Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
  • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/12—Ophthalmic agents for cataracts
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a pharmaceutical comprising, as an active ingredient, a urea derivative having a specific chemical structure having an excellent anti-feeding action or a pharmacologically acceptable salt thereof.
• Non-Patent Document 1 Non-Patent Document 2
• the increase in obesity patients has led to an increase in the prevalence of these diseases and has had a major impact on the medical economy.
• Obesity is a state in which surplus energy is stored in adipose tissue because the energy consumed is greater than the energy consumed, which is excessive. Therefore, for the treatment of obesity, it is necessary to reduce energy intake or improve energy consumption. Dietary restrictions and exercise recommendations often do not give sufficient results!
• Non-patent Document 3 mazindol
• sibutramine Non-patent Document 4
• Non-patent Document 5 Non-patent Document 5
• roar constipation
• stomach discomfort sometimes hallucinations
• visual hallucinations May have side effects in the gastrointestinal tract such as diarrhea, incontinence, fatty stool, and defecation, and the development of a more powerful and less adverse drug is desired.
• active research and development aimed at developing new anti-obesity drugs, many of which are appetite suppressants.
• An appetite suppressant is a force that directly or indirectly regulates the appetite control system. Its mechanism of action is roughly classified into central and peripheral.
• a centrally acting appetite suppressant is a hypothalamic nervous system in the presence of the feeding and satiety centers and the brain monoa that regulates the nervous system It acts on the minced nervous system and directly suppresses appetite.
• the appetite suppressant acting on the periphery acts on the mechanism that senses and transmits the intake of nutrients and the accumulation of surplus energy, and indirectly suppresses appetite.
• Patent Document 1 Japanese Patent Document 1
• Patent Document 2 Japanese Patent Document 2
• Patent Document 1 WO2005Z072740
• Patent Document 2 EP 1411881
• Patent Document 3 Pamphlet of International Publication No. 03Z045926
• Non-patent document 1 Allison, DB et al., JAMA., 1999, 282, p. 1530-1538
• Non-patent document 2 Kral, JG et al., Surg. Clin. North Am "2001, 81st, p.1039-10 61
• Non-Patent Document 3 Engstrom, R. G. et al., Arch. Intern. Pharmacodyn., 1975, 214, p.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 Strader, AD et al., Gastroenterology, 2005, No. 128, p.175-191
• Non-patent Reference 7 Campfield, A. et al., Science, 1995, No. 269, p .546- 549 Disclosure of the Invention
• urea compounds having a specific chemical structure have an excellent antifeeding effect.
• this urea compound is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, complications of diabetes (diabetes mellitus).
• the urea derivative of the present invention has an anti-feeding action and is considered useful as a novel therapeutic agent for obesity and related diseases.
• the present invention relates to (1) the general formula (I)
• R 1 is selected from a C 1 -C alkyl group, a C—C cycloalkyl group, and a substituent group a.
• a C 1 -C aryl group or a substituent group a which may be independently substituted with 1 to 5 groups
• a heterocyclic group which may be independently substituted with 1 to 3 groups independently of the selected group;
• R 2 is a group selected from a hydrogen atom, a C—C alkyl group, and a substituent group a.
• a C 1 -C aralkyl group or a C-C alkyl group which may be independently substituted with 1 to 3 heterocyclic groups optionally substituted with 1 to 3 groups independently selected from the substituent group a.
• E represents a group having the formula ( ⁇ ), formula (III), formula (XXXIX) or formula (XL)
• R 3 represents a hydrogen atom, a C—C alkyl group, a halogen atom or a cyano group
• R 4 represents a hydrogen atom or a C 1 -C alkyl group
• R 5 represents a hydrogen atom or a C 1 -C alkyl group
• 1 6 1 6 represents a group
• X and U are the same or different and represent a group represented by the formula CH or a nitrogen atom
• m and n are the same or different and represent an integer of 1 or 2.
• the X side of the group having the formula ( ⁇ ) and the nitrogen atom side of the group having the formula ( ⁇ ), formula (XXXIX) and formula (XL) are the same as A of the compound represented by the general formula (I).
