WO2020013116A1 - Inhibiteur de ptp-1b et son utilisation - Google Patents

Inhibiteur de ptp-1b et son utilisation Download PDF

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Publication number
WO2020013116A1
WO2020013116A1 PCT/JP2019/026956 JP2019026956W WO2020013116A1 WO 2020013116 A1 WO2020013116 A1 WO 2020013116A1 JP 2019026956 W JP2019026956 W JP 2019026956W WO 2020013116 A1 WO2020013116 A1 WO 2020013116A1
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compound
tetrahydroisoquinoline
optionally substituted
group
mmol
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PCT/JP2019/026956
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English (en)
Japanese (ja)
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幸倫 庄子
滋充 武田
弘明 白波瀬
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京都薬品工業株式会社
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Publication of WO2020013116A1 publication Critical patent/WO2020013116A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a compound having a protein tyrosine phosphatase-1B (PTP-1B; Protein @ Tyrosine @ phosphatase-1B) inhibitory activity and exhibiting a blood glucose lowering effect, a blood lipid lowering effect and / or an insulin resistance improving effect, or a pharmaceutical thereof.
  • PTP-1B protein tyrosine phosphatase-1B
  • the present invention also relates to a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a therapeutic agent for diabetes, an agent for improving insulin resistance, an agent for improving glucose intolerance, a therapeutic agent for diabetic complications, an antiobesity agent, an antihyperglycemic agent comprising the above compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a symptomatic agent, a therapeutic agent for fatty liver, an anti-hyperlipidemic agent, an anti-atherosclerotic agent, and an agent for preventing or treating metabolic
  • Diabetes is a disease that causes various metabolic abnormalities characterized by chronic hyperglycemia, and various complications such as retinopathy, nephropathy, peripheral neuropathy, myocardial infarction based on arteriosclerosis, cerebral infarction, etc. cause.
  • Metabolic syndrome refers to a state in which visceral fat obesity is combined with two or more of hyperglycemia, hypertension, and hyperlipidemia, and has a high mortality due to coronary artery disease.
  • Type II diabetes insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Representative therapeutic agents for type II diabetes include insulin secretagogues (sulfonylurea compounds, sulfonamide compounds, phenylalanine derivatives, GLP-1 analogs, DPP-4 inhibitors, etc.), biguanide compounds, ⁇ -glucosidase inhibition Agents, Peroxisome Proliferator-activated Receptor ⁇ (PPAR ⁇ ) activator (thiazolidinedione derivative, etc.).
  • insulin secretagogues sulfonylurea compounds, sulfonamide compounds, phenylalanine derivatives, GLP-1 analogs, DPP-4 inhibitors, etc.
  • biguanide compounds ⁇ -glucosidase inhibition Agents
  • PPAR ⁇ activator thiazolidinedione derivative, etc.
  • biguanides and PPAR ⁇ activators increase insulin sensitivity and lower blood glucose without depending on insulin secretion.
  • biguanide compounds cause lactic acidosis, diarrhea, vomiting, etc.
  • PPAR ⁇ activators cause side effects such as liver damage, weight gain, fluid retention, hemodilution, edema, cardiac hypertrophy, and increased risk of fracture. Therefore, development of a more effective and safe therapeutic agent for insulin-sensitized diabetes is desired.
  • Insulin is a hormone involved in blood sugar regulation produced by pancreatic ⁇ cells.
  • tyrosine kinase phosphorylates tyrosine residues present in the intracellular domain of the insulin receptor .
  • tyrosine residues such as insulin receptor substrate (IRS) and APS (adapter protein protein containing PH and SH2 domain), which are substrates of the insulin receptor, are phosphorylated, and the PI3 kinase-Akt pathway is activated by activating the PI3 kinase-Akt pathway.
  • tyrosine phosphatase that negatively regulates intracellular signal transduction by insulin by dephosphorylating phosphorylated tyrosine, thereby suppressing the action of insulin. That is, phosphorylation of tyrosine in insulin signaling is regulated by the balance between tyrosine kinase and tyrosine phosphatase. Thus, inhibiting tyrosine phosphatase enhances insulin action.
  • Tyrosine phosphatase is also involved in the signaling of leptin, a peptide hormone secreted by adipocytes.
  • Leptin is a hormone that has a strong suppressive effect on food intake and enhances energy consumption, and is involved in suppressing obesity.
  • Leptin signal like insulin signal, phosphorylation of tyrosine residues in the intracellular domain of the leptin receptor is regulated by tyrosine kinase and tyrosine phosphatase. Therefore, by enhancing tyrosine phosphatase activity, dephosphorylation of phosphorylated tyrosine is enhanced, leading to leptin resistance (Non-Patent Document 1).
  • PTP-1B is considered to be a major phosphatase involved in insulin and leptin signaling.
  • PTP-1B gene expression is increased in high glucose culture, and its intracellular localization is changed, and tyrosine phosphorylation of insulin receptor and IRS-1 is reduced, and insulin resistance is induced (non-patented).
  • Non-patent Document 5 drugs that suppress and / or inhibit PTP-1B activation inhibit dephosphorylation by PTP-1B and enhance insulin and leptin signaling, thereby increasing insulin resistance and leptin resistance to diabetes. It is thought to improve obesity and the like. Since this PTP-1B inhibitor has an effect of normalizing and enhancing intracellular signal transduction, it can be a new type of diabetes therapeutic agent that avoids the problems of existing diabetes therapeutic agents.
  • Non-patent Documents 6 to 9 and Patent Documents 1 to 12 disclose a compound having a structure such as the compound of the present invention, and of course, does not disclose any description that suggests such a compound.
  • An object of the present invention is to have excellent PTP-1B inhibitory activity and good oral absorbability, and further, have a blood glucose lowering effect, a blood lipid lowering effect and / or an insulin resistance improving effect, and have few side effects and safety. To provide a high therapeutic agent for diabetes.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a compound having a novel structure represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, is represented by PTP-1B Having an inhibitory action, and exhibiting a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, and the like due to such an action, the present inventors have found that the compound is a very excellent compound as a medicament and completed the present invention.
  • PTP-1B Having an inhibitory action, and exhibiting a blood glucose lowering action, a blood lipid lowering action, an insulin resistance improving action, and the like due to such an action
  • R represents a halogen atom or a C 1-6 alkyl group
  • R 1 is an optionally substituted C 1-15 alkyl group, an optionally substituted C 2-15 alkenyl group, an optionally substituted aryl group, an optionally substituted aryl C 1-6 alkyl group, an optionally substituted aryl C 2-6 alkenyl group, an optionally substituted heteroaryl C 1-6 alkyl group or an optionally substituted heteroaryl C 2-6 alkenyl group
  • R 2 is optionally substituted C 2-6 alkenyl group, an optionally substituted aryl C 2-6 alkenyl group or an optionally substituted heteroaryl C 2-6 alkenyl group
  • R 1 is optionally substituted C 7-15 alkyl group, an optionally substituted C 7-15 alkenyl group, optionally substituted aryl C 2-6 alkenyl group or substituted, A compound or a pharmaceutically acceptable salt thereof according to the above [1], wherein the compound is a heteroaryl C 2-6 alkenyl group, and A is —O—;
  • R 1 is tridecyl, nonyl, 7-methyloctyl, 9-methyldec-2,4-dienyl, optionally substituted 5-phenyl-penta-2,4-dienyl, or 5- (thiophene- 3-yl) penta-2,4-dienyl, the compound of the above-mentioned [1], or a pharmaceutically acceptable salt thereof, [5] The above-mentioned [1], wherein R 2 is penta-1,3-dienyl, styryl, (furan-2-yl) vinyl
  • a pharmaceutical composition comprising the compound according to any one of the above [1] to [7] or a pharmaceutically acceptable salt thereof as an active ingredient, [9] a PTP-1B inhibitor comprising, as an active ingredient, the compound according to any of the above [1] to [7] or a pharmaceutically acceptable salt thereof; [10] a medicament comprising the PTP-1B inhibitor according to the above [9] as an active ingredient; [11] The pharmaceutical composition according to the above [8], for preventing or treating a disease selected from the group consisting of diabetes, hyperglycemia, a disease caused by insulin resistance, a diabetic complication, and impaired glucose tolerance. And [12] the pharmaceutical composition of the above-mentioned [8], for preventing or treating a disease selected from the group consisting of arteriosclerosis, hyperlipidemia, obesity, and metabolic syndrome; About.
  • the compound of the present invention represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and a medicament containing the compound of the present invention as an active ingredient have a PTP-1B inhibitory effect, they have a hypoglycemic effect, Shows a blood lipid lowering effect and / or an insulin resistance improving effect, and is an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance improving agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, and an agent for improving glucose intolerance , An anti-atherosclerotic agent, an anti-obesity agent, and a prophylactic / therapeutic agent for metabolic syndrome.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • alkyl means a linear or branched monovalent saturated hydrocarbon group.
  • C 1-6 alkyl means a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 4-methylpentyl, hexyl and the like.
  • C 1-15 alkyl means a linear or branched monovalent saturated hydrocarbon group having 1 to 15 carbon atoms.
  • the “C 1-15 alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1,1-dimethylpentyl, isopentyl, neopentyl, 4-methylpentyl Hexyl, heptyl, octyl, nonyl, 1,1-dimethylnonyl, decyl, undecyl, 1,1-dimethylundecyl, dodecyl, tridecyl, 1,1-dimethyltridecyl and the like.
  • C 7-15 alkyl means a linear or branched monovalent saturated hydrocarbon group having 7 to 15 carbon atoms.
  • the “C 7-15 alkyl” includes, for example, heptyl, octyl, nonyl, 1,1-dimethylnonyl, decyl, undecyl, 1,1-dimethylundecyl, dodecyl, tridecyl, 1,1-dimethyltridecyl and the like. Is mentioned.
  • haloalkyl means a group in which one or more hydrogen atoms in the “alkyl” group have been substituted with halogen. Specifically, for example, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, , 2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl And the like.
  • C 1-6 alkoxy means a group in which the above “C 1-6 alkyl” group is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • C 2-6 alkenyl refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon double bond and having 2 to 6 carbon atoms. means.
  • the “C 2-6 alkenyl” includes, for example, vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, -Buten-2-yl, 3-methyl-2-butenyl, 3-methyl-2-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 2-pentene -2-yl, 2-penten-3-yl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl and the like.
  • C 2-15 alkenyl refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon double bond and having 2 to 15 carbon atoms. means.
  • the “C 2-15 alkenyl” includes, for example, vinyl, 1-propenyl (allyl), 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, -Buten-2-yl, 3-methyl-2-butenyl, 3-methyl-2-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 2-pentene -2-yl, 2-penten-3-yl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 5-methyl-1-hexenyl, butadienyl (eg, -Dien-1-yl), penta
  • C 7-15 alkenyl refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 7 to 15 carbon atoms. means.
  • C 7-15 alkenyl for example, 5-methyl-1-hexenyl, heptatrienyl (eg, hepta-1,3,5-trien-1-yl) and the like can be mentioned.
  • aryl means a monovalent aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • examples of the “aryl” include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), indenyl, fluorenyl, acenaphthenyl, azulenyl, anthryl, phenanthryl and the like.
  • aryl C 1-6 alkyl means a monovalent group in which the “aryl” group is bonded to the “C 1-6 alkyl” group.
  • Examples of the “aryl C 1-6 alkyl” include benzyl, 2-phenylethyl, 2-naphthylethyl, 4-phenylbutyl and the like.
  • aryl C 2-6 alkenyl means a monovalent group in which the "aryl” group is bonded to the “C 2-6 alkenyl” group.
  • arylalkenyl include phenylvinyl (styryl), naphthylvinyl, phenylbutadienyl (eg, 4-phenylbut-1,3-dien-1-yl) and the like.
  • heteroaryl refers to a monovalent monocyclic aromatic heterocycle and a fused aromatic heterocycle containing at least one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • monocyclic aromatic heterocyclic ring include a 5- or 6-membered monocyclic aromatic heterocyclic ring. Specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and triazolyl.
  • condensed aromatic heterocycle examples include bicyclic or tricyclic condensed aromatic heterocycles. Specific examples include indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, and benzooxazolyl.
  • Benzothiazolyl quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, furo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, quinolyl, Carbazolyl, dibenzothiophenyl and the like.
  • heteroaryl C 1-6 alkyl means a monovalent group in which the “heteroaryl” group is bound to the “C 1-6 alkyl” group.
  • the “heteroaryl C 1-6 alkyl” includes, for example, furylmethyl, thienylmethyl, imidazolylmethyl, pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidinyl Methyl, furylethyl, thienylethyl, imidazolylethyl, pyrazolylethyl, oxazolylethyl, isoxazolylethyl, thiazolylethyl, pyridylethyl, pyridazinylethyl, pyrimidinylethyl and the like.
  • heteroaryl C 2-6 alkenyl means a monovalent group in which the above “heteroaryl” group is bonded to the above “C 2-6 alkenyl” group.
  • the “heteroarylalkenyl” includes, for example, furylvinyl, furylbutadienyl (eg, 4- (2-furyl) but-1,3-dien-1-yl) and the like.
  • R 1 , R 2 or R 4 means unsubstituted or 1 to 3 substituted.
  • each substituent may be the same or different.
  • the substituent include a halogen atom, hydroxy, amino, carboxy, cyano, nitro, alkyl (eg, C 1-6 alkyl), haloalkyl (eg, halo C 1-6 alkyl), hydroxyalkyl (eg, hydroxy C 1 -6 alkyl), alkoxy (eg, C 1-6 alkoxy), alkenyl (eg, C 2-6 alkenyl), alkenyloxy (eg, C 2-6 alkenyloxy), methylenedioxy, ethylenedioxy, aryl ( For example, phenyl and the like).
  • the “pharmaceutically acceptable salt” refers to a salt that can be used as a medicament.
  • the compound of the present invention When the compound of the present invention has an acidic group or a basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or an acid.
  • the pharmaceutically acceptable “basic salt” of compound (I) of the present invention is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth salt such as a magnesium salt or a calcium salt.
  • Metal salts organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or It is an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate and an aspartate, and is preferably an alkali metal salt.
  • organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or It is an amino acid salt such as a glycine salt, a lysine salt, an argin
  • the pharmaceutically acceptable “acid salt” of compound (I) of the present invention is preferably a hydrogen halide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide
  • Inorganic salts such as acid salts, nitrates, perchlorates, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, and benzenesulfonate
  • Arylsulfonate such as p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.
  • An organic acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, or an aspartate, and most preferably a hydrohalide (particularly hydrochloride).
  • prevention refers to, for example, a patient who has not developed the disease or symptom that is expected to have a high risk of developing due to some factor related to the disease or symptom, or is aware that the patient has developed the disease or symptom.
  • Treatment is the cure of a disease or condition.
  • R represents a halogen atom or a C 1-6 alkyl group.
  • R is preferably a halogen atom (eg, a fluorine atom) or a methyl group.
  • n represents an integer of 0 to 3. n is preferably 0 or 1, and more preferably 0.
  • R 1 is an optionally substituted C 1-15 alkyl group, an optionally substituted C 2-15 alkenyl group, an optionally substituted aryl group, an optionally substituted aryl C 1-6 alkyl group, an optionally substituted aryl C 2-6 alkenyl group, an optionally substituted heteroaryl C 1-6 alkyl group or an optionally substituted heteroaryl C 2-6 alkenyl groups.
  • R 1 is more preferably tridecyl, nonyl, 7-methyloctyl, 9-methyldec-2,4-dienyl, optionally substituted 5-phenyl-penta-2,4-dienyl, or 5- (thiophene -3-yl) penta-2,4-dienyl, particularly preferably tridecyl, nonyl, 7-methyloctyl, 9-methyldec-2,4-dienyl, or optionally substituted 5-phenyl-pentane -2,4-dienyl.
  • Examples of the “optionally substituted” substituent in R 1 include the groups described above, and preferably, a halogen atom, hydroxy, cyano, alkyl (eg, C 1-6 alkyl), haloalkyl (eg, haloalkyl) C 1-6 alkyl), hydroxyalkyl (eg, hydroxy C 1-6 alkyl), alkoxy (eg, C 1-6 alkoxy), alkenyl (eg, C 2-6 alkenyl), alkenyloxy (eg, C 2- 6 alkenyloxy), methylenedioxy or ethylenedioxy, more preferably a halogen atom (eg, fluorine atom), hydroxy, alkyl (eg, methyl, ethyl), haloalkyl (eg, trifluoromethyl), hydroxyalkyl (Eg, hydroxymethyl, hydroxyethyl), methylenedioxy or ethylenedioxy You.
  • a halogen atom e
  • R 2 represents an optionally substituted C 2-6 alkenyl group, an optionally substituted aryl C 2-6 alkenyl group or an optionally substituted heteroaryl C 2-6 alkenyl groups.
  • R 2 is preferably a C 2-6 alkenyl group, an optionally substituted phenyl C 2-6 alkenyl group, or a heteroaryl C 2-6 alkenyl group, more preferably penta-1,3- Dienyl, styryl, (furan-2-yl) vinyl, (thiophen-2-yl) vinyl or (thiazol-2-yl) vinyl, particularly preferably penta-1,3-dienyl, styryl, (furan -2-yl) vinyl or (thiophen-2-yl) vinyl.
  • Examples of the “optionally substituted” substituent in R 2 include the groups described above, and preferably, a halogen atom, cyano, alkyl (eg, C 1-6 alkyl), haloalkyl (eg, halo C 1) -6 alkyl), alkoxy (eg, C 1-6 alkoxy), methylenedioxy or ethylenedioxy, more preferably a halogen atom (eg, fluorine atom), haloalkyl (eg, trifluoromethyl), methylenedioxy. Oxy or ethylenedioxy.
  • R 3 represents hydroxy or —NHSO 2 R 4 (in the formula, R 4 represents a C 1-6 alkyl group which may be substituted).
  • R 3 is preferably hydroxy or —NHSO 2 CH 3 .
  • Examples of the “optionally substituted” substituent in R 4 include the groups described above, and are preferably a halogen atom (eg, a fluorine atom).
  • R 4 represents an optionally substituted C 1-6 alkyl group.
  • R 4 is preferably methyl.
  • A is preferably -O- or * -CONH-.
  • the 3-position carbon atom in the general formula (I) is an asymmetric carbon.
  • the stereochemistry (absolute configuration) of the carbon atom at the 3-position may be any of the R configuration, the S configuration, or a mixture thereof (eg, a racemic form), but is preferably the S configuration.
  • Suitable compounds (I) include the following compounds.
  • R is a halogen atom (eg, a fluorine atom) or a methyl group
  • n is 0 or 1
  • R 1 is an optionally substituted C 7-15 alkyl group
  • R 2 is a C 2-6 alkenyl group, an optionally substituted phenyl C 2-6 alken
  • R is a halogen atom (eg, a fluorine atom) or a methyl group; n is 0 or 1; R 1 is optionally substituted C 7-15 alkyl group, an optionally substituted C 7-15 alkenyl group, optionally substituted aryl C 2-6 alkenyl group, or optionally substituted A good heteroaryl C 2-6 alkenyl group; R 2 is a C 2-6 alkenyl group, an optionally substituted phenyl C 2-6 alkenyl group, or a heteroaryl C 2-6 alkenyl group; A is —O—; and R 3 is hydroxy or —NHSO 2 CH 3 ; Compound (I).
  • R 1 is optionally substituted C 7-15 alkyl group, an optionally substituted C 7-15 alkenyl group, optionally substituted aryl C 2-6 alkenyl group, or optionally substituted A good heteroaryl C 2-6 alkenyl group
  • R 2 is a C 2-6 alkenyl
  • n is 0;
  • R 1 is tridecyl, nonyl, 7-methyloctyl, 9-methyldec-2,4-dienyl, optionally substituted 5-phenyl-penta-2,4-dienyl or 5- (thiophen-3-yl ) Penta-2,4-dienyl;
  • R 2 is penta-1,3-dienyl, styryl, (furan-2-yl) vinyl, (thiophen-2-yl) vinyl, or (thiazol-2-yl) vinyl;
  • A is -O- or * -CONH-; and
  • R 3 is hydroxy or -NHSO 2 CH 3 ;
  • Compound (I) Compound (I).
  • n is 0;
  • R 1 is tridecyl, nonyl, 7-methyloctyl, 9-methyldec-2,4-dienyl, or optionally substituted 5-phenyl-penta-2,4-dienyl;
  • R 2 is penta-1,3-dienyl, styryl, (furan-2-yl) vinyl, or (thiophen-2-yl) vinyl;
  • A is -O- or * -CONH-; and
  • R 3 is hydroxy or -NHSO 2 CH 3 ;
  • Preferred specific examples of the compound (I) include, for example, the compounds of Examples 1 to 29 (hereinafter, also referred to as compounds 1 to 29) described in Tables 1-1 to 1-5 below.
  • the compound (I) of the present invention can be produced by applying various known production methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • Known methods include, for example, methods described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989.
  • it is effective in production technology to protect the functional group with an appropriate protecting group at the stage of a raw material or an intermediate, or to replace the functional group with a group that can be easily converted to the functional group. It may be.
  • Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like.
  • Examples of such a protecting group include TWGreene and PG Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”. And the protecting group described in ", and may be appropriately selected and used according to the reaction conditions. According to such a method, a desired compound can be obtained by introducing the substituent and performing a reaction, and then removing a protecting group or converting it into a desired group as necessary.
  • the prodrug of the compound of the present invention can be produced by introducing a specific group at the stage of a raw material or an intermediate, or by performing a reaction using the obtained compound of the present invention, in the same manner as the above protective group. it can.
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
  • a method for producing the compound of the present invention will be described.
  • the manufacturing method is not limited to the following method at all.
  • a specific production method is not described, a raw material compound in each reaction can be easily obtained and used as a commercially available product, or can be produced according to a method known per se or a method analogous thereto. .
  • Production method A is a method for producing a novel tetrahydroisoquinoline compound (Ia) in which A in the general formula (I) is an oxygen atom and R 3 is hydroxy.
  • Compound (1) and compound (7) can be produced, for example, according to the method described in WO01 / 040192.
  • R 1 and R 2 are as defined above, R 5 is carboxy protected by a protecting group, PG is an amino protecting group, X is hydroxy, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, A leaving group such as iodine atom) or alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.) and arylsulfonyloxy (eg, phenylsulfonyloxy, tolylsulfonyloxy, etc.) Show. ]
  • Examples of the carboxy protecting group for R 5 and the amino protecting group for PG include the protecting groups described in “Protective Groups in Organic Synthesis (Third Edition, 1999)” by TWGreene and PG Wuts.
  • Step ⁇ A-1 This step is a step of producing compound (3) by reacting compound (1) with compound (2).
  • X of the compound (2) is a hydroxy group
  • the compound is subjected to a dehydration reaction as exemplified by the Mitsunobu reaction (“Reagents for Organic Synthesis” by Fisser & Fieser, Vol. 6, 645) and the like.
