[go: up one dir, main page]

AU6868000A - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

Info

Publication number
AU6868000A
AU6868000A AU68680/00A AU6868000A AU6868000A AU 6868000 A AU6868000 A AU 6868000A AU 68680/00 A AU68680/00 A AU 68680/00A AU 6868000 A AU6868000 A AU 6868000A AU 6868000 A AU6868000 A AU 6868000A
Authority
AU
Australia
Prior art keywords
group
hydrogen atom
lower alkyl
formula
halogen
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
AU68680/00A
Inventor
Katsuichi Sudo
Yasuo Sugiyama
Yasuhiko Wada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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
Publication of AU6868000A publication Critical patent/AU6868000A/en
Abandoned legal-status Critical Current

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

WO 01/17513 PCT/JPOO/05951 DESCRIPTION PHARMACEUTICAL COMPOSITION TECHNICAL FIELD 5 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). 10 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 1 3 adrenergic receptor agonists. 15 2) Diabetes Frontier, Vol. 8, p.499 (1997) describes that when CL316243 (33 adrenergic receptor agonist) and troglitazone were administered to obese rats, "CL316243 completely inhibited a weight increase in brown adipose tissues caused by troglitazone". 20 3) JP-A H5(1993)-148496 describes that 4-[2-(2-hydroxy 2-phenyl-ethylamino)ethoxy]phenylacetic acid and its precursors are 13 adrenergic receptor agonists. 4) W096/16938 describes a novel indole derivative having a potent 133 adrenergic receptor stimulating activity. 25 Development of excellent drugs which are sufficiently improved as medicines having an excellent diabetic treatment effect without apparent detection of side effects is desired. 30 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 35 unexpectedly excellent effects. Based on this finding, the present inventors have completed the present invention.
WO 01/17513 PCT/JPOO/05951 2 Namely, the present invention relates to (1) a pharmaceutical composition which comprises an insulin sensitizer in combination with at least one member selected 5 from the group consisting of 1) a compound of the formula [I] R, W N N I R2 R3 wherein Ri represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, 10 a lower alkylsulfonylamino 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 15 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; 20 (b) a group of the formula : -[O(CH 2 )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, 25 (c) a group of the formula : -O(CH 2 )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)(OR)(OR,) wherein RA is hydrogen atom or a lower alkyl group, r is 30 an integer of 1 to 4, (d) a group of the formula : -Ya-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower WO 01/17513 PCT/JPOO/05951 3 alkoxycarbonyl group, s is an integer of 1 to 4,
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 5 (b) or (c), or combines with Ri to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group,
R
3 represents hydrogen atom or a lower alkyl group, 10 W represents a group of the formula which bonds to the 2 or 3-position of the indole ring in the formula [I]: R
CH-CH
2 -NH -CH -CH 2 I I OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt 15 thereof; 2) a compound of the formula [III
R
6 CH H-CH 2 -NH -CH -CH 2 -I R R OH R7 N H wherein R, represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl 20 group or a halogeno lower alkyl group, R, 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] : OH H R 12 1CH2- HCH N-C--(--X' k N--02(CH6R ( R 1 5 R 25 wherein j represents an integer of 0 to 7, WO 01/17513 PCT/JPOO/05951 4 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 5 selected from 0, S and N; benzene ring condensed with C, 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 10 N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"'R",
SR
8 , a halogeno lower alkyl, C1.
6 alkyl, Cl, alkoxy, C 3 -_ 15 cycloalkyl, phenyl, SO 2
R'
9 , NR 8 COR1 9 , COR' 9 , NR 8 S0 2 R",
NR'
8 C0 2 R1 8 ; or a C 1
_
6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR1 8 R"', SR' 8 , a halogeno lower alkyl, C.
6 alkoxy, C3- 8 cycloalkyl, phenyl, NR 8
COR'
9 , COR' 9 , S0 2
R
9 , NR1 8
SO
2 R' or NR"CO 2 R18; 20 or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N;
R
2 and R 3 represent independently hydrogen atom, C, 6 alkyl, or C1- alkyl substituted by hydroxy, C1- 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2
-CH
2 -, -CH=CH- or -CH 2 0-; 25 R 4 and R1 5 represent independently hydrogen atom, C.
6 alkyl, halogen, NHR 8 , OR 8 , SO 2
R
9 or NHSO 2
R'
9 ; R1" represents hydrogen atom or C1.
6 alkyl;
R
7 represents C,- 6 alkyl, C 3
-
8 cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; 30 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
.
cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 35 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 WO 01/17513 PCT/JPOO/05951 5 N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; Ri 8 represents hydrogen atom; C.
10 alkyl; C 3 , cycloalkyl; 5 phenyl substituted by halogen, C 1
_
6 alkyl or C 1
-
6 alkoxy; C.
10 alkyl substituted by hydroxy, halogen, CO 2 H, CI_6 alkoxy-carbonyl, C 3 , cycloalkyl, C 1
_
6 alkoxy, or phenyl substituted by halogen, C,- 6 alkyl or C1- alkoxy;
R
1 * represents R1 8 , NHR 18 or NR" wherein R1 8 has the same 10 meaning as above, or a salt thereof; 4) a compound of the formula [VI
OR
20 H R 0 Xb R 2 *3 R R 2na R 28 wherein R 20 represents hydrogen atom or methyl group,
R
21 represents hydrogen atom, halogen atom, hydroxy group, 15 benzyloxy group, amino group or hydroxymethyl group,
R
2 represents hydrogen atom, hydroxymethyl group, NHR,
SO
2 NR2'R24- or nitro group,
R
2 represents hydrogen atom, methyl group, S0 2
NR
2 s, formyl 26' group or CONHR 20 R 5 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, R26' represents hydrogen atom or a lower alkyl group, R 2 represents hydrogen atom or a lower alkyl group, 25 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, 30 R 28 is hydrogen atom, and R 27 is hydrogen atom, amino group, WO 01/17513 PCT/JPOO/05951 6 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
2 " are respectively not hydrogen atom, or a salt thereof; 5 and 5) a compound of the formula [VI]
OR
30 H R31 *4 0 Xc R 3 9
R
3 6 32 RR 37/ 38 wherein R 30 represents hydrogen atom or methyl group,
R
2 1 represents hydrogen atom, a halogen atom, hydroxy group, 10 benzyloxy group, amino group or hydroxymethyl group,
R
3 represents hydrogen atom, hydroxymethyl group, NHR, S0 2
NR
34
R
34 ' or nitro group,
R
3 represents hydrogen atom, methyl group, S0 2
NR
35 , formyl 36' group or CONHR 15 R 3 -represents a lower alkyl group, benzyl group or NR 34
R
34 ,
R
3 4 and R 34 ' 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, R 3 represents hydrogen atom or a lower alkyl group, 20 Xc represents secondary nitrogen atom, 0, S or methylene group,
R
39 is hydrogen atom, one of R 37 or R 3 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or 25 S,
R
3 and R3 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, 30 *5 represents an asymmetric carbon atom when R 36 is a lower- WO 01/17513 PCT/JPOO/05951 .7 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] : L M R _ R-(Y -(CH 2 )n -CH E A-CH -C C==O Q NH 5 0 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 -NR- 3 wherein R 3 represents an alkyl group that may be substituted; m is 0 10 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 0 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 15 with R'; 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 20 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), 25 which comprises pioglitazone or its hydrochloride in combination with 2-[3-(7-carboxymethoxyindol-3-yl) (2R)-2-propylamino]-(lR)-1-(3-chlorophenyl)ethanol; (6) a pharmaceutical composition according to the above (1), which comprises rosiglitazone or its maleate in combination 30 with 2-[3-(7-carboxymethoxyindol-3-yl)-(2R)-2 propylamino]-(lR)-1-(3-chlorophenyl)ethanol; WO 01/17513 PCT/JPOO/05951 8 (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 5 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, 10 polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases, syndrome X, visceral fat obesity syndrome or diabetic complications; 15 (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 20 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 25 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; 30- 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 35 consisting of 1) a compound of the formula [I] or a salt thereof; WO 01/17513 PCT/JPOO/05951 9 2) a compound of the formula [III or a salt thereof; 3) a compound of the formula [III] or a salt thereof; 4) a compound of the formula [VI or a salt thereof; and 5) a compound of the formula [VI] or a salt thereof; 5 (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 10 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 [VI .or a salt thereof; and 5) a compound of the formula [VII or a salt thereof; 15 (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, 20 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 25 selected from the group consisting of 1) a compound of the formula [I] or a salt thereof; 2) a compound of the formula [III 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 30 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 35 gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease or WO 01/17513 PCT/JPOO/05951 10 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 5 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; 10 4) a compound of the formula [VI 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 15 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; 20 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 25 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 30 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; 35 3) a compound of the formula [III] or a salt thereof; 4) a compound of the formula [VI or a salt thereof; and WO 01/17513 PCT/JPOO/05951 11 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; 5 (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, 10 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 15 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; 20 (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 [III or a salt thereof; 3) a compound of the formula [III] or a salt thereof; 25 4) a compound of the formula [VI or a salt thereof; and 5) a compound of the formula [VII or a salt thereof, for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, 30 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; 35 which is used in combination with an insulin sensitizer; (22) use according to the above (20) or (21), wherein the WO 01/17513 PCT/JPOO/05951 12 diabetic complications are retinopathy, nephropathy, neuropathy, macroangiopahty, diabetic hyperosmolar coma, infectious disease, diabetic osteoporosis, diabetic gangrene, xerostomia, lowered sense of hearing, myocardial 5 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; 10 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 15 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; 20 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 25 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 30 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. 35 Referring to the formula (IV), examples of the WO 01/17513 PCT/JPOO/05951 13 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, 5 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 Cj., aliphatic hydrocarbon group. Examples of the aliphatic 10 hydrocarbon group includes saturated Cj.
8 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, aliphatic 15 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, 20 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. 25 The alicyclic hydrocarbon group is preferably a C 3 _, alicyclic hydrocarbon group. Examples of the alicyclic hydrocarbon group include saturated C 3 , alicyclic hydrocarbon groups (e.g. cycloalkyl groups, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 30 cycloheptyl, etc. and unsaturated C,, 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 35 cycloheptenyl, 3-cycloheptenyl, and 2,4-cycloheptadienyl.
WO 01/17513 PCT/JPOO/05951 14 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 5 preferably a C4_, alicyclic-aliphatic hydrocarbon group. Examples of the alicyclic-aliphatic hydrocarbon group include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2 cyclopentenylmethyl, 3-cyclopentenylmethyl, 10 cyclohexylmethyl, 2-cyclohexenylmethyl, 3 cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc. The aromatic-aliphatic hydrocarbon group is preferably a C- 13 aromatic-aliphatic hydrocarbon group (e. g. 15 aralkyl groups, etc.). Examples of the aromatic-aliphatic hydrocarbon group include C 7 ., phenylalkyl such as benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; Cll 1 3 naphthylalkyl such as a naphthylmethyl, a -naphthylethyl, 3 -naphthylmethyl, and 2d 3-naphthylethyl. The aromatic hydrocarbon group is preferably a C 6 -, aromatic hydrocarbon group (e.g. aryl groups, etc.). Examples of the aromatic hydrocarbon group include phenyl and naphthyl ( a -naphthyl, /3-naphthyl) . 25 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 ito 4 hetero-atoms selected from oxygen, sulfur, and nitrogen in addition to carbon as ring members or a 30 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. 35 Examples of the heterocyclic group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- WO 01/17513 PCT/JPOO/05951 15 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 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, 1H-pyrrolo[2,3-blpyrazin-2-yl, 1H pyrrolo[2,3-blpyridin-6-yl, 1H-imidazo[4,5-blpyridin-2 10 yl, 1H-imidazo[4,5-c]pyridin-2-yl, 1H-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 15 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 20 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 esterified, amidino, carbamoyl, sulfamoyl, sulfo, cyano, azido, and 25 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. 30 The preferred alkyl group is a C 1
-
0 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, 35 hexyl, pentyl, octyl, nonyl, and decyl. The preferred alkenyl group is a C 2
-
0 alkenyl group, WO 01/17513 PCT/JPOO/05951 16 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, 5 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, 10 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. 15 The preferred cycloalkyl group is a C,-,, cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.l]octyl, bicyclo[3.2.2]nonyl, 20 bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, and bicyclo[4.3.1]decyl. The preferred cycloalkenyl group is a C 3
-
0 cycloalkenyl group, such as 2-cyclopenten-1-yl, 3 cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen 25 1-yl. The preferred cycloalkadienyl group is a C 4
..
1 cycloalkadienyl group, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexadien-1-yl. The preferred aryl group is a CI_ 14 aryl group, such 30 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, 35 isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- WO 01/17513 PCT/JPOO/05951 17 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 5 benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, 10 purinyl, pteridinyl, carbazolyl, a-carbolinyl, 13 carbolinyl, T-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-alpyridyl, 15 imidazo[1,2-alpyridyl, imidazo[1,5-alpyridyl, imidazo(1,2-blpyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-alpyridyl, and 1,2,4-triazolo[4,3 b]pyridazinyl. The preferred non-aromatic heterocyclic group 20 includes oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidino, piperidino, morpholino, and thiomorpholino. 25 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 30 groups. Examples of the substituted amino group include amino groups having one or two substituents selected from the group consisting of C- 10 alkyl groups, C 2
-
10 alkenyl groups, C 2
-
1 0 alkynyl groups, C 3 -_1 cycloalkyl groups, aromatic groups (e.g., phenyl), heterocyclic groups, or 35 C._-,, acyl groups (e.g., C 1
.
10 alkanoyl groups, benzoyl, nicotinoyl) (e.g. methylamino, dimethylamino, ethylamino, WO 01/17513 PCT/JPOO/05951 18 diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). 5 Examples of the acyl group in the acyl groups that may be substituted include C 113 acyl groups, for example, C 1 i 0 alkanoyl groups, C 3 -1 alkenoyl groups, C 4 1 0 cycloalkanoyl groups, C 4