• the carbon atom side of the aromatic ring of the group having the formula ( ⁇ ), formula (III), formula (XXXIX) and formula (XL) is bonded to the nitrogen atom of the compound represented by the general formula (I) .
• R 4 and R 5 may be bonded to different carbon atoms or bonded to the same carbon atom. May be combined. )
• R 2 represents a hydrogen atom and A represents a single bond
• Substituent group a is a halogen atom, C C alkyl group, C C halogenated alkyl group
• Lamino group mono-C-C alkylamino group, di- (C-C alkyl) amino group, N- (
• Nitrogen-containing heterocyclic group which may be substituted by 1 amino group, cyano group, nitro group or hydroxy group, 1 to 3 groups independently selected from substituent group b 1 to 3 groups each independently substituted with a group selected from C aryl group and substituent group b.
• Substituent group b is a halogen atom, C 1 -C alkyl group or C 1 -C alkyl halide
• a group consisting of groups is shown. ] An eating inhibitor and a Z or appetite suppressant containing a urea derivative having a salt or a pharmacologically acceptable salt thereof as an active ingredient.
• R 1 is selected from the group consisting of a halogen atom, a C—C alkyl group and a C 1 -C alkoxy group.
• a phenyl group independently substituted with 1 to 3 groups selected by the selected group, or a C-C alkyl group.
• R 1 is 2 fluorophenol group, 2-methoxyphenol group, 5 black 2 ethoxyphenol group, 2-methoxy-5-methylphenol group, 2, 3 dimethoxyphenol group, 4,5 dimethylamine 2
• R 1 is 2 fluorophenyl group, 2 ethoxyphenyl group, 3 ethoxyphenyl group, 5—fluoro-2-methoxyphenyl group, 2 ethoxy-5 fluorophenyl group, 5 chlorophenol —2-methoxyphenyl group 5
• Urea derivatives that are 2 ethoxyphenyl groups, 2-methoxy-1-5-methylphenol groups, or 3,5-dimethoxymethylphenol groups, or pharmaceutically acceptable salts thereof as active ingredients Contains antifeedant and Z or appetite suppressant.
• R 2 is a nitrogen atom, CC alkyl group, CC halogenated alkyl group, CC
• a urea derivative or a pharmacologically acceptable salt thereof which is a phenyl group or a pyridyl group, which may be substituted by 3 or more.
• R 2 is 2—black mouth 6-methyl phenol, 2—black mouth 4— (2-hydroxyethoxy) phenyl, 2 black mouth 4— (2,3 dihydroxypropoxy) far 4-amino-2-chlorophenyl, 4-hydroxymethyl-2-methylphenyl, 4- (2-hydroxyethoxy) -2 trifluoromethylphenol or 4- (2,3 dihydroxypropoxy ) —
• An antifeedant and Z or appetite suppressant containing urea derivatives which are 2-trifluoromethylphenol groups or pharmacologically acceptable salts thereof as active ingredients.
• R 2 is 2-chloro 1- 2— (2-hydroxyethoxy) phenyl group, 2-chloro 1-phenyl group, 4- (2-hydroxyethoxy) 2— Trifluoromethyl phenol group, 2-chloro mouth 4— (2,3 dihydroxypropoxy) phenol group, 4 -— (2,3 dihydroxypropoxy) one 2-trifluoromethyl phenol group, 2 Oral depressant and Z or food containing urea derivatives or pharmacologically acceptable salts thereof as an active ingredient, 5— (2,3 dihydroxypropoxy) phenol group or 3-methyl-2-pyridyl group Greedy suppressant.
• E is a group having the above formula ( ⁇ ), R 3 is a hydrogen atom or a chlorine atom, R 4 is a hydrogen atom, R 5 is a hydrogen atom, X is a nitrogen atom, m and n
• An antifeedant and Z or appetite suppressant containing as an active ingredient a urea derivative or a pharmacologically acceptable salt thereof wherein E is a group having the above formula (III).
