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WO1999027965A1 - Agents anti-hyperlipemiques - Google Patents

Agents anti-hyperlipemiques Download PDF

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Publication number
WO1999027965A1
WO1999027965A1 PCT/JP1998/005358 JP9805358W WO9927965A1 WO 1999027965 A1 WO1999027965 A1 WO 1999027965A1 JP 9805358 W JP9805358 W JP 9805358W WO 9927965 A1 WO9927965 A1 WO 9927965A1
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WIPO (PCT)
Prior art keywords
group
aryl
lower alkyl
heteroaryl
alkyl group
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PCT/JP1998/005358
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English (en)
Japanese (ja)
Inventor
Takehiro Fukami
Kuroda Takahiro F
Akio Kanatani
Masaki Ihara
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Banyu Pharmaceutical Co., Ltd.
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Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to AU12621/99A priority Critical patent/AU1262199A/en
Publication of WO1999027965A1 publication Critical patent/WO1999027965A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention is useful in the field of medicine. More specifically, the present invention relates to a novel agent for treating hypercholesterolemia, hyperlipidemia and arteriosclerosis, which comprises a nerve peptide 5 receptor antagonist as an active ingredient.
  • a novel agent for treating hypercholesterolemia, hyperlipidemia and arteriosclerosis which comprises a nerve peptide 5 receptor antagonist as an active ingredient.
  • arteriosclerosis In recent years, due to the aging of the population and changes in eating habits, it has been pointed out that arteriosclerosis and the accompanying frequency of various coronary and cerebral artery diseases have increased. Although various factors are thought to contribute to the occurrence of arteriosclerosis, elevation of blood cholesterol is one of the most important risk factors, and lowering of blood cholesterol is necessary for treatment and prevention of arteriosclerosis. Agents Used to Treat Hyperlipidemia, Drug Evaluations 6th. Edition, 903 Drugs are known to be effective [Ajazin 'Used' Two 'Treats' Hyper Revidea, Drug Evaluate Sections' Sixth Edition. -926 (1986)].
  • non-HDL (high-density lipoprotein) cholesterol such as LDL (low-density lipoprotein) cholesterol is typically important as a risk factor for the above diseases.
  • NPY Neuropeptide Y
  • NPY is widely distributed in the central nervous system and the peripheral nervous system, and as one of the most abundant peptides in the nervous system, controls various functions in living organisms. That is, NPY acts centrally as an appetite-stimulating substance and remarkably promotes fat accumulation through secretion of various hormones or the action of the nervous system. Continuous intraventricular administration of NPY is known to induce obesity and insulin resistance based on these effects. It is also related to the control of emotions and the function of the central autonomic nervous system. Furthermore, in the periphery, NPY coexists with norepinephrine at sympathetic nerve endings and is associated with sympathetic tone.
  • NPY peripheral administration of NPY causes vasoconstriction and enhances the action of other vasoconstrictors such as norepinephrine [International jounal of obesity] 19, 517 (1995); Endocrinology. 133, 1753 (1993); Pretty 'Journal' Obb. Pharmacology, 95 , 419 (1988)].
  • NPY The function of NPY is expressed by binding to NPY receptors present in the central or peripheral nervous system, but NPY receptors have so far been classified into six subtypes, Yl, ⁇ 2, ⁇ 3, ⁇ 4, ⁇ 5, and ⁇ 6. The type is known [Annual Reports in Medicinal Chemistry, 32, 21 (1997)].
  • the NPY Y5 receptor was cloned in 1996 and is thought to be involved in the appetite-inducing action of ⁇ [Nature, 382, 168 (1996)] ]. In fact, it has been reported that intracerebral administration of the Y5 receptor antisense deoxyribonucleotide significantly suppresses fasting-induced appetite in rats [Diabetes.
  • An object of the present invention is to provide a safer and more effective agent for treating hypercholesterolemia, hyperlipidemia and arteriosclerosis.
  • NPY Y5 receptor antagonists have an effect of lowering blood cholesterol, particularly non-HDL cholesterol, in vivo, and as a result, hypercholesterolemia, hyperlipidemia and arteriosclerosis
  • the present invention was found to be effective as a therapeutic agent for the present invention, and the present invention was completed.
  • the present invention relates to a therapeutic agent for hypercholesterolemia, hyperlipidemia and arteriosclerosis, which comprises an NPY Y5 receptor antagonist as an active ingredient.
  • the “neuropeptide Y Y5 receptor antagonist” is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • the general formula [I-a] is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • the general formula [I-a] is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • A is a nitrogen atom or a group represented by C—R 5 ;
  • Ar 1 is an aryl which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group.
  • Ar 2 comprises a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group
  • R 1 is a hydrogen atom or a lower alkyl group or a bond linked to R 5 ;
  • R 2 is a hydrogen atom or a lower alkyl group;
  • R 3 and R 4 are the same or different and are a hydrogen atom or a lower alkyl group, or R 3 and R 4 are linked to each other to form an alkylene group having 2 to 4 carbon atoms which may have a lower alkyl group;
  • R 5 is a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower
  • ring A and ring B are ortho-fused with each other, ring A is an aromatic carbon or heterocyclic ring; ring B is a 4- to 7-membered aliphatic carbon or nitrogen-containing heterocyclic ring, and the nitrogen atom Is a ring that can be present only at the condensed site with ring A;
  • Ar is a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower group
  • An aromatic carbon or a heterocyclic group which may have a substituent selected from the group consisting of an alkylamino group and an aromatic carbocyclic group;
  • R is a halogen atom, a nitrogen atom, a lower alkyl group, A substituent or a hydrogen atom selected from the group consisting of a lower alkoxy group,
  • Ar 1 represents an aryl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group
  • Ar 2 is a halogen atom, a lower alkyl group, a lower alkyl group
  • An aryl group which may have a substituent selected from the group consisting of an alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group
  • R 1 and R 2 are the same or different and are a hydrogen atom or a lower alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom or a lower alkyl group, or R 3 and R And R 4 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, wherein both
  • Ar 1 is a group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, an acyl group and an aryl group.
  • Ar 2 is a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, which may have a substituent selected from the group consisting of an aryl group and a heteroaromatic ring group.
  • Ar is a halogen atom, a nitro group, an amino group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoyl group, and aryl.
  • An aryl group or a heteroaromatic group which may have a substituent selected from the group consisting of: R 1 and R 2 are the same or different, and a lower alkyl group or both R 1 and R 2 are R 3 represents an amino group, a lower alkyl group or a lower alkylamino group which may be connected to each other via an oxygen atom or a sulfur atom;
  • Y represents an ethylene group, a trimethylene group, a vinylene group, a propenylene group; Or a group represented by 1—CH 2 —, 1 S—CH 2 — or —C3 ⁇ 4—NH—] and a salt thereof,
  • R 1 represents a hydrogen atom or a lower alkyl group, or a lower alkylene group which may be interposed with R 2 to interpose an oxygen atom
  • R 2 represents a lower alkyl group Or together with R 1 has the meaning described above
  • R 3 and R 4 together represent a hydrogen atom, or together form a single bond
  • R 5 and R 6 represents a hydrogen atom at the same time, or a lower alkylidene group which may be joined together and intervened by an oxygen atom
  • R 7 and R 8 independently represent a hydrogen atom, a halogen atom, a nitro group
  • X represents an oxygen
  • B is 1 or 2; j is an integer of 0 to 3; K is —CH 2 —NR 8 —CHR 5- (CH 2 ) j-, -CH 2 -NR 8 -CO- (CH 2) "or one CH 2 - NH - CO - NH - a (CH 2) j- group represented by; L is a pentamethylene group, hepta 'group or the formula
  • P is an integer of 0 to 2;
  • Q is a nitrogen atom, an oxygen atom, a sulfur atom or a group represented by —NR 7 — or —C (R 4 ) 2 —;
  • RR 2 and R 3 Is Independently a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a halo lower alkyl group or a group represented by —N (R 4 ) 2 ;
  • R 4 is independently a lower group;
  • R 5 is independently a hydrogen atom, a hydroxymethyl group or a lower alkoxymethyl group;
  • R 6 is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, an oxo group, a lower alkyl group, a lower alkoxy group, Xy-lower alkyl group, methoxy
  • alk represents a single bond or a lower alkylene group
  • n represents 0 or 1
  • Means i) a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, a heteroaryl group or a (aryl or heteroaryl) lower alkyl group, A nitrogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a substituted amino group, a propyloxy group, a lower alkoxycarbonyl group, an (aryl or heteroaryl) lower alkoxycarbonyl group, a carbamoyl group or N-substituted (Ii) an amino group or a substituted amino group; (iii) a hydroxyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group,
  • halogen atoms lower alkyl groups, lower alkenyl groups, lower alkynyl groups, aryl groups, heteroaryl groups, lower alkoxy groups, lower alkenyloxy groups, lower alkynyloxy groups, hydroxyl groups, lower alkanoyloxy groups (Aryl or heteroaryl) lower alkanoyloxy group, lower alkanol group, (aryl or heteroaryl) lower alkanol group, (aryl or heteroaryl) carbonyl group, nitro group, cyano group; (ii) halogen atom, hydroxyl group , Lower alkoxy group, (aryl or heteroaryl) oxy group, aryl group, heteroaryl group, amino group, substituted amino group, carboxy group, lower alkoxycarbonyl group, lower alkoxy lower alkoxycarbonyl group, (aryl Or heteroaryl) a lower alkoxy group, a lower alkyl group substituted by a nitromoyl group or an N-
  • (aryl or heteroaryl) mono-substituted by lower alkyl group That properly it may be disubstituted independently of one another; (ii) ⁇ said lower alkylene group to be disubstituted by lower alkylene group bonded through an oxygen atom or S (0) n or a group represented by NR ° Or may be condensed with a benzene ring at two adjacent carbon atoms ⁇ ; or (iii) monosubstituted by a group represented by —CO— (O) v —R or V means 0 or 1; n means 0, 1 or 2; R 0 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, Heteroari Ichiru group, ( ⁇ Li one Norre or to Teroari one Honoré) lower alk kill group, a lower Arukanoinore group, (Arinore or Heteroarin
  • alk 1 and alk 2 independently represent a single bond or a lower alkylene group
  • R 1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group
  • R 2 represents an alkyl group, lower alkoxy lower alkyl group, aryl group, heteroaryl group or (aryl or heteroaryl) lower alkyl group
  • R 2 represents (i) a hydrogen atom, a halogen atom, Group, cyano group, lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group, heteroaryl group or (aryl or heteroaryl) lower alkyl group, or halogen atom, hydroxyl group, lower alkoxy group, amino group, Substituted amino, carboxy, lower alkoxycarbonyl, (aryl or heteroaryl (Ii) a lower
  • the lower alkylene group may be via an oxygen atom or a group represented by S (O) n or NR °, and may be fused to a benzene ring at two adjacent carbon atoms. Or a group represented by (vii) -X 1 (X 2 ) (X 3 ); wherein (a) X 1 is a group represented by —CH— When X 2 and X 3 together, —X 4 — (CO) p-(CH 2 ).
