WO2009148004A1 - Nouveau composé et son application pharmaceutique - Google Patents

Nouveau composé et son application pharmaceutique Download PDF

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WO2009148004A1
WO2009148004A1 PCT/JP2009/059943 JP2009059943W WO2009148004A1 WO 2009148004 A1 WO2009148004 A1 WO 2009148004A1 JP 2009059943 W JP2009059943 W JP 2009059943W WO 2009148004 A1 WO2009148004 A1 WO 2009148004A1
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group
general formula
optionally substituted
carbon atoms
atom
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PCT/JP2009/059943
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Japanese (ja)
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雅宏 吉田
将夫 坂入
義治 鍔本
敬志 中村
幸恵 水野
卓司 垣上
広志 木下
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株式会社 三和化学研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel compound and its pharmaceutical use.
  • the compounds in particular have various pharmaceutical uses as GIP receptor binding inhibitors.
  • GIP gastric inhibitory polypeptide
  • GIP gastric inhibitory polypeptide
  • K cells present in the small intestine at the time of feeding and promotes glucose-responsive insulin secretion in pancreatic ⁇ cells, thereby regulating the pharmacokinetics of nutrients accompanying feeding.
  • the GIP receptor gene is widely expressed not only in pancreatic ⁇ cells but also in cells of various tissues including adipocytes, and research on the details of the function has been advanced.
  • Obesity is one of the risk factors for lifestyle-related diseases such as diabetes, hypertension, and hyperlipidemia. In recent years, the increase in obesity has become a global problem. Obesity is defined as an excessive accumulation of adipose tissue and is diagnosed as obesity and subject to medical treatment if it is or is predicted to be associated with obesity-related or associated health disorders It becomes. Treatment of obesity is first performed by combining diet therapy and exercise therapy, and drug therapy is applied when the therapeutic effect is insufficient.
  • central appetite suppressant As a preventive or ameliorating agent for obesity, various researches such as central appetite suppressant, ⁇ 3 adrenergic receptor agonist, digestion absorption inhibitor, lipid synthesis inhibitor, leptin have been developed. Only the central appetite suppressant mazindol (Sanolex: registered trademark) is clinically used as an adjunct to diet and exercise therapy for severe obesity. However, mazindol has been pointed out a problem of dependence because of its central clinical effect and inadequate clinical effect. Other central appetite suppressants with different mechanisms of action have been developed, but there are concerns about central side effects such as increased blood pressure, anxiety, and headache.
  • Orlistat which is clinically used in Europe and the United States, is a lipase inhibitor that suppresses fat absorption by suppressing degradation of ingested fat in the small intestine.
  • Orlistat no serious side effects have been reported, but side effects of gastrointestinal symptoms such as fatty stool, loose stool and abdominal pain have been reported.
  • leptin has been reported to be a novel anti-obesity drug because it has been reported to suppress body weight gain by reducing food intake and increasing energy consumption.
  • its therapeutic effect has been limited.
  • ⁇ 3 receptor agonists are also expected as anti-obesity agents, but high receptor selectivity is essential, and if the selectivity is insufficient, there are concerns about side effects on the heart and the like.
  • anti-obesity drugs based on various mechanisms of action are on the market or are under research and development, but there are no drugs that have sufficient body weight suppression action and safety.
  • insulin resistance is defined as a state of insufficient insulin action due to decreased insulin sensitivity in peripheral tissues, and becomes a state of hyperinsulinemia due to a compensatory increase in insulin secretion.
  • Insulin resistance is attracting attention not only as one of the onset factors of type 2 diabetes caused by obesity but also as one of the causes of hyperglycemia and abnormal lipid metabolism. It is thought to play a central role.
  • pioglitazone Actos: registered trademark
  • GIP function inhibitors include suppression of lipid accumulation in the liver observed in GIP receptor gene-deficient mice loaded with a high-fat diet and also in wild-type mice loaded with a high-fat diet. Has been reported (see Non-Patent Document 1).
  • Examples of the compound having a GIP receptor binding inhibitory action include GIP (6-30) -NH 2 (see Non-Patent Document 4), GIP (7-30) -NH 2 (see Non-Patent Document 5), (Pro (3)) GIP (see Non-Patent Document 6) and the like.
  • GIP (6-30) -NH 2 see Non-Patent Document 4
  • GIP (7-30) -NH 2 see Non-Patent Document 5
  • (Pro (3)) GIP see Non-Patent Document 6
  • these are long-chain peptides and have problems with oral absorption and blood stability, it is not appropriate to use them as anti-obesity agents.
  • Patent Document 1 As a low molecular weight compound that inhibits the function of GIP, there is 3-bromo-5-methyl-2-phenylpyrazolo [1,5-A] pyrimidin-7-ol disclosed in Patent Document 1. The inhibitory activity is weak with an IC 50 value of about 40 ⁇ M.
  • Patent Document 2 discloses that a methylidene hydrazide compound exhibits an inhibitory action on GIP function. Among these compounds, 3-cyano-4-hydroxybenzoic acid [1- (2,3,5,6-tetramethylbenzyl) -1H-indole-4-ylmethylene] hydrazide shows a strong inhibitory action. Is extremely difficult to use as a pharmaceutical because it has extremely low solubility and is physically and metabolically unstable.
  • Patent Document 3 discloses that a pyrazolopyrimidine compound exhibits an inhibitory action on GIP function, but cannot be said to have sufficient activity. Thus, none of the compounds that have been reported so far that inhibit the function of GIP are satisfactory as pharmaceuticals.
  • Patent Document 4 discloses a compound exhibiting glucagon antagonistic activity. However, there is no description about the inhibitory action of GIP function here, and the inhibitory action of GIP function is shown by patent document 2 about some compounds.
  • the long-chain peptide compounds having a GIP receptor binding inhibitory activity reported so far have problems in oral absorption and blood stability.
  • low molecular weight compounds that inhibit the function of GIP reported so far have problems such as insufficient activity, low solubility, and physical and metabolic instability. Therefore, the present invention provides a compound that inhibits the function of GIP, which is sufficiently satisfactory as a pharmaceutical, and further, obesity, insulin resistance, or It is an object to provide an agent for preventing or improving lipid accumulation in the liver.
  • a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein W represents a nitrogen atom or CR 1 , R 1 represents a halogen atom, a cyano group, or a nitro group, and Z represents the following general formula (V1), the following general formula (V2), or the following general formula Formula (Y1):
  • A means an optionally substituted aryl group
  • R 2 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted group.
  • An aryl group means R 3 is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkylmethyl group having 4 to 8 carbon atoms, or an optionally substituted alkyl group.
  • R 4 and R 5 each independently represents a hydrogen atom, a hydroxyl group or an optionally substituted carbon atom having 1 to 6 carbon atoms.
  • R 6 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms
  • 7 and R 8 are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkyl group having 3 to 7 carbon atoms, or optionally substituted.
