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WO2002066479A1 - Derives de l'isoindole - Google Patents

Derives de l'isoindole Download PDF

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Publication number
WO2002066479A1
WO2002066479A1 PCT/JP2002/001576 JP0201576W WO02066479A1 WO 2002066479 A1 WO2002066479 A1 WO 2002066479A1 JP 0201576 W JP0201576 W JP 0201576W WO 02066479 A1 WO02066479 A1 WO 02066479A1
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Prior art keywords
group
aliphatic
groups
alkoxy
alkyl
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PCT/JP2002/001576
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English (en)
Japanese (ja)
Inventor
Tomoharu Iino
Makoto Bamba
Jun-Ichi Eiki
Toshio Nagase
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Banyu Pharmaceutical Co.,Ltd.
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Publication of WO2002066479A1 publication Critical patent/WO2002066479A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is clearly useful in the field of medicine. More specifically, since the isindole derivative of the compound of the present invention has an activity of exhibiting a high blood GLP-1 concentration, it is useful as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an antiobesity agent. Is
  • the blood sugar level of a healthy person is constantly controlled by the action of insulin. Diabetes refers to the failure of this control to become chronically hyperglycemic and the disease caused by it.
  • diabetes treatment The basis of diabetes treatment is to correct hyperglycemia, i.e., to return blood glucose levels to normal levels.In recent years, however, it has been particularly important in recent years to prevent a rapid rise in blood glucose after eating without affecting fasting blood glucose. It has been recognized that it is extremely important in terms of treatment to control the amount of the drug.
  • the first is a group of drugs called insulin-releasing drugs typified by sulfonylprea drugs, which stimulate insulin secretion directly from the glands and lower blood sugar levels.
  • the second is a drug that has recently been launched on the market, called an insulin sensitizer.This drug lowers blood glucose by promoting glucose uptake in peripheral tissues without directly promoting insulin release. It is.
  • the third ⁇ -darcosidase inhibitor is a drug that controls the rapid rise in blood glucose by delaying the digestion and absorption of carbohydrates in the gastrointestinal tract and suppressing the temporary rise in blood glucose after eating. .
  • GLP-1 glucagon-like peptide-1
  • L cells endocrine cells present in the small intestinal intestinal epithelium due to intense effects. It is present in the spectacular islets of Langernouns. (Eur. J. Clin. Invest, 22, 154, 1992). Insulin secretion by GLP-1 is dependent on blood glucose level. Insulin secretion by GLP-1 is not observed in normoglycemia, and it is reported that insulin secretion is enhanced only in hyperglycemia. (Lanc et, Vol. 2, p. 1300, 1987).
  • GLP-1 not only enhances insulin secretion but also enhances insulin biosynthesis (Endocrinology, 130, 159, 1992), and promotes the proliferation of j8 cells (Diab) eto 1 ogia, vol. 42, p. 856, 1999), which is an indispensable factor for the maintenance of 3 cells.
  • GLP-1 is not limited to cells but also enhances sugar utilization in peripheral tissues (Endocrinolgy, 135, 2070, 1994 or Diab). eto 1 ogia, Vol. 37, p. 1163, 1994), and it has been reported that intracerebroventricular administration of GLP-1 exerts an antifeeding effect (Digestion, Vol. 54). , P. 360, 1993). It has also been reported that GLP-1 administration has a gastrointestinal motility inhibitory effect (Dig. Dis. Sci., Vol. 43, p. 113, 1998).
  • Reference I Reference I
  • Reference J US Pat. No. 3,336,306
  • Reference J British Patent No. 1 509 175
  • Reference K Japanese Patent Application Laid-Open No. Hei 4-172084
  • References A to L describe compounds having an oxazoloisoindole skeleton, an imidazoisoindole skeleton and a thiazoloisoindole skeleton.
  • the compound of the present invention has an oxazoloisoindole skeleton, an imidazoisoindole skeleton, or a thiazoloisoindole skeleton which is common to the compounds of References A to L.
  • Two substituent groups in series have an aryl group, a carbon aromatic ring and a heteroaromatic ring group (R 8 —R 7 —R), specifically a functional group such as N-methylcarbamoylmethoxyphenyl group
  • the compounds of Reference A to Reference L which do not have the substituent groups are compounds having completely different structures.
  • Reference A to Reference C are used for antiviral drugs
  • Reference D to Reference K are used for anti-inflammatory drugs, anticonvulsants, analgesics, mydriatics or antidepressants. Is the same, but is completely unrelated to the use of the present invention.
  • Reference L is a heat-sensitive and pressure-sensitive coloring agent
  • the present invention is a completely unrelated application having a different field of industrial application.
  • Reference M U.S. Pat. No. 3,922,597
  • Reference N U.S. Pat. No. 3,936,471
  • This invention is directed to a method for treating anti-hyperglycemia, characterized in that the compound has an imidazoisoindole skeleton.
  • the imidazoisoindole skeleton is common to the compounds of Reference M and Reference N
  • the compound of the present invention has two substituent groups at the 9-position substituent on the skeleton.
  • Compounds with different structures are, for example, as described in the description of Reference M, column 4, lines 3.9 to 45, as described in 2,3-dihydroimidazo.
  • An antihyperglycemic effect achieved by administering an isoindolelol compound and an imidazolylphenylphenyl ketone compound is a 2,3-dihydroimidazoisoledol compound and It is only an intermediate for the synthesis of imidazolyl fuel phenol ketone compounds, and it is not disclosed in the patent specification that it is useful as a therapeutic agent for diabetes or a preventive agent for chronic complications of diabetes.
  • the gist of the invention is essentially different from the present invention.
  • Reference O Japanese Patent Publication No. 49-450400 (hereinafter referred to as Reference O) is mentioned.
  • Reference 0 is an invention of a method for producing an appetite-reducing drug characterized by orally or parenterally administering an imidazosindolol compound in which a hydroxy group is substituted at the 5-position of the imidazosindole skeleton. Compounds having an imidazoisindole skeleton have been described.
  • the compound of the present invention has an imidazoisoindole skeleton common to the compound of Reference O, an aryl group in which two substituent groups are substituted in series at the 9-position substituent on the skeleton,
  • the compound of Reference O which does not have the substituent group or the like is a compound having a completely different structure.
  • the feature of the invention of Reference O is an anorectic effect achieved by administering an imidazoisoindole compound.
  • drugs such as sulfonylprea drugs, insulin sensitizers, and a-dalcosidase inhibitors are widely used in the clinical field as antidiabetic drugs, but they have the following problems. Not enough medicine. That is, the sulfonylurea agent has a slow onset of action and a long duration of action, It may be difficult to exert a tailoring effect during postprandial hyperglycemia, and it may also lower fasting blood glucose and cause severe, often life-threatening hypoglycemic attacks. Insulin sensitizers often have side effects on the liver and require careful use under strict control. In addition, there may be side effects such as edema. In addition, side effects such as bloating and diarrhea have become a problem with ⁇ -dalcosidase inhibitors.
  • An object of the present invention is to provide a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, an anti-obesity drug, and the like, which exhibit an activity of exhibiting a high blood GLP-1 concentration.
  • the present inventors have conducted intensive studies for the purpose of creating a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an anti-obesity agent capable of controlling blood glucose level depending on the blood glucose level.
  • I] and the compound represented by the following general formula [II] have been found to achieve high blood GLP-1 concentrations in vivo, and have completed the present invention.
  • R is a hydrogen atom, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, Aralkyl group, N-aralkylamino group, aralkyloxy group, N-aralkyl amino group, aryl group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfamoyl group, N-arylalkyl group, arylo group , Alkoxy group, C 2 —C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, N—C 6 alkylamino group, N—C 6
  • Alkyl rubamoyl group N—C 2 _C 6 alkenylcarbamoyl group, N-amino ( ⁇ -1.
  • Alkyl rubamoyl group N—C i— Ce alkoxy-C 1 () alkyl rubamoyl group, N—C 6 Alkoxy compounds
  • Rbamoyl group N-Ci—C 6 alkoxy compounds R 1- (1) alkylcarbamoyl group, ( ⁇ — ( ⁇ alkirchio group, N—C 6 alkylsulfur moil group, C i-C 6 alkylsulfinyl group, C x - C 6 alkylsulfonyl group, N-C ⁇ - C 6 alkylsulfonyl ⁇ amino group, CI- C 6 alkoxy group, d-C 6 alkoxycarbonyl alkylsulfonyl group , N—C 3 —C 6 cycloalkylamino group, C 3
  • R 1 and R 2 are the same or different, and each represents a hydrogen atom, an amino group, a rubamoyl group, a rubamoylamino group, a rubamoyloxy group, a carboxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy atom.
