WO2001072710A1 - Dérivés et médicaments hétérocycliques - Google Patents

Dérivés et médicaments hétérocycliques Download PDF

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Publication number
WO2001072710A1
WO2001072710A1 PCT/JP2001/002822 JP0102822W WO0172710A1 WO 2001072710 A1 WO2001072710 A1 WO 2001072710A1 JP 0102822 W JP0102822 W JP 0102822W WO 0172710 A1 WO0172710 A1 WO 0172710A1
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group
compound
alkyl
substituted
amidino
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PCT/JP2001/002822
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English (en)
French (fr)
Japanese (ja)
Inventor
Masahiko Okano
Kazuya Mori
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Nippon Shinyaku Co., Ltd.
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Priority to AT01917752T priority Critical patent/ATE449084T1/de
Priority to EP01917752A priority patent/EP1306372B1/en
Priority to KR1020027012917A priority patent/KR20020083533A/ko
Priority to CA002403605A priority patent/CA2403605A1/en
Priority to US10/239,750 priority patent/US6794389B2/en
Priority to DE60140545T priority patent/DE60140545D1/de
Priority to AU2001244688A priority patent/AU2001244688A1/en
Publication of WO2001072710A1 publication Critical patent/WO2001072710A1/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel heterogene derivative or a salt thereof useful as a medicament, and a pharmaceutical composition containing the same as an active ingredient.
  • Narcotic analgesics (morphine, etc.), non-narcotic analgesics (aspirin, indomethacin, etc.), and narcotic antagonistic analgesics (pentazosin, etc.) are used as analgesics.
  • Narcotic analgesics exert their analgesic effects primarily by inhibiting the transmission of painful excitability in the center.
  • Non-narcotic analgesics exert their analgesic action mainly by suppressing the production of pain-causing substances in the periphery.
  • narcotic antagonists exhibit analgesic action by a mechanism similar to narcotic analgesics.
  • analgesics useful for chronic pain or herpes zoster that cannot be controlled by morphine, or for hyperalgesia, and the creation of superior analgesics has been desired.
  • Nociceptin is a ⁇ peptide you Sekisaegi to a variety of neural activity was tempering started the pain in the body.
  • Japanese Patent Application Laid-Open No. 10-212290 states that nociceptin agonist and no or antagonist are used for the treatment of mental disorders, neurological disorders and physiological disorders, in particular, anxiety and stress disorders, depression, traumatic disorders. , Memory loss due to Alhaima disease or other dementia, symptoms of epilepsy and convulsions, acute and / or chronic pain symptoms, withdrawal symptoms from drug addiction, control of fluid balance, Na + excretion, arterial blood pressure It is described as being useful in the improvement of dietary disorders such as disability and obesity.
  • Non-peptidic compounds that act on nociceptin receptors include lofentanil, naloxone benzoylhydrazone, and 2-oxin.
  • Kisoimidazole derivatives International Publication WO09854168
  • Various compounds are known as compounds similar to the quinazoline derivative in the heterocyclic derivative of the compound of the present invention (International Publication WO9307124, Patent Publication 2923742, International Publication WO9720821).
  • International Publication WO 9720821 states that a 2-acylaminoquinazoline derivative has a neuropeptide ⁇ ( ⁇ ⁇ ) receptor subtype ⁇ 5 inhibitory effect, It is described as useful for improvement. Disclosure of the invention
  • An object of the present invention is to provide a novel compound having an excellent analgesic action. In particular, it acts on nociceptin receptor to cause chronic pain and herpes zoster. It is an object of the present invention to provide a novel analgesic having a wide range of analgesic effects, which is also effective for allodyurea and the like.
  • the present inventors have synthesized and studied various compounds, and in the process of synthesizing the compounds, the compounds represented by the following general formula (1) were converted to agonist and / or nociceptin receptor.
  • the present invention has been found to be an antagonist and has an excellent analgesic effect, and has completed the present invention.
  • the present invention provides the following general formula (1)
  • X and Y are the same or different and each represents a nitrogen atom or CH;
  • R 1 represents a hydrogen atom or an alkyl
  • a 1 and A 2 are the same or different and are (1) a single bond or (2) a divalent group which may be substituted and may have 1 to 3 unsaturated bonds at arbitrary positions.
  • aliphatic hydrocarbon groups such aliphatic hydrocarbon groups may have one intervening heteroatom selected from the group consisting of NH—, O, or S). Then;
  • Q represents (1) a single bond, (2) an optionally substituted 3- to 8-membered cycloalkylene group, (3) an optionally substituted phenylene group, and (4) an optionally substituted phenylene group.
  • R 2 A, R 2 C, R 2. Is the same or different and represents a hydrogen atom, alkyl or phenyl;
  • R 2 B represents a hydrogen atom, alkyl, cyano, nitro or phenyl, or two nitrogen atoms of a guanidino group Represents a saturated or unsaturated 5- or 6-membered ⁇ with one or two of R 2 B , R 2c or R 2D which is a substituent thereof;
  • E is (1) ethenylene, (2) —NRCO—, (3) —NRCONH—, (4) CONR—, (5) ethinylene, (6) —NRSO 2 —, or (7) amino Alkylene (where R represents hydrogen or alkyl which may be g-substituted);
  • R 3 represents a phenyl group or a heterocyclic group which may be substituted;
  • X and Y each represent a nitrogen atom or CH;
  • R 1 represents a hydrogen atom or alkyl;
  • a 1 and A 2 may be the same or different, and may be (1) a single bond or (2) alkyl, carbamoyl ole, monoanolequinoleca norenomoine, dianolequinoreca norenomoine, or An alkylene which may be substituted by hydroxyl, alkoxy or trifluoromethyl and which may have 1 to 3 unsaturated bonds at any position S;
  • Q may be substituted by (1) a single bond, (2) alkyl, alkoxycarbonyl, carbamoyl, monoanolequinolecarbamoinole, dialquinolecanolenomoyl or alkoxy. 8-membered cycloalkylene group, (3) alkynole, anorecoxy, anoreco xikanoleboninore, kanorenokumoinore, monoorenokinore kanorenomoinore, jianorekinorekanorenomoinore, snolemorey And substituted with halogen, cyano, or trifluoromethyl, guanolequinolenos / refamoimole, diaminolequinoles / refamoineole, .amino, monoanolequinolemino, dialkylamino, nitro, halogen, cyano, or trifluoromethyl.
  • R 2 A , R 2 C and R 2 D are the same or different and each represent a hydrogen atom, alkyl or phenyl; and R 2 B represents a hydrogen atom, alkyl, cyano group, or nitro group.
  • R 2 B represents a hydrogen atom, alkyl, cyano group, or nitro group.
  • N R Lee A i—Q— A 2 —N (R 2A ) — represents a 5- to 7-membered ring;
  • E is (1) etylene, (2) —NRCO—, (3) — NRCONH—, (4) — CONR—, (5) ethinylene, (6) — NRSO 2 — or (7) aminoalkylene (where R represents hydrogen or an optionally substituted alkyl) );
  • R 3 is Anorekinore, ⁇ Noreko alkoxy, Anoreko key deer Noreboninore, Kanorenoku Moi Honoré, mono Anore Kino Leka Noreno Moi Honoré, Jianorekinorekanorenoku Moi Honoré, Sunorefu ⁇ mode I Honoré, mono Anorekinoresu Norefmo-no-nore, Gianorequinoreno-no-remo-no-re, Anore-quinoreno-reno-no-inorea-mino, ⁇ ⁇ (Alkyl) alkylsnorefonylamino, Amino, Monoalkylamino, Dialkylamino Nitro, halogen, Represents a phenyl group or a heterocyclic tomb, which may be substituted by cyano, hydroxy or trifluoromethyl;
  • X and Y are each a nitrogen atom
  • R 1 is a hydrogen atom or alkyl
  • a 1 and A 2 are the same or different
  • X and Y are nitrogen atoms
  • R 1 is a hydrogen atom
  • a 1 and A 2 are the same or different and are (1) a single bond or (2) substituted.
  • R 2 A , R 2 B , R 2 C , and R 2 D are the same or different, and a hydrogen atom, an alkyl or phenyl
  • E is (1) eturene or (2) —NRCO—
  • R 4 And R 5 are the same or different and are a hydrogen atom, an alkyl, an alkoxy, an aralkyloxy, a halogen or dinitro.
  • the present invention relates to a pharmaceutical composition containing such a compound or a salt thereof as an active ingredient, especially an analgesic.
  • a structural feature of the compound of the present invention is that a substituent at the 4-position of the quinazoline or quinoline skeleton or the 1-position of the isoquinoline skeleton, i.e., N i R 1 ) —A 1 —Q— A 2
  • the force with a guanidino group at one end or the two NHs of the guanidino group are in ⁇ that form ⁇ with their substituents.
  • the compound of the present invention having the above structural characteristics is a novel compound not described in any literature.
  • the compound of the present invention acts on a nociceptin receptor and has an excellent anti-inflammatory effect.
  • alkyl in the present invention, a linear or branched one having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-alkyl
  • alkyl examples include soptynole, sec'butyl, tert-butyl, ⁇ -pentinole, 5-isopentyl, ⁇ -hexyl, and isohexyl.
  • those having 1 to 4 carbon atoms are preferred.
  • Alkoxy includes linear or branched ones having 1 to 6 carbon atoms, for example, methoxy, ethoxy, ⁇ 'propoxy, isopropoxy, ⁇ -butoxy, iso. Butoxy ', sec-butoxy, tert-butoxy, ⁇ -pentynoleoxy, isopentinoleoxy, ⁇ ⁇ hexynoleo.xy, isohexynoleoxy and the like. In particular, those having 1 to 4 carbon atoms are preferred.
  • aralkyloxy j examples include those having 7 to 1 ° carbon atoms, such as benzyloxy and phenethyloxy. Particularly preferred is benzyloxy.
  • Examples of the “divalent aliphatic hydrocarbon group” include straight-chain or branched alkylene having 1 to 6 carbon atoms (eg, methylene, ethylene: trimethylene, tetramethylene, etc.). , Pentamethylene, hexamethylene, 2-ethynoletrimethylene, 1-methyltetramethylene), a bottom-chain or branched C 2-6 alkulylene (eg, vinylene) Propylene, or straight-chain or branched alkynylene having 2 to 6 carbon atoms (eg, ethinylene).
  • Such aliphatic hydrocarbon groups consist of NH, oxygen atoms or sulfur atoms in between It may contain one heteroatom selected from the group.
  • alkylene of the “amino alkylene” examples include the alkylenes listed in the “divalent aliphatic hydrocarbon group”.
  • Cycloalkylene includes those having 3 to 8 carbon atoms, for example, sig-mouth propylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylen, cyclooctylene. ⁇ ⁇ .
  • Such a cycloalkylene may have one or two substituents, and examples of such a g-substituent include anolequinole, anorecoxicanololeboninole, canoleno moinole, and mono-anolekill / rebamoinolene.
  • ianolequinolecanolebamoyl or anoreoxy Further, it may contain an unsaturated bond, and examples of such an unsaturated bond include cyclohexenylene, cycloheptenylene, cyclooctenylene, and the like. You.
  • Halogen includes fluorine, chlorine, bromine and iodine atoms.
  • the heterocyclic ring in the “heterocyclic group” and the “divalent heterocyclic group” includes 1 to 2 hetero atoms selected from the group consisting of NH, an oxygen atom, and a sulfur atom; And a 4- to 8-membered mono- or condensed compound may be used.
  • R 3 is, for example, 2-pyridyl, 3-pyridyl 4-pyridyl, 2-pyrimidel, 4-pyrimidinole, 5-pyridininole, 3-pyridinyl Dazinole, 4-Pi Dazino-Linore, 2-Pilajur, 3-Pirajur.
  • Such a heterocyclic ring may have 1 to 2 substituents, and examples of the substituent include alkyl, alkoxy, alkoxycanoleboninole, phenol, phenol, and phenol.
  • norequils norefino ninorea mino amino, monoanolequinolea mino, dianolequinolea mino, nitro, norlogen, cyano, hydroxy or trifluoromethyl.
  • heterocyclic ring in the heterocyclic group Q examples include pyridine, pyrimidine, piperazine, homopyrazine, furan, thiophene and the like.
  • the complex group Q may have 1 to 2 substituents, and For example, anore quinore, anore koxy, anorekoxyka noreponinore, kanorenoku moore, monoa / rekinoreka norebamoi nore, gianorequinorecanoreno moi nore, ami nono, or motono akia And so on.
  • the “phenylene group” may have 1 to 2 substituents, and examples of such substituents include alkyl, alkoxy, alkoxycarbonyl, carnomoine, mononolequinoleca, and norebamoynole. , ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • R 1 — N (R 1 ) — A 1 — Q— A 2 — N (R 2A ) — ⁇ is a 5- to 7-membered, saturated ⁇ , for example, piperazino or homopiperazino. Can be done.
  • Examples of the “salt” of the compound (1) included in the present invention include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, and the like.
  • Acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methansnolefonic acid, ethanesnolefonic acid, benzenesnolefonic acid, tonolensnolefonic acid, naphthalenesnolefonic acid, camphorsnolefole Salts of organic acids such as fonic acid can be mentioned.
  • Particularly preferred compounds are (1S, 2R) -N-amidino-1 2 — ⁇ [2— (4—cyclo-benzo-noreamino) 16-methoxyquinazoline-1 4 N-amidino 1- 2- [6-methoxy-14- 1 ⁇ 2- [2— (2-pyridyl) ether] quinazoline — 4 — yl ⁇ aminoethyl] phenylethylamine trihydrochloride, cis-41-guanidino methinolysis—2—methinoly N— ⁇ 6—methoxy-2— [2 -— (2—pyridinole) [Tum] quinazoline 1 4 1) ⁇ cyclohexinole amine trihydrochloride, N-amidino N'— ⁇ 6 — methino 1 2 — [2 — (2 — [Risyl) ethinyl] quinazoline-1 4-yl ⁇ — 1, 6 — hexanediamine trihydr
  • the compound of the present invention has cis (Z form) and trans (E form) isomers, and each isomer and a mixture thereof are also included in the present invention.
  • the optical isomer is, for example, an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphor) by utilizing the basicity of the racemic isomer obtained as described above.
  • the compound can be optically resolved by a known method using monosulfonic acid or the like, or can be produced using a previously prepared optically active compound as a raw material.
  • the compound (1) of the present invention can be produced, for example, by the following method.
  • R 2 b R 2 c represents the same or different and represents a hydrogen atom, alkyl, phenyl, cyano or a protective group, and L represents a leaving group.
  • Examples of the protecting group include tertiary butoxycarbyl, benzyloxycarbonyl, benzyl and the like.
  • Examples of the leaving group include pyrazole-1-yl, methylthio, methoxy, halogen, and the like.
  • Compound (2) and 1 equivalent to excess amount of compound (3) are combined with a hydrocarbon solvent such as benzene and toluene, an ether solvent such as dioxane and tetrahydrofuran, a formaldehyde, and a methylene chloride.
  • 1, 2 — Halo such as dichloroethane Gen solvents, New, in a solvent such as New ⁇ dimethyl Chiruhorumua Mi de, 0 ° and reacted for several hours to several ® at a temperature of the boiling point of the solvent medium used from C, is et to R 2 b, R 2.
  • compound (1) can be obtained by deprotection using a method known per se. Among them, pyrazolyl-11-yl as a leaving group L of compound (3), tert-butoxycarbonyl as a protecting group, and 1,2-dichloroethane as a solvent, After reacting at room temperature for 1 to 48 hours, deprotection with hydrochloric acid is preferred.
  • the compound (la) is prepared by reacting the ligated compound (2) with R 2 c R 2 DN —CN according to a known method (eg, J. Med. Chem. 18_, 90, 1975). Can be manufactured.
  • Compound (1) can be produced from compound (120) according to a known method (Synthesis, 460, 1988, etc.).
  • the alkyl as R 8 is preferably one having 1 to 4 carbon atoms, and among them, methyl is preferred. Manufacturing method E
  • the compound (1A) of the compound (1) in which E is etulene and X and Y are both N can be produced also by the following reaction steps.
  • the compound (1Z) of the compound (1) wherein E is —NRCO—, X and Y are all N can also be produced by the following reaction steps.
  • the compound (37B) and 1 equivalent to an excess of the compound (3) are combined with a hydrocarbon solvent such as benzene and toluene, an ether solvent such as dioxane and tetrahydrofuran, and a solvent.
  • a hydrocarbon solvent such as benzene and toluene
  • an ether solvent such as dioxane and tetrahydrofuran
  • a solvent such as ⁇ ⁇ , ⁇ -dimethylformamide, or a halogen-based solvent such as 1,2-dichloroethane or 1,2-dichloroethane.
  • the compound (1Z) can be obtained by deprotection by a method known per se.
  • the compound (1) thus produced can be produced by a method known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, chromatography, or the like. Can be isolated and purified.
  • the starting compound (2) can be produced according to the following reaction formula. (a) Eich compound (2) where E is ethenylene and X and Y are both N.
  • RR 2 A , R 3 , R 4 , R 5 , AA 2 and Q are as defined above, and P 1 represents a protecting group.
  • Examples of the protecting group include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • a mixture of (13) (obtained in the same manner as in International Publication WO9909986 pl3 "15) and 1 equivalent to an excess amount of amine (14) is a hydrocarbon solvent such as benzene or toluene. , Dioxane, ether solvents such as tetrahydrofuran, In alcoholic solvents such as ethanol and isopropanol, and organic solvents such as ⁇ , ⁇ -dimethylformamide, bases such as triethylamine and ⁇ , ⁇ -diisopropylamine as required.
  • a hydrocarbon solvent such as benzene or toluene.
  • Dioxane ether solvents such as tetrahydrofuran
  • alcoholic solvents such as ethanol and isopropanol
  • organic solvents such as ⁇ , ⁇ -dimethylformamide
  • bases such as triethylamine and ⁇ , ⁇ -diisopropylamine as required.
  • the compound (2A) can be obtained.
  • the compound (1 3) and ⁇ Mi emissions (1 4) P 1 is tert- butoxide aryloxycarbonyl 1-2 equivalents in toluene solvent, Application Benefits Echirua Mi emissions (TEA) the presence, in 1 0 0 After reacting for 24 to 48 hours at 1130, it is preferable to carry out deprotection with hydrochloric acid.
  • R ′, R 2 A R 3 , RRA 1 , AQ and P 1 are as defined above.
  • the compound (19) can be obtained from the compound (19) by a known method (see JACS 70, 4065 (1948); JACS 70, 2402 (1948); JOC 12, 456 (1947)). To manufacture. Compound (19) and aldehyde (11) are reacted in a solvent such as acetic anhydride, acetic acid or trifluoroacetic acid at room temperature to the boiling point of the solvent used for 1 to 48 hours, preferably anhydrous. The compound (20) can be obtained by reacting at 80 ° C. to 100 ° C. for 5 to 24 hours in an acetic acid solvent. Aldehyde (1 1) is commercially available or can be produced by a known method.
  • a solvent such as acetic anhydride, acetic acid or trifluoroacetic acid
  • the compound (20) is used without solvent, or in a solvent such as toluene, xylene, 1,2-dichloroethane or the like at a temperature from room temperature to the boiling point of the solvent to be used.
  • the compound is obtained by reacting with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride for 124 hours at the temperature of the boiling point of the crosslinking agent.
  • (2 1) can be obtained.
  • tertiary amines such as dimethylaniline and triethylamine may be coexisted.
  • the compound (21) is reacted with 1 equivalent to an excess amount of the amine (14) as described in (a) above, and if necessary, deprotected by a method known per se. Thereby, compound (2B) can be obtained.
  • compound (21) and P 1 s-tert-butoxycarbonyl amide (14) 12 equivalents are added in toluene solvent in the presence of triethylamine at 100 ° C.
  • the reaction is carried out at 30 ° C for 244 hours, and the resulting compound (22) is preferably deprotected with trifluoroacetic acid in methylene chloride.
  • R 1 R 2 A R 3 R 4 RAAQ and P 1 are as defined above, and Ph represents phenyl.
  • Compound (24) can be produced from compound (23) according to a known method (J. Chem. Soc. Pei'kin Trans 1, 1990, 1770).
  • the compound (24) and 1 to 3 equivalents of selenium dioxide are added at room temperature in an ethereal solvent such as dioxane and tetrahydrofuran or an alcoholic solvent such as ethanol, i-sopronoxanol and the like.
  • the compound (25) is obtained by reacting at a temperature of the boiling point of the solvent to be used for several hours to several S, preferably in dioxane at 50 ° C. to 100 t for 5 to 48 hours. Can be done.
  • the compound (25) and the compound (26) or the compound (27) are treated with n-butyllithium, hydrogenated in a solvent that does not participate in the reaction, such as dioxane or tetrahydrofuran.
  • a solvent that does not participate in the reaction, such as dioxane or tetrahydrofuran.
  • a base such as sodium or sodium hexamyl disilazide, at a temperature of from 178 ° C to the boiling point of the solvent used, for several hours to several days, preferably tetrahydrofura.
  • the compound (28) can be obtained by reacting at 120 ° C to room temperature for 1 to 5 hours.
  • the compound (28) is reacted with a chlorinating agent such as phosphorus oxychloride or pentasalt ⁇ : lin for 1 to 24 hours to give the compound (29). And can be.
  • a chlorinating agent such as phosphorus oxychloride or pentasalt ⁇ : lin for 1 to 24 hours.
  • the compound (29) and 1 equivalent to an excess amount of the amine (14) are reacted as described in the above (a), and if necessary, a method known per se is used.
  • Compound (2C) can be obtained by deprotection.
  • R, R ⁇ R 2 A , R 3 , R 4 , R s , A 1 A 2 , Q and P 1 have the same meanings as described above.
  • X represents a hydroxy group or an amino group.
  • P 2 represents a hydrogen atom or a protecting group (for example, benzyl, 4-methoxybenzyl).
  • Compound (34) can be produced from compounds (31) and (32) according to a known method (see Japanese Patent No. 29233742).
  • the compound (3) can be obtained by reacting in the presence of 0 t at the temperature of the boiling point of the solvent to be used for several hours to several days, preferably in the presence of triethylamine at room temperature for 5 to 48 hours. 5) can be obtained.
  • the compound (35) and 1 equivalent to an excess amount of the amine (36) are optionally mixed in a boiling point solvent such as phenol or diphenyl ether, and then purified as necessary.
  • a boiling point solvent such as phenol or diphenyl ether
  • Min The ability to react for several hours to several days at room temperature to the boiling point of the solvent to be used in the presence of a base such as N, N-diisopropylpropylamine, or a hydrocarbon solvent such as benzene, toluene, xylene, or dioxane
  • Metal catalysts such as palladium acetate, and 2,2'-bis in ethereal solvents such as tetrahydrofuran and tetrahydrofuran
  • Compound (37) and one equivalent to an excess of acid chloride are combined with a hydrocarbon solvent such as benzene or rene, an ether solvent such as dioxane or tetrahydrofuran, methylene chloride, As necessary in the presence of a base such as triethylamine, ⁇ , ⁇ -diisopropylpropylamine or pyridin in a solvent such as 1,2-dichlorotan or chloroform.
  • ⁇ Compound (38) can be obtained by adding a catalyst such as dimethylaminopyridine and reacting at room temperature to the boiling point of the solvent to be used for several hours to several days.
  • the compound (38) can be deprotected by a method known per se to give the compound (2D).
  • reaction is carried out for 24 to 48 hours at room temperature using methylene chloride as a solvent and adding a catalytic amount of 4-dimethylaminopyridine in the presence of triethylamine.
  • methylene chloride as a solvent
  • a catalytic amount of 4-dimethylaminopyridine in the presence of triethylamine.
  • the acid chlorides are known or can be prepared by known methods.
  • Compound (41) can be produced from compound (39) according to a known method (see J0C 27, 4672 (1962)).
  • the compound (42) can be obtained by reacting the compound (41) with 1 equivalent to an excess amount of the amine (14) in the same manner as in the above (a). Above all, 1 to 2 equivalents of the compound (41) and the amide (14) in toluene solvent at 100 ° C to 1.30 ° C in the presence of triethylamine (TEA) It is preferable to carry out the reaction for 24 to 48 hours.
  • the compound (43) is obtained by hydrolyzing the compound (42) using a method known per se. Among them, it is preferable to react the compound (42) in ethanol in the presence of a 1N aqueous sodium hydroxide solution at room temperature to 60 ° C for 1 to 3 hours.
  • Compound (43) is converted to diphenyldiazinylazide (DPPA) in the presence of a base such as triethylamine or N ,,-diisopropylpropylamine in an alcohol solvent such as ethanol or benzyl alcohol.
  • DPPA diphenyldiazinylazide
  • the compound (44) can be obtained by reacting for several hours to several days at a temperature from room temperature to the boiling point of the solvent used. Among them, it is preferable to react the compound (43) in refluxing ethanol in the presence of triethylamine for 24 to 48 hours.
  • Compound (45) and one equivalent to an excess of acid chloride are combined with hydrocarbon solvents such as benzene and toluene, ether solvents such as dioxane and tetrahydrofuran, and methylene chloride.
  • hydrocarbon solvents such as benzene and toluene
  • ether solvents such as dioxane and tetrahydrofuran
  • methylene chloride in a halogen-based solvent such as 1,2-dichloroethane or the like, in the presence of a base such as triethylamine, ⁇ , ⁇ -diisopropylpropylamine or pyridine, 4-dimethylamine as necessary.
  • Compound (46) can be obtained by adding a catalyst such as nopyridine and reacting at room temperature to the boiling point of the solvent used for several hours to several days. Above all, it is preferable to use methylene chloride as a solvent, add a catalytic amount of 4-dimethylaminovin
  • Compound (46) can be produced by deprotecting compound (46) using a method known per se. If [rho 1 is tert- blanking bets butoxycarbonyl, in chloride main Ji Ren, at room temperature, collected by Li Furuoro arbitrary preferable that to 1-5 more hours the reaction of acetic acid. When P 1 is benzyloxycarbonyl, hydrogenation is preferably performed at room temperature and normal pressure in the presence of 5% palladium-carbon in methanol.
  • R 1 R 2 A , R 3 , R 4 , R 5 , A 1 , A 2 , Q and P 1 are as defined above.
  • the compound (200) can be produced according to a known method (such as Heterocycles 24, 2311 (1986)) from the compound (35).
  • the compound (2F) can be obtained by deprotecting the compound (200) using a method known per se.
  • Compound (210) can be produced from compound (43) according to a known amidation method. Further, the compound (2G) can be obtained by deprotecting the compound (210) using a method known per se. (h) When E is one of NRS 0 2 —, and X and Y are both N,
  • R, R 1 R 2 A , R 3 , R 4 , R 6 , AA 2 , Q and P 1 are as defined above.
  • Compound (220) can be produced from compound (45) according to a per se known sulfonamide formation method. Further, compound (2H) can be obtained by deprotecting compound (220) using a method known per se.
  • the compound (230) can be produced from the compound (45) by reacting it with an isocyanate by a method known per se. Further, the compound (231) can be obtained by deprotecting the compound (230) by a method known per se.
  • Hara I. danigaid (3) was prepared by a known method (J. Org. Chein. 34-616, 1969; Synthesis).
  • the starting compound (4) can be produced according to the following reaction formula.
  • the starting compound (4) can be produced by reacting the compound (100) as in the above-mentioned production method A.
  • This starting compound (100) can be produced by a commercially available method or by a method known per se.
  • the starting compound (120) can be produced according to the following reaction formula.
  • the amino group and the hydroxyl group are protected with a commonly used protecting group, if necessary, and subjected to the above reaction, followed by acid treatment, alkaline treatment, catalytic reduction, etc. at an appropriate stage.
  • the protecting group can be removed by a known method.
  • a protecting group for an amino group for example, benzyl, benzyloxycarbonyl, t-butoxycanoleboninole, and trifluoroacetyl can be used.
  • hydroxyl-protecting group examples include methoxymethyl, 2-methoxyethoxymethyl, methinolethiomethine, tetrahydro vinola, tert-butinole, benzinole, trimethylinole, Tert-butyl dimethyinole resin or the like can be used.
  • the salt of the compound (1) of the present invention can be produced by a method known per se.
  • the hydrochloride of the compound of the present invention (1) is prepared by treating the compound of the present invention (1) with an alcohol solution of hydrogen chloride or an ethyl ether solution, and collecting the precipitated crystals by filtration. Can be obtained by concentrating the precipitate to precipitate crystals, and then collecting by filtration.
  • the compound of the present invention represented by the formula (1) binds to a nociceptin receptor and exerts an agonist action or an antagonist action as shown in the test examples described below, so that analgesic action is obtained. It is useful as a drug, an anti-inflammatory drug, a diuretic, an anesthetic, an anti-hypertensive, an anxiolytic, an anti-obesity drug, a hearing control drug, an antidepressant, an anti-dementia drug, and a drug for overcoming narcotic analgesics.
  • the compound of the present invention When the compound of the present invention is administered as a medicament, the compound of the present invention is used as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5%. It is administered to mammals including humans as a pharmaceutical composition containing up to 90%.
  • one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries are used as the carrier.
  • the pharmaceutical compositions are desirably administered in unit dosage form. Since the compound of the present invention is soluble in water, it can be used not only as a solid preparation but also as a liquid preparation (eg, an injection for intravenous administration, an injectable bladder, or a syrup for oral administration).
  • the pharmaceutical composition may be administered in a braid, orally, It can be administered topically (such as transdermally) or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, oral or intravenous administration is preferred.
  • Intra-tissue administration can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular, intravesical or intravenous injection, for example, a solution or suspension. These are accomplished by suspending or dissolving a fixed amount of the compound in a non-toxic liquid vehicle suitable for injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. Manufactured. Alternatively, an aliquot of the compound may be placed in a vial and the vial and its contents then sterilized and sealed. Spare vials or carriers may be provided with the powdered or lyophilized active ingredient for dissolving or mixing immediately prior to administration. A non-toxic salt or salt solution may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination.
  • solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, suppositories It can be carried out depending on the preparation and other dosage forms.
  • Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance with a suitable fineness and then admixing it with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • Capsules are first powdered as described above, powdered, or granulated as described in the section on tablets, and the inside of a capsule shell such as a gelatin capsule, for example. It is manufactured by filling into. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered form The filling operation can be performed later.
  • Disintegrants and solubilizers such as carboxymethyl cellulose, carboxymethyl cellulose calcium, low-substituted hydroxypropyl pill cellulose, cross-force normelo-tridium, and canoleboxy starch sodium
  • the addition of calcium carbonate and sodium carbonate can improve the efficacy of the drug when the capsule is taken.
  • the fine powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and surfactant, and this can be wrapped in a gelatin sheet to make a soft capsule.
  • Tablets are produced by preparing a powder mixture, granulating or slugging, adding a disintegrant or a lubricant, and tableting.
  • the powder mixture is made by mixing the appropriately powdered material with the above-mentioned diluents and bases and, if necessary, binding agents (e.g. sodium carboxymethylcellulose, hydroxypropinoresenolerose, mesylate).
  • the powder mixture can be first wetted with a binder, for example, syrup, starch paste, arabian gum, cellulose solution or polymer solution, and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first crush the powder in a tableting machine and then crush the imperfect form of the obtained slag to form granules.
  • a binder for example, syrup, starch paste, arabian gum, cellulose solution or polymer solution
  • the granules thus produced adhere to one another by adding stearic acid, stearic acid salts, talc, mineral oil and other lubricants. Can be prevented. A mixture lubricated in this way is Then tablet.
  • the uncoated tablets thus produced can be coated with a film coating or sugar coating.
  • the drug may be directly tableted after being mixed with a fluid inert carrier without going through the steps of granulation and slagging as described above.
  • Transparent or translucent protective coatings consisting of sealing shells, coatings of sugar or polymeric materials, and waxy topcoats may also be used.
  • oral dosage forms such as solutions, syrups and elixirs can also be in dosage unit form so that a given quantity contains a certain amount of the drug.
  • Syrup is made by dissolving the compound in an appropriate aqueous flavor solution
  • elixir is made by using a non-toxic alcoholic carrier. It is prescribed by dispersing in it.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives eg, palmit oil, saccharin
  • flavor enhancers eg, palmit oil, saccharin
  • dosage unit formulations for oral administration can be micro-encapsulated.
  • the formulation can also provide an extended duration of action or sustained release by coating or embedding in a polymer 'wax or the like. .
  • suppositories containing the compound soluble or insoluble in low-melting water such as polyethylene glycol, cocoa butter, higher esters (eg myristyl palmitate), and mixtures thereof This can be done by using.
  • Low-melting water such as polyethylene glycol, cocoa butter, higher esters (eg myristyl palmitate), and mixtures thereof
  • triphenylphosphine was added to a solution of 500 mg of (1R, 2R) -N-tert-butoxycarbonyl-2-2-hydroxycyclohexylamine in 20 ml of anhydrous tetrahydrofuran.
  • 6-Amino-l-hexanol 5.1 g was added to a 100 ml solution of honolem.
  • Di-tert-butyl-carbonate 10.4 g was added dropwise to the solution, and the mixture was stirred for 12:00.
  • the reaction solution was concentrated, and the residue was washed with n-hexane to obtain 9.40 g of the desired compound as white crystals.
  • Cis-one _jt-one tri-funole ⁇ b acetylinorea
  • Cis 4 Amino octyl carboxylate methyl ester hydrochloride 2.64 g in a 30 ml solution of black mouth form, 1.52 g of triethylamine, and 3.27 g of G-tert-butyl-G carbonate was added dropwise. Three hours later, water was added to the reaction solution, and the mixture was extracted with a mouth-mouth form and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform) to obtain 3.62 g of the desired compound.
  • Cis-1 4 tri-Finoleoloacetinorea Mino-methyl hexinoleminin cis-1 N— (tert-butoxycanoleboninole) 1-4 — Tri-Finoleoloacetinorea mino methinoresic To the mouth To a solution of 0.53 g of xylamine in methylene chloride was added 2 ml of trifluoroacetic acid, and the mixture was stirred for 2 hours. A saturated sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline, and the mixture was extracted with a black hole form. After drying over sodium sulfate, the mixture was concentrated to give 0.19 g of the desired compound as a pale yellow oil.
  • Cis-1 2 Trifluoroacetinorea Minomethyltinoxycyclohexylamine Reference Example 5
  • Cis-1-N-amidino-1 2 “2— (4—chlorostyrene) 1 6—methoxyquinazoline 1 4—yl] aminocyclohexylamine dihydrochloride Process 1
  • Cis-1-N “N., N'-bis (ter-butoxycanolebonyl)] amidino 2— [2- (4-chlorostyrene) 1-6-methoxyquinazoline 1-4 Amino cyclohexinorea min.
  • 5 ml of a 4N hydrogen chloride acetate solution was added, and the mixture was reacted at 50 ° C. for 48 hours. . After concentration, the residue was crystallized from ethyl acetate to obtain 310 mg of the desired compound as pale yellow crystals.
  • Cis-1-N-ter butoxycanoleponinole 2 [2— (4—black benzoinolenomine) 1 6—methoxyquinazoline 1 4-yl] to amino
  • Cis-1 2-[2-(41-Mouth Benzoy Nore Amino) 16-Methoxyquinazoline 14-Inno] Amino Cyclohexinoleamine 80mg of Dichloroethane To 5 ml and 1 ml of ⁇ , ⁇ -dimethylformamide, 58 mg of ⁇ , ⁇ '-bis (tert-butoxycanolevonyl) -11H-pyrazole-1 monopotent norboxiamidine was added and stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was further washed with water and a saturated saline solution, and dried with magnesium sulfate. After concentration, the residue was purified by silica gel chromato-daraphy (clo-form: methanol: 30: 1) to obtain 120 mg of the desired compound.
  • Cis-1 4-trifluoroacetylaminomethyl ⁇ — ⁇ 2- (2- (2-pyridyl) ether) 1-16-methoxyquinazoline 1-4-cyclohexylamine
  • Cis-1 4 trifnorelolo acetinolea minometinoreschi hexinoreamin 140 ml of a 15 ml solution of tomerene in a 40 ml solution of 4-merone 16 — methoxy 2 — [2 — (2 — (2 — — pyridyl) ethenyl) quinazo 180 mg of phosphorus, 500 mg of triethynoleamine and 20 mg of 4-dimethylaminopyridine were added, and the mixture was heated under reflux for 15 hours.
  • methanol 45 ml
  • water 5 ml
  • Cis-1-4 guanidinomethyl-1N— ⁇ 2- (2— (2—pyridyl) ethenyl 1-6—methoxyquinazoline 1-4—inole) cyclohexylamine trihydrochloride
  • Cis- 1-amino-methyl N- ⁇ 2- (2— (2—pyridyl) etheninole) — 6 — methoxyquinazoline 1—4—inole ⁇ Add 150 mg of N, N ' ⁇ bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxyamidine to 15 ml of 120 mg of dichloroethane and 3 ml of ⁇ , ⁇ -dimethylformamide. The mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was further washed with water and saturated saline, and dried over magnesium sulfate.
  • Example 2 In the same manner as in Example 1, the following compounds of Examples 6 to 48, 52 to 59, 61 and 64 to 68 were produced.
  • Motosaku analysis value (as a C 20 H 21 C1N 6 '2HC There H 2 0)
  • Motosaku analysis value (as a C 2 4 H 2 7 C1N 6 '2HC1'H 2 0)
  • Cis-1 N-amidino 1 2 “2— (4-chlorostyrene) 1 6.7—d Tylquinazoline 1-4yl 1 Aminocyclohexylamine dihydrochloride Positive ion FAB— MS m / z: 449 [M + H] +
  • Cis-1-N-amidino-1 3 “2- (4-chlorostyrene) 1-6—methinolequinazoline—41-yl] aminocyclohexylamine dihydrochloride
  • Cis-1-N-amidino 2 [2— (4—chlorostyrene) 1 6—isop u_pyrquinazoline 1-4—yl 1 aminocyclohexylamine dihydrochloride Positive ion FAB—MS m / z: 4 6 4 [M + H] +
  • Cis-1-N-amidino1-2-C2- (4-chlorostyrene) -4-6-ethoxyquinazoline-4-yl] aminocyclohexylamine dihydrochloride Light yellow powder
  • Example 3 7 (1 R, 2 S)-N-Amidino 2-C 2-(4-Chlorostyrenol) 1-6-Methoxyquinazoline 1-4-yl] Aminocyclopentylamine Disalt Acid salt
  • Example 4 cis-N-amidino 2-(6-methoxy-2-(2-pyridyl) ethenyl] quinazoline-1-innole ⁇ Min trihydrochloride
  • Cis-N-amidino-2 [6—Methoxy-1- (2-methoxystyryl) quinazoline-14-yl-1aminocyclohexacycline dihydrochloride cation FAB — MS m / z: 4 4 7 [M + H] +
  • Motosaku analysis value (as a C 2 4 H 3 N 7 0-3HCM.5H 2 0) '
  • Cis-1 N-amidino 1 2 “2— (4-chlorostyrene) 1 6-methylinoquinoline 4-inole] aminocyclinehexylamin dihydrochloride
  • Cis-1-N-amidino 2 “2— (4-chlorostyrene) 1 6—methoxyquinoline 14-yl 1-aminocyclohexylamin dihydrochloride
  • N-Amidino 4 ⁇ 6-Methyl-2— [2- (2—pyridyl) ethyl] quinazoline-1 4-inole ⁇ aminomethyl-benzylamine trihydrochloride Properties: White Powder
  • Example 60 In the same manner as in Example 60, the following compounds of Example 62 and Example 63 were produced.
  • 2,4-Dichloro mouth 6-Methoxyquinazoline 710 mg of triethylamine in a 20 ml solution of methylene chloride 471 mg and (IS, 2R) -2—tert'butoxycarbonylaminoaminohexylamine 750 mg was added and the mixture was stirred at room temperature for 48 hours. After concentration, water was added, and the mixture was extracted with methylene chloride and dried. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform: methanol 20: 1) to obtain 1.20 g of the desired compound.
  • Example 70 The following compound of Example 70 was produced in the same manner as in Example 69.
  • the cell membrane suspension obtained from the cells expressing the human cytoseptin was treated with Tris buffer [50 mM Tris-HCl (pH 7.8), 5 mM MgCl 2 , ImM EGTA, 0.1% BSA] to reduce the membrane protein amount to 5%. It was adjusted to be about 10 ⁇ g / ml. This was mixed with [3H] nociceptin (diluted to a final concentration of 0.08 nM in Tris buffer) and the test substance, and incubated at 25 ° C for 60 minutes.
  • Tris buffer 50 mM Tris-HCl (pH 7.8), 5 mM MgCl 2 , ImM EGTA, 0.1% BSA] to reduce the membrane protein amount to 5%. It was adjusted to be about 10 ⁇ g / ml. This was mixed with [3H] nociceptin (diluted to a final concentration of 0.08 nM in Tris buffer) and the test substance, and incubated at 25 ° C for 60 minutes.
  • Test example 2 receptor binding experiment
  • the filter was transferred to a vial, a scintillator was added, and the radioactivity was measured using a liquid scintillation counter.
  • the non-specific binding was defined as binding in the presence of M-naloxone, and the difference between total binding and non-specific binding was defined as specific binding.
  • the IC 60 value was determined from the binding inhibition rate in the presence of the test substance, and the Ki value of the test substance was calculated from the IC 60 value and the Kd value of [ 3 H] diprenorphin. Table 2 shows the results.
  • Test example 3 Mouse acetate riding test
  • mice Male mice (Slc: ddY, 4 to 5 weeks old) were used in 10 cases per group. Under anesthesia, incision was made on the back skin of the mouse about 3 cm laterally, and after habituation for 30 minutes or more, the 27G needle attached to the tip of the silicon tube connected to the micro syringe was used. It was inserted near L3-L4, and the drug solution was injected into the spinal subarachnoid space with 51 injections. The test drug was dissolved in physiological saline and administered at 10 nmol / animal. Physiological saline was similarly administered as a control.
  • mice fasted from the day before the experiment were placed in observation cages (20 ⁇ 20 ⁇ 15 cm), acclimated for 30 minutes or more, and then 0.6% acetic acid solution was injected intraperitoneally with a 100 ⁇ l / 27G injection needle per 10 g body weight.
  • the data obtained are shown as the standard error of the mean.
  • a significant difference test was performed using the t-test for two groups between the control group and the test substance-administered substance, and for multiple groups—by one-way ANOVA followed by Dunnett's multiple comparison. When P ⁇ 0.05, it was determined that there was a significant difference.
  • Table 3 The results are shown in Table 3.
  • the compound of the present invention showed a significant reduction in the number of writhing times and an analgesic effect.
  • Example 70 Fluid bed granulation drying of 100 g of the compound of Example 100, 292 g of D-mannitol, 120 g of corn starch, and 28 g of hydroxypropyl cellulose having a low degree of substitution And a predetermined amount of 5% aqueous hydroxypropylcellulose is sprayed and granulated. After drying, crushing ⁇ The particles are sized using a sizing machine (Cominore; NOREC), and mixed with a predetermined amount of magnesium stearate in a mixing machine (Bore Re-Container Mixer MC20; Kotopuki Giken). Then, it is formed into 7 mm diameter, 140 mg Z tablets using a rotary tableting machine (Collect 12 HUK; Kikusui) to obtain a disintegrant containing 25 mg of this drug.
  • a sizing machine Cominore; NOREC
  • MC20 mixing machine
  • Kotopuki Giken Kotopuki Giken
  • the compound of the present invention has an excellent nociceptin receptor binding action, It can be safely used for a long period of time as a therapeutic agent for painful diseases such as pain, migraine, chronic rheumatism, neuralgia, or a drug for overcoming resistance with morphine.

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002036577A1 (fr) * 2000-11-02 2002-05-10 Nippon Shinyaku Co., Ltd. Derives quinazoline et medicaments
WO2002074341A1 (fr) * 2001-03-19 2002-09-26 Nippon Shinyaku Co., Ltd. Antiprurigineux
WO2003091224A1 (fr) 2002-04-26 2003-11-06 Nippon Shinyaku Co., Ltd. Derive et medicament de quinazoline
WO2007040231A1 (ja) * 2005-10-03 2007-04-12 Nippon Shinyaku Co., Ltd. キナゾリン誘導体及び医薬
RU2314295C2 (ru) * 2006-03-01 2008-01-10 Федеральное Государственное Образовательное Учреждение Высшего Профессионального Образования "Южный Федеральный Университет" 2-гетарилзамещенные 1,3-трополона, способ их получения (варианты) и фармацевтическая композиция антимикробного действия
JP2008044960A (ja) * 2002-12-16 2008-02-28 Kissei Pharmaceut Co Ltd 経口固形医薬
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
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US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors

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EP2017294A1 (de) 2007-07-16 2009-01-21 Sika Technology AG Hitzehärtender Schaum
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US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
JP4803181B2 (ja) * 2005-10-03 2011-10-26 日本新薬株式会社 キナゾリン誘導体及び医薬
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US8357694B2 (en) 2008-12-30 2013-01-22 Arqule, Inc. Substituted 5,6-dihydro-6-phenylbenzo[F]isoquinolin-2-amine compounds
US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors

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CN1242993C (zh) 2006-02-22
ATE449084T1 (de) 2009-12-15
US20030119855A1 (en) 2003-06-26
CN1422255A (zh) 2003-06-04
EP1306372A1 (en) 2003-05-02
US6794389B2 (en) 2004-09-21
EP1306372B1 (en) 2009-11-18
KR20020083533A (ko) 2002-11-02
DE60140545D1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2009-12-31
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CA2403605A1 (en) 2002-09-18
RU2002129100A (ru) 2004-02-27
AU2001244688A1 (en) 2001-10-08

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