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WO2006019020A1 - Urées de substitution - Google Patents

Urées de substitution Download PDF

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Publication number
WO2006019020A1
WO2006019020A1 PCT/JP2005/014633 JP2005014633W WO2006019020A1 WO 2006019020 A1 WO2006019020 A1 WO 2006019020A1 JP 2005014633 W JP2005014633 W JP 2005014633W WO 2006019020 A1 WO2006019020 A1 WO 2006019020A1
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Prior art keywords
group
methyl
phenyl
urea
compound
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Japanese (ja)
Inventor
Ichiro Hayakawa
Masao Yoshida
Yuichi Sugano
Hitoshi Kurata
Tatsuo Tanimoto
Hiroshi Karasawa
Takafumi Kohama
Yoshikazu Uto
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a specific chemical structure having an excellent inhibitory action on asilcoenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT). And a pharmacologically acceptable salt thereof.
  • DGAT diacylglycerol acyltransferase
  • Obesity is caused by accumulation of neutral fat (triacinoleglycerol or triglyceride, hereinafter referred to as TG) in fat cells due to the persistence of excessive intake energy compared to energy consumption.
  • the weight is significantly increased compared to the standard weight (Non-patent Document 1).
  • Obesity includes hyperlipidemia, hyper-TGemia, diabetes, hypertension, arteriosclerosis and other lifestyle-related diseases, cerebrovascular disorders, coronary artery disease, respiratory abnormalities, low back pain, knee osteoarthritis, gout, cholelithiasis, etc.
  • Obesity that has these complications or that may cause these complications in the future is defined as obesity and is treated as a disease.
  • Non-patent Document 2 a non-patent Document 2
  • fatty acids and TNF-spleen factors such as fatty acids and TNF-spleen, which cause insulin resistance in skeletal muscle, liver and adipose tissue, and synthesis of neutral fat in the liver.
  • TNF-spleen factors such as fatty acids and TNF-spleen, which cause insulin resistance in skeletal muscle, liver and adipose tissue, and synthesis of neutral fat in the liver.
  • hyperlipidemia In addition, elevated blood insulin levels caused by insulin resistance cause impaired glucose tolerance and diabetes, and peripheral vascular resistance through increased Na ion reabsorption and sympathetic activation in the kidney. Increases and causes hypertension.
  • hyperlipidemia, diabetes and hypertension caused by obesity are thought to cause vascular disorders such as cerebrovascular disorders and coronary artery diseases based on arteriosclerosis, resulting in serious life-threatening medical conditions. Yes.
  • Non-patent Document 3 central appetite suppressants
  • sibutramine Non-patent Document 4
  • knee lipase inhibitors such as orlistat. Harmful agents are known.
  • central appetite suppressants side effects such as roar, constipation, stomach discomfort, and sometimes hallucinations and hallucinations, and orlistat (Non-patent Document 5)
  • side effects in the gastrointestinal tract such as diarrhea, incontinence, fatty stool, and feces.
  • the development of effective drugs with fewer side effects is desired.
  • TG ingested by meals is broken down into free fatty acids and monoacylglycerol by the action of bile acids and sputum lipase in the small intestinal lumen.
  • Micelles consisting of free fatty acids, monoacinoleglycerol, and bile acids are absorbed into small intestinal epithelial cells, and in the endoplasmic reticulum, they are asilcoenzyme A synthase (hereinafter referred to as ACS), asilcoenzyme A: monoacyl.
  • ACS asilcoenzyme A synthase
  • TG is newly synthesized by the action of glycerol acyltransferase and DGAT.
  • TG combined with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. In addition, TG is secreted into the blood via the lymphatic duct and transported to the periphery for use.
  • TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acidoletransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 6). . This excessive intake of TG accumulates in adipose tissue, resulting in obesity.
  • DGAT is an enzyme present in the endoplasmic reticulum in the cell.
  • DGAT1 is highly expressed in the small intestine and adipose tissue
  • DGAT2 is highly expressed in the liver and adipose tissue
  • DGAT1 is mainly used for fat absorption and fat accumulation in adipose tissue
  • DGAT2 is used for TG synthesis in the liver. It is also thought to be involved in VLDL (very low density lipoproteins) secretion and fat accumulation in adipose tissue.
  • VLDL very low density lipoproteins
  • DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue
  • a drug that inhibits DGAT suppresses TG synthesis, thereby suppressing fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue, obesity, obesity, hyperlipidemia, hyperTGemia, lipid Metabolic disorders, insulin resistance syndrome, diabetes, or hyperlipidemia caused by obesity, hyperTGemia, dyslipidemia, insulin resistance syndrome, diabetes, hypertension, arteriosclerosis, cerebrovascular disorder, Alternatively, it is expected to be useful as a therapeutic or prophylactic agent for coronary artery disease (Non-patent Documents 13 to 16).
  • Patent Document 1 Japanese Patent Laid-Open No. 2002-306199
  • Patent Document 2 International Publication No. 03/045926 Pamphlet
  • Non-Patent Document 1 Eiji Itagaki, “STEP Metabolism 'Endocrine”, Kaiba Shobo, 1st Edition, 1998, p.105
  • Non-Patent Document 2 Zimmet, P. et al., Nature, 2001, 414, p.782- 787
  • Non-Patent Document 3 Engstrom, R. G. et al "Arch. Intern. Pharmacodyn., 1975, 214, .308-321
  • Non-Patent Document 4 Bray, G.A. et al., Obes. Res., 1996, IV, p.263-270
  • Non-Patent Document 5 Davidson, M. H. et al., The Journal of the American Medical Association, 1999, 281, p.235-242
  • Non-Patent Document 6 Coleman, R "Bell, R., J. Biol. Chem., 1976, No. 251, .4537-4543
  • Non-Patent Document 7 Coleman, R., Methods in Enzymology, 1992, No. 209, .98-104
  • Non-Patent Document 8 Lehner, R., Kuksis, A "Prog. Lipid Res., 1996, 35th, p.169-201
  • Non-Patent Document 9 R. Bell., Ann Rev. Biochem., 1980, 49th, .459-487
  • Non-Patent Document 10 Cases, S. et al, Proc. Natl. Acad. Sci. USA., 1998, 95th, p.13
  • Non-Patent Document 11 Cases, S. et al, J. Biol. Chem., 2001, 276, .38870-38876
  • Non-Patent Document 12 Coleman, RA, Lee, DP, Progress in Lipid Research, 2004 , No. 43, p.134-176
  • Non-Patent Document 13 Smith, S. J. et al., Nat. Genet., 2000, 25th, .87-90
  • Non-Patent Document 14 Chen, HC, J. Clin. Invest., 2002, 109, p.1049-1055
  • Non-Patent Document 15 Buhman, KK, J. Biol. Chem., 2002, 277 , p.25474-25479
  • Non-patent document 16 Gaziano, J., et al "Circulation, 1997, Vol. 96, p.2520-2525
  • Non-patent document 17 Tomoda, H. et al" J. Antibiot. Tokyo), 1995, No. 48, p. 937-941
  • Non-patent literature 18 Yang, DJ et al., J. Antibiot. (Tokyo), 1996, No. 49, p.
  • Non-patent literature 19 Tomoda, H. et al "J. Antibiot. (Tokyo), 1999, 52nd pp. 689-694
  • Non-patent literature 20 Tabata, N. et al., Phytochemistry, 1997, 46th , P.683-687 Disclosure of the Invention
  • urea compounds having a specific chemical structure have an excellent DGAT inhibitory action, particularly a high inhibitory action on DGAT1. It was found to have, the present inventors have found that this urea compound is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetes mellitus).
  • the present invention provides (1) a general formula
  • R 1 represents one group selected from substituent group a and / or one or more groups independently selected from one to four groups independently selected from substituent group b. Select from
  • R 2 is a CC aryl group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b, or a substituent.
  • Group a is a CC aryl group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b, or a substituent.
  • R 3 represents a hydrogen atom, a C 1 -C alkyl group or a halogen atom
  • R 4 represents a hydrogen atom or a C 1 -C alkyl group
  • A is a methylene group, vinylene group, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, or one of the main chain methylene groups is replaced by a vinylene group, oxygen atom, sulfur atom, sulfinyl group or sulfonyl group.
  • Q represents a group represented by the formula —N (Me) — or a sulfur atom
  • the substituent group a is a C—C aryl group which may be substituted with 1 to 3 groups independently selected from the substituent group c, and 1 to 3 groups independently selected from the substituent group c. Substituted with group
  • a substituted group a group of nitrogen-containing heterocyclic groups
  • Substituent group b is a halogen atom, C C alkyl group, C C halogenated alkyl group
  • Substituent group c is a halogen atom, a C—C alkyl group, or a C—C halogenated alkyl group.
  • R 1 is a halogen atom, C —C alkyl group, C —C halogenated alkyl group, CC termination
  • R 1 is fluorine atom, chlorine atom, C-C alkyl group, trifluoromethyl group, C — C
  • 1 4 1 4 Substituted by 1 or 2 groups independently selected from the group consisting of a alkoxy group, a trifluoromethoxy group, and a methylcarbonyl group; may be substituted, substituted, phenyl, or naphthyl groups; 5-membered aromatic heterocycles optionally substituted with 1 or 2 CC alkyl groups
  • a cyclic group or a fused bicyclic heterocyclic group a C C alkyl group; a C C aralkyl group; or
  • a urea derivative which is a C C cycloalkyl group optionally substituted by one phenyl group
  • R 1 is a phenyl group; a phenyl group substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a methinore group, a trifluoromethyl group and a methoxy group; a fluorine atom, a chlorine atom, A phenyl group substituted with two groups independently selected from the group consisting of a methyl group and a methoxy group; a phenyl group; a C 1 -C alkyl group; a C 1 -C aralkyl group; or 1 Urea derivatives which are c-c cycloalkyl groups optionally substituted by 1 phenyl group
  • R 1 is a phenyl group, 2_fluorophenyl group, 3_fluorophenyl group, 2_triphenylolone methylphenyl group, 2,4 difluorophenyl group, 5 fluoro-2-methylphenyl group, 5_chloro_2 _ 2 methoxyphenyl group, 2 methoxy_ group
  • a urea derivative which is 5_methylphenyl group, n-hexyl group, 1_phenylethyl group or 2_phenylcyclopropyl group, or a pharmacologically acceptable salt thereof,
  • R 2 is a halogen atom, C—C alkyl group, C—C halogenated alkyl group, C—C
  • alkylaminocarbonyl group a cyano group, a strong rubamoyl group, a 5 (1H-tetrazolyl) group, and a heterocyclic group optionally substituted with one or two groups independently selected from the group consisting of an oxo group A urea derivative which is a cyclic group or a pharmacologically acceptable salt thereof,
  • R 2 is a halogen atom, c-C alkyl group, C-C halogenated alkyl group, C-C
  • 1 6 1 2 1 6 1 or 2 independently selected from the group consisting of a alkoxy group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, a strong rubamoyl group and a 5_ (1H-tetrazolyl) group Or substituted with 1 or 2 groups independently selected from the group consisting of a halogen atom and an oxo group.
