WO2001017513A2 - Pharmaceutical composition comprising an insulin sensitizer - Google Patents

Pharmaceutical composition comprising an insulin sensitizer Download PDF

Info

Publication number
WO2001017513A2
WO2001017513A2 PCT/JP2000/005951 JP0005951W WO0117513A2 WO 2001017513 A2 WO2001017513 A2 WO 2001017513A2 JP 0005951 W JP0005951 W JP 0005951W WO 0117513 A2 WO0117513 A2 WO 0117513A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
lower alkyl
formula
halogen
Prior art date
Application number
PCT/JP2000/005951
Other languages
French (fr)
Other versions
WO2001017513A3 (en
Inventor
Katsuichi Sudo
Yasuhiko Wada
Yasuo Sugiyama
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to CA002383946A priority Critical patent/CA2383946A1/en
Priority to KR1020027002851A priority patent/KR20020063555A/en
Priority to PL00354295A priority patent/PL354295A1/en
Priority to HU0203285A priority patent/HUP0203285A3/en
Priority to EP00956872A priority patent/EP1212090A2/en
Priority to AU68680/00A priority patent/AU6868000A/en
Publication of WO2001017513A2 publication Critical patent/WO2001017513A2/en
Publication of WO2001017513A3 publication Critical patent/WO2001017513A3/en
Priority to NO20021036A priority patent/NO20021036L/en
Priority to HK02105969.4A priority patent/HK1044711A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition which is useful as an agent for preventing or treating diabetes, etc. , comprising an insulin sensitizer (insulin resistance-improving agent).
  • JP-A H5( 1993) -148496 describes that 4- [2- ( 2-hydroxy- 2-phenyl-ethylamino)ethoxy]phenylacetic acid and its precursors are ⁇ 3 adrenergic receptor agonists.
  • 096/16938 describes a novel indole derivative having a potent ⁇ 3 adrenergic receptor stimulating activity.
  • the present invention relates to ( 1 ) a pharmaceutical composition which comprises an insulin sensitizer in combination with at least one member selected from the group consisting of
  • R x represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonyla ino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R 2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
  • R 2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
  • R 3 represents hydrogen atom or a lower alkyl group
  • W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
  • R 4 represents a halogen atom or a halogeno lower alkyl group, R s represents a lower alkyl group, or a salt thereof ; 2) a compound of the formula [II] :
  • R 6 represents a halogen atom or a halogeno lower alkyl group
  • R 7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group
  • R 8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof
  • ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C 3 _ 8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
  • R 11 represents hydroxy, oxo, halogen, cyano, nitro, NR 18 R 18 , SR 18 , a halogeno lower alkyl, C ⁇ alkyl, C 1 . 6 alkoxy, C 3 . ⁇ cycloalkyl, phenyl, S0 2 R 19 , NR 18 COR 19 , COR 19 , NR 18 S0 2 R 19 ,
  • NR 18 C0 2 R 18 or a C 1 . 6 alkyl group substituted by hydroxy, nitro , halogen, cyano, NR 18 R 18 , SR 18 , a halogeno lower alkyl, C x , 6 alkoxy, C 3 .
  • R 8 cycloalkyl, phenyl, NR l ⁇ COR 19 , COR 19 , S0 2 R 19 , NR 18 S0 2 R 19 or NR 18 C0 2 R 18 ; or R 11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R 12 and R 13 represent independently hydrogen atom, C ⁇ alkyl, or C j ⁇ .g alkyl substituted by hydroxy, C x .
  • R 14 and R 15 represent independently hydrogen atom, C ⁇ alkyl, halogen, NHR 18 , OR 18 , S0 2 R 19 or NHSO-R 19 ;
  • R 16 represents hydrogen atom or C 1-6 alkyl;
  • R 17 represents C ⁇ alkyl, C 3 .
  • ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 .
  • R 18 represents hydrogen atom; C ⁇ ,, alkyl; C 3 . 8 cycloalkyl; phenyl substituted by halogen, C 1 . 6 alkyl or C ⁇ alkoxy; C 1 . 10 alkyl substituted by hydroxy, halogen, C0 2 H, C 1 . 6 alkoxy-carbonyl, C 3 . 8 cycloalkyl, C ⁇ 6 alkoxy, or phenyl substituted by halogen, C x _ 6 alkyl or C ⁇ alkoxy; R 19 represents R 18 , NHR 18 or NR 18 wherein R 18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
  • R represents hydrogen atom or methyl group
  • R 21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
  • R 22 represents hydrogen atom, hydroxymethyl group, NHR 23
  • R 23 represents hydrogen atom, methyl group, S0 2 NR 25 , formyl group or CONHR 26'
  • R 2S represents a lower alkyl group, benzyl group or NR 24 R 24 ,
  • R 24 and R 24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
  • R 26' represents hydrogen atom or a lower alkyl group.
  • R 26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
  • Xb represents secondary nitrogen atom, 0 or S
  • one of R 27 or R 28 is hydrogen atom
  • the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
  • R 28 is hydrogen atom, and R 27 is hydrogen atom, amino group. acetylamino group or hydroxy group , when na is 2 ,
  • *1 represents an asymmetric carbon atom
  • *2 and *3 represent an asymmetric carbon atom when R 26 and
  • R 28 are respectively not hydrogen atom, or a salt thereof.
  • R represents hydrogen atom or methyl group.
  • R represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
  • R 32 represents hydrogen atom, hydroxymethyl group, NHR 33 ,
  • R 33 represents hydrogen atom, methyl group, S0 2 NR 35 , formyl group or CONHR 36 ,
  • R 35 represents a lower alkyl group, benzyl group or NR 34 R 34 , R 34 and R 34' are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
  • R J represents hydrogen atom or a lower alkyl group.
  • R represents hydrogen atom or a lower alkyl group
  • Xc represents secondary nitrogen atom, O, S or methylene grou ,
  • R 39 is hydrogen atom, one of R 37 or R 38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
  • R 37 and R 38 are both hydrogen atom, and R 39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
  • *4 represents an asymmetric carbon atom
  • *5 represents an asymmetric carbon atom when R 36 is a lower- alkyl group, or a salt thereof;
  • R represents a hydrocarbon group or a heterocyclic group, each of which may be substituted
  • Y represents a group of the formula : -CO-, -CH(OH)- or -NR 3 - wherein R 3 represents an alkyl group that may be substituted
  • m is 0 or 1
  • n is 0, 1 or 2
  • X represents CH or N
  • A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms
  • Q represents O or S
  • R 1 represents hydrogen atom or an alkyl group
  • ring E may have further 1 to 4 substituents, which may form a ring in combination with R 1
  • L and M respectively represent hydrogen atom or may be combined with each other to form a chemical bond, or a salt thereof;
  • ( 5 ) a pharmaceutical composition according to the above ( 1 ) , which comprises pioglitazone or its hydrochloride in combination with 2- [3- ( 7-carboxymethoxyindol-3-yl) - (2R) -2-propylamino] - (IR) -1- ( 3-chlorophenyl) ethanol;
  • ( 6 ) a pharmaceutical composition according to the above ( 1 ) , which comprises rosiglitazone or its maleate in combination with 2-[3-(7-carboxymethoxyindol-3-yl)-(2R) -2- propylamino] - ( IR) - 1- ( 3-chlorophenyl ) ethanol;
  • ( 7 ) a pharmaceutical composition according to the above ( 1 ) , which is for preventing or treating diabetes;
  • ( 9 ) a pharmaceutical composition according to the above ( 1 ) , which is for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications ; (10) a pharmaceutical composition according to the above (9), wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris , cerebrovascular disease or peripheral circulatory disturbance;
  • a pharmaceutical composition for inhibiting body weight increase after stopping a smoking habit which comprises at least one member selected from the group consisting of
  • a pharmaceutical composition for inhibiting body weight increase after stopping alimentary therapy which comprises at least one member selected from the group consisting of
  • a compound of the formula [VI] or a salt thereof (13) a method for preventing or treating diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] or a salt thereof;
  • a compound of the formula [VI] or a salt thereof (14) a method for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis , glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of
  • the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance;
  • a method for inhibiting body weight increase after stopping alimentary therapy in human in need thereof which comprises administering to said human an effective amount of at least one member selected from the group consisting of
  • a compound of the formula [V] or a salt thereof and 5) a compound of the formula [VI] or a salt thereof, for the manufacture of a pharmaceutical preparation for treating diabetes, which is used in combination with an insulin sensitizer; (20) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, which is used in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] or a salt thereof;
  • the insulin sensitizer used in the present invention means any and all drugs that restore the impaired insulin receptor function and improve insulin resistance.
  • insulin sensitizer examples include compounds having thiazolidinedione or oxazolidinedione skeletons, preferably the above-mentioned compound of the formula (IV) or a salt thereof.
  • examples of the hydrocarbon group in the hydrocarbon group that may be substituted for R include aliphatic hydrocarbon groups , alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups , aromatic-aliphatic hydrocarbon groups , and aromatic hydrocarbon groups.
  • the number of carbon atoms constituting such hydrocarbon groups is preferably 1 to 14.
  • the aliphatic hydrocarbon group is preferably a aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group includes saturated C ⁇ aliphatic hydrocarbon groups (e.g. alkyl groups, etc.) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t. -butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, and octyl; and unsaturated C 2 . 8 aliphatic hydrocarbon groups (e.g.
  • alkenyl groups alkadienyl groups , alkynyl groups , alkadiynyl groups , etc .
  • alkenyl groups such as vinyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexy
  • the alicyclic hydrocarbon group is preferably a C 3 . 7 alicyclic hydrocarbon group.
  • the alicyclic hydrocarbon group include saturated C 3 . 7 alicyclic hydrocarbon groups (e.g. cycloalkyl groups, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. and unsaturated C 5 . 7 alicyclic hydrocarbon groups (e.g.
  • cycloalkenyl groups such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl , 3-cyclohexenyl, 1-cycloheptenyl, 2- cycloheptenyl, 3-cycloheptenyl, and 2 , 4-cycloheptadienyl .
  • the alicyclic-aliphatic hydrocarbon group is a group consisting of the above-described alicyclic hydrocarbon group and aliphatic hydrocarbon group (e.g.
  • cycloalkyl- alkyl groups ' cycloalkenyl-alkyl groups, etc.
  • the alicyclic-aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl , cyclobutylmethyl , cyclopentylmethyl, 2- cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl , 2-cyclohexenylmethyl, 3- cyclohexenylmethyl , cyclohexylethyl, cyclohexylpropyl , cycloheptylmethyl , cycloheptylethyl, etc.
  • the aromatic-aliphatic hydrocarbon group is preferably a C 7 _ 13 aromatic-aliphatic hydrocarbon group (e.g. aralkyl groups, etc. ) .
  • the aromatic-aliphatic hydrocarbon group include C 7 . 9 phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; C l ⁇ _ 13 naphthylalkyl such as Ot - naphthylmethyl , a -naphthylethyl, ⁇ -naphthylmethyl, and ⁇ -naphthylethyl.
  • the aromatic hydrocarbon group is preferably a C 6 . 14 aromatic hydrocarbon group (e.g. aryl groups, etc.).
  • the aromatic hydrocarbon group include phenyl and naphthyl ( a -naphthyl, ⁇ -naphthyl) .
  • examples of the heterocyclic group in the heterocyclic group that may be substituted for R is a 5- to 7-membered heterocyclic group containing 1 to 4 hetero-atoms selected from oxygen, sulfur, and nitrogen in addition to carbon as ring members or a condensed ring group.
  • Examples of the condensed ring include one consisting of such 5- to 7-membered heterocyclic group with a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom.
  • heterocyclic group examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4- oxadiazol-5-yl, 1 , 2 , 4-triazol-3-yl, 1 , 2 , 3-triazol-4-yl , tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl
  • the hydrocarbon group and heterocyclic group for R may respectively have 1 to 5 , preferably 1 to 3 substituents at substitutable positions.
  • substituents include for example aliphatic hydrocarbon groups , alicyclic hydrocarbon groups , aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen, nitro, amino groups that may be substituted, acyl groups that may be substituted, hydroxy groups that may be substituted, thiol groups that may be substituted, carboxyl groups that may be esterifled, amidino, carbamoyl, sulfamoyl, sulfo, cyano, azido, and nitroso.
  • Examples of the aliphatic hydrocarbon group include straight-chain or branched aliphatic hydrocarbon groups having 1 to 15 carbon atoms, such as alkyl groups, alkenyl groups , and alkynyl groups .
  • the preferred alkyl group is a C ⁇ alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t.
  • the preferred alkenyl group is a C 2 . 1Q alkenyl group. such as vinyl, allyl, isopropenyl, 1-propenyl, 2- methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.
  • the preferred alkynyl group is a C 2 .
  • alkynyl group such as 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, and 5-hexynyl.
  • Examples of the alicyclic hydrocarbon group includes saturated or unsaturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms, such as cycloalkyl groups , cycloalkenyl groups , and cycloalkadienyl groups .
  • the preferred cycloalkyl group is a C 3 .
  • cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2] octyl , bicyclo [3.2.1] octyl , bicyclo [3.2.2] nonyl , bicyclo [3.3.1] nonyl, bicyclo [ 4.2.1 ] nonyl, and bicyclo [4.3.1] decyl .
  • the preferred cycloalkenyl group is a C 3 . 10 cycloalkenyl group, such as 2-cyclopenten-l-yl, 3- cyclopenten-1-yl, 2-cyclohexen-l-yl, and 3-cyclohexen- 1-yl.
  • the preferred cycloalkadienyl group is a C 4 . 10 cycloalkadienyl group, such as 2, 4-cyclopentadien-l-yl, 2, 4-cyclohexadien-l-yl, and 2, 5-cyclohexadien-l-yl.
  • the preferred aryl group is a C 6 . 14 aryl group, such as phenyl, naphthyl (1- naphthyl, 2 -naphthyl), anthryl, phenanthryl, and acenaphthylenyl .
  • the preferred aromatic heterocyclic group includes monocyclic aromatic heterocyclic groups, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 , 2 , 3-oxadiazolyl, 1, 2 , 4-oxadiazolyl, 1 , 3 , 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1 , 2, 4-thiadiazolyl, 1 , 3 , 4-thiadiazolyl, 1, 2, 3-triazolyl, 1 , 2 , 4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and condensed aromatic heterocyclic groups, such as benzofuranyl, isobenzofuranyl, benzo[b] hienyl
  • the preferred non-aromatic heterocyclic group includes oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl , thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl , thiomorpholinyl . piperazinyl, pyrrolidino, piperidino, morpholino, and thiomorpholino .
  • the halogen include fluorine, chlorine, bromine, and iodine.
  • examples of the substituted amino group include N-mono- substituted amino groups and N,N-di-substituted amino groups.
  • examples of the substituted amino group include amino groups having one or two substituents selected from the group consisting of C 1 . 10 alkyl groups, C 2 . 10 alkenyl groups , C 2 . 10 alkynyl groups , C 3 _ 10 cycloalkyl groups , aromatic groups (e.g., phenyl), heterocyclic groups, or C ⁇ o acyl groups (e.g., C ⁇ ,, alkanoyl groups, benzoyl, nicotinoyl) (e.g.
  • acyl group in the acyl groups that may be substituted include C 1 . 13 acyl groups, for example, C ⁇ alkanoyl groups , C 3 . 10 alkenoyl groups , C 4 _ 10 cycloalkanoyl groups, C 4 .
  • C 6 . 12 aromatic carbonyl groups cycloalkenoyl groups, C 6 . 12 aromatic carbonyl groups .
  • Preferred examples of the C ⁇ Q alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and octanoyl.
  • Preferred examples of the C 3 . 10 alkenoyl groups include acryloyl, methacryloyl , crotonoyl, and isocrotonoyl .
  • Preferred examples of the C 4 . 10 cycloalkanoyl groups include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, and cycloheptanecarbonyl .
  • Preferred examples of the C 4 . 10 cycloalkenoyl groups include 2-cyclohexenecarbonyl.
  • Preferred examples of the C 6-12 aromatic carbonyl groups include benzoyl, naphthoyl, and nicotinoyl.
  • substituents in the substituted acyl groups include alkoxy groups , halogen (e.g. chlorine, fluorine, bromine, etc.), nitro, hydroxy, and amino.
  • examples of the substituted hydroxy includes alkoxy groups , cycloalkyloxy groups , alkenyloxy groups , cycloalkenyloxy groups, aralkyloxy groups, acyloxy groups, and aryloxy groups .
  • the preferred alkoxy group includes C ⁇ ,, alkoxy groups , such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. -butoxy, t. -butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, and nonyloxy.
  • the preferred cycloalkyloxy group includes C 3 . 10 cycloalkyloxy groups , such as cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
  • the preferred alkenyloxy group includes C 2 . 10 alkenyloxy groups, such as allyloxy, crotyloxy, 2- pentenyloxy, and 3-hexenyloxy.
  • the preferred cycloalkenyloxy group includes C 3 . 10 cycloalkenyloxy groups, such as 2-cyclopentenyloxy, and 2-cyclohexenyloxy.
  • the preferred aralkyloxy group includes C 7 . 10 aralkyloxy groups, such as phenyl-C ⁇ alkyloxy (e.g. benzyloxy, phenethyloxy, etc.).
  • the preferred acyloxy group includes C 2 . 13 acyloxy groups, more preferably C 2 . 4 alkanoyloxy groups (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc. ) .
  • the preferred aryloxy group includes C 6 . 14 aryloxy groups, such as phenoxy, and naphthyloxy. This aryloxy group may have 1 or 2 substituents. Examples of the substituents include halogen (e.g. chlorine, fluorine, bromine, etc. ) . Examples of the substituted aryloxy group includes 4-chlorophenoxy.
  • examples of the substituted thiol group include alkylthio groups, cycloalkylthio groups, alkenylthio groups, cycloalkenylthio groups , aralkylthio groups , acylthio groups , and arylthio groups .
  • the preferred alkylthio group includes C ⁇ , alkylthio groups, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. -butylthio, t. -butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.
  • alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. -butylthio, t. -butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.
  • the preferred cycloalkylthio group includes C 3 . 10 cycloalkylthio groups such as cyclobutylthio, cyclopentylthio, and cyclohexylthio .
  • the preferred alkenylthio group includes C 2 . 10 alkenylthio groups, such as allylthio, crotylthio, 2- pentenylthio, and 3-hexenylthio.
  • the preferred cycloalkenylthio group includes C 3 . 10 cycloalkenylthio groups such as 2-cyclopentenylthio, and 2-cyclohexenylthio.
  • the preferred aralkylthio group includes C 7 . 10 aralkylthio groups, such as phenyl-C 1 . 4 alkylthio (e.g. benzylthio, phenethylthio, etc.).
  • the acylthio group is preferably a C 2 . 13 acylthio group, more preferably a C 2 . 4 alkanoylthio group (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
  • the preferred arylthio group includes C 6 . 14 arylthio groups , such as phenylthio , and naphthylthio .
  • This arylthio group may have 1 or 2 substituents. Examples of the substituents include halogen (e.g. chlorine, fluorine, bromine, etc.). Examples of the substituted arylthio group includes 4-chlorophenylthio.
  • the carboxyl group that may be esterified includes alkoxycarbonyl groups, aralkyloxycarbonyl groups, and aryloxycarbonyl groups .
  • the preferred alkoxycarbonyl group includes C 2 . 5 alkoxycarbonyl groups , such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , and butoxycarbonyl .
  • the preferred aralkyloxycarbonyl group includes C 8 . 10 aralkyloxycarbonyl groups , such as benzyloxycarbonyl .
  • the preferred aryloxycarbonyl group includes C 7 . 15 aryloxycarbonyl groups, such as phenoxycarbonyl , and p- tolyloxycarbonyl .
  • the preferred substituent on the hydrocarbon group or heterocyclic group for R includes C ⁇ alkyl groups , aromatic heterocyclic groups , and C 6 . 14 aryl groups . Further preferred is C ⁇ alkyl, furyl, thienyl, phenyl, or naphthyl .
  • substituent on the hydrocarbon group or heterocyclic group for R is an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group
