Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/12—Oxygen or sulfur atoms

Definitions

• the present invention relates to novel carbapenem (7- oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylic acid) compounds, antibacterial agents containing such compounds as active ingredients, and a process for producing such compounds.
• DHP-I renal dehydropeptidase I
• Imipenem has antibacterial activities of an equal or higher level than thienamycin against various types of bacteria and has /?-lactamase resistance. Especially against Pseudomonas aeruqinosa, its antibacterial activities are superior to thienamycin by from 2 to 4 times. Further, the stability of imipenem in the solid form or in an aqueous solution is remarkably improved over thienamycin.
• imipenem is likely to be decomposed by DHP-I in the human kidney. Therefore, it can not be used for treatment of the urinary-tract infection. Further, it presents toxicity against the kidney due to the decomposition products. Therefore, imipenem can not be administered alone and is required to be used in combination with a DHP-I inhibitor like cilastatin (J. Antimicrob. Chemother., vol. 12 (Suppl. D), p. 1 (1983)). In recent years, imipenem has been frequently used for the treatment and prevention of infectious diseases.
• the side chain at the 2-position of the pyrrolidinyl group is restricted to the one substituted on the pyrrolidinyl group via a linear C ⁇ g alkylene group, and furthermore, the compound having an aminoalkyl group at the 2-position of the pyrrolidinyl group is limited to a compound having an (acetylamino)methyl group [the compound of specific example 24 in European Patent Publication No. 182213 (p. 116) (the compound of REFERENCE EXAMPLE 13 in this specification) or the compound of specific example 23 (EXAMPLE 19)].
• carbapenem compounds wherein, as a feature of the present invention, the lower alkylene group of the side chain at the 2-position of the pyrrolidinyl group substituted at the 2-position of the carbapenem struct ⁇ re has a primary, secondary or tertiary amino group or an ammonio group at its terminal and has a branched structure (a structure having a branched lower alkylene
• ⁇ group or a structure in which a linear lower alkylene group has a substituent are novel compounds not disclosed or suggested in any prior art literatures or patent specifications.
• ?-Lactam antibiotics exhibit selective toxicity against bacteria and show no substantial effects against animal cells. Therefore, they are widely used for treatment of infectious diseases caused by bacteria, as rare antibiotics having little side effects, and thus are highly useful drugs.
• R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, - an amino group, an N-lower alkylamino group, an N,N-di- lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group, a cyano group, a nitro group, a group of -COOR 4 (wherein R 4 is a hydrogen atom or a lower alkyl group) or a group of -CON(R 5 )R 6 (wherein each of R 5 and R 6 which may be the same or different, is a hydrogen atom or a lower alkyl group, or R 5 and R 6 form together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of an aziridin
• gram positive bacteria such as Staphylococcus aureus and against gram negative bacteria including Pseudomonas aeruqinosa and further exhibit excellent stability against DHP-I.
• the present invention has been accomplished on the basis of this discovery.
• the present invention provides a compound of the formula:
• R 1 is a hydrogen atom or a methyl group
• R 2 is a hydrogen atom or a negative charge
• R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, an N- lower alkylamino group, an N,N-di-lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group, a cyano group, a nitro group, a group of -COOR 4 (wherein R 4 is a hydrogen atom or a lower alkyl group) or a group of -CON(R 5 )R 6 (wherein each of R 5 and R 6 which may be the same or different, is a hydrogen atom or a lower alkyl group, or R 5
• A is a linear or branched lower alkylene group
• X is a group of -N(R 7 )R 8 (wherein each of R 7 and R 8 which may be the same or different, is a hydrogen atom or a lower alkyl group) or a group of -N + (R 9 ) (R 10 )R 1:L (wherein each of R 9 , R 10 and R 11 which may be the same or different, is a lower alkyl group), provided that when A is a linear lower alkylene group, R 3 is other than a hydrogen atom; or a pharmaceutically acceptable salt or ester thereof.
• the present invention also provides a process for producing the compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof, which comprises reacting a compound of the formula:
• R 1 is as defined above, R 12 is a hydrogen atom or a hydroxyl-protecting group, and R 20 is a hydrogen atom or a carboxyl-protecting group, or a reactive derivative thereof, with a compound of the formula:
• R 13 is a hydrogen atom or an imino-protecting group
• R 30 is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a lower alkoxy group, a lower alkanoyloxy group, an amino or N-lower alkylamino group which may be protected, an N,N-di-lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group which may be protected, a cyano group, a nitro group, a group of -COOR 40 (wherein R 40 is a hydrogen atom, a lower alkyl group or a carboxyl-protecting group) or a group of -CON(R 50 )R 60 (wherein each of R 50 and R 60 which may be the same or different, is a hydrogen atom, a
• R 1 , R 12 , R 13 , R 20 , R 30 , A and X 1 are as defined above, and if necessary, removing any protecting groups of the compound of the formula (IV).
