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WO2004080965A1 - Antagoniste du recepteur du neuropeptide ff - Google Patents

Antagoniste du recepteur du neuropeptide ff Download PDF

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Publication number
WO2004080965A1
WO2004080965A1 PCT/JP2004/003273 JP2004003273W WO2004080965A1 WO 2004080965 A1 WO2004080965 A1 WO 2004080965A1 JP 2004003273 W JP2004003273 W JP 2004003273W WO 2004080965 A1 WO2004080965 A1 WO 2004080965A1
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Prior art keywords
substituted
unsubstituted
acceptable salt
indole derivative
compound
Prior art date
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Ceased
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PCT/JP2004/003273
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English (en)
Japanese (ja)
Inventor
Naoto Osakada
Katsumi Shinoda
Shunji Kunori
Tomomi Shirai
Shinichiro Toki
Shunji Ichikawa
Nobuo Kosaka
Michio Ichimura
Junichi Shimada
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KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
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Priority to JP2005503594A priority Critical patent/JPWO2004080965A1/ja
Publication of WO2004080965A1 publication Critical patent/WO2004080965A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • Neuropeptide FF receptor antagonist N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe FF receptor antagonist
  • the present invention relates to a neuropeptide FF receptor antagonist containing an indole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • Neurobeptide FF (hereinafter abbreviated as NPFF) is an index of the reactivity to the antibody to FMRF-amide (Fenilalanine-Methionine-Arginine-Fenalalanine-Amide), which is a molluscan neuropeptide.
  • FMRF-amide Feenilalanine-Methionine-Arginine-Fenalalanine-Amide
  • a peptide consisting of eight amino acids isolated and identified from cerebral brain [ Procedings of National Academy of Sciences-USA ( Proc . Natl. Acad. Sci. USA), 1985] Year 82, p.7757]. ⁇ acts on an NPFF receptor distinct from the Obioid receptor [Peptides, 1889, Vol. 19, p.727] and is involved in the sensory system, especially pain and morphine analgesia [Eur. J.
  • Intraventricular administration of NPFF has been reported to cause hyperalgesia, antagonism of morphine analgesia, and enhance the symptoms of withdrawal syndrome in animals that have developed morphine tolerance [Proceedings National Academy of Ops' Science USA (Proc. Natl. Acad. Sci. USA) ⁇ 1985, Vol. 82, p. 7757; Peptides ⁇ 1993, Vol. 14, p. 77 919].
  • intraventricular administration of anti-NPFF antibody enhances morphine analgesia and reduces withdrawal syndrome symptoms in morphine-resistant animals [Peptides ), 198.9, Vol. 10, p.
  • NPFF1 and NPIT2 Two types of G-protein coupled receptors (GPCRs), NPFF1 and NPIT2, are known as NPFF receptors [WO00 / 31107; W000 / 18438; Journal of Biological 'Chemistry (J. Biol. Chem. 2000, Vol. 275, p. 25965; Journal- Bob Biological 'Chemistry, 2000, Vol. 275, p.39324]. Since these NPFF receptors are expressed in the dorsal horn, lateral hypothalamus, spinal trigeminal nucleus, thalamic nuclei and other sites related to the control of nociception, NPFF is also involved in the control of nociception. The possibilities are shown. ,
  • ⁇ A substance that specifically inhibits the binding of NPFF to its receptor is an analgesic, a hyperalgesic drug for neuropathic pain, a drug for treating hyperalgesia, and a drug that overcomes resistance to narcotic analgesics such as morphine It is considered to be useful as a drug for overcoming dependence on narcotic analgesics represented by morphine, an analgesic enhancer, and the like.
  • NPFF receptors such as NPFF1 receptor or NPFF2 receptor
  • NPFF1 receptor or NPFF2 receptor include peptide derivatives [W093 / 06841; Journal of Medicinal Chemistry (J. Med. Chem. 2001, Vol. 44, p. 1623], arginine derivative BIBP3226
  • indole derivatives represented by the following general formula (I) include fatty acid synthase inhibitors (W002 / 00646), cannabinoid receptor function modulators and respiratory and non-respiratory diseases (W001 / 58869), therapeutic agent for osteoporosis [W097 / 03965; JP-A-2000-256286; J. Heterocycl. Chein.), 2000, Vol. 37, p.
  • N C phospholipase A2 inhibitor (W098 / 08818), detergents (W097 / 48786), neurological and neuropsychiatric disorders therapeutic agent (W097 / 45U5), neuropeptide Y receptor antagonists
  • An object of the present invention is to provide an indole derivative or a pharmacologically acceptable salt thereof as an active ingredient, and various diseases derived from NPFF receptor hyperactivity (eg, hyperalgesia at the time of neuropathic pain, arodinia,
  • An object of the present invention is to provide a receptor antagonist useful for the treatment and Z or prevention of resistance to a narcotic analgesic represented by morphine (dependence on a narcotic analgesic represented by morphine).
  • an object of the present invention is to provide a novel indole derivative having the above-mentioned characteristics or a pharmacologically acceptable salt thereof.
  • the present invention relates to the following (1) to (52).
