WO1996026207A1 - Composes de thiazolidine et d'oxazolidine de type indoles avec action hypoglycemique - Google Patents

Composes de thiazolidine et d'oxazolidine de type indoles avec action hypoglycemique Download PDF

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WO1996026207A1
WO1996026207A1 PCT/JP1996/000403 JP9600403W WO9626207A1 WO 1996026207 A1 WO1996026207 A1 WO 1996026207A1 JP 9600403 W JP9600403 W JP 9600403W WO 9626207 A1 WO9626207 A1 WO 9626207A1
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group
alkyl
hydrogen atom
atom
hydroxyl
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PCT/JP1996/000403
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English (en)
Inventor
Yoshio Ohara
Mikio Suzuki
Keisuke Ohdoi
Nobuhide Miyachi
Katsuhiro Kato
Tetsuya Kobayashi
Ken-Ichi Shikada
Masaki Kitahara
Takeshi Naito
Takashi Yotsumoto
Chie Miyakoshi
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Nissan Chemical Industries, Ltd.
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Priority to AU47311/96A priority Critical patent/AU4731196A/en
Publication of WO1996026207A1 publication Critical patent/WO1996026207A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel indole type thiazolidines having a hypoglycemic effect and aldosereductase inhibitory activities, which are useful in medical and veterinary fields, particularly useful for preventing or treating diabetes mellitus and diabetic complications.
  • No. 332332 disclose various thiazolidindiones which achieve a hypoglycemic effect, and these are particularly useful for treating Type II diabetes and are noted as agents for hardly causing such hypoglycemic symptoms as caused by the above-mentioned oral
  • hypoglycemic agents have a function of effectively lowering a blood sugar level, it is not proved that these compounds have effects for reducing or preventing various chronic symptoms caused by diabetes, such as diabetic nephropathy,
  • diabetic cataract diabetic cataract
  • diabetic retinopathy diabetic retinopathy
  • hypoglycemic effect on yellow obese diabetes mellitus mice but its effect is not satisfactory.
  • aldose reductase is known to be an enzyme for reducing aldoses such as glucose and galactose to polyols such as sorbitol and galactitol in a living body. It is also known that accumulation of the polyols thus produced by the enzyme in organs induces or exacerbates various diabetic complications such as diabetic retinopathy, diabetic neuropathy and diabetic nephropathy, and therefore an inhibitor against this enzyme is useful as an agent for treating these diabetic complications.
  • the present inventors have synthesized various thiazolidines which are not disclosed in the above-mentioned literatures, and have studied their properties. As this result, the present inventors have found compounds having excellent hypoglycemic effects and aldose-reductase inhibitory activities which were not exhibited by the above-mentioned known
  • the present invention provides indole type thiazolidines capable of preventing or treating diabetes mellitus and diabetic complications.
  • novel indole type thiazolidine derivatives of the present invention are indole type thiazolidines of the following formula (I) and their salts:
  • X 1 is S or O
  • X 2 is S, O or NH
  • Y is CR 6 R 7 (R 6 is a hydrogen atom, a C 1 -C 7 alkyl group or a C 3 -C 7 cycloalkyl group, and R 7 is a hydrogen atom, a C 1 -C 7 alkyl group or a C 3 -C 7 cycloalkyl group, or forms a bond together with R 4 );
  • R 1 is a substituent at the 2-, 3-, 4-, 5-, 6- or 7-position of an indole ring, examples of which include a C 3 -C 10 alkyl group, a C 2 -C 10 alkenyl group, a C 2 -C 10 alkynyl group, a C 1 -C 10 alkoxy group, a C 2 -C 10 alkenyloxy group, a C 1 -C 10 alkylthio group, a C 1 -C 10 monoalkylamino group or a di-C 1 -C 10 alkylamino group (each of said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyloxy, C 1 -C 10 alkylthio, C 1 -C 10 monoalkylamino and di-C 1 -C 10 alkylamino groups may be substitute
  • Z is a C 3 -C 10 cycloalkyl group, a C 3 -C 7 cycloalkenyl group, a C 6 -C 14 aromatic group, a C 1 -C 12 heterocyclic aromatic group (said heterocyclic aromatic group may contain at most 5 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as constituents for the heterocyclic ring), or a C 1 -C 6 heterocycloaliphatic group (said heterocycloaliphatic group may contain at most 3 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom as constituents for the heterocyclic ring) (each of said C 3 -C 10
  • cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 14 aromatic, C 1 -C 12 heterocyclic aromatic and C 1 -C 6 heterocycloaliphatic groups may have at most 5 substituents selected from the group consisting of a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 , cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide
  • cycloalkyl group a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3- tetrazolyl group, a 5-tetrazolyl group, a
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group),
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, and
  • each of k and l is 0 or 1)
  • V, W and Z are as defined above
  • V, W and Z are as defined above, and two W's may be the same or different), or
  • R 1 may be a hydrogen atom when Y is bonded at the 4-, 5-, 6- or 7-position of an indole ring,
  • each of R 2 and R 3 is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group (said C 1 -C 7 alkyl and C 3 -C 7 cycloalkyl groups may be substituted with a hydroxyl group), a C 1 -C 7 alkyloxy group, a benzyloxy group, a phenyl group, a naphthyl group, a benzyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a furanyl group, a thienyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a pyranyl group, a quinolyl group, a benzoxazolyl group, a
  • benzothiazolyl group or a benzimidazolyl group (each of said phenyl, naphthyl, benzyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl. imidazolyl, pyranyl, quinolyl, benzoxazolyl,
  • benzothiazolyl and benzimidazolyl groups may be
  • R 4 is a hydrogen atom or a C 1 -C 7 alkyl group, or forms a bond together with R 7 ;
  • R 5 is a hydrogen atom or a carboxymethyl group
  • R n is a substituent at the 1-positon of an indole ring, examples of which include a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 4
  • alkoxymethyl group an aryloxymethyl group, a C 1 -C 4 alkylaminomethyl group, a substituted acetamidemethyl group, a substituted thiomethyl group, a carboxyl group, a C 1 -C 7 acyl group, an arylcarbonyl group, a C 1 -C 4 alkoxycarbonyl group, an aryloxycarbonyl group, a C 1 -C 4 alkylaminocarbonyl group, an arylaminocarbonyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkoxyalkyloxy group, a trialkylsilyl group, a trialkylarylsilyl group, an alkylsulfonyl group or an arylsulfonyl group.
  • R 1 is a substituent at the 2-, 3-, 4-, 5-, 6- or 7-position, preferably at the 2- or 5-position of an indole ring.
  • the C 1 -C 10 alkyl group includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, t-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-1-ethyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, 1-heptyl, 2-heptyl, 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-
  • C 4 -C 10 alkyl group which includes, for example, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neo-pentyl, t-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-1-ethyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, 1-heptyl, 2-heptyl, 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-methyl-2-n-heptyl, 2-propyl-1-n
  • the C 2 -C 10 alkenyl group includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-ethyl-2-vinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-1-propylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,
  • C 5 -C 10 alkenyl group which includes, for example, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 1-1-propylvinyl, 2,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-methyl-1-pentenyl, 1-heptenyl, 1-octenyl, 1-nonenyl and 1-decenyl.
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 2 -C 10 alkynyl group includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- heptynyl, 1-octynyl, 1-nonynyl, and 1-decynyl.
  • a C 5 -C 10 alkynyl group which includes, for example, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl and 1-decynyl.
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 1 -C 10 alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy,
  • heptyloxy octyloxy, nonyloxy and decyloxy.
  • Preferred is a C 4 -C 10 alkoxy group which includes, for example, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy,
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 2 -C 10 alkenyloxy group includes, for example, ethenyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 2,4-pentadienyloxy, 1-hexenyloxy, 2-hexenyloxy, 3-hexenyloxy, 4-hexenyloxy, 5-hexenyloxy, 2,4-hexadienyloxy, 1-heptenyloxy, 1-octenyloxy, 1-nonenyloxy and 1-decenyloxy.
  • a C 5 -C 10 alkenyloxy which includes, for example, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 2,4-pentadienyloxy, 1-hexenyloxy, 2-hexenyloxy, 3- hexenyloxy, 4-hexenyloxy, 5-hexenyloxy, 2,4-hexadienyloxy, 1-heptenyloxy, 1-octenyloxy, 1-nonenyloxy and 1-decenyloxy.
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 1 -C 10 alkylthio group includes, for example, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio,
  • pentylthio, hexylthio, heptylthio, octylthio, nonylthio and decylthio Preferred is a C 5 -C 10 alkylthio which includes, for example, pentylthio, hexylthio, heptylthio, octylthio, nonylthio and decylthio.
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 1 -C 10 monoalkylamino group includes, for
  • octylamino nonylamino and decylamino.
  • Preferred is a C 5 -C 10 monoalkylamino group which includes, for example, pentylamino, hexylamino, heptylamino, octylamino,
  • nonylamino and decylamino Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the di-C 1 -C 10 alkylamino group includes, for example, dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, d-n-hexylamino, N-methyl-N-n-pentylamino, N-methyl-N-n-hexylamino, N-methyl-N-n-heptylamino, N-methyl-N-n-octylamino, N-methyl-N-n-nonylamino, and N-methyl-N-n-decylamino.
  • N- methyl-N-n-pentylamino N-methyl-N-n-hexylamino, N- methyl-N-n-heptylamino, N-methyl-N-n-octylamino, N- methyl-N-n-nonylamino, and N-methyl-N-n-decylamino.
  • Each group may be substituted by a hydroxyl group or a C 1 -C 7 alkyl group.
  • the C 3 -C 10 cycloalkyl group includes, for example, cyclopropyl, 1-methyl-cyclopropyl, 2-methyl-cyclopropyl, 4-methyl-cyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
  • a C 6 -C 10 cycloalkyl group which includes, for example, cyclohexyl, bicyclo[2.2.1]heptyl,
  • substituents may, for example, be a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a
  • hydroxyl group a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a
  • the C 3 -C 7 cycloalkenyl group includes, for example, cyclohexenyl (said cyclohexenyl includes 1-cyclohexenyl, 2-cyclohexenyl, and 3-cyclohexenyl), cyclopentadienyl, 2-bicyclo[2.2.1]heptenyl, and 2,5-bicyclo[2.2.l]heptadienyl.