• an antibacterial agent comprising an antibacterially effective amount of the compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or diluent.
• the compound of the present invention has a basic structure of the formula:
• the present invention includes optical isomers based on the asymmetrical carbon atoms at the 1-position, 5- position, 6-position and 8-position of the carbapenem structure and stereoisomers.
• optical isomers based on the asymmetrical carbon atoms at the 1-position, 5- position, 6-position and 8-position of the carbapenem structure and stereoisomers.
• preferred is a compound of a (5R,6S,8R) configuration i.e. a compound having a steric configuration of (5R,6S) (5,6-trans) like thienamycin and in which the carbon atom at the 8-position takes a R-configuration, or a compound of a (1R,5S,6S,8R) configuration in a case where a methyl group is present at the 1-position.
• the present invention includes isomers based on the asymmetrical carbon atoms at the 2-position and 4- position of the pyrrolidine structure and in the side chain at the 2-position.
• isomers preferred are compounds of the formula: - 12 -
• R 1 , R 2 , R 3 , A and X are as defined above, and compounds of the formula:
• R 1 , R 2 , R 3 , A and X are as defined above.
• the lower alkyl group means a linear or branched alkyl group having from 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group or a hexyl group, preferably a methyl group, an ethyl group or a tert-butyl group.
• the lower alkoxy group means an alkoxy group having from 1 to 6 carbon atoms with the above lower alkyl group substituted on a hydroxyl group, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group or a tert-butoxy group, - 13 -
• a methoxy group preferably a methoxy group, an ethoxy group or a tert- butoxy group.
• the lower alkanoyloxy group means an alkanoyloxy group having from 1 to 6 carbon atoms with a lower alkanoyl group substituted on a hydroxyl group, such as a formyloxy group, an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a valeryloxy group or a pivaloyloxy group, preferably a formyloxy group or an acetoxy group.
• the N-lower alkylamino group means an N-alkylamino group having from 1 to 6 carbon atoms with the above lower alkyl group mono-substituted on an amino group, such as an N-methylamino group, an N-ethylamino group, an N-propylamino group, an N-isopropylamino group or an N- butylamino group, preferably an N-methylamino group or an N-ethylamino group.
• the N,N-di-lower alkylamino group means an N,N- dialkylamino group having from 2 to 12 carbon atoms with the above-mentioned two lower alkyl groups substituted on an amino group, such as an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-dipropylamino group, an N,N-diisopropylamino group, an N,N-dibutylamino group, an N-ethyl-N-methylamino group, an N-methyl-N-propylamino group or an N-ethyl-N-propylamino group, preferably an N,N-dimethylamino group or an N,N-diethylamino group.
• the lower alkanoylamino group means an alkanoylamino group having from 1 to 6 carbon atoms with a lower - 14 -
• alkanoyl group substituted on an amino group such as a formylamino group, an acetyla ino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a valerylamino group, an isovalerylamino group or a pivaloylamino group, preferably a formylamino group or an acetylamino group.
• the aroylamino group means an aroylamino group having from 7 to 11 carbon atoms, such as a benzoylamino group.
• the (lower alkylsulfonyl)amino group means an (alkylsulfonyl)amino group having from 1 to 6 carbon atoms with the above lower alkyl-substituted sulfonyl group substituted on an amino group, such as a (methylsulfonyl)amino group, an (ethylsulfonyl)amino group, a (propylsulfonyl)amino group, an (isopropylsulfonyl)amino group, a (butylsulfony1)amino group, a (sec-butylsulfonyl)amino group, a (tert- butylsulfonyl)amino group or a (pentylsulf
• the linear or branched lower alkylene group means a linear or branched alkylene group having from 1 to 6 carbon atoms, such as a methylene group, an ethylene group, a propylene group, a butylene group, a me hylmethylene group, an ethyl ethylene group, a di ethylmethylene group, a 1-methylethylene group, a 2- methylethylene group, a 1-ethylethylene group, a 2- ethylethylene group, a 1,1-dimethylethylene group, a 1,2- dimethylethylene group, a 2,2-dimethylethylene group, a - 15 -
• the halogen atom may, for example, be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• the carboxyl-protecting group may, for example, be a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group; a halogenated lower alkyl group such as a 2,2,2- trichloroethyl group or a 2,2,2-trifluoroethyl group; a lower alkanoyloxyalkyl group such as an acetoxymethyl group, a propionyloxymethyl group, a pivaloyloxymethyl group, a 1-acetoxyethyl group or a 1-propionyloxyethyl group; a lower alkoxycarbonyloxyalkyl group such as a 1- (methoxycarbonyloxy)ethyl group
• (isopropoxycarbonyloxy)ethyl group a lower alkenyl group such as a 2-propenyl group, a 2-chloro-2-propenyl group, a 3-methoxycarbonyl-2-propenyl group, a 2-methyl-2- propenyl group, a 2-butenyl group or a cinnamyl group; an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzyl group, a benzhydryl group or a - 16 -
• a (5-substituted 2-oxo- l,3-dioxol-4-yl)methyl group such as a (5-methyl-2-oxo- l,3-dioxol-4-yl)methyl group
• a lower alkylsilyl group such as a trimethylsilyl group or a tert- butyldimethylsilyl group
• an indanyl group a phthalidyl group or a methoxymethyl group.
• a 2-propenyl group a p-nitrobenzyl group, a p- methoxybenzyl group, a benzhydryl group and a tert- butyldimethylsilyl group.