  • R 3 , R 4 , R 5, and R 6 each independently represent a hydrogen atom, an amino group, a carbamoyl group, a phorbamoylamino group, a phorbamoyloxy group, a lipoxyl group, a cyano group, a sulfamoyl group, a sulfo group , nitro group, halogen atom, hydroxy group, formyl group, formylamino group, C 2 - C 6 Arukanoiru group, N- C 2 - (6 Aruka Noiruamino group, N- C ⁇ - C 6 alkylamino group, N-Ci - C 10 alkyl cull Bamoiru group, (: 1 over Ji 6 Arukiruchio group, CI- Ce alkylsulfamoyl group, C ⁇ N-- C 6 alkylsulfinyl group, CI- C 6 alkylsulfonyl group, NC,
  • R 3 , R 4 , R 5 and R 6 are taken together to form a fused aryl group, a bicyclic or tricyclic saturated or unsaturated C 6 -C 15 condensed carbocyclic group or a 6-membered heterocyclic group or a nitrogen atom, oxygen
  • a bicyclic or tricyclic fused heteroaromatic group having from 1 to 5 heteroatoms per ring system selected from the group consisting of atoms and sulfur atoms;
  • R 7 is a hydrogen atom, or a linear saturated mono-C 9 aliphatic group substituted with R 8 , a linear unsaturated mono-C 9 aliphatic group, a branched saturated mono-C 9 aliphatic group, Branched-chain unsaturated C i-C 9 aliphatic, aralkyl, aralkyloxy, aralkylcarbonyl, N-aralkylcarbonyl, aryl, aryloxy, arylsulfonyl, arylsulfamoyl, N-arylcarbamoyl group, aroyl group, alkoxy group, C 2 —C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, C 2 —C 6 alkanoyloxy group, N—Ci— Ce alkylamino group, N, N- di - A C 6 alkylamino group, N- one C 10 alkyl force Rubamoiru group
  • R 8 is azide, amino, carbamoyl, carbamoylamino, carbamoyloxy, carboxyl, sulfamoyl, sulfo, nitro, formyl, formylamino, aralkyl, N-aralkylamino, Aralkyloxy group, N-aralkyl amino group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfamoyl group, N-arylalkamoyl group, aroyl group, alkoxy group, N- Aroiruamino group, C 2 - C 6 Arukanoiru group, N- C 2 - C 6 alkanoyloxy noisy Rua amino group, N- one C 6 Arukirua amino group, N, N- di -C i-C 6 alkylamino group, N- Ci—C 10 alkylcarbamoyl group, N—C ⁇ —.
  • Alkylthio Scarpa moil group N, N- di C ⁇ - C 1 0 alkyl Scarpa moil group, N- C 2 - ⁇ 6 Aruke carbamoylmethyl group, N- amino C E - C 0 alkyl force Rubamoiru group, N- C C 6 alkoxy C—C ⁇ 0 alkyl force rubamoyl group, N—C i —C 6 alkoxycarbonyl C ⁇ C i.
  • Alkyl power Rubamoyl group N—C 1 C 6 Alkoxy power Luponylamino C 1 C i.
  • Alkyl force Rubamoiru group N- ⁇ - C 6 alkoxy force Ruponiruamino C ⁇ - C 6 alkoxy force Ruponiru group, one C 6 alkylthio group, N- one C 6 alkylsulfamoyl group, Ji E one C 6 alkylsulfinyl group, C—C 6 alkylsulfonyl group, N—C x —C 6 alkylsulfonylamino group, mono-C 6 alkoxycarbonyl group, N—C 3 —C 6 cycloalkylamino group, and N—C 3 —C 6 cyclo A substituent selected from the group consisting of an alkylcarbamoyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a thiadiazolyl group, a chenyl group, a triazolyl group, a pyridyl group,
  • X is an oxygen atom or a sulfur atom
  • Z is condensed Ariru group, C 6 - (: 8 cycloalkanyl group, C 6 - ⁇ 8 cycloalk force Jeniru group and C 6 - C 8 2 to be selected from the group consisting of cycloalkenyl groups tricyclic Saturated or unsaturated C 6 - ⁇ 5 fused carbocyclic group or ethylenedioxyphenyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group
  • a 6-membered heterocyclic group selected from the group consisting of a benzofuranyl group and a methylenedioxyphenyl group or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in an amount of from 1 to And represents 5 to 6 condensed heterocyclic aromatic
  • R is a hydrogen atom, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, aralkyl group, N-aralkylamino group, aralkyloxy group, N-aralkyl group , Aroyl group, alkoxy group, C 2 -C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, N—Ci—C 6 alkylamino group, N, N—di-C 6 alkylamino group, N — Ci—.
  • Alkyl rubamoyl groups N_C 1 —C 1 . Arkirchocarpamoyl group, N, N—Gee Ci—. Alkyl rubamoyl group, N_C 2 — C 6 alkenylcarbamoyl group, N-amino-C 10 Alkyl rubamoyl group, NC 1- C 6 alkoxy Ci 1 G 10 Alkyl rubamoyl group, N-Ci-C 6 alkoxy Ruponiru one G 10 alkyl force Rubamoiru group, NC x - C 6 alkoxy force Lupo Niruamino one C 10 alkyl force Rubamoiru group, one C 6 alkylthio group, NC ⁇ C 6 alkylsulfamoyl group, C! One C 6 alkylsulfinyl group,
  • -C 9 aliphatic groups C ⁇ —C 6 alkoxy groups, Ci—Ce alkylthio groups, and N—Ci—C 6 alkylamino groups.
  • R 3 , R 4 , R 5, and R 6 each independently represent a hydrogen atom, an amino group, a carbamoyl group, a phorbamoylamino group, a phorbamoyloxy group, a lipoxyl group, a cyano group, a sulfamoyl group, a sulfo group , Nitro group, halogen atom, hydroxy group, formyl group, formylamino group, C 2 _C fi alkanol group, N—C 2 —C 6 Nylamino group, N—Ci—Cg alkylamino group, N—C ⁇ —C 10 alkyl carbamoyl group, Ci—Ce alkylthio group, N—C—C 6 alkylsulfamoyl group, C 6 alkylsulfinyl group, Ci — C 6 alkylsulfonyl, N— ⁇ — C 6 alkylsulfonyla
  • C 6 alkylsulfonyl group, N-C 6 alkylsulfonylamino group, Ci—C 6 alkoxy group, 1 c 6 alkoxycarbonyl group, N - C 3 - C 6 cycloalkyl group, and N- C 3 - C 6 cycloalkyl force Rubamoiru may be substituted with from a substituent and the substituent is selected the group consisting of groups, a saturated one linear C 9 aliphatic group, linear unsaturated Ci—Cg aliphatic group, branched saturated mono-C 9 aliphatic group, branched unsaturated Ci—C 9 aliphatic group, C-C 6 It may have one or more substituents selected from the group consisting of an alkoxy group and a substituent selected from the group consisting of an N—C 1 C 6 alkylamino group, an aryl group, or an imidazolyl group, oxazolyl Group, thiazolyl group, thiadiazoly
  • a linear saturated C 9 aliphatic group, a linear unsaturated C — C 9 aliphatic group, a branched saturated C x -C 9 aliphatic group or branched chain Forms an unsaturated C x -C 9 aliphatic group or a 5- or 6-membered saturated carbocyclic group, a 5- or 6-membered unsaturated carbocyclic ring or a 5- or 6-membered heterocyclic group, or , R 3 , R 4 , R 5 and R 6 are taken together to form a fused aryl group, a bicyclic or tricyclic saturated or unsaturated C 6 -C 15 conden
  • R 7 is a linear saturated mono-C 9 aliphatic group substituted with R 8 , a linear unsaturated mono-C 9 aliphatic group, a branched saturated C.-C 9 aliphatic group, a branched chain Unsaturated C i -C 9 aliphatic groups, aralkyl groups, aralkyloxy groups, aralkylcarbonyl groups, N-aralkyl carbamoyl groups, aryl groups, aryloxy groups, arylsulfonyl groups, arylsulfamoyl groups, and N-arylalkyl rubamoyl Group, aroyl group, alkoxy group, C 2 —C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, C 2 —C 6 alkanol group Nyloxy group, N—C 1 -C 6 alkylamino group, N , N- di eleven C 6 alkyl Ruamino
  • R 8 is azide, amino, carpamoyl, carbamoylamino, carbamoyloxy, carboxyl, sulfamoyl, sulfo, nitro, formyl, formylamino, aralkyl, N-aralkylamino, aralkyl Ruxyoxy group, N-aralkyl rubamoyl group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfamoyl group, N-arylalkyl group, aryloyl group, alkoxy group, N-aroylamino group, C 2 —C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, N——C 6 alkylamino group, N, N—di-C 6 alkylamino group, N——C 10 alkylcarbamoyl Group, N—Ci—C.
  • Alkylthiol carbamoyl group N, N-di ⁇ -C 10 alkyl carbamoyl group, N—C 2 — ( 6 alkenyl carbamoyl group, N-amino C i-C 0 alkyl alkyl group, N— — C 6 Alkoxy-C 10 alkyl carpamoyl group, N—C i-C 6 alkoxycarponyl C 1 -C 10 alkyl force Rubamoyl group, N—C-C 1 C 6 alkoxy force luponylamino C-C i Q alkyl force Rubamoyl group, N— C ⁇ —C 6 alkoxyl rupponylamino C ⁇ 1 C 6 alkoxyl ruponyl, Ci—Cealkylthio, N——C 6 alkylsulfamoyl, Ci—C 6 alkylsulfinyl, C 6 alkylsulfonyl
  • X is an oxygen atom or a sulfur atom
  • Z is condensed Ariru group, C 6 - (8 cycloalkanyl group, C 6 -. 8 cycloalk force Jeniru group and C 6 - C 8 2 to be selected from the group consisting of cycloalkenyl groups tricyclic saturated Or unsaturated C 6 -C i 5 condensed carbocyclic group or ethylenedioxyphenyl group, pyridyl group, virazinyl group, pyrimigel group, pyridazinyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group A 6-membered heterocyclic group selected from the group consisting of a benzofuranyl group and a methylenedioxyphenyl group or a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom per ring system A bicyclic or tricyclic condensed heteroaromatic group having from 1 to 5
  • the present invention relates to an isoindole derivative and a use thereof.
  • These inventions relate to a novel compound (compound represented by the above general formula [II]) and a known compound (the above general formula [II] [I]), but it was not known at all to use it for the above purposes.
  • aryl group an aryl group having 6 to 15 carbon atoms is preferable, and examples thereof include a naphthyl group and a phenyl group.
  • Examples of 5- or 6-membered heterocyclic groups include imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, chenyl, triazolyl, pyridyl, pyrazinyl, pyrimigel, pyridazinyl, pyrazolyl, furyl, Examples include a trahydrofruel group, a pyrrolidinyl group, a dioxanyl group, and a morpholino group.
