WO2003000697A1 - Derive de furo-isoquinoline, procede de production de ce compose et utilisation de ce compose - Google Patents

Derive de furo-isoquinoline, procede de production de ce compose et utilisation de ce compose Download PDF

Info

Publication number
WO2003000697A1
WO2003000697A1 PCT/JP2002/006158 JP0206158W WO03000697A1 WO 2003000697 A1 WO2003000697 A1 WO 2003000697A1 JP 0206158 W JP0206158 W JP 0206158W WO 03000697 A1 WO03000697 A1 WO 03000697A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
substituent
atom
ruponiru
Prior art date
Application number
PCT/JP2002/006158
Other languages
English (en)
Japanese (ja)
Inventor
Yasuhiko Kawano
Tatsumi Matsumoto
Nobuhiro Fujii
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Publication of WO2003000697A1 publication Critical patent/WO2003000697A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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 has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's dementia, memory impairment, diabetes, arteriosclerosis
  • PDE phosphodiesterase
  • the present invention relates to novel freusoquinoline derivatives useful as preventive and therapeutic agents, their production methods and uses. Background art
  • cAMP cyclic guanosine-3 ', 5'-phosphate
  • the PDE has identified 11 isozymes, [Proceedings of the National Academy of Sciences of the National Academy of Sciences of the United States. 97, p. 3702 (2000).], in various cells such as the central, circulatory, respiratory, digestive, genital, blood cells, and tracheal smooth muscle. Regulates intracellular cAMP and cGMP levels and regulates cell functions. It is known that inflammatory cells such as eosinophils, neutrophils, monocytes, T-lymphocytes, and macrophages mainly contain PDE IV, one of the isozymes of PDE. Perimental allergy (Clinical and Experimental Allergy), 22, 337 (1992).].
  • bronchodilators e.g., beta-adrenergic receptor agonists
  • anti-inflammatory drugs e.g., corticosteroids
  • xanthine derivatives having both bronchodilator and anti-inflammatory effects
  • theophylline has been widely used as a therapeutic agent for asthma since ancient times. It has been shown that theophylline's bronchodilator activity is based on PDE inhibitory activity, and has recently attracted attention. However, theophylline is a non-selective PDE inhibitor, and cardiovascular side effects are often observed and require strict control of blood levels. Therefore, there is a demand for a therapeutic drug for inflammatory diseases such as asthma that selectively inhibits only PDE IV and does not act on other PDE isozymes.
  • PDE IV selective inhibitors may be effective therapeutic agents for inflammatory diseases such as asthma [Pulmonary Pharmacology, 7, 1 (1994) ⁇ ].
  • inflammatory diseases such as asthma [Pulmonary Pharmacology, 7, 1 (1994) ⁇ ].
  • PDE IV selective inhibitory action As a compound having a PDE IV selective inhibitory action,
  • W001 / 70746 includes, as a compound having a PDE IV selective inhibitory action, The compound which has the partial structure represented by these is disclosed.
  • W002 / 04455 includes a formula as a therapeutic agent for neurological and psychiatric deficiencies based on the reuptake inhibitory effect of the norepinephrine transporter protein.
  • R 1 is - 6 have alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 6 consequent opening alkyl, a C 4 _ 7 cycloalkylalkyl or base Njiru (These particular substituent May be)
  • R 2 is a hydrogen atom, alkyl, C 26 alkenyl, C 2 _ 6 alkynyl, C. 6 A cycloalkyl, C 4 7 cycloalkylalkyl or C ⁇ 6 eight-necked alkyl,
  • R 3 is a hydrogen atom, a halogen atom, alkyl, haloalkyl or C 3 _ 6 cycloalkyl (said C i 6 alkyl, (6 haloalkyl, C 3 6 cycloalkyl may have a specific substituent),
  • R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, nitro, etc., and R 7 represents a hydrogen atom, a halogen atom, etc.
  • the present invention provides a novel heterocyclic compound having a selective inhibitory effect on PDE IV, a bronchodilator effect and an anti-inflammatory effect by increasing the intracellular cAMP concentration, and further having excellent safety and other aspects.
  • a novel furoisoquinoline compound having a partial structure represented by the following formula (hereinafter abbreviated as compound (I) )
  • compound (I) A novel furoisoquinoline compound having a partial structure represented by the following formula (hereinafter abbreviated as compound (I) )
  • compound (I) A novel furoisoquinoline compound having a partial structure represented by the following formula (hereinafter abbreviated as compound (I) )
  • compound (I) A novel furoisoquinoline compound having a partial structure represented by the following formula (hereinafter abbreviated as compound (I) )
  • it has a great chemical structural characteristic when a substituent is introduced at the 1st, 2nd, 4th, 5th, 6th, 7th, 8th, 9th, etc. positions of the furoisoquinoline skeleton .
  • R 1 represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • R 2 and R 3 each represent a hydrogen atom or a substituent.
  • R 2 and R 3 may have a substituent together with adjacent carbon atoms to form a 3- to 8-membered ring.
  • R 4 and R 5 each represent a hydrogen atom or a hydrocarbon group which may have a substituent
  • R 6 and R 7 each represent a hydrogen atom or a hydrocarbon group which may have a substituent
  • 13 ⁇ 4 6 and 1 ⁇ 7 may form a 8-membered ring to 3 which may have a substituent together with the adjacent carbon atoms
  • R 8 is (1) a hydrogen atom, Yure (2) substituent hydrocarbon group which may be substituted, (3) Ashiru group, (4) an optionally substituted heterocyclic group, (5) halogen atom, (6) -OR 10
  • R 1Q is a hydrogen atom Substituent has optionally may hydrocarbon group, was Ashiru group or indicates a heterocyclic group which may have a substituent
  • (7) -SR 11 R 11 is a hydrogen atom, a substituent A hydrocarbon group, an acyl group or an optionally substituted heterocyclic group
  • (8) -S (0) R 12 where R 12 has a substituent A
  • R 1 represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent] or a salt thereof.
  • R 1 represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • R 2 and R 3 each represent a hydrogen atom or a substituent.
  • R 2 and R 3 may form a 3- to 8-membered ring which may have a substituent together with an adjacent carbon atom
  • R 6 and R 7 each represent a hydrogen atom or an optionally substituted hydrocarbon group
  • R 6 And R 7 may form a 3- to 8-membered ring which may have a substituent together with an adjacent carbon atom
  • R 8 is (1) a hydrogen atom, or (2) A good hydrocarbon group, (3) an acyl group, (4) an optionally substituted heterocyclic group, (5) a halogen atom, (6) -OR 10 (R 1Q is a hydrogen
  • R 1 represents any of the following (i) or (ii): (i) (1) halogen atom, (2) alkylenedioxy group, (3) nitro group,
  • R 2 and R 3 each represent one of the following (i) to (iii):
  • (iii) said may have 1 to 5 substituents selected from the substituent group A, E mill, force Rupokishi force Rubamoiru, alkyl Ichiriki Ruponiru, C 3 - 6 cycloalkyl Alkyl - carbonyl, C 6 alkoxy Ichiriki Ruponiru, c 6 _ 14 ⁇ Li one Rukarubo alkenyl, C 7 _ 16 Ararukiru Ichiriki Ruponiru, C 6 _ 14 Ariruokishi Ichiriki Ruponiru, C
  • Ichiriki 7 _ 16 Ararukiruokishi Ruponiru nitrogen atom in addition to carbon atom, a sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic force Ruponiru selected from oxygen atom, mono- C - 6 alkyl Ichiriki Rubamoiru, di - 6 alkyl - power resolver moil, c 6 - 14 Ariru Ichiriki Rubamoiru, nitrogen atom in addition to carbon atoms, 5 or containing 1 to heteroatoms three of the selected sulfur atom Contact and oxygen atom 6 membered double ring force Rubamoiru, C _ 6 alkyl one Chiokaruponiru, C 3 _ 6 cycloalkyl over Ji Okaruboniru, C 6 alkoxy - Chio force Ruponiru, C 6 _ 14 ⁇ Li one Ruchiokarupo alkenyl, c 7 _ 16 Ararukiru one Chiokaruponir
  • R 2 and R 3 together with the adjacent carbon atom, alkyl, C 6 _ 14 7 reel, C 7 - 16 Ararukiru, Amino, mono- Arukiruamino, mono- C 6 - 14 Arirua amino, di- (: Preparative 6 Arukiruamino, di one C 6 — 14 arylamino and a C 3 _ 8 cycloalkane optionally having 1 to 3 substituents selected from a 4- to 10-membered aromatic heterocyclic group or a 3- to 8-membered heterocyclic group Often ;
  • R 4 and R 5 may have, respectively (i) a hydrogen atom or (ii) the substituent, 1 to selected Ru substituents from group A 5 each - 6 alkyl group, C 2 _ 6 Al Kenyir group, c 2 - 6 alkynyl group, c 3 _ 6 cycloalkyl group, c 3 - 6 Shikuroaruke two Le group, c 6 _ 14 Ariru group or c 7 - 16 Ararukiru group;
  • R 6 and R 7 are each (i) a hydrogen atom or (ii) an alkyl group, a C 2 _ 6 alkenyl group which may have 1 to 5 substituents each selected from the aforementioned substituent group A, C 2 _ 6 alkynyl, C 3 - 6 cycloalkyl group, C 3 _ 6 Shikuroaruke two Le group, C 6 - 14 Ariru radical or C 7 - 16 show the Ararukiru group,
  • R 6 and R 7 together with the adjacent carbon atom, alkyl, C 6 one 14 Ariru, C 7 _ 1 6 Ararukiru, Amino, mono- - 6 Arukiruamino, mono- C 6 _ 14 Arirua amino, di- (6 Arukiruamino, di C 6 - 14 to Ariruamino and 3 good C 3 no one 8 cycloalkane or 3 have respectively, 1 to substituents selected from 4- to 10-membered aromatic heterocyclic group may form a 8-membered heterocyclic ring;
  • R 8 represents one of the following (i) to (X):
  • the substituents selected from substituent group A may have 1 to have five, Ho mill, carboxy, force Rubamoiru, CI- 6 alkyl one carbonyl, C 3 one 6 cycloalkyl - Power Ruponiru, C ⁇ _ 6 alkoxy Ichiriki Ruponiru, C 6 _ 14 Ariru Ichiriki Lupo El, C 7 _ 16 Ararukiru Ichiriki Ruponiru, C 6 - 14 Ariruokishi Ichiriki Ruponiru, C 7 _ 16 Ararukiruokishi Ichiriki Ruponiru, in addition to carbon atoms nitrogen atom, sulfur atom and 1 to containing heteroatoms three of the 5 or 6-membered heterocyclic force Ruponiru selected from oxygen atom, mono-one C DOO 6 alkyl - force Rubamoiru, di - alkyl Ichiriki resolver moil, C 6 - 14 Ariru Ichiriki Rubamoiru, nitrogen atom,
  • R 1Q is (i ′) a hydrogen atom, and (ii ′) a C i-6 alkyl group which may have 1 to 5 substituents each selected from the aforementioned substituent group A.
  • R 12 is (i,) a Ci- 6 alkyl group optionally having 1 to 5 substituents selected from the aforementioned substituent group A, C 2 - 6 alkenyl, C 2 one 6 alkynyl group, C 3 _ 6 cycloalkyl group, C 3 - 6 cycloalkenyl group, C 6 - 14 ⁇ aryl group or C 7 - 16 Ararukiru group or (ii ') the substituent Group A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5 substituents selected from group A ),
  • R 13 is (i,) an alkyl group optionally having 1 to 5 substituents selected from the above-mentioned substituent group A, C 2 _ 6 alkenyl group, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl group, C 3 - 6 cycloalkenyl group, (6 - 14 ⁇ aryl group or ⁇ 7 _ 16 Ararukiru group or (ii,) the substituent group A A 5- to 14-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have 1 to 5 substituents selected from) ,
  • R 14 and R 15 are each a ( ⁇ ′) hydrogen atom, (ii,) the above substitution , 1 to substituents selected from group A five may have respective C ⁇ 6 Al kill groups, C 2 - 6 alkenyl groups, C 2 - 6 alkynyl groups, C 3 _ 6 cycloalkyl groups, C 3 - 6 cycloalkenyl group, (6 _ 14 Ariru group or C 7 _ 16 Ararukiru group, (iii 5) said may have 1 to 5 substituents selected from the substituent group a, formyl, Karupamoiru , alkyl Ichiriki Ruponiru, C 3 - 6 cycloalkyl - force Ruponiru, alkoxy Ichiriki Ruponiru, C 6 - 14 Ariru Ichiriki Ruponiru, C 7 - 16 Araruki Lou force Ruponiru, C 6 _ 14 ⁇ Li one Ruok
  • R 9 is (i) a hydrogen atom, (ii) a cyano group,
  • 1 to substituents selected from the substituent group A may have five, respectively - 6 alkyl group, C 2 _ 6 alkenyl, C 2 - 6 alkynyl group, C 3 - 6 Shikuroa alkyl group, C 3 _ 6 cycloalkenyl group, C 6 _ 14 Ariru group or C 7 - 16 Araruki group,
  • the substituents selected from substituent group A may have 1-5 amino acids, formyl, carboxy, force Rubamoiru, ⁇ - 6 alkyl - carbonyl, C 3 _ 6 Shikuroa Ruki Lou carbonyl, C _ 6 alkoxy - force Ruponiru, C 6 _ 14 ⁇ Li one Roux force Lupo two Le, C 7 _ 6 Ararukiru Ichiriki Ruponiru, C 6 - 14 ⁇ Li one Ruokishi - force Ruponiru, C 7 - 16 Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atoms, to 1 selected from sulfur atom and oxygen radicals three of the 5 or 6-membered heterocyclic ring force containing heteroatoms Ruponiru, mono one C Bok 6 alkyl - force Rubamoiru, di - CI- 6- alkyl-carbamoyl, 4- aryl-lubamoyl, 5-
  • 1 to substituents selected from the substituent group A may have five each C Bok 6 alkyl group, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 6 cycloalkyl Le group , C 3 - 6 cycloalkenyl group, C 6 _ 14 ⁇ Li Ichiru group or C 7 _ 16 Ararukiru group or,
  • said substituent selected from the substituent group A may have 1-5 amino acids, formyl, force Rubamoiru, C WINCH 6 alkyl one carbonyl, C 3 - 6 cycloalkyl Ichiriki Ruponiru, c i_ 6 alkoxy one power Ruponiru, c 6 _ 14 ⁇ Li one Roux carbonyl, c 7 _ 16 Araruki Lou force Ruponiru, c 6 - 14 Ariruokishi - force Ruponiru, c 7 - 16 Ararukiruokishi Ichiriki Ruponiru, nitrogen atom in addition to carbon atom, sulfur atom and 5- or 6-membered heterocyclic carbonyl containing 1 to 3 heteroatoms selected from oxygen atoms, mono-C 6 alkyl mono-rubamoyl, di-C r — 6 alkyl mono-rubamoyl, C 6 — 14 aryl mono-rubamoyl , nitrogen atom in addition to carbon
  • X is 1a methylene group which may have a substituent selected from the above-mentioned substituent group A or 2a carpenyl group;
  • R 2 and R 3 are each ( ⁇ _ 6 alkyl group [3]
  • R 4 and R 5 are the represents a hydrogen atom, respectively [3]
  • R 1 is the formula
  • R 16 is a hydrogen atom, which may have a substituent C 6 - 14 Ariru group, an optionally substituted amino group, heterocyclic group which may have a substituent R 2 and R 3 each represent an alkyl group; R 4 and R 5 each represent a hydrogen atom; R 6 and R 7 each represent a Ci- 6 alkyl group; and R 8 represents a halogen atom.
  • a hydrogen atom or a monovalent R 1Q (R 1Q represents a hydrogen atom, which may have a substituent—a 6-alkyl group or an acyl group), R 9 represents a hydrogen atom, and n represents 0; 3] The compound as described;
  • R 1 () is (1) a hydrogen atom, (2) a C— 6 alkyl group optionally substituted with pyridyl, or (3) a Ct- 6 alkylsulfonyl substituted with a halogen atom
  • R 16 is selected from (1) hydrogen atom, (2) phenyl substituted by acetylamino, (S Ci- 6 alkylsulfonyl group, (ii) pyridyl carpoel or (iii) sulfamoyl-Ci-e alkyl group
  • the compound of the above-mentioned [10] which represents an amino which may be mono- or di-substituted by a substituent, (4) a pyridyl or (5) a halogen atom;
  • R 17 represents a vinyl group or an aryl group which may have a substituent] or a compound having a partial structure represented by the formula:
  • R 1 has the same meaning as described in the above [2]] or a salt thereof.
  • R 1 is as defined above; or a method for producing a compound having a partial structure represented by the formula:
  • ninini represents a single bond or a double bond
  • compound (A-1) ninini represents a single bond or a double bond
  • R 16' is hydrogen atom, which may have a substituent ⁇ 6 _ 14 Ariru group, a substituted An amino group which may have a group, a heterocyclic group which may have a substituent or a halogen atom], or a salt thereof.
