WO2002094825A1 - Nouveau derive de spiropiperidine - Google Patents

Nouveau derive de spiropiperidine Download PDF

Info

Publication number
WO2002094825A1
WO2002094825A1 PCT/JP2002/004954 JP0204954W WO02094825A1 WO 2002094825 A1 WO2002094825 A1 WO 2002094825A1 JP 0204954 W JP0204954 W JP 0204954W WO 02094825 A1 WO02094825 A1 WO 02094825A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
alkyl group
phenyl
pyrimidinyl
Prior art date
Application number
PCT/JP2002/004954
Other languages
English (en)
Japanese (ja)
Inventor
Takehiro Fukami
Minoru Moriya
Takuya Suga
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 WO2002094825A1 publication Critical patent/WO2002094825A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • 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
    • 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
    • A61P25/04—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
    • A61P25/22—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention is clearly useful in the field of medicine. More specifically, the novel spiro piperidine derivative of the present invention is useful as a neuropeptide Y receptor antagonist as a treatment for various cardiovascular diseases, central nervous system diseases, metabolic diseases, etc. . 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 Tatsumoto et al. In 1982 [Nature, 296, 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. That is, NPY acts as an appetite-stimulating substance in the central nervous system 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 Giannare obobesity 1 (Inte rna tiona lJ).
  • NPY neuropeptide
  • NPY has a wide variety of pharmacological effects via receptors that are partly common to its analogs, peptide YY and pancreatic polypeptide. It is known that the pharmacological effects of these NPYs are elicited through the interaction of at least 5 types of receptors alone or through interaction [Trend sin Neuroscienc, 20 Volume, 294 pages (1997
  • the NPY Y3 receptor is mainly expressed in the brain stem and heart, and has been reported to be involved in the control of blood pressure and heart rate [The Journal of Pharmaceutical Sciences] 'The Journal of Therapeutics and Experimental Therapeutics, Vol. 258, 633, 1991 (1991); Peptides, 11 Vol., P. 545 (1990)].
  • the adrenal gland is involved in the secretion of catecholamines [The Journal of Pharmaceutical Therapy and The Experimental Therapeutics]. Exp e ri menta 1 Therapeutics), 244, 468 (1988); Life Science, 50, PL 7 (1992)].
  • the NPY Y4 receptor has a particularly high affinity for pancreatic polypeptides, and its pharmacological effects have been reported to be Teng exocrine secretion and suppression of gastrointestinal motility [Gastroen terol. ogy), 85, 1411 (1983)]. Furthermore, it is known that it promotes the secretion of sex hormones in the center [Endocrinology, Vol. 140, p. 5171 (1999)].
  • NPY functions are expressed by binding NPY receptors present in the central or peripheral nervous system. Therefore, by inhibiting the binding of NPY to the NPY receptor, it is possible to prevent the expression of ⁇ ⁇ .
  • substances that antagonize the ⁇ receptor binding of ⁇ are various diseases that involve ⁇ , such as hypertension, kidney disease, heart disease, and cardiovascular diseases such as vasospasm, such as bulimia, depression, anxiety, and convulsions.
  • Epilepsy dementia, pain, alcoholism, withdrawal symptoms accompanying withdrawal of drugs, circadian rhythm modulation, central diseases such as schizophrenia (schizophrenia), for example, obesity, diabetes, hormonal abnormalities, etc.
  • NPY receptor antagonists are useful in the prevention or treatment of hypercholesterolemia, hyperlipidemia, and arteriosclerosis (International Publication W099 / 27965; W00 / 27845; WO01Z14376).
  • WO098 / 35957 discloses amide derivatives and NPY antagonism.
  • the compounds of the present invention are not specifically disclosed or suggested in this publication. Disclosure of the invention
  • An object of the present invention is to provide a novel drug having NP Y antagonism.
  • the present inventors have found that the general formula (I)
  • ⁇ represents a linear alkylene group having 1 to 3 carbon atoms which may have a substituent selected from the group consisting of a lower alkyl group, an aralkyl group and an aryl group
  • Ar 1 represents halogen Atoms, nitro, oxo, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl, lower-alkenyl, lower-alkoxy, halo-lower-alkoxy, lower-alkylthio, carboxyl, lower Arukanoiru group may have a substituent selected from the group consisting of groups represented by lower alkoxy force Ruponiru groups and single Q-a r 2, means Teroari Ichiru groups to also Ariru group
  • Ar 2 is a halogen atom, a cyano group, a lower alkyl group, an octa lower alkyl group, a hydroxy lower alkyl group, a hydroxy
  • N represents 0 or 1;
  • Q represents a single bond or a radical group;
  • R 1 represents a lower alkyl group, an aralkyl group or an aryl group;
  • R 2 and R 5 are each independently A hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group;
  • R 3 and R 4 each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group;
  • T, U, V and W are each independently a methine group 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 A nitrogen atom, and meaning taste at least 2 Tsuga ⁇ methine group of them;
  • X one N (S0 2 R x) one, - N (COR 2) - or -CO- group represented by Y represents a group represented
