WO2000034282A1 - Derives de 1-methylcarbapenem - Google Patents

Derives de 1-methylcarbapenem Download PDF

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Publication number
WO2000034282A1
WO2000034282A1 PCT/JP1999/006824 JP9906824W WO0034282A1 WO 2000034282 A1 WO2000034282 A1 WO 2000034282A1 JP 9906824 W JP9906824 W JP 9906824W WO 0034282 A1 WO0034282 A1 WO 0034282A1
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Prior art keywords
group
compound
carbon atoms
pyrrolidine
hydrogen atom
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PCT/JP1999/006824
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English (en)
Japanese (ja)
Inventor
Isao Kawamoto
Yasuo Shimoji
Katsuya Ishikawa
Katsuhiko Kojima
Satoshi Ohya
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Sankyo Company, Limited
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Priority to AU14155/00A priority Critical patent/AU1415500A/en
Publication of WO2000034282A1 publication Critical patent/WO2000034282A1/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-methylcarbazane compound having excellent antibacterial activity or a pharmacologically acceptable salt or derivative thereof, a pharmaceutical composition containing them as an active ingredient for preventing or treating bacterial infections, and bacterial infections.
  • the present invention relates to their use for the manufacture of a medicament for the prevention or treatment of diseases, a method for preventing or treating bacterial infections by administering a pharmacologically effective amount thereof to a warm-blooded animal, or a method for producing them.
  • Melipenem a 1-methylcarbanemene compound (US Pat. No. 5,122,604)
  • US Pat. No. 5,122,604 is a clinically useful antibacterial agent that is stable in vivo and effective against / 3-lactam resistant bacteria.
  • merodenem-resistant strains in Pseudomonas aeruginosa has been recognized. Therefore, there is a need for the development of a potent rubenem derivative having a more potent and balanced antibacterial activity against a wide range of bacteria, including Pseudomonas aeruginosa, which is resistant to merodenem.
  • the inventors have conducted various studies on 1-methylcarbanemene compounds over the years, and as a result, the compound (I) of the present invention has a stronger antibacterial activity than conventional 1-methylcarbanemene derivatives, and is more resistant to melanopenem. It was also found that Pseudomonas aeruginosa exhibiting excellent antibacterial activity. Furthermore, they have found that the compound (I) of the present invention has low toxicity and is effective as an antibacterial agent for treating or preventing (especially treating) bacterial infections, thereby completing the present invention.
  • JP-A-5-310740 and WO97 / 411123 each disclose a 1-methylcarbapenem compound having a structure similar to that of the present invention (where ⁇ is 0 in the general formula (I)). Or 1) is disclosed, but the compound (I) of the present invention exhibits excellent antibacterial activity as compared with the compound.
  • the present invention provides a compound represented by the general formula (I):
  • n 2, 3 or 4
  • R ′ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • R 2 is the same or different among n repeating units, and represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • R 4 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a substituent (the substituent is a hydroxyl group, a halogen atom, a carbamoyl group, a carbon atom having 1 to 4 carbon atoms)
  • R 3 and R 4 may be a group bonded to each other, and may be an alkylene group having 2 to 6 carbon atoms which may be via one oxygen atom, nitrogen atom or sulfur atom (the nitrogen atom is a carbon atom Which may be substituted with an alkyl group of 1 to 4).
  • an alkyl group having 1 to 4 carbon atoms in the definition of R ′, R 2 , R 3 , R 4 and R 5 is a linear or branched alkyl group having 1 to 4 carbon atoms.
  • Hot Examples thereof include a methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group, preferably a methyl or ethyl group, and more preferably a methyl group.
  • Halogen atom in the definition of R 4 can be, for example, a fluorine, chlorine or bromine atom, and is preferably a fluorine atom.
  • a carbamoyl group substituted with an alkyl group having 1 to 4 carbon atoms in the definition of R 4 includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, and getylcarbamoyl. Preferably, it is a methylcarbamoyl or dimethylcarbamoyl group.
  • a carbamoyloxy group substituted by an alkyl group having 1 to 4 carbon atoms is, for example, a methylcarbamoyloxy, an ethylcarbamoyloxy, a dimethylcarbamoyloxy, a getylcarbamoyloxy group. And preferably a methylcarbamoyloxy group or a dimethylcarbamoyloxy group.
  • the "amino group substituted by an alkyl group having 1 to 4 carbon atoms" in the definition of R 4 includes, for example, methylamino, ethylamino, dimethylamino, and ethylamino groups, and is preferably a methylamino or dimethylamino group. .
