WO2004101483A1 - Nouveau derive benzene trisubstitue, procede de production de ce dernier et composition de medicament contenant ce derive - Google Patents

Nouveau derive benzene trisubstitue, procede de production de ce dernier et composition de medicament contenant ce derive Download PDF

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WO2004101483A1
WO2004101483A1 PCT/JP2004/006546 JP2004006546W WO2004101483A1 WO 2004101483 A1 WO2004101483 A1 WO 2004101483A1 JP 2004006546 W JP2004006546 W JP 2004006546W WO 2004101483 A1 WO2004101483 A1 WO 2004101483A1
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group
hydrogen atom
alkyl group
hydroxymethyl
pharmaceutically acceptable
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PCT/JP2004/006546
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English (en)
Japanese (ja)
Inventor
Hiroyuki Osada
Hideaki Kakeya
Yujiro Hayashi
Mitsuru Shoji
Saeko Uchida
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Riken
Taisho Pharmaceutical Co., Ltd.
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Priority to JP2005506199A priority Critical patent/JP4624260B2/ja
Publication of WO2004101483A1 publication Critical patent/WO2004101483A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds

Definitions

  • the present invention relates to a novel trisubstituted benzene derivative, a method for producing the same, and a pharmaceutical composition containing the trisubstituted benzene derivative.
  • diabetes is a disease that produces characteristic symptoms such as polyuria and polysaccharide as a result of insufficient insulin secretion in the islets of Langerhans or tissue resistance of insulin action at target tissues.
  • characteristic symptoms such as polyuria and polysaccharide as a result of insufficient insulin secretion in the islets of Langerhans or tissue resistance of insulin action at target tissues.
  • One of the factors that attenuates the insulin action is considered to be a decrease in the activation of the insulin receptor in target cells.
  • One possible cause of the decrease in insulin receptor activation is the decrease in the activity of the tyrosine kinase (an enzyme that phosphorylates tyrosine residues in proteins) possessed by the insulin receptor.
  • Factors that attenuate tyrosine kinase activity include, for example, PTPlB (protein tyrosine phosphatase IB), one of tyrosine phosphatases (protein phosphatases specific to phosphorylated tyrosine residues in proteins), antagonize insulin action.
  • PTPlB protein tyrosine phosphatase IB
  • tyrosine phosphatases protein phosphatases specific to phosphorylated tyrosine residues in proteins
  • LAR lukocyte common antigen-related phosphatase
  • the protein nerve growth factor NGF which is thought to be useful as a therapeutic and / or prophylactic agent for neurodegenerative diseases, undergoes neuronal dendrites via its receptor Trk family, and the like. It forms a network circuit and exerts a neuroprotective effect.
  • the Trk family is a receptor that has tyrosine kinase activity, and compounds that enhance the action of this nerve growth factor NGF are useful for preventing nerve damage, Alzheimer's disease, Parkinson's disease, etc. It may be a therapeutic and / or prophylactic agent for diseases such as neurosis (Neuroscience Lett., 66, 175 (1986), Brain Res. 661, 137 (1994)).
  • the present invention provides a novel compound for overcoming diseases including neuropathy such as diabetes or obesity, or nerve damage, Alzheimer's disease, and Parkinson's disease, and a drug containing the same. is there. More specifically, the present invention provides a compound capable of enhancing the action of insulin or NGF, and a drug containing the compound.
  • the present inventor has proposed and synthesized a compound that effectively enhances the action of insulin and NGF, and as a result of repeated studies, has led to the development of the compound according to the present invention.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have found a novel 3-substituted benzene, and a composition containing the same has been used for diabetes or obesity, nerve damage, Alzheimer's disease, Parkinson's disease, etc. Have been found to be drugs that can overcome diseases including neurosis.
  • the present invention is as follows.
  • -R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 2 represents a formyl group
  • a carboxy group, -CH _0 (C 0)
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group.
  • R 3 is hydrogen
  • R 4 / R 5 is a hydrogen atom / methyl group or a methyl group / hydrogen atom
  • the substitution position of OR 1 group / R 2 group is benzene.
  • a compound at the 3- or 2-position on the ring and Excluding a compound in which one of R 4 or R 5 is a propyl group), a geometric isomer or an optically active isomer, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 is a hydrogen atom, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 2 represents a formyl group
  • a carboxy group, -CH _0 (C 0)
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH_R 1Q .
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH_R 1Q .
  • R 3 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a group having 4 or more carbon atoms.
  • -R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 2 represents a formyl group
  • a carboxy group, -CH _0 (C 0)
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group.
  • composition according to (8) which is a prophylactic or therapeutic agent for diabetes, obesity, nerve injury, or neurosis, or a protein tyrosine phosphorylation enhancer.
  • -R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group)
  • a prophylactic drug for diabetes or obesity which comprises one or more of any of the compounds represented by the following, geometric isomers or optically active forms thereof, pharmaceutically acceptable salts thereof, or hydrates thereof: Therapeutic drugs.
  • a preventive or therapeutic agent for diabetes or obesity comprising one or more of any of the following: a body or an optically active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • _R 6 R 6 is an alkyl
  • R 7 R 7 represents an alkyl group, an aryl group, or an alkylamino group.
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group)
  • a preventive agent for nerve damage or neuropathy comprising one or more of the compounds represented by the following formulas, geometric isomers or optically active forms thereof, pharmaceutically acceptable salts thereof, or hydrates thereof: Or therapeutic drugs.
  • R 1 is a hydrogen atom, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • a preventive or therapeutic agent for nerve damage or neurosis including one or more of the following.
  • a preventive or therapeutic agent for nerve damage or neuropathy comprising one or more of any of the following: a body or an optically active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • -R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 2 represents a formyl group
  • a carboxy group, -CH _0 (C 0)
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 5 independently represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group), a geometric isomer or an optical isomer thereof
  • An agent for enhancing protein tyrosine phosphorylation which comprises one or more of the active substance, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 1 , R 3 , R 6 , R 7 , R 8 , R 9 or R 1 May be independently any linear, branched or cyclic alkyl group, preferably an alkyl group having 110 carbon atoms, more preferably a methyl group, an ethyl group, or a propyl group.
  • R 4 and R 5 are each independently a linear, branched or cyclic alkyl group, preferably a carbon atom.
  • 110 alkyl groups more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s_butyl, t-butyl, pentyl, s-pentyl, isopentyl , 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylopentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylopentyl (s-hexyl) ) Group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutynole Group
  • R 1 or R 8 each independently represents a force that can be any linear, branched or cyclic alkenyl group. It is a 2-10 alkenyl group, more preferably a vinyl group, a propenyl group, an isopropyl group, a cyclopropenyl group, a butenyl group, a pentenyl group, a hexenyl group, a styryl group and the like.
  • R 2 is a force S that can be a carboxyl group, the carboxyl group is a salt thereof, and a compound in which hydrogen of the carboxyl group is substituted with an arbitrary group. (Eg, esters).
  • R 3 , R 4 , R 5 , R 6 or R 7 may be each independently any substituted or unsubstituted aryl group, but is preferably A substituted or unsubstituted phenyl group can be mentioned.
  • R 6 or R 7 is each independently any alkylamino group
  • R 1Q is any alkyloxycarbonyl group or any alkyloxycarbinolealkyl group
  • R 3 may be an arbitrary alkoxy group (alkyloxy group).
  • preferred groups of these groups include an alkyl moiety having 1 to 10 carbon atoms, more preferably methynole, ethyl and propyl.
  • R 3 may be a halogen atom, such as a fluorine atom, a black atom, and a bromo atom.
  • R 3 may be any amino group.
  • the amino group also includes an arylamino group such as an anolequinolamino group, a dianolequinolamino group, and aniline.
  • preferred compounds are those in which R 1 is hydrogen and / or Compounds in which 2 is a hydroxymethyl group are exemplified. Further, a compound in which the substitution position of the OR 1 group / R 2 group on the benzene ring is 2-position, 3-position, or 3-position, Z2-position, respectively, is also a preferred compound.
  • More preferred conjugates are those wherein R 1 is hydrogen and / or R 2 is a hydroxymethyl group, and the substitution positional force of the OR 1 group / R 2 group on the benzene ring is 2 / A compound at the 3-position or 3-position / 2 position, more preferably R 1 is hydrogen and / or R 2 is a hydroxymethyl group, and OR 1 group / R 2 group on the benzene ring Is a compound having a 3-position / 2-position.
  • the most preferred compounds according to the present invention include the following compounds, but the present invention is not limited to these compounds.
  • each of the following compounds may be referred to by using the code number shown in the parentheses in this specification.
  • R 6 represents an alkyl group, an aryl group, or an alkylamino group
  • R 2 represents a formyl group
  • a carboxy group, -CH _0 (C 0)
  • R 7 represents an alkyl group, an aryl group, or an alkylamino group
  • R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group
  • R 9 represents a hydrogen atom or an alkyl group
  • -CH CH-R 1Q
  • R 1Q represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxyl
  • R 1 and R 2 may be cyclized by linking.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group or a hydroxy group.