  • R 9 and R 10 each represent an integer, and are each a 5- to 6-membered heterocyclic ring formed together with R 9 and R 10 and the nitrogen atom at the base or with another nitrogen atom or oxygen atom.
  • the compounds of the present invention represented by the general formula (I) can be divided into the following two groups of compounds.
  • the first form is a compound represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.
  • W has the same meaning as in the general formula (I)
  • V means a group represented by the general formula (V1) or the general formula (V2).
  • V in the general formula (II) is the following general formula (V3) or the following general formula (V4): [Wherein all symbols have the same meanings as in the general formula (V1) and the general formula (V2). ] It is preferable to make it group represented by these.
  • A is preferably an optionally substituted phenyl group
  • R 2 is a hydrogen atom or a substituted one. It is preferably an alkyl group having 1 to 3 carbon atoms which may be substituted, or a phenyl group which may be substituted.
  • W in the general formula (II) is preferably CR 1 and R 1 is preferably a halogen atom or a cyano group.
  • the second form is a compound represented by the following general formula (III) or a pharmaceutically acceptable salt thereof.
  • W has the same meaning as in the general formula (I)
  • Y means a group represented by the general formula (Y1).
  • Y in the general formula (III) is the following general formula (Y2): [Wherein all symbols have the same meanings as in the general formula (Y1). ] It is preferable to make it group represented by these.
  • R 4 and R 5 are preferably both hydrogen atoms or optionally substituted alkyl groups having 1 to 3 carbon atoms, and a methyl group is most preferred.
  • R 3 is preferably an optionally substituted phenylsulfonyl group.
  • W in the general formula (III) is preferably CR 1 and R 1 is preferably a halogen atom or a cyano group.
  • the present invention further relates to a use invention and a pharmaceutical composition invention of the compound of the present invention. That is, the present invention also provides a GIP receptor binding inhibitor containing the compound of the present invention as an active ingredient and a pharmaceutical composition containing the compound of the present invention as an active ingredient.
  • the pharmaceutical composition of the present invention is used for prevention or improvement of obesity, prevention or improvement of insulin resistance, prevention or improvement of lipid accumulation in the liver.
  • the compound of the present invention is an agent for preventing or improving obesity, an agent for preventing or improving insulin resistance, an agent for preventing or improving lipid accumulation in the liver, or a GIP receptor binding inhibitor. It becomes use of this invention compound for manufacturing.
  • the compound of the present invention has an excellent inhibitory effect on GIP receptor binding, and is useful as an agent for preventing or improving obesity, insulin resistance, or lipid accumulation in the liver.
  • the first form of the compound of the present invention is represented by the following general formula (II).
  • W represents a nitrogen atom or CR 1
  • R 1 represents a halogen atom, a cyano group, or a nitro group.
  • the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
  • V means the following general formula (V1) or the following general formula (V2).
  • A represents an optionally substituted aryl group
  • R 2 represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group.
  • V in the general formula (II) is preferably the following general formula (V3) or the following general formula (V4).
  • A is preferably an optionally substituted phenyl group, and in particular, phenyl group, methylphenyl group, methoxyphenyl group, ethoxyphenyl group, t-butylphenyl Group, trifluoromethylphenyl group, trifluoromethoxyphenyl group, hydroxyphenyl group, phenoxyphenyl group, dimethylaminophenyl group and the like are preferable.
  • R 2 is preferably a hydrogen atom, an optionally substituted alkyl group having 1 to 3 carbon atoms, or an optionally substituted phenyl group.
  • W in the general formula (II) selects CR 1 and R 1 is preferably a halogen atom or a cyano group, and more preferably a chlorine atom or a cyano group.
  • W represents a nitrogen atom or CR 1
  • R 1 represents a halogen atom, a cyano group, or a nitro group.
  • the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
  • Y means the following general formula (Y1).
  • R 3 is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkylmethyl group having 4 to 8 carbon atoms, or an optionally substituted carbon atom having 1 to 6 carbon atoms.
  • Alkylsulfanyl group optionally substituted phenylsulfanyl group, optionally substituted alkylsulfinyl group having 1 to 6 carbon atoms, optionally substituted phenylsulfinyl group, optionally substituted carbon number 1 To 6 alkylsulfonyl groups, an optionally substituted phenylsulfonyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted aroyl group, or an optionally substituted Means a good aralkyloxycarbonyl group.
  • Preferred examples of the substituent include a hydrogen atom, an optionally substituted alkyl group having 1 to 3 carbon atoms, an optionally substituted cycloalkylmethyl group having 6 to 8 carbon atoms, and an optionally substituted carbon number 1 -3 alkylsulfonyl groups, an optionally substituted phenylsulfonyl group, or an optionally substituted aralkyl group.
  • R 4 and R 5 each independently represents a hydrogen atom, a hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, COOR 6 , CONR 7 R 8 , or an optionally substituted aryl group. means.
  • R 6 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms
  • R 7 and R 8 each independently represents a hydrogen atom or an optionally substituted carbon atom having 1 to 6 carbon atoms.
  • n represents an integer of 1 to 3
  • R 9 and R 10 represent a 5- to 6-membered heterocyclic ring formed together with R 9 and R 10 and the root nitrogen atom or further with another nitrogen atom or oxygen atom.
  • Y in general formula (III) is preferably the following general formula (Y2).
  • R 4 and R 5 are preferably both hydrogen atoms or optionally substituted alkyl groups having 1 to 3 carbon atoms, and a methyl group is most preferable.
  • R 3 is preferably an optionally substituted phenylsulfonyl group.
  • W in the general formula (III) is preferably CR 1 and R 1 is preferably a halogen atom or a cyano group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the “optionally substituted alkyl group having 1 to 6 carbon atoms” means a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted, and has 1 to 6 carbon atoms.
  • Arbitrary (“arbitrary” includes a plurality of cases, the same applies hereinafter) of a linear or branched alkyl group, a hydrogen atom is a halogen atom, a nitro group, a cyano group, a hydroxyl group, or a carbon number of 1 It means that it may be substituted by 6 to 6 linear or branched alkoxy groups or the like.
  • the aryl group of the “optionally substituted aryl group” is a monocyclic or bicyclic aromatic hydrocarbon or aromatic heterocyclic ring, and any hydrogen atom of the aryl group is a halogen atom Substituted with a hydroxyl group, a mono- or di-substituted amino group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms.
  • a 5- to 6-membered cyclic amino group (which may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom or a sulfur atom), a nitro group, a cyano group, a hydroxyl group, 1 carbon atom 1 to 6 linear or branched acyl group, 1 to 6 carbon straight chain or branched alkyl group, 1 to 6 carbon straight chain or branched alkoxy group, phenyl group, etc. Means that it may be substituted by That.