  • Each group may have at most 5 substituents (said substituents may, for example, be a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a
  • hydroxyl group a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a
  • the C 6 -C 14 aromatic group includes, for example, phenyl, naphthyl (said naphthyl includes ⁇ -naphthyl, and ⁇ -naphthyl), indenyl (said indenyl includes 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, and 7-indenyl), indanyl (said indanyl includes 1-indanyl, 2-indanyl, 4-indanyl, and 5-indanyl), and fluorenyl (said fluorenyl includes 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl, and 9-fluorenyl).
  • a C 6 -C 14 aromatic group which includes, for example, phenyl, naphthyl (said naphthyl includes ⁇ -naphthyl, and ⁇ -naphthyl), and fluorenyl (said fluorenyl includes 1-fluorenyl, 2-fluorenyl, 3-fluorenyl, 4-fluorenyl, and 9-fluorenyl).
  • Each group may have at most 5 substituents (said substituents may, for example, be a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a
  • methanesulfonylamide group a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, naphthyl, furanyl, thienyl,
  • imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a
  • the C 1 -C 12 heterocyclic aromatic group is a
  • heterocyclic group having a 5-15 membered monocyclic or condensed ring containing at most 5 hetero-atoms in the ring, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom.
  • heterocyclic aromatic group include furyl (said furyl includes 2-furyl, and 3-furyl), thienyl (said thienyl includes 2-thienyl, and 3-thienyl), pyrrolyl (said pyrrolyl includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), oxazolyl (said oxazolyl includes 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), thiazolyl (said thiazolyl includes 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), isoxazolyl (said isoxazolyl includes 3-isoxazolyl, 4-isoxazolyl, and 5-isox
  • isothiazolyl includes 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl), furazanyl (said furazanyl includes 3-furazanyl), pyrazolyl (said pyrazolyl includes 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl), oxopyrazolyl (said oxopyrazolyl includes 3-oxopyrazol-1-yl, 3-oxopyrazol-2-yl, 3-oxopyrazol-3-yl, 3-oxopyrazol-4-yl, and 4-oxopyrazol-3-yl), imidazolyl (said imidazolyl includes 1-imidazolyl, 2-imidazolyl, and 4-imidazolyl), oxoimidazolyl (said oxoimidazolyl includes 2-oxoimidazol-1-yl, and 2-oxoimidazol-4-yl), triazo
  • tetrazolyl includes 1-tetrazolyl, 2-tetrazolyl, and 5-tetrazolyl
  • pyranyl includes 2-pyranyl, 3-pyranyl, and 4-pyranyl
  • pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl
  • pyridonyl includes 2-pyridon-1-yl, 2-pyridon-3-yl, 2-pyridon-4-yl, 2-pyridon-5-yl, 2-pyridon-6-yl, 4-pyridon-1-yl, 4-pyridon-2-yl,
  • pyrimidinyl includes 2-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl
  • pyrimidinonyl includes (2(1H)-pyrimidinon-1-yl, 2(1H)-pyrimidinon-4-yl, 2(1H)-pyrimidinon-5-yl, 2(1H)- pyrimidinon-6-yl, 4(3H)-pyrimidinon-2-yl, 4(3H)-pyrimidinon-3-yl, 4(3H)-pyrimidinon-5-yl, 4(3H)-pyrimidinon-6-yl, 4(1H)-pyrimidinon-1-yl, 4(1H)-pyrimidinon-2-yl, 4(1H)-pyrimidinon-5-yl, and 4(1H)-pyrimidinon-6-yl), pyrazinyl (said pyrazinyl includes 2-
  • indolyl includes 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, and 7-indolyl
  • quinolyl includes 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8-quinolyl
  • quinolonyl includes 2-quinolon-1-yl, 2-quinolon-3-yl, 2-quinolon-4-yl, 2-quinolon-5-yl, 2-quinolon-6-yl, 2-quinolon-7-yl, 2-quinolon-8-yl, 4-quinolon-1-yl, 4-quinolon-2-yl, 4-quinolon-3-yl, 4-quinolon-5-
  • benzothiazinyl includes 1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4-benzothiazin-4-yl, 1,4-benzothiazin-5-yl, 1,4-benzothiazin-6-yl, 1,4-benzothiazin-7-yl, and 1,4-benzothiazin-8-yl
  • pteridinyl includes 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, and 7-pteridinyl
  • pyrazolo[1,5-a]pyrimidinyl is said
  • pyrazolo[1,5-a]pyrimidinyl includes pyrazolo[1,5-a]pyrimidin-2-yl, pyrazolo[1,5-a]pyrimidin-3-yl,
  • thiazolo[3,2-b]triazolyl includes thiazolo[3,2-b]triazol-2-yl
  • benzopyrano[2,3-b]pyridyl includes benzopyrano[2,3-b]pyridin-2-yl, benzopyrano[2,3-b]pyridin-3-yl, benzopyranof 2,3-b]pyridin-4-yl, benzopyrano[2,3-b]pyridin-5-yl,
  • said furyl includes 2-furyl, and 3-furyl
  • thienyl includes 2-thienyl, and 3-thienyl
  • pyrrolyl includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl
  • oxazolyl includes 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl
  • thiazolyl includes 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl
  • isoxazolyl isoxazolyl
  • isoxazolyl includes 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl
  • isothiazolyl isothiazolyl
  • isothiazolyl includes 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl), imidazolyl (said imidazolyl includes 1-imidazolyl, 2-imidazolyl, and 4-imidazolyl), pyridyl (said pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyridazinyl (said pyridazinyl includes 3-pyridazinyl, and 4-pyridazinyl), pyridazinonyl (said pyridazinonyl includes 3 (2H)-pyridazinon-2-yl, 3(2H)-pyridazinon-4-yl, 3(2H)-pyridazinon-5-yl, and 3(2H)-pyridazinon-6-yl), pyrimidinyl (said pyrimidinyl includes 2-pyrimi
  • benzothiazinyl includes 1,4-benzothiazin-2-yl, 1,4-benzothiazin-3-yl, 1,4-benzothiazin-4-yl, 1,4-benzothiazin-5-yl, 1,4-benzothiazin-6-yl, 1,4-benzothiazin-7-yl, and 1,4-benzothiazin-8-yl
  • pyrazolo[1,5-a]pyrimidinyl includes pyrazolo[1,5-a]pyrimidin-2-yl, pyrazolo[1,5-a]pyrimidin-3-yl
  • pyrazolo[1,5-a]pyrimidin-5-yl pyrazolo[1,5-a]pyrimidin- 6-yl, and pyrazolo[1,5-a]pyrimidin-7-yl
  • pyrazolof 5,1- c][1,2,4]triazinyl pyrazolo[5,1-c][1,2,4]triazinyl includes pyrazolo[5,1-c][1,2,4]triazin-3-yl
  • thiazolo[3,2-b]triazolyl includes thiazolo[3,2-b] triazol-2-yl, thiazolo[3,2-b]triazol-5-yl, and thiazolof 3,2-b]triazol- 6-yl
  • benzopyrano[2,3-b]pyridyl is said
  • benzopyrano[2,3-b]pyridyl includes benzopyrano[2,3-b]pyridin-2-yl, benzopyrano[2,3-b]pyridin-3-yl,
  • Each group may have at most 5 substituents (said
  • substituents may, for example, be a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7
  • cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a
  • methanesulfonylamide group a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 al
  • the C 1 -C 8 heterocycloaliphatic group is a
  • heterocyclic group having a 3-8 membered monocyclic or condensed dicyclic ring containing at most 3 hetero-atoms in the ring, selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom.
  • heterocycloaliphatic group include piperidyl (said piperidyl includes 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl), pyrrolidinyl (said pyrrolidinyl
  • tetrahydrofuranyl includes 2- tetrahydrofuranyl, and 3-tetrahydrofuranyl.
  • Each group may have at most 5 substituents (said substituents may, for example, be a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be
  • a hydroxyl group substituted with a hydroxyl group
  • a hydroxyl group a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phen
  • cycloalkyl group a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a
  • R a , R b and R c are defined in the definitions of R a , R b and R c :
  • the C 1 -C 7 alkyl group includes, for example, methyl. ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and n-heptyl. Preferred are methyl, ethyl and n-propyl. Each group may be
  • the C 3 -C 7 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and
  • bicyclo[3.1.1]heptyl Preferred are cyclopropyl and cyclohexyl. Each group may be substituted by a hydroxyl group.
  • the C 3 -C 7 cycloalkenyl group includes, for example, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
  • cyclopentadienyl 2-bicyclo[2.2.1]heptenyl and 2,5-bicyclo[2.2.1]heptadienyl.
  • Each group may be substituted by a hydroxyl group.
  • the C 1 -C 7 alkoxy group includes, for example,
  • the C 1 -C 7 alkylthio group includes, for example, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-buthylthio, t-butylthio, pentylthio, hexylthio and heptylthio.
  • the tri-C 1 -C 7 -alkylsilyloxy group includes, for example, trimethylsilyloxy, triethylsilyloxy,
  • the naphthyl group includes an ⁇ -naphthyl group, a ⁇ -naphthyl group.
  • the furanyl group includes a 2-furanyl group and a 3-furanyl group.
  • the thienyl group includes a 2-thienyl group and a 3-thienyl group.
  • the imidazolyl group includes a 1-imidazolyl group, a 2-imidazolyl group and a 4-imidazolyl group.
  • the pyridyl group includes a 2-pyridyl group and a 3-pyridyl group and a 4-pyridyl group.
  • Each groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group.
  • the phenyl and the benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group.
  • the C 1 -C 3 alkoxycarbonyl group includes, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl and i-propoxycarbonyl.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Preferred are a fluorine atom, a chlorine atom and a bromine atom.
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or C 1 -C 3 alkyl (which may, for example, be methyl, ethyl, n-propyl or i-propyl, preferably methyl)). It is
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3, preferably at most 2, of hydroxyl, oxo and C 1 -C 7 alkyl groups.
  • the C 1 -C 7 alkyl group includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl. Preferred may, for example, be methyl.
