WO1996011196A1 - Pyrazolylmethyl-thiazolidines useful as hypoglycemic agents - Google Patents

Pyrazolylmethyl-thiazolidines useful as hypoglycemic agents Download PDF

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Publication number
WO1996011196A1
WO1996011196A1 PCT/JP1995/002041 JP9502041W WO9611196A1 WO 1996011196 A1 WO1996011196 A1 WO 1996011196A1 JP 9502041 W JP9502041 W JP 9502041W WO 9611196 A1 WO9611196 A1 WO 9611196A1
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group
hydrogen atom
atom
alkyl
compound
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PCT/JP1995/002041
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French (fr)
Inventor
Yoshio Ohara
Mikio Suzuki
Nobuhide Miyachi
Katsuhiro Kato
Keisuke Ohdoi
Tetsuya Kobayashi
Ken-Ichi Shikada
Takeshi Naito
Takashi Yotsumoto
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Nissan Chemical Industries, Ltd.
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Priority to AU36190/95A priority Critical patent/AU3619095A/en
Publication of WO1996011196A1 publication Critical patent/WO1996011196A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 pyrazole type thiazolidines having a hypoglycemic effect and an antiglycation effect, 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 value, 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 retinopathy, diabetic
  • 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 a compound having an anti-glycation effect and aldose-reductase inhibitory activities which were not exhibited by the above-mentioned known compounds.
  • the present invention provides pyrazole type
  • thiazolidines capable of preventing or treating diabetes mellitus and diabetic complications.
  • novel pyrazole type thiazolidine derivatives of the present invention are pyrazole 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 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
  • 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
  • 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 4 -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 4 -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 4 -C 12 heterocyclic aromatic and C 4 -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,
  • 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 thiazolidindion-5-yl group and 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, and two V's and W's may, respectively, be the same or different
  • -W-V-W-Z V, W and Z are as defined above, and two W's may be the same or different
  • V, W and Z are as defined above, and two V's may be the same or different), or
  • V, W and Z are as defined above
  • 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 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,
  • benzothiazolyl and benzimidazolyl groups may be
  • R 2 or R 3 may further be a halogen atom when it is bonded to a carbon atom at the 3-, 4- or 5-position of the pyrazole ring;
  • 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.
  • 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, 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
  • 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-n-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,
  • a 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.
  • Preferred is 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
  • 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-1-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,
  • Each group may have at most 5 substituents (the 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, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,
  • 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 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 thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
  • the C 4 -C 12 heterocyclic aromatic group includes, for example, 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-isoxazolyl), isothiazolyl (said isothiazolyl includes 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl), furazanyl
  • 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), triazolyl (said triazolyl includes 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4
  • 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-pyrimidinon-1-yl, 2(1H)-pyrimidin
  • 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,
  • Preferred examples of the C 4 -C 12 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-isoxazolyl), isothiazolyl (said
  • 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-
  • thiazolo[3,2-b]triazolyl includes thiazolo[3,2-b]triazol-2-yl, thiazolo[3,2-b]triazol-5-yl, and thiazolo[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 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 4 -C 6 heterocycloaliphatic group includes, for example, piperidyl (said piperidyl includes 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl), pyrrolidinyl (said pyrrolidinyl includes 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl (said imidazolidinyl includes 1-imidazolidinyl, 2-imidazolidinyl, and 4-imidazolidinyl), pyrazolidinyl (said pyrazolidinyl includes 1-pyrazolidinyl, 3-pyrazolidinyl, and 4-pyrazolidinyl), morpholinyl (said morpholinyl includes 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl), and tetrahydrofuranyl (said
  • 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 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
  • 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]hehptyl.
  • 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 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.
  • 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 naphthyl group (which may be an ⁇ - naphthyl group, or a ⁇ -naphthyl group), a benzyl group, a pyridyl group (which may, for example, be a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, preferably a 2-pyridyl group), a pyrimidinyl group (which may, for example, be a 2-pyrimidinyl group, a 4-pyrimidinyl group or a 5-pyrimidinyl group), a 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
  • the halogen atom in a case where R 2 and R 3 are bonded to a carbon atom at the 3-, 4- or 5-position of the pyrazole ring may 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, more preferably a chlorine atom or a bromine atom.
  • 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, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i- butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy and heptyloxy.
  • 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 2 and R 3 are preferably bonded on the nitrogen atom at the 1-position or on the carbon atom at the 4-position of the pyrazole ring.
  • each of R 2 and R 3 is more preferably hydrogen, methyl, ethyl, phenyl, fluorine, chlorine or bromine.
  • each of them is more preferably hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 2-pyridyl or benzyl.
  • 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 preferably, it is a hydrogen atom, or forms a bond together with R 7 .
  • R 5 is a hydrogen atom or a carboxymethyl group, preferably a hydrogen atom.
  • 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 cyclopropyl, 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.
  • 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 preferably O, S or NR 8 , more preferably O.
  • W is a divalent C 1 -C 8 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 are independently 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 O are not hydroxyl groups or do not together form an oxo group).
  • Y is preferably bonded on the carbon atom at the 3- or 5-position of the pyrazole ring
  • R 1 is preferably bonded on the carbon atom at the 3-, 4- or 5-position of the pyrazole ring, more preferably on the carbon atom at the 3- or 5-position.
  • R 1 may be -V k -W l -Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z in addition to the one mentioned above.
  • -V k -W l -Z may, for example, be -O-W-Z or -W-Z.
  • the above -O-W- may, for example, be
  • -W- may, for example, be
  • -V-W-V-W-Z may, for example, be -O-W-V-W-Z. More preferably, it may, for example, be
  • -W-V-W-Z may, for example, be
  • -V-W-V-Z may, for example, be -O-W-V-Z. More preferably, it may, for example, be ,
  • -W-V may, for example, be
  • 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 1 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
  • 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 4 -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.
  • benzotriazolyl benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl, naphthyridinyl,
  • quinoxalinyl quinazolinyl, cinnolinyl, benzodioxanyl, oxonaphthalenyl, dihydrobenzofuranyl, benzothiazinyl, pteridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[5,1-c][1,2,4]triazinyl, thiazolo[3,2-b]triazolyl,
  • benzopyrano[2,3-b]pyridyl 5H-benzopyrano[2,3-b]pyridonyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or thianthrenyl, and said C 4 -C 8 heterocycloaliphatic group is piperidyl, pyrrolidinyl, imidazolidinyl,
  • heterocycloaliphatic groups may have at most 5
  • 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 8 saturated or C 2 -C 8 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 i is 0 or 1)
  • V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different),
  • V, W and Z are as defined above, and two W's may be the same or different
  • V, W and Z are as defined above, and two V's may be the same or different), or
  • 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, and 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 phenyl, ⁇ -naphthyl, ⁇ -naphthyl, furanyl, thienyl, imidazolyl, pyridyl or
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 8 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group or a pyridyl group, when it is on the nitrogen atom at the 1-position of the pyrazole ring; and
  • R 2 or R 3 is a hydrogen atom, a C 1 -C 4 alkyl group, a phenyl group or a halogen atom, when it is on the carbon atom at the 4-position of the pyrazole ring.
  • Y is CR 6 R 7 (R 6 is a hydrogen atom or a methyl group, and R 7 is a hydrogen atom, or forms a bond
  • R 1 is -V-W-Z, -W-Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-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 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
  • 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 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 5 is a hydrogen atom or a carboxymethyl group.
  • R 1 is -O-W-Z, wherein W is a divalent C 1 -C 6 saturated or C 2 -C 8 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C 1 -C 7 alkyl groups (provided that the first carbon atom bonded with the oxygen atom is not substituted with a hydroxyl group or an oxo group).
  • R 1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein V is O or NR 8 (R 8 is a hydrogen atom or a C 1 -C 3 alkyl group), W is a divalent C 1 -C 8 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 (provided that the first carbon atom bonded with the oxygen atom 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).
  • R 1 is -W-Z, wherein W is a divalent C 1 -C 8 saturated or C 2 -C 6 unsaturated hydrocarbon group which may be substituted with at most 2 hydroxyl, oxo and C 1 -C 7 alkyl groups.
  • R 1 is -O-W-Z, wherein W is
  • 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 O are not hydroxyl groups or do not together form an oxo group) .
  • R 1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein W is
  • R 1 is -W-Z, wherein W is
  • 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 -O-W-Z, wherein -O-W- is
  • R 1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein -O-W-V-W- is
  • R 1 is -W-Z, wherein W is (14)
  • R 1 is -O-W-Z, wherein -O-W- is
  • R 1 is -W-Z, wherein W is
  • R 4 is a hydrogen atom.
  • Y is CHR 7 (R 7 forms a bond together with R 4 );
  • R 4 forms a bond together with R 7 .
  • each of R a , R b and R c is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom)
  • R 2 is a hydrogen atom, a C 1 -C 7 alkyl group or a phenyl group
  • R 3 is a hydrogen atom or a C 1 -C 7 alkyl group
  • Y is CR 6 R 7 (R 6 is a hydrogen atom or a methyl group, and R 7 is a hydrogen atom, or forms a bond together with R 4 ), and R 4 is a hydrogen atom, or forms a bond together with R 7 .
  • each of R a , R b and R c is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R 2 is a hydrogen atom, a C 1 -C 7 alkyl group or a phenyl group.
  • each of R a , R b and R c is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom),
  • R 2 is a hydrogen atom, a C 1 -C 7 alkyl group or a phenyl group
  • R 3 is a hydrogen atom or a C 1 -C 7 alkyl group,
  • Y is CR 6 R 7 (R 6 is a hydrogen atom or a methyl group, and R 7 is a hydrogen atom, or forms a bond together with R 4 ), and R 4 is a hydrogen atom, or forms a bond together with R 7 .
  • each of R a , R b and R c is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom),
  • R 2 is a hydrogen atom, a C 1 -C 7 alkyl group or a phenyl group
  • R 3 is a hydrogen atom or a C 1 -C 7 alkyl group,
  • Y is CR 6 R 7 (R 6 is a hydrogen atom or a methyl group, and R 7 is a hydrogen atom, or forms a bond together with R 4 ), and R 4 is a hydrogen atom, or forms a bond together with R 7 .
  • each of R a , R b and R c is independently a hydrogen atom, a C 1 -C 7 alkyl group, a C 1 -C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom),
  • R 2 is a hydrogen atom, a C 1 -C 7 alkyl group or a phenyl group
  • R 3 is a hydrogen atom or a C 1 -C 7 alkyl group,
  • Y is CR 6 R 7 (R 6 is a hydrogen atom or a methyl group, and R 7 is a hydrogen atom, or forms a bond together with R 4 ), and R 4 is a hydrogen atom, or forms a bond together with R 7 .
  • Tables 1 to 23 illustrate examples of the compounds of the present invention. Further, the salts derived by treating a 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.
  • R 1 is as identified in the following Table.
  • R a , R b and R c are as identified in the following Table.
  • R a and R b are as identified in the following Table.
  • R a and R b are as identified in the following Table.
  • R a , R b and R c are as identified in the following
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 and W 9 are as identified in the following Table. wherein W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 and W 9 are as identified in the following Table.
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 and W 8 are as identified in the following Table.
  • 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. pyrazole 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
  • solvents are optionally selected depending on the reactivity of the aimed reaction, and are respectively used alone or in a mixture. In some cases, there are used as a non-aqueous solvent by using a dehydrating agent or a drying agent.
  • a dehydrating agent or a drying agent there are used as a non-aqueous solvent by using a dehydrating agent or a drying agent.
  • the above-mentioned solvents are merely examples which can be used in the reaction of the present invention, and the present invention is not limited to these conditions.
  • R 1 , R 2 , R 3 , R 6 , X 1 and X 2 are as defined above, and R 9 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 (VI).
  • the compound of the formula (VI) is a well known compound or can be synthesized by the method disclosed in "J.
  • 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,
  • inorganic alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium
  • This reaction can be accelerated by removing water formed during reaction out of the system by using an appropriate dehydrating agent such as molecular sieves and anhydrous sodium sulfate or by azeotropic
  • This reaction is conducted usually at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 20°C to 120°C, for from 0.5 to 30 hours.
  • R 1 , R 2 , R 3 and R 6 are as defined above, R 10 is C 1 -C 4 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, and Hal is a chlorine atom, a bromine atom or an iodine atom).
  • R 4 and R 7 are hydrogen, X 1 is S and X 2 is NH, i.e.
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base or acid.
  • Examples of the solvent used include alcohols,
  • cellosolves and aprotic polar organic solvents and preferably sulfolane is used.
  • This reaction is conducted usually at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 50°C to 150°C, for 0.5 to 10 hours.
  • Examples of the base thus used include organic amines (such as dimethylamine,
  • This reaction is conducted usually in water or an appropriate organic solvent, or in a mixture thereof.
  • Examples of the solvent thus used include alcohols, cellosolves and aprotic polar organic solvents.
  • This reaction is conducted usually at a temperature ranging from -10°C to 50°C, preferably from 0°C to 30°C, for 0.5 to 50 hours.
  • Examples of the base thus used include organic amines (such as dimethylamine,
  • the adduct thus obtained is treated with an acid (such as hydrochloric acid) to obtain a compound of the formula (I-2b).
  • an acid such as hydrochloric acid
  • This reaction is conducted usually in an appropriate organic solvent.
  • the solvent thus used include aprotic polar organic solvents.
  • This reaction is conducted usually at a temperature ranging from 50°C to 150°C, preferably from 80°C to 120°C, for 0.5 to 10 hours.
  • a compound of the formula (XIII) is isolated, or it is further subjected to acid treatment in the reaction system without being isolated therefrom to obtain the aimed compound of the formula (I-2a).
  • the acid thus used include hydrochloric acid, and the acid treatment is conducted in an alcohol or an aprotic polar organic solvent. This reaction is conducted at a temperature of from 50°C to 150°C, preferably from 70°C to 100°C, for 5 to 50 hours.
  • 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 (VI) can be obtained by reacting a compound of the formula (VI) with a halomethylpyrazole of the formula (IX).
  • the compound of the formula (VI) used herein is a well known compound or can be synthesized by a method disclosed in "Ukr. Khim. Zh.” (vol. 16, p. 545, 1950), “J. Med. Chem.” (vol. 34, p. 1538, 1991), "J.
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base.
  • the solvent thus used include aprotic polar organic solvents, ethers and alkoxyalkanes.
  • the base thus used include a strong base such as alkali metal amides (e.g. sodium amide and potassium amide). These materials are selected optionally depending on the reactivity of the aimed reaction.
  • 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 (VI) 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 a halomethylpyrazole of the formula (IX) 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 halomethylpyrazole takes from 0.5 to 5 hours.
  • an amide group at the 3-position of thiazolidine of the compound of the formula (1-2) thus obtained may be deprotected by a well-known method.
  • R 9 is Tr (trityl)
  • this method is conducted by using an organic acid such as trifluoroacetic acid and
  • 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.
  • a solvent such as ethers including tetrahydrofuran and dioxane and halogenated solvents including chloroform and dichloromethane
  • R 2 , R 3 , R 4 , R 9 , V, W, Y and Z are as defined above, and R 12 is an appropriate leaving group in
  • nucleophilic substitution reaction examples of which include a halogen such as chlorine, bromine and iodine, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy and
  • 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
  • such a compound can be obtained by halogenating Z-COCH-, (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.
  • Heterocycles, 26(3), p. 745 (1987) disclose a compound wherein Z is triazole) as a starting material by means of an appropriate well known halogenation method (e.g. a method disclosed in Japanese Unexamined Patent
  • W CH 2 CH 2
  • R 12 is a substituent explained above
  • Such a compound is well known and is commercially available, or can be obtained by a well known method, for example, by a method disclosed in J. Med. Chem., 1994, vol., 37, p3980.
  • a compound of the formula (I) can also be obtained by reacting a compound of the formula (XI) with a hydroxyl group, a thiol group or an amino group of a compound of the formula (X) by nucleophilic substitution reaction.
  • the compound of the formula (X) is preferably protected by substituting hydrogen of R 9 with an appropriate substituent (e.g. 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.
  • R 2 , R 3 , R 6 , R 12 , V, W and Z are as defined above, and R 13 is a C 1 -C 7 alkyl group, or a benzyl group which may be substituted by a methoxy group or an ethoxy group).
  • the carboxylic acid ester group of the compound (IV) is reduced to obtain a compound of the formula (III).
  • the compound (III) can be converted to a compound of the formula (II) by oxidizing its
  • a compound wherein VH is a hydroxyl group can be prepared by methods disclosed in, for example, Chem.
  • pyrazole carboxylic acid esters of the formula (V) a compound wherein VH is a thiol group, can be obtained, for example, by preparing a pyrazolesulfonyl halide using a pyrazolesulfonic acid disclosed in e.g. J. Org. Chem., vol.
  • V pyrazole carboxylic acid esters of the formula (V)
  • German Laid Open Patent Application No. 2838029 Japanese Unexamined Patent Publication No. 65089/1984, J. Org. Chem., vol. 54(2), P428(1989), Chem. Pharm. Bull., vol. 35(8), P3235 (1987) and the like
  • the step for preparing the compound of the formula (IV) is usually carried out in the same manner under the same condition as described in Process 6.
  • the step for preparing the compound of the formula (III) is carried out by using a conventional appropriate reducing agent (for example, a metal hydrogen complex compound such as LAH: lithium aluminum hydride, SAH:
  • a metal hydrogen complex compound such as LAH: lithium aluminum hydride, SAH:
  • Red-Al bis( 2-methoxyethoxy)aluminum sodium hydride
  • SBH sodium boron hydride or LBH: lithium boron hydride
  • DIBAH a metal hydride compound such as DIBAH:
  • the compound of the formula (III) can be obtained also by subjecting a hydroxymethylpyrazole derivative of the formula (XVIII) wherein R 2 , R 3 , R 6 and V are as defined above, to nucleophilic substitution with a compound of the formula (XI).
  • the compound of the formula (XIII) can be prepared also by the method
  • the step of preparing the compound of the formula (II) can be conducted by using an appropriate oxidizing agent (such as manganese dioxide, PCC: pyridinium
  • This step can be conducted by a method using
  • R 1 , R 2 , R 3 , R 6 , R 10 and Hal are as defined above, and R 11 represents OR 10 (R 10 is as defined above) or C 1 -C 3 alkyl such as methyl, ethyl, n-propyl and i-propyl).
  • a halocarboxylic acid ester of the formula (VII) can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a malonic acid ester or a lower acylacetic acid ester by a known method to form a
  • the halomethylpyrazole of the formula (XVI) can be obtained also by halogenating a hydroxymethylpyrazole derivative of the formula (XIII) wherein R 2 , R 3 , R 6 and V are as defined above, by a conventional method, for example by using e.g. SOCl 2 , POCl 3 , PCl 5 , HCl , SnCl 4 , HBr, PBr 3 , Br 2 , POBr 3 , mecylchloride or tosylchloride.
  • a compound wherein R 11 is C 1 -C 3 alkyl can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a lower acylacetic acid ester such as methyl acetoacetate and ethyl acetoacetate in the presence of an appropriate base (such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide,
  • an appropriate base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide
  • a compound wherein R 11 is OR 10 can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a malonic acid ester such as diethyl malonate and di-t-butyl malonate in the presence of an appropriate base as mentioned above, in accordance with such a method as described in "J. Amer. Chem. Soc, vol. 74, p. 831
  • the step of synthesizing a compound of the formula (VII) can be conducted by using an appropriate
  • halogenating agent such as bromine and N-chlorosuccinimide
  • an appropriate base such as potassium hydroxide, sodium methoxide and potassium carbonate
  • a compound of the formula (VII) can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a diazoacetic acid ester in the presence of a copper catalyst in accordance with such a method as described in "Zur. Russ. Fiz-Chim., vol. 21, p. 851 (1951)".
  • R 2 , R 3 , R 9 , R 13 , Hal and V are as defined above, Y is CR 6 R 7 (R 6 is hydrogen atom, and R 7 forms a bond together with R 4 ), and R 14 is a protecting group for the V-H substituent on the pyrazole ring).
  • An intermediate of the formula (X) can be prepared also by the following method. Namely, V-H of a compound of the formula (V) is protected by an appropriate
  • the compound (XII-1) or the compound (XII-2) can be converted to a compound (X-1) or a compound (X-2), respectively.
