WO2004101483A1 - Novel trisubstituted benzene derivative, process for producing the same and medical drug composition containing the derivative - Google Patents
Novel trisubstituted benzene derivative, process for producing the same and medical drug composition containing the derivative Download PDFInfo
- Publication number
- 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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- WO
- WIPO (PCT)
- Prior art keywords
- group
- hydrogen atom
- alkyl group
- hydroxymethyl
- pharmaceutically acceptable
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 9
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 28
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- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 81
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 36
- 125000003282 alkyl amino group Chemical group 0.000 claims description 26
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 150000004677 hydrates Chemical class 0.000 claims description 22
- 230000026731 phosphorylation Effects 0.000 claims description 22
- 238000006366 phosphorylation reaction Methods 0.000 claims description 22
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
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- 230000000069 prophylactic effect Effects 0.000 claims description 9
- DCLJORLKXICIIJ-UHFFFAOYSA-N 3-hexyl-2-(hydroxymethyl)phenol Chemical compound CCCCCCC1=CC=CC(O)=C1CO DCLJORLKXICIIJ-UHFFFAOYSA-N 0.000 claims description 8
- XLXZRDMCQYZOHP-UHFFFAOYSA-N 2-(hydroxymethyl)-3-(2-phenylethenyl)phenol Chemical compound OCC1=C(O)C=CC=C1C=CC1=CC=CC=C1 XLXZRDMCQYZOHP-UHFFFAOYSA-N 0.000 claims description 7
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- 238000006467 substitution reaction Methods 0.000 claims description 5
- BZOHHLMTCXVRJE-UHFFFAOYSA-N 2-(hydroxymethyl)-1,3-dihydroinden-2-ol Chemical compound C1=CC=C2CC(CO)(O)CC2=C1 BZOHHLMTCXVRJE-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 4
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
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- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- PWATWSYOIIXYMA-UHFFFAOYSA-N Pentylbenzene Chemical compound CCCCCC1=CC=CC=C1 PWATWSYOIIXYMA-UHFFFAOYSA-N 0.000 description 1
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- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 description 1
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- 125000001769 aryl amino group Chemical group 0.000 description 1
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- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
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- 159000000007 calcium salts Chemical class 0.000 description 1
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- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
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- 150000004676 glycans Chemical class 0.000 description 1
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- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- QJDCJRCNGGXETD-UHFFFAOYSA-N hex-1-enoxyboronic acid Chemical compound CCCCC=COB(O)O QJDCJRCNGGXETD-UHFFFAOYSA-N 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
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- 230000003914 insulin secretion Effects 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
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- 239000003446 ligand Substances 0.000 description 1
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- 238000004949 mass spectrometry Methods 0.000 description 1
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- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
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- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
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- 239000005017 polysaccharide Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
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- AHEHMEDQTGXXRH-UHFFFAOYSA-N prop-1-enoxyboronic acid Chemical compound CC=COB(O)O AHEHMEDQTGXXRH-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
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- 238000010561 standard procedure Methods 0.000 description 1
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- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
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Classifications
-
- 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.
Abstract
A novel compound for overcoming diseases including diabetes, obesity and neuroses such as nerve damage, Alzheimer and Parkinson's disease; and a medical agent comprising the same. In particular, there are provided a compound of the following general formula (I) or (II), a process for producing the same and a medical drug composition comprising the compound. (I) (II)
Description
明 細 書 Specification
新規 3置換ベンゼン誘導体、その製造方法、およびそれを含む医薬組成 物 Novel trisubstituted benzene derivative, production method thereof, and pharmaceutical composition containing the same
技術分野 Technical field
[0001] 本発明は、新規な 3置換ベンゼン誘導体、その製法、および該 3置換ベンゼン誘導 体を含む医薬組成物に関する。 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.
背景技術 Background art
[0002] 近年、さまざまな疾病について、細胞内情報伝達系の異常がその要因の一つとし て考えられている。その中でも、チロシンキナーゼ活性を有する細胞膜結合型受容 体や細胞質受容体の制御の乱れが、細胞内情報伝達系における異常の要因となる 場合が多い。 [0002] In recent years, abnormalities in the intracellular signal transduction system have been considered as one of the factors for various diseases. Among them, disturbance of the control of cell membrane-bound receptors and cytoplasmic receptors having tyrosine kinase activity often causes abnormalities in the intracellular signal transduction system.
[0003] 例えば、糖尿病は、膝ランゲルハンス島のインスリン分泌不全または標的組織での インスリン作用の組織抵抗性の結果、多尿 ·多糖などの特徴ある症状を生じる疾患で ある。このインスリン作用を減弱する要因の一つとして、標的細胞におけるインスリン 受容体の活性化の減弱が考えられる。インスリン受容体の活性化の減弱の要因とし て、インスリン受容体の有しているチロシンキナーゼ（タンパク質中のチロシン残基を リン酸化する酵素）活性の減弱が考えられる。チロシンキナーゼ活性の減弱の要因と しては、例えば、チロシンホスファターゼ（タンパク質中のリン酸化チロシン残基に特 異的なプロテインホスファターゼ）の一つである PTPlB(protein tyrosine phosphatase IB)がインスリン作用を拮抗的に阻害すること、および LAR (lukocyte common antigen-related phosphatase)がインスリン作用を拮抗的に阻害することなどが報告さ れている（J. Biol. Chem" 267， 13811 (1992)， J. Biol. Chem" 268， 22456 (1993))。 [0003] For example, 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. 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. And LAR (lukocyte common antigen-related phosphatase) have been reported to inhibit insulin action antagonistically (J. Biol. Chem "267, 13811 (1992), J. Biol. Chem "268, 22456 (1993)).
[0004] 一方、神経変性疾患の治療薬および/または予防薬に役立つと考えられている蛋 白性神経増殖因子 NGFは、その受容体 Trkファミリーを介する神経樹状突起の誘導 などを経て、神経ネットワーク回路を形成し、神経保護作用を発揮する。 Trkファミリー は、チロシンキナーゼ活性を有している受容体であり、この神経増殖因子 NGFの作 用を増強させる化合物は、神経損傷およびアルツハイマー病、パーキンソン病等を
含む神経症などの疾患の治療薬および/または予防薬となりうる（Neuroscience Lett., 66, 175 (1986), Brain Res. 661, 137 (1994))。 [0004] On the other hand, 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)).
[0005] 従って、インスリン作用や NGFの作用を増強させる化合物を見出すことは、これらの 疾患を治療および/または予防するための新たな薬剤の開発につながるが、レ、まだ に十分な検討がされているとはいえない。 [0005] Therefore, finding a compound that enhances the action of insulin or NGF leads to the development of a new drug for treating and / or preventing these diseases, but it has not been sufficiently investigated. I can't say that.
[0006] 本発明の化合物に、構造的に類似する化合物として、 Deuteromycete strain 45-93 [0006] As a compound structurally similar to the compound of the present invention, Deuteromycete strain 45-93
から単離精製された、 1-ヒドロキシ- 2 -ヒドロキシメチル- 3_ (1-ペンテュル）ベンゼン が報告されている力 この物質の活性としては、 TPA(12-0 -テトラデカノィルホルボー ル -13-ァセタート)によって誘導される NF -カッパ Bや AP-1の転写因子の活性化を抑 制することから抗炎症剤としての効果が示唆されているのみである (J. Antibiot. 51, 455 (1998))。 1-Hydroxy-2-hydroxymethyl-3_ (1-pentyl) benzene, isolated and purified from water The reported activity of this substance is TPA (12-0-tetradecanoylphorbol-13) Inhibition of NF-kappa B and AP-1 transcription factors induced by -acetate) only suggests an effect as an anti-inflammatory agent (J. Antibiot. 51, 455 ( 1998)).
発明の開示 Disclosure of the invention
[0007] 本発明は、糖尿病もしくは肥満症、または神経損傷、アルツハイマー病、およびパ 一キンソン病などの神経症を含む疾病を克服するための新規な化合物、およびそれ を含む薬剤を提供するものである。より具体的には、インスリンや NGFの作用を増強 することができる化合物、およびそれを含む薬剤を提供する。 [0007] 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.
[0008] 本発明者は、インスリンや NGFの作用を効果的に増強させる化合物の発案 ·合成を 行い、種々検討を重ねた結果、本発明に係る化合物の開発に至った。本発明者は、 上記課題の解決のために鋭意検討した結果、新規の 3置換ベンゼンを見出し、それ を含む組成物が、糖尿病もしくは肥満症、または神経損傷、アルツハイマー病、およ びパーキンソン病などの神経症を含む疾病を克服しうる薬剤であることを見出した。 [0008] 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.
[0009] すなわち本発明は以下の通りである。 [0009] That is, the present invention is as follows.
(1) 下記一般式 (I)または (II)
[化 1] (1) The following general formula (I) or (II) [Formula 1]
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリーノレ基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents a formyl group , A carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、 R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、もしくは炭素数 4以上を有するアルキル基、またはァリール基 を示す）で表される化合物（但し、一般式 (I)において、 R3が水素であり、 R4/R5が水素 原子/メチル基またはメチル基/水素原子であり、かつ OR1基/ R2基の置換位置がベン ゼン環上の 3位 /2位である化合物、および一般式 (I)において R4もしくは R5の一方がプ 口ピル基である化合物を除く）、その幾何異性体もしくは光学活性体、それらの製薬 上許容される塩、またはそれらの水和物。 -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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. Wherein 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. However, in the general formula (I), R 3 is hydrogen, R 4 / R 5 is a hydrogen atom / methyl group or a methyl group / hydrogen atom, and 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.
(2) R1が水素原子であることを特徴とする、（1)に記載の化合物、その幾何異性体 もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物。 (2) The compound according to (1), wherein R 1 is a hydrogen atom, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(3) R2がヒドロキシメチル基であることを特徴とする、（1)または（2)に記載の化合物 、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれら
の水和物。 (3) The compound according to (1) or (2), wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a compound thereof. Hydrate.
(4) OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特 徴とする、 （1)一（3)のいずれかに記載の化合物、その幾何異性体もしくは光学活性 体、それらの製薬上許容される塩、またはそれらの水和物。 (4) The compound according to any one of (1) to (3), wherein OR 1 is at the 3-position on the benzene ring, and R 2 is at the 2-position on the benzene ring. Geometric isomers or optically active isomers, pharmaceutically acceptable salts thereof, or hydrates thereof.
(5) 3-(1_へキセニル) -2- (ヒドロキシメチル)フエノール、 2 -(ヒドロキシメチル )_3 -ビニ ルフエノール、 2 -(ヒドロキシメチル )_3 -スチリルフエノール、 3_へキシル -2- (ヒドロキシ メチノレ)フエノール、 2 -(ヒドロキシメチル )_3_(1-メチル -1-プロぺニル)フエノールである ことを特徴とする、（1)一（4)のいずれかに記載の化合物、その幾何異性体もしくは 光学活性体、それらの製薬上許容される塩、またはそれらの水和物。 (5) 3- (1_Hexenyl) -2- (hydroxymethyl) phenol, 2- (hydroxymethyl) _3-vinylphenol, 2- (hydroxymethyl) _3-styrylphenol, 3_hexyl-2- ( (1) The compound according to any one of (1) to (4), wherein the compound is hydroxymethylaminophenol or 2- (hydroxymethyl) _3_ (1-methyl-1-propenyl) phenol. Or an optically active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(6) 下記一般式 (III)で表される化合物および (IV)で表される化合物をカップリング反 応させるステップを含むことを特徴とする、下記一般式 (I)で表される化合物の製造方 法。 (6) A compound represented by the following general formula (I), which comprises a step of performing a coupling reaction between a compound represented by the following general formula (III) and a compound represented by the following (IV): Production method.
[化 2] [Formula 2]
(式中 R1は水素原子、アルキル基、アルケニル基、または- C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents a formyl group , A carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 - CH=CH_R1Q 。は アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R3は水素原子、ハロゲン原子、アルキル基、アルコ キシ基、ァリール基、アミノ基またはヒドロキシ基を示し、 R4, R5はそれぞれ独立に水素 原子、メチル基、ェチル基、プロピル基、イソプロピル基、あるいは、炭素数 4以上を
有するアルキル基、あるいはァリール基を示し、 Lはスルホネート基またはハロゲン原 子を示し、 Xは B(ORU) (R11は水素またはアルキル基を表す)または Sn(R12) (R12はアル キル基を表す)を示す。 ) -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH_R 1Q . Represents an alkyl group, an alkyloxycarbonyl group, a honolemil group, or an alkyloxycarbonylalkyl group), and 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. Alkyl or indicates Ariru group, L is shown sulfonate group or a halogen atom, X is B (OR U) (R 11 represents hydrogen or an alkyl group) or Sn (R 12) (R 12 is Al, has Represents a kill group). )
(7) 下記一般式 (I)で表される化合物を水素添加反応させることを特徴とする、下記 一般式 (Π)で表される化合物を製造する方法。 (7) A method for producing a compound represented by the following general formula (II), comprising subjecting a compound represented by the following general formula (I) to a hydrogenation reaction.
[化 3] [Formula 3]
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリーノレ基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents a formyl group , A carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、 R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、もしくは炭素数 4以上を有するアルキル基、またはァリール基 を示す。 ) -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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. )
(8) (1)—（5)のいずれかに記載の化合物、それらの化合物の幾何異性体もしくは 光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1
または 2以上を有効成分として含有する医薬組成物。 (8) Any one of the compound according to any one of (1) to (5), a geometric isomer or an optically active form of the compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Or a pharmaceutical composition containing two or more as active ingredients.
(9) 糖尿病、肥満症、神経損傷、もしくは神経症の予防薬もしくは治療薬、またはタ ンパク質チロシンリン酸化亢進剤であることを特徴とする、 (8)に記載の医薬組成物。 (9) The pharmaceutical composition according to (8), which is a prophylactic or therapeutic agent for diabetes, obesity, nerve injury, or neurosis, or a protein tyrosine phosphorylation enhancer.
(10) 下記一般式 (I)または (Π) (10) The following general formula (I) or (Π)
[化 4] [Formula 4]
(式中、 R1は水素原子、アルキル基、アルケニル基、または- C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents formyl Group, carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、 R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、もしくは炭素数 4以上を有するアルキル基、またはァリール基 を示す） -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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)
で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許容され る塩、またはそれらの水和物のいずれかの 1または 2以上を含む、糖尿病、肥満症の 予防薬、または治療薬。 Or 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.
