WO2002074771A1 - Compose heterocyclique a trois cycles, son procede de preparation et son utilisation - Google Patents

Compose heterocyclique a trois cycles, son procede de preparation et son utilisation Download PDF

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WO2002074771A1
WO2002074771A1 PCT/JP2002/002624 JP0202624W WO02074771A1 WO 2002074771 A1 WO2002074771 A1 WO 2002074771A1 JP 0202624 W JP0202624 W JP 0202624W WO 02074771 A1 WO02074771 A1 WO 02074771A1
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group
compound
reaction
naphthyridine
methyl
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PCT/JP2002/002624
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Japanese (ja)
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Yoshinori Ikeura
Tadatoshi Hashimoto
Naoki Tarui
Izumi Kamo
Junya Shirai
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Takeda Chemical Industries, Ltd.
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Publication of WO2002074771A1 publication Critical patent/WO2002074771A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Definitions

  • Tricyclic hetero compounds their production methods and applications
  • the present invention relates to a novel tricyclic heterocyclic compound having excellent tachykinin receptor antagonism, a method for producing the same, and a use thereof.
  • An object of the present invention is to provide a tricyclic heterocyclic compound having a stronger action than a conventional compound having a tachykinin receptor antagonistic action, a method for producing the same, a urination disorder improving agent containing the compound, and the like. .
  • the present inventors have conducted intensive studies in view of the above circumstances, and as a result,
  • R 2 represents a hydrogen atom, a halogen atom or an optionally halogenated alkyl group
  • R 3 represents a hydrogen atom or an alkyl group
  • R is the same or different and represents a halogen atom, an optionally halogenated C ⁇ 6 alkyl group, an optionally substituted C, _ 6 alkoxy group, a cyano group or a hydroxy group,
  • n is an integer from 0 to 3
  • n 1 or 2
  • p represents an integer of 0 to 3.
  • the tricyclic heterocyclic compound (hereinafter also referred to as compound (I)) represented by the formula (I) or a salt thereof has an unexpectedly strong tachycun receptor antagonistic activity (in particular, substance P) based on its unique chemical structure. Receptor antagonism), etc., and were found to be sufficiently satisfactory as a medicament, and the present invention was completed based on this finding.
  • R 2 represents a hydrogen atom, a halogen atom or an optionally halogenated alkyl group
  • R 3 represents a hydrogen atom or a _ 6 alkyl group
  • R may be the same or different halogen atom, an optionally halogenated C ⁇ _ 6 alkyl group, Ji may be halogenated! Alkoxy group, a Shiano group or a hydroxy group,
  • n is an integer from 0 to 3
  • n 1 or 2
  • p represents an integer of 0 to 3.
  • R 1 ′ is (1) an alkyl group optionally having a substituent, (2) an alkoxy group optionally having a substituent, and (3) Ce—i optionally having a substituent.
  • Karuboyuru group, (6) - substituted may have a group C, - 6 alkylthio group, (7) may have a substituent group ⁇ 6-1.
  • R 1 'force S (1) may have a substituent group C - e alkyl group, (2) optionally halogenated or Bok 6 alkoxy group, (3) C alkoxy - carbonyl group, (4) halogenated may CI_ 6 alkylthio group, (5) C 6 one] 0 Ariru group, (6) Ji Ashiruamino group, (7) C Medicine 6 Ashiruokishi group, (8) hydroxy group, (9 ) Nitro group, (10) halogen atom, (11) cyano group, (12) amino group, (13) mono- or dialkylamino group, (14) other than one nitrogen and carbon atom oxygen atom or a nitrogen atom which may contain 5 or 6-membered cyclic amino group, (15) C, _ 6 alkyl chromatography sulfonyl ⁇ amino group, (16) carboxyl group, (1-7) had 6 alkyl one group , (18) carbamoyl group, (19) mono or di-C ⁇ e alkyl
  • Ring A is (1) a 6- alkyl group which may be substituted with a hydroxy group, a halogen atom or a cyano group, (2) a heterocyclic oxy group, (3) a halogen atom, (4) a cyano group, (5 ) A mono- or di-alkyl 1-6 alkyl group, (6) a 5- or 6-membered cyclic aminocarbonyl group which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and carbon atom , (7) C, _ e alkyl - carbonyl ⁇ amino group, (8) a heterocyclic carbonyl ⁇ amino group or (9) a compound of the [1], wherein a pyridine ring substituted with a heterocyclic group.
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group which may be halogenated, ⁇ , a C! -E alkoxy group which may be Show. ]
  • R 1 ′ is (1) an optionally substituted S group—a 6-alkyl group, (2) an optionally substituted 6- alkoxy group, (3) an optionally substituted group Ce— !.
  • Aryloxy group (4) heterocyclic oxy group optionally having substituent (s), (5) dioxyalkoxycarbonyl group, (6) C ⁇ eT alkylthio group optionally having substituent, ( 7) C 6 _, which may have a substituent.
  • R 3 ' represents an alkyl group
  • R 4 'and R 5' are the same or different which may be halogenated C, _ 3 alkyl group.
  • a ′ ′ represents a pyridine ring that has been N-oxidized, and the other symbols have the same meanings as described in the item [1].
  • R 1 ′ represents a halogen atom, and other symbols have the same meanings as described in the item [1].
  • R lb represents a cyano group, and other symbols have the same meanings as described in item [1]].
  • Hydrolysis, amidation, acylation, substitution, alkylation A process for producing compound (I) or a salt thereof according to item [1], wherein a reaction, a transfer reaction, an addition reaction, a cyclization reaction and an oxidation reaction are used in combination as necessary.
  • a pharmaceutical composition comprising the compound according to [1] or a prodrug thereof and a pharmaceutically acceptable carrier.
  • composition according to [22] which is an agent for preventing or treating substance P-related diseases.
  • composition according to item [22] which is an agent for improving abnormal urination.
  • composition according to the above [22] which is an agent for preventing or treating sexual disorders, manic dysfunction or schizophrenia.
  • [30] A method for preventing and treating pollakiuria and urinary incontinence, comprising administering to a mammal an effective amount of the compound according to [1] or a prodrug thereof.
  • an effective amount of the compound according to (1) or a prodrug thereof for a mammal a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, Diuretics, chemotherapeutic agents, immunotherapy agents, cachexia improving agents, anti-inflammatory agents, glycation inhibitors, nerve regeneration promoters, antidepressants, antiepileptics, antiarrhythmic drugs, acetylcholine receptor ligands, endothelin receptor body antagonists, monoamine uptake inhibitors, Indoruamin uptake inhibitors, narcotic analgesics, GABA receptor agonists, GABA uptake inhibitors, alpha 2 receptor agonists, topical analgesics, Protein kina one peptidase C inhibitor, Anxiolytics, phosphodiesterase inhibitors, dopamine receptor agonistsAntagonists, serotonin receptor agonistsAn
  • the compound (I) or a salt thereof of the present invention includes stereoisomers such as cis and trans isomers, racemic forms, and optically active forms such as R-form and S-form. Further, depending on the size of the ring, an isomer due to conformation may be formed, and such an isomer is also included in the compound (I) of the present invention or a salt thereof.
  • Ring A represents a substituted pyridine ring, and the position of the nitrogen atom is not particularly limited.
  • ring A the number of substituents (hereinafter, this substituent is also referred to as R 1 ) substituting on the pyridine ring is not particularly limited, and one to three substitutions can be considered. No. Is not particularly limited position when the substituent R 1 of monosubstitution, preferably ⁇ next to the nitrogen atom of the pyridine ring. More specifically, ring A is, for example,
  • R 1 is not particularly limited
  • (1) may have a substituent group CI- e alkyl group, (2) an optionally substituted C I 6 alkoxy group, (3) may have a substituent C 6 _ 1Q 7-yloxy group, (4) optionally substituted heterocyclic oxy group, (5) alkoxymonocarbonyl group, (6) optionally substituted — 6-alkylthio group, ( 7) may have a substituent group C e - 10 ⁇ Li one thio group, (8) optionally substituted heterocyclic Chio group, may have a (9) substituents .
  • Aryl group (10) heterocyclic group which may have a substituent, (1 1) C] - beta Ashiruokishi group, (12) hydroxy group, (13) a nitro group, (14) a halogen atom, (15) Shiano group, (16) an amino group which may have a substituent, (17 Amidino group which may have a substituent, (18) oxime group, (19) carboxyl group, (20) acyl group which may have a substituent, (21) Preferred are (ii) a carbamoyl group which may be substituted, (22) a thiocarbamoyl group which may have a substituent, and (23) an alkylsnorefonyl group.
  • R 1 The number of substituents shown in (23) is not particularly limited as long as it is a number that can be chemically substituted with the group to be substituted. And 4 or more, preferably 1 or 2.
  • Examples of the 6 alkyl groups represented by RR 2 , R 3 and R include, for example, methinole, ethyl, propynole, isopropyl, butyl, sec-butyl, tert-butynole, pentyl, hexyl and the like.
  • Preferred are alkyl groups such as ethyl, propyl and isopropyl, and particularly preferred is methyl.
  • halogen atom a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom is preferable.
  • the mono- or di-Ji Bok 6 Arukiruamino for example, Mechiruamino, Echiru Amino, Jimechiruamino, etc. Jechiruamino are used, in particular Mechiruamino, such as mono- or di-one C i _ 3 Arukiruamino such dimethyl Chiruamino is preferred.
  • C 6 alkyl-carboxy for example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like are used.
  • Preferred are c-alkyl-carbonyloxy such as rucarponyloxy, ethylcarbonyloxy and propylcarbonyloxy.
  • Parogen of which do good C i _ 6 alkoxy optionally, For instance, main butoxy, ethoxy alkoxy, propoxy, butoxy, Torifuruorome butoxy, 2, 2, 2-Torifuruoroe butoxy are used, Tokunime butoxy, ethoxy and the like Noji, alkoxy, etc. are preferred.
  • the I 6 Ashiruokishi for example, Horumiruokishi, Asetokishi, C, such as propionitrile two Ruokishi -! S alkyl one carbonyl O carboxymethyl are used, among others, such as C i _ 3 Ashiruokishi such Asetokishi are preferred.
  • the C Bok 6 alkylsulfonyl for example, methylsulfonyl, Echirusuruhoni Le, such as professional buildings sulfonyl is used, inter alia methylsulfonyl, etc. alkylsulfonyl such Echirusuruho sulfonyl is preferred.
  • alkoxy one carbonyl for example, main butoxycarbonyl, ethoxycarbonyl, propoxycarbonyl carbo - le, etc. are used, among others main butoxycarbonyl, etc. ⁇ I 3 alkoxy Ichiriki Ruponiru such ethoxycarbonyl are preferable.
  • Examples of the mono- or di-alkyl carbamoyl include methylcarbamoyl, ethylcarbamoyl, propylcarbamyl, dimethylcarbamoyl, dimethylcarbamoyl, and dicarbylpylbamoyl, and methylcarbamoyl, ethylcarbamoyl, and the like.
  • Ji carbamoyl, dimethylcarbamoyl, mono- if Ku is Gee ⁇ such Jefferies Ji carbamoyl, etc. _ 3 alkyl Ichiriki Rubamoiru are preferred.
  • Examples of mono- or di-alkyl-sulfamoyl include, for example, methyl sulfamoyl, ethinolesulfamoyl, propyl sulfamoyl, dimethylsnorefamoyl, getyl sulfamoyl, dipropyl sulfamoyl, etc., and methyl sulfamoyl, Ethyl sulfamoyl, dimethyl sulfamoyl, Jethyl sulfam Mono or dialkyl 3- alkyl-sulfamoyl such as amoyl is preferred.
  • the Flip 6 _ 1 4 Ariru for example, phenyl, naphthyl and the like.
  • the 5- to 14-membered heterocyclic group includes, for example, 1 to 4, preferably 1 or 2 hetero atoms selected from nitrogen, oxygen, sulfur and the like in addition to carbon atoms.
  • Member preferably 5 to 9 members, particularly preferably 5 or 6 members
  • a heterocyclic group is used, among which phenyl (2-phenyl, 3-phenyl), furyl (2-furyl, 3-furyl) , Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolinyl, 5-quinolyl, 8-quinolyl), isoquinolyl (1- ⁇ soquinolyl, 3-) Isoquinolyl, 4-isoquinolyl, 5-isoquinolinol), virazinyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl), piralyl (3-pyrrolyl), imidazolyl (2-imida
  • the 0 ⁇ _ 6 alkoxy group represented by R 1 for example, methoxy, ethoxy, Provo alkoxy, such as butoxy are used, Tokunime butoxy, ethoxy, preferably such Bok 3 alkoxy groups such as Buropokishi, especially methoxy are preferred .
  • Examples of the substituent which the alkoxy group represented by R 1 may have include, for example, the alkyl group represented by R 1 and those exemplified as the substituent thereof, and particularly, carboxyl, ethoxycarbonyl , Pyrrolidinyl, pyridyl, halogen and the like are preferred.
  • R 1 C 6 denoted by R 1 .
  • substituent which the aryloxy group may have include, for example, the 6- alkyl group represented by R 1 and those exemplified as the substituent thereof.Amino which may have a substituent is preferable. .
  • substituent of the amino which may have a substituent examples include a -6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl, and methyl snorehoni is preferred.
  • the heterocyclic oxy group represented by R 1 includes, for example, a heterocyclic moiety having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom. And a pyridyloxy group is preferred.
  • the heterocyclic Okishi substituent which may be have represented by R 1, for example, but such as those exemplified as C i _ 6 alkyl groups and substituents thereof are shown by R 1 can be mentioned, methylcarbamoyl And an alkyl group such as phenyl.
  • alkoxymonocarbonyl group represented by R 1 examples include methoxycarbonyl, ethoxyquinolebonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, among which methoxycarbonyl, ethoxycarbonyl and the like are used.
  • Carbonyl, C such as propoxycarbonyl, lay like are preferable _ 3 alkoxy one carbonyl group, including Tokunime butoxycarbonyl is preferred.
  • C— s alkylthio group represented by R 1 for example, methylthio, ethylthio, propylthio, isopropinorethio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc. are used, and in particular, methylthio, ethylthio, Alkylthio groups such as propylthio and isopropylthio are preferred, and methylthio is particularly preferred.
  • C represented by R 1, - a 6 have an alkylthio group les, even substituent, for example, those exemplified as Arukinore groups and substituents thereof represented by R 1, but a halogen and the like, Carpamoyl, mono- or di-alkyl rubamoyl, trifluoromethyl and the like are preferred.
  • the heterocyclic thio group represented by R 1 has, for example, a heterocyclic moiety having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom Examples include a heterocyclic thio group, and pyridylthio and the like are used.
  • heterocyclic Chio substituent group may even have to be represented by R 1, for example, C represented by R 1, _ 6 alkyl and illustrated ones but like as a substituent, carboxyl Is preferred.
  • R 1 Represented by R 1.