  • the compound (X-1) or the compound (X-2) can be converted to a compound (1-1) or a compound (1-2), respectively, by introducing a -W-V-W-Z group to the V-H group on the respective pyrazole ring by nucleophilic substitution with a compound (XI).
  • the compound of the formula (XV) can be obtained by protecting the V-H group of a pyrazole carboxylic acid ester derivative of the formula (V) wherein R 2 , R 3 , R 13 and V are as defined above, with an appropriate
  • protecting group R 14 As such a protecting group, the one which is stable under the reaction conditions of the subsequent steps, is preferred.
  • 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 or SEM:
  • t-butyldimethylsilyl preferably t-butyldimethylsilyl
  • a trialkylarylsilyl group such as DPMS: diphenylmethylsilyl, TBDPS: t-butyldiphenylsilyl, TBMPS: t-butyldimethoxyphenylsilyl, or TPS: triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TBDPS t-butyldiphenylsilyl
  • TBMPS t-butyldimethoxyphenylsilyl
  • TPS triphenylsilyl
  • an alkoxyalkyl group such as MOM: a
  • MEM methoxyethoxymethyl group
  • MEM methoxyethoxymethyl group
  • a substituted silyl group such as TBDMS: a t- butyldimethylsilyl group, may, for example, be mentioned.
  • Particularly preferred is a methoxymethyl group.
  • reaction can be conducted in accordance with the method disclosed e.g. by T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis” (1991).
  • R 14 is a methoxymethyl group
  • the reaction can be conducted at room temperature by using e.g.
  • the compound (XV) thus obtained is subjected to reduction of the ester group in the same method as in the step for producing a compound (II) from a compound (IV) as disclosed in Process 7, to obtain a compound (XIV), which is further oxidized to obtain a compound (XIII).
  • the step for preparing the compound of the formula (XII-1) is a step of dehydrating and condensing the compound (XIII) and a thiazolidine derivative of the formula (VI) wherein X 1 is S, X 2 is O, and R 9 is a
  • the compound (XII-1) thus obtained can be converted to a compound (XII-2) by reducing the olefin bond portion under an appropriate reducing condition.
  • Such a method will be described in detail in the paragraph relating to mutual conversion of a partial structure of the compound
  • the compound (XII) can be converted to a compound (X) by removing the protecting group R 14 for the V-H group.
  • Such a reaction can be conducted in accordance with e.g. the method disclosed by T.W. Greene, P.G.M. Wuts in
  • R 14 is an alkoxyalkyl group such as MOM: a methoxymethyl group or MEM: a methoxyethoxymethyl group
  • the reaction can be conducted within a temperature range of from room temperature to the boiling point of the solvent in methanol, ethanol or tetrahydrofuran by means of an inorganic acid such as hydrochloric acid or
  • reaction can be conducted within a temperature range of from -78°C to the boiling point of the solvent used, in
  • the substituent R 9 on the thiazolidine ring is a hydrogen atom, such acidic proton may be protected by means of an appropriate protecting group.
  • the protecting group is preferably the one which is stable even in the nucleophilic substitution reaction of the V-H group as described in Process 6.
  • a C 1 -C 4 alkoxymethyl group such as MOM: methoxymethyl
  • a substituted silyl group such as TBDMS: t-butyldimethylsilyl
  • an arylmethyl group such as Tr:
  • trityl DMTr : Di(4-methoxyphenyl)phenylmethyl, or DAM: di(4-methoxyphenyl)methyl
  • an aryloxycarbonyl group such as Z: benzyloxycarbonyl
  • a C 1 -C 4 alkoxycarbonyl group such as BOC: t-butoxycarbonyl
  • Preferred may, for example, be trityl or
  • Such a protecting group may be introduced or removed in accordance with e.g. the methods disclosed by T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis” (1991).
  • the reactions may be conducted under such conditions as follows: MOM:
  • TBDMS t-butyldimethylsilyl (introduction: t-butyldimethylsilyl chloride; removal: tetrabutylammonium fluoride), Tr: trityl (introduction: trityl chloride, triethylamine; removal: hydrochloric acid or
  • pyrazole ring and a thiazolidine or oxazolidine ring for example by catalytic hydrogenation in the presence of an appropriate catalyst, by using an appropriate metalhydrogen complex compound, or by using magnesium or sodium amalgam in a lower alcohol such as methanol).
  • the catalytic hydrogenation is conducted usually in alcohols, cellosolves, aprotic polar organic solvents, ethers, alkoxyalkanes, lower aliphatic acid esters or lower aliphatic acids, and particularly methanol,
  • tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or acetic acid is preferably used alone or in a mixture.
  • the catalyst used include palladium black, palladium carbon and platinum oxide. This reaction can proceed at normal temperature under normal pressure, but it is preferable to conduct the reaction at an elevated temperature under a increased pressure depending on the reactivity of the aimed reaction.
  • the reduction by a metal-hydrogen complex compound is conducted by using sodium borohydride, potassium
  • borohydride lithium borohydride, tetramethyl ammonium borohydride or zinc borohydride in an aprotic polar organic solvent at a temperature ranging from 0°C to 150°C, preferably from 0°C to 30°C.
  • a Co reagent such as CoCl 2 , CoCl 3 or Co(OAc) 2 in the presence of a ligand such as dimethyl glyoxime, 2,2'-bipyridyl or 1,10-phenanthroline (see WO93/13095).
  • the reduction can be conducted usually in an alcohol, preferably in methanol or ethanol, within a temperature range of from -20°C to the boiling point of the solvent, preferably from 0°C to 50°C. Further, the reduction method by
  • alkylating agent such as alkyl halide including methyl iodide or ethyl iodide, alkyl sulfate including dimethyl sulfate or diethyl sulfate, and aliphatic or aromatic sulfonic acid esters including methyl tosylate or methyl mesylate
  • alkylating agent such as alkyl halide including methyl iodide or ethyl iodide, alkyl sulfate including dimethyl sulfate or diethyl sulfate, and aliphatic or aromatic sulfonic acid esters including methyl tosylate or methyl mesylate
  • This reaction is conducted usually in an appropriate organic solvent in the presence of base.
  • the solvent thus used include aprotic polar organic solvents, ethers, alkoxyalkanes and the like, and among them, tetrahydrofuran and dimethoxyethane are particularly preferable.
  • the base include alkali metal amides (such as lithium diisopropylamide (LDA) and potassium amide) and aliphatic or aromatic lithium compounds (such as n-butyl lithium, t-butyl lithium and phenyl lithium). These materials are selected
  • This reaction is conducted usually at a temperature ranging from -20°C to 100°C, preferably from -10°C to 30°C, for from 0.1 to 10 hours.
  • This reaction is conducted usually in an appropriate organic solvent in the presence of water or acid.
  • solvent examples include alcohols, cellosolves, aprotic polar organic solvents, ethers, alkoxyalkanes, and the like, and particularly methanol, ethanol, methoxyethanol, sulfolane, dioxane and
  • dimethoxyethane are preferably used.
  • the acid thus used include inorganic acids (such as
  • hydrochloric acid sulfuric acid and hydrobromic acid. These materials are selected appropriately depending on the reactivity of the aimed reaction.
  • This reaction is conducted usually at a temperature of from 50°C to a boiling point of a solvent used, preferably from 80°C to 150°C, for from 0.5 to 30 hours.
  • This reaction is conducted by using an appropriate oxidizing agent (such as hydrogen peroxide, an organic peroxide including peracetic acid, perbenzoic acid, methachloroperbenzoic acid, monopermaleic acid,
  • an appropriate oxidizing agent such as hydrogen peroxide, an organic peroxide including peracetic acid, perbenzoic acid, methachloroperbenzoic acid, monopermaleic acid,
  • monoperphthalic acid and the like, mercury ion, bromine, chlorine and meta-periodic acid generally in water or in a solvent such as aprotic polar organic solvents (e.g. dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylurea, sulfolane and N,N-dimethylimidazolidinone), ethers (e.g. tetrahydrofuran and dioxane), and alkoxyalkanes (e.g. dimethoxyethane and diethoxyethane).
  • aprotic polar organic solvents e.g. dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylurea, sulfolane and N,N-dimethylimidazolidinone
  • ethers e.g. tetrahydrofuran and dioxane
  • alkoxyalkanes e.g. dimethoxyethane
  • This reaction is conducted generally at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 20°C to 100°C, for from 0.5 to 30 hours.
  • This compound was obtained also by the manganese dioxide oxidation method and the PCC oxidation method shown in Step 3 in Example 1.
  • XII-2-1 was obtained as pale yellow powder by using 144 mg (0.533 mmol) of 5-((5-methoxmethoxy-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. XII-1-1) and 129 mg of 10% palladium carbon,
  • mice Around 40 g-weighted mice were examined.
  • Blood (20 ⁇ e) 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
  • hypoglycemic activity was expressed by the percentage of reducing blood glucose calculated before and 24 hours after the administration.
  • the compounds of the present invention exhibited hypoglycemic activities at substantially the same or higher degree as compared with CS-045 and CP-86325 used as controls. Glibenclamide (insulin-releasing agent) did not exhibit hypoglycemic activity in this test.
  • glycated protein is fluorescent, the amount of glycated protein can be determined using fluorescence, according to the previous reports (Doi et al., Proc.
  • BSA bovine serum albumin
  • DMSO dimethyl sulfoxide
  • the dialyzed solution was diluted in water 4 times and was determined the fluorescence (ex. 370 nm-em. 440 nm).
  • the protein concentration of the dialyzed solution (10 ⁇ L of which was diluted to 20 times with distilled water) was determined by Lowry-method and the fluorescence was expressed per mg protein. Control (100%) was positive control minus blank. Anti-glycation effect was
  • the compounds of the present invention exhibited anti-glycation activities stronger than aminoguanidine used as a control.
  • CS-045 and CP-86325 did not exhibit anti-glycation activities.
  • 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 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%. The effects of inhibitors were estimated as the concentration of test compounds required for 50% inhibition of enzyme activity
  • the compounds of the present invention exhibited stronger aldose-reductase inhibitory activities than sulindac, quercetin or alrestatin used as control.
  • 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, an anti-glycation activity 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

A pyrazole type thiazolidine compound of formula (I) and its salt, wherein X1 is S or O; X2 is S, O or NH; Y is CR6R7 (R6 is a hydrogen atom, a C¿1?-C7 alkyl group or a C3-C7 cycloalkyl group, and R?7¿ is a hydrogen atom, a C¿1?-C7 alkyl group or a C3-C7 cycloalkyl group, or forms a bond together with R?4); R1¿ is a C¿1?-C10 alkyl group, a C1-C10 alkoxy group, etc., or -Vk-W1-Z (Z is a C3-C10 cycloalkyl group, a C6-C14 aromatic group, a C4-C12 heterocyclic aromatic group, etc., V is O, S, SO, SO2 or NR?8 (R8¿ is a hydrogen atom or a C¿1?-C3 alkyl group), W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, and each of k and l is 0 or 1), -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z, or -W-V-Z (V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different); each of R?2 and R3¿ is independently a hydrogen atom, a C¿1?-C7 alkyl group, etc.; R?4¿ is a hydrogen atom or a C¿1?-C7 alkyl group, etc.; and R?5¿ is a hydrogen atom or a carboxymethyl group. The compound of formula (I) and its salt are useful for a preventive or curative agent for diabetes mellites and diabetic complications.

Description

DESCRIPTION
TITLE OF THE INVENTION PYRAZOLYLMETHYL-THIAZOLIDINES USEFUL AS HYPOGLYCEMIC AGENTS
TECHNICAL FIELD
The present invention relates to novel pyrazole type thiazolidines having a hypoglycemic effect and an antiglycation effect, which are useful in medical and
veterinary fields, particularly useful for preventing or treating diabetes mellitus and diabetic complications.
BACKGROUND ART
Heretofore, various sulfonylurea derivatives and biguanide derivatives have been widely used as oral hypoglycemic agents for lowering blood sugar values.
However, these agents had disadvantages of causing serious hypoglycemic coma and lactic acidosis revelation, and therefore every possible care must have been taken for practical use. "Chem. Pharm. Bull., vol. 30, p. 3563 (1982)", "J. Med. Chem., vol. 32, p. 421 (1989)", "J.
Med. Chem., vol. 34, p. 318 (1991)", "J. Med. Chem., vol. 33, p. 1418 (1990)", Japanese Unexamined Patent
Publication No. 64586/1980, and European Laid Open Patent Publications No. 177353, No. 283035, No. 283036, No.
332331, and 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. However, although these compounds have a function of effectively lowering a blood sugar value, 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 retinopathy, diabetic
neuropathy and the like.
Further, some compounds having a pyrazole methylene bonded to the 5-position of a thiazolidindione ring, have been known. For example, U.S. Patent 3,615,608 discloses N-ethylthiazolidindione derivatives, and Japanese
Unexamined Patent Publications No. 204640/1991 and No. 224749/1989 disclose N-sulfoethyl or N-carboxyethyl-thiazolidindione derivatives, as compounds useful for silver halide photographic materials. However, it has never been known that these compounds have a hypoglycemic effect.
On the other hand, non-enzymatic glycosylation of vital protein has been recently noted for causing various diseases accompanied by diabetes and arteriosclerosis. Generally, the reaction of reducing sugars with amino acids and proteins caused by heat treatment of foods or during storing foods is known as Maillard reaction. It was recognized in 1970' s that the Maillard reaction is actually caused in a living body, and this reaction is recently called as glycation (see "J. Biol. Chem., vol. 252, p. 2998 (1977)"). Also, it has been proved that glycation is exacerbated in such chronic hyperglycemic state as in diabetes, and it is presumed that the glycation becomes a trigger for causing various diabetic complications (see "New Eng. J. Med., vol. 314, p. 403( 1986)"). The process of glycation is not completely clear, but it is considered that various vital proteins are reacted with reducing sugars to non-enzymatically form Schiff base, and that this is crosslinked after causing Amadori rearrangement and is converted to fluorescent browning materials, i.e. AGE (advanced glycosylation end products). It was recognized in rat's diabetic cataract that glycation of crystalline of lens protein is exacerbated. Also, it is presumed that glycation of myelin protein causes diabetic neuropathy and that glycation of collagen and elastin present in connective tissue causes renal dysfunction-inducing thickening of renal glomerular basement membrane and atherosclerosis. Brownlee et al reported that the anti-glycation effect of aminoguanidine prevents formation of AGE protein on arterial walls of a rat suffering from diabetes, and the aminoguanidine becomes remarkable as an agent for preventing diseases including diabetes mellitus (see "Science, vol. 232, p. 1629 (1986)"). However, the above-mentioned function of aminoguanidine is not always sufficient, and an agent achieving an anti-glycation effect satisfactory for practical use has not been found yet .
On the other hand, aldose reductase (AR) 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.
Under these circumstances, 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 a compound having an anti-glycation effect and aldose-reductase inhibitory activities which were not exhibited by the above-mentioned known compounds. Thus, the present invention provides pyrazole type
thiazolidines capable of preventing or treating diabetes mellitus and diabetic complications.
DISCLOSURE OF THE INVENTION
The novel pyrazole type thiazolidine derivatives of the present invention are pyrazole type thiazolidines of the following formula (I) and their salts:
Figure imgf000007_0001
wherein X1 is S or O;
X2 is S, O or NH;
Y is CR6R7 (R6 is a hydrogen atom, a C1-C7 alkyl group or a C3-C7 cycloalkyl group, and R7 is a hydrogen atom, a C1-C7 alkyl group or a C3-C7 cycloalkyl group, or forms a bond together with R4);
R1 is a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a C2-C10 alkenyloxy group, a C1-C10 alkylthio group, a C1-C10 monoalkylamino group or a di-C1-C10 alkylamino group (each of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10
alkynyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C1-C10
alkylthio, C1-C10 monoalkylamino and di-C1-C10 alkylamino groups may be substituted with a hydroxyl group or a C1-C7 alkyl group), or
-Vk-Wl-Z (Z is a C3-C10 cycloalkyl group, a C3-C7 cycloalkenyl group, a C6-C14 aromatic group, a C4-C12 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 C4-C6 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 C3-C10
cycloalkyl, C3-C7 cycloalkenyl, C6-C14 aromatic, C4-C12 heterocyclic aromatic and C4-C6 heterocycloaliphatic groups may have at most 5 substituents selected from the group consisting of a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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 thiazolidindion-5-yl group and a
thiazolidindion-5-yl methyl group), V is O, S, SO, SO2 or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group),
W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, and
each of k and ℓ is 0 or 1),
-V-W-V-W-Z (V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different), -W-V-W-Z (V, W and Z are as defined above, and two W's may be the same or different),
-V-W-V-Z (V, W and Z are as defined above, and two V's may be the same or different), or
-W-V-Z (V, W and Z are as defined above);
each of R2 and R3 is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group (said C1-C7 alkyl and C3-C7 cycloalkyl groups may be substituted with a hydroxyl 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
substituted with at most 5 members selected from the group consisting of a hydroxyl group, a C1-C 7 alkyl group, a C1-C 7 alkoxy group and a halogen atom), and R2 or R3 may further be a halogen atom when it is bonded to a carbon atom at the 3-, 4- or 5-position of the pyrazole ring;
R4 is a hydrogen atom or a C1-C 7 alkyl group, or forms a bond together with R7; and
R5 is a hydrogen atom or a carboxymethyl group.
The substituents of the compound of the formula (I) of the present invention will be explained with reference to typical examples, but it should be understood that the scope of the present invention is by no means limited by these examples.
Each substituent in the formula (I) will be
specifically described hereinafter.
In the definition of R1:
The C1-C10 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, 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-heptyl, 2,4,4-trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n-heptyl, 3-ethyl-2,2-dimethyl-3-n-pentyl, 3,5,5-trimethyl- 1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1-n- octyl, and 3,7-dimethyl-3-n-octyl. Preferred is a C4-C10 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-heptyl, 2,4,4- trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n- heptyl, 3-ethyl-2,2-dimethyl-3-n-pentyl, 3,5,5-trimethyl- 1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1-n-octyl and 3,7-dimethyl-3-n-octyl. Each group may be substituted by a hydroxyl group or a C1-C7 alkyl group.
The C2-C10 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, 2,4-hexadienyl, 1-methyl-1-pentenyl, 1-heptenyl, 1-octenyl, 1-nonenyl and 1-decenyl.
Preferred is a C5-C10 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 C1-C 7 alkyl group.
The C2-C10 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. Preferred is a C5-C10 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 C1-C7 alkyl group.
The C1-C10 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 C4-C10 alkoxy group which includes, for example, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy,
hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy.
Each group may be substituted by a hydroxyl group or a C1-C7 alkyl group.
The C2-C10 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. Preferred is a C5-C10 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 C1-C7 alkyl group.
The C1-C10 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 C5-C10 alkylthio which includes, for example, pentylthio, hexylthio, heptylthio, octylthio, nonylthio and decylthio. Each group may be substituted by a hydroxyl group or a C1-C7 alkyl group.
The C1-C10 monoalkylamino group includes, for
example, methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino and decylamino. Preferred is a C5-C10 monoalkylamino group which includes, for example, pentylamino, hexylamino, heptylamino, octylamino, nonylamino and decylamino. Each group may be substituted by a hydroxyl group or a C1-C7 alkyl group.
The di-C1-C10 alkylamino group includes, for example, dimethylamino, diethylamino, di-n-propylamino, di-1-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. Preferred are, for example, 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 C1-C7 alkyl group.
In the definition of Z:
The C3-C10 cycloalkyl group includes, for example, cyclopropyl, 1-methyl-cyclopropyl, 2-methyl-cyclopropyl, 4-methyl-cyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl,
bicyclo[2.2.2]octyl, 1-adamantyl, and 2-adamantyl.