• R 1 is selected from the group consisting of a halogen atom, a C—C alkyl group and a C—C alkoxy group.
• a phenyl group independently substituted with 1 to 3 groups selected by the selected group, or a C-C alkyl group.
• R 2 is a halogen atom, a C—C alkyl group, C
• the group force is also selected from a group independently selected from 1 to 3 Is a pyridyl group and E is a group having the formula (IV)
• R 1 is 2 fluorophenol group, 2-methoxyphenyl group, 5 black 2 ethoxyphenol group, 2-methoxy-5-methylphenol group, 2,3 dimethoxyphenyl group, 4,5 dimethyl 2 Thiazolyl group or 2-methoxy-3-pyridyl group
• R 2 is 2-chloro 6-methyl phenol, 2-chloro mono 4-(2-hydroxyethoxy) phenol, 2-cyclo 4- — (2,3 dihydroxypropoxy) phenol group, 4 amino-2 chlorophenol group, 4 hydroxymethyl-2-methylphenol group, 4- (2 hydroxyethoxy) 2 trifluoromethylphenol A group or 4 (2,3 dihydroxypropoxy) 2 trifluoromethylphenol group
• E is a group having the formula (IV)
• U is a group represented by the formula CH
• R 1 is a halogen atom, C—C alkyl group, C—C halogenated alkyl group, C—C
• R 2 is a halogen atom, C—C alkyl
• E is a group having the formula (IV) or a group having the formula (XL), and U is a group represented by the formula CH or a nitrogen atom.
• R 1 is selected from the group consisting of a halogen atom, a C—C alkyl group and a C—C alkoxy group.
• R 2 is a halogen atom, C—C
• R 1 is a fluorine group, a chlorine atom, a methyl group, a methoxy group, and a group force that is selected from the group forces of ethoxy group, a phenyl group substituted at the 2-position or 3-position; a fluorine atom, a chlorine atom, a methyl group, Methoxy group and ethoxy group group power is a group selected by independently substituting two 2-, 3-, or 5-positions for a phenyl group; or 5-methyl-2 thiazolyl group, R 2 Is a group consisting of a group consisting of a fluorine atom, a chlorine atom, a methyl group and a trifluoromethyl group, which is substituted at the 2-position with a selected group, and further comprising a group consisting of a 2-hydroxyethoxy group and a 2,3-dihydroxypropoxy group.
• the 4- or 5-position is substituted with a selected group, a phenyl group; a 3 methyl 2 pyridyl group; a 3-cyano 2 pyridyl group; or a 3, 5 diphf Luoro 2-pyridyl group
• E is a group having the formula (IV)
• U is a group represented by the formula CH or a nitrogen atom
• R 1 is 2 fluorophenyl group, 2 ethoxyphenyl group, 3 ethoxyphenyl group, 5—fluoro-2-methoxyphenyl group, 2 ethoxy-5 fluorophenyl group, 5 chlorophenol —2-methoxyphenyl group , 5 chlorophenol, 2-methoxyphenyl, 2-methoxy-1-methylphenol, or 3,5-dimethoxymethylphenol
• R 2 is chlorobenzene— 4— (2-hydroxyethoxy) 2- (2-hydroxyethoxy) phenol group, 4- (2-hydroxyethoxy) 2-trifluoromethylphenol group, 2-chloro-monophenyl group— 2,3 dihydroxypropoxy) phenol group, 4 (2,3 dihydroxypropoxy) 2 —trifluoromethylphenol group, 2 chloromethyl 5— (2,3 dihydroxypropoxy) phenol group or 3 —Methyl-2-pyridyl group
• E is a group having the formula (IV)
• U is a group represented
• An antifeedant and Z or appetite suppressant comprising the urea derivative according to (1) or a pharmacologically acceptable salt thereof as an active ingredient.
• An antifeedant and Z or appetite suppressant comprising the urea derivative or the pharmacologically acceptable salt thereof according to (1) as an active ingredient.
