WO2002022574A1 - Compose tricyclique heterocyclique, son procede de fabrication et son utilisation - Google Patents

Compose tricyclique heterocyclique, son procede de fabrication et son utilisation Download PDF

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WO2002022574A1
WO2002022574A1 PCT/JP2001/007815 JP0107815W WO0222574A1 WO 2002022574 A1 WO2002022574 A1 WO 2002022574A1 JP 0107815 W JP0107815 W JP 0107815W WO 0222574 A1 WO0222574 A1 WO 0222574A1
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group
alkyl
hydrogen atom
alkoxy
salt
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PCT/JP2001/007815
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Japanese (ja)
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Yoshinori Ikeura
Tadatoshi Hashimoto
Naoki Tarui
Izumi Kamo
Junya Shirai
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Takeda Chemical Industries, Ltd.
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Priority to AU2001286188A priority Critical patent/AU2001286188A1/en
Publication of WO2002022574A1 publication Critical patent/WO2002022574A1/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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

Definitions

  • Tricyclic heterocyclic compound its production method and its use
  • the present invention relates to a novel 3 ⁇ -heterocyclic compound having an excellent kinkinin receptor antagonistic activity, a method for producing the same, and a use thereof.
  • An object of the present invention is to provide a tricyclic heterocyclic compound having an action stronger than that of a conventional compound having an inhibitory action on evening kikinin receptor, a method for producing the same, and an agent for improving abnormal urination including the compound.
  • R 1 represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ 6 alkoxy (6 Ashiru, C 6 alkylsulfonyl, carboxyl, CI- C6 alkoxy - carbonyl, force Rubamoiru, mono- or di - C i-6 alkyl - force Rubamoiru, sulfamoyl, mono- or di-one CI- e alkyl - Surufamoi Le, C 6 - 14 Ariru and 5 to have a substituent group selected from the group consisting of 14-membered heterocyclic group C i-6 alkyl group, (3) ⁇ 6 _ 14 aryl group, (4) Ci-e acyl group, (5) C i-6 alkoxymonocarbonyl group, (6) carbamoyl group, (7 ) mono- or di - 6 alkyl Ichiriki Rubamoiru group or (8) - 6 alkyl sulfonyl group, R 2
  • n 1 or 2
  • p represents an integer of 0 to 3.
  • R 1 is a methyl group
  • R 2 is a methyl group
  • R 3 is a hydrogen atom
  • the formula I is a group represented by the formula
  • n 1
  • the 3 ⁇ -heterocyclic compound or salt thereof has unexpectedly strong tachykinin receptor antagonism (particularly substance P receptor antagonism) based on its unique chemical structure.
  • the present inventors have found that the present invention is sufficiently satisfactory as a medicine and completed the present invention based on these findings. That is, the present invention
  • R 1 represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ 6 alkoxy Ashiru, C ⁇ 6 alkylsulfonyl, carboxyl, - 6 alkoxy - carbonyl, force Rubamoiru, mono- or di - C i 6 alkyl - force Rubamoiru, sulfamoyl which may have a substituent selected from the group consisting of mono- or di-one Ci e alkyl one Surufamoi Le, C 6 _ 14 Ariru and 5 to 14-membered heterocyclic group - !
  • R 2 is a hydrogen atom, a halogen atom or a halogenated which may be C ⁇ 6 alkyl group,: R 3 is a hydrogen atom or a C i-6
  • the alkyl group, R represents the same or are different and each represents a hydrogen atom, a halogen atom, an optionally halogenated C [Al Kill group or halogenated which may be C I 6 alkoxy group, m is 0 to 3 An integer, n represents 1 or 2, and p represents an integer of 0 to 3.
  • R 1 is a methyl group
  • R 2 is a methyl group
  • R 3 is a hydrogen atom
  • R 3 is a hydrogen atom
  • n 1
  • compound (I) or a salt thereof
  • R 4 and R 5 are the same or different and each represent a hydrogen atom, or a halogenated group (showing a 6 alkyl group or a C ⁇ -e alkoxy group).] [1] The compound described in the item,
  • R 1 ′ is an alkyl group or a acyl group
  • R 2 ′ is a hydrogen atom or a halogen atom
  • R 3 ′ is an alkyl group
  • R 4 ′ and R 5 ′ are the same or different.
  • a C Bok 3 alkyl group optionally, n represents 1 or 2.
  • R 1 a is as defined for R 1 of the [1], wherein.
  • R 1 a is as defined for R 1 of the [1], wherein.
  • 1 a is not a hydrogen atom.
  • a salt thereof to form a quaternary salt is not a hydrogen atom.
  • R 1 represents (1) hydrogen atom, (2) a halogen atom, Shiano, hydroxy, _ 6 alkoxy Ashiru, C alkylsulfonyl, carboxyl, (6 alkoxy one carbonyl, force Rubamoiru, mono- or di - C i - e alkyl - force Rubamoiru, sulfamoyl which may have a substituent selected from the group consisting of mono- or di C 6 alkyl one Surufamoi Le, C 6 _ 14 Ariru and 5 to 14-membered heterocyclic group C i- 6 alkyl group, (3) C 6 -!
  • R 2 is a hydrogen atom, a halogen atom or an optionally halogenated C [Bok 6 alkyl group
  • R 3 is a hydrogen atom or a Ci-e
  • the alkyl radical, R is different from a hydrogen atom was the same or a halogen atom, an optionally halogenated C [i_ 6 Al Kill group or halogenated which may be C I 6 alkoxy group
  • m is 0 to N is 1 or 2
  • p is an integer of 0 to 3, provided that R 1 is a methyl group, R 2 is a methyl group, R 3 is a hydrogen atom,
  • n 1
  • n 1
  • a salt thereof or a prodrug thereof, and a pharmacologically acceptable carrier 1.
  • composition according to (11), which is a substance P receptor antagonist, is a substance P receptor antagonist
  • composition according to (11), which is an agent for improving urinary abnormality is an agent for improving urinary abnormality
  • composition according to (11) which is a preventive and therapeutic agent for pollakiuria and urinary incontinence,
  • composition according to (11) which is an agent for preventing or treating HIV infection, chronic obstructive pulmonary disease, depression, anxiety, manic depression or schizophrenia,
  • the compound (I) of the present invention or a salt thereof includes stereoisomers such as cis- and trans-isomers, racemic forms, and optically active forms such as R-form and S-form. Depending on the size of the ring, conformational isomers may be formed. Such isomers are also included in the compound (I) of the present invention or a salt thereof.