  • n 0, 1 or 2
  • X 1 is C 3 —. 8 cycloalkylene group, C 3 - C 8 Shikuroaruke two alkylene groups, C 3 one C e cycloalkylidene group, c 3 - c 8 Shikuroaruke two alkylidene group, Okiso c 3 - c 8 cycloalkylene group, Okiso C 3 - C 8 Shikuroaruke two lens groups, Okiso C 3 - C 8 cycloalkylidene group or Okiso C 3 - C 8 Shikuroaruke two isopropylidene group;
  • X 2 represents an oxygen atom or - S (0) n - or single n (R 4) - in formula A compound represented by the formula: alk 2 , R ′, R 2 , R 3 , R 4 and benzo ring A have the same meaning as defined in the above general formula [I-i].
  • one or more drugs selected from the group consisting of and salts thereof.
  • Treatment agent means a drug that is provided for the purpose of treatment and / or prevention of various diseases.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like.
  • halo lower alkyl group means the lower alkyl group having the halogen atom, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, and a 2,2,2-trifluoroalkyl group. And a chloroethyl group, a pentafluoroethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a 1-chloroethyl group, and a 2-chloroethyl group.
  • Aryl group means a phenyl group, a naphthyl group or an anthryl group, and a phenyl group and a naphthyl group are preferred.
  • “Lower alkenyl group” means a straight-chain or branched alkenyl group having 2 to 7 carbon atoms, such as vinyl group, 2-propenyl group, isopropenyl group, 3-butenyl group, 2- Butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl-2-propenyl group, 2-methyl-1-propenyl Group, 3-methyl-2-butenyl group, 4-pentenyl group and the like.
  • lower alkoxy group means an alkoxy group having a lower alkyl group, that is, an alkoxy group having 1 to 7 carbon atoms or an alkylene dioxy group having 1 to 3 carbon atoms, such as a methoxy group and an ethoxy group.
  • propyloxy group isopropyloxy group, butoxy group, isoptyloxy group, tert-butoxy group, pentylokine group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, Shi Chloropropylmethyloxy, 1-cyclopropylethyloxy, 2-cyclopropylpropyloxy, 1-cyclopropylpropyloxy, 2-cyclopropylpropyloxy, 3-cyclo Examples include a propylpropyloxy group, a cyclopentylmethyloxy group, a 2-cyclopentylethyloxy group, a cyclohexylmethyloxy group, a methylenedioxy group, an ethylenedioxy group, and a trimethylenedioxy group.
  • “Lower alkylthio group” means an alkylthio group having a lower alkyl group, that is, an alkylthio group having 1 to 7 carbon atoms, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group.
  • lower alkylamino group means an amino group mono-substituted by the lower alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino. And the like.
  • the “di-lower alkylamino group” means an amino group di-substituted by the lower alkyl group, for example, a dimethylamino group, a getylamino group, an ethylmethylamino group, a dipropylamino group, a methylpropylamino group, a diisopropylamino group and the like. No.
  • Heteroaromatic group means a 5- or 6-membered group containing one or more, preferably 1 to 3, complex atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, which are the same or different.
  • a condensed ring in which the monocyclic aromatic heterocyclic group or the monocyclic aromatic heterocyclic group is condensed with the aryl group, or in which the same or different monocyclic aromatic heterocyclic groups are condensed with each other Means an aromatic heterocyclic group of the formula, for example, a piperyl group, a furyl group, a cyenyl group, an imidazolyl group, a virazolyl group, Thiazolinole group, isothiazolyl group, oxazolinole group, isoxazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group, pyridyl group, virazinyl group, pyrimidinyl group, pyridazinyl group, indolinole group, benzofuranyl group, benzocenyl Midazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, be
  • alkylene group having 2 to 4 carbon atoms in the general formula [Ia] or [Ic] means a linear alkylene group, that is, an ethylene group, a trimethylene group, or a tetramethylene group.
  • “Aromatic carbon ring” means a benzene ring, a naphthalene ring or an anthracene ring.
  • “Aromatic heterocyclic ring” refers to a 5- or 6-membered member containing one or more, preferably one to three, atoms which are the same or different and are selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a fused aromatic heterocyclic ring in which the monocyclic aromatic heterocyclic ring is fused with the aromatic carbocyclic ring or in which the same or different monocyclic aromatic heterocyclic rings are fused with each other
  • Means for example, a pyrrole ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a triazole ring, an oxaziazole ring, a thiaziazole ring, pyridine Ring, virazine ring, pyrimidine ring, pyridazine ring, indole ring, benzofuran ring, benzothiophene ring, benzimidazo Ring, benzoxazolyl ring, benzoisoxazolyl ring, benzothiazole
  • “Aliphatic carbocycle” means a carbocycle in which the bonds between the ring atoms except for the fused site are saturated, for example, a cyclobutane ring, a cyclobutene ring, a cyclopentane ring, a cyclopentene ring, a cyclohexane ring Ring, cyclohexyl A sen ring, a cycloheptane ring, a cycloheptene ring and the like are mentioned.
  • aliphatic nitrogen-containing heterocyclic ring means a nitrogen-containing heterocyclic ring containing one nitrogen atom and having at least a saturated bond between the ring atoms excluding the condensed site.
  • an azetidine ring, A lysine ring, piperidine ring, perhydroazepine ring and the like can be mentioned.
  • “Aromatic carbocyclic group” means a group formed from the aromatic carbocyclic ring, and means a phenyl group, a naphthyl group or an anthryl group.
  • “Aromatic heterocyclic group” means a group formed from the aromatic heterocyclic ring, for example, a pyrrolyl group, a furyl group, a cyenyl group, an imidazolyl group, a virazolinole group, a thiazolyl group, an isothiazolyl group, an oxazolyl group , Isoxazolyl, triazolyl, oxaziazolyl, thiadiazolyl, pyridyl, vilazinyl, pyrimidininole, pyridazinyl, indolyl, benzofuranyl, benzochenyl, benzoimidazolyl, benzoxoxa Zolyl, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, indazolinole, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl
  • acyl group means a lower alkanoyl group, a lower alkenoyl group, a lower alkynyl group or an aroyl group, and among them, a lower alkanoyl group, an aroyl group and the like are preferable.
  • lower alkanoyl group means an alkanoyl group having 1 to 7 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutylyl group, valeryl group, isopararyl group, pinoyl group and the like.
  • lower alkenoyl group means an alkenoyl group having 3 to 7 carbon atoms, and examples thereof include an acryloyl group, a methacryloyl group, and a crotonyl group.
  • lower alkynyl group means an alkinoinole group having 3 to 7 carbon atoms, and examples thereof include a propioyl group.
  • aroyl group means an arylonyl group having 7 to 11 carbon atoms, and examples thereof include a benzoyl group, a naphthoyl group and a 2-naphthoyl group.
  • ⁇ alkylene group '' means an alkylene group having 2 or 6 carbon atoms which may be interposed through an oxygen atom or a sulfur atom, and the alkylene group together with an adjacent nitrogen atom is, for example, a pyrrolidinyl group, an oxazolidinyl group, an isoxoxa group.
  • the “lower alkylene group” in the general formula [I-f] means a linear or branched alkylene group having 2 to 6 carbon atoms, for example, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, Hexamethylene group and the like.
  • the “lower alkylene group optionally interposed with an oxygen atom” in the general formula [If] means a group in which any one methylene group of the lower alkylene group or the alkylene group is replaced by an oxygen atom.
  • the group is, together with an adjacent ring carbon, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane A ring, an oxetane ring, an oxolane ring, an oxane ring, an oxepane ring, etc.
  • an adjacent ring carbon for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane A ring, an oxetane ring, an oxolane ring, an oxane ring, an oxepane ring, etc.
  • the “lower alkylidene group optionally interposed with an oxygen atom” in the general formula [If] is a straight-chain, branched or cyclic alkylidene group having 2 to 6 carbon atoms or any one of the alkylidene groups.
  • a methylene group is a group in which an oxygen atom has been replaced by an oxygen atom.