Preferred is a C6-C10 cycloalkyl group which includes, for example, cyclohexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 1-adamantyl and 2-adamantyl. Each group may have at most 5 substituents (the substituents may, for example, be a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
The C3-C7 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 have at most 5 substituents (said substituents may, for example, be a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
The C6-C14 aromatic group includes, for example, phenyl, naphthyl (said naphthyl includes α-naphthyl, and β-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). Preferred is a C6-C14 aromatic group which includes, for example, phenyl, naphthyl (said naphthyl includes α-naphthyl, and β- 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7
cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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 thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
The C4-C12 heterocyclic aromatic group includes, for example, 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-isoxazolyl), isothiazolyl (said 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), triazolyl (said triazolyl includes 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl , and 1, 2, 4-triazol-4-yl ) , triazolonyl ( said triazolonyl includes 1,2,4(2H,4H)-triazol-3-on-2-yl, 1,2,4-(2H,4H)-triazol-3-on-4-yl, 1,2,4(2H,4H)-triazol-3-on-5-yl, 1,2,4(1H,2H)-triazol-3-on-1-yl, 1,2,4(1H,2H)-triazol-3-on-2-yl, and 1,2,4(1H,2H)-triazol- 3-on-5-yl), tetrazolyl (said tetrazolyl includes 1- tetrazolyl, 2-tetrazolyl, and 5-tetrazolyl), pyranyl (said pyranyl includes 2-pyranyl, 3-pyranyl, and 4- pyranyl), pyridyl (said pyridyl includes 2-pyridyl, 3- pyridyl, and 4-pyridyl), pyridonyl (said 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, and 4-pyridon-3-yl), 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, 3(2H)-pyridazinon-6-yl, 4(1H)-pyridazinon-1-yl, 4(1H)-pyridazinon-3-yl, 4(1H)-pyridazinon-5-yl, and 4(1H)-pyridazinon-6-yl),
pyrimidinyl (said pyrimidinyl includes 2-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl), pyrimidinonyl (said 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-pyrazinyl, 2(1H)-pyrazin-1-yl, 2(1H)-pyrazin-3-yl, 2(1H)-pyrazin-5-yl, and 2(1H)-pyrazin-6-yl), triazinyl (said triazinyl includes 1,2,3-triazin-4-yl, 1,2,3-triazin-5- yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, and 1,2,4- triazin-6-yl), tetrazinyl (said tetrazinyl includes
1,2,3,4-tetrazin-5-yl, and 1,2,4,5-tetrazin-3-yl), indolyl (said indolyl includes 1-indolyl, 2-indolyl, 3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, and 7-indolyl), quinolyl (said quinolyl includes 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8-quinolyl), quinolonyl (said 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-yl, 4-quinolon-6-yl, 4-quinolon-7-yl, and 4-quinolon-8-yl), benzofuranyl (said benzofuranyl includes 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, and 7-benzofuranyl), benzothienyl (said benzothienyl includes 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, and 7-benzothienyl), isoquinolyl (said isoquinolyl includes 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, and 8-isoquinolyl), isoquinolonyl (said isoquinolonyl includes 1-isoquinolon-2-yl, 1-isoquinolon-3-yl, 1-isoquinolon-4-yl, 1-isoquinolon-5-yl, 1-isoquinolon-6-yl, 1-isoquinolon-7-yl, 1-isoquinolon-8-yl, 3-isoquinolon-2-yl, 3-isoquinolon-4-yl, 3-isoquinolon-5-yl, 3-isoquinolon-6-yl, 3-isoquinolon-7-yl, and 3-isoquinolon-8-yl), benzoxazolyl (said benzoxazolyl includes 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, and 7-benzoxazolyl), benzothiazolyl (said benzothiazolyl includes 2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, and 7-benzothiazolyl), benzopyrazolyl (said benzopyrazolyl includes 1-benzopyrazolyl, 2-benzopyrazolyl, 3- benzopyrazolyl, 4-benzopyrazolyl, 5-benzopyrazolyl, 6- benzopyrazolyl, and 7-benzopyrazolyl), benzimidazolyl (said benzimidazolyl includes 1-benzimidazolyl, 2- benzimidazolyl, 4-benzimidazolyl, and 5-benzimidazolyl), benzotriazolyl (said benzotriazolyl includes 1-benzotriazolyl, 4-benzotriazolyl, and 5-benzotriazolyl), benzopyranyl (said benzopyranyl includes 2-benzopyranyl, 3-benzopyranyl, 4-benzopyranyl, 5-benzopyranyl, 6-benzopyranyl, 7-benzopyranyl, and 8-benzopyranyl), indolizinyl (said indolizinyl includes 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, and 8-indolizinyl), purinyl (said purinyl includes 2-purinyl, 6-purinyl, 7-purinyl, and 8-purinyl), phthalazinyl (said phthalazinyl includes 1-phthalazinyl, 5-phthalazinyl, and 6-phthalazinyl), oxophthalazinyl (said oxophthalazinyl includes 1-oxophthalazin-2-yl, 1-oxophthalazin-4-yl, 1-oxophthalazin-5-yl, 1-oxophthalazin-6-yl, 1-oxophthalazin-7-yl, and 1-oxophthalazin-8-yl), naphthyridinyl (said naphthyridinyl includes 2-naphthyridinyl, 3-naphthyridinyl, and 4-naphthyridinyl), quinoxalinyl (said quinoxalinyl includes 2-quinoxalinyl, 5-quinoxalinyl, and 6-quinoxalinyl), quinazolinyl (said quinazolinyl includes 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, and 8-quinazolinyl), cinnolinyl (said cinnolinyl includes 3-cinnolinyl, 4-cinnolinyl, 5- cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, and 8-cinnolinyl), benzodioxanyl (said benzodioxanyl includes 1,4-benzodioxan-2-yl, 1,4-benzodioxan-5-yl, and 1,4-benzodioxan-6-yl), oxonaphthalenyl (said oxonaphthalenyl includes 1,4-oxonaphthalen-2-yl, 1,4-oxonaphthalen-5-yl, and 1,4-oxonaphthalen-6-yl), 2,3-dihydrobenzofuranyl (said 2,3-dihydrobenzofuranyl includes 2,3-dihydro-4-benzofuranyl, 2 ,3-dihydro-5-benzofuranyl, 2,3-dihydro-6-benzofuranyl, and 2,3-dihydro-7-benzofuranyl),
benzothiazinyl (said 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 (said pteridinyl includes 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, and 7-pteridinyl), pyrazolo[1,5-a]pyrimidinyl (said
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), pyrazolo[5,1-c][1,2,4]triazinyl (said pyrazolo[5,1-c][1,2,4]triazinyl includes pyrazolo[5,1-c][1,2,4]triazin-3-yl, pyrazolo[5,1-c][1,2,4]triazin-4-yl, pyrazolo[5,1- c][1,2,4]triazin-7-yl, and pyrazolo[5,1-c][1,2,4]triazin- 8-yl), thiazolo[3,2-b]triazolyl (said thiazolo[3,2- b]triazolyl includes thiazolo[3,2-b] triazol-2-yl, thiazolo[3,2-b]triazol-5-yl, and thiazolo[3,2-b] triazol- 6-yl), benzopyrano[2,3-b]pyridyl (said benzopyrano[2,3- b]pyridyl includes benzopyrano[2,3-b]pyridin-2-yl, benzopyrano[2,3-b]pyridin-3-yl, benzopyrano[2,3- b]pyridin-4-yl, benzopyranof 2, 3-b]pyridin-5-yl,
benzopyranof 2,3-b]pyridin-6-yl, benzopyrano[2,3- b]pyridin-7-yl, benzopyrano[2,3-b]pyridin-8-yl, and benzopyrano[2,3-b]pyridin-9-yl), 5H-benzopyrano[2,3- b]pyridonyl (said 5H-benzopyrano[2,3-b]pyridonyl includes 5H-benzopyrano[2,3-b]pyridin-5-on-2-yl, 5H- benzopyrano[2,3-b]pyridin-5-on-3-yl, 5H-benzopyrano[2,3- b]pyridin-5-on-4-yl, 5H-benzopyrano[2,3-b]pyridin-5-on-6-yl, 5H-benzopyrano[2,3-b]pyridin-5-on-7-yl, and 5H-benzopyrano[2,3-b]pyridin-5-on-8-yl), xanthenyl (said xanthenyl includes 1-xanthenyl, 2-xanthenyl, 3-xanthenyl, 4-xanthenyl, and 9-xanthenyl), phenoxathiinyl (said phenoxathiinyl includes 1-phenoxathiinyl, 2-phenoxathiinyl, 3-phenoxathiinyl, and 4-phenoxathiinyl), carbazolyl (said carbazolyl includes 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl, and 9-carbazolyl), acridinyl (said acridinyl includes 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, and 9-acridinyl), phenazinyl (said phenazinyl includes 1- phenazinyl, 2-phenazinyl, 3-phenazinyl, and 4- phenazinyl), phenothiazinyl (said phenothiazinyl includes 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4- phenothiazinyl, and 10-phenothiazinyl), phenoxazinyl (said phenoxazinyl includes 1-phenoxazinyl, 2- phenoxazinyl, 3-phenoxazinyl, 4-phenoxazinyl, and 10-phenoxazinyl), and thianthrenyl (said thianthrenyl includes 1-thianthrenyl, 2-thianthrenyl, 3-thianthrenyl, 4-thianthrenyl, 6-thianthrenyl, 7-thianthrenyl, 8- thianthrenyl, and 9-thianthrenyl). Preferred examples of the C4-C12 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-isoxazolyl), isothiazolyl (said
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-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl), pyrazinyl (said pyrazinyl includes 2-pyrazinyl), indolyl (said indolyl includes 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, and 7-indolyl), quinolyl (said quinolyl includes 2-quinolyl, 3-quinolyl, 4- quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8- quinolyl), benzoxazolyl (said benzoxazolyl includes 2- benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6- benzoxazolyl, and 7-benzoxazolyl), benzothiazolyl (said benzothiazolyl includes 2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, and 7-benzothiazolyl), benzimidazolyl (said benzimidazolyl includes 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, and 5-benzimidazolyl), phthalazinyl (said phthalazinyl includes 1-phthalazinyl, 5-phthalazinyl, and 6-phthalazinyl), quinoxalinyl (said quinoxalinyl includes 2-quinoxalinyl, 5-quinoxalinyl, and 6-quinoxalinyl), benzothiazinyl (said 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 (said 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), pyrazolo[5,1- c][1,2,4]triazinyl (said pyrazolo[5,1-c][1,2,4]triazinyl includes pyrazolo[5,1-c][1,2,4]triazin-3-yl,
pyrazolo[5,1-c][1,2,4]triazin-4-yl, pyrazolo[5,1- c][1,2,4]triazin-7-yl, and pyrazolo[5,1-c][1,2,4]triazin- 8-yl), thiazolo[3,2-b]triazolyl (said thiazolo[3,2- b]triazolyl includes thiazolo[3,2-b]triazol-2-yl, thiazolo[3,2-b]triazol-5-yl, and thiazolo[3,2-b]triazol- 6-yl), and benzopyrano[2,3-b]pyridyl (said
benzopyrano[2,3-b]pyridyl includes benzopyrano[2,3-b]pyridin-2-yl, benzopyrano[2,3-b]pyridin-3-yl,
benzopyrano[2,3-b]pyridin-4-yl, benzopyrano[2,3-b]pyridin-5-yl, benzopyrano[2,3-b]pyridin-6-yl,
benzopyrano[2,3-b]pyridin-7-yl, benzopyrano[2,3-b]pyridin-8-yl, and benzopyrano[2,3-b]pyridin-9-yl).
Each group may have at most 5 substituents (said
substituents may, for example, be a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7
cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7
cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
The C4-C6 heterocycloaliphatic group includes, for example, piperidyl (said piperidyl includes 1-piperidyl, 2-piperidyl, 3-piperidyl, and 4-piperidyl), pyrrolidinyl (said pyrrolidinyl includes 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), imidazolidinyl (said imidazolidinyl includes 1-imidazolidinyl, 2-imidazolidinyl, and 4-imidazolidinyl), pyrazolidinyl (said pyrazolidinyl includes 1-pyrazolidinyl, 3-pyrazolidinyl, and 4-pyrazolidinyl), morpholinyl (said morpholinyl includes 2-morpholinyl, 3-morpholinyl, and 4-morpholinyl), and tetrahydrofuranyl (said
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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group or a thiazolidindion-5-yl methyl group).
In the definitions of Ra, Rb and Rc:
The C1-C7 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
substituted with a hydroxyl group.
The C3-C7 cycloalkyl group includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, and bicyclo[3.1.1]hehptyl. Preferred are cyclopropyl and cyclohexyl. Each group may be substituted by a hydroxyl group.
The C3-C7 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 C1-C7 alkoxy group includes, for example,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy and heptyloxy.
The C1-C7 alkylthio group includes, for example, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-buthylthio, t-butylthio, pentylthio, hexylthio and heptylthio.
The naphthyl group includes an α-naphthyl group, a β-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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a nitro group and a dimethylamino group.
The C1-C3 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.
Each of R2 and R3 independently is a hydrogen atom, a C1-C7 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 C1-C7 alkyl group may be substituted with at most two hydroxyl groups, preferably one hydroxyl group), a C3-C7 cycloalkyl group (which may, for example, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl or
bicyclo[3.1.1]heptyl, preferably cyclopropyl or
cyclohexyl, and said C3-C7 cycloalkyl group may be substituted with at most 2 hydroxyl group, preferably one hydroxyl group), a naphthyl group (which may be an α- naphthyl group, or a β-naphthyl group), a benzyl group, a pyridyl group (which may, for example, be a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group, preferably a 2-pyridyl group), a pyrimidinyl group (which may, for example, be a 2-pyrimidinyl group, a 4-pyrimidinyl group or a 5-pyrimidinyl group), a 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, be 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 bezoxazolyl group (which may, for example, be a 2-benzoxalyl group, a 4-benzoxazolyl group, a 5-benzoxazolyl group, a 6-benzoxazolyl group or a 7-benzoxazolyl group, preferably a 2-benzoxazolyl group), a benzothiazolyl group (which may, for example, be a 2- benzothiazolyl group, a 4-benzothiazolyl group, a 5- benzothiazolyl group, a 6-benzothiazolyl group or a 7-benzothiazolyl group, preferably a 2-benzothiazolyl group), or a benzimidazolyl group (which may, for example, be a 1-benzimidazolyl group, a 2-benzimidazolyl group, a 4-benzimidazolyl group or a 5-benzimidazolyl group, preferably a 2-benzimidazolyl group).
The halogen atom in a case where R2 and R3 are bonded to a carbon atom at the 3-, 4- or 5-position of the pyrazole ring, may 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, more preferably a chlorine atom or a bromine atom.
When R2 or R3 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 C1-C7 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 C1-C7 alkoxy group includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i- butoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy and heptyloxy. 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.
R2 and R3 are preferably bonded on the nitrogen atom at the 1-position or on the carbon atom at the 4-position of the pyrazole ring. When R2 and R3 are bonded on the carbon atom at the 4-position of the pyrazole ring, each of R2 and R3 is more preferably hydrogen, methyl, ethyl, phenyl, fluorine, chlorine or bromine. When R2 and R3 are bonded on the nitrogen atom at the 1-position of the pyrazole ring, each of them is more preferably hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, α-naphthyl, β-naphthyl, 2-pyridyl or benzyl.
R4 is a hydrogen atom or a C1-C7 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 R7. It is preferably a hydrogen atom or a methyl group, or forms a bond together with R7. More preferably, it is a hydrogen atom, or forms a bond together with R7.
R5 is a hydrogen atom or a carboxymethyl group, preferably a hydrogen atom.
R6 is a hydrogen atom, a C1-C7 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 C3-C7 cycloalkyl group (which may, for example, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl). It is preferably a hydrogen atom or methyl, more preferably a hydrogen atom.
R7 is a hydrogen atom, a C1-C7 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 C3-C7 cycloalkyl group (which may, for example, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl), or forms a bond together with R4. It is preferably a hydrogen atom, or forms a bond together with R4.
X1 is S or O, preferably S.
X2 is S, O or NH, preferably O or S, more preferably O.
V is O, S, SO, SO2 or NR8 (R8 is a hydrogen atom or C1-C3 alkyl (which may, for example, be methyl, ethyl, n-propyl or i-propyl, preferably methyl)). It is preferably O, S or NR8, more preferably O.
W is a divalent C1-C8 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3, preferably at most 2, of hydroxyl, oxo and C1-C7 alkyl groups.
The C1-C7 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
Figure imgf000035_0001
wherein m is from 1 to 5, and each of Rd and Re is a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd,s together form a double bond, or adjacent Rd's and Re ' s together form a triple bond (provided that Rd and Re on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group).
Y is preferably bonded on the carbon atom at the 3- or 5-position of the pyrazole ring, and R1 is preferably bonded on the carbon atom at the 3-, 4- or 5-position of the pyrazole ring, more preferably on the carbon atom at the 3- or 5-position.
R1 may be -Vk-Wl-Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z in addition to the one mentioned above. -Vk-Wl-Z may, for example, be -O-W-Z or -W-Z. Preferably, the above -O-W- may, for example, be
—
Figure imgf000036_0001
More preferably, it may, for example, be
Figure imgf000036_0002
Preferably, -W- may, for example, be
*
Figure imgf000037_0001
More preferably, it may, for example, be
Figure imgf000038_0001
Preferably, -V-W-V-W-Z may, for example, be -O-W-V-W-Z. More preferably, it may, for example, be
Figure imgf000038_0002
Preferably, -W-V-W-Z may, for example, be
Figure imgf000039_0001
Preferably, -V-W-V-Z may, for example, be -O-W-V-Z. More preferably, it may, for example, be ,
Figure imgf000039_0002
Preferably, -W-V may, for example, be
Figure imgf000040_0001
In the present specification, "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.
Among these compounds, there is a compound having an asymmetric carbon atom at the 5-position of thiazolidine ring. The compound having the above formula (I) includes all of these optical isomers and their mixtures.
The following compounds (1) to (23) may be mentioned as preferred examples of the compound of the formula (I) of the present invention.
(1) The pyrazole type thiazolidine compound and its salt of the present invention, wherein the compound of the formula (I) is represented by the following formula (la):
Figure imgf000041_0001
wherein R1 is a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a C2-C10 alkenyloxy group, a C1-C10 alkylthio group, a C1- C10 monoalkylamino group or a di-C1-C10 alkylamino group (each of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10
alkynyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C1-C10
alkylthio, C1-C10 monoalkylamino and di-C1-C10 alkylamino groups may be substituted with a hydroxyl group or a C1-C7 alkyl group), or
-Vk-Wl-Z (among groups of Z as defined for the formula (I), said C3-C10 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 C3-C7 cycloalkenyl group is cyclohexenyl,
cyclopentadienyl, 2-bicylo[2.2.1]heptenyl or 2,5-bicyclo[2.2.1]heptadienyl, said C6-C14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, said C4-C12 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, tetrazinyl, indolyl, quinolyl, quinolonyl, benzofuranyl, benzothienyl, isoquinolyl, isoquinolonyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl,
benzotriazolyl, benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxanyl, oxonaphthalenyl, dihydrobenzofuranyl, benzothiazinyl, pteridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[5,1-c][1,2,4]triazinyl, thiazolo[3,2-b]triazolyl,
benzopyrano[2,3-b]pyridyl, 5H-benzopyrano[2,3-b]pyridonyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or thianthrenyl, and said C4-C8 heterocycloaliphatic group is piperidyl, pyrrolidinyl, imidazolidinyl,
pyrazolidinyl, morpholinyl, or tetrahydrofuranyl, (each of said C3-C10 cycloalkyl, C3-C7 cycloalkenyl, C6-C14 aromatic, C4-C12 heterocyclic aromatic and C4-C6
heterocycloaliphatic groups may have at most 5
substituents selected from the group consisting of a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group and a thiazolidindion-5-yl methyl group),
V is O, S, SO, SO2 or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group),
W is a divalent C1-C8 saturated or C2-C8 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, and
each of k and i is 0 or 1),
-V-W-V-W-Z (V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different),
-W-V-W-Z (V, W and Z are as defined above, and two W's may be the same or different),
-V-W-V-Z (V, W and Z are as defined above, and two V's may be the same or different), or
-W-V-Z (V, W and Z are as defined above); (2) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (1), wherein the compound of the formula (la) is represented by the formula (lb):
Figure imgf000044_0001
(3) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (2), wherein R1 is -V-W-Z, -W-Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z (V is O, S or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C8 saturated or C2-C6
unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, when two V's or W's are present, such V's or W's may be the same or different, and Z is
Figure imgf000045_0001
Figure imgf000046_0001
wherein each of Ra and Rb is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3- C7 cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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 thiazolidindion-5-yl methyl group, and Rc is a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group or a hydroxymethyl group);
R2 or R3 is a hydrogen atom, a C1-C4 alkyl group, a C3-C8 cycloalkyl group, a phenyl group, a naphthyl group, a benzyl group or a pyridyl group, when it is on the nitrogen atom at the 1-position of the pyrazole ring; and
R2 or R3 is a hydrogen atom, a C 1-C4 alkyl group, a phenyl group or a halogen atom, when it is on the carbon atom at the 4-position of the pyrazole ring.
