WO1991000864A1 - Derives de carbapenemes - Google Patents

Derives de carbapenemes Download PDF

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Publication number
WO1991000864A1
WO1991000864A1 PCT/JP1990/000866 JP9000866W WO9100864A1 WO 1991000864 A1 WO1991000864 A1 WO 1991000864A1 JP 9000866 W JP9000866 W JP 9000866W WO 9100864 A1 WO9100864 A1 WO 9100864A1
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Prior art keywords
group
hydrogen atom
general formula
compound
piperazinyl
Prior art date
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PCT/JP1990/000866
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English (en)
Japanese (ja)
Inventor
Yoshiaki Kato
Hiroshi Fukatsu
Susumu Nakagawa
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Banyu Pharmaceutical Co., Ltd.
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Publication of WO1991000864A1 publication Critical patent/WO1991000864A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems

Definitions

  • the present invention relates to a novel luminocenem derivative useful in the field of medicine as a therapeutic agent for bacterial infection. Background technology
  • the heteroarylalkylthio group described in JP-A-59-89683 is, for example, a pyridinylalkylthio group, an imidazolylalkylthio group, a thiazolylalkylthio group, a triazolylalkylalkylthio group, a thiaziazolylalkylthio group. And tetrazoliumalkylthio groups.
  • the heteroarylalkylthio groups described in JP-A-61-63678 and JP-A-61-83183 are, for example, pyridinylalkylthio, imidazoliumalkylthio, thiazolylalkylthio and the like. And a triazolium alkylthio group and a pyridazinium alkylthio group. No specific details have been found so far on the power vane compounds having a bicyclic pyrididimethylside characteristic of the present invention.
  • potent rubanem derivatives are useful for the treatment of diseases caused by pathogenic bacteria in humans and animals, the antibacterial activity of existing horvalinem derivatives is still satisfactory. Rather, it is widely used by the Chemical Society to show excellent antibacterial activity against various pathogenic bacteria.
  • the present inventors have conducted intensive studies to create a potent rubebenem derivative exhibiting excellent antibacterial activity against various pathogenic bacteria, and as a result, a novel potent rubenene represented by the following general formula [I] has been obtained.
  • the inventors have found that nem derivatives have excellent antibacterial activity, and have completed the present invention.
  • the present invention has the general formula
  • R 1 is a hydrogen atom or a methyl group
  • R 2 is a hydrogen atom, a cyano group, a carboxyl group, an alkoxycarbonyl group, or a group represented by —CON (R 3 ) R 4
  • R 3 and R 4 represent a hydrogen atom or a lower alkyl group
  • R 3 and R 4 together with an adjacent nitrogen atom represent an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, and a 4-lower alkylpiperazinyl group.
  • R 6 represents a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl group, or a group represented by -C ⁇ N (R 3 ) R 4 (where , R 3 and R 4 represent a hydrogen atom or a lower alkyl group, or R 3 and R 4 together with an adjacent nitrogen atom, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl group A heterocyclic group selected from the group consisting of a chloro group, a morpholino group and a thiomorpholino group), n represents an integer of 1 to 3], and a compound represented by the general formula
  • R 6 represents a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl group or a group represented by —CON (R 3 ) R 4 (here, R 3 and R 4 represent a hydrogen atom or a lower alkyl group, or R 3 and R 4 together with an adjacent nitrogen atom, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl group , you form a heterocyclic group selected from the group consisting of moles Horino group and thiomorpholino group), eta is an integer of 1 to 3, X s is related to compounds represented by represents an anion.
  • class means that the group to which g is attached has 1 to 6 carbon atoms.
  • Lower alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butynole group, isobutyl group, rt-butyl group, w-pentyl group, n-hexyl group, isohexyl And an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group and a teri-butyl group.
  • the lower alkoxyl propyl group refers to an oxycarbonyl group substituted by the above-mentioned lower alkyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, an rz-propoxycarbonyl group, an iert-butoxycarbonyl group and the like.
  • Means A C2-C5 alkoxylponyl group such as a methoxycarbonyl group, an ethoxycarbonyl group and an ieri-butoxycarbonyl group is preferred.
  • R 1 represents a hydrogen atom or a methyl group, and a compound of the general formula [I] in which R 1 is a methyl group is preferable.
  • R 2 and R 6 can be substituted on any ring as long as it is on the bicyclic heterocyclic group at the 2-position of the pendenem skeleton.