  • R 1 is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aromatic heterocyclic oxy or -im ⁇ ⁇ ⁇ s "
  • R 5 and R 6 are the same or different and are hydrogen or
  • E 7 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted aliphatic alkyl, amino, substituted or unsubstituted monoalkyl; Or di-lower alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic heterocyclic group, and k is 0 to 6 (provided that R 7 There through a nitrogen atom in R 7 (C3 ⁇ 4) 3 ⁇ 4 and one time of binding represents a] represents an integer of 2-6), or R 5 and together such connection replaced with the nitrogen atom to which R 6 is adjacent Or which forms an unsubstituted alicyclic heterocyclic group,
  • ⁇ 8 is hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted Lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, amino, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted Represents mono- or diarylamino or substituted or unsubstituted mono- or di-aromatic heterocyclic amino, and m represents an integer of 0 to 6), or
  • ⁇ represents hydrogen or hydroxy, the R 1Q and R u same or different, hydrogen, a substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, and the properly substituted unsubstituted lower alkynyl
  • R 3 represents hydrogen, halogen, nitro, cyano, hydroxy, substituted or unsubstituted lower alkoxy, amino or substituted or unsubstituted mono- or di-lower alkylamino;
  • B 4 is hydrogen or
  • R 1 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, Amino, substituted or unsubstituted mono or di-lower alkylamino, substituted or unsubstituted mono or diarylamino, substituted or unsubstituted aromatic heterodioxy, substituted or unsubstituted mono or diaromatic heterocyclic amino ,
  • E 8 is as defined above.
  • the neuropeptide FF receptor antagonist c according to (1) or (2),
  • R 1A is -NR 5A R 6A (wherein R 5A and R 6A are the same or different and represent hydrogen or an alicyclic alkyl having 3 to 7 carbon atoms, or R 5A and R 6A Forms a substituted or unsubstituted alicyclic heterocyclic group together with an adjacent nitrogen atom), q represents 3 or 4, and R 3A has the same meaning as R 3 above. Indole derivatives or pharmacologically acceptable salts thereof.
  • R 5C represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic alkyl
  • R lffi represents a substituted or unsubstituted aromatic heterocyclic group, and has the same meaning as R 3 above.
  • ⁇ 5 ⁇ represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic argyl
  • ⁇ 1 9 ⁇ represents hydrogen or hydroxy
  • R 1QD represents hydrogen, or ⁇ and 8 ⁇ come together to represent oxo
  • ⁇ ⁇ represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted alicyclic alkyl or a substituted or unsubstituted aryl,
  • r represents an integer of 2 to 6
  • l m and 15D are the same or different and represent a substituted or unsubstituted lower alkyl, or and and ⁇ are combined with an adjacent nitrogen atom to form a substituted or unsubstituted alicyclic heterocyclic group ) Or a pharmacologically acceptable salt thereof.
  • E 2E represents a substituted or unsubstituted aryl
  • R 5E represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic alkyl
  • R 3E has the same meaning as described above
  • s represents an integer of 2 to 6
  • R 14E and R i5E are the same or different and are substituted or unsubstituted.
  • a medicament comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (6) to (12) as an active ingredient.
  • a neurobeptide FF receptor antagonist comprising, as an active ingredient, the indole derivative or the pharmacologically acceptable salt thereof according to any of (6) to (12).
  • a therapeutic and / or prophylactic agent for neuropathic pain comprising, as an active ingredient, the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a drug for overcoming a narcotic analgesic resistance comprising as an active ingredient the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • An analgesic enhancer for an analgesic comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) as an active ingredient.
  • a therapeutic and / or preventive agent for neuropathic pain comprising as an active ingredient the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12).
  • An analgesic comprising the indole derivative according to any one of (6) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a drug for overcoming a narcotic analgesic resistance comprising as an active ingredient the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12).
  • An analgesic potentiator comprising an indole derivative or a pharmaceutically acceptable salt thereof according to any of (6) to (12) as an active ingredient.
  • a drug for overcoming a narcotic analgesic dependence comprising as an active ingredient the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a drug for overcoming a narcotic analgesic dependence comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (6) to (12) as an active ingredient.
  • An analgesic method comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a method for overcoming the resistance to a narcotic analgesic comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a method for enhancing an analgesic action of an analgesic comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a method for overcoming the dependence of a narcotic analgesic comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).
  • a method for treating and / or preventing neuropathic pain comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any of (6) to (12). Law.
  • An analgesic method comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12).
  • a method for overcoming narcotic analgesic resistance comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12).
  • a method for overcoming the dependence of a narcotic analgesic comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12).
  • the lower alkyl moiety of the lower alkyl, lower alkoxy and mono- or di-lower alkylamino includes, for example, linear or branched alkyl having 1 to 6 carbon atoms, and more specifically, methyl, ethyl, Propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • the two lower alkyl moieties in the di-lower alkylamino may be the same or different.
  • Examples of the lower alkenyl include straight-chain or branched alkenyl having 2 to 6 carbon atoms, and more specifically, vinyl, aryl, 1-propenyl, methacryl, crotyl, -Butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl and the like.
  • Examples of the lower alkynyl include straight-chain or branched alkynyl having 2 to 6 carbon atoms, and more specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • Examples of the alicyclic alkyl include cycloalkyl having 3 to L0 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Is raised.
  • Aryl, aryloxy, monoarylamino and the aryl portion of mono- or diarylamino include, for example, aryl having 6 to 14 carbon atoms, more specifically phenyl, naphthyl, And anthryl.
  • the two reel parts in a journal may be the same or different.
  • aromatic heterocyclic group aromatic heterocyclic oxy, monoaromatic heterocyclic amino and
  • aromatic heterocyclic group moiety of the diaromatic heteroamino is, for example, a 5- or 6-membered monocyclic aromatic containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • the two aromatic heterocyclic groups in the diaromatic heterocyclic amino may be the same or different.
  • Examples of the alicyclic heterocyclic group include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least ⁇ atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, 3 to 8 And a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is condensed with a two-membered ring.