  • R 2 is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group A group independently selected from the group consisting of a sil group, a methoxycarbonyl group, a methylaminocarbonyl group, a force rubamoyl group and a 5_ (1H-tetrazolyl) group; Phenyl groups substituted at the 2- and 4-positions; fluorine atom, chlorine atom, methyl group, trifluoromethyl group, methoxy group, carboxyl group, methoxycarbonyl group, methinoaminocanorepoinore group, force A phenyl group substituted at the 2-position with a group selected from the group consisting of a ruberamoyl group and a 5_ (1H-tetrazolyl) group; a fluorine atom, a chlorine atom, a methyl group, a trifluor
  • R 2 is 2, 6 dichlorophenyl group, 2 carboxy 1-6 chlorophenyl group, 2 chloro 6-methoxycarbonylphenyl group, 2 force rubamoyl-6 chlorophenyl group or 2 chloro-6- [5 (1H-tetrazolyl ]
  • a urea derivative which is a phenyl group or a pharmacologically acceptable salt thereof,
  • a urea derivative in which A is a vinylene group, an ethylene group, a methyleneoxy group or a methylenethio group, or a pharmacologically acceptable salt thereof, (15) In any one item selected from (1) to (12),
  • a urea derivative or a pharmacologically acceptable salt thereof, wherein U is a group represented by the formula CH_,
  • a urea derivative or a pharmacologically acceptable salt thereof, wherein V is a group represented by the formula CH
  • the general formula (I) is the general formula (la), and R 1 is one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group b. C -C optionally substituted
  • C—C aralkyl group optionally substituted with 1 to 4 groups independently selected from 1 group selected from substituent group a and / or independently selected from substituent group b, or 1 C —C
  • R 7 16 6 10 is an optionally substituted C—C cycloalkyl group, and R 2 is selected from the substituent group a.
  • Z or a heterocyclic group which may be substituted with one or two groups independently selected from substituent group b is a hydrogen atom, a C_C alkyl group or a halogen atom, and R
  • A is a hydrogen atom or C 1 -C alkyl group
  • A is a methylene group, vinylene group, oxygen atom
  • substituent group a is substituted with 1 to 3 groups independently selected from substituent group c
  • substituent group c is substituted with 1 to 3 groups independently selected from the CC aryl group and substituent group c.
  • R 1 is fluorine atom, chlorine atom, c-c alkyl group, trifluoromethyl group, C—Ca
  • 1 4 1 4 Substituted by 1 or 2 groups independently selected from the group consisting of a alkoxy group, a trifluoromethoxy group, and a methylcarbonyl group; may be substituted, substituted, phenyl, or naphthyl groups; 5-membered aromatic heterocycle optionally substituted by 1 or 2 C-C alkyl groups
  • a cyclic group or a fused bicyclic heterocyclic group a c-c alkyl group; a c-c aralkyl group; or
  • 1 6 1 2 1 6 independently selected from the group consisting of a group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, a force rubamoyl group and a 5_ (1H-tetrazolyl) group 1 or 2 Substituted with 1 group, or may be substituted with 1 or 2 groups independently selected from the group consisting of a halogen group and an oxo group;
  • the general formula (I) is the general formula (la), and R 1 is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group
  • R 1 is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group
  • R 2 is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a strong rubermoyl group, and a 5- (1H-tetrazolyl) group independently selected from the group consisting of 2 and 6 position, 2 and 5 position, or 2 and 4 position substituted phenyl group; fluorine atom, chlorine 2-position selected from the group consisting of an atom, a methyl group, a trifluoromethyl group, a methoxy group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a force rubamoyl group and a 5- (1H-tetrazolyl) group Is substituted with a phenyl group; a fluorine atom, a chlorine atom, a methyl group,
  • the general formula (I) is the general formula (la), and R 1 is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group
  • R 1 is substituted with one group selected from the group consisting of a phenyl group; a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, and a methoxy group
  • R 2 is 2,6-dichlorophenyl group, 2-carboxy 1-chlorophenyl group, 2_black port _6-methoxycarbophenyl group, 2_force rubamoinole 6_black port A phenyl group or a 2_black opening—6_ [5_ (1H-tetrazolyl)] phenyl group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, and A is a vinylene group or an ethylene group.
  • R 1 is phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 2-trifluoromethylphenyl group, 2, 4-difluorophenyl group, 5-Fenoreolo 2-Methylenophenyl group, 5-Chlorodi-2-methoxyphenyl group, 2-Methoxy-5-methylphenyl group, n-hexyl group, 1-phenylethyl group or 2-phenylcyclopropyl group Yes, R 2 is 2, 6-dichlorophenyl group, 2-carboxy-6-chlorophenyl group, 2-chloro 6-methoxycarbonyl phenyl group, 2-force rubamoyl 6-chlorophenyl group or 2-chloro group 6 — [5— (1H-tetrazolyl)] phenyl group, is a hydrogen atom, R 4 is a hydrogen atom, A is a vinylene group or ethylene
  • a urea derivative represented by or a pharmacologically acceptable salt thereof
  • a urea derivative represented by or a pharmacologically acceptable salt thereof
  • a urea derivative represented by or a pharmacologically acceptable salt thereof
  • a urea derivative represented by or a pharmacologically acceptable salt thereof
  • Asilcoenzyme A diacylglycerol containing the urea derivative or pharmacologically acceptable salt thereof described in any one of (1) to (27) as an active ingredient A syltransferase inhibitor,
  • the pharmaceutical composition is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy , Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, pregnancy diabetes, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases mentioned above and below)
  • arteriosclerosis arteriosclerosis caused by the diseases mentioned above and below
  • Cataract gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases shown above and below), atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder ,
  • arteriosclerosis including arteriosclerosis caused by the diseases shown above and below
  • atherosclerosis including arteriosclerosis caused by the diseases shown above and below
  • diabetic arteriosclerosis hypertension
  • cerebrovascular disorder The pharmaceutical composition according to (30) for the treatment and / or prevention of coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis,
  • the pharmaceutical composition is (30) for the treatment and Z or prevention of obesity, obesity, or hyperlipidemia, hyperTG, diabetes, hypertension or arteriosclerosis caused by obesity.
  • composition is a composition for inhibiting asilcoenzyme A: diacylglycerolsacyltransferase;
  • the pharmaceutical composition is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, Nunsulin resistance syndrome, glucose intolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational glucoseuria, polycyst It is a composition for the treatment and Z or prevention of ovarian syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases described above and below), atherosclerosis or diabetic arteriosclerosis (36 )
  • the pharmaceutical composition is a composition for the treatment and / or prevention of obesity, obesity or hyperlipidemia caused by obesity, hyper-TGemia, diabetes, hypertension or arteriosclerosis (3 6) Use as described in
  • (45) Diseases are obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, sugar Urinary nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases mentioned above and below), The method according to (44), which is atherosclerosis or diabetic arteriosclerosis,
  • the following diseases caused by obesity hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes mellitus, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis caused by the diseases mentioned above and below), atheroma Atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis (44),
  • C_C aryl group means, for example, phenyl, indur or naphthyl.
  • heterocyclic group refers to a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and examples thereof include furyl, chenyl, pyrrolyl, and azepi.
  • “5-membered aromatic heterocyclic group” such as binoyl, pyrazolyl, imidazolinole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3_oxadiazolyl, triazolyl or thiadiazolyl group, biranyl, pyridyl, pyridazinyl, pyrimigel or birazinyl group of Such as ⁇ 6-membered aromatic heterocyclic group '', tetrahydrobiranyl, tetrahydrochenyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl , A “partially or fully reduced
  • C C alkyl group means, for example, methinole, ethyl, propyl, i
  • a hexyl group, and in substituent group b more preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms (C 1 -C alkyl group), and even more preferably methyl.
  • C-C aralkyl group means that one "C-C aralkyl group” is A group bonded to the “C 1 -C alkyl group”, for example, benzyl,
  • Til ⁇ -naphthylmethyl, indenylmethyl, 1_phenylethyl, 2-phenylethyl, 1_naphthylethyl, 2_naphthylethyl, 1_phenylpropyl, 2_phenylpropenore, 3-phenethylpropinore, 1_naphthinole Propinole, 2_Naphthinorepropinole, 3-Naphthylpropyl, 1_Phenylbutyl, 2-Phenylbutyl, 3_Phenylbutyl, 4-Fuenino lebutinore, 1-Naftino lebutinore, 2-Naphtino lebutinore, 3-— Naphthinorebutinore, 4_Naphtylbutyl, 1_Phenylpentyl, 2_Phenylpentyl, 3_
  • 6 10 aryl group is a group (C C aralkyl group) bonded to the above “C C alkyl group”.
  • a benzyl, 1 phenylethyl, 2-phenylethyl or 1 phenylpropyl group and even more preferably a benzyl, 1 phenylethyl or 2-phenylethyl group (C 1 -C aralkyl group), Particularly preferably, 1 phenyl group
  • C 1 -C cycloalkyl group means cyclopropyl, cyclobutyl, silane
  • It is a clopentyl or cyclohexyl group, and is preferably a cyclohexyl group.
  • the “6 10 3 6 alkyl group” may be substituted with one “c -c aryl group”.
  • C cycloalkyl group '' for example, cyclopropyl, cyclobutyl, cyclopentyl
  • Cyclohexyl 2_phenylcyclopropyl, 2_phenylcyclobutyl, 2_phenylcyclopentyl, 2_phenylcyclohexyl, 4_phenylcyclohexyl or 2_naphthylcyclopropyl, preferably It is cyclohexyl or 2_phenylcyclopropyl group, more preferably 2-phenylcyclopropyl group.
  • CC alkyl group means, for example, methyl, ethyl, propyl, iso Propyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2_methylbutyl, neopentyl, 1_ethylpropyl, hexyl, isohexyl, 4 methylenopentyl, 3 methylpentyl, 2 methylpentyl, 1-methylpentyl 3,3_dimethylbutyl, 2,2_dimethylbutyl, 1,1_dimethylbutyl, 1,2_dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1_ethylbutyl or 2-ethylbutyl
  • a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as a group, preferably a straight-chain or branched
  • it is a methyl group or an ethyl group (C 1 -C alkyl group), and even more preferably
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a fluorine atom.
  • C C alkylene group is, for example, an ethylene group, a propylene group, 1
  • 2-Divalent groups formed by the loss of two hydrogen atoms from two different carbon atoms of an aliphatic hydrocarbon having 2 to 4 carbon atoms such as a dimethylethylene group, an ethylethylene group, a trimethylene group or a tetramethylene group
  • a divalent group formed by losing two hydrogen atoms from two different carbon atoms of an aliphatic hydrocarbon having 2 or 3 carbon atoms (“CC alkyl”).
  • the “main chain” of the “methylene group of the main chain” represents the triazole ring of the general formula (I) and R
  • this is a carbon chain excluding the side chain.