  • R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, an alkyl group having 4 or more carbon atoms, or an aryl group, and L represents a sulfonate group or a halogen atom.
  • X represents B (OR u ) (R 11 represents hydrogen or an alkyl group) or Sn (R 12 ) (R 12 represents an alkyl group).
  • L may be any substituent or atom as long as the compound represented by ( ⁇ ) is a substituent or an atom capable of undergoing an oxidative addition reaction to the catalyst in Scheme 1.
  • R 11 in X is hydrogen or any alkyl group including an isopropyl group.
  • Sell force is preferably hydrogen, also R 12 is force-methyl group can be any alkyl group, a butyl group and the like.
  • reaction shown in Scheme 1 is performed by reacting a compound represented by the general formula (III) and a compound represented by the general formula (IV) in an inert solvent in the presence of a base and in the presence of a transition metal catalyst.
  • a compound represented by the general formula (III) and a compound represented by the general formula (IV) in an inert solvent in the presence of a base and in the presence of a transition metal catalyst.
  • a base and in the presence of a transition metal catalyst.
  • a transition metal catalyst can be.
  • another compound for example, a phosphine ligand
  • the inert solvent used in the reaction shown in Scheme 1 is not particularly limited as long as it is inert to the reaction, and examples thereof include aliphatic hydrocarbons such as hexane, benzene, and toluene. And aryl hydrocarbons, chloroform, halogenated hydrocarbons such as dichloromethane, and ethers such as getyl ether and tetrahydrofuran.
  • the base used in the reaction shown in Scheme 1 is not particularly limited as long as it does not affect the other parts of the compound, and may be an organic base or an inorganic base. Force Preferably, potassium carbonate etc. are mentioned, for example.
  • a transition metal complex such as a palladium catalyst or a nickel catalyst can be mentioned, preferably a palladium catalyst, and particularly preferably tetrakis (triphenylphosphine) palladium Is mentioned.
  • the reaction temperature of the reaction shown in Scheme 1 is a force that can be appropriately selected depending on the starting compound, the solvent, and the like, and is usually 40 to 80 ° C.
  • the reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 2 to 12 hours.
  • the compound represented by the general formula (III) may be protected (for example, cyclized) with a protecting group, if necessary.
  • Examples of the protected compound include a compound represented by the following general formula (m) _i.
  • the compound represented by the general formula ( ⁇ ) can be produced, for example, by subjecting a compound represented by the general formula (I) to a hydrogenation reaction as shown in the following scheme. it can.
  • a person skilled in the art can select an appropriate hydrogenation reaction in this reaction, but a hydrogenation reaction using a heterogeneous catalyst containing palladium-carbon, or a hydrogenation reaction using a homogeneous catalyst containing a Wilkinson complex is preferable. Is also good.
  • a preferable hydrogenation reaction can be carried out, for example, by performing the reaction in methanol using a palladium-carbon catalyst under a hydrogen atmosphere.
  • the compound represented by the general formula (I) or ( ⁇ ) is analyzed by melting point, infrared absorption spectrum, 1 H_NMR spectrum, 13 C_NMR spectrum, mass spectrometry, X-ray structure analysis, etc., as necessary. , Confirmation and identification.
  • salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, and copper salt.
  • Metal salts such as salts, nickel salts, cobalt salts and the like can be mentioned.
  • the compound according to the present invention may have one or more asymmetric carbon atoms depending on the type of the substituent.
  • stereoisomers such as optical isomers or diastereomers based on these asymmetric carbons exist, the scope of the present invention includes pure stereoisomers as well as mixtures or racemates of any stereoisomers. Is included.
  • the compound according to the present invention may have an olefinic double bond, and may have a geometrical isomer based on a double bond. Mixtures of isomers are also within the scope of the present invention.
  • the compound according to the present invention can exist in any crystalline form, and may exist as a hydrate or a solvate. It goes without saying that all of these substances are included in the scope of the present invention. Further, the present invention relates to the present invention Compounds that are converted to trisubstituted benzene derivative compounds, ie, all so-called prodrugs are also included.
  • the compounds according to the present invention exhibit excellent insulin action enhancing action and Z or neurotrophic factor enhancing action as described in Test Examples described later.
  • composition according to the present invention can be used as a therapeutic or therapeutic agent for various diseases such as diabetes and obesity, and diseases such as nerve damage and neurosis. It can be used as a prophylactic, and can be administered to humans, for example.
  • the composition containing the compound according to the present invention can be used as a protein tyrosine phosphorylation enhancer, and can be administered to a human, for example.
  • the protein tyrosine phosphorylation enhancer can be used, for example, as a therapeutic or preventive agent for diseases such as diabetes and obesity, and nerve damage and neurosis. That is, the therapeutic or prophylactic agent for diseases such as diabetes and obesity and nerve damage and neuropathy of the present invention may be an embodiment of a protein tyrosin phosphorylation enhancer.
  • Examples of the dosage form of the reagent containing the compound according to the present invention include a solid agent such as a powder, and a liquid agent dissolved in an organic solvent or a water-containing organic solvent.
  • examples of the organic solvent that can be used include methanol and dimethyl sulfoxide.
  • the effective dose is 0.1 to 100 ⁇ g / ml. The appropriate dose depends on the type and purpose of the cultured cell line and can be appropriately selected. . If necessary, an amount outside the above range may be used.
  • composition according to the present invention is mixed with excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives as appropriate for the dosage form. May be. That is, except for containing the compound according to the present invention, a pharmaceutical preparation can be prepared by a usual method. Book Examples of the dosage form of the composition according to the present invention include powders, granules, tablets, capsules, pills, solutions, injections, suppositories, transdermal absorbents, inhalants and the like. When preparing an injection, it can be formulated by sterilizing with an appropriate carrier.
  • composition according to the present invention is orally administered in the case of powders, granules, tablets, capsules, pills, liquids, and the like, or injections, suppositories, transdermal absorbents, inhalants. In such cases, it can be administered parenterally.
  • the dose of the compound according to the present invention also varies depending on the disease state, administration route, patient's age, or body weight, and is ultimately left to the judgment of a physician.
  • Mouse preadipocytes 3T3-L1 were cultured and maintained in a DMEM medium containing 10% fetal calf serum (FBS). 3T3-L1 cells were seeded on a 12-well plastic plate at 5xl0 5 cells / ml, cultured for 3 days (37 ° C, 5% CO 2), and synchronized with the GO phase by contact inhibition. Next, the medium
  • the medium was replaced with a 10% FBS_DMEM medium, and 500 ⁇ M 3_isobutyl_1_methylxanthine ( ⁇ ), 1 ⁇ dexamethasone, and 1 ⁇ g / ml insulin were added. This was cultured for 2 days as a differentiation induction medium. Then remove the medium and wash with phosphate buffer. After purification, the cells were differentiated into mature adipocytes cultured for 5 days.
  • RKTS-101 or RKTS-102 in a series of dilution series (0.31030 ⁇ m) was added to mature adipocytes, and after 1 hour of culture, ⁇ insulin was added. After 4 hours, each cell is solubilized and subjected to SDS (sodium lauryl sulfate) -polyacrylamide electrophoresis, and then the degree of intracellular cleaved phosphorylation is detected by Western blotting using anti-phosphotyrosine antibody (UPSTATE) did.
  • SDS sodium lauryl sulfate
  • UPSTATE anti-phosphotyrosine antibody
  • RKTS-101 and RKTS-102 markedly induced insulin-induced enhancement of intracellular tyrosine phosphorylation in mature 3T3-L1 cells in the concentration range of 3-100 ⁇ g / ml, respectively.
  • Table 1 This indicates that the compound of the present invention has an insulin action-enhancing activity and is useful as a preventive or therapeutic drug for diabetes and obesity.
  • the degree of intracellular tyrosine phosphorylation is classified into three stages.
  • the degree of intracellular tyrosine phosphorylation by stimulation with insulin alone (+) is 2
  • An increase of about two-fold (++) and an increase of more than two-fold relative to the degree of intracellular tyrosine phosphorylation by stimulation with insulin alone (+++) are shown.
  • Rat pheochromocytoma cells were maintained in DMEM medium containing 5% fetal calf serum (FBS) and 5% bovine serum (CS). 24 ⁇ El plastic plate so as to 3xl0 4 cells / 500 ⁇ 1 seeded PC12 cells were over ⁇ cultured (37 ° C 5% CO) . Then a series of dilution series RKTS-101,
  • a novel trisubstituted benzene derivative can be provided.
  • the preferred conjugate according to the present invention has an effect of enhancing the protein tyrosine phosphorylation level at the cultured cell level.
  • preferred compositions comprising the compounds according to the invention Is useful as a preventive and therapeutic drug for neuropathy including diabetes, obesity, nerve damage, Alzheimer's disease, Parkinson's disease and the like.

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Abstract

La présente invention concerne un nouveau composé qui est utile pour le traitement des maladies telles que le diabète, l'obésité et les maladies des nerfs telles que l'atteinte nerveuse, les maladies d'Alzheimer et de Parkinson; et un agent thérapeutique comprenant ce composé. Cette invention concerne plus particulièrement un composé représenté par la formule (I) ou par la formule (II), un procédé de production de ce dernier et une composition de médicament comprenant ledit composé. Formules (I) et (II)
PCT/JP2004/006546 2003-05-14 2004-05-14 Nouveau derive benzene trisubstitue, procede de production de ce dernier et composition de medicament contenant ce derive WO2004101483A1 (fr)

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