WO2001014385A1 - Derives de dihydrobenzofuran, leur procede de preparation et agents - Google Patents
Derives de dihydrobenzofuran, leur procede de preparation et agents Download PDFInfo
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- WO2001014385A1 WO2001014385A1 PCT/JP2000/005524 JP0005524W WO0114385A1 WO 2001014385 A1 WO2001014385 A1 WO 2001014385A1 JP 0005524 W JP0005524 W JP 0005524W WO 0114385 A1 WO0114385 A1 WO 0114385A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a novel dihydrobenzofuran derivative having an excellent lipid peroxide production inhibitory action, a method for producing the same, and a medicament containing the same.
- R 1 is a hydrocarbon group which may have a substituent, an amino group which may have a substituent or a heterocyclic group which may have a substituent
- R 2 is hydrogen.
- R 3 is a hydrogen atom
- X is CHR 4 , NR 4 , ⁇ or S
- R 4 represents a hydrogen atom or a hydrocarbon group optionally having substituent (s))
- Y is C, CH or N (where X is CH 2 , Y is C or CH)
- Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent
- ring B is a benzene ring which may have a substituent
- m is an integer of 1 to 4.
- WO 93/22317 states that the formula is useful as a therapeutic agent for heart disease.
- a ring represents a furan ring, a dihydrofuran ring or a dioxolane ring.
- R 2 is the same or different and represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group, an acyl group or a hydroxyl group.
- R 3 and R 4 may be the same or different and may have a hydrogen atom, a halogen atom, or a substituent
- R 5 , R 6 , R 7 , R 8 identical or different, each representing a hydrogen atom or an alkyl group.
- Y represents O or S
- Z represents —CH 2 — or one C ⁇ _
- R 1 represents hydrogen or a lower alkyl group.
- 2,3_g] pyrido [3,2,1-i , j] quinoline-l-6-carboxylic acid derivative or a salt thereof is used as a synthetic intermediate thereof.
- R 3 represents a lower alkyl group, and the other symbols have the same meanings as described above. ], Etc. are described.
- Lipid peroxide production inhibitors with excellent pharmacokinetics, which have lipid peroxide production inhibitory activity based on superior antioxidant activity, are used for diseases and disorders of the central nervous system (for example, ischemic central nervous system).
- Neuropathy eg, cerebral infarction, cerebral hemorrhage, cerebral edema etc.
- central nervous system injury eg, head trauma, spinal cord injury, whiplash etc.
- neurodegenerative disease eg, Alzheimer's disease, Parkinson's disease, Huntington's chorea, Amyotrophic lateral sclerosis, etc.
- vascular dementia eg, multiple infarct dementia, Binswanger's disease, etc.
- cardiovascular Diseases or disorders of the system eg ischemic heart disease (eg, myocardial infarction, angina etc.), arteriosclerosis, arterial restenosis after PTCA (percutaneous transluminal coronary angioplasi
- the present inventors have conducted various studies on compounds having an excellent lipid peroxide production inhibitory action, and found that a nitrogen-containing non-aromatic heterocycle is condensed at the 4- and 5-positions of the dihydrobenzozofuran ring.
- ring A is a non-aromatic 5- to 7-membered nitrogen-containing heterocyclic group which may further have a substituent.
- a ring, B ring represents a benzene ring which may further have a substituent, C ring represents a dihydrofuran ring which may further have a substituent, and R represents a hydrogen atom or an acyl group.
- R ′ is a hydrocarbon group which may have a substituent
- m is 1 to 4
- ring B is further substituted with a benzene ring, and ring A is substituted with oxo.
- ring B represents a fully substituted benzene ring.
- a salt thereof hereinafter sometimes abbreviated as compound (I) for the first time
- ring A a is a non-aromatic 5- to 7-membered nitrogen-containing complex ring which may further have a substituent
- ring Ba is a benzene ring which may further have a substituent
- the ring a represents a dihydrofuran ring which may further have a substituent
- Ra represents a hydrogen atom or an acyl group.
- a salt thereof hereinafter sometimes abbreviated as compound (()) also has an excellent inhibitory effect on lipid peroxide production, and has excellent effects and properties as a drug used clinically. The present invention was completed based on these.
- R 4 and R 5 are the same or different and each may be a hydrogen atom, a halogen atom, a hydroxy group, an amino group, or an oxygen atom, a nitrogen atom or a sulfur atom, and may have a substituent.
- the other symbols have the same meanings as described in the above (1). However, both R 4 and R 5 do not simultaneously represent a hydrogen atom.
- the compound according to the above (1) which is a compound represented by the formula or a salt thereof,
- R 1 and R 2 are the same or different and each represents a hydrogen atom, a carboxyl group or a hydrocarbon group which may have a substituent, and R 3 may have a hydrogen atom or a substituent
- R 1 is a lower alkyl group
- R 2 is a halogen atom, hydroxy or a lower alkyl group which may be substituted with a cyclic amino group which may have a substituent
- R 3 is a hydrogen atom or a substituted
- R 1 is a lower alkyl group
- R 2 is a halogen atom, hydroxy or a lower alkyl group which may be substituted by a cyclic amino group which may have a substituent
- R 3 is a hydrogen atom or a substituted A non-aromatic 5- to 7-membered nitrogen-containing nitrogen atom, wherein R 4 and R 5 are each a lower alkyl group, and ring A may be further substituted with a lower alkyl group;
- R 1 is a lower alkyl group
- R 2 is a halogen atom, hydroxy or a lower alkyl group which may be substituted with a cyclic amino group which may have a substituent
- R 3 is a hydrogen atom or A phenyl group which may have a substituent
- R 4 and R 5 are each a lower alkyl group, and ring A may be further substituted with a lower alkyl group.
- X represents an aryl group which may have a substituent, and other symbols are as defined above. Wherein the substituent X on the ring B and the hydroxy group of the compound or a salt thereof are closed with a hydroxy group. (20) a pharmaceutical composition comprising compound (I) or a prodrug thereof,
- composition according to (20) which is a prophylactic or therapeutic agent for cerebrovascular disorder, head injury or neurodegenerative disease.
- composition according to (21), wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.
- a prophylactic / therapeutic agent for dysuria or urinary incontinence which comprises the compound (II) or a prodrug thereof;
- a prophylactic / therapeutic agent for restenosis after percutaneous transluminal coronary angioplasty characterized by containing the compound () or a prodrug thereof;
- (26) a method for preventing or treating cerebrovascular disease, head trauma or neurodegenerative disease, wherein the mammal comprises the compound (I) or a prodrug thereof;
- (28) a method for preventing or treating restenosis after percutaneous transluminal coronary angioplasty, which comprises containing a compound (1 ′) or a prodrug thereof for a mammal;
- (29) a method for suppressing the production of lipid peroxide, which comprises administering an effective amount of the compound (1 ′) or a prodrug thereof to a mammal,
- the present invention relates to the use of the compound (II) or a prodrug thereof for producing a lipid peroxide production inhibitor.
- hydrocarbon group examples include a chain or cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl and the like). Among them, the following chain or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferred.
- lower alkyl eg, C ⁇ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- lower alkenyl e.g., vinyl, Ariru, isoproterenol base alkenyl, butenyl, isobutenyl, C 2 etc. sec- butenyl - 6 alkenyl and the like
- lower alkynyl e.g., Echiniru, Bok propynyl, propargyl, butynyl, and hexynyl, etc., to 1-C 2 - 6 alkynyl and the like
- C 3 _ 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl, cycloheptyl, etc. cyclohexylene
- C 7 - 16 Ararukiru e.g., benzyl, phenethyl, Jifue two Rumechiru, 1 one naphthylmethyl, 2-naphthylmethyl, 2, 2-Jifueniruechiru, 3 Hue Nirupuropiru, 4-phenylbutyl, 5-phenylene Rupenchiru etc. , Preferably benzyl, etc.).
- the “substituent” which the “hydrocarbon group” may have is, for example, (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), or (2) a halogenated atom. lower alkyl, (3) lower alkenyl (e.g., vinyl, Ariru, isoproterenol base alkenyl, butenyl, isobutenyl, C 2 _ 6 alkenyl such as sec- butenyl), (4) lower alk Kiniru (e.g., Echiniru, Bok propynyl, propargyl, heptynyl, 1 one to key Shin Il etc.
- a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- lower alkyl e.g., vinyl, Ariru, isoproterenol base alkenyl, butenyl, isobutenyl, C
- cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, C 3 _ 6 cycloalkyl cyclohexyl like cyclohexane, etc.
- Ariru e.g., phenyl, 1 one-naphthyl, 2-naphthyl, Bifue two Lil, and 2-anthryl C 6 _ 1 () Ariru etc.
- Ararukiru For example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2, 2- Jifueniruechiru, 3-phenylpropyl, 4-phenylbutyl, 5 - C 7, such as phenylene Rupenchiru - Ararukiru etc.
- optionally halogenated substituted e.g., cyclopropyl, cyclobutyl,
- Arukanoiru e.g., Asechiru, propionyl, Puchiriru, such Isopuchiriru - 6 alkyl - carbonyl, etc.
- ⁇ such as Nafutoiruokishi (14) carboxyl, (15) lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarponyl, propoxyl-proponyl, isopropoxyl-lponyl, butoxycarbonyl, isobutoxycarbonyl, tert-) (16) carbamoyl, thiocarbamoyl, etc.
- mono-lower alkyl rubamoyl eg, mono-6-alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl
- (16) 18) G-lower alkyl rubamoyl for example, dimethyl carbamoyl, getyl carbamoyl, etc., dialkyl mono-rubumoyl
- (19) Aryl-carbamoyl eg, phenylcarbamoyl, naphthylcarbamoyl, etc.
- (20) amidino, (21) imino, (22) amino, (23) mono-lower alkylamino e.g, phenylcarbamoyl, naphthylcarbamoyl, etc.
- di-lower alkylamino for example, dialkylamino such as dimethylamino, getylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.
- alkylenedioxy eg, methylenedioxy, ethylendioxy, etc .; alkylenedioxy, etc.
- sulfo (31) sulfino, (32) phosphono, (33) Rufamoiru
- mono- lower alkylsulfamoyl e.g., Mechirusuru Famoiru, E chill sulfamoyl, propyl sulfamoyl, isopropylamino
- di-lower alkylamino for example, dialkylamino such as dimethylamino, getylamino, ethylmethylamino, dipropylamino, diisopropylamino
- lower alkyl which may be halogenated as a substituent of “hydrocarbon group” include, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- Lower alkyl eg, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluorotrifluoropropyl , Isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo pen Le, 5, 5, 5-triflate Ruo b pentyl, hexyl, 6, 6, hexyl or the like to 6 _ triflate Ruo port, preferably methyl, and the like.
- the “(8) lower alkoxy which may be halogenated” as a substituent of the “hydrocarbon group” has, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- Lower alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, such as tert- butoxy C ⁇ - 6 alkoxy and the like
- Specific examples are methoxy, difluoromethyl O b methoxy, triflumizole Ruo b methoxy, ethoxy, 2, 2, 2-Bok Rifuruoroe Bok alkoxy, Purobokishi, Isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
- Examples of “(36) lower alkylthio which may be halogenated” as a substituent of “hydrocarbon group” include, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- Lower alkylthio which may be possessed (for example, methylthio, methylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc., and the like), and specific examples thereof include methylthio, Difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.
- (42) optionally substituted heterocyclic group as a substituent of "hydrocarbon group” includes the term “optionally substituted heterocyclic group” used in the present specification. And the same groups as those described above.
- heterocyclic group in the term “heterocyclic group optionally having substituent (s)” used in the present specification includes, as atoms (ring atoms) constituting a ring system, an oxygen atom, a sulfur atom and a nitrogen atom.
- aromatic heterocyclic group examples include, for example, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4—oxaziazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3—triazolyl, 1,2,4—triazolyl, tetrazolyl
- a 5- or 6-membered aromatic monocyclic heterocyclic group such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and, for example, benzofuranyl, isobenzofuranyl, benzochenyl, indolyl, isoindolyl,
- non-aromatic heterocyclic group examples include 3 to 4 such as oxilanyl, azetidinyl, oxetanyl, cesinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.
- examples thereof include an 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group.
- the “substituent” which the “heterocyclic group” may have is, for example, (1) an alkyl group optionally having a substituent, (2) an amino group optionally having a substituent (3) an aryl group optionally having a substituent, (4) a cycloalkenyl group optionally having a substituent, (5) a cycloalkyl group optionally having a substituent, (6 ) An alkenyl group which may have a substituent, (7) an alkynyl group which may have a substituent, (8) an amidino group which may have a substituent, and (9) an amidino group which may have a substituent.
- An optionally substituted hydroxy group (10) an optionally substituted thiol group, (11) an optionally esterified hydroxyl group, and (12) an optionally substituted substituent.
- (14) acyl group (15) halogen atom (for example, , Chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), (16) cyano group, (17) double-mouth group and the like. May be substituted (preferably 1 to 3).