  • aryl group for example, phenyl, naphthyl and the like are used.
  • heterocyclic group represented by R 1 examples include a heterocyclic group having 1 to 4, preferably 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom.
  • pyridyl, imidazolyl, tetrazolyl, pyrazolyl, triazolyl, thianolyl, oxdiazolyl, tetrahydrotriazinyl, dioxanyl, thiazolyl and the like are used.
  • the substituent which may be heterocyclic group possessed by R 1, for example, C represented by R 1, _ 6 alkyl and illustrated ones but like as a substituent, methyl, I alkyl such as an isopropyl, phenylmethyl, hydroxycarbonyl, alkoxy one carbonyl such as ethoxycarbonyl, halogenated flicking 6 alkyl, such as trichloromethyl, pyrrolidinyl, Okiso, Benzuimi Doiruamino (C 6 H S C ( NH) - NH-), hydroxy Is preferred.
  • C represented by R 1, _ 6 alkyl and illustrated ones but like as a substituent methyl
  • I alkyl such as an isopropyl, phenylmethyl, hydroxycarbonyl, alkoxy one carbonyl such as ethoxycarbonyl, halogenated flicking 6 alkyl, such as trichloromethyl, pyrrolidinyl, Okiso, Benzuimi Doir
  • the 6 Ashiruokishi group for example, Horumiruokishi, Aseto alkoxy, propionic - - that represented by by by R 1 Ruokishi etc. - 5 Ashiruokishi group is used, inter alia formyl Ruokishi, Asetokishi, etc. Ashiruokishi such propionyl Ruo alkoxy is not preferred .
  • the halogen atom represented by R 1 a fluorine atom, a chlorine atom, a bromine atom, used is iodine atom is preferable among them a fluorine atom, etc. Shiosaku atom.
  • R 1 examples include, for example, an unsubstituted amino group, a monosubstituted amino group, and a disubstituted amino group. Groups are also used.
  • Examples of the optionally substituted cyclic amino group represented by R 1 include a 5- or 6-membered cyclic group which may contain an oxygen atom or a nitrogen atom in addition to one nitrogen atom and a carbon atom.
  • An amino group is used, and in particular, pyrrolidino, piperidino, piperazino, morpholino and the like are used, and among them, morpholino is preferable.
  • Examples of the substituent of an amino group which may have a substituent represented by R 1, for example, but such as those exemplified as C t 6 alkyl groups and substituents thereof represented by R 1 can be mentioned,
  • alkyl methyl, ethyl, propyl, dimethyl, getyl, dipropyl and the like are preferable, and particularly, mono or dialkyl such as methyl, ethyl, dimethyl, dimethyl and propyl is preferable, and methyl and dimethyl are particularly preferable.
  • 6-Alkyl-carbonyl includes methylcarbonyl, ethylcarbonyl and propylcarbonyl.
  • the C 6 _ 10 ⁇ Li one Honoré carbonyl include phenylalanine carbonyl.
  • heterocarboxy examples include pyridylcarbonyl.
  • 6- alkoxymonocarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycanolebonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like. is used, inter alia main butoxycarbonyl, ethoxycarbonyl, propoxy Shikarubo two Honoré, n- butoxycarbonyl two Honoré, sec- butoxide Shikano levo Nino les, C, such as tert- butoxycarbonyl, etc. _ 4 alkoxy one carbonyl are preferred.
  • the C 6 alkylsulfonyl for example, methylsulfonyl Nino les, E chill sulfo Nino les, CI_ 5 alkylsulfonyl is used, such as propylsulfonyl, among others Mechirusuru Honiru, C, such as engineering Chirusuruhoniru, preferably _ 3 alkyl sulfo El.
  • an acyl such as formyl, acetyl or propionyl is preferable, and an acyl such as forminole, acetyl or propionyl is particularly preferable.
  • the amino group substituted by an aminocarbonyl which may have a substituent include an ureido group which may have a substituent, and the ureide group includes mono-, di- or tri-C.
  • N monomethyl ureide
  • ' N, Methyl ureide, ⁇ , ⁇ ', ⁇ ' — Trimethyl ureide
  • Examples of the substituent of the optionally substituted cyclic aminocarbonyl include acetyl.
  • Examples of the substituent of the amidino which may have a ⁇ ⁇ group include hydroxy. Examples of the substituent of oxaziazolyl which may have a substituent include methyl and trifluoromethyl.
  • Examples of the substituent which the amidino group represented by R 1 may have include, for example, the 6- alkyl group represented by R 1 and those exemplified as the substituents thereof. Is preferred.
  • the Okishimu group represented by R 1 for example, need use the formaldehyde Okishimu.
  • Examples of the acyl group represented by R 1 include formyl or Ci-B alkyl-carbonyl group, which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and a carbon atom.
  • a 3-membered cyclic aminocarbonyl group is used, and among them, C 1-3 acyl such as formyl, acetyl, propionyl and the like are preferable.
  • R 1 examples of the substituent that the Ashiru groups have represented by R 1, for example, C represented by R 1, - although such as those exemplified as e alkyl group and the substituent group, such as Metokishika carbonyl Ci-ealkoxy-carbonyl and the like are preferred.
  • the group, for example, Asechiru, CI_ such propionyl 5 Arekiru - carbonyl group are used, inter alia Asechiru, such as propionyl
  • Examples of the 5- or 6-membered cyclic aminocarbonyl group which may contain an oxygen atom, a nitrogen atom or a sulfur atom in addition to one nitrogen atom and carbon atom include, for example, (pyrrolidine-111) carbonyl, morpholinocarbonyl , (Isothiazolidine-1-yl) carbonyl, thiomorpholinocarbonyl and the like are used.
  • the cyclic amino group may form a condensed ring with another ring structure.
  • Ring structures that can form a condensed ring together include C ⁇ , such as phenyl.
  • Cyclic Aminokarubo alkenyl group may have a substituent, the substituent
  • et al are And alkyl such as methyl, oxo, hydroxy, tert-butoxycarbonyl, and alkoxy-carbonyl such as methoxycarbonyl.
  • Examples of the group which the carpamoyl group represented by R 1 may have include, for example, those represented by R 1 Is the C, _ 6 alkyl and illustrated but like those as a substituent, in particular, C - 5 alkyl, cyclopentyl, C 5 _ 8 cycloalkyl such as cyclohexyl, Jii such main bets alkoxy 6 Carboxyalkyls such as alkoxy and carboxymethyl, and hydroxyalkyls such as formyl, phenyl, benzyl and hydroxyethyl are preferred.
  • methyl, ethyl, propyl, isopropyl, tert-butyl, dimethyl, getyl, dibutyl pill, and the like are preferable, and particularly, mono- or dialkyl such as methyl, ethyl, dimethyl, and getyl are preferable. It is.
  • —6 alkylsulfonyl group represented by R 1 for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like are used, and among them, C 3 alkylsulfonyl groups such as methylsulfonyl and ethylsulfoyl are preferable.
  • Examples of the substituent of the amidino group which may have a substituent represented by R 1 include methoxy, hydroxy, amino which may have a substituent, and 1,3-dihydroxyacetimino.
  • Examples of the substituent of the amino which may have a substituent include methyl and tert-butoxycarbonyl.
  • R 1 is (1) a C, -6 alkyl group optionally substituted with a hydroxy group, a halogen atom or a cyano group, (2) a heterocyclic oxy group, (3) a halogen atom, (4) a cyano group, ( 5) Mo no or di CI_ 6 alkyl force Rubamoiru group, (6) one nitrogen atom and carbon atom other than an oxygen atom, ⁇ atom or a sulfur atom which may contain 5 or 6 membered cyclic aminocarbonyl A group, (7) a Ct-6 alkyl-carbo-amino group, (8) a heterocyclic carbonylamino group or (9) a heterocyclic group.
  • R 1 is (1) an alkyl group which may have a substituent, (2) a 6- alkoxy group which may be halogenated, (3) -6-alkoxy-carbonyl group, (4) a halogeno May be down of - 6 alkylthio group, (5) C 6 _ 10 7 aryl group, (6) 6 ⁇ Shinoreamino group, (7) Ci-e Ashiruokishi group, (8) hydroxy group, (9) nitro Group, (10) halogen atom, (11) cyano group, (12) amino group, (13) mono or di-- 6 alkylamino group, (14) one nitrogen atom and carbon atom other than oxygen atom or 5- or 6-membered cyclic amino group which may contain a nitrogen atom, (15) C 1-6 alkyl-sulfoylamino group, 46) carboxyl group, 17) alkyl-carbonyl group, i
  • 8) a formyl group, (19) force Rubamoiru group, (20) mono- or di one C] _ 6 alkyl force Norebamoiru group, (21) alkylsulfonyl groups, (22) mono- mono-, di- one or tri- one - 6 Arukiruureido group And (23) a C 1-6 alkoxy-carbonylamino group or (24) C, _ 6 alkoxy-carboxyalkylamino group.
  • halogen atom which the optionally halogenated C- 6 alkyl group represented by R 2 and R may have include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a d-e alkyl group optionally substituted with 1 to 3 halogen atoms is used.
  • halogen atom represented by R 2 and R a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.
  • a d-e alkoxy group optionally substituted with 1 to 3 halogen atoms is used, and examples thereof include methoxy, ethoxy, and propoxy.
  • examples thereof include methoxy, ethoxy, and propoxy.
  • Butoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, and the like, and among them, an optionally halogenated alkoxy group such as methoxy, ethoxy, propoxy, and trinoleolomethoxy is preferable.
  • halogen atom which the optionally halogenated C 6 alkoxy group represented by R may have, a fluorine atom, a chlorine atom, a bromine atom and a iodine atom are used.
  • R 1 the following (A) to (F) are also preferable.
  • Aryl, ⁇ - amino, 6- hydroxy, hydroxy, nitro, halogen, cyano, amino, mono- or di- ⁇ - alkylamino, one nitrogen and one carbon atom in addition to the carbon atom or nitrogen atoms contain an be 5 or 6-membered cyclic amino groups, C, _ 6 alkyl chromatography sulfo - Ruamino groups, C I 6 alkyl - carbonyl group, a force Rubamoiru group, mono- or di - CI_ 6 alkyl Scarpa moil !
  • C, _ 6 alkyl group In particular, C, _ 6 alkyl group.
  • C 3 alkyl groups (eg, methyl), C, — 3 alkoxy groups (eg, methoxy), C, _ 3 alkoxy monocarbonyl groups (eg, methoxycarbonyl), d_ 3 alkylthio groups (eg, methylthio), halogen atom (e.g., fluorine atom, chlorine atom), Shiano group, an amino group, model no or di one 3 alkylamino group (e.g., Mechiruamino, Jimechiruamino), oxygen atom in addition to one nitrogen atom and carbon atoms Or a 5- or 6-membered cyclic amino group that may contain a nitrogen atom (eg, morpholino).
  • R 2 is preferably a halogen atom such as a hydrogen atom or a fluorine atom, or a C ⁇ 3 alkyl group such as methyl, ethyl, propyl, or isopropyl.
  • a halogen atom such as a hydrogen atom or a fluorine atom, or methyl is preferable.
  • Preferred is a hydrogen atom or a fluorine atom.
  • R 1 is methyl
  • R 2 is preferably a fluorine atom
  • R 1 is cyano
  • R 2 is preferably a hydrogen atom.
  • R 3 a hydrogen atom or a methyl, Echiru, propyl, preferably _ 3 alkyl groups such as isopropyl, especially ⁇ Bok 3 alkyl group such as methyl preferred.
  • R 3 is coordinated.
  • the general formula (I) is
  • R 1 ′ has the same meaning as R 1 defined above, and each of the other symbols has the same meaning as described above. ] Is represented.
  • Ring A represents a pyridine ring, and the position of the nitrogen atom is not particularly limited.
  • R 1 ′ substituted on the ring A ′ is not particularly limited, but is preferably substituted next to the nitrogen atom on the pyridine ring. More specifically,
  • Etc. are used, especially Is preferred.
  • R is preferably a hydrogen atom, a C, -3 alkyl group which may be substituted by 1 to 3 halogen atoms (particularly, a fluorine atom) such as methyl, ethyl, propyl, trifluoromethyl, etc. Methyl or trifluoromethyl is preferred.
  • p represents an integer of 0 to 3, and represents that 0 to 3 Rs may be substituted on the phenyl group. p is preferably 2.
  • substitution position of R is not particularly limited.
  • p is 2, the 3- and 5-positions of the phenyl group are preferred.
  • R 4 , R 5 and R 6 are the same or different and are each a hydrogen atom, Which may C, _ e alkyl group, an alkoxy group which may be halogenated, showing the Shiano group or arsenate Dorokishi group. And a group represented by the formula:
  • R 4 and R 5 are as defined above.
  • R 4 , R s and R s — ⁇ - alkyl groups include, for example, methyl, ethanol, propynole, isopropinole, butizole, sec-butyl, tert-butynole, pentynole, hexyl and the like.
  • C! 3 alkyl groups such as methyl, engineered, propyl, and isopropyl are preferable, and methyl is particularly preferable.
  • halogen atom which may be possessed by the —6 alkyl group represented by R ⁇ R 5 and R 5 , a fluorine atom, a clay atom, a bromine atom and an iodine atom are used.
  • a _ 6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, a fluorine atom) is used.
  • an alkyl group which may be substituted with 1 to 3 halogen atoms (eg, a fluorine atom) such as methyl, ethyl, propyl, and trifluoromethyl is preferable, and methyl, trifluoromethyl and the like are particularly preferable.
  • a Ci 3 alkyl group which may be substituted with a fluorine atom such as is preferred.
  • alkoxy group represented by R 4 , R 5 and R 6 for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy and the like are used. Among them, alkoxy groups such as methoxy, ethoxy, propyloxy and isopropyloxy are preferred, and methoxy is particularly preferred.
  • the R ⁇ R 5 and optionally halogen atom have the C i-s alkoxy group represented by R 6, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.
  • an alkoxy group optionally substituted by 1 to 3 halogen atoms is used.
  • R ⁇ The R s and R 6, a hydrogen atom, 1 to 3 halogen atoms (e.g., knots atom) optionally C, and preferably such _ 3 alkoxy group optionally substituted with, among others 1 a stone 3 halogen atoms (e.g., fluorine atom) Ji may be substituted by, preferably an alkoxy group, Tokunime butoxy, C physician 3 alkoxy group optionally substituted with a fluorine atom such as Torifuruorome butoxy are preferred.
  • 1 to 3 halogen atoms e.g., knots atom
  • Ji may be substituted by, preferably an alkoxy group, Tokunime butoxy, C physician 3 alkoxy group optionally substituted with a fluorine atom such as Torifuruorome butoxy are preferred.
  • m is preferably 1 or 2, and particularly preferably 1.
  • n is preferably 2.