-
1 cycloalkenoyl groups, C6-12 aromatic carbonyl groups. 10 Preferred examples of the C- 10 alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and octanoyl. Preferred examples of the C 3
-
1 alkenoyl groups include acryloyl, methacryloyl, crotonoyl, and isocrotonoyl. 15 Preferred examples of the C,-,, cycloalkanoyl groups include cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, and cycloheptanecarbonyl. Preferred examples of the C,-, cycloalkenoyl groups include 2-cyclohexenecarbonyl. 20 Preferred examples of the C6 12 aromatic carbonyl groups include benzoyl, .naphthoyl, and nicotinoyl. Examples of the substituents in the substituted acyl groups include C,.- alkyl groups, C,.-, alkoxy groups, halogen (e.g. chlorine, fluorine, bromine, etc.), nitro, hydroxy, 25 and amino. Referring to the hydroxy group that maybe substituted, examples of the substituted hydroxy includes alkoxy groups, cycloalkyloxy groups, alkenyloxy groups, cycloalkenyloxy 30 groups, aralkyloxy groups, acyloxy groups, and aryloxy groups. The preferred alkoxy group includes C 110 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, 35 isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, and nonyloxy.
WO 01/17513 PCT/JPOO/05951 19 The preferred cycloalkyloxy group includes C 310 cycloalkyloxy groups, such as cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. The preferred alkenyloxy group includes C 2 1 0 5 alkenyloxy groups, such as allyloxy, crotyloxy, 2 pentenyloxy, and 3-hexenyloxy. The preferred cycloalkenyloxy group includes C3-1 cycloalkenyloxy groups, such as 2-cyclopentenyloxy, and 2-cyclohexenyloxy. 10 The preferred aralkyloxy group includes C.,- 0 aralkyloxy groups, such as phenyl-C.
4 alkyloxy (e.g. benzyloxy, phenethyloxy, etc.). The preferred acyloxy group includes C 2 .,, acyloxy groups, more preferably C 24 alkanoyloxy groups (e.g. 15 acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.). The preferred aryloxy group includes C 6
.
4 aryloxy groups, such as phenoxy, and naphthyloxy. This aryloxy group may have 1 or 2 substituents. Examples of the 20 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 25 groups, cycloalkylthio groups, alkenylthio groups, cycloalkenylthio groups, aralkylthio groups, acylthio groups, and arylthio groups. The preferred alkylthio group includes C- 1 ,o alkylthio groups, such as methylthio, ethylthio, propylthio, 30 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, 35 cyclopentylthio, and cyclohexylthio. The preferred alkenylthio group includes C 2
-
1 WO 01/17513 PCT/JPOO/05951 20 alkenylthio groups, such as allylthio, crotylthio, 2 pentenylthio, and 3-hexenylthio. The preferred cycloalkenylthio group includes C 3
-
1 1 cycloalkenylthio groups such as 2-cyclopentenylthio, and 5 2-cyclohexenylthio. The preferred aralkylthio group includes C 7 .1 0 aralkylthio groups, such as phenyl-C 1
.
4 alkylthio (e.g. benzylthio, phenethylthio, etc.). The acylthio group is preferably a C 2
-
1 acylthio group, 10 more preferably a C 2 - alkanoylthio group (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.). The preferred arylthio group includes C 6 _1 4 arylthio groups, such as phenylthio, and naphthylthio. This arylthio group may have 1 or 2 substituents. Examples of 15 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 20 alkoxycarbonyl groups, aralkyloxycarbonyl groups, and aryloxycarbonyl groups. The preferred alkoxycarbonyl group includes C 2 -, alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. 25 The preferred aralkyloxycarbonyl group includes C,- 0 aralkyloxycarbonyl groups, such as benzyloxycarbonyl. The preferred aryloxycarbonyl group includes C,_ 1 , aryloxycarbonyl groups, such as phenoxycarbonyl, and p tolyloxycarbonyl. 30 The preferred substituent on the hydrocarbon group or heterocyclic group for R includes C,- 0 alkyl groups, aromatic heterocyclic groups, and C 6
_
1 4 aryl groups. Further preferred is C 1 3 alkyl, furyl, thienyl, phenyl, or naphthyl. 35 Referring to the formula (IV), when the substituent WO 01/17513 PCT/JPOO/05951 21 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 5 1 to 3 suitable substituents. Examples of such substituents include C 1
_
6 alkyl groups, C 2
-
6 alkenyl groups,
C
2
-
6 alkynyl groups, C 3
-
7 cycloalkyl groups, C6_1, aryl groups, aromatic heterocyclic groups (e.g. thienyl, furyl, pyridyl, oxazolyl, thiazolyl, etc.), non-aromatic heterocyclic 10 groups (e.g. tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperazino, etc.), C 7 , aralkyl groups, amino, N-mono-C. alkylamino groups, N,N-di-Cl-, alkylamino groups, C 2 - acylamino groups (e.g. acetylamino, propionylamino, benzoylamino, etc.), amidino, C 2 . acyl 15 groups (e.g. C 2 -, alkanoyl groups, etc.), carbamoyl, N mono-Cl-, alkylcarbamoyl groups, N,N-di-Cl 4 alkylcarbamoyl groups, sulfamoyl, N-mono-C. alkylsulfamoyl groups, N,N-di-Cl 4 alkylsulfamoyl groups, carboxyl, C 2
-
8 alkoxycarbonyl groups, hydroxy, C 1
-
4 alkoxy groups, C 2
-
5 20 alkenyloxy groups, C 3
-
7 cycloalkyloxy groups, C 7
_
9 aralkyloxy groups, C6-1 aryloxy groups, mercapto, C-4 alkylthio groups,
C
7
-
9 aralkylthio groups, C 6
_
14 arylthio groups, sulfo, cyano, azido, nitro, nitroso, and halogen. Referring to the formula (IV), R is preferably a 25 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 1
_
3 alkyl, furyl, thienyl, phenyl, and naphthyl. 30 Referring to the formula (IV), 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 -. Examples of an alkyl group in the alkyl group that may be 35 substituted for R 3 , include C 1
-
4 alkyl groups, such as methyl, ethyl,' propyl, isopropyl, butyl, isobutyl, sec. -butyl, and WO 01/17513 PCT/JPOO/05951 22 t.-butyl. Examples of the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine), Cl-, alkoxy groups (e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec. -butoxy, t. -butoxy, etc. ) , hydroxy, nitro, and C-. acyl 5 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. 10 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, for example, -CH 2 -, -CH(CH 3 )-, -(CH 2
)
2 -, 15 -CH(C 2 H,)-, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2 )s-, -(CH 2
)
6 -, -(CH 2
)
7 -, etc. can be mentioned for the saturated bivalent aliphatic hydrocarbon group, while -CH=CH-, -C(CH 3 )=CH-, -CH=CH-CH 2 -,
-C(C
2 H)=CH-, -CH 2
-CH=CH-CH
2 -, -CH 2
-CH
2
-CH=CH-CH
2 -, CH=CH-CH=CH-CH2-, -CH=CH-CH=CH-CH=CH-CH 2 -, etc. can be 20 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 -(CH 2
)
2 - 25 The alkyl group for R' includes the similar one to the alkyl group for the above-described R 3 . R' is preferably hydrogen atom. Referring to the formula (IV), the partial structural 30 formula: is preferably .E E the formula X wherein each symbol has the same meanings as described above. Furthermore, ring E may optionally have further 1 to WO 01/17513 PCT/JPOO/05951 23 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 5 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: R2 -~ is preferably i the formula : 10 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. The alkyl group, hydroxy group that may be substituted, 15 halogen, acyl group that may be substituted, and amino group that may be substituted, for R 2 , are similar to those on the hydrocarbon group or heterocyclic group for the above-described R. R 2 is preferably hydrogen atom, a hydroxy group that may be substituted, or halogen. R 2 is 20 more preferably hydrogen atom, or a hydroxy group that may be substituted. R 2 is especially preferably hydrogen atom, or a C1-4 alkoxy group. Referring to the formula (IV), L and M respectively 25 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 30 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 WO 01/17513 PCT/JPOO/05951 24 (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. 5 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 1 3 alkyl, furyl, 10 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: R2 E is the formula : 15 wherein R 2 is hydrogen or a C, 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 20 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] 25 2,4-thiazolidinedione(generic name: rosiglitazone); 5-[3-[4-(5-methyl-2-phenyl-4 thiazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione; 5-[4-(6-methoxy-1-H-benzimidazol-2-ylmethoxy)benzyl] 2,4-thiazolidinedione; and 30 5-[4-(6-methoxy-1-methylbenzimidazol-2 ylmethoxy)benzyl]-2,4-thiazolidinedione. A salt of a compound represented by the formula (IV) is preferably a pharmacologically acceptable salt, which WO 01/17513 PCT/JPOO/05951 25 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 5 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, 10 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. 15 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. 20 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. 25 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 30 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 35 S60(1985)-208980 (EP-A-155845), JP-A S61(1986)-286376 (EP-A-208420), JP-A S61(1986)-85372 (EP-A-177353), JP-A WO 01/17513 PCT/JPOO/05951 26 S61(1986)-267580 (EP-A-193256), JP-A H5(1993)-86057 (WO-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 5 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 10 yl)ethoxy]benzyl]isoxazolidin-3,5-dione (JTT-501) or its salt; 5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6 yl]methyl]-2,4-thiazolidinedione (generic name: englitazone) or its salt (preferably sodium salt); 15 5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1 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 20 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; 25 5-[[6-(2-fluorobenzyloxy)-2-naphthyl]methyl]-2,4 thiazolidinedione (MCC-555) or its salt; (i±)-[5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy N-[[4-(trifluoromethyl)phenyl]methyl]benzamido
(AHG
255) or its salt; 30 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8 tetrahydronaphthalen-2-yl)ethenyl]benzoic acid (LGD1069) or its salt; 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8 tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid 35 (LGD100268) or its salt; 1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2- WO 01/17513 PCT/JPOO/05951 27 yl)methyl]phenoxyl-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; GW-2570; GW-2433; 5 MXC-3255; L-746449; L-767827; L-783281; GW-409544; CS-Oil; etc. Salts of these compounds include those similar to the salt of a compound of the formula (IV) mentioned above. 10 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 15 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. 20 The compound of the formula (I) or its salt is a known compound which is described in W096/16938 and possesses a 3 3 adrenergic receptor stimulating activity, or a compound produced in accordance with an analogous method to a method 25 described in WO96/16938. 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 30 2-[3-(7-methoxyindol-3-yl)-2-propylaminol-1-(3 chlorophenyl)ethanol; 2-[3-(7-ethoxyindol-3-yl)-2-propylamino]-1-(3 chlorophenyl)ethanol; 2-[3-(7-methoxycarbonylmethoxyindol-3-yl)-2 35 propylamino]-1-(3-chlorophenyl)ethanol; 2-[3-(7-carboxymethoxyindol-3-yl)-2-propylamino]-1-(3- WO 01/17513 PCT/JPOO/05951 28 chlorophenyl)ethanol; and their optical isomers or salts. Among these, preferred is 2-[3-(7-carboxymethoxyindol 3-yl)-(2R)-2-propylamino]-(1R)-1-( 3 chlorophenyl)ethanol, also called as 2-[[3-[(2R)-2 5 [[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]aminolpropyl] 1H-indol-7-yl]oxy]acetic acid (hereafter abbreviated as Compound A). The compound of the formula (II) or its salt is a known 10 compound which is described in JP-A H6(1994)-345731 and possesses a 133 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" 15 and "halogeno-lower alkyl group" means C 1
-
3 alkyl group. Examples of the preferred compound of the formula (II) or its salt includes 2-[(1R)-2-(indol-3-yl)-1-methylethylamino]-(1R)-1-(3 chlorophenyl) ethanol (hereafter abbreviated as Compound B) 20 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 33 adrenergic receptor agonistic activity. 25 Examples of the preferred compound of the formula (III) or its salt includes N-[4-[2-[[2-hydroxy-3-(4 hydroxyphenoxy)propyl aminolethyl]phenylIbenzene sulfonamide; 30 N-[4-[2-[[2-hydroxy-3-(4 hydroxyphenoxy)propyl]amino]ethyl phenyl]-4 iodobenzenesulfonamide; N-[4-[2-[[2-hydroxy-3-(4 hydroxyphenoxy)propyllamino]ethyl]phenyl]-2 35 naphthalenesulfonamide; N-[4-[2-[[2-hydroxy-3-(4- WO 01/17513 PCT/JPOO/05951 29 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 5 phenylethanesulfonamide; N-[4-[2-[[3-(4-fluorophenoxy)-2 hydroxypropyllamino]ethyl]phenyl]-4-benzenesulfonamide; N-[4-[2-[[3-[(2-amino-5-pyridinyl)oxy]-2 hydroxy]propyllamino]ethyllphenyl]-2 10 naphthalenesulfonamide. The compound of the formula (V) or its salt is a known compound which is described in W099/01431 and possesses a 3 3 agonistic activity. In the formula (V), groups having 15 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 20 yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyll-N,N dimethylsulfamide hydrochloride. The compound of the formula (VI) or its salt is a known compound which is described in W097/23511 and possesses a 25 /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 30 ( ±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylaminol-1 hydroxyethyl]-2-hydroxyphenyl methanesulfonamide hydrochloride; ( ±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1 hydroxyethyl]phenyl]methanesulfonamide hydrochloride; 35 ( ±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]aminol-1 phenylethanol hydrochloride; and their optical isomers.
WO 01/17513 PCT/JPOO/05951 30 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), 5 (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 10 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 15 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. 20 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, 25 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 30 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, 35 impaired glucose tolerance means a condition wherein a fasting glucose level (glucose concentration in venous WO 01/17513 PCT/JPOO/05951 31 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. 5 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 10 200 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 15 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. 20 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 25 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 110mg/dl or more and less than 126mg/dl, is 30 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 35 less than 140mg/dl, is called IFG (Impaired Fasting Glycemia).