(11) R1が水素原子であることを特徴とする（10)に記載の化合物、その幾何異性体
もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれ 力の 1または 2以上を含む、糖尿病、肥満症の予防薬、または治療薬。 (11) The compound according to (10), wherein R 1 is a hydrogen atom, and geometric isomers thereof. Alternatively, a prophylactic or therapeutic agent for diabetes or obesity, which comprises one or more of optically active substances, pharmaceutically acceptable salts thereof, and hydrates thereof.
(12) R2がヒドロキシメチル基であることを特徴とする（10)または（11)に記載の化合 物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、糖尿病、肥満症の予防薬、または治 療薬。 (12) The compound according to (10) or (11), wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A preventive or remedy for diabetes, obesity, which contains any one or more of the following hydrates:
(13) OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特 徴とする（10) （12)のいずれかに記載の化合物、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含む、糖尿病、肥満症の予防薬、または治療薬。 (13) The compound according to any one of (10) and (12), wherein OR 1 is located at the 3-position on the benzene ring, and R 2 is located at the 2-position on the benzene ring. 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.
(14) 2- (ヒドロキシメチル) -3- (1-プロぺニル)フエノール、 3-(1-へキセニル) -2- (ヒド 口キシメチル)フエノール、 2- (ヒドロキシメチル )_3 -ビュルフエノール、 2- (ヒドロキシメチ ル) -3-スチリルフエノール、 3-へキシル -2- (ヒドロキシメチル)フエノール、または 2- (ヒド 口キシメチル) -3-(1-メチル -1-プロぺニル)フエノール、その幾何異性体もしくは光学 活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2以上を含むことを特徴とする、（10)—（13)のいずれかに記載の糖尿病、肥満症の 予防薬、または治療薬。 (14) 2- (hydroxymethyl) -3- (1-propenyl) phenol, 3- (1-hexenyl) -2- (hydroxymethyl) phenol, 2- (hydroxymethyl) _3-bulfenol, 2- (hydroxymethyl) -3-styrylphenol, 3-hexyl-2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) -3- (1-methyl-1-propenyl) phenol, (10)-(13), characterized in that it contains one or more of geometric isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof. 3. The preventive or therapeutic agent for diabetes or obesity according to the above.
(15) 下記一般式 (I)または (Π) (15) The following general formula (I) or (Π)
[化 5] [Formula 5]
(式中、 R1は水素原子、アルキル基、アルケニル基、または- C(=0)_R6 (R6はアルキル
基、ァリール基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein, R 1 is a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) _R 6 (R 6 is an alkyl R 2 represents a formyl group, a carboxy group, -CH_0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group). Represent
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、 R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、もしくは炭素数 4以上を有するアルキル基、またはァリール基 を示す） -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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)
で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許容され る塩、またはそれらの水和物のいずれかの 1または 2以上を含む、神経損傷、または 神経症の予防薬、または治療薬。 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.
(16) R1が水素原子であることを特徴とする（15)に記載の化合物、その幾何異性体 もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれ かの 1または 2以上を含む、神経損傷、または神経症の予防薬、または治療薬。(16) Any of the compound according to (15), wherein 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.
(17) R2がヒドロキシメチル基であることを特徴とする（15)または（16)に記載の化合 物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、神経損傷、または神経症の予防薬、 または治療薬。 (17) The compound according to (15) or (16), wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a compound thereof. A preventive or therapeutic agent for nerve damage, or neurosis, containing any one or more of the hydrates.
(18) OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特 徴とする（15) （17)のいずれかに記載の化合物、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含む、神経損傷、または神経症の予防薬、または治療薬。 (18) The compound according to any one of (17) and (17), wherein OR 1 is at the 3-position on the benzene ring, and R 2 is at the 2-position on the benzene ring. 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.
(19) 2- (ヒドロキシメチル) -3- (1-プロぺニル)フエノール、 3-(1-へキセニル) -2- (ヒド 口キシメチル)フエノール、 2- (ヒドロキシメチル )_3 -ビュルフエノール、 2- (ヒドロキシメチ ル) -3-スチリルフエノール、 3-へキシル _2 -(ヒドロキシメチル)フエノール、または 2- (ヒド ロキシメチル )_3_(1-メチル -1-プロぺニル)フエノール、その幾何異性体もしくは光学
活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2以上を含むことを特徴とする、（15)—（18)のいずれかに記載の神経損傷、または 神経症の予防薬、または治療薬。 (19) 2- (hydroxymethyl) -3- (1-propenyl) phenol, 3- (1-hexenyl) -2- (hydroxymethyl) phenol, 2- (hydroxymethyl) _3-bulfenol, 2- (hydroxymethyl) -3-styrylphenol, 3-hexyl_2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) _3_ (1-methyl-1-propenyl) phenol, geometric isomer Or optical (15) The nerve injury according to any one of (18) to (18), which comprises one or more of an active form, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Or a preventive or therapeutic drug for neurosis.
(20) 下記一般式 (I)または (Π) (20) The following general formula (I) or (Π)
[化 6] [Formula 6]
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリーノレ基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents a formyl group , A carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、
R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、もしくは炭素数 4以上を有するアルキル基、またはァリール基 を示す)で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許 容される塩、またはそれらの水和物のいずれかの 1または 2以上を含む、タンパク質 チロシンリン酸化亢進剤。 -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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. Indicates that 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.
(21) R1が水素原子であることを特徴とする（20)に記載の化合物、その幾何異性体 もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれ
かの 1または 2以上を含む、タンパク質チロシンリン酸化亢進剤。 (21) The compound according to (20), wherein R 1 is a hydrogen atom, a geometric isomer or an optically active isomer, a pharmaceutically acceptable salt thereof, or a hydrate thereof. A protein tyrosine phosphorylation enhancer comprising one or more of the foregoing.
(22) R2がヒドロキシメチル基であることを特徴とする（20)または（21)に記載の化合 物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、タンパク質チロシンリン酸化亢進剤 (22) The compound according to (20) or (21), wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A protein tyrosine phosphorylation enhancer, comprising one or more of the hydrates of
(23) OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特 徴とする（20) (22)のレ、ずれかに記載の化合物、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含む、タンパク質チロシンリン酸化亢進剤。 (23) The compound according to (20) or (22), wherein OR 1 is at the 3-position on the benzene ring and R 2 is at the 2-position on the benzene ring. A protein tyrosine phosphorylation enhancer comprising one or more of geometric isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof.
(24) 2- (ヒドロキシメチル) -3- (1-プロぺニル)フエノール、 3-(1-へキセニル) -2- (ヒド 口キシメチル)フエノール、 2- (ヒドロキシメチル )_3 -ビュルフエノール、 2- (ヒドロキシメチ ル) -3-スチリルフエノール、 3-へキシル _2 -(ヒドロキシメチル)フエノール、または 2- (ヒド 口キシメチル) -3-(1-メチル -1-プロぺニル)フエノール、その幾何異性体もしくは光学 活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2以上を含むことを特徴とする、 (20)一 (23)のいずれかに記載のタンパク質チロシ ンリン酸化亢進剤。 (24) 2- (hydroxymethyl) -3- (1-propenyl) phenol, 3- (1-hexenyl) -2- (hydroxymethyl) phenol, 2- (hydroxymethyl) _3-bulfenol, 2- (hydroxymethyl) -3-styrylphenol, 3-hexyl_2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) -3- (1-methyl-1-propenyl) phenol, Any one of (20)-(23), characterized in that it contains one or more of geometric isomers or optically active isomers, pharmaceutically acceptable salts thereof, or hydrates thereof. The protein tyrosine phosphorylation enhancer according to the above.
[0016] 以下、上記一般式 (I)で表される化合物（但し、一般式 (I)において、 R3が水素であり 、 R4/R5が水素原子/メチル基またはメチル基/水素原子であり、かつ OR1基/ R2基の置 換位置がベンゼン環上の 3位 /2位である化合物、および一般式 (I)において R4もしくは R5の一方がプロピル基である化合物を含む）を、単に「一般式 (I)で表される化合物」と 称する。 Hereinafter, a compound represented by the above general formula (I) (provided that, in the general formula (I), R 3 is hydrogen, and R 4 / R 5 is a hydrogen atom / methyl group or a methyl group / hydrogen atom And the compound in which the substitution position of OR 1 group / R 2 group is the 3-position / 2-position on the benzene ring and the compound in which R 4 or R 5 in the general formula (I) is a propyl group ) Are simply referred to as “compounds represented by the general formula (I)”.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
[0017] 一般式 (I)または (Π)において R1, R3, R6, R7, R8, R9または R1。は、それぞれ独立して任 意の直鎖状、分岐鎖状または環状のアルキル基であり得るが、好ましくは炭素数 1一 10のアルキル基であり、さらに好ましくはメチル基、ェチル基、プロピル基、イソプロピ ル基、ブチル基、イソブチル基、 s-ブチル基、 t-ブチル基、ペンチル基、 s-ペンチル 基、イソペンチル基、 2-メチルブチル基、ネオペンチル基、 1-ェチルプロピル基、へ キシル基、 4-メチルペンチル（イソへキシル）基、 3-メチルペンチル基、 2-メチルペン
チノレ基、 1-メチルペンチル（s-へキシル）基、 3,3-ジメチルブチル基、 2, 2-ジメチルブ チル基、 1, 1-ジメチルブチル基、 1,2-ジメチルブチル基、 1,3-ジメチルブチル基、 2,3-ジメチルブチル基および 2-ェチルブチル基などを挙げることができる。 In the general formula (I) or (Π), 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. Isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4 -Methylpentyl (isohexyl) group, 3-methylpentyl group, 2-methylpen Tinole group, 1-methylpentyl (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-dimethylbutyl group and 2-ethylbutyl group.
[0018] 一般式 (I)または (Π)におレ、て R4または R5は、それぞれ独立して任意の直鎖状、分岐 鎖状または環状のアルキル基であり得る力 好ましくは炭素数 1一 10のアルキル基で あり、さらに好ましくはメチル基、ェチル基、プロピル基、イソプロピル基、ブチル基、 イソブチル基、 s_ブチル基、 t-ブチル基、ペンチル基、 s-ペンチル基、イソペンチル 基、 2-メチルブチル基、ネオペンチル基、 1_ェチルプロピル基、へキシル基、 4-メチ ノレペンチル（イソへキシル）基、 3 -メチルペンチル基、 2-メチルペンチル基、 1-メチノレ ペンチル（s-へキシル）基、 3, 3 -ジメチルブチル基、 2, 2 -ジメチルブチル基、 1，1 -ジメ チルブチル基、 1,2-ジメチルブチル基、 1,3-ジメチルブチル基、 2, 3 -ジメチルブチノレ 基および 2-ェチルブチル基などを挙げることができる。 In the general formula (I) or (Π), 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 and 2-ethylbutyl group Rukoto can.
[0019] 一般式 (I)または (Π)におレ、て R1または R8は、それぞれ独立して任意の直鎖状、分岐 鎖状または環状のアルケニル基であり得る力 好ましくは炭素数 2— 10のアルケニル 基であり、さらに好ましくはビニル基、プロぺニル基、イソプロぺニル基、シクロプロべ ニル基、ブテニル基、ペンテニル基、へキセニル基、スチリル基などを挙げることがで きる。 In the general formula (I) or (Π), 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.
[0020] 一般式 (I)または (Π)におレ、て R2はカルボキシル基であり得る力 S、該カルボキシル基 には、その塩、およびカルボキシル基の水素に任意の基を置換した化合物（例えば エステル）が含まれる。 In the general formula (I) or (Π), 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).
[0021] 一般式 (I)または (Π)において R3， R4, R5, R6または R7は、それぞれ独立して任意の置 換もしくは無置換のァリール基であり得るが、好ましくは置換もしくは無置換のフエ二 ル基を挙げることができる。 In the general formula (I) or ()), 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.
[0022] 一般式 (I)または (Π)において R6または R7はそれぞれ独立して任意のアルキルアミノ 基、 R1Qは任意のアルキルォキシカルボニル基または任意のアルキルォキシカルボ二 ノレアルキル基、また R3は任意のアルコキシ基（アルキルォキシ基）であってょレ、が、こ れらの基の好ましレ、アルキル部分としては炭素数 1一 10のァノレキノレ、さらに好ましく はメチノレ、ェチル、プロピル、イソプロピノレ、ブチル、イソブチル、 s -ブチル、 t -ブチノレ
、ペンチル、 s-ペンチル、イソペンチル、 2-メチルブチル、ネオペンチル、 1-ェチルプ 口ピル、へキシル、 4-メチルペンチル（イソへキシル）、 3-メチルペンチル、 2-メチルぺ ンチル、 1-メチルペンチル（s-へキシル）、 3,3-ジメチルブチル、 2,2-ジメチルブチル 、 1，1 -ジメチルブチル、 1，2-ジメチルブチル、 1，3-ジメチルブチル、 2, 3-ジメチルブチ ルおよび 2-ェチルブチルなどを挙げることができる。 In the general formula (I) or (Π), 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). However, preferred groups of these groups include an alkyl moiety having 1 to 10 carbon atoms, more preferably methynole, ethyl and propyl. , Isopropynole, butyl, isobutyl, s-butyl, t-butynole , Pentyl, s-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpentyl pill, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl ( s-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and And ethyl butyl.
[0023] 一般式 (I)または (Π)において R3はハロゲン原子であり得る力 フッ素原子、クロ口原 子、ブロモ原子が挙げられる。また、 R3は任意のアミノ基であり得る力 該ァミノ基には ァノレキノレアミノ基、ジァノレキノレアミノ基、ァニリン等のァリールアミノ基も含まれる。 In the general formula (I) or (Π), 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.
[0024] 一般式 (I)または (Π)で表される化合物（以下、「本発明に係る化合物」ともいう）のうち 、好ましい化合物としては、 R1が水素であって、かつ/または R2がヒドロキシメチル基 である化合物が挙げられる。また、 OR1基/ R2基のベンゼン環上における置換位置が 、それぞれ 2位 Z3位、または 3位 Z2位である化合物も好ましい化合物として挙げられ る。さらに好ましいィ匕合物としては、 R1が水素であって、かつ/または R2がヒドロキシメ チル基であって、 OR1基/ R2基のベンゼン環上における置換位置力 それぞれ 2位 /3位、または 3位 /2位である化合物、さらに好ましくは R1が水素であって、かつ/ま たは R2がヒドロキシメチル基であって、 OR1基/ R2基のベンゼン環上における置換位 置力 それぞれ 3位 /2位である化合物である。 Among the compounds represented by the general formula (I) or (（) (hereinafter, also referred to as “the compound according to the present invention”), 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.
[0025] もっとも好ましい本発明に係る化合物として、以下の化合物を挙げることができるが 、本発明はこれらの化合物に限定されるものではない。なお、下記の各化合物を本 明細書においてカツコ内に示したコード番号を用いて称することがある。 [0025] The most preferred compounds according to the present invention include the following compounds, but the present invention is not limited to these compounds. In addition, each of the following compounds may be referred to by using the code number shown in the parentheses in this specification.
(E)-2- (ヒドロキシメチル) -3-(1-プロぺニル)フエノール (RKTS-101) (E) -2- (Hydroxymethyl) -3- (1-propenyl) phenol (RKTS-101)
(Z)_2 -(ヒドロキシメチル )_3_(1-プロべニル)フエノール (RKTS-107) (Z) _2- (Hydroxymethyl) _3_ (1-probenyl) phenol (RKTS-107)
(E)_3_(l_へキセニル) -2- (ヒドロキシメチノレ)フエノール（RKTS-102) (E) _3_ (l_hexenyl) -2- (hydroxymethinole) phenol (RKTS-102)
2- (ヒドロキシメチル) -3-ビュルフヱノール (RKTS-103) 2- (hydroxymethyl) -3-bulphenol (RKTS-103)
(E)_2 -(ヒドロキシメチル )_3 -スチリルフエノール (RKTS-104) (E) _2- (Hydroxymethyl) _3-styrylphenol (RKTS-104)
3-へキシル _2 -(ヒドロキシメチル)フエノール (RKTS-105) 3-Hexyl_2- (hydroxymethyl) phenol (RKTS-105)
2- (ヒドロキシメチル) -3-[(Ε)-1-メチル -1-プロべニル]フエノール (RKTS-106) 2- (hydroxymethyl) -3-[() -1-methyl-1-probenyl] phenol (RKTS-106)
[0026] 一般式 (I)で表される化合物は、スキーム 1に示されるステップを含む合成ルートで
製造することができる。 [0026] The compound represented by the general formula (I) is synthesized by a synthetic route including the steps shown in Scheme 1. Can be manufactured.
[化 7] [Formula 7]
(式中 R1は水素原子、アルキル基、アルケニル基、または- C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 R2はホルミル基、カルボキシ ル基、 -CH _0(C=0)R7(R7はアルキル基、ァリール基、またはアルキルアミノ基を表す(Wherein R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group), and R 2 represents a formyl group , A carboxy group, -CH _0 (C = 0) R 7 (R 7 represents an alkyl group, an aryl group, or an alkylamino group
)、 -CH O-R8 (R8は水素原子、アルキル基、またはアルケニル基を表す)、 ), -CH OR 8 (R 8 represents a hydrogen atom, an alkyl group, or an alkenyl group),
-CH=N-OR9(R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q (R1Qは アルキル基、アルキルォキシカルボニル基、ホノレミル基、またはアルキルォキシカル ボニルアルキル基を表す)を示し、 R1と R2が連結されることにより環化していてもよぐ R 3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基または ヒドロキシ基を示し、 R4， R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピ ル基、イソプロピル基、または炭素数 4以上を有するアルキル基、あるいはァリール基 を示し、 Lはスルホネート基またはハロゲン原子を示し、 Xは B(ORu) (R11は水素または アルキル基を表す)または Sn(R12) (R12はアルキル基を表す)を示す。） -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -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). )
一般式 (III)において Lは、（ΠΙ)で表される化合物がスキーム 1における触媒に酸化的 付加反応しうるような置換基または原子であれば、任意の置換基または原子でよぐ 当業者が適宜選択することができる。好ましくはスルホネート基、ハロゲン原子などが 挙げられ、より好ましくはトリフルォロメタンスルホネート基である。また、一般式 (IV)に ついて、 Xにおける R11は、水素またはイソプロピル基を含む任意のアルキル基であり
うる力 好ましくは水素であり、また R12は、任意のアルキル基でありうる力 メチル基、 ブチル基があげられる。 In the general formula (III), L may be any substituent or atom as long as the compound represented by (ΠΙ) is a substituent or an atom capable of undergoing an oxidative addition reaction to the catalyst in Scheme 1. Can be appropriately selected. Preferred are a sulfonate group, a halogen atom and the like, and more preferred is a trifluoromethanesulfonate group. In the general formula (IV), 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.
[0029] スキーム 1に示される反応は、一般式 (III)で表される化合物および一般式 (IV)で表さ れる化合物を不活性溶媒中、塩基存在下、遷移金属触媒存在下で行うことができる 。さらに、必要に応じてその他の化合物（例えばホスフィン配位子）が存在していても よい。 [0029] The 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. Can be. Further, another compound (for example, a phosphine ligand) may be present as necessary.
[0030] スキーム 1に示される反応で用いられる不活性溶媒としては、本反応に不活性であ れば特に限定されないが、例えば、へキサンのような脂肪族炭化水素類、ベンゼン、 トルエンのようなァリール炭化水素類、クロ口ホルム、ジクロロメタンのようなハロゲン化 炭化水素類、ジェチルエーテル、テトラヒドロフランのようなエーテル類などが挙げら れる。 [0030] 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.
[0031] スキーム 1に示される反応で用いられる塩基としては、化合物の他の部分に影響を 与えなレ、ものであれば特に限定されず、有機塩基類または無機塩基類とも用いるこ とができる力 好ましくは、例えば、炭酸カリウムなどが挙げられる。 [0031] 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.
[0032] スキーム 1に示される反応で用いられる触媒としては、パラジウム触媒、ニッケル触 媒などの遷移金属錯体があげられる力 好ましくはパラジウム触媒が挙げられ、特に 好ましくは、テトラキス (トリフエニルホスフィン)パラジウムが挙げられる。 As a catalyst used in the reaction shown in Scheme 1, 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.
[0033] スキーム 1に示される反応の反応温度は、原料化合物、溶媒等により適宜選択する ことができる力 通常は 40-80 °Cである。反応時間は、原料化合物、溶媒、反応温度 等により異なるが、通常は 2-12時間である。 [0033] 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.
[0034] 一般式 (III)で表される化合物は、必要に応じて、保護基により保護 (例えば環化）さ れていてもよい。保護された化合物としては、例えば下記一般式 (m)_iで表されるィ匕 合物が挙げられる。一般式 (m)_iで表される化合物を用いて、スキーム 1と同様の反 応を行うことにより、（IHで表される化合物が得られる。（iHを、当業者に周知の方法 で、脱保護、還元することにより (I)_iiに導くことができる。
[0035] [化 8] 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. By performing the same reaction as in Scheme 1 using a compound represented by the general formula (m) _i, a compound represented by (IH can be obtained. (IH can be obtained by a method well known to those skilled in the art. Deprotection and reduction can lead to (I) _ii. [0035]
[0036] また、一般式 (m)-iで表される化合物は、例えば、以下のスキームに従って製造する こと力 Sできる。すなわち、 2,6-ジヒドロキシ安息香酸、 2，3-ジヒドロキシ安息香酸、 2，4_ ジヒドロキシ安息香酸、 2，5-ジヒドロキシ安息香酸を原料として用いることにより、それ ぞれ対応する (m)-i(L = OSO CF )を得ること力 Sできる。 The compound represented by the general formula (m) -i can be produced, for example, according to the following scheme. That is, by using 2,6-dihydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, and 2,5-dihydroxybenzoic acid as raw materials, the corresponding (m) -i ( L = OSO CF) can get S.
[0037] [化 9] [0037] [Formula 9]
[0038] また、一般式 (Π)で表される化合物は、例えば、以下のスキームで示されるように、一 般式 (I)で表される化合物を水素添加反応させることにより製造することができる。当 業者は本反応における適当な水素添加反応を選択することができるが、パラジウム— 炭素を含む不均一系触媒を用いる水素添加反応、またはウィルキンソン錯体を含む 均一系触媒を用いる水素添加反応であってもよい。好ましい水素添加反応は、例え ば水素雰囲気下、パラジウム-炭素触媒を用いて、メタノール中で反応を行うことによ り実施すること力できる。
[0039] [化 10] The compound represented by the general formula (一般) 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. [0039] [Formula 10]
[0040] 一般式 (I)または (Π)で表される化合物は、必要に応じて、融点、赤外吸収スペクトル 、 1H_NMRスペクトル、 13C_NMRスペクトル、質量分析、 X線構造解析などによって 分析し、確認、同定することができる。 The compound represented by the general formula (I) or (Π) 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.
[0041] 下記の実施例において、本発明に係る化合物の好ましい製造方法の一例を、具体 的に記載した力 本発明がこれにより限定されるわけではない。 [0041] In the following examples, an example of a preferred method for producing the compound according to the present invention is specifically described. The present invention is not limited thereto.
[0042] 本発明に係る化合物は、フエノール部位を有しうる（ = H)が、フエノール部位を有 する場合、常法に従って塩にすることができる。そのような塩としては、例えば、ナトリ ゥム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム 塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッケル塩、コ バルト塩等の金属塩を挙げることができる。 [0042] The compound according to the present invention may have a phenol moiety (= H), but when it has a phenol moiety, it can be converted to a salt according to a conventional method. Examples of such 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.
[0043] 本発明に係る化合物は、置換基の種類によっては一または複数の不斉炭素を有す る場合がある。これらの不斉炭素に基づく光学異性体またはジァステレオマーなどの 立体異性体が存在するが、本発明の範囲には、純粋な形態の立体異性体のほか、 任意の立体異性体の混合物またはラセミ体などが含まれる。 The compound according to the present invention may have one or more asymmetric carbon atoms depending on the type of the substituent. Although 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.
[0044] 本発明に係る化合物は、ォレフィン性の二重結合を有することがあり、二重結合に 基づく幾何異性体が存在することがある力 純粋な形態の幾何異性体のほか、任意 の幾何異性体の混合物も本発明の範囲に含まれる。 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.
[0045] 本発明に係る化合物は任意の結晶形として存在することができ、水和物または溶 媒和物として存在する場合もある。これらの物質がいずれも本発明の範囲に含まれる ことはいうまでもない。さらに、本発明には、生体内において代謝されて本発明に係る
3置換ベンゼン誘導体化合物に変換される化合物、すなわち、いわゆるプロドラッグ 体も全て含むものである。 [0045] 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.
[0046] 本発明に係る化合物は、後述する試験例に記載の通り、優れたインスリン作用増強 作用、および Zまたは神経栄養因子増強作用を示す。 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.
従って、該化合物を含む組成物（以下、「本発明に係る組成物」とも称する）は、様 々な疾病、例えば糖尿病や肥満症、及び神経損傷や神経症などの疾病の治療薬あ るいは予防薬として使用することができ、例えばヒトに投与することができる。 Therefore, a composition containing the compound (hereinafter, also referred to as “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.
[0047] 本発明に係る化合物を含む試薬を調製し、各種培養細胞系へ直接投与すると、増 殖因子刺激におけるタンパク質チロシンリン酸化の亢進などが観察できる場合がある 。このことは、下記の試験例において、本発明に係る化合物を含む試薬を各種培養 細胞系へ直接投与し、増殖因子刺激におけるタンパク質チロシンリン酸化の亢進に っレ、て観察して得られた結果力 もわかる。 [0047] When a reagent containing the compound according to the present invention is prepared and directly administered to various cultured cell lines, in some cases, enhancement of protein tyrosine phosphorylation upon stimulation of a growth factor may be observed. This result was obtained by observing the increase in protein tyrosine phosphorylation upon growth factor stimulation by directly administering a reagent containing the compound of the present invention to various cultured cell lines in the following test examples. I understand the power.
[0048] 従って、本発明に係る化合物を含む組成物はタンパク質チロシンリン酸化亢進剤と して使用することができ、例えばヒトに投与することができる。該タンパク質チロシンリ ン酸化亢進剤は、例えば糖尿病や肥満症、及び神経損傷や神経症などの疾病の治 療薬あるいは予防薬として用いることができる。すなわち、本発明の糖尿病や肥満症 、及び神経損傷や神経症などの疾病の治療薬あるいは予防薬は、タンパク質チロシ ンリン酸化亢進剤の一態様であり得る。 [0048] Therefore, 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.
[0049] 本発明に係る化合物を含む試薬の剤型としては、例えば粉末などの固形剤、又は 有機溶媒若しくは含水有機溶媒に溶解した液体剤などを挙げることができる。この場 合に使用可能な有機溶媒としては、例えばメタノールやジメチルスルホキシド等を挙 げること力 Sできる。通常、本発明に係る化合物を試薬として用いる場合の効果的な使 用量は、 0.1 100 μ g/mlである力 適切な使用量は培養細胞系の種類や使用目的 により異なり、適宜選択可能である。また、必要により上記範囲外の量を用いてもよい [0049] 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. In this case, examples of the organic solvent that can be used include methanol and dimethyl sulfoxide. Usually, when the compound according to the present invention is used as a reagent, the effective dose is 0.1 to 100 μg / 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.
[0050] 本発明に係る組成物には、必要に応じて、その剤型に適した賦形剤、結合剤、湿 潤剤、崩壊剤、滑沢剤等の医薬用添加剤が混合されていてよい。すなわち、本発明 に係る化合物を含むこと以外は、通常の方法により医薬製剤化することができる。本
発明に係る組成物の剤形としては、散剤、顆粒剤、錠剤、カプセル剤、丸剤、液剤、 注射剤、坐剤、経皮吸収剤、吸入剤等が挙げられる。注射剤とする場合には、適当 な担体とともに滅菌処理を行って製剤化することができる。 [0050] The 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.
[0051] 本発明に係る組成物は、散剤、顆粒剤、錠剤、カプセル剤、丸剤、液剤等とした場 合には経口的に、または注射剤、坐剤、経皮吸収剤、吸入剤等とした場合には非経 口的に投与することができる。 [0051] The 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.
[0052] 本発明に係る化合物の投与量は、疾患の状態、投与ルート、患者の年齢、または 体重によっても異なり、最終的には医師の判断に委ねられるが、成人に経口で投与 する場合、通常、 0.1-100mg/kg/日、好ましくは、 l-20mg/kg/日、非経口で投与する 場合、通常、 0.01_10mg/kg/日、好ましくは、 0.1-2mg/kg/日を投与する。これを 1回 あるいは複数回に分割して投与すればょレ、。 [0052] 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. Usually, 0.1-100 mg / kg / day, preferably l-20 mg / kg / day, when administered parenterally, usually 0.01_10 mg / kg / day, preferably 0.1-2 mg / kg / day . This can be administered once or divided into multiple doses.
[0053] 以下に実施例および試験例をあげて本発明をさらに詳細に説明するが、本発明は これらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.
[0054] <実施例 > <Example>
本発明化合物の具体的な合成経路の一例を下記のスキーム 2に示し、それを参照 して、実施例を以下に示す。
An example of a specific synthetic route of the compound of the present invention is shown in the following scheme 2, and examples are shown below with reference to it.
[0055] [化 11] [0055] [Formula 11]
(E)(E)
RKTS-104 R=Ph (E) RKTS-104 R = Ph (E)
[0056] トリフルォロメタンスルホン酸 2,2-ジメチル -4-ォキソ -4H-ベンゾ [1,3]ジォキシン- 5- ィル エステル (化合物 3)の合成 [0056] Synthesis of 2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxin-5-yl ester of trifluoromethanesulfonic acid (Compound 3)
2,6-ジヒドロキシ安息香酸 (ィ匕合物 1)を原料として、文献既知の方法 (Synth. Starting from 2,6-dihydroxybenzoic acid (I-Danied Compound 1), a method known in the literature (Synth.
Commun., 24, 1025 (1994))に従レ、、 5_ヒドロキシ _2，2_ジメチルベンゾ [1,3]ジォキシン -4-オン（化合物 2)を得た（収率 75%)。続いて、トリフルォロメタンスルホン酸 2，2 -ジメ チル -4-ォキソ -4H-ベンゾ [1,3]ジォキシン- 5-ィル エステル（ィ匕合物 3)を文献既知 の方法 (Tetrahedron, 52, 15071 (1996》により 80%の収率で合成した。 According to Commun., 24, 1025 (1994), 5_hydroxy_2,2-dimethylbenzo [1,3] dioxin-4-one (compound 2) was obtained (yield: 75%). Subsequently, 2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxin-5-yl ester of trifluoromethanesulfonic acid (dithiol 3) was prepared by a method known in the literature (Tetrahedron, 52). , 15071 (1996) in an 80% yield.
[0057] (E)_2, 2 -ジメチル- 5_プロぺニルベンゾ [1，3]ジォキシン- 4_オン (ィ匕合物 4)及び (E) _2,2-dimethyl-5_propenyl benzo [1,3] dioxin-4_one (I-drug 4) and
(Z)_2,2 -ジメチル- 5_プロぺニルベンゾ [1，3]ジォキシン- 4_オン (ィ匕合物 5)の合成 アルゴン気流下、 Pd(PPh ) 21.9mg (0.0190mmol, 0.05eq)、トリフルォロメタンスルホ Synthesis of (Z) _2,2-dimethyl-5_propionylbenzo [1,3] dioxin-4_one (I-Dai-Dai 5) Pd (PPh) 21.9mg (0.0190mmol, 0.05eq) under argon stream , Trifluoromethanesulfo
3 4 3 4
ン酸 2，2-ジメチル- 4_ォキソ -4H -ベンゾ [1，3]ジォキシン _5 -ィル エステル (ィ匕合物 3) 123. lmg (0.377mmol, leq)、 1_プロぺニルホウ酸 86.5mg (l.Olmmol, 2.7eq)の THF溶
液 (6.0ml)に、 2M-K CO水溶液 1.51mlを加え、 75°Cで 4.5時間加熱撹拌した。室温に2,2-Dimethyl-4_oxo-4H-benzo [1,3] dioxin_5-yl ester (I-Daijutsu 3) 123.lmg (0.377mmol, leq), 1_propenyl boric acid 86.5 mg (l.Olmmol, 2.7eq) in THF To the solution (6.0 ml) was added 1.51 ml of a 2M-K 2 CO aqueous solution, and the mixture was heated and stirred at 75 ° C for 4.5 hours. At room temperature
2 3 twenty three
まで冷却後、塩ィ匕アンモニゥム水溶液をカ卩ぇ反応を停止させた。有機物を酢酸ェチ ルで 3回抽出し、合わせた有機層を飽和食塩水で 3回洗浄した。無水硫酸ナトリウム で乾燥させ、ろ過後溶媒を減圧濃縮し、薄層クロマトグラフィー（「シリカゲルプレート」 の薄層クロマトグラフィーをいう。以下において同様である。） (展開溶媒;へキサン:酢 酸ェチル = 3 : 1)で精製し、化合物 4および化合物 5の混合物を 70.3mg得た（85%, conv.99%,化合物 4 :化合物 5 = 5 : 1) After cooling to room temperature, the aqueous solution of salted sodium ammonia was stopped from the kagami reaction. The organic matter was extracted three times with ethyl acetate, and the combined organic layers were washed three times with saturated saline. After drying over anhydrous sodium sulfate, filtration and concentration of the solvent under reduced pressure, thin-layer chromatography (referred to as thin-layer chromatography on a “silica gel plate”; the same applies hereinafter) (developing solvent; hexane: ethyl acetate = Purification was performed in 3: 1) to obtain 70.3 mg of a mixture of compound 4 and compound 5 (85%, conv.99%, compound 4: compound 5 = 5: 1).
(E)_2, 2 -ジメチル- 5_プロぺニルベンゾ [1，3]ジォキシン- 4_オン（ィ匕合物 4)の物性値 'H-NMR (400MHZ, CDCl ) δ =1.66 (6Η， s，— CH— (CH* ) ), 1.90 (3H， dd， Physical Properties of (E) _2,2-Dimethyl-5_propenylbenzo [1,3] dioxin-4_one (I-Daijutsu 4) 'H-NMR (400MHZ, CDCl) δ = 1.66 (6Η, s , — CH— (CH *)), 1.90 (3H, dd,
3 3 2 3 3 2
-CH=CH-CH*， J=1.6， 6.6 Hz), 6.20 (1H， dq,— CH=CH*— CH， J=6.6， 15.5 Hz), -CH = CH-CH *, J = 1.6, 6.6 Hz), 6.20 (1H, dq, — CH = CH * —CH, J = 6.6, 15.5 Hz),
3 3 3 3
6.77 (1H, d， aromatic, J=8.1 Hz), 7.17 (1H， d, aromatic, J=7.8 Hz), 7.37 (1H, t, aromatic, J=8.0 Hz), 7.43 (1H, dd， - CH*=CH_CH， J=1.4, 15.6 Hz). 6.77 (1H, d, aromatic, J = 8.1 Hz), 7.17 (1H, d, aromatic, J = 7.8 Hz), 7.37 (1H, t, aromatic, J = 8.0 Hz), 7.43 (1H, dd, -CH * = CH_CH, J = 1.4, 15.6 Hz).
3 Three
13C-NMR (100MHz, CDCl ) δ =18.7, 25.5, 105.0, 110.4, 115.4, 121.2, 129.2， 13 C-NMR (100 MHz, CDCl) δ = 18.7, 25.5, 105.0, 110.4, 115.4, 121.2, 129.2,
3 Three
130.1， 134.9, 142.5, 156.7, 160.3. 130.1, 134.9, 142.5, 156.7, 160.3.
(Z)-2, 2-ジメチル -5-プロぺニルベンゾ [1,3]ジォキシン- 4-オン（ィ匕合物 5)の物性値 'H-NMR (400MHZ, CDCl ) δ =1.67 (6Η， s,—CH— (CH* ) ), 1.74 (3H， dd， Physical properties of (Z) -2,2-dimethyl-5-propenylbenzo [1,3] dioxin-4-one (di-conjugated compound 5) 'H-NMR (400MHZ, CDCl) δ = 1.67 (6Η, s, —CH— (CH *)), 1.74 (3H, dd,
3 3 2 3 3 2
- CH=CH- CH*， J=0.9， 7.1 Hz), 5.87 (1H， dq, - CH=CH* - CH， J=7.1, 14.4 Hz), -CH = CH- CH *, J = 0.9, 7.1 Hz), 5.87 (1H, dq,-CH = CH *-CH, J = 7.1, 14.4 Hz),
3 3 3 3
6.82 (1H, d, aromatic, J=8.2 Hz), 6.97 (1H， d, aromatic, J=7.9 Hz), 6.97 (1H, d, -CH*=CH-CH， J=14.4 Hz), 7.41 (1H, dd, aromatic, J=7.1, 7.9 Hz). 6.82 (1H, d, aromatic, J = 8.2 Hz), 6.97 (1H, d, aromatic, J = 7.9 Hz), 6.97 (1H, d, -CH * = CH-CH, J = 14.4 Hz), 7.41 ( 1H, dd, aromatic, J = 7.1, 7.9 Hz).
3 Three
13C-NMR (100MHz, CDCl ) δ =14.4, 25.6, 105.2, 111.1, 115.7， 125.0, 127.2， 13 C-NMR (100 MHz, CDCl) δ = 14.4, 25.6, 105.2, 111.1, 115.7, 125.0, 127.2,
3 Three
128.9， 134.6, 141.1, 156.9, 160.0. 128.9, 134.6, 141.1, 156.9, 160.0.
(E)- 2- (ヒドロキシメチル) - 3- (1-プロぺニル)フエノール (RKTS-101)および (Z)-2- (ヒド ロキシメチル )_3_(1-プロべニル)フヱノール (RKTS-107)の合成 (E) -2- (Hydroxymethyl) -3- (1-propenyl) phenol (RKTS-101) and (Z) -2- (hydroxymethyl) _3_ (1-probenyl) phenol (RKTS-107 Synthesis of)
アルゴン気流下、 2，2 -ジメチル- 5_プロぺニルベンゾ [1，3]ジォキシン- 4-オン 333.5mg (1.54mmol, leq, E： Z = 5： 1)の THF溶液 (3.0ml)に、氷冷下、 LiAlH Under a stream of argon, a solution of 2,3-dimethyl-5-propenylbenzo [1,3] dioxin-4-one in 333.5 mg (1.54 mmol, leq, E: Z = 5: 1) in THF (3.0 ml) was added. Under ice cooling, LiAlH
4 Four
233.5mg (6.15mmol, 4eq)を加え、室温に戻して 5時間撹拌した。再び氷冷し、 IN— HClaqを加えて反応を停止させ、有機物をクロ口ホルムで 3回抽出し、合わせた有機 層を飽和食塩水で 3回洗浄した。無水硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減
圧濃縮し、薄層クロマトグラフィー（展開溶媒:へキサン:エーテル = 1 : 1)で分離精製 し、（E)-2- (ヒドロキシメチル) -3-(1-プロぺニル)フエノール (RKTS-101)を無色粉末とし て 152.2mg (60%)、（Z)_2_ (ヒドロキシメチル) -3_(1_プロぺニル)フエノール (RKTS-107) を 30.7mg (12%)得た。 233.5 mg (6.15 mmol, 4 eq) was added, and the mixture was returned to room temperature and stirred for 5 hours. The mixture was cooled on ice again, the reaction was stopped by adding IN-HClaq, the organic matter was extracted three times with chloroform, and the combined organic layers were washed three times with saturated saline. After drying over anhydrous sodium sulfate and filtering, the solvent was reduced. The solution was separated and purified by thin-layer chromatography (developing solvent: hexane: ether = 1: 1), and (E) -2- (hydroxymethyl) -3- (1-propenyl) phenol (RKTS- 101) was obtained as a colorless powder (152.2 mg, 60%), and (Z) _2_ (hydroxymethyl) -3_ (1_propenyl) phenol (RKTS-107), 30.7 mg (12%).
(E)_2 -(ヒドロキシメチル) _3_(1_プロぺニル)フエノール (RKTS-101)の物性値 Physical properties of (E) _2-(hydroxymethyl) _3_ (1_propenyl) phenol (RKTS-101)
IR (neat) 3300， 2960, 1653， 1608, 987, 968， 758, 731 cm—1. IR (neat) 3300, 2960, 1653, 1608, 987, 968, 758, 731 cm— 1 .
'H-NMR (400MHZ, CDCl ) δ =1.86 (3H， dd, -CH=CH-CH* J=1.6, 6.5 Hz), 2.24 'H-NMR (400MHZ, CDCl) δ = 1.86 (3H, dd, -CH = CH-CH * J = 1.6, 6.5 Hz), 2.24
3 3, 3 3,
(1H, s, alcohol), 4.96 (2H, s, benzyl), 5.99 (1H， dq, -CH=CH*-CH， J=6.6, 15.4 (1H, s, alcohol), 4.96 (2H, s, benzyl), 5.99 (1H, dq, -CH = CH * -CH, J = 6.6, 15.4
3 Three
Hz), 6.51 (1H， dd,— CH*=CH_CH， J=1.2, 15.5 Hz), 6.74 (1H, d， aromatic, J=8.0 Hz), 6.51 (1H, dd, — CH * = CH_CH, J = 1.2, 15.5 Hz), 6.74 (1H, d, aromatic, J = 8.0
3 Three
Hz), 6.89 (1H， d, aromatic, J=7.7 Hz), 7.10 (1H, t, aromatic, J=7.9 Hz), 7.48 (1H, s, phenol). Hz), 6.89 (1H, d, aromatic, J = 7.7 Hz), 7.10 (1H, t, aromatic, J = 7.9 Hz), 7.48 (1H, s, phenol).
13C-NMR (100MHz, CDCl ) δ = 18.6， 59.1, 114.7, 118.6, 121.9, 127.7, 128.7, 13 C-NMR (100 MHz, CDCl) δ = 18.6, 59.1, 114.7, 118.6, 121.9, 127.7, 128.7,
3 Three
129.2， 137.9, 155.7. 129.2, 137.9, 155.7.
(Z)-2- (ヒドロキシメチル) -3-(l-プロぺニル)フエノール (RKTS-107)の物性値 Physical properties of (Z) -2- (hydroxymethyl) -3- (l-propenyl) phenol (RKTS-107)
IR (neat) 3282， 3016, 2935， 2856, 1647, 1608， 748, 732 cm"1. IR (neat) 3282, 3016, 2935, 2856, 1647, 1608, 748, 732 cm " 1 .
JH-NMR (400MHz, CDCl ) δ =1.62 (3H， dd,— CH=CH— CH* J=1.6， 6.9 Hz), 2.59 J H-NMR (400MHz, CDCl) δ = 1.62 (3H, dd, — CH = CH— CH * J = 1.6, 6.9 Hz), 2.59
3 3, 3 3,
(1H， br, alcohol), 5.78-5.86 (1H， m, - CH=CH*- CH )， 6.39 (1H， d, - CH*=CH_CH , (1H, br, alcohol), 5.78-5.86 (1H, m,-CH = CH *-CH), 6.39 (1H, d,-CH * = CH_CH,
3, 3 3, 3
J=11.3 Hz), 6.69 (1H， d, aromatic, J=7.6 Hz), 6.75 (1H, d, aromatic, J=8.0 Hz), 7.12 (1H, d, aromatic, J=8.0 Hz), 7.76 (1H， broad, phenol). J = 11.3 Hz), 6.69 (1H, d, aromatic, J = 7.6 Hz), 6.75 (1H, d, aromatic, J = 8.0 Hz), 7.12 (1H, d, aromatic, J = 8.0 Hz), 7.76 ( 1H, broad, phenol).
13C-NMR (100MHz, CDCl ) δ =14.3, 61.0, 115.2, 121.4, 122.5， 127.6, 128.4, 1 3 C-NMR (100 MHz, CDCl) δ = 14.3, 61.0, 115.2, 121.4, 122.5, 127.6, 128.4,
3 Three
128.6， 136.4, 156.4. 128.6, 136.4, 156.4.
HRMS (EI) Found: m/z 164.0837 calcd for C H 〇： M， 164.0875. HRMS (EI) Found: m / z 164.0837 calcd for CH H: M, 164.0875.
10 12 2 10 12 2
(E)_5_(l_へキセニル) -2，2-ジメチルベンゾ [1,3]ジォキシン- 4-オン（化合物 6)の合 成 Synthesis of (E) _5_ (l_hexenyl) -2,2-dimethylbenzo [1,3] dioxin-4-one (compound 6)
アルゴン気流下、 Pd(PPh ) 114.5mg (0.099mmol, 0.03eq)、トリフルォロメタンスルホ Under an argon stream, Pd (PPh) 114.5mg (0.099mmol, 0.03eq), trifluoromethanesulfo
3 4 3 4
ン酸 2，2 -ジメチル- 4_ォキソ -4H -ベンゾ [1，3]ジォキシン _5 -ィル エステル (ィ匕合物 3) 1080mg (3.31mmol, leq)、 1-へキセニルホウ酸 1400mg (16.3mmol, 4.9eq)の THF溶 液 (59ml)に 2M— K CO水溶液 6.5mlをカ卩え、 75°Cで 7時間加熱撹拌した。室温に冷却
後、塩化アンモニゥム水溶液を加え反応を停止させた。有機物を酢酸ェチルで 3回 抽出し、合わせた有機層を飽和食塩水で 3回洗浄した。無水硫酸ナトリウムで乾燥さ せ、ろ過後、溶媒を減圧濃縮し、シリカゲルカラムクロマトグラフィー (hexaneん thyl acetate=50/l)で精製し、（Ε)_5_(1-へキセニル) _2，2_ジメチルベンゾ [1,3]ジォキシン -4-オン (化合物 6) 860mgを定量的に得た。 2,2-Dimethyl-4_oxo-4H-benzo [1,3] dioxin_5-yl ester (Y-drug 3) 1080 mg (3.31 mmol, leq), 1-hexenyl boric acid 1400 mg (16.3 mmol) , 4.9 eq) of a THF solution (59 ml) was combined with 6.5 ml of a 2M-K 2 CO aqueous solution, and heated and stirred at 75 ° C for 7 hours. Cool to room temperature Thereafter, an aqueous solution of ammonium chloride was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, and the combined organic layers were washed three times with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent is concentrated under reduced pressure and purified by silica gel column chromatography (hexane thyl acetate = 50 / l) to give (Ε) _5_ (1-hexenyl) _2,2_dimethyl 860 mg of benzo [1,3] dioxin-4-one (compound 6) was obtained quantitatively.
IR (neat) 2956, 2929, 2871, 2858, 1731, 1170， 1145, 966， 777, 721 cm—1. IR (neat) 2956, 2929, 2871, 2858, 1731, 1170, 1145, 966, 777, 721 cm- 1 .
'H-NMR (400MHZ, CDCl ) δ =0.82 (3H， t, _CH=CH_CH -CH— CH -CH* , J=7.3 'H-NMR (400MHZ, CDCl) δ = 0.82 (3H, t, _CH = CH_CH -CH— CH -CH *, J = 7.3
3 2 2 2 3 3 2 2 2 3
Hz), 1.28 (2H, sextet, _CH=CH_CH -CH - CH*— CH , J=7.2 Hz), 1.38 (2H, Hz), 1.28 (2H, sextet, _CH = CH_CH -CH-CH * — CH, J = 7.2 Hz), 1.38 (2H,
2 2 2 3 2 2 2 3
quintet, -CH二 CH-CH -CH* -CH— CH J=2.7 Hz), 1.59 (6H， s， - C(CH* ) ), 2.17 quintet, -CH2 CH-CH -CH * -CH— CH J = 2.7 Hz), 1.59 (6H, s, -C (CH *)), 2.17
2 2 2 3, 3 2 2 2 2 3, 3 2
(2H, q, -CH=CH-CH*— CH -CH— CH J=7.0 Hz), 6.12 (1H， dt, -CH=CH*-CH— CH (2H, q, -CH = CH-CH * — CH -CH— CH J = 7.0 Hz), 6.12 (1H, dt, -CH = CH * -CH— CH
2 2 2 3, 2 2 2 2 3, 2
— CH -CH , J=7.0, 15.7 Hz), 6.69 (1H, dd， aromatic, J=0.7， 8.0 Hz), 7.14 (1H, d，— CH -CH, J = 7.0, 15.7 Hz), 6.69 (1H, dd, aromatic, J = 0.7, 8.0 Hz), 7.14 (1H, d,
2 2 3 2 2 3
aromatic, J=10.2 Hz), 7.29 (1H, t, aromatic, J=8.0 Hz), 7.35 (1H, d， - CH*=CH_CH aromatic, J = 10.2 Hz), 7.29 (1H, t, aromatic, J = 8.0 Hz), 7.35 (1H, d,-CH * = CH_CH
2 Two
-CH -CH -CH， J=15.8 Hz). -CH -CH -CH, J = 15.8 Hz).
2 2 3 2 2 3
13C-NMR (100MHz, CDCl ) δ =13.8, 22.2, 25.5, 31.2, 32.8， 104.9, 110.5， 115.3, 13 C-NMR (100 MHz, CDCl) δ = 13.8, 22.2, 25.5, 31.2, 32.8, 104.9, 110.5, 115.3,
3 Three
121.1， 127.9, 134.9, 135.5, 142.6, 156.7， 160.2. 121.1, 127.9, 134.9, 135.5, 142.6, 156.7, 160.2.
(E)-3-(l-へキセニル) -2- (ヒドロキシメチノレ)フエノール（RKTS-102)の合成 アルゴン気流下、（E)-5-(l-へキセニル) -2,2-ジメチルベンゾ [1,3]ジォキシン- 4-ォ ン（ィ匕合物 6) 99. Omg (0.38mmol, leq)の THF溶液 (lml)に、氷冷下、 LiAlH 43.5mg Synthesis of (E) -3- (l-hexenyl) -2- (hydroxymethinole) phenol (RKTS-102) (E) -5- (l-Hexenyl) -2,2-dimethyl under a stream of argon Benzo [1,3] dioxin-4-one (diamide 6) 99. Omg (0.38 mmol, leq) in THF solution (1 ml) under ice-cooling, 43.5 mg of LiAlH
4 Four
(1.15mmol, 3eq)をカ卩え、室温に戻して 3時間撹拌した。氷冷し、 1N— HC1水溶液を加 え反応を停止させ、有機物をクロ口ホルムで 3回抽出し、合わせた有機層を飽和食塩 水で 3回洗浄した。無水硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧濃縮し、薄層 クロマトグラフィー（展開溶媒： hexane/ethyl acetate=l/l)で精製し、（E)- 3-ひ-へキセ 二ル)- 2 -(ヒドロキシメチル)フエノール（RKTS-102)を無色結晶として 65.4mg (83%)得 た。 (1.15 mmol, 3 eq) was recovered, returned to room temperature and stirred for 3 hours. After cooling on ice, the reaction was stopped by adding a 1N-HC1 aqueous solution, and the organic matter was extracted three times with chloroform. The combined organic layer was washed three times with saturated saline. After drying over anhydrous sodium sulfate and filtration, the solvent is concentrated under reduced pressure and purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = l / l) to give (E) -3-H-hexenyl). 65.4 mg (83%) of 2--2- (hydroxymethyl) phenol (RKTS-102) was obtained as colorless crystals.
Mp. 69.0-70.0°C Mp. 69.0-70.0 ° C
IR (neat) 3311， 2922, 2858, 2850, 1651, 1604, 970, 754, 723 cm— IR (neat) 3311, 2922, 2858, 2850, 1651, 1604, 970, 754, 723 cm—
'H NMR (400MHZ, CDCl ) δ =0.91 (3H， t,— CH二 CH—CH -CH— CH— CH* , J=7.2 'H NMR (400MHZ, CDCl) δ = 0.91 (3H, t, — CH2 CH—CH —CH— CH— CH *, J = 7.2
3 2 2 2 3 3 2 2 2 3
Hz), 1.37 (2H, sextet, _CH=CH_CH -CH - CH* - CH , J=7.7 Hz), 1.44 (2H,
quintet,— CH=CH— CH— CH* - CH— CH J=7.0 Hz), 2.03 (1H， t, alchol, J=5.7 Hz), Hz), 1.37 (2H, sextet, _CH = CH_CH -CH-CH *-CH, J = 7.7 Hz), 1.44 (2H, quintet, — CH = CH— CH— CH *-CH— CH J = 7.0 Hz), 2.03 (1H, t, alchol, J = 5.7 Hz),
2 2 2 3, 2 2 2 3,
2.19 (2H, dt, -CH=CH-CH* - CH - CH— CH J=7.0 Hz), 4.98 (2H, d, benzyl, J=5.7 2.19 (2H, dt, -CH = CH-CH *-CH-CH— CH J = 7.0 Hz), 4.98 (2H, d, benzyl, J = 5.7
2 2 2 3, 2 2 2 3,
Hz), 5.98 (1H， dt, - CH=CH*- CH— CH - CH - CH , J=7.0, 15.5 Hz), 6.49 (1H， dd, Hz), 5.98 (1H, dt,-CH = CH *-CH— CH-CH-CH, J = 7.0, 15.5 Hz), 6.49 (1H, dd,
2 2 2 3 2 2 2 3
-CH*=CH-CH -CH -CH— CH， J=15.5 Hz), 6.75 (1H， d, aromatic, J=8.1 Hz), 6.90 -CH * = CH-CH -CH -CH— CH, J = 15.5 Hz), 6.75 (1H, d, aromatic, J = 8.1 Hz), 6.90
2 2 2 3 2 2 2 3
(1H， d, aromatic, J=7.6 Hz), 7.11 (IH, t, aromatic, J=7.9 Hz), 7.40 (1H， s, phenol). (1H, d, aromatic, J = 7.6 Hz), 7.11 (IH, t, aromatic, J = 7.9 Hz), 7.40 (1H, s, phenol).
13C NMR (100MHz, CDC1 ) δ =13.9， 22.2, 31.4, 32.9, 59.8, 115.0， 118.8, 121.7, 1 3 C NMR (100MHz, CDC1 ) δ = 13.9, 22.2, 31.4, 32.9, 59.8, 115.0, 118.8, 121.7,
3 Three
126.4, 128.8, 134.9, 137.9, 156.0. 126.4, 128.8, 134.9, 137.9, 156.0.
HRMS (FAB) Found: m/z 206.1307 calcd for C H 〇： M,206.1313. HRMS (FAB) Found: m / z 206.1307 calcd for C H 〇: M, 206.1313.
13 18 2 13 18 2
[0061] 2- (ヒドロキシメチル) -3-ビュルフエノール (RKTS-103)の合成 [0061] Synthesis of 2- (hydroxymethyl) -3-bulphenol (RKTS-103)
化合物 3から RKTS-102の合成と同様の手順で合成した。 Compound 3 was synthesized from compound 3 in the same manner as in the synthesis of RKTS-102.
IR (neat) 3311， 3087, 3016， 2966, 1606, 1412, 989, 918， 748, 723 cm"1. JH-NMR (400MHz, CDC1 ) δ =2.28 (1H， broad, alcohol), 4.97 (2H, s， benzyl), IR (neat) 3311, 3087, 3016, 2966, 1606, 1412, 989, 918, 748, 723 cm " 1. JH-NMR (400MHz, CDC1) δ = 2.28 (1H, broad, alcohol), 4.97 (2H, s, benzyl),
3 Three
5.32 (IH, dd, - CH=CH* J=1.4, 17.3 Hz), 5.54 (IH, dd, - CH=CH* , J=1.4, 17.2 5.32 (IH, dd,-CH = CH * J = 1.4, 17.3 Hz), 5.54 (IH, dd,-CH = CH *, J = 1.4, 17.2
2, 2 twenty two
Hz), 6.80 (1H， d, aromatic, J=8.1 Hz), 6.86 (IH, dd, - CH*=CH , J=11.0, 17.3 Hz), Hz), 6.80 (1H, d, aromatic, J = 8.1 Hz), 6.86 (IH, dd,-CH * = CH, J = 11.0, 17.3 Hz),
2 Two
6.96 (IH, d, aromatic, J=7.6 Hz), 7.14 (1H， t, aromatic, J=7.9 Hz), 7.52 (1H， broad: phenol). 6.96 (IH, d, aromatic, J = 7.6 Hz), 7.14 (1H, t, aromatic, J = 7.9 Hz), 7.52 (1H, broad: phenol).
13C-NMR (100MHz, CDC1 ) δ =60.2, 116.1, 117.7, 118.7, 121.8， 129.0, 134.0, 13 C-NMR (100 MHz, CDC1) δ = 60.2, 116.1, 117.7, 118.7, 121.8, 129.0, 134.0,
3 Three
137.5, 156.4. 137.5, 156.4.