• the hydroxyl-protecting group may, for example, be a lower alkylsilyl group such as a trimethylsilyl group or a tert-butyldimethylsilyl group; a lower alkoxymethyl.
• aralkyl group such as a benzyl group, a p-methoxybenzyl group, a 2,4-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzyl group or a trityl group
• an acyl group such as a formyl group or an acetyl group
• a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group, a 2-iodoethoxycarbonyl group or a 2,2,2- trichloroethoxycarbonyl group
• an alkenyloxycarbonyl group such as a 2-propenyloxycarbonyl group, a 2-chloro- 2-propenyloxycarbonyl group, a 3-methoxycarbonyl-2- propenyloxycarbonyl group,
• the amino- or imino-protecting group may, for example, be an aralkylidene group such as a benzylidene group, a p-chlorobenzylidene group, a p-nitrobenzylidene group, a salicylidene group, an ⁇ -naphthylidene group or a /?-naphthylidene group; an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a 3,4- dimethoxybenzyl group, an o-nitrobenzyl group, a p- nitrobenzyl group, a benzhydryl group, a bis(p- methoxyphenyl)methyl group or a trityl group; a lower alkanoyl group such as a formyl group, an acetyl group, a i propionyl group/ a butyryl group, an ox
• R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, an N-lower alkylamino group, an N,N-di- lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group, a cyano group, a nitro group, a group of -COOR 4 (wherein R 4 is a hydrogen atom or a lower alkyl group) or a group of -CON(R 5 )R 6 (wherein each of R 5 and R 6 which may be the same or different, is a hydrogen atom or a lower alkyl group, or R 5 and R 6 form together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of an aziridinyl group
• R 3 may be substituted at an optional position on the linear or branched lower alkylene group represented by A.
• R 3 is preferably a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a
• X is a group of -N(R 7 )R 8 (wherein each of R 7 and R 8 10 which may be the same or different, is a hydrogen atom or a lower alkyl group) or a group of -N + (R 9 ) (R 10 )R 1:L (wherein each of R 9 , R 10 and R 11 which may be the same or different, is a lower alkyl group).
• X may, for example, be an amino group, an N-methylamino group, an N- 15 ethylamino group, an N-propylamino group, an N-isopropyl amino group, an N-butylamino group, an N,N-dimethylamino group, an N,N-diethylamino group, an N,N-dipropylamino group, an N,N-diisopropylamino group, an N,N-dibutylamino group, ' an N-ethyl-N-methylamino group, an N-methyl-N- 20 propylamino group, an N-ethyl-N-propylamino group, an N,N,N-trimethylammonio group, an N,N,N-triethylammonio group, an N,N-dimethyl-N-ethylammonio group or an N,N- diethyl-N-methylammonio group,
• R 2 is a hydrogen atom or a negative charge.
• R 2 is a negative charge and forms a pair together with the ammonium ion, whereby the compound of the formula (I) forms an intramolecular salt.
• the salt of the compound of the formula (I) is a common pharmaceutically acceptable salt and may, for example, be a salt at the carboxyl group at the 3- position of the carbapenem structure, or at the pyrrolidine base or the base on the side chain substituted on the pyrrolidine ring.
• the basic addition salt at said carboxyl group includes, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an ammonium salt; an aliphatic amine salt such as a trimethylamine salt, a triethylamine salt, a dicyclohexylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt or a procaine salt; an aralkylamine salt such as an N,N'- dibenzylethylenediamme salt; an aromatic heterocyclic amine salt such as a pyridine salt, a picoline salt, a quinoline salt or an isoquinoline salt; a quaternary ammonium salt such as a tetramethylammonium salt, a tetraethylammoniu salt, a benzyltrimethylammonium salt, a benzyltriethylammoni
• the acid addition salt at the pyrrolidine base or at the base on the side chain substituted on the pyrrolidine ring includes, for example, an inorganic salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, a carbonate, a hydrogencarbonate or a perchlorate; an organic salt such as an acetate, a propionate, a lactate, a maleate, a fumarate, a tartrate, a malate, a succinate or an ascorbate; a sulfonate such as a methanesulfonate, an isethionate, a benzenesulfonate or a p- toluenesulfonate; and an acidic amino acid salt such as an aspartate or a glutamate.
• an inorganic salt such as a hydrochloride, a sulfate, a nitrate, a phosphate,
• the non-toxic ester of the compound of the formula (I) means a common pharmaceutically acceptable ester at the carboxyl group at the 3-position of the carbapenem structure.
• it includes an ester with an alkanoyloxymethyl group such as an acetoxymethyl group or a pivaloyloxymethyl group, an ester with an alkoxycarbonyloxyalkyl group such as a 1- (ethoxycarbonyloxy)ethyl group, an ester with a phthalidyl group and an ester with a (5-substituted-2- oxo-l,3-dioxol-4-yl)methyl group such as a (5-methyl-2- oxo-l,3-dioxol-4-yl)methyl group.
• R 1 is a hydrogen atom or a methyl group
• R 2 is a hydrogen atom or a negative charge
• R 3a is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, an N- lower alkylamino group, a lower alkanoylamino group, a (lower alkylsulfonyl)amino group, a cyano group or a carbamoyl group
• A is a linear or branched lower alkylene group
• X is a group of -N(R 7 )R 8 (wherein each of R 7 and R 8 which may be the same or different, is a hydrogen atom or a lower alkyl group) or a group of -N + (R 9 ) (R 10 )R 11 (wherein each of R 9 , R 10 and