  • JI represents a single bond or a double bond
  • a compound having a partial structure represented by Prophylactic / therapeutic agents for autoimmune diseases depression, Alzheimer's dementia, memory impairment, diabetes or arteriosclerosis;
  • R 2 ', R 3 ,, R 6' and R 7 ' is a C ⁇ 6 alkyl groups, respectively, R 16, are hydrogen atoms, which may have a substituent C 6 _ 14 Ariru group Represents an amino group which may have a substituent, a heterocyclic group which may have a substituent or a halogen atom), or an effective amount of a salt thereof.
  • ninii represents a single bond or a double bond
  • R 2 , R 3 , R 6 , and R 7 ′ are each —6 alkyl groups
  • R 16 is a hydrogen atom, and a C 6 14 aryl group which may have a substituent.
  • ⁇ represents a single bond or a double bond
  • ⁇ Z represents a single bond or a double bond
  • R 2a and an R 3a are each an aliphatic substituted hydrocarbon group
  • R 4a and R 5 a may hydrocarbons which also each have a hydrogen atom or a substituent group
  • R 6 a and R 7a each represents a hydrogen atom or an optionally substituted carbon hydrocarbon radical
  • R 6a and R 7a are optionally substituted with adjacent carbon atoms
  • R 8a may form a (1) hydrogen atom, (2) a hydrocarbon group which may have a substituent, (3) an acyl group, or (4) a substituent.
  • (6) -OR 10a (R 1Ga represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or a substituent.
  • R lla is hydrogen atom, which may have a substituent charcoal hydrocarbon group, a Ashiru group or substituent
  • R 9a represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a hydroxyl group which may have a substituent
  • ring A, ring B and ring C may each have a substituent. Or a salt thereof;
  • the substituents on ring A, ring B and ring C are (1) a hydrocarbon group which may have a substituent, (2) a heterocyclic group which may have a substituent, 3) an amino group which may have a substituent, (4) an acyl group, (5) a hydroxyl group which may have a substituent, (6) a sulfenyl group which may have a substituent, (7) halogen atom, (8) lower alkylene dioxy group, (9) nitro group, (10) cyano group, (11) imino group which may have a substituent, (12) oxo group, (13) A ureido group which may have a substituent, (14) an azide group, (15) an amidino group which may have a substituent, (16) a guanidino group which may have a substituent, ( 17) The compound according to the above [29], wherein the compound is 1-5 substituents selected from the group consisting of a hydrazino group which may have
  • Compound (A-1) has the formula (-1)
  • the compound (A), (.1), ( ⁇ ), ( ⁇ -1), (1-1), (I, 1-1), (A-2) or a salt thereof has an asymmetric carbon in the structure.
  • both optically active forms and racemic forms are included in the scope of the present invention, and the compounds (A), (I), ( ⁇ ), (A-1), (1-1), (1 , ⁇ 1), (A-2) or salts thereof may be either hydrates or anhydrides.
  • the compounds of the present invention have the formula
  • It is 1000 or less, preferably about 900 or less, more preferably about 800 or less, and particularly preferably about 700 or less.
  • ring A, ring B and ring C have a substitutable number of substituents at substitutable positions. You may have.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • lower alkylenedioxy O carboxymethyl group e.g., Mechirenjiokishi, etc. ⁇ 3 alkylenedioxy O alkoxy groups such Echirenjiokishi
  • Examples of the “optionally substituted hydrocarbon group” used as a substituent on the ring A, ring B and ring C include, for example, an alkyl group, an alkenyl group, an alkynyl group, and a cycloalkyl group.
  • a chain or cyclic hydrocarbon group such as a cycloalkenyl group, an aryl group or an aralkyl group is used.
  • a linear (branched or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is used.
  • an alkyl group [preferably a lower alkyl group (eg, methyl, ethyl, propyl) Le, isopropyl, butyl, isobutyl, sec- butyl, ter t-butyl, pentyl, (such as ⁇ -6 alkyl group) such as cyclohexyl,
  • alkenyl group preferably a lower alkenyl group (for example, C 2 _ such as vinyl, aryl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl and the like); 6 alkenyl groups)]
  • C 2 _ such as vinyl, aryl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl and the like
  • 6 alkenyl groups preferably a lower alkenyl group (for example, C 2 _ such as vinyl, aryl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyl and the like); 6 alkenyl groups)]
  • alkynyl groups [preferably, lower alkynyl group (e.g., propargyl, E Ji sulfonyl, 2-Bucheru, C 2 such hexynyl to 2 - such as 6 alkynyl group)]
  • lower alkynyl group e.g., propargyl, E Ji sulfonyl, 2-Bucheru, C 2 such hexynyl to 2 - such as 6 alkynyl group
  • cycloalkyl groups [preferably, a lower cycloalkyl group (e.g., Shikuropuro pills, cyclobutyl, cyclopentyl, c 3 _ 6 cycloalkyl Le group such as cyclohexyl), may be condensed with a benzene ring,
  • a lower cycloalkyl group e.g., Shikuropuro pills, cyclobutyl, cyclopentyl, c 3 _ 6 cycloalkyl Le group such as cyclohexyl
  • a cycloalkenyl group [preferably, a lower cycloalkenyl group (for example, 1 over sheet Kuropuro Bae cycloalkenyl, 1 Shikurobuarticulu, -1-cyclopentenyl, C 3 _ 6 cycloalkenyl group such as xenon alkenyl to 1 Shikuro) benzene May be condensed with a ring].
  • a cycloalkenyl group preferably, a lower cycloalkenyl group (for example, 1 over sheet Kuropuro Bae cycloalkenyl, 1 Shikurobuarticulu, -1-cyclopentenyl, C 3 _ 6 cycloalkenyl group such as xenon alkenyl to 1 Shikuro) benzene May be condensed with a ring].
  • Aromatic hydrocarbon group preferably, a lower cycloalkenyl group (for example, 1 over sheet Kuropuro Bae cycloalkeny
  • Ariru group e.g., phenyl, 1 one-naphthyl, 2-Nafuchirire, 1 one anthryl, 2-anthryl, 9 one anthryl, 1 one Fuenantoriru, 2 Fuenantoriru, three to Fuenantoriru, C 6, such as 4 _ Fuenantoriru or 9 one Fuenantoriru such as _ 1 4 Ariru group, preferably a phenyl group
  • Lower aralkyl groups e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3 - phenylpropyl, 4 one Hue Nirupuchiru, etc.
  • Flip 7 _ 1 6 Ararukiru groups such as 5-phenylene Rupenchiru, preferably benzyl group).
  • substituent of these hydrocarbon groups include (1) a halogen atom (for example, fluorine, chlorine, bromine, and iodine), and (2) a lower alkylenedioxy group (for example, methylenedioxy, ethylenedioxy and the like). (3) nitro group, (4) cyano group, (5) lower alkyl group which may be halogenated, (6) Lower alkenyl group which may be halogenated, (7) lower alkynyl group which may be halogenated, (8) lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • a halogen atom for example, fluorine, chlorine, bromine, and iodine
  • a lower alkylenedioxy group for example, methylenedioxy, ethylenedioxy and the like.
  • C such as 3 _ 6 cycloalkyl group
  • C 6 - 1 4 ⁇ Li Ichiru group e.g., phenyl, 2 - naphthyl
  • 10 optionally halogenated substituted lower alkoxy group
  • 11 Lower alkylthio group which may be halogenated
  • mono-lower alkylamino group e.g., monoamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.
  • C such as E _ 6 Arukiruamino group
  • mono- C 6 one 1 4 Ariruamino group eg, Fueniruamino, 2 - etc.
  • G C 6 - 1 4 Ariruamino group eg, Jifueeruamino, di (2-naphthyl) Amino etc.
  • Ashiru group eg, Jifueeruamino, di (2-naphthyl) Amino etc.
  • (21) 4- to 14-membered heterocyclic group (preferably 4- to 10-membered, more preferably 4- or 7-membered heterocyclic group, particularly preferably 5- or 6-membered heterocyclic group) (eg, 4-pyridyl, 2 1-Cenyl, 2-furyl, 2-thiazolyl, 3-indolyl, morpholino, 1-piperazinyl, piperidino, 1-pyrrolidinyl, 2-isoindolyl, etc., other than carbon, nitrogen, sulfur, oxygen, etc.
  • 4-pyridyl 2 1-Cenyl, 2-furyl, 2-thiazolyl, 3-indolyl, morpholino, 1-piperazinyl, piperidino, 1-pyrrolidinyl, 2-isoindolyl, etc., other than carbon, nitrogen, sulfur, oxygen, etc.
  • a lower alkyl group optionally having 1 to 3 halogen atoms eg, fluorine, chlorine, bromine, iodine
  • alkyl group e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec - heptyl, tert- butyl, pentyl, etc.
  • ( ⁇ _ 6 alkyl groups such as hexyl) and the like are used, as a specific example, Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ether, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluorotrifluoropropyl, isopropyl, butyl, 4 , 4,4-Trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neope Chill, 5, 5, 5-triflate Ruo b hexyl pentyl to,, 6, 6, etc. hexyl and the like to 6 Torifuruo port.
  • the “lower alkenyl group optionally octogenated” in the substituent group A may have, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) lower alkenyl groups (e.g., vinyl, Ariru, isoproterenol base alkenyl, 2-butenyl, 2-methyl-2 _ propenyl, 4 one-pentenyl, 5 one hexenyl such which C 2 - 6 alkenyl group) and the like.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • lower alkenyl groups e.g., vinyl, Ariru, isoproterenol base alkenyl, 2-butenyl, 2-methyl-2 _ propenyl, 4 one-pentenyl, 5 one hexenyl such which C 2 - 6 alkenyl group
  • the “lower alkynyl group optionally octogenated” in the substituent group A may have, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) a lower alkynyl group (e.g., propargyl, Echiniru, 2-Petit El and C 2 _ 6 alkynyl group such as hexynyl to 2) and the like.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • a lower alkynyl group e.g., propargyl, Echiniru, 2-Petit El and C 2 _ 6 alkynyl group such as hexynyl to 2
  • Examples of the “optionally halogenated lower alkoxy group” in the above-mentioned substituent group A include, for example, lower optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) an alkoxy group (e.g., methoxy, ethoxy, Purobokishi, iso-propoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyl Ruokishi, isopentyl Ruo alkoxy, neopentyl Ruo alkoxy, to a C ⁇ _ 6 alkoxy group such as Kishiruokishi
  • Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trichloromethoxy, 3,3,3-trifluoropropoxy, 4,4, 4 Trifluorobutoxy, 5, 5, 5—Trifluoropentyloxy, 6,
  • halogenated lower alkylthio group in the above-mentioned Substituent group A, for example, may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) ( ⁇ - 6 alkylthio group (e.g., methylthio, Echiruchio, pro Piruchio, isopropylthio, Puchiruchio, isobutylthio, sec- butylthio, ter t one Puchiruchio, pentylthio, cyclohexylthio C WINCH 6 alkylthio group such as to) and the like are used, specifically Examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio
  • C 3 _ 6 cycloalkyl - Karuponiru e.g., cyclopentyl Luca Lupo, cycloalkenyl, cycloheteroalkyl, etc. keys Shirukaruponiru
  • C ⁇ - 6 alkoxy Ichiriki Ruponiru e.g., methoxy Cal Poni le, X Tokishikaruponiru, Isopuropokishi force Ruponiru, t er t-butoxycarbonyl etc.
  • C 6 _ 1 4 Ariru - Karuponiru eg, Benzoiru and 2 one naphthoyl
  • C 7 _ 1 6 Ararukiru Ichiriki Ruponiru eg, phenylene Ruasechiru, 3-phenylpropyl propionyl, etc.
  • C 6 _ 1 4 Aryloxy-one-strand eg, phenoxy-th, 2-nap
  • Jechirukarubamo I le C 6 - 1 4 ⁇ Li one Roux force Rubamoiru (e.g., Hue carbamoylmethyl, 2-naphthylcarbamoyl etc.), 5- or 6-membered heterocyclic ring force Rubamoiru (eg, 1 one Pyrrolidinylcarbamoyl, 4-piberidylcarbamoyl, 1-piperazinylcarbamoy Selected from nitrogen atoms, sulfur atoms, oxygen atoms, etc., in addition to carbon atoms such as 1, 2-morpholinylcarbamoyl, 4-pyridylcarbamoyl, 3-chlorocarbamoyl, 2-furyl-rubamoyl, 2-thiazolylcarbamoyl, etc.
  • Roux force Rubamoiru e.g., Hue carbamoylmethyl, 2-naphthylcarbamoyl etc.
  • Chiokarubamoiru eg, phenylene Lucio force Rubamoiru, 2- 5- or 6-membered heterocyclic thiocarbamoyl (e.g., 2-pyrrolidinylthio-potassium, 2-piperidylthio-potassium, 2-piperazinyl-thio-potsubamoyl, 2-morpholinyl-thio-potsubamoyl, 4-pyridylthio-potassium) Containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon atoms such as 3-chlorothiocarbamoyl, 2-furylthiocarbamoyl, 2-thiazolylthiocarbamoyl, etc.
  • 2-pyrrolidinylthio-potassium e.g., 2-piperidylthio-potassium, 2-piperazinyl-thio-potsubamoyl, 2-morpholinyl-thio-potsubam
  • C 6 — 14 arylsulfamoyl eg, phenylsulfamoyl
  • 0 _ 6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.)
  • C 6 _ 14 arylsulfonyl eg, phenyl
  • sulfonyl such as 2 one-naphthylsulfonyl
  • G 6 alkylsulfinyl e.g., methylsulfinyl, etc.
  • E chill sulfide El C 6 - 14 ⁇ reel sulfinyl (e.g., Hue Nils sulfinyl, such as 2 one Nafuchirusurufu Iniru), sulfino, sulfo, C ⁇ _ 6 alkoxysulfinyl sulfinyl (e.g., methoxide Shisurufiniru, e Toki cis sulfinyl), Ji 6 _ 14 ⁇ reel O carboxymethyl sulfinyl (e.g., full enoki cis sulfinyl), Ci-e alkoxy sulfonyl (e.g., main Bok Kishisu Ruhoniru , E butoxy-benzenesulfonyl) and C 6 - 14 ⁇ reel O carboxymethyl sulfonyl (e.g., Fueno Shisuruhoniru) and the like
  • Substituent Group A for example, Horumiruamino, C ⁇ 6 alkyl Ichiriki Rupokisamido (eg, Asetoamido and propionamide), C 6 - 14 Ariru Ichiriki Rupokisamido (e.g., benzamide, 2- naphthyl Cal poke Sami Donado), alkoxy Ichiriki Rupokisamido (e.g., methoxy carboxamide, X Toki deer Lupo alkylcarboxamide, isopropoxycarbonyl carboxamide, such as tert- Butokishikarupoki Samido), C 6 alkylsulfonyl ⁇ amino (e.g., methylsulfonyl ⁇ Mino, E such as chill sulfonyl ⁇ Mino), bis (( ⁇ - 6 alkylsulfonyl) amino (e.g., bis (methylsulf) amino (e.g., bis (methylsulf
  • Ruo carboxymethyl C 6 one 1 4 ⁇ Li one Luca Lupo sulfonyl O carboxymethyl (e.g., Benzoyloxy, 2-naphthoyloxy, etc.), alkoxy monopropyloxy (e.g., methoxycarboxy, ethoxypropyloxy, isopropoxyoxy, tert-butoxycarboxy), mono-Ci- 6 alkyl monorubamoyloxy (e.g.
  • 6 alkyl Ichiriki Ruponiruokishi, - 6 C 2 _ 7 Ashiruokishi groups such as alkoxy Ichiriki Ruponiruokishi are preferred.
  • Examples of the group formed by bonding two or three members selected from the groups (1) to (32) include, for example,
  • R 18 and R 19 each represent (i) a 5- or 6-membered heterocyclic ring (eg, a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, etc., in addition to a carbon atom) Or 6-membered heterocycle) monoalkyl, (iDCi-ealkoxy mono-propionyl-alkyl), (iii) dialkyl 6- alkylamino-methylene-sulfamoyl-alkyl, (iv) di-rubmoyl-C 6- alkyl, (V) sulfamoyl - 6 alkyl le, (vi) C 6 alkyl chromatography alkylsulfonyl, (VIOC -e alkoxy - carbonyl, (viii) di - C i_ 6 alkoxy Ichiriki Lupo two Lou C 2 _ 6 alkenyl, (ix) 5 or 6-member
  • R 2Q and R 21 each represent (i) a 5- or 6-membered heterocyclic ring (eg, 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon atoms such as pyridyl and imidazolyl) 5 or 6 membered heterocyclic ring containing) -C ⁇ e alkyl, (ii) Karupoki sheet - - 6 alkyl, (iii) C Les 6 alkoxy - force Lupo two Lou C 6 alkyl, (iv) di - C e _ 6- Alkylamino—C 6- Alkyl, (V) Alkyl C 6 Alkyl, (vi) Alkyl Rubamoyl—— 6 Alkyl, (vii) 5- or 6-membered Heterocycle
  • the 4- to 10-membered heterocyclic group may have one or two substituents selected from a halogen atom, alkyl, oxo, etc.], (xiii) C 6 — 14 arylene 6 alkyl, etc.],
  • halogenated C ⁇ - 6 alkyl Cal poke Sami de e.g., 2-Kuroroaseta bromide, 2, 2-dichloro-acetamide, 2, 2, 2-trichloro acetamide, etc.