• the pharmaceutical composition is obesity, obesity, hyperlipidemia, hyperTGemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral nerve Disorders, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases listed above and below)
• a pharmaceutical composition comprising obesity, obesity, or the treatment and Z or prevention of hyperlipidemia, hyperTG, diabetes, hypertension or arteriosclerosis caused by obesity (31) Use.
• the disease 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, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (including arteriosclerosis due to the diseases mentioned above and below), (36) The method according to (36), wherein the method is atherosclerosis or diabetic arteriosclerosis.
• the following diseases are caused by obesity: hyperlipidemia, hyperTGemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic complications) Neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, polycystic ovary syndrome, arteriosclerosis (arteriosclerosis caused by the diseases mentioned above and below) Atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis (36 ) Method.
• C—C alkyl group means a straight or branched chain having 1 to 10 carbon atoms.
• alkyl group For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 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, 2-ethylbutyl, heptyl , An octyl, nonyl or decyl group, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (C 1 -
• a linear or branched alkyl group having 1 to 4 carbon atoms (C 1 -C alkyl group) is more preferable, and a methyl group or ethyl is more preferable.
• C 1 -C alkyl group a linear or branched alkyl group having 1 to 4 carbon atoms
• a methyl group or ethyl is more preferable.
• C 1 -C cycloalkyl group means cyclopropyl, cyclobutyl, silane
• It is a clopentyl or cyclohexyl group, and is preferably a cyclohexyl group.
• the “C—C alkyl group” means a straight or branched chain alkyl group having 1 to 6 carbon atoms. It is an alkyl group.
• a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sbutyl, t-butyl, pentyl or hexyl group preferably a linear or branched alkyl group having 1 to 4 carbon atoms ( C 2 -C alkyl group), and in R 2 ,
• R 3 , R 4 , R 5 or substituent group b More preferably, it is a t-butyl group, and in R 3 , R 4 , R 5 or substituent group b, more preferably, a linear or branched alkyl group having 1 to 4 carbon atoms (CC alkyl group). Group) and
• a methyl group or an ethyl group (C—C alkyl group), and particularly preferably
• the “1 6 3 6 alkyl group” is the above “optionally substituted“ c group ”.
• cyclohexyl 2-methylcyclopropyl, 2-methylcyclobutyl, 2-methylcyclopentyl, 2-methylcyclohexyl or 4-methylcyclohexyl, and preferably 2-methylcyclohexyl.
• C—C bicycloalkyl group means two or more having 7 to 10 carbon atoms.
• the “tetralyl group” is a 5, 6, 7, 8-tetrahydronaphthyl group. Preferred is a 5-tetralyl group.
• the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred are a fluorine atom, a chlorine atom or a bromine atom, and more preferred is a fluorine atom or a chlorine atom.
• the “C 1 -C 6 halogenated alkyl group” is 1 to 5 identical or different.
• halogen atom is bonded to the “c alkyl group”.
• the same or different 1 to 5 “halogen atoms” are bonded to the “C—C alkyl group” (C—C halogenated group). More preferably, a group (CC halogenoalkyl group) in which 1 to 5 of the same or different “norogen atoms” are bonded to the “CC alkyl group”.
• C 1 -C hydroxyalkyl group means that one hydroxyl group is the above-mentioned “C 1 -C hydroxy group”.
• a hydroxymethyl, hydroxyethyl, or hydroxypropyl group preferably a group in which one hydroxyl group is bonded to a linear or branched alkyl group having 1 to 3 carbon atoms (C 1 -C hydroxy group).
• Alkyl group more preferably
• “1 6 2 1 6 alkyl group” is a group in which two oxygen atoms bonded to a phosphoryl group are bonded. Preferred is phosphonic acid jetyl ester or phosphonic acid dimethyl ester, and more preferred is phosphonic acid jetyl ester.
• methyl phosphonate methyl ester or ethyl phosphonate ester ethyl ester Preferred is methyl phosphonate methyl ester or ethyl phosphonate ester ethyl ester, and more preferred is phosphonic acid ethyl ester methyl ester.
