WO2005012326A1 - Novel compounds having inhibitory activity against sodium-dependant transporter - Google Patents

Novel compounds having inhibitory activity against sodium-dependant transporter Download PDF

Info

Publication number
WO2005012326A1
WO2005012326A1 PCT/JP2004/011312 JP2004011312W WO2005012326A1 WO 2005012326 A1 WO2005012326 A1 WO 2005012326A1 JP 2004011312 W JP2004011312 W JP 2004011312W WO 2005012326 A1 WO2005012326 A1 WO 2005012326A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
ring
mono
compound
halogen atom
Prior art date
Application number
PCT/JP2004/011312
Other languages
French (fr)
Inventor
Sumihiro Nomura
Eiji Kawanishi
Kiichiro Ueta
Original Assignee
Tanabe Seiyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34115515&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005012326(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AU2004260761A priority Critical patent/AU2004260761B2/en
Priority to NZ545304A priority patent/NZ545304A/en
Priority to EA200600351A priority patent/EA010299B1/en
Priority to MXPA06001274A priority patent/MXPA06001274A/en
Priority to CA002534024A priority patent/CA2534024C/en
Priority to MEP-2008-612A priority patent/ME00411B/en
Priority to UAA200602259A priority patent/UA83243C2/en
Priority to EP17173376.9A priority patent/EP3251679B1/en
Priority to DK04771314.4T priority patent/DK1651658T4/en
Priority to EP04771314.4A priority patent/EP1651658B2/en
Priority to ES04771314T priority patent/ES2402098T5/en
Priority to SI200432007T priority patent/SI1651658T2/en
Priority to JP2006519251A priority patent/JP4130466B2/en
Priority to BRPI0413232A priority patent/BRPI0413232B8/en
Priority to EP14194507.1A priority patent/EP2896397B2/en
Priority to RS20060079A priority patent/RS53365B/en
Priority to PL04771314T priority patent/PL1651658T5/en
Application filed by Tanabe Seiyaku Co., Ltd. filed Critical Tanabe Seiyaku Co., Ltd.
Priority to US11/045,446 priority patent/US7943788B2/en
Publication of WO2005012326A1 publication Critical patent/WO2005012326A1/en
Priority to IL173050A priority patent/IL173050A/en
Priority to NO20060220A priority patent/NO333933B1/en
Priority to HK06108470.6A priority patent/HK1086277A1/en
Priority to IL206831A priority patent/IL206831A/en
Priority to US13/005,757 priority patent/US8202984B2/en
Priority to US13/174,814 priority patent/US8222219B2/en
Priority to NO20120585A priority patent/NO334706B1/en
Priority to US13/494,602 priority patent/US8785403B2/en
Priority to HRP20130124TT priority patent/HRP20130124T4/en
Priority to HUS1400021C priority patent/HUS1400021I1/en
Priority to FR14C0034C priority patent/FR14C0034I2/en
Priority to CY2014016C priority patent/CY2014016I1/en
Priority to NO2014009C priority patent/NO2014009I2/en
Priority to BE2014C027C priority patent/BE2014C027I2/nl
Priority to NL300670C priority patent/NL300670I2/nl
Priority to US14/299,470 priority patent/US20140296506A1/en
Priority to US14/981,728 priority patent/US20160108078A1/en
Priority to US16/000,079 priority patent/US20180282363A1/en

Links

Classifications

    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/10—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 aromatic rings
    • 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
    • C07D407/02—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 two hetero rings
    • C07D407/10—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 two hetero rings linked by a carbon chain containing aromatic 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/10—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 aromatic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the present invention relates to a novel compound having an inhibitory activity against sodium-dependent ' glucose transporter (SGLT) being present in the intestine or kidney.
  • SGLT sodium-dependent ' glucose transporter
  • hyperglycemia participates in the onset and progressive impairment of diabetes mellitus, i.e., glucose toxicity theory. Namely, chronic hyperglycemia leads to decrease insulin secretion and further to decrease insulin sensitivity, and as a result, the blood glucose concentration is increased so that diabetes mellitus is self-exacerbated [cf., Diabetologia, vol. 28, p. 119 (1985); Diabetes Care, vol. 13, p. 610 (1990), etc.]. Therefore, by treating hyperglycemia, the aforementioned self-exacerbating cycle is interrupted so that the prophylaxis or treatment of diabetes mellitus is made possible.
  • the methods for treating hyperglycemia it is considered to excrete an excess amount of glucose directly into urine so that the blood glucose concentration is normalized. For example, by inhibiting sodium-dependent glucose transporter being present at the proximal convoluted tubule of kidney, the re-absorption of glucose at the kidney s inhibited, by which the excretion of glucose into urine is promoted so that the blood glucose level is decreased.
  • hyperglycemia is normalized and the blood glucose level thereof can be kept normal for a long time so that the insulin secretion and insulin resistance are improved [cf., Journal of Clinical Investigation, vol. 79, p.
  • SGLT inhibitors may be expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and further prevent the onset and progress of diabetes mellitus and diabetic complications .
  • WO 01/27128 discloses an aryl C-glycoside compound having the following structure.
  • This compound is disclosed to be useful in the prophylaxis or treatment of diabetes mellitus, etc., as an SGLT inhibitor.
  • the present invention relates to a compound of the following formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof-
  • Ring A and Ring B are one of the followings : (1) Ring
  • Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring
  • Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring
  • Ring A is an optionally substituted benzene ring
  • Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring wherein Y is linked to the heterocyclic ring of the fused heterobicyclic ring
  • Ring A is an optionally substituted unsaturated fused heterobicyclic ring, wherein the sugar moiety X- (sugar) and the moiety -Y-(Ring B) are both on the same heterocyclic ring of the fused heterobicyclic ring
  • Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused
  • X is a carbon atom or a nitrogen atom
  • Y is -(CH 2 ) n - (wherein n is 1 or 2) .
  • the compound of the formula I exhibits an ' inhibitory activity against sodium-dependent glucose transporter being present in the intestine and the kidney of mammalian species, and is useful in the treatment of diabetes mellitus or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and delayed wound healing.
  • halogen atom or the “halo” means chlorine, bromine, fluorine and iodine, and chlorine and fluorine are preferable.
  • alkyl group means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms.
  • the straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable.
  • alkyl group examples thereof are methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4, 4-dimethylpentyl group, octyl group, 2, 2, 4-trimethylpentyl group, nonyl group, de ⁇ yl group, and various branched chain isomers thereof.
  • the alkyl group may optionally and independently be substituted by 1 to 4 substituents as listed below, if necessary.
  • alkylene group or the “alkylene” means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms.
  • the straight chain or branched chain alkylene group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkylene group having 1 to 4 carbon atoms is more preferable. Examples thereof are methylene group, ethylene group, propylene group, trimethylene group, etc. If necessary, the alkylene group may optionally be substituted in the same manner as the above-mentioned "alkyl group".
  • alkylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle together with the carbon atoms to which they are attached, and may pptionally be substituted by one or more substituents defined below.
  • alkenyl group means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond.
  • Preferable alkenyl group is a straight chain or branched chain alkenyl group having 1 to 6 carbon atoms, and the straight chain or branched chain alkenyl group having 1 to 4 carbon atoms is more preferable.
  • Examples thereof are vinyl group, 2-propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group, 3-undecenyl group, 4-dodecenyl group, 4, 8, 12-tetradecatrienyl group, etc.
  • the alkenyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • alkenylene group means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond.
  • the straight chain or branched chain alkenylene group having 2 to 6 carbon atoms is preferable, and the straight chain or branched chain alkenylene group having
  • 2 to 4 carbon atoms is more preferable.
  • examples thereof are vinylene group, propenylene group, butadienylene group, etc.
  • the alkylene group may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • alkenylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle (e.g., a fused benzene ring) together with the carbon atoms to which they are attached, and may optionally be substituted by , one or more substituents defined below.
  • alkynyl group means a straight or branched monovalent hydrocarbon chain having at least one triple bond.
  • the preferable alkynyl group is a straight chain c>r branched chain alkynyl group having 1 to 6 carbon atoms, and the straight chain or branched chain alkynyl group having 1 to 4 carbon atoms is more preferable.
  • alkynyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the "cycloalkyl group” means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having
  • 3 to 7 carbon atoms is more preferable.
  • Examples thereof are a monocyclic alkyl group and a bicyclic alkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S0 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • the "cycloalkylidene group” means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms is preferable.
  • Examples thereof are a monocyclic alkylidene group and a bicyclic alkylidene group such as cyclopropylidene group, cyclobutylidene group, cyclopentylidine group, cyclohexylidene group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkylidene group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S0 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • the "cycloalkenyl group” means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond.
  • the preferable cycloalkenyl group is a monocyclic unsaturated hydrocarbon group having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkenyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S0 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • the "cycloalkynyl group” means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and having at least one triple bond.
  • the preferable cycloalkynyl group is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl group, cyclodecynyl group. These _ groups may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkynyl group may optionally and independently be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S0 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • aryl group means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof are phenyl group, naphthyl group (including 1-naphthyl group and 2-naphthyl group) . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the aryl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S0 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • the "unsaturated monocyclic heterocyclic ring” means an unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferable one is a 4- to 7-membered saturated or unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazole can be preferably used.
  • the "unsaturated monocyclic heterocyclic ring" may optionally and independently be substituted by 1-4 substituents as mentioned below, if necessary.
  • the "unsaturated fused heterobicyclic ring” means hydrocarbon ring comprised of a saturated or a unsaturated hydrocarbon ring condensed with the above mentioned unsaturated monocyclic heterocyclic ring where said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or S0 2 within the ring, if necessary.
  • the "unsaturated fused heterobicyclic ring” includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydro- isoquinoline, etc. Further, the "heterocyclic ring” also includes possible N- or S-oxides thereof.
  • heterocyclyl means a monovalent group of the above-mentioned unsaturated monocyclic heterocyclic ring or unsaturated fused heterobicyclic ring and a monovalent group of the saturated version of the above-mentioned unsaturated monocyclic heterocyclic or unsaturated fused heterobicyclic ring. If necessary, the heterocyclyl may optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • alkanoyl group means a formyl group and ones formed by binding an "alkyl group” to a carbonyl group.
  • the "alkoxy group” means ones formed by binding an "alkyl group” to an oxygen atom.
  • the substituent for the above each group includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) , a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalky
  • haloalkyl group a halo-lower alkyl group, a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or a haloheterocyclyl group
  • a haloalkyl group a halo-lower alkyl group, a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or a haloheterocyclyl group
  • an alkyl group an alkoxy group, a lower alkoxy group, a phenyl group or a heterocyclyl group (hereinafter, referred to as an alkyl group, etc.) being substituted by one or more halogen atoms, respectively.
  • Preferable ones are an alkyl group, etc.
  • a hydroxyalkyl group, a hydroxy-lower alkyl group, a hydroxy- alkoxy group, a hydroxy-lower alkoxy group and a hydroxyphenyl group mean an alkyl group, etc., being substituted by one or more hydroxy groups.
  • Preferable ones are an alkyl group, etc. , being substituted by 1 to 4 hydroxy groups, and more preferable ones are an alkyl group, etc . , being substituted by 1 to 2 hydroxy groups.
  • an alkoxyalkyl group a lower alkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-lower alkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, an alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, an alkoxyphenyl group, and a lower alkoxyphenyl group means an alkyl group, etc., being substituted by one or more alkoxy groups.
  • Preferable ones are an alkyl group, etc. , being substituted by 1 to 4 alkoxy groups, and more preferable ones are an alkyl group, etc., being substituted by 1 to 2 alkoxy groups.
  • arylakyl and arylalkoxy as used alone or as part of another group refer to alkyl and alkoxy groups as described above having an aryl substituent.
  • lower used in the definitions for the formulae in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless defined otherwise. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms.
  • the “prodrug” means an ester or carbonate, which is formed by reacting one or more hydroxy groups of the compound of the formula I with an acylating agent substituted by an alkyl, an alkoxy or an aryl by a conventional method to produce acetate, pivalate, methylcarbonate, benzoate, etc. Further, the prodrug includes also an ester or amide, which is similarly formed by reacting one or more hydroxy groups of the compound of the formula I with an ⁇ -amino acid or a ⁇ -amino acid, etc. using a condensing agent by a conventional method.
  • the pharmaceutically acceptable salt of the compound of the formula I includes, for example, a salt with an alkali metal such as lithium, sodium, potassium, etc.; a salt with an alkaline earth metal such as calcium, magnesium, etc.; a salt with zinc or aluminum; a salt with an organic base such as ammonium, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl glucosamine, triethanolamine and dehydroabietyla ine; a salt ' with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • an alkali metal such as lithium, sodium, potassium, etc.
  • an alkaline earth metal such as calcium, magnesium, etc.
  • a salt with zinc or aluminum a salt with an organic base such as ammonium, choline,
  • a salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc. ; or a salt with an acidic amino acid such as aspartic acid, glutamic acid, etc.
  • an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.
  • an acidic amino acid such as aspartic acid, glutamic acid, etc.
  • the compound of the present invention also includes a mixture of stereoisomers, or each pure or substantially pure isomer.
  • the present compound may optionally have one or more asymmetric centers at a carbon atom containing any one of substituents. Therefore, the compound of the formula I may exist in the form of enantiomer or diastereomer, or a mixture thereof.
  • the present compound (I) contains a double bond
  • the present compound may exist in the form of geometric isomerism (cis-compound, trans-compound)
  • the present compound (I) contains an unsaturated bond such as carbonyl
  • the present compound may exist in the form of a tautomer, and the present compound also includes these isomers or a mixture thereof.
  • the starting compound in the form of a racemic mixture, enantiomer or diastereomer may be used in the processes for preparing the present compound.
  • the present compound When the present compound is obtained in the form of a diastereomer or enantiomer, they can be separated by a conventional method such as chromatography or fractional crystallization.
  • the optionally substituted unsaturated monocyclic heterocyclic ring of the present invention is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxyl group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyl
  • the optionally substituted unsaturated fused heterobicyclic ring of the present invention is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidene- methyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group
  • the optionally substituted benzene ring of the present invention is a benzene ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an 'aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an al
  • the optionally substituted benzene ring includes a benzene ring substituted with an alkylene group to form an annelated carbocycle together with the carbon atoms to which they are attached, and also includes a benzene ring substituted with an alkenylene group to form an ' annelated carbocycle such as a fused benzene ring together with the carbon atoms to which they are attached.
  • the optionally substituted unsaturated monocyclic heterocyclic ring is preferably an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonyla
  • the optionally substituted unsaturated fused heterobicyclic ring is preferably an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cyclo- alkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alk
  • the optionally substituted benzene ring is preferably a benzene ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl
  • the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxy
  • the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, and an oxo group;
  • the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group consisting of
  • Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an -amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di--fluorine
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino- , group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di
  • Ring A is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an al
  • Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group
  • Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or an oxo group
  • Ring B is (a) a benzene ring which may optionally be substituted by a halogen atom; a cyano group; a lower alkyl group; a halo-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a hal
  • Ring A is a benzene ring which may optionally be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a phenyl group, or a lower alkenylene group
  • Ring B is (a) an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a halogen atom; a cyano group; a lower alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower
  • Ring A is a benzene ring which is substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a phenyl group, and a lower alkenylene group
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group,
  • Ring A is an unsaturated monocyclic heterocyclic ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and an oxo group
  • Ring B is a benzene ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, , a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a
  • Ring A is an unsaturated monocyclic heterocyclic ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and an oxo group
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group,
  • a compound in which X is a carbon atom and Y is -CH 2 - is mentioned.
  • Ring A is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, a phenyl group, and a lower alkenylene group
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a pheny
  • Ring B is a benzene ring which may optionally be' substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a
  • Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group .consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a
  • Ring A is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituerrts, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group,
  • Ring B is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a
  • Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group,
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl, group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a
  • Ring A is a benzene ring which may optionally be substituted by a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group, or a phenyl group
  • Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom or a phenyl group; a lower alkoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; a heterocyclyl group optional
  • Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a substituent selected from a halogen atom, a lower alkyl group, and an oxo group
  • Ring B is a benzene ring which may optionally be substituted by a substituent selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom or a phenyl group; a lower alkoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo
  • Preferable unsaturated monocyclic heterocyclic ring includes a 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 hetero atoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom. More specifically, preferred are furan, thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine and tetrazole.
  • Preferable unsaturated fused heterobicyclic ring includes a 9- or 10-membered unsaturated fused heterocyclic ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom. More specifically, preferred are indoline, isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline, benzothiophene, benzofuran, thienothiophene, and dihydroisoquinoline.
  • More preferred compounds include a compound wherein Ring A is a benzene ring which may optionally be substituted by a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and a phenyl group, and Ring B is a heterocyclic ring selected from the group consisting of thiophene, furan, benzofuran, benzothiophene, and benzothiazole, wherein the heterocyclic ring may optionally be substituted by a substituent selected from the following group: a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a lower alkylphenyl
  • Ring A is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring selected from the group consisting of thiophene, dihydroisoquinpline, dihydroisoxazole, triazole, pyrazole, dihydropyridine, dihydroindole, indole, indazole, pyridine, pyrimidine, pyrazine, quinoline, and a isoindoline, wherein the heterocyclic ring may optionally substituted by a substituent selected from the following group: a halogen atom, a lower alkyl group, and an oxo group, and Ring B is a benzene ring which may optionally be substituted by a substituent selected from the following group: a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy
  • R la , R 2a , R 3a , R lb ,' R 2b , and R 3b are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, a phenyl group, a phenylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamo
  • R 4a and R 5a are each independently a hydrogen atom; a - halogen atom; a hydroxy group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkylidenemethyl group; a cycloalkenyl group; a cycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; a mono- or di-alkylamino group; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamo
  • R la , R 2a , R 3a , R lb , R 2b , and R 3b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a phenyl group;
  • R 4a and R 5a are each independently a hydrogen atom; a halogen atom; a lower alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, or R 4a and R 5a are bonded to each other at the terminals thereof to form a lower alkylene group; and
  • R 4b , R 5b , R c and R 5c are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
  • R a is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R 5a is a hydrogen atom, or R 4a and R 5a are bonded to each other at the terminals thereof to form a lower alkylene group.
  • R la is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R 2a and R 3a are hydrogen atoms; and Ring B is
  • R 4a is a phenyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, and a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R 5a is a hydrogen atom, and Y is —CH 2 — .
  • a preferable compound in another preferable embodiment of the present invention, can be represented by the following formula IA:
  • R A is a halogen atom, a lower alkyl group or a lower alkoxy group
  • R B is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a mono- or di-lower alkylamino group
  • R c is hydrogen atom
  • R B and R c taken together are a fused benzene ring which may be substituted by a halogen atom, a lower alkyl group
  • R B is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group is preferred.
  • a preferred heterocyclyl group includes a 5- or 6-membered heterocyclyl group containing 1 or 2 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, or a 9- or 10-membered heterocyclyl group containing 1 to 4 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a thienyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, pyrazolyl group, a thiazolyl group, a quinolyl group, and a tetrazolyl group are preferred.
  • R la is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R 2a and R 3a are hydrogen atoms; and Ring B is
  • R 4b and R 5b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
  • R 8 , R 9 and R 10 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an ' alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group,
  • R 6a and R 7a are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkan
  • R 8 , R 9 and R 10 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloaikoxy group, a halo-lower alkoxy group, or a lower alkoxy-lower alkoxy group, and a group represented by:
  • R 6a , R 7a are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloaikoxy group, a halo-lower alkoxy group, or a lower alkoxy-lower alkoxy group, or a group represented by:
  • R 6b and R 7b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group.
  • Ring B' is an optionally substituted benzene ring, an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring.
  • Ring B' include a benzene ring and a heterocyclic ring, both of which may have a substituent (s) selected from the group consisting of a halogen atom; a cyano group; a lower alkyl group optionally substituted by a halogen atom; a lower alkoxy group optionally substituted by a halogen atom; a lower alkanoyl group; a mono- or di-lower alkylamino group; a lower alkoxycarbonyl group; a carbamoyl group; a mono- or di-lower alkylcarbamoyl group; a phenyl group optionally substituted by a substituent (s) selected from a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom, a lower alkanoyl group, a mono
  • Ring B' include a benzene ring which may be substituted by a substituent selected from the group consisting of a halogen atom; a cyano group; a lower alkyl group optionally substituted by a halogen atom; a lower alkoxy group optionally substituted by a halogen atom; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom.
  • Preferred compound of the present invention may be selected from the following group: 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- ( 6-ethylbenzo [b] thiophen- 2-ylmethyl) benzene;
  • the compound (I) of the present invention exhibits an excellent inhibitory activity against sodium-dependent glucose transporter, and an excellent blood glucose lowering effect. Therefore, the compound of the present invention is useful in the treatment or the prophylaxis of diabetes mellitus (type 1 and type 2 diabetes mellitus, etc.) or diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or is useful in the treatment of postprandial hyperglycemia.
  • diabetes mellitus type 1 and type 2 diabetes mellitus, etc.
  • diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or is useful in the treatment of postprandial hyperglycemia.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered either orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation.
  • suitable pharmaceutical preparation for oral administration includes, for example, solid preparation such as tablets, granules, capsules, powders, etc., or solution preparations, suspension preparations, or emulsion preparations, etc.
  • Suitable pharmaceutical preparation for parenteral administration includes, for example, suppositories; injection preparations and intravenous drip preparations using distilled water for injection, physiological saline solution or aqueous glucose solution; or inhalant preparations .
  • the dosage of the present compound (I) or a pharmaceutically acceptable salt thereof may vary.according to the administration routes, ages, body weight, conditions of a patient, or kinds and severity of a disease to be treated, and it is usually in the range of about 0.1 to 50 mg/kg/day, preferably in the range of about 0.1 to 30 mg/kg/day.
  • the compound of the formula I may be used, if necessary, in combination with one or more of other antidiabetic agents and/or one or more agents for treatment of other diseases.
  • the present compound and these other agents may be administered in the same dosage form, or in a separate oral dosage form or by injection.
  • the other antidiabetic agents include, for example, antidiabetic or antihyperglycemic agents including insulin, insulin secretagogues, or insulin sensitizers, or other antidiabetic agents having an action mechanism different from SGLT inhibition, and 1, 2, 3 or 4 of these other antidiabetic agents may preferably be used.
  • biguanide compounds sulfonylurea compounds, ⁇ -glucosidase inhibitors, PPARy agonists (e.g., thiazolidinedione compounds), PPAR ⁇ / ⁇ dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, mitiglinide compounds, and/or nateglinide compounds, and insulin, glucagon-like peptide-1 (GLP-1) , PTP1B inhibitors, glycogen phosphorylase inhibitors, RXR modulators, and/or glucose 6-phosphatase inhibitors.
  • PPARy agonists e.g., thiazolidinedione compounds
  • DPP4 dipeptidyl peptidase IV
  • mitiglinide compounds mitiglinide compounds
  • nateglinide compounds nateglinide compounds
  • insulin glucagon-like peptide-1 (GLP-1) , PTP1B inhibitors, glycogen phosphorylase inhibitors, R
  • the agents for treatment of other diseases include, for example, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent.
  • the SGLT inhibitors of the formula I may be used in combination with agents for treatment of diabetic complications, if necessary. These agents include, for example, PKC inhibitors and/or ACE inhibitors .
  • the dosage of those agents may vary according to ages, body weight, and conditions of patients, and administration routes, dosage forms, etc.
  • compositions may be orally administered to mammalian species including human beings , apes , dogs, etc., for example, in the dosage form of tablet, capsule, granule or powder, or parenterally administered in the form of injection preparation, or intranasally, or in the form of transdermal patch.
  • the present compound of the formula I may be prepared by the following Processes. Process 1
  • the compound of the formula I may be prepared by a method as shown in the following scheme:
  • R lla is a hydrogen atom or a protecting group for a hydroxy group
  • R llb , R llc and R are each independently a protecting group for a hydroxy group, and other symbols are as defined above .
  • the compound of the formula I may be prepared by deprotecting the compound of the formula II.
  • the protecting group for hydroxy group may be any conventional protecting groups, and a benzyl group, an acetyl group, and an alkylsily group such as a trimethylsilyl group may be used. Further, the protecting group for hydroxy group may form acetal or silylace ' tal together with adjacent hydroxy groups.
  • Examples of such protecting group include an alkylidene group such as an isppropylidene group, a sec-butylidene group, etc., a benzylidene group, or a dialkylsilylene group such as di-tert-butylsilylene group, etc., which can be formed, for example, by combining R llc and R lld at the terminal thereof.
  • the deprotection can be carried out according to the kinds of protecting group to be removed, for example, by conventional processes such as reduction, hydrolysis, acid treatment, fluoride treatment, etc.
  • the deprotection can be carried out by (1) catalytic reduction using a palladium catalyst (e.g., palladium-carbon, palladium hydroxide) under hydrogen atmosphere in a suitable solvent (e.g., methanol, ethanol, ethyl acetate); (2) treatment with an dealkylating agent such as boron tribromide, boron trichloride, boron trichloride • dimethylsulfide complex, or iodotrimethylsilane in a suitable solvent (e.g., dichloromethane) ; or (3) treatment with a lower alkylthiol such as ethanethiol in the presence of a Lewis acid (e.g., boron trifluoride • diethyl ether complex) in a suitable solvent (e.g., dichloromethane) .
  • a suitable solvent e.g., methanol, ethanol, ethyl acetate
  • an dealkylating agent such as
  • the hydrolysis can be carried out by treating the compound of formula II with a base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, etc.) in a suitable solvent (e.g., tetrahydrofuran, dioxane, methanol, ethanol, water, etc.).
  • a base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, etc.
  • a suitable solvent e.g., tetrahydrofuran, dioxane, methanol, ethanol, water, etc.
  • Acid treatment can be carried out by treating the compound of formula II with an acid (e.g., hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc. ) .
  • an acid e.g., hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.
  • a suitable solvent e.g., methanol, ethanol, etc.
  • the fluoride treatment it can be carried out by treating the compound of formula II with a fluoride (e.g., hydrogen fluoride, hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.) in a suitable solvent (e.g., acetic acid, a lower alcohol (methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, etc.).
  • a fluoride e.g., hydrogen fluoride, hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.
  • a suitable solvent e.g., acetic acid, a lower alcohol (methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, etc.
  • the deprotection reaction can be preferably carried out under cooling or with heating, for example, at a temperature of from 0°C to 50 °C, more preferably at a temperature of from 0°C to room temperature
  • the compound of the ( formula I-a may be prepared by reducing the compound of the formula III.
  • the reduction can be carried out by treatment with a silane reagent, in the presence of an acid, in a suitable solvent or in the absence of a solvent.
  • a Lewis acid such as boron trifluoride • diethyl ether complex, titanium tetrachloride, etc.
  • a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc.
  • silane reagent for example, a trialkylsilane such as triethylsilane, triisopropylsilane, etc. may preferably be used.
  • solvent any kinds of solvent may be- , used as long as it does not affect the reaction, and for example, acetonitrile, dichloromethane, or an acetonitrile/dichloromethane mixture may preferably be used.
  • the compound of the formula I-b may be prepared by reducing the compound of the formula IV.
  • the reduction can be carried out in a manner similar to Process 2.
  • a silane reagent e.g., triethylsilane, etc.
  • a Lewis acid e.g., boron trifluoride • diethyl ether complex, etc.
  • a suitable solvent e.g., acetonitrile, dichloromethane, etc.
  • the compound of the present invention thus obtained may be isolated and purified by a conventional method well known in the organic synthetic chemistry such as recrystallization, column chromatography, etc.
  • the starting compound represented by the formula (II) , (III) or (IV) may be prepared by either one of the following steps (a) - (j ) . Steps (a) and (b) :
  • R .13 is (1) a bromine atom or an iodine atom when X is a carbon atom; or (2) a hydrogen atom when X is a nitrogen atom, R lle is a protecting group for hydroxy group, and the other symbols are as defined above.
  • the compound wherein X is a carbon atom may be prepared by coupling the compound of the formula VII with the compound of the formula VI to give the compound of formula V, followed by reduction of the compound of the formula V.
  • the coupling reaction can be carried out by lithiating the compound of the formula VII, followed by reacting the resultant with the compound of the formula VI. ⁇
  • the compound of the formula VII can be treated with an alkyllithium, followed by reacting the resultant with the compound of the formula VI.
  • alkyllithium methyl lithium, n-butyl lithium, t-butyl lithium, etc. are preferably used.
  • the solvent may be any solvent which does not disturb the reaction, and ethers such as tetrahydrofuran, diethyl ether, etc., are ' preferably used.
  • This reaction can be carried out from under cooling (e.g., at
  • Process 2 it can be carried out by treating the compound of formula V with a silane reagent (e.g., triethylsilane, etc.) in the presence of a Lewis acid (e.g., boron trifluoride • diethyl ether complex, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.).
  • a silane reagent e.g., triethylsilane, etc.
  • a Lewis acid e.g., boron trifluoride • diethyl ether complex, etc.
  • a suitable solvent e.g., acetonitrile, dichloromethane, etc.
  • the compound wherein X is a nitrogen atom may be prepared by silylating the compound of the formula VII in a solvent, followed by reacting the resultant with the compound of the formula VIII (e.g., an - or ⁇ -D-glucose pentaacetate, etc. ) in the presence of a Lewis acid.
  • the compound of the formula VIII e.g., an - or ⁇ -D-glucose pentaacetate, etc.
  • the silylation reaction can be carried out by treating the compound of formula VII with a silylating agent in a solvent.
  • the silylating agent includes, for example,
  • the solvent may be, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, etc., acetonitrile, etc.
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc.
  • ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, etc., acetonitrile, etc.
  • This reaction is preferably carried out under cooling or with heating, for example, at a temperature of from 0°C to 60°C, preferably at a temperature of from room temperature to 60 °C.
  • reaction with the compound of the formula VIII can be carried out in a solvent in the presence of a Lewis acid.
  • the Lewis acid includes, for example, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, boron trifluoride • diethyl ether complex.
  • the solvent may be, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., acetonitrile, etc.
  • This reaction can be carried out under cooling or with heating, for example, at a temperature of from 0°C to 100 °C, _ preferably at a temperature of from room temperature to 60 °C.
  • the compound wherein X is a carbon atom and R lla is a hydrogen atom may be prepared by a method as shown in the following scheme:
  • R 13a is a bromine atom or an iodine atom, and the other symbols are as defined above.
  • the compounds of the formula Il-a may be prepared by coupling the compound of the formula Vll-a with the compound of the formula X or an ester thereof to give the ' compound of the formula IX, followed by hydrating the compound of the formula IX.
  • the ester of the compound of the formula X includes, for example, a lower alkyl ester thereof, and a compound represented by the formula XI:
  • R 14 is a lower alkyl group, is 0 or 1, and the other " symbols are as defined above.
  • the coupling reaction of the compound of the formula Vll-a with the compound of -the formula X or an ester thereof can be carried out in the presence of a base and a palladium catalyst in a suitable solvent.
  • the base includes an inorganic base such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), potassium fluoride, potassium phosphate, etc., and an organic base such as a tri-lower alkylamine (e.g., triethylamine, diisopropylethylamine, etc.), a cyclic tertiary amine (e.g., 1, 4-diazabicyclo [2.2.2] octane, 1, 5-diazabicyclo [4.3.0]- nona-5-ene, 1, 8-diazabicyclo [5.4.0] undeca-7-ene, etc.).
  • an organic base such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc
  • the palladium catalyst may be a conventional catalyst such as tetrakis (triphenyl) phosphinepalladium (0) , palladium (II) acetate, palladiu (II) chloride, bis (triphenyl) phosphine palladium (II) chloride, palladium (II) chloride • 1, 1-bis (diphenylphosphino) ferrocene complex, etc.
  • a conventional catalyst such as tetrakis (triphenyl) phosphinepalladium (0) , palladium (II) acetate, palladiu (II) chloride, bis (triphenyl) phosphine palladium (II) chloride, palladium (II) chloride • 1, 1-bis (diphenylphosphino) ferrocene complex, etc.
  • the solvent may be any inert solvent which does not disturb the reaction, for example, ethers such as tetrahydrofuran, dioxane, etc., amide solvents such as N,N-dimethylformamide, 1, 3-dimethyl-2-imidazolidinone, etc., aromatic hydrocarbons such as toluene, xylene, etc., dimethylsulfoxide, water, and if desired, a mixture of two or more of these solvents.
  • ethers such as tetrahydrofuran, dioxane, etc.
  • amide solvents such as N,N-dimethylformamide, 1, 3-dimethyl-2-imidazolidinone, etc.
  • aromatic hydrocarbons such as toluene, xylene, etc., dimethylsulfoxide, water, and if desired, a mixture of two or more of these solvents.
  • This reaction is preferably carried out with heating, for example, at a temperature of from 50 °C to a boiling point of the reaction mixture,' and more preferably at a temperature of from 50°C to 100°C.
  • the hydration reaction of the compound of the formula IX can be carried out, for example, by hydroboration, more specifically, by reacting with diborane, borane • tetrahydrofuran complex, or 9-borabicyclononane, etc. in a suitable solvent, followed by treating with hydrogen peroxide solution in the presence of a base (e.g., an alkali metal hydroxide such as sodium hydroxide, etc.) , or by treating with an oxidizing reagent such as sodium perborate, and oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) in a suitable solvent.
  • a base e.g., an alkali metal hydroxide such as sodium hydroxide, etc.
  • an oxidizing reagent such as sodium perborate, and oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) in a suitable solvent.
  • the solvent may be any inert solvent which does not disturb the reaction, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxy- ethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., water, and if desired, a mixture of two or more of these solvents.
  • This reaction can be carried out at a temperature of a broad range such as under cooling or with heating, and preferably carried out at a temperature of from -10 °C to a boiling point of the reaction mixture.
  • Ring A is a benzene ring may be prepared in a method as shown in the following scheme:
  • the compounds" of the formula Il-b may be prepared by coupling the compound of the formula XIV with the compound of the formula XIII, to give the compound of the formula XII, followed by reduction of the compound of the formula XII.
  • the coupling reaction can be carried out in a manner similar to Step (a). Namely, it can be carried out by lithiating the compound of formula XIV with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), followed by reacting the resultant with the compound (XIII).
  • an alkyl lithium e.g., n-butyl lithium, tert-butyl lithium, etc.
  • a suitable solvent e.g., diethyl ether, tetrahydrofuran, etc.
  • the reduction reaction can be carried out by (1) treatment with a silane reagent (e.g., trialkyl silane such as triethyl silane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), at -30°C to 60°C, in the presence of a Lewis acid such as boron trifluoride • diethyl ether complex or trifluoroacetic acid, (2) treatment with iodotrimethylsilane, or (3) treatment with a reducing agent (e.g., borohydrides such as sodium boron hydride, sodium triacetoxyborohydride, etc., aluminum hydrides such as lithium aluminum hydride, etc.) in the presence of an acid (e.g., a strong acid such as trifluoroacetic acid, etc. , and a Lewis acid such as aluminum chloride, etc.).
  • a silane reagent e.g., trialkyl silane such as triethyl
  • the compound of the formula III may be prepared by deprotecting the compound of the formula V which is a synthetic intermediate of Step (a) , followed by treating the resultant compound with an acid in an alcohol solvent.
  • the deprotection reaction can be carried out in a manner similar to Process 1. Namely, it can be carried out by subj ecting the compound V to an acid treatment, reduction, or a fluoride treatment, etc.
  • the resultant compound is treated with an acid in a suitable alcohol.
  • the acid includes, for example, an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, etc., an organic acid such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.
  • the alcohol includes a conventional alkyl alcohol which does not disturb the reaction, for example, methanol, ethanol, n-propanol, i-propanol, n-butanol, etc.
  • Step (f) the deprotection reaction and acid treatment may be carried out in the same step, depending on the kind of the protecting group.
  • the compound of the formula IV may be prepared by a method as shown in the following scheme:
  • the coupling reaction can be carried out in a manner similar to Step (a) .
  • the compound XVI is treated with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium, etc,) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc. ) , ,followed by reacting the resultant with the compound VI .
  • an alkyl lithium e.g., n-butyl lithium, tert-butyl lithium, etc,
  • a suitable solvent e.g., diethyl ether, tetrahydrofuran, etc.
  • Step (e) The removal of protecting groups and the acid treatment are carried out in a manner similar to Step (e) . Namely, it can be carried out by subjecting the compound XV to reduction, acid treatment or fluoride treatment, depending on the kind of the protecting group to be removed, followed by treating the resultant with an acid (e.g., hydrochloric acid, ' p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc. ) .
  • an acid e.g., hydrochloric acid, ' p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.
  • a suitable solvent e.g., methanol, ethanol, etc.
  • R 20 is a trialkylstannyl group, or a dihydroxyboryl group or an ester thereof, and the other symbols are as defined above.
  • the compound of the formula II may be prepared by coupling the compound XVII with the compound XVIII in a suitable solvent, in the presence of a palladium catalyst, and in the presence or in the absence of a base.
  • the coupling reaction can be carried out in a manner similar to Step (c) .
  • Step (h) :
  • the compound wherein n is 1 may be prepared in a method as shown in the following scheme: ⁇
  • the compound of the formula IV may be prepared by the following steps : (1) treating the compound of the formula _ XXII with a halogenating agent in a suitable solvent or in the absence of a solvent, followed by condensation of the resultant with the compound of the formula XXI in the presence of a Lewis acid to give the compound of formula XX, (2) reducing the compound of formula XX, and (3) removing the protecting groups from the compound of formula XIX.
  • the halogenating agent includes a conventional halogenating agent such as thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.
  • the solvent may be any solvent which does not disturb the reaction, and for example, dichloromethane, carbon tetrachloride, tetrahydrofuran, toluene, etc. may be mentioned.
  • the reaction suitably proceeds by adding a catalyst such as dimethylformamide, etc.
  • a catalyst such as dimethylformamide, etc.
  • the condensation reaction of the compound (XXII) and the compound (XXI) can be carried out according to a conventional method as known as Friedel-Crafts reaction, in the presence of a Lewis acid and in a suitable solvent.
  • the Lewis acid includes aluminum chloride, boron trifluoride • diethyl ether complex, tin (IV) chloride, titanium tetrachloride, etc. which are conventionally used in Friedel-Crafts reaction.
  • the solvent includes halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, dichloroethane, etc.
  • the reduction reaction can be carried out by treating the compound of formula XX with a silane reagent (e.g., trialkyl silane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g., a Lewis acid such as boron trifluoride • diethyl ether complex, etc., and a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc.), or by treating with a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassium hydroxide, etc.).
  • a silane reagent e.g., trialkyl silane, etc.
  • a suitable solvent e.g.
  • the present reaction can be carried out under cooling or with heating, for example, at a temperature of from -30 °C to 60°C.
  • Step (i) Among the compounds of the formula II, the compound wherein X is a nitrogen atom may be prepared by a method as shown in the following scheme:
  • R 21 is a leaving group, and the other symbols are as defined above.
  • Examples of the leaving group include a halo'gen atom such as chlorine atom and bromine atom.
  • the compound of the formula Il-d may be prepared by condensation of the compound of the formula XXIII with the compound of the formula XXIV. : • >
  • the condensation reaction can be carried out in a suitable solvent such as acetonitrile, etc., in the presence of a base (e.g., an alkali metal hydroxide, such as potassium hydroxide, etc. ) .
  • a base e.g., an alkali metal hydroxide, such as potassium hydroxide, etc.
  • the compound wherein Ring A is a pyrazole substituted by a lower alkyl group, X is a nitrogen atom and Y is -CH 2 - may be prepared by a method as shown in the following scheme:
  • the compound Il-e may be prepared by condensation of the compound of the formula XXV with the compound of the formula XXVI in a suitable solvent (e.g., ethers such as tetrahydrofuran, etc. , an aromatic hydrocarbons such as toluene, etc. ) .
  • a suitable solvent e.g., ethers such as tetrahydrofuran, etc. , an aromatic hydrocarbons such as toluene, etc.
  • the compound of the present invention may be converted to each other within the objective compounds of the present invention.
  • Such conversion reaction may be carried out according to a conventional method, depending on the kind of the objective substituents.
  • an aryl group such as phenyl group, or a heterocyclyl group may be prepared by coupling the compound in which substituents of the Ring B is a halogen atom such as a bromine atom, with a suitable phenylboronic acid, phenyltin, hetercyc ⁇ -ylboronic acid, or heterocyclyltin.
  • the coupling reaction may be carried out in a manner similar to Step (c) or Step (g) , or in a method as described in the following Examples.
  • the compound wherein heteroatom is oxidized e.g., S-oxide, S,S-oxide, or N-oxide compounds
  • S-oxide, S,S-oxide, or N-oxide compounds may be prepared by oxidizing a corresponding S-form or N-form.
  • the oxidation reaction can be carried out by a conventional method, for example, by treatment with an oxidizing agent (e.g., peracids such as hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.) in a suitable solvent (e.g., halogenated hydrocarbons such as dichloromethane, etc.).
  • an oxidizing agent e.g., peracids such as hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.
  • a suitable solvent e.g., halogenated hydrocarbons such as dichloromethane, etc.
  • the starting compounds of the respective steps described above may be prepared by the methods as disclosed in Reference Examples or a process as mentioned below.
  • the compound wherein Y is -CH 2 - may be prepared by a method as shown in the following scheme: wherein R 15 is a hydrogen atom or a halogen atom, and the other symbols are as defined above.
  • the compound of the formula Vll-b may be prepared by coupling the compound of the formula XXVIII with the compound of the formula XXIX to give the compound of the formula XXVII, followed by reducing the obtained compound of the formula XXVII .
  • the coupling reaction of the present step may be carried out in a manner similar to Step (a) .
  • the compound of the formula XXVIII is treated with an alkyl lith-um (e.g., n-butyl lithium, tert-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), followed by reacting the resultant with the compound of the formula XXIX.
  • an alkyl lith-um e.g., n-butyl lithium, tert-butyl lithium, etc.
  • a suitable solvent e.g., diethyl ether, tetrahydrofuran, etc.
  • the reduction reaction may be carried out in a manner similar to Step (d) , more specifically, by (1) treatment with a silane reagent such as triethylsilane, etc., in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), at -30°C to 60°C, in the presence of a Lewis acid such as boron trifluoride • diethyl ether complex or trifluoroacetic acid, (2) treatment with iodotrimethylsilane , or (3) treatment with a reducing agent (e.g., borohydrides such as sodium boron hydride, sodium triacetoxyborohydride, etc., aluminum hydrides such as lithium aluminum hydride, etc.) in the presence of an acid (e.g., a strong acid such as trifluoroacetic acid, etc., a Lewis acid such as aluminum chloride, etc.).
  • a silane reagent such as triethylsilane, etc.
  • the compound wherein X is a carbon atom and Y is -CH 2 - may be prepared by a method as shown in the following scheme:
  • R 16 is a halogen atom, and the other symbols are as defined above.
  • the present process may be carried out in a manner similar to Step (h) as mentioned above.
  • the compound of the formula VII-c may be prepared by treating the compound of the formula XXXIII wi'th a halogenating reagent (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.) in a suitable solvent (e.g., dichloromethane, carbon tetrachloride, tetrahydrofuran, toluene, etc.) or in the absence of a solvent, to give the compound of the formula XXXII, subsequently by condensing this compound with the compound of the formula XXXI in a suitable solvent (e.g., dichloromethane, carbon tetrachloride, dichloroethane, etc.) in the presence of a Lewis acid (e.g., aluminum chloride, zinc chloride, titanium tetrachloride, etc.), to give the compound of the formula XXX, and further by reducing the obtained compound.
  • the reduction reaction can be carried out by treating with a silane reagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g., a Lewis acid such as boron trifluoride • diethyl ether complex, etc., and a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc.), or by treating with a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassium hydroxide, etc.).
  • a silane reagent e.g., triethylsilane, etc.
  • a suitable solvent e.g., acetonitrile, dichloromethane, etc.
  • an acid e.g., a Lewis acid such as boron trifluoride
  • the compound wherein X is a carbon atom and Y is -CH 2 - may be prepared by a method as shown in the following scheme:
  • the compound of the formula VII-c may be prepared by coupling the compound of the formula XXXV with the compound of the formula XXXIV to give the compound of the formula XXX, and subsequently by reducing the obtained compound .
  • the coupling reaction may be carried out in a manner similar to Step (a) .
  • the compound of the formula (XXV) is lithiated with an alkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), and subsequently, by reacting the resultant with the compound (XXIV) .
  • the reduction reaction may be carried out in a manner similar to Step (a) .
  • a silane reagent e.g., triethylsilane, etc.
  • a suitable solvent e.g., acetonitrile, dichloromethane, etc.
  • an acid e.g. , boron trifluoride • diethyl ether complex, etc
  • the compound wherein X is a carbon atom and Y is -CH 2 - may be prepared by a method as shown in the following scheme: wherein R 18 is a lower alkyl group, and the other, symbols are as defined above.
  • the compound of the formula VII-c may be prepared by coupling the compound of the formula XXVIII with the compound of the formula XXXVI to give the compound of the formula XXX, and subsequently by reducing the compound.
  • the present process may be carried out in a manner similar to Step (3) .
  • the compound of the formula (XXVIII) is lithiated with an alkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), and subsequently, by reacting the resultant with the compound (XXXVI) to give the compound of the formula (XXX) .
  • an alkyllithium e.g., tert-butyl lithium, n-butyl lithium, etc.
  • a suitable solvent e.g., diethyl ether, tetrahydrofuran, etc.
  • the compound of the formula XXX is treated with a silane reagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.) in the presence of an acid (e.g., boron trifluoride • diethyl ether complex, etc) , to give the compound of the formula (VII-c) .
  • a silane reagent e.g., triethylsilane, etc.
  • a suitable solvent e.g., acetonitrile, dichloromethane, etc.
  • an acid e.g., boron trifluoride • diethyl ether complex, etc
  • the compound of the formula VI is disclosed in WO 01/27128 or Benhaddu, S. Czernecki et al . , Carbohydr. Res., vol. 260, p. 243-250, 1994.
  • the compound of the formula VIII may be prepared from D- (+) -glucono-1, 5-lactone according to the method disclosed in USP 6515117.
  • the compound of the formula XXXVII is lithiated with t-butyl lithium in a suitable solvent (e.g., tetrahydrofuran, etc.) under cooling (e.g., -78°C), followed by reacting with trimethyl borate to give the compound of the formula X.
  • a suitable solvent e.g., tetrahydrofuran, etc.
  • cooling e.g., -78°C
  • the compound of the formula X is reacted with a 1,2-diol (e.g., pinacol, etc.) or 1,3-diol (e.g., 2, 4-dimethyl-2, 4-pentanediol, etc.) to give the compound of the formula XI .
  • a 1,2-diol e.g., pinacol, etc.
  • 1,3-diol e.g., 2, 4-dimethyl-2, 4-pentanediol, etc.
  • the other starting compounds are commercially available or may easily be prepared by a standard method well known to an ordinary skilled person in this field.
  • Example 1 1- ( ⁇ -D-glucopyranosyl) -3- (5-ethyl-2-thienyl- methyl ) benzene
  • Me is a methyl group
  • Et is an ethyl group
  • TMSO and OTMS are a trimethylsilyloxy group.
  • tBu is a tert-butyl group
  • OTIPS is a triisopropylsilyloxy group
  • the other symbols are as defined above.
  • Bn is a benzyl group.
  • Example 106 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- (1-oxy- b.enzo [b] thiophen-2-ylmethyl) benzene
  • the target compound was prepared in a manner similar to Example 106.
  • n-Bu is n-butyl group, and other symbols are as defined above.
  • ' A solution of 4- (bromomethyl) -1- (2,3,4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosy 1) -1, 2, 3-triazole 32 (500 mg) (See Federico G. H. et al. , J. Med. Chem .
  • Example 110 4- (4-Ethylphenylmethyl) -1- ( ⁇ -D-glucopyranosyl) pyrazole
  • TMS is a trimethylsilyl group, and other symbols are as defined above.
  • Example 110 In a manner similar to Example 110, the compounds shown in Table 3 below were prepared from corresponding starting materials.
  • 6-fluoropyridine-3-boronic acid 58 (117 mg) , tri-tert-butylphosphine ⁇ tetrafluoroboric acid adduct (24 mg) , potassium fluoride (80 mg) and tris (dibenzylideneacetone) dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 2 days under argon atmosphere. Added thereto was a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate .
  • the target compound was obtained in a manner similar to Example 1, from 5-bromo-2-chloro-l- (2- (5-phenyl-2-thienyl) ethyl) - benzene.
  • APCI-Mass m/Z 478/480 (M+NH 4 ) .
  • Example 120 -3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acid were used and treated in a manner- similar to Example 120- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5- (3-dimethylaminophenyl) -2-thienylmethyl) -4-methylbenz ene.
  • APCI-Mass m/Z 638 M+H
  • the target compound was prepared in a manner similar to Example 1, starting from
  • Example 19 -4-chloro-3- (5-chloro-2-thienylmethyl) benzene obtained in Example 19 was used and treated in a manner similar to Example 106- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D- glucopyranosyl) 4-chloro-3- (5-chloro-2-thienylmethyl) benzene as colorless crystals.
  • APCI-Mass m/Z 590/592 (M+NH 4 ) APCI-Mass m/Z 590/592 (M+NH 4 ) .
  • Example 120- (1) obtained in Example 120- (1) and 3-cyanophenylboronic acid were used and treated in a manner similar to Example 120- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5— (3-cyano phenyl) -2-thienylmethyl) -4-methylbenzene.
  • APCI-Mass m/Z 637 M+NH 4
  • the solution was washed with successively with water, 2N aqueous hydrochloride acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate.
  • the solvent was evaporated under reduced pressure to give a compound 68 as pale yellow powder, which was dissolved in methanol (50 ml) without further purification.
  • sodium methoxide (28% methanol solution, 5 drops) was added, and then the mixture was stirred at room temperature for 2.5 hours.
  • the solvent was evaporated under reduced pressure to give a deacetylated compound 69 as pale yellow powder.
  • Example 157 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- ( 6- isopropyloxybenzo [b] thiophen-2-ylmethyl) benzene 5-Bromo-2-chloro-l- ( 6-isopropyloxybenzo [b] thiophen-2-ylmeth yl) benzene was treated in a manner similar to Example 1 to give the target compound.
  • APCI-Mass m/Z 496/498 (M+NH 4 ) .
  • Example 158 1- ( ⁇ -D-glucopyranosyl) -4-methy.l-3- (2- thienylmethyl) benzene (1)
  • 2- (2, 3, 4, 6-tetra-0-acetyl- ⁇ -D-glucopyranosyl)-3- (5- chloro-2-thienylmethyl) -4-methylbenzene 57 (12.0' g) obtained in Example 120- (1) was dissolved in tetrahydrofuran (120 ml) and methanol (360 ml), and added thereto were triethylamine (24.2 ml) and 10% palladium carbon catalyst (wet, 3.6 g) , and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere under normal pressure.
  • Example 159- (1) (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene (500 mg) obtained in Example 159- (1) was dissolved in N, N-dimethylacetamide (10 ml), and added thereto were zinc cyanide (98 mg) , tris (dibenzylideneacetone) dipalladium (0) (77 mg) , 1, 1 ' -bis (diphenylphosphino) ferrocene (47 mg) and zinc power (14 mg) . The mixture was heated under stirring at 120°C overnight.
  • Example 128- (4) was treated in a manner similar to Example 106- (3) to give the target compound.
  • APCI-Mass m/Z 466/468 (M+NH 4 ) .
  • APCI-Mass m/Z 634/636 M+H
  • Example 170 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- (5- (6- methoxy-2-pyridyl) -2-thienylmethyl) benzene
  • Example 171 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- (l-oxo-2- isoindolinylmethyl) benzene
  • Example 174 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- (6-n- propyloxybenzo [b] thiophen-2-ylmethyl) benzene 5-Bromo-2-chloro-l- ( 6-n-propyloxybenzo [b] thiophen-2-ylmethy 1) benzene was treated in a manner similar to Example 1 to give the target compound.
  • Example 176 1- ( ⁇ -D-glucopyranosyl) -3- (5- (4- difluoromethylphenyl) -2-thienylmethyl) -4-methylbenzene (1) 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-methylbenzene from Example 159- (1) and 4-formylphenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5- (4-formy lphenyl) -2-thienylmethyl) -4-methylbenzene as a colorless solid.
  • APCI-Mass m/Z 640 M+NH 4 ) .
  • Example 179 1- ( ⁇ -D-glucopyranosyl) -4-chloro-3- (5- (4- difluoromethylphenyl) -2-thienylmethyl) benzene (1)
  • 1- (2, 3, 4, 6-tetra-O-acetyl- ⁇ -D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) and 4-formylphenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4, 6-tetra-O- acetyl- ⁇ -D-glucopyranosyl) -4-chloro-3- (5- (4-formylphenyl) - 2-thienylmethyl) benzene as a colorless solid.
  • APCI-Mass m/Z 660/662 M+NH 4
  • 3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow syrup.
  • APCI-Mass m/Z 279/281 M+H-H 2 0
  • To the mixture were added triethylsilane (6.18 ml) and boron trifluoride • diethyl ether complex (2.45 ml) , and the mixture was gradually warmed to room temperature over a period of one hour.
  • N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to -78 °C under argon atmosphere.
  • diisobutyl aluminum hydride 1.0 M toluene solution, 75 ml
  • 10% aqueous hydrochloric acid solution 50 ml was added thereto, and the mixture was warmed to room temperature.
  • the mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine.
  • 5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended in dichloromethane (10 ml) , and thereto were added oxalyl chloride (2.2 ml) and N, N-dimethylformamide (2 drops) . The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and
  • 2-ethylthiophene (2.38 g) were dissolved in dichloromethane (20 ml), and thereto was added aluminum chloride (3.11 g) at 0°C. The mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a cold 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried over magnesium sulfate.
  • reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate.
  • the extract was washed with water, and dried over sodium sulfate.
  • 5-Bromo-2-chloro-l- (2-thieno [3, 2-b] thienylmethyl) benzene (1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar to Reference Example 4- (2) and (3) to give 5-bromo-2-chlorobenzaldehyde. APCI-Mass m/Z 233/235 (M+H+MeOH-H 2 0) . (2) The above 5-bromo-2-chlorobenzaldehyde and thieno [3, 2-b] thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem . Soc.
  • Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
  • Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
  • N-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) in N-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124 mg) and methyl fluorosulfonyl (difluoro) acetate (1.34 ml), and the mixture was stirred under heating for 1.5 hours.
  • the reaction mixture was cooled to room temperature, and then, a diluted aqueous ammonia was added thereto, and the mixture was extracted with ethyl acetate .
  • the extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure.
  • Example 4-(l) were treated in a manner similar to Reference
  • Example 4-(l) were treated in a manner similar to Reference
  • the mixture was stirred at the same temperature for 30 minutes, " and thereto was added dropwise 1, 2-dibromo-l, 1, 2, 2-tetrafluoroethane (6.0 ml) .
  • the mixture was stirred at the same temperature for one hour, and then, warmed to room temperature.
  • the mixture was poured into a diluted aqueous hydrochloric acid solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate.
  • N-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow oil.
  • reaction mixture was poured into ice-cold water, and the solution was extracted with hexane twice, and the extract was washed successively with water and brine, and dried over sodium sulfate.
  • the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane) to give
  • 5-Bromo-2-chloro-l- (2- (5-phenyl-2-thienyl) ethyl) benzene (1) To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml) , and pyridine (2 drops) , and the mixture was stirred under heating at 100 °C overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate . The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate.
  • Reference Example 121 were treated in a manner similar to Reference Example 5 to give the target compound as a colorless solid.
  • APCI-Mass m/Z 367/369 (M+H) APCI-Mass m/Z 367/369 (M+H) .
  • N, N-dimethylformamide 50 ml was added 1, 1' -carbonyldiimidazole (8.10 g), and the mixture was stirred under heating at 40 °C for one hour. Thereto were added t-butanol (7.40 g) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (7.60 g) , and the mixture was further stirred under heating at 40 °C overnight. The mixture was diluted with diethyl ether, and washed successively wi ' th water (3 times), 2% aqueous hydrochloric acid solution (twice) , a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give t-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.
  • 6-Fluoro-2-pyridylboronic acid pinacol ester A solution of 2-bromo-6-fluoropyridine (1.0 g) in tetrahydrofuran (10 ml) was cooled to -78 °C under argon atmosphere, and thereto was added a solution of n-butyl lithium (2.59 M hexane solution, 2.24 ml) in tetrahydrofuran (10 ml) . The mixture was stirred at the same temperature for 45 minutes, and thereto was added dropwise a solution of triisopropoxyborane (1.28 g) in tetrahydrofuran (10 ml) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A compound of the formula (I) wherein Ring A and Ring B are: (1) Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring, (2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring, or (3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, and Ring B are independently an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; X is a carbon atom or a nitrogen atom; Y is -(CH2)n- (n is 1 or 2); a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Description

DESCRIPTION
NOVEL COMPOUNDS HAVING INHIBITORY ACTIVITY AGAINST SODIUM-DEPENDANT TRANSPORTER
TECHNICAL FIELD
The present invention relates to a novel compound having an inhibitory activity against sodium-dependent 'glucose transporter (SGLT) being present in the intestine or kidney.
BACKGROUND ART
Although diet therapy and exercise therapy are essential in the treatment of diabetes mellitus, when these therapies do not sufficiently control the conditions of patients, insulin or an oral antidiabetic agent is additionally used. At the present, there have been used as an antidiabetic agent biguanide compounds, sulfonylurea compounds, insulin resistance improving agents and α-glucosidase inhibitors . However, these antidiabetic agents have various side effects. For example, biguanide compounds cause lactic acidosis, sulfonylurea compounds cause significant hypoglycemia, insulin resistance improving agents cause edema and heart failure, and α-glucosidase inhibitors cause abdominal bloating and diarrhea. Under such circumstances, it has been desired to develop novel drugs for treatment of diabetes mellitus having no such side effects .
Recently, it has been reported that hyperglycemia participates in the onset and progressive impairment of diabetes mellitus, i.e., glucose toxicity theory. Namely, chronic hyperglycemia leads to decrease insulin secretion and further to decrease insulin sensitivity, and as a result, the blood glucose concentration is increased so that diabetes mellitus is self-exacerbated [cf., Diabetologia, vol. 28, p. 119 (1985); Diabetes Care, vol. 13, p. 610 (1990), etc.]. Therefore, by treating hyperglycemia, the aforementioned self-exacerbating cycle is interrupted so that the prophylaxis or treatment of diabetes mellitus is made possible. As one of the methods for treating hyperglycemia, it is considered to excrete an excess amount of glucose directly into urine so that the blood glucose concentration is normalized. For example, by inhibiting sodium-dependent glucose transporter being present at the proximal convoluted tubule of kidney, the re-absorption of glucose at the kidney s inhibited, by which the excretion of glucose into urine is promoted so that the blood glucose level is decreased. In fact, it is confirmed that by continuous subcutaneous administration of phlorizin having SGLT inhibitory activity to diabetic animal models, hyperglycemia is normalized and the blood glucose level thereof can be kept normal for a long time so that the insulin secretion and insulin resistance are improved [cf., Journal of Clinical Investigation, vol. 79, p. 1510 (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991), etc.]. In addition, by treating diabetic animal models with SGLT inhibitory agents for a long time, insulin secretion response and insulin sensitivity of the animals are improved without incurring any adverse affects on the kidney or imbalance in blood levels of electrolytes, and as a result, the onset and progress of diabetic nephropathy and diabetic neuropathy are prevented [cf., Journal of Medicinal Chemistry, vol.42, p.5311 (1999); British Journal of Pharmacology, vol.132, p.578 (2001), etc. ] .
From the above, SGLT inhibitors may be expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and further prevent the onset and progress of diabetes mellitus and diabetic complications . WO 01/27128 discloses an aryl C-glycoside compound having the following structure.
Figure imgf000004_0001
This compound is disclosed to be useful in the prophylaxis or treatment of diabetes mellitus, etc., as an SGLT inhibitor.
DISCLOSURE OF INVENTION
The present invention relates to a compound of the following formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof-
Figure imgf000004_0002
wherein Ring A and Ring B are one of the followings : (1) Ring
A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring, (2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring wherein Y is linked to the heterocyclic ring of the fused heterobicyclic ring, or (3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, wherein the sugar moiety X- (sugar) and the moiety -Y-(Ring B) are both on the same heterocyclic ring of the fused heterobicyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring;
X is a carbon atom or a nitrogen atom; and
Y is -(CH2)n- (wherein n is 1 or 2) .
The compound of the formula I exhibits an' inhibitory activity against sodium-dependent glucose transporter being present in the intestine and the kidney of mammalian species, and is useful in the treatment of diabetes mellitus or diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and delayed wound healing.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present compound (I) is illustrated in more detail.
The definitions for each term used in the description of the present invention are listed below. The "halogen atom" or the "halo" means chlorine, bromine, fluorine and iodine, and chlorine and fluorine are preferable.
The "alkyl group" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. The straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable. Examples thereof are methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, isobutyl group, pentyl group, hexyl group, isohexyl group, heptyl group, 4, 4-dimethylpentyl group, octyl group, 2, 2, 4-trimethylpentyl group, nonyl group, deαyl group, and various branched chain isomers thereof. Further, the alkyl group may optionally and independently be substituted by 1 to 4 substituents as listed below, if necessary.
The "alkylene group" or the "alkylene" means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms. The straight chain or branched chain alkylene group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkylene group having 1 to 4 carbon atoms is more preferable. Examples thereof are methylene group, ethylene group, propylene group, trimethylene group, etc. If necessary, the alkylene group may optionally be substituted in the same manner as the above-mentioned "alkyl group".
Where alkylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle together with the carbon atoms to which they are attached, and may pptionally be substituted by one or more substituents defined below.
The "alkenyl group" means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. Preferable alkenyl group is a straight chain or branched chain alkenyl group having 1 to 6 carbon atoms, and the straight chain or branched chain alkenyl group having 1 to 4 carbon atoms is more preferable. Examples thereof are vinyl group, 2-propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group, 3-undecenyl group, 4-dodecenyl group, 4, 8, 12-tetradecatrienyl group, etc. The alkenyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. The "alkenylene group" means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. The straight chain or branched chain alkenylene group having 2 to 6 carbon atoms is preferable, and the straight chain or branched chain alkenylene group having
2 to 4 carbon atoms is more preferable. Examples thereof are vinylene group, propenylene group, butadienylene group, etc. If necessary, the alkylene group may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
Where alkenylene groups as defined above attach at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle (e.g., a fused benzene ring) together with the carbon atoms to which they are attached, and may optionally be substituted by , one or more substituents defined below.
The "alkynyl group" means a straight or branched monovalent hydrocarbon chain having at least one triple bond. The preferable alkynyl group is a straight chain c>r branched chain alkynyl group having 1 to 6 carbon atoms, and the straight chain or branched chain alkynyl group having 1 to 4 carbon atoms is more preferable. Examples thereof are 2-propynyl group, 3-butynyl group, 2-butynyl group, 4-pentynyl group, 3-pentynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynyl group, 4-decynyl group, 3-undecynyl group, 4-dodecynyl group, etc. The alkynyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. The "cycloalkyl group" means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having
3 to 7 carbon atoms is more preferable. Examples thereof are a monocyclic alkyl group and a bicyclic alkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclodecyl group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. The cycloalkyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S02 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below. The "cycloalkylidene group" means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and the monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms is preferable. Examples thereof are a monocyclic alkylidene group and a bicyclic alkylidene group such as cyclopropylidene group, cyclobutylidene group, cyclopentylidine group, cyclohexylidene group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkylidene group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S02 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The "cycloalkenyl group" means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond. The preferable cycloalkenyl group is a monocyclic unsaturated hydrocarbon group having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, etc. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkenyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S02 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The "cycloalkynyl group" means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and having at least one triple bond. The preferable cycloalkynyl group is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl group, cyclodecynyl group. These _ groups may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkynyl group may optionally and independently be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S02 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The "aryl group" means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof are phenyl group, naphthyl group (including 1-naphthyl group and 2-naphthyl group) . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the aryl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or S02 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferable one is a 4- to 7-membered saturated or unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 4, 5-dihydrooxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, etc. Among them, pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazole can be preferably used. The "unsaturated monocyclic heterocyclic ring" may optionally and independently be substituted by 1-4 substituents as mentioned below, if necessary.
The "unsaturated fused heterobicyclic ring" means hydrocarbon ring comprised of a saturated or a unsaturated hydrocarbon ring condensed with the above mentioned unsaturated monocyclic heterocyclic ring where said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or S02 within the ring, if necessary. The "unsaturated fused heterobicyclic ring" includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydro- isoquinoline, etc. Further, the "heterocyclic ring" also includes possible N- or S-oxides thereof.
The "heterocyclyl" means a monovalent group of the above-mentioned unsaturated monocyclic heterocyclic ring or unsaturated fused heterobicyclic ring and a monovalent group of the saturated version of the above-mentioned unsaturated monocyclic heterocyclic or unsaturated fused heterobicyclic ring. If necessary, the heterocyclyl may optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The "alkanoyl group" means a formyl group and ones formed by binding an "alkyl group" to a carbonyl group.
The "alkoxy group" means ones formed by binding an "alkyl group" to an oxygen atom. t The substituent for the above each group includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) , a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl' group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cycloalkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoyla ino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkylsulfonylaminoι group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenyl- sulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group, a cycloalkynylsulfonyl group, an aryl- sulfonyl group, and a heterocyclylsulfonyl group. Each group as mentioned above may optionally be substituted by these substituents .
Further, the terms such as a haloalkyl group, a halo-lower alkyl group, a haloalkoxy group, a halo-lower alkoxy group, a halophenyl group, or a haloheterocyclyl group mean an alkyl group, a lower alkyl group, an alkoxy group, a lower alkoxy group, a phenyl group or a heterocyclyl group (hereinafter, referred to as an alkyl group, etc.) being substituted by one or more halogen atoms, respectively. Preferable ones are an alkyl group, etc. being substituted by 1 to 7 halogen atoms, and more preferable ones are an alkyl group, etc. being substituted by 1 to 5 halogen atoms. Similarly, the terms such as a hydroxyalkyl group, a hydroxy-lower alkyl group, a hydroxy- alkoxy group, a hydroxy-lower alkoxy group and a hydroxyphenyl group mean an alkyl group, etc., being substituted by one or more hydroxy groups. Preferable ones are an alkyl group, etc. , being substituted by 1 to 4 hydroxy groups, and more preferable ones are an alkyl group, etc . , being substituted by 1 to 2 hydroxy groups. Further, the terms such as an alkoxyalkyl group, a lower alkoxyalkyl group, an alkoxy-lower alkyl group, a lower alkoxy-lower alkyl group, an alkoxyalkoxy group, a lower alkoxyalkoxy group, an alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy group, an alkoxyphenyl group,, and a lower alkoxyphenyl group means an alkyl group, etc., being substituted by one or more alkoxy groups. Preferable ones are an alkyl group, etc. , being substituted by 1 to 4 alkoxy groups, and more preferable ones are an alkyl group, etc., being substituted by 1 to 2 alkoxy groups.
The terms "arylakyl" and "arylalkoxy" as used alone or as part of another group refer to alkyl and alkoxy groups as described above having an aryl substituent.
The term "lower" used in the definitions for the formulae in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless defined otherwise. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms.
The "prodrug" means an ester or carbonate, which is formed by reacting one or more hydroxy groups of the compound of the formula I with an acylating agent substituted by an alkyl, an alkoxy or an aryl by a conventional method to produce acetate, pivalate, methylcarbonate, benzoate, etc. Further, the prodrug includes also an ester or amide, which is similarly formed by reacting one or more hydroxy groups of the compound of the formula I with an α-amino acid or a β-amino acid, etc. using a condensing agent by a conventional method.
The pharmaceutically acceptable salt of the compound of the formula I includes, for example, a salt with an alkali metal such as lithium, sodium, potassium, etc.; a salt with an alkaline earth metal such as calcium, magnesium, etc.; a salt with zinc or aluminum; a salt with an organic base such as ammonium, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl glucosamine, triethanolamine and dehydroabietyla ine; a salt' with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc. ; or a salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc. ; or a salt with an acidic amino acid such as aspartic acid, glutamic acid, etc.
The compound of the present invention also includes a mixture of stereoisomers, or each pure or substantially pure isomer. For example, the present compound may optionally have one or more asymmetric centers at a carbon atom containing any one of substituents. Therefore, the compound of the formula I may exist in the form of enantiomer or diastereomer, or a mixture thereof. When the present compound (I) contains a double bond, the present compound may exist in the form of geometric isomerism (cis-compound, trans-compound) , and when the present compound (I) contains an unsaturated bond such as carbonyl, then the present compound may exist in the form of a tautomer, and the present compound also includes these isomers or a mixture thereof. The starting compound in the form of a racemic mixture, enantiomer or diastereomer may be used in the processes for preparing the present compound. When the present compound is obtained in the form of a diastereomer or enantiomer, they can be separated by a conventional method such as chromatography or fractional crystallization.
In addition, the present compound (I) includes an intramolecular salt, hydrate, solvate or polymorphism thereof . The optionally substituted unsaturated monocyclic heterocyclic ring of the present invention is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxyl group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a hetero- cyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkyloxycarbonyl • group, a cycloalkenyloxycarbonyl group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cycloalkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a, mono- or di-alkylamino group, a mono- or di-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkylsulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenyl- sulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group, a cycloalkynylsulfoηyl group, an arylsulfonyl group, and a heterocyclylsulfonyl group wherein each substituent may optionally be f rther substituted by these substituents .
The optionally substituted unsaturated fused heterobicyclic ring of the present invention is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidene- methyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenyl- carbonyl group, a cycloalkynyl- carbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxy- carbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxy- carbonyl group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cyclo- alkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cyclo- alkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclyl- carbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoyl- amino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkyl- sulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl groups, an alkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cyclo- alkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl. group, a cyclo- alkenylsulfonyl group, a cycloalkynylsulfonyl group, an arylsulfonyl group, and a heterocyclylsulfonyl group, wherein each substituent may optionally be further substituted by these substituents.
The optionally substituted benzene ring of the present invention is a benzene ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an 'aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, a cycloalkynylox'ycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cycloalkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkylsulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group,, a cycloalkynylsulfonyl group, an arylsulfonyl group, and a heterocyclylsulfonyl group, an alkylene group, an alkyleneoxy group, an alkylenedioxy group, and an alkenylene group wherein each substituent may optionally be further substituted by these substituents. Moreover, the optionally substituted benzene ring includes a benzene ring substituted with an alkylene group to form an annelated carbocycle together with the carbon atoms to which they are attached, and also includes a benzene ring substituted with an alkenylene group to form an' annelated carbocycle such as a fused benzene ring together with the carbon atoms to which they are attached.
The optionally substituted unsaturated monocyclic heterocyclic ring is preferably an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, and an oxo group. The optionally substituted unsaturated fused heterobicyclic ring is preferably an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cyclo- alkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, and an oxo group. The optionally substituted benzene ring is preferably a benzene ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, an alkylene group, an alkyleneoxy group, an alkylenedioxy group, and an alkenylene group.
In another preferable embodiment, the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, and an oxo group; the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkyl- sulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, phenylsulfonyl group, a heterocyclyl group, and an oxo group; and the optionally substituted benzene ring is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; wherein each of the above-mentioned substituents on the unsaturated monocyclic heterocyclic ring, the unsaturated fused heterobicyclic ring and the benzene ring may further be substituted by 1-3 substituents, independently s,elected from the group consisting of a halogen atom, a hydroxy group, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, a mono- or di-alkylamino group,t a carboxyl group, an alkoxycarbonyl group, a phenyl group, an alkyleneoxy group, an alkylenedioxy group, and an oxo group.
As a preferable embodiment, there is mentioned a compound in which the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, and an oxo group; the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, and an oxo group; and the optionally substituted benzene ring is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group,, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; wherein each of the above-mentioned substituents on the unsaturated monocyclic heterocyclic ring, the unsaturated fused heterobicyclic ring and the benzene ring may further be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, a carboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxy group, and an alkoxycarbonyl group.
As another preferable embodiments, there are mentioned (1) a compound in which Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an -amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, and an oxo group, and Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting 'of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkl- sulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; (2) a compound in which Ring A is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group, and
Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino-, group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group and an oxo group; and
(3) a compound in which Ring A is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, and an oxo group, and
Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group and an oxo group; wherein each of the above-mentioned substituents on Ring A and Ring B may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, a carboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxy group, and an alkoxycarbonyl group.
As more preferable embodiments, there is mentioned a compound in which Ring A and Ring B are
(1) Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or an oxo group, and Ring B is (a) a benzene ring which may optionally be substituted by a halogen atom; a cyano group; a lower alkyl group; a halo-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; (b) an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-lower alkylamino group, a phenyl group which may be substituted with a halogen atom, cyano group, a' lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; and a heterocyclyl, group which may optionally be substituted with a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or -(c) an unsaturated fused heterobicyclic ring which may optionally be substituted by a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-lower alkylamino group, a phenyl group which may be substituted with a halogen atom, cyano group, a lower alkyl group, .a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; and a heterocyclyl group which may optionally be substituted with a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group;
(2) Ring A is a benzene ring which may optionally be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a phenyl group, or a lower alkenylene group, and Ring B is (a) an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a halogen atom; a cyano group; a lower alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; (b) an unsatμrated fused heterobicyclic ring which may optionally be substituted by a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a lower alkoxy group, ,a halo-lower alkoxy group, a mo- or di-lower alkylamino group, a phenyl group which may be substituted with a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; and a heterocyclyl group which may optionally be substituted with a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or (3) Ring A is an unsaturated fused heterobicyclic ring which may optionally be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or an oxo group, and Ring B is (a) a benzene ring which may optionally be substituted by a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-lower alkylamino group, a phenyl group which may be substituted with a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; and a heterocyclyl group which may optionally be substituted with a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; (b) an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a halogen atom; a cyano group; a lower alkyl group; a halo-lower alkyl group; a lower alkoxy group; a halo-lower alkoxy group; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; or (c) an unsaturated fused heterobicyclic ring, which may optionally be substituted by a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mo- or di-lower alkylamino group, a phenyl group which may be substituted with a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group; and a heterocyclyl group which may optionally be substituted with a group selected from a halogen atom, cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a mono- or di-lower alkylamino group.
In another preferable embodiment, there is mentioned a compound of the formula I, wherein Y is -CH2- and is linked at the 3-position of Ring A, with respect to X being the 1-position, Ring A is a benzene ring which is substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a phenyl group, and a lower alkenylene group, and Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a halo-lower alkoxy phenyl group, a lower alkylenedioxyphenyl group, a lower alkyleneoxy phenyl group, a mono- or di-lower alkylaminophenyl group, a heterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, a lower alkoxyheterocyclyl group, and a mono- or di-lower alkylaminoheterocycyclyl group. In yet another preferable embodiment, there -is mentioned a compound of the formula I wherein Y is -CH2- and is linked at the 3-position of Ring A, with respect to X being the 1-position, Ring A is an unsaturated monocyclic heterocyclic ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and an oxo group, and Ring B is a benzene ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, , a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a heterocyclyl group, a haloheterocyclyl group, and a lower alkylheterocyclyl group. Further, as another preferable embodiment, there is mentioned a compound of formula I wherein Y is -CH2- and is linked at the 3-position of Ring A, with respect to X being the 1-position, Ring A is an unsaturated monocyclic heterocyclic ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and an oxo group, and Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, a heterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, a lower alkoxyheterocyclyl group, and a lower alkoxyheterocyclyl group
As a more preferable compound, a compound in which X is a carbon atom and Y is -CH2- is mentioned.
Further, as another preferable compound, there is mentioned a compound in which Ring A and Ring B are (1) Ring A is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, a phenyl group, and a lower alkenylene group, and Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; and an oxo group, (2) Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group, and
Ring B is a benzene ring which may optionally be' substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a lower alkylene group,
(3) Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a halogen atom or a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group, Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group .consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; and an oxo group;
(4) Ring A is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituerrts, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group,
Ring B is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; and a lower alkylene group, or
(5) Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a lower alkyl group optionally substituted by a lower alkoxy group, a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group, a cycloalkyl group, a cycloaikoxy group, and an oxo group,
Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a phenyl group; a lower alkoxy group optionally substituted by a halogen atom or a lower alkoxy group; a cycloalkyl group; a cycloaikoxy group; a phenyl, group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; and an oxo group.
Preferred is a compound wherein Y is linked at the 3-position of Ring A, with respect to X being the 1-position, Ring A is a benzene ring which may optionally be substituted by a halogen atom, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group, or a phenyl group, and Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom or a phenyl group; a lower alkoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; and an oxo group.
Preferred is a compound wherein Y is linked at the 3-position of Ring A, with respect to X being the 1-position, Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by a substituent selected from a halogen atom, a lower alkyl group, and an oxo group, and Ring B is a benzene ring which may optionally be substituted by a substituent selected from the group consisting of a halogen atom; a lower alkyl group optionally substituted by a halogen atom or a phenyl group; a lower alkoxy group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group; and a lower alkylene group.
Preferable unsaturated monocyclic heterocyclic ring includes a 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 hetero atoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom. More specifically, preferred are furan, thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine and tetrazole. Preferable unsaturated fused heterobicyclic ring includes a 9- or 10-membered unsaturated fused heterocyclic ring containing 1 to 4 hetero atoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom. More specifically, preferred are indoline, isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline, benzothiophene, benzofuran, thienothiophene, and dihydroisoquinoline.
More preferred compounds include a compound wherein Ring A is a benzene ring which may optionally be substituted by a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and a phenyl group, and Ring B is a heterocyclic ring selected from the group consisting of thiophene, furan, benzofuran, benzothiophene, and benzothiazole, wherein the heterocyclic ring may optionally be substituted by a substituent selected from the following group: a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a lower alkylphenyl group, a lower alkoxyphenyl group, a thienyl group, a halothienyl group, a pyridyl group, a halopyridyl group, and a thiazolyl group.
Another preferred compounds include a compound wherein Y is -CH2-, Ring A is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring selected from the group consisting of thiophene, dihydroisoquinpline, dihydroisoxazole, triazole, pyrazole, dihydropyridine, dihydroindole, indole, indazole, pyridine, pyrimidine, pyrazine, quinoline, and a isoindoline, wherein the heterocyclic ring may optionally substituted by a substituent selected from the following group: a halogen atom, a lower alkyl group, and an oxo group, and Ring B is a benzene ring which may optionally be substituted by a substituent selected from the following group: a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, and a halo-lower alkoxy group. Further, a preferable compound of the formula I includes a compound wherein Ring A is
Figure imgf000036_0001
wherein Rla, R2a, R3a, Rlb,' R2b, and R3b are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, a phenyl group, a phenylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, or, a phenylsulfonyl group, and Ring B is
Figure imgf000037_0001
wherein R4a and R5a are each independently a hydrogen atom; a - halogen atom; a hydroxy group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkylidenemethyl group; a cycloalkenyl group; a cycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; a mono- or di-alkylamino group; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an 'alkylenedioxy group, an alkyleneoxy group, or a mono- or di-alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group, or R4a and R5a are bonded to each other at the terminals thereof to form an alkylene group; and R4b, R5b, R4c and R5c are each independently a hydrogen atom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkylidenemethyl group; a cycloalkenyl group; a cycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; a mono- or di-alkylamino group; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group.
More preferred is a compound wherein Rla, R2a, R3a, Rlb, R2b, and R3b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a phenyl group;
R4a and R5a are each independently a hydrogen atom; a halogen atom; a lower alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, or R4a and R5a are bonded to each other at the terminals thereof to form a lower alkylene group; and
R4b, R5b, Rc and R5c are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
Further preferred is a compound in which Ring B is
Figure imgf000039_0001
wherein Ra is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R5a is a hydrogen atom, or R4a and R5a are bonded to each other at the terminals thereof to form a lower alkylene group.
Further more preferred is a compound in which Ring A is
Figure imgf000039_0002
wherein Rla is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R2a and R3a are hydrogen atoms; and Ring B is
Figure imgf000039_0003
wherein R4a is a phenyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, and a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R5a is a hydrogen atom, and Y is —CH2— .
In another preferable embodiment of the present invention, a preferable compound can be represented by the following formula IA:
Figure imgf000040_0001
wherein RA is a halogen atom, a lower alkyl group or a lower alkoxy group; RB is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, or a mono- or di-lower alkylamino group; and Rc is hydrogen atom; or RB and Rc taken together are a fused benzene ring which may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group.
Among them, a compound in which RB is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or a halo-lower alkoxy group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group is preferred.
A preferred heterocyclyl group includes a 5- or 6-membered heterocyclyl group containing 1 or 2 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, or a 9- or 10-membered heterocyclyl group containing 1 to 4 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Specifically, a thienyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, pyrazolyl group, a thiazolyl group, a quinolyl group, and a tetrazolyl group are preferred.
In another preferable embodiment of the present invention, preferred is a compound in which Ring A is
Figure imgf000041_0001
wherein Rla is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R2a and R3a are hydrogen atoms; and Ring B is
Figure imgf000041_0002
wherein R4b and R5b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
Another preferable embodiment includes a compound represented by the following formula IB:
Figure imgf000042_0001
wherein R8, R9 and R10 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an ' alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, * an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, or an- arylsulfonyl group; and a group represented by:
Figure imgf000042_0002
is
Figure imgf000042_0003
wherein R6a and R7a are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkylcarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, or an arylsulfonyl group and R6 and R7b are each independently a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, or an alkoxy group.
Among the compounds represented by the formula IB, more preferred is a compound in which R8, R9 and R10 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloaikoxy group, a halo-lower alkoxy group, or a lower alkoxy-lower alkoxy group, and a group represented by:
Figure imgf000043_0001
wherein R6a, R7a are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkoxy group, a cycloaikoxy group, a halo-lower alkoxy group, or a lower alkoxy-lower alkoxy group, or a group represented by:
Figure imgf000044_0001
wherein R6b and R7b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxy group.
Another preferable embodiment includes a compound represented by the following formula IC:
Figure imgf000044_0002
Wherein Ring B' is an optionally substituted benzene ring, an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring.
Preferable examples of Ring B' include a benzene ring and a heterocyclic ring, both of which may have a substituent (s) selected from the group consisting of a halogen atom; a cyano group; a lower alkyl group optionally substituted by a halogen atom; a lower alkoxy group optionally substituted by a halogen atom; a lower alkanoyl group; a mono- or di-lower alkylamino group; a lower alkoxycarbonyl group; a carbamoyl group; a mono- or di-lower alkylcarbamoyl group; a phenyl group optionally substituted by a substituent (s) selected from a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom, a lower alkanoyl group, a mono- or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylcarbamoyl group; a heterocyclyl group optionally substituted by a substituent (s) selected from a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower .alkoxy group optionally substituted by a halogen atom, a lower alkanoyl group, a mono- or di-lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, or a mono- or di-lower alkylcarbamoyl group; an alkylene group; and an oxo group. , More preferable examples of Ring B' include a benzene ring which may be substituted by a substituent selected from the group consisting of a halogen atom; a cyano group; a lower alkyl group optionally substituted by a halogen atom; a lower alkoxy group optionally substituted by a halogen atom; a mono- or di-lower alkylamino group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom; a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group optionally substituted by a halogen atom.
Preferred compound of the present invention may be selected from the following group: 1- ( β-D-glucopyranosyl) -4-chloro-3- ( 6-ethylbenzo [b] thiophen- 2-ylmethyl) benzene;
1- ( β-D-glucopyfanosyl) -'4-chloro-3- [5- (5-thiazolyl) -2- thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- (5-phenyl-2-thienyl- methyl) benzene;
1- ( β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2- thienylmethyl ] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (2-pyrimidinyl) -2- thienylmethyl] benzene;
1- ( β-D-glucopyranosyl) -4-methyl-3~ [5- (2-pyrimidinyl) -2- thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (3-cyanoph'enyl) -2- thienylmethyl] benzene; 1- (β-D-glucopyranosyl) -4-chloro-3- [5- (4-cyanophenyl) -2- thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridyl) -
2-thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridyl) - 2-thienylmethyl] benzene;
1- ( β-D-glucopyranosyl) -4-methyl-3- [5- (3-difluoromethyl- phenyl) -2-thienylmethyl] benzene; the pharmaceutically acceptable salt thereof; and the prodrug thereof. The compound (I) of the present invention exhibits an excellent inhibitory activity against sodium-dependent glucose transporter, and an excellent blood glucose lowering effect. Therefore, the compound of the present invention is useful in the treatment or the prophylaxis of diabetes mellitus (type 1 and type 2 diabetes mellitus, etc.) or diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or is useful in the treatment of postprandial hyperglycemia.
The compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered either orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation. Suitable pharmaceutical preparation for oral administration includes, for example, solid preparation such as tablets, granules, capsules, powders, etc., or solution preparations, suspension preparations, or emulsion preparations, etc. Suitable pharmaceutical preparation for parenteral administration includes, for example, suppositories; injection preparations and intravenous drip preparations using distilled water for injection, physiological saline solution or aqueous glucose solution; or inhalant preparations .
The dosage of the present compound (I) or a pharmaceutically acceptable salt thereof may vary.according to the administration routes, ages, body weight, conditions of a patient, or kinds and severity of a disease to be treated, and it is usually in the range of about 0.1 to 50 mg/kg/day, preferably in the range of about 0.1 to 30 mg/kg/day. The compound of the formula I may be used, if necessary, in combination with one or more of other antidiabetic agents and/or one or more agents for treatment of other diseases. The present compound and these other agents may be administered in the same dosage form, or in a separate oral dosage form or by injection.
The other antidiabetic agents include, for example, antidiabetic or antihyperglycemic agents including insulin, insulin secretagogues, or insulin sensitizers, or other antidiabetic agents having an action mechanism different from SGLT inhibition, and 1, 2, 3 or 4 of these other antidiabetic agents may preferably be used. Concrete examples thereof are biguanide compounds, sulfonylurea compounds, α-glucosidase inhibitors, PPARy agonists (e.g., thiazolidinedione compounds), PPARα/γ dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors, mitiglinide compounds, and/or nateglinide compounds, and insulin, glucagon-like peptide-1 (GLP-1) , PTP1B inhibitors, glycogen phosphorylase inhibitors, RXR modulators, and/or glucose 6-phosphatase inhibitors. The agents for treatment of other diseases include, for example, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent. The SGLT inhibitors of the formula I may be used in combination with agents for treatment of diabetic complications, if necessary. These agents include, for example, PKC inhibitors and/or ACE inhibitors .
The dosage of those agents may vary according to ages, body weight, and conditions of patients, and administration routes, dosage forms, etc.
These pharmaceutical compositions may be orally administered to mammalian species including human beings , apes , dogs, etc., for example, in the dosage form of tablet, capsule, granule or powder, or parenterally administered in the form of injection preparation, or intranasally, or in the form of transdermal patch.
The present compound of the formula I may be prepared by the following Processes. Process 1
The compound of the formula I may be prepared by a method as shown in the following scheme:
Figure imgf000048_0001
( ID ( I ) wherein Rlla is a hydrogen atom or a protecting group for a hydroxy group, and Rllb, Rllc and R are each independently a protecting group for a hydroxy group, and other symbols are as defined above .
The compound of the formula I may be prepared by deprotecting the compound of the formula II.
In the compound of the formula II, the protecting group for hydroxy group may be any conventional protecting groups, and a benzyl group, an acetyl group, and an alkylsily group such as a trimethylsilyl group may be used. Further, the protecting group for hydroxy group may form acetal or silylace'tal together with adjacent hydroxy groups. Examples of such protecting group include an alkylidene group such as an isppropylidene group, a sec-butylidene group, etc., a benzylidene group, or a dialkylsilylene group such as di-tert-butylsilylene group, etc., which can be formed, for example, by combining Rllc and Rlld at the terminal thereof. , The deprotection can be carried out according to the kinds of protecting group to be removed, for example, by conventional processes such as reduction, hydrolysis, acid treatment, fluoride treatment, etc.
For example, when a benzyl group is to be removed, the deprotection can be carried out by (1) catalytic reduction using a palladium catalyst (e.g., palladium-carbon, palladium hydroxide) under hydrogen atmosphere in a suitable solvent (e.g., methanol, ethanol, ethyl acetate); (2) treatment with an dealkylating agent such as boron tribromide, boron trichloride, boron trichloride • dimethylsulfide complex, or iodotrimethylsilane in a suitable solvent (e.g., dichloromethane) ; or (3) treatment with a lower alkylthiol such as ethanethiol in the presence of a Lewis acid (e.g., boron trifluoride • diethyl ether complex) in a suitable solvent (e.g., dichloromethane) .
When a protecting' group is removed by hydrolysis, the hydrolysis can be carried out by treating the compound of formula II with a base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, etc.) in a suitable solvent (e.g., tetrahydrofuran, dioxane, methanol, ethanol, water, etc.).
Acid treatment can be carried out by treating the compound of formula II with an acid (e.g., hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc. ) .
In case of the fluoride treatment, it can be carried out by treating the compound of formula II with a fluoride (e.g., hydrogen fluoride, hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.) in a suitable solvent (e.g., acetic acid, a lower alcohol (methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, etc.). The deprotection reaction can be preferably carried out under cooling or with heating, for example, at a temperature of from 0°C to 50 °C, more preferably at a temperature of from 0°C to room temperature. Process 2 The compound of the formula I wherein X is a carbon atom may be prepared by a method as shown in the following scheme:
Figure imgf000050_0001
( '" ) ( l-a ) wherein R12 is a lower alkyl group, and other symbols are as defined above.
The compound of the(formula I-a may be prepared by reducing the compound of the formula III.
The reduction can be carried out by treatment with a silane reagent, in the presence of an acid, in a suitable solvent or in the absence of a solvent.
As the acid, for example, a Lewis acid such as boron trifluoride • diethyl ether complex, titanium tetrachloride, etc., and a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc., may preferably be used.
As the silane reagent, for example, a trialkylsilane such as triethylsilane, triisopropylsilane, etc. may preferably be used. As the solvent, any kinds of solvent may be-,used as long as it does not affect the reaction, and for example, acetonitrile, dichloromethane, or an acetonitrile/dichloromethane mixture may preferably be used.
Process 3 The compound of the formula I wherein X is a carbon atom may be prepared by a method as shown in the following scheme:
Figure imgf000051_0001
wherein the symbols are as defined above.
Namely, the compound of the formula I-b may be prepared by reducing the compound of the formula IV.
The reduction can be carried out in a manner similar to Process 2. In other words, it can be carried out by treatment with a silane reagent (e.g., triethylsilane, etc.), in the presence of a Lewis acid (e.g., boron trifluoride • diethyl ether complex, etc.), in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.).
The compound of the present invention thus obtained may be isolated and purified by a conventional method well known in the organic synthetic chemistry such as recrystallization, column chromatography, etc.
The starting compound represented by the formula (II) , (III) or (IV) may be prepared by either one of the following steps (a) - (j ) . Steps (a) and (b) :
Figure imgf000052_0001
In the above scheme, R .13 is (1) a bromine atom or an iodine atom when X is a carbon atom; or (2) a hydrogen atom when X is a nitrogen atom, Rlle is a protecting group for hydroxy group, and the other symbols are as defined above. Step (a) :
Among the compounds of the formula II, the compound wherein X is a carbon atom may be prepared by coupling the compound of the formula VII with the compound of the formula VI to give the compound of formula V, followed by reduction of the compound of the formula V.
The coupling reaction can be carried out by lithiating the compound of the formula VII, followed by reacting the resultant with the compound of the formula VI. ~
In particular, the compound of the formula VII can be treated with an alkyllithium, followed by reacting the resultant with the compound of the formula VI. As the alkyllithium, methyl lithium, n-butyl lithium, t-butyl lithium, etc. are preferably used. The solvent may be any solvent which does not disturb the reaction, and ethers such as tetrahydrofuran, diethyl ether, etc., are ' preferably used.
This reaction can be carried out from under cooling (e.g., at
-78 °C) to room temperature. The reduction can be carried out in a manner similar to
Process 2. Namely, it can be carried out by treating the compound of formula V with a silane reagent (e.g., triethylsilane, etc.) in the presence of a Lewis acid (e.g., boron trifluoride • diethyl ether complex, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.).
Step (b)
Among the compounds of the formula II, the compound wherein X is a nitrogen atom may be prepared by silylating the compound of the formula VII in a solvent, followed by reacting the resultant with the compound of the formula VIII (e.g., an - or β-D-glucose pentaacetate, etc. ) in the presence of a Lewis acid.
The silylation reaction can be carried out by treating the compound of formula VII with a silylating agent in a solvent. The silylating agent includes, for example,
N, O-bis (trimethylsilyl),acetamide, 1,1,1,3,3, 3-hexamethyl- disilazane, etc.
The solvent may be, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, etc., acetonitrile, etc.
This reaction is preferably carried out under cooling or with heating, for example, at a temperature of from 0°C to 60°C, preferably at a temperature of from room temperature to 60 °C.
The reaction with the compound of the formula VIII can be carried out in a solvent in the presence of a Lewis acid.
The Lewis acid includes, for example, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, boron trifluoride • diethyl ether complex.
The solvent may be, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., acetonitrile, etc. This reaction can be carried out under cooling or with heating, for example, at a temperature of from 0°C to 100 °C, _ preferably at a temperature of from room temperature to 60 °C. Step (c) :
Among the compounds of the formula II, the compound wherein X is a carbon atom and Rlla is a hydrogen atom may be prepared by a method as shown in the following scheme:
Figure imgf000054_0001
wherein R13a is a bromine atom or an iodine atom, and the other symbols are as defined above.
Namely, the compounds of the formula Il-a may be prepared by coupling the compound of the formula Vll-a with the compound of the formula X or an ester thereof to give the ' compound of the formula IX, followed by hydrating the compound of the formula IX.
The ester of the compound of the formula X includes, for example, a lower alkyl ester thereof, and a compound represented by the formula XI:
Figure imgf000055_0001
wherein R14 is a lower alkyl group, is 0 or 1, and the other "symbols are as defined above.
The coupling reaction of the compound of the formula Vll-a with the compound of -the formula X or an ester thereof can be carried out in the presence of a base and a palladium catalyst in a suitable solvent.
The base includes an inorganic base such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), potassium fluoride, potassium phosphate, etc., and an organic base such as a tri-lower alkylamine (e.g., triethylamine, diisopropylethylamine, etc.), a cyclic tertiary amine (e.g., 1, 4-diazabicyclo [2.2.2] octane, 1, 5-diazabicyclo [4.3.0]- nona-5-ene, 1, 8-diazabicyclo [5.4.0] undeca-7-ene, etc.).
The palladium catalyst may be a conventional catalyst such as tetrakis (triphenyl) phosphinepalladium (0) , palladium (II) acetate, palladiu (II) chloride, bis (triphenyl) phosphine palladium (II) chloride, palladium (II) chloride • 1, 1-bis (diphenylphosphino) ferrocene complex, etc.
The solvent may be any inert solvent which does not disturb the reaction, for example, ethers such as tetrahydrofuran, dioxane, etc., amide solvents such as N,N-dimethylformamide, 1, 3-dimethyl-2-imidazolidinone, etc., aromatic hydrocarbons such as toluene, xylene, etc., dimethylsulfoxide, water, and if desired, a mixture of two or more of these solvents.
This reaction is preferably carried out with heating, for example, at a temperature of from 50 °C to a boiling point of the reaction mixture,' and more preferably at a temperature of from 50°C to 100°C.
The hydration reaction of the compound of the formula IX can be carried out, for example, by hydroboration, more specifically, by reacting with diborane, borane • tetrahydrofuran complex, or 9-borabicyclononane, etc. in a suitable solvent, followed by treating with hydrogen peroxide solution in the presence of a base (e.g., an alkali metal hydroxide such as sodium hydroxide, etc.) , or by treating with an oxidizing reagent such as sodium perborate, and oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) in a suitable solvent.
The solvent may be any inert solvent which does not disturb the reaction, for example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxy- ethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., water, and if desired, a mixture of two or more of these solvents. This reaction can be carried out at a temperature of a broad range such as under cooling or with heating, and preferably carried out at a temperature of from -10 °C to a boiling point of the reaction mixture.
Step (d) :
Among the compound of the formula II, the compound wherein
Ring A is a benzene ring may be prepared in a method as shown in the following scheme:
Figure imgf000057_0001
( Il- ) wherein the symbols are as defined above.
Namely, the compounds" of the formula Il-b may be prepared by coupling the compound of the formula XIV with the compound of the formula XIII, to give the compound of the formula XII, followed by reduction of the compound of the formula XII.
The coupling reaction can be carried out in a manner similar to Step (a). Namely, it can be carried out by lithiating the compound of formula XIV with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), followed by reacting the resultant with the compound (XIII).
The reduction reaction can be carried out by (1) treatment with a silane reagent (e.g., trialkyl silane such as triethyl silane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), at -30°C to 60°C, in the presence of a Lewis acid such as boron trifluoride • diethyl ether complex or trifluoroacetic acid, (2) treatment with iodotrimethylsilane, or (3) treatment with a reducing agent (e.g., borohydrides such as sodium boron hydride, sodium triacetoxyborohydride, etc., aluminum hydrides such as lithium aluminum hydride, etc.) in the presence of an acid (e.g., a strong acid such as trifluoroacetic acid, etc. , and a Lewis acid such as aluminum chloride, etc.). Step (e) : The compound of the formula III may be prepared by a method as shown in the following scheme:
Figure imgf000058_0001
wherein the symbols are as defined above.
Namely, the compound of the formula III may be prepared by deprotecting the compound of the formula V which is a synthetic intermediate of Step (a) , followed by treating the resultant compound with an acid in an alcohol solvent.
The deprotection reaction can be carried out in a manner similar to Process 1. Namely, it can be carried out by subj ecting the compound V to an acid treatment, reduction, or a fluoride treatment, etc.
Following the deprotection reaction, the resultant compound is treated with an acid in a suitable alcohol. The acid includes, for example, an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, etc., an organic acid such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc. The alcohol includes a conventional alkyl alcohol which does not disturb the reaction, for example, methanol, ethanol, n-propanol, i-propanol, n-butanol, etc.
Additionally, the deprotection reaction and acid treatment may be carried out in the same step, depending on the kind of the protecting group. Step (f) :
The compound of the formula IV may be prepared by a method as shown in the following scheme:
Figure imgf000059_0001
wherein the symbols are as defined as above.
First, the compound of the formula XVI is coupled with the compound of the formula VI to give the compound of the formula
XV. Then, after protecting groups are removed from the compound of the formula XV, the resultant is treated with an acid in an alcohol to give the compound of the formula IV.
The coupling reaction can be carried out in a manner similar to Step (a) . Namely, the compound XVI is treated with an alkyl lithium (e.g., n-butyl lithium, tert-butyl lithium, etc,) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc. ) , ,followed by reacting the resultant with the compound VI .
The removal of protecting groups and the acid treatment are carried out in a manner similar to Step (e) . Namely, it can be carried out by subjecting the compound XV to reduction, acid treatment or fluoride treatment, depending on the kind of the protecting group to be removed, followed by treating the resultant with an acid (e.g., hydrochloric acid,' p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.) in a suitable solvent (e.g., methanol, ethanol, etc. ) . Step (g) : The compound of the formula II may be prepared by a method as shown in the following scheme:
Figure imgf000060_0001
( XVII )
( ID wherein R20 is a trialkylstannyl group, or a dihydroxyboryl group or an ester thereof, and the other symbols are as defined above.
Namely, the compound of the formula II may be prepared by coupling the compound XVII with the compound XVIII in a suitable solvent, in the presence of a palladium catalyst, and in the presence or in the absence of a base. The coupling reaction can be carried out in a manner similar to Step (c) . Step (h) :
Among the compound of the formula IV, the compound wherein n is 1 may be prepared in a method as shown in the following scheme: <
Figure imgf000061_0001
( XX )
( XXII )
Figure imgf000061_0002
wherein the symbols are as defined above.
Namely, the compound of the formula IV may be prepared by the following steps : (1) treating the compound of the formula _ XXII with a halogenating agent in a suitable solvent or in the absence of a solvent, followed by condensation of the resultant with the compound of the formula XXI in the presence of a Lewis acid to give the compound of formula XX, (2) reducing the compound of formula XX, and (3) removing the protecting groups from the compound of formula XIX.
The halogenating agent includes a conventional halogenating agent such as thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.
The solvent may be any solvent which does not disturb the reaction, and for example, dichloromethane, carbon tetrachloride, tetrahydrofuran, toluene, etc. may be mentioned.
Further, in the present reaction, the reaction suitably proceeds by adding a catalyst such as dimethylformamide, etc. The condensation reaction of the compound (XXII) and the compound (XXI) can be carried out according to a conventional method as known as Friedel-Crafts reaction, in the presence of a Lewis acid and in a suitable solvent.
The Lewis acid includes aluminum chloride, boron trifluoride • diethyl ether complex, tin (IV) chloride, titanium tetrachloride, etc. which are conventionally used in Friedel-Crafts reaction.
The solvent includes halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, dichloroethane, etc. The reduction reaction can be carried out by treating the compound of formula XX with a silane reagent (e.g., trialkyl silane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g., a Lewis acid such as boron trifluoride • diethyl ether complex, etc., and a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc.), or by treating with a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassium hydroxide, etc.).
The present reaction can be carried out under cooling or with heating, for example, at a temperature of from -30 °C to 60°C.
The removal of the protecting groups from the compound of formula XIX can be carried our in a manner similar to Process 1.
Step (i) : Among the compounds of the formula II, the compound wherein X is a nitrogen atom may be prepared by a method as shown in the following scheme:
Figure imgf000063_0001
wherein R21 is a leaving group, and the other symbols are as defined above.
Examples of the leaving group include a halo'gen atom such as chlorine atom and bromine atom.
Namely, the compound of the formula Il-d may be prepared by condensation of the compound of the formula XXIII with the compound of the formula XXIV. : •>
The condensation reaction can be carried out in a suitable solvent such as acetonitrile, etc., in the presence of a base (e.g., an alkali metal hydroxide, such as potassium hydroxide, etc. ) . Step (j) :
Among the compound of the formula II, the compound wherein Ring A is a pyrazole substituted by a lower alkyl group, X is a nitrogen atom and Y is -CH2- may be prepared by a method as shown in the following scheme:
Figure imgf000063_0002
( XXVI )
( ll-e ) wherein R22 and R23 are each independently a lower alkyl group, and the other symbols are as defined above.
Namely, the compound Il-e may be prepared by condensation of the compound of the formula XXV with the compound of the formula XXVI in a suitable solvent (e.g., ethers such as tetrahydrofuran, etc. , an aromatic hydrocarbons such as toluene, etc. ) . Further, the compound of the present invention may be converted to each other within the objective compounds of the present invention. Such conversion reaction may be carried out according to a conventional method, depending on the kind of the objective substituents. For example, a compound having as a substituent of Ring
B, an aryl group such as phenyl group, or a heterocyclyl group may be prepared by coupling the compound in which substituents of the Ring B is a halogen atom such as a bromine atom, with a suitable phenylboronic acid, phenyltin, hetercyc^-ylboronic acid, or heterocyclyltin.
The coupling reaction may be carried out in a manner similar to Step (c) or Step (g) , or in a method as described in the following Examples.
In the present compound, the compound wherein heteroatom is oxidized (e.g., S-oxide, S,S-oxide, or N-oxide compounds) may be prepared by oxidizing a corresponding S-form or N-form.
The oxidation reaction can be carried out by a conventional method, for example, by treatment with an oxidizing agent (e.g., peracids such as hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, etc.) in a suitable solvent (e.g., halogenated hydrocarbons such as dichloromethane, etc.).
The starting compounds of the respective steps described above may be prepared by the methods as disclosed in Reference Examples or a process as mentioned below.
(1) Among the compounds of the formula VII, the compound wherein Y is -CH2- may be prepared by a method as shown in the following scheme:
Figure imgf000065_0001
wherein R15 is a hydrogen atom or a halogen atom, and the other symbols are as defined above.
Namely, the compound of the formula Vll-b may be prepared by coupling the compound of the formula XXVIII with the compound of the formula XXIX to give the compound of the formula XXVII, followed by reducing the obtained compound of the formula XXVII .
The coupling reaction of the present step may be carried out in a manner similar to Step (a) . Namely, the compound of the formula XXVIII is treated with an alkyl lith-um (e.g., n-butyl lithium, tert-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), followed by reacting the resultant with the compound of the formula XXIX. The reduction reaction may be carried out in a manner similar to Step (d) , more specifically, by (1) treatment with a silane reagent such as triethylsilane, etc., in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), at -30°C to 60°C, in the presence of a Lewis acid such as boron trifluoride • diethyl ether complex or trifluoroacetic acid, (2) treatment with iodotrimethylsilane , or (3) treatment with a reducing agent (e.g., borohydrides such as sodium boron hydride, sodium triacetoxyborohydride, etc., aluminum hydrides such as lithium aluminum hydride, etc.) in the presence of an acid (e.g., a strong acid such as trifluoroacetic acid, etc., a Lewis acid such as aluminum chloride, etc.).
(2) Among the compound of the formula VII, the compound wherein X is a carbon atom and Y is -CH2- may be prepared by a method as shown in the following scheme:
Figure imgf000066_0001
(XXXIII) (XXXII) (χχχ|) (XXX)
Figure imgf000066_0002
wherein R16 is a halogen atom, and the other symbols are as defined above.
The present process may be carried out in a manner similar to Step (h) as mentioned above.
Namely, the compound of the formula VII-c may be prepared by treating the compound of the formula XXXIII wi'th a halogenating reagent (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc.) in a suitable solvent (e.g., dichloromethane, carbon tetrachloride, tetrahydrofuran, toluene, etc.) or in the absence of a solvent, to give the compound of the formula XXXII, subsequently by condensing this compound with the compound of the formula XXXI in a suitable solvent (e.g., dichloromethane, carbon tetrachloride, dichloroethane, etc.) in the presence of a Lewis acid (e.g., aluminum chloride, zinc chloride, titanium tetrachloride, etc.), to give the compound of the formula XXX, and further by reducing the obtained compound.
The reduction reaction can be carried out by treating with a silane reagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.), in the presence of an acid (e.g., a Lewis acid such as boron trifluoride • diethyl ether complex, etc., and a strong organic acid such as trifluoroacetic acid, methanesulfonic acid, etc.), or by treating with a hydrazine in a suitable solvent (e.g., ethylene glycol, etc.) in the presence of a base (e.g., potassium hydroxide, etc.).
(3) Among the compounds of the formula VII, the compound wherein X is a carbon atom and Y is -CH2- may be prepared by a method as shown in the following scheme:
Figure imgf000067_0001
wherein R17 is a lower alkyl group, and the other symbols are as defined above. The compound of the formula VII-c may be prepared by coupling the compound of the formula XXXV with the compound of the formula XXXIV to give the compound of the formula XXX, and subsequently by reducing the obtained compound .
The coupling reaction may be carried out in a manner similar to Step (a) . Namely, the compound of the formula (XXV) is lithiated with an alkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), and subsequently, by reacting the resultant with the compound (XXIV) . The reduction reaction may be carried out in a manner similar to Step (a) . Namely, it can be carried out by treating the compound of formula XXX with a silane reagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc. ) , in the presence of an acid (e.g. , boron trifluoride • diethyl ether complex, etc) .
(4) Among the compound of the formula VII, the compound wherein X is a carbon atom and Y is -CH2- may be prepared by a method as shown in the following scheme:
Figure imgf000068_0001
wherein R18is a lower alkyl group, and the other, symbols are as defined above.
Namely, the compound of the formula VII-c may be prepared by coupling the compound of the formula XXVIII with the compound of the formula XXXVI to give the compound of the formula XXX, and subsequently by reducing the compound.
The present process may be carried out in a manner similar to Step (3) . Namely, the compound of the formula (XXVIII) is lithiated with an alkyllithium (e.g., tert-butyl lithium, n-butyl lithium, etc.) in a suitable solvent (e.g., diethyl ether, tetrahydrofuran, etc.), and subsequently, by reacting the resultant with the compound (XXXVI) to give the compound of the formula (XXX) . Subsequently, the compound of the formula XXX is treated with a silane reagent (e.g., triethylsilane, etc.) in a suitable solvent (e.g., acetonitrile, dichloromethane, etc.) in the presence of an acid (e.g., boron trifluoride • diethyl ether complex, etc) , to give the compound of the formula (VII-c) . The compound of the formula XIV wherein Ring A is a benzene ring is disclosed in WO 01/27128 pamphlet.
The compound of the formula VI is disclosed in WO 01/27128 or Benhaddu, S. Czernecki et al . , Carbohydr. Res., vol. 260, p. 243-250, 1994. The compound of the formula VIII may be prepared from D- (+) -glucono-1, 5-lactone according to the method disclosed in USP 6515117.
The compound of the formula X and the compound of the formula XI may be prepared by the following Reaction Scheme:
Figure imgf000069_0001
wherein the symbols are as defined above.
First, the compound of the formula XXXVII is lithiated with t-butyl lithium in a suitable solvent (e.g., tetrahydrofuran, etc.) under cooling (e.g., -78°C), followed by reacting with trimethyl borate to give the compound of the formula X.
Then, the compound of the formula X is reacted with a 1,2-diol (e.g., pinacol, etc.) or 1,3-diol (e.g., 2, 4-dimethyl-2, 4-pentanediol, etc.) to give the compound of the formula XI .
The other starting compounds are commercially available or may easily be prepared by a standard method well known to an ordinary skilled person in this field.
Hereinafter, the present invention will be illustrated by Examples and Reference Examples, but the present invention should not be construed to be limited thereto. Example 1 1- (β-D-glucopyranosyl) -3- (5-ethyl-2-thienyl- methyl ) benzene
Figure imgf000070_0001
In the above scheme, Me is a methyl group, Et is an ethyl group,
TMSO and OTMS are a trimethylsilyloxy group.
(1) 3-Bromo- (5-ethyl-2-thienylmethyl) benzene 1 (211 mg) was dissolved in tetrahydrofuran (2 ml) - toluene (4 ml) , and the mixture was cooled to -78 °C under argon atmosphere. To the mixture was added dropwise n-butyl lithium (2.44 M hexane solution, 0.29 ml), and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2, 3, 4 , 6-tetrakis-O-trimethylsilyl-D-glucono-l, 5-lactone 2
(see USP 6, 515, 117) (233 mg) in toluene (5 ml) was added dropwise, and the mixture was further stirred at the same temperature for one hour to give a lactol compound 3. Without isolating this compound, a solution of methanesulfonic acid (0.1 ml) in methanol (5 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give a methyl ether compound 4 (136 mg) of the lactol. APCI-Mass m/Z 412 (M+NH4) . (2) A solution of the above methyl ether compound 4 (100 mg) in dichloromethane (5 ml) was cooled to -78 °C under argon atmosphere, and thereto were added dropwise successively triisopropylsilane (0.16 l), and boron trifluoride • diethyl ether complex (0.10 ml) . The mixture was stirred at the same temperature for 10 minutes, and warmed. The mixture was stirred at 0°C for 1 hour and 20 minutes, and then further stirred at room temperature for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 19:1) to give the desired 1- ( β-D-glucopyranosyl) -3- (5-ethyl-2-thienylmethyl) benzene 5
(59 mg) . APCI-Mass m/Z 382 (M+NH4) .
Example 2 5- ( β-D-glucopyranosyl) -1- (4-ethylphenyl- methyl) -lH-pyridin-2-one
Figure imgf000071_0001
In the above scheme, tBu is a tert-butyl group, OTIPS is a triisopropylsilyloxy group, and the other symbols are as defined above. (1) 5-Bromo-l- (4-ethylphenylmethyl) -lH-pyridin-2-one 6 (293mg) and boronic acid ester of glucal 7 (l.Og) were dissolved in dimethoxyethane (5 ml) . To the mixture were added bis (triphenyl) phosphine palladium (II) dichloride (35 mg) and 2M sodium carbonate (2.5 ml), and the mixture was" heated with stirring under reflux under argon atmosphere for 5 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5-70:30) to give glucal derivative 8 (276 mg) as colorless powder. APCI-Mass m/Z 654 (M+H) .
(2) A solution of glucal derivative 8 (260 mg) in tetrahydro- furan (5 ml) was cooled to 0°C under argon atmosphere, and thereto was added dropwise a solution of borane • tetrahydrofuran complex (1.13 M tetrahydrofuran solution, 1.06 ml) , and the reaction solution was stirred at the same temperature overnight. A mixture of an aqueous hydrogen peroxide solution (31 %, 5.0"ml) and 3N aqueous sodium hydroxide solution (5.0 ml) was added to the reaction solution, and the mixture was warmed to room temperature, and stirred for 30 minutes. To the mixture was added 20 % aqueous sodium thiosulfate solution (30 ml), and the mixture was extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 96:4 - 66.34) to give C-glucoside compound 9 (59 mg) as colorless powder. APCI-Mass m/Z 672 (M+H) .
(3) The above C-glucoside compound 9 (55 mg) was dissolved in tetrahydrofuran (2 ml) , and thereto was added tetrabutyl ammonium fluoride (1.0 M tetrahydrofuran solution, 0.41 ml) . The mixture was heated with stirring under reflux for 3 hours under argon atmosphere, and the reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 - 88:12) to give the desired 5- (β-D-glucopyranosyl) -1- (4-ethylphenylmethyl) - lH-pyridin-2-one 10 (10 mg) as colorless powder . APCI-Mass m/Z 376 (M+H) .
Example 3 1- ( β-D-glucopyranosyl) -3- (benzo [b] thiophen-2- ylmethyl) benzene
Figure imgf000073_0001
13 14
In the above scheme, Bn is a benzyl group.
(1) β-m-Bromophenyl-tetra-O-benzyl-C-glucoside 11 (see WO 01/27128) (1.00 g) was dissolved in diethyl ether (60 ml), and the mixture was cooled to -78 °C under argon atmosphere. To the mixture was added dropwise t-butyl lithium (1.49 M pentane solution, 0.99 ml), and the mixture was stirred at the same temperature for 10 minutes. Then, a solution of 2-formylbenzo [b] thiophene (286 mg) in diethyl ether (2 ml) was added dropwise, and the mixture was further stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was warmed to room temperature. The mixture was extracted with diethyl ether, the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10-50:50) to give an" alcohol compound 12 (835 mg) . APCI-Mass m/Z 780 (M+NH4) . (2) A solution of the above alcohol compound 12 (820 mg) in dichloromethane (15 ml) was cooled to -78 °C under argon atmosphere, and thereto were added dropwise successively triethylsilane (0.52 ml), and boron trifluoride • diethyl ether complex (0.20 ml) . The reaction mixture was warmed to room temperature and stirred at the same temperature for 30 minutes. Added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 94:6-75:25) to give the compound 13 (703 mg) . APCI-Mass m/Z 764 (M+NH4) . (3) A solution of the above compound 13 (690 mg) in dichloromethane (20 ml) was cooled to 0°C, and iodotrimethylsilane (0.66 ml) was added thereto and the mixture was stirred at room temperature for one hour. Addition of iodotrimethylsilane and stirring at room temperature were repeated in the same manner for 3 times. Total amount of the iodotrimethylsilane was summed up to 2.64 ml. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether twice, and washed with an aqueous sodium thiosulfate solution. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (chloroform: methanol = 100:0 - 89:11) to give the desired 1- (β-D-glucopyranosyl) -3- (benzo [b] thiophen- 2-ylmethyl) benzene 14 (180 mg) . APCI-Mass m/Z 404 (M+NH )
Example 4 1- (β-D-glucopyranosyl) -3- (5-chloro-2-thienyl- methyl) -4-methylbenzene
Figure imgf000075_0001
In the above scheme, the symbols are as defined above. (1) A solution of 2-chlorothiophene (447 mg) in tetrahydrofuran (10 ml) was cooled to -78°C under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 2. -61 ml) . The mixture was stirred at the same temperature for one hour, and added dropwise thereto was a solution of 5-bromo-2-methylbenzaldehyde 15 (750 mg) in tetrahydrofuran (5 ml) . The mixture was stirred at the same temperature for 30 minutes to give a compound 16. Toluene (30 ml) was added, and further added dropwise thereto was n-butyl lithium (1.59 M hexane solution, 2.37 ml). The mixture was further stirred at the same temperature for 30 minutes, and a solution of 2, 3, 4, 6-tetrakis-O-trimethylsilyl-D-glucono- 1,5-lactone 2 (see USP 6,515,117) (1.76 g) in toluene (5 ml) was added dropwise, and the mixture was further stirred at the same temperature for one and a half hours to give a lactol compound 17. Subsequently, a solution of methanesulfonic acid (1.22 ml) in methanol (25 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude methyl ether compound 18, which was used in the subsequent step without further purification. (2) A solution of the above crude methyl ether compound 18 in dichloromethane (25 ml) was cooled to -78 °C under argon atmosphere, and thereto were added dropwise sucpessively triethylsilane (3.01ml), and boron trifluoride • diethyl ether complex (2.39 ml). The reaction mixture was warmed to 0°C, and stirred at the same temperature for 3 hours. Added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100:0-92:8) to give the desired l-(β-D- glucopyranosyl) -3- (5-chlorb-2-thienylmethyl) -4-methylbenzen e 19 (183 mg) . APCI-Mass m/Z 402/404 (M+NH4) .
In a manner similar to the method disclosed in any of the above Examples 1 to 4, the compounds shown in Table 1 below were prepared from corresponding starting materials. The numbers shown in a column of "preparation method" in the Table indicates the Example number, according to which the preparation was carried out. Table 1
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Example 103 1- (β-D-glucopyranosyl) -3- (benzothiazol-2-yl- methyl) -4-methylbenzene
Figure imgf000088_0001
In the above scheme, the symbols are as defined above. (1) 1- (benzothiazol-2-ylmethyl) -5-bromo-2-methylbenzene 20 (495 mg) was dissolved in tetrahydrofuran (5 ml) - toluene (10 ml), and the mixture was cooled to -78°C under argon atmosphere. To the mixture was added dropwise n-butyl lithium (2.44 M hexane solution, 0.67 ml), and successively was added dropwise t-butyl lithium (2.44 M pentane solution, 1.57 ml). The mixture was stirred at the same temperature for 10 minutes, and then, a solution of
2,3,4, 6-tetrakis-O-trimethylsilyl-D-gluconol, 5-lactone 2 (see USP 6, 515, 117) (2.17 g) in toluene (5ml) was added dropwise, and the mixture was further stirred at the same temperature for 15 minutes to give a lactol compound 21. Without isolating this compound, a solution of methanesulfonic acid (1.5 ml) in methanol (25 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give a methyl ether compound 22, which was used in the subsequent step without further purification. (2) A solution of the above methyl ether compound 22 in dichloromethane (20 ml)- acetonitrile (10 ml) was cooled to -78 °C under argon atmosphere, and thereto were added dropwise successively triethylsilane (1.24 ml), and boron trifluoride • diethyl ether complex (0.99 ml) . The mixture was warmed to room temperature and stirred at the same temperature for 30 minutes. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (chloroform:methanol = 100:0-85:15) to give 1- ( β-D-glucopyranosyl) -3- (benzothiazol-2-ylmethyl) - 4-methylbenzene 23 (200 mg) as colorless powder. APCI-Mass m/Z 402 (M+H) .
In a manner similar to Examples 103, the compounds shown in Table 2 below were prepared from corresponding starting materials.
Table 2
Figure imgf000090_0002
Example 106 1- ( β-D-glucopyranosyl) -4-chloro-3- (1-oxy- b.enzo [b] thiophen-2-ylmethyl) benzene
Figure imgf000090_0001
In the above scheme, AcO and OAc are an acetyloxy group. (1) The compound 24 (9.61 g) obtained in Example 31 was dissolved in chloroform (100 ml) , and to the mixture were added acetic anhydride (21.6 ml), pyridine (18.5 ml), and 4-dimethylaminopyridine (128 mg) , and the mixture was stirred at room temperature for 3.5 days. Then, Chloroform was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml) . The solution was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, dried over magnesium sulfate, and treated with activated carbon. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol to give a tetraacetate compound 25 (6.14 g) . APCI-Mass m/Z 606/608 (M+NH4) .
(2) The above tetraacetate compound 25 (1.00 g) was dissolved in dichloromethane (20 ml) , and under ice-cooling, m-chloroperbenzoic acid (439 mg) was added thereto, and the mixture was stirred a room temperature overnight. m-Chloroperbenzoic acid was further added thereto, and the mixture was stirred again at room temperature overnight. The reaction mixture was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1-1:2) to give a sulfoxide compound 26 (295 mg) . APCI-Mass m/Z 622/624 (M+NH4) .
(3) The above sulfoxide compound 26 (293 mg) was dissolved in a mixture of methanol (10 ml) - tetrahydrofuran (5ml) , and sodium methoxide (28% methanol solution, 2 drops) was added thereto, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to give
1- (β-D-glucopyranosyl) -4-chloro-3- (1-oxybenzo [b] thiophen-2- ylmethyl) benzene as pale yellow powder. APCI-Mass m/Z 454/456 (M+NH4) . Example 107 ■!- (β-D-glucopyranosyl) -4-chloro-3- (1, 1-dioxy- benzo [b] thiophen-2-ylmethyl) benzene
The target compound was prepared in a manner similar to Example 106. APCI-Mass m/Z 470/472 (M+NH4) .
Example 108
3, 5-dimethyl-4- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) pyrazole
Figure imgf000092_0001
In the above scheme, the symbols are as defined above. (1) 3- (4-ethylphenylmethyl) -2, 4-pentanedione 28 (700 mg) and 2, 3, 4, 6-tetra-0-benzyl-α, β-D-glucosehydrazone 29 (1.70 g) (See Schmidt, R. R. et al., ieb±gs Ann . Chem . 1981, 2309) were dissolved in tetrahydrofuran (20 ml) , and the mixture was stirred at room temperature for 18 hours under argon atmosphere . The solvent was evaporated under reduced pressure, and the residue was dissolved in toluene (20 ml) , and the mixture was heated with stirring under reflux for 2 hours. The mixture was left alone until it was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 65:35) to give 3,
5-dimethyl-4- (4-ethylphenylmethyl) -1- (2,3,4, 6-tetra-O-benzy 1-β-D-glucopyranosyl) pyrazole 30 (299 mg) as a pale yellow semisolid. APCI-Mass m/Z 737 (M+H) .
(2) The above tetrabenzyl compound 30 (294 mg) was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (4 ml) , and added thereto was palladium hydroxide (100 mg) , and the mixture was stirred at room temperature for 16 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the solvent was evaporated under reduced pressure. The residue was crystallized from diethyl ether to give the desired
3, 5-dimethyl-4- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) pyrazole 31 (118 mg) as colorless powder. APCI-Mass m/Z 377
(M+H) .
Example 109
4- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) -1,2, 3-triazo le
Figure imgf000093_0001
In the above scheme, n-Bu is n-butyl group, and other symbols are as defined above. ' (1) A solution of 4- (bromomethyl) -1- (2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosy 1) -1, 2, 3-triazole 32 (500 mg) (See Federico G. H. et al. , J. Med. Chem . (1979) 29, 496), tri-n-butyl (4-ethylphenyl) tin 33 (604 mg) and tetrakis (triphenylphosphine) palladium (0) (59 mg) in tetrahydrofuran (10 ml) was stirred under heating at 70°C for 12 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and then, an aqueous potassium fluoride solution was added thereto and the mixture was stirred at room temperature for one hour. Insoluble materials were filtered off, and the filtrate was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90:10 - 50:50) to give 4- (4-ethylphenylmethyl) -1- (2,3,4, 6-tetra-O-acetyl-β-D-gluco pyranosyl) -1, 2, 3-triazole 34 (90 mg) as a colorless solid. APCI-Mass m/Z 518 (M+H) .
(2) From the above tetraacetate compound 34, the desired 4- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) - 1, 2, 3-triazole 35 was prepared in a manner similar to Example 106- (3) as a colorless solid. APCI-Mass m/Z 350 (M+H) .
Example 110 4- (4-Ethylphenylmethyl) -1- ( β-D-glucopyranosyl) pyrazole
Figure imgf000095_0001
In the above scheme, TMS is a trimethylsilyl group, and other symbols are as defined above.
(1) To a solution of 4- (4-ethylphenylmethyl) pyrazole 36 (495 mg) in acetonitrile (2.0 ml) was added .,
N, O-bis (trimethylsilyl) acetamide (1.05 ml), and the mixture was stirred under heating at 60 °C for 2.5 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give crude
4- (4-ethylphenylmethyl) -1-trimethylsilylpyrazole 37, which was used in the subsequent reaction without further purification.
(2) The above N-silyl compound 37 was dissolved in dichloroethane (7.0 ml), and added thereto were molecular sieve 4A powder (500 mg) ,
1, 2, 3, 4, 6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) and trimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture was stirred under heating at heating at 80 °C for 3 hours under argon atmosphere . The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Subsequently, the filtrate was poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with dichloromethane, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 - 50:50) to give
4- (4-ethylphenylmethyl) -1- (2,3,4, 6-tetra-0~acetyl-β-D-gluco pyranosyl) pyrazole 39 (610 mg) as a colorless semisolid. APCI-Mass m/Z 517 (M+H) .
(3) From the above tetraacetate compound 39, the desired 4- (4-ethylphenylmethyl ) -1- (β-D-glucopyranosyl) pyrazole 40 was prepared in a manner similar to Example 106- (3) as colorless oil. APCI-Mass m/Z 349 (M+H) .
In a manner similar to Example 110, the compounds shown in Table 3 below were prepared from corresponding starting materials.
Figure imgf000097_0001
Example 118 3--5- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) -2, 3-dihydroindole
Figure imgf000098_0001
In the above scheme, the symbols are as defined above. (1) To a suspension of potassium hydroxide power ('953 mg) and sodium sulfate (6.0 g) in acetonitrile (50 ml) was added 3- (4-ethylphenylmethy) -lH-indole 41 (500 mg) , and the mixture - was stirred at room temperature for one hour under argon atmosphere. To the reaction mixture was added a solution of benzylchloro-α-D-glucose 42 (3.0 g) (see Cicchillo R. M. et al . , Carbohydra te Research (2000) 328, 431) in acetonitrile (20 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2N aqueous hydrochloric acid solution, and the mixture was extracted with diethyl ether . The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 85:15) to give 3- (4-ethylphenylmethyl) -1- (2,3,4, 6-tetra-O-benzyl-αβ-D-gluc opyranosyl) -lH-indole 43 (1.04 g) as a pale yellow syrup. APCI-Mass m/Z 758 (M+H) .
(3) From the above tetrabenzyl compound 43, the desired 3-RS- (4-ethylphenylmethyl) -1- ( β-D-glucopyranosyl) - -2, 3—dihydroindole 44 was prepared in a manner similar to Example 108- (2) as pale pink powder. APCI-Mass m/Z 400 (M+H). Example 119
1- (β-D-glucopyranosyl) -4-chloro-3- (5- (2-pyrimidinyl) -2-thie nylmethyl) benzene
Figure imgf000099_0001
In the above scheme, the symbols are as defined above.
(1) To a solution of 5-boromo-2-chlorobenzoic acid 45 (1.22 g) in a mixture of tetrahydrofuran (20 ml) - toluene (20 ml) was added dropwise n-butyl lithium (2.44 M hexane solution, 4.26 ml) at -78 °C under argon atmosphere. The mixture was stirred at -78 °C for 30 minutes, and added dropwise thereto was a solution of 2, 3, 4, 6-tetra-O-benzyl-β-D-glucolactone 46 (2.16 g) in toluene (10 ml) , and the mixture was further stirred at the same temperature for 2 hours. To the mixture was added a saturated aqueous ammonium chloride solution, and the mixture was warmed to room temperature. The reaction mixture was made acidic by addition of 10% aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude compound 47 as oil, which was used in the subsequent step without further purification.
(2) The above crude compound 47 was dissolved in dichloromethane (30 ml) , and thereto were added dropwise triisopropylsilane (2.46 ml) and boron trifluoride • diethyl ether complex (1.52 ml) at -78°C. Subsequently, the mixture was stirred at 0°C for one hour, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was further stirred for 20 minutes. The reaction mixture was made acidic by addition of 10% aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol = 100:1 - 50:1) to give a compound 48 (1.41 g) as oil.
(3) The compound 48 (1.41 g) was dissolved in dichloromethane (10 ml) , and added thereto" was oxalyl chloride (2ml) . The . mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give a corresponding acid chloride. The compound was dissolved in chloroform (10 ml), and added dropwise to a solution of N, O-dimethylhydroxyamine hydrochloride (390 mg) and triethyl amine (1.12 ml) in chloroform (10 ml) at 0°C. The mixture was stirred at room temperature overnight, and the reaction mixture was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1-2:1) to give a compound 49 (784 mg) as pale yellow oil. APCI-Mass m/Z 739/741 (M+NH4) . (4) The compound 49 (1.22 g) was dissolved in tetrahydrofuran (20 ml), and the mixture was cooled to -78°C under argon atmosphere. To the mixture was added dropwise diisobutylaluminum hydride (1.0 M toluene solution, 4.2 ml), and the mixture was stirred at the same temperature for 3 hours. Added thereto was 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate =9:1) to give a compound 50 (771 mg) as pale yellow oil. APCI-Mass m/Z 680/682 (M+NH4) . (5) 2, 5-dibromothiophene 51 (1.31 g) was dissolved in tetrahydrofuran (30 ml) and the mixture was cooled to -78 °C under argon atmosphere. To the mixture was added dropwise n-butyl lithium (2.59 M hexane solution, 2.01 ml), and the mixture was stirred at the same temperature for 30 minutes. Added dropwise thereto was a solution of the above compound 50 (2.40 g) in tetrahydrofuran (15 ml), and the mixture was stirred at -78 °C for 2 hours. Added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate and washed with brine. The extract was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 9:1 - 4:1) to give a compound 52 (2.62 mg) as pale brown oil . APCI-Mass m/Z 842/844 (M+NH4) . (6) The compound 52 was treated in a manner similar to Example 3- (2) to give 1- (2, 3, 4f 6-tetra-O-benzyl-β-D-glucopyranosyl) -3- (5-bromo-2-thienylmethyl) -4-chlorobenzene 53 as a pale yellow solid. APCI-Mass m/Z 826/828 (M+NH4) . (7) A mixed solution of the above
1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 53 (200 mg) , tri-n-butyl (2-pyrimidinyl) tin 54 (137 mg) and bis (triphenylphosphine) palladium (II) dichloride (9 mg) in N-methyl-2-pyrrolidinone (5 ml) was stirred at 100°C four 7 hours under argon atmosphere. The mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate . The extract was washed with water and subsequently with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. . The residue was purified by silica gel column ' chromatography (hexane : ethyl acetate = 4:1 - 2:1) to give 1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) -4-chloro-3- (5 - (2-pyrimidinyl) -2-thienylmethyl) benzene 55 (93 mg) as pale brown oil. APCI-Mass m/Z 826/828 (M+NH4) .
(8) To a solution of the above
1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) -4-chloro-3- (5 - (2-pyrimidinyl) -2-thienylmethyl) benzene 55 (90 mg) in ethanethiol (1.5ml) was added boron trifluoride • ether complex (0.42 ml) at 0°C, and the mixture was stirred at room temperature overnight. The mixture was cooled again to 0°C, and added thereto were a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution. The mixture was extracted with ethyl acetate and tetrahydrofuran, and the extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1 - 9:1) to give the desired 1- (β-D-glucopyranosyl) -4-chloro-3- (5- (2-pyrimidinyl) -2- thienylmethyl) benzene 56 (27 mg) as pale yellow powder. APCI-Mass m/Z 449/451 (M+H) . Example 120 1- (β-D-glucopyranosyl) -3- (6- (2-fluoro-3-pyridyl) -2-thienylmethyl) -4-methylbenzene
Figure imgf000103_0001
In the above scheme, the symbols are as defined as above. (1) The compound 19 obtained in Example 4 was treated in a manner similar to Example 106- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 as colorless crystals. APCI-Mass m/Z 570/572 (M+NH4) . (2) A solution of the above
1- (2, 3, 4, 6-tetra-0-acetyl-3-D-glucopyranosyl)
-3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 (200 mg) ,
6-fluoropyridine-3-boronic acid 58 (117 mg) , tri-tert-butylphosphine ■ tetrafluoroboric acid adduct (24 mg) , potassium fluoride (80 mg) and tris (dibenzylideneacetone) dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 2 days under argon atmosphere. Added thereto was a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate . The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 70:30) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- - (6-fluoro-3-pyridyl) -2-thienylmethyl) -4-methylbenzene 59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH4) .
(3) The above
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- - ( 6-fluoro-3-pyridyl) -2-thienylmethyl) -4-methylbenzene 59 (39 mg) was dissolved in 1,4-dioxane (4 ml) -tetrahydrofuran (4 ml) , and added thereto was 2N sodium hydroxide (2 ml) . The mixture was stirred at room temperature for one hour. The mixture was made acidic by addition of an aqueous' citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired 1- (β-D-glucopyranosyl) -3- (5- (6-fluoro-3-pyridyl) -2-thienyl- methyl) -4-methylbenzene 60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH) .
Example 121
1- ( β-D-glucopyranosyl) -4-chloro-3- (2- (5-phenyl-2-thienyl) et hyl) benzene
The target compound was obtained in a manner similar to Example 1, from 5-bromo-2-chloro-l- (2- (5-phenyl-2-thienyl) ethyl) - benzene. APCI-Mass m/Z 478/480 (M+NH4) .
Example 122
1- (β-D-glucopyranosyl) -3- (5- (3-dimethylaminophenyl) -2-thien ylmethyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl)
-3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acid were used and treated in a manner- similar to Example 120- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (3-dimethylaminophenyl) -2-thienylmethyl) -4-methylbenz ene. APCI-Mass m/Z 638 (M+H) .
(2) the above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (3-dimethylaminophenyl) -2-thienylmethyl) -4-methylbenz ene was treated in a manner similar to Example 106- (3) to give the target compound. APCI-Mass m/Z 470 (M+H) . Example 123
1- (β-D-glucopyranosyl) -4-chloro-3- (5- (3-cyanophenyl) -2-thie nylmethyl) benzene (1) A mixed solution of 1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl)
-3- (5-bromo-2-thienylmethyl) -4-chlorobenzene 53 (1.24 g) obtained in Example 119 -(6), 3-cyanophenylboronic acid (270 ml), bis (triphenylphosphine) palladium (II) dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1, 2-dimethoxyethane (12 ml) was heated under reflux for 4 hours . The mixture was diluted with ethyl acetate and washed successively with a saturate aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 7:1 - 5:1) to give
1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) -4-chloro-3- (5 - (3-cyanophenyl) -2-thienylmethyl) benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4) . (2) The above
1- (2, 3, 4, 6-tetra-O-benzyl-β-D-glucopyranosyl) -4-chloro-3- (5 - (3-cyanophenyl) -2-thienylmethyl) benzene was used and treated in a manner similar to Example 3- (3) to give the target compound as colorless powder. APCI-Mass m/Z 489/491 (M+NH4) .
Example 124
1- (β-D-glucopyranosyl) -4-methyl-3- (5- (5-pyrimidinyl) -2-thie nylmethyl) benzene (1) A mixed solution of
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 (600 mg) obtained in Example 120- (1), tri-n-butyl (5-pyrimidinyl) tin (600 mg) , tri-tert-butylphosphine- tetrafluoroboric acid adduct (116 mg) , cesium fluoride (414 mg) , and tris (dibenzylideneacetone) dipalladium (0) (91 mg) in 1, 4-dioxane (18 ml) was heated under reflux at 100°C for 3 hours under argon atmosphere. Insoluble materials were filtered off, and the filtrate was diluted with ethyl acetate and washed with brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography
(hexane: ethyl acetate = 75:25 - 40:60) to give
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-methyl-3- (5 - (5-pyrimidinyl) -2-thienylmethyl) benzene (266 mg) as colorless crystals. APCI-Mass m/Z 597 (M+H).
(2) The above
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-methyl-3- (5 - (5-pyrimidinyl) -2-thienylmethyl) benzene was used and treated in a manner similar to Example 106- (3) to give the target compound as colorless powder. APCI-Mass m/Z 429 (M+H) .
Example 125
1- (β-D-glucopyranosyl) -4-chloro-3- (2-phenyl-5-thiazolylmeth ylbenzene
The target compound was prepared in a manner similar to Example 1, starting from
5-bromo-2-chloro-l- (2-phenyl-5-thiazolylmethyl ) benzene . APCI-Mass m/Z 448/450 (M+H) .
Example 126
1- (β-D-glucopyranosyl) -4-chloro-3- (5- (3-pyridyl) -2-thienylmethyl ) benzene (1) 1- (β-D-glucopyranosyl)
-4-chloro-3- (5-chloro-2-thienylmethyl) benzene obtained in Example 19 was used and treated in a manner similar to Example 106- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) 4-chloro-3- (5-chloro-2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 590/592 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) - 4-chloro-3- (5-chloro-2-thienylmethyl) benzene and tri-n-butyl (3-pyridyl) tin were used and treated in a manner similar to Example 124 to give the target compound as colorless powder. APCI-Mass m/Z 448/450 (M+H) .
Example 127
1- (β-D-glucopyranosyl) -3- (5- (3-cyanophenyl) -2-thienyl- methyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl)
-3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 obtained in Example 120- (1) and 3-cyanophenylboronic acid were used and treated in a manner similar to Example 120- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5— (3-cyano phenyl) -2-thienylmethyl) -4-methylbenzene. APCI-Mass m/Z 637 (M+NH4) .
(2) The above
1- (2, 3, 4, 6-tetra-0-acetyl-β-D-glucopyranosyl) -3- (5— (3-cyano phenyl) -2-thienylmethyl) -4-methylbenzene was used and treated in a manner similar to Example 106- (3) to give the target compound as colorless powder. APCI-Mass m/Z 469 (M+NH4) .
Example 128 1- (β-D-glucopyranosyl)—4-chloro-3- (5-pyrazinyl-2-thienyl- methyl) benzene
Figure imgf000108_0001
In the above scheme, the symbols are as defined above. (1) A solution of mesityl bromide (4.74 g) in tetrahydrofuran (100 ml) was cooled to -78 °C under argon atmosphere, and thereto was added dropwise t-butyl lithium (1.43 M pentane solution, 33 ml) . The mixture was stirred at -30 to -20°C for one hour, and then, a mixed solution of t-butyl 5-bromo-2-chlorobenzoate 61 (4.94 g) and
2,3,4, 6-tetrakis-O-trimethylsilyl-D-glucono-l, 5-lactone 2 (see USP 6,515,117) (11.10 g) in tetrahydrofuran (70 ml) was added dropwise thereto at -78 °C. The mixture was stirred at the same temperature for one hour to give a compound 62. Without isolating this compound, a solution of methanesulfonic acid (3.75 ml) in methanol (50 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution at 0°C, and the mixture was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (chloroform:methanol = 19:1) to give a methyl ether compound 63 (4.55 g) of the lactol as pale yellow powder. APCI-Mass m/Z 422/424 (M+NH4) .
(2) The compound 63 was treated in a manner similar to Example 106- (1) to give the compound 64. APCI-Mass m/Z 590/592 (M+NH4) .
(3) A solution of the above compound 64 (7.10 g) in formic acid (50 ml) was stirred at 50 °C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene, twice, to give a compound 65 as colorless powder. Without further purification, this compound was dissolved in dichloromethane (50 ml). Added thereto were oxalyl chloride (1.3 ml) and N, N-dimethylformamide (one'drop) , and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give a corresponding acid chloride, which was dissolved in dichloroethane (50 ml) , without further purification. To the solution was added 2-bromothiophene 66 (2.63 g) and the mixture was cooled to 0°C. Added gradually thereto was aluminum chloride (8.26 g) , and subsequently, the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice-cold water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate =10:1-5:1) to give a compound 67 (7.01 g) as pale yellowish powder. APCI-Mass m/Z 678/680 (M+NH4) . (4) The above ketone compound 67 (7.01 g) was dissolved in ethanol (50 ml), and thereto was added sodium borohydride (401mg) , and the mixture was stirred at room temperature for 30 minutes . The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with successively with water, 2N aqueous hydrochloride acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a compound 68 as pale yellow powder, which was dissolved in methanol (50 ml) without further purification. To the solution, sodium methoxide (28% methanol solution, 5 drops) was added, and then the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure to give a deacetylated compound 69 as pale yellow powder. Without further purification, it was dissolved in dichloromethane (170 ml) - acetonitrile (70 ml) , and added thereto was triethylsilane "(10.2 ml) , and the mixture was cooled to 0°C. Added dropwise thereto was boron trifluoride • diethyl ether complex (8.1 ml), and the mixture was stirred at room temperature for 5 hours. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude
1- (β-D-glucopyranosyl) -3- (5-bromo-2-thienylmethyl) 4-chlorob enzene 70 as pale brown powder. Without further purification, this was dissolved in dichloromethane (30 ml), and added thereto were acetic anhydride (10.0 ml), pyridine (8.57 ml) and 4-dimethylaminopyridine (258 mg) , and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the solution was washed successively with water, IN aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The solution was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol to give
1- (2, 3, 4, 6-tetra-0-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) 4-chlorobenzene 71 (3.17 g) as colorless crystals. APCI-Mass m/Z 634/636 (M+NH4) .
(5) The above
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) 4-chlorobenzene 71 (600 mg) was dissolved in 1,4-dioxane (11 ml). Added thereto were tri-n-butyl (pyrazinyl) tin 72 (720 mg) , tetrakis (triphenylphosphine) palladium (0) (206 mg) and copper
(I) iodide (51 mg) , and the mixture was stirred under heating at 100°C for 1.5 hours, under irradiation by a microwave (500
W) . The mixture was diluted with ethyl acetate, the insoluble materials were filtered off, and the filtrate was washed with water. The solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate =75:25-30:70), and crystallized from hexane-diethyl ether to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-chloro-3- (5 -pyrazinyl-2-thienylmethyl) benzene 73 (263 mg) as pale yellow crystals. APCI-Mass m/Z 617/619 (M+H).
(6) The above
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-chloro-3- (5 -pyrazinyl-2-thienylmethyl) benzene 73 was used and treated in a manner similar to Example 106- (3) -to give the desired 1- (β-D-glucopyranosyl) -4-chloro-3- (5-pyrazinyl-2-thienylmet hyl) benzene 74 as colorless powder. APCI-Mass m/Z 449/451 (M+H) .
Example 129
1- (β-D-glucopyranosyl) -4-chloro-3- (6-ethoxybenzo [b] thiophen -2-ylmethyl) benzene
5-Bromo-2-chloro-l- ( 6-ethoxybenzo [b] thiophen-2-ylmethyl) ben zene was used and treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 482/484' (M+NH4) .
Example 130
1- (β-D-glucopyranosyl) -3- (5- (3-difluoromethylphenyl) -2-thie nylmethyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-chloro-2-thienylmethyl) -4-methylbenzene 57 obtained in Example 120- (1) and 3-formylphenylboronic acid were used and treated in a manner similar to Example 120- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (3-formylphenyl) -2-thienylmethyl) -4-methylbenzene. APCI-Mass m/Z 640 (M+NH4) . (2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (3-formylphenyl) -2-thienylmethyl) -4-methylbenzene (100 mg) was dissolved in dichloromethane (2 ml) , and added thereto was (diethylamino) sulfur trifluoride (0.30 ml). The mixture was stirred at room temperature overnight. Water was added to the mixture and the mixture was extracted with chloroform. The extract was washed with brine and dried over magnesium sulfate, and then, the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate =9:1-1:1) to give 1- (2, 3, 4 , 6-tetra-O-acetyl-β-D-glucopyranosyl)
-3- (5- (3-difluoromethylphenyl) -2-thienylmethyl) -4-methylben zene (82 mg) . APCI-Mass m/Z 662 (M+NH4) . (3) The above obtained 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (3-difluoromethylphenyl) -2-thienylmethyl) -4-methylben zene was used and treated in a manner similar to Example 120- (3) to give the desired 1- ( β-D-glucopyranosyl) -3- (5- (3-difluoromethylphenyl) -2-thienylmethyl) -4-methylben zene as colorless powder. APCI-Mass m/Z 494 (M+NH ) .
Example 131
1- (β-D-glucopyranosyl) -4-chloro-3- ( 6-phenyl-3-pyridylmethyl ) benzene
5-Bromo-2-chloro-l- ( 6-phenyl-3-pyridylmethyl) benzene was used and treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 442/444 (M+H) .
In a manner similar to the method disclosed in any of the above Examples, the compounds shown in Table 4 below were prepared from corresponding starting materials. The numbers shown in a column of "preparation method" in the Table indicates the Example number, according to which the preparation was carried out in the similar manner."
Table 4
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Example 157 1- ( β-D-glucopyranosyl) -4-chloro-3- ( 6- isopropyloxybenzo [b] thiophen-2-ylmethyl) benzene 5-Bromo-2-chloro-l- ( 6-isopropyloxybenzo [b] thiophen-2-ylmeth yl) benzene was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 496/498 (M+NH4) .
Example 158 1- (β-D-glucopyranosyl) -4-methy.l-3- (2- thienylmethyl) benzene (1) 1- (2, 3, 4, 6-tetra-0-acetyl-β-D-glucopyranosyl)-3- (5- chloro-2-thienylmethyl) -4-methylbenzene 57 (12.0' g) obtained in Example 120- (1) was dissolved in tetrahydrofuran (120 ml) and methanol (360 ml), and added thereto were triethylamine (24.2 ml) and 10% palladium carbon catalyst (wet, 3.6 g) , and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere under normal pressure. The insoluble materials were filtered off, washed with tetrahydrofuran, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-methyl-3- (2-thienylmethyl) benzene (7.79 g) as colorless crystals. APCI-Mass m/Z 536 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-methyl3- (2-thienylmethyl) benzene was treated in a manner similar to Example 106- (3) to give the desired 1- (β-D-glucopyranosyl) -4-methyl-3- (2-thienylmethyl) benzene as colorless powder . APCI-Mass m/Z 368 (M+NH) .
Example 159 1- ( β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -4-methyl- 3- (2-thienylmethyl) benzene (11.08 g) obtained in Example 158- (1) was dissolved in chloroform (100 ml), and added dropwise thereto at 0°C was a solution of bromine (3.71 g) in chloroform (13ml). The mixture was stirred at 0°C for 1.5 hours, and then, at room temperature for 1 hour, and the mixture was poured into a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel -column chromatography (hexane: ethyl acetate = 80:20 - 67:33) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene (7.13 g) as a colorless solid. APCI-Mass m/Z 614/616 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5-bromo-2-thienylmethyl) -4-methylbenzene was treated in a manner similar to Example 106- (3) to give the desired 1- (β-D-glucopyranosyl) -3- (5-bromo-2-thienylmethyl) - 4-methylbenzene as colorless powder. APCI-Mass m/Z 446/448 (M+NH4) .
Example 160 1- (β-D-glucopyranosyl) -3- (5-phenyl-2- thienylmethyl) benzene
2-Phenylthiophene and 3-bromobenzadlehyde was treated in a manner similar to Example 4 to give the target compound. APCI-Mass m/Z 430 (M+NH4) . Example 161 1- (β-D-glucopyranosyl) -3- (5-cyano-2- thienylmethyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene (500 mg) obtained in Example 159- (1) was dissolved in N, N-dimethylacetamide (10 ml), and added thereto were zinc cyanide (98 mg) , tris (dibenzylideneacetone) dipalladium (0) (77 mg) , 1, 1 ' -bis (diphenylphosphino) ferrocene (47 mg) and zinc power (14 mg) . The mixture was heated under stirring at 120°C overnight. The reaction solution was cooled, diluted with ethyl acetate and water, and the insoluble materials were filtered off. The organic layer of the filtrate was washed twice with water and successively washed with brine. After drying the same over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 50:50) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5-cyano-2-thienylmethyl) -4-methylbenzene (207 mg) as colorless crystals. APCI-Mass m/Z 561 (M+NH4) . (2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5-cyano-2-thienylmethyl) -4-methylbenzene was treated in a manner similar to Example 106- (3) to give the desired 1- (β-D-glucopyranosyl) -3- (5-cyano-2-thienylmethyl) - 4-methylbenzene as colorless powder. APCI-Mass m/Z 393 (M+NH4) .
Example 162 1- ( β-D-glucopyranosyl) -4-fluoro-3- (5- (2- pyridyl) -2-thienylmethyl) naphthalene
4-Bromo-l-fluoro-2- (5- (2-pyridyl) -2-thienylmethyl) naphthale ne was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 482 (M+H) . Example 163 1- (β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-chlorobenzene
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) was treated in a manner similar to Example 106- (3) to give the target compound. APCI-Mass m/Z 466/468 (M+NH4) .
Example 164 1- (β-D-glucopyranosyl) -4-methyl-3- (5- (2- pyrimidinyl) -2-thienylmethyl) benzene
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene obtained in Example 159- (1) and tri-n-butyl (2-pyrimidinyl) tin 54 were treated in a manner similar to Example 128- (5) and (6) to give the target compound. APCI-Mass m/Z 429 (M+H) .
Example 165 1- (β-D-glucopyranosyl) -4-methyl-3- (5- (2- thiazolyl) -2-thienylmethyl) benzene
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-methylbenzene obtained in Example 159- (1) and tri-n-butyl (2-thiazolyl) tin were treated in a manner similar to Example 128- (5) and (6) to give the target compound. APCI-Mass m/Z 434 (M+H) .
Example 166 1- (β-D-glucopyranosyl) -4-chloro-3- (6-ethyl-3- pyridylmethyl) benzene
5-Bromo-2-chloro-l- ( 6-ethyl-3-pyridylmethyl) benzene was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 394/396 (M+H) .
Example 167 1- ( β-D-glucppyranosyi) -4-chloro-3- ( 6- ethylbenzo [b] thiophen-2-ylmethyl) benzene
6-Ethylbenzo [b] thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Example 4 to give the target compound. APCI-Mass m/Z 466/468 (M+H) .
Example 168 1- (β-D-glucopyranosyl) -4-chloro-3- (5- ( 6-fluoro- 3-pyridyl) -2-thienylmethyl) benzene
(1) l-(2,3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 71 (500 g) obtained in Example 128- (4) was dissolved in 1, 2-dimethoxyethane (15ml), and added thereto were 6-fluoropyridine-3-boronic acid 58 (228 mg) , tetrakis (triphenylphosphine) palladium(O) (94 mg) and cesium fluoride (738 mg) . The mixture was heated under reflux for 30 minutes. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 75:25 - 60:40) to give l-(2, 3,4,6- tetra-O-acetyl-β-D-glucopyranosyl) -4-chloro-3- (5- (6-fluoro- 3-pyridyl) -2-thienylmethyl) benzene (454 mg) as a colorless solid. APCI-Mass m/Z 634/636 (M+H) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- ( 6-fluoro-3-pyridyl) -2-thieny lmethyl) benzene was treated in a manner similar to Example 106- (3) to give the desired 1- (β-D-glucopyranosyl) - 4-chloro-3- (5- ( 6-fluoro-3-pyridyl) -2-thienylmethyl) benzene as colorless powder. APCI-Mass m/Z 483 (M+NH4) , 466 (M+H).
Example 169 1- ( β-D-glucopyranosyl) -4-chloro-3- (5- ( 6- methoxy-3-pyridyl ) -2-thienylmethyl ) benzene
1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) and 6-methoxypyridine-3-boronic acid were treated in a manner similar to Example 168 to give the target compound. APCI-Mass m/Z 478/480 (M+H) .
Example 170 1- ( β-D-glucopyranosyl) -4-chloro-3- (5- (6- methoxy-2-pyridyl) -2-thienylmethyl) benzene
1- (2, 3,4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5-bromo-2- thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) and tri-n-butyl (6-methoxy-2-pyridyl) tin (see Gros, Philippe; Fort, Yves. Synthesis (1999), 754-756) were treated in a manner similar to Example 128- (5) and (6) to give the target compound. APCI-Mass m/Z 478/480 (M+H) .
Example 171 1- ( β-D-glucopyranosyl) -4-chloro-3- (l-oxo-2- isoindolinylmethyl) benzene
5-Bromo-2-chloro-l- (l-oxo-2-isoindolynilmethyl) benzene was treated in a manner similar to Example 2 to give the target compound. APCI-Mass m/Z 437/439 (M+NH4) .
Example 172 1- ( β-D-glucopyranosyl) -4-chloro-3- (l-phenyl-4- pyrazolylmethyl) benzene
5-Bromo-2-chloro-l- (l-phenyl-4-pyrazolylmethyl) benzene was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 431/433 (M+H) .
Example 173 1- ( β-D-glucopyranosyl) -4-chloro-3- (5- ( 6-ethoxy-
2-pyridyl) -2-thienylmethyl) benzene
(1) l-(2,3,4, 6-tetra-0-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 71 obtained in Example 128-(4) and tri-n-butyl (6-ethoxy-2-pyridyl) tin (see WO
00/74681) were treated in a manner similar to Example 128- (5) to give 1- (2, 3, , 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (6-ethoxy-2-pyridyl) -2-thieny lmethyl) benzene as colorless crystals. APCI-Mass m/Z 660/662
(M+H) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (6-ethoxy-2-pyridyl) -2-thieny lmethyl) benzene (245 mg) was dissolved in tetrahydrofuran (5 ml) , added thereto was a solution of sodium hydride (oil, 9 mg) in ethanol (5 ml) , and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 - 90:10) to give the desired 1- (β-D-glucopyranosyl) -4-chloro- 3- (5- (6-ethoxy-2-pyridyl) -2-thienylmethyl)'benzene (145 mg) as colorless powder. APCI-Mass m/Z 429/494 (M+H) . i
Example 174 1- (β-D-glucopyranosyl) -4-chloro-3- (6-n- propyloxybenzo [b] thiophen-2-ylmethyl) benzene 5-Bromo-2-chloro-l- ( 6-n-propyloxybenzo [b] thiophen-2-ylmethy 1) benzene was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 496/498 (M+NH4) .
Example 175 1- ( β-D-glucopyranosyl) -4-chloro-3- ( 6- (2- fluoroethyloxy) benzo [b] thiophen-2-ylmethyl) benzene
5-Bromo-2-chloro-1- (6- (2-fluoroethyloxy) benzo [b] thiophen-2- ylmethyl) benzene was treated in a manner similar to Example 1 to give the target compound. APCI-Mass m/Z 500/502 (M+NH ) .
Example 176 1- ( β-D-glucopyranosyl) -3- (5- (4- difluoromethylphenyl) -2-thienylmethyl) -4-methylbenzene (1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-methylbenzene from Example 159- (1) and 4-formylphenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- (4-formy lphenyl) -2-thienylmethyl) -4-methylbenzene as a colorless solid. APCI-Mass m/Z 640 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5- (4-formylphenyl) -2-thienylmethyl) -4-me thylbenzene was treated in a manner similar to Example 130- (2) to give the desired 1- (2, 3, 4 , 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5- (4-difluoromethylphenyl) -2-thienylmeth yl) -4-mehylbenzene as colorless crystals. APCI-Mass m/Z 662
(M+NH ) . " (3) The above 1- (2, 3, 4 , 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5- (4-difluoromethylphenyl) -2- thienylmethyl) -4-methylbenzene was treated in a manner similar to Example 106- (3) to give the desired 1- ( β-D-glucopyranosyl) - 3- (5- (4-difluoromethylphenyl) -2-thienylmethyl) -4-methyl- benzene as colorless powder. APCI-Mass m/Z 494 (M+NH ) .
Example 177 1- (β-D-glucopyranosyl) -3- (5- (3, 4- difluorophenyl) -2-thienylmethyl) -4-methylbenzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-methylbenzene obtained in Example 159- (1) and 3, 4-difluorophenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4 , 6-tetra-0- acetyl-β-D-glucopyranosyl) -3- (5- (3, 4-difluorophenyl) -2- thienylmethyl) -4-methylbenzene as colorless crystals. APCI-Mass m/Z 648 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -3- (5- (3, 4-difluorophenyl) -2-thienylmethyl) - 4-methylbenzene was treated in a manner similar to Example 106- (3) to give the desired 1- (β-D-glucopyranosyl) -3- (5- (3, 4-difluorophenyl) -2-thienylmethyl) -4-methylbenzene as colorless powder. APCI-Mass m/Z 480 (M+NH4) .
Example 178 1- ( β-D-glucopyranosyl) -4-chloro-3- (5- (3- difluoromethylphenyl) -2-thienylmethyl) benzene
(1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) and 3-formylphenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4, 6-tetra-O-acetyl- β-D-glucopyranosyl) -4-chloro-3- (5- (3-formylphenyl) -2-thieny lmethyl) benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (3-formylphenyl) -2- thienylmethyl) benzene was treated in a manner similar to Example 130- (2) to give 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (3-difluoromethylphenyl) -2-th ienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 682/684 (M+NH4) .
(3) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (3-difluoromethylphenyl) -2- thienylmethyl) benzene was treated in a manner similar to Example 120- (3) to give the desired 1- ( β-D-glucopyranosyl) - 4-chloro-3- (5- (3-difluorome'thylphenyl) -2-thienylmethyl) benz ene as colorless powder. APCI-Mass m/Z 514/516 (M+NH ) .
Example 179 1- (β-D-glucopyranosyl) -4-chloro-3- (5- (4- difluoromethylphenyl) -2-thienylmethyl) benzene (1) 1- (2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl) -3- (5- bromo-2-thienylmethyl) -4-chlorobenzene 71 obtained in Example 128- (4) and 4-formylphenylboronic acid were treated in a manner similar to Example 168- (1) to give 1- (2, 3, 4, 6-tetra-O- acetyl-β-D-glucopyranosyl) -4-chloro-3- (5- (4-formylphenyl) - 2-thienylmethyl) benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4) .
(2) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (4-formylphenyl) -2- thienylmethyl) benzene was treated in a manner similar to Example 130- (2) to give 1- (2, 3, 4, 6-tetra-0-acetyl- β-D-glucopyranosyl) -4-chloro-3- (5- (4-difluoromethylphenyl) - 2-thienylmethyl) benzene as colorless crystals. APCI-Mass m/Z 682/684 (M+NH4) .
(3) The above 1- (2, 3, 4, 6-tetra-O-acetyl-β-D- glucopyranosyl) -4-chloro-3- (5- (4-difluoromethylphenyl) -2-th ienylmethyl) benzene was treated in a manner similar to Example 120- (3.) to give the desired 1- ( β-D-glucopyranosyl) - 4-chloro-3- (5- (4-difluoromethylphenyl) -2-thienylmethyl) - benzene as colorless powder. APCI-Mass m/Z 514/516 (M+NH4 ') .
The compounds shown in Table 5 below were prepared in a manner similar to one of the above Examples from the corresponding starting materials.
Table 5
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Reference Example 1
3-Bromo-l- (5-ethyl-2-thienylmethyl) benzene
(1) A solution of 1, 3-dibromobenzene (3.7 g) in tetrahydrofuran (25 ml) was cooled to -78 °C under argon atmosphere, and thereto was added dropwise -n-butyl lithium (2.44 M hexane solution, 5.55 ml) . The reaction mixture was stirred at the same temperature for 10 minutes, and thereto was added dropwise a solution of 5-ethyl-2-thiophenecarboxaldehyde (2.0 g) in tetrahydrofuran (10 ml) . The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated ammonium chloride solution, and the reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97:3 - 85:15) to give
3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow syrup. APCI-Mass m/Z 279/281 (M+H-H20) . (2) The above 3-bromophenyl-5-ethyl-2-thienylmethanol (2.90 g) was dissolved in dichloromethane (38 ml), and the mixture was cooled to -78 °C under argon atmosphere. To the mixture were added triethylsilane (6.18 ml) and boron trifluoride • diethyl ether complex (2.45 ml) , and the mixture was gradually warmed to room temperature over a period of one hour. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and the dichloromethane layer was collected, dried over magnesium sulfate, and the solvent was 'evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the desired 3-bromo- (5-ethyl-2-thienylmethyl) benzene (2.57 g) as a colorless syrup. APCI-Mass m/Z 281/283 (M+H) .
Reference Example 2
5-Bromo-l- (4-ethylphenylmethyl) -lH-pyridin-2-one
5-Bromo-lH-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g) were dissolved in N, -dimethylformamide (15 ml), and thereto was added potassium carbonate (1.66 g) . The mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed successively with water and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10:1 - 3:1) to give
5-bromo-l- (4-ethylphenylmethyl) -lH-pyridin-2-one (1.58 g) as colorless crystals. APCI-Mass m/Z 292/294 (M+H).
Reference Example 3
Figure imgf000132_0001
In the above scheme, the symbols are as defined above. (1) A solution of silylated glucal 75 (see Parker et al ., Org. Lett. 2000, 2, 497-499) (7.00 g) in tetrahydrofuran (70 ml) was cooled to -78 °C under argon atmosphere. Thereto was added dropwise t-butyl lithium (1.45 M pentane solution, ,49.0 ml) over a period of 10 minutes. The mixture was stirred at the same temperature for 15 minutes, and then warmed to room temperature, and further stirred for 30 minutes. The mixture was cooled again to -78 °C, and thereto was added trimethyl borate (8.90 ml) in one portion. After 15 minutes, the reaction solution was warmed to room temperature over a period of one hour, and thereto was added water (100 ml) at 0°C. The mixture was stirred for 30 minutes, and extracted twice with diethyl ether. The extract was washed with water, and then washed with brine. The resultant was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the compound 76, which was used in the subsequent reaction without further purification. (2) The whole amount of the above compound 76 was dissolved in toluene (65 ml), and thereto was added pinacol (2.24 g). The mixture was stirred at room temperature under argon atmosphere for 17 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the compound 7 (10.4 g) as a yellow semisolid, which was used in the subsequent reaction without further purification. APCI-Mass m/Z 569 (M+H) . Reference Example 4 5-Bromo-2-methylbenzaldehyde
(1) Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was' added 10% aqueous sodium hydroxide solution (50 ml) . The mixture was stirred at 50 °C for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water . Precipitated powder was ' collected by filtration, and dried to give
5-bromo-2-methylbenzoic acid (14.1 g) . ESI-Mass m/Z 213/215 (M-H) .
(2) The above 5-bromo-2-methylbenzoic acid (10.0 g) was suspended in dichloromethane (100 ml), and thereto were added oxalyl chloride (8.1ml) and N, N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-methylbenzoyl chloride. This benzoyl chloride was dissolved in dichloromethane (200 ml) , and thereto was added N,0-dimethylhydroxylamine hydrochloride (12.3 g). To the mixture was added dropwise triethylamine (20 ml) at 0°C, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and washed successively with water, 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.25 g) as oil. APCI-Mass m/Z 258/260 (M+H) .
(3) A solution of the above
N-methoxy-N-methyl-5-bromo-2-methylbenzamide (12.2 g) in tetrahydrofuran (100 ml) was cooled to -78 °C under argon atmosphere. To the mixture was added dropwise diisobutyl aluminum hydride (1.0 M toluene solution, 75 ml), and the mixture was stirred at the same temperature for one hour. 10% aqueous hydrochloric acid solution (50 ml) was added thereto, and the mixture was warmed to room temperature. ' The mixture was extracted with ethyl acetate twice, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure . The residue was ' solidified to give 5-bromo-2-methylbenzaldehyde (8.73 g) . APCI-Mass m/Z 213/215 (M+H+MeOH-H20) .
Reference Example 5
5-Bromo-2—chloro-1- (5-ethyl-2-thienylmethyl) benzene (1) 5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended in dichloromethane (10 ml) , and thereto were added oxalyl chloride (2.2 ml) and N, N-dimethylformamide (2 drops) . The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and
2-ethylthiophene (2.38 g) were dissolved in dichloromethane (20 ml), and thereto was added aluminum chloride (3.11 g) at 0°C. The mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a cold 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:1) to give 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) as an oil. APCI-Mass m/Z 329/331 (M+H). (2) A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) in dichloromethane (50 ml) -acetonitrile (50 ml) was cooled under ice-cooling, and thereto were added dropwise triethylsilane (7.69 ml) and boron trifluoride • diethyl ether complex (6.1 ml). Subsequently, the mixture was stirred at room temperature for 3.5 hours, and was cooled again under ice-cooling. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform, washed with brine, and dried over magnesium sulfate . The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give
5-bromo-2-chloro-l- (5-ethyl-2-thienylmethyl) benzene (4.52 g) as a colorless liquid.
Reference Example 6
3-Bromo-l- (5-n-propyl-2-thienylmethyl) benzene 3-Bromobenzoic acid and 2-n-propylthiophene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reference Example 7
5-Bromo- (5-ethyl-2-thienylmethyl) 2-methoxybenzene
(1) A solution of 2-ethylthiophene (3.00 g) in tetrahydrofuran (36 ml) was cooled to 0°C under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.56 M hexane solution, 17.1 ml). The mixture was stirred at the same temperature for 30 minutes, and cooled to -78 °C, and thereto was added • dropwise a suspension of 5-bromo-2-methoxybenzaldehyde (5.74 g) in tetrahydrofuran (60 ml) . The mixture was stirred at the same temperature for 2 hours, warmed to 0°C, and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0 - 85:15) to give 5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanόl (5.99 g) as a pale yellow syrup. APCI-Mass m/Z 309/311 (M+H-H20) . (2) The above
5-bromo-2-methoxyphenyl-5-ethyl-2-thienylmethanόl was treated in a manner similar to Reference Example l-(2) to give 5-bromo- (5-ethyl-2-thienylmethyl) -2-methoxybenzene as oil. APCI-Mass m/Z 311/313 (M+H) .
Reference Example 8 3-Bromo-l- (5-ethyl-2-thienylmethyl) -4- methoxybenzene 2-Ethylthiophene and 3-bromo-4-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 9 3-Bromo-l- (4-n-propyl-2-thienylmethyl) benzene
(1) 3-n-Propylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 7 -(1) to give 3-bromophenyl-4-n-propyl-2-thienyl methanol. APCI-Mass m/Z 293/295 (M+H-H20) . (2) A solution of the above
3-bromophenyl-4-n-propyl-2-thienyl methanol (2.4 g) in acetonitrile (10 ml) was added dropwise to a mixed solution of chlorotrimethylsilane (4.54 ml) and sodium iodide (5.36 g) in acetonitrile (10 ml) at 0°C, over a period of 2 hours. The mixture was further stirred at room temperature for 5 minutes, and cooled again to 0°C. _ An aqueous solution (10 ml) of sodium hydroxide (1.0 g) was added thereto, and the mixture was stirred at 0 °C for 0.5 hours. The mixture was extracted with ethyl acetate, washed successively with an aqueous sodium thiosulfate solution, water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 3-bromo-l- (4-n-propyl-2-thienyl) benzene (1/97 g) as colorless oil.
Reference Example 10
5-Bromo-2-chloro-l- (5-n-propyl-2-thienylmethyl) benzene 5-Bromo-2-chlorobenozoic acid and 2-n-propylthi phene were used and treated in a manner similar to Reference Example 5 to give the target compound.
Reference Example 11 5-Bromo-2-methoxy-l- (5-n-propyl-2-thienylmethyl) benzene
2-n-Propylthiophene and 5-bromo-2-methoxybenzaldehyde were used and treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 325/327 (M+H) .
Reference Example 12
3-Bromo-l- (4-ethyl-2-thienylmethyl) benzene
3-Ethylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 281/283 (M+H) .
Reference Example 13
3-Bromo-l- (4-chloro-5-ethyl-2-thienylmethyl) benzene (1) To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in N, -dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g) , and the mixture was stirred at room temperature for 2 hours, and subsequently stirred under heating at 60 °C for 2 hours. N-chlorosuccinimide (4.00 g) was further added thereto, and the mixture was further stirred under heating at 60 °C for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 33:1) to give
4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil.
(2) The above 4-chloro-5-ethyl-2-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 1 to give 3-bromo-l- (4-chloro-5-ethyl-2-thienylmethyl) benzene as yellow oil. APCI-Mass m/Z 347/349 (M+H+MeOH) .
Reference Example 14 5-Bromo-2-chloro-l- (4,5,6, 7-tetrahydrobenzo [b] thiophen-2- ylmethyl) benzene
(1) To a solution of 4-keto-4, 5, 6, 7-tetrahydrothianaphthene (9.83 g) in ethylene glycol (100 ml) were added hydrazine hydrate (10.4 ml) and potassium hydroxide (13.0 g) , and the mixture was stirred under argon atmosphere at 190°C for 4 hours .
The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate.
The extract was washed with water, and dried over sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography
(hexane) to give 4, 5, 6, 7-tetrahydrothianaphthene (2.75g) as colorless oil.
(2) The above 4,5,6, 7-tetrahydrothianaphthene was treated in a manner similar to Reference Example 5 to give 5-bromo-2-chloro-l- (4,5,6, 7-tetrahydrobenzo [b] thiophen-2-yl methyl) benzene as a colorless solid. APCI-Mass m/Z 341/343 (M+H) . Reference Example 15
5-Bromo-2-chloro-l- (5-ethyl-4-methyl-2-thienylmethyl) - benzene
(3) 2-Acetyl-3-methylthiophene was treated in a manner similar to Reference Example 14 to give the targ'et compound. APCI-Mass m/Z 329/331 (M+H) .
Reference Example 16
5-Bromo-2-chloro-l- (2-thieno [3, 2-b] thienylmethyl) benzene (1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar to Reference Example 4- (2) and (3) to give 5-bromo-2-chlorobenzaldehyde. APCI-Mass m/Z 233/235 (M+H+MeOH-H20) . (2) The above 5-bromo-2-chlorobenzaldehyde and thieno [3, 2-b] thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem . Soc. Perkin Trans 11997 , 3465 - 3470) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-l- (2-thieno [3, 2-b] thienylmethyl) benzene as colorless oil. APCI-Mass m/Z 343/345 (M+H).
Reference Example 17
5-Bromo-2-chloro-l- (5-chloro-2-thienylmethyl) enzene 2-Chlorothiophene was treated in a manner similar to Reference Example 5 to give the target compound.
Reference Example 18
5-Bromo-2-chloro-l- (5-phenylmethyl-2-thienylmethyl) benzene 2-Benzoylthiophene was treated in a manner similar to Reference Example 14 to give the target compound. APCI-Mass m/Z 377/379 (M+H) . Reference Example 19
5-Bromo-2-chloro-l- (5- (2-thienyl) -2-thienylmethyl) benzene 2,2' -Bithiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 369/371 (M+H) .
Reference Example 20 5-Bromo-l-
(5- (5-chloro-2-thienyl) -2-thienylmethyl) -2-methylbenzene (1) To a solution of 2-bromo-5-chlorothiophene (4.11 g) , thiophene-2-boronic acid (4.00 g) , tetrakis (triphenylphosphine) palladium (0)' (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane
(100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give
2- (5-chloro-2-thienyl) thiophene (3.37 g) as pale yellow oil. (2) The above 2- (5-chlorσ-2-thienyl) thiophene and
5-bromo-2-methylbenzoic acid obtained in Reference Example
4-(l) were used and treated in a manner similar to Reference
Example 5 to give
5-bromo-l- (5- (5-chloro-2-thienyl) -2-thienylmethyl) -2-methyl benzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H) .
Reference Example 21
5-Bromo-2-chloro-l- (4-chloro-5-ethyl-2-thienylmethyl) - benzene 2-Acetyl-3-chlorothiophene (see Japanese Unexamined Patent Publication No. 2000-34230) was treated in a manner similar to Reference Example 14 to give the target compound. APCI-Mass m/Z 347/349 (M+H) . Reference Example 22 5-Chloro-4-methylthiophene The target compound was prepared according to a method described in Japanese Unexamined Patent Publication No. 10-324632.
Reference Example 23
5-Bromo-2-chloro-l- (5- (5-chloro-2-thienyl) -2-thienylmethyl) benzene
2- (5-Chloro-2-thienyl) thiophene and 5-bromo-2-chlorobenzoic acid were treated in a manner similar to Reference Example 5 to give the target compound.
Reference Example 24
5-Bromo-2-chloro-l- (5-trifluoromethyI-2-thienylmethyl) - benzene
2-Trifluoromethylthiophene (see Japanese Unexamined Patent Publication No. 2000-34239) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 25
5-Bromo-2-chloro-l- (5- (2-pyridyl) -2-thienylmethyl) benzene
(1) 2- (2-Pyridyl) thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7-(l) to give
5-bromo-2-chlorophenyl-5- (2-pyridyl) -2-thienylmethanol as colorless powder. APCI-Mass m/Z 380/382 (M+H) .
(2) A solution of the above 5-bromo-2-chlorophenyl-5- (2-pyridyl) -2-thienylmethanol (3.52 g) in trifluoroacetic acid (45 ml) was added to a solution of sodium borohydride (1.75 g) in trifluoroacetic acid (45 ml), and the mixture was stirred at room temperature for 4 hours. Trifluoroacetic acid was evaporated under reduced pressure. The residue was basified with an aqueous potassium hydroxide solution, and extracted with diethyl ether. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9:1-4:1) "to give
5-bromo-2-chloro-l- (5- (2-pyridyl) -2-thienylmethyl) benzene (2.42 g) as a colorless solid. APCI-Mass m/Z 364/366 (M+H).
Reference Example 26 5-Bromo-l- (5-chloro-2-thienylmethyl) -2-phenylbenzene
(1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A. -Dieter Schluter Synthesis 1997, 1301-1304) and 2-chlorothiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-l- (5-chloro-2-thienylmethyl) -2-iodobenzene as colorless oil.
(2) To a solution of the above
5-bromo-l- (5-chloro-2-thienylmethyl) -2-iodobenzene (1.0 g) in dimethoxyethane (10 ml) were added phenylboronic acid (310 mg) , bis (triphenylphosphine) palladium (II) dichloride (85 mg) and 2M aqueous sodium carbonate solution (3.8 ml), and the mixture was stirred at 50 °C overnight. Added thereto was a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give
5-bromo-l- (5-chloro-2-thienylmethyl) -2-phenylbenzene ( 683 mg) as oil.
Reference Example 27 2-Chlorothieno [3, 2-b] thiophene
(1) A solution of thieno [3, 2-b] thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem . Soc . Perkin Trans 1 1997, 3465 - 3470) (1.27 g) in tetrahydrofuran (30 ml) was cooled to -78°C under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 5.70 ml). The mixture was stirred at 0°C for 30 minutes, and cooled again to -78°C. Added thereto was a solution of hexachloroethane (2.14 g) in tetrahydrofuran (5 ml) . The mixture was stirred' at the same temperature for one hour, and warmed to 0°C. Added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give
2-Chlorothieno [3, 2-b] thiophene (1.19 g) as a solid.
Reference Example 28
1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-methoxybenzene Thianaphthene was treated in a manner similar to Reference Example 7 to give the target compound. ESI-Mass m/Z 331/333 (M-H) .
Reference Example 29 1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-chlorobenzene
Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 30
3-Bromo-l- (5-methylbenzo [b] thiophen-2-ylmethyl) benzene 5-Methylbenzo [b] thiophene and 3-bromobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 31
3-Bromo-l- ( 6-fluorobenzo [b] thiophen-2-ylmethyl) benzene (1) To a solution of 2, -difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80 °C overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 7:1) to give 6-fluoro-2-methoxycarbonylbenzo [b] thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M) .
(2) The above 6-fluoro-2-methoxycarbonylbenzo [b] thiophene was treated in a manner similar to Reference Example 4-(l) to give 6-fluorobenzo [b] thiophen-2-ylcarboxylic acid as colorless powder. ESI-Mass m/Z 195 (M-H) . (3) The above 6-fluorobenzo [b] thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 4- (2) to give
6-fluoro-2- (N-methoxy-N-methylcarbamoyl) benzo [b] thiophene as colorless powder. APCI-Mass m/Z 240 (M+H) . (4) A solution of 1, 3-dibrOmobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to -78 °C under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above
6-fluoro-2- (N-methoxy-N-methylcarbamoyl) benzo [b] thiophene (500 mg) in tetrahydrofuran (3 ml) . The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5-85:15) to give 3-bromophenyl 6-fluorobenzo [b] thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4) .
(5) The above 3-bromophenyl 6-fluorobenzo [b] thiophen-2-yl ketone was treated in a manner similar to Reference Example 5- (2) to give
3-bromo-l- ( 6-fluorobenzo [b] thiophen-2-ylmethyl) benzene as a colorless solid.
Reference Example 32 1- (Benzo [b] thiophen-2-ylmethyl) -3-bromo-4-fluorobenzene
Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 33
1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-ethoxybenzene Thianaphthene and 5-bromo-2-ethoxybenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 34
1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-fluorobenzene Thianaphthene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 35
2- (Benzo [b] thiophen-2-ylmethyl) -4-bromo-l-methoxy- naphthalene 2, 4-Dibromo-l-methoxynaphthalene (see J. Clayden, et al . Org. Lett . , 5, (2003) 831) and benzo [b] thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound. Reference Example 36
3-Bromo-l- (5-trifluoromethylbenzo [b] thiophen-2- ylmethyl) benzene 5-Trifluoromethylbenzo [b] thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 31- (3) , (4) , and (5) to give the target compound.
Reference Example 37 3-Bromo-l- (3-methylbenzo [b] thiophen-2-ylmethyl) benzene
3-Methylbenzo [b] thiophene-2-carboxaldehyde was treated in a manner similar to Reference Example 1 to give the target compound .
Reference Example 38
3-Bromo-l- (5-fluorobenzo [b] thiophen-2-ylmethyl) benzene
2, 5-Difluorobenzaldehyde was treated in a manner similar to
Reference Example 31 to give the target compound.
Reference Example 39
1- (Benzo [b] thiophen-2-ylmethyl) -3-bromo-4-methylbenzene
(1) 3-Bromo-4-methylbenzoic acid was treated in a manner similar to Reference Example 4- (2) and (3) to give 3-bromo-4-methylbenzaldehyde as colorless crystals. APCI-Mass m/Z 213/215 (M+H+MeOH) .
(2) The above 3-bromo-4-methylbenzaldehyde and thianaphthene were treated in a manner similar to Reference Example 7 to give
(Benzo [b] thiophen-2-ylmethyl) -3-bromo-4-methylbenzene as a colorless solid.
Reference Example 40
1- (Benzo [b] thiophen-2-ylmethyl) -3-bromo-5-methylbenzene
3, 5-Dibromotoluene and benzo [b] thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reference Example 41
5-Bromo-2-chloro-l- ( 5-methylbenzo [b] thiophen-2- ylmethyl) benzene
5-Methylbenzo [b] thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 42
5-Bromo-2-chloro-l- (7-methylbenzo [b] thiophen-2- ylmethyl) benzene
7-Methylbenzo [b] thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95) and 5-bromo-2-chlorobenzaldehyde obtained in
Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 43 5-Bromo-2-chloro-l- (5-chlorobenzo [b] thiophen-2- ylmethyl) benzene
5-Chlorobenzo [b] thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 44
5-Bromo-2-chloro-l- (5, 7-dimethylbenzo [b] thiophen-2- ylmethyl) benzene 5, 7-Dimethylbenzo [b] thiophene (see Yoshimura, Y. etal., J. Med. Chem . 43 (2000) 2929-2937) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 45
1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-methylbenezene (1) A solution of thianaphthene (543 mg) in diethyl ether (20 ml) was cooled to 0°C under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 1.74 ml) . The reaction mixture was stirred at the same' temperature for 3 hours. The reaction mixture was added dropwise to a solution of N-methoxy-N-methyl-5-bromo-2-methylbenzamide
(1.15 g) obtained in Reference Example 4- (2) in diethyl ether (10 ml) cooled to -78°C. The mixture was warmed to room temperature and stirred for one hour. Added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0-95:5) to give 5-bromo2-methylphenyl benzo [b] thiophen-2-yl ketone (995 mg) as a pale yellow syrup. APCI-Mass m/Z 331/333 (M+H).
(2) The above 5-bromo2-methylphenyl benzo [b] thiophen-2-yl ketone was treated in a manner similar to Reference Example 5- (2) to give 1- (benzo [b] thiophen-2-ylmethyl) -5-bromo-2-methylbenezene as colorless oil.
Reference Example 46
5-Bromo-2-chloro-l- (6-methoxybenzo [b] thiophen-2-ylmethyl) - benzene 6-Methoxybenzo [b] thiophene (see WO 97/25033) and
5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound. Reference Example 47
5-Bromo-2-chloro-l- (6-chlorobenzo [b] thiophen-2-ylmethyl) - benzene (1) 4-Chloro-2-fluorobenzaldehyde was treated 'in a manner similar to Reference Example 31- (1) and (2) to give 6-chlorobenzo [b] thiophen-2-ylcarboxylic acid as colorless crystals. ESI-Mass m/Z 211/213 (M-H). (2) A solution of the above 6-chlorobenzo [b] thiophen-2-ylcarboxylic acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at 210°C for 40 minutes. The mixture was cooled to room temperature and diluted with diethyl ether, and insoluble materials were filtered off. The filtrate was washed successively with 10% aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 6-chlorobenzo [b] thiophene (1.79 g) as colorless crystals. (3) The above 6-chlorobenzO [b] thiophene and
5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give. 5-bromo-2-chloro-l- ( 6-chlorobenzo [b] thiophen-2-ylmethyl) ben zene as colorless crystals.
Reference Example 48
5-Bromo-2-chloro-l- ( 6-trifluoromethylbenzo [b] thiophen-2- ylmethyl ) benzene 2-Fluoro-4-trifluoromethylbenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound. Reference Example 49
1-Benzo [b] thiophen-2-ylmethyl) -3-bromo-4-chlorobenzene 3-Bromo-4-chlorobenzoic acid was treated in a manner similar to Reference Example 39 to give the target compound.
Reference Example 50
5-Bromo-2-chloro-l- ( 6-fluorobenzo [b] thiophen-2-ylmethyl) - benzene
2, 4-Difluorobenzaldehyde was treated in a manner similar to Reference' Example 47 to give the target compound.
Reference Example 51
5-Bromo-2-fluoro-1- ( 6-fluorobenzo [b] thiophen-2-ylmethyl) - benzene , > 6-Fluorobenzo [b] thiophene produced in the preparation process of Reference Example 50 and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 52
1- (Benzo [b] thiophen-2-ylmethyl) -3-bromo-5-chlorobenzene l-Chloro-3, 5-dibromobenzene and benzo [b] thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reference Example 53
5-Bromo-2-chloro-l- (7-methoxybenzo [b] thiophen-2-ylmethyl) - benzene
7-Methoxybenzo[b] thiophene (see WO 02/094262) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example
16- (1) were treated in a manner similar to Reference Example
9 to give the target compound. APCI-Mass m/Z 367/369 (M+H) . Reference Example 54
5-Bromo-2-chloro-l- (5-methoxybenzo [b] thiophen-2-ylmethyl) - benzene
5-Methoxybenzo [b] thiophene (see WO 97/25033) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 367/369 (M+H) .
Reference Example 55 5-Bromo-2-chloro-l- (5-fluorobenzo [b] thiophen-2-ylmethyl) - benzene
2, 5-Difluorobenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound.
Reference Example 56
5-Bromo-2-chloro-l- (7-fluoro-6-methylbenzo [b] thiophen-2- ylmethyl) benzene
2, 3-Difluoro-4-methylbenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound. APCI-Mass m/Z 369/371 (M+H)".
Reference Example 57
5-Bromo-2-chloro-l- (4-fluorobenzo [b] thiophen-2-ylmethyl) - benzene 2, 6-Difluorobenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound.
Reference Example 58
5-Bromo-2-chloro-l- (7-fluorobenzo [b] thiophen-2-ylmethyl) - benzene
2, 3-difluorobenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound. Reference Example 59
5-Bromo-2-chloro-l- (4-chlorobenzo [b] thiophen-2-ylmethyl) - benzene
2-Chloro-6-fluorobenzaldehyde was treated in a manner similar to Reference Example 47 to give the target compound.
Reference Example 60
5-Bromo-2-fluoro-l- (5-fluorobenzo [b] thiophen-2-ylmethyl) - benzene 5-Fluorobenzo [b] thiophene produced in the preparation process of Reference Example 55 and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 61
3-Bromo-2-chloro-l- (benzo [b] thiophen-2-ylmethyl) benzene
(1) 3-Bromo-2-chlorobenzoic acid (see Frederic Gohier et al., J. Org. Chem . (2003) 68 2030-2033.) was treated in a manner similar to Reference Example 4- (2) to give N-methoxy-N-methyl-3-bromo^2-chlorobenzamide as oil. APCI-Mass m/Z 278/280/282 (M+H) .
(2) The above N-methoxy-N-methyl-3-bromo-2-chlorobenzamide was treated in a manner similar to Reference Example 45 to give 3-bromo-2-chloro-l- (benzo [b] thiophen-2-ylmethyl) benzene as a colorless solid.
Reference Example 62
1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-ethylbenzene (1) To a solution of 2-ethylbenzoic acid (10.0 g) in dichloromethane (50 ml) were added oxalyl chloride (7.0 ml) and N, N-dimethylformamide (3 drops) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give a corresponding acid chloride. The acid chloride was dissolved in methanol (60 ml) and the mixture was stirred at room temperature for 3 hours, and then, the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate . The solvent was evaporated under reduced pressure to give methyl 2-ethylbenzoate, which was used in the subsequent step without further purification.
(2) The above methyl 2-ethylbenzoate was mixed with molecular sieve 13X (powder, 70 g) , and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80°C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g) , water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml) - water (500 ml) , and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g) . APCI-Mass m/Z 260/262 (M+NH ) .
(3) The above methyl 5-bromo-2-ethylbenzoate was treated in a manner similar to Reference Example 4-(l) and (2) to give N-methoxy-N-methyl-5-bromo-2-ethylbenzamide as colorless oil. APCI-Mass m/Z 272/274 (M+H) .
(4) The above N-methoxy-N-methyl-5-bromo~2-ethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-ethylbenzene as oil.
Reference Example 63 1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-trifluoromethyl- benzene
(1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A. -Dieter Schluter Synthesis 1997, 1301-1304) was treated in a manner similar to Reference Example 4- (2) to give N-methoxy-N-methyl-5-bromo-2-iodobenzamide as a pale yellow solid. APCI-Mass m/Z 370/372 (M+H) .
(2) To a solution of the above
N-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) in N-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124 mg) and methyl fluorosulfonyl (difluoro) acetate (1.34 ml), and the mixture was stirred under heating for 1.5 hours. The reaction mixture was cooled to room temperature, and then, a diluted aqueous ammonia was added thereto, and the mixture was extracted with ethyl acetate . The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 85:15) to give N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide (1.59 g) as colorless oil. APCI-Mass m/Z 312/314 (M+H).
(3) The above
N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-trifluoromethylbe nzene as a colorless solid. ESI-Mass m/Z 369/371 (M-H) .
Reference Example 64 5-Bromo-2-chloro-l- (5-phenyl-2-thienylmethyl) benzene 2-Phenylthiophene was treated in a manner similar to Reference Example 5 to give the target compound. APCI-Mass m/Z 363/365 (M+H) .
Reference Example 65
5-Bromo-2-chloro-l- (5- (4-methylphenyl) -2-thienylmethyl) - benzene
(1) 2-Iodothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give 2- (4-methylphenyl) thiophene as colorless crystals. APCI-Mass m/Z 175 (M+H) .
(2) The above 2- (4-methylphenyl) thiophene was treated in a manner similar to Reference Example 5 to give 5-bromo-2-chloro-l- (5- (4-methylphenyl) -2-thienylmethyl) benz ene as colorless crystals. APCI-Mass m/Z 377/379 (M+H).
Reference Example 66
5-Bromo-2-chloro-l- (5- (2-fluorophenyl) -2-thienylmethyl) - benzene
(1) 2-Fluorobromobenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 26-(2) to give 2- (2-fluorophenyl) thiophene as a colorless liquid.
(2) The above 2- (2-fluorophenyl) thiophene was treated in a manner similar to Reference Example 5 to give
5-bromo-2-chloro-l- (5- (2-fluorophenyl) -2-thienylmethyl) benz ene as a colorless solid. APCI-Mass m/Z 381/383 (M+H) .
Reference Example 67 5-Bromo-2-chloro-l- (5- (4-fluorophenyl) -2-thienylmethyl) - benzene ,
(1) 2-Iodothiophene and 4-fluorophenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give 2- (4-fluorophenyl) thiophene as colorless powder. (2) The above 2- (4-fluorophenyl) thiophene was treated in a manner similar to Reference Example 5 to give 5-bromo-2-chloro-l- (5- (4-fluorophenyl) -2-thienylmethyl) benz ene as colorless powder.
Reference Example 68
5-Bromo-2-chloro-l- (5- (4-ethoxyphenyl) -2-thienylmethyl) - benzene (1) 2-Bromothiophene and 4-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 20- (1) to give
2- (4-ethoxyphenyl) thiophene as a colorless solid. APCI-Mass m/Z 205 (M+H) .
(2) The above 2- (4-ethoxyphenyl) thiophene was treated in a manner similar to Reference Example 5 to give
5-bromo-2-chloro-l- (5- (4-ethoxyphenyl) -2-thienylmethyl) benz ene as a colorless solid. APCI-Mass m/Z 407/409 (M+H) .
Reference Example 69 5-Bromo-2-chloro-l- (5- (3-ethoxyphenyl) -2-thienylmethyl) - benzene
(1) 2-Bromothiophene and 3-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 20- (1) to give 2- (3-ethoxyphenyl) thiophene as colorless oil. APCI-Mass m/Z 205 (M+H) .
(2) The above 2- (3-ethoxyphenyl) thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-l- (5- (3-ethoxyphenyl) -2-thienylmethyl) benz ene as colorless oil. APCI-Mass m/Z 407/409 (M+H) . Reference Example 70
5-Bromo-2-chloro-l- (5- (2-ethoxyphenyl) -2-thienylmethyl) - benzene
(1) 2-Iodothiophene and 2-ethoxyphenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give 2- (2-ethoxyphenyl) thiophene as a pale yellow solid.
(2) The above 2- (2-ethoxyphenyl) thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 9 to give
5-bromo-2-chloro-l- (5- (2-ethoxyphenyl) -2-thienylmethyl) benz ene as colorless oil. APCI-Mass m/Z 407/409 (M+H).
Reference Example 71 5-Bromo-2-fluoro-1- (5-phenyl-2-thienylmethyl) benzene
2-Phenylthiophene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 347/349 (M+H) .
Reference Example 72
5-Bromo-l- (5- (4-ethoxyphenyl) -2-thienylmethyl) -2- fluorobenzene
2- (4-Ethoxyphenyl) thiophene obtained in Reference Example
68- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 391/393 (M+H) .
Reference Example 73
5-Bromo-l- (5- (2-ethoxyphenyl) -2-thienylmethyl) -2- fluorobenzene
2- (2-Ethoxyphenyl) thiophene obtained in Reference Example 70- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 391/393 (M+H) .
Reference Example 74
5-Bromo-2-fluoro-1- (5- (2-fluorophenyl) -2-thienylmethyl) - benzene
2- (2-Fluorophenyl) thiophene obtained in Reference Example
66- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 365/367 (M+H) .
Reference Example 75
5-Bromo-2-chloro-l- (5- (3-fluorophenyl) -2-thienylmethyl) - benzene
(1) 2-Iodothiophene and 3-fluorophenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give 2- (3-fluorophenyl) thiophene as oil.
(2) The above 2- (3-fluoropheny) thiophene was treated in a manner similar to Reference Example 5 to give the target compound as powder.
Reference Example 76 5-Bromo-
1- (5- (3-ethoxyphenyl) -2-thienylmethyl) -2-fluorobenzene 2- (3-Ethoxyphenyl) thiophene obtained in Reference Example 69- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 391/393 (M+H) .
Reference Example 77
5-Bromo-2-fluoro-l- (5- (3-fluorophenyl) -2-thienylmethyl) - benzene
2- (3-Fluorophenyl) thiophene obtained in Reference Example 75- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound .
Reference Example 78
5-Bromo-2-fluoro-1- (5- (4-fluorophenyl) -2-thienylmethyl) - benzene
2- (4-Fluorophenyl) thiophene obtained in Reference Example
67- (1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 79
5-Bromo-2-methyl-l- (5-phenyl-2-thienylmethyl) benzene 2-Phenylthiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(l) were treated in a manner similar to Reference Example 5 to give the target compound. APCI-Mass m/Z 343/345 (M+H) .
Reference Example 80
5-Bromo-l- (5- (3-fluorophenyl) -2-thienylmethyl) -2- methylbenzene
2- (3-Fluorophenyl) thiophene obtained in Reference Example
75- (1) and 5-bromo-2-methylbenzoic acid obtained in Reference
Example 4-(l) were treated in a manner similar to Reference
Example 5 to give the target compound.
Reference Example 81
5-Bromo-l- (5- (4-fluorophenyl) -2-thienylmethyl) -2- methylbenzene
2- (4-Fluorophenyl) thiophene obtained in Reference Example 67- (1) and 5-bromo-2-methylbenzoic acid obtained in Reference
Example 4-(l) were treated in a manner similar to Reference
Example 5 to give the target compound. Reference Example 82
5-Bromo-2-methoxy-l- (5-phenyl-2-thienylmethyl) benzene 2-Phenylthiophene was treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 359/361 (M+H) .
Reference Example 83
5-Bromo-2-methyl-l- (5- (3-methylphenyl) -2-thienylmethyl) - benzene (1) 2-Bromothiophene and 3-methylphenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give
2- (3-methylphenyl) thiophene as colorless oil.
(2) The above 2- (3-methylphenyl) thiophene and
5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 357/359 (M+H) .
Reference Example 84
5-Bromo-2-chloro-l- (5- (3-methylphenyl) -2-thienylmethyl) - benzene
2- (3-Methylphenyl) thiophene obtained in Reference Example 83- (1) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 377/379/381 (M+H) .
Reference Example 85
5-Bromo-2-chloro-l- (5- (3-chlorophenyl) -2-thienylmethyl) - benzene (1) 2-Bromothiophene and 3-chlorophenylboronic acid were treated in a manner similar to Reference Example 26- (2) to give
2- (3-chlorophenyl) thiophene as colorless oil.
(2) The above 2- (3-chlorophenyl) thiophene was treated in a manner similar to Reference Example 5 to give the target compound as colorless oil.
Reference Example 86 5-Bromo-l- (5- (3-chlorophenyl) -2-thienylmethyl) -2- methylbenzene
2- (3-Chlorophenyl) thiophene obtained in Reference Example 85- (1) and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(l) were treated in a manner similar to Reference Example 5 to give the target compound as colorless oil.
Reference Example 87
5-Bromo-l- (5- (3-methoxyphenyl) -2-thienylmethyl) -2- methylbenzene (1) 3-Methoxybromobenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 26- (2) to give 2- (3-methoxyphenyl) thiophene as a yellow liquid. APCI-Mass m/Z 191 (M+H) . (2) The above 2- (3-methoxyphenyl) thiophene and 5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 9 to give the target compound as yellow oil. APCI-Mass m/Z 373/375 (M+H).
Reference Example 88 4-Bromo-2- (4-ethylphenylmethyl) -2H-isoquinolin-l-one
4-Bromo-2H-isoquiolin-l-one (see EP0355750) was treated in a manner similar to Reference Example 2 to give the target compound. APCI-Mass m/Z 342/344 (M+H) .
Reference Example 89
4-Bromo-2- (4-ethylphenylmethyl) -8-methyl-2H-isoquinolin-l- one
(1) To a solution of 8-methyl-2H-isoquiolin-l-one (1.15 g) in dichloromethane (20 ml) was added dropwise a solution of bromine
(1.26 g) in dichloromethane (4 ml) at room temperature. The mixture was stirred at the same temperature for one hour, and the solvent was evaporated under reduced pressure. The residue was crystallized from ether to give
4-bromo-8-methyl-2H-isoquinolin-l-one (1.86 g) as colorless crystals. APCI-Mass m/Z 238/240 (M+H).
(2) The above 4-bromo-8-methyl-2H-isoquinolin-l-one was treated in a manner similar to Reference Example 2 to give the target compound as colorless crystals. APCI-Mass m/Z 356/358M+H) .
Reference Example 90
4-Bromo-2- (4-ethylphenylmethyl) thiophene (1) A solution of 4-bromo-2-thiophenecarboxaldehyde (4.78 g) in tetrahydrofuran (40 ml) was cooled to 0°C under argon atmosphere, and thereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 M tetrahydrofuran solution, 50 ml) . The mixture was stirred at the same temperature for 30 minutes," and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate . The extract was washed with brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 97:3 - 84:16) to give 4-bromo-2-thienyl-4-ethylphenylmethanol (5.37 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H-H20) . (2) The above 4-bromo-2-thienyl-4-ethylphenylmethanol was treated in a manner similar to Reference Example l-(2) to give the target compound as colorless oil. Reference Example 91
5-Bromo-2- (4-ethylphenylmethyl) thiophene
5-Bromo-2-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 90 to give the target compound. ESI-Mass m/Z 279/281 (M-H) .
Reference Example 92
3-Bromo-2- (4-ethylphenylmethyl) thiophene
(1) 2, 3-Dibromothiophene and 4-ethylbenzaldehyde were treated in a manner similar to Reference Example 1-(1) to give
3-bromo-2-thienyl-4-ethylphenylmethanol as yellow oil. APCI-Mass m/Z 279/281 (M+H-H20) .
(2) A solution of the above
3-bromo-2-thienyl-4-ethylphenylmethanol (12.4 g) in diethyl
> ether (10 ml) was added dropwise into a suspension of lithium aluminum hydride (2.6 g) and aluminum chloride (9.0 g) in diethyl ether (35 ml) at 0°C. Subsequently, the mixture was stirred at room temperature overnight, and then poured onto ice . The mixture was extracted with diethyl ether, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 3-bromo-2- (4-ethylphenylmethyl) thiophene (8.77 g) as colorless oil. APCI-Mass m/Z 279/281 (M+H).
Reference Example 93
5-Bromo-3- (4-ethylphenylmethyl) thiophene
5-Bromo-3-thiophenecarboxaldehyde (see Amishiro, N. et al., Chem . Pharm . Bull . 47 (1999) 1393-1403.) was treated in a manner similar to Reference Example 90 to give the target compound.
Reference Example 94 5-Bromo-2-chloro-3- (4-ethylphenylmethyl) thiophene
(1) 5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese Unexamined Patent Publication No. 10-324632) was treated in a manner similar to Reference Example 4- (2) and (3) to give
5-bromo-2-chloro-3-thiophenecarboxaldehyde as pale yellow oil, APCI-Mass m/Z 239/241/243 (M+H+MeOH-H20) .
(2) The above 5-bromo-2-chloro-3-thiophenecarboxaldehyde was treated in a manner similar to Reference Example 90 to give the target compound as colorless oil.
Reference Example 95
5-Bromo-3-chloro-2- (4-ethylphenylmethyl) thiophene
(1) A solution of diisopropylamine (6.8 ml) in tetrahydrofuran (75 ml) was cooled to -78 °C under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 30.5 ml) . The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of 3-chloro-2-thiophenecarboxylic acid (3.92 g) in tetrahydrofuran (40 ml) . The mixture was stirred at the same temperature for 30 minutes," and thereto was added dropwise 1, 2-dibromo-l, 1, 2, 2-tetrafluoroethane (6.0 ml) . The mixture was stirred at the same temperature for one hour, and then, warmed to room temperature. The mixture was poured into a diluted aqueous hydrochloric acid solution, and the solution was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixed solvent of diisopropyl ether and hexane to give 5-bromo-3-chloro-2-thiophenecarboxylic acid (3.79 g) as a yellow solid. ESI-Mass m/Z 239/241 (M-H).
(2) The above 5-bromo-3-chloro-2-thiophenecarboxylic acid was treated in a manner similar to Reference Example 94 to give 5-bromo-3-chloro-2- (4-ethylphenylmethyl) thiophene as colorless oil.
Reference Example 96
3-Bromo-l- (benzo [b] thiophen-3-ylmethyl) benzene Thianaphthene-3-carboxaldehyde was treated in a manner similar to Reference Example 1 to give the target compound.
Reference Example 97
3-Bromo-l- (5-ethyl-2-furylmethyl) benzene N I ) 5-Ethyl-2-furaldehyde was treated in a manner similar to
Reference Example 1-(1) to give
3-bromophenyl-5-ethyl-2-furylmethanol as oil. APCI-Mass m/Z
263/265 (M+H-H20) .
(2) The above 3-bromophenyl-5-ethyl-2-furylmethanol was treated in a manner similar to Reference Example 9- (2) to give the target compound as oil.
Reference Example 98
3-Bromo-l- (benzo [b] furan-2-ylmethyl) benzene 2-Benzo [b] furancarboxaldehyde was treated in a manner similar to Reference Example 97 to give the target compound.
Reference Example 99
1- (Benzo [b] furan-2-ylmethyl) -5-bromo-2-chlorobenzene Benzo [b] furan and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reference Example 100 1- (Benzothiazol-2-ylmethyl) -5-bromo-2-methylbenzene
(1) Benzothiazole and 5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7-(l) to give 5-bromo-2-methylphenyl- (benzothiazol-2-yl)methanol as pale yellow crystals. APCI-Mass m/Z 334/336 (M+H).
(2) To a solution of the above 5-bromo-2-methylphenyl- (benzothiazol-2-yl) methanol (2.60 g) in dichloromethane (30 ml) -toluene (10 ml) was "added manganese (IV) oxide (3.42 g) , and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give 5-bromo-2-methylphenyl benzothiazol-2-yl ketone (2.45 g) as colorless crystals. APCI-Mass m/Z 332/334 (M+H) .
(3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone was treated in a manner similar to Reference Example 14- (1) to
- give 1- (benzothiazol-2-ylmethyl) -5-bromo-2-methylbenzene as oil. APCI-Mass m/Z 318/320 (M+H) .
Reference Example 101
1- (Benzothiazol-2-ylmethyl) -5-bromo-2-chlorobenzene Benzothiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 100 to give the target compound. APCI-Mass m/Z 338/340 (M+H) .
Reference Example 102 5-Bromo-2-chloro-l- (5-phenyl-2-thiazolylmethyl) benzene
(1) A solution of thiazole (10.0 g) , iodobenzene (2.63 ml), tetrakis (triphenylphosphine) palladium (0) (1.36 g) and potassium acetate (3.46 g) in N, N-dimethylacetamide (100 ml) was stirred under heating at 100 °C overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H) . (2) The above 5-phenylthiazole and
5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16- (1) were treated in a manner similar to Reference Example 100 to give
5-bromo-2-chloro-l- (5-phenyl-2-thiazolylmethyl) benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H) .
Reference Example 103
3- (4-Ethylphenylmethyl) -2, 4-pentanedione
A suspension of sodium iodide (15. Og) in acetonitrile (100ml) was cooled to 0°C under argon atmosphere, and thereto were added dropwise chlorotrimethylsilane (12.7ml), 2, 4-pentanedione
(2.05ml) and 4-ethylbenzaldehide (2.68g), successively. The reaction mixture was stirred at room temperature for 17 hours, and further stirred at 60 °C for 10 hours. The reaction mixture was cooled to room temperature and poured into an aqueous sodium thiosulfate solution. The mixture was extracted with diethyl ether, and the extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9:1) to give 3- (4-ethylphenylmehyl) -2, 4-pentanedione (2.72g) as pale yellow oil. APCI-Mass m/Z 219 (M+H).
Reference Example 104 Tri-n-butyl (4-ethylphenyl) tin To a solution of magnesium (896 mg) in tetrahydrofuran (20 ml) was added dibromoethan (0.1 ml), and the mixture was stirred at room temperature for 15 minutes. Thereto was added dropwise a solution of l-bromo-4-ethylbenzene (5.7 g) in tetrahydrofuran (20 ml) , and subsequently, the mixture was stirred at room temperature for one hour. The reaction mixture was cooled to -78 °C, and thereto was added dropwise tributyltin chloride (9.49 g) . The mixture was stirred at the same temperature for 30 minutes, and then at room temperature for one hour. To the reaction mixture were added 10% aqueous potassium fluoride solution and ethyl acetate, and the mixture was stirred at room temperature for 30 minutes. Insoluble materials were filtered off. The organic layer of the filtrate was washed with water and brine successively, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by alumina column chromatography (hexane) to give the desired tri-n-butyl (4-ethylphenyl) tin (10.7 g) as colorless oil. El-Mass m/Z 337 (M-Bu) .
> Reference Example 105 4- (4-Ethylphenylmethyl) pyrazole
(1) A mixed solution of 4-ethylbenzyl bromide (10.0 g) , malononitrile (6.64 g) , potassium carbonate (6.94 g) and tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was agitated at room temperature for 17 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate twice. The extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 6:1) to give 2- (4-ethylphenylmethyl) malononitrile (3.28 g) as a colorless solid.
(2) A solution of the above
2- (4-ethylphenylmethyl) malononitrile (1.30 g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was heated under reflux for 4 hours. Hydrazine hydrate (0.43 ml) was further added thereto and the mixture was further heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether to give 3, 5-diamino-4- (4-ethylphenylmethyl) pyrazole (2.63 g) as pale pink powder. APCI-Mass m/Z 217 (M+H) .
(3) The above 3, 5-diamino-4- (4-ethylphenylmethyl) pyrazole (1.30 g) was added to 50% aqueous phosphoric acid solution (19 ml) , and further added thereto was water (10 ml) . The mixture was cooled to 0°C, and thereto was added dropwise an aqueous solution (4 ml) of sodium nitrite (912 mg) . The' mixture was stirred at the same temperature for 30 minutes, and further 'stirred at room temperature for 4 hours. The reaction mixture was cooled again to 0°C, 10% aqueous sodium hydroxide solution was added thereto to adjust pH of the reaction mixture to 7. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 - 90:10) to give the desired 4- (4-ethylphenylmethyl) pyrazole (414 mg) as a pale brown semisolid. APCI-Mass m/Z 187 (M+H) .
Reference Example 106
3- (4-Ethylphenylmethyl) -5-methyl-lH-pyrazole
(1) 4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N, N-dimethylformamide (one drop) . The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification.
(2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0°C, and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml) . The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. ' The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate =15:1) to give t-butyl
2-acetyl-4- (4-ethylphenyl) -3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH ) .
(3) A solution of the above t-butyl
2-acetyl-4- (4-ethylphenyl) -3-oxobutyrate in trifluoroacetic acid (60 'ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1- (4-ethylphenyl) -4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H).
(4) A solution of the above
1- (4-ethylphenyl) -4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100 ° C for 1.5 hours . The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate =2:1) to give 3- (4-ethylphenylmethyl) -5-methyl-lH-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H). Reference Example 107
3- (4-Ethylphenylmethyl) -6-hydroxypyridine
(1) To a solution of 6-chloronicotinoyl chloride (10.0 g) and N,0-dimethylhydroxyamine hydrochloride (6.65 g) in dichloromethane (200 ml) was added dropwise triethylamine (17.2 g) at 0°C. Subsequently the mixture was stirred at room temperature overnight. The mixture was washed successively with water, 5% aqueous citric acid solution, water and brine, and then, dried over sodium sulfate . The solvent was evaporated under reduced pressure to give
N-methoxy-N-methyl-6-chloronicotinamide (11.73 g) as pale yellow oil. APCI-Mass m/Z 201/203 (M+H) .
(2) • A solution of the N-methoxy-N-methyl-6-chloronicotineamide (4.2 g) in tetrahydrofuran (40 ml) was cooled to 0 °C, and thereto was added dropwise 4-ethylphenylmagnesium bromide (0.5 M tetrahydrofuran solution, 55 ml) . The mixture was stirred at 0 ° C for 4 hours , and then at the room temperature for 10 minutes . The reaction mixture was cooled again to 0°C, and added thereto was 10% aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 20:1) to give 6-chloro-3-pyridyl 4-ethylphenyl ketone (3.68 g) as colorless crystals. APCI-Mass m/Z 246/248 (M+H).
(3) The above 6-chloro-3-pyridyl 4-ethylphenyl ketone (1.68 g) was dissolved in N-methyl-2-pyrrolidinone (20 ml) , and thereto were added benzylalcohol (815 ml) and 60% sodium hydride (275 mg) . The mixture was stirred at room temperature for 6 hours, and then at 90 °C for one hour. The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and subsequently with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 95:5) to give 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.68 g) as colorless oil. APCI-Mass m/Z 318 (M+H).
(4) The above 6-benzyloxy-3-pyridyl 4-ethylphenyl ketone (865 mg) was dissolved in ethylene glycol (8.5 ml) , and thereto were added hydrazine hydrate (0.44 ml) and potassium hydroxide (550 mg) . The mixture was stirred under heating at 190 °C for 8 hours . The reaction mixture was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water three times, and subsequently with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0 - 0:100) to give the desired , 3- (4-ethylphenylmethyl) -6-hydoroxypyridine (256 mg) as colorless powder. APCI-Mass m/Z 214 (M+H) .
Reference Example 108
3- (4-Ethylphenylmethyl) -2-hydroxypyridine
(1) 2-Chloronicotinoyl chloride was treated in a manner similar to Reference Example 107- (1), (2) and (3) to give
2-benzyloxy-3-pyridyl 4-ethylphenyl ketone as colorless oil. APCI-Mass m/Z 318 (M+H) .
(2) The above 2-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.69 g) was dissolved in ethanol (15 ml), and thereto was added sodium borohydride (403 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate . The mixture was washed with water and successively with brine, and dried over sodium sulfate . The solvent was evaporated under reduced pressure to give crude
2-benzyloxy-3-pyridyl-4-ethylphenylmethanol as colorless oil, which was used in the subsequent step without further purification.
(3) The above 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol was dissolved in methanol (10 ml) , and thereto were added concentrated hydrochloric acid (1.0 ml) and 10%- palladium-carbon (500 mg) . The mixture was stirred at room temperature for 15 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the' solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and successively with brine, and dried over sodium sulfate . The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 - 97:3) to give the desired 3- (4-ethylphenylmethyl) -2-hydoroxypyridine (307 mg) as a pale brown solid. APCI-Mass m/Z 214 (M+H) .
Reference Example 109 3- (4-Ethylphenylmethyl) -lH-indole
(1) To a solution of indole (6.00 g) in methanol (60 ml) were added sodium hydroxide (2.25 g) and 4-ethylbenzaldehyde (7.56 g) , and the mixture was stirred at room temperature for 3 days under argon atmosphere. Added thereto was water, and methanol was evaporated under reduced pressure. The residue was extracted with diethyl ether, and the extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98:2 - 70:30) to give 4-ethylphenyl- (lH-indol-3-yl) methanol (2.10 g) as a colorless solid. APCI-Mass m/Z 234 (M+H-H20) .
(2) The above 4-ethylphenyl- (lH-indol-3-yl) methanol was treated in a manner similar to Reference Example l-(2) to give the desired 3- (4-ethylphenylmethyl) -lH-indole as colorless crystals. APCI-Mass m/Z 236 (M+H).
Reference Example 110 3- (4-Ethylphenylmethyl) -l'H-indazole
(1) A mixture of zinc powder (712 mg) and dibromoethane (0.04 ml) in N, N-dimethylformamide (2.5 ml) were stirred under heating at 70 °C for 10 minutes under argon atmosphere. The reaction mixture was cooled to room temperature, and chlorotrimethylsilane (0.04 ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes. To the activated zinc solution was added dropwise a solution of 4-ethylbenzyl bromide (1.74 g) in N, N-dimethylformamide (10ml) at 0°C over a period of 2 hours. Subsequently, the mixture was stirred at 0°C for 2 hours, to prepare a solution of
4-ethylbenzylzinc bromide in N, N-dimethylformamide, which was used in the subsequent step without further purification.
(2) A solution of tris (dibenzylideneacetone) dipalladium (0) (167 mg) and tri (2-furyl) phosphine (135 mg) in tetrahydrofuran (20 ml) was stirred at room te'mperature for 5 minutes under argon atmosphere. Thereto were added l-t-butoxycarbonyl-3-iodo-lH-indazole (2.0 g) and the above 4-ethylbenzylzinc bromide (N, N-dimethylformamide solution) at 0 °C, and the mixture was stirred at room temperature for 5 hours . The reaction mixture was poured into water, and the mixture was extracted with diethyl ether . The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0 - 92:8) to give l-t-butoxycarbonyl-3- (4-ethylphenylmethyl) -lH-indazole (1.37 g) as colorless oil. APCI-Mass m/Z 337 (M+H).
(3) The above l-t-butoxycarbonyl-3- (4-ethylphenylmethyl) -lH-indazole (1.35 g) was dissolved in methanol (15 ml), and added thereto was 28% sodium methoxide solution (methanol solution, 1.0 ml) , and the mixture was stirred at room temperature for one hour. Added thereto was an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from hexane to give the desired 3- (4-ethylphenylmethyl) -lH-indazole, (800 mg) as colorless crystals. APCI-Mass m/Z 237 (M+H).
Reference Example 111 5-Bromo—2-methyl-l- (5- (4-trifluoromethylphenyl) -2- thienylmethyl) benzene
(1) 4-Bromobenzotrifluoride and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give
2- (4-trifluoromethylphenyl) thiophene as colorless crystals. (2) The above 2- (4-trifluoromethylphenyl) thiophene and
5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7 to give the desired
5-bromo—2-methyl-l- (5- (4-trifluoromethylphenyl) -2-thienylme thyl)benzene as colorless crystals. APCI-Mass m/Z 425/427
(M+H+MeOH) .
Reference Example 112
5-Bromo—2-methyl-l- (5- (3-trifluoromethylphenyl) -2- thienylmethyl) benzene
(1) 3-Bromobenzotrifluoride and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give 2- (3-trifluoromethylphenyl) thiophene as colorless oil. (2) The above 2- (3-trifluoromethylphenyl) thiophene and 5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7 to give the desired
5-bromo—2-methyl-l- (5- (3-trifluoromethylphenyl) -2-thienylme thyl) benzene as colorless oil.
Reference Example 113 2- (4-Ethylphenyl) thiophene 2-Bromothiophene and 4-ethylphenylboronic acid were treated in a manner similar to Reference Example 20- (1) to give the target compound.
Reference Example 114 2- (4-Methylphenyl) thiophene 2-Bromothiophene and 4-methylphenylboronic acid were treated in a manner similar to Reference Example 20- (1) to give the target compound.
Reference Example 115 2- (2, 3-Dihydro-5-benzo [b] fύranyl) thiophene
(1) 5,7-Dibromo-2,3-dihydrobenzo[b]furan (see WO 02/070020) (3.0 g) in diethyl ether was cooled to -78°C under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 5.09 ml) . The mixture was stirred at the same temperature for 30 minutes, and poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2, 3-dihydrobenzo [b] furan (2.0 g) as pale yellow crystals, which was used in the subsequent step without further purification. (
(2) The above 5-bromo-2, 3-dihydrobenzo [b] furan and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give the desired
2- (2, 3-dihydro-5-benzo [b] furanyl) thiophene as pale yellow crystals. APCI-Mass m/Z 203 (M+H).
Reference Example 116
4-Bromo-2- (5-chloro-2-thienylmethyl) -1-fluoronaphthalene
(1) A solution of 2, 2, 6, 6-tetramethylpiperidine (1.04 g) in tetrahydrofuran (15 ml) was cooled to -78 °C under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.58 M hexane solution, 4.43 ml). The reactionι mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of l-bromo-4-fluoronaphthalene (1.50 g) in tetrahydrofuran (12 ml) at-78°C. The mixture was stirred at the same temperature for one hour, and thereto was added dropwise a solution of 5-chloro-2-thiophenecarboxaldehyde
(1.07 g) in tetrahydrofuran (11 ml) at -78°C. The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate . The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by an aminosilane-treated silica gel column chromatography (hexane: ethyl acetate = 3:1) to give 4-bromo-l-fluoro-2-naphthyl-5-chloro-2-thienylmethanol (2.00 g) as pale yellow powder. APCI-Mass m/Z 353/355 (M+H-H20) .
(2) The above
4-bromo-1-fluoro-2-naphthyl-5-chloro-2-thienylmethanol was treated in a manner similar to Reference Example l-(2) to give the desired
4-bromo-2- (5-chloro-2-thienylmethyl) -1-fluoronaphthalene as a yellow solid. Reference Example 117
5-Bromo-2 , 4-dimethyl-l~ ( 5-phenyl-2-thienylmethyl) benzene
(1) 2, 4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N, N-dimethylformamide (2 drops) . The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate . The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2, 4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification.
(2) To a mixture of the above methyl 2, 4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature . The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml) . The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2, 4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2, 4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(l) to give 5-bromo-2, 4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M-H) (4) The above 5-bromo-2, 4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give
5-bromo-2, 4-dimethyl-l- (5-phenyl-2-thienylmethyl) benzene as colorless crystals.. APCI-Mass m/Z 357/359 (M+H)\
Reference Example 118
5-Bromo-l- (5-phenyl-2-thienylmethyl) -2-trifluorbmethyl- benzene (1) 5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A. -Dieter
Schluter Synthesis 1997, 1301-1304) was treated in a manner similar to Reference Example 117- (1) to give methyl 5-bromo-2-iodobenzoate as a brown solid.
(2) To a solution of the above methyl 5-b'romo-2-iodobenzoate (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper
(I) bromide (235 mg) and methyl
2, 2-difluoro-2- (fluorosulfonyl) acetate (2.6 ml), and the mixture was stirred under heating at 120 °C for 1.5 hours. The reaction mixture was cooled, and added thereto were 10% aqueous hydrochloric acid solution" and ethyl acetate. Insoluble materials were filtered off, and an organic layer of the filtrate was washed with water for 4 times, and subsequently washed with a saturated aqueous sodium hydrogen carbonate solution and brine . The filtrate was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexan:ethyl acetate = 80:1) to give methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil.
(3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in a manner similar to Reference Example 4-(l) to give
5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Mass m/Z 267/269 (M-H) .
(4) The above 5-bromo-2-trifluoromethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5-(l) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z 411/413 (M+H) . (5) To a mixed solution of the above
5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml) -tetrahydrofuran (10 ml) was added sodium borohydride (62 mg) , and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml) - acetonitrile (20 ml) . Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0°C. Thereto was added dropwise boron trifluoride • diethyl ether complex (0.52 ml) . The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to" give the desired
5-bromo-l- (5-phenyl-2-thienylmethyl) -2-trifluoromethylbenze ne (565 mg) as colorless oil.
Reference Example 119 5-Bromo-l- (5- (3-ethylphenyl) -2-thienylmethyl) -2-methyl- benzene
(1) l-Bromo-3-ethylbenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give 2- (3-ethylphenyl) thiophene as a pale yellow liquid. (2) The above 2- (3-ethylphenyl) thiophene and
5-bromo-2-methylbenzald,ehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 9 to give 5-bromo-l- (5- (3-ethylphenyl) -2-thienylmethyl) -2-methylbenze ne as pale yellow oil. APCI-Mass m/Z 371/373 (M+H).
Reference Example 120
5-Bromo-2-methyl-l- (5- (2-pyridyl) -2-thienylmethyl) benzene (1) 2- (2-Pyridyl) thiophene and 5-bromo-2-mehtylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7-(l) to give
5-bromo-2-methylphenyl-5- (2-pyridyl) -2-thienylmethanol as colorless oil. APCI-Mass m/Z 360/362 (M+H). (2) A solution of the above
5-bromo-2-methylphenyl-5- (2-pyridyl) -2-thienylmethanol
(1.59 g) in trifluoroacetic acid (40 ml) was cooled to 0°C, and thereto were added gradually sodium triacetoxyborohydride
(4.68 g) . The mixture was stirred at room temperature for one hour, and cooled again to 0°C. 10% aqueous sodium hydroxide solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3:1) to give the desired 5-bromo-2-methyl-l- (5- (2-pyridyl) -2-thienylmethyl) benzene
(1.38 g) as a colorless solid. APCI-Mass m/Z 344/346 (M+H).
Reference Example 121
2- (5-Fluoro-2-thienyl) thiophene
2, 2' -Bithiophene (7.40 g) in tetrahydrofuran (90 ml) was cooled to -78 °C under argon atmosphere, and thereto were added dropwise n-butyl lithium (1.59 M hexane solution, 28.0 ml). The mixture was stirred at 0°C for one 30 minutes, and cooled again to -78 °C. Added thereto was N-fluorobenzenesulfonimide (15.5 g) , and the mixture was gradually warmed, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice-cold water, and the solution was extracted with hexane twice, and the extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane) to give
2- (5-fluoro-2-thienyl) thiophene (5.89 g) as colorless oil.
Reference Example 122
5-Bromo-2-methyl-l- (5- (3-pyridyl) -2-thienylmethyl) benzene 2- (3-Pyridyl) thiophene was treated in a manner βimilar to
Reference Example 120 to give the target compound as colorless crystals. APCI-Mass m/Z 344/346 (M+H).
Reference Example 123 5-Bromo-l- (5- (4-methoxyphenyl) -2-thienylmethyl) -2- methylbenzene
(1) p-Bromoanisole and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give
2- (4-methoxyphenyl) thiophene as a pale yellow solid. APCI-Mass m/Z 191 (M+H) .
(2) The above 2- (4-methoxyphenyl) thiophene and 4-bromo-2-methylbenzoic acid obtained in Reference Example 4-(l) were treated in a manner similar to Reference Example 5 to give 5-bromo-l- (5- (4-methoxyphenyl) -2-thienylmethyl) -2-methylben zene as a pale yellow solid. APCI-Mass m/Z 373/375 (M+H) .
Reference Example 124
5-bromo-2-methyl-l- (5- (1, 2-Methylenedioxybenzen-4-yl) -2- thienylmethyl) benzene
4-Bromo-l, 2- (methylenedioxy) benzene was treated in a manner similar to Reference Example 119 to give the target compound as colorless powder. Reference Example 125
5-Bromo-2-chloro-l- (2- (5-phenyl-2-thienyl) ethyl) benzene (1) To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml) , and pyridine (2 drops) , and the mixture was stirred under heating at 100 °C overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate . The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0°C. Added thereto was tetraethylammonium cyanide (8.8 g) , and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, ■Which was used in the subsequent step without further purification.
(3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml) - sulfuric acid (75 ml), and the mixture was stirred under heating at 160°C overnight. The mixture .was further diluted with water, and cooled to 0°C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M-H).
(4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118- (4) and (5) to give the desired 5-bromo-2-chloro-l- (2- (5-phenyl-2-thienyl) ethyl) benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H) .
Reference Example 126
5-Bromo-l- (5- ( 6-fluoro-2-pyridyl) -2-thienylmethyl) 2- ethylbenzene
(1) 2-Bromo-6-fluoropyridine and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20- (1) to give 2- (6-fluoro-2-pyridyl) thiophene as yellow oil. APCI-Mass m/Z 180 (M+H) . (2) The above 2- ( 6-fluoro-2"-pyridyl) thiophene was treated in a manner similar to Reference Example 120 to give the desired 5-bromo-l- (5- ( 6-fluoro-2-pyridyl) -2-thienylmethyl) 2-methylb enzene as a colorless solid. APCI-Mass m/Z 362/364 (M+H) .
Reference Example 127
5-Bromo-2-methyl-l- (5-trifluoromethyl-2-thienylmethyl) - benzene
2-Trifluoromethylthiophene (see Japanese Unexamined Patent
Publication No. 2000-34239) and 5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7 to give the target compound as colorless oil . Reference Example 128
5-Bromo-l- (5- (5-fluoro-2-thienyl) -2-thienylmethyl) -2-methyl benzene
5-Bromo-2-methylbenzoic acid obtained in Reference Example 4-(l) and 2- (5-fluoro-2-thienyl) thiophene obtained in
Reference Example 121 were treated in a manner similar to Reference Example 5 to give the target compound as a colorless solid. APCI-Mass m/Z 367/369 (M+H) .
Reference Example 129
3-Bromo-2-fluoro-6-methyl-l- (5-phenyl-2-thienylmethyl) benze ne
4-Bromo-3-fluorotoluene and
5-phenyl-2-thiophenecarboxaldehyde were treated in a manner similar to Reference Example 116 to give the target compound as pale blue powders. APCI-Mass m/Z 361/363 (M+H).
Reference Example 130
5-Bromo-2-chloro-l- (2-phenyl-5-thiazolylmethyl) benzene (1) 5-Bromo-2-chlorophenylacetic acid (2.0 g) obtained in Reference Example 125- (3) was dissolved in dichloromethane (40 ml), and thereto were added oxalyl chloride (0.77 ml) and N, N-dimethylformamide (one drop) at 0°C. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give
5-bromo-2-chlorophenylacetyl chloride, which was used in the subsequent step without further purification. (2) A solution of potassium t-butoxide (1.35 g) in tetrahydrofuran (20 ml) was cooled to 0°C, and thereto was added methyl isocyanoacetate (1.33 ml). Then, a solution of the above 5-bromo-2-chlorophenylacetyl chloride in tetrahydrofuran (20 ml) was added thereto, and the mixture was stirred at 0°C for 2 hours, and then at room temperature overnight. The mixture was cooled again to 0°C. 10% aqueous citric acid solution was added thereto, and the mixture was extracted with ethyl acetate . The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica" gel column chromatography (hexane : ethyl acetate = 3:1) to give 5-bromo-2-chloro-l- ( 4-methoxycarbonyl-5-oxazolylmethyl) benz ene (1.12 g) as a yellow solid. APCI-Mass m/Z 33O/332 (M+H).
(3) The above ' 5-bromo-2-chloro-l- (4-methoxycarbonyl-5-oxazolylmethyl) benz ene (1.37 g) was heated under reflux in 6N aqueous hydrochloric acid solution (20 ml) overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol, and treated with carbon powder. The carbon powder was filtered off, and the filtrate was evaporated under reduced pressure to give crude
1- (3-amino-2-oxopropyl) -5-bromo-2-chlorobenzene • hydrochlori de (1.73 g) as a pale brown solid, which was used in the subsequent step without further purification. APCI-Mass m/Z 262/264 (M+H) .
(4) A mixed solution of the above
1- (3-amino-2-oxopropyl) -5-bromo-2-chlorobenzene • hydrochlori de (1.70 g) in ethyl acetate (30 ml) - water (15 ml) was cooled to 0°C. Added thereto were benzoyl chloride (0.99 ml) and sodium hydrogen carbonate (2.39 g) , and the mixture was stirred at the same temperature for 3 hours. The organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 95:5) to give
1- (3-benzoylamino-2-oxopropyl) -5-bromo-2-chlorobenzene (710 mg) as a colorless solid. APCI-Mass m/Z 366/368 (M+H) .
(5) To a solution of the above 1- (3-benzoylamino-2-oxopropyl) -5-bromo-2-chlorobenzene (710 mg) in toluene (20 ml) was added Lawesson reagent (2.35 g) , and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 90:10) to give the desired
5-bromo-2-chloro-l- (2-phenyl-5-thiazolylmethyl) benzene (512 mg) as a colorless solid. APCI-Mass m/Z 364/366 (M+H) .
Reference Example 131 t-Butyl 5-bromo-2-chlorobenzoic acid
To a solution of 5-bromo-2-chlorobenzoic acid (11.75 g) in
N, N-dimethylformamide (50 ml) was added 1, 1' -carbonyldiimidazole (8.10 g), and the mixture was stirred under heating at 40 °C for one hour. Thereto were added t-butanol (7.40 g) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (7.60 g) , and the mixture was further stirred under heating at 40 °C overnight. The mixture was diluted with diethyl ether, and washed successively wi'th water (3 times), 2% aqueous hydrochloric acid solution (twice) , a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give t-butyl 5-bromo-2-chlorobenzoate (12.53 g) as pale yellow oil.
Reference Example 132
5-Bromo-2-chloro-l- ( 6-ethoxybenzo [b] thiophen-2- ylmethyl) benzene (1) A solution of 5-bromo-2-chloro-l-
(6-methoxybenzo [b] thiophen-2-ylmethyl) benzene (2.70 g) obtained in Reference Example 46 in dichloromethane (27 ml) was cooled to 0°C under argon atmosphere, and thereto was added dropwise boron tribromide (0.83 ml) . The mixture was warmed to room temperature, and stirred for 30 minutes. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and subsequently, the reaction mixture was made acidic with a saturated aqueous citric acid solution. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from chloroform-hexane to give 5-bromo-2-chloro-l- ( 6-hydroxybenzo [b] thiophen-2-ylmethyl) be nzene (2.01 g) as pale green crystals. ESI-Mass, m/Z 351/353 (M-H) .
(2) The above 5-bromo-2-chloro-l- (6-hydroxybenzo [b] thiophen-2-ylmethyl) benzene (500 mg) was dissolved in N, N-dimethylformamide (5ml), and thereto were added iodoethane (0.23 ml) and potassium carbonate (390 mg) . The mixture was stirred at room temperature for 2 days .' Added thereto .was water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98:2 -80:20) to give the desired 5- bromo-2-chloro-l- ( 6-ethoxybenzo [b] thiophen-2-ylmethyl) benze ne (492 mg) as pale pink oil. APCI-Mass m/Z 381/383 (M+H).
Reference Example 133
5-Bromo-2-chloro-3- (5-phenyl-2-thienylmethyl) thiophene 5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese Unexamined Patent Publication No. 10-324632) and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give the target compound as a colorless solid. APCI-Mass m/Z 367/369 (M+H) . Reference Example 134
6-Fluoro-2-pyridylboronic acid pinacol ester A solution of 2-bromo-6-fluoropyridine (1.0 g) in tetrahydrofuran (10 ml) was cooled to -78 °C under argon atmosphere, and thereto was added a solution of n-butyl lithium (2.59 M hexane solution, 2.24 ml) in tetrahydrofuran (10 ml) . The mixture was stirred at the same temperature for 45 minutes, and thereto was added dropwise a solution of triisopropoxyborane (1.28 g) in tetrahydrofuran (10 ml) . The mixture was stirred at the same temperature for 2 hqurs, warmed, and further stirred at room temperature for one hour. Subsequently, a solution of pinacol (0.91 g) in tetrahydrofuran (10 ml) was added dropwise thereto, and stirred at room temperature for 20 minutes. Insoluble materials were filtered off. The filtrate was extracted with 2.5% sodium hydroxide, and the extract was cooled to 0°C, and was made weakly acidic with 2N aqueous hydrochloric acid solution. It was extracted with diethyl ether, washed with a small amount of brine, and dried over magnesium sulfate . The solvent was evaporated under reduced pressure and the residue was solidified with hexane to give 6-fluoro-2-pyridylboronic acid pinacol ester (850 mg) as a colorless solid. APCI-Mass m/Z 224 (M+H) .
Reference Example 135 5-Bromo-2-chloro-l- ( 6-phenyl-3-pyridylmethyl) benzene
(1) 5-Bromo-2-chlorobenzoic acid was treated in a manner similar to Reference Example 4- (2) to give
N-methoxy-N-methyl-5-bromo-2-chlorobenzamide as a colorless solid. APCI-Mass m/Z 278/280 (M+H) . (2) The above N-methoxy-N-methyl-5-bromo-2-chlorobenzamide' and 2, 5-dibromopyridine, were treated in a manner similar to
Reference Example 31- (4) to give 5-bromo-2-chlorophenyl
6-bromo-3-pyridyl ketone as a pale yellow solid. APCI-Mass m/Z 374/376 (M+H) .
(3) The above 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone and phenylboronic acid were treated in a manner similar to Reference Example 20- (1) to give 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone as yellow crystals. APCI-Mass m/Z 372/374 (M+H) .
(4) The above 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone was treated in a manner similar to Reference Example 14- (1) to give the desired 5-bromo-2-chloro-l- (6-phenyl-3-pyridylmethyl) benzene as colorless crystals. APCI-Mass m/Z 358/360 (M+H).
Reference Example 136
5-Bromo-2-chloro-l- ( 6-isopropyloxybenzo [b] thiophen-2- ylmethyl) benzene
5-Bromo-2-chloro-l- ( 6-hydroxybenzo [b] thiophen-2-ylmethyl) be _ nzene obtained in Reference Example 132- (1) and 2-iodopropane were treated in a manner similar to Reference Example 132- (2) to give the titled compound. APCI-Mass m/Z 395/397 (M+H) .
Reference Example 137 4-Bromo-l-fluoro-2- (5- (2-pyridyl) -2- thienylmethyl) naphthalene
(1) A solution of 2, 2, 6, 6-tetramethylpiperidine (4.13 ml) in tetrahydrofuran (40 ml) was cooled to -78°C under argon atmosphere, and added dropwise thereto was n-butyl lithium (2.44 M hexane solution, 10.0 ml) . The mixture was stirred at the same temperature for 30 minutes, and added dropwise thereto at -78°C was a solution of l-bromo-4-fluoronaphthalene (5.0 g) in tetrahydrofuran (20 ml) . The mixture was stirred at the same temperature for 1 hour, and added dropwise thereto at -78°C was N, N-dimethylformamide (5.16 ml). The mixture was stirred at the same temperature for 1 hour, and added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether and hexane to give
4-bromo-l-fluoro-2-naphthaldehyde (4.43 g) as pale yellow crystals. APCI-Mass m/Z 267/269 (M+NH4) . (2) The above 4-bromo-l-fluoro-2-naphthaldehyde' and 2- (2-pyridyl) thiophene were treated in a manner similar to Reference Example 120 to give the desired 4-bromo-l- fluoro-2- (5- (2-pyridyl ) -2-thienylmethyl ) naphthalene as colorless powder. APCI-Mass m/Z 398/400 (M+H) .
Reference Example 138 5-Bromo-2-chloro-l- ( 6-ethyl-3-pyridylmethyl) benzene
(1) 5-Bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone (3.2 g) from Reference Example 135- (2 ) was dissolved in tetrahydrofuran
(80 ml) , and added thereto were triethylaluminium (1.0 M hexane solution, 9.9 ml), tetrakis (triphenylphosphine) palladium (0) (570 mg) and cerium (III) chloride (7.3 g) , and the mixture was stirred at 30°C for 1.5 hours . The reaction mixture was diluted with methanol, and the reaction solution was basified with a saturated aqueous sodium hydrogen carbonate solution. The insoluble materials were filtered off and, the filtrate was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 99:1 - 85:15) to give 5-bromo-2-chlorophenyl 6-ethyl-3-pyridyl ketone (1.98 g) as a colorless solid. APCI-Mass m/Z 324/326 (M+H) .
(2) The above 5-bromo-2-.chlorophenyl 6-ethyl-3-pyridyl ketone was treated in a manner similar to Reference Example 14- (1) to give the desired 5-bromo-2-chloro-l- (6-ethyl-3-pyridylmethyl) benzene as a colorless oil. APCI-Mass m/Z 310/312 (M+H).
Reference Example 139 6-Ethylbenzo [b] thiophene (1) 4-Bromo-2-flurobenzaldehyde and ethyl thiogϊycolate were treated in a manner similar to Reference Example 31- (1) to give 6-bromo-2-ethoxycarbonylbenzo [b] thiophene as a colorless solid.
(2) The above 6-bromo-2-ethoxycarbonylbenzo [b] thiophene was treated in a manner similar to Reference Example 13,8- (1) to give
6-ethyl-2-ethoxycarbonylbenzo [b] thiophene as colorless oil. APCI-Mass m/Z 235 (M+H) .
(3) The above 6-ethyl-2-ethoxycarbonylbenzo [b] thiophene (1.26 g) was dissolved in tetrahydrofuran (4 ml) and methanol (8 ml) , and added thereto was lithium hydroxide monohydrate (677 mg) , and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and the solution was made acidic with a 10% aqueous hydrochloric acid solution. The precipitates were collected by filtration and washed with water to give 6-ethylbenzo [b] thiophen-2-ylcarboxylic acid (1.15 g) as colorless crystals. ESI-I-Mass m/Z 205 (M-H).
(4) The above 6-ethylbenzo [b] thiophen-2-ylcarboxylic acid was tread in a manner similar to Reference Example 47- (2) to give the desired 6-ethylbenzo [b] thiophene as colorless oil.
Reference Example 140
5-Bromo-2-chloro-l- (l-oxo-2-isoindolinylmethyl) benzene (1) 5-Bromo-2-chlorobenzyl alcohol (3.0 g) was dissolved in toluene (30 ml) , and added thereto were thionyl chloride (2.35 ml) and pyridine (two dr,ops) , and the mixture was heated under stirring at 100°C for 2 hours. The mixture was cooled, washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give
5-bromo-2-chlorobenzyl chloride (3.34 g) as pale brown oil, which was used in the subsequent step without further purification.
(2) The above 5-bromo-2-chlorobenzyl chloride (3.34 g) was dissolved in N, N-dimethylformamide (30 ml) , and added thereto was potassium phthalimide (2.63 g) , and the mixture was heated under stirring at 70°C for 3 hours. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from diisopropyl ether to give 5-bromo-2-chloro-l- (phthalimid-2-ylmethyl) - benzene (3.33 g) as colorless crystals. APCI-Mass m/Z 350/352 (M+H) . (3) The above 5-bromo-2-chloro-l- (phthalimid-2-ylmethyl) - benzene (4.3 g) was dissolved in acetic acid (43 ml) , and added thereto was zinc powder (8.02 g) , and the mixture was heated at reflux for 3 days. The mixture was cooled and diluted with chloroform and it was basified with an aqueous sodium hydroxide solution. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6:1 - 4:1) to give the desired
5-bromo-2-chloro-l- (l-oxo-2-isoindolinylmethyl) benzene (1.39 g) as colorless powder. APCI-Mass m/Z 336/338 (M+H).
Reference Example 141 5-Bromo-2-chloro-l- (l-phenyl-4-pyrazolylmethyl) benzene
(1) A solution of l-phenyl-4-bromopyrazole (see M. A. Khan, et al., Can. J. Chem., (1963) 41 1540) (2.23 g) in diethyl ether (30 ml) wad cooled to -78°C under argon atmosphere, and added dropwise thereto was n-butyl lithium (1.59 M hexane solution, 6.9 ml) . The mixture was stirred at -20°C to -10°C for 5 hours, and added dropwise thereto at the same temperature was a solution of 5-bromo-2-chlorobenzaldehyde (2.19 g) obtained in Reference Example 16- (1) in diethyl ether (30 ml) . The mixture was stirred at the same temperature for 30 minutes, and added thereto was tetrahydrofuran (30 ml) , and the mixture was stirred at 0°C for further 30 minutes. A saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 83:17 - 80:20) to give 5-bromo-2-chlorophenyl-l-phenyl-4-pyrazpl.ylmethanol (831 mg) as yellow oil. APCI-Mass m/Z 363/365 (M+H). (2) The above - 5-bromo-2-chlorophenyl-l-phenyl-4-pyrazolylmethanol was treated in a manner similar to Reference Example 120- (2) to give the desired 5-bromo-2-chloro-l- (l-phenyl-4-pyrazolylmethyl) benzene as colorless powder. APCI-Mass m/Z 347/349 (M+H) .
Reference Example 142
5-Bromo-2-chloro-l- ( 6-n-propyloxybenzo [b] thiophen-2-yl- methyl) enzene
5-Bromo-2-chloro-l- (6-hydroxybenzo [b] thiophen-2-ylmethyl) e nzene obtained in Reference Example 132- (1) and 1-bromoproρane were treated in a manner similar to Reference Example 132- (2) to give the target compound. APCI-Mass m/Z 395/397 (M+H) .
Reference Example 143 -
5-Bromo-2-chloro-l- (6- (2-fluoroethyloxy) benzo [b] thiophen-2- ylmethyl) benzene 5-Bromo-2-chloro-l- (6-hydroxybenzo [b] hiophen-2-ylmethyl) be nzene obtained in Reference Example 132- (1) and l-bromo-2-fluoroethane were treated in a manner similar to Reference Example 132- (2) to give the target compound. APCI-Mass m/Z 399/401 (M+H) .

Claims

C L A I M S
1. A compound of formula :
Figure imgf000196_0001
wherein Ring A and Ring B are one of the followings: (1) Ring A is an optionally substituted unsaturated monocyclic heterocyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring, (2) Ring A is an optionally substituted benzene ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, or an optionally substituted unsaturated fused heterobicyclic ring wherein Y is linked to the heterocyclic ring of said fused heterobicyclic ring, or (3) Ring A is an optionally substituted unsaturated fused heterobicyclic ring, wherein the sugar moiety X- (sugar) and the moiety -Y-(Ring B) are both on the same heterocyclic ring of said fused heterobicyclic ring, and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring, an optionally substituted unsaturated fused heterobicyclic ring, or an optionally substituted benzene ring; X is a carbon atom or a nitrogen atom; and Y is -(CH2)n- (wherein n is 1 or 2); a pharmaceutically acceptable salt thereof, or a prodrug thereof .
2. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1 , wherein the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxyl group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a hetero- cyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cycloalkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkylsulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenyl- sulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cycloalkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group, a cycloalkynylsulfonyl group, an arylsulfonyl group, and a heterocyclylsulfonyl group; the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, an oxo group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidene- methyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenyl- carbonyl group, a cycloalkynyl- carbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxy- carbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxy- carbonyl group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cyclo- alkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cyclo- alkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclyl- carbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoyl- amino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, an alkylsulfinylamino group, an alkyl- sulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cyclo- alkenylsulfinyl group, a cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cyclo- alkenylsulfonyl group, a cycloalkynylsulfonyl group, an arylsulfonyl group, and a heterocyclylsulfonyl group; and the optionally substituted benzene ring is a benzene ring which may optionally be substituted by 1-5 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxy group, a mercapto group, a carboxyl group, a sulfo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heterocyclyl group, an alkoxy group, an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, a cycloalkynyloxy group, an aryloxy group, a heterocyclyloxy group, an alkanoyl group, an alkenylcarbonyl group, an alkynylcarbonyl group, a cycloalkylcarbonyl group, a cycloalkenylcarbonyl group, a cycloalkynylcarbonyl group, an arylcarbonyl group, a heterocyclylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, a cycloalkynyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclyloxycarbonyl group, an alkanoyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, a cycloalkylcarbonyloxy group, a cycloalkenylcarbonyloxy group, a cycloalkynylcarbonyloxy group, an arylcarbonyloxy group, a heterocyclylcarbonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, a cycloalkylthio group, a cycloalkenylthio group, a cycloalkynylthio group, an arylthio group, a heterocyclylthio group, an amino group, a mono- or di-alkylamino group, a mono- or di-alkanoylamino group, a mono- or di-alkoxycarbonylamino group, a mono- or di-arylcarbonylamino group, arj alkylsulfinylamino group, an alkylsulfonylamino group, an arylsulfinylamino group, an arylsulfonylamino group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a mono- or di-arylcarbamoyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, a cycloalkylsulfinyl group, a cycloalkenylsulfinyl group, a _ cycloalkynylsulfinyl group, an arylsulfinyl group, a heterocyclylsulfinyl group, an alkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group, a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group, a cycloalkynylsulfonyl group, an arylsulfonyl group, a heterocyclylsulfonyl group, an alkylene group, an alkyleneoxy group, an alkylenedioxy group, and an alkenylene group.
3. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, and an oxo group; the optionally substituted unsaturated fused
■ heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl ^roup, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, and an oxo group; and the optionally substituted benzene ring is a benzene ring which may optionally be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, an aryl group, an aryloxy group, an arylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, a heterocyclyl group, an alkylene group, an alkyleneoxy group, an alkylenedioxy group, and an alkenylene group.
4. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, and an oxo group; the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents selected from the group ςonsisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkylthio group, an alkylsulfonyl group, an alkylsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkyl- sulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, phenylsulfonyl group, a heterocyclyl group, and an oxo group; and the optionally substituted benzene ring is a,benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; wherein the substituents on the unsaturated monocyclic heterocyclic ring, the unsaturated fused heterobicyclic ring and the benzene ring may further be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, a mono- or di-alkylamino group, a carboxyl group, an alkoxycarbonyl group, a phenyl group, an alkylenedioxy group, an alkyleneoxy group, and an oxo group.
5. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein the optionally substituted unsaturated monocyclic heterocyclic ring is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, and an oxo group; the optionally substituted unsaturated fused heterobicyclic ring is an unsaturated fused heterobicyclic ring which may optionally be substituted by 1-3 substituents independently selected from the group' consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, and an oxo group; and the optionally substituted benzene ring is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkanoyl group, a mono- or di-alkylamino group, an alkanoylamino group, an alkoxycarbonylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, a phenyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; wherein the substituents on the unsaturated monocyclic heterocyclic ring, the unsaturated fused heterobicyclic ring and the benzene ring may further be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, a carboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxy group, and an alkoxycarbonyl group.
6. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein Ring A and Ring B are:
(1) Ring A is an unsaturated monocyclic heterocyclic ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, and an oxo group, and Ring B is an unsaturated monocyclic heterocyclic ring, an unsaturated fused heterobicyclic ring, or a benzene ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl, group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group; or
(2) Ring A is a benzene ring which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or _ di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group, and an alkenylene group, and
Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylidenemethyl group, an alkoxy group, an alkanoyl group, an alkylthio group, an alkylsulfonyl group, an alklsulfinyl group, an amino group, a mono- or di-alkylamino group, a sulfamoyl group, a mono- or di-alkylsulfamoyl group, a carboxyl group, an alkoxycarbony-μ group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsufonylamino group, a phenyl group, a phenoxy group, a phenylsulfonylamino group, a phenylsulfonyl group, a heterocyclyl group, an alkylene group and an oxo group; wherein the substituent on Ring A and Ring B may optionally be substituted by 1-3 substituents, independently selected from the group consisting of a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkanoyl group, a mono- or di-alkylamino group, a carboxyl group, a hydroxy group, a phenyl group, an alkylenedioxy group, an alkyleneoxy group, and an alkoxycarbonyl group.
7. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein Y is -CH2- and is linked at the 3-position of Ring A, with respect to X being the 1-position,
Ring A is a benzene ring which is substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, and a phenyl group, and a lower alkenylene group, and
Ring B is an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a phenyl-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, a lower alkylenedioxyphenyl group, a lower alkyleneoxy phenyl group, a mono- or di-lower alkylaminophenyl group, a heterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, a lower alkoxyheterocyclyl group, and a mono- or di-lower alkylaminoheterocycycly.l group.
8. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein Y is -CH2- and is linked at the 3-position of Ring A, with respect to X being the 1-position,
Ring A is an unsaturated monocyclic heterocyclic ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halogen atom, a lower alkoxy group, and an oxo group, and
Ring B is (a) a benzene ring which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, a heterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, and a lower alkoxyheterocyclyl group, or (b) an unsaturated monocyclic heterocyclic ring or an unsaturated fused heterobicyclic ring, each of which may be substituted by 1-3 substituents selected from the group consisting of a lower alkyl group, a halo-lower alkyl group, a halogen atom, a lower alkoxy group, a halo-lower alkoxy group, a phenyl group, a halophenyl group, a cyanophenyl group, a lower alkylphenyl group, a halo-lower alkylphenyl group, a lower alkoxyphenyl group, a halo-lower alkoxyphenyl group, a heterocyclyl group, a haloheterocyclyl group, a cyanoheterocyclyl group, a lower alkylheterocyclyl group, a lower alkoxyheterocyclyl group, and a lower alkoxyheterocyclyl group.
9. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to any one of claims 1-8, wherein the unsaturated monocyclic heterocyclic ring is furan, thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, or thiazole; and the unsaturated fused heterobicyclic ring is indoline, isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline, benzothiophene, benzofuran, thienothiophene, or dihydroisoquinoline.
10. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein Ring A is
Figure imgf000209_0001
wherein Rla, R2a, R3a, Rlb, R2b, and R3 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a _ cycloalkylidenemethyl group, a cycloalkenyl group, a cycloalkyloxy group, a phenyl group, a phenylalkoxy group, a cyano group, a nitro group, an amino group, a mono- or di-alkylamino group, an alkanoylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkanoyl group, an alkylsulfonylamino group, a phenylsulfonylamino group, an alkylsulfinyl group, an alkylsulfonyl group, or a phenylsulfonyl group, and
Ring B is
Figure imgf000209_0002
wherein R4a and R5a are each independently a hydrogen atom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkylidenemethyl group; a cycloalkenyl group; a cycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; a mono- or di-alkylamino group; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an alkylsulfonyl group; a phenylsulfonyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylenedioxy group, an alkyleneoxy group, or a mono- or di-alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group, or Ra and R5a are bonded to each other at the terminals thereof to form an alkylene group; and R4b, R5b, R4c and R5c are each independently a hydrogen atom; a halogen atom; a hydroxy group; an alkoxy group; an alkyl group; a haloalkyl group; a haloalkoxy group; a hydroxyalkyl group; an alkoxyalkyl group; a phenylalkyl group; an alkoxyalkoxy group; a hydroxyalkoxy group; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkylidenemethyl group; a cycloalkenyl group; a cycloalkyloxy group; a phenyloxy group; a phenylalkoxy group; a cyano group; a nitro group; an amino group; a mono- or di-alkylamino group; an alkanoylamino group; a carboxyl group; an alkoxycarbonyl group; a carbamoyl group; a mono- or di-alkylcarbamoyl group; an alkanoyl group; an alkylsulfonylamino group; a phenylsulfonylamino group; an alkylsulfinyl group; an .alkylsulfonyl group; a phenylsulfonyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxy group or a haloalkoxy group.
11. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 10, wherein Rl , Ra, R3a, Rlb, R2 , and R3b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a phenyl group;,
R4a and R5a are each independently a hydrogen atom; a halogen atom; a lower alkyl group; a halo-lower alkyl group; a phenyl-lower alkyl group; a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, or Ra and R5a are bonded to each other at the terminals thereof to form a lower alkylene group; and
R4b, R5b, R4c and Rc are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
12. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 11, wherein Ring B is
Figure imgf000211_0001
wherein R ,44aa is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, or a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R5a is a hydrogen atom, or
Ra and R5a are bonded to each other at the terminals thereof to form a lower alkylene group.
13. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 12, wherein Ring A is
Figure imgf000212_0001
wherein Rla is a halogen atom, a lower alkyl group, or a lower alkoxy group, and R2a and R3a are hydrogen atoms; and Ring B is
Figure imgf000212_0002
wherein R4a is a phenyl group optionally substituted by a substituent selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, and a mono- or di-lower alkylamino group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group, and R5a is a hydrogen atom, and Y is —CH2— .
14. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 13, wherein Ra is a phenyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group; or a heterocyclyl group optionally substituted by a halogen atom, a cyano group, a lower alkyl group, or a lower alkoxy group.
15. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 14, wherein, the heterocyclyl group is a thienyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, pyrazolyl group, a thiazolyl group, a quinolyl group, or a tetrazolyl group.
16. The compound, the pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 10, wherein Ring A is
Figure imgf000213_0001
wherein Rla is a halogen atom, a lower alkyl group, , or a lower alkoxy group, and R2a and R3a are hydrogen atoms; and Ring B is
Figure imgf000213_0002
wherein R4b and R5b are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a halo-lower alkoxy group.
17. The compound, a pharmaceutically acceptable salt thereof or a prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of: 1- (β-D-glucopyranosyl) -4-chloro-3- (6-ethylbenzo [b] thiophen-
2-ylmethyl) benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (5-thiazolyl) -2- thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- (5-phenyl-2-thienyl- methyl) benzene;
1- (β-D-glucopyranosyl) -,4-methyl-3- [5- (4-fluorophenyl) -2- thienylmethyl] benzene ;
1- ( β-D-glucopyranosyl) -4-chloro-3- [5- (2-pyrimidinyl) -2- thienylmethyl] benzene;
1- ( β-D-glucopyranosyl) -4-methyl-3- [5- (2-pyrimidinyl) -2- thienylmethyl] benzene;
1- ( β-D-glucopyranosyl) -4-chloro-3- [5- (3-cyanophenyl) -2- thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (4-cyanophenyl) -2- thienylmethyl] benzene;
1- ( β-D-glucopyranosyl) -4-methyl-3- [5- ( 6-fluoro-2-pyridyl) -
2-thienylmethyl] benzene; 1- (β-D-glucopyranosyl) -4-chloro-3- [5- ( 6-fluoro-2-pyridyl) -
2-thienylmethyl] benzene;
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (3-difluoromethylphenyl) -2-thienylmethyl] benzene; the pharmaceutically acceptable salt thereof; and the prodrug thereof.
18. A pharmaceutical composition, which comprises the compound as set forth in any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier or diluent.
19. The pharmaceutical composition according to claim
18, which further comprises another antidiabetic agent.
20. A method for treating or delaying the progression or onset of diabetes mellitus, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis, or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of the compound, a pharmaceutically acceptable salt thereof, or a prodrug thereof as set forth in claim 1.
21. A method for treatment of type 1 and 2 diabetes mellitus, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as set forth in claim 1 alone, or in combination with another antidiabetic agent, an agent for treating diabetic complications, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent.
22. A compound of the formula:
Figure imgf000215_0001
wherein Rllb, Rllc and Rlld are each independently a .protecting group for a hydroxy group, or an ester thereof^
23. A compound according to claim 22, wherein the ester is the compound of the following formula:
Figure imgf000215_0002
wherein Rllb, Rllc and Rlld are the same as defined in claim 22, and R14 is a lower alkyl group, and m is 0 or 1.
24. A compound of the formula:
Figure imgf000215_0003
wherein Ring A, Ring B and Y are as defined in Claim 1, and Rllb, Rllc and Rlld are as defined in Claim 22.
25. A compound of the formula (Il-a) :
Figure imgf000216_0001
wherein Ring A, Ring B and Y are as defined in Claim 1, and R - lib, Rllc and Rlld are as defined in Claim 22.
26. A process for preparing a compound of formula I:
Figure imgf000216_0002
wherein Ring A, Ring B, X and Y are as defined in claim 1, which comprises deprotecting a compound of formula II:
Figure imgf000216_0003
wherein Ring A, Ring B and Y are as defined in claim 1, R is a hydrogen atom or a protecting group for a hydroxy group and Rllb, Rllc and Rlld are each independently a protecting group for a hydroxy group.
27. A process for preparing a compound of formula I-a:
Figure imgf000217_0001
wherein Ring A, Ring B and Y are as defined in claim 1 , which comprises reducing a compound of formula III :
Figure imgf000217_0002
wherein Ring A, Ring B and Y are as defined in cla'i 1 , and R12 is a lower alkyl group .
28 . A process for preparing a compound of formula I-a :
Figure imgf000217_0003
wherein Ring A, Ring B and Y are as defined in claim 1, which comprises coupling a compound of formula Vll-a:
Figure imgf000217_0004
wherein Ring A, Ring B and Y are as defined in claim 1, and R13a is a bromine atom or an iodine atom, with a boronic acid compound of formula X:
Figure imgf000218_0001
wherein Rllb, Rllc and Rlld are each independently a protecting group for a hydroxy group, or an ester thereof, hydrating the resulting compound of formula IX:
Figure imgf000218_0002
wherein the symbols are as defined above, and removing the protecting groups from the resulting compound of formula Il-a:
Figure imgf000218_0003
wherein the symbols are as defined above
PCT/JP2004/011312 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter WO2005012326A1 (en)

Priority Applications (36)

Application Number Priority Date Filing Date Title
AU2004260761A AU2004260761B2 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependent transporter
NZ545304A NZ545304A (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
EA200600351A EA010299B1 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
MXPA06001274A MXPA06001274A (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter.
CA002534024A CA2534024C (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
MEP-2008-612A ME00411B (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
UAA200602259A UA83243C2 (en) 2003-08-01 2004-07-30 Compounds having inhibitory activity against sodium-dependant transporter
EP17173376.9A EP3251679B1 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant glucose transporter
DK04771314.4T DK1651658T4 (en) 2003-08-01 2004-07-30 NEW CONNECTIONS WITH INHIBITIVE ACTIVITY AGAINST SODIUM DEPENDENT TRANSPORT
EP04771314.4A EP1651658B2 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
ES04771314T ES2402098T5 (en) 2003-08-01 2004-07-30 Novel compounds that have inhibitory activity against the sodium-dependent transporter
SI200432007T SI1651658T2 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
JP2006519251A JP4130466B2 (en) 2003-08-01 2004-07-30 New compounds
BRPI0413232A BRPI0413232B8 (en) 2003-08-01 2004-07-30 compound having inhibitory activity against sodium-dependent carrier, pharmaceutical composition comprising the compound, use of the compound in the preparation of a medicine, and process for preparing the compound
EP14194507.1A EP2896397B2 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant glucose transporter
RS20060079A RS53365B (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
PL04771314T PL1651658T5 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter
US11/045,446 US7943788B2 (en) 2003-08-01 2005-01-31 Glucopyranoside compound
IL173050A IL173050A (en) 2003-08-01 2006-01-10 Glucopyranosyl derivatives, pharmaceutical compositions containing the same and uses thereof
NO20060220A NO333933B1 (en) 2003-08-01 2006-01-16 Compounds, Pharmaceutical Compositions and Uses thereof, and Process for Preparing Said Compounds
HK06108470.6A HK1086277A1 (en) 2003-08-01 2006-07-31 Novel compounds having inhibitory activity against sodium-dependant transporter
IL206831A IL206831A (en) 2003-08-01 2010-07-06 Glucopyranosyl derivatives and pharmaceutical compositions containing the same and uses thereof
US13/005,757 US8202984B2 (en) 2003-08-01 2011-01-13 Glucopyranoside compound
US13/174,814 US8222219B2 (en) 2003-08-01 2011-07-01 Glucopyranoside compound
NO20120585A NO334706B1 (en) 2003-08-01 2012-05-18 Compounds, pharmaceutical compositions and uses of such compounds, and processes for the preparation of said compounds
US13/494,602 US8785403B2 (en) 2003-08-01 2012-06-12 Glucopyranoside compound
HRP20130124TT HRP20130124T4 (en) 2003-08-01 2013-02-12 Novel compounds having inhibitory activity against sodium-dependant transporter
HUS1400021C HUS1400021I1 (en) 2003-08-01 2014-04-09 Novel compounds having inhibitory activity against sodium-dependant transporter
FR14C0034C FR14C0034I2 (en) 2003-08-01 2014-04-18 NEW COMPOUNDS WITH INHIBITORY ACTIVITY DIRECTED AGAINST THE SODIUM-DEPENDENT TRANSPORTER
CY2014016C CY2014016I1 (en) 2003-08-01 2014-04-24 NOVEL COMPOUNDS HAVING INHIBITORY ACTIVITY AGAINST THE SODIUM-DEPENDENT TRANSPORTER
NO2014009C NO2014009I2 (en) 2003-08-01 2014-04-25 Compounds, pharmaceutical compositions and uses thereof, and process for the preparation of said compounds
BE2014C027C BE2014C027I2 (en) 2003-08-01 2014-04-29
NL300670C NL300670I2 (en) 2003-08-01 2014-05-14
US14/299,470 US20140296506A1 (en) 2003-08-01 2014-06-09 Glucopyranoside compound
US14/981,728 US20160108078A1 (en) 2003-08-01 2015-12-28 Glucopyranoside compound
US16/000,079 US20180282363A1 (en) 2003-08-01 2018-06-05 Glucopyranoside compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49153403P 2003-08-01 2003-08-01
US60/491,534 2003-08-01

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/045,446 Continuation-In-Part US7943788B2 (en) 2003-08-01 2005-01-31 Glucopyranoside compound

Publications (1)

Publication Number Publication Date
WO2005012326A1 true WO2005012326A1 (en) 2005-02-10

Family

ID=34115515

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/011312 WO2005012326A1 (en) 2003-08-01 2004-07-30 Novel compounds having inhibitory activity against sodium-dependant transporter

Country Status (37)

Country Link
US (3) US7943788B2 (en)
EP (4) EP3251679B1 (en)
JP (2) JP4130466B2 (en)
KR (2) KR100942622B1 (en)
CN (4) CN103819465A (en)
AR (1) AR045173A1 (en)
AU (1) AU2004260761B2 (en)
BE (1) BE2014C027I2 (en)
BR (1) BRPI0413232B8 (en)
CA (1) CA2534024C (en)
CR (2) CR8188A (en)
CY (3) CY1113813T1 (en)
DK (2) DK2896397T4 (en)
EA (2) EA015104B1 (en)
ES (4) ES2402098T5 (en)
FR (1) FR14C0034I2 (en)
HK (1) HK1086277A1 (en)
HR (2) HRP20130124T4 (en)
HU (2) HUE037320T2 (en)
IL (2) IL173050A (en)
LT (1) LT2896397T (en)
LU (1) LU92426I2 (en)
ME (1) ME00411B (en)
MX (1) MXPA06001274A (en)
MY (1) MY143203A (en)
NL (1) NL300670I2 (en)
NO (3) NO333933B1 (en)
NZ (2) NZ575711A (en)
PL (2) PL1651658T5 (en)
PT (2) PT2896397T (en)
RS (1) RS53365B (en)
SG (1) SG145694A1 (en)
SI (2) SI2896397T2 (en)
TW (2) TWI385177B (en)
UA (1) UA83243C2 (en)
WO (1) WO2005012326A1 (en)
ZA (5) ZA200601685B (en)

Cited By (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1609785A1 (en) * 2003-03-14 2005-12-28 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
WO2006011502A1 (en) * 2004-07-27 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
WO2006035796A1 (en) * 2004-09-29 2006-04-06 Kissei Pharmaceutical Co., Ltd. 1-(β-D-GLYCOPYRANOSYL)-3-SUBSTITUTED NITROGENOUS HETEROCYCLIC COMPOUND, MEDICINAL COMPOSITION CONTAINING THE SAME, AND MEDICINAL USE THEREOF
WO2007031548A2 (en) * 2005-09-15 2007-03-22 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
WO2008013280A1 (en) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Substituted spiroketal derivative and use thereof as drug for treating diabetes
WO2008013322A1 (en) * 2006-07-27 2008-01-31 Mitsubishi Tanabe Pharma Corporation 1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors.
WO2008013321A1 (en) * 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Novel sglt inhibitors
WO2008013277A1 (en) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Fused ring spiroketal derivative and use thereof as drug for treating diabetes
JP2008508213A (en) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング D-glucopyranosyl-phenyl-substituted cyclics, pharmaceuticals containing such compounds, their use and methods for their production
WO2008044762A1 (en) 2006-10-13 2008-04-17 Chugai Seiyaku Kabushiki Kaisha Thioglucose spiroketal derivative and use thereof as therapeutic agent for diabetes
WO2008069327A1 (en) * 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation CRYSTALLINE FORM OF 1- (β-D-GLUCOPYRANOSYL) -4 -METHYL- 3- [5- (4 -FLUOROPHENYL) -2-THIENYLMETHYL] BENZENE HEMIHYDRATE
WO2008070609A1 (en) 2006-12-04 2008-06-12 Janssen Pharmaceutica N.V. Thienyl-containing glycopyranosyl derivatives as antidiabetics
WO2008075736A1 (en) * 2006-12-21 2008-06-26 Astellas Pharma Inc. Method for producing c-glycoside derivative and synthetic intermediate thereof
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2009035969A1 (en) * 2007-09-10 2009-03-19 Janssen Pharmaceutica N.V. Process for the preparation of compounds useful as inhibitors of sglt
WO2009091082A1 (en) * 2008-01-17 2009-07-23 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising sglt inhibitors and dpp4 inhibitors
WO2009096455A1 (en) 2008-01-31 2009-08-06 Astellas Pharma Inc. Pharmaceutical composition for treatment of fatty liver diseases
US7579449B2 (en) 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
EP2112928A1 (en) * 2007-02-22 2009-11-04 University of Utah Research Foundation Synthesis of novel xylosides and potential uses thereof
JP2010504300A (en) * 2006-09-21 2010-02-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, pharmaceuticals containing the compounds and methods of use and preparation thereof
US7662790B2 (en) 2005-04-15 2010-02-16 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7683160B2 (en) 2005-08-30 2010-03-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2010031820A1 (en) * 2008-09-19 2010-03-25 Novartis Ag Glucoside derivatives and uses thereof as sglt inhibitors
US7687469B2 (en) 2004-12-16 2010-03-30 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7713938B2 (en) 2005-05-03 2010-05-11 Boehringer Ingelheim International Gmbh Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7745414B2 (en) 2006-02-15 2010-06-29 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
JP2010523620A (en) * 2007-04-11 2010-07-15 ナームローゼ・フエンノートチヤツプ・オルガノン Preparation method of mirtazapine
US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
US7772378B2 (en) 2005-02-23 2010-08-10 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)arylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US7776830B2 (en) 2006-05-03 2010-08-17 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
WO2010092125A1 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
US7851602B2 (en) 2005-07-27 2010-12-14 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2011003976A1 (en) 2009-07-10 2011-01-13 Janssen Pharmaceutica Nv CRYSTALLISATION PROCESS FOR 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL] BENZENE
KR20110086039A (en) * 2008-10-17 2011-07-27 얀센 파마슈티카 엔.브이. Process for the preparation of compounds useful as inhibitors of sglt
WO2011091710A1 (en) 2010-01-26 2011-08-04 天津药物研究院 Phenyl c-glucoside derivatives, preparation methods and uses thereof
WO2011120923A1 (en) 2010-03-30 2011-10-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8039441B2 (en) 2006-08-15 2011-10-18 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture
WO2011143296A1 (en) 2010-05-11 2011-11-17 Janssen Pharmaceutica Nv Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt
WO2011142478A1 (en) 2010-05-11 2011-11-17 Mitsubishi Tanabe Pharma Corporation Canagliflozin containing tablets
WO2011146308A1 (en) 2010-05-18 2011-11-24 Corning Incorporated Methods of making fused thiophenes
US8080580B2 (en) 2008-08-28 2011-12-20 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US8097592B2 (en) 2006-04-05 2012-01-17 Astellas Pharma Inc. Cocrystal of C-glycoside derivative and L-proline
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012041898A1 (en) 2010-09-29 2012-04-05 Celon Pharma Sp. Z O.O. Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes
WO2012055169A1 (en) 2010-10-27 2012-05-03 上海艾力斯医药科技有限公司 C-arylglucoside derivative, preparation method therefor, and use thereof
WO2012062698A1 (en) 2010-11-08 2012-05-18 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2012107476A1 (en) 2011-02-09 2012-08-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2012109996A1 (en) 2011-02-18 2012-08-23 上海璎黎科技有限公司 Aryl glycoside compound, preparation method and use thereof
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8283326B2 (en) 2006-10-27 2012-10-09 Boehringer Ingelheim International Gmbh Crystalline form of 4-(beta-D-glucopyranos-1-yl)-1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012163990A1 (en) 2011-06-03 2012-12-06 Boehringer Ingelheim International Gmbh Sglt-2 inhibitors for treating metabolic disorders in patients treated with neuroleptic agents
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
EP2604612A1 (en) * 2010-08-10 2013-06-19 Shanghai Hengrui Pharmaceutical Co. Ltd. C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof
WO2013090550A1 (en) * 2011-12-15 2013-06-20 National Health Research Institutes Novel glycoside compounds
US8507450B2 (en) 2005-09-08 2013-08-13 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
EP2697203A1 (en) * 2011-04-13 2014-02-19 Merck Sharp & Dohme Corporation Mineralocorticoid receptor antagonists
US8669380B2 (en) 2009-11-02 2014-03-11 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
JP2014510776A (en) * 2011-04-13 2014-05-01 ヤンセン ファーマシューティカ エヌ．ベー． Process for preparing compounds useful as inhibitors of SGLT2
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
WO2014101865A1 (en) 2012-12-31 2014-07-03 上海璎黎科技有限公司 Composition of glucose derivative and proline, crystal, preparation method and application
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
CN103980263A (en) * 2014-04-17 2014-08-13 海门瑞一医药科技有限公司 New synthesis process of canagliflozin
WO2014132940A1 (en) 2013-02-26 2014-09-04 田辺三菱製薬株式会社 Method for producing α-halo-tetraacyl glucose
US8828951B2 (en) 2009-10-20 2014-09-09 Novartis Ag Glycoside derivatives and uses thereof
WO2014164286A1 (en) * 2013-03-11 2014-10-09 Janssen Pharmaceutica Nv Dual sglt1/sglt2 inhibitors
WO2014161836A1 (en) 2013-04-04 2014-10-09 Boehringer Ingelheim Vetmedica Gmbh Treatment of metabolic disorders in equine animals
CN104109157A (en) * 2014-08-04 2014-10-22 山东康美乐医药科技有限公司 Preparation method of canagliflozin
CN104119324A (en) * 2014-07-23 2014-10-29 齐鲁天和惠世制药有限公司 Preparation method of canagliflozin
WO2014195966A2 (en) 2013-05-30 2014-12-11 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
CN104478968A (en) * 2015-01-14 2015-04-01 佛山市赛维斯医药科技有限公司 O-galactoside derivative with thiazolyl and preparation method and application thereof
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9035044B2 (en) 2011-05-09 2015-05-19 Janssen Pharmaceutica Nv L-proline and citric acid co-crystals of (2S, 3R, 4R, 5S,6R)-2-(3-((5-(4-fluorophenyl)thiopen-2-yl)methyl)4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
EP2918579A1 (en) 2014-03-14 2015-09-16 LEK Pharmaceuticals d.d. Synthesis of 2-arylmethyl-5-aryl-thiophene
EP2933255A1 (en) 2014-04-17 2015-10-21 LEK Pharmaceuticals d.d. Novel crystalline form of 1-(beta-D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
US9174971B2 (en) 2009-10-14 2015-11-03 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of SGLT2
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
EP2947077A1 (en) 2014-05-19 2015-11-25 LEK Pharmaceuticals d.d. Stereoselective synthesis of intermediates in the preparation of ß-C-arylglucosides
CN105085454A (en) * 2014-05-13 2015-11-25 北京韩美药品有限公司 SGLT inhibitor and pharmaceutical composition
EP2990029A1 (en) 2014-08-29 2016-03-02 Sandoz Ag Pharmaceutical compositions comprising Canagliflozin
WO2016041530A1 (en) 2014-09-16 2016-03-24 Zentiva, K.S. Complexes of canagliflozin and cyclodextrins
CN105541815A (en) * 2015-12-24 2016-05-04 寿光富康制药有限公司 Preparation method for canagliflozin
WO2016074566A1 (en) * 2014-11-10 2016-05-19 镇江新元素医药科技有限公司 Glucoside derivative and pharmaceutical composition thereof
WO2016142950A1 (en) * 2015-03-11 2016-09-15 Harman Finochem Limited A novel process for preparing (2s,3r,4r,5s,6r)-2-{3-[5-[4-fluoro-phenyl)- thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5- triol and its stable amorphous hemihydrate form
US9505734B2 (en) 2012-12-17 2016-11-29 Tianjin Institute Of Pharmaceutical Research Phenyl C-glucoside derivative containing deoxyglucose structure, preparation method and use thereof
WO2016206660A1 (en) 2015-06-25 2016-12-29 Zentiva K.S. Solid forms of amorphous canagliflozin
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2017046655A1 (en) * 2015-09-16 2017-03-23 Optimus Drugs (P) Ltd A novel process for the preparation of canagliflozin
WO2017064679A1 (en) * 2015-10-15 2017-04-20 Lupin Limited Process for the preparation of amorphous canagliflozin
WO2017063617A1 (en) 2015-10-13 2017-04-20 Zentiva, K.S. Preparation of intermediates for the synthesis of canagliflozin and dapagliflozin
WO2017101890A1 (en) * 2015-12-17 2017-06-22 上海艾力斯医药科技有限公司 Spiroketal derivative, preparation method therefor and application
EP3148979A4 (en) * 2014-05-27 2018-01-03 Glenmark Pharmaceuticals Limited Process for preparation of canagliflozin
WO2018020506A1 (en) 2016-07-25 2018-02-01 Natco Pharma Ltd Process for the preparation of amorphous form of canagliflozin
US9914724B2 (en) 2014-04-14 2018-03-13 Shanghai De Novo Pharmatech Co., Ltd. C-aryl glycosid derivatives, pharmaceutical composition, preparation process and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2018073154A1 (en) 2016-10-19 2018-04-26 Boehringer Ingelheim International Gmbh Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
WO2018149327A1 (en) 2017-02-20 2018-08-23 浙江华海药业股份有限公司 Method for preparing canagliflozin amorphous form
US20180244661A1 (en) * 2015-02-27 2018-08-30 Msn Laboratories Private Limited Process for the preparation of amorphous (1s)-1,5-anhvdro-1-[3-[[5-(4 fluorophenyl)-2-thienyl]-4-methylphenyl]-d-glucitol and its polymorphs thereof
US10174010B2 (en) 2014-03-19 2019-01-08 Hangzhou Pushai Pharmaceutical Technology Co., Ltd. Canagliflozin monohydrate and its crystalline forms, preparation methods and uses thereof
EP3485890A1 (en) 2014-01-23 2019-05-22 Boehringer Ingelheim Vetmedica GmbH Treatment of metabolic disorders in canine animals
US10323025B2 (en) 2015-12-21 2019-06-18 Janssen Pharmaceutica Nv Crystallization procedure for obtaining canagliflozin hemihydrate crystals
US10323056B2 (en) 2013-05-08 2019-06-18 Lek Pharmaceuticals D.D. Crystalline hydrates of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
US10370365B2 (en) 2015-09-16 2019-08-06 Optimus Drugs (P) Limited Process for the preparation of Canagliflozin
WO2019201752A1 (en) 2018-04-17 2019-10-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2020039394A1 (en) 2018-08-24 2020-02-27 Novartis Ag New drug combinations
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
WO2020095010A1 (en) 2018-11-05 2020-05-14 Balticgruppen Bio Ab Methods of treating diabetes in severe insulin-resistant diabetic subjects
EP1651658B2 (en) † 2003-08-01 2020-08-12 Mitsubishi Tanabe Pharma Corporation Novel compounds having inhibitory activity against sodium-dependant transporter
EP3721882A1 (en) 2014-04-01 2020-10-14 Boehringer Ingelheim Vetmedica GmbH Treatment of metabolic disorders in equine animals
WO2021105152A1 (en) 2019-11-28 2021-06-03 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors in the drying-off of non-human mammals
EP3862003A1 (en) 2013-12-17 2021-08-11 Boehringer Ingelheim Vetmedica GmbH An sglt-2 inhibitor for use in the treatment of a metabolic disorder in feline animals
WO2021165177A1 (en) 2020-02-17 2021-08-26 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in felines
WO2021214023A1 (en) 2020-04-22 2021-10-28 Bayer Aktiengesellschaft Combination of finerenone and a sglt2 inhibitor for the treatment and/or prevention of cardiovascular and/or renal diseases
US11207337B2 (en) 2015-09-15 2021-12-28 Janssen Pharmaceutica Nv Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders
WO2023006747A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of renal diseases in non-human mammals
WO2023006745A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of hypertension in non-human mammals
WO2023006718A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in non-human mammals excluding felines, in particular canines
US11576894B2 (en) 2009-07-08 2023-02-14 Janssen Pharmaceutica Nv Combination therapy for the treatment of diabetes
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2023129595A1 (en) 2021-12-30 2023-07-06 Newamsterdam Pharma B.V. Obicetrapib and sglt2 inhibitor combination
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2023227492A1 (en) 2022-05-25 2023-11-30 Boehringer Ingelheim Vetmedica Gmbh Aqueous pharmaceutical compositions comprising sglt-2 inhibitors
EP4403230A2 (en) 2014-09-25 2024-07-24 Boehringer Ingelheim Vetmedica GmbH Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals
RU2824129C2 (en) * 2009-11-13 2024-08-06 Астразенека Аб Two-layer tablet composition
WO2024184293A1 (en) 2023-03-06 2024-09-12 Boehringer Ingelheim Vetmedica Gmbh Systems for delivery of liquid pharmaceutical compositions in particular comprising one or more sglt-2 inhibitor(s)

Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101141558B1 (en) * 2004-03-04 2012-05-03 깃세이 야쿠힌 고교 가부시키가이샤 Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
JP4496174B2 (en) * 2005-01-31 2010-07-07 田辺三菱製薬株式会社 Pharmaceutical composition
AR053329A1 (en) * 2005-01-31 2007-05-02 Tanabe Seiyaku Co INDOL DERIVATIVES USEFUL AS INHIBITORS OF GLUCOSE CONVEYORS DEPENDENT ON SODIUM (SGLT)
MY147375A (en) * 2005-01-31 2012-11-30 Mitsubishi Tanabe Pharma Corp Indole derivatives
TW200726755A (en) * 2005-07-07 2007-07-16 Astellas Pharma Inc A crystalline choline salt of an azulene derivative
WO2007140191A2 (en) 2006-05-23 2007-12-06 Theracos, Inc. Glucose transport inhibitors and methods of use
US7795228B2 (en) * 2006-12-28 2010-09-14 Theracos, Inc. Spiroheterocyclic glycosides and methods of use
BRPI0809607A2 (en) * 2007-04-02 2014-09-30 Theracos Inc COMPOUND, PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL COMBINATION, AND METHOD FOR TREATING A DISEASE
WO2009026537A1 (en) * 2007-08-23 2009-02-26 Theracos, Inc. Benzylbenzene derivatives and methods of use
UA101004C2 (en) 2007-12-13 2013-02-25 Теракос, Инк. Derivatives of benzylphenylcyclohexane and use thereof
UY31651A1 (en) * 2008-02-13 2009-09-30 NEW DERIVATIVES OF AROMATIC FLUOROGLYCHIDS, MEDICINES THAT UNDERSTAND THESE COMPOUNDS AND USE OF THEM.
BRPI0913129A2 (en) 2008-05-22 2016-01-05 Bristol Myers Squibb Co method for treating hyperuricemia employing an sglt2 inhibitor and composition containing the same
BRPI0917196B8 (en) 2008-08-22 2021-05-25 Theracos Sub Llc crystalline form of a compound being (2s,3r,4r,5s,6r)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2h complex - pyran-3,4,5-triol, bis(1-proline)
CN101830876A (en) * 2009-03-12 2010-09-15 上海恒瑞医药有限公司 C-aryl glucoside derivative, preparation method thereof and application thereof in medicine
IN2012DN02711A (en) 2009-09-15 2015-09-11 Janssen Pharmaceutica Nv
CN102115468B (en) * 2009-12-31 2014-06-11 上海特化医药科技有限公司 Synthesis method of 2, 5-disubstituted thiophene compound
WO2011153712A1 (en) 2010-06-12 2011-12-15 Theracos, Inc. Crystalline form of benzylbenzene sglt2 inhibitor
ES2609791T3 (en) 2010-07-06 2017-04-24 Janssen Pharmaceutica, N.V. Formula for diabetes co-therapy treatments
KR101513234B1 (en) * 2010-09-10 2015-04-17 주식회사 녹십자 Novel thiophene derivative as sglt2 inhibitor and pharmaceutical composition comprising same
KR20140019834A (en) * 2011-04-14 2014-02-17 노파르티스 아게 Glycoside derivatives and uses thereof
ES2626038T3 (en) * 2011-05-20 2017-07-21 Janssen Pharmaceutica, N.V. Processes for the preparation of compounds useful as sglt-2 inhibitors
ES2638915T3 (en) * 2011-05-20 2017-10-24 Janssen Pharmaceutica, N.V. Method of preparing compounds used as SGLT-22 inhibitors
US9034921B2 (en) * 2011-06-01 2015-05-19 Green Cross Corporation Diphenylmethane derivatives as SGLT2 inhibitors
CN102827122B (en) * 2011-06-17 2015-01-14 山东轩竹医药科技有限公司 Glucoside derivate
WO2013061105A2 (en) * 2011-10-28 2013-05-02 Debreceni Egyetem Glycogen phosphorylase inhibitors
US9193751B2 (en) 2012-04-10 2015-11-24 Theracos, Inc. Process for the preparation of benzylbenzene SGLT2 inhibitors
CN103570671B (en) * 2012-09-26 2016-03-30 上海天慈生物谷生物工程有限公司 A kind of hypoglycemic compound and method for making thereof and application
EP2968375B1 (en) 2013-03-14 2019-06-12 MSD International GmbH Methods for preparing sglt2 inhibitors
CA2907079C (en) 2013-03-15 2021-06-22 Janssen Pharmaceutica Nv Combination of canagliflozin and probenecid for the treatment of hyperuricemia
CN104418834B (en) * 2013-08-23 2017-09-15 重庆博腾制药科技股份有限公司 A kind of synthetic method of antidiabetic medicine intermediate
CN105611920B (en) 2013-10-12 2021-07-16 泰拉科斯萨普有限责任公司 Preparation of hydroxy-diphenylmethane derivatives
CN104557894A (en) * 2013-10-18 2015-04-29 上海信谊药厂有限公司 Canagliptin crystal form and preparation method thereof
CN113144204A (en) 2014-01-31 2021-07-23 詹森药业有限公司 Method for treating and preventing renal and fatty liver diseases
CN103936725B (en) * 2014-04-01 2016-07-27 天津大学 The C crystal form of canagliflozin and crystallization preparation method thereof
CN103936800A (en) * 2014-05-08 2014-07-23 安徽联创药物化学有限公司 Preparation method of 1-(1-methoxy pyran glucosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene
CN105319294B (en) * 2014-06-20 2021-03-30 重庆医药工业研究院有限责任公司 Method for separating and determining canagliflozin and related substances thereof
US20160002275A1 (en) * 2014-07-03 2016-01-07 Cadila Healthcare Limited Process for preparation and purification of canagliflozin
US20170247359A1 (en) 2014-09-05 2017-08-31 Mylan Laboratories Ltd. Process for the preparation of canagliflozin
CN104292209A (en) * 2014-09-11 2015-01-21 浙江丽晶化学有限公司 Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V)
CN104478969A (en) * 2015-01-14 2015-04-01 佛山市赛维斯医药科技有限公司 O-galactoside derivative with alcoxyl phenyl group thiazolyl and preparation method and application thereof
CN104447906A (en) * 2015-01-14 2015-03-25 佛山市赛维斯医药科技有限公司 Alcoxyl phenyl group diosgenin-diglucoside derivative and preparation method and application thereof
CN104447905A (en) * 2015-01-14 2015-03-25 佛山市赛维斯医药科技有限公司 Derivative containing nitrobenzene and bis-O-glucoside and preparation method and application of derivative
CN104447907A (en) * 2015-01-14 2015-03-25 佛山市赛维斯医药科技有限公司 Compound containing nitro biphenyl diosgenin-diglucoside structure and preparation method and application thereof
CN104478962A (en) * 2015-01-15 2015-04-01 佛山市赛维斯医药科技有限公司 Class of halogenated phenyl group S-glucoside derivative and preparation method and application of class of halogenated phenyl group S-glucoside derivative
WO2016128995A1 (en) 2015-02-09 2016-08-18 Indoco Remedies Limited Process for the preparation of sglt inhibitor compounds
CN105884755B (en) * 2015-02-14 2019-05-28 正大天晴药业集团股份有限公司 The carbon glycoside derivative of deuterium modification
EP3260451A4 (en) * 2015-02-19 2018-07-18 JNC Corporation Liquid crystalline compound having benzothiophene, liquid crystal composition and liquid crystal display element
CN104803977A (en) * 2015-03-03 2015-07-29 佛山市赛维斯医药科技有限公司 PTP1B derivatives containing tetrazole structures as well as preparation methods and applications of derivatives
WO2016191173A1 (en) 2015-05-22 2016-12-01 Janssen Pharmaceutica Nv Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
CN104926803B (en) * 2015-06-17 2017-12-22 南通常佑药业科技有限公司 A kind of preparation method of new SGLT2 inhibitor medicine
CN104987320A (en) * 2015-08-03 2015-10-21 沧州那瑞化学科技有限公司 Preparation method of canagliflozin intermediates
US10428053B2 (en) 2015-09-15 2019-10-01 Laurus Labs Limited Co-crystals of SGLT2 inhibitors, process for their preparation and pharmaceutical compositions thereof
CN105503845A (en) * 2015-12-01 2016-04-20 北京普德康利医药科技发展有限公司 Defluorinated canagliflozin compound, and preparation method and application thereof
WO2017093949A1 (en) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Substantially pure canagliflozin
WO2017141202A1 (en) 2016-02-17 2017-08-24 Lupin Limited Complex of sglt2 inhibitor and process for preparation thereof
HRP20211670T8 (en) * 2016-06-17 2022-03-18 Daewoong Pharmaceutical Co., Ltd. Diphenylmethane derivative in crystalline form
WO2018207113A1 (en) 2017-05-09 2018-11-15 Piramal Enterprises Limited A process for the preparation of sglt2 inhibitor and intermediates thereof
TWI835735B (en) 2017-06-12 2024-03-21 比利時商健生藥品公司 Methods for reducing or preventing cardiovascular events in patients with type ii diabetes mellitus
CN108017612B (en) * 2017-11-29 2020-06-09 南通常佑药业科技有限公司 Preparation method of canagliflozin intermediate
SG11202100417RA (en) 2018-07-19 2021-02-25 Astrazeneca Ab Methods of treating hfpef employing dapagliflozin and compositions comprising the same
JPWO2020050361A1 (en) * 2018-09-06 2021-08-30 株式会社トクヤマ Method for Producing β-C-aryl Glycosid Derivative
TW202103709A (en) 2019-03-26 2021-02-01 比利時商健生藥品公司 Methods for treating subjects with chronic kidney disease
CN110981851A (en) * 2019-12-24 2020-04-10 艾希尔（深圳）药物研发有限公司 Preparation method of canagliflozin impurity
US20220023252A1 (en) 2020-07-27 2022-01-27 Astrazeneca Ab Methods of treating chronic kidney disease with dapagliflozin
AU2022251165A1 (en) 2021-04-01 2023-11-09 Astrazeneca Uk Limited Systems and methods for managing prediabetes with a gliflozin sodium-glucose cotransport 2 inhibitor pharmaceutical composition
CN113429379A (en) * 2021-06-28 2021-09-24 江苏法安德医药科技有限公司 LH-1801 intermediate and preparation method and application thereof
CN118510504A (en) 2022-01-26 2024-08-16 阿斯利康(瑞典)有限公司 Dapagliflozin for use in the treatment of pre-diabetes or in reducing the risk of developing type 2 diabetes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2359554A (en) * 2000-02-02 2001-08-29 Kotobuki Pharmaceutical Compan C-Glycosides and preparation thereof as antidiabetic agents
US6562791B1 (en) * 2002-03-29 2003-05-13 Council Of Scientific And Industrial Research Glucopyranoside, process for isolation thereof, pharmaceutical composition containing same and use thereof
US20030114390A1 (en) * 2001-03-13 2003-06-19 Washburn William N. C-aryl glucoside SGLT2 inhibitors and method
WO2004080990A1 (en) * 2003-03-14 2004-09-23 Astellas Pharma Inc. C-glycoside derivatives and salts thereof

Family Cites Families (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1476537A (en) * 1965-05-10 1967-04-14 Chimetron Sarl Glucosides derived from benzimidazole
US4160861A (en) * 1977-10-03 1979-07-10 Merck & Co., Inc. Method for the separation of antibiotic macrolides
US4584369A (en) * 1981-07-31 1986-04-22 Sloan-Kettering Institute For Cancer Research Anti-leukemic beta-glycosyl C-nucleosides
JP2544609B2 (en) 1986-10-07 1996-10-16 和光純薬工業株式会社 TCNQ complex
CA1334969C (en) 1988-08-19 1995-03-28 Mark James Suto Substituted dihydroisoquinoline and phthalazine derivatives as potentiators of the lethal effects of radiation and certain chemotherapeutic agents, selected compounds, analogs andprocess
HU203896B (en) 1988-10-26 1991-10-28 Biogal Gyogyszergyar Process for producing glycosides of aromatic amines
JPH04253974A (en) 1991-02-05 1992-09-09 Ishihara Sangyo Kaisha Ltd Sulfonylurea compound, its production and herbicide containing the same
US5149838A (en) * 1991-09-20 1992-09-22 Merck & Co., Inc. Intermediates for substituted azetidinones useful as anti-inflammatory and antidegenerative agents
GB9208161D0 (en) 1992-04-14 1992-05-27 Pfizer Ltd Indoles
US5334225A (en) 1992-07-15 1994-08-02 Kao Corporation Keratinous fiber dye composition containing a 2-substituted amino-5-alkylphenol derivative coupler
US5731292A (en) * 1992-11-12 1998-03-24 Tanabe Seiyaku Co., Ltd. Dihydrochalcone derivatives which are hypoglycemic agents
CA2102591C (en) * 1992-11-12 2000-12-26 Kenji Tsujihara Hypoglycemic agent
US6297363B1 (en) * 1993-02-12 2001-10-02 Nomura Co., Ltd. Glycoside indoles
US5830873A (en) * 1994-05-11 1998-11-03 Tanabe Seiyaku Co., Ltd. Propiophenone derivative and a process for preparing the same
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
WO1997025033A1 (en) 1995-10-31 1997-07-17 Eli Lilly And Company Antithrombotic diamines
JP3059088B2 (en) * 1995-11-07 2000-07-04 田辺製薬株式会社 Propiophenone derivatives and their production
JPH09263549A (en) 1996-01-25 1997-10-07 Fujisawa Pharmaceut Co Ltd Production of benzene derivative
TW406086B (en) * 1996-12-26 2000-09-21 Tanabe Seiyaku Co Propiophenone derivatives and process for preparing the same
US6153632A (en) * 1997-02-24 2000-11-28 Rieveley; Robert B. Method and composition for the treatment of diabetes
JPH10324632A (en) 1997-03-25 1998-12-08 Takeda Chem Ind Ltd Pharmaceutical composition
JP2000034239A (en) 1998-07-16 2000-02-02 Asahi Glass Co Ltd Production of trifluoromethylated aromatic compound
JP3857429B2 (en) 1998-07-17 2006-12-13 ポーラ化成工業株式会社 Sulfur-containing antifungal agent
US20020032164A1 (en) * 1998-12-30 2002-03-14 Dale Roderic M. K. Antimicrobial compounds and methods for their use
GB9912961D0 (en) 1999-06-03 1999-08-04 Pfizer Ltd Metalloprotease inhibitors
PH12000002657B1 (en) 1999-10-12 2006-02-21 Bristol Myers Squibb Co C-aryl glucoside SGLT2 inhibitors
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
JP4456768B2 (en) 2000-02-02 2010-04-28 壽製薬株式会社 Drug containing C-glycoside
BR0108908A (en) 2000-03-03 2002-12-24 Pfizer Prod Inc Derivatives of pyrazole ethers as anti-inflammatory / analgesic agents
DE60115623T2 (en) 2000-03-17 2006-07-06 Kissei Pharmaceutical Co., Ltd., Matsumoto GLUCOPYRANOSYLOXY-BENZYL BENZEN DERIVATIVES, MEDICAL COMPOSITION AND INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THE DERIVATIVES
US6683056B2 (en) * 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
US6555519B2 (en) * 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
WO2002036602A1 (en) 2000-11-02 2002-05-10 Ajinomoto Co., Inc. Novel pyrazole derivatives and diabetes remedies containing the same
US6476352B2 (en) * 2000-12-18 2002-11-05 General Electric Company Laser beam stop sensor and method for automatically detecting the presence of laser beam stop material using a laser beam stop sensor
ES2326158T3 (en) 2000-12-28 2009-10-02 Kissei Pharmaceutical Co., Ltd. DERIVATIVES OF GLUCOPIRANOSILOXIPIRAZOL AND ITS USE AS MEDICINES.
US7087579B2 (en) * 2001-02-26 2006-08-08 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
US7294618B2 (en) * 2001-02-27 2007-11-13 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
CA2710031A1 (en) 2001-03-02 2002-09-12 University Of Western Ontario Polymer precursors of radiolabeled compounds, and methods of making and using the same
AU2002254567B2 (en) * 2001-04-11 2007-10-11 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
WO2002088157A1 (en) * 2001-04-27 2002-11-07 Ajinomoto Co., Inc. N-substituted pyrazolyl-o-glycoside derivatives and remedial agent for diabetes containing the same
GB0112122D0 (en) 2001-05-18 2001-07-11 Lilly Co Eli Heteroaryloxy 3-substituted propanamines
WO2003000712A1 (en) 2001-06-20 2003-01-03 Kissei Pharmaceutical Co., Ltd. Nitrogenous heterocyclic derivative, medicinal composition containing the same, medicinal use thereof, and intermediate therefor
JP4115105B2 (en) 2001-07-02 2008-07-09 協和醗酵工業株式会社 Pyrazole derivative
WO2003011880A1 (en) 2001-07-31 2003-02-13 Kissei Pharmaceutical Co., Ltd. Glucopyrano syloxybenzyl benzene derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof
EP1432720A1 (en) 2001-09-05 2004-06-30 Bristol-Myers Squibb Company O-pyrazole glucoside sglt2 inhibitors and method of use
US7384763B2 (en) * 2001-10-24 2008-06-10 Michael Burton Method of detecting β-D-ribofuranosidase activity
EA009281B1 (en) 2001-11-16 2007-12-28 Катаникс Корпорейшн Pharmaceutical and cosmetic compositions containing oxy group-bearing aromatic aldehydes
US6617313B1 (en) * 2002-03-13 2003-09-09 Council Of Scientific And Industrial Research Glucopyranoside and process of isolation thereof from pterocarpus marsupium pharmaceutical composition containing the same and use thereof
NZ561993A (en) 2002-04-18 2008-09-26 Astrazeneca Ab Spiroazabicyclic heterocyclic amines as potent ligands for nicotinic acetylcholine receptors
DE10230605A1 (en) 2002-07-08 2004-01-29 Bayer Ag Substituted imidazotriazines
DE10231370B4 (en) * 2002-07-11 2006-04-06 Sanofi-Aventis Deutschland Gmbh Thiophene glycoside derivatives, medicaments containing these compounds and methods of making these medicaments
TWI254635B (en) 2002-08-05 2006-05-11 Yamanouchi Pharma Co Ltd Azulene derivative and salt thereof
KR20050056194A (en) 2002-08-09 2005-06-14 다이쇼 세이야꾸 가부시끼가이샤 Process for Selective Production of Aryl 5-Thio-β-D-Aldohexopyranosides
AU2003262262A1 (en) 2002-08-27 2004-03-19 Kissei Pharmaceutical Co., Ltd. Pyrazole derivatives, medicinal composition containing the same, and medicinal use thereof
DE10258007B4 (en) * 2002-12-12 2006-02-09 Sanofi-Aventis Deutschland Gmbh Aromatic fluoroglycoside derivatives, medicaments containing these compounds and methods for the preparation of these medicaments
DE10258008B4 (en) 2002-12-12 2006-02-02 Sanofi-Aventis Deutschland Gmbh Heterocyclic fluoroglycoside derivatives, medicaments containing these compounds and methods of making these medicaments
BR0317929A (en) 2003-01-03 2006-04-11 Bristol Myers Squibb Co methods of producing c-aryl glycoside sglt2 inhibitors
JP2004300102A (en) 2003-03-31 2004-10-28 Kissei Pharmaceut Co Ltd Condensed heterocyclic derivative, pharmaceutical composition containing the same and its pharmaceutical application
AU2003902263A0 (en) 2003-05-12 2003-05-29 Fujisawa Pharmaceutical Co., Ltd. Monosaccharide compounds
ES2377741T3 (en) 2003-06-20 2012-03-30 Kissei Pharmaceutical Co., Ltd. Pyrazole derivatives, pharmacological composition that contains them and production intermediates thereof
UA86042C2 (en) * 2003-08-01 2009-03-25 Янссен Фармацевтика Н.В. Substituted indazole-o-glucosides
EA011515B1 (en) * 2003-08-01 2009-04-28 Янссен Фармацевтика Н.В. Substituted benzimidazole-, benztriazole-, and benzimidazolone-o-glucosides
EP1680131A4 (en) * 2003-08-01 2009-05-27 Janssen Pharmaceutica Nv Substituted indole-o-glucosides
AR048376A1 (en) * 2003-08-01 2006-04-26 Janssen Pharmaceutica Nv C- SUBSTITUTED FUSIONED GLYCYCLE GLYCYCLES
TWI385177B (en) † 2003-08-01 2013-02-11 Mitsubishi Tanabe Pharma Corp Glucopyranosyl derivative and method for making same
RS20060320A (en) * 2003-08-01 2008-08-07 Janssen Pharmaceutica N.V., Substituted indazole-o-glucosides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2359554A (en) * 2000-02-02 2001-08-29 Kotobuki Pharmaceutical Compan C-Glycosides and preparation thereof as antidiabetic agents
US20030114390A1 (en) * 2001-03-13 2003-06-19 Washburn William N. C-aryl glucoside SGLT2 inhibitors and method
US6562791B1 (en) * 2002-03-29 2003-05-13 Council Of Scientific And Industrial Research Glucopyranoside, process for isolation thereof, pharmaceutical composition containing same and use thereof
WO2004080990A1 (en) * 2003-03-14 2004-09-23 Astellas Pharma Inc. C-glycoside derivatives and salts thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AHMAD R ET AL: "SYNTHESIS AND STRUCTURE DETERMINATION OF SOME OXADIAZOLE-2-THIONE AND TRIAZOLE-3-THIONE GALACTOSIDES", NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS, MARCEL DEKKER, ANN HARBOR, MI, US, vol. 20, no. 9, 2001, pages 1671 - 1682, XP009039308, ISSN: 1525-7770 *
MAATOOQ G T ET AL: "C-p-hydroxybenzoylglycoflavones from citrullus colocynthis", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 44, no. 1, January 1997 (1997-01-01), pages 187 - 190, XP004292916, ISSN: 0031-9422 *
ZAMANI, KHOSROW ET AL: "Synthesis and structure determination of some new N-glycosides of 4,5-disubstituted-1,2,4-triazole-3-thiones", JOURNAL OF THE CHINESE CHEMICAL SOCIETY (TAIPEI, TAIWAN) , 49(6), 1041-1044 CODEN: JCCTAC; ISSN: 0009-4536, 2002, XP009039279 *