• R 1 is a hydrogen atom or a methyl group
• R 2 is a hydrogen atom or a negative charge
• R 3b is a hydrogen atom, a hydroxyl group, an amino group, a lower.
• alkanoylamino group a (lower alkylsulfonyl)amino group, a cyano group or a carbamoyl group
• A is a linear or branched lower alkylene group
• X is a group of -N(R 7 )R 8 (wherein each of R 7 and R 8 which may be the same or different, is a hydrogen atom or a lower alkyl group) or a group of -N + (R 9 ) (R 10 )R 1:L (wherein each of R 9 , R 10 and R 11 which may be the same or different, is a lower alkyl group), provided that when A is a linear lower alkylene group, R 3b is other than a hydrogen atom; or a pharmaceutically acceptable salt or ester thereof; and a compound of the formula:
• R 1 is a hydrogen atom or a methyl group
• R 2 is a hydrogen atom or a negative charge
• R 3c is a halogen atom, a lower alkoxy group, an N-lower alkylamino group or a lower alkanoyloxy group
• A is a linear or a branched lower alkylene group
• X is a group of -N(R 7 )R 8 (wherein each of R 7 and R 8 which may be the same or different, is a hydrogen atom or a lower alkyl group) or a group of -N + (R 9 )(R 10 )R 1:L (wherein each of R 9 , R 10 and R 11 which may be the same or different, is a lower alkyl group), provided that when A is a linear lower alkylene group, R 3c is other than a hydrogen atom; or a pharmaceutically acceptable salt or ester thereof.
• the compound of the present invention is characterized in that the terminal of the lower alkylene group as the side chain at the 2-position of the pyrrolidinyl group substituted at the 2-position of the carbapenem structure is a primary, secondary or tertiary amino group or an ammonio group, and the lower alkylene group has a branched structure.
• the "branched structure” means that the lower alkylene group of the compound of the formula (I) has a substituent or is branched. Specifically, it includes a case where the lower alkylene group is a linear lower alkylene group which has a substituent, and a case where the lower alkylene group is a branched lower alkylene group.
• the branched lower alkylene group may or may not have a substituent.
• the substituent (R 3 ) is preferably a halogen atom, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkanoylamino group, a (lower alkylsulfonyl)amino group, a cyano group or a carbamoyl group.
• the substituent (R 3 ) is preferably a hydrogen atom, a hydroxyl group or a carbamoyl group.
• Specific examples of the compound of the formula (I) include, for example, the following compounds. The following abbreviations in the table have the following meanings .
• ⁇ preferred are compounds identified by compound Nos. 2, 4, 5, 6, 9, 11, 12, 13, 14, 16, 17, 18, 19, 20, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 35, 36, 37, 38, 41, 43, 44, 48, 49, 53, 56, 57, 58, 59, 61, 62, 63, 64, 67, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 84, 88, 89, 90, 91, 92, 94, 95, 99, 101, 102, 104, 105, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 and 117.
• compound No. 57 i.e. (lR,5S,6S)-6-[ (lR)-l-hydroxyethyl]-2-[(2S,4S)-2-[(1- hydroxy-3-methylamino)propyl]pyrrolidin-4-ylthio]-1- methyl-l-carbapen-2-em-3-carboxylic acid.
• R 1 is a hydrogen atom or a methyl group
• R 12 is a hydrogen atom or a hydroxyl-protecting group
• R 20 is a hydrogen atom or a carboxyl-protecting group, in an inert organic solvent in the presence of a base to form a reactive derivative of the formula (II'):
• R 1 , R 12 and R 20 are as defined above, and Y is a leaving group.
• the inert organic solvent to be used for the reaction may, for example, be diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethylene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, hexamethylphosphoric tria ide or a mixture of such solvents. Particularly preferred are acetonitrile and benzene.
• the base to be used for the reaction may, for example, be a tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N- methylpiperidine, N,N-dimethylaniline, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5- diazabicyclo[4.3.0]non-5-ene (DBN); or an aromatic amine such as pyridine, 4-N,N-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline. Particularly preferred are N,N-diisopropylethylamine and triethylamine.
• a tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine
• the activating reagent to be used for the reaction may, for example, be an acid anhydride such as trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride; or an acid chloride such as methanesulfonyl - 40 -
• an acid anhydride such as trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride or p-toluenesulfonic anhydride
• an acid chloride such as methanesulfonyl - 40 -
• diphenyl chlorophosphate Particularly preferred is diphenyl chlorophosphate.
• Y is a leaving group such as a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group or a diphenoxyphosphoryloxy group. Particularly preferred is a diphenoxyphosphoryloxy group.
• the reaction is conducted usually within a temperature range of from -40 to 50°C, preferably from -20 to 20°C, and usually completed quantitatively in from
• reaction product is treated in accordance with a usual method to obtain the reactive derivative (II 1 ) of the compound of the formula (II) quantitatively.
• R 13 is a hydrogen atom or an imino-protecting - 41 -
