WO2005090340A1 - Dérivé de piperidine-1-carboxamide - Google Patents

Dérivé de piperidine-1-carboxamide Download PDF

Info

Publication number
WO2005090340A1
WO2005090340A1 PCT/JP2005/004871 JP2005004871W WO2005090340A1 WO 2005090340 A1 WO2005090340 A1 WO 2005090340A1 JP 2005004871 W JP2005004871 W JP 2005004871W WO 2005090340 A1 WO2005090340 A1 WO 2005090340A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
alkyl group
represented
halo
Prior art date
Application number
PCT/JP2005/004871
Other languages
English (en)
Japanese (ja)
Inventor
Toshiyuki Takahashi
Akio Kanatani
Original Assignee
Banyu Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Publication of WO2005090340A1 publication Critical patent/WO2005090340A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is useful in the field of medicine. More specifically, the piperidine-111-potassium lipoxamide derivative of the present invention can be used as a neuropeptide Y receptor antagonist for various cardiovascular, nervous, metabolic, reproductive, and gastrointestinal disorders. It is useful as an agent for treating respiratory diseases, inflammatory diseases or glaucoma. Background technology
  • NPY Neuropeptide Y
  • NPY Neuropeptide Y
  • NPY is a peptide consisting of 36 amino acids, and was first isolated from pig brain by Tachimoto et al. In 1982 [Nature, Vol. 296, p. 659 (1982)]. .
  • 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. In other words, NPY acts centrally as an appetite-stimulating substance and significantly promotes fat accumulation through secretion of various hormones or nervous system action. Based on these effects, continuous intraventricular administration of NPY is known to induce obesity and insulin resistance [International Journal 1 of Obesity, 19 Vol., Pp.
  • NPY has a wide variety of pharmacological effects via receptors that are partially shared with its analogs, peptide YY and pancreatic polypeptide. It is known that the pharmacological effects of these NPYs are triggered by the interaction of at least five types of receptors alone or by interaction [Trends in Neurosciences, 20: 294]. P. (1997)].
  • NPY Y 2 receptor-mediated action is known to inhibit the release of various neurotransmitters at nerve endings [British Journal of Pharmaceutical Sciences (British Journal of Pharmacy). Chem., 102, 41 (1991); Synapse 2, 299 (1988)].
  • the control or direct action of these neurotransmitters involves the contraction of blood vessels or the vas deferens [The Journal of Pharmaceuticals' And'Experimental'Therapeutics (Th. e J ourna 1 of Pharmacolology and Experimental Therapeutics), Volume 261, p. 863 (1992); British Journal of Pharmacology (British J ournalof Pharmacology) , 100 volumes, 190 pages (1990)].
  • the NPY Y3 receptor is mainly expressed in the brainstem and heart, and has been reported to be involved in the control of blood pressure and heart rate [The Journal of Pharmacy and Pharmacology. Therapeutic Therapeutics (The Journal of Pharmaceuticals and Ex perimental Therapeutics), 258, 633 (1991); Peptides, 11, 545 (1990) Year) ] . In addition, it is known to be involved in the secretion of catecholamines in the adrenal gland [The Journal of Opharma lipotherapy and Thexperimenta ⁇ ] Ex oerl me nta 1 T herapeutics) N 24 vol.4, p.468 (1989); Life Sciences, vol.50, PL, p.7 (1992)].
  • the NPY Y 4 receptor has particularly high affinity for pancreatic polypeptides, and its pharmacological effects have been reported to be extrinsic secretion and suppression of gastrointestinal motility [Gas astroenterology, 8 5th, 1 4 1 1 page. (1 9 '8 3 years)]. Further, it is known that the secretion of sex hormones is promoted at the center [Endocrinology (Endocrinolgoy), Vol. 140, pp. 5171 (1989)].
  • NPY functions are expressed by binding NPY receptors present in the central or peripheral nervous system. Therefore, ⁇ ? ⁇ Inhibiting the binding to the receptor can block the expression of NPY. As a result, substances that antagonize the binding of NPY to NPY receptors.
  • Cardiovascular diseases such as bulimia, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with drug withdrawal, circadian rhythm modulation, schizophrenia, memory impairment, sleep disorders
  • Central nervous system diseases such as cognitive impairment, such as obesity, diabetes, abnormal hormonal secretion, gout, fatty liver, etc., reproductive diseases such as infertility, premature birth, sexual dysfunction, gastrointestinal diseases, P can be expected to be useful in the prevention or treatment of organ-related diseases, inflammatory diseases or glaucoma, etc. (Trendsin Pharmacological Sciences), 15, 153, 19 Life Sciences, Vol.
  • NPY receptor antagonists are useful in the prevention or treatment of hypercholesterolemia, hyperlipidemia, and arteriosclerosis. (WO 99/27965 pamphlet).
  • Patent Document 1 discloses a compound similar to the compound of the present invention. However, the document does not disclose or suggest the NPY receptor antagonism of the compound or the compound of the present invention.
  • Patent Document 1 Disclosure of International Patent Publication No. WO 95/02405 Pamphlet An object of the present invention is to provide a novel drug having NPY antagonism.
  • Ar 1 is a halogen atom, a nitro group, a lower alkyl group, a halo lower alkyl group, a hydroxy lower alkyl group, a cyclo lower alkyl group, a lower alkenyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, a lower alkyl group.
  • RR 2, R 3, R 4, R 5, R 6, R 7, R 8,! ⁇ ! ⁇ Each independently represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group; T, U, V and W each independently represent a halogen atom, a lower alkyl group A methine group or a nitrogen atom which may have a substituent selected from the group consisting of a hydroxyl group and a lower alkoxy group, at least one of which means the methine group; X is a single bond, methylene Group or an ethylene group; Y is a single bond or one 0—, one C (R 1 ) (R 2 ) one, one O— C (R
  • the compound (I) of the present invention has NPY antagonism, particularly NPY Y5 receptor antagonism, and has excellent pharmacokinetics such as cerebral distribution or cerebrospinal fluid distribution, and is also highly safe Therefore, various diseases involving NPY, such as angina, acute depressive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, and other cardiovascular diseases, such as bulimia , Depression, anxiety, convulsions, epilepsy, dementia, pain, alcohol dependence, withdrawal symptoms associated with withdrawal of drugs, circadian rhythm modulation, schizophrenia, memory disorders, sleep disorders, cognitive disorders, etc.
  • NPY antagonism particularly NPY Y5 receptor antagonism
  • various diseases involving NPY such as angina, acute depressive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, and other cardiovascular diseases, such as bul
  • Metabolic diseases such as obesity, diabetes, hormone secretion abnormalities, hypercholesterolemia, hyperlipidemia, gout, fatty liver, etc.
  • reproductive diseases such as infertility, premature birth, sexual dysfunction, gastrointestinal tract System diseases, respiratory diseases, Symptomatic disease or glaucoma, and also for example atherosclerosis; hypogonadism; hyperandrogenesis; polycystic ovary syndrome; hirsutism; gastrointestinal motility disorders; gastroesophageal reflux associated with obesity; Ventilation syndrome (Pick Wick syndrome); sleep apnea syndrome group; inflammation; systemic vasculitis; osteoarthritis; insulin resistance; bronchoconstriction; alcohol preference; tabolics yn drome; syndrome X); Alzheimer's disease; cardiac hypertrophy; left ventricular hypertrophy; hypertriglyceridemia; low HDL cholesterolemia; eg coronary heart disease (CHD); Cardiovascular diseases such as sexual diseases, strokes, peripheral vascular diseases, sudden death, etc
  • the compound (I) of the present invention is useful as an agent for treating, for example, bulimia, obesity, diabetes, and the like. Useful.
  • the present invention relates to a compound represented by the general formula (I), a salt or ester thereof, and a production method and use thereof.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutynole group, sec-butyl group. Group, tert-butyl group, pentyl group, isopentynole group, hexyl group, isohexyl group and the like.
  • Halo-lower alkyl group means the lower alkyl group in which any substitutable position is substituted by one or more, preferably 1 to 3 identical or different halogen atoms, such as fluoromethyl group, difluoromethyl Group, trifluoromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, chloromethyl group, 2-chloroethynole group, 1,2-dichloromethyl group, bromomethyl group, and oxymethyl group.
  • halogen atoms such as fluoromethyl group, difluoromethyl Group, trifluoromethyl group, 2-fluoroethyl group, 1,2-difluoroethyl group, chloromethyl group, 2-chloroethynole group, 1,2-dichloromethyl group, bromomethyl group, and oxymethyl group.
  • “Hydroxy lower alkyl group” means the above lower alkyl group in which any substitutable position is substituted by one or more, preferably one or two hydroxyl groups, such as a hydroxymethyl group, Examples include a hydroxyxetyl group, a 1-hydroxy-11-methylethyl group, a 1,2-dihydroxyethyl group, and a 3-hydroxypropyl group.
  • Cyclo lower alkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • “Lower alkenyl group” means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as a bier group, a 1-propenyl group, a 2-propenyl group, an isopropyl group. , 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propeninole, 1-methyl-1-propeninole, 1-ethyl-1 1-ethenyl, 2-methyl-2 Propenyl group, 2-methyl-1-propenyl group, 3-methyl-2-butene And a 4-pentenyl group.
  • “Lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, Examples include an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isontyloxy group, a hexyloxy group, and an isohexyloxy group.
  • Halo lower alkoxy group means the lower alkoxy group in which any substitutable position is substituted with one or more, preferably 1 to 3 identical or different halogen atoms, such as fluorome. Toxic group, difluoromethyoxy group, trifluoromethyoxy group, 2-fluoroethoxy group, 1,2-diphenoleoethoxy group, chloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, promethoxy group, And an odomethoxy group.
  • lower alkylamino group means an amino group mono-substituted with the lower alkyl group, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group, and a tert-butylamino group. And the like.
  • Di-lower alkylamino group means an amino group di-substituted with the same or different lower alkyl group, for example, dimethylamino, getylamino, ethylmethylamino, dipropylamino, methylpropylamino, diisopropyl And an amino group.
  • “Lower alkylthio group” means a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, Examples include an isoptylthio group, a tert-butylthio group, a pentylthio group, an isopentylthio group, a hexylthio group, and an isohexylthio group.
  • “Lower alkanoyl group” means an alkanoyl group having a lower alkyl group, that is, an alkanoyl group having 2 to 7 carbon atoms. Group, isovaleryl group, pinocylyl group and the like.
  • the term "lower alkoxycarbonyl group” means an alkoxycarbonyl group having a lower alkoxy group, that is, an alkoxycarbonyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxy group.