- Examples of the “(1) alkyl group” as a substituent of the “heterocyclic group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl C, such as isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl — 6- alkyl and the like.
- substituent of the “(1) alkyl group” examples include lower alkoxy (eg, alkoxy such as methoxy, ethoxy, propoxy, etc.), halogen (eg, fluorine, chlorine, bromine, iodine, etc.) and lower alkyl (eg, methyl, ethyl, propyl C doctor 6 alkyl such as), Amino, hydroxy, Shiano, amidino and Ariru (eg, it may also be substituted with a substituent selected from C 6 _ 1 4 7 reels, etc.) of phenyl such as I Ararukiruokishi ( for example, it includes C 7 _ 1 6 Ararukiruokishi etc.) such as Benjiruokishi, these optional substituents may be substituted one or two at substitutable position.
- lower alkoxy eg, alkoxy such as methoxy, ethoxy, propoxy, etc.
- halogen eg, fluorine, chlorine, bro
- Examples of the substituent of the “(4) cycloalkenyl group” include the same number of the same substituents as those of the above-mentioned “(1) alkyl group”.
- C 3 _ 7 cycloalkyl groups heptyl like cyclohexane is .
- Examples of the substituent of “(2) cycloalkyl group” include the same number and the same as the substituent of “(1) alkyl group” described above. It is.
- the “(6) alkenyl group” as a substituent of the “heterocyclic group” includes, for example, vinyl, aryl, isopropyl, 2-methylaryl, 1-propyl, 2-methyl-1-probenyl, Butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl , 4 _-methyl-3-Bae Nparu, 1 one hexenyl, cyclohexenyl 2, cyclohexenyl 3 _, to 4 _ hexenyl, etc.
- substituent of the “(6) alkenyl group” include the same and similar substituents as those of the above-mentioned “(1) alkyl group”.
- alkynyl group as a substituent of the “heterocyclic group”, for example, ethynyl, 1_propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3 - pentynyl, 4-pentynyl, 1 one to key Shin Il, to 2 _ hexynyl, to 3-hexynyl, hexynyl to 4 include C 2 _ 6 alkynyl group hexynyl, etc., to 5.
- substituent of "(7) alkynyl group” include the same number and similar substituents as those of the above-mentioned "(1) alkyl group”.
- Examples of the substituent in “(2) amino group”, “(8) amidino group”, “(9) hydroxy group” and “(10) thiol group” include a lower alkyl group (eg, methyl , Echiru, propyl, isopropyl, butyl, isobutyl, t- butyl, etc. C physician 6 alkyl group hexyl etc.
- heterocyclic group those similar to the “heterocyclic group” in the above “heterocyclic group optionally having substituent (s)” and the like are used.
- “(2) amino group” as a substituent means that two substituents together with a nitrogen atom form a cyclic amino group.
- examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, and a lower alkyl group at the 4-position (eg, methyl, ethyl, propyl, isopropyl, butyl, t-yl).
- Alkyl groups such as monobutyl, pentyl, hexyl, etc.
- aralkyl groups eg, C 7 _ 1 () aralkyl groups such as benzyl and phenethyl
- aryl groups eg, phenyl, 1-naphthyl, 2-naphthyl
- C 6 _ 1 0 Ariru group) 3 to 8-membered, etc. may also be 1-piperazinyl piperazinyl optionally having like (preferably Ru include cyclic amino such as 5- or 6-membered).
- Examples of the “(11) carboxyl group which may be esterified” include, in addition to a free carboxyl group, for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group and the like.
- lower alkoxycarbonyl group examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl And i-pentyloxycarbonyl, neopentyloxycarbonyl and the like, and a C i- 6 alkoxy-carbonyl group.
- ⁇ Lal Kill O propoxycarbonyl group is, for example, benzyl O carboxymethyl Cal Po sulfonyl, Hue phenethyl Ruo alkoxycarbonyl C 7 _ 1 0 Ararukiruokishi Ichiriki Ruponiru group such like.
- Examples of “(12) optionally substituted rubamoyl group” include unsubstituted rubamoyl group, N-monosubstituted rubamoyl group, and N, N-disubstituted rubamoyl group.
- N-monosubstituent rubamoyl group means a carbamoyl group having one substituent on a nitrogen atom, and examples of the substituent include lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.). , Isobutyl, t-butyl, pentyl, And C 6 alkyl groups such as hexyl).
- N, N-disubstituted rubamoyl group means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is an “N-monosubstituted carbamoyl group” described above. like can be mentioned a substituent in ", as the other example, a lower alkyl group (e.g. methyl for example, Echiru, propyl, isopropyl, heptyl, t-butyl, pentyl, the hexyl or the like to ( ⁇ _ 6 alkyl group etc.), C 3 _ 6 cycloalkyl Le group (e.g.
- Examples of the yl group include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholino-capillonyl, 1-piperazinylcarbonyl, and a lower alkyl group at the 4-position (for example, methyl, ethyl, propyl, isopropyl, Alkyl groups such as butyl, t-butyl, pentyl, hexyl, etc., aralkyl groups (eg, C 7 _ 1 () aralkyl groups such as benzyl and phenethyl), and aryl groups (eg, phenyl, 1-naphthyl, And a 3- to 8-membered (preferably 5- or 6-membered) cyclic amino-carbonyl such as 1-piperazinylcarbonyl which may have a C 6 such as 2-naphthyl or the like.
- aralkyl groups e
- Examples of the substituent of the “(13) thiocarbamoyl group” as the substituent of the “heterocyclic group” include the same substituents as those of the above-mentioned “(12) Levamoyl group”.
- the ⁇ heterocyclic group '' may have 1 to 4, preferably 1 or 2 at the substitutable position on the ring, and when the number of substituents is 2 or more, They may be the same or different.
- optionally substituted amino group includes Examples thereof include an amino group optionally having one or two substituents, a cyclic amino group optionally having a substituent, and the like.
- amino group optionally having one or two substituents include mono-lower alkylamino (for example, mono-lower alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) (: I 6 alkylamino, etc.), di - lower alkylamino (e.g., Jimechiruamino, Jechiruamino, Echirume Chiruamino, Jipuropiruamino, diisopropyl ⁇ amino, di such Jibuchiruamino - flicking 6 alkylamino and the like) and the like.
- mono-lower alkylamino for example, mono-lower alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) (: I 6 alkylamino, etc
- cyclic amino group of the “optionally substituted cyclic amino group” include a hetero atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom and one nitrogen atom.
- 3 to 6-membered cyclic amino group which may contain 1 to 3
- substituent of the “amino group” examples include a hydrocarbon group which may have a substituent.
- hydrocarbon group which may have a substituent the same as the above-mentioned “hydrocarbon group which may have a substituent” is used.
- each substituent may be the same or different.
- Examples of the “substituent” of the “cyclic amino group” include a hydrocarbon group which may have a substituent.
- the “hydrocarbon group which may have a substituent” the same as the above-mentioned “hydrocarbon group which may have a substituent” is used.
- the ⁇ cyclic amino group '' may have 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions of the cyclic amino group, and when the number of the substituents is 2 or more, Each substituent may be the same or different.
- acyl group includes, for example, acyl derived from carboxylic acid or sulfonic acid.
- formyl lower alkyl carbonyl (for example, d-alkyl monopropanol such as acetyl, propionyl, butyryl, isoptyryl, etc.), aryl Rucarponyl (for example, C6 ⁇ 0 aryl-carbonyl such as benzoyl and naphthoyl), aralkylcarbonyl (for example, benzylcarbonyl, phenethylcarbonyl, naphthylmethylcarbonyl, etc., aryl-C ⁇ -ealkyl-carbonyl) ), Lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycalponyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc., 6-alkoxycarbonyl, etc.), aralkylo alkoxycarbonyl (e.g., C 6
- C 6 ⁇ may have a lower alkyl.
- reel sulfonyl e.g., phenylalanine sulfonyl, Nafuchirusuru Honiru, tosyl, etc.
- Lal Kill sulfonyl e.g., benzylsulfonyl, full energy chill sulfonyl, C 6 _ i such naphthylsulfonyl methylsulfonyl.
- C 6 _ i such naphthylsulfonyl methylsulfonyl.
- Li one root ci _ 6 ⁇ Rukylsulfonyl and the like.
- These groups may further have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
- ring A represents a non-aromatic 5- to 7-membered nitrogen-containing heterocyclic ring which may further have a substituent.
- non-aromatic 5- to 7-membered nitrogen-containing heterocycle represented by ring A includes, for example, a 5- to 7-membered (preferably 5- or 6-membered) non-aromatic containing at least one nitrogen atom in addition to a carbon atom.
- examples thereof include a nitrogen heterocycle, and specific examples thereof include 2,3-dihydro-1H-pyrrolyl, 1,2-dihydropyridine, 1,2,3,4-tetrahydropyridine, 2,3,4,5 —Tetrahydro-1H-azepine, 2,3-dihydro-1H-azepine and the like.
- Examples of the substituent which the “non-aromatic 5- to 7-membered nitrogen-containing heterocycle” may further have include, for example, a hydrocarbon group which may have a substituent, a lower alkoxy group which may be halogenated , optionally halogenated substituted lower alkylthio group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), Ariruokishi group (e.g., C 6, such as phenoxy - 1 0 Ariruokishi etc.), lower Arukanoiru (e.g., Asechi , Propionyl, butyryl, isobutyryl and other alkyl monocarbonyl), Ariru force Ruponiru group (e.g., Benzoiru, such as naphthoyl C 6 - 1 () Ariru - carbonyl), lower alkanoyloxy noisy Ruo alkoxy group (e.g., Asechiruokish
- a 3- to 6-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atom and one nitrogen atom) 3 to 6 such as aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, morpholino, thiomorpholino, dihydropyridyl, pyridyl, N-methylbiperazinyl, N-ethylpyperazinyl Membered cyclic amino, etc.), alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, etc., 3-alkylenedioxy etc.), hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamo
- Arylthio group for example, c 6 _ 1 () arylthio such as phenylthio, naphthylthio, etc.), lower alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.) C- 6 alkylsulfinyl, etc.), arylsulfinyl group (eg, C6 such as phenylsulfinyl, naphthylsulfinyl, etc.) and lower alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl) , Buchi Cis- 6 alkylsulfonyl such as rusulfonyl, etc., and an arylsulfonyl group (for example,
- the ⁇ non-aromatic 5- to 7-membered nitrogen-containing heterocyclic ring '' represented by ring A is, for example, as described above, having 1 to 4, preferably 1 or 2 substituents at substitutable positions on the ring. When the number of substituents is two or more, they may be the same or different.
- the ring A is, for example, a non-aromatic which may be further substituted by a hydrocarbon group which may have a substituent (preferably a lower (C ⁇ e) alkyl group which may have a substituent)
- a substituent preferably a lower (C ⁇ e) alkyl group which may have a substituent
- a 5- to 7-membered nitrogen-containing heterocyclic ring or the like is preferable, and a non-aromatic 5- to 7-membered nitrogen-containing heterocyclic ring which may be further substituted by a lower alkyl group (preferably an alkyl group such as methyl) is more preferable.
- Particularly preferred are aromatic 5-membered nitrogen-containing heterocycles and the like.
- ring B represents a benzene ring further having a substituent.
- a halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
- a hydroxy group for example, an amino group, and an oxygen atom, a nitrogen atom or a sulfur atom
- examples include a hydrocarbon group which may have a substituent.
- Examples of the “benzene ring” as a substituent such as “a hydrocarbon group optionally interposed through an oxygen atom, a nitrogen atom or a sulfur atom, and having a substituent” include, for example, a substituent A hydrocarbon group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an amino group which has a substituent, and a group which has a substituent Examples thereof include a good alkylthio group and an arylthio group which may have a substituent.
- alkoxy group” in the “optionally substituted alkoxy group” as the substituent of the “benzene ring” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- And lower (C ⁇ ) alkoxy such as butoxy.
- substituent that the “alkoxy group” may have include the same as the “substituent” in the aforementioned “hydrocarbon group optionally having a substituent”.
- the ⁇ alkoxy group '' may have 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions, and when the number of substituents is 2 or more, each substituent is the same or It may be different.
- substituent which the “aryloxy group” may have include the same as the “substituent” in the above-mentioned “hydrocarbon group which may have a substituent”.
- the “aryloxy group” may have 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions. It may be different.
- amino group having a substituent as a substituent of the “benzene ring” include, for example, an amino group having one or two substituents, a cyclic amino group which may have a substituent, and the like.
- amino group having one or two substituents and the “cyclic amino group optionally having a substituent” include the above-mentioned “heterocyclic group optionally having a substituent” as a substituent.
- cyclic amino group optionally having substituent (s) in "2amino group optionally having substituent (s)” . .
- alkylthio group in the “alkylthio group optionally having substituent (s)” as a substituent of the “benzene ring” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert- And C, 6 alkylthio such as butylthio.
- substituent which may have “alkylthio group” include the same as the “substituent” in the above-mentioned “hydrocarbon group which may have substituent”.