  • the ( ⁇ _ 6 alkyl group represented by RR 2 R 3 and R if example embodiment, using methyl, Echiru, propyl, isopropyl, heptyl, sec- butyl, tert- butyl, pentyl, hexyl is to Among them, ( ⁇ alkyl groups such as methyl, ethyl, propyl, and isopropyl are preferable, and methyl is particularly preferable.
  • halogen atom which the C—e alkyl group represented by R 1 may have, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used, and among them, a fluorine atom is preferable.
  • the C 6 optionally C 6 Ashiru the alkyl group has represented by R 1, if example embodiment, formyl, C - 5 alkyl - carbonyl (e.g., Asechiru, propionyl, etc.) is used, inter alia formyl, Asechiru, such as propionyl - 3 etc. ⁇ Shi Le is preferred.
  • formyl, C - 5 alkyl - carbonyl e.g., Asechiru, propionyl, etc.
  • Shi Le is preferred.
  • the C i may have is _ 6 alkyl C 6 alkyl sulfonyl Le represented by R 1, for example, methylsulfonyl, Echirusuruhoniru and propylsulfonyl two Le is used, inter alia methylsulfonyl, C alkylsulfonyl such as ethylsulfonyl is preferred.
  • C i-e alkoxy-carbonyl which the C alkyl group represented by R 1 may have, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are used, among which methoxycarbonyl, ethoxycarbonyl and the like are used.
  • C I 3 alkoxy one carbonyl such carbonylation le are preferred.
  • Examples of the mono- or di-C alkyl monofunctional rubamoyl which the C i-6 alkyl group represented by R 1 may have include, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl, dipropyl Carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, dimethylcarbamoyl, etc. Alkyl-alkavamoyl and the like are preferred.
  • the C i-6 alkyl group has optionally may mono- or di-be C Bok 6 alkylene loose sulfamoyl represented by R 1, for example, methylsulfamoyl, Echirusu Rufamoiru, propyl sulfamoyl, dimethylsulfamoyl And dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl and the like, and mono- or dialkylsulfamoyl and the like.
  • R 1 mono- or di-be C Bok 6 alkylene loose sulfamoyl represented by R 1, for example, methylsulfamoyl, Echirusu Rufamoiru, propyl sulfamoyl, dimethylsulfamoyl And dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, dimethylsulfam
  • C alkyl group may also have ⁇ 6 represented by R 1 - Examples 1 4 Ariru, for example, Fuweniru, naphthyl and the like.
  • Examples of the 5- to 14-membered heterocyclic group which may be possessed by the —6 alkyl group represented by R 1 include a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. 5 to 14 members, preferably 4 or 1 or 2
  • Heterocyclic groups are used, and among them, phenyl (2-phenyl, 3-phenyl), furyl (2-furyl, 3-furyl) , Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl
  • C i _ 6 halogen atom may have an alkyl group represented by R 2 and R, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.
  • C alkyl group represented by R 2 and R is used a C alkyl group which may be substituted by 1 to 3 halogen atoms, specifically, methyl, Echiru, propyl, triflumizole Ruo b such 1 to 3 substituents C Bok 3 alkyl group optionally substituted with fluorine atoms, such as methyl is not preferable.
  • the C i _ 6 Ashiru group represented by R 1 for example, a formyl group, ( ⁇ alkyl - carbonyl group (e.g., Asechiru, propionyl, etc.) is used, inter alia formyl, Asechiru, C i, such as propionyl - A gacyl group is preferred.
  • a formyl group ( ⁇ alkyl - carbonyl group (e.g., Asechiru, propionyl, etc.) is used, inter alia formyl, Asechiru, C i, such as propionyl - A gacyl group is preferred.
  • Examples of the mono- or di-C i-e alkyl mono-rubamoyl group represented by R 1 include methylcarbamoyl, ethylcarbamoyl, propyl-rubamoyl, dimethyl-carbamoyl, getylcarbamoyl, di-propyl-carbamoyl and the like. , Especially methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoy Or a mono- or di-C-alkyl-carbamoyl group such as benzyl or getylcarbamoyl.
  • halogen atom represented by R 2 and R a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.
  • C ⁇ alkoxy group represented by R for example, methoxy, ethoxy, propyloxy, butoxy and the like are used, and among them, C alkoxy groups such as methoxy, ethoxy and propoxy are preferable.
  • halogen atom which the C 6 alkoxy group represented by R may have, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.
  • the R 1, - 3 alkyl group e.g., methyl, Echiru, propyl, isopropyl, etc.
  • ⁇ 6 _ 14 Ariru group e.g., such as phenyl
  • Ci-g Ashiru group e.g., formyl, Asechiru, propionyl etc.
  • C Bok 3 alkoxy one carbonyl group e.g., main bets alkoxycarbonyl, such as ethoxycarbonyl
  • mono- or di- ( ⁇ alkyl Ichiriki Rubamoiru group e.g., methylcarbamoyl, E Ji carbamoyl, dimethyl Cal Bamoiru, GETS Ji carbamoyl etc.
  • C 3 alkylsulfonyl group e.g., methylcarbamoyl Rusuruhoniru, etc.
  • Shiano alkyl group e.g., Shianome chill etc.
  • ⁇ _ 3 alkyl group a formyl group
  • ⁇ Alkyl-carbonyl groups and the like are preferred, and methyl and acetyl are particularly preferred.
  • R 2 a hydrogen atom, a halogen atom, such as full Uz atom, methyl, Echiru, propyl, are preferred, such as ( ⁇ _ 3 alkyl groups such as isopropyl, inter alia a hydrogen atom, a halogen atom such as fluorine atom, methyl Preference is given, particularly preferred is a fluorine atom.
  • R 3 is preferably a hydrogen atom or a Ci- 3 alkyl group such as methyl, ethyl, propyl, and isopropyl, and particularly preferably a Ci- 3 alkyl group such as methyl. Further, it is preferable that R 3 is in the /? Configuration. In this case, the general formula (I) is
  • R may be substituted with 1 to 3 halogen atoms (particularly, fluorine atom) such as hydrogen atom, methyl, ethyl, propyl, trifluoromethyl, etc.
  • halogen atoms particularly, fluorine atom
  • C! —3 alkyl group and the like are preferable, and methyl and trifluoromethyl are particularly preferable.