  • this substituent may further have one or more, preferably 1 to 3 suitable substituents.
  • substituents include C ⁇ alkyl groups, C 2 . 6 alkenyl groups, C 2 . 6 alkynyl groups , C 3 . 7 cycloalkyl groups , C 6 . 14 aryl groups , aromatic heterocyclic groups (e.g.
  • thienyl furyl, pyridyl, oxazolyl, thiazolyl, etc.
  • non-aromatic heterocyclic groups e.g. tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.
  • C 7 . 9 aralkyl groups amino, N-mono-Ci.,, alkylamino groups, N,N-di-C 1-4 alkylamino groups , C 2 . 8 acylamino groups (e.g.
  • C 2 _ 8 acyl groups e.g. C 2 _ 8 alkanoyl groups, etc.
  • carbamoyl N- mono-C ⁇ alkylcarbamoyl groups, N.N-di-C ⁇ ,, alkylcarbamoyl groups, sulfamoyl, N-mono-Ci. 4 alkylsulfamoyl groups, alkylsulfamoyl groups, carboxyl, C 2 . 8 alkoxycarbonyl groups, hydroxy, C x . 4 alkoxy groups, C 2 .
  • R is preferably a heterocyclic group that may be substituted. More preferably, R is pyridyl, oxazolyl, or thiazolyl group, which may have 1 to 3 substituents selected from the group consisting of C x . 3 alkyl, furyl, thienyl, phenyl, and naphthyl .
  • Y represents -CO-, -CH(OH) - or -NR 3 - wherein R 3 represents an alkyl group that may be substituted. Preferred is -CH(OH)- or -NR 3 -.
  • R 3 represents an alkyl group that may be substituted.
  • Examples of an alkyl group in the alkyl group that may be substituted for R 3 include C 1-4 alkyl groups, such as methyl, ethyl , propyl , isopropyl, butyl, isobutyl, sec. -butyl, and t. -butyl.
  • the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine), C j _.
  • alkoxy groups e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec. -butoxy, t. -butoxy, etc.
  • acyl groups e.g. formyl, acetyl, propionyl, etc.
  • the symbol m represents 0 or 1 , and is preferably 0.
  • the symbol n represents 0, 1 or 2, and is preferably 0 or 1.
  • X represents CH or N, and is preferably CH.
  • A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms .
  • This aliphatic hydrocarbon group may be straight-chain or branched and may further be saturated or unsaturated.
  • A preferably represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 4 carbon atoms , which is preferably a saturated group . More preferably, A represents a chemical bond or -(CH 2 ) 2 -.
  • the alkyl group for R 1 includes the similar one to the alkyl group for the above-described R 3 .
  • R 1 is preferably hydrogen atom.
  • ring E may optionally have further 1 to 4 substituents at substitutable positions.
  • substituents include an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, and an amino group that may be substituted. These substituents are similar to those on the hydrocarbon group and heterocyclic group for the above-described R.
  • Ring E namely the partial structural formula: is preferably the formula : wherein R 2 represents hydrogen atom, an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, or an amino group that may be substituted.
  • R 2 is preferably hydrogen atom, a hydroxy group that may be substituted, or halogen.
  • R 2 is more preferably hydrogen atom, or a hydroxy group that may be substituted.
  • R 2 is especially preferably hydrogen atom, or a C 1 . i alkoxy group.
  • L and M respectively represent hydrogen atom or may be combined with each other to form a chemical bond, and preferably they are hydrogen atom.
  • the compound in which L and M are combined with each other to form a chemical bond may exist as (E)- and (Z)- isomers, owing to the double bond at 5-position of the azolidinedione ring.
  • the compound in which L and M respectively represent hydrogen atom may exist as optical isomers, i.e. (R)- and (S) -forms, with respect to the asymmetric carbon at 5- position of the azolidinedione ring.
  • This compound includes these optically active compounds, i.e. (R)- and (S) -forms, as well as the racemic form.
  • the preferred compound of the formula (IV) includes the compound in which R represents pyridyl, oxazolyl, or thiazolyl group, each of which may have 1 to 3 substituents selected from the group consisting of C ⁇ alkyl, furyl, thienyl, phenyl, and naphthyl; m is 0; n is 0 or 1; X represents CH; A represents a chemical bond or -(CH 2 ) 2 -; R 1 represents hydrogen; ring E, namely the partial structural formula:
  • R 2 is hydrogen or a C x _ 4 alkoxy group; and L and M represent hydrogen atom.
  • Examples of the preferred compound of the formula (IV) includes
  • a salt of a compound represented by the formula (IV) is preferably a pharmacologically acceptable salt, which includes salts with inorganic bases, salts with organic bases, salts with inorganic acids , salts with organic acids , and salts with basic or acidic amino acids.
  • the preferred salt with an inorganic base includes salts with alkali metal such as sodium, potassium, etc.; alkaline earth metal such as calcium, magnesium, etc.; aluminum; ammonium etc.
  • the preferred salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine , N.N-dibenzylethylenediamine, .etc.
  • the preferred salt with an inorganic acid includes salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • the preferred salt with an organic acid includes salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • the preferred salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc.
  • the preferred salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc.
  • a compound represented by the formula (IV) or salt thereof is preferably pioglitazone, troglitazone, rosiglitazone or their salts; more preferably pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate; especially preferably pioglitazone hydrochloride.
  • a compound represented by the formula (IV) or salt thereof can be produced in accordance with methods described in JP-A S55(1980)-22636 (EP_-A-8203), JP-A S60(1985)-208980 (EP-A-155845 ) , JP-A S61 ( 1986 ) -286376
  • Salts of these compounds include those similar to the salt of a compound of the formula (IV) mentioned above.
  • An insulin sensitizer is preferably pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, or ( ⁇ ) -4- [4- [ 2- (5-methyl-2-phenyloxazol-4- yl )ethoxy] benzyl ] isoxazolidin- 3 , 5-dione , especially preferably pioglitazone hydrochloride.
  • the insulin sensitizer can be employed as a mixture of two or more species in an appropriate ratio.
  • the compound of the formula ( I ) or its salt is a known compound which is described in 096/16938 and possesses a ⁇ 3 adrenergic receptor stimulating activity, or a compound produced in accordance with an analogous method to a method described in W096/16938.
  • groups having the term "lower" mean that these groups have 1 to 4 carbon atoms .
  • Examples of the preferred compound of the formula ( I ) or its salt includes 2- [ 3- ( 7 -methoxyindol-3-yl ) -2-propylamino ] - 1- ( 3- chlorophenyl) ethanol ;
  • the compound of the formula (II) or its salt is a known compound which is described in JP-A H6( 1994) -345731 and possesses a ⁇ 3 adrenergic receptor stimulating activity, or a compound produced in accordance with an analogous method to a method described in JP-A H6( 1994 ) -345731.
  • "lower alkyl group” in “lower alkyl group” and “halogeno-lower alkyl group” means C ⁇ alkyl group.
  • Examples of the preferred compound of the formula ( II ) or its salt includes
  • the compound of the formula ( III ) or its salt is a known compound which is described in USP 5451677 and possesses a j33 adrenergic receptor agonistic activity. Examples of the preferred compound of the formula
  • the compound of the formula (V) or its salt is a known compound which is described in WO99/01431 and possesses a /33 agonistic activity.
  • groups having the term "lower” mean that these groups have 1 to 4 carbon atoms.
  • Examples of the preferred compound of the formula (V) or its salt includes (R)-N'-[5-[2-[2-(5,6,7,8-tetrahydro-9H-carbazol-2- yloxy)ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N,N- dimethylsulfamide hydrochloride .
  • the compound of the formula (VI) or its salt is a known compound which is described in 097/23511 and possesses a ⁇ 3 agonistic activity.
  • groups having the term "lower" mean that these groups have 1 to 4 carbon atoms .
  • Examples of the preferred compound of the formula (VI) or its salt includes ( ⁇ ) -N- [ 5- [ 2- [ 2- ( 9H-carbazol-2-yloxy)ethylamino] -1- hydroxyethyl] -2-hydroxyphenyl ]methanesulfonamide hydrochloride;
  • Salts of the compound of the formula (I) , (II), (III), (V) or (VI) include those similar to the salt of a compound of the formula (IV) mentioned above.
  • combination of an insulin sensitizer and a compound of the formula (I) is preferable.
  • Preferred examples of the pharmaceutical composition of the present invention include
  • a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating diabetes .
  • the diabetes include insulin-dependent (type I) diabetes mellitus , noninsulin-dependent (type II) diabetes mellitus, etc.
  • a pharmaceutical composition of the present invention and its active ingredient is especially preferably employed for noninsulin-dependent diabetes mellitus.
  • impaired glucose tolerance means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is less than 140mg/dl, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, ranges from 140 to 199 mg/dl.
  • Diabetes means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is 140mg/dl or more, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 200 mg/dl or more.
  • diabetes means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is 126mg/dl or more, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 200 mg/dl or more.
  • impaired glucose tolerance means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is less than 126mg/dl, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 140mg/dl or more and less than 200 mg/dl.
  • IFG Impaired Fasting Glucose
  • IFG Impaired Fasting Glycemia
  • the pharmaceutical composition of the present invention and its active ingredient can be also used as an agent for preventing or treating diabetes , impaired glucose tolerance, IFG (Impaired Fasting Glucose), IFG (Impaired Fasting Glycemia) , all of which is defined by the above new criteria.
  • the pharmaceutical composition of the present invention and its active ingredient can also prevent progress to diabetes from impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) .
  • a pharmaceutical composition of the present invention and its active ingredient can be also used as an agent for preventing or treating diseases such as hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-high-density-lipoproteinemia, postprandial hyperlipidemia, etc.), hyperinsulinemia, obesity (including body weight increase after stopping a smoking habit, after stopping alimentary therapy, or after stopping exercise), hyperphagia, hypertension, cardiovascular diseases (e.g., atherosclerosis, etc.), polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases (e.g., inflammatory colitis , ulcerative colitis ) , etc.; or syndromes (e.g. , syndrome X, visceral fat obesity syndrome, etc.) having some of these diseases in combination.
  • hyperlipidemia e.g., hypertriglyceridemia,
  • a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating diabetic complications (e.g., retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection, urinary tract infection, gastrointestinal tract infection, dermal soft tissue infection, inferior limb infection) , diabetic osteoporosis , diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris , cerebrovascular disease (e.g., cerebral apoplexy, cerebral infarction) or peripheral circulatory disturbance, etc.).
  • diabetic complications e.g., retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma
  • infectious diseases e.g., respiratory infection, urinary tract infection, gastrointestinal tract infection, dermal soft tissue infection, inferior limb infection
  • a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating irritable bowel syndrome, acute or chronic diarrhea; or for ameliorating bellyache, nausea, vomiting, or dysphoria in epigastrium, each of which is accompanied by gastrointestinal ulcer, acute or chronic gastritis, biliary dyskinesia, or cholecystitis.
  • a pharmaceutical composition of the present invention and its active ingredient possess an effect of ameliorating cachexia, namely an effect of ameliorating the systematic syndrome featuring progressive loss of body weight (inclusive of loss of body weight due to lipolysis and loss of body weight due to myolysis), anemia, edema, and anorexia in chronic diseases such as malignant tumor, tuberculosis, diabetes, blood dyscrasia, endocrine diseases, infectious diseases, and acquired immunodeficiency syndrome .
  • a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating TNF- a mediated inflammatory diseases.
  • the TNF- mediated inflammatory diseases mean inflammatory diseases which occur in the presence of TNF- ot and can be treated by way of a TNF- a inhibitory action.
  • examples of such inflammatory diseases include diabetic complications (e.g., retinopathy, nephropathy, neuropathy, macroangiopahty), rheumatoid arthritis, osteoarthritis of the spine, osteoarthritis , low back pain, gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, laryngopharyngitis , cystitis.
  • hepatitis pneumonia, gastric ucosal injury (including aspirin-induced gastric mucosal injury), etc.
  • a pharmaceutical composition of the present invention and its active ingredient have an apoptosis inhibitory activity, and can be used as an agent for preventing or treating diseases mediated by promotion of apoptosis.
  • diseases mediated by promotion of apoptosis include viral diseases (e.g., AIDS, fulminant hepatitis), neurodegenerative diseases (e.g., Arzheimer's disease, Parkinson' s disease, amyotropic lateral sclerosis , retinitis pigmentosa, cerebellar degeneration), myelodysplasia (e.g.
  • viral diseases e.g., AIDS, fulminant hepatitis
  • neurodegenerative diseases e.g., Arzheimer's disease, Parkinson' s disease, amyotropic lateral sclerosis , retinitis pigmentosa, cerebellar degeneration
  • myelodysplasia e.g.
  • ischemic diseases e.g., myocardial infarction, cerebral apoplexy
  • hepatic diseases e.g., alcoholic hepatitis, hepatitis B, hepatitis C
  • joint-diseases e.g., osteoarthritis
  • atherosclerosis etc.
  • a pharmaceutical composition of the present invention and its active ingredient can be used for reducing visceral fats, inhibiting accumulation of visceral fats, ameliorating glucose metabolism, ameliorating lipid metabolism, ameliorating insulin resistance, inhibiting production of oxidized LDL, ameliorating lipoprotein metabolism, ameliorating coronary artery metabolism, preventing or treating cardiovascular complications, preventing or treating heart failure complications, lowering blood remnant , preventing or treating anovulation , preventing or treating hirsutism, preventing or treating hyperandrogenism, etc.
  • a pharmaceutical composition of the present invention and its active ingredient possess an action of controlling appetite, and thus can be used for treating emaciation or refusal of food.
  • a pharmaceutical composition of the present invention and its active ingredient can be used for secondary prevention and for inhibition in progress, both of various diseases described above (e.g. , cardiovascular events such as myocardial infarction, etc.). Further, a pharmaceutical composition of the present invention and its active ingredient can be used in combination with midazolam, ketoconazole, etc.
  • a pharmaceutical composition of the present invention can be obtained by combining active ingredients , an insulin sensitizer and at least one member selected from the group consisting of a compound of the formula (I) or its salt, a compound of the formula (II) or its salt, a compound of the formula (III) or its salt, a compound of the formula (V) or its salt, and a compound of the formula (VI) or its salt (hereafter also abbreviated as compound (I) to (III) , (V) , (VI) , respectively) .
  • active ingredients may be subjected to pharmaceutical manufacturing processes by admixing separately or concomitantly with pharmaceutically acceptable carriers in accordance with per se known means [conventional means in fields of pharmaceutical manufacturing techniques, for instance, means described in the Pharmacopoeia of Japan (e.g.. Thirteenth Edition, etc. ) ] .
  • Examples of dosage forms of a pharmaceutical composition of the present invention or its respective active ingredients include oral dosage forms such as tablets, capsules (including soft capsules and microcapsules) , powders, granules, syrups, etc.; and non-oral dosage forms such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external application forms (e.g., nasal spray preparations, transdermal preparations , ointments, etc.), suppositories (e.g., rectal suppositories, vaginal suppositories, etc.), pellets, drip infusions, sustained-release preparations, etc.
  • oral dosage forms such as tablets, capsules (including soft capsules and microcapsules) , powders, granules, syrups, etc.
  • non-oral dosage forms such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitone
  • Oral dosage forms are produced by adding to the active ingredient (s) , for instance, an excipient (e.g., lactose, sucrose, starch, D-mannitol, xylitol, sorbitol, erythritol, crystalline cellulose, light silicic anhydride, etc.), a disintegrator (e.g., calcium carbonate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, light silicic anhydride, etc.), a binder (e.g., ⁇ -starch, gum arable, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, methylcellulose, sucrose, D- mannitol, trehalose, dextrin, etc.), or a lubricant (e.g., talc
  • acids such as hydrochloric acid, phosphoric acid, malonic acid, succinic acid, DL-malic acid, tartaric acid, maleic acid, fumaric acid, citric acid, etc.
  • bases such as sodium carbonate , sodium hydrogencarbonate, sodium citrate, sodium tartrate, etc. can be added for the purpose of promoting dissolution of the active ingredient(s) .
  • the oral dosage forms can be coated, by the per se known method, for masking the taste or for enteric dissolution or sustained release.
  • a coating material that can be employed includes, enteric coating polymers such as cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, etc.; gastric coating polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, etc.; water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.; water-insoluble polymers such as ethylcellulose, aminoalkyl methacrylate copolymer RS, ethylacrylate-methylmethacrylate copolymer, etc.; wax, etc.
  • plasticizers such as
  • Injections can be produced by dissolving, suspending or emulsifying the active ingredient (s) in an aqueous vehicle (e.g., distilled water, physiological saline, Ringer's solution, etc.) or an oily vehicle (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc.; or propylene glycol , macrogol, tricaprylin, etc. ) together with a dispersant (e.g.
  • an aqueous vehicle e.g., distilled water, physiological saline, Ringer's solution, etc.
  • an oily vehicle e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc.; or propylene glycol , macrogol, tricaprylin, etc.
  • a dispersant e.g.
  • Tween 80 (produced by Atlas Powder, U.S.A.), HCO 60 (produced by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonizing agent (e.g., sodium chloride, glycerol, D-sorbitol, D-mannitol, xylitol, glucose, fructose, etc.) etc.
  • a preservative e.g., methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.
  • an isotonizing agent e.g., sodium chloride, glycerol, D-sorbitol, D-mannitol, xylitol,
  • additives such as a solubilizer (e.g., sodium salicylate, sodium acetate, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. ) , a suspending agent (e.g. , surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.
  • a solubilizer e.g., sodium salicylate, sodium acetate, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
  • ,- and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium. methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), a buffering agent (e.g. , buffer solutions such as phosphate, acetate, carbonate, citrate, etc.), a stabilizer (e.g., human serum albumin, etc.), a soothing agent (e.g., propylene glycol, lidocaine hydrochloride , benzyl alcohol, etc. ) , an antiseptic (e.g. , p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. ) , etc.
  • a buffering agent e.g. , buffer solutions such as phosphate, acetate, carbonate, citrate, etc.
  • External application forms can be produced by processing the active ingredient(s) into a solid, semi- solid or liquid composition.
