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US20080318922A1 - Bicyclic Pyrrole Derivatives - Google Patents

Bicyclic Pyrrole Derivatives Download PDF

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Publication number
US20080318922A1
US20080318922A1 US11/722,037 US72203705A US2008318922A1 US 20080318922 A1 US20080318922 A1 US 20080318922A1 US 72203705 A US72203705 A US 72203705A US 2008318922 A1 US2008318922 A1 US 2008318922A1
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Prior art keywords
group
optionally substituted
compound
formula
prodrug
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US11/722,037
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Inventor
Hiroyuki Nakahira
Hidenori Kimura
Hitoshi Hochigai
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Assigned to DAINIPPON SUMITOMO PHARMA CO., LTD reassignment DAINIPPON SUMITOMO PHARMA CO., LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOCHIGAI, HITOSHI, KIMURA, HIDENORI, NAKAHIRA, HIROYUKI
Publication of US20080318922A1 publication Critical patent/US20080318922A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to bicyclic pyrrole derivatives useful as drugs. More particularly, it relates to novel bicyclic pyrrole derivatives effective as a dipeptidyl peptidase IV (DPP-IV) inhibitor. Furthermore, it relates to a pharmaceutical composition for the treatment of diabetes containing a bicyclic pyrrole derivative effective as a dipeptidyl peptidase IV (DPP-IV) inhibitor, as an active ingredient.
  • DPP-IV dipeptidyl peptidase IV
  • DPP-IV is a serine protease widely present in the body, is one of dipeptidyl aminopeptidases capable of hydrolyzing and releasing a N-terminal dipeptide and markedly acts on, in particular, peptides containing proline as the second amino acid from the N-terminal. Therefore, DPP-IV is referred to also as prolyl end peptidase. DPP-IV is known to accept, as substrates, various biological peptides concerned in the endocrine system, the neuroendocrine system, immunological functions and the like.
  • pancreatic polypeptides such as pancreatic polypeptides (PP), neuropeptide Y (NPY) and the like; the glucagon/VIP family represented by vasoactive intestinal polypeptides (VIP), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptides (GIP), growth hormone-releasing factor (GRF) and the like; and the chemocaine family are substrates for DPP-IV and are subject to the influences of DPP-IV, such as activation/inactivation, metabolism acceleration and the like (non-patent document 1).
  • PP pancreatic polypeptides
  • NPY neuropeptide Y
  • glucagon/VIP family represented by vasoactive intestinal polypeptides (VIP), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptides (GIP), growth hormone-releasing factor (GRF) and the like
  • chemocaine family are substrates for DPP-IV and are
  • DPP-IV severs two amino acids (His-Ala) from the N-terminal of GLP-1. It is known that although the severed peptide binds weekly to a GLP-1 receptor, it has no activating effect on the receptor and acts as an antagonist (non-patent document 2). The metabolism of GLP-1 by DPP-IV in blood is known to be very rapid, and the concentration of active GLP-1 in blood is increased by the inhibition of DPP-IV (non-patent document 3). GLP-1 is a peptide secreted from intestinal tract by the ingestion of sugars and is a main accelerating factor for the glucose-responsive secretion of insulin by pancreas.
  • GLP-1 is known to have accelerating effect on insulin synthesis in pancreatic ⁇ cells and accelerating effect on ⁇ cell proliferation.
  • GLP-1 receptors appear also in digestive tracts, liver, muscle, adipose tissue and the like, and it is also known that in these tissues, GLP-1 affects working of the digestive tracts, the secretion of acid in stomach, the synthesis and degradation of glycogen, insulin-dependent glucose uptake, and the like.
  • non-insulin-dependent diabetes a DPP-IV inhibitor effective against type 2 diabetes (non-insulin-dependent diabetes) which brings about effects such as the acceleration of insulin secretion dependent on blood sugar level, the improvement of pancreas function, the improvement of a high postprandial blood sugar level, the improvement of glucose tolerance abnormality, the improvement of insulin resistance, and the like, by increasing the concentration of GLP-1 in blood (non-patent document 4).
  • An object of the present invention is to provide a novel compound having an excellent DPP-IV inhibiting activity.
  • the present inventors earnestly investigated in order to achieve the above object, and consequently found that the following compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug (if necessary, they are hereinafter abbreviated as the present inventive compounds in some cases) has an excellent DPP-IV inhibiting effect, whereby the present invention has been accomplished.
  • the present invention relates to the following:
  • R 1 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
  • a 1 is a group represented by the formula C ⁇ O and A 2 is a group represented by the formula N(R 5 ), in the case of the solid line and dotted line between A 1 and A 2 being a single bond (A 1 -A 2 );
  • R 2 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group;
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, a formyl group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted cycloalkylcarbonyl group, an optionally substituted aroyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted carbamoyl group, a hydroxyl group, an optionally substituted alkoxy group, or the formula: -Rd-C(O)O—Re
  • R 4 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a formyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, a carboxyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted arylthio group, an optionally substituted arylsulfinyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylthio group, an optionally substituted al
  • R 5 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted vinyl group, an optionally substituted nitrogen-containing saturated heterocyclic group, or an optionally substituted heteroaryl group;
  • —Y is a group represented by any of the formula (A), formula (B), formula (C) and formula (D) shown below:
  • R 6 is absent or one or two R 6 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 6 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;
  • R 7 is absent or one or two R 7 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 7 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring;
  • R 8 is absent or one or two R 8 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 8 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring; and
  • R 9 is absent or one or two R 9 s are present and are independently a halogen atom, a hydroxyl group, an oxo group, an optionally substituted alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, a carboxyl group, an optionally substituted alkoxycarbonyl group or an optionally substituted carbamoyl group, or two R 9 s, when taken together, represent methylene or ethylene and may bind to two carbon atoms constituting the ring, to form a new ring, and R 10 and R 11 are independently a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R 10 and R 11 , when taken together, represent cyclopropyl, cyclobutyl or cyclopentyl, a prodrug of said compound, or a pharmaceutically acceptable
  • R 1 , R 2 , R 3 and Y are as defined in [1] and R 12 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
  • R 12 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
  • R 1 , R 2 , R 3 and Y are as defined in [1] and R 13 is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aralkyl group, an optionally substituted aralkyloxy group, an optionally substituted aroyl group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylcarbonyl group, an optionally substituted heteroaryloxy group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxy
  • R 13 is a hydrogen atom, a hydroxyl group, a cyano group, a carboxyl group, a trifluoromethyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted aroyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted aralkyloxycarbonyl group, an optionally substituted cycloalkyloxycarbonyl group, an optionally substituted alkylsulfonyl group, or the formula: -Rd-C(O)O—Re wherein Rd and Re are as defined in [1].
  • each of Z 1 and Z 2 is an oxygen atom, the formula S(O) p or the formula N(R 22 );
  • each of R 14 and R 20 is absent or one or two R 14 s and/or one or two R 20 s are present and are independently a halogen atom, a hydroxyl group, a formyl group, a carboxyl group, a cyano group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a cycloalkylcarbonyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted nitrogen-containing heteroaryl group, or two R 14 s or two R 20 s, when taken together, represent a C 1-3 al
  • each of R 15 and R 21 is absent or one or two R 15 s and/or one or two R 21 s are present and are independently a halogen atom, a cyano group, an alkyl group, a haloalkyl group, a cycloalkyl group, an alkoxy group or a haloalkoxy group;
  • R 16 is methyl, ethyl, a chlorine atom or a bromine atom
  • R 17 is a hydrogen atom, methyl, ethyl, a chlorine atom or a bromine atom
  • R 18 is a hydrogen atom, methyl or ethyl
  • R 19 is a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl;
  • p 0, 1 or 2;
  • R 22 is a hydrogen atom or an alkyl group.
  • R 2 is a group represented by any of the formula (E), formula (H) and formula (I).
  • R 1 is a group represented by the formula: —Ra—Rb—Rc in which
  • Ra is an alkylene group
  • Rb is a single bond or a carbonyl group
  • Rc is an optionally substituted alkyl group
  • R 1 is a hydrogen atom, methyl or ethyl.
  • R 1 and R 3 are as defined in [1];
  • R 23 is a hydrogen atom or an optionally substituted alkyl group;
  • R 24 is a halogen atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group;
  • R 25 is a hydrogen atom, a fluorine atom or a chlorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
  • R 26 is a hydrogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted carbamoyl group, a hydroxyl group or an optionally substituted alkoxy group
  • R 27 is a chlorine atom, a bromine atom, a cyano group, a carbamoyl group, a methyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a methoxy group, a trifluoromethoxy group, difluoromethoxy group or a monofluoromethoxy group
  • R 28 is a hydrogen atom or a fluorine atom, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
  • R 27 is a chlorine atom or a cyano group.
  • R 2 and Y are as defined in [1] and R 29 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, a prodrug of the compound or a pharmaceutically acceptable salt of the compound or prodrug.
  • a pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient.
  • a dipeptidyl peptidase IV inhibitor comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient.
  • a pharmaceutical composition for the treatment of diabetes comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] as an active ingredient.
  • [20] Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] in the manufacture of a pharmaceutical composition for the treatment of diabetes.
  • a method for treating diabetes comprising administering an effective amount of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] to a patient who needs the treatment.
  • the compound represented by the formula (I), a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug is hereinafter generically named “the present inventive compound” if necessary.
  • the present inventive compound has an excellent DPP-IV inhibiting activity and is useful as a therapeutic agent for diabetes.
  • the number of substituents of each group defined by the term “optionally substituted” or “substituted” is not particularly limited as long as the substitution is possible, and it is 1 or more. Unless otherwise specified, the explanation of each group applies also to the case where the group is a portion or the substituent of another group.
  • halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom and iodine atom.
  • alkyl group includes, for example, linear or branched alkyl groups of 1 to 6 carbon atoms. Specific examples thereof are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.
  • Preferable examples thereof are linear or branched alkyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
  • alkenyl group includes, for example, alkenyl groups of 2 to 6 carbon atoms. Specific examples thereof are vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl, etc.
  • alkynyl group includes, for example, alkynyl groups of 2 to 6 carbon atoms. Specific examples thereof are ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl, etc.
  • cycloalkyl group includes, for example, cycloalkyl groups of 3 to 10 carbon atoms. Specific examples thereof are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, etc. Preferable examples thereof are cycloalkyl groups of 3 to 6 carbon atoms. Specific examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • alkylene group includes, for example, alkylene groups of 1 to 3 carbon atoms. Specific examples thereof are methylene, ethylene, trimethylene, etc.
  • alkenylene group includes, for example, alkenylene groups of 2 to 4 carbon atoms. Specific examples thereof are vinylene, propenylene, butenylene, etc.
  • aryl group includes, for example, aryl groups of 6 to 10 carbon atoms. Specific examples thereof are phenyl, 1-naphthyl, 2-naphthyl, etc.
  • the “aralkyl group” includes, for example, groups formed by bonding of an aryl group to an alkylene group. Specific examples thereof are benzyl, 2-phenylethyl, 1-naphthylmethyl, etc.
  • heteroaryl group includes, for example, 5- to 10-membered monocyclic or polycyclic groups containing one or more (for example, 1 to 4) heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom.
  • specific examples thereof are pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl,
  • heteroaryl portion of the “heteroarylalkyl group” includes the groups exemplified above as the heteroaryl group.
  • alkylcarbonyl group includes, for example, alkylcarbonyl groups of 2 to 4 carbon atoms. Specific examples thereof are acetyl, propionyl, butyryl, etc.
