WO1994027604A1 - Utilisation medicale d'un derive de pyridine - Google Patents

Utilisation medicale d'un derive de pyridine Download PDF

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Publication number
WO1994027604A1
WO1994027604A1 PCT/JP1994/000842 JP9400842W WO9427604A1 WO 1994027604 A1 WO1994027604 A1 WO 1994027604A1 JP 9400842 W JP9400842 W JP 9400842W WO 9427604 A1 WO9427604 A1 WO 9427604A1
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Prior art keywords
group
compound
phenyl
formula
pyridin
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PCT/JP1994/000842
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English (en)
Japanese (ja)
Inventor
Hirofusa Shirai
Kenji Hanabusa
Yuki Takahashi
Fumio Mizobe
Kazunori Hanada
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Taisho Pharmaceutical Co., Ltd.
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Priority to AU68079/94A priority Critical patent/AU6807994A/en
Publication of WO1994027604A1 publication Critical patent/WO1994027604A1/fr

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/57—Nitriles
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a pharmaceutical use of a pyridin derivative having a nerve growth factor (hereinafter referred to as NGF) production promoting action or a neurotrophic factor action. More specifically, it also improves a neurodegenerative disease comprising a pyridin derivative as an active ingredient or a therapeutic pharmaceutical composition, and also improves a neurodegenerative disease comprising administering a pyridin derivative. Or treatment o
  • NGF nerve growth factor
  • Alzheimer's senile dementia which has been increasing in recent years, it is suggested that degeneration and loss of acetylcholinergic neurons, which are basal ganglia neurons, are closely related to memory impairment and decreased intellectual activity.
  • acetylcholinergic neurons which are basal ganglia neurons
  • NGF inhibits the degeneration and loss of central acetylcholinergic nerves caused by fiber cutting [Korsing et al., Neuroscience Lett., Vol. 66, p. 6 years)] and to improve the maze learning disability of old rats and to suppress the atrophy of acetylcholinergic neurons (Takashi Shigeno et al., Medical History, Vol. 144, No. 5). 579 (1996)] These are the things that NGF Arunno and Ima Type 1 have been shown to be therapeutic agents for senile dementia.
  • NGF has been confirmed to prevent hippocampal neuronal cell death in cerebral ischemic gerbils, and is considered to be useful as a therapeutic drug for stroke.
  • NGF has an effect of accelerating the recovery of peripheral nerve damage, and it has been clearly demonstrated that NGF is also useful as a therapeutic drug for peripheral neuropathy.
  • neurotrophic factors In addition to NGF, a large number of biological components exhibiting a survival / function maintenance activity or degenerative repair activity of nerve cells have been found, and are called neurotrophic factors. Therefore, these neurotrophic factors are considered to be useful as therapeutic agents for central neuropathy and peripheral neuropathy associated with neuronal degeneration.
  • neurotrophic factors are all proteins. When proteins are used as therapeutic drugs for central neuropathy, it is expected that direct intraventricular administration will be required, judging from their physical properties, and there are many practical problems. Therefore, there is a demand for a therapeutic agent of a low-molecular compound having a neurotrophic factor action itself or a neurotrophic factor production-promoting action, which allows a simpler administration method.
  • An object of the present invention is to provide a novel physiologically active substance having one or both of an NGF production promoting action and a neurotrophic factor action, and to administer a symptom associated with neurodegeneration, improvement of a disease, and therapeutic use. This is to simplify the method.
  • the substance is a physiologically active substance having one or both of an NGF production promoting action and a neurotrophic factor action, and completed the present invention.
  • R 1 is a hydrogen atom; an unsubstituted phenyl group; an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, a benzyloxy group, Tyryleneoxy, trifluoromethyl, trifluoroxy, methylthio, hydroxyl, nitro, amino, N-ethylamino Group, N, N — dimethylamino group, carboxyl group, bromomethyl group, acetamido group, cyano group, N, N — dimethylaminopropoxy group
  • R 4 and R 5 are the same or different and each represent a hydrogen atom; an alkyl group; or both of them represent a 5-membered ring.