  • the “alkoxy group having 1 to 4 carbon atoms” in the definition of R 4 includes, for example, methoxy, ethoxy, propoxy and butoxy groups, and is preferably a methoxy group.
  • the “substituent for the“ alkyl group having 1 to 4 carbon atoms having a substituent ”” is preferably a hydroxyl group, a fluorine atom, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methoxy, , Amino, methylamino or dimethylamino groups.
  • alkyl group having 1 to 4 carbon atoms having a substituent examples include, for example, 2-hydroxyhydryl, 3-hydroxypropyl, 2-hydroxypropynole, and 2,3-dihydroxypropyl.
  • the “cycloalkyl group” in the definition of R 4 is a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group, preferably cyclopropyl or cyclopropyl. It is a cyclobutyl group, more preferably a cyclopropyl group.
  • alkylene group of the "alkylene group having 2 to 6 carbon atoms which may be linked through a sulfur atom” is a linear or branched alkylene group having 2 to 6 carbon atoms, for example, ethylene, propylene. , Trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene and the like.
  • the alkylene group may be via one oxygen atom, nitrogen atom or sulfur atom.
  • an alkylene group for example, ethyleneoxyethyl
  • the nitrogen atom which may be interposed in the alkylene group may be substituted with an alkyl group having 1 to 4 carbon atoms, and the alkyl group is preferably a methyl group.
  • alkylene group having 2 to 6 carbon atoms which may be through one oxygen atom, nitrogen atom or sulfur atom is, for example, ethylene, trimethylene, tetramethylene, pentamethylene, ethyleneoxetinole, ethylene
  • examples include thietinore, ethyleneaminoethyl, ethyleneaminopropyl, ethylene (methylamino) ethyl, ethylene (ethylamino) ethyl, ethylene (methylamino) propyl, and the like.
  • n is preferably 2 or 3, and more preferably 2.
  • R 1 is preferably a hydrogen atom, a methyl group or an ethyl group, and more preferably a hydrogen atom or a methyl group.
  • R 2 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 3 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably water It is an elemental atom or a methyl group, most preferably a hydrogen atom.
  • R 4 is particularly preferably a formimidoyl group, an acetimidoyl group or an amidino group.
  • R 4 is most preferably an amidino group.
  • the compound (I) of the present invention can be converted into a “pharmacologically acceptable salt or derivative” as necessary.
  • “Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; methanesulfonate, ethanesulfonate Sulfonates such as salts, benzenesulfonate, p-toluenesulfonate; oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, Acid addition salts such as organic acid salts such as ascorbate, lactate, dalconate, malate, amino acid salts such as glycine, lysine, arginine, olnitine, glutamate, and aspartate Or inorganic or ammonium salts such as lithium, sodium, potassium, calcium, and magnesium salts, triethylamine salts, diisopropyl Min salts, may be mentioned salts with organic bases such as Kis
  • the compound (I) of the present invention absorbs water by leaving it in the air, freeze-dried from an aqueous solution, or recrystallized to form adsorbed water or a hydrate. In some cases, such salts are also included in the present invention.
  • a pharmacologically acceptable derivative thereof refers to a group that is cleaved in a human or animal body by a chemical or biological method such as hydrolysis to form an original compound or a salt thereof.
  • esters and amide derivatives, etc. in which the carboxyl group, hydroxyl group, amino group, etc. of compound (I) are protected by a compound (a group forming a so-called prodrug).
  • a test animal can be administered orally or intravenously, and then the body fluid of the animal can be examined to determine the original compound or its salt.
  • protecting groups such as carboxyl group, hydroxyl group and amino group include groups known in the field of medicinal chemistry, for example, acyloxy C
  • Examples of the above-mentioned “di-, azyloxyalkyl group” include, for example, bivaloyloxymethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, acetoxymethinole, 1- (acetoxy) ethynole, 1-methynolecyclohexynole Bonoleoxymethylinole and 1-methylcyclohexyl benzoin canoleboninoleoxymethine.
  • alkoxycarbonyloxy C w alkyl group examples include, for example, t_butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, and 1- (isopropoxycarbonyloxy).
  • the "Ashiru group” for example Asechiru, propionyl, butyryl, Kisanoiru to pentanol, Okutanoiru, Dekanoiru, Dodekanoiru, Kisadekanoiru to Tetoradekano, Arukanoiru groups such as Okutadekanoiru group, Baie Nzoiru, c fi _,.