(4) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (3), wherein said compound is represented by the formula:
Figure imgf000048_0001
wherein Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond
together with R4);
R1 is -V-W-Z, -W-Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z (V is O, S or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, when two V's or W's are present, such V's or W's may be the same or different, and Z is
Figure imgf000049_0001
wherein each Ra and Rb is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a phenoxy group, a benzyloxy group, a phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5
substituents selected from the group consisting of a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 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 Rc is a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group or a hydroxymethyl group);
R4 is a hydrogen atom or a methyl group, or forms a bond together with R7;
R5 is a hydrogen atom or a carboxymethyl group.
(5) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (4), wherein:
R1 is -O-W-Z, wherein W is a divalent C1-C6 saturated or C2-C8 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C1-C7 alkyl groups (provided that the first carbon atom bonded with the oxygen atom is not substituted with a hydroxyl group or an oxo group).
(6) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (4), wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein V is O or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C8 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C1-C7 alkyl groups (provided that the first carbon atom bonded with the oxygen atom 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).
(7) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (4), wherein:
R1 is -W-Z, wherein W is a divalent C1-C8 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 2 hydroxyl, oxo and C1-C7 alkyl groups.
(8) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (5), wherein:
R1 is -O-W-Z, wherein W is
Figure imgf000052_0002
wherein m is from 1 to 5, and each of Rd and Re is independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent Rd's and Re's together form a triple bond (provided that Rd and Re on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group) .
(9) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (6), wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein W is
Figure imgf000052_0001
wherein m is from 1 to 5, and each of Rd and Re is independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent Rd's and Re's together form a triple bond (provided that Rd and Re on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group). (10) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (7), wherein:
R1 is -W-Z, wherein W is
Figure imgf000053_0001
wherein m is from 1 to 5, each of Rd and Re is
independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent
Rd's and Re's together form a triple bond.
(11) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (8), wherein:
R1 is -O-W-Z, wherein -O-W- is
Figure imgf000054_0001
(12) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (9), wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein -O-W-V-W- is
Figure imgf000055_0001
-W-V-W- is
Figure imgf000055_0002
-O-W-V- is
Figure imgf000056_0001
and -W-V- is
,
Figure imgf000056_0002
(13) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (10), wherein:
R1 is -W-Z, wherein W is
Figure imgf000057_0001
(14) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (11), wherein:
R1 is -O-W-Z, wherein -O-W- is
Figure imgf000058_0002
(15) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (13), wherein:
R1 is -W-Z, wherein W is
Figure imgf000058_0001
(16) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (5), (6) or (7), wherein:
Y is -CH2-; and
R4 is a hydrogen atom.
(17) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (5), (6) or (7), wherein:
Y is CHR7 (R7 forms a bond together with R4); and
R4 forms a bond together with R7.
(18) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000059_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C 7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C 7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
(19) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000059_0002
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom) , R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
(20) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000060_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group. is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
(21) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000061_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
(22) The pyrazole type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000062_0002
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C 7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
(23) The pyrazole. type thiazolidine compound and its salt according to the above-mentioned (14), which is represented by the formula:
Figure imgf000062_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C 7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
The following Tables 1 to 23 illustrate examples of the compounds of the present invention. Further, the salts derived by treating a 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.
In the Tables, Q1 to Q90 and J1 to J54 represent the following substituents:
Figure imgf000064_0001
Figure imgf000065_0001
M
Q
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000071_0002
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
wherein R1 is as identified in the following Table.
Figure imgf000077_0002
Figure imgf000077_0003
wherein Z is as identified in the following Table.
Figure imgf000078_0001
Figure imgf000078_0002
wherein Ra, Rb and Rc are as identified in the following Table.
Figure imgf000078_0003
Figure imgf000079_0001
wherein Ra and Rb are as identified in the following Table.
Figure imgf000079_0002
Figure imgf000079_0003
wherein Ra and Rb are as identified in the following Table.
Figure imgf000080_0001
Figure imgf000080_0002
wherein Ra, Rb and Rc are as identified in the following
Table.
Figure imgf000081_0001
Figure imgf000081_0002
wherein W1, W2, W3, W4, W5, W6, W7, W8 and W9 are as identified in the following Table.
Figure imgf000082_0001
Figure imgf000082_0002
wherein W1, W2, W3, W4 , W5, W6, W7, W8 and W9 are as identified in the following Table.
Figure imgf000082_0003
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000087_0002
wherein W1, W2, W3, W4, W5, W6, W7 and W8 are as identified in the following Table.
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0001
invention has acidic hydrogen on a thiazolidine ring or on an oxazolidine ring. Further, when substituent Z is a heterocyclic aromatic group or a heterocyclicaliphatic group, it sometimes has a basic nitrogen. Such a
compound may be converted to a pharmaceutically
acceptable non-toxic salt with an appropriate base or acid, if desired. 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. Examples of 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,
triethylamine salt, cyclohexylamine salt, ethylenediamine salt, bicyclohexylamine salt, ethanolamine 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. Examples of an acid-addition salt include a mineral acid salt (hydrochloride, hydrobromide, sulfate,
hydrogensulfate, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate and the like), an organic acid salt (formate, acetate, propionate, succinate, malonate, oxalate, maleate, fumarate, malate, citrate, tartrate, lactate, glutamate, asparate, picrate, carbonate and the like), a sulfonic acid salt (methanesulfonate,
benzenesulfonate, toluenesulfonate and the like), and the like. Each of these salts can be prepared by a known method.
The compound having the formula (I), i.e. pyrazole 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. Examples of 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,
dimethylsulfoxide, dimethylacetamide, tetramethylurea, sulfolane and N,N-dimethylimidazolidinone), 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), alkoxy alkanes (such as dimethoxyethane and diethoxyethane), acetonitrile, and the like. These solvents are optionally selected depending on the reactivity of the aimed reaction, and are respectively used alone or in a mixture. In some cases, there are used as a non-aqueous solvent by using a dehydrating agent or a drying agent. The above-mentioned solvents are merely examples which can be used in the reaction of the present invention, and the present invention is not limited to these conditions.
Process 1
Figure imgf000099_0001
(wherein R1, R2, R3, R6, X1 and X2 are as defined above, and R9 is a hydrogen atom or a protecting group of amide (such as Tr: trityl)). A compound wherein R4 and R7 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 (VI). The compound of the formula (VI) is a well known compound or can be synthesized by the method disclosed in "J.
Prakt. Chem." (vol. 2, p. 253, 1909), "J. Prakt. Chem." (vol. 3, p. 45, 1919), "Chem. Ber." (vol. 118, p. 774, 1985), and German Laid Open Patent Publication No. DE-3045059. The compound of the formula (VI) wherein R9 is hydrogen, can be used in this reaction after protecting its acidic amideproton at the 3-position of thiazolidine or oxazolidine with an appropriate substituent (such as TR: trityl) by a well known method.
This reaction is conducted usually in an appropriate organic solvent in the presence of base or acid.
Examples of such a solvent include alcohols, cellosolves, aprotic polar organic solvents, ethers, aromatic
hydrocarbons, halogenated hydrocarbons, alkoxyalkanes and acetonitrile.
Examples of the base and the acid include organic amines (such as dimethylamine, diethylamine,
diisopropylamine, diisopropylethylamine, trimethylamine, triethylamine, piperidine, piperazine, pyrrolidine, morpholine, pyridine, methanolamine and ethanolamine), metal alkoxides (such as sodium methoxide, sodium
ethoxide and lithium isopropoxide), inorganic alkali metal salts (such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium
hydrogencarbonate, sodium hydride, sodium acetate and potassium acetate), organic acids (such as acetic acid, trichloroacetic acid and trifluoroacetic acid), inorganic acids (such as phosphoric acid), and the like. These materials are selected appropriately depending on the reactivity of the aimed reaction.
This reaction can be accelerated by removing water formed during reaction out of the system by using an appropriate dehydrating agent such as molecular sieves and anhydrous sodium sulfate or by azeotropic
distillation using Dean-Stark tube.
This reaction is conducted usually at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 20°C to 120°C, for from 0.5 to 30 hours. Process 2
Figure imgf000101_0001
(wherein R1, R2, R3 and R6 are as defined above, R10 is C1-C4 alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, and Hal is a chlorine atom, a bromine atom or an iodine atom). A compound of the formula (I) wherein R4 and R7 are hydrogen, X1 is S and X2 is NH, i.e. a compound of the formula (I-2e) (R4, R7=H, XX=S, X2=NH), can be obtained by reacting thiourea with a halocarboxylic acid ester of the formula (VII).
This reaction is conducted usually in an appropriate organic solvent in the presence of base or acid.
Examples of the solvent used include alcohols,
cellosolves and aprotic polar organic solvents, and preferably sulfolane is used.
This reaction is conducted usually at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 50°C to 150°C, for 0.5 to 10 hours.
During the reaction, hydrogen halide is by-produced, but can be captured with an appropriate base to
accelerate the reaction. Examples of the base thus used 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.
Process 3
Figure imgf000102_0001
(wherein R1, R2, R3, R6, R10 and Hal are as defined above).
A compound of the formula (I) wherein R4 and R7 are H, and X1 and X2 are S, i.e. a compound of the formula (I-2b) (R4, R7=H, X1, X2=S), can be obtained by reacting ammonium dithiocarbamate with a halocarboxylic acid ester of the formula (VII) and by treating the compound with acid.
This reaction is conducted usually in water or an appropriate organic solvent, or in a mixture thereof.
Examples of the solvent thus used include alcohols, cellosolves and aprotic polar organic solvents.
This reaction is conducted usually at a temperature ranging from -10°C to 50°C, preferably from 0°C to 30°C, for 0.5 to 50 hours.
During this reaction, hydrogen halide is by-produced, but can be captured with an appropriate base to
accelerate the reaction. Examples of the base thus used 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 potassium carbonate, sodium carbonate, sodium acetate and potassium acetate), and the like.
The adduct thus obtained is treated with an acid (such as hydrochloric acid) to obtain a compound of the formula (I-2b).
Process 4
Figure imgf000104_0001
( wherein R1 , R" R3 , Rc R 10 and Hal are as defined above).
A compound of the formula (I) wherein R4 and R7 are H, X1 is S and X2 is O, i.e. a compound of the formula (I-2a) (R4, R7=H, X1=S, X2=O), can be obtained by reacting an alkalithiocyanate (such as potassium
thiocyanate or sodium thiocyanate) with a halocarboxylic acid ester of the formula (VII) to prepare a compound of the formula (XIII) and by treating the compound with an acid.
This reaction is conducted usually in an appropriate organic solvent. Examples of the solvent thus used include aprotic polar organic solvents.
This reaction is conducted usually at a temperature ranging from 50°C to 150°C, preferably from 80°C to 120°C, for 0.5 to 10 hours.
A compound of the formula (XIII) is isolated, or it is further subjected to acid treatment in the reaction system without being isolated therefrom to obtain the aimed compound of the formula (I-2a). Examples of the acid thus used include hydrochloric acid, and the acid treatment is conducted in an alcohol or an aprotic polar organic solvent. This reaction is conducted at a temperature of from 50°C to 150°C, preferably from 70°C to 100°C, for 5 to 50 hours.
Process 5
Figure imgf000105_0001
)
(wherein R1, R2, R3, R4, R6, R7, R9, X1, X2 and Hal are as defined above).
A compound of the formula (I) other than the one wherein R4 and R7 together form a bond, i.e. a compound of the formula (1-2), can be obtained by reacting a compound of the formula (VI) with a halomethylpyrazole of the formula (IX). The compound of the formula (VI) used herein is a well known compound or can be synthesized by a method disclosed in "Ukr. Khim. Zh." (vol. 16, p. 545, 1950), "J. Med. Chem." (vol. 34, p. 1538, 1991), "J.
Prakt. Chem." (vol. 2, 79, P. 259 (1909), "J. Prakt.
Chem." (vol. 2, 99, P. 56 (1919) or Japanese Unexamined Patent Publication No. 216882/1984. The compound of the formula (VI) wherein R9 is hydrogen, is used in this reaction preferably after protecting its acidic amide proton with an appropriate substituent (such as Tr :
trityl) by a known method.
This reaction is conducted usually in an appropriate organic solvent in the presence of base. Examples of the solvent thus used include aprotic polar organic solvents, ethers and alkoxyalkanes. Examples of the base thus used include a strong base such as alkali metal amides (e.g. sodium amide and potassium amide). These materials are selected optionally depending on the reactivity of the aimed reaction.
Also, 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). In such a case, a compound of the formula (VI) 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 a halomethylpyrazole of the formula (IX) 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 halomethylpyrazole takes from 0.5 to 5 hours.
In some cases, an amide group at the 3-position of thiazolidine of the compound of the formula (1-2) thus obtained may be deprotected by a well-known method. When R9 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. Process 6
Figure imgf000108_0001
(wherein R2, R3, R4, R9, V, W, Y and Z are as defined above, and R12 is an appropriate leaving group in
nucleophilic substitution reaction, examples of which include a halogen such as chlorine, bromine and iodine, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy and
methanesulfonyloxy).
Among compounds of formula (I), a compound wherein R1 is -V-W-Z and W is COCH2, can be obtained by using a compound of Z-COCH2-Hal (W=COCH2, R12=Hal, Z and Hal are substituents explained above) instead of the formula (XI). Such 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). Also, such a compound can be obtained by halogenating Z-COCH-, (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. Pharm., 316(7), p. 608 (1983)" and "Synlett., (7), p. 483 (1991)" disclose a compound wherein Z is pyrazole, "J. Heterocyclic Chem., 17(8), p. 1723 (1980)" discloses a compound wherein Z is imidazole, and "J. Chem. Soc. C(20), p. 2005 (1976)" and
"Heterocycles, 26(3), p. 745 (1987)" disclose a compound wherein Z is triazole) as a starting material by means of an appropriate well known halogenation method (e.g. a method disclosed in Japanese Unexamined Patent
Publication No. 85372/1986). Also, such a compound can be obtained by subjecting Z-CO2R' (R'=lower alkyl or substituted or unsubstituted benzyl) (for example, "Z. Chem., 9(1), p. 22 (1969)" and "Synth. Commun., 20(16), p. 2537 (1990)" disclose a compound wherein Z is
thiophene, "J. Org. Chem., 55(15), p. 4735 (1990)" and "Chem. Pharm. Bull., 17(3), p. 582 (1969)" disclose a compound wherein Z is pyrrole, European Laid Open Patent Publication No. 506194 discloses a compound wherein Z is imidazole, and "Chem. Ber., 117(3), p. 1194 (1984)" discloses a compound wherein Z is pyrazole or triazole) as a starting material to an appropriate well known reduction-oxidation reaction (for example, reduction by diisobutyl aluminum hydride and then oxidation by
manganese dioxide) to obtain Z-CHO, and further by converting the product thus obtained to Z-COCH2-hal by an appropriate method (e.g. a method disclosed in
"Tetrahedron Letters, p. 4661 (1972)").
Among compounds of formula (I), a compound wherein R1 is -O-W-N(R8)-Z and W is CH2CH2, can be obtained by using a compound of Z-N(R8)-CH2CH2-R12 (W=CH2CH2, R12 is a substituent explained above) among the compounds of the formula (XI). Such a compound is well known and is commercially available, or can be obtained by a well known method, for example, by a method disclosed in J. Med. Chem., 1994, vol., 37, p3980.
A compound of the formula (I) can also be obtained by reacting a compound of the formula (XI) with a hydroxyl group, a thiol group or an amino group of a compound of the formula (X) by nucleophilic substitution reaction. The compound of the formula (X) is preferably protected by substituting hydrogen of R9 with an appropriate substituent (e.g. Tr: trityl).
This reaction is usually conducted in an appropriate organic solvent in the presence of base. Examples of the 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,
pyridine, methanolamine and ethanolamine), Acid Captor H: 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one and 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
hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, sodium acetate and potassium acetate), and alkali metal amides (such as sodium amide). These materials are selected appropriately depending on the reactivity of the aimed reaction.
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.
Among compounds thus obtained, the one having a protecting group on the thiazolidine ring, as represented by the formula (XVIII) can be led to a compound of the formula (I) either in accordance with the method
disclosed by T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis" (1991) or deprotecting the amide group at the 3-position of the thiazolidine ring by the method described in Process 5.
Now, processes for producing intermediates useful for the preparation of the compounds of the present invention will be described.
Process 7
Figure imgf000112_0001
- Ill
Figure imgf000113_0001
(wherein R2, R3, R6, R12, V, W and Z are as defined above, and R13 is a C1-C7 alkyl group, or a benzyl group which may be substituted by a methoxy group or an ethoxy group).
A compound of the formula (II) wherein R6 is
hydrogen, can be prepared by using a pyrazole carboxylic acid ester of the formula (V) as a starting material.
Namely, a hydroxyl group, a thiol group or an amino group directly bonded to the pyrazole of the compound (V) (VH, V=O, S, NR8) is subjected to nucleophilic substitution with a compound of the formula (XI) to obtain a compound of the formula (IV). The carboxylic acid ester group of the compound (IV) is reduced to obtain a compound of the formula (III). The compound (III) can be converted to a compound of the formula (II) by oxidizing its
hydroxymethyl group.
Among pyrazole carboxylic acid esters of the formula (V), a compound wherein VH is a hydroxyl group can be prepared by methods disclosed in, for example, Chem.
Pharm. Bull., vol. 31(4), P1228 (1983) (R2=H, R3=H), Can. J. Chem., vol 55(1), pl45 (1977) (R2=H, R3=Ph), J. Heterocyclic Chem., vol 30(4), P1097 (1993), Japanese Unexamined Patent Publication No. 185964/1988, Chem.
Pharm. Bull., vol. 31(4), P1228 (1983), Chem. Ber., vol. 109(1), P253(1976) and the like (R2=1-Me, R3=H), German Laid Open Patent Application No. 2219484 (R2=1-Me,
R3=Me), German Laid Open Patent Application 2219484 (R2=1-Me, R3=CO, Chem. Ber., vol. 109(1), P261 (1976) (R2=1-Me, R3=Br), German Laid Open Patent Application 2928136 (R2=1-Ph, R3=H), Chem. Ber., vol. 112(5), P1712 (1979) (R2=1-CH2Ph, R3=H), Justus Liebigs Ann. Chem., vol., 757, P100 (1972) (R2=1-( 2-Py), R3=H), J. Chem.
Soc, Perkin Trans. 1, vol. (2), P297 (1974) (R2=1-(2-benzthiazolyl), R3=H), J. Chem. Soc, Perkin Trans. 1, vol. (2), P297 (1974) (R2=1-(2-benzimidazolyl), R3=H). Further, a compound represented by (R2=2-Me, R3=H) can be obtained by hydrolyzing, by a conventional method, a benzoyloxy compound obtained by the method disclosed in Chem. Ber., vol. 111(2), P780 (1978). Likewise, a compound represented by (R2=2-Et, R3=H) can be obtained by hydrolyzing, by a conventional method, an acetoxy compound obtained by the method disclosed in Chem. Ber., vol. 107(4), P1318 (1974). Similarly, a compound represented by (R2=2-Ph, R3=H) can be obtained by
hydrolyzing, by a conventional method, an acetoxy compound obtained by the method disclosed in e.g.
Yakugaku Zasshi, vol. 83, P725 (1963).
Further, a compound represented by (R2=2-Me, R3=Me) or (R2=2-Me, R3=Br) can also be prepared by subjecting a methoxypyrazole carboxylic acid amide derivative obtained by the method disclosed in European Patent Publication No. 394043 to methyl removal and hydrolysis of the amide group by appropriate conventional methods to obtain a pyrazole carboxylic acid, and esterifying the pyrazole carboxylic acid by means of a conventional method.
Among pyrazole carboxylic acid esters of the formula (V), a compound wherein VH is a thiol group, can be obtained, for example, by preparing a pyrazolesulfonyl halide using a pyrazolesulfonic acid disclosed in e.g. J. Org. Chem., vol. 28(12), P3433 (1963) (V=S, R2=H, R3=H) as a starting material and a conventional appropriate halogenating agent such as phosphorus pentachloride, phosphoryl chloride or chorosulfuric acid, and then reducing the pyrazolesulfonyl halide with an appropriate reducing agent such as zinc/hydrochloric acid, zinc amalgam, tin chloride, lithium aluminum hydride or diborane.