  • the “optionally substituted cycloalkylmethyl group having 4 to 8 carbon atoms” means that any hydrogen atom of the cycloalkylmethyl group having 4 to 8 carbon atoms is a halogen atom, nitro group, cyano group, hydroxyl group, carbon It means that it may be substituted by a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • cyclopropylmethyl group cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, 1-cyclohexylethyl group, (1-cyclohexyl-1-methyl) ethyl group, methylcyclohexylmethyl group Chlorocyclohexylmethyl group, cyanocyclohexylmethyl group, nitrocyclohexylmethyl group, hydroxycyclohexylmethyl group, methoxycyclohexylmethyl group, ethoxycyclohexylmethyl group and the like.
  • the “optionally substituted alkylsulfanyl group having 1 to 6 carbon atoms” refers to an alkylsulfanyl group in which the alkyl moiety is an optionally substituted alkyl group having 1 to 6 carbon atoms (as defined above).
  • methylsulfanyl group trifluoromethylsulfanyl group, ethylsulfanyl group, cyanoethylsulfanyl group, nitroethylsulfanyl group, n-propylsulfanyl group, i-propylsulfanyl group, n-butylsulfanyl group, i -Butylsulfanyl group, t-butylsulfanyl group, pentylsulfanyl group, hexylsulfanyl and the like.
  • the “optionally substituted phenylsulfanyl group” means that any hydrogen atom of the phenyl group is a halogen atom, a nitro group, a cyano group, a hydroxyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms. Or, it may be substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • methylphenylsulfanyl group methoxyphenylsulfanyl group, dimethylphenylsulfanyl group, ethylphenylsulfanyl group, ethoxyphenylsulfanyl group, n-propylphenylsulfanyl group, i-propylphenylsulfanyl group, chlorophenylsulfanyl group, nitrophenyl A sulfanyl group, a cyanophenylsulfanyl group, a hydroxyphenylsulfanyl group and the like can be mentioned.
  • the “optionally substituted alkylsulfinyl group having 1 to 6 carbon atoms” refers to an alkylsulfinyl group in which the alkyl moiety is an optionally substituted alkyl group having 1 to 6 carbon atoms (as defined above).
  • methylsulfinyl group trifluoromethylsulfinyl group, ethylsulfinyl group, cyanoethylsulfinyl group, nitroethylsulfinyl group, n-propylsulfinyl group, i-propylsulfinyl group, n-butylsulfinyl group, i -Butylsulfinyl group, t-butylsulfinyl group, pentylsulfinyl group, hexylsulfinyl and the like.
  • the “optionally substituted phenylsulfinyl group” means that any hydrogen atom of the phenyl group is a halogen atom, a nitro group, a cyano group, a hydroxyl group, a linear or branched alkyl group having 1 to 6 carbon atoms. Or, it may be substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • methylphenylsulfinyl group methoxyphenylsulfinyl group, dimethylphenylsulfinyl group, ethylphenylsulfinyl group, ethoxyphenylsulfinyl group, n-propylphenylsulfinyl group, i-propylphenylsulfinyl group, chlorophenylsulfinyl group, nitrophenyl A sulfinyl group, a cyanophenylsulfinyl group, a hydroxyphenylsulfinyl group and the like can be mentioned.
  • the “optionally substituted alkylsulfonyl group having 1 to 6 carbon atoms” means an alkylsulfonyl group in which the alkyl moiety is an optionally substituted alkyl group having 1 to 6 carbon atoms (as defined above).
  • methylsulfonyl group trifluoromethylsulfonyl group, ethylsulfonyl group, cyanoethylsulfonyl group, nitroethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i -Butylsulfonyl group, t-butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl and the like.
  • the “optionally substituted phenylsulfonyl group” means that any hydrogen atom of the phenyl group is a halogen atom, a nitro group, a cyano group, a hydroxyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms. Or, it may be substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • methylphenylsulfonyl group methoxyphenylsulfonyl group, dimethylphenylsulfonyl group, ethylphenylsulfonyl group, ethoxyphenylsulfonyl group, n-propylphenylsulfonyl group, i-propylphenylsulfonyl group, chlorophenylsulfonyl group, nitrophenyl
  • the “optionally substituted aralkyl group” means that an optionally substituted aryl group (as defined above) is substituted on an optionally substituted alkyl group having 1 to 6 carbon atoms (as defined above).
  • benzyl group methylbenzyl group, methoxybenzyl group, n-butylbenzyl group, i-butylbenzyl group, t-butylbenzyl group, ethylbenzyl group, ethoxybenzyl group, n-butoxy Benzyl group, i-butoxybenzyl group, t-butoxybenzyl group, fluorobenzyl group, chlorobenzyl group, nitrobenzyl group, cyanobenzyl group, trifluoromethylbenzyl group, dimethylaminobenzyl group, morpholinobenzyl group, piperazinobenzyl Group, N-methylpiperazinobenzyl group, piperidinobenzyl group, 1-phen
  • the “optionally substituted aroyl group” is a group in which an optionally substituted aryl group (as defined above) is substituted on a carbonyl group, and specifically includes a benzoyl group, a methylbenzoyl group, n-propylbenzoyl group, i-propylbenzoyl group, methoxybenzoyl group, n-propoxybenzoyl group, i-propoxybenzoyl group, chlorobenzoyl group, nitrobenzoyl group, cyanobenzoyl group, hydroxybenzoyl group, naphthanoyl group, methylnaphthanoyl group Group, n-propylnaphthanoyl group, i-propylnaphthanoyl group, methoxynaphthanoyl group, n-propoxynaphthanoyl group, i-propoxynaphthanoyl group, chloronaph
  • the “optionally substituted aralkyloxycarbonyl group” is a group in which an aralkyl group which may be substituted via an oxygen atom is substituted on a carbonyl group, specifically, a benzyloxycarbonyl group, phenethyl or the like.
  • the “5- to 6-membered heterocyclic ring formed together with R 6 and R 7 and the base nitrogen atom or further with another nitrogen atom or oxygen atom” specifically means a pyrrolidino group, piperidino group, piperazino group, morpholino Groups and the like.
  • the “5- to 6-membered heterocyclic ring formed with R 8 and R 9 and the base nitrogen atom or with another nitrogen atom or oxygen atom” specifically includes pyrrolidino group, piperidino group, piperazino group, morpholino Groups and the like.
  • “Pharmaceutically acceptable salts” of the compounds represented by the general formula (I), general formula (II) and general formula (III) of the present invention include inorganic acid addition salts (for example, hydrochloric acid, hydrobromic acid, etc.). , Hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts (eg methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid , Salts with malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methylsulfuric acid, etc.), salts with amino acids (eg, lysine, arginine, etc.) Salts), alkali metal addition salts (eg, salts
  • Step 1-1 An appropriate solvent (for example, methanol, toluene, N, N-dimethylformamide) containing a hydrazide compound represented by the general formula (IV-1) and an aldehyde compound represented by the general formula (V-1)
  • a compound represented by the general formula (II-1) can be produced by reacting in the presence of an appropriate acid catalyst (for example, acetic acid or trifluoroacetic acid). This reaction is carried out by stirring from 0 ° C. to the solvent reflux temperature for a reaction time of 1 to 24 hours.