  • a solid composition is produced by processing the active ingredient (s) , either as such or in admixture with an excipient (e.g., lactose, D-mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickner (e.g., natural gums, cellulose derivatives, acrylic acid polymers, etc.), etc., into powders.
  • an excipient e.g., lactose, D-mannitol, starch, microcrystalline cellulose, sucrose, etc.
  • a thickner e.g., natural gums, cellulose derivatives, acrylic acid polymers, etc.
  • the above liquid composition is produced in substantially the same manner as in the case of injections.
  • the semi-solid composition is preferably provided in a hydrous or oily gel form or an ointment form.
  • compositions may optionally contain a pH control agent (e.g., phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic (e.g., p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), etc.
  • a pH control agent e.g., phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.
  • an antiseptic e.g., p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • Suppositories can be produced by processing the active ingredient(s) into an oily or aqueous composition, whether solid, semi-solid or liquid.
  • oleaginous bases that can be used in producing the composition include higher fatty acid glycerides [e.g., cacao butter, Witepsols (huels Aktiengesellschaft , Germany), etc.], medium-chain fatty acid triglycerides [e.g., Migriols(huels Aktiengesellschaft, Germany) , etc. ] , vegetable oils (e.g. , sesame oil, soybean oil, cottonseed oil, etc.), etc.
  • aqueous bases include polyethylene glycols, propylene glycol, etc.
  • examples of the aqueous gel bases include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers, etc.
  • the method for administrating a pharmaceutical composition of the present invention is not limited as long as an insulin sensitizer and any of compounds [I] to [III] ,
  • Examples of such methods include 1) administration of a single preparation prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] at the same time; 2) concomitant administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by the same administration route; 3) staggered administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [ I ] to [III], [V] and [VI] separately by the same administration route; 4) concomitant administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by different administration routes ; 5) staggered administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by different administration routes (e.g. , administration of an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] in this order,
  • Preferred embodiments include processing an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately into oral dosage forms such as tablets, and administering the oral dosage forms concomitantly or with a staggered time.
  • a pharmaceutical composition of the present invention and its active ingredient are low in potential toxicity, and can be safely used in mammals (e.g. , human, mouse, rat, rabbit, dog, cat, bovine, equine, swine, monkey, etc.), either orally or non-orally.
  • mammals e.g. , human, mouse, rat, rabbit, dog, cat, bovine, equine, swine, monkey, etc.
  • the dosage of a pharmaceutical composition of the present invention may be appropriately determined with reference to the dosage recommended for the respective active ingredient (s) , and can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, method of administration, combination of the drug(s) , etc.
  • the dosage of an insulin sensitizer and compounds [I] to [III] , [V] and [VI] can be selected appropriately based on clinically used dosage.
  • the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once to several times a day.
  • the dose of pioglitazone hydrochloride per day is usually 7.5 to 60 mg, preferably 15 to 45 mg.
  • the dose of troglitazone per day is usually 100 to 1000 mg, preferably 200 to 600 mg.
  • the dose of rosiglitazone (or its maleate) is employed as the insulin sensitizer, the dose of rosiglitazone per day is usually 1 to 12 mg, preferably 2 to 8 mg.
  • the dose per day is usually 0.1 to 500 mg, preferably 0.1 to 200 mg, more preferably 0.1 to 50 mg.
  • the dose of compound A per day is usually 0.1 to 10 mg, preferably 0.2 to 3 mg.
  • an insulin sensitizer and compounds [I] to [III], [V] and [VI] in a pharmaceutical composition of the present invention can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, method of administration, combination of the drug(s), etc.
  • compounds [I] to [III], [V] and [VI] are used in a proportion of usually about 0.005 to 1 weight part and preferably about 0.001 to 0.2 weight parts relative to one weight part of an insulin sensitizer.
  • a pharmaceutical composition of the present invention possesses an enhanced blood sugar lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.
  • a pharmaceutical composition of the present invention possesses an enhanced blood lipid lowering action or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds
  • a pharmaceutical composition of the present invention possesses an excellent effect of treating diabetes, and therefore, the amount of drugs used can be reduced as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.
  • the pharmaceutical composition of the present invention when administered to a diabetic patient, a tendency of decrease in the patient ' s body weight as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone is observed.
  • concomitant drugs which do not interfere with an insulin sensitizer or compounds [I] to [III], [V] and [VI] can be used for the purpose of "enhancing the diabetes treating effects of an insulin sensitizer or compounds [I] to [III], [V] and [VI]", “reducing the dose of an insulin sensitizer or compounds [I] to [III] , [V] and [VI]", “reducing the side effects of an insulin sensitizer or compounds [I] to [III], [V] and [VI]", etc.
  • the concomitant drugs include "agents for treating diabetes", “agents for treating diabetic complications",
  • anti-obesity agents agents for treating hypertension
  • a dietetic therapy (therapy by restriction of nutrition or calories) or a therapeutic exercise can be employed at the time of using a pharmaceutical composition of the present invention.
  • agents for treating diabetes include insulin, insulin secretion enhancers, biguanides, a - glucosidase inhibitors, etc.
  • Insulin means any and all substances having an insulin action, and exemplified by, for instance, animal insulin extracted from bovine or porcine pancreas; semi- synthesized human insulin which is enzymatically synthesized from insulin extracted from porcine pancreas,- and human insulin synthesized by genetic engineering techniques typically using Escherichia coli or yeasts ; etc .
  • insulin-zinc containing 0.45 to 0.9 (w/w) % of zinc; protamine- insulin-zinc produced from zinc chloride, protamine sulfate and insulin; etc.
  • Insulin may be in the form of its fragments or derivatives (e.g., INS-1).
  • Insulin may be insulin-like substances (e.g., L83281, insulin agonists) . While insulin is available in a variety of types such as super immediate-acting, immediate-acting, bimodal- acting, intermediate-acting, long-acting, etc., these types can be appropriately selected according to the patient's condition.
  • a pharmaceutical composition of the present invention in combination with insulin enables reduction of the dose of insulin as compared with the dose at the time of administration of insulin alone. Therefore, risk of blood vessel complication and hypoglycemia induction, both of which are problems with large amounts of insulin administration, is low.
  • a pharmaceutical composition of the present invention possesses an excellent effect of treating diabetes, a satisfactory effect of treating diabetes can be obtained even if the dose of insulin is reduced as compared with administration of insulin alone.
  • insulin secretion enhancers examples include sulfonylureas .
  • Specific examples of the sulfonylureas include tolbutamide, chlorpropamide , tolazamide, acetohexamide , glyclopyramide and its ammonium salt, glibenclamide , gliclazide, l-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride, etc.
  • insulin secretion enhancers examples include nateglinide(AY-4166) , calcium ( 2S) -2-benzyl-3- (cis-hexahydro-2- isoindolinylcarbonyl)propionate dihydrate (mitiglinide, KAD-1229), repaglinide, etc.
  • biguanides examples include phenformin, metformin, buformin, etc.
  • a -glucosidase inhibitors examples include acarbose, voglibose, miglitol, emiglitate, etc.
  • the "agents for treating diabetes” include ergoset, pramlintide, leptin, BAY-27-9955, T-1095, etc.
  • the dose per day is usually 0.1 to 2500 mg, preferably 0.5 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 10 to 100 U (Units) , preferably 10 to 80 U (Units) . This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 1000 mg, preferably 1 to 100 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 10 to 2500 mg, preferably 100 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 400 mg, preferably 0.6 to 300 mg. This dose can be administered once to several times a day.
  • Examples of the "agents for treating diabetic complications” include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, etc.
  • Examples of the aldose reductase inhibitors include tolurestat; epalrestat; 3 , 4-dihydro-2 , 8-diisopropyl-3- thioxo-2H-l , 4-benzoxazine-4-acetic acid; imirestat; zenarestat ; 6-fluoro-2 , 3-dihydro-2 ' , 5 ' -dioxo-spiro[ 4H- l-benzopyran-4 , 4 ' -imidazolidine] -2-carboxamide (SNK- 860); zopolrestat; sorbinil; 1- [ ( 3-bromo-2- benzofuranyl)sulfonyl] -2 , 4-imidazolidinedione (M- 16209 ) ; CT-
  • glycation inhibitors examples include pimagedine, etc.
  • protein kinase C inhibitors examples include NGF, LY-333531, etc.
  • agents for treating diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentaenoate, memantine, pimagedline (ALT-711), etc.
  • the dose per day is usually 0.1 to 2000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 2000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 100 mg. This dose can be administered once to several times a day.
  • agents for treating obesity include lipase inhibitors, anorectics, etc.
  • lipase inhibitors examples include orlistat, etc.
  • anorectics examples include dexfenfluramine, fluoxetine, sibutramine, baiamine, etc.
  • the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once to several times a day.
  • agents for treating hypertension include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists, etc.
  • angiotensin converting enzyme inhibitors examples include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat , fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, manidipine, etc.
  • Examples of the calcium antagonists include nifedipine, amlodipine, efonidipine, nicardipine, etc.
  • Examples of the potassium channel openers include leveromakalim, L-27152, AL 0671, NIP-121, etc.
  • angiotensin II antagonists examples include losartan, candesartan cilexetil, valsartan, irbesartan, (5-methyl-2-oxo-l,3-dioxoran-4-yl)methyl 4- ( 1-hydroxy- 1-methylethyl) -2-propyl-1- [ 2 ' - ( IH-tetrazol-5- yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (CS-866) , E4177, etc.
  • the dose per day is usually 0.01 to 1000. mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.01 to 500 mg, preferably
  • This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 500 mg, preferably 1 to 200 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.01 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 500 mg, preferably 1 to 100 mg.
  • This dose can be administered once to several times a day.
  • agents for treating hyperlipidemia include, HMG-CoA reductase inhibitors, fibrate compounds, etc.
  • HMG-CoA reductase inhibitors examples include pravastatin and its sodium salt, cerivastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, itavastatin, ZD-4522, etc.
  • fibrate compounds examples include bezafibrate, beclofibrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, etc.
  • the dose per day is usually 0.01 to 3000 mg, preferably 1 to 2000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 0.01 to 100 mg, preferably 0.5 to 50 mg.
  • This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 2000 mg, preferably 10 to 1500 mg. This dose can be administered once to several times a day.
  • diuretics examples include xanthine derivative preparations, thiazide preparations, antialdosterone preparations, carbonate dehydratase inhibitors, chlorbenzenesulfonamide preparations, etc.
  • xanthine derivative preparations examples include theobromine and sodium salicylate, theobromine and calcium salicylate, etc.
  • thiazide preparations examples include ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide , hydroflumethiazide , benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, etc.
  • antialdosterone preparations examples include spironolactone, triamterene, etc.
  • Examples of the carbonate dehydratase inhibitors include acetazolamide, etc.
  • chlorbenzenesulfonamide preparations examples include chlorthalidone , mefruside, indapamide, etc.
  • examples of the "diuretics” include azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.
  • the dose per day is usually 0.01 mg to 100 g, preferably 0.05 mg to 10 g. This dose can be administered once to several times a day.
  • the dose per day is usually 0.1 to 100 g, preferably 0.5 to 10 g. This dose can be administered once to several times a day.
  • the dose per day is usually 0.01 to 2000 mg, preferably 0.05 to 500 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 2000 mg, preferably 10 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 10 to 5000 mg, preferably 50 to 2000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 2000 mg, preferably 10 to 1000 mg. This dose can be administered once to several times a day.
  • the dose per day is usually 1 to 2000 mg, preferably 10 to 1000 mg. This dose can be administered once to several times a day.
  • the concomitant drugs mentioned above can be used as a mixture of two or more species optionally selected.
  • Specific examples of combination when two kinds of concomitant drugs are used in combination include "combination of an insulin secretion enhancer and a biguanide”, “combination of an insulin secretion enhancer and an a -glucosidase inhibitor”, “combination of insulin and a biguanide”, “combination of insulin and an - glucosidase inhibitor”, etc.
  • the administration method of a pharmaceutical composition of the present invention and a concomitant drug is not limited as long as these are used in combination at the time of administration.
  • the proportion of an a pharmaceutical composition of the present invention and a concomitant drug can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, administration method, etc.
  • a concomitant drug is used in a proportion of 0.0001 to 10000 weight parts relative to one weight part of a pharmaceutical composition of the present invention.
  • Specific combination of compounds [I] to [III], [V] and [VI] with the above concomitant drugs includes, for instance, “combination of Compound A and an insulin”, “combination of Compound B and an insulin”, “combination of Compound A and an insulin secretion enhancer (preferably sulfonylureas such as glibenclamide ; repaglinide, nateglinide, mitiglinide, etc. ) " , “combination of Compound B and an insulin secretion enhancer (preferably sulfonylureas such as glibenclamide; repaglinide, nateglinide, mitiglinide, etc.
  • a pharmaceutical composition of the present invention or its active ingredient e.g., pioglitazone hydrochloride, rosiglitazone maleate.
  • Compound A, Compound B, etc. in combination with the above concomitant drugs (e.g., insulin; insulin secretion enhancers such as sulfonylureas ; biguanides such as metformin; HMG-CoA reductase inhibitors such as cerivastatin sodium salt, etc.) provides enhancement in various pharmaceutical effects referred to as those for a pharmaceutical composition of the present invention, such as effects of treating diabetes , hyperlipidemia, hyperinsulinemia, etc.
  • concomitant drugs e.g., insulin; insulin secretion enhancers such as sulfonylureas ; biguanides such as metformin; HMG-CoA reductase inhibitors such as cerivastatin sodium salt, etc.
  • a pharmaceutical composition of the present invention or its active ingredient e.g., pioglitazone hydrochloride, rosiglitazone maleate.
  • active ingredient e.g., pioglitazone hydrochloride, rosiglitazone maleate.
  • concomitant drugs e.g., insulin; insulin secretion enhancers such as sulfonylureas ; biguanides such as metformin; HMG-CoA reductase inhibitors such as cerivastatin sodium salt, etc.
  • the blood sugar lowering effect of a pharmaceutical composition in the present invention can be evaluated by determining concentration of glucose or Hb (hemoglobin)A lc in venous blood plasma in the subject before and after administration, and then comparing the obtained concentration between before administration and after administration.
  • HbA l0 means glycosylated hemoglobin, and is gradually produced in response to blood glucose concentration. Therefore, HbA lc is thought important as an index of blood sugar control which is not easily influenced by rapid blood sugar changes in diabetic patients .
  • a fluidized-bed granulating and drying machine (produced by Powerex) was charged with 2479.5 g of pioglitazone hydrochloride (2250 g in terms of pioglitazone), 13930.5 g of lactose and 540 g of carboxymethylcellulose calcium (carmellose calcium) , followed by mixing at the preheating temperature and spraying 7500 g of an aqueous solution containing 450 g of hydroxypropylcellulose to yield granules. 16820 g of the granules were processed with cutter-mill (produced by Showa Kagaku Kikai Kousakusho) to yield milled granules.
  • 16530 g of the milled granules, 513 g of carmellose calcium and 57 g of magnesium stearate were mixed to yield mixed powders by using a tumbling mixer (produced by Showa Kagaku Kikai Kousakusho). 16800 g of the mixed powders were tabletted by using a tabletting machine (produced by Kikusui
  • Example 1 When pioglitazone hydrochloride (30 mg/day, oral administration) and Compound A (0.5 mg/day, oral administration) are concomitantly administered to a NIDDM patient over the period of 8 weeks, an excellent blood glucose lowering action is observed.
  • Example 2 When pioglitazone hydrochloride (30 mg/day, oral administration) and Compound B (0.5 mg/day, oral administration) are concomitantly administered to a NIDDM patient over the period of 8 weeks, an excellent blood glucose lowering action is observed.
  • Groups A to D Twenty three Wistar fatty rats, genetically obese and noninsulin-dependent diabetic (type 2 diabetic) models, (16 weeks old, male) were divided into Groups A to D. To Group A (6 rats), a 0. 5% (w/w) methylcellulose/physiological saline suspension (2 ml/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) were orally administered for 14 days. This group was considered as a control group.
  • Group B To Group B (6 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) containing pioglitazone hydrochloride (1 mg/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) were orally administered for 14 days.
  • Group C To Group C (6 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) and a 0.5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) containing Compound A (0.1 mg/kg body weight/day) were orally administered for 14 days.
  • Group D To Group D (5 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) containing pioglitazone hydrochloride (1 mg/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) containing Compound A (0.1 mg/kg body weight/day) were orally administered for 14 days. The rats were allowed to take food freely.
  • use of pioglitazone hydrochloride in combination with Compound A provided excellent effects of lowering a plasma glucose and a plasma triglyceride.
  • use of pioglitazone hydrochloride in combination with Compound A unexpectedly provided an effect of inhibiting a body weight increase.
  • the body weight increase in Group D was expected to be 26.4 (36.5 - 10.1) g because of the f ct that the body weight increase in Group B was 36.5 (641.9 - 605.4) g and the body weight increase in Group C was -10.1 (595.3 - 605.4) g.
  • the body weight increase in Group D was unexpectedly low and was 14.8 (620.2 - 605.4) g.
  • a pharmaceutical composition of the present invention possesses an enhanced blood sugar lowering action, blood lipid lowering action or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.