  • R 2 and R 3 are the same or different. Differently represent a hydrogen atom; an alkyl group; an alkoxy group; a hydroxyl group; a nitro group or a halogen atom. And a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide the above pyridin derivative or a pharmaceutically acceptable salt thereof for use as an active ingredient of a pharmaceutical composition. .
  • Another object of the present invention is to provide the above pyridin derivative or its pharmaceutically acceptable for preparing a pharmaceutical composition for ameliorating or treating a neurodegenerative disease.
  • salt In providing the use of salt.
  • Another object of the present invention is to administer an effective amount of the above-mentioned pyridin derivative or a pharmaceutically acceptable salt thereof to a human. It is to provide improvements or treatments.
  • examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, and butyric. And alkyl groups having 1 to 6 carbon atoms such as butyl, t-butyl, pentyl and hexyl. For example, methoxy, ethoxy, probox, isoprobox, butoxy, pentox, hexoxy, etc. And an alkoxy group having 1 to 6 carbon atoms.
  • alkenyloxy group examples include alkenyloxy having 2 to 6 carbon atoms, such as vinyloxy, aryloxy, propenyloxy, 2—propenyloxy, butenyloxy, pentenoxy, hexenyloxy, and the like.
  • halogen atom examples include a halogen atom such as fluorine, chlorine, and bromine.
  • salts of pyridin derivatives include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or succinic acid, succinic acid, tartaric acid and methansulfo acid.
  • Acid addition salts with organic acids such as acid. Examples thereof include salts with alkaline metals such as sodium and potassium, and salts with alkaline earth metals such as canolesium.
  • the pyridin derivative of the formula (I) of the present invention is partially a novel compound, but also includes known compounds.
  • R 1 is a hydrogen atom; a non-substituted phenyl group; or an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, Benzyloxy group, methylenedioxyl group, trifluoromethyl group, trifluoromethyl group, methylthio group, hydroxyl group, nitro group, amino group , N —ethyl amino group, N, N -Dimethylamino, carboxyl, and bromomethyl.
  • Acetamido, cyano, N, N — dimethylaminophenol, poxoxy and halogen represents a furyl group substituted by at least one substituent selected from the group consisting of atoms, and R 2 and R 3 are the same or different and represent a hydrogen atom or Pyridine derivatives representing a methyl group or pharmaceutically acceptable salts thereof are preferred.
  • R 1 represents a hydrogen atom; or a methyl group or a phenyl group substituted by an N, N-dimethylamino group;
  • R 2 , R 3 Is preferably a pyridin derivative which is the same or different and represents a hydrogen atom or methyl, or a pharmaceutically acceptable salt thereof.
  • the pyridin derivative of the present invention can be produced, for example, according to the following method.
  • R 1 is an unsubstituted phenyl group, or an alkyl group, a phenyl group, an anoreoxy group, an alkenyl oxy group, a phenyloxy group, N, N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N , Carboxyl, acetamido, cyano, N, N-dimethylaminopropoxy or phenyl-substituted phenyl group, Oh Ru have the pin lysyl group, thienyl group, disadvantageous group, Ri i Mi Dazo Li Le 'Motodea, is R 2, R 3, identical or different I hydrogen
  • R ′′ is a phenyl group or an alkyl group, a phenyl group, an alkoxy group, an alkenyloxy group, a phenyloxy group, a benzyloxy group, a methyloxy group.
  • R 2 ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a nitro group or a halogen atom.
  • the alkali used in the condensation reaction includes sodium hydroxide, sodium hydroxide, sodium methoxide, and t-butane.
  • Reaction solvents containing tokidide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, etc. are methanol, ethanol, etc. , N — professional, isop.
  • Knol, t-butanol, etc. can be used alone or with the addition of water.
  • the reaction temperature can be appropriately selected from 0 ° C to the boiling point of the solvent used.
  • R 3 ′ represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a nitro group, or a halogen atom
  • X represents bromine or iodine.
  • ammonium acetate was used in an amount of 110 times the molar amount of the compound of the formula (V), and the reaction solvents were methanol, ethanol, and n-butyl.
  • the reaction solvents were methanol, ethanol, and n-butyl.
  • Isop,. Knol, t-butanol, acetic acid, etc. can be used.
  • the reaction temperature can be appropriately selected from room temperature to the boiling point of the solvent used.