• R 30 is a hydrogen atom, a halogen atom, a hydroxyl group which may be protected, a lower alkoxy group, a lower alkanoyloxy group, an amino or N-lower alkylamino group which may be protected, an N,N-di-lower alkylamino group, a lower alkanoylamino group, an aroylamino group, a (lower alkylsulfonyl)amino group, a sulfamoylamino group which may be protected, a cyano group, a nitro group, a group of -COOR 40 (wherein R 40 is a hydrogen atom, a lower alkyl group or a carboxyl-protecting group) or a group of -CON(R 50 )R 60 (wherein each of R 50 and R 60 which may be the same or different, is a hydrogen atom, a lower alkyl group or an amino- or imino-protecting group,
• R 30 is other than a hydrogen atom, is conducted using the above-mentioned inert organic solvent and base to form a - 42 -
• R 1 , R 12 , R 13 , R 20 , R 30 , A and X 1 are as defined above.
• the reaction is conducted using from 1 to 2 mols, preferably from 1 to 1.5 mols, of the base and from 1 to 1.2 mols of the compound of the formula (III), per mol of the reactive derivative of the formula (II 1 ).
• the reaction is conducted usually within a temperature range of from -40 to 50°C, preferably from -20 to 20°C, and the reaction is completed usually in from 0.5 to 3 hours.
• the compound of the formula (IV) can be prepared in one step from the compound of the formula (II). Namely, without isolating the reactive derivative of the formula (II') prepared from the compound of the formula (II), the compound of the formula (III) is reacted thereto in the same reaction system to prepare the compound of the formula (IV) efficiently.
• a compound of the formula (I) can be obtained, if necessary, by conducting a reaction for removing a protecting group for a hydroxyl group, an amino or imino group and a carboxyl group.
• the method varies depending upon the type of the protecting groups. However, the removal can be conducted in accordance with conventional methods, for example, by solvolysis, by chemical reduction or by hydrogenation.
• the protecting group for the hydroxyl group and/or for the amino or imino group is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a p- nitrobenzyloxycarbonyl group
• the protecting group for the carboxyl group is an aralkyl group such as a benzyl group, a p-nitrobenzyl group or a benzhydryl group
• such protecting groups can be removed by catalytic hydrogenation by means of a platinum catalyst such as platinum oxide, platinum wire or platinum black, or a palladium catalyst such as palladium black, palladium oxide, palladium-carbon or palladium hydroxide-carbon.
• a solvent to be used for such a catalytic hydrogenation reaction methanol, ethanol, tetrahydrofuran, dioxane, acetic acid or a solvent mixture of such an organic solvent with water or with a buffer solution of e.g. a phosphate, may be used.
• the reaction can be completed in from 0.5 to 4 hours at a temperature within a range of from 0 to 50°C under hydrogen gas stream of from 1 to 4 atm.
• the protecting group for the hydroxyl group and/or the amino or imino group is an allyloxycarbonyl group
• the protecting group for the carboxyl group is an allyl group
• such protecting groups can be removed by reacting an organo-soluble palladium complex catalyst in an inert organic solvent containing an allyl group-capturing agent (method by W. McCombie et al., J. Org. Chem., vol. 47, p. 587-590
• the solvent useful for the reaction includes, for example, water, acetone, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, methylene chloride, chloroform and a solvent mixture thereof.
• the palladium compound complex useful for this reaction includes, for example, palladium-carbon, palladium hydroxide-carbon, palladium(II) chloride, palladium(II) acetate, tetrakis(triphenylphosphine)palladium (0), tetrakis(triphenoxyphosphine)palladium (O), tetrakis(triethoxyphosphine)palladium (0) , bis[ethylenebis(diphenylphosphine) ]palladium (0) , tetrakis[tri(2-furyl)phosphine]palladium (0) , bis(triphenylphosphine)palladium(II) chloride and bis(triphenylphosphine)palladium(II) acetate.
• the allyl group-capturing agent may, for example, be dimedone, formic acid, acetic acid, ammonium formate, sodium formate, sodium 2-ethylhexanoate, potassium 2- ethylhexanoate, pyrrolidine, piperidine and tributyltin hydride.
• the reaction is conducted usually within a temperature range of from -10 to 50°C, preferably from 0 to 30°C using from 0.01 to 0.5 mol of the catalyst and from 1 to 6 mols of the allyl group-capturing agent relative to 1 mol of the compound of the formula (IV), and the reaction is completed usually in from 0.5 to 3 hours.
• the protecting group for the hydroxyl group and/or the amino or imino group is an o-nitrobenzyloxycarbonyl group
• the protecting group for the carboxyl group is an o- nitrobenzyl group
• such protecting groups can be removed by a photo reaction (method by Amit et al., J. Org. Chem., vol. 39, p. 192-196 (1974)).
• the compound of the formula (I) can be isolated by usual treatment such as column chromatography - 46 - using silica gel or adsorptive resin, freeze-drying or crystallization.
• the protecting group for the carboxyl group at the 3-position of the compound of the formula (IV) is a lower alkanoyloxyalkyl group such as an acetoxymethyl group or a pivaloyloxymethyl group, a methoxymethyl group, an indanyl group or a phthalidyl group, such an ester will be physiologically hydrolyzed in vivo. Therefore, such a compound can directly be administered to a human being or to an animal without preliminarily removing the protecting group.
• the compound of the formula (I) can be converted to a pharmaceutically acceptable salt or ester by a conventional method.
• the compound of the formula (III) may be used without protecting its functional group such as an imino group on the pyrrolidine ring, or an amino group, a hydroxyl group or a sulfamoyl group as the substituent on the side chain at the 2-position of the pyrrolidine structure.