  • a ′ ring is a pyridine ring, R 1 ′ is as defined above, R 2 ′ is a hydrogen atom, a halogen atom or a d-3 alkyl group, R 3 ′ is an alkyl group, R 4 ′ and R 5 'may be halogenated same or different C, shows a _ 3 alkyl group.
  • Compounds and the like are preferred.
  • R 1 ' is (1) an alkyl group optionally substituted by a hydroxy group, a halogen atom or a cyano group, (2) a heterodioxy group, (3) A halogen atom, (4) a cyano group, (5) a mono- or dialkylcarbamoyl group, (6) an oxygen atom, a nitrogen atom or a sulfur atom other than one nitrogen atom and a carbon atom 5 or 6-membered cyclic aminocarbonyl group, (7) - 6 alkyl one carbonyl ⁇ amino group, (8) a heterocyclic carbonyl ⁇ amino group or (9) a compound showing a heterocyclic group (I ').
  • the ring A is a pyridine ring, R 1 ′ alkyl group, (2) 3 alkoxy group, (3) C 3 alkoxy monocarbonyl group, (4) alkylthio group, (5) halogen Atom, (6) cyano group, (7) amino group, (8) mono- or di-C ⁇ 3 alkylamino group or (9) oxygen atom or nitrogen atom in addition to one nitrogen atom and carbon atom a cyclic amino group which may 5 or 6 membered
  • R 2 ' is a hydrogen atom, a halogen atom or Ji
  • the _ 3 alkyl group, R 3' and 3 alkyl groups the same is R 4 'and R 5'
  • the compound may be halogenated differently.
  • alkyl group represented by R 2 ′, R 3 ′, R 4 ′, and R 5 ′ for example, methyl, ethyl, propyl, and isopropyl are used, and among them, cyano is preferable.
  • R 4 'and R s' are Flip 3 halogen atom with the alkyl group optionally having the indicated by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used.
  • R 4 'and R 5' may be halogenated shown in C, and as the _ 3 alkyl group, 1 to optionally substituted with 1-3 halogen atoms C, - 3 alkyl group Re et al used Specifically, a Ci- 3 alkyl group which may be substituted by 1 to 3 fluorine atoms, such as methyl, ethyl, propyl, and small trifluoromethyl, is preferred.
  • halogen atom represented by R 2 ′ a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are used, and among them, a fluorine atom and the like are preferable.
  • R 1 ' is methyl, methoxy, methoxycarbonyl, methylthio, halogen W
  • R 2 ′ a hydrogen atom, a halogen atom such as a fluorine atom, a methyl group, and the like are preferable, and a hydrogen atom and a fluorine atom are particularly preferable. Furthermore, 'if the methyl, R 2' R 1 fluorine atom is, 'when it is Shiano, R 2' R 1 a hydrogen atom is preferred as.
  • R 3 ′ is coordinate.
  • the general formula () is
  • R 3 ′ methyl is preferable.
  • R 4 ′ and R 5 ′ an alkyl group which may be substituted by 1 to 3 halogen atoms (eg, a fluorine atom) is preferable, and trifluoromethyl and the like are particularly preferable.
  • halogen atoms eg, a fluorine atom
  • the compound (I) of the present invention includes the compounds of Examples 1 to 199 described below, and among them,
  • Examples of the salt of the compound (I) of the present invention include a metal salt, an ammonium salt, a salt with an organic group, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or amino acid.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolanolamine, cyclohexylamine, dicyclohexylamine.
  • Salts with rumamine, N, N'-dibenzylethylenediamine and the like can be mentioned.
  • the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, Examples include salts with acids, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, lingic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, or oleetin, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, etc. Is mentioned.
  • salts are preferred.
  • inorganic compounds such as alkali metal spots (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt, barium salt, etc.) Salts, ammonium salts, etc.
  • compound (I) has a basic functional group
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • the prodrug of the compound (I) of the present invention or a salt thereof (hereinafter sometimes abbreviated as the compound (I) of the present invention) can be produced by reacting with an enzyme, gastric acid, or the like under physiological conditions in a living body.
  • a compound that converts to the compound (I), that is, a compound that enzymatically oxidizes, reduces, hydrolyzes, etc., and changes to the compound (1) of the present invention; I) is a compound that changes to
  • a compound in which the amino group of the compound (I) of the present invention is acylated, alkylated or phosphorylated for example, the amino group of the compound (I) of the present invention is eicosanoyl
  • Araerylation, pentylaminocarbonylation, (5-methyl-1-oxo-1,1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofurolation, pyrrolidylmethylation Viva
  • the hydroxyl group of the compound (I) of the present invention has been acylated, alkylated, phosphorylated, or borated (for example, a compound of the present invention (eg, a compound of the present invention)
  • the hydroxyl group of (I) is acetylated, palmitoylated, propanoylated, bivaloylated, succinylated,
  • the prodrug of the compound (I) of the present invention can be produced under physiological conditions as described in Hirokawa Shoten, 1990, Developing Pharmaceuticals, Vol. 7, Molecular Design, pp. 163-198. May be changed to the compound (I) of the present invention.
  • Compound (I) or a salt thereof of the present invention can be produced according to a method known per se, for example, a production method described in JP-A-9-263585 (EP-A-7333362) can do.
  • the compound (I) of the present invention or a salt thereof has the formula
  • L is a leaving group, and other symbols have the same meanings as described above, or a salt thereof is subjected to a cyclization reaction, followed by ring closure (Method A).
  • Examples of the leaving group represented by L include a halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.) or a substituted sulfonyloxy group (for example, methanesulfonyloxy, ethanesnolefuroxy, trifluoro) b methanesulfonyl O carboxymethyl optionally substituted C t-6 alkylsulfonyl O alkoxy group such as; benzenesulfonyl O carboxymethyl, p - toluenesulfonyl O carboxymethyl C 6 _ 1 4 Arirusuruho such - such Ruokishi group) etc. Is used.
  • a halogen atom for example, a chlorine atom, a bromine atom, an iodine atom, etc.
  • a substituted sulfonyloxy group for example, methanesulfony
  • the compound (II) may be used as a free compound, or may be subjected to the reaction in the form of a salt thereof (eg, an alkali metal salt such as lithium, sodium, potassium and the like).
  • the reaction is usually performed in a solvent inert to the reaction.
  • the solvent include: hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ditrinoles such as acetonitrile; ethers such as dimethyloxetane and tetrahydrofuran; dimethylformamide And aprotic polar solvents such as dimethinoresulfoxide and hexamethyl phosphoramide.
  • the reaction can advantageously proceed by adding a base.
  • bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and the like).
  • Alkali metal hydrides such as alkali metal carbonates, sodium hydride, potassium hydride, alkoxides such as sodium amide, sodium methoxide, sodium methoxide, sodium t-butoxide and potassium t-butoxide, and organic bases (trimethyl Amines, triethynoleamines, diamines such as diisopropylethylamine, and cyclic amines such as pyridine are preferred.
  • the compound (II) may be converted to a salt with a base (for example, the alkali metal salt, alkaline earth metal salt, or the like) and reacted.
  • a base for example, the alkali metal salt, alkaline earth metal salt, or the like
  • the amount of the base varies depending on the compound (II) to be used, the kind of the solvent and other reaction conditions, and is usually about 1 to about 10 mol, preferably about 1 to about 5 mol per 1 mol of compound (II). It is about a mole.
  • the reaction temperature is, for example, about -5O to about 200C, preferably about -20 to about 150 ° C, and the reaction time is the kind of the compound ( ⁇ ) or the kind of the salt thereof.
  • the reaction time varies depending on the reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.
  • Compound (II) or a salt thereof can be produced according to a method known per se, for example, a method described in JP-A-10-10989.
  • the nucleophilic reaction can be performed by various known methods.For example, a method using various nucleophiles as necessary in the presence of an activator is preferable, but in some cases, the activator itself is nucleophilic. May work as an agent.
  • Examples of the activator used include methanesulfonyl chloride, tansulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, benzoyl chloride, acetic anhydride, methyl carbonate, methyl isobutyl carbonate, and dimethylcarbamoyl chloride.
  • lid, dimethylcarbamoyl chloride, phosphorus oxychloride, trimethylsilyl nitrile, dimethyl sulfate, and getyl cyanophosphonate are used.
  • nucleophile for example, carbon nucleophiles such as potassium cyanide and Grignard reagent; alkoxides such as sodium methoxide and sodium methoxide are used, and they can be used together with an activating agent if necessary.
  • Reaction conditions vary depending on the type of activator and nucleophile used.
  • the reaction is usually performed in a solvent inert to the reaction.
  • the solvent include hydrocarbons such as benzene and acetone, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethyloxetane and tetrahydrofuran.
  • Alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide, hexamethylphosphorore?
  • Non-protonic polar solvents water or mixtures thereof.
  • the reaction can advantageously proceed by adding a base.
  • bases include, for example, inorganic bases (such as sodium hydroxide, alkali metal hydroxides such as hydroxylating hydroxides, alkali metal bicarbonates such as sodium carbonate and potassium hydrogen carbonate, and carbonates).
  • Alkali gold carbonates such as sodium and potassium carbonate, alkoxides such as sodium methoxide and sodium ethoxide, etc.
  • organic bases amines such as trimethylamine, triethylamine, diisopropylethylamine, and pyridine-like cyclic Are preferred.
  • the amounts of the activator, nucleophile and base vary depending on the type of solvent and other reaction conditions, and are usually about 1 to 10 mol, preferably about 1 to about 10 mol, respectively, per 1 mol of compound (III). It is about 5 mol.
  • the reaction temperature ranges, for example, from about 150 to about 200, preferably from about ⁇ 20 ⁇ to about 150 ⁇ , and the reaction time varies depending on the type of the compound ( ⁇ ) or the salt thereof. It depends on the type, reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.
  • Compound (IV) can be produced by Method A, Method B or a method analogous thereto.
  • halogen atom represented by R 1 ′ a fluorine atom, a chlorine atom, a bromine atom, etc. are used. You can.
  • the substitution reaction can be carried out by various known methods. For example, a method using various nucleophiles is preferable, and a transition metal catalyst can be used if necessary.
  • nucleophilic reagent examples include potassium cyanide, cyanide, Grignard reagent (eg, methylmagnesium bromide), organic dumbbell reagent, organic boron reagent (eg, methylboronic acid, phenylpoic acid)
  • Carbon nucleophiles such as organotin reagents; optionally substituted alkyl alcohols such as methanol, ethanol, and pyridylmethanol; aromatic alcohols such as phenol and pyridinol; methyl mercaptan and thiophenol Thiols such as mercaptopyridine; alkoxides such as sodium methoxide and sodium methoxide; aromatic alkoxides such as sodium phenoxide; thioalkoxides such as sodium thiomethoxide and sodium thiomethoxide.
  • the amount of the nucleophile to be used varies depending on its type, and is usually 1 mol or more, preferably about 1 to about 5 mol, per 1 mol of compound (IV), but it may be used as a solvent in some cases.
  • transition metal catalyst for example, a palladium catalyst such as palladium acetate, palladium chloride, and palladium tetrakis (triphenylphosphine); a nickel catalyst such as nickel chloride; and the like.
  • Organic phosphorus reagents such as, 1'-bis (diphenylphosphino) phenene (dppf) can be used.
  • the amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (IV).
  • the amount of the organic phosphorus reagent is preferably about 0.01 to about 2 mol.
  • Reaction conditions vary depending on the type of nucleophile and catalyst used.
  • the reaction is usually performed in a solvent inert to the reaction.
  • solvents For example, hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile; ethers such as dimethoxetane, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol.
  • Aprotic polar solvents such as dimethylhonolemamide, dimethylsulfoxide, and hexamethylphosphoramide; water or a mixture thereof.
  • the reaction can be advantageously promoted by adding a base.
  • bases include, for example, inorganic bases (such as sodium hydroxide, alkali metal hydroxides such as hydroxylating limes, sodium bicarbonate, alkali metal hydrogen carbonates such as bicarbonate limes, sodium carbonate, etc.).
  • Alkali metal carbonates such as potassium carbonate, metal hydrides such as sodium hydride, potassium hydride, etc.
  • organic bases amines such as trimethinoleamine, triethylamine, disopropylethylamine, pyridine, etc.
  • the amount of the base varies depending on the type of the nucleophile, the catalyst and the solvent, and other reaction conditions, and is usually about 1 to about 100 mol, preferably about 1 to about 1 mol, per 1 mol of compound (IV). It is about 0 mol.
  • the reaction temperature is, for example, in the range of about 150 to about 200 ⁇ , preferably about 120 to about 15, and the reaction time is the kind of the compound (IV) or the kind of the salt thereof,
  • the reaction time varies depending on the reaction temperature and the like, and is, for example, about 1 to about 72 hours, preferably about 1 to about 24 hours.
  • a compound having an alkylsulfonyl group as R 1 can be produced by oxidizing a compound having an alkylthio group as R 1 in the compound (I) obtained by the reaction by a method known per se.
  • a carboxyl group (VI) may be prepared by a method analogous below D method or this I can do it.
  • R 7 represents an alkynole group or a hydrogen atom, and other symbols have the same meanings as described above].
  • Examples of the alkyl group represented by R 7 include methyl, ethyl, and propyl.
  • Compound (IV) to be used as the conjugate in this step can be produced by Method A, Method B or a method analogous thereto.
  • This reaction is carried out in a solvent inert to the reaction under a carbon monoxide atmosphere using a transition metal catalyst, dimethyl alcohol, or an alkyl alcohol.
  • a reaction reagent can be used.
  • the transition metal catalyst for example, a palladium catalyst such as palladium nitrate, palladium chloride, and tetrakis (triphenylphosphine) palladium; a nickel catalyst such as nickel chloride are used.
  • triphenylphosphine, 1 , 1 'An organic phosphorus reagent such as bis (diphenylphosphino) phenecene (dppf) can be used.
  • the amount of the catalyst used varies depending on the type of the catalyst, and is usually about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (IV). Yes, the amount of the organic phosphorus reagent used is preferably about 0.01 to about 2 mol.
  • C as the _ 6 alkyl alcohol, usually an excess amount of methanol or ethanol is used.
  • solvent inert to the reaction examples include hydrocarbons such as benzene and toluene; nitriles such as acetonitrile; ethers such as dimethoxetane, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; dimethylform Aprotic poles such as amides, dimethyl sulfoxide, hexamethylphosphoramide Water or a mixture thereof is used.
  • the reaction can be advantageously promoted by adding a base or a salt.
  • bases include, for example, inorganic bases (such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium carbonate, and potassium carbonate).
  • Alkali metal carbonates and organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, cyclic amines such as pyridine, etc.) are preferred.
  • the salt include sodium acetate, lithium chloride, sodium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide and the like.
  • the amount of the base or salt to be used is about 1-about 100 mol, preferably about 1-about 10 mol, per 1 mol of compound (IV).
  • the reaction is usually carried out in a carbon monoxide atmosphere at normal pressure, but can be carried out under pressure (for example, about 3 to about 10 atm) if necessary.