  • “Hydroxy lower alkyl group” means the lower alkyl group having a hydroxyl group, that is, a hydroxyalkyl group having 1 to 7 carbon atoms, such as a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group. , 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- Examples include a hydroxybutyl group, a 2-hydroxybutyl group, a 3-hydroxybutyl group, and a 4-hydroxybutyl group.
  • “Methoxy lower alkyl group” means the lower alkyl group having a methoxy group, that is, a methoxyalkyl group having 2 to 8 carbon atoms, such as a methoxymethyl group, a 1-methoxyl group, Methoxytyl group, 1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group, 1-methoxybutyl group, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group, etc. Is mentioned.
  • the “lower alkylene group” of alk, alk 1 or alk 2 means a linear or branched alkylene group having 1 to 7 carbon atoms, such as a methylene group, an ethylene group, a propylene group, a butylene group, Examples include a 2-propylene group, a 2-methyl-1,3-propylene group, a 3-methyl-1,5-pentylene group, and a 2,2-dimethyl-1,3-propylene group.
  • “Lower alkynyl group” means a straight or branched alkynyl group having 2 to 7 carbon atoms, such as ethynyl group, 2-propynyl group, 1-methyl-2-propynyl group, 2-butynyl group. , 1-methyl-2-butynyl group, 2-pentynyl group and the like.
  • heteroaryl group has the same meaning as the above-mentioned heteroaromatic ring group.
  • Aryl lower alkyl group means the lower alkyl group having the aryl group, for example, benzyl group, 1-phenylethyl group, 2-phenylethylenol group, 1-phenylpropyl group, 3-phenylpropyl group. , 1-phenylbutyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 1- (1-naphthyl) ethyl, 2- (1-naphthyl) ethyl, 1- (2-na And a 2- (2-naphthyl) ethyl group.
  • heteroaryl lower alkyl group means the lower alkyl group having the heteroaryl group, for example, a 2-pyridylmethinole group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, a 1- (2-pyridyl group.
  • lower alkoxycarbonyl group means an alkoxycarbonyl group having a lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 8 carbon atoms, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxy group.
  • Cyclocarbonyl group isopropyloxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group , Cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, cyclopropylmethyloxycarbonyl, 1-cyclopropylethyloxycarbonyl, 2-cyclopropylethyloxycarbonyl 1-cyclopropylpropyloxycarbonyl group, 2-cyclopropylpropyloxycarbonyl group, 3-cyclopropylpropyloxycarbonyl group, cyclopentylmethyloxycarbonyl group, 2-cyclopentylethyloxycarbonyl group And cyclohexylmethyloxycarbonyl group.
  • lower alkoxycarbonylamino group means an alkoxycarbonylamino group having the lower alkoxycarbonyl group, such as a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, A propoxycarbonylamino group, a butoxycarbonylamino group, a tert-butoxycarbonylamino group and the like.
  • Aryl lower alkoxycarbonyl group means the above-mentioned lower alkoxycarbonyl group having the aforementioned aryl group, for example, benzyloxycarbonyl, 1-phenylethyloxycarbonyl, 2-phenyl Ethyloxycarbonyl, 3-phenylpropyloxycarbonyl, 1-naphthylmethyloxycarbonyl, 2-naphthylmethyloxycarbonyl, 1- (1-naphthyl) ethyloxycarbonyl 1- (2-naphthyl) ethyloxycarbonyl group, 2- (1-naphthyl) ethyloxycarbonyl group, 2- (2-naphthyl) ethyloxycarbonyl group, 3- (1— A naphthyl) propyloxycarbonyl group; a 3- (2-naphthyl) propyloxycarbonyl group; “Heteroarylene lower alkoxycarbonyl,
  • “Lower alkenyloxy group” means an alkenyloxy group having a lower alkenyl group, that is, an alkenyloxy group having 2 to 7 carbon atoms, for example, a vinyloxy group, a 2-propenyloxy group, an isopropenyloxy group.
  • “Lower alkynyloxy group” means an alkynyloxy group having a lower alkynyl group, that is, an alkynyloxy group having 2 to 7 carbon atoms, such as an ethynyloxy group, a 2-propynyloxy group, and a monomethyl group. —2-propynyloxy group, 2-butynyloxy group, 1-methyl-2-butynyloxy group, 2-pentynyloxy group and the like.
  • “Hydroxy lower alkoxy group” means a hydroxyalkoxy group having the hydroxy lower alkyl group.
  • the “lower alkoxy lower alkoxy group” means an alkoxyalkoxy group having the lower alkoxy group, for example, a methoxymethyloxy group, an ethoxymethyloxy group, a 1-methoxyshetyloxy group, a 1-ethoxyshetyl. Methoxy group, 2-methoxyloxy group, 2-ethoxyloxyl group, 1-methoxypropyloxy group, 2-methoxypropyloxy group, 3-methoxypropyloxy group, and the like. .
  • aralkyloxy group or the “aryl lower alkoxy group” means the lower alkoxy group having the aryl group, for example, a benzyloxy group,
  • heteroaryl lower alkoxy group means the lower alkoxy group having the heteroaryl group, for example, a 2-pyridylmethyloxy group, a 4-pyridylmethyloxy group, a 2- (2-pyridyl) ethyloxy group. And 2- (4-pyridyl) ethyloxy, 3- (2-pyridinole) propyloxy, and 3- (4-pyridyl) propyloxy.
  • the “lower alkoxycarbonyloxy group” means an alkoxycarboxy group having the lower alkoxycarbonyl group.
  • Aryl lower alkoxycarbonyloxy group means an aryl alkoxycarboxy group having the above aryl lower alkoxycarbonyl group.
  • heteroaryl lower alkoxycarbonyloxy group means a heteroarylalkoxycarbonyloxy group having the above-mentioned heteroaryl lower alkoxycarbonyl group.
  • “Lower alkoxy lower alkoxycarbonyl group” means an alkoxyalkoxyl alkoxyl group having the lower alkoxy lower alkoxy group.
  • the “amino group di-substituted by a lower alkylene group” for example, a 1-azetidino group, a 1-pyrrolidino group, a 1-piperidino group and the like are preferable.
  • Examples of the “lower alkylene group optionally interposed through an oxygen atom or a group represented by S (0) n or NR °” include a morpholino group, a thiomorpholino group, a thiomorpholino S-oxide group, Morpholino S, S-dioxide group, 4-R. — A piperazino group and the like are preferred.
  • “Lower alkanoyloxy group” means an alkanoyloxy group having the lower alkanoyl group.
  • Aryl lower alkyl group means the lower alkanoyl group having the aryl group, for example, phenylacetyl group, 3-phenylpropionyl group, 4-phenylbutyryl group, 1 One naphthyl acetyl group, 2-naphthyl acetyl Butyl, 3- (1-naphthyl) propionyl, 3- (2-naphthyl) propionyl, 4- (1-naphthyl) butylinole, and 4- (2-naphthyl) butylyl.
  • Heteroaryl lower alkynyl group means the lower alkynyl group having the heteroaryl group, for example, 2-pyridylacetyl, 4-pyridylacetyl, 3- (2-pyridinoleyl).
  • Aryl lower alkanoyloxy group means an aryl alkanoyloxy group having the above aryl lower alkanoyl group.
  • Heteroaryl lower alkanoyloxy group means a heteroaryl lower alkanoyloxy group having the above heteroaryl lower alkanoyloxy group.
  • arylcarbonyl group means an arylcarbinyl group having the aryl group, and examples thereof include a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group.
  • arylcarbonylamino group means an arylcarbonylamino group having the arylcarbonyl group, and examples thereof include a benzoylamino group, a 1-naphthoylamino group, and a 2-naphthoylamino group.
  • Heteroarylcarbonyl group means a heteroarylcarbonyl group having a heteroaryl group, such as a 2-furoyl group, a 3-furoyl group, a 2-tenoinole group, and a 3-tenoinole group. , 2-pyridinole, 3-pyridinole, 4-pyridyl and the like.
  • aryloxy group means an aryloxy group having the above aryl group, and examples thereof include a phenyloxy group, a 1-naphthoxy group, and a 2-naphthoxy group.
  • heteroaryloxy group means a heteroaryloxy group having the above-mentioned heteroaryl group. Examples thereof include a 2-furyloxy group, a 3-furyloxy group, a 2-phenyloxy group, a 3-phenyloxy group, and a 2-phenyloxy group. Examples include a pyridyloxy group and a 3-pyridyloxy group.
  • “Arylene group” means an arylene group in which the aryl group has become a divalent group, for example, 1,2-phenylene group, 1,3-phenylene group, 1,4-phenylene group.
  • heteroarylene group means a heteroarylene group in which the heteroaryl group has become a divalent group, for example, 2,3-furylene group, 2,4-furylene group, 3,4-monofurylene group, Examples thereof include a 2,3-Chenylene group, a 2,4-Chenylene group, a 3,4-Chenylene group, a 2,3-pyridylene group, and a 2,4-pyridylene group.
  • C 3 -C 8 cycloalkylene group means a cycloalkylene group having 3 to 8 carbon atoms, such as 1,3-cyclopentylene group, 1,3-cyclohexylene group, 1,4-cyclohexane group.
  • Xylene groups and the like can be mentioned.
  • C 3 -C 8 cycloalkenylene group means a cycloalkenylene group having 3 to 8 carbon atoms, for example, 1,3-cyclopenter-2-enylene group, 1,3-cyclohexene. Examples include a phenylene group and a 1,4-cyclohexyl 2-phenylene group.