  • an appropriate acid catalyst for example, acetic acid or trifluoroacetic acid
  • Step 1-2 In the same manner as in the reaction step 1-1, from the hydrazide compound represented by the general formula (IV-1) and the aldehyde compound represented by the general formula (V-2), the general formula The compound represented by (III-1) can be produced.
  • reaction is carried out with the method for producing the compounds represented by the general formula (II-2) and general formula (III-2) wherein W is CR 1b and R 1b is a cyano group. It shows in process formula 2.
  • Reaction process formula 2 (In the formula, all symbols are as defined above.)
  • Step 2-1 In the same manner as in the reaction step 1-1, from the hydrazide compound represented by the general formula (IV-2) and the aldehyde compound represented by the general formula (V-1), the general formula A compound represented by (VI) can be produced.
  • Step 2-2 A compound represented by the general formula (VI) is mixed with a suitable demethylating agent (for example, methylene chloride, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide)
  • a suitable demethylating agent for example, methylene chloride, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide
  • a compound represented by the general formula (II-2) can be produced.
  • the reaction is carried out by stirring at 0 ° C. to solvent reflux temperature for 1 to 24 hours.
  • Step 2-3 In the same manner as in the reaction step 1-1, from the hydrazide compound represented by the general formula (IV-2) and the aldehyde compound represented by the general formula (V-2), the general formula A compound represented by (VII) can be produced.
  • Step 2-4 In the same manner as in the reaction step 2-2, the compound represented by the general formula (III-2) can be produced from the compound represented by the general formula (VII).
  • reaction process formula 3 As the hydrazide compounds represented by the general formulas (IV-1) and (IV-2), commercially available products or those prepared by the method described later can be used.
  • a process for producing hydrazide compounds represented by general formula (IV-1) and general formula (IV-2) is shown in reaction process formula 3.
  • Reaction process 3 (Wherein R 11 represents an alkyl group having 1 to 6 carbon atoms. W 1 has the same meaning as described above.)
  • Step 3-1 Preparation of the compound represented by the general formula (IV-1) is carried out according to J. Med. Chem., Vol.44, 3141-3149 (2001), J. Med. Chem., Vol.45, This can be done with reference to 5755-5775 (2002). That is, the ester compound represented by the general formula (VIII-1) is added with an equivalent amount of anhydrous hydrazine or an excess amount of hydrazine monohydrate in an appropriate solvent (for example, methanol, ethanol, 2-methoxyethanol). Then, the compound represented by the general formula (IV-1) can be produced by heating. The reaction is carried out by stirring at the solvent reflux temperature for 1 to 24 hours.
  • an appropriate solvent for example, methanol, ethanol, 2-methoxyethanol
  • Step 3-2 Appropriate condensation of the carboxylic acid compound represented by the general formula (VIII-2) and hydrazine anhydride in an appropriate solvent (eg, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane)
  • an agent for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / 1-hydroxybenzotriazole, N, N′-carbonyldiimidazole.
  • the compound represented by 1) can be produced.
  • the reaction is carried out by stirring at 0 ° C. to solvent reflux temperature, preferably at room temperature to 50 ° C. for 1 to 24 hours.
  • Step 3-3 In the same manner as the method described in Step 3-1, a compound represented by the general formula (IV-2) can be produced from an ester compound represented by the general formula (VIII-3). it can.
  • Step 4-1 The production of biaryl compounds using the Suzuki coupling reaction is reviewed by Fine Chemical, Vol. 26 (6), 5-15 (1997), Fine Chemical, Vol. 26 (7), 13-26 (1997). Etc. can be performed with reference to the above.
  • the palladium catalyst include tetrakis (triphenylphosphine) palladium (0), palladium carbon, palladium acetate (II), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), and the like.
  • Sodium carbonate (aqueous solution), potassium carbonate (aqueous solution), sodium hydroxide (aqueous solution), barium hydroxide (aqueous solution) and the like are solvents such as methanol, ethanol, 1,4-dioxane, toluene, xylene, 1,2-dimethoxy. Ethane and the like can be mentioned.
  • the reaction is carried out at room temperature to solvent reflux temperature.
  • One suitable combination of reaction conditions is [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) as a catalyst in a 1,2-dimethoxyethane solvent at a reaction temperature of 80 ° C. The time is 10 to 16 hours.
  • Step 4-2 In the same manner as in Reaction Step 4-1, the compound represented by the general formula (XI) and the compound represented by the general formula (X) are reacted to give a compound represented by the general formula (V-1-2). ) Can be produced.
  • Step 5-1 In the same manner as in Reaction Step 4-1, the compound represented by the general formula (XIII) is reacted with the compound represented by the general formula (XII) to react with the compound represented by the general formula (XIII). Can be produced.
  • Step 5-2 Establishing an ester of the compound represented by the general formula (XIII) with an appropriate reducing agent (for example, diisobutylaluminum hydride, triethoxysilane-cesium fluoride, sodium borohydride, lithium borohydride, hydrogenation) Using lithium aluminum, borane, 9-borabicyclo [3.3.1] nonane, etc.) in a suitable solvent (eg, methanol, ethanol, tetrahydrofuran, diethyl ether, etc.) at -78 ° C. to solvent reflux temperature.
  • an appropriate reducing agent for example, diisobutylaluminum hydride, triethoxysilane-cesium fluoride, sodium borohydride, lithium borohydride, hydrogenation
  • a suitable solvent eg, methanol, ethanol, tetrahydrofuran, diethyl ether, etc.
  • a suitable combination of reaction conditions is a reaction for 1 to 24 hours at room temperature using lithium aluminum hydride as a reducing agent in a tetrahydrofuran solvent, or at room temperature using sodium borohydride as a reducing agent in a methanol solvent. Examples include a reaction for 1 to 24 hours.
  • Step 5-3 A compound represented by the general formula (V-1-1) can be produced by oxidizing the primary alcohol of the compound represented by the general formula (XIV).
  • the oxidation reaction may be carried out using a suitable oxidizing agent ⁇ eg, chromic acid, pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide-oxalyl chloride (Swern method), dimethyl sulfoxide-trifluoroacetic anhydride (Swern method), dimethyl sulfoxide-anhydride.
  • a suitable oxidizing agent ⁇ eg, chromic acid, pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide-oxalyl chloride (Swern method), dimethyl sulfoxide-trifluoroacetic anhydride (Swern method), dimethyl sulfoxide-anhydride.