  • p represents an integer of 0 to 3, and represents that 0 to 3 of the phenyl groups may have 0 to 3 substituents. p is preferably 2.
  • substitution position of p is not particularly limited.
  • p is 2, the 3- and 5-positions of the phenyl group are preferable.
  • R 4 , R 5 and R 6 are the same or different and each represent a hydrogen atom, an optionally halogenated C alkyl group or a C alkoxy group.
  • the group represented by the formula is used.
  • R 4 and R 5 are as defined above. ] Is preferable.
  • Examples of the alkyl group represented by R 4 , R 5 and are, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., among which methyl, ethyl, propyl And a C i 3 alkyl group such as isopropyl is preferable, and methyl is particularly preferable.
  • the R 4, R 5 and C i_ 6 halogen atom may have an alkyl group represented by R 6, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.
  • R 4 R 5 and optionally halogenated C [Bok 6 alkyl group represented by R 6, which may be substituted with 1 to 3 halogen atoms (e.g., full Uz atom) C 6 alkyl group is used, specifically, methyl, Echiru, propyl, one to three full Uz may be substituted by atom C _ 3 alkyl group, such as preparative Rifuruoromechiru is preferred.
  • halogen atoms e.g., full Uz atom
  • C 6 alkyl group which may be substituted with 1 to 3 halogen atoms (e.g., full Uz atom) C 6 alkyl group is used, specifically, methyl, Echiru, propyl, one to three full Uz may be substituted by atom C _ 3 alkyl group, such as preparative Rifuruoromechiru is preferred.
  • alkoxy group represented by R 4 , R 5 and R 6 for example, methoxy, ethoxy, propoxy, butoxy and the like are used, and among them, C alkoxy group such as methoxy, ethoxy and propoxy is preferable.
  • R ⁇ R 5 and R 6 are preferably a hydrogen atom, an alkyl group optionally substituted by 1 to 3 halogen atoms (eg, a fluorine atom) or a C alkoxy group, and among them, 1 to 3 Alkyl groups which may be substituted with two halogen atoms (eg, fluorine atoms) are preferred, and in particular, methyl, trifluoro A C 3 alkyl group which may be substituted by a fluorine atom such as methyl is preferred.
  • m is preferably 1 or 2, and particularly preferably 1.
  • n is preferably 2.
  • R 1 is a methyl group
  • R 2 is a methyl group
  • R 3 is a hydrogen atom
  • R 1 ′ is — 3 alkyl group or acyl group
  • R 2 ′ is hydrogen atom or halogen atom
  • R 3 ′ is Ci-a alkyl group
  • R 4 ′ and: 5 ′ are the same or different.
  • one and a halogenated C Bok 3 optionally alkyl radical
  • n is 1 or 2. And the like.
  • ⁇ 1 ', R 3' as the CI- s alkyl group represented by R 4 'and R 5', for example, methyl, Echiru, propyl, isopropyl are used, these, methyl is preferred.
  • the halogen atom which the C-3 alkyl group represented by R 4 ′ and R 5 ′ may have a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are used.
  • R 4 'and R 5' optionally halogenated and C 3 alkyl group represented by the 1 to 3 substituents C Bok 3 alkyl group optionally substituted by a halogen atom is used, specifically
  • a Ci-g alkyl group which may be substituted by 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, and trifluoromethyl, is preferred.
  • acetyl group represented by R 1 ′ a formyl group or a Ci 2 alkyl-carbonyl group (eg, acetyl, propionyl) is used, and among them, acetyl is preferable.
  • halogen atom represented by R 2 ′ a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.
  • R 1 ′ is preferably methyl or acetyl.
  • R 2 ′ a hydrogen atom, a fluorine atom and the like are preferable, and a fluorine atom is particularly preferable.
  • R 3 ' is preferably in the /? Configuration.
  • the general formula ( ⁇ ) is
  • R 3 ′ methyl is preferable.
  • R 4 ′ and R 5 ′ are preferably an alkyl group which may be substituted by 1 to 3 halogen atoms (eg, a fluorine atom), and particularly preferably trifluoromethyl.
  • R 1 ′ is a C ⁇ 2 alkyl monocarbonyl group (eg, Compounds in which R 4 ′ and R 5 ′ are C 3 alkyl groups (eg, methyl) are also preferable.
  • Examples of the salt of compound (I) of the present invention include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
  • Can be Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, tolylamine, cyclohexylamine, Salts with dicyclohexylamine, N, N'-dibenzylethylenediamin and the like can be mentioned.
  • salts with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid And salts with benzenesulfonic acid, p_toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin, and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid And the like.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, fluoric acid
  • organic acids such as fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonate, and P-toluenesulfonic acid.
  • the prodrug of the compound (I) of the present invention or a salt thereof (hereinafter, may be abbreviated as the compound (I) of the present invention) can be obtained by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body.
  • a compound that converts into the compound (I) of the present invention that is, a compound that changes into the compound (I) of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like;
  • Examples of the prodrug of the compound (I) of the present invention include a compound in which the amino group of the compound (I) of the present invention is acylated, alkylated or phosphorylated (for example, a compound of the present invention)
  • the amino group of (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-12-oxo-1,3-dioxolen-14-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated
  • a compound in which the hydroxyl group of the compound (I) of the present invention is acylated, alkylated, phosphorylated or borated for example, the compound of the present invention).
  • Compounds in which the carboxy group is esterified or amidated for example, the compound (I) of the present invention is obtained by converting the carboxy group into ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, or vivaloyl) Oxymethyl esterification, ethoxycarbonyloxysethyl esterification, fluoridyl esterification, (5-methyl-21-oxo-1,3-dioxolen-1-yl) methyl esterification, cyclohexyloxy Carbonylethyl esterified, methylamidated compounds, etc.).
  • the prodrug of the compound (I) of the present invention may be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163 to 198. May be changed to the compound (I) of the present invention.
  • the compound (I) or a salt thereof of the present invention can be produced according to a method known per se, for example, the production method described in JP-A-9-136585 (EP-A-7333362) can do.
  • the compound (I) of the present invention or a salt thereof has the formula
  • L is a leaving group, and other symbols are as defined above. Or a salt thereof, by subjecting it to a cyclization reaction to close the ring.
