WO1991000864A1 - Carbapenem derivatives - Google Patents

Carbapenem derivatives 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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French (fr)
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/en

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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].

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Abstract

Compounds represented by general formula (I), pharmaceutically acceptable salts and esters thereof, and preparation and uses thereof, wherein R1 represents hydrogen or methyl; R2 represents hydrogen, cyano, carboxyl, lower alkoxycarbonyl, or -CON(R3)R4, wherein R?3 and R4¿ each represents hydrogen or lower alkyl, or R?3 and R4¿ may form together with the adjacent nitrogen atom a heterocyclic group selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-(lower alkyl)piperazinyl, morpholino, and thiomorpholino; and n is an integer of 1 to 3.

Description

明 鈿 書 力ルバぺネム誘導^ 技 術 分 野  Myan mother's book
本発明は医薬の分野において、 細菌感染症の治療剤として有用な新規な力 ルノくベネム誘導体に関するものである。 背 景 技 術  TECHNICAL FIELD The present invention relates to a novel luminocenem derivative useful in the field of medicine as a therapeutic agent for bacterial infection. Background technology
抗菌剤として有用な活性を示すチェナマイシンが発見されて以来、 数多く の力ルバぺネム誘導体が合成され、 特許出願されている。 例えば特開昭 59 - 89683号公報、 同 61 - 63678号公報および同 61 - 83183号公報等には力ルノ ぺネムの 2位側鎖として、 ヘテロァリールアルキルチオ基が広範に一般的に 記述され、 さまざまなヘテロァリール基がリスト化され開示されている。 し かしながら、 当業者が「発明の詳細な説明」、就中、実験に裏づけられた説明 から確認または容易に示唆できるヘテロァリールアルキルチオ基は、 そのへ テロァリール部分が単環のありふれたヘテロァリールアルキルチオ基に限ら れている。 特開昭 59- 89683号に記載のへテロアリールアルキルチオ基は、 例えばピリジニゥムアルキルチオ基、 ィミダゾリゥムアルキルチオ基、 チア ゾリゥムアルキルチオ基、 トリアゾリゥムアルキルチオ基、 チアジァゾリゥ ムアルキルチオ基およびテトラゾリゥムアルキルチオ基である。 特開昭 61 - 63678号公報および特開昭 61 - 83183号公報に記載のへテロァリールアルキ ルチオ基は、 例えばピリジニゥムアルキルチオ基、 ィミダゾリウムアルキル チォ基、 チアゾリゥムアルキルチオ基、 トリァゾリウムアルキルチオ基およ びピリダジニゥムアルキルチオ基である。 本発明の特徴とする二環性ピリジ 二ゥムチォ基を有する力'しバぺネム化合物に関しては、 現在まで具体的には 何も知られていない。  Since the discovery of chenamycin, which has useful activity as an antibacterial agent, a large number of rubanem derivatives have been synthesized and patented. For example, JP-A-59-89683, JP-A-61-63678 and JP-A-61-83183 widely and generally describe a heteroarylalkylthio group as the 2-position side chain of a phenol compound. Various heteroaryl groups are listed and disclosed. However, those skilled in the art will appreciate that heteroarylalkylthio groups, which can be ascertained or readily suggested from the "Detailed Description of the Invention", especially from the experimental description, are those in which the heteroaryl moiety is a monocyclic heterocycle. Limited to arylalkylthio groups. 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.
力ルバぺネム誘導体はヒト及び動物の病原性細菌により生ずる疾病の治療 に有用であるが、 既存の力ルバぺネム誘導体の抗菌活性は十分満足できるも のではなく、 各種の病原性結菌に対して優れた抗菌作 を示す化会 ¾の ώ 力、 Ήまれている。 Although the 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.
また ¾床に^されている力ルバぺネ厶化会 ¾であるィミぺネ厶は、 チェナ マイシンと同様に腎デヒドロべプチダーゼによって分解されるため、 シラス 夕チンのような DHP阻害剤とともに併用されている。 従って、 DHPに対する 安定性の改善された良好な抗菌作用を有する力ルバぺネム化合物が求められ ている。 発 明 の 開 示  In addition, imimenem, which is an active chemical compound, is degraded by renal dehydrobeptidase, similar to chenamycin, and is therefore used together with DHP inhibitors such as Shirasu Yutin. Has been used together. Accordingly, there is a need for a potent rubenem compound having improved antimicrobial activity with improved stability against DHP. Disclosure of the invention
本発明者らは、 各種病原性細菌に対して優れた抗菌活性を示す力ルべベネ ム誘導体を創製するべく鋭意研究した結果、 後記の一般式 [ I ] で表される 新規な力ルバぺネム誘導体が優れた抗菌活性を有することを見出し、 本発明 を完成した。  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.
本発明は一般式  The present invention has the general formula
Figure imgf000004_0001
Figure imgf000004_0001
[式中、 R1は水素原子またはメチル基、 R2は水素原子、 シァノ基、 カルボキシ ル基、 £ ^アルコキシカルボニル基または- CON (R3) R4で表される基（ここ において、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R4は隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジ ニル基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、モ ルホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成 する）、 nは 1ないし 3の整数を示す] で表される化合物またはその医薬とし て許容される塩またはエステル、 該化合物またはその医薬として許容される 塩またはエステルの製法、 該化合物またはその医薬として許容される塩また はニステルを有効成分とする抗菌剤および一般式 [Wherein, 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 (wherein R 3 and R 4 represent a hydrogen atom or a lower alkyl group, and 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. A heterocyclic group selected from the group consisting of a chloro group, a morpholino group and a thiomorpholino group), and n represents an integer of 1 to 3] or a pharmaceutically acceptable salt or ester thereof. A method for producing the compound or a pharmaceutically acceptable salt or ester thereof, a method for producing the compound or a pharmaceutically acceptable salt thereof or Is an antibacterial agent containing Nistel as an active ingredient and a general formula
Figure imgf000005_0001
Figure imgf000005_0001
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- C〇N ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 nは 1ないし 3の整数を示す] で表される化合物ならびに一般式 [Wherein, 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〇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
Figure imgf000005_0002
Figure imgf000005_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 ηは 1ないし 3の整数、 Xsは陰イオンを示す] で表される化合物に関す る。 一般式 [ Π ] の化合物および一般式 [W] の化合物は、 文献未記載の新 規化合物であり、 一般式 [ I ] の化合物を製造するための重要な中間体であ る。 次に、 本明^書において言及される各種 E語および子適な化合 tj例につ 、 て説明する。 [In the 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. The compound of the general formula [[] and the compound of the general formula [W] are new compounds not described in the literature, and are important intermediates for producing the compound of the general formula [I]. Next, various E-words and examples of suitable compounds tj mentioned in this specification will be described.
「 級」なる語は、 この gが付された基の炭素原子数が 1ないし 6倡である ことを意味する。  The term "class" means that the group to which g is attached has 1 to 6 carbon atoms.
低級アルキル基とは、 例えばメチル基、 ェチル基、 n-プロピル基、 イソプ 口ピル基、 n-ブチノレ基、 イソブチル基、 rt -ブチル基、 w-ペンチル基、 n-へ キシル基、 イソへキシル基等のアルキル基を意味し、 メチル基、ェチル基、 n - プロピル基、 n-ブチル基、 teri-ブチル基等の炭素数 1ないし 4個のアルキル 基が好適である。  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.
低級アルコキシ力ルポニル基とは、 前記の低級アルキル基が置換したォキ シカルボ二ル基を示し、 例えばメ トキシカルボニル基、 エトキシカルボニル 基、 rz -プロボ シカルボニル基、 iert-ブトキシカルボ二ル基等を意味する。 メ ト午シカルボニル基、 エトキシカルボニル基、 ieri-ブトキシカルボニル基 等の炭素数 2ないし 5個のアルコキシ力ルポニル基が好適である。  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.
R1は水素原子またはメチル基を意味し、 R1がメチル基である一般式 [ I ] の化合物が好適である。 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.
R2および R6は力ルノ ぺネム骨格の 2位の二環性複素環基上であれば、 ヽず れの環上でも置換することができる。 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.
一般式 [ I ] の化合物中、 好適な化合物群は、 一般式  Among the compounds of general formula [I], a preferred group of compounds is
[I一 a]
Figure imgf000006_0001
o 一 [I-a]
Figure imgf000006_0001
o one
一般式 General formula
[I一 b]
Figure imgf000007_0001
中、 R1および R2は前記の意味を有する] で表される化合物であり、 特に 一般式 [ I - a] の化合物が好適である。 [I-b]
Figure imgf000007_0001
Wherein R 1 and R 2 have the above-mentioned meanings], and a compound of the general formula [I-a] is particularly preferable.
本発明は、 力ルバぺネム骨格の 1位、 5位、 6位および 8位の不斉炭素原子 に基づく光学異性体を包含するが、 これらの異性体で好適な化合物は、 チェ ナマイシンのような立体配位を有する （5R,6S)配置であり、かつ 8位の炭素 原子が R配置である （5R,6S，8R) 配置の化合物、 または 1位にメチル基を有 する場合は、 （1R，5S，6S,8R) 配置の化合物を挙げることができる。  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. 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).
次に、 一般式 [ I ] の化合物の具体例を例示する。  Next, specific examples of the compound of the general formula [I] will be illustrated.