- the ⁇ alkylthio group '' may have 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions, and when the number of the substituents is 2 or more, each substituent is the same or It may be different.
- arylthio group in the “arylthio group optionally having substituent (s)” as the substituent of the “benzene ring”
- substituent (s) substituent of the “benzene ring”
- examples of the “arylthio group” in the “arylthio group optionally having substituent (s)” as the substituent of the “benzene ring” include, for example, phenylthio, naphthylthio and the like. Arylthio and the like. "Arylthio group” may have
- substituteduent examples include those similar to the “substituent” of the “hydrocarbon group which may have a substituent” described above.
- the "arylthio group” may have 1 to 5, preferably 1 to 3 of the above substituents at replaceable positions, and when the number of the substituents is 2 or more, each substituent is the same Or it may be different.
- the ⁇ benzene ring '' represented by ring B has one or two, preferably two, of the above substituents at substitutable positions on the ring, and when the number of substituents is 2, they are the same or different. Is also good.
- the ring B is preferably an all-substituted benzene ring.
- a halogen atom or an electron donating group (a hydroxy group, an amino group, or an oxygen atom, a nitrogen atom, or a sulfur atom) Or a hydrocarbon group which may have a substituent).
- the ring C represents a dihydrofuran ring which may further have a substituent.
- substituents which the “dihydrofuran ring” represented by the ring C may further have include, for example, a carboxyl group, a hydrocarbon group optionally having a substituent, an amino group optionally having a substituent And the like.
- Examples of the “optionally substituted hydrocarbon group” as the substituent of the “dihydrofuran ring” include the same as the aforementioned “optionally substituted hydrocarbon group”.
- a “cyclic amino group optionally having substituent (s)” can also be preferably used.
- Z c is a hydrogen atom, an alkyl group which may have a substituent or an aromatic group which may have a substituent
- Ring D may have a substituent and may be condensed with a benzene ring 5 to 8
- Y is a carbon atom or a nitrogen atom
- Z a is a bond, an oxygen atom, a sulfur atom, a group represented by the formula NR 9 (wherein R 9 represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group), and Z b represents a divalent aliphatic hydrocarbon group which may have a bond or a substituent and may be via an oxygen atom, a nitrogen atom or a sulfur atom. And the like.
- alkyl group of the “optionally substituted alkyl group” represented by Z c examples include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and other C—e alkyls, etc.).
- lower alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and other C—e alkyls, etc.
- Examples of the “aromatic group” of the “aromatic group which may have a substituent” represented by Z c include, for example, an aromatic hydrocarbon group, an aromatic heterocyclic group and the like.
- aromatic hydrocarbon group examples include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
- aromatic hydrocarbon group examples include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
- phenyl, 1-naphthyl, 2-naphthyl, C 6 such as anthryl - 1 4 Ariru the like.
- phenyl, 1-naphthyl, 2-naphthyl, etc. are Ce- !.
- Particularly preferred is phenyl.
- aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom, And a 5- to 10-membered monocyclic ring containing 1 or more (for example, 1 to 4) heteroatoms selected from oxygen and oxygen atoms, or a fused aromatic heterocyclic group thereof.
- aromatic rings eg, benzene ring, pyridine ring, etc.
- Preferred examples of the “aromatic heterocyclic group” include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, _ Isoquinolyl, 4-isoquinolyl, 5 _ isoquinolyl, 1 _ indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzothenyl, benzofuranyl, 2-phenyl, 3- phenyl, 2- benzoxazolyl, 2 — Benzimidazolyl, 2-
- Examples of the “substituent” of the “aromatic group which may have a substituent” represented by Z c include, for example, an octagonogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a ⁇ 3 alkylene dioxy ( examples, Mechirenjiokishi, Echirenjiokishi etc.), nitro, Shiano, optionally halogenation d - 6 alkyl, C 3 - 6 cycloalkyl (e.g., Shikuropuro pills, cyclobutyl, cyclohexyl, etc.
- an octagonogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- a ⁇ 3 alkylene dioxy examples, Mechirenjiokishi, Echirenjiokishi etc.
- nitro Shiano
- cyclopentyl, cyclohexylene halogenated D-6 alkoxy, optionally halogenated d- 6 alkylthio, hydroxy, amino, mono-d- 6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), G d-6 alkylamino (eg, dimethylamino, getylamino, ethylmethylamino) Bruno, jib port Piruamino, Jibuchiruamino etc.), C, - 6 alkyl one carbonyl (eg, Asechiru, Propionyl, etc.), carboxyl, alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxyl-ponyl, butoxycarbonyl, etc.), l-rubamoyl, mono-alkyl l-rubamoyl (e
- Alirubolmoyl eg, phenylcarbamoyl, naphthylcarbamoyl, etc.
- sulfo 6- alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C 6-,.
- Aryl eg, phenyl, naphthyl, etc.
- C6- eg, phenyloxy, naphthyloxy, etc.
- Aryloxy eg, phenyloxy, naphthyloxy, etc.
- the substituent is Ci-3 alkylenedioxy, it is desirable to form a ring with two adjacent carbon atoms.
- halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
- Ci- 6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
- Specific examples are methyl, chloromethyl, difluoromethyl.
- Trichloromethyl trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluoro Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like.
- Optionally halogenated C, - 6 alkoxy The above-mentioned, for example, 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) but it may also have a C, - 6 alkoxy and the like. Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-1 Trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
- 1 to 3 halogen atoms e.g., fluorine, chlorine, bromine, iodine, etc.
- Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, but
- Optionally halogenated C, - 6 alkylthio The above-mentioned, for example 1 a stone 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) which may have a Good C, - 6 alkylthio (e.g., methylthio, Echiruchio, propylthio, iso Piruchio, Puchiruchio, sec- Puchiruchio, tert- Puchiruchio etc.) and the like, as completely as example, methylthio, difluoromethyl O b methyl thio, triflumizole Ruo b methylthiopyrimidine And ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.
- halogen atoms e.g.,
- the “aromatic group” of the “aromatic group optionally having substituent (s)” includes, for example, 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions on the ring. May be present, and when the number of substituents is two or more, they may be the same or different.
- Z c is preferably a substituent an aromatic group optionally having, more preferably which may have a substituent, respectively C 6 - 14 7 reel (preferably phenyl), 2-pin lysyl, 3 _Pyridyl, 4-pyridyl, 2_indolyl, 3'indolyl or benzoimidazole, particularly preferably C 6 -i which may have a substituent. It is a file.
- substituteduent preferably, eight androgenic atom, C, - a 6 alkoxy and C, -6 alkyl.
- Z c is more preferably a halogen atom, C t - 6 alkoxy and C, - 6 to the substituents 1 are selected from alkyl which may have three C 6 - 14 Ariru (preferably phenyl) is . Further, Z c is 1 or 2 C 6 _ 14 ⁇ Li - may be substituted with Le. An alkyl is also preferred.
- Examples of the "5- to 8-membered nitrogen-containing heterocycle" of the "5- to 8-membered nitrogen-containing heterocycle optionally having a substituent and optionally condensed with a benzene ring" for ring D include, for example, Examples thereof include a 5- to 8-membered saturated or unsaturated heterocyclic ring containing at least one nitrogen atom in addition to a carbon atom.
- piperidine piperazine, 1,2,5,6-tetrahydropyridine, pyrrolidine, 1H-azepine, 1H—2,3-dihydroazepine, 1H—2,3,4,5-tetrahydro Azepine, 1H—2,3,6,7-tetrahydroazepine, 1H—2,3,4,5,6,7—hexahydroazepine, 1H—1,4-diazepine, 1H—2,3-dihydro-1 , 4-Diazepine, 1H—2,3,4,5-tetrahydro_1,4_dazepine, 1H—2,3,6,7-tetrahydro-1,4-diazepine, 1H—2,3,4,5 , 6,7-hexahydro-1,4-diazepine, 1,2-dihydroazosin, 2,3,4,5-tetrahydroazosin, 1,2,3,4,5,6_hexahydroa Zosin, 1,2,3,
- the “optionally substituted aromatic group” represented by the aforementioned Zc has One to three of the same substituents may be used. When the number of substituents is two or more, each substituent may be the same or different.
- Ring D may have a substituent, may be condensed with a benzene ring, and may be a 6- or 7-membered nitrogen-containing heterocycle, more preferably 1,2,4,5-tetrahydro-3H-benzazepine. , Piperidine or piperazine.
- R 1 represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, optionally halogenated d-6 alkyl, C 3
- - 6 cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like to the consequent opening
- G-d- 6 alkylamino eg, dimethylamino, getylamino, ethylmethylamino, dipropylamino, dipropylamino, etc.)
- D-6 alkyl monopropionyl eg, acetyl, propionyl, etc.
- carboxyl d- ⁇ - alkoxy monopropionyl (eg, methoxycarbonyl,
- R 1Q is preferably a hydrogen atom, Shiano, d 6 alkyl (e.g., cyclohexyl and methyl, E chill, propyl, isopropyl, butyl, isobutyl, pentyl,), d-6 alkoxy (e.g., methoxy, ethoxy, Purobokishi , Isopurobokishi, butoxy, isobutoxy, Kishiruokishi like Penchiruokishi to,), hydroxy, Amino, mono - d 6 Arukiruamino, di - -6 Arukiruamino, -6 alkyl - carbonyl, or the like.
- d 6 alkyl e.g., cyclohexyl and methyl
- E chill propyl
- isopropyl butyl, isobutyl, pentyl
- d-6 alkoxy e.g., methoxy, ethoxy, Purobo
- Za is preferably a bond.
- Y is preferably CH or N. More preferably, it is CH.
- R 9 is preferably a hydrogen atom or d-6 alkyl. More preferably, it is a hydrogen atom.
- Za is preferably a bond or a group represented by the formula NR 9 (wherein each symbol has the same meaning as described above).
- Examples of the divalent aliphatic hydrocarbon group which may be via an atom include, for example,
- M is preferably ⁇ is NR 11.
- R 1 ′ is preferably a hydrogen atom.
- P and Q are preferably each an integer of 0 to 5. More preferably, it is an integer of 0 to 4.
- the “substituent” which the “divalent aliphatic hydrocarbon group optionally interposed with through an oxygen atom, a nitrogen atom or a sulfur atom” may be, for example, an octogen atom (eg, fluorine, chlorine , bromine, iodine), nitro, Shiano, but it may also be halogenated d-6 alkyl, C 3 - 6 cycloalkyl (e.g., cyclopropyl, Shikuropuchi Le, cyclopentyl, cyclohexyl, etc.) optionally halogenated Alkoxy, optionally halogenated C, -6 alkylthio, hydroxy, amino, mono-C6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) di-C, — 6 if alkylamino (eg, Jimechiruamin
- Ararukiru e.g., benzyl, phenethyl, etc.
- Ariruokishi e.g., Fueniruokishi, Nafuchiruokishi etc.
- Okiso Ashiru the like are the "halogenated May be d-one Alkyl ",” optionally halogenated or d-6 alkoxy "and” optionally halogenated good C, - The 6 alkylthio ", details substitution of the aromatic group represented by Z c The same ones as mentioned above can be mentioned.
- the substituent may be substituted with 1 to 5 substituents at substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different.
- Z b is preferably a bond or a group represented by the formula: — (CH 2 ) p—M— (CH 2 ) q_ (wherein the symbols have the same meanings as described above). More preferably, it is a bond or a group represented by the formula: (CH 2 ) p—NR 11 — (CH 2 ) q_ (wherein the symbols have the same meanings as described above).
- amino group optionally having substituent (s) as a substituent of "dihydrofuran ring
- amino group optionally having substituent (s) described above as a substituent of "heterocyclic group optionally having substituent (s)”
- amino group optionally having a group the amino group optionally having a group
- the ⁇ dihydrofuran ring '' represented by ring C may have 1 to 3 of the above substituents at substitutable positions on the ring, and when there are two substituents, they may be the same or different. Is also good.
- R represents a hydrogen atom or an acyl group.
- ring B represents a benzene ring further having a substituent.
- R ′ represents an optionally substituted hydrocarbon group
- ⁇ optionally substituted hydrocarbon group '' or ⁇ may have a substituent ''
- non-aromatic 5-membered nitrogen-containing heterocycle represented by ring A
- examples of the “non-aromatic 5-membered nitrogen-containing heterocycle” represented by ring A include the same as those described above, for example, pyrrolidine and the like.
- ring A is a non-aromatic 6-membered nitrogen-containing heterocyclic ring substituted with oxo
- ring B represents a fully substituted benzene ring.
- non-aromatic 6-membered nitrogen-containing heterocycle represented by ring A
- examples of the “non-aromatic 6-membered nitrogen-containing heterocycle” represented by ring A include the same as those described above, for example, piperidine and the like.