  • a chenyl group, a tetrahydrofuranyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a furyl group, a dioxanyl group, and a morpholino group are preferable.
  • Examples of the mono- to tri-cyclic heteroaromatic ring group having 1 to 5 hetero atoms per ring system selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom include, for example, an ethylenedioxyphenyl group and a dibenzo group.
  • Xyphenyl, dibenzofuranyl, dibenzothiophenyl, methylenedioxyphenyl and the like are preferred.
  • the halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and among them, for example, a fluorine atom, a chlorine atom, an iodine atom and the like are preferable, and for example, a fluorine atom, a chlorine atom and the like are more preferable.
  • an aralkyl group having 7 to 15 carbon atoms is preferable.
  • benzyl group, ⁇ -methylbenzyl group, phenethyl group, 3-phenylpropyl group 1-naphthylmethyl group, 2 —Naphthylmethyl group, a-methyl (1-naphthyl) methyl group, ⁇ -methyl (2-naphthyl) methyl group, hyethyl (1-naphthyl) methyl group, ⁇ -ethyl (2-naphthyl) methyl group, diphenylmethyl And a dinaphthylmethyl group, and particularly, for example, a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a high-methylbenzyl group, and a phenethyl group.
  • a aralkylamino group is a group in which an aralkyl group is substituted with the above aralkyl group. And specifically, for example, N-benzylamino group, N- (1-methylbenzyl) amino group, N-phenethylamino group, N- (3-phenylpropyl) amino group, N- (1-naphthylmethyl) amino Group, N— (2-naphthylmethyl) amino group,
  • An amino group and a ⁇ -phenethylamino group are preferred.
  • An aralkyloxy group means a group in which an oxygen atom is substituted by the above aralkyl group.
  • a benzyloxy group, an ⁇ -methylbenzyloxy group, a phenethyloxy group, a 3-phenylpropoxy group an Naphthyl methoxy group, 2-naphthyl methoxy group, ⁇ -methyl (1-naphthyl) methoxy group, ⁇ -methyl (2-naphthyl) methoxy group, ⁇ -ethyl (1-naphthyl) methoxy group, ⁇ -ethyl (2- Naphthyl) methoxy group, diphenylmethoxy group, dinaphthylmethoxy group and the like, and particularly preferably, for example, benzyloxy group, ⁇ -methylbenzyloxy group, phenethyloxy group and the like.
  • the aralkylcarbonyl group refers to a group in which the aralkyl group is substituted for a carbonyl group, specifically, for example, a benzylcarbonyl group, an ⁇ -methylbenzylcarbonyl group, a phenethylcarbonyl group, —Phenylpropylcarbonyl group, 1-naphthylmethylcarbonyl group, 2-naphthylmethylcarbonyl group, ⁇ -methyl (1-naphthyl) methylcarbonyl group, 1-methyl (2-naphthyl) methylcarbonyl group, _ethyl (1-11 Naphthyl) methyl carbonyl group, ⁇ -ethyl (2-naphthyl) methyl carbonyl group, diphenylmethyl carbonyl group, dinaphthyl methyl carbonyl group, etc., and particularly, for example, benzylcarponyl group, ⁇ -methyl
  • aralkyl molybmoyl group means a group obtained by substituting the above-mentioned aralkyl group with a molybmoyl group, and specifically includes, for example, ⁇ -benzylcarbamoyl group, ⁇ - ( ⁇ -methylbenzyl) immobilo group, Phenethylcarbamoyl group, ⁇ -(3- Phenylpropyl) dirubamoyl group, N— (1-naphthylmethyl) dirubamoyl group, N— (2-naphthylmethyl) dirubamoyl group, N— (1-methyl (1-naphthyl) methyl) dirubamoyl group, N— ( ⁇ -methyl (2-naphthyl) methyl) force rubamoyl group, ⁇ — (one-ethyl (one-naphthyl) methyl) force rubamoyl group, ⁇ — ( ⁇ -( ⁇
  • the arylamino group means a group in which the above aryl group is substituted on the amino group, and specifically, for example, a phenylamino group, an amino (1-1naphthyl) amino group, an amino group, Naphthyl) amino group and the like, and among them, for example, ⁇ -phenylamino group and the like are preferable.
  • the aryloxy group means a group in which an oxygen atom is substituted by the above aryl group, and specifically includes, for example, a phenoxy group, a naphthyloxy group and the like, among which a phenoxy group and the like are preferable.
  • the arylsulfonyl group means a group in which the above-mentioned aryl group is substituted on the sulfonyl group, specifically, for example, phenylsulfonyl group, naphthylsulfonyl group, and the like. Sulfonyl groups and the like are preferred.
  • arylcarbamoyl group means a group obtained by substituting the above-mentioned aryl group with a carbamoyl group, and specifically includes, for example, a phenylcarbamoyl group, and a napthyl carbamoyl group.
  • a ⁇ -phenylcarbamoyl group is preferred.
  • the arylsulfamoyl group means a group in which a sulfamoyl group is substituted with the above aryl group, and specific examples include a phenylsulfamoyl group and a naphthylsulfamoyl group. Nylsulfamoyl and the like are preferred.
  • the arylcarbamoyl group means a group obtained by substituting the aryl group by a carbamoyl group, specifically, for example, a phenylcarbamoyl group, a naphthylcarbamoyl group and the like.
  • a phenylcarbamoyl group is preferable.
  • C 2 —C 6 alkenyl groups include carbonyl groups having 1 to 5 carbon atoms.
  • Preferred are groups substituted by an alkyl group such as an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a paleryl group, an isovaleryl group, a pivaloyl group, and a pentanoyl group.
  • a propionyl group, a pivaloyl group and the like are preferred.
  • the N—C 2 —C 6 alkanoylamino group means a group in which the above C 2 —C 6 alkanoyl group is substituted for the amino group. Mouth pionylamino, N-butyrylamino, N-isobutyrylamino, N-valerylamino, N-isovalerylamino, N-pivaloylamino, N-pentanoylamino, and the like. —Acetylamino, N-propionylamino, N-pivaloylamino and the like are preferred.
  • C 2 - A C 6 Al force Noiruokishi group the above C 2 oxygen atoms - C 6 Al force Noiru group means a group obtained by substituting; e.g. Asetokishi group, a propionyloxy Ruo alkoxy group, Puchiriruokishi group, Examples include an isoptyryloxy group, a valeryloxy group, an isoparyloxy group, a pivaloyloxy group, a pentanoyloxy group and the like, and among them, for example, an acetyloxy group, a propionyloxy group, a piperyloxy group and the like are preferable.
  • An aroyl group means a group in which a carbonyl group is substituted by the above-mentioned aryl group, and specifically includes, for example, a benzoyl group and a naphthylcarbonyl group. Among them, for example, a benzoyl group is preferable.
  • the alkoxy group means a group in which the above-mentioned aroyl group is substituted by an oxygen atom, and specifically includes, for example, a benzoyloxy group, a naphthylcarponyloxy group and the like, among which a benzoyloxy group and the like are preferable.
  • the N-aroylamino group means a group in which the above-mentioned arylo group is N-substituted on the amino group, and specifically includes, for example, an N-benzoylamino group, an N-naphthylcarponylamino group and the like. —A benzoylamino group and the like are preferable.
  • N——C 6 alkylamino group a group in which an amino group having 1 to 6 carbon atoms is N-substituted is preferable.
  • N-methylamino group N-ethylamino group, -Propylamino, N-isopropylamino, N-butylamino, N-isobutylamino, N-tert-butylamino and the like are preferred.
  • the N, N-di-C 6 alkylamino group is preferably a group in which an alkyl group having 1 to 6 carbon atoms is N, N-disubstituted on an amino group, specifically, for example, an N, N-dimethylamino group N, N-diethylamino, N, N-dipropylamino, N, N-diisopropylamino, N, N-dibutylamino, N, N-ditert-butylamino, N, N-dipentylamino, N, N-dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-1-N-methylamino, N-tert-butyl-N-methylamino, N-ethyl-N-isopropylamino group and the like, among which, for example, N, N-dimethylamino group
  • N-Ci-Cio alkyl carbamoyl group a group in which a carbamoyl group is N-substituted with an alkyl group having 1 to 10 carbon atoms, for example, an N-methylcarbamoyl group, N-Ethylcarbamoyl group, N-Propyl rubamoyl group, N-Isopropyl rubamoyl group, N-butyl carbamoyl group, N-Isobutyl carbamoyl group, N-sec-butyl carbamoyl group, N-tert-butyl carbamoyl group , N-pentylcarbamoyl, N-neopentylcarbamoyl, N-hexylcarbamoyl, N-isohexylcarbamoyl, N-octylcarbamoyl, N-decylcarbamoyl, and the
  • the N, N-di-Ci-C alkyl rubamoyl group is preferably a carbamoyl group in which an alkyl group having 1 to 10 carbon atoms is N, N-disubstituted.
  • N-Ci-Cio alkylthiolrubamoyl group a group in which a thiocarbamoyl group is N-substituted with an alkyl group having 1 to 10 carbon atoms is preferable.
  • an N-methylthiolrubamoyl group N-ethylthiolrubamoyl, N-propylthiolrubamoyl, N-isopropylthiolrubamoyl, N-butylthiolrubamoyl, N-isobutylthiolrubamoyl, N-sec—butylthiocarbamoyl, N-tert N-pentylthiocarbamoyl, N-neopentylthiocarbamoyl, N-hexylti talented rubamoyl, N-isohexylthiocarbamoyl, N-isobutylthiocarbamoyl, N-pentylthiocarbamoyl, N-pentylthiocarbamoyl And N-decylthiol-rubaoil groups.
  • N-methylthiol-rubamoyl group N-ethyl N-propylthiocarbamoyl, N-isopropylthiocarbamoyl, N-isobutylthiolrubamoyl, N-sec-butylthiothiorubamoyl, N-tert-butylthiocarbamoyl, N-octylthiocarbamoyl And an N-decylthiocaproluvyl group and the like are preferred.