Cited By (244)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7977466B2 (en) 2003-03-14 2011-07-12 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
EP1980560A3 (en) * 2003-03-14 2008-10-29 Astellas Pharma Inc. C-glycoside derivatives for the treatment of diabetes
EP1609785A4 (en) * 2003-03-14 2008-10-22 Astellas Pharma Inc C-glycoside derivatives and salts thereof
US7772407B2 (en) 2003-03-14 2010-08-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
US7202350B2 (en) 2003-03-14 2007-04-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
EP1609785A1 (en) * 2003-03-14 2005-12-28 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
EP1651658B2 (en) † 2003-08-01 2020-08-12 Mitsubishi Tanabe Pharma Corporation Novel compounds having inhibitory activity against sodium-dependant transporter
US7579449B2 (en) 2004-03-16 2009-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2006011502A1 (en) * 2004-07-27 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Novel glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
US7943748B2 (en) 2004-07-27 2011-05-17 Chugai Seiyaku Kabushiki Kaisha Glucitol derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
JP2008508213A (en) * 2004-07-27 2008-03-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング D-glucopyranosyl-phenyl-substituted cyclics, pharmaceuticals containing such compounds, their use and methods for their production
JP5046370B2 (en) * 2004-09-29 2012-10-10 キッセイ薬品工業株式会社 1- (β-D-glycopyranosyl) -3-substituted nitrogen-containing heterocyclic compound, pharmaceutical composition containing the same, and pharmaceutical use thereof
WO2006035796A1 (en) * 2004-09-29 2006-04-06 Kissei Pharmaceutical Co., Ltd. 1-(β-D-GLYCOPYRANOSYL)-3-SUBSTITUTED NITROGENOUS HETEROCYCLIC COMPOUND, MEDICINAL COMPOSITION CONTAINING THE SAME, AND MEDICINAL USE THEREOF
JPWO2006035796A1 (en) * 2004-09-29 2008-05-15 キッセイ薬品工業株式会社 1- (β-D-glycopyranosyl) -3-substituted nitrogen-containing heterocyclic compound, pharmaceutical composition containing the same, and pharmaceutical use thereof
US7687469B2 (en) 2004-12-16 2010-03-30 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7767651B2 (en) 2005-01-28 2010-08-03 Chugai Seiyaku Kabushiki Kaisha Spiroketal derivatives and use thereof as diabetic medicine
US7772378B2 (en) 2005-02-23 2010-08-10 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)arylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7662790B2 (en) 2005-04-15 2010-02-16 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted (heteroaryloxy-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7723309B2 (en) 2005-05-03 2010-05-25 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7713938B2 (en) 2005-05-03 2010-05-11 Boehringer Ingelheim International Gmbh Crystalline form of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
US7772191B2 (en) 2005-05-10 2010-08-10 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US10442795B2 (en) 2005-05-10 2019-10-15 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein
US9127034B2 (en) 2005-05-10 2015-09-08 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein
US7851602B2 (en) 2005-07-27 2010-12-14 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7683160B2 (en) 2005-08-30 2010-03-23 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US8507450B2 (en) 2005-09-08 2013-08-13 Boehringer Ingelheim International Gmbh Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments
US7847074B2 (en) 2005-09-15 2010-12-07 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
JP2009507898A (en) * 2005-09-15 2009-02-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Process for producing glucopyranosyl-substituted (ethynyl-benzyl) -benzene derivative and its intermediate
WO2007031548A3 (en) * 2005-09-15 2007-04-26 Boehringer Ingelheim Int Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
WO2007031548A2 (en) * 2005-09-15 2007-03-22 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted (ethynyl-benzyl)-benzene derivatives and intermediates thereof
US7745414B2 (en) 2006-02-15 2010-06-29 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US8097592B2 (en) 2006-04-05 2012-01-17 Astellas Pharma Inc. Cocrystal of C-glycoside derivative and L-proline
US8557782B2 (en) 2006-05-03 2013-10-15 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
US7776830B2 (en) 2006-05-03 2010-08-17 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
EP2351568A2 (en) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Uses of dpp-iv inhibitors
WO2007128761A2 (en) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Uses of dpp-iv inhibitors
EA016819B1 (en) * 2006-07-27 2012-07-30 Мицубиси Танабе Фарма Корпорейшн 1- (-d-glycopyranosyl)-3-(4-cyclopropylphenylmethyl)-4-halogenoindole derivatives and use thereof as sglt inhibitors
WO2008013280A1 (en) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Substituted spiroketal derivative and use thereof as drug for treating diabetes
JP2009544693A (en) * 2006-07-27 2009-12-17 田辺三菱製薬株式会社 1- (β-D-glycopyranosyl) -3- (4-cyclopropylphenylmethyl) -4-halogenoindole derivatives and their use as SGLT inhibitors
US7851617B2 (en) 2006-07-27 2010-12-14 Mitsubishi Tanabe Pharma Corporation Indole derivatives
WO2008013322A1 (en) * 2006-07-27 2008-01-31 Mitsubishi Tanabe Pharma Corporation 1- (-d-glycopyranosyl) - 3 - (4-cyclopropylphenylmethyl) - 4 - halogeno indole derivatives and use thereof as sglt inhibitors.
US8207134B2 (en) 2006-07-27 2012-06-26 Chugai Seiyaku Kabushiki Kaisha Fused ring spiroketal derivative and use thereof as anti-diabetic drug
WO2008013277A1 (en) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Fused ring spiroketal derivative and use thereof as drug for treating diabetes
JP5165565B2 (en) * 2006-07-27 2013-03-21 中外製薬株式会社 Fused ring spiroketal derivatives and their use as antidiabetic agents
TWI403516B (en) * 2006-07-27 2013-08-01 Chugai Pharmaceutical Co Ltd To replace spirocyclic alcohol derivatives, and its use as a therapeutic agent for diabetes
JP2009544572A (en) * 2006-07-28 2009-12-17 田辺三菱製薬株式会社 Novel SGLT inhibitor
WO2008013321A1 (en) * 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Novel sglt inhibitors
US8039441B2 (en) 2006-08-15 2011-10-18 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture
JP2010504300A (en) * 2006-09-21 2010-02-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, pharmaceuticals containing the compounds and methods of use and preparation thereof
WO2008044762A1 (en) 2006-10-13 2008-04-17 Chugai Seiyaku Kabushiki Kaisha Thioglucose spiroketal derivative and use thereof as therapeutic agent for diabetes
US8283326B2 (en) 2006-10-27 2012-10-09 Boehringer Ingelheim International Gmbh Crystalline form of 4-(beta-D-glucopyranos-1-yl)-1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments
KR101146095B1 (en) 2006-12-04 2012-05-16 미쓰비시 타나베 파마 코퍼레이션 Crystalline form of 1-?-d-glucopyranosyl-4-methyl-3-[5-4-fluorophenyl-2-thienylmethyl]benzene hemihydrate
JP2010511724A (en) * 2006-12-04 2010-04-15 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Thienyl-containing glycopyranosyl derivatives as antidiabetic agents
JP2010511602A (en) * 2006-12-04 2010-04-15 田辺三菱製薬株式会社 Crystalline form of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate
NO344354B1 (en) * 2006-12-04 2019-11-11 Mitsubishi Tanabe Pharma Corp Crystalline form of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate
TWI403325B (en) * 2006-12-04 2013-08-01 Mitsubishi Tanabe Pharma Corp Crystalline form of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
WO2008069327A1 (en) * 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation CRYSTALLINE FORM OF 1- (β-D-GLUCOPYRANOSYL) -4 -METHYL- 3- [5- (4 -FLUOROPHENYL) -2-THIENYLMETHYL] BENZENE HEMIHYDRATE
WO2008070609A1 (en) 2006-12-04 2008-06-12 Janssen Pharmaceutica N.V. Thienyl-containing glycopyranosyl derivatives as antidiabetics
AU2007329895B2 (en) * 2006-12-04 2011-09-08 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1- (beta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate
US7666845B2 (en) 2006-12-04 2010-02-23 Janssen Pharmaceutica N.V. Compounds having inhibitory activity against sodium-dependent glucose transporter
US8513202B2 (en) 2006-12-04 2013-08-20 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate
US7943582B2 (en) 2006-12-04 2011-05-17 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1-(β-D-glucopyransoyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene hemihydrate
CN101611032B (en) * 2006-12-04 2012-07-18 詹森药业有限公司 Thienyl-containing glycopyranosyl derivatives as antidiabetics
AU2007329895C1 (en) * 2006-12-04 2014-03-13 Mitsubishi Tanabe Pharma Corporation Crystalline form of 1- (beta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate
CN102675380A (en) * 2006-12-04 2012-09-19 田边三菱制药株式会社 Crystalline form of 1- (beta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate
EA017103B1 (en) * 2006-12-04 2012-09-28 Мицубиси Танабе Фарма Корпорейшн CRYSTALLINE FORM OF 1-(β-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL]BENZENE HEMIHYDRATE
AU2007329490B2 (en) * 2006-12-04 2012-05-17 Janssen Pharmaceutica N.V. Thienyl-containing glycopyranosyl derivatives as antidiabetics
WO2008075736A1 (en) * 2006-12-21 2008-06-26 Astellas Pharma Inc. Method for producing c-glycoside derivative and synthetic intermediate thereof
JPWO2008075736A1 (en) * 2006-12-21 2010-04-15 アステラス製薬株式会社 Method for producing C-glycoside derivative and synthetic intermediate thereof
US8198464B2 (en) 2006-12-21 2012-06-12 Astellas Pharma Inc. Method for producing C-glycoside derivative and intermediate for synthesis thereof
EP2112928A4 (en) * 2007-02-22 2014-01-08 Univ Utah Res Found Synthesis of novel xylosides and potential uses thereof
EP2112928A1 (en) * 2007-02-22 2009-11-04 University of Utah Research Foundation Synthesis of novel xylosides and potential uses thereof
JP2010523620A (en) * 2007-04-11 2010-07-15 ナームローゼ・フエンノートチヤツプ・オルガノン Preparation method of mirtazapine
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
AU2008299102B2 (en) * 2007-09-10 2014-08-28 Janssen Pharmaceutica N.V. Process for the preparation of compounds useful as inhibitors of SGLT
KR101552187B1 (en) * 2007-09-10 2015-09-10 얀센 파마슈티카 엔.브이. Process for the preparation of compounds useful as inhibitors of sglt
US9024009B2 (en) 2007-09-10 2015-05-05 Janssen Pharmaceutica N.V. Process for the preparation of compounds useful as inhibitors of SGLT
EP2200606A1 (en) * 2007-09-10 2010-06-30 Janssen Pharmaceutica, N.V. Process for the preparation of compounds useful as inhibitors of sglt
EP2200606A4 (en) * 2007-09-10 2012-04-18 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt
EA020209B1 (en) * 2007-09-10 2014-09-30 Янссен Фармацевтика Н.В. Process for the preparation of compounds useful as inhibitors of sodium-dependent glucose transporter
WO2009035969A1 (en) * 2007-09-10 2009-03-19 Janssen Pharmaceutica N.V. Process for the preparation of compounds useful as inhibitors of sglt
EP2252289B1 (en) 2008-01-17 2019-10-23 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising sglt inhibitors and dpp4 inhibitors
US8853385B2 (en) 2008-01-17 2014-10-07 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
WO2009091082A1 (en) * 2008-01-17 2009-07-23 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising sglt inhibitors and dpp4 inhibitors
AU2009205060C1 (en) * 2008-01-17 2013-12-19 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
AU2009205060B2 (en) * 2008-01-17 2013-06-27 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
WO2009096455A1 (en) 2008-01-31 2009-08-06 Astellas Pharma Inc. Pharmaceutical composition for treatment of fatty liver diseases
US8080580B2 (en) 2008-08-28 2011-12-20 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2010031820A1 (en) * 2008-09-19 2010-03-25 Novartis Ag Glucoside derivatives and uses thereof as sglt inhibitors
JP2012505858A (en) * 2008-10-17 2012-03-08 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Process for preparing compounds useful as inhibitors of SGLT
US9056850B2 (en) 2008-10-17 2015-06-16 Janssen Pharmaceutica N.V. Process for the preparation of compounds useful as inhibitors of SGLT
KR101724598B1 (en) * 2008-10-17 2017-04-07 얀센 파마슈티카 엔.브이. Process for the preparation of compounds useful as inhibitors of sglt
EP2457908A1 (en) 2008-10-17 2012-05-30 Janssen Pharmaceutica N.V. Process for the Preparation of Compounds useful as inhibitors of SGLT
JP2014167030A (en) * 2008-10-17 2014-09-11 Janssen Pharmaceutica Nv Process for preparation of compounds useful as inhibitors of sglt
CN103467439A (en) * 2008-10-17 2013-12-25 詹森药业有限公司 Process for the preparation of compounds useful as inhibitors of SGLT
EP2455374A1 (en) 2008-10-17 2012-05-23 Janssen Pharmaceutica N.V. Process for the Preparation of Compounds useful as inhibitors of SGLT
WO2010043682A3 (en) * 2008-10-17 2011-08-11 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt
EA021373B1 (en) * 2008-10-17 2015-06-30 Янссен Фармацевтика Нв Process for the preparation of compounds useful as inhibitors of sodium-dependent glucose transporter (sglt)
KR20110086039A (en) * 2008-10-17 2011-07-27 얀센 파마슈티카 엔.브이. Process for the preparation of compounds useful as inhibitors of sglt
AU2009305413B2 (en) * 2008-10-17 2015-07-09 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of SGLT
US12115179B2 (en) 2009-02-13 2024-10-15 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2010092125A1 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof
US11576894B2 (en) 2009-07-08 2023-02-14 Janssen Pharmaceutica Nv Combination therapy for the treatment of diabetes
WO2011003976A1 (en) 2009-07-10 2011-01-13 Janssen Pharmaceutica Nv CRYSTALLISATION PROCESS FOR 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL] BENZENE
US8772512B2 (en) 2009-07-10 2014-07-08 Janssen Pharmaceutica Nv Crystallisation process for 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene
US9024010B2 (en) 2009-09-30 2015-05-05 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US9873714B2 (en) 2009-09-30 2018-01-23 Boehringer Ingelheim International Gmbh Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives
US8802842B2 (en) 2009-09-30 2014-08-12 Boehringer Ingelheim International Gmbh Method for the preparation of a crystalline form
US10610489B2 (en) 2009-10-02 2020-04-07 Boehringer Ingelheim International Gmbh Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof
US9174971B2 (en) 2009-10-14 2015-11-03 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of SGLT2
US9895389B2 (en) 2009-10-20 2018-02-20 Novartis Ag Glycoside derivatives and uses thereof
USRE49080E1 (en) 2009-10-20 2022-05-24 Novartis Ag Glycoside derivatives and uses thereof
US8828951B2 (en) 2009-10-20 2014-09-09 Novartis Ag Glycoside derivatives and uses thereof
US9439901B2 (en) 2009-11-02 2016-09-13 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9439902B2 (en) 2009-11-02 2016-09-13 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US8669380B2 (en) 2009-11-02 2014-03-11 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
US9308204B2 (en) 2009-11-02 2016-04-12 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
RU2824129C2 (en) * 2009-11-13 2024-08-06 Астразенека Аб Two-layer tablet composition
WO2011091710A1 (en) 2010-01-26 2011-08-04 天津药物研究院 Phenyl c-glucoside derivatives, preparation methods and uses thereof
AU2011209004B2 (en) * 2010-01-26 2015-04-30 Tianjin Institute Of Pharmaceutical Research Phenyl C-glucoside derivatives, preparation methods and uses thereof
EP2530079A4 (en) * 2010-01-26 2013-06-19 Tianjin Inst Pharm Research Phenyl c-glucoside derivatives, preparation methods and uses thereof
US9062087B2 (en) 2010-01-26 2015-06-23 Tianjin Institute Of Pharmaceutical Research Phenyl C-glucoside derivatives, preparation methods and uses thereof
EP2530079A1 (en) * 2010-01-26 2012-12-05 Tianjin Institute Of Pharmaceutical Research Phenyl c-glucoside derivatives, preparation methods and uses thereof
WO2011120923A1 (en) 2010-03-30 2011-10-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof
WO2011127051A1 (en) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US10617668B2 (en) 2010-05-11 2020-04-14 Janssen Pharmaceutica Nv Pharmaceutical formulations
WO2011143296A1 (en) 2010-05-11 2011-11-17 Janssen Pharmaceutica Nv Pharmaceutical formulations comprising 1 - (beta-d-glucopyranosyl) - 2 -thienylmethylbenzene derivatives as inhibitors of sglt
WO2011142478A1 (en) 2010-05-11 2011-11-17 Mitsubishi Tanabe Pharma Corporation Canagliflozin containing tablets
US9655852B2 (en) 2010-05-11 2017-05-23 Mitsubishi Tanabe Pharma Corporation Tablets containing a 1-(β-D-glucopyranosyl)-3-(phenylthienylmethyl)benzene compound
CN102985075A (en) * 2010-05-11 2013-03-20 田边三菱制药株式会社 Canagliflozin containing tablets
WO2011146308A1 (en) 2010-05-18 2011-11-24 Corning Incorporated Methods of making fused thiophenes
EP2604612A1 (en) * 2010-08-10 2013-06-19 Shanghai Hengrui Pharmaceutical Co. Ltd. C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof
EP2604612A4 (en) * 2010-08-10 2013-07-24 Shanghai Hengrui Pharm Co Ltd C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof
WO2012040279A1 (en) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
EP3323818A1 (en) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012041898A1 (en) 2010-09-29 2012-04-05 Celon Pharma Sp. Z O.O. Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes
US8871726B2 (en) 2010-10-27 2014-10-28 Shanghai Allist Pharmaceuticals, Inc. C-aryl glucoside derivative, preparation method therefor, and use thereof
US20130225514A1 (en) * 2010-10-27 2013-08-29 Shanghai Allist Pharmaceuticals, Inc. C-aryl glucoside derivative, preparation method therefor, and use thereof
CN103270033B (en) * 2010-10-27 2015-07-29 上海艾力斯医药科技有限公司 C-aryl glucoside derivative and its preparation method and application
WO2012055169A1 (en) 2010-10-27 2012-05-03 上海艾力斯医药科技有限公司 C-arylglucoside derivative, preparation method therefor, and use thereof
CN103270033A (en) * 2010-10-27 2013-08-28 上海艾力斯医药科技有限公司 C-aryl glucoside derivative, preparation method therefor, and use thereof
EP3539540A1 (en) 2010-11-08 2019-09-18 Boehringer Ingelheim International GmbH Pharmaceutical composition, methods for treating and uses thereof
WO2012062698A1 (en) 2010-11-08 2012-05-18 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2012107476A1 (en) 2011-02-09 2012-08-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US8980829B2 (en) 2011-02-18 2015-03-17 Shanghai Yingli Science And Technology Co., Ltd Aryl glycoside compound, preparation method and use thereof
WO2012109996A1 (en) 2011-02-18 2012-08-23 上海璎黎科技有限公司 Aryl glycoside compound, preparation method and use thereof
US10596120B2 (en) 2011-03-07 2020-03-24 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US11564886B2 (en) 2011-03-07 2023-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
JP2014510776A (en) * 2011-04-13 2014-05-01 ヤンセン ファーマシューティカ エヌ．ベー． Process for preparing compounds useful as inhibitors of SGLT2
US10544135B2 (en) 2011-04-13 2020-01-28 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of SGLT2
US9487506B2 (en) 2011-04-13 2016-11-08 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
EP2697203A1 (en) * 2011-04-13 2014-02-19 Merck Sharp & Dohme Corporation Mineralocorticoid receptor antagonists
EP2697203A4 (en) * 2011-04-13 2014-10-15 Merck Sharp & Dohme Mineralocorticoid receptor antagonists
WO2012145361A1 (en) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145604A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2012145603A1 (en) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US9035044B2 (en) 2011-05-09 2015-05-19 Janssen Pharmaceutica Nv L-proline and citric acid co-crystals of (2S, 3R, 4R, 5S,6R)-2-(3-((5-(4-fluorophenyl)thiopen-2-yl)methyl)4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
WO2012163990A1 (en) 2011-06-03 2012-12-06 Boehringer Ingelheim International Gmbh Sglt-2 inhibitors for treating metabolic disorders in patients treated with neuroleptic agents
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013090550A1 (en) * 2011-12-15 2013-06-20 National Health Research Institutes Novel glycoside compounds
US8697658B2 (en) 2011-12-15 2014-04-15 National Health Research Institutes Glycoside compounds
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9192617B2 (en) 2012-03-20 2015-11-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
US9505734B2 (en) 2012-12-17 2016-11-29 Tianjin Institute Of Pharmaceutical Research Phenyl C-glucoside derivative containing deoxyglucose structure, preparation method and use thereof
US10294259B2 (en) 2012-12-17 2019-05-21 Tianjin Institute Of Pharmaceutical Research Phenyl c-glucoside derivative containing deoxyglucose structure, preparation method and use thereof
US9738603B2 (en) 2012-12-31 2017-08-22 Shanghai Yingli Pharmaceutical Co., Ltd. Complex of glucose derivative and proline, crystal, preparation method and use
WO2014101865A1 (en) 2012-12-31 2014-07-03 上海璎黎科技有限公司 Composition of glucose derivative and proline, crystal, preparation method and application
WO2014132940A1 (en) 2013-02-26 2014-09-04 田辺三菱製薬株式会社 Method for producing α-halo-tetraacyl glucose
WO2014164286A1 (en) * 2013-03-11 2014-10-09 Janssen Pharmaceutica Nv Dual sglt1/sglt2 inhibitors
AU2014249535B2 (en) * 2013-03-11 2018-03-22 Janssen Pharmaceutica Nv Dual SGLT1/SGLT2 inhibitors
US9012412B2 (en) 2013-03-11 2015-04-21 Janssen Pharmaceutica Nv Dual SGLT1/SGLT2 inhibitors
EP4245765A2 (en) 2013-04-04 2023-09-20 Boehringer Ingelheim Vetmedica GmbH Treatment of metabolic disorders in equine animals
WO2014161836A1 (en) 2013-04-04 2014-10-09 Boehringer Ingelheim Vetmedica Gmbh Treatment of metabolic disorders in equine animals
US9949997B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10258637B2 (en) 2013-04-05 2019-04-16 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11833166B2 (en) 2013-04-05 2023-12-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11090323B2 (en) 2013-04-05 2021-08-17 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11918596B2 (en) 2013-04-05 2024-03-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US9949998B2 (en) 2013-04-05 2018-04-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11666590B2 (en) 2013-04-18 2023-06-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US10323056B2 (en) 2013-05-08 2019-06-18 Lek Pharmaceuticals D.D. Crystalline hydrates of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
WO2014195966A2 (en) 2013-05-30 2014-12-11 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
EP3862003A1 (en) 2013-12-17 2021-08-11 Boehringer Ingelheim Vetmedica GmbH An sglt-2 inhibitor for use in the treatment of a metabolic disorder in feline animals
EP4285995A2 (en) 2013-12-17 2023-12-06 Boehringer Ingelheim Vetmedica GmbH An sglt-2 inhibitor for use in the treatment of a metabolic disorder in feline animals
EP4234012A2 (en) 2014-01-23 2023-08-30 Boehringer Ingelheim Vetmedica GmbH Sglt2 inhibitors for treatment of metabolic disorders in canine animals
EP3485890A1 (en) 2014-01-23 2019-05-22 Boehringer Ingelheim Vetmedica GmbH Treatment of metabolic disorders in canine animals
EP2918579A1 (en) 2014-03-14 2015-09-16 LEK Pharmaceuticals d.d. Synthesis of 2-arylmethyl-5-aryl-thiophene
US10954223B2 (en) 2014-03-19 2021-03-23 Hangzhou Solipharma Co., Ltd. Canagliflozin monohydrate and its crystalline forms, preparation methods and uses thereof
US10174010B2 (en) 2014-03-19 2019-01-08 Hangzhou Pushai Pharmaceutical Technology Co., Ltd. Canagliflozin monohydrate and its crystalline forms, preparation methods and uses thereof
EP3721882A1 (en) 2014-04-01 2020-10-14 Boehringer Ingelheim Vetmedica GmbH Treatment of metabolic disorders in equine animals
US9914724B2 (en) 2014-04-14 2018-03-13 Shanghai De Novo Pharmatech Co., Ltd. C-aryl glycosid derivatives, pharmaceutical composition, preparation process and uses thereof
WO2015158839A1 (en) 2014-04-17 2015-10-22 Lek Pharmaceuticals D.D. Novel crystalline form of 1-(beta-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
EP2933255A1 (en) 2014-04-17 2015-10-21 LEK Pharmaceuticals d.d. Novel crystalline form of 1-(beta-D-glucopyranosyl)-4- methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
CN103980263B (en) * 2014-04-17 2016-08-03 海门瑞一医药科技有限公司 The synthesis technique of canagliflozin
CN103980263A (en) * 2014-04-17 2014-08-13 海门瑞一医药科技有限公司 New synthesis process of canagliflozin
CN105085454A (en) * 2014-05-13 2015-11-25 北京韩美药品有限公司 SGLT inhibitor and pharmaceutical composition
WO2015177083A1 (en) 2014-05-19 2015-11-26 Lek Pharmaceuticals D.D. STEREOSELECTIVE SYNTHESIS OF INTERMEDIATES IN THE PREPARATION OF ß-C-ARYLGLUCOSIDES
EP2947077A1 (en) 2014-05-19 2015-11-25 LEK Pharmaceuticals d.d. Stereoselective synthesis of intermediates in the preparation of ß-C-arylglucosides
EP3148979A4 (en) * 2014-05-27 2018-01-03 Glenmark Pharmaceuticals Limited Process for preparation of canagliflozin
CN104119324A (en) * 2014-07-23 2014-10-29 齐鲁天和惠世制药有限公司 Preparation method of canagliflozin
CN104119324B (en) * 2014-07-23 2016-03-30 齐鲁天和惠世制药有限公司 The preparation method that a kind of Ka Gelie is clean
CN104109157A (en) * 2014-08-04 2014-10-22 山东康美乐医药科技有限公司 Preparation method of canagliflozin
EP2990029A1 (en) 2014-08-29 2016-03-02 Sandoz Ag Pharmaceutical compositions comprising Canagliflozin
WO2016030502A1 (en) 2014-08-29 2016-03-03 Sandoz Ag Pharmaceutical compositions comprising canagliflozin
WO2016041530A1 (en) 2014-09-16 2016-03-24 Zentiva, K.S. Complexes of canagliflozin and cyclodextrins
EP4403230A2 (en) 2014-09-25 2024-07-24 Boehringer Ingelheim Vetmedica GmbH Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals
WO2016074566A1 (en) * 2014-11-10 2016-05-19 镇江新元素医药科技有限公司 Glucoside derivative and pharmaceutical composition thereof
CN104478968A (en) * 2015-01-14 2015-04-01 佛山市赛维斯医药科技有限公司 O-galactoside derivative with thiazolyl and preparation method and application thereof
US10633372B2 (en) * 2015-02-27 2020-04-28 Msn Laboratories Private Limited Process for the preparation of amorphous (1S)-1,5-anhydro-1-[3-[[5-(4 fluorophenyl)-2-thienyl]-4-methylphenyl]-D-glucitol and its polymorphs thereof
US20180244661A1 (en) * 2015-02-27 2018-08-30 Msn Laboratories Private Limited Process for the preparation of amorphous (1s)-1,5-anhvdro-1-[3-[[5-(4 fluorophenyl)-2-thienyl]-4-methylphenyl]-d-glucitol and its polymorphs thereof
WO2016142950A1 (en) * 2015-03-11 2016-09-15 Harman Finochem Limited A novel process for preparing (2s,3r,4r,5s,6r)-2-{3-[5-[4-fluoro-phenyl)- thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5- triol and its stable amorphous hemihydrate form
WO2016206660A1 (en) 2015-06-25 2016-12-29 Zentiva K.S. Solid forms of amorphous canagliflozin
US11207337B2 (en) 2015-09-15 2021-12-28 Janssen Pharmaceutica Nv Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders
WO2017046655A1 (en) * 2015-09-16 2017-03-23 Optimus Drugs (P) Ltd A novel process for the preparation of canagliflozin
US10370365B2 (en) 2015-09-16 2019-08-06 Optimus Drugs (P) Limited Process for the preparation of Canagliflozin
WO2017063617A1 (en) 2015-10-13 2017-04-20 Zentiva, K.S. Preparation of intermediates for the synthesis of canagliflozin and dapagliflozin
WO2017064679A1 (en) * 2015-10-15 2017-04-20 Lupin Limited Process for the preparation of amorphous canagliflozin
WO2017101890A1 (en) * 2015-12-17 2017-06-22 上海艾力斯医药科技有限公司 Spiroketal derivative, preparation method therefor and application
CN106892929A (en) * 2015-12-17 2017-06-27 上海艾力斯医药科技有限公司 Spiroketals derivative and its preparation method and application
US10323025B2 (en) 2015-12-21 2019-06-18 Janssen Pharmaceutica Nv Crystallization procedure for obtaining canagliflozin hemihydrate crystals
CN105541815A (en) * 2015-12-24 2016-05-04 寿光富康制药有限公司 Preparation method for canagliflozin
CN105541815B (en) * 2015-12-24 2018-07-13 寿光富康制药有限公司 A kind of preparation method of canagliflozin
WO2018020506A1 (en) 2016-07-25 2018-02-01 Natco Pharma Ltd Process for the preparation of amorphous form of canagliflozin
WO2018073154A1 (en) 2016-10-19 2018-04-26 Boehringer Ingelheim International Gmbh Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof
WO2018149327A1 (en) 2017-02-20 2018-08-23 浙江华海药业股份有限公司 Method for preparing canagliflozin amorphous form
WO2019201752A1 (en) 2018-04-17 2019-10-24 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2020039394A1 (en) 2018-08-24 2020-02-27 Novartis Ag New drug combinations
WO2020095010A1 (en) 2018-11-05 2020-05-14 Balticgruppen Bio Ab Methods of treating diabetes in severe insulin-resistant diabetic subjects
WO2021105152A1 (en) 2019-11-28 2021-06-03 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors in the drying-off of non-human mammals
WO2021165177A1 (en) 2020-02-17 2021-08-26 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in felines
WO2021214023A1 (en) 2020-04-22 2021-10-28 Bayer Aktiengesellschaft Combination of finerenone and a sglt2 inhibitor for the treatment and/or prevention of cardiovascular and/or renal diseases
WO2023006718A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in non-human mammals excluding felines, in particular canines
WO2023006745A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of hypertension in non-human mammals
WO2023006747A1 (en) 2021-07-28 2023-02-02 Boehringer Ingelheim Vetmedica Gmbh Use of sglt-2 inhibitors for the prevention and/or treatment of renal diseases in non-human mammals
WO2023129595A1 (en) 2021-12-30 2023-07-06 Newamsterdam Pharma B.V. Obicetrapib and sglt2 inhibitor combination
WO2023227492A1 (en) 2022-05-25 2023-11-30 Boehringer Ingelheim Vetmedica Gmbh Aqueous pharmaceutical compositions comprising sglt-2 inhibitors
WO2024184293A1 (en) 2023-03-06 2024-09-12 Boehringer Ingelheim Vetmedica Gmbh Systems for delivery of liquid pharmaceutical compositions in particular comprising one or more sglt-2 inhibitor(s)

Also Published As

Publication number Publication date
KR100778988B1 (en) 2007-11-28
CY2014016I2 (en) 2015-12-09
LU92426I9 (en) 2019-01-16
US7943788B2 (en) 2011-05-17
AU2004260761B2 (en) 2008-01-31
IL206831A (en) 2012-06-28
MXPA06001274A (en) 2006-04-11
EP1651658B2 (en) 2020-08-12
EP3251679B1 (en) 2020-12-16
TW201038588A (en) 2010-11-01
CN103214471B (en) 2018-02-06
EA010299B1 (en) 2008-08-29
BE2014C027I2 (en) 2023-12-14
AU2004260761A1 (en) 2005-02-10
EA200600351A1 (en) 2006-08-25
ES2649737T5 (en) 2021-07-07
JP4130466B2 (en) 2008-08-06
EA015104B1 (en) 2011-06-30
DK2896397T4 (en) 2020-11-16
HRP20130124T4 (en) 2020-11-13
KR20070065454A (en) 2007-06-22
CY1119814T1 (en) 2018-06-27
ME00411B (en) 2011-10-10
ZA200603882B (en) 2010-03-31
EP1651658A1 (en) 2006-05-03
HK1086277A1 (en) 2006-09-15
CR11263A (en) 2010-05-19
ZA200601685B (en) 2007-05-30
EP3251679A1 (en) 2017-12-06
SI1651658T2 (en) 2020-12-31
ES2402098T5 (en) 2021-06-09
HRP20130124T1 (en) 2013-04-30
US20110105424A1 (en) 2011-05-05
KR100942622B1 (en) 2010-02-17
NO333933B1 (en) 2013-10-28
SI2896397T2 (en) 2020-12-31
NZ575711A (en) 2010-05-28
EP2514756A1 (en) 2012-10-24
PL1651658T5 (en) 2020-11-30
CN1829729A (en) 2006-09-06
TWI385177B (en) 2013-02-11
EA200800924A1 (en) 2008-08-29
PT1651658E (en) 2013-03-07
DK1651658T3 (en) 2013-02-18
CN103214471A (en) 2013-07-24
EP2514756B1 (en) 2014-12-17
ZA200603881B (en) 2010-01-27
PL2896397T5 (en) 2023-06-19
CR8188A (en) 2006-07-14
EP2896397B1 (en) 2017-09-06
EP2896397A1 (en) 2015-07-22
FR14C0034I1 (en) 2014-06-13
NO334706B1 (en) 2014-05-12
NO20120585L (en) 2006-05-02
CN103819465A (en) 2014-05-28
TW200510441A (en) 2005-03-16
JP2007518683A (en) 2007-07-12
RS53365B (en) 2014-10-31
TWI365190B (en) 2012-06-01
SI1651658T1 (en) 2013-04-30
BRPI0413232B8 (en) 2021-05-25
ES2531660T3 (en) 2015-03-18
PL2896397T3 (en) 2018-03-30
UA83243C2 (en) 2008-06-25
US20120058941A1 (en) 2012-03-08
CY1113813T1 (en) 2015-12-09
LU92426I2 (en) 2014-06-10
US8202984B2 (en) 2012-06-19
EP1651658B1 (en) 2013-01-16
US8222219B2 (en) 2012-07-17
BRPI0413232A (en) 2006-10-03
FR14C0034I2 (en) 2014-11-14
NO2014009I2 (en) 2016-08-01
CA2534024C (en) 2009-06-02
NL300670I2 (en) 2016-09-22
IL173050A (en) 2011-06-30
PL1651658T3 (en) 2013-05-31
ES2402098T3 (en) 2013-04-26
ES2844401T3 (en) 2021-07-22
MY143203A (en) 2011-03-31
LT2896397T (en) 2017-11-27
NO20060220L (en) 2006-05-02
EP2896397B2 (en) 2020-10-07
KR20060057589A (en) 2006-05-26
NZ545304A (en) 2009-04-30
ZA200700550B (en) 2009-08-26
CN104109155A (en) 2014-10-22
AR045173A1 (en) 2005-10-19
BRPI0413232B1 (en) 2018-03-06
NO2014009I1 (en) 2014-06-02
IL206831A0 (en) 2011-08-01
US20050233988A1 (en) 2005-10-20
DK1651658T4 (en) 2020-11-09
PT2896397T (en) 2017-11-23
HRP20171838T1 (en) 2018-01-12
HRP20171838T4 (en) 2021-02-05
ES2649737T3 (en) 2018-01-15
CA2534024A1 (en) 2005-02-10
HUE037320T2 (en) 2018-08-28
IL173050A0 (en) 2006-06-11
MEP61208A (en) 2011-05-10
JP2008266328A (en) 2008-11-06
RS20060079A (en) 2008-04-04
CY2014016I1 (en) 2015-12-09
SI2896397T1 (en) 2018-01-31
HUS1400021I1 (en) 2016-08-29
JP5065135B2 (en) 2012-10-31
SG145694A1 (en) 2008-09-29
DK2896397T3 (en) 2017-11-06
ZA200603879B (en) 2010-01-27

Similar Documents

Publication Publication Date Title
EP2896397B2 (en) Novel compounds having inhibitory activity against sodium-dependant glucose transporter
US20180282363A1 (en) Glucopyranoside compound
JP5317951B2 (en) Pharmaceutical composition
AU2008200240B2 (en) Novel compounds having inhibitory activity against sodium-dependent transporter

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480022007.8

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 11045446

Country of ref document: US

AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: CR2006-008188

Country of ref document: CR

ENP Entry into the national phase

Ref document number: 2534024

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12006500233

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 1020067002144

Country of ref document: KR

Ref document number: PA/a/2006/001274

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2006519251

Country of ref document: JP

Ref document number: P-2006/0079

Country of ref document: YU

WWE Wipo information: entry into national phase

Ref document number: 06012956

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 545304

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1200600270

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 2004771314

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006/01685

Country of ref document: ZA

Ref document number: 200601685

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2004260761

Country of ref document: AU

Ref document number: 734/CHENP/2006

Country of ref document: IN

Ref document number: 200600351

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 2004260761

Country of ref document: AU

Date of ref document: 20040730

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004260761

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2004771314

Country of ref document: EP

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
WWP Wipo information: published in national office

Ref document number: 1020067002144

Country of ref document: KR

ENP Entry into the national phase

Ref document number: PI0413232

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 206831

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 201011875

Country of ref document: CR

Ref document number: CR2010-011875

Country of ref document: CR