  • the compound (I) of the present invention can be used for various diseases involving NPY, for example, circulatory diseases such as hypertension, kidney disease, heart disease, vasospasm and arteriosclerosis, for example, bulimia, depression, Central disorders such as anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with withdrawal of drugs, circadian rhythm modulation, schizophrenia (schizophrenia), for example, obesity, diabetes, hormones Useful as a treatment for metabolic disorders such as abnormalities, hypercholesterolemia, and hyperlipidemia, sexual and reproductive dysfunctions, such as digestive tract disorders such as gastrointestinal motility disorders, respiratory disorders, inflammation and glaucoma It is.
  • circulatory diseases such as hypertension, kidney disease, heart disease, vasospasm and arteriosclerosis
  • arteriosclerosis for example, bulimia
  • depression Central disorders such as anxiety, convulsions, epilepsy, dementia, pain, alcoholism, withdrawal symptoms associated with withdrawal of drugs, circadian rhythm modulation, schizophrenia (schi
  • the compound (I) of the present invention is useful as an agent for treating, for example, bulimia, obesity, diabetes and the like.
  • 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, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. Tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.
  • aryl group means a group formed from an aromatic hydrocarbon having 6 to 16 carbon atoms and a derivative thereof, such as a phenyl group, a tolyl group, a xylyl group, and a mesityl group. , Cumenyl, naphthyl, anthryl, phenanthryl, pyrenyl, indanyl, 1,2,3,4-tetrahydronaphthyl, acenaphthenyl, fluorenyl and the like.
  • aralkyl group means the lower alkyl group substituted at one or more, preferably one or more of the substitutable positions with the aralkyl group, for example, benzyl group, 1-phenylethyl group, phenethyl group. And 11-naphthylmethyl group, 2-naphthylmethyl group and the like.
  • the “C 1-3 straight-chain alkylene group” means a methylene group, an ethylene group, or a trimethylene group.
  • octa lower alkyl group means the lower alkyl group in which any substitutable position is substituted with one or more, preferably 1 to 3 identical or different halogen atoms. Fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl, bromomethyl, eodomethyl, etc. No.
  • Hydroxy lower alkyl group means the lower alkyl group in which any substitutable position is substituted with one or more, preferably one or two hydroxyl groups, such as hydroxymethyl group, 2-hydroxyethyl Groups, 1-hydroxy_1-methylethyl group, 1,2-dihydroxyethyl group, 3-hydroxypropyl group and the like.
  • 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 bier group, 1-propenyl group, 2-propenyl group, isopropyl group, 3 —Butyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propyl And a 2-methyl-1-propenyl group, a 3-methyl-2-butenyl group and a 4-pentenyl group.
  • “Lower alkoxy group” means a straight or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, Examples include an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, and an isohexyloxy group.
  • Halo-lower alkoxy group means the lower alkoxy group substituted at any substitutable position by one or more, preferably 1 to 3 identical or different halogen atoms, such as fluoromethoxy group. , Difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,2-difluoroethoxy group, chloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, bromomethoxy group, pseudomethoxy And the like.
  • “Lower alkylthio group” means a straight 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 alkanol group means an alkanol group having a lower alkyl group, that is, an alkanol group having 2 to 7 carbon atoms, for example, an acetyl group, a pentionyl group, a butyryl group, an isoptyryl group, a valeryl group, and an isovaleryl group. And piva groups.
  • the “lower alkoxycarbonyl group” means an alkoxycarbonyl group having a lower alkoxy group, that is, an alkoxyl group having 2 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxy group.
  • Heteroaryl group means a 5- or 6-membered monocyclic ring containing one or more, preferably one to three, hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • a fused aromatic heterocyclic group in which the formula aromatic heterocyclic group or the monocyclic aromatic complex ring group is condensed with the aryl group, or in which the same or different monocyclic aromatic heterocyclic groups are fused together; And includes, for example, a pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a driazolyl group, a tetrazolyl group, an oxadiazolyl group, 1,2,3-thiadiazolyl group Group, 1, 2, 4 —thiadiazolyl group, 1,3,4-
  • lower alkylamino group means an amino group mono-substituted with the lower alkyl group. Examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group, and a tert-amino group. And a butylamino group.
  • di-lower alkylamino group means an amino group di-substituted by the same or different lower alkyl groups, for example, dimethylamino, getylamino, ethylmethylamino, dipropylamino, methylpropylamino. And diisopropylamino group.
  • the “salt” of the compound represented by the general formula (I) means a pharmaceutically acceptable and conventional one, for example, when the compound has a carboxyl group, And a salt of an acid addition salt in the basic heterocyclic group in the case of having an amino group or a basic heterocyclic group.
  • the base addition salt examples include: alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; eg, trimethylamine salt, triethylamine salt, dicyclohexyl Examples thereof include amine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, proforce salts, and organic amine salts such as N, N, -dibenzylethylenediamine salts.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, and ascorbate. And organic salts such as trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
  • 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 in the carboxyl group having a carbonyl 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, Esters with aralkyl groups such as phenethyl groups, esters with lower alkenyl groups such as aryl, 2-butenyl groups, esters with lower alkoxy groups such as methoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, etc.
  • a lower alkenyloxy lower alkyl group such as an oxexetyl group
  • an ester with a lower alkoxycarbonyl lower alkyl group such as a methoxycarbonylmethyl group, an isopropoxylpropylmethyl group
  • a carboxy lower alkyl group such as a carbonyloxymethyl group.
  • Esters esters with lower (alkoxycarbonyloxy) lower alkyl groups such as 11- (ethoxycarbonyloxy) ethyl group and 11- (cyclohexyloxy) propyl groups, and lower alkyl groups such as lower alkoxycarbonyloxy methyl groups Ester, phthalidyl group and Esters of (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group and other (5-substituted-1-oxo-1,1,3-dioxol-4-yl) methyl groups And the like.
  • Treatment agent means a drug that is used for the purpose of treatment and Z or prevention of various diseases.
  • A represents a linear alkylene group having 1 to 3 carbon atoms which may have a substituent selected from the group consisting of a lower alkyl group, an aralkyl group and an aryl group.
  • a straight-chain alkylene group having 1 to 3 carbon atoms which may have a substituent selected from the group consisting of a lower alkyl group, an aralkyl group and an aryl group refers to the unsubstituted carbon A linear alkylene group having 1 to 3 carbon atoms or a linear alkylene group having 1 to 3 carbon atoms having a substituent at any substitutable position, wherein the substituent is a lower alkyl group or an aralkyl group; And one or two or more, preferably one or two, the same or different from the group consisting of
  • the lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.
  • aralkyl group for the substituent for example, a benzyl group, a phenethyl group and the like are preferable.
  • the aryl group of the substituent is, for example, preferably a phenyl group.
  • a lower alkyl group is suitable.
  • linear alkylene group having 1 to 3 carbon atoms of A for example, a methylene group, an ethylene group and the like, more preferably a methylene group and the like are suitable.
  • A specifically, for example, a methylene group, an ethylene group, a trimethylene group, an ethylidene group, a propylidene group, an isopropylidene group, a benzylidene group, a phenethylidene group, a 1-methylethylene group, a 1,2-dimethyl
  • Examples include an ethylene group and the like. Among them, a methylene group, an ethylene group, an ethylidene group and the like are more preferable, and a methylene group and the like are more preferable.
  • Ar 1 is a halogen atom, a nitro group, an oxo 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 lower alkoxy group, an octa lower alkoxy group, a lower alkylthio group force Rupokishiru group, a lower Arukanoiru group, lower alkoxycarbonyl group and -Q- a r 2 in which may have a substituent selected from the group consisting of groups represented, Ariru group or to Teroari Ichiru group Means
  • Arukanoiru group may have a substituent selected from the group consisting of groups represented by lower alkoxy force Ruponiru groups and single Q-a r 2, the Ariru group or to Teroa aryl group J
  • 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.
  • hydroxy lower alkyl group for the substituent for example, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-11-methylethyl group and the like are preferable.
  • the cyclo lower alkyl group for the substituent is, for example, preferably a cyclopropyl group, a cyclobutyl group.
  • 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 for example, a methoxy group, an ethoxy group and the like are common.
  • octanol lower alkoxy group for the substituent for example, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy 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 for example, an acetyl group, a propionyl group and the like are preferable.
  • Preferred examples of the lower alkoxycarbonyl group for the substituent include a methoxycarbonyl group and an ethoxycarbonyl group.
  • Ar 2 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
  • An aryl group or a heteroaryl group which may have a substituent selected from the group consisting of a lower alkylamino group, a di-lower alkylamino group, a lower alkyl group and an aryl group;
  • Q means a single bond or a radical group.
  • aryl group or a heteroaryl group which may have a substituent selected from the group consisting of: the unsubstituted aryl group or the heteroaryl group, or any substitutable position Represents a aryl group or a heteroaryl group having a substituent, wherein 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, Octa lower alkoxy group, lower alkyl amino group, di lower alkyl amino group,
  • 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-11-methylethyl 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 fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy 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 alkanol 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.
  • a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a hydroxyl group, a halo-lower alkoxy group and the like are preferable.
  • the aryl group of Ar 2 is preferably, for example, a phenyl group, and the heteroaryl group is preferably, for example, an imidazolyl group, a pyridyl group, a benzofuranyl group, a quinolyl group.
  • the group represented by a Q-A r 2 for example phenyl group, 2-off Ruorofeniru group, 3-fluorophenyl group, 4-Furuorofu Engineering group, 2, 3 - difluorophenyl group, 2, 4 —Difluorophenyl group, 3,5-difluorophenyl group, 2-cyclophenyl group, 3_chlorophenyl group, 4-chlorophenyl group , A 2-cyanophenyl group, a 3-cyanophenyl group, a 4-cyanophenyl group,
  • 3-difluoromethoxyphenyl group 3- (2-hydroxyethyl) phenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 1-ethyl-2-imidazolyl group, 2-pyridyl group, A 7-benzo [b] furanyl group, a 2-quinolyl group, a 3-quinolyl group, a benzoyl group, a 2-pyridylcarbonyl group, and the like, more preferably a phenyl group, a benzoyl group, and the like are preferred.
  • Examples of the substituent of A r 1 include an octogen atom, an oxo group, a lower alkyl group, a halo-lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkanoyl group, and a group represented by —Q—A r 2 , more preferably, a halogen atom, Okiso group, a lower alkyl group, a lower alkoxy group, a lower Arukanoiru group, represented by a Q-A r 2 Are preferred.
  • Examples of the aryl group of Ar 1 include a phenyl group, a naphthyl group, a fluorenyl group and the like, and more preferably a phenyl group.
  • Examples of the heteroaryl group include an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, pyrido [3,2-d] Thiazolyl, quinolyl, quinoxalinyl, 1,5-naphthyridinyl and the like are preferred.
  • a r 1 is, for example, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl Group, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl, 4-acetyl-3-trifluoromethylphenyl, 2-biphenylyl, 3- Biphenylyl, 4-biphenylyl, 4- (1-methyl-12-imidazolyl) phenyl, 4- (1-ethyl-2-imidazolyl) phenyl, 4- (2-thiazolyl) phenyl, 4 1- (2-ethyl-41-thiazolyl) phenyl, 3- (2-pyridyl) phenyl, 3- (4-pyridyl) phenyl, 4- (2-pyridyl) phen
  • n means 0 or 1, with 0 being preferred.
  • 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. At least two of them mean the methine group.
  • a methine group optionally having a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxyl group and a lower alkoxy group means an unsubstituted methine group or a methine group having a substituent.
  • 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 halogen atom or the like is preferable.
  • T, U, V and W include, for example, T, U, V and W are each independently the above substituent, more preferably a methine group optionally having a halogen atom Or when any one of T, U, V and W is a nitrogen atom.
  • X represents a group represented by one N (S 0 2 R x ) —, —N (COR 2 ) or —CO—;
  • Y represents — C (R 3 ) (R 4 ) —, one O — Or — means a group represented by N (R 5 ) —;
  • R 1 represents a lower alkyl group, an aralkyl group or an aryl group;
  • R 2 and R 5 are each independently R 3 and R 4 each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group; a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group;
  • As the lower alkyl group for R ⁇ R 2 , R 3 , R 4 and R 5 for example, a tyl group, an ethyl group, a propyl group and the like, more preferably a methyl group and the
  • aralkyl group for RR 2 , R 3 , R 4 and R 5 for example, a benzyl group and the like are preferable.
  • R ⁇ R 2 , R 3 , R 4 and R 5 for example, a phenyl group and the like are preferable.
  • R 1 and R 2 for example, a lower alkyl group is suitable.
  • R 3 and R 4 include, for example, when both R 3 and R 4 are hydrogen atoms.
  • R 5 for example, a hydrogen atom, a lower alkyl group, etc., more preferably a hydrogen atom, etc. are suitable.
  • X a preferred embodiment of the Y and n, e.g., X gar N (SO ⁇ 1) - Wakashi Ku of the group represented by a N (COR 2) one, more preferably - N (SOgR 1) - And n is 0, and Y is a group represented by —C (R 3 ) (R 4 ) —, or X is a group represented by —CO—. And Y is a group represented by —0— or 1 N (R 5 ) —, and more preferably a group represented by 1 O—.
  • R 1 has the meaning of the 'like group represented by the like ( Equation (C)
  • the compound of the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituents. Includes all stereoisomers, tautomers and mixtures thereof I do.
  • the term “administration” refers not only to the administration of the specified compound, but also to the compound that is converted into the specified compound in vivo after administration to a patient. Including administration.
  • Conventional methods for the selection and manufacture of suitable prodrug derivatives are described, for example, in "De sign of Prodrug rug se d. H. Bundgaad, Elsevier, 1985," which is hereby incorporated by reference in its entirety. Metabolites of these compounds include active compounds produced by placing the compounds of the present invention in a biological environment and are within the scope of the present invention.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Ph represents a phenyl group.

Abstract

Composé représenté par la formule générale (I), dans laquelle A est un alkylène linéaire C1-C3 éventuellement substitué, Ar1 est un aryle ou hétéroaryle éventuellement substitué, n est 0 ou 1, chacun de T, U et V désigne un groupe méthine éventuellement substitué ou un atome d'azote, à condition que les deux autres désignent un groupe méthine, X est un groupe représenté par -N(SO¿2R?1)-, -N(COR2)- ou -CO-; et Y est un groupe représenté par -C(R3) (R4)-, -O- ou -N(R5)-. Le composé possède un antagonisme NPY et est de ce fait utile en tant que médicament dans le traitement de diverses maladies à médiation par NPY telles que les troubles de la circulation, à savoir l'hypertension, des maladies du SNC telles que l'hyperphagie, des troubles métaboliques tels que l'obésité et le diabète, des dysfonctionnements sexuel et de la reproduction, des maladies de la digestion telles que celles affectant les mouvements du système digestif, des maladies respiratoires, l'inflammation, le glaucome.
PCT/JP2002/004954 2001-05-22 2002-05-22 Nouveau derive de spiropiperidine WO2002094825A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001152019 2001-05-22
JP2001-152019 2001-05-22

Publications (1)

Publication Number Publication Date
WO2002094825A1 true WO2002094825A1 (fr) 2002-11-28

Family

ID=18996754

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/004954 WO2002094825A1 (fr) 2001-05-22 2002-05-22 Nouveau derive de spiropiperidine

Country Status (1)