  • the present invention encompasses optical isomers based on the asymmetric carbon atoms at positions 1, 5, 6, and 8 of the carbane skeleton, and compounds suitable for these isomers include, but are not limited to, chenamycin.
  • compounds suitable for these isomers include, but are not limited to, chenamycin.
  • 5R, 6S In the (5R, 6S) configuration where the carbon atom at the 8-position is in the R configuration (5R, 6S, 8R), or when the compound has a methyl group at the 1-position, 1R, 5S, 6S, 8R).
  • (1), (5), (25), (47), (58) and (72) are preferred.
  • the compound of the general formula [I] can be converted into a pharmaceutically acceptable non-toxic salt or an ester thereof by a conventional method.
  • the non-toxic salt of the compound of the general formula [I] means a pharmaceutically acceptable and conventional salt, which is on the 3-position carboxyl group or 2-position bicyclic pyridinium ring of carbane.
  • the substituent is a carboxyl group, it means a salt at the carboxyl group.
  • Salts with alkali metals such as sodium, potassium and lithium; salts with alkaline earth metals such as calcium and magnesium; salts such as ⁇ , ⁇ '-dibenzylethylenediamine, ethanolamine and triethylamine Salts with organic amines; for example, salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as citric acid and acid; for example, methyl sulfonic acid, ⁇ -toluene sulfonic acid, and the like Or a salt with an aminosulfonic acid such as aspartic acid, glutamic acid and lysine.
  • inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid
  • salts with organic acids such as citric acid and acid
  • methyl sulfonic acid, ⁇ -toluene sulfonic acid, and the like Or a salt with an
  • the non-toxic ester of the general formula [I] means a conventional pharmaceutically acceptable carboxy group at the 3-position of carbane or a carboxyl group at 2-position on the pyridinium ring.
  • an ester with an alkanoinoleoxymethyl group such as an acetooxymethyl group, a bivaloyloxymethinole group
  • an ester with an alkoxycarbonyloxyalkyl group such as a 1- (ethoxycarbonyloxy) ethyl group
  • an ester with a phthalidyl group and a 5-methyl- Estenoles with 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl groups such as 2-oxo-1,3-dioxol-4-ylmethyl group.
  • R 1 is a hydrogen atom or a methyl group
  • R 5 is a carboxyl protecting group
  • Z is a leaving group
  • R 6 represents a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxycarbonyl group, or a group represented by —CON (R 3 ) R 4 (wherein R 3 and R 4 is a hydrogen atom or lower alkyl group, R 3 and R 4 are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, piperazinyl, 4-lower alkylpiperazinyl, with adjacent nitrogen atoms
  • a heterocyclic group selected from the group consisting of a holino group and a thiomorpholino group), represents an integer of 1 to 3], and then subjected to an N-methylation reaction. Further, the compound of the general formula [I] can be produced by removing the protecting group.
  • the reaction between the compound of the general formula [ ⁇ ] and the compound of the general formula [m] is performed by diisopropyl Reaction of acetonitrile, ⁇ , ⁇ -dimethylformamide, -dimethylacetamide or- ⁇ : -nitylpyrrolidine in the presence of a barrier group such as ethylethylamine, triethylamine or 4-N, X-dimethylaminopyridine 5 minutes to 10 hours at a temperature of -40 to 25 ° C with an inert solvent that does not affect the temperature.
  • a barrier group such as ethylethylamine, triethylamine or 4-N
  • X-dimethylaminopyridine 5 minutes to 10 hours at a temperature of -40 to 25 ° C with an inert solvent that does not affect the temperature.
  • the N-methylation reaction for quaternization can be carried out according to a conventional method using a usual methinolelating agent such as methyl iodide, methyl triflate, methyl fluorosulfonate, dimethyl sulfate and the like.
  • a usual methinolelating agent such as methyl iodide, methyl triflate, methyl fluorosulfonate, dimethyl sulfate and the like.
  • examples of the protecting group for the carboxyl group include protecting groups usually used in the art.
  • carboxyl protecting group examples include an iert-butyl group, a 2,2,2-trichloroethyl group, an acetoxmethyl group, a propionylloquinmethyl group, a bivaloyloxymethyl group, a 1-acetoxicetyl group, and a 1-propionyloxethyl group.
  • nitrobenzyl group, Benzhydryl, teri-butyl, silyl and the like are preferred.
  • a compound of the general formula [I] can be obtained by performing a deprotection reaction known per se depending on the type of the protecting group.
  • the protecting group is a nitrobenzyl group, for example, tetrahydrofuran monohydrate, dioxane, including phosphate buffer of ⁇ 7, 3-morpholinopropanesulfonic acid buffer, dibasic phosphate, etc.
  • the leaving group represented by Z means an anl group derived from an organic phosphoric acid or an organic sulfonic acid, for example, a diphenyloxyphosphoryloxy group, a methanesulfonyloquine group, Trifluoromethanesulfonyloxy, toluenesulfonyloxy, etc.
  • a phosphoryl group and a methanesulfonyloxy group are preferred.