Abstract

A pharmaceutical composition which comprises an insulin sensitizer in combination with a compound (a) of formula (I), wherein R1 represents a lower alkyl group optionally substituted by hydroxyl group, etc., R2 represents hydrogen atom, etc., R3 represents hydrogen atom, etc., W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in formula (I), wherein R4 represents a halogen atom, etc., R5 represents a lower alkyl group, or a salt thereof, which is useful as an agent for preventing or treating diabetes.

Description

DESCRIPTION PHARMACEUTICAL COMPOSITION
TECHNICAL FIELD The present invention relates to a pharmaceutical composition which is useful as an agent for preventing or treating diabetes, etc. , comprising an insulin sensitizer (insulin resistance-improving agent).
BACKGROUND ART
Examples of prior art references which describe a 33 adrenaline receptor agonist are shown below. 1) W098/32753 describes that thiazole substituted benzenesulfonamides are β 3 adrenergic receptor agonists. 2) Diabetes Frontier, Vol. 8, p.499 (1997) describes that when CL316243 ( β 3 adrenergic receptor agonist) and troglitazone were administered to obese rats, "CL316243 completely inhibited a weight increase in brown adipose tissues caused by troglitazone". 3) JP-A H5( 1993) -148496 describes that 4- [2- ( 2-hydroxy- 2-phenyl-ethylamino)ethoxy]phenylacetic acid and its precursors are β 3 adrenergic receptor agonists. 4) 096/16938 describes a novel indole derivative having a potent β 3 adrenergic receptor stimulating activity.
Development of excellent drugs which are sufficiently improved as medicines having an excellent diabetic treatment effect without apparent detection of side effects is desired.
DISCLOSURE OF INVENTION
As a result of various studies in use of an insulin sensitizer in combination with other drugs, the present inventors have found a novel combination that provides unexpectedly excellent effects. Based on this finding, the present inventors have completed the present invention. Namely, the present invention relates to ( 1 ) a pharmaceutical composition which comprises an insulin sensitizer in combination with at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000003_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonyla ino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (0RA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with R to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group ,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000004_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, Rs represents a lower alkyl group, or a salt thereof ; 2) a compound of the formula [II] :
Figure imgf000004_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000004_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3_8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C^ alkyl, C1.6 alkoxy, C3.β cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19 ,
NR18C02R18; or a C1.6 alkyl group substituted by hydroxy, nitro , halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, Cx,6 alkoxy, C3.8 cycloalkyl, phenyl, NRlβCOR19, COR19, S02R19, NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or Cj^.g alkyl substituted by hydroxy, Cx.6 alkoxy or halogen; X' represents -CH2-, -CH2-CH2- , -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, C^ alkyl, halogen, NHR18, OR18, S02R19 or NHSO-R19; R16 represents hydrogen atom or C1-6 alkyl; R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-fR11)., wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N;
R18 represents hydrogen atom; C^,, alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C1.6 alkyl or C^ alkoxy; C1.10 alkyl substituted by hydroxy, halogen, C02H, C1.6 alkoxy-carbonyl, C3.8 cycloalkyl, C^6 alkoxy, or phenyl substituted by halogen, Cx_6 alkyl or C^ alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
0R!0
Figure imgf000006_0001
wherein R represents hydrogen atom or methyl group,
R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R22 represents hydrogen atom, hydroxymethyl group, NHR 23
S02NR24R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR 26'
R2S represents a lower alkyl group, benzyl group or NR24R24 ,
R24 and R24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R 26' represents hydrogen atom or a lower alkyl group.
R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, 0 or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group. acetylamino group or hydroxy group , when na is 2 ,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI] :
OR30
Figure imgf000007_0001
wherein R represents hydrogen atom or methyl group.
R represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R32 represents hydrogen atom, hydroxymethyl group, NHR33,
S02NR34R34' or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36 ,
R35 represents a lower alkyl group, benzyl group or NR34R34 , R34 and R34' are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
RJ represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene grou ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower- alkyl group, or a salt thereof;
( 2 ) a pharmaceutical composition according to the above ( 1 ) , wherein the insulin sensitizer is a compound of the formula
[IV] :
Figure imgf000008_0001
° wherein R represents a hydrocarbon group or a heterocyclic group, each of which may be substituted; Y represents a group of the formula : -CO-, -CH(OH)- or -NR3- wherein R3 represents an alkyl group that may be substituted; m is 0 or 1; n is 0, 1 or 2 ; X represents CH or N; A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q represents O or S; R1 represents hydrogen atom or an alkyl group; ring E may have further 1 to 4 substituents, which may form a ring in combination with R1; L and M respectively represent hydrogen atom or may be combined with each other to form a chemical bond, or a salt thereof;
( 3 ) a pharmaceutical composition according to the above ( 2 ) , wherein the compound of the formula [IV] or a salt thereof is pioglitazone or its salt;
( 4 ) a pharmaceutical composition according to the above ( 2 ) , wherein the compound of the formula [IV] or a salt thereof is rosiglitazone or its salt;
( 5 ) a pharmaceutical composition according to the above ( 1 ) , which comprises pioglitazone or its hydrochloride in combination with 2- [3- ( 7-carboxymethoxyindol-3-yl) - (2R) -2-propylamino] - (IR) -1- ( 3-chlorophenyl) ethanol; ( 6 ) a pharmaceutical composition according to the above ( 1 ) , which comprises rosiglitazone or its maleate in combination with 2-[3-(7-carboxymethoxyindol-3-yl)-(2R) -2- propylamino] - ( IR) - 1- ( 3-chlorophenyl ) ethanol; ( 7 ) a pharmaceutical composition according to the above ( 1 ) , which is for preventing or treating diabetes;
( 8 ) a pharmaceutical composition according to the above ( 7 ) , wherein the diabetes is noninsulin-dependent diabetes mellitus;
( 9 ) a pharmaceutical composition according to the above ( 1 ) , which is for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications ; (10) a pharmaceutical composition according to the above (9), wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris , cerebrovascular disease or peripheral circulatory disturbance;
(11) a pharmaceutical composition for inhibiting body weight increase after stopping a smoking habit , which comprises at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof; 4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof;
(12) a pharmaceutical composition for inhibiting body weight increase after stopping alimentary therapy, which comprises at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof; 2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof; (13) a method for preventing or treating diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof; (14) a method for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis , glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and 5) a compound of the formula [VI] or a salt thereof;
(15) a method according to the above (14), wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance;
(16) a method for inhibiting body weight increase after stopping a smoking habit in human in need thereof, which comprises administering to said human an effective amount of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof; 4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof;
(17) a method for inhibiting body weight increase after stopping alimentary therapy in human in need thereof , which comprises administering to said human an effective amount of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof ,- 4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof;
(18) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetes, which is used in combination with at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and 5) a compound of the formula [VI] or a salt thereof;
(19) use of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof ,-
2) a compound of the formula [II] or a salt thereof; 3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and 5) a compound of the formula [VI] or a salt thereof, for the manufacture of a pharmaceutical preparation for treating diabetes, which is used in combination with an insulin sensitizer; (20) use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, which is used in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof; (21) use of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof;
2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof; 4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof, for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases, syndrome X, visceral fat obesity syndrome or diabetic complications; which is used in combination with an insulin sensitizer; (22) use according to the above (20) or (21), wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance;
(23) use of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof; 2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping a smoking habit ;
(24) use of at least one member selected from the group consisting of
1) a compound of the formula [I] or a salt thereof; 2) a compound of the formula [II] or a salt thereof;
3) a compound of the formula [III] or a salt thereof;
4) a compound of the formula [V] or a salt thereof; and
5) a compound of the formula [VI] or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping alimentary therapy.
The insulin sensitizer used in the present invention means any and all drugs that restore the impaired insulin receptor function and improve insulin resistance.
Specific examples of the insulin sensitizer include compounds having thiazolidinedione or oxazolidinedione skeletons, preferably the above-mentioned compound of the formula (IV) or a salt thereof.
Referring to the formula (IV), examples of the hydrocarbon group in the hydrocarbon group that may be substituted for R include aliphatic hydrocarbon groups , alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon groups , aromatic-aliphatic hydrocarbon groups , and aromatic hydrocarbon groups. The number of carbon atoms constituting such hydrocarbon groups is preferably 1 to 14.
The aliphatic hydrocarbon group is preferably a
Figure imgf000014_0001
aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group includes saturated C^ aliphatic hydrocarbon groups (e.g. alkyl groups, etc.) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t. -butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, heptyl, and octyl; and unsaturated C2.8 aliphatic hydrocarbon groups (e.g. alkenyl groups , alkadienyl groups , alkynyl groups , alkadiynyl groups , etc . ) such as vinyl , 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2 , 4-hexadiynyl, 5-hexynyl, 1-heptynyl, and 1-octynyl. The alicyclic hydrocarbon group is preferably a C3.7 alicyclic hydrocarbon group. Examples of the alicyclic hydrocarbon group include saturated C3.7 alicyclic hydrocarbon groups (e.g. cycloalkyl groups, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. and unsaturated C5.7 alicyclic hydrocarbon groups (e.g. cycloalkenyl groups , cycloalkadienyl groups, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl , 3-cyclohexenyl, 1-cycloheptenyl, 2- cycloheptenyl, 3-cycloheptenyl, and 2 , 4-cycloheptadienyl . The alicyclic-aliphatic hydrocarbon group is a group consisting of the above-described alicyclic hydrocarbon group and aliphatic hydrocarbon group (e.g. cycloalkyl- alkyl groups', cycloalkenyl-alkyl groups, etc.) and is preferably a C4.9 alicyclic-aliphatic hydrocarbon group. Examples of the alicyclic-aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl , cyclobutylmethyl , cyclopentylmethyl, 2- cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl , 2-cyclohexenylmethyl, 3- cyclohexenylmethyl , cyclohexylethyl, cyclohexylpropyl , cycloheptylmethyl , cycloheptylethyl, etc.
The aromatic-aliphatic hydrocarbon group is preferably a C7_13 aromatic-aliphatic hydrocarbon group (e.g. aralkyl groups, etc. ) . Examples of the aromatic-aliphatic hydrocarbon group include C7.9 phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; Clλ_13 naphthylalkyl such as Ot - naphthylmethyl , a -naphthylethyl, β -naphthylmethyl, and β -naphthylethyl.
The aromatic hydrocarbon group is preferably a C6.14 aromatic hydrocarbon group (e.g. aryl groups, etc.). Examples of the aromatic hydrocarbon group include phenyl and naphthyl ( a -naphthyl, β -naphthyl) . Referring to the formula (IV), examples of the heterocyclic group in the heterocyclic group that may be substituted for R is a 5- to 7-membered heterocyclic group containing 1 to 4 hetero-atoms selected from oxygen, sulfur, and nitrogen in addition to carbon as ring members or a condensed ring group. Examples of the condensed ring include one consisting of such 5- to 7-membered heterocyclic group with a 6-membered ring containing 1 or 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom. Examples of the heterocyclic group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4- oxadiazol-5-yl, 1 , 2 , 4-triazol-3-yl, 1 , 2 , 3-triazol-4-yl , tetrazol-5-yl, benzimidazol-2-yl, indol-3-yl, 1H- indazol-3-yl, lH-pyrrolo[ 2 , 3-b]pyrazin-2-yl, 1H- pyrrolo[2 , 3-b]pyridin-6-yl, lH-imidazo[4 , 5-b]pyridin-2- yl, lH-imidazo[4 , 5-c]pyridin-2-yl, lH-imidazo [ 4 , 5- b]pyrazin-2-yl, benzopyranyl and dihydrobenzopyranyl . The heterocyclic group is preferably pyridyl , oxazolyl or thiazolyl group.
Referring to the formula (IV), the hydrocarbon group and heterocyclic group for R may respectively have 1 to 5 , preferably 1 to 3 substituents at substitutable positions.
Such substituents include for example aliphatic hydrocarbon groups , alicyclic hydrocarbon groups , aryl groups, aromatic heterocyclic groups, non-aromatic heterocyclic groups, halogen, nitro, amino groups that may be substituted, acyl groups that may be substituted, hydroxy groups that may be substituted, thiol groups that may be substituted, carboxyl groups that may be esterifled, amidino, carbamoyl, sulfamoyl, sulfo, cyano, azido, and nitroso.
Examples of the aliphatic hydrocarbon group include straight-chain or branched aliphatic hydrocarbon groups having 1 to 15 carbon atoms, such as alkyl groups, alkenyl groups , and alkynyl groups . The preferred alkyl group is a C^^ alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t. -butyl, pentyl, isopentyl, neopentyl, t.- pentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2, 2-dimethylbutyl, 3 , 3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.
The preferred alkenyl group is a C2.1Q alkenyl group. such as vinyl, allyl, isopropenyl, 1-propenyl, 2- methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2- ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. The preferred alkynyl group is a C2.10 alkynyl group, such as 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, and 5-hexynyl.
Examples of the alicyclic hydrocarbon group includes saturated or unsaturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms, such as cycloalkyl groups , cycloalkenyl groups , and cycloalkadienyl groups . The preferred cycloalkyl group is a C3.10 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2] octyl , bicyclo [3.2.1] octyl , bicyclo [3.2.2] nonyl , bicyclo [3.3.1] nonyl, bicyclo [ 4.2.1 ] nonyl, and bicyclo [4.3.1] decyl .
The preferred cycloalkenyl group is a C3.10 cycloalkenyl group, such as 2-cyclopenten-l-yl, 3- cyclopenten-1-yl, 2-cyclohexen-l-yl, and 3-cyclohexen- 1-yl.
The preferred cycloalkadienyl group is a C4.10 cycloalkadienyl group, such as 2, 4-cyclopentadien-l-yl, 2, 4-cyclohexadien-l-yl, and 2, 5-cyclohexadien-l-yl.
The preferred aryl group is a C6.14 aryl group, such as phenyl, naphthyl (1- naphthyl, 2 -naphthyl), anthryl, phenanthryl, and acenaphthylenyl .
The preferred aromatic heterocyclic group includes monocyclic aromatic heterocyclic groups, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 , 2 , 3-oxadiazolyl, 1, 2 , 4-oxadiazolyl, 1 , 3 , 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1 , 2, 4-thiadiazolyl, 1 , 3 , 4-thiadiazolyl, 1, 2, 3-triazolyl, 1 , 2 , 4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and condensed aromatic heterocyclic groups, such as benzofuranyl, isobenzofuranyl, benzo[b] hienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1 , 2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , purinyl, pteridinyl, carbazolyl, a -carbolinyl, ]3 - carbolinyl, 7 -carbolinyl, acridinyl , phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl , phenanthrolinyl, indolizinyl, pyrrolof 1, 2-b]pyridazinyl , pyrazolof 1, 5-a]pyridyl, imidazo[ 1,2-a]pyridyl, imidazo[ 1 , 5-a]pyridyl, imidazof 1 , 2-b]pyridazinyl, imidazof 1 , 2-a]pyrimidinyl, 1 , 2 , 4-triazolo[4 , 3-a]pyridyl, and 1 , 2 , 4-triazolo[ 4 , 3- b]pyridaziny1.
The preferred non-aromatic heterocyclic group includes oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl , thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl , thiomorpholinyl . piperazinyl, pyrrolidino, piperidino, morpholino, and thiomorpholino . Examples of the halogen include fluorine, chlorine, bromine, and iodine.
Referring to the amino group that may be substituted, examples of the substituted amino group include N-mono- substituted amino groups and N,N-di-substituted amino groups. Examples of the substituted amino group include amino groups having one or two substituents selected from the group consisting of C1.10 alkyl groups, C2.10 alkenyl groups , C2.10 alkynyl groups , C3_10 cycloalkyl groups , aromatic groups (e.g., phenyl), heterocyclic groups, or C^o acyl groups (e.g., C^,, alkanoyl groups, benzoyl, nicotinoyl) (e.g. methylamino, dimethylamino , ethylamino. diethylamino , dibutylamino, diallylamino, cyclohexylamino , phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). Examples of the acyl group in the acyl groups that may be substituted include C1.13 acyl groups, for example, C^^ alkanoyl groups , C3.10 alkenoyl groups , C4_10 cycloalkanoyl groups, C4.10 cycloalkenoyl groups, C6.12 aromatic carbonyl groups . Preferred examples of the C^Q alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and octanoyl.
Preferred examples of the C3.10 alkenoyl groups include acryloyl, methacryloyl , crotonoyl, and isocrotonoyl . Preferred examples of the C4.10 cycloalkanoyl groups include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, and cycloheptanecarbonyl .
Preferred examples of the C4.10 cycloalkenoyl groups include 2-cyclohexenecarbonyl. Preferred examples of the C6-12 aromatic carbonyl groups include benzoyl, naphthoyl, and nicotinoyl.
Examples of the substituents in the substituted acyl groups include
Figure imgf000019_0001
alkoxy groups , halogen (e.g. chlorine, fluorine, bromine, etc.), nitro, hydroxy, and amino.
Referring to the hydroxy group that may be substituted, examples of the substituted hydroxy includes alkoxy groups , cycloalkyloxy groups , alkenyloxy groups , cycloalkenyloxy groups, aralkyloxy groups, acyloxy groups, and aryloxy groups .
The preferred alkoxy group includes C^,, alkoxy groups , such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. -butoxy, t. -butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, and nonyloxy. The preferred cycloalkyloxy group includes C3.10 cycloalkyloxy groups , such as cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
The preferred alkenyloxy group includes C2.10 alkenyloxy groups, such as allyloxy, crotyloxy, 2- pentenyloxy, and 3-hexenyloxy.
The preferred cycloalkenyloxy group includes C3.10 cycloalkenyloxy groups, such as 2-cyclopentenyloxy, and 2-cyclohexenyloxy. The preferred aralkyloxy group includes C7.10 aralkyloxy groups, such as phenyl-C^ alkyloxy (e.g. benzyloxy, phenethyloxy, etc.).
The preferred acyloxy group includes C2.13 acyloxy groups, more preferably C2.4 alkanoyloxy groups (e.g. acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc. ) .
The preferred aryloxy group includes C6.14 aryloxy groups, such as phenoxy, and naphthyloxy. This aryloxy group may have 1 or 2 substituents. Examples of the substituents include halogen (e.g. chlorine, fluorine, bromine, etc. ) . Examples of the substituted aryloxy group includes 4-chlorophenoxy.
Referring to the thiol group that may be substituted, examples of the substituted thiol group include alkylthio groups, cycloalkylthio groups, alkenylthio groups, cycloalkenylthio groups , aralkylthio groups , acylthio groups , and arylthio groups .
The preferred alkylthio group includes C^,, alkylthio groups, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec. -butylthio, t. -butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, and nonylthio.
The preferred cycloalkylthio group includes C3.10 cycloalkylthio groups such as cyclobutylthio, cyclopentylthio, and cyclohexylthio .
The preferred alkenylthio group includes C2.10 alkenylthio groups, such as allylthio, crotylthio, 2- pentenylthio, and 3-hexenylthio.
The preferred cycloalkenylthio group includes C3.10 cycloalkenylthio groups such as 2-cyclopentenylthio, and 2-cyclohexenylthio.
The preferred aralkylthio group includes C7.10 aralkylthio groups, such as phenyl-C1.4 alkylthio (e.g. benzylthio, phenethylthio, etc.).
The acylthio group is preferably a C2.13 acylthio group, more preferably a C2.4 alkanoylthio group (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.).
The preferred arylthio group includes C6.14 arylthio groups , such as phenylthio , and naphthylthio . This arylthio group may have 1 or 2 substituents. Examples of the substituents include halogen (e.g. chlorine, fluorine, bromine, etc.). Examples of the substituted arylthio group includes 4-chlorophenylthio.
The carboxyl group that may be esterified includes alkoxycarbonyl groups, aralkyloxycarbonyl groups, and aryloxycarbonyl groups .
The preferred alkoxycarbonyl group includes C2.5 alkoxycarbonyl groups , such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , and butoxycarbonyl . The preferred aralkyloxycarbonyl group includes C8.10 aralkyloxycarbonyl groups , such as benzyloxycarbonyl . The preferred aryloxycarbonyl group includes C7.15 aryloxycarbonyl groups, such as phenoxycarbonyl , and p- tolyloxycarbonyl . The preferred substituent on the hydrocarbon group or heterocyclic group for R includes C^^ alkyl groups , aromatic heterocyclic groups , and C6.14 aryl groups . Further preferred is C^ alkyl, furyl, thienyl, phenyl, or naphthyl .
Referring to the formula (IV), when the substituent on the hydrocarbon group or heterocyclic group for R is an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group, this substituent may further have one or more, preferably 1 to 3 suitable substituents. Examples of such substituents include C^ alkyl groups, C2.6 alkenyl groups, C2.6 alkynyl groups , C3.7 cycloalkyl groups , C6.14 aryl groups , aromatic heterocyclic groups (e.g. thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic groups (e.g. tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), C7.9 aralkyl groups, amino, N-mono-Ci.,, alkylamino groups, N,N-di-C1-4 alkylamino groups , C2.8 acylamino groups (e.g. acetylamino, propionylamino , benzoylamino, etc.), amidino, C2_8 acyl groups (e.g. C2_8 alkanoyl groups, etc.), carbamoyl, N- mono-C^ alkylcarbamoyl groups, N.N-di-C^,, alkylcarbamoyl groups, sulfamoyl, N-mono-Ci.4 alkylsulfamoyl groups,
Figure imgf000022_0001
alkylsulfamoyl groups, carboxyl, C2.8 alkoxycarbonyl groups, hydroxy, Cx.4 alkoxy groups, C2.5 alkenyloxy groups , C3.7 cycloalkyloxy groups , C7.9 aralkyloxy groups , C6.14 aryloxy groups , mercapto , Cx_4 alkylthio groups , C7.9 aralkylthio groups, C6.14 arylthio groups, sulfo, cyano, azido, nitro, nitroso, and halogen.
Referring to the formula (IV), R is preferably a heterocyclic group that may be substituted. More preferably, R is pyridyl, oxazolyl, or thiazolyl group, which may have 1 to 3 substituents selected from the group consisting of Cx.3 alkyl, furyl, thienyl, phenyl, and naphthyl .
Referring to the formula (IV), Y represents -CO-, -CH(OH) - or -NR3- wherein R3 represents an alkyl group that may be substituted. Preferred is -CH(OH)- or -NR3-. Examples of an alkyl group in the alkyl group that may be substituted for R3, include C1-4 alkyl groups, such as methyl, ethyl , propyl , isopropyl, butyl, isobutyl, sec. -butyl, and t. -butyl. Examples of the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine), Cj_.4 alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec. -butoxy, t. -butoxy, etc.), hydroxy, nitro, and Cx.4 acyl groups (e.g. formyl, acetyl, propionyl, etc.).
The symbol m represents 0 or 1 , and is preferably 0. The symbol n represents 0, 1 or 2, and is preferably 0 or 1.