  • a C 1 -C alkylene group in which one of the methylene groups in the main chain may be replaced by a vinylene group, an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group”
  • Preferred is an ethylene group, a methyleneoxy group or a methylenethio group
  • An ethylene group or a methylenethio group is an ethylene group or a methylenethio group.
  • the “vinylene group” is a force S including both Z_ conformation and E_ conformation, preferably E_ conformation.
  • the “C—C aryloxy group” means that the “C_C aryl group” is an acid.
  • a group bonded to an elementary atom for example, an aryloxy group having 6 to 10 carbon atoms such as a phenyloxy, induloxy or naphthyloxy group, preferably a phenyl or naphthyloxy group, more preferably , A phenyloxy group.
  • the “nitrogen-containing heterocyclic group” refers to a 4- to 7-membered heterocyclic group containing 1 to 4 nitrogen atoms, such as a tetrazolyl, azetidyl, pyrrolidinyl, piperidinyl, virazolidinyl or piperazinyl group.
  • aromatic heterocyclic group or “partially or fully reduced saturated heterocyclic group”, preferably a tetrazolyl or pyrrolidinyl group, and more preferably a 5 (1H-tetrazolyl) group. Or 1 pyrrolidinyl group.
  • halogen atom represents a group bonded to the “C 1 -c alkyl group”.
  • the “C 1 -C hydroxyalkyl group” has one hydroxyl group as the above “C 1 -C 4 C”.
  • 1 6 1 6 alkyl group represents, for example, hydroxymethyl, hydroxyethyl or hydroxypropyl group, and preferably a single hydroxyl group is a straight chain having 1 to 3 carbon atoms or A group bonded to a branched alkyl group (C 1 -C hydroxyalkyl group), more preferably
  • Hydroxymethyl 2 hydroxyethyl or 3 hydroxypropyl groups, and even more Preferably, it is a hydroxymethyl group.
  • ⁇ 1 6 2 1 6 alkyl group '' represents a group in which two oxygen atoms are bonded to a phosphoryl group, preferably phosphonic acid jetyl ester or phosphonic acid dimethyl ester, more preferably phosphonic acid It is a chill ester.
  • the “C 1 -C alkoxy group” means that the “C 1 -C alkyl group” is oxygen
  • An alkoxy group (C-C alkoxy group), and even more preferably a methoxy group or an ethoxy group.
  • halogen atom represents a group bonded to the “c-c alkoxy group”, for example,
  • the same or different 1 to 5 “halogen atoms” are the above “C”.
  • Preferred is a trifluoromethoxy group.
  • hydroxyethoxy, hydroxypropoxy, dihydroxypropoxy, hydroxybutoxy or dihydroxybutoxy group Preferably, 1 or 2 hydroxyl group is a linear or branched alkoxy group having 2 to 4 carbon atoms.
  • ⁇ 3 6 1 6 Si group '' means that one ⁇ c-c cycloalkyl group '' is bonded to the ⁇ C-c alkoxy group ''.
  • cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, 2-cyclopropylethoxy, 2-cyclobutylethoxy, 1-cyclopropyl Ethoxy, 1-cyclobutylethoxy, 3-cyclopropylpropoxy or 3-cyclobutylpropoxy group preferably one of said “C-C cycloalkyl group” is bonded to said “C-C alkoxy group”
  • one said “C—C cycloalkyl group” is the above “C—C alkoxy”.
  • C—C alkenyloxy group means the above “C 1 -C alkoxy group”.
  • a group having 2 to 6 carbon atoms and having one double bond such as 1-ethroxy, 2_propenyloxy, 1_propenyloxy, 3-butyroxy, 2 —Butuloxy, 1-buturoxy or 5-hexenyloxy group, preferably C—C alkenyloxy group, more preferably 2_propenyloxy
  • the “C—C alkynyloxy group” means the above —C alkoxy group ”.
  • a group having 2 to 6 carbon atoms and having one triple bond such as 1-ethuroxy, 2_propynyloxy, 1_propynyloxy, 3-buturoxy, 2— A butyroxy, 1-butroxy or 5_hexoxy group, preferably a C 1 -C alkynyloxy group, more preferably 2_propynyloxy group
  • (C_C alkoxy)-(C 1 -C alkyl) group represents one of the above "
  • ⁇ c-c alkoxy group '' represents a group bonded to the ⁇ c-c alkyl group '', for example,
  • C 1 -C alkylthio group means one of the above “C 1 -C alkyl group”.
  • a tilthio group (c-c alkylthio group), and even more preferably a methylthio group.
  • C—C alkylcarbonyl group is the above “C—C alkyl group”.
  • C 1 -C alkoxycarbonyl group means the aforementioned —C alkoxy
  • 2 7 1 6 group '' represents a group bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycananol, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, S butoxycarbonyl, t butoxycarbonyl, pentoxycarbonyl, iso Pentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3, 3 dimethylbutoxycarbonyl, 2, 2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl group
  • the "C -C alkoxy group" Cal
  • a group bonded to a bonyl group (c-c alkoxycarbonyl group), more preferably meth
  • a xoxycarbonyl or ethoxycarbonyl group (c-c alkoxycarbonyl group)
  • the “mono_C 1 -C alkylcarbonylamino group” represents one of the above “C
  • -c alkyl group '' represents a group in which a carbonyl group bonded to an amino group is bonded, for example,
  • a group in which a bonded carbonyl group is bonded to an amino group (mono-C C alkylcarbonyl group)
  • acetoamide or ethylcarbonylamino group (mono-C).
  • the “mono-C 1 -C alkylsulfonylamino group” represents one of the above “C
  • -C alkyl group '' represents a group in which a sulfonyl group bonded to an amino group is bonded.
  • Tylsulfonylamino ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, S-butylsulfonylamino, t-butylsulfonylamino, pentylsulfonylamino, Isopentylsulfonylamino, 2-methylbutylsulfonylamino, neopentylsulfonylamino, 1-ethylpropylsulfonylamino, hexylsulfonylamino, isohexylsulfonylamino, 4_methylpentylsulfonylamino, 3_methyl Pentylsulfonylamino, 2_methylpentylsulfonyla
  • a group in which a bonded sulfonyl group is bonded to an amino group (mono-c-c alkylsulfonyl group)
  • Mino group more preferably methylsulfonylamino or ethylsulfonylamino group (mono_c-calkylsulfonylamino group), and even more preferably methylsulfoamino group.
  • the “mono-C 1 -C alkylamino group” means one of the above-mentioned “C 1 -C alkyl groups”.
  • '' Group represents a group bonded to an amino group, for example, methylamino, ethinoreamino, propylamino, isopropylamino, butinoreamino, isobutylamino, s-butylamino, t_butylamino, pentylamino-containing isopentylamino, 2_ Methyl butylamino, neopentylamino, 1_ethylpropylamino, hexylamino, isohexylamino, 4_methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-Dimethinolevinoreamino, 2,2-Dimethinolevinoreamino
  • “14 alkyl group” is a group bonded to an amino group (mono-C C alkylamino group), more suitable
  • the “zie (C C alkyl) amino group” is the same or different two groups
  • -C alkyl group '' represents a group bonded to an amino group, such as dimethylamino
  • Tyramino dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, diisopentylamino, dineopentylamino, dihexylamino
  • N-ethyl-N-methylamino N-methylolene N-propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-isobutyl-1-N-methylamino, N-methyl-1-N-pentylamino, N-isopentinole-N-methyl Tinoleamino, N-ethyl-1-N-propylamino, N-ethyl-1-N-isopropylamino, N_butyl _N-ethylamino, N_ethyl _N-isobutylamino, N_ethyl _N —pentylamino or N_ethyl _N-isopentyl
  • An amino group preferably a group in which two identical or different “C 1 -C alkyl groups” are bonded to an amino group (di-C—
  • N_ (C 1 -C alkyl) _N_ (C 1 -C hydroxyalkyl) amino
  • Group means one“ c-c alkyl group ”and one“ c-c hydroxyalkyl ”.
  • the "Zee (C 1 -C hydroxyalkyl) amino group” is the same or different.
  • C 1 -C hydroxyalkyl groups represent groups bonded to an amino group, for example,
  • a bonded group (di-C—C hydroxyalkylamino group), more preferably di- (2—
  • “mono-C—C alkylaminocarbonyl group” means one “C-C”.
  • -C alkyl group "represents an amino group bonded to a carbonyl group, for example,
  • a group in which the amino group to which the “14 group” is bonded is bonded to the carbonyl group (mono-c-canolenoquinamino)
  • a carbonyl group more preferably a methylaminocarbonyl or ethylaminocarbonyl group (mono-c-c alkylaminocarbonyl group), and even more preferably a methyl group.
  • the "CC aryl group optionally substituted with 1 to 3 groups independently selected from substituent group c" is 1 to 3 independently selected from substituent group c.
  • C C aryl group which may be substituted with, preferably a fluorine atom
  • the “CC aryloxy group which may be substituted with 1 to 3 groups independently selected from substituent group c” is 1 to 3 independently selected from substituent group c.
  • a phenyloxy group which may be substituted at the 2-position, 3-position or 4-position with a group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group or a trifluoromethyl group.
  • the "nitrogen-containing heterocyclic group optionally substituted with one group selected from substituent group c" is substituted with one group selected from substituent group c.
  • a CC group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group Place 1 group selected from the substituent group a and the above-mentioned “C 1 -C aryl group” which may be substituted with 1 to 4 groups independently selected from Z or the substituent group b;
  • a CC group which may be substituted with one group selected from the substituent group a and / or 1 to 4 groups independently selected from the substituent group Place 1 group selected from the substituent group a and the above-mentioned “C 1 -C aryl group” which may be substituted with 1 to 4 groups independently selected from Z or the substituent group b;
  • halogen atom a C—C alkyl group, a C—c halogenated alkyl group, c ⁇
  • a phenyl group which may be substituted with one or two groups independently selected from the group consisting of groups, more preferably a phenyl group; a fluorine atom, a chlorine atom, a methyl group, trifluoromethyl
  • Particularly preferred are phenyl group, 2 fluorophenyl group, 3 fluorophenyl group, 2 trifluoromethylphenyl group, 2, 4 difunoleorhophenylol group, 5 2-methylolene 2-phenyl group, 5-methoxy 2-phenyl group or 2-methoxy-5-methyl phenyl group.
  • R 2 is preferably a halogen atom, a C-C alkyl group, C -C halogenated
  • 2 7 2 7 C 1 -C 8 may be substituted with 1 to 3 groups independently selected from the group consisting of alkylaminocarbonyl group, cyano group, strong rubermoyl group and 5_ (1H-tetrazolyl) group Re
  • halogen atom More preferably a halogen atom, a C—C alkyl group, a C—C halogenated group.
  • a heterocyclic group more preferably a benzyl group, even more preferably a 2-phenyl group, and R 2 is preferably a halogen atom, a CC alkyl group, a carboxy group.
  • 1 or 2 groups independently selected from the group consisting of a syl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group, a strong rubermoyl group and a 5 (1H-tetrazolyl) group.
  • a 6-membered aromatic heterocyclic group or a group force consisting of a halogen atom and an oxo group is a condensed bicyclic heterocyclic group optionally substituted with 1 or 2 groups independently selected, more preferably 3-position substituted with a group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a force rubamoyl group and a 5_ (1H-tetrazolyl) group 2_Pyridinole group, chlorine atom and oxo group independently selected from the group consisting of 1 or 2 groups 1,3_dihydro-1-1-isobenzazofuranyl group, 1-indolyl group Is a 1-indolinyl group, and even more preferably, 3 1-indolyl group, 7 1-indolyl group, 2 oxo 1-indolinino group
  • 1 group selected from the substituent group a and Z or 1 to 4 groups independently selected from the substituent group b represent the above-mentioned ⁇ C 1 -C aralkyl group '' which may be substituted,
  • a benzyl group or a 1-phenylethyl group which may be substituted with 1 to 3 groups independently selected from the group consisting of a mino group, a cyano group, a nitro group and a phenyl group, and more preferred Is a group independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, a hydroxymethyl group, a carboxyl group, an amino group or a nitro group, and the 2-position and the 6-position.
  • a substituted benzinole group a benzyl group substituted at the 2-position with a group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a trifluoromethyl group; or 1 phenyl group More preferably, 2-fluorophenylmethyl group, 2,6 difluorophenylmethyl or 1 phenylethyl group, and particularly preferably 1 phenylethyl group.
  • a group More preferably, 2-fluorophenylmethyl group, 2,6 difluorophenylmethyl or 1 phenylethyl group, and particularly preferably 1 phenylethyl group.
  • preferred general formula (I) is general formula (la).
  • R 1 is preferably a halogen atom, a C 1 -C alkyl group, or a C 1 -C halogen.
  • An optional heterocyclic group c-c alkyl group; halogen atom, C-C alkyl group, c-
  • R 1 is a fluorine atom, a chlorine atom, C
  • a phenyl or naphthyl group optionally substituted with one or two groups independently selected from the group consisting of a methylcarbonyl group; independently one or two C 1 -C 8 alkyl groups
  • 1 4 may be substituted with a kill group, may be 5-membered aromatic heterocyclic group or condensed bicyclic heterocyclic group; c-c alkyl group; c-c aralkyl group; or substituted with 1 phenyl group And
  • R 1 is a phenyl group; a fluorine atom, A phenyl group substituted by one group selected from the group consisting of a chlorine atom, a methyl group, a trifluoromethyl group and a methoxy group; a fluorine atom, a chlorine atom, a methyl group and a methoxy group independently of the group Substituted with two selected groups; phenyl, cenyl; c-c alkyl; c-c aralkyl; or substituted with one phenyl.
  • C 1 -C cycloalkyl group particularly suitable R 1 is phenyl group, 2_fluoro
  • Eninole group 3 _Fluorophenyl group, 2 _Trifluoromethylphenyl group, 2,4-Difunole orophenoleol group, 5-Funoreo port _2 Metino lefinore group, 5 _Chloro port _ 2 Methoxyphenyl group, 2— Methoxy 5-methylphenyl group, n-hexyl group, 1-phenylethyl group or 2-phenylcyclopropyl group.
  • R 2 is preferably a halogen atom, a CC alkyl group, or a CC halogen.
  • a C 1 -C aryl group optionally substituted with 1 to 3 groups independently selected from the group consisting of one (1H-tetrazolyl) group; or a halogen atom, C—C alkyl group, C —C group
  • a rubonyl group a mono-c-c alkylaminocarbonyl group, a cyano group, a strong rubermoyl group,
  • a 5- (1H-tetrazolyl) group and a heterocyclic group which may be substituted with 1 or 2 groups independently selected from the group consisting of an oxo group, and more preferably R 2 is a halogen atom, C ⁇ C alkyl group, C—C halogenated alkyl group, C—C alkoxy group, carboxynole
  • R 2 is a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group; , 2- and 6-positions, 2- and 5-positions independently selected from the group consisting of a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a strong rubamoyl group and a 5_ (1H_tetrazolyl) group, Or phenyl group substituted at the 2-position and 4-position; fluorine atom, chlorine atom, methyl group, trifluoro
  • preferred R 3 is a hydrogen atom.
  • R 4 is preferably a hydrogen atom.
  • A is preferably a vinylene group or a C C alkylene group in which one of the methylene groups of the main chain may be replaced with a vinylene group, an oxygen atom or a sulfur atom.
  • More preferred A is a vinylene group, ethylene group, methyleneoxy group or methylenethio group, and even more preferred A is a vinylene group, ethylene group or methylenethio group, and particularly preferred A is a vinylene group or ethylene group. is there.
  • preferred Q is a group represented by the formula 1 N (Me) —.
  • preferred T is a nitrogen atom.
  • the "pharmacologically acceptable salt” means that the urea derivative having the general formula (I) of the present invention is reacted with an acid when it has a basic group such as an amino group.
  • an acidic group such as a carboxyl group, it can be converted into a salt by reacting with a base, so that salt is shown.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrates, perchlorates, Sulfate, phosphate, etc.
  • Inorganic acid salts C-C alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfate
  • Organic acid salts such as aryl sulfonates such as phosphates, acetates, malates, fumarate, succinates, succinates, ascorbates, tartrates, succinates, maleates; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
  • aryl sulfonates such as phosphates, acetates, malates, fumarate, succinates, succinates, ascorbates, tartrates, succinates, maleates
  • amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.
  • examples of the salt based on an acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and iron salt.
  • Metal salts such as ammonium salt, toctylamine salt, dibenzylamine salt, morpholine salt, darcosamine salt, phenyldaricin alkyl ester salt, ethylenediamine salt, N-methyldarcamamine salt, guanidine salt, jetylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammoni Um salt, tris (hydroxymethyl) aminomethane salt
  • Such amine salts such as organic salts; and, glycine salts, lysine salts, arg
  • the urea derivative having the general formula (I) or the pharmacologically acceptable salt thereof of the present invention absorbs moisture by leaving it in the atmosphere or by recrystallization, and is attached with adsorbed water.
  • the hydrate is also included in the salt of the present invention.
  • the urea derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb some other solvent to form a solvate, and such a solvate.
  • a solvate may be also included in the salts of the present invention.
  • i_Pr i—propyl group
  • NMe a group represented by the formula NMe.

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Abstract

Dérivés de l’urée ayant une excellente activité d’inhibition des DGAT ou de leurs sels pharmacologiquement acceptables, à savoir, les dérivés de l’urée représentés par la formule générale (I) ou leurs sels pharmacologiquement acceptable : dans laquelle R1 est un aryle en C6 à C10 qui peut être substitué par un membre sélectionné dans le groupe (a) des substituants et/ou de un à quatre membres indépendamment sélectionnés dans le groupe (b) des substituants, ou similaires ; R2 est un aryle C6-10 qui peut être substitué par un membre sélectionné dans le groupe (a) des substituants et/ou de un à quatre membres sélectionnés indépendamment dans le groupe (b) des substituants, ou similaires ; R3 et R4 sont chacun indépendamment de l’hydrogène ou similaire ; A est un alkylène en C2 à C4 où l’un des groupes de méthylène constituant la chaîne principale peut être remplacé par du vinylène, de l’oxygène, du sulfure, du sulfinyl, ou du sulfonyl, ou similaires ; Q est -N(Me)- ou un sulfure; T est =CH- ou de l’azote ; et U et V sont chacun indépendamment =CH- ou similaires.
PCT/JP2005/014633 2004-08-16 2005-08-10 Urées de substitution Ceased WO2006019020A1 (fr)

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US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
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US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
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US7749997B2 (en) 2005-12-22 2010-07-06 Astrazeneca Ab Pyrimido [4,5-B] -Oxazines for use as DGAT inhibitors
US8017603B2 (en) 2005-12-22 2011-09-13 Astrazeneca Ab Pyrimido [4,5-B]-oxazines for use as DGAT inhibitors
CN101415683B (zh) * 2006-03-31 2013-07-17 诺瓦提斯公司 新化合物
EP2301923A1 (fr) 2006-03-31 2011-03-30 Novartis AG Nouveaux composés
EP2402317A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteur de la DGAT
JP2009532355A (ja) * 2006-03-31 2009-09-10 ノバルティス アクチエンゲゼルシャフト 新規化合物
EP2402320A1 (fr) 2006-03-31 2012-01-04 Novartis AG Agents anorectiques
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US8835451B2 (en) 2006-03-31 2014-09-16 Novartis Ag Compounds
EP2402318A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2402319A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2418202A1 (fr) 2006-03-31 2012-02-15 Novartis AG Nouveaux composés
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EP2404905A1 (fr) 2006-03-31 2012-01-11 Novartis AG Nouveaux composés
WO2007126957A2 (fr) 2006-03-31 2007-11-08 Novartis Ag Nouveaux composés
WO2007137103A3 (fr) * 2006-05-19 2008-01-24 Abbott Lab Inhibiteurs de l'enzyme diacylglycérol o-acyltransférase de type 1
WO2007137107A3 (fr) * 2006-05-19 2008-01-10 Abbott Lab Inhibiteurs de l'enzyme diacylglycerol o-acyltransférase de type 1
US8003676B2 (en) 2006-05-30 2011-08-23 Astrazeneca Ab 1,3,4-oxadiazole derivatives as DGAT1 inhibitors
US8084478B2 (en) 2006-05-30 2011-12-27 Asstrazeneca Ab Substituted 5- phenylamino- 1, 3, 4-oxadiazol-2-ylcarbonylamino-4-phenoxy-cyclohexane carboxylic acid as inhibitors of acetyl coenzyme A diacylglycerol acyltransferase
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
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US8304448B2 (en) 2006-09-27 2012-11-06 Korea Research Institute Of Bioscience And Biotechnology Method for the treatment of metabolic disorder containing benzazole derivatives as an active ingredient
JP2010526781A (ja) * 2007-04-30 2010-08-05 アボット・ラボラトリーズ ジアシルグリセロールｏ−アシル転移酵素１型酵素の阻害剤
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US8735425B2 (en) 2008-03-26 2014-05-27 Daiichi Sankyo Company, Limited Tetrahydroisoquinoline derivative
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US8324241B2 (en) 2008-04-11 2012-12-04 Bristol-Myers Squibb Company Triazolo compounds useful as DGAT1 inhibitors
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WO2010111665A1 (fr) 2009-03-27 2010-09-30 Bristol-Myers Squibb Company Procédés destinés à prévenir des événements cardiovasculaires indésirables majeurs par des inhibiteurs de la dpp-iv
US8188092B2 (en) 2009-06-19 2012-05-29 Astrazeneca Ab Substituted pyrazines as DGAT-1 inhibitors
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011055289A2 (fr) 2009-11-05 2011-05-12 Piramal Life Sciences Limited Composés hétéroaryle en tant qu'inhibiteurs de dgat-1
WO2011123401A1 (fr) 2010-03-30 2011-10-06 Novartis Ag Utilisations d'inhibiteurs de dgat1
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