(以下余白） (Hereinafter the margin)
R' CH「N' R 'CH "N'
COO COO
cccccccc c c c cc ccccc c c c  cccccccc c c c cc ccccc c c c
化合物 RTPT T-FTTrr FTFT ϊr' R2 R2の置 i;化合 ¾ R' の置 換位置卩番 号 R2 ¾ !Ξ置Compound RTPT T-FTTrr FTFT ϊr 'R 2 R 2 substitution i; Compound R' substitution position R 2 ¾! Substitution
1 H 24 CH3 CON^S 1 H 24 CH 3 CON ^ S
2 CN 5 25 H H  2 CN 5 25 H H
3 CN 6 26 H COOH o 4 COOH H 5 27 H COOH 6 5 COOH 6 28 H CONH, o 6 COOCH3 5 29 H C〇NH2 6 7 COOCH3 6 30 H CONHCH3 5 8 COOC2¾ 5 31 H CONHCH3 6 9 COOC2H5 6 32 H CON(CH3): 5 10 CONH2 5 33 H C〇N(CH3): 63 CN 6 26 H COOH o 4 COOH H 5 27 H COOH 6 5 COOH 6 28 H CONH, o 6 COOCH 3 5 29 HC〇NH 2 6 7 COOCH3 6 30 H CONHCH3 5 8 COOC 2 ¾ 5 31 H CONHCH3 6 9 COOC 2 H 5 6 32 H CON (CH 3 ) : 5 10 CONH 2 5 33 HC〇N (CH 3 ) : 6
11 CONH2 6 34 H CON 1 11 CONH 2 6 34 H CON 1
12 CONHCH3 5 35 H CON I 6 13 CONHCH3 6 36 H CON' 6 12 CONHCH3 5 35 H CON I 6 13 CONHCH 3 6 36 H CON '6
14 CON(CH3)z 37 H CON O δ14 CON (CH 3 ) z 37 H CON O δ
15 CON(CH3)2 6 38 CH3 CONH2 2 16 CON(C2H5)2 5 39 CH3 CONHCH3 3 17 CON(C2¾)2 6 40 CH3 CON(CH3)2 415 CON (CH 3 ) 2 6 38 CH 3 CONH 2 2 16 CON (C 2 H 5 ) 2 5 39 CH 3 CONHCH 3 3 17 CON (C 2 ¾) 2 6 40 CH 3 CON (CH 3 ) 2 4
18 CONコ 5 41 CH3 CON;] 4 19 CONつ 6 42 CH3 CONC] iD 20 CON 5 CH3 CON^] 6 21 CON 6 CH3 CO ^> 4 18 CON 5 5 CH 3 CON;] 4 19 CON 6 42 CH 3 CONC] iD 20 CON 5 CH 3 CON ^] 6 21 CON 6 CH 3 CO ^> 4
22 !CH3| CON -CH3 6 ！ 45 CH3 C0N> 522! CH 3 | CON -CH 3 6! 45 CH 3 C0N > 5
23 iCHs CON 0 5 ；； 46 CH3 CON^ 6
Figure imgf000009_0001
上記の化合 ti群中、 好適な化合物は、 23 iCHs CON 0 5 ;; 46 CH 3 CON ^ 6
Figure imgf000009_0001
Among the above compounds ti, preferred compounds are
(I) (1R,5S;6S) -2- [卜メチル - 6，7-ジヒドロ- 5 f-シクコベンタ [&]ピリジ ニゥム -7-ィル] チォ- 6- [(1R) -i-ヒドロキシニチル] - メチルカ ルバペン- 2-ェム -3-カルボキシラート (I) (1R, 5S ; 6S) -2- [Trimethyl-6,7-dihydro-5f-siccobenta [&] pyridinium-7-yl] thio-6-[(1R) -i-hydroxy Nityl] -Methylcarbapene-2-em-3-carboxylate
(2) (1 5S,6S)- 2— [5-シァノ -1-メチノレ— 6,7 -ジヒドロ— 5H-シクロペン タ [6]ピリジニゥム- 7-ィル] チォ- 6- [(1R) -トヒドロキシェチノレ] - 1-メチルカルバペン- 2-ェム- 3-カルボキシラート (2) (15S, 6S) -2- [5-Cyano-1-methynole-6,7-dihydro-5H-cyclopenta [6] pyridinium-7-yl] thio-6-[(1R)- Tohydroxyethynole]-1-methylcarbapene-2-em-3-carboxylate
(3) (1R.5S.6S) -2- [6-シァノ -1-メチル -6,7-ジヒドロ- 5ii-シクロペン タ [6]ピリジニゥム- 7-ィル] チォ- 6- [(1R) -トヒドロキシェチル] - 1-メチルカルバペン- 2-ェム- 3-カルボキシラート  (3) (1R.5S.6S) -2- [6-cyano-1-methyl-6,7-dihydro-5ii-cyclopenta [6] pyridinium-7-yl] thio-6-[(1R) -Trihydroxyethyl]-1-methylcarbapene-2-em-3-carboxylate
(4) (1R.5S.6S) -2- [5-カルボキシ- 1-メチル -6,7-ジヒドロ- 5H-シクロ ペンタ [&]ピリジニゥム- 7-ィル] チォ- 6- [(1R) -卜ヒドロキシェチ ル] -1-メチルカルバペン- 2-ェム- 3-カルボキシラート  (4) (1R.5S.6S) -2- [5-carboxy-1-methyl-6,7-dihydro-5H-cyclopenta [&] pyridinium-7-yl] thio-6-[(1R) -Trihydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate
(5) (1R，5S,6S) - 2- [6-カルボキシ-卜メチル -6,7 -ジヒドロ- 5H-シクロ ペンタ [ ピリジニゥム- 7-ィル] チォ- 6- [(1R) - 1-ヒ ドロキシ ェチル] -1-メチルカルバペン- 2-ェム -3 -カルボキシラート  (5) (1R, 5S, 6S) -2- [6-Carboxy-methyl-6,7-dihydro-5H-cyclopenta [pyridinium-7-yl] thio-6-[(1R) -1- [Hydroxyethyl]]-1-methylcarbapene-2-em-3-carboxylate
(6) (1R，5S,6S)- 2- [5-メ トキシカルボニル- 1-メチル -6,7-ジヒドロ- 5H - シクロペンタ [&〗ピリジニゥム -7-ィノレ] チォ- 6- [(1R)- 1-ヒドロキ シェチル] -1-メチルカルバペン -2-ェム- 3-カルボキシラート (7) (lR，5S,6S)-2- [6-メ トキシカルボニル - メチル - 6,7-ジヒドロ- 5H - シクロペン夕 [&]ピリジニゥム -7-ィル] チォ -6- [(1R)- 1-ヒドロキ シェチル ] -卜メチルカルバペン- 2-ェム- 3-カルボキシラート (10) (1R,5S,6S) -2- [5-ァミノカルボ二ル- 1-メチル -6,7-ジヒドロ- 5H- シクロペンタ [&]ピリジニゥム -7-ィル] チォ -6- [(1R)-1-ヒドロキ シェチル] - メチルカルバペン- 2-ェム -3-カルボキシラート (6) (1R, 5S, 6S)-2- [5-Methoxycarbonyl-1-methyl-6,7-dihydro-5H-cyclopenta [&〗 pyridinium-7-inole] thio-6-[(1R) -1-hydroxysethyl] -1-methylcarbapene-2-em-3-carboxylate (7) (lR, 5S, 6S) -2- [6-methoxycarbonyl-methyl-6,7-dihydro- 5H-cyclopentyl [&] pyridinium-7-yl] thio-6-[(1R) -1-hydroxystyl] -trimethylcarbapene-2-em-3-carboxylate (10) (1R, 5S , 6S) -2- [5-Aminocarbyl-1-methyl-6,7-dihydro-5H-cyclopenta [&] pyridinium-7-yl] thio-6-[(1R) -1-hydroxyethyl] -Methylcarbapene-2-em-3-carboxylate
(II) (1R,5S,6S) -2- [6-ァミノカルボ二ル-: I-メチル -6,7-ジヒドロ- 5H - シクロペンタ [&]ピリジニゥム— 7—ィル] チォ -6- [(1R) - 1-ヒドロキ シェチル] -1-メチルカルバペン- 2-ェム- 3-カルボキシラート(II) (1R, 5S, 6S) -2- [6-Aminocarbonyl-: I-methyl-6,7-dihydro-5H-cyclopenta [&] pyridinium-7-yl] thio-6-[( 1R)-1-Hydroxyshetyl] -1-methylcarbapene-2-em-3-carboxylate
(18) (1R,5S,6S) -2- [1-メチル -5- [1-ピロリジニルカルボニル] -6,7 -ジ ヒドロ- 5H-シクロペン夕 [&]ピリジニゥム- 7-ィノレ] チォ- 6- [(1R) - 1 -ヒ ドロキシェチル] - 1-メチルカルバペン- 2-ェム- 3-カルボキシ ラート (18) (1R, 5S, 6S) -2- [1-Methyl-5- [1-pyrrolidinylcarbonyl] -6,7-dihydro-5H-cyclopentene [&] pyridinium-7-inole] thio -6- [(1R)- 1-Hydroxityl]-1-methylcarbapene-2-em-3-carboxylate
(19) (1R.5S,6S) -2- [トメチル- 6- -ピロリジニルカルボ二ル - 6，7 -ジ ヒ ドロ- 5 -シクロペンタ [ό]ピリジニゥム- 7 -ィル] チ才 -6- [(1R) - 1-ヒ ドロキシェチル] - 1-メチルカルバペン- 2-ェム- 3-カルボキシ フート  (19) (1R.5S, 6S) -2- [Tomethyl-6--pyrrolidinylcarbonyl-6,7-dihydro-5-cyclopenta [ό] pyridinium-7-yl] 6- [(1R)-1-hydroxyxethyl]-1-methylcarbapene-2-em-3-carboxyfoot
(25) (5R.6S) -2- -メチル -6,7-ジヒ ドロ - 5//-シクロペン夕 [ ]ピリジニ ゥム- 7-ィル] チォ -6- [(1R)- 1-ヒ ドロキシェチル] -トカルバペン- (25) (5R.6S) -2- -Methyl-6,7-dihydro-5 //-cyclopentyl [] pyridinium-7-yl] thio-6-[(1R) -1-H Droxitytil] -Tocarbapene-
2 -ェム- 3-カルボキシラート 2-Em-3-carboxylate
(26) (5R.6S) -2- [5 -カルボキシ- 1 -メチル -6,7-ジヒ ドロ- 5H-シクロペン 夕 [ ]ピリジニゥム- 7-ィル] チォ- 6- [(1R) -— 1-ヒ ドロキシェチル]― 1-力ルバペン- 2-ェム- 3-カルボキシラート (26) (5R.6S) -2- [5-Carboxy-1-methyl-6,7-dihydro-5H-cyclopene [] pyridinium-7-yl] thio-6-[(1R)- 1-Hydroxityl] — 1-Lybapene-2-em-3-carboxylate
(27) (5R，6S)-2- [6-カルボキシ- 1-メチル - 6,7-ジヒ ドロ- 5H-シクロペン タ [6]ピリジニゥム- 7 -ィル] チォ -6- [(1R) -1-ヒ ドロキシェチル] - 1-力ルバペン- 2-ェム- 3-カルボキンラート (27) (5R, 6S) -2- [6-carboxy-1-methyl-6,7-dihydro-5H-cyclopenta [6] pyridinium-7-yl] thio-6-[(1R)- 1-Hydroxyshetil]-1-Lybapene-2-Em-3-Carboquinolate
(47) (1R,5S,6S) -2- [1-メチル -5，6，7，8-テトラヒ ドロキノ リニゥム- 8-ィ ル] チォ- 6- [(1R)-卜ヒ ドロキシェチノレ] - 1 -メチルカルバペン- 2- ェム- 3-カルボキシラート  (47) (1R, 5S, 6S) -2- [1-Methyl-5,6,7,8-tetrahydroquinoline-8-yl] thio-6-[(1R) -Trihydroxishechinole]-1 -Methylcarbapene-2-em-3-carboxylate
(48) (1R5S.6S) -2- [5-カルボキン- 1-メチル -5,6,7,8-テトラヒ ドロキノ リニゥム -8-ィル] チォ- 6- [(1R) -トヒ ドロキシェチル] -トメチル 力ルバペン- 2-ェム- 3-カルボキシラート  (48) (1R5S.6S) -2- [5-Carboquin-1-methyl-5,6,7,8-tetrahydroquinoline-8-yl] thio-6-[(1R) -tohydroxitytyl]- Tolyl sorbapene-2-em-3-carboxylate
(51) (1R,5S，6S) - 2- [5 -ァミノカルボニル- 1-メチル- 5,6，7，8 -テトラヒ ド 口キノリニゥム— 8-ィル] チォ -6- [(1R)— 1—ヒ ドロキシェチノレ]一 1一 メチルカルバペン- 2-ェム- 3-カルボキシラート (51) (1R, 5S, 6S)-2- [5-Aminocarbonyl-1-methyl-5,6,7,8-tetrahydroquinolininum — 8-yl] thio-6-[(1R) — 1—Hydroxyshetinole] 1-1 1 Methylcarbapene-2-em-3-carboxylate
(57) (1R,5S,6S) -2- [5-ジメチルァミノカルボニル- 1-メチル - 5,6,7,8 -テ トラヒ ドロキノリニゥム— 8-ィノレ] チォ- 6- [(1R)-卜ヒ ドロキシェチ ル] -卜メチルカルバペン- 2 -ェム- 3-カルボキシラート (57) (1R, 5S, 6S) -2- [5-Dimethylaminocarbonyl-1-methyl-5,6,7,8-tetrahydroquinolininum-8-inole] thio-6-[(1R)- Trihydrocarboxyl] -trimethylcarbapene-2-em-3-carboxylate
(60) (1R5S.6S) -2- [トメチノレ- 5- [1-ピロリジニルカルボニル] -5,6,7,8- テトラヒドロキノ リニゥム- 8-ィノレ] チォ- 6- [(1R) -1-ヒ ドロキシェ チノレ Ί - 1-メチルカルバペン- 2-ェム- 3-カルボキシラート (67) (5R.6S) -2- [トメチル- 5,6,7,8 -テトラヒドロキノリニゥム- 8-ィル：： チォ一 6— [(1R)— 1—ヒ ド キシニチノレ]— 1—力ゾレノくベン一 2—ニム一 3—力 ノレボキシラート (60) (1R5S.6S) -2- [Tomethinole-5- [1-pyrrolidinylcarbonyl] -5,6,7,8-tetrahydroquinolinindium-8-inole] thio-6-[(1R)- 1-Hydroxysche chinole Ί-1-methylcarbapene-2-em-3-carboxylate (67) (5R.6S) -2- [Tomethyl-5,6,7,8-tetrahydroquinolininum-8-yl :: thio-1 6— [(1R) — 1—Hydroxynitinole] — 1—force zolenox 1—nim 3—force norreboxylate
(68) (5R,6S) -2- [5-ァミノカルボ二ル-： I-メチノい 5，6，7，8-テトラヒドロキ ノリ二ゥム- 8-ィル] チォ- 6- [(1R) -卜ヒドロキシェチル] -卜カル バペン- 2-ェム- 3-カルボキシラート  (68) (5R, 6S) -2- [5-Aminocarbonyl-: I-methino-5,6,7,8-tetrahydroquinolinidum-8-yl] thio-6-[(1R )-Trihydroxyethyl]-tricarbapen-2-em-3-carboxylate
(72) (5R.6S) -2- [6-ジメチルァミノカルボニノレ-トメチル- 5，6,7，8-テトラ ヒドロキノリニゥム -8-ィル] チォ- 6- [(1R) - 1-ヒドロキシェチル] - 1 -力ルノくぺン- 2-ェム- 3-力ルボキシラートであり、 (72) (5R.6S) -2- [6-Dimethylaminocarboninoletomethyl-5,6,7,8-tetrahydroquinolininum-8-yl] thio-6-[(1R)- 1-Hydroxyethyl]-1-forceno-2-ene-3-em-3-oxylboxylate,
特に （1)、 （5)、 （25)、 (47) (58) および （72) が好適である。 In particular, (1), (5), (25), (47), (58) and (72) are preferred.
一般式 [ I ]の化合物は、常法により医薬として許容される無毒性塩または そのエステルとすることができる。  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.