Among pyrazole carboxylic acid esters of the formula (V), a compound wherein VH is an amino group can be prepared in accordance with a method disclosed in e.g. Khim.-Farm. Zh., vol. 20(8), P947 (1986) (V=NH, R2=H, R3=H), German Laid Open Patent Application No. 2838029, Japanese Unexamined Patent Publication No. 65089/1984, J. Org. Chem., vol. 54(2), P428(1989), Chem. Pharm. Bull., vol. 35(8), P3235 (1987) and the like (V=NH, R2=1-Me, R3=H), Japanese Unexamined Patent Publication No.
20955/1992 (V=NH, R2=1-Ph, R3=H) .
The step for preparing the compound of the formula (IV) is usually carried out in the same manner under the same condition as described in Process 6.
Further, among compounds of the formula (IV), a compound represented by (-V-Z=NHPh, R2=H, R3=H) can be prepared also in accordance with the method disclosed in Collect. Czech. Chem. Commun., vol. 57(3), P656 (1992). A compound represented by (-V-Z=SPh, R2=1-Ph, R3=H) can be prepared also by the method disclosed in Chem. Ber., vol. 112(4), P1193 (1979). Likewise, a compound
represented by (-V-Z=SPh, R2=2-Ph, R3=H) can be prepared also by the method disclosed in Chem. Ber., vol. 112(4), P1206 (1979). Similarly, a compound represented by
(-V-Z=SO2Ph, R2=H, R3=Me) can be prepared also by the method disclosed in Bull. Soc Chim. Fr., vol. 9-10, Pt.2, P2746 (1973).
The step for preparing the compound of the formula (III) is carried out by using a conventional appropriate reducing agent (for example, a metal hydrogen complex compound such as LAH: lithium aluminum hydride, SAH:
sodium aluminum hydride, triethoxyaluminum sodium
hydride, Red-Aℓ: bis( 2-methoxyethoxy)aluminum sodium hydride, SBH: sodium boron hydride or LBH: lithium boron hydride, a metal hydride compound such as DIBAH:
diisobutyl aluminum hydride, or catalytic hydrogenation using CuBaCrO as the catalyst).
Further, the compound of the formula (III) can be obtained also by subjecting a hydroxymethylpyrazole derivative of the formula (XVIII) wherein R2, R3, R6 and V are as defined above, to nucleophilic substitution with a compound of the formula (XI). The compound of the formula (XIII) can be prepared also by the method
disclosed in e.g. J. Heterocycl. Chem., vol. 16(3), P505 (1979) (R2=H, l-CH2Ph, 1-Ph, R3=H, R6=H, Me) or Arabian J- Sci. Eng., vol 6(1), P3 (1981) (R2=1-Me, R3=H, R6=H,
Me). This step is usually carried out in the same manner under the same condition as described in Process 6.
The step of preparing the compound of the formula (II) can be conducted by using an appropriate oxidizing agent (such as manganese dioxide, PCC: pyridinium
chlorochromate, PDC: pyridinium dichromate, DDQ:
dichlorodicyanobenzoquinone, chloranil, Swern oxidation: oxalylchloride-dimethylsulfoxide-tertiary amine, and sulfur trioxide-pyridine complex).
The compound of the formula (II) (R6=H) obtained by the above-mentioned method, can be further modified into a compound of the formula (II) (R6≠H) by alkylating a formyl group with an appropriate alkylating agent by means of a well known method.
This step can be conducted by a method using
diazomethane as described in "Tetrahedron Letters, p. 955 (1963)" and "Chem. Ber. vol. 40, p 479 (1907)", a method using alkyl halide as described in "Synth. Commun., vol. 14(8), p. 743 (1984)" or a method using alkyl lithium as described in "J. Org. Chem., vol. 30, p. 226 (1965)".
Figure imgf000118_0001
(wherein R1, R2, R3, R6, R10 and Hal are as defined above, and R11 represents OR10 (R10 is as defined above) or C1-C3 alkyl such as methyl, ethyl, n-propyl and i-propyl).
A halocarboxylic acid ester of the formula (VII) can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a malonic acid ester or a lower acylacetic acid ester by a known method to form a
compound of the formula (XVII), and by halogenating the compound thus formed.
The halomethylpyrazole of the formula (XVI) can be obtained also by halogenating a hydroxymethylpyrazole derivative of the formula (XIII) wherein R2, R3, R6 and V are as defined above, by a conventional method, for example by using e.g. SOCℓ2, POCℓ3, PCℓ5, HCℓ , SnCℓ4, HBr, PBr3, Br2, POBr3, mecylchloride or tosylchloride. Among the compounds having the formula (XVII), a compound wherein R11 is C1-C3 alkyl, can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a lower acylacetic acid ester such as methyl acetoacetate and ethyl acetoacetate in the presence of an appropriate base (such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium amide,
potassium amide, diisopropyl amide, butyl lithium, metal sodium and potassium carbonate) in accordance with such a method as described in "J. Amer. Chem. Soc, vol. 64, p. 435 (1942)".
Among the compounds having the formula (VII), a compound wherein R11 is OR10, can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a malonic acid ester such as diethyl malonate and di-t-butyl malonate in the presence of an appropriate base as mentioned above, in accordance with such a method as described in "J. Amer. Chem. Soc, vol. 74, p. 831
(1952)" and "Org. Synth. Coll. vol. 3, p. 705 (1955)".
The step of synthesizing a compound of the formula (VII) can be conducted by using an appropriate
halogenating agent (such as bromine and N-chlorosuccinimide) in the presence of an appropriate base (such as potassium hydroxide, sodium methoxide and potassium carbonate) in accordance with such a method as described in "J. Amer. Chem. Soc, vol. 71, p. 3107
(1949)" and "Tetrahedron Letters, vol. 28, p. 5505 ( 1987 ) " .
Also, a compound of the formula (VII) can be obtained by reacting a halomethylpyrazole of the formula (XVI) with a diazoacetic acid ester in the presence of a copper catalyst in accordance with such a method as described in "Zur. Russ. Fiz-Chim., vol. 21, p. 851 (1951)".
Figure imgf000120_0001
Figure imgf000121_0001
(wherein R2, R3, R9, R13, Hal and V are as defined above, Y is CR6R7 (R6 is hydrogen atom, and R7 forms a bond together with R4), and R14 is a protecting group for the V-H substituent on the pyrazole ring).
An intermediate of the formula (X) can be prepared also by the following method. Namely, V-H of a compound of the formula (V) is protected by an appropriate
protecting group R14 to obtain a compound (XV). The ester group of this compound is reduced to obtain a compound (XIV), which is further oxidized to obtain a compound (XIII). This compound (XIII) can be condensed with a compound (VI) (X1=S, X2=O, R9 is a hydrogen atom or a protecting group for amide, e.g. Tr : a trityl group) to obtain a compound (XII-1). The compound (XII-1) can be converted to a compound (XII-2) by reducing its olefin bond portion. By removing the protecting group R14 for V-H, the compound (XII-1) or the compound (XII-2) can be converted to a compound (X-1) or a compound (X-2), respectively. The compound (X-1) or the compound (X-2) can be converted to a compound (1-1) or a compound (1-2), respectively, by introducing a -W-V-W-Z group to the V-H group on the respective pyrazole ring by nucleophilic substitution with a compound (XI).
The compound of the formula (XV) can be obtained by protecting the V-H group of a pyrazole carboxylic acid ester derivative of the formula (V) wherein R2, R3, R13 and V are as defined above, with an appropriate
protecting group R14. As such a protecting group, the one which is stable under the reaction conditions of the subsequent steps, is preferred. For example, a C1-C4 alkoxymethyl group (such as MOM: methoxymethyl, MEM: 2-methoxyethoxymethyl, ethoxymethyl, n-propoxymethyl, i-propoxymethyl, n-butoxymethyl, iBM-isobutyloxymethyl, BUM: t-butoxymethyl, POM: pivaloyloxymethyl or SEM:
trimethylsilylethoxymethyl, preferably a ^-^
alkoxymethyl), a substituted thiomethyl group (such as MTM: methylthiomethyl), a trialkylsilyl group (such as TMS: trimethylsilyl, TES: triethylsilyl, TIPS:
triisopropylsilyl, DEIPS: diethylisopropylsilyl, DMIPS : dimethylisopropylsilyl, DTBMS: di-t-butylmethylsilyl, IPDMS: isopropyldimethylsilyl, TBDMS: t-butyldimethylsilyl or TDS: thexyldimethylsilyl,
preferably t-butyldimethylsilyl) or a trialkylarylsilyl group (such as DPMS: diphenylmethylsilyl, TBDPS: t-butyldiphenylsilyl, TBMPS: t-butyldimethoxyphenylsilyl, or TPS: triphenylsilyl), may be mentioned. More
preferably, an alkoxyalkyl group such as MOM: a
methoxymethyl group, or MEM: a methoxyethoxymethyl group. or a substituted silyl group such as TBDMS: a t- butyldimethylsilyl group, may, for example, be mentioned. Particularly preferred is a methoxymethyl group.
Such a reaction can be conducted in accordance with the method disclosed e.g. by T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis" (1991). In a case where R14 is a methoxymethyl group, the reaction can be conducted at room temperature by using e.g.
methoxymethyl chloride in the presence of
diisopropylethylamine.
The compound (XV) thus obtained is subjected to reduction of the ester group in the same method as in the step for producing a compound (II) from a compound (IV) as disclosed in Process 7, to obtain a compound (XIV), which is further oxidized to obtain a compound (XIII).
The step for preparing the compound of the formula (XII-1) is a step of dehydrating and condensing the compound (XIII) and a thiazolidine derivative of the formula (VI) wherein X1 is S, X2 is O, and R9 is a
hydrogen atom or a protecting group for amide (such as Tr : trityl) under an appropriate condition, and such dehydration condensation can be carried out in the same manner under the same condition as described in Process 1.
The compound (XII-1) thus obtained can be converted to a compound (XII-2) by reducing the olefin bond portion under an appropriate reducing condition. Such a method will be described in detail in the paragraph relating to mutual conversion of a partial structure of the compound
(I).
The compound (XII) can be converted to a compound (X) by removing the protecting group R14 for the V-H group. Such a reaction can be conducted in accordance with e.g. the method disclosed by T.W. Greene, P.G.M. Wuts in
"Protective Groups in Organic Synthesis" (1991). In a case where R14 is an alkoxyalkyl group such as MOM: a methoxymethyl group or MEM: a methoxyethoxymethyl group, the reaction can be conducted within a temperature range of from room temperature to the boiling point of the solvent in methanol, ethanol or tetrahydrofuran by means of an inorganic acid such as hydrochloric acid or
sulfuric acid, or an organic acid such as trifluoroacetic acid, or within a temperature range of from room
temperature to -78°C in methylene chloride by means of e.g. zinc bromide, dimethylborane bromide,
diisopropylthioborane bromide or diphenylborane bromide. Further, in a case where R14 is substituted silyl group such as TBDMS: a t-butyldimethylsilyl group, the reaction can be conducted within a temperature range of from -78°C to the boiling point of the solvent used, in
tetrahydrofuran, dioxane or acetonitrile by means of tetrabutylammonium fluoride, potassium fluoride, a
pyridine/hydrogen fluoride complex, or a
trifluoroborane/ether complex. In a case where a substituent is to be introduced by nucleophilic substitution to the V-H group on the pyrazole ring in the compound of the formula (X), it is preferred to protect the acidic hydrogen atom at the thiazolidine ring with an appropriate protecting group. In such a case, in the process for obtaining the compound (XII-1) from the compound (XIII), it is possible to employ a compound (VI) wherein hydrogen for R9 is
protected by an appropriate substituent (such as Tr :
trityl), as the starting material. Further, in the compound (XII-1), the compound (XII-2) and the compound (X), the substituent R9 on the thiazolidine ring is a hydrogen atom, such acidic proton may be protected by means of an appropriate protecting group. In such a case, the protecting group is preferably the one which is stable even in the nucleophilic substitution reaction of the V-H group as described in Process 6. For example, a C1-C4 alkoxymethyl group (such as MOM: methoxymethyl), a substituted silyl group (such as TBDMS: t-butyldimethylsilyl), an arylmethyl group (such as Tr:
trityl, DMTr : Di(4-methoxyphenyl)phenylmethyl, or DAM: di(4-methoxyphenyl)methyl), an aryloxycarbonyl group (such as Z: benzyloxycarbonyl), or a C1-C4 alkoxycarbonyl group (such as BOC: t-butoxycarbonyl) may be mentioned. Preferred may, for example, be trityl or
benzyloxycarbonyl.
Such a protecting group may be introduced or removed in accordance with e.g. the methods disclosed by T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis" (1991). For example, the reactions may be conducted under such conditions as follows: MOM:
methoxymethyl (introduction: methoxymethyl chloride; removal: hydrochloric acid or trifluoroacetic acid), TBDMS: t-butyldimethylsilyl (introduction: t-butyldimethylsilyl chloride; removal: tetrabutylammonium fluoride), Tr: trityl (introduction: trityl chloride, triethylamine; removal: hydrochloric acid or
trifluoroacetic acid), Z: benzyloxycarbonyl
(introduction: benzyloxycarbonyl chloride; removal:
catalytic hydrogenation in the presence of a palladium carbon catalyst), and BOC: t-butoxycarbonyl
(introduction: t-butoxycarbonyl anhydride; removal:
catalytic hydrogenation in the presence of a
palladium/carbon catalyst).
Now, with respect to the compound of the formula (I) thus obtained, a method for mutual conversion of its partial structure, will be described.
Figure imgf000126_0001
(wherein R1, R2, R3, R6, R9, X1 and X2 are as defined above).
A compound of the formula (I-1) (wherein R4 and R7 are bonded together) obtained by the above method can be modified into a compound of the formula (I-2) (R4, R7=H) by appropriately reducing a double bond between a
pyrazole ring and a thiazolidine or oxazolidine ring (for example by catalytic hydrogenation in the presence of an appropriate catalyst, by using an appropriate metalhydrogen complex compound, or by using magnesium or sodium amalgam in a lower alcohol such as methanol).
The catalytic hydrogenation is conducted usually in alcohols, cellosolves, aprotic polar organic solvents, ethers, alkoxyalkanes, lower aliphatic acid esters or lower aliphatic acids, and particularly methanol,
ethanol, methoxyethanol, dimethylformamide,
tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or acetic acid is preferably used alone or in a mixture. Examples of the catalyst used include palladium black, palladium carbon and platinum oxide. This reaction can proceed at normal temperature under normal pressure, but it is preferable to conduct the reaction at an elevated temperature under a increased pressure depending on the reactivity of the aimed reaction.
The reduction by a metal-hydrogen complex compound is conducted by using sodium borohydride, potassium
borohydride, lithium borohydride, tetramethyl ammonium borohydride or zinc borohydride in an aprotic polar organic solvent at a temperature ranging from 0°C to 150°C, preferably from 0°C to 30°C. In this reduction, undesired side-reaction can be inhibited by using a Co reagent such as CoCℓ2 , CoCℓ3 or Co(OAc)2 in the presence of a ligand such as dimethyl glyoxime, 2,2'-bipyridyl or 1,10-phenanthroline (see WO93/13095).
In the case of using amalgam, the reduction can be conducted usually in an alcohol, preferably in methanol or ethanol, within a temperature range of from -20°C to the boiling point of the solvent, preferably from 0°C to 50°C. Further, the reduction method by
magnesium/methanol as disclosed in J. Org. Chem., vol. 40, P127 (1975), may also be employed.
Figure imgf000128_0001
(wherein R1, R2, R3, R4, R6, R9, X1 and X2 are as defined above).
A compound of the formula (I-2) (R4, R7=H) can be modified into a compound of the formula (I-2) (R4≠H, R7=H) by alkylating hydrogen at the 5-position of thiazolidine or oxazolidine with an appropriate
alkylating agent (such as alkyl halide including methyl iodide or ethyl iodide, alkyl sulfate including dimethyl sulfate or diethyl sulfate, and aliphatic or aromatic sulfonic acid esters including methyl tosylate or methyl mesylate) in accordance with a well known method.
This reaction is conducted usually in an appropriate organic solvent in the presence of base. Examples of the solvent thus used include aprotic polar organic solvents, ethers, alkoxyalkanes and the like, and among them, tetrahydrofuran and dimethoxyethane are particularly preferable. Examples of the base include alkali metal amides (such as lithium diisopropylamide (LDA) and potassium amide) and aliphatic or aromatic lithium compounds (such as n-butyl lithium, t-butyl lithium and phenyl lithium). These materials are selected
appropriately depending on the reactivity of the aimed reaction.
This reaction is conducted usually at a temperature ranging from -20°C to 100°C, preferably from -10°C to 30°C, for from 0.1 to 10 hours.
Figure imgf000129_0001
(wherein R1, R2, R3 and R6 are as defined above).
A compound of the formula (I-2e) (X1=S, X2=NH) can be modified into a compound of the formula (I-2a) (X1=S, X2=O) by hydrolyzing an imino group at the 2-position of the thiazolidine in accordance with a well known method.
This reaction is conducted usually in an appropriate organic solvent in the presence of water or acid.
Examples of the solvent thus used include alcohols, cellosolves, aprotic polar organic solvents, ethers, alkoxyalkanes, and the like, and particularly methanol, ethanol, methoxyethanol, sulfolane, dioxane and
dimethoxyethane are preferably used. Examples of the acid thus used include inorganic acids (such as
hydrochloric acid, sulfuric acid and hydrobromic acid). These materials are selected appropriately depending on the reactivity of the aimed reaction.
This reaction is conducted usually at a temperature of from 50°C to a boiling point of a solvent used, preferably from 80°C to 150°C, for from 0.5 to 30 hours.
Figure imgf000130_0001
A compound of the formula (Ic) (X1=O, X2=S) can be modified into a compound of the formula (Id) (X1=O, X2=O) by oxidizing a thioxo group at the 2-position of
thiazolidine in accordance with a well known method.
This reaction is conducted by using an appropriate oxidizing agent (such as hydrogen peroxide, an organic peroxide including peracetic acid, perbenzoic acid, methachloroperbenzoic acid, monopermaleic acid,
monoperphthalic acid and the like, mercury ion, bromine, chlorine and meta-periodic acid) generally in water or in a solvent such as aprotic polar organic solvents (e.g. dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylurea, sulfolane and N,N-dimethylimidazolidinone), ethers (e.g. tetrahydrofuran and dioxane), and alkoxyalkanes (e.g. dimethoxyethane and diethoxyethane). These materials are selected
appropriately depending on the reactivity of the aimed reaction, and are used respectively alone or in
combination.
This reaction is conducted generally at a temperature ranging from 0°C to a boiling point of a solvent used, preferably from 20°C to 100°C, for from 0.5 to 30 hours.
The above-mentioned compounds (II), (III), (IV), (VII), (VIII), (IX), (X), (XII), (XIII), (XIV), (XV), (XVI) and (XVII) are novel compounds, and are useful as intermediate products for preparing the compound of the formula (I) of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention will be described in further detail with reference to Examples for preparation of the compounds of the present invention,
Pharmacological Test Examples and Formulation Examples. However, it should be understood that the present
invention is by no means restricted by such specific Examples.
EXAMPLE 1
Preparation of 5-((5-(2-hydroxy-2-phenylethoxy)-1-methyl- 3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. I-1a-1)
Figure imgf000132_0001
Step 1
Ethyl 1-methyl-5-phenacyloxy-3-pyrazolecarboxylate
( Compound No . IV-1 )
Figure imgf000132_0002
171 mg (1.00 mmol) of ethyl 5-hydroxy-1-methyl-3-pyrazolecarboxylate (Compound No. V-l) (prepared in accordance with a method disclosed in Japanese Unexamined Patent Publication No. 185964/1988) and 170 mg (1.10 mmol) of phenacyl chloride (TCI) were dissolved in dimethylformamide dehydrated with molecular sieves. To this solution, 144 mg of anhydrous potassium carbonate was added, and the mixture was stirred at room
temperature overnight. To this reaction solution, 5 mℓ of a saturated sodium chloride aqueous solution was added, and the mixture was extracted with 45 m£ of chloroform. The organic layer was washed with a
saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane = 2/1) to obtain 285 mg (98.6%) of the desired substance (Compound No. IV-1) as colorless powder.