  • Examples include a carbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isoptoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbol group and the like.
  • aryl group for example, a phenyl group, a naphthinole group and the like can be mentioned.
  • Heteroaryl group means a 5- or 6-membered group containing one or more, preferably one to three, heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • a monocyclic aromatic heterocyclic group or a condensed cyclic aromatic heterocyclic ring in which the monocyclic aromatic heterocyclic group and the aryl group are condensed, or in which the same or different monocyclic aromatic heterocyclic groups are condensed with each other A pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, a virazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4_ Triazolyl group, tetrazolyl group, oxaziazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadia
  • the “aralkyl group” means the lower alkyl group in which any substitutable position is substituted with one or more, preferably one or two araryl groups, such as a benzyl group, a 2-phenylethyl group, Examples thereof include a 3-phenylethyl group and an 11-phenylethyl group.
  • the “salt” of the compound represented by the general formula (I) means a conventional pharmaceutically acceptable salt, for example, a base addition salt or an amino group or a base at the carboxyl group having a carbonyl group.
  • Basic heterocyclic group having a heterocyclic group Salts of acid addition salts in the ring group can be mentioned.
  • the base addition salt examples include alkaline metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; eg trimethylamine salt and triethylamine Organic amine salts such as salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, propylene salts, N, N, dibenzylethylenediamine salts and the like.
  • alkaline metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt eg trimethylamine salt and triethylamine
  • Organic amine salts such as salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, propylene salts, N, N, dibenzylethylenediamine salts and the like.
  • the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .; for example, maleate, fumarate, tartrate, citrate, and ascorbate. And organic salts such as trifluoroacetate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, perchlorate, etc .
  • organic salts such as trifluoroacetate
  • sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • esters of the compound represented by the general formula (I) means, for example, a pharmaceutically acceptable conventional compound having a carboxyl group, such as a methyl group, an ethyl group, and a propyl group.
  • Esters with lower alkyl groups such as isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, benzyl, phenethyl
  • An ester with an aralkyl group such as a group, an ester with a lower alkenyl group such as an aryl group or a 2-butenyl group, an ester with a lower alkoxy lower alkyl group such as a methoxymethyl group, a 2-methoxyethyl group, or a 2-ethoxyethyl group; Acetoxymethyl group, piperyloxymethyl group,
  • Treatment agent refers to a drug that is provided for the purpose of treatment, prevention or prevention of various diseases. .
  • Ar 1 is a nitrogen atom, a nitro group, a lower alkyl group, a halo lower alkynole group, a hydroxy lower alkyl group, a cyclo lower alkyl group, a lower alkenyl group, a hydroxyl group, a lower alkoxy group, a halo lower alkoxy group, lower alkylamino group, a di-lower alkylamino amino group, a lower alkylthio group, a carboxyl group, a lower Arukanoiru group, have a substituent selected from the group consisting of groups represented by lower an alkoxy group and a single Q-a r 2 Represents an aryl group or a heteroaryl group.
  • Halogen atom, nitro group, lower alkynole group, halo lower alkyl group, hydroxy lower alkyl group, cyclo lower alkyl group, lower alkenyl group, hydroxyl group, lower alkoxy group, halo lower alkoxy group, lower alkylamino group, di-lower alkylamino group, a lower alkylthio group, a carboxyl group, a lower Arukanoiru group may have a substituent selected from the group consisting of groups represented by lower Arukokishikaru Poniru group and one Q-a r 2, Ariru group or
  • the heteroaryl group J means the unsubstituted aryl group or the heteroaryl group, or the aryl group or the heteroaryl group having a substituent at any substitutable position.
  • Substituents are halogen atom, nitro group, lower alkyl group, halo lower alkyl group, hydroxy lower Lower alkyl group, cyclo-lower alkyl group, lower alkenyl group, hydroxyl group, lower alkoxy group, halo-lower alkoxy group, lower alkylamino group, di-lower alkylamino group, lower alkylthio group, thioloxyl group, lower alkanol group, lower From the group consisting of the alkoxycarbonyl group and the group represented by Q—Ar 2 , one or two or more, preferably one or two, same or different can be selected.
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group.
  • the halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.
  • the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group.
  • the lower alkyl group in the mouth is preferably a propyl group in the mouth and a butyl group in the mouth.
  • the lower alkenyl group for the substituent is, for example, preferably a vinyl group, a 1-propenyl group, a 2-methyl-11-propenyl group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
  • the halo-lower alkoxy group for the substituent is, for example, preferably a fluoromethyoxy group, a difluoromethyoxy group, a trifluoromethyoxy group.
  • the lower alkylamino group for the substituent for example, a methylamino group, an ethylamino group, a propylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group, a methylamino group and the like are preferable.
  • the lower alkylthio group for the substituent is, for example, preferably a methylthio group, an ethylthio group.
  • the lower alkanol group for the substituent is, for example, preferably an acetyl group, a propioyl group.
  • the lower alkoxycarbol group for the substituent for example, a methoxycarbonyl group, an ethoxycarbonyl group and the like are preferable.
  • a r 2 represents a halogen atom, Shiano group, a lower alkyl group, a halo-lower alkyl group, human Dorokishi lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo-lower Q represents an aryl group or a heteroaryl group, which may have a substituent selected from the group consisting of an alkoxy group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanol group and an aryl group; Represents a single bond, a carbonyl group or a group represented by 1 O—.
  • “An aryl group or a heteroaryl group” refers to the unsubstituted aryl group or the heteroaryl group, or the aryl group or the heteroaryl group having a substituent at any substitutable position.
  • the substituent is a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a hydroxyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkylamino group, a di-lower group. 1 or 2 or more, identical or different, preferably from the group consisting of alkylamino group, lower alkyl group and aryl group It is a 1 or 2 selected child.
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group.
  • the halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.
  • the hydroxy lower alkyl group for the substituent is, for example, preferably a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethynole group.
  • the lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.
  • the halo-lower alkoxy group for the substituent is, for example, preferably a fluoromethyoxy group, a difluoromethyoxy group, a trifluoromethyoxy group.
  • the lower alkylamino group for the substituent for example, a methylamino group, an ethylamino group and the like are preferable.
  • di-lower alkylamino group for the substituent for example, a dimethylamino group, a methylamino group and the like are preferable.
  • the lower alkanoyl group for the substituent for example, an acetyl group, a propionyl group and the like are preferable.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • Examples of the substituent of Ar 2 include a halogen atom, a cyano group, a lower alkyl group, and a halo.
  • a lower alkyl group, a hydroxy lower alkyl group, a hydroxyl group, a halo lower alkoxy group and the like are preferred.
  • the aryl group of Ar 2 is preferably, for example, a phenyl group, and the heteroaryl group is, for example, an imidazolyl group, a pyridyl group, a benzofuranyl group, a quinolyl group, or the like.
  • Q is preferably, for example, a single bond, a carboxy group or the like.
  • the group represented by 1Q—Ar is, for example, a phenyl group, a 2-fluorene phenyl group, a 3-phenyl phenol group, a 4-phenyl phenol group, a 2, 3- Diphtholorenophenyle, 2,4-diphneololophenynole, 3,5-diphneololophenynole, 2-chlorophenynole, 3-chlorophenole, 4-chloro Mouth phenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methynolephenyl group, 2-fluoro-1-methyl-5-methylphenylene group, 3-furyl 2-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl Nore group, 4-
  • Examples of the substituent of Ar 1 include a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkenyl group, a lower alkoxy group, a di-lower alkylamino group, a lower alkanoyl group, and a group represented by Q—Ar 2 .
  • group is more preferably is suitable groups represented by one Q-a r 2.
  • Examples of the aryl group of Ar 1 include a phenyl group, and examples of the heteroaryl group include a pyrazolyl group, a thiazolyl group, an oxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-thiadiazolyl group, and a 1,3. , 4-thiadiazolyl group, pyradinole group, pyrimidinyl group and the like, and more preferably virazolyl group and the like.
  • a r 1 may be, for example, a 3-fluorophenyl group, a 4-fluorophenyl group, a 3,4-difluorophenyl group, a 3-chlorophenol group, a 4-chlorophenyl group, 4-dichlorophenyl, 4-acetylphenyl, 4-acetinol-3-trifluoromethylphenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 4-biphenyl — (1-Methyl-2-imidazolyl) phenyl group, 4- (1-ethyl-2-imidazolyl) phenyl group, 4- (2-thiazolyl) phenyl group, 4- (2-ethyl-4-1-thiazolyl) phenyl group, 3 — (2-pyridyl) phenyl, 3- (4-pyridyl) phenyl, 4- (2-pyridyl) phenyl, 4-, 4-
  • 4-benzoylphenyl, 1- (2-fluorophenyl) -13-pyrazolyl, 5- (4-chlorophenyl) 13-pyrazolyl, 11- (4-methylphenyl) 13 —Pyrazolyl group, 5-phenyl-1,2,4-thiadiazol-13-yl group, 5-phenyl-2-pyrazinyl group, 5- (3-methoxyphenyl) —2-virazinyl group and the like are preferable.
  • T, U, V and W are each independently a methine group or a nitrogen atom which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group; Wherein at least one of them means the methine group.
  • a methine group which may have a substituent selected from the group consisting of a nitrogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group refers to an unsubstituted methine group or a methine group having a substituent. This means that the substituent can be selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group.
  • the halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.
  • 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 ethoxy group.
  • a nitrogen atom or the like is preferable.