一般式 [ I ]の化合物の無毒性塩としては、医薬上許容される慣用的なもの を意味し、力ルバぺネムの 3位のカルボキシル基または 2位の二環性ピリジニ ゥム環上の置換基がカルボキシル基のとき、 該カルボキシル基における塩を 意味する。 例えばナトリウム、カリウム、 リチウム等のアルカリ金属との塩； 例えばカルシウム、マグネシゥム等のアル力リ土類金属との塩；例えば Ν,Ν' - ジベンジルエチレンジァミン、 エタノールァミン、 トリェチルァミン等の有 機ァミンとの塩；例えば塩酸、 硝酸、 硫酸、 りん酸等の無機酸との塩；例え ばクェン酸、 酸等の有機酸との塩；例えばメ夕ンスルホン酸、 Ρ-トルェ ンスルホン酸等の有機スルホン酸との塩または例えばァスパラギン酸、 グル タミン酸、 リジン等のァミノ酸との塩等が挙げられる。  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. When 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 Ν, Ν'-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, Ρ-toluene sulfonic acid, and the like Or a salt with an aminosulfonic acid such as aspartic acid, glutamic acid and lysine.
一般式 [ I ]の無毒性エステルとしては、力ルバぺネムの 3位のカルボキシ ル基または 2位の該ピリジニゥム環上の力ルボキシル基における医薬上許容 される慣用的なものを意味する。 例えばァセトキシメチル基、 ビバロイルォ キシメチノレ基等のアルカノイノレオキシメチル基とのエステル、 1- (エトキシ 力ルボニルォキシ） ェチル基等のアルコキシカルボニルォキシアルキル基と のエステル、 フタリジル基とのエステル、 5-メチル - 2-ォキソ - 1,3-ジォキ ソール -4-ィルメチル基等の 5-置換- 2-ォキソ - 1,3-ジォキソ一ル -4 -ィルメ チル基とのエステノレ等が挙げられる。 次に本発明のー設式 [ 1〗 の化合物の製法について說¾する- 一 弍 [ I の化合物は以下の製造 SA、製造 HB、製造 HCおよび製造 HDのいずれのフ 法によっても製造することができる。 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. For example, 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. Next, the method for producing the compound of formula [1] of the present invention will be described. The compound of [I] must be produced by any one of the following production SA, production HB, production HC and production HD. Can be.
製造法 A Manufacturing method A
—般式 —General formula
Figure imgf000013_0001
中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物と一般式
Figure imgf000013_0001
Wherein R 1 is a hydrogen atom or a methyl group, R 5 is a carboxyl protecting group, and Z is a leaving group.
Figure imgf000013_0002
Figure imgf000013_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシカルボニル基または- CON (R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 は 1ないし 3の整数を示す] で表される化合物とを反応させ、 次いで N -メチル化反応に付し、更に保護基を除去することにより一般式 [ I ] の化 合物を製造することができる。 [Wherein, 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.
一般式 [ Π ] の化合物と一般式 [m] の化合物との反応は、 ジイソプロピル ェチル了ミン、 トリェチルァミンまたは 4- N，X-ジメチルァミノピリジン等の 垣基の存在下、ァセトニトリノレ、 Ν,Ν-ジメチルホルムァミ ド、 -ジメチル ァセトアミ ドまたは-ヽ :-ニチルピロリジン等の反応に惠影響を及ぼさない不 S 性溶媒 で、 5分〜 10時間、 - 40〜25 °Cの温度で行うことができる。 The reaction between the compound of the general formula [Π] and the compound of the general formula [m] is performed by diisopropyl Reaction of acetonitrile, Ν, Ν-dimethylformamide, -dimethylacetamide or-ヽ: -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.
次いで四級化のための N-メチル化反応は、 ヨウ化メチル、 メチルトリフ レート、 フルォロスルホン酸メチル、 ジメチル硫酸等の通常のメチノレ化剤に より、 常法に従って行うことができる。  Next, 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.
一般式 [ π ] および一般式 [ ] において、カルボキシル基の保護基として は、 当該分野で通常使用される保護基が挙げられる。  In the general formula [π] and the general formula [], examples of the protecting group for the carboxyl group include protecting groups usually used in the art.
該カルボキシル保護基としては、 例えば iert-ブチル基、 2,2,2-トリクロ口 ェチル基、 ァセトキシメチル基、 プロピオニルォキンメチル基、 ビバロイル ォキシメチル基、 1 -ァセトキシェチル基、 1 -プロピオニルォキシェチル基、 1 - （エトキンカルボニルォキシ） ェチル基、 フタリジル基、 ベンジル基、 P- メ トキシベンジル基、 3,4-ジメ トキシベンジノレ基、 -ニトロべンジル基、 ベ ンズヒドリル基、 ビス （4-メ トキシフヱニル） メチル基、 （5-メチル - 2-ォキ ソ - 1,3-ジォキソ一ノレ- 4-ィノレ） メチル基、 トリメチルシリル基、 iert-ブチル ジメチルシリル基等が挙げられ、 特に ニトロべンジル基、 ベンズヒドリル 基、 teri-ブチル基、 シリル基等が好ましい。  Examples of the carboxyl protecting group 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. , 1- (ethoxyquincarbonyloxy) ethyl group, phthalidyl group, benzyl group, P-methoxybenzyl group, 3,4-dimethoxybenzinole group, -nitrobenzyl group, benzhydryl group, bis (4-methoxyphenyl) ) Methyl group, (5-methyl-2-oxo-1,3-dioxo-mono-4-ynole) methyl group, trimethylsilyl group, iert-butyldimethylsilyl group, and the like. Particularly, nitrobenzyl group, Benzhydryl, teri-butyl, silyl and the like are preferred.
N-メチル化反応終了後、該保護基の種類により、 それ自体既知の脱保護反 応を行うことにより、 一般式 [ I ] の化合物を得ることができる。 典型的に は、保護基が ニトロべンジル基の場合、例えば ρΗ7のりん酸緩衝液、 3 -モ ルホリノプロパンスルホン酸緩衝液、 りん酸 2力リウム等を含む、テトラヒド 口フラン一水、 ジォキサン—エタノール一水、 ブタノール一水等の混合溶媒 中で、パラジウム-活性炭、水酸化パラジウム、酸化白金等の水添触媒の存在 下、 1〜4気圧の水素下、 0〜50°Cの温度で、 20分〜 4時間処理することによ り行うことができる。  After completion of the N-methylation reaction, 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. Typically, when the protecting group is a nitrobenzyl group, for example, tetrahydrofuran monohydrate, dioxane, including phosphate buffer of ρΗ7, 3-morpholinopropanesulfonic acid buffer, dibasic phosphate, etc. —In a mixed solvent of ethanol-water, butanol-water, etc., in the presence of a hydrogenation catalyst such as palladium-activated carbon, palladium hydroxide, platinum oxide, etc., under 1 to 4 atm of hydrogen, at a temperature of 0 to 50 ° C It can be performed by treating for 20 minutes to 4 hours.
一般式 [m] において、 Zで示される脱離基とは、有機りん酸または有機ス ルホン酸から誘導されるアンル基を意味し、 例えばジフヱノキシホスホリル ォキシ基、 メタンスルホニルォキン基、 トリフルォロメタンスルホ二ルォキ シ基、 トルエンスルホニルォキシ基等が挙げられ、 特にジフヱノキシホス ホリルォキシ基、 メタンスルホニルォキシ基が好適である。 In the general formula [m], 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.
上記製造 Sにおいて、縮合反応、 X-メチル化反応および説屎護反応を行う 際に、 原料会 ¾反応を含めて各反応生或 ¾を旱 ϋまたは することなく次 の反応を行うことができる。  In the above-mentioned Production S, when performing a condensation reaction, an X-methylation reaction, and a preservation reaction, the following reaction can be performed without drying or reacting each reaction product, including the raw material group reaction. .
一般式 [M] の化合物は、例えば T. N. Salzmann et al., J. Am. Chem. Soc" 102, 6161 (1980) または D. H. Shih et al" Heterocycles, 21, 29 (1984) 等に記載の方法で二環性ケトエステル体から得られる。 この方法で 得られるエステルは、 単離または単離することなく本反応に用いることがで きる。  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.
製造法 B  Manufacturing method B
—般式 —General formula
Figure imgf000015_0001
Figure imgf000015_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物と一般式 Wherein R 1 is a hydrogen atom or a methyl group, R 5 is a carboxyl-protecting group, and Z is a leaving group.
Figure imgf000015_0002
Figure imgf000015_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチ才モルホリノ基からなる群から選ばれる複素環基を¾¾す る）、 nは 1ないし 3の整数、 Xsは陰イオンを示す] で表される化会 ¾と反 させて、 一般式 [Wherein, 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 さ れ る represented by
Figure imgf000016_0001
Figure imgf000016_0001
[式中、 Rl、 R5、 R6、 nおよび Χθは前記の意味を有する] で表される化合物 とし、 次いで保護基を除去することにより、 一般式 [ I ] の化合物を製造す ることができる。 Wherein, 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
Χθで示される陰イオンとしては、例えば塩素イオン、臭素イオン、 ヨウ素 イオン等のハロゲンイオン、 硫酸イオン、 硫酸水素イオン、 硫酸メチルイォ ン、 -トルエンスルホン酸イオン、 メ夕ンスルホン酸イオンまたはトリフル ォロ酢酸イオン等が挙げられる。 The anion represented by θ 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. Acetate ion and the like.
"^式 cm] の化合物と一般式 [IV] の化合物とを反応させて一般式 [V] の化合物を得る反応は、 製造法 Aにおける一般式 [ Π ] の化合物と一般式 [Π] の化合物と同様に行うことができる。 一般式 [V] の化合物の脱保護反 応は、 製造法 Aの脱保護反応と同様に行うことができる。 その際に一般式 [V] の化合物は単離または単離することなく反応させることができる。  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 [Π] and the compound of the general formula [Π] 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. At that time, the compound of the general formula [V] is a simple compound The reaction can be performed without separation or isolation.
製造法 C  Manufacturing method C
—般式
Figure imgf000017_0001
—General formula
Figure imgf000017_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物を一般式 [Wherein, R 1 represents a hydrogen atom or a methyl group, R 5 represents a carboxyl-protecting group, and Z represents a leaving group].
Figure imgf000017_0002
中、 R1および R5は前記の意味を有する] で表される化合物とし、 次いで 一般式 [VI] の化合物と一般式
Figure imgf000017_0002
Wherein 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
Figure imgf000017_0003
Figure imgf000017_0003
K中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシカルボニル基または- C〇N (R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 Yは脱離基、 ηは 1ないし 3の整数を示す] で表される化合物とを反 させ、次いで Ν-メチル化反^に付し、更に保護基を除去することにより、一 ¾式 [.1〕 の化合物を製造することか'できる。 In K, 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〇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, η represents an integer of 1 to 3], and then subjected to Ν-methylation reaction, and further removing the protecting group to obtain化合物 Can the compound of formula [.1] be prepared?
一般式 [VI] の化合物は、一般式 [ffl] の化合物と水硫化ナトリウムとを、 5分〜 1時間ヽ- 50分〜- 20°Cの温度で、 N，N-ジメチルホルムアミ ド、 Ν,Ν- ジメチルァセトアミ ド等の不活性溶媒中で反応させることにより得られ、 通 常単離することなく、 次の反応に用いることができる。 一般式 [VI] の化合 物と一般式 [W] の化合物との反応は、 例えば、 ジイソプロピルェチルアミ ン、 トリェチルァミン、 4- Ν,Ν-ジメチルァミノピリジン等の塩基の存在下、 ァセトニトリル、 Ν，Ν-ジメチルホルムァミ ド、 Ν，Ν -ジメチルァセトアミ ド等 の不活性溶媒中で行うことができる。 反応温度は- 40〜25°C、反応時間は 10 分〜 8時間である。  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 ヽ -50 minutes to -20 ° C. in N, N-dimethylformamide, It is obtained by reacting in an inert solvent such as Ν, Ν-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-Ν, Ν-dimethylaminopyridine in the presence of acetonitrile, It can be carried out in an inert solvent such as Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide. The reaction temperature is −40 to 25 ° C., and the reaction time is 10 minutes to 8 hours.
上記反応に引きつづいて行う N-メチル化反応および脱保護反応は、製造法 Aの N -メチル化反応および脱保護反応と同様に行うことができる。  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.
一般式 [W] において、 Yで示される脱離基としては、塩素原子、臭素原子、 ヨウ素原子等のハロゲン原子、 メタンスルホニルォキシ基、 -トルエンスル ホニルォキシ基等のスルホニルォキン基等が挙げられる。  In the general formula [W], 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. Can be
製造法 D Manufacturing method D
一般式 General formula
Figure imgf000018_0001
Figure imgf000018_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物を一般式 [Wherein, R 1 represents a hydrogen atom or a methyl group, R 5 represents a carboxyl-protecting group, and Z represents a leaving group].
Figure imgf000019_0001
Figure imgf000019_0001
[式中、 R1および R5は前記の意味を有する] で表される化合物とし、 次いで 一般式 [VI] の化合物と一般式 Wherein 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
X9 [
Figure imgf000019_0002
X 9 [
Figure imgf000019_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポニル基または- C〇N ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 Χθは陰イオン、 Υは脱離基、 ηは 1ないし 3の整数を示す] で表される 化合物とを反応させて、 一般式
Figure imgf000020_0001
[Wherein, 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〇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
Figure imgf000020_0001
[式中、 R R5、 R6、 nおよび Χθは前記の意味を有する] で表される化合物 とし、 次いで保護基を除去することにより、 一般式 [ I ] の化合物を得るこ とができる。 Wherein, 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] .
一般式 [V のィヒ合物は、製造法 Cと同様の反応で得られる一般式 [VI] の 化合物と一般式 CM] の化合物とを反応させることにより製造することがで きる。 一般式 [VI] の化合物と一般式 [M] の化合物との反応は、製造法 Cの 一般式 [VI] の化合物と一般式 [W] の化合物との反応と同様に行うことが できる。 一般式 [V] の化合物の脱保護反応は製造法 Cの脱保護反応と同様 に行うことができる。  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.
—般式 [ ] において、 Yで示される脱離基は、一般式 [ ] の脱離基が好 適である。  —In the general formula [], the leaving group represented by Y is preferably a leaving group represented by the general formula [].
次に、本発明の一般式 [ I ] の化合物の側鎖として有用な一般式 [Π ]の化 合物、 一般式 [IV] の化合物およびそれらの製造法について説明する。 Next, the compound of the general formula [Π], the compound of the general formula [IV] and the method for producing them, which are useful as a side chain of the compound of the general formula [I] of the present invention, will be described.
—般式 [Π]の化合物および一般式 [IV]の化合物は文献未記載の新規ィヒ合 物であり、 "^般式 [ I ] の化合物を製造するための重要な中間体である。 本発明は、 一般式 —The compound of the general formula [Π] and the compound of the general formula [IV] are novel compounds which have not been described in the literature, and are “important intermediates for producing the compound of the general formula [I]”. The present invention has the general formula
Figure imgf000020_0002
Figure imgf000020_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、 級アルコキシ力ルボニル基または- CON ( R3 ) P,4で表される基 （ここにおい て、 R3および R4は水素原子または 級アルキル基を示すか、 R3および は 陵接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル 5、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 nは 1ないし 3の整数を示す] で表される化合物、 一般式 [Wherein, 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 Aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidino group, piperazinyl group, 4-lower alkylpiperazinyl 5, morpholino group and thiomorpholino group), n is 1 A compound represented by the general formula:
Figure imgf000021_0001
Figure imgf000021_0001
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 nは 1ないし 3の整数、 Xsは陰イオンを示す] で表される化合物および それらの製造法にも関する。 [In the 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 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] .
一般式 [ Π ]の化合物は、例えば以下に示す方法によって製造することがで きる。 The compound of the general formula [[] can be produced, for example, by the following method.
Figure imgf000022_0001
Figure imgf000022_0001
[式中、 Rsおよび nは前記の意味を有し、 R7は水酸基またはハロゲン原子を、 R8はメルカプト基の保護基を示す] [Wherein, Rs and n have the above-mentioned meaning, R 7 represents a hydroxyl group or a halogen atom, and R 8 represents a mercapto-protecting group]
本方法は化合物丄を出発原料として A工程を行い化合物 2を得、 メルカプ ト基の保護基を除去するものである。  In this method, 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.
A工程： Process A:
本工程は、 公知化合物または公知化合物から容易に誘導可能な化合物 の R7を保護されたメルカプト基に変換する工程である。 変換する方法は、各種 の公知の方法が可能である。 例えば R7が水酸基の場合、 該水酸基を塩素原 子、 臭素原子、 ヨウ素原子等のハロゲン原子またはメシルォキシ基、 トシル ォキシ基等の脱離基に誘導し、 化合物 の反応性誘導体とする。 該反応性誘 導体とチォ 酸、 チォ安息香酸、 トリチルメルカブタン、 メ トキシベンジ ルメルカプタン等の各種チォ化試薬とを、 例えばトリェチルァミン、 ジィソ プロピルェチルァミン、 Ν-メチルモルホリン、 1,8-ジァザビシクロ [5.4.0] - 7-ゥンデセン、水酸化ナトリウム、 カリウム tert-プトキシド、 ナトリウムメ トキシド、 水素化ナトリウム等の塩基の存在下で反応させることにより、 本 工程は達成できる。 反応溶媒としては、 例えばジクロロメタン、 テトラヒド 口フラン、 Ν,Ν-ジメチルホルムァミ ド等の反応に悪影響を及ぼさない溶媒な らばいずれでもよく、 これらの混合溶媒でもよい。 反応温度は通常 - 60〜80 °C、特に - 20°C〜室温が好適である。 反応時間は通常 分〜 16時間、特に 30 分〜 2時間が好適である。 また本工程は、化合物丄をトリフニニルホスフィ ン およびジェチルァゾジカルボキシラ-トの存在下に、テトラヒド フラン等の 不活性溶媒中、 チォ詐酸等のチォ化試薬と反応させて得ることもできる。 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. For example, when 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, ァ -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. The reaction solvent may be any solvent that does not adversely affect the reaction, such as dichloromethane, tetrahydrofuran, and Ν, Ν-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. In this step, compound 丄 is obtained by reacting compound と 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.
丄 ·  丄 ·
本工程は化合物 の保護されたメルカプト基の保護基を除去する工程であ る。  This step is a step of removing the protected mercapto group-protecting group of the compound.
各種公知のメルカプト基の保護基の脱保護法が可能である。 例えば R8がァ シル基である場合はアルカリ加水分解による方法、 トリチル基、 メ トキシ ベンジル基等の場合はトリフルォロ酢酸、 トリフルォロメタンスルホン酸等 の酸による方法によって除去することができる。 Various known methods for deprotection of a mercapto group-protecting group are possible. For example, 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.
R7力塩素原子、臭素原子、 ヨウ素原子等のハロゲン原子の場合、 前記の方 法の他に、化合物丄とチォ尿素とを反応させて得られる S-アルキルイソチォ ゥロニゥム塩、化合物上と、 チォ硫酸ナトリウムとを反応させて得られる S - アルキルチオ硫酸塩、化合物丄と Ν，Ν-ジメチルジチ才力ルバミン酸ナ卜リウ ムとを反応させて得られるジチォカルバミン酸エステル、 化合物丄とジチォ 炭酸〇-ェチルカリウムとを反応させて得られるジチォ炭酸エステノレ等の中間 体を加水分解することにより、 一般式 [ Π] の化合物を得ることもできる。 次に一般式 [IV] の化合物の製造法について説明する。 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 丄 with thiourea, S-alkylthiosulfate obtained by reacting sodium thiosulfate, dithiocarbamic acid ester obtained by reacting compound 丄 with Ν, Ν-dimethyldithiol sodium rubamate, compound 丄 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.
一般式 [IV]の化合物は、例えば以下に示す方法によって製造することがで さる。 The compound of the general formula [IV] can be produced, for example, by the following method.
Figure imgf000024_0001
Figure imgf000024_0001
[式中、 R6 R\ R8 nおよび ΧΘは前記の意味を有する] [Wherein R 6 R \ R 8 n and Χ を have the above-mentioned meaning]
本方法は化合物 を出発原料として前記の Α工程を行い化合物 を得、 次 いで N-メチルイ匕反応に付し、化合物^とし、次いでメルカプト基の保護基を 除去するものである。  In this 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.
A工程：前記のとおり  Step A: As described above
C工程： Step C:
本工程は化合物 2を N-メチル化反応に付し、化合物^を製造する工程であ る  In this step, compound 2 is subjected to an N-methylation reaction to produce compound ^.
N-メチルイ匕反応は、各種の公知の方法が可能である。 例えば製造法 Aで説 明した N-メチルイヒ反応に従って行うの力好適である。  Various known methods are possible for the N-methylidani reaction. For example, it is preferable to carry out the reaction according to the N-methyl hydride reaction described in Production method A.
D工程： D process:
本工程は化合物 3のメルカプト基の保護基を除去する工程である。  This step is for removing the protecting group for the mercapto group of compound 3.
メルカプト基の保護基の除去反応は、 各種の公知の方法が可能である。 例 えば前述の B工程で行われる脱保護方法に従つて行うのが好適である。  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.
以上の方法により得られる一般式 [ Π]の化合物および一般式 [IV]の化合 物は、 単離または単離することなく一般式 [ΙΠ] の化合物と反応させること ができる。  The compound of the general formula [Π] and the compound of the general formula [IV] obtained by the above method can be reacted with the compound of the general formula [ΙΠ] without isolation or isolation.
また、一般式 [孤] の化合物および一般式 [珊] の化合物は、 般式 [ I ] の化合物の製造のための重要な中間体である。 ー殺弍 の化合物は、公知化合物であるかもしくは公知化会¾から容易 に誘導可能である。 すなわち、 一般式 [Π ] の化合物またはー設 [IV] の 化会物を製造するための ώ癸原料化合物丄において、 R7がハロゲン原子の場 合は ~ 式 [w] の化合物中、 Υがハロゲン原子の場合に相当し、 この場合、 一般式 [W] の化合物となる。 化合物丄の R7が水酸基の場合は公知の方法に より、 該水酸基を塩素原子、 臭素原子、 ヨウ素原子等のハロゲン原子または メシルォキシ基、 トシルォキン基等の脱離基に容易に誘導し、一般式 [W]の 化合物を製造することができる。 一般式 [VI] の化合物は、 一般式 [W] の 化合物を Ν -メチルイヒ反応に付すことにより容易に製造できる。 Ν-メチル化 反応は、各種の公知の方法カ坷能であり、例えば製造法 Αで説明した Ν-メチ ル化反応に従つて行うのが好適である。 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 [Π] 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. When 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 Ν-methyl reaction. The Ν-methylation reaction is a function of various known methods, and is preferably performed, for example, according to the Ν-methylation reaction described in Production Method Α.
本発明の化合物は、 優れた抗菌活性を示し、 医薬品として有用な新規化合 物であり細菌感染症、 例えば呼吸器感染症、 尿路感染症、 化膿性疾患または 外科感染症等の治療および予防に用いることができる。 また、 その投与方法 としては、 静脈内注射、 筋肉内注射もしくは坐剤等による非経口投与または 錠剤、散剤、 カプセル剤もしくはシロップ剤等による経口投与が適用される。 なお、 これらの剤形を製造するに際しては、 この分野における常法によるこ とができ、 例えば助剤、 湿潤剤、 乳化剤、 結合剤、 賦形剤等の通常使用され る添加剤が含まれていてもよい。 その投与量は、 年齢、 性別、 体重、 感受性 差、投与方法、投与の時間および間隔、病状の程度、 体調、 医薬製剤の性質、 調剤の種類または有効成分の種類等を考慮して決定されるが、 通常は 1日当 り l〜100mgZ gの範囲であり、 1日当り 5~30mg /も gで 2〜4回に分けて投 与することが好ましい。  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. Can be used. As the administration method, parenteral administration by intravenous injection, intramuscular injection or suppository or oral administration by tablet, powder, capsule or syrup is applied. In preparing these dosage forms, 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.
本発明の化合物の有用性を具体的に示すために、 細菌に対する試験管内抗 菌活性を下記の寒天平板希釈法により測定した。 すなわち、 ミューラー - ヒ ントン ·ブロス中で一夜培養した各試験菌株の一白金耳 （接種菌量： 10s CFU/772i) をミユーラ一'ヒントン'ァガ一に接種した。 この培地には、 浜 試薬剤が所定の濃度含まれており、 37°Cで 16時間培養した後、最小発育阻止 濃度 (MIC, μς/τηί) を測定した。 その結果を表に示す。 最小発育阻止濃度 （M I C ) To demonstrate the usefulness of the compounds of the present invention, the in vitro antibacterial activity against bacteria was measured by the following agar plate dilution method. In other words, 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. After culturing at 37 ° C for 16 hours, the minimum growth inhibitory concentration (MIC, μς / τηί) was measured. The results are shown in the table. Minimum inhibitory concentration (MIC)
Figure imgf000026_0001
Figure imgf000026_0001
表から明らかな如く、本発明の化合物は優れた抗菌力を示すことがわかる。 以下に本発明を実施例および参考例に従ってさらに詳細に説明する力 本 発明はこれらに限定されるものではない。  As is clear from the table, the compounds of the present invention exhibit excellent antibacterial activity. Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples. The present invention is not limited thereto.
なお以下の実施例および参考例で用 、た略号の意味は次の通りである。 The abbreviations used in the following Examples and Reference Examples have the following meanings.
