons such as hexane, cyclohexane, benzene, and toluene. Dry solvents of halogenated hydrocarbons such as dichloromethane and dichloroethane; and preferred is dry acetate nitrile.
  • Examples of the condensing agent to be used include 1, ⁇ ⁇ -carbodildimidazole, dicyclohexylcarbodiimid, diisopropylcarbodiimid, and triphenylphosphine-carbon tetrachloride.
  • '-It is a carbonidimidazole.
  • reaction temperature is not particularly limited, it is usually 10 ° C to 40 ° C (preferably 10 ° C to room temperature ° C), and the reaction time depends on the type of the solvent, the reaction temperature and the type of the reaction reagent. Different forces Usually between 30 minutes and 24 hours (preferably between 1 and 9 hours).
  • compound (X) is collected from the reaction mixture according to a conventional method.
  • the solvent can be obtained by distilling off the solvent from the reaction mixture under reduced pressure, adding water-immiscible ethyl acetate and the like, washing with saturated saline and the like, and concentrating the organic solvent.
  • the obtained compound can be purified, if necessary, by a conventional method such as a recrystallization method and column chromatography.
  • Step C2 is a step of producing compound (XI).
  • R 14 which is a protecting group for a terminal amino group in the structure of compound (X) is selectively used. It is achieved by removing
  • solvent used examples include water; alcohols such as methanol and ethanol; hydrocarbons such as hexane, cyclohexane, benzene and toluene; or, ethyl ether, tetrahydrofuran, 1,4-dioxane, Ethers such as 2-dimethyloxetane are preferred, and alcohols are preferred.
  • the catalyst examples include palladium catalysts such as palladium carbon, palladium black, and palladium hydroxide; platinum catalysts such as platinum oxide; and rhodium alumina and the like. Rhodium catalysts and the like are preferable, and a palladium catalyst (particularly palladium carbon) is preferable.
  • Examples of the hydrogen donor include hydrogen gas, formic acid, sodium formate, ammonium formate, and the like. Hydrogen gas is preferred.
  • the reaction temperature for the hydrogenolysis is usually between 0 ° C and room temperature (preferably room temperature), and the reaction time depends on the protective groups that are mainly to be removed, usually between 10 minutes and 8 hours (preferably 30 to 2 hours).
  • compound (XI) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst and concentrating the filtrate under reduced pressure. The obtained compound (XI) can be used as a starting material in Step C3 without further purification.
  • Step C3 is a step of producing compound (XIII), and is accomplished by condensing compound (XI) and compound (XII) in a solvent.
  • Solvents used include, for example, halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; sulfoxides such as dimethyl sulfoxide; amides such as N, N-dimethylformamide; Nitriles such as acetonitrile; and ethers such as geethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxetane, and the like, preferably ethers, and more preferably ethers Is tetrahydrofuran.
  • halogenated hydrocarbons such as dichloromethane and dichloroethane
  • ketones such as acetone and 2-propanone
  • sulfoxides such as dimethyl sulfoxide
  • amides such as N, N-dimethylformamide
  • Nitriles such as acetonitrile
  • ethers such as geethylether,
  • the reaction temperature is usually from 0 ° C to room temperature (preferably room temperature), and the reaction time is mainly different depending on the reaction reagent.
  • the reaction time is usually 10 minutes to 8 hours (preferably 30 to 2 hours). It is.
  • compound (XIII) is collected from the reaction mixture according to a conventional method.
  • the solvent can be obtained by distilling off the solvent under reduced pressure, adding a solvent that does not mix with water such as ethyl acetate, and washing with an aqueous solvent.
  • the obtained compound (XIII) can be purified, if necessary, by a conventional method such as a recrystallization method or column chromatography.
  • Step C4 is a step of producing compound (VII), in which the protecting group for the secondary amino group in the ring of compound (XIII) is selectively removed by operating a deprotecting reagent in a solvent. Is achieved by
  • Solvents used are, for example, halogenated hydrocarbons such as dichloromethane and dichloroethane; ketones such as acetone and 2-propanone; esters such as ethyl acetate; alcohols such as methanol and ethanol; Examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane, and preferred is dichloromethane or ethyl acetate.