  • the ⁇ optionally substituted heterocyclic group '' used as a substituent on the ring A, ring B and ring C includes, for example, nitrogen, sulfur, oxygen and the like in addition to carbon.
  • a 4- to 14-membered heterocyclic group containing 1 to 4 (preferably 1 to 3) heteroatoms to be selected and the like are used. Specifically, (a) a 4- to 14-membered aromatic heterocyclic group,
  • the 4- to 14-membered aromatic heterocyclic group includes, for example, 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom. Or a 14-membered aromatic heterocyclic group or the like. Specific examples thereof include thiophene, furan, indolizine, pyrrole, imidazole, triazole, thiazole, thixazole, pyrazole, pyridine, and N-dioxide.
  • pyridine, thiophene, furan and the like are preferably used.
  • Examples of the 4- to 14-membered aliphatic heterocyclic group include 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms.
  • a 4-membered aliphatic heterocyclic group or the like is used, and specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine, imidazolidine and the like.
  • the bicyclic or tricyclic fused ring group of a 4- to 14-membered heterocyclic ring and a benzene ring may include, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (preferably (1 to 3) and a bicyclic or tricyclic fused ring group of a benzene ring and a heterocyclic ring, such as benzo [b] thiophene, benzofuran, 1H-benzimidazole, and benzzo Xazole, benzothiazole, 1,2-benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxatiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine, quinoxaline, Quinazoline, cinnoline, carbazole,) 3-caprolactin, phenanthridine
  • substituent of these heterocyclic groups 1 to 5, preferably 1 to 3 selected from the above-mentioned substituent group A are used.
  • the “optionally substituted amino group” used as a substituent on the A ring, the B ring and the C ring includes the “optionally substituted hydrocarbon group” and the “optionally substituted hydrocarbon group”.
  • an amino group which may have one or two substituent (s) selected from the above.
  • acyl group used as a substituent of the ring A, ring B and ring C, those similar to the “acyl group” in the aforementioned substituent group A can be used.
  • This “acyl group” may further have 1 to 5, preferably 1 to 3 substituents selected from substituent group A.
  • R 1 represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent].
  • R 1 represents (1) a hydrogen atom, (2) a hydrocarbon group optionally having a substituent, or (3) a heterocyclic group optionally having a substituent.
  • R 1 (1) an aromatic hydrocarbon group optionally having a substituent, (2) a heterocyclic group optionally having a substituent, (3) an optionally substituted substituent A good aliphatic cyclic hydrocarbon group, (4) Formula 1: L—R la wherein L is methylene or carbonyl, R la is a hydrogen atom, an aromatic group which may have a substituent, a substituent A hydroxyl group optionally having a substituent or an amino group optionally having a substituent].
  • the “aromatic hydrocarbon group optionally having substituent (s)” and the “heterocyclic group optionally having substituent (s)” are represented by the formula:
  • R lb represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent
  • the ring D is an aromatic which may have a substituent.
  • Group E is a bond, methylene, oxygen atom, acid Optionally substituted sulfur atom, optionally substituted nitrogen atom or formula —CS—O—, one CO—O—, one S—CO—, one (CH 2 ) k —CO—, one NR lc - CO - (CH 2 ) m -, -NR lc -S0 2 - (CH 2) m -, one S_ ⁇ 2 - NR lc - (CH 2 ) m -, one ⁇ - CS-NR lc - (CH 2 ) m- , one NR lc — CO-NR lc — (CH 2 ) m —, — NR lc _C ⁇ one CH 2 — (
  • Ha 1 represents a halogen atom
  • ring D has the same meaning as described above].
  • R 1 "aromatic hydrocarbon group", for example, etc.
  • C 6 -C 14 membered monocyclic or condensed polycyclic aromatic hydrocarbon group (C 6 _ 14 Ariru group) Is used.
  • the C 6 _ 14 Ariru group e.g., phenyl, 1 one-naphthyl, 2-naphthyl, 1 one anthryl, 2 one anthryl, 9 _ anthryl, 1 one Fouesnant tolyl, 2 _ Fuenantoriru, 3 Fuenantoriru, 4 one Fuenantoriru, 9-phenanthryl and the like are used, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable, and phenyl and the like are particularly preferable.
  • substituent for the “aromatic hydrocarbon group” 1 to 5, preferably 1 to 3 selected from the above-mentioned substituent group A is used.
  • substituents (1) a halogen atom,
  • the ( ⁇ -6 alkyl group is a halogen atom, cyano, carbamoyl, 6- alkaryl pamoyl, C i _ 6 alkyl monopropylamine, alkoxy-carbonyl- 6 alkyl monorubumoyl, 5- or 6-membered heterocycle (Eg, 1 to 3 carbon atoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon such as pyridyl 5 or 6 membered heterocyclic ring) -C x _ 6 alkyl Ichiriki Rubamoiru containing hetero atoms,
  • Horumiruamino may have a halogen atom or carboxy alkyl - carbonyl amino (eg, Asechiruamino, propionyl Rua Mino, triflumizole Ruo b acetylide relay amino, Bibaroiruamino), c 6 one 14 Ariru Ichiriki Ruponiruamino (eg, Benzoiruami Bruno), ( ⁇ _ 6 alkoxy - power Ruponiruamino (e.g., methoxy Karuponiruamino), ureido, mono- or di- (: e alkylureido, 6 alkylsulfonyl amino (e.g., methylsulfony
  • Ci- 6 alkoxy group which may have a —6 alkoxy-C 6 _ 14 aryl (eg, methoxy, trifluoromethoxy, isopropoxy, 2- (4-methoxy Phenyl) ethoxy)),
  • C- 6 alkylthio group which may have carbamoyl (eg, methylthio, carbamoylmethylthio),
  • alkylsulfinyl group which may have a carpamoyl (eg, methylsulfinyl, carbamoylmethylsulfinyl),
  • the heterocyclic group is old Kiso, Karubokishi alkyl, alkyl Ichiriki Honoré Boniruokishi - C i _ 6 alkyl, (6 alkyl, C i-6 alkoxy - Karuponiru - alkyl, C x _ 6 alkoxy Ichiriki Ruponiru force Rubamoiru - C - 6 alkyl Le, C x _ 6 alkyl - may have a force Rubamoiru C i _ 6 substituents selected from an alkyl, (13) a carboxy group,
  • alkyl-sulfonyl group eg, methylsulfonyl, etc.
  • the sulfamoyl group, (_ 6 alkyl, force Rubamoiru C Bok 6 alkyl, C, ⁇ - 6 alkoxy Ichiriki Ruponiru - d_ 6 alkyl, 5 to may have Okiso group 7-membered Hajime Tamaki ( Example: 5- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc.
  • R a and R b each represent (i) a hydrogen atom, (iO ⁇ -e alkyl, (iii) a 5- or 6-membered heterocyclic ring (eg, a nitrogen atom, a sulfur atom, an oxygen atom, etc.
  • 5- or 6-membered heterocyclic ring in addition to carbon such as pyrrolidinyl, pyridyl, etc.
  • One-strand ruponyl (xxii i) 5- or 6-membered heterocyclic ring (eg, one or three selected from nitrogen, sulfur, oxygen, etc.
  • a heteroatom 5 or 6 membered heterocyclic ring) i ( ⁇ _ 6 alkyl Ichiriki Lupo two Le has, fcdv) C 6 - 14 Ariru one Okishi Ichiriki Ruponiru, (XXV) force Rupokishi - C - 6 ⁇ alkyl, (xxvi) force Rubamoiru , (xxvii) optionally halogenated good alkylcarbamoyl, (xxviii) C ⁇ alkyl one carbonyl ⁇ Mino but it may also have a C 6 _ 14 ⁇ Lee carbamoyl, (xxix) 5 or 6-membered heterocyclic ring ( examples, nitrogen atom in addition to a pyridyl that any carbon atom, a sulfur atom, 1 selected from oxygen atom, etc.
  • Rc and R d are each (i) hydrogen atom, (i C ⁇ - 6 alkyl, (iii) 5 or 6-membered heterocyclic ring (e.g., pyridyl, nitrogen atom in addition to carbon atoms, such as imidazolyl, sulfur atom, an oxygen atom 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of: 1 Ci- 6 alkyl, (iv) carboxy-alkyl, WCi- 6 alkoxy-carbocarbonyl C 6 alkyl, (vi) G C ⁇ 6 alkylamino one C Bok 6 alkyl, (vii) force Rubamoiru 6 alkyl, (viii) C 6 alkyl force Rubamoiru - C E _ 6 alkyl, (ix) 5 or 6-membered heterocyclic ring (e.g., carbon, such as pyridyl A 5- or 6-membered heterocyclic ring containing
  • heterocyclic group represented as a preferable group of R 1
  • examples of the “heterocyclic group” represented as a preferable group of R 1 include pyridyl, phenyl, furyl, imidazolyl, thiazolyl, quinolyl, 1,2-dihydropyridyl, dihydrobenzofuranyl, benzodioxolyl, and benzothiazolyl.
  • Piperidyl, piperazinyl and the like are preferable, and pyridyl, 1,2-dihydropyridyl and the like are particularly preferable.
  • Ci- 6 alkyl group eg, methyl, ethyl, etc.
  • alkyl, force Rupokishi, 6 alkoxy, alkoxy - has Karupamoiru, a Okiso - force Lupo two Le, mono one C ⁇ - 6 Arukiruamino, di - 6 Arukiruamino force Rubamoiru, alkyl which may have hydroxy
  • a 4- to 10-membered heterocyclic group e.g., containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc. in addition to carbon such as pyridyl and quinolyl
  • 10-membered heterocyclic group 4- to 10-membered heterocyclic ring (eg, containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.
  • the C 7 _ 1 6 Ararukiru is carboxy, alkoxy one carbonyl, force Luba moil, hydroxy may have - 6 alkyl Ichiriki Rubamoiru, 4 to 1 0-membered heterocyclic ring (e.g., carbon atoms, such as pyridyl A 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.) — Which may have a substituent selected from rubamoyl, etc.] ,
  • 4- to 10-membered heterocyclic group eg, charcoal such as pyridyl, quinolyl, isoquinolyl, etc.
  • heterocyclic group in which R 1 has an oxoxide group for example, N-aminopyridyl pyridyl and the like are preferable.
  • Aliphatic cyclic hydrocarbon group represented as preferable groups for R 1, for example, cyclopropyl, cyclobutyl, cyclopentyl, C 3 _ 6 shea click port alkyl groups such as cyclohexyl may be used, in particular cyclopentyl, Cyclohexyl is preferred.
  • This “aliphatic cyclic hydrocarbon group” may have the same substituent as the substituent that the hydrocarbon group represented by R 1 may have.
  • Examples of the preferred group for R 1 include an “optionally substituted aromatic hydrocarbon group” and an “optionally substituted heterocyclic group”.
  • the “optionally substituted hydrocarbon group” represented by R lb may be the same as the “optionally substituted optionally substituted hydrocarbon group” exemplified as the substituent for the ring A. Is used. Above all,
  • Ci- 6 alkyl group (methyl, isopropyl, tert-butyl, etc.)
  • This alkyl group is a halogen atom, cyano, hydroxy, C- 6 alkoxy Sheet - Power Ruponiru, di - C ⁇ e Arukiruamino may be halogenated - 6 alkyl - force Lupo two Ruamino force Rupokishi force Rubamoiru, C ⁇ -e alkyl Ichiriki 'Rubamoiru, C 6 alkyl one Karuboniruo Xy, alkoxy-carbonyl-alkyl-alkanoyl, 5- or 6-membered heterocyclic ring (eg, 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.
  • Yl, 5- or 6-membered heterocycle eg, 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc.
  • the C 6 _ 14 Ariru groups, - 6 alkoxy (e.g., methoxy) Amino, carboxy may be halogenated d-6 alkyl Ichiriki Ruponiruamino (eg, ⁇ Se Chiruamino, triflumizole Ruo b acetyl ⁇ Mino ), C ⁇ -e alkoxy - Karuponiruami Bruno (e.g., methoxy Cal Poni Rua Mino), Horumiruamino, ureido, 6 alkynyl Le sulfonyl ⁇ amino (e.g., methylsulfonyl ⁇ Mino), (CI- 6 alkyl) (d - 6 alkyl Sulfonyl) amino (eg, methyl (methylsulfonyl) amino, etc.), C 6 alkoxy-potassium C 6 alkylamino (eg, 2-ethoxycarbo 2-ru-propy
  • a C 2 _ 6 alkenyl group is preferred.
  • heterocyclic group optionally having substituent (s) represented by R lb
  • those similar to the “heterocyclic group optionally having substituent (s)” exemplified as the substituent for ring A are used. It is possible. Among them, halogen atom, C 6 alkyl, carboxyl-C ⁇ -e alkyl, C 6 alkoxy mono-potential C 6- alkyl, C 6 alkoxy mono-proponyl, dipotamoyl, oxo, 4- to 10-member complex A ring group (eg, a 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, sulfur, oxygen, etc.
  • substituents E.g., azetinyl, piperidinyl, piperidyl, isothiazolidinyl, thiadiazolidinyl, hexahydrroazepier, frill, chenyl, pyridyl, quino
  • the aromatic hydrocarbon ring represented by D ring e.g., C 6 -C to 1 4-membered monocyclic or condensed polycyclic aromatic hydrocarbon ring (C 6 1 4 Ariru ring), and the like Ru is used.
  • C 6 14 aryl ring for example, a benzene ring, a naphthalene ring, an anthryl ring, a phenanthryl ring and the like are used, and among them, a benzene ring, a naphthylene ring and the like are preferable, and a benzene ring is particularly preferable. .
  • aromatic hydrocarbon rings may have 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A.
  • heterocycle represented by the ring D examples include a 5- to 14-membered heterocyclic ring having 1 to 4 (preferably 1 to 3) heteroatoms selected from nitrogen, sulfur, oxygen and the like in addition to carbon atoms. Heterocycles and the like are used. Specific examples include (a) a 5- to 14-membered aromatic heterocycle, (b) a 5- to 14-membered aliphatic heterocycle, and (c) a 5- to 14-membered heterocycle. A bicyclic or tricyclic fused ring with a zen ring is used.
  • Examples of the 5- to 14-membered aromatic heterocycle include a nitrogen atom and a sulfur atom in addition to a carbon atom.
  • a 5- to 14-membered aromatic heterocycle containing 1 to 4 (preferably 1 to 3) heteroatoms selected from a yellow atom, an oxygen atom and the like is used, and specifically, thiophene, furan, indolizine and the like are used.
  • pyridine Pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, N-oxidized pyridine, pyrazine, pyrimidine, pyridazine, purine, 4H-quinolizine, naphthyridine, isothiazole, isoxazole, furazan, etc. .
  • pyridine, thiophene, furan and the like are preferably used.
  • the 5- to 14-membered aliphatic heterocycle includes 1 to 4 (preferably 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom.
  • a membered aliphatic heterocycle or the like is used, and specific examples include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,2-dihydropyridine, imidazolidine and the like.
  • bi- or tricyclic fused ring of the 5- to 14-membered heterocyclic ring and a benzene ring one to four heteroatoms (preferably one to four) selected from nitrogen, sulfur and oxygen other than carbon atoms And 3 or more condensed rings of a benzene ring with a heterocyclic ring containing benzene [b] thiophene, benzofuran, 1H-benzimidazole, benzoxazole, benzo Thiazole, 1,2-benzisothiazol, naphtho [2,3-b] thiophene, thianthrene, xanthene, phenoxatiin, indole, isoindole, 1H-indazole, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, Cinnoline, carbazole, 3-ketoporin, phenanthridine, acridine, phenazine, phenothia
  • pyridine, thiophene, furan, imidazole, thiazole, quinoline, N-hydroxylated pyridine, 1,2-dihydropyridine, dihydrobenzofuran, benzodioxole, Benzothiazole, piperidine, piperazine and the like are preferable, and pyridine, 1,2-dihydropyridine and the like are particularly preferable.
  • heterocycles may have 1 to 5, preferably 1 to 3, substituents selected from the aforementioned substituent group A.
  • substituents selected from the aforementioned substituent group A As the “optionally oxidized sulfur atom” represented by E, S, SO, and SO 2 are used.
  • Examples of the optionally substituted nitrogen atom represented by E include (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group, and (iii) an acyl group. A nitrogen atom which may be present is used.
  • hydrocarbon group optionally having substituent (s) those similar to the “hydrocarbon group optionally having substituent (s)” exemplified as the substituent for ring A can be used.