• the reaction of the reactive derivative (II 1 ) and the compound of the formula (III) can be conducted under the same conditions as described above. For example, a compound of the formula: - 47 -
• This thiol compound and the reactive derivative (II 1 ) are subjected to a coupling reaction, and then a buffer solution such as MOPS buffer is added to the reaction solution. The mixture is then subjected to catalytic hydrogenation under a mild condition to obtain the desired compound.
• a buffer solution such as MOPS buffer
• the protecting groups of the compound of the formula (III) may optionally be selected. In order to increase the yield for the reaction for removing the protecting groups to obtain the desired compound, it is advisable to use the minimum protecting groups.
• the starting material of the formula (II) can be prepared, for example, by a method by Salzmann et al. when R 1 is a hydrogen atom (J. Am. Chem. Soc, vol. 102, p.6161-6163 (1981)) or by a method by Shih et al. when R 1 is a methyl group (Heterocycles, vol. 21, p.29-40 (1984)).
• - 48
• the starting material of the formula (III) can be synthesized by the following method.
• the hydroxyl group of the compound 1 is activated by a usual method, and a thioacetate such as potassium thioacetate is reacted thereto to convert it to an acetylthio derivative 3_, followed by alkali or acid hydrolysis to obtain a thiol derivative of the formula (III).
• a thioacetate such as potassium thioacetate is reacted thereto to convert it to an acetylthio derivative 3_, followed by alkali or acid hydrolysis to obtain a thiol derivative of the formula (III).
• R 14 is a hydrogen atom or a hydroxyl-protecting group
• Z is a leaving group selected from the group consisting of a chlorine atom, a bromine atom, an iodine atom, a trifluoroacetoxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group
• Ac is an acetyl group
• R 13 , R 30 , A and X 1 are as defined above.
• a group of compounds having the formula 1_ can be prepared in accordance with the methods described in the Reference Examples.
• the compounds of the present invention exhibit strong antibacterial activities against various gram positive bacteria and gram negative bacteria.
• DHP-I susceptibility was quantitatively analyzed by the method by Kropp et al., Antimicrob. - 50 -
• the compounds of the present invention have excellent antibacterial activities against various gram positive bacteria and gram negative bacteria and are useful as antibacterial agents for the treatment and prevention of the human infectious diseases caused by such bacteria.
• Typical pathogens sensitive to the antibacterial agents of the present invention include, for example, species of genus Staphylococcus, genus Enterococcus, genus Escherichia, genus Enterobacter, genus Klebsiella, genus Serratia, genus Proteus and genus Pseudomonas.
• the compounds of the present invention exhibit excellent antibacterial activities particularly against Methicillin resistant Staphylococcus aureus and against thienamycin resistant Pseudomonas aeruqinosa.
• the compounds of the present invention are very stable against DHP-I although the stability varies depending upon the individual compounds, and they are excellent also in the physicochemical stability and in the solubility in water. Pharmacokinetics in Mice Materials and Methods
• mice Groups of three 20 g ddY male mice were given a single dose of 20 mg/kg of the compound of EXAMPLE 19 and imipenem by sc route. One group of three mice was placed in a metabolism cage designed to collect the urine free from fecal contamination. At a specified time after dosing, blood and urine samples were - 53 -
• the pharmacokinetic parameters and urinary recoveries of the compound of EXAMPLE 19 and imipenem which were determined in mice after subcutaneous administration are summarized in Table 2.
• the compound of EXAMPLE 19 0 distinctly showed more favorable pharmacokinetic profile than imipenem ( Figure).
• the plasma half life (0.13 hr) and the area under the curve (AUC; 13.8 / /g-hr/ml) of the compound of EXAMPLE 19 were much greater than those of imipenem.
• Urinary recovery of 62.5% for the compound of EXAMPLE 19 was about 3-fold that of imipenem. 0
• the compounds of the present invention may be used in the form of drug formulations suitable for non-oral - 54 -
• Drug formulations include liquid formulations such as injection solutions, syrups or emulsions, solid formulations such as tablets, capsules or granules, and external application formulations such as ointments or suppositories. These formulations may contain additives such as a base, an assisting agent, a stabilizer, a wetting agent, an emulsifier, an absorption-promoting agent, a surfactant, etc. which are commonly employed, as the case requires.
• the additives include, for example, distilled water for injection. Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacao butter, ethylene glycol, sucrose, corn starch, magnesium stearate and talc.
• a preferred daily dose of the active ingredient to an adult is from about 5 to 50 mg/kg, and a preferred daily dose to a child is within a range of from about 5 to 25 mg/kg, which is preferably administered once a day or in a few times a day.
• the compound of the present invention may be - 55 -
• a DHP-I inhibiting agent such as cilastatin [sodium (Z)-7-(L-amino-2- carboxyethylthio)-2-(2,2- dimethylcyclopropanecarboxamide)-2-heptenoate] (Japanese Unexamined Patent Publication No. 81518/1981; European Patent No. 28,778; J. Med. Chem., vol. 30, p. 1074 (1987)).