  • R 1 is a phenyl group substituted by an amino group
  • R 2 and R 3 are the same or different and are each a hydrogen atom, an alkyl group, or a nitro group.
  • the pyridin derivative of the present invention which is a group or a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R 1 is an acetate amine.
  • the derivative can be obtained by hydrolyzing the derivative in the presence of an acid or alkali.
  • R 1 is a phenyl group substituted by an N-ethylamino group
  • R 2 and R 2 are the same or different and are a hydrogen atom, an alkyl group, an alkoxy group.
  • the pyridine derivative of the present invention which is a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R 1 is substituted with a nitro group.
  • Pyridin derivatives in which R 2 and R 3 are the same or different and are a hydrogen atom, an alkyl group, an alkoxy group or a nitrogen atom; It can be obtained by reduction in the title.
  • a catalytic hydrogenation method using palladium carbon as a catalyst can be used as a reduction method.
  • R 1 is a bromomethylphenyl group
  • R 2 and R are the same or different and are each a hydrogen atom, an alkoxy group, a nitro group, and a halogen atom.
  • the pyridin derivative of the present invention which is an atom, is a pyridine derivative of the formula (I) obtained by the above method, wherein R 1 is substituted with a methyl group.
  • a pyridin derivative wherein R 2 and R 3 are the same or different and are a hydrogen atom, an alkoxy group, a nitro group or a halogen atom Ru is possible to get Ri by the and this (in here, as the blow motor method can and this using conventional methods, for example, halo gain down solvent, N- Bro motor co Nono click acid Lee A method of reacting with a mid can be used.
  • R 1 is a group represented by the formula (II), and R 2 and R 3 are the same or different and are each a hydrogen atom, an alkoxy group, a nitro group or
  • the pyridin derivative of the present invention which is a halogen atom, is a pyridin derivative of the formula (I) obtained by the above method, wherein R 1 is substituted with a bromomethyl group.
  • a phenyl group wherein R 2 and R 3 are the same or different and are hydrogen atoms, alkoxy groups, nitro groups or halogen atoms; It can be obtained by an amination reaction in which the corresponding amine is reacted.
  • water, acetone, alcohols (eg, methanol, ethanol, etc.), getyl ether benzene, and acetonitrite are used as solvents.
  • Rill can be used alone or as a mixture.
  • the reaction temperature can be appropriately selected from 0 ° C. to the boiling point of the solvent used.
  • the pharmaceutically acceptable salt of the pyridin derivative of the present invention can be obtained by subjecting the pyridin derivative of the formula (I) to a salt-forming reaction known per se.
  • Table 1 shows representative pyridin derivatives of the present invention.
  • 2629-26 (1949) show compounds 1, 29 , 39, and 40; Michel Simalty et al., Bull. Soc. Cini. Fr., 11, Vol. 39, pp. 39-26 (1970 ) Describes compound 18; EA Zvezdina et al., Kim. Geterotsikl. Soedin., Pp. 1025 to 1028 (1976) describe compound 18. 54 are described; Gerhard W. Fischer et al., J. Prakt. Chem., Vol. 326, pp. 287-302 (1994) describes compound 3 And 8 are listed; Naresh K. Mis hra et al., Indian J Agric. Chem. Vol. 21, pp. 91-93 (1989) describes compound 77; Rupert
  • the dose of the pyridin derivative of the present invention is usually preferably 1 mg to 100 mg per day for an adult.
  • excipients for oral administration, excipients, disintegrants, binders, lubricants, antioxidants, coding agents, coloring agents, flavoring agents, surfactants, plasticizers, etc. are mixed. It can be administered in the form of granules, powders, capsules, tablets, or parenteral administration by injection, infusion, or suppository.
  • Excipients include, for example, mannitol, xylitol, sorbitol, budou sugar, sucrose, lactose, and crystal cell mouths.
  • Tilcello "Sntrium, calcium hydrogen phosphite, column starch, rice starch, corn starch, no 3D-cyclodextrin, dextrin, dextrin, tri-cyclodextrin, 3D cyclodextrin Phosphorus, carboxyvinyl polymer, light gay anhydride, titanium oxide, magnesium silicate magnesium, polyethylene glycol, Medium-chain fatty acid triglycerides and the like.