  • acyl group those similar to the “acyl group” exemplified as the substituent for the ring A are used, and this acyl group further has 1 to 5, preferably 1 to 5, substituents selected from the substituent group A. May have one to three.
  • alkyl group represented by R examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl - butyl, etc.
  • C WINCH 6 alkyl groups such as pentyl, carboxymethyl Le is used.
  • the alkyl group represented by R le may have 1 to 5, preferably 1 to 3 substituents selected from the aforementioned substituent group A.
  • acyl group represented by R lc those similar to the ⁇ acyl group '' exemplified as the substituent for the ring A are used, and the acyl group further has 1 to 5 substituents selected from the substituent group A. Preferably, it may have one to three.
  • k represents 0 or 1, particularly preferably 0.
  • n represents an integer of 0 to 3, and among them, 0 or 1 is preferable.
  • ⁇ 6 alkyl group e.g., methyl
  • R m is hydrogen or ⁇ - group 6 alkyl group (e.g., methylation) and represented by m6 is 0 or 1]
  • Examples of the preferred group for R 1 include an “optionally substituted aromatic hydrocarbon group” and an “optionally substituted heterocyclic group”.
  • halogen atom represented by H a1 a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are used, and among them, a chlorine atom is preferable.
  • L is preferably methylene or heptonyl.
  • R 1 a The aromatic group represented by R 1 a, for example,
  • 1Monocyclic or condensed polycyclic aromatic hydrocarbons more specifically phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1.1-phenanthryl, 2- 1 4 Ariru group (preferably, phenyl, 1 - - naphthyl or 2-naphthyl, particularly preferably phenyl)
  • one or more heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom and the like in addition to a carbon atom may be used.
  • monocyclic heterocyclic group preferably 5 to 8 members
  • a fused aromatic heterocyclic group thereof more specifically, thiophene, benzo [b] thiophene, benzofuran, 1 H-benzimidazole, benzoxazole, benzothiazole, 1,2-benzisothiazole, naphth C2,3-b] thiophene, thianthrene, furan, indolizine, xanthene, phenoxatiin, pyrrole, Imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole 1 H one-in
  • R 1 The aromatic group which may have a substituent represented by a, alkyl, 1 to 5 optionally having C 4 Ariru group (e.g., phenyl) substituents such as alkoxy and preferable.
  • a substituent represented by a, alkyl, 1 to 5 optionally having C 4 Ariru group (e.g., phenyl) substituents such as alkoxy and preferable.
  • R la As the “optionally substituted hydroxyl group” represented by R la , those similar to the aforementioned “optionally substituted hydroxyl group” exemplified as the substituent of the ring A described above are used. Among them, a hydroxyl group which may have a C 6 alkyl group (eg, methyl) is preferable.
  • Examples of the “amino group optionally having substituent (s)” represented by R la include, for example, an alkyl group optionally having a substituent, an aryl group optionally having a substituent, and the like. And an amino group which may have 2 or more, particularly preferably a 4- to 10-membered heterocyclic group (1 to 3 hetero atoms selected from nitrogen atom, oxygen atom, sulfur atom and the like in addition to carbon atom) May be substituted with a 4- to 10-membered heterocyclic group having an atom, eg, pyridyl) — 6-alkyl-amino group, 2 C 6 4 aryl-amino group, 3 4- to 10-membered heterocyclic ring (nitrogen other than carbon atom)
  • a 4- to 10-membered heterocyclic ring having 1 to 3 heteroatoms selected from an atom, an oxygen atom, a sulfur atom and the like, eg, pyridyl) -amino group is preferred.
  • R 16 is a hydrogen atom, which may have a substituent C 6 _ 14 ⁇ Li Ichiru group, an optionally substituted amino group, which may have a substituent A heterocyclic group or a halogen atom].
  • R 16 is a substituent selected from (1) a hydrogen atom, (2) phenyl substituted with an acetylamino group, (3) (i) an alkylsulfonyl group, (ii) pyridylcarbonyl or (iii) a sulfamoyl-alkyl group.
  • Preferred are mono- or di-substituted amino, (4) pyridyl or (5) halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom).
  • the ⁇ optionally substituted hydrocarbon group '' represented by R 2 and R 3 is the same as the ⁇ optionally substituted hydrocarbon group '' exemplified as the substituent of ring A Is used.
  • 10-membered heterocyclic group which may have a substituent (for example, which may have an oxo group, other than carbon atom, is selected from nitrogen atom, oxygen atom, sulfur atom, etc.
  • 4- to 10-membered heterocyclic group having one heteroatom eg, phthalimide, imidazolyl, piperidyl, pyrrolidinyl)
  • a hydrocarbon group which may be substituted by, for example, is used.
  • 1 halogen atom especially, bromine atom
  • 2 hydroxy especially, 3 _ 6 alkyl Le - Karuponiruokishi (eg, Asetokishi)
  • 4 Amino, 5 4 which may have a Okiso group to 1 0-membered heterocyclic group (Substituted with a 4- to 10-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen, sulfur, etc. in addition to carbon (eg, phthalimide, imidazolyl, piperidyl, pyrrolidinyl)) etc.
  • C 6 alkyl group is preferable be news halogen atom (especially, bromine atom) may be halogenated and the like - 6 alkyl group (e.g., methyl, etc. Echiru) and the like are preferable, especially methyl Groups are preferred.
  • R 2 and R 3 Represented by R 2 and R 3 as “Ashiru group", those similar to the Ru is exemplified as the substituents for ring A “Ashiru group” is used, inter alia - 6 alkoxy - Karuponiru groups are preferred, especially methoxycarbonyl Groups are preferred.
  • the 3- to 8-membered homocyclic R 2 and R 3 form together with the adjacent carbon atom, 3- to consist carbon atom used cyclic hydrocarbons to 8-membered, particularly, C 3 _ 8 consequent Roarukan (e.g., cyclobutane, cyclopentane, cyclohexane, heptane cyclohexane, cyclooctane), C 3 _ 8 Shikuroarugen (e.g., cyclobutene, consequent opening pentene, cyclohexene, cycloheptene, Shikurookuten) etc. is Ru mentioned. Of these C 3 8 cycloalkane is preferred, cyclopentane, 5 or 6-membered homocyclic ring such as key San cyclohexane (especially, cyclohexane) are preferred.
  • C 3 _ 8 consequent Roarukan e.g., cyclobutane, cyclopentane,
  • the 3- to 8-membered heterocyclic ring formed by R 2 and R 3 together with adjacent carbon atoms includes, in addition to a carbon atom, one or two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • a 5- to 8-membered aliphatic heterocycle (preferably a 5- or 6-membered aliphatic heterocycle) containing at least one (for example, 1 to 4, preferably 1 to 3) is used.
  • piperidine, piperazine, morpholine, thiomorphol 5 to 8 members preferably 5 or 6) containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon and nitrogen atoms, such as a nitrogen atom, a pyrrolidine and an imidazolidine ring. Member
  • a nitrogen atom such as a nitrogen atom, a pyrrolidine and an imidazolidine ring. Member
  • the 3- to 8-membered allo-heterocyclic or heterocyclic ring formed by R 2 and R 3 together with the adjacent carbon atom has the same substituent as the above-mentioned substituent which the heterocyclic ring represented by R 1 may have. It may have 1 to 5, preferably 1 to 3.
  • Substituents include: — 6-alkyl, C 6 — 14 aryl, C 7 — 16 aralkyl, amino, mono— — 6-alkylamino, mono-C 6 — 14 arylamino, di- 6 alkylamino, di— C 6 — 14 arylamino
  • a 4- to 10-membered heterocyclic group eg, a 4- to 10-membered (preferably 5- or 6-membered) containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms) 1 to 3 members selected from heterocycles
  • a 4- to 10-membered heterocyclic group eg, a 4- to 10-membered (preferably 5- or 6-membered) containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms) 1 to 3 members selected from heterocycles
  • R 2 and R 3 respectively a halogen atom, respectively a halogen atom, and a 6- alkoxy-carbonyl group is preferred, and a methyl group and a methoxycarbonyl group are particularly preferred.
  • C 3 8 cycloalkane together with the carbon atoms to which R 2 and R 3 are adjacent preferably cyclopentane, 5 or 6-membered homocyclic ring such as cyclohexane (in particular, key San cyclohexylene) may form a preferable.
  • ⁇ optionally substituted hydrocarbon group '' represented by R 4 and R 5
  • the same as the ⁇ optionally substituted hydrocarbon group '' exemplified as the substituent of ring A Things are used.
  • (1) halogen atom, (2) halogenated alkyl, (3) optionally halogenated — 6 alkoxy, (4) halogenated alkylthio, (5 ) May have 1 to 5 substituents selected from hydroxy, (6) amino, (7) monoalkylamino, (8) dialkylamino, etc. — 6 alkyl group, C 26 alkenyl group or C preferably 2 _ 6 alkynyl group, particularly an alkyl group (e.g., methyl, etc. Echiru) are preferred.
  • R 4 and R 5 for example, a hydrogen atom, an alkyl group (eg, methyl, ethyl) and the like are preferable, and a hydrogen atom is particularly preferable.
  • a hydrogen atom is particularly preferable.
  • the ⁇ optionally substituted hydrocarbon group '' represented by R 6 and R 7 the same as the ⁇ optionally substituted hydrocarbon group '' exemplified as the substituent of the ring A Of these, a (-6) alkyl group (eg, methyl, ethyl, etc.) is preferred, and a methyl group is particularly preferred.
  • the above-mentioned “replacement formed by R 2 and R 3 together with adjacent carbon atoms” have a substituent like are used and may also be 3 to 8-membered ring ", among them is preferably 8-membered homocyclic to 3 which may have a substituent, of these C 3 _ 8 Preferred are cycloalkanes (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane), and particularly preferred are 5- or 6-membered homocyclic rings (particularly, cyclopentane) such as cyclopentane and cyclohexane.
  • cycloalkanes eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane
  • 5- or 6-membered homocyclic rings particularly, cyclopentane
  • C 2 - 6 alkenyl group e.g., Ariru, such as 2-methyl-2-propenyl
  • C 2 _ 6 alkynyl group e.g., propargyl, etc.
  • C 3 _ 6 cycloalkyl group
  • substituent of the hydrocarbon group examples include (1) a halogen atom (for example, fluorine, chlorine, bromine, and iodine), (2) a hydroxy group, (3) an amino group, (4) lipoxy, and (5) rubamoyl.
  • a halogen atom for example, fluorine, chlorine, bromine, and iodine
  • a hydroxy group for example, an amino group, (4) lipoxy, and (5) rubamoyl.
  • C- 6 alkoxy monopropionyl eg, methoxycarbonyl, X toxiccarbonyl, etc.
  • Monono C i _ 6 alkyl monopotassium rubamoyl eg, methylcarbamoyl, ethylcarbamoyl, etc.
  • G-alkyl-carbamoyl eg, dimethylcarbamoyl, getylcarbamoyl, etc.
  • one to three carbon atoms which may have an oxo atom, other than nitrogen atom, sulfur atom, oxygen atom, etc.
  • Hetero atom-containing 4- to 10-membered heterocyclic groups eg, pyridyl, 2-isoindolyl, etc.
  • C 6 monoaryl groups eg, phenyl, etc.
  • acyl group '' represented by R 8 those similar to the ⁇ acyl group '' exemplified as the substituent for the ring A are used, and this acyl group further has a substituent selected from the group of substituents A to 1 to 5 , Preferably one to three.
  • the heterocyclic group represented by R 8 is a 4- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
  • ring groups eg, tetrazolyl, etc.
  • the substituent of the heterocyclic group, C 6 - 1 4 Ariru group (e.g., phenyl etc.) and the like are preferable.
  • the halogen atom represented by R 8 fluorine atom, chlorine atom, bromine atom, iodine atom are used, inter alia as chlorine atom is preferable. ,
  • Examples of the hydrocarbon group represented by R 1 G include (OC ⁇ -e alkyl group (eg, methyl, ethyl, isopropyl, butyl, etc.) [the 6- alkyl group is (1) halogen atom, (2) hydroxy Group, (3) amino group, (4) diluvamoyl, (5) diluvamoyl, (6) alkoxy-diluponyl, (7) monol-alkyl diluvamoyl, (8) Di--6 alkyl monorubumoyl, (9) containing from 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, etc., in addition to carbon which may have oxo, 10-membered aromatic Hajime Tamaki (e.g., pyridyl, 2-isoindolyl, etc.) which may have a substituent selected from such], (ii) C 2 _ 6 alkenyl group (e.g., ⁇ Lil, 2-methyl 2-propeny
  • the “acyl group” represented by R 1Q includes, for example, formyl, sorbamoyl, —6 alkyl monopropionyl (eg, acetyl, propionyl, etc.), c 3 _ 6 Cycloalkyl-carbonyl (eg, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C 6 alkoxy mono-proponyl (eg, methoxy-proponyl, ethoxycarbonyl, isopropoxy-proponyl, tert-butoxycarbonyl, etc.), C 6 _ 14 Ariru - carbonyl (e.g., Benzoiru, 2 Nafutoi Le etc.), C 7 _ 16 Ararukiru - Karuponiru (eg, phenylene Ruasechiru, 3-phenylene Rupuropioniru), C 6 ⁇ 4 ⁇ Li one
  • E Ji carbamoyl di -C - 6 alkyl Ichiriki Rubamoiru (e.g., dimethyl carbamoyl, such as GETS Ji carbamoyl), C 6 - 14 ⁇ Li one Roux force Rubamoiru (eg, full E carbamoylmethyl Such as 2 _ naphthylcarbamoyl), 5- or 6-membered heterocyclic Cal Bamoiru (e.g., 1-pyrrolidinylmethyl carbamoyl, 4 one piperidylcarbamoyl, 1 —Selected from nitrogen, sulfur, oxygen, etc.
  • cyclohexyl Chiokaruponiru alkoxy - Chiokaruponiru (e.g., methoxide ⁇ Chioka Ruponiru, Etokishichi Sairyoku Ruponiru, propoxycarbonyl Chio carbonyl, etc.
  • E chill sulfamoyl E chill sulfamoyl
  • G ⁇ _ 6 alkyl - sulfamoyl (e.g., dimethylsulfamoyl, etc. Jechirusu Rufamoiru)
  • C 6 ⁇ 4 Ariru - sulfamoyl e.g., such as Fuenirusurufa Moyle
  • ⁇ _ 6 alkylsulfonyl e.g., methylsulfonyl, etc.
  • Echirusuruho sulfonyl C 6 - 14 ⁇ reel sulfonyl ( examples, phenylalanine sulfonyl, such as 2-naphthyl Rusuruhoniru), ( ⁇ 6 alkylsulfinyl (e.g., methylsulfinyl, etc.
  • C 6 _ 14 ⁇ reel sulfinyl e.g., Hue Nils sulfinyl, 2- Nafuchirusuru Fiel, etc.
  • sulfino e.g., sulfo
  • alkoxys Rufiniru e.g., methoxysulfinyl, E Toki cis sulfinyl
  • c 6 - 14 ⁇ reel O carboxymethyl sulfinyl e.g., full enoki cis Luffy El
  • Arukokishisu Ruhoniru e.g., methoxysulfonyl, E butoxy-benzenesulfonyl
  • c 6 _ 14 Ari Ruo Xylsulfonyl e.g, phenoxysulfonyl
  • this acyl group may further have 1 to 5, preferably 1 to 3, substituents selected from the substituent group A.
  • ⁇ 6 alkoxy carbonyl group eg, methoxycarbonyl, ethoxycarbonyl, etc.
  • V monomer
  • Other di primary alkyl one Chiokarubamoiru group e.g., methylthio Scarpa moil, such as di-methylthio force Rubamoiru
  • halogenated may CI_ 6 alkyl one sulfonyl group (e.g., methyl sulfonyl), etc. are preferable.
  • examples of the heterocyclic group represented by R 1Q include a 4- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, sulfur, and oxygen atoms in addition to carbon atoms. (eg, such as tetrazolyl) [this double ring group C 6 - 14 Ariru (e.g., phenyl) which may have a. ] Is preferred.
  • SR 11 may be a ⁇ carbonized optionally having substituent (s) '' represented by R 11 As the “hydrogen group”, those similar to the “optionally substituted carbon hydride group” exemplified as the substituent for the ring A are used.
  • the hydrocarbon group represented by R 11, are preferred, such as ( ⁇ _ 6 alkyl group (e.g., methyl, etc. Echiru).
  • acyl group represented by R 11 in the formula—31 11 of the formula—31 11 represented by the scale 8 the same “acyl group” represented by R 1Q can be used. It may have 1 to 5, preferably 1 to 3, substituents selected therefrom.
  • the “acyl group” represented by R 11 is preferably a monol or dialkyl-carbamoyl group (eg, methylcarbamoyl, dimethylcarbamoyl, etc.).
  • the “optionally substituted hydrocarbon group” represented by R 12 includes the “substituent having a substituent” exemplified as the substituent for ring A.
  • the same hydrocarbon groups as those described above may be used.