  • C 3 -C 8 cycloalkylidene group means a cycloalkylidene group having 3 to 8 carbon atoms, such as cyclopropylidene group, cyclobutylidene group, cyclopentylidene group, cyclohexylidene group, etc. .
  • the - "Ji 8 cycloalkenylene isopropylidene group C 3" carbon number of 3 means Shikuroaruke two isopropylidene groups 8, for example 1, 1 Shikuropenta - 2 Eniriden group, 1, 1 Kisa 2 Eniriden group to Shikuro , 1,1-cyclohexa-3-enylidene group and the like.
  • "Okiso C 3 - Ji 8 cycloalkylene group" and the C 3 having Okiso group - means a C 8 cycloalkylene group, such as 2-Okiso one 1, 3-cyclopentylene group, 2-Okiso one 1 2,3-cyclohexylene group, 2-oxo-1,4-cyclohexylene group, 3-oxo-1,3-cyclohexylene group, 3-oxo-1,4-cyclohexylene group, etc.
  • 2-Okiso one 1, 3-cyclopentylene group 2-Okiso one 1 2,3-cyclohexylene group
  • 2-oxo-1,4-cyclohexylene group 3-oxo-1,3-cyclohexylene group
  • 3-oxo-1,4-cyclohexylene group etc.
  • "Okiso C 3 - 0 8 cycloalkenylene group" and the C 3 having Okiso group - mean C 8 Shikuroaruke two alkylene groups, such as 2-Okiso one 1, 3-cyclopenta-5 Eniren group, 2- Oxo-1,3-cyclohexa-1-enylene group, 2- Oxo-1,4-cyclohexa 5-enylene group, 3-oxo-1,4-cyclohexa 5-enylene group and the like.
  • the - "Okiso C 3. 8 cycloalkylidene group" means a C 8 cycloalkylidene group, for example, 2-year old Kiso cyclopropylidene group, 2-O ROCEPHIN black butylidene group, 2 — Oxocyclopentylidene group, 2-oxo hexylidene group and the like.
  • the “oxo C 3 —c 8 cycloalkenylidene group” means the above-mentioned c 3 -C 8 cycloalkenylidene group having an oxo group, for example, a 2-oxo-1,1-cyclobenzene-3-enylidene group, —Oxo-1,5-cyclohexyl-5-enylidene group, 3-oxo-1,1-cyclohexyl 5-enylidene group, and the like.
  • the “salt” of the compound represented by [I-i] or [I-j] means a pharmaceutically acceptable conventional one, for example, a basic group such as a basic heterocyclic group or an amino substituent. And salts of a base addition salt at the carboxyl group in the case of having a carboxyl group.
  • the acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and P-toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate
  • maleate, fumarate, tartrate, citrate, ascorbate Organic acid salts such as trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate and P-toluenesulfonate.
  • the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; for example, ammonium salt; for example, trimethylamine salt, triethylamine salt; And organic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, and ⁇ , ⁇ ′ dibenzylethylenediamine salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt for example, trimethylamine salt, triethylamine salt
  • organic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, and ⁇ , ⁇ ′ dibenzylethylenediamine salt.
  • the “neuropeptide ⁇ 5 receptor antagonist other than cholesterol lowering agent” is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • hydroxymethyl dalaryl CoA reductase Inhibitors are preferred, among which, for example, Nature, 343, 425 (1990) Preferred are lovastatin, simvastatin, pravastatin, fluvastatin and the like described in (1).
  • A represents a group represented by a nitrogen atom or C one R 5.
  • A is preferably a nitrogen atom.
  • Ar 1 represents an aryl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group.
  • aryl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group refers to the unsubstituted aryl group or any substitutable position. Means the aryl group having a substituent, and the substituent is the same or different from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group, and one or more, preferably one or two, are selected. be able to.
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent for example, a methyl group, an ethyl group, a propanol group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like are more preferable.
  • the halo-lower alkyl group for the substituent is, for example, preferably a trifluoromethyl group.
  • a halogen atom and the like are preferable.
  • aryl group for Ar 1 for example, a phenyl group is suitable.
  • examples of Ar 1 include a phenyl group and a 3-chlorophenyl group, and among them, a 3-chlorophenyl group and the like are preferable.
  • Ar 2 is a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkenyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group.
  • a halogen atom a lower alkyl group
  • a lower alkenyl group a halo-lower alkenyl group
  • a lower alkoxy group a lower alkylthio group
  • a lower alkylamino group a di-lower alkylamino group
  • aryl group With Represents an aryl group or a heteroaromatic ring group.
  • An aryl group or a heteroaromatic ring group which may have an unsubstituted aryl group or a heteroaromatic ring group, or the aryl group having a substituent at any substitutable position.
  • the substituent is a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group. And one or two or more, preferably one or two, identical or different from the group consisting of
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • Examples of the lower alkenyl group for the substituent include a vinyl group, a 2-propenyl group, an isopropyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and more preferably a vinyl group, Propenyl groups and the like are preferred.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propyloxy group, a methylenedioxy group, and the like, and more preferably a methoxy group, a methylenedioxy group, and the like.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • the lower alkylamino group of the substituent is, for example, preferably a methylamino group.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group is preferred.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a di-lower alkylamino group and the like are preferable.
  • the aryl group of Ar 2 is preferably, for example, a phenyl group, and the heteroaromatic group is, for example, a pyridyl group.
  • Ar 2 for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 2-pyridinole group, a 3-pyridinole group, a 4-pyridyl group, a 2-chlorophenyl group, a 3-chlorophenyl group , 4-chlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-chloro-3-pyridyl, 5-bromo-3-pyridyl, 2 —Methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl, 5-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6- Ethyl-3-pyridyl, 2-methyl-4-pyridyl, 2-
  • 4-pyridyl group 2-methyl-4-pyridyl group, 2-ethyl-4-pyridinole group, 2-propyl-4-pyridyl group, 2-butyl-4-pyridyl group, 3- Black phenyl group, 4-Monophenyl group, 3,4-Dichlorophenyl group, 3-Bromophenyl group, 4-Bromophenyl group, 2-Methylphenyl group, 3-Methylphenyl group, 4-Methylphenyl group, 4 —Ethylphenyl group, 3-methyl-4-pyridyl group, 3-ethyl-4-pyridyl group, 4-vinylphenyl group, 4- (2-propenyl) Phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3-methoxy-14-pyridyl
  • R 1 represents a bond connected to a hydrogen atom or a lower alkyl group or R 5 .
  • R 1 for example, a methyl group, an ethyl group, and the like are preferable.
  • R 5 ' when the group A is represented by C-R 5, a double bond with an existing bond linked both R 1 and R 5 together form To do.
  • R 1 represents a bond in connection with a hydrogen atom or R 5 .
  • R 2 represents a hydrogen atom or a lower alkyl group.
  • the lower alkyl group for R 2 for example, a methyl group, an ethyl group and the like are preferable.
  • R 2 a hydrogen atom is preferable.
  • R 3 and R 4 may be the same or different and each may be a hydrogen atom or a lower alkyl group, or both R 3 and R 4 may be linked to each other to have a lower alkyl group; Means an alkylene group.
  • R 3 and R 4 for example, a methyl group, an ethyl group and the like are preferable.
  • the ⁇ alkylene group having 2 to 4 carbon atoms which may have a lower alkyl group '' is the unsubstituted alkylene group or the same or different 1 or 2 or more lower alkyl groups at any substitutable position. And the unsubstituted alkylene group is preferable.
  • the lower alkyl group as a substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, etc., and more preferably a methyl group.
  • R 3 and R 4 are the same or different and are a lower alkyl group, or a carbon which may have a lower alkyl group by linking both R 3 and R 4 to each other.
  • R 5 represents a bond in connection with a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group, or R 1 .
  • the lower alkyl group for R 5 for example, a methyl group, an ethyl group, and the like are preferable.
  • the lower alkoxy group for R 5 for example, a methoxy group, an ethoxyquin group, a propyloxy group and the like are preferable.
  • R 5 represents a bond in connection with a hydrogen atom or a hydroxyl group or R 1 .
  • Ring A and ring B are ortho-fused with each other; ring A is an aromatic carbon or heterocycle; ring B is a 4- to 7-membered aliphatic carbon or nitrogen-containing heterocycle, wherein the nitrogen atom is Means a ring that can only exist at the fused site of
  • Preferred examples of the aromatic carbon ring A include a benzene ring and a naphthalene ring
  • examples of the aromatic heterocycle include an indole ring, a benzofuran ring, a benzothiophene ring, and a quinoline ring.
  • a cyclopentane ring for example, a cyclopentene ring, a cyclohexane ring, a cyclohexene ring and the like are preferable.
  • the 4- to 7-membered aliphatic nitrogen-containing heterocyclic ring of the B ring for example, a pyrrolidine ring and the like are preferable.
  • R represents a substituent or a hydrogen atom selected from the group consisting of a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, an aromatic carbocyclic group and a carbonyl group having an aromatic carbocyclic group.
  • the bond between the group represented by and the carbonyl group adjacent thereto is preferably a case where the group is bonded to the carbon atom of the carbonyl group on the ring atom of the ring B excluding the condensed site with the ring A.
  • R represents a hydrogen atom or a substituent selected from the group consisting of a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, an aromatic carbocyclic group, and a hydrocarbon group having an aromatic carbocyclic group.
  • the substituent is the same or different from one or more of the group consisting of a halogen atom, a nitro group, a lower alkyl group, a lower alkoxy group, an aromatic carbocyclic group and a functional group having an aromatic carbocyclic group, Preferably 1 or 2 can be selected and the formula
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxyquin group, a propyloxy group, an isopropyloxy group, a methylenedioxy group, and more preferably a methoxy group, a methylenedioxy group.
