Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

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

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