PNB P -二 PNB P-2
Ph フェニル基  Ph phenyl group
Ac ァセチル基  Ac acetyl group
(以下余白） (Hereinafter the margin)
伊 j11 Italy j 1 1
iIR.5S,6S) -2- 「卜メチル -6.7-ジヒド n- 5ii-シクロペンタ [ ]ピリジニ ゥム- 7 -ィ ォ- 6- QPJ-トヒドコキシニチル^-1-メチルカルバペン - -ニム- 3-カルボキシラート  iIR.5S, 6S) -2- (Trimethyl-6.7-dihydrid n-5ii-cyclopenta [] pyridinidium-7-di-6-QPJ-tridoxyxinitil ^ -1-methylcarbapene- -Nim -3-carboxylate
Figure imgf000027_0001
Figure imgf000027_0001
a) ニトロべンジル （1R5S6S) -2-ジフヱニルホスホリルォキシ - 6 - [(1R) - 1-ヒ ドロキシェチル] -1-メチルカルバペン- 2-ェム- 3-カルボキシ ラート 900mg (l.olmmo ) をァセトニトリル 30m に溶かし、 窒素気流下、 一 10°Cでジィソプロピルェチルァミン 0.267m （1.53mmoめ のァセトニトリ ル （0.6m 溶液を加え、 次に 7-メルカプト- 6,7-ジヒドロ- 5 H-シクロペン 夕 [&]ピリジン 347mg (2.30mmo£) のァセトニトリル（lm 溶液を加え、同 温度で 2時間撹拌した。 さらに、 7-メルカプト- 6,7-ジヒドロ- 5H-シクロべ ン夕 [δ]ピリジン 347 (2.30mmo£) のァセトニトリル （lm 溶液とジィ ソプロピルェチルァミン 0.267mi (1.53mmo£) のァセトニトリノレ ひ mf) 溶 液を加え、 - 20°Cで 2日間放置した。 反応混合物に酢酸ェチルを加え、飽和炭 酸水素ナトリウム水溶液、 次に飽和食塩水で洗浄後、 無水硫酸マグネシウム で乾燥し、 溶媒を留去した。 残渣をシリカゲルカラムクロマトグラフィー (Wakogel®C- 300 1 %メタノール—クロ口ホルムで溶出） で精製し、 p~二 トロべンジル （1R5S6S) - 2- [6,7-ジヒ ドロ- シクロペンタ [6]ピリ ジン- 7-ィル] チォ- 6- [(1R) - 1-ヒドロキシェチル] -1-メチルカルバペン- 2 -ェム- 3-カルボキシラート 391mg (収率： 52.3%) を得た。 a) Nitrobenzyl (1R5S6S) -2-diphenylphosphoryloxy-6-[(1R) -1-hydroxyhexyl] -1-methylcarbapen-2-em-3-carboxylate 900 mg (l. olmmo) in 30m of acetonitrile, and at 110 ° C under nitrogen flow, add disopropylethylamine 0.267m (1.53mmo of acetonitrile (0.6m solution, then add 7-mercapto-6,7- Dihydro-5H-cyclopentene [&] Pyridine 347 mg (2.30 mmol) of acetonitrile (lm solution) was added, and the mixture was stirred at the same temperature for 2 hours. Furthermore, 7-mercapto-6,7-dihydro-5H-cycloben was added. Evening [δ] A solution of pyridine (347) (2.30mmo £) in acetonitrile (lm solution and disopropylethylamine 0.267mi (1.53mmo £) in acetonitrile (mf)) was added and left at -20 ° C for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and then with a saturated saline solution. The residue was purified by silica gel column chromatography (eluted with Wakogel® C-300 1% methanol-chloroform), and p-nitrobenzil (1R5S6S) -2- [6,7-dihydro-cyclopenta [6] pyridin-7-yl] thio-6-[(1R) -1-hydroxyethyl] -1-methylcarbapene- 391 mg (yield: 52.3%) of 2-em-3-carboxylate were obtained.
IR (KBr) c -1 : 3400, 2960. 1770 1710, 1520, 1340, 1210, 1130 NMR (DMSO-d5) 5： 1.18 (3H,ciJ = 6Hz) , 2.2S (3H cL J— = 6Kz), 2.00 -2.20 (1H, m)， 2.40 3.80 (5H, m), 3.92 4.10 (1H, m)， 4.30 (1H, dd, J = 3, 9Hz), 4.84-4.96 (1H m), 5.14 (1H d, J = 5Hz), 5.28お よび 5.47 (2H, ABq, J = 13Hz), 7.28 (1H, dd, J = 5, 8Hz), 7.71 (2H, d, J = 9Hz), 7.74 (1H, d, J = 8Hz), 8.23 (2H d, J = 9Hz), 8.42 (1H, d, J = 5Hz) IR (KBr) c - 1: 3400, 2960. 1770 1710, 1520, 1340, 1210, 1130 NMR (DMSO-d 5) 5: 1.18 (3H, ciJ = 6Hz), 2.2S (3H cL J- = 6Kz) , 2.00 -2.20 (1H, m), 2.40 3.80 (5H, m), 3.92 4.10 (1H, m), 4.30 (1H, dd, J = 3, 9Hz), 4.84-4.96 (1H m), 5.14 (1H d, J = 5Hz), 5.28 and 5.47 (2H, ABq, J = 13Hz), 7.28 (1H, dd, J = 5, 8Hz), 7.71 (2H, d, J = 9Hz), 7.74 (1H, d , J = 8Hz), 8.23 (2H d, J = 9Hz), 8.42 (1H, d, J = 5Hz)
b) a) で得られた化合物 260mg (0.525mmo ) のジクロロメタン （6.7 溶液に窒素気流下、 0 °Cでメチルトリフラート 0.065m (0.57mmo£) のジク ロロメタン （3m 溶液を加えた後、 室温で 2時間撹拌した。 溶媒を留去し、 残渣をエーテルでトリチュレートし、 N-メチル化物の粉末 354 gを得た。 b) Add 260 mg (0.525 mmo) of the compound obtained in a) to dichloromethane (6.7 solution of methyltriflate 0.065 m (0.57 mmo £) of dichloromethane (3 m solution at 0 ° C in a nitrogen stream at 0 ° C, then add The solvent was distilled off, and the residue was triturated with ether to obtain 354 g of N-methylated powder.
IR (KBr) cm"1 :3450, 2970, 1770, 1720, 1520, 1280, 1160 1030, 640 c) b)で得られた N-メチル化物をテトラヒドロフラン 40m および 0·1Μり ん酸緩衝液（pH7.0) 40m の溶液に溶解し、 10%パラジウム一炭素 260mgを 加え、約 3.1 g/cw2で 1.5時間室温で接触水添を行った。 反応液を濾過した 後、 濃縮し、 生成した不溶物を濾去した後、 逆相カラムクロマトグラフィー (ケムコ LC- SORB®, SP-B- ODS,10%メタノール—水で溶出） で精製し、凍 結乾燥を行い、 標記化合物 52.5mg [b) からの収率： 26.70 ] を得た。 IR (KBr) cm " 1 : 3450, 2970, 1770, 1720, 1520, 1280, 1160 1030, 640 c) The N-methylated product obtained in b) was converted to tetrahydrofuran 40m and 0.1 phosphate buffer (pH 7 .0) dissolved in a 40-m solution, added 260 mg of 10% palladium-carbon, and subjected to catalytic hydrogenation at about 3.1 g / cw 2 for 1.5 hours at room temperature.The reaction solution was filtered, concentrated, and the resulting insoluble After filtration, the residue was purified by reverse phase column chromatography (Chemco LC-SORB®, SP-B-ODS, eluted with 10% methanol-water), freeze-dried, and 52.5 mg of the title compound (b) Yield: 26.70].
IR (KBr) cm—1 : 3400, 1760, 1600, 1380, 1270 IR (KBr) cm— 1 : 3400, 1760, 1600, 1380, 1270
UV ス (0.1M 3-モルホリノプロパンスルホナート緩衝液、 pH7.0) ： UV (0.1M 3-morpholinopropane sulfonate buffer, pH 7.0):
284nm (e = 7,200)284nm (e = 7,200)
MR (D20) δ 1.22 (6H d, J = 6Hz), 2.30-2.50 (1H, m), 2.50 2.86 (1H m)， 2.96 3.56 (3H m), 3.46 (1H dd, J = 3 7Hz), 410 4.36 (2H m), 4.36 (3H, s)， 5.04 (1H, d, J = 8Hz), 7.78 (1H dd,MR (D 2 0) δ 1.22 (6H d, J = 6Hz), 2.30-2.50 (1H, m), 2.50 2.86 (1H m), 2.96 3.56 (3H m), 3.46 (1H dd, J = 37Hz) , 410 4.36 (2H m), 4.36 (3H, s), 5.04 (1H, d, J = 8Hz), 7.78 (1H dd,
J = 7, 8Hz), 8.31 (1H, d, J = 8Hz), 8.50 (1H, d, J = 7Hz) 実施例 2 J = 7, 8Hz), 8.31 (1H, d, J = 8Hz), 8.50 (1H, d, J = 7Hz)
( R.5S.6S) -2- (1—メチル-56,78-テトラヒ ドロキノリニゥム- 8-ィル） チォ. -6- 「（1R) -： [-ヒ ドロキンェチノレ Ί -トメチルカルバペン- 2 -ェム- 3 -力 ノレボキシラー上 (R.5S.6S) -2- (1-Methyl-56,78-tetrahydroquinolininum-8-yl) thio. -6- "(1R)-: [-Hydroquinechinole-to-methylcarbapene-2 -Em-3 -Power on Noreboxillar
Figure imgf000029_0001
p -二トロべンジル （1R,5S，6S) -2-ジフヱニルホスホリルォキシ -6 - [(1R) - 1-ヒ ドロキシェチル] -1-メチルカルバペン- 2-ェム- 3-カルボキシ ラート 900mgと 8-メルカプト - 5，6，7,8-テトラヒ ドロキノ リン 760mgを用い て、 実施例 1と同様の方法で標記化合物を 85.3mff得た。
Figure imgf000029_0001
p-Nitrobenzil (1R, 5S, 6S) -2-diphenylphosphoryloxy-6-[(1R) -1-hydroxystyl] -1-methylcarbapene-2-em-3-carboxy The same procedure as in Example 1 was used to obtain 85.3 m ff of the title compound, using 900 mg of methoxide and 760 mg of 8-mercapto-5,6,7,8-tetrahydroquinoline.
IR (KBr) cm-1： 3400' 1760, 1600, 1380, 1280 IR (KBr) cm- 1 : 3400 '1760, 1600, 1380, 1280
UV Amax (0.1M 3-モルホリノプロパンスルホナート緩衝液、 pH7.0) ： 283.5nm (ε = 10,120) UV A max (0.1 M 3-morpholinopropane sulfonate buffer, pH 7.0): 283.5 nm (ε = 10,120)
NMR φ20) δ ： 1.18 (6Η， d, J = 6Hz), 1.62〜2.32 (4H, m), 2.72〜NMR φ 20 ) δ: 1.18 (6Η, d, J = 6Hz), 1.62 to 2.32 (4H, m), 2.72 to
3.22 (3H,m)， 3.44 ひ H， dd, J = 3, 7Hz), 4.02-4.36 (2H, m), 4.46 (3H， s), 7.70 (lH,dd, J = 6, 7Hz), 8.16 (1H， d, J = 7Ηζ),8.δ3 (1H, d, J = 6Hz) 3.22 (3H, m), 3.44h H, dd, J = 3, 7Hz), 4.02-4.36 (2H, m), 4.46 (3H, s), 7.70 (lH, dd, J = 6, 7Hz), 8.16 (1H, d, J = 7Ηζ), 8.δ3 (1H, d, J = 6Hz)
実施例 3 Example 3
(5R.6S) -2- [トメチル- 6,7-ジヒ ドロ- 5 H-シクロペン夕 [&]ピリジニ ゥム- 7-ィル Ί チォ- 6- 「C1R) - 1-ヒ ドロキシェチル Ί - 1 -力ルバペン -2 - ェム- 3-カルボキシラート (5R.6S) -2- [Tomethyl-6,7-dihydro-5H-cyclopentyl [&] pyridinium-7-yl thio-6- "C1R)-1-Hydroxyshetyl -1 -Kirubapen -2-hem-3-carboxylate
Figure imgf000030_0001
Figure imgf000030_0001
Figure imgf000030_0002
a) ニトロべンジル （3R,5R，6S) - 2-ォキソ - 6- [(1R) -1-ヒ ドロキ シェチル]- 1-カルバぺナム- 3-カルボキシラート 1.39g (4.00mmo のァセ トニトリル （22m 溶液に窒素気流下、 - 10°Cでジィソプロピルェチルァミ ン 0.712m£ (4.04 mmo£) のァセトニトリノレ （2.8m）溶液、 次にクロ口りん 酸ジフヱニノ W).844 め のァセトニトリル（2.8m 溶液を加え、同温度で 15 分間撹拌した。 次にジイソプロピルェチルァミン 0.712??^ (4.04mmoi) のァ セトニトリノレ （1.6mf) 溶液、 次いで 7 -メルカプト - 6，7-ジヒドロ- 5H-シク 口ペン夕 [b]ピリジン 924mg (6.\2mmo£) のァセトニトリノレ （1.6 溶液を - 1CTCで加え、 2時間撹拌したのち、 さらに 0°Cで 2時間撹拌した。 反応液を 再び— 10°Cに冷却し、 さらにジイソプロピルェチルァミン 0.712m (4.04 oi), 7-メノレカプト- 6，7-ジヒドロ— 5H-シクロペンタ [&]ピリジン 924mg (6.12mmoi) のァセトニトリノレ （1.6mi)溶液を加え、 0°Cで 1時間撹拌した。 反応液に酢酸ェチルを加え、 飽和炭酸水素ナトリウム水溶液、 次に飽和食塩 水で洗浄し、 無水硫酸マグネシウムで乾燥し、 溶媒を留去した。 残渣をシリ 力ゲル力ラムクロマトグラフィー（Wakogel® C-300,酢酸ェチルで溶 ）で 精製し、 ニトロべンジル （5R.6S) - 2- [6,7-ジヒドロ- 5//-シクロペン タ [ ]ピリジン- 7-ィノレ] チォ -6- [(1R) -1 -ヒドロキシェチル] -1-力ルバ 一 2S—
Figure imgf000030_0002
a) Nitrobenzyl (3R, 5R, 6S) -2-oxo-6-[(1R) -1-hydroxyshetyl] -1-carbazin-3-carboxylate 1.39g (4.00mmo of acetonitrile (0.72 m £ (4.04 mmo £) of acetonitrile (2.8 m) solution of disopropylethylamine at -10 ° C under a nitrogen stream in a 22 m solution, followed by difinino phosphate W). Acetonitrile (2.8m solution was added and stirred at the same temperature for 15 minutes. Diisopropylethylamine 0.712 ?? ^ (4.04mmoi) in acetonitrile (1.6mf) solution, then 7-mercapto-6,7-dihydro -5H-Six mouth pen [b] Pyridine 924 mg (6. \ 2mmo £) acetonitrile (1.6 solution was added at -1 CTC, stirred for 2 hours, and further stirred at 0 ° C for 2 hours. — Cool to 10 ° C and add diisopropylethylamine 0.712m (4.04 oi), 7-menolecapto-6,7-dihydro-5H- A solution of 924 mg (6.12 mmoi) of clopenta [&] pyridine in acetone (1.6 mi) was added and stirred for 1 hour at 0 ° C. Ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution. The residue was purified by silica gel gel column chromatography (Wakogel® C-300, dissolved in ethyl acetate) to give nitrobenzyl (5R.6S) -2. -[6,7-Dihydro-5 //-cyclopenta [] pyridine-7-inole] thio-6-[(1R) -1-hydroxyethyl] -1-butyl One 2S—
ペン- 2-ェム- 3-カルボキシラートの旦粉末 2.07g得た。 2.07 g of pen-2-em-3-carboxylate powder was obtained.
IR (KBr) cm'1： 3400, 2920, 1780, 1730, 1690, 1520, 1340 IR (KBr) cm ' 1 : 3400, 2920, 1780, 1730, 1690, 1520, 1340
UV Amax (MeOIT) ： 272nm (ε = 16,500), 32Ιηιη ( ε = 5.400) b) a) で得られた化合物 1.19g (2.30mmo£) のジクロロメタン （29 i) § 液に、 0°Cでメチルトリフラート 0.287mi (2.53mmoi)のジクロロメタン（15 mi) 溶液を加え、 室温で 2時間撹拌した。 溶媒を留去し、 残渣をエーテルで トリチュレートし、 N-メチル化物の粉末 1.59gを得た。 UV A max (MeOIT): 272 nm ( ε = 16,500), 32Ιηιη (ε = 5.400) b) Compound obtained in a) 1.19 g (2.30 mmo £) of dichloromethane (29 i) § solution at 0 ° C A solution of 0.287 mi (2.53 mmoi) of methyl triflate in dichloromethane (15 mi) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was triturated with ether to obtain N-methylated powder (1.59 g).
IR (KBr) cm-1： 3450, 1780, 1700, 1520, 1270, 1160, 1030, 640 UV XmM (MeOH) ： 278匪 (ε = 17,500) IR (KBr) cm- 1 : 3450, 1780, 1700, 1520, 1270, 1160, 1030, 640 UV X mM (MeOH): 278 bandages (ε = 17,500)
c) b)で得られた N-メチル化物をテトラヒドロフラン 70m および 0.1Mり ん酸緩衝液 （pH7.0) 70m£に溶解し、 10 % 、。ラジウム—炭素 500mgを加え、 約 3.1 gZcmで 1時間室温で接触水添を行つた。 反応液を濾過した後、 濃縮 し、 生成した不溶物を濾去した後、 逆相カラムクロマトグラフィー （ケムコ LC-SORB®, SP-B-ODS, 20 %メタノール一水で溶出） で精製し、凍結乾燥 を行い、 標記化合物 45.4mg (収率： 5.4%) を得た。 c) The N-methylated product obtained in b) was dissolved in 70 mL of tetrahydrofuran and 70 mL of 0.1 M citrate buffer (pH 7.0), and 10%. 500 mg of radium-carbon was added, and the mixture was subjected to catalytic hydrogenation at about 3.1 gZcm for 1 hour at room temperature. The reaction mixture was filtered, concentrated, and the resulting insolubles were removed by filtration. The residue was purified by reversed-phase column chromatography (Chemco LC-SORB®, SP-B-ODS, eluted with 20% methanol-water). Lyophilization was performed to obtain 45.4 mg (yield: 5.4%) of the title compound.
IR (KBr) cm-1： 3400, 1750, 1600, 1390, 1270 IR (KBr) cm- 1 : 3400, 1750, 1600, 1390, 1270
UV Amax (0.1M 3-モルホリノプロパンスルホナ一ト緩衝液， pH7.0) ：UV A max (0.1 M 3-morpholinopropane sulfonate buffer, pH 7.0):
281雇 （ε = 8,865) 281 employment (ε = 8,865)
NMR (DzO 6 ： 1.20 (3H， d, J = 6Hz), 2.16-3.62 (7H, m), 4.08- NMR (DzO 6: 1.20 (3H, d, J = 6 Hz), 2.16-3.62 (7H, m), 4.08-
4.44 (2H， m),4.30 (3H, s), 7.76 (1H, dd, 1 = 7, 8Hz),8.30 (1H, d,4.44 (2H, m), 4.30 (3H, s), 7.76 (1H, dd, 1 = 7, 8Hz), 8.30 (1H, d,
J = 8Hz), 8.49 (1H, d， J = 7Hz) J = 8Hz), 8.49 (1H, d, J = 7Hz)
実施例 4 Example 4
(5R.6S) -2- (1-メチノレ- 5,6,7,8-テトラヒドロキノリニゥム- 8 -ィル） チ ォ- 6- 「（1R) - 1-ヒドロキシェチル 1 -トカルバペン- 2-ェム- 3-カルボキシ ラート (5R.6S) -2- (1-Methinole-5,6,7,8-tetrahydroquinolininum-8-yl) thio-6- "(1R) -1-hydroxyethyl 1-tocarbapene -2-Em-3-carboxylate
Figure imgf000032_0001
Figure imgf000032_0001
-ニトロべンジル （3R5R6S) - 2-ォキソ - 6- [(1R) -卜ヒ ドロキシェ チル] -卜カノレバべナム- 3-カルボキシラート 696mgと 8-メルカルプト- 5,6, 78 -テ卜ラヒドロキノリン l.lgを用いて、実施例 3と同様の方法で標記化合 物を 18.6mg得た。  -Nitrobenzyl (3R5R6S)-2-oxo-6- [(1R)-Trihydroxyl]-Tokanorebabenam-3- carboxylate 696mg and 8-mercarpto-5,6,78-Tetrahydro Using quinoline l.lg, 18.6 mg of the title compound was obtained in the same manner as in Example 3.
IR (KBr) cm"1 3400, 1750, 1600 1390 IR (KBr) cm " 1 3400, 1750, 1600 1390
UV ス (0.1M 3-モルホリノプロパンスルホナート緩衝液， pH7.0) ： UV solution (0.1M 3-morpholinopropane sulfonate buffer, pH 7.0):
282nm (ε = 9,510) 282nm (ε = 9,510)
NMR (D20) δ ： 1.22 (3Η, d J = 5Hz), 1.80—3.62 (9H, m), 3.94- 4.34 (2H,m), 4.44 (3H, s)， 5.29 (1H, br)， 7.74 (1H, dd, J = 7， 8Hz)，NMR (D 2 0) δ: 1.22 (3Η, d J = 5 Hz), 1.80-3.62 (9H, m), 3.94- 4.34 (2H, m), 4.44 (3H, s), 5.29 (1H, br), 7.74 (1H, dd, J = 7, 8Hz),
8.22 (lHd, J = 8Hz), 8.57 (1H d J = 7Hz) 8.22 (lHd, J = 8Hz), 8.57 (1Hd J = 7Hz)
実施例 5 Example 5
7-メノレ力ブト— 6,7-ジヒ ドロ— 5H—シクロペン夕 [δ]ピリジン  7-Menolebut-6,7-dihydro-5H-cyclopentyl [δ] pyridine
Figure imgf000032_0002
a) 23-シクロペンテノピリジン 10g (84mmo£) の酢酸 （50m 溶液に 35 %過酸化水素水 12m を加え、. 70 80°Cで 3時間撹拌した。 反応液を濃縮乾 固した後、さらに氷 200/ ^を加え、再び濃縮乾固した。 残渣を水 50m に溶解 し、 炭酸水素ナトリゥム水溶液で PH8.0とし、 クロロホルムで抽出し、 無水 硫酸マグネシウムで乾燥後、 溶媒を留去し、 粗 N-ォキシド体 16.3gを得た。 これに =水酢 37m£を ¾Dえ、 80〜90 °Cで 15分揎持した後、 濃縮乾固した。 残渣を水 50miに溶かし、炭酸水素ナトリゥ厶水溶液で pH8.0とし、酢 ニチ ルで ¾出し、 水硫酸マグネシウムで乾燥後、溶媒を留去し、 ¾状¾ 12.^得 た。 これを 3N塩酸 37miに溶かし、 90°Cで 1時間^した後、冷却し、 2N水 酸化ナトリゥム水溶液で ρΗΙΟ.Οとし、 クロロホルムで抽出し、無水硫酸マグ ネシゥムで乾燥後、 溶媒を留去した。 残渣をイソプロピルエーテルでトリ チュレートして 7-ヒドロキシ- 6,7-ジヒドロ- 5 ί -シクロペン夕 [&]ピリジン を 7.45g (収率： 65.7 %) 得た。
Figure imgf000032_0002
a) A solution of 10 g (84 mmol) of 23-cyclopentenopyridine in acetic acid (12 m of 35% hydrogen peroxide solution in a 50 m solution) was stirred for 3 hours at 70 ° C. After the reaction solution was concentrated to dryness, it was further dried. The residue was dissolved in 50 m of water, adjusted to pH 8.0 with aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off. 16.3 g of N-oxide was obtained. To this was added 37 ml of water vinegar, kept at 80-90 ° C for 15 minutes, and concentrated to dryness. The residue was dissolved in 50 mi of water, adjusted to pH 8.0 with an aqueous solution of sodium hydrogen carbonate, extracted with sodium acetate, dried over magnesium sulfate, and the solvent was distilled off to obtain 12. ^. This was dissolved in 37N of 3N hydrochloric acid, heated at 90 ° C for 1 hour, cooled, made ρΗΙΟ with 2N aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off. . The residue was triturated with isopropyl ether to give 7.45 g (yield: 65.7%) of 7-hydroxy-6,7-dihydro-5 \ -cyclopentyl [&] pyridine.
IR (KBr) cm—1： 3240, 1590, 1330, 1008, 800 IR (KBr) cm— 1 : 3240, 1590, 1330, 1008, 800
NMR {CDC ) δ 1.96-2.00 (1Η, m) , 2.24-2.70 (1H， m)， 2.72〜 NMR (CDC) δ 1.96-2.00 (1Η, m), 2.24-2.70 (1H, m), 2.72-
2.96 (lH,m) , 2.96-3.18 (1H, m) , 5.28 (1H, dd,J = 7， 8Hz)， 5.39 (1H， bs)， 7.17 (lH'dd, J = 5, 8Hz) , 7.59 (1H, d, J = 8Hz) , 8.44 (1H, d, J = 5Hz) 2.96 (lH, m), 2.96-3.18 (1H, m), 5.28 (1H, dd, J = 7, 8Hz), 5.39 (1H, bs), 7.17 (lH'dd, J = 5, 8Hz), 7.59 (1H, d, J = 8Hz), 8.44 (1H, d, J = 5Hz)
b) a) で得られた化合物 3.7g {llAmmoSt) のクロ口ホルム （8m 溶液に 冷却下、塩化チォニル 2.39771 (33mmo£) のクロ口ホルム （2.3m 溶液を加 え、室温で 30分間撹拌した。 反応液を炭酸力リウム 4.99gを含む水溶液 12m に加え、 クロ口ホルムで抽出し、 無水硫酸マグネシウムで乾燥後、 溶媒を留 去し、 クロ口体を 3.91g得た。 50 %油性水素化ナトリゥム 1.72g (35.9mmo£) のジメチルホルムァミ ド（92m 懸濁液に、窒素気流下、 0°Cでチォ酢酸 2.39 mi .5mmo£) を加え、 室温で 25分間撹拌した。 さらにヨウ化ナトリウム 4.96g (33.1mmo 、次に前記クロ口体を加え、室温で一夜撹拌した。 反応液 に酢酸ェチルを加え、有機層を水洗した後、無水硫酸マグネシウムで乾燥し、 溶媒を留去した。 残渣をシリカゲルカラムクロマトグラフィー （Wakogel® C- 300,へキサン-酢酸ェチルで溶出） で精製し、 7-ァセチルチオ- 6,7-ジヒ ドロ- 5H-シクロペン夕 [&]ピリジン 4.04g (収率： 76.3 %) を得た。 b) A solution of 3.7 g (llAmmoSt) of compound obtained in a) in form of chloroform (8 m solution was cooled, and a solution of 2.39771 (33 mmo £) in thionyl chloride (2.3 m solution) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was added to 12 m of an aqueous solution containing 4.99 g of lithium carbonate, extracted with chloroform and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 3.91 g of a chloroform. 1.72 g (35.9 mmol) of sodium dimethylformamide (2.39 mi.5 mmol of thioacetic acid) was added to a 92 m suspension at 0 ° C. in a nitrogen stream, and the mixture was stirred at room temperature for 25 minutes. 4.96 g (33.1 mmol) of sodium was added, followed by stirring at room temperature overnight, and ethyl acetate was added to the reaction solution. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (Wakogel® C-300, hexane-acetic acid Purification by elution) yl, 7-Asechiruchio - 6,7 dihydric mud - 5H-Shikuropen evening [&] pyridine 4.04 g (yield: 76.3%) was obtained.
IR (KBr) cm" 1 : 2950， 1690, 1580， 1420, 1130， 790， 630 IR (KBr) cm " 1 : 2950, 1690, 1580, 1420, 1130, 790, 630
NMR (CDC£3) δ： 2.02—2.24 (1Η, m) , 2.40 (3H, s)， 2.68—2.92 (1H, m) , 2.92-3.10 (2H, m) , 5.08 (1H, dd, J = 7, 8Hz) , 7.12 (1H, dd, J = 5, 8Hz)， 7.56 (1H， d, J = 8Hz) , 8.46 (1H, d， J = 5Hz) c) b) で得られた化合物 4.02g (20.8m o を窒素ガスを十分通じたメタ ノール 17?7i£に溶かし、窒素気流下、 IX水酸化ナトリゥム水溶液 21.1miを力 え、室温で 15分間撹捽した。 反応液に IN塩酸 を ¾0え、護縮し、残渣 を詐酸ェチルに溶解した。 これを水 ¾した後、 ^水硫酸マグネシゥムで乾燥 し、 溶媒を留去し、標記化合物 2.81g (収率：89.5%) を油状物として得た。 NMR (CDC £ 3 ) δ: 2.02-2.24 (1Η, m), 2.40 (3H, s), 2.68-2.92 (1H, m), 2.92-3.10 (2H, m), 5.08 (1H, dd, J = 7,8Hz), 7.12 (1H, dd, J = 5, 8Hz), 7.56 (1H, d, J = 8Hz), 8.46 (1H, d, J = 5Hz) c) Compound 4.02g obtained from b) (20.8mo is meta- The solution was dissolved in 17 to 7 ml of ethanol, and 21.1 mi of IX sodium hydroxide aqueous solution was stirred under a nitrogen stream at room temperature for 15 minutes. The 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.
IR (KBr) cm"1： 2950, 2530, 1580, 1420, 790 IR (KBr) cm " 1 : 2950, 2530, 1580, 1420, 790
NMR (CDCi3) δ： 1.96-2.20 (1Η, m), 2.22 (1H, d, J = 5Hz), 2.50— 2.80 (1H， m), 2.80—3.36 (2H, m), 4.40—4.60 (1H， m), 7.12 (1H, dd, J = 5, 8Hz), 7.56 (1H， d, J = 8Hz), 8.46 (1H, d, J = 5Hz) 実施例 6 NMR (CDCi 3 ) δ: 1.96-2.20 (1Η, m), 2.22 (1H, d, J = 5 Hz), 2.50— 2.80 (1H, m), 2.80—3.36 (2H, m), 4.40—4.60 (1H , M), 7.12 (1H, dd, J = 5, 8Hz), 7.56 (1H, d, J = 8Hz), 8.46 (1H, d, J = 5Hz) Example 6
8-メルカプト- 5 ，7,8-テトラヒドロキノリン  8-mercapto-5,7,8-tetrahydroquinoline
Figure imgf000034_0001
Figure imgf000034_0001
雄例 5と同様の方法で 5,6,7,8-テトラヒドロキノリン 10gから 8-クロロ- 5,6,7,8-テトラヒドロキノリン 4.92gを得、 これを 2.6g用いて標記化合物を 1.39g得た。 Oleyl 5 and in the same manner 5,6,7,8-tetrahydroquinoline from 10 g 8- chloro - 5,6,7,8 obtain tetrahydroquinoline 4.92 g, of the title compound which is used 2.6 g 1.39 g Obtained.
IR (KBr) cm-1： 2930, 2550, 1570, 1440, 790 IR (KBr) cm- 1 : 2930, 2550, 1570, 1440, 790
NMR (CDCi3) δ ： 1.72-1.96 (1Η. m), 1.96〜2·52 (5H， m)， 2.66〜 2.98 (2H, m), 4.42—4.56 (1H， m), 7.08 (1H， dd, J = 5， 8Hz), 7.40 ひ H， d, J = 8Hz), 8.44 (1H， d, J = 5Hz) 産 業 上 の 利 用 可 能 性 NMR (CDCi 3 ) δ: 1.72-1.96 (1Η.m), 1.96 to 2.52 (5H, m), 2.66 to 2.98 (2H, m), 4.42 to 4.56 (1H, m), 7.08 (1H, dd , J = 5, 8Hz), 7.40h H, d, J = 8Hz), 8.44 (1H, d, J = 5Hz) Industrial applicability
本発明の"^式 [I]の化合物は、グラム陽性菌およびグラム陽性菌に対し て優れた抗菌活性を示すので、 抗菌剤として有用である。  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.
更には、一般式 [Π] の化合物および一般式 [W] の化合物は、文献未記載 の新規化合物であり、一般式 [I] の化合物の合成中間体として有用である。  Furthermore, the compound of the general formula [Π] 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].

Claims

請 求 の 範 @  Range of claims @
(1) 一般式 (1) General formula
Figure imgf000035_0001
Figure imgf000035_0001
[式中、 R1は水素原子またはメチル基、 R2は水素原子、 シァノ基、カルボキン ノレ基、低級アルコキシカルボニル基または- C〇N (R3) R4で表される基（ここ において、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R4は隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジ ニル基、 ピペリジノ基、 ピペラジニノレ基、 4-低級アルキルピペラジニル基、モ ルホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成 する）、 nは 1ないし 3の整数を示す] で表される化合物またはその医薬とし て許容される塩またはエステル。 [Wherein, R 1 is a hydrogen atom or a methyl group, R 2 is a hydrogen atom, a cyano group, a carboxy group, a lower alkoxycarbonyl group, or a group represented by —C〇N (R 3 ) R 4 (wherein 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, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinino group, and a 4-lower alkyl pipe A heterocyclic group selected from the group consisting of a radinyl group, a morpholino group and a thiomorpholino group), and n represents an integer of 1 to 3] or a pharmaceutically acceptable salt or ester.
(2) R2が水素原子であり、 nが 1または 2の整数を示す第 1請求項記載の化 合物。 (2) The compound according to claim 1, wherein R 2 is a hydrogen atom and n is an integer of 1 or 2.
(3) 力ルバぺネムの骨格の立体配位が （5R，6S，8R) または （1R,5S,6S,8R) である第 1請求項記載の化合物。  (3) The compound according to the above (1), wherein the configuration of the skeleton of the carbane is (5R, 6S, 8R) or (1R, 5S, 6S, 8R).
(4) (1R,5S,6S) - 2- [1 -メチノレ- 6,7 -ジヒドロ- 5H -シクロペン夕 [ό]ピリ ジニゥム- 7-ィル] チォ - 6- [(1R) - ヒドロキシェチル] -卜メチルカルバ ペン- 2-ェム- 3-カルボキシラート、  (4) (1R, 5S, 6S) -2- [1-Methynole-6,7-dihydro-5H-cyclopentyl [ό] pyridinium-7-yl] thio-6-[(1R) -hydroxy Tyl] -trimethylcarbapen-2-em-3-carboxylate,
(1R,5S,6S) - 2- ひ -メチル -5,6,7,8-テトラヒドロキノリニゥム - 8-ィル） チ ォ- 6- [ (1R) - 1 -ヒドロキシェチル] - 1 -メチルカルバペン- 2 -ェム- 3 -カル ボキシラート、  (1R, 5S, 6S)-2-Hy-methyl-5,6,7,8-tetrahydroquinolininum-8-yl) thio-6-[(1R) -1-hydroxyethyl]- 1-methylcarbapene-2-em-3-carboxylate,
(5R，6S) - 2- -メチル - 6,7-ジヒドロ- 5H-シクロペンタ [&]ピリジニゥム- 7-ィル] チォ- 6- [(1R) - 1 -ヒ ドロキシェチル] - 1 -力ルバペン- 2-ェ厶- 3- カルボキシラートおよび (5R, 6S)-2- -Methyl-6,7-dihydro-5H-cyclopenta [&] pyridinium- 7-yl] thio-6-[(1R) -1 -Hydroxitytyl]-1-potassyl-2-apenyl-3-carboxylate and
(5R,6S) -2- (1 -メチル- 5,6，7，8 -テトラヒドロキノリニゥム- S -ィル） チォ- 6- [(1R) - 1 -ヒ ドロキシェチノレ] -卜力ルバペン- 2-ェム- 3-カルボキシラー トである第 1請求項記載の化合物。  (5R, 6S) -2- (1-Methyl-5,6,7,8-tetrahydroquinolinium-S-yl) thio-6-[(1R) -1-Hydroxyshetinole] -The compound according to claim 1, which is 2-em-3-carboxylate.
(5) (1R,5S,6S) - 2- [卜メチノレ- 6,7 -ジヒドロ- 5H-シクロペン夕 [ ピリ ジニゥム -7-ィル] チォ- 6- [(1R) - 1-ヒドロキシェチノレ] - 1 -メチルカルバ ぺン- 2-ェム- 3-力ルボキシラートである第 1請求項記載の化合物。  (5) (1R, 5S, 6S)-2- [Tomethinole-6,7-dihydro-5H-cyclopentyl [pyridinid-7-yl] thio-6-[(1R)-1-hydroxyethino [11] The compound according to the above [1], which is [1-]-methylcarbazine-2-em-3-hexylcarboxylate.
(6) —般式  (6) — General formula
Figure imgf000036_0001
Figure imgf000036_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物と一般式 Wherein R 1 is a hydrogen atom or a methyl group, R 5 is a carboxyl-protecting group, and Z is a leaving group.
Figure imgf000036_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 ηは 1ないし 3の整数を示す] で表される化合物とを反応させ、 次いで ヽ— -メチル化反^に付し、 更に 護基を除去することを特徵とする、 一 ¾弍
Figure imgf000036_0002
[In the 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 together with an adjacent nitrogen atom, an aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidino group, piperazinyl group, 4-lower alkylpiperazinyl group, mol Forms a heterocyclic group selected from the group consisting of folino and thiomorpholino Η represents an integer of 1 to 3], followed by subjecting to a ヽ -methylation reaction and further removing the protecting group.
Figure imgf000037_0001
[式中、 R2は水素原子、 シァノ基、 カルボキシル基、低級アルコキシカルボ二 ル基または- CON (R3) R4で表される基 （ここにおいて、 R3および ま水素 原子または低級アルキル基を示すか、 R3および R4は隣接する窒素原子と共 に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル基、 ピペリジノ基、 ピ ペラジニル基、 4-低級アルキルピペラジニル基、 モルホリノ基およびチォモ ルホリノ基からなる群から選ばれる複素環基を形成する）、 riは 1ないし 3の 整数を示し、 R1および nは前記の意味を有する] で表される化合物またはそ の医薬として許容される塩またはエステルの製造法。
Figure imgf000037_0001
[Wherein, R 2 is a hydrogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, or a group represented by —CON (R 3 ) R 4 (where R 3 is a hydrogen atom or a lower alkyl group) Or R 3 and R 4 together with the adjacent nitrogen atom represent an aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkylpiperazinyl, morpholino and thiomorpholino group Ri represents an integer of 1 to 3, and R 1 and n have the above-mentioned meanings, or a pharmaceutically acceptable salt or ester thereof. Manufacturing method.
(7) 一般式  (7) General formula
Figure imgf000037_0002
Figure imgf000037_0002
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物と一般式
Figure imgf000038_0001
Wherein R 1 is a hydrogen atom or a methyl group, R 5 is a carboxyl-protecting group, and Z is a leaving group.
Figure imgf000038_0001
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポニル基または- CON ( R3) R4で表される基 （ここにおい て、 ^および R4は水素原子または低級アルキル基を示す力、、 R3および R4は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 nは 1ないし 3の整数、 Xeは陰イオンを示す] で表される化合物とを反 応させて、 一般式 [Wherein, R 6 represents a hydrogen atom, a cyano group, a carboxyl group which may be protected, a lower alkoxyl propyl group, or a group represented by —CON (R 3 ) R 4 (wherein ^ 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 you form a heterocyclic group selected from the group consisting of Horino group and thiomorpholino group), and n is an integer of 1 to 3, X e is allowed to reaction with the compound represented by represents an anion, generally formula
Figure imgf000038_0002
Figure imgf000038_0002
[式中、 R\ R\ R nおよび Χθは前記の意味を有する] で表される化合物 とし、 次いで保護基を除去することを特徴とする、 一般式 Wherein the R \ R \ R n and chi theta as defined above] and a compound represented by then and removing the protecting group, the general formula
Figure imgf000038_0003
[式 Φ、 R:は水素原子、 シァノ基、 カルボキシル基、 級アルコキシカルボ二 ル基または- COX (R3) R4で表される基 （ここにおいて、 R3および R4は水 ¾ 原子または' 級アルキル基を示すか、 R3および R4は隣接する望素层子と = に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル基、 ピペリジノ基、 ピ ペラジニル基、 4-低級アルキルピペラジニル基、 モルホリノ基およびチォモ ルホリノ基からなる群から選ばれる複素環基を形成する） を示し、 R1および nは前記の意味を有する] で表される化合物またはその医薬として許容され る塩またはエステルの製造法。
Figure imgf000038_0003
[Formulas Φ and R : are hydrogen atoms, cyano groups, carboxyl groups, alkoxyalkoxycarbonyl groups or groups represented by —COX (R 3 ) R 4 (where R 3 and R 4 are hydrogen atoms or '' Represents a lower alkyl group, or R 3 and R 4 are aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, piperazinyl, 4-lower alkylpiperazinyl, morpholino A heterocyclic group selected from the group consisting of a group and a thiomorpholino group), and R 1 and n have the above-mentioned meanings, or a pharmaceutically acceptable salt or ester thereof. .
(8) 一般式  (8) General formula
Figure imgf000039_0001
Figure imgf000039_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物を一般式 [Wherein, R 1 represents a hydrogen atom or a methyl group, R 5 represents a carboxyl-protecting group, and Z represents a leaving group].
Figure imgf000039_0002
Figure imgf000039_0002
[式中、 R1および Rsは前記の意味を有する] で表される化合物とし、 次いで 一般式 [ Ί] の化合物と一般式
Figure imgf000040_0001
[Wherein, R 1 and R s have the same meaning as above], and then a compound of the general formula [Ί] and a compound of the general formula
Figure imgf000040_0001
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシカルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示すか、 R3および ま 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジソ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 Yは脱離基、 nは 1ないし 3の整数を示す] で表される化合物とを反応 させ、次いで N-メチルイ匕反応に付し、更に保護基を除去することを特徵とす る、 一般式 [In the 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 —CON (R 3 ) R 4 (here, R 3 And R 4 represent a hydrogen atom or a lower alkyl group, or together with R 3 and an adjacent nitrogen atom, an aziridinyl group, a azetidinyl group, a pyrrolidinyl group, a piperidiso group, a piperazinyl group, a 4-lower alkylpiperazinyl group, morpholino A heterocyclic group selected from the group consisting of a thiomorpholino group and a thiomorpholino group), Y represents a leaving group, and n represents an integer of 1 to 3]. A general formula characterized by subjecting to a dani reaction and further removing a protecting group.
Figure imgf000040_0002
Figure imgf000040_0002
[式中、 R2は水素原子、 シァノ基、 カルボキシル基、低級アルコキシカルボ二 ル基または- CON (R3) R4で表される基 （ここにおいて、 R3および R4は水素 原子または低級アルキル基を示すか、 R3および R4は隣接する窒素原子と共 に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル基、 ピペリジノ基、 ピ ペラジニル基、 4-低級ア キルピペラジニル基、 モルホリノ基およびチォモ ルホリノ基からなる群から選ばれる複素環基を形成する） を示し、 および nは前記の意味を有する] で表される化合物またはその医薬として許容され る塩またはエステルの製造法。 (δ) 一般式 [Wherein R 2 is a hydrogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a group represented by —CON (R 3 ) R 4 (where R 3 and R 4 are a hydrogen atom or a lower Represents an alkyl group, or R 3 and R 4 together with an adjacent nitrogen atom represent an aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkylpiperazinyl, morpholino and thiomorpholino group And n has the meaning described above], or a pharmaceutically acceptable salt or ester thereof. (δ) General formula
Figure imgf000041_0001
Figure imgf000041_0001
[式中、 R1は水素原子またはメチル基、 R5はカルボキシル基の保護基、 Zは脱 離基を示す] で表される化合物を一般式 [Wherein, R 1 represents a hydrogen atom or a methyl group, R 5 represents a carboxyl-protecting group, and Z represents a leaving group].
Figure imgf000041_0002
Figure imgf000041_0002
[式中、 R1および R5は前記の意味を有する] で表される化合物とし、 次いで 一般式 [VI] の化合物と一般式 Wherein 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
Figure imgf000041_0003
Figure imgf000041_0003
〔式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ビベリジノ基、 ピペラジニル基、 4-g級アルキルピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複¾¾基を形成す る）、 Xsは陰イオン、 Yは脱離基、 nは 1ないし 3の整数を示す： で表される 化合物とを反応させて、 一般式 [In the 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, R 3 and R together with an adjacent nitrogen atom, an aziridinyl group, an azetidinyl group, a pyrrolidinyl Group, Biberijino group, piperazinyl group, 4-g loweralkyl piperazinyl group, that form a double ¾¾ group selected from the group consisting of moles Horino group and thiomorpholino group), X s is the anion, Y is desorption The group, n represents an integer of 1 to 3: reacting with a compound represented by the general formula
Figure imgf000042_0001
Figure imgf000042_0001
[式中、 Rl R R6 nおよび Xeは前記の意味を有する] で表される化合物 とし、 次いで保護基を除去することを特徴とする、 一般式 [Wherein, R 1 RR 6 n and X e have the same meanings as above], and then removing the protecting group.
Figure imgf000042_0002
Figure imgf000042_0002
[式中、 R2は水素原子、 シァノ基、 カルボキシル基、低級アルコキシカルボ二 ル基または- CON (R3) R4で表される基 （ここにおいて、 R3および R4は水素 原子または 級アルキル基を示すか、 R3および R4は隣接する窒素原子と共 に、 アジリジニノレ基、 ァゼチジニル基、 ピロリジニル基、 ピペリジノ基、 ピ ペラジニル基、 4-低級アルキルピペラジニル基、 モルホリノ基およびチォモ ルホリノ基からなる群から選ばれる複素環基を形成する） を示し、 および nは前記の意 を有する〗 で表される化合物またはその [S薬として許容され る塩またはエステルの製造法。 [Wherein R 2 is a hydrogen atom, a cyano group, a carboxyl group, a lower alkoxycarbonyl group or a group represented by —CON (R 3 ) R 4 (where R 3 and R 4 are a hydrogen atom or a class Represents an alkyl group, or R 3 and R 4 together with an adjacent nitrogen atom represent an aziridininole, azetidinyl, pyrrolidinyl, piperidino, piperazinyl, 4-lower alkylpiperazinyl, morpholino and thiomorpholino A heterocyclic group selected from the group consisting of groups), and n is a compound represented by the above formula (1) or a [S-drug-acceptable salt or ester thereof].
(10) —般^:
Figure imgf000043_0001
(10) —General ^:
Figure imgf000043_0001
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシカルボニル基または- CON ( R3 ) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および は 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニノレ 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキル-ピペラジニル基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成す る）、 nは 1ないし 3の整数を示す] で表される化合物。 [Wherein, 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 are, together with an adjacent nitrogen atom, an aziridinyl, azetidinyl, pyrrolidinole, piperidino, piperazinyl, 4-lower alkyl-piperazinyl, morpholino and A heterocyclic group selected from the group consisting of thiomorpholino groups), and n represents an integer of 1 to 3.]
(11) 一般式  (11) General formula
Figure imgf000043_0002
Figure imgf000043_0002
[式中、 R6は水素原子、 シァノ基、保護されていてもよいカルボキシル基、低 級アルコキシ力ルポ二ル基または- CON ( R3) R4で表される基 （ここにおい て、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R ま 隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジニル 基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニノレ基、 モル ホリノ基およびチオモルホリノ基からなる群から選ばれる複素璟基を形成す る）、. nは 1ないし 3の整数、 Xeは陰イオンを示す] で表される化合物。 (12) ~¾式 [In the 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; R 3 and R or an adjacent nitrogen atom, together with an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinole group , you form a heterocyclic璟基selected from the group consisting of moles Horino group and thiomorpholino),. n is an integer of 1 to 3, X e is represented by represents an anion] compound. (12) ~ ¾
Figure imgf000044_0001
Figure imgf000044_0001
[式中、 R1は水素原子またはメチノレ基、 R2は水素原子、 シァノ基、 カルボキシ ノレ基、低級アルコキシカルボニル基または- CON (R3) R4で表される基 （ここ において、 R3および R4は水素原子または低級アルキル基を示す力、、 R3および R4は隣接する窒素原子と共に、 アジリジニル基、 ァゼチジニル基、 ピロリジ ニル基、 ピペリジノ基、 ピペラジニル基、 4-低級アルキルピペラジニル基、モ ルホリノ基およびチオモルホリノ基からなる群から選ばれる複素環基を形成 する）、 IIは 1ないし 3の整数を示す] で表される化合物またはその医薬とし て許容される塩またはエステルを有効成分とする抗菌剤。 [Wherein, R 1 is a hydrogen atom or a methoxy group, R 2 is a hydrogen atom, a cyano group, a carboxy group, a lower alkoxycarbonyl group, or a group represented by —CON (R 3 ) R 4 (wherein 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, an aziridinyl group, a azetidinyl group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a 4-lower alkylpiperazinyl , A morpholino group and a thiomorpholino group to form a heterocyclic group), II represents an integer of 1 to 3, or a pharmaceutically acceptable salt or ester thereof. Antibacterial agent as an active ingredient.
PCT/JP1990/000866 1989-07-07 1990-07-06 Carbapenem derivatives WO1991000864A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6163679A (en) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド 1-methylcarbapenems having 2-quaternary heteroarylalkylthio substituent
JPS6163678A (en) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド Carbapenems having alkylated mono- or bicyclic 2-quaternary heteroarylalkylthio substituent
JPS6183184A (en) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド Carbapenems having 2-quaternary heteroarylalkylthio substituent
JPS6183183A (en) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 1-methylcarbapenems having alkylated mono-or bi-cyclic 2-quaternary heteroarylalkylthio substituent
JPS63255284A (en) * 1987-04-11 1988-10-21 Nippon Redarii Kk (1r,5s,6s)-2-((substituted pyridinium-2-yl)methyl)thio-6-((r)-1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6163679A (en) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド 1-methylcarbapenems having 2-quaternary heteroarylalkylthio substituent
JPS6163678A (en) * 1984-07-02 1986-04-01 メルク　エンド　カムパニ−　インコ−ポレ−テツド Carbapenems having alkylated mono- or bicyclic 2-quaternary heteroarylalkylthio substituent
JPS6183184A (en) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド Carbapenems having 2-quaternary heteroarylalkylthio substituent
JPS6183183A (en) * 1984-07-02 1986-04-26 メルク　エンド　カムパニ−　インコ−ポレ−テツド 1-methylcarbapenems having alkylated mono-or bi-cyclic 2-quaternary heteroarylalkylthio substituent
JPS63255284A (en) * 1987-04-11 1988-10-21 Nippon Redarii Kk (1r,5s,6s)-2-((substituted pyridinium-2-yl)methyl)thio-6-((r)-1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate

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