Country Link
WO (1) WO2002094825A1 (fr)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
WO2005061500A1 (fr) * 2003-12-12 2005-07-07 Syngenta Participations Ag Dérivés de spiropipéridine pour lutter contre les nuisibles
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
JP2009528319A (ja) * 2006-03-03 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ シグマ受容体に対する薬学的活性を有するイミダゾール化合物
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
JP2011513226A (ja) * 2008-02-21 2011-04-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節するアミン化合物及びエーテル化合物
WO2011110612A1 (fr) 2010-03-10 2011-09-15 Ingenium Pharmaceuticals Gmbh Inhibiteurs de protéine kinases
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
US8716296B2 (en) 2007-10-12 2014-05-06 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
CN105829311A (zh) * 2013-12-24 2016-08-03 硕腾服务有限责任公司 螺吲哚啉抗寄生虫衍生物
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013696A1 (fr) * 1992-12-11 1994-06-23 Merck & Co., Inc. Spiro-piperidines et homologues favorisant la liberation de l'hormone de croissance
WO1994019367A1 (fr) * 1992-12-11 1994-09-01 Merck & Co., Inc. Spiro piperidines et composes homologues favorisant la liberation de l'hormone de croissance
EP0747378A1 (fr) * 1995-06-07 1996-12-11 Bristol-Myers Squibb Company Dérivés de la dihydropyridine avec une activité antagoniste du NPY
WO1999029696A1 (fr) * 1997-12-11 1999-06-17 F.Hoffmann-La Roche Ag Derives de piperidine
WO1999064002A1 (fr) * 1998-06-11 1999-12-16 Merck & Co., Inc. Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine
WO2000027845A1 (fr) * 1998-11-10 2000-05-18 Merck & Co., Inc. Spiro-indolines en tant qu'antagonistes du recepteur y5
WO2001013917A1 (fr) * 1999-08-26 2001-03-01 Bristol-Myers Squibb Company Antagonistes des neuropeptides y: derives de spiroisoquinolinone
WO2001014376A1 (fr) * 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Nouveaux composes spiro
WO2002048152A2 (fr) * 2000-12-12 2002-06-20 Neurogen Corporation Spiro[isobenzofuran-1,4'-piperidine]-3-ones et 3h-spiroisobenzofuran-1,4'-piperidines

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994013696A1 (fr) * 1992-12-11 1994-06-23 Merck & Co., Inc. Spiro-piperidines et homologues favorisant la liberation de l'hormone de croissance
WO1994019367A1 (fr) * 1992-12-11 1994-09-01 Merck & Co., Inc. Spiro piperidines et composes homologues favorisant la liberation de l'hormone de croissance
EP0747378A1 (fr) * 1995-06-07 1996-12-11 Bristol-Myers Squibb Company Dérivés de la dihydropyridine avec une activité antagoniste du NPY
WO1999029696A1 (fr) * 1997-12-11 1999-06-17 F.Hoffmann-La Roche Ag Derives de piperidine
WO1999064002A1 (fr) * 1998-06-11 1999-12-16 Merck & Co., Inc. Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine
WO2000027845A1 (fr) * 1998-11-10 2000-05-18 Merck & Co., Inc. Spiro-indolines en tant qu'antagonistes du recepteur y5
WO2001014376A1 (fr) * 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Nouveaux composes spiro
WO2001013917A1 (fr) * 1999-08-26 2001-03-01 Bristol-Myers Squibb Company Antagonistes des neuropeptides y: derives de spiroisoquinolinone
WO2002048152A2 (fr) * 2000-12-12 2002-06-20 Neurogen Corporation Spiro[isobenzofuran-1,4'-piperidine]-3-ones et 3h-spiroisobenzofuran-1,4'-piperidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MALMSTROM RICKARD E.: "Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y1 receptor antagonist, in vivo", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 418, no. 1-2, April 2001 (2001-04-01), pages 95 - 104, XP002956699 *