- R 4 and R 5 may be the same or different and each may be a hydrogen atom, a halogen atom, a hydroxy group, an amino group, or an oxygen atom, a nitrogen atom or a sulfur atom, and may have a substituent. Other symbols are as defined above. However, both R 4 and R 5 do not simultaneously represent a hydrogen atom. Or a salt thereof, and the like.
- Examples of the ⁇ halogen atom '' and ⁇ hydrocarbon group optionally intervening through an oxygen atom, a nitrogen atom or a sulfur atom and having a substituent '' represented by R 4 or R 5 include the ring B described above.
- R 4 and R 5 are the same or different and do not represent a hydrogen atom at the same time, and may each be via an oxygen atom, a nitrogen atom or a sulfur atom, and may have a substituent.
- each is preferably a lower alkyl group (preferably an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.) or a lower alkoxy group (preferably methoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, s - C i _ 6 butoxy, more preferably if t is an alkoxy group butoxy, etc.), each lower alkyl group (preferably methyl, t like one-butyl An alkyl group or the like is particularly preferable.
- R 1 and R 2 are the same or different and each is a hydrogen atom, an optionally esterified or amidated may force even if Rupokishiru group or hydrocarbon group which may have a substituent
- R 3 is A hydrogen atom, a hydrocarbon group which may have a substituent or an amino group which may have a substituent
- the compound represented by the formula or a salt thereof is more preferred.
- Examples of the ⁇ hydrocarbon group optionally having substituent (s) '' represented by R 1 and R 2 include the ⁇ hydrocarbon group optionally having substituent (s) '' as the substituent of the aforementioned ring C. Similar ones can be mentioned.
- R 1 is a lower alkyl group (e.g. methyl, Echiru, propyl, isopropyl, blanking chill, Isopuchiru, s- butyl, t one heptyl, C of hexyl etc. pentyl, - 6 ⁇ And the like.
- R 1 is a lower alkyl group (e.g. methyl, Echiru, propyl, isopropyl, blanking chill, Isopuchiru, s- butyl, t one heptyl, C of hexyl etc. pentyl, - 6 ⁇ And the like.
- R 2 is a halogen atom, hydroxy or a cyclic amino group which may have a substituent (the above-mentioned “cyclic amino group which may have a substituent (s)”, in particular, wherein the ring D is 1,2,4,5-tetrahydro- 3H-benzazepine, piperidine or piperazine, Y is CH, Za is a bond or a group represented by formula NR 9 (R 9 is as defined above), Zb is a bond or formula ( CH 2) p- M- (CH 2 ) q- ( in groups symbols in the formula represented by as defined above), substituted with a Z c force I) 1 or 2 C 6 _ 14 Ariru which may be Al kill or (2) eight-neck Gen atom, C i _ 6 alkoxy and C!
- the substituents 1 are selected from alkyl to optionally each have three to C 6 _ 14 Ariru, 2 _ pyridyl, 3 - pyridyl, 4 _ pyridyl, 2-indolyl, 3 _ indolyl or base Nzoimi imidazole Certain cases are preferred.
- R 3 represents a hydrogen atom, a hydrocarbon group which may have a substituent, or an amino group which may have a substituent.
- R 3 is preferably a hydrogen atom or a phenyl group which may have a substituent (eg, a 6- alkyl group such as methyl), and more preferably a hydrogen atom.
- R 1 is a lower alkyl group (for example, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.) and R 2 is a halogen.
- R 1 is a lower alkyl group (for example, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, etc.) and R 2 is a halogen.
- a lower alkyl group which may be substituted with an atom, hydroxy or a cyclic amino group which may have a substituent (the above-mentioned "cyclic amino group which may have a substituent") (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t-butyl, the like d_ 6 alkyl group hexyl etc.
- R 3 is a hydrogen atom or a substituent (such as alkyl group such as methyl)
- R 4 and R 5 are each an optionally substituted phenyl group Is a lower alkyl group (preferably methyl, alkyl groups such as t one-butyl) at,
- a ring is a lower alkyl group (preferably methyl, etc.
- Bok 6 further optionally substituted non-aromatic alkyl group
- It is preferably a 5- to 7-membered nitrogen-containing heterocyclic group (preferably a non-aromatic 5-membered nitrogen-containing heterocyclic ring).
- the ring Aa represents a non-aromatic 5- to 7-membered nitrogen-containing heterocyclic ring which may further have a substituent.
- non-aromatic 5- to 7-membered nitrogen-containing heterocyclic ring optionally having a substituent represented by the ring A a
- non-aromatic 5- to 7-membered nitrogen-containing heterocycle
- the Ba ring represents a benzene ring which may further have a substituent.
- Examples of the substituent that the benzene ring which is the Ba ring may have include the same substituents as those described above for the benzene ring which is the B ring.
- the ring Ca represents a dihydrofuran ring which may further have a substituent.
- Ra represents a hydrogen atom or an acyl group.
- acyl group represented by R a examples include the same as the above-mentioned “acyl group” represented by R.
- the ring Aa, ring Ba, ring Ca and ring Ra are preferably the same as the above-mentioned rings or groups as preferable in ring A, ring B, ring C and R.
- a pharmacologically acceptable salt or the like is used as the salt of the compound (I) or (1 ′).
- examples include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
- the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and an aluminum salt.
- salt with an organic base examples include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, Salts with dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned.
- salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, Salts with benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned.
- Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
- Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, etc. Salts.
- pharmaceutically acceptable salts are preferable.
- the pharmaceutically acceptable salt include those having a basic functional group in the compound (I) or (II), for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphorus.
- Salts with inorganic acids such as acids, for example, organic acids such as acetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid
- organic acids such as acetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid
- alkali metal salts such as sodium salts and potassium salts
- alkaline earth metal salts such as calcium salts and magnesium salts
- ammonium salts examples thereof include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts.
- Compound (II) can be produced by the same method as compound (I) or a method analogous thereto.
- the compound in the reaction formula includes a case where a salt is formed, and examples of the salt include those similar to the salt of compound (I).
- Compound (I) is produced by the steps shown in Synthetic Method 1.
- R a and Rb in the formula are substituents forming a part of R 1 and include the same substituents as the “hydrocarbon group” may have.
- the “leaving group” represented by L includes, for example, hydroxy, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), optionally halogenated Cis ssulfonyloxy (eg, methanesulfonyloxy) Xy, sulfonyloxy, trichloromethyl sulfonyloxy, etc.) and C 6 _ 1 () arylsulfonyloxy which may have a substituent.
- halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- Cis ssulfonyloxy eg, methanesulfonyloxy
- Xy e.g, sulfonyloxy
- sulfonyloxy e.g, trichloromethyl sulfonyloxy, etc.
- C 6 _ 1 arylsulfony
- C 60 arylsulfonyloxy optionally having substituent (s) includes, for example, a substituent selected from alkyl (eg, methyl, ethyl, etc.), alkoxy (eg, methoxy, ethoxy, etc.) and nitro , 1 to group optionally having three C 6 - 10 ⁇ reel sulfonyl O carboxymethyl (eg, phenylalanine sulfonyl O carboxymethyl, naphthylsulfonyl O carboxymethyl, etc.) and the like, and specific examples, benzenesulfonyl O carboxymethyl , M-nitrobenzenesulfonyloxy, -toluenesulfonyloxy and the like.
- alkyl eg, methyl, ethyl, etc.
- alkoxy eg, methoxy, ethoxy, etc.
- nitro , 1 to group optionally having three C 6 -
- the amount of compound (III) to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (II).
- base examples include inorganic bases such as sodium hydroxide and potassium hydroxide. , Basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogen carbonate; aromatic amines such as pyridine and lutidine; triethylamine; trippyramine; triptylamine; Tertiary amines such as N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diamine Metal amides such as isopropylamide and lithium hexamethyldisilazide; and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.
- the amount of the base to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (II).
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides or a mixed solvent thereof are preferred.
- the reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours.
- the reaction temperature is usually about -20 to about 150 ° (:, preferably about 0 to about 100 ° C).
- compound (II) and compound (III) in which L is OH are reacted with an azodicarboxylate (eg, getyl azodicarboxylate, etc.) and a phosphine (eg, trif. (Enyl phosphine, tributyl phosphine, etc.).
- an azodicarboxylate eg, getyl azodicarboxylate, etc.
- a phosphine eg, trif. (Enyl phosphine, tributyl phosphine, etc.
- the amount of the compound in which L is ⁇ H is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of the compound (II).
- the "azodicarboxylates” and “phosphines” are used in an amount of about 1.0 to about 5.0 mol, preferably about 1.0 to about 5.0 mol, per 1 mol of compound (II), respectively. 2.0 moles.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent inert to the reaction.
- the reaction is not particularly limited as long as the reaction proceeds.
- solvents such as ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, and the like are preferred.
- the reaction time is generally about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
- the reaction temperature is usually about 120 to about 200 ° C, preferably about 0 to about 10 °.
- Compound (V) is produced by subjecting compound (IV) to Claisen rearrangement.
- This reaction is advantageously performed without a solvent or using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, anilines, halogenated hydrocarbons Alternatively, a mixed solvent thereof is used.
- This reaction may be carried out using an acid catalyst, if desired.
- the acid catalyst Lewis acids such as aluminum chloride and boron tribromide are used.
- the amount of the acid catalyst used is, for example, in the case of a Lewis acid, usually about 0.1 to about 20 mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (IV).
- the reaction time is generally about 30 minutes to about 24 hours, preferably about 1 hour to about 6 hours.
- the reaction temperature is usually about -70 to about 30 O :, preferably about 150 to about 25.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by a usual separation method (eg, recrystallization, distillation, chromatography, etc.) Can be easily purified.
- a usual separation method eg, recrystallization, distillation, chromatography, etc.
- Compound (la) can be produced by cyclizing compound (V) in the presence of a protonic acid or a Lewis acid.
- the protic acid include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and fluorosulfonic acid.
- the Lewis acids include aluminum chloride and aluminum bromide. , Titanium tetrachloride, tin (IV) chloride, zinc chloride, boron trichloride, boron tribromide, boron trifluoride and the like are used. Usually, each of the protonic acid and the Lewis acid is used alone, but they may be combined as desired.
- a protonic acid When a protonic acid is used, it is used in an amount of about 1.0 to about 200 mol, preferably about 1.0 to about 100 mol, per 1 mol of compound (V).
- compound (V) When a Lewis acid is used, compound (V) About 1.0 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol is used.
- a solvent inert is not particularly limited as long as the reaction proceeds, but examples thereof include solvents such as ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, octogenated hydrocarbons, nitrils, and sulfoxides. Alternatively, a mixed solvent thereof is preferable.
- the reaction temperature is usually about 120 to about 15 Ot, preferably about 0 to about 100 ° C.
- the reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
- the product (VI) can be used in the next reaction as a reaction solution or as a crude product.However, it can be isolated from the reaction mixture according to a conventional method, and can be separated by separation means such as recrystallization, distillation, and chromatography. It can be easily purified.
- Compound (la) can also be produced by reacting compound (V) with a halogenating reagent.
- halogenating reagent examples include halogens such as bromine, chlorine and iodine, imides such as N-bromosuccinimide, halogen addition such as benzyltrimethylammonium dichloride and benzyltrimethylammonium tribromide. Objects etc. are used.
- the amount of the halogenating reagent to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (V).
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, amides, octogenated hydrocarbons, nitriles, sulfoxides, Organic acids, nitroalkanes, aromatic amines, or a mixed solvent thereof are used.
- This reaction is carried out, if desired, in the presence of a base or a radical initiator, or under light irradiation.
- base examples include basic salts such as sodium carbonate, calcium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, and potassium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, and tributylamine. , Cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N_dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methyl And tertiary amines such as tylmorpholine.
- the amount of the base to be used is about 0.8 to about 10 mol per 1 mol of compound (V).
- radical initiator for example, benzoyl peroxide, azobisisobutyl nitrile and the like can be mentioned.
- the amount of the radical initiator to be used is about 0.01 to 1 mol per 1 mol of compound (V).
- a halogen lamp In the case of light irradiation, a halogen lamp can be used.
- the reaction temperature is usually about -50 to about 150, preferably about 0 to about 10 Ot.
- the reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.
- ordinary separation means eg, recrystallization, distillation, chromatography, etc.
- Compound (la) can also be produced by cyclizing compound (V) by treating it with an organic peracid in the presence of a base, if desired.
- Organic peracids include m-chloroperbenzoic acid, peracetic acid and the like.
- the organic peracid is used in an amount of about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (V).
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds. Examples thereof include water, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, and: sulfoxide.
- Organic acids, aromatic amines and the like, or a mixed solvent thereof is preferred.
- the optionally used base include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, aromatic amines such as pyridine, lutidine, triethylamine, tripropylamine, and the like.
- aromatic amines such as pyridine, lutidine, triethylamine, tripropylamine, and the like.
- Tertiary amines such as triptylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like. It is.
- the reaction temperature is usually about 120 to about 150, preferably about 0 to about 100.