  • the hydrocarbon group represented by R 12, ⁇ alkyl group (e.g., methyl, etc. Echiru) is preferable.
  • hydrocarbon group represented by R 13 (: Preparative 6 alkyl group (e.g., methyl, etc. Echiru) is preferably such.
  • Examples of the hydrocarbon group represented by R 14 and R 15 include a C 6 alkyl group (eg, methyl, ethyl, etc.) [This alkyl group may have an alkoxyl monopropyl. And the like are preferred.
  • acyl group represented by R 14 and R 15 of the formula 1 NR 14 R 15 represented by R 8
  • R 1Q can be used.
  • substituents selected from substituent group A.
  • formyl, c ⁇ 6 alkyl-caprolponyl group eg, acetyl, propionyl, etc.
  • alkoxy-carbonyl group eg, methoxycarbonyl, ethoxycarponyl, etc.
  • caprolvamoyl group mono- or dialkyl Carbamoyl groups (eg, methylcarbamoyl, dimethylcarbamoyl, etc.)
  • C ⁇ - 6 alkyl chromatography sulfonyl group e.g., methyl sulfonyl, etc. are preferable.
  • Examples of the ⁇ heterocyclic group optionally having substituent (s) '' represented by R 14 and R 15 in the formula 1 NR 14 R 15 represented by R 8 include ⁇ substituents exemplified as substituents on ring A. The same ones as those described for the "heterocyclic group which may be possessed" are used.
  • R 14 is a hydrogen atom, (2) a 6- alkyl group (eg, methyl, ethyl, etc.) [This alkyl group has 6 alkoxy-carbonyl Is also good.
  • R 15 is 1 a hydrogen atom , 2 (: preparative 6 alkyl (e.g., methyl, Echiru, propyl Le, isopropyl, etc.), 3 C 6 - 14 Ariru (e.g., phenyl, 2-naphthyl, etc.) or 4 C 7 - 16 Ararukiru (e.g., benzyl, phenethyl
  • R 14 is preferably a hydrogen atom, or an alkyl group (eg, methyl, ethyl, etc.) [this alkyl group May have alkoxy-carbonyl No.
  • R 8 represents a hydrogen atom or a formula —OR 1Q (R 1Q represents a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic group which may have a substituent) Is preferred.
  • R 8 a hydrogen atom, a hydroxyl group (where R 1Q is a hydrogen atom), an optionally substituted Ci-e alkoxy (R 1G may have a substituted C Preferred are i- 6 alkyl) or acyloxy (where R 10 is acyl).
  • substituent for the hydrocarbon group examples include an ⁇ halogen atom (for example, fluorine, chlorine, bromine, and iodine), (2) a cyano group, (3) a lower alkoxy group (eg, methoxy, ethoxy), and (4) hydroxy.
  • acyl group represented by R 9
  • those similar to the “acyl group” exemplified as the substituent for the ring A can be used. Specifically, (1) formyl, (2) 0 ⁇ 6 alkyl- power Lupo sulfonyl group (e.g., Asechiru, propionyl and the like), (3) C 6 _ 14 Ariru - power Ruponiru group (eg, a Benzoiru), (4) C 7 - 16 Ararukiru - carbonyl group (e.g., Fuenirua cetyl etc.) , (5) C ⁇ 6 alkoxy Ichiriki Ruponiru group (e.g., methoxy Cal Poni Le, an ethoxy Cal Poni le), (6) force Rubamoiru group, (7) mono - or di C ⁇ - 6 Al kill Ichiriki Rubamoiru group (e.g., methylcarbamoyl, etc.
  • dimethylcarbamoyl dimethylcarbamoyl
  • mono- or di-primary alkyl one Chiokarubamoiru group eg, Mechiruchiokaru Bamoiru, dimethylthiocarbamoyl Kalpa moil etc.
  • C _ 6 alkyl one sulfonyl group e.g. And methylsulfonyl
  • C 1 _ 6 alkyl one sulfinyl group e.g., a methylcarbamoyl Rusurufiniru
  • R 9 As the "optionally substituted hydroxy group" represented by R 9, for example, the formula - OR 9 '(R 9' may be a hydrogen atom, an optionally substituted hydrocarbon group or Ashiru group The group represented by is used.
  • optionally substituted hydrocarbon group represented by R 9 those similar to the “optionally substituted hydrocarbon group” exemplified as the substituent for the ring A can be mentioned. Used, and among them, alkyl and the like are preferable.
  • acyl group represented by R 9 those similar to the “acyl group” represented by R 1Q can be used, and among them, Ci- 6 alkyl-pyruonyl and the like are preferable.
  • R 9 is preferably a hydrogen atom, a cyano group, an alkyl group optionally substituted with cyano, formyl, and the like, and particularly preferably a hydrogen atom.
  • X represents (1) a methylene group which may have a substituent or (2) a carbonyl group.
  • substituent of the methylene group a group selected from the above-mentioned substituent group A is used, and among them, one or two alkyl groups (eg, methyl, ethyl, etc.) and a hydroxyl group are preferable.
  • the X (1) one or two ( ⁇ _ 6 alkyl group (e.g., methyl, good methylene group or (2) a carbonyl group which may have a like) or a hydroxyl group Echiru preferable, 1 or A methylene group which may have two methyl groups is preferred, and a methylene group is particularly preferred.
  • ⁇ _ 6 alkyl group e.g., methyl, good methylene group or (2) a carbonyl group which may have a like
  • a hydroxyl group Echiru preferable 1 or
  • a methylene group which may have two methyl groups is preferred, and a methylene group is particularly preferred.
  • n 0 or 1, and particularly preferably 0.
  • R 1 is the formula
  • R 2 and R 3 each represent a hydrocarbon group which may have a substituent
  • R 4 and R 5 represent A hydrogen atom
  • R 6 and R 7 each represent a hydrocarbon group which may have a substituent
  • R 8 represents a hydrogen atom or a formula OR 1Q (R 1Q represents a hydrogen atom or a substituent A hydrocarbon group, an acyl group or a heterocyclic group which may have a substituent)
  • R 9 is a hydrogen atom
  • X is methylene
  • n is 0 ( ⁇ ) Or its salt.
  • R 1 is the formula
  • R 16 is a hydrogen atom, which may have a substituent C 6 _ 14 Ariru group, an optionally substituted amino group, optionally substituted heterocyclic group Or a halogen atom), R 2 and R 3 each may have an alkyl group, R 4 and R 5 may represent a hydrogen atom, and R 6 and R 7 may represent a hydrogen atom.
  • R 8 represents a hydrogen atom or a group represented by the formula OR 1 Q (R 1 ° represents a hydrogen atom, a hydrocarbon group optionally having a substituent, an acyl group or A compound ( ⁇ ) or a salt thereof, wherein R 9 represents a hydrogen atom, X represents methylene, and n is 0.
  • R 1 is the formula
  • R 16 represents (1) a hydrogen atom, (2) phenyl substituted with an acetylamino group, (3) (i) C i_ 6 alkylsulfonyl group, (ii) pyridylcarponyl or (iii) sulfamoyl ⁇ _ 6 represents an amino, which may be mono- or di-substituted by a substituent selected from an alkyl group, (4) pyridyl or (5) a halogen atom], wherein R 2 and R 3 are each Ce alkyl R 4 and R 5 are hydrogen atoms; R 6 and R 7 are each 6 alkyl groups; R 8 is a hydrogen atom or a formula —OR 1 Q (R 1Q is (1) hydrogen atom, (2 ) Represents an alkyl group optionally substituted with pyridyl or (3) alkylsulfonyl substituted with a halogen atom), R 9 represents a hydrogen atom, represents methylene
  • ring A, ring B and ring C may each have the same substituent as described above], and the like.
  • R 2 ,, R 3 ', R 6' and R 7, each represents an alkyl group
  • R 16 are hydrogen atoms, which may have a substituent C 6 14 Ariru group, a substituent Which may have an amino group, a heterocyclic group which may have a substituent or a halogen atom].
  • the compound (A-1), (1-1) or ( ⁇ ′-1) of the present invention specifically, the compounds produced in Examples 1 to 16 and the like are used.
  • Compound (la) is a compound included in compound (I).
  • the compounds (I) and ( ⁇ ) of the present invention can be obtained, for example, by the method represented by the following reaction formulas 1 and 2, or a method analogous thereto.
  • Compounds (A), (A-1), (1-1) and (II-1) can also be produced according to the following production method.
  • the compounds ( ⁇ ) to (VI) and ( ⁇ ') to ( ⁇ ) in the reaction formula include those in the form of a salt.
  • Examples of the salt include the same as the salt of the compound (I) or ( ⁇ ). And the like.
  • Alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, etc.
  • Ethers such as getyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2 —Dimethoxyethane, etc.
  • Hydrocarbons such as benzene, toluene, cyclohexane and hexane, and amides such as N, N-dimethylformamide, N, N—dimethylacetamide, hexamethylphosphoric triamide
  • Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and ethyl methyl ketone
  • Organic acids such as formic acid, acetic acid, Acid, Torifuruoro acetic acid, methanesulfonic acid, aromatic Amin compounds show pyridine, 2, 6-lutidine, quinoline, etc., and etc. dimethylsulfoxide as sulfoxides.
  • the bases used in the following reactions and represented by a generic name include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide as inorganic bases, sodium carbonate as basic salts, and the like. Potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate, etc. Pyridine, lutidine, etc.
  • Sodium hydride, alkali metal hydrides such as amine, cyclohexyl dimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine Metals such as potassium Alkoxides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide; alkyl metals such as butyllithium and tert-butyllithium; aryl metals such as phenyllithium; and metal alkoxides such as sodium methoxide and sodium ethoxide.
  • 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.
  • Compound (la) wherein the C ′ ring may have a substituent other than RR 2 and R 3 is produced by the process shown in Reaction Scheme 1.
  • Compound (III) is produced by converting compound (II) into an organometallic compound using magnesium or a base, and reacting the compound with a formylating agent.
  • base examples include alkyl metals, aryl metals and the like.
  • the amount of the base to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (II).
  • the "formylating agent” examples include N, N-dimethylformamide, 1-formylpiperidine, 4-formylmorpholine, N-methylformanilide and the like.
  • the amount of the formylide used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).
  • 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 is preferably, for example, a solvent such as ethers or hydrocarbons, or a mixed solvent thereof.
  • the reaction time is generally about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is usually about ⁇ 100 to about 150 ° C., preferably about 180 to about 100 ° C.
  • hydrocarbon group include chain or cyclic hydrocarbon group (e.g., _ 6 ⁇ alkyl (e.g., methyl, Echiru, propyl, isopropyl, butyl, Isopuchiru, sec - heptyl, ter t-heptyl, pentyl , the like hexyl), C 3 _ 6 cycloalkyl (eg example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene hexyl, etc.), C 6 - 1 4 Ariru (e.g., phenyl, 1 one-naphthyl, 2-naphthyl, Bifue two Lilly, 2-anthryl, etc.).
  • alkyl e.g., methyl, Echiru, propyl, isopropyl, butyl, Isopuchiru, sec - heptyl, ter t
  • the amount of compound (IV) to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (III).
  • base examples include inorganic bases, basic salts, aromatic amines, tertiary amines, alkali metal hydrides, alkyl metals, aryl metals, metal amides, metal alkoxides and the like. Is mentioned.
  • the amount of base used is the same as that of compound (III) About 1 to about 5 moles, preferably about 1 to about 2 moles, based on
  • 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, hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, and water. 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 100 to about 200 ° C, preferably about 180 to about 150 ° C.
  • Compound (la) is produced by reacting compound (V) with compound (VI) in the presence of an acid.
  • the amount of compound (VI) to be used is about 0.5 to about 5 mol, preferably about 0.5 to about 2 mol, per 1 mol of compound (V).
  • Examples of the “acid” include mineral acids such as sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, and perchloric acid; boron trifluoride dimethyl ether complex; Lewis acids such as zinc chloride and aluminum chloride; .
  • the amount of the acid to be used is about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound (V).
  • 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 is preferably, for example, a hydrocarbon, an organic acid, a halogenated hydrocarbon, or a mixture thereof.
  • the reaction time is generally about 10 minutes to about 48 hours, preferably about 15 minutes to about 24 hours.
  • the reaction temperature is usually about 120 to about 150 ° C, preferably about 0 to about 10 ° C.
  • the compound ( ⁇ ′) is a compound ( ⁇ ) and a compound ( ⁇ ) wherein R 23 and R 24 are a hydrocarbon group which may form a part of R 7 and may have a substituent. those similar to R 7 can be exemplified, W is is prepared by reacting in the presence of a base as desired and represents a leaving group].
  • Examples of the “leaving group” include hydroxy, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and optionally halogenated Ci-s alkylsulfonyloxy (eg, methanesulfonyloxy, E evening down sulfonyl O carboxymethyl, trichloro methane sulfonyl O carboxymethyl, etc.), one C 6 which may have a substituent 1 () Arirusuruhoni Ruokishi the like. ".
  • ⁇ Li one Rusuruhoni Ruokishi as, for example (6 alkyl (e.g., methyl, Echiru etc.), selected from (6 ⁇ alkoxy (e.g., methoxy, ethoxy, etc.) and nitro C 6 _ 1Q 7 reelsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.) which may have 1 to 3 substituents, and specific examples thereof include benzenesulfonyl Xy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like.
  • 6 alkyl e.g., methyl, Echiru etc.
  • 6 ⁇ alkoxy e.g., methoxy, ethoxy, etc.
  • nitro C 6 _ 1Q 7 reelsulfonyloxy e.g., phenylsul
  • the amount of compound (VIII ′) to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound (VII ′).
  • base examples include inorganic bases, basic salts, aromatic amines, tertiary amines, metal hydrides, metal amides, metal alkoxides and the like.
  • the amount of the base to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of compound ( ⁇ ).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, and sulfoxides. Alternatively, a mixed solvent thereof is preferable.
  • the reaction time is usually about 15 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.
  • the reaction temperature is generally about 120 to about 150 ° C, preferably about 0 to about 100 ° C.
  • the compound ( ⁇ ⁇ ) and the compound ( ⁇ ⁇ ⁇ ) in which W is ⁇ ⁇ are reacted with an azodicarboxylate (eg, getyl azodicarboxylate, etc.) and a phosphine (Eg, triphenylphosphine, tributylphosphine, etc.).
  • an azodicarboxylate eg, getyl azodicarboxylate, etc.
  • a phosphine eg, triphenylphosphine, tributylphosphine, etc.
  • the amount of the compound in which W is ⁇ in the compound ( ⁇ ⁇ ′) is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound ( ⁇ ⁇ ).
  • the amount of the “azodicarboxylates” and “phosphines” to be used is about 1 to about 5 mol, preferably about 1 to about 2 mol, per 1 mol of the compound ( ⁇ )).
  • 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 ethers, hydrocarbons, amides, halogenated carbons, nitriles, ketones, and sulfoxides. Preferred are mixed solvents thereof.
  • the reaction time is generally about 5 minutes to about 48 hours, preferably about 10 minutes to about 24 hours.
  • the reaction temperature is usually about 120 to about 200, preferably about 0 to about 100.
  • Compound ( ⁇ ′) is produced by subjecting compound ( ⁇ ′) 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, hydrocarbons, organic acids, ethers, and anilines eg, ⁇ , ⁇ -dimethyl aniline, ⁇ , ⁇ — Phenethylaniline, etc.
  • phenols eg, 2,6-dimethylphenol
  • halogenated hydrocarbons or a mixed solvent thereof.
  • This reaction may be performed using an acid catalyst, if desired.
  • the acid catalyst Lewis acids such as aluminum chloride and boron bromide are used.
  • the amount of the acid catalyst to be 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 (IX ').
  • the reaction time is usually about 30 minutes to about 24 hours, preferably about 1 to about 8 hours.
  • the reaction temperature is usually about -70 to About 30 Ot: preferably about 150 to about 250 ° C.
  • Compound ( ⁇ ) can be produced by cyclizing compound ( ⁇ ') in the presence of a protonic acid, a Lewis acid or iodine.
  • protic acids include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and fluorosulfonic acid.
  • Lewis acids include aluminum chloride, aluminum bromide, and the like. Titanium chloride ( ⁇ ), tin chloride ⁇ ), zinc chloride, boron trichloride, boron tribromide, boron trifluoride and the like are used.
  • a protonic acid or a Lewis acid is used alone, but both may be combined as desired.
  • protonic acid it is used in an amount of about 1 to about 200 mol, preferably about 1 to about 100 mol, per 1 mol of the compound ⁇ ').
  • a Lewis acid it is used in an amount of about 1 to about 5 mol, preferably about 1 to about 3 mol, per 1 mol of compound ( ⁇ ′).
  • iodine it is used in an amount of about 0.05 to about 1 mol, preferably about 0.1 to about 0.5 mol, per 1 mol of the compound ( ⁇ ′).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent inert there is no particular limitation as long as the reaction proceeds as such a solvent, but examples thereof include ethers, hydrocarbons, alcohols, amides, halogenated hydrocarbons, nitriles, ketones, and sulfoxides. Or a mixed solvent thereof is preferred.