  • the reaction temperature ranges, for example, from about 150 to about 200, preferably from about 20 ° to about 150 ⁇
  • the reaction time ranges from compound (IV), metal catalyst, organophosphorus reagent, It depends on the type of base and salt, the reaction temperature, the reaction pressure and the like, and is, for example, about 0.5 to about 72 hours, preferably about 0.5 to about 24 hours.
  • the compound (VIII, IX, XI) in which R 1 has a C—s alkyl group which may have a substituent can be prepared by the following method E It can also be manufactured by the method described above or a method analogous thereto.
  • R 7 ′ is an alkyl group
  • R 8 is a halogen atom, an optionally substituted oxygen atom, an optionally substituted amino group or a cyano group, and other symbols are as defined above. Is shown).
  • Examples of the alkyl group represented by R 7 ′ include the same ones as described in the description of R 1 .
  • Examples of the halogen atom represented by R 8 include the same ones as described in the description of R 1 .
  • substituent of the oxygen atom examples include -6 alkyl which may be halogenated (for example, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2,2-triphnoleroethyl), and acyl (for example, acetyl, Propionyl).
  • Substituents on an amino group include mono or di-C alkyl (eg, methyl, ethyl, dimethyl, getyl).
  • Compound (VII) used as a starting compound in this step can be produced by Method A, Method C or a method analogous thereto. ,
  • the oxidation reaction of the pyridine ring can be carried out according to a method known per se, for example, a method described in JP-A-10-109989.
  • the transfer reaction of the obtained N-oxide is carried out using a reactive derivative of carboxylic acid, and an inert solvent can be used if necessary.
  • Examples of the reactive derivative of a carboxylic acid include an acid anhydride.
  • the amount of the reactive derivative of carboxylic acid to be used is usually 1 equivalent or more per 1 mol of N-oxide, and it can be used as a solvent.
  • Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as dimethoxetane and tetrahydrofuran; dimethylformamide and dimethyl sulfoxide.
  • An aprotic polar solvent, a protic polar solvent such as acetic acid, or a mixture thereof is used.
  • reaction temperature ranges, for example, from about 0 to about 200 "C, preferably from about 50 to about 15, and the reaction time is usually about 0.5 to about 72 hours, preferably about 1 to about 72 hours. About 24 hours.
  • This step is a step of subjecting the acyloxy form (VIII) to a hydrolysis reaction to convert it into the alcohol form (IX).
  • This reaction is usually performed in the presence of an acid or a base, and a solvent that does not adversely influence the reaction can be used, if necessary.
  • the acid mineral acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (for example, formic acid, acetic acid, propionic acid, etc.) are used, and among them, hydrochloric acid, sulfuric acid, etc. are preferable.
  • the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; and alkali metals such as calcium hydroxide and potassium hydroxide.
  • Earth metal salts alkoxides such as sodium methoxide and sodium ethoxide; and among them, potassium hydroxide, sodium hydroxide, sodium methoxide and the like are preferable.
  • the amount of the acid or base to be used is, for example, about 0.01 to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol of compound (VIII).
  • solvents that do not adversely affect the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, and tert-butanol; and aromatic hydrocarbons such as benzene, toluene, and xylene.
  • Aliphatic hydrocarbons such as hexane and heptane; ethers such as getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane; dimethylformamide, dimethylacetamide and the like Amides; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the reaction temperature is usually about 0 ⁇ to about 150 ⁇ , preferably about 10 to about 100.
  • the reaction time varies depending on the compound (VII1), the type of acid and base, the reaction temperature, and the like, and is, for example, about 0.1 to about 100 hours, and preferably about 0.1 to about 24 hours. (Process 3)
  • the alcohol form (IX) is subjected to an oxidation reaction to produce an aldehyde form (X).
  • the oxidizing agent examples include a manganese compound such as manganese dioxide, a chromic acid compound such as chromium (IV) oxide, and nitric acid.
  • the amount of the oxidizing agent is preferably about 1 to about 3 based on 1 mol of the compound (IX). 0 mole.
  • Reaction conditions (solvent, temperature, time, etc.) vary depending on the type of filtration agent and substrate used. For example, the reaction is usually performed in a solvent that does not interfere with the reaction. Examples of the solvent include acetone, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, acetic acid, sulfuric acid, pyridine, water, or a mixture thereof. Things.
  • the reaction temperature varies depending on the type of the oxidizing agent and the solvent used, but is usually about 15 to about 150.
  • the reaction time is generally about 1 to about 72 hours, preferably about 1 to about 24 hours.
  • step 4 compound (X) obtained in this step can be subjected to a substitution reaction in the following step 4.
  • This step is a step of subjecting the hydroxy group of compound (IX) to an alkylation, acylation or substitution reaction by a method known per se to convert it into various substituents. If necessary, a combination of alkylation, acylation or transformation reaction can be used. This step is usually performed in a solvent inert to the reaction, and the reaction can be advantageously performed by adding a base.
  • alkylating agent examples include halides of alkanes which may have a substituent (eg, chloride, bromide, iodide, etc.), sulfates or sulfonates (eg, methanesulfonate, p-toluenesulfonate, benzene) Sulfonate and the like).
  • the amount of the alkylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX).
  • acylating agent examples include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid, and reactive derivatives thereof (for example, acid halide, acid anhydride, mixed acid anhydride, active ester, etc.), isocyanate, and isothiocyanate. Esters and the like.
  • the amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX).
  • the substitution reaction can be performed using various reaction reagents.
  • the reaction reagent include carbon nucleophiles such as potassium cyanide and Grignard reagents; alkoxides such as sodium methoxide and sodium ethoxide; potassium fluoride, tris (dimethylamino) sulfonium difluorotrimethyl silica gel, [bis (2-Methoxyxyl) Amino] -Fluoride such as sulfur trifluoride is used.
  • the amount of the reaction reagent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (IX). Quantity.
  • Examples of the base include amines (eg, alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] ndecaene-7-ene, etc.
  • amines eg, alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] ndecaene-7-ene, etc.
  • the amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (IX).
  • the solvent examples include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and ethers such as ethyl acetate.
  • Esters aromatic amines such as pyridine; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide and mixtures thereof.
  • the reaction temperature is usually about -50 to about 150, preferably about 110 to about 10OX.
  • the reaction time varies depending on the type of the compound (IX) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.
  • Compounds having a good thiocarbamoyl group (VI, XII, XIII) can also be produced by the following steps of Method F or a method analogous thereto.
  • R s and R 1 Q are the same or different and may be substituted alkyl groups or C! -B Ashiru group, they may form a heterocyclic ring together.
  • Other symbols are as defined above.
  • Examples of the optionally substituted C ⁇ 6 alkyl group represented by R 0 and R 10 include the same ones as described in the description of R 1 .
  • the ci-s Ashiru group include the same as those shown in the description of R 1.
  • the heterocyclic ring formed by R 9 and R 1 Q together includes, for example, a cyclic amino group (for example, a compound containing an oxygen atom or a nitrogen atom in addition to one nitrogen atom and a carbon atom. Or a 6-membered cyclic amino group, in particular, pyrrolidino, piperidino, piperazino, morpholino, etc.).
  • a cyclic amino group for example, a compound containing an oxygen atom or a nitrogen atom in addition to one nitrogen atom and a carbon atom.
  • a 6-membered cyclic amino group in particular, pyrrolidino, piperidino, piperazino, morpholino, etc.
  • Compound (V) used as a starting material compound in this step can be produced according to the above-mentioned Method A, Method B or Method C according to a method analogous thereto.
  • Examples of the C ⁇ ⁇ alkyl alcohol include methanol and ethanol, and can also be used as a solvent.
  • Acid catalysts include inorganic acids (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, boron trifluoride, etc.) and organic acids (for example, methanesulfonic acid, benzenesulfonic acid, ⁇ -toluenesulfonic acid, etc.) Is raised.
  • the amount of the acid catalyst to be used is about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (V).
  • Examples of the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as dimethyloxetane and tetrahydrofuran; dimethylformamide and dimethylsulfoxide.
  • An aprotic polar solvent such as hexamethylphosphoramide or a mixture thereof is used.
  • the reaction temperature is, for example, about 0 to about 20 O, preferably about 50 °: to about 150, and the reaction time varies depending on the type of the compound (V), the reaction temperature, and the like. For example, about 0.5 to about 72 hours, preferably about 1 to about 24 hours.
  • This step is generally performed in the presence of an acid or a base, and a solvent inert to the reaction may be used as necessary.
  • mineral acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • carboxylic acids for example, formic acid, drunk acid, propionic acid, etc.
  • hydrochloric acid, sulfuric acid, etc. are used. preferable.
  • lithium metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium carbonate and the like; calcium hydroxide, hydroxide Alkaline earth metal salts such as valium; amines such as trimethylamine, triethylamine, ethyldiisopropylamine, N-methylmorpholine and the like, among which potassium hydroxide and sodium hydroxide are preferable.
  • the amount of the acid or base to be used is, for example, about 0.01 to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol of compound (VI).
  • solvents inert to the reaction include alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, isobutanol and tert-butanol; and aromatic hydrocarbons such as benzene, toluene and xylene.
  • Aliphatic hydrocarbons such as xane and heptane; ethers such as getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, and dimethoxetane; dimethylformamide, dimethylacetamide And the like; dimethyl sulfoxide and the like; sulfoxide; water and the like.
  • These solvents may be used as a mixture of two or more kinds at an appropriate ratio.
  • the reaction temperature is usually about 0 to about 150, preferably about: I0 ⁇ to about 100.
  • the reaction time varies depending on the type of compound (VI), the type of acid / base, the reaction temperature and the like, and is, for example, about 0.1 to about 100 hours, preferably about 0.1 to about 24 hours.
  • This step is a step of producing an amide form (XII) by reacting the compound (Via) with a desired amine.
  • This reaction can be carried out usually using a compound (VIa) or its reactive derivative at the carboxyl group and an amine in a solvent inert to the reaction.
  • the reactive derivative include acid halide, mixed acid anhydride, imidazolide, active ester and the like.
  • the solvent examples include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; esters such as ethyl acetate; An aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide, water, or a mixture thereof is used.
  • the amount of the amine to be used is generally 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of the compound (Via) or its reactive derivative.
  • the reaction can advantageously proceed by adding a base.
  • bases include, for example, organic bases (trimethylamine, triethylamine, diisopropyl Alkylamines such as ethylamine, N-methylmorpholine, cyclic amines such as pyridine, aromatic amines such as N, N-dimethylaniline, etc., inorganic bases (alkali metals such as sodium hydrogencarbonate and hydrogencarbonate) Hydrogen carbonate, sodium carbonate, alkali metal carbonates such as carbonated lime, sodium hydroxide, alkali metal hydroxides such as hydroxylated lime, etc.).
  • the amount of the base to be used is, for example, about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (VIa) or a reactive derivative thereof.
  • the reaction temperature is usually about 130 to about 150, preferably about 0 to about 10 Ot :.
  • the reaction time varies depending on the type of the compound (Via), the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.
  • This step is performed in the presence of a sulfurizing agent in a solvent inert to the reaction.
  • Examples of the sulfurizing agent include phosphorus pentasulfide, Lowesson reagent and the like.
  • the solvent inert to the reaction include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane, and mixtures thereof. Used.
  • the amount of the sulfurizing agent to be used is generally about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (XII).
  • the reaction temperature is, for example, about 20 ⁇ to about 15 O ⁇ C, and the reaction time varies depending on the compound (XI 1), the type of the sulfurizing agent, the reaction temperature, and the like. For example, about 0.5 to about 24 hours It is about.
  • the compound (XIV) wherein R 1 has an optionally substituted acyl group can be produced by the following Method G or a method analogous thereto. I can do it.
  • R 11 is an alkyl group or. And the other symbols are as defined above.
  • C 6 - The 10 Ariru group include the same as those shown in the description of R 1.
  • Compound (XII) used as a starting compound in this step can be produced by Method F, Step 7, or a method analogous thereto.
  • This step is a step of producing an acyl form (XIV) by reacting the amide group of the compound (XII) with a carbon nucleophile, and can be carried out in a solvent inert to the reaction.
  • a carbon nucleophile examples include Grignard reagents such as methylmagnesium bromide and phenylmagnesium bromide, and organic lithium reagents such as methyllithium and phenyllithium.
  • Examples of the solvent inert to the reaction include hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane.
  • a non-protonic polar solvent such as hexamethylphosphoramide or a mixture thereof is used.
  • the amount of the carbon nucleophile to be used is generally 1 to 10 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of compound (XII).
  • the reaction temperature is, for example, about -78 to about 150, and preferably about 1 to about 30.
  • the reaction time varies depending on the compound (XII), the type of the carbon nucleophile, the reaction temperature and the like, and is, for example, about 0.1 to about 24 hours.
  • R 1 may have a substituent.
  • Compounds (XV I, XV II) having a thio group can be produced by the following Method H or a method ⁇ :
  • R] 2 and R 13 are the same or different and each may have a hydrogen atom, an alkyl group which may have a substituent, or a substituent.
  • An aryl group, an acyl group, an alkylsulfonyl group, an alkoxycarbonyl group, or a sulfamoyl group, and other symbols have the same meanings as described above.
  • R 12, R 13 which may have a substituent group represented in C, and as the _ 6 alkyl group include the same as those shown in the description of R 1.
  • the Ariru groups may be the same as those shown in the description of R 1.
  • acyl group examples include the same as those described in the description of R 1 .
  • alkylsulfonyl group examples include those described in the description of R 1 . The same as the alkylsulfonyl group can be mentioned.
  • the alkoxycarbonyl group include the same C] _ 6 alkoxy one carboxy group shown in the description of R 1.
  • This step is a step of converting the carboxyl group of the compound (VIa) into an isocyanate group.
  • the compound (VIa) is converted into an acid azide form, and then subjected to a Curtius transfer reaction, whereby the isocyanate form (XV) is converted. Is used.
  • any of these methods can be applied to (Via). For example, by reacting an azidating agent such as diphenylphosphoryl azide with (Via), an acid azide of (Via) can be produced.
  • the amount of the azidating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (Via).
  • This reaction is generally performed in a solvent inert to the reaction.
  • a solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethyls such as ethyl ether, dimethoxetane, tetrahydrofuran, and dioxane; ethyl acetate; Esters; ketones such as acetone and 2-butanone; aromatic amines such as pyridine; amides such as N, N-dimethylformamide and mixtures thereof.
  • the reaction may proceed in the presence of a base.
  • a base examples include amines such as trimethylamine, triethylamine, N-methylmorpholine, tetramethylethylenediamine, and 4-dimethylaminopyridine.
  • the amount of the base used is based on the compound (Via). It is preferably 1 to 5 molar equivalents.
  • the reaction temperature is usually on the order of about 110 to about 150, preferably about 15 to about 120.