  • Disintegrators include low-substituted hydroxypropyl cercellose, carboxymethylcellulose, carboxymethylcellulose calcium, Call Box Me Trim, cross-force, no-mellow sodium, A-type (actile), starch, crystalline cellulose, hydroxypropyl Examples include start and partial alpha dumping.
  • Binders include, for example, methylcellulose, hydroxypropyl propylcellulose, hydroxypropyl propylmethylcellulose, and polyhydroxyl cellulose.
  • Lubricants include, for example, stearic acid, magnesium stearate, calcium stearate, and poly stearate. Seals, selenol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, microcrystalline wax, Mitsurou, Sarahitsu Mitsuro and the like.
  • Antioxidants include, for example, dibutyl hydridoxitrite ( ⁇ ⁇ ⁇ ), propyl gallate, and butyl hydroxyanifur ( ⁇ ⁇ ). ⁇ ⁇ ), ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ , citric acid, etc.
  • Coating agents include, for example, hydroxypropyl methylcellulose, hydroxypropyl propylcellulose, methylcellulose Source, ethyl cellulose, hydroxypropyl methyl chloride methyl phosphate rate, hydroxypropyl Methylcellulose acetate succinate, carboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetate Acetaminopropyl acetate, aminopropyl methacrylate copolymer, hydroxypropyl methylenolose acetate Xinate, methylacrylate copolymer, cellulosic acetate trimethylate (CAT), polyvinyl acetate phthalate And cell phones.
  • CAT cellulosic acetate trimethylate
  • Examples of the colorant include an orange dye, titanium oxide, and the like.
  • Flavoring agents include citric acid, adipic acid, ascorbic acid, menthol, and the like.
  • Surfactants include, for example, pooxyethylene-hardened castor oil, glycerin monostearate, sorbitan monostearate, mono, . Sorbitan Lumicitrate, Sorbitan Monophosphate, Polyoxyethylene Polypropylene Block Copolymer, Polymer Examples include sorbates, sodium raurylsulfate, macrogol, and sucrose fatty acid esters.
  • plasticizer examples include triethyl citrate and triacetin phenol.
  • Acetofenon 24.0 g, p — dimethylaminobenz To a mixture of 25.0 g of aldehyde and 300 ml of ethanol was added 1.12 g of potassium hydroxide, and the mixture was stirred at 50 ° C for 8 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 23.0 g of the title compound.
  • Compound 6 100 mg White sugar 200 mg Mannitol 200 mg Corn decane 47 0 mg Hydroxypropyl propyl cellulose 20 mg Poly Solvent 800 mg Production method
  • Compound 610 g was ground with Benomile, 200 g of sucrose and 470 g of corn starch were added and mixed, followed by mixing with hydroxypropyl pilcellulose 20 g and polysorbate in a mixture of purified water and ethanol (1: 2) (250 g) were added, followed by mixing with a mixer. This was extruded using a screen of 0.5 mm in diameter and granulated by a granulator, and then dried by a fluid bed dryer to obtain a granule containing 10% of compound 6. .
  • Compound 510,000 g was ground with a jet mill, and lactose 300 g, glucose 230 g, and corn starch 330 g were obtained.
  • lactose 300 g, glucose 230 g, and corn starch 330 g were obtained.
  • 30 g of hydroxypropyl cellulose and 800 g of polysorbate dissolved in 800 g of purified water were used as the binder.
  • the mixture was granulated with a fluid bed granulator and dried to obtain a fine granule containing 10% of compound 59.
  • a powder was prepared by uniformly mixing Compound 720 and lactose 800 g to obtain a powder containing Compound 73 at 20%.
  • Compound 7100 g was pulverized with ball mill, lactose 100 g, mannitol 290 g, and low-substituted hydroxypropylcellulose 30 g were added. After mixing, 25 g of hydroxypropyl methyl senorelose and 800 g of polysorbate are dissolved in 800 g of a mixture of purified water and ethanol (1: 2). The mixture was added as a binder, granulated by a fluidized bed granulator, dried, and sieved using a No. 30 sieve. This Steer Li Nsanka Le Siu arm 1 5 g, a - added hydrogenated oil 2 0 g, 3 0 0 mg was filled into No. 1 month capsule to give a mosquito capsule agent compound 7 containing 5 0 m g Was.
  • Distilled water for injection was added to and dissolved in 6810 g of the compound, and the total amount was adjusted to 2000 m1. This was dispensed into 2 ml ampules by a conventional method to obtain an injection containing 10 mg of compound 68 (0.5%, 2 ml).
  • Test example 1 NGF production promoting effect test
  • the test for promoting NGF production was evaluated using the following method.
  • Each compound shown in Table 1 was dissolved in DMS0, and the concentration was adjusted to 2 mg / ml to 50 mg / ml.
  • Astrocyte glial cells prepared from mouse forebrain were used in 20% fetal calf serum, 100 units Zm1 Benicillin, 100 units ⁇ Prepare 8 x 10 5 cells in Z ml in Dulbecco's modified medium (Gibco, containing high glucose) containing gZm1 streptomicin. and, 9 6 Anapu les over preparative (area of Ri per culture hole 0. 3 2 cm 2, full ⁇ manufactured le co emissions Co.) to,-out 0. 1 m 1 Z hole Zutsuma, at 37, 5 Cultured in% CO 2 .
  • the ratio is shown by the ratio when the NGF amount of (DMSO) is set to 1.0.
  • Table 2 shows the results.
  • Neurotrophic factor action was evaluated using the following method. Specimen
  • the compound was dissolved in DMS and the concentration was 2 mgZml to 10 mg / ml.
  • test cells were mixed in an equal volume of Dulbecco's minimum essential medium (manufactured by Gibco) and Ham F-12 medium (manufactured by Gibco) containing 20% fetal bovine serum in an equal volume of DF medium.
  • Dulbecco's minimum essential medium manufactured by Gibco
  • Ham F-12 medium manufactured by Gibco
  • X 10 6 cells / ml and transfer to a 24-well plate (area per culture hole: 2 cm3-Ning Co.) coated with polyethylene imine. Each 5 ml Z hole was sown and cultured at 37 ° C and 5% CO 2 .
  • the neurotrophic factor activity of the compound of the present invention was expressed as a ratio when the fluorescence intensity of the control (with the addition of DMS) was 1.0.
  • Table 3 shows the results. Table 3: Neurotrophic factor activity Neurotrophic factor activity Specimen Concentration
  • the inhibitory effect on neuronal damage caused by cerebral ischemia was evaluated using a gerbil_bilateral common carotid artery occlusion model.
  • Test method Male gerbils weighing 6900 g (New Japan animals, Saitama Japan) were used. Test method
  • Gerbils were lightly anesthetized with ether and fixed in a dorsal position. After local infiltration with xylokine, the bilateral common carotid artery was exposed by incising the midline of the neck and carefully separated from the nearby vagus nerve. The artery was stopped with an aneurysm clip for 3 minutes, then the clip was removed and the skin was sutured. The sham-operated group was treated similarly except that the bilateral common carotid artery was not occluded. The animal was anesthetized with ether for 7 minutes after cerebral ischemia for 3 minutes, and the brain was perfused from the left ventricle with 10% formalin buffer.
  • the hippocampus region was cut out as a slice with a thickness of 3 to 4 mm in an annular shape, and sections were prepared after paraffin embedding. Slices were stained with hematoxylin and eosin. Ischemic cytotoxicity was evaluated on a scale from 0 to 3.
  • NGF plays a role in maintaining the survival and function of certain types of nerve cells, and has a degenerative repair and protective action.
  • the terpyridin derivative of the present invention has one or both of the activity of promoting NGF production and the activity of prolonging the survival of cultured cerebral cortical neurons. Therefore, the pyridin derivative of the present invention is expected to act on nerve cells directly or indirectly in vivo, and to exhibit an effect of improving and treating neuropathy associated with neurodegeneration.
  • it can be used as a therapeutic agent for traumatic, alcohol-related drugs such as anticancer drugs, inflammatory, metabolic properties such as diabetes, and symptoms associated with idiopathic peripheral neurodegeneration. Can be used.