MS (FAB) m/e: 289(M+H)+
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 3.79(3H, s), 4.33(2H, q), 5.31(2H, s), 5.98(1H, s), 7.40-7.65 (3H, m), 7.8-8.0(2H, m)
In the same manner as above, Compounds Nos. IV-2 to IV-13 were prepared by using Compound No. V-1, ethyl 1-t-butyl-5-hydroxy-3-pyrazolecarboxylate (Compound No. V-2) and ethyl 5-hydroxy-1-phenyl-3-pyrazolecarboxylate
(Compound No. V-3) as starting materials. (R2, R3, R13, W and Z in the Table correspond to the substituents of Compound No. IV.)
Figure imgf000134_0001
Figure imgf000135_0001
IV-2
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 3.07(2H, t),
3.66(3H, s), 4.29(2H, t), 4.3(2H, q), 6.07(1H, s),
7.25(5H, s)
IV-3
60 MHz 1H-NMR(CDCl3)δ: 1.34(3H, t), 1.68(9H, s),
4.30(2H, q), 5.32(2H, s), 6.02(1H, s), 7.3-7.6(3H, m),
7.8-8.0(2H, m)
IV-4
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 4.35(2H, q),
5.38(2H, s), 6.12(1H, s), 7.3-7.6(6H, m), 7.7-7.9(4H, m)
IV-5 60 MHz 1H-NMR(CDCl3)δ: 1.40(3H, t), 2.73(3H, s),
3.86(3H, s), 4.35(2H, q), 5.36(2H, s), 6.06(1H, s), 7.3-7.5(3H, m), 7.8-8.1(2H, m)
IV-6
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 1.70(9H, s),
2.72(3H, s), 4.32(2H, q), 5.33(2H, s), 6.07(1H, s), 7.4-8.1(5H, m)
IV-7
60 MHz 1H-NMR(CDCl3)δ: 1.37(3H, t), 2.72(3H, s),
4.37(2H, q), 5.42(2H, s), 6.18(1H, s), 7.3-8.1(10H, m) IV-8
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 2.79(3H, s),
3.85(3H, s), 4.35(2H, q), 5.18(2H, s), 6.07(1H, s), 7.42-7.55(2H, m), 7.78-7.98 (2H, m)
IV-9
60 MHz 1H-NMR(CDCl3)δ: 1.40(3H, t), 3.88(3H, s),
4.39(2H, q), 5.38(2H, s), 6.12(1H, s), 7.32-7.88 (5H, m) IV-10
60 MHz 1H-NMR(CDCl3)δ: 1.37(3H, t), 2.61(3H, s),
3.85(3H, s), 4.36(2H, q), 5.11(2H, s), 6.07(1H, s),
7.50(5H, s), 8.09(1H, s)
IV-11
60 MHz 1H-NMR(CDCl3)δ: 1.36(3H, t), 3.84(3H, s),
4.01(3H, s), 4.37(2H, q), 5.51(2H, s), 6.07(1H, s), 7.11-7.77(4H, m)
IV-12
60 MHz 1H-NMR(CDCl3)δ: 1.35(3H, t), 3.26(2H, t). 3.66(3H, s), 4.31(2H, t), 4.37(2H, q), 6.03(1H, s), 7.05- 8.1(6H, m)
IV-13
60 MHz 1H-NMR(CDCl3)δ: 1.37(3H, t), 3.87(3H, s),
4.37(2H, q), 5.35(2H, s), 6.07(1H, s), 7.35-7.92 ( 6H, m) Step 2
3-Hydroxymethyl-5-(2-hydroxy-2-phenylethoxy)-1-methylpyrazole (Compound No. Ill-l)
Figure imgf000137_0001
A suspension of 897 mg (23.6 mmol) of lithium
aluminum hydride in 50 mℓ of tetrahydrofuran dehydrated by molecular sieves, was cooled to 0°C in a nitrogen atmosphere, and a solution of 4.53 g (15.7 mmol) of
Compound IV-1 in 100 m£ of tetrahydrofuran dehydrated by molecular sieves, was gradually dropwise added thereto. After the dropwise addition, ice bath was taken off, and the mixture was stirred at room temperature for 5.5 hours. To this reaction solution, hydrous magnesium sulfate was added to terminate the reaction. Then, the inorganic salt was removed by filtration with celite and thoroughly washed with tetrahydrofuran. The solvent in the filtrate was distilled off under reduced pressure.
The residue thereby obtained was subjected to silica gel column chromatography (eluent: 6% methanol/chloroform) to obtain 4.44 g (quantitative) of the desired substance (Compound No. III-1) as pale yellow solid.
MS(EI) m/e: 248(M)+
60 MHz 1H-NMR(CDCl3)δ: 3.2-4.2(2H, br), 3.44(3H, s), 4.06(2H, d), 4.41(2H, s), 5.02(1H, t), 5.44(1H, s), 7.30(5H, s)
In the same manner, Compounds Nos. III-2 to 111-13 were prepared by using Compounds Nos. IV-2 to IV-13 as starting materials. (R2, R3, W and Z in the Table correspond to the substituents of Compound No. III.)
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000139_0002
Compound No. (III-2)
60 MHz 1H-NMR(CDCl3)δ: 3.0(1H, br s), 3.03(2H, t),
3.48(3H, s), 4.16(2H, t), 4.48(2H, br s), 5.46(1H, s), 7.16(5H, s)
Compound No. (III-3)
60 MHz 1H-NMR(CDCl3)δ: 1.46(9H, s), 2.9(2H, br),
4.08(2H, d), 4.43(2H, s), 5.04(1H, t), 5.50(1H, s), 7.31(5H, s)
Compound No. (III-4)
60 MHz 1H-NMR(CDCl3) δ: 2.2(2H, br), 4.19(2H, d),
4.60(2H, s), 5.1(1H, t), 5.66(1H, s), 7.2-7.5(10H, m) Compound No. (III-5)
60 MHz 1H-NMR(CDCl3)δ: 2.42(3H, s), 2.6(2H, br s), 3.57(3H, s), 4.26(2H, m), 4.49(2H, s), 5.0(1H, m),
5.54(1H, s), 7.3-8.1(5H, m)
Compound No. (III-6)
60 MHz 1H-NMR(CDCl3)δ: 1.48(9H, s), 2.40(3H, s), 2.4(2H, br s), 4.28(2H, d), 4.51(2H, s), 5.03(1H, t), 5.57(1H, s), 7.2-8.0(5H, m)
Compound No. (III-7)
60 MHz 1H-NMR(CDCl3)δ: 2.25(3H, s), 4.33(2H, d),
4.55(2H, s), 4.98(1H, t), 5.70(1H, s), 7.2-8.0(10H, m) Compound No. (III-8)
60 MHz 1H-NMR(CDCl3)δ: 2.42(3H, s), 3.3(2H, br),
3.59(3H, s), 4.26(2H, d), 4.46(2H, s), 5.53(1H, t),
5.58(1H, s), 7.35-7.92(4H, m)
Compound No. (III-9) 60 MHz 1H-NMR(CDCl3)δ: 3.53(3H, s), 4.4(2H, s), 4.40(2H, br), 4.43(2H, d), 5.22(1H, t), 5.68(1H, s), 6.79(1H, s), 7.12-7.57(4H, m)
Compound No. (III-10)
60 MHz 1H-NMR(CDCl3)δ: 2.31(3H, s), 3.55(3H, s), 3.7(2H, br), 4.19(2H, d), 4.48(2H, s), 5.05(1H, m), 5.55(1H, s), 7.40(5H, s), 7.59(1H, s)
Compound No. (III-11)
60 MHz 1H-NMR(CDCl3)δ: 2.96(3H, s), 3.50(2H, s),
3.88(3H, s), 4.35(2H, d), 4.46(2H, s), 5.53(1H, s),
5.6(1H, m), 7.00-7.57(4H, m)
Compound No. (III-12)
60 MHz 1H-NMR(CDCl3)δ: 2.53(1H, s), 3.22(2H, t),
3.53(3H, s), 4.27(2H, t), 4.51(2H, s), 5.49(1H, s), 7.05-8.29(6H, m)
Compound No. (III-13)
60 MHz 1H-NMR(CDCl3)δ: 3.49(3H, s), 3.6(2H, br),
4.32(2H, d), 4.49(2H, s), 5.23(1H, t), 5.56(1H, s),
6.62(1H, s), 7.25-7.86(5H, m)
Step 3
5-(2-Hydroxy-2-phenylethoxy)-1-methylpyrazole-3-carbaldehyde (Compound No. II-1)
Figure imgf000141_0001
Preparation of Compound No. 2 by oxidation of manganese dioxide
2.72 g (11.0 mmol) of Compound No. III-l was
dissolved in 108 mℓ of chloroform and 2 mℓ of methanol.
To this solution, 5.23 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 8 hours. The oxidant residue was removed by
filtration with celite. Then, the solvent in the obtained filtrate was distilled off under reduced
pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane = 5/2) to obtain 1.53 g (56.6%) of the desired substance (Compound
No. II-1) as colorless oil.
MS(EI) m/e: 246(M)+
60 MHz 1H-NMR(CDCl3)δ: 2.80(1H, brs), 3.69(3H, s),
4.13(2H, d), 5.07(1H, t), 5.95(1H, s), 7.34(5H, s),
9.62(1H, s)
In the same manner, Compounds Nos. II-2 to II-6 were prepared by using Compounds Nos. III-2 to III-5 as starting materials. Compounds Nos. II-3 and II-4 were simultaneously formed by the reaction of Compound No.
III-3 as the starting material. (R2, R3, W and Z in the
Table correspond to the substituents of Compound No. II.)
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000143_0002
Compound No. (II-2)
60 MHz 1H-NMR(CDCl3)δ: 3.08(2H, t), 3.67(3H, s), 4.25(2H, t), 5.95(1H, s), 7.21(5H, s), 9.67(1H, s)
Compound No. (II-3)
60 MHz 1H-NMR(CDCl3)δ: 1.56(9H, s), 2.69(1H, br),
4.16(2H, d), 5.10(1H, t), 6.01(1H, s), 7.32(5H, s),
9.65(1H, s)
Compound No. (II-4) 60 MHz 1H-NMR(CDCl3)δ: 3.84(3H, s), 5.34(2H, s), 5.96(1H, s), 7.4-7.9(5H, m), 9.70(1H, s)
Compound No. (II-5)
60 MHz 1H-NMR(CDCl3)δ: 2.63(1H, br), 4.19(2H, d),
5.05(1H, t), 6.11(1H, s), 7.2-7.6(10H, m), 9.77(1H, s) Compound No. (II-6)
60 MHz 1H-NMR(CDCl3)δ: 2.36(3H, s), 3.6(1H, br s),
3.65(3H, s), 4.3(2H, m), 5.02(1H, t), 6.01(1H, s), 7.2- 8.0(5H, m), 9.63(1H, s)
1-Methyl-5-phenacyloxypyrazole-3-carbaldehyde (Compound No. II-7)
Figure imgf000144_0001
Preparation of Compound No. II by Swern oxidation
A solution of 175 μ£ (2.01 mmol) of oxalyl chloride in 2.5 mℓ of dichloromethane dehydrated by molecular sieves was cooled to -78°C in a nitrogen atmosphere, and a solution of 353 mg (4.98 mmol) of dimethylsulfoxide dehydrated by molecular sieves in 1.5 mℓ of
dichloromethane dehydrated by molecular sieves, was dropwise added thereto, and the mixture was stirred at -78°C for 30 minutes. To this solution, a solution of 124 mg (0.500 mmol) of Compound No. III-1 in 3.0 mℓ of dichloromethane dehydrated by molecular sieves, was gradually dropwise added, and then the mixture was stirred at -78°C for one hour. To this reaction solution, 1.4 mℓ of triethylamine dehydrated by molecular sieves, was dropwise added. Then, the temperature was raised to room temperature, and 5 mℓ of water was added thereto. The mixture was extracted with 45 mℓ of
chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the drying agent was filtered off. Then, the solvent in the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl
acetate/hexane = 1/1) to obtain 101 mg (82.4%) of the desired substance (Compound No. II-7) as colorless needles.
mp 140-141°C
MS(EI) m/e: 244(M)+
60 MHz 1H-NMR(CDCl3)δ: 3.84(3H, s), 5.34(2H, s), 5.96(1H, s), 7.4-7.9(5H, m), 9.70(1H, s)
In the same manner, Compounds Nos. II-8 to 11-14 were prepared by using Compounds Nos. III-5 to III-11 as starting materials. (R2, R3, W and Z in the Table
correspond to the substituents of Compound No. II.)
Figure imgf000145_0001
Figure imgf000146_0002
Figure imgf000146_0001
Compound No. (II-8)
60 MHz 1H-NMR(CDCl3)δ: 2.69(3H, s), 3.86(3H, s), 5.37(2H, s), 5.99(1H, s), 7.39-7.53(3H, m), 7.90-8.09 ( 2K, m),
9.73(1H, s)
Compound No. (II-9)
60 MHz 1H-NMR(CDCl3)δ: 1.74(9H, s), 2.72(3H, s), 5.40(2H, s), 6.09(1H, s), 7.4-7.6(3H, m), 7.9-8.1(2H, m), 9.77(1H, s)
Compound No. (11-10)
60 MHz 1H-NMR(CDCl3)δ: 2.67(3H, s), 5.43(2H, s), 6.13(1H, s), 7.3-8.1(10H, m), 9.86(1H, s)
Compound No. (11-11)
60 MHz 1H-NMR(CDCl3)δ: 2.79(3H, s), 3.90(3H, s), 5.18(2H, s), 6.02(1H, s), 7.42-8.10(4H, m), 9.72(1H, s)
Compound No. (11-12)
60 MHz 1H-NMR(CDCl3)δ: 3.89(3H, s), 5.38(2H, s), 6.06(1H, s), 7.28-7.84(5H, m), 9.78(1H, s)
Compound No. (11-13)
60 MHz 1H-NMR(CDCl3)δ: 2.59(3H, s), 3.89(3H, s), 5.12(2H, s), 6.01(1H, s), 7.50(5H, s), 8.07(1H, s), 9.79(1H, s) Compound No. (11-14)
60 MHz 1H-NMR(CDCl3)δ: 3.87(3H, s), 4.00(3H, s), 5.53(2H, s), 6.03(1H, s), 7.40-7.76(4H, m), 9.75(1H, s)
Preparation of Compound No. II by PCC oxidation
To a suspension of 1.041 g (4.828 mmol) of pyridinium chlorochromate, 401 mg (4.89 mmol) of sodium acetate, 0.50 g of pulverized molecular sieves 4A and 1.01 g of celite in 30 mℓ of dichloromethane dehydrated by
molecular sieves, a solution of 210 mg (0.846 mmol) of Compound III-l in 10 m€ of dichloromethane dehydrated by molecular sieves, was dropwise added at 0°C, and the mixture was stirred at 0°C for 90 minutes and then at room temperature for 140 minutes. The inorganic salt was filtered off. Then, the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to silica gel column chromatography (eluent: 4% methanol/chloroform) to obtain 86 mg (41.5%) of the desired substance (Compound No. II-7) as colorless needles.
Preparation of Compound No. II by oxidation of a sulfur trioxide-pyridine complex salt
To a solution of 80 mg (0.32 mmol) of Compound No. III-1 in 4 mℓ of dimethylsulfoxide dehydrated by
molecular sieves, a solution of 304 mg (1.91 mmol) of a sulfur trioxide-pyridine complex salt and 196 mg (1.94 mmol) of triethylamine in 4 mℓ of dimethylsulfoxide dehydrated by molecular sieves, was dropwise added, and the mixture was stirred at room temperature for 4 hours. Ice water was added thereto, and the mixture was
extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate, and the drying agent was filtered off. Then, the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to thin layer chromatography (developer: ethyl acetate/hexane = 1/1) to obtain 39 mg (48.9%) of the desired substance (Compound No. II-1) as colorless oil and 3 mg (4.0%) of Compound No. II-7 as colorless needles.
Step 4
5-((5-(2-Hydroxy-2-phenylethoxy)-1-methyl-3- pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No.
I-1a-1)
Figure imgf000149_0001
1.53 g (6.21 mmol) of Compound No. II-1 and 974 mg of thiazolidinedione were suspended in 60 mέ of toluene. To this solution, 108 μ€ of glacial acetic acid and then 122 μ€ of piperidine were added, and the mixture was stirred at 130°C for 140 minutes. After confirming disappearance of the starting material by thin layer chromatography, the solvent was distilled off under reduced pressure.
The residue thereby obtained was dissolved in
tetrahydrofuran/chloroform. This solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off. Then, the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to silica gel column chromatography
(eluent: tetrahydrofuran/hexane = 1/2) and then to thin layer chromatography (developer: tetrahydrofuran/hexane = 1/2) to obtain 2.11 g (98.3%) of the desired substance (Compound No. I-1a-1) as colorless powder.
mp 172.8-174.3°C
MS(EI) m/e: 345(M)+
500 MHz 1H-NMR(d6-acetone)δ: 3.70(3H, s), 4.21(1H, dd, 2JHH = 10.3 Hz, 3JHH = 7.6 Hz), 4.27(1H, dd, 2JHH = 10.3 Hz, 3JHH = 3.9 Hz), 4.94(1H, d, 3JHH = 4 Hz), 5.15(1H, ddd, 3JHH = 7.6 Hz, 3JHH = 3.9 Hz, 3JHH = 4 Hz), 5.77(1H, s), 7.30(1H, t, 3JHH = 7.3 Hz), 7.38(2H, dd, 3JHH = 7.3 Hz, 3JHH = 7.6 Hz), 7.5K1H, s), 7.52(2H, d, 3JHH = 7.6 Hz), 12.3(1H, s)
In the same manner, Compounds Nos. I-1a-2 to I-1a-14 were prepared by using Compounds Nos. II-2 to II-14 as starting materials. R2, R3, W and Z in the Table correspond to the substituents of Compound No. 1-la.)