  • the alicyclic heterocyclic group formed together with an adjacent nitrogen atom includes, for example, a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one nitrogen atom (The monocyclic alicyclic heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom), and at least one bicyclic or tricyclic fused 3- to 8-membered ring.
  • a condensed alicyclic heterocyclic group containing a nitrogen atom may contain another nitrogen atom, an oxygen atom or a sulfur atom
  • the condensed alicyclic heterocyclic group may contain another nitrogen atom, an oxygen atom or a sulfur atom
  • Specific examples include pyrrolidinyl, piperidino, piperazinyl, imidazolidinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetravidolinyl and the like.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • Substituents in substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted alicyclic alkyl, substituted lower alkoxy and substituted mono- or di-lower alkylamino are, for example, the same or different and may have 1 to 3 substituents.
  • Halogen hydroxy, oxo, cyano, nitro, substituted or unsubstituted lower alkoxy, amino, substituted or unsubstituted mono- or di-lower alkylamino (substituent in the substituted mono- or di-lower alkylamino), Or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted monoarylamino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic Heterocyclic amino, substituted or unsubstituted alicyclic compound Ring group, and the like.
  • aromatic heterocyclic amino and alicyclic heterocyclic groups are as defined above.
  • examples of the substituent in the substituted lower alkoxy, the substituted mono- or di-lower alkylamino and the substituted alicyclic heterocyclic group may be the same or different and have 1 to 3 substituents such as halogen, hydroxy, oxo, nitro, Cyan, lower alkoxy, amino, mono- or di-lower alkylamino, aryl, alicyclic heterocyclic group, aromatic heterocyclic group and the like, wherein the lower alkyl moiety of halogen, lower alkoxy and mono- or di-lower alkylamino , Aryl, an alicyclic heterocyclic group and an aromatic heterocyclic group are as defined above.
  • the substituents in the substituted aryl, the substituted aryloxy, the substituted monoarylamino, the substituted aromatic heterocyclic group, the substituted aromatic heteropropyl and the substituted aromatic heteroamino are, for example, the same or different.
  • the halogen, the lower alkyl, the lower alkoxy, the lower alkyl portion of the mono- or di-lower alkylamino, the lower alkenyl, the lower alkynyl, the alicyclic alkyl, the aryl, the arylyl and the aryl of the monoarylamino are particularly preferable.
  • the aromatic heterocyclic groups have the same meanings as described above, respectively.
  • Substituents in mono- or di-lower alkanoylamino, substituted lower-alkoxycarbonyl, substituted mono- or di-lower-alkyl rubamoyl and substituted mono- or di-lower-alkyl lower rubamoyloxy are, for example, the same or different and may have 1 to 3 substituents.
  • substituent in the substituted aryloxy and the substituted arylylamino include, for example, the same or different halogen having 1 to 3 substituents, hydroxy, nitro, cyano, lower alkyl, lower alkenyl, lower alkynyl, alicyclic alkyl, lower alkoxy, amino, Mono- or di-lower alkylamino, aryl, aromatic heterocyclic group, etc., wherein halogen, lower alkyl, lower alkoxy and lower alkyl part of mono- or di-lower alkylamino, lower alkenyl, lower alkynyl, alicyclic Alkyl
  • the pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate and the like.
  • Organic acid salts, and pharmacologically acceptable metal salts include sodium salt, potassium salt and the like.
  • pharmacologically acceptable ammonium salts include ammonium, tetramethylammonium, etc.
  • the pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine.
  • the pharmacologically acceptable amino acid addition salts include glycine and phenine. Additional salts such as dilualanine, lysine, aspartic acid, and glutamic acid are included. -Next, methods for producing compounds (1), (IA), (IB), (IC), (ID) and (IE) will be described.
  • Compound (I) can be produced, for example, by the following method.
  • I and R 31 are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aromatic complex.
  • R 31 and R 31 together with the adjacent nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic group, wherein the substituted or unsubstituted lower alkyl, substituted or unsubstituted A substituted aryl, a substituted or unsubstituted aromatic heterocyclic group and a substituted or unsubstituted alicyclic heterocyclic group formed together with an adjacent nitrogen atom are as defined above.)
  • a compound (IC) can be produced by the following steps.
  • R ⁇ R 3 , R 12 , R 30 s R 31 and p are as defined above, and X, X 1 and X 2 are the same or different and represent chlorine, bromine or iodine)
  • Compound (IB) can be produced by the method described in W097 / 03965 or a method analogous thereto. That is, of compound (I), compound (IA) in which R 4 is hydrogen and ⁇ 5 equivalents, preferably 1-2 equivalents of compound (a), are mixed with 2-10 equivalents, preferably 3 equivalents. By reacting in the presence of up to 4 equivalents of an appropriate base in a solvent or in a solvent inert to the reaction, usually at a temperature between -10 ° C and the boiling point of the solvent to be used, for 5 minutes to 24 hours, the compound ( I-B) can be manufactured.
  • Suitable bases used include, for example, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydroxide Barium, calcium hydroxide, sodium acetate, 1, limethylamine, triethylamine, triptylamine, diisopropyl: t-tylamine, N-methylmorpholine, 1,8-diazabicyclo mouth [5.4.0] -7-pandecene, pyridine, etc. Among them, a hydroxylating rim is preferred.
  • Solvents inert to the reaction include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol, acetonitrile, nitromethane, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, Propyl acetate, Jethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, Toluene, xylene, double-ended benzene, HI,, a-Trifluorotonoleene, pen, hexane, heptane, cyclohexane, N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide , ⁇ -methylpyrrolidone, ⁇ , ⁇
  • the starting compound ( ⁇ - ⁇ ) can be obtained as a commercial product, or can be obtained from the literature [Organic Reactions, Vol. 10, p. 153, JHON ILEY & SONS, Inc.] THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, Volume 25, Part 1, page 232, JHON WILEY & SONS, Inc .; Journal O J. Am. Chem. Soc., 1945, Vol. 67, p. 423; Journal of Medicinal, J. Med. Chem., 1974 , Vol. 17, p. 1298; Journal Off "Medical 'Chemistry (J. Med. Chem.), 1989, Vol. 32, p. 1681; Chemical and Pharmaceutical Brain ( Chem. Pharm. Bull.), 1973, Vol. 21, p. 1481; Naru-O Bed Heterocyclic. Chemistry (j. Heterocycl. Chem.), Can be 2000, Vol. 37, obtained according methods or those described in p.1103 like.
  • Compound (IA) is reacted with 1 to 5 equivalents, preferably 1 to 2 equivalents of compound (b) in the presence of 2 to 10 equivalents, preferably 3 to 4 equivalents of a suitable base, without solvent or in a reaction.
  • the compound (c) can be produced by reacting in an inert solvent at a temperature usually between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 24 hours.
  • Suitable bases to be used are, for example, sodium hydrogen carbonate, hydrogen bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, hydroxylase, hydroxide Sodium, barium hydroxide, calcium hydroxide, sodium acetate, trimethylamine, triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-dendecene, pyridine, etc.
  • potassium hydroxide is preferable.
  • Solvents inert to the reaction include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, Butanol, acetonitrile, nitromethane, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, propyl acetate, getyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, dichloromethane, 1,2-dichloroethane, Benzene, Toluene, Xylene, Nitrobenzene, Hi, Hi, Hi-Trifluorotoluene, Pentane, Hexane, Heptane, Cyclohexane, ⁇ , ⁇ -Dimethylformamide, ⁇ , ⁇ -Dimethylacetamide, ⁇ -Methylpyrrolidone, ⁇ ,
  • the compound (c) obtained in the above step 2 is mixed with 1 to 50 equivalents, preferably 6 to 8 equivalents of the compound (d), in a solvent free or in a solvent inert to the reaction, usually from 0 ° C.
  • the compound (IC) can be produced by reacting at a temperature between the boiling points for 5 minutes to 24 hours. At this time, 2 to 50 equivalents, preferably 2 to 10 equivalents of a suitable base may be present.
  • reaction-inert solvents examples include water, methanol, ethanol, propanol, isopropyl alcohol, butyl alcohol, acetonitrile, nitromethane, methyl acetate, ethyl acetate, propyl acetate, getyl ether, and diisopropyl ether.
  • Suitable bases include, for example, sodium bicarbonate, hydrogen bicarbonate, carbon dioxide, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, hydroxylase, Sodium hydroxide, barium hydroxide, calcium hydroxide, sodium acetate, trimethylamine, triethylamine, triptylamine, diisopropylethylamine, n-methylmorpholine, 1,8-diazabicyclo [5.4.0]-7-
  • R 32 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted alicyclic, each as defined above.
  • Alkyl which represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
  • R 32 has the same meaning as described above, and R 33 has the same meaning as the above, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted
  • the compound (IH) which is an alicyclic alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group) can be produced by the following steps.
  • Compound (I-E) was used as a commercial product or using compound (ID) obtained by the method described in Production Method 1 or a method analogous thereto, and was described in the literature [Chemical and 'Pharmaceutical' Bretane (Chem. Pharm. Bull), 1985, Vol. 33, p. 4707] or a method analogous thereto. That is, the compound (ID) is reacted with 1 to 5 equivalents of the compound (e) in the presence of 1 to 5 equivalents of trifluoroacetic anhydride and 1 equivalent of a suitable acid from a catalytic amount without using a solvent or being inert to the reaction.
  • the compound (IE) can be produced by reacting in a solvent at a temperature usually between ⁇ 10 ° C.
  • Suitable acids to be used include, for example, polyphosphoric acid, phosphoric acid and the like.
  • the solvent inert to the reaction include acetonitrile, nitromethane, methyl ethyl ketone, methyl acetate, ethyl acetate, propyl acetate, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, and chloroform.
  • the compound (IF) is described in the literature [Journal of Heterocyclism, Chemistry (J. Heterocycl. Chem.) S 2000, Vol. 37, 1103; Laboratory Chemistry 26, Maruzen, .185] It can be manufactured by a method or according to them. That is, the compound obtained in step 4 above
  • (I-E) is used in a solvent such as 5 to 100 equivalents, preferably 20 to 30 equivalents of trifluoroacetic acid, usually at -10 ° C in the presence of 2 to 5 equivalents of a silicon compound or a boron compound. Treatment at a temperature between the boiling points of the solvents for 5 minutes to 24 hours (Compound (IF) can be produced therefrom.
  • a solvent such as 5 to 100 equivalents, preferably 20 to 30 equivalents of trifluoroacetic acid, usually at -10 ° C in the presence of 2 to 5 equivalents of a silicon compound or a boron compound.
  • Treatment at a temperature between the boiling points of the solvents for 5 minutes to 24 hours (Compound (IF) can be produced therefrom.
  • the silicate or boron compound used include triethylsilane, trichlorosilane, Examples thereof include dimethylphenylsilane and sodium borohydride, and preferably include triethylsilane.