  • the reaction time is usually about 0.5 to about 100 hours, preferably about 0.5 to about 6 hours.
  • the generated acid azide can be isolated and purified by a step known per se.
  • the reaction solution is usually heated as it is without isolation, and is converted to an isocyanate (XV).
  • This conversion reaction is preferably carried out by using the same solvent as that used for the azidation, usually by heating to about 20: to 200 2, preferably to about 30 to 15 ⁇ .
  • the reaction time is generally 0.1 to 10 hours, preferably 0.1 to 6 hours.
  • the cyanate compound (XV) can be used for the next step without isolation or isolation without any means known per se.
  • This step is a step of converting the isocyanate group of the compound (XV) into an amino group to obtain the compound (XVI).
  • This step is usually performed under hydrolysis conditions.
  • This reaction can be performed under acidic or basic conditions, and a solvent can be used if necessary.
  • a solvent for example, phenols such as methanol, ethanol, propanol, and butanol; ethers such as tetrahydrofuran, dioxane, and dimethoxetane; water, and mixtures thereof.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid is used.
  • a hydroxide of an alkali or alkaline earth metal such as sodium hydroxide or barium hydroxide is preferably used.
  • Reaction temperatures are usually on the order of about 0 to about 120, preferably about 15 to about 100.
  • the reaction time is usually about 0.5 to about 36 hours, preferably about 0.5 to about 20 hours.
  • reaction is carried out in the presence of alcohols or amines, if necessary, in a solvent that does not adversely affect the reaction, whereby R 12 or R 13 of compound (XVII) is converted to an alkoxycarbonyl group.
  • R 12 or R 13 of compound (XVII) is converted to an alkoxycarbonyl group.
  • a compound having an amino group or an alkyl ureide group can be produced.
  • Such alcohols include 6- alkyl alcohols such as methanol, ethanol, and butanol, and amines include primary or secondary C, 6- alkylamino such as methylamine, ethylamine, dimethylamine, and getylamine. And the like.
  • the amount of the alcohol or amine to be used is about 1 molar equivalent or more per 1 mol of compound (XV), and it can be used as a solvent.
  • Solvents that do not adversely affect the reaction include, for example, hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; Aprotic polarities such as N, N-dimethylformamide, dimethylsulfoxide Solvents or mixtures thereof are used.
  • the reaction temperature is usually about 0 ° C to about 150X, preferably about 15 ⁇ : to about 10 Ot :.
  • the reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours. This reaction may be carried out in the presence of a catalytic amount of a base such as N, N-dimethylaminopyridine. Further, if necessary, the compound obtained in the above step can be subjected to the alkylation reaction shown in Step 11.
  • This step is a step of subjecting the amino group of compound (XVI) to alkylation or acylation by a method known per se to obtain compound (XVII). If necessary, an alkylation reaction and an acylation reaction can be used in combination. This step is usually performed in a solvent inert to the reaction, and the reaction can be advantageously performed by adding a base.
  • alkylating agent examples include halides of alkanes which may have a substituent (eg, chloride, bromide, chloride), sulfates or sulfonates (eg, methanesulfonate, p-toluenesulfonate) , Benzenesulfonate, etc.).
  • the amount of the alkylating agent to be used is generally 1-based on compound (XVI).
  • acylating agent examples include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid and reactive derivatives thereof (for example, acid halide, acid anhydride, mixed acid anhydride, active ester, ester, etc.), isocyanate ester, isothiocyanate Acid esters and the like.
  • the amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XVI).
  • the base examples include amines (eg, trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] Alkylamines, pyridine, aromatic amines such as N, N-dimethylaniline, etc.), alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.), metal hydrides (eg, hydrogen Potassium hydride, sodium hydride, etc.), and alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, etc.).
  • the amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XVI).
  • the solvent examples include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and ethers such as ethyl acetate.
  • Esters aromatic amines such as pyridine; amides such as N, N-dimethylformamide or a mixture thereof.
  • the reaction temperature is usually about 150 to about 150 ⁇ , preferably about -10 to about 10.
  • the reaction time varies depending on the type of the compound (XVI) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.
  • compounds (XIX, XX) in which R 1 has an optionally substituted amidino group or an optionally substituted heterocyclic group It can be produced by each step of the following method I or a method analogous thereto.
  • R 14 is a C ⁇ 6 alkyl group which may have a substituent, a hydroxy group, an amino group which may have a substituent, and R 15 is hydrogen or a group which has a substituent. also good C, _ 6 alkyl group, B ring a heterocyclic group, and other symbols are as defined above].
  • Examples of the alkyl group which may have a substituent represented by R 14 include the same ones as those described in the description of R 1 .
  • Examples of the optionally substituted 6- alkyl group represented by R 15 include methyl.
  • Examples of the heterocyclic group represented by Ring B include tetrazolyl, pyrazolyl, triazolyl, dihydrotriazolyl, thiazolyl, dihydrothiazolyl, oxadiazolyl, and tetrahydrotriazinyl.
  • Compound (V) used as a starting compound in this step can be produced by Method A, Method B, Method C or a method analogous thereto.
  • This step is a step of converting a cyano group of compound (V) to an amidino group.
  • various methods are known in the literature, [for example, The Chemistry of the cyano group, Zvi Rappoport (1970), Interscience Publishers (1970) Interscience Publishers)], and any of these methods can be applied to compound (V).
  • this reaction can be carried out by using a desired amine or a salt thereof in a solvent inert to the reaction, if necessary, using an acid or a base.
  • Examples of the acid include Lewis acids such as aluminum chloride, tin chloride, copper chloride, and titanium chloride.
  • Examples of the base include amines (eg, trimethinoleamine, triethylamine, diisopropylethylamine) , N-methylmorpholine, 1,8-diazabicyclo [5.4.0] alkylamines such as 7-diene, pyridine, aromatic amines such as N, N-dimethylaniline, etc.
  • Alkali metal salts eg, hydrogen carbonate Sodium, potassium bicarbonate, sodium carbonate, potassium carbonate, etc., metal peroxides (eg, hydrogen hydride, sodium hydride, etc.), metal alkoxides (eg, sodium methoxide, sodium ethkind, sodium) t-butoxide, potassium t-butoxide, etc.
  • the amount of the acid or base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (V).
  • inert solvents examples include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane. Alcohols such as methanol and ethanol; nitriles such as acetonitrile; non-protonic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide; or mixtures thereof.
  • the reaction temperature is usually about 0 ⁇ to about 150 ⁇ , preferably about 15 to about 100.
  • the reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours.
  • reaction shown in the following step 13 may proceed at the same time, and the compound (XX) may be directly obtained.
  • This step is a step of converting the amidino group of compound (XIX) into various heterocyclic groups.
  • various methods have been known in the literature (for example, The Chemistry of the cyano group, Zvi Rappoport, ed. Yaz (Interscience Publ ishers)], and any method can be applied to compound (XIX).
  • this reaction can be carried out in a solvent inert to the reaction, if necessary, by using various reactive derivatives of a carboxylic acid together with an acid or a base.
  • the reactive derivative of the carboxylic acid include an acid halide, an acid anhydride, a mixed acid anhydride, an active ester, an ester, an orthoester, and the like.
  • the amount of the reactive derivative of the carboxylic acid to be used is generally about 1 molar equivalent or more, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIX).
  • the acid include sulfuric acid and p-toluenesulfonic acid.
  • sulfonic acid is used, and as the base, for example, amines (eg, trimethylamine, triethylamine, diisopropyletylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] I-Alkylamines such as 7-ene, pyridine, aromatic amines such as N, N-dimethylaniline), alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) ), Metal hydrides (eg, potassium hydride, sodium hydride, etc.), alkali metal alkoxides (eg, sodium methoxide, sodium methoxide, sodium tert-butoxide, potassium t-butoxide, etc.) Used.
  • amines eg, trimethylamine, triethylamine, diisopropyletylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0]
  • the amount of the acid or base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIX).
  • Solvents inert to the reaction include, for example, hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethyloxetane, tetrahydrofuran, and dioxane; Alcohols such as methanol and ethanol; -tolyls such as acetonitrile; non-protonic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide; water; and mixtures thereof.
  • the reaction temperature is usually about
  • reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours.
  • This step is a step of converting a cyano group of compound (V) to a tetrazole group.
  • Various methods are known in the literature [for example, The Chemistry of the cyano group, Zabi ⁇ popo HZvi Rappopor 1970, Interscience Publisher ⁇ " Interscience Publishers) and any of these methods can be applied to compound (V).
  • this reaction can be carried out using an azide in a solvent inert to the reaction.
  • azides include sodium azide, lithium azide, and trimethylsilyl azide.
  • the amount of azide used is usually about 1 to 1 mole per mole of compound (V). It is about 10 molar equivalents, preferably about 1 to about 5 molar equivalents.
  • the solvent inert to the reaction include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; and ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane.
  • reaction temperatures are usually on the order of about 0 * C to about 150, preferably about 501: to about 120.
  • the reaction time is generally about 0.5 to about 48 hours, preferably about 0.5 to about 20 hours. This reaction may be promoted by adding ammonium chloride, triethylammonium chloride, dibutyltin oxide, zinc chloride, acetic acid or the like.
  • Compound (XXI I) of compound (I) of the present invention or a salt thereof, wherein R 1 has an optionally substituted heterocyclic amino group can be produced by the following method J or a method analogous thereto. You can do it.
  • This step is a step of converting the amidino group of the compound (XIXa) to a cyanamide group, and is a method known per se, for example, subjecting the compound (XIXa) to an acylation reaction and then to a transfer reaction. It can be done by doing.
  • the acylation reaction is usually carried out using an acylating agent in a solvent inert to the reaction, and a base can be used if necessary.
  • acylating agent examples include carboxylic acid, sulfonic acid, phosphoric acid, carbonic acid and reactive derivatives thereof (eg, acid halide, acid anhydride, mixed acid anhydride, active ester, etc.).
  • the amount of the acylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (XIXa).
  • the base examples include amines (eg, alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] pendecane-7-ene, etc. Pyridine, aromatic amines such as N, N-dimethylaniline, etc.), and alkali metal salts (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.).
  • the amount of the base to be used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of compound (XIXa).
  • the solvent examples include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; and esters such as ethyl acetate.
  • Aromatic amines such as pyridine; amides such as N, N-dimethylformamide; water or a mixture thereof.
  • the reaction temperature is usually about 150 to about 150, preferably about -10 to about 100.
  • the reaction time varies depending on the type of the compound (XlXa) and the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.
  • the transfer reaction is usually performed in the presence of a base in a solvent inert to the reaction.
  • Such bases include, for example, amines (eg, trimethylamine, triethylamine, diisopropinoleetamine, di-methyl / ⁇ remo ⁇ holin, 1,8-diazabicyclo [5.4.0]
  • Alkylamines such as pendecar 7-ene, pyridine, aromatic amines such as ⁇ , ⁇ -dimethylaniline, etc.
  • metal salts of alkali metal eg, sodium hydrogen carbonate Vium, potassium hydrogen carbonate, carbonate
  • Sodium carbonated lime, sodium hydroxide, potassium hydroxide, etc.
  • the amount of the base used is, for example, about 1 to about 10 molar equivalents, preferably about 1 to about 5 molar equivalents, per 1 mol of the substrate.
  • the solvent include hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as ethyl ether, dimethoxetane, tetrahydrofuran, and dioxane; aromatic amines such as pyridine Amides such as ⁇ , ⁇ -dimethylformamide, water or a mixture thereof.
  • the reaction temperature is usually about 150 to about 150, preferably about -10 to about 100.
  • the reaction time varies depending on the type of the substrate, the type of the base, the reaction temperature and the like, and is, for example, about 0.5 to about 100 hours, preferably about 0.5 to about 24 hours.
  • the compound (XIX, XX, XXI, XXII) obtained by the above-mentioned Method I or Method J can be subjected to an acylation reaction or an alkylation reaction shown in Step 11 of Method H, if necessary.
  • an inorganic acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • an organic acid for example, methane snorephonic acid, benzene snorehon
  • Acids for example, tonorenensnoleonic acid, oxalic acid, fumarenoleic acid, maleic acid, tartaric acid, etc.
  • inorganic bases for example, sodium / potassium etc./recalium metals, alkaline earth metals such as canoleicum, magnesium, aluminum or
  • an organic base eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-dibenzylethylenediamine, etc.
  • Can also form salts with Can, if I ⁇ compound (I) is obtained in the form of
  • the compound (I) or a salt thereof produced by these methods can be separated and purified by using conventional separation and purification means (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • conventional separation and purification means for example, concentration, solvent extraction, column chromatography, recrystallization, etc.
  • the compound (I) is an optically active compound, it can be separated into a d-isomer and a single isomer by a conventional optical resolution method.
  • the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent in each reaction of the target compound and the starting material synthesis
  • these groups are protected groups such as those commonly used in peptide chemistry and the like. May be protected.
  • the desired compound can be obtained by removing the protecting group, if necessary.
  • the protecting group for an amino group include a formyl group and a C i -e alkyl monocarbonyl group.
  • O alkoxycarbonyl group e.g., main-butoxycarbonyl, ethoxycarbonyl group
  • ⁇ reel O alkoxycarbonyl group e.g., phenylalanine O alkoxycarbonyl group
  • Ararukiru one carbonyl group e.g., Benjiruo Xycarbonyl group
  • trityl group e.g., trityl group
  • phthaloyl group e.g., phthaloyl group and the like
  • substituents include a halogen atom (for example, fluorine, chlorine, bromine, and iodine atom), a C, alkyl-carbonyl group (for example, acetyl, propionyl, butylcarbonyl group, etc.), a nitro group And the number of substituents is about 1 to 3.
  • the carboxyl-protecting group include an alkyl group (eg, methyl, ethyl, II-propyl, i-propyl, n-butyl, tert-butyl group, etc.), a phenyl group, a trityl group, a silyl group, and the like. These protecting groups may have a substituent.
  • substituents for example, a halogen atom (fluorine, chlorine, bromine, iodine), formyl, - 6 alkyl - group (e.g., Asechiru, pro Pioniru, etc. Buchirukaruponiru group), like nitro groups
  • the number of substituents is about 1 to 3.
  • hydroxyl-protecting group examples include, for example, an alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group, etc.) Eniru group, C 7 - 1 0 Ararukiru group (e.g., benzyl group), a formyl group, C i - e ⁇ Rukirukarubo - Le group (e.g., Asechiru, etc.
  • an alkyl group eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group, etc.
  • Eniru group e.g., benzyl group
  • Ararukiru group e.g., benzyl group
  • a formyl group C i - e ⁇ Rukirukarubo
  • Puropioyuru group Ariruokishi carbonyl group (e.g., Fueyuruokishi carbo - such as Le group), c 7 _ 1 0 Ararukiru Ichiriki carbonyl group (e.g., benzyl O alkoxycarbonyl group), Villa group, a furanyl group, a silyl group, and these protecting groups substituent May be provided.
  • These location substituent for example, a halogen atom (fluorine, chlorine, bromine, iodine), C, _ B alkyl group, phenyl group, C 7 _ i. Examples include an aralkyl group and a nitro group, and the number of substituents is about 1 to 4.
  • the protecting group can be removed by a known or equivalent method, for example, treatment with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiorubbamate, tetrabutylammonium fluoride, palladium acetate, etc. There is a method available.
  • the compound (I) of the present invention produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • the compound (I) thus obtained is in a free form, it can be converted into a salt by a known method or a method analogous thereto (for example, neutralization), and conversely, it can be obtained.
  • compound (I) is obtained in the form of a salt, it can be converted to a free form or another salt by a known method or a method analogous thereto.
  • the compound (I) of the present invention or a salt or a prodrug thereof (hereinafter may be abbreviated as the compound of the present invention) has an effect of suppressing the enhancement of tracheal vascular permeability induced by cabsaicin and an excellent tachykinin receptor. It has body antagonism, especially substance P receptor antagonism, and neurocun A receptor antagonism.
  • the compounds of the present invention have low toxicity and are safe.
  • the compounds of the present invention having excellent substance P receptor antagonism, neurokinin A receptor antagonism and the like can be used in mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, dogs, higgies) , Monkeys, humans, etc., against substance P-related diseases, such as inflammatory or allergic diseases (eg, atopy, dermatitis.
  • Psoriasis asthma, bronchitis, chronic obstructive pulmonary disease, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.
  • pain migraine, neuralgia, Pruritus, cough, HIV infection, and diseases of the central nervous system [eg, schizophrenia, Parkinson's disease, depression, manic depression, anxiety 'neurosis, obsessive-compulsive disorder, panic disorder, dementia (eg, Alzheimer's) Disease) etc.), digestive disorders [eg, irritable bowel disease, ulcerative colitis, Crohn's disease, urease-positive helical gram-negative bacteria (eg, Helicobacter pylori, etc.) (eg, , Gastritis, gastric ulcer, etc.), vomiting, urinary abnormalities (eg, frequent urination, incontinence, etc.), cardiovascular disorders (eg,
  • the compound of the present invention is also useful as an agent for preventing or treating diseases such as depression, anxiety, manic depression, and schizophrenia.
  • the pharmaceutical preparation containing the compound of the present invention may be any of solid preparations such as powders, granules, tablets, capsules and suppositories, and liquid preparations such as syrups, syrups, injections and suspensions. ,.
  • the pharmaceutical preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc., depending on the form of the preparation.
  • a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc., depending on the form of the preparation.
  • each section of the Japanese Pharmacopoeia Act general rules for drug products can be referred.
  • the content of the compound salt of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.01% by weight, based on the whole preparation. It is about 1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • a pharmaceutically acceptable carrier for example, an excipient (eg, starch, lactose, sucrose, calcium carbonate, canolecitrate, etc.) Binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polybutylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate) , Calcium stearate, etc.), disintegrants (eg, power Ruboxymethylcellulose calcium, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and additives as necessary (stabilizers, preservatives, coloring agents, fragrances, dissolution aids, emulsifiers, buffers, And is orally or parenterally administered in the form of powders, fine
  • the dosage varies depending on the type of the compound of the present invention or a pharmaceutically acceptable salt thereof, the administration route, the symptom, the age of the patient, and the like.
  • About 0.05 to 50 mg, preferably about 0.05 to: 0 mg, and more preferably about 0.2 to 4 mg of the compound of the present invention per kg of body weight per day can be administered in 1 to 3 divided doses.
  • the compound of the present invention can be used as appropriate or in combination with other pharmaceutically active ingredients in an appropriate amount or in combination.
  • the dose can be reduced as compared with the case where the compound of the present invention or other pharmaceutically active ingredient is administered alone. More specifically, when the compound of the present invention is used in combination with an anticholinergic agent or a NK-2 receptor antagonist, the dose of the compound is reduced as compared with the case where the anticholinergic agent or the NK-2 receptor antagonist is administered alone. Therefore, for example, it is possible to reduce side effects such as roasting.
  • the drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.)
  • the treatment period can be set longer by selecting another pharmaceutically active ingredient having a different mechanism of action from the compound of the present invention.
  • concomitant drug a drug that can be combined with or used in combination with the compound of the present invention.
  • concomitant drug a drug that can be combined with or used in combination with the compound of the present invention.
  • Insulin preparations eg, animal insulin preparations extracted from the lungs of pigs and pigs; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin insulin clamp; protamine insulin zinc; insulin fragments or Derivatives (eg, INS-1 etc.), insulin sensitive drugs (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK_614, CS-011, etc.), ⁇ -Darcosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonyl II Rare agents (eg, tolptamide, glibenclamide, daliclazide, black /
  • Aldose reductase inhibitors eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (AR I-509), CT-112, etc.
  • neurotrophic factors eg, NGF , NT-3, etc.
  • AGE inhibitors eg, ALT-945, pimagedin, pyratoxatin, N-phenacyl thiazolidumbumid (ALT-766), EXO-226, etc.
  • active oxygen scavengers eg, And cerebral vasodilators (eg, chopride.).
  • Statin compounds that are cholesterol synthesis inhibitors (eg, bravastatin, simpastatin, oral pastatin, atorvastatin, fuorepastatin, cerivastatin or salts thereof (eg, sodium salt, etc.)), squalene synthase inhibitors or birds Fibrate compounds having a glyceride-lowering effect (eg, bezafibrate, clotofibrate, simfibrate, clinofibrate, etc.) and the like.
  • cholesterol synthesis inhibitors eg, bravastatin, simpastatin, oral pastatin, atorvastatin, fuorepastatin, cerivastatin or salts thereof (eg, sodium salt, etc.)
  • Fibrate compounds having a glyceride-lowering effect eg, bezafibrate, clotofibrate, simfibrate, clinofibrate, etc.
  • Angiotensin-converting enzyme inhibitors eg, captobril, enalapril, delapril, etc.
  • angiotensin II antagonists eg, oral sultan, candesartan cilexetil, etc.
  • calcium antagonists eg, manidibin, nifendipine, amlodipine, efonidipine) , Dicardipine etc.
  • clonidine eg, captobril, enalapril, delapril, etc.
  • angiotensin II antagonists eg, oral sultan, candesartan cilexetil, etc.
  • calcium antagonists eg, manidibin, nifendipine, amlodipine, efonidipine
  • Dicardipine etc. Dicardipine etc.
  • Central antiobesity drugs eg, dexfenfluamine, fenfluramine, phentermine, sibutramine, ampuebramon, dexoxuefamine, mazindol, phenylpropanolamine, clovenzolex, etc.
  • lipase inhibitors eg, , Orlistat, etc.
  • ⁇ 3-agonist eg, CL-316162, SR-586111-A, UL-TG-307, AJ-9677, ⁇ 40140
  • peptide Anorectic drugs eg, lebutin, CNTF (ciliary neurotrophic factor), etc.
  • cholecystokinin agonists eg, lynch tryp, FPL-15849, etc.
  • Xanthine derivatives eg, sodium theobromine salicylate, calcium thiomide, etc.
  • thiazide-based preparations eg, ethiazide, cyclopentiazide, trichlormethiazide, hydroclothiazide, hydroflumethiazide, benzylhydrothiazide, benzothiclotide, thiazide
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, Mefluside, indapamide, etc.
  • azosemide isosorbide, ethacrynic acid, pyretide, butanide, furosemide,
  • Alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexet, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plant-derived Anticancer agents eg, vincristine, vindesine, taxol, etc.
  • cisplatin carpoplatin, etopoxide, etc., among others, furtulon or neofurz mouth, which is a 5-fluorouracil derivative.
  • Microbial or bacterial components eg, muramyl dipeptide derivatives, picibanil, etc.
  • polysaccharides with immunopotentiating activity eg, lentinan, schizophyllan, krestin, etc.
  • cytokines obtained by gene transfer techniques (eg, , Interferon, interleukin (IL), etc., colony stimulating factor (eg, granulocyte co-stimulatory factor, erythropoietin, etc.), among others, IL-11, IL-2, IL-12, etc.
  • Progesterone derivatives eg, megesterol acetate
  • metoclopramide e.g., metoclopramide
  • tetrahydro Cannabinoid drugs all references are as described above
  • fat metabolism improvers eg, eicosapentaenoic acid, etc.
  • growth hormone IGF-1, or TNF-a, LIF, IL-16, a factor that induces cachexia, and antibodies to oncostatin M.
  • Steroids eg, dexamethasone, etc.
  • sodium hyaluronate e.g., sodium hyaluronate
  • cyclooxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, amploxicam, celecoxib, oral fuecoxib, etc.
  • Saccharification inhibitors eg, ALT-711 etc.
  • nerve regeneration promoters eg, Y-128, VX853, prosaptide, etc.
  • central nervous system drugs eg, dempramine, amitriptyline, imibramine, floxetine, paroxetine, doxepin Antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT_594), endothelin receptor antagonists (eg, ABT-627) ), Monoamine uptake inhibitors (eg, tramadol), indolamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gyabapentin), GABA uptake inhibitors (e.g., tiagabine), alpha 2 receptor
  • Anticholinergic agents include, for example, atotopin, scopolamine, homatropine, tropi Forcemid, cyclopentolate, butyl scopolamine bromide, propantheline bromide, methyl benactidium bromide, mepenzolate bromide, flavoxait, pyrensebine, ipratopium bromide, trihexyphenidyl, oxyptinin, propiverine, Darifue nacin, tolterodine, temiverine, trospium chloride or a salt thereof (eg, atotopine sulfate, scopolamine hydrobromide, omatopine hydrobromide pin, cyclopentolate hydrochloride, braboxate hydrochloride, pyrensebine hydrochloride, trihexyfe hydrochloride) Nidyl, oxybutynin chloride, tolterodine tartrate, etc.) are used, among which oxybutynin
  • NK-2 receptor antagonists examples include GR159897, GR149861, SR48968 (saredutant), SR144190, YM35375, Y38336, ZD7944L-1 743986, MDL105212A, ZD6021, MDL105172 A, pyridine derivatives such as SCH 205528, SCH62373, R-1 13281, perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrovirimidine derivatives such as ZM-253270, MEN 1 Pseudopeptide derivatives such as 1420 (nepadutant), SCH21 7048, L — 659877, PD-147714 (CAM-2291) MENl 0376, S 16474, etc., GR 100679, DNK 333, GR 94800, UK—224671, MEN 10376, MEN 10627, or salts thereof.
  • pyridine derivatives such as
  • compositions comprising the compound of the present invention and a concomitant drug include or are combined with: (1) a single pharmaceutical composition containing the compound of the present invention and a concomitant drug; (2) the present invention And the concomitant drug are separately formulated.
  • these are collectively abbreviated as the concomitant drug of the present invention.
  • the concomitant drug of the present invention comprises the compound of the present invention and the active ingredient of the concomitant drug separately or separately.
  • a pharmaceutically acceptable carrier for example, solid preparations such as powders, granules, tablets, capsules, syrups, emulsions, injections (subcutaneous injection, intravenous injection, intramuscular injection) And intravenous administration), or sublingual tablets, buccals, lozenges, sustained-release preparations such as microcapsules, orally disintegrating agents, and suppositories can be administered orally or parenterally.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids Formulation, suspending agent, tonicity agent, buffering agent, soothing agent, etc.
  • pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
  • excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light gay anhydride, calcium carbonate, calcium phosphate and the like.
  • lubricant examples include stearic acid, magnesium stearate, calcium stearate, Tanolek, and colloid silica.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropyl-methylpyrrolidone, polybutyrrolidone, gum arabic, and gelatin.
  • disintegrant examples include starch, carboxymethylcellulose, carboxymethinoresel monosaccharide, cross-force noremelose sodium, carboxymethyl starch sodium and the like.
  • Preferred examples of the solvent include water for injection, physiological saline, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizer examples include, for example, polyethylene glycol, propylene glycol, D-mantol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium radium sodium sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate.
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methinoresenolose, hydroxymethinoresenorelose, hydroxyxetinoresenorelose, and hydroxypropylcellulose. Is it possible?
  • the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.
  • the moderating agent include, for example, buffers such as phosphate, acetate, carbonate, and citrate.
  • Preferable examples of the soothing agent include benzyl alcohol and the like.
  • Preferable examples of the above preservatives include, for example, paraoxybenzoic acid esters, butanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sonolevic acid.
  • antioxidant examples include, for example, sulfite, ascorbic acid and the like.
  • the coloring agent include, for example, a water-soluble edible tar dye, a water-insoluble lake dye, and a natural dye (for example, Ichiroku rotin, chlorophyll, bengalara, and the like).
  • sweetener examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • 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, USA), HC060 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, anoreggin Sodium acid, hydroxypropyl methylcellulose, dextrin, etc.), stabilizers (eg, ascorbic acid, pyrosulfite) ⁇ ', sodium, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solvents (eg, glycerin, ethanol, etc.), buffers (eg, phosphoric acid and its alkali metal salts, citrate and 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, sodium
  • the compound of the present invention or the concomitant drug is used in a manner known per se, for example, with an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.).
  • an excipient eg, lactose, sucrose, starch, etc.
  • a disintegrant eg, starch, calcium carbonate, etc.
  • Binders eg, starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.
  • lubricants eg, talc, magnesium stearate, polyethylene glycol 600, etc.
  • the preparation can be made into an oral administration preparation by coating with a method known per se for the purpose of taste masking, enteric coating or persistence.
  • the coating agent include hydroxypropyl methylcellulose, ethyl / resenolose, hydroxymethylinoresenolose, hydroxypropinoresenolose, polyoxyethylene glycol, Tween 80, and pull Mouth nick F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohme ⁇ 3 ⁇ 4, Germany, methacrylic acid / acrylic acid copolymerization) and dyes (eg, Bengala , Titanium dioxide, etc.).
  • the preparation for oral administration may be any of an immediate release preparation and a sustained release preparation.
  • the compound of the present invention or the concomitant drug can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se.
  • the oleaginous bases used include, for example, glycerides of higher fatty acids (eg, cocoa butter, Witepsols (manufactured by Dynamite Nobel, Germany), etc.), and medium fatty acids [eg, miglyols (dynamite Or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • aqueous base examples include polyethylene glycols and propylene glycol
  • examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl 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 microgapsel.
  • 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 of the present invention can be in the above-mentioned dosage form depending on the type of 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 or Z and 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.
  • salts of benzoic acid and salicylic acid include, but are not limited to, sodium metal salts such as sodium and potassium, metal salts such as potassium and magnesium, ammonium salts, meglumine salts, and organic compounds such as trometamol. Acid salts and the like.
  • the concentration of the compound of the present invention or the concomitant drug in the injection is about 0.5 to 5 OwZv%, preferably about 3 to 2 OwZv%.
  • the concentration of benzoate and / or salicylate Is 0.5 to 50 w / v ° / 0, preferably 3 to 20 wZ v%.
  • the drug also contains additives commonly used in injections, such as stabilizers (ascorbic acid, sodium pyrosulfate, etc.), surfactants (polysorbate 80, macrogol, etc.), Glycerin, ethanol, etc.), 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), pH regulators (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl ethyl parabenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, medalmine, etc.), solubilizers (propylene glycol, sucrose, etc.) And soothing agents such as glucose, benzyl alcohol, etc.
  • additives are generally used in injections. It is blended in a proportion of.
  • the pH of the injection should be adjusted to pH 2 to 12, preferably 2.5 to 8.0, by adding a pH regulator.
  • An injection can be obtained by dissolving the compound of the present invention or the concomitant drug and, if desired, both benzoate or Z and salitate, 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 provided as an injection by, for example, sterilizing by filtration or subjecting to high-pressure heating as in the case of usual injections.
  • the aqueous solution for injection is preferably subjected to high-pressure heat sterilization at 100 to 121 ⁇ for 5 minutes to 30 minutes, for example.
  • the formulation may be provided with antimicrobial properties of the solution so that it can be used as a multiple-dose formulation.
  • a sustained-release preparation comprising a nucleus containing 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 cell.
  • Cellulose ethers such as loin; cellulose esters such as cellulose acetate; cellulose propylate; polyvinyl acetates such as polyvinyl acetate, polyvinyl butyl ether; methacrylic acid acrylate copolymer; methyl methacrylate -Copolymer, ethoxyxyl methacrylate nosinnamoetyl methacrylate aminoamino methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkyl methacrylate amide copolymer, poly (methyl methacrylate), poly Methacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Eudragit RS-100, RL-100, RS-30D, RL-3 OD,
  • swellable polymer a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable.
  • the swelling is small in an acidic region such as the stomach and large in a neutral region such as the small intestine and the large intestine.
  • Polymers having acidic dissociative groups are preferred.
  • polymers having such a ⁇ dissociating group and exhibiting pH-dependent swelling include, for example, Carbomer 934 P, 940, 941, 974 P, 980, 1342, etc., polycarbophil, calcium polycarbophil, etc.
  • Tachibana-type polyacrylic acid polymers such as carcium polycarbophil (all of which are manufactured by BF Goodrich) and Hibis ⁇ ko 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.). .
  • 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, and alkali metal alginate; and hydroxypropylcellulose.
  • Polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as xypropylmethylcellulose and carboxymethylcell mouth-sunatium, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like can be mentioned.
  • 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 about 75% (w / w), the swellable polymer content is about 3 to about 30% (w / w); preferably about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). ), More preferably from about 5 to about 35% (w / w).
  • the above% (w / w) indicates the 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.
  • Sustained-release preparations are 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, swellable polymer, or the like in a solvent. Manufactured by coating.
  • nucleus containing the drug to be coated with the coating agent is not particularly limited, but is preferably formed into particles such as granules or fine granules.
  • the average particle size is preferably about 150 to 2,000 ⁇ , more preferably about 500 to about 1,400 ⁇ .
  • the nucleus can be prepared by a usual production method.
  • a drug is mixed with appropriate excipients, binders, disintegrants, lubricants, anti-agglomeration agents, lubricants, stabilizers, etc., and prepared by wet extrusion granulation, fluidized bed granulation, etc. .
  • the drug content of the core is from about 0.5 to about 95% (w / w), preferably from about 5.0 to about 80% (w / w). More preferably, from about 30 to about 70 ° / w. 0 (w / w).
  • excipients contained in the core include sugars such as sucrose, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, and corn starch. You. Among them, crystalline cellulose and corn starch are preferred.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, punorelonic F68, arabic gum, gelatin, starch and the like are used.
  • Disintegrators include, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), citrus-type polybulpyrrolidone (crospovidone), low-substituted hydroxypropyl cellulose (L-HPC) ) Is used.
  • hydroxypropylcellulose, polyvinylpyrrolidone and low-conversion hydroxypropylcellulose are preferred.
  • talc, magnesium stearate and its inorganic salts are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol is used as a lubricant.
  • Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.
  • the nucleus can be prepared by spraying a binder dissolved in a suitable solvent such as water or lower alcohol (eg, methanol, ethanol, etc.) on inert carrier particles, which are the core of the nucleus, in addition to the above-mentioned production method. It can also be prepared by the tumbling granulation method, pan coating method, fluidized bed coating method or melt granulation method in which a drug or a mixture of this and excipients, lubricants, etc. is added little by little. .
  • 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 / m to about 1,500 ⁇ m. Are 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.
  • the protective agent preferably a polysaccharide having a polyethylenedaricol-hydroxyalkyl group or a carboxyalkyl group is used, and more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose is 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.
  • a protective agent When a protective agent is used, 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. ° / 0 (w / w).
  • the protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.
  • Examples of the method of coating the core with the agent solution include a method of spray coating.
  • composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating agent 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%, 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 methyl alcohol, ethyl alcohol, isopropyl alcohol, and ⁇ -butyl alcohol, lower alkanones such as acetone, acetonitrile, and chloroform. And methylene chloride are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol 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 stabilizing the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by a usual coating method.
  • the coating agent solution is applied, for example, by a fluidized bed coating method, a pan coating method. It can be carried out by spray coating the nucleus by the wing method or the like.
  • talc titanium oxide, magnesium stearate, stearic acid noresicum, light caffeic anhydride, etc.
  • lubricants glycerin fatty acid ester, hydrogenated castor oil, triethyl tantalate, cetyl alcohol, stearyl Alcohol or the like may be added as a plasticizer.
  • an antistatic agent such as talc may be mixed as necessary.
  • the immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.).
  • Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred.
  • Immediate release preparations usually contain, in addition to the drug as an active ingredient, carriers, additives and excipients (hereinafter sometimes collectively abbreviated as excipients) commonly used in the pharmaceutical field. May be included.
  • excipients commonly used in the pharmaceutical field. May be included.
  • the formulation excipient used is not particularly limited as long as it is an excipient commonly used as an excipient in the field of formulation.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Avicel PH101, etc., manufactured by Asahi Kasei Corporation), powdered sugar, granulated sugar, mannitol, light caffeic anhydride, magnesium carbonate , Calcium carbonate, L-cysteine and the like, and preferably corn starch and mannitol.
  • lactose starch
  • corn starch crystalline cellulose
  • crystalline cellulose Avicel PH101, etc., manufactured by Asahi Kasei Corporation
  • the content of the excipient is, for example, about 4.5 to about 99.4 w / w ° / 0, preferably about 20 to about 98.5 w / w%, based on the total amount of the immediate-release preparation, Preferably it is from about 30 to about 97 w / w ° / 0 .
  • 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 in addition to the above-mentioned components.
  • disintegrants include carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (eg, Axizol, manufactured by Asahi Kasei Corporation), crospovidone (eg, manufactured by BASF) , Corydon CL), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (pine) Chemical Co.), carboxymethyl starch sodium ⁇ beam (Exprotab, manufactured by Kimura Sangyo), partially ⁇ starch (manufactured by Asahi Kasei Corporation, PCS) and the like are used, for example in contact with water and water, ⁇ Alternatively, a substance that disintegrates the granules by, for example, forming a channel between the active ingredient constituting the core and the excipient can be used.
  • disintegrants can be used alone or in combination of two or more.
  • the amount of the disintegrant is appropriately selected depending on the kind and amount of the drug used, the design of the release preparation, and the like. For example, about 0.05 to about 30 w / w based on the total amount of the immediate release preparation %, Preferably from about 0.5 to about 15 w / w%.
  • the immediate-release preparation is an oral solid preparation
  • the solid preparation may further contain a conventional additive.
  • an additive for example, an additive capable of absorbing water, swelling upon contact with water, or disintegrating a granule by forming a channel between the excipient and the excipient that constitute the core can be used.
  • Binders eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropyl cellulose, hydroxypropinolemethinolecellulose, carboxymethylcellulose, polyvinylpyrrolidone, bunolellan, dextrin, etc.
  • Lubricants for example, polyethylene glycol, magnesium stearate, talc, light caffeic anhydride (for example, AEROSIL (Nippon AEROSIL))
  • surfactants for example, anionic surfactants such as sodium alkyl sulfate, poly) Oxyethylene fatty acid ester and polyoxy Nonionic surfactants such as ethylene sorbitan fatty acid esters and polyoxyethylene castor oil derivatives, etc.
  • coloring agents eg, tar dyes, caramel, red bengalah, titanium oxide, riboflavins
  • Hashimi Agents eg, sweeteners, flavors, etc.
  • adsorbents preservatives, wetting agents
  • Stabilizers include organic acids such as tartaric acid, citric acid, succinic acid, and fumaric acid.
  • organic acids such as tartaric acid, citric acid, succinic acid, and fumaric acid.
  • binder hydroxypropylcellulose, polyethylene glycol and polyvinylpyrrolidone are preferably used.
  • An immediate release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation manufacturing technique.
  • the mixing is performed by a commonly used method such as mixing and kneading.
  • quick release When the agent is formed into particles, a particle granulator, a universal kneader (manufactured by Hata Iron Works), a fluidized bed granulator FD-5S can be prepared in the same manner as the method for preparing the core of the sustained-release preparation. (Manufactured by Perec Co., Ltd.) and then granulation by wet extrusion granulation or fluidized bed granulation.
  • immediate-release preparation and sustained-release preparation can be administered as is or as appropriate, separately and in combination with excipients, etc., in a conventional manner, and then administered simultaneously or in combination at an arbitrary administration interval
  • both preparations may be used alone or as appropriate, together with a pharmaceutical excipient and the like, into a single oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.).
  • Both preparations may be made into granules or fine granules and filled into the same capsule or the like to prepare a preparation for oral administration.
  • the concomitant drug of the present invention when manufactured as a sublingual tablet, a puccal preparation, or a rapidly disintegrating agent for the oral cavity, it may be a solid preparation such as a tablet or an oral mucosal patch (film). ,.
  • puccal or intraoral quick disintegrant 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.
  • ⁇ -cyclodextrin or a 3-cyclodextrin derivative eg, hydroxypropyl-1-j3-cyclodextrin, etc.
  • excipients examples include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light caffeic anhydride.
  • lubricant examples include magnesium stearate, canolecidium stearate, talc, colloid silica and the like, and magnesium stearate and colloidal silica are particularly preferable.
  • tonicity agent examples include sodium chloride, dalcose, funolectose, mannitol, sonolebitol, 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, citrus polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate.
  • swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, citrus polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate.
  • crystalline cellulose eg, microcrystalline cellulose
  • Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginate (eg, sodium anoregate), senorellose derivatives (eg, methylcellulose, carboxymethinolese / relulose, hydroxymethylinole) Senorelose, Hydroxypropinoreserenololose, Hydroxypropyl methylcellulose), Gelatin, Water-soluble starch, Polyacrylic acid (eg, Riki-boma), Polymethacrylic acid, Polybutyl alcohol, Polyethylene glycol, Polyvinylpyrroli And polycarbophil, such as hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, and polyethylene glycol.
  • gums eg, tragacanth gum, acacia gum, guar gum
  • alginate eg, sodium anoregate
  • the sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug with the above-mentioned excipient by a method known per se.
  • 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.
  • a lubricant 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
  • a lubricant 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
  • 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. And then cast the resulting solution into a (cast) 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 dalicol are included to give the film adequate elasticity, and a bioadhesive film is used to enhance the adhesion of the film to the oral mucosal lining.
  • Remars eg, polycarbophil, carbopol
  • 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 to form a film. This is achieved by forming The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.
  • Preferred rapid oral disintegrating agents include solid rapid forms 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. Diffusion administration agents are included.
  • the network can be obtained by evaporating the solvent from the solid composition comprising 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, and animal or vegetable proteins such as soybean, wheat and psyl 1ium seed proteins; gums such as gum arabic, guar gum, agar, and xanthan.
  • saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inexpensive such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartate Amino acids having 2 to 12 carbon atoms, such as L-glutamic acid, L-hydroxyproline, L-isoleucine, L-mouth isine, and L-phenylalanine.
  • One or more matrix-forming agents can be introduced into the solution or suspension prior to solidification.
  • a matrix forming agent may be present in addition to the surfactant, or may be present without the surfactant.
  • Matric In addition to forming the matrix, the solution-forming agent can help maintain the solution state of the compound of the present invention or the concomitant drug in suspension in solution.
  • Suitable preservatives include parabens, sorbic acid.
  • Suitable antioxidants include sulfites and ascorbic acid.
  • Suitable surfactants include Polysorbate 80, Macrogol.
  • Suitable thickeners include natural gums and cell mouth derivatives.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis 'and' Everard.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH adjusters 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 compounds.
  • Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, of the compound of the present invention or the concomitant drug, and for about 1 minute to about 60 minutes.
  • Fast disintegrants are preferred.
  • Content relative to the whole preparation of the excipient is from about 1 0 to about 9 9 weight 0/0, preferably about 3 0 to about 9 0 wt%.
  • the content of the / 3 -cyclodextrin or -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant with respect to 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 90% by weight. 70% by weight.
  • the content of the hydrophilic carrier based on the whole preparation is about 0.1 to about 50% by weight / 0 , preferably about 10 to about 30% by weight / 0 .
  • the content of the water-dispersible polymer 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 in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. / 0 .
  • the above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary.
  • the daily dose of the concomitant drug of the present invention depends on the severity of symptoms, age, sex, body weight, susceptibility difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc.
  • the dose of the compound of the present invention is not particularly limited as long as it does not cause side effects, but is usually about 0.005 to 100 mg, preferably about 0.05 mg / kg body weight of a mammal by oral administration. 5050 mg, more preferably about 0.2-30 mg, which is usually administered once to three times a day.
  • the daily dose of the compound of the present invention or the concomitant drug may include the degree of symptoms, age, gender, weight, receptivity difference, administration timing, interval, properties of pharmaceutical preparation, preparation, type, and active ingredient of the administration subject.
  • the amount of the active ingredient varies depending on the type and the like, but is not particularly limited.
  • the amount of the active ingredient is, for example, about 0.001-2 OO mg per kg body weight of a mammal by oral administration, preferably about 0.01-500 mg, more preferably about 0.01-500 mg.
  • About I0 Omg which is usually administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, but the compound of the present invention may be administered after the concomitant drug is administered first.
  • the compound of the present invention may be administered first, and then the concomitant drug may be administered.
  • administration is carried out with a time difference, the time difference varies depending on the active ingredient, dosage form and administration method to be administered.
  • 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 compound of the present invention is administered first, the compound of the present invention is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably 15 minutes to 1 hour.
  • a method of administering a concomitant drug within the above is mentioned.
  • a preferred administration method for example, about 0.01 to 20 OmgZkg of the concomitant drug formed into an oral administration preparation is orally administered, and after about 15 minutes, about 0 to 10 mg of the compound of the present invention formed into an oral administration preparation is obtained. OO 5-10 Omg / kg orally as daily dose.
  • the content of the compound of the present invention in the whole preparation varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, based on the whole preparation. %, More preferably about 0.5 to 20% by weight.
  • TLC Thin Layer Chromatography
  • 60 F254 manufactured by Merck was used as a TLC plate
  • the solvent used as an elution solvent in column chromatography was used as a developing solvent.
  • a UV detector was used for detection.
  • silica gel for column chromatography Merck silica gel 60 (70-230 mesh) was used. Room temperature usually means a temperature of about 10 to 35. Further, sodium sulfate or magnesium sulfate was used for drying the extract.
  • reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid and saturated saline, dried, and the solvent was distilled off under reduced pressure to give N- (3,5-dimethylbenzyl) -18-oxo-one.
  • 5-phenyl-8H-pyrano [3,4-b] pyridine-16-carboxamide was obtained as colorless prisms (4.90 g, 92%).
  • Triethylamine (2.9 OmL) and methanesulfonyl chloride (1.60 mL) were added to a solution of the compound (4.30 g) obtained in step 2 in THF (2 OmL) at 0 ⁇ , and the mixture was added at 0 ° C. Stir for 30 minutes. Further, triethylamine (2.9 OmL) and methanesulfuryl chloride (1.6 OmL) were added to the reaction solution with O :, and the mixture was stirred at 0 for 30 minutes. To the reaction solution was added a 1 N aqueous solution of sodium hydroxide (2 OmL), and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried, and then the solvent was distilled off under reduced pressure.
  • Sodium hydride (60% oil, 0.72 g) was added at 0 to the THF (30 OmL) solution of the obtained residue, and the mixture was stirred at 8010 for 1 hour.
  • the reaction solution was poured into water and extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure.
  • Step 2 The compound obtained in Step 2 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as colorless prisms (948 mg, 76%).
  • Step 2 This compound was used for the reaction of Step 2 without purification.
  • Step 2 The compound (12.78 g) obtained in Step 1 was reacted and treated in the same manner as in Step 6 of Example 10 to give N- [3,5-bis (trifluoromethyl) benzyl] 1-oxo-l- 4-fluoro-1H-pyrano [3,4-c] pyridine-l-carboxamide was obtained as colorless prisms (14.4 g, 61%).
  • Step 5 The compound (0.81 g) obtained in Step 5 was reacted and treated in the same manner as in Step 3 of Reference Example 1, and the title compound was obtained as a colorless powder (0.43 g, 54%).
  • Step 2 To a solution of the compound obtained in Step 1 (22.9 g) in THF (18 OmL) was added a 2 N aqueous potassium hydroxide solution (9 OmL), and the mixture was stirred at 60 ° for 2 hours. After neutralizing the reaction solution with a 2N aqueous hydrochloric acid solution, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure. (19.2 g, 88%). The obtained compound was used for the next step without further purification.
  • Step 4 The compound (22.0 g) obtained in Step 4 was reacted and treated in the same manner as described in Step 1 of Reference Example 3 to give the title compound as colorless prisms (17.5 g, 67% ).
  • Step 1 The compound (0.82 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 3 of Reference Example 1 to give the title compound as colorless prisms (0.44 g, 54% ).
  • Step 3 The compound obtained in Step 2 (1.95 g) was reacted and treated in the same manner as in Step 3 of Reference Example 1 to give the title compound as colorless prisms (1.33 g, 76%). Obtained.
  • Step 2 The compound obtained in Step 2 (1.47 g) was reacted and treated in the same manner as in Step 3 of Reference Example 1 to give the title compound as colorless prisms (1.14 g, 87%). Obtained.
  • Step 2 The compound obtained in Step 2 (2.07 g) was reacted and treated in the same manner as described in Step 3 of Reference Example 1.
  • the title compound was colorless amorphous (1.77 g, 88%). ).
  • Step 2 of Reference Example 7 Using the compound obtained in Step 1 (2.90 g), the method described in Step 2 of Reference Example 7 was used. The same reaction and treatment gave crude 3- (4-fluorobenzoyl) -16-isopropyl-1-pyridine-monocarboxylic acid as a pale yellow oil (1.90 g, 88%). . The obtained compound was used for the next step without further purification.
  • Step 4 The compound (4.52 g) obtained in Step 4 was reacted and treated in the same manner as described in Step 1 of Reference Example 3, and the title compound was converted to colorless prism crystals (1.75 g, 33% ).
  • Example 13 To a solution of the compound obtained in Example 13 (8.78 g) and concentrated sulfuric acid (19 mL) in nitromethane (65 mL) was added sodium nitrate at ⁇ 40 °. After the reaction mixture was slowly heated to room temperature, the reaction mixture was treated with sodium hydrogen carbonate (42 g) in water (15 OmL) and vinegar. Ethyl acid (1 O OmL) was poured into the solution. The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (6.88 g, 73%).
  • Step 1 The compound (23.4 g) obtained in Step 1 was reacted and treated in the same manner as described in Step 3 of Reference Example 1, and the title compound was converted to pale yellow amorphous (13.2 g, 58% ).
  • Step 2 The compound obtained in Step 2 (6.90 g) was reacted and treated in the same manner as described in Step 3 of Reference Example 1 to give the title compound as a colorless amorphous (3.30 g, 49% ).
  • step 1 phosphorus oxychloride (5. OmL), was stirred at 100 for 1 hour. After the reaction solution was poured into water (5 OmL), an aqueous solution of potassium carbonate was added to make it alkaline. The product was extracted with a mixed solution of ethyl acetate and THF. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried, and the solvent was distilled off under reduced pressure.
  • Example 5 The compound (0.35 g) obtained in Example 5 was reacted and treated in the same manner as in Example 3, and as a result, the title compound was obtained as colorless prisms (0.14 g, 43%).
  • Example 8 (9 S) 1-2-chloro- 1 7-(3,5-dimethylbenzyl) 1-5-(4-fluorophenyl)-1-9-methyl-7, 8, 9, 10-tetrahydro [1, 4] diazepino [ 2, 1— &] [1, 7] naphthyridine-one 6, 12-dione
  • Example 8 The compound (329 mg) obtained in Example 8 was reacted and treated in the same manner as in Example 3, and as a result, the title compound was obtained as colorless prisms (128 mg, 41%).
  • 6-methylpyridine-1,2,3-dicarboxylic acid (53.9 g) in acetic anhydride (312 mL) was stirred at 150 for 3 hours. After evaporating the solvent under reduced pressure, 6-methylpyridin-1,2,3-dicarboxylic anhydride was obtained as a brown powder (45.0 g, 94%).
  • the obtained aqueous layer was acidified with 2 N hydrochloric acid (20 OmL), and extracted three times with a mixed solution of ethyl acetate and THF.
  • the organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure.
  • step 5 To a solution of the compound obtained in step 5 (0.80 g) in DMF (2 OmL) was added 3,5-bis (trifluoromethyl) benzylamine (0.68 g), WSC (l. 07 g), HOB t (0.64 g) was added at room temperature, and the mixture was stirred for 14 hours.
  • the reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure.
  • Step 7 To a mixed solution of the compound (0.80 g) obtained in the stem 6 (0.80 g) in THF (15 mL) —methanol (5 mL) was added (R) —3-amino-1-methyl-1-propanol (0.23 g). ) Was added at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and THF.
  • the organic layer was washed with a 10 ° / 0 aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure.
  • To a mixed solution of the obtained residue in toluene (30 mL) -acetonitrile (5 mL) was added DBU (0.48 mL) at room temperature, and the mixture was stirred at 130 for 2 hours.
  • the reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and HF.
  • the organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure.
  • Example 11 The compound (0.34 g) obtained in Example 11 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (0.11 g. 32%). Melting point: 121-123 (recrystallized from methylene chloride-1'hexane).
  • Example 13 (a R, 9R) —7— [3,5-Bis (trifluoromethyl) benzyl] —9—Methyl-6, .13—Dioxo-1-5-Feneru 6, 8, 9, 10, 1 1 , 13—Hexahi Draw 7 H— [1, 4] diazocino [2, 1-g] [1, 7] naphthyridine-one 2—force rubonitrile
  • Example 14 The compound (0.32 g) obtained in Example 14 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (0.081 g, 26%).
  • Example 17 The compound (150 mg) obtained in Example 17 was reacted and treated in the same manner as in Step 3 of Example 1 to give the title compound as pale-yellow prism crystals (95 mg, 64%).
  • Example 20 The compound (140 mg) obtained in Example 17 was reacted and treated in the same manner as in Example 2, and the title compound was obtained as colorless prisms (109 mg, 76%). Melting point: 244-245X (recrystallized from ethyl acetate-diisopropyl ether).
  • Example 20 The compound (140 mg) obtained in Example 17 was reacted and treated in the same manner as in Example 2, and the title compound was obtained as colorless prisms (109 mg, 76%). Melting point: 244-245X (recrystallized from ethyl acetate-diisopropyl ether).
  • Example 17 A 50% aqueous solution of dimethylamine (2 mL) of the compound (0.15 g) obtained in Example 17 was visually stirred at 180 for 14 hours. The reaction solution was poured into water and extracted with a mixed solution of ethyl acetate and HF. The organic layer was washed with a 10% aqueous solution of citric acid and saturated saline, dried, and then the solvent was distilled off under reduced pressure to give the title compound as colorless prisms (0.13 g, 90%).
  • Example 25 The compound (0.37 g) obtained in Example 25 was reacted and treated in the same manner as in Example 3, and the title compound was obtained as a pale-yellow powder (0.099 g, 27%).
  • Example 28 The compound (147 mg) obtained in Example 28 was reacted and treated in the same manner as in Example 3, and the title compound was obtained as amorphous (45 mg, 32%).
  • Example 31 The compound (52 Omg) obtained in Example 31 was reacted and treated in the same manner as in Example 3 to give the title compound as colorless prisms (126 mg, 25%). Melting point: 103-105 (recrystallized from ethanol).
  • Example 33 [1, 4] diazocino [1, 2-b] [2, 7] naphthyridin-1,8-dione
  • the compound (0.22 g) obtained in Example 33 was reacted and treated in the same manner as in Example 3.
  • the title compound was obtained as a pale yellow powder (0.16 g, 75%).
  • Example 34 To a methyl ether (30 mL) of the compound (1.50 g) obtained in Example 34 (1) was added a 1M p-toluenesulfonic acid monohydrate Z methanol solution (2.55 mL), and the mixture was stirred at room temperature for 30 minutes. Stirred. The title compound was obtained as colorless prisms (1.87 g, 96%) by filtering the resulting white precipitate with a jet filter.
  • Example 34 (1) To a solution of the compound obtained in Example 34 (1) (1.50 g) in getyl ether (3 OmL) was added a 1M solution of hydrobromic acid in methanol (2.55 mL), and the mixture was stirred at room temperature for 30 minutes. .
  • the title compound was obtained as colorless prisms (1.46 g, 85%) by filtering the precipitated white precipitate with getyl ether.
  • Triethylamine (0.50 mL) and methanesulfonyl chloride (0.30 mL) were added to a solution of the compound (0.68 g) obtained in Step 1 in THF (1 OmL) at 0, and the mixture was stirred at 0 at 30 minutes. did. Further, triethylamine (0.50 mL) and methanesulfonyl chloride (0.30 mL) were added to the reaction solution by Ot: and the mixture was stirred at 0 for 30 minutes. A 1N aqueous sodium hydroxide solution (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, and extracted with ethyl acetate.
  • Example 11 To a methanol solution (10 OmL) of the compound (5.00 g) obtained in Example 11 was added 1,1′-bis (diphenylphosphino) phenoctene (dppf) (0.23 g), acetic acid Palladium (0.095 g) and triethylamine (2.9 mL) were added, and the mixture was stirred under 100 atmospheres of carbon monoxide at 5 atm for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 2N hydrochloric acid. After pouring the reaction solution into water, the product was extracted with a mixed solution of ethyl acetate and THF.
  • dppf 1,1′-bis (diphenylphosphino) phenoctene
  • acetic acid Palladium 0.095 g
  • triethylamine 2.9 mL

Abstract

La présente invention concerne un composé représenté par la formule (I) dans laquelle: le cycle A représente un cycle pyridine substitué; R2 représente hydrogène, halogéno, ou alkyle en C1-6 éventuellement halogéné; R3 représente hydrogène ou alkyle en C1-6; les R sont identiques ou différents et représentent respectivement halogéno, alkyle en C1-6 éventuellement halogéné, alcoxy en C1-6 éventuellement halogéné, cyano, ou hydroxy; m est un nombre entier de 0 à 3; n vaut 1 ou 2; et p est un nombre entier de 0 à 3. Cette invention concerne également un sel dudit composé, ou un promédicament du composé ou de son sel. Le composé à une excellente activité d'antagoniste du récepteur de la tachykinine, notamment du récepteur de la substance P.
PCT/JP2002/002624 2001-03-19 2002-03-19 Compose heterocyclique a trois cycles, son procede de preparation et son utilisation WO2002074771A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112666A1 (fr) * 2005-04-20 2006-10-26 Sk Chemicals Co., Ltd. Derives de pyridine, procedes de preparation de ces composes et compositions pharmaceutiques contenant ces composes
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02263585A (ja) * 1989-04-03 1990-10-26 Sumitomo Metal Ind Ltd 複合熱源溶接装置
JPH09263587A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤
JPH10109989A (ja) * 1996-08-14 1998-04-28 Takeda Chem Ind Ltd 含窒素環状化合物、その製造法および剤
JPH1143489A (ja) * 1997-05-30 1999-02-16 Takeda Chem Ind Ltd ヘテロ環化合物、その製造法および剤
WO2002022574A1 (fr) * 2000-09-11 2002-03-21 Takeda Chemical Industries, Ltd. Compose tricyclique heterocyclique, son procede de fabrication et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02263585A (ja) * 1989-04-03 1990-10-26 Sumitomo Metal Ind Ltd 複合熱源溶接装置
JPH09263587A (ja) * 1995-03-24 1997-10-07 Takeda Chem Ind Ltd 環状化合物、その製造法および剤
JPH10109989A (ja) * 1996-08-14 1998-04-28 Takeda Chem Ind Ltd 含窒素環状化合物、その製造法および剤
JPH1143489A (ja) * 1997-05-30 1999-02-16 Takeda Chem Ind Ltd ヘテロ環化合物、その製造法および剤
WO2002022574A1 (fr) * 2000-09-11 2002-03-21 Takeda Chemical Industries, Ltd. Compose tricyclique heterocyclique, son procede de fabrication et son utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112666A1 (fr) * 2005-04-20 2006-10-26 Sk Chemicals Co., Ltd. Derives de pyridine, procedes de preparation de ces composes et compositions pharmaceutiques contenant ces composes
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

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