  • N- amino ( ⁇ one C 1 0 alkyl force Rubamoiru group, force Rubamoiru preferably a group of carbon number 1 to amino alkyl group of from 1 zero has been substituted with groups, specifically, for example N _ amino methylcarbamoyl group , N-aminoethylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminomethylethylcarbamoyl group, N-aminobutylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminopentylcarbamoyl group, N —Aminohexylcarbamoyl group and the like, and among them, for example, N-aminomethylcarbamoyl group, N-aminoethylcarbamoyl group, N-aminoaminopropylcarbamoyl group, N-aminomethyle
  • C 1 -C 6 alkoxy d—C ⁇ alkyl rubamoyl group includes the above C i -C i.
  • the alkyl group is a group in which an alkoxy group having 1 to 6 carbon atoms is N-substituted with an alkyl group, specifically, for example, N-methoxymethylcarbamoyl group, N-methoxyethylcarbamoyl group, N-methoxypropyl group.
  • N-methoxymethylcarbamoyl group N-methoxyethylcarbamoyl group, —Methoxypropyl carbamoyl, N-methoxybutylcarbamoyl and the like are preferred.
  • One C i0 alkyl group as a rubamoyl group is the above C i C i.
  • An alkyl-substituted carbamoyl group is preferably an N-substituted alkoxycarbonyl group having 1 to 6 carbon atoms, specifically, for example, an N-methoxycarbonylmethylcarbamoyl group, an N-methoxycarbenylethylcarbamoyl group.
  • N-methoxycarbonylpropylcarbamoyl group N-methoxycarboxybutylcarbamoyl group, N-ethoxycarbonylpentylcarbamoyl group, N-butoxycarbonylhexylcarbamoyl group, N-tert-butoxycarponylethylcarbamoyl group, etc.
  • N-methoxycarbonylmethylcarbamoyl group N-methoxycarbonylethylcarbamoyl group, N-methoxycarbonylpropylcarbamoyl group, N-methoxycarbonylbutylcarbamoyl group, N-tert-butoxycarbo group Nyruech A rucarbamoyl group and the like are preferred.
  • Alkyl rubamoyl groups include C-Ci.
  • An alkyl-substituted alkamoyl group is preferably an N-substituted alkoxycarbonylamino group having 1 to 6 carbon atoms. Specific examples include N-methoxycarbonylaminomethylcarbamoyl and N-methoxycarbonylaminoethylcarbamoyl.
  • N-C x -C 6 alkoxycarbonylamino C 1 -C 6 alkoxyl carbonyl group includes an alkoxycarbonylamino group having 1 to 6 carbon atoms in a C ⁇ —Ce alkoxycarbonyl group. Substituted groups are preferred.
  • N-methoxycarbonylaminomethoxycarbonyl N-methoxycarbonylaminoethoxycarbonyl, N-methoxycarbonylaminopropoxycarbonyl, N-methoxycarbonylaminobutoxycarbonyl, —Ethoxycarbonylaminopentyloxycarbonyl group, N-butoxycarbonylaminohexylcarbonyl group, N-tert-butoxycarbonylaminoethoxycarbonyl group, and the like.
  • Methoxy carbonyl group, N-methoxy carbonyl Mino ethoxy Cal Poni Le group, N- meth carboxymethyl Cal Poni Rua amino propoxy Cal Poni Le group, N- methoxy Cal Poni Rua amino butoxide deer Lupo sulfonyl group, N- tert - butoxide deer Lupo arylsulfonylamino ethoxy cull Boniru group, and the like are preferable.
  • the N—C 2 —C 6 alkenylcarbamoyl group is preferably a group in which an alkenyl group having 2 to 6 carbon atoms is substituted with N-substituted carbamoyl group.
  • N-C x -C 6 alkylsulfamoyl group a group in which a sulfamoyl group is N-substituted with an aralkyl group having 1 to 6 carbon atoms, and specifically, for example, an N-methylsulfamoyl group N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, N-isobutylsulfamoyl, N-sec-butylsulfamoyl , N-tert-butylsulfamoyl, N-pentylsulfamoyl, N-neopentylsulfamoyl, N-hexylsulfamoyl, N-isohexylsulfamoyl and the like.
  • N-methylsulfamoyl, N-ethylsulfamoyl, N-isopropylsulfamoyl, N-tert-butylsulfamoyl and the like are preferable.
  • alkylsulfinyl group a group in which a sulfinyl group is substituted by an alkyl group having 1 to 6 carbon atoms is preferable.
  • C i -C e alkylsulfonyl group a group in which a sulfonyl group is substituted by an alkyl group having 1 to 6 carbon atoms is preferable.
  • N—C C 6 alkylsulfonylamino group a group in which a sulfonylamino group is substituted by an alkyl group having 1 to 6 carbon atoms is preferable.
  • N-methylsulfonyl Amino, N-ethylsulfonylamino, N-propylsulfonylamino, N-butylsulfyl Preference is given to a phonylamino group, an N-tert-butylsulfonylamino group and the like.
  • C x -C 6 alkylthio group a group in which a sulfur atom is substituted with an alkyl group having 1 to 6 carbon atoms is preferable.
  • the C j -C g alkoxy group is preferably a group in which an oxygen atom is substituted by an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methoxy group, an ethoxy group, a popoxy group, an isopropoxy group , Butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, hexyloxy group, isohexyloxy group and the like. Among them, for example, methoxy group, ethoxy group, propoxy group Group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group and the like.
  • alkoxycarbonyl group a group in which a carbonyl group is substituted by an alkoxy group having 1 to 5 carbon atoms is preferable.
  • the N—C 3 — ⁇ 6 cycloalkylamino group is preferably a group in which an amino group is N-substituted with a cyclic alkyl group having 3 to 6 carbon atoms, for example, N-cyclopropylamino group, N-cyclobutylamino And N-cyclopentylamino, N-cyclohexylamino and the like. Among them, N-cyclopropylamino, N-cyclopentylamino and N-cyclohexylamino are preferred.
  • a group in which an oxygen atom is substituted by a cyclic alkyl group having 3 to 6 carbon atoms is preferable.
  • an N-cyclopropoxy group, an N-cyclobutoxy group, an N-cyclopentyloxy group And N-cyclohexyloxy group, among which N-cyclopropoxy group, N-cyclopentyloxy group, N-cyclohexyloxy group and the like are preferable.
  • N _ C 3 — ⁇ 6 cycloalkyl group a group in which a cyclic alkyl group having 3 to 6 carbon atoms is N-substituted in the group is preferably a N-C 3 — ⁇ 6 cycloalkyl group.
  • Cyclobutyl carpamoyl group, N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group and the like are preferred.
  • the saturated C 9 -C 9 aliphatic group is preferably an alkyl group having 1 to 9 carbon atoms, and may be linear or branched. Among them, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable.
  • alkyl group examples include a methyl group, an ethyl group, a propyl group and an isopropyl group.
  • Methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl and the like are preferred.
  • the unsaturated C 9 -C 9 aliphatic group is preferably an alkenyl group or an alkynyl group having 1 to 9 carbon atoms, and may be linear or branched. Among them, a linear or branched alkenyl or alkynyl group having 1 to 6 carbon atoms is preferred.
  • alkenyl group examples include a vinyl group, an aryl group, a 1-propenyl group, an isopropenyl group, a 2-butenyl group, an isobutenyl group, a 2-pentenyl group, a 2-hexenyl group, a 2-heptyl group, Examples thereof include a 2-octyl group and the like, and among them, for example, a vinyl group, an aryl group, and a 1-propenyl group are preferable.
  • alkynyl group examples include an ethynyl group, a 1-propynyl group, a 1-butenyl group, a 1-pentenyl group, a 1-hexynyl group, a 1-heptynyl group, and a 1-octynyl group. Groups, and 11-propyl groups are preferred.
  • Examples of the 5- or 6-membered saturated carbocyclic group include a cyclopentyl group and a cyclohexyl group, and among them, for example, a cyclopentyl group is preferable.
  • Examples of the 5- or 6-membered unsaturated carbocyclic group include a cyclopentenyl group and a cyclohexenyl group. Among them, for example, a cyclopentenyl group is preferable.
  • N- C E - C i 0 alkyl force Rubamoi group or N- one C 1 0 alkylthio force Rubamoiru group is substituted, N - C i - C io alkyl force Rubamoiru group or N - 0, - 0 1 0 alkyl thio force Rubamoiru group is preferable, specifically, for example, N- i Mi Dazo such Lil methyl mosquito Rubamoiru group N- imidazolylalkyl N-oxazolyl alkyl group such as N-oxazolyl alkyl group N-thiazolyl alkyl group such as N-oxazolylmethylcarbamoyl group N-thiazolyl alkyl group N-thiadiazolylmethylcarbamoyl group N-thiadiazolylalkylcarbamoyl group such as N-thiazylalky
  • N-pyridazinylalkyl rubamoyl group N-pyrazolylmethylcarbamoyl group, etc.
  • N-pyrazolylalkyl rubamoyl group N-furylmethylcarbamoyl group, etc.
  • N-furylalkyl rubamoyl group N-tetrahydrofuranylmethylcarba N-tetrahi such as moyl group N-pyrrolidinyl alkyl rubamoyl group such as roflauel alkyl rubamoyl group, N-pyrrolidinylmethyl carbamoyl group, N-morpholinoalkyl rubamoyl group such as N-morpholinomethylcarbamoyl group; etc .; N-imidazolylmethylthio rubamoyl group N-imidazolylalkylthiothiorubamoyl group, N-oxazolylmethylthiothiorubamoyl group, N-oxazolylalkylthiothiorubamoyl group, N-thiazolylmethylthiocarbamoyl group, etc.