  • Acetic acid (Albright-Goldman method), dimethyl sulfoxide-dicyclohexylcarbodiimide (Pfitzinger-Moffatt method), dimethyl sulfoxide-sulfur trioxide / pyridine complex (Parikh-Doering method, etc.) ⁇ In pyridine, N, N-dimethylformamide, etc.) at ⁇ 78 ° C. to solvent reflux temperature for 1 to 24 hours.
  • dimethyl sulfoxide-oxalyl chloride is used in methylene chloride for 1-24 hours at -78 ° C. to room temperature, or dimethyl sulfoxide-sulfur trioxide / pyridine complex is used at room temperature for 1 hour.
  • a reaction of up to 24 hours is mentioned.
  • Step 5-4 In the same manner as in Reaction Step 4-1, the compound represented by the general formula (XVI) is reacted with the compound represented by the general formula (X) to react with the compound represented by the general formula (XVI). Can be produced.
  • Step 5-5 In the same manner as in Reaction Step 5-2, the compound represented by the general formula (XVII) can be produced from the compound represented by the general formula (XVI).
  • Step 5-6 In the same manner as in Reaction Step 5-3, the compound represented by the general formula (V-1-2) can be produced from the compound represented by the general formula (XVII).
  • reaction process formula 6 A process for producing an aldehyde compound represented by the general formula (V-2-1) in which R 4 and R 5 are both hydrogen atoms in the general formula (V-2) is shown in reaction process formula 6.
  • Reaction process formula 6 (In the formula, R 3 has the same definition as shown in the general formula (III).)
  • a compound represented by general formula (XVIII) and an amine compound represented by general formula (XIX) (for example, primary amine, ammonia, ammonium chloride, ammonium carbonate, etc.) using the pyrrole synthesis method by Pearl-Kunol method
  • an acidic solution for example, acetic acid, hydrochloric acid, etc.
  • an acid catalyst for example, Lewis acid such as titanium tetrachloride, aluminum chloride, p-toluenesulfonic acid, ( ⁇ ) -camphor-10-sulfonic acid, etc.
  • the compound represented by the general formula (V-2-1) can be produced by reacting in the presence of
  • reaction process formula 7 A process for producing aldehyde compounds represented by general formula (V-2-2) and general formula (V-2-3) is shown in reaction process formula 7.
  • Reaction process formula 7 (Wherein X represents a halogen atom, R 12 is an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkylmethyl group having 4 to 8 carbon atoms, An optionally substituted alkylsulfanyl group having 1 to 6 carbon atoms, an optionally substituted phenylsulfanyl group, an optionally substituted alkylsulfinyl group having 1 to 6 carbon atoms, an optionally substituted phenylsulfinyl group, C1-C6 alkylsulfonyl group which may be substituted, phenylsulfonyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, and may be substituted An aroyl group or
  • Step 7-1 The formyl form (V-2-2) can be produced by subjecting the compound represented by the general formula (XX) to formylation by the Vilsmeier reaction. The reaction is carried out by stirring at 0 ° C. to room temperature for 30 minutes to 6 hours.
  • Step 7-2 After activating the 1-position amino group of pyrrole represented by the general formula (V-2-2) with sodium hydride or the like, various halides represented by the general formula (XXI) are reacted. Thus, a compound represented by the general formula (V-2-3) can be produced.
  • the reaction is carried out in an appropriate solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, etc.), the activation temperature of the pyrrole amino group is -20 ° C to room temperature, preferably 0 ° C, halide (
  • the reaction with XXI) is carried out by stirring at a temperature between room temperature and 50 ° C. for 30 minutes to 24 hours.
  • an organolithium reagent etc. can also be used as an activator of a pyrrole amino group.
  • Reaction Process Formula 8 A process for producing the aldehyde compound represented by the general formula (V-2-4) using the diketone compound represented by the general formula (XXII) as a starting material is shown in Reaction Process Formula 8.
  • Reaction process formula 8 (In the formula, all symbols are as defined above.)
  • Step 8-1 In the same manner as in the reaction step 6, the diketone compound represented by the general formula (XXII) and the amine compound represented by the general formula (XIX) are represented by the general formula (XXIII). A pyrrole compound can be produced.
  • Step 8-2 In the same manner as in the reaction step 7-1, the pyrrole compound represented by the general formula (XXIII) is formylated to form the general formula (V-2-4). Compounds can be produced.
  • reaction process formula 9 A process for producing aldehyde compounds represented by general formula (V-2-5) to general formula (V-2-8) is shown in reaction process formula 9.
  • Reaction process formula 9 In the formula, R 7 and R 7 have the same definitions as those shown in the general formula (III). Other symbols have the same meanings as described above.
  • Step 9-1 In the same manner as in the reaction step 7-1, the pyrrole compound represented by the general formula (XXIV) is formylated to represent the general formula (V-2-5). Compounds can be produced.
  • Step 9-2 A compound represented by the general formula (V-2-6) can be produced by hydrolyzing an ester of the compound represented by the general formula (V-2-5).
  • the reaction is carried out using an appropriate solvent (for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.) or a base (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.).
  • a solvent for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc.
  • a base for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.
  • water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane and the like The reaction is carried out by stirring at a temperature from 0 ° C. to solvent reflux temperature, preferably from room temperature to 60 ° C. for 30 minutes to 24 hours.
  • Step 9-3 From the compound represented by the general formula (V-2-6) and the amine compound represented by the general formula (XXV), an acid amide compound represented by the general formula (V-2-7) Can be manufactured.
  • Various methods can be used as a method for obtaining the acid amide.
  • the reaction is carried out in an appropriate solvent (for example, methylene chloride, ethylene dichloride, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.) at a temperature of 0 ° C. to solvent reflux temperature, preferably room temperature to 60 ° C. It is carried out by stirring for min to 24 hours.
  • an appropriate solvent for example, methylene chloride, ethylene dichloride, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc.
  • Step 9-4 In the same manner as in Reaction Step 7-2, the compound represented by the general formula (V-2-7) is reacted with various halides represented by the general formula (XXI). Thus, the compound represented by the general formula (V-2-8) can be produced.
  • reaction process formula 10 A process for producing compounds represented by general formula (V-2-9) to general formula (V-2-11) using an amino acid derivative represented by general formula (XXVI) as a starting material is represented by reaction process formula 10. Shown in Reaction process formula 10 (Wherein R 13 is an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted cycloalkylmethyl group having 4 to 8 carbon atoms, an optionally substituted aryl group, substituted (The other symbols are as defined above.)
  • Step 10-1 Referring to J. Org. Chem., Vol.55 (15), 4735-4740 (1990), the compound represented by the general formula (XXVI) and the general formula (XXVII) By reacting the compound, the compound represented by the general formula (V-2-9) can be produced.
  • Step 10-2 In the same manner as in the reaction step 9-2, the ester of the compound represented by the general formula (V-2-9) is hydrolyzed to give the general formula (V-2-10). ) Can be produced.