  • T, U, V and W include, for example, a substitution wherein any one of T, U, V and W is selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group.
  • X represents a single bond, a methylene group or an ethylene group
  • Y represents a single bond or one o—, one C (R 1 ) (R 2 ) one, one hundred one C (R 3 ) (R 4 ) one, one C (R 5 ) (R 6 ) one O— or one C (R 7 ) (R 8 ) one C (R 9 ) (R 10 ) — means a group represented by;
  • RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group.
  • Examples of the lower alkyl group of RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 include, for example, a methyl group, an ethyl group, a propyl group and the like, and more preferably a methyl group Etc. are preferred.
  • aralkyl group represented by R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 1 ° for example, a benzyl group is preferable.
  • aryl group of RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 for example, a phenyl group and the like are preferable.
  • Each of RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is preferably a hydrogen atom or the like.
  • Preferred embodiments of X and Y include, for example, when X is a single bond and Y is a group represented by 1 o-; when X is a methylene group and Y is a single bond; or when X is a single bond and And when Y is a group represented by one C (R 1 ) (R 2 ).
  • the group represented by is fisted, and above all, the formula (B-1) A group represented by the formula (B) is particularly preferable.
  • Ra is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group.
  • Ar 1 has the meaning described above (however, when Ar 1 is a phenyl group, the phenyl group has a substituent represented by 1 Q—Ar 2 )] Are included in the compounds represented by the general formula (I).
  • Ra a hydrogen atom or the like is preferable.
  • the compound of the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers or tautomers, depending on the mode of the substituents. It also includes stereoisomers, tautomers and mixtures thereof. Various crystals, hydrates and solvates of the compound of the present invention also belong to the scope of the present invention. Furthermore, prodrugs of the compounds of the present invention also fall within the scope of the present invention. In general, such prodrugs will be functional derivatives of the compounds of the present invention which are readily convertible in vivo into the required compound.
  • the term “administration” refers to not only administration of the specified compound but also conversion to the specified compound in vivo after administration to a patient. Including administration of the compound.
  • Conventional methods for selection and production of suitable prodrug derivatives are described, for example, in "Design of Prodrugsed. H. Bundgaard, J. lsevier, 1998, and the like. Metabolites of these compounds include the active compounds produced by placing the compounds of the present invention in a biological milieu and fall within the scope of the present invention.
  • the compound (I) of the present invention can be produced, for example, by the following production methods or the methods shown in Examples. However, the production method of the compound (I) of the present invention is not limited to these reaction examples.
  • Ar lp represents a halogen atom, a nitro group, a lower alkyl group, a halo-lower alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halo-lower alkoxy.
  • Ar 2p means a halogen atom, a cyano group, a lower alkyl group, an aryl group or a heteroaryl group which may have a substituent selected from the group consisting of a lower alkylamino group and a carboxy group; Halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, di-lower alkylamino group, lower alkanol group and aryl group, and optionally protected hydroxy lower alkyl group, hydroxyl group and lower alkylamino group A aryl group or a heteroaryl group, which may have a substituent selected from the group; r 3 represents a
  • R lp , R 2p , R 3p , R 4p , R. p , R 6p , R 7p , R 8p , R 9p and R 10p each independently represent a hydrogen atom, an optionally protected hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group;
  • U, V and W each independently have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and a hydroxyl group which may be protected.
  • a methine group or a nitrogen atom, at least one of which means the methine group; y is a single bond or 1 O 1, 1 C (R lp ) (R 2p ) 1, 1 O — C ( R 3p ) (R 4p ) —, a group represented by -C (R 5p ) (R 6 p ) one O— or one C (R 7p ) (R 8p ) — C (R 9p ) (R 10p ) — X has the meaning described above], and a compound represented by the general formula (IV)
  • the reaction when an amino group, a hydroxyl group, a carboxyl group, an oxo group, a carbonyl group, or the like which does not participate in the reaction is present in the reaction substance, the amino group, the hydroxyl group, the carboxyl group, the oxo group, and the carboxyl group are If necessary, the reaction may be performed after protecting with an amino group-protecting group, a hydroxyl group-protecting group, a carboxyl group-protecting group, or an oxo group or a carboxyl group, and the protective group may be removed after the reaction. .
  • protecting group for an amino group examples include a benzyl group, a ⁇ -methoxybenzyl group, a 3,4-dimethoxybenzinole group, an ⁇ -nitrobenzinole group, a ⁇ -trobenzinole group, a benzhydryl group, a trityl group
  • Aralkyl groups such as formyl group, acetyl group, propionyl group, butyryl group, and piperoyl group; lower alkenyl groups; such as benzoyl group; A noyl group; for example, a lower alkoxycarbonyl group such as a methoxycarboyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, a tert-butoxycarbonyl group; for example, a pendinoreoxycanoleboninole group, a p-ditobenzobenzene group Aralkyloxycarboxy such as xycanole
  • hydroxyl protecting group examples include lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower alkyl silyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group A lower alkoxymethyl group such as a methoxymethyl group or a 2-methoxyethoxymethyl group; a tetrahydrovinylyl group; for example, a trimethylsilylethoxymethyl group; for example, a benzylinole group, a ⁇ -methoxybenzyl group, Aralkyl groups such as dimethoxybenzinole group, o-nitrobenzoyl group, p-to-benzyl group, and trityl group; for example, acetyl groups such as formyl group and acetyl group; Toxicmethyl group, tetrahydrovinylyl group, trity
  • Examples of the "protecting group for a carbonyl group” include: lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and tert-butyl group; lower haloalkyl groups such as 2,2,2-trichloroethyl group; For example, a lower alkenyl group such as a 2-propenyl group; an aralkyl group such as a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a benzhydryl group, and a trityl group; Groups, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzinole group, a p-methoxybenzyl group, a benzhydryl group and the like.
  • lower alkyl groups such as methyl group, ethyl group, propyl group, isoprop
  • Examples of the “protecting group for an oxo group or a carbonyl group” include acetal such as ethylene ketal, trimethyl ketanol, and dimethyl ketal, and ketal.
  • the method for removing the protecting group varies depending on the type of the protecting group and the stability of the target compound (I).
  • the method described in the literature [Protective Groups in Organic Synthesis (Protative Gr. up sin Organic Synthesis) s TW Greene (Tw Greene, John Wieey & Sons, Inc. (1981)) or a method analogous thereto, for example, solvolysis using an acid or base.
  • the reaction of the compound represented by the general formula (II) with the compound represented by the general formula (III) is usually performed by reacting the compound represented by the general formula (III) with 1 mol of the compound represented by the general formula (II).
  • the reaction is carried out using an equimolar to excess mole, preferably an equimolar to 1.5 mole of the compound represented.
  • the reaction is usually performed in an inert solvent
  • suitable examples of the inert solvent include, for example, methylene chloride, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like, or a mixed solvent thereof.
  • the above reaction is preferably carried out in the presence of a base.
  • a base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, and sodium hydroxide and hydroxide.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine and the like, and sodium hydroxide and hydroxide.
  • Inorganic bases such as steel rims can be used.
  • the amount of the base to be used is generally equimolar or excess, preferably 1 to 5 mol, per 1 mol of the compound represented by the general formula (II).
  • the reaction temperature is usually from 130 ° C. to 200 ° C. (preferably from 20 ° C. to 100 ° C.).
  • the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • the compound of the general formula (I) 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.
  • These compounds can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and conversely, conversion of a salt or ester into a free compound can be performed according to a conventional method.
  • the compound represented by the general formula (II) or (III) may be, for example, a commercially available product, The following method, a known method [Tetrahedron Lett., Vol. 42, No. 39, 6943-6946 (2001); Giannareo Rob 'Medicinal' Chemistry (J. Med. Chem.), 36, No. 14, 201 1-2017 (1993); Journal, 38, 23, 4634-463, 6 (195); Chemical. Pharmaceutical Bulletin (Ch. em. Ph arm. Bull.), Vol. 33, No. 3, 1104-1-1115 (1985); Anoreheaf der Fanorematsui (Arch. Pharm.), 308 vol. 910 — 916 (1975); Dot published patent D ⁇ 2533567; J.
  • This production method is a method for producing a compound represented by the general formula (II).
  • the compound represented by the general formula (II) can be produced by reacting the compound represented by the general formula (V) with the compound represented by the general formula (V).
  • the reaction between compound (V) and compound 1 is generally carried out using 1 mole of compound (V) in an equimolar to excess mole, preferably equimolar to 1.5 mole.
  • the reaction is usually carried out in an inert solvent, and examples of the inert solvent include, for example, methylene chloride, chlorophonolem, tetrahydrofuran, ethynoleatenole, tonolene, dimethylformamide, dimethyl sulfoxide and the like, or a mixed solvent thereof. Is preferred.
  • the above reaction is preferably performed in the presence of a base.
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, and sodium hydroxide and water.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine
  • sodium hydroxide and water examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, and sodium hydroxide and water.
  • Inorganic bases such as oxidizing lime, sodium carbonate, potassium carbonate and sodium hydrogen carbonate can be used.
  • the base is usually preferably used in an equimolar amount or an excess amount per 1 mol of the general formula (V).
  • the base When the base is a liquid, the base can be used as a solvent and a base.
  • the reaction temperature is usually -78 ° C to 100 ° C, preferably -20 ° C to 50 ° C.
  • the reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.