  • the reaction temperature is usually about -20 to about 150, preferably about 0 to about 120 ° C.
  • the reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.
  • Compound (II) is produced from compound (II) in the same manner as when producing compound (III) from compound (II).
  • Compound ( ⁇ ') can be prepared in the same manner as in the production of compound (V) from compound (III) and compound (IV); compound ⁇ ) and compound (IV) wherein R 22 and hal are as defined above. Show the same significance].
  • Compound ( ⁇ ) is produced from compound ⁇ ′) and compound (VI) in the same manner as in the production of compound (la) from compound (V) and compound (VI).
  • a compound in which X is methylene in compound (r) can be produced.
  • the compound thus obtained is optionally subjected to a functional group conversion based on a reaction known per se, whereby X is a substituted methylene and a carbonyl compound.
  • X is a substituted methylene and a carbonyl compound.
  • a protecting group generally used in peptide chemistry or the like may be introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary.
  • the protecting group of Amino for example, formyl or each alkyl Ichiriki be substituted Ruponiru (e.g., Asechiru, propionyl, etc.), benzo I Le, C WINCH 6 alkoxy - carbonyl (e.g., methoxy Cal Poni Le, Etokishika Ruponiru etc.), phenylalanine O carboxymethyl Cal Poni le, c 7 _ 1 6 Ararukiruokishi Ichiriki Lupo two Le (e.g., benzyl O carboxymethyl cull Poni Le etc.), trityl, phthaloyl and the like Ru is used.
  • Ruponiru e.g., Asechiru, propionyl, etc.
  • benzo I Le C WINCH 6 alkoxy - carbonyl (e.g., methoxy Cal Poni Le, Etokishika Ruponiru etc.), phenylalanine O carboxymethyl Cal Poni le,
  • halogen atom for example, fluorine, chlorine, bromine, iodine, etc.
  • 6- alkyl monopropanol for example, acetyl, propionyl, parryl, etc.
  • nitro and the like are used. Is about one to three.
  • Examples of the protecting group for alkoxy include alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. .
  • alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc.
  • substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), formyl, ( ⁇ _ 6 Al kills one force Ruponiru (e.g., Asechiru, propionyl, butylcarbonyl, etc.), Two Toro, C - 6 alkyl (e.g., methyl, Echiru, ter t-butyl, etc.), C 6 - 1 4 ⁇ Li - Le (e.g., phenyl, naphthyl and the like) and the like are used, and the number of substituents is 3 or so from 1 .
  • halogen atom e.g., fluorine, chlorine, bromine, iodine
  • formyl e.g., ⁇ _ 6 Al kills one force Ruponiru (e.g., Asechiru, propionyl, butylcarbonyl, etc.), Two Toro, C - 6 alkyl
  • hydroxy-protecting group examples include formyl, or each of which may have a substituent — 6-alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, ⁇ 7 _ 1 6 Ararukiru (e.g., benzyl, etc.), single 6 alkyl Ichiriki Ruponiru (e.g., Asechiru, propionyl, etc.), Fueniruo Kishikaruponiru, C 7 - 1 6 Ararukiruokishi Ichiriki Ruponiru (e.g., Benjiruoki aryloxycarbonyl, etc.), tetrahydronaphthalene Villa alkenyl, Tetrahydrofurel, silyl, etc.
  • substituent — 6-alkyl eg, methyl, ethyl, propyl, isopropyl, butyl
  • substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), 6- alkyl (eg, methyl, ethyl, tert-butyl, etc.), C 7 - 1 6 Ararukiru (e.g., benzyl etc.), C 6 _ 1 4 7 reel (e.g., phenyl, naphthyl, etc.), nitro and the like are used, and the number of the substituents is about four from 1.
  • halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • 6- alkyl eg, methyl, ethyl, tert-butyl, etc.
  • C 7 - 1 6 Ararukiru e.g., benzyl etc.
  • C 6 _ 1 4 7 reel e.g., phenyl, naphthyl, etc.
  • nitro and the like are used
  • 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-methyldithiocarbamate, and tetrabutylammonium fluoride. , A method of treating with palladium (II) 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.
  • compounds (A), (I), (1 ′), (A-1), (1-1) or ( ⁇ ′-1) can be synthesized.
  • the methods described in New Experimental Chemistry Lectures 14, 15 and 1977 are adopted.
  • the compound (A;), (1), ( ⁇ ), ( ⁇ -1), (I-1) or (-1) thus obtained can be obtained by known means such as phase transfer, concentration, solvent extraction, fractionation, It can be isolated and purified from the reaction solution by crystallization, recrystallization, chromatography and the like.
  • Compound (A), (I), (), (A-1), (1-1) or ( ⁇ -1) is a conjugated isomer (configuration isomer), diastereomer, conformer, etc. If present, each can be isolated by the above-mentioned separation and purification means, if desired. Further, when the compound (A), (I), ( ⁇ ), (A-1), (1-1) or ( ⁇ -1) is a racemate, the S-isomer and the S-isomer are obtained by ordinary optical resolution means. Can be separated into R-forms.
  • Compounds (A), (I), (), (A-1), (1-1) or (I, -1) may be hydrates or non-hydrates.
  • Compound (A), (1), ( ⁇ ), (A- 1), (I - 1) or (I, - 1) is (For example, 3 H, 14 35 S) isotopes are labeled with like You may.
  • R 2a and R 3a each may be an aliphatic hydrocarbon group which may have a substituent
  • R 4a and R 5a may each have a hydrogen atom or a substituent
  • the hydrocarbon group, R 6 a and R 7 a are each a hydrogen atom or an optionally substituted carbon hydrocarbon group, the substituent together with the carbon atoms R 6 a and R 7 a is adjacent May form a 3- to 8-membered ring
  • R 8a is (1) a hydrogen atom, (2) a hydrocarbon group which may have a substituent, (3) an acyl group, (4) a heterocyclic group which may have a substituent, (5) a halogen atom, (6) -OR 10a
  • R 1Qa represents a hydrogen atom, a hydrocarbon group which may have a substituent
  • —SR lla R lla is a hydrogen atom, a hydrocarbon group which may have a substituent, an acyl group or a heterocyclic
  • R 12a R 12a is have may have a substituent hydrocarbon group or a substituted group (9) — S (O) 2 R 13a (where R 13a is a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent) the illustrated) or (10) _NR 14a R 15a ( R 14 a and R 15 a are each a hydrogen atom, may be an optionally substituted hydrocarbon group, which may have a Ashiru group or substituent heterocyclic R 9a represents a hydrogen atom, a hydrocarbon group optionally having substituent (s), an acyl group or a hydroxyl group optionally having substituent (s), or a salt thereof. Is a novel compound.
  • Alkyl group [preferably, a lower alkyl group (e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, etc. ( ⁇ _ 6 alkyl groups such as hexyl)],
  • a lower alkyl group e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, etc. ( ⁇ _ 6 alkyl groups such as hexyl)
  • Cycloalkyl groups [preferably, a lower cycloalkyl group (e.g., Shikuropuropi Le, cyclobutyl, cyclopentyl, C 3 _ 6 cycloalkyl group such as cyclohexyl), may be condensed with a benzene ring,
  • a lower cycloalkyl group e.g., Shikuropuropi Le, cyclobutyl, cyclopentyl, C 3 _ 6 cycloalkyl group such as cyclohexyl
  • substituent of these "aliphatic hydrocarbon group” for example, (1) a halogen atom, (2) 0, _ 3 alkylene O alkoxy group, (3) a nitro group, be (4) a halogenated good C ⁇ - 6 alkyl group, (5) C 3 _ 6 cycloalkyl group, (6) C 6 - 14 Ariru group, (7) optionally halogenated alkoxy group, optionally be (8) halogenated also alkylthio group, (9) hydroxy group, (10) amino group, (11) mono - 6 alkylamino group, (12) mono- C 6 _ 14 Ariruamino group, (13) G ⁇ - 6 alkylamino group, (14) G C 6 - 14 ⁇ Li one Ruamino group, (15) formyl, carboxy, force Rubamoiru, alkyl one carbonyl, C 3 - 6 cycloalkyl one carbonyl, c I 6 alkoxy one carbonyl, C 6 _
  • substituent group B A group selected from the group consisting of groups formed by bonding three groups (hereinafter, abbreviated as substituent group B) is used. Specific examples of these substituents include the same as those exemplified in the above-mentioned substituent group A.
  • R 6 a and R 7 a it is may be formed together with the adjacent carbon atoms as "no 3 may have a substituent to 8-membered ring" formed together with the carbon atom to which R 6 and R 7 adjacent And the same as the “3- to 8-membered ring optionally having substituent (s)” may be used.
  • R 8a represents a “hydrocarbon group which may have a substituent”, an “acyl group”, a “heterocyclic group which may have a substituent”, a “halogen atom”, or a compound represented by the formula R 1 () a , “Formula — SR lla ”, “Formula —S (O) R 12a J”, “Formula —S (O) 2 R 13a ” or “Formula — N 1 a R 15a j, "optionally substituted hydrocarbon group” represented by 8 "Ashiru group", "substituted heterocyclic group which may have a", “halogen atom", “formula - OR 10"
  • the same formulas as those of “Formula—SR 11 ,“ Formula—S (O) R 12 ”,“ Formula 1 S (0) 2 R 13 ”or“ Formula 1 NR 14 R 15 ” are used.
  • Examples of the “optionally substituted hydrocarbon group”, “acyl group” and “optionally substituted hydroxyl group” represented by R 9a include “substituents” represented by R 9 The same groups as those described for the "hydrocarbon group optionally having", the "acyl group” and the “hydroxyl group optionally having a substituent" are used.
  • R 2 a and R 3 a are each 1 halogen atoms, 2 Ji 6 alkyl, - 6 Al kill one Karuboeru, substituted by C i _ 6 alkylsulfonyl and C 7 _ 16 substituents
  • Ru is selected from Ararukiru hydroxy which may, 3 1 or 2 CI- 6 alkyl, Ji E - 6 alkyl Ichiriki Ruponiru and C e- i 4 Ariru Ichiriki optionally substituted amino group with a substituent selected from Ruponiru, 4 A 4- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, a thio group optionally substituted with ⁇ ⁇ ⁇ alkyl, 6 — 6 A C 6 alkyl group optionally substituted with an alkylsulfinyl group or a ⁇ C alkyl-sulfonyl group,
  • R 8a is 1 (: 6 alkyl group, 2 Nono androgenic atoms, 3 Shiki ⁇ _R 10a
  • R 10a is, (i) a hydrogen atom, (ii) ( ⁇ -6 alkyl [the alkyl group (1) halogen atom, (2) hydroxy group, (3) amino group, (4) force Rupokishi, (5) force Rubamoiru, (6) ( ⁇ - 6 alkoxy - power Ruponiru, (7) mono - alkyl Ichiriki Rubamoiru, (8 ) Di-C- 6- alkyl-rubamoyl, (9) containing from 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may have oxo.
  • R 9 a is (i) a hydrogen atom, (ii) a C 6 alkyl group [this — 6 alkyl group is (1) a halogen atom, (2) 6 alkoxy group, (3) hydroxy group,) amino group, (5 ) Mono C 1-6 alkylamino group, (6) di-alkylamino group, (7) A 4- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; (8) C 6 _ 1 4 Arylthio, (9) Ureido, (10) Power Lupoxyl, (11) Power Lubamoyl, (12) (: 6 Alkoxy One Power Luponil, (13) Mono-( ⁇ _ 6 alkyl-Power Lubamoyl, (14) Formylamino and (15) it may have a substituent selected from alkyl-carboxamides] or (iii) a compound showing a formyl group (B)
  • the prodrugs of the compounds (I), (1 '), (1-1) and (-1) are prepared by reacting the compounds (I), ( ⁇ ), (1) (1) or (1'-1), that is, compounds (I), ( ⁇ ), (1-1) or (1, -1) which are enzymatically oxidized, reduced, hydrolyzed, etc. ), Or a compound that undergoes hydrolysis by gastric acid or the like to change to a compound (I), ( ⁇ ), (1-1) or ( ⁇ -l).
  • a prodrug of the compound (I), (1,), (1-1) or (1′_1) a prodrug of the compound (I), (I ⁇ , (1-1) or (1′-1)
  • the group is acylated, alkylated or phosphorylated (for example, the amino group of compound (I), (I ⁇ , (1-1) or (1′-1) is eicosanoylated, araellated, pentylized) Minocarbonylation, (5-methyl_2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinomethylation, pivaloyloxymethylation, tert- Compounds in which the hydroxyl group of the compound (I), ( ⁇ ), (1-1) or (1′-1) is acylated, alkylated, phosphorylated, or borated (for example, The hydroxyl group of compound (I), ( ⁇ ), (1-1) or (1'
  • prodrugs of compounds (I), (), (1-1) or (1'-1) are disclosed in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, 163-1. It may be changed to the compound (I), ( ⁇ ), (1-1) or ( ⁇ '-1) under physiological conditions as described in 98.
  • Examples of the salt of the compound (A), (1), ( ⁇ ), (A-1), (1-1), ( ⁇ -1) or (B) include, for example, pharmacologically acceptable salts and the like. Used. 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. Preferred examples of 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.
  • Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine. , N, N 'salts with dibenzyldiethylenediamine and the like.
  • Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone And salts with an acid, p-toluenesulfonic acid and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine, and the like.
  • Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.
  • salts are preferable.
  • examples thereof include compounds having a basic functional group in compound (I) or (III), for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid Salts with inorganic acids such as acetic acid, fumaric acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.
  • examples thereof include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metals such as calcium salts and magnesium salts. Genus salts, ammonium salts and the like.
  • ninii represents a single bond or a double bond
  • a salt thereof has a PDE inhibitory activity, particularly a PDE IV inhibitory activity, and is caused by PDE. It can be used as an agent for preventing and treating diseases.
  • the salt of the compound (A-2) include the salt of the above compound (A), (1), (I,), (A-1), (1-1), (-1) or (B). Similar ones can be mentioned.
  • the compounds (A), (1), (1,), (A-1), (1-1), ( ⁇ -1) of the present invention included in the above compound (A-2) or a salt thereof Or a salt thereof (including prodrugs of compounds (I), (1-1), ( ⁇ ), and ( ⁇ -l)) (hereinafter abbreviated as compound of the present invention) is excellent: PDE inhibitory action
  • PDE IV inhibitory activity is low in toxicity, and is safe, so it can be used in mammals (eg, humans, mice, dogs, rats, mice, etc.) for inflammatory diseases, autoimmune diseases, Diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, central dysfunction after cerebral vascular obstruction, cerebrovascular dementia, Alzheimer's dementia, memory impairment, obesity, Heart failure, pulmonary fibrosis, allergic disease, angina, myocardial infarction, hypertension, pulmonary hypertension, Disease, brain function disorders, immunodefici
  • inflammatory disease asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, diabetes, arteriosclerosis, graft-versus-host disease, multiple sclerosis, sepsis, psoriasis, osteoporosis, depression, cerebral vascular obstruction Later central dysfunction, cerebral vascular dementia, dementia of aruhaima type 1, memory impairment, obesity, heart failure, pulmonary fibrosis, allergic diseases (eg, atopic dermatitis, allergic rhinitis, juniper measles) ) Can be used as prophylactic or therapeutic agents, and PDE IV inhibitors.
  • the route of administration may be oral or parenteral.
  • dosage forms include, for example, tablets (including sugar-coated tablets and film-coated tablets), Pills, capsules (including microcapsules), granules, fine granules, powders, tablets, emulsions, suspensions, injections, inhalants, ointments, eye drops, aerosols, eye ointments, plasters Suppositories, troches, cataplasms, liniments and the like are used.
  • These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).
  • the content of the compound of the present invention varies depending on the form of the preparation, but is usually from 0.01 to 100% by weight, preferably from 0.1 to 50% by weight, based on the whole preparation. % By weight, more preferably about 0.5 to 20% by weight.
  • the drug was used as is, and excipients, binders, disintegrants, or other appropriate additives were added, and the mixture was uniformly mixed to obtain granules by an appropriate method.
  • a lubricant is added and compression molding is performed, or the medicine is directly mixed or directly mixed with excipients, binders, disintegrants or other suitable additives.
  • the granules can be produced by compression-molding the granules prepared beforehand as they are, or after adding an appropriate additive thereto and mixing them uniformly.
  • the present agent can contain a coloring agent, a flavoring agent, and the like as needed.
  • the agent can be coated with an appropriate coating agent.
  • a certain amount of a drug is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, or vegetable oil in the case of a non-aqueous solvent, to make a certain amount.
  • a predetermined amount of the drug can be taken and sealed in a container for injection.
  • the pharmaceutical carrier for oral use for example, substances commonly used in the pharmaceutical field such as starch, mannitol, crystalline cellulose, sodium propyloxymethylcellulose and the like are used.
  • the carrier for injection for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used.
  • additives generally used in pharmaceutical preparations can be appropriately added.