  • halogenated hydrocarbons such as dichloromethane and dichloroethane
  • ketones such as acetone and 2-propanone
  • esters such as ethyl acetate
  • alcohols such as methanol and ethanol
  • Examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxetane, and preferred is dichloromethane or ethyl acetate.
  • Examples of the deprotecting reagent used include mineral acids such as hydrochloric acid and sulfuric acid; sulfonic esters such as methanesulfonic acid ester, trifluoromethanesulfonic acid ester and toluenesulfonic acid ester; and carboxylic acids such as trifluoroacetic acid. Hydrochloric acid or trifluoroacetic acid is preferred, and hydrochloric acid is more preferred.
  • the reaction temperature is usually from o ° C to room temperature (preferably room temperature), and the reaction time is mainly from 10 minutes to 8 hours (preferably 30 to 2 hours), depending mainly on the reaction reagent. .
  • compound (VII) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure and washing with a solvent which does not dissolve the compound (VII) such as ethyl acetate or ether. The obtained compound (VII) can be used as a starting material in Step B1 without further purification.
  • the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof includes, for example, Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacteria, Serratia, Enterobacter, Shows strong and balanced antibacterial activity against a wide range of pathogens including gram-negative bacteria such as Pseudomonas aeruginosa and anaerobic bacteria such as Pacteroides fragilis, and is resistant to melopenem, a potent antibacterial agent. It also has excellent antibacterial activity against Pseudomonas aeruginosa.
  • the compound (I) of the present invention exhibits excellent pharmacokinetics such as a long half-life in blood, and has low renal toxicity. Therefore, the compound of the present invention having the general formula (I), a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is useful as a medicament, and is particularly useful for inhibiting bacterial infections caused by various pathogenic bacteria. It is useful as an antibacterial agent for treatment or prevention (preferably treatment).
  • Compound (I) or its pharmacologically acceptable prodrug or their pharmacologically acceptable When the salt to be used is used as a medicament, especially as an antibacterial agent, it is mixed with itself or an appropriate pharmacologically acceptable excipient, diluent, etc., to give tablets, capsules, granules, powders Alternatively, it can be administered orally with a syrup or the like or parenterally with an injection or the like.
  • These preparations may contain excipients (e.g., lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch, etc.).
  • excipients e.g., lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch, etc.
  • Starch derivatives crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium and other cellulosic derivatives; gum arabic; dextran; pullulan Silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate silicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; Sulphate derivatives such as sodium chloride, binders (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.); disintegrants (eg, the above-mentioned excipients; cross-force lumelo) Monosodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc;
  • the dosage may vary depending on the symptoms, age, etc. of the patient (warm-blooded animal, especially human).
  • the lower limit is 10 mg (preferably 50 mg) and the upper limit is 200 Omg (preferably).
  • the lower limit is 1 Omg (preferably lO Omg) and the upper limit is 3000 mg (preferably 200 Omg) per dose. It is desirable to administer 1 to 6 times daily depending on the symptoms.
  • reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 1 A solution of the compound (888 mg) obtained in item (2) (88 mg) in tetrahydrofuran (24 ml) -water (12 ml) was added with 7.5% palladium-carbon catalyst. (65 Omg), and hydrogen was absorbed for 2 hours while stirring at 30 ° C and normal pressure. The catalyst was filtered off, the filtrate was washed with ether, and concentrated under reduced pressure (20 ml). The residue was subjected to reverse phase silica gel column chromatography [Cosmo Seal 75 C18 PREP (Nacalai Tester)], and eluted with acetonitrile-water. The fractions containing the desired compound were combined, concentrated under reduced pressure, and lyophilized to give the title compound (153 mg) as a powder.
  • Infrared absorption vector (KBr) cm- 1 3314, 1771, 1740, 1710, 1645, 1609, 1554, 1522, 1494, 1433, 1378, 1347.
  • Example 2 A solution of the compound (0.79 g) obtained in (1) in tetrahydrofuran (20 ml) —water (12 ml) was added to a 7.5% palladium-carbon catalyst (0 ml). 79 g) was added, and hydrogen was absorbed for 2 hours while stirring at 35 ° C. and normal pressure. The catalyst was filtered off, the filtrate was washed with ether and concentrated under reduced pressure (2 Om 1). The residue was subjected to reversed-phase silica gel column chromatography “Cosmo Seal 75 C 1 8 PRE P (Naka G) and eluted with acetonitrile-water. The fractions containing the desired compound were combined, concentrated under reduced pressure, and lyophilized to give the title compound (256 mg) as a powder.
  • the reaction mixture was poured into a 1% aqueous sodium hydrogen carbonate solution, and the precipitated powder was collected by filtration, washed with water, and dissolved in ethyl acetate. Next, the ethyl acetate solution was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (5% methanol Z).
  • Example 3- (1) A solution of the compound (1.50 g) obtained in Example 3- (1) (1.50 g) in tetrahydrofuran (50 ml) -water (30 ml) was added with a 7.5% palladium-carbon catalyst (1.50 g). g), absorb hydrogen for 2 hours while stirring at 30 ° C and normal pressure, and treat in the same manner as in Example 11- (3) to give the title compound (38) as a pale yellow powder. 8 mg).
  • Example 4 A solution of the compound obtained in step (1) (1.68 g) in tetrahydrofuran (42 ml) -water (34 ml) was added to a solution of 7.5% palladium carbon catalyst (1. 68 g), absorb hydrogen for 2 hours while stirring at 35 ° C and normal pressure, and treat in the same manner as in Example 11- (2) to give a pale yellow powder. Compound (593 mg) was obtained.
  • Nuclear magnetic resonance scan Bae-vector (400MHz, D 2 0) 8 ppm: 1.07-1.38 (9H, m), 1.52-1.80 (1H, m), 2.20-2.47 (3H, m), 2.73-2.95 (2H, m), 3.00-3.73 (8H, m), 3.80-3.98 (1H, m), 4.03-4.47 (6H, m).
  • the reaction mixture was added to a 1 o / o aqueous sodium hydrogen carbonate solution, and the precipitated crystals were collected by filtration, washed with water, dissolved in THF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Infrared absorption spectrum (KBr) level cm- 1 3385, 1768, 1704, 1647, 1608, 1522, 1489, 1454, 1435, 1378, 1347, 1279, 1210, 1182, 1135, 1104.
  • Example 6 A solution of the compound (400 mg) obtained in (1) in tetrahydrofuran (20 ml) —water (20 ml) was added with a 20% palladium hydroxide carbon catalyst. (4 O Omg), absorb hydrogen for 4 hours while stirring at 35 ° C and normal pressure, and treat in the same manner as in Example 1-1 (2) to obtain a powdery title. The compound (122 mg) was obtained.
  • Infrared absorption spectrum (KBr) level cnr 1 3308, 1740, 1697, 1647, 1627, 1553, 1524, 1458, 1416, 1378, 1367, 1347.
  • the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue to dissolve the residue, and the mixture was washed with a saturated aqueous solution of citric acid, water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. It was concentrated.
  • Infrared absorption spectra (KBr) cm- 1 3430, 3316, 1737, 1710, 1649, 1609, 1584, 1552, 1521, 1497, 1430, 1407, 1378, 1347, 1323, 1286.
  • Infrared absorption vector (KBr) cm- 1 3432, 1739, 1684, 1646, 1552, 1523, 1495, 1464, 1431, 1378, 1347, 1325, 1310, 1286.
  • Infrared absorption vector (KBr) cm- 1 1750, 1689, 1655, 1615, 1588, 1525, 1482, 1424, 1390, 1367, 1347, 1301, 1239, 1166.
  • Infrared absorption spectrum (KBr) level cm 1 3371, 3309, 1748, 1686, 1649, 1575, 1521, 1481, 1432, 1347, 1290, 1262, 1180, 1109.
  • the antibacterial activity was measured by the agar plate dilution method, and the minimum inhibitory concentration (g / ml) for various pathogens was determined.
  • Tributosoyvion medium manufactured by Eiken Chemical Co., Ltd.
  • the following three bacterial species A to C were cultured at 37 ° C. for 18 to 20 hours.
  • the culture was adjusted to 10 7 cfu / ml and used as an inoculum.