X represents CH or N, and is preferably CH. Referring to the formula (IV) , A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms . This aliphatic hydrocarbon group may be straight-chain or branched and may further be saturated or unsaturated. Thus, forexample, -CH2-, -CH(CH3)-, -(CH2)2-, -CH(C2H5)-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)5-, -(CH2)7-, etc. can be mentioned for the saturated bivalent aliphatic hydrocarbon group, while -CH=CH-, -C(CH3)=CH-, -CH=CH-CH2-, -C(C2H5)=CH-, -CH2-CH=CH-CH2-, ■CH2-CH2-CH=CH-CH2-, - CH=CH-CH=CH-CH2-, -CH=CH-CH=CH-CH=CH-CH2-, etc. can be mentioned for the unsaturated bivalent aliphatic hydrocarbon group. A preferably represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 4 carbon atoms , which is preferably a saturated group . More preferably, A represents a chemical bond or -(CH2)2-. The alkyl group for R1 includes the similar one to the alkyl group for the above-described R3. R1 is preferably hydrogen atom.
Referring to the formula (IV) , the partial structural formula:
is preferably the formula :
Figure imgf000023_0001
Figure imgf000023_0002
wherein each symbol has the same meanings as described above .
Furthermore, ring E may optionally have further 1 to 4 substituents at substitutable positions. Examples of such substituents include an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, and an amino group that may be substituted. These substituents are similar to those on the hydrocarbon group and heterocyclic group for the above-described R.
Ring E, namely the partial structural formula: is preferably the formula :
Figure imgf000024_0002
Figure imgf000024_0001
wherein R2 represents hydrogen atom, an alkyl group, a hydroxy group that may be substituted, halogen, an acyl group that may be substituted, nitro, or an amino group that may be substituted.
The alkyl group, hydroxy group that maybe substituted, halogen, acyl group that may be substituted, and amino group that may be substituted, for R2, are similar to those on the hydrocarbon group or heterocyclic group for the above-described R. R2 is preferably hydrogen atom, a hydroxy group that may be substituted, or halogen. R2 is more preferably hydrogen atom, or a hydroxy group that may be substituted. R2 is especially preferably hydrogen atom, or a C1.i alkoxy group.
Referring to the formula (IV), L and M respectively represent hydrogen atom or may be combined with each other to form a chemical bond, and preferably they are hydrogen atom.
The compound in which L and M are combined with each other to form a chemical bond, may exist as (E)- and (Z)- isomers, owing to the double bond at 5-position of the azolidinedione ring.
The compound in which L and M respectively represent hydrogen atom, may exist as optical isomers, i.e. (R)- and (S) -forms, with respect to the asymmetric carbon at 5- position of the azolidinedione ring. This compound includes these optically active compounds, i.e. (R)- and (S) -forms, as well as the racemic form.
The preferred compound of the formula (IV) includes the compound in which R represents pyridyl, oxazolyl, or thiazolyl group, each of which may have 1 to 3 substituents selected from the group consisting of C^ alkyl, furyl, thienyl, phenyl, and naphthyl; m is 0; n is 0 or 1; X represents CH; A represents a chemical bond or -(CH2)2-; R1 represents hydrogen; ring E, namely the partial structural formula:
s the formula
Figure imgf000025_0002
Figure imgf000025_0001
wherein R2 is hydrogen or a Cx_4 alkoxy group; and L and M represent hydrogen atom.
Examples of the preferred compound of the formula (IV) includes
5- [ 4- [ 2- ( 5-ethyl-2-pyridyl) ethoxy]benzyl] -2 , 4- thiazolidinedione (generic name: pioglitazone);
5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1- benzopyran-2-yl)methoxy]phenyl]methyl] -2,4- thiazolidinedione( generic name: troglitazone);
5- [ [ 4- [2- (methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2, 4-thiazolidinedione(generic name: rosiglitazone);
5- [ 3- [ 4- ( 5-methyl-2-phenyl-4- thiazolylmethoxy]phenyl]propyl] -2 , 4-oxazolidinedione;
5- [ 4- ( 6-methoxy-l-H-benzimidazol-2-ylmethoxy)benzyl] -
2, 4-thiazolidinedione; and 5- [ 4- ( 6-methoxy-l-methylbenzimidazol-2- ylmethoxy)benzyl] -2 , 4-thiazolidinedione .
A salt of a compound represented by the formula (IV) is preferably a pharmacologically acceptable salt, which includes salts with inorganic bases, salts with organic bases, salts with inorganic acids , salts with organic acids , and salts with basic or acidic amino acids.
The preferred salt with an inorganic base includes salts with alkali metal such as sodium, potassium, etc.; alkaline earth metal such as calcium, magnesium, etc.; aluminum; ammonium etc.
The preferred salt with an organic base includes salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine , N.N-dibenzylethylenediamine, .etc.
The preferred salt with an inorganic acid includes salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. The preferred salt with an organic acid includes salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. The preferred salt with a basic amino acid includes salts with arginine, lysine, ornithine, etc. The preferred salt with an acidic amino acid includes salts with aspartic acid, glutamic acid, etc.
A compound represented by the formula (IV) or salt thereof is preferably pioglitazone, troglitazone, rosiglitazone or their salts; more preferably pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate; especially preferably pioglitazone hydrochloride.
A compound represented by the formula (IV) or salt thereof can be produced in accordance with methods described in JP-A S55(1980)-22636 (EP_-A-8203), JP-A S60(1985)-208980 (EP-A-155845 ) , JP-A S61 ( 1986 ) -286376
(EP-A-208420) , JP-A S61 ( 1986 ) -85372 (EP-A-177353 ) , JP-A S61(1986)-267580 (EP-A-193256 ) , JP-A H5 ( 1993 ) -86057
( O-A-92/18501) , JP-A H7 ( 1995 ) -82269 (EP-A-605228 ) , JP-
AH7(1995)-101945 (EP-A-612743 ) , EP-A-643050, EP-A-710659,
USP 5002953, JP-A H9 ( 1997 ) -295970 , etc., or methods analogous thereto.
Examples of the insulin sensitizer employed in the present invention include, in addition to the above- described compounds ,
( ± )-4-[4-[2-(5-methyl-2-phenyloxazol-4- yl)ethoxy]benzyl]isoxazolidin-3, 5-dione (JTT-501) or its salt;
5- [ [ 3 , 4-dihydro-2- (phenylmethyl) -2H-l-benzopyran-6- yl]methyl] -2, 4-thiazolidinedione (generic name: englitazone) or its salt (preferably sodium salt); 5-[ [4-[3-(5-methyl-2-phenyl-4-oxazolyl)-l- oxopropyl ] phenyl ]methyl ] - 2 , 4-thiazolidinedione ( generic name: darglitazone/CP-86325) or its salt (preferably sodium salt) ;
5- [ 2- ( 5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5- ylmethyl]-2,4-oxazolidinedione (CP-92768) or its salt;
5- ( 2-naphthalenylsulfonyl) -2 , 4-thiazolidinedione (AY-
31637) or its salt;
4- [ ( 2-naphthalenyl)methyl] -3H-1,2,3, 5-oxathiadiazol-2- oxide (AY-30711) or its salt; 5-[ [6-(2-fluorobenzyloxy) -2-naphthyl]methyl] -2 , 4- thiazolidinedione (MCC-555) or its salt;
( ± ) - [ 5- [ ( 2 » 4-dioxothiazolidin-5-yl)methyl] -2-methoxy-
N- [ [ 4- ( trifluoromethyl)phenyl]methyl ]benzamido (AHG-
255) or its salt; 4-[l-(3,5, 5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)ethenyl]benzoic acid (LGD1069) or its salt;
6-[l-(3,5,5,8, 8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl ) cyclopropyl] nicotinic acid (LGD100268) or its salt;
1,4-bis [4- [ (3, 5-dioxo-l, 2 , 4-oxadiazolidin-2- yl )methyl ]phenoxy] -2 -butene (YM-440) or its salt; R-119702; dexlipotam; GI-262570; INS-1; AR-H-0329242 ; CLX-0901; FK-614; KRP-297; CRE-16336; NN-2344; BM-13-1258 S-15261; KB-R-7785; DN-108; DRF-2725; G -2570; G -2433 MXC-3255; L-746449; L-767827; L-783281; G -409544; CS-011 etc.
Salts of these compounds include those similar to the salt of a compound of the formula (IV) mentioned above.
An insulin sensitizer is preferably pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, or ( ± ) -4- [4- [ 2- (5-methyl-2-phenyloxazol-4- yl )ethoxy] benzyl ] isoxazolidin- 3 , 5-dione , especially preferably pioglitazone hydrochloride.
In the present invention, the insulin sensitizer can be employed as a mixture of two or more species in an appropriate ratio.
The compound of the formula ( I ) or its salt is a known compound which is described in 096/16938 and possesses a β 3 adrenergic receptor stimulating activity, or a compound produced in accordance with an analogous method to a method described in W096/16938. In the formula ( I ), groups having the term "lower" mean that these groups have 1 to 4 carbon atoms .
Examples of the preferred compound of the formula ( I ) or its salt includes 2- [ 3- ( 7 -methoxyindol-3-yl ) -2-propylamino ] - 1- ( 3- chlorophenyl) ethanol ;
2 - [ 3- ( 7 -ethoxyindol-3-yl ) - 2-propylamino ] -1- ( 3- chlorophenyl) ethanol ;
2- [ 3- ( 7-methoxycarbonylmethoxyindol-3-yl) -2- propylamino] -1- ( 3-chlorophenyl) ethanol;
2- [3- ( 7-carboxymethoxyindol-3-yl) -2-propylamino] -1- ( 3- chlorophenyl)ethanol; and their optical isomers or salts. Among these, preferred is 2- [3- ( 7-carboxymethoxyindol- 3-yl ) - ( 2R) - 2-propylamino ] - ( IR) - 1- ( 3- chlorophenyl) ethanol, also called as 2-[[3-[(2R)-2- [ [ (2R) -2-(3-chlorophenyl) -2-hydroxyethyl] amino ]propyl] - lH-indol-7-yl]oxy]acetic acid (hereafter abbreviated as Compound A) .
The compound of the formula (II) or its salt is a known compound which is described in JP-A H6( 1994) -345731 and possesses a β 3 adrenergic receptor stimulating activity, or a compound produced in accordance with an analogous method to a method described in JP-A H6( 1994 ) -345731. In the formula ( II ) , "lower alkyl group" in "lower alkyl group" and "halogeno-lower alkyl group" means C^ alkyl group. Examples of the preferred compound of the formula ( II ) or its salt includes
2- [ ( IR) -2- ( indol-3-yl) - 1-methylethylamino] - ( IR) - 1- ( 3- chlorophenyl)ethanol (hereafter abbreviated as Compound B) and its pharmacologically acceptable acid-addition salt.
The compound of the formula ( III ) or its salt is a known compound which is described in USP 5451677 and possesses a j33 adrenergic receptor agonistic activity. Examples of the preferred compound of the formula
(III) or its salt includes
N-[4-[2-[ [2-hydroxy-3-(4- hydroxyphenoxy)propyl]amino]ethyl]phenyl]benzene- sulfonamide ; N-[4-[2-[ [2-hydroxy-3-(4- hydroxyphenoxy)propyl ] amino ] ethyl] phenyl] - 4- iodobenzenesulfonamide;
N-[4-[2-[ [2-hydroxy-3-(4- hydroxyphenoxy) propyl ] amino ] ethyl ] phenyl ] - 2- naphthalenesulfonamide ;
N-[4-[2-[ [2-hydroxy-3-(4- hydroxyphenoxy)propyl] amino ] ethyl]phenyl] -4- (benzo- 2,1, 3-thiadiazol)sulfonamide; N-[4-[2-[ [2-hydroxy-3-(4- hydroxyphenoxy)propyl] amino] ethyl]phenyl] -2- phenylethanesulfonamide;
N-[4-[2-[[3-(4-fluorophenoxy) -2- hydroxypropyl] amino] ethyl]phenyl] -4-benzenesulfonamide; N-[4-[2-[[3-[ (2-amino-5-pyridinyl)oxy] -2- hydroxy]propyl]amino ] ethyl]phenyl] -2- naphthalenesulfonamide.
The compound of the formula (V) or its salt is a known compound which is described in WO99/01431 and possesses a /33 agonistic activity. In the formula (V), groups having the term "lower" mean that these groups have 1 to 4 carbon atoms.
Examples of the preferred compound of the formula (V) or its salt includes (R)-N'-[5-[2-[2-(5,6,7,8-tetrahydro-9H-carbazol-2- yloxy)ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N,N- dimethylsulfamide hydrochloride .
The compound of the formula (VI) or its salt is a known compound which is described in 097/23511 and possesses a β 3 agonistic activity. In the formula (VI) , groups having the term "lower" mean that these groups have 1 to 4 carbon atoms .
Examples of the preferred compound of the formula (VI) or its salt includes ( ± ) -N- [ 5- [ 2- [ 2- ( 9H-carbazol-2-yloxy)ethylamino] -1- hydroxyethyl] -2-hydroxyphenyl ]methanesulfonamide hydrochloride;
( ± ) -N- [ 3- [ 2- [ 2- ( 9H-carbazol-2-yloxy)ethylamino] -1- hydroxyethyl]phenyl]methanesulfonamide hydrochloride; ( ± ) -2- [N- [ 2- (9H-carbazol-2-yloxy)ethyl]amino] -1- phenylethanol hydrochloride; and their optical isomers. Further, examples of the compound of the formula (V) or (VI), or its salt include AZ40140, etc.
Salts of the compound of the formula (I) , (II), (III), (V) or (VI) include those similar to the salt of a compound of the formula (IV) mentioned above.
In the pharmaceutical composition of the present invention, combination of an insulin sensitizer and a compound of the formula (I) is preferable.
Preferred examples of the pharmaceutical composition of the present invention include
1) a pharmaceutical composition comprising pioglitazone or its hydrochloride in combination with Compound A;
2) a pharmaceutical composition comprising troglitazone in combination with Compound A;
3) a pharmaceutical composition comprising rosiglitazone or its maleate in combination with Compound A.
A pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating diabetes . Examples of the diabetes include insulin-dependent (type I) diabetes mellitus , noninsulin-dependent (type II) diabetes mellitus, etc. A pharmaceutical composition of the present invention and its active ingredient is especially preferably employed for noninsulin-dependent diabetes mellitus.
Further, a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for treating impaired glucose tolerance. Referring to the definition of impaired glucose tolerance, WHO (World Health Organization) suggests a criterion in a 75g oral glucose tolerance test (75g OGTT) . According to this criterion, impaired glucose tolerance means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is less than 140mg/dl, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, ranges from 140 to 199 mg/dl. Diabetes means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is 140mg/dl or more, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 200 mg/dl or more.
Regarding the criterion of diabetes, new criteria are reported from ADA (American Diabetic Association) on 1997 and from WHO on 1998.
According to these reports , diabetes means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is 126mg/dl or more, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 200 mg/dl or more. According to the above reports, impaired glucose tolerance means a condition wherein a fasting glucose level (glucose concentration in venous plasma) is less than 126mg/dl, and a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is 140mg/dl or more and less than 200 mg/dl.
According to the ADA reports, a condition wherein a fasting glucose level (glucose concentration in venous plasma) is HOmg/dl or more and less than 126mg/dl, is called IFG (Impaired Fasting Glucose). According to the WHO report, a condition, among this IFG (Impaired Fasting Glucose), wherein a 2hr after glucose level (glucose concentration in venous plasma) , when a 75g oral glucose tolerance test is conducted after an overnight fasting, is less than 140mg/dl, is called IFG (Impaired Fasting Glycemia) . The pharmaceutical composition of the present invention and its active ingredient can be also used as an agent for preventing or treating diabetes , impaired glucose tolerance, IFG (Impaired Fasting Glucose), IFG (Impaired Fasting Glycemia) , all of which is defined by the above new criteria. The pharmaceutical composition of the present invention and its active ingredient can also prevent progress to diabetes from impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) .
Further, a pharmaceutical composition of the present invention and its active ingredient can be also used as an agent for preventing or treating diseases such as hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-high-density-lipoproteinemia, postprandial hyperlipidemia, etc.), hyperinsulinemia, obesity (including body weight increase after stopping a smoking habit, after stopping alimentary therapy, or after stopping exercise), hyperphagia, hypertension, cardiovascular diseases (e.g., atherosclerosis, etc.), polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases (e.g., inflammatory colitis , ulcerative colitis ) , etc.; or syndromes (e.g. , syndrome X, visceral fat obesity syndrome, etc.) having some of these diseases in combination.
Further, a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating diabetic complications (e.g., retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection, urinary tract infection, gastrointestinal tract infection, dermal soft tissue infection, inferior limb infection) , diabetic osteoporosis , diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris , cerebrovascular disease (e.g., cerebral apoplexy, cerebral infarction) or peripheral circulatory disturbance, etc.).
Further, a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating irritable bowel syndrome, acute or chronic diarrhea; or for ameliorating bellyache, nausea, vomiting, or dysphoria in epigastrium, each of which is accompanied by gastrointestinal ulcer, acute or chronic gastritis, biliary dyskinesia, or cholecystitis.
Further, a pharmaceutical composition of the present invention and its active ingredient possess an effect of ameliorating cachexia, namely an effect of ameliorating the systematic syndrome featuring progressive loss of body weight (inclusive of loss of body weight due to lipolysis and loss of body weight due to myolysis), anemia, edema, and anorexia in chronic diseases such as malignant tumor, tuberculosis, diabetes, blood dyscrasia, endocrine diseases, infectious diseases, and acquired immunodeficiency syndrome .
Further, a pharmaceutical composition of the present invention and its active ingredient can be used as an agent for preventing or treating TNF- a mediated inflammatory diseases. The TNF- mediated inflammatory diseases mean inflammatory diseases which occur in the presence of TNF- ot and can be treated by way of a TNF- a inhibitory action. Examples of such inflammatory diseases include diabetic complications (e.g., retinopathy, nephropathy, neuropathy, macroangiopahty), rheumatoid arthritis, osteoarthritis of the spine, osteoarthritis , low back pain, gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, laryngopharyngitis , cystitis. hepatitis, pneumonia, gastric ucosal injury (including aspirin-induced gastric mucosal injury), etc.
A pharmaceutical composition of the present invention and its active ingredient have an apoptosis inhibitory activity, and can be used as an agent for preventing or treating diseases mediated by promotion of apoptosis.
Examples of the diseases mediated by promotion of apoptosis include viral diseases (e.g., AIDS, fulminant hepatitis), neurodegenerative diseases (e.g., Arzheimer's disease, Parkinson' s disease, amyotropic lateral sclerosis , retinitis pigmentosa, cerebellar degeneration), myelodysplasia (e.g. , aplastic anemia) , ischemic diseases (e.g., myocardial infarction, cerebral apoplexy), hepatic diseases (e.g., alcoholic hepatitis, hepatitis B, hepatitis C) , joint-diseases (e.g., osteoarthritis), atherosclerosis, etc.
Further, a pharmaceutical composition of the present invention and its active ingredient can be used for reducing visceral fats, inhibiting accumulation of visceral fats, ameliorating glucose metabolism, ameliorating lipid metabolism, ameliorating insulin resistance, inhibiting production of oxidized LDL, ameliorating lipoprotein metabolism, ameliorating coronary artery metabolism, preventing or treating cardiovascular complications, preventing or treating heart failure complications, lowering blood remnant , preventing or treating anovulation , preventing or treating hirsutism, preventing or treating hyperandrogenism, etc.
A pharmaceutical composition of the present invention and its active ingredient possess an action of controlling appetite, and thus can be used for treating emaciation or refusal of food.
A pharmaceutical composition of the present invention and its active ingredient can be used for secondary prevention and for inhibition in progress, both of various diseases described above (e.g. , cardiovascular events such as myocardial infarction, etc.). Further, a pharmaceutical composition of the present invention and its active ingredient can be used in combination with midazolam, ketoconazole, etc.
A pharmaceutical composition of the present invention can be obtained by combining active ingredients , an insulin sensitizer and at least one member selected from the group consisting of a compound of the formula (I) or its salt, a compound of the formula (II) or its salt, a compound of the formula (III) or its salt, a compound of the formula (V) or its salt, and a compound of the formula (VI) or its salt (hereafter also abbreviated as compound (I) to (III) , (V) , (VI) , respectively) . These active ingredients may be subjected to pharmaceutical manufacturing processes by admixing separately or concomitantly with pharmaceutically acceptable carriers in accordance with per se known means [conventional means in fields of pharmaceutical manufacturing techniques, for instance, means described in the Pharmacopoeia of Japan (e.g.. Thirteenth Edition, etc. ) ] .
Examples of dosage forms of a pharmaceutical composition of the present invention or its respective active ingredients include oral dosage forms such as tablets, capsules (including soft capsules and microcapsules) , powders, granules, syrups, etc.; and non-oral dosage forms such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external application forms (e.g., nasal spray preparations, transdermal preparations , ointments, etc.), suppositories (e.g., rectal suppositories, vaginal suppositories, etc.), pellets, drip infusions, sustained-release preparations, etc.
Methods of producing oral dosage forms and non-oral dosage forms are specifically explained below.
Oral dosage forms are produced by adding to the active ingredient (s) , for instance, an excipient (e.g., lactose, sucrose, starch, D-mannitol, xylitol, sorbitol, erythritol, crystalline cellulose, light silicic anhydride, etc.), a disintegrator (e.g., calcium carbonate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, light silicic anhydride, etc.), a binder (e.g., α -starch, gum arable, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, methylcellulose, sucrose, D- mannitol, trehalose, dextrin, etc.), or a lubricant (e.g., talc, magnesium stearate, calcium stearate, talc, colloidal silica, polyethylene glycol 6000, etc. ) , and then compressing and molding the resulting mixture. To the oral dosage form, acids such as hydrochloric acid, phosphoric acid, malonic acid, succinic acid, DL-malic acid, tartaric acid, maleic acid, fumaric acid, citric acid, etc. ; or bases such as sodium carbonate , sodium hydrogencarbonate, sodium citrate, sodium tartrate, etc. can be added for the purpose of promoting dissolution of the active ingredient(s) .
The oral dosage forms can be coated, by the per se known method, for masking the taste or for enteric dissolution or sustained release. Examples of a coating material that can be employed includes, enteric coating polymers such as cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, etc.; gastric coating polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, etc.; water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.; water-insoluble polymers such as ethylcellulose, aminoalkyl methacrylate copolymer RS, ethylacrylate-methylmethacrylate copolymer, etc.; wax, etc. When coating is carried out, plasticizers such as polyethylene glycol, etc.; and sunscreens such as titanium oxide, iron sesquioxide, etc. can be employed together with the above coating material.
Injections can be produced by dissolving, suspending or emulsifying the active ingredient (s) in an aqueous vehicle (e.g., distilled water, physiological saline, Ringer's solution, etc.) or an oily vehicle (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc.; or propylene glycol , macrogol, tricaprylin, etc. ) together with a dispersant (e.g. , Tween 80 (produced by Atlas Powder, U.S.A.), HCO 60 (produced by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonizing agent (e.g., sodium chloride, glycerol, D-sorbitol, D-mannitol, xylitol, glucose, fructose, etc.) etc.
If desired, also employed are additives such as a solubilizer (e.g., sodium salicylate, sodium acetate, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. ) , a suspending agent (e.g. , surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc. ,- and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium. methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), a buffering agent (e.g. , buffer solutions such as phosphate, acetate, carbonate, citrate, etc.), a stabilizer (e.g., human serum albumin, etc.), a soothing agent (e.g., propylene glycol, lidocaine hydrochloride , benzyl alcohol, etc. ) , an antiseptic (e.g. , p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. ) , etc.
External application forms can be produced by processing the active ingredient(s) into a solid, semi- solid or liquid composition. For instance, a solid composition is produced by processing the active ingredient (s) , either as such or in admixture with an excipient (e.g., lactose, D-mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickner (e.g., natural gums, cellulose derivatives, acrylic acid polymers, etc.), etc., into powders. The above liquid composition is produced in substantially the same manner as in the case of injections. The semi-solid composition is preferably provided in a hydrous or oily gel form or an ointment form. These compositions may optionally contain a pH control agent (e.g., phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), an antiseptic (e.g., p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), etc.
Suppositories can be produced by processing the active ingredient(s) into an oily or aqueous composition, whether solid, semi-solid or liquid. Examples of oleaginous bases that can be used in producing the composition include higher fatty acid glycerides [e.g., cacao butter, Witepsols (huels Aktiengesellschaft , Germany), etc.], medium-chain fatty acid triglycerides [e.g., Migriols(huels Aktiengesellschaft, Germany) , etc. ] , vegetable oils (e.g. , sesame oil, soybean oil, cottonseed oil, etc.), etc. Examples of aqueous bases include polyethylene glycols, propylene glycol, etc. Further, examples of the aqueous gel bases include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers, etc.
The method for administrating a pharmaceutical composition of the present invention is not limited as long as an insulin sensitizer and any of compounds [I] to [III] ,