  • N-thiadiazolylalkylthiocapillyl groups such as N-thiadiazolylmethylthiocaptamyl group N-thenylalkylthiocarbamoyl groups, such as N-thiadiazolylmethylthiocaptamyl group, N-triazolylmethylthio group Lubamoyl group N-triazolylalkylthiocapillyl groups such as N-pyridylmethylthiocarbamoyl group, N-pyridylalkylthiocaptamyl groups, N-pyrazylmethylthiocaptamyl groups, etc.
  • N-pyrazinylalkylthio-capitarubumoyl groups such as radinylmethylthiocarbamoyl groups, N-pyrimidinylalkylthio-captamyl groups such as N-pyrimidinylalkylthiocaptamyl groups N-Bilazolyl alkylthio group, such as dazinylalkylthiol-rubamoyl group, N-pyrazolylmethylthio group, and N-furylalkylthiocarbamoyl group, such as N-furylmethylthio group, and N-tetrahydrofuranylmethylthio group.
  • Yl N- tetrahydrofuranyl alkyl thio force Rubamoiru group such as, N- pyromellitic
  • R a is an amino group, a halogen atom, hydroxy group, one C 6 alkylthio O group, 0, selected from the group consisting of -0 6 alkylsulfinyl group, C x -C 6 alkylsulfonyl group and a C alkoxy group
  • Substituents imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, virazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, tetrahydrofureryl group, pyrrolidinyl group, A 5- or 6-membered heterocyclic group selected from the group consisting of a dioxanyl group and a morpholino group; And a substituent selected from the group consisting of: a linear saturated 9 aliphatic group, and a linear uns
  • N-pyrrolidinylalkylthiocarbamoyl groups such as lysinylmethylthiol-rubamoyl groups; N-morpholinoalkylthiocarbamoyl groups such as N-morpholinomethylthiol-rubamoyl groups; among them, for example, chenyl group, pyridyl group, pyra N-C! -Cio alkyl carbamoyl or N substituted with a dinyl, pyrimidinyl, furyl, tetrahydrofuranyl, morpholino, etc. Alkyl thiocarbamoyl groups and the like are preferred.
  • the fused aryl group refers to, for example, a group in which a phenyl group or a naphthyl group is bonded to another ring to form a fused benzene ring or a fused naphthalene ring.
  • Bicyclic or tricyclic saturated or unsaturated C 6 -C! The 5 fused carbocyclic groups, in particular ⁇ 3 6 _ (8 cycloalkanyl group, C 6 - (8 cycloalkadienyl group, C 6 - C 8 cycloalkenyl group, and among them for example c 6 -c 8 cycloalkanyl group,
  • C 6 - C 8 cycloalk force Jeniru group C 6 - C 8 cycloalkenyl group and the like.
  • Examples of the 8- cycloalkanyl group include a cyclohexanyl group, a cycloheptanyl group, a cyclooctanyl group and the like, and among them, for example, a cyclohexanyl group and the like are preferable.
  • Examples of the C 6 -C 8 cycloalkajenyl group include a cyclohexenyl group, a cycloheptaenyl group, a cyclooctenyl group and the like, and among them, a cyclohexenyl group and the like are preferable.
  • the C 6 - The (3 8 cycloalkenyl group, for example cyclohexenyl group cycloheteroalkyl, cycloalkyl heptenyl group, Shikurookuteyuru group and the like, hexenyl Le group are preferable among them for example cyclohexylene.
  • a 6-membered heterocyclic group or a bi- or tri-cyclic fused heteroaromatic group having 1 to 5 hetero atoms per ring system selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom For example, ethylenedioxyphenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl or methylenedioxyphenyl Among them, for example, an ethylenedioxyphenyl group, a pyridyl group, a pyrazinyl group, a pyrimigel group, a pyridazinyl group or a methylenedioxyphenyl group are preferable.
  • Aryl which may have one or more substituents selected from the group consisting of a group selected from the group consisting of a group selected from the group consisting of a C i-C 6 alkylthio group and an N-C i-C 6 alkylamino group.
  • R 3 a, R 4a , R 5 a ⁇ Pi R 6 a are each independently a hydrogen atom, an amino group, Karubamo I group, the force Rubamoiruamino group, forces Rubamoiruokishi group, forces Rupokishiru group, Xia Group, sulfamoyl group, sulfo group, nitro group, halogen atom, hydroxy group, Formyl group, formylamino group, C 2 —C 6 alkanoyl group, N—C 2 — (: 6- alkaneylamino group, N—Ci—Ce alkylamino group, N—Ci—C 10 alkylcarbamoyl group, ⁇ —Ce an alkylthio group, N-d-C 6 alkylsulfamoyl group, CI- C
  • C 6 alkylsulfamoyl group E one C 6 alkyl sulfide El group, one C 6 alkylsulfonyl group, N-- C 6 alkylsulfonyl ⁇ amino group, one C 6 alkoxy, CI- C 6 alkoxy carbo alkenyl group, N-C 3 - C 6 cycloalkyl group, and N-C 3 - substituent and is selected from the group consisting of C 6 consequent opening alkyl force Rubamoiru group may be replacement by the substituent, saturated CC 9 aliphatic groups, straight-chain, unsaturated mono C 9 aliphatic groups, straight, branched, saturated ⁇ - ⁇ 9 aliphatic groups, branched-chain Having one or more substituents selected from the group consisting of: an aliphatic group, an aliphatic group, a C i -C 6 alkoxy group and an N-Ci-Cg alkylamino group.
  • An aryl group, or an imidazolyl group, an oxazolyl group, Azolyl group, thiadiazole A 5- or 6-membered member selected from the group consisting of a ruyl group, a phenyl group, a triazolyl group, a pyridyl group, a virazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a tetrahydrofurer group, a pyrrolidinyl group, a dioxanyl group and a morpholino group Terrorist ring group or ethylenedioxyphenyl group, dibenzofurayl group, dibenzothiophenyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofurazoyl group and methylenedioxyphenyl Or a tricycl
  • a C 9 aliphatic group or a branched unsaturated C i C 9 aliphatic group or a 5- or 6-membered saturated carbocyclic group, a 5- or 6-membered unsaturated carbocycle or 5 or more Forms a 6-membered heterocyclic group, or R 3a , R 4a , R 5a and R 6a together form a fused aryl group, a di- or tricyclic saturated or unsaturated C 6 — C 15 condensed carbocyclic group or 6-membered heterocyclic group or 2- to 3-cyclic fused heteroaromatic having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur to form a ring group, R 7a is hydrogen, X a is an oxygen atom or a sulfur atom, Y a represents an oxygen atom, a group: S (wherein n shows the an integer of 0 to 2) O n or Group: NR 9a (where R 9a is a hydrogen atom
  • a telocyclic group or a fused bicyclic heteroaromatic ring group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur atoms] or Its pharmaceutically acceptable salts are preferred.
  • the compound of the general formula [II] of the present invention will be described.
  • R b is a hydrogen atom, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a carboxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, Aralkyl group, N-aralkylamino group, aralkyloxy group, N-aralkyl sorbamoyl group, aryl group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfamoyl group, N-arylcarbamoyl group, aroyl group, Arokishi group, C 2 - C 6 Arukanoiru group, N- C 2 - C 6 Arukanoirua amino group, N- CI-
  • Alkyl force Rubamoiru group N- one C 1 () alkylthio force Luba moil group, N, N- di - ⁇ - C 1 C) alkyl force Rubamoiru group, N- C 2 - C 6 Al en carbamoyl group, N- Ami one C 10 alkyl force Rubamoiru group, N-C i one C 6 alkoxy C ⁇ one C E 0 alkyl force Rubamoiru group, N-C ⁇ - C 6 alkoxy force Lupo sulfonyl ⁇ 1 one C 1 Q alkyl force Rubamoiru group, N-Ci-Ce alkoxy alkoxyl.
  • Alkyl rubamoyl CA C 6 alkylthio, N—d—C 6 alkylsulfamoyl, C ⁇ _C 6 alkylsulfinyl, 1 C 6 alkylsulfonyl, N—1 C 6 alkylsulfonylamino , CI- C 6 alkoxy group, CI- C 6 alkoxy Cal Poni Le group, N- C 3 - C 6 cycloalkyl Ruamino group, C 3 - C 6 cycloalkyl O alkoxy group, and N- C 3 - C 6 cycloalkyl force Rubamoiru group
  • Substituents selected from the group consisting of: imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, pyragel group, pyrimidinyl group, pyridazinyl group
  • a substituent selected from the group consisting of an N—C-Ci0 alkyl group and a N- ⁇ ⁇ ⁇ , - ⁇ , ⁇ alkylthio group substituted with the heterocyclic group May be substituted with a linear saturated C aliphatic group, linear unsaturated-C 9 aliphatic group, branched chain saturated mono C 9 aliphatic group, branched unsaturated Ci—
  • substituents selected from the group consisting of a Cg aliphatic group, a C 6 alkoxy group, a C 6 alkylthio group and an N—C—C 6 alkylamino group Aryl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, chenyl, triazolyl, pyridyl, virazinyl, pyrimigel, pyridazinyl, pyrazolyl, furyl, tetrahyl Russia 5- or
  • R 3b and R 4b or R 5 b and R 6 b are such with each connexion, saturated C.-C 9 aliphatic groups, straight-chain, straight-chain unsaturated C.-C 9 aliphatic groups, branched-chain Saturated C x -C 9 aliphatic group or branched unsaturated Ci-Cg aliphatic group or 5- or 6-membered saturated carbocyclic group, 5- or 6-membered unsaturated carbocyclic ring or 5 or 6 Or R 3b , R 4b , R 5b and R 6b together form a fused aryl group, a di- or tricyclic saturated or unsaturated C 6 -C x 5 A condensed carbocyclic group or a 6-membered heterocycl
  • Alkylthio rubamoyl group N, N-di 0, -0 10 Alkyl rubamoyl group, N—C 2 —C 6 alkenylcarbamoyl group, Ci—C 6 alkylthio group, N—Ci—C 6 alkylsulfamoyl group, one C 6 alkyl sulfide El group, ⁇ - C 6 alkylsulfonyl group, N- one C 6 alkynyl Le sulfonyl ⁇ amino group, ⁇ - C e alkoxy group, one C 6 alkoxycarbonyl group, N- C 3 - C 6 cycloalkyl Arukiruamino group and N- C 3 _ C 6 cycloalkyl force Rubamoiru substituents selected from the group consisting of group, a pyridyl group, a pyrazinyl group, Te A substituent selected from the group consisting of a 5- or 6-membered heterocycl
  • X b is an oxygen atom or a sulfur atom
  • Y b3 ⁇ 4 is an oxygen atom
  • R c is an amino group, a carbamoyl group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, a formylamino group, an aralkyl group, an aryl group , N- ⁇ Li one Ruamino group, ⁇ Li one Ruokishi group, ⁇ reel sulfonyl group, ⁇ Li one Rusurufamoiru group, N- Ariru force Rubamoiru group, Aroiru group, Arokishi group, ⁇ 2 - (6 Arukanoiru group, N- C 2 — C fi alkanoylamino group, N— C — C fi alkylamino group, N, N-di-one C 6 alkylamino group, N—C 10 alkyl rubamoyl group, N
  • C 6 alkylamino group, one C 6 alkylthio group, Cj; may be substituted with a substituent or the substituents selected from a C 6 alkoxy and C one C 6 alkoxy group consisting of local Poni group, straight chain saturated one c 9 aliphatic groups, straight-chain unsaturated ⁇ - c 9 aliphatic group, a saturated one C 9 aliphatic group branched, branched-chain unsaturated.