WO 01/17513 PCT/JPOO/05951 32 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 5 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 10 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 15 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 20 stopping exercise), hyperphagia, hypertension, cardiovascular diseases (e.g., atherosclerosis, etc.), polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases 25 (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 30 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, 35 gastrointestinal tract infection, dermal soft tissue infection, inferior limb infection), diabetic osteoporosis, WO 01/17513 PCT/JPOO/05951 33 diabetic gangrene, xerostomia, lowered sense of hearing, myocardial infarction, angina pectoris, cerebrovascular disease (e.g., cerebral apoplexy, cerebral infarction) or peripheral circulatory disturbance, etc.). 5 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, 10 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 15 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, 20 and anorexia in chronic diseases such as malignant tumor, tuberculosis, diabetes, blood dyscrasia, endocrine diseases, infectious diseases, and acquired -immunodeficiency syndrome. 25 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- a mediated inflammatory diseases mean inflammatory diseases which occur in the presence of TNF 30 a 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, 35 gout, postoperative or traumatic inflammation, remission of swelling, neuralgia, laryngopharyngitis, cystitis, WO 01/17513 PCT/JPOO/05951 34 hepatitis, pneumonia, gastric mucosal injury (including aspirin-induced gastric mucosal injury),etc. A pharmaceutical composition of the present invention 5 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 10 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 15 diseases (e.g., alcoholic hepatitis, hepatitis B, hepatitis C), joint-diseases (e.g., osteoarthritis)', atherosclerosis, etc. Further, a pharmaceutical composition of the present 20 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 25 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 30 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. 35 A pharmaceutical composition of the present invention WO 01/17513 PCT/JPOO/05951 35 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.). 5 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 10 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 15 (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 20 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.)]. 25 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 30 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 35 preparations, transdermal preparations, ointments, etc.), suppositories (e.g., rectal suppositories, vaginal WO 01/17513 PCT/JPOO/05951 36 suppositories, etc.), pellets, drip infusions, sustained-release preparations, etc. Methods of producing oral dosage forms and non-oral 5 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 10 disintegrator (e.g., calcium carbonate, starch, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylstarch sodium, light silicic anhydride, etc.), a binder (e.g., a-starch, gum arabic, 15 carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, crystalline cellulose, methylcellulose, sucrose, D mannitol, trehalose, dextrin, etc.), or alubricant (e.g., talc, magnesium stearate, calcium stearate, talc, 20 colloidalsilica, 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.; orbases 25 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 30 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, 35 hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, etc.; gastric coating WO 01/17513 PCT/JPOO/05951 37 polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, etc. ; water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.; water-insoluble 5 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 10 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, 15 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 20 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., sodiumchloride, glycerol, D-sorbitol, D-mannitol, xylitol, 25 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, 30 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, 35 etc.; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, WO 01/17513 PCT/JPOO/05951 38 methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), a buffering agent (e.g., buffer solutions such as phosphate, acetate, carbonate, citrate, etc.), a stabilizer (e.g., 5 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.), 10 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 15 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 20 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 25 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. 30 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 35 fatty acid glycerides [e. g. , cacao butter, Witepsols (huels Aktiengesellschaft, Germany), etc.], medium-chain fatty WO 01/17513 PCT/JPOO/05951 39 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, 5 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 10 composition of the present invention is not limited as long as an insulin sensitizer and any of compounds [I] to [III], [VI 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 15 any of compounds [I] to [III], [VI 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 20 kinds of preparations prepared from an insulin sensitizer and any of compounds [I] to [III], [VI 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], 25 [VI 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 30 sensitizer and any of compounds [I] to [III], [VI 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], [VI and [VI] 35 separately into oral dosage forms such as tablets, and administering the oral dosage forms concomitantly or with WO 01/17513 PCT/JPOO/05951 40 a staggered time. A pharmaceutical composition of the present invention and its active ingredient are low in potential toxicity, 5 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 10 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 15 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 20 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 25 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 30 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, 35 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 WO 01/17513 PCT/JPOO/05951 41 to 10 mg, preferably 0.2 to 3 mg. The proportion of an insulin sensitizer and compounds [I] to [III], [VI and [VI] in a pharmaceutical composition 5 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], [VI 10 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 15 possesses an enhanced blood sugar lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [VI and [VI] alone. Further, a pharmaceutical composition of the present invention possesses an enhanced blood lipid lowering action 20 or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [VI and [VI] alone. Further, a pharmaceutical composition of the present invention possesses an excellent effect of treating 25 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], [VI and [VI] alone. Further, when the pharmaceutical composition of the 30 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. 35 Referring to a pharmaceutical composition of the WO 01/17513 PCT/JPOO/05951 42 present invention, concomitant drugs which do not interfere with an insulin sensitizer or compounds [I] to [III], [VI and [VI] can be used for the purpose of "enhancing the diabetes treating effects of an insulin sensitizer or 5 compounds [ I I to [ II I ], [VI 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], [VI and [VI]", etc. Examples of the concomitant drugs include "agents for treating 10 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 15 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 20 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 25 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 30 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). 35 While insulin is available in a variety of types such as super immediate-acting, immediate-acting, bimodal- WO 01/17513 PCT/JPOO/05951 43 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 5 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 10 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 15 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, 20 glibenclamide, gliclazide, 1-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride, etc. 25 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. 30 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 35 treating diabetes" include ergoset, pramlintide, leptin, BAY-27-9955, T-1095, etc.
WO 01/17513 PCT/JPOO/05951 44 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, 5 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 10 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: 50kg), for instance, the dose per day is usually 0.1 to 1000 mg, preferably 1 15 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. 20 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 25 times a day. Examples of the "agents for treating diabetic complications" include aldose reductase inhibitors, glycation inhibitors, protein kinase C inhibitors, etc. 30 Examples of the aldose reductase inhibitors include tolurestat; epalrestat; 3,4-dihydro-2,8-diisopropyl-3 thioxo-2H-1,4-benzoxazine-4-acetic acid; imirestat; zenarestat; 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H 1-benzopyran-4,4'-imidazolidine]-2-carboxamide
(SNK
35 860); zopolrestat; sorbinil; 1-[(3-bromo-2 benzofuranyl)sulfonyl]-2,4-imidazolidinedione
(M-
WO 01/17513 PCT/JPOO/05951 45 16209); CT-112; NZ-314; ARI-509; etc. Examples of the glycation inhibitors include pimagedine, etc. Examples of the protein kinase C inhibitors include 5 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, 10 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 15 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 20 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. 25 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. 30 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, 35 fluoxetine, sibutramine, baiamine, etc. For administration of the "agents for treating WO 01/17513 PCT/JPOO/05951 46 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. 5 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 10 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" 15 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, 20 delapril, ramipril, lisinopril, imidapril, benazepril, ceronapril; cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, manidipine, etc. Examples of the calcium antagonists include 25 nifedipine, amlodipine, efonidipine, nicardipine, etc. Examples of the potassium channel openers include levcromakalim, L-27152, AL 0671, NIP-121, etc. Examples of the angiotensin II antagonists include losartan, candesartan cilexetil, valsartan, irbesartan, 30 (5-methyl-2-oxo-1,3-dioxoran-4-yl)methyl 4-(1-hydroxy 1-methylethyl)-2-propyl-1-[2'-(lH-tetrazol-5 yl)biphenyl-4-ylmethyllimidazol-5-carboxylate (CS-866), E4177, etc. For administration of the "agents for treating 35 hypertension" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 to WO 01/17513 PCT/JPOO/05951 47 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 5 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 10 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 15 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. 20 Examples of the "agents for treating hyperlipidemia" include, HMG-CoA reductase inhibitors, fibrate compounds, etc. Examples of the HMG-CoA reductase inhibitors include 25 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, 30 clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, etc. For administration of the "agents for treating 35 hyperlipidemia" to an adult diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 to WO 01/17513 PCT/JPOO/05951 48 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 5 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 10 can be administered once to several times a day. Examples of the "diuretics" include xanthine derivative preparations, thiazide preparations, antialdosterone preparations, carbonate dehydratase 15 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 20 ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide, etc. Examples of the antialdosterone preparations include 25 spironolactone, triamterene, etc. Examples of the carbonate dehydratase inhibitors include acetazolamide, etc. Examples of the chlorbenzenesulfonamide preparations include chlorthalidone, mefruside, indapamide, etc. 30 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 35 diabetic patient (body weight: 50 kg), for instance, the dose per day is usually 0.01 mg to 100 g, preferably 0.05 WO 01/17513 PCT/JPOO/05951 49 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 5 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 10 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. 15 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. 20 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. 25 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 30 "combination of an insulin secretion enhancer and a biguanide", "combination of an insulin secretion enhancer and an O -glucosidase inhibitor", "combination of insulin and a biguanide", "combination of insulin and an a glucosidase inhibitor", etc. 35 The administration method of a pharmaceutical WO 01/17513 PCT/JPOO/05951 50 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 5 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 10 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 15 [III], [VI 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 a'n excellent 20 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 25 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, 30 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.)", 35 "combination of Compound B and an a -glucosidase inhibitor (preferably acarbose, etc.)", "combination of Compound A WO 01/17513 PCT/JPOO/05951 51 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 5 sodium salt, cerivastatin or its sodium salt, atorvastatin, etc.)", etc. When any of compounds [I] to [III], [VI and [VI] is used alone, the method of use in the above mentioned pharmaceutical composition of the present invention can be 10 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 15 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, 20 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 25 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 30 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 35 composition in the present invention can be evaluated by determining concentration of glucose or Hb (hemoglobin)Alc WO 01/17513 PCT/JPOO/05951 52 in venous blood plasma in the subject before and after administration, and then comparing the obtained concentration between before administration and after administration. HbA 0 means glycosylated hemoglobin, and 5 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. 10 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. 15 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 20 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 25 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 30 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 35 2) Lactose 92.87 3) Carmellose calcium 7.2 WO 01/17513 PCT/JPOO/05951 53 4) Hydroxypropylcellulose 3.0 5) Magnesium stearate 0.4 Total: 120.0 5 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): 10 1) Pioglitazone hydrochloride 33.06 2) Lactose 76.34 3) Carmellose calcium 7.2 4) Hydroxypropylcellulose 3.0 5) Magnesium stearate 0.4 15 Total: 120.0 Reference Example 3 In the similar manner to Reference Example 2, 140000 tablets having the following composition and each 20 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 25 4) Hydroxypropylcellulose 4.5 5) Magnesium stearate 0.6 Total: 180.0 Example 1 30 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. 35 Example 2 WO 01/17513 PCT/JPOO/05951 54 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 5 glucose lowering action is observed. Example 3 Twenty three Wistar fatty rats, genetically obese and noninsulin-dependent diabetic (type 2 diabetic) models, 10 (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 15 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 20 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) 25 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) 30 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. 35 The rats were allowed to take food freely. After completion of administration over 14 days, blood WO 01/17513 PCT/JPOO/05951 55 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 5 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. 10 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] Plasma glucose Plasma triglyceride (mg/dl) (mg/dl) Group A(Control) 352.1±89.0 362.9± 76.6 Group B(pio) 235.0±56.6 143.1± 33.0 Group C(cpd A) 230.6±88.1 210.6±125.4 Group D(pio+cpd A) 148.5±20.1 76.2± 14.2 15 [Table 2] Body weight (g) Group A(Control) 605.4±34.0 Group B(pio) 641.9±15.9 Group C(cpd A) 595.3±26.0 Group D(pio+cpd A) 620.2±24.2 As shown in Table 1, use of pioglitazone hydrochloride in combination with Compound A provided excellent effects 20 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 25 expected to be 26.4 (36.5 - 10.1) g because of the fact that WO 01/17513 PCT/JPOO/05951 56 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. 5 Industrial Applicability A pharmaceutical composition of the present invention possesses an enhanced blood sugar lowering action, blood 10 lipid lowering action or blood insulin lowering action as compared with administration of an insulin sensitizer or any of compounds [I] to [III], [VI and [VII alone.