[V] and [VI] are combined at the time of administration.
Examples of such methods include 1) administration of a single preparation prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] at the same time; 2) concomitant administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by the same administration route; 3) staggered administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [ I ] to [III], [V] and [VI] separately by the same administration route; 4) concomitant administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by different administration routes ; 5) staggered administration of two kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately by different administration routes (e.g. , administration of an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] in this order, or reverse order); etc. Among others, the above 2) and 3) are preferred.
Preferred embodiments include processing an insulin sensitizer and any of compounds [I] to [III], [V] and [VI] separately into oral dosage forms such as tablets, and administering the oral dosage forms concomitantly or with a staggered time.
A pharmaceutical composition of the present invention and its active ingredient are low in potential toxicity, and can be safely used in mammals (e.g. , human, mouse, rat, rabbit, dog, cat, bovine, equine, swine, monkey, etc.), either orally or non-orally.
The dosage of a pharmaceutical composition of the present invention may be appropriately determined with reference to the dosage recommended for the respective active ingredient (s) , and can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, method of administration, combination of the drug(s) , etc.
The dosage of an insulin sensitizer and compounds [I] to [III] , [V] and [VI] can be selected appropriately based on clinically used dosage.
For administration of an insulin sensitizer to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once to several times a day. Especially, when pioglitazone hydrochloride is employed as the insulin sensitizer, the dose of pioglitazone hydrochloride per day is usually 7.5 to 60 mg, preferably 15 to 45 mg. When troglitazone is employed as the insulin sensitizer, the dose of troglitazone per day is usually 100 to 1000 mg, preferably 200 to 600 mg. When rosiglitazone (or its maleate) is employed as the insulin sensitizer, the dose of rosiglitazone per day is usually 1 to 12 mg, preferably 2 to 8 mg.
For administration of compounds [I] to [III], [V] and [VI] to an adult diabetic patient (body weight: 50 kg) , for instance, the dose per day is usually 0.1 to 500 mg, preferably 0.1 to 200 mg, more preferably 0.1 to 50 mg. Especially, the dose of compound A per day is usually 0.1 to 10 mg, preferably 0.2 to 3 mg.
The proportion of an insulin sensitizer and compounds [I] to [III], [V] and [VI] in a pharmaceutical composition of the present invention can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, method of administration, combination of the drug(s), etc. For instance, compounds [I] to [III], [V] and [VI] are used in a proportion of usually about 0.005 to 1 weight part and preferably about 0.001 to 0.2 weight parts relative to one weight part of an insulin sensitizer.
A pharmaceutical composition of the present invention possesses an enhanced blood sugar lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.
Further, a pharmaceutical composition of the present invention possesses an enhanced blood lipid lowering action or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds
[I] to [III], [V] and [VI] alone.
Further, a pharmaceutical composition of the present invention possesses an excellent effect of treating diabetes, and therefore, the amount of drugs used can be reduced as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.
Further, when the pharmaceutical composition of the present invention is administered to a diabetic patient, a tendency of decrease in the patient ' s body weight as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone is observed.
Referring to a pharmaceutical composition of the present invention, concomitant drugs which do not interfere with an insulin sensitizer or compounds [I] to [III], [V] and [VI] can be used for the purpose of "enhancing the diabetes treating effects of an insulin sensitizer or compounds [I] to [III], [V] and [VI]", "reducing the dose of an insulin sensitizer or compounds [I] to [III] , [V] and [VI]", "reducing the side effects of an insulin sensitizer or compounds [I] to [III], [V] and [VI]", etc. Examples of the concomitant drugs include "agents for treating diabetes", "agents for treating diabetic complications",
"anti-obesity agents" . "agents for treating hypertension" ,
"agents for treating hyperlipidemia", "diuretics", etc.
Further, a dietetic therapy (therapy by restriction of nutrition or calories) or a therapeutic exercise can be employed at the time of using a pharmaceutical composition of the present invention.
Examples of the "agents for treating diabetes" include insulin, insulin secretion enhancers, biguanides, a - glucosidase inhibitors, etc.
Insulin means any and all substances having an insulin action, and exemplified by, for instance, animal insulin extracted from bovine or porcine pancreas; semi- synthesized human insulin which is enzymatically synthesized from insulin extracted from porcine pancreas,- and human insulin synthesized by genetic engineering techniques typically using Escherichia coli or yeasts ; etc .
Further, as insulin employed are insulin-zinc containing 0.45 to 0.9 (w/w) % of zinc; protamine- insulin-zinc produced from zinc chloride, protamine sulfate and insulin; etc. Insulin may be in the form of its fragments or derivatives (e.g., INS-1). Insulin may be insulin-like substances (e.g., L83281, insulin agonists) . While insulin is available in a variety of types such as super immediate-acting, immediate-acting, bimodal- acting, intermediate-acting, long-acting, etc., these types can be appropriately selected according to the patient's condition.
Use of a pharmaceutical composition of the present invention in combination with insulin enables reduction of the dose of insulin as compared with the dose at the time of administration of insulin alone. Therefore, risk of blood vessel complication and hypoglycemia induction, both of which are problems with large amounts of insulin administration, is low.
Since a pharmaceutical composition of the present invention possesses an excellent effect of treating diabetes, a satisfactory effect of treating diabetes can be obtained even if the dose of insulin is reduced as compared with administration of insulin alone.
Examples of the insulin secretion enhancers include sulfonylureas . Specific examples of the sulfonylureas include tolbutamide, chlorpropamide , tolazamide, acetohexamide , glyclopyramide and its ammonium salt, glibenclamide , gliclazide, l-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride, etc. In addition to the above, examples of the insulin secretion enhancers include nateglinide(AY-4166) , calcium ( 2S) -2-benzyl-3- (cis-hexahydro-2- isoindolinylcarbonyl)propionate dihydrate (mitiglinide, KAD-1229), repaglinide, etc. Examples of the biguanides include phenformin, metformin, buformin, etc.
Examples of the a -glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate, etc.
In addition to the above, examples of the "agents for treating diabetes" include ergoset, pramlintide, leptin, BAY-27-9955, T-1095, etc. For administration of the "agents for treating diabetes" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.1 to 2500 mg, preferably 0.5 to 1000 mg. This dose can be administered once to several times a day.
For administration (usually administration in the form of injections) of insulin to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 10 to 100 U (Units) , preferably 10 to 80 U (Units) . This dose can be administered once to several times a day. For administration of insulin secretion enhancers to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.1 to 1000 mg, preferably 1 to 100 mg. This dose can be administered once to several times a day.
For administration of biguanides to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 10 to 2500 mg, preferably 100 to 1000 mg. This dose can be administered once to several times a day.
For administration of a -glucosidase inhibitors to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.1 to 400 mg, preferably 0.6 to 300 mg. This dose can be administered once to several times a day.
Examples of the "agents for treating diabetic complications" include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, etc. Examples of the aldose reductase inhibitors include tolurestat; epalrestat; 3 , 4-dihydro-2 , 8-diisopropyl-3- thioxo-2H-l , 4-benzoxazine-4-acetic acid; imirestat; zenarestat ; 6-fluoro-2 , 3-dihydro-2 ' , 5 ' -dioxo-spiro[ 4H- l-benzopyran-4 , 4 ' -imidazolidine] -2-carboxamide (SNK- 860); zopolrestat; sorbinil; 1- [ ( 3-bromo-2- benzofuranyl)sulfonyl] -2 , 4-imidazolidinedione (M- 16209 ) ; CT- 112 ; NZ - 314 ; ARI - 509 ; etc .
Examples of the glycation inhibitors include pimagedine, etc.
Examples of the protein kinase C inhibitors include NGF, LY-333531, etc.
In addition to the above, examples of the "agents for treating diabetic complications" include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentaenoate, memantine, pimagedline (ALT-711), etc.
For administration of the "agents for treating diabetic complications" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.1 to 2000 mg. This dose can be administered once to several times a day.
For administration of aldose reductase inhibitors to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 1 to 1000 mg. This dose can be administered once to several times a day.
For administration of glycation inhibitors to an adult diabetic patient (body weight: 50 kg) , the dose per day is usually 1 to 2000 mg. This dose can be administered once to several times a day. For administration of protein kinase C inhibitors to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.1 to 100 mg. This dose can be administered once to several times a day.
Examples of the "agents for treating obesity" include lipase inhibitors, anorectics, etc.
Examples of the lipase inhibitors include orlistat, etc.
Examples of the anorectics include dexfenfluramine, fluoxetine, sibutramine, baiamine, etc.
For administration of the "agents for treating obesity" to an adult diabetic patient (body weight: 50 kg) , for instance, the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 1000 mg. This dose can be administered once to several times a day. For administration of lipase inhibitors to an adult diabetic patient (body weight: 50 kg) , the dose per day is usually 0.1 to 1000 mg. This dose can be administered once to several times a day.
For administration of anorectics to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose can be administered once to several times a day.
Examples of the "agents for treating hypertension" include angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists, etc.
Examples of the angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat , fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, manidipine, etc.
Examples of the calcium antagonists include nifedipine, amlodipine, efonidipine, nicardipine, etc. Examples of the potassium channel openers include leveromakalim, L-27152, AL 0671, NIP-121, etc.
Examples of the angiotensin II antagonists include losartan, candesartan cilexetil, valsartan, irbesartan, (5-methyl-2-oxo-l,3-dioxoran-4-yl)methyl 4- ( 1-hydroxy- 1-methylethyl) -2-propyl-1- [ 2 ' - ( IH-tetrazol-5- yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (CS-866) , E4177, etc.
For administration of the "agents for treating hypertension" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 to 1000. mg. This dose can be administered once to several times a day.
For administration of angiotensin converting enzyme inhibitors to an adult diabetic patient (body weight: 50 kg) , the dose per day is usually 0.01 to 500 mg, preferably
0.1 to 100 mg . This dose can be administered once to several times a day.
For administration of calcium antagonists to an adult diabetic patient (body weight: 50 kg) , the dose per day is usually 0.1 to 500 mg, preferably 1 to 200 mg. This dose can be administered once to several times a day.
For administration of potassium channel openers to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.01 to 1000 mg. This dose can be administered once to several times a day.
For administration of angiotensin II antagonists to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.1 to 500 mg, preferably 1 to 100 mg.
This dose can be administered once to several times a day.
Examples of the "agents for treating hyperlipidemia" include, HMG-CoA reductase inhibitors, fibrate compounds, etc.
Examples of the HMG-CoA reductase inhibitors include pravastatin and its sodium salt, cerivastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, itavastatin, ZD-4522, etc.
Examples of the fibrate compounds include bezafibrate, beclofibrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, etc.
For administration of the "agents for treating hyperlipidemia" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 to 3000 mg, preferably 1 to 2000 mg. This dose can be administered once to several times a day.
For administration of HMG-CoA reductase inhibitors to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.01 to 100 mg, preferably 0.5 to 50 mg.
This dose can be administered once to several times a day.
For administration of fibrate compounds to an adult diabetic patient (body weight: 50 kg) , the dose per day is usually 1 to 2000 mg, preferably 10 to 1500 mg. This dose can be administered once to several times a day.
Examples of the "diuretics" include xanthine derivative preparations, thiazide preparations, antialdosterone preparations, carbonate dehydratase inhibitors, chlorbenzenesulfonamide preparations, etc.
Examples of the xanthine derivative preparations include theobromine and sodium salicylate, theobromine and calcium salicylate, etc.
Examples of the thiazide preparations include ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide , hydroflumethiazide , benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, etc.
Examples of the antialdosterone preparations include spironolactone, triamterene, etc.
Examples of the carbonate dehydratase inhibitors include acetazolamide, etc.
Examples of the chlorbenzenesulfonamide preparations include chlorthalidone , mefruside, indapamide, etc. In addition to the above, examples of the "diuretics" include azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.
For administration of the "diuretics" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 mg to 100 g, preferably 0.05 mg to 10 g. This dose can be administered once to several times a day.
For administration of xanthine derivative preparations to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.1 to 100 g, preferably 0.5 to 10 g. This dose can be administered once to several times a day.
For administration of thiazide preparations to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 0.01 to 2000 mg, preferably 0.05 to 500 mg. This dose can be administered once to several times a day. For administration of antialdosterone preparations to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 1 to 2000 mg, preferably 10 to 1000 mg. This dose can be administered once to several times a day. For administration of carbonate dehydratase inhibitors to an adult (body weight: 50 kg), the dose per day is usually 10 to 5000 mg, preferably 50 to 2000 mg. This dose can be administered once to several times a day. For administration of chlorbenzenesulfonamide preparations to an adult diabetic patient (body weight: 50 kg), the dose per day is usually 1 to 2000 mg, preferably 10 to 1000 mg. This dose can be administered once to several times a day.
The concomitant drugs mentioned above can be used as a mixture of two or more species optionally selected. Specific examples of combination when two kinds of concomitant drugs are used in combination include "combination of an insulin secretion enhancer and a biguanide", "combination of an insulin secretion enhancer and an a -glucosidase inhibitor", "combination of insulin and a biguanide", "combination of insulin and an - glucosidase inhibitor", etc.
The administration method of a pharmaceutical composition of the present invention and a concomitant drug is not limited as long as these are used in combination at the time of administration.
The proportion of an a pharmaceutical composition of the present invention and a concomitant drug can be selected appropriately according to the subject, the age and body weight of the subject, current clinical status, administration time, dosage form, administration method, etc. For instance, a concomitant drug is used in a proportion of 0.0001 to 10000 weight parts relative to one weight part of a pharmaceutical composition of the present invention.
Use of at least one species among compounds [I] to [III] . [V] and [VI] in combination with at least one species among the concomitant drug mentioned above, without using an insulin sensitizer, provides various pharmaceutical effects referred to as those for a pharmaceutical composition of the present invention, such as ah excellent effect of treating diabetes.
Specific combination of compounds [I] to [III], [V] and [VI] with the above concomitant drugs includes, for instance, "combination of Compound A and an insulin", "combination of Compound B and an insulin", "combination of Compound A and an insulin secretion enhancer (preferably sulfonylureas such as glibenclamide ; repaglinide, nateglinide, mitiglinide, etc. ) " , "combination of Compound B and an insulin secretion enhancer (preferably sulfonylureas such as glibenclamide; repaglinide, nateglinide, mitiglinide, etc. ) " , "combination of Compound A and a biguanide (preferably metformin, etc.)", "combination of Compound B and a biguanide (preferably metformin, etc.)", "combination of Compound A and an a -glucosidase inhibitor (preferably acarbose, etc.)", "combination of Compound B and an a -glucosidase inhibitor (preferably acarbose, etc.)", "combination of Compound A and a HMG-CoA reductase inhibitor (preferably pravastatin or its sodium salt, cerivastatin or its sodium salt, atorvastatin, etc.)", "combination of Compound B and a HMG-CoA reductase inhibitor (preferably pravastatin or its sodium salt, cerivastatin or its sodium salt , atorvastatin, etc. ) " , etc.
When any of compounds [I] to [III], [V] and [VI] is used alone, the method of use in the above mentioned pharmaceutical composition of the present invention can be appropriately applied, and a known method of use can also be appropriately applied.
Use of a pharmaceutical composition of the present invention or its active ingredient (e.g., pioglitazone hydrochloride, rosiglitazone maleate. Compound A, Compound B, etc.) in combination with the above concomitant drugs (e.g., insulin; insulin secretion enhancers such as sulfonylureas ; biguanides such as metformin; HMG-CoA reductase inhibitors such as cerivastatin sodium salt, etc.) provides enhancement in various pharmaceutical effects referred to as those for a pharmaceutical composition of the present invention, such as effects of treating diabetes , hyperlipidemia, hyperinsulinemia, etc. Further, such combination enables reduction in the dose of "a pharmaceutical composition of the present invention or its active ingredient (e.g., pioglitazone hydrochloride, rosiglitazone maleate. Compound A, Compound B, etc.)" or "concomitant drugs (e.g., insulin; insulin secretion enhancers such as sulfonylureas ; biguanides such as metformin; HMG-CoA reductase inhibitors such as cerivastatin sodium salt, etc. )" as compared with the dose at the time of administration of these alone.
The blood sugar lowering effect of a pharmaceutical composition in the present invention can be evaluated by determining concentration of glucose or Hb (hemoglobin)Alc in venous blood plasma in the subject before and after administration, and then comparing the obtained concentration between before administration and after administration. HbAl0 means glycosylated hemoglobin, and is gradually produced in response to blood glucose concentration. Therefore, HbAlc is thought important as an index of blood sugar control which is not easily influenced by rapid blood sugar changes in diabetic patients .
BEST MODE FOR CARRYING OUT THE INVENTION
The following Reference Examples and Examples are intended to describe the present invention in further detail and should by no means be construed as defining the scope of the invention. Reference Example 1
A fluidized-bed granulating and drying machine (produced by Powerex) was charged with 2479.5 g of pioglitazone hydrochloride (2250 g in terms of pioglitazone), 13930.5 g of lactose and 540 g of carboxymethylcellulose calcium (carmellose calcium) , followed by mixing at the preheating temperature and spraying 7500 g of an aqueous solution containing 450 g of hydroxypropylcellulose to yield granules. 16820 g of the granules were processed with cutter-mill (produced by Showa Kagaku Kikai Kousakusho) to yield milled granules. 16530 g of the milled granules, 513 g of carmellose calcium and 57 g of magnesium stearate were mixed to yield mixed powders by using a tumbling mixer (produced by Showa Kagaku Kikai Kousakusho). 16800 g of the mixed powders were tabletted by using a tabletting machine (produced by Kikusui
Seisakusho) to yield 140000 tablets having the following composition and each containing 15 mg of pioglitazone. Composition per tablet (Unit: mg) :
1) Pioglitazone hydrochloride 16.53 2) Lactose 92.87
3) Carmellose calcium 7.2 4 ) Hydroxypropylcellulose 3.0
5) Magnesium stearate 0.4
Total: 120.0
Reference Example 2
In the similar manner to Reference Example 1, 140000 tablets having the following composition and each containing 30 mg of pioglitazone were obtained. Composition per tablet (Unit: mg) : 1) Pioglitazone hydrochloride 33.06
2) Lactose 76.34
3) Carmellose calcium 7.2
4 ) Hydroxypropylcellulose 3.0
5) Magnesium stearate 0.4 Total: 120.0
Reference Example 3
In the similar manner to Reference Example 2, 140000 tablets having the following composition and each containing 45 mg of pioglitazone were obtained. Composition per tablet (Unit: mg) :
1) Pioglitazone hydrochloride 49.59
2) Lactose 114.51
3) Carmellose calcium 10.8 4) Hydroxypropylcellulose 4.5
5) Magnesium stearate 0.6
Total: 180.0
Example 1 When pioglitazone hydrochloride (30 mg/day, oral administration) and Compound A (0.5 mg/day, oral administration) are concomitantly administered to a NIDDM patient over the period of 8 weeks, an excellent blood glucose lowering action is observed.
Example 2 When pioglitazone hydrochloride (30 mg/day, oral administration) and Compound B (0.5 mg/day, oral administration) are concomitantly administered to a NIDDM patient over the period of 8 weeks, an excellent blood glucose lowering action is observed.
Example 3
Twenty three Wistar fatty rats, genetically obese and noninsulin-dependent diabetic (type 2 diabetic) models, (16 weeks old, male) were divided into Groups A to D. To Group A (6 rats), a 0. 5% (w/w) methylcellulose/physiological saline suspension (2 ml/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) were orally administered for 14 days. This group was considered as a control group.
To Group B (6 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) containing pioglitazone hydrochloride (1 mg/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) were orally administered for 14 days.
To Group C (6 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) and a 0.5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) containing Compound A (0.1 mg/kg body weight/day) were orally administered for 14 days.
To Group D (5 rats), a 0. 5% (w/w) methylcellulose/ physiological saline suspension (2 ml/kg body weight/day) containing pioglitazone hydrochloride (1 mg/kg body weight/day) and a 0. 5% (w/w) tragacanth gum aqueous suspension (2 ml/kg body weight/day) containing Compound A (0.1 mg/kg body weight/day) were orally administered for 14 days. The rats were allowed to take food freely.
After completion of administration over 14 days, blood was collected from the tail vein of the rats, and plasma was separated. Then, glucose and triglyceride in the plasma were quantified by L Type Wako Glu 2 (Wako Pure Chemical Industries, Ltd. ) and L Type Wako TG • H (Wako Pure Chemical Industries, Ltd. ) , respectively. The results are shown in Table 1.
After completion of administration over 14 days, body weights of the rats were determined. The results are shown in Table 2.
In the following tables, "pio" and "cpd A" mean pioglitazone hydrochloride and Compound A, respectively.
Figures in the tables represent mean ± SD (standard deviation) . [Table 1]
Figure imgf000056_0001
[Table 2]
Figure imgf000056_0002
As shown in Table 1, use of pioglitazone hydrochloride in combination with Compound A provided excellent effects of lowering a plasma glucose and a plasma triglyceride. Further, as shown in Table 2, use of pioglitazone hydrochloride in combination with Compound A unexpectedly provided an effect of inhibiting a body weight increase. Namely, the body weight increase in Group D was expected to be 26.4 (36.5 - 10.1) g because of the f ct that the body weight increase in Group B was 36.5 (641.9 - 605.4) g and the body weight increase in Group C was -10.1 (595.3 - 605.4) g. Actually, the body weight increase in Group D was unexpectedly low and was 14.8 (620.2 - 605.4) g.
Industrial Applicability
A pharmaceutical composition of the present invention possesses an enhanced blood sugar lowering action, blood lipid lowering action or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [V] and [VI] alone.