Figure imgf000150_0001
Figure imgf000151_0002
Figure imgf000151_0001
Figure imgf000152_0001
Compound No. (I-1a-2)
500 MHz 1H-NMR(d6-DMSO)δ: 3.06(2H, t, 3JHH = 6.7 Hz),
3.59(3H, s), 4.31(2H, t, 3JHH = 6.7 Hz), 6.12(1H, s),
7.24-7.48(5H, m), 7.48(1H, s),12.3(1H, br s)
Compound No. (I-1a-3)
500 MHz 1H-NMR(CDCl3)δ: 1.58(9H, s), 2.35(1H, d, 3JHH =
3.2 Hz), 4.18(2H, m), 5.15(1H, m), 5.77(1H, s), 7.36- 7.45(5H, m), 7.56(1H, s), 8.20(1H, s)
Compound No. (I-1a-4)
500 MHz 1H-NMR(d6-DMSO)δ: 1.63(9H, s), 5.70(2H, s),
6.15(1H, s), 7.44(1H, s), 7.58(2H, dd, 3JHH = 7.4, 7.8
Hz), 7.71(1H, t, 3JHH = 7.4 Hz), 8.00(2H, d, 3JHH = 7.8
Hz), 12.26(1H, s)
Compound No. (I-1a-5)
500 MHz 1H-NMR(CDCl3)δ: 2.40(1H, d), 4.29(2H, d),
5.17(1H, m), 5.91(1H, s), 7.23-7.46 (8H, m), 7.62(1H, s),
7.75(2H, d, 3JHH = 7.6 Hz), 8.12(1H, br s) Compound No. (I-1a-6)
500 MHz 1H-NMR(d6-DMSO)δ: 2.50(3H, s), 3.65(3H, s), 4.31(2H, d, 3JHH = 5.4 Hz), 4.97(1H, dt, 3JHH = 4.9 Hz, 3JHH = 5.4 Hz), 5.75(1H, d, 3JHH = 4.9 Hz), 6.12(1H, s), 7.47(1H, s), 7.50(3H, m), 7.92(2H, d, 3JHH = 8.1 Hz), 12.3(1H, s)
Compound No. (I-1a-7)
500 MHz 1H-NMR(d6-DMSO)δ: 3.76(3H, s), 5.74(2H, s), 6.11(1H, s), 7.44(1H, s), 7.58(2H, t, 3JHH = 7.3, 7.7 Hz), 7.71(1H, t, 3JHH = 7.7 Hz), 7.88(2H, d, 3JHH = 7.3 Hz), 12.4(1H, br s)
Compound No. (I-1a-8)
500 MHz 1H-NMR(CDCl3)δ: 2.74(3H, s), 3.87(3H, s),
5.41(2H, s), 5.76(1H, s), 7.49-7.52 ( 3H, m), 7.56(1H, s), 8.03-8.05(2H, m), 8.14(1H, br s)
Compound No. (I-1a-9)
500 MHz 1H-NMR(CDCl3)δ: 1.71(9H, s), 2.75(3H, s),
5.39(2H, s), 5.81(1H, s), 7.50-7.51 ( 3H, m), 7.56(1H, s), 8.04-8.06(2H, m), 8.08(1H, br s)
Compound No. (I-1a-10)
500 MHz 1H-NMR(CDCl3)δ: 2.71(3H, s), 5.68(2H, s),
6.38(1H, s), 7.41(1H, t, 3JHH = 7.3 Hz), 7.52(1H, s), 7.56-7.60(5H, m), 7.91-7.93 (2H, m), 8.02-8.04 (2H, m), 12.4(1H, br s)
Compound No. (I-1a-11)
500 MHz 1H-NMR(d6-DMSO)δ: 2.77(3H, s), 3.77(3H, s), 5.62(2H, s), 6.16(1H, s), 7.44(1H, s), 7.53(1H, dd, 3JHH = 7.2, 8.3 Hz), 7.60(1H, dd, 3JHH = 7.2, 8.3 Hz),
8.07(1H, d, 3JHH = 8.3 Hz), 8.09(1H, d, 3JHH = 8.3 Hz), 12.4(1H, br s)
Compound No. (I-1a-12)
500 MHz 1H-NMR(d6-DMSO)δ: 3.77(3H, s), 5.64(2H, s),
6.16(1H, s), 7.41(1H, dd, 3JHH = 7.1, 7.9 Hz), 7.45(1H, s), 7.60(1H, dd, 3JHH = 7.1, 8.3 Hz), 7.77(1H, d, 3JHH = 8.3 Hz), 7.90(1H, d, 3JHH = 7.9 Hz), 8.06(1H, s),
12.4(1H, br s)
Compound No. (I-1a-13)
500 MHz 1H-NMR(d6-DMSO)<δ: 2.52(3H, s), 3.76(3H, s), 5.47(2H, s), 6.10(1H, s), 7.46(1H, s), 7.52-7.60 (5H, m), 8.37(1H, s), 12.4(1H, br s)
Compound No. (I-1a-14)
500 MHz 1H-NMR(d6-DMSO)δ: 3.76(3H, s), 3.96(3H, s),
5.69(2H, s), 6.16(1H, s), 7.30(1H, dd, 3JHH = 7.3, 7.9 Hz), 7.46(1H, s), 7.50(1H, dd, 3JHH = 7.3, 8.5 Hz), 7.64(1H, d, 3JHH = 7.9 Hz), 7.70(1H, d, 3JHH = 8.5 Hz), 12.3(1H, br s)
EXAMPLE 2
Step 5
Preparation of 5-((5-(2-hydroxy-2-phenylethoxy)-1-methyl-3-pyrazolyl)methyl)thiazolidin-2,4-dione (Compound No. I-2a-1)
Figure imgf000154_0001
348 mg (1.01 mmol) of 5-((5-(2-hydroxy-2- phenylethoxy)-1-methyl-3- pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. I-1a-1) was dissolved in 15 m€ of tetrahydrofuran
dehydrated by molecular sieves. To this solution, 271 mg of 10% palladium carbon was added, followed by catalytic reduction at room temperature under hydrogen pressure of 5 atm for 48.5 hours. The catalyst was filtered off.
Then, the solvent was distilled off under reduced
pressure. The residue thereby obtained was subjected to silica gel column chromatography (eluent: 6%
methanol/chloroform) to obtain 363 mg (quantitative) of the desired substance (Compound No. I-2a-1) as colorless powder.
mp 68-71°C
MS(EI) m/e: 347(M)+
60 MHz 1H-NMR(CDCl3)δ: 3.23(2H, m), 3.54(3H, s),
4.10(2H, d), 4.56(1H, dd), 5.08(1H, t), 5.37(1H, s), 7.36(5H, s)
In the same manner. Compounds Nos. I-2a-2 to I-2a-8 were prepared by using Compounds Nos. I-1a-2 to I-1a-6, I-1a-11 and I-1a-12 as starting materials. (R2, R3, W and Z in the Table correspond to the substituents of Compound No. I-2a.)
Figure imgf000156_0001
Figure imgf000156_0002
Compound No. (I-2a-2)
500 MHz 1H-NMR(CDCl3)δ:2.95(2H, t), 3.0-3.5(2H, m), 3.43(3H, s), 4.08(2H, t), 4.5(1H, m), 5.27(1H, s),
7.14(5K, s), 7.60(1H, br s)
Compound No. (I-2a-3)
500 MHz 1H-NMR(CDCl3)δ: 1.50(9H, s), 3.06(1H, m),
3.44(1H, m), 4.11(2H, m), 4.66(1H, m), 5.11(1H, m), 5.40(1H, s), 7.3-7.5(5H, m), 8.89(1H, s), 9.08(1H, br s) Compound No. (I-2a-4)
500 MHz 1H-NMR(CDCl3)δ: 1.4(9H, s), 3.00-3.07 (1H, m),
3.40-3.46(1H, m), 4.65-4.70 (1H, m), 5.25(2H, s), 5.38(1H, s), 7.50-7.55(2H, m), 7.63-7.65 (1H, m) , 7.95-7.98 (2H, m), 8.45(1H, s)
Compound No. (I-2a-5)
500 MHz 1H-NMR(CDCl3)δ: 2.45(1H, br s), 3.16(1H, m),
3.56(1H, m), 4.20-4.21(2H, m), 4.75(1H, m), 5.13(1H, m), 5.56(1H, s), 7.25-7.42(8H, m), 7.61(1H, m), 8.10(1H, s) Compound No. (I-2a-6)
500 MHz 1H-NMR(CDCl3)δ: 2.42(3H, s), 3.11(1H, dd),
3.41(1H, dd), 3.58(3H, s), 4.22(1H, dd), 4.35(1H, dd), 4.61(1H, dd), 5.04(1H, dd), 5.44(1H, s), 7.43(3H, m), 7.97(2H, m), 9.0(1H, s)
Compound No. (I-2a-7)
500 MHz 1H-NMR(d6-DMSO)δ: 2.75(3H, s), 2.95(1H, dd, 2JHH = 15.5 Hz, 3JHH = 10-6 Hz), 3.24(1H, dd, 2JHH = 15.5 Hz, 3JHH = 3.6 Hz), 3.59(3H, s), 4.77(1H, dd, 3JHH = 3.6, 10.6 Hz), 5.49(2H, s), 5.62(1H, s), 7.52(1H, dd, 3JHH = 7.1, 8.1 Hz), 7.59(1H, dd, 3JHH = 7.1, 8.2 Hz), 8.06(1H, d' 3jHH = 8.2 Hz), 8.08(1H, d, 3JHH = 8.1 Hz), 12.0(1H, br s)
Compound No. (I-2a-8)
500 MHz 1H-NMR(d6-DMSO)δ: 2.52(3H, s), 2.97(1H, m), 3.26(1H, m), 3.58(3H, s), 4.78(1H, m), 5.34(2H, s), 5.56(1H, s), 7.54-7.59(5H, m), 8.35(1H, s), 12.0(1H, br s)
EXAMPLE 3
Preparation of 5-((1-methyl-5-phenacyloxy-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. I-1a-7)
Figure imgf000158_0001
127 mg (0.367 mmol) of 5-((5-(2-hydroxy-2-phenylethoxy)-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. I-1a-1) was dissolved in 6 mℓ of dichloromethane
dehydrated by molecular sieves, together with 114 mg (0.527 mmol) of pyridinium chlorochromate and 549 mg of celite, and the mixture was stirred at 0°C for 40 minutes and then at room temperature for 3.75 hours under a nitrogen atmosphere. Further, 90 mg (0.42 mmol) of pyridinium chlorochromate was added thereto, and the mixture was stirred at room temperature overnight. The inorganic salt was filtered off. Then, the solvent was distilled off. The residue thereby obtained was
subjected to silica gel column chromatography (eluent: ethyl acetate/benzene = 1/2) to obtain 120 mg (95.5%) of the desired substance (Compound No. I-1a-7) as colorless powder.
EXAMPLE 4
Preparation of 5-((1-methyl-5-phenacyloxy-3- pyrazolyl)methyl)thiazolidin-2,4-dione (Compound No. I- 2a-9)
Figure imgf000159_0001
204 mg (0.946 mmol) of pyridinium chlorochromate, 96 mg of anhydrous sodium acetate and 503 mg of celite were suspended in 10 mέ of dichloromethane dehydrated by molecular sieves. To this suspension, a solution of 135 mg (0.390 mmol) of 5-((5-(2-hydroxy-2-phenylethoxy)-1-methyl-3-pyrazolyl)methyl)thiazolidin-2,4-dione (Compound No. I-2a-1) in 5 mℓ of dichloromethane dehydrated by molecular sieves, was dropwise added. The mixture was stirred at 0°C for 1.5 hours and then at room temperature for 1.75 hours. Then, the inorganic salt was filtered off, and the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to silica gel column chromatography (eluent: 4%
methanol/chloroform), followed by recrystallization from ethyl acetate/hexane to obtain 69 mg (51.2%) of the desired substance (Compound No. I-2a-9) as colorless crystals.
mp 141-143°C
MS(EI) m/e: 345(M)+
500 MHz 1H-NMR(CDCl3)δ: 3.06(1H, dd, 2JHH = 15.4 Hz, 3JHH = 10.0 Hz), 3.44(1H, dd, 2JHH = 15.4 Hz, 3JHH = 3.8 Hz), 3.68(3H, s), 4.63(1H, dd, 3JHH = 3.8 Hz, 3JHH = 10.0 Hz), 5.27(2H, s), 5.35(1H, s), 7.52(1H, dd, 3JHH = 7.6 Hz, 3JHH = 7.9 Hz), 7.64(1H, t, 3JHH = 7.6 Hz), 7.94(2H, d, 3JHH = 7.9 Hz), 8.33(1H, br s)
EXAMPLE 5
Preparation of sodium salt of 5-((1-methyl-5-(2-(3-methylbenzo[b]thiophen-2-yl)-2-oxoethoxy)-3-pyrazolypmethylidene)thiazolidin-2,4-dione (Compound No. I-1a-11-Na)
Figure imgf000160_0001
69 mg (0.17 mmol) of 5-((1-methyl-5-(2-(3-methylbenzofb]thiophen-2-yl)-2-oxoethoxy-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. I-1a-11) was dissolved in 5 me of tetrahydrofuran and 3 me of chloroform. To this solution, 0.32 me (0.17 mmol) of an aqueous solution of 0.5 mol/£ of sodium hydroxide was dropwise added at room temperature. The solvent was distilled off under reduced pressure. Then, 5 mℓ of deionized water was added, and the solution thereby obtained was freeze-dried to obtain 69 mg (94.9%) of the desired substance (Compound No. I-1a-11-Na) as pale brown powder.
mp 180-240°C (decomp.)
MS (FAB) m/e: 436 (M+H) +
In the same manner, Compounds Nos. I-1a-13-Na, I-2a-7-Na and I-2a-8-Na were prepared by using Compounds Nos. I-1a-13, I-2a-7 and I-2a-8, respectively, as starting materials.
Figure imgf000161_0001
Compound No. I-1a-13-Na
Colorless powder
mp 200-220°C (decomp.)
MS(FAB) m/e: 446(M+H)+
Figure imgf000162_0001
Compound No. I-2a-7-Na
Pale pink powder
mp 90-110°C (decomp.)
MS(FAB) m/e: 438(M+H)+
Figure imgf000162_0002
Compound No. I-2a-8-Na
Colorless powder
mp 185-220°C (decomp.)
MS(FAB) m/e: 448(M+H)+
EXAMPLE 6
Preparation of 5-((5-methoxymethoxy-1-methyl-3-pyrazolypmethylidene)thiazolidin-2,4-dione (Compound No, XII-1-1)
Figure imgf000162_0003
Ethyl 5-methoxymethoxy-1-methyl-3-pyrazolecarboxylate (Compound No. XV-1)
Figure imgf000163_0001
In the same manner as in Step 1 in Example 1, 3.09 g (81.8%) of the desired substance (Compound No. XV-1) was obtained as pale yellow oil by using 3.00 g (17.6 mmol) of ethyl 5-hydroxy-1-methyl-3-pyrazolecarboxylate
(Compound No. V-1), 2.0 mℓ (26 mmol) of chloromethyl methyl ether and 4.0 me (23 me ) of diisopropylethylamine. MS(EI) m/e: 214(M)+
60 MHz 1H-NMR(CDCl3)δ': 1.38(3H, t), 3.49(3H, s),
3.74(3H, s), 4.35(2H, q), 5.13(2H, s), 6.17(1H, s)
In the same manner, Compounds Nos. XV-2 and XV-3 were prepared using Compound No. V-1 as starting material.
(R2, R3, R13 and R14 in the Table correspond to the substituents of Compound No. XV.)
Figure imgf000163_0002
Figure imgf000164_0002
XV-2
60 MHz 1H-NMR(CDCl3)δ: 1.39(3H, t), 3.42(3H, s),
3.75(3H, s), 3.4-3.9(4H, m), 4.39(2H, q), 5.25(2H, s), 6.22(1H, s)
XV-3
60 MHz 1H-NMR(CDCl3)δ: 0.28(6H, s), 1.00(9H, s),
1.37(3H, t), 3.70(3H, s), 4.28(2H, q), 5.89(1H, s) 3-Hydroxymethyl-5-methoxymethoxy-1-methylpyrazole
(Compound No. XIV-1)
Figure imgf000164_0001
In the same manner as in Step 2 in Example 1, 54 mg (64%) of the desired substance (Compound No. XIV-1) was obtained as pale yellow oil by using 105 mg (0.488 mmol) of Compound No. XV-1 and 108 mg (2.83 mmol) of lithium aluminum hydride.
MS(FAB) m/e: 173(M+H)+
60 MHz 1HNMRfCDCl3)δ: 2.6(1H, br), 3.47(3H, s),
3.62(3H, s), 4.53(2H, s), 5.10(2H, s), 5.65(1H, s)
5-Methoxymethoxy-1-methylpyrazole-3-carbaldehyde (Compound No. XIII-1)
Figure imgf000165_0002
In the same manner as the Swern oxidation shown in Step 3 in Example 1, 132 mg (95.2%) of the desired substance (Compound No. XIII-1) was obtained as pale brown oil by using 141 mg (0.817 mmol) of Compound No. XIV-1, 277 μe (3.18 mmol) of oxalyl chloride, 622 mg
(7.96 mmol) of dimethylsulfoxide dehydrated by molecular sieves and 2.2 mℓ (16 mmol) of triethylamine dehydrated by molecular sieves.
This compound was obtained also by the manganese dioxide oxidation method and the PCC oxidation method shown in Step 3 in Example 1.
MS (FAB) m/e: 171 (M+H) +
60 MHz 1H-NMR(CDCl3)δ: 3.50(3H, s), 3.77(3H, s),
5.12(2H, s), 6.16(1H, s), 9.74(1H, s)
5-((5-Methoxymethoxy-1-methyl-3-pyrazolyl)methylidene)-thiazolidin-2,4-dione (Compound No. XII-1-1)
Figure imgf000165_0001
In the same manner as in Step 4 in Example 1, 337 mg (99.9%) of the desired substance (Compound No. XII-1-1) was obtained as pale brown needles by using 213 mg (1.25 mmol) of Compound No. XIII-1, 164 mg (1.26 mmol) of thiazolidinedione (Compound No. VI-1) , 25 μe of
piperidine and 22 μe of acetic acid.
mp 161-164°C
MS(EI) m/e: 269(M)+
60 MHz 1H-NMR(CDCl3)δ: 3.52(3H, s), 3.76(3H, s), 5.16(2H, s), 5.92(1H, s), 7.30(1H, t,3JHH = 7.3 Hz), 7.38(2H, dd,3JHH = 7.3 Hz,3JHH = 7.6 Hz), 7.59(1H, s), 8.17(1H, br s)
Preparation of 5-((5-methoxymethoxy-1-methyl-3-pyrazolypmethyl)thiazolidin-2,4-dione (Compound No. XII- 2-1)
Figure imgf000166_0001
In the same manner as in Example 2, 167 mg
(quantitative) of the desired substance (Compound No.
XII-2-1) was obtained as pale yellow powder by using 144 mg (0.533 mmol) of 5-((5-methoxmethoxy-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. XII-1-1) and 129 mg of 10% palladium carbon,
mp 114-117°C
MS(EI) m/e: 271(M)+
60 MHz 1H-NMR(CDCl3)δ: 3.09-3.5(2H, m), 3.46(3H, s), 3.61(3H, s), 4.48-4.72(1H, m), 5.05(2H, s), 5.51(1H, s), 10 . 13 ( 1H , br s )
Protection by Z group ( benzyloxycarbonyl ) of 5- ( ( 5- methoxymethoxy-1-methyl-3-pyrazolyl ) methylidene ) - thiazolidin-2 , 4-dione ( Compound No . XII-1-1 )
Figure imgf000167_0001
To a solution of 81 mg (0.30 mmol) of 5-((5-methoxymethoxy-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. XII-1-1) in 10 mℓ of tetrahydrofuran dehydrated by molecular sieves, 49 mg (0.46 mmol) of anhydrous sodium carbonate and then 64 μe (0.45 mmol) of benzyl
chloroformate were added at room temperature, and the reaction solution was stirred overnight. To this
solution, 5 me of a saturated sodium chloride aqueous solution was added, and the mixture was extracted with 45 me of ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off. Then, the solvent was distilled off under reduced pressure. The residue thereby obtained was recrystallized from ethyl acetate and hexane to obtain 71 mg (59%) of the desired substance (Compound No. XII-1-2) as colorless crystals.
MS(EI) m/e: 403(M)+
500 MHz 1H-NMR(CDCl3)δ: 3.53(3H, s), 3.77(3H, s), 5.14(2H, s), 5.46(2H, s), 5.92(1H, s), 7.42(5H, s),
7.66(1H, s)
REFERENCE EXAMPLE 1
Removal of protective Z group of Compound No. XII-1-2
19 mg (0.047 mmol) of Compound No. XII-1-2 was dissolved in 10 me of tetrahydrofuran dehydrated by molecular sieves. To this solution, 6 mg of 10%
palladium carbon was added, followed by catalytic
reduction at room temperature under a hydrogen pressure of 1 atm overnight and then for 3 days by an addition of
6 mg of the catalyst. The catalyst was filtered off, and then the solvent was distilled off under educed
pressure. The residue thereby obtained was subjected to thin layer chromatography (developer: 5%
methanol/chloroform) to obtain 16 mg (quantitative) of the desired substance (Compound No. XII-1-1) as pale brown powder.
Preparation of 5-((5-hydroxy-1-methyl-3-pyrazolypmethylidene)thiazolidin-2,4-dione (Compound No. X-1-1) (Removal of protective MOM group)
Figure imgf000168_0001
To a solution of 54 mg (0.20 mmol) of 5-((5-methoxymethoxy-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No, XII-1-1) in 5 mℓ of tetrahydrofuran and 1 me of methanol, one drop of concentrated hydrochloric acid was added at room temperature, and the reaction solution was stirred at 56°C for 5 hours. To the reaction solution, toluene was added, and the solvent was distilled off under reduced pressure. The residue thereby obtained was recrystallized from methanol to obtain 31 mg (69%) of the desired substance (Compound No. X-1-1) as yellow
crystals.
mp 248-250°C (decomp.)
MS(EI) m/e: 225(M)+
500 MHz 1H-NMR(CDCl3)δ: 3.61(3H, s), 5.76(1H, s),
7.46(1H, s), 11.5(1H, br), 12.3(1H, br )
In the same manner, Compound No. X-1-2 was prepared by using Compound (XII-1-2) as starting material.
Figure imgf000169_0001
Pale yellow powder
mp 153-158°C (decomp.)