Claims (16)

1. A pharmaceutical composition which comprises an insulin sensitizer in combination with at least one member selected from the group consisting of 5 1) a compound of the formula [I] R 1 N I R2 R3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower 10 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, 15 (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 : -[O(CH 2 )P-CH(Rb)]qRbb 20 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 : -O(CH 2 )r-Rc 25 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)(OR)(OR) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4, 30 (d) a group of the formula : -Ya-(CH 2 )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, WO 01/17513 PCT/JPOO/05951 58 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 (b) or (c), or combines with R 1 to form the above 5 methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2 10 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 - I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt thereof; 15 2) a compound of the formula [II] R CH-CH 2 -NH -CH -CH 2 R - I 1 8 OH RTN H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents 20 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] OH H RR I 1 1 (CH R 17 A' OCH -CHCH 2 N C-(-X' kN-SO2 ( '22 113 k 16 R Ris R wherein j represents an integer of 0 to 7, 25 k represents 0 or 1, WO 01/17513 PCT/JPOO/05951 59 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 C 3 -1 5 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 10 ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"R", SR", a halogeno lower alkyl, Ci_ 6 alkyl, CI_ 6 alkoxy, C 3 .1 cycloalkyl, phenyl, SO 2 R1 9 , NR 18 COR1 9 , COR' 9 , NR 8 SO 2 R' 9 , 15 NR' 8 C0 2 R 1; or a C 1 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR 8 R", SR18, a halogeno lower alkyl, C1. 6 alkoxy, C 3 _1 cycloalkyl, phenyl, NR' 8 COR 19 , COR 19 , SO 2 R 9 , NR 8 S0 2 R' 9 or NR 18 CO 2 R' 8 ; or R" represents a 5- or 6-membered heterocyclic group 20 containing 1 to 3 hetero atoms selected from 0, S and N; R 2 and R 3 represent independently hydrogen atom, C 1 . 6 alkyl, or C 1 - 6 alkyl substituted by hydroxy, C, alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; R 4 and R 1 represent independently hydrogen atom, C1_6 alkyl, 25 halogen, NHRi 8 , OR 8 , S0 2 R' 9 or NHSO 2 R 9 ; R 1 represents hydrogen atom or C 1 - 6 alkyl; R 7 represents C1 6 alkyl, C 3 _ 8 cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 30 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 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 35 ring containing 1 to 3 hetero atoms selected from 0, S and N which is condensed with a 5- or 6-membered heterocyclic WO 01/17513 PCT/JPOO/05951 60 ring containing 1 to 3 hetero atoms selected from 0, S and N; Ri 8 represents hydrogen atom; C 1 o alkyl; C 3 -3 cycloalkyl; phenyl substituted by halogen, C 1 . 6 alkyl or C, 6 alkoxy; Cl- 10 5 alkyl substituted by hydroxy, halogen, CO 2 H, CI_ 6 alkoxy-carbonyl, C 3 -_ cycloalkyl, C 1 ,. 6 alkoxy, or phenyl substituted by halogen, C 1 6 alkyl or CI- 6 alkoxy; R'" represents R 18 , NHR" or NR"' wherein Ri 8 has the same meaning as above, or a salt thereof; 10 4) a compound of the formula [V] OR 2 0 H R" 0 Xb R26 R *3 Rzz na R 2 wherein R represents hydrogen atom or methyl group, R represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 22 23 15 R represents hydrogen atom, hydroxymethyl group, NHR SO 2 NR24 R or nitro group, R represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 26' group or CONHR R 2 s represents a lower alkyl group, benzyl group or NR2R 20 R 2 4 and R 24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, R2' represents hydrogen atom or a lower alkyl group, R 2 represents hydrogen atom or a lower alkyl group, na is 1 or 2, 25 Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 is hydrogen atom, and R 27 is hydrogen atom, amino group, 30 acetylamino group or hydroxy group, when na is 2, WO 01/17513 PCT/JPOO/05951 61 *1 represents an asymmetric carbon atom, *2 and *3 represent an asymmetric carbon atom when R 26 and R 2 are respectively not hydrogen atom, or a salt thereof; and 5 5) a compound of the formula [VI] OR 30 H R N 0 Xc R3 R 3 6 ' R 32 R 37 wherein R 30 represents hydrogen atom or methyl group, R represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 10 R" represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 34 R 4 ' or nitro group, R" represents hydrogen atom, methyl group, SO 2 NR 35 , formyl 36' group or CONHR R 35 represents a lower alkyl group, benzyl group or NR 34 , 34 15 R and R 34 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, R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene 20 group, R 39 is hydrogen atom, one of R 37 or R 3 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, 25 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 R36 is a lower 30 alkyl group, or a salt thereof. WO 01/17513 PCT/JPOO/05951 62 2. A pharmaceutical composition according to claim 1, wherein the insulin sensitizer is a compound of the formula [IV] : L M R-(Y -(CH 2 )n -CH E A -CH -C C==O X Q NH x ~ 'NCY 5 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 -NR 3 - wherein R 3 represents an alkyl group that may be substituted; m is 0 10 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 1to 7 carbon atoms; Q represents 0 or S; R' represents hydrogen atom or an alkyl group; ring E may have further 1 to 4 substituents, which may form a ring in combination 15 with R'; 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, 20 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 25 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) 30 (2R)-2-propylamino]-(lR)-1-(3-chlorophenyl)ethanol. WO 01/17513 PCT/JPOO/05951 63 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]-(1R)-1-(3-chlorophenyl)ethanol. 5
7. A pharmaceutical composition according to claim 1, which is for preventing or treating diabetes.
8. A pharmaceutical composition according to claim 7, 10 wherein the diabetes is noninsulin-dependent diabetes mellitus.
9. A pharmaceutical composition according to claim 1, which is for preventing or treating impaired glucose 15 tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases, 20 syndrome X, visceral fat obesity syndrome or diabetic complications.
10. A pharmaceutical composition according to claim 9, wherein the diabetic complications are retinopathy, 25 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 30 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 35 consisting of 1) a compound of the formula [I] WO 01/17513 PCT/JPOO/05951 64 R, N I R2 R3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower 5 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, 10 (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 : -[O(CH 2 )p-CH(Rb)],Rbb 15 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 : -O(CH 2 )r-Rc 20 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(=O)(ORA)(ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4, 25 (d) a group of the formula : -Ya-(CH 2 )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, R 2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl 30 group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being WO 01/17513 PCT/JPOO/05951 65 optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2 5 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 - I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R. represents a lower alkyl group, or a salt thereof; 10 2) a compound of the formula [II] R6 CH-CH2 -- NH -H -CH 2 R OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents 15 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] : OH H R1 2 0CH 2 -CHCH N- -(-X' k 02 (CH2 tR (R R" R 15 R wherein j represents an integer of 0 to 7, 20 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 C 3 -. 25 cycloalkyl ring; benzene ring condensed with a 5- or 6- WO 01/17513 PCT/JPOO/05951 66 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 5 ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"R"1, SR 8 , a halogeno lower alkyl, C,- 6 alkyl, C1-6 alkoxy, C 3 . cycloalkyl, phenyl, SOR' 9 , NR 8 COR 9 , COR 9 , NR' 8 SO,R' 9 , 10 NR1 8 C0 2 R 8 ; or a C1_ 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'Rl", SR 8 , a halogeno lower alkyl, C1-6 alkoxy, C,- 8 cycloalkyl, phenyl, NR 8 COR 9 , COR 9 , SO2R 9 , NR 8 S0 2 R- 9 or NR1 8 C02R1 8 ; or R" represents a 5- or 6-membered heterocyclic group 15 containing 1 to 3 hetero atoms selected from 0, S and N; R and R" represent independently hydrogen atom, C 1 - 6 alkyl, or CI, 6 alkyl substituted by hydroxy, C1. 6 alkoxy or halogen; X' represents -CH2-, -CH 2 -CH2-, -CH=CH- or -CH20-; R1 4 and R 1 represent independently hydrogen atom, C, 6 alkyl, 20 halogen, NHR' 8 , OR", SOR 9 or NHSO2R 9 ; R 6 represents hydrogen atom or C1. 6 alkyl; R 7 represents C1. 6 alkyl, C3, 8 cycloalkyl or -B'-(RD), wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 25 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, 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 30 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; R1 8 represents hydrogen atom; C,-1 0 alkyl; C 3 -1 cycloalkyl; 35 phenyl substituted by halogen, C,- 6 alkyl or C,. 6 alkoxy; Cl.. 0 alkyl substituted by hydroxy, halogen, CO2H, C 1 _ 6 WO 01/17513 PCT/JPOO/05951 67 alkoxy-carbonyl, C,_, cycloalkyl, C 1 . 6 alkoxy, or phenyl substituted by halogen, C 1 . 6 alkyl or C 1 . 6 alkoxy; R' 9 represents Ri 8 , NHR 8 or NR 8 wherein R 1 " has the same meaning as above, or a salt thereof; 5 4) a compound of the formula [V] OR 20 H R 0 Xb R *3 R R 2 7 na R 28 wherein R20 represents hydrogen atom or methyl group, R 2 " represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 10 R 22 represents hydrogen atom, hydroxymethyl group, NHR 23 S0 2 NR 24 R 24 -or nitro group, R represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl group or CONHR 26 , R represents a lower alkyl group, benzyl group or NR 24 R 2 4 15 R 2 4 and R 2 4 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, 20 Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 8 is hydrogen atom, and R 2 7 is hydrogen atom, amino group, 25 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 2 are respectively not hydrogen atom, or a salt thereof; and 30 5) a compound of the formula [VI] WO 01/17513 PCT/JPOO/05951 68 OR 30 H R31 *4 N0 X c3R R 3 329 R 37 R R wherein R 30 represents hydrogen atom or methyl group, R 21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 32 3 5 R represents hydrogen atom, hydroxymethyl group, NHR", S0 2 NR 3 4 R 34 ' or nitro group, R" represents hydrogen atom, methyl group, S0 2 NR 35 , formyl 36' group or CONHR R 3 " represents a lower alkyl group, benzyl group or NR 34 R 34 10 R 34 and R 34 ' 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, R 3 represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene 15 group, R 39 is hydrogen atom, one of R 37 or R 3 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, 20 R 37 and R 38 are both hydrogen atom, and R 3 9 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 25 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 30 consisting of WO 01/17513 PCT/JPOO/05951 69 1) a compound of the formula [I] R 1 N I R2 R 3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, 5 a lower alkylsulfonylamino 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 10 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; 15 (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb 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, 20 (c) a group of the formula : -O(CH 2 )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)(OR)(ORA) wherein RA is hydrogen atom or a lower alkyl group, r is 25 an integer of 1 to 4, (d) a group of the formula : -Ya-(CH 2 )B-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl 30 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 1 to form the above WO 01/17513 PCT/JPOO/05951 70 methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, 5 W represents a group of the formula which bonds to the 2 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 -I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt 10 thereof; 2) a compound of the formula [II] R 6 CH-CH -NH-CH-CH 2 R - RR OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl 15 group or a halogeno lower alkyl group, R, 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] : OH H RR A' 1C 2 C 1 17 0CH2- CHH - C-(-X' N-SO 2 (CH 2 -+,-R (R 1 R)j R 15 R 1 20 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 25 selected from 0, S and N; benzene ring condensed with C 3 , WO 01/17513 PCT/JPOO/05951 71 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 5 N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR 18 R" 8 , SR 18 , a halogeno lower alkyl, C 1 _6 alkyl, C 1 _6 alkoxy, C 3 , 10 cycloalkyl, phenyl, S0 2 R 19 , NR 1 8 COR 1 9 , COR 19 , NR 18 SO 2 R' 9 , NR'"C0 2 R"B; or a C 1 _- alkyl group substituted by hydroxy, nitro, halogen, cyano, NR 18 R 18 , SR 1 ", a halogeno lower alkyl, Ci_6 alkoxy, C 3 . cycloalkyl, phenyl, NR1 8 COR 9 , COR 19 , SO 2 R' 9 , NR'S0 2 R' 9 or NR 8 CO 2 R' 8 ; 15 or R"' represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R and R" represent independently hydrogen atom, C 1 _ 6 alkyl, or Ci_ 6 alkyl substituted by hydroxy, C 1 - 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; 20 R"3 and R 15 represent independently hydrogen atom, C 16 alkyl, halogen, NHR 8 , OR 18 , S0 2 R 19 or NHSO 2 R' 9 ; R represents hydrogen atom or C 1 . 6 alkyl; R" represents C, 6 alkyl, C 3 , cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; 25 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.-, cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 30 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 hetdro atoms selected from 0, S and N; 35 R" represents hydrogen atom; Co 10 alkyl; C 3 -_ cycloalkyl; phenyl substituted by halogen, C 1 _ 6 alkyl or C. 6 alkoxy; C_ 10 WO 01/17513 PCT/JPOO/05951 72 alkyl substituted by hydroxy, halogen, CO 2 H, C 1 . 6 alkoxy-carbonyl, C 3 _- cycloalkyl, CI_6 alkoxy, or phenyl substituted by halogen, C 1 _6 alkyl or C1- 6 alkoxy; R 19 represents R"8, NHR"' or NR' 8 wherein R 18 has the same 5 meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R R Xb R R na R 28 wherein R 20 represents hydrogen atom or methyl group, R 2 represents hydrogen atom, halogen atom, hydroxy group, 10 benzyloxy group, amino group or hydroxymethyl group, R 22 represents hydrogen atom, hydroxymethyl group, NHR, SO 2 NR 24R 24 or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR 2 , formyl group or CONHR" , 15 R 25 represents a lower alkyl group, benzyl group or NR2R 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 2 represents hydrogen atom or a lower alkyl group, 20 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 2 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, 25 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 2 are respectively not hydrogen atom, or a salt thereof; 30 and WO 01/17513 PCT/JPOO/05951 73 5) a compound of the formula [VI] OR 30 H R31 *4 N0 'Xc R 3 R XLR 3 36 R 3 R 2R 37 R38 wherein R 30 represents hydrogen atom or methyl group, R represents hydrogen atom, a halogen atom, hydroxy group, 5 benzyloxy group, amino group or hydroxymethyl group, R 32 represents hydrogen atom, hydroxymethyl group, NHR 33 , SO 2 NR 34 R34' or nitro group, R" represents hydrogen atom, methyl group, S0 2 NR 35 , formyl 36' group or CONHR 10 R 35 represents a lower alkyl group, benzyl group or NR 3 R 34 ', R 34 and R 34 ' 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 3 represents hydrogen atom or a lower alkyl group, 15 Xc represents secondary nitrogen atom, 0, S or methylene group, R 3 9 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 20 S, R 37 and R3" 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, 25 *5 represents an asymmetric carbon atom when R 36 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 30 said mammal an effective amount of an insulin sensitizer WO 01/17513 PCT/JPOO/05951 74 in combination with at least one member selected from the group consisting of 1) a compound of the formula [I] Ri N SR2 R 3 5 wherein R 1 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 R 2 to form 10 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 15 alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower 20 alkoxycarbonyl group or carboxyl group, p is an integer of .0 to 3, q is 0 or 1, (c) a group of the formula : -O(CH 2 )r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl 25 group or a group of the formula : -P(=0)(OR,)(OR,) 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-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower 30 alkoxycarbonyl group, s is an integer- of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl WO 01/17513 PCT/JPOO/05951 75 group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower 5 alkoxycarbonyl group, 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]: R4 CH-CH 2 -NH -CH -CH 2 I I OH R5 10 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] R 6 CH-CH 2 -NH -CH -CH2 R - II jj OH R 7 N H 15 wherein R, represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents hydrogen atom, a halogen atom, a halogeno lower alkyl group, nitro group or cyano group, or a salt thereof; 20 3) a compound of the formula [III] : OH H R12 R I 1 1 17 OCH 2 -CHCH N- C-(-X' N--S0 2 (CH 2 R 2 13 k 116 2 2 t (R > R R 1 5 R wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, 25 ring A' represents benzene ring; naphthalene ring; a 5- or WO 01/17513 PCT/JPOO/05951 76 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C3-1 cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 5 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; 10 R" represents hydroxy, oxo, halogen, cyano, nitro, NR1 8 R 8 , SR 8 , a halogeno lower alkyl, C, 6 alkyl, C1, 6 alkoxy, C 3 -, cycloalkyl, phenyl, SO2R", NR1 8 COR' 9 , COR' 9 , NR1"S02R' 9 , NR1 8 CO2R3 8 ; or a C 1 - 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'R' 8 , SR8, a halogeno lower alkyl, C 1 - 6 15 alkoxy, C3, cycloalkyl, phenyl, NR 8 COR' 9 , COR 9 , SO 2 R 9 , NR 8 SO2R' or NR"'C02R' 8 ; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R1 and R1 represent independently hydrogen atom, C, 6 alkyl, 20 or C, 6 alkyl substituted by hydroxy, C,. 