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514429B2 (en) 2002-04-09 2009-04-07 Esteve Laboratorios Dr. Esteve S.A. Benzoxazinone-derived compounds, their preparation and use as medicaments
WO2003084952A1 (fr) * 2002-04-09 2003-10-16 Laboratorios Del Dr. Esteve S.A. Composes derives de benzoxazinone, leur preparation et utilisation comme medicaments
US7056914B2 (en) 2002-04-09 2006-06-06 Esteve Laboratorios Dr. Esteve S.A. Benzoxazinone-derived compounds, their preparation and use as medicaments
CN1894249B (zh) * 2003-12-12 2011-06-15 辛根塔参与股份公司 控制害虫的螺哌啶衍生物
AP2294A (en) * 2003-12-12 2011-10-31 Syngenta Participations Ag Spiropiperidine derivatives for controlling pests.
WO2005061500A1 (fr) * 2003-12-12 2005-07-07 Syngenta Participations Ag Dérivés de spiropipéridine pour lutter contre les nuisibles
JP2007516972A (ja) * 2003-12-12 2007-06-28 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 害虫を制御するためのスピロピペリジン誘導体
US7960401B2 (en) 2003-12-12 2011-06-14 Syngenta Crop Protection, Inc. Spiropiperidine derivatives for controlling pests
EA014114B1 (ru) * 2003-12-12 2010-10-29 Зингента Партисипейшнс Аг Производные спиропиперидина, предназначенные для борьбы с вредителями
AU2004303618B2 (en) * 2003-12-12 2010-08-05 Syngenta Participations Ag Spiropiperidine derivatives for controlling pests
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
JP2009528319A (ja) * 2006-03-03 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ シグマ受容体に対する薬学的活性を有するイミダゾール化合物
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
US8716296B2 (en) 2007-10-12 2014-05-06 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
JP2011513226A (ja) * 2008-02-21 2011-04-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｂ２受容体を調節するアミン化合物及びエーテル化合物
US8957063B2 (en) 2008-02-21 2015-02-17 Boehringer Ingelheim International Gmbh Amine and ether compounds which modulate the CB2 receptor
WO2010051236A1 (fr) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Antagonistes d'isonicotinamide des récepteurs de l'orexine
US9067888B2 (en) 2010-03-10 2015-06-30 Astrazeneca Ab Inhibitors of protein kinases
US8518948B2 (en) 2010-03-10 2013-08-27 Ingenium Pharmaceuticals Gmbh Inhibitors of protein kinases
WO2011110612A1 (fr) 2010-03-10 2011-09-15 Ingenium Pharmaceuticals Gmbh Inhibiteurs de protéine kinases
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
WO2013059222A1 (fr) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. Antagonistes des récepteurs de l'orexine à base de 2-pyrydyloxy-4-nitrile
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
CN105829311A (zh) * 2013-12-24 2016-08-03 硕腾服务有限责任公司 螺吲哚啉抗寄生虫衍生物
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
WO2020167706A1 (fr) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021026047A1 (fr) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine et pipéridine hétéroaryle
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2022040070A1 (fr) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type bicycloheptane pyrrolidine
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Similar Documents

Publication Publication Date Title
WO2002094825A1 (fr) Nouveau derive de spiropiperidine
CA2484159C (fr) Sulfamides spirocycliques substitues par heteroaryle utilises comme inhibiteurs de la gamma-secretase
ES2450594T3 (es) Derivados de indol como antagonistas del receptor CRTH2
US7514441B2 (en) Substituted pyrazolo [1,5-A]pyrimidines as calcium receptor modulating agents
US8518953B2 (en) Aminopyrimidines useful as inhibitors of protein kinases
US8338614B2 (en) Tertiary carbinamines having substituted heterocycles which are active as β-secretase inhibitors for the treatment of alzheimer's disease
CZ2002533A3 (cs) Nové spirosloučeniny
WO2001062738A1 (fr) Composes a base d'imidazoline
WO2007055418A1 (fr) Derive spiro aza-substitue
TW201028408A (en) Compounds
CA2894399A1 (fr) Inhibiteurs de l'histone demethylase
US8049013B2 (en) 5- [4-(azetidin-3-yloxy)-phenyl]-2-phenyl-5H-thiazolo[5,4-C] pyridin-4-one derivatives and their use as MCH receptor antagonists
JP6224832B2 (ja) Ｒｏｒｃ２阻害薬およびその使用方法
KR20140129068A (ko) 질소 함유 방향족 헤테로환 화합물
US20150011556A1 (en) Pyrrolopyrazone inhibitors of tankyrase
US20230303573A1 (en) 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives
JP2018510135A (ja) ＲＯＲγＴ阻害剤としての置換ピラゾール化合物及びその使用
WO2016120850A1 (fr) Modulateurs indole de rorc2 substitués par sulfonamide et leurs procédés d'utilisation
US20090170830A1 (en) Tricyclic Beta-Secretase Inhibitors for the Treatment of Alzheimer's Disease
JP3411262B2 (ja) 新規スピロ化合物
EP2801573A1 (fr) Dérivés d'hydantoïne en tant qu'inhibiteurs de CD38
JP3553560B2 (ja) 新規スピロ化合物
JP2024512557A (ja) Ｌｐａ受容体２阻害物質としての８－シクロ－置換キナゾリン誘導体
JP2006505625A (ja) Ｈｉｖ感染症を治療するためのピラゾールアミド

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 BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE 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 NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE 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
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

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

Ref country code: JP