  • Step 10-3 By reacting a compound represented by the general formula (V-2-10) with an amine compound represented by the general formula (XXV) in the same manner as in the reaction step 9-3. A compound represented by the general formula (V-2-11) can be produced.
  • reaction process formula 11 A process for producing an aldehyde compound represented by general formula (V-2-12) using a dialkoxy compound represented by general formula (XXVIII) as a starting material is shown in reaction process formula 11.
  • Reaction process formula 11 (In the formula, R 14 represents an optionally substituted alkyl group having 1 to 6 carbon atoms. Other symbols are as defined above.)
  • Step 11-1 A diformyl compound represented by the general formula (XXX) can be produced from a dialkoxy compound represented by the general formula (XXVIII). After reacting the compound represented by the general formula (XXVIII) and the compound represented by the general formula (XXIX) in an ether solvent (for example, diethyl ether, diisopropyl ether, tetrahydrofuran, etc.) using sodium hydride, Deprotection of the acetal protecting group is performed with an acidic aqueous solution (for example, 2N aqueous hydrochloric acid solution) to obtain a compound represented by the general formula (XXX). The reaction is carried out by stirring at ⁇ 10 ° C. to solvent reflux temperature, preferably 0 ° C. to room temperature, for 30 minutes to 24 hours.
  • an ether solvent for example, diethyl ether, diisopropyl ether, tetrahydrofuran, etc.
  • an acidic aqueous solution for example
  • Step 11-2 A pyrrole compound represented by the general formula (V-2-12) is produced by reacting the compound represented by the general formula (XXX) with the compound represented by the general formula (XXVI). be able to.
  • the reaction is carried out in an alcohol solvent (eg, methanol, ethanol, etc.) in the presence of a base (eg, sodium hydride, sodium alkoxide, etc.).
  • the reaction is carried out by stirring at 0 ° C. to solvent reflux temperature, preferably at solvent reflux temperature, for 1 to 24 hours.
  • reaction process formula 12 A process for producing the compound represented by the general formula (V-2-13) is shown in reaction process formula 12.
  • Reaction process formula 12 Wherein E represents an imino group (NH), an oxygen atom, or a sulfur atom, R 15 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted group.
  • a C 1-6 alkoxy group, a cyano group, a nitro group, or NR 16 R 17 means R 16 and R 17 each independently a hydrogen atom, an optionally substituted carbon atom of 1 to 6 alkyl group, an optionally substituted cycloalkyl group having 3 to 7 carbon atoms, an optionally substituted aryl group, or an optionally substituted aralkyl group.
  • Step 12-1 By reacting compound (XXXI) with a halogenating reagent (eg, thionyl chloride, oxalyl dichloride, thionyl bromide) in an appropriate solvent (eg, chlorinated solvent, toluene, tetrahydrofuran, etc.) Acid halides can be produced.
  • This acid halide is reacted with a compound represented by the general formula (XXXII) in the presence of a base (for example, triethylamine, pyridine, etc.) in an appropriate solvent (for example, tetrahydrofuran, etc.) to obtain an amide form.
  • a base for example, triethylamine, pyridine, etc.
  • an appropriate solvent for example, tetrahydrofuran, etc.
  • the compound represented by the general formula (XXIII) can be produced by heating.
  • the reaction for producing the acid halide is carried out by stirring at 0 ° C. to room temperature for 1 to 6 hours.
  • the reaction to obtain the general formula (XXXIII) via the amide is carried out by stirring at ⁇ 20 ° C. to solvent reflux temperature, preferably 0 ° C. to 60 ° C. for 1 to 24 hours.
  • Step 12-2 A compound represented by the general formula (V-2-13) is produced by formylating the compound represented by the general formula (XXXIII) in the same manner as in the reaction step 7-1. Can do.
  • reaction process formula 13 A process for producing the compounds represented by general formula (V-2-14) and general formula (V-2-15) is shown in reaction process formula 13.
  • Reaction process formula 13 (In the formula, R 18 represents a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms. Other symbols are as defined above.)
  • Step 13-1 Using a Friedel-Crafts reaction, a compound represented by the general formula (XXXIV) and a compound represented by the general formula (XXXV) in an appropriate solvent (chlorine solvent, benzene solvent) By reacting in the presence of a catalyst (aluminum chloride, metal halide, etc.), a compound represented by the general formula (XXXVI) can be produced.
  • the reaction is carried out by stirring at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 60 ° C. for 1 to 24 hours.
  • Step 13-2 In the same manner as in Reaction Step 6, the compound represented by the general formula (XXXVII) can be produced by reacting the diketone compound represented by the general formula (XXXVI) with ammonium acetate.
  • Step 13-3 A compound represented by the general formula (V-2-14) is produced by formylating the compound represented by the general formula (XXXVII) in the same manner as in the reaction step 7-1. Can do.
  • Step 13-4 In the same manner as in the reaction step 7-2, the compound represented by the general formula (V-2-14) is reacted with various halides represented by the general formula (XXI). Thus, the compound represented by the general formula (V-2-15) can be produced.
  • a reaction process formula 14 shows a method for producing the compounds represented by the general formula (V-2-16) and the general formula (V-2-17). Reaction process formula 14 (In the formula, all symbols are as defined above.)
  • Step 14-1 A compound represented by the general formula (XXXVIII) is reacted with magnesium metal in an appropriate solvent (eg, diethyl ether, tetrahydrofuran, etc.) to prepare a Grignard reagent, and then represented by the general formula (XXXIX). And a compound represented by the general formula (XXXX) can be produced.
  • the reaction is carried out by stirring at ⁇ 78 ° C. to room temperature for 1 to 24 hours.
  • Step 14-2 In the same manner as in Reaction Step 6, the acetal protecting group of the compound represented by the general formula (XXXX) is deprotected with hydrochloric acid or the like to form formyl group, and then reacted with ammonium acetate. A compound represented by the formula (XXXXI) can be produced.
  • Step 14-3 A compound represented by the general formula (V-2-16) is produced by formylating the compound represented by the general formula (XXXXI) in the same manner as in the reaction step 7-1. Can do.
  • Step 14-4 In the same manner as in Reaction Step 7-2, the compound represented by the general formula (V-2-16) is reacted with various halides represented by the general formula (XXI). Thus, a compound represented by the general formula (V-2-17) can be produced.
  • the compound of the present invention that can be produced as described above has a GIP receptor binding inhibitory action that inhibits the function of GIP, it is used as an agent for preventing or improving obesity, insulin resistance, or lipid accumulation in the liver. It can be set as a pharmaceutical composition.
  • a receptor binding inhibitor of GIP can be used as a preventive or ameliorating agent for obesity or insulin resistance is shown in the aforementioned Patent Document 1 and Non-Patent Document 2 by experimental facts.
  • Non-patent document 1 reports that GIP receptor gene-deficient mice loaded with a high-fat diet suppress the lipid accumulation in the liver, which is also observed in wild-type mice loaded with a high-fat diet. Has been.
