WO2010050456A1 - Composé pipéridine ayant une structure di- ou tri-arylméthyle - Google Patents

Composé pipéridine ayant une structure di- ou tri-arylméthyle Download PDF

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WO2010050456A1
WO2010050456A1 PCT/JP2009/068375 JP2009068375W WO2010050456A1 WO 2010050456 A1 WO2010050456 A1 WO 2010050456A1 JP 2009068375 W JP2009068375 W JP 2009068375W WO 2010050456 A1 WO2010050456 A1 WO 2010050456A1
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alkyl
compound
methyl
hydrogen atom
difluorophenyl
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PCT/JP2009/068375
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Japanese (ja)
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稔 亀田
香織 上条
隆雄 鈴木
彰紘 竹澤
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萬有製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • 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
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to a piperidine compound having a novel di- or triarylmethyl structure.
  • the compound acts as a melanin-concentrating hormone receptor antagonist and is useful as a preventive, therapeutic or therapeutic agent for various cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, respiratory diseases, gastrointestinal diseases, etc. It is.
  • MCH Melanin concentrating hormone
  • MCH In mammals, the cell bodies of neurons containing MCH are localized in the hypothalamic lateral cortex and uncertain zone, but their nerve fibers are projected to a very wide area in the brain [The Journal of. Comparative Neurology, Vol. 319, 218 (1992)], MCH is considered to control various central functions in the living body.
  • the hypothalamic lateral field has long been known as a feeding center, and in recent years, much molecular biological and pharmacological knowledge suggesting its involvement in the control of MCH energy homeostasis has been accumulated. That is, it has been reported that mRNA expression of MCH precursor is enhanced in the brains of genetic obesity model animals such as ob / ob mice, db / db mice, KKAy mice, Zucker fatty rats and fasted mice. [Nature, Vol. 380, 243 (1996); Diabetes, Vol. 47, 294 (1998); Biochemical and Biophysical Research Communications, Vol. 268, 88 (2000); Molecular Brain Research, Vol. 92, 43 (2001)].
  • MCH is an important factor in the formation of obesity, and is suggested to be involved in metabolic disorders and respiratory diseases in which obesity is a risk factor.
  • MCH is known to have anxiety-inducing action, epilepsy, memory / learning, diuretic action, sodium / potassium excretion action, oxytocin secretion action, and reproductive / sexual function involvement [Peptides, Vol. 17, 171 (1996); Peptides, Vol. 18, 1095 (1997); Peptides, Vol. 15, 757 (1994); Journal of Neuroendocrinology, Vol. 8, 57 (1996); Critical Reviews in Neurobiology, Vol. 8, 221 (1994)].
  • MCH induces various pharmacological actions mainly through MCH receptors present in the central nervous system.
  • MCH receptors at least two types of receptors, type 1 receptor (MCH-1R or SLC-1) and type 2 receptor (MCH-2R or SLT), are known [Nature, Vol. 400, 261 (1999); Nature, Vol. 400, 265 (1999); Biochemical and Biophysical Research Communications, Vol. 261, 622 (1999); Nature Cell Biology, Vol. 1,267 (1999); FEBS Letters, Vol. 457, 522 (1999); Biochemical and Biophysical Research Communications, vol. 283, 1013 (2001); The Journal of Biological Chemistry, Vol. 276, 20125 (2001); Proceedings of the National Academy of Sciences of The United States of America, Vol.
  • MCH-1R the pharmacological action observed in rodents is mainly induced through MCH-1R [see Genomics, Vol, 79, 785 (2002)]. It is known that overeating and obesity are not observed even when chronic administration of MCH is carried out to MCH-1R gene-deficient mice, so that energy metabolism control by MCH is induced via MCH-1R. Furthermore, MCH-1R deficiency is known to increase the amount of activity in mice [Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, 3240 (2002)], and is strongly suggested to be involved in central diseases accompanied by behavioral abnormalities such as attention deficit / hyperactivity disorder, schizophrenia depression, etc. [Molecular Medicine Today, Vol. 6, 43 (2000); see Trends in Neuroscience, Vol, 24, 527 (2001)].
  • MCH-1R autoantibodies against MCH-1R exist in the serum of patients with vitiligo vulgaris [see The Journal of Clinical Investigation, Vol, 109, 923 (2002)]. Furthermore, the expression of MCH-1R in certain cancer cells has been reported. From the expression site of MCH and MCH-1R in vivo, MCH cancer, sleep / wake, drug dependence, and gastrointestinal diseases [Biochemical and Biophysical Research Communications, Vol. 289, 44 (2001); Neuroendocrinology, Vol. 61, 348 (1995); Endocrinology, Vol. 137, 561 (1996); The Journal of Comparative Neurology, Vol. 435, 26 (2001)].
  • MCH The function of MCH is expressed when MCH binds to the MCH receptor. Therefore, if MCH receptor binding is inhibited, the action expression of MCH can be prevented. Therefore, a substance that antagonizes MCH receptor binding may be used for various diseases involving MCH, such as obesity, diabetes, hormone secretion abnormalities, hyperlipidemia, gout, fatty liver, and other metabolic diseases; Cardiovascular diseases such as hyperphagia, affective disorder, depression, anxiety, hemorrhoids, delirium, dementia, integration, etc., such as hypertension, acute congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities Central and peripheral nervous system diseases such as ataxia, attention deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormalities, olfactory disturbance, morphine tolerance, drug dependence, alcoholism; Reproductive system diseases such as infertility, premature birth, and sexual dysfunction; in addition, it is expected to be useful
  • Patent Document 1 As compounds having an MCH receptor antagonistic action, for example, WO03 / 004027 (Patent Document 1) and US2006 / 79683A1 (Patent Document 2) disclose a number of piperidine derivatives. However, for a specific compound in which a mono- or diaryl (or heteroaryl) methyl-substituted arylmethyl group is bonded to the 1-position of the piperidine ring and an aryl (or heteroaryl) ring or the like is further bonded to the 4-position of the piperidine, It is not disclosed in the specification. WO03 / 004027 US2006 / 79683A1
  • an arylmethyl group having a mono- or diaryl (or heteroaryl) methyl substituent is bonded, and further, aryl at the 4-position of the piperidine.
  • a specific compound to which a (or heteroaryl) ring is bonded is a novel compound unknown in the literature, and has an excellent MCH receptor antagonistic action, for prevention or treatment of various diseases related to MCH receptor. As a result, the present invention has been found to be effective.
  • R 1a and R 1b independently represent a hydrogen atom or a C 1-6 alkyl group
  • R 2a and R 2b independently represent a hydrogen atom or a C 1-6 alkyl group
  • R 3a and R 3b independently represent a hydrogen atom or a C 1-6 alkyl group
  • Z represents C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl or nitrogen-containing heterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl , Heteroaryl or nitrogen-containing heterocyclyl are halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy, C 1 May be independently 1 to 3 substituted with -6 alkylcarbonylamino, C 3-6 cyclo
  • Ar 2 is a divalent group and represents a 6-membered aryl ring, a 5- to 6-membered heteroaryl ring or a pyridone ring, and the aryl, heteroaryl or pyridone is selected from the group consisting of group ⁇ Independently substituted with 1 to 3 substituents of the formula
  • ring A Represents a 6-membered aryl ring, a 5- to 6-membered nitrogen-containing heteroaryl ring or a 5- to 6-membered nitrogen-containing heterocyclyl ring, and the aryl ring, nitrogen-containing heteroaryl ring or nitrogen-containing heterocyclyl ring has 5 to A 6-membered aryl ring or heteroaryl ring may be condensed, and the aryl ring, nitrogen-containing heteroaryl ring or nitrogen-containing heterocyclyl ring is halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy, C 1-6 alkylcarbonylamino or oxo may be independently substituted by 1 to 3 or a pharmaceutically acceptable compound Its salt.
  • Substituent group consisting of group ⁇ , halogen, cyano, hydroxy, amino, mono C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyloxy Halo C 1-6 alkyloxy, C 1-6 alkyloxy C 1-6 alkyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyloxycarbonylamino, C 1-6 alkyloxycarbonyl (C 1-6 Alkyl) amino, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl (C 1-6 alkyl) amino, carbamoyl, mono C 1-6 alkyl Carbamoyl, di-C 1-6 alkylcarbamoyl, carbamoylamino, mono-C 1-6 alkyl Carbamoylamino, di-C
  • the present invention provides (2) A melanin-concentrating hormone receptor antagonist containing the compound according to (1) as an active ingredient, (3) a pharmaceutical composition comprising a medically acceptable additive and the compound according to (1), (4) A preventive or therapeutic agent for obesity, diabetes, fatty liver, bulimia, depression or anxiety, comprising the compound according to (1) as an active ingredient, (5) A medicament based on melanin-concentrating hormone receptor antagonism, comprising the compound according to (1) as an active ingredient.
  • Halogen includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • C 1-6 alkyl includes straight-chain alkyl having 1 to 6 carbon atoms or branched alkyl having 3 to 6 carbon atoms, and specifically includes, for example, methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, 2-propyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl , Isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethyl Propyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methyl
  • C 3-6 cycloalkyl means cycloalkyl having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Halo C 1-6 alkyl includes C 1-6 alkyl in which part or all of the hydrogen atoms of C 1-6 alkyl are replaced by halogen, for example, fluoromethyl, difluoromethyl, trifluoro Examples include methyl, 2-fluoroethyl, 1,2-difluoroethyl and the like.
  • C 1-6 alkyloxy includes a group in which C 1-6 alkyl is bonded to an oxygen atom, and specifically includes methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, isobutoxy, Examples thereof include tert-butoxy and n-pentyloxy.
  • Halo C 1-6 alkyloxy includes a group in which halo C 1-6 alkyl is bonded to an oxygen atom, specifically, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, Examples include trichloromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy and the like.
  • “Mono C 1-6 alkylamino” is a group in which one of the hydrogen atoms of amino (—NH 2 ) is substituted with a C 1-6 alkyl group. Specifically, for example, methylamino, ethylamino, Examples include n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino and the like.
  • “DiC 1-6 alkylamino” is a group in which two hydrogen atoms of an amino group are substituted with C 1-6 alkyl. Specifically, for example, dimethylamino, diethylamino, ethylmethylamino, di ( n-propyl) amino, methyl (n-propyl) amino, diisopropylamino and the like.
  • C 1-6 alkyloxy C 1-6 alkyl is C 1-6 alkyl substituted with C 1-6 alkyloxy, and examples thereof include methoxymethyl, ethoxymethyl, n-propyl. Examples include oxymethyl, isopropyloxymethyl, 1-methoxyethyl, 2-methoxyethyl and the like.