  • the dosage of these preparations varies depending on age, body weight, symptoms, route of administration, number of administrations, etc. For example, for adult asthma patients, it is converted into the active ingredient (compound of the present invention) per day. Usually 0.1 to 100 mg / kg, preferably 0.1 to 5.0 mg / kg, more preferably 0.5 to 10 mg / kg, divided orally once or twice daily It should be administered.
  • the compound of the present invention exhibits excellent PDE IV inhibitory activity even when used as a single agent, it is also used in combination with other pharmaceutical ingredients other than the compound of the present invention (hereinafter abbreviated as concomitant drug) (multiple drug combination) You can also.
  • concomitant drugs include anti-asthmatic agents (eg, flutidinzone propionate, beclomethasone propionate, theophylline, propoterol, ketotifen, azelastine, seratrodast, etc.), antiallergic agents (eg, fexofenadine, etc.) , Epinastine, ebastine, etc.), anticholinergic agents (eg, ipratropium bromide, fructophorium pium bromide, oxotropium bromide, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, loxoprofen sodium, etc.), Antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin tosylate, lepofloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.), antidia
  • the timing of administration of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be simultaneously administered to a subject to be administered. It may be administered at a time interval.
  • the dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination, and the like.
  • the administration form of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing a compound of the present invention and a concomitant drug, and (2) separate administration of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained as a formulation by the same administration route, (3) the time difference between the same administration route of the two preparations obtained by separately preparing the compound of the present invention and the concomitant drug.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se to obtain a pharmaceutical composition such as a tablet.
  • Injectables can be administered intravenously, intramuscularly, subcutaneously, in organs, intranasally, intradermally, instilled, in the brain, rectum, intravaginally and intraperitoneally, inside tumors, near tumors, or directly into lesions It can be administered.
  • the same carriers as those used in the aforementioned pharmaceutical composition of the present invention can be used.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the combination preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0. It is about 1 to about 50% by weight, more preferably about 0.5 to about 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation. %, More preferably about 0.5 to about 20% by weight.
  • the content of additives such as carriers in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to 10% by weight, based on the whole preparation. It is about 90% by weight.
  • the same content may be used when the compound of the present invention and the concomitant drug are separately formulated.
  • preparations can be produced by a method known per se that is generally used in the preparation process.
  • the compound of the present invention or the concomitant drug may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HC060 (manufactured by Nikko Chemicals), polyethylene) Glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, etc., stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), possible Solvents (eg, glycerin, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citrate and its alkali metal salts, etc.), tonicity agents (eg, sodium chloride, potassium chloride, mannitol) Sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethoxych
  • the compound of the present invention or the concomitant drug is used in accordance with a method known per se, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.) , A binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 600, etc.)
  • excipients eg, lactose, sucrose, starch, etc.
  • disintegrants eg, starch, calcium carbonate, etc.
  • a binder eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.
  • a lubricant eg, talc, magnesium stearate, polyethylene glycol 600, etc.
  • the coating agent examples include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, tween 80, pull mouth nick F68, cellulose acetate phthalate, and hydroxypropylmethyl cellulose.
  • tyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, copolymerization of methacrylic acid / acrylic acid), and pigments (eg, bengara, titanium dioxide, etc.) are used.
  • the preparation for oral administration may be either a quick release preparation or a sustained release preparation.
  • a compound of the present invention or a concomitant drug may be prepared according to a method known per se.
  • the product can be an oily or aqueous solid, semi-solid or liquid suppository.
  • the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.), intermediate fatty acids [eg, migliols (manufactured by Dynamite Nobel And vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • the aqueous base include polyethylene glycols and propylene glycol
  • examples of the aqueous gel base include natural gums, cellulose derivatives, bier polymers, and acrylic acid polymers.
  • sustained-release preparation examples include sustained-release micro force capsules.
  • a method known per se can be used to prepare a sustained release microcapsule.
  • the compound of the present invention is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository.
  • a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository.
  • preparations for oral administration are preferred.
  • the concomitant drug can be in the above-mentioned dosage form depending on the type of the drug.
  • An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection can be obtained by dissolving the compound of the present invention or the concomitant drug and, if desired, both benzoate or Z and salicylate in water.
  • Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, medalmine salts, and organic acid salts such as trometamol. .
  • the concentration of the compound of the present invention or the concomitant drug in the injection is about 0.5 to about 50 w / v%, preferably about 3 to about 20 wZV%.
  • Also benzoate or and salic The concentration of the luate is preferably from about 0.5 to about 50 w / v%, preferably from about 3 to about 20 wZ v%.
  • this agent contains additives commonly used for injections, such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), and solvents.
  • stabilizers ascorbic acid, sodium pyrosulfite, etc.
  • surfactants polysorbate 80, macrogol, etc.
  • solvents such as buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin, etc.) ), PH regulators (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl ethyl parabenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.) And soothing
  • the pH of the injection can be adjusted to 2 to 12, preferably 2.5 to 8.0 by adding a pH regulator.
  • An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, if desired, a benzoate and / or a salicylate, and if necessary, the above-mentioned additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably heated, and can be used as an injection by performing, for example, filtration sterilization or high-pressure heat sterilization in the same manner as an ordinary injection.
  • the aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes.
  • a formulation having antimicrobial properties of the solution may be used so that it can be used as a multiple-dose formulation.
  • a sustained-release preparation comprising a core comprising the compound of the present invention or the concomitant drug optionally coated with a film-forming agent such as a water-insoluble substance-swellable polymer is preferred.
  • a once-daily sustained release preparation for oral administration is preferred.
  • water-insoluble substance used in the coating agent examples include ethyl cellulose and butyl cellulose.
  • Cellulose ethers such as cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polybier acetate and polypinyl butyrate, acrylic acid Z methacrylic acid copolymer, methyl methacrylate copolymer, X toki Shetyl methacrylate / cinnamethyl methacrylate Z-aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly methacrylate, polymethacrylamide, Aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-100, RS-3OD, RL-3OD
  • hardened oils such as hardened castor oil (eg, Secondary wax (Freund Corporation)), carnauba wax, fatty acids glycerin ester, waxes such as paraffin, polyglycerin fatty acid esters, and the like.
  • swellable polymer a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable.Swelling is less in an acidic region such as in the stomach and swelling in a neutral region such as the small intestine and the large intestine. Polymers having an acidic dissociating group that grows are preferred.
  • Examples of the polymer having such an acidic dissociating group and exhibiting pH-dependent swelling include, for example, carbomer 934P, 940, 941, 944, 980, 1342, and the like, such as polycarbophil 1 , Calcium polycarbophil (all of which are manufactured by BF Goodrich), and Hibis Pico 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.). Coalescence.
  • the coating agent used in the sustained-release preparation may further contain a hydrophilic substance.
  • hydrophilic substance examples include polysaccharides which may have a sulfate group, such as pullulan, dextrin, alkali metal alginate, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose-snadium, and the like.
  • the content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 4 0 to 75% (w / w), swellable polymer content of about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w) .
  • the coating may further comprise a hydrophilic substance, in which case the content of the hydrophilic substance in the coating is not more than about 50% (w / w), preferably about 5 to about 40% (w / w), more preferably from about 5 to about 35% (w / w).
  • the above-mentioned% (w / w) refers to% by weight based on the coating composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating composition liquid.
  • the sustained-release preparation is prepared by preparing a nucleus containing a drug as exemplified below, and then dissolving the obtained nucleus by heating or dissolving or dispersing a water-insoluble substance or a swellable polymer in a solvent. It is manufactured by coating with
  • the form of the nucleus containing the drug to be coated with the coating agent (hereinafter sometimes simply referred to as the nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules.
  • the average particle size is preferably from about 150 to about 2,000 um, more preferably from about 500 to about 1,400 x m.
  • the nucleus can be prepared by a usual production method.
  • a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer, and the like, and the mixture is prepared by wet extrusion granulation, fluidized bed granulation, or the like.
  • the drug content of the core is about 0.5 to about 95% (w / w), preferably about 5 to about 80% (w / w), and more preferably about 30 to about 70% (w / w). w).
  • excipients contained in the core include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Among them, crystalline cellulose and corn starch are preferred.
  • binder examples include polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, pull nick F68, and Arabic Rubber, gelatin, starch and the like are used.
  • Disintegrants include, for example, carboxymethylcellulose calcium (ECG505), croscarmethylene monosodium sodium (Ac-Di-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) Are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred.
  • talc and magnesium stearate are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol and the like are used as a lubricant.
  • Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.
  • the nucleus may be formed by spraying a binder dissolved in a suitable solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) onto the inert carrier particles serving as the center of the nucleus, in addition to the above-mentioned production method.
  • a suitable solvent such as water, lower alcohol (eg, methanol, ethanol, etc.)
  • It can be prepared by the tumbling granulation method, pan coating method, fluidized bed coating method or melt granulation method, in which a small amount of a drug or a mixture of an excipient and a lubricant is added. it can.
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and the average particle size is about 100 111, or about 1,500 m. Is preferred.
  • the surface of the nucleus may be coated with a protective agent.
  • a protective agent for example, the above-mentioned hydrophilic substances, water-insoluble substances and the like are used.
  • a polysaccharide having a polyethylene glycol-hydroxyalkyl group or a carboxyalkyl group is preferably used, and hydroxypropylmethyl cellulose and hydroxypropylcellulose are more preferably used.
  • the protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc.
  • its coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% based on the core. (w / w).
  • the protective agent can be coated by a usual coating method.
  • the protective agent can be coated by spray-coating the nucleus by, for example, a fluidized-bed coating method or a pan coating method. .
  • a sustained-release preparation is produced by heating and dissolving a hydrophilic substance or coating with a coating agent solution in which a hydrophilic substance is dissolved or dispersed in a solvent.
  • Examples of the method of coating the core with a coating agent solution include a spray coating method.
  • composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), based on the core (not including the protective agent). Preferably it is about 5 to 35% (w / w).
  • the solvent for the coating agent solution water or an organic solvent can be used alone or in a mixture of both.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, and is preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves a water-insoluble substance. Examples thereof include lower alcohols such as methanol, ethanol, 2-propanol and 1-butanol, lower alkynones such as acetone, acetonitrile, and the like. Chloroform, dichloromethane and the like are used. Of these, lower alcohols are preferred, and ethanol and 2-propanol are particularly preferred.
  • Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution for stabilization.
  • the operation for coating by spray coating can be performed by a usual coating method.
  • the coating agent solution is spray-coated on the nucleus by, for example, a fluidized bed coating method or anadoo coating method. It can be implemented at At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light gay anhydride, etc. are used as lubricants, and glycerin fatty acid ester, hydrogenated castor oil, triethyl quenate, cetyl alcohol, stearyl alcohol are used. May be added as a plasticizer.
  • an antistatic agent such as talc may be mixed as necessary.
  • Immediate release preparations can be liquid (solutions, suspensions, emulsions, etc.) or solid (particles, Pills, tablets, etc.).
  • Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred.
  • Immediate release preparations may generally contain, in addition to the drug as an active ingredient, carriers, additives and excipients (hereinafter sometimes abbreviated as excipients) commonly used in the pharmaceutical field.
  • excipients commonly used in the pharmaceutical field.
  • the formulation excipient used is not particularly limited as long as it is a commonly used excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (such as Avicel PH101, manufactured by Asahi Kasei Corporation), powdered sugar, granulated sugar, mannitol, light caffeic anhydride, magnesium carbonate, carbonate Calcium, L-cysteine and the like, preferably corn starch and mannitol.
  • excipients can be used alone or in combination of two or more.
  • the content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30 to It is about 97w / w%.
  • the content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60%, based on the total amount of the immediate release preparation.
  • the immediate release preparation When the immediate release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (eg, Asahi Kasei Co., Ltd., AXIDISOL), crospovidone (eg, BASF Corporation, Kolydone CL) , Low-substituted hydroxypropylcells (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), carboxymethyl starch sodium (Kimura Sangyo, X Kisprotab), part Pregelatinized starch (PCS, manufactured by Asahi Kasei Corporation) is used.
  • PCS Pregelatinized starch
  • Granules are formed by, for example, contacting with water to absorb water, swell, or create a channel between the active ingredient constituting the core and the excipient. Can be used. These disintegrants can be used alone or in combination of two or more. The blending amount of the disintegrant is appropriately selected depending on the kind and blending amount of the drug to be used, the design of the release preparation, and the like. Is from about 0.5 to about 15 w / w%.
  • the immediate-release preparation is an oral solid preparation, or if it is an oral solid preparation, it is added to the above composition.
  • the solid preparation may further contain an additive for placement.
  • additives include binders (for example, sucrose, gelatin, gum arabic, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.) Sourcing agents (eg, polyethylene glycol, magnesium stearate, talc, light gay anhydride (eg, AEROSIL (Nippon AEROSIL)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters) And non-ionic surfactants such as polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, etc.), coloring agents (for example, tar pigments, caramel, bengara, acid) Titanium,
  • binders for example
  • hydroxypropyl cellulose polyethylene glycol, polyvinyl pyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation production technique.
  • the mixing is performed by a generally used method such as mixing and kneading.
  • a rapid-release preparation is formed into particles, a vertical granulator, a universal kneading machine (Hata Tekko And fluidized-bed granulator FD-5S (manufactured by Palek Co., Ltd.), followed by granulation by wet extrusion granulation, fluidized bed granulation, or the like.
  • the immediate-release preparation and the sustained-release preparation thus obtained can be administered as they are, or separately, separately and in combination with excipients, etc., according to a conventional method, and then administered simultaneously or in combination at an arbitrary administration interval.
  • both preparations may be formulated as a single orally administered preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate, together with excipients.
  • Both preparations may be made into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.
  • Sublingual tablet, puccal or oral fast disintegrating agent and its preparation The sublingual tablet, the puccal preparation, and the quick disintegrating agent in the oral cavity may be a solid preparation such as a tablet or an oral mucosa patch (film).
  • a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable.
  • auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer may be contained. Further, it may contain a / 3-cyclodextrin or
  • 3-cyclodextrin derivative eg, hydroxypropyl-13-cyclodextrin
  • excipients examples include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light caffeic anhydride and the like.
  • examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like, and magnesium stearate-colloidal silica is particularly preferable.
  • examples of the tonicity agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, with mannitol being particularly preferred.
  • hydrophilic carrier examples include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polybierpyrrolidone, light caffeic anhydride, citric acid, dicalcium phosphate, and calcium carbonate. Microcrystal cell openings) are preferred.
  • Water-dispersible polymers include gums (eg, tragacanth, acacia, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose) , Hydroxypropyl methylcellulose), gelatin, water-soluble starch, polyacrylic acid (eg, carpomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarpyl, ascorbic acid palmitate, and the like. Propyl methylcellulose, polyacrylic acid, alginate, gelatin, carboxymethyl cellulose, polypierpyrrolidone, polyethylene Glycol is preferred.
  • gums eg, tragacanth, acacia, guar gum
  • alginates eg, sodium alginate
  • cellulose derivatives eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropyl
  • hydroxypropyl methylcellulose is preferable.
  • the stabilizer include cystine, thiosorbitol, tartaric acid, cunic acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, and the like. Good.
  • the sublingual disintegrant, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug with an excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetening agent and a preservative may be mixed. By mixing the above components at the same time or with a time difference, and then press-molding, sublingual tablets, buccal tablets or intraorally rapidly disintegrating tablets can be obtained. In order to obtain an appropriate hardness, it may be manufactured by humidifying and moisturizing with a solvent such as water or alcohol before and after the tableting process, if necessary, molding, and then drying.
  • a solvent such as water or alcohol
  • the compound of the present invention or the concomitant drug When molded into a mucosa-adhered tablet (film), the compound of the present invention or the concomitant drug, the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient, etc. Dissolve in a solvent and cast the resulting solution into a film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added.
  • Glycols such as polyethylene glycol and propylene glycol can be included to impart appropriate properties to the film, and bioadhesive polymers (eg, Polycarbophil, Carbofil, etc.) can be used to enhance the adhesion of the film to the oral mucosal lining. Paul) may be contained. Casting involves pouring the solution onto the non-adhesive surface, spreading it to a uniform thickness (preferably about 100 to 100 microns) with an application tool such as a doctor blade, and then drying the solution. This is achieved by forming a film. The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.
  • bioadhesive polymers eg, Polycarbophil, Carbofil, etc.
  • Paul may be contained. Casting involves pouring the solution onto the non-adhesive surface, spreading it to a uniform thickness (preferably about 100 to 100 microns) with an application tool such as a doctor blade, and then drying the solution. This is achieved
  • a preferred rapid intraoral disintegrant is a solid rapid diffusion administration comprising a network of the compound of the present invention or the concomitant drug and a water-soluble or water-diffusible carrier inactive with the compound of the present invention or the concomitant drug.
  • Agents. The network can be obtained by sublimating the solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in a suitable solvent. .
  • composition of the oral disintegrating agent preferably contains a matrix-forming agent and a secondary component in addition to the compound of the present invention or the concomitant drug.