  • the compound represented by the general formula (1) can be produced by using a commercially available product, or by appropriately combining a known method, a method described in Examples, or a method analogous thereto as needed.
  • the cDNA sequence encoding human NPY Y5 receptor [see International Patent Application WO 96/16542] was converted to expression vector pc DNA3, pRc / RSV (manufactured by Invitrogen) and pCI-neo ( (Promega).
  • the resulting expression vector was converted to the cationic lipid method [Proceedings, Op., The National, Academy, Ob, Sciences, Ob, The United States, State, Ob, United States, Proceedingsofthenation alacademyofsciencesof the unitedstatesof. America), vol. 84, p. 7413 (1987)], and transfected into host cells COS-7, CHO and LM (tk-I) (American 'type' culture 'collection), and NPY Y5 Receptor expressing cells were obtained.
  • Membrane preparations prepared from cells expressing the NPY Y5 receptor were combined with the test compound and 20, Acetate buffer solution (10 mM magnesium chloride, ImM phenylmethylsulfonyl fluoride, [ 125 I] peptide YY (NEN) of OOO cpm)
  • Example 11 As described above, compounds of the present invention potently inhibited the binding of peptide YY (NPY and congeners) to the NPY Y5 receptor.
  • Pharmacological test example 2 (Antagonism test on feeding behavior induced by D-T rp 34 NPY) Under ketamine / xylazine anesthesia (single administration of 74 and 1 lmg / kg intraperitoneally), male SD rat (7-8 weeks old) Insert a chronic guide cannula (26 gauge, length 11 mm) into the third ventricle of 200-300 g) in a stereotaxic manner and fix it with a dental resin. Guide Force-The tip of the tip of Yure should be 2.2 mm behind bregma, on the midline, 8 mm deep from the skull surface.
  • D-T rp 34 NPY (NP / homologous, l / zg / O. 4 ⁇ L / head, 0.05%) was added to artificial cerebrospinal fluid containing 5% serum albumin. Is administered into the third ventricle. The test compound was suspended in 0.5% methylcellulose aqueous solution 2 hours prior to D- T rp 3 NP Y administered orally, measuring the food intake D-T rp 34 NPY administration after 2 hours.
  • Pharmacological test example 3 The test compound is orally or intravenously administered to male SD rats (7-10 weeks old, 200-400 g) that have been fasted overnight, and about 100 ⁇ l from the tail vein at predetermined time using a heparinized capillary capillary. Collect L. Blood is centrifuged (4 ° C, 6000 rpm, 10 minutes) to obtain plasma. Add three times the volume of ethanol (including internal standard) to the plasma, stir, leave at 20 ° C for 20 minutes, then centrifuge (4 ° C, 10,000 rpm,
  • the supernatant is analyzed by LCZMSZMS, and the plasma concentration is determined by the relative calibration curve method.
  • Pharmacological test example 4 (brain Z cerebrospinal fluid migration test)
  • test conjugate was orally or intravenously administered to male SD rats (7-10 weeks old, 200-400 g), and all were given through a heparin-treated syringe from the abdominal aorta at a predetermined time under ether anesthesia. Collect blood. After that, an incision is made on the upper skin, a 30G dental needle is inserted between the cervical vertebrae, and further inserted into the subarachnoid space. Collect 50-100 ⁇ L of cerebrospinal fluid through a tube connected to a dental 30G needle into a 1 mL syringe, and then remove the brain.
  • Centrifuge the blood sample (4 ° C, 6000 rpm, 10 minutes), add 3 volumes of ethanol (including the internal standard) to the plasma, and stir.
  • the compound represented by the general formula (I) can be administered orally or parenterally, and when formulated into a form suitable for such administration, for example, angina pectoris, acute-depressive Cardiovascular diseases such as heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, such as bulimia, depression, anxiety, convulsions, epilepsy, dementia, pain, alcoholism, and drugs Central nervous system disorders such as withdrawal symptoms, circadian rhythm modulation, schizophrenia, memory disorders, sleep disorders, and cognitive disorders associated with withdrawal, such as obesity, diabetes, abnormal hormone secretion, hypercholesterolemia, and high fat Dysfunctional diseases such as hematosis, gout, and fatty liver, such as reproductive diseases such as infertility, premature birth, and sexual dysfunction, gastrointestinal diseases, respiratory diseases, inflammatory diseases or glaucoma, and, for example, Atheromatous Arteriosclerosis; hypogonadism Hyperthyroidism; polycy
  • Diseases related to the nervous system symptoms related to pain or nociception; diseases related to abnormal gastrointestinal motility or secretion such as various forms of intestinal obstruction, urinary incontinence and Crohn's disease; eating disorders such as anorexia nervosa and bulimia nervosa Symptoms or diseases associated with inflammation; asthma; bronchiole constriction, or a disease associated with abnormal hormone secretion such as luteinizing hormone, growth hormone, insulin, luteinizing hormone and the like.
  • the compound of the present invention can be administered after formulating various formulations by adding pharmaceutically acceptable additives according to the administration form.
  • additives As the additives at that time, various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethyl cenorellose, and canoleboxy.
  • Methynoresenorelose corn starch, micro talistalin wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, citrate, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, shobit Sugar fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, Arabic gum, propi Glycol, polyalkylene glycol, cyclodextrin or hydroxycarboxylic cyclodextrin and the like.
  • Dosage forms formulated as a mixture with these additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; or liquids such as syrups, elixirs or injections Preparations and the like can be mentioned, and these can be prepared according to a usual method in the field of preparations.
  • liquid preparations they may be dissolved or suspended in water or another appropriate medium before use.
  • it may be dissolved or suspended in a physiological saline solution or a glucose solution as necessary, and a buffering agent and a preservative may be added.
  • the compound of the present invention is effective for mammals including humans and others, which require treatment with the compound.
  • the mammal is preferably a human, and may be male or female.
  • mammals other than humans include pet animals such as dogs and cats.
  • the compound of the present invention is also effective against obesity or diseases related to obesity such as dogs and cats. Whether or not treatment with the compound is required can be readily determined by a routine physician, veterinarian or clinician.
  • the dose and frequency of administration vary depending on the patient's sex, age, weight, degree of symptoms, and the type and range of the intended treatment effect.
  • 0.001 to 100 mg / kg in the case of oral administration, 0.01 to 100 mg / kg, preferably 0.03 to lmg / kg, in one or several doses per adult per day, and in the case of parenteral administration, 0.001 to 100 mg / kg. It is preferred to administer 1 OmgZkg, preferably 0.001 to 0.1 mgZkg, more preferably 0.01 to 0.1 mg / kg, in 1 to several divided doses.
  • a routine physician, veterinarian or clinician can readily determine and treat the effective amount of drug required to prevent, counter or arrest the progress of the condition.
  • These preparations may contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the whole drug. These formulations may also contain other therapeutically active compounds.
  • the compounds of the present invention can be used in combination with other agents useful for treating metabolic disorders and Z or eating disorders.
  • the individual components of such combinations can be administered in divided or single formulations during the treatment period, at different times or simultaneously.
  • the present invention should be construed to include all simultaneous or different time administrations, The administration according to the invention should be construed accordingly.
  • the range of the combination of the compound of the present invention and other drugs useful for treating metabolic disorders and / or eating disorders is, in principle, a combination with any pharmaceutical preparation useful for treating metabolic disorders and / or eating disorders. Is also included.
  • Type 1 diabetes mellitus IDM
  • Type 2 insulin-independent diabetes (NI DDM)
  • NI DDM insulin-independent diabetes
  • Type 1 diabetes is usually treated by administration of exogenous insulin by injection.
  • type 2 diabetes often exhibits increased insulin resistance, which reduces the action of insulin, which promotes glucose and fat metabolism in the main insulin-sensitive tissues, ie, muscle, liver and adipose tissue.
  • NIDDM non-insulin-dependent diabetes mellitus
  • insulin resistance inhibits dalcose uptake in muscle, reduces glucose oxidation, accumulates glycogen, inhibits lipolysis in adipose tissue, and produces glucose in the liver. This leads to abnormal secretion. Leaving hyperglycemia in diabetes is associated with high V, disease morbidity and mortality. Type 2 diabetes has an increased risk of cardiovascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, kidney disease, neuropathy and retinopathy I do.
  • Non-insulin-dependent diabetes is also associated with cardiac hypertrophy, especially left ventricular hypertrophy (DeVereu X, RB, Circulation, 101: 2271-2276 (2000)).
  • Cardiac hypertrophy such as left ventricular hypertrophy, is due to a chronic increase in blood pressure or circulating blood volume.
  • Left ventricular hypertrophy (LVH) including increased left ventricular mass Thickening of the ventricular wall is characterized by the exponent represented by left ventricular mass per body surface area, i.e.
  • Left ventricular hypertrophy has been implicated in the increased incidence of cardiovascular diseases such as congestive heart failure, ischemic heart failure, cardiovascular and other deaths, sudden death and stroke. Therefore, regression of left ventricular hypertrophy is associated with reduced cardiovascular disease. Patients with advanced left ventricular hypertrophy have been reported to be at higher risk for severe events than those with regressed left ventricular hypertrophy.
  • metabolic syndrome metabolics yn drome X
  • metabolic disorder syndrome also called polymetabolism disorder syndrome
  • 5 to 10 years before glucose intolerance is associated with many hormonal imbalances, which promotes visceral fat accumulation, hypertension, insulin resistance and hyperlipidemia (B jornstop, P., Current Be, 1 fore, F-, Bergman. RN, and Mo linat h. GM, Front diabetes, Basel, Karger, 12: 182—192 (1993) )).
  • the metabolic syndrome is characterized by visceral fat accumulation, hyperinsulinemia, hyperglycemia, insulin resistance with Syndrome X, hypoHDLemia and VLDLemia.
  • Type 2 diabetes includes, for example, PPAR agonists such as glitazone, biguanides, protein tyrosine kinase 1 BP inhibitors, dipeptidyl peptidase IV inhibitors, insulin, insulin mimetics, sulfonylureas, meglitinides, It is treated with a wide variety of therapeutic agents, such as para-darcoside hydrolase inhibitors and 0! -Amylase inhibitors.
  • PPAR agonists such as glitazone, biguanides, protein tyrosine kinase 1 BP inhibitors, dipeptidyl peptidase IV inhibitors, insulin, insulin mimetics, sulfonylureas, meglitinides.
  • PPAR agonists such as glitazone, biguanides, protein tyrosine kinase 1 BP inhibitors, dipeptidyl peptidase IV inhibitors, insulin, insulin mimetics, sulfon
  • the viscera the administration of sulfonylureas (eg, tolptamide and glipizide) or meglitinides, which stimulate cells to secrete more insulin, and injection of insulin when these drugs become ineffective, resulting in insulin in the plasma. Concentration levels reach high enough to also stimulate insulin-resistant tissue. However, it can cause hypoglycemia, where blood glucose levels can reach dangerously low levels, and further promote insulin resistance. Biguanides increase insulin sensitivity and work to improve hyperglycemia somewhat. ⁇ -Amylase inhibitors inhibit the enzymatic degradation of starch or glycogen to maltose, slow the absorption of sugars in the intestine, and reduce the amount of available sugars.
  • sulfonylureas eg, tolptamide and glipizide
  • meglitinides which stimulate cells to secrete more insulin, and injection of insulin when these drugs become ineffective, resulting in insulin in the plasma. Concentration levels reach high enough to also stimulate insulin-resistant tissue.
  • Methoformin monotherapy is often used to treat obese and / or dyslipidemic type 2 diabetic patients. If metformin does not show adequate efficacy, treatment can be continued with sulfonylurea, thiazolidinediamine, insulin or ⁇ -darcoside inhibitors. However, the two biguanides, phenformin and metformin, also induce lactic acidosis and nausea and diarrhea, respectively. ⁇ - Dal cosidase inhibitors such as acarbose cause intestinal dysfunction.
  • Thiazolidinedione for example, 5-benzylthiozolidine-1,2,4-dione
  • Glitazone also known as one of the most recently reported compounds as a new mode of action, ameliorates many symptoms of type 2 diabetes.
  • These drugs are agonists of the peroxisome proliferator-activated receptor (P PAR) 7 subtype and essentially enhance insulin sensitivity in muscle, liver and adipose tissue in some animal models of type 2 diabetes. Elevates and partially or completely ameliorates elevated glucose levels in plasma without inducing hypoglycemia.
  • Newer PPAR agonists that are being developed for the treatment of type 2 diabetes and dyslipidemia are agonists of one or more of the PPAR ⁇ , ⁇ and ⁇ subtypes.
  • Type 2 diabetes usually involves weight adjustment through exercise and diet. Exercise and reduced dietary calories dramatically improve the condition of diabetes Diabetes Compliant with this treatment because of the poorly exercised lifestyle and overeating, especially overeating of foods containing saturated lipids Sex is very bad. Furthermore, weight loss due to exercise enhancement is difficult for many diabetics due to the associated medical condition. Aberrant glucose homeostasis is also directly or indirectly associated with obesity, hypertension and lipid metabolism disorders. Obesity also promotes insulin resistance, and the resulting insulin resistance contributes to weight gain. Therefore, the management of glucose homeostasis, dyslipidemia, obesity and hypertension is crucial for the clinical management and treatment of diabetes.
  • Obesity defined as being over 20% above ideal body weight, is a major health concern in Western societies. It is estimated that one in three adults in the United States is overweight or obese. Obesity results from a positive energy balance due to higher caloric intake than energy expenditure. (B. Stae 1 seta 1., J. Biol. Chem. 270 (27), 15958 (1 995); F. Lonn quisteta 1., Nature Medicinal (9), 950 (1 995)). Although some of the molecular factors that regulate food intake and weight balance are not yet fully understood, several genetic factors have been identified.
  • obesity causes or exacerbates many health problems independently or in association with other diseases.
  • Serious and life-threatening obesity-related medical problems include type 2 diabetes, hypertension, high insulin, insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, kidney Cancer and colorectal cancer, osteoarthritis, respiratory complications, including non-obstructive sleep apnea, gallstones, arteriosclerosis, heart disease, abnormal heart rhythms and arrhythmias (Ko pel ma n, PG, Nature 404, 635—643 (2000)).
  • Obesity can also lead to abnormalities and circulatory disorders such as cardiac hypertrophy, especially left ventricular hypertrophy, premature death and stroke mortality, severely increased morbidity, myocardial infarction, congestive heart failure, coronary heart disease. Related to sudden death.
  • Visceral obesity is associated with coronary artery disease at a high risk rate, and is also linked to three main risk factors: hypertension, diabetes that develops in adulthood, and hyperlipidemia. Weight loss dramatically reduces these risks.
  • visceral obesity is associated with abnormal metabolic syndrome (such as impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, decreased high density lipoprotein (HDL), and increased very low density lipoprotein (VLDL). It is closely related to other diseases (VLDL) related to the syndrome X) (Montagueeta 1., Diabetes, 2000, 49: 883-888).
  • VLDL diseases related to the syndrome X
  • Treatment methods are recommended that encourage patients to lose weight by reducing dietary intake or increasing exercise to increase energy expenditure. Maintaining weight loss of 5 to 10% can also improve obesity-related diseases such as diabetes, left ventricular hypertrophy, osteoarthritis and cardiopulmonary dysfunction.
  • diabetes refers to insulin-dependent diabetes (ie, IDDM, also known as type 1 diabetes) and non-insulin-dependent diabetes (ie, NIDDM, also known as type 2 diabetes). It includes both.
  • IDDM insulin-dependent diabetes
  • NIDDM non-insulin-dependent diabetes
  • the compositions of the present invention are useful for treating both Type 1 and Type 2 diabetes.
  • the compositions are particularly useful for treating type 2 diabetes.
  • the compositions of the present invention are also particularly useful for treating and preventing or preventing gestational diabetes.
  • the compounds or combination compositions of the present invention are effective for treating diabetes.
  • One outcome of treatment is to reduce elevated glucose levels.
  • Another outcome of treatment is reducing the elevated levels of insulin.
  • Another outcome of treatment is reducing elevated blood triglyceride levels.
  • Another outcome of treatment is reducing the elevated levels of LDL cholesterol.
  • Another outcome of treatment is that it can raise low levels of HD L cholesterol.
  • Another outcome of treatment is increasing insulin sensitivity.
  • Another outcome of treatment is ameliorating impaired glucose tolerance.
  • Another outcome of treatment is that insulin resistance may be reduced.
  • the compounds or combination compositions of the present invention are effective in preventing diabetes.
  • hypertension refers to essential hypertension and its causes, for which the cause is unknown or results in a change in both the heart and the blood vessels, from one or more causes. Including secondary hypertension is known. Causes of secondary hypertension include, but are not limited to, obesity, including those caused by renal disease, hormonal imbalance, and the use of certain medications such as oral contraceptives, corticosteroids, and cyclosporine .
  • hypertension refers to hypertension in which both systolic and diastolic blood pressure are elevated, and diastolic blood This includes the case where the pressure is less than 90 mmHg and the systolic blood pressure is 140 mmHg or more. One outcome of treatment is reducing elevated blood pressure.
  • lipid metabolism or disorders of lipid metabolism include one or more lipids (eg, cholesterol and triglycerides) and no or apolipoproteins (eg, apolipoproteins A, B, C, and E) and Z or lipoproteins (eg, For example, various types of lipids are formed from lipids and lipoproteins that circulate lipids into the blood, and are characterized by abnormal concentrations of macromolecular complexes such as LDL, ⁇ 1 ⁇ 01 ⁇ and 1DL). State. Hyperlipidemia is associated with lipid poor, LDL and VLDL cholesterol and / or triglyceride abnormal elevation.
  • lipids eg, cholesterol and triglycerides
  • Z or lipoproteins eg,
  • various types of lipids are formed from lipids and lipoproteins that circulate lipids into the blood, and are characterized by abnormal concentrations of macromolecular complexe
  • Methodabolic Disorder Syndrome also known as Syndrome X, stands for "Third R eportoftheNational Ch olesterol E ducati on P rogr am Expert Pan anel on De tecti on, Ev aluation and Treat me ntof High Glo Chlo olesterolin (ATP-III) (ES Fordeta 1., JAMA, ol. 287 (3), Jan. 16, 2002, pp 356-359).
  • ATP-III High Glo Chlo olesterolin
  • a person is defined as having a metabolic syndrome if they have three or more symptoms of visceral obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and fasting hyperglycemia . These criteria are defined in ATP-II I.
  • the three types are typical examples of centripetal LVH with a left ventricular mass index of 144 and a relative wall thickness of 0.52, a left ventricular mass index of 136 and a relative wall thickness of 0.38.
  • a deformed afferent left ventricle is typically exemplified when the centrifugal LVH and LVMI are 93 as a typical example and the relative wall thickness is 0.38.
  • a typical value for a normal LVMI is 85 and a typical value for a normal RWT is about 0.36.
  • the risk of progression to cardiovascular disease in patients with deformed afferent left ventricle (LV) is between patients with normal left ventricular structure and those with left ventricular hypertrophy To do.
  • One outcome of diabetes treatment with minimal cardiac or left ventricular hypertrophy is the ability to reduce ventricular mass. Another outcome of treating diabetes with minimizing cardiac or left ventricular hypertrophy is that it can reduce the rate of increase in ventricular mass. Another outcome of treating diabetes with minimizing cardiac or left ventricular hypertrophy is that it can reduce left ventricular wall thickness. Another outcome of diabetes treatment with minimal cardiac or left ventricular hypertrophy is that it can reduce the rate of increase in left ventricular wall thickness.
  • the term "obesity" as used herein refers to a condition in which there is an excess of body fat. Based on the body mass index definition of obesity which is calculated by dividing the weight by the square of height (BMI) (kg / m 2 ) Iteiru. In Europe, refers to a BMI of 3 O k gZm health of a person who has two or more healthy individuals or B Ml is 27 kg / m 2 or more at least one complications and obesity. Healthy person BMI of less than 25 kg / m 2 or more 30 kgm 2 and subject at risk of obesity, or a BMI those with 25 kg / m 2 or more 27 k gZm 2 less than at least one of the complications Say that.