HRMS (EI) Found: m/z 150.0681 calcd for C H O： M, 150.0673. HRMS (EI) Found: m / z 150.0681 calcd for C H O: M, 150.0673.
9 10 2 9 10 2
[0062] (E)-2- (ヒドロキシメチル) -3-スチリルフエノール (RKTS-104)の合成 [0062] Synthesis of (E) -2- (hydroxymethyl) -3-styrylphenol (RKTS-104)
RKTS-102の合成と同様の手順で合成した。 It was synthesized by the same procedure as the synthesis of RKTS-102.
Mp. 120.0-121.0°C Mp. 120.0-121.0 ° C
IR (neat) 3398， 3149, 3023, 1599, 1502, 1039， 985, 746, 711 cm— IR (neat) 3398, 3149, 3023, 1599, 1502, 1039, 985, 746, 711 cm—
'H-NMR (400MHZ, CDCl ) δ =2.25 (1H， broad, alcohol), 5.05 (2H, s， benzyl), 'H-NMR (400MHZ, CDCl) δ = 2.25 (1H, broad, alcohol), 5.05 (2H, s, benzyl),
3 Three
6.82 (IH, d， aromatic, J=8.0 Hz), 6.89 (1H， d, _CH*=CH— Ph, J=16.0 Hz), 7.09 (1H， d, aromatic, J=7.5 Hz), 7.17 (IH, d, aromatic, J=7.8 Hz), 7.24 (2H, ddt, aromatic and— CH二 CH*— Ph, J=1.6, 7.0, 15.7 Hz), 7.35 (2H， t， aromatic, J=1.6, 7.8 Hz), 7.47 (3H， d, aromatic and phenol, J=3.8 Hz).
C-NMR (100MHz, CDC1 ) δ =60.3, 116.0, 118.7, 122.2, 125.5， 126.6, 127.9， 6.82 (IH, d, aromatic, J = 8.0 Hz), 6.89 (1H, d, _CH * = CH—Ph, J = 16.0 Hz), 7.09 (1H, d, aromatic, J = 7.5 Hz), 7.17 (IH , d, aromatic, J = 7.8 Hz), 7.24 (2H, ddt, aromatic and— CH2CH * —Ph, J = 1.6, 7.0, 15.7 Hz), 7.35 (2H, t, aromatic, J = 1.6, 7.8 Hz), 7.47 (3H, d, aromatic and phenol, J = 3.8 Hz). C-NMR (100MHz, CDC1) δ = 60.3, 116.0, 118.7, 122.2, 125.5, 126.6, 127.9,
3 Three
128.7， 129.1, 132.4, 137.1, 137.2, 156.6. 128.7, 129.1, 132.4, 137.1, 137.2, 156.6.
HRMS (FAB) Found: m/z 226.0994 calcd for C H O： M,226.1022. HRMS (FAB) Found: m / z 226.0994 calcd for C H O: M, 226.1022.
15 14 2 15 14 2
[0063] 5-へキシル -2,2 -ジメチルベンゾ [1，3]ジォキシン- 4_オン（化合物 7)の合成 [0063] Synthesis of 5-hexyl-2,2-dimethylbenzo [1,3] dioxin-4-one (compound 7)
(E)_5_(l -へキセニル -2，2-ジメチルベンゾ [1,3]ジォキシン- 4-オン（ィ匕合物 6) 20.6mg (0.079mmol, leq)のメタノール溶液（300ml)に、 5%Pd/Cを 16.9mg (O. leq)加 え、水素雰囲気下 15分間反応を行った。セライトろ過により Pd/Cを除き、ろ液の溶媒 を減圧濃縮し、薄層クロマトグラフィー（展開溶媒;へキサン:酢酸ェチル = 3 : 1)で精 製して、 5-へキシル -2, 2 -ジメチルベンゾ [1，3]ジォキシン- 4_オン（ィ匕合物 7)を無色油 状物質として 11.2mg (42%)得た。 (E) _5_ (l-Hexenyl-2,2-dimethylbenzo [1,3] dioxin-4-one (di-conjugate 6) 20.6 mg (0.079 mmol, leq) in methanol (300 ml) After adding 16.9 mg (O. leq) of% Pd / C and reacting under a hydrogen atmosphere for 15 minutes, Pd / C was removed by celite filtration, the solvent of the filtrate was concentrated under reduced pressure, and thin layer chromatography (developing solvent). Hexane: ethyl acetate = 3: 1) to give 5-hexyl-2,2-dimethylbenzo [1,3] dioxin-4_one (colored compound 7) as a colorless oil 11.2 mg (42%).
IR (neat) 2956, 2929, 2858, 1739, 1167, 1147, 777, 726 cm"1. IR (neat) 2956, 2929, 2858, 1739, 1167, 1147, 777, 726 cm " 1 .
JH-NMR (400MHz, CDC1 ) δ =0.86 (3H， t, _CH— CH— CH _CH— CH _CH* JH-NMR (400MHz, CDC1) δ = 0.86 (3H, t, _CH— CH— CH _CH— CH _CH *
3 2 2 2 2 2 3, 3 2 2 2 2 2 3,
J=6.9 Hz), 1.21-1.42 (6H， m, - CH— CH - CH* - CH* - CH*— CH ), 1.57 (2H, J = 6.9 Hz), 1.21-1.42 (6H, m,-CH— CH-CH *-CH *-CH * —CH), 1.57 (2H,
2 2 2 2 2 3 2 2 2 2 2 3
quintet, - CH - CH* - CH— CH - CH - CH , J=4.6 Hz), 1.67 (6H, - C(CH* ) ), 3.07 quintet,-CH-CH *-CH— CH-CH-CH, J = 4.6 Hz), 1.67 (6H,-C (CH *)), 3.07
2 2 2 2 2 3 3 2 2 2 2 2 2 3 3 2
(2H， t, - CH* - CH— CH - CH— CH— CH J=7.9 Hz), 6.77 (1H, d, aromatic, J=8.2 (2H, t,-CH *-CH— CH-CH— CH— CH J = 7.9 Hz), 6.77 (1H, d, aromatic, J = 8.2
2 2 2 2 2 3, 2 2 2 2 2 3,
Hz), 6.91 (1H， d, aromatic, J=7.7 Hz), 7.37(1H, t, aromatic, J=7.9 Hz). Hz), 6.91 (1H, d, aromatic, J = 7.7 Hz), 7.37 (1H, t, aromatic, J = 7.9 Hz).
[0064] 3-へキシル -2- (ヒドロキシメチル)フエノール (RKTS-105)の合成 Synthesis of 3-hexyl-2- (hydroxymethyl) phenol (RKTS-105)
アルゴン気流下、 5-へキシル -2, 2-ジメチルベンゾ [1,3]ジォキシン- 4-オン（化合物 7) 11.2mg(0.043mmol, leq)の THF溶液 (300ml)に、氷冷下、 LiAlH 5.5mg Under a stream of argon, a solution of 11.2 mg (0.043 mmol, leq) of 5-hexyl-2,2-dimethylbenzo [1,3] dioxin-4-one (compound 7) in THF (300 ml) was added with LiAlH 5.5mg
4 Four
(0.171mmol, 4eq)を加え、室温に戻して 1時間撹拌した。再び氷冷し、 1N—HC1水溶 液を加えて反応を終了させ、有機物をクロ口ホルムで 3回抽出し、合わせた有機層を 緩衝液、飽和食塩水でそれぞれ 3回洗浄した。無水硫酸ナトリウムで乾燥させ、ろ過 後、溶媒を減圧濃縮し、シリカゲルカラムクロマトグラフィー (展開溶媒:へキサン/酢 酸ェチル = 10/1)で精製し、 3-へキシル -2- (ヒドロキシメチル)フヱノール (RKTS-105) を無色固体として 7.8mg得た (79%)。 (0.171 mmol, 4 eq), and the mixture was returned to room temperature and stirred for 1 hour. The mixture was ice-cooled again, the reaction was terminated by the addition of a 1N-HC1 aqueous solution, and the organic matter was extracted three times with a chloroform form. After drying over anhydrous sodium sulfate and filtration, the solvent is concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to give 3-hexyl-2- (hydroxymethyl). 7.8 mg (79%) of phenol (RKTS-105) was obtained as a colorless solid.
IR (neat) 3320, 2927, 2856, 1466, 1186, 752, 725 cm-1. IR (neat) 3320, 2927, 2856, 1466, 1186, 752, 725 cm -1 .
'H-NMR (400MHZ, CDCl ) δ =0.87 (3H， t, -CH— CH— CH -CH— CH -CH* 'H-NMR (400MHZ, CDCl) δ = 0.87 (3H, t, -CH— CH— CH -CH— CH -CH *
3 2 2 2 2 2 3, 3 2 2 2 2 2 3,
J=6.6 Hz), 1.24-1.36 (6H， m, -CH - CH -CH* -CH* - CH* - CH ), 1.48 (2H,
quintet, - CH - CH* - CH— CH - CH - CH , J=7.7 Hz), 2.19 (1H, broad, alcohol),J = 6.6 Hz), 1.24-1.36 (6H, m, -CH-CH -CH * -CH *-CH *-CH), 1.48 (2H, quintet,-CH-CH *-CH— CH-CH-CH, J = 7.7 Hz), 2.19 (1H, broad, alcohol),
2 2 2 2 2 3 2 2 2 2 2 3
2.55 (2H, t, -CH* - CH - CH— CH - CH— CH J=7.7 Hz), 4.92 (2H, s, benzyl), 6.68 2.55 (2H, t, -CH *-CH-CH— CH-CH— CH J = 7.7 Hz), 4.92 (2H, s, benzyl), 6.68
2 2 2 2 2 3, 2 2 2 2 2 3,
(1H， d, aromatic, J=7.6 Hz), 6.72 (1H, d, aromatic, J=8.0 Hz), 7.08 (1H, dd, aromatic, J=7.6, 8.0 Hz), 7.42 (1H， broad, phenol). (1H, d, aromatic, J = 7.6 Hz), 6.72 (1H, d, aromatic, J = 8.0 Hz), 7.08 (1H, dd, aromatic, J = 7.6, 8.0 Hz), 7.42 (1H, broad, phenol ).
13C-NMR (100MHz, CDC1 ) δ =14.0, 22.6, 29.2, 31.7, 31.7, 33.3, 60.2, 114.5, 1 3 C-NMR (100 MHz, CDC1) δ = 14.0, 22.6, 29.2, 31.7, 31.7, 33.3, 60.2, 114.5,
3 Three
121.5, 122.6, 128.9, 141.2, 156.7. 121.5, 122.6, 128.9, 141.2, 156.7.
HRMS (FAB) Found: m/z 208.1463 calcd for C H 〇： M,208.1489. HRMS (FAB) Found: m / z 208.1463 calcd for C H 〇: M, 208.1489.
13 20 2 13 20 2
[0065] 2- (ヒドロキシメチル) -3-[(E)-l-メチル -1-プロべニル]フエノール (RKTS-106)の合成 化合物 3から RKTS-102を合成したのと同様の手順で調製した。 Synthesis of 2- (hydroxymethyl) -3-[(E) -1-methyl-1-probenyl] phenol (RKTS-106) A procedure similar to that for synthesizing RKTS-102 from compound 3 was used. Prepared.
Mp. 85.8— 86.8。C Mp. 85.8—86.8. C
IR (neat) 3354, 3039, 2981, 2883, 1664, 1604, 1454, 1379， 1205, 1024, 974, 742, 690 cm"1. IR (neat) 3354, 3039, 2981, 2883, 1664, 1604, 1454, 1379, 1205, 1024, 974, 742, 690 cm " 1 .
JH-NMR (400MHz, CDC1 ) δ =1.72 (3H， d, - C(CH )=CH- CH*， J=6.0 Hz), 1.87 J H-NMR (400MHz, CDC1) δ = 1.72 (3H, d, -C (CH) = CH-CH *, J = 6.0Hz), 1.87
3 3 3 3 3 3
(3H， d, - C(CH* )=CH-CH， J=l. l Hz), 2.41 (1H, s, alcohol), 4.83 (2H， s, benzyl), (3H, d,-C (CH *) = CH-CH, J = l. L Hz), 2.41 (1H, s, alcohol), 4.83 (2H, s, benzyl),
3 3 3 3
5.26-5.32 (1H， m, - C(CH )=CH*_CH，)， 6.63 (1H, d, aromatic, J=7.7 Hz), 6.74 5.26-5.32 (1H, m, -C (CH) = CH * _CH,), 6.63 (1H, d, aromatic, J = 7.7 Hz), 6.74
3 3 3 3
(1H， d, aromatic, J=4.0 Hz), 7.09 (1H, t, J=7.8 Hz), 7.59 (1H， s, phenol). (1H, d, aromatic, J = 4.0 Hz), 7.09 (1H, t, J = 7.8 Hz), 7.59 (1H, s, phenol).
13C NMR (100MHz, CDC1 ) δ =14.2, 18.9, 61.8， 115.2, 120.8, 122.2, 124.9,129.1, 1 3 C NMR (100 MHz, CDC1) δ = 14.2, 18.9, 61.8, 115.2, 120.8, 122.2, 124.9, 129.1,
3 Three
135.6, 146.3, 156.9. 135.6, 146.3, 156.9.
HRMS (EI) Found: m/z 178.0994 calcd for C H O： M， 178.0977. HRMS (EI) Found: m / z 178.0994 calcd for CHO: M, 178.0977.
11 14 2 11 14 2
[0066] <試験例 > [0066] <Test Example>
試験例 1 Test example 1
本発明に係る化合物による成熟脂肪細胞におけるインスリン作用増強活性作用 マウス前脂肪細胞 3T3-L1を、 10%ゥシ胎児血清 (FBS)を含有する DMEM培地で培 養維持した。 12ゥヱルプラスチックプレートに 5xl05cells/mlとなるように 3T3-L1細胞を まき、 3日間培養し (37 °C、 5% CO )、接触阻害により GO期に同調させた。次に、培地 Insulin Action Enhancing Activity of Mature Adipocytes by the Compound of the Present Invention 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
2 Two
をリン酸緩衝液で洗浄後、 10%FBS_DMEM培地に交換し、 500 μ M 3_イソブチル _1_ メチルキサンチン (ΙΒΜΧ)、 1 μ Μデキサメタゾン、 1 μ g/mlのインスリンを添加した。こ れを分化誘導培地として 2日間培養した。その後、培地を除去し、リン酸緩衝液で洗
浄後、 5日間培養成熟した脂肪細胞へ分化させた。 After washing with a phosphate buffer, the medium was replaced with a 10% FBS_DMEM medium, and 500 μM 3_isobutyl_1_methylxanthine (ΙΒΜΧ), 1 μΜ dexamethasone, and 1 μg / 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.
[0067] 成熟した脂肪細胞に一連の希釈系列（0 3 10 30 ΙΟΟ μ Μ)の RKTS-101また は RKTS-102を添加し、 1時間培養後に、 ΙΟηΜのインスリンを添加した。 4時間後に各 細胞を可溶化し、 SDS (ラウリル硫酸ナトリウム) -ポリアクリルアミド電気泳動後、抗ホス ホチロシン抗体（UPSTATE社製）を用いたウェスタンブロッテイング法により細胞内チ 口シンリン酸化の度合いを検出した。 [0067] RKTS-101 or RKTS-102 in a series of dilution series (0.31030 µm) was added to mature adipocytes, and after 1 hour of culture, {η} 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.
[0068] その結果、 RKTS-101, RKTS-102は、それぞれ 3-100 μ g/mlの濃度域で、成熟化 した 3T3-L1細胞においてインスリンによる細胞内チロシンリン酸化の亢進を顕著に誘 導することが明らかになった (表 1)。このことは、本発明化合物が、インスリン作用増強 活性を有し、糖尿病、肥満症の予防薬 ·治療薬などとして有用であることを示している [0068] As a result, 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 µg / 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.
[0069] [表 1] 表 1 [0069] [Table 1] Table 1
本発明化合物のィンスリン作用増強活性 a) Insulin action enhancing activity of the compound of the present invention a)
a)細胞内チロシンリン酸化の度合いを 3段階に分類し、 インスリン単独刺激での細胞内チ 口シンリン酸化の度合いを（+〉、インスリン単独刺激での細胞內チロシンリン酸化の度合い に対して 2倍程度の亢進を（++)、 インスリン単独刺激での細胞内チロシンリン酸化の度合 いに対して 2倍以上の亢進を（+++)で表した。 a ) 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.
[0070] 試験例 2 [0070] Test example 2
本発明化合物によるラット褐色腫細胞 PC12における NGF効果増強作用 NGF effect enhancing effect on rat pheochromocytoma cells PC12 by the compound of the present invention
ラット褐色腫細胞は、 5%ゥシ胎児血清 (FBS)および 5%牛血清 (CS)を含有する DMEM 培地で維持した。 24ゥエルプラスチックプレートに 3xl04cells/500 μ 1となるように PC12 細胞をまき、ー晚培養した（37 °C 5% CO )。その後、一連の希釈系列の RKTS-101, 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 μ 1 seeded PC12 cells were over晚cultured (37 ° C 5% CO) . Then a series of dilution series RKTS-101,
2 Two
RKTS-102を添カ卩し 1時間培養後に 0.3 ng/mlの NGFを添カ卩し 48時間培養後、顕微鏡 下、神経樹状突起の伸張作用を検討した。
[0071] その結果、 RKTS-101, RKTS-102は、それぞれ 3-100 μ g/mlの濃度域で NGFによる 神経樹状突起の伸展を顕著に促進することが明らかとなった。 （表 2)。このことは、本 発明化合物が、 NGF作用増強活性を有し、神経損傷、神経症などの予防薬'治療薬 などとして有用であることを示している。 After adding RKTS-102 and culturing for 1 hour, adding 0.3 ng / ml NGF and culturing for 48 hours, the elongation effect of the neural dendrites was examined under a microscope. [0071] As a result, it was revealed that RKTS-101 and RKTS-102 significantly promote NGF-induced dendritic outgrowth in the concentration range of 3 to 100 µg / ml, respectively. (Table 2). This indicates that the compound of the present invention has NGF action-enhancing activity and is useful as a preventive or therapeutic agent for nerve damage, neurosis and the like.
[0072] [表 2] 表 2 . [Table 2] Table 2.
本発明化合物の NGF作用增強活性 a) NGF action of compound of the present invention 增 Strong activity a)
a)顕微鏡観察結果を細胞の突起長で 4段階に分類し、 細胞体の直径以内の突起を有するも の（+)、 10- 30%の細胞で細胞体の直径以上の長さの突起を有するものを（++)、 30- 60 の細胞 で細胞体の直径以上の長さの突起を有するものを（+++)、 60%以上の細胞で細胞体の直径以 上の長さの突起を有するものを（++++)で表した。 a ) Microscopic observation results are classified into four stages according to the cell projection length, and those with projections within the cell body diameter (+) and projections longer than the cell body diameter in 10-30% of cells (++), 30-60 cells with protrusions longer than the cell body diameter (+++), 60% or more cells with a protrusion longer than the cell body diameter. Those having protrusions are represented by (++++).
[0073] 製剤例 1 :注射 ·点滴剤 Formulation Example 1: Injection · Infusion
本発明に係る任意の化合物 10 mgを含有するように、粉末ブドウ糖 5 gを加えて、バ ィアルに無菌的に分配して密封し、窒素、ヘリウムなどの不活性ガスを封入して冷喑 所に保存した。使用前にエタノールに溶解し、 0.85 %生理的食塩水 100 mlを添加し て静脈内注射剤とした。一日あたり 10— 100 mlを症状に応じて静脈内注射または点 滴で投与することができる。 5 g of powdered glucose is added so as to contain 10 mg of an arbitrary compound according to the present invention, and the vial is aseptically distributed and sealed, and an inert gas such as nitrogen or helium is sealed therein and cooled. Saved. Before use, it was dissolved in ethanol, and 100 ml of 0.85% physiological saline was added to prepare an intravenous injection. 10-100 ml per day can be administered by intravenous injection or infusion depending on the condition.
[0074] 製剤例 2 :顆粒剤 Formulation Example 2: Granules
任意の本発明に係る化合物 1 g、乳糖 98 g、およびヒドロキシプロピルセルロース 1 gをそれぞれ取り、よく混和した後、定法にしたがって粒状に成形し、それをよく乾燥し て、瓶やヒートシール包装などに適した顆粒剤を製造した。一日あたり 100— 1000 mg を症状に応じて経口投与できる。 Take 1 g of the compound of the present invention, 98 g of lactose, and 1 g of hydroxypropylcellulose, mix well, form into granules according to a standard method, dry well, and use in bottles, heat-sealed packaging, etc. A granule suitable for was prepared. 100 to 1000 mg per day can be administered orally depending on the symptoms.
産業上の利用可能性 Industrial applicability
[0075] 本発明により、新規な 3置換ベンゼン誘導体を提供することができる。さらに、本発 明に係る好ましいィ匕合物は、培養細胞レベルにおいてタンパク質チロシンリン酸化レ ベルを亢進させる効果を示す。従って、本発明に係る化合物を含む好ましい組成物
は、糖尿病、肥満症、神経損傷、アルツハイマー病、パーキンソン病等を含む神経症 の予防および治療薬に有用である。
According to the present invention, a novel trisubstituted benzene derivative can be provided. Further, the preferred conjugate according to the present invention has an effect of enhancing the protein tyrosine phosphorylation level at the cultured cell level. Thus, 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.
Claims
請求の範囲 The scope of the claims
下記一般式 (I)または (π) The following general formula (I) or (π)
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミノレ基、カルボキシル基、 -CH -〇(C=0)R7 (R7はァノレキノレ基、ァリーノレ基、 R 2 is a honoleminole group, a carboxyl group, -CH -〇 (C = 0) R 7 (R 7 is an anolequinole group, an arylene group,
2 Two
またはアルキルアミノ基を表す)、 -CH 0_R8(R8は水素原子、アルキル基、またはァノレ Or represents an alkylamino group), -CH 0_R 8 (R 8 is a hydrogen atom, an alkyl group,
2 Two
ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ルキルォキシカルボニルアルキル基を表す)を示し、 A phenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl group, a formyl group) Or represents an alkyloxycarbonylalkyl group).
R1と R2が連結されることにより環化してレ、てもよく、 R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基ま たはヒドロキシ基を示し、 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,
R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピル 基もしくは炭素数 4以上を有するアルキル基、またはァリール基を示す） 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)
で表される化合物（但し、一般式 (I)において、 R3が水素であり、 R4/R5が水素原子/メ チル基またはメチル基/水素原子であり、かつ OR1基/ R2基の置換位置がベンゼン環 上の 3位 /2位である化合物、および一般式 (I)において R4もしくは R5の一方がプロピル 基である化合物を除く）、その幾何異性体もしくは光学活性体、それらの製薬上許容 される塩、またはそれらの水和物。
[2] R1が水素原子であることを特徴とする、請求項 1に記載の化合物、その幾何異性体 もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物。 (Wherein, in the general formula (I), R 3 is hydrogen, R 4 / R 5 is hydrogen atom / methyl group or methyl group / hydrogen atom, and OR 1 group / R 2 Excluding compounds in which the substitution position of the group is the 3- or 2-position on the benzene ring, and compounds in which either R 4 or R 5 in formula (I) is a propyl group), its geometric isomer or optically active isomer , Their pharmaceutically acceptable salts, or their hydrates. [2] The compound according to claim 1, wherein R 1 is a hydrogen atom, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
[3] R2がヒドロキシメチル基であることを特徴とする、請求項 1または 2に記載の化合物、 その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれらの 水和物。 [3] The compound according to claim 1 or 2, wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydration thereof. object.
[4] OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特徴と する、請求項 1一 3のいずれか一項に記載の化合物、その幾何異性体もしくは光学 活性体、それらの製薬上許容される塩、またはそれらの水和物。 [4] The compound according to any one of claims 13 to 13, wherein OR 1 is located at the 3-position on the benzene ring, and R 2 is located at the 2-position on the benzene ring. Isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof.
[5] 3-(1_へキセニル)- 2 -(ヒドロキシメチル)フエノール、 2 -(ヒドロキシメチル )_3 -ビュルフ エノーノレ、 2- (ヒドロキシメチル) -3-スチリルフエノール、 3-へキシル -2- (ヒドロキシメチ ル)フエノール、 2 -(ヒドロキシメチル )_3_(1-メチル -1-プロぺニル)フエノールであること を特徴とする、請求項 1一 4のいずれか一項に記載の化合物、その幾何異性体もしく は光学活性体、それらの製薬上許容される塩、またはそれらの水和物。 [5] 3- (1_Hexenyl) -2- (hydroxymethyl) phenol, 2- (hydroxymethyl) _3-Burf enolole, 2- (hydroxymethyl) -3-styrylphenol, 3-hexyl-2- The compound according to claim 14, wherein the compound is (hydroxymethyl) phenol, 2- (hydroxymethyl) _3_ (1-methyl-1-propenyl) phenol. Geometric isomers or optically active isomers, pharmaceutically acceptable salts thereof, or hydrates thereof.
[6] 下記一般式 (III)で表される化合物および (IV)で表される化合物をカップリング反応さ せるステップを含むことを特徴とする、下記一般式 (I)で表される化合物の製造方法。 [6] A method of coupling a compound represented by the following general formula (III) and a compound represented by the following formula (IV): Production method.
[化 2] [Formula 2]
(式中 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミノレ基、カルボキシル基、 -CH -0(C=0)R? (R7はァノレキノレ基、ァリール基、 R 2 is a honoleminole group, a carboxyl group, -CH-0 (C = 0) R ? (R 7 is an anolequinole group, an aryl group,
2 Two
またはアルキルアミノ基を表す)、 -CH 0_R8(R8は水素原子、アルキル基、またはアル Or represents an alkylamino group), -CH 0_R 8 (R 8 is a hydrogen atom, an alkyl group, or an
2 Two
ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、
-CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ルキルォキシカルボニルアルキル基を表す)を示し、 A phenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl group, a formyl group, or an alkyloxycarbonylalkyl group),
R1と R2が連結されることにより環化してレ、てもよく、 R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリーノレ基、アミノ基ま たはヒドロキシ基を示し、 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,
R4, R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピノレ 基、もしくは炭素数 4以上を有するアルキル基、またはァリール基を示し、 R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyline group, an alkyl group having 4 or more carbon atoms, or an aryl group;
Lはスルホネート基またはハロゲン原子を示し、 L represents a sulfonate group or a halogen atom,
Xは B(ORu) (R11は水素またはアルキル基を表す)または Sn(R12) (R12はアルキル基を 表す)を示す。 ) X represents a B (OR u) (R 11 represents hydrogen or an alkyl group) or Sn (R 12) (R 12 represents an alkyl group). )
下記一般式 (I)で表される化合物を水素添加反応させることを特徴とする、下記一 般式 (Π)で表される化合物を製造する方法。 A method for producing a compound represented by the following general formula (II), comprising subjecting a compound represented by the following general formula (I) to a hydrogenation reaction.
[化 3] [Formula 3]
(式中、 R1は水素原子、アルキル基、アルケニル基、または- C(=0)_R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) _R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミル基、カルボキシル基、 -CH - 0(C=0)R7 (R7はアルキル基、ァリーノレ基、 またはアルキルアミノ基を表す)、 -CH 0_R8(R8は水素原子、アルキル基、またはァノレ ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ルキルォキシカルボニルアルキル基を表す)を示し、
R1と R2が連結されることにより環化してレ、てもよく、 R 2 is a honolemil group, a carboxyl group, -CH-0 (C = 0) R 7 (R 7 represents an alkyl group, aryl group, or alkylamino group), -CH 0_R 8 (R 8 is a hydrogen atom, alkyl , Or an anolycenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl Group, formyl group, or alkyloxycarbonylalkyl group). R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基ま たはヒドロキシ基を示し、 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,
R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピノレ 基、もしくは炭素数 4以上を有するアルキル基、またはァリール基を示す。） R 4 and R 5 each independently represent a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropylinole group, an alkyl group having 4 or more carbon atoms, or an aryl group. )
[8] 請求項 1一 5のいずれか一項に記載の化合物、その幾何異性体もしくは光学活性 体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2以 上を含む医薬組成物。 [8] One or more of the compound according to any one of claims 115, a geometric isomer or an optically active isomer, a pharmaceutically acceptable salt thereof, or a hydrate thereof. A pharmaceutical composition comprising the above.
[9] 糖尿病、肥満症、神経損傷、もしくは神経症の予防薬もしくは治療薬、またはタンパ ク質チ口シンリン酸化亢進剤であることを特徴とする、請求項 8に記載の医薬組成物 [9] The pharmaceutical composition according to claim 8, which is a preventive or therapeutic agent for diabetes, obesity, nerve damage, or neurosis, or a protein ostium synphosphorylation enhancer.
[10] 下記一般式 (I)または (Π) [10] The following general formula (I) or (Π)
[化 4] [Formula 4]
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミル基、カルボキシル基、 -CH - 0(C=0)R7 (R7はアルキル基、ァリーノレ基、 R 2 is a honolemil group, a carboxyl group, -CH-0 (C = 0) R 7 (R 7 is an alkyl group, an arylene group,
2 Two
またはアルキルアミノ基を表す)、 -CH 0- R8(R8は水素原子、アルキル基、またはァノレ Or an alkylamino group), -CH 0- R 8 (R 8 is a hydrogen atom, an alkyl group or Anore,
2 Two
ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ルキルォキシカルボニルアルキル基を表す)を示し、
R1と R2が連結されることにより環化してレ、てもよく、 A phenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl group, a formyl group) Or represents an alkyloxycarbonylalkyl group). R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリール基、アミノ基ま たはヒドロキシ基を示し、 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,
R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピノレ 基、もしくは炭素数 4以上を有するアルキル基、またはァリール基を示す） 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)
で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許容され る塩、またはそれらの水和物のいずれかの 1または 2以上を含む、糖尿病、肥満症の 予防薬、または治療薬。 Or 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.
[11] R1が水素原子であることを特徴とする、請求項 10に記載の化合物、その幾何異性 体もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいず れかの 1または 2以上を含む、糖尿病、肥満症の予防薬、または治療薬。 [11] The compound according to claim 10, wherein 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 drug for diabetes or obesity, including one or more of the above.
[12] R2がヒドロキシメチル基であることを特徴とする、請求項 10または 11に記載の化合 物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、糖尿病、肥満症の予防薬、または治 療薬。 [12] The compound according to claim 10 or 11, wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A preventive or remedy for diabetes, obesity, including one or more of the hydrates.
[13] OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特徴と する、請求項 10— 12のいずれか一項に記載の化合物、その幾何異性体もしくは光 学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1また は 2以上を含む、糖尿病、肥満症の予防薬、または治療薬。 [13] The compound according to any one of claims 10 to 12, wherein OR 1 is at the 3-position on the benzene ring, and R 2 is at the 2-position on the benzene ring, and the geometry thereof. A preventive or therapeutic agent for diabetes or obesity, which comprises one or more of any of the isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof.
[14] 2- (ヒドロキシメチル) -3-(1-プロぺニル)フエノール、 3-(1-へキセニル) -2- (ヒドロキシ メチノレ)フエノール、 2- (ヒドロキシメチル) -3-ビニルフエノール、 2- (ヒドロキシメチル )-3-スチリルフエノール、 3-へキシル _2 -(ヒドロキシメチル)フエノール、または 2- (ヒドロ キシメチル) _3_(1_メチル _1_プロぺニル)フエノール、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含むことを特徴とする、請求項 10— 13のいずれか一項に記載の糖尿病、肥 満症の予防薬、または治療薬。 [14] 2- (hydroxymethyl) -3- (1-propenyl) phenol, 3- (1-hexenyl) -2- (hydroxymethinole) phenol, 2- (hydroxymethyl) -3-vinylphenol, 2- (hydroxymethyl) -3-styrylphenol, 3-hexyl_2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) _3_ (1_methyl_1_propenyl) phenol, geometric isomers or optical The diabetes according to any one of claims 10 to 13, which comprises one or more of the active substance, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Prophylactic or therapeutic drug for hypertension.
[15] 下記一般式 (I)または (Π) [15] The following general formula (I) or (Π)
[化 5]
[Formula 5]
(式中、 R1は水素原子、アルキル基、アルケニル基、または- C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or -C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミル基、カルボキシル基、 -CH - 0(C=0)R7 (R7はアルキル基、ァリーノレ基、 R 2 is a honolemil group, a carboxyl group, -CH-0 (C = 0) R 7 (R 7 is an alkyl group, an arylene group,
2 Two
またはアルキルアミノ基を表す)、 -CH 0- R8(R8は水素原子、アルキル基、またはァノレ Or an alkylamino group), -CH 0- R 8 (R 8 is a hydrogen atom, an alkyl group or Anore,
2 Two
ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ノレキルォキシカルボニルアルキル基を表す)を示し、 A phenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl group, a formyl group) Or represents an anoalkyloxycarbonylalkyl group)
R1と R2が連結されることにより環化してレ、てもよく、 R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリーノレ基、アミノ基ま たはヒドロキシ基を示し、 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,
R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピノレ 基、もしくは炭素数 4以上を有するアルキル基、またはァリール基を示す） 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)
で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許容され る塩、またはそれらの水和物のいずれかの 1または 2以上を含む、神経損傷、または 神経症の予防薬、または治療薬。 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.
[16] R1が水素原子であることを特徴とする、請求項 15に記載の化合物、その幾何異性 体もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいず れかの 1または 2以上を含む、神経損傷、または神経症の予防薬、または治療薬。 [16] The compound according to claim 15, wherein 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 them.
[17] R2がヒドロキシメチル基であることを特徴とする、請求項 15または 16に記載の化合
物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、神経損傷、または神経症の予防薬、 または治療薬。 [17] The compound according to claim 15 or 16, wherein R 2 is a hydroxymethyl group. Prophylactic or therapeutic agent for nerve damage or neuropathy, which contains one or more of any of the following substances, its geometric isomers or optically active isomers, pharmaceutically acceptable salts thereof, or hydrates thereof: medicine.
[18] OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特徴と する、請求項 15— 17のいずれか一項に記載の化合物、その幾何異性体もしくは光 学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1また は 2以上を含む、神経損傷、または神経症の予防薬、または治療薬。 [18] The compound according to any one of claims 15 to 17, wherein OR 1 is at the 3-position on the benzene ring, and R 2 is at the 2-position on the benzene ring, and the geometry thereof. A preventive or therapeutic agent for nerve damage or neurosis, comprising one or more of any of the isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof.
[19] 2- (ヒドロキシメチル) -3-(1_プロぺニル)フエノール、 3-(1_へキセニル)- 2 -(ヒドロキシ メチノレ)フエノール、 2 -(ヒドロキシメチル )_3 -ビュルフエノール、 2- (ヒドロキシメチル )-3-スチリルフエノール、 3-へキシル _2 -(ヒドロキシメチル)フエノール、または 2- (ヒドロ キシメチル) _3_(1_メチル _1_プロぺニル)フエノール、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含むことを特徴とする、請求項 15— 18のいずれか一項に記載の神経損傷、 または神経症の予防薬、または治療薬。 [19] 2- (hydroxymethyl) -3- (1_propenyl) phenol, 3- (1_hexenyl) -2- (hydroxymethinole) phenol, 2- (hydroxymethyl) _3-bulfenol, 2 -(Hydroxymethyl) -3-styrylphenol, 3-hexyl_2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) _3_ (1_methyl_1_propenyl) phenol, its geometric isomer or optical activity Nerve damage according to any one of claims 15 to 18, characterized in that it comprises one or more of any of the following: a body, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Or prophylactic or therapeutic drugs for neurosis.
[20] 下記一般式 (I)または (Π) [20] The following general formula (I) or (Π)
[化 6] [Formula 6]
(式中、 R1は水素原子、アルキル基、アルケニル基、または _C(=0)-R6 (R6はアルキル 基、ァリール基、またはアルキルアミノ基を表す)を示し、 (Wherein, R 1 represents a hydrogen atom, an alkyl group, an alkenyl group, or _C (= 0) -R 6 (R 6 represents an alkyl group, an aryl group, or an alkylamino group),
R2はホノレミノレ基、カルボキシル基、 -CH -〇(C=0)R7 (R7はァノレキノレ基、ァリーノレ基、 R 2 is a honoleminole group, a carboxyl group, -CH -〇 (C = 0) R 7 (R 7 is an anolequinole group, an arylene group,
2 Two
またはアルキルアミノ基を表す)、 -CH 0_R8(R8は水素原子、アルキル基、またはアル
ケニル基を表す)、 -CH=N-OR9 (R9は水素原子またはアルキル基を表す)、または、 -CH=CH-R1Q(R1Qはアルキル基、アルキルォキシカルボニル基、ホルミル基、またはァ ルキルォキシカルボニルアルキル基を表す)を示し、 Or represents an alkylamino group), -CH 0_R 8 (R 8 is a hydrogen atom, an alkyl group, or an A phenyl group), -CH = N-OR 9 (R 9 represents a hydrogen atom or an alkyl group), or -CH = CH-R 1Q (R 1Q represents an alkyl group, an alkyloxycarbonyl group, a formyl group) Or represents an alkyloxycarbonylalkyl group).
R1と R2が連結されることにより環化してレ、てもよく、 R 1 and R 2 may be cyclized by being linked,
R3は水素原子、ハロゲン原子、アルキル基、アルコキシ基、ァリーノレ基、アミノ基ま たはヒドロキシ基を示し、 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,
R4、 R5はそれぞれ独立に水素原子、メチル基、ェチル基、プロピル基、イソプロピノレ 基、もしくは炭素数 4以上を有するアルキル基、またはァリール基を示す） 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)
で表される化合物、その幾何異性体もしくは光学活性体、それらの製薬上許容され る塩、またはそれらの水和物のいずれかの 1または 2以上を含む、タンパク質チロシン リン酸化亢進剤。 Or a geometric isomer or optically active form thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising a protein tyrosine phosphorylation enhancer.
[21] R1が水素原子であることを特徴とする、請求項 20に記載の化合物、その幾何異性 体もしくは光学活性体、それらの製薬上許容される塩、またはそれらの水和物のいず れかの 1または 2以上を含む、タンパク質チロシンリン酸化亢進剤。 [21] The compound according to claim 20, wherein 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 protein tyrosine phosphorylation enhancer, comprising one or more of them.
[22] R2がヒドロキシメチル基であることを特徴とする、請求項 20または 21に記載の化合 物、その幾何異性体もしくは光学活性体、それらの製薬上許容される塩、またはそれ らの水和物のいずれかの 1または 2以上を含む、タンパク質チロシンリン酸化亢進剤 [22] The compound according to claim 20 or 21, wherein R 2 is a hydroxymethyl group, a geometric isomer or an optically active form thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A protein tyrosine phosphorylation enhancer containing one or more of hydrates
[23] OR1がベンゼン環上の 3位にあり、かつ R2がベンゼン環上の 2位にあることを特徴と する、請求項 20— 22のいずれか一項に記載の化合物、その幾何異性体もしくは光 学活性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1また は 2以上を含む、タンパク質チロシンリン酸化亢進剤。 [23] The compound according to any one of claims 20 to 22, wherein OR 1 is at the 3-position on the benzene ring, and R 2 is at the 2-position on the benzene ring, and the geometry thereof. A protein tyrosine phosphorylation enhancer comprising one or more of any of isomers or optically active forms, pharmaceutically acceptable salts thereof, or hydrates thereof.
[24] 2- (ヒドロキシメチル) -3-(1_プロぺニル)フエノール、 3-(1_へキセニル)- 2 -(ヒドロキシ メチノレ)フエノール、 2 -(ヒドロキシメチル )_3 -ビュルフエノール、 2- (ヒドロキシメチル )-3-スチリルフエノール、 3-へキシル _2 -(ヒドロキシメチル)フエノール、または 2- (ヒドロ キシメチル) _3_(1_メチル _1_プロぺニル)フエノール、その幾何異性体もしくは光学活 性体、それらの製薬上許容される塩、またはそれらの水和物のいずれかの 1または 2 以上を含むことを特徴とする、請求項 20— 23のいずれか一項に記載のタンパク質チ
口シンリン酸化亢進剤。
[24] 2- (hydroxymethyl) -3- (1_propenyl) phenol, 3- (1_hexenyl) -2- (hydroxymethinole) phenol, 2- (hydroxymethyl) _3-bulfenol, 2 -(Hydroxymethyl) -3-styrylphenol, 3-hexyl_2- (hydroxymethyl) phenol, or 2- (hydroxymethyl) _3_ (1_methyl_1_propenyl) phenol, geometric isomer or optical activity The protein according to any one of claims 20 to 23, wherein the protein comprises one or more of the following: a pharmaceutically acceptable salt, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Mouth syn phosphorylation enhancer.
Priority Applications (1)
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| Country | Link |
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|---|---|---|---|---|
| JPS6434913A (en) * | 1987-07-31 | 1989-02-06 | Mitsubishi Chem Ind | Antitumor agent |
| WO2002096866A2 (en) * | 2001-05-30 | 2002-12-05 | Guilford Pharmaceuticals Inc. | Thiolalkyl benzoic acid derivatives |
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| SE8400239D0 (en) * | 1984-01-19 | 1984-01-19 | Pharmacia Ab | NEW ARYLETIC ACID DERIVATIVES |
| JPS63115834A (en) * | 1986-10-31 | 1988-05-20 | Green Cross Corp:The | Aromatic compound |
| JPH02170165A (en) * | 1988-12-23 | 1990-06-29 | Hitachi Ltd | Radiation sensitive composition and pattern forming method using this composition |
| US6177401B1 (en) * | 1992-11-13 | 2001-01-23 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften | Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis |
| FR2785284B1 (en) * | 1998-11-02 | 2000-12-01 | Galderma Res & Dev | VITAMIN D ANALOGS |
| CA2410889A1 (en) * | 2000-05-30 | 2001-12-06 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors for treating retinal disorders and glaucoma |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6434913A (en) * | 1987-07-31 | 1989-02-06 | Mitsubishi Chem Ind | Antitumor agent |
| WO2002096866A2 (en) * | 2001-05-30 | 2002-12-05 | Guilford Pharmaceuticals Inc. | Thiolalkyl benzoic acid derivatives |
Non-Patent Citations (1)
| Title |
|---|
| FÜRSTNER A. ET AL: "Shortcut syntheses of naturally occurring 5-alkylresorcinols with DNA-cleaving properties", J. ORG. CHEM., vol. 62, no. 8, 1997, pages 2332 - 2336, XP002980998 * |
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