  • C 1-6 alkyloxycarbonyl is a group in which C 1-6 alkyloxy is bonded to carbonyl (—CO—) and includes alkyloxycarbonyl having 1 to 6 carbon atoms. Examples include methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl and the like.
  • C 1-6 alkyloxycarbonylamino is a group in which one of the hydrogen atoms of amino is replaced with C 1-6 alkyloxycarbonyl, including alkyloxycarbonylamino having 1 to 6 carbon atoms, Examples include methoxycarbonylamino, ethoxycarbonylamino, n-propyloxycarbonylamino, isopropyloxycarbonylamino, n-butoxycarbonylamino, tert-butoxycarbonylamino and the like.
  • C 1-6 alkyloxycarbonyl (C 1-6 alkyl) amino is a group in which C 1-6 alkyloxycarbonyl is bonded in place of a hydrogen atom on the nitrogen atom of mono-C 1-6 alkylamino. Specific examples include methoxycarbonyl (methyl) amino, ethoxycarbonyl (methyl) amino, n-propyloxycarbonyl (methyl) amino and the like.
  • C 1-6 alkylcarbonyl is a group in which C 1-6 alkyl is bonded to carbonyl, and includes alkylcarbonyl having 1 to 6 carbons, specifically, for example, acetyl, propionyl, butyryl, Examples include isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
  • C 1-6 alkylcarbonyloxy is a group in which C 1-6 alkylcarbonyl is bonded to an oxygen atom, and specifically includes, for example, acetoxy, propionyloxy, valeryloxy, isovaleryloxy, pivaloyloxy and the like. Can be mentioned.
  • C 1-6 alkylcarbonylamino is a group in which one of the hydrogen atoms of amino is replaced with C 1-6 alkylcarbonyl. Specifically, for example, acetylamino, propionylamino, isobutyrylamino, Valerylamino, isovalerylamino, pivaloylamino and the like can be mentioned.
  • C 1-6 alkylcarbonyl (C 1-6 alkyl) amino is a group in which a hydrogen atom on a nitrogen atom of mono C 1-6 alkylamino is substituted with C 1-6 alkylcarbonyl, for example, methyl
  • Examples include carbonyl (methyl) amino, ethylcarbonyl (methyl) amino, n-propylcarbonyl (methyl) amino and the like.
  • “Mono C 1-6 alkylcarbamoyl” is a group in which one hydrogen atom of carbamoyl (—CONH 2 ) is substituted with C 1-6 alkyl, and specifically includes, for example, methylcarbamoyl, ethylcarbamoyl, n -Propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl and the like.
  • “DiC 1-6 alkylcarbamoyl” is a group in which two hydrogen atoms of carbamoyl are substituted with C 1-6 alkyl. Specifically, for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di ( n-propyl) carbamoyl, methyl (n-propyl) carbamoyl, diisopropylcarbamoyl and the like.
  • “Mono C 1-6 alkylcarbamoylamino” is a group in which one of hydrogen atoms of amino is substituted with mono C 1-6 alkylcarbamoyl. Specifically, for example, methylcarbamoylamino, ethylcarbamoylamino, n -Propylcarbamoylamino, isopropylcarbamoylamino and the like.
  • the "di-C 1-6 alkylcarbamoyl amino" is 1 Tsugaji C 1-6 alkylcarbamoyl and substituted groups of the hydrogen atom of an amino, specifically, for example, dimethylcarbamoylamino, diethylcarbamoyl, di (N-propyl) carbamoylamino, diisopropylcarbamoylamino and the like.
  • the "mono-C 1-6 alkylcarbamoyl (C 1-6 alkyl) amino” is a group wherein a hydrogen atom on the nitrogen atom of mono-C 1-6 alkylamino is substituted with a mono C 1-6 alkylcarbamoyl, specific Specifically, for example, monomethylcarbamoyl (methyl) amino, monoethylcarbamoyl (methyl) amino, [mono (n-propyl) carbamoyl] (methyl) amino and the like can be mentioned.
  • “DiC 1-6 alkylcarbamoyl (C 1-6 alkyl) amino” is a group in which a hydrogen atom on the nitrogen atom of mono-C 1-6 alkylamino ”is substituted with diC 1-6 alkylcarbamoyl; Specific examples include dimethylcarbamoyl (methyl) amino, diethylcarbamoyl (methyl) amino, [di (n-propyl) carbamoyl] (methyl) amino, and the like.
  • “Mono C 1-6 alkylcarbamoyloxy” is a group in which mono C 1-6 alkylcarbamoyl is bonded to an oxygen atom, and specifically includes, for example, methylcarbamoyloxy, ethylcarbamoyloxy, n-propylcarbamoyloxy. Isopropylcarbamoyloxy, n-butylcarbamoyloxy, tert-butylcarbamoyloxy and the like.
  • DiC 1-6 alkylcarbamoyloxy is a group in which diC 1-6 alkylcarbamoyl is bonded to an oxygen atom. Specifically, for example, dimethylcarbamoyloxy, diethylcarbamoyloxy, ethylmethylcarbamoyloxy, And di (n-propyl) carbamoyloxy.
  • C 1-6 alkylsulfonyl is a group in which C 1-6 alkyl is bonded to sulfonyl (—SO 2 —). Specifically, for example, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, isopropyl Pansulfonyl, n-butanesulfonyl and the like can be mentioned.
  • C 1-6 alkylsulfonylamino is a group in which one of the hydrogen atoms of amino is replaced with C 1-6 alkylsulfonyl. Specifically, for example, methanesulfonylamino, ethanesulfonylamino, n-propane Examples include sulfonylamino, isopropanesulfonylamino, n-butanesulfonylamino and the like.
  • C 1-6 alkylsulfonyl (C 1-6 alkyl) amino is a group in which a hydrogen atom on a nitrogen atom of mono C 1-6 alkylamino is substituted with C 1-6 alkylsulfonyl, specifically Examples include methanesulfonyl (methyl) amino, ethanesulfonyl (methyl) amino, and the like.
  • “Mono C 1-6 alkylsulfamoyl” is a group in which one of the hydrogen atoms of sulfamoyl (—SO 2 NH 2 ) is substituted with C 1-6 alkyl.
  • monomethylsulfamoyl examples include moyl, monoethylsulfamoyl, mono (n-propyl) sulfamoyl, monoisopropylsulfamoyl and the like.
  • Di-C 1-6 alkylsulfamoyl is a group in which two hydrogen atoms of sulfamoyl are substituted with C 1-6 alkyl. Specifically, for example, dimethylsulfamoyl, diethylsulfamoyl, Examples include di (n-propyl) sulfamoyl, diisopropylsulfamoyl and the like.
  • “Mono C 1-6 alkylsulfamoylamino” is a group in which one of hydrogen atoms of amino is substituted with mono C 1-6 alkylsulfamoyl. Specifically, for example, (monomethylsulfamoyl) ) Amino, (monoethylsulfamoyl) amino, [mono (n-propyl) sulfamoyl] amino, (monoisopropylsulfamoyl) amino and the like.
  • (di-C 1-6 alkylsulfamoyl) amino a 1 Tsugaji C 1-6 alkylsulfamoyl and substituted groups of the hydrogen atom of an amino, specifically, for example, (Jimechirusuru (Famoyl) amino, (diethylsulfamoyl) amino, (ethylmethylsulfamoyl) amino and the like.
  • the "mono-C 1-6 alkylsulfamoyl (C 1-6 alkyl) amino” refers to the group in which a hydrogen atom on the nitrogen atom of mono-C 1-6 alkylamino is substituted with a mono C 1-6 alkylsulfamoyl Specifically, for example, monomethylsulfamoyl (methyl) amino, monoethylsulfamoyl (methyl) amino, [mono (n-propyl) sulfamoyl] (methyl) amino and the like can be mentioned.
  • Di-C 1-6 alkylsulfamoyl (C 1-6 alkyl) amino is a group in which a hydrogen atom on a nitrogen atom of mono-C 1-6 alkylamino is substituted with di-C 1-6 alkylsulfamoyl. Specifically, for example, dimethylsulfamoyl (methyl) amino, diethylsulfamoyl (methyl) amino, [di (n-propyl) sulfamoyl] (methyl) amino and the like can be mentioned.
  • aryl examples include phenyl, naphthyl, tolyl and the like.
  • Heteroaryl is a 5-membered or 6-membered monocyclic ring containing 1 or 2 or more, preferably 1 to 3 heteroatoms, which are the same or different from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a fused cyclic heteroaryl in which the monocyclic heteroaryl is fused with the aryl, or the same or different monocyclic heteroaryl is fused with each other, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl , Thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2 , 3-Triazini 1,2,4-triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzo
  • Nonrogen-containing heterocyclyl is a monocyclic or bicyclic ring containing 3 to 10 atoms containing a nitrogen atom, saturated, partially saturated or unsaturated, and further containing an oxygen atom or Sulfur atoms may be included, for example, pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, pyridine-2 (1H) -one, pyrimidin-2 (1H) -one, pyridazine-3 (2H) -one, etc. Illustrated.
  • the “pharmaceutically acceptable salt” of the derivative represented by the formula (I) includes a pharmaceutically acceptable ordinary salt, and an acid addition salt or a nitrogen-containing complex at the amine site of the compound of the formula (I). Examples include acid addition salts in the ring, or base addition salts in the group where the compound of formula (I) has an acidic substituent.
  • the acid addition salt examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate, maleate, fumarate, tartrate, citrate, ascorbate, trifluoro Organic acid salts such as acetates; sulfonates such as methane sulfonates, isothiocyanates, benzene sulfonates, and p-toluene sulfonates.
  • inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate, maleate, fumarate, tartrate, citrate, ascorbate, trifluoro Organic acid salts such as acetates
  • sulfonates such as methane sulfonates, isothiocyanates, benzene sulfonates, and p-toluene sulfonates.
  • 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, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, And organic amine salts such as diethanolamine salt, triethanolamine salt, procaine salt, and N, N′-dibenzylethylenediamine salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt
  • organic amine salts such as diethanolamine salt, triethanolamine salt, procaine salt, and N, N′-dibenzylethylenediamine salt.
  • R 1a and R 1b independently represent a hydrogen atom or C 1-6 alkyl.
  • R 1a or R 1b include a hydrogen atom, methyl, ethyl and the like, and preferably a hydrogen atom or methyl is recommended.
  • R 2a and R 2b independently represent a hydrogen atom or C 1-6 alkyl.
  • R 2a or R 2b include a hydrogen atom, methyl, ethyl, and the like, and preferably a hydrogen atom is recommended.
  • R 3a and R 3b independently represent a hydrogen atom or C 1-6 alkyl.
  • R 3a or R 3b include a hydrogen atom, methyl, ethyl, and the like, and preferably a hydrogen atom is recommended.
  • W represents a hydrogen atom, hydroxy, C 1-6 alkyloxy or N (R 4a ) (R 4b ).
  • R 4a represents a hydrogen atom, hydroxy, C 1-4 alkyloxy or haloC 1-4 alkyloxy
  • R 4b represents a hydrogen atom or C 1-6 alkyl.
  • R 4a examples include a hydrogen atom; hydroxy; C 1-4 alkyloxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, 2-hydroxy-2-methylpropyloxy; chloromethoxy, Illustrative are halo C 1-4 alkyloxy such as fluoromethoxy, trichloromethoxy, trifluoromethoxy, chloroethoxy, fluoroethoxy and the like, preferably hydrogen atom, hydroxy, methoxy, fluoroethoxy and the like are recommended.
  • R 4b examples include a hydrogen atom, C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, and n-butyl, and a hydrogen atom is recommended.
  • W include a hydrogen atom; hydroxy; C 1-6 alkyloxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy; amino, methylamino, dimethylamino, ethylmethylamino, etc.
  • N (R 4a ) (R 4b ) is exemplified.
  • W is preferably a hydrogen atom, hydroxy or C 1-6 alkyloxy.
  • W is preferably N (R 4a ) (R 4b ), R 4a is a hydrogen atom, hydroxy, methoxy or fluoroethoxy, and R 4b is a hydrogen atom.
  • Y 1 represents a hydrogen atom or OR 5 ;
  • Y 2 represents a hydrogen atom or OR 6 , or Y 1 and Y 2 together form —O—C (R 7a ) (R 7b ) —.
  • R 5 and R 6 independently represent a hydrogen atom or C 1-6 alkyl.
  • R 5 is preferably a hydrogen atom, methyl, ethyl or cyclopropyl, and R 6 is preferably a hydrogen atom.
  • R 7a and R 7b independently represent a hydrogen atom or C 1-6 alkyl.
  • Y 1 and Y 2 are preferably Y 1 is OR 5 , R 5 is a hydrogen atom, methyl, ethyl or cyclopropyl, Y 2 is a hydrogen atom, Both Y 1 and Y 2 are hydrogen atoms, Y 1 and Y 2 together are exemplified by —O—CH 2 —, and it is particularly recommended that both Y 1 and Y 2 are hydrogen atoms.
  • Z represents C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl or nitrogen-containing heterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl , Heteroaryl or nitrogen-containing heterocyclyl are halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy, C 1 It may be independently 1 to 3 substituted with -6 alkylcarbonylamino, C 3-6 cycloalkyl or tri (C 1-3 ) alkylsilyl.
  • Z include C such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 2,2-dimethylpropyl, difluoromethyl, trifluoromethyl, and 1-methyl-1-hydroxyethyl.
  • C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, 1-hydroxycyclopropyl, 1-methylcyclopropyl; C 2-6 alkenyl such as vinyl; ethynyl, cyclopropylethynyl or 3-hydroxy-3 C 2-6 alkynyl such as methylbutyn-1-yl; aryl such as phenyl, 4-fluorophenyl, 3,4-difluorophenyl, naphthyl; pyridyl, 2-fluoropyridin-3-yl, 2-fluoropyridine-4 -Yl, 6-fluoropyridyl, 6- (fluoroethoxy) pyridine-3 Yl, pyrimidinyl, 2-methoxy-6-pyrimidinyl, pyrimidin-4-yl, pyridazinyl, 6-fluoropyridazinyl, pyrazinyl, pyrimidinoy
  • Z are methyl, isopropyl, cyclopropyl, cyclopropylethynyl, 3-hydroxy-3-methylbutyn-1-yl and the like.
  • aryl, heteroaryl or nitrogen-containing heterocyclyl is also preferable.
  • R 9a represents a hydrogen atom, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy or C 1-6 alkylcarbonylamino.
  • R 9b represents a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl].
  • R 9a is preferably a hydrogen atom, a fluorine atom, methoxy, fluoroethoxy and the like
  • R 9b is preferably a hydrogen atom, methyl, fluoroethyl and the like.
  • Z is more preferably fluorophenyl, pyridyl, fluoropyridyl, fluoroethoxypyridyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl, methylimidazolyl, methyltriazolyl, pyridin-2 (1H) -one, 1- (2- Fluoroethyl) pyridin-2 (1H) -one, 1- (2-fluoroethyl) pyrimidin-2 (1H) -one or 2- (2-fluoroethyl) pyridazin-3 (2H) -one is recommended.
  • Ar 1 represents 6-membered aryl or 6-membered nitrogen-containing heteroaryl, and the aryl or nitrogen-containing heteroaryl is independently substituted with 1 to 4 substituents selected from the group consisting of group ⁇ . Also good.
  • Preferred examples of the substituent selected from the group consisting of group ⁇ in Ar 1 include halogen such as fluorine atom, chlorine atom and bromine atom; C 1-6 alkyl such as methyl, ethyl, n-propyl and isopropyl. It may have 1 to 4, preferably 1 to 3 substituents.
  • Ar 1 examples include 6-membered aryls such as phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4,5-trifluorophenyl, and the like. 6-membered nitrogen-containing heteroaryl And pyridyl, 5-fluoropyridin-2-yl, 5-chloropyridin-2-yl, 6-chloropyridin-3-yl and the like, and preferably substituted with 1 to 3 fluorine atoms or chlorine atoms.
  • 6-membered aryl especially phenyl
  • 6-membered nitrogen-containing heteroaryl especially pyridyl
  • 3,4-difluorophenyl, 2,4,5-trifluorophenyl, 3,4 , 5-Trifluorophenyl or 5-chloropyridin-2-yl is recommended.
  • Ar 2 is a divalent group and represents a 6-membered aryl ring, a 5- to 6-membered heteroaryl ring or a pyridone ring, and more specifically, a 6-membered aryl, 5- to 6-membered ring A group formed by removing two hydrogen atoms from a ring heteroaryl or pyridone, wherein the aryl, heteroaryl or pyridone is independently substituted with 1 to 3 substituents selected from the group consisting of group ⁇ It may be.
  • Examples of the 6-membered aryl ring in Ar 2 include a benzene ring, and examples of the 5-membered heteroaryl ring include a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, and an isothiazole ring.
  • Oxadiazole ring, thiadiazole ring, pyrrole ring, pyrazole ring and imidazole ring are exemplified, and the 6-membered heteroaryl ring is preferably exemplified by nitrogen-containing heteroaryl, specifically pyridine ring and pyrazine ring , Pyrimidine ring, and pyridazine ring.
  • Preferred examples of the substituent selected from the group consisting of group ⁇ in Ar 2 include fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, chloromethyl, fluoromethyl, methoxy, ethoxy, methylcarbonyl, methanesulfonyl and the like. Is done.
  • the substituent selected from the group consisting of group ⁇ in Ar 1 and the substituent selected from the group consisting of group ⁇ in Ar 2 may be the same or different.
  • Preferred examples of 6-membered aryl in Ar 2 include 1,4-phenylenediyl; Preferred examples of the 5-membered heteroaryl include thiophene-2,5-diyl, and preferred examples of the 6-membered heteroaryl include pyridine-2,5-diyl and pyrimidine-2,5-diyl.
  • ring A Represents a 6-membered aryl ring, a 5- to 6-membered nitrogen-containing heteroaryl ring, or a 5- to 6-membered nitrogen-containing heterocyclyl ring, and the aryl ring, nitrogen-containing heteroaryl ring or nitrogen-containing heterocyclyl ring further includes 5 1 to 6-membered aryl ring or heteroaryl ring may be condensed, and these aryl ring, nitrogen-containing heteroaryl ring or nitrogen-containing heterocyclyl ring is halogen, hydroxy, C 1-6 alkyl, halo C 1-6. It may be independently 1 to 3 substituted with alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy, C 1-6 alkylcarbonylamino or oxo.
  • a ring group examples include the following.
  • R 8a represents a hydrogen atom, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyloxy or C 1-6 alkylcarbonylamino.
  • R 8b represents a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl, and Y 2 is the same as defined above]
  • R 8a include hydrogen atom; halogen such as fluorine atom, chlorine atom and bromine atom; hydroxy; C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; fluoromethyl , chloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, halo C 1-6 alkyl such as difluoroethyl, methoxy, ethoxy, n- propyloxy, isopropyloxy, C 1-6 alkyloxy n- butoxy ; methylcarbonylamino, ethylcarbonyl C 1-6 alkyl amino, such as; chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, chloroethoxy, halo C 1-6 alkyloxy,
  • R 8b include a hydrogen atom; C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, Illustrative are haloC 1-6 alkyls such as chloroethyl, difluoroethyl and the like.
  • a 5- to 6-membered nitrogen-containing heteroaryl ring a 5- to 6-membered nitrogen-containing heterocyclyl ring, a 5- to 6-membered nitrogen-containing heteroaryl ring, or a 5- to 6-membered nitrogen-containing heterocyclyl ring is preferable.
  • a 5- to 6-membered nitrogen-containing heteroaryl ring a 5- to 6-membered nitrogen-containing heterocyclyl ring, or a 5- to 6-membered nitrogen-containing heterocyclyl ring is preferable.
  • R 8a a hydrogen atom, and fluorine atom is preferred as R 8b, a hydrogen atom, methyl or the like is recommended.
  • Examples of the compound represented by the formula (I) include: (3,4-difluorophenyl) (4-fluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) pyrimidine -2-yl] methanol, (3,4-difluorophenyl) (4-fluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl)- 2-thienyl] methanol, Bis (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidin] -1′-ylmethyl) pyrazin-2-yl] methanol, Cyclopropyl (3,4-difluorophenyl)
  • the compound of the present invention can be produced according to the procedures of the following schemes and examples, but is not limited thereto.
  • Examples of the amount of the compound represented by the formula (III) include 3.0 to 5.0 mol with respect to 1 mol of the compound represented by the formula (II).
  • organic solvent examples include tetrahydrofuran (hereinafter referred to as “THF”), diethyl ether, ethylene glycol dimethyl ether, or a mixture thereof.
  • THF tetrahydrofuran
  • diethyl ether diethyl ether
  • ethylene glycol dimethyl ether or a mixture thereof.
  • reaction temperature ⁇ 100 to 30 ° C. is exemplified, preferably ⁇ 100 to 0 ° C. is recommended, and the reaction is usually completed in 1 to 8 hours.
  • Examples of the compound represented by the formula (III) include those represented by the following formula (III-1).
  • the compound represented by the formula (III) can also be prepared from compounds of the following formulas (III-2) to (III-5).
  • the compound represented by the formula (III) can be prepared by mixing the above compound and isopropyl magnesium chloride.
  • the compound represented by the formula (III) can be prepared by mixing the above compound and butyl lithium.
  • the compound represented by the formula (III) is prepared by mixing the above compound and lithium 2,2,6,6-tetramethylpiperidide. Is possible.
  • the compound represented by the formula (III) is It can be prepared by mixing the above compound and butyl lithium.
  • Manufacturing method 1-1 In the production method 1, the compound represented by the formula (Ia) is obtained also by performing the same reaction using the compound represented by the formula (IIb) instead of the compound represented by the formula (II). Can do.
  • the reaction can be performed according to step 1.
  • the compound represented by the formula (II) or the compound represented by the formula (IIb) can be prepared by the following method and can be prepared by the method described in WO2008 / 38692.
  • Process 2 A compound represented by the formula (II) or the formula (IIb) by condensing the compound represented by the formula (IV) and the compound represented by the formula (V) in an organic solvent, preferably in the presence of a base. Get.
  • the amount of the compound represented by the formula (V) is 1.0 to 3.0 mol, preferably 1.0 to 2.0 mol per 1 mol of the compound represented by the formula (IV). Recommended.
  • Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.
  • the amount of the base used is, for example, 3.0 to 10 mol, preferably 3.0 to 10 mol per mol of the compound represented by the formula (IV). 5.0 moles is recommended.
  • reaction solvent examples include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as THF and dioxane; N, N-dimethylformamide (hereinafter referred to as “DMF”) and dimethyl sulfoxide (hereinafter referred to as “DMSO”). Is done.
  • halogenated hydrocarbons such as methylene chloride and chloroform
  • ethers such as THF and dioxane
  • N, N-dimethylformamide hereinafter referred to as “DMF”
  • DMSO dimethyl sulfoxide
  • the reaction temperature is, for example, ⁇ 20 to 30 ° C., preferably 0 to 30 ° C., and the reaction is usually completed in 1 to 24 hours.
  • Examples of the compound represented by the formula (IV) include the following, and the compound represented by the formula (V) can be prepared by the method described below.
  • Production method 2-1 is a method of condensing a compound represented by formula (VI) and a compound represented by formula (IV) to obtain a compound represented by formula (I).
  • the reaction conditions are the same as in step 2.
  • Process 3 The protective group is removed from Compound 1 by a conventionally known method to obtain Compound 2.
  • the method of deprotection is described in Protective Groups in Organic Synthesis, T.W. W. It can be carried out by the method described in Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto.
  • Compound 1 can be prepared by the method described in WO2008 / 38692.
  • Process 4 A leaving group is introduced into the hydroxy of compound 2 to obtain a compound represented by the formula (VI).
  • Examples of the leaving group include methanesulfonyl, p-toluenesulfonyl, and benzenesulfonyl.
  • a conventionally known method may be used.
  • a corresponding halogenating agent (mesyl chloride, tosyl chloride) and a compound in an organic solvent such as THF or methylene chloride in the presence of a base. 2 may be reacted.
  • a compound in which W is hydroxy that is, a compound represented by formula (VIa) can be prepared by the following method.
  • Process 5 The hydroxy of compound 3 is protected to give compound 4.
  • the above-mentioned “Protective Groups in Organic Synthesis” can be referred to.
  • the protecting group include trimethylsilyl, t-butyldimethylsilyl and the like.
  • Compound 3 can be prepared by the method described in WO2008 / 38692.
  • Step 6 In an organic solvent, compound 4 is reacted with the compound represented by formula (III) according to step 1 to obtain compound 5.
  • Step 7 Compound 5 is reacted according to Step 3 and Step 4 to obtain a compound represented by the formula (VIa).
  • a compound in which D is Z that is, a compound represented by the formula (Va) or the formula (VIa) can be prepared by the following method.
  • Process 8 Compound 6 and methylhydroxyamine hydrochloride are condensed in the presence of trimethylaluminum to obtain compound 7.
  • the amount of methylhydroxyamine hydrochloride used is, for example, 1.0 to 3.0 moles with respect to 1 mole of compound 6, and the amount of trimethylaluminum used is 1 with respect to 1 mole of compound 6. 0.0 to 3.0 moles are exemplified.
  • reaction solvent examples include methylene chloride and toluene.
  • reaction temperature -20 to 30 ° C. is exemplified, and the reaction is usually completed in 1 to 24 hours.
  • Compound 6 can be a commercially available reagent, or can be prepared by the method described in WO2008 / 38692.
  • Step 9 Compound 7 and compound 8 are condensed in the presence of n-butyllithium in an organic solvent to obtain compound 9.
  • the amount of compound 8 used is, for example, 1.0 to 3.0 moles per mole of compound 7, and the amount of n-butyllithium used is 1. Examples are 0 to 3.0 moles.
  • reaction solvent examples include THF, diethyl ether, toluene and the like.
  • reaction temperature -78 to 0 ° C is exemplified, and the reaction is usually completed in 1 to 5 hours.
  • Compound 8 can be prepared by the method described in WO2008 / 38692.
  • Step 10 Removal of the hydroxy protecting group of compound 9 provides compound 10.
  • the “Protective Groups in Organic Synthesis” can be referred to.
  • Step 11 A leaving group is introduced into compound 10 to obtain a compound represented by formula (Va).
  • the leaving group is introduced according to step 4.
  • Step 12 The compound 9 was reacted with the compound represented by the formula (III-1) used in the production method 1-1 to obtain the compound 5, and then the obtained compound 5 was reacted according to the step 7, A compound represented by (VIa) is obtained.
  • Manufacturing method 3 is a method for producing a compound in which W is —N (R 4a ) (R 4b ), that is, a compound represented by formula (Ib).
  • Step 13 Chlorine is introduced into hydroxy of the compound represented by the formula (Ia) to obtain a compound 11.
  • a chlorinating reagent such as thionyl chloride or phosphorus oxychloride.
  • the amount of the chlorinating reagent used is, for example, from 10 moles to a large excess mole per mole of the compound represented by the formula (Ia), and the solvent amount from 100 moles is preferably used.
  • reaction solvent examples include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as THF and dioxane.
  • a chlorinating reagent may be used as a reaction solvent.
  • reaction temperature 0 to 100 ° C. is exemplified, preferably 20 to 50 ° C. is recommended, and the reaction is usually completed in 0.1 to 1 hour.
  • Step 14 Compound 11 and compound 12 are condensed in an organic solvent, preferably in the presence of a base, to obtain a compound represented by formula (Ib).
  • the amount of compound 12 used is, for example, 1.0 to 10 moles per mole of compound 11, preferably 3.0 to 10 moles.
  • Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.
  • the amount of the base used is, for example, 2.0 to excess moles per 1 mole of the compound 11, preferably 5.0 to 30 moles is recommended. .
  • reaction solvent examples include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as THF and dioxane.
  • reaction temperature 0 to 50 ° C. is exemplified, preferably 0 to 30 ° C. is recommended, and the reaction is usually completed in 1 to 24 hours.
  • Examples of the compound 12 include ammonia, hydroxylamine, O-methylhydroxylamine, O- (2-fluoroethyl) hydroxylamine and the like.
  • Manufacturing method 4 is a method for producing a compound represented by formula (Ib ′) (W ⁇ NH 2 ) using a compound represented by formula (II) as a raw material.
  • W amino group
  • Step 15 In the presence of titanium tetraethoxide, the compound represented by formula (II) is reacted with t-butylsulfinylamide in an organic solvent to obtain compound 13.
  • the amount of titanium tetraethoxide used is, for example, from 1 mole to an excess mole per mole of the compound represented by the formula (II), preferably 1.3 to 2.2 moles.
  • the amount of t-butylsulfinylamide used is, for example, 1.0 to 5.0 mol, preferably 1.2 to 2.0 mol based on 1 mol of the compound represented by the formula (II).
  • reaction solvent examples include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as THF and dioxane, toluene, xylene and the like.
  • reaction temperature 20 to 110 ° C. is exemplified, preferably 50 to 100 ° C. is recommended, and the reaction is usually completed in 3 to 24 hours.
  • Step 16 Compound 13 is reacted with the compound represented by formula (III) to obtain compound 14.
  • the reaction method is the same as in Step 1.
  • Step 17 The compound represented by the formula (Ib ′) is obtained by deprotecting the t-butylsulfinyl group of Compound 14.
  • deprotection methods refer to “Protective Groups in Organic Synthesis”.
  • deprotection can be performed using trifluoroacetic acid or an aqueous hydrochloric acid solution at 0 ° C. to room temperature.
  • Production method 5 is a method for producing a compound represented by formula (I) in which W is a hydrogen atom, that is, a compound represented by formula (Ic).
  • Step 18 The carbonyl group of the compound represented by formula (II) is reduced by a conventionally known method to obtain the compound represented by formula (IIc).
  • the reducing agent include sodium borohydride, lithium aluminum hydride and the like.
  • Step 19 In the presence of an acid, the compound represented by the formula (IIc) and the compound 15 are reacted in an organic solvent to obtain the compound represented by the formula (Ic).
  • the amount of compound 15 used is, for example, 1.0 to 5.0 mol, preferably 1.5 to 3.0 mol based on 1 mol of the compound represented by formula (II).
  • Examples of the acid include concentrated sulfuric acid, and the amount of acid used is 0.1 to 1.0 mol with respect to 1 mol of the compound represented by the formula (IIc).
  • reaction solvent preferably acetic acid is exemplified.
  • the reaction temperature is 100 to 200 ° C., preferably 160 to 180 ° C., and the reaction is usually completed in 24 to 72 hours.
  • Examples of the compound 15 include 2-methylimidazole, 3-methyl-1,2-4-triazole and the like.
  • Step 20 The compound represented by the formula (IIc) and the compound 15 are subjected to Mitsunobu reaction conditions in an organic solvent to obtain a compound represented by the formula (Ic).
  • Examples of the azo compound include dimethyl azodicarboxylate, diethyl azodicarboxylate (hereinafter referred to as “DEAD”), diisopropyl azodicarboxylate (hereinafter referred to as “DIAD”), 1,1 ′-(azodicarbonyl) dipiperidide. (Hereinafter referred to as “DPPA”), tetramethylazodicarboxamide, and the like.
  • Examples of the triarylphosphine include triphenylphosphine, tolylphosphine, and the like.
  • Examples of the trialkylphosphine include triethylphosphine, tributylphosphine, and the like. Illustrated.
  • the amount of compound 15 used is, for example, 1.0 to 10 moles, preferably 1.0 to 1.5 moles per mole of the compound represented by formula (IIc).
  • the amount of the azo compound and the organophosphorus compound used is, for example, 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol per 1 mol of the compound represented by the formula (IIc). Mole is recommended, and 1.0 to 3.0 mol of the organophosphorus compound is exemplified with respect to 1 mol of compound 15, preferably 1.0 to 1.5 mol.
  • reaction solvent examples include methylene chloride, chloroform, n-heptane, n-hexane, benzene, toluene, xylene, diethyl ether, THF, 1,4-dioxane, DMF, DMSO and the like.
  • reaction temperature 0 to 100 ° C. is exemplified, preferably 0 to 50 ° C. is recommended, and the reaction is usually completed in 2 to 24 hours.
  • a protecting group varies depending on the type of protecting group and the stability of the target compound.
  • a base ie, for example, 0.01 mole to large excess of acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, etc., or equimolar to large excess of base, preferably potassium hydroxide, calcium hydroxide
  • a metal hydride complex or the like a catalytic reduction using a palladium-carbon catalyst, a Raney nickel catalyst, or the like.
  • the protecting group for amino and imino is not particularly limited as long as it has the function, and examples thereof include aralkyl such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzhydryl, and trityl; Lower alkanoyl such as acetyl and pivaloyl; benzoyl; aryl alkanoyl such as phenylacetyl; lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; alkyloxycarbonyl such as benzyloxycarbonyl; trimethylsilyl, tert-butyldimethylsilyl and the like Tetrahydropyranyl; trimethylsilylethoxymethyl; lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl; benzenesulfonyl, toluene
  • the hydroxy protecting group is not particularly limited as long as it has the function, and examples thereof include lower alkyl such as methyl, ethyl and tert-butyl; lower alkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl; Lower alkoxymethyl such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl and trityl; acyl such as formyl and acetyl In particular, methyl, methoxymethyl, tetrahydropyranyl, trityl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl and the like are preferable.
  • the carboxyl protecting group is not particularly limited as long as it has the function, and examples thereof include lower alkyl such as methyl, ethyl and tert-butyl; halo lower alkyl such as 2,2,2-trichloroethyl and the like. Lower alkenyl such as 2-propenyl group; aralkyl such as benzyl, p-methoxybenzyl, benzhydryl, trityl and the like, and in particular, methyl, ethyl, tert-butyl, 2-propenyl, benzyl, p-methoxybenzyl, benzhydryl Etc. are preferred.
  • the carbonyl protecting group is not particularly limited as long as it has the function, and examples thereof include acetals such as ethylene ketal, dimethyl ketal, and S, S′-dimethyl ketal, and ketals.
  • the compound represented by the formula (I) thus obtained can be easily isolated and purified by ordinary separation means such as solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography, high performance chromatography and the like. Can do.
  • MCH binding inhibition test cDNA sequence encoding human MCH-1R [FEBS Letters, Vol. 398, 253 (1996); Biochimica et Biophisica Acta, Vol. 1401,216 (1998)] was cloned into the plasmid vector pEF / myc / cyto (Invitrogen). The obtained expression vector was transfected into host cell CHO-K1 (American Type Culture Collection) using Lipofectamine Plus reagent (Life Technology) to obtain MCH-1R expressing cells.
  • Membrane preparations prepared from cells expressing MCH-1R together with a test compound and 50 pM [ 125 I] MCH (manufactured by NEN), assay buffer (10 mM magnesium chloride, 2 mM ethylenediaminetetraacetic acid, 0.01 After incubation in 50 mM Tris buffer (pH 7.4) containing 1% bacitracin and 0.2% bovine serum albumin at 25 ° C. for 1 hour, the mixture was filtered with a glass filter GF / C (Whatman).
  • the glass filter was washed with 50 mM Tris buffer containing 10 mM magnesium chloride, 2 mM ethylenediaminetetraacetic acid and 0.04% Tween-20, pH 7.4, and then the radioactivity on the glass filter was determined. Non-specific binding was measured in the presence of 1 ⁇ M human MCH, and the 50% inhibitory concentration (IC 50 value) of the test compound for specific [ 125 I] MCH binding was determined. The results are shown in Table 1.
  • the compound of the present invention strongly inhibited the binding of MCH to MCH-1R and exhibited an excellent action as an MCH-1R antagonist.
  • the compound of the present invention is used for various diseases involving MCH, such as obesity, diabetes, hormonal secretion abnormalities, hyperlipidemia, gout, fatty liver, etc .; for example, angina pectoris, acute / congestion Cardiovascular diseases such as congenital heart failure, myocardial infarction, arteriosclerosis, hypertension, kidney disease, electrolyte abnormalities; eg, bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit ⁇ Central and peripheral nervous system diseases such as hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormality, olfactory disorder, morphine tolerance, drug dependence, alcoholism; for example, infertility, premature birth, Reproductive system diseases such as sexual dysfunction; Others, Gastrointestinal diseases; Respiratory diseases, Cancer or skin pigmentation preventive or therapeutic agents, especially obesity, diabetes, fatty liver, bulimia, depression or anxiety Available as a preventive or therapeutic agent It is.
  • angina pectoris
  • composition Comprising a Compound Represented by Formula (I)
  • the compound of the present invention can be administered orally or parenterally, and can be formulated into a form suitable for its administration, thereby preventing the above-mentioned diseases.
  • additives generally used in the pharmaceutical field can be used. Specifically, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxy Methylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, Hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, poly Ruki glycol, cyclodextrin or
  • Examples of the dosage form formulated using these additives include solid preparations such as tablets, capsules, granules, powders, suppositories; and liquid preparations such as syrups, elixirs and injections. These can be prepared according to the usual methods in the pharmaceutical field.
  • the liquid preparation may be dissolved or suspended in water or other appropriate medium at the time of use.
  • they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.
  • compositions can contain the compound of the present invention in a proportion of 1 to 99.9% by weight, preferably 1 to 60% by weight, based on the pharmaceutical composition. These formulations may further contain other therapeutically effective compounds.
  • the dose and the number of administrations are the patient's sex, age, weight, degree of symptoms and the type and range of the desired therapeutic effect.
  • the dose is usually 0.001 to 50 mg / kg body weight per day, and can be administered once or multiple times.
  • the dosage is preferably about 0.01 to about 25 mg / kg per day, more preferably about 0.05 to about 10 mg / kg per day.
  • the compound of the present invention is used as a combination therapy as a drug effective for hypertension, obesity-related hypertension, hypertension-related diseases, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity-related diseases, etc. Can be used in combination.
  • Such agents can be administered simultaneously, separately or sequentially in the prevention, treatment or treatment of the above diseases.
  • the compound of the present invention is used simultaneously with one or more concomitant drugs, it can be made into a pharmaceutical composition in a single dosage form.
  • the composition containing the compound of the present invention and the concomitant drug may be administered to the administration subject in different packages simultaneously, separately or sequentially. They may be administered at a time lag.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of the dosage form include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) obtained by separately formulating the compound of the present invention and the concomitant drug. Simultaneous administration of two preparations by the same administration route, 3) Administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals by the same administration route, 4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, 5) Two types of compounds obtained by separately formulating the compound of the present invention and a concomitant drug Administration of the preparation at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ concomitant drug, or administration in the reverse order) and the like.
  • the ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like
  • concomitant drug used in the present invention examples include antidiabetic drugs, hyperlipidemia drugs, antihypertensive drugs, anti-obesity drugs and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
  • Examples of the therapeutic agent for diabetes include 1) glidazones (for example, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), etc.), pioglitazone (pioglitazone), PPAR ⁇ agonists such as rosiglitazone, troglitazone, BRL49653, CLX-0921, 5-BTZD, GW-0207, LG-100641, LY-300512; 2) metformin, buformin, phenformin Biguanides such as (phenformin); 3) protein tyrosine phosphatase-1B inhibitors; 4) acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride ( glimepiride), gliclazide, grippenge Sulfonylureas such as glipentide, gliquidone, glisolamide, to
  • antihyperlipidemic drug examples include 1) bile acids such as cholesterylamine, colesevelem, colestipol, cross-dextran dialkylaminoalkyl derivatives, Colestid registered trademark, LoCholest registered trademark, Questran registered trademark, etc.
  • Absorption enhancer 2) atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, ZD- HMG-CoA reductase inhibitors such as 4522; 3) HMG-CoA synthesis inhibitors; 4) cholesterol absorption inhibitors such as snatol ester, ⁇ -sitosterol, sterol glucoside, ezetimibe; 5) avasimibe , Ehur Acylcoenzyme A cholesterol acyltransferase inhibitors such as eflucimibe, KY-505, SMP-709; 6) JTT705, torcetrapib, CP532632, BAY-63-2149, SC-591, SC-795, etc.
  • CETP inhibitors 7) Squalene synthesis inhibitors, 8) Antioxidants such as probucol, 9) Beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, gemfibrozil ( gemfibrozil), GW-7647, BM-170744, LY-518674, PPAR ⁇ agonists such as fibric acid derivatives (eg, Atromid registered trademark, Rapid registered trademark, Tricor registered trademark, etc.); 10) GW-4064, SR-103912, etc.
  • fibric acid derivatives eg, Atromid registered trademark, Rapid registered trademark, Tricor registered trademark, etc.
  • FXR receptor antagonist 11
  • LXR receptor agonist such as GW3965, T9013137, XTCO-179628
  • Lipoprotein synthesis inhibitor such as niacin
  • 14 microsomal triglyceride transport inhibitor
  • 15 bile acid reabsorption inhibitor such as BARA1453, SC435, PHA384640, S-435, AZD7706
  • 16 PPAR ⁇ agonist such as GW501516, GW590735; 17)
  • 18) MTTP inhibitors such as LAB687 and CP346086
  • 21 Platelet aggregation inhibitor
  • 22) 5 such as MK-591 -Lipoxygenase activating protein inhibitors and the like.
  • antihypertensive agent examples include 1) thiazides such as chlorothiaridone, chlorothiazide, dichlorophenamide, hydrofluorothiazide, indapamide, hydrochlorothiazide; bumetanide, ethacrynic acid, Diuretics such as loops such as furosemide and torsemide, sodiums such as amiloride and triamterene, aldosterone antagonists such as spironolactone and epilenone; 2) acebutolol, atenolol, betaxolol, bevantolol, bisoprolol ( bisoprolol), bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metapro ⁇ -adrenergic blockers such as metaprolol, nadolol, nebivolol, penbuto
  • Vasodilators such as hydralazine, clonidine, minoxidil, nicotinyl alcohol; 8) candesartan, eprosartan, irbesartan, losartan, pratosartan, tasosartan, telmisartan, telmisartan, valsartan, EXP -3137, FI6828K, RNH6270 and other angiotensin II antagonists; 9) ⁇ / ⁇ -adrenergic blockers such as nipradilol, arotinolol, amosulalol; 10) Terazosin, urapidil, prazosin, bunazosin, trimmer ⁇ 1 blockers such as syn, doxazosin, naphthopidyl, indolamine, WHIP164, XEN010; 11) ⁇ 2 agonists such as lofexidine
  • anti-obesity drugs examples include 1) 5HT (serotonin) transporter inhibitors such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, imipramine; 2) Norepinephrine transporter inhibitors such as GW320659, desipramine, talsupram, nomifensine; 3) rimonabant (Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), BAY-65-2520 (Bayer), SLV-319 (Solvay) ), USP5,532,237, USP4,973,587, USP5,013,837, USP5,081,122, USP5,112,820, USP5,292,736, USP5,624,941, USP6,028,084, WO96 / 33159, WO98 / 33765, WO98 / 43636, WO98 / 43635 , WO01 / 09120, WO01
  • MCH-1R antagonists 7) MCH-2R agonist / antagonist; 8) 3- Chloro-5- (1- (6- [2- (5-ethyl-4-methyl-thiazol-2-yl) -ethyl] -4-morpholinyl-4-yl-pyridin-2-ylamino) -ethyl) phenyl ] Carbamate isopropyl ester, BIBP3226, BIBO3304, LY-357897, CP-671906, GI-264879, other USP6001836, WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 / 85690, WO01 / 85098, WO01 / 85173 and WO01 9) 152804, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR235,208, FR226928, FR240662, FR2523
  • the combination drug is obtained by combining one or more of the compound of the present invention and the combination drug.
  • the combination drug is useful for prevention, treatment or treatment of metabolic diseases by combining with one or more drugs selected from the group consisting of antidiabetic drugs and hyperlipidemia drugs.
  • the combination containing a hypertension drug and an anti-obesity drug is useful for the prevention or treatment of metabolic diseases with a synergistic effect by adding a diabetes drug and / or a hyperlipidemia drug.
  • the compound of the present invention can also be used in combination with an antipsychotic drug.
  • Antipsychotic drugs particularly atypical antipsychotic drugs, are known to have a side effect of weight gain, and the combined use of the compound of the present invention and an antipsychotic drug is useful for suppressing such side effects.
  • antipsychotics include olanzapine (olanzapine I), risperidone, quetiapine, ziprasidone, aripiprazole, and paliperidone.
  • metabolic parameters such as blood pressure, glucose and lipid elevation induced by the antipsychotic drug are improved.
  • the above-described methods can be applied to conditions such as dosage, administration subject, administration route, and administration form.
  • Wakogel TM C-200 (Wako Pure Chemical Industries, Ltd.) is used as the silica gel for the column, and the FLASH + TM cartridge, KP-Sil or FPNH, FLASH12 + M, FLASH25 + S, FLASH25 + M, FLASH40 + M, etc. Biotage Japan Co., Ltd.), Kieselgel 60F254 (Merck) was used as a preparative thin layer chromatograph, and PLC05NH (FUJI Silysia) was used as a basic preparative thin layer chromatography.
  • 1 HNMR is JNM-AL400 (manufactured by JEOL) or MERCURYvx400 (manufactured by VARIAN) and UNITY INOVA400 (manufactured by VARIAN), and mass spectrum is Quattro II (manufactured by Micromass) or ZQ2000 (manufactured by Waters). It was measured.
  • Reference Example 1 Synthesis of Ketone (II)
  • Reference Example 1-1 Synthesis of methyl 6-methoxypyridazine-3-carboxylate 3-chloro-6-methoxypyridazine (3.00 g), palladium (II) acetate (466 mg), 1,1′-bisdiphenylphosphinoferrocene (2.30 g)
  • To a methanol solution (100 mL) of triethylamine (5.84 mL) was added t-butyldimethylsilyl chloride (668 mg) at room temperature, and the mixture was stirred overnight at 50 ° C. in a carbon monoxide atmosphere.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • Reference Example 2-16 Synthesis of (3,4-difluorophenyl) [4- (hydroxymethyl) phenyl] pyridin-2-ylmethanol Into an ethanol solution (1.00 mL) of the crude product obtained in Reference Example 2-2, a 5.00 M aqueous hydrochloric acid solution (100 ⁇ L) was added at room temperature and stirred for 30 minutes. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate.
  • Reference Example 4 Synthesis of Diphenylmethanol (IIb)
  • Reference Example 4-1 Synthesis of (3,4-difluorophenyl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidin] -1′-ylmethyl) phenyl] methanol (3 , 4-difluorophenyl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidine] -1′-ylmethyl) phenyl] methanone (1.60 g) Sodium borohydride (144 mg) was added to a methanol solution (32.0 mL) at room temperature and stirred for 1 hour.
  • Reference Example 5-5 Synthesis of 4-[(3,4-difluorophenyl) (1H-1,2,3-triazol-1-yl) methyl] benzyl acetate
  • Acetic acid solution of the compound (350 mg) obtained in Reference Example 5-1 (7. 1H-1,2,3-triazole (240 ⁇ L) and concentrated sulfuric acid (350 ⁇ L) were added to room temperature and stirred at 130 ° C. for 2 days.
  • the reaction mixture was concentrated, diluted with ethyl acetate, and basified with 5.00 M aqueous sodium hydroxide solution.
  • the aqueous layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate.
  • 1H-1,2,3-triazole (396 ⁇ L) was added at room temperature, and the mixture was stirred at 100 ° C. overnight. Further, 1H-1,2,3-triazole (396 ⁇ L) was added at room temperature, and the mixture was stirred at 120 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the title compound can also be synthesized by the following method.
  • Reference Example 5-9 Synthesis of ⁇ 6-[(3,4-difluorophenyl) (1H-pyrazol-1-yl) methyl] pyridin-3-yl ⁇ methanol
  • a solution of the compound (20.2 mg) obtained in Reference Example 5-10 in acetonitrile ( Pyrazole (10.1 mg) was added to 1 mL) and stirred at 100 ° C. for 2 hours. Pyrazole (10.1 mg) was further added to this reaction solution, and the mixture was stirred at 110 ° C. overnight.
  • a sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Reference Example 5-11 Synthesis of ⁇ 4-[(3,4-difluorophenyl) (1H-1,2,3-triazol-1-yl) methyl] phenyl ⁇ methanol
  • a solution of the compound (307 mg) obtained in Reference Example 5-5 in methanol ( 6.00 mL) was added with 5.00 M aqueous sodium hydroxide solution (600 ⁇ L) at room temperature and stirred for 30 minutes.
  • the reaction mixture was diluted with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate.
  • Example 1-1-1 (3,4-difluorophenyl) (4-fluorophenyl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) phenyl
  • methanol (3,4-difluorophenyl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) phenyl] methanone
  • To a THF solution (2.0 mL) of (50.2 mg) was added 2.0 M 4-fluorophenylmagnesium bromide in diethyl ether (0.12 mL) at ⁇ 78 ° C., and the mixture was stirred for 2 hours.
  • Example 1-1-2 (3,4-Difluorophenyl) (4-fluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) pyridine Synthesis of -2-yl] methanol (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl ) Pyridin-2-yl] methanone was used for the same operation as in Example 1-1-1 to give the title compound.
  • Example 1-1-3 (3,4-difluorophenyl) (4-fluorophenyl) [6- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) pyridine Synthesis of -3-yl] methanol (3,4-difluorophenyl) [6- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl The title compound was obtained by the same procedures as in Example 1-1-1 using) pyridin-3-yl] methanone.
  • Example 1-1-4 (3,4-difluorophenyl) (4-fluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) pyrimidine Synthesis of -2-yl] methanol (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl ) Pyrimidin-2-yl] methanone was used for the same operation as in Example 1-1-1 to give the title compound.
  • Example 1-1-5 (3,4-difluorophenyl) (4-fluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl)- Synthesis of 2-thienyl] methanol (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl)
  • the title compound was obtained by the same procedures as in Example 1-1-1 using -2-thienyl] methanone.
  • Example 1-1-6 Bis (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidin] -1′-ylmethyl) pyrazin-2-yl] Synthesis of methanol (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) pyrazine-2- Yl] methanone and 0.5M 3,4-difluorophenylmagnesium bromide in THF were used for the same operation as in Example 1-1-1 to obtain the title compound.
  • Example 1-1-7 (3,4-Difluorophenyl) (6-methoxypyridazin-3-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′ Synthesis of —ylmethyl) phenyl] methanol
  • Example 1-1-8 1- (3,4-difluorophenyl) -1- ⁇ 4-[(6-fluoro-1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′ Synthesis of -yl) methyl] phenyl ⁇ ethanol (3,4-difluorophenyl) ⁇ 4-[(6-fluoro-1H, 1'H-spiro [furo [3,4-c] pyridine-3,4'- The title compound was obtained by the same procedures as in Example 1-1-1 using piperidine] -1′-yl) methyl] phenyl ⁇ methanone and 1.0 M methylmagnesium bromide in THF.
  • Example 1-1-9 Cyclopropyl (3,4-difluorophenyl) [5- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidin] -1′-ylmethyl) pyridin-2-yl Synthesis of methanol The title compound was obtained in the same manner as in Example 1-1-2 using 0.5M cyclopropylmagnesium bromide in THF.
  • Example 1-1-10 1- (3,4-Difluorophenyl) -2-methyl-1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1′- Synthesis of ( Ilmethyl ) phenyl] propan-1-ol
  • the title compound was obtained by the same procedures as in Example 1-1-1 using 2.0M isopropylmagnesium chloride in THF.
  • Example 1-2-1 (3,4-Difluorophenyl) (2-fluoropyridin-3-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′ Synthesis of -ylmethyl) phenyl] methanol
  • 2-fluoro-3-iodopyridine 530 mg
  • THF 6.0 mL
  • 2.0 M isopropylmagnesium chloride in THF (1.14 mL) at -45 ° C. Stir for minutes.
  • Example 1-2-2 (3,4-difluorophenyl) (2-fluoropyridin-4-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′ Synthesis of -ylmethyl) phenyl] methanol
  • the title compound was obtained by the same procedure as in Example 1-2-1 using 2-fluoro-4-iodopyridine.
  • Example 1-3-1 (3,4-difluorophenyl) (6-fluoropyridin-2-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′
  • 2-bromo-6-fluoropyridine 525 mg
  • THF 8.0 mL
  • 1.6M n-butyllithium in hexane 1.8 mL
  • Example 1-3-2 (3,4-difluorophenyl) (6-fluoropyridin-3-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′ Synthesis of —ylmethyl) phenyl] methanol
  • the title compound was obtained by the same procedure as in Example 1-3-1 using 5-bromo-2-fluoropyridine.
  • Example 1-3-3 (3,4-Difluorophenyl) (2-methoxypyrimidin-5-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 ′
  • Synthesis of -ylmethyl) phenyl] methanol A solution of 5-bromo-2- (methyloxy) pyrimidine (338 mg) in THF (5.0 mL) and a 1.6 M n-butyllithium hexane solution (1.1 mL) at -100 ° C. And stirred for 30 minutes.
  • Example 1-3-4 (3,4-difluorophenyl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidine] -1′-ylmethyl) phenyl] 1,3-thiazole Synthesis of -5-ylmethanol The title compound was obtained in the same manner as in Example 1-3-1 using 2- (trimethylsilyl) -1,3-thiazole.
  • Example 1-3-5 (3,4-Difluorophenyl) (1-methyl-1H-imidazol-2-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] Synthesis of -1′-ylmethyl) phenyl] methanol
  • the title compound was obtained by the same procedure as in Example 1-3-3 using 1-methyl-1H-imidazole.
  • Example 1-3-6 (3,4-difluorophenyl) ⁇ 6-[(6-fluoro-1H, 1′H-spiro [furo [3,4-c] pyridin-3,4′-piperidin] -1′-yl) methyl] Synthesis of Pyridin-3-yl ⁇ (1-methyl-1H-pyrazol-5-yl) methanol (3,4-difluorophenyl) ⁇ 6-[(6-Fluoro-1H, 1′H-spiro [Furo [3 , 4-c] pyridin-3,4-piperidin] -1′-yl) methyl] pyridin-3-yl ⁇ methanone and 1-methyl-1H-pyrazole as in Example 1-3-1.
  • Example 1-3-7 3- (3,4-difluorophenyl) -1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) phenyl] Synthesis of prop-2-yn-1-ol (1) A 1.6M n-butyllithium hexane solution (0.85 mL) was added to a THF solution (2.0 mL) of trimethylsilylacetylene (162 mg) at ⁇ 78 ° C., Stir at 0 ° C. for 30 minutes.
  • Example 1-3-8 3- (3,4-difluorophenyl) -1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidin] -1′-ylmethyl) phenyl] Synthesis of But-2-yne-1,4-diol (1) A solution of tert-butyldimethyl (2-propynyloxy) silane (313 mg) in THF (3.5 mL) in 1.6 M n-butyllithium in hexane ( 0.89 mL) was added at ⁇ 78 ° C., and the mixture was stirred for 1 hour.
  • Example 2-1 1 '- ⁇ 4-[(3,4-Difluorophenyl) (hydroxy) pyridin-2-ylmethyl] benzyl ⁇ -5-methyl-1H-spiro [furo [3,4-c] pyridine-3,4'- Synthesis of piperidin] -6 (5H) -one
  • the title compound was obtained by the same procedures as in Reference Example 1-6 using the compound obtained in Reference Example 2-16.
  • Example 2-2 Reference example for the synthesis of 5- (1- ⁇ 4-[(3,4-difluorophenyl) (hydroxy) pyridin-2-ylmethyl] benzyl ⁇ piperidin-4-yl) -1-methylpyridin-2 (1H) -one
  • the title compound was obtained by the same procedures as in Reference Example 1-5 using the compound obtained in 2-16 and 1-methyl-5-piperidin-4-ylpyridin-2 (1H) -one monohydrochloride. It was.
  • Example 2-3 (3,4-difluorophenyl) (6-fluoropyridin-3-yl) ⁇ 4-[(6-fluoro-1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Synthesis of Piperidine] -1′-yl) methyl] phenyl ⁇ methanol
  • the title compound was obtained by the same procedures as in Reference Example 1-5 using monohydrochloride.
  • Example 2-4 3- (3,4-Difluorophenyl) -4-methyl-1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1′- Synthesis of [Ilmethyl ) phenyl] pent-2-yne- 1,4-diol
  • the title compound was obtained by the same procedures as in Reference Example 1-5 using a salt.
  • Example 2-5 1 ′- ⁇ 4-[(3,4-Difluorophenyl) (hydroxy) pyrazin-2-ylmethyl] benzyl ⁇ -5-methyl-3,5-dihydro-6H-spiro [furo [3,4-c] pyridine Synthesis of -1,4′ -piperidin] -6-one The compound obtained in Reference Example 2-19 and tert-butyl 5-methyl-6-oxo-5,6-dihydro-1′H, 3H-spiro [furo] The title compound was obtained by the same procedures as in Reference Example 1-6 using [3,4-c] pyridine-1,4′-piperidine] -1′-carboxylate.
  • Example 2-6 1 ′- ⁇ 4-[(3,4-Difluorophenyl) (hydroxy) pyrimidin-4-ylmethyl] benzyl ⁇ -5-methyl-3,5-dihydro-6H-spiro [furo [3,4-c] pyridine Synthesis of -1,4′-piperidin] -6-one The title compound was obtained by the same procedures as in Example 2-5 using the compound obtained in Reference Example 2-20.
  • Example 2-7 1 ′-( ⁇ 6- [3-cyclopropyl-1- (3,4-difluorophenyl) -1-hydroxy-2-propyn-1-yl] -3-pyridylyl ⁇ methyl) -5-methyl-3, Synthesis of 5-dihydro-6H-spiro [furo [3,4-c] pyridin-1,4′-piperidin] -6-one Similar to Example 2-5 using the compound obtained in Reference Example 2-7 The title compound was obtained by various operations.
  • Example 2-8 1 ′- ⁇ 4-[(3,4-difluorophenyl) (5-fluoropyridin-2-yl) hydroxymethyl] benzyl ⁇ -5-methyl-1H-spiro [furo [3,4-c] pyridine-3 , 4′-piperidin] -6 (5H) -one
  • the title compound was obtained by the same procedures as in Example 2-1 using the compound obtained in Reference Example 2-21.
  • Example 2-9 (3,4-difluorophenyl) (pyrimidin-2-yl) ⁇ 4-[(4- [1,2,4] triazolo [4,3-a] pyridin-7-ylpiperidin-1-yl) methyl] Synthesis of Phenyl ⁇ methanol Reference Example 1-5 and the compound obtained in Reference Example 2-22 and 7-piperidin-4-yl [1,2,4] triazolo [4,3-a] pyridine dihydrochloride The title compound was obtained by carrying out the same operation.
  • Example 2-10 (3,4-difluorophenyl) (1,3-oxazol-4-yl) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1 Synthesis of '-ylmethyl) phenyl] methanol
  • the title compound was obtained by the same procedures as in Example 2-4 using the compound obtained in Reference Example 2-23.
  • Example 2-12 Synthesis of 5- (1- ⁇ 4- [hydroxy (dipyridin-2-yl) methyl] benzyl ⁇ piperidin-4-yl) -1-methylpyridin-2 (1H) -one Compound obtained in Reference Example 2-25 was used for the same operation as in Example 2-2 to give the title compound.
  • Example 3-1 (3,4-Difluorophenyl) -2-methyl-1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] -1′- Synthesis of (Ilmethyl ) phenyl] propane-1,2-diol (1) Thionyl chloride (1.0 mL) was added to the compound (50.1 mg) obtained in Example 1-1-10 at room temperature and stirred for 20 minutes. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform (2.5 mL).
  • Example 4-1 3- ⁇ (3,4-Difluorophenyl) (hydroxy) [4- (1H, 1'H-spiro [furo [3,4-c] pyridine-3,4'-piperidin] -1'-ylmethyl) phenyl Synthesis of methyl ⁇ pyridin-2 (1H) -one
  • 6M aqueous hydrochloric acid 4.0 mL
  • the mixture was heated to reflux for 2 hours. After cooling, it was azeotroped with toluene.
  • To the residue was added 2M aqueous sodium hydroxide solution, and the mixture was extracted with chloroform.
  • Example 4-2 (3,4-difluorophenyl) [2- (2-fluoroethoxy) pyridin-3-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Piperidine] -1′-ylmethyl) phenyl] methanol and 3- ⁇ (3,4-difluorophenyl) (hydroxy) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methyl ⁇ -1- (2-fluoroethyl) pyridin-2 (1H) -one The racemate (97.4 mg) obtained in Example 4-1 To a DMF aqueous solution (3.0 mL) were added cesium fluoride (220 mg) and 2-fluoroethyl 4-methylbenzenesulfonate (190 mg) in DMF (1.5 m
  • Example 4-3 (3,4-difluorophenyl) [2- (2-fluoroethoxy) pyridin-4-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Piperidine] -1′-ylmethyl) phenyl] methanol and 4- ⁇ (3,4-difluorophenyl) (hydroxy) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methyl ⁇ -1- (2-fluoroethyl) pyridin-2 (1H) -one
  • Example using the compound obtained in Example 1-2-2 The title compound was obtained by the same procedures as in 4-1 and 4-2.
  • Example 4-4 (3,4-difluorophenyl) [6- (2-fluoroethoxy) pyridin-3-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Piperidine] -1′-ylmethyl) phenyl] methanol and 5- ⁇ (3,4-difluorophenyl) (hydroxy) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methyl ⁇ -1- (2-fluoroethyl) pyridin-2 (1H) -one Example using the compound obtained in Example 1-3-2 The title compound was obtained by the same procedures as in 4-1 and 4-2.
  • Example 4-5 (3,4-difluorophenyl) [6- (2-fluoroethoxy) pyridin-2-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Synthesis of piperidin] -1′-ylmethyl) phenyl] methanol
  • the title compound was obtained by the same procedures as in Examples 4-1 and 4-2 using the compound obtained in Example 1-3-1. .
  • Example 4-6 (3,4-difluorophenyl) [2- (2-fluoroethoxy) pyrimidin-5-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Piperidine] -1′-ylmethyl) phenyl] methanol and 5- ⁇ (3,4-difluorophenyl) (hydroxy) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methyl ⁇ -1- (2-fluoroethyl) pyrimidin-2 (1H) -one
  • Example using the compound obtained in Example 1-3-3 The title compound was obtained by the same procedures as in 4-1 and 4-2.