  • the compound of the general formula [M] can be prepared, for example, by the method described in TN Salzmann et al., J. Am. Chem. Soc "102, 6161 (1980) or DH Shih et al" Heterocycles, 21, 29 (1984). Obtained from a bicyclic ketoester. The ester obtained by this method can be used for this reaction without isolation or isolation.
  • R 1 is a hydrogen atom or a methyl group
  • R 5 is a carboxyl-protecting group
  • Z is a leaving group
  • R 6 is a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl group or a group represented by —CON (R 3 ) (wherein R 3 and R 4 represents a hydrogen atom or a lower alkyl group; R 3 and R 4 together with an adjacent nitrogen atom are an aziridinyl group, an azetidinyl group, a pyrrolidinyl , A piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl group, a morpholino group and a thiaminomorpholino group), n is an integer of 1 to 3, X s Represents an anion. Contrary to the chemical compound ⁇ ⁇ ⁇ represented by
  • R l, R 5 are R 6, n and chi theta have the meanings given above] as represented by compounds, by removing the protecting group then to produce a compound of the general formula [I] Can be
  • the anion represented by ⁇ is, for example, a chloride ion, a bromine ion, a halogen ion such as an iodine ion, a sulfate ion, a hydrogen sulfate ion, a methyl sulfate ion, a -toluenesulfonic acid ion, a methylsulfonic acid ion, or a trifluorofluoride ion.
  • the reaction of reacting the compound of the formula [IV] with the compound of the formula [IV] to obtain the compound of the general formula [V] is carried out by the compound of the general formula [ ⁇ ] and the compound of the general formula [ ⁇ ] in the production method A.
  • the deprotection reaction of the compound of the general formula [V] can be carried out in the same manner as in the deprotection reaction of the production method A.
  • the compound of the general formula [V] is a simple compound
  • the reaction can be performed without separation or isolation.
  • R 1 represents a hydrogen atom or a methyl group
  • R 5 represents a carboxyl-protecting group
  • Z represents a leaving group
  • R 1 and R 5 have the same meanings as defined above, and then a compound of the general formula [VI] and a compound of the general formula
  • R 6 is a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxycarbonyl group or a group represented by —C ⁇ N (R 3 ) R 4 (here, R 3 and R 4 represents a hydrogen atom or a lower alkyl group, R 3 and R 4 together with an adjacent nitrogen atom, an aziridinyl group, a azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl group, Forms a heterocyclic group selected from the group consisting of morpholino and thiomorpholino , Y represents a leaving group, ⁇ represents an integer of 1 to 3], and then subjected to ⁇ -methylation reaction, and further removing the protecting group to obtain ⁇ Can the compound of formula [.1] be prepared?
  • the compound of the general formula [VI] is obtained by reacting the compound of the general formula [ffl] with sodium hydrosulfide at a temperature of 5 minutes to 1 hour ⁇ -50 minutes to -20 ° C. in N, N-dimethylformamide, It is obtained by reacting in an inert solvent such as ⁇ , ⁇ -dimethylacetamide and can be used for the next reaction without isolation.
  • the reaction between the compound of the general formula [VI] and the compound of the general formula [W] can be carried out, for example, in the presence of a base such as diisopropylethylamine, triethylamine, 4- ⁇ , ⁇ -dimethylaminopyridine in the presence of acetonitrile, It can be carried out in an inert solvent such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide.
  • a base such as diisopropylethylamine, triethylamine, 4- ⁇ , ⁇ -dimethylaminopyridine in the presence of acetonitrile
  • an inert solvent such as ⁇ , ⁇ -dimethylformamide and ⁇ , ⁇ -dimethylacetamide.
  • the reaction temperature is ⁇ 40 to 25 ° C., and the reaction time is 10 minutes to 8 hours.
  • the N-methylation reaction and deprotection reaction that is carried out subsequent to the above reaction can be carried out in the same manner as in the N-methylation reaction and deprotection reaction of Production method A.
  • examples of the leaving group represented by Y include halogen atoms such as chlorine atom, bromine atom and iodine atom, and sulfonyloquine groups such as methanesulfonyloxy group and -toluenesulfonyloxy group.
  • halogen atoms such as chlorine atom, bromine atom and iodine atom
  • sulfonyloquine groups such as methanesulfonyloxy group and -toluenesulfonyloxy group.
  • R 1 represents a hydrogen atom or a methyl group
  • R 5 represents a carboxyl-protecting group
  • Z represents a leaving group
  • R 1 and R 5 have the same meanings as described above, and then a compound of the general formula [VI] and a compound of the general formula