  • Asians the risks associated with obesity derive from lower BMI than in Westerners.
  • obesity is defined as at least one obesity-induced force that requires or will be reduced by weight loss, or a complication associated with obesity, of 25 kg gm
  • a subject at risk of obesity 23 kg / m 2 or more refers to a person with a 25 kg / m 2 less than BMI.
  • obesity includes all obesity as defined above.
  • Complications caused by or associated with obesity include, but are not limited to, diabetes, impaired glucose tolerance, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricemia, gout, Coronary artery disease, myocardial infarction, angina, sleep apnea syndrome, Pick Wick syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disease, osteoarthritis, low back pain, menstruation Includes abnormalities and infertility.
  • the comorbidities include hypertension, hyperlipidemia, dyslipidemia, impaired glucose tolerance, cardiovascular disease, sleep apnea syndrome, diabetes mellitus and other obesity-related conditions.
  • Treatment of obesity and obesity-related disorders means administering a compound or combination composition of the present invention to reduce or maintain the weight of obese patients.
  • One outcome of treatment is that the weight of the obese patient may begin to decrease as compared to the patient's weight prior to administration of the compound or combination composition of the present invention.
  • Another outcome of treatment is the ability to maintain weight loss as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of treatment may be reducing the incidence and / or severity of obesity-related diseases.
  • the outcome of treatment is a reduction in food intake and food intake. That is, a reduction in the total amount of food intake or a reduction in the intake of special food components such as carbohydrates or fats, and an inhibition of the absorption of nutrients, and an inhibition of the rate of metabolism or metabolism.
  • the outcome of treatment is a change in metabolic rate. That is, changes in metabolic rate, such as preventing a decrease in metabolic rate or increasing metabolic rate, and minimizing metabolic resistance, which usually results from weight loss.
  • Prevention of obesity and obesity-related disorders means administering a compound or mixed composition of the present invention to reduce or maintain the weight of those at risk of developing obesity.
  • the result of prophylaxis is that the weight of a subject at risk of developing obesity may begin to decrease compared to the weight of the patient prior to administration of a compound or combination composition of the present invention.
  • Another outcome of prevention is the ability to maintain weight loss as a result of diet, exercise, or pharmacotherapy.
  • Another outcome of prevention is that if treatment is initiated before obesity at risk for obesity, obesity may be prevented.
  • Another outcome of prevention is that if treatment is initiated before obesity at risk for obesity, obesity-related illness may be reduced and the Z or severity reduced.
  • treatment of obese individuals may prevent or reduce the onset or progression of fertility-related diseases.
  • Such obesity-related diseases include arteriosclerosis, type 2 diabetes, polycystic ovary syndrome, cardiovascular disease, osteoarthritis, skin disease, high blood pressure, insulin resistance, hypercholesterolemia, and high triglycerides. But are not limited to blood and cholelithiasis.
  • Atherosclerosis includes vascular diseases and conditions that are identified and understood by a physician through experience gained through the administration of drugs in the art.
  • Atherosclerosis, coronary heart disease (also known as coronary artery disease or ischemic heart failure), cerebrovascular disease and peripheral vasodilator disease are all clinical symptoms of atherosclerosis.
  • a potentially present combination composition of a therapeutically effective amount of an anti-diabetic agent and a therapeutically effective amount of an anti-obesity agent, coronary heart disease, Can be administered to prevent or reduce the risk of developing or recurring cerebrovascular disease or intermittent claudication
  • Coronary heart disease events include CHD death, myocardial infarction (eg, heart attack) and revascularization
  • Cerebral vascular disease events are meant to include ischemic or hemorrhagic stroke (also known as cerebral vascular accidents) and transient ischemic attacks.
  • the term "atherosclerotic disease event" as used herein is meant to encompass coronary heart disease events, cerebrovascular disease events and intermittent claudication. Or more non-fatal attacks
  • a person suffering from a somatic arterial schizophrenia event is one who has the potential for recurrence of that event.
  • Circadian rhythm affects physiological parameters.
  • Physiological parameters include rest and activity, sleep and wake cycles, body temperature, rhythms of hormone levels, and fluctuations in general physiological functions. When these parameters deviate from synchrony with daily time courses, circadian rhythms that affect physiology, ability to perform various tasks, and emotional health are modulated.
  • the present invention is useful in preventing or treating circadian rhythm-related symptoms as well as mental and physical disorders related to, for example, travel across time zones and shift work.
  • the present invention provides prevention of circadian rhythm disorders in mammals, including mammal groups, shift work disorders, sleep phase depression syndrome, sleep phase progression syndrome, and non-24 hour sleep-wake disorders.
  • a method of treatment is provided.
  • the present invention provides a method for re-entraining a patient having an abnormal sleep-wake cycle (returning to a normal circadian rhythm, meaning synchronizing to an environmental light-dark cycle). Provide a way to shorten.
  • the present invention provides a method for mitigating a traveler's jet lag.
  • the purpose of this embodiment is to assist the body in physiologically adapting to changes in sleep and eating patterns when crossing time zones many times.
  • a preferred embodiment is to provide a method of resetting a patient's biological clock to the patient's current activity / sleep cycle. For example, if the shift worker is It is effective when working hours are changed from night to night.
  • the present invention provides methods for increasing sleep efficiency and enhancing or improving sleep quality by increasing sleep persistence. Further, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances. The present invention further provides pharmaceutical compositions for enhancing or improving sleep quality and for increasing sleep efficiency and sleep continuity.
  • the present invention may be based on psychophysiological causes as a result of psychopathological disorders (especially related to anxiety), drug use and alcohol overdose (especially during the withdrawal and abstinence phases), early childhood DIMS, It is useful in treating sleep disorders, including nocturnal myoclonus, leg restlessness found in the elderly and non-specific REM (eye movement) disorders and sleep onset disorders and persistent sleep disorders ("DIMS").
  • the following results on the patient's body brought about by the present invention may be related to improving sleep quality.
  • Increased value obtained by dividing the patient's sleep time by the time they try to sleep, sleep latency (time to fall asleep), reduced number of wake-ups during sleep, complete after first sleep Decreased time to wake up, increased total sleep time, increased amount and percentage of REM sleep, increased duration and incidence of REM sleep, decreased disruption of REM sleep, slow wave sleep (eg Increasing the amount and proportion of stage 3 or 4), increasing the amount and proportion of stage 2 sleep, especially reducing the number of wakefulnesses in the early morning, improving consciousness and arousal during daylight, and increasing sleep sustainability Can be.
  • Secondary outcomes provided by the present invention include enhanced cognitive function and increased memory retention.
  • a "method of enhancing sleep quality" includes, but is not limited to, an outcome related to sleep quality enhancement as described above, a method of producing a patient-related outcome related to sleep quality enhancement. Means
  • the invention further includes insomnia, hypersomnia, sleep apnea, narcolepsy, night myoclonus, REM sleep disturbance, jet lag, shift work sleep disturbance, dysomnias, night phobia, night Eating and drinking syndrome, depression associated with sleep (abnormal sleep behavior), emotional / mood disorders, insomnia related to dysfunction, sleep disorders associated with dysuria, aging It is useful for the prevention and treatment of sleep disorders and sleep disturbances, including sleep problems with sleep. Sleep disorders and sleep disturbances generally have difficulty starting or sustaining sleep, or having difficulty resting or getting enough sleep. In addition, certain drugs may cause reduced REM sleep as a side effect, and the present invention may be used to correct these types of sleep disorders.
  • the present invention will also be useful in the treatment of apnea sleep associated with non-restorative sleep and fibromyalgia exhibiting muscle pain or breathing disorders during sleep. It is clear that the present invention is not limited to sleep disorders and sleep disturbances, but can be applied to a wide range of conditions resulting from reduced sleep quality.
  • the combination of the compound of the present invention and its composition or a combination thereof with another agent is useful for treating and preventing these conditions.
  • the target mammal is preferably a human.
  • the invention is applicable to older and younger men and women, but may have greater applicability to older men and women. Further, while the present invention is applied to improve the sleep quality of healthy people, it may be particularly effective in improving the sleep quality of people suffering from sleep disorders or sleep disturbances.
  • composition of the present invention is useful for treating, preventing or managing hypertension, hypertension associated with obesity, hypertension-related disorders, cardiac hypertrophy, left ventricular hypertrophy, and disorders such as metabolic disorder syndrome, obesity and obesity-related disorders.
  • Such other drugs can be administered in a conventional manner, in an amount and a route commonly used, simultaneously or sequentially with the composition of the present invention.
  • a composition of the present invention is administered contemporaneously with one or more other drugs, it is preferably a dosage unit form of the pharmaceutical composition containing such other drugs and the composition of the present invention.
  • combination therapy also includes therapies in which the combination drug of the drug of the present invention and one or more other drugs is administered on various overlapping dosing schedules.