• C C alkoxy group means that the “C C alkyl group” is oxygen
• a group bonded to an atom which is a linear or branched alkoxy group having 1 to 10 carbon atoms
• methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, S-butoxy, t-butoxy, pentoxy, 2-methylbutoxy, 2-ethylpropoxy, heptyloxy, octyloxy, noroxy or decyloxy groups suitable Is a linear or branched alkoxy group having 1 to 6 carbon atoms (CC alkoxy group), and more
• it is a linear or branched alkoxy group having 1 to 4 carbon atoms (C—C alkoxy group)
• Particularly preferred is a methoxy group.
• the “C 1 -C halogenated alkoxy group” is 1 to 5 identical or different.
• halogen atom is bonded to the “c-c alkoxy group”.
• Rifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy or fluoromethoxy group, and preferably the same or different 1 to 5 "halogen atoms" are the "C-C alkoxy groups” Group attached to (C—C halogenial
• 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 or 1-cyclopropylethoxy group suitable Is a group in which one “C 1 -C cycloalkyl group” is bonded to the above “C 1 -C alkoxy group”.
• one said “c—C cycloalkyl group” is the above “C—C alkoxy group”.
• the “C 1 -C alkoxy group” is the above “C—C alkoxy group”.
• a group having 2 to 6 carbon atoms and having one double bond For example, 1-ethenyloxy, 2-propenyloxy, 1-propenyloxy, 3-butenyloxy, or 2-butyroxy group, preferably C-C alkenyloxy group.
• the “C—C alkyloxy group” means the “C—C alkoxy group”.
• the group having 2 to 6 carbon atoms and having one triple bond For example , 1-ethynyloxy, 2 propynyloxy, 1 propynyloxy, 3 butyninoreoxy or 2-butyroxy group, preferably CC alkyloxy group
• (C—C alkoxy) mono (C—C alkyl) group means one of the above “
• a “C—C alkoxy group” is a group bonded to the “C—C alkyl group”. For example, Meto
• one said “c—C alkoxy group” is the above “C—C alkyl group”.
• C C alkylthio group means one of the above “C C alkyl group”
• methylthio, ethylthio, propylthio, isopropylthio, isopropylthio, isobutylthio, sbutylthio, t-butylthio, pentylthio, 2-methylptylthio or neopentylthio group preferably a straight chain having 1 to 4 carbon atoms Or a branched chain alkylthio group (C 1 -C alkylthio group), more preferably methylthio group.
• a ethylthio group (c-c alkylthio group), and even more preferably, methyl
• the “C 1 -C alkoxycarbonyl group” is the above “C—C alkoxy group”.
• a “group” is a group bonded to a carbo group.
• the “mono-C 1 -C alkyl carbo-lumino group” represents one of the above “C
• a carbo group to which a “C alkyl group” is bonded is a group bonded to an amino group.
• Bound to amino group
• Is an ethylcarbonylamino group (mono-C-C alkylcarbonylamino group).
• the "mono-C-C alkylsulfo-lumino group” represents one of the above "C
• a sulfo group having a —C alkyl group is a group bonded to an amino group.
• one sulfo group to which the above-mentioned “c-C alkyl group” is bonded is an amino group.
• a bonded group (mono-C-C alkylsulfonylamino group), more preferably methyl
• Mino group and more preferably a methylsulfonylamino group.
• “mono-C—C alkylamino group” means one “C—C alkyl group”.
• “1 6 1 6 group” is a group bonded to an amino group.
• a methylamino-containing propylamino-containing isopropylamino or butylamino group preferably one of the above-mentioned “C—C” groups.
• ⁇ 14 alkyl group '' is a group bonded to an amino group (mono-C-C alkylamino group), more preferable
• the “di- (C—C alkyl) amino group” is the same or different two groups
• the “C—C alkyl group” is a group bonded to an amino group.
• Group means one“ c C alkyl group ”and one“ C—C hydroxyalkyl ”.
• Group " is a group bonded to an amino group.
• N- (2-hydroxyethyl) -N-methylamino-containing N- (3-hydroxypropyl) N-methylamino-containing N-ethyl-N- (2 hydroxyethyl) amino, N-ethyl N- (3 hydroxypropyl) amino N— (2 hydroxyethyl) N propylamino or N— (3 hydroxypropyl) -N propylamino groups preferably one said “CC alkyl group” and one
• the "Zee (C 1 -C hydroxyalkyl) amino group” is the same or different.
• the two “C—C hydroxyalkyl groups” are groups bonded to an amino group.
• C—C hydroxyalkyl groups are groups bonded to an amino group.
• Di (2hydroxyethyl) amino di (3hydroxypropyl) amidi (2hydroxypropyl) amidi (4-hydroxybutyl) amidi (5-hydroxypentyl) amino Di- (6-hydroxyhexyl) amino-containing N— (2 hydroxyethyl) N— (3-hydroxypropyl) amino-containing N— (2-hydroxyethyl) N— (2-hydroxypropyl) amino or N— (4 hydroxybutyl) -N- (2 hydroxyethyl) amino group, and preferably two of the same or different “C 1 -C hydroxyalkyl groups” are the amino groups.
• the "nitrogen-containing heterocyclic group” is a 4- to 7-membered heterocyclic group containing 1 or 2 nitrogen atoms.
• “partially or fully reduced saturated heterocyclic group” such as azetidyl, pyrrolidyl, piperidyl, bisazolyl or piperazyl group, preferably pyrrolidyl group.
• the “nitrogen-containing heterocyclic group which may be substituted by one hydroxy group” may be the above-mentioned “nitrogen-containing heterocycle which may be substituted by one hydroxy group”. "Base”.
• a 3-hydroxy-1-azetidinyl group a 3-hydroxy-1-pyrrolidinyl group, a 4-hydroxy-1-piperidyl group, or a 3-hydroxy-1-piperazyl group, and preferably a 3-hydroxy-1-pyrrolidyl group.
• C—C aryl group means an aromatic hydrocarbon having 6 to 10 carbon atoms.
• a phenyl group or a naphthyl group is preferable, and a phenyl group is more preferable.
• a C—C aryl group which may be independently substituted with 1 to 3 groups selected from the substituent group b is independently a group selected from the substituent group b. 1 to 3
• the “C—C aryl group” may be substituted.
• fluorine atom preferably, chlorine
• a phenyl group may be substituted by one of the 2-position, 3-position or 4-position with an atom, bromine atom, methyl group, ethyl group or trifluoromethyl group.
• the “C—C aryloxy group” means that the “C—C aryl group” is an acid.
• It is a group bonded to an elementary atom, and is an aryloxy group having 6 to 10 carbon atoms. Preferred is a phenoxy group or a naphthyloxy group, and more preferred is a phenoxy group.
• the “C—C aroxy group optionally substituted by 1 to 3 groups independently selected from the substituent group b” is independently selected from the group selected from the substituent group b. 1 to
• the “C—C aryloxy group” may be substituted by three.
• fluorine preferably, fluorine
• a 2-, 3-, or 4-position is substituted with an atom, chlorine atom, bromine atom, methyl group, ethyl group, or trifluoromethyl group, or a phenoxy group.
• the hydroxy group is a group bonded to the “C—C alkyl group”.
• C—C alkyl group more preferably 2, 3 dihydroxy group.
• C C alkyl group monosubstituted with a carboxyl group means one force.
• a lupoxyl group is a group bonded to the “C—C alkyl group”.
• the hydroxyl is a group bonded to the “C—C alkyl group”.
• the hydroxyl is a group bonded to the “C—C alkyl group”.
• It is a carboxymethyl group or a hydroxy carboruethyl group, and more preferably a hydroxy carbomethyl group.
• C—C alkyl substituted with a C—C alkoxycarbo group is used.
• the “heterocyclic group” is a 4- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms, or Z and nitrogen atoms.
• benzothiazolyl, benzoxazolyl, dihydrobenzofuryl, quinolyl, or quinazolyl group preferably an aromatic heterocyclic group or a fused bicyclic heteroaryl group, more preferably pyridyl, thiazolyl, benzo O hexa benzisoxazolyl or dihydro base Nzofuriru group, in R 1 is further preferably more, a 2-thiazolyl group or a 3-pyridyl group, in R 2 is even more favorable In is a 2-pyridyl group.
• C—C aralkyl group means that one “C—C aralkyl group” is
• a group preferably one of the “C—C aryl group” bonded to the “C—C alkyl group”, and more preferably,
• a C—C aryl group which may be independently substituted with 1 to 5 groups selected from the substituent group a is independently 1 to 5 groups selected from the substituent group a.
• the “C—C aryl group” may be substituted.
• R 1 preferably
• a substituted phenyl group and even more preferably a fluorine atom, a chlorine atom, a methyl group, a methoxy group, and an ethoxy group.
• R 2 is preferably a halogen atom, C—C alkyl.
• a halogen atom a C C alkyl group, a C—C halogenated alkyl group, a C—C hydroxyalkyl group, a hydro group.
• amino group and cyano group substituted by 1 or 2 with xoxy group Is also a phenyl group which may be independently substituted with 1 to 3 groups selected, and even more preferably, a group force having a fluorine atom, a chlorine atom, a methyl group and a trifluoromethyl group force.
• the 2-position is substituted with a selected group, and the 4-position with a group selected from the group consisting of a methyl group, a hydroxymethyl group, a 2-hydroxyethoxy group, a 2,3-dihydroxypropoxy group, and an amino group.
• a heterocyclic group which may be independently substituted with a group selected from substituent group a is independently substituted with 1 to 3 groups independently selected from substituent group a.
• the above-mentioned “heterocyclic group” may be used.
• R 1 is preferably a methyl group, an ethyl group, a t-butyl group and a cyclopropyl group.
• the group force is one or two independently substituted with a selected group, and may be a 2-thiazolyl group; or methoxy A 2-substituted pyridyl group, a 3-pyridyl group or a 4-pyridyl group, even more preferably a 5-methyl-2-thiazolyl group or a 2-methoxy-3-pyridyl group, and R 2 Is preferably a fluorine atom, a chlorine atom Group power of methyl group, trifluoromethyl group, hydroxymethyl group, carboxyl group and cyano group Power group selected 1 or 2 independently substituted with 2 pyridyl group, 3 pyridyl group or 4 pyridyl group More preferably, a 2-pyridyl group or fluorine substituted with a group selected from the group power consisting of a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a hydroxymethyl group and a cyano
• the "C-C aralkyl group which may be independently substituted with 1 to 3 groups selected from the substituent group a" independently represents a group selected from the substituent group a. 1 to 3
• Group, nitro group, and phenoxy group are also selected benzyl groups that may be independently substituted with 1 to 3 groups, more preferably 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 benzyl group substituted at the 2-position and the 6-position; or a fluorine atom, a chlorine atom, a bromine atom, a methyl group Alternatively, it is a benzyl group substituted at the 2-position with a trifluoromethyl group, and more preferably a 2-fluorophenylmethyl group or a 2,6-difluorophenylmethyl.
• A represents a single bond
• group R 2 —A—E force ⁇ group R 2 —E ”.
• R 1 is preferably a halogen atom, a C—C alkyl group, or a C—C halogen.
• R 1 6 independently 1 or 2 is substituted with a group
• Ru is a pyridyl group
• R 1 is a group selected from the group consisting of halogen atom, C-C alkyl group and C-C alkoxy group Independent
• a thiazolyl group or a C C alkoxy group independently substituted by 1 or 2
• R 1 is more preferably R 1 and is substituted with a group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a methoxy group, and an ethoxy group.