• silica gel for column chromatography used herein is WakogelTM C-300 (Wakojunyaku), and the reverse phase silica gel for column chromatography is LC-SORBTM SP-B-ODS (Chemco) .
• LC-SORBTM SP-B-ODS Chroxane-based reverse phase silica gel for column chromatography
• TMS tetramethylsilane
• DSS 2,2-dimethyl-2-silapentane-5-sulfonate
• (2S,4R)-2-(1-Cyano-l-p-nitrobenzyloxycarbonylamino)- methy1-4-mercapto-N-(p-nitrobenzyloxycarbonyl)- pyrrolidine was obtained as a crude product from (2S,4R)-4-acetylthio-2-(1-cyano-l-p-nitrobenzyloxy- carbonylamino)methyl-N-(p-nitrobenzyloxycarbonyl)- pyrrolidine prepared in REFERENCE EXAMPLE 5 (88.1 mg, 0.158 mmol) in the same manner as in EXAMPLE 1-1.
• p-Nitrobenzyl (IR,5S,6S)-6-[(IR)-l-hydroxyethyl]-2- [(2S,4R)-N-(p-nitrobenzyloxylcarbonyl)-2-(l-cyano-l-p- nitrobenzyloxycarbonylaminomethyl)pyrrolidin-4-ylthio]- l-methyl-l-carbapen-2-em-3-carboxylate (103.8 mg, yield : 76.4 %) was obtained from the above compound and p-nitrobenzyl (IR,5R,6S)-2-diphenoxyphosphoryloxy-6- [(IR)-l-hydroxyethyl]-l-methyl-l-carbapen-2-em-3- carboxylate (93 mg, 0.158 mmol) in the same manner as in EXAMPLE 1-2.
• IRfKBrJcm- 1 3400,2250,1760,1600,1400
• IRfKBrJciir 1 3410,1770,1700,1520,1345,1205,1135
• IRtKBrJc ⁇ r 1 3400,1770,1700,1600,1520,1340
• IRfKBrJc ⁇ r 1 3450,2100,1770,1700,1600,1520,1340
• IRfKBrJc ⁇ r 1 3400,2950,1750,1730,1600,1390
• IRfKBrJc ⁇ r* 3400,2950,1780,1700,1650,1540,1410
• IRfKBrJc ⁇ r 1 3420,2960,1775,1700,1605,1520,1400,1345, 1205,1140,1105,850,735
• IRfKBrJc ⁇ r 1 3420,1770,1700,1605,1520,1345,1205,1140, 1110,850,735
• N,N-diisopropyl- i ethylamine (0.22 ml, 1.25 mmol)
• N,N-diisopropyl- i ethylamine 0.22 ml, 1.25 mmol
• a solution of p-nitrobenzyl (IR,5S,6S)-2-diphenoxyphosphoryloxy-6- [ (I )-l-hydroxyethyl]-1-methy1-1-carbapen-2-em-3- carboxylate (344 mg, 0.579 mmol) in acetonitrile (8 ml) and N,N-diisopropylethylamine (0.11 ml, 0.62 mmol), and the mixture was stirred overnight at 5 °C.
• IR(KBr)cm- 1 3450,2950,1770,1700,1610,1520,1400,1340
• IRtKBrJc ⁇ r 1 3440,2970,2940,1770,1700,1610,1520,1400, 1340,1210,1140,1110 NMR(CDC1 3 ) ⁇ :
• IRfKBrJcirr 1 3420,2970,1760,1600,1400
• IRfKBrJc ⁇ r 1 3420,2970,1760,1600,1455,1390,1260,1150,
• IR(KBr)cm ⁇ 1 3440,1770,1695,1450,1405,1325,1280,1205, 1140,970,765
• IR(KBr)cm- 1 3420,2970,1760,1585,1395,1290,1265,1180, 1150
• IR(KBr)cm _1 3400,2920,1770,1700,1600,1520,1340,1200, 1130,1100,845,730
• IRtKBrJc ⁇ T 1 3400,2940,1770,1700,1605,1520,1345,1205, 1140,1110,850,740
• IR(KBr)cm -1 3450,2930,2880,1770,1700,1605,1520,1345,
• IRfKBrJc ⁇ T 1 3400,2950,1760,1580,1390
• UV ⁇ ma --(0.1 M MOPS buffer, pH 7.0): 298 nm ( ⁇ 8500)
• IRCKBrJc ⁇ T 1 3420,2970,1760,1590,1390 -
• the reaction mixture was poured into a mixture of water (30 ml) and 1 N aqueous potassium hydrogensulfate (30 ml), and extracted with ethyl acetate (1 X 100 ml, 2 X 50 ml).
• the combined organic layer was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate.
• IRfKBrJc ⁇ r 1 3450,2960,1760,1740,1705,1495,1450,1410,
• IRfKBrJc ⁇ r 1 3400,3320,1680,1530,1450,1410,1340,1255, 1200,745,705 NMR(CDC1 3 ) ⁇ :
• reaction mixture was diluted with ethyl acetate (150 ml), and successively washed with 1 N aqueous potassium hydrogensulfate, water, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2R,4R)-N-tert-butoxy- carbonyl-4-tert-butyldimethylsiloxy-2-[ (2-methyl-3-p- nitrobenzyloxycarbonylamino)propyl]pyrrolidine (750 mg, yield : 90 %).
• reaction mixture was diluted with ethyl acetate (150 ml), and washed successively with water, 1 N aqueous potassium hydrogensulf te, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (methylene chloride - ethyl acetate) to give (2S,4R)-4- hydroxy-2-(2-methyl-3-p-nitrobenzyloxycarbonylamino)- propyl-N-p-nitrobenzyloxycarbonylpyrrolidine (640 mg, yield : 92 %).
• IR(KBr)cm- 1 3400,2940,1700,1605,1520,1430,1400,1345, 1240,1105,850,735
• IRfKBrJcirr 1 3450,2930,1720,1700,1690,1600,1520,1340, 1240,1165,1105,900,735
• IRC BrJcm- 1 3400,2950,1700,1605,1520,1400,1345,1240, 1110,1010,855,740
• IRfKBrJcitT 1 3400,1700,1600,1520,1350
• reaction mixture was diluted with ethyl acetate (100 ml), and washed successively with 1 N hydrochloric acid, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2S, 4R)-N-allyloxycarbonyl-2-(2-allyloxycarbonyl- amino-1-hydroxy)ethyl-4-hydroxypyrrolidine diastereomer
• Diastereomer A of the title compound (165 mg, yield : 47 %) was obtained from the above diastereomer A (298 mg, 0.949 mmol) in the same manner as in REFERENCE EXAMPLES 7-5 and 7-6.
• Diastereomer B of the title compound (183 mg, yield : 55 %) was obtained from the above diastereomer B (280 mg, 0.892 mmol) in the same manner.
• DIASTEREOMER B IR(KBr)cm- 1 : 3400,2940,1690,1520,1410 NMR(CDC1 3 ) ⁇ :
• reaction mixture was diluted with ethyl acetate (70 ml), and washed successively with 1 N aqueous potassium hydrogensulfate, water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2R,4R)- N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[2,2- dimethyl-3-(p-nitrobenzyloxycarbonylamino)propyl]- pyrrolidine (730 mg, yield : 59 %).
• the crude amine compound was obtained from (2R,4R)- N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2- cyano-2,2-dimethyl)ethylpyrrolidine prepared in REFERENCE EXAMPLE 10-1 (1.44 g, 3.76 mmol) in the same manner as in REFERENCE EXAMPLE 10-2).
• the reaction mixture was diluted with ethyl acetate (150 ml), and washed successively with 1 N aqueous potassium hydrogensulfate, water and saturated aqueous sodium chloride.
• IR( Br)cm- 1 2900,1715,1680,1530,1470,1400,1360,1245, 1170,1105,835,770