  • cycloalkylcarbonyl group includes cycloalkylcarbonyl groups of 4 to 11 carbon atoms, and the like. Specific examples thereof are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, norbornylcarbonyl, etc. Preferable examples thereof are cycloalkylcarbonyl groups of 4 to 7 carbon atoms. Specific examples of such groups are cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • the “aroyl group” includes, for example, aroyl groups of 7 to 11 carbon atoms. Specific examples thereof are benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
  • heteroaryl portion of the “heteroarylcarbonyl group” includes the groups exemplified above as the heteroaryl group.
  • alkoxycarbonyl group includes, for example, alkoxycarbonyl groups of 2 to 5 carbon atoms. Specific examples thereof are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, etc.
  • aryloxycarbonyl group includes aryloxycarbonyl groups of 7 to 11 carbon atoms, and the like. Specific examples thereof are phenyloxycarbonyl, 2-naphthyloxycarbonyl, 1-naphthyloxycarbonyl, etc.
  • alkoxy group includes, for example, alkoxy groups of 1 to 4 carbon atoms. Specific examples thereof are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.
  • cycloalkyloxy group includes, for example, cycloalkyloxy groups of 3 to 10 carbon atoms. Specific examples thereof are cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, adamantyloxy, norbornyloxy, etc. Preferable examples thereof are cycloalkyloxy groups of 3 to 6 carbon atoms. Specific examples of such groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.
  • the cycloalkyloxy portion of the “cycloalkyloxycarbonyl group” includes the groups exemplified above as the cycloalkyloxy group.
  • aryloxy group includes, for example, aryloxy groups of 6 to 10 carbon atoms. Specific examples thereof are phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc.
  • the aralkyl portion of the “aralkyloxy group” includes the groups exemplified above as the aralkyl group. Specific examples thereof are benzyloxy, 2-phenylethyloxy, etc.
  • the aralkyl portion of the “aralkyloxycarbonyl group” includes the groups exemplified above as the aralkyl group.
  • heteroaryl portion of the “heteroaryloxy group” includes the groups exemplified above as the heteroaryl group.
  • alkylthio group includes, for example, alkylthio groups of 1 to 6 carbon atoms. Specific examples thereof are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc. Preferable examples thereof are alkylthio groups of 1 to 4 carbon atoms. Specific examples of such groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.
  • alkylsulfinyl group includes, for example, alkylsulfinyl groups of 1 to 6 carbon atoms. Specific examples thereof are methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc. Preferable examples thereof are alkylsulfinyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.
  • alkylsulfonyl group includes, for example, alkylsulfonyl groups of 1 to 6 carbon atoms. Specific examples thereof are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc. Preferable examples thereof are alkylsulfonyl groups of 1 to 4 carbon atoms. Specific examples of such groups are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, etc.
  • arylthio group includes, for example, arylthio groups of 6 to 10 carbon atoms. Specific examples thereof are phenylthio, 1-naphthylthio, 2-naphthylthio, etc.
  • arylsulfinyl group includes, for example, arylsulfinyl groups of 6 to 10 carbon atoms. Specific examples thereof are phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.
  • arylsulfonyl group includes, for example, arylsulfonyl groups of 6 to 10 carbon atoms. Specific examples thereof are phenylsulfonyl, tosyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.
  • the “nitrogen-containing saturated heterocyclic group” includes, for example, 5- or 6-membered saturated heterocyclic groups which have one or two nitrogen atoms and may further have an oxygen atom or a sulfur atom. Specific examples thereof are pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, etc.
  • the substituent(s) of the “optionally substituted alkyl group” includes, for example, (1) halogen atoms, (2) hydroxyl group, (3) cyano group, (4) carboxyl group, (5) optionally substituted cycloalkyl groups, (6) optionally substituted aryl groups, (7) optionally substituted heteroaryl groups, (8) optionally substituted aroyl groups, (9) optionally substituted heteroarylcarbonyl groups, (10) optionally substituted arylaminocarbonyl groups, (11) optionally substituted heteroarylaminocarbonyl groups, (12) optionally substituted aryloxy groups, (13) optionally substituted arylsulfonyl groups, (14) optionally substituted aralkylsulfonyl groups, (15) optionally substituted alkoxy groups, (16) optionally substituted cycloalkyloxy groups, (17) optionally substituted alkoxycarbonyl groups, (18) optionally substituted aryloxycarbonyl groups, (19) optionally substituted amino
  • substituents of the “optionally substituted cycloalkyl groups” of the above item (5) include, for example, alkyl groups, aralkyl groups, alkoxy groups, alkoxycarbonyl groups and fluorine atom.
  • substituents of the “optionally substituted aryl groups” of the above item (6) include those exemplified hereinafter as the substituent(s) of the “optionally substituted aryl group”.
  • the substituents of the “optionally substituted aroyl groups” of the above item (8) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).
  • the substituents of the “optionally substituted heteroarylcarbonyl groups” of the above item (9) include those exemplified as the substituents of the “optionally substituted heteroaryl groups” of the above item (7).
  • the substituents of the “optionally substituted arylaminocarbonyl groups” of the above item (10) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).
  • the substituents of the “optionally substituted heteroarylaminocarbonyl groups” of the above item (11) include those exemplified as the substituents of the “optionally substituted heteroaryl groups” of the above item (7).
  • substituents of the “optionally substituted aryloxy groups” of the above item (12) and the “optionally substituted arylsulfonyl groups” of the above item (13) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).
  • the aralkyl portion of the “optionally substituted aralkylsulfonyl group” of the above item (14) includes the groups exemplified above as the aralkyl group.
  • substituents of the “optionally substituted aralkylsulfonyl groups” include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).
  • substituents of the “optionally substituted alkoxy groups” of the above item (15) include, for example,
  • substituents of the “optionally substituted cycloalkyloxy groups” of the above item (16) and the “optionally substituted alkoxycarbonyl groups” of the above item (17) include those exemplified as the substituents of the “optionally substituted alkoxy groups” of the above item (15).
  • the substituents of the “optionally substituted aryloxycarbonyl groups” of the above item (18) include those exemplified as the substituents of the “optionally substituted aryl groups” of the above item (6).
  • alkyl groups (a) alkyl groups, (b) alkylcarbonyl groups, (c) aroyl groups, (d) alkylsulfonyl groups, (e) arylsulfonyl groups, (f) optionally substituted aryl groups (their substituents include, for example, halogen atoms, alkyl groups and alkoxy groups), (g) alkoxycarbonylmethyl groups (the carbon atom of the methyl portion may be substituted by one or two alkyl groups, and the two alkyl groups on the carbon atom of the methyl portion may bind to each other to form cyclopropyl, cyclobutyl or cyclopentyl together with the carbon atom of the methyl portion), and (h) aralkyl groups.
  • the substituents of the “optionally substituted carbamoyl groups” of the above item (20) include, for example, alkyl groups and cycloalkyl groups.
  • the two substituents of the carbamoyl group may bind to each other to form an aliphatic heterocyclic ring which may contain carbon atoms, a nitrogen atom(s) and/or an oxygen atom(s), such as pyrrolidine (which may be substituted by a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by methyl or ethyl), or the like.
  • carbamoyl groups are carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, cyclopropylcarbamoyl, cyclopropylmethylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.
  • substituents of the “optionally substituted alkylcarbonyl groups” of the above item (22) include, for example,
  • each of the “optionally substituted alkylthio group”, “optionally substituted alkylsulfinyl group” and “optionally substituted alkylsulfonyl group” includes those exemplified as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • each of the “optionally substituted alkenyl group” and the “optionally substituted alkynyl group” includes, for example,
  • alkoxy group(s) which may be substituted by a halogen atom(s) or an alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy),
  • a halogen atom(s) for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluor
  • cyano group (9) carboxyl group, (10) alkoxycarbonyl groups, (11) carbamoyl groups which may be substituted by an alkyl group(s) (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl), (12) alkylsulfonyl groups, and (13) phenyloxy group.
  • alkyl group(s) for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl
  • alkylsulfonyl groups for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl
  • phenyloxy group for example, carbamoyl,
  • the substituent(s) of the “optionally substituted vinyl group” includes, for example, halogen atoms and alkyl groups.
  • substituted vinyl groups are 1-propylene, 2-methyl-1-propylene, 2-chloro-1-propylene, etc.
  • the substituent(s) of the “optionally substituted cycloalkyl groups” includes those exemplified as the substituents of (5) the “optionally substituted cycloalkyl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • the substituent(s) of the “optionally substituted aryl group” includes, for example,
  • hydroxyl group (2) halogen atoms, (3) alkyl groups, (4) alkyl groups substituted by a halogen atom(s), an alkoxy group or a cycloalkyl group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropyl), (5) phenyl groups which may be substituted by the following (aa), (bb) or (cc):
  • alkoxy group(s) which may be substituted by a halogen atom(s) or an alkoxy group (for example, methioxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy),
  • a halogen atom(s) for example, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluor
  • alkoxycarbonyl groups which may be substituted by a halogen atom(s) (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, fluoromethoxycarbonyl, difluoromethoxycarbonyl, 2,2-difluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, methoxycarbonyl and ethoxycarbonyl), (9) carbamoyl groups which may be substituted by an alkyl group(s) (for example, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl), (10) alkylsulfonyl groups, (11) C
  • methoxycarbonylmethyl, ethoxycarbonylmethyl or isopropoxycarbonylmethyl an alkyl group, a fluoroalkyl group (e.g. fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or perfluoroethyl), an alkoxyalkyl group (e.g. methoxymethyl, ethoxymethyl or isopropoxymethyl), a cycloalkyloxyalkyl group (e.g.
  • alkoxy groups which may be substituted by a hydroxyl group, an oxo group, a carboxyl group, an alkoxycarbonyl group, a cycloalkyl group, an alkoxy group, a cycloalkyloxy group, an optionally substituted oxygen-containing heterocyclic group (e
  • the substituent(s) includes, for example, halogen atoms, oxo group and alkoxy groups), or a halogen atom(s) (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-hydroxyethoxy, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, cyclopropylmethoxy, cyclobutylmethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, isopropoxymethoxy, cyclopropyloxymethoxy, cyclobutoxymethoxy
  • alkylcarbonyloxy groups for example, methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy
  • cycloalkyl groups which may be substituted by a fluorine atom (for example, cyclopropyl, cyclobutyl, cyclopentyl, 2-fluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutylcyclobutyl, adamantyl and norbornyl),
  • cycloalkylcarbonyl groups which may be substituted by a fluorine atom (for example, cyclopropylcarbonyl, 2-fluorocyclopropylcarbonyl, cyclobutylcarbonyl and cyclopentylcarbonyl)
  • alkylthio groups for example, cyclopropylcarbonyl, 2-fluorocyclopropylcarbonyl, cyclobutylcarbonyl and cyclopentylcarbon
  • R T is absent or one or more R T s are present and are independently a halogen atom, a hydroxyl group, an oxo group, a carboxyl group, an optionally substituted alkyl group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted alkoxycarbonyl group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted alkoxy group (its substituent(s) includes, for example, halogen atoms and alkoxy groups), an optionally substituted carbamoyl group (its substituent(s) includes, for example, alkyl groups), or a saturated heterocyclic group oxycarbonyl group (the saturated heterocyclic group includes, for example, 5- or 6-membered saturated heterocyclic groups having an oxygen atom(s), a nitrogen atom(s) and/or a sulfur atom(s), each in a number of 1 or 2, specific examples of which
  • the substituent(s) of the “optionally substituted alkylcarbonyl group” includes those exemplified as the substituents of (22) the “optionally substituted alkylcarbonyl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • the substituent(s) of the “optionally substituted cycloalkylcarbonyl group” includes, for example, halogen atoms and alkoxy groups.
  • each of the “optionally substituted alkoxy group” and the “optionally substituted alkoxycarbonyl group” includes those exemplified as the substituents of (15) the “optionally substituted alkoxy groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • each of the “optionally substituted cycloalkyloxy group” and the “optionally substituted cycloalkyloxycarbonyl group” includes those exemplified as the substituents of (16) the “optionally substituted cycloalkyloxy groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • the substituent(s) of the “optionally substituted amino group” includes those exemplified as the substituents of (19) the “optionally substituted amino groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • the substituent(s) of the “optionally substituted carbamoyl group” includes, for example,
  • optionally substituted alkyl groups include, for example, hydroxyl group, halogen atoms, alkoxy groups optionally substituted by a halogen atom(s), cycloalkoxy groups optionally substituted by a halogen atom(s), and tetrahydrofuranyl
  • substituents include, for example, hydroxyl group, halogen atoms, alkoxy groups optionally substituted by a halogen atom(s), cycloalkoxy groups optionally substituted by a halogen atom(s), and tetrahydrofuranyl
  • cycloalkyl groups which may be substituted by a halogen atom(s)
  • aryl groups which may be substituted by the following (aa), (bb), (cc) or (dd):
  • a halogen atom(s) for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroe
  • (cc) an alkyl group(s) which may be substituted by a halogen atom(s) (for example, methyl, ethyl, propyl, isopropyl, butyl, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-1-(fluoromethyl)ethyl and 1-(difluoromethyl)-2,2-difluoroethyl),
  • a halogen atom(s) for example, methyl, ethyl, propyl, isopropyl, butyl, methyl, ethyl, propyl, isopropyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroeth
  • alkylsulfonyl groups (5) cycloalkylsulfonyl groups, (6) optionally substituted arylsulfonyl groups (their substituents include, for example, halogen atoms, alkyl groups, haloalkyl groups, alkoxy groups and haloalkoxy groups), (7) alkylcarbonyl groups, (8) alkoxycarbonyl groups, (9) optionally substituted aroyl groups (their substituents include, for example, halogen atoms, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkoxycarbonyl groups and C 1-3 alkylenedioxy groups), (10) cycloalkylalkyl groups, (11) isoxazolyl group, and (12) optionally substituted adamantyl groups (their substituents include, for example, hydroxyl group).
  • carbamoyl group examples include carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, phenylcarbamoyl, phenylmethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopropylmethylcarbamoyl, cyclohexylmethylcarbamoyl, 2,3-dihydroxypropylcarbamoyl, tetrahydrofuranylalkylcarbamoyl, methoxyethylcarbamoyl, trifluoroethylcarbamoyl, adamantylcarbamoyl, hydroxyadamantylcarbamoyl, etc.
  • the two substituents of the carbamoyl group may bind to each other to form a 4- to 6-membered aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen or sulfur, such as pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by methyl, ethyl or propyl), or the like, and the carbamoyl group may be further substituted by a hydroxyl group.
  • a 4- to 6-membered aliphatic heterocyclic ring which may contain carbon, nitrogen, oxygen or sulfur, such as pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by methyl, ethyl or propyl), or the like, and the carbamoy
  • Such a substituted carbamoyl group are pyrrolidinocarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, 4-hydroxypiperidinocarbamoyl, etc.
  • the substituent(s) of the “optionally substituted nitrogen-containing saturated heterocyclic group” includes, for example,
  • halogen atoms (2) alkyl groups, (3) alkyl groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, perfluoroethyl and methoxyethyl), (4) alkoxy groups, (5) alkoxy groups substituted by a halogen atom(s) or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy), (6) cyano group, and (7) oxo group.
  • alkoxy group for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroeth
  • R 6 s, R 7 s, R 8 s or R 9 s When two R 6 s, R 7 s, R 8 s or R 9 s are present, they may be present on one and the same carbon atom or may be present on different carbon atoms, respectively.
  • haloalkoxy group includes, for example, alkoxy groups of 1 to 4 carbon atoms substituted by a halogen atom(s). Specific examples thereof are fluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.
  • haloalkyl group includes, for example, alkyl groups of 1 to 4 carbon atoms substituted by a halogen atom(s). Specific examples thereof are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, perfluoroethyl, etc.
  • the “C 1-3 alkylenedioxy group” includes, for example, methylenedioxy, ethylenedioxy and trimethylenedioxy.
  • the “substituted alkyl group” for R 4b includes, for example, alkyl groups of 1 to 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Specific examples thereof are benzyl, p-chlorobenzyl, p-methoxybenzyl, p-fluorobenzyl, cyclopentylmethyl, cyclohexymethyl, etc.
  • the “substituted alkenyl group” for R 4b includes, for example, alkenyl groups of 2 or 3 carbon atoms substituted by a cycloalkyl group of 5 to 7 carbon atoms (e.g. cyclopentyl, cyclohexyl or cycloheptyl) or an aryl group (e.g. phenyl group). Examples thereof are vinyl, propenyl, allyl, isopropenyl, etc., which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
  • alkenyloxy group for R 4b includes, for example, linear or branched alkenyloxy groups of 2 to 8 carbon atoms. Specific examples thereof are allyloxy, isobutenyloxy, etc.
  • the “substituted alkoxy group” for R 4b includes, for example, alkoxy groups of 1 to 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Specific examples thereof are benzyloxy, phenethyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclopentylmethyloxy, etc.
  • the “substituted alkenyloxy group” for R 4b includes, for example, alkenyloxy groups of 2 or 3 carbon atoms substituted by a cycloalkyl group of 3 to 7 carbon atoms (e.g. cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or an optionally substituted aryl group (e.g. phenyl group). Examples thereof are vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc., which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
  • R 4b Specific examples of the “optionally substituted aryloxy group” for R 4b are phenoxy, p-nitrophenoxy, p-methoxyphenoxy, p-fluorophenoxy, naphthoxy, etc.
  • each of the “optionally substituted alkyl group” and the “optionally substituted alkoxy group” for Rc includes, for example, halogen atoms, alkoxy groups and cycloalkyl groups.
  • the substituent(s) of the “optionally substituted heteroarylamino group” for Rc includes those exemplified as the substituents of (7) the “optionally substituted heteroaryl groups” as the substituent(s) of the above-mentioned “optionally substituted alkyl group”.
  • alkylene group for Rd, there are exemplified the above-exemplified ones, preferably methylene.
  • alkenylene group for Rd, there are exemplified the above-exemplified ones, preferably vinylene.
  • prodrug there are exemplified those which can easily be hydrolyzed in a living body to regenerate the compound (1) of the present invention.
  • Specific examples thereof are compounds obtained by converting the amino group of the compound represented by the formula (I) to —NHQ X .
  • Q X the following are exemplified as Q X :
  • R 33 is a hydrogen atom, an alkyl group or an optionally substituted aryl group
  • R 34 and R 35 are independently a hydrogen atom or an alkyl group
  • R 36 is a hydrogen atom, an alkyl group, an aryl group or a benzyl group
  • R 37 is an alkyl group or a benzyl group.
  • Preferable examples of Q X are the group of (1) and the groups of (3).
  • Preferable examples of the groups of (3) are groups in which R 34 is a hydrogen atom, R 35 is a hydrogen atom, methyl or ethyl and R 36 is methyl or ethyl.
  • R 34 is a hydrogen atom
  • R 35 is a hydrogen atom
  • R 36 is methyl or ethyl.
  • the prodrug may be one which is converted to the original compound under physiological conditions, such as those described in “Development of Medicines Vol. 7, Molecular Design”, pp. 163-198, Hirokawa Shoten, 1990.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc.
  • organic acid salts such as acetic acid salt, propionic acid salt, oxalic acid salt, succinic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, maleic acid salt, fumaric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt, ascorbic acid salt, etc.
  • the present invention includes compounds represented by the formula (I), prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs.
  • the present invention also includes their hydrates or solvates (e.g. ethanol solvates).
  • the present invention includes all tautomers, all existing stereoisomers and all crystal forms of the compound (1) of the present invention.
  • bicyclic pyrrole derivatives are more preferable in which the amino group at the 3-position is in an absolute configuration represented by the following formula (F 1 ):
  • a bond shown by a wedge-shaped solid line or broken line as in the formula (J 1 ) and formula (J 2 ) indicates an absolute configuration relating to an amino group
  • a bond shown by a thick line as in the formula (J 3 ) indicates a relative configuration relating to an amino group (for example, the formula (J 3 ) represents a ( ⁇ )-cis form).
  • the compound represented by the formula (I) may be synthesized from a well-known compound by a combination of well-known synthesis processes. It may be synthesized, for example, by any of the following processes.
  • a compound represented by the formula (1-17) or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 29 , m 1 , m 2 , m 3 , m 4 and m 5 are as defined above;
  • X 1 is a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy);
  • R 51 is Alloc, N ⁇ C(Ph) 2 , NHBoc, NHCbz or the following formula (G1):
  • R 52 is Alloc, Boc or Cbz; and Y 1 is the protected state of the primary or secondary amino group in Y described in the item [1].
  • a compound (1-8) may be produced by reacting a compound (1-1) with a compound selected from a compound (1-2), a compound (1-3), a compound (1-4), a compound (1-5), a compound (1-6) and a compound (1-7) in an inert solvent in the presence or absence of a base.
  • the base includes, for example, organic bases (e.g.
  • 1-hydroxybenzotriazole N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline), and inorganic bases (e.g. sodium ethoxide, sodium methoxide, potassium tert-butoxide and sodium hydride). The amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-1).
  • the amount of the compound (1-2), compound (1-3), compound (1-4), compound (1-5), compound (1-6) or compound (1-7) used is usually chosen in the range of 1 to 2 equivalents per equivalent of the compound (1-1).
  • the inert solvent includes, for example, alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (tetrahydrofuran and 1,4-dioxane), and mixed solvents thereof.
  • the reaction temperature may be chosen in the range of about 50° C. to about 120° C.
  • the compound (1-2) may be produced by the process described in the production process 19 described hereinafter, the compound (1-3) by the process described in the production process 20 described hereinafter, and the compound (1-5) by the process described in the production process 21 described hereinafter.
  • the compound (1-6) a commercial reagent may be used, or the compound (1-6) may be produced by the process described in literature (for example, Synthesis 391 (1994), Org. Lett. 5, 1591 (2003), Synthesis 1065 (1992), Synlett 755 (2002), J. Org. Chem. 56, 3063 (1991), J. Org. Chem. 60, 4177 (1995) and J. Org. Chem. 57, 6653 (1992)).
  • the compound (1-7) may be produced by the same process as that described in literature (for example, J. Org. Chem. 61, 6700 (1996)) or the like.
  • a compound (1-10) is produced by reacting the compound (1-8) with a compound (1-9) in an inert solvent.
  • the amount of the compound (1-9) used is usually chosen in the range of 1 equivalent to excess equivalents per equivalent of the compound (1-8).
  • the inert solvent includes, for example, organic bases (e.g.
  • 1-hydroxybenzotriazole N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline), alcohol solvents (e.g. methanol, ethanol and 2-propanol), acetic acid, and mixed solvent thereof.
  • the reaction temperature is chosen in the range of about 50° C. to about 150° C. and the reaction is usually carried out with refluxing.
  • a compound (1-12) may be produced by reacting the compound (1-10) with a compound (1-11) in an inert solvent in the presence or absence of a base (see, for example, J. Heterocycl. Chem. 37, 1033 (2000), J. Chem. Soc., Perkin Trans. 1, 13, 1833 (1999) and J. Med. Chem. 38, 3838 (1995)).
  • the amount of the compound (1-11) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-10).
  • the base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydrides (e.g.
  • the inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof. Suitable examples thereof are N,N-dimethylformamide and dimethyl sulfoxide.
  • the reaction temperature may be chosen in the range of about 10° C. to about 180° C.
  • a compound (1-13) may be produced by reacting the compound (1-12) with a base in an inert solvent (see, for example, WO02/068420).
  • the base includes alkali hydrides (e.g. sodium hydride and potassium hydride) and the like. A suitable example thereof is sodium hydride.
  • the amount of the base used is usually chosen in the range of 1 to 3 equivalents per equivalent of the compound (1-12).
  • the inert solvent includes N,N-dimethylformamide, ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), and mixed solvents thereof.
  • a suitable example thereof is tetrahydrofuran.
  • the reaction temperature may be chosen in the range of about 10° C. to about 100° C.
  • a compound (1-15) may be produced from the compound (1-13) by carrying out the following reactions (1) to (3).
  • the compound (1-13) is reacted with a compound (1-14) in pyridine in the presence of a base.
  • the reaction temperature may be chosen in the range of about 50° C. to about 160° C.
  • the amount of the compound (1-14) used is usually chosen in the range of 1 to 5 equivalents.
  • a base is added to the reaction mixture obtained in the above item (1) and the reaction is carried out.
  • the base includes cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • the amount of the base used is usually chosen in the range of 1 to 5 equivalents.
  • the reaction temperature is chosen in the range of about 50° C. to about 160° C.
  • Methyl iodide is added to the reaction mixture obtained in the above item (2) and the reaction is carried out.
  • the amount of methyl iodide used is usually chosen in the range of 1 to 5 equivalents.
  • the reaction temperature is chosen in the range of about 10° C. to about 40° C.
  • Production process (A) A compound (1-16) may be produced by reacting the compound (1-15) with a mixture of sodium tungstate and an aqueous hydrogen peroxide solution in an inert solvent.
  • the inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), organic acids (e.g. acetic acid and propionic acid), etc.
  • a mixed solvent of the alcohol solvent and the organic acid is usually used as the inert solvent.
  • the amount of sodium tungstate used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (1-15).
  • a compound (1-16) may be produced by reacting the compound (1-15) with Oxon (a registered trade name; Aldrich) in an inert solvent.
  • the inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), etc.
  • the amount of Oxon (a registered trade name; Aldrich) used is usually chosen in the range of 1 to 20 equivalents per equivalent of the compound (1-15).
  • the reaction temperature may be chosen in the range of about ⁇ 10° C. to about 70° C.
  • the compound (1-17) may be produced from the compound (1-16) by the same process as in the step 2 described in production process 2.
  • R 1 , R 2 , R 4 , X 1 , Y 1 and Y are as defined above.
  • a compound (2-1) may be produced by reacting a compound (1-16) with a base in an inert solvent.
  • the base includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, etc. A suitable example thereof is sodium hydroxidec.
  • the amount of the base used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (1-16).
  • the inert solvent includes, for example, water, alcohol solvents (e.g. methanol, ethanol and 2-propanol), tetrahydrofuran, and mixed solvents thereof.
  • the reaction temperature is chosen in the range of about 50° C. to about 100° C.
  • a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases.
  • the compound (2-1) in which the primary amino group or secondary amino group in Y has been protected again with a protective group may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).
  • the compound (2-2) may be produced from the compound (2-1) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.
  • a compound (2-4) may be produced by reacting the compound (2-1) with a compound (2-3) in an inert solvent in the presence of a base.
  • the amount of the compound (2-3) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (2-1).
  • the base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydrides (e.g. sodium hydride and potassium hydride), and alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide).
  • alkali carbonates e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate
  • alkali hydrides e.g. sodium hydride and potassium hydride
  • alkali hydroxides e.g. potassium hydroxide and sodium hydroxide
  • a suitable example thereof is potassium carbonate.
  • the amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent
  • the inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof.
  • aprotic solvents e.g. N,N-dimethylformamide and dimethyl sulfoxide
  • ether solvents e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane
  • ketones e.g. acetone
  • mixed solvents thereof e.g. N,N-dimethylformamide.
  • the reaction temperature may be chosen in the range of about 0° C. to about 180° C.
  • the compound (2-5) may be produced from the compound (2-4) by the same process as in the above step 2.
  • a compound of the formula (3-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , Y 1 and Y are as defined above, and R 54 O is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group” or “an optionally substituted cycloalkyloxy group”.
  • a compound (3-2) may be produced by reacting a compound (1-16) with a compound (3-1) in an inert solvent in the presence of a base.
  • the base includes potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenoxide, potassium phenoxide, sodium hydride, etc.
  • a suitable example thereof is sodium hydride.
  • the amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (3-1).
  • the inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc.
  • the reaction temperature may be chosen in the range of about ⁇ 10° C. to about 50° C.
  • the compound (3-3) may be produced from the compound (3-2) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (4-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , Y 1 and Y are as defined above, and R 55 s is “an optionally substituted alkylthio group” or “an optionally substituted arylthio group”.
  • a compound (4-2) may be produced from a compound (1-16) by the same process as in the step 1 described in production process 3.
  • the compound (4-3) may be produced from the compound (4-2) by the same process as in the step 2 described in production process 2.
  • R 1 , R 2 , Y 1 and Y are as defined above.
  • a compound (5-1) may be produced by reacting a compound (1-16) with sodium cyanide or potassium cyanide in an inert solvent.
  • the amount of sodium cyanide or potassium cyanide used is usually chosen in the range of 0.8 to 5 equivalents per equivalent of the compound (1-16).
  • the inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc.
  • the reaction temperature may be chosen in the range of about 10° C. to about 100° C.
  • the compound (5-2) may be produced from the compound (5-1) by the same process as in the step 2 described in production process 2.
  • a compound (5-3) may be produced by reacting the compound (5-1) with an aqueous hydrogen peroxide solution in an inert solvent in the presence of a base.
  • the base includes, for example, inorganic bases such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.
  • the amount of the base used is usually chosen in the range of 0.5 to 10 equivalents per equivalent of the compound (5-1).
  • the amount of the aqueous hydrogen peroxide solution used is usually chosen in the range of 1 to 20 equivalents per equivalent of the compound (5-1).
  • the inert solvent includes dimethyl sulfoxide, acetone, etc. A suitable example thereof is dimethyl sulfoxide.
  • the reaction temperature may be chosen in the range of about 1° C. to about 100° C.
  • the compound (5-4) may be produced from the compound (5-3) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (6-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , Y 1 and Y are as defined above, and R 56 R 57 N is “an optionally substituted nitrogen-containing saturated heterocyclic group” or “an optionally substituted amino group”.
  • a compound (6-2) may be produced by reacting a compound (1-16) with a compound (6-1) in the presence or absence of an inert solvent.
  • the amount of the compound (6-1) used is usually chosen in the range of 1 to 100 equivalents per equivalent of the compound (1-16).
  • the inert solvent includes alcohol solvents (e.g. ethanol, methanol and 2-propanol), etc.
  • the reaction temperature may be chosen in the range of about 50° C. to about 150° C.
  • the compound (6-3) may be produced from the compound (6-2) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (7-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 18 is “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted heteroarylalkyl group” or “an optionally substituted aralkyl group”; and M 1 is lithium, magnesium chloride or magnesium bromide.
  • a compound (7-2) may be produced by reacting a compound (1-16) with a compound (7-1) in an inert solvent.
  • the amount of the compound (7-1) used is usually chosen in the range of 1 to 10 equivalents per equivalent of the compound (1-16).
  • the inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc.
  • the reaction temperature may be chosen in the range of about ⁇ 10° C. to about 50° C.
  • the compound (7-3) may be produced from the compound (7-2) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (8-3) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , Y 1 and Y are as defined above, and R 59 C(O) is “an optionally substituted aroyl group”, “an optionally substituted heteroarylcarbonyl group” or “an optionally substituted alkylcarbonyl group”.
  • a compound (8-2) may be produced by reacting a compound (1-16) with a compound (8-1) in an inert solvent in the presence of a base.
  • the amount of the compound (8-1) used is usually chosen in the range of 1 to 10 equivalents per equivalent of the compound (1-16).
  • the base includes sodium hydride, etc.
  • the inert solvent includes tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixed solvents thereof, etc.
  • the reaction temperature may be chosen in the range of about 50° C. to about 150° C.
  • the compound (8-3) may be produced from the compound (8-2) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (9-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , R 4 , Y 1 and Y are as defined above, and X 3 is a leaving group (e.g. an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy).
  • X 3 is a leaving group (e.g. an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy).
  • R 2 in the item [4] is a group of any of the formula (E), formula (F), formula (G) and formula (H), a compound (9-1) may be produced from a compound (2-4) by the following process 1.
  • a compound (9-1) may be produced by reacting a compound (2-4) with an acid in an inert solvent.
  • the acid includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • a suitable example thereof is sulfuric acid.
  • the amount of the acid used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (2-4).
  • the inert solvent includes water and the like.
  • the reaction temperature is chosen in the range of about 50° C. to about 200° C.
  • a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases.
  • the compound (9-1) in which the primary amino group or secondary amino group in Y has been protected again with a protective group may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).
  • R 2 in the item [4] is a group of either the formula (I) or the formula (J)
  • a compound (9-1) may be produced from a compound (2-4) by the following process 2 [(1) (2)].
  • R 2 of the compound (2-4) is removed by the same method as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.), Tetrahedron 27, 5523 (1971) and Aus. J. Chem. 22, 1321 (1969)) or the like.
  • a compound (9-3) may be produced from the compound (9-1) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, Bioorg. Med. Chem. Lett. 11, 1993 (2001), Organic Letters 4, 4033 (2002), Organic Letters 5, 4987 (2003), Synlett 128 (2004), and J. Am. Chem. Soc. 124, 116847 (2002)) or the like.
  • R 2 in the item [4] is a group of any of the formula (E), formula (F), formula (G) and formula (H), a compound (9-3) may be produced from the compound (9-1) by the same process as in the step 3 described in production process 1.
  • the compound (9-4) may be produced from the compound (9-3) by the same process as in the step 2 described in production process 2.
  • R 1 , R 2 , X 3 , Y 1 and Y are as defined above, and R 60 is the above-mentioned R 54 O, R 55 S or R 56 R 57 N.
  • a compound (10-1) may be produced from a compound (2-1) by the same process as in the step 1 described in production process 9.
  • a compound (10-2) may be produced from the compound (10-1) by the same production process as described in literature (for example, WO03/104229 and Chem. Pharm. Bull. 50, 1163 (2002)).
  • a compound (10-3) may be produced from the compound (10-2) by the same process as in the step 2 described in production process 9.
  • a compound (10-5) may be produced from the compound (10-3) by the same process as in the step 1 described in production process 3, the step 1 described in production process 4 or the step 1 described in production process 6.
  • the compound (10-6) may be produced from the compound (10-5) by the same process as in the step 2 described in production process 2.
  • a compound (10-7) may be produced from the compound (10-3) by the same process as in the step 1 described in production process 5.
  • the compound (10-8) may be produced from the compound (10-7) by the same process as in the step 2 described in production process 2.
  • a compound (10-9) may be produced from the compound (10-7) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, WO03/104229 and WO03/104229).
  • a compound in which a protective group for the primary amino group or secondary amino group in Y has been removed is produced in some cases.
  • the compound (10-9) in which the primary amino group or secondary amino group in Y has been protected again with a protective group may be produced by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).
  • the compound (10-10) may be produced from the compound (10-9) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (11-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 1 , R 2 , Y 1 and Y are as defined above, and R 61 is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group”, “an optionally substituted cycloalkyloxy group”, “an optionally substituted alkylthio group”, “an optionally substituted arylthio group”, cyano, “an optionally substituted nitrogen-containing saturated heterocyclic group”, “an optionally substituted amino group”, “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted heteroarylalkyl group”, “an optionally substituted aralkyl group”, “an optionally substituted aroyl group”, “an optionally substituted heteroarylcarbonyl group
  • a compound (11-1) may be produced by reacting a compound (10-3) with sodium methanethiol in an inert solvent in the presence or absence of a base.
  • the base includes, for example, inorganic bases such as sodium hydride, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.; and organic bases such as 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc.
  • the amount of the base used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (10-3).
  • the amount of sodium methanethiol used is usually chosen in the range of 1 equivalent to large-excess equivalents per equivalent of the compound (10-3).
  • the inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof.
  • the reaction temperature may be chosen in the range of about 10° C. to about 120° C.
  • a compound (11-2) may be produced from the compound (11-1) by the same process as in the step 6 described in production process 1.
  • a compound (11-3) may be produced from the compound (11-2) by the same process as in the step 1 described in production process 3, the step 1 described in production process 4, the step 1 described in production process 5, the step 1 described in production process 6, the step 1 described in production process 7 or the step 1 described in production process 8.
  • the compound (11-4) may be produced from the compound (11-3) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (12-1) includes the compound (9-3) described in production process 9 and the compound (11-3) described in production process 11;
  • L1 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;
  • R 62 is “an optionally substituted alkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted alkynyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted aralkyl group” or “an optionally substituted heteroarylalkyl group”.
  • a compound (12-2) may be produced from a compound (12-1) by the same production process as described in literature (for example, Synth. Commun. 33, 2671 (2003), Tetrahedron Letters 42, 863 (2001), Synthesis 926 (1995), Tetrahedron Letters 37, 1095 (1996), J. Org. Chem. 64, 5366 (1999), Indian J. Chem., Sect B 35, 141 (1996) and J. Heterocycl. Chem. 24, 1313 (1987)).
  • the compound (12-3) may be produced from the compound (12-2) by the same process as in the step 2 described in production process 2.
  • a compound (12-4) may be produced from the compound (12-2) by the same production process as described in literature (for example, Chem. Rev. 95, 2457 (1995), Chem. Rev. 103, 1979 (2003), Chem. Rev. 100, 3009 (2000), Organic Process Research & Development 5, 254 (2001), J. Med. Chem. 45, 999 (2002), Synthesis 563 (1997), J. Org. Chem. 65, 9001 (2000), J. Org. Chem. 64, 4196 (1999), J. Org. Chem. 67, 3904 (2002), Adv. Synth. Catal. 345, 620 (2003) and J. Med. Chem. 43, 675 (2000)).
  • the compound (12-5) may be produced from the compound (12-4) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (13-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • a 1 , A 2 , R 1 , R 2 , M, Y 1 and Y are as defined above; a compound of the formula (12-1) is as described above; and R 63 is “an optionally substituted alkyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group” or “an optionally substituted heteroaryl group”.
  • a compound (13-1) may be produced from a compound (12-1) by the same production process as described in literature (for example, J. Heterocycl. Chem. 30, 957 (1993), Chem. Pharm. Bull. 42, 237 (1994), Aust. J. Chem. 47, 1009 (1994) and J. Heterocycl. Chem. 12, 517 (1975)).
  • a compound (13-3) may be produced from the compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • a commercial one may be used, or the compound (13-2) may be produced by the process described, for example, in Japanese Chemical Association, Jikken Kagaku Koza (Experimental Chemistry) Vol. 25, Maruzen Co., Ltd.
  • the compound (13-4) may be produced from the compound (13-3) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (14-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • a 1 , A 2 , R 1 , R 2 , R 63 , Y 1 and Y are as defined above.
  • a compound (14-1) may be produced from a compound (13-3) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • the compound (14-2) may be produced from the compound (14-1) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (15-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 64 O is “an optionally substituted alkoxy group”, “an optionally substituted aryloxy group”, “an optionally substituted aralkyloxy group”, “an optionally substituted heteroaryloxy group” or “an optionally substituted cycloalkyloxy group”; and
  • X 2 is a hydroxyl group or a leaving group (e.g. an iodine atom, a bromine atom, a chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy).
  • a compound (15-3) may be produced from a compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), Organic Reactions (New York) 42, 335-656 (1992), Tetrahedron Lett. 44, 4873 (2003) and J. Am. Chem. Soc. 125, 4978 (2003)).
  • the compound (15-4) may be produced from the compound (15-3) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (16-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • a 1 , A 2 , R 1 , R 2 , R 63 , Y 1 and Y are as defined above.
  • a compound (16-1) may be produced from a compound (13-3) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), J. Org. Chem. 65, 6179 (2000), J. Org. Chem. 58, 6913 (1993), Bull. Chem. Soc. Jpn. 67, 1107 (1994) and J. Org. Chem. 60, 2430 (1995).
  • the compound (16-2) may be produced from the compound (16-1) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (17-2) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 65 C(O) is a carboxyl group, “an optionally substituted carbamoyl group”, “an optionally substituted alkoxycarbonyl group”, “an optionally substituted aryloxycarbonyl group”, “an optionally substituted aralkyloxycarbonyl group”, “an optionally substituted cycloalkyloxycarbonyl group”, “an optionally substituted alkylcarbonyl group”, “an optionally substituted heteroarylcarbonyl group”, “an optionally substituted aroyl group” or “an optionally substituted cycloalkylcarbonyl group”.
  • a compound (17-1) may be produced from a compound (13-1) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989) and A. Hassner et al., Organic Synthesis Based On Name Reactions And Unnamed Reactions, Elsevier Science Ltd., (1994)).
  • the compound (17-2) may be produced from the compound (17-1) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (18-4) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • a 1 , A 2 , R 1 , R 2 , R 3 , X 1 , Y 1 and Y are as defined above;
  • CO 2 H shown in a compound (18-1) indicates that R 3 or R 4 shown in the formula (I) is a carboxyl group or that a carboxyl group is present in the partial structure of R 3 , R 4 or R 5 ;
  • CO 2 R 66 shown in a compound (18-3) and the compound (18-4) indicates a state in which the CO 2 H of the compound (18-1) has been converted to CO 2 R 66 , and specifically, CO 2 R 66 indicates, for example, the formula: C(O)O—Re wherein Re is as defined above.
  • a compound (18-3) may be produced by reacting a compound (18-1) with a compound (18-2) in an inert solvent in the presence of a base.
  • the amount of the compound (18-2) used is usually chosen in the range of 1 to 3 equivalents per equivalent of the compound (18-1).
  • the base includes, for example, alkali carbonates (e.g. potassium carbonate, sodium carbonate, potassium hydrogencarbonate and sodium hydrogencarbonate), alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide), alkali hydrides (e.g. sodium hydride and potassium hydride), and alkoxyalkalis (e.g. potassium tert-butoxide). Suitable examples thereof are potassium carbonate and sodium hydride.
  • the amount of the base used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (18-1).
  • the inert solvent includes, for example, aprotic solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide), ether solvents (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), and mixed solvents thereof.
  • a suitable example thereof is N,N-dimethylformamide.
  • the reaction temperature may be chosen in the range of about 10° C. to about 100° C.
  • the compound (18-2) a commercial reagent may be used, or the compound (18-2) may be produced by the same production process as described in literature (for example, WO03/027098, WO00/06581, and R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • the compound (18-4) may be produced from the compound (18-3) by the same process as in the step 2 described in production process 2.
  • the compound (1-2) described in production process 1 may be produced, for example, by the following process:
  • a compound (19-2) may be produced from a compound (19-1) by the same production process as described in literature (for example, J. Org. Chem. 58, 879 (1993)).
  • the compound (1-2) may be produced from the compound (19-2) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.
  • the compound (1-3) described in production process 1 may be produced, for example, by the following process:
  • R 80 is an alkyl group.
  • a compound (20-2) may be produced by reacting a compound (20-1) with thionyl chloride in an alcohol solvent.
  • the alcohol solvent includes methanol, ethanol, etc.
  • the amount of thionyl chloride used is usually chosen in the range of 2 to 10 equivalents per equivalent of the compound (20-1).
  • the reaction temperature may be chosen in the range of about ⁇ 90° C. to about 30° C.
  • a compound (20-3) may be produced by reacting the compound (20-2) with a base in water solvent.
  • the base includes sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.
  • the reaction temperature may be chosen in the range of about 30° C. to about 100° C.
  • a compound (20-4) may be produced from the compound (20-3) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.
  • the compound (1-3) may be produced by reacting the compound (20-4) with a reducing agent in an inert solvent.
  • the reducing agent includes aluminum lithium hydride, borane complexes (e.g. borane-dimethyl sulfide complexes and borane-tetrahydrofuran complexes) and the like.
  • the inert solvent includes tetrahydrofuran, 1,4-dioxane, mixed solvents thereof, and the like.
  • the reaction temperature is chosen in the range of about ⁇ 20° C. to about 60° C.
  • the compounds (1-2a) to (1-2j) include pharmaceutically acceptable salts thereof.
  • hydrochloride of the compound (1-2e) a commercial one may also be used. It is also possible to synthesize the compound (1-2) from a substituted DL-ornithine by a well-known process. A specific example of the process is that described in literature (for example, R. C. Ralock, “Comprehensive Organic transformation”, VCH publisher Inc., 1989).
  • the compounds (1-3a) to (1-31) include pharmaceutically acceptable salts thereof.
  • the compounds (1-3j) to (1-3v) include pharmaceutically acceptable salts thereof.
  • Examples of the synthesis of compounds (1-3w) to (1-3dd) as specific examples of the compound (1-3) are given below.
  • the compounds (1-3w) to (1-3dd) include pharmaceutically acceptable salts thereof.
  • the compound (1-3) may be synthesized from a substituted D-ornithine by a well-known process.
  • a specific example of the process is that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • the compound (1-5) described in production process 1 may be produced, for example, by the following process:
  • a compound (21-2) may be produced from a compound (21-1) by the same process as that described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)) or the like.
  • the compound (1-5) may be produced from the compound (21-2) by the same process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • Examples of the synthesis of compounds (1-5a) to (1-5aa) as specific examples of the compound (1-5) are given below.
  • the compounds (1-5a) to (1-5aa) include pharmaceutically acceptable salts thereof.
  • the compounds (1-5a) to (1-5aa) may be produced according to the processes described in literature (for example, WO01/74774 and R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).
  • R 51 is as defined above.
  • Examples of the synthesis of compounds (1-5bb) to (1-5tt) as specific examples of the compound (1-5) are given below.
  • the compounds (1-5bb) to (1-5tt) include pharmaceutically acceptable salts thereof.
  • the compounds (1-5bb) to (1-5tt) may be produced according to the processes described in literature (for example, WO01/74774, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, and Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).
  • R 51 is as defined above.
  • a compound (22-10) as a specific example of the compound (1-6) described in production process 1 may be produced, for example, by the following process:
  • R 100 , R 101 and R 102 are independently a hydrogen atom, “an optionally substituted alkyl group”, “an optionally substituted aryl group” or “an optionally substituted aralkyl group”, and R 99 is a hydrogen atom or methoxy.
  • a compound (22-3) may be produced by carrying out reductive amination of a compound (22-1) with a compound (22-2) by the same method as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989). 2) Steps 2 to 4
  • a compound (22-7) may be produced from the compound (22-3) by the same production process as described in literature (e.g. WO01/07436).
  • a compound (22-8) may be produced from the compound (22-7) by the same production process as described in literature (for example, Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.)).
  • a compound (22-9) may be produced from the compound (22-8) by the same production process as described in literature (for example, J. Chem. Soc. Perkin Trans. 13281 (2001), Heterocycles 38, 17 (1994), Tetrahedron Lett. 34, 6673 (1993), J. Org. Chem. 60, 4602 (1995) and J. Med. Chem. 38, 2866 (1995)).
  • the compound (22-10) may be produced from the compound (22-9) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.
  • Examples of the synthesis of compounds (22-10a) to (22-101) as specific examples of the compound (22-10) are given below.
  • the compounds (22-10a) to (22-101) include pharmaceutically acceptable salts thereof.
  • a 1 , A 2 , R 1 , R 2 and Y 1 are as defined above; R 67 O is “an optionally substituted alkoxy group”; and each of M 2 and M 3 is lithium, sodium or potassium.
  • the compound (23-2) may be produced from a compound (23-1) by the same production process as described in literature (for example, Can. J. Chem. 78, 697 (2000)).
  • the compound (23-3) may be produced by reacting the compound (23-2) with 2,5-dimethoxytetrahydrofuran in the presence of thionyl chloride and in the presence or absence of an inert solvent.
  • the amount of thionyl chloride used is usually chosen in the range of 0.1 to 3 equivalents per equivalent of the compound (23-2).
  • the amount of 2,5-dimethoxytetrahydrofuran used is usually chosen in the range of 10 to 100 equivalents per equivalent of the compound (23-2), and 2,5-dimethoxytetrahydrofuran may be used also as a solvent.
  • the inert solvent includes, for example, aprotic solvents (e.g.
  • N,N-dimethylformamide and dimethyl sulfoxide N,N-dimethylformamide and dimethyl sulfoxide
  • ether solvents e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane
  • ketones e.g. acetone
  • aprotic solvents e.g. acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide
  • mixed solvents thereof e.g. acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide
  • Suitable examples thereof are N,N-dimethylformamide and dimethyl sulfoxide.
  • the reaction temperature may be chosen in the range of about 10° C. to about 80° C.
  • the compound (23-5) may be produced by reacting the compound (23-3) with a compound (23-4) in an inert solvent.
  • the amount of the compound (23-4) used is usually chosen in the range of 1 to 5 equivalents per equivalent of the compound (23-3).
  • the inert solvent includes alcohol solvents (e.g. methanol, ethanol and 2-propanol) and the like.
  • the reaction temperature may be chosen in the range of about 30° C. to about 100° C.
  • the compound (23-6) may be produced by reacting the compound (23-5) with a base in an inert solvent.
  • a base alkali hydroxides (e.g. potassium hydroxide and sodium hydroxide) are exemplified, and an aqueous solution of the base may be used.
  • the amount of the base used is usually chosen in the range of 1 to 30 equivalents per equivalent of the compound (23-5).
  • the inert solvent includes alcohol solvents (e.g. methanol, ethanol and 2-propanol), water, mixed solvents thereof, and the like.
  • the reaction temperature may be chosen in the range of about 30° C. to about 130° C.
  • the compound (23-7) may be produced from the compound (23-5) by the same process as in the step 2 described in production process 2.
  • the compound (23-8) may be produced from the compound (23-7) by the same process as in the above step 4.
  • the compound (12-1) may be produced by reacting the compound (23-6) in an inert solvent in the presence or absence of an organic acid.
  • the organic acid includes, for example, acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid and ascorbic acid.
  • the inert solvent includes, for example, alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (e.g. tetrahydrofuran and 1,4-dioxane), ketones (e.g.
  • reaction temperature may be chosen in the range of about 0° C. to about 100° C.
  • a 1 , A 2 , R 1 , R 2 , Y 1 and Y are as defined above; C(O)NR 68 R 69 is “an optionally substituted carbamoyl group”; and R 70 is “an optionally substituted alkyl group”, “an optionally substituted alkenyl group”, “an optionally substituted alkynyl group”, “an optionally substituted cycloalkyl group”, “an optionally substituted aryl group”, “an optionally substituted heteroaryl group”, “an optionally substituted aralkyl group” or “an optionally substituted heteroarylalkyl group”.
  • a compound (24-2) may be produced from a compound (23-6) by the same production process as described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 972-976 (1989)).
  • Step 2 Step 6 and Step 8
  • the compound (24-3) may be produced from the compound (24-2), the compound (24-6) from a compound (24-5), and the compound (24-8) from a compound (24-7).
  • a compound (24-4) may be produced from a compound (23-6) by the same production process as described in literature (for example, Bioorg. Med. Chem. Lett. 11, 2951 (2001), Tetrahedron Letters 42, 8955 (2001), Organic Letters 2, 4091 (2000), Synlett 5, 715 (2002), Bioorg. Med. Chem. Lett. 11, 287 (2001), Tetrahedron Letters 45, 7107 (2004) and Tetrahedron Letters 42, 3763 (2001)).
  • the compound (13-1) may be produced from the compound (24-4) by the same production process as described in literature (for example, Tetrahedron Letters 45, 7107 (2004)).
  • the compound (24-5) may be produced from the compound (13-1) by the same production process as described in literature (for example, Indian J. Chem. 33B, 1103 (1994)).
  • the compound (24-6) may be produced from the compound (24-5) by the same process as in the step 2 described in production process 2.
  • the compound (24-7) may be produced from the compound (24-5) by the same process as that described in literature (for example, R. C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.
  • a compound of the formula (25-1) as the compound of the formula (I), or a salt thereof is produced, for example, by the following process:
  • R 2 , R 29 , Y and Y 1 are as defined above.
  • the compound (25-1) may be produced from a compound (1-13) by the same process as in the step 2 described in production process 2.
  • a 1 , A 2 , R 1 , R 2 , Y 1 and Y are as defined above, and R 71 is an alkyl group.
  • a compound (26-3) may be produced from a compound (12-1) by the same production process as described in literature (for example, J. Am. Chem. Soc. 74, 3916 (1952)).
  • the compound (26-2) may be produced from a compound (26-1) by the same process as in the step 2 described in production process 2.
  • the compound (26-4) may be produced from the compound (26-3) by the same process as in the step 2 described in production process 2.
  • a compound (26-7) may be produced from a compound (26-1) by the same production process as described in literature (for example, J. Org. Chem. 22, 355 (1957)).
  • the compound (26-6) may be produced from a compound (26-5) by the same process as in the step 2 described in production process 2.
  • the compound (26-8) may be produced from the compound (26-7) by the same process as in the step 2 described in production process 2.
  • a compound of the formula (27-2) as the compound of the formula (23-1) described in production process 23 is produced, for example, by the following process:
  • R 1 , R 2 , R 29 and Y 1 are as defined above.
  • a compound (27-1) may be produced from a compound (1-13) by the same production process as described in literature (for example, Tetrahedron 50, 3259 (1994)).
  • the compound (27-2) may be produced from the compound (27-1) by the same production process as described in literature (for example, Tetrahedron 50, 3259 (1994)).
  • the starting materials, reagents and the like used above may be commercial compounds or may be produced from well-known compounds by well-known processes.
  • the reactive group in a site other than a site where the reaction is desired is previously protected with a suitable protective group if necessary, and the protective group is removed after carrying out each reaction or after carrying out several reactions, whereby a desired compound may be obtained.
  • a suitable protective group for protecting the hydroxyl group, amino group, carboxyl group or the like
  • conventional protective groups used in the field of organic synthetic chemistry may be used. The introduction and removal of such a protective group may be carried out according to a conventional method (for example, the method described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).
  • the protective group for the hydroxyl group includes tert-butyldimethylsilyl group, methoxymethyl group, tetrahydropyranyl group and the like.
  • the protective group for the amino group includes tert-butoxycarbonyl group, benzyloxycarbonyl group and the like.
  • Such a protective group for the hydroxyl group may be removed by reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid.
  • tert-butyldimethylsilyl group it is also possible to carry out the removal in a solvent such as tetrahydrofuran in the presence of, for example, tetrabutylammonium fluoride.
  • the protective group for the amino group is tert-butoxycarbonyl group, it may be removed, for example, by reaction in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.
  • the removal may be carried out, for example, by reaction in a solvent such as acetic acid in the presence of an acid such as hydrobromic acid.
  • tert-butyl esters As a form in which the carboxyl group is protected, tert-butyl esters, orthoesters and acid amides are exemplified.
  • the protective group used for this protection is removed as follows.
  • the tert-butyl esters the removal is carried out, for example, by reaction in an aqueous solvent in the presence of hydrochloric acid.
  • the removal is carried out, for example, by treatment with an acid and then an alkali such as sodium hydroxide in a solvent such as aqueous methanol, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane.
  • the removal may be carried out, for example, by reaction in a solvent such as water, aqueous methanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.
  • a solvent such as water, aqueous methanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.
  • the compound of the formula (I) includes those having a center for optical activity.
  • a compound having a center for optical activity may be obtained as a racemic modification, or it may be obtained as an optically active substance when an optically active starting material is used.
  • the racemic modification obtained may be physically or chemically resolved into optical antipodes by a well-known method.
  • diastereomers are formed from the racemic modification by a reaction using a reagent for optical resolution.
  • the diastereomers different in form may be resolved by a well-known method such as fractional crystallization.
  • the compound or prodrug thereof of the present invention may be converted to a salt, for example, by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol or acetone.
  • a pharmaceutically acceptable acid includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.
  • the present inventive compounds are expected to be usable for the treatment of various diseases because of their inhibitory effect on DPP-IV.
  • the compounds described in the present description are useful for the suppression of postprandial hyperglycemia in prediabetes, the treatment of non-insulin-dependent diabetes, the treatment of autoimmune diseases such as arthritis and articular rheumatism, the treatment of intestinal mucosa diseases, growth acceleration, the inhibition of transplantation rejection, the treatment of obesity, the treatment of eating disorder, the treatment of HIV infection, the suppression of cancer metastasis, the treatment of prostatomegaly, the treatment of periodontitis, and the treatment of osteoporosis.
  • compositions for the oral administration include, for example, tablets, capsules, pills, granules, powders, solutions and suspensions.
  • compositions for the parenteral administration include, for example, aqueous or oily preparations for injection, ointments, creams, lotions, aerosols, suppositories and patches.
  • These pharmaceutical compositions are prepared by conventional techniques and may contain non-toxic and inactive carriers or excipients conventionally used in the field of formulation.
  • the bicyclic pyrrole derivative of the present invention, the prodrug thereof or the pharmaceutically acceptable salt of the derivative or prodrug is administered to an adult (body weight: 50 kg) usually in a dose of 0.1 to 1000 mg/day, preferably 1 to 300 mg/day in one portion or two or three portions a day. It is also possible to administer the derivative, prodrug or salt at intervals of several days to several weeks.
  • the present inventive compounds may be used in combination with drugs such as remedies for diabetes, remedies for diabetic complications, hypolipidemic drugs, hypotensors, antiobesity drugs, diuretics, etc. (these drugs are hereinafter abbreviated as concomitant drugs) in order to enhance the effects of the compounds.
  • drugs such as remedies for diabetes, remedies for diabetic complications, hypolipidemic drugs, hypotensors, antiobesity drugs, diuretics, etc.
  • concomitant drugs drugs such as remedies for diabetes, remedies for diabetic complications, hypolipidemic drugs, hypotensors, antiobesity drugs, diuretics, etc.
  • concomitant drugs drugs such as remedies for diabetes, remedies for diabetic complications, hypolipidemic drugs, hypotensors, antiobesity drugs, diuretics, etc.
  • the timing of administration of the present inventive compound and the concomitant drug(s) is not limited. They may be administered to an object of administration either at the same time or at different times. It is also possible
  • the proportions of the present inventive compound and the concomitant drug(s) may be properly chosen depending on an object of administration, an administration route, a disease to be treated, symptoms, a combination of the compound and the concomitant drug(s), and the like.
  • the object of administration is a human being
  • the concomitant drug(s) is used in an amount of 0.01 to 100 parts by weight per part by weight of the present inventive compound.
  • the remedies for diabetes include insulin products (e.g. animal insulin products extracted from bovine or porcine pancreas; and human insulin products synthesized by a genetic engineering technique by the use of Escherichia coli or yeast), insulin resistance improving agents (e.g. pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297 and CS-011), ⁇ -glucosidase inhibitors (e.g. voglibose, acarbose, miglitol and emiglitate), biguanide preparations (e.g.
  • insulin products e.g. animal insulin products extracted from bovine or porcine pancreas; and human insulin products synthesized by a genetic engineering technique by the use of Escherichia coli or yeast
  • insulin resistance improving agents e.g. pioglitazone or its hydrochloride,
  • insulin secretion accelerators e.g. sulfonylurea preparations such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.; repaglinide, senaglinide, nateglinide and mitiglinide
  • GLP-1 GLP-1 analogs (e.g. exenatide, liraglutide, SUN-E7001, AVEO10, BIM-51077 and CJC1131), protein tyrosine phosphatase inhibitors (e.g. vanadates), and ⁇ 3 agonists (e.g. GW-427353B and N-5984).
  • the remedies for diabetic complications includes aldose reductase inhibitors (e.g. tolrestat, epalresat, zenarestat, zopolrestat, minarestat, fidarestat, SK-860 and CT-112), neurotrophic factors (e.g. NGF, NT-3 and BDNF), PKC inhibitors (e.g. LY-333531), AGE inhibitors (e.g. ALT946, pimagedine, pyratoxathine and N-phenacylthiazolium bromide (ALT766)), active-oxygen removers (e.g. thioctic acid), and cerebrovasodilators (e.g. tiapride and mexiletine).
  • aldose reductase inhibitors e.g. tolrestat, epalresat, zenarestat, zopolrestat, minarestat, fidarestat, SK-860 and CT-112
  • neurotrophic factors e.
  • hypolipidemic drugs include HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, and their sodium salts), squalene synthetase inhibitors, ACAT inhibitors, and the like.
  • the hypotensors include angiotensin-converting-enzyme inhibitors (e.g. captopril, enalapril, aracepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril and trandolapril), angiotensin II antagonists (e.g.
  • calcium antagonists e.g. nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine and amlodipine
  • the antiobesity drugs include, for example, central antiobesity drugs (e.g. phentermine, sibutramine, amfepramone, dexamfetamine, mazindol and SR-141716A), pancreas lipase inhibitors (e.g. orlistat), peptidergic anorexiants (e.g. leptin and CNTF (ciliary nerve trophic factor)) and cholecystokinin agonists (e.g. lintitript and FPL-15849).
  • the diuretics include, for example, xanthine derivatives (e.g.
  • thiazide preparations e.g. ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide and methyclothiazide
  • anti-aldosterone preparations e.g. spironolactone and triamterene
  • carbonate dehydratase inhibitors e.g. acetazolamide
  • chlorobenzenesulfoneamide preparations e.g. chlorthalidone, mefruside and indapamide
  • azosemide isosorbide, ethacrynic acid, piretanide, bumetanide and furosemide.
  • the concomitant drugs are preferably GLP-1, the GLP-1 analogs, the ⁇ -glucosidase inhibitors, the biguanide preparations, the insulin secretion accelerators, the insulin resistance improving agents, and the like.
  • the above-exemplified concomitant drugs may be used in combination of two or more thereof in proper proportions.
  • the amount of the drug(s) used may be reduced so as to be within a safe range in view of the side effects of the drug(s).
  • the dose of the biguanide preparations may be reduced as compared with a conventional dose. Therefore, side effects causable by these drugs are safely preventable.
  • the doses of the remedies for diabetic complications, the hypolipidemic drugs, the hypotensors and the like may be reduced. As a result, side effects causable by these drugs are effectively preventable.
  • Example No. R 3 Example 21 C(O)NH 2 Example 22
  • Example 23 C(O)OCH 3
  • Example 24 C(O)OCH 2 CH 3
  • Example 25 C(O)N(CH 3 ) 2
  • Example 26 Example 27
  • Example 28 Example 29
  • Example 31 Example 32
  • Example 33 Example 34
  • Example 35 Example 35
  • Example No. R 3 Example 36 C(O)N(CH 3 ) 2 Example 37 C(O)NHCH 3 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44
  • Example No. R 3 Salt Example 55 2 HCl
  • Example 56 CH 2 OCH 3 HCl
  • Example 58 F CF 3 CO 2 H
  • Example 59 CH 3 HCl
  • Example 60 CHO CF 3 CO 2 H
  • Example 61 CH 3 C(O) CF 3 CO 2 H
  • Example 62 CF 3 CO 2 H
  • Example No. R 2 R 3 Example 63 CN
  • Example 64 H Example 65 C(O)N(CH 3 ) 2
  • Example 72 The compound of Example 72 was synthesized from a corresponding compound according to the process described in Example 1.
  • Trifluoroacetic acid (1.5 ml) was added to a solution of tert-butyl ⁇ (3R)-1-[5-(2-chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl ⁇ carbamate (54 g) in chloroform (1 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (45 mg).
  • Methyl cyanoformate (170 ⁇ l) was added to a solution of ethyl 3-amino-5- ⁇ (3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl ⁇ -1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (104 mg) in hydrochloric acid-methanol reagent 10 (4 ml), and the resulting mixture was stirred with heating at 90° C. in a sealed tube for 15 hours. The reaction solution was concentrated under reduced pressure and chloroform was added to the residue. The solid precipitated was removed by filtration and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, and the solid precipitated was collected by filtration to obtain a crude product of the title compound (107 mg).
  • the reaction mixture (9.82 g) thus obtained was dissolved in acetone (90 ml), followed by adding thereto potassium carbonate (6.2 g) and ethyl bromoacetate (1.5 ml), and the resulting mixture was stirred at 60° C. for 3 hours.
  • the reaction solution was cooled to 25° C. and water was added thereto, followed by extraction with ethyl acetate.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure.
  • the resulting residue (7.53 g) was dissolved in tetrahydrofuran (150 ml) and the resulting solution was cooled to 0° C.
  • methyl isothiocyanate (71 ⁇ l) and potassium carbonate (143 mg) were added to a solution (2.5 ml) of ethyl 3-amino-5- ⁇ (3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl ⁇ -1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (260 mg) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 3 hours. After the reaction solution was cooled to 25° C. and then concentrated under reduced pressure, toluene (5 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times.
  • the reaction solution was extracted with chloroform and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure.
  • di-tert-butyl dicarbonate (372 mg), 1,4-dioxane (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml), and the resulting mixture was stirred at room temperature for 8 hours.
  • Water was added to the reaction solution, followed by extraction with chloroform.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure.
  • diethyl ether followed by filtration, and the precipitate was washed with hexane to obtain the title compound (200 mg) as a light-yellow solid.
  • Methyl iodide 25 ⁇ l was added to a solution of tert-butyl ⁇ (3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl ⁇ carbamate (112 mg) in acetone (5 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature.
  • the reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in methanol (2 ml) was added 28% methanol methoxide (2 ml), followed by stirring with heating at 60° C. for 4 hours.
  • the methanol was distilled off under reduced pressure and the residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (100 ml).
  • the organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure.

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Cited By (34)

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Publication number Priority date Publication date Assignee Title
US20080249089A1 (en) * 2002-08-21 2008-10-09 Boehringer Ingelheim Pharma Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20080312243A1 (en) * 2004-06-24 2008-12-18 Matthias Eckhardt Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US20090192138A1 (en) * 2005-12-23 2009-07-30 Daniel Kaspar Baeschlin compounds
US20090325926A1 (en) * 2006-08-08 2009-12-31 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus
US20100144703A1 (en) * 2002-11-08 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US12312352B2 (en) 2012-05-14 2025-05-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in SIRS and/or sepsis

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7569574B2 (en) 2002-08-22 2009-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Purine derivatives, the preparation thereof and their use as pharmaceutical compositions
US7495005B2 (en) 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
DE10254304A1 (de) 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel
US7566707B2 (en) 2003-06-18 2009-07-28 Boehringer Ingelheim International Gmbh Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
DE10355304A1 (de) 2003-11-27 2005-06-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004009039A1 (de) 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel
US7393847B2 (en) 2004-03-13 2008-07-01 Boehringer Ingleheim International Gmbh Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions
US7439370B2 (en) 2004-05-10 2008-10-21 Boehringer Ingelheim International Gmbh Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides
DE102004043944A1 (de) 2004-09-11 2006-03-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
DE102004044221A1 (de) 2004-09-14 2006-03-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
JPWO2006068163A1 (ja) * 2004-12-24 2008-06-12 大日本住友製薬株式会社 二環性ピロール誘導体
DOP2006000008A (es) 2005-01-10 2006-08-31 Arena Pharm Inc Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1
PE20071221A1 (es) 2006-04-11 2007-12-14 Arena Pharm Inc Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas
BRPI0715160A2 (pt) 2006-08-08 2013-06-11 Sanofi Aventis imidazolidina-2,4-dionas substituÍdas por arilamimoaril-alquil-, processo para preparÁ-las, medicamentos compeendendo estes compostos, e seu uso
DK2073810T3 (da) * 2006-09-13 2011-10-31 Takeda Pharmaceutical Anvendelse af 2-6-(3-aminio-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl-4-fluor-benzonitril til behandling af diabetes, cancer, autoimmune sygdomme og HIV infektion
US8093236B2 (en) * 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
EP2025674A1 (fr) 2007-08-15 2009-02-18 sanofi-aventis Tetrahydronaphthaline substituée, son procédé de fabrication et son utilisation en tant que médicament
PE20090938A1 (es) 2007-08-16 2009-08-08 Boehringer Ingelheim Int Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo
CN101784278A (zh) 2007-08-17 2010-07-21 贝林格尔.英格海姆国际有限公司 用于治疗fab-相关的疾病的嘌呤衍生物
TW200938200A (en) * 2007-12-28 2009-09-16 Dainippon Sumitomo Pharma Co Methyl-substituted piperidine derivative
WO2009113423A1 (fr) 2008-03-10 2009-09-17 大日本住友製薬株式会社 Composé de pyrrole bicyclique
EP2146210A1 (fr) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Procédés d'utilisation du récepteur couplé aux protéines A G pour identifier les secrétagogues de peptide YY (PYY) et composés utiles dans le traitement d'états modulés par PYY
WO2009128360A1 (fr) * 2008-04-18 2009-10-22 大日本住友製薬株式会社 Agent thérapeutique pour le diabète
TW201014822A (en) 2008-07-09 2010-04-16 Sanofi Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
MX370599B (es) 2008-08-15 2019-12-18 Boehringer Ingelheim Int Derivados de purina para su uso en el tratamiento de enfermedades relacionadas con fab.
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
TWI466672B (zh) 2009-01-29 2015-01-01 Boehringer Ingelheim Int 小兒科病人糖尿病之治療
KR101694136B1 (ko) 2009-02-13 2017-01-09 베링거 인겔하임 인터내셔날 게엠베하 Ｓｇｌｔ２ 억제제, ｄｐｐ－ｉｖ 억제제 및 임의로 추가의 당뇨병 치료제를 포함하는 약제학적 조성물 및 이의 용도
MX387264B (es) 2009-02-13 2025-03-18 Boehringer Ingelheim Int Medicaciones antidiabeticas que comprenden un inhibidor de dpp-4 (linagliptina) opcionalmente en combinacion con otros antidiabeticos.
WO2010117935A1 (fr) * 2009-04-06 2010-10-14 Schering Corporation Composés et procédés pour un traitement antiviral
US9198907B2 (en) 2009-04-06 2015-12-01 Ptc Therapeutics, Inc. Combinations of a HCV inhibitor such as bicyclic pyrrole derivatives and a therapeutic agent
JPWO2011002011A1 (ja) * 2009-07-01 2012-12-13 キッセイ薬品工業株式会社 Ｓｇｌｔ１阻害薬とｄｐｐ−ｉｖ阻害薬を組み合わせてなる医薬
AR077642A1 (es) 2009-07-09 2011-09-14 Arena Pharm Inc Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo
JP2013503135A (ja) 2009-08-26 2013-01-31 サノフイ 新規な結晶性複素芳香族フルオログリコシド水和物、その化合物を含んでなる医薬及びその使用
NZ625577A (en) 2009-10-02 2015-12-24 Boehringer Ingelheim Int Therapeutic uses of pharmaceutical compositions
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
US20130109703A1 (en) 2010-03-18 2013-05-02 Boehringer Ingelheim International Gmbh Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions
US20130023494A1 (en) 2010-04-06 2013-01-24 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
AR082091A1 (es) 2010-05-05 2012-11-14 Boehringer Ingelheim Int Composiciones farmaceuticas que comprenden pioglitazona y linagliptina y procedimiento de preparacion
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
PH12013500547A1 (en) 2010-09-22 2013-06-10 Arena Pharm Inc Modulators of the gpr119 receptor and the treatment of disorders related thereto
US8907086B2 (en) * 2011-03-03 2014-12-09 Merck Sharp & Dohme Corp. Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
EP2683700B1 (fr) 2011-03-08 2015-02-18 Sanofi Dérivés d'oxathiazine tétra-substitués, leur procédé de fabrication, leur utilisation comme médicament ainsi que médicaments en étant pourvu et leur utilisation
EP2766349B1 (fr) 2011-03-08 2016-06-01 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
US8828994B2 (en) 2011-03-08 2014-09-09 Sanofi Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8710050B2 (en) 2011-03-08 2014-04-29 Sanofi Di and tri- substituted oxathiazine derivatives, method for the production, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
US20140066369A1 (en) 2011-04-19 2014-03-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140051714A1 (en) 2011-04-22 2014-02-20 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140038889A1 (en) 2011-04-22 2014-02-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
EP2760862B1 (fr) 2011-09-27 2015-10-21 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
US20130172244A1 (en) 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
WO2013174768A1 (fr) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans le traitement du diabète auto-immun, notamment du lada
EP2854824A1 (fr) 2012-05-25 2015-04-08 Boehringer Ingelheim International GmbH Utilisation de kératinocytes en tant que substance biologiquement active dans le traitement des plaies, par exemple des plaies diabétiques, facultativement en combinaison avec un inhibiteur de la dpp-4
US20150246117A1 (en) 2012-09-24 2015-09-03 Ulf Eriksson Treatment of type 2 diabetes and related conditions
US20150297573A1 (en) 2012-10-24 2015-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING Beta-CELL SURVIVAL
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
KR20150128726A (ko) 2013-03-15 2015-11-18 베링거 인겔하임 인터내셔날 게엠베하 심장보호 및 신장보호 항당뇨병 치료요법에서의 리나글립틴의 사용
ES2805743T3 (es) 2015-03-24 2021-02-15 Inst Nat Sante Rech Med Método y composición farmacéutica para uso en el tratamiento de la diabetes
WO2018104263A1 (fr) 2016-12-06 2018-06-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés d'amélioration de l'activité de médicaments à base d'incrétine chez des sujets en ayant besoin
US11247965B2 (en) 2017-12-11 2022-02-15 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators
CN110117284B (zh) * 2018-02-06 2021-11-19 江苏奥赛康药业有限公司 含氮杂环类化合物及其制备方法和用途
AU2019284617A1 (en) 2018-06-11 2021-01-28 VenatoRx Pharmaceuticals, Inc. Hepatitis B capsid assembly modulators
WO2021178362A1 (fr) * 2020-03-03 2021-09-10 VenatoRx Pharmaceuticals, Inc. Modulateurs d'assemblage de capside de l'hépatite b
EP4608388A1 (fr) 2022-10-25 2025-09-03 Starrock Pharma Inc. Polythérapies combinatoires et rotationnelles pour l'obésité et d'autres maladies
WO2025140592A1 (fr) * 2023-12-29 2025-07-03 华润医药研究院（深圳）有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation pharmaceutique
WO2025227129A2 (fr) 2024-04-25 2025-10-30 Starrock Pharma Llc Vecteurs de délivrance comprenant des polypeptides dérivés de proglucagon et des polypeptides anaboliques et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030105077A1 (en) * 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030199528A1 (en) * 2001-09-19 2003-10-23 Kanstrup Anders B. Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV
US20040116328A1 (en) * 2002-06-06 2004-06-17 Eisai Co., Ltd. Condensed imidazole derivatives
US20090192138A1 (en) * 2005-12-23 2009-07-30 Daniel Kaspar Baeschlin compounds
US7601728B2 (en) * 2004-12-24 2009-10-13 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic pyrrole derivatives

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2097384C1 (ru) * 1989-10-31 1997-11-27 Биокрист Фармасьютикалз Инк. Производные 2-амино-7-(chr2r3)-3н,5н-пирроло[3,2-d]-пиримидин-4-она, способы их получения и способ селективного ингибирования пролиферации т-лимфоцитов млекопитающего и не оказывающий воздействия на b-лимфоциты
GB9928330D0 (en) 1999-11-30 2000-01-26 Ferring Bv Novel antidiabetic agents
HRPK20110926B3 (hr) 2001-02-24 2013-05-31 Boehringer Ingelheim Pharma Gmbh & Co.Kg. Derivati ksantina, njihova proizvodnja i upotreba kao lijekova
ATE388951T1 (de) * 2001-07-03 2008-03-15 Novo Nordisk As Dpp-iv-inhibierende purin-derivative zur behandlung von diabetes
JP2003300977A (ja) * 2002-04-10 2003-10-21 Sumitomo Pharmaceut Co Ltd キサンチン誘導体
JPWO2006112331A1 (ja) * 2005-04-13 2008-12-11 大日本住友製薬株式会社 新規縮合ピロール誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030105077A1 (en) * 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030199528A1 (en) * 2001-09-19 2003-10-23 Kanstrup Anders B. Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV
US20040116328A1 (en) * 2002-06-06 2004-06-17 Eisai Co., Ltd. Condensed imidazole derivatives
US7601728B2 (en) * 2004-12-24 2009-10-13 Dainippon Sumitomo Pharma Co., Ltd. Bicyclic pyrrole derivatives
US20090192138A1 (en) * 2005-12-23 2009-07-30 Daniel Kaspar Baeschlin compounds

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20080249089A1 (en) * 2002-08-21 2008-10-09 Boehringer Ingelheim Pharma Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10023574B2 (en) 2002-08-21 2018-07-17 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9108964B2 (en) 2002-08-21 2015-08-18 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9321791B2 (en) 2002-08-21 2016-04-26 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8119648B2 (en) 2002-08-21 2012-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
US8178541B2 (en) 2002-08-21 2012-05-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20100144703A1 (en) * 2002-11-08 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US20080312243A1 (en) * 2004-06-24 2008-12-18 Matthias Eckhardt Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
US9751855B2 (en) 2004-11-05 2017-09-05 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8883805B2 (en) 2004-11-05 2014-11-11 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US9499546B2 (en) 2004-11-05 2016-11-22 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8541450B2 (en) 2004-11-05 2013-09-24 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US8637530B2 (en) 2005-07-30 2014-01-28 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US20090192138A1 (en) * 2005-12-23 2009-07-30 Daniel Kaspar Baeschlin compounds
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US8673927B2 (en) 2006-05-04 2014-03-18 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US12171767B2 (en) 2006-05-04 2024-12-24 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10301313B2 (en) 2006-05-04 2019-05-28 Boehringer Ingelheim International Gmbh Polymorphs
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US9173859B2 (en) 2006-05-04 2015-11-03 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11919903B2 (en) 2006-05-04 2024-03-05 Boehringer Ingelheim International Gmbh Polymorphs
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US12178819B2 (en) 2006-05-04 2024-12-31 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US9493462B2 (en) 2006-05-04 2016-11-15 Boehringer Ingelheim International Gmbh Polymorphs
US20090325926A1 (en) * 2006-08-08 2009-12-31 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus
US8071583B2 (en) 2006-08-08 2011-12-06 Boehringer Ingelheim International Gmbh Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10022379B2 (en) 2008-04-03 2018-07-17 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9415016B2 (en) 2008-04-03 2016-08-16 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US9212183B2 (en) 2008-12-23 2015-12-15 Boehringer Ingelheim International Gmbh Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US10004747B2 (en) 2010-05-05 2018-06-26 Boehringer Ingelheim International Gmbh Combination therapy
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US8962636B2 (en) 2011-07-15 2015-02-24 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9199998B2 (en) 2011-07-15 2015-12-01 Boehringer Ingelheim Internatioal Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US12312352B2 (en) 2012-05-14 2025-05-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in SIRS and/or sepsis
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US10351571B2 (en) 2014-12-30 2019-07-16 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10377760B2 (en) 2014-12-30 2019-08-13 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US12018030B2 (en) 2014-12-30 2024-06-25 Valo Health, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US9902728B2 (en) 2014-12-30 2018-02-27 Forma Therapeutics, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US10934299B2 (en) 2014-12-30 2021-03-02 Valo Early Discovery, Inc. Pyrrolo and pyrazolopyrimidines as ubiquitin-specific protease 7 inhibitors
US10000495B2 (en) 2014-12-30 2018-06-19 Forma Therapeutics, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US11795171B2 (en) 2014-12-30 2023-10-24 Valo Health, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10981915B2 (en) 2014-12-30 2021-04-20 Valo Early Discovery, Inc. Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors
US10377773B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10519129B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10906916B2 (en) 2015-02-05 2021-02-02 Valo Early Discovery, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9840491B2 (en) 2015-02-05 2017-12-12 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10836741B2 (en) 2015-02-05 2020-11-17 Valo Early Discovery, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519130B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519128B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10519127B2 (en) 2015-02-05 2019-12-31 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US11739071B2 (en) 2015-02-05 2023-08-29 Valo Health, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10927130B2 (en) 2015-02-05 2021-02-23 Valo Early Discovery, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10513508B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10513507B2 (en) 2015-02-05 2019-12-24 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10508098B2 (en) 2015-02-05 2019-12-17 Forma Therapeutics, Inc. Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors
US10377767B2 (en) 2015-02-05 2019-08-13 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US12364700B2 (en) 2016-06-10 2025-07-22 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition

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CA2590912A1 (fr) 2006-06-29
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EP1829877A1 (fr) 2007-09-05
WO2006068163A1 (fr) 2006-06-29
JPWO2006068163A1 (ja) 2008-06-12
US7601728B2 (en) 2009-10-13
RU2007128322A (ru) 2009-01-27
EP1829877A4 (fr) 2009-10-14
KR20070090206A (ko) 2007-09-05
CN101103032A (zh) 2008-01-09
AU2005320134A1 (en) 2006-06-29
BRPI0518651A2 (pt) 2008-12-02
MX2007007483A (es) 2007-07-20
US20090149483A1 (en) 2009-06-11
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CN101103032B (zh) 2011-05-11
RU2382786C2 (ru) 2010-02-27

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