  • Such as naphthoyl examples thereof include a 5- or 6-membered heterocarbonyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms such as arylcarbonyl group, pyridylcarbonyl group and phenylcarbonyl group.
  • C 1-fi alkoxycarbonyl group examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarboninole, octinoleoxycarbonyl, and desinoleoxycarbonyl. And octadecyloxycarbonyl group.
  • amino C 1 -fiacyl group examples include amino acid groups such as glycyl, aranyl, j3-aranyl, leucyl, isoleucyl, fenaralarinole, histidyl, asparagyl, prolyl, and lysyl.
  • More preferred protecting groups among the above are 5-methyl-2-oxo-11,3-dioxolen-14-inolemethyl, acetomethoxymethinole, bivaloyoxymethyl, 1-methylcyclohexynolecarbonyloxy.
  • Compound (I) of the present invention represents one or a mixture of isomers.
  • the 2- and 4-positions of the 2-substituted pyrrolidine-14-yl group are (2S, 4S) Arrangement is preferred.
  • the configuration at the 3-position of the 3-substituted pyrrolidine-11-yl group is not particularly limited.
  • the compounds of the present invention represented by the general formula (I) the following compounds are preferred.
  • R 1 is a hydrogen atom, a methyl group or an ethyl group.
  • R 4 force A compound that is a formimidoyl group, an acetimidoyl group, or an amidino group (15) The compound wherein R 4 is an amidino group.
  • n 2 or 3
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom or a methyl group
  • R 3 is a hydrogen atom or a methyl group
  • R ' is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 A compound that is a formimidyl group, an acetateimidyl group, or an amidino group.
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom
  • R : i is a hydrogen atom
  • CH 2 0C0N (CH,) - 499 CH, 4 CH, CH:!.
  • CH 2 CH 2 NH - 500 CH, 4 CH 2 CH 3 CH, CH 9 NHCH-501 CH, 4 CH, CH, CH 2 CH 2 N (CH,)-502 CH, 4 CH 2 CH 3 c- Pro
  • the 1-methylcarbapanem derivative having the general formula (I) of the present invention can be produced by the following method.
  • the sulfur in the 2-position side chain of the compound represented by the general formula (I) will be described.
  • the substituent of the atom is represented by R, and the general formula (I) is abbreviated as follows.
  • Rp is protected when R contains a hydroxyl group, an amino group or an imino group.
  • Indicates R that may be The compound can be produced by reacting a mercaptan derivative represented by) and removing a protecting group as necessary. It can also be converted into a pharmacologically acceptable salt or derivative if necessary;
  • the compound (I) of the present invention can be produced by the method illustrated below.
  • R in , L and R p have the same meanings as described above.
  • Examples of the “protecting group for the carboxy group” of R in include a C W alkyl group such as methyl, ethyl or t-butyl; benzyl, 4-methoxybenzyl, 4-nitrobenzyl or 2-nitrobenzyl.
  • a benzyl group which may have a substituent such as: a benzhydryl group; an aryl group which may have a substituent at the 2-position such as arinole, 2-chloroallyl or 2-methylaryl; 2, 2, 2 Examples thereof include a halogenoethyl group such as trichloroethyl, 2,2-dibromoethyl or 2,2,2-tribromoethyl, or a 2-trimethylsilylethyl group, and preferably a 4-nitole benzyl or benzyl group. It is.
  • a “leaving group” is, for example, a group having the formula one OR 11 or one S (O) R 12 .
  • R is methane scan Honoré Honi Honoré, Application Benefits Funoreorome chest Honoré Honi Honoré, Etansunorehoni Le, propanesulfonyl, Isopurono, 3 CH
  • Anore force Nsuruhoniru groups such as Nsuruhoniru or butanesulfonyl group; Hue Nino les sulfonyl, preparative Rinoresuruhoniru also Or like naphthylsulfonyl.
  • dialkylphosphoryl group such as dimethylphosphoryl, getylphosphoryl, dipropylphosphoryl, diisopropylphosphoryl, dibutylphosphoryl, dipentylphosphoryl or dihexylphosphoryl, or diphenylphosphoryl or ditolylphosphoryl
  • a diphenylphosphoryl group preferably a diphenylphosphorinole group.