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oncology (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Communicable Diseases (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pyrrole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• External Artificial Organs (AREA)
• Plural Heterocyclic Compounds (AREA)
• Cephalosporin Compounds (AREA)
• Materials For Medical Uses (AREA)
• Hydrogenated Pyridines (AREA)

Priority Applications (6)

Applications Claiming Priority (4)

Publications (1)

Family

ID=26520964

Family Applications (1)

Country Status (18)

Families Citing this family (5)

Citations (3)

Family Cites Families (2)

• 1992
  • 1992-11-14 TW TW081109118A patent/TW209220B/zh active
  • 1992-11-19 IL IL103807A patent/IL103807A0/xx unknown
  • 1992-11-24 YU YU100792A patent/YU100792A/sh unknown
  • 1992-11-25 AU AU29632/92A patent/AU651505B2/en not_active Ceased
  • 1992-11-26 AT AT92120226T patent/ATE195736T1/de not_active IP Right Cessation
  • 1992-11-26 CZ CS931501A patent/CZ150193A3/cs unknown
  • 1992-11-26 HU HU9302170A patent/HUT64345A/hu unknown
  • 1992-11-26 PL PL92300122A patent/PL300122A1/xx unknown
  • 1992-11-26 DE DE69231375T patent/DE69231375T2/de not_active Expired - Fee Related
  • 1992-11-26 EP EP92120226A patent/EP0545290B1/en not_active Expired - Lifetime
  • 1992-11-26 WO PCT/JP1992/001544 patent/WO1993011128A1/en not_active Ceased
  • 1992-11-26 KR KR1019930702228A patent/KR0175674B1/ko not_active Expired - Fee Related
  • 1992-11-27 MX MX9206838A patent/MX9206838A/es unknown
  • 1992-11-27 CN CN92114620A patent/CN1032061C/zh not_active Expired - Fee Related
  • 1992-11-27 CA CA002083980A patent/CA2083980C/en not_active Expired - Fee Related
• 1993
  • 1993-07-16 BG BG97965A patent/BG97965A/xx unknown
  • 1993-07-26 FI FI933346A patent/FI933346A7/fi unknown
• 1994
  • 1994-09-27 US US08/312,619 patent/US5550121A/en not_active Expired - Fee Related
  • 1994-10-18 AU AU75894/94A patent/AU667786B2/en not_active Ceased
• 1995
  • 1995-03-29 HU HU95P/P00093P patent/HU210817A9/hu unknown

Patent Citations (3)

Also Published As

Similar Documents

Legal Events