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WO1999043315A1 - Agent therapeutique utilisable en cas de complication de diabetes - Google Patents

Agent therapeutique utilisable en cas de complication de diabetes Download PDF

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Publication number
WO1999043315A1
WO1999043315A1 PCT/JP1999/000651 JP9900651W WO9943315A1 WO 1999043315 A1 WO1999043315 A1 WO 1999043315A1 JP 9900651 W JP9900651 W JP 9900651W WO 9943315 A1 WO9943315 A1 WO 9943315A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
alkyl
substituted
diabetic
Prior art date
Application number
PCT/JP1999/000651
Other languages
English (en)
Japanese (ja)
Inventor
Yoshiyuki Matsuo
Takuji Mizui
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU24405/99A priority Critical patent/AU2440599A/en
Publication of WO1999043315A1 publication Critical patent/WO1999043315A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

  • the present invention relates to a diabetic complication preventive and / or therapeutic agent containing a chromene compound.
  • aldose reductase inhibitors are used for diabetic neuropathy
  • ACE inhibitors are used for diabetic nephropathy
  • prostaglandin preparations are used for macrovascular disease. No effective remedy has been found for all diseases.
  • the present invention provides a compound of the formula (I)
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, substituted Optionally substituted cycloalkyl, hydroxy, halogen, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted cycloalkoxy, substituted R 5 is alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, aryl which may be substituted Is an optionally substituted heterocycle or an optionally substituted cycloalkyl,
  • R 6 is hydrogen, an optionally substituted alkyl or an optionally substituted aryl
  • R 7 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, halogen, optionally substituted alkoxy, substituted Optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted A good heterocyclic oxy, an optionally substituted acyloxy, an optionally substituted alkylthio, an optionally substituted alkenylthio, an optionally substituted alkynylthio or an optionally substituted amino,
  • A is S or O, and the broken line represents the presence or absence of a bond.
  • R 7 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, a substituted Cycloalkyl which may be substituted, alkenyloxy which may be substituted, alkynyloxy which may be substituted, aryl which may be substituted, aryloxy which may be substituted, substituted Optionally substituted heterocycle, optionally substituted heterocycle, optionally substituted acyloxy, optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynyl Or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter, a compound represented by the formula Object (I ')
  • R l ′, R 2 ′, R 3 ′ and R 4 ′ each independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cyclo Alkyl, hydroxy, halogen, optionally substituted alkoxy, optionally substituted acyloxy or optionally substituted amino
  • R 6 ′ is hydrogen or alkyl
  • a r 1 and A r 2 are each independently an optionally substituted aryl or an optionally substituted heteroaryl,
  • a prophylactic and / or therapeutic agent for diabetic neuropathy containing the above compounds (I), (I ′) and / or (I ′ ′) (hereinafter collectively referred to as “the compound of the present invention”).
  • a diabetic wound healing improving agent and a diabetic peripheral circulation improving agent are examples of a prophylactic and / or therapeutic agent for diabetic neuropathy containing the above compounds (I), (I ′) and / or (I ′ ′) (hereinafter collectively referred to as “the compound of the present invention”).
  • a diabetic wound healing improving agent and a diabetic peripheral circulation improving agent a prophylactic and / or therapeutic agent for diabetic neuropathy containing the above compounds (I), (I ′) and / or (I ′ ′)
  • the present invention provides a method for preventing and treating diabetic complications, which comprises administering the compound according to the present invention.
  • a method for preventing and treating diabetic complications which comprises administering the compound according to the present invention.
  • the use of a compound according to the present invention for the manufacture of a medicament for the prevention and / or treatment of diabetic complications is provided.
  • alkyl means a straight-chain or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, and specifically, methyl, ethyl, n— Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, nonyl And decyl.
  • R i to R 4 are “optionally substituted alkyl” or “alkyl”, alkyl having 3 to 6 carbon atoms is preferable, and other “optionally substituted alkyl” or “alkyl” Is preferably a group having 1 to 3 carbon atoms.
  • Optionally substituted alkyl includes halogen, hydroxy, cyano, cycloalkyl, carboxy, and optionally substituted alkoxy [where the substituent is, for example, cycloalkyl, optionally substituted hetero. Ring (here, for example, alkyl is a substituent), hydroxy, cyano, alkoxy, acyl, amino, alkamino, alkoxy, aryl which may be substituted (here, for example, alkyl, alkoxy, Carboxyalkoxy, alkylenedioxy, halogen, amino, alkylamino, carboxy, alkoxycarbonyl, acyl, etc.), acyl, alkylenedioxy (eg, methylenedioxy, ethylene) Dioxy etc.), optionally substituted amino (here, a substituent is, for example, alkyl; for example, dimethylamino, getylamino, etc.), optionally substituted aryl (where the substituent is, for
  • R 1 to R 4 are ⁇ optionally substituted alkyl ''
  • the substituent is cycloalkyl, optionally substituted alkoxy (where the substituent is, for example, cycloalkyl, substituted A heterocyclic ring (here, as a substituent, for example, alkyl), an alkoxy, an aryl which may be substituted (here, as a substituent, for example, alkyl, alkoxy, alkylenedioxy, etc.), an alkylene dioxy (for example, Methylenedioxy, ethylenedioxy, etc.), optionally substituted aryl (here, as a substituent, for example, alkyl, alkoxy, alkylenedioxy, etc.) or optionally substituted heterocycle (here, as a substituent, for example, alkyl, More preferably, it is an alkoxy, an alkylenedioxy or the like.
  • substituted alkyl examples include, for example, cycloalkylalkyl (cyclopropylmethyl, cyclobutylethyl, etc.), haloalkyl (chloromethyl, trifluoromethyl, etc.), arylalkyl (methoxyphenylalkyl, etc.), and alkoxyaryl Examples include alkyl (such as methoxybenzyl), alkoxyalkyl (such as methoxypropyl), cycloalkylalkyl (such as cyclohexylmethyl), hydroxyalkyl (such as hydroxybutyl), and aldehyde alkyl (such as formylpropyl).
  • alkyl such as methoxybenzyl
  • alkoxyalkyl such as methoxypropyl
  • cycloalkylalkyl such as cyclohexylmethyl
  • hydroxyalkyl such as hydroxybutyl
  • aldehyde alkyl such as formylpropy
  • alkyl portions of “alkylthio”, “optionally substituted alkylthio”, “alkylamino”, “haloalkyl”, “arylalkyl”, “alkylsulfonyloxy”, and “cycloalkylalkyl” are the same as above. .
  • alkyl part of “alkoxy” is the same as the above-mentioned alkyl.
  • lower alkoxy means alkoxy having 1 to 4 carbon atoms.
  • R 7 is “optionally substituted alkoxy” or “alkoxy”, it preferably has 3 to 7 carbon atoms.
  • the other “optionally substituted alkoxy” or “alkoxy” preferably has 1 to 3 carbon atoms.
  • substituents of the “optionally substituted alkoxy” are the same as the above-mentioned substituents in the alkyl.
  • substituted alkoxy include, for example, cyclopropylmethoxy, 2-cyclopropylethoxy, benzyloxy, dimethylaminoethoxy, formylethoxy, Examples include formylpropoxy, hydroxypentyloxy, dihydroxyethoxy, dimethoxybutoxy, jetoxetoxy, cyanopropyloxy, and 4-methoxyphenylethoxy.
  • alkoxycarbonyl and “optionally substituted alkoxyl propyl” are the same as described above.
  • lower alkoxycarbonyl means alkoxycarbonyl having alkyl having 1 to 4 carbon atoms.
  • alkoxy moiety and the substituent of “optionally substituted alkoxycarbonyl” and “carboxyalkoxy” are the same as described above.
  • Alkylenedioxy means alkylenedioxy having 1 to 3 carbon atoms, and specifically includes methylenedioxy, ethylenedioxy, propylenedioxy and the like.
  • Alkenyl means a straight-chain or branched alkenyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. , Probenyl, isopropenyl, butenyl, pentenyl, hexenyl, hept And phenyl, octenyl, nonenyl, decenyl and the like. These have one or more double bonds at any positions.
  • the substituent of "optionally substituted alkenyl” is the same as the above-mentioned substituent of alkyl.
  • alkenyl part and the substituent of "alkenyloxy”, “optionally substituted alkenyloxy”, “alkenylthio”, “optionally substituted alkenylthio” are the same as described above.
  • Alkynyl means a straight-chain or branched alkynyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and specifically ethynyl. , Propynyl, butynyl, pentynyl, hexynyl, heptynyl, octyl, nonyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond.
  • the substituent of "optionally substituted alkynyl" is the same as the above alkyl.
  • alkynyl part and the substituent of “alkynyloxy”, “optionally substituted alkynyloxy”, “alkynylthio” and “optionally substituted alkynylthio” are the same as described above.
  • Cycloalkyl means a cyclic alkyl having 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms, and more preferably 3 to 5 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl and the like.
  • substituents of “optionally substituted cycloalkyl” include the substituents of the above alkyl, alkyl and alkenyl.
  • cycloalkyl portion of “cyclalkyl” is the same as described above.
  • cycloalkyl part of “cycloalkoxy” is the same as described above, and examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy and the like.
  • substituents of “optionally substituted cycloalkoxy” are the same as described above.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • the halogen part of “haloalkyl” is the same as above.
  • acyl means a linear or branched acyl having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms derived from an aliphatic carboxylic acid, Specific examples include formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, vivaloyl, hexanoyl and the like.
  • the substituent of the “optionally substituted acyl” is the same as the above-mentioned substituent of the alkyl.
  • acyl part of "asiloxy” is the same as the above-mentioned acyl, and examples include formyloxy, acetyloxy, propionyloxy, petyriloxy, valeryloxy, vivaloyloxy, hexanoyloxy and the like.
  • substituent of "optionally substituted alkoxy” is the same as the above-mentioned substituent of alkyl.
  • the “optionally substituted amino” includes unsubstituted amino and substituted amino.
  • substituted amino include alkylamino (methylamino, ethylamino, etc.), dialkylamino (dimethylamino, acetylamino, etc.), cycloalkylamino (cycloalkylamino, etc.).
  • Mono- or di-substituted aminos such as hexylamino), phenylamino, diphenylamino, and acylamino (such as acetylamino); and cyclic amino such as piperidino, piperazino, and morpholino.
  • Aryl means a monocyclic or condensed ring having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, and specifically includes phenyl, naphthyl (eg, 1-naphthyl, 21-naphthyl) , Anthryl (eg, 1-anthryl, 2-anthryl), indanyl (eg, 1-indanyl, 6-indanyl), indenyl (eg, 1-indenyl, 7-indenyl), phenanthryl (eg, 1-phenanthryl, 2-phenanthryl) and the like. Particularly, phenyl is preferred.
  • substituent of the “optionally substituted aryl” include the substituents of the above alkyl, alkyl and alkenyl.
  • substituted aryls include 2-, 3- or 4-methoxyphenyl, 2,4_ or 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-cyclophenyl, 3 1- or 4-fluorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-dimethylaminophenyl, 2-carboxymethoxy-4-methoxyphenyl, 3 , 4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl and the like.
  • Heterocycle means an optionally selected saturated or unsaturated 3- to 7-membered, preferably 5- to 7-membered ring containing one or more oxygen, sulfur and or nitrogen atoms in the ring. These may be condensed with another carbon ring or another hetero ring. These can be bonded at any substitutable position.
  • oxylanil dioxanyl, thiranyl, dioxolanyl, oxathiolanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, vilazolidinyl, pyrazolinyl, piberidinyl, piperazinyl, morpholinyl, morpholinyl, morpholinyl, hydromorphinyl, morpholinyl, hydromorphinyl, hydromorphinyl, hydromorphinyl
  • Non-aromatic heterocycles such as benzofuryl, 2,3-dihydro-1-6-benzofuryl), pyrrolyl (eg, 1-pyrrolyl), indolyl (eg, 2- or 6-indolyl), carpazolyl (eg, 3 _) Force rubazolyl), imidazolyl (eg, 1-imidazolyl), pyrazo
  • heterocyclic moiety and the substituent of "heterocyclic oxy" and “optionally substituted heterocyclic oxy” are the same as described above.
  • the compounds according to the present invention also include pharmaceutically acceptable salts and hydrates.
  • Pharmaceutical The above acceptable salts include, for example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), ammonium or organic bases (triethylamine, pyridine, etc.), salts of amino acids, and inorganic salts. Salts of acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) or organic acids (eg, citric acid, p-toluenesulfonic acid, methanesulfonic acid, etc.). These salts can be formed by a commonly used method.
  • the hydrate may have any number of water molecules coordinated to one molecule of the compound according to the present invention.
  • the compounds according to the present invention include racemates, both enantiomers and all stereoisomers (such as diastereomers, epimers, enantiomers and the like).
  • FIG. 1 is a graph showing nerve conduction velocity when a compound (I-11) was administered to a diabetic rat.
  • the vertical axis indicates nerve conduction velocity (mZ s).
  • Compound (1-1) 3 mg / kg diabetic rat (n 9)
  • FIG. 2 is a graph showing intraneuronal blood flow when the compound (1-1) was administered to a diabetic rat.
  • FIG. 3 is a graph showing the wound healing process of a diabetic rat.
  • the vertical axis indicates the wound area (%), and the horizontal axis indicates the administration period (days). * Indicates comparison with control group (D unnet's T est) indicates that P ⁇ 0.05.
  • All of the compounds according to the present invention have a diabetic complication preventive and / or therapeutic action.
  • a diabetic complication preventive and / or therapeutic agent containing the following compounds is particularly preferable.
  • R 1 is hydrogen, optionally substituted alkyl, hydroxy or optionally substituted alkoxy
  • R 1 is abbreviated as R 1 -1
  • R 1 is abbreviated as R 1 -2
  • R 1 is abbreviated as R 1 -3
  • R 2 is hydrogen, an optionally substituted alkyl, hydroxy or an optionally substituted alkoxy
  • R 2 is abbreviated as R 2 -1
  • R 2 is abbreviated as R 2 -1
  • R 2-2 is an optionally substituted alkoxy (where the substituent is hydroxy, alkoxy , Formyl or heterocycle)
  • R 2 is abbreviated as R 2 — 3).
  • R 3 is hydrogen, optionally substituted alkyl, hydroxy or optionally substituted alkoxy
  • R 3 is abbreviated as R 3 -1
  • R 3-2 a compound which is optionally substituted alkoxy
  • R 3-3 a hydrogen compound
  • R 4 is hydrogen, alkyl optionally substituted, a human Dorokishi or optionally substituted alkoxy (hereinafter, R 4 is R 4 - is abbreviated as 1) compound, preferably hydrogen is alkyl or optionally substituted alkoxy (hereinafter, R 4 is R 4 - abbreviated as a 2) compound, preferably hydrogen (hereinafter, abbreviated to R 4 is R 4-3 Do) compounds, (5) R 5 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl or an optionally substituted heterocycle (hereinafter, R 5 is R 5 — A compound, which is preferably a substituted or unsubstituted aryl or a substituted heterocycle (hereinafter, abbreviation 5 is a 5-2).
  • the aryl may be substituted (where the substituent is alkyl, alkoxy or alkylenedioxy) or the hetero ring may be substituted (where the substituent is halogen, alkyl, alkoxy or alkylenedioxy.
  • R 5 is R 5 - abbreviated as a 3) compound, more preferably an optionally substituted Ariru (wherein the substituents are alkyl, ⁇ Rukoki Or alkylene O carboxymethyl) (hereinafter, R 5 is R 5 - If it is 4 substantially serial) compound, most preferably in ⁇ reel be substituted with alkylene O carboxymethyl (hereinafter, R 5 is R 5 — abbreviated as 5),
  • R 6 is hydrogen or alkyl
  • R 6 is abbreviated as R 6 —2
  • R 6 is abbreviated as R 6 —2
  • R 7 is optionally substituted alkyl, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, an optionally substituted Arukeniruokishi, substituted Optionally substituted alkynyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclic oxy, substituted An optionally substituted alkoxy, an optionally substituted alkenylthio or an optionally substituted alkynylthio (hereinafter, R 7 is abbreviated as R 7 -1),
  • R 7 is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkenyloxy, optionally substituted aryl, optionally substituted aryloxy or optionally substituted phenyl. (Hereafter, R 7 is abbreviated as R 7 — 2.)
  • R 7 is abbreviated as R 7 — 3
  • R 7 is R 7 - abbreviated as a 4) compounds,
  • R 7 is abbreviated as R 7 — 5
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - compound is 2
  • R 1 is R 1 —3, R 2 is R 2 —3, R 3 is R 3 —3, and R 4 is R 4 —3;
  • R 1 is R 11
  • R 2 is R 2 - is 1
  • R 3 is R 3 - is 1
  • R 4 is R 4 - is 1
  • R 5 is R 5 - 1
  • R 6 is R 6 — 1 and R 7 is
  • R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, R 4 is R 4 —1, and R 5 is R 5 — 2 R 6 is R 6 — 1, R 7 is R 7 — 1 and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — l
  • R 5 is R 5 — 3
  • a compound wherein R 6 is R 6 — 1, 17 is a scale 7 — 1, and A is O,
  • R 1 is R 1 _ 1
  • R 2 is R 2 - is 1
  • R 3 is R 3 - 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 1
  • R 6 is R 6—2, and R? Is R 7 — 1 and A is O,
  • R 1 is R 1 _1, R 2 is R 2 — 1, R 3 is R 3 — 1, R 4 is R 4 -1, and R 5 is R 5 — 1.
  • R 6 is R 6-1, R 7 is R 7 — 2 and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 1.
  • R 6 is R 6-1
  • R 7 is R 7 — 3, and A is O,
  • R 1 is R 1 _1, R 2 is R 2 — 1, R 3 is R 3 — 1, R 4 is R 4 — 1, and R 5 is R 5 _ 2.
  • R 6 is R 6 — 2 and R 7 is
  • R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, R 4 is R 4 —1, and R 5 is R 5 — 3
  • R 6 is R 6-2, R 7 is R 7 — 1 and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3
  • R 4 is R 4 — 1
  • R 5 is R 5 — 2
  • R 6 is R 6-1
  • R 7 is R 7 —2, and A is O
  • R 1 is R 1 —1, R 2 is R 2 —1, R 3 is R 3 —1, R 4 is R 4 —1, and R 5 is R 5 — 3 R 6 is R 6 — 1, R 7 is R 7 — 2 and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — I
  • R 4 is R 4 — 1
  • R 5 is R 5 — 2
  • R 6 is R 6-1
  • R 7 is R 7 _ 3
  • A is O
  • R 1 is R 1 - is 1, R 2 is R 2 - are 1, Ri R 3 is R 3- 1 der, R 4 is R 4 - is 1, R 5 is R 5 - 3 R 6 is R 6 —1, R 7 is R 7 —3, and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 5
  • R 6 is R 6 — 1
  • a compound wherein R 7 is R 7 — 5 and A is ⁇ ,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 1.
  • R 6 is R 6 —2, R 7 is R 7 —2, and A is O,
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 1.
  • R 6 is R 6 - is 2
  • R 7 is R 7- 3
  • compound a is O
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 2
  • R 6 is R 6-2
  • R 7 is R 7 —2, and A is O
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 2
  • R 6 is R 6 —2, R 7 is R 7 —3, and A is O
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 3
  • R 6 is R 6 — 2
  • R 7 is R 7 — 2 and A is ⁇
  • R 1 is R 1 — 1
  • R 2 is R 2 — 1
  • R 3 is R 3 — 1
  • R 4 is R 4 — 1
  • R 5 is R 5 — 3
  • R 6 is R 6 —2, R 7 is R 7 —3, and A is O
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3-2
  • R 4 is R 4 — 2
  • R 5 is R 5 — 1
  • R 6 is R 6 — 1
  • R 7 is R 7 — 1
  • A is O
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 2
  • R 6 is R 6 — 1
  • R 7 is R 7 _1 and A is O
  • R 1 is R 1 —?
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 4 is R 4 — 2
  • R 5 is R 5 — 3
  • R 6 is R 6 — 1, R 7 is R 7 — 1, and A is O
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 4 is R 4 — 2
  • R 5 is R 5 ⁇ 1 in and
  • R 6 is R 6- 2
  • R 7 is R 7- 1, compound a is O
  • compound a is O
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 4 is R 4 — 2
  • R 5 is R 5 — l
  • R 6 is R 6 — 1 and R 7 is
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 _ I
  • R 6 is R 6 — I, R
  • R 1 is R 1 —2, R 2 is R 2 —2, R 3 is R 3 —2, R 4 is R 4 —2, and R 5 is R 5 — 1
  • R 6 is R 6 —l, R 7 is R 7 —4, and A is O
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 4 is R 4 and 2
  • R 5 is R 5 and 2
  • R 6 is R 6-2
  • R 7 is R 7-1
  • A is O
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 3
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 — 2
  • R 4 is R 4 _2
  • R 5 is R 5 — 2
  • R6 is R6_i
  • R7 is
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 3
  • R 6 is R 6 — 1
  • R 7 is R 7 — 2 and A is O
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 2
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - 2 der
  • R 4 is R 4 —2
  • R 5 is R 5 —3
  • R 6 is R 6 —1
  • R 7 is R 7 —3, and A is ⁇ ,
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 _2
  • R 4 is R 4 — 2
  • R 5 is R 5 — 1
  • R 6 is R 6 —2
  • R 7 is R 7 —2
  • A is O
  • R 1 is R 1 _ 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 1
  • R 6 is R 6 — 2
  • R 7 is R 7 — 3
  • A is ⁇
  • R 1 is R 1 _2
  • R 2 is R 2 —2
  • R 3 is R 3 —2
  • R 4 is R 4 —2
  • R 5 is R 5 — 1
  • R 6 is R 6 — 2
  • R 7 is R 7 — 4, and A is ⁇
  • R 1 is R 1 — 2
  • R 2 is R 2 — 2
  • R 3 is R 3 _2
  • R 4 is R 4 — 2
  • R 5 is R 5 — 2
  • R 6 is R 6 —2
  • R 7 is R 7 —2
  • A is O
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 2
  • R 1 is R 1 - 2
  • R 2 is R 2 - is 2
  • Ri is R 3- 2 der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 3
  • R 6 is R 6 —2
  • R 7 is R 7 —2, and A is 0,
  • R 1 is R 1 - is 2
  • R 2 is R 2 - is 2
  • R 3 is R 3 - are two der
  • R 4 is R 4 - is 2
  • R 5 is R 5 - 3
  • R 6 is R 6 — 2
  • R 7 is R 7 — 3
  • A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1
  • R 6 is R 6 — 1
  • R 7 is
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2.
  • R 6 is R 6 — l and R A compound wherein 7 is R 7 — 1 and A is O,
  • R 1 is R 1 - is 3
  • R 2 is R 2 - is 3
  • R 3 is Ri R 3 one 3 der
  • R 4 is R 4 - is 3
  • R 5 is R 5 - 3
  • R 6 is R 6 — 1
  • R 7 is R 7 _1 and A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1
  • R 6 is R 6 — 1
  • R 7 is R 7 — 2 and A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 _3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1
  • R 6 is R 6-1
  • R 7 is R 7 — 3 and A is O;
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1.
  • R 6 is R 6—i
  • R 7 is R 7 — 4 and A is O
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6 —2, R 7 is R 7 —1 and A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 —2, R 7 is R 7 —1, and A is O
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6 — 1
  • R 7 is R 7 — 2 and A is O
  • R 1 is R 1 — 3, R 2 is R 2 — 3, R 3 is R 3 — 3, R 4 is R 4 — 3, and R 5 is R 5 — 3
  • R 6 is R 6 — 1, R 7 is R 7 — 2 and A is O
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6 —1, R 7 is R 7 —3, and A is ⁇ ,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 —1, R 7 is R 7 —3, and A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1.
  • a compound wherein R 6 is R 6 — 2, R 7 is R 7 — 2 and A is ⁇ ,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 1.
  • R 6 is R 6 —2, R 7 is R 7 _3, and A is O,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6-2
  • R 7 is R 7 —2, and A is 0,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6 —2, R 7 is R 7 —3, and A is 0,
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 — 2
  • R 7 is R 7 — 2 and A is ⁇
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 —2, R 7 is R 7 —3, and A is O
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 4
  • R 6 is R 6 —2, R 7 is R 7 —3, and A is O
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3.
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 — 2
  • R 7 is R 7 _4, and A is O,
  • R 1 is R 1 — 3, R 2 is R 2 — 3, R 3 is R 3 — 3, R 4 is R 4 — 3, and R 5 is R 5 — 4 A compound wherein R 6 is R 6 — 2, R 7 is R 7 _ 4 and A is O;
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2
  • R 6 is R 6 —2
  • R 7 is R 7—2
  • A is O and the dashed line represents a bond
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 2 in and
  • R 6 is R 6 - is 2
  • R 7 is R 7 one 3
  • a is ⁇ compound dotted line represents a bond
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3
  • R 6 is R 6 —2
  • R 7 is R 7—2
  • A is O and the dashed line represents a bond
  • R 1 is R 1 — 3
  • R 2 is R 2 — 3
  • R 3 is R 3 — 3
  • R 4 is R 4 — 3
  • R 5 is R 5 — 3 in and
  • R 6 is R 6 - is 2
  • R 7 is R 7 one 3
  • a is O
  • compounds dashed line represents a bond
  • R 1 is hydrogen
  • R 2 is optionally substituted alkoxy
  • R 3 and R 4 are both hydrogen
  • R 5 is benzo [1,3] dioxo-l-u
  • R 6 is hydrogen
  • R 7 is hydrogen, halogen, optionally substituted alkoxy, thienyl, optionally substituted amino or optionally substituted alkylthio, A Is 0 or S, and the broken line represents a bond
  • a r 1 and A r 2 are each independently optionally toying substituted phenyl, optionally substituted Fueniruokishi or optionally substituted Ru good thienyl der compound,
  • Al 1 and Ar 2 may be each independently substituted alkyl.
  • Phenyl, phenyloxy or phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of optionally substituted alkoxy, halogen, alkylenedioxy, optionally substituted amino
  • Ar 1 and Ar 2 are each independently 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, halogen, alkylenedioxy, optionally substituted amino and carboxyalkoxy A compound which is phenyl, phenyloxy or phenyl, optionally substituted with
  • a r 1 is alkyl, alkoxy and alkylene O carboxymethyl 1-3 good phenyl optionally substituted with a substituent or off is selected from the ing group from Eniruokishi, A r 2 is alkyl, A compound which is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of alkoxy and alkylenedioxy,
  • R 1 ′, R 2 ′, R 3 ′ and R 4 ′ are each independently hydrogen, optionally substituted alkyl, hydroxy or optionally substituted alkoxy,
  • R 1 ′ a compound wherein R 2 ′, R 3 ′ and R 4 ′ are each independently hydrogen or an optionally substituted alkoxy,
  • R 1 ′, R 2 ′, R 3 ′ and R 4 ′ are each independently hydrogen or alkoxy
  • R 1 ′, R 2 ′, R 3 ′ and R 4 ′ are each independently hydrogen or optionally substituted alkoxy
  • Ar 1 and Ar 2 are each independently alkyl or alkylenedialkyl.
  • Phenyl or a phenyloxy compound optionally substituted with 1 to 3 substituents selected from the group consisting of oxy and alkoxy More preferably, R 1 ′, R 3 ′ and R 4 ′ are hydrogen; R 2 ′ is hydrogen or optionally substituted alkoxy, and Ar 1 and Ar 2 are each independently an alkyl A compound which is phenyl substituted with 1 to 3 substituents selected from the group consisting of alkylenedioxy and alkoxy,
  • R 1 ′, R 3 ′ and R 4 ′ are hydrogen
  • R 2 ′ is hydrogen or optionally substituted alkoxy
  • Ar 1 is selected from the group consisting of alkyl, alkylenedioxy and alkoxy Phenyl or phenoxy substituted with 1 to 3 substituents, wherein Ar 2 is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkylenedioxy and alkoxy
  • the compound (I) can be produced, for example, as a key intermediate using a compound (III) or (IV) that can be synthesized by the steps shown in the following methods A, B, C, D, or E.
  • the first step is a step in which R 5 is introduced at the same time as the ring closure of the starting compound (II) to form a chromanone (V), and the second step involves adding R 8 and a leaving group Z to the compound (V). These are the steps to be introduced respectively.
  • Chromanone (V) can be obtained by condensing compound (II) with aldehyde R 5 —CH — (R 5 is as defined above) in the presence of a base.
  • a base an inorganic base such as sodium hydroxide, potassium hydroxide, or sodium hydride or an organic base such as potassium t-butoxide or piperidine can be used.
  • the solvent lower alcohols such as methanol and toluene, ether solvents such as tetrahydrofuran and dioxane, water or a mixed solvent thereof can be used.
  • the starting compound (II) is available as a commercial product or can be synthesized from a commercial product according to a known method. Specific examples of the starting compound (II) include orthohydroxyacetophenone, 2 ', 3'dihydroxyacetophenone, 2', 4'dihydroxyacetophenone, and 2 ', 5'-dihydroxyacetophenone.
  • Method A, 2nd step This step is a reaction generally known as a Vi 1 smeier reaction.
  • an N, N'-disubstituted formamide eg, dimethylformamide
  • a chlorinating agent such as phosphorus oxychloride or thionyl chloride
  • Z is chloro and R 8 is formyl.
  • An intermediate (III) is obtained. If oxybromide or thionyl bromide is used instead of the chlorinating agent, a compound (III) in which Z is bromide and R 8 is formyl can be obtained.
  • the reaction temperature is from ⁇ 30 ° C. to 100 ° C.
  • the compound (III) in which Z is alkoxy and R 8 is formyl is obtained by reacting the compound (III) obtained by the above method with an alkali metal salt or an alkaline earth metal salt of an alcohol. Obtainable. The reaction is carried out in a solvent such as methanol, dimethylformamide, tetrahydrofuran or 1,4-dioxane at room temperature to the reflux temperature of the solvent.
  • a solvent such as methanol, dimethylformamide, tetrahydrofuran or 1,4-dioxane
  • Oxidation may be carried out in accordance with the usual conditions for the oxidation reaction of aldehydes, but is most preferably a method of oxidizing with chlorite (Acta. Chem. Scand., 1973, 2). 7 (3), 888-890).
  • the oxidizing agent include sodium chlorite and potassium chlorite, and usually carry out a reaction in the presence of sulfamic acid, dimethyl sulfoxide, hydrogen peroxide or 2-methyl-2-butene. If necessary, a buffer such as sodium dihydrogen phosphate may be added.
  • dichloromethane chloroform, dichloroethane, dimethyl sulfoxide, acetone, acetonitrile, water or a mixed solvent thereof can be used.
  • the reaction temperature is usually from 0 to 40 ° C.
  • the compound (III) in which R 8 is an ester group can be derived from the corresponding carboxyl compound (III). Esterification is not required for those skilled in the art, but for example, a method using diazomethane, a method of refluxing in an alcohol in the presence of an acid catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and the like.
  • a dehydrating agent such as pomidide is condensed in the presence of a base catalyst such as dimethylaminopyridine, and a carboxylic acid in the presence of a base such as potassium carbonate in dimethylformaldehyde. Examples of the method include a method of reacting a halide, and a method of first converting into a corresponding acid chloride using oxalyl chloride or thionyl chloride and then reacting with an alcohol.
  • the first step is a method generally called a Vi 1 smeier reaction, in which the compound (II), which is a starting material, is ring-closed and simultaneously formylated to give a compound (VI).
  • the second step is a step of oxidizing formyl of the compound (VI).
  • As third E is a substituent introduced R 5 at the 2-position of the compound (VII), it is a step of the compound (IV).
  • the fourth step is a step of converting the carbonyl of compound (IV) to a suitable leaving group Z.
  • This step can be carried out according to the method described in Tetrahedron, 1974, 30, 3553-3-3551. That is, the compound (II) is reacted with an N, N'-disubstituted formamide (for example, dimethylformamide) in the presence of phosphorus oxychloride or thionyl chloride for several hours to several tens of hours, preferably for 3 to 24 hours. And the compound (VI).
  • the starting compound (II) is a known compound or a compound that can be synthesized from a known material by a conventional method.
  • the starting compound (II) include: orthohydroxyacetophenone, 2, 3 * -dihydroxyacetophenone, 2 ′, 4′-dihydroxyacetophenone, 2 ′, 5 ′ dihydroxyacetophenone , 2 ', 6'Dihydroxyacetophenone, 2'-Hydroxy-1'-propoxyacetophenone, 5'-Cyclopropylmethyl-1,2-hydroxyacetophenone, 5'-Benzyloxy-1'-H Droxyacetophenone, 2'-hydroxy-5'-propoxyacetophenone, 2'-hydroxy-1 4'-propoxyacetophenone, 2'-hydroxy-1 3'-propoxyacetophenone, 2'-hydroxy-1 5 ' —Isopropoxyacetophenone, 2 ′ —hydroxy— 5 ′ —Nitroacetophenone, 2 ′ —Hydroxy-1 3 ′ —Nitroacetof Non, 2 '- hydroxy 1'-propoxy-1'--
  • the aldehyde (VI) is oxidized to the carboxyl form (VII) (where R 6 is hydrogen), the corresponding ester form (VII) (where R 6 is an optionally substituted alkyl or (This is a reel that may be substituted.)
  • the oxidation reaction may be carried out in accordance with the usual conditions for the oxidation reaction of aldehydes. In particular, a method of irradiating with N-bromosuccinic acid imide in carbon tetrachloride (Synth. Commun., 1980, 10) , 899-1890), or a method of oxidizing with chlorite in the presence of a chlorine scavenger (Acta. Chem.
  • a substituent R5 is introduced into the 2-position of the ester (VII), and specifically, the method is carried out according to the method described in Org. Reaction, 1972, 19, and 1. Is done.
  • a Grignard reagent R 5 MgX (R 5 is as defined above, and X represents halogen) is prepared by a conventional method.
  • R 4 MgX is 1,4-added to compound (VII) in the presence of a copper catalyst such as copper iodide to give (IV).
  • a copper catalyst such as copper iodide
  • the solvent tetrahydrofuran or ether is used, and preferably tetrahydrofuran.
  • Copper (I) iodide, copper (I) cyanide, copper (I) bromide (I) dimethyl complex and the like can be used as the copper catalyst.
  • the reaction is usually carried out at a temperature from room temperature to the reflux temperature of the solvent.
  • Compound (IV) has a 3-position ester group and a 4-position carbon
  • keto-enol tautomerization by a thiol group results in a mixture of keto-enol tautomers, which may further give stereoisomers between the 2-position and the 3-position.
  • only one of the possible structural formulas is shown for convenience. Use these isomers as a mixture without isolation and purification in the following step 4 of Method B, or use them as intermediates for conversion to compound (I) by the following methods a, b, c or d Can be.
  • This step is to introduce a leaving group Z at the 4-position of compound (IV).
  • Z is preferably halogen, optionally substituted alkoxy or optionally substituted alkylsulfonyloxy, particularly preferably chloro, methoxy, perfluoroalkylsulfonyloxy [preferably trifluoromethyl].
  • Sulphonyloxy hereinafter abbreviated as triflate.
  • Z is an alkylsulfonyloxy or arylsulfonyl
  • R 8 is an optionally substituted alkoxycarbonyl or an optionally substituted aryloxycarbonyl
  • the compound (III) in which Z is methanesulfonyloxy (hereinafter abbreviated as mesylate), para-toluenesulfonyloxy (hereinafter abbreviated as tosylate), triflate or perfluorobutanesulfonyloxy is dichloromethane, dimethylformamide, or tetrahydrofuran.
  • the compound (IV) is reacted with the sulfonyl chloride compound or sulfonic anhydride corresponding to the target compound in the presence of a tertiary base such as pyridine, triethylamine or ethyldiisopropylamine in a solvent such as it can.
  • the reaction is usually carried out at 0 ° C to room temperature.
  • Compound (III) in which Z is triflate can be obtained by reacting compound (IV) in a solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride, lithium diisopropylamide, or lithium hexamethyldisilazane.
  • a base such as sodium hydride, lithium diisopropylamide, or lithium hexamethyldisilazane.
  • 2- [N, N'-bistrifluoromethanesulfonylamino] pyridine or N, N'-bis (trifluoromethanesulfonyl) aniline 5 Can also be made.
  • the reaction is usually carried out at a temperature of 178 ° C to room temperature.
  • the compound (III) in which Z is a halogen and R 8 is an optionally substituted alkoxycarbonyl or an optionally substituted aryloxycarbonyl is obtained by converting the compound (IV) in the presence of triphenylphosphine. It can be produced by reacting with tetrahalogenated methane. For example, if you react with carbon tetrachloride
  • Compound (III) in which Z is chloro and R 8 is optionally substituted alkoxycarbonyl or optionally substituted aryloxycarbonyl can be synthesized.
  • the solvent chloroform, carbon tetrachloride, ether and the like can be used.
  • the reaction temperature is usually from room temperature to the reflux temperature of the reaction solvent.
  • Z is an optionally substituted alkoxy, an optionally substituted alkenyloxy or an optionally substituted alkynyloxy
  • R 8 is an optionally substituted alkoxycarbonyl or an optionally substituted Compound (III), which is a ryloxycarbonyl, can be obtained by reacting compound (IV) with a diazotizing agent (for example, diazomethane), or by reacting compound (IV) with triphenylphosphine or tributylphosphine, Dicarboxylates (eg, getyl azodicarboxylate) or tetraalkyl azodicarboxamides (eg, 1,1 ′-(azodicarponyl) dipiperidine, N, N, N ′, N′-tetramethyl azodicarboxamide) ) By reacting with the corresponding alcohol in the presence (Minob reaction) It is possible to elephants.
  • a diazotizing agent for example, diazomethane
  • a lower alcohol such as ethanol, acetone, ether, or tetrahydrofuran, or a mixed solvent thereof can be used as a reaction solvent.
  • the reaction temperature is usually 0 to room temperature.
  • the Mitsunobu reaction is performed according to the method described in Synthesis, 1998, 1, 1, 1.
  • An ether solvent such as tetrahydrofuran, benzene or toluene is used as a reaction solvent.
  • the reaction is usually performed at a temperature of 15 ° C. to room temperature.
  • the first step is a step of converting a compound (II) as a starting material into a ketoester (VIII).
  • the compound (VIII) is converted to a carboxylic acid halide R
  • This is a step of condensing with 5 C OX (wherein R 5 and X are as defined above) or aldehyde R 5 C HO.
  • the third step is a step of reducing the intra-ring double bond of compound (IX) to lead to compound (IV).
  • the fourth step is the same as the fourth step of Method B.
  • Dialkyl carbonates include dimethyl carbonate, getyl carbonate, dipropyl carbonate and the like, and diaryl carbonates include diphenyl carbonate and the like.
  • the base include sodium hydride, lithium hydride, lithium hexamethyldisilazane, and the like. Usually, tetrahydrofuran or the like is used as a solvent.
  • This step can be carried out according to the method of J. Org. Chem., 1984, 49 (7), 128-128.
  • compound (VIII) is treated with metallic magnesium in the presence of ethanol to form a magnesium salt, and then reacted with carboxylic acid halide R 5 COX to obtain compound (IX).
  • carboxylic acid halide R 5 COX carboxylic acid halide R 5 COX
  • the reaction temperature is usually from room temperature to the reflux temperature of the reaction solvent.
  • compound (VIII) and an aldehyde R 5 CHO are combined with a catalytic amount of acetic acid and an organic base, particularly preferably piperidine, in an organic solvent, Particularly preferably, the compound (IV) can be directly obtained by refluxing while dehydrating in toluene.
  • the following third step is omitted.
  • the aldehyde use may be made of periron, 4-methoxybenzaldehyde, 4-isopropylbenzylaldehyde and the like.
  • the reduction reaction in this step may use catalytic reduction, hydride reduction or the like.
  • a catalyst for the catalytic reduction method a noble metal catalyst such as palladium held on a carrier such as platinum oxide or carbon can be used.
  • the solvent is not particularly limited as long as it is a solvent usually used for catalytic reduction, but is preferably a lower alcohol, acetic acid, acetic ester, tetrahydrofuran or a mixed solvent thereof.
  • the reaction is carried out under atmospheric pressure to pressurization, and the reaction temperature is usually from room temperature to 50 ° C.
  • Hydride reduction is carried out under acidic conditions using a reducing agent such as sodium borohydride or triethylsilane, preferably sodium cyanoborohydride in a solvent such as lower alcohol or tetrahydrofuran at 0 ° C to room temperature.
  • a reducing agent such as sodium borohydride or triethylsilane, preferably sodium cyanoborohydride in a solvent such as lower alcohol or tetrahydrofuran at 0 ° C to room temperature.
  • the reaction may be performed in 0 minutes to 24 hours.
  • the obtained compound (IV) can be converted to compound (III) by the method described in Method B, Step 4.
  • the first step is the same as the first step in the method C, and the second step is a step of closing the ring of the compound (VIII) to give (VIII).
  • the third and fourth steps are the same as the third and fourth steps of Method B.
  • Compound (VIII) is condensed with a formaldehyde equivalent, such as dimethylformamide dialkyl acetal or orthoformate, and compound (VII) (where R 6 is optionally substituted alkyl or substituted ) Are synthesized.
  • the reaction can be carried out in a solvent such as benzene, toluene or acetic anhydride or without a solvent.
  • the reaction temperature is usually from 0 ° C to the reflux temperature of the reaction solvent.
  • the obtained compound (VII) can be converted to compound (III) by the methods described in Method B, Step 3 and Method B, Step 4.
  • the intermediate (III) or (IV) thus obtained is further converted to the compound (I) by the following methods a, b, c or d.
  • Compound (I) (wherein R 7 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl or Optionally substituted heteroaryl) is (III-a) (where Z is halogen or optionally substituted alkoxy) and the Grignard reagent R 7 — MgX (where R 7 is , Replace Alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted or heteroaryl which may be substituted. , X is a halogen).
  • the Grignard reagent can be prepared by a conventional method.
  • a catalyst ferric chloride, tris (dibenzoyl methanate) iron (III) or iron (III) acetyl acetate may be added as necessary.
  • an anhydrous ether solvent eg, tetrahydrofuran, ether
  • the reaction is usually carried out at a temperature of 0 ° C to the reflux temperature of the reaction solvent.
  • R 7 — M includes, for example, organoboron compounds (Suzuki reaction, Chem. Rev. 1995, 95, 24557), organotin compounds (Still reaction, Chem. Int.) E d. 196, 25, 508) or an organic zinc halide compound represented by ZnX (wherein X is as defined above) can be used.
  • the Suzuki reaction uses a boron compound.
  • the palladium catalyst usually, 0.1 to 0.1 equivalents of tetrakistriphenylphosphine palladium (0), bis (triphenylphosphine) palladium (II) chloride or palladium with respect to (III-a) (II) Acetate triphenylphosphine complex or the like is used.
  • an inorganic base such as sodium carbonate, potassium carbonate, thallium carbonate, barium hydroxide or thallium hydroxide, and an inorganic salt such as copper salt or lithium chloride are usually added.
  • Solvents include dioxane, 1,2-dimethoxetane, tetrahydrofuran, toluene, and benzene P99 / 0651 Zen, acetonitrile, DMF or water is used alone or as a mixture.
  • the reaction is usually performed at room temperature to the reflux temperature of the reaction solvent.
  • Compound (I) in which R 7 is an optionally substituted alkylamino and R 6 is an optionally substituted alkyl or an optionally substituted aryl are a compound (III-a) wherein Z is a halogen, Is an optionally substituted alkylsulfonyloxy or an optionally substituted arylsulfonyloxy, and R 6 is an optionally substituted alkyl or an optionally substituted aryl.) It can be produced by reacting with a substituted amine.
  • the solvent used is tetrahydrofuran, dimethylformamide or the like, and the reaction is usually performed at 0 ° (: to 60 ° C).
  • R 6 can and child converted to a compound is a good Ariru be a substituted alkyl or substituted or optionally substituted if hydrolyzing (I) compounds wherein R 6 is hydrogen (I).
  • R 6 is hydrogen, optionally substituted alkyl or optionally substituted aryl, particularly preferably hydrogen, and R 7 is optionally substituted alkoxy, optionally substituted aryloxy
  • a compound which is an alkenyloxy which may be substituted, an alkynyloxy which may be substituted, an alkylthio which may be substituted, an alkenylthio which may be substituted or an alkynylthio which may be substituted ( I) is a compound (III-a) wherein R 6 is hydrogen and Z is halogen, optionally substituted alkylsulfonyloxy or optionally substituted arylsulfonyloxy.
  • It can be produced by reacting the corresponding alkali metal salt or alkaline earth metal salt of alcohol or thioalcohol.
  • a reaction solvent tetrahydrofuran or dimethylformamide is used.
  • the reaction temperature is usually from room temperature to 50.
  • Compound (III-a) can be converted to another compound (III-a) by an appropriate reaction.
  • the ester form (III-a) can be hydrolyzed with an acid or alkali according to a conventional method to give a carboxylic acid (III-a).
  • the acid (III-a) is esterified by the same method as in Method A, Step 2,
  • R 7 — M (where R 7 is an optionally substituted alkyl, an optionally substituted alkenyl, or a substituted Alkynyl, cycloalkyl which may be substituted, aryl which may be substituted or heteroaryl which may be substituted, and M is the same as defined above. Can be manufactured That.
  • R 7 is optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aryloxy, optionally substituted alkylthio, substituted
  • the compound (XII), which is an optionally substituted alkenylthio or an optionally substituted alkynylthio, corresponds to the compound (III-b) (where Z is a halogen) exactly as in the above method a-4. It can also be obtained by reacting an alkaline metal salt or an alkaline earth metal salt of an alcohol or thioalcohol.
  • a reaction solvent tetrahydrofuran, dimethylformamide, dimethylsulfoxide or a corresponding alcohol (for example, methanol) is used.
  • the reaction temperature is usually from room temperature to the reflux temperature of the solvent.
  • Compound (I) (where R 6 is hydrogen) can be produced by oxidizing the corresponding formyl form (XII).
  • the oxidation of the formyl form to the carboxy form is exactly the same as the reaction described in Step 2 of Method B.
  • the target compound (I) can be produced by the above-mentioned method a.
  • R 7 is an optionally substituted alkoxy, an optionally substituted alkenyloxy or an optionally substituted alkynyloxy
  • R 6 is an optionally substituted alkyl or an optionally substituted aryl.
  • the compound (I) is a compound (IV) (wherein R 6 is an optionally substituted alkyl or an optionally substituted aryl), and is converted to triphenylphosphine or tributylphosphine and a dialkyl Azodicarboxylates (eg, getyl azodicarboxylate) or tetraalkyl azodicarboxamides (eg, 1,1 ′-(azodicarbonyl) dipiperidine, N, N, ⁇ ′, N′-tetra Can be synthesized by reacting with the corresponding alcohol in the presence of methyl azodicarboxamide).
  • the reaction is performed according to the method (Mitsunobu reaction) described in Synthesis 1981, 1, 1.
  • the solvent is preferably an ether solvent such as tetrahydrofuran, benzene or toluene.
  • the reaction is usually carried out at a temperature of 15 ° C. to room temperature.
  • Reduction of the C3-C4 double bond is carried out by catalytic reduction.
  • a platinum catalyst such as platinum oxide, a palladium catalyst supported on a carrier such as palladium carbon, palladium oxide, palladium chloride, palladium-calcium carbonate, and palladium-barium sulfate can be used.
  • Lower alcohols, acetates, acetic acid, acidic lower alcohols and the like are used as solvents.
  • the reaction is preferably carried out at normal pressure, but when the reaction is slow, medium pressure catalytic reduction is preferred.
  • the reaction temperature is usually from room temperature to 50. Double When the bond is reduced, a stereoisomer may be generated depending on the reaction conditions.
  • the chroman derivative may be a mixture of the stereoisomers, a single substance, or a racemate. It may be an optically active substance.
  • the ester (I) (where R 6 is an optionally substituted alkyl or an optionally substituted aryl) is a carboxylic acid (I) free from hydrolysis (where R 6 is hydrogen) ).
  • the method of hydrolysis does not need to be explained by those skilled in the art, but it is preferable to carry out the reaction with an inorganic base in water-lower alcohol or water-dimethyl sulfoxide.
  • the inorganic base include sodium hydroxide and lithium hydroxide
  • a hydration or hydration power is used.
  • the reaction temperature is usually from ice-cooling to the reflux temperature of the solvent.
  • the free carboxylic acid (I) (where R 6 is hydrogen) is esterified according to the method described in the above-mentioned Method A, Step 2, and the ester compound (I) (where R 6 is an optionally substituted alkyl) Or a reel that may have been replaced).
  • the free carboxylic acid (I) can be converted to the corresponding salt by treating it with various organic and inorganic bases.
  • the method for producing the salt does not need to be explained again by those skilled in the art, but for example, the reaction of (I) (where R 6 is hydrogen) with an equivalent amount of sodium hydroxide in water or a mixed solvent of water and a lower alcohol. And sodium salts are formed.
  • the salt can be purified by means such as recrystallization or lyophilization.
  • R 1, R 2, R 3 and R 4 are each independently nitro, it can be induced to amino by catalytic reduction.
  • the reduction of nitro is carried out using a noble metal catalyst such as palladium supported on a carrier such as carbon, and usually in a solvent such as a lower alcohol or an acetate ester at normal pressure and room temperature.
  • R 1 R 2, R 3 and R 4 are each independently hydroxy, in the presence of a base such as potassium carbonate, cesium carbonate or sodium hydride in a solvent such as acetone, acetonitrile, dimethylformamide, etc.
  • a base such as potassium carbonate, cesium carbonate or sodium hydride
  • a solvent such as acetone, acetonitrile, dimethylformamide, etc.
  • alkyl halide alkenyl halide or alkynyl halide
  • R 1 , R 2 , R 3 and R 4 are each independently hydroxy, triphenylphosphine or tributylphosphine and a dialkylazodicarboxylate (for example, getylazodicarboxylate) are used.
  • tetraalkylazodicarboxamides or tetraalkylazodicarboxamides eg, 1,1 '-(azodicarbonyl) dipiperidine, N, N, N', N'-tetramethylazodicarboxamide.
  • Mitsunobu reaction to convert to an optionally substituted alkyloxy, optionally substituted alkenyloxy or optionally substituted alkynyloxy.
  • R 1 , R 2 , R 3 and R 4 are each independently hydroxy or amino, it is not necessary for those skilled in the art to explain, but an acid chloride or an acid anhydride in the presence of a base such as pyridine Can be converted to acyloxy or amino.
  • protecting groups are benzyl, acetyl, benzoyl and the like.
  • the protecting group is benzyl, it can be deprotected by catalytic reduction.
  • the protecting group is an acyl such as acetyl or benzoyl, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydroxide, or a mixed solvent of a lower alcohol and one water or a solvent to which tetrahydrofuran or dioxane is added. It can be removed by hydrolysis with lithium hydroxide or the like.
  • a carbonyl such as an aldehyde is deprotected by acid hydrolysis at an appropriate stage after introduction as a suitable base or ketal.
  • the compound (I) having an asymmetric carbon atom includes a racemic form and an optically active form ((+)-isomer, (one) unity), and both of them are included.
  • An optically active form of the compound (I) can be obtained by optically resolving a racemate.
  • an appropriate synthetic intermediate may be optically resolved and then converted into the optically active compound (I) through the same steps as in the case of the racemic form.
  • Examples of the method of optical resolution include a method using an enzyme, a method of converting into a diastereomer salt or a diastereomer derivative and then separating it by fractional recrystallization or chromatography, a method of synthesizing by asymmetric synthesis, and the like.
  • the compound according to the present invention has a preventive and / or therapeutic effect for diabetic complications, it can be used as a therapeutic and / or ameliorating agent for diabetes, and as a preventive and / or therapeutic agent for diabetic complications. .
  • diabetic complications refer to pathological conditions caused by various metabolic abnormalities, which are caused primarily by persistent metabolic abnormalities, especially persistent hyperglycemia, and include acute complications and chronic complications .
  • the preventive and / or therapeutic agent for diabetic complications of the present invention is particularly effective for chronic complications (microangiopathy, macrovascular disorder, etc.).
  • Acute complications include, for example, diabetic ketoacidosis, non-ketonic hyperosmolar coma, lactic acidosis, alcoholic acidosis, hypoglycemic coma.
  • Chronic complications include, for example, diabetic nephropathy, urinary tract infection, bladder relaxation, pyelonephritis, renal fibrosis, renal failure, diabetic retinopathy, diabetic cataract, neovascular glaucoma, ophthalmoplegia, old neuritis , Diabetic neuropathy (sensory neuropathy, motor neuron disorder and autonomic neuropathy, etc.), diabetic peripheral circulatory failure, diabetic cerebrovascular disorder (cerebral atherosclerosis, cerebral infarction, cerebral hemorrhage, etc.), auditory neuropathy, ischemic Heart disease (myocardial infarction, heart failure, angina, asymptomatic myocardial ischemia, etc.), diabetic cardiomyopathy, poor diabetic wound healing, peripheral arteriosclerosis
  • administering the compound of the present invention as a diabetic complication preventive agent and z or a therapeutic agent it can be administered orally or parenterally.
  • Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, liquid, syrup, buccal or sublingual preparation and administering it in a commonly used form.
  • any commonly used dosage form such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents and inhalants, can be suitably administered.
  • oral administration is preferred.
  • An effective amount of the compound according to the present invention is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants, and diluents, which are suitable for the dosage form, if necessary.
  • various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants, and diluents, which are suitable for the dosage form, if necessary.
  • It can be a pharmaceutical preparation. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.
  • excipients such as lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose
  • binders such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polypinylpyrrolidone, etc.
  • the agent include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cocoa butter, macrogol, methyl cellulose or the like can be used.
  • solubilizers when preparing a liquid formulation or an emulsion or suspension injection, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added.
  • a flavoring agent In the case of oral administration, a flavoring agent, a fragrance and the like may be added.
  • the dose of the compound of the present invention as a preventive and / or therapeutic agent for diabetic complications is preferably set in consideration of the patient's age, body weight, type and degree of disease, administration route, and the like.
  • it When administered orally to an adult, it is usually 0.1 OSg OmgZkg g day, preferably within the range of 0.1-1 OmgZkg / day.
  • parenteral administration it varies greatly depending on the administration route, but is usually 0.005 to 10 mg / kg day, preferably within the range of 0.01 to 1 mgZkg day. this It may be administered once to several times a day.
  • streptozotocin A SmgZkg was added to 20-week-old male SD rats. It was administered intravenously to produce an animal model for diabetes.
  • compound (1-1) Six weeks after administration of streptozotocin, compound (1-1): In formula (I), R 1, R 3 and R 4 are hydrogen, R 2 is isopropyloxy, and R 5 is 3,4-methylene a Jiokishifueniru, R 6 is hydrogen, an R 7 is 4 main Tokishifu Eniru, 3 compounds) which broken line indicates the presence of a coupling, 1 0, S OmgZk g once a day 3 Mice were orally administered for a week, and methylcellulose (MC) was administered to the control group and the untreated group (normal rats).
  • the conduction velocities of the motor and sensory nerves of the sciatic nerve (S ciaticner V e) or the tibial nerve (Tibia 1 nerve) were determined using electrophysiological techniques and were reported in Peptides, vol. 8, 4 15—422, 1 98 7) Measured according to the method described.
  • a probe of a Doppler blood flow meter manufactured by Omega Wave was brought into contact with the exposed tibial nerve to measure the blood flow in the nerve.
  • FIGS. 1 and 2 The results are shown in FIGS. 1 and 2. Nerve conduction velocity and intraneuronal blood flow were significantly lower in the control group than in the untreated group. In the compound (I-11) administration group, such a decrease in nerve conduction velocity and intraneuronal blood flow was suppressed in a dose-dependent manner, and the effect was significant from 1 OmgZkg. From this, the inhibitory effect of compound (1-1) on diabetic neuropathy was clarified.
  • Test Example 2 Improvement of poor healing of diabetic wound 26
  • a 6-week-old male GK rat type II diabetes model rat
  • the effect of I-1) was investigated by measuring the wound area.
  • the compound (I-1) was orally administered with 3.1 OmgZkg once a day for 12 days.
  • the control group and the Wistar rats received MC.
  • the compound according to the present invention has an effect of producing diabetic neuropathy, improving diabetic wound healing, improving diabetic peripheral circulation, and the like. Therefore, the compound according to the present invention is very useful as a diabetic complication preventive agent and Z or a therapeutic agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent préventif et/ou thérapeutique utilisable en cas de complication de diabètes, caractérisé en ce qu'il comprend un composé de formule (I), dans laquelle chacun des R?1, R2, R3 et R4¿ désigne, indépendamment, l'hydrogène, un alcoxy substitué ou non substitué ou analogue, R5 désigne un alkyle substitué ou non substitué, un aryle substitué ou non substitué ou analogue, R6 désigne l'hydrogène, un alkyle substitué ou non substitué ou analogue, R7 désigne l'hydrogène, un alkyle substitué ou non substitué ou analogue, A représente S ou O, une ligne en traits interrompus indiquant la présence, ou l'absence, d'une liaison. L'invention concerne également des sels pharmaceutiquement acceptables ou un hydrate de ces composés.
PCT/JP1999/000651 1998-02-25 1999-02-16 Agent therapeutique utilisable en cas de complication de diabetes WO1999043315A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24405/99A AU2440599A (en) 1998-02-25 1999-02-16 Therapeutic agent for complication of diabetes

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JP10/42723 1998-02-25
JP4272398 1998-02-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063295A1 (fr) * 2003-12-22 2005-07-14 Alcon, Inc. Agents pour traiter la retinopathie glaucomateuse et la neuropathie optique
CN112168817A (zh) * 2020-10-21 2021-01-05 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） 3-芳基香豆素类化合物的应用
CN112645922A (zh) * 2020-12-24 2021-04-13 中国人民解放军空军军医大学 香豆素类化合物、制备方法及应用

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JPH0586952B2 (fr) * 1986-01-17 1993-12-14 Pfizer
WO1998008836A1 (fr) * 1996-08-27 1998-03-05 Shionogi & Co., Ltd. Derives de chromene-3-carboxylate
JPH10158260A (ja) * 1996-11-26 1998-06-16 Adir ベンゾピラン誘導体、それらの製造法、およびそれらを含有する医薬組成物

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JPS6113716B2 (fr) * 1978-11-08 1986-04-15 Pfizer
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JPH0586952B2 (fr) * 1986-01-17 1993-12-14 Pfizer
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063295A1 (fr) * 2003-12-22 2005-07-14 Alcon, Inc. Agents pour traiter la retinopathie glaucomateuse et la neuropathie optique
CN112168817A (zh) * 2020-10-21 2021-01-05 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） 3-芳基香豆素类化合物的应用
CN112645922A (zh) * 2020-12-24 2021-04-13 中国人民解放军空军军医大学 香豆素类化合物、制备方法及应用
CN112645922B (zh) * 2020-12-24 2022-01-07 中国人民解放军空军军医大学 香豆素类化合物、制备方法及应用

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