  • Examples of the leaving group represented by L include a halogen atom (eg, a chlorine atom, a bromine atom, an iodine atom, etc.) and a substituted sulfonyloxy group (eg, C i such as methanesulfonyloxy, phenylsulfonyloxy, etc.) _ 6 alkylsulfonyl O dimethylvinylsiloxy groups; benzenesulfonyl O C 6 _ i 4 ⁇ Li one Le sulfonyl O alkoxy group such as alkoxy; and C sheet 1 6 Arukiruari one Le sulfonyl O alkoxy group such as p- toluenesulfonyl O carboxymethyl) etc. Is used.
  • a halogen atom eg, a chlorine atom, a bromine atom, an iodine atom, etc.
  • the compound (II) may be used as a free compound, or may be subjected to the reaction in the form of a salt thereof (eg, an alkali metal salt such as lithium, sodium, or potassium).
  • a salt thereof eg, an alkali metal salt such as lithium, sodium, or potassium.
  • the reaction is usually performed in a solvent inert to the reaction.
  • the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and hexane.
  • An aprotic polar solvent such as methylphosphoramide is preferably used.
  • the reaction can advantageously proceed by adding a base.
  • a base examples include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate).
  • Alkali metal carbonates such as sodium carbonate and lium carbonate; Alkali metal hydrides such as sodium hydride and hydrogen hydride; sodium amide; Alkoxides such as sodium methoxide and sodium ethoxide )
  • organic bases amines such as trimethylamine, triethylamine, diisopropylethylamine, and the like; cyclic amines such as pyridine, etc. are preferred.
  • the amount of the base varies depending on the compound (II) to be used, the type of the solvent, and other reaction conditions, and is usually about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of the compound (II). It is.
  • the reaction temperature is, for example, about 150 ° C. to 200 ° C., preferably about ⁇ 20 ° C. to 150 ° C.
  • the reaction time is the kind of the compound (II) or a salt thereof.
  • the reaction time varies depending on the type, reaction temperature and the like, and is, for example, 1 to 72 hours, preferably about 1 to 24 hours.
  • This reduction reaction can be performed by various methods.
  • a method of reducing in the presence of a metal catalyst for catalytic reduction is preferable.
  • the catalyst used in the catalytic reduction method include a platinum catalyst such as platinum black, platinum oxide, and platinum carbon; a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, and palladium carbon; reduced nickel; Nickel catalysts such as nickel, Raney nickel and Urushibara nickel are examples.
  • the amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.1 to 10% (w / w) based on the compound (I) or a salt thereof.
  • the reduction reaction is usually performed in a solvent.
  • the solvent include alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as tetrahydrofuran and dioxane; and esters such as ethyl acetate.
  • the reaction temperature is, for example, about 0 ° C to 200 ° C, preferably about 20 ° C to 110 ° C, and the reaction time is usually about 0.5 to 48 hours, preferably about 1 to 16 hours. .
  • the reaction is usually carried out under normal pressure. However, if necessary, the reaction is carried out under pressure (for example, about 3 to 10 atm).
  • Such a reduction reaction can also be applied to a method of converting another aromatic heterocycle into a non-aromatic heterocycle.
  • R 1 is a group other than a hydrogen atom
  • I ⁇ a has the same meaning as R 1 above. However, H 1 a is not a hydrogen atom. Other symbols are as defined above. Or a salt thereof], a compound of (III) or a salt thereof, - OH wherein, R 1 a is as defined above. ⁇ so It can also be produced by reacting with a reactive derivative of the compound or a salt thereof to form a quaternary salt, and then subjecting the resulting quaternary salt to a reduction reaction.
  • the reactive derivative of the compound represented by 1 ⁇ & -011 or a salt thereof include, for example, a compound represented by the formula
  • R x a - 'in (IV) [wherein, L' L is a leaving group, R 1 a is as defined above. Or a salt thereof, or the like.
  • R 1 a- L used for conversion to a quaternary salt, as is specifically pay de of R 1 a (for example, chloride, bromide, etc. ® one iodide), sulfate ester or sulfo phosphate ester (for example, methanesulfonate, P-toluenesulfonate, benzenesulfonate and the like are used, and halides are particularly preferably used.
  • the amount of compound (IV) or a salt thereof to be used is, for example, about 1 to 100 equivalents, preferably about 1 to 30 equivalents, per 1 mol of substrate. '
  • the reaction with compound (IV) or a salt thereof is usually performed in a solvent.
  • the solvent include alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate; dichloromethane; and 1,2-dichloromethane.
  • Halogenated hydrocarbons such as butane may be used, and compound (IV) itself may be used as a solvent.
  • the reaction temperature is, for example, 10 ° C to 200 ° C, preferably 20 ° C! ⁇ 110 ° C,
  • the reaction time is generally about 0.5 to 24 hours, preferably about 1 to 16 hours.
  • the reduction reaction of the generated quaternary salt to the tetrahydropyridine ring can be performed in an inert solvent in the presence of a reducing agent such as a metal hydride.
  • a reducing agent such as a metal hydride.
  • the metal hydride as the reducing agent include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium aluminum hydride and the like.
  • Preferred metal hydrides include sodium borohydride and the like.
  • the amount of the reducing agent used is, for example, 1 to 10 equivalents to the quaternary salt, preferably:! ⁇ 2 equivalents.
  • reaction solvent examples include lower alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; and hydrocarbons such as benzene and toluene. These solvents may be used alone. Or mixed and used.
  • the reaction temperature is usually about —100 ° C. to 40 ° C .; preferably about ⁇ 80 ° C. to 25 ° C., and the reaction time is usually 5 minutes to 10 hours. Preferably, it is about 10 minutes to 5 hours.
  • a compound having a dihydropyridine ring may be produced depending on the kind of the compound.
  • This dihydropyridine ring can be converted to a further reduced tetrahydropyridine ring by, for example, the above-described catalytic reduction method.
  • a compound having an R 1 group introduced into the nitrogen atom can be obtained by subjecting the nitrogen atom to an alkylation or acylation reaction.
  • R 1 a- 0 H As the reactive derivative of the compound represented by R 1 a- 0 H indicates, for example, in R ⁇ -L 5 [wherein, L, is a leaving group, R 1 a is as defined above . Or a salt thereof.
  • the alkylation reaction can be performed by reacting an alkylating agent in a solvent in the presence of a base.
  • the solvent include alcohols such as methanol, ethanol, and propanol; ethers such as dimethoxyethane, dioxane, and tetrahydrofuran; ketones such as acetone; and amides such as N, N-dimethylformamide.
  • Bases include, for example, organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide. Bases are included.