  • Example 4-7 (3,4-Difluorophenyl) [6- (2-fluoroethoxy) pyridazin-3-yl] [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′- Piperidine] -1′-ylmethyl) phenyl] methanol and 6- ⁇ (3,4-difluorophenyl) (hydroxy) [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methyl ⁇ -2- (2-fluoroethyl) pyridazin-3 (2H) -one
  • Example using the compound obtained in Example 1-1-7 The title compound was obtained by the same procedures as in 4-1 and 4-2.
  • Example 5-1 5- (3,4-difluorophenyl) -5-methoxy-2-methyl-5- [4- (1H, 1'H-spiro [furo [3,4-c] pyridine-3,4'-piperidine] Synthesis of -1'-ylmethyl) phenyl] pent-3-yn-2-ol
  • p-toluenesulfonic acid (1 capsule) was added at 0 ° C. and stirred at 50 ° C. for 14 hours.
  • the reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
  • Example 5-2 1- (3,4-difluorophenyl) -1- (2-fluoropyridin-3-yl) -1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3, Synthesis of 4′-piperidine] -1′-ylmethyl) phenyl] methanamine
  • sulfonyl chloride 1.0 mL
  • Example 5-4 (3,4-Difluorophenyl) -1- (6-fluoropyridin-3-yl) -N-methoxy-1- [4- (1H, 1′H-spiro [furo [3,4-c] Synthesis of Pyridine-3,4′-piperidine] -1′-ylmethyl) phenyl] methanamine
  • Example 5- using the compound obtained in Example 1-3-2, O-methylhydroxylamine hydrochloride and diisopropylethylamine The title compound was obtained by the same operation as 2.
  • Example 5-5 1- (3,4-difluorophenyl) -N- (2-fluoroethoxy) -1- (1-methyl-1H-imidazol-2-yl) -1- [4- (1H, 1′H-spiro [ Synthesis of furo [3,4-c] pyridin-3,4'-piperidin] -1'-ylmethyl) phenyl] methanamine Compound obtained in Example 1-3-5, O- (2-fluoroethyl) hydroxylamine The title compound was obtained by the same procedures as in Example 5-2 using hydrochloride and diisopropylethylamine.
  • Example 6-1 3- (3,4-Difluorophenyl) -1- (4-fluorophenyl) -1- [4- (1H, 1′H-spiro [furo [3,4-c] pyridine-3,4′-piperidine ] -1′-ylmethyl) phenyl] methanamine synthesis
  • a solution (0.18 mL) was added at ⁇ 78 ° C., and the mixture was stirred at 0 ° C. for 3 hours, and then stirred at room temperature overnight.
  • Example 7-1 1 ′- ⁇ 4-[(3,4-difluorophenyl) (2-methyl-1H-imidazol-4-yl) methyl] benzyl ⁇ -1H-spiro [furo [3,4-c] pyridine-3,4 Synthesis of '-piperidine] 2-Methylimidazole (38.9 mg) and concentrated sulfuric acid (50 ⁇ L) were added to an acetic acid solution (2.0 mL) of the compound (100 mg) obtained in Reference Example 4-1 at room temperature, and 180 ° C. Stir for 3 days. The reaction mixture was concentrated under reduced pressure, and 10N aqueous sodium hydroxide solution was added to the residue at 0 ° C.
  • Example 7-2 In Example 7-2, the following compounds were synthesized. 1 ′- ⁇ 4-[(3,4-Difluorophenyl) (1H-imidazol-1-yl) methyl] benzyl ⁇ -1H-spiro [furo [3,4-c] pyridine-3,4′-piperidine] Tri-n-butylphosphine (35.0 ⁇ L) and 1,1'-azobis (N , N-dimethylformamide) (12.2 mg) was added at room temperature and stirred for 2 hours. To the reaction solution was added an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.
  • Example 7-3 In Example 7-3, the following compounds were synthesized. 1 ′- ⁇ 4-[(3,4-Difluorophenyl) (2-methyl-1H-imidazol-1-yl) methyl] benzyl ⁇ -1H-spiro [furo [3,4-c] pyridine-3,4 '-Piperidine] The title compound was obtained by the same procedures as in Example 7-2 using 2-methyl-1H-imidazole.
  • Example 7-4 In Example 7-4, the following compounds were synthesized. (R) or (S) 1 ′- ⁇ 4-[(3,4-difluorophenyl) (5-methyl-1H-1,2,4-triazol-1-yl) methyl] benzyl ⁇ -1H-spiro [ Furo [3,4-c] pyridine-3,4′-piperidine], and (R) or (S) 1 ′- ⁇ 4-[(3,4-difluorophenyl) (3-methyl-1H-1, 2,4-triazol-1-yl) methyl] benzyl ⁇ -1H-spiro [furo [3,4-c] pyridine-3,4'-piperidine]
  • the mixture of the title compounds was obtained by the same procedures as in Example 7-2 using 2-methyl-1H-imidazole.
  • Example 8-1 Reference for the synthesis of 5- (1- ⁇ 4-[(3,4-difluorophenyl) (1H-1,2,3-triazol-1-yl) methyl] benzyl ⁇ piperidin-4-yl) -2-fluoropyridine
  • the title compound was obtained by the same procedures as in Reference Example 1-5 using the compound obtained in Example 5-11 and 2-fluoro-5-piperidin-4-ylpyridine monohydrochloride.
  • Example 8-2 Reference for the synthesis of 5- (1- ⁇ 4-[(3,4-difluorophenyl) (1H-1,2,4-triazol-1-yl) methyl] benzyl ⁇ piperidin-4-yl) -2-fluoropyridine
  • the title compound was obtained by the same procedures as in Example 8-1 using the compound obtained in Example 5-12.
  • 1 HNMR 400 MHz, CDCl 3 , ⁇ ppm): 1.66-1.85 (4H, m), 2.07-2.14 (2H, m), 2.50-2.60 (1H, m), 2.97-3.03 (2H, m), 3.55 (2H, s), 6.70 (1H, s), 6.85-6.90 (2H, m), 6.94-6.
  • Example 8-3 1 ′-( ⁇ 5-[(3,4-difluorophenyl) (2H-1,2,3-triazol-2-yl) methyl] pyridin-2-yl ⁇ methyl) -5-methyl-3,5- Synthesis of dihydro-6H-spiro [furo [3,4-c] pyridin-1,4′-piperidin] -6-one
  • the same procedure as in Example 2-5 was carried out using the compound obtained in Reference Example 5-13.
  • Example 8-4 3- [1-( ⁇ 5-[(3,4-Difluorophenyl) (1H-1,2,3-triazol-1-yl) methyl] pyridin-2-yl ⁇ methyl) piperidin-4-yl] pyrazolo Synthesis of [1,5-b] pyridazine
  • the same procedure as in Reference Example 1-5 using the compound obtained in Reference Example 5-14 and 3-piperidin-4-ylpyrazolo [1,5-b] pyridazine dihydrochloride To give the title compound.
  • Example 8-5 2-[(3,4-Difluorophenyl) (1H-1,2,3-triazol-1-yl) methyl] -5- ⁇ [4- (6-fluoropyridin-3-yl) piperidin-1-yl Synthesis of methyl ⁇ pyridine
  • the title compound was obtained by the same procedures as in Example 8-1 using the compound obtained in Reference Example 5-8.
  • Example 8-6 1 ′-( ⁇ 6-[(3,4-difluorophenyl) (1H-pyrazol-1-yl) methyl] pyridin-3-yl ⁇ methyl) -5-methyl-3,5-dihydro-6H-spiro [ Synthesis of furo [3,4-c] pyridin-1,4′-piperidin] -6-one By using the compound obtained in Reference Example 5-9, the same procedure as in Example 2-5 was performed. A compound was obtained.
  • the compounds of the present invention have MCH-1R antagonistic activity, and are, for example, obesity, diabetes, abnormal hormone secretion, hyperlipidemia, gout, fatty liver, hepatitis, cirrhosis, etc., such as angina pectoris, acute -Cardiovascular diseases such as congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, electrolyte abnormalities, such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention Central and peripheral nervous system diseases such as deficit / hyperactivity disorder, memory disorder, sleep disorder, cognitive disorder, movement disorder, sensory abnormality, olfactory disorder, morphine tolerance, drug dependence, alcoholism, such as infertility, premature birth, Reproductive system diseases such as sexual dysfunction, other prophylactic or therapeutic agents such as promotion of arousal, digestive tract disease, respiratory disease, cancer or skin pigmentation, especially obesity, diabetes, fatty liver, bulimia, depression Preventive or

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Abstract

La présente invention concerne un antagoniste du récepteur de l’hormone concentrant la mélanine qui est utile comme produit pharmaceutique destiné à des maladies du système nerveux central, des maladies cardiovasculaires et des maladies métaboliques. Z : un alkyle en C1 à C6, un aryle ou équivalents ; W : un H, un OH, un NH2 ou équivalents ; Ar1 : un aryle à 6 chaînons ou équivalent ; Ar2 : un hétéroaryle à 6 chaînons ou équivalent ; R1a-R3a, R1b-R3b : un H, un alkyle en C1 à C6 ou équivalents ; Y1, Y2 : un H ou équivalent ; ou combinés tous les deux pour former un -O-CH2- ou équivalent ; cycle A : un cycle benzénique, un cycle pyridine ou équivalents.
PCT/JP2009/068375 2008-10-30 2009-10-27 Composé pipéridine ayant une structure di- ou tri-arylméthyle WO2010050456A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064764A2 (fr) * 2003-01-14 2004-08-05 H. Lundbeck A/S Peperidines amido alkyle substitues
WO2004069798A1 (fr) * 2003-02-10 2004-08-19 Banyu Pharmaceutical Co.,Ltd. Antagonistes des recepteurs de l'hormone concentrant la melanine contenant des derives de piperidine en tant que principe actif
WO2008016811A2 (fr) * 2006-07-31 2008-02-07 Neurogen Corporation Aminopipéridines et composés apparentés
WO2008047544A1 (fr) * 2006-09-28 2008-04-24 Banyu Pharmaceutical Co., Ltd. Dérivé diarylcétimine
WO2009119726A1 (fr) * 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064764A2 (fr) * 2003-01-14 2004-08-05 H. Lundbeck A/S Peperidines amido alkyle substitues
WO2004069798A1 (fr) * 2003-02-10 2004-08-19 Banyu Pharmaceutical Co.,Ltd. Antagonistes des recepteurs de l'hormone concentrant la melanine contenant des derives de piperidine en tant que principe actif
WO2008016811A2 (fr) * 2006-07-31 2008-02-07 Neurogen Corporation Aminopipéridines et composés apparentés
WO2008047544A1 (fr) * 2006-09-28 2008-04-24 Banyu Pharmaceutical Co., Ltd. Dérivé diarylcétimine
WO2009119726A1 (fr) * 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine

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