• -Phenyl group a phenyl group in which two of the 2-, 3-, or 5-positions are independently substituted with a group selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a methoxy group, and an ethoxy group
• R 1 is a 2-fluorophenol group, a 2-methoxyphenyl group, a 5-chlorophenyl group, an ethoxyphenol group,
• R 2 is preferably a halogen atom, a C 1 -C alkyl group, or a C 2 -C halogen.
• R 2 is a halogen atom, C — C, more preferably a phenyl group or a pyridyl group.
• the group strength is also a phenyl group or a pyridyl group which may be independently substituted with 1 to 3 groups selected, and even more preferred R 2 is also a fluorine atom, a chlorine atom, a methyl group and a trifluoromethyl group force. Is selected from the group consisting of a methyl group, a hydroxymethyl group, a 2-hydroxyethoxy group, a 2,3-dihydroxypropoxy group, and an amino group. A group in which the 4-, 5- or 6-position is substituted with a group;
• R 2 is 2-chloro 6-methyl phenol, 2-chloro 2-
• preferred E is a group having the above formula ( ⁇ ) or a group having the formula ( ⁇ ), and more preferred E is a group having the above formula (II).
• preferred R 3 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, more preferred R 3 is a hydrogen atom, a fluorine atom or a chlorine atom, and even more preferred R 3 is a hydrogen atom. Or a chlorine atom, and particularly preferred R 3 is a hydrogen atom.
• preferred R is a hydrogen atom or a methyl group, and more preferred R is a hydrogen atom.
• preferred R 5 is a hydrogen atom or a methyl group, and more preferred R 5 is a hydrogen atom.
• X is preferably a nitrogen atom.
• preferred U is a group represented by the formula CH.
• m is preferably 1.
• n is preferably 1.
• the urea derivative having the general formula (I) or the pharmacologically acceptable salt thereof of the present invention has all isomers (ketenols isomers, diastereoisomers, optical isomers, rotational isomers, etc.).
• the urea derivative having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers since an asymmetric carbon atom is present in the molecule.
• these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers in any proportion.
• the stereoisomers as described above can be synthesized by synthesizing the compound according to the present invention using the force of using a stereospecific raw material or a compound, or using a method of asymmetric synthesis or asymmetric induction. Shi Further, the compound according to the present invention can be obtained by isolating the compound according to the present invention, if desired, using a conventional optical resolution method or separation method.
• the "pharmacologically acceptable salt thereof” 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 a basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrates, perchlorates, Inorganic acid salts such as sulfates and phosphates; C-C alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfo
• Organic acid salts such as arylate sulfonates such as phosphate, acetate, malate, fumarate, succinate, succinate, ascorbate, tartrate, succinate, maleate; and And amino acid salts such as glycine salt, lysine salt, arginine salt, ornitine salt, glutamate salt, and aspartate salt.
• arylate sulfonates such as phosphate, acetate, malate, fumarate, succinate, succinate, ascorbate, tartrate, succinate, maleate
• amino acid salts such as glycine salt, lysine salt, arginine salt, ornitine salt, glutamate salt, and aspartate salt.
• 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, and aluminum salt.
• Metal salts such as iron salts; inorganic salts such as ammonium salts, toctylamine salts, dibenzylamine salts, morpholine salts, darcosamine salts, glycine alkyl ester salts, ethylenediamine salts, N-methyl darcamamine salts , Guanidine salt, jetylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, -dibenzylethylenediamine salt, black pro-in salt, pro-in salt, diethanolamine salt, N-benzylphene Organics such as tyramine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt And amine salts such as salts
• the urea derivative having the general formula (I) or the pharmacologically acceptable salt thereof of the present invention absorbs moisture by attaching it to the atmosphere by leaving it in the atmosphere or by recrystallization.
• the hydrate is also included in the salt of the present invention.
• the urea derivative having the general formula (I) or the pharmacologically acceptable salt thereof of the present invention may absorb a certain other solvent and become a solvate, and such a solvate. Are also included in the salts of the present invention.
• Ph (B) -NH-C (: 0)-CH 2-0Me-5-Me-Ph -628 Ph (B) -NH-C (CH 2-0Et-5-Me-Ph

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