  • R 12 is a C w alkyl group such as methyl, ethyl, propyl or isopropyl; fluoromethinole, chloromethinole, phnoreolechinole, chloroethyl, phleoleno bropinole, diphneoleolomethinole, diphnoleoletinole, dichloroethinole, Halogeno-C I alkyl group such as trifrenorelomethyl or trifluoroethyl; 2-acetylaminoethyl group; 2-acetylaminovinyl group; optionally substituted C such as phenyl or naphthyl 6 _ H1 Ariru group (said Ariru group may have the same or different 1 to 3 substituents below the substituent are fluorine, chlorine, halogen atom such as bromine;.
  • Alkyl groups such as propyl, isopropyl; methoxy, ethoxy, propoxy, iso CH-alkoxy, such as ropoxy: 3-xy group; (C w alkoxy) carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, and t-butoxycarbonyl; dirubamoyl, mono- or di- (CHalkyl) dirubamoyl group A nitro group; a hydroxyl group or a cyano group.) Or a heteroaryl group optionally having 1 to 2 nitrogen atoms such as pyridyl or pyrimidinyl which may have a substituent (the heteroaryl group is the following). It may have 1 to 3 identical or different substituents shown below, and the substituents represent a halogen atom or a CH alkyl group as a substituent of the above aryl group.
  • R p examples include tri-C 1 alkylsilyl groups such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl; benzinoleoxycanoleboninole, 4-nitrobenzylinole An optionally substituted benzyloxycarbonyl group such as xycanoleboninole, 4-chlorobenzyloxycarbonyl, or 4-methoxybenzyloxycarbonyl (the substituent is nitro, methyl, chlorine or Methoxy)); aryloxycarbonyl, 2-chloroallyloxy An aryloxycarbonyl group which may be substituted at the 2-position such as cyclocarbonyl or 2-methylaryloxycarbonyl (the substituent is chlorine or methyl); trimethylsilylethyloxycarbonyl, An ethyloxycarbonyl group substituted at the 2-position with tri-CHalkylsilyl or chlorine, such as
  • R p As the “protecting group for imino or amino” contained in R p, for example, even if 2-position is substituted such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylaryloxycarbonyl A good aryloxycarbonyl group (the substituent is chlorine or methyl); benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-cyclobenzyloxy Optionally substituted benzyloxycarbonyl groups such as carbonyl and 4-nitrobenzoyloxycarbonyl (the substituent is methyl, methoxy, chlorine or nitro); An aryloxycarbonyl group or a 412-nitrobenzyloxycarbonyl group, more preferably a 412-nitrobenzoyloxycarbonyl group.
  • the method 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) (first step), To produce a compound (I) (Step A2).
  • L is a group represented by the formula OR 11
  • the compound having the formula (II) as a starting material is produced by the method described in DH Shih et al., Heterocycles 21, 29 (1984). Is done.
  • L is a group represented by the formula one S ( ⁇ ) R 12
  • starting compound (II) is prepared according to the process disclosed in JP-A 6 2 3 0 7 8 No. 1.
  • each step will be described:
  • the first step is a step of producing a compound having the general formula (IV), This is achieved by reacting the compound (II) with a mercaptan derivative having the general formula (III) in the presence of a base.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform
  • nitriles such as acetonitril Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, esters such as ethyl acetate and methyl acetate
  • ethers such as getyl ether, tetrahydrofuran and dioxane.
  • Preferred are acetonitrile, N, N-dimethylformamide or tetrahydrofuran, and particularly preferred is acetonitrile.
  • the base used in this step is not particularly limited, but preferably includes organic amines such as triethylamine and disopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate. And preferably diisopropylethylethylamine.
  • reaction temperature is not particularly limited, the reaction is usually carried out at a temperature of from 20 to 40 ° C (preferably from 10 to 20 ° C).
  • the reaction time is 30 minutes to 108 hours (preferably 1 hour to 18 hours).
  • the solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, water, and a mixed solvent thereof. Acetonitrile.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, particularly the 0-lactam ring.
  • diisopropylethylamine, triethylamine, N-methylbiperidine, 4-dimethylamine examples include organic bases such as minopyridine or inorganic bases such as carbonated lime and sodium bicarbonate, and preferably diisopropylethylamine.
  • 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, and it is usually -20 ° C to 40 ° C (preferably 10 ° C to 20 ° C). Done in It is.
  • the reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 18 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 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.
  • the second step is a step of converting the compound (IV) into the compound (I), which is achieved by removing the protecting group of the compound.