  • aromatic carbocyclic group for the substituent for example, a phenyl group is suitable.
  • carbonyl group having an aromatic carbocyclic group as the substituent for example, a benzyl group or the like is suitable.
  • a substituent such as a halogen atom or a lower alkyl group in addition to a hydrogen atom is preferable.
  • Ar is a halogen atom, lower alkyl group, lower alkenyl group, halo-lower alkyl Or a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aromatic carbocyclic group, which may have an aromatic carbon or heterocyclic group.
  • An aromatic carbon or heterocyclic group which may have an unsubstituted aromatic carbocyclic group or an aromatic heterocyclic group, or the aromatic having a substituent at any substitutable position.
  • One or more, preferably one or two, preferably the same or different from the group consisting of an alkylamino group and an aromatic carbocyclic group can be selected. Kill.
  • Suitable examples of the halogen atom for the substituent include a chlorine atom and a bromine atom.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, a butyl group.
  • the lower alkenyl group for the substituent includes, for example, a vinyl group, a 2-propenyl group, an isopropyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and more preferably a vinyl group, a 2-propyl group A benzyl group and the like are preferred.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a methylenedioxy group, and more preferably a methoxy group, a methylenedioxy group.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • a methylthio group for example, a methylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent examples include a dimethylamino group and the like. Is preferred.
  • aromatic carbocyclic group for the substituent for example, a phenyl group is suitable.
  • substituent a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a di-lower alkylamino group and the like are preferable.
  • aromatic carbocyclic group for Ar for example, a funyl group, a naphthyl group and the like are preferable, and as the aromatic heterocyclic group, for example, a pyridyl group and the like are preferable.
  • Ar for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group , 3,4-dichlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 5-chloro-3-pyridyl group, 5-bromo-3-pyridyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-propylphenyl, 5-methyl-2-pyridyl, 6-methyl-3-pyridyl, 6-ethyl-3-pyridyl, 2-methyl-4-pyrid
  • -Biphenylinole group 4-biphenylinole group and the like.
  • 4-pyridinole group 2-methyl-4-1-pyridyl group, 2-ethyl-4-pyridyl group, 2-propyl-1 group
  • Ar is a phenyl group, and a compound represented by the formula:
  • Ar 1 represents an aryl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group.
  • aryl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a halo-lower alkyl group is the unsubstituted aryl group or any substitutable aryl group.
  • Suitable examples of the halogen atom for the substituent include a chlorine atom and a bromine atom.
  • the lower alkyl group for the substituent for example, a methyl group, an ethyl group, a propanol group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and the like are more preferable.
  • the halo-lower alkyl group for the substituent is, for example, preferably a trifluoromethyl group.
  • a halogen atom and the like are preferable.
  • aryl group for Ar 1 for example, a phenyl group is suitable.
  • examples of Ar 1 include a phenyl group and a 3-chlorophenyl group, and among them, a 3-chlorophenyl group and the like are preferable.
  • Ar 2 is a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group. It means an aryl group or a heteroaromatic group which may be present.
  • It has a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group.
  • a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group.
  • the aryl group or the heteroaromatic group which may be substituted or unsubstituted, the aryl group or the heteroaromatic ring group, or the aryl group or the heteroaromatic group having a
  • a cyclic group wherein the substituent is a group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, and an aryl group.
  • the same or different one or more, preferably one or two can be selected.
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group. It is.
  • Examples of the lower alkenyl group for the substituent include a vinyl group, a 2-propenyl group, an isopropyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and more preferably a vinyl group, a 2-propyl group.
  • a benzyl group and the like are preferred.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propyloxy group, a methylenedioxy group, and the like, and more preferably a methoxy group, a methylenedioxy group, and the like.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • a methylthio group for example, a methylamino group and the like are preferable.
  • the di-lower alkylamino group for the substituent is, for example, preferably a dimethylamino group.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a halogen atom a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a di-lower alkylamino group and the like are preferable.
  • the aryl group of Ar 2 is preferably, for example, a phenyl group, and the heteroaromatic group is, for example, a pyridyl group.
  • Ar 2 includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-pyridinole, 3-pyridyl, 4-pyridyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, Monochlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-chloro-3-pyridyl, 5-bromo-3-pyridyl Group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 5-methyl-2-pyridyl group, 6-methyl-3-pyridyl group 6-ethyl-3-pyridyl group, 2-methyl-4 monopyridyl group, 2-ethyl-4-pyridyl group, 2-
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group.
  • the lower alkyl group for R 1 and R 2 for example, a methyl group, an ethyl group and the like are preferable.
  • R 1 and R 2 both are preferably hydrogen atoms.
  • R 3 and R 4 are the same or different and each may be a hydrogen atom or a lower alkyl group, or both R 3 and R 4 may be linked to each other to form a lower alkyl group; Means a group.
  • R 3 and R 4 for example, a methyl group, an ethyl group and the like are preferable.
  • C2-C4 alkylene group optionally having lower alkyl group and Represents an unsubstituted alkylene group or an alkylene group having one or more lower alkyl groups which are the same or different at any substitutable position, and the unsubstituted alkylene group is preferable.
  • the lower alkyl group as a substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, etc., and more preferably a methyl group.
  • R 3 and R 4 even if R 3 and R 4 are the same or different and are a lower alkyl group, or both R 3 and R 4 are linked to each other to have a lower alkyl group Preferred are alkylene groups having 2 to 4 carbon atoms, particularly alkylene groups having 2 carbon atoms.
  • R 5 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group.
  • the lower alkyl group for R 5 for example, a methyl group, an ethyl group, and the like are preferable.
  • alkoxy groups of from 1 to 7 carbon atoms i.e., for example, main butoxy group, an ethoxy group, etc.
  • Puropiruokishi group more preferably a suitable main preparative alkoxy group.
  • the R 5, are preferable a hydrogen atom.
  • Ar 1 is selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, an acyl group and an aryl group. It means an aryl group or a heteroaromatic ring group which may have a substituent.
  • the aryl group or the heteroaromatic ring group '' may be the unsubstituted aryl group or the heteroaromatic ring group, or the aryl group having the substituent at any substitutable position or the aryl group A heteroaromatic group, wherein the substituent is a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkynoleamino group, or an acyl group; And one or more, preferably one or two, identical or different from the group consisting of Can be
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • Examples of the lower alkenyl group for the substituent include a vinyl group, a 2-propenyl group, an isopropenyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and more preferably a vinyl group, Propenyl groups and the like are preferred.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propyloxy group, a methylenedioxy group, and the like, and more preferably a methoxy group, a methylenedioxy group, and the like.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • the lower alkylamino group for the substituent is, for example, preferably a methylamino group.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group is preferred.
  • acyl group for the substituent for example, a formyl group, an acetyl group, a benzoyl group and the like, and more preferably a benzoyl group and the like are suitable.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a halogen atom As the substituent, a halogen atom, a lower alkyl group, an acyl group and the like are preferable.
  • the aryl group of Ar 1 is preferably, for example, a phenyl group or a naphthyl group, and the heteroaromatic group is, for example, a pyridyl group or a benzoxazolyl group.
  • Ar 1 is, for example, phenyl, 1-naphthinole, 2-naphthyl, 2-pyridinole, 3-pyridinole, 4-pyridyl, 2-benzoxazolyl, 4-isobutylphenyl Group, 3-benzoylphenyl group, 2-funololol 4-biphenylyl group and the like, and among them, 111-naphthyl group, 2-naphthinolene group, 3-benzoylphenyl group and the like are preferable. is there.
  • Ar 2 is a halogen atom, lower alkyl group, lower alkenyl group, halo-lower alkyl Aryl, heteroalkyl, lower alkylthio, lower alkylamino, di-lower alkylamino, and aryl, which may have a substituent selected from the group consisting of aryl and heteroaryl. It means an aromatic ring group.
  • a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group and an aryl group.
  • the aryl group or the heteroaromatic ring group which may be substituted '' is the unsubstituted aryl group or the heteroaromatic ring group, or the aryl group or the heteroaryl group having a substituent at any substitutable position.
  • substituent is a halogen atom, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, and aryl.
  • One or two or more, preferably one or two, identical or different groups can be selected from the group consisting of one group.
  • halogen atom for the substituent for example, a chlorine atom, a bromine atom and the like are preferable.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • Examples of the lower alkenyl group for the substituent include a vinyl group, a 2-propenyl group, an isopropyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, and more preferably a vinyl group, Propenyl groups and the like are preferred.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxyquin group, a propyloxy group, a methylenedioxy group, and the like, and more preferably a methoxy group, a methylenedioxy group, and the like.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • a methylthio group for example, a methylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent examples include a dimethylamino group and the like. Is preferred.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a halogen atom a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a di-lower alkylamino group and the like are preferable.
  • the aryl group of Ar 2 is preferably, for example, a phenyl group, and the heteroaromatic ring group is, for example, a pyridyl group.
  • Ar 2 for example, phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridinole, 2-chlorophenyl, 3-chloro Phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 5-chloro-3-pyridyl, 5-bromo-3-pyridyl Group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 5-methyl-12-pyridyl group, 6-methyl-3 —Pyridyl, 6-ethyl-3-pyridyl, 2-methyl-4-pyridyl, 2-ethyl-4-pyridyl, 2-propyl-4-pyri
  • n 0, 1 or 2.
  • n 0 or 1 is preferable.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group.
  • the lower alkyl group for R 1 and R 2 for example, a methyl group, an ethyl group and the like are preferable.
  • R 1 and R 2 both are preferably hydrogen atoms.
  • Ar is selected from the group consisting of a halogen atom, a nitro group, an amino group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoyl group and an aryl group. Or an aryl group or a heteroaromatic group which may have a substituent.
  • aryl group or a heteroaromatic group which may have a substituent selected from the group consisting of The substituted aryl group or the heteroaromatic ring group, or the aryl group or the heteroaromatic ring group having a substituent at any substitutable position, wherein the substituent is a halogen atom, a nitro group, The same or different from the group consisting of: an amino group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanol group and an aryl group or a heteroaromatic group, which may have a substituent selected from the group consisting of The substituted aryl group or the heteroaromatic ring group, or the aryl group or the heteroaromatic ring group having a substituent at any substitutable position, wherein the substituent is a
  • halogen atom for the substituent include a chlorine atom and a bromine atom.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • the halo-lower alkyl group for the substituent is, for example, preferably a fluoromethyl group, a trifluoromethyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group, a propyloxy group, a methylenedioxy group, and the like, and more preferably a methoxy group, a methylenedioxy group, and the like.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group, a propylthio group, and more preferably a methylthio group.
  • a methylthio group for example, a methylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group is preferred.
  • an acetyl group is not preferred.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a halogen atom, a nitro group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkanoyl group and the like are preferable.
  • Examples of the aryl group of Ar include a phenyl group and a naphthyl group, and examples of the heteroaromatic ring group include a pyridyl group, an indolinole group, a benzoimidazolyl group and a benzyl group. Nzoxazolyl groups and the like are preferred.
  • Ar for example, phenyl, 1-naphthyl, 2-naphthinole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-indolinole, 3-indolyl, 2-benzoyl Midazolyl group, 2-benzoxazolyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group , 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl group, 3,5-bis (trifluoromethyl) phenyl group, 2-methoxy Phenyl, 3-
  • R 1 and R 2 are the same or different and each represents a lower alkyl group or an alkylene group in which both R 1 and R 2 may be linked to each other and may be via an oxygen atom or a sulfur atom.
  • alkyl group for R 1 and R 2 for example, a methyl group, an ethyl group and the like are preferable.
  • alkylene group optionally interposed through an oxygen atom or a sulfur atom more preferably, for example, a pyrrolidinyl group, a thiazolidinyl group, a piperidino group, a monorefolino group, a hexahydro-1H-azepinyl group, etc. together with an adjacent nitrogen atom.
  • R 1 and R 2 an alkylene group in which both R 1 and R 2 may be connected to each other via an oxygen atom or a sulfur atom is preferable.
  • R 3 represents an amino group, a lower alkyl group or a lower alkylamino group.
  • the lower alkyl group for R 3 for example, a methyl group, an ethyl group, a propyl group, an isopropyl group and the like are preferable.
  • the lower alkylamino group for R 3 for example, a methylamino group, an ethylamino group and the like are preferable.
  • R 3 is preferably a lower alkyl group or a lower alkylamino group.
  • Y is an ethylene group, a trimethylene group, a vinylene group, a probenylene group or
  • Y a group represented by an ethylene group, a vinylene group, a propenylene group, or 1 O—CH 2 — is preferable.
  • the position number of the xanthene skeleton is expressed in principle by the position number given to the skeleton in the general formula [If], or, if necessary, by adding a braille to the position number.
  • R 1 represents a hydrogen atom or a lower alkyl group, or a lower alkylene group together with R 2 even if an oxygen atom is interposed.
  • the lower alkyl group for R 1 for example, a methyl group, an ethyl group, and the like are preferable.
  • R 1 and R 2 together mean, for example, a trimethylene group, a tetramethylene group, a pentamethylene group and the like are preferable.
  • R 2 represents a lower alkyl group or, together with R 1 , has the meaning described above.
  • R 3 and R 4 represent a hydrogen atom at the same time, or both are a single bond Means
  • R 3 and R 4 be a single bond when they are taken together.
  • R 5 and R 6 represent a hydrogen atom at the same time, or a lower alkylidene group which may be taken together to intervene with an oxygen atom.
  • R 5 and R 6 be a lower alkylidene group, even if both are joined together and an oxygen atom is interposed.
  • the lower alkylidene group for example, an isopropylidene group, an ethylpyridene pyridene group, a cyclobutylidene group, a cyclopentylidene group, a cyclohexylidene group and the like are preferable.
  • RR 2 , R 5 and R 6 include, for example, R 1 and R 2 are both a lower alkyl group, and R 5 and R 6 are taken together to form a linear or branched lower alkylidene.
  • R 1 and R 2 are together, an oxygen atom may be intervened, or when R 1 and R 2 are a lower alkylene group, and R 5 and R 6 are together, an oxygen atom may be intervened.
  • R 5 and R 6 are together, an oxygen atom may be intervened.
  • it is a cyclic lower alkylidene group.
  • R 7 and R 8 are independently a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aryl group, an aralkyloxy group, a di-lower alkylamino group, a lower alkoxycarbonylamino group or
  • Aryl means a luponylamino group, or a combination of both, a lower alkylene group, or a benzene ring which is ortho-condensed with an adjacent ring.
  • halogen atom for R 7 or R 8 for example, a fluorine atom, a chlorine atom, a bromine atom and the like, more preferably a fluorine atom and the like are suitable.
  • R 7 or R 8 for example, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, and the like, and more preferably a methyl group, an ethyl group, and the like are preferable.
  • R 7 or R 8 for example, a methoxy group, an ethoxyquin group, a propoxy group and the like, and more preferably a methoxy group and the like are preferred.
  • aryl group for R 7 or R 8 for example, a phenyl group is suitable.
  • aralkyloxy group for R 7 or R 8 for example, a benzyloxy group or the like can be obtained in a good time.
  • Examples of the di-lower alkylamino group for R 7 or R 8 include a dimethylamino group, Getylamino groups and the like are preferred.
  • R 7 or R 8 for example, an isopropoxycarbonylamino group is suitable.
  • the ⁇ reel carbonyl ⁇ amino group R 7 or R 8 for example, base Nzoiruami amino group and the like.
  • R 7 and R 8 together mean, for example, a trimethylene group, a tetramethylene group, and the like are suitable, and both ends of the group are compounds represented by a general formula [If]. It is more preferable to bind to the 5- and 6-positions of the above.
  • R 7 and R 8 together represent a benzene ring which is ortho-fused to an adjacent ring, the benzene ring is fused to the 5- and 6-positions of the compound represented by the general formula [If]. Is preferred.
  • R 7 and R 8 are each present at the 5- or 6-position, and independently represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.
  • X represents an oxygen atom or a sulfur atom, and an oxygen atom is preferred.
  • Y means a methine group or a nitrogen atom, with a methine group being preferred.
  • the compound according to the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, and geometric isomers, depending on the mode of the substituent. It also includes stereoisomers and tautomers and mixtures thereof.
  • 6-Ethyl-9-1 (2-hydroxy-4,4-dimethyl-6-oxo-1-cyclohexenyl) -1,3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthene-1
  • 6-tert-butyl-1-9-1 (2-hydroxy-4,4-dimethyl-6-oxo-11-cyclohexenyl) -1,3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthene-1
  • 6-benzoylamino-9-1 (2-hydroxy-1,4-dimethyl-6-oxo-11-cyclohexenyl) -1,3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one ,
  • Naphthalene-1-sulfonic acid 4-[(4-aminoquinazoline-12-inoleamino) methyl] benzylamide hydrochloride
  • trans-N- ⁇ 4 [(4-aminoquinazoline-1-2-ylamino) methyl] cyclohexylmethyl ⁇ —2,5-dimethoxybenzenesulfonamide hydrochloride
  • trans-N- ⁇ 4 [(4- Aminoquinazoline-2-ylamino) methyl] cyclohexylmethyl ⁇ benzenesulfonamide hydrochloride
  • trans-naphthalene-12-sulfonic acid ⁇ 4-[(4-aminoquinazoline-12-inoleamino) methinole] cyclohexylmethyl ⁇ amide hydrochloride,
  • trans-N- ⁇ 4 [(4-aminoquinazoline-1-2-ylamino) methyl] cyclohexylmethynole ⁇ 1- (4-tert-butylbenzenesulfonamide hydrochloride, trans—N— ⁇ 4-((4- Aminoquinazoline- 1-2-ylamino) methyl] cyclohexylmethyl ⁇ 1,2,4,6-trimethylbenzenesulfonamide hydrochloride, trans-N- ⁇ 4-[(4-aminoquinazoline-12-ylamino) methyl] Hexylmethyl ⁇ —4-methylbenzenesulfonamide hydrochloride, trans-N- ⁇ 4-[(4-aminoquinazoline-1-ylamino) methyl] hexylhexylmethyl ⁇ benzamide hydrochloride,
  • Morpholine-1-sulfonic acid ⁇ 4-[(4-aminoquinazoline-12-inorenamino) methyl] cyclohexylmethyl ⁇ amide
  • Naphthalene-1-sulfonic acid ⁇ 4 [(4-amino-8-methoxethoxyquina Zoline-2-ylamino) methyl] cyclohexylmethyl ⁇ amide, naphthalene-1-sulfonic acid ⁇ 4- ⁇ 4-amino-8- (N, N-dimethylaminoaminoethoxy) quinazoline-1-ylamino] methyl ⁇ cyclohexylmethyl ) Amido,
  • trans-N- ⁇ 4 [(4-aminoquinazoline-1-2-ylamino) methyl] cyclohexylmethyl ⁇ —4-fluorobenzenesulfonamide hydrochloride
  • trans-N- ⁇ 4 [(4- Aminoquinazoline—2-ylamino) methyl] cyclohexylmethyl ⁇ —2-nitrobenzenesulfonamide hydrochloride
  • trans-piperidine-11-sulfonic acid ⁇ 4 -— ((4-aminoquinazoline-12-inoleamino) methyl] cyclo Hexylmethyl ⁇ amide hydrochloride
  • trans-naphthalene-1-sulfonic acid ⁇ 4-1 ⁇ [4- (3-methoxypropylamino) quinazoline-1-2-inoleamino] methyl ⁇ cyclohexylmethyl ⁇ amide
  • trans-naphthalene-1-sulfonic acid ⁇ 4-[(4-aminoquinazoline-2-ylamino) methyl] cyclohexylmethyl ⁇ methylamide hydrochloride
  • trans-naphthalene-1-methyl sulfonate ⁇ 4-[(4-phenyl Aminoquinazoline-2-ylamino) methyl] cyclohexylmethyl ⁇ amide hydrochloride
  • trans-naphthalene-11-methylsulfonate ⁇ 4-1 [1- (4-aminoquinazolin-2-ylamino) -1-methylethyl] cyclohexylmethyl ⁇ Amide hydrochloride,
  • ⁇ trans-1-41 ⁇ [4-1- (3-ethylpyraminopropylamino) -1,6,8-dimethylquinazoline-12-ylamino] methyl ⁇ cyclohexyl ⁇ phenylmethanone.
  • the compounds represented by the general formulas [I-a], [I-b], [I-c], [I-d], [I-e], or [I-f] are represented by And the compounds described in the international applications PCT / JP97 04399, PCT / JP97 04567, PCT / JP97 / 0457U PCT / JP97 / 04569, PCT / JP98 / 01015, PCT / JP98Z01855, and PCTZJP98 / 04314, etc. And has NPY Y5 receptor antagonism.
  • the compounds represented by the general formulas [I-g], [I-h], [I-i], and [I-j] are described in International Publication Nos. W097Z19682, WO97 / 20820, WO97Z20821, and W097, respectively. No. 20822, WO97Z20823 and the like, and have NPY Y5 receptor antagonistic activity.
  • the compound represented by the general formula [I-a] can be produced, for example, by the following Production Method 1 or the method shown in Production Examples.
  • Ar 2 has the meaning as defined in the general formula [I-a], and a compound represented by the general formula [III-a] O
  • Ar 3 is a halogen atom or a phenyl group which may be substituted with a nitro group
  • X represents a halogen atom, and a compound represented by the general formula [IV-a]
  • the reaction between the compound represented by the general formula [II-a] and the compound represented by the general formula [III-a] is usually performed with respect to 1 mol of the compound represented by the general formula [ ⁇ -a].
  • the reaction is carried out using the compound represented by the general formula [III-a] in an amount of 0.5 mol to excess mol, preferably equimolar or 1.5 mol.
  • the reaction is usually performed in an inert solvent.
  • the inert solvent include methylene chloride, chloroform, tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide and the like, or a mixed solvent thereof. It is suitable.
  • the above reaction is preferably carried out in the presence of a base.
  • the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydroxide, and water.
  • Use inorganic bases such as oxidized lime, sodium carbonate, lium carbonate, sodium hydrogen carbonate Can be
  • the base is usually preferably used in an equimolar amount or an excess amount relative to 1 mol of the compound represented by the general formula [ ⁇ -a].
  • the base can be used as a solvent and a base.
  • the reaction temperature is generally -78 ° C to 100 ° C, preferably -20 ° C to 50 ° C.
  • the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • the compound represented by the general formula [IV-a] obtained by the above reaction is isolated. Without isolation or isolation, the compound represented by the general formula [Va] is usually equimolar to excess mol, preferably equimolar or 1.5 mol per mol of the compound [IV-a]. It is performed using a mole.
  • the reaction is usually performed in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide and the like, or a mixed solvent thereof are suitable.
  • inert solvent for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide and the like, or a mixed solvent thereof are suitable.
  • the above reaction is preferably performed in the presence of a base.
  • a base for example, triethylamine, diisopropylethylamine, and the like are preferable.
  • the amount of the base to be used is generally equimolar to excess, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula [IV-a].
  • the reaction temperature is usually-30 ° C to 200 ° C, preferably 20 ° C to 100 ° C.
  • the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • the target compound in each of the above steps can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin-layer chromatography, and the like.
  • the compound of the general formula [Ia] can be converted into a pharmaceutically acceptable salt by a conventional method, and conversely, the conversion of the salt into a free compound can be performed by a conventional method.
  • the compound represented by the general formula (la) and acetonitrile are reacted in the presence of a base group.
  • the compound represented by the general formula [II-a] can be produced by reacting the compound to give a compound represented by the general formula (3a) and then reacting the compound (3a) with hydrazine.
  • reaction conditions vary depending on the type of base used.
  • the reaction is usually carried out in an inert solvent such as tetrahydrofuran or ethyl ether, and the reaction temperature is usually -78 ° C to room temperature. Yes, the reaction time is usually 30 minutes to 6 hours.
  • the reaction is usually performed in an inert solvent such as tetrahydrofuran, ethyl ether, or dimethylformamide, and the reaction temperature is usually from room temperature to 100 ° C. Yes, the reaction time is usually 1 hour to 6 hours.
  • an inert solvent such as tetrahydrofuran, ethyl ether, or dimethylformamide
  • the reaction of compound (3a) with hydrazine is usually carried out, for example, with ethanol, propanol, isoamyl alcohol, acetic acid, benzene, toluene, xylene or In an inert solvent such as a mixed solvent thereof, hydrazine is used in an amount of 0.5 mol to 10 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound (3a).
  • the reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction, preferably from 50 ° C to the boiling point of the solvent used in the reaction.
  • the reaction time is generally 30 minutes to 7 days, preferably 1 hour to 48 hours.
  • the hydrazine used for the reaction may be an anhydride or a hydrate.
  • the compound represented by the general formula (3a) is replaced with a compound represented by the general formula (2a) instead of the compound represented by the general formula (la), and by reacting the compound with cyanide. It can also be manufactured.
  • the compound represented by the general formula (la) or (2a) can be produced by using a commercially available product, or by appropriately combining a known method or a method analogous thereto as necessary.
  • the compound represented by the general formula [III-a] or [Va] can be produced by using a commercially available product, or by appropriately combining a known method or a method analogous thereto as necessary.
  • the compound represented by the general formula [I-b] can be produced, for example, by the following production method 2, 3, 4, or 5 or a method shown in Production Examples.
  • a ring, B ring and R have the meanings as defined in the above general formula [I-b].
  • the compound represented by the general formula [I-b] can be produced by reacting the compound with the carboxylic acid represented by the formula [Ib] or a reactive derivative thereof.
  • the reaction between the compound represented by the general formula [ ⁇ —b] and the carboxylic acid represented by the general formula [III-b] is usually performed with respect to 1 mol of the compound represented by the general formula [ ⁇ —b].
  • the reaction is carried out using a carboxylic acid represented by the general formula [III-b] in an amount of 0.5 mol to excess mol, preferably 1 mol to 1.5 mol.
  • the reaction is usually carried out in an inert solvent.
  • the inert solvent for example, dimethylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine and the like or a mixed solvent thereof are suitable.
  • the above reaction is preferably carried out in the presence of a condensing agent.
  • the condensing agent include N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylpyrucarpoimide, and 3- (3-dimethylaminopropyl) -1-3-ethylcarbodiimide, 1-1- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride, benzotriazo-1-yl-11-ylokistris- (dimethylamino) phosphonium hexane Fluorophosphate, benzotriazole-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate, bromotris- (dimethylamino) phosphonium hexafluorophosphate, diphenylphosphoric azide , 1, ⁇ -carbonyldiimidazole and the like can be used
  • the condensing agent can be used usually in an amount of 1 mol to excess mol, preferably 1 mol to 1.5 mol, per 1 mol of the compound represented by the general formula [ ⁇ -b].
  • the reaction temperature is usually from -50 ° C to 100 ° C, preferably from -20 ° C to 50 ° C.
  • the reaction time is generally 30 minutes to 7 days, preferably 1 hour to 24 hours.
  • the reactive derivative of the carboxylic acid represented by the general formula [III-b] for example, an acid halide, a mixed acid anhydride, an active ester, an active amide and the like are used.
  • the acid halide of the carboxylic acid of the general formula [III-b] can be obtained by reacting the carboxylic acid of the general formula [III-b] with a halogenating agent according to a conventional method. it can.
  • a halogenating agent for example, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, oxalyl chloride, phosgene and the like are used.
  • the mixed acid anhydride of the carboxylic acid of the general formula [III-b] is obtained by converting the carboxylic acid of the general formula [III-b] to a carboxylic acid according to a conventional method, for example, an alkyl carbonate such as ethyl ethyl carbonate; It can be obtained by reacting with an aromatic carboxylic acid chloride or the like.
  • the active ester of a carboxylic acid of the general formula [III-b] can be prepared by reacting the carboxylic acid of the general formula [III-b] with N, N'-dicyclohexylcarbodiimide, e.g. Dimethylaminopropyl)
  • N, N'-dicyclohexylcarbodiimide e.g. Dimethylaminopropyl
  • a condensing agent such as 1-3-ethylcarbodiimide, for example, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, etc.
