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WO2012033195A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2012033195A1
WO2012033195A1 PCT/JP2011/070601 JP2011070601W WO2012033195A1 WO 2012033195 A1 WO2012033195 A1 WO 2012033195A1 JP 2011070601 W JP2011070601 W JP 2011070601W WO 2012033195 A1 WO2012033195 A1 WO 2012033195A1
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Prior art keywords
compound
tetrahydroisoquinoline
ylmethoxy
general formula
furan
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PCT/JP2011/070601
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English (en)
Japanese (ja)
Inventor
智 小豆澤
俊吉 田中
知紘 三池
正恭 笠井
弘明 白波瀬
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京都薬品工業株式会社
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Priority to JP2012533042A priority Critical patent/JPWO2012033195A1/ja
Publication of WO2012033195A1 publication Critical patent/WO2012033195A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention provides a novel heterocycle having a peroxisome proliferator-responsive receptor gamma (PPAR ⁇ ) partial agonistic action, a PPAR ⁇ modulator action or a PPAR ⁇ antagonistic action and exhibiting a blood glucose lowering action, a blood lipid lowering action, and an insulin resistance improving action. It relates to compounds and pharmaceutically acceptable salts thereof.
  • the present invention also relates to a pharmaceutical composition comprising the novel heterocyclic compound and a pharmaceutically acceptable salt thereof.
  • the present invention provides a therapeutic agent for diabetes, an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance ameliorating agent, a diabetic complication comprising the novel heterocyclic compound and a pharmaceutically acceptable salt thereof.
  • the present invention relates to a therapeutic agent, a glucose intolerance ameliorating agent, an anti-arteriosclerosis agent, an anti-obesity agent, an anti-inflammatory agent, an osteoporosis therapeutic agent, a PPAR-mediated disease prevention / treatment agent and a metabolic syndrome prevention / treatment agent.
  • PPAR ⁇ belongs to the nuclear hormone receptor superfamily and functions as an important regulator in adipocyte differentiation, lipid and glucose metabolism, inflammatory response, and energy homeostasis. PPAR ⁇ forms a heterodimer with the retinoid X receptor (RXR) and binds to the peroxisome proliferator response element (PPRE) to activate transcription.
  • RXR retinoid X receptor
  • PPRE peroxisome proliferator response element
  • Non-Patent Documents 1 and 2 ligands that act on PPAR ⁇ are useful for the prevention and treatment of diseases related to metabolic syndrome such as type 2 diabetes, hyperinsulinemia, lipid metabolism abnormality, obesity, hypertension, arteriosclerosis, insulin resistance, etc.
  • the ligand that acts on PPAR ⁇ suppresses the production of inflammatory cytokines from inflammatory diseases (Non-patent Documents 3 and 4), and induces apoptosis and suppresses the proliferation of cancer cells (Non-patent Document 5).
  • Is also useful for prevention and treatment.
  • it is also useful for the prevention and treatment of bone diseases such as osteoporosis (Patent Documents 1 and 2).
  • pioglitazone and rosiglitazone which are used clinically as therapeutic agents for type 2 diabetes, exhibit PPAR ⁇ agonist activity, thereby improving insulin resistance in peripheral tissues and thus exhibiting a hypoglycemic action without causing hypoglycemia.
  • PPAR ⁇ agonist activity a substance that has been used clinically to improve insulin resistance in peripheral tissues and thus exhibiting a hypoglycemic action without causing hypoglycemia.
  • farglitazar has been abandoned in clinical trials because it cannot avoid the occurrence of edema due to fluid retention, and development of a safer anti-diabetic drug that reduces these side effects is desired.
  • the object of the present invention is to have PPAR ⁇ partial agonistic action, PPAR ⁇ modulator action or PPAR ⁇ antagonistic action, exhibit blood glucose lowering action, blood lipid lowering action, insulin resistance improving action, side effects such as fluid retention, edema, cardiac hypertrophy It is to provide an anti-diabetic drug that is low in safety and high in safety.
  • the present invention also provides other diseases whose symptoms can be alleviated by PPAR ⁇ activation, PPAR ⁇ modulator action or PPAR ⁇ antagonist action, for example, arteriosclerosis, obesity, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder
  • Another object of the present invention is to provide preventive and / or therapeutic agents for autoimmune diseases, Crohn's disease, osteoporosis, coronary artery disease and the like.
  • R 1 represents —COR 3 (wherein R 3 represents —OH, —NH 2 or R 4 SO 2 NH— (wherein R 4 represents alkyl or aryl)), —SO 2 R 5 (Wherein R 5 represents —NH 2 or R 4 CONH— (wherein R 4 represents alkyl or aryl)), —NR 6 R 7 (wherein R 6 and R 7 are the same or Differently represents a hydrogen atom, optionally substituted alkyl, R 4 CO— or R 4 SO 2 —), nitrile, hydroxy, alkoxy, heterocyclyl, aryl or heteroaryl;
  • R 10 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkynyl, cycloalkylalkynyl, alkylthio, alkylthioalkyl optionally substituted with halogen.
  • R 10 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkynyl, cycloalkylalkynyl, alkylthio, alkylthioalkyl optionally substituted with halogen.
  • Aryl, heterocyclyl, heteroaryl, an optionally substituted indane ring or —NR 13 R 14 (wherein R 13 and R 14 are the same or different and each represents a hydrogen atom or alkyl), R 11 represents a hydrogen atom or lower alkyl).
  • the heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of the above [1] to [3], [5]
  • Y is
  • A is a single bond, alkylene, alkenylene, — (CH 2 ) n —NH—, 1,4-phenylene, 2,5-furylene, or 1,4-piperidinylene.
  • A is a single bond, alkylene, or alkenylene
  • A is a single bond
  • R 1 is —CO 2 H
  • the heterocyclic compound represented by the above general formula (I) of the present invention and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the heterocyclic compound (I) of the present invention” or “the present compound”).
  • the heterocyclic compound (I) of the present invention has a PPAR ⁇ partial agonistic action, a PPAR ⁇ modulator action or a PPAR ⁇ antagonistic action, and thus exhibits a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, and is a therapeutic agent for diabetes, antihyperglycemia, It is useful as a hyperlipidemia agent, an insulin resistance improving agent, a diabetic complication therapeutic agent, and a glucose intolerance improving agent.
  • the compound of the present invention is also useful as an anti-arteriosclerotic agent, anti-obesity agent, osteoporosis therapeutic agent, anti-inflammatory agent, PPAR-mediated disease preventive / therapeutic agent and metabolic syndrome preventive / therapeutic agent.
  • a medicament containing the compound of the present invention as an active ingredient has few side effects such as fluid retention, edema and cardiac hypertrophy, it can be a highly safe therapeutic drug for diabetes.
  • PPAR ⁇ partial agonist means a compound that binds to a PPAR ⁇ receptor and exhibits agonistic activity but is less effective than a full agonist.
  • the compound is a drug that competitively binds with a PPAR ⁇ full agonist at the point of action of the receptor and has antagonist activity at the same time.
  • PPAR-mediated disease means a disease involving PPAR ⁇ , which can relieve symptoms by a PPAR ⁇ partial agonistic action, a PPAR ⁇ modulator action, or a PPAR ⁇ antagonistic action.
  • Examples of the disease include diabetes, hyperglycemia, hyperlipidemia, insulin resistance, diabetic complications, glucose intolerance, arteriosclerosis, obesity, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disorder, self Examples include immune disease, Crohn's disease, osteoporosis, coronary artery disease and the like.
  • the term “lower” for an organic group such as an alkyl group means that it has 1 to 6 carbon atoms.
  • the “lower” organic group preferably has 1 to 4 carbon atoms.
  • halogen is a chlorine atom, a bromine atom, an iodine atom or a fluorine atom.
  • alkyl means a linear or branched monovalent saturated hydrocarbon group having 1 to 10 carbon atoms.
  • straight-chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 4-methylpentyl, Hexyl and the like can be mentioned, and more preferred are linear or branched alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • alkyl optionally substituted with halogen means a group in which one or more hydrogen atoms in the “alkyl” group may be substituted with halogen.
  • halogen for example, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2 , 3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, etc. More preferred are 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl.
  • alkoxy means a group in which an oxygen atom is bonded to the “alkyl” group, that is, a linear or branched alkoxy group having 1 to 10 carbon atoms.
  • straight-chain or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy Hexyloxy and the like, and more preferable are straight-chain or branched alkoxy having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, butoxy.
  • cycloalkyl means a monovalent alicyclic hydrocarbon group having 3 to 12 carbon atoms. Preferably, it represents a cyclic alkyl group having 3 to 10 carbon atoms and may be crosslinked. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bicyclo [2.2.1] heptyl, and more preferably, cyclopropyl, cyclobutyl, cyclopentyl having 3 to 6 carbon atoms. Cyclohexyl.
  • alkenyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 10 carbon atoms.
  • cycloalkenyl means a monovalent alicyclic hydrocarbon group having one or more carbon-carbon double bonds and having 3 to 12 carbon atoms.
  • a cyclic alkenyl group having 3 to 10 carbon atoms which may be bridged, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Cyclopropienyl, cyclobutenyl, cyclopentenyl and cyclohexenyl having 3 to 6 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms.
  • ethynyl 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl , 3-hexynyl and the like, more preferably ethynyl, 1-propynyl and the like.
  • aryl means a monovalent aromatic hydrocarbon group.
  • Preferable examples include phenyl, naphthyl, biphenyl, indenyl, fluorenyl, acenaphthylenyl and the like, and more preferable is phenyl.
  • heteroaryl refers to a monovalent monocyclic aromatic heterocyclic ring and condensed aromatic heterocyclic ring containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Means.
  • the fused aromatic heterocycle in the present invention is a bicyclic system, and both rings may have heteroatoms. Suitable monocyclic aromatic heterocycles include 5- or 6-membered rings, suitable fused aromatic heterocycles include 5- or 6-membered heterocycles, and 5 as non-heteroatom rings. Or a 6-membered ring is mentioned.
  • monocyclic aromatic heterocycles such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, etc., indolyl, isoindolyl, indazolyl Benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, furo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, Examples thereof include condensed aromatic heterocycles such as imidazopyrid
  • heterocyclyl is substituted with one or two monocyclic heterocycles containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur atoms, and oxo or thioxo Means heterocycle.
  • heterocyclic ring examples include azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, 2,4-dioxoimidyl, Lysinyl, 2,4-dioxothiazolidinyl, 2,4-dithiothiazolidinyl, 4-oxo-2-thioxothiazolidinyl, 2,4-dioxooxazolidinyl, 2 , 4-dithioxooxazolidinyl, 4-oxo-2-thioxooxazolidinyl, 5-oxo [1,2,4] oxadia
  • aralkyl means a monovalent group in which the “aryl” group is bonded to the “alkyl” group.
  • aryl in aralkyl include phenyl, naphthyl, and the like
  • alkyl in aralkyl preferably include methyl, ethyl, propyl, butyl, and the like.
  • Suitable aralkyls include benzyl, phenylethyl, phenylpropyl, ⁇ -naphthylmethyl, 1- ( ⁇ -naphthyl) ethyl, 2- ( ⁇ -naphthyl) ethyl, 1- ( ⁇ -naphthyl) propyl, ⁇ -naphthylmethyl. , 1- ( ⁇ -naphthyl) ethyl, 2- ( ⁇ -naphthyl) ethyl, 1- ( ⁇ -naphthyl) propyl and the like, and more preferably benzyl.
  • cycloalkylalkyl means a monovalent group in which the “cycloalkyl” group is bonded to the “alkyl” group.
  • cycloalkenylalkyl means a monovalent group in which the “cycloalkenyl” group is bonded to the “alkyl” group.
  • Preferable examples include 1-cyclopentenylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 1-cyclohexenylmethyl, and the like, more preferably 1-cyclopentenylmethyl, 3-cyclopentenylmethyl, 1-cyclohexenylmethyl.
  • cycloalkylalkynyl means a monovalent group in which the “cycloalkyl” group is bonded to the “alkynyl” group.
  • Preferable examples include cyclopropylethynyl, cyclobutylethynyl, cyclopentylethynyl, cyclohexylethynyl and the like, and more preferable is cyclopropylethynyl.
  • alkylthio means a group in which a sulfur atom is bonded to the “alkyl” group, that is, a linear or branched alkylthio group having 1 to 10 carbon atoms.
  • Preferable examples include methylthio, ethylthio, propylthio, isopropylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, 5-methylpentylthio, and the like.
  • Methylthio, ethylthio, propylthio isopropylthio.
  • alkylthioalkyl means a monovalent group in which the “alkylthio” group is bonded to the “alkyl” group.
  • alkylene means a linear or branched divalent saturated hydrocarbon group having 1 to 10 carbon atoms.
  • Preferable examples include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and the like, and particularly preferable are methylene and ethylene.
  • alkenylene means a linear or branched divalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 10 carbon atoms.
  • Preferable examples include ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the like, and particularly preferable is ethenylene.
  • cycloalkylene means a divalent alicyclic hydrocarbon group having 3 to 12 carbon atoms. Preferably, it means a cyclic alkylene group having 3 to 10 carbon atoms. Preferably, for example, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cyclooctyl- 1,5-diyl and the like, and more preferable are cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1 having 3 to 6 carbon atoms. 4-diyl.
  • arylene means a divalent aromatic hydrocarbon group.
  • benzene-1,4-diyl hereinafter also referred to as 1,4-phenylene
  • 1,4-phenylene benzene-1,3-diyl
  • benzene-1,2-diyl benzene-1,2-diyl
  • naphthalene-1,8-diyl anthracene- Examples
  • 1,4-diyl and the like 1,4-phenylene is more preferable.
  • heteroarylene refers to a divalent monocyclic aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and a condensed aromatic heterocycle. Means a cyclic group.
  • furan-2,5-diyl hereinafter also referred to as 2,5-furylene
  • thiophene-2,4-diyl thiophene-2,5-diyl
  • 2,5-thienylene thiophene-2,5-diyl
  • heterocyclylene means a divalent monocyclic heterocyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • heterocyclylene a divalent monocyclic heterocyclic group containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, morpholine-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4- Examples include diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, and more preferably piperidine-1,4-diyl.
  • Examples of the substituent in the “optionally substituted alkyl” in R 6 and R 7 include lower alkoxy having 1 to 6 carbon atoms, hydroxy and the like.
  • Preferred examples of the alkyl when substituted include methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, hydroxyethyl, hydroxypropyl and the like, and hydroxyethyl is more preferred.
  • heteroaryl optionally substituted with fluorine atom is preferably, for example, 5-fluorofuran-2-yl, 4-fluorofuran-2-yl, 5-fluorothiophen-2-yl. 4-fluorothiophen-2-yl and the like, more preferably 5-fluorofuran-2-yl.
  • substituent in the “optionally substituted heteroaryl” in Y include optionally substituted alkyl (described above), cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl (described later), Cycloalkenylalkyl, alkynyl, cycloalkylalkynyl, alkylthio, alkylthioalkyl, alkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen atom, optionally substituted aryl (described later), heterocyclyl, heteroaryl, optionally substituted indane And a ring (described later) or —NR 13 R 14 (wherein R 13 and R 14 are the same or different and each represents a hydrogen atom or alkyl), and preferably an optionally substituted alkyl or cycloalkyl , Cycloa Killalkyl, alkenyl, optionally substituted cycloalkenyl, cycloal
  • the substituent in “optionally substituted cycloalkenyl” for R 10 is a lower alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl and the like.
  • the substituted cycloalkenyl is preferably, for example, 1-methyl-3-cyclopentenyl, 1-ethyl-3-cyclopentenyl, 1,3-dimethyl-3-cyclopentenyl, 3,4-dimethyl- 3-cyclopentenyl, 1,3,4-trimethyl-3-cyclopentenyl, 1-methyl-3-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1,3-dimethyl-3-cyclohexenyl, 3,4 -Dimethyl-3-cyclohexenyl, 1,3,4-trimethyl-3-cyclohexenyl and the like, more preferably 1-methyl-3-cyclopentenyl, 1,3,4-trimethyl-3-cyclo Pentenyl.
  • substituent in “optionally substituted aryl” in R 10 include a lower alkyl group having 1 to 6 carbon atoms, an optionally substituted amino group, and an alkoxy group.
  • Ethyl, propyl isopropyl, dimethylamino, diethylamino, methoxy, ethoxy and the like.
  • the “optionally substituted aryl” is preferably, for example, methylphenyl, dimethylphenyl, trimethylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, dimethylaminophenyl, diethylaminophenyl, methoxyphenyl, ethoxyphenyl and the like. More preferred are dimethylphenyl, isopropylphenyl, and dimethylaminophenyl.
  • the substituent in the “optionally substituted indane ring” in R 10 is a lower alkyl group having 1 to 6 carbon atoms, and preferable examples include methyl, ethyl, propyl, isopropyl and the like.
  • Preferred examples of the indan when substituted include 2-methylindane and 2-ethylindane, and 2-methylindane is more preferred.
  • R 1 represents —COR 3 (wherein R 3 represents —OH, —NH 2 or R 4 SO 2 NH— (wherein R 4 represents alkyl or aryl)), —SO 2 R 5 (Wherein R 5 represents —NH 2 or R 4 CONH— (wherein R 4 represents alkyl or aryl)), —NR 6 R 7 (wherein R 6 and R 7 are the same or Differently represents a hydrogen atom, optionally substituted alkyl, R 4 CO— or R 4 SO 2 —), nitrile, hydroxy, alkoxy, heterocyclyl, aryl or heteroaryl;
  • R 1 is —COR 3 (wherein R 3 is as defined above), —SO 2 R 5 (wherein R 5 is as defined above), —NR 6 R 7 (wherein R 6 and R 7 are as defined above), heterocyclyl, or heteroaryl, R 2 is —COR 8 (wherein R 8 is as defined above), Y is
  • R 10 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkynyl, cycloalkylalkynyl, alkylthio, alkylthioalkyl optionally substituted with halogen.
  • R 13 and R 14 are the same or different and each represents a hydrogen atom or alkyl
  • R 11 is a hydrogen atom or lower alkyl
  • R 12 is alkyl, cycloalkyl or cycloalkylalkyl
  • X represents an oxygen atom or a sulfur atom
  • A is a single bond, alkylene, alkenylene, — (CH 2 ) n —NH—, 1,4-phenylene, 2,5-furylene, or 1,4-piperidinylene
  • B is —O— or —S—
  • n is 1 to 4,
  • R 1 is —COR 3 (wherein R 3 is as defined above), heterocyclyl or heteroaryl; A is a single bond, alkylene or alkenylene, The heterocyclic compound of the above (2) or a pharmaceutically acceptable salt thereof.
  • R 1 is —CO 2 H,
  • R 10 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkynyl, cycloalkylalkynyl, alkylthio, alkylthioalkyl optionally substituted with halogen.
  • R 2 is —COR 8 (wherein R 8 represents —CH ⁇ CHR 9 (wherein R 9 represents alkenyl or heteroaryl)), The heterocyclic compound according to (6) above or a pharmaceutically acceptable salt thereof.
  • Y is
  • R 10 is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkylthio, aryl, heterocyclyl, heteroaryl, optionally substituted indane ring or — NR 13 R 14 (wherein R 13 and R 14 are the same or different and each represents a hydrogen atom or alkyl) and R 11 represents lower alkyl) or a heterocyclic compound according to the above (7) or a compound thereof Pharmaceutically acceptable salt.
  • R 10 represents alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, optionally substituted cycloalkenyl, cycloalkenylalkyl, alkylthio, aryl, heterocyclyl, heteroaryl or optionally substituted indane ring.
  • R 11 represents lower alkyl).
  • R 10 represents heterocyclyl or —NR 13 R 14 (wherein R 13 and R 14 are the same or different and represent a hydrogen atom or alkyl), and R 11 represents lower alkyl) is there,
  • the compound represented by the general formula (I) is: 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline, 7- (2-Cyclopentyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline, 7- [2- (Cyclohex-1-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-
  • the heterocyclic compound (I) of the present invention may form a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt in this specification may be any salt as long as it is a pharmaceutically non-toxic salt.
  • the heterocyclic compound (I) has a basic group, it can form an acid addition salt, but the acid for forming such an acid addition salt can form a salt with a basic moiety, And if it is a pharmaceutically acceptable acid, there will be no restriction
  • acids examples include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and toluenesulfonic acid.
  • organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and toluenesulfonic acid.
  • an alkali metal salt for example, sodium salt, potassium salt
  • an alkaline earth metal salt for example, calcium salt, magnesium salt
  • Organic base salts such as triethylamine salts, dicyclohexylamine salts, pyridine salts, etc.
  • the heterocyclic compound (I) and pharmaceutically acceptable salt thereof of the present invention can be produced by any one of the following production methods. (Production method 1)
  • R 15 represents a hydrogen atom or lower alkyl
  • R 16 represents an amino protecting group
  • Z represents a hydroxy, halogen atom (fluorine Atom, chlorine atom, bromine atom, iodine atom) or alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy (eg, phenylsulfonyloxy, tolylsulfonyloxy) Etc.) leaving group.
  • halogen atom fluorine Atom, chlorine atom, bromine atom, iodine atom
  • alkanesulfonyloxy eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfony
  • Production method 1 is a method for producing novel tetrahydroisoquinoline compounds (Ia) and (Ib) in which R 1 in formula (I) is a carboxylic acid or acylsulfonamide derivative and A is a single bond.
  • amino protecting group for R 16 examples include formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethylcarbonyl Methoxymethyloxycarbonyl, trimethylsilyl, 2,2,2-trichloroethoxycarbonyl, 2-methylsulfonylethyloxycarbonyl, tert-butoxycarbonyl (hereinafter also referred to as Boc), trityl and the like.
  • the production method 1 comprises a compound having the general formula (3) (compound (3)) and a compound having the general formula (1) (compound (1)) or a compound having the general formula (2) (compound (2)).
  • a compound having the general formula (4) (compound (4)) is obtained, and the amino protecting group of the compound (4) is eliminated by a method known per se, and a compound having the general formula (5) (compound ( 5)), and the compound (5) obtained is reacted with the compound having the general formula (6) (compound (6)) to produce the compound having the general formula (Ia) (compound (Ia)).
  • compound (Ia) and a sulfonamide derivative in the presence of a condensing agent and a base to produce compound (Ib).
  • azo compounds examples include diC 1-4 alkyl azodicarboxylate (eg, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate), azodicarboxamide (eg, 1,1′-azobis (N , N′-dimethylformamide, 1,1 ′-(azodicarbonyl) dipiperidine, etc.)
  • phosphines examples include triarylphosphine (for example, triphenylphosphine), triC 1-8 alkylphosphine ( For example, tri-n-butylphosphine, tri-n-hexylphosphine, tri-n-octylphosphine, etc.) are used, and the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • dioxane acetonitrile, teto And hydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N′-dimethylformamide, N, N′-dimethylacetamide, dimethyl sulfoxide, and the like, and mixtures thereof.
  • the amount used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound (1).
  • the amounts of azo compounds and phosphines used are compound (1) 1 The amount is usually 1 to 5 mol, preferably 1 to 3 mol, relative to mol.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 50 ° C. and 30 minutes to 20 hours.
  • Production method 1-b In the production method 1, the reaction between the compound (3) and the compound (1) or the compound (2) is carried out in such a manner that Z is a halogen atom or alkanesulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc. ), Arylsulfonyloxy (eg, phenylsulfonyloxy, tolylsulfonyloxy, etc.) leaving group is carried out in the same solvent as in Production Method 1-a in the presence of a base.
  • Z is a halogen atom or alkanesulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc. )
  • the base used in the reaction is not particularly limited, and alkali metal carbonates (for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.), metal hydride compounds (for example, sodium hydride) Inorganic bases such as potassium hydride, calcium hydride, etc .; alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide), amines (eg, triethylamine, diisopropylethylamine, etc.) A base.
  • alkali metal carbonates for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.
  • metal hydride compounds for example, sodium hydride
  • Inorganic bases such as potassium hydride, calcium hydride, etc .
  • alkali metal alcoholates eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide
  • amines
  • the amount of compound (3) to be used is not particularly limited, and is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound (1) or (2).
  • the amount is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol.
  • a catalyst can also be used in a solvent in the presence of a base.
  • Suitable solvents are toluene and benzene, and catalysts include, for example, quaternary ammonium salts such as tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, tetraethylammonium chloride, tetraethylammonium fluoride, benzyltrimethylammonium bromide, Another example is tris [2- (2-methoxyethoxy) ethyl] amine.
  • Preferred is tetraethylammonium fluoride or tris [2- (2-methoxyethoxy) ethyl] amine.
  • the amount of the catalyst to be used is generally 0.1-1 mol, preferably 0.1-0.5 mol, per 1 mol of compound (1) or (2).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • the compound (6) is not only in the form of a free acid, but also a salt (eg, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.) or a reactive derivative (eg, acid halide such as acid chloride or acid bromide).
  • Acid anhydrides substituted phosphoric acids such as dialkyl phosphoric acids, mixed acid anhydrides with alkyl carbonic acids such as monoethyl carbonate; active amides that are amides with imidazoles, etc .; esters such as cyanomethyl esters and 4-nitrophenyl esters) And so on.
  • the reaction is preferably performed in the presence of a condensing agent.
  • the condensing agent include N, N′-dicyclohexylcarbodiimide and the like.
  • N, N′-disubstituted carbodiimides 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4-diethylaminocyclohexyl) )
  • Carbodiimide compounds such as carbodiimide; azolide compounds such as N, N′-carbonyldiimidazole and N, N′-thionyldiimidazole are used.
  • the condensing agent is used, the reaction is considered to proceed through a reactive derivative of compound (6).
  • the reaction of compound (5) and compound (6) is usually performed in an inert solvent.
  • the solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N′-dimethylformamide, pyridine, or a mixture thereof.
  • a base such as triethylamine, pyridine, 4-dimethylaminopyridine, or potassium carbonate can be used. When the base is used, it is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound (5).
  • the amount of compound (6) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (5).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • R 15 is preferably an alkyl group having 1 to 6 carbon atoms.
  • a compound (Ia) in which R 15 is an alkyl group having 1 to 6 carbon atoms can be obtained. It can be hydrolyzed by a known method to lead to compound (Ia) in which R 15 is a hydrogen atom.
  • N, N′-disubstituted compounds such as N, N′-dicyclohexylcarbodiimide Carbodiimides; carbodiimide compounds such as 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4-diethylaminocyclohexyl) carbodiimide; N , N′-carbonyldiimidazole, azolide compounds such as N, N′-thionyldiimidazole and the like are used, and the base is not particularly limited.
  • Alkali metal carbonates for example, sodium carbonate, sodium bicarbonate, potassium carbonate, Potassium hydrogen carbonate, cesium carbonate, etc.
  • Inorganic bases such as metal hydride compounds (eg, sodium hydride, potassium hydride, calcium hydride); alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide), amines (For example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene) and the like.
  • metal hydride compounds eg, sodium hydride, potassium hydride, calcium hydride
  • alkali metal alcoholates eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide
  • amines for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine,
  • R 8 , R 10 , R 16 , X and Z are as defined above.
  • Production method 2 is a method for producing a novel tetrahydroisoquinoline compound (Ic) in which R 1 in formula (I) is an amide and A is a single bond.
  • the compound having the general formula (8) (compound (8)) has the same reaction form and reaction conditions as the reaction between the compound (3) and the compound (1) in Production Method 1, and the compound (3) and the general formula (7). And a compound (compound (7)) having).
  • the compound having the general formula (Ic) (compound (Ic)) is prepared by removing the amino protecting group of the compound (8) by a method known per se and the compound having the general formula (9) (compound (9)).
  • the obtained compound (9) can be produced by reacting with the compound (6) in the same reaction form and reaction conditions as the reaction between the compound (5) and the compound (6) in Production Method 1.
  • R 4 , R 8 , R 10 , R 16 , X and Z are as defined above.
  • Production method 3 is a method for producing novel tetrahydroisoquinoline compounds (Id) and (Ie) in which R 1 in formula (I) is a sulfonamide or acylsulfonamide and A is a single bond.
  • the compound having the general formula (Id) (compound (Id)) is prepared in the same reaction form and reaction conditions as the method for producing the compound (Ic) from the compound (7) in the production method 2 via the compounds (8) and (9). Can be produced from the compound (10).
  • the compound having the general formula (Ie) (compound (Ie)) can be produced by reacting the compound (Id) with an acid anhydride ((R 4 CO) 2 O) in the presence of a base.
  • the base used in the reaction is not particularly limited, and alkali metal carbonates (for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.), metal hydride compounds (for example, sodium hydride) Inorganic bases such as potassium hydride, calcium hydride, etc .; alkali metal alcoholates (eg sodium methoxide, sodium ethoxide, potassium t-butoxide etc.), amines (eg triethylamine, diisopropylethylamine, 4-dimethyl) And organic bases such as aminopyridine and 1,8-diazabicyclo [5,4,0] undeca-7-ene).
  • alkali metal carbonates for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.
  • metal hydride compounds for example, sodium hydride
  • Inorganic bases such as potassium hydride, calcium hydride, etc .
  • alkali metal alcoholates e
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • examples thereof include dimethylformamide, N, N′-dimethylacetamide, and a mixture thereof.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • R 8 , R 10 , R 16 , X and Z are as defined above.
  • Production method 4 is a method for producing a novel tetrahydroisoquinoline compound (If) in which R 1 in the general formula (I) is tetrazole and A is a single bond.
  • the compound having the general formula (12) (compound (12)) can be produced by subjecting the amide group of the compound (8) to a dehydration reaction.
  • Examples of the dehydrating agent used in the reaction include diphosphorus pentoxide, thionyl chloride, phosphoryl chloride, N, N′-dicyclohexylcarbodiimide and the like.
  • the amount of the dehydrating agent to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (8).
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • Etc. bases such as triethylamine, pyridine, 4-dimethylaminopyridine can be used. When the base is used, it is generally 1-5 mol, preferably 1-3 mol, per 1 mol of compound (8).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • the compound having the general formula (13) (compound (13)) can be produced by reacting the compound (12) with an azide.
  • Examples of the azide used in the reaction include sodium azide and tri-n-butyltin azide.
  • the amount of the azide to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (12).
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 30 hours.
  • the compound having the general formula (If) (compound (If)) is obtained by removing the amino protecting group of the compound (13) by a method known per se, and the compound having the general formula (14) (compound (14)).
  • the compound (14) obtained and obtained can be produced by reacting with the compound (6) in the same reaction form and reaction conditions as the reaction of the compound (5) and the compound (6) in the production method 1.
  • R 8 , R 10 , R 16 , X and Z are as defined above, and R 17 is a tetrazole protecting group.
  • Examples of the tetrazole protecting group for R 17 include methoxymethyl and trityl.
  • the compound having the general formula (16) (compound (16)) has the same reaction form and reaction conditions as the reaction between the compound (3) and the compound (1) in Production Method 1, and the compound (3) and the general formula (15). ) Can be produced by reacting the compound (compound (15)).
  • Compound (If) is obtained by removing the amino-protecting group and tetrazole-protecting group of compound (16) by a method known per se to obtain compound (17), and the obtained compound (17) is combined with compound (5) in production method 1 It can manufacture by making it react with a compound (6) by the reaction form and reaction conditions similar to reaction with a compound (6).
  • the compound having the general formula (18) (compound (18)) can be produced by hydrolyzing the ester of the compound (4) by a method known per se and reacting with ammonia.
  • the compound having the general formula (Ig) (compound (Ig)) is produced from the compound (18) in the same reaction form and reaction conditions as in the method for producing the compound (If) from the compound (8) in the production method 4-a. be able to.
  • R 8 , R 10 , R 16 and X are as defined above.
  • Production Method 5 is a method for producing a novel tetrahydroisoquinoline compound (Ih) in which R 1 in the general formula (I) is 4H- [1,2,4] oxadiazol-5-one and A is a single bond.
  • the compound having the general formula (21) (compound (21)) can be produced by reacting the compound (12) with hydroxylamine.
  • hydroxylamine is usually 1 to 20 mol per 1 mol of compound (12).
  • an inorganic acid salt such as hydrochloride, sulfate or an organic acid salt such as oxalate
  • the reaction is carried out in the presence of an equimolar amount or a slight excess of base.
  • the base is not particularly limited, and alkali metal carbonates (for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.), metal hydride compounds (for example, sodium hydride, potassium hydride, hydrogen) Inorganic bases such as calcium hydroxide; alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amines (eg, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8 An organic base such as diazabicyclo [5,4,0] undec-7-ene).
  • alkali metal carbonates for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.
  • metal hydride compounds for example, sodium hydride, potassium hydride, hydrogen
  • Inorganic bases such as calcium hydroxide; alkali metal alcoholates (eg, sodium methoxid
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 50 to 150 ° C. and 30 minutes to 20 hours.
  • the compound having the general formula (22) (compound (22)) can be produced by reacting the compound (21) with a carbonylating reagent in the presence of a base.
  • Examples of the carbonylation reagent in the reaction include N, N′-carbonyldiimidazole, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and the like.
  • Examples of the base include triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, potassium carbonate, sodium carbonate and the like.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • Reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 50 to 150 ° C. and 30 minutes to 20 hours.
  • Compound (Ih) can be produced from compound (22) in the same reaction form and reaction conditions as the method for producing compound (Ic) from compound (8) in production method 2 via compound (9).
  • Production method 6 is a method for producing a novel tetrahydroisoquinoline compound (Ii) in which R 1 in the general formula (I) is 4H- [1,2,4] oxadiazole-5-thione and A is a single bond.
  • the compound having the general formula (23) (compound (23)) can be produced by reacting the compound (21) with a thiocarbonylating reagent in the presence of a base.
  • Examples of the thiocarbonylation reagent in the reaction include N, N′-thiocarbonyldiimidazole.
  • Examples of the base include triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, potassium carbonate, sodium carbonate and the like.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 50 to 150 ° C. and 30 minutes to 20 hours.
  • Compound (Ii) can be produced from compound (23) in the same reaction form and reaction conditions as the method for producing compound (Ic) from compound (8) in production method 2 via compound (9).
  • R 8 , R 10 , R 15 , R 16 , A and X are as defined above.
  • Production method 7 is a method for producing a novel tetrahydroisoquinoline compound (Ij) in which R 1 in formula (I) is a carboxylic acid and A is alkylene or alkenylene.
  • the compound having the general formula (24) (compound (24)) can be produced by reducing the compound (4).
  • Examples of the reducing agent in the reaction include diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride, and borane.
  • the amount of the reducing agent to be used is generally 0.5 to 20 mol, preferably 1 to 10 mol, per 1 mol of compound (4).
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • a compound having the general formula (25) in which A is alkenylene (compound (25)) is converted to an aldehyde by a method known per se and then reacted with ethyl diethylphosphonoacetate in the presence of a base. Can be manufactured.
  • the solvent in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • dioxane, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N′-dimethylformamide, N examples thereof include N′-dimethylacetamide and the like, and mixtures thereof.
  • the base include sodium hydride.
  • the compound (25) in which A is alkylene can be produced by reducing the compound (25) in which A is alkenylene using a catalyst such as palladium-activated carbon.
  • the compound having the general formula (Ij) (compound (Ij)) is prepared in the same reaction form and under the same reaction conditions as in the method for producing compound (Ia) from compound (4) in production method 1 via compound (5). ).
  • R 8 , R 10 , R 16 and X are as defined above.
  • Production method 8 is a method for producing a novel tetrahydroisoquinoline compound (Ik) in which R 1 in formula (I) is 1,2,3-triazole and A is a single bond.
  • the compound having the general formula (27) (compound (27)) can be produced by oxidizing the hydroxyl group of the compound (24) to an aldehyde by a method known per se, and then reacting with nitromethane in the presence of ammonium acetate. it can.
  • a solvent can be used and is not particularly limited as long as the reaction is not inhibited.
  • the compound having the general formula (28) (compound (28)) can be produced by reacting the compound (27) with trimethylsilyl azide in the presence of tetrabutylammonium fluoride.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • the compound having the general formula (Ik) (compound (Ik)) was prepared in the same reaction form and under the same reaction conditions as in the method for producing compound (Ic) from compound (8) in production method 2 via compound (9). ).
  • Production method 9 is a method for producing a novel tetrahydroisoquinoline compound (Il) in which R 1 in formula (I) is 1,2,4-triazole and A is a single bond.
  • the compound having the general formula (29) (compound (29)) is produced by reacting the compound (8) with N, N′-dimethylformamide dimethyl acetal and then reacting with hydrazine monohydrate in acetic acid. be able to.
  • the compound having the general formula (Il) (compound (Il)) was prepared in the same reaction form and under the same reaction conditions as in the method for producing compound (Ic) from compound (8) in production method 2 via compound (9). ).
  • Production method 10 is a method for producing a novel tetrahydroisoquinoline compound (Im) in which R 1 in formula (I) is tetrazole, A is a single bond and Y has a pyrazole ring.
  • the compound having the general formula (31) (compound (31)) has the same reaction form and reaction conditions as the reaction between the compound (3) and the compound (1) in production method 1-a, and the compound (15) and the general formula It can manufacture by making the compound (compound (30)) which has (30) react.
  • the compound having the general formula (Im) (compound (Im)) is a compound having the same reaction form and reaction conditions as those of the method for producing compound (If) from compound (16) in production method 4-b via compound (17). (31).
  • R 8 , R 10 , R 13 , R 14 , R 16 and X are as defined above, and R 18 represents a hydroxy protecting group.
  • Production method 11 is a method for producing novel tetrahydroisoquinoline compounds (In) and compounds (Io) in which R 1 in formula (I) is —NR 6 R 7 , heterocyclyl or heteroaryl, and A is a single bond.
  • a nitro group is introduced onto the benzene ring of the compound (33) by a method known per se, and the hydroxy group is protected with a protecting group, followed by palladium-activity. It can be produced by catalytic hydrogenation using a catalyst such as carbon or reduction of a nitro group using a metal such as zinc or iron under acidic conditions.
  • the compound having the general formula (35) (compound (35)) is obtained by alkylating, amidating or sulfonamidating the amino group of the compound (34) by a method known per se, and then deprotecting the hydroxy protecting group. Can be manufactured.
  • the compound having the general formula (36) (compound (36)) can be produced by deprotecting the hydroxy protecting group of the compound (34) by a method known per se.
  • the compound having the general formula (37) (compound (37)) can be synthesized by reacting the compound (36) with 2,5-dimethoxytetrahydrofuran in acetic acid.
  • the compounds having the general formulas (In) and (Io) have the same reaction form and reaction conditions as in the method for producing compound (Id) from compound (10) in Production Method 3. It can be produced from compound (35) or compound (37).
  • R 8 and R 17 are as defined above.
  • Production method 12 is a method for producing a novel tetrahydroisoquinoline compound (Ip) in which R 1 in formula (I) is tetrazole, A is a single bond, and Y is an imidazole derivative.
  • Compound (39) can be produced by tosylating compound (38) by a method known per se, and then reducing using a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • Compound (40) can be produced in the same reaction form and reaction conditions as the reaction of compound (15) and compound (3) in production method 4-b.
  • Compound (41) can be produced in the same reaction form and reaction conditions as in the method of producing compound (If) from compound (16) in production method 4-b.
  • Compound (Ip) can be produced by removing the tosyl group of compound (41) by a method known per se.
  • R 15 , R 16 and R 18 are as defined above.
  • Production method 13 is a method for producing compound (1) which is an intermediate tetrahydroisoquinoline derivative.
  • hydroxy protecting group for R 18 examples include ethers and acetals such as methyl ether, isopropyl ether, tert-butyl ether, benzyl ether, allyl ether, methoxymethyl ether, tetrahydropyranyl ether, p-bromophenacyl ether, and trimethylsilyl ether.
  • the compound having the general formula (33) (compound (33)) is compound (42) [Kucznierz R. , Et. al. , J .; Med. Chem. , 41, 4984-4994] can be reduced to lead to a tetrahydroisoquinoline derivative, and the amino group can be protected.
  • the compound having the general formula (43) (compound (43)) can be produced by reacting the compound (33) with hexamethylenetetramine in trifluoroacetic acid and introducing a formyl group.
  • the compound having the general formula (45) (compound (45)) is obtained by protecting the hydroxy group of the compound (43) to obtain the compound having the general formula (44) (compound (44)), and then oxidizing the formyl group. Can be manufactured.
  • Compound (1) can be produced by esterifying the carboxylic acid of compound (45) by a method known per se, and then removing the hydroxy protecting group.
  • Production method 14 is a method for producing compound (7) which is an intermediate tetrahydroisoquinoline derivative.
  • Compound (7) is prepared from Compound (45) to Compound (46) in the same reaction form and under the same reaction conditions as in the method for producing Compound (18) from Compound (4) in which R 15 is a hydrogen atom in Production Method 4-c. And can be produced by removing the hydroxy protecting group by a method known per se.
  • R 16 , R 17 and R 18 are as defined above.
  • Production method 15 is a method for producing compound (15) which is an intermediate tetrahydroisoquinoline derivative.
  • the compound having the general formula (48) (compound (48)) is prepared in the same reaction form and reaction conditions as in the method for producing the compound (13) from the compound (8) in the production method 4-a through the compound (12). It can be produced from compound (46).
  • Compound (15) is obtained by protecting the tetrazole group of compound (48) to obtain a compound having the general formula (49) (compound (49)), and then removing the hydroxy protecting group by a method known per se. Can be manufactured.
  • R 15 and R 16 are as defined above.
  • Production method 16 is a method for producing compound (2) which is an intermediate tetrahydroisoquinoline derivative.
  • the compound having the general formula (50) (compound (50)) can be produced by reacting the compound (1) with N, N′-dimethylthiocarbamoyl chloride in the presence of a base.
  • Examples of the base used in the reaction include triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and the like.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • the compound having the general formula (51) (compound (51)) can be produced by heating the compound (50) in n-tetradecane and subjecting it to a rearrangement reaction.
  • the dimethylcarbamoyl group of the compound (51) is eliminated, and the resulting disulfide is converted to tris (2-carboxyl in the presence of triethylamine in N, N′-dimethylformamide. It can be prepared by reduction with ethyl) phosphine hydrochloride.
  • Production method 17 is a method for producing compound (10) which is an intermediate tetrahydroisoquinoline derivative.
  • the compound having the general formula (52) (compound (52)) can be produced by protecting the hydroxy group of the compound (33) by a method known per se and reacting with chlorosulfonic acid in methylene chloride. .
  • the compound having the general formula (10) (compound (10)) is obtained by reacting the compound (52) with aqueous ammonia in tetrahydrofuran to convert it to a sulfonamide, and then deprotecting the hydroxy protecting group by a method known per se. Can be manufactured.
  • R 1 , R 16 and R 18 are as defined above.
  • the compound having the general formula (53) (compound (53)) is obtained by reacting the compound (44) with m-chloroperbenzoic acid in methylene chloride and converting the resulting hydroxy group to trifluoromethanesulfonate by a method known per se. Can be manufactured.
  • a compound having the general formula (54) (compound (54)) is obtained by reacting the compound (53) with an optionally substituted arylboric acid or an optionally substituted heteroarylboric acid in the presence of a transition metal catalyst and a base. After the coupling, it can be produced by deprotecting the hydroxy protecting group by a method known per se.
  • transition metal catalyst used in the reaction examples include tetrakistriphenylphosphine palladium and [1,1'-bis (diphenylphosphino) ferrocene] palladium.
  • the amount of the transition metal catalyst to be used is generally 0.001 to 2 mol, preferably 0.01 to 0.1 mol, per 1 mol of compound (53).
  • Examples of the base used in the reaction include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, Examples include diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, sodium acetate, potassium acetate and the like.
  • Examples of the aryl boric acid and heteroaryl boric acid include phenyl boric acid, 2-furyl boric acid, 2-thienyl boric acid and the like.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • Examples include dimethylformamide, dimethyl sulfoxide, water and the like, and mixtures thereof.
  • R 1 , R 16 and R 18 are as defined above.
  • Production method 19 is an intermediate in which R 1 is a carboxylic acid and A is 1,4-piperidinylene, and R 1 is a heterocyclyl such as azetidine, pyrrolidine, piperidine, morpholine, and an intermediate tetrahydroisoquinoline derivative in which A is a single bond.
  • R 1 is a heterocyclyl such as azetidine, pyrrolidine, piperidine, morpholine, and an intermediate tetrahydroisoquinoline derivative in which A is a single bond.
  • the compound having the general formula (54) (compound (54)) is obtained by converting the compound (53) into a transition metal catalyst such as palladium acetate and a ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. And by coupling with a heterocyclic ring such as piperidine, azetidine, pyrrolidine and the like which may be substituted in the presence of a base such as cesium carbonate and then deprotecting the hydroxy protecting group by a method known per se. Can do.
  • a transition metal catalyst such as palladium acetate
  • a ligand such as 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl.
  • a heterocyclic ring such as piperidine, azetidine, pyrrolidine and the like which may be substituted in the presence of a base such as cesium carbonate and then deprotecting the hydroxy protecting group by
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • the compound represented by the general formula (I) can be produced from the intermediate (54) synthesized by the production methods 18 and 19 by the same method as the production method 1 or 4.
  • Production method 20 is a method for producing compound (3) which is an intermediate oxazole or thiazole derivative.
  • Compound (56) can be produced by introducing a nitro group into compound (55) by a method known per se, and reducing the nitro group using a catalyst such as palladium-activated carbon.
  • the compound having the general formula (58) (compound (58)) can be produced by reacting the compound (56) with a compound having the general formula (57) (compound (57)).
  • Compound (57) is not only in the form of a free acid, but also a salt (for example, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.) or a reactive derivative (for example, an acid halide such as acid chloride or acid bromide; acid anhydride; A substituted phosphoric acid such as a dialkyl phosphoric acid, a mixed acid anhydride with an alkyl carbonate such as monoethyl carbonate; an active amide that is an amide with imidazole; an ester such as a cyanomethyl ester or 4-nitrophenyl ester) Subject to reaction.
  • a salt for example, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.
  • a reactive derivative for example, an acid halide such as acid chloride or acid bromide; acid anhydride;
  • a substituted phosphoric acid such as a dialkyl phosphoric acid, a mixed acid anhydride with
  • reaction when compound (57) is used in this reaction in the form of a free acid or salt, the reaction is preferably performed in the presence of a condensing agent.
  • a condensing agent examples include N, N′-dicyclohexylcarbodiimide and the like.
  • N, N′-disubstituted carbodiimides 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-(4-diethylaminocyclohexyl) )
  • a carbodiimide compound such as carbodiimide; and a dehydrating agent such as an azolide compound such as N, N′-carbonyldiimidazole and N, N′-thionyldiimidazole.
  • the reaction of the compound (56) and the compound (57) is usually performed in an inert solvent.
  • the solvent include acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N′-dimethylformamide, pyridine, water, and mixtures thereof. It is done.
  • a base such as triethylamine, pyridine, 4-dimethylaminopyridine, or potassium carbonate can be used. When the base is used, the amount is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (56).
  • the amount of compound (57) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (56).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • the compound having the general formula (59) where X is an oxygen atom can be produced by subjecting the compound (58) to a dehydration reaction.
  • the dehydration reaction is performed using a method of treating with phosphorus oxychloride or a method of treating with iodine, triphenylphosphine and triethylamine.
  • the amount of phosphorus oxychloride used is usually 1 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of compound (58).
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dioxane, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, and mixtures thereof. Can be mentioned.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • the amount of iodine used is usually 1 to 5 mol, preferably 1 to 3 mol, and the amount of triphenylphosphine and triethylamine used relative to 1 mol of compound (58). Is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (58).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • Compound (59) in which X is a sulfur atom can be produced by treating compound (58) with a Lawesson reagent.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • dioxane, tetrahydrofuran, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, etc. And mixtures thereof.
  • Compound (3) wherein Z is a hydroxy group can be produced by reducing compound (59) using a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • Compound (3) wherein Z is a leaving group is obtained by reacting the hydroxy group of compound (3) with a halogen atom (chlorine atom, bromine atom, iodine atom) or alkanesulfonyloxy (eg, methanesulfonyloxy, ethane) by a method known per se.
  • a halogen atom chlorine atom, bromine atom, iodine atom
  • alkanesulfonyloxy eg, methanesulfonyloxy, ethane
  • arylsulfonyloxy for example, phenylsulfonyloxy, tolylsulfonyloxy and the like.
  • R 10 has the same meaning as described above.
  • R 10 is heterocyclyl such as thiazolyl, piperidyl or pyrrolinyl, R 13 R 14 N— such as dimethylamino or dimethylamino (wherein R 13 and R 14 are as defined above), or imidazolyl.
  • R 10 is heterocyclyl such as thiazolyl, piperidyl or pyrrolinyl, R 13 R 14 N— such as dimethylamino or dimethylamino (wherein R 13 and R 14 are as defined above), or imidazolyl.
  • Compound (61) can be produced by introducing a bromine atom into compound (60) by a method known per se.
  • Compound (62) can be produced by reacting compound (61) with urea.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • methanol, ethanol, dioxane, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N examples include '-dimethylformamide, dimethyl sulfoxide, and the like, and mixtures thereof.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • Compound (63) can be produced by reacting compound (62) with tert-butyl nitrite and copper chloride in acetonitrile.
  • Compound (64) can be produced by reacting with a corresponding amine when R 10 is heterocyclyl such as thiazolyl, piperidyl, pyrrolinyl, or R 13 R 14 N— such as dimethylamino or dimethylamino.
  • R 10 is heterocyclyl such as thiazolyl, piperidyl, pyrrolinyl, or R 13 R 14 N— such as dimethylamino or dimethylamino.
  • a solvent and a base can also be used in the reaction, and the solvent used is not particularly limited as long as it does not inhibit the reaction.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction.
  • the base is not particularly limited, and alkali metal carbonates (for example, sodium carbonate, sodium bicarbonate, potassium carbonate, carbonate Inorganic bases such as potassium hydride, cesium carbonate, etc.), metal hydride compounds (eg, sodium hydride, potassium hydride, calcium hydride, etc.), and organic bases of amines (eg, triethylamine, diisopropylethylamine, etc.) .
  • alkali metal carbonates for example, sodium carbonate, sodium bicarbonate, potassium carbonate, carbonate Inorganic bases such as potassium hydride, cesium carbonate, etc.
  • metal hydride compounds eg, sodium hydride, potassium hydride, calcium hydride, etc.
  • organic bases of amines eg, triethylamine, diisopropylethylamine, etc.
  • the reaction is preferably performed in the presence of a base.
  • R 10 is imidazolyl
  • the reaction is performed using a solvent and a base.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction.
  • the base include sodium hydride.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagent and reaction solvent used, but are usually ⁇ 30 to 150 ° C. and 30 minutes to 20 hours.
  • Compound (3) can be produced by reducing compound (64) using a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • R 10 has the same meaning as described above.
  • Production method 22 is a method for producing compound (3) which is an intermediate oxazole derivative.
  • the compound having the general formula (65) (compound (65)) can be produced by converting the compound (57) into an aldehyde by a method known per se.
  • Compound (57) is subjected not only to the free acid form but also to the reaction as an ester (for example, methyl, ethyl, propyl, butyl ester, etc.).
  • an ester for example, methyl, ethyl, propyl, butyl ester, etc.
  • the compound having the general formula (66) (compound (66)) can be produced by reacting the compound (65) with biacetyl monooxime in the presence of hydrogen chloride in ethyl acetate.
  • Compound (3) can be produced by reacting compound (66) with phosphorus oxychloride in chloroform.
  • R 10 has the same meaning as described above.
  • Production method 23 is a method for producing compound (3) which is an intermediate oxazole derivative.
  • the compound having the general formula (67) (compound (67)) can be produced by amidating the compound (57) by a method known per se.
  • Compound (3) can be produced by reacting compound (67) with 1,3-dichloropropan-2-one.
  • R 12 has the same meaning as described above.
  • the compound having the general formula (69) (compound (69)) can be produced by reacting trichloroacetyl chloride with 1-ethoxy-1-propene and then reacting the compound (68).
  • Compound (30) can be produced by reducing compound (69) using a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • a reducing agent such as lithium aluminum hydride or sodium borohydride.
  • the compound represented by the general formula (I) can be produced from the intermediate (30) obtained by the production method 24 by the same method as the production method 10.
  • Manufacturing method 25 is Y in general formula (I)
  • the compound having the general formula (71) (compound (71)) is obtained by brominating the compound having the general formula (70) (compound (70)) by a method known per se and then reacting with methylamine in tetrahydrofuran. Can be manufactured.
  • the compound having the general formula (72) (compound (72)) can be produced by reacting the compound (71) with formamide.
  • the compound having the general formula (73) (compound (73)) can be produced by treating the compound (72) with n-butyllithium or the like and lithiating it, and then reacting with paraformaldehyde.
  • the compound represented by the general formula (I) can be produced from the intermediate (73) obtained by the production method 25 by the same method as the production method 10.
  • the heterocyclic compound (I) obtained by the above production method 1-12 can be isolated by a conventional method, and if necessary, a conventional method such as a recrystallization method, preparative thin layer chromatography, column chromatography, etc. Can be purified by.
  • heterocyclic compound (I) of the present invention can be converted to a pharmaceutically acceptable salt thereof by a method known per se.
  • the pharmaceutical composition containing the heterocyclic compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be blended with additives and the like.
  • additives include excipients (eg, starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants, and the like.
  • Agents eg, magnesium stearate, talc, etc.
  • disintegrating agents eg, carboxymethylcellulose, talc, etc.
  • the mixture is subjected to per se known means, for example, for oral administration such as capsules, tablets, fine granules, granules, dry syrups, or for parenteral administration such as injections and suppositories. It can be a formulation.
  • the dose of the heterocyclic compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and other factors, but for example, for patients with diabetes, diabetic complications or hyperlipidemia. In the case of oral administration to adults, a single dose of about 1 to 500 mg is given about 1 to 3 times a day.
  • the heterocyclic compound (I) of the present invention or a pharmaceutically acceptable salt thereof has a peroxisome proliferator-responsive receptor gamma (PPAR ⁇ ) partial agonistic action, a PPAR ⁇ modulator action, or a PPAR ⁇ antagonistic action, and is a mammal (human, Equine, cattle, dogs, cats, rats, mice, hamsters, etc.) excellent blood glucose lowering effect, blood lipid lowering effect, insulin resistance improving action, antihyperglycemic agent, antihyperlipidemic agent , Insulin resistance improving agent, diabetes therapeutic agent, diabetic complication therapeutic agent, glucose intolerance ameliorating agent, anti-arteriosclerotic agent, anti-obesity agent, anti-inflammatory agent, osteoporosis therapeutic agent, prophylactic / therapeutic agent for PPAR-mediated diseases and It is useful as a preventive / therapeutic agent for metabolic syndrome.
  • PPAR ⁇ peroxisome proliferator-responsive receptor gamma
  • heterocyclic compound (I) of the present invention results from hyperglycemia, hyperlipidemia, diabetes, diabetic complications, diseases caused by insulin resistance, or glucose intolerance. It is useful as a preventive and therapeutic agent for diseases, arteriosclerosis, obesity, inflammation, osteoporosis, PPAR-mediated diseases and metabolic syndrome.
  • Reference example 1 4-Chloromethyl-2-isopropyl-5-methyloxazole (1)
  • Reference example 2 4-chloromethyl-2- (cyclopent-3-enyl) oxazole (1) 5.00 g of 3-cyclopentene-1-carboxylic acid was dissolved in 50 mL of tetrahydrofuran, and 5.40 mL of N-methylmorpholine and isobutyl chlorocarbonate were cooled with ice. After adding 6.45 mL and stirring at the same temperature for 30 minutes, 9.04 mL of 28% aqueous ammonia was added dropwise. After stirring at the same temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Reference example 3 4-Hydroxymethyl-5-methyl-2- (3-pyrrolin-1-yl) oxazole (1) Dissolve 50.0 g of DL-2-hydroxybutyric acid in 500 mL of ethanol, and add 20 mL of 8.6 M hydrogen chloride 2-propanol solution. And refluxed for 22 hours. Ethanol was distilled off under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over sodium sulfate, and then ethyl acetate was distilled off under reduced pressure to obtain 48.9 g of 2-hydroxybutyric acid ethyl ester.
  • Reference example 4 1-Cyclopentyl-3-hydroxymethyl-4-methylpyrazole (1) After separately adding 3.62 g of barium oxide to 70 mL of methanol at ⁇ 5 ° C., 15.7 mL of hydrazine monohydrate was added under ice cooling. The mixture was stirred at the same temperature for 10 minutes. To the reaction solution, a solution of 27.1 g of cyclopentanone in 20 mL of methanol was added dropwise and stirred at room temperature for 2 hours. 150 mL of diethyl ether and sodium sulfate were added to the reaction solution, and the mixture was stirred for 15 minutes, then filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure.
  • the obtained residue was dissolved in 60 mL of ethanol, and a solution of 13.7 g of the compound obtained in (1) in 60 mL of ethanol was added dropwise, followed by stirring at 80 ° C. for 3 hours. After allowing to cool, ethanol was distilled off under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the two layers were separated. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and ethyl acetate was distilled off under reduced pressure.
  • Reference Example 5 4-Chloromethyl-2- (cyclopent-3-enyl) -5-methylthiazole (1)
  • the following compounds were synthesized according to (1) to (3) of Reference Example 1.
  • Reference Example 6 4-chloromethyl-5-methyl-2- (3-methylbutyl) oxazole (1) 2.0 g of 4-methylpentanoic acid is dissolved in 90 mL of methylene chloride, 1.62 mL of oxalyl chloride and N, N′-dimethylformamide 3 Drops were added and stirred at room temperature for 30 minutes. Under ice-cooling, 3.75 g of the compound obtained in Reference Example 1 (2) and then 8.9 mL of N, N′-diisopropylethylamine were added to the resulting solution, followed by stirring at the same temperature for 30 minutes.
  • Reference Example 8 4-Hydroxymethyl-5-methyl-2- (thiazolidin-3-yl) oxazole (1) 500 mg of the compound obtained in Reference Example 3 (3) was dissolved in 5 mL of N, N′-dimethylformamide. 23 mL and 0.55 mL of N, N′-diisopropylethylamine were added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 1.5 hours. Thereafter, 0.55 mL of thiazolidine was added, and the mixture was further stirred at 60 ° C. for 19 hours.
  • the obtained powder was dissolved in 1.5 L of water and adjusted to pH 9 with concentrated aqueous ammonia.
  • the precipitate was collected by filtration and washed successively with water and acetonitrile to obtain 28.1 g of 7-hydroxyisoquinoline.
  • the precipitated crystals were collected by filtration, washed with n-hexane, 7-benzyloxy-6-formyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline and 7-benzyloxy-8-formyl-2. 87.2 g of a mixture of -trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline was obtained.
  • Reference Example 11 2-tert-butoxycarbonyl-6-carbamoyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (1) 21.6 g of the compound of (8) of Reference Example 10 was suspended in tetrahydrofuran, and the mixture was ice-cooled. N-methylmorpholine (6.5 mL) was added, and isobutyl chlorocarbonate (7.7 mL) was added dropwise, followed by stirring at the same temperature for 20 minutes. Furthermore, 22 mL of 28% aqueous ammonia was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes.
  • Reference Example 13 2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-6-acetic acid methyl ester (1) 1.61 g of the compound of (9) of Reference Example 10 was dissolved in 15 mL of tetrahydrofuran, and ice Under cooling, 154 mg of lithium aluminum hydride was added and stirred at the same temperature for 30 minutes. Water was added to the reaction solution, the insoluble material was filtered off, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 14 7-Hydroxy-6-nitro-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (1) Dissolve 2.49 g of the compound obtained in Reference Example 10 (4) in 8 mL of acetic anhydride Then, under ice cooling, 0.55 mL of 94% fuming nitric acid was added dropwise and stirred at the same temperature for 1 hour and 20 minutes. Water was added to the reaction mixture, the pH was adjusted to about 8.0 with sodium hydrogen carbonate, and the mixture was extracted twice with ethyl acetate. After washing with saturated brine and drying over sodium sulfate, the solvent was distilled off under reduced pressure.
  • Reference Example 15 6-Dimethylamino-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (1) 0.88 g of the compound of Reference Example 14 was dissolved in 5 mL of acetic acid, 15 g was added and stirred at room temperature for 1 hour. The zinc powder was filtered off, neutralized with sodium bicarbonate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Reference Example 16 7-hydroxy-6- (pyrrol-1-yl) -2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (1) 600 mg of the compound of (1) of Reference Example 14 was dissolved in 5 mL of acetic acid, 795 mg of zinc powder was added, and the mixture was stirred at room temperature for 1 hour. The zinc powder was filtered off, neutralized with sodium bicarbonate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 1 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (3-methylbutyl) oxazol-4-ylmethoxy] -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline (1)
  • 500 mg of the compound obtained in Reference Example 11 and 380 mg of the compound obtained in Reference Example 6 were dissolved in 10 mL of N, N′-dimethylformamide, and cesium carbonate 1 .39 g was added and stirred at 80 ° C. for 30 minutes.
  • Example 2 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1, 2,3,4-Tetrahydroisoquinoline (1) 1.00 g of the compound of Reference Example 11 and 830 mg of the compound of Reference Example 1 are dissolved in 16 mL of N, N′-dimethylformamide, added with 3.34 g of cesium carbonate, and at 60 ° C. Stir for 2 hours. After allowing to cool, 80 mL of water was added to the reaction solution, and the precipitated powder was collected by filtration.
  • the obtained powder was dissolved in chloroform, and the chloroform layer was washed with water and saturated brine, and dried over sodium sulfate. Chloroform was distilled off under reduced pressure, and diisopropyl ether was added to the obtained powder, followed by filtration, and 2-tert-butoxycarbonyl-6-carbamoyl-7- (2-isopropyl-5-methyloxazol-4-ylmethoxy)- 974 mg of 1,2,3,4-tetrahydroisoquinoline powder was obtained.
  • Example 3 7- [2-Cyclopent-3-enyl-5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline (1) 9.79 g of the compound of Reference Example 11 and 8.51 g of the compound of Reference Example 2 were dissolved in 100 mL of N, N'-dimethylformamide, and 27.3 g of cesium carbonate was obtained. And stirred at 60 ° C. for 1 hour. After allowing to cool, 500 mL of water was added to the reaction solution, and the precipitated powder was collected by filtration.
  • Example 5 7- (2,5-Dimethyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1,2, 3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1653, 1614. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.35 (3H, s), 2.59 (3H, s), 2.90-3.10 (2H, br), 3.85-4.
  • Example 6 7- (2-Ethyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1645.
  • Example 7 2-[(E) -3- (furan-2-yl) acryloyl] -7- (5-methyl-2-propyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649.
  • Example 8 7- (2-butyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 9 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isobutyl-5-methyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1608.
  • Example 10 7- (2-tert-Butyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1,2, 3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1647,1603. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.51 (9H, s), 2.37 (3H, s), 2.90-3.10 (2H, br), 3.85-4.
  • Example 12 7- [2- (2,2-Dimethylpropyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole- 5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1608.
  • Example 13 7- ⁇ 2-[(E) -1-ethylpropenyl] -5-methyloxazol-4-ylmethoxy ⁇ -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H- Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1646,1606.
  • Example 14 7- [2- (2-Cyclopropyl) ethyl-5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm -1 ; 1649,1610.
  • Example 17 7- (2-Cyclopropylmethyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl)- 1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 18 7- (2-Cyclobutyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1,2,3 , 4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 19 7- (2-Cyclobutylmethyl-5-methyloxazol-4-ylmethoxy) 2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1 , 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.74-2.02 (2H, m), 2.13-2.24 (2H, m), 2.35 (3H, s), 2.
  • Example 20 7- (2-Cyclopentyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 21 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(2E, 4E) -hexa-2,4-dienoyl] -6- (1H-tetrazole-5- Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1655, 1624.
  • Example 22 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (1-methylcyclopent-3-enyl) oxazol-4-ylmethoxy] -6- (1H -Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1647,1601. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.62 (3H, s), 2.37 (3H, s), 2.50-2.63 (2H, m), 2.90-3.
  • Example 24 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -3-methylbut-1-enyl] oxazol-4-ylmethoxy ⁇ -6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1608.
  • Example 25 7- [2- (Cyclopent-1-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1608. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.97-2.20 (2H, m), 2.40 (3H, s), 2.55-2.70 (2H, m), 2.
  • Example 26 7- (2-Cyclopentylmethyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1 , 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 27 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (1,3,4-trimethylcyclopent-3-enyl) oxazol-4-ylmethoxy] -6- (1H -Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651,1603.
  • Example 28 7- (2-cyclohexyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1610.
  • Example 29 7- [2- (Cyclohex-1-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 30 2-[(E) -3- (furan-2-yl) acryloyl] -7- (5-methyl-2-phenyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1, 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1610.
  • Example 32 2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl) -7- [2- (thiophen-2-yl) -5-methyloxazole-4 -Ylmethoxy] -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1650,1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.45 (3H, s), 2.90-3.10 (2H, m), 3.86-4.02 (2H, m), 4.
  • Example 33 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (indan-2-yl) -5-methyloxazol-4-ylmethoxy] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648,1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.38 (3H, s), 2.90-3.03 (2H, m), 3.48-3.55 (4H, m), 3.
  • Example 34 2-[(2E, 4E) -Hexa-2,4-dienoyl] -7- [2- (Indan-2-yl) -5-methyloxazol-4-ylmethoxy] -6- (1H-tetrazole-5- Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1618. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.86 (3H, s), 2.37 (3H, s), 2.88-3.02 (2H, m), 3.47-3.
  • Example 37 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(Z) -3-methylbut-1-enyl] oxazol-4-ylmethoxy ⁇ -6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1610.
  • Example 38 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2-trifluoromethyloxazol-4-ylmethoxy] -6- (1H-tetrazol-5-yl)- 1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1608. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.51 (3H, s), 2.90-3.08 (2H, m), 3.86-4.00 (2H, m), 4.
  • Example 39 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (3,3,3-trifluoropropyl) oxazol-4-ylmethoxy] -6- (1H -Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.38 (3H, s), 2.79-2.93 (2H, m), 2.94-3.06 (2H, br), 3.
  • Example 40 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -3,3,3-trifluoropropenyl] oxazol-4-ylmethoxy ⁇ - 6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.46 (3H, s), 2.90-3.07 (2H, br), 3.86-3.99 (2H, br), 4.
  • Example 41 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (4,4,4-trifluorobutyl) oxazol-4-ylmethoxy] -6- (1H -Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.18-2.35 (4H, m), 2.38 (3H, s), 2.92-3.04 (2H, br), 2.
  • Example 42 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (1-fluoro-1-methylethyl) -5-methyloxazol-4-ylmethoxy] -6- (1H- Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 2159,1648.
  • Example 44 7- (2-Ethylsulfanylmethyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl)- 1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649,1601.
  • Example 45 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (2-methylsulfanylethyl) oxazol-4-ylmethoxy] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.19 (3H, s), 2.37 (3H, s), 2.88-3.04 (2H, br), 3.05-3.
  • Example 46 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropylsulfanyl-5-methyloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl) -1 , 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1646,1608.
  • Example 50 7-[(E) -2-cyclopropylvinyl-5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651,1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 0.97-1.01 (4H, m), 1.49-1.58 (1 H, m), 2.38 (3H, s), 2.
  • Example 51 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (3-methylbut-1-ynyl) oxazol-4-ylmethoxy) -6- (1H-tetrazole -5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm -1 ; 1649, 1606.
  • Example 52 7- (2-Buta-3-ynyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 53 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -2-methylpropenyl] oxazol-4-ylmethoxy ⁇ -6- (1H- Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1646,1602. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.02 to 2.04 (3H, m), 2.26-2.28 (3H, m), 2.39 (3H, s), 2.
  • Example 54 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-[(E) -2- (1-methylpropenyl)] oxazol-4-ylmethoxy ⁇ -6- ( 1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1608.
  • Example 55 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -1-methylbut-1-enyl] oxazol-4-ylmethoxy ⁇ -6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 56 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -4-methyl-1-pentenyl] oxazol-4-ylmethoxy ⁇ -6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608, 1583, 1552, 1485.
  • Example 58 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyridin-3-yl) oxazol-4-ylmethoxy] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1604. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.50 (3H, s), 2.87-3.07 (2H, br), 3.86-3.98 (2H, br), 4.
  • Example 61 7- [2- (1,2-Dimethylpropenyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazole- 5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1648, 1608.
  • Example 62 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(Z) -1-methylprop-1-enyl] oxazol-4-ylmethoxy ⁇ -6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • Example 65 7- [2- (2-Cyclopent-3-enyl) oxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1644,1602.
  • Example 66 2-[(E) -3-Cyclopropylacryloyl] -7- [2- (2,2-dimethylpropyl) -5-methyloxazol-4-ylmethoxy] -6- (1H-tetrazol-5-yl)- 1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1654, 1604. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 0.60-0.69 (2H, m), 0.88-0.98 (2H, m), 1.07 (9H, s), 1.
  • Example 68 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-hexanoyl-6- (1H-tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1643, 1566.
  • Example 70 7- [2- (Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -6- (1H-tetrazol-5-yl) -2-[(E) -3- (2-thiophenyl) acryloyl ] -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1637. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.37 (3H, s), 2.81-3.05 (6H, m), 3.80-4.00 (2H, br), 4.
  • Example 71 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (5-fluorofuran-2-yl) acryloyl] -6- (1H- Tetrazol-5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651,1601.
  • Example 72 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2- [3- (5-fluorofuran-2-yl) propionyl] -6- (1H-tetrazole-5- Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1637.
  • Example 73 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2- (hex-2-inoyl) -6- (1H-tetrazol-5-yl) -1,2,3 , 4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1618.
  • Example 74 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2- (4-methylpent-2-inoyl) -6- (1H-tetrazol-5-yl) -1,2 , 3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1620.
  • Example 75 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3-cyclopropylacryloyl] -6- (1H-tetrazol-5-yl) -1 , 2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1655, 1614, 1566.
  • Example 76 7-[(2-Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(2E, 4E) -5-methylhexa-2,4-dienoyl] -6- (1H-tetrazole- 5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1618, 1568.
  • Compound (2-tert-butoxycarbonyl-7-hydroxy-6- (1-methoxymethyl-1H-tetrazol-5-yl) -1, obtained in Reference Example 12 2,3,4-tetrahydroisoquinoline) and 153 mg of the compound obtained in Reference Example 7 were dissolved in 10 mL of toluene, and 0.42 mL of tri-n-butylphosphine and 1,1′-azodicarbonyldipiperidine were added under ice cooling.
  • Example 80 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (3-pyrrolin-1-yl) oxazol-4-ylmethoxy] -6- (1H-tetrazole -5-yl) -1,2,3,4-tetrahydroisoquinoline (1)
  • Compound (2-tert-butoxycarbonyl-7-hydroxy-6- (1-methoxymethyl-1H-tetrazole) obtained in Reference Example 12 -5-yl) -1,2,3,4-tetrahydroisoquinoline) 6.34 g and 3.16 g of the compound obtained in Reference Example 3 were dissolved in 150 mL of toluene, and 11.0 mL and 1, 11.1 g of 1′-azodicarbonyldipiperidine was added, and the mixture was stirred at room temperature for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, the precipitate was filtered off, diethyl ether was distilled off under reduced pressure, and the resulting residue was purified by column chromatography.
  • Examples 82 to 85 were synthesized according to Examples 79 to 81.
  • Example 82 7- (2-Dimethylamino-5-methyloxazol-4-ylmethoxy)-[(E) -3- (furan-2-yl) acryloyl-6- (1H-tetrazol-5-yl) -1,2, 3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.27 (3H, s), 2.90-3.05 (2H, br), 3.20 (6H, s), 3.85-4. 02 (2H, br), 4.85-4.92 (2H, br), 5.00 (2H, s), 6.47 (1H, dd, J 3.4, 1.7 Hz), 6.
  • Example 86 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyrrolidin-1-yl) oxazol-4-ylmethoxy] -6- (1H-tetrazole-5 -Yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.00-2.12 (4H, m), 2.27 (3H, s), 2.88-3.09 (2H, br), 3.
  • Example 88 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2-pyrrol-1-yloxazol-4-ylmethoxy] -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1651,1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.41 (3H, s), 2.84-3.09 (2H, br), 3.86-4.00 (2H, br), 4.
  • Example 90 2-[(E) -3- (furan-2-yl) acryloyl] -7- (5-methyl-2-piperidin-1-yloxazol-4-ylmethoxy) -6- (1H-tetrazol-5-yl ) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.57-1.82 (6H, m), 2.26 (3H, s), 2.88-3.07 (2H, br), 3.
  • Example 93 2-[(E) -3- (furan-2-yl) acryloyl] -7- (1-isopropyl-4-methyl-1H-pyrazol-3-ylmethoxy) -6- (1H-tetrazol-5-yl) -1,2,3,4-Tetrahydroisoquinoline
  • the title compound was synthesized according to Example 80 using the compound of Reference Example 4 and the compound of Reference Example 12.
  • Example 94 2-[(E) -3- (furan-2-yl) acryloyl] -7- [1- (3-methylbutyl) -4-methyl-1H-pyrazol-3-ylmethoxy] -6- (1H-tetrazole- 5-yl) -1,2,3,4-tetrahydroisoquinoline IR ⁇ (ATR) cm ⁇ 1 ; 1649, 1608.
  • the title compound was synthesized according to Example 1 using the compound of Reference Example 5.
  • Example 97 The compound of Example 97 was synthesized according to Example 1.
  • Example 98 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6-carvone Acid tert-butylamine salt (1) 3.7 g of the compound of Reference Example 10 was suspended in 37 mL of N, N′-dimethylformamide, 2.36 g of the compound of Reference Example 1 and 2.56 g of potassium carbonate were added, and the mixture was stirred at room temperature for 14 hours. did.
  • reaction solution was added with 100 mL of water, extracted with 80 mL of ethyl acetate, washed with saturated brine, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography. 5.4 g of tert-butoxycarbonyl-7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester was obtained.
  • Example 99 2-[(2E, 4E) -Hexa-2,4-dienoyl] -7- [5-methyl-2- (2-methylindan-2-yl) oxazol-4-ylmethoxy] -1,2,3 4-tetrahydroisoquinoline-6-carboxylic acid 2-[(2E, 4E) -hexa-2,4-dienoyl] -7- [5-methyl-2 synthesized according to Example 98 (1)-(3) Dissolve 0.43 g of-(2-methylindan-2-yl) oxazol-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester in 3 mL of methanol and 7 mL of tetrahydrofuran; 2.4 mL of 0 M lithium hydroxide aqueous solution was added, and the mixture was stirred at 40 ° C.
  • Example 100 7- (2-tert-Butyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4-tetrahydroisoquinoline-6 Carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1647,1614.
  • Example 103 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (1-methylcyclopent-3-enyl) oxazol-4-ylmethoxy] -1,2, 3,4-tetrahydroisoquinoline-6-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1645, 1608.
  • Example 104 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (1,3,4-trimethylcyclopent-3-enyl) oxazol-4-ylmethoxy]- 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1651,1610.
  • Example 105 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (indan-2-yl) -5-methyloxazol-4-ylmethoxy] -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid IR ⁇ (ATR) cm ⁇ 1 ; 1647,1604.
  • Example 106 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (2-methylindan-2-yl) oxazol-4-ylmethoxy] -1,2,3 , 4-Tetrahydroisoquinoline-6-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1647,1610.
  • Example 107 2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -4-methyl-1-pentenyl] oxazol-4-ylmethoxy ⁇ -1, 2,3,4-tetrahydroisoquinoline-6-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1647,1610.
  • Example 108 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyridin-4-yl) oxazol-4-ylmethoxy] -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid IR ⁇ (ATR) cm ⁇ 1 ; 1647, 1614.
  • Example 109 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyridin-3-yl) oxazol-4-ylmethoxy) -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid IR ⁇ (ATR) cm ⁇ 1 ; 1647, 1608.
  • Example 110 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyrrolidin-1-yl) oxazol-4-ylmethoxy] -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1647,1614. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.23 (9H, s), 1.89-1.97 (4H, m), 2.20 (3H, s), 2.30-3.
  • Example 111 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyrrol-1-yl) oxazol-4-ylmethoxy] -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid IR ⁇ (ATR) cm ⁇ 1 ; 1647, 1618. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.41 (3H, s), 2.84-3.01 (2H, br), 3.84-3.97 (2H, br), 4.
  • Example 116 7- (4-Dimethylaminophenyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4-tetrahydroisoquinoline-6 Carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1639, 1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.40 (3H, s), 2.80-2.98 (2H, br), 3.02 (6H, s), 3.78-3.
  • Example 118 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (imidazol-1-yl) -5-methyloxazol-4-ylmethoxy] -1,2,3,4 Tetrahydroisoquinoline-6-carboxylic acid hydrochloride 2-[(E) -3- (furan-2-yl) acryloyl] -7- [2- (imidazole) synthesized according to Example 98 (1)-(3) 1-yl) -5-methyloxazol-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (206 mg) was dissolved in 5 mL of methanol-tetrahydrofuran (1: 3).
  • Example 119 3- ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline- 6-yl ⁇ -4H- [1,2,4] oxadiazol-5-one (1) 505 mg of hydroxyammonium chloride was suspended in 10 mL of dimethyl sulfoxide, 2.13 mL of triethylamine was added, and the mixture was stirred at room temperature for 15 minutes. Insoluble matters were filtered off, and 500 mg of the compound obtained in (2) of Example 2 was added to the filtrate, followed by stirring at 120 ° C. for 3 hours.
  • the obtained powder was suspended in 10 mL of dichloromethane, 0.065 mL of triethylamine, 78 mg of (E) -3-furan-2-ylacrylic acid, and 135 mg of N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride And stirred at room temperature for 15 hours.
  • the reaction solution was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue and collected by filtration to obtain 109 mg of the title compound.
  • Example 120 3- ⁇ 7- (2-Cyclopropyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4-tetrahydroisoquinoline -6-yl ⁇ -4H- [1,2,4] oxadiazol-5-one
  • Example 122 3- ⁇ 7- [2- (1-Methylcyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -1 , 2,3,4-tetrahydroisoquinolin-6-yl ⁇ -4H- [1,2,4] oxadiazol-5-one
  • Example 124 (E) -3-furan-2-yl-1- [7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -6- (5-thioxo-4,5-dihydro- [1,2, 4] oxadiazol-3-yl) -1,2,3,4-tetrahydroisoquinolin-2-yl] propenone (1) 505 mg of hydroxyammonium chloride is suspended in 10 mL of dimethyl sulfoxide, and 2.13 mL of triethylamine is added to room temperature. For 15 minutes. Insoluble matters were filtered off, and 500 mg of the compound obtained in (2) of Example 2 was added to the filtrate, followed by stirring at 120 ° C. for 3 hours.
  • the obtained powder was suspended in 10 mL of dichloromethane, and 0.059 mL of triethylamine, 70 mg of (E) -3-furan-2-ylacrylic acid and 121 mg of N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride were added. The mixture was further stirred at room temperature for 15 hours. The reaction solution was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. A mixture of ethyl acetate and diisopropyl ether 1: 1 was added to the obtained residue and collected by filtration to obtain 186 mg of the title compound.
  • Example 125 The compounds of Examples 125 and 126 were synthesized according to Example 124.
  • Example 126 1- [7- (2,5-Dimethyloxazol-4-ylmethoxy) -6- (5-thioxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) -1,2 , 3,4-tetrahydroisoquinolin-2-yl]-(E) -3-furan-2-ylpropenone IR ⁇ (ATR) cm ⁇ 1 ; 1651, 1604. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 2.33 (3H, s), 2.70 (3H, s), 2.86-3.00 (2H, m), 3.86-3.
  • Example 127 6-cyano-7-[(2-cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -1,2, 3,4-Tetrahydroisoquinoline
  • the title compound was synthesized according to (5) and (6) of Example 1 using the compound of (2) of Example 3.
  • Example 128 6-carbamoyl-7-[(2-cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -1,2, 3,4-Tetrahydroisoquinoline
  • the title compound was synthesized according to (5) and (6) of Example 1 using the compound of (3) of Example 3.
  • 1.61 g of the compound of (9) of Reference Example 10 was dissolved in 15 mL of tetrahydrofuran, and 154 mg of lithium aluminum hydride was added under ice cooling, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution, the insoluble material was filtered off, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 131 7- [2- (Cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -6-dimethylamino-1,2 , 3,4-Tetrahydroisoquinoline hydrochloride (1) Using the compounds of Reference Example 2 and Reference Example 15, the following compounds were synthesized.
  • Example 132 The compounds of Examples 132 and 133 were synthesized according to Example 131.
  • Example 135 7- (2,5-Dimethyloxazol-4-ylmethoxy) -2-[(2E, 4E) -hexa-2,4-dienoyl] -1,2,3,4-tetrahydroisoquinoline (1)
  • Reference Example 14 1.60 g of the compound was dissolved in 40 mL of toluene, 871 mg of 4-chloromethyl-2,5-dimethyloxazole, 2.26 g of potassium carbonate and 800 mg of tetraethylammonium fluoride were added, and the mixture was stirred at 70-80 ° C. for 1 hour and 20 minutes.
  • Example 136 ⁇ [2- (2E, 4E) -Hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinolin-6-yl ⁇ Aminoacetic acid tert-butylamine salt (1) 6-amino-7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2 synthesized according to Example 135 (1) to (2) , 3,4-Tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (430 mg) is dissolved in 4.3 mL of N, N′-dimethylformamide. did.
  • Example 138 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (1-methylcyclopent-3-enyl) oxazol-4-ylmethoxy] -1,2, 3,4-Tetrahydroisoquinoline-6-sulfonamide (1) 12.1 g of the compound obtained in (4) of Reference Example 10 was dissolved in 150 mL of N, N′-dimethylformamide, and 6.15 mL of methyl iodide, 20.5 g of potassium was added and stirred for 16 hours. Diethyl ether was added to the reaction mixture, washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 139 N-acetyl-2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (1-methylcyclopent-3-enyl) oxazol-4-ylmethoxy]- 1,2,3,4-Tetrahydroisoquinoline-6-sulfonamide 50 mg of the compound of Example 138 is dissolved in 3 mL of dichloromethane, and 0.080 mL of triethylamine, 1 fragment of 4-dimethylaminopyridine and 0.027 mL of acetic anhydride are added, and For 2 hours. Water was added to the reaction solution and stirred for 30 minutes.
  • Example 140 5- ⁇ 7- (2-Cyclopropyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4-tetrahydroisoquinoline -6-yl ⁇ -imidazolidine-2,4-dione
  • Example 141 7- (2-Cyclopropyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (4H- [1,2,4] triazole -3-yl) -1,2,3,4-tetrahydroisoquinoline (1) 7- (2-cyclopropyl-5-methyloxazol-4-ylmethoxy) -6-carbamoyl-1,2,3,4-tetrahydro 500 mg of isoquinoline-2-carboxylic acid tert-butyl ester was dissolved in 3 mL of N, N′-dimethylformamide dimethyl acetal and stirred at 120 ° C.
  • reaction solution was evaporated under reduced pressure, and 5 mL of acetic acid and 0.068 mL of hydrazine hydrate were added to the resulting residue, followed by stirring at 90 ° C. for 5 hours.
  • the reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The extract was washed with water, 5% aqueous citric acid solution and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 142 2-[(E) -3- (furan-2-yl) acryloyl] -6- (1H-imidazol-2-yl) -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1, 2,3,4-Tetrahydroisoquinoline (1) 740 mg of the compound of Example 98 (1) was dissolved in 15 mL of tetrahydrofuran, 62 mg of lithium aluminum hydride was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, the insoluble material was filtered off, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in dichloromethane, 0.57 mL of diisopropylethylamine, 0.46 mL of dimethyl sulfoxide and 519 mg of sulfur trioxide pyridine salt were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography, and 6-formyl-7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert -720 mg of butyl ester were obtained.
  • Example 143 The compounds of Examples 143 and 144 were synthesized according to Example 142.
  • Example 145 7- (2-Cyclopropyl-5-methyloxazol-4-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -6- (3H- [1,2,4] triazole -4-yl) -1,2,3,4-tetrahydroisoquinoline (1) 7- (2-cyclopropyl-5-methyloxazol-4-ylmethoxy) -6- synthesized according to Example 142 (1) Nitromethane (5 mL) and ammonium acetate (151 mg) were added to formyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (540 mg), and ultrasonic waves were applied for 1 hour and 20 minutes.
  • the reaction mixture was diluted with ethyl acetate, washed with 5% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by column chromatography, and 7- (2-cyclopropyl-5-methyloxazol-4-ylmethoxy) -6- (2-nitrovinyl) -1,2,3,4-tetrahydroisoquinoline- 418 mg of 2-carboxylic acid tert-butyl ester was obtained.
  • Example 147 The compound of Example 147 was synthesized according to Example 146.
  • Example 148 3- ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline- 6-yl ⁇ propionic acid (1) 100 mg of the compound of Example 146 (1) was dissolved in 10 mL of methanol, added to 10 mg of 10% Pd—C, and contact hydrogenated at 0.4 MPa at room temperature for 4 hours.
  • Example 149 The compounds of Examples 149 and 150 were synthesized according to Example 148.
  • Example 149 3- ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (pyrrolidin-1-yl) oxazol-4-ylmethoxy] -1,2,3 , 4-Tetrahydroisoquinolin-6-yl ⁇ propionic acid IR ⁇ (ATR) cm ⁇ 1 ; 1647,1610. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.93-2.02 (4H, m), 2.28 (3H, s), 2.58-2.70 (2H, m), 2.
  • Example 150 3- ⁇ 7- (1-Cyclopentyl-4-methyl-1H-pyrazol-3-ylmethoxy) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4 Tetrahydroisoquinolin-6-yl ⁇ propionic acid IR ⁇ (ATR) cm ⁇ 1 ; 1718, 1647. 1 H-NMR (CDCl 3 ) ⁇ (ppm); 1.65-1.75 (2H, m), 1.79-2.01 (4H, m), 2.09 (3H, s), 2.
  • Example 151 ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- (5-methyl-2-trifluoromethyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline- 6-Carbonyl ⁇ methanesulfonamide 2-[(E) -3-furan-2-ylacryloyl] -7- (5-methyl-2-trifluoromethyloxazol-4-ylmethoxy) synthesized according to Example 98 -1,2,3,4-Tetrahydroisoquinoline-6-carboxylic acid (140 mg) was dissolved in N, N'-dimethylformamide (1.4 mL), 1,1'-carbonyldiimidazole (99.5 mg) was added, and the mixture was stirred at room temperature for 1 hour Stir.
  • Example 152 ⁇ 2-[(2E, 4E) -Hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6-carbonyl ⁇ Methanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1682,1601.
  • Example 153 (2-[(2E, 4E) -hexa-2,4-dienoyl] -7- ⁇ 5-methyl-2-[(E) -5-methylhex-1-enyl] oxazol-4-ylmethoxy ⁇ -1, 2,3,4-tetrahydroisoquinoline-6-carbonyl) methanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1682,1651,1616.
  • Example 154 (2-[(E) -3- (furan-2-yl) acryloyl] -7- ⁇ 5-methyl-2-[(E) -4-methyl-1-pentenyl] oxazol-4-ylmethoxy ⁇ -1 , 2,3,4-tetrahydroisoquinoline-6-carbonyl) methanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1680, 1649, 1612.
  • Example 156 ⁇ 7-[(4-Dimethylaminophenyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4-tetrahydro Isoquinoline-6-carbonyl ⁇ methanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1687,1647,1610.
  • Example 157 ⁇ 7-[(2,5-Dimethylphenyl) -5-methyloxazol-4-ylmethoxy] -2-[(E) -3- (furan-2-yl) acryloyl] -1,2,3,4 Tetrahydroisoquinoline-6-carbonyl ⁇ methanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1682, 1647, 1610.
  • Example 158 ⁇ 2-[(2E, 4E) -Hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6-carbonyl ⁇ Pentanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1682, 1653, 1616.
  • Example 161 ⁇ 2-[(E) -But-2-enoyl] -7- [2- (cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-6 -Carbonyl ⁇ benzenesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1614, 1427.
  • Example 162 ⁇ 2-[(E) -But-2-enoyl] -7- [2- (cyclopent-3-enyl) -5-methyloxazol-4-ylmethoxy] -1,2,3,4-tetrahydroisoquinoline-6 -Carbonyl ⁇ pentanesulfonamide IR ⁇ (ATR) cm ⁇ 1 ; 1614, 1427.
  • Example 163 [(E) -3- ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3 4-Tetrahydroisoquinolin-6-yl ⁇ acryloyl] methanesulfonamide
  • the title compound was synthesized according to Example 151 using the compound of Example 146.
  • Example 164 7- (2-Cyclopropyl-5-methyloxazol-4-ylmethoxy) -6- (furan-2-yl) -2-[(E) -3- (furan-2-yl) acryloyl] -1,2 , 3,4-Tetrahydroisoquinoline (1)
  • Compound 7-benzyloxy-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester obtained in Reference Example 10 (9) was used to synthesize the following compounds according to (1) of Example 140.
  • Example 165 The compound of Example 165 was synthesized according to Example 164.
  • Example 166 5- ⁇ 2-[(2E, 4E) -hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6 -Il ⁇ furan-2-carboxylic acid (1)
  • the following compounds were synthesized according to Example 164 (1) to (4).
  • Example 167 5- ⁇ 2-[(2E, 4E) -hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6 -Yl ⁇ benzoic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1652, 1623.
  • Example 168 1- ⁇ 2-[(2E, 4E) -Hexa-2,4-dienoyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6 -Yl ⁇ piperidine-4-carboxylic acid tert-butylamine salt IR ⁇ (ATR) cm ⁇ 1 ; 1650, 1621.
  • Example 170 1- [6- (4-Hydroxypiperidin-1-yl) -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinolin-2-yl] -2 -(2E, 4E) -hexa-2,4-dien-1-one IR ⁇ (ATR) cm -1 ; 1650, 1621.
  • Example 171 ⁇ 2-[(E) -3- (furan-2-yl) acryloyl] -7- (2-isopropyl-5-methyloxazol-4-ylmethoxy) -1,2,3,4-tetrahydroisoquinoline-6- Yl ⁇ hydrogen phosphate ethyl ester IR ⁇ (ATR) cm ⁇ 1 ; 1644,1606.
  • Example 172 6-carbamoyl-7- [2- (cyclopent-3-enyl) -5-methyloxazol-4-ylmethylsulfanyl] -2-[(E) -3- (furan-2-yl) acryloyl] -1, 2,3,4-tetrahydroisoquinoline (1) 5.67 g of 7-hydroxy-2- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester After dissolving in 60 mL of 1,4-dioxane, 5.33 mL of triethylamine, 0.46 g of 4-dimethylaminopyridine and 4.62 g of N, N′-dimethylcarbamoyl chloride were added, and the mixture was stirred at 80 ° C.
  • Example 173 6-cyano-7- [2- (cyclopent-3-enyl) -5-methyloxazol-4-ylmethylsulfanyl] -2-[(E) -3- (furan-2-yl) acryloyl] -1, 2,3,4-Tetrahydroisoquinoline (1)
  • the following compound was synthesized according to (1) of Reference Example 12 using the compound obtained in Example 172 (7).
  • the following compounds were synthesized using the compound obtained in (4) of Example 172 and the compound of Reference Example 2.
  • Example 175 2-[(E) -3- (furan-2-yl) acryloyl] -7- [5-methyl-2- (3-pyrrolin-1-yl) oxazol-4-ylmethoxy] -6- (1H-tetrazole -5-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride 1.0 g of the compound of Example 80 is dissolved in 100 mL of chloroform, and 0.47 mL of an 8.6M hydrogen chloride 2-propanol solution is added to the solution at room temperature. And stirred for 10 minutes.

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Abstract

La présente invention concerne la découverte d'un nouveau composé hétérocyclique représenté par la formule générale (I) (les symboles étant tels que définis dans la description) ou son sel pharmaceutiquement acceptable, qui sert de composé efficace pour réduire le taux de glycémie, pour réduire le niveau de lipide dans le sang, et pour améliorer la résistance à l'insuline par une action agoniste partielle de PPARγ, une action de modulateur PPARγ ou une action antagoniste PPARγ. L'invention porte en outre sur un produit pharmaceutique contenant ledit composé en tant qu'agent thérapeutique et prophylactique extrêmement sûr pour le diabète, le syndrome métabolique et analogue, ledit agent ayant peu d'effets secondaires.
PCT/JP2011/070601 2010-09-10 2011-09-09 Composé hétérocyclique WO2012033195A1 (fr)

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CN110483433A (zh) * 2019-08-30 2019-11-22 厦门金达威维生素有限公司 4-甲基-5-乙氧基噁唑酸乙酯的合成方法
WO2020231808A1 (fr) 2019-05-10 2020-11-19 Deciphera Pharmaceuticals, Llc Hétéroarylaminopyrimidine amides inhibiteurs d'autophagie et leurs procédés d'utilisation
WO2020257180A1 (fr) 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Inhibiteurs de l'autophagie à base d'amide d'aminopyrimidine et leurs procédés d'utilisation
WO2022202864A1 (fr) 2021-03-24 2022-09-29 塩野義製薬株式会社 Composition pharmaceutique contenant un agoniste du récepteur glp-1 comportant un cycle fusionné

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WO2002096904A1 (fr) * 2001-05-29 2002-12-05 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques et utilisation medicale de ces derives
WO2005051945A1 (fr) * 2003-11-20 2005-06-09 Eli Lilly And Company Composes heterocycliques utilises comme modulateurs des recepteurs actives proliferateurs du peroxysome (ppar), utiles dans le traitement et/ou la prevention de troubles modules par un ppar

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WO2001040192A1 (fr) * 1999-12-03 2001-06-07 Kyoto Pharmaceutical Industries, Ltd. Nouveaux composes heterocycliques et sels de ces derniers, utilisations de ces composes en medecine
WO2002096880A1 (fr) * 2001-05-29 2002-12-05 Kyoto Pharmaceutical Industries, Ltd. Nouveau compose heterocyclique et son utilisation medicinale
WO2002096904A1 (fr) * 2001-05-29 2002-12-05 Kyoto Pharmaceutical Industries, Ltd. Nouveaux derives heterocycliques et utilisation medicale de ces derives
WO2005051945A1 (fr) * 2003-11-20 2005-06-09 Eli Lilly And Company Composes heterocycliques utilises comme modulateurs des recepteurs actives proliferateurs du peroxysome (ppar), utiles dans le traitement et/ou la prevention de troubles modules par un ppar

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020231808A1 (fr) 2019-05-10 2020-11-19 Deciphera Pharmaceuticals, Llc Hétéroarylaminopyrimidine amides inhibiteurs d'autophagie et leurs procédés d'utilisation
EP4295846A2 (fr) 2019-05-10 2023-12-27 Deciphera Pharmaceuticals, LLC Hétéroarylaminopyrimidine amides inhibiteurs d'autophagie et leurs procédés d'utilisation
WO2020257180A1 (fr) 2019-06-17 2020-12-24 Deciphera Pharmaceuticals, Llc Inhibiteurs de l'autophagie à base d'amide d'aminopyrimidine et leurs procédés d'utilisation
CN110483433A (zh) * 2019-08-30 2019-11-22 厦门金达威维生素有限公司 4-甲基-5-乙氧基噁唑酸乙酯的合成方法
WO2022202864A1 (fr) 2021-03-24 2022-09-29 塩野義製薬株式会社 Composition pharmaceutique contenant un agoniste du récepteur glp-1 comportant un cycle fusionné

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