Claims

CLAIMS 1. A pharmaceutical composition which comprises an insulin sensitizer in combination with at least one member selected from the group consisting of 1 ) a compound of the formula [ I ] :
Figure imgf000058_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group , p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4 , (d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S. Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000059_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000059_0002
wherein R5 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group , nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000059_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to ,3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C^ alkyl, C _6 alkoxy, C3_8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19, NR18C02R18; or a Cx_6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18 , a halogeno lower alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19 , COR19, S02R19, NR18S02R19 or NR18C02R18; or Ru represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, Cx_6 alkyl, or Ci.g alkyl substituted by hydroxy,
Figure imgf000060_0001
alkoxy or halogen; X' represents -CH2-. -CH2-CH2- , -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, C^ alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or C^ alkyl;
R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-fR11)., wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and
N;
R18 represents hydrogen atom; C^,, alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C1.6 alkyl or C1.6 alkoxy; C^,, alkyl substituted by hydroxy, halogen, C02H, C^ alkoxy-carbonyl, C3.8 cycloalkyl, C^ alkoxy, or phenyl substituted by halogen, Cx,6 alkyl or C1_6 alkoxy;
R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound of the formula [V] :
0RM
Figure imgf000061_0001
wherein R 20 represents hydrogen atom or methyl group, R »"21 represents hydrogen atom, halogen atom, hydroxy group. benzyloxy group, amino group or hydroxymethyl group. R >22 represents hydrogen atom, hydroxymethyl group, NHR 23 S02NR2R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR26' ,
R25 represents a lower alkyl group, benzyl group or NR2R24 , R24 and R2 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R is hydrogen atom, and R is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI] :
OR30
Figure imgf000062_0001
wherein R represents hydrogen atom or methyl group,
R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R32 represents hydrogen atom, hydroxymethyl group, NHR33,
S02NR34R34' or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36',
R35 represents a lower alkyl group, benzyl group or NR3R34 ,
R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
RJ represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
2. A pharmaceutical composition according to claim 1, wherein the insulin sensitizer is a compound of the formula [IV] :
Figure imgf000063_0001
° wherein R represents a hydrocarbon group or a heterocyclic group, each of which may be substituted; Y represents a group of the formula : -CO-, -CH(OH)- or -NR3- wherein R3 represents an alkyl group that may be substituted; m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a chemical bond or a bivalent aliphatic hydrocarbon group having 1 to 7 carbon atoms; Q represents O or S; R1 represents hydrogen atom or an alkyl group; ring E may have further 1 to 4 substituents, which may form a ring in combination with R1; L and M respectively represent hydrogen atom or may be combined with each other to form a chemical bond, or a salt thereof.
3. A pharmaceutical composition according to claim 2, wherein the compound of the formula [IV] or a salt thereof is pioglitazone or its salt.
4. A pharmaceutical composition according to claim 2, wherein the compound of the formula [IV] or a salt thereof is rosiglitazone or its salt.
5. A pharmaceutical composition according to claim 1, which comprises pioglitazone or its hydrochloride in combination with 2- [3- ( 7-carboxymethoxyindol-3-yl) - (2R) -2-propylamino] -(IR) -1- ( 3-chlorophenyl) ethanol .
6. A pharmaceutical composition according to claim 1, which comprises rosiglitazone or its maleate in combination with 2- [ 3- ( 7-carboxymethoxyindol-3-yl) - ( 2R) -2- propylamino] - ( IR) -1- (3-chlorophenyl)ethanol.
7. A pharmaceutical composition according to claim 1, which is for preventing or treating diabetes.
8. A pharmaceutical composition according to claim 7, wherein the diabetes is noninsulin-dependent diabetes mellitus .
9. A pharmaceutical composition according to claim 1, which is for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications .
10. A pharmaceutical composition according to claim 9, wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance.
11. A pharmaceutical composition for inhibiting body weight increase after stopping a smoking habit, which comprises at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000065_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4 , (d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000066_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, Rs represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000066_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000066_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring,- a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C^ alkyl, C^ alkoxy, C3_ cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19 NR ,18,C-02nR18; or a C^ alkyl group substituted by hydroxy, nitro, halogen , cyano , NR R , SR , a halogeno lower alkyl , Cx_ -6 alkoxy, C3.8 cycloalkyl , phenyl , NR18COR19 , COR19 , S02R19 ,
NR 1188CSQ02 TR51199 o Λr-»~ NDRlJββCΛ02 DR1 or R 11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, C1.6 alkyl, or C-L.6 alkyl substituted by hydroxy, C^ alkoxy or halogen; X' represents -CH2-, -CH2-CH2- , -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, C1.6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or C^6 alkyl;
R17 represents C1.6 alkyl, C3_8 cycloalkyl or -B'-fR11), wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; R18 represents hydrogen atom; C :i0 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C1_6 alkyl or C^ alkoxy; C^Q alkyl substituted by hydroxy, halogen, C02H, Cx.6 alkoxy-carbonyl, C3.8 cycloalkyl,
Figure imgf000068_0001
alkoxy, or phenyl substituted by halogen, C1.6 alkyl or Cx_6 alkoxy;
R19 represents R18, NHR18 or NR18 wherein R1 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
0R!°
Figure imgf000068_0002
wherein R20 represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group. R represents hydrogen atom, hydroxymethyl group, NHR 23
S02NR24R24 ' or nitro group .
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR 26' R25 represents a lower alkyl group, benzyl group or NR2R24 , R24 and R24 are the same or different , and represent hydrogen atom, a lower alkyl group or benzyl group.
R 26' represents hydrogen atom or a lower alkyl group.
R ,2*6° represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI]
Figure imgf000069_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34' or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR 36'
R represents a lower alkyl group, benzyl group or NR 3 ,R13 ' R34 and R34 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R36 represents hydrogen atom or a lower alkyl group,
R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
12. A pharmaceutical composition for inhibiting body weight increase after stopping alimentary therapy, which comprises at least one member selected from the group consisting of 1 ) a compound of the formula [ I ] :
Figure imgf000070_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]gRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4 ,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000071_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000071_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000071_0003
wherein j represents an integer of 0 to 7 , k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C^ alkyl, C1_6 alkoxy, C3_β cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19,
NR18C02R18; or a C1_6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C _ alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19. COR19, S02R >1199
NR , 1l8o 0S/0~i2 rR>1i9:' o Λr_ nNτrR>i8°ιC-'0(->2 rR>1i8 . or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or Ci.s alkyl substituted by hydroxy, C-^ alkoxy or halogen; X' represents -CH2-. -CH2-CH2-, -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, Cλ_6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19; R16 represents hydrogen atom or Cλ_6 alkyl; R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-fR11)^ wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R18 represents hydrogen atom; C1.10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C^ alkyl or Cx_6 alkoxy; C1.10 alkyl substituted by hydroxy, halogen, C02H, C1_6 alkoxy-carbonyl, C3.8 cycloalkyl, C1-6 alkoxy, or phenyl substituted by halogen, C1.6 alkyl or C^ alkoxy;
R19 represents R18, NHR1 or NR wherein R has the same meaning as above, or a salt thereof;
4) a compound of the formula [V] :
OR20
Figure imgf000073_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23, S02NR2R24' or nitro group.
R represents hydrogen atom, methyl group, S02NR , formyl group or CONHR 26' R represents a lower alkyl group, benzyl group or NR 24RD24'
R )2"4 and R are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R 26' represents hydrogen atom or a lower alkyl group.
R ,2"6 represents hydrogen atom or a lower alkyl group, na is 1 or 2,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1 ,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI]
OR30
Figure imgf000074_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R32 represents hydrogen atom, hydroxymethyl group, NHR33,
S02NR34R34 ' or nitro group.
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR
R represents a lower alkyl group, benzyl group or NR 34rR>34' R34 and R34 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R3 represents hydrogen atom or a lower alkyl group.
R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
13. A method for preventing or treating diabetes in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000075_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d) , or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4 ,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000076_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof,- 2) a compound of the formula [II] :
Figure imgf000076_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof ; 3) a compound of the formula [III] :
Figure imgf000076_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C1.6 alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19 , COR19, NR18S02R19, NR18C02R18; or a C^ alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C1_6 alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19, NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or C1.6 alkyl substituted by hydroxy, C^ alkoxy or halogen; X' represents -CH2-, -CH2-CH2-. -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, Cx.6 alkyl, halogen, NHR18. OR18, S02R19 or NHS02R19;
R ,16 represents hydrogen atom or C1_6 alkyl; R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-(R11) wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R18 represents hydrogen atom; C^,, alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C^ alkyl or Cx,6 alkoxy,- C^^ alkyl substituted by hydroxy, halogen, C02H, C1.t alkoxy-carbonyl, C3.8 cycloalkyl, C^ alkoxy, or phenyl substituted by halogen, C1.6 alkyl or C^ alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
0RM
Figure imgf000078_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23,
S02NR24R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR2
R25 represents a lower alkyl group, benzyl group or NR2R24' , R24 and R2 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2,
Xb represents secondary nitrogen atom, 0 or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R is hydrogen atom, and R is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI] :
OR30
Figure imgf000079_0001
wherein R30 represents hydrogen atom or methyl group,
R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34' or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR 36'
R represents a lower alkyl group, benzyl group or NR 34τR->34' R34 and R3 are the same or different , and represent hydrog atom, a lower alkyl group or benzyl group.
R 36' represents hydrogen atom or a lower alkyl group.
R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
14. A method for preventing or treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis , glomerulonephritis , glomerular sclerosis , hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, in a mammal in need thereof, which comprises administering to said mammal an effective amount of an insulin sensitizer in combination with at least one member selected from the group consisting of 1 ) a compound of the formula [ I ] :
Figure imgf000080_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group , hydroxyl group , cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000081_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000081_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof;
3) a compound of the formula [III] :
Figure imgf000082_0001
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C1.6 alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19, NR18C02R18 ; or a C1.6 alkyl group substituted by hydroxy, nitro , halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C1.6 alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19. NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or C^ alkyl substituted by hydroxy, C^ alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, Cα„6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19; R15 represents hydrogen atom or Cλ_6 alkyl; R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-(R )3 wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R18 represents hydrogen atom; Cλ_1Q alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C^ alkyl or C^ alkoxy; Cα_10 alkyl substituted by hydroxy, halogen, C02H, C^ alkoxy-carbonyl, C3.8 cycloalkyl, Cx.6 alkoxy, or phenyl substituted by halogen, C^ alkyl or Cx,6 alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound ooff the formula [V] .20
0R!
Figure imgf000083_0001
wherein R20 represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23,
S02NR2R24 or nitro group.
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR2
R represents a lower alkyl group, benzyl group or NR 24τR-,24'
R and R .24' are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R^ represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom or a lower alkyl group, na is 1 or 2,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI] :
OR30
Figure imgf000084_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR3R34' or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR 36'
R represents a lower alkyl group, benzyl group or NR 34-Rr,34' R34 and R34 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R36 represents hydrogen atom or a lower alkyl group, R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, 0, S or methylene grou ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or S ,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, *4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
15. A method according to claim 14, wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris , cerebrovascular disease or peripheral circulatory disturbance.
16. A method for inhibiting body weight increase after stopping a smoking habit in human in need thereof, which comprises administering to said human an effective amount of at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000085_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra wherein Xa is 0, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4 , (d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4 , R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000086_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] :
Figure imgf000087_0001
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000087_0002
wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and
N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and
N;
R represents hydroxy, oxo, halogen, cyano, nitro, NRlβRτ-,18 SR18, a halogeno lower alkyl, C1_6 alkyl, C1.6 alkoxy, C3.8 cycloalkyl , phenyl , SO^1 NR18COR19 , COR 19 NR1BS02R 19 NR C02R ; or a C^ alkyl group substituted by hydroxy, nitro. halogen, cyano, NR^R1 SR1 a halogeno lower alkyl , C^ alkoxy, C3.8 cycloalkyl , phenyl , NR^COR1 COR1 SO^1
NR 18 S02R 19 or NR^CO.R1 or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or Ci.g alkyl substituted by hydroxy, C1_6 alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20- ;
R14 and R15 represent independently hydrogen atom, C1.6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or
Figure imgf000088_0001
alkyl;
R17 represents C1_6 alkyl, C3.8 cycloalkyl or -B'-CR11)., wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R18 represents hydrogen atom; Cx.10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, Cα.6 alkyl or Cx,6 alkoxy; C1.10 alkyl substituted by hydroxy, halogen, C02H, Cx.6 alkoxy-carbonyl, C3.8 cycloalkyl, C^ alkoxy, or phenyl substituted by halogen, C^ alkyl or Cx.6 alkoxy;
R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
OR30
Figure imgf000088_0002
wherein R represents hydrogen atom or methyl group. R represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group.
R represents hydrogen atom, hydroxymethyl group, NHR 23
S02NR 2'4l-RT.24' or nitro group.
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR
R represents a lower alkyl group, benzyl group or NR 24πR24' R24 and R24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1 ,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI] :
OR30
Figure imgf000089_0001
wherein R30 represents hydrogen atom or methyl group,
R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34' or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36 ' ,
R35 represents a lower alkyl group, benzyl group or NR3R34',
R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R36 represents hydrogen atom or a lower alkyl group,
R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene grou ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
17. A method for inhibiting body weight increase after stopping alimentary therapy in human in need thereof, which comprises administering to said human an effective amount of at least one member selected from the group consisting of 1) a compound of the formula [I] :
Figure imgf000090_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000091_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof ;
2) a compound of the formula [II]
Figure imgf000092_0001
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000092_0002
wherein j represents an integer of 0 to 7 , k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- me bered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and
N;
R represents hydroxy, oxo, halogen, cyano, nitro, NRlβRτ-,18 SR18, a halogeno lower alkyl, C1_6 alkyl, C1.6 alkoxy, C3 cycloalkyl , phenyl , SO^1 NR18COR19 , COR 19
NR18S02R19 ,
NR C02R ; or a Ci.s alkyl group substituted by hydroxy, nitro , halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19,
NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0. S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or C^ alkyl substituted by hydroxy, C^ alkoxy or halogen;
X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-;
R14 and R1S represent independently hydrogen atom, C1_6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19; R16 represents hydrogen atom or C1.6 alkyl;
R17 represents C^ alkyl, C3.8 cycloalkyl or -B'-ζR11).) wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and
N;
R18 represents hydrogen atom; C1.10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C^ alkyl or C^ alkoxy; Cx.10 alkyl substituted by hydroxy, halogen, C02H, C^ alkoxy-carbonyl, C3.8 cycloalkyl, Cα.6 alkoxy, or phenyl substituted by halogen, Cλ_6 alkyl or Cx_6 alkoxy;
R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
Figure imgf000094_0001
wherein R20 represents hydrogen atom or methyl group,
R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23,
S02NR24R24' or nitro group,
R23 represents hydrogen atom, methyl group, SOzNR25, formyl group or CONHR26'.
R2S represents a lower alkyl group, benzyl group or NR2R24 , R24 and R2 are the same or different , and represent hydrogen atom, a lower alkyl group or benzyl group,
R26 represents hydrogen atom or a lower alkyl group,
R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 , Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1 ,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI]
Figure imgf000095_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR 33 S02NR34R34' or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36',
R35 represents a lower alkyl group, benzyl group or NR34R34 , R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R36 represents hydrogen atom or a lower alkyl group, R36 represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, O, S or methylene group,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or S, R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom, *5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
18. Use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating diabetes, which is used in combination with at least one member selected from the group consisting of 1 ) a compound of the formula [ I ] :
Figure imgf000096_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (0RA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rj to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000097_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof ; 2) a compound of the formula [II] :
Figure imgf000097_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000097_0003
wherein j represents an integer of 0 to 7 , k represents 0 or 1, t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C _6 alkyl, Cx_6 alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19,
NR18C02R18; or a C1.6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl. NR18COR19, COR19, S02R19, NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R12 and R13 represent independently hydrogen atom, C^ alkyl, or Cx_6 alkyl substituted by hydroxy, C^ alkoxy or halogen; X' represents -CH2-, -CH2-CH2- , -CH=CH- or -CH20-,- R14 and R15 represent independently hydrogen atom, C1.6 alkyl, halogen. NHR18. OR18, S02R19 or NHS02R19; R16 represents hydrogen atom or C^ alkyl; R17 represents Cx_6 alkyl, C3.B cycloalkyl or -B'-JR11)^ wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; R18 represents hydrogen atom; C _10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, C1.6 alkyl or Cλ.6 alkoxy; Cx.10 alkyl substituted by hydroxy, halogen, C02H, C^ alkoxy-carbonyl, C3.8 cycloalkyl, C^ alkoxy, or phenyl substituted by halogen, Cλ_6 alkyl or Cx.6 alkoxy;
R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound of the formula [V] :
Figure imgf000099_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R22 represents hydrogen atom, hydroxymethyl group, NHR23, S02NR2R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR26', R25 represents a lower alkyl group, benzyl group or NR2R24 , R24 and R2 are the same or different , and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, 0 or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI]
Figure imgf000100_0001
wherein R represents hydrogen atom or methyl group,
R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R32 represents hydrogen atom, hydroxymethyl group, NHR33,
S02NR34R34' or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36',
R35 represents a lower alkyl group, benzyl group or NR34R34 ,
R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
RJ represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom "or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S.
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
19. Use of at least one member selected from the group consisting of 1) a compound of the formula [I] : I R2
R3 wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (0RA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4, (d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with Rλ to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group ,
R3 represents hydrogen atom or a lower alkyl group.
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000102_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] :
Figure imgf000102_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000102_0003
wherein j represents an integer of 0 to 7 , k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl,
Figure imgf000103_0001
alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19. NR18C02R18; or a
Figure imgf000103_0002
alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18, a halogeno lower alkyl,
Figure imgf000103_0003
alkoxy. C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19, NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom,
Figure imgf000103_0004
alkyl, or Ci.g alkyl substituted by hydroxy,
Figure imgf000103_0005
alkoxy or halogen; X' represents -CH2- , -CH2-CH2-, -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom,
Figure imgf000103_0006
alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19.-
R16 represents hydrogen atom or
Figure imgf000103_0007
alkyl;
R17 represents
Figure imgf000103_0008
alkyl, C3.8 cycloalkyl or -B'-(R11);j wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R18 represents hydrogen atom; Cj.10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen,
Figure imgf000103_0009
alkyl substituted by hydroxy, halogen, C02H, Cλ_6 alkoxy-carbonyl, C3.8 cycloalkyl,
Figure imgf000104_0001
alkoxy, or phenyl substituted by halogen, Cλ,6 alkyl or C^ alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound of the formula [V] OR30
Figure imgf000104_0002
wherein R20 represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23, S02NR2R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR26',
R2S represents a lower alkyl group, benzyl group or NR2R24', R24 and R24 are the same or different , and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI]
Figure imgf000105_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group.
R represents hydrogen atom, hydroxymethyl group, NHR 33
Figure imgf000105_0002
or nitro group.
R33 represents hydrogen atom, methyl group , S02NR35 , formyl group or CONHR36 ' ,
R3S represents a lower alkyl group, benzyl group or NR3R34 ,
R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group,
R36 represents hydrogen atom or a lower alkyl group,
R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S.
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for treating diabetes, which is used in combination with an insulin sensitizer.
20. Use of an insulin sensitizer for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis , inflammatory bowel diseases , syndrome X, visceral fat obesity syndrome or diabetic complications, which is used in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] :
Figure imgf000106_0001
wherein R1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (0RA) wherein RA is hydrogen atom or a lower alkyl group , r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S , Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000107_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000107_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000108_0001
wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C1.6 alkyl, C1-6 alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19, NR18C02R18; or a
Figure imgf000108_0002
alkyl group substituted by hydroxy, nitro , halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C^ alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19. S02R19,
NR18S02R19 or NR1BC02R or R 11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N;
R12 and R13 represent independently hydrogen atom,
Figure imgf000108_0003
alkyl, or Ci.g alkyl substituted by hydroxy, Cj.g alkoxy or halogen;
X' represents -CH2-, -CH2-CH2- , -CH=CH- or -CH20- ;
R14 and R15 represent independently hydrogen atom,
Figure imgf000108_0004
alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or C1_6 alkyl; R17 represents Cx.6 alkyl, C3.8 cycloalkyl or -B'-(R11)j wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N;
R18 represents hydrogen atom; C^^ alkyl; C3.8 cycloalkyl; phenyl substituted by halogen,
Figure imgf000109_0001
alkyl substituted by hydroxy, halogen, C02H, Cx.6 alkoxy-carbonyl, C3.8 cycloalkyl,
Figure imgf000109_0002
alkoxy, or phenyl substituted by halogen,
Figure imgf000109_0003
alkyl or
Figure imgf000109_0004
alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound of the formula [V]
Figure imgf000109_0005
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23, S02NR2R24' or nitro group, R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR 26'
R represents a lower alkyl group, benzyl group or NR 24τR-,24' R24 and R2 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group. na is 1 or 2 ,
Xb represents secondary nitrogen atom, 0 or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group , when na is 2 , *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof,- and 5) a compound of the formula [VI] :
OR30
Figure imgf000110_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34' or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36',
R35 represents a lower alkyl group, benzyl group or NR34R34 , R34 and R34 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
RJ represents hydrogen atom or a lower alkyl group. R36 represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or s,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, *4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof.
21. Use of at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000111_0001
wherein R represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d) , or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula -Ya-(CH2) -Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4 ,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000112_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] :
Figure imgf000112_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000113_0001
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl, C^ alkyl, Cι-6 alkoxy, C3.8 cycloalkyl, phenyl, S02R19, NR18COR19, COR19, NR18S02R19, NR18C02R18 ; or a C^ alkyl group substituted by hydroxy, nitro , halogen, cyano, NR18R18, SR18, a halogeno lower alkyl, C1-6 alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19,
NRlβS02R19 or NR^COjR1 or R represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom, C1-6 alkyl, or Cj.g alkyl substituted by hydroxy, C^ alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom, C1.6 alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R ,16 represents hydrogen atom or
Figure imgf000113_0002
alkyl; R17 represents
Figure imgf000113_0003
alkyl, C3.8 cycloalkyl or -B'-(R11) wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N;
R18 represents hydrogen atom; Cλ_10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen,
Figure imgf000114_0001
alkyl or
Figure imgf000114_0002
alkoxy; C1_10 alkyl substituted by hydroxy, halogen, C02H,
Figure imgf000114_0003
alkoxy-carbonyl, C3.8 cycloalkyl,
Figure imgf000114_0004
alkoxy, or phenyl substituted by halogen, C1.6 alkyl or C1.6 alkoxy,- R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
Figure imgf000114_0005
wherein R20 represents hydrogen atom or methyl group, R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23,
S02NR2R24' or nitro group,
R represents hydrogen atom, methyl group, S02NR , formyl group or CONHR26',
R25 represents a lower alkyl group, benzyl group or NR2R24 , R24 and R2 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R^ represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom or a lower alkyl group. na is 1 or 2 ,
Xb represents secondary nitrogen atom, 0 or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI] :
OR30
Figure imgf000115_0001
wherein R30 represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34- or nitro group, R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR 36'
R represents a lower alkyl group, benzyl group or NR 34Rr>34'
R and R are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R 36' represents hydrogen atom or a lower alkyl group. R represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, O or S .
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, *4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases, syndrome X, visceral fat obesity syndrome or diabetic complications; which is used in combination with an insulin sensitizer.
22. Use according to claim 20 or 21, wherein the diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or peripheral circulatory disturbance.
23. Use of at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000116_0001
wherein x represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d). or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4,
R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above
(b) or (c), or combines with Rx to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000118_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof;
2) a compound of the formula [II] :
Figure imgf000118_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000118_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1 , t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N ;
R11 represents hydroxy , oxo , halogen , cyano , nitro , NR18R18 , SR18 , a halogeno lower alkyl ,
Figure imgf000119_0001
alkoxy , C3.8 cycloalkyl , phenyl , S02R19 , NR18COR19 , COR19 , NR18S02R19 , NR18C02R18 ; or a
Figure imgf000119_0002
alkyl group substituted by hydroxy , nitro , halogen , cyano , NR18R18 , SR18 , a halogeno lower alkyl , Cx alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R > 1199
NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom,
Figure imgf000119_0003
alkyl, or alkyl substituted by hydroxy,
Figure imgf000119_0004
alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-; R14 and R15 represent independently hydrogen atom,
Figure imgf000119_0005
alkyl, halogen. NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or
Figure imgf000119_0006
alkyl;
R17 represents Cλ_6 alkyl, C3.8 cycloalkyl or -B'-tR11)., wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R18 represents hydrogen atom; C1.10 alkyl; C3.8 cycloalkyl; phenyl substituted by halogen,
Figure imgf000119_0007
alkyl or
Figure imgf000119_0008
alkoxy; C1-10 alkyl substituted by hydroxy, halogen, C02H, Cx.g alkoxy-carbonyl, C3.8 cycloalkyl, C1_6 alkoxy, or phenyl substituted by halogen, C1.6 alkyl or Cj.g alkoxy; R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] :
Figure imgf000120_0001
wherein R20 represents hydrogen atom or methyl group,
R21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group,
R22 represents hydrogen atom, hydroxymethyl group, NHR23,
S02NR2R24' or nitro group,
R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR26'.
R25 represents a lower alkyl group, benzyl group or NR2R24 ,
R24 and R2 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group,
R26 represents hydrogen atom or a lower alkyl group,
R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2,
*1 represents an asymmetric carbon atom,
*2 and *3 represent an asymmetric carbon atom when R26 and
R28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI]
Figure imgf000121_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR3R34' or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR36',
R35 represents a lower alkyl group, benzyl group or NR3R34 , R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group.
R 36' represents hydrogen atom or a lower alkyl group.
R represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or
S,
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom. amino group, acetylamino group or hydroxy group, when Xc is methylene group,
*4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping a smoking habit .
24. Use of at least one member selected from the group consisting of
1 ) a compound of the formula [ I ] :
Figure imgf000122_0001
wherein Rx represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower alkylaminosulfonyl group, or a group selected from the following (a) to (d), or combines with R2 to form methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
(a) a group of the formula : -Xa-Ra wherein Xa is O, S or NH, Ra is hydrogen atom or a lower alkyl group, provided that Ra is a lower alkyl group when Xa is S;
(b) a group of the formula : - [0(CH2)p-CH(Rb) ]qRbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1,
(c) a group of the formula : -0(CH2)r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl group or a group of the formula : -P(=0) (ORA) (0RA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4,
(d) a group of the formula : -Ya- (CH2)S-Rd wherein Ya is NH or S , Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R3 represents hydrogen atom or a lower alkyl group,
W represents a group of the formula which bonds to the 2- or 3-position of the indole ring in the formula [I]:
Figure imgf000123_0001
wherein R4 represents a halogen atom or a halogeno lower alkyl group, R5 represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] :
Figure imgf000123_0002
wherein R6 represents a halogen atom or a halogeno lower alkyl group, R7 represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R8 represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 3) a compound of the formula [III] :
Figure imgf000123_0003
wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, ring A' represents benzene ring; naphthalene ring; a 5- or
6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3_8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R11 represents hydroxy, oxo, halogen, cyano, nitro, NR18R18, SR18, a halogeno lower alkyl,
Figure imgf000124_0001
alkyl,
Figure imgf000124_0002
alkoxy, C3.8 cycloalkyl. phenyl, S02R19, NR18C0R19, COR19, NR18S02R19, NR18C02R18; or a
Figure imgf000124_0003
alkyl group substituted by hydroxy, nitro, halogen, cyano, NR18R18, SR18, a halogeno lower alkyl,
Figure imgf000124_0004
alkoxy, C3.8 cycloalkyl, phenyl, NR18COR19, COR19, S02R19, NR18S02R19 or NR18C02R18; or R11 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from O, S and N; R12 and R13 represent independently hydrogen atom,
Figure imgf000124_0005
alkyl, or alkyl substituted by hydroxy, C1.6 alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-;
R14 and R15 represent independently hydrogen atom,
Figure imgf000124_0006
alkyl, halogen, NHR18, OR18, S02R19 or NHS02R19;
R16 represents hydrogen atom or
Figure imgf000124_0007
alkyl;
R17 represents
Figure imgf000124_0008
alkyl, C3-8 cycloalkyl or -B'-fR11)., wherein R11 and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from O, S and N; benzene ring condensed with C3.8 cycloalkyl ring; benzene ring condensed with a 5- or 6- membered heterocyclic ring containing 1 to 3 hetero atoms selected from O, S and N; or a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N;
R18 represents hydrogen atom,- C^^ alkyl; C3.8 cycloalkyl; phenyl substituted by halogen, alkyl or
Figure imgf000125_0001
alkoxy; C1_10 alkyl substituted by hydroxy, halogen, C02H,
Figure imgf000125_0002
alkoxy-carbonyl, C3.8 cycloalkyl,
Figure imgf000125_0003
alkoxy, or phenyl substituted by halogen,
Figure imgf000125_0004
alkyl or
Figure imgf000125_0005
alkoxy;
R19 represents R18, NHR18 or NR18 wherein R18 has the same meaning as above, or a salt thereof;
4) a compound of the formula [V] :
OR30
Figure imgf000125_0006
wherein R 20 represents hydrogen atom or methyl group, R >2"1 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R22 represents hydrogen atom, hydroxymethyl group, NHR23, S02NR24R24' or nitro group, R23 represents hydrogen atom, methyl group, S02NR25, formyl group or CONHR26 ,
RS represents a lower alkyl group, benzyl group or NR2R24 , R24 and R24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R26 represents hydrogen atom or a lower alkyl group, R26 represents hydrogen atom or a lower alkyl group, na is 1 or 2 ,
Xb represents secondary nitrogen atom, O or S, one of R27 or R28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1,
R28 is hydrogen atom, and R27 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R26 and R28 are respectively not hydrogen atom, or a salt thereof; and
5) a compound of the formula [VI]
OR30
Figure imgf000126_0001
wherein R represents hydrogen atom or methyl group, R21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R32 represents hydrogen atom, hydroxymethyl group, NHR33, S02NR34R34- or nitro group,
R33 represents hydrogen atom, methyl group, S02NR35, formyl group or CONHR 36'
R35 represents a lower alkyl group, benzyl group or NR3R34 , R34 and R3 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group,
RJ represents hydrogen atom or a lower alkyl group. R represents hydrogen atom or a lower alkyl group,
Xc represents secondary nitrogen atom, O, S or methylene group ,
R39 is hydrogen atom, one of R37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or S.
R37 and R38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, *4 represents an asymmetric carbon atom,
*5 represents an asymmetric carbon atom when R36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping alimentary therapy.
PCT/JP2000/005951 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer WO2001017513A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002383946A CA2383946A1 (en) 1999-09-03 2000-09-01 Pharmaceutical composition
KR1020027002851A KR20020063555A (en) 1999-09-03 2000-09-01 Pharmaceutical composition
PL00354295A PL354295A1 (en) 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer
HU0203285A HUP0203285A3 (en) 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer and its use
EP00956872A EP1212090A2 (en) 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer
AU68680/00A AU6868000A (en) 1999-09-03 2000-09-01 Pharmaceutical composition
NO20021036A NO20021036L (en) 1999-09-03 2002-03-01 Pharmaceutical preparation
HK02105969.4A HK1044711A1 (en) 1999-09-03 2002-08-15 Pharmaceutical composition comprising an insulin sensitizer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP11/250443 1999-09-03
JP25044399 1999-09-03
JP2000/56021 2000-02-28
JP2000056021 2000-02-28