  • the reaction is usually performed by using an azo compound and a phosphine in the presence of a solvent.
  • azo compounds examples include di-C 1-4 alkyl azodicarboxylates (eg, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate), and azodicarboxamides (eg, 1,1′-azobis (N , N′-dimethylformamide, 1,1 ′-(azodicarbonyl) dipiperidine, etc.
  • phosphines include triarylphosphines (eg, triphenylphosphine, etc.) and tri-C 1-8 alkylphosphines (eg, triphenylphosphine).
  • tri-n-butylphosphine tri-n-hexylphosphine, tri-n-octylphosphine and the like are used, etc.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction. No, for example, dioxane, acetonitrile, tetrahydrofura , Chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide, and the like, and mixtures thereof.
  • the amount is not particularly limited and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (1), and the amount of the azo compound and the phosphine used is 1 mol of compound (1), respectively. Is usually 1 to 5 mol, preferably 1 to 3 mol.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents, reaction solvents and the like used, but are usually from -30 to 50 ° C and from 30 minutes to 20 hours.
  • X of compound (2) is a halogen atom, alkanesulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy (eg, phenylsulfonyloxy, tolylsulfonyloxy, etc.)
  • alkanesulfonyloxy eg, methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • arylsulfonyloxy eg, phenylsulfonyloxy, tolylsulfonyloxy, etc.
  • the base used in the reaction is not particularly limited, and includes an alkali metal carbonate (eg, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.), a metal hydride compound (eg, sodium hydride)
  • alkali metal carbonate eg, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, etc.
  • a metal hydride compound eg, sodium hydride
  • Organic bases such as alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, potassium tert-butoxide), and amines (eg, triethylamine, diisopropylethylamine, etc.). Bases.
  • the amount of the compound (2) to be used is not particularly limited and is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the compound (1). It is usually 1 to 5 mol, preferably 1 to 3 mol, per mol.
  • a catalyst can 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, etc. Or tris [2- (2-methoxyethoxy) ethyl] amine.
  • the catalyst to be used is generally 0.1 to 1 mol, preferably 0.1 to 0.5 mol, per 1 mol of compound (1).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents, reaction solvents and the like used, but are usually from -30 to 150 ° C and from 30 minutes to 20 hours.
  • Step ⁇ A-2 This step is a step of removing a PG (amino protecting group) of compound (3) according to a method known per se to obtain compound (4).
  • the amino protecting group can be removed according to, for example, the method described in "Protective Groups in Organic Synthesis” (Third Edition, 1999) by T.W. Greene and P.G.
  • Step ⁇ A-3 This step is a step of producing compound (6) by reacting compound (4) with compound (5).
  • the compound (5) is not only in the form of a free acid, but also in the form of a salt (eg, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.) or a reactive derivative (eg, acid chloride, acid bromide, etc.).
  • the reaction is preferably performed in the presence of a condensing agent.
  • a 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 reaction between compound (4) and compound (5) 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 and the like, and mixtures thereof.
  • bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and potassium carbonate can be used.
  • the base is used, it is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (4).
  • the amount of compound (5) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (4).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents, reaction solvents and the like used, but are usually from -30 to 150 ° C and from 30 minutes to 20 hours.
  • Step ⁇ A-4 This step is a step of producing compound (8) by reacting compound (7) with compound (5). This step can be performed according to Step # A-3.
  • Step ⁇ A-5 This step is a step of producing compound (6) by reacting compound (8) with compound (2). This step can be performed according to Step A-1.
  • Step A-6 This step is a step of obtaining a carboxy compound (Ia) by hydrolyzing the carboxy protecting group in R 5 of the compound (6) according to a method known per se.
  • the method for removing the carboxy protecting group (ester) can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TWGreene and PG Wuts.
  • R 1 , R 2 , R 5 and PG are as defined above.
  • Step ⁇ B-1 This step is a step of producing compound (11) by reacting compound (9) with compound (10). This step can be performed according to Step # A-3.
  • Step ⁇ B-2 This step is a step of removing a PG (amino protecting group) of compound (11) according to a method known per se to obtain compound (12).
  • the amino protecting group can be removed according to, for example, the method described in "Protective Groups in Organic Synthesis” (Third Edition, 1999) by T.W. Greene and P.G.
  • Step ⁇ B-3 This step is a step of producing compound (13) by reacting compound (12) with compound (5). This step can be performed according to Step # A-3.
  • Step B-4 This step is a step of obtaining a carboxy compound (Ib) by hydrolyzing the carboxy protecting group in R 5 of the compound (13) according to a method known per se.
  • the method for removing the carboxy protecting group (ester) can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TWGreene and PG Wuts.
  • Compound (14) and compound (16) can be produced by a method known per se.
  • Step ⁇ C-1 This step is a step of producing a compound (15) by subjecting the cyano group of the compound (14) to a reduction reaction.
  • This step is performed by using a reducing agent such as Raney nickel which selectively reduces a cyano group to an aldehyde.
  • a reducing agent such as Raney nickel which selectively reduces a cyano group to an aldehyde.
  • the solvent used in this step is not particularly limited as long as it does not inhibit the reaction.
  • dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, N, N′- Examples include dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide, and the like, and mixtures thereof.
  • reaction conditions such as reaction temperature and reaction time vary depending on the used reaction reagents, reaction solvents and the like, but are usually -30 to 100 ° C and 30 minutes to 20 hours.
  • Step ⁇ C-2 This step is a step of producing compound (17) by reacting compound (15) with compound (16).
  • the reaction between compound (15) and compound (16) 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 and the like, and mixtures thereof.
  • the amount of compound (16) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (15).
  • reaction conditions such as reaction temperature and reaction time vary depending on the used reaction reagents, reaction solvents and the like, but are usually -30 to 100 ° C and 30 minutes to 20 hours.
  • Step C-3 This step is a step of obtaining a carboxy compound (Ic) by hydrolyzing the carboxy protecting group in R 5 of the compound (17) according to a method known per se.
  • the method for removing the carboxy protecting group (ester) can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TWGreene and PG Wuts.
  • Production method D is a method for producing a novel tetrahydroisoquinoline compound (Id) in which R 3 in the general formula (I) is —NHSO 2 R 4 .
  • Compound (18) can be produced by a method known per se.
  • R 1 , R 2 and R 4 are as defined above.
  • Step ⁇ D-1 This step is a step of producing compound (Id) by reacting compound (I ') with compound (18).
  • This step is a method for producing a compound (Id) by subjecting a carboxy group of the compound (I ') to an amidation reaction.
  • This reaction can be carried out by a method known per se, for example, a method of directly condensing compound (I ′) with compound (18) or a method of reacting a reactive derivative of compound (I ′) with compound (18). It is performed using.
  • the method of directly condensing the compound (I ') and the compound (18) is performed in the presence of a condensing agent in a solvent that does not adversely influence the reaction.
  • a condensing agent examples include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N′-morpholinoethylcarbodiimide, N-cyclohexyl-N ′-( Carbodiimide compounds such as 4-diethylaminocyclohexyl) carbodiimide; azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole; condensing agents such as phosphorus compounds such as diethyl cyanophosphate and diphenylphosphoryl azide.
  • the amount of compound (18) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (I ′).
  • the amount of the condensing agent to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (I ').
  • a condensation accelerator for example, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc.
  • the reaction yield can be improved.
  • the reaction yield can be improved by adding an organic base such as triethylamine or N, N-diisopropylethylamine as needed.
  • azolide compound when used as a condensing agent, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] undec-7-ene, etc.
  • the organic base is preferably reacted in the presence of a base such as an alkali metal carbonate such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, and cesium carbonate.
  • the amount of the condensation accelerator, organic base and alkali metal carbonate to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (I ').
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but are usually from ⁇ 30 to 150 ° C. and from 30 minutes to 20 hours.
  • Production method D also includes a method of reacting a reactive derivative of compound (I ′) with compound (18) to produce compound (Id).
  • the reactive derivative of the compound (I ′) include acid halides such as acid chloride and acid bromide; acid anhydrides; substituted phosphoric acid such as dialkyl phosphoric acid, methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate.
  • acid halides such as acid chloride and acid bromide
  • substituted phosphoric acid such as dialkyl phosphoric acid, methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate.
  • Mixed acid anhydrides with chlorocarbonates active amides with imidazole and the like
  • esters such as cyanomethyl ester and 4-nitrophenyl ester.
  • the reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
  • the base used in the reaction is not particularly limited, and organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, and 4-dimethylaminopyridine; sodium carbonate, sodium hydrogencarbonate, potassium carbonate, hydrogencarbonate And alkali metal carbonates such as potassium and cesium carbonate.
  • the amount of compound (18) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (I ′).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but are usually from ⁇ 30 to 150 ° C. and from 30 minutes to 20 hours.
  • the compound (I ′) and the substituted phosphoric acid or chlorocarbonate are converted into a base (eg, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine). , N, N-dimethylaniline and the like; alkali metal carbonates such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate, etc.) to form a reactive derivative, and further react with the compound (18).
  • the amount of compound (18) to be used is generally 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (I ′).
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents, reaction solvents and the like used, but are usually from -30 to 150 ° C and from 30 minutes to 20 hours.
  • Compound (18) used in the present production method can be produced according to a method known per se.
  • the compound (I) of the present invention produced by the above method may be purified to any purity by subjecting it to conventional purification means, for example, concentration, extraction, chromatography, reprecipitation, recrystallization and the like. Can be. Further, if necessary, a pharmaceutically acceptable salt can be obtained by treating with an acid or a base in an appropriate solvent. Further, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is allowed to stand in the air, treated with water, a water-containing solvent or another solvent (eg, alcohol, etc.), or recrystallized. As a result, water (or solvent) may be absorbed and may become hydrate (or solvate) with adsorbed water (or adsorption solvent). Such various hydrates, solvates and polymorphic compounds are also included.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be a geometric isomer such as a cis-form or a trans-form, a tautomer or an optical isomer such as a d-form or an l-form depending on the type and combination of substituents.
  • a geometric isomer such as a cis-form or a trans-form
  • a tautomer or an optical isomer such as a d-form or an l-form depending on the type and combination of substituents.
  • the compound (I) of the present invention includes all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Is also included.
  • These optical isomers and a mixture of isomers can be isolated by a known resolving means (for example, see J.
  • the compound (I) of the present invention is a labeled compound, that is, one or more atoms constituting the compound (I) of the present invention are isotopes (for example, 2 H, 3 H, 13 C, 14 C, Compounds substituted with 35 S etc. are also included.
  • the present invention also includes pharmaceutically acceptable so-called prodrugs of compound (I) of the present invention.
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxy group, or the like of compound (I) of the present invention by hydrolysis or under physiological conditions. Examples of a group that forms such a prodrug include Prog. @Med., Vol. 5, pp. 2157-2161, 1985, and "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. It is the group described on the page.
  • a compound (I) of the present invention when a compound (I) of the present invention has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, the amino group Is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation Tert-butylated compound, etc.).
  • the amino group Is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation Tert-butylated compound, etc. the
  • the hydroxyl group is acylated, alkylated, phosphorylated, boronated, or the like.
  • Oxidized compounds eg, whose hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, Cycloalkenyl of a dimethylaminomethyl carbonylated compounds and the like.
  • the carboxy group is esterified or amidated (for example, the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified). Dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1-ethoxycarbonyloxyethyl esterification, 1-cyclohexyloxycarbonyloxyethyl esterification, amidation or methylamidation, etc.). No.
  • the compound (I) or a pharmaceutically acceptable salt thereof of the present invention has protein tyrosine phosphatase-1B (PTP-1B; Protein @ Tyrosine @ Phosphatasase-1B) inhibitory activity and can be used in mammals (human, horse, cow, dog, Cat, rat, mouse, hamster, etc.) have an excellent hypoglycemic effect, hypolipidemic effect, and insulin resistance improving effect, and are antihyperglycemic agents, antihyperlipidemic agents, and insulin sensitizers.
  • PTP-1B protein tyrosine phosphatase-1B
  • mammals human, horse, cow, dog, Cat, rat, mouse, hamster, etc.
  • have an excellent hypoglycemic effect, hypolipidemic effect, and insulin resistance improving effect and are antihyperglycemic agents, antihyperlipidemic agents, and insulin sensitizers.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof includes hyperglycemia, hyperlipidemia, diabetes, diabetic complications, diseases caused by insulin resistance, diseases caused by impaired glucose tolerance, It can be used as a prophylactic and therapeutic agent for arteriosclerosis, obesity and metabolic syndrome.
  • the compound (I) of the present invention may be used as it is or in combination with a pharmaceutically acceptable carrier, and may be orally or parenterally administered to a mammal (preferably a human) as a medicament (ie, a pharmaceutical composition). Can be administered.
  • the medicament of the present invention can be produced by a known production method generally used in the field of formulation technology (eg, a method described in the Japanese Pharmacopoeia).
  • the medicament of the present invention may contain, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, and coloring agents that are commonly used in the field of formulation.
  • Additives such as preservatives, fragrances, flavors, stabilizers, thickeners and the like can be appropriately contained in appropriate amounts.
  • the above-mentioned pharmaceutically acceptable carriers include these additives.
  • the dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and other factors. For example, for a patient with diabetes, diabetic complications or hyperlipidemia, For oral administration to an adult (body weight: about 60 kg), a dose of about 1 to 500 mg is given about 1 to 3 times a day.
  • the obtained powder was dissolved in 200 mL of hot ethyl acetate, and the filtrate was extracted with 200 mL of ethyl acetate. The ethyl acetate layers were combined, washed with saturated saline, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from diisopropyl ether and then isopropanol to give the title compound (4.22 g, yield: 41%) as a yellow powder.
  • Example 2 250 mg (0.647 mmol) of the compound produced in Example 1 (1d) was suspended in 5 mL of methylene chloride, 3 mL of N, N-dimethylformamide, 73 mg (0.65 mmol) of sorbic acid and 1-ethyl-3- ( 149 mg (0.777 mmol) of 3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate, and dried (Na 2 SO 4 ).
  • Methyl (S) -2-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate 500 mg (1.63 mmol) produced according to the method described in WO01 / 040192 After dissolving in 5 mL of N, N-dimethylformamide, 247 mg (1.79 mmol) of potassium carbonate and 402 mg (1.63 mmol) of 4-bromomethylbiphenyl were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and then dried (Na 2 SO 4 ).
  • Example 3 2.83 g (15.4 mmol) of the compound prepared in (3a) was dissolved in 150 mL of methylene chloride, and 46 mL (46 mmol) of a 1.0 M diisobutylaluminum hydride toluene solution was added dropwise at -10 ° C over 15 minutes. The mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, the insolubles were filtered off through celite, the two layers were separated, the aqueous layer was extracted with methylene chloride, the organic layer was dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. Was distilled off.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 3: 2 ⁇ 3: 7, V / V), and the solvent of the objective fraction was distilled under reduced pressure.
  • the title compound (2.71 g, yield: 90%) was obtained as a colorless oil.
  • the solvent of the target fraction was distilled off under reduced pressure, and the obtained residue was dissolved in 2.3 mL of 0.01 M KH 2 PO 4 water-acetonitrile-acetic acid (20: 80: 0.2), followed by HPLC [COSMOSIL (registered trademark) 5C18- AR-II Packed Column 20mm ID ⁇ 250mm, 0.01M KH 2 PO 4 water-acetonitrile-acetic acid (20: 80: 0.2) eluted at 20 mL / min].
  • the obtained solution was concentrated under reduced pressure, extracted with ethyl acetate, and the organic layer was washed successively with water and saturated saline.
  • the obtained residue was purified by column chromatography (chloroform: methanol, 99: 1, V / V), the solvent of the target fraction was distilled off under reduced pressure, and 0.01 M KH 2 PO 4 water-acetonitrile (20: 80) was added, and the precipitate was collected by filtration and washed with a solution of water-acetonitrile (1: 1) to obtain the title compound (29 mg, yield: 23%) as a pale yellow powder.
  • Example 8 150 mg (0.720 mmol) of the compound prepared in (8b) was dissolved in 8 mL of methylene chloride, and 2.2 mL (2.2 mmol) of a 1.0 M isobutylaluminum hydride in toluene solution was added dropwise at -10 ° C, and the solution was heated at the same temperature. For 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution, the insolubles were filtered off through celite, the two layers were separated, and the aqueous layer was extracted twice with chloroform.
  • the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by column chromatography (n-hexane: ethyl acetate, 9: 1 ⁇ 1: 1, V / V), and the solvent of the objective fraction is distilled under reduced pressure.
  • the obtained residue was purified again by column chromatography (n-hexane: ethyl acetate, 9: 1 ⁇ 7: 3, V / V) to obtain 100 mg of a pale yellow oil.
  • the obtained residue was purified by column chromatography (chloroform: methanol, 99: 1 ⁇ 95: 5, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • Tert-butyl methyl ether was added to the precipitated residue, and the insolubles were collected by filtration to give the title compound (6 mg, yield: 2.2%) as a pale-yellow powder.
  • N-hydroxyphthalimide 2.34 g (14.3 mmol) of N-hydroxyphthalimide was dissolved in 30 mL of N, N-dimethylformamide, and 572 mg (14 mmol) of sodium hydride (60% in oil) was added in portions under ice-cooling. And stirred for 20 minutes. A solution of the oil obtained above in 10 mL of N, N-dimethylformamide was added dropwise, and the mixture was stirred at 80 ° C. for 2 hours. After allowing the reaction solution to cool, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate.
  • Methyl (S) -2-tert-butoxycarbonyl-7-cyano-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (317 mg, 1.00 mmol) was suspended in formic acid (2 mL), and cooled under ice-cooling. 0.36 mL (3.0 mmol) of 8.3 M hydrogen chloride-isopropanol solution was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted twice with chloroform. The organic layer was dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 ⁇ 1: 1 ⁇ 1: 2, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • the compound (70 mg, yield: 26%) was obtained as a colorless oil.
  • Example 9d 70 mg (0.21 mmol) of the compound prepared in Example 9 (9d) and 27 mg (0.21 mmol) of the compound prepared in Example 9 (9b) were dissolved in 1 mL of ethanol, and the mixture was stirred at room temperature for 25 minutes. 27 mg (0.21 mmol) of the compound produced in Example 9 (9b) was added, and the mixture was stirred at 50 ° C for 15 minutes, and then heated under reflux for 30 minutes. After cooling, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate.
  • Example 7 120 mg (0.230 mmol) of the compound prepared in (7) was dissolved in 1 mL of N, N-dimethylformamide, and 57 mg (0.35 mmol) of 1,1-carbonyldiimidazole was added, and the mixture was added at room temperature for 30 minutes. Stirred. To the reaction solution were added methanesulfonamide (67 mg, 0.70 mmol) and diazabicycloundecene (0.11 mL, 0.71 mmol), and the mixture was stirred at room temperature for 1 hour. Water and 2 mL of 1.0 M hydrochloric acid were added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed twice with water and once with saturated saline, and then dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure to obtain 143 mg of an orange powder.
  • 2 mL of tert-butyl methyl ether was added to the obtained powder, and the insoluble matter was collected by filtration to obtain 121 mg of a pale yellow powder.
  • the obtained powder was dissolved by heating in 4 mL of ethyl acetate-tert-butyl methyl ether (1: 4), stirred at room temperature for 3 hours, and the insoluble material was collected by filtration to obtain 90.5 mg of a white powder.
  • Test Example 1 Measurement of PTP-1B Inhibitory Activity
  • PTP-1B inhibitory activity was measured by using recombinant human PTP-1B as an enzyme (Enzo Life Sciences, Inc., Farmingdale, NY, USA) and p-nitrophenyl phosphate (substrate) as a substrate. (pNPP).
  • pNPP p-nitrophenyl phosphate
  • a DMSO solution of the test compound was prepared at a concentration of 10 ⁇ 6 M to 10 ⁇ 3 M, and 2 ⁇ L was added to each well of the 96-well plate (final concentration: 10 ⁇ 8 M to 10 ⁇ 5 M).
  • Test Example 2 Antidiabetic Action of Example Compound in Type 2 Diabetes Model Mouse (db / db Mouse) (Test Method) A 9-week-old male db / db mouse was divided into a control group and a 30 mg / kg / day administration group of the test compound as 6 animals / group so that the average values of body weight, plasma glucose and triglyceride concentrations were almost equal.
  • the test compound was suspended in a 0.5% methylcellulose solution and orally administered for 4 weeks.
  • the control group was orally administered only a 0.5% methylcellulose solution.
  • Reduction rate (%) [(mean of control group ⁇ mean of test compound administration group) / mean of control group] ⁇ 100
  • Reduction rate (%) [(mean of control group ⁇ mean of test compound administration group) / mean of control group] ⁇ 100
  • a 0.5% methylcellulose solution or a 0.5% methylcellulose suspension of the test compound (30 mg / kg) was orally administered, and fasted overnight.
  • Inhibition rate (%) [(average value of control group ⁇ average value of test compound administration group) / average value of control group] ⁇ 100 (result) Mice in the control group showed marked hyperglycemia and hypertriglyceridemia in the measurement of blood collected under non-fasting conditions.
  • the compound of Example 7 reduced plasma glucose by 37% and plasma triglyceride by 63% by repeated oral administration of 30 mg / kg / day for 4 weeks.
  • the plasma glucose concentration of the control group mice significantly increased in the glucose tolerance test under oral non-fasting, but the plasma glucose concentration of the compound administration group mice of Example 7 increased compared to the control group. Decreased by 41%.
  • the present invention relates to an antihyperglycemic agent, an antihyperlipidemic agent, an insulin sensitizer, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an agent for improving glucose intolerance, an antiarteriosclerosis agent, an antiobesity agent, It is useful as a prophylactic / therapeutic agent for inflammatory agents, diseases mediated by PTP-1B, and as a prophylactic / therapeutic agent for metabolic syndrome. Further, a medicament containing the compound of the present invention as an active ingredient can be a highly safe therapeutic agent for diabetes because it has few side effects.

Abstract

La présente invention concerne un composé représenté par la formule générale (I) [chacun des symboles dans la formule est tels que définis dans la description] ou un sel acceptable sur le plan pharmacologique de celui-ci, et une composition pharmaceutique contenant ledit composé en tant que principe actif. Le composé fourni par la présente invention a une activité inhibitrice de PTP-1B, ce qui permet d'obtenir un agent pharmaceutique utile en tant qu'agent pour traiter le diabète, un agent pour améliorer la résistance à l'insuline, un agent pour améliorer l'intolérance au glucose, un agent pour traiter des complications du diabète, un agent anti-obésité, un agent anti-hyperglycémique, un agent pour traiter le foie gras, un agent anti-hyperlipidémique, un agent anti-artériosclérose, et un agent pour prévenir et/ou traiter un syndrome métabolique.
PCT/JP2019/026956 2018-07-10 2019-07-08 Inhibiteur de ptp-1b et son utilisation WO2020013116A1 (fr)

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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
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