- the reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
- the product (la) can also be isolated from the reaction mixture in a customary manner, by recrystallization, distillation, C which can be easily purified by Matogurafi Chief separating means
- R c represents an acyl group, and examples thereof include the same as the above-mentioned “acyl group”.
- R d and R e are substituents forming a part of R 6 and include the same substituents as the “hydrocarbon group” may have.
- Compound (XI) is produced by reacting compound (IX) with compound (X), if desired, in the presence of a base.
- the amount of compound (X) to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (IX).
- base examples include inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogen carbonate; aromatic amines such as pyridine and lutidine; Triethylamine, Trip Tertiary amines such as oral pyramine, triptylamine, cyclohexyldimethylamine, 4_dimethylaminopyridine, N, N_dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, Alkali metal hydrides such as potassium hydride, metal amides such as sodium amide, lithium disopropylamide, lithium hexamethyldisilazide, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Is mentioned.
- the amount of the base to be used is about 1.0 to about 5.0 mol, preferably about 1.0
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, Solvents such as sulfoxides or a mixed solvent thereof are preferred.
- the reaction time is generally about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours.
- the reaction temperature is usually about -20 to about 150, preferably about 0 to about 100.
- the amount of the compound in which L is OH is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of the compound (IX). It is.
- the amount of the "azodicarboxylates” and “phosphines” used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol per 1 mol of the compound (IX), respectively. 0.0 mole.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, and sulfur. Solvents such as ruboxides or a mixed solvent thereof are preferred.
- the reaction time is generally about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
- the reaction temperature is usually about 120 to about 15 Ot :, preferably about 0 to about 10 ° C.
- Compound (lb) is prepared by subjecting compound (XI) to Claisen rearrangement followed by ring closure in the presence of an acid catalyst.
- the acid catalyst for example, Lewis acids such as zinc chloride, aluminum chloride and tin chloride are used.
- the amount of the acid catalyst to be used is generally about 0.1 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XI).
- This reaction is advantageously performed without a solvent or using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, anilines, halogenated hydrocarbons Alternatively, a mixed solvent thereof is used.
- the reaction time is generally about 30 minutes to about 24 hours, preferably about 1 to about 6 hours.
- the reaction temperature is usually about -70 to about 300 ° C, preferably about 150 to about 250 ° C.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.
- ordinary separation means eg, recrystallization, distillation, chromatography, etc.
- the 2,3-dihydro-5-hydroxyindole derivative used in the synthesis method 1 is produced by the steps shown in the synthesis methods 3-1, 3-2 and 3-3.
- Compound (XIII) is produced by reducing compound (X11).
- the reducing agent for example, sodium octidosulfite, tin (II) chloride and the like are used.
- the reducing agent in the case of sodium hydrosulfite, the reducing agent is used in an amount of about 1.0 to about 30 mol, preferably about 2.0 to about 5.0 mol, per 1 mol of compound (XII).
- tin (II) chloride it is used in an amount of about 1.0 to about 10 mol, preferably about 2.0 to about 5.0 mol, per 1 mol of the compound (II).
- the reaction is usually performed in the presence of a mineral acid such as hydrochloric acid in an acidic condition.
- a mineral acid such as hydrochloric acid in an acidic condition.
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds.
- water or a mixed solvent of water and alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, and the like is preferable.
- the reaction time is generally about 10 minutes to about 10 hours, preferably about 10 minutes to about 2 hours.
- the reaction temperature is usually about 0 to about 100 :, preferably about 5 to about 80 :.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography can do.
- the compound (XIII) can be produced by reducing the compound (XIII) using hydrogen and a hydrogenation catalyst such as platinum oxide, palladium carbon, Raney nickel, Raney cobalt, or the like.
- a hydrogenation catalyst such as platinum oxide, palladium carbon, Raney nickel, Raney cobalt, or the like.
- the amount of the hydrogenation catalyst to be used is about 0.1 to about 1000% by weight, preferably about 1 to about 300% by weight, relative to compound (XII).
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, organic acids such as formic acid and acetic acid, and the like. Preferred are mixed solvents thereof.
- the reaction time varies depending on the activity and amount of the catalyst used, but is usually about 10 minutes to about 100 hours, preferably about 10 minutes to about 10 hours.
- the reaction temperature is usually about 0 to about 12 O :, preferably about 20 to about 80 ° C. When a hydrogenation catalyst is used, the pressure of hydrogen is usually about 1 to about 100 atm.
- the product can be used as is in the reaction solution or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, or chromatography. can do.
- Compound (XIV) is produced by alkylating compound (XI II). In this reaction, compound (XIII) is reacted with a corresponding alkylating agent (eg, a corresponding alkyl octalide, a sulfonic acid ester of an alcohol, etc.) in the presence of a base, if desired.
- a corresponding alkylating agent eg, a corresponding alkyl octalide, a sulfonic acid ester of an alcohol, etc.
- the alkylating agent is used in an amount of about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of the compound (XI).
- the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogencarbonate; aromatic amines such as pyridine and lutidine; triethylamine; tripropylamine; triptylamine; cyclohexyldimethylamine.
- Tertiary amines such as amine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, lithium hydride, etc.
- the base is used in an amount of about 2.0 to about 10.0 mol, preferably about 2.0 to about 5.0 mol, per 1 mol of compound (XIII).
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, for example, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides Or a mixed solvent thereof is preferred.
- the reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours.
- the reaction temperature is usually about 120 to about 200 ° C, preferably about 0 to about 150.
- Compound (XV) is produced by formylating compound (XIV).
- the compound (XIV) is reacted with dichloromethyl alkyl ethers in the presence of an acid catalyst, and then hydrolyzed to obtain a formyl compound.
- the dichloromethyl alkyl ethers include dichloromethyl methyl ether and dichloromethyl butyl ether.
- the dichloromethyl alkyl ether is used in an amount of about 1.0 to 10.0 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XIV).
- the acid catalyst include titanium (IV) chloride, aluminum chloride and tin (IV) chloride.
- the acid catalyst is generally used in an amount of about 1.0 to 10.0 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XIV).
- This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited, as long as the reaction proceeds. Is preferred.
- the reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually from 120 to 100 T, preferably from 0 to 80 C.
- Subsequent hydrolysis is performed by mixing the reaction with water. Formylation can also be carried out under Vilsmeier reaction conditions. In this method, formamides are obtained by reacting formamides in the presence of an acid catalyst, followed by hydrolysis with a base.
- Formamides include methylformamide and dimethylformamide.
- Formamides are compound (XIV) 1 mole About 1.0 to 10.0 moles, and preferably about 1.0 to 5.0 moles.
- the acid catalyst include phosphoryl chloride and thionyl chloride.
- the acid catalyst is generally used in an amount of about 1.0 to 10.0 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XIV).
- This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. Preferred are mixed solvents thereof.
- the reaction time is generally 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
- the reaction temperature is usually from ⁇ 20 to 100 :, preferably from 0 to 80 ° C.
- Subsequent hydrolysis is performed by mixing the reaction with a base.
- the base include inorganic bases such as sodium hydroxide and potassium hydroxide, and basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate.
- the amount of the base to be used is about 1.0 to 30.0 mol, preferably about 5.0 to 10.0 mol, per 1 mol of compound (XIV).
- the product can be used as a reaction solution or as a crude product in the next reaction. can do.
- Compound (XVI) is produced by reducing compound (XV), octalogenating the resulting alcohol form, and subsequently substituting with a cyano group.
- the reducing agent used for the reduction include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, porantetrahydrofuran complex, and porandimethylsulfur Polane complexes such as sulfide complexes, alkylporans such as texyl borane and diciamylporane, dipolane, or metals such as zinc, aluminum, tin, and iron; alkali metals such as sodium and lithium; Z liquid ammonia (perch reduction); Is mentioned.
- the hydrogenation catalyst for example, a catalyst such as palladium carbon, platinum oxide, Raney nickel, and Raney cobalt is used.
- the amount of the reducing agent used is, for example, in the case of metal hydrides, about 1.0 to about 10 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of the compound (XV), In the case of complex compounds, about 1.0 per mole of compound (XV) About 10 mol, preferably about 1.0 to about 3.0 mol, and in the case of borane complex, alkylporane or dipolane, about 1.0 to about 5.0 mol per 1 mol of compound (XV).
- the catalyst such as carbon, platinum oxide, Raney nickel and Raney cobalt is used in an amount of about 5 to 100% by weight, preferably about 10 to about 300% by weight, based on the compound (XV).
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, but for example, a solvent such as alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, and organic acids, or a mixed solvent thereof is preferable. .
- the reaction time varies depending on the type and amount of the reducing agent used or the activity and amount of the catalyst, but is usually about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours.
- the reaction temperature is usually about 0 to about 120 T :, preferably about 20 to about 80 :.
- the hydrogen pressure is usually about 1 to about 100 atmospheres.
- the product can be used in the next reaction as a reaction solution or as a crude product. It can be purified.
- halogenating agent examples include, for example, thionyl halides such as thionyl chloride and thionyl bromide, halogenated phosphoryls such as phosphoryl chloride and phosphoryl bromide, phosphorus pentachloride, phosphorus trichloride, and pentabromide Phosphorus halides such as phosphorus and phosphorus tribromide; oxalyl halides such as oxalyl chloride; phosgene;
- the halogenating agent is used in an amount of about 1.0 to about 30 moles, preferably about 1.0 to about 10 moles, per mole of the alcohol compound.
- This reaction is advantageously performed without a solvent, or using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, but for example, a solvent such as an aliphatic hydrocarbon, an aromatic hydrocarbon, an ether, an amide, a halogenated hydrocarbon, or a mixed solvent thereof.
- the reaction time is generally about 10 minutes to about 12 hours, preferably about 10 minutes to about 5 hours.
- the reaction temperature is usually about ⁇ 10 to about 200 ° C., preferably about 110 to about 120 ° C.
- the product can be used as a reaction solution or as a crude product for the next reaction. It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization, distillation, or chromatography.
- an inorganic cyanide such as sodium cyanide and potassium cyanide is used.
- the inorganic cyanide is used in an amount of about 0.8 to about 10 moles, preferably about 1.0 to about 5 moles, per mole of the halide.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, but for example, a solvent such as ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides or the like; These mixed solvents are preferred.
- the reaction temperature is generally about _20 to about 150 ° (: preferably about 0 to about 100.
- the reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 100 minutes.
- the product (XV) can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be recrystallized, distilled, or chromatographed. Can be easily purified by such separation means.
- Compound (XVI I) is produced by reducing compound (XVI).
- the reducing agent used in the reduction include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, porane tetrahydrofuran complex, porane Borane complexes such as dimethylsulfide complex, alkylporans such as texylporan and disiamylporan, dipolane, or metals such as zinc, aluminum, tin and iron; alkali metals such as sodium and lithium / liquid ammonia (batch reduction) ) And the like.
- the hydrogenation catalyst for example, a catalyst such as palladium carbon, platinum oxide, Raney-nickel, Raney-cobalt, or the like is used.
- the amount of the reducing agent used is, for example, in the case of metal hydrides, about 1.0 to about 10 moles, preferably about 1.0 to about 3.0 moles, and preferably about 1.0 to about 3.0 moles, per mole of compound (XVI).
- a catalyst such as palladium carbon, platinum oxide, Raney nickel, and Raney cobalt is used as a compound ( XVI) is about 5 to about 1000% by weight, preferably about 10 to about 300% by weight.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds, but examples thereof include solvents such as alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, and organic acids, and mixed solvents thereof. I like it.
- the reaction time varies depending on the type and amount of the reducing agent used or the activity and amount of the catalyst, but is usually about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours.
- the reaction temperature is usually about 0 to about 120 ° C, preferably about 20 to about 80. When a hydrogenation catalyst is used, the hydrogen pressure is usually about 1 to about 100 atmospheres.
- the product (XVI I) can be used in the next reaction as a reaction solution or as a crude product. It can be easily purified.
- Compound (XVI II) is produced by oxidizing compound (XVI I) with an oxidizing agent, followed by treatment with a base to effect cyclization.
- Nummonium nitrate is widely used as an oxidizing agent.
- the oxidizing agent is used in an amount of about 1.0 to about 10 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XVII).
- This reaction is advantageously performed in a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, but examples thereof include a mixed solvent of water and nitriles, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, and the like. preferable.
- the reaction time varies depending on the type and amount of the oxidizing agent used or the activity and amount of the catalyst, but is usually about 10 minutes to about 5 hours, preferably about 30 minutes to about 1 hour.
- the reaction temperature is generally about 110 to about 120 ° (preferably, about 0 to about 60 ° C.
- Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and sodium hydrogencarbonate; aromatic amines such as pyridine and lutidine; Triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine; The same reaction solvent as used in the oxidation reaction is used.
- the reaction temperature is usually about ⁇ 20 to about 150, preferably about 0 to about 100 ° C.
- the reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
- the product (XVI II) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by a separation method such as recrystallization, distillation, or chromatography.
- Compound (XIX) is produced by reducing compound (XVI 11).
- the reducing agent for example, rhodium, sodium hydrosulfite, tin (II) chloride and the like are used.
- the amount of the reducing agent to be used is, for example, in the case of sodium hydrosulfite, about 1.0 to about 30 mol, preferably about 2.0 to about 5.0 mol, per 1 mol of compound (XVIII),
- tin (II) chloride the amount is about 1.0 to about 10 mol, preferably about 2.0 to about 5.0 mol, per 1 mol of compound (XVI II).
- the reaction is usually carried out under acidic conditions in the presence of a mineral acid such as hydrochloric acid.
- a mineral acid such as hydrochloric acid.
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds.
- the reaction time is usually about 10 minutes to about 10 hours, preferably about 10 minutes to about 2 hours.
- the reaction temperature is usually about 0 to about 100, preferably about 5 to about 80.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.
- Compound (IIa) is synthesized by acylating compound (XIX).
- Compound (XIX) is reacted with an acylating agent, if desired, in the presence of a base or an acid.
- the acylating agent include a corresponding carboxylic acid or a reactive derivative thereof (eg, acid octylide, acid anhydride, ester, etc.).
- the acylating agent is used in an amount of about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XIX). This reaction is advantageously performed without a solvent or in a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, for example, ethers, Preferred are solvents such as aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitrils, sulfoxides, and aromatic amines, and mixed solvents thereof.
- the base optionally used include triethylamine, pyridine and the like.
- the acid used if desired include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.
- the reaction temperature is about ⁇ 20 to about 150, preferably about 0 to about 100.
- the reaction time is generally about 5 minutes to about 24 hours, preferably 10 minutes to about 5 hours.
- the product (Ila) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by recrystallization, distillation, chromatography, chromatography, etc. Can be easily purified.
- Compound (XIX) can also be produced by the steps shown in Synthesis method 3-2.
- Halogen Compound (XXI I) is produced by selectively hydroxymethylating compound (XX) to the ortho position of phenol via compound (XXI).
- Compound (XXI) is produced by reacting compound (XX) with phenylpolonic acid and paraformaldehyde in the presence of an acid catalyst while removing water produced using a Deans trap.
- Phenylporonic acid is used in an amount of about 1.0 to about 10 mol, preferably about 1.0 to about 1.5 mol, per 1 mol of compound (XX).
- Paraformaldehyde is used in an amount of about 1.0 to about 30 mol, preferably about 3 to about 5 mol, per 1 mol of compound (XX).
- the acid catalyst for example, an organic acid such as acetic acid, propionic acid, and trichloroacetic acid is used.
- the reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, but is usually a solvent such as ethers, aliphatic hydrocarbons, aromatic hydrocarbons or a mixed solvent thereof, preferably benzene or toluene.
- the reaction temperature is usually about 0 to about 200, preferably about 50 to about 150.
- the reaction time varies depending on the amount of reagents used, the type of solvent and the reaction temperature, but is usually about 10 minutes to about 10 hours, preferably about 30 minutes to about 3 hours.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.
- Compound (XXI I) is produced by deprotecting phenylporonic acid from compound (XXI) using hydrogen peroxide, 1,3-propanediol, genoleamine and the like.
- a solvent inert to the reaction such as benzene or toluene, may be used as the auxiliary solvent.
- the reaction time varies depending on the amount of reagents used, the type of solvent and the reaction temperature, but is usually about 10 minutes to about 48 minutes. Hours, preferably from about 5 hours to about 16 hours.
- the product can be used as a reaction solution or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography. can do.
- Compound (XXI II) can be obtained by selectively alkylating the phenolic hydroxyl group of compound (XXI I) with an alkylating agent represented by R g L.
- R g is Al Represents a kill (eg, methyl, ethyl, etc.), and the “leaving group” represented by L is the same as described above.
- the amount of the alkylating agent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XXII).
- base examples include inorganic bases such as sodium hydroxide and hydroxylated lime; basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate; aromatic amines such as pyridine and lutidine; Tertiary amines such as triethylamine, trippropylamine, triptylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpiperidine, and N_methylmorpholine; Alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropyl pyramide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Metal alkoki Earth, and the like.
- the amount of the base to be used is about 0.8 to about 5.0 mol, preferably about 1.0
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- a solvent such as sulfoxides or a mixed solvent thereof is preferred.
- the reaction time is generally about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours.
- the reaction temperature is usually about ⁇ 20 to about 150 T, preferably about 0 to about 100 T.
- Compound (XXIV) can be obtained by converting the hydroxyl group of compound (XXI11) to halogen with a halogenating reagent.
- halogenating reagent examples include phosphorus tribromide, phosphorus pentabromide, phosphorus halide such as phosphorus trichloride or phosphorus pentachloride, thionyl halide such as thionyl chloride, triphenylphosphine-tetrahalogenated carbon, diphenyl Trihalogenophosphorane, triphenylphosphine dihalogenide, and triphenyldihalide phosphonate are used.
- the amount of halogenating reagent used is about 1 per mole of compound ( ⁇ ⁇ ) About 5 moles, preferably about 1 to about 2 moles.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, amides, octogenated hydrocarbons, nitriles, sulfoxides, Organic acids, nitroalkanes, aromatic amines, or a mixed solvent thereof are used.
- the reaction temperature is usually about -50 to about 150, preferably about 0 to about 100 :.
- the reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). Can be easily purified.
- ordinary separation means eg, recrystallization, distillation, chromatography, etc.
- Compound (XXV) can be obtained by converting the halogen of compound (XXIV) to cyano with a cyanating agent in the same manner as in the cyanation performed when compound (XVI) is produced from compound (XV).
- a cyanating agent in the same manner as in the cyanation performed when compound (XVI) is produced from compound (XV).
- Compound (XXVI) can be obtained by reducing compound (XXV) with a reducing agent in the same manner as in the production of compound (XVI) from compound (XVI).
- Compound (XXVI I) can be obtained by protecting the amino group of compound (XXVI) with a acylating agent in the presence of a base or an acid, if desired.
- the amount of the acylating agent to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XXVI).
- acylating agent for example, carboxylic acid corresponding to an acyl group usually used as a protecting group (for example, formyl group, acetyl group, trifluoroacetyl group, etc.) or a reactive derivative thereof (for example, Acid halides, acid anhydrides, esters and the like).
- the amount of the base or acid to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XXVI).
- Examples of the “base” include triethylamine, pyridine, 4-dimethylaminopyridine and the like.
- Examples of the “acid” include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.
- This reaction is advantageously performed without a solvent or in the presence of a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, and aromatic amines. Or a mixture of two or more of these.
- the reaction temperature is about ⁇ 20 to about 150 t :, preferably about 0 to about 1001 :.
- the reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
- the product can be used in the next reaction as a reaction solution or as a crude product.However, it can be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. It can be purified.
- Compound (XXVI 11) is obtained by oxidizing compound (XXVI I) to quinone with an oxidizing agent. Chromic acid is frequently used as an oxidizing agent.
- the oxidizing agent is used in an amount of about 1.0 to about 10 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXVII).
- the reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, and examples thereof include organic acids, acetic anhydride, aliphatic hydrocarbons, aromatic hydrocarbons, octogenated hydrocarbons, aromatic amines, and A mixed solvent of these and water, water and the like are preferable.
- the reaction time varies depending on the type and amount of the oxidizing agent used, but is usually about 10 minutes to about 5 hours, preferably about 30 minutes to about 1 hour.
- the reaction temperature is usually about -10 to about 120 ° C, preferably about 0 to about 60 ° C.
- Compound (XXIX) can be obtained by deprotecting the amino-protecting group of compound (XXVI) using an acid or a base.
- the amount of the acid and base to be used is about 0.1 to about 50 mol, preferably about 1 to about 20 mol, per 1 mol of compound (XXVI II), respectively.
- Examples of the “acid” include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, and the combined use of Lewis acids with thiols or sulfides; Organic acids such as trifluoroacetic acid and p-toluenesulfonic acid are used.
- Examples of the “base” include metal hydroxides such as sodium hydroxide, potassium hydroxide, and potassium hydroxide, basic salts such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide, and potassium.
- Metal alkoxides such as tert-butoxide, and organic bases such as triethylamine, imidazole, and formamidine are used.
- This reaction is advantageously performed without a solvent or in the presence of a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds.
- examples of the solvent include alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water, and water. Mixtures of more than one species are used.
- the reaction time is generally about 10 minutes to about 50 hours, preferably about 30 minutes to about 12 hours.
- the reaction temperature is usually about 0 to about 200, preferably about 20 to about 120.
- Compound (XIX) can be obtained by cyclizing compound (XXIX) followed by reduction.
- the cyclization reaction can be produced by treating a benzoquinone compound with a base.
- the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and sodium hydrogen carbonate; aromatic amines such as pyridine and lutidine; triethylamine; tripropylamine; triptylamine; cyclohexyldimethylamine.
- tertiary amines such as 4-, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, and N-methylmorpholine.
- the same reaction solvent as used in the oxidation reaction is used.
- the reaction temperature is usually about 120 to about 150 t :, preferably about 0 to about 100.
- the reaction time is generally about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
- the product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. In the subsequent reduction reaction, the same conditions as in producing compound (XIX) from compound (XVI II) are used.
- Compound (XIX) can also be produced by the steps shown in Synthesis Method 3-3. Synthesis method 3-3
- Compound (XXXI) can be obtained from compound (XXX) by the method described in Gasman (J. Am. Chem. Soc.) 95, 6508-6509, 1973, Journal of American Chemical Society. According to these methods, the compound (XXX) can be reacted with an alkylchlorosulfonium ethyl acetate, and then reacted in the presence of a base, and then, if necessary, heat-treated or acid-treated to form an oxindole ring. it can. Alkyl chlorosulfonium acetate can be obtained by chromatizing alkyl thioacetate with chlorine, sulfuryl chloride, hypocrite and the like.
- the alkylchlorosulfonium acetate is used in an amount of about 0.9 to about 1.5 mol, preferably about 1.0 to about 1.2 mol, per 1 mol of compound (XXX).
- This reaction is advantageously performed using a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, but halogenated hydrocarbons and the like are preferable.
- the reaction time is generally about 5 minutes to about 5 hours, preferably about 30 minutes to about 2 hours.
- the reaction temperature is usually about -100 to about 50 ° C, preferably about 180 to about 50 ° C.
- Bases include aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, N, N, ⁇ ', N'-tetramethyl-1,8-naphthylenediamine, Tertiary amines such as 4-dimethylaminopyridine, ⁇ , ⁇ -dimethylaniline, ⁇ -methylbiperidine, ⁇ -methylpyrrolidine, ⁇ -methylmorpholine and the like.
- the reaction temperature is usually about -80 to about 50, preferably about 0 to about 2O.
- the acid used if desired for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and fluorosulfonic acid, formic acid, acetic acid, and trichloroacetic acid are used.
- the acid is used in an amount of about 1 to about 200 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXX).
- the reaction time is generally about 1 minute to about 5 hours, preferably about 30 minutes to about 2 hours.
- the reaction temperature is usually about -50 to about 150: preferably about 0 to about 5.
- a solvent inert to the reaction such as getyl ether, dichloromethane, and toluene
- synthesis can be performed by heating instead of acid treatment.
- the reaction temperature is 50 to 250 T :, preferably 50 to 150.
- the reaction time is 10 minutes to 48 hours, preferably 30 minutes to 5 hours.
- a solvent inert to the reaction such as toluene, hexane or decalin, may be used as an auxiliary solvent.
- the product can be used as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by a separation means such as recrystallization, distillation, or chromatography. .
- Compound (XXXI I) is obtained by desulfurizing compound (XXXI) using a metal catalyst such as Raney nickel or tin, preferably Raney nickel catalyst, or thinlet
- the Raney nickel catalyst is used in an amount of about 0.1 to about 20 g, preferably about 1 to about 5 g, per 1 mmol of compound (XXXI).
- This reaction is advantageously carried out without solvent or in a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, but examples thereof include solvents such as alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, nitriles and the like, or a mixed solvent thereof. preferable.
- the reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 10 hours.
- the reaction temperature is usually about 0 to about 150 ° C, preferably about 20 to about 100.
- the product can be used as a crude product in the next reaction after removing the catalyst, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, and chromatography. To be refined Can be.
- Compound (XXXI I) is produced by reducing compound (XXXI I).
- the reducing agent used in the reduction include metal hydrides such as aluminum hydride and diisobutyl hydride, metal aluminum complex compounds such as lithium aluminum hydride, sodium borohydride and Red-A1, and porane tetrahydrofuran.
- Complexes, porane complexes such as borane dimethyl sulfide complex, alkyl porans such as texyl porane, diciamyl porane, and dipolane.
- the amount of the reducing agent used is, for example, in the case of metal hydrides and metal hydride complex compounds, about 0.3 to about 10 moles, preferably about 0.5 to about 3 moles per mole of compound (XXXII). 1.0 mole, about 1.0 to about 5.0 moles for 1 mole of compound (XXXII) in the case of poran complex, alkylborane or diporane, and about 1.0 to about 20 equivalents for metal. It is preferably about 1 to about 5 equivalents.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent for example, a solvent such as ethers, aliphatic hydrocarbons, and aromatic hydrocarbons, or a mixed solvent thereof is preferable.
- the product After removing the catalyst, the product can be used as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by separation means such as recrystallization, distillation, and chromatography. It can be easily purified.
- Compound (XIX) can also be produced by the steps shown in Synthetic Methods 3-4.
- Compound (XXXVI) is produced by condensing compound (XXXIV) with compound (XXXV) in the presence of a base.
- Compound (XXXV) is used in an amount of about 1.0 to about 300 mol, preferably about 3.0 to about 100 mol, per 1 mol of compound (XXXIV).
- the base examples include ammonium salts such as ammonium acetate and ammonium formate, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and sodium hydrogencarbonate; aromatic amines such as pyridine and lutidine; triethylamine; Tertiary amines such as trippyramine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylbiperidine, N-methylpyrrolidine, N-methylmorpholine, etc. Is mentioned.
- ammonium salts such as ammonium acetate and ammonium formate
- inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and sodium hydrogencarbonate
- aromatic amines such as pyridine and lutidine
- triethylamine Tertiary amines such as trippyramine, tributylamine, cyclohe
- the base is used in an amount of about 0.1 to about 10.0 mol, preferably about 0.2 to about 5.0 mol, per 1 mol of compound (XXXIV).
- This reaction is advantageously performed without a solvent or in a solvent inert to the reaction.
- the solvent is not particularly limited as long as the reaction proceeds, for example, alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides Or a mixed solvent thereof is preferred.
- Reaction time is usually about 30 minutes to about 48 o'clock For about 1 to about 24 hours.
- the reaction temperature is usually about 0 to about 15O :, preferably about 20 to about 100 ° C.
- Compound (XXXVI I) is produced by reducing compound (XXXVI).
- the reducing agent used in the reduction include metal hydrides such as aluminum hydride and diisobutyl aluminum hydride; metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride; porantetrahydrofuran complex; Borane complexes such as polandimyl sulfide complex, alkylboranes such as texyl borane and diciamylporan, dipolane or metals such as zinc, aluminum, tin and iron, alkali metals such as sodium and lithium, liquid ammonia (perch reduction), etc. No.
- the hydrogenation catalyst for example, a catalyst such as palladium carbon, platinum oxide, Raney nickel, Raney cobalt and the like are used.
- the amount of the reducing agent used is, for example, in the case of metal hydrides, about 1.0 to about 10 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXXVI),
- metal hydrides about 1.0 to about 10 moles, preferably about 1.0 to about 3.0 moles, per mole of compound (XXXVI)
- a poran complex, an alkylporane or dipolane about 1.0 to about 5.0 moles, preferably about 1.0 to about 20 equivalents, preferably about 1 to about 5 equivalents for metals, and about 1 to about 5 equivalents for 1 mole of compound (XXXVI).
- a catalyst such as palladium carbon, platinum oxide, Raney nickel, and Raney cobalt is used in an amount of about 5 to about 10 equivalents relative to compound (XXXVI). % By weight, preferably about 10 to about 300% by weight.
- This reaction is advantageously performed using a solvent inert to the reaction.
- a solvent is not particularly limited as long as the reaction proceeds.
- a solvent such as alcohols, ethers, aliphatic hydrocarbons, aromatic hydrocarbons, amides, and organic acids, or a mixed solvent thereof are preferred.
- amines such as ammonia may be further added to suppress side reactions.
- the reaction time varies depending on the type and amount of the reducing agent used or the activity and amount of the catalyst, but is usually about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours.
- the reaction temperature is usually about 0 to about 120, preferably about 20 to about 80 ° C.
- the hydrogen pressure is usually about 1 to about 100 atmospheres.
- the product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography can do.
- Compound (XXXVI 11) is produced from compound (XXXVI I) in the same manner as in producing compound (XVI 11) from compound (XVI I).
- Compound (XXXIX) is produced from compound (XXXVI11) in the same manner as in producing compound (XIX) from compound (XVIII).
- Compound (lib) is produced from compound (XXXV IX) in the same manner as in producing compound (Ila) from compound (XIX).
- Examples of the protecting group for amino include formyl or an alkyl-carbonyl (for example, acetyl, propionyl, etc.) which may have a substituent, phenylcarbonyl, alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, etc.), Phenyloxycarponyl, C? ⁇ .
- Aralkyloxy monocarbonyl for example, benzyloxycarbonyl and the like
- trityl phthaloyl and the like are used.
- substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), C i _ 6 alkyl - Karuponiru (e.g., Asechiru, pro Pioniru, valeryl etc.), nitro and the like are used, a substituent The number is about one to three.
- carboxyl protecting group for example, C 6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. are used. .
- substituents examples include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, Ci-6 alkyl-monocarbonyl (eg, acetyl, propionyl, butyl carboxyl, etc.), nitro, (: ⁇ 6 alkyl (for example, methyl, ethyl, tert-butyl, etc.), aryl (for example, phenyl, naphthyl, etc.) and the like are used, and the number of substituents is About 1 to 3 pieces.
- halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
- formyl e.g, acetyl, propionyl, butyl carboxyl, etc.
- Ci-6 alkyl-monocarbonyl eg, acetyl, propionyl, butyl carboxyl, etc.
- nitro e.g.
- hydroxy-protecting group examples include formyl, or an alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7 -diaralkyl (Eg, benzyl, etc.), 6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenyloxycarbonyl, dialkylalkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.), tetrahydroviranyl, tetrahydrofuranyl, silyl, etc.
- a substituent eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
- phenyl, C 7 -diaralkyl Eg, benzyl, etc.
- substituents examples include halogen atom (e.g., fluorine, chlorine, bromine, iodine), C i -. e alkyl (e.g., methyl, Echiru, tert- Petit Le etc.), C 7 - ⁇ Ararukiru ( For example, benzyl, etc.), C 6 - 1 0 Ariru (eg If, phenyl, naphthyl, etc.), nitro and the like are used, and the number of the substituents is about four from 1.
- halogen atom e.g., fluorine, chlorine, bromine, iodine
- C i -. e alkyl e.g., methyl, Echiru, tert- Petit Le etc.
- C 7 - ⁇ Ararukiru For example, benzyl, etc.
- C 6 - 1 0 Ariru eg If, phenyl, naphthyl, etc.
- a method for removing the protecting group a method known per se or a method analogous thereto is used. Examples thereof include an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiolrubamate, and tetrabutylammonium.
- a method of treating with fluoride, palladium acetate, or the like, or a reduction reaction is used.
- a deprotection reaction an acylation reaction, an alkylation reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a carbon chain extension reaction, and a substituent exchange reaction may be used alone or in combination of two or more.
- Compound (I) can be synthesized by combining the above. For these reactions, for example, the methods described in New Experimental Chemistry Courses 14, 15 and 1977 (Maruzen Publishing) are adopted.
- alcohols examples include methanol, ethanol, propanol, isopropanol, tert-butanol and the like.
- ethers examples include getyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxetane and the like.
- halogenated hydrocarbons examples include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like.
- Examples of the “aliphatic hydrocarbons” include hexane, pentane, and cyclohexane. And xane.
- aromatic hydrocarbons examples include benzene, toluene, xylene, and benzene.
- aromatic amines examples include pyridine, lutidine, quinoline and the like.
- amides examples include ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetoamide, hexamethylphosphoric triamide and the like.
- ketones examples include acetone, methylethyl ketone, and the like.
- sulfoxides examples include dimethyl sulfoxide.
- nitrile examples include acetonitrile, propionitrile and the like.
- organic acids examples include acetic acid, propionic acid, trifluoroacetic acid and the like.
- anilines examples include ⁇ , ⁇ -ethylylaniline, ⁇ , ⁇ -dimethylaniline and the like.
- nitroalkanes examples include nitromethane, nitrene, and the like.
- the target product When the target product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. Can also.
- the compound (I) thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like.
- the compound (I) or ( ⁇ ) exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, each of them may be separated by the aforementioned separation and purification means, if desired. Can be isolated.
- the compound (I) or (1 ′) is a racemate, it can be separated into an S-isomer and an R-isomer by ordinary optical resolution means.
- the compound (I) or (III) has a stereoisomer, the case where the isomer is used alone and the case where the isomer is a mixture thereof are also included in the present invention.
- Compound (I) or (II) may be a hydrate or a non-hydrate.
- Compound (I) or (II) may be labeled with an isotope (eg, 3 H, 14 C, 35 S) or the like.
- an isotope eg, 3 H, 14 C, 35 S
- a prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, the compound (I) is enzymatically oxidized, reduced, hydrolyzed, or the like. ) Or a compound that is converted to compound (I) by hydrolysis or the like by stomach acid or the like.
- a compound in which the amino group of compound (I) is acylated, alkylated, or phosphorylated for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarponylated
- the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarponylated
- compound Compounds in which the hydroxyl group of (I) is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivalylated
- prodrugs of compound (I) are compounds that change to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Vol. 7, Molecular Design, pp. 163 to 198. It may be.
- the compound (I) or ( ⁇ ) of the present invention has an excellent lipid peroxide production inhibitory action, It is also useful as a pharmaceutical because it has low toxicity and few side effects.
- the compound (I) or ( ⁇ ) of the present invention has excellent antioxidant activity against mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, higgies, monkeys, humans, etc.). Inhibits the production of lipid peroxide based on its action, and has a central nervous system disease or disorder such as ischemic central nervous system disorder (eg, cerebral infarction, cerebral hemorrhage, cerebral edema), central nervous system injury (eg, head) Trauma, spinal cord injury, whiplash, etc., neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), vascular dementia (eg, multiple infarct dementia, Binswanger) Disease), manic depression, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, cardiovascular diseases and disorders, such as ischemic heart disease (eg, myocardial infarction, angina), arteriosclerosis, after PTCA Arterial restenos
- the compound (I) or ( ⁇ ) has low toxicity, and can be used as it is or according to a method known per se, in a pharmaceutical composition mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets and film-coated tablets), As powders, granules, capsules (including soft capsules), liquids, injections, nasal drops, suppositories, sustained release, patches, chewing gum, etc., orally or parenterally (eg, topically, It can be safely administered rectally or intravenously.
- a pharmacologically acceptable carrier for example, tablets (including sugar-coated tablets and film-coated tablets), As powders, granules, capsules (including soft capsules), liquids, injections, nasal drops, suppositories, sustained release, patches, chewing gum, etc., orally or parenterally (eg, topically, It can be safely administered rectally or intravenously.
- the compound (I) when administered as an oral agent to an adult as a therapeutic agent for Alzheimer's disease, is used in an amount of about 0.1 to 0.1 as an active ingredient.
- other active ingredients eg, cholinesterase inhibitors (eg, alicebut (donebezil), etc.
- brain function stimulants eg, idebenone, vinpocetine, etc.
- Parkinson's disease drugs eg, L-1 And neurotrophic factors, etc.
- the other active ingredient and compound (I) or (II) are mixed according to a method known per se, and one pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule), liquid, Injections, suppositories, sustained-release preparations, etc.)
- one pharmaceutical composition for example, tablet, powder, granule, capsule (including soft capsule), liquid, Injections, suppositories, sustained-release preparations, etc.
- Each may be formulated separately and administered to the same subject simultaneously or at staggered times.
- Examples of the pharmacologically acceptable carrier that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as a raw material for the preparation, for example, excipients, lubricants, Binders, disintegrants; solvents in liquid preparations, dissolution aids, suspending agents, tonicity agents, buffers, soothing agents and the like. If necessary, conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
- Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light gay anhydride and the like.
- lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
- binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.
- disintegrant examples include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like.
- solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
- solubilizers examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
- suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinyl Pyrrolidone, carboxymethylcellulose sodium And hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
- surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
- polyvinyl alcohol polyvinyl Pyrrolidone
- carboxymethylcellulose sodium And hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose
- tonicity agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
- buffers such as phosphate, acetate, carbonate, and citrate.
- Examples of the soothing agent include benzyl alcohol and the like.
- preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
- antioxidant examples include sulfite, ascorbic acid, and heart tocopherol.
- Root temperature in the following Reference Examples and Examples usually indicates about 10 to about 35 ° C. % Indicates weight percent unless otherwise specified. However, the yield shows mol / mol%.
- As the basic silica gel NH-DM1020 manufactured by Fuji Silicon Chemical Co., Ltd. was used.
- As the Raney nickel catalyst NDHT-90 manufactured by Kawaken Fine Co., Ltd. was used. Data that does not include NMR spectrum that cannot be confirmed by broadband, such as H and NH protons, is not described in the data.
- Acetic anhydride (0.76 mL, 8.1 mmol) was added to formic acid (4 mL), and the mixture was stirred at room temperature for 15 minutes.
- 2,3-Dihydro-2,6,7-trimethyl-1H-indol-5-ol (0.71 g, 4.0 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 hours. Ice was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 0.40 g of the title compound.
- the mixture was filtered, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate.
- the combined organic layer was washed with water, mixed with a solution of 803 ⁇ 4 sodium hydrosulfite (21.8 g, 0.10 mol) in water (200 mL), shaken, and the aqueous layer was separated.
- the organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethanol diisopropyl ether to obtain 5.79 g of the title compound.
- the reaction mixture was added dropwise to a suspension of sodium hydrogen carbonate (20 g, 0.24 mol) in water (100 mL) —ethyl acetate (100 mL) for neutralization, the organic layer was separated, and the aqueous layer was washed with ethyl acetate. Extracted twice. The combined organic layer was washed with water and saturated saline, dried over magnesium sulfate, treated with activated carbon, and filtered. The resulting solution was concentrated under reduced pressure to about 100 mL, di-tert-butyl dicarbonate (12.7 g, 58.2 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours.
- reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1), and recrystallized from ethyl acetate-hexane to obtain 15.8 g of the title compound.
- Zinc chloride (8.80 g, 64.6 mmol) was added to a solution of 2,3-dimethyl-N- (2-methyl-2-propenylbenzeneamine (3.77 g, 21.5 ol) in xylene (35 mL), and the solution was added. The heating was stopped, and a solution of sodium acetate (10.6 g, 0.129 mol) in water (30 mL) was carefully added dropwise to the resulting hot mixture, and the resulting solution was cooled and the organic layer was separated.
- the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.51 g of an oil. This was dissolved in N, N-getylaniline (5 mL) and stirred at 200 ° C for 8 hours under a nitrogen atmosphere. After cooling, the reaction mixture was crystallized by adding hexane, and recrystallized from ethanol-hexane to obtain 1.71 g of the title compound. Yield 74%.
- the reaction mixture was ice-cooled, neutralized with 25% aqueous ammonia, and extracted twice with ethyl acetate.
- the combined organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
- Diisopropyl ether was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure.
- the residue was dissolved in methanol, 103 ⁇ 4 hydrogen chloride-methanol solution (ll mL) was added, and the mixture was concentrated under reduced pressure.
- the residue was recrystallized from methanol-diisopropyl ether to give the title compound (2.53 g).
- Triphenylphosphine (40 g) was added to a solution of 6,7-dimethyl-5-methoxy-3- (methylthio) -1,3-dihydro-2H-indol-2-one (30 g, 126 mmol) in dichloromethane (600 mL). , 153 mmol) and toluenesulfonic acid monohydrate (29 g, 153 mmol) were added at room temperature, and the mixture was stirred for 3 hours. The reaction solution was poured into cold water, and the precipitated crystals were collected by filtration. After washing with dichloromethane and water, 17.5 g of the title compound was obtained.
- ⁇ -band R (DMSO-d 6 ) ⁇ 2.05 (3 ⁇ , s), 2.10 (3H, s), 3.37 (1H, br), 3.42 (2H, s), 3.70 (3H, s), 6.76 (1H, s).
- Triethylamine (2.4 mL, 17.2 mmol) was added to a solution of 6,7-dimethyl-5-methoxy-1,2-dihydro-1H-indole (2.0 g, 11.3 carbonyl) in THF (20 mL).
- Di-tert-butyl dicarbonate (2.68 g, 12.3 t) was added at 0 ° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure and crystallized from hexane to obtain 2.27 g of the title compound.
- N, N- (2,3-dihydro-2,2,6,7-tetramethyl-1-benzofuran-5-yl) tert-butyl lubamate (0.50 g, 1.7 mmol) N, N —To the dimethylformamide solution was added 66 sodium hydride oil dispersion (83 mg, 2.3 mL), and the mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes. To this was added dropwise 3-methyl-2-methyl-1-propene (0.28 mL, 2.8 mmol), and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
- the combined organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 637 mg of an oil.
- a 10% hydrogen chloride-methanol solution (3 mL) was added, and the mixture was stirred at 50 ° C for 40 minutes under a nitrogen atmosphere.
- the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to neutralize, and extracted twice with ethyl acetate.
- the combined organic layer was washed with water and saturated saline, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 350 mg of an oil.
- the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure.
- the residue was dissolved in acetic acid (10 mL), 48% -hydrobromic acid (5 mL) was added, and the mixture was stirred under reflux for 3 hours.
- the reaction solution was concentrated under reduced pressure, 10% aqueous potassium carbonate solution was added for neutralization, and the mixture was extracted with ethyl acetate.
- the organic layer was washed with a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure.
- the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 5: 1). The solvent was distilled off under reduced pressure, and the residue was crystallized from hexane to give the title compound (0.36 g) as an oil.
- Example compound 1 11.0 g
- Example compound 1 1 1 100 g
- Compound 10.0 g and magnesium stearate 3.0 g were granulated with 70 mL of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, and then lactose 70.0 g and corn starch 50.0 g And mixed. Compress the mixture to obtain 1000 tablets.
- the animals used were 10- to 13-week-old male Jcl: Wistar rat brains.
- the rat cerebral cortex was excised by decapitation and homogenized (Nissone Microhomogenizer, S-310E) in ice-cold phosphate buffered saline (50 mM pH 7.4). After centrifugation for 10 minutes (Hitachi CF15D type, RT15A6 angle row), the supernatant was used for the experiment.
- the supernatant is diluted with 3 volumes of the same buffer, and the test drug dissolved in 1 mL of dimethyl sulfoxide (DMS0) at a final concentration of 0.0125, 0.025, 0.05, 0.10, 0.20, 0.40, 0.80, 1.60 M was added, and the mixture was incubated at 37 for 30 minutes. The reaction was stopped by adding 200 L of 35% perchloric acid, and centrifuged at 13,000 g for 10 minutes.
- DMS0 dimethyl sulfoxide
- the compound (I) or ( ⁇ ) of the present invention has an excellent lipid peroxide production inhibitory action and is useful as a lipid peroxide production inhibitor.
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Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00953480A EP1213290B1 (en) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuran derivatives, process for the preparation thereof and agents |
AT00953480T ATE293628T1 (de) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuranderivate, verfahren zu ihrer herstellung und mittel |
US10/069,314 US7008940B1 (en) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuran derivatives, process for the preparing thereof and agents |
AU65950/00A AU6595000A (en) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuran derivatives, process for the preparation thereof and agents |
CA002382418A CA2382418A1 (en) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuran derivatives, process for preparing thereof and agents |
DE60019619T DE60019619T2 (de) | 1999-08-20 | 2000-08-18 | Dihydrobenzofuranderivate, verfahren zu ihrer herstellung und mittel |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11/234719 | 1999-08-20 | ||
JP23471999 | 1999-08-20 |
Publications (1)
Publication Number | Publication Date |
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WO2001014385A1 true WO2001014385A1 (fr) | 2001-03-01 |
Family
ID=16975313
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/005524 WO2001014385A1 (fr) | 1999-08-20 | 2000-08-18 | Derives de dihydrobenzofuran, leur procede de preparation et agents |
Country Status (7)
Country | Link |
---|---|
US (1) | US7008940B1 (ja) |
EP (1) | EP1213290B1 (ja) |
AT (1) | ATE293628T1 (ja) |
AU (1) | AU6595000A (ja) |
CA (1) | CA2382418A1 (ja) |
DE (1) | DE60019619T2 (ja) |
WO (1) | WO2001014385A1 (ja) |
Families Citing this family (5)
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ATE423109T1 (de) | 2003-04-14 | 2009-03-15 | Nippon Soda Co | Diaminderivat, herstellungsverfahren und antioxidations-arzneimittel |
WO2005000829A1 (ja) * | 2003-06-26 | 2005-01-06 | Takeda Pharmaceutical Company Limited | カンナビノイド受容体調節剤 |
WO2005095431A1 (ja) * | 2004-03-31 | 2005-10-13 | Kuraray Co., Ltd. | 5α-プレグナン誘導体の製造方法 |
EP1743902A4 (en) * | 2004-03-31 | 2009-04-01 | Kuraray Co | METHOD OF PREPARING A 5-ALPHA PRIMING DERIVATIVE |
EP2246326A1 (de) * | 2009-05-02 | 2010-11-03 | Bayer CropScience AG | Verfahren zur Herstellung von Oxindolen und ortho-substituierten Anilinen und ihre Verwendung als Zwischenprodukte für Synthesen |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0638571A1 (en) * | 1992-05-01 | 1995-02-15 | Kowa Co. Ltd. | Quinoline derivative or salt thereof and remedy for cardiac diseases containing the same |
WO1997032871A1 (en) * | 1996-03-08 | 1997-09-12 | Takeda Chemical Industries, Ltd. | Tricyclic compounds, their production and use |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54163598A (en) | 1978-06-13 | 1979-12-26 | Daiichi Seiyaku Co | Pyridoquinoline derivative |
US5071875A (en) | 1989-09-25 | 1991-12-10 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
FR2680366B1 (fr) | 1991-08-13 | 1995-01-20 | Adir | Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2681862B1 (fr) | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
FR2713636B1 (fr) | 1993-12-07 | 1996-01-05 | Adir | Nouveaux dérivés naphtaléniques, leur procédé de préparation, et les compositions pharmaceutiques qui les contiennent. |
GB9326192D0 (en) | 1993-12-22 | 1994-02-23 | Glaxo Group Ltd | Chemical compounds |
GB9407919D0 (en) | 1994-04-21 | 1994-06-15 | Glaxo Group Ltd | Chemical compounds |
US5856124A (en) | 1994-06-17 | 1999-01-05 | The General Hospital Corporation | DNA encoding high-affinity melatonin receptors |
US6071946A (en) | 1994-10-21 | 2000-06-06 | Adir Et Compagnie | Tricyclic urea compounds |
US5998461A (en) | 1994-10-21 | 1999-12-07 | Adir Et Compagnie | Tricyclic amide compounds |
FR2725985B1 (fr) | 1994-10-21 | 1996-11-15 | Adir | Nouveaux composes tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US5661186A (en) | 1995-02-24 | 1997-08-26 | Bristol-Myers Squibb Co. | Tetralinyl-and indanyl-ethylamides |
US6034239A (en) * | 1996-03-08 | 2000-03-07 | Takeda Chemical Industries, Ltd. | Tricyclic compounds, their production and use |
TW416953B (en) | 1996-09-25 | 2001-01-01 | Takeda Chemical Industries Ltd | Tricyclic compounds for eliciting a prostaglandin I2 receptor agonistic effect, their production and use |
US6872718B1 (en) | 1999-08-20 | 2005-03-29 | Takeda Chemical Industries, Ltd. | Tricyclic dihydrobenzofuran derivatives, process for the preparation thereof and agents |
-
2000
- 2000-08-18 AU AU65950/00A patent/AU6595000A/en not_active Abandoned
- 2000-08-18 EP EP00953480A patent/EP1213290B1/en not_active Expired - Lifetime
- 2000-08-18 CA CA002382418A patent/CA2382418A1/en not_active Abandoned
- 2000-08-18 US US10/069,314 patent/US7008940B1/en not_active Expired - Fee Related
- 2000-08-18 WO PCT/JP2000/005524 patent/WO2001014385A1/ja active IP Right Grant
- 2000-08-18 AT AT00953480T patent/ATE293628T1/de not_active IP Right Cessation
- 2000-08-18 DE DE60019619T patent/DE60019619T2/de not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0638571A1 (en) * | 1992-05-01 | 1995-02-15 | Kowa Co. Ltd. | Quinoline derivative or salt thereof and remedy for cardiac diseases containing the same |
WO1997032871A1 (en) * | 1996-03-08 | 1997-09-12 | Takeda Chemical Industries, Ltd. | Tricyclic compounds, their production and use |
Non-Patent Citations (2)
Title |
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DUFRESNE CLAUDE ET AL.: "The synthesis of phenylhydrazines from bis(2,2,-trichloroethyl)azodicarboxylates and electron-rich arenes", SYNTH. COMMUN., vol. 27, no. 20, 1997, pages 3613 - 3624, XP002934753 * |
MACRO JOHN E. ET AL.: "The synthesis of pyrano(3,2-e)indoles and pyrano(2,3-f)indoles as rotationally restricted phenolic analogs of the neurotransmitter serotonin", TETRAHEDRON, vol. 48, no. 6, 1992, pages 1039 - 1052, XP002934755 * |
Also Published As
Publication number | Publication date |
---|---|
EP1213290A4 (en) | 2002-09-04 |
DE60019619D1 (de) | 2005-05-25 |
US7008940B1 (en) | 2006-03-07 |
DE60019619T2 (de) | 2006-03-02 |
AU6595000A (en) | 2001-03-19 |
EP1213290B1 (en) | 2005-04-20 |
ATE293628T1 (de) | 2005-05-15 |
EP1213290A1 (en) | 2002-06-12 |
CA2382418A1 (en) | 2001-03-01 |
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