  • W is preferably
  • R d and R e is a hydrogen atom, a methyl group or a hydroxyl group, or R d and R e together form an oxo group, or adjacent R d 's together form a double bond, or adjacent R d 's and R e 's together form a triple bond (provided that R d and R e on the first carbon atom ad]acent to N are not hydroxyl groups and provided that R d and R e on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group).
  • R 1 may be -W k -V l -Z, -V-W-Z or -W-V-W-Z in addition to the one mentioned above.
  • -W k -V l -Z may, for example, be -W-Z, -V-Z or -W-V-Z.
  • preferable examples of -V- in the above -V-Z include S, SO and SO 2 .
  • -W-V- in the above -W-V-Z include -CO-NR 8 - (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group (e.g. methyl, ethyl, n-propyl or i-propyl, preferably methyl)).
  • preferable examples of -V-W- in the above -V-W-Z include -O-(CH 2 ) n -(n is from 1 to 5).
  • -W-V-W- in the above -W-V-W-Z include -(CH 2 ) n -NR 8 -CO- (n is from 1 to 5, R 8 is a hydrogen atom or a C 1 -C 3 alkyl group (e.g. methyl, ethyl, n-propyl or i-propyl, preferably methyl)).
  • Each of R 2 and R 3 independently is a hydrogen atom, a C 1 -C 7 alkyl group (which may, for example, be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, and said C 1 -C 7 alkyl group may be substituted with at most two hydroxyl groups, preferably one hydroxyl group), a C 3 -C 7 cycloalkyl group (which may, for example, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty
  • bicyclo[3.1.1]heptyl preferably cyclopropyl
  • cyclohexyl and said C 3 -C 7 cycloalkyl group may be substituted with at most 2 hydroxyl group, preferably one hydroxyl group), a C 1 -C 7 alkoxy group (which may, for example, be methoxy, ethoxy n-propoxy, i-propoxy, n- butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy or heptyloxy, preferably methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy), a benzyloxy group, a phenyl group, a naphthyl group (which may be an ⁇ -naphthyl group, or a ⁇ -naphthyl group), a benzyl group, a pyridyl group (which may, for example
  • pyridazinyl group (which may, for example, be a 3-pyridazinyl group or a 4-pyridazinyl group), a furanyl group (which may, for example, be a 2-furanyl group or a 3-furanyl group), a thienyl group (which may, for example,
  • a 2-thienyl group or a 3-thienyl group a pyrrolyl group (which may, for example, be a 1-pyrrolyl group, a 2-pyrrolyl group or a 3-pyrrolyl group), a pyrazolyl group (which may, for example, be a 1-pyrazolyl group, a 3-pyrazolyl group or a 4-pyrazolyl group), an imidazolyl group (which may, for example, be a 1-imidazolyl group, a 2-imidazolyl group or a 4-imidazolyl group), a pyranyl group (which may, for example, be 2-pyranyl, 3-pyranyl or 4-pyranyl, preferably 2-pyranyl), a quinolyl group (which may, for example, be 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl, preferably 2-quinolyl), a benzoxazoly
  • R 2 or R 3 is a phenyl, naphthyl, benzyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, quinolyl, benzoxazolyl, benzothiazolyl, or benzimidazolyl group, the substituents for such a phenyl, naphthyl, benzyl, pyridyl,
  • pyrimidinyl pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, quinolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl group may be as follows.
  • the C 1 -C 7 alkyl group includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl.
  • Preferred may, for example, be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl.
  • the C 1 -C 7 alkoxy group includes, for example,
  • Preferred may, for example, be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy.
  • the halogen atom may, for example, be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably, a fluorine atom, a chlorine atom or a bromine atom.
  • R 4 is a hydrogen atom or a C 1 -C 7 alkyl group (which may, for example, be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl, preferably methyl), or forms a bond together with R 7 . It is preferably a hydrogen atom or a methyl group, or forms a bond together with R 7 . More
  • R 5 is a hydrogen atom or a carboxymethyl group, preferably a hydrogen atom.
  • R n is a substituent at the 1-position of an indole ring, and is a hydrogen atom, a C 1 -C 7 alkyl group (such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl,
  • a C 1 -C 3 alkyl group preferably a C 1 -C 3 alkyl group
  • a C 3 -C 7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and
  • cyclohexyl preferably cyclopropyl
  • a C 1 -C 4 alkoxymethyl group such as MOM: methoxymethyl
  • MEM 2-methoxyethoxymethyl, ethoxymethyl, n-propoxymethyl, i-propoxymethyl, n-butoxymethyl
  • iBM isobutyloxymethyl
  • BUM t-butoxymethyl
  • POM pivaloyloxymethyl
  • trimethylsilylethoxymethyl preferably a C 1 -C 2 alkoxy methyl group
  • an aryloxymethyl group such as BOM:
  • benzyloxymethyl p-methoxybenzyloxymethyl
  • p-AOM p-anisyloxymethyl, preferably a benzyloxymethyl group
  • C 1 -C 4 alkylaminomethyl group such as
  • trimethylacetamidemethyl a substituted thiomethyl group (such as MTM: methylthiomethyl, PTM: phenylthiomethyl and Btm: benzylthiomethyl), a carboxyl group, a C 1 -C 7 acyl group (such as formyl, acetyl, fluoroacetyl,
  • allyloxycarbonyl, Teoc 2-(trimethylsilyl)ethoxycarbonyl, and Troc: 2,2,2-trichloroethoxycarbonyl, preferably methoxycarbonyl), an aryloxycarbonyl group (such as Z: benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and MOZ: p-methoxybenzyloxycarbonyl), a C 1 -C 4 alkylaminocarbonyl group (such as methylcarbamoyl, Ec: ethylcarbamoyl and n-propylcarbamoyl), an arylaminocarbonyl group (such as phenylcarbamoyl), a C 1 -C 7 alkoxy group (such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, n
  • TBDMS t-butyldimethylsilyl
  • TDS thexyldimethylsilyl, preferably t-butyldimethylsilyl
  • a trialkylarylsilyl group such as DPMS: diphenylmethylsilyl
  • TBDPS t-butyldiphenylsilyl
  • TBMPS t-butyldimethoxyphenylsilyl
  • TPS a trialkylarylsilyl group
  • triphenylsilyl an alkylsulfonyl group (such as Ms:
  • aryl sulfonyl group such as benzene sulfonyl, Ts: p-toluene sulfonyl, p-chlorobenzene sulfonyl, MBS: p-methoxybenzene sulfonyl, m-nitrobenzene sulfonyl, iMds: 2,6-dimethoxy-4-methylbenzene sulfonyl, Mds: 2,6-dimethyl-4-methoxybenzene sulfonyl, Mtb: 2, 4,6-trimethoxybenzene sulfonyl, Mte: 2,3,5,6-tetramethyl-4-methoxybenzene sulfonyl, Mtr: 2,3,6-trimethyl-4-methoxybenzene sulfonyl, Mt
  • pentamethylbenzene sulfonyl preferably a hydrogen atom, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, methoxy, ethoxy, n-propoxy, i-propoxy, methoxymethyl,
  • ethoxymethyl, carboxyl and methoxycarbonyl preferably a hydrogen atom, methyl, methoxymethyl, carboxyl and methoxycarbonyl.
  • Y is bonded on the carbon atom at the 2-, 3-, 4-, 5-, 6- or 7-position of the indole ring, more preferably on the carbon atom at the 2- or 5-position.
  • R 6 is a hydrogen atom, a C 1 -C 7 alkyl group (which may, for example, be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl, preferably methyl) or a C 3 -C 7 cycloalkyl group (which may, for example, be cy.clopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl). It is preferably a hydrogen atom or methyl, more preferably a hydrogen atom.
  • R 7 is a hydrogen atom, a C 1 -C 7 alkyl group (which may, for example, be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl, preferably methyl) or a C 3 -C 7 cycloalkyl group (which may, for example, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl), or forms a bond together with R 4 . It is preferably a hydrogen atom, or forms a bond together with R 4
  • X 1 is S or O, preferably S
  • X 2 is S, O or NH, preferably O or S, more preferably O.
  • n means normal, "i” means iso, “s” means secondary, “t” means tertiary, “c” means cyclo, "Me” means methyl, “Et” means ethyl, “Pr” means propyl, “Bu” means butyl, “Pen” means pentyl, “Hex” means hexyl, “Ph” means phenyl, and "Hal” means halogen.
  • R 2 is a substituent at the 3-positon of an indole ring and is a hydroxyl group
  • the following tautomer may form between the 2-position and the 3- position of an indole ring.
  • the present invention includes all of these tautomers.
  • R 1 is a substituent at the 2-, 4-, 5-, 6- or 7-position of an indole ring and is a substituent as defined in the formula (I);
  • R 2 is a hydroxyl group at the 3-position of an indole ring; and
  • R 3 is a substituent at the 2-, 4-, 5-, 6- or 7-position of an indole ring and is a substituent as defined in the formula (I)).
  • R 1 is a substituent at the 2-, 3-, 4-, 6- or 7-position of an indole ring, and is a hydrogen atom, a C 1 -C 10 alkyl group, a C 1 -C 10 alkenyl group, a C 2 -C 10 alkynyl group, a C 1 -C 10 alkoxy group, a C 2 -C 10 alkenyloxy group, a C 1 -C 10 alkylthio group, a C 1 -C 10 monoalkylamino group or a di-C 1 -C 10 alkylamino group (each of said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 2 -C 10
  • alkenyloxy, C 1 -C 10 alkylthio, C 1 -C 10 monoalkylamino and di-C 1 -C 10 alkylamino groups may be substituted with a hydroxyl group or a C 1 -C 7 alkyl group), or
  • said C 3 -C 10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, or adamantyl
  • said C 3 -C 7 cycloalkenyl group is cyclohexenyl
  • cyclopentadienyl 2-bicylo[2.2.1]heptenyl or 2,5-bicyclo[2.2.1]heptadienyl
  • said C 6 -C 14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl
  • said C 1 -C 12 heterocyclic aromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl, imidazolyl,
  • oxoimidazolyl triazolyl, triazolonyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, triazinyl,
  • benzotriazolyl benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl, naphthyridinyl,
  • heterocycloaliphatic group is piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, or tetrahydrofuranyl, (each of said C 3 -C 10 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 14 aromatic, C 1 -C 12 heterocyclic aromatic and C 1 -C 6 heterocycloaliphatic groups may have at most 5 substituents selected from the group consisting of a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7
  • cycloalkyl group a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group),
  • W is a divalent C 1 -C 6 saturated or C 2 -C 3 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, and
  • each of k and l is 0 or 1)
  • V, W and Z are as defined above
  • V, W and Z are as defined above, and two W's may be the same or different).