  • R 3c R 4c R 5c and R 6c each independently represent a hydrogen atom, an amino group, a carbamoyl group, a carboxyl group, a cyano group.
  • C 9 aliphatic groups, linear unsaturated — C 9 aliphatic groups, branched saturated ci— C 9 aliphatic groups or branched unsaturated C x --C 9 represents an aliphatic group
  • R 3e and R 4e or R 5e and R 6e are taken together to form a linear saturated C.-C 9 aliphatic group, Forming a saturated C x -C 9 aliphatic group or a branched unsaturated C, -C 9 aliphatic group or a 5- or 6-membered heterocyclic group, Or, R 3c , R 4c , R 5C and R 6c together form a condensed aryl group, and R 7c is a linear saturated C 9 aliphatic group substituted by R 8c , a linear unsaturated mono c 9 aliphatic group, a saturated ci _ C 9 aliphatic group branched, unsaturated branched C - C 9 alipha
  • R d is an amino group, a sulfamoyl group, a cyano group, a sulfamoinole group, a halogen atom, a hydroxy group, a formylamino group, an N-arylamino group, an aryloxy group, an arylsulfonyl group, an aryls Rufamoiru group, N- Ariru force Rubamoiru group, Aroiru group, Arokishi group, C 2 - C 6 Arukanoiru group, N- C 2 - C 6 alkanoyloxy noisy Rua amino group, N- one C 6 alkylamino group, N- - C 1 0 aralkyl kill force Rubamoiru group, N- scratch.
  • Alkylthiocaproluvamoyl N _ C 2 —C 6 alkenylcarbamoyl, C ⁇ —C 6 alkylthio, N—C ⁇ —Ce alkyl sulfamoyl, C ⁇ —C 6 alkylsulfinyl, ⁇ —c 6 alkyl sulfonyl group, N- ( ⁇ - C 6 alkylsulfonyl ⁇ amino group, C - C 6 alkoxy group and C -!
  • a C 6 alkoxy substituent selected from the group consisting of local Poni Le group optionally having 1 or its been more
  • a 5- or 6-membered heterocyclic group selected from the group consisting of an aryl group, a pyridyl group, a pyrazinyl group, a tetrahydrofuranyl group, a dioxanyl group and a morpholino group, or an ethylenedioxyphenyl group and a methylenedioxyphenyl group.
  • heteroaromatic ring groups, R ld and R 2d are the same or different and are a hydrogen atom, amino group, carpamoyl group, cyano group, sulfamoyl group, halogen atom, hydroxy group, formylamino group, N——C 6 alkyl Amino group, Ci—C 6 alkylthio group, C! -C 6 alkoxy group and C!
  • R 3d , R 4d , R 5d and R 6d are each independently a hydrogen atom, an amino group, a carbamoyl group, a carboxyl group, a cyano group; group, a sulfamoyl group, Ha androgenic atom, hydroxy group, over an alkylthio group, - alkoxy Moto ⁇ beauty C i one C 6 alkoxy substituent selected from the group consisting of local Poni group, may be substituted with the substituent, Linear saturated — C 9 aliphatic group, linear unsaturated C — C 9 aliphatic group, branched saturated Ci— Cg aliphatic group and branched unsaturated d— C 9 aliphatic group or a substituent selected from the group consisting of, or, R 3d and R 4d or R 5 d and R 6 d are each together such connection, unsaturated C E one C
  • Z d is a condensed aryl group, or a 6-membered heterocyclic group or a nitrogen atom selected from the group consisting of ethylene dioxyphenyl group, pyridyl group, birazinyl group, pyrimidinyl group, pyridazinyl group and methylenedioxyphenyl group;
  • suitable compounds are, for example, Compound Examples 1001 to 1024, 1028, 1034 to 1043, 1045, 1062, 1065, 1093, 1094, 1095, 1104, 1108, 1110, 1115, 1116, 1117 , 1118, 1130, 1131, 1132, 1133, 1134, 1135, 1143, 1147, 1157, 1158, 1159, 1160, 1 161, 1162, 1166, 1167, 2018, 2025, 2026, 20 27, 2028, 2047, 2048 , 2049, 2050, 2051, 206 8, 2071, 2160, 2178, 2180, 2181, 2182, 2183, 3001, 3014, 3025, 3026, 3027, 3028, 3029, 3 030, 3031, 3032, 3033, 3036, 3038 , 3039, 30
  • the compound represented by the general formula [II] can be produced by the following production method A or production method B.
  • a compound represented by the general formula [I 1-2] or a compound represented by the general formula [I 1-3], wherein the intermediate represented by the general formula [V] This is a production method characterized by passing through an equilibrium mixture of a compound represented by the general formula [VI] and a compound represented by the general formula [VI].
  • R Q represents a hydrogen atom, an amino group which may be protected, a carbamoyl group, a carbamoylamino group, a carpamoyloxy group, a carboxy group which may be protected, a cyano group, a sulfamoyl group, Sulfo group, nitro group, halogen atom, hydroxy group which may be protected, formyl group, formylamino group, aralkyl group, N-aralkylamino group, aralkyloxy group, N-aralkylcarbamoyl group, aryl group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfamoyl group, N-arylarylbamoyl group, aryloyl group, alkoxy group, C 2 —C 6 alkanoyl group, N—C 2 —C 6 alkanoylamino group, N
  • substituent is selected from the group consisting of alkyl thio Cal Bamoiru group, a saturated c "c 9 aliphatic groups, straight-chain, straight-chain unsaturated c 9 aliphatic groups, branched saturated chain (: ⁇ C 9 fl fact aliphatic group, one C 9 fl fact aliphatic group of unsaturated branched, c 6 an alkoxy group, C ⁇ - Ce alkylthio group and N- one C 6 alkylamino A aryl group, or an imidazolyl group, an oxazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, which may have one or more substituents selected from the group consisting of substituents selected from the group consisting of 5 or 6 selected from the group consisting of triazolyl group, pyridyl group, pyrazinyl group, pyrimidiny
  • Alkylti Talented Lubamoyl group N, N-di-Ci-.
  • Alkyl radicals N_C 2 —C 6 alkenylcarbamoyl, C ⁇ —Cealkylthio, N—C “C 6 alkylsulfamoyl, C 1 C 6 alkylsulfinyl, 1 C 6 alkylsulfonyl, N— — Consists of C 6 alkylsulfonylamino, C—C 6 alkoxy, C 6 alkoxycarbonyl, N—C 3 —C 6 cycloalkylamino, and N—C 3 —C 6 cycloalkyl rubamoyl
  • C 10 alkylthio force Rubamoiru group N, N-di-primary alkyl force Rubamoiru group, N-C 2 - ⁇ 6 Aruke carbamoylmethyl group, a protected or N- amino one also be C 10 alkyl force Rubamoiru group, N _ C i- C 6 alkoxy C i-C i Q alkyl force Rubamoiru group, N- C i-C 6 alkoxy force Luponyl C ⁇ C ⁇ Alkyl Rubamoyl, N— ⁇ — C 6 Alkoxycarbonylamino C ”C.
  • R 3Q , R 4G , R 5G and R 6D are each independently a hydrogen atom, an amino group which may be protected, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a protected Carboxyl group, cyano group, sulfamoyl group, sulfo group, nitro group, halogen atom, optionally protected hydroxy group, formyl group, formylamino group, C 2 —C 6 alkanoyl group, N—C 2 — C 6 alkenyl group, N— — C 6 alkylamino group, N— Ci— C 10 alkylcarbamoyl group, C 6 alkylthio group, N_Ci— C 6 alkylsulfamoyl group, Ci-Ce alkylsulfinyl group , C x one C 6 alkylsulfonyl group, NC One C 6 alkylsul
  • R 9G has a protecting group for a hydroxy group, a protecting group for a mercapto group, or a protecting group for an amino group
  • the protecting group is appropriately removed to obtain a compound of the general formula [V]
  • Y t represents an oxygen atom or a sulfur atom or a group: in NR 9 Q (wherein, R 9 0 is a hydrogen atom, an optionally protected hydroxy group, formyl group, one C 6 7 Le Kill sulfonyl deflection group, N-C one C 6 alkylsulfonyl ⁇ amino groups, C one C 6 Al
  • Chain Saturation —C 9 aliphatic group, branched unsaturated C ”(indicating 9 aliphatic group or C ⁇ —Cealkylsulfonyl group), 1 ⁇ is hydrogen atom, R 0 , R 10 R 20 , R 3 , R 4 , R 50 , R 60 , R 70 , R 8 °, X and Z have the above-mentioned meanings].