  • alkylating agent examples include, for example, halides of alkanes which may have a substituent (eg, chloride, bromide, chloride, etc.), sulfates, or sulfonates (eg, methanesulfonate, p-toluene) Sulfonate, benzenesulfonate, etc.) are used, and halides are particularly preferably used.
  • halides of alkanes which may have a substituent (eg, chloride, bromide, chloride, etc.), sulfates, or sulfonates (eg, methanesulfonate, p-toluene) Sulfonate, benzenesulfonate, etc.) are used, and halides are particularly preferably used.
  • the amount of the alkylating agent to be used is, for example, about 1 to 5 equivalents, preferably about 1 to 3 equivalents, per 1 mol of the substrate.
  • the reaction temperature is usually -10 ° ( ⁇ 200 ° C, preferably about 0 ° C-110 ° C), and the reaction time is usually 0.5-48 hours, preferably 0.5 hours. ⁇ 16 hours.
  • Ashiru reaction is desired I ⁇ a- OH wherein, R 1 a is C i-6 Ashiru group, Ci-e alkoxy one carbonyl group, the force Rubamoiru group, mono- or di - CI- e alkyl It represents a one-piece rubamoyl group or a C i-e alkylsulfonyl group. ] Or a reactive derivative of the salt thereof.
  • This reaction varies depending on the type of acylating agent and the type of substrate, but is usually performed in a solvent, and a convenient base may be added to promote the reaction.
  • the solvent examples include hydrocarbons such as benzene and toluene, ethers such as ethyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethan; Examples include amides such as N-dimethylformamide and aromatic amines such as pyridine.
  • the base include, for example, bicarbonates such as sodium bicarbonate and potassium bicarbonate, carbonates such as sodium carbonate and potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and pyridine. And aromatic amines.
  • R 1 a- OH is C i-e Ashiru group, (Bok 6 alkoxy one carbonyl group, the force Rubamoiru group, a mono- or di-one C alkyl Ichiriki Rubamoiru group or a C i.sub.- 6 alkylsulfonyl group.
  • Examples of the reactive derivative of the compound or a salt thereof include acid anhydrides, mixed acid anhydrides, and acid halides (eg, chloride, promide). Can be used.
  • the amount of these acylating agents to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the substrate.
  • the reaction temperature is usually from 10 ° C to 150 ° C, preferably from about 0 ° C to 10 ° C. C, and the reaction time is usually about 15 minutes to 24 hours, preferably about 30 minutes to 16 hours.
  • Compound (I) or a salt thereof can also be produced by reacting a compound having a hydrogen atom at the nitrogen atom of the tetrahydropyridine ring with an aldehyde in the presence of a reducing agent such as a metal hydride.
  • a reducing agent such as a metal hydride.
  • Metal hydrides as reducing agents include, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, aluminum hydride Lithium and the like are included.
  • Preferred metal hydrides include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the amount of the reducing agent to be used is, for example, about 1 to 50 equivalents, preferably about 1 to 10 equivalents, per 1 mol of the substrate.
  • the aldehyde for example, formalin, C i _ 5 alkyl one aldehyde ( ⁇ acetaldehyde, etc.) is used, the amount used, for example from 1 to 100 equivalents relative to 1 mol of the substrate, preferably 1 to 20 equivalents It is.
  • the reaction solvent include lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and hydrocarbons such as benzene and toluene.These solvents may be used alone or as a mixture. Can be used.
  • the reaction temperature is usually about -80 ° C to 40 ° C, preferably about -50 ° C to 25 ° C, and the reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. It is about.
  • compound (I) or a salt thereof can also be produced by reacting a compound having a hydrogen atom at the nitrogen atom of the tetrahydropyridine ring with a C60 aryl metal reagent in the presence of a metal salt. I can do it.
  • the reaction is usually performed in a solvent inert to the reaction.
  • the solvent include hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyene and tetrahydrofuran, and dimethylformamide.
  • An aprotic polar solvent such as dimethylsulfoxide and hexamethylphosphoramide is preferably used.
  • C 6 _ 10 ⁇ Li Ichiru metal reagent as triarylbismuth di ⁇ Sete Ichito, such as triaryl bismuth ditolyl full O lower cell Tate is preferably used as the metal salt is copper acetate (11), pivalic copper ( Copper salts such as II) are preferably used.
  • the amount of c 6 _ 10 Ariru metal reagent if example embodiment, 1 to 10 equivalents relative to 1 mol of the substrate, preferably 1 to 5 equivalents, the amount of gold Shokushio, for example, to 1 mole of the substrate On the other hand, it is 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent.
  • the reaction temperature is usually about -10 ° C to 150 ° C, preferably about 0 ° C; to about 100 ° C, and the reaction time is usually 5 minutes to 48 hours, preferably 30 minutes. Minutes to 24 hours.
  • an inorganic acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • an organic acid for example, methanesulfonic acid, benzene Sulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.
  • inorganic bases eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum
  • an organic base eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine
  • compound (I) is obtained in the form of a salt, it can be converted into a free compound or another salt according to a conventional method.
  • the compound (I) or a salt thereof produced by these methods can be separated and purified by using a conventional separation and purification means (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • a conventional separation and purification means for example, concentration, solvent extraction, column chromatography, recrystallization, etc.
  • the compound (I) is an optically active form, it can be separated into d-form and 1-form by a conventional optical resolution method.
  • the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent in each reaction of the target compound and the starting material synthesis
  • these groups may be protected groups such as those commonly used in peptide chemistry and the like. May be protected.
  • the target compound can be obtained by removing the protecting group, if necessary, after the reaction.
  • Examples of the protecting group for an amino group include a formyl group, a C 6 alkyl-carbonyl group (for example, acetyl and propionyl groups), a phenylcarbonyl group, and a C 6 alkyl-oxycarbonyl group (for example, methoxycarbonyl, Etokishikaru etc. Boniru group), ⁇ reel O alkoxycarbonyl group (e.g., phenylalanine O carboxymethyl carbonylation Le group), C 7 _ 1 0 Ararukiru - carbonyl group (e.g., benzyl O propoxycarbonyl group), trityl group, And a fluoroyl group.
  • These protecting groups may have a substituent.
  • substituents include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), an alkylcarbonyl group (for example, acetyl, propionyl, and butylcarbonyl group), and a nitro group.
  • halogen atom for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
  • alkylcarbonyl group for example, acetyl, propionyl, and butylcarbonyl group
  • carboxyl-protecting group examples include a C-e alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc.), a phenyl group, a trityl group, a silyl group, and the like. These protecting groups may have a substituent.