  • R 1 is a substituent at the 2-position of an indole ring, and is -W-Z, -V-Z, -W-V-Z, -V-W-Z or
  • V is O, S, SO, SP 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group)
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, when two W's are present, such W's may be the same or different
  • Z is
  • each of R a and R b is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furany
  • thienyl imidazolyl, pyridyl or benzyl group (each of said phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolid
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group, a pyridyl group or a halogen atom; and
  • R 5 is a hydrogen atom.
  • R 1 is a substituent at the 2-positioin of an indole ring, and is -W-Z, -V-Z, -W-V-Z, -V-W-Z or
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group)
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, when two W's are present, such W's may be the same or different
  • Z is
  • each of R a and R b is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furany
  • thienyl imidazolyl, pyridyl or benzyl group (each of said phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolid
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group, a pyridyl group or a halogen atom; and
  • R 5 is a hydrogen atom.
  • R 1 is a substituent at the 2-position of an indole ring, and is -W-Z, -V-Z, -W-V-Z, -V-W-Z or -W-V-W-Z (V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group), W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups (provided that the first carbon atom bonded to N is not substituted with a hydroxyl group, and also provided that the first carbon atom bonded to O is not substituted with a hydroxyl group or an oxo group) when two W's are present, such W's may be the same or different, and Z is
  • each R a and R b is independently a hydrogen atom, a C 1 --C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a
  • cycloalkyl group a C 1 -C 3 alkoxy group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group, and R c is a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group or a hydroxymethyl group);
  • R 4 is a hydrogen atom or a methyl group, or forms a bond together with R 7 ;
  • R n is a substituent at the 1-position of an indole ring, and is a hydrogen atom, a C 1 -C 3 alkyl group, a cyclopropyl group, a C 1 -C 2 alkoxymethyl group, a
  • methoxycarbonyl group a C 1 -C 3 alkoxy group, and a trialkylsilyl group.
  • R 1 is -W-Z, wherein W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C 1 -C 7 alkyl groups.
  • R 1 is -W-Z, wherein W is
  • R d and R e are independently a hydrogen atom, a methyl group or a hydroxyl group, or R d and R e together form an oxo group, or adjacent R d 's together form a double bond, or adjacent
  • R d 's and R e 's together form a triple bond.
  • R 1 is -W-Z, wherein W is
  • R 1 is -V-Z, wherein V is S, SO or SO 2 .
  • R 1 is -W-V-Z, wherein W is
  • R d and R e is independently a hydrogen atom, a methyl group or a hydroxyl group, or R d and R e together form an oxo group, or adjacent R d 's together form a double bond, or adjacent R d 's and R e 's together form a triple bond (provided that R d and R e on the first carbon atom adjacent to N are not hydroxyl groups and also provided that R d and R e on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group),
  • V is NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group).
  • R 1 is -W-V-Z, wherein -W-V- is -CO-NR 8 - (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group).
  • R 1 is a substituent at the 3-, 4-, 5-, 6- or 7- position of an indole ring, and is a C 1 -C 10 alkyl group, a C 2 -C 10 alkenyl group, a C 2 -C 10 alkynyl group, a C 1 -C 10 alkoxy group, a C 2 -C 10 alkenyloxy group, a C 1 -C 10
  • alkylthio group a C 1 -C 10 monoalkylamino group or a di- C 1 -C 10 alkylamino group (each of said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyloxy, C 1 -C 10 alkylthio, C 1 -C 10 monoalkylamino and di-C 1 -C 10 alkylamino groups may be substituted with a hydroxyl group or a C 1 -C 7 alkyl group), or
  • said C 3 -C 10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • cyclooctyl cyclononyl, cyclodecyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, or adamantyl
  • said C 3 -C 7 cycloalkenyl group is cyclohexenyl
  • cyclopentadienyl 2-bicylo[2.2.1]heptenyl or 2,5-bicyclo[2.2.1]heptadienyl
  • said C 6 -C 14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl
  • said C 1 -C 12 heterocyclic aromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl, imidazolyl, oxoimidazolyl, triazolyl, triazolonyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, tri
  • benzotriazolyl benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl, naphthyridinyl,
  • heterocycloaliphatic group is piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, or
  • each of said C 3 -C 10 cycloalkyl, C 3 -C 7 cycloalkenyl, C 6 -C 14 aromatic, C 1 -C 12 heterocyclic aromatic and C 1 -C 6 heterocycloaliphatic groups may have at most 5 substituents selected from the group consisting of a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7
  • cycloalkyl group a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl,
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, and
  • each of k and l is 0 or 1)
  • V, W and Z are as defined above
  • V, W and Z are as defined above, and two W's may be the same or different).
  • R 1 is a substituent at the 5-position of an indole ring, and is -W-Z, -V-Z, -W-V-Z, -V-W-Z or
  • V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group)
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, when two W's are present, such W's may be the same or different
  • Z is
  • each of R a and R b is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 6 alkoxy group, a C 1 -C 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furany
  • thienyl imidazolyl, pyridyl or benzyl group (each of said phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolid
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group, a pyridyl group or a halogen atom; and
  • R 5 is a hydrogen atom.
  • R 1 is -V-W-Z, -W-Z, -V-W-V-W-Z, -W-V-W-Z,
  • V is O, S or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group)
  • W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups, when two V's or W's are present, such V's or W's may be the same or different
  • Z is
  • each of R a and R b is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 -C 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 -C 7 -alkylsilyloxy group, a phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furany
  • thienyl imidazolyl, pyridyl or benzyl group (each of said phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 1-tetrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolid
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group, a pyridyl group or a halogen atom; and R 5 is a hydrogen atom.
  • R 1 is a substituent at the 5-position of an indole ring, and is -W-Z, -V-Z, -W-V-Z, -V-W-Z or -W-V-W-Z (V is O, S, SO, SO 2 or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group), W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C 1 -C 7 alkyl groups (provided that the first carbon atom bonded to N is not substituted with a hydroxyl group, and also provided that the first carbon atom bonded to O is not substituted with a hydroxyl group or an oxo group), when two W's are present, such W's may be the same or different, and Z is
  • each R a and R b is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 cycloalkenyl group (said alkyl, cycloalkyl and
  • cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C 1 -C 7 alkoxy group, a
  • cycloalkyl group a C 1 -C 3 alkoxy group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group), a 5-tetrazolyl group, a thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group, and R c is a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 7 cycloalkyl group or a hydroxymethyl group);
  • R 4 is a hydrogen atom or a methyl group, or forms a bond together with R 7 ;
  • R n is a substituent at the 1-position of an indole ring, and is a hydrogen atom, a C 1 -C 3 alkyl group, a cyclopropyl group, a C 1 -C 2 alkoxymethyl group, a
  • methoxycarbonyl group a C 1 -C 3 alkoxy group, and a trialkylsilyl group.
  • R 1 is -W-Z, wherein W is a divalent C 1 -C 6 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C 1 -C 7 alkyl groups.
  • R 1 is -W-Z, wherein W is
  • R d and R e are independently a hydrogen atom, a methyl group or a hydroxyl group, or R d and R e together form an oxo group, or adjacent R d 's together form a double bond, or adjacent
  • R d 's and R e 's together form a triple bond.
  • R 1 is -W-Z, wherein W is (20) The indole type thiazolidine compound and its salt according to the above-mentioned (16), wherein:
  • R 1 is -V-Z, wherein V is S, SO or SO 2 .
  • R 1 is -W-V-Z, wherein W is wherein m is from 1 to 5, and each of R d and R e is independently a hydrogen atom, a methyl group or a hydroxyl group, or R d and R e together form an oxo group, or adjacent R d 's together form a double bond, or adjacent R d, s and R e 's together form a triple bond (provided that R d and R e on the first carbon atom adjacent to N are not a hydroxyl group, and also provided that R d and R e on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group), and
  • V is NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group).
  • R 1 is -W-V-Z, wherein -W-V- is -CO-NR 8 - (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group).
  • R 4 is a hydrogen atom.
  • the compound of the above formula (I) of the present invention has acidic hydrogen on a thiazolidine ring or on an oxazolidine ring. Further, when substituent Z is a heterocyclic aromatic group or a heterocyclic aliphatic group, it sometimes has a basic nitrogen. Such a
  • the compound of the formula (I) can be used for the purpose of the present invention either in the free form or in the form of a pharmaceutically acceptable salt.
  • the basic salt include an alkali metal salt (lithium salt, sodium salt, potassium salt and the like), an alkali earth metal salt (calcium salt, magnesium salt and the like), an aluminum salt, an ammonium salt which may be unsubstituted or substituted with a methyl, ethyl or benzyl group, an organic amine salt (methylamine salt, ethylamine salt, dimethylamine salt, diethylamine salt, trimethylamine salt,
  • diethanolamine salt triethanolamine salt, piperazine salt, dibenzylpiperidine salt, dehydroabietilamine salt, N,N'-bisdehydroabietilamine salt, benzathine(N,N'-dibenzylethylenediamine) salt, glucamine salt,
  • meglumine(N-methylglucamine) salt benetamine(N-benzylphenetylamine)salt, trometamine(2-amino-2-hydroxymethyl-1,3-propanediol)salt, choline salt, procaine salt), a basic amino acid salt (lysine salt, ornithine salt, arginine salt and the like), a pyridine salt, a collidine salt, a quinoline salt, and the like.
  • an acid-addition salt include a mineral acid salt (hydrochloride, hydrobromide, sulfate,
  • the compound having the formula (I), i.e. indole type thiazolidines, can be prepared by the following synthetic methods.
  • a reaction solvent used in the preparation is stable under the reaction conditions, and is preferably so inert as not to inhibit the reaction.
  • the reaction solvent include water, alcohols (such as methanol, ethanol, propanol, butanol and octanol), cellosolves (such as methoxyethanol and ethoxyethanol), aprotic polar organic solvents (such as dimethylformamide,
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • aliphatic hydrocarbons such as pentane, n-hexane, c-hexane, octane, decaline and petroleum ether
  • aromatic hydrocarbons such as benzene, chlorobenzene, nitrobenzene, toluene, xylene and tetralin
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • ketones such as acetone, methyl ethyl ketone and methyl butyl ketone
  • lower aliphatic acid esters such as methyl acetate, ethyl acetate and methyl propionate
  • R 10 is a hydrogen atom or a protecting group of amide (such as Tr : trityl)).
  • a compound wherein R 4 and R 7 are bonded together in the formula (I), i.e. a compound of the formula (1-1), can be obtained by dehydration-condensation of a compound of the formula (II) and a compound of the formula (V).
  • the compound of the formula (II) is a well known compound or can be synthesized by the method disclosed in Japanese Unexamined Patent Publication No. 271288/1991, Japanese Unexamined Patent Publication No. 277660/1988, Japanese Unexamined Patent Publication No. 71321/1975 or Japanese Examined patent Publication No. 34986/1974.
  • the compound of the formula (V) is a well known compound or can be synthesized by the method disclosed in "J. Prakt. Chem.” (vol.
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base or acid.
  • solvents examples include alcohols, cellosolves, aprotic polar organic solvents, ethers, aromatic
  • hydrocarbons hydrocarbons, halogenated hydrocarbons, alkoxyalkanes and acetonitrile.
  • Examples of the base and the acid include organic amines (such as dimethylamine, diethylamine,
  • Acid Capture H 3,4-dihydro-2H-pyrid[1,2-a]pyrimidin-2-one
  • Acid Capture 9M 9-methyl-3,4-dihydro-2H-pyrid[1,2-a]pyrimidin-2-one, and the like, or metal alkoxides (such as sodium methoxide, sodium ethoxide, lithium
  • inorganic alkali metal salts such as potassium carbonate, sodium
  • This reaction can be accelerated by removing water formed during the reaction out of the system by using an appropriate dehydrating agent such as molecular sieves and anhydrous sodium sulfate or by azeotropic
  • a compound of the formula (I-I) (R 4 and R 7 together form a bond) obtained by the above method can be
  • the reduction reaction by catalytic hydrogenation is conducted usually in a solvent such as water, alcohols, cellosolves, aprotic polar organic solvents, ethers, alkoxyalkanes, lower aliphatic acid esters or lower aliphatic acids, preferably water, methanol, ethanol, methoxyethanol, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, dimethoxyethane, ethylacetate or acetic acid.
  • the solvent may be used alone or in a mixture.
  • the catalyst used in this reaction include Raney nickel, palladium black, palladium carbon, ruthenium carbon, platinum oxide and the like. This reaction proceeds usually at normal temperature and a atmospheric pressure but it is preferable for
  • a reaction is conducted in water or an appropriate organic solvent at a temperature of from 0°C to 150°C, preferably from 0°C to 30°C, and examples of the metal-hydrogen complex compound include sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium tri-s-butylborohydride, potassium triethylborohydride, lithium triethylborohydride, sodium triethylborohydride,
  • tetraethylammonium borohydride methyltrioctylammonium boronydride, calcium borohydride bis(tetrahydrofuran), lithium dimethylborohydride, zinc borohydride and the like.
  • an undesired side reaction can be inhibited by adding a Co reagent such as CoCl 2 , CoCl 3 and Co(OAc) 2 in the presence of a ligand such as dimethyl glyoxime, 2,2'-dipyridyl and 1,10- phenanthroline (see WO 93/13095).
  • the reaction is conducted in a solvent such as alcohols, preferably ethanol or ethanol at a temperature of from - 20°C to a boiling point of a solvent used, preferably from 0°C to 50°C.
  • a solvent such as alcohols, preferably ethanol or ethanol at a temperature of from - 20°C to a boiling point of a solvent used, preferably from 0°C to 50°C.
  • magnesium/methanol can be employed, as described in "J. Org. Chem.”, vol. 40, P 127 (1975).
  • R n is a substituent (other than a hydrogen atom) at the 1-position of an indole ring).
  • the R n substituent other than a hydrogen atom at the 1-position of an indole ring can be converted to a hydrogen atom by a well known appropriate method.
  • the following reaction conditions can be employed depending on the type of the substituent R n .
  • the displacement of the R n substituent can be conducted by heat-refluxing for 1 to 12 hours in a mixture solution of sodium hydroxide aqueous
  • R n is a benzenesulfonyl group, a p-toluenesulfonyl group or a p-methoxybenzenesulfonyl group; by catalytically reducing in the presence of palladium carbon, lithium aluminum hydride or Raney nickel in methanol, ethyl acetate or tetrahydrofuran when R n is a methoxy group, a methoxymethyloxy group, a methoxyethyloxy group or a benzyloxymethyloxy group; by stirring at room temperature in trifluoroacetic acid, a mixture solution of sodium hydroxide/methanol or a mixture solution of hydrochloric acid aqueous
  • R n is a tertiary butylamino carbonyl group or a tertiary butoxy carbonyl group; by using tetra-n-butylammonium fluoride or cesium fluoride in tetrahydrofuran at room temperature when R n is a trimethylsilyl group, a tertiary butyldimethylsilyl group, a tertiary butyldiphenylsilyl group or a
  • alkylating hydrogen at the 5-position of a thiazolidine or oxazolidine ring with an appropriate alkylating agent such as alkylhalides including methyliodide and
  • alkylsulfates including dimethylsulfate and diethylsulfate, or aliphatic or aromatic sulfonic acid esters including methyltosylate and methylmesylate).
  • This reaction is conducted usually in the presence of a base in an appropriate organic solvent.
  • a solvent used include aprotic polar organic solvents, ethers, and alkoxy alkanes, preferably tetrahydrofuran and dimethoxy ethane.
  • the base include alkali metal amides (such as LDA: lithium diisopropyl amide and potassium amide), aliphatic or aromatic lithium compounds (such as n-butyl lithium, t-butyl lithium and phenyl lithium), and the like. These materials are selected optionally depending on the reactivity of the aimed reaction.
  • This reaction is conducted usually at a temperature in the range of from -20°C to 100°C, preferably from - 10°C to 30°C for 0.1 to 10 hours.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , R n , X 1 and X 2 are as defined above, and R 12 is an appropriate leaving group in nucleophilic displacement in the present reaction, examples of which include a halogen such as chloro, bromo and iodo, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy and methanesulfonyloxy).
  • a compound of the formula (I) other than the one wherein R 4 and R 7 together form a bond i.e. a compound of the formula (1-2)
  • a compound of the formula (V) can be obtained by reacting a compound of the formula (V) with an indole derivative of the formula (VI).
  • the compound of the formula (V) used herein is a well known compound or can be synthesized by a method disclosed in "Ukr. Khim. Zh.” (vol. 16, p. 545,
  • Patent Publication No. 216882/1984 The compound of the formula (V) wherein R 10 is hydrogen, is used in this reaction preferably after displacing its acidic hydrogen with an appropriate substituent (such as Tr : trityl) by a known method.
  • an appropriate substituent such as Tr : trityl
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base.
  • the solvent thus used include aprotic polar organic solvents (such as HMPA: hexamethylphosphoric triamide and DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine), ethers (such as THF: tetrahydrofuran) and alkoxyalkanes, and the solvent may be used respectively alone or in a mixture.
  • Examples of the base thus used include a strong base such as alkali metal amides (e.g. LDA: lithium diisopropyl amide, sodium amide and potassium amide) and aliphatic or aromatic lithium compounds (e.g. n-butyl lithium, t-butyl lithium and phenyl lithium). These materials are
  • reaction time may be varied depending on the materials used, but is usually from 0.5 to 1 hour for the formation of an anion and from 0.5 to 5 hours for the reaction with an indole compound.
  • this reaction can be conducted in accordance with a method disclosed in "J. Amer. Chem. Soc.” (vol. 87, p. 4588, 1965) or "J. Med. Chem.” (vol. 34, p. 1538, 1991).
  • a compound of the formula (V) is reacted with magnesium methylcarbonate in an inert gas atmosphere such as nitrogen and in an aprotic polar organic solvent such as dimethylformamide to form a chelate compound, and the chelate compound thus formed is further reacted with an indole compound of the formula (VI) to obtain a compound of the formula (1-2).
  • This reaction is conducted usually at a temperature ranging from 20°C to 150°C, preferably from 70°C to 100°C.
  • the reaction time varies depending on the materials used, but the formation of the chelate compound takes from 0.5 to 2 hours and the reaction with the indole compound takes from 0.5 to 5 hours.
  • an amide group at the 3-position of thiazolidine ring of the compound of the formula (1-2) thus obtained may be deprotected by a well-known method.
  • R 10 is Tr (trityl)
  • this method is conducted by using an organic acid such as trifluoroacetic acid and trichloroacetic acid or an inorganic acid such as hydrochloric acid and sulfuric acid.
  • This reaction is conducted in the absence of a solvent or in the presence of a solvent such as ethers including tetrahydrofuran and dioxane and halogenated solvents including chloroform and dichloromethane, at a temperature ranging from 0°C to 100°C, preferably from 10°C to 50°C, for 0.1 to 5 hours.
  • R 1 , R 2 , R 3 and R 6 are as defined above, and R 11 is C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, and Hal is a halogen atom such as a chlorine atom, a bromine atom and an iodide atom).
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base or acid.
  • solvent used examples include alcohols, cellosolves and aprotic polar organic solvents,
  • This reaction is conducted at a temperature of from 0°C to a boiling point of a solvent used, preferably from 50°C to 150°C, for 0.5 to 10 hours.
  • base examples include organic amines (such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, methanolamine and ethanolamine), inorganic alkali metal salts (such as sodium acetate and potassium acetate) and the like.
  • organic amines such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, methanolamine and ethanolamine
  • inorganic alkali metal salts such as sodium acetate and potassium acetate
  • R 1 , R 2 , R 3 , R 6 and R n are as defined above.
  • This reaction is conducted usually in the presence of water and an acid in an appropriate organic solvent.
  • Examples of the solvent include usually alcohols,
  • cellosolves preferably methanol, ethanol,
  • methoxyethanol methoxyethanol, sulfolane, dioxane and dimethoxyethane.
  • the acid include inorganic acids (such as hydrochloric acid, sulfuric acid and hydrobromic acid), and these materials are selected optionally depending on the reactivity of the aimed reaction.
  • This reaction is conducted usually at a temperature in the range of from 50°C to a boiling point of a solvent used in the reaction, preferably from 80°C to 150°C.
  • the reaction time is usually from 0.5 to 30 hours.
  • the compound of the formula (XIV) is preferably protected by substituting hydrogen of R 10 with an appropriate substituent (such as Tr : trityl).
  • This reaction is usually conducted in an appropriate organic solvent in the presence of base.
  • solvent used include aprotic polar organic solvents, ethers, aromatic hydrocarbons, hydrogenated hydrocarbons, alkoxyalkanes, acetonitrile, and the like.
  • Examples of the base thus used include organic amines (such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine,
  • Acid Captor H 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one
  • Acid Captor 9M 9-methyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one
  • metal alkoxides such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide
  • inorganic alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium
  • alkali metal amides such as sodium amide
  • This reaction is conducted usually at a temperature ranging from -20°C to a boiling point of the solvent used, preferably from 20°C to 150°C, for from 0.5 to 30 hours.
  • a compound is well known and is commercially available, or can be obtained by a well known method (for example, British Laid Open Patent Publication No. 1107677 discloses a compound wherein Z is pyrrole, Japanese Unexamined Patent Publication No. 85372/1986 discloses a compound wherein Z is oxazole or thiazole and U.S. Patent No. 4,167,626 discloses a compound wherein Z is triazole).
  • Such a compound can be obtained by halogenating Z-COCH 3 (for example, "Bull. Soc. Chim. Fr., p. 1760 (1973)” discloses a compound wherein Z is furan, “Tetrahedron, 29(2), p. 413 (1973)” discloses a compound wherein Z is thiophene, "J. Heterocyclic Chem., 27(5), p. 1209 (1990)” discloses a compound wherein Z is pyrrole, "Bull. Soc. Chim. Fr., p. 540 (1988)", “Bull. Soc. Chim. Fr., p. 318 (1987)", “J. Heterocyclic Chem., 23(1), P. 275 (1986)", "Arch.
  • the compound of the formula (XIX) is preferably protected by substituting hydrogen of
  • R 10 with an appropriate substituent (such as Tr : trityl)
  • the compound having a protective group introduced into a thiazolidine ring part of the formula (XX) can be converted into a compound of the formula (I) by deprotecting an amino group at the 3-position of the thiazolidine ring in accordance with the method disclosed by T.W. Greene, P.G.M. Wuts "Protective Groups in Organic Synthesis” (1991) or the method disclosed in the Process 5.
  • Process 11
  • the compound of the formula (XIX) is preferably protected by substituting hydrogen of R 10 with an appropriate substituent (such as Tr : trityl).
  • the compound having a protective group introduced into a thiazolidine ring part of the formula (XXI) can be converted to a compound of the formula (I) by deprotecting an amino group at the 3-position of the thiazolidine ring in accordance with the method disclosed by T.W. Green,
  • the compound of the formula (XXII) is preferably protected by substituting hydrogen of R 10 with an appropriate substituent (such as Tr :
  • a compound having a protective group introduced into a thiazolidine ring part of the formula (XXIV) can be converted to a compound of the formula (I) by deprotecting an amino group at the 3-position of the thiazolidine ring in accordance with the method disclosed by T.W. Greene, P.G.M. Wuts
  • the compound of the formula (XXII) is preferably protected by substituting hydrogen of R 10 with an
  • a compound having a protective group introduced into a thiazolidine ring part of the formula (XXVI) can be converted to a compound of the formula (I) by deprotecting an amino group at the 3-position of the thiazolidine ring in accordance with the method disclosed by T.W. Greene, P.G.M. Wuts
  • R 1 , R 2 , R 3 and R n are as defined above, and R 8 is a hydrogen atom, a C 1 -C 4 alkyl group, a phenyl group or a benzyl group).
  • the step of synthesizing the compound of the formula (III) can be conducted by using a well known appropriate reducing agent (e.g. metal hydride complex compounds such as LAH: lithium aluminum hydride, SAH: sodium aluminum hydride, sodium triethoxyaluminum hydride, Red-Al: sodium bis(2-methoxyethoxy) aluminum hydride, SBH: sodium borohydride and LBH: lithium borohydride, and metal hydride compounds such as DIBAH: diisobutyl aluminum hydride, and catalytic hydrogenation using CuBaCrO as a catalyst).
  • metal hydride complex compounds such as LAH: lithium aluminum hydride, SAH: sodium aluminum hydride, sodium triethoxyaluminum hydride, Red-Al: sodium bis(2-methoxyethoxy) aluminum hydride, SBH: sodium borohydride and LBH: lithium borohydride
  • metal hydride compounds such as DIBAH: diisobutyl aluminum hydride
  • R 9 is a protecting group (such as t-butyldimethylsilyl group) of a primary hydroxymethyl group).
  • a compound having a hydrogen atom at the 2-position of an indole ring can get a carbon functional group: R 1 (Z-W-, Z-V-W-, Z-W-V- and Z-V-) introduced at the 2-position by means of the following method.
  • a compound (VII) can be obtained by protecting a primary hydroxymethyl group of hydroxymethyl indole of the formula (III) by means of a well known method.
  • protection of these alcohols can be conducted in accordance with the method disclosed by T.W. Greene, P.G M. Wuts in " Protective Groups in Organic Synthesis” (1991).
  • a protective group: R 9 is preferably stable under basic conditions in the following step, examples of which include a substituted silyl group (such as trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
  • Step b at the 2-position of the indole ring of the compound (VII) thus obtained, a carbon functional group: Z-W-, Z-V-W- or Z-V- can be introduced in
  • a compound of the formula (VIII) means an
  • electrophilic reagent which can be reacted with an indole ring metalated in step b.
  • a substrate usable in such a reaction are illustrated below.
  • a compound of the formula Z-A (A is -CH 2 -B (B is a leaving group in this reaction, such as a chlorine atom, a bromine atom, an iodine atom, methanesulfonyl, benzenesulfonyl and p-toluenesulfonyl)) can be employed.
  • B is a leaving group in this reaction, such as OH, OLi, ONa, OK, a chlorine atom, a bromine atom, an iodine atom and methoxymethylamino, preferably OK, a chlorine atom, a bromine atom and methoxymethylamino
  • a compound of the formula (VIII) may be a
  • t-butyl lithium the reaction is conducted at a temperature of from -100°C to 100°C, preferably at -78°C, for 1 to 2 hours, and the reaction with a compound of the formula (VIII) is then conducted at -78°C.
  • Deprotection of a primary hydroxylmethyl group is conducted by means of a well known method. For example, deprotection of these alcohols is conducted in accordance with the method disclosed by T.W. Greene, P.G.M. Wuts "Protective Groups in Organic Synthesis” (1991) to obtain a compound (III) wherein R 1 is introduced at the 2-position.
  • R 9 is t-butyldimethylsilyl
  • this reaction is conducted by using tetra-n-butylammonium fluoride in THF: Tetrahydrofuran at 0°C-30°C in accordance with the method disclosed in J. Amer. Chem. Soc, vol. 94,
  • a compound having an indole ring having hydrogen at the 1-position and the 2-position can be converted to the corresponding hydroxymethyl indole (compound (III)) by introducing a carbon functional group: R 1 (Z-W-) by means of the following method.
  • the alkoxycarbonyl indole of the formula (IV) used may be a commercially available reagent or may be
  • R n ( ⁇ H) is introduced at the 1-position of an indole ring of alkoxycarbonyl indole (IV).
  • R n include a C 1 - C 7 alkyl group, a C 1 -C 4 alkoxymethyl group, a C 1 -C 4 alkylaminomethyl group, a carboxyl group, a C 1 -C 4
  • alkoxycarbonyl group a C 1 -C 4 alkylaminocarbonyl group, a C 1 -C 7 alkoxy group, a C 1 -C 7 alkoxyalkylmethyloxy group, an alkylsulfonyl group and an aryl sulfonyl group, preferably methyl, methoxymethyl, dimethylaminomethyl, carboxyl, t-butyloxycarbonyl, methylcarbamoyl, methoxy, methoxymethyloxy, mesyl, benzene sulfonyl, p-toluenesulfonyl, p-methoxybenzenesulfonyl, p-fluorobenzenesulfonyl and p-chlorobenzenesulfonyl, more preferably benzene sulfonyl.
  • the alkoxycarbonyl group of the compound (IV) thus obtained is reduced by using an appropriate reducing agent such as DIBAL: diisobutylaluminium hydride and LAH: lithium aluminum hydride by means of a well known method to obtain the corresponding hydroxymethyl indole
  • a compound of the formula (VII) is reacted with a base to anionize the 2-position under an inert gas atmosphere such as nitrogen or argon in an aprotic organic solvent such as tetrahydrofuran, ether, isopropyl ether, n-pentane, i-pentane, cyclopentene, n-hexane, cyclohexane, HMPA: hexamethylphosphoric triamide, HMPT: hexamethylphosphorous triamide, N,N,N',N'tetramethylethylenediamine, dioxane, dimethylsulfoxide or dimethylformamide.
  • an inert gas atmosphere such as nitrogen or argon in an aprotic organic solvent
  • aprotic organic solvent such as tetrahydrofuran, ether, isopropyl ether, n-pentane, i-pentane, cyclopentene, n-hexane,
  • Examples of the base used include n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, methyl lithium, LDA: lithium diisopropyl amide, potassium bis ( trimethylsilyl)amide, calcium hydride, sodium hydride, potassium hydride, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium, sodium, potassium, zinc, magnesium or copper, preferably n-butyl lithium, s-butyl lithium, t-butyl lithium or LDA.
  • the reaction is conducted at a temperature of from -100°C to 100°C, preferably from -78°C to 0°C, for 10 to 120 minutes, and then the reaction with a compound of the formula (VIII) is conducted to introduce a carbon
  • a compound of the formula (VIII) may be a commercially available reagent or may be synthesized in the same manner as above.
  • R 1 , R 2 , R 3 , R 6 and R n are as defined above.
  • a carbonyl indole of the formula (II) is a well known compound or can be obtained by oxidizing a hydroxymethyl indole of the formula (III).
  • This step is conducted by using an appropriate oxidizing agent (such as manganese dioxide, PCC: pyridiniumchlorochromate, PDC: pyridiniumdichromate, DDQ: dichlorodicyanobenzoquinone, chloranil, Swern oxidizing agent: oxalyl chloridedimethylsulfoxide-tertiary amine or sulfur trioxidepyridine complex).
  • an appropriate oxidizing agent such as manganese dioxide, PCC: pyridiniumchlorochromate, PDC: pyridiniumdichromate, DDQ: dichlorodicyanobenzoquinone, chloranil, Swern oxidizing agent: oxalyl chloridedimethylsulfoxide-tertiary amine or sulfur trioxidepyridine complex
  • This step can be conducted by the method using diazomethane as disclosed in "Tetrahedron Letters” P955 (1963) and “Chem. Ber.” vol. 40, P479 (1907), the method using alkyl halide as disclosed in “Synth. Commun.” vol. 14(8), P743 (1984) or the method using alkyl lithium as disclosed in "J. Org. Chem.” vol. 30, P226 (1965).
  • a compound having a formyl group at the 2-positon of an indole ring and having a carbon functional group R 1 at the 4-, 5-, 6- or 7-position can be synthesized by the following method.
  • R 1 can be introduced in the indole nucleus by protecting a nitrogen atom at the 1-position of haloindole of the formula (IX) with a lower alkoxy group, particularly a methoxy group, conducting formylation at the 2-position, conducting metalation of the haloindole in the presence of a strong base and then reacting with an aldehyde compound of the formula (XI). (Reduction of indole ring)
  • a haloindole (IX) used as a starting material has a hydrogen atom at the 1-positon and a halogen atom at the 4-, 5-, 6- or 7-position.
  • the halogen atom is preferably bromine or iodine, more preferably bromine, and the haloindole (IX) used is a commercially available reagent or can be synthesized by a well known method.
  • the haloindole (IX) can be converted into the corresponding indoline (compound (X)) by reducing at the 2- and 3-positions of the indole ring, for example, by the method disclosed in "J. Amer. Chem. Soc " vol. 96, P7812
  • the indoline (compound (X)) can be converted into the corresponding 1-methoxyhaloindole (compound (IX)) by conducting oxidation and methylation at the 2-, 3- and 1-positions in accordance with the method disclosed in Japanese Unexamined Patent Publication No. 31257/1991 (M. Somei). This reaction is conducted by oxidizing with a 30% hydrogen peroxide aqueous solution in a
  • 1-methoxyhaloindole (compound (IX)) can be converted to the aimed formylindole (compound (II)) by conducting formylation at the 2-positon and then reacting with compound (VIII) in accordance with the method disclosed in "Heterocycles" by M. Somei, vol. 132, P221 (1991).
  • the 2-position of 1-methoxyhaloindole is anionized by reacting with a base under an inert gas atmosphere such as nitrogen or argon in an aprotic organic solvent such as tetrahydrofuran, ether, isopropyl ether, n-pentane, i-pentane, cyclopentane, n-hexane, cyclohexane, HMPA:
  • HMPT hexamethylphosphoric triamide
  • hexamethylphosphorous triamide N,N,N',N'-tetramethylethylene diamine, dioxane, dimethylsulfoxide or dimethylformamide.
  • examples of such a base include n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, methyl lithium, LDA: lithium diisopropyl amide, potassium bis( trimethylsilyl)amide, calcium hydride, sodium hydride, potassium hydride, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium, sodium, potassium, zinc, magnesium and copper, preferably phenyl lithium, n-butyl lithium and LDA.
  • the reaction is conducted for 10-120 minutes by lithium-modifying the 2- position in tetrahydrofuran at a temperature of from -100°C to 100°C, preferably from -78°C to 0°C, and
  • reaction with N,N'-dimethylformamide, N,N'-methoxymethylformamide is then conducted for 5 to 120 minutes. Thereafter, the 5-position is anionized by further reacting with a base at a temperature of from -100°C to 100°C, preferably from -78°C to 0°C.
  • a base at a temperature of from -100°C to 100°C, preferably from -78°C to 0°C.
  • the base used include n-butyl lithium, s-butyl
  • lithium, sodium, potassium, zinc, magnesium and copper preferably s-butyl lithium and t-butyl lithium.
  • s-butyl lithium and t-butyl lithium preferably s-butyl lithium and t-butyl lithium.
  • reaction with the compound of the formula (VIII) is conducted to obtain the aimed formyl indole (compound (II)).
  • haloindole of the formula (IX) After protecting a nitrogen atom at the 1-position of a haloindole of the formula (IX) with a substituted silyl group, the haloindole is subjected to metalation in the presence of a strong base and was reacted with an
  • the halogen atom is preferably bromine or iodine, more preferably bromine and the haloindole used may be a commercially available reagent or may be prepared by a well known method.
  • an appropriate substituent is introduced into the haloindole (IX) by a well known method.
  • the substituent include a substituted silyl group, a C 1 -C 7 acyl group, a C 1 -C 4 alkoxycarbonyl group and a C 1 -C 4 alkylaminocarbonyl group, preferably pivaloyl, t-butyl oxycarbonyl, t-butyl carbamoyl, triisopropylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, more
  • HMPT hexamethylphosphoric triamide
  • hexamethylphosphorous triamide N,N,N',N'-tetramethylethylene diamine, dioxane, dimethylsulfoxide or dimethylformamide, preferably tetrahydrofuran or ether.
  • the based used include n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl
  • lithium, methyl lithium, LDA lithium diisopropyl amide, potassium bis(trimethylsilyl)amide, calcium hydride, sodium hydride, potassium hydride, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium, sodium, potassium, zinc, magnesium and copper, preferably n-butyl lithium, s-butyl lithium, t-butyl lithium and methyl lithium.
  • the formylated product (II) can be obtained by reducing a cyano group of an indole of the formula
  • This step can be conducted by using an
  • reducing agent such as Raney nickel, nickel, sodium aluminum hydride, sodium triethoxyaluminum
  • a halocarboxylic acid ester of the formula (XII) can be obtained by reacting a halomethylindole of the formula (VI) with a malonic acid ester or a lower acylacetic acid ester by a well known method to obtain a compound of the formula (XI) and halogenating the compound of the formula (XI) thus obtained.
  • halomethylindole of the formula (VI) can be synthesized by the method disclosed in "Org. Prep.
  • halomethylindole of the formula (VI) can be obtained by halogenating a hydroxymethylindole of the formula (III) with an appropriate halogenating agent (such as SOCl 2 , POCl 3 , PCl 5 , HCl, SnCl 4 , HBr, PBr 3 , Br 2 , POBr 3 ,
  • an appropriate halogenating agent such as SOCl 2 , POCl 3 , PCl 5 , HCl, SnCl 4 , HBr, PBr 3 , Br 2 , POBr 3 ,
  • methanesulfonic acid chloride methanesulfonic acid chloride, p-toluenesulfonic acid chloride, N-bromosuccinimide-triphenylphosphine and N-chlorosuccinimide-triphenylphosphine).
  • a compound wherein R 13 is C 1 -C 3 alkyl can be obtained by reacting a halomethylindole of the formula (VI) with a lower
  • acylacetic acid ester such as methyl acetoacetate or ethyl acetoacetate in the presence of an appropriate base (such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylamide, butyl lithium, metallic sodium, potassium carbonate, sodium hydride, potassium hydride and calcium hydride) in accordance with the method disclosed in "J. Amer. Chem. Soc.” vol 64, P435 (1942).
  • an appropriate base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide, potassium amide, diisopropylamide, butyl lithium, metallic sodium, potassium carbonate, sodium hydride, potassium hydride and calcium hydride
  • a compound wherein R 13 is OR 11 can be obtained by reacting a halomethylindole of the formula (VI) with a malonic acid ester such as diethyl malonate or di-t-butyl malonate in the presence of such a base as mentioned above, in accordance with the method disclosed in "J. Amer. Chem. Soc.” vol 74, P831 (1952).
  • the step for preparing a compound of the formula (XII) is conducted by using an appropriate halogenating agent (such as bromine or N-chlorosuccinimide) in the presence of an appropriate base (such as potassium hydroxide, sodium methoxide or potassium carbonate) in accordance with the method disclosed in "J. Amer. Chem. Soc.” vol 71, P3107 (1949) or “Tetrahedron Letters" vol. 28, P5505 (1987).
  • an appropriate halogenating agent such as bromine or N-chlorosuccinimide
  • an appropriate base such as potassium hydroxide, sodium methoxide or potassium carbonate
  • a compound of the formula (XII) can be obtained by reacting a halomethylindole of the formula (VI) with a diazoacetic acid ester in the presence of a copper catalyst in accordance with the method disclosed in "Zur. Russ. Fiz-Chim.” vol. 21, P851 (1951).
  • the compound having a carbon functional group as R 1 is a novel compound and is useful as an intermediate for preparing the compound of the formula (I).
  • Examples of the compound of the present invention are illustrated as compounds of the formulas (1-1) and (1-2) in Tables 1 to 10. Also, the above described salts derived by reacting basic nitrogen at the 3-position of the thiazolidine ring by means of a well known method are also the compounds of the present invention.
  • Me is a methyl group
  • Et is an ethyl group
  • Pr is a propyl group
  • Bu is a butyl group
  • Pen is a pentyl group
  • Hex is a hexyl group
  • Hep is a heptyl group
  • Ph is a phenyl group
  • n means "normal”
  • i means "iso”
  • s means "secondary”
  • t means “tertiary”
  • c means "cyclo”.
  • Q1 to Q317 and J1 to J42 represent the following substituents.
  • X 1 , X 2 , R 4 , R 6 and R 7 are selected from the following Table 1.
  • X 1 , X 2 and R 6 are selected from the following Table 2.
  • R n is selected from the following Table 3.
  • R 2 and R 3 are selected from the following Table 4.
  • W is selected from the following Table 5.
  • R 1 is selected from the following Table 6.
  • Z and W are selected from the following Tables 7 to 22.
  • R a , R b and R c are selected from the following Table 23.
  • R a , R b and R c are selected from the following Table 24.
  • R a , R b and R c are selected from the following Table 25.
  • the compound (I) or its pharmaceutically acceptable salt of the present invention has a hypoglycemic activity, and can be used alone or in a mixture with a known
  • the compound (I) or its pharmaceutically acceptable salt of the present invention can also be used for preventing or treating diabetic complications including diabetic eye diseases (such as diabetic cataract and diabetic
  • the compound (I) or its pharmaceutically acceptable salt of the present invention can also be used in combination with various oral disorders
  • hypoglycemic agents such as insulin derivatives
  • the compounds (I) of the present invention may be formulated into various suitable formulations depending upon the manner of administration.
  • the compounds of the present invention may be administered in the form of free thiazolidindione or in the form of physiologically hydrolyzable and acceptable pharmaceutically acceptable salts (such as sodium salts or potassium salts).
  • the pharmaceutical composition of the present invention is preferably administered orally in the form of the compound of the present invention by itself or in the form of powders, granules, tablets or capsules formulated by mixing the compound of the present
  • a suitable pharmaceutically acceptable carrier including a binder (such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol,
  • tragacanth gum polyvinyl pyrrolidone or CMC-Ca
  • an excipient such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine or microcrystal cellulose powder
  • a lubricant such as magnesium stearate, talc, polyethylene glycol or silica
  • a disintegrator such as potato starch
  • composition of the present invention is not limited to such oral
  • parenteral administration and it is applicable for parenteral administration.
  • it may be administered in the form of e.g. a suppository formulated by using oily base material such as cacao butter, polyethylene glycol, lanolin or fatty acid triglyceride, a transdermal
  • therapeutic base formulated by using liquid paraffin, white vaseline, a higher alcohol, Macrogol ointment, hydrophilic ointment or hydro-gel base material, an injection formulation formulated by using one or more materials selected from the group consisting of
  • polyethylene glycol polyethylene glycol, hydro-gel base material, distilled water, distilled water for injection and an excipient such as lactose or corn starch, or a formulation for administration through mucous membranes such as an ocular mucous membrane, a nasal mucous membrane and an oral mucous membrane.
  • invention is from 0.05 to 50 mg, preferably from 0.1 to 10 mg per kg weight of a patient, and it is administered from once to three times per day.
  • the dose may of course be varied depending upon the age, the weight or the condition of illness of a patient.
  • Compound (II-b) can be obtained by conducting formylation at the 2-position of 5-bromo-1- methoxyindole synthesized through 5-boromoindoline using 5-bromoindole as a starting material.
  • KK mouse and KKA y mouse NIDDM models (male, 6-7 weeks old) (Nakamura, Proc. Jpn. Acad., vol. 38, 348-352, 1962; Iwatsuka et al. Endocrinol. Jpn., vol. 17, 23-35, 1970) were purchased from Nihon Clea. They were allowed free access to high-calories' chow (CMF, Oriental Yeast) and water. Around 40 g-weighted mice were examined.
  • Blood (20 ⁇ l) collected from the retro-orbital sinus was diluted in 60 units heparin sodium-solution and was centrifuged in a microfuge. The supernatant was assayed. The glucose concentration was determined by glucose oxidase method (Glucose Analyzer II, Beckman). A group of 3 to 4 mice having a blood glucose value of higher than 200 mg/dl, the blood glucose value of which did not reduce by more than 10% for 24 hours after once oral administration of 0.5% carboxymethyl cellulose (CMC)-saline, were tested.
  • CMC carboxymethyl cellulose
  • CMC carboxy-methyl cellulose
  • the compounds of the present invention exhibited hypoglycemic activities at substantially higher degree as compared with CS-045 used as controls. Glibenclamide (insulin-releasing agent) did not exhibit hypoglycemic activity in this test.
  • mice db/db mice, NIDDM model (male 6 weeks old), were db/db mice, NIDDM model (male 6 weeks old).
  • Blood (20 ⁇ l ) collected from the retro-orbital sinus was diluted in 60 units heparin sodium-solution and was centrifuged in a microfuge. The supernatant was assayed. The glucose concentration was determined by glucose oxidase method (Glucose Analyzer II, Beckman). A group of 6 mice were tested.
  • CMC carboxy-methyl cellulose
  • the total cholesterol (TC) amounts in bloods collected before drug-administration and 4 days after the drug-administration were measured in accordance with the cholesterol oxidase method and the triglyceride (TG) amounts in theses bloods were measured by the end point method employing glycerol oxidase method.
  • the neutral lipid reducing activity in each blood was expressed by a reducing rate relative to the value before the drug- administration.
  • the compounds of the present invention exhibited higher hypoglycemic activities and higher neutral lipid reducing activities as compared with CS-045 used as controls.
  • Rat kidney AR was prepared as follows; Rat kidney was perfused by ice-cold saline to remove blood and then homogenized in a Teflon homogenizer with 3 time volumes of cold 5 mM Tris-HCl buffer (pH 7.4). The homogenate was centrifuged at 45,000 ⁇ g for 40 minutes to remove insoluble materials, and the supernatant fraction was dialyzed overnight against 0.05 M sodium chloride
  • the dialyzed solution was centrifuged again at 11,000 ⁇ g for 20 minutes and the supernatant fraction was used as an aldose reductase sample.
  • AR activity was assayed by the modified method of Inukai et al. (Jpn. J. Pharmacol. 61, 221-227, 1993).
  • the assay was carried out in 0.1M sodium phosphate (pH 6.2) containing 0.4M lithium
  • test compounds concentrations of test compounds and 10 mM DL-glyceraldehyde.
  • the reference blank contained all of the above ingredients, except for DL-glyceraldehyde.
  • the reaction was started by addition of the substrate (DL-glyceraldehyde). The reaction rate was measured at 30°C for 2 minutes. All test compounds were dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO in reaction mixture never exceeded 1%.
  • DMSO dimethyl sulfoxide
  • the compounds of the present invention exhibited equivalent or stronger aldose-reductase inhibitory activities than sulindac, quercetin or alrestatin used as control. Further, CS-045 exhibited no activities.
  • the above components were mixed by a usual method and then tabletted to produce 100 tablets each containing 10 mg of the active ingredient.
  • the above components were melt-mixed by a usual method and poured into suppository containers, followed by cooling for solidification to obtain 100 suppositories of 1 g each containing 10 mg of the active ingredient.
  • the above components were granulated by a usual method and packaged to obtain 100 packages each containing 200 mg of the granules so that each package contains 10 mg of the active ingredient.
  • the compound of the present invention has a hypoglycemic effect and an aldose-reductase inhibitory activity and has less toxicity, it is useful for preventing or treating diabetic complications including diabetic eye diseases (such as diabetic cataract and diabetic retinopathy), diabetic neuropathy, diabetic nephropathy, diabetic gangrene, and the like.
  • diabetic eye diseases such as diabetic cataract and diabetic retinopathy
  • diabetic neuropathy diabetic nephropathy
  • diabetic gangrene diabetic gangrene

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Abstract

Composé de thiazolidine de type indole, de formule (I) et son sel: où X1 est S ou O; X2 est S, O ou NH; Y est CR6R7 (R6 est un atome d'hydrogène ou un groupe alkyle C¿1?-C7); R1 se substitue en position 2-, 3-, 4-, 5-, 6, ou 7- d'un noyau indole et consiste en un groupe alkyle C1-C10, -Wk-Vl-Z (Z est un groupe cycloalkyle C3-C10, un groupe aromatique hétérocyclique C1-C12, un groupe hétérocycloaliphatique C1-C16, etc., V est O, S, etc., W est un groupe hydrocarbone divalent saturé C1-C6 ou insaturé C2-C6, qui peut comporter au plus 3 substitutions par des groupes hydroxyle, oxo et alkyle C1-C7, k et l étant égaux à 0 ou à 1), -V-W-Z (V, W et Z sont conformes aux définitions données plus haut), -W-V-W-Z (V, W et Z sont conformes aux définitions données plus haut, et les deux radicaux W peuvent être identiques ou différents), ou R1 peut être un atome d'hydrogène si Y est lié à la position 4-, 5- ou 7- d'un noyau indole; chacun des groupes R?2 et R3¿ se substitue à la position 2-, 3-, 4-, 5-, 6-, ou 7- d'un noyau indole, et est constitué, de façon indépendante, d'un atome d'hydrogène, d'un groupe alkyle C¿1?-C7 ou d'un groupe similaire; R?4¿ est un atome d'hydrogène ou un groupe alkyle C¿1?-C7; R5 est un atome d'hydrogène ou un groupe carboxyméthyle; et R?n¿ se substitue à la position 1- d'un noyau indole, et est constitué d'un atome d'hydrogène, d'un groupe alkyle C¿1?-C7, d'un groupe alkoxy, d'un group alkylsulfonyle, d'un groupe arylsulfonyle, ou d'un groupe similaire.
PCT/JP1996/000403 1995-02-23 1996-02-22 Composes de thiazolidine et d'oxazolidine de type indoles avec action hypoglycemique WO1996026207A1 (fr)

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US5889032A (en) * 1996-05-06 1999-03-30 Dr. Reddy's Research Foundation Heterocyclic compounds having antidiabetic, hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
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WO2000018748A1 (fr) * 1998-09-30 2000-04-06 Roche Diagnostics Gmbh Derives de rhodanine utiles pour le traitement et la prevention de troubles metaboliques des os
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WO2000032180A2 (fr) * 1998-12-01 2000-06-08 The Institutes For Pharmaceutical Discovery, Inc. Techniques permettant de reduire les taux de glucose serique et de triglycerides et d'inhiber l'angiogenese a l'aide d'acides indolealcanoiques substitues
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