  • R 0 , R 10 , R 20 , R 30 , R 40 , R 5 . , R 60 , R 70 , R 8 °, new X, and z have the above-mentioned meanings].
  • the compound represented by the general formula [V] and the compound represented by the general formula [VI] are useful as intermediates for producing the compound represented by the general formula [II] of the present invention, and are used for the reaction. In this case, it is usually used as an equilibrium mixture.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in a dehydrated inert organic solvent with a carboxylic acid or thiocarboxylic acid represented by the general formula [III].
  • the amine derivative represented by the formula [IV] can be added to a solvent, if necessary, in the presence of a base, a condensing auxiliary agent and z or a condensing agent, from — loot: the boiling point of the solvent, preferably from 0 to 30, for from 0.5 to 96 hours.
  • the reaction can be carried out preferably for 3 to 24 hours.
  • the condensed compound has a protecting group for an amino group, a protecting group for a hydroxy group or a protecting group for a mercapto group, the reaction is completed by appropriately removing the protecting group.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.
  • Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and the like.
  • N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, acetic anhydride, methyl alcohol, ethyl alcohol, benzene, xylene, water, acetic acid, toluene, 1,4-dioxane, tetrahydrofuran and the like are preferred.
  • reaction temperature in particular, for example, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, 1,4-dioxane, toluene are preferred.
  • Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1 Tertiary fats such as, 8-diazabicyclo [5.4.0] pendant 7-ene (DBU) and 1,5-azabicyclo [4.3.0] nona-5-ene (DBN)
  • Aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline and the like; Alkali metals such as potassium metal, sodium metal and lithium metal; sodium hydride, hydrogenation power Alkali metal hydrides such as lime; Alkali metal alkylates such as butyllithium; Potassium tert-butylate, Sodium ethyla And alkali metal alkoxides such as sodium methylate; for example, al
  • condensation adjuvant used in the reaction examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norporene-1,2,3-dicarpoxyimide, 3-hydroxy-3, 4-dihydro-41-oxo-1,2,3-benzotriazole and the like, among which N-hydroxybenzotriazole and the like are preferable.
  • condensing agent used in the reaction examples include thionyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N'-carbonyldiimidazole, Enylphosphoryl chloride, diphenylphosphoryl azide, N, N'-disuccinimidyl carbonate, N, N'-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylamino Propyl) carbodiimide hydrochloride, ethyl ethyl chloroformate, isoptyl chloroformate, benzotriazo-1-l-loxoquistris (dimethylamino) phosphoniumhexafluorophosphate and the like, among which, for example, N, N-dicyclohexylcarboimide , 1-Ethyl-3- (3-dimethylaminopropyl
  • the amount of the reagent used in the reaction o can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 0.02 to 50 equivalents to the carboxylic acid or thiocarponic acid represented by the general formula [III].
  • Preferably 0.2 to 2 equivalents of the amine derivative represented by the general formula [IV] 1 to 50 equivalents, preferably 3 to 5 equivalents of a base, 1 to 50 equivalents, preferably 1 to 5 equivalents of condensation aid and / or 1 to 50 equivalents, preferably 1 to 5 equivalents, of condensing agent are used.
  • the base, the condensation aid and the condensing agent can be used alone or in appropriate combination of two or more.
  • the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.
  • the reaction is carried out in a dehydrated inert organic solvent using a compound represented by the general formula [V] and a compound represented by the general formula [VI]
  • the reaction can be carried out by reacting an equilibrium mixture of the compound represented by the formula with a catalytic amount of an acid at a temperature of from 100 to the boiling point of the solvent, preferably from 0 to 30, preferably from 0.5 to 96 hours, preferably from 2 to 24 hours. it can.
  • Protecting groups that protect other functional groups other than those described above can be selected from N-protecting groups, carboxyl protecting groups, and hydroxy groups by appropriately selecting the type of protecting group, the method for removing the protecting group, or the reaction conditions. Can be removed at the same time. Further, any one of an N-protecting group, a protecting group for a carbonyl group, and a protecting group for a hydroxy group can be selectively removed. Furthermore, the order of removing the protecting group is not particularly limited. It is not something to be done.
  • hydroxy-protecting group examples include lower alkylsilyl groups such as tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; An aralkyl group such as a benzyl group and a p-methoxybenzyl group; an acetyl group such as a formyl group and an acetyl group; and the like, particularly a tert-butyldimethylsilyl group and an acetyl group;
  • Examples of the mercapto group-protecting group include an aralkyl group such as a benzyl group and a p-methoxybenzyl group; and an acetyl group such as a formyl group, a benzoyl group and an acetyl group. Particularly, a benzoyl group and an acetyl group are preferable. .
  • Examples of the protecting group for an amino group include: aralkyl groups such as benzyl group and p-nitrobenzyl group; for example, acyl groups such as formyl group and acetyl group; and lower alkoxy groups such as ethoxycarbonyl group and tert-butoxycarbonyl group.
  • a ruponyl group for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p_nitrobenzyloxycarbonyl group; and particularly, a p-nitrobenzyl group, a tert-butoxycarbonyl group, A benzyloxycarbonyl group and the like are preferred.
  • carboxyl-protecting group examples include lower alkyl groups such as methyl group, ethyl group and tert-butyl group; and aralkyl groups such as benzyl group and p-methoxybenzyl group. Preferred are an ethyl group, a tert-butyl group and a benzyl group.
  • the removal of the protecting group depends on the type and stability of the compound.
  • the method described in the literature [Protective Group 'In' Organic Synthesis (Protective Group Organic Synthesis), TW Green ( TW Greene), John Wiley & Sons (1981)] or a method analogous thereto, for example, solvolysis using an acid or base, chemical reduction using a metal hydride complex, or palladium. It can be carried out by catalytic reduction using a carbon catalyst, Raney nickel catalyst or the like.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include the inert solvents described above.
  • the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid and perchloric acid; Lewis acids such as trifluoroboric acid; Sulfonic acids such as fluoromethanesulfonic acid and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and, for example, Lewis acids such as trifluoroboric acid and organic acids such as trifluoroacetic acid are preferable. .
  • Examples of the oxidizing agent used in the reaction include inorganic peracids such as hydrogen peroxide; inorganic persalts such as potassium permanganate, sodium hypochlorite, and sodium periodate; Organic peracids such as peroxybenzoic acid and the like are preferable.
  • inorganic peracids such as hydrogen peroxide
  • organic peracids such as m-mouth perbenzoic acid are preferable.
  • the product is further purified by a commonly known method to obtain a compound represented by the general formula [I1-1] or a compound represented by the general formula [I1-2].
  • Isolation and purification of a compound represented by the general formula [I1-1], a compound represented by the general formula [II-12], a compound represented by the general formula [I1-3], or a salt thereof from the reaction solution Can be carried out by known separation means such as solvent extraction, recrystallization and chromatography. Manufacturing method B
  • a method for producing a compound represented by the general formula [V] and a compound represented by the general formula [VI] which is a cyclization without passing through an equilibrium mixture of the compound represented by the general formula [VI] and the compound represented by the general formula [VI] It is a manufacturing method characterized by the following.
  • Y 2 represents an oxygen atom or a sulfur atom or a group: NR 9 Q (where R 9 has the above-mentioned meaning), L 2 represents a hydrogen atom, and R 3G , R 4Q , R 5Q and R 6Q have the same meaning as described above], by reacting the compound with an acid in an inert organic solvent to obtain a compound of the general formula [VII ′]
  • the reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.
  • the reaction is carried out in a dehydrated inert organic solvent using a compound represented by the general formula [III] and a compound represented by the general formula [VIII] With a catalytic amount of an acid from-loot: at the boiling point of the solvent, preferably 0 to 30 for 0.5 to 96 hours, preferably 2 to 24 hours. .
  • an amino-protecting group, a hydroxy-protecting group, or a hydroxyl group-protecting group is present, the amino-protecting group, the hydroxy-protecting group, or the hydroxyl-protecting group is appropriately removed.
  • the reaction is completed.
  • the protecting group for protecting the functional group can be selected from N-protecting group, carboxyl protecting group, hydroxy group protecting group, and the like by appropriately selecting the type of protecting group, the method for removing the protecting group, or the reaction conditions. Can be removed at the same time. In addition, any one of N-protecting group, carboxyl protecting group, and hydroxy protecting group can be selectively removed, and the order of removing the protecting group is not particularly limited. Absent.
  • Examples of the protecting group for the hydroxy group include lower alkylsilyl groups such as tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; An aralkyl group such as a benzyl group or a p-methoxybenzyl group; an acyl group such as a formyl group or an acetyl group; and the like, particularly a tert-butyldimethylsilyl group and an acetyl group;
  • amino-protecting group examples include aralkyl groups such as benzyl group and P-nitrobenzyl group; acyl groups such as formyl group and acetyl group; lower alkoxy groups such as ethoxycarponyl group and tert-butoxycarponyl group.
  • a luponyl group for example, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group; and particularly, a p-nitrobenzyl group, t An ert-butoxycarbonyl group, a benzyloxycarbonyl group and the like are preferable.