  • the compound (IE) is reacted with 2 to 5 equivalents of lithium aluminum hydride in a solvent inert to the reaction at a temperature usually between -90 ° C and the boiling point of the solvent used for 5 minutes to 24 hours.
  • the compound (IF) can be produced.
  • the solvent which is inert to the reaction used include getyl ether, diisopropyl ether, dimethyloxetane, tetrahydrofuran, dioxane, benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and the like. These can be used alone or in combination.
  • Compound (I-G) can be produced according to the method described in the literature [New Experimental Chemistry Lecture 15, Maruzen, p.158 or p.179], or according to them. That is, the compound (IE) obtained in the above step 4 is mixed with 2 to 5 equivalents of a suitable reducing agent in a solvent inert to the reaction, usually at a temperature between -90 ° C and the boiling point of the solvent used. Minutes to 24 hours
  • Suitable reducing agents to be used include, for example, sodium borohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride and the like.
  • Solvents inert to the reaction include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol, dimethyl ether, diisopropyl ether, dimethoxymethane, tetrahydrofuran, dioxane, dichloromethane, chloroform.
  • 1,2-dichloroethane, benzene, toluene, xylene, Pentane, hexane, heptane, cyclohexane and the like can be mentioned, and these can be used alone or as a mixture.
  • sodium borohydride or lithium borohydride is used as a reducing agent, and water, methanol, ethanol, isopropyl alcohol or the like may be used alone or in combination as a solvent inert to the reaction.
  • the compound (I-E) obtained in the above step 4 and 1 to 5 equivalents of the compound (f) are mixed in a solvent inert to the reaction at a temperature between ⁇ 90 ° C. and a temperature between the boiling points of the solvents used.
  • the compound (IH) can be obtained by reacting the mixture for 1 minute to 24 hours.
  • Solvents inert to the reaction used include, for example, getyl ether, diisopropyl ether, dimethyloxetane, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, tolylene, xylene, and benzene.
  • the compound (f) to be used can be obtained as a commercial product, a method described in the literature [New Experimental Chemistry Course 12, Maruzen, p. 7, p. 49 or p. 62], or a method similar thereto. be able to.
  • R 1 is a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted aryloxy
  • the compound (f) is preferably used in an equivalent amount to the compound (IE).
  • R 4 is
  • R ⁇ R 32 s X 2 and p are as defined above.
  • Compound (I-1) can be produced according to the method described in Production Method 1, Step 3, using compound (g) obtained in Step 8 above.
  • Compound (h) can be produced according to the method described in Production Method 2, Step 5, using Compound (g) obtained in Step 8 above.
  • Compound (I-J) can be produced according to the method described in Production Method 1, Step 3, using compound () obtained in Step 10 above.
  • R 2 , R 3 , R 4 , R 5 and R 6 are each as defined above.
  • the compound (I-K) which can be obtained as a commercial product or according to the methods described in the above Production Methods 1 to 3 or in accordance with them, is added in a suitable solvent to 1 to 1 equivalent of L00, preferably 1 to 5 equivalents.
  • the compound (IL) can be produced by treating the mixture in the presence of a suitable base at a temperature usually between 0 ° C. and the boiling point of the solvent used for 5 minutes to 24 hours.
  • Suitable solvents used include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol, acetonitrile, acetone, getyl ether, diisopropanol, dimethyl ether, dimethoxetane, tetrahydrofuran, dioxane, dichloromethane, chloroform.
  • Suitable bases to be used include, for example, sodium bicarbonate, bicarbonate lime, carbonate lime, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, potassium hydroxide, hydroxy acid Sodium, barium hydroxide, calcium hydroxide, sodium acetate, f-methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-pentacene And pyridine. These can be used alone or in combination. (Step 13)
  • the compound (IL) obtained in the above step 12 is mixed with 1 to 5 equivalents of the compound (i) in the absence of a solvent or an inert solvent in the presence of 1 to 5 ′ equivalent, preferably 2 equivalents of a suitable condensing agent. And usually at a temperature between -10 ° C and the boiling point of the solvent to be used, for 5 minutes to 24 hours to produce compound (IM).
  • Solvents inert to the reaction include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol, acetonitrile, nitromethane, acetone, methyl acetate, ethyl acetate , Propyl acetate, dimethyl ether, diisopropyl ether, dimethoxyethyl, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, benzene,,,, -Trifnoreoluene, pentane, hexane, heptane, cyclohexane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetoamide, ⁇ -methylpyrrolidone, ⁇ , ⁇ -dimethylimidazolidinone
  • Suitable condensing agents to be used include, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or its hydrochloride, benzotriazole- Examples thereof include 1-yl-tris (dimethylamino) phosphoniumhexafluorophosphoride, diphenylphosphorylazide, carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and the like.
  • Suitable additives to be used include, for example, ⁇ -hydroxysuccinimide, hydroxybenzotriazole, 3-hydroxy-4-oxo -3,4-dihydro-1,2,3-benzotriazine and the like.
  • Compound ( ⁇ - ⁇ ) can also be produced by the following steps.
  • the compound (I-L) obtained in the previous step 12 is used in the absence of a solvent or in a solvent inert to the reaction, in the presence of ⁇ to 100 equivalents of a chlorinating agent, usually between -10 ° C and the boiling point of the solvent.
  • Compound (j) can be obtained by treating at a temperature for 5 minutes to 24 hours.
  • solvent inert to the reaction for example, acetonitrile, nitromethane, methyl ethyl ketone, methyl acetate, ethyl acetate, propyl acetate, dimethyl ether, diethyl Isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, nitrobenzene, hi, hi, hi-trifluorotoluene, pentane, hexane , Heptane, cyclohexane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, NJ-dimethylimidazolidinone, sulfolane, and the like.
  • chlorinating agent examples include, for example, thionyl chloride, sulfuryl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, and the like.
  • Solvents inert to the reaction include, for example, water, methanol, ethanol, propanol, isopropyl alcohol, toluene, acetonitrile, nitromethane, acetone, methyl acetate, ethyl acetate, propyl acetate, getyl ether, diisopropyl ether, dimethyl Tokishe Yun, tetrahydrofuran, Jiokisan, Jikurorome evening down, Kurorohozoremu, 1 3 2 - Jikuroroe Yun, benzene, Tofureen, xylene, Nitorope benzene, arsenic, arsenic, alpha-triflate Ruo Russia toluene, pentane, Hexane, heptane, cyclohexane, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrol
  • Suitable bases include, for example, sodium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, and hydroxide. Potassium, sodium hydroxide, barium hydroxide, calcium hydroxide, sodium acetate, trimethylamine, triethylamine, triptylamine, diisopropylethylamine, ⁇ -methylmorpholine, 1,8-diazabicyclo [5.4.0]- 7-Pendecene, pyridine and the like. Manufacturing method 5
  • the compound (I-N) wherein R 1 is a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryloxy or a substituted or unsubstituted aromatic heterocyclic oxy is obtained by the following steps. Can be manufactured.
  • OR 34 represents a substituted or unsubstituted lower alkoxy, a substituted or unsubstituted aryloxy or a substituted or unsubstituted aromatic heterocyclic oxy in the definition of R 1 )
  • the compound (j) obtained in Step 4 of the above-mentioned production method 4 is mixed with 1 to; ⁇ 0 equivalent of the compound (k) without solvent or in a solvent inert to the reaction and the boiling point of the solvent usually used at -10 ° C.
  • the compound (IN) can be produced by reacting at a temperature between 5 minutes and 24 hours. At this time, it is preferable to use 1 to 100 equivalents of a suitable base as an additive.
  • Solvents inert to the reaction include, for example, acetonitrile, nitromethane, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, propyl acetate, getyl ether, diisopropyl ether, dimethyloxetane, tetrahydrofuran, dioxane, dichloromethane 1,2-dichloroethane, benzene, toluene, xylene, ditoluene benzene,, a, a-trifluorotoluene toluene, pentane, hexane, heptane, cyclohexane, N, N-dimethylformami , ⁇ , ⁇ -dimethylacetamide, ⁇ -methylpyrrolidone, ⁇ , ⁇ -dimethylimidazolidinone, dimethylsulfoxide, s
  • Suitable bases include, for example, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, lithium hydroxide, and hydroxylic acid.
  • Potassium sodium hydroxide, barium hydroxide, calcium hydroxide, sodium acetate, sodium hydride, potassium hydride, trimethylamine, triethylamine, triptylamine, diisopropyletylamine, ⁇ -methylmorpholine, 1, 8-diazabicyclo [5.4.0]-7-pandene, pyridine and the like. Manufacturing method 6
  • R 1 is a NR3 ⁇ 4 6
  • R 4 is
  • the intermediate compound (n) can be produced using the compound (m) obtained in the above step 17, according to the method described in the production method 5, step 13, or steps 14 and 15.
  • Compound (1-0) can be produced according to the method described in Production Method 1, Step 3, using Compound (n) obtained in Step 18 above.
  • R36 (Wherein, R 35 and R 36 are the same or different and each represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, wherein the substituted or unsubstituted aryl and the substituted Or the unsubstituted aromatic heterocyclic group is as defined above) can be produced by the production method described in W097 / 03965 or according to it. Manufacturing method 8
  • R 37 and R 38 are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted. Or R 37 and R 38 together with the adjacent nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic group, wherein the substituted or unsubstituted A lower alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group and a substituted or unsubstituted alicyclic heterocyclic group formed together with an adjacent nitrogen atom are as defined above. Is synonymous) can also be produced by the following steps.
  • Production Method 4 Compound 13 (IR) can be produced according to the method described in Step 13 or Steps 14 and 15 or a method analogous thereto.
  • the intermediates and target compounds in each production method are isolated by separation and purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. It can be purified. Further, the intermediate can be subjected to the next reaction without particular purification.
  • Some of the compounds (I) may have stereoisomers such as geometric isomers, optical isomers and tautomers, but the ⁇ receptor antagonist of the present invention includes these. It is possible to use all possible isomers and mixtures thereof in any ratio.
  • compound (I) When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, purification may be carried out as it is. If compound (I) is obtained in a free form, compound (I) What is necessary is just to dissolve or suspend in a solvent, add an acid or a base, and isolate and purify.
  • Compound (I) and a pharmacologically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also present as NPFF receptor antagonists of the present invention.
  • the membrane was collected on a G / FB filter using Cellhabeth Yuichi (Branded M-24), and the reaction was stopped. After an additional four washes, the radioactivity of the filter was measured (Packard, Cobra).
  • the non-specific binding amount was defined as the binding amount in the presence of 1 ⁇ mol / L NPFF, and the difference between the total binding amount and the non-specific binding amount was defined as the specific binding amount.
  • Table 4 shows the [ 13 ⁇ 4i I] NPFF binding inhibition rate with respect to the specific binding of the test compound.
  • Test Example 2 Examination of analgesic effect by hot plate test
  • a rat SD male, 240-280 g in weight was placed on a hot plate (53 ° C), and the time (latency) until pain behavior (licking or swinging the hind limbs) was measured.
  • the maximum heat stimulation time was set to 20 seconds to avoid damage to the skin tissue on the soles of the limbs.
  • the control (control solvent administration) group and the test compound administration group were divided without any bias.
  • Compound 30 was dissolved in physiological saline and administered intraperitoneally.
  • the control solvent was physiological saline. Latencies until a pain response was measured before administration of the test compound and 15, 30, 45, 60s 75, 90, and 120 minutes after administration of the test compound.
  • Test Example 3 Examination of the effect on morphine tolerance by the til pinch test
  • the test was performed according to the Tail-pinch method (Biological Science, 1994, Vol. 45, p. 474).
  • the ridge of a mouse ICR male, weighing 22 to 26 g was pinched with tweezers, and the time (latency) until pain behavior (sticking to the tweezers or squeaking) was measured.
  • the maximum stimulation time was 6 seconds.
  • the animals were divided into three groups without bias. Intraperitoneally administered distilled water to the first and second groups, Compound 30 dissolved in distilled water to the third group, 15 minutes later, physiological saline to the first group, and second group And group 3 were subcutaneously administered morphine (10 mg '/ kg ) dissolved in physiological saline.
  • Latency was measured by a tilpinch test before morphine or saline administration and at 15-minute intervals up to 90 minutes after administration.
  • the area under the curve (AUC) at latency up to 90 minutes after morphine or saline administration was calculated and used as an index of analgesic effect. The same operation was performed once for 5 days.
  • the effects of compound 30 were examined using a neuropathic pain model, a strangulated nerve injury rat.
  • the production of rats with strangulated nerve injury was performed with reference to the literature [Pain, 1988, Vol. 33, p. 87].
  • the left sciatic nerve was lightly ligated four times with a 4-0 silk thread to a rat (SD male, weight 190-220 g) under pentovalpital anesthesia.
  • the following tests were performed 14 days after the operation.
  • the time (latency) until the pain behavior (licking or swinging the hind limbs) of the rats with strangulated nerve injury to the thermal stimulus was measured by the hot plate test (temperature of 53 ° C), and the value and weight were measured.
  • test group was divided into a control (control solvent administration) group and a test compound administration group without bias. Latency of 2-3 seconds was observed in rats with strangulated nerve injury compared to sham-operated rats.
  • Compound 30 was dissolved in physiological saline and administered intraperitoneally.
  • the control solvent was physiological saline. Latencies until a pain response was measured before administration of the test compound and at 30, 6, 90 and 120 minutes after administration of the test compound.
  • the maximum heat stimulation time was set to 20 seconds to avoid damage to the skin tissue of the limb.
  • the significance test was performed between the control group and the test compound administration group using the Dunnett test.
  • compound (I) or a pharmacologically acceptable salt thereof has NPFF receptor antagonism, and various diseases caused by NPFF receptor hyperactivity (for example, in the case of neuropathic pain) Hyperalgesia, and resistance to narcotic analgesics such as arodinia morphine).
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations.
  • the pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient.
  • these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well-known in the technical field of pharmaceuticals.
  • the administration route it is desirable to use the most effective one for treatment, and it can be oral or parenteral such as intravenous.
  • Dosage forms include tablets, injections and the like.
  • Suitable for oral administration for example, tablets are excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binding with hydroxypropylcellulose, etc. , A surfactant such as a fatty acid ester, and a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration comprise sterile aqueous solutions containing the active compound, which is preferably isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier composed of a salt solution, a glucose solution, or a mixture of a salt water and a vudose solution.
  • parenteral preparations are also selected from diluents, preservatives, flavors, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparations. Seeds or more auxiliary ingredients may be added.
  • the dosage and frequency of compound (I) or a pharmacologically acceptable salt thereof will vary depending on the dosage form, the age and weight of the patient, and the nature or severity of the condition to be treated. 0.01 mg 'to lg, preferably 0.05 to 50 m, per adult is administered once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. However, these dosages and the number of administrations vary depending on the various conditions described above.
  • FIG. 1 shows the analgesic effect of Compound 30 in a hot plate test.
  • FIG. 2 is a graph showing the inhibitory effect of compound 30 on morphine tolerance in tilpin titers.
  • Ichinichi distilled water + morphine administration group
  • FIG. 3 is a graph showing the inhibitory effect of Compound 30 on neuropathic pain in rats with strangulated nerve injury.
  • a tablet having the following composition is prepared by a conventional method.
  • the title tablet (containing 20 active ingredients per tablet) is obtained in the same manner as in Example 1 by using 40 g of the compound 21.
  • An injection having the following composition is prepared by a conventional method.
  • Example 16 3- [l- (2-chlorophenyl) -hydroxymethyl] -N-cyclooctyl-; I- [4- (topyrrolidinyl) butyl] indole-2-carboxamide (compound 13 Compound 13 (25 mg, 0.047 mmol) was obtained as a colorless oil by using Compound 6 obtained in Example 9 instead of Compound 2 in the same manner as in Example 1. %).
  • Example 17 Synthesis of 3- [tri (3-chlorophenyl) -hydroxymethyl] -N-cyclooctyl-tri [4- (topyrrolidinyl) butyl] indole-2-carboxamide (Compound 14) 3- (3-chlorobenzoyl) -N-cyclooctyl-1- [4- (1-) synthesized in the same manner as in Example 12 using 3-chlorobenzoic acid instead of compound 2 in the same manner as in Example 5. Pyrrolidi Compound 14 (27 mg 0.050 mmol) was obtained as a colorless oil by using [nyl) butyl] indole-2-carboxamide (61% yield).
  • Example 18 N-cyclooctyl-1- [4- (1-pyrrolidinyl) butyl] -3- (2,2,2-trifluoro-1-hydroxyethyl) indole-2-carboxamide (Compound 15)
  • Compound 15 (57 mg, 0.115 mmol) was obtained as a colorless oil by using compound 8 obtained in Example 11 instead of compound 2 in the same manner as in Example 12. ).
  • Step 2 of Reference Example 1 Compound 16 (14 mg, 0.029 mmol) was obtained as a brown solid using Compound jj (35 mg, 0.077 mmol) obtained in Step 1 in place of Compound aa ( Yield 37%).
  • Stage 1 In the same manner as in Steps 3 and 4 of Example 5, a method described in the literature [Journal of "Ob-Heterocyclic” Chemistry (J. Heterocycl. Chem.), 2000, Vol. 37, p. 1103] By using 3-phenylindole-2-ethyl carboxylate (479 mg, 1.81 mol ol) obtained in Step 5 instead of Compound cc, N-cyclooctyl-3-phenylindole-2-force lipoxamide (Compound ⁇ ) (387 mg, 1.12 mmol) was obtained as a white solid (total yield 62%). Stage 2
  • Example 27 3- (1, Diphenylmethyl) -2- (pyrrolidinylcarbonyl) -1- [4--pyrrolidinyl) butyl] carbonylindole.1 Maleate (Compound 26) Compound 26 (98 mg, 0.16 mmol) was obtained in the same manner as in Example 23, using pyrrolidine instead of cycloheptylamine (yield: 71%).
  • Example 28 3- (1, Tridiphenylmethyl) -N- [2- (2-oxopyrrolidine-1-yl) ethyl] -1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamido (Compound 27)
  • Compound 27 (22 mg 0.04 mmol) was obtained in the same manner as in Example 24 except that 2-oxopyrrolidine-: I-ylethylamine was used instead of cyclohexylamine (yield: 4 °).
  • various diseases derived from NPFF receptor hyperactivity eg, hyperalgesia at the time of neuropathic pain, arodinia, morphine
  • an indole derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • molar tolerance to narcotic analgesics represented by NPFF receptor antagonists useful for treatment and / or prevention of narcotic analgesics such as chicks are provided.
  • the present invention provides a novel indole derivative having the above-mentioned characteristics or a pharmaceutically acceptable salt thereof.

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Abstract

L'invention concerne un antagoniste du récepteur NPFF qui contient en tant que principe actif un dérivé d'indole représenté par la formule générale (I) [dans laquelle R1 représente hydroxy, alcoxy inférieur (non)substitué, aryloxy (non)substitué, (hétérocycle aromatique)oxy (non)substitué, ou NR5R6 ; R2 représente hydrogène, aryle (non)substitué, un groupe hétérocyclique aromatique (non)substitué, etc ; R3 représente hydrogène, halogéno, nitro, cyano, hydroxy, alcoxy inférieur (non)substitué, etc ; R4 représente hydrogène ou (CH2)p-R12] ou un sel dudit dérivé, acceptable au plan pharmacologique.
PCT/JP2004/003273 2003-03-14 2004-03-12 Antagoniste du recepteur du neuropeptide ff Ceased WO2004080965A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040111A3 (fr) * 2003-10-23 2005-12-08 Hoffmann La Roche Bibliotheque combinatoire d'acides 3-aryl-1h-indole-2-carboxyliques
JP2008231030A (ja) * 2007-03-20 2008-10-02 Aphoenix Inc インドール化合物の新規医薬用途及び新規インドール化合物
US7696240B2 (en) 2005-12-15 2010-04-13 Hoffmann-La Roche Inc. Fused pyrrole derivatives
CN110546136A (zh) * 2017-02-14 2019-12-06 研究三角协会 基于脯氨酸的神经肽ff受体调节剂
CN114269730A (zh) * 2019-08-06 2022-04-01 多曼治疗学公司 作为神经肽ff受体拮抗剂的5-杂芳基-吡啶-2-胺化合物

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WO2005040111A3 (fr) * 2003-10-23 2005-12-08 Hoffmann La Roche Bibliotheque combinatoire d'acides 3-aryl-1h-indole-2-carboxyliques
US7696240B2 (en) 2005-12-15 2010-04-13 Hoffmann-La Roche Inc. Fused pyrrole derivatives
JP2008231030A (ja) * 2007-03-20 2008-10-02 Aphoenix Inc インドール化合物の新規医薬用途及び新規インドール化合物
CN110546136A (zh) * 2017-02-14 2019-12-06 研究三角协会 基于脯氨酸的神经肽ff受体调节剂
EP3583090A1 (fr) 2017-02-14 2019-12-25 Research Triangle Institute, International Modulateurs du récepteur ff de neuropeptide à base de proline
EP3583090A4 (fr) * 2017-02-14 2020-12-30 Research Triangle Institute, International Modulateurs du récepteur ff de neuropeptide à base de proline
US11491136B2 (en) 2017-02-14 2022-11-08 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
CN110546136B (zh) * 2017-02-14 2023-07-18 研究三角协会 基于脯氨酸的神经肽ff受体调节剂
US11826350B2 (en) 2017-02-14 2023-11-28 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
US12390446B2 (en) 2017-02-14 2025-08-19 Research Triangle Institute Proline-based neuropeptide FF receptor modulators
CN114269730A (zh) * 2019-08-06 2022-04-01 多曼治疗学公司 作为神经肽ff受体拮抗剂的5-杂芳基-吡啶-2-胺化合物

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