6 alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-; R and R" represent independently hydrogen atom, CI-6 alkyl, halogen, NHR 8 , OR 8 , SO2R' 9 or NHSO2R' 9 ; R1 6 represents hydrogen atom or C, 6 alkyl; 25 R 7 represents CI, 6 alkyl, C 3 -. cycloalkyl or -B'-(R"), wherein R" 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 C,- 8 30 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 35 ring containing 1 to 3 hetero atoms selected from 0, S and N; WO 01/17513 PCT/JPOO/05951 77 R 18 represents hydrogen atom; C 1 _ 10 alkyl; C 3 .B cycloalkyl; phenyl substituted by halogen, C 1 . 6 alkyl or C 1 - 6 alkoxy; C_- 10 alkyl substituted by hydroxy, halogen, CO 2 H, C 1 - 6 alkoxy-carbonyl, C 3 -_ cycloalkyl, C 1 - 6 alkoxy, or phenyl 5 substituted by halogen, C 1 - 6 alkyl or C, 6 alkoxy; R 19 represents R", NHR 1 8 or NR- 8 wherein R'" has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H RT. Xb R 2 *3 R R 27 na R2 10 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 S0 2 NR 2 4 R 2 4 - or nitro group, 15 R 23 represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 26' group or CONHR R represents a lower alkyl group, benzyl group or NR 24 R 24 R24 and R 24 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, 20 R26' represents hydrogen atom or a lower alkyl group, R2 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, and the other is hydrogen 25 atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 is hydrogen atom, and R 2 7 is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 2, *1 represents an asymmetric carbon atom, 30 *2 and *3 represent an asymmetric carbon atom when R 26 and WO 01/17513 PCT/JPOO/05951 78 R 2 8 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI: OR 3 0 H R31 *4 N 0 Xc R 39 R 36 R 3 2 R 3 7 R 38 5 wherein R represents hydrogen atom or methyl group, R 21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 34 R 3 4 ' or nitro group, 10 R" represents hydrogen atom, methyl group, S0 2 NR 35 , formyl group or CONHR 3 ', R 35 represents a lower alkyl group, benzyl group or NR 34 R34' R 34 and R 34 are the same or different, and represent hydrogen atom, a lower alkyl group or benzyl group, 15 R 36 ' represents hydrogen atom or a lower alkyl group, R 3 represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, R 39 is hydrogen atom, one of R 37 or R 38 is hydrogen atom, and 20 the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or S, R 37 and R 38 are both hydrogen atom, and R 39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc 25 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. 30 14. A method for preventing or treating impaired glucose WO 01/17513 PCT/JPOO/05951 79 tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, 5 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 10 selected from the group consisting of 1) a compound of the formula [I] R 1 N R2 R 3 wherein Ri represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, 15 a lower alkylsulfonylamino 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 20 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; 25 (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb 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, 30 (c) a group of the formula : -O(CH 2 )r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl WO 01/17513 PCT/JPOO/05951 80 group or a group of the formula : -P(=0)(OR,)(OR,) 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-(CH 2 ) 5 -Rd 5 wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, 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 10 (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, 15 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 CH -CH 2 -NH -CH -CH 2 OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt 20 thereof; 2) a compound of the formula [II: R6 CH-CH 2 -NH -CH -CH 2 R _ I R 8 OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl 25 group or a halogeno lower alkyl group, R. 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] WO 01/17513 PCT/JPOO/05951 81 OH H R1 R1 I 1\ 17 A'UCH2-CCH 2 N - C-(-X' N-S02 (CH2-t R (R 1 13 R1 RR 15 wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, 5 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 C 3 _1 cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 10 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; 15 R" represents hydroxy, oxo, halogen, cyano, nitro, NR 8 R 8 , SR1", a halogeno lower alkyl, Cl_, alkyl, C, 6 alkoxy, C 3 -. cycloalkyl, phenyl, S0 2 R 9 , NR1 8 COR1 9 , COR 9 , NR 8 SO 2 R' 9 , NR"'C0 2 R1 8 ; or a C,, alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'R-a, SR"', a halogeno lower alkyl, C, 6 20 alkoxy, C3-3 cycloalkyl, phenyl, NR 18 COR' 9 , COR' 9 , S0 2 R 9 , NR 8 S0 2 R' 9 or NR"C0 2 R 8 ; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R1 2 and R" represent independently hydrogen atom, C,.. alkyl, 25 or C, 6 alkyl substituted by hydroxy, C 1 _ 6 alkoxy or halogen; X' represents -CH 2 -, -CH2-CH 2 -, -CH=CH- or -CH 2 0-; R 4 and R" represent independently hydrogen atom, C 1 _ 6 alkyl, halogen, NHR" 8 , OR' 8 , SO 2 R' 9 or NHSO 2 R' 9 ; R16 represents hydrogen atom or C.. 6 alkyl; 30 R 7 represents Cl_, alkyl, C 3 _1 cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or WO 01/17513 PCT/JPOO/05951 82 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 -, cycloalkyl ring;.benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 5 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; 10 R1 8 represents hydrogen atom; C,-., alkyl; C 3 .- cycloalkyl; phenyl substituted by halogen, C 1 _ 6 alkyl or C 1 . 6 alkoxy; C 1 .. 1 alkyl substituted by hydroxy, halogen, CO 2 H, CI_ 6 alkoxy-carbonyl, C.-, cycloalkyl, CI_ 6 alkoxy, or phenyl substituted by halogen, C 1 . 6 alkyl or C 1 _ 6 alkoxy; 15 R 19 represents R", NHR' 8 or NR 18 wherein R"' has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R N R26 *3 R R 27 na R2 wherein R 20 represents hydrogen atom or methyl group, 20 R 21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 22 2 R represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 24 R 24 ' or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR", formyl 25 group or CONHR 26 R represents a lower alkyl group, benzyl group or NR24R24 R 24 and R 24 ' 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, 30 R represents hydrogen atom or a lower alkyl group, WO 01/17513 PCT/JPOO/05951 83 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when 5 na is 1, R 2 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 10 R 28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI] OR 30 H R31 * 0 Xc R 39 R 3 6 R 3 7 R wherein R 30 represents hydrogen atom or methyl group, 15 R represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR 33 , SO 2 NR 34 R 3' or nitro group, R 3 represents hydrogen atom, methyl group, S0 2 NR 35 , formyl 20 group or CONHR 3 ', R" 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 36 ' represents hydrogen atom or a lower alkyl group, 25 R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, R 3 is hydrogen atom, one of R 37 or R38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group 30 or hydroxy group, when Xc is secondary nitrogen atom, 0 or WO 01/17513 PCT/JPOO/05951 84 S, R 37 and R 38 are both hydrogen atom, and R39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, 5 *4 represents an asymmetric carbon atom, *5 represents an asymmetric carbon atom when R 36 is a lower alkyl group, or a salt thereof.
15. A method according to claim 14, wherein the diabetic 10 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 15 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 20 of at least one member selected from the group consisting of 1) a compound of the formula [I] R, N SR2 R3 wherein R 1 represents a lower alkyl group optionally 25 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 R 2 to form methylenedioxy group, said methylenedioxy group being 30 optionally substituted by carboxyl group or a lower alkoxycarbonyl group, (a) a group of the formula : -Xa-Ra WO 01/17513 PCT/JPOO/05951 85 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 : -[O(CH 2 )p-CH(Rb)]qRbb 5 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 : -O(CH 2 )r-Rc 10 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, 15 (d) a group of the formula : -Ya-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl 20 group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, 25 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 ' CH-CH 2 -NH -CH -CH 2 ~ - I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower 30 alkyl group, R, represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] WO 01/17513 PCT/JPOO/05951 86 CH-CH 2 -NH -CH -CH 2 R OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents 5 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] : OH H R12 R1 1 1 /1 17 A 0CH -CHCH N- C-(-X' )k/S0 (CH2 R (R 1 13 k 1 R R 15 wherein j represents an integer of 0 to 7, 10 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 C, 15 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 20 ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR 8 R' 8 , SR' 8 , a halogeno lower alkyl, C, 6 alkyl, C1. 6 alkoxy, C, cycloalkyl, phenyl, S0 2 R' 9 , NR' 8 COR' 9 , COR 9 , NR1 8 SO 2 R' 9 , 25 NR' 8 C0 2 R1 8 ; or a C, 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'R' 8 , SR 18 , a halogeno lower alkyl, C,-6 alkoxy, C3-8 cycloalkyl, phenyl, NR 8 COR' 9 , COR' 9 , SO 2 R' 9 , NR1 8 S0 2 R' 9 or NRa'C0 2 R"1; WO 01/17513 PCT/JPOO/05951 87 or R' 1 represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R 2 and R1 3 represent independently hydrogen atom, CI_6 alkyl, or C 16 alkyl substituted by hydroxy, C 1 6 alkoxy or halogen; 5 X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; R 4 and R1 5 represent independently hydrogen atom, C,- alkyl, halogen, NHR", OR", SO 2 R1 9 or NHSO 2 R 19 ; R 1 represents hydrogen atom or Ci_6 alkyl; R 7 represents C, 6 alkyl, C 3 , cycloalkyl or -B'-(R"), 10 wherein R 1 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 15 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 20 N; Ri" represents hydrogen atom; Clo, alkyl; C,_, cycloalkyl; phenyl substituted by halogen, C, 6 alkyl or C 1 .3 6 alkoxy; C 1 - 1 alkyl substituted by hydroxy, halogen, CO 2 H, C1, 6 alkoxy-carbonyl, C 3 - 8 cycloalkyl, CI_ 6 alkoxy, or phenyl 25 substituted by halogen, Ci_ 6 alkyl or C, 6 alkoxy; R19 represents R 1, NHRia or NR 8 wherein R' 8 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R N 0 Xb R 2 R 2 6 -*3 R na R 30 wherein R 2 0 represents hydrogen atom or methyl group, WO 01/17513 PCT/JPOO/05951 88 R 2 " represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R 2 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 24 R 24 - or nitro group, 5 R 2 represents hydrogen atom, methyl group, S0 2 NR , formyl 26' group or CONHR R 2 s 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, 10 R 26' represents hydrogen atom or a lower alkyl group, R2 represents hydrogen atom or a lower alkyl group, na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R or R is hydrogen atom, and the other is hydrogen 15 atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 8 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, 20 *2 and *3 represent an asymmetric carbon atom when R 26 and R" are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI] OR 30 H R31 R 3 6 0XC R 3 R32 37/ 38 R R 25 wherein R 30 represents hydrogen atom or methyl group, R 2 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R 3 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 34 R 34 ' or nitro group, 30 R 3 represents hydrogen atom, methyl group, S0 2 NR 3 , formyl WO 01/17513 PCT/JPI00/05951 89 group or CONHR, 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, 5 R 36 ' represents hydrogen atom or a lower alkyl group, R 3 represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, R 39 is hydrogen atom, one of R 37 or R 3 5 is hydrogen atom, and 10 the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or S, R 37 and R 3 " are both hydrogen atom, and R 39 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc 15 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. 20 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 25 1) a compound of the formula [I] RI N R 3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower 30 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 WO 01/17513 PCT/JPOO/05951 90 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 5 alkyl group, provided that Ra is a lower alkyl group when Xa is S; (b) a group of the formula : -[O(CH 2 )P-CH(Rb) ],Rbb wherein Rb is hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or carboxyl group, Rbb is a lower 10 alkoxycarbonyl group or carboxyl group, p is an integer of 0 to 3, q is 0 or 1, (c) a group of the formula : -O(CH 2 )r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl 15 group or a group of the formula : -P(=0)(OR)(OR) 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-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower 20 alkoxycarbonyl group, s is an integer of 1 to 4, 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 (b) or (c), or combines with R 1 to form the above 25 methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2 30 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 I I OH R 5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt WO 01/17513 PCT/JPOO/05951 91 thereof; 2) a compound of the formula [II: R6 CH-CH 2 -NH -CH -CH 2 R 8 OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower 5 alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, 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] : OH H R1 I I 1 17 OCH2-CHCH N- C--X' ) k N-SO 2 (CH 2 --- R 2 23 k 1 (R 1 R1 1RR 10 w R R1 K 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 15 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 , 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 20 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; R" represents hydroxy, oxo, halogen, cyano, nitro, NR 8 R", 25 SR18, a halogeno lower alkyl, C1_ 6 alkyl, C 1 . 6 alkoxy, C 3 - 8 cycloalkyl, phenyl, SO 2 R 9 , NR1 8 COR' 9 , COR 9 , NR'SO 2 R 9 , NR1 8 C0 2 R 8 ; or a C 1 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR' 8 R 8 , SR 8 , a halogeno lower alkyl, C1.6 WO 01/17513 PCT/JPOO/05951 92 alkoxy, C 3 , cycloalkyl, phenyl, NR 8 COR' 9 , COR' 9 , SO 2 R 9 , NR"'S0 2 R' 9 or NR' 8 CO 2 R' 8 ; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; 5 R 2 and R" represent independently hydrogen atom, C,-6 alkyl, or C,- 6 alkyl substituted by hydroxy, C1. 6 alkoxy or halogen; X' represents -CH 2 -, -CH2-CH2-, -CH=CH- or -CH20-; R 4 and R"' 5 represent independently hydrogen atom, C, 6 alkyl, halogen, NHR', OR 8 , SO 2 R' 9 or NHSO 2 R 9 ; 10 R 6 represents hydrogen atom or C, 6 alkyl; R 7 represents CI- 6 alkyl, C 3 - cycloalkyl or -B'-(R")j wherein R" 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 15 selected from 0, S and N; benzene ring condensed with C,_, 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 20 N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R"' represents hydrogen atom; Clo, alkyl; C,.- cycloalkyl; phenyl substituted by halogen, C, 6 alkyl or C. 6 alkoxy; C.1 0 25 alkyl substituted by hydroxy, halogen, CO 2 H, CI, 6 alkoxy-carbonyl, C,_, cycloalkyl, C, 6 alkoxy, or phenyl substituted by halogen, CI, 6 alkyl or C, 6 alkoxy; R' 9 represents R1 8 , NHR 8 or NR' wherein R'" has the same meaning as above, or a salt thereof; 30 4) a compound of the formula [V] WO 01/17513 PCT/JPOO/05951 93 OR 20 H R 0 X b R 26 X R na R 2 wherein R20 represents hydrogen atom or methyl group, R represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 5 R 22 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 2 4 R 24 - or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR , formyl 26' group or CONHR Rs represents a lower alkyl group, benzyl group or NR 24R24 10 R 2 4 and R 24 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, R represents hydrogen atom or a lower alkyl group, na is 1 or 2, 15 Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and 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, 20 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 6 and R are respectively not hydrogen atom, or a salt thereof; and 25 5) a compound of the formula [VI] WO 01/17513 PCT/JPOO/05951 94 R 3 0 OR H R R 36 0 XC R R 3 37/ 38 RR wherein R 30 represents hydrogen atom or methyl group, R" represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 5 R 3 represents hydrogen atom, hydroxymethyl group, NHR", S0 2 NR 34 R 34 ' or nitro group, R" represents hydrogen atom, methyl group, SO 2 NR , formyl group or CONHR 6 R" represents a lower alkyl group, benzyl group or NR 34 R 34 10 R 3 4 and R 34 ' 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, 0, S or methylene 15 group, R 39 is hydrogen atom, one of R 37 or R 3 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, 20 R 3 7 and R 3 e 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 25 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 30 from the group consisting of WO 01/17513 PCT/JPOO/05951 95 1) a compound of the formula [I] R, N I R2 Ra wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, 5 a lower alkylsulfonylamino 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 10 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; 15 (b) a group of the formula : -[O(CH 2 )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, 20 (c) a group of the formula : -O(CH 2 )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(=O)(OR)(OR) wherein RA is hydrogen atom or a lower alkyl group, r is 25 an integer of 1 to 4, (d) a group of the formula : -Ya-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl 30 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 1 to form the above WO 01/17513 PCT/JPOO/05951 96 methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, 5 W represents a group of the formula which bonds to the 2 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt 10 thereof; 2) a compound of the formula [II] R6 CH-CH2 -NH -CH -CH 2 R OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl 15 group or a halogeno lower alkyl group, R, 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] : OH H R12 R1 1I 1 /1 17 A CH2-CHCHN - -(-X' N-SO2(CH-,R 2 2 113kS1 0 2 C 2 --)t ( )R" Ris5 R4 20 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 25 selected from 0, S and N; benzene ring condensed with C 3 _1 WO 01/17513 PCT/JPOO/05951 97 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 5 N which is condensed with a 5- or 6-membered heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"R 1, SR 8 , a halogeno lower alkyl, Ci, 6 alkyl, C, 6 alkoxy, C_ 8 10 cycloalkyl, phenyl, SO 2 R' 9 , NR"'COR' 9 , COR' 9 , NR' 8 S0 2 R' 9 , NR 8 C0 2 R1"; or a C, 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR'"R", SR 1 8 , a halogeno lower alkyl, C1-6 alkoxy, C,, cycloalkyl, phenyl, NR'"COR' 9 , COR' 9 , S0 2 R 9 , NR' 8 S0 2 R' 9 or NR"'C0 2 R 8 ; 15 or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R 12 and R1 3 represent independently hydrogen atom, Ci_ 6 alkyl, or C, 6 alkyl substituted by hydroxy, C, 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 O-; 20 R1 4 and R1 5 represent independently hydrogen atom, C,. 6 alkyl, halogen, NHR 8 , OR"', SOR' 9 or NHSO 2 R' 9 ; R1 6 represents hydrogen atom or CI, 6 alkyl; R 7 represents C, 6 alkyl, C 3 _1 cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; 25 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 -1 cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 30 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; 35 R"' represents hydrogen atom; Co, 0 alkyl; C 3 -1 cycloalkyl; phenyl substituted by halogen, C,- 6 alkyl or C, 6 alkoxy; C:,_1 0 WO 01/17513 PCT/JPOO/05951 98 alkyl substituted by hydroxy, halogen, CO 2 H, C 1 - 6 alkoxy-carbonyl, C 3 -_ cycloalkyl, C 16 alkoxy, or phenyl substituted by halogen, C 1 - 6 alkyl or C1. 6 alkoxy; R 19 represents R 1, NHR" or NR" wherein R 8 has the same 5 meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R" 21N T2z Xb R 2 6 *3 R R 27 na R 28 wherein R 20 represents hydrogen atom or methyl group, R 21 represents hydrogen atom, halogen atom, hydroxy group, 10 benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR 23 S0 2 NR 2 4 R 2 4 - or nitro group, R 23 represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 26' group or CONHR 15 R 25 represents a lower alkyl group, benzyl group or NR2R R24 and R 24 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, R 2 represents hydrogen atom or a lower alkyl group, 20 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, 25 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 2 8 are respectively not hydrogen atom, or a salt thereof; 30 and WO 01/17513 PCT/JPOO/05951 99 5) a compound of the formula [VI] OR 3 0 H R 31_ *4 N0 Xc R9 R R 32R 37 R wherein R 30 represents hydrogen atom or methyl group, R represents hydrogen atom, halogen atom, hydroxy group, 5 benzyloxy group, amino group or hydroxymethyl group, R 3 represents hydrogen atom, hydroxymethyl group, NHR, SO 2 NR 34 R34' or nitro group, R" represents hydrogen atom, methyl group, S0 2 NR 35 , formyl 36' group or CONHR 10 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, R36' represents hydrogen atom or a lower alkyl group, R 3 represents hydrogen atom "or a lower alkyl group, 15 Xc represents secondary nitrogen atom, 0, S or methylene group, R 39 is hydrogen atom, one of R 37 or R 3 " is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, 0 or 20 S, R and R 3 " 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, 25 *5 represents an asymmetric carbon atom when R 36 is a lower alkyl group, or a salt thereof.
19. Use of at least one member selected from the group consisting of 30 1) a compound of the formula [I] WO 01/17513 PCT/JPOO/05951 100 R 1 N I ~R 2 R3 wherein R, represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower 5 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, 10 (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 : -[O(CH 2 )p-CH(Rb)],Rbb 15 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 : -O(CH 2 )r-Rc 20 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(=O)(OR)(ORA) wherein RA is hydrogen atom or a lower alkyl group, r is an integer of 1 to 4, 25 (d) a group of the formula : -Ya-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by hydroxyl group, hydroxyl 30 group, a lower alkoxy group, or the same group as the above (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being WO 01/17513 PCT/JPOO/05951 101 optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2 5 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 I I OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt thereof; 10 2) a compound of the formula [II] R6 CH-CH 2 -NH -CH -CH 2 R OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents 15 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] : OH H R12 R1 S CH-CHCH N - C-(-Xk N-SO 2 (CH 2 --- R R 1 R 15 R 1 wherein j represents an integer of 0 to 7, 20 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 C 3 -. 25 cycloalkyl ring; benzene ring condensed with a,5- or 6- WO 01/17513 PCT/JPOO/05951 102 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 5 ring containing 1 to 3 hetero atoms selected from 0, S and N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR1 8 R 1, SR 8 , a halogeno lower alkyl, Cl, alkyl, C, 6 alkoxy, C 3 _ 8 cycloalkyl, phenyl, SO 2 R 9 , NR 8 COR1 9 , COR 19 , NR 8 SO 2 R' 9 , 10 NR 8 C0 2 R1 8 ; or a C1, alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'R'", SR' 8 , a halogeno lower alkyl, C, 6 alkoxy, C 3 , cycloalkyl, phenyl, NR' 8 COR1 9 , COR' 9 , SO 2 R' 9 , NR' 8 S0 2 R' 9 or NR"'C0 2 R' 8 ; or R" represents a 5- or 6-membered heterocyclic group 15 containing 1 to 3 hetero atoms selected from 0, S and N; R and R 3 represent independently hydrogen atom, C, 6 alkyl, or C1, alkyl substituted by hydroxy, C, 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; R 4 and R' 5 represent independently hydrogen atom, C, 6 alkyl, 20 halogen, NHR", OR' 8 , SO 2 R' 9 or NHSO2R' 9 ; R1" represents hydrogen atom or C1- 6 alkyl; R1 7 represents CI, 6 alkyl, C 3 - 8 cycloalkyl or -B'-(R"), wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 25 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 -_ 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 30 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; R 8 represents hydrogen atom; C,_, alkyl; C 3 _ 8 cycloalkyl; 35 phenyl substituted by halogen, C1. 6 alkyl or C,. 6 alkoxy; C,-,( alkyl substituted by hydroxy, halogen, CO 2 H, C, 6 WO 01/17513 PCT/JPOO/05951 103 alkoxy-carbonyl, C 3 , cycloalkyl, C 1 6 alkoxy, or phenyl substituted by halogen, C1_ 6 alkyl or C 1 - 6 alkoxy; R 19 represents R 1 ", NHRi 8 or NR 8 wherein R 18 has the same meaning as above, or a salt thereof; 5 4) a compound of the formula [V] OR 20 H R 0 X T, Xb R *3 R 2 27/ Q 28 R na R 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, 10 R" represents hydrogen atom, hydroxymethyl group, NHR, SO 2 NR 24R 24 or nitro group, R represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 26' group or CONHR R 2 s represents a lower alkyl group, benzyl group or NR 24 R 24 15 R 2 4 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 2 6 represents hydrogen atom or a lower alkyl group, na is 1 or 2, 20 Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 2 8 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 8 is hydrogen atom, and R 2 1 is hydrogen atom, amino group, 25 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 2 are respectively not hydrogen atom, or a salt thereof; and 30 5) a compound of the formula [VI] WO 01/17513 PCT/JPOO/05951 104 OR 3 0 H R R \/Xc R R" 3 7 3 wherein R 30 represents hydrogen atom or methyl group, R 2 1 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 5 R" represents hydrogen atom, hydroxymethyl group, NHR", S0 2 NR 3 4 R 34 ' or nitro group, R 3 represents hydrogen atom, methyl group, S0 2 NR", formyl group or CONHR 36 , R 35 represents a lower alkyl group, benzyl group or NR 34 R 34 , 10 R 34 and R 34 ' 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, R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene 15 group, R 39 is hydrogen atom, one of R 37 or R 3 8 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, 20 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 25 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. 30 20. Use of an insulin sensitizer for the manufacture of WO 01/17513 PCT/JPOO/05951 105 a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, 5 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 10 1) a compound of the formula [I] RI w I N I R2 R 3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower 15 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, 20 (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 : -[O(CH 2 )p-CH(Rb)]qRbb 25 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 : -O(CH 2 )r-Rc 30 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)(OR)(OR,) WO 01/17513 PCT/JPOO/05951 106 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-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower 5 alkoxycarbonyl group, s is an integer of 1 to 4, 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 (b) or (c), or combines with R 1 to form the above 10 methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, R 3 represents hydrogen atom or a lower alkyl group, W represents a group of the formula which bonds to the 2 15 or 3-position of the indole ring in the formula [I]: R4 CH-CH 2 -NH -CH -CH 2 - I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt thereof; 20 2) a compound of the formula [II] R 6 / \ CH-CH 2 -NH -CH -CH2 R OH R7 N 8 H wherein 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, represents 25 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] WO 01/17513 PCT/JPOO/05951 107 OH H R 12 X) (CH/ 17 OCH 2 - CHCH 2 N - C-(-X' )k N-S0 2 (CH 2 -t-R k1 116 (R 1 )j R" Rs R1 wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, 5 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 C 3 . cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 10 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; 15 R" represents hydroxy, oxo, halogen, cyano, nitro, NR 8 R 8 , SR 18 , a halogeno. lower alkyl, C,- 6 alkyl, C1- 6 alkoxy, C 3 _1 cycloalkyl, phenyl, SO 2 R 9 , NR 8 COR1 9 , COR' 9 , NR1"S0 2 R 9 , NR'"C0 2 R 8 ; or a C, 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR 8 Rl", SR 8 , a halogeno lower alkyl, C,- 6 20 alkoxy, C3, 8 cycloalkyl, phenyl, NR 8 COR' 9 , COR' 9 , S0 2 R 9 , NR 8 S02R' 9 or NR"'C02R' 8 ; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R1 and R" represent independently hydrogen atom, C, 6 alkyl, 25 or C, 6 alkyl substituted by hydroxy, C,- 6 alkoxy or halogen; X' represents -CH2-, -CH2-CH2-, -CH=CH- or -CH20-; R" and R" represent independently hydrogen atom, C, 6 alkyl, halogen, NHR' 8 , OR' 8 , SO2R 9 or NHSO2R' 9 ; R 1 represents hydrogen atom or C,.. 6 alkyl; 30 R 7 represents C, 6 alkyl, C, cycloalkyl or -B'-(Ru) wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or WO 01/17513 PCT/JPOO/05951 108 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C,_, cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 5 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; 10 R1 8 represents hydrogen atom; C,-,, alkyl; C 3 -1 cycloalkyl; phenyl substituted by halogen, C 1 - 6 alkyl or C 1 ., alkoxy; Ci. 10 alkyl substituted by hydroxy, halogen, CO 2 H, Ci_ 6 alkoxy-carbonyl, C 3 -_ cycloalkyl, C 1 _ 6 alkoxy, or phenyl substituted by halogen, C 1 . 6 alkyl or C, 6 alkoxy; 15 R1 9 represents R'", NHR'" or NR"' wherein Ri8 has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R21 *l 0 Xb R *3 R 27 na R28 wherein R 20 represents hydrogen atom or methyl group, 20 R represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R 2 represents hydrogen atom, hydroxymethyl group, NHR, SO 2 NR R 24 or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 26' 25 group or CONHR R 2 s represents a lower alkyl group, benzyl group or NR 24 R 24 ' R24 and R 24 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, 30 R represents hydrogen atom or a lower alkyl group, WO 01/17513 PCT/JPOO/05951 109 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when 5 na is 1, R 2 8 is hydrogen atom, and R 2 7 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 10 R 28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VI] OR 30 H R4 0 R 39 R31 *4 N CR R 3 6 R 2R 3XR 3 wherein R represents hydrogen atom or methyl group, 15 R 2 1 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR S0 2 NR 34 R 34 ' or nitro group, R 33 represents hydrogen atom, methyl group, S0 2 NR 3 s, formyl 20 group or CONHR 36 R 35 represents a lower alkyl group, benzyl group or NR 34 R 34 , R 3 ' and R 34 ' 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, 25 R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, 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 30 or hydroxy group, when Xc is secondary nitrogen atom, 0 or WO 01/17513 PCT/JPOO/05951 110 S, R 37 and R 3 " are both hydrogen atom, and R 3 9 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, 5 *4 represents an asymmetric carbon atom, *5 represents an asymmetric carbon atom when R 36 is a lower alkyl group, or a salt thereof.
21. Use of at least one member selected from the group 10 consisting of 1) a compound of the formula [I] R, N R2 R3 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, 15 a lower alkylsulfonylamino 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 20 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; 25 (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb 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, 30 (c) a group of the formula : -O(CH 2 )r-Rc wherein Rc is a lower alkanoyl group, hydroxyl group, cyano group, phenyl group, a mono- or di-lower alkylaminocarbonyl WO 01/17513 PCT/JPOO/05951 111 group or a group of the formula : -P(=O)(OR)(OR) 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-(CH 2 ),-Rd 5 wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, 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 10 (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, R 3 represents hydrogen atom or a lower alkyl group, 15 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 CH-CH 2 -NH -CH -CH 2 - R OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R, represents a lower alkyl group, or a salt 20 thereof; 2) a compound of the formula [II] R 6 CH-CH -NH-CH-CH 2 _2 R I- I R 8 OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl 25 group or a halogeno lower alkyl group, R, 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] WO 01/17513 PCT/JPOO/05951 112 OH H R12 R1 ' I 1 /1 17 11 aA 0CH2~- LHCH2 -- -(-X' )kN-SO2(CH2tR (R 1 k R1R R R 15 K wherein j represents an integer of 0 to 7, k represents 0 or 1, t represents an integer of 0 to 3, 5 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_1 cycloalkyl ring; benzene ring condensed with a 5- or 6 membered heterocyclic ring containing 1 to 3 hetero atoms 10 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; 15 R" represents hydroxy, oxo, halogen, cyano, nitro, NR 8 R'", SR 8 , a halogeno lower alkyl, C, 6 alkyl, C 1 - 6 alkoxy, C 3 -_ cycloalkyl, phenyl, SOR 9 , NR 8 COR 9 , COR' 9 , NR 8 SO 2 R 9 , NR'"CO 2 R' 8 ; or a C, 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR1 8 R'", SR1 8 , a halogeno lower alkyl, C 1 . 6 20 alkoxy, C 3 -_ cycloalkyl, phenyl, NR 8 COR' 9 , COR' 9 , S0 2 R 9 , NR' 8 S0 2 R' or NR1CO 2 R8; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R- 2 and R1 3 represent independently hydrogen atom, C1. 6 alkyl, 25 or C_, 6 alkyl substituted by hydroxy, C1 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; R 4 and R' 5 represent independently hydrogen atom, C 1 - 6 alkyl, halogen, NHR' 8 , OR"', SO 2 R' 9 or NHSO 2 R' 9 ; R' 6 represents hydrogen atom or C,_ 6 alkyl; 30 R 7 represents C 1 - 6 alkyl, C3_1 cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or WO 01/17513 PCT/JPOO/05951 113 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, 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 5 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; 10 R1 8 represents hydrogen atom; C 1 10 alkyl; C 3 -1 cycloalkyl; phenyl substituted by halogen, C,. 6 alkyl or C 1 . 6 alkoxy; C.. 10 alkyl substituted by hydroxy, halogen, CO 2 H, C 1 . 6 alkoxy-carbonyl, C 3 -_ cycloalkyl, C 1 _ 6 alkoxy, or phenyl substituted by halogen, C 1 . 6 alkyl or C 1 - 6 alkoxy; 15 R1 9 represents R", NHR 18 or NR" wherein R'" has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R 0 Xb R 2 6 *3 R R 27 na R 28 wherein R 2 ' represents hydrogen atom or methyl group, 20 R 21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R 2 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 24 R 2 4 - or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR , formyl 26' 25 group or CONHR 25 24 4 R - represents a lower alkyl group, benzyl group or NR 4 R 24 R24 and R 2 4 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, 30 R represents hydrogen atom or a lower alkyl group, WO 01/17513 PCT/JPOO/05951 114 na is 1 or 2, Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when 5 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 10 R 28 are respectively not hydrogen atom, or a salt thereof; and 5) a compound of the formula [VII OR 30 H R31 *4 0 Xc R 39 R 3 332 R2 37/ 38 wherein R 30 represents hydrogen atom or methyl group, 15 R represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 34 R 34 ' or nitro group, R" represents hydrogen atom, methyl group, S0 2 NR", formyl 36' 20 group or CONHR R 35 represents a lower alkyl group, benzyl group or NR 34 R, R 34 and R 34 ' 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, 25 R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, R 3 9 is hydrogen atom, one of R 37 or R 38 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group 30 or hydroxy group, when Xc is secondary nitrogen atom, 0 or WO 01/17513 PCT/JPOO/05951 115 S, R 37 and R 3 " are both hydrogen atom, and R 3 9 is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is methylene group, 5 *4 represents an asymmetric carbon atom, *5 represents an asymmetric carbon atom when R 36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for treating impaired glucose tolerance, hyperlipidemia, 10 hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular diseases, polycystic ovary syndrome, gestational diabetes, pancreatitis, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, inflammatory bowel diseases, syndrome X, visceral fat 15 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, 20 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. 25
23. Use of at least one member selected from the group consisting of 1) a compound of the formula [I] RI W N R2 R3 30 wherein R 1 represents a lower alkyl group optionally substituted by hydroxyl group, phenylsulfonylamino group, a lower alkylsulfonylamino group, a mono- or di-lower WO 01/17513 PCT/JPOO/05951 116 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 5 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; 10 (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb 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, 15 (c) a group of the formula : -O(CH 2 )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(=O)(OR)(OR) wherein RA is hydrogen atom or a lower alkyl group, r is 20 an integer of 1 to 4, (d) a group of the formula : -Ya-(CH 2 ).-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, R 2 represents hydrogen atom, a halogen atom, a lower alkyl 25 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 1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower 30 alkoxycarbonyl group, 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]: WO 01/17513 PCT/JPOO/05951 117 R 4 CH-CH 2 -NH -CH -CH 2 OH R5 wherein R 4 represents a halogen atom or a halogeno lower alkyl group, R. represents a lower alkyl group, or a salt thereof; 5 2) a compound of the formula [II] R 6 CH-CH 2 -NH -CH -- CH 2 __ 2 R OH R7 N H wherein R 6 represents a halogen atom or a halogeno lower alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R, represents 10 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] : OH H R 12 R1 I 1 /1 17 A LCH -CHCH N- C-(-X' ) N--SO 2 (CH -)--R (R2 2 13 k 11I R R 15 R 1 wherein j represents an integer of 0 to 7, 15 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 C 3 -, 20 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 25 ring containing 1 to 3 hetero atoms selected from 0, S and WO 01/17513 PCT/JPOO/05951 118 N; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"'R' 8 , SR 8 , a halogeno lower alkyl, C 1 _ 6 alkyl, C,- alkoxy, C 3 -_ cycloalkyl, phenyl, SO 2 R 9 , NR"'COR 9 , COR 9 , NR"'SO 2 R' 9 , 5 NR"'C0 2 R'e; or a Cl_, alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"'R"', SR", a halogeno lower alkyl, CI-6 alkoxy, C 3 _, cycloalkyl, phenyl, NR"'COR 9 , COR 9 , SO 2 R 9 , NR1 8 SO 2 R' 9 or NR 8 CO 2 R' 8 or R" represents a 5- or 6-membered heterocyclic group 10 containing 1 to 3 hetero atoms selected from 0, S and N; R" and R" represent independently hydrogen atom, CI, 6 alkyl, or C,. 6 alkyl substituted by hydroxy, C, 6 alkoxy or halogen; X' represents -CH 2 -, -CH 2 -CH 2 -, -CH=CH- or -CH 2 0-; R" and R"' represent independently hydrogen atom, C, 6 alkyl, 15 halogen, NHR", OR", SO 2 R' 9 or NHSO 2 R; R 1 represents hydrogen atom or C, 6 alkyl; R1 7 represents C1- 6 alkyl, C 3 -_ cycloalkyl or -B'-(R")j wherein R" and j have the same meanings as above; ring B' represents benzene ring; naphthalene ring; a 5- or 20 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from 0, S and N; benzene ring condensed with C 3 ., 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 25 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; R"' represents hydrogen atom; C,, 0 alkyl; C 3 - cycloalkyl; 30 phenyl substituted by halogen, C,-, alkyl or CI, 6 alkoxy; C.., 0 alkyl substituted by hydroxy, halogen, CO 2 H, C,._ 6 alkoxy-carbonyl, C 3 _. cycloalkyl, C,- 6 alkoxy, or phenyl substituted by halogen, C. 6 alkyl or C, 6 alkoxy; R' 9 represents R 18 , NHR"' or NR' 8 wherein R 8 has the same 35 meaning as above, or a salt thereof; 4) a compound of the formula [V] WO 01/17513 PCT/JPOO/05951 119 OR 20 H N R 210 R 2 6 X R b *3 R 2na R 2 8 wherein R20 represents hydrogen atom or methyl group, R 21 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 5 R 2 2 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 24 R 24 - or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl group or CONHR 2 e R represents a lower alkyl group, benzyl group or NR 4 R 2 4 2 10 R 2 4 and R 24 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, R 2 represents hydrogen atom or a lower alkyl group, na is 1 or 2, 15 Xb represents secondary nitrogen atom, 0 or S, one of R 27 or R 28 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when na is 1, R 2 8 is hydrogen atom, and R 27 is hydrogen atom, amino group, 20 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 2 6 and R2e are respectively not hydrogen atom, or a salt thereof; and 25 5) a compound of the formula [VI] WO 01/17513 PCT/JPOO/05951 120 OR 30 H R31_ *4 N 3 0 XCR 3 32 3 RR/ R Xc' 3 R 32 R 3 7 R wherein R 30 represents hydrogen atom or methyl group, R represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, 5 R 3 represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 34 R 34 ' or nitro group, R" represents hydrogen atom, methyl group, S0 2 NR 35 , formyl group or CONHR" , Ras represents a lower alkyl group, benzyl group or NR 34 R 34 ', 10 R 34 and R 34 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, R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, O, S or methylene 15 group, R1 is hydrogen atom, one of R or R is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when Xc is secondary nitrogen atom, or S, 20 R 37 and R 3 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 25 alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping a smoking habit. 30 24. Use of at least one member selected from the group WO 01/17513 PCT/JPOO/05951 121 consisting of 1) a compound of the formula [I] R, N R2 R 3 wherein R 1 represents a lower alkyl group optionally 5 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 R 2 to form methylenedioxy group, said methylenedioxy group being 10 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 15 Xa is S; (b) a group of the formula : -[O(CH 2 )p-CH(Rb)],Rbb 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 20 0 to 3, q is 0 or 1, (c) a group of the formula : -O(CH 2 )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)(OR,)(OR,) 25 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-(CH 2 ),-Rd wherein Ya is NH or S, Rd is carboxyl group or a lower alkoxycarbonyl group, s is an integer of 1 to 4, 30 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 WO 01/17513 PCT/JPOO/05951 122 (b) or (c), or combines with R 1 to form the above methylenedioxy group, said methylenedioxy group being optionally substituted by carboxyl group or a lower alkoxycarbonyl group, 5 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]: R4 CH -CH 2 -NH -CH -CH 2 - I R OH R5 wherein R 4 represents a halogen atom or a halogeno lower 10 alkyl group, R, represents a lower alkyl group, or a salt thereof; 2) a compound of the formula [II] R6 /\ CH-CH2 -NH -CH -CH 2 N I II R OH R7 N J H wherein R 6 represents a halogen atom or a halogeno lower 15 alkyl group, R, represents hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, R. 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] R4 OH H R 1 2 R A CH 2 -CHCH N- -(-X' N--SO 2 (CH 2 -);--R (R 1 )j R13 k R 2 20 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 25 6-membered heterocyclic ring containing 1 to 4 hetero atoms WO 01/17513 PCT/JPOO/05951 123 selected from 0, S and N; benzene ring condensed with C, 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 5 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; R" represents hydroxy, oxo, halogen, cyano, nitro, NR"'R' 8 , 10 SR 18 , a halogeno lower alkyl, C1_ 6 alkyl, C1. 6 alkoxy, C 3 , cycloalkyl, phenyl, SO 2 R 9 , NR"'COR 9 , COR 9 , NR 8 SO 2 R' 9 , NR"'C02R1 8 ; or a C 1 6 alkyl group substituted by hydroxy, nitro, halogen, cyano, NR"R 8 , SR", a halogeno lower alkyl, C1-6 alkoxy, C,_, cycloalkyl, phenyl, NR1 8 COR' 9 , COR' 9 , SO2R 9 , 15 NR1 8 S02R 9 or NR1 8 CO2R 8 ; or R" represents a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N; R and R" represent independently hydrogen atom, C, 6 alkyl, or C, 6 alkyl substituted by hydroxy, C, 6 alkoxy or halogen; 20 X' represents -CH2-, -CH2-CH 2 -, -CH=CH- or -CH,0-; R" and R" represent independently hydrogen atom, C- 6 alkyl, halogen, NHR 8 , OR"', SO2R1 9 or NHSO2R 9 ; R 1 represents hydrogen atom or C, 6 alkyl; R 7 represents C, 6 alkyl, C3, 8 cycloalkyl or -B'-(R") 25 wherein R" 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 C 3 -_ cycloalkyl ring; benzene ring condensed with a 5- or 6 30 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 35 N; R 8 represents hydrogen atom; C,, alkyl; C3- cycloalkyl; WO 01/17513 PCT/JPOO/05951 124 phenyl substituted by halogen, CI_ 6 alkyl or C 1 . 6 alkoxy; C 1 _-, alkyl substituted by hydroxy, halogen, CO 2 H, C 1 . 6 alkoxy-carbonyl, C,, cycloalkyl, C 1 - 6 alkoxy, or phenyl substituted by halogen, C 1 - 6 alkyl or CI_ 6 alkoxy; 5 R" represents R 18 , NHR"' or NR 8 wherein R"' has the same meaning as above, or a salt thereof; 4) a compound of the formula [V] OR 20 H R N 0 Xb R 2 7 *3 R 2R na R2 8 wherein R 20 represents hydrogen atom or methyl group, 10 R 2 1 represents hydrogen atom, halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R represents hydrogen atom, hydroxymethyl group, NHR, SO 2 NR2R2' or nitro group, R 2 represents hydrogen atom, methyl group, S0 2 NR 2 s, formyl 15 group or CONHR 6 25 24 24' R23 represents a lower alkyl group, benzyl group or NR R R 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, 20 R 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, and the other is hydrogen atom, amino group, acetylamino group or hydroxy group, when 25 na is 1, R 28 is hydrogen atom, and R 2 7 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 30 R 28 are respectively not hydrogen atom, or a salt thereof; WO 01/17513 PCT/JPOO/05951 125 and 5) a compound of the formula [VI] OR 30 H R 0 Xc R 39 32 3 R 37 R wherein R 30 represents hydrogen atom or methyl group, 5 R 21 represents hydrogen atom, a halogen atom, hydroxy group, benzyloxy group, amino group or hydroxymethyl group, R" represents hydrogen atom, hydroxymethyl group, NHR, S0 2 NR 3 4 R 34 ' or nitro group, R 3 represents hydrogen atom, methyl group, S0 2 NR 35 , formyl 10 group or CONHR" R 3 -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, R36' represents hydrogen atom or a lower alkyl group, 15 R represents hydrogen atom or a lower alkyl group, Xc represents secondary nitrogen atom, 0, S or methylene group, R 3 9 is hydrogen atom, one of R 37 or R 3 is hydrogen atom, and the other is hydrogen atom, amino group, acetylamino group 20 or hydroxy group, when Xc is secondary nitrogen atom, 0 or S, 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, 25 *4 represents an asymmetric carbon atom, *5 represents an asymmetric carbon atom when R 36 is a lower alkyl group, or a salt thereof, for the manufacture of a pharmaceutical preparation for inhibiting body weight increase after stopping alimentary 30 therapy.
AU68680/00A 1999-09-03 2000-09-01 Pharmaceutical composition Abandoned AU6868000A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP11/250443 1999-09-03
JP25044399 1999-09-03
JP2000056021 2000-02-28
JP2000/56021 2000-02-28
PCT/JP2000/005951 WO2001017513A2 (en) 1999-09-03 2000-09-01 Pharmaceutical composition comprising an insulin sensitizer

Publications (1)

Publication Number Publication Date
AU6868000A true AU6868000A (en) 2001-04-10

Family

ID=26539777

Family Applications (1)

Application Number Title Priority Date Filing Date
AU68680/00A Abandoned AU6868000A (en) 1999-09-03 2000-09-01 Pharmaceutical composition

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)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60123665T2 (en) 2000-12-26 2007-08-16 Sankyo Co., Ltd. MEDICAL COMPOSITIONS WITH DIURETIC AND INSULIN RESISTANCE TO IMPROVE MEDIUM
ES2321815T3 (en) 2001-04-04 2009-06-12 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. THERAPEUTIC COMBINATION THAT INCLUDES REABSORTION AND GLUCOSE INHIBITORS AND PPAR MODULATORS.
ATE442148T1 (en) 2001-04-04 2009-09-15 Ortho Mcneil Janssen Pharm COMBINATION THERAPY USING GLUCOSE ABSORPTION INHIBITORS AND RETINOID X RECEPTOR MODULATORS
FR2838968A1 (en) * 2002-04-30 2003-10-31 Lipha ASSOCIATION OF INSULIN AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR TREATING DIABETES
JPWO2003106418A1 (en) * 2002-06-12 2005-10-13 住友製薬株式会社 Indole, indazole, and benzazoles

Family Cites Families (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
ES2059121T5 (en) * 1990-02-09 2000-12-01 Upjohn Co USE OF INSULIN SENSITIZING AGENTS TO TREAT HYPERTENSION.
CA2206307A1 (en) * 1994-11-29 1996-06-06 Dainippon Pharmaceutical Co., Ltd. Indole derivative

Also Published As

Publication number Publication date
PL354295A1 (en) 2004-01-12
AR031674A1 (en) 2003-10-01
CN1372476A (en) 2002-10-02
RU2002108346A (en) 2003-11-20
WO2001017513A3 (en) 2001-09-20
HK1044711A1 (en) 2002-11-01
HUP0203285A3 (en) 2003-02-28
CA2383946A1 (en) 2001-03-15
NO20021036D0 (en) 2002-03-01
CO5180632A1 (en) 2002-07-30
KR20020063555A (en) 2002-08-03
WO2001017513A2 (en) 2001-03-15
EP1212090A2 (en) 2002-06-12
PE20010580A1 (en) 2001-05-25
HUP0203285A2 (en) 2003-01-28
NO20021036L (en) 2002-04-26

Similar Documents

Publication Publication Date Title
CA2369694C (en) Agent for improving ketosis
AU754740B2 (en) Pharmaceutical composition for the treatment of diabetes
JP3148973B2 (en) Medicine
US20030134884A1 (en) Neovascularization inhibitors
US20030060488A1 (en) Drug comprising combination
AU6868000A (en) Pharmaceutical composition
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
JP2001342135A (en) Neovascularization inhibitor
MXPA00010582A (en) Pharmaceutical composition for the treatment of diabetes
JP2003012551A (en) Abc expression promoter

Legal Events

Date Code Title Description
DA3 Amendments made section 104

Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 20020417