  • a GIP receptor binding inhibitor or a GIP production inhibitor can be used as an agent for preventing or improving lipid accumulation in the liver. Since lipid accumulation in the liver is associated with progression from fatty liver to hepatitis and further to cirrhosis, the above facts indicate that GIP receptor binding inhibitors and GIP production inhibitors are alcoholic liver disorders and nonalcoholic fats. This suggests that it is also promising as an agent for preventing or improving hepatitis.
  • various dosage forms described in the “Japanese Pharmacopoeia” preparation general rules can be selected according to the purpose. For example, when it is formed into a tablet form, it is generally sufficient to select an orally ingestible component used in the field. For example, excipients such as lactose, crystalline cellulose, sucrose, potassium phosphate and the like are examples. Furthermore, if desired, various additives commonly used in the field of pharmaceutical preparations such as a binder, a disintegrant, a lubricant, and an aggregation inhibitor may be blended.
  • the amount of the active ingredient compound represented by the general formula (II) and general formula (III) to be contained in the preparation of the present invention is not particularly limited and is appropriately selected from a wide range.
  • the dose of the active ingredient compound is appropriately selected depending on its usage, patient age, gender and other conditions, and the degree of disease.
  • the amount of the compound of the present invention is about 0.01 to 500 mg per kg body weight per day. Conceivable.
  • the preparation can be administered in 1 to 4 divided doses per day. However, the dosage and frequency will be determined in light of the relevant circumstances including the extent of the condition to be treated, the selection of the compound to be administered and the route of administration selected, and thus the dosage range and frequency described above are It is not intended to limit the scope of the invention.
  • Reference Example 14 3-cyano-N ′- ⁇ [2,5-dimethyl-1- (4-methylbenzenesulfonyl) -1H-pyrrol-3-yl] methylidene ⁇ -4-methoxybenzohydrazide prepared in Reference Example 18 Operation similar to Reference Example 1 using -4-methoxybenzohydrazide and 2,5-dimethyl-1- (4-methylbenzenesulfonyl) -1H-pyrrole-3-carbaldehyde prepared in Reference Example 103 Gave the title compound.
  • Tables 4 and 5 show the structures and instrumental analysis data of the compounds produced by the same method as in Reference Example 20.
  • Tables 6 and 7 show the structures and instrumental analysis data of the compounds produced by the same method as in Reference Example 43.
  • Tables 8 and 9 show the structures and instrumental analysis data of the compounds produced by the same method as in Reference Example 60.
  • Reference Example 86 Reference example 84 using 1- (1-methyl-1-phenylethyl) -1H-pyrrole-3-carbaldehyde 1-methyl-1-phenylethylamine and 2,5-dimethoxytetrahydrofuran-3-carbaldehyde as raw materials To give the title compound.
  • Tables 10 and 11 show the structures and instrumental analysis data of the compounds produced by the same method as in Reference Example 88.
  • Tables 12 and 13 show the structures and instrumental analysis data of the compounds produced by the same method as in Reference Example 103.
  • Table 14 shows the structure and instrumental analysis data of the compound produced by the same method as in Reference Example 117.
  • Reference Example 133 The title compound was obtained in the same manner as in Reference Example 131, using N-cyclohexyl-4-formyl-1H-pyrrole-2-carboxamide 4-formyl-1H-pyrrole-2-carbonyl chloride and cyclohexylamine as raw materials.
  • Reference Example 135 4-Formyl-1-methyl-N- (4-methylbenzyl) -1H-pyrrole-2-carboxamide 4-formyl-1-methyl-1H-pyrrole-2-carboxylic acid and 4-methyl prepared in Reference Example 130 The title compound was obtained in the same manner as in Reference Example 134 using benzylamine as a starting material.
  • Reference Example 136 4-Formyl-1-methyl-N- (2-piperidin-1-ylethyl) -1H-pyrrole-2-carboxamide 4-formyl-1-methyl-1H-pyrrole-2-carboxylic acid prepared in Reference Example 130 The title compound was obtained in the same manner as in Reference Example 134 using 2-piperidin-1-ylethylamine as a starting material. ESI-MS; 264 [M + H] + , 262 [MH] - .
  • Reference Example 140 1- (4-Methoxyphenyl) pentane-1,4-dione
  • Aluminum chloride (1.9 g) is suspended in ethylene dichloride (5 mL) and 5-methyl-3H-furan-2-one (0.63 mL) at 0 ° C.
  • anisole 0.5 mL was added and stirred at room temperature for 1 hour.
  • Water was added at 0 ° C., and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with 2N hydrochloric acid aqueous solution and saturated sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate.
  • Reference Example 144 4- (4-Methoxyphenyl) -4-oxobutyraldehyde 3- [1,3] dioxan-2-yl-1- (4-methoxyphenyl) propan-1-one prepared in Reference Example 142 is used as a raw material. Then, the title compound was obtained in the same manner as in Reference Example 143.
  • Example 1 3-Chloro-4-hydroxy-N '- ⁇ [2- (4-methoxyphenyl) pyridin-4-yl] methylidene ⁇ benzohydrazide
  • Compound 1 3-Chloro-4-hydroxybenzohydrazide (49 mg) and 2- (4-methoxyphenyl) pyridine-4-carbaldehyde (56 mg) prepared in Reference Example 60 were suspended in methanol (1.5 mL) and acetic acid (50 ⁇ L) Was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was cooled in an ice bath, and the precipitated solid was collected by filtration and washed with cold methanol to give the title compound (81 mg).
  • Example 27 3-Cyano-4-hydroxy-N ′- ⁇ [2- (4-methoxyphenyl) pyridin-4-yl] methylidene ⁇ benzohydrazide (Compound 2) 3-Cyano-4-methoxy-N ′- ⁇ [2- (4-methoxyphenyl) pyridin-4-yl] methylidene ⁇ benzohydrazide (88 mg) prepared in Reference Example 1 was replaced with N, N-dimethylformamide (4 mL). Then, lithium chloride (48 mg) was added, and the mixture was stirred for 17 hours with heating under reflux. After allowing to cool to room temperature, water was added and the mixture was concentrated under reduced pressure.
  • Example 40 3-Chloro-4-hydroxy-N '- ⁇ [1- (4-methylbenzenesulfonyl) -1H-pyrrol-3-yl] methylidene ⁇ benzohydrazide (Compound 41)
  • the title compound was prepared in the same manner as in Example 1, using 3-chloro-4-hydroxybenzohydrazide and 1- (toluene-4-sulfonyl) -1H-pyrrole-3-carbaldehyde prepared in Reference Example 84 as raw materials. Got.
  • Example 95 3-Cyano-N '- ⁇ [2,5-dimethyl-1- (4-methylbenzenesulfonyl) -1H-pyrrol-3-yl] methylidene ⁇ -4-hydroxybenzohydrazide (Compound 44) Using 3-cyano-N ′- ⁇ [2,5-dimethyl-1- (4-methylbenzenesulfonyl) -1H-pyrrol-3-yl] methylidene ⁇ -4-methoxybenzohydrazide prepared in Reference Example 14 as a raw material And the title compound was obtained in the same manner as in Example 40.
  • a buffer for cell disruption (10 mM Tris-HCl, pH 7.5, 30 mM NaCl, 1 mM Dithiothreitol, Protease Inhibitor Cocktail (SIGMA, P8340)) was applied to human GIP receptor-expressing CHO-k1 cells collected by centrifugation. The mixture was added and crushed with a homogenizer for 30 seconds. The cell lysate was overlaid on a 41% (W / V) sucrose solution and centrifuged at 95,000 g for 75 minutes.
  • a buffer solution (0.1 mM CaCl 2 , 1 mM MgCl 2 , 50 mM HEPES, pH 7.4) containing 0.1% casein to each well, perform blocking for 30 minutes, and then remove the buffer solution to remove binding. Used for.
  • Inhibitory activity was expressed by their IC 50 value (concentration of compound required to inhibit GIP binding by 50%). The results are shown in Table 28.
  • IC 50 value concentration of compound required to inhibit GIP binding by 50%.
  • Table 28 As a comparative compound, 3-chloro-4-hydroxy-N ′-[(pyridin-2-yl) methylidene] benzohydrazide (Comparative Compound 1) produced according to the method described in International Publication No.
  • the compound of the present invention exhibits potent GIP receptor binding inhibitory activity and can be used as an agent for preventing or improving obesity, insulin resistance, or lipid accumulation in the liver.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

L'invention porte sur un composé représenté par la formule générale (I) ou sur un sel pharmaceutiquement acceptable de celui-ci, destiné à des applications pharmaceutiques ; et sur un agent de blocage de la fixation au récepteur du GIP pour prévenir ou améliorer l'obésité, la résistance à l'insuline ou l'accumulation de lipide dans le foie en bloquant la fonction du GIP et, plus précisément, en bloquant la fixation au récepteur du GIP, ledit composé formant le composant efficace. [Dans cette formule, par exemple, W représente CR1 (où R1 est un atome d'halogène ou un groupe cyano) etc. et Z est un groupe représenté par la formule générale (VI), (V2) ou (Y1).] [Dans ces formules, par exemple, A représente un groupe aryle facultativement substitué, etc., R2 représente un groupe aryle facultativement substitué, etc., R3 représente un groupe phénylsulfonyle facultativement substitué, etc. et R4 et R5 représentent hydrogène ou un groupe alkyle facultativement substitué, etc. ayant 1 à 3 atomes de carbone.]
PCT/JP2009/059943 2008-06-02 2009-06-01 Nouveau composé et son application pharmaceutique WO2009148004A1 (fr)

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WO2012036193A1 (fr) * 2010-09-15 2012-03-22 アステラス製薬株式会社 Agent thérapeutique pour stéatose hépatique contenant une substance inhibitrice du récepteur p2x7 en tant qu'ingrédient actif
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
US8536186B2 (en) 2008-08-04 2013-09-17 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9493449B2 (en) 2013-03-15 2016-11-15 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
CN108358838A (zh) * 2018-04-26 2018-08-03 河南师范大学 具有生物活性的新型喹啉取代希夫碱衍生物及其合成方法和应用
CN108467363A (zh) * 2018-04-26 2018-08-31 河南师范大学 具有生物活性的新型苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
WO2019094319A1 (fr) 2017-11-07 2019-05-16 Bristol-Myers Squibb Company Dérivés de pyrrolopyrazine à utiliser en tant qu'inhibiteurs de l'intégrine alpha v
WO2021019051A1 (fr) 2019-07-30 2021-02-04 Karl-Franzens-Universität Graz Inhibiteurs de l'atgl humain
CN116496198A (zh) * 2023-06-26 2023-07-28 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种4-羟基-2'-(1-苄基-5-硝基吡咯甲叉)-苯甲酰肼衍生物及其制备方法和应用

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US8536186B2 (en) 2008-08-04 2013-09-17 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9145373B2 (en) 2008-08-04 2015-09-29 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US8883785B2 (en) 2010-01-25 2014-11-11 Chdi Foundation, Inc. Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
WO2012036193A1 (fr) * 2010-09-15 2012-03-22 アステラス製薬株式会社 Agent thérapeutique pour stéatose hépatique contenant une substance inhibitrice du récepteur p2x7 en tant qu'ingrédient actif
US9611222B2 (en) 2010-09-17 2017-04-04 Purdue Pharma L.P. Pyridine compounds and the uses thereof
US9056832B2 (en) 2010-09-17 2015-06-16 Purdue Pharma L.P. Pyridine compounds and the users thereof
JP2013538227A (ja) * 2010-09-17 2013-10-10 パーデュー、ファーマ、リミテッド、パートナーシップ ピリジン化合物およびその使用
US20130303526A1 (en) * 2010-09-17 2013-11-14 Purdue Pharma L.P. Pyridine Compounds and the Uses Thereof
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
US9981918B2 (en) 2011-08-30 2018-05-29 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US9428464B2 (en) 2011-08-30 2016-08-30 Chdi Foundation, Inc. Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
US10005768B2 (en) 2013-03-15 2018-06-26 Purdue Pharma L.P. Carboxamide derivatives and use thereof
AU2014235063B2 (en) * 2013-03-15 2017-05-04 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US9493449B2 (en) 2013-03-15 2016-11-15 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US10258621B2 (en) 2014-07-17 2019-04-16 Chdi Foundation, Inc. Methods and compositions for treating HIV-related disorders
WO2019094319A1 (fr) 2017-11-07 2019-05-16 Bristol-Myers Squibb Company Dérivés de pyrrolopyrazine à utiliser en tant qu'inhibiteurs de l'intégrine alpha v
CN108358838A (zh) * 2018-04-26 2018-08-03 河南师范大学 具有生物活性的新型喹啉取代希夫碱衍生物及其合成方法和应用
CN108467363A (zh) * 2018-04-26 2018-08-31 河南师范大学 具有生物活性的新型苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用
CN108467363B (zh) * 2018-04-26 2021-01-05 河南师范大学 具有生物活性的苯并[h]喹啉取代希夫碱衍生物及其合成方法和应用
CN108358838B (zh) * 2018-04-26 2021-05-18 河南师范大学 具有生物活性的新型喹啉取代希夫碱衍生物及其合成方法和应用
WO2021019051A1 (fr) 2019-07-30 2021-02-04 Karl-Franzens-Universität Graz Inhibiteurs de l'atgl humain
CN116496198A (zh) * 2023-06-26 2023-07-28 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种4-羟基-2'-(1-苄基-5-硝基吡咯甲叉)-苯甲酰肼衍生物及其制备方法和应用

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