  • R 6 is a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl propyl group, or a group represented by —C ⁇ N (R 3 ) R 4 (wherein R 3 and R 4 represent a hydrogen atom or a lower alkyl group; R 3 and R together with an adjacent nitrogen atom are an aziridinyl group, a azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl group, mol Horino you form a heterocyclic group selected from the group consisting of groups and thiomorpholino), chi theta anion, Upsilon is a leaving group, eta is a compound represented by from 1 represents an integer of 3] And the general formula
  • RR 5, R 6, n and chi theta are as defined above] and represented by the compound, by removing the protecting group then, it is possible to obtain a compound of general formula [I] .
  • the compound of general formula [V] can be produced by reacting a compound of general formula [VI] and a compound of general formula CM obtained by the same reaction as in production method C.
  • the reaction between the compound of the general formula [VI] and the compound of the general formula [M] can be carried out in the same manner as in the reaction of the compound of the general formula [VI] with the compound of the general formula [W] in Production method C.
  • the deprotection reaction of the compound of the general formula [V] can be carried out in the same manner as in the deprotection reaction of Production method C.
  • the leaving group represented by Y is preferably a leaving group represented by the general formula [].
  • R 6 is a hydrogen atom, a cyano group, an optionally protected carboxyl group, Grade alkoxy force carbonyl group or - CON (R 3) P, 4 a group represented by (wherein smell Te, R 3 and R 4 represents a hydrogen atom or a grade alkyl group, with R 3 and the ridge contact nitrogen atom
  • n is 1
  • R 6 represents a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl group or a group represented by —CON (R 3 ) R 4 (here, R 3 and R 4 represent a hydrogen atom or a lower alkyl group, or R 3 and together with an adjacent nitrogen atom, an aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidino group, piperazinyl group, 4-lower alkylpiperazinyl group, mol you form a heterocyclic group selected from the group consisting of Horino group and thiomorpholino group), n is also directed to compounds and their preparation expressed by an integer of 1 to 3, X s represents an anion] .
  • the compound of the general formula [[] can be produced, for example, by the following method.
  • R 7 represents a hydroxyl group or a halogen atom
  • R 8 represents a mercapto-protecting group
  • compound A is used as a starting material to perform step A to obtain compound 2, and the protecting group for the mercapto group is removed.
  • This step is a step of converting R 7 of a known compound or a compound easily derivable from the known compound into a protected mercapto group.
  • Various known methods can be used for the conversion.
  • R 7 is a hydroxyl group
  • the hydroxyl group is converted into a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a leaving group such as a mesyloxy group or a tosyloxy group to obtain a reactive derivative of the compound.
  • the reactive derivative and various thiolating reagents such as thioic acid, thiobenzoic acid, trityl mercaptan, methoxybenzyl mercaptan, and the like, for example, triethylamine, disopropylethylamine, ⁇ -methylmorpholine, 1,8-diazabicyclo [5.4.0]-This step can be achieved by reacting in the presence of a base such as 7-pentane, sodium hydroxide, potassium tert-butoxide, sodium methoxide, and sodium hydride.
  • a base such as 7-pentane, sodium hydroxide, potassium tert-butoxide, sodium methoxide, and sodium hydride.
  • the reaction solvent may be any solvent that does not adversely affect the reaction, such as dichloromethane, tetrahydrofuran, and ⁇ , ⁇ -dimethylformamide, and may be a mixed solvent thereof.
  • the reaction temperature is usually from -60 to 80 ° C, preferably from -20 ° C to room temperature.
  • the reaction time is usually between minutes and 16 hours, especially 30 minutes. Minutes to 2 hours are preferred.
  • compound ⁇ is obtained by reacting compound ⁇ with a thiolating acid or another thiolating reagent in an inert solvent such as tetrahydrofuran in the presence of trifuninylphosphine and getylazodicarboxylate. You can also.
  • This step is a step of removing the protected mercapto group-protecting group of the compound.
  • R 8 when R 8 is an acyl group, it can be removed by a method using alkali hydrolysis, and when R 8 is a trityl group, methoxybenzyl group or the like, it can be removed by a method using an acid such as trifluoroacetic acid or trifluoromethanesulfonic acid.
  • R 7 In the case of a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom, in addition to the above-described methods, an S-alkylisothioperonium salt obtained by reacting compound ⁇ with thiourea, S-alkylthiosulfate obtained by reacting sodium thiosulfate, dithiocarbamic acid ester obtained by reacting compound ⁇ with ⁇ , ⁇ -dimethyldithiol sodium rubamate, compound ⁇ and dithiocarbonate By hydrolyzing an intermediate such as estenole dithiocarbonate obtained by reacting with ethyl potassium, the compound of the general formula [III] can also be obtained. Next, a method for producing the compound of the general formula [IV] will be described.
  • the compound of the general formula [IV] can be produced, for example, by the following method.
  • the compound is subjected to the above step (2) using the compound as a starting material to obtain a compound, and then subjected to an N-methyl iodide reaction to obtain a compound ( ⁇ ), and then the protective group for the mercapto group is removed.
  • Step A As described above
  • compound 2 is subjected to an N-methylation reaction to produce compound ⁇ .
  • N-methylidani reaction it is preferable to carry out the reaction according to the N-methyl hydride reaction described in Production method A.
  • This step is for removing the protecting group for the mercapto group of compound 3.
  • reaction for removing the protecting group of the mercapto group Various known methods can be used for the reaction for removing the protecting group of the mercapto group. For example, it is preferable to carry out according to the deprotection method carried out in the above-mentioned step B.
  • the compounds of the general formula [Alone] and the compounds of the general formula [Cor] are also important intermediates for the preparation of the compounds of the general formula [I].
  • the second compound is a known compound or can be easily derived from a publicly known association. That is, in the compound of the formula [ ⁇ ] or the compound of formula [IV] for producing a compound of the formula [IV], when R 7 is a halogen atom: Is a halogen atom, and in this case, a compound of the general formula [W] is obtained.
  • R 7 of the compound is a hydroxyl group
  • the hydroxyl group is easily derived to a halogen atom such as a chlorine atom, a bromine atom or an iodine atom or a leaving group such as a mesyloxy group or a tosylquine group by a known method
  • the compound of [W] can be produced.
  • the compound of the general formula [VI] can be easily produced by subjecting the compound of the general formula [W] to a ⁇ -methyl reaction.
  • the ⁇ -methylation reaction is a function of various known methods, and is preferably performed, for example, according to the ⁇ -methylation reaction described in Production Method ⁇ .
  • the compound of the present invention exhibits excellent antibacterial activity and is a novel compound useful as a pharmaceutical, and is useful for the treatment and prevention of bacterial infections such as respiratory infections, urinary tract infections, suppurative diseases, and surgical infections.
  • bacterial infections such as respiratory infections, urinary tract infections, suppurative diseases, and surgical infections.
  • parenteral administration by intravenous injection, intramuscular injection or suppository or oral administration by tablet, powder, capsule or syrup is applied.
  • it is possible to employ conventional methods in this field for example, including commonly used additives such as auxiliaries, wetting agents, emulsifiers, binders, and excipients. You may.
  • the dosage is determined in consideration of age, gender, body weight, difference in sensitivity, administration method, time and interval of administration, degree of medical condition, physical condition, nature of pharmaceutical preparation, type of preparation or type of active ingredient, etc. However, it is usually in the range of 1 to 100 mgZg per day, and it is preferable to administer 5 to 30 mg / g per day in 2 to 4 divided doses.
  • the in vitro antibacterial activity against bacteria was measured by the following agar plate dilution method.
  • one platinum loop (each inoculation amount: 10 s CFU / 772i) of each test strain cultured overnight in Muller-Hinton's broth was inoculated into 'Myton' agar.
  • This medium contained the Hama reagent at a predetermined concentration.
  • the minimum growth inhibitory concentration (MIC, ⁇ / ⁇ ) was measured. The results are shown in the table.
  • the compounds of the present invention exhibit excellent antibacterial activity.
  • the present invention will be described in more detail with reference to Examples and Reference Examples. The present invention is not limited thereto.
  • UV 0.1M 3-morpholinopropane sulfonate buffer, pH 7.0:
  • UV A max (0.1 M 3-morpholinopropane sulfonate buffer, pH 7.0):
  • UV solution 0.1M 3-morpholinopropane sulfonate buffer, pH 7.0:
  • reaction solution was treated with IN hydrochloric acid, shrunk, and the residue was dissolved in ethyl acetate. After this was water-dried, it was dried over magnesium sulfate water and the solvent was distilled off to obtain 2.81 g (yield: 89.5%) of the title compound as an oil.
  • the compounds of the formula [I] of the present invention are useful as antibacterial agents because they exhibit excellent antibacterial activity against Gram-positive bacteria and Gram-positive bacteria.
  • the compound of the general formula [ ⁇ ] and the compound of the general formula [W] are novel compounds not described in the literature, and are useful as intermediates for synthesizing the compound of the general formula [I].