  • Test method The test compound was adjusted to 2,000 with sterile distilled water, and this was further diluted by a factor of 2 to prepare each dilution solution. 1 ml of each of these dilution solutions was dispensed into a sterile plastic petri dish (manufactured by Terumo), and 9 ml of ordinary agar medium (manufactured by Eiken Chemical Co., Ltd.) was added and mixed to form a plate. One spot was inoculated with the inoculum using a nichrome wire loop. This was cultured at 37 ° C for 18 to 20 hours, and the minimum concentration of the drug that inhibited growth was defined as the minimum inhibitory concentration (g / ml). Table 2 shows the obtained results. In the table, specific bacteria A, B and C are as follows.
  • Infected mice (7 mice / group) were subcutaneously administered 0.1 ml of the compound to be studied (a solution of a 2-fold serial dilution from a maximum dose of 6.25 mgAg) dissolved in sterile physiological saline 0 and 4 hours later.
  • E E. coli 704 strains
  • Example 2 1.00 0.915 0.184 From Test Examples 1 and 2, the compounds of the present invention have excellent antibacterial activity against a wide range of bacteria including Pseudomonas aeruginosa, for which resistance is a problem. Became clear.
  • Test Example 3 Blood concentration half-life and blood concentration
  • the compound of Example 2 (10 mg / kg) was administered to mice (1 group, 3 animals, ddY male, manufactured by Japan SLC), rats (1 group, 3 animals, SD male, Charl Sliver), dogs (1 group) 3 animals, male, Nippon Agricultural Industry Co., Ltd.), Egret (3 animals per group, JW male, Funabashi Farm Co., Ltd.), Rinkuisaru (3 animals per group, male)
  • the drug concentration in plasma at each blood sampling time after administration was measured by the bioassay method described below.
  • Bioassay method The obtained plasma sample was diluted 2-fold with 500 mM M0PS (4-morpholinepropanesulfonic acid aqueous solution, pH 7) to obtain a measurement sample.
  • M0PS 4-morpholinepropanesulfonic acid aqueous solution, pH 7.
  • test bacteria Using Escherichia coli NIHJ and Antibiotic Medium 1 (manufactured by Diico) as medium, add about 30 samples for measurement to a paper disk (diameter 6 mm).
  • Table 4 shows the obtained pharmacokinetic parameters.
  • T 1/2 represents the plasma concentration half-life
  • AUC : NF represents the area under the plasma concentration-time curve extrapolated to infinity time.
  • Test Example 3 suggested that the compound of the present invention has a long half-life in blood concentration, so that its pharmacological effect is maintained for a long time, and it has been clarified that the compound can be an excellent drug.
  • Test Example 4 ⁇ Accumulation in the heron renal cortex
  • the powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 20 Omg per tablet. These tablets can be sugar-coated if necessary.
  • the 1-methylcarbazane compound having the above general formula (I), the pharmaceutically acceptable prodrug thereof, or the pharmaceutically acceptable salt thereof of the present invention has excellent antibacterial activity and has a half-life in blood. It shows excellent pharmacokinetics such as long term and low renal toxicity, so it is useful as a medicine (especially antibacterial agent).

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Abstract

L'invention se rapporte à des composés 1-Méthylcarbapedem représentés par la formule (I), qui présentent d'excellentes propriétés antimicrobiennes, à des promédicaments pharmacologiquement acceptables de ces composés ou à des sels pharmacologiquement acceptables de ces composés et promédicaments. Dans la formule (I), R1 est alkyle ou analogue; R2 et R3 sont chacun indépendamment hydrogène ou analogue; R4 est hydrogène ou analogue; R5 est un groupe ayant la formule: -C(=NH)R?6 (où R6¿ est amino ou analogue); n est égal à 0, 1 ou 2; et A est alcylène ou analogue.
PCT/JP2001/000664 2000-01-31 2001-01-31 Composes 1-methylcarbapedem WO2001057041A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000344A1 (fr) * 1991-06-20 1993-01-07 Daiichi Pharmaceutical Co., Ltd. Derive de carbapenem
JPH0616671A (ja) * 1992-06-30 1994-01-25 Dai Ichi Seiyaku Co Ltd カルバペネム誘導体の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000344A1 (fr) * 1991-06-20 1993-01-07 Daiichi Pharmaceutical Co., Ltd. Derive de carbapenem
JPH0616671A (ja) * 1992-06-30 1994-01-25 Dai Ichi Seiyaku Co Ltd カルバペネム誘導体の製造方法

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