MS(FAB) m/e: 360(M+H)+
In the same manner, Compound No. X-2-1 was prepared by using Compound No. XII-2-1 as starting material.
Figure imgf000170_0002
Pale yellow crystals
mp 150-154°C
MS(FAB) m/e: 228(M+H)+
EXAMPLE 7
Preparation of 5-((1-methyl-5-phenacyloxy-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No, 1-1a-7)
Figure imgf000170_0001
69 mg (0.31 mmol) of 5-((5-hydroxy-1-methyl-3-pyrazolyl)methylidene)thiazolidin-2,4-dione (Compound No. X-1-1) and 57 mg (0.37 mmol) of phenacyl chloride were dissolved in 2 me of dimethylformamide dehydrated by molecular sieves. To this solution, 65 μe of
triethylamine was added, and the mixture was stirred at room temperature overnight. To this reaction solution, 1 mℓ of a saturated sodium chloride aqueous solution was added, and the mixture was extracted with 120 me of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The residue thereby obtained was subjected to silica gel column chromatography (eluent: ethyl
acetate/hexane = 5/6) to obtain 17 mg (16%) of the desired substance (Compound No. l-1a-7) as pale yellow powder.
In the same manner, Compound No. I-2a-9 was prepared by using Compound No. X-2-1 by the reaction with phenacyl chloride.
Further, using Compound No. X-1-2 (Z group protected product of Compound No. X-1-1) as starting material, R1 substituent was introduced in the same manner to obtain Compound No. XVIII-1, followed by removal of the
protective group in the same manner as in Example 6 to obtain the desired Compound No. I-1a-7.
Figure imgf000171_0001
Pale yellow powder (yield: 16.6%)
MS(EI) m/e: 477(M)+
500 MHz 1H-NMR(CDCl3)δ: 3.80(3H, s), 5.15(2H, s),
5.33(2H, s), 6.42(1H, s), 7.36-7.63 ( 8H, m), 7.70(1H, s), 7.99(2H, m)
In the same manner, using Compound No. X-1-2 and phenetyl bromide as starting materials, Z group protected product of Compound I-1a-2 (Compound No. XVIII-2) was prepared, followed by removal of the protective group in the same manner as in Example 6 to obtain the desired Compound I-1a-2.
Figure imgf000172_0001
Pale brown powder (yield: 35.1%)
MS(EI) m/e: 463(M)+
500 MHz 1H-NMR(CDCl3)δ: 2.96(2H, t, 3JHH = 7.8 Hz), 3.78(3H, s), 3.95(2H, t, 3JHH = 7.8 Hz), 5.32(2H, s), 6.39(1H, s), 7.21-7.45(10H, m), 7.62(1H, s)
TEST EXAMPLE 1: Measurement of hypoglycemic effect
XX mouse and KXAy mouse, NIDDM models (male, 6-7 weeks old) (Nakamura, Proc. Jpn. Acad. 38, 348-352, 1962;
Iwatsuka et al. Endocrinol. Jpn., 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 μe) 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.
All test-compounds suspended in 0.5% carboxy-methyl cellulose (CMC)-saline were orally administered in mice. Before and 24 hours after the administration, blood was collected from the retro-orbital sinus, and a blood glucose value was measured in the above-mentioned manner.
The hypoglycemic activity was expressed by the percentage of reducing blood glucose calculated before and 24 hours after the administration.
Figure imgf000174_0001
The compounds of the present invention exhibited hypoglycemic activities at substantially the same or higher degree as compared with CS-045 and CP-86325 used as controls. Glibenclamide (insulin-releasing agent) did not exhibit hypoglycemic activity in this test.
TEST EXAMPLE 2: Measurement of anti-glycation effect
When high-glucose concentrations in diabetic patients sustain for a long time, some kinds of proteins are glycated non-enzymatically. It is considered that the glycated proteins induce diabetic complications
(Brownlee, Diabetes, 41 suppl 2, 57-60, 1992).
Because glycated protein is fluorescent, the amount of glycated protein can be determined using fluorescence, according to the previous reports (Doi et al., Proc.
Natl. Acad. Sci. U.S.A., 89, 2873-2877, 1992: Mitsuhashi et al., Diabetes, vol. 42, 826-832, 1993). The
experimental procedure was modified as follows. Five percent of bovine serum albumin (BSA) containing 0.5M glucose-6-phosphate-2Na (5% BSA-0.5M G6P) was filtrationsterilized (with 0.45 μm-pore size filter) and was incubated at 37°C; positive control was incubated with 1% dimethyl sulfoxide (DMSO) at 37°C; blank was incubated at 4°C. All test-compounds dissolved in DMSO (final
concentration of DMSO was less than 1%) were added in 5% BSA-0.5M G6P. After 10 day-incubation 5% BSA-0.5M G6P with a compound, positive control and blank were dialyzed against 2L phosphate buffered saline for 24 hours
(fractional molecular weight: 12,000-14,000). The dialyzed solution was diluted in water 4 times and was determined the fluorescence (ex. 370 nm-em. 440 nm). The protein concentration of the dialyzed solution (10 μL of which was diluted to 20 times with distilled water) was determined by Lowry-method and the fluorescence was expressed per mg protein. Control (100%) was positive control minus blank. Anti-glycation effect was
calculated as the percentage of the control.
Figure imgf000176_0001
The compounds of the present invention exhibited anti-glycation activities stronger than aminoguanidine used as a control. CS-045 and CP-86325 did not exhibit anti-glycation activities.
TEST EXAMPLE 3: Measurement of aldose-reductase
inhibitory activities
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 used as an aldose reductase sample.
Determination of AR and effects of test compounds
AR activity was assayed by the modified method of Inukai et al. (Jpn. J. Pharmacol. 61, 221-227, 1993). The absorbance of NADPH (340 nm), oxidation of the co-factor for AR, was determined by spectrophotometer (UV- 240, Shimadzu, Kyoto). The assay was carried out in 0.1M sodium phosphate (pH 6.2) containing 0.4M lithium
sulfate, 0.15 mM NADPH, the enzyme, various
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%. The effects of inhibitors were estimated as the concentration of test compounds required for 50% inhibition of enzyme activity
(IC50). Aldose-reductase inhibitory activities
Figure imgf000178_0001
The compounds of the present invention exhibited stronger aldose-reductase inhibitory activities than sulindac, quercetin or alrestatin used as control.
Further, CS-045 and CP-86325 exhibited no activities. FORMULATION EXAMPLE 1
Tablets
Figure imgf000179_0001
The above components were mixed by a usual method and then tabletted to produce 100 tablets each containing 10 mg of the active ingredient.
FORMULATION EXAMPLE 2
Capsules
Figure imgf000179_0002
The above components were mixed by a usual method and then packed in No. 4 gelatin capsules to obtain 100 capsules each containing 10 mg of the active ingredient. FORMULATION EXAMPLE 3
Soft capsules
Figure imgf000180_0001
The above compounds were mixed and packed in No. 3 soft gelatin capsules by a usual method to obtain 100 soft capsules each containing 10 mg of the active
ingredient.
FORMULATION EXAMPLE 4
Ointment
Figure imgf000180_0002
The above components were mixed by a usual method to obtain a 1% (10%) ointment.
FORMULATION EXAMPLE 5
Suppository
Figure imgf000181_0001
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.
FORMULATION EXAMPLE 6
Granules
Figure imgf000181_0002
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.
INDUSTRIAL APPLICABILITY
Since the compound of the present invention has a hypoglycemic effect, an anti-glycation activity 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.

Claims

CLAIMS :
1. A pyrazole type thiazolidine compound of the
following formula (I) and its salt:
Figure imgf000183_0001
wherein X1 is S or O;
X2 is S, O or NH;
Y is CR6R7 (R6 is a hydrogen atom, a C1-C 7 alkyl group or a C3-C7 cycloalkyl group, and R7 is a hydrogen atom, a C1-C7 alkyl group or a C3-C 7 cycloalkyl group, or forms a bond together with R4);
R1 is a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a C2-C10 alkenyloxy group, a CJ-CJQ alkylthio group, a C1-C10 monoalkylamino group or a di-C1-C10 alkylamino group (each of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10
alkynyl, C1-C10 alkoxy, C2-Cl0 alkenyloxy, C1-C10
alkylthio, C1-C1Q monoalkylamino and di-C1-C10 alkylamino groups may be substituted with a hydroxyl group or a C1-C7 alkyl group), or
-Vk-Wl-Z (Z is a C3-C10 cycloalkyl group, a C3-C7 cycloalkenyl group, a C6-C14 aromatic group, a C4-C12 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 C4-C6 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 C3-C10
cycloalkyl, C3-C7 cycloalkenyl, C6-C14 aromatic, C4-C12 heterocyclic aromatic and C4-C6 heterocycloaliphatic groups may have at most 5 substituents selected from the group consisting of a hydrogen atom, a C1-C 7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C6 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, a hydroxyl group, a halogen atom, a nitro group and a dimethylamino group), a i-tecrazolyl group, a 3-tetrazolyl group, a 5-tetrazolyl group, a thiazolidindion-5-yl group and a
thiazolidindion-5-yl methyl group),
V is O, S, SO, SO2 or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group),
W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, and
each of k and e is 0 or 1),
-V-W-V-W-Z (V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different),
-W-V-W-Z (V, W and Z are as defined above, and two W's may be the same or different),
-V-W-V-Z (V, W and Z are as defined above, and two V's may be the same or different), or
-W-V-Z (V, W and Z are as defined above);
each of R2 and R3 is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group (said C1-C 7 alkyl and C3-C7 cycloalkyl groups may be substituted with a hydroxyl 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
substituted with at most 5 members selected from the group consisting of a hydroxyl group, a C1-C7 alkyl group, a C1-C7 alkoxy group and a halogen atom), and R2 or R3 may further be a halogen atom when it is bonded to a carbon atom at the 3-, 4- or 5-position of the pyrazole ring;
R4 is a hydrogen atom or a C1-C7 alkyl group, or forms a bond together with R7; and
R5 is a hydrogen atom or a carboxymethyl group.
2. The pyrazole type thiazolidine compound and its salt according to Claim 1, wherein the compound of the formula (I) is represented by the following formula (la):
Figure imgf000186_0001
wherein R1 is a C1-C10 alkyl group, a C2-C10 alkenyl group, a C2-C10 alkynyl group, a C1-C10 alkoxy group, a C2-C10 alkenyloxy group, a C1-C10 alkylthio group, a C1-C10 monoalkylamino group or a di-C1-C10 alkylamino group (each of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10
alkynyl, C1-C10 alkoxy, C2-C10 alkenyloxy, C1-C10
alkylthio, C1-C10 monoalkylamino and di-C1-Cj^ alkylamino groups may be substituted with a hydroxyl group or a C1-C7 alkyl group), or -Vk-Wl-Z (among groups of Z as defined for the formula (I), said C3-C10 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 C3-C7 cycloalkenyl group is cyclohexenyl,
cyclopentadienyl, 2-bicylo[2.2.1]heptenyl or 2,5- bicyclo[2.2.1]heptadienyl, said C6-C14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl, said C4- C12 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,
tetrazinyl, indolyl, quinolyl, quinolonyl, benzofuranyl, benzothienyl, isoquinolyl, isoquinolonyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl,
benzotriazolyl, benzopyranyl, indolizinyl, purinyl, phthalazinyl, oxophthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxanyl, oxonaphthalenyl, dihydrobenzofuranyl, benzothiazinyl, pteridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[5,1-c][1,2,4]triazinyl, thiazolo[3,2-b]triazolyl,
benzooyrano[2,3-b]pyridyl, 5H-benzopyrano[2,3-b]pyridonyl, xanthenyl, phenoxathiinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or thianthrenyl, and said C4-C6 heterocycloaliphatic group is piperidyl, pyrrolidinyl, imidazolidinyl,
pyrazolidinyl, morpholinyl, or tetrahydrofuranyl, (each of said C3-C10 cycloalkyl, C3-C7 cycloalkenyl, C6-C14 aromatic, C4-C12 heterocyclic aromatic and C4-C6
heterocycloaliphatic groups may have at most 5
substituents selected from the group consisting of a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy 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 C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-C3 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
thiazolidindion-5-yl group and a thiazolidindion-5-yl methyl group),
V is O, S, SO, SO2 or NR8 (R8 is a hydrogen atom or a C1-C 3 alkyl group),
W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, and
each of k and e is 0 or 1),
-V-W-V-W-Z (V, W and Z are as defined above, and two V's and W's may, respectively, be the same or different), -W-V-W-Z (V, W and Z are as defined above, and two W's may be the same or different),
-V-W-V-Z (V, W and Z are as defined above, and two V's may be the same or different), or
-W-V-Z (V, W and Z are as defined above).
3. The pyrazole type thiazolidine compound and its salt according to Claim 2, wherein the compound of the formula (la) is represented by the formula (lb):
Figure imgf000189_0001
4. The pyrazole type thiazolidine compound and its salt according to Claim 3, wherein R1 is -V-W-Z, -W-Z,
-V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z (V is O, S or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C6 saturated or C2-C6 unsaturated
hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-C7 alkyl groups, when two V's or W's are present, such V's or W's may be the same or different, and Z is
Figure imgf000190_0001
Figure imgf000191_0001
wherein each of Ra and Rb is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3- C7 cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy group, a C1-C7 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, c-naphthyl, /9-naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5 substituents selected from the group consisting of a C1-C 7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 alkoxy group, a C1-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 thiazolidindion-5-yl methyl group, and Rc is a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group or a hydroxymethyl group);
R2 or R3 is a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a naphthyl group. a benzyl group or a pyridyl group, when it is on the nitrogen atom at the 1-position of the pyrazole ring; and
R2 or R3 is a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a halogen atom, when it is on the carbon atom at the 4-position of the pyrazole ring.
5. The pyrazole type thiazolidine compound and its salt according to Claim 4, wherein said compound is
represented by the formula:
Figure imgf000193_0001
wherein Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond
together with R4);
R1 is -V-W-Z, -W-Z, -V-W-V-W-Z, -W-V-W-Z, -V-W-V-Z or -W-V-Z (V is O, S or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 3 of hydroxyl, oxo and C1-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, and Z is
Figure imgf000194_0001
wherein each Ra and Rb is independently a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C3-C7 cycloalkenyl group (said alkyl, cycloalkyl and
cycloalkenyl groups may be substituted with a hydroxyl group), a hydroxyl group, a C1-C7 alkoxy 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 C1-C3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a phenoxy group, a benzyloxy group, a phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl or benzyl group (each of said phenyl, α-naphthyl, β-naphthyl, furanyl, thienyl, imidazolyl, pyridyl and benzyl groups may be substituted with at most 5
substituents selected from the group consisting of a C1-C7 alkyl group, a C3-C7 cycloalkyl group, a C1-C3 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 Rc is a hydrogen atom, a C1-C7 alkyl group, a C3-C7 cycloalkyl group or a hydroxymethyl group);
R4 is a hydrogen atom or a methyl group, or forms a bond together with R7;
R5 is a hydrogen atom or a carboxymethyl group.
6. The pyrazole type thiazolidine compound and its salt according to Claim 5, wherein:
R1 is -O-W-Z, wherein W is a divalent C1-C6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C1-C 7 alkyl groups (provided that the first carbon atom bonded with the oxygen atom is not substituted with a hydroxyl group or an oxo group).
7. The pyrazole type thiazolidine compound and its salt according to Claim 5, wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein V is O or NR8 (R8 is a hydrogen atom or a C1-C3 alkyl group), W is a divalent C1-C 6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 2 of hydroxyl, oxo and C1-C7 alkyl groups (provided that the first carbon atom bonded with the oxygen atom 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).
8. The pyrazole type thiazolidine compound and its salt according to Claim 5, wherein:
R1 is -W-Z, wherein W is a divalent C1-C 6 saturated or C2-C6 unsaturated hydrocarbon group which may be substituted with at most 2 hydroxyl, oxo and C1-C7 alkyl groups.
9. The pyrazole type thiazolidine compound and its salt according to Claim 6, wherein:
R1 is -O-W-Z, wherein W is
Figure imgf000197_0001
wherein m is from 1 to 5, and each of Rd and Re is independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent Rd's and Re's together form a triple bond (provided that Rd and Re on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group).
10. The pyrazole type thiazolidine compound and its salt according to Claim 7, wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein W is
Figure imgf000197_0002
wherein m is from 1 to 5, and each of Rd and Re is independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent Rd's and Re's together form a triple bond (provided that Rd and Re on the first carbon atom adjacent to O are not hydroxyl groups or do not together form an oxo group).
11. The pyrazole type thiazolidine compound and its salt according to Claim 8, wherein:
R1 is -W-Z, wherein W is
Figure imgf000198_0001
wherein m is from 1 to 5, each of Rd and Re is
independently a hydrogen atom, a methyl group or a hydroxyl group, or Rd and Re together form an oxo group, or adjacent Rd's together form a double bond, or adjacent Rd's and Re's together form a triple bond.
12. The pyrazole type thiazolidine compound and its salt according to Claim 9, wherein:
R1 is -O-W-Z, wherein -O-W is
Figure imgf000199_0001
13. The pyrazole type thiazolidine compound and its salt according to Claim 10, wherein:
R1 is -O-W-V-W-Z, -W-V-W-Z, -O-W-V-Z or -W-V-Z, wherein -O-W-V-W- is
-
Figure imgf000200_0001
-W-V-W- is
Figure imgf000200_0002
-O-W-V- is
Figure imgf000201_0001
and -W-V- is
Figure imgf000201_0002
14. The pyrazole type thiazolidine compound and its salt according to Claim 11, wherein:
R1 is -W-Z, wherein W is
Figure imgf000202_0002
15. The pyrazole type thiazolidine compound and its salt according to Claim 12, wherein:
R1 is -O-W-Z, wherein -O-W- is
16. The pyrazole type thiazolidine compound and its salt according to Claim 14, wherein:
R1 is -W-Z, wherein W is
Figure imgf000203_0001
17. The pyrazole type thiazolidine compound and its salt according to Claim 6 , 7 or 8 , wherein :
Y is -CH2- ; and
R4 is a hydrogen atom.
18. The pyrazole type thiazolidine compound and its salt according to Claim 6, 7 or 8, wherein:
Y is CHR7 (R7 forms a bond together with R4); and R4 forms a bond together with R7.
19. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula:
Figure imgf000204_0002
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
20. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula:
Figure imgf000204_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C 7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
21. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula :
Figure imgf000205_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a
fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
22. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula:
Figure imgf000206_0002
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom) , R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
23. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula:
Figure imgf000206_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
24. The pyrazole type thiazolidine compound and its salt according to Claim 15, which is represented by the formula :
Figure imgf000207_0001
wherein each of Ra, Rb and Rc is independently a hydrogen atom, a C1-C7 alkyl group, a C1-C7 alkoxy group, a fluorine atom, a chlorine atom, a bromine atom or a phenyl group (said phenyl group may be substituted with at most 3 of a methyl group, a methoxy group and a chlorine atom), R2 is a hydrogen atom, a C1-C7 alkyl group or a phenyl group, R3 is a hydrogen atom or a C1-C7 alkyl group, Y is CR6R7 (R6 is a hydrogen atom or a methyl group, and R7 is a hydrogen atom, or forms a bond together with R4), and R4 is a hydrogen atom, or forms a bond together with R7.
25. A hypoglycemic agent containing the pyrazole type thiazolidine compound or its salt according to Claim 1 as an active agent.
26. An anti-glycation agent containing the pyrazole type thiazolidine compound or its salt according to Claim 1 as an active agent.
27. An aldose reductase inhibitor containing the pyrazole type thiazolidine compound or its salt according to Claim 1 as an active agent.
28. A pharmaceutical agent for preventing and treating diabetes mellitus and diabetic complications, which contains the pyrazole type thiazolidine compound or its salt according to Claim 1 as an active agent.
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US5889025A (en) * 1996-05-06 1999-03-30 Reddy's Research Foundation Antidiabetic compounds having hypolipidaemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
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US6313113B1 (en) 1997-04-15 2001-11-06 Reddy-Cheminor, Inc. Heterocyclic compounds having antidiabetic, hypolipidemic and antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US6011031A (en) * 1997-05-30 2000-01-04 Dr. Reddy's Research Foundation Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
US6159966A (en) * 1997-05-30 2000-12-12 Reddy-Cheminor Inc. Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them
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US6756360B1 (en) 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
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