  • 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 & Wutts, Pro- tective Grouping Organic Synthesis, 2nd Edition, 1999). 1, J ohn W iley & S ons, In
  • the protecting group R l ( ) is a benzyl group or a benzhydryl group which may have a substituent such as benzyl or 412 trobenzyl, and a hydroxyl group or an amino group contained in Rp
  • Substituents such as benzyl or benzyloxycarbonyl which may have a substituent such as benzyl or 4-nitrobenzyl for the protecting group of the group or imino group
  • the protective group can be removed by reacting with hydrogen and a reducing agent using a catalytic reduction catalyst or an alkali metal sulfide.
  • the reducing agent may be, for example, a catalytic reduction catalyst such as hydrogen and palladium on carbon or an alkali metal sulfide such as sodium sulfide or lithium sulfide. And preferably hydrogen and palladium-carbon catalysts.
  • a catalytic reduction catalyst such as hydrogen and palladium on carbon
  • an alkali metal sulfide such as sodium sulfide or lithium sulfide.
  • hydrogen and palladium-carbon catalysts preferably hydrogen and palladium-carbon catalysts.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • the solvent is anorecone such as methanol or ethanol, ethers such as tetrahydrofuran or dioxane, or these organic solvents. It is a mixed solvent with water.
  • the reaction temperature is usually 0 ° C to 50 ° C (preferably 10 ° C to 40 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 5 minutes to 12 hours. (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.
  • protecting group R 10 is an aryl group which may be substituted at the 2-position such as aryl, 2-chloroallyl or 2-methylaryl, and protection of hydroxyl group, amino group and imino group contained in Rp
  • group is an aryloxycarbonyl group which may be substituted at the 2-position, such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl, bis (triphenylphosphine) Palladium chloride-tributyltin hydride, tetrakis (triphenylphosphine) palladium such as palladium-tributyltin hydride-trialkyltin hydride or tetrakis (triphenylphosphine) palladium- 1
  • a deprotecting agent such as an alkali metal salt of organic
  • the deprotecting agent is preferably bis (triphenylphosphine) palladium chloride tributyltin hydride or tetrakis (triphenylphosphine) palladium-1-ethylhexanoate.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate.
  • Ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxetane, such as acetonitrile
  • examples thereof include nitriles, alcohols such as methanol, ethanol and propanol, water and a mixed solvent thereof, preferably methylene chloride, ethyl acetate or a mixed solvent thereof.
  • the reaction temperature is not particularly limited but is usually carried out in one 20 ° C to 1 00 ° C (preferably 0 D C to 6 0 ° C), the reaction time is generally 30 minutes to 48 hours (preferably 30 minutes To 12 hours).
  • the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent.
  • the protecting group R 111 is a halogenoethyl group such as 2,2-dibromoethyl or 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 participate in this 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 40 ° C (preferably 10 ° C to 30 ° C), and the reaction time varies depending on the type of the starting compound and the reducing agent, but is usually 5 minutes to 12 hours. (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, for example, a recrystallization method, a preparative thin-layer chromatography, a column chromatography and the like.
  • 1-methylcarbazanem compound having the general formula (I) thus obtained Can be converted, if necessary, to derivatives such as esters that undergo hydrolysis in vivo, according to methods or techniques known in the field of medicinal chemistry, especially; 3-lactam antibiotics, Further, it can be purified as a pharmacologically acceptable salt.
  • the raw material mercaptan compound (III) used in the present method can be prepared by a known method, for example, I. Kawamo toetal., Synlett, 1995, 575; JP-A-2-28180; No. 3687, described according to the method described in JP-A-4-21083, JP-A-5-339269 or JP-A-10-36370, or described in Reference Examples described later.
  • the compound of the present invention having the general formula (I) 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, enteropatar, Shows strong and balanced antibacterial activity against a wide range of pathogenic bacteria including gram-negative bacteria such as Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis. Also exhibits excellent antibacterial activity against.
  • Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis
  • Escherichia coli Shigella
  • Klebsiella pneumoniae deformed bacteria
  • Serratia enteropatar
  • the compound (I) of the present invention has a high stability to lactamase, is stable to dehydrobeptidase-1 I, and has a high urinary recovery rate. Furthermore, the compound (I) of the present invention has excellent pharmacokinetics such as half-life in blood and has low toxicity to the kidney. Therefore, the compound of the present invention having the above general formula (I) or a pharmaceutically acceptable salt or derivative thereof is useful, for example, as a medicament, particularly for treating or preventing bacterial infections caused by various pathogenic bacteria (preferably It is useful as an antibacterial agent to treat.