Abstract

L'invention concerne des composés représentés par la formule générale (I), leurs sels et esters pharmaceutiquement acceptables, leur préparation et leurs utilisations. Dans la formule générale (I), R1 représente hydrogène ou méthyle; R2 représente hydrogène, cyano, carboxyle, alkoxycarbonyle inférieur ou -CON(R?3)R4, où R3 et R4¿ représentent chacun hydrogène ou alkyle inférieur, ou peuvent représenter ensemble avec l'atome d'azote adjacent un groupe hétérocyclique sélectionné dans le groupe formé d'aziridinyle, azétidinyle, pyrrolidinyle, pipéridino, pipérazinyle, 4-(alkyle inférieur)pipérazinyle, morpholino et thiomorpholino; et n est un nombre entier compris entre 1 et 3.
PCT/JP1990/000866 1989-07-07 1990-07-06 Derives de carbapenemes WO1991000864A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP17694689 1989-07-07
JP1/176946 1989-07-07

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WO1991000864A1 true WO1991000864A1 (fr) 1991-01-24

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PCT/JP1990/000866 WO1991000864A1 (fr) 1989-07-07 1990-07-06 Derives de carbapenemes

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6163678A (ja) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド 外的にアルキル化されたモノ又はビサイクリツク２−第４級ヘテロアリ−ルアルキルチオ置換分を有するカルバペネム類
JPS6163679A (ja) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド ２−四級ヘテロアリ−ルアルキルチオ置換基を有する１−メチルカルバペネム類
JPS6183183A (ja) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 外的にアルキル化されたモノ−またはビ−サイクリツク２−第４級ヘテロアリ−ルアルキルチオ置換基を持つ１−メチルカルバペネム類
JPS6183184A (ja) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド ２−第四級ヘテロアリ−ルアルキルチオ置換基を有するカルバペネム類
JPS63255284A (ja) * 1987-04-11 1988-10-21 Nippon Redarii Kk （１ｒ，５ｓ，６ｓ）−２−〔（置換ピリジニウム−２−イル）メチル〕チオ−６−〔（ｒ）−１−ヒドロキシエチル〕−１−メチル−カルバペネム−３−カルボキシレ−ト

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6163678A (ja) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド 外的にアルキル化されたモノ又はビサイクリツク２−第４級ヘテロアリ−ルアルキルチオ置換分を有するカルバペネム類
JPS6163679A (ja) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド ２−四級ヘテロアリ−ルアルキルチオ置換基を有する１−メチルカルバペネム類
JPS6183183A (ja) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 外的にアルキル化されたモノ−またはビ−サイクリツク２−第４級ヘテロアリ−ルアルキルチオ置換基を持つ１−メチルカルバペネム類
JPS6183184A (ja) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド ２−第四級ヘテロアリ−ルアルキルチオ置換基を有するカルバペネム類
JPS63255284A (ja) * 1987-04-11 1988-10-21 Nippon Redarii Kk （１ｒ，５ｓ，６ｓ）−２−〔（置換ピリジニウム−２−イル）メチル〕チオ−６−〔（ｒ）−１−ヒドロキシエチル〕−１−メチル−カルバペネム−３−カルボキシレ−ト

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