Publications (2)

Publication Number Publication Date
WO2001017513A2 true WO2001017513A2 (en) 2001-03-15
WO2001017513A3 WO2001017513A3 (en) 2001-09-20

Family

ID=26539777

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/005951 WO2001017513A2 (en) 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer

Country Status (14)

Country Link
EP (1) EP1212090A2 (en)
KR (1) KR20020063555A (en)
CN (1) CN1372476A (en)
AR (1) AR031674A1 (en)
AU (1) AU6868000A (en)
CA (1) CA2383946A1 (en)
CO (1) CO5180632A1 (en)
HK (1) HK1044711A1 (en)
HU (1) HUP0203285A3 (en)
NO (1) NO20021036L (en)
PE (1) PE20010580A1 (en)
PL (1) PL354295A1 (en)
RU (1) RU2002108346A (en)
WO (1) WO2001017513A2 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051441A1 (en) * 2000-12-26 2002-07-04 Sankyo Company, Limited Medicinal compositions containing diuretic and insulin resistance-improving agent
FR2838968A1 (en) * 2002-04-30 2003-10-31 Lipha ASSOCIATION OF INSULIN AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR TREATING DIABETES
WO2003106418A1 (en) * 2002-06-01 2003-12-24 住友製薬株式会社 Indole, indazole, and benzazole derivative
US6838442B2 (en) 2001-04-04 2005-01-04 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and retinoid-X receptor modulators
US8278268B2 (en) 2001-04-04 2012-10-02 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and PPAR modulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005721A1 (en) * 1988-11-14 1990-05-31 The Upjohn Company Alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents
WO1991012003A1 (en) * 1990-02-09 1991-08-22 The Upjohn Company Use of insulin sensitizing agents to treat hypertension
US5817689A (en) * 1994-11-29 1998-10-06 Dainippon Pharmaceutical Co., Ltd. Indole derivatives having a 2-phenyl-ethanolamino-substituted lower alkyl group at the 2-or 3-position thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005721A1 (en) * 1988-11-14 1990-05-31 The Upjohn Company Alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents
WO1991012003A1 (en) * 1990-02-09 1991-08-22 The Upjohn Company Use of insulin sensitizing agents to treat hypertension
US5817689A (en) * 1994-11-29 1998-10-06 Dainippon Pharmaceutical Co., Ltd. Indole derivatives having a 2-phenyl-ethanolamino-substituted lower alkyl group at the 2-or 3-position thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051441A1 (en) * 2000-12-26 2002-07-04 Sankyo Company, Limited Medicinal compositions containing diuretic and insulin resistance-improving agent
US7199139B2 (en) 2000-12-26 2007-04-03 Sankyo Company, Limited Medicinal compositions containing diuretic and insulin resistance-improving agent
US6838442B2 (en) 2001-04-04 2005-01-04 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and retinoid-X receptor modulators
US8183213B2 (en) 2001-04-04 2012-05-22 Ortho Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and retinoid-X receptor modulators
US8278268B2 (en) 2001-04-04 2012-10-02 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising glucose reabsorption inhibitors and PPAR modulators
FR2838968A1 (en) * 2002-04-30 2003-10-31 Lipha ASSOCIATION OF INSULIN AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR TREATING DIABETES
WO2003092726A1 (en) * 2002-04-30 2003-11-13 Merck Patent Gmbh Combination of insulin and a thiazolidinedione derivative, and use thereof for treating diabetes
WO2003106418A1 (en) * 2002-06-01 2003-12-24 住友製薬株式会社 Indole, indazole, and benzazole derivative
US7217724B2 (en) 2002-06-12 2007-05-15 Dainippon Sumitomo Pharma Co., Ltd. Indole, indazole, and benzazole derivative

Also Published As

Publication number Publication date
NO20021036D0 (en) 2002-03-01
AR031674A1 (en) 2003-10-01
NO20021036L (en) 2002-04-26
CA2383946A1 (en) 2001-03-15
HUP0203285A2 (en) 2003-01-28
AU6868000A (en) 2001-04-10
RU2002108346A (en) 2003-11-20
PL354295A1 (en) 2004-01-12
CN1372476A (en) 2002-10-02
CO5180632A1 (en) 2002-07-30
EP1212090A2 (en) 2002-06-12
HUP0203285A3 (en) 2003-02-28
KR20020063555A (en) 2002-08-03
HK1044711A1 (en) 2002-11-01
WO2001017513A3 (en) 2001-09-20
PE20010580A1 (en) 2001-05-25

Similar Documents

Publication Publication Date Title
US6677363B1 (en) Agent for improving ketosis
EP1093370B1 (en) Pharmaceutical composition for the treatment of diabetes
JP3148973B2 (en) Medicine
US20030134884A1 (en) Neovascularization inhibitors
US20030060488A1 (en) Drug comprising combination
EP1212090A2 (en) Pharmaceutical composition comprising an insulin sensitizer
CA2445322C (en) Use of the abc expression promoting agent pioglitazone for the treatment of arteriosclerosis obliterans
JP2001316292A (en) Pharmaceutical
JP2000080047A (en) Medicine
ZA200201151B (en) Pharmaceutical composition.
JP2001294537A (en) Combined medicine
JP2000355550A (en) Ketosis improver
MXPA00010582A (en) Pharmaceutical composition for the treatment of diabetes
JP2003012551A (en) Abc expression promoter
JP2001342135A (en) Neovascularization inhibitor

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AU AZ BA BB BG BR BY BZ CA CN CR CU CZ DM DZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MA MD MG MK MN MX MZ NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AU AZ BA BB BG BR BY BZ CA CN CR CU CZ DM DZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MA MD MG MK MN MX MZ NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 2002/01151

Country of ref document: ZA

Ref document number: 200201151

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 68680/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2383946

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 10069930

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1020027002851

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 008124205

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2000956872

Country of ref document: EP

ENP Entry into the national phase

Ref country code: RU

Ref document number: 2002 2002108346

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 2000956872

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020027002851

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: 2000956872

Country of ref document: EP