  • the compound (I) and its pharmacologically acceptable derivative or salt are used as a medicament, especially as an antibacterial agent, the compound (I) is mixed with itself or an appropriate pharmacologically acceptable excipient or diluent. It can be administered orally, such as tablets, capsules, granules, powders, or syrups, or parenterally, such as injections.
  • excipients eg, lactose, sucrose, glucose, mannitol, sol Sugar derivatives such as bit; corn denan, potato starch, starch derivatives such as ⁇ -starch, dextrin, carboxymethyl starch; crystalline senorelose, low-substituted hydroxypropylcellulose, hydroxypropylmethyl senorelose Cellulose derivatives such as carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, metasilicate aluminate Silicate derivatives such as magnesium; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; and binders (for example, Excipient; Zera Polyvinylpyrrolidone; macrogol, etc.), disintegrants (for example, the above-mentione
  • the amount used depends on the symptoms, age, etc., but in the case of oral administration, the lower limit is 10 mg (preferably 5 O mg) per dose, the upper limit is 200 mg (preferably 10 mg). 0 0 m g), in the case of intravenous administration, the lower limit is 10 mg (preferably 100 mg) and the upper limit is 300 Omg (preferably 200 Omg) per dose, 1 to 6 times per day for adults It is desirable to administer according to.
  • reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography.
  • 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 200 mg per tablet. These tablets can be sugar-coated if necessary.

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Abstract

L'invention concerne des composés de 1-méthylcarbapenem de la formule (I) ou des sels ou dérivés pharmacologiquement acceptables desdits composés, qui ont une excellente activité antibactérienne. Dans ladite formule, n est 2, 3 ou 4; R1 est hydrogène ou alkyle C¿1?-C4; nR?2¿s sont chacun, indépendamment, hydrogène ou alkyle C¿1?-C4; R?3¿ est hydrogène ou alkyle C¿1?-C4; et R?4¿ est hydrogène, alkyle C¿1?-C4, alkyle C1-C4 substitué, cycloalkyle, ou un groupe représenté par la formule générale: C(=NH)R?5¿ (dans laquelle R5 est hydrogène, alkyle C¿1?-C4 ou amino).
PCT/JP1999/006824 1998-12-07 1999-12-06 Derives de 1-methylcarbapenem WO2000034282A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14155/00A AU1415500A (en) 1998-12-07 1999-12-06 1-methylcarbapenem derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/346375 1998-12-07
JP34637598 1998-12-07

Publications (1)

Publication Number Publication Date
WO2000034282A1 true WO2000034282A1 (fr) 2000-06-15

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WO (1) WO2000034282A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518558A1 (fr) * 1991-06-04 1992-12-16 Sankyo Company Limited Dérivés de méthyl-1-carbapénème, leur préparation et leur application comme antibiotiques
EP0560613A1 (fr) * 1992-03-11 1993-09-15 Sankyo Company Limited Dérivés antimicrobiens du carbapenem, leur préparation et leur utilisation thérapeutique
JPH05310740A (ja) * 1992-05-11 1993-11-22 Dai Ichi Seiyaku Co Ltd カルバペネム誘導体
JPH0748375A (ja) * 1994-05-09 1995-02-21 Sankyo Co Ltd １−メチルカルバペネム誘導体
WO1997023483A1 (fr) * 1995-12-21 1997-07-03 Sankyo Company, Limited Derives de 1-methylcarbapenem
WO1997041123A1 (fr) * 1996-04-26 1997-11-06 Sankyo Company, Limited Derives de 1-methylcarbapeneme

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0518558A1 (fr) * 1991-06-04 1992-12-16 Sankyo Company Limited Dérivés de méthyl-1-carbapénème, leur préparation et leur application comme antibiotiques
EP0560613A1 (fr) * 1992-03-11 1993-09-15 Sankyo Company Limited Dérivés antimicrobiens du carbapenem, leur préparation et leur utilisation thérapeutique
JPH05310740A (ja) * 1992-05-11 1993-11-22 Dai Ichi Seiyaku Co Ltd カルバペネム誘導体
JPH0748375A (ja) * 1994-05-09 1995-02-21 Sankyo Co Ltd １−メチルカルバペネム誘導体
WO1997023483A1 (fr) * 1995-12-21 1997-07-03 Sankyo Company, Limited Derives de 1-methylcarbapenem
WO1997041123A1 (fr) * 1996-04-26 1997-11-06 Sankyo Company, Limited Derives de 1-methylcarbapeneme

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