  • Examples of the protecting group for the carbonyl group include lower alkyl groups such as methyl group, ethyl group and tert-butyl group; and aralkyl groups such as benzyl group and p-methoxybenzyl group. , An ethyl group, a tert-butyl group, a benzyl group and the like.
  • the removal of the protecting group depends on the type and stability of the compound.
  • the method described in the literature [Protective Group's Organic Synthesis (Protective Group Organic Synthesis), TW Green ( TW Greene), John Wiley & Sons (1981)] or a method analogous thereto, for example, solvolysis using an acid or a base, chemical reduction using a metal hydride complex, or palladium. It can be carried out by catalytic reduction using a carbon catalyst, Raney nickel catalyst or the like.
  • the inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include the inert solvents described above.
  • Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid; Lewis acids such as trifluoroboric acid; Sulfonic acids such as trifluoromethanesulfonic acid and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and, for example, Lewis acids such as trifluoroboric acid and organic acids such as trifluoroacetic acid are preferable. is there.
  • inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid
  • Lewis acids such as trifluoroboric acid
  • Sulfonic acids such as trifluoromethanesulfonic acid and methanesulfonic acid
  • organic acids such as formic acid, trifluoroacetic acid, and acetic acid
  • Lewis acids such
  • Examples of the oxidizing agent used in the reaction include inorganic peracids such as hydrogen peroxide; inorganic persalts such as potassium permanganate, sodium hypochlorite, and sodium periodate; Organic peracids such as perbenzoic acid and the like are preferable.
  • inorganic peracids such as hydrogen peroxide
  • organic peracids such as m-chloroperbenzoic acid are preferable.
  • the product is further purified by a commonly known method to give a compound represented by the general formula [I1-1] or a compound represented by the general formula [II-2] or A compound represented by the general formula [I 1-3] can be obtained.
  • a compound represented by the general formula [II-11] or a compound represented by the general formula [II-11] can be isolated and purified by a known separation means such as solvent extraction, recrystallization, and chromatography.
  • the carboxylic acid or thiocarboxylic acid represented by the general formula [III] is known in the literature, or is represented by the general formula [IX]
  • L 3 Represents a hydrogen atom or a protecting group for a carboxylic acid or a protecting group for a thiocarboxylic acid
  • R Q , R 1G , R 2 °, X and Z have the above-mentioned meanings.
  • A represents a halogen atom, a leaving group such as a methyl sulfonyloxy group or a tributyltin group, or a reactive substituent
  • R 7Q and R 8Q have the above-mentioned meanings
  • a compound such as acetonitrile or N, N-dimethylformamide in the presence of a base such as potassium carbonate at a low temperature to the boiling point of the solvent, or an appropriate solvent such as toluene.
  • the reaction is carried out at a low temperature to the boiling point of the solvent in the presence of a suitable base such as potassium carbonate or the like, and L 3 .
  • a carboxylic acid protecting group or a thiocarboxylic acid protecting group it can be produced by removing the protecting group.
  • L 4Q is a hydrogen atom or, for example, a methanesulfonyl group ⁇ p-toluenesulfur A substituent which becomes a leaving group by being substituted by an oxygen atom such as a honyl group; Is a protecting group for an amino group, Y 4 () represents an oxygen atom, and R 3Q , R 4Q , R 5Q and R 6Q have the above-mentioned meanings] and an alcohol or alcohol derivative represented by the general formula [XII]
  • L 41 represents a hydrogen atom or an amino-protecting group, and R 9Q has the above-mentioned meaning], or is reacted with an amine derivative represented by the general formula [XI].
  • L 42 represents a protecting group of the mercapto group] is reacted with a mercapto derivative represented by, subsequently, if L 41 or L 42 is a protective group protecting group or a mercapto group Amino group protection It can be produced by removing a group.
  • a method for producing the compound represented by the general formula [I] of the present invention will be described.
  • the compound represented by the general formula [I] can be produced by the following production method C or production method D in the same manner as in the production method of the compound represented by the general formula [II]. Manufacturing method c
  • Y is an oxygen atom
  • S O n (where n represents an integer of 0 to 2) or A compound represented by the general formula [I-1] or a compound represented by the general formula [I-12] of the present invention, which is a group: NR 9 (where R 9 has the above-mentioned meaning);
  • This is a production method characterized by passing through an equilibrium mixture.
  • R 3Q , R 4Q , R 5Q , R 6Q,. And L 1 () have the same meaning as described above], in the same manner as in the reaction of the first step of Production Method A, and then Yi.
  • R 9 G has a protecting group for a hydroxy group, a protecting group for a mercapto group, or a protecting group for an amino group, the protecting group is appropriately removed to obtain a compound of the general formula [V_2]
  • the compound represented by the general formula [CV-2] can be prepared by reacting the compound represented by the general formula [VI-2] in a solvent.
  • the 7J acid group is a mercapto group or the group: NR 9Q (Where R 9G represents a hydrogen atom, an optionally protected hydroxy group, formyl group, ⁇ —C 6 alkylsulfonyl group, N—Ci—C 6 alkyl sulfonylamino group, Ci—C 6 alkoxy group
  • R 9G represents a hydrogen atom, an optionally protected hydroxy group, formyl group, ⁇ —C 6 alkylsulfonyl group, N—Ci—C 6 alkyl sulfonylamino group, Ci—C 6 alkoxy group
  • the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 0.02 to 50 or the like based on the carboxylic acid or thiocarbonic acid represented by the general formula [III-12].
  • the base, the condensation aid and the condensing agent can be used alone or in appropriate combination of two or more.

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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle R représente un groupe amino, etc., R1 et R2 sont identiques ou différents et représentent chacun un atome d'hydrogène, etc., R?3, R4, R5 et R6¿ représentent chacun indépendamment un atome d'hydrogène, etc., R7 représente un atome d'hydrogène, etc., X représente un atome d'oxygène, etc., Y représente un atome d'oxygène, etc. et Z représente un groupe aryle fusionné, etc. Du fait de leur activité favorisant une concentration élevée de GLP-1 dans le sang, ces composés sont utiles comme médicaments dans le traitement du diabète ou la prévention de complications chroniques du diabète, comme agents contre l'obésité, etc.
PCT/JP2002/001576 2001-02-23 2002-02-22 Derives de l'isoindole WO2002066479A1 (fr)

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WO2005061513A1 (fr) * 2003-12-24 2005-07-07 Biota Scientific Management Pty Ltd Agents polycycliques pour le traitement d'infections par le virus syncytial respiratoire
US7081239B2 (en) 1995-05-17 2006-07-25 Cedars-Sinai Medical Center Burns And Allen Research Center Methods for manipulating upper gastrointestinal transit, blood flow, and satiety, and for treating visceral hyperalgesia
US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
AU2004273615B2 (en) * 2003-09-23 2009-01-15 Novartis Ag Combination of a VEGF receptor inhibitor with a chemotherapeutic agent
EP2329839A1 (fr) 2002-01-10 2011-06-08 Imperial Innovations Limited Modification du comportement d'alimentation par GLP-1 et PYY
EP2371378A1 (fr) 2003-01-10 2011-10-05 Imperial Innovations Limited Modification des habitudes alimentaires
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour
US8598194B2 (en) 2006-09-28 2013-12-03 Biota Scientific Management Pty Ltd. Polycyclic agents for the treatment of respiratory syncytial virus infections
US8604034B2 (en) 2010-02-08 2013-12-10 Biota Scientific Management Pty Ltd. Substituted imidazo[1,2-α]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus (RSV) infections
US8796303B2 (en) 2010-11-26 2014-08-05 Biota Scientific Management Pty Ltd. Imidazo[2,1-G][1,7]naphthyridines for treating respiratory syncytial virus infections

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US7615207B2 (en) 2000-04-10 2009-11-10 Cedars-Sinai Medical Center Methods for treating irritable bowel syndrome
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US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
EP2329839A1 (fr) 2002-01-10 2011-06-08 Imperial Innovations Limited Modification du comportement d'alimentation par GLP-1 et PYY
EP2371378A1 (fr) 2003-01-10 2011-10-05 Imperial Innovations Limited Modification des habitudes alimentaires
AU2004273615B2 (en) * 2003-09-23 2009-01-15 Novartis Ag Combination of a VEGF receptor inhibitor with a chemotherapeutic agent
EP2287167A1 (fr) 2003-12-24 2011-02-23 Biota Scientific Management Pty. Ltd. Agents polycycliques pour le traitement des infections de virus respiratoire syncytial
WO2005061513A1 (fr) * 2003-12-24 2005-07-07 Biota Scientific Management Pty Ltd Agents polycycliques pour le traitement d'infections par le virus syncytial respiratoire
JP2007516983A (ja) * 2003-12-24 2007-06-28 バイオウタ サイエンティフィック マネジメント プロプライエタリー リミテッド 呼吸器合胞体ウイルス感染の処置のための多環式薬剤
US8598193B2 (en) 2003-12-24 2013-12-03 Biota Scientific Management Pty Ltd. Polycyclic agents for the treatment of respiratory syncytial virus infections
US8598194B2 (en) 2006-09-28 2013-12-03 Biota Scientific Management Pty Ltd. Polycyclic agents for the treatment of respiratory syncytial virus infections
US9675694B2 (en) 2006-09-28 2017-06-13 Biota Scientific Management Pty Ltd Polycyclic agents for the treatment of respiratory syncytial virus infections
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour
US8604034B2 (en) 2010-02-08 2013-12-10 Biota Scientific Management Pty Ltd. Substituted imidazo[1,2-α]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus (RSV) infections
US9163029B2 (en) 2010-02-08 2015-10-20 Biota Scientific Management Pty Ltd. Substituted imidazo[1,2-a]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus infections
US8796303B2 (en) 2010-11-26 2014-08-05 Biota Scientific Management Pty Ltd. Imidazo[2,1-G][1,7]naphthyridines for treating respiratory syncytial virus infections

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