  • substituents include, for example, halogen atom (fluorine atom, chlorine Atom, a bromine atom, an iodine atom), formyl groups, C WINCH 6 alkyl - if carbonyl group (eg, Asechiru, propionyl, butyl group), a nitro group and the like, the number of the substituents is one to three or so It is.
  • hydroxyl-protecting group examples include ( ⁇ alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc.), phenyl group, aralkyl group (eg, benzyl group, etc.), formyl Group, C i- 6 alkyl-carbonyl group (eg, acetyl, propionyl group, etc.), aryloxycarbonyl group (eg, phenyloxycarbonyl group, etc.), C 7 _ 1 (3 aralkyl monocarbonyl group (eg, benzyl group) Oxycarbonyl group), a vinyl group, a furanyl group, a silyl group, etc., and these protecting groups may have a substituent.
  • alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc.
  • the compound (I) of the present invention produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • the compound (I) thus obtained is a free compound, it can be converted to a salt by a known method or a method analogous thereto (eg, neutralization, etc.), and conversely
  • compound (I) is obtained in the form of a salt, it can be converted to a free form or another salt by a known method or a method analogous thereto.
  • the compound (I) of the present invention or a salt or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention) has an excellent effect of suppressing the increase in tracheal vascular permeability induced by cabsaicin, It has an inhibitory action on evening kinkinin receptor, especially a substance P receptor antagonism and a neurokinin A receptor antagonism.
  • the compounds of the present invention have low toxicity and are safe. Therefore, the compounds of the present invention having excellent substance P receptor antagonism, neurokinin A receptor antagonism, etc.
  • mammals for example, mice, rats, hamus yuichi, egrets, cats, dogs, dogs, Inflammation or allergic diseases (eg atopic, monkey, human) such as atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, polymorphism (Sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, HIV infection, chronic obstructive pulmonary disease, and diseases of the central nervous system (e.g., schizophrenia, Parkinson's disease) , Psychosomatic disease, dementia (eg, Alzheimer's disease, etc.), gastrointestinal diseases [eg, irritable bowel disease, ulcerative colitis, Crohn's disease, urease-positive Abnormalities (eg, gastritis, gastric ulcers, etc.
  • the compound of the present invention is also useful as an agent for preventing and treating diseases such as depression, anxiety, manic depression, and schizophrenia.
  • the pharmaceutical preparation containing the compound of the present invention may be any of solid preparations such as powders, granules, tablets, capsules and suppositories, and liquid preparations such as syrups, emulsions, injections and suspensions.
  • the pharmaceutical preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilizing treatment, emulsification, etc., depending on the form of the preparation.
  • a conventional method such as mixing, kneading, granulation, tableting, coating, sterilizing treatment, emulsification, etc., depending on the form of the preparation.
  • each section of the Japanese Pharmacopoeia Act general rules for drug products can be referred to.
  • the content of the compound salt of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.01% by weight, based on the whole preparation.
  • the content is about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.
  • the compound of the present invention when used as the above-mentioned pharmaceutical preparation, it may be used as such or as a suitable pharmacologically acceptable carrier, for example, an excipient (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), a binder (Eg, starch, arabic Rubber, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc., lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, carboxymethylcellulose calcium) , Talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and additives (stabilizers, preservatives, coloring agents, fragrances, dissolution aids, emulsifiers, buffers, isotonic agents, if necessary) ) Can be administered orally
  • the dose varies depending on the type of the compound of the present invention or a pharmaceutically acceptable salt thereof, the administration route, symptoms, age of the patient, and the like.
  • About 0.05 to 5 Omg, preferably about 0.05 to: L Omg, and more preferably about 0.2 to 4 mg of the compound of the present invention per kg of body weight per day can be administered in 1 to 3 divided doses.
  • the compound of the present invention can be used by being appropriately compounded with other pharmaceutically active ingredients in an appropriate amount.
  • other pharmaceutically active ingredients for example, the following are used as such active ingredients.
  • Insulin preparations eg, animal insulin preparations extracted from the tongue of P. and Bush; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; prominin insulin zinc; insulin Fragments or derivatives (eg, INS-1 etc.)), insulin sensitizers (eg, pioglicusone hydrochloride, troglisuzone, mouth diglyuzone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP_297, FK-614, CS-011, etc., Hi-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, Metformin, buformin, etc.), sulfonylurea agents (eg, tolptamide, glibenclamide, gliclazide, chlorpropamide) , Trazamide
  • Aldose reductase inhibitors eg, Torres evening, Epalles evening, Zenares evening, Zobolles evening, Fidalest evening (SNK-860), Minareth evening (AR I_509), CT — 112, etc.
  • neurotrophic factor eg, NGF, NT—3, etc.
  • AGE inhibitor eg, ALT—945, pimagedin, pyratoxatin, N—phenacylthiazolium promide (ALT—766), EXO — 226, etc.
  • active oxygen scavengers eg, thioctic acid, etc.
  • cerebral vasodilators eg, thiopride, etc.
  • a cholesterol synthesis inhibitor such as a suvatin-tin compound (eg, pravasu-tin, roba-sutin, atorba-sutin, full-basin-sutin, seribas-sutin, or a salt thereof (eg, sodium salt)) ), Fibrates based on squalene synthase inhibitors or triglycerides (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).
  • Angiotensin converting enzyme inhibitors eg, captopril, enalapril, derapril, etc.
  • angiotensin ⁇ antagonists eg, oral sultan, candesartan cilexetil, etc.
  • calcium antagonists eg, manidipine, diflupine, amlodipine, etc.
  • Ejonidipi, n, dicardipine etc. clonidine etc.
  • Central anti-obesity drugs eg, dexfenfluamine, fenfluramine, fuentermin, cyptramine, ampuepramone, dexfenfemin, mazindol, phenylpropanolamine, clovenzolex, etc.
  • Teng lipase inhibitor eg, Orlistat, etc.
  • ⁇ 3agonist eg, CL-316243, SR-5861 1-A, UL-TG-307, AJ-9677, AZ40140, etc.
  • peptide anorectic eg, lebutin, CNTF (hairy) Somatic neurotrophic factor
  • cholecystokinin agonist eg, lynch tribute, FPL-15849, etc.
  • Xanthine derivatives eg, sodium theopromine salicylate, calcium thiophene salicylate, etc.
  • thiazide-based preparations eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochloride thiazide, hydroflumethiazide, benzyl hydrochlorothiazide, penflutide, polythiazide, polythiazide) Methiclothiazide, etc.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetone zolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapami) Etc.
  • azosemide isosorbide, phosphoric acid, pyreinide, bumeinide, furosemid
  • Alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plant-derived anticancer agents eg, mitomycin, adriamycin
  • 5-fluorouracil derivatives such as fluperon or neofluronone c
  • Microbial or bacterial components eg, muramyl dipeptide derivatives, picibanil, etc.
  • polysaccharides with immuno-enhancing activity eg, lentinan, schizophyllan, krestin, etc.
  • site-specific proteins obtained by genetic engineering techniques
  • examples include interferon, inulin-leukin (IL), colony-stimulating factors (eg, granulocyte colony-stimulating factor, erythropoietin, etc.), among which IL-1, IL-2, IL-12, etc.
  • Cyclooxygenase inhibitors eg, indomethacin, etc.
  • progesterone derivatives eg, megestrol acetate
  • carbohydrate steroids eg, dexamethasone, etc.
  • metoclobramide drugs tetrahydrocannabinol drugs Drugs (all references are the same as above)
  • Fat metabolism improvers eg, eicosapenic acid, etc.
  • growth hormone IGF-1, or TNF, which is a factor that induces cachexia, LIF, IL-6, and antibodies to Oncoscintin M.
  • Saccharification inhibitors eg, ALT-711 etc.
  • nerve regeneration promoters eg, Y-128, VX853, prosaptide, etc.
  • central nervous system drugs eg, antidepressants such as desibramine, amitriptyline, imipramine
  • anti- Epilepsy drugs eg, lamotrigine
  • antiarrhythmic drugs eg, mexiletine
  • acetylcholine receptor ligands eg, ABT-594
  • endothelin receptor antagonists eg, ABT-627
  • monoamine uptake inhibitors eg, Tramadol
  • narcotic analgesics eg, morphine
  • GABA receptor agonists eg, gearbapentin
  • spermatid-2 receptor agonists eg, clonidine
  • topical analgesics eg, capsaicin
  • protein kinase C Inhibitors eg, LY-333531
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran
  • DM S 0 dimethyl sulfoxide
  • CD C 1 3 Black port Holm
  • Mg S 0 4 sulfuric mug Neshiumu
  • Hz Herudzu
  • J a coupling constant
  • m Maruchipuredzuto
  • Q quartet
  • t triplet
  • d doublet
  • s singlet
  • br * broad, like: approximation.
  • Step 4 To a solution of the compound obtained in step 3 (1.50 g) in DMF (20 ml) was added 3,5-dimethoxybenzylamine (1.01 g) and N- (3-dimethylaminopropyl) -N'-e Tilcarbodiimide hydrochloride (2.01 g) and 1-hydroxy-1H-benzotriazole monohydrate (1.21 g) were added at room temperature, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF.
  • Step 2 The compound (1.56 g) obtained in Step 2 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was converted to colorless prism crystals (0.86 g, 65%). Was obtained.
  • N— (3,5-dimethylbenzyl) _4_ (4-fluorophenyl) 11-oxo-1 H-pyrano [3,4-1c] pyridine-13-carboxamide is a colorless powder (1.71 g ⁇ ) 80%).
  • Step 3 The compound obtained in Step 2 (0.74 g) was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was converted to a non-powder (0.33 g, 46%). Obtained.
  • Step 1 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as colorless crystals (0.095 g, 30%).
  • Step 1 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, whereby the title compound (0.25 g, 42%) was obtained as colorless crystals.
  • Step 1 The compound (0.85 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a colorless powder (0.68 g, 83%). Melting point: 186-188 ° C.
  • Step 1 The compound (0.81 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a colorless powder (0.43 g, 54%). Melting point: 193-195 ° C.
  • the title compound was obtained as a colorless powder (0.59 g, 66%) by reacting and treating the compound (0.92 g) obtained in Step 1 in the same manner as in Step 6 of Reference Example 1. .
  • Step 1 The compound obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Reference Example 1, and the title compound was obtained as a pale-yellow oil (0.38 g, 66%).
  • NaBH sodium triacetoxyborohydride
  • Triphenyl bismuth diacetate was added to a solution of the compound (0.10 g) obtained in Example 3 and copper (II) pivalate (Cu (Pi ⁇ ) 2 ) (0.016 g) in methylene chloride (5 ml).
  • (Ph 3 B i (OAc) 2 ) (0.12 g) was added, and the mixture was stirred at room temperature for 14 hours.
  • the reaction solution was poured into water and extracted with a mixture of ethyl acetate and THF.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried (MgSO 4), the solvent was distilled off under reduced pressure.
  • the title compound was obtained as pale yellow powder (0.058 g, 51%).
  • Acetyl chloride (0.028 g) was added to a solution of the compound obtained in Example 3 (0.10 g) and triethylamine (0.036 g) in THF (5 ml) at 0 ° C, and the mixture was added at room temperature.
  • Example 16 The compound (0.20 g) obtained in Example 13 was reacted and treated in the same manner as in Example 7, to give the title compound as colorless crystals (0.18 g, 85%). Melting point: 237-239 ° C (recrystallized from ethyl isopropyl ether).
  • Example 16
  • Example 23 When the compound (0.20 g) obtained in Example 23 was reacted and treated in the same manner as in Example 7, the title compound (0.18 g, 81%) was obtained as colorless prism crystals. Melting point 180-182 ° C (recrystallized from ethyl isopropyl ether).
  • Example 23 When the compound (0.20 g) obtained in Example 23 was reacted and treated in the same manner as in Example 16, the title compound (0.096 g, 42%) was obtained as colorless prism crystals. Melting point 140-142 ° C (from methylene diisopropyl ether).
  • coated tablets are obtained in the same manner except that any of the compounds of Examples 2 to 26 is used in place of the compound of Example 1.
  • tablets are obtained in the same manner except that the compound of Example 1 is replaced with any of the compounds of Examples 2 to 26.
  • Radioligand receptor binding activity (receptor binding activity using receptor from human lymphoblastoid cells (IM-9))
  • IM-9 human lymphoblast cells
  • Receptors were prepared from human lymphoblast cells (IM-9). After inoculation of IM-9 cells (2 ⁇ 10 5 cells / ml), the cells were cultured for 3 days (1 liter), and then centrifuged at 500 ⁇ G for 5 minutes to obtain a cell pellet. The obtained pellet was washed once with a phosphate buffer (Flow Laboratories, CAT. No.