  • Hydroxy compound can be obtained by reacting with a phenol compound such as 412 trophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol, etc. .
  • the active amide of the carboxylic acid of the general formula [III-b] can be prepared by reacting the carboxylic acid of the general formula [III-b] with 1,1-carbonyldiimidazole, 1,1-carbonylbis (2 —Methylimidazole) and the like.
  • the reaction between the compound represented by the general formula [II-b] and the reactive derivative of the carboxylic acid represented by the general formula [III-b] is usually carried out by the compound 1 represented by the general formula [ ⁇ -b].
  • the reaction is carried out using a reactive derivative of a carboxylic acid represented by the general formula [III-b] in an amount of 0.5 mol to excess mol, preferably 1 mol to 1.5 mol, per mol.
  • the reaction is usually carried out in an inert solvent.
  • the inert solvent for example, dimethylene chloride, chloroform, tetrahydrofuran, dimethylformamide, pyridine and the like or a mixed solvent thereof are suitable.
  • the above reaction proceeds even in the absence of a base, but is preferably performed in the presence of a base to promote the reaction more smoothly.
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, and sodium hydroxide.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine
  • sodium hydroxide examples include sodium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, and sodium hydrogencarbonate.
  • the base is preferably used in an amount of 1 mol or less, relative to 1 mol of the compound represented by the general formula [ ⁇ -b].
  • the base can be used as a solvent and a base.
  • the reaction temperature is generally-50 ° C to 100 ° C, preferably-20 ° C to 50 ° C.
  • the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • Ar 1 is selected from the group consisting of a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, and an aromatic carbocyclic group
  • X 1 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • a ring, B ring and R have the above-mentioned meanings.
  • R 1 is a lower alkyl group, a lower alkenyl group or an aromatic carbocyclic group
  • R a represents a lower alkyl group] with a compound represented by the following formula: Equation [1— 1— b]
  • a ring, B ring, ON! "1, R and R 1 are as defined above] can be prepared a compound represented by.
  • the reaction between the compound represented by the general formula [VI-b] and the compound represented by the general formula [VII-b] is usually performed based on 1 mol of the compound represented by the general formula [VI-b].
  • the reaction is performed using the compound represented by the general formula [VII-b] in an amount of 0.5 mol to 10 mol, preferably 1 mol to 3 mol.
  • the reaction is usually performed in an inert solvent, and as the inert solvent, for example, benzene, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and the like, or a mixed solvent thereof are suitable.
  • the inert solvent for example, benzene, toluene, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and the like, or a mixed solvent thereof are suitable.
  • Examples of the palladium catalyst used in the reaction include tetrakistriphenylphosphine. Sphine palladium, bistriphenylphosphine palladium chloride, palladium acetate, trisdibenzylideneacetone dipalladium and the like can be used.
  • the palladium catalyst can be used usually in an amount of 0.001 to 1 mol, preferably 0.01 to 0.1 mol, per 1 mol of the compound represented by the general formula [VI-b].
  • a phosphine ligand such as 2-furylphosphine or lithium chloride can be allowed to coexist.
  • the reaction temperature is usually from room temperature to 200 ° C, preferably from 60 ° C to 150 ° C.
  • the reaction time is usually 30 minutes to 7 hours, preferably 1 hour to 24 hours.
  • Ar 2 is selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, a di-lower alkylamino group, and an aromatic carbocyclic group.
  • R 2 represents a lower alkenyl group, and A ring, B ring and R have the above-mentioned meanings.
  • R 3 represents a lower alkyl group, and A ring, B ring, Ar 2 and R have the above-mentioned meanings].
  • the reaction is usually performed in an inert solvent, and examples of the inert solvent include, for example, Methanol, ethanol, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, acetic acid and the like, or a mixed solvent thereof are suitable.
  • the catalyst used in the reaction is, for example, preferably a "radium-carbon catalyst".
  • the reaction temperature is usually room temperature.
  • the hydrogen pressure is usually 1 to 50 atm, preferably 1 to 5 atm.
  • the reaction time is generally 30 minutes to 7 days, preferably 1 hour to 24 hours. Manufacturing method 5
  • R 4 is a substituent selected from the group consisting of a nitro group, a lower alkyl group, a lower alkoxy group, an aromatic carbocyclic group, and a hydrocarbon group having an aromatic carbocyclic group, or a hydrogen atom;
  • a ring, B ring, Ar and X 1 have the above-mentioned meaning], and a compound represented by the general formula [IX—b]
  • R 5 represents a lower alkyl group or an aromatic carbocyclic group, and Ra has the above-mentioned meaning] with a compound represented by the following formula: [I one 41 b]
  • the reaction between the compound represented by the general formula [VIII-b] and the compound represented by the general formula [IX-b] is carried out by reacting the compound represented by the general formula [VI-b] in the production method 2 described above.
  • the reaction can be carried out in the same manner as in the reaction with the compound represented by the general formula [VII-b]. Accordingly, the same conditions can be applied to the reaction conditions and the like.
  • the compound represented by the general formula [I-b], [I-1-b], [I-3-b] or [I-4-1b] can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin-layer chromatography, and the like.
  • carboxylic acid represented by the general formula [III-b] used in the present invention a commercially available product, a known method or a method analogous thereto, or a method described in Reference Examples, etc., may be appropriately combined as necessary. Can be manufactured.
  • the compound represented by the general formula [VI-b] used in the present invention can be obtained by using a raw material corresponding to a desired compound, a method for producing the compound represented by the general formula [ ⁇ -b] and a method according to the production method 2, and It can be produced by appropriately combining known methods as necessary.
  • the compound represented by the general formula [VII-b] used in the present invention can be produced by using a commercially available product or by appropriately combining a known method or a method analogous thereto as needed.

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Abstract

Cette invention a trait à des médicaments traitant l'hypercholesterolémie, l'hyperlipémie et l'artériosclérose qui contiennent comme ingrédient actif des antagonistes du récepteur du neuropeptide Y Y5, se présentant, notamment, sous la forme d'un composé représenté par la formule [I-f-1].
PCT/JP1998/005358 1997-11-28 1998-11-27 Agents anti-hyperlipemiques WO1999027965A1 (fr)

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043246A (en) * 1996-12-03 2000-03-28 Banyu Pharmaceutical Co., Ltd. Urea derivatives
US6057335A (en) * 1996-12-12 2000-05-02 Banyu Pharmaceutical Co., Ltd. Pyrazole derivatives
US6166038A (en) * 1996-12-13 2000-12-26 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
US6180653B1 (en) 1996-12-16 2001-01-30 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
JP2001131151A (ja) * 1999-11-02 2001-05-15 Shionogi & Co Ltd オレフィン誘導体の新規用途
US6258837B1 (en) 1997-04-23 2001-07-10 Banyu Pharmaceutical Co., Ltd. Neuropeptide Y receptor antagonist
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
WO2005080348A1 (fr) 2004-02-19 2005-09-01 Banyu Pharmaceutical Co., Ltd. Nouveau dérivé de sulfonamide
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
US7304072B2 (en) 2002-03-08 2007-12-04 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
US8053445B2 (en) 2001-09-14 2011-11-08 Shionogi & Co., Ltd. Utilities of olefin derivatives
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine

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WO1997019682A1 (fr) * 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Derives aryle sulfonamide et sulfamide, et leurs utilisations
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WO1997020822A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y
WO1997020820A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles

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WO1997019682A1 (fr) * 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Derives aryle sulfonamide et sulfamide, et leurs utilisations
WO1997020823A2 (fr) * 1995-12-01 1997-06-12 Novartis Ag Antagonistes de recepteurs
WO1997020821A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Derives heteroaryles
WO1997020822A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y
WO1997020820A1 (fr) * 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles

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MASSICOT F., ET AL.: "ANTIOBESITY ACTIVITY OF A NEW CYCLIC AMINO ARYLOXYACETATE IN OBESE MICE AND RATS.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY., EDITIONS SCIENTIFIQUE ELSEVIER, PARIS., FR, vol. 20., no. 06., 1 January 1985 (1985-01-01), FR, pages 559 - 562., XP002920020, ISSN: 0223-5234 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043246A (en) * 1996-12-03 2000-03-28 Banyu Pharmaceutical Co., Ltd. Urea derivatives
US6057335A (en) * 1996-12-12 2000-05-02 Banyu Pharmaceutical Co., Ltd. Pyrazole derivatives
US6166038A (en) * 1996-12-13 2000-12-26 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
US6180653B1 (en) 1996-12-16 2001-01-30 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
US6258837B1 (en) 1997-04-23 2001-07-10 Banyu Pharmaceutical Co., Ltd. Neuropeptide Y receptor antagonist
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
JP2001131151A (ja) * 1999-11-02 2001-05-15 Shionogi & Co Ltd オレフィン誘導体の新規用途
US8124625B2 (en) 2001-09-14 2012-02-28 Shionogi & Co., Ltd. Method of enhancing the expression of apolipoprotein AI using olefin derivatives
US8053445B2 (en) 2001-09-14 2011-11-08 Shionogi & Co., Ltd. Utilities of olefin derivatives
US7304072B2 (en) 2002-03-08 2007-12-04 Banyu Pharmaceutical Co., Ltd. Spiro compounds
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2005080348A1 (fr) 2004-02-19 2005-09-01 Banyu Pharmaceutical Co., Ltd. Nouveau dérivé de sulfonamide
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
US7592461B2 (en) 2005-12-21 2009-09-22 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US8324401B2 (en) 2005-12-21 2012-12-04 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine

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