  • the matrix forming agent examples include gelatins, dextrins, soybeans, and wheat. And animal or plant proteins such as psyl 1 ium seed protein; gums such as gum arabic, guar gum, agar and xanthan; polysaccharides; alginic acids; carboxymethylcellulose; Dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex.
  • animal or plant proteins such as psyl 1 ium seed protein; gums such as gum arabic, guar gum, agar and xanthan; polysaccharides; alginic acids; carboxymethylcellulose; Dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex.
  • saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, Includes amino acids with 2 to 12 carbon atoms such as L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine. '
  • One or more matrix-forming agents can be introduced into a solution or suspension before solidification.
  • a matrix forming agent may be present in addition to the surfactant, or may be present without the surfactant.
  • the matrix former in addition to forming its matrix, can help maintain the compound or compound of the invention or the concomitant drug in a dispersed state in the solution or suspension.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red 40 from Ellis' Anderbergerd.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH regulators include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K and thaumatin.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
  • Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of book. Comprising between about 1 minute and about 60 minutes, preferably between about 1 minute and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in water) comprising the compound of the invention or the concomitant drug.
  • Formulations capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (the above-mentioned sublingual tablets, puccal, etc.), and preferably within about 1 to about 60 seconds after being placed in the oral cavity Is preferably a fast disintegrating agent in the oral cavity that disintegrates within about 1 to about 30 seconds, more preferably within about 1 to about 10 seconds.
  • the content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of the 3-cyclodextrin or) 3-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible lima in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer relative to the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary.
  • the dose of the concomitant drug of the present invention varies depending on the type, age, body weight, symptom, dosage form, administration method, administration period, and the like of the compound of the present invention. Usually, about 0.01 to about 1000 mgZkg, preferably about 0.01 to about 100 mgZkg per day, as the compound of the present invention and the concomitant drug, is more preferable. 1 to about 10 Omg Zkg, especially about 0.1 to about 5 OmgZkg, especially about 1.5 to about 30 mgZkg, is administered intravenously once or several times a day. You. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range.
  • the concomitant drug can be used in any amount as long as side effects are not a problem.
  • the daily dosage of the concomitant drug varies depending on the severity of symptoms, age, gender, body weight, sensitivity difference, administration timing, interval, characteristics of pharmaceutical preparation, preparation, type, type of active ingredient, etc.
  • the amount of the drug is usually The dose is about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 10 Omg per kg body weight of the mammal, and is usually administered in 1 to 4 times a day.
  • the concomitant drug may be administered at the same time, but after administering the concomitant drug first, the compound of the present invention may be administered, or the compound of the present invention may be administered first. Thereafter, the concomitant drug may be administered.
  • the time difference depends on the active ingredient to be administered, dosage form, and administration method.For example, when the concomitant drug is administered first, within 1 minute to 3 days after administration of the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention.
  • Method. BEST MODE FOR CARRYING OUT THE INVENTION
  • the transformant Escherichia coli BL21ZPPDE4D3 obtained in Test Example 1 described below was deposited with the National Institute of Advanced Industrial Science and Technology (NI BH) on March 8, 2000 under the deposit number FERM BP. -Deposited with the Fermentation Research Institute (IFO) under the accession number IF 216 383 from February 24, 2000 as 7075.
  • NI BH National Institute of Advanced Industrial Science and Technology
  • IFO Fermentation Research Institute
  • sequence numbers in the sequence listing in the present specification indicate the following sequences.
  • Example 3 shows the amino acid sequence encoded by the nucleotide sequence of cDNA carried by Escherichia coli BL21 / pPDE4D3 obtained in Test Example 1.
  • 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 a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Hexane / ethyl acetate (4: 1) mixture was added to the residue, the insolubles were filtered and concentrated under reduced pressure.
  • the residue was subjected to silica gel column chromatography (hexane / ethyl acetate 100: 1 followed by 10: 1) to give the title compound (11.0 g, yield 94). .
  • the reaction mixture was ice-cooled, water was added, neutralized with concentrated aqueous ammonia, and extracted twice with ethyl acetate. The combined organic layer was washed twice with water and concentrated under reduced pressure. The residue was suspended in ethanol (30 mL), a 2 M aqueous sodium hydroxide solution (30 mL, 60 mmol) was added, and the mixture was heated under reflux for 1 hour. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with water, and concentrated under reduced pressure.
  • Orchid ol was added, and the mixture was stirred at room temperature for 10 minutes and at 80 for 4 hours.
  • 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 twice with water and concentrated under reduced pressure.
  • 6- (3-bromophenyl) -1,2,8,9-tetrahydro-4-methoxy-2,2,8,8-tetramethylfuro [3,2-f] isoquinoline (207 mg, 0.500 mmol), 4 ' -(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) acetanilide (144mg, 0.551 bandol ol), sodium carbonate Thorium (133 mg, 1.25 bandol) and tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.010 mmol) in 1,2-dimethoxyethane (1.5 mL), ethanol (0.8 mL) and water (0.8 mL) mL) suspension was stirred at 85 under a nitrogen atmosphere for 16 hours.
  • Trifluoromethanesulfonic acid 6- [4 '-(acetylamino) [1, ⁇ -biphenyl] -3-yl] -1,2,8,9-tetrahydrido-2,2,8,8-tetramethylfur [ 3, 2-f] isoquinoline-4-yl ester
  • Trifluoromethanesulfonic acid 6- [4 '-(acetylamino) [1,1'-biphenyl] -3-yl] -1,2,8,9-tetrahydro-2,2,8,8-tetramethylphenyl Mouth [3,2-f] isoquinoline-4-yl ester (470 mg, 0.801 virgin ol), triethylamine (0.34 mL, 2.4 mmol), palladium (II) acetate (4.5 m.
  • Omg and corn starch 35.0 fflg was granulated through a 1-mesh mesh sieve using 0.03 ml of 10% gelatin aqueous solution (3.0 mg as gelatin). Thereafter, it was dried at 40 ° C. and sieved again.
  • the granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed.
  • the obtained central tablets were coated with a sugar coating using an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic.
  • the coated tablets were glazed with beeswax to obtain coated tablets.
  • Example 2 5.0 mg of the compound obtained in Example 1 and 20.0 mg of common salt were dissolved in distilled water, and water was added to make a total volume of 2.0 ml. Filter the solution into 2 ml ampules under aseptic conditions Filled. The ampoule was sterilized and sealed to obtain a solution for injection.
  • a water-absorbing ointment having the above composition (100 g) was previously heated to 70 ° C, and a solution prepared by heating 1 g of the compound obtained in Example 1 in 20 ml of methanol was added to the solution. Was. The mixture was heated and mixed at the same temperature for 10 minutes to remove residual methanol, and cooled to room temperature to obtain a water-absorbing ointment.
  • PCR was performed using MiniCycler TM (MJRESERCH) using Taq (Takara Shuzo) (reaction conditions: 0.5 min at 94 ° C, 0.5 min at 55T, 4 min at 72 ° C). 30 cycles).
  • the PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 2.4 kb was recovered. After blunting the fragment with Pfu DNA polymerase (STRATAGENE), Zero Blunt PCR Cloning
  • the PDE 4D3 gene was cloned using Kit (Invitrogen).
  • the plasmid obtained in the above (1) was digested with restriction enzyme EcoRI (Takara Shuzo), and then subjected to agarose gel electrophoresis to recover a DNA fragment of about 2.4 kb.
  • the PNA fragment was digested with restriction enzyme EcoRI (Takara Shuzo) and ligated with pAPEX4T-3 (Pharmacia) treated with BAP (Takara Shuzo).
  • the obtained cDNA fragment has the nucleotide sequence represented by SEQ ID NO: 3, and encodes the amino acid sequence represented by SEQ ID NO: 4 at the 74th to 2092th positions of the nucleotide sequence. I understood that it was.
  • This cDNA fragment was transformed into Escherichia coli BL21 (Funakoshi) using a ligase solution to obtain Escherichia coli BL21ZPPDE4D3 expressing the PDE4D3 gene.
  • the airway constriction response was measured by a modification of the Konzett-Rossler method.
  • Hartley male guinea pigs weighing 400-500 g were intravenously administered with 1.0 ml of anti-OA serum diluted 8 to 16 times under ether anesthesia, and used for experiments 16 to 24 hours later.
  • Anesthetize with urethane (1.2 g / kg, ip) (manufactured by Aldrich), inject tracheal force in the trachea, and in order to stop spontaneous breathing, garamine trietiodide (lmg / kg, iv) ( (Sigma).
  • Example compound ling / kg was dissolved in 25% dimethylacetamide, 25% polyethylene glycol 400, and 50% physiological saline, and administered intravenously 5 minutes before antigen induction.
  • the inhibition rate was calculated by comparing with the control group (intravenous administration of a mixture of 25% dimethylacetamide, 25% polyethylene glycol 400, and 50% saline).
  • Table 3 shows the inhibition rates of the compounds of the present invention.
  • the furoisoquinoline derivative of the present invention has an excellent PDE IV inhibitory action, and is used for inflammatory disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, autoimmune disease, depression, Alzheimer's disease, memory It is useful as a prophylactic and therapeutic agent for disorders, diabetes, arteriosclerosis, etc.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un composé présentant la structure partielle représentée par la formule (I) ou à un sel de ce composé; ainsi qu'à un composé représenté par la formule (II), où R1 représente un groupe hydrocarbure éventuellement substitué, etc.; R2 et R3 représentent chacun un groupe hydrocarbure éventuellement substitué, etc.; R4 et R5 représentent chacun hydrogène, etc.; R6 et R7 représentent chacun un groupe hydrocarbure éventuellement substitué, etc.; R8 représente hydrogène, -OR10 (R10 représente un groupe hydrocarbure éventuellement substitué, etc.), etc.; R9 représente hydrogène, etc.; X représente méthylène éventuellement substitué, etc.; et n est égal à 0 ou à 1, ou à un sel de ce composé. Ces composés ont une excellente activité inhibitrice de la phosphodiestérase IV et ils sont utiles comme médicaments/prophylactiques contre les maladies inflammatoires, l'asthme, la broncho-pneumopathie chronique obstructive, la polyarthrite rhumatoïde chronique, les maladies auto-immunes, la dépression, la démence sénile du type maladie d'Alzheimer, les troubles de la mémoire, le diabète et l'artériosclérose.
PCT/JP2002/006158 2001-06-22 2002-06-20 Derive de furo-isoquinoline, procede de production de ce compose et utilisation de ce compose WO2003000697A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-190338 2001-06-22
JP2001190338 2001-06-22

Publications (1)

Publication Number Publication Date
WO2003000697A1 true WO2003000697A1 (fr) 2003-01-03

Family

ID=19029122

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/006158 WO2003000697A1 (fr) 2001-06-22 2002-06-20 Derive de furo-isoquinoline, procede de production de ce compose et utilisation de ce compose

Country Status (1)

Country Link
WO (1) WO2003000697A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9399094B2 (en) 2006-06-06 2016-07-26 Novo Nordisk A/S Assembly comprising skin-mountable device and packaging therefore
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
CN113717185A (zh) * 2021-08-19 2021-11-30 云南省烟草农业科学研究院 雪茄烟根茎中一种具有抗菌活性的喹啉生物碱化合物及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07267961A (ja) * 1994-03-30 1995-10-17 Taisho Pharmaceut Co Ltd ベンゾフロ［３，２−ｄピリミジン−４−オン誘導体
WO1996036624A1 (fr) * 1995-05-19 1996-11-21 Kyowa Hakko Kogyo Co., Ltd. Composes heterocycliques contenant de l'oxygene
WO1999033460A1 (fr) * 1997-12-24 1999-07-08 Bristol-Myers Squibb Company Acyl guanidines inhibiteurs d'echange sodium/proton
WO2001070746A1 (fr) * 2000-03-23 2001-09-27 Takeda Chemical Industries, Ltd. Derives de furoisoquinoleine, leur procede de production et leur utilisation
WO2002004455A2 (fr) * 2000-07-11 2002-01-17 Albany Molecular Research, Inc Tetrahydroisoquinoleines 4-phenyle substituees et leur utilisation therapeutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07267961A (ja) * 1994-03-30 1995-10-17 Taisho Pharmaceut Co Ltd ベンゾフロ［３，２−ｄピリミジン−４−オン誘導体
WO1996036624A1 (fr) * 1995-05-19 1996-11-21 Kyowa Hakko Kogyo Co., Ltd. Composes heterocycliques contenant de l'oxygene
WO1999033460A1 (fr) * 1997-12-24 1999-07-08 Bristol-Myers Squibb Company Acyl guanidines inhibiteurs d'echange sodium/proton
WO2001070746A1 (fr) * 2000-03-23 2001-09-27 Takeda Chemical Industries, Ltd. Derives de furoisoquinoleine, leur procede de production et leur utilisation
WO2002004455A2 (fr) * 2000-07-11 2002-01-17 Albany Molecular Research, Inc Tetrahydroisoquinoleines 4-phenyle substituees et leur utilisation therapeutique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BULLETIN SOCIETY CHIM. FR., vol. 11, 1972, pages 4201 - 4208 *
CHEMICAL ABSTRACTS, vol. 78, 1973, Columbus, Ohio, US; abstract no. 71948M, RENE ROYER ET AL.: "Benzofurans. L. Access to furoisoquinolines" page 457-458; XP002957192 *
SHIOTANI SHUNSAKU: "Furopyridines. IV. Unexpected dimerization of 5-methyl-4,5,6,7-tetrahydrofuro(3,2-c)- and 6-methyl-4,5,6,7-tetrahydrofuro(2,3-c)pyridine by acidic hydrolysis", J. HETEROCYCL. CHEMICAL, vol. 23, no. 1, 1986, pages 233 - 240, XP002957193 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9399094B2 (en) 2006-06-06 2016-07-26 Novo Nordisk A/S Assembly comprising skin-mountable device and packaging therefore
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9815832B2 (en) 2013-02-19 2017-11-14 Pfizer Inc. Azabenzimidazole compounds
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US10077269B2 (en) 2014-08-06 2018-09-18 Pfizer Inc. Imidazopyridazine compounds
US10669279B2 (en) 2014-08-06 2020-06-02 Pfizer Inc. Imidazopyridazine compounds
CN113717185A (zh) * 2021-08-19 2021-11-30 云南省烟草农业科学研究院 雪茄烟根茎中一种具有抗菌活性的喹啉生物碱化合物及其制备方法和应用

Similar Documents

Publication Publication Date Title
DE60125026T2 (de) Fluorisochinolinderivate, verfahren zu ihrer herstellung und ihre anwendung
EP2380881B1 (fr) Nouveau composé hétérocyclique à cycle double
TWI296625B (en) Novel cyclic amide derivatives
US10676438B2 (en) KCNQ2-5 channel activator
TW201307284A (zh) 脂肪酸醯胺水解酶（ｆａａｈ）抑制劑
ZA200603181B (en) 3-(4-aminophenyl) thienopyrimid-4-one derivatives as MCH R1 antagonists for the treatment of obesity, diabetes, depression and anxiety
SK932003A3 (en) Cyclopentanoindoles, compositions containing such compounds and methods of treatment
TW401299B (en) Use of 5-substituted pyridine-and hexahydroquinoline-3-carboxylic acid derivatives for the treatment of disorders of the central nervous system, novel active compounds, a process for their preparation and their use
PT2592081T (pt) Derivado de tetrahidrocarbolina
CA3157798A1 (fr) Heteroarylaminosulfonamides a 6 chainons pour le traitement de maladies et d'etats medies par une activite cftr deficiente
JP2007297283A (ja) 新規桂皮酸関連化合物
WO2003000697A1 (fr) Derive de furo-isoquinoline, procede de production de ce compose et utilisation de ce compose
KR20050063747A (ko) 1-치환-1,2,3-트리아졸 유도체, 그 중간체, 및 이들의제조 방법
WO2004011470A1 (fr) Derive de furoisoquinoline et utilisation
JP2003171381A (ja) エントリー阻害剤
TW200900408A (en) Fused pyridine derivative
TW200836726A (en) Pyrrolopyridine-2-carboxamide derivatives, preparation thereof and therapeutic use thereof
ES2866324T3 (es) Derivados de 1-(1-hidroxi-2,3-dihidro-1H-inden5-il)-urea y compuestos similares como activadores del canal KCNQ2-5 para el tratamiento de la disuria
WO2001014385A1 (fr) Derives de dihydrobenzofuran, leur procede de preparation et agents
JP2003073380A (ja) フロイソキノリン誘導体、その製造法および用途
JP2004067690A (ja) フロイソキノリン誘導体およびその用途
TW202410897A (zh) 聯芳醚脲化合物
JPH0517441A (ja) スピロイソインドリン化合物、その製造方法、それを含有する神経症を治療するための医薬およびそれを製造するための中間体
JPH09118660A (ja) 芳香族ヒドロキサム酸誘導体、製造法および剤
JP2001335579A (ja) フロイソキノリン誘導体、その製造法および用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP