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WO1998034937A1 - Composes heterocycliques tricycliques - Google Patents

Composes heterocycliques tricycliques Download PDF

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Publication number
WO1998034937A1
WO1998034937A1 PCT/JP1998/000531 JP9800531W WO9834937A1 WO 1998034937 A1 WO1998034937 A1 WO 1998034937A1 JP 9800531 W JP9800531 W JP 9800531W WO 9834937 A1 WO9834937 A1 WO 9834937A1
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group
formula
hydrogen atom
substituent
substituents
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PCT/JP1998/000531
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English (en)
Japanese (ja)
Inventor
Isao Kawamoto
Osamu Kanno
Shino Kobayashi
Yasuo Shimoji
Satoshi Ohya
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Sankyo Co Ltd
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Sankyo Co Ltd
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Priority to AU57814/98A priority Critical patent/AU5781498A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a tricyclic heterocyclic compound having excellent antibacterial activity, a composition for preventing or treating infectious diseases containing them as an active ingredient, and a medicament for preventing or treating infectious diseases. And a method for preventing or treating infectious diseases, which comprises administering a pharmacologically effective amount thereof to a warm-blooded animal, or a method for producing them.
  • chenamycin derivatives Although chenamycin derivatives have excellent antibacterial activity, they are degraded by dehydrobeptidase-I, an enzyme that inactivates the chenamycin derivatives present in the human body, and lose their activity.
  • tribactam or trinem As tricyclic 13-lactam compounds, some compounds are reported in JP-A-3-167187, JP-A-4-178389, and the like. Compounds belonging to this system are called tribactam or trinem, and among them, Sanfe trinem represented by the following chemical formula is well known (DiMo du gnoetal., Antimi cr ob. Agent s Cemother., 38, 2362 (1994)).
  • Chenamycin derivatives generally exhibit excellent antibacterial activity, but have a problem with chemical stability, i.e., dehydrobeptidase I.
  • trinem derivatives represented by sanfetrinem are dehydrobeptidase I.
  • the antibacterial activity is slightly inferior to the chenamycin derivative. Therefore, the appearance of trinem compounds having good stability against dehydrolipeptidase-I and exhibiting excellent antibacterial activity is desired.
  • the present inventors have conducted various studies to solve these drawbacks, and found that the novel tricyclic heterocyclic derivative (I), its pharmacologically acceptable salts and derivatives, have a strong antibacterial activity, and have a dehydrobeptidase activity.
  • the present inventors have found that the present invention is stable with respect to 1I and has a high urinary content, thereby completing the present invention.
  • the tricyclic heterocyclic compound of the present invention has the general formula
  • A represents any of the following formulas (2), (3), (4) or (5)
  • R 7 represents a hydrogen atom or a C 4 alkyl group
  • R 9 is a phenyl group which may have 1 to 3 substituents (the substituents are d to C 4 alkyl groups, to C 4 alkoxy groups, nitro groups, halogen atoms, hydroxyl groups, cyano groups, shows d -C 4 alkyl force Rubamoiru group, a sulfamoyl group or 1-3 nitrogen, and shows the Teroariru group to 5-6 membered containing oxygen or sulfur atom) - group, mono - or di. ]
  • r 0, 1, 2 or 3;
  • R IQ represents a hydrogen atom or a d-C 4 alkyl group
  • R 12 is a hydrogen atom,-(: a 4- alkyl group or a group represented by the formula —C (—NH) R 4 , wherein R 4 is a hydrogen atom, a d-C 4 alkyl group, an amino group Or mono- or di-d ⁇ (: represents 4 alkylamino group),
  • R 13 is d to (: 4 alkyl groups having 1 to 3 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C 3 to C 6 cycloalkyl group, and 1 to 3 C s -C, which may have a substituent, aryl group, C 7 -C aralkyl group which may have 1 to 3 substituents (the substituent is a nitro group, a halogen atom, a methyl , Amino, sulfamoyl, sulfamoyl, methylcarbamoyl, dimethylcarbamoyl, 5- or 6-membered heteroaryl containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy, difluoromethoxy Group, a methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetylamino group), and 1 to 3 nitrogen
  • the substituent may be: (indicating: 4 alkyl groups, 2-hydroxyethyl group, carbamoylmethyl group) or 1 to 3 nitrogens, acids which may be substituted with a methyl group 5- or 6-membered heteroaryl group containing an elemental or sulfur atom.]
  • R 2 , R 4 , R 4a , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 R 12 , R 13 and the substituent group (a) “C, to (: 4 alkyl Group and the ( ⁇ to (: 4 alkylamino) group and the “ ⁇ to (: 4 alkyl) portion of the“ d to (: 4 alkylamino group) are linear or branched having 1 to 4 carbon atoms.
  • branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl group, and is preferably a methyl or ethyl group, more preferably Is a methyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom and a bromine atom, and a fluorine atom or a chlorine atom is preferable. Preferably it is a fluorine atom.
  • the “C 7 -C 14 aralkyl group” of R 2 represents the aforementioned re,-(: 4 alkyl group) substituted with “C 6 -Ci.
  • Aryl group such as phenyl, naphthyl, and indul groups. Benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, indenylmethyl, indenylethyl groups and the like can be mentioned, preferably benzyl, 1-naphthylmethyl, 2-naphthylmethyl or phenylethyl group. And more preferably a benzyl or phenethyl group, and even more preferably a benzyl group.
  • a ⁇ 5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms '' is a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms. indicating the -C 4 alkyl group substituted with (5-6 membered aromatic heterocyclic group).
  • the 5- to 6-membered heteroaryl group for example, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, triazolyl, thiazolyl, thiaziazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, chenyl, etc. And preferably a pyridyl, imidazolyl, thiazolyl or thiadiazolyl group.
  • d -C 4 alkyl group is defined agree with the, preferably a methyl or Echiru group, more preferably is a methyl group
  • Examples of the above "5- to 6-membered alkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms” include, for example, pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyrazinylmethyl, pyrimidylmethyl, pyridazinylmethyl, imidazolylmethyl, Imidazolylethyl, thiazolylmethyl, thiazolylethyl, pyrrolylmethyl, virazolylmethyl, isoxazolylmethyl, isothiazolylmethyl, isoxazolylmethyl, isothiazolylmethyl, chenylmethyl and the like, and preferably pyridylmethyl.
  • Examples of the “C 7 -C 14 aralkyl group which may have a substituent” for R 2 include, for example, benzyl, phenethyl, 4-fluorobenzyl, 4-butyrubamoyl pendyl, and 4-methylbenzyl group. Can be.
  • Examples of the “5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may have a substituent” for R 2 include 2-pyridylmethyl, 3-pyridylmethyl, 4 Examples thereof include monopyridylmethyl, 2-imidazolylmethyl, N-methyl-2-imidazolylmethyl, 2-thiadiazolylmethyl, and 2- (4-methyl-5-thiazolyl) ethyl group.
  • R 4 a and R 5 - as "mono- or di-d -C 4 alkylamino group" Ki de e.g. Mechiruamino, Echiruamino, Puropiruamino, Puchiruamino, Jimechiruamino, be mentioned Jechiruamino or dipropylamino group, It is preferably a methylamino or dimethylamino group, and more preferably a dimethylamino group.
  • 4 or R 4a include a hydrogen atom, methyl, ethyl, propyl, butyl, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, and acetylamino group, preferably a hydrogen atom, methyl or amino group. It is.
  • Examples include formimidyl, acetimidoyl, propionimidoyl, amidino, methylamidino, ethylamidino or N, N-dimethylamidino groups, preferably formimidyl, acetimidoyl or amidino groups.
  • R 2 is a 5- to 6-membered 'acrylic group containing 1 to 3 nitrogen, oxygen or sulfur atoms' is a 5- to 6-membered aliphatic heterocyclic ring containing 1 to 3 nitrogen, oxygen or sulfur atoms And represents, for example, pyrrolidinyl, piberidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, imidazolinyl, thiazolinyl, piperazinyl and the like.
  • a preferred group among these is a 2-imidazolinyl or 2-thiazolinyl group, more preferably a 2-imidazoline-12-yl or 2-thiazoline-2-yl group.
  • a ⁇ 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms '' is a 5- to 6-membered aromatic complex containing 1 to 3 nitrogen, oxygen or sulfur atoms.
  • k is preferably 0 or 1
  • m is 0, 1 or 1.
  • 2 are both preferred.
  • Suitable groups for R 2 as a whole are a hydrogen atom, a C 4 alkyl group, benzyl optionally having 1 to 2 substituents, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or thiadiazo.
  • a hydrogen atom, a methyl group, an ethyl group, a benzyl or pyridylmethyl group which may have 1 to 2 substituents (the substituents represent a fluorine atom, a methyl group or a carbamoyl group)
  • a formimidyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group and more preferably a hydrogen atom, a methyl group, an ethyl group, or a benzyl group.
  • n is preferably 1, and in the group represented by the formula (s 2), s is preferably 1, and p is either 0 or 1. Is also preferred.
  • R 6 is (In the formula, R 4a is a hydrogen atom, a methyl group or an amino group) preferably a hydrogen atom, d -C 4 alkyl group, a group represented by the formula one C (two NH) R 4a, A 2-imidazolinyl group or a 2-thiazolinyl group, more preferably a hydrogen atom, methyl, ethyl, formimidoyl, acetimidoyl, 2-imidazoline-1-yl or 2-thiazoline-2-yl group; .
  • R 7 and R 1Q are preferably a hydrogen atom, a methyl or an ethyl group.
  • Examples of the “group represented by C 0 R 5 ” of R 3 include, for example, carbamoyl, methyl carbamoyl, dimethylcarbamoyl, 1-piperazulcarbonyl, 1-homopiperazinylcarbonyl, 4-methylbiperazine 1-ylcarbonyl, 4-methylhomopyrazine-l-ylcarbonyl, 4-formimidylpyrazine- 1-ylcarbonyl, 4-acetamidoylpyrazine- 1-ylcarbonyl, 4-amidino piperazine 1-ylcarbonyl, 4- (2-imidazoline 1- 2-yl) piperazine- 1-ylcarbonyl, 4- 1- (2-thiazoline-2-yl) piperazine- 1-ylcarbonyl, 3-aminopyrrolidine- 1-ylcarbonyl, 3-aminomethylpyrrolidine- 1-ylcarbonyl, 3 —Methylaminopyrrolidin — 1 —ylcarbonyl, 3 —Met
  • R 3 is a group consisting of sorbamoyl, 1-piperazinylcarbonyl, 3-aminopyrrolidine-1-ylcarbonyl or 3-aminomethylpyrrolidine-1-ylcarbonyl.
  • Suitable groups for R 3 as a whole are a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a sorbamoyl group, a dimethylcarbamoyl group, a 1-piperazinylcarbonyl group, an aminopyrrolidine-1-ylcarbonyl group or an aminomethylpyrrolidine
  • a 1-ylcarbonyl group more preferably a hydrogen atom, a carbamoyl group, a 1-piperazinylcarbonyl group, a 3-aminopyrrolidine-1-ylcarbonyl group or a 3-aminomethylpyrrolidine-1-ylcarbonyl group.
  • q is a hydrogen atom.
  • Examples of the “mono- or di-d to C 4 alkyl rubamoyl group” in the substituent of R 9 include, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl or dibuyl pill.
  • Examples include a rubamoyl group, preferably a methylcarbamoyl group or a dimethylcarbamoyl group.
  • the “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms” in the substituent of R 9 is defined as “5 to 6-membered heteroaralkyl group” in R 2 in the definition of A 6-membered heteroaryl group ", preferably an imidazolyl, triazolyl, pyridyl or thiazolyl group, more preferably 1-imidazolyl, 1- (1,2,3-triazolyl), 4 It is a monopyridyl or 2-thiazolyl group.
  • the d -C 4 alkoxy substituents R 9, methoxy, ethoxy, pro epoxy, Isopurobokishi, can be mentioned butoxy group, preferably a was methoxy or ethoxy group, and more preferably a methoxy group It is.
  • R 9 is preferably a phenyl group optionally having 1 to 2 substituents (the substituents may be C 1 to (: 4 alkyl groups, d to C 4 alkoxy groups, nitro groups, halogen atoms, water an acid group, Shiano group, forces Rubamoiru group, mono- or di-d ⁇ C 4 alkyl force Luba moil group, a sulfamoyl group or 1-3 nitrogen, heteroaryl groups 5-6 membered containing oxygen or sulfur atom, ), And more preferably 1 to 2 A phenyl group which may have a substituent (the substituent is a methyl group, a methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, A pyridyl group
  • r is preferably 0, 1 or 2.
  • Examples of the substituent of "d to (: 4 alkyl group having 1 to 3 substituents)" of R 13 include a fluorine atom, a chlorine atom, a carbamoyl group and a hydroxyl group. It is a fluorine atom, a sulfamoyl group or a hydroxyl group, and more preferably a fluorine atom.
  • Examples of the “d to C 4 alkyl group having 1 to 3 substituents” for R 13 include 2-fluoroethyl, 2-chloroethyl, 2-bidroxethyl, 2-carbamoylethyl, dicarbamoylmethyl, difluoromethyl, trifluoromethyl.
  • Methyl, hydroxypropyl, 2,3-dihydroxy-11-propyl group and the like can be mentioned, preferably 2-fluoroethyl, 2-hydroxyethyl or potassium rubamoylmethyl group, more preferably 2 —It is a fluoroethyl group.
  • C 3 -C 6 cycloalkyl group for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like can be mentioned, and a cyclopropyl group is preferable.
  • Aryl group for example, phenyl, naphthyl or An indenyl group can be mentioned, preferably a phenyl or naphthyl group, and more preferably a phenyl group.
  • the “C 7 -C 14 aralkyl group” for R 13 is d-(: 4 alkyl group substituted with the aforementioned “C 6 -d.
  • Aryl group for example, benzyl, phenethyl, phenylpropyl, phenyl, phenylphenyl. And naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, indenylmethyl, indenylethyl and the like, preferably benzyl, naphthylmethyl or phenethyl, and more preferably benzyl.
  • Ariru group" of the R 1 3 and "C 7 -C 1 4 Ararukiru group preferably a nitro, halogen It is an atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy group.
  • a ⁇ 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms or a 5- to 6-membered heteroaryl group condensed with a benzene ring '' Has the same meaning as described above, and “benzene-fused 5- to 6-membered heteroaryl group” represents the above-mentioned “5- to 6-membered heteroaryl group” fused to a benzene ring.
  • Examples of the “benzene-fused 5- to 6-membered heteroaryl group” include, for example, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzophenyl, quinolyl, isoquinolyl, and indolyl groups. It is an imidazolyl, benzothiazolyl or quinolyl group.
  • Examples of the “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms or a 5- to 6-membered heteroaryl group condensed with benzene ring” include, for example, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, Imidazolyl, triazolyl, thiazolyl, pyrrolyl, thiadiazolyl, oxazolyl, isothiazolyl, Examples include soxazolyl, furyl, chenyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzocenyl, quinolyl, isoquinolyl, and indolyl groups.
  • benzothiazolyl group more preferably, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 2-imidazolyl, 3- (1,2,4-triazolyl), 2-thiazolyl, 2- (1,3,4-thiadiazolyl), 2-benzimidazolyl or 2-benzothiazolyl group.
  • Examples of the above "5- to 6-membered heteroaralkyl group containing 1 to 3 nitrogen, oxygen or sulfur atoms or 5- to 6-membered heteroaralkyl group condensed with benzene ring” include, for example, pyridylmethyl, pyridylethyl, pyridylpropyl, Pyridylbutyl, virazinylmethyl, virazylethyl, pyrimidylmethyl, pyrimidylethyl, pyridazinylmethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, thiazolylpropyl, pyrrolylmethyl, vilazolylmethyl, isoxazolylmethyl, isothiazolylmethyl ' Xazolylmethyl, disothiazolylmethyl, chenylmethyl, chenylethyl, benzothiazolylmethyl, benzimid
  • Examples of the “ ⁇ > to C 4 alkoxycarbonyl group” of the substituent group (a) include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl group, preferably methoxycarbonyl or ethoxycarbonyl. Group.
  • amino group which may have a substituent examples include, for example, amino, carbamoylamino (ureido), thiocarbamoylamino (thioureido), methylamino, ethylamino, 2-hydroxyethylamino.
  • carbamoylmethylamino or carboxymethylamino groups can be mentioned, preferably an amino group.
  • the “sulfamoyl group optionally having substituent (s)” in the substituent group (a) includes, for example, sulfamoyl, phenylsulfamoyl, methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl or butylsulfamoyl group. And preferably a sulfamoyl, phenylsulfamoyl or methylsulfamoyl group, more preferably a sulfamoyl group.
  • phenylthio group which may be substituted with a halogen atom examples include, for example, phenylthio, 4-fluorophenyl'thio, 4-chlorophenylthio, 4-bromophenylthio, and the like. , 2,4-difluorophenylthio and 2,4-dichlorophenylthio groups, preferably phenylthio or 4-chlorophenylthio groups.
  • Examples of the “C 7 -C 14 aralkyl group optionally substituted with a methoxy group” in the substituent group (a) include, for example, benzyl, phenethyl, methoxybenzyl, methoxyphenyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl group And preferably a benzyl, phenethyl or methoxybenzyl group.
  • the “C,-(: 4 alkyl group optionally having substituent (s)” in the substituent group (a) includes, for example, methyl, ethyl, propyl, butyl, carboxymethyl, carboxyethyl, hydroxymethyl, hydroxyethyl , Hydroxypropyl, pyrrolidinylmethyl, pyrrolidinylethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piberidinylethyl, imidazolylmethyl, imidazolylethyl, N-methylimidazolylmethyl, N-methyl Imidazolylethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl, dichloroethyl, dimethylaminomethyl, dimethylaminoethyl, methylaminomethyl, methylaminoe
  • phenyl or naphthyl group optionally having substituent (s)” in the substituent group (a) include, for example, phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, methylphenyl. Phenyl, methoxyphenyl, dimethoxyphenyl, sulfamoylphenyl, hydroxyphenyl, dihydroxyphenyl, (carboxymethoxy) phenyl,
  • Examples of the “d to (: 4 alkylthio group) which may have a substituent” in the substituent group (a) include, for example, methylthio, ethylthio, propylthio, butylthio, hydroxyethylthio, dihydroxypropylthio, benzylthio, phenethylthio, and pyridylmethylthio. And a pyridylethylthio group, preferably a methylthio or ethylthio group.
  • Examples of the “pyridino group having a substituent at the N atom” in the substituent group (a) include N-methylpyridinio, N-capilluvylmethylpyridinio, N-2-hydroxyshethylpyridinio, N-carboxy A methylpyridino group and the like can be mentioned, and an N-methylpyridino group is preferable.
  • Examples of the “optionally substituted rubamoyl or thiolrubamoyl group” in the substituent group (a) include, for example, rubamoyl, thiocarbamoyl, methylcarbamoyl, methylthiolrubamoyl, ethylcarbamoyl, And ethyl thiocarbamoyl group. Group.
  • Examples of the “5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may be substituted by a methyl group” in the substituent group (a) include, for example, pyridyl, methylpyridyl, pyrimidyl , Methylpyrimidyl, thiazolyl, methylthiazolyl, thiadiazolyl, methylthiadiazolyl, triazolyl, imidazolyl, methylimidazolyl, chenyl, furyl, isoxazolyl, methylisoxazolyl, and oxazolyl groups. Or a methylimidazolyl group.
  • substituent group (a) include a halogen atom, an amino group, a carbamoyl group, a sulfamoyl group, a hydroxymethyl group, a carbamoylmethyl group, a phenyl group, an ethylthio group, a pyridyl group, a 1-imidazolylmethyl group, and a trimethyl group.
  • R 13 as a whole is preferably a d to C 4 alkyl group having 1 to 2 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C 3 to C 6 cycloalkyl group , 1-2 good C 6 ⁇ may have a substituent (:., Ariru group Wakashi Ku is C 7 ⁇ (: 1 4 Ararukiru group (the substituent is a nitro group, a halogen atom, a methyl group , Amino group, sulfamoyl group, carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, 5- to 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group , A methylenedioxy group, a benzyloxy group, a pyridylmethoxy group or an acetyla
  • R 13 is more preferably a d to C 4 alkyl group having 1 to 2 substituents (the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), a C 3 to C 6 cycloalkyl group.
  • R 13 is more preferably a d to (: 4 alkyl group having 1 to 2 substituents, wherein the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), C 3 to (: 6 2-cycloalkyl group, phenyl or benzyl group optionally having 1 to 2 substituents (the substituents may be nitro, halogen atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4 Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolyl, which may have 1 to 2 substituents.
  • Benzimidazolylmethyl or quinolylmethyl group (the substituent may be a halogen atom, an amino group, a sulfamoyl group, a sulfamoyl group, a hydroxymethyl group, a sulfamoylmethyl group, a phenyl group, an ethylthio group, a pyridyl group 1 one imidazolylmethyl group, trimethyl ammonium Nio group is an is) Chiokarubamoiru group also Namib Njiru group.
  • R 13 is most preferably 2-fluoroethyl, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-pyridylmethyl, 3 —Pyridylmethyl, 4-pyridylmethyl, 4- (1-imidazolyl) benzyl, 4-benzyloxybenzyl, 2-thiazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4- (4-pyridyl) thiazol —2-yl, 4-phenylthiazole—2-yl, 4-benzylthiazol-2-yl, 6-amino-benzothiazol-2-yl, 4 -— (1-imidazolylmethyl) thiazole-2— 1,3,4-thiadiazol—Lu2-yl, 5-phenyl—1,3,4-thiadiazol-2-yl, 5— (4-pyrid
  • “Pharmacologically acceptable salts” include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; methanesulfonate, phosphate salt Sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Salts; organic such as oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate Acid addition salts such as acid salts, glycine salts, lysine salts, arginine salts, amino acids salts such as olnitine salts, glutamates, aspartates, or lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, etc.
  • mineral salts such as hydrochloride, hydrobromide, hydroiodide,
  • Inorganic salts or salts with organic bases such as ammonium salts, tritylamine salts, diisopropylamine salts, cyclohexylamine salts, preferably hydrochloride, hydrobromide, phosphate, sulfate, methane. Sulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, acetate, lactate, gluta Emissions salt, Asuparagin salt, sodium salt, potassium salt, a Anmoniumu salt or Toryechi Ruamin salt, is more preferably Natoriumu salts, hydrochlorides or sulfates.
  • the compound (I) of the present invention absorbs water by leaving it in the air, freeze-dried from an aqueous solution, or recrystallized to form adsorbed water or a hydrate. In some cases, such salts are also included in the present invention.
  • a “pharmacologically acceptable derivative” is a group that is cleaved in a human or animal body by a chemical or biological method such as hydrolysis or the like to form the original compound or a salt thereof (which forms a so-called prodrug).
  • Examples of such a protecting group such as a carboxyl group, a hydroxyl group, and an amino group include groups known in the field of medicinal chemistry, such as an acyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a phthalidyl group, and 5-methyl-2- Oxo-1,3-dioxolen-1-ylmethyl group, acyl group, alkoxycarbonyl group, aminoacyl group and the like.
  • Examples of the above-mentioned xyalkyl group include, for example, bivaloyloxymethyl, isoptyryloxymethyl, 11- (isobutyryloxy) ethyl, acetomethoxymethyl, 11- (acetyloxy) ethyl and 1-methylcyclohexylcarbonyloxy. Methyl and 1-methylcyclopentylcarbonyl.
  • Examples of the alkoxycarbonyloxyalkyl group include t-butoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, and 1- (isopropoxycarbonyloxy) ethyl. And 1- (t-butoxycarbonyloxy) ethyl, 11- (cyclohexyloxycarbonyloxy) ethyl and 11- (cyclopentyloxycarbonyloxy) ethyl groups.
  • acyl group examples include alkanol groups such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanol, hexadecanyl, octadecanoyl, carbonylpyridyl, carbonylpyridyl, carbonylpyridyl, and carbonyl.
  • alkanol groups such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanol, hexadecanyl, octadecanoyl, carbonylpyridyl, carbonylpyridyl, carbonylpyridyl, and carbonyl.
  • Examples include a heteroary
  • alkoxycarbonyl group examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl, octadecyloxycarbonyl, etc. Is mentioned.
  • the aminoacyl group includes, for example, amino acid groups such as glycyl, alanyl, leucyl, isopenyl, fenylalanil, histidyl, asparagyl, prolyl, and lysyl.
  • Preferred protecting groups among the above are 5-methyl-2-hydroxy-1,4-dioxolen-41-methyl, acetoxymethyl, bivaloyloxymethyl, 1-methylcyclohexylcarbonyloxymethyl, 1- (isopropoxycarbonyl Ethoxy) ethyl is a (cyclohexyloxycarbonyloxy) ethyl group.
  • the following compounds may be mentioned as preferred compounds (I) having a group represented by Formula A.
  • R 2 is a hydrogen atom, d to (: 4 alkyl group, benzyl optionally having 1 to 2 substituents, phenethyl, naphthylmethyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, thiazolylethyl or Thiadiazolylmethyl group (wherein the substituent represents a fluorine atom, a methyl group or a carbamoyl group);
  • R 2 a hydrogen atom, a methyl group, an ethyl group, a benzyl or pyridylmethyl group optionally having 1 to 2 substituents (the substituent is a fluorine atom, a methyl group or a Which is a formimidoyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or a 2-thiazoline-2-yl group.
  • R 2 is a hydrogen atom, a methyl group, an ethyl group, a benzyl group, a pyridylmethyl group, a formimidyl group, an acetimidoyl group, an amidino group, a 2-imidazoline-2-yl group or 2-thiazoline A compound that is a 2-yl group.
  • R 3 is a hydrogen atom, an oxo group, a sulfamoylaminomethyl group, a sulfamoyl group, a dimethylcarbamoyl group, a 1-pyrazulcarbonyl group, an aminopyrrolidine-1-ylcarbonyl group or an aminomethylpyrrolidine (I) A compound that is a 1-yl carbonyl group.
  • R 3 A compound which is a hydrogen atom, a rubamoyl group, a 1-piperazinylcarbonyl group, a 3-aminopyrrolidine-1-ylcarbonyl group or a 3-aminomethylpyrrolidine-1-ylcarbonyl group.
  • Suitable compounds (I) in which A has a group represented by the general formula (2) include the following compounds.
  • R 9 force A functional group which may have 1 to 2 substituents (the substituents may be C 1, C 4 alkyl groups, dC 4 alkoxy groups, nitro groups, halogen atoms, water Acid group, cyano group, carbamoyl group, mono- or di-d ⁇ (shows a 4- alkylcarbamoyl group, a sulfamoyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms)
  • substituents may be C 1, C 4 alkyl groups, dC 4 alkoxy groups, nitro groups, halogen atoms, water Acid group, cyano group, carbamoyl group, mono- or di-d ⁇ (shows a 4- alkylcarbamoyl group, a sulfamoyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 nitrogen, oxygen or sulfur atoms)
  • (III-3) A phenyl group which may have 1 to 2 substituents (the substituents may be a methyl group, a methoxy group, a nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, A dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a thiazolyl group).
  • R 3 force A phenyl group which may have 1 to 2 substituents (the substituent is a nitro group, a fluorine atom, a carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group) Which represents a group).
  • Preferred compounds (I) in which A has a group represented by the general formula (3) include the following compounds.
  • (3-1) A compound in which r is 0, 1 or 2.
  • R 1D is a hydrogen atom, a methyl group or an ethyl group.
  • R 11 force A compound that is a hydrogen atom, a methyl group, an ethyl group, a formimidyl group, an acetimidoyl group, or an amidino group.
  • R 12 A compound that is a hydrogen atom, a methyl group, an ethyl group, a formimidoyl group, an acetimidoyl group, or an amidino group.
  • R 13 force d to (: 4 alkyl groups having 1 to 2 substituents (the substituents represent a halogen atom, a carbamoyl group or a hydroxyl group), a C 3 -C 6 cycloalkyl group, C 6- (: aryl group or C 7 -C 14 aralkyl group which may have 1 to 2 substituents (the substituent is a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, Carbamoyl, dimethylcarbamoyl, dimethylcarbamoyl, 5- to 6-membered heteroaryl containing 1 to 3 nitrogen, oxygen or sulfur atoms, methoxy, difluoromethoxy, methylenedioxy, A benzyloxy group, a pyridylmethoxy group or an acetylamino group.)
  • R 13 is a -C 4 alkyl group having 1 to 2 substituents (the substituent represents a halogen atom, a carbamoyl group or a hydroxyl group), a C 3 -C 6 cycloalkyl group, A phenyl, naphthyl, benzyl, phenethyl or naphthylmethyl group which may have 2 to 2 substituents (the substituent is a nitro group, a halogen atom, a methyl group, an amino group, a sulfamoyl group, a carbamoyl group, Methylcarbamoyl group, dimethylcarbamoyl group, 5- to 6-membered heteroaryl group containing 1-3 nitrogen, oxygen or sulfur atoms, methoxy group, difluoromethoxy group, methylenedioxy group, benzyloxy group, pyridylmethoxy group or Or an acetylylamino group.) Or
  • R 13 is a C 4 alkyl group having 1 to 2 substituents (the substituent represents an octogen atom, a carbamoyl group or a hydroxyl group), and a C 3 to (: 6 cycloalkyl Group, phenyl or benzyl group which may have 1 to 2 substituents (the substituent is nitro, halogen atom, carbamoyl, sulfamoyl, imidazolyl, thiazolyl, 1, 2, 4-triazolyl or benzyloxy) Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzothiazolyl, pyridylmethyl, imidazolylmethyl, thiazolylmethyl, benzothiazolylmethyl, which may have 1 to 2 substituents A benzimidazolylmethyl or quinolylmethyl group (the substituent is a
  • R 13 is 2-fluoroethyl, cyclopropyl, phenyl, 3-pyridyl, 4-pyridyl, benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4- (1-imidazolyl) benzyl, 4-benzyloxybenzyl, 2-thiazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4- (4-pyridyl) thiazole— 2-yl, 4-phenylthiazole-2-yl, 4-benzylthiazole-2-yl, 6-amino-benzothiazoyl 2-yl, 4-yl
  • A is a group represented by the general formula 1, k is 0 or 1, m is 0, 1 or 2, R 2 is a hydrogen atom, methyl group, ethyl group, 1-2 substitution A benzyl or pyridylmethyl group which may have a group (the substituent is a fluorine atom, a methyl group or a rubamoyl group), a formimidyl group, an acetimidoyl group, an amidino group, 2-imidazoline-2-y Or a 2-thiazoline-2-yl group, and R 3 is a hydrogen atom.
  • A is a group represented by the general formula ⁇ , k is 0 or 1, m is 0, 1 or 2, R 2 is a hydrogen atom, a methyl group, an ethyl group ', a benzyl group, a pyridylmethyl A compound wherein R 3 is a hydrogen atom, which is a group, formimidyl group, acetimidoyl group, amidino group, 2-imidazoline-1-yl group or 2-thiazoline-2-yl group.
  • A is a group represented by the general formula ⁇ , q is 0 or 1, and R 9 is a phenyl group which may have 1 to 2 substituents (the substituent is a methyl group, a methoxy group , A nitro group, a fluorine atom, a hydroxyl group, a cyano group, a carbamoyl group, a dimethylcarbamoyl group, a sulfamoyl group, an imidazolyl group, a triazolyl group, a pyridyl group or a thiazolyl group).
  • A is a group represented by the general formula (1), q is 0 or 1, and R 9 is a phenyl group which may have 2 substituents (the substituent is a nitro group, a fluorine atom, A carbamoyl group, a dimethylcarbamoyl group, an imidazolyl group, a triazolyl group or a thiazolyl group).
  • A is represented by the group of general formula (3), r is 0, 1 or 2, and R 1 .
  • A is a group represented by the general formula (3), r is 0, 1 or 2, R 1Q is a hydrogen atom, a methyl group or an ethyl group, and R 11 is a hydrogen atom, a methyl group or an ethyl group A compound which is a formimidyl group, an acetimidoyl group or an amidino group.
  • A is a group represented by the general formula ⁇
  • a 5- or 6-membered heteroaryl group a methoxy group, a difluoromethoxy group, a methylenedioxy group, a benzyl group, a pyridylmethoxy group or an acetylamino group.
  • a substituent group (a) Pyridyl, pyrimidyl, imidazolyl, triazolyl, thiazolyl, thiayl optionally having 1 to 2 substituents
  • R 1 2 is hydrogen atom, a methyl group, Echiru group, formimidoyl group, an Asetoimidoiru group or amidino group
  • R 1 3 is 2- P
  • the configuration at the 9-position and the 10-position are (9R, 10S) configuration which is the same configuration as that of chenamycin;
  • the configuration at the ⁇ -position having a hydroxyl group is the R configuration, and the 8-position and the 4-position indicate one or a mixture of isomers.
  • Preferable ones of the isomers are compounds in which the 8-position is S-configuration.
  • 4-28, 4-29, 4-30, 4-41, 4-42, 447, @ -51, 4-55, @ -60, 4-71, 4-74, 4-86, Compounds of 4-95, 4-100, 4-105, 4-112 can be mentioned, and more preferably, compound No. 1- 1, 1-2, 1--3, 1--4, 1--5 , 1-9, 1-10, 1-11, 1-12, 2-14, 2-15, 1-34, 1-36, 1-51, 1-54, 3--1, 3-6, 4-3, 1-11, 4-12, 4-13, 4-16, 4-29, 4-30, 4-41, 4-47, 4-47, 4-55, 4-60, 4-74, 4 over 86, 4 over 95, 4 one 100, 4 one 105, can be force s include compounds of 4-1 12. Particularly preferred compounds include the following compounds.
  • R 14 represents a protecting group for a hydroxyl group
  • R 15 represents an alkyl group or an aryl group
  • R 16 represents a protecting group for a carboxy group
  • Ap represents When A contains a hydroxyl group, an amino group and / or an imino group, these A which may be force-protected are shown.
  • A is a group having a quaternary ammonium group or a pyridino group
  • Ap includes a group having a corresponding tertiary amino or pyridyl group.
  • the "protecting group for the hydroxyl group" of R is, for example, a trialkylsilyl group such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl;
  • An aralkyloxycarbonyl group such as oxycarbonyl and benzyloxycarbonyl; chlorine or 2-aryloxycarbonyl such as aryloxycarbonyl, 2-chloroallyloxycarbonyl and 2-methylaryloxycarbonyl;
  • a diaryloxycarbonyl group which may be substituted by methyl; 2-position such as trimethylsilylethyloxycarbonyl or 2,2,2-trichloroethyloxycarbonyl is substituted by trialkylsilyl or chlorine;
  • an ethyl carbonyl group preferably a t-butyldimethylsilyl group or an aryloxycarbonyl group, and particularly preferably a t-butyldimethylsilyl group.
  • the ⁇ alkyl group '' of R 15 represents a C 4 alkyl group which may be substituted with 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, isopropyl, trifluoromethyl and butyl.
  • the “aryl group” is C 6 which may be substituted with a methyl group such as phenyl, tolyl, and naphthyl. Represents an aryl group.
  • R 1 S is preferably a methyl group or a fuunyl group, particularly preferably a methyl group.
  • the “carboxyl-protecting group” of R 16 is a protecting group commonly used in the field of synthetic organic chemistry.
  • the 2-position such as aryl, 2-chloroallyl, and 2-methylaryl is substituted with chlorine or methyl.
  • Aralkyl groups such as benzyl and 412-trobenzyl; and benzhydryl groups, which are preferably aryl groups and 412-nitrobenzyl groups, and particularly preferably Is an aryl group.
  • the “protecting group for hydroxyl group, imino group and amino group” contained in A is a protecting group usually used in the field of organic synthetic chemistry, such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, — An aryloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl, such as methylaryloxycarbonyl; an arylalkyloxy group such as benzyloxycarbonyl, 412-trobenzylyloxycarbonyl An xyloxycarbonyl group is preferred, and an aryloxycarbonyl group or a 412-hydroxybenzyloxycarbonyl group is preferred, and an aryloxycarbonyl group is particularly preferred.
  • a compound having the formula (III) is reacted with a compound having the formula (II) in the presence of a base to produce a compound having the formula (III) (Step A1), and the obtained compound (II
  • converting the compound into a pharmacologically acceptable salt or an ester that undergoes hydrolysis in vivo (Step A5) to produce a compound having the general formula (I).
  • each step will be described in detail.
  • the A1 step is a step of producing a compound having the formula (III) by reacting a compound having the formula (III) with a sulfonylating agent in an inert solvent in the presence of a base.
  • the compound having the formula (II) as a starting material was synthesized according to Reference Example 1.
  • Sulfonylation agents include, for example, alkanesulfonyl chlorides such as methanesulfonyl chloride and ethanesulfonyl chloride; arylsulfonyl chlorides such as benzenesulfonyl chloride and p-toluenesulfonyl chloride; methanesulfonic anhydride Sulfonic anhydrides such as trifluoromethanesulfonic anhydride and ethanesulfonic anhydride; and arylsulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride. Sulfoyluryl chloride and P-toluenesulfonyl chloride.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, N, N—
  • ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane
  • nitriles such as acetonitrile
  • amides such as dimethylformamide or N, N-dimethylacetamide or sulfoxides such as dimethylsulfoxide, and are preferably tetrahydrofuran or acetate nitrile.
  • the base used is not particularly limited as long as it does not affect other parts of the compound, especially
  • triethylamine, diisopropylethylamine or 4-dimethylamino is used.
  • examples include organic bases such as pyridine, preferably triethylamine or diisopropylethylamine.
  • the reaction temperature is not particularly limited, but is usually from -20 ° C to room temperature (preferably 0 ° C to room temperature), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours). ).
  • the target compound (III) of this reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent from the reaction mixture, washing with water, and distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or mouth chromatography.
  • Step A2 is a step of reacting compound (III) with a compound represented by the formula HAp in the presence of a base to obtain compound (IV).
  • Solvents used are, for example, amides such as N, N-dimethylformamide or N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, tetrahydrofuran, dioxane or 1 And ethers such as 2,2-dimethoxyethane, and preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide.
  • amides such as N, N-dimethylformamide or N, N-dimethylacetamide
  • sulfoxides such as dimethylsulfoxide
  • nitriles such as acetonitrile
  • tetrahydrofuran dioxane or 1
  • ethers such as 2,2-dimethoxyethane, and preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide.
  • the base used is, for example, an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, or an inorganic base such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate. Triethylamine or disopropylethylamine.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out at -20 ° C to 100 ° C (preferably at room temperature to 60 ° C), and the reaction time is 30 minutes to 48 hours (preferably 30 minutes to 10 hours). Time).
  • the target compound (IV) of this reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the A 3 is a step for preparing a compound (IV) is reacted with the formula C 1 COCOOR 1 compound represented by 6 in the presence of a basic compound (V).
  • Solvents used are, for example, methylene chloride, chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile, tetrahydrofuran, dioxane or 1,2-dimethyloxetane Ethers such as the following are preferred, and methylene chloride or chloroform is preferred.
  • the base used is, for example, an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, preferably triethylamine or diisopropylpropylethylamine.
  • reaction temperature is not particularly limited, it is usually carried out at ⁇ 20 ° C. to 60 ° C. (preferably 0 ° C. to room temperature), and the reaction time is 30 minutes to 24 hours (preferably 3 hours). 0 minutes to 12 hours).
  • the target compound (V) of the reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reaction, chromatography or the like.
  • Step A4 is a step of subjecting compound (V) to a ring closure reaction in a molecule using a trivalent phosphorus compound to produce compound (V I).
  • Trivalent phosphorus compounds used include, for example, triethyl phosphites such as triethyl phosphite, trimethyl phosphite, tripropyl phosphite, tributyl phosphite, getyl methylphosphonite, Dialkylalkylphosphonites such as chillethylphosphonite are preferred, and triethyl phosphite and lithite are preferred.
  • Solvents used are, for example, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, aliphatic hydrocarbons such as cyclohexane and decalin, Ethers such as oxane, tetrahydrofuran, and 1,2-dietoxetane; and toluene, xylene or mesitylene is preferred.
  • aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene
  • aliphatic hydrocarbons such as cyclohexane and decalin
  • Ethers such as oxane, tetrahydrofuran, and 1,2-dietoxetane
  • toluene, xylene or mesitylene is preferred.
  • the reaction temperature is not particularly limited, but the reaction is usually performed at 40 ° C to 200 ° C (preferably 40 ° C to 160 ° C), and the reaction time is 30 minutes to 24 hours (preferably 30 minutes to 24 hours). (Between).
  • the target compound (VI) of the reaction can be further purified by a conventional method, if necessary, for example, recrystallization, reprecipitation or chromatography, if necessary, by removing the solvent from the reaction solution. .
  • A is a group having a quaternary ammonio group or a pyridino group
  • the compound (VI) is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method. be able to.
  • step A5 when the protecting group R I4 of the hydroxyl group of the compound (VI), the protecting group R 16 of the carboxy group, and the protecting group s are contained in Ap, the protecting group is removed and the desired compound (I) is removed. ).
  • the removal of the protecting groups contained in the protecting groups R 14 , R 16 and Ap depends on the type of the protecting group, but it is generally known by methods known in the art (“Protective Groups in Organic Synthesis, 2nd Edition” Ed. By TWGreene and PGMWuts, 1991, John Wiley Sons, Inc.).
  • the deprotecting agent may be an organic fluorine such as ammonium hydrogen fluoride or tetrabutylammonium fluoride.
  • organic fluorine such as ammonium hydrogen fluoride or tetrabutylammonium fluoride.
  • examples thereof include a compound and an inorganic fluorine compound such as potassium fluoride, and preferred is ammonium hydrogen fluoride or tetrabutylammonium fluoride.
  • the solvent used depends on the type of the deprotecting agent.
  • S ethers such as tetrahydrofuran, dioxane or 1,2-dimethyloxetane, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, a Nitriles such as cetonitrile; hydrogen halides such as methylene chloride, chloroform and 1,2-dichloroethane; Furan or dimethylformamide.
  • reaction temperature is not particularly limited, it is generally carried out at ⁇ 20 ° C. to 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours.
  • the deprotected compound is collected from the reaction mixture according to a conventional method, and then subjected to a reaction for removing a protecting group and removing a protecting group R 16 when Ap contains a protecting group. it can.
  • Protecting group R 1 4 is, for example trimethylsilyl E chill O alkoxycarbonyl, 2, 2, 2-position, such as 2-Bok Li chloro E chill O alkoxycarbonyl group
  • Bok trialkyl silyl Wakashi Ku is substituted by chlorine Echiruo
  • the deprotecting agent include Lewis acids such as boron trifluoride etherate and metal-organic acids such as zinc monoacetic acid. Zinc monoacetic acid.
  • the solvent used depends on the type of the deprotecting agent, but includes hydrogen halides such as chloroform and 1,2-dichloroethane, esters such as ethyl acetate, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Ethers, nitriles such as acetonitrile, and alcohols such as methanol, ethanol or propanol, preferably methylene chloride, ethyl acetate or tetrahydrofuran.
  • hydrogen halides such as chloroform and 1,2-dichloroethane
  • esters such as ethyl acetate, tetrahydrofuran, dioxane or 1,2-dimethoxyethane.
  • Ethers nitriles such as acetonitrile
  • alcohols such as methanol, ethanol or propanol, preferably methylene chloride, ethyl acetate or tetrahydr
  • reaction temperature is not particularly limited, it is generally carried out at a temperature of from 20 ° C to 100 ° C (preferably from 0 ° C to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours ( (30 minutes to 12 hours).
  • the deprotected compound is collected from the reaction mixture according to a conventional method, and then subjected to a reaction for removing a protecting group and removing a protecting group R 16 when Ap contains a protecting group. it can.
  • An aryloxycarbonyl group which may be substituted at the 2-position with chlorine or methyl such as an aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylallyloxycarbonyl in which R 14 is a protective group;
  • R 16 is substituted with chlorine or methyl at the 2-position such as aryl, 2-chloroallyl, 2-methylaryl.
  • the protecting group contained in Ap is substituted with chlorine or methyl at the 2-position such as aryloxycarbonyl, 2-chloroallyloxycarbonyl, or 2-methylaryloxycarbonyl.
  • deprotecting agents include palladiums such as bis (triphenylphosphine) palladium chloride tributyltin hydride and tetrakis (triphenylphosphine) palladium tributyltin hydride — Trialkyltin hydrides or tetrakis (triphenylphosphine) palladium—Palladiums such as 2-ethylhexanoic acid or sodium 2-ethylhexanoate—metals of organic carboxylic acids Salts, preferably bis ( Riff enyl) palladium black Li dough tributyltin Hyde Lai de tetrakis (triflate Nini Le phosphine) palladium - a hexanoic acid force Li to 2 Echiru.
  • palladiums such as bis (triphenylphosphine) palladium chloride tributyltin hydride and tetrakis (triphen
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate.
  • ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof.
  • reaction temperature is not particularly limited, it is generally ⁇ 20 ° C. to 100 ° C. (preferably 0 ° C. to 60 ° C.), and the reaction time is usually 30 minutes to 4.8 hours ( (30 minutes to 12 hours).
  • the deprotected compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off insolubles precipitated from the reaction mixture and then distilling off the solvent.
  • the protecting group R 14 is an aralkyloxycarbonyl group such as benzyloxycarbonyl and 412 trobenzyloxycarbonyl
  • the protecting group R 16 is benzyl and 412 trobenzylyl
  • the protecting group contained in Ap is benzyloxycarbonyl, 412-trobenzylo, etc.
  • the deprotecting agent may be hydrogen and a catalytic reduction catalyst such as palladium on carbon or an alkali metal sulfide such as sodium sulfide or lithium sulfide. And preferably hydrogen and palladium-carbon.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • the solvent include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, and esters such as ethyl acetate.
  • ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, nitriles such as acetonitrile, alcohols such as methanol, ethanol or propanol, water or a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but it is usually from room temperature to 100 ° C (preferably from room temperature to 60 ° C), and the reaction time is usually from 30 minutes to 48 hours (preferably from 30 minutes to 48 hours). 20 hours).
  • compound (I) is collected from the reaction mixture according to a conventional method. For example, it can be obtained by filtering off the catalyst used for the reaction and the precipitated insoluble matter from the reaction mixture, and then distilling off the solvent.
  • R 14 , R 16 or Ap uses a protecting group which is removed by the same deprotecting agent, those protecting groups can be removed at the same time.
  • the compound (I) thus obtained can be purified, if necessary, by a conventional method such as a recrystallization method, column chromatography, or preparative liquid chromatography. If necessary, it can be converted into an ester or other derivative that undergoes hydrolysis in vivo by a conventional method (Japanese Patent Laid-Open No. 5-502404), and is pharmacologically acceptable by a conventional method. Can be purified as a salt.
  • the tricyclic heterocyclic compound having the general formula (I) of the present invention can also be produced by the following method B (method B).
  • R 14 , R 1S , A and Ap have the same meanings as described above in Method A. Hereinafter, each step will be described.
  • Step B1 is a step of reacting a compound having the formula HAp with a compound having the general formula (VII) to produce a compound having the formula (VI).
  • the compound (V I I) as a starting material is produced according to Reference Example 2.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • examples thereof include ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, and nitriles such as acetonitrile. Is tetrahydrofuran.
  • the condensing agent to be used is a combination of phosphines such as triphenylphosphine-getylazodicarboxylate and azodicarboxylates.
  • the reaction temperature is not particularly limited, but is preferably triphenylphosphine-getylazodicarboxylate.
  • the reaction is preferably carried out at a relatively low temperature in order to suppress a side reaction.
  • the reaction time performed at a temperature of from room temperature to room temperature (preferably from ⁇ 40 ° C. to room temperature) depends mainly on the reaction temperature and the type of the reaction reagent, but is usually from 15 minutes to 75 hours (preferably from 30 minutes to 6 hours).
  • the target compound (VI) of the reaction can be collected from the reaction mixture according to a conventional method.
  • a p corresponds to the group represented by the general formula (3) as A
  • this reaction is achieved by a condensation reaction between the compound (V I I) and the carboxylic acid component (H A p) in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxyethane Ethers such as tan, nitriles such as acetonitrile, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, water or a mixed solvent thereof, and preferably methylene chloride.
  • tetrahydrofuran halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxyethane Ethers such as tan, nitriles such as acetonitrile, amides such as dimethylformamide, sulfoxides such as dimethylsulfoxide, water or a mixed
  • condensing agent examples include carbodiimides such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 4-dimethylaminopyridine. And 1-hydroxybenzotriazole may be used together.
  • 1,3-dicyclohexylcarbodiimide is used as a condensing agent, and 4-dimethylaminopyridine is also used.
  • the reaction temperature is not particularly limited, but the reaction is preferably carried out at a relatively low temperature to suppress the lj reaction, preferably at a temperature of 120 ° C to 4 CTC (preferably 120 ° C to room temperature).
  • the reaction time depends mainly on the reaction temperature and the type of the reaction reagent, but is usually 15 minutes to 75 hours (preferably 30 minutes to 12 hours).
  • the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound (VI) can be reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method. it can.
  • Step B2 Deprotection reaction Step B2 is a step of producing a compound (I) by removing the protecting group contained in the compound (VI), and is accomplished according to the method of the aforementioned step A5. .
  • tricyclic heterocyclic compound having the general formula (I) of the present invention can also be produced by the following method (Method C).
  • R 14 , R 16 , A and Ap have the same meanings as described above in Method A.
  • Step C1 a compound having the general formula (VII) is subjected to an oxidation reaction to produce a compound having the formula (VIII) (Step C1).
  • Step C2 a compound having the formula (VI) is produced by condensation under the following conditions
  • Step C3 a protecting group is removed to produce a compound having the general formula (I) (Step C3).
  • This synthesis method is used for a group represented by the general formula (A).
  • each step will be described.
  • Step C1 is a step of reacting the compound (VII) with an oxidizing agent to produce a compound having the formula (VIII).
  • the oxidizing agent is, for example, an oxidizing agent using a dimethylsulfoxide-based reagent such as dimethylsulfoxide doxalyl chloride or dimethylsulfoxide anhydrous trifluoroacetic anhydride in the presence of an organic base, or a chromic acid-based oxidizing agent such as pyridinamide or lorochromate. And preferably dimethylsulfoxide-oxalyl chloride.
  • a dimethylsulfoxide-based reagent such as dimethylsulfoxide doxalyl chloride or dimethylsulfoxide anhydrous trifluoroacetic anhydride in the presence of an organic base
  • a chromic acid-based oxidizing agent such as pyridinamide or lorochromate.
  • dimethylsulfoxide-oxalyl chloride preferably dimethylsulfoxide-oxalyl chloride.
  • the organic base used is not particularly limited as long as it does not affect the other parts of the compound, and examples thereof include organic bases such as triethylamine, diisopropylamine, and ⁇ -methylbiperidine. Is triethylamine.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxy Ethers such as ethane, ketones such as acetone or methyl ether ketone, nitriles such as acetonitrile, amides such as dimethylformamide or dimethylacetamide, and sulfoxides such as dimethyl sulfoxide or these And preferably a mixed solvent of methylene chloride and tetrahydrofuran.
  • halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, tetrahydrofuran, dioxane or 1,2-dimethoxy Ethers
  • ketones such as acetone or methyl ether ketone
  • nitriles such as acetonitrile
  • amides such as dimethylformamide or dimethylacetamide
  • the reaction temperature is not particularly limited, but is usually from -75 ° C to room temperature (preferably from -60 ° C to room temperature) in order to suppress a side reaction.
  • the reaction time varies depending on the reaction temperature and the type of reaction reagent, and is usually 15 minutes to 48 hours (preferably 30 minutes to 12 hours).
  • compound (VIII) obtained by this reaction is collected according to a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, and the solvent is distilled off after washing with water.
  • the obtained compound (VIII) can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step C2 is a step of subjecting compound (VIII) to a condensation reaction in the presence of a compound represented by the formula HAp and a reducing agent to produce compound (VI).
  • the reducing agent used is, for example, sodium cyanoborohydride, hydrogen-palladium carbon catalyst or platinum platinum monohydrogen, and is preferably sodium cyanoborohydride.
  • the solvent used is not particularly limited as long as it does not participate in the reaction.
  • alcohols such as methanol, ethanol or propanol
  • ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane are used.
  • nitriles such as acetate nitrile, water or a mixed solvent thereof, and preferably methanol or ethanol.
  • the reaction temperature is not particularly limited, but is usually -20 ° C to 40 ° C (preferably o ° C to room temperature) in order to suppress a side reaction.
  • the reaction time varies depending on the reaction temperature and the type of the reaction reagent.
  • the reaction time is usually 30 minutes to 48 hours (preferably 30 minutes to 12 hours).
  • the target compound (VI) of this reaction is collected from the reaction mixture according to a conventional method.
  • it can be obtained by adding an organic solvent immiscible with water to a reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water and distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • A is a group having a quaternary ammonio group or a pyridino group
  • the compound (VI) is reacted with a desired alkyl halide or the like to obtain a quaternized compound (VI) according to a conventional method.
  • a desired alkyl halide or the like can be.
  • Step C3 is a step of producing compound (I) by removing the protecting group contained in compound (VI), and is accomplished according to the method of step A5 described above.
  • the compound having the general formula (I) thus produced by Method A, Method B or Method C may be used, if necessary, in medicinal chemistry, especially in the field of (3-lactam antibiotics). It can be converted to a derivative such as an ester that undergoes hydrolysis in vivo according to a known method or technique, and can be purified as a pharmacologically acceptable salt.
  • the tricyclic heterocyclic compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt or derivative thereof has excellent antibacterial activity and has an activity of inhibiting 3-lactamase. That is, the compound (I) of the present invention is a gram-positive bacterium such as Staphylococcus aureus and enterococcus, a gram-negative bacterium such as Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacterium, Serratia, Enterobacter, and Pseudomonas aeruginosa.
  • a gram-positive bacterium such as Staphylococcus aureus and enterococcus
  • a gram-negative bacterium such as Escherichia coli, Shigella, Klebsiella pneumoniae, deformed bacterium, Serratia, Enterobacter, and Pseudomonas aeruginosa.
  • the compound (I) of the present invention has excellent stability against dehydrobeptidase-I, which is known as an enzyme that catalyzes the inactivation of chenamycin.
  • the urine recovery rate is high.
  • compound (I) has low toxicity. Therefore, the tricyclic heterocyclic compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt or derivative thereof is useful as a medicament, and particularly for treating or preventing (preferably treating) bacterial infections. Useful as an antibacterial agent.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used as an antibacterial agent
  • the compound (I) itself or an appropriate pharmacologically acceptable excipient, diluent or the like may be used. They can be mixed and administered orally by tablets, capsules, granules, powders or syrups, or parenterally by intravenous or intramuscular injection.
  • These preparations may contain excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbite; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch).
  • excipients eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbite
  • starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch.
  • Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked carboxymethylcellulose sodium; gum arabic; dextran; pullulan; light silicic anhydride Silicate derivatives such as synthetic aluminum silicate, magnesium metasilicate aluminate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; calcium sulfate , A binder (eg, the above-mentioned excipient; gelatin; polyvinylpyrrolidone, magrogol, etc.); a disintegrant (eg, the above-mentioned excipient; croscarmellose sodium, carboxy) Chemically modified starch such as sodium methyl starch, crosslinked polyvinylpyrrolidone, starch, cellulose derivatives, etc., lubricants (eg, talc; stearic acid; calcium stearate
  • Salts leucine; sodium lauryl sulfate, lauryl sulfate Lauryl sulfates such as gnesium; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, paraoxybenzoic acid esters such as methylparaben and propylparaben) Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzolconidum chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; Commonly used sweeteners, acidulants, flavors, etc., suspending agents (eg, polysorbate 80, sodium carboxymethylcellulose, etc.), diluents, formulation solvents (eg, water, ethanol, glycerin) And the like, and is manufactured by a known method using additives such as The
  • the Jiasutereoma mixture is purified using reverse phase column prep (Cosmosil 5 C 18 AR 28 X 25 Omm ) by high performance liquid chromatography, (6S) body (0. 72 g), (6 R) body (1.03 g) as a colorless oil
  • the intermediate was dissolved in 2 ml of toluene, dimethylethylphosphonite (617 mg) was added, and the mixture was stirred at 60 ° C for 1.5 hours.
  • Toluene was distilled off once, mesitylene (50 ml) was added, and 140 was added for 1 hour. 120. Heated for 1.5 hours.
  • Example 1- (3) The compound (250 mg) obtained in Example 1- (3) was dissolved in dichloromethane. Under ice-cooling, water (51 mg), bis (triphenylphosphine) palladium (II) chloride (18 mg) and tri-n-butyltin hydride (1.05 g) were added, and the mixture was stirred for 5 minutes, and further stirred at room temperature. For 30 minutes. Dichloromethane (30 ml) was added, extracted with water (30 ml X 3), and the aqueous layer was collected and water was distilled off under reduced pressure.
  • dichloromethane (30 ml) was added, extracted with water (30 ml X 3), and the aqueous layer was collected and water was distilled off under reduced pressure.
  • Example 1- (3) The same reaction and isolation procedure as in Example 1- (3) were carried out using the compound (140 mg) obtained in Example 2- (1) to give the title compound (65 mg) as a colorless oil.
  • Example 11 The same reaction and isolation procedure as in Example 1- (1) using the compound (1.45 g) obtained in (8) and N, N-dimethylcarbamoylthiophenol (986 mg). To give the title compound as a diastereomer mixture.
  • Example 3-f 1 Using the (6S) form (800 mg) obtained in Example 3-f 1), the same reaction and isolation procedure as in Example 1- (2) were carried out to give the title compound (715 mg) as a colorless oil. As obtained.
  • Example 3 The compound (650 mg) obtained in (2) was dissolved in tetrahydrofuran (5 ml), and acetic acid (655 mg) and a 1.0 M tetrahydrofuran solution of tetrabutylammonium fluoride (7.60 ml) were added. The mixture was stirred at room temperature for 16 hours, added with a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2-18 ml), and stirred for 4 hours.
  • Example 3- using the compound (6R) form (1.15 g) obtained in (1), the same reaction and isolation procedure as in Example 2-(1) were carried out to give the title compound (937 mg) Was obtained as a colorless oil.
  • Example 4- Using the compound (800 mg) obtained in (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to give the title compound (559rag) as a colorless amorphous powder. .
  • Example 4 The same reaction and purification as in Example 3- (4) were carried out using the compound (350 mg) obtained in (2) to give the desired compound (227 mg) as the title dry powder.
  • Example 1- (2) The same reaction and isolation procedure as in Example 1- (2) was carried out using the compound (6S) form (330 mg) obtained in Example 5- (1) to give the title compound (200 mg) as a colorless oil. Obtained.
  • Example 3- (3) The same reaction and isolation procedure as in Example 3- (3) were carried out using the compound (190 mg) obtained in Example 5- (2) to give the title compound (120 mg) as a colorless oil.
  • Example 5- (1) Using the compound (6R) form (500 mg) obtained in Example 5- (1), the same reaction and isolation procedure as in Example 2- (1) were carried out to give the title compound (265 mg) in an unoccupied oil. Obtained as material.
  • Example 6- (1) Using the compound (250 mg) obtained in Example 6- (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to obtain the title compound (127 mg) as a colorless oil. .
  • Example 2- (1) Using the compound (340 mg) obtained in Reference Example 2- (1), the same reaction and isolation procedure as in Example 1- (3) were performed to give the title compound (80 mg) as a colorless oil.
  • Example 7- (2) Using the compound (80 mg) obtained in Example 7- (2), the same reaction and purification as in Example 1- (4) were carried out to obtain the target compound (19 mg) as a lyophilized powder.
  • KB r) v max cm ' 1 3409, 2933, 1 751, 1591, 1396, 1223.
  • Example 7- (1) Using the compound (600 mg) obtained in Reference Example 2- (2) and aryloxycarbonyl-1-13-alanine, the same reaction and isolation procedure as in Example 7- (1) were carried out to give the title compound ( 532 mg) as a colorless oil.
  • Example 1- (3) The same reaction and isolation procedure as in Example 1- (3) were carried out using the compound (510 mg) obtained in Example 8- (1) to give the title compound (137 mg) as a colorless oil. .
  • Example 8 Using the compound (130 mg) obtained in (2), the same reaction and purification as in Example 11 (4) were carried out to obtain the desired compound (46 mg) as a lyophilized powder.
  • Example 8 Using the compound (130 mg) obtained in (2), the same reaction and purification as in Example 11 (4) were carried out to obtain the desired compound (46 mg) as a lyophilized powder.
  • Example 9 The compound (600 mg) obtained in (1) was dissolved in methanol (10 ml), benzylamine (163 mg) and anhydrous magnesium sulfate were added, and the mixture was stirred for 1 hour. Under ice-cooling, sodium cyanoborohydride (96 mg) was added, and the mixture was further stirred for 1 hour. DMF (10 ml) was added to the reaction solution, methanol was distilled off under reduced pressure, and acryloyl formate (333 mg) and triethylamine (279 mg) were added under ice cooling, followed by stirring for 30 minutes.
  • Example 9 The same reaction and isolation procedure as in Example 3- (3) were carried out using the mixture (530 mg) obtained in (2) to give the title compound (98 mg) as a colorless oil.
  • Example 9 The compound (90 mg) obtained in (3) was subjected to the same reaction and purification as in Example 1- (4) to obtain the desired compound (24 mg) as a lyophilized powder.
  • Example 9 The same reaction and isolation procedure as in Example 9- (2) was carried out using the compound (300 mg) obtained in Example 1 (1) and 41-picolylamine (94 mg) to obtain the title compound (131). mg) as a colorless oil. '
  • Example 10- (1) Using the compound (160 mg) obtained in Example 10- (1), the same reaction and isolation procedure as in Example 3- (3) were carried out to give the title compound (95 mg) as a colorless oil. Obtained.
  • Example 10- (2) Using the compound (90 mg) obtained in Example 10- (2), the same reaction and purification as in Example 11- (4) were performed. The crystals precipitated from the aqueous solution were filtered to obtain a crystalline target compound (22 mg).
  • Nuclear magnetic resonance scan Bae spectrum (270MHz, CDC1 3) ⁇ ppm : 0.05, 0.07, 0.09 (6H, sx3), 0.87, 0.88, 0.89 (9H, sx3), 2.25 ⁇ 1.06 (9H, m), 2.52 ⁇ 3.89 ( 7H, m), 3.87 to 4.29 (3H, m), 4.39 to 69 (3H, m), 5.18 to 5.36 (2H, m), 5.75 to 5.95 (lH, m).
  • Example 12- (1) The (6R) form (250 mg) obtained in Example 12- (1) was subjected to the same reaction and isolation procedures as in Example 1-2 (2) to give the title compound (30 mg).
  • Example 11 The compound (29 mg) obtained in Example 1 2— (2) was used as Example 11 (3). The same reaction and isolation procedure were performed to give the title compound (14 mg) as an oil.
  • Example 13- The compound (265 mg) obtained in Example 13-) was subjected to the same reaction and isolation procedure as in Example 11- (3) to give the title compound (52 mg) as an oil.
  • Example 11 (1), 2- (1) , 2- (2) and 1- (4) were carried out in the same reaction and isolation procedure to obtain the target compound as a freeze-dried powder.
  • Example 11 The compound obtained in (8) was subjected to the same reaction and isolation procedure as in Example 11 (1 (4)) using 4- (1-imidazolyl) benzylamine. Thus, the target compound can be obtained as a lyophilized powder.
  • the compound obtained in Reference Example 1- (8) was subjected to the same reaction and isolation procedures as in Examples 11- (1) to (4) using 4-benzyloxybenzylamine to give the compound.
  • the target compound can be obtained as a lyophilized powder.
  • Example 21 The compound obtained in 1- (1) was subjected to the same reaction and separation procedure as in Example 11- (3) to give the title compound (144 mg) as an oil.
  • Example 21 The compound obtained in 1- (2) was subjected to the same reaction and
  • Example 21 using the compound obtained in (2) using 2-aryloxycarbonylamino-6-phenyl-1,3,4-thiadiazole, Example 21— (1) to (3)
  • the target compound can be obtained by carrying out the same reaction and isolation procedure as described above. (Example 26)
  • the target compound is obtained by subjecting the compound obtained in Example 1- (8) to the same reaction and isolation procedure as in Examples 11- (1) to (4) using 2-aminothiazole. be able to. (Example 28)
  • Example 11 The compound obtained in Example 11 (8) was subjected to the same reaction and isolation procedures as in Examples 11-1 (1) to (4) using 2-amino-benzothiazole to obtain the desired compound. Can be obtained.
  • Example 11 The compound obtained in Example 11 (8) was subjected to the same reaction and isolation procedures as in Examples 11-1 (1) to (4) using 2-amino-4-phenylthiazol to obtain the desired compound. A compound can be obtained. (Example 30)
  • Example 11 By subjecting the compound obtained in (8) to the same reaction and isolation procedure as in Example 11- (1) (4) using 2-amino-4-benzylthiazole, the title compound was obtained. Can be obtained.
  • Example 11 The compound obtained in (8) was subjected to the same reaction and isolation procedures as in Example 11 (1) (4) using 2-amino-5-phenyl-13,4-thiadiazole. By doing so, the target compound can be obtained. (Reference example 1)
  • Ethyl 2-cyclohexanone carboxylate (10.2 g) was dissolved in 200 ml of methanol, cooled to 140 ° C, sodium borohydride (2.72 g) was added, and the mixture was heated at the same temperature for 3 hours. After stirring, the temperature was raised to room temperature. After treating with an appropriate amount of acetic acid, the reaction solution was diluted with water, extracted with ethyl acetate (200 ml ⁇ 4), the organic layer was washed with aqueous sodium hydrogen carbonate and saturated saline, and the solvent was distilled off under reduced pressure.
  • the antibacterial activity of the compound (I) of the present invention against various bacteria was measured by an agar plate dilution method.
  • Table 5 shows the minimum inhibitory concentration (M I C / m 1) against Staphylococcus aureus containing methicillin-resistant Staphylococcus aureus (MRSA).
  • Example 21 1 Compound 0.02 0.05.
  • MRSA Staphylococcus aureus 535
  • MRSA methicillin-resistant Staphylococcus aureus
  • the compounds of the present invention exhibited superior antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which is considered a clinical problem, as compared with Sanfetrin em known as Trinem. (Test Example 2)
  • the compound represented by the general formula (I) obtained in the Examples was recovered in urine at a high rate when administered subcutaneously to mice.
  • 500 mg of the compound of Example 1 is dissolved in 5 ml of distilled water for injection, passed through a filter for sterilization, and then lyophilized to give a lyophilized preparation for injection.
  • the powder After mixing the powder of the above formulation and passing through a 60 mesh sieve, the powder is placed in a 25 Omg No. 3 gelatin capsule to form a capsule.
  • the powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give 20 Omg tablets per tablet. These tablets can be sugar-coated if necessary.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés hétérocycliques tricycliques représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables ou des dérivés de ceux-ci possédant des activités anti-microbiennes excellentes, formule dans laquelle A représente un pyrrolidinylalkylthio, un phénylalkylthio ou un aminoalkanoyloxy, chacun présentant éventuellement un ou des substituant(s) ou un amino substitué.
PCT/JP1998/000531 1997-02-10 1998-02-10 Composes heterocycliques tricycliques Ceased WO1998034937A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0416953A2 (fr) * 1989-09-08 1991-03-13 GLAXO S.p.A. Dérivés d'acide 10-(1-hydroxyéthyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undéc-2-ène-2-carboxylique
JPH0586062A (ja) * 1991-04-05 1993-04-06 Takeda Chem Ind Ltd 多環性カルバペネム化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0416953A2 (fr) * 1989-09-08 1991-03-13 GLAXO S.p.A. Dérivés d'acide 10-(1-hydroxyéthyl)-11-oxo-1-azatricyclo[7.2.0.0.3,8]undéc-2-ène-2-carboxylique
JPH03167187A (ja) * 1989-09-08 1991-07-19 Glaxo Spa ヘテロ環化合物
JPH0586062A (ja) * 1991-04-05 1993-04-06 Takeda Chem Ind Ltd 多環性カルバペネム化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GHIRON C., ROSSI T., THOMAS R. J.: "THE STEREOSELECTIVE SYNTHESIS OF 4-FORMYLTRINEM, A KEY INTERMEDIATE FOR NOVEL TRINEMS.", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 38., no. 20., 1 January 1997 (1997-01-01), GB, pages 3569 - 3572., XP002912300, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(97)00665-5 *

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