  • symptoms associated with central neurodegeneration- Diseases for example, Alzheimer's disease, cerebrovascular dementia, Dunn's syndrome, Parkinson's disease, Non-Tinton's chorea, cerebral ischemia, cerebral infarction, cerebral hemorrhage, head injury, etc. It can also be used as an agent for improving and treating mental and motor dysfunction, spontaneous nerve palsy, etc. that occur.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un dérivé de pyridine représenté par la formule générale (I), dans laquelle R?1, R2 et R3¿ représentent chacun hydrogène, pyridyle, phényle substitué ou non substitué, etc. Ledit dérivé présente une activité stimulant la production du facteur de croissance nerveuse ou une activité de facteur neurotrophique. Par conséquent, on peut l'utiliser comme agent de traitement ou remède dans le cas de symptomes ou de maladies accompagnant une dégénérescence nerveuse périphérique due à un trauma, à des médicaments tels que des médicaments à base d'alcool ou antimoraux, des inflammations, ou un métabolisme tel que celui observé dans le diabète, ainsi que d'autres de nature idiopathique. De plus, on peut l'utiliser comme agent de traitement ou remède dans le cas de symptomes ou de maladies accompagnant une dégénérescence nerveuse centrale, telle que la démence sénile de type Alzheimer, la démence cérébrovasculaire, la trisomie 21, la maladie de Parkinson ou la chorée de Huntington, les insuffisances mentales et motrices provoquées par une ischémie cérébrale, un infarctus cérébral, une hémorragie cérébrale ou des lésions à la tête, ainsi qu'une neuroparalysie spinale.
PCT/JP1994/000842 1993-05-28 1994-05-27 Utilisation medicale d'un derive de pyridine WO1994027604A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68079/94A AU6807994A (en) 1993-05-28 1994-05-27 Medicinal use of pyridine derivative

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JP5/126541 1993-05-28
JP12654193 1993-05-28

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WO1994027604A1 true WO1994027604A1 (fr) 1994-12-08

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000213A1 (fr) * 1994-06-24 1996-01-04 Taisho Pharmaceutical Co., Ltd. Derive de pyridine
WO1996016942A1 (fr) * 1994-11-28 1996-06-06 Taisho Pharmaceutical Co., Ltd. Derives de pyridine
WO1999032447A3 (fr) * 1997-12-11 1999-10-14 American Home Prod Pyridines a trisubstitution en positions 2, 4, 6 a activite oestrogenique et leurs procedes de synthese en phase solide
JP2000169448A (ja) * 1998-12-07 2000-06-20 Minolta Co Ltd 新規アミノ化合物とその製造方法、および用途
WO2001025204A1 (fr) * 1999-10-06 2001-04-12 Astrazeneca Ab Nouveaux composes de pyridine trisubstitues
US6384058B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisubstituted pryridines with estrogenic activity and methods for the solid phase synthesis thereof
WO2002076438A2 (fr) * 2001-03-23 2002-10-03 Chugai Seiyaku Kabushiki Kaisha Ligands flt-1 et utilisations de ceux-ci
US6503917B1 (en) 1998-12-10 2003-01-07 Wyeth, Five Giralda Farms 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
EP1426046A1 (fr) * 2001-09-14 2004-06-09 Shionogi & Co., Ltd. Nouvelle utilisation de composes tricycliques
EP1805142A2 (fr) * 2004-09-23 2007-07-11 Reddy US Therapeutics, Inc. Composes a base de pyridine, leur procede de preparation et compositions les contenant
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation
CN105237466A (zh) * 2015-10-26 2016-01-13 南阳师范学院 一种合成三取代吡啶衍生物的方法
CN108727253A (zh) * 2018-05-10 2018-11-02 江苏师范大学 芳环-三芳基吡啶化合物及其制备方法和应用
CN114105753A (zh) * 2021-09-17 2022-03-01 温州医科大学 漆黄素衍生物及其在制备抗炎药物中的应用

Citations (6)

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Publication number Priority date Publication date Assignee Title