  • compositions and other active ingredients of the present invention may require lower dosages than if they were taken alone. Expected. Accordingly, the drug compositions of the present invention include those that contain one or more other active ingredients, in addition to the compositions of the present invention.
  • compositions according to the invention examples include, but are not limited to:
  • glitazones eg, ciglitazone, darglitazone, englita Zon, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, BRL49 653, CLX-0921, 5-BTZD, etc.), and GW-0207, LG-100641, And PAR-3 ⁇ agonists such as LY-3005 12 and the like;
  • biguanides such as pformin, metformin, fenformin and the like; and
  • protein tyrosine phosphorylase 1B PTP-1B
  • Inhibitors (iv) acetate hexamide, chronorepronomide, diabinase, gliben clamide, glipizide, glyburide, glimepiride, daliclazide, glipentide, glyquidone, glisolamide, tolazamide, and tolptamide urine And meglitinides such as (V) repaglinide and nateglinide, (V i) acarbose, adiposin, and force miglipose Emiglitate, Migiri tall, Bog ribose, pradimicin one Q, Saruposutachin, CKD- 7 1 1, MDL - 2 5,
  • ⁇ -darcoside hydrolytic enzyme inhibitors such as 637, MDL-73, 945, and M ⁇ R14;
  • V ii ⁇ -amylase inhibitors such as tendamistat, trestatin, and A1-36888
  • Viii linoglylide, and insulin secretagogues such as A-416
  • chromoxyl and fatty acid oxidation inhibitors such as etemoxil,
  • x midaglizole, isaglidol, delidaridol, A2 antagonists such as idazoxan, aeroxane and fluparoxane;
  • Non-thiazolidinedione such as (xiii) MK-076 7, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-1796449 PPAR ⁇ / ⁇ dual agonists, such as LR-90 and SB219994, (xi ⁇ ) other insulin sensitizing drugs and (XV) VP AC2 receptor agonists, etc.
  • Antidiabetic drugs such as (xiii) MK-076 7, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-1796449 PPAR ⁇ / ⁇ dual agonists, such as LR-90 and SB219994, (xi ⁇ ) other insulin sensitizing drugs and (XV) VP AC2 receptor agonists, etc.
  • Antidiabetic drugs such as (xiii) MK-076 7, CLX-0940, GW-1536, GW-1929, GW-2433,
  • Bile acid absorption inhibitors such as Cholest (R) and Questran (R), (ii) atorpastatin, itapastatin, flupastatin, lovastatin, pravastatin, linocstatin, rosuvastatin, simpastatin Statins and HMG-CoA reductase inhibitors such as ZD-4522, (iii) HMG-CoA synthase inhibitors, (iv) sterol glycosides such as stanol esters, j3-sitosterol, and ticqueside Cholesterol absorption inhibitors such as azetidinones such as zetimibe, etc .; (V) acetyl acyl coenzymes such as apasimibe, F ⁇ / simibe, KY505, SMP797, etc.
  • ⁇ -cholesterol acyl transferase (ACAT) inhibitors ⁇ -cholesterol acyl transferase (ACAT) inhibitors;
  • CETP inhibitors such as J TT705, torcetraviv, CP 532, 632, BAY 63-2149, SC 591, SC 795, etc.
  • squalene synthase Inhibitors squalene synthase Inhibitors
  • antioxidants such as propriol, etc.
  • fibric acid derivatives such as Gemfibrodinole, GW7647, BM170744, LY518674, and Atromid (registered trademark '), Lopid (registered trademark), and Tricor (registered trademark).
  • FXR receptor modulators such as (X) GW4064, SR 103912, LXR receptors such as (Xi) GW3965, T901 3137, and XTCO 179628, and (xii) liposomes such as niacin Protein synthesis inhibitor, (xiii) renin 'angiotensin system inhibitor, (X i V) PPARS partial agonist, (xv) bile such as BAR1 1453, SC435, PH A384640, S 8921, AZD 7706 Acid reabsorption inhibitor, (xV i) GW 501516, And PPAR ⁇ agonists such as GW590735, ( ⁇ vii)
  • X i V transcription modulator
  • XX squalene epoxidase inhibitor
  • XX i low density lipoprotein (LDL) receptor inducer
  • XX iii platelet aggregation inhibitor
  • XX iii 5— A lipid-lowering drug such as a LO or FLAP inhibitor
  • a niacin receptor agonist and
  • Drugs aldosterone antagonists such as spironolactone, epilenone, etc .
  • Calcium channel blockers such as Nicanorepine, Nifedipine, Ninorevadipine, Nimodipine, Nisonorepipine, Nitrendipine, Manidipine, Pranidipine, Verapamil, etc.
  • ACE angiotensin-converting enzyme
  • V omapatrilat, cadoxatril and ekadotril, fosidotril, sampatrilat, AVE 768
  • a neutral endopeptidase inhibitor such as ER4030, an endothelin antagonist such as (Vi) tezosentan, A308816, and YM62889, etc.
  • Vasodilators such as hydralazine, clonidine, minoxidil, nicotinyl alcohol, etc.
  • A1 blockers such as NO10, etc., (xi) a2 agonists such as lofexidine, thiamenidine, moxonidine, rilmenidine, and guanobenz, etc., ii) antihypertensives such as aldosterone inhibitors, and
  • EP-6658546 CB-1 cannabinoid indone 1 receptor antagonists / antagonists, such as the compounds disclosed in US Pat. Antagonists, (v) thioperamide, 3- (1H-imidazole-41-yl) propyl N- (4-pentenyl) potambamate, clobenpropit, iodofenpropit, imoproxyxifan, GT 23 94 (glial Tech), ⁇ Pi A3 3 1440, ⁇ Pi WO 02 Bruno 1 590 5 disclosed drug in, ⁇ Pi O- [3- (1H-imidazol - 4 - Inore) Purono ⁇ 0 Nonore] Kanorebameto compound ( Eta 1., Pharma zie, 55: 349-55 (2000)), piperidine-containing histamine H3-receptor Anti-drug (Lazewska, D.
  • H3 histamine H3 antagonists
  • proxy proxy derivatives Sasse, A. et al., J. Med. Chem., 43: 3335-43 (2000).
  • Anti-agonists (vi) T-226296 (Takeda), SN P-7941 (Synaptic), and WO 01/82924, WO 01/878 34, WO 02/051809, WO 02/06245, WO 02/076929 , WOO 2/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, and Japanese Patent Application No.
  • JP 13226269 Formone 1 receptor (MCH1R) antagonist, (vii) MCH2R (melanin-enriched honolemon 2R) agonist, (viii) BI BP 3226 2— [1— (5-chloro-1-3-isopropyloxycarbonyla) Minofenino) etinoleamino] 1 6— [2— (5-ethinole 4-methinole 1,3-thiazonole 1-innole) etinole] 14 1 morpholinopyridine, BI BO3304 LY-357897, CP-671906, and G1-264879A, and U.S. Patent Nos. 6, 001, 836, and WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 85690, WO 01/85098, WO 01 no 85173, and WO 01/8
  • NPY1 neuropeptide YY1
  • NPY1 neuropeptide YY1 antagonist, such as the drug disclosed in 9528, (ix)
  • NPY5 neuropeptide YY5
  • Amdin methioninoleph leptin
  • Leptin derivatives such as 3515, WO 96/23516, WO 96/2351 7, WO 96/235 18, WO 96/23519, and WO 96/23520;
  • nalmefene (Revex®), 3-methoxalnaltrexone, naloxone, and naltrexone, and opioid antagonists such as the compounds disclosed in WO 00/21509; (xiii) SB-334867-A; And olexin antagonists such as the compounds disclosed in WOO 1 96302, WOO 1/68609, WO 02/51232, WOO 2/51838, and WOO 3/023561, (xiv) BR S 3 (Bombesin Receptor subtype 3) agonist, (XV) compounds disclosed in AR-R1 5849, GI 181771, JMV-180, A-71378, A-71623, and SR 146131, and U.S.
  • Revex® 3-methoxalnaltrexone, naloxone, and naltrexone
  • opioid antagonists such as the compounds disclosed in WO 00/21509;
  • olexin antagonists such as the
  • CCK-A cholecystokinin-A
  • GI-181 771 Grama Source Smith Kline
  • SR 146 131 Sporab
  • Puta Vinzide and PD 1 70292
  • CN TF ciliary neurotrophic factor
  • PD 149164 Faiza
  • CNTF derivatives such as the compounds disclosed in WO 94/09134, WO 98/221 28, and WO 99/4381 3; (xviii) NN703, hexarelin, MK-0677, SM-1 30686, CP-424, 391, L-692, 429 and L-163, 255, and U.S. Patent No. 6, 358,951, U.S. Patent Application No. 2002Z049196 and 2002-022637, and WO 01/5
  • GHS growth hormone secretagogue receptor
  • Mc4r (melanocortin 4 receptor) agonist, such as the compounds disclosed in 7949 and WO 03-009847, (XXii) siptratomin (Meridia)
  • Acylestrogens such as oleoyl-estrone disclosed in 202-9 (2001), (XXXV i) darcocorticoid antagonists, (XXXV ii) B VT 3498, BVT 2733, and WO 01/90091, WO 01/90090 11 J3HSD-1 (11-1) 3 hydroxysteroid dehydrogenase type 1) inhibitor, such as the compounds disclosed in WO 01/90092, (XXXV iii) SCD-1 (stearoyl-CoA desaturase 1) 1) Inhibitors, (xx xix) isocyanate thiazolidide, valine pyrrolidide, NVP—DPP728, LAF237, T / JP2005 / 004871
  • WO 03/004496 EP 1258476, WO 02/0831 28, WO 02/062764, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO 03 / 000180, and dipeptidyl peptidase IV (DP-IV) inhibitors such as the compounds disclosed in WO 03/000181, (xXXx) tetrahydroribstatin (Orlista tZXenical (registered trademark)), Triton WR
  • Melanocortin agonists such as those compounds described, (XXXXV i) melanin-concentrating hormone antagonists, (XXXXV ii) galanin ⁇ antagonists, (XXXXV iii) CCK agonists, (xxxxix) corticotropin-releasing hormone agonists, (XXXXX) phosphodiesterase-1 3B (PDE3B) inhibitor, etc.
  • Anti-obesity drugs like.
  • combinations of the present invention include combinations of the present invention not only with one other active substance, but also with two or more other active substances.
  • combinations of the compositions of the present invention with one, two or more activators selected from lipid lowering agents and antihypertensive agents.
  • the combination of the composition of the present invention with one, two or more activators selected from lipid-lowering drugs and antidiabetic drugs is useful for the treatment, management or prevention of metabolic syndrome.
  • a composition comprising an anti-obesity drug and an anti-hypertensive drug in addition to an anti-diabetic drug and / or a lipid-lowering drug may be useful for treating, managing or treating the syndrome.
  • Example 2 The compound of Example 1 (20.0 g), lactose (417 g), crystalline cellulose (80 g) and partially graphitized starch (80 g) were mixed using a V-type mixer, and then magnesium stearate (3.0 g) was added. I do.
  • the mixed powder is tableted according to the usual method, and the diameter is 7.0mm, 1 tablet Tablets weighing 150 mg to obtain 3000 tablets. Content per 1 tablet (150 mg)
  • Titanium dioxide 0.7mg Industrial applicability
  • the compound of the present invention has an NPY antagonistic action, particularly an antagonistic action at the NPY Y5 receptor, and has excellent pharmacokinetics such as cerebral distribution or cerebrospinal fluid distribution, and is also highly safe.
  • Circulatory diseases such as angina pectoris, acute 'depressive heart failure, myocardial infarction, hypertension, kidney disease, electrolyte abnormalities, vasospasm, arteriosclerosis, etc., eg bulimia, depression , Anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with withdrawal of drugs, circadian rhythm modulation, schizophrenia, memory impairment, sleep
  • Central nervous system disorders such as disorders and cognitive disorders, such as obesity, diabetes, abnormal hormone secretion, hypercholesterolemia, hyperlipidemia, gout, fatty liver, etc.
  • Reproductive system diseases Reproductive system diseases, gastrointestinal system diseases, respiratory system diseases, inflammatory diseases, glaucoma, etc., and, for example, atherosclerosis; hypogonadism; hyperandrogensia; polycystic ovary syndrome Hirsutism; gastrointestinal motility disorder; gastroesophageal reflux associated with obesity; obesity hypoventilation syndrome (Pickwick syndrome); sleep apnea syndrome group; inflammation; systemic vasculitis; osteoarthritis; insulin resistance Bronchoconstriction; alcohol preference, metabolic disorder (syndrome X); Alzheimer's disease; cardiac hypertrophy; left ventricular hypertrophy; hypertriglyceridemia; low HDL cholesterolemia ;
  • Example coronary heart disease (CHD); cerebrovascular disease, circulatory disease such as stroke, peripheral vascular disease, sudden death; gallbladder disease; cancer (breast cancer, endometrial cancer, colon cancer); shortness of breath; Hyperuricemia; reproductive disorders; low back pain; anes