  • reaction buffer [50 mM Tris' hydrochloric acid buffer (pH 7.4), 0.02% bovine serum albumin, ImM phenylmethylsulfonylfluoride so as to have a protein concentration of 0.5 mg / ml.
  • the antagonistic activity of the compounds obtained in Examples was determined as the drug concentration (IC50 value) required to exhibit 50 % inhibition under the above conditions. I got
  • Radio 'ligand refers to substance P labeled with [ 125 1].
  • Table 3 shows that the compounds of the present invention have excellent substance P receptor antagonism.
  • Test Example 2 Inhibitory activity of NK1 (neurokinin 1) agonist GR 73632 on hyperlocomotion induced by intracerebroventricular injection of guinea pig
  • the experiment was performed with reference to the method of Rupniak et al. (Neuropharmacology, 39, 1413-1421, 2000).
  • a Hartley white male guinea pig anesthetized with ether was fixed to the head with a stereotaxic apparatus (David Kopf, USA). Insert a 27G injection needle so that the tip reaches the third ventricle (7.5 to 8 mm below bregma), and GR73632 (Bachem, Switzerland) dissolved in saline for injection 0.1 nmol in a volume of 51 Injected over 1 minute.
  • the incision was sutured, and the locomotor activity was measured for 30 minutes using a locomotor activity analyzer (ANIMEX AUTO MK-110, Muromachi Kikai, Japan) immediately after the animal awakened from anesthesia.
  • the test drug was suspended in a 0.5% methylcellulose solution and orally administered at a volume of 2 mL / kg 45 minutes before administration of GR73632. 0.5% ethylcelliilose solution for control group The same volume was orally administered.
  • a sham treatment group in which physiological saline was administered into the ventricle instead of the GR73632 solution was also provided. Each treatment group consisted of 4 or more patients.
  • the evaluation of the drug was evaluated by calculating the inhibition rate according to the following formula. In addition, if necessary, ID 5. The value was calculated using the suppression rate (Table 4).
  • the compound (I) of the present invention or a salt thereof or a prodrug thereof has a high kinkinin receptor antagonism, particularly a substance P receptor antagonism, is low in toxicity, and is safe as a drug. Therefore, the compound (I) or a salt thereof or a prodrug thereof of the present invention is useful as a pharmaceutical composition, for example, a quinkinin receptor antagonist, a dysuria improving agent and the like.
  • This application is based on a patent application No. 2000-280154 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

Cette invention concerne un composé représenté par la formule (I) ainsi qu'un sel de ce composé. Dans cette formule, R1 représente hydrogène, alkyle éventuellement substitué, aryle, acyle, alkoxycarbonyle, carbamoyle, mono- ou dialkylcarbamoyle, ou alkylsulfonyle ; R2 représente hydrogène, halogéno ou alkyle éventuellement halogéné ; R3 représente hydrogène ou alkyle ; R représente hydrogène, halogéno, alkyle éventuellement halogéné ou alkoxy éventuellement halogéné ; m est un entier entre 0 et 3 ; n vaut 1 ou 2 ; et p est un entier entre 0 et 3, à condition que lorsque R1 et R2 sont méthyle, R3 est hydrogène, le groupe représenté par la formule (A) est le groupe représenté par la formule (B), et m vaut 1, alors n est égal à 1. Ce composé a un effet antagoniste sur les récepteurs de la tachykinine, en particulier sur un récepteur de la substance P, et convient bien comme médicament permettant d'atténuer les troubles urinaires.
PCT/JP2001/007815 2000-09-11 2001-09-10 Compose tricyclique heterocyclique, son procede de fabrication et son utilisation WO2002022574A1 (fr)

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AU2001286188A AU2001286188A1 (en) 2000-09-11 2001-09-10 Tricyclic heterocyclic compound, process for producing the same, and use thereof

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JP2000-280154 2000-09-11
JP2000280154 2000-09-11

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074771A1 (fr) * 2001-03-19 2002-09-26 Takeda Chemical Industries, Ltd. Compose heterocyclique a trois cycles, son procede de preparation et son utilisation
WO2006112666A1 (fr) * 2005-04-20 2006-10-26 Sk Chemicals Co., Ltd. Derives de pyridine, procedes de preparation de ces composes et compositions pharmaceutiques contenant ces composes
US7211572B2 (en) 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
KR20150095638A (ko) * 2012-12-20 2015-08-21 얀센 파마슈티카 엔.브이. 감마 세크레타제 조절 인자로서의 신규 삼환 3,4-디하이드로-2H-피리도[1,2-α]피라진-1,6-디온 유도체
US10246454B2 (en) 2013-01-17 2019-04-02 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
US10562897B2 (en) 2014-01-16 2020-02-18 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09263585A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09263585A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074771A1 (fr) * 2001-03-19 2002-09-26 Takeda Chemical Industries, Ltd. Compose heterocyclique a trois cycles, son procede de preparation et son utilisation
US7211572B2 (en) 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
WO2006112666A1 (fr) * 2005-04-20 2006-10-26 Sk Chemicals Co., Ltd. Derives de pyridine, procedes de preparation de ces composes et compositions pharmaceutiques contenant ces composes
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
KR20150095638A (ko) * 2012-12-20 2015-08-21 얀센 파마슈티카 엔.브이. 감마 세크레타제 조절 인자로서의 신규 삼환 3,4-디하이드로-2H-피리도[1,2-α]피라진-1,6-디온 유도체
JP2016503775A (ja) * 2012-12-20 2016-02-08 ヤンセン ファーマシューティカ エヌ．ベー． γセクレターゼ調節剤としての新規な三環式３，４−ジヒドロ−２Ｈ−ピリド［１，２−ａ］ピラジン−１，６−ジオン誘導体
US10112943B2 (en) 2012-12-20 2018-10-30 Janssen Pharmaceutica Nv Substituted imidazoles as gamma secretase modulators
KR102209418B1 (ko) 2012-12-20 2021-01-29 얀센 파마슈티카 엔.브이. 감마 세크레타제 조절 인자로서의 신규 삼환 3,4-디하이드로-2H-피리도[1,2-α]피라진-1,6-디온 유도체
US10246454B2 (en) 2013-01-17 2019-04-02 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators
US10562897B2 (en) 2014-01-16 2020-02-18 Janssen Pharmaceutica Nv Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators

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