DE2736791A1 (de) * 1977-08-16 1979-03-01 Degussa Verfahren zur herstellung substituierter pyridine
JPS62149662A (ja) * 1985-12-12 1987-07-03 Fujisawa Pharmaceut Co Ltd Ｎ−含有複素環化合物
EP0261602A2 (fr) * 1986-09-20 1988-03-30 BASF Aktiengesellschaft Composés de la pyridine et leur utilisation
JPS6479155A (en) * 1987-06-11 1989-03-24 Fujisawa Pharmaceutical Co Diphenylpyridine compound
WO1989011279A1 (fr) * 1988-05-16 1989-11-30 Georgia State University Foundation, Inc. Compose heteropolycyclique non fusionne ayant une interaction avec des acides nucleiques
DE4020257A1 (de) * 1990-06-26 1992-01-02 Bayer Ag 2,6-diarylpyridin-derivate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2736791A1 (de) * 1977-08-16 1979-03-01 Degussa Verfahren zur herstellung substituierter pyridine
JPS62149662A (ja) * 1985-12-12 1987-07-03 Fujisawa Pharmaceut Co Ltd Ｎ−含有複素環化合物
EP0261602A2 (fr) * 1986-09-20 1988-03-30 BASF Aktiengesellschaft Composés de la pyridine et leur utilisation
JPS6479155A (en) * 1987-06-11 1989-03-24 Fujisawa Pharmaceutical Co Diphenylpyridine compound
WO1989011279A1 (fr) * 1988-05-16 1989-11-30 Georgia State University Foundation, Inc. Compose heteropolycyclique non fusionne ayant une interaction avec des acides nucleiques
DE4020257A1 (de) * 1990-06-26 1992-01-02 Bayer Ag 2,6-diarylpyridin-derivate

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000213A1 (fr) * 1994-06-24 1996-01-04 Taisho Pharmaceutical Co., Ltd. Derive de pyridine
WO1996016942A1 (fr) * 1994-11-28 1996-06-06 Taisho Pharmaceutical Co., Ltd. Derives de pyridine
US5922743A (en) * 1994-11-28 1999-07-13 Taisho Pharmaceutical Co., Ltd. Pyridine derivative
WO1999032447A3 (fr) * 1997-12-11 1999-10-14 American Home Prod Pyridines a trisubstitution en positions 2, 4, 6 a activite oestrogenique et leurs procedes de synthese en phase solide
US6384058B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisubstituted pryridines with estrogenic activity and methods for the solid phase synthesis thereof
US6384060B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisbstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
US6384057B1 (en) 1997-12-11 2002-05-07 American Home Products Corporation 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis
JP2000169448A (ja) * 1998-12-07 2000-06-20 Minolta Co Ltd 新規アミノ化合物とその製造方法、および用途
US6503917B1 (en) 1998-12-10 2003-01-07 Wyeth, Five Giralda Farms 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
WO2001025204A1 (fr) * 1999-10-06 2001-04-12 Astrazeneca Ab Nouveaux composes de pyridine trisubstitues
WO2002076438A2 (fr) * 2001-03-23 2002-10-03 Chugai Seiyaku Kabushiki Kaisha Ligands flt-1 et utilisations de ceux-ci
WO2002076438A3 (fr) * 2001-03-23 2003-05-01 Chugai Pharmaceutical Co Ltd Ligands flt-1 et utilisations de ceux-ci
EP1426046A1 (fr) * 2001-09-14 2004-06-09 Shionogi & Co., Ltd. Nouvelle utilisation de composes tricycliques
EP1426046A4 (fr) * 2001-09-14 2005-11-02 Shionogi & Co Nouvelle utilisation de composes tricycliques
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
EP1805142A2 (fr) * 2004-09-23 2007-07-11 Reddy US Therapeutics, Inc. Composes a base de pyridine, leur procede de preparation et compositions les contenant
EP1805142A4 (fr) * 2004-09-23 2009-06-10 Reddy Us Therapeutics Inc Composes a base de pyridine, leur procede de preparation et compositions les contenant
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation
CN105237466A (zh) * 2015-10-26 2016-01-13 南阳师范学院 一种合成三取代吡啶衍生物的方法
CN108727253A (zh) * 2018-05-10 2018-11-02 江苏师范大学 芳环-三芳基吡啶化合物及其制备方法和应用
CN114105753A (zh) * 2021-09-17 2022-03-01 温州医科大学 漆黄素衍生物及其在制备抗炎药物中的应用
CN114105753B (zh) * 2021-09-17 2024-02-20 温州医科大学 漆黄素衍生物及其在制备抗炎药物中的应用

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