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Reproductive Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pregnancy & Childbirth (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Anesthesiology (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Child & Adolescent Psychology (AREA)

Abstract

Est ici révélé un composé représenté par la formule générale suivante (I) : (I) où Ar1 représente un groupe aryle éventuellement substitué ou un groupe hétéroaryle ; R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 représentent indépendamment un atome d’hydrogène, un groupe hydroxyle, un groupe alkyle inférieur, un groupe aralkyle ou un groupe aryle ; T, U, V et W représentent indépendamment un groupe méthine éventuellement substitué ou un atome d’azote et au moins l’un d’entre eux représente un groupe méthine ; X représente une liaison simple, un groupe méthylène ou un groupe éthylène ; et Y représente une liaison simple ou un groupe exprimé par -O-, -C(R1)(R2)-, -O-C(R3)(R4)-, -C(R5)(R6)-O- or -C(R7)(R8)-C(R9)(R10)-]. Ce composé est utilisable comme agent de traitement de diverses maladies associées au NPY.
PCT/JP2005/004871 2004-03-22 2005-03-14 Dérivé de piperidine-1-carboxamide WO2005090340A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004082405 2004-03-22
JP2004-082405 2004-03-22

Publications (1)

Publication Number Publication Date
WO2005090340A1 true WO2005090340A1 (fr) 2005-09-29

Family

ID=34993628

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/004871 WO2005090340A1 (fr) 2004-03-22 2005-03-14 Dérivé de piperidine-1-carboxamide

Country Status (1)

Country Link
WO (1) WO2005090340A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1848435A2 (fr) * 2005-01-25 2007-10-31 Synta Pharmaceuticals Corporation Composes destines a etre utilises contre les inflammations et les troubles immunitaires
WO2011078369A1 (fr) * 2009-12-25 2011-06-30 持田製薬株式会社 Nouveau derive aryl-uree
US20140364393A1 (en) * 2011-12-06 2014-12-11 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as scd 1 inhibitors
CN110483401A (zh) * 2019-09-11 2019-11-22 何琴 艾沙利酮药用盐及其制备方法和医药应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0887747A (ja) * 1994-02-02 1996-04-02 Sanyo Electric Co Ltd ディスク及びディスク再生方法
JP2001519812A (ja) * 1997-04-04 2001-10-23 メルク エンド カンパニー インコーポレーテッド ソマトスタチン作動薬
WO2002051806A1 (fr) * 2000-12-22 2002-07-04 Astrazeneca Ab Derives de carbazole et utilisation de ces derniers en tant que ligands du recepteur du neuropeptide y5
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite
WO2003045313A2 (fr) * 2001-11-27 2003-06-05 Merck & Co. Inc. Composés de 2-aminoquinoline
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
WO2004011440A1 (fr) * 2002-07-30 2004-02-05 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur d'hormone concentrant de la melanine comprenant un derive de benzimidazole en tant qu'ingredient actif

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0887747A (ja) * 1994-02-02 1996-04-02 Sanyo Electric Co Ltd ディスク及びディスク再生方法
JP2001519812A (ja) * 1997-04-04 2001-10-23 メルク エンド カンパニー インコーポレーテッド ソマトスタチン作動薬
WO2002051806A1 (fr) * 2000-12-22 2002-07-04 Astrazeneca Ab Derives de carbazole et utilisation de ces derniers en tant que ligands du recepteur du neuropeptide y5
WO2003037332A1 (fr) * 2001-10-12 2003-05-08 Bayer Pharmaceuticals Corporation Heterocycles utiles pour le traitement de l'obesite
WO2003045313A2 (fr) * 2001-11-27 2003-06-05 Merck & Co. Inc. Composés de 2-aminoquinoline
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
WO2004011440A1 (fr) * 2002-07-30 2004-02-05 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur d'hormone concentrant de la melanine comprenant un derive de benzimidazole en tant qu'ingredient actif

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TORRENS A. ET AL.: "Synthesis of new benzoxazione derivatives as neuropeptide Y5 antagonist for the treatment of obesity.", J. MED.CHEM., vol. 48, 2005, pages 2080 - 2092, XP002986119 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1848435A2 (fr) * 2005-01-25 2007-10-31 Synta Pharmaceuticals Corporation Composes destines a etre utilises contre les inflammations et les troubles immunitaires
EP1848435A4 (fr) * 2005-01-25 2010-09-29 Synta Pharmaceuticals Corp Composes destines a etre utilises contre les inflammations et les troubles immunitaires
US8518950B2 (en) 2005-01-25 2013-08-27 Synta Pharmaceuticals Corp. 2-amido pyrazines for inflammation and immune related uses
US9090570B2 (en) 2005-01-25 2015-07-28 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US9493427B2 (en) 2005-01-25 2016-11-15 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2011078369A1 (fr) * 2009-12-25 2011-06-30 持田製薬株式会社 Nouveau derive aryl-uree
US20140364393A1 (en) * 2011-12-06 2014-12-11 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as scd 1 inhibitors
US9238658B2 (en) * 2011-12-06 2016-01-19 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as SCD 1 inhibitors
CN110483401A (zh) * 2019-09-11 2019-11-22 何琴 艾沙利酮药用盐及其制备方法和医药应用

Similar Documents

Publication Publication Date Title
CN1918128B (zh) 稠环4-氧代-嘧啶衍生物
CN1922183B (zh) 含氮的稠合杂芳环衍生物
JP4595542B2 (ja) ベンズイミダゾール誘導体を有効成分とするメラニン凝集ホルモン受容体拮抗剤
CN100567270C (zh) 磺酰胺衍生物
CN100528864C (zh) N-取代的-2-氧代二氢吡啶衍生物
US7589096B2 (en) Azole derivatives
TW200406411A (en) Novel benzimidazole derivatives
JPWO2005115993A1 (ja) キナゾリン誘導体
CN101111480A (zh) 取代的吡啶酮衍生物
WO2004069798A1 (fr) Antagonistes des recepteurs de l'hormone concentrant la melanine contenant des derives de piperidine en tant que principe actif
WO2005016928A1 (fr) Derives d'imidazopyridines
US20110015181A1 (en) Alkylaminopyridine derivative
WO2005090340A1 (fr) Dérivé de piperidine-1-carboxamide
WO2004089919A1 (fr) Derive de cyclohexanecarboxamido
JP4453320B2 (ja) Ｎ−置換−２−オキソジヒドロピリジン誘導体
JP4496722B2 (ja) 新規ベンズイミダゾール誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP