WO2004080965A1

WO2004080965A1 - Neuropeptide ff receptor antagonist

Info

Publication number: WO2004080965A1
Application number: PCT/JP2004/003273
Authority: WO
Inventors: Naoto Osakada; Katsumi Shinoda; Shunji Kunori; Tomomi Shirai; Shinichiro Toki; Shunji Ichikawa; Nobuo Kosaka; Michio Ichimura; Junichi Shimada
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2003-03-14
Filing date: 2004-03-12
Publication date: 2004-09-23
Also published as: JPWO2004080965A1

Abstract

An NPFF receptor antagonist which contains as an active ingredient either an indole derivative represented by the general formula (I): (I) [wherein R1 represents hydroxy, (un)substituted lower alkoxy, (un)substituted aryloxy, (un)substituted (aromatic heterocycle)oxy, or -NR5R6; R2 represents hydrogen, (un)substituted aryl, an (un)substituted aromatic heterocyclic group, etc.; R3 represents hydrogen, halogeno, nitro, cyano, hydroxy, (un)substituted lower alkoxy, etc.; and R4 represents hydrogen or -(CH2)p-R12] or a pharmacologically acceptable salt of the derivative.

Description

Specification

Neuropeptide FF receptor antagonist

Technical field

The present invention relates to a neuropeptide FF receptor antagonist containing an indole derivative or a pharmacologically acceptable salt thereof as an active ingredient.

Background technology

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. 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].作用 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. Pharmacol.], 1998, Vol. 345, p. L]. 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) ヽ 1985, Vol. 82, p. 7757; Peptides ヽ 1993, Vol. 14, p. 77 919]. On the other hand, it has been reported that intraventricular administration of anti-NPFF antibody enhances morphine analgesia and reduces withdrawal syndrome symptoms in morphine-resistant animals [Peptides ), 198.9, Vol. 10, p. 741; Neuroscience Lett. S 1991, Vol. 132, .29; Peptides, 1990, Vol. 11, p. 969] o Intraspinal administration of NPFF has also been reported to cause analgesic effects on noxious stimuli [Eur. J. Pharmacol., 1993 Year, Vol. 237, p. 73].

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. ,

Therefore, 物質 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.

Substances that inhibit the binding of NPFF to NPFF receptors such as 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

[Eur. J. Pharmacol. _S 2002, Vol. 451, p. 45].

On the other hand, some of the 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. 1103 ], Factor XA inhibitor (W099 / 03380), CCK-A agonist (W098 / 51686), glutamate blocker (JP-A-3-14562), CCK antagonist (JP-A-10-130147), anti- Antiarrhythmic agent (W001 / 62775), Nicotine receptor agonist (W001 / 32622), PPM gamma agonist antagonist and antiobesity agent (W001 / 30343), Cdc25 inhibitor (W001 / 27077), Antibacterial agent (W098 / 57931), agent for treating neurological and neuropsychiatric disorders (US6191165), anti-inflammatory agent

(WO00 / 46198; 000/46199) _s Periodontal disease therapeutic agent (W000 / 10568), phospholipase A2 inhibitor (W099 / 43672) _s MCP-1 derived disease therapeutic agent (volume 99/07351), 5HT uptake inhibitor

(W098 / 57953) _N C phospholipase A2 inhibitor (W098 / 08818), detergents (W097 / 48786), neurological and neuropsychiatric disorders therapeutic agent (W097 / 45U5), neuropeptide Y receptor antagonists

(W097 / 09308) _s Uses as a cGMP-PDE inhibitor (W096 / 32379), a fungicide for plants (US5994270), and an HIV reverse transcriptase inhibitor (JP-A-5-208910) have been reported. Disclosure of the invention

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). Furthermore, 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).

(1) General formula (I)

Wherein R ¹ is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aromatic heterocyclic oxy or -im または^s "

R ⁵ and R ⁶ are the same or different and are hydrogen or

-(CH2) _k -R ⁷

[Wherein, 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 (C¾) _¾ and one time of binding represents a] represents an integer of 2-6), or R ⁵ and together such connexion replaced with the nitrogen atom to which R ⁶ is adjacent Or which forms an unsubstituted alicyclic heterocyclic group,

Is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group,

0

I I

"(^^ p-^ -n

(Wherein β 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

(Wherein ^ 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 Substituted or unsubstituted alicyclic alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted mono- or di-lower alkylamino, substituted 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 monoaromatic heterocyclic amino or substituted or Represents an unsubstituted alicyclic heterocyclic group, and n represents an integer of 0 to 6)

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

Ichi (CHy R ¹²

Wherein 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 , Substituted or unsubstituted aryl, substituted or unsubstituted Represents an aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group, and P is 1 to 6 (provided that when R ¹² is bonded to (C¾) _p via a nitrogen atom in R ¹² , A neurobeptide FF receptor antagonist comprising, as an active ingredient, an indole derivative represented by the following formula: or a pharmacologically acceptable salt thereof.

(2) The neurobeptide FF receptor antagonist according to (1), wherein R ¹ is —NR¾ ⁶ (wherein and R ⁶ are as defined above).

(3) R ² is'

O

— CR ⁸

(Wherein, E ⁸ is as defined above). The neuropeptide FF receptor antagonist according to (1) or (2).

(4) R ²

The neuropeptide FF receptor antagonist c according to (1) or (2),

(5) R ⁴

— (CH2) _F '

(Wherein P has the same meaning as described above).

(6) General formula (IA)

Wherein 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.

(7) General formula (IB)

(IB)

(Wherein IP represents a substituted or unsubstituted alicyclic heterocyclic group, and R ^3B has the same meaning as the above ^), or a pharmaceutically acceptable salt thereof.

(8) —General formula (IC)

( I C )

(Wherein, 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. A) or a pharmacologically acceptable salt thereof.

(9) General formula (ID)

(ID)

(In the formula, ^δ5δ 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,

Η ^ω represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted alicyclic alkyl or a substituted or unsubstituted aryl,

D is as defined above,

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.

(10) The indole derivative or the pharmaceutically acceptable salt thereof according to (9), wherein R ^5D is an aliphatic alkyl. '

(11) The compound according to (9) or (10), wherein I is 3 or 4, and R ^MD and R together with an adjacent nitrogen atom form a substituted or unsubstituted aliphatic heterocyclic group. Indole derivative or a pharmacologically acceptable salt thereof.

(12) General formula (IE)

(IE)

(Wherein, 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, and s ^Represents an integer of 2 to 6, and R ^14E and R ^i5E are the same or different and are substituted or unsubstituted. Represent a lower alkyl-substituted, or Indoru derivative or its藥理science represented by ^ϋ 14Ε and beta ¹ to form an alicyclic璟式complex璟基of connexion substituted or unsubstituted, such together with the adjacent nitrogen atom) Acceptable salts.

(13) A medicament comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (6) to (12) as an active ingredient.

(14) 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).

(15) Indole induction according to any one of (6) to (12): or a disease derived from enhanced function of neuropeptide FF receptor containing a pharmacologically acceptable salt thereof as an active ingredient A therapeutic and / or prophylactic agent.

(16) Treatment and treatment of a disease derived from hyperactivity of a neuropeptide receptor containing the indole derivative according to any one of (1) to (5) or a pharmacologically acceptable salt thereof as an active ingredient. / Or prophylactic agent

(17) 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).

(18) An analgesic containing the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) as an active ingredient.

(19) 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).

(20) 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.

(21) 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).

(22) An analgesic comprising the indole derivative according to any one of (6) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.

(23) 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).

(24) An analgesic potentiator comprising an indole derivative or a pharmaceutically acceptable salt thereof according to any of (6) to (12) as an active ingredient. (25) 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).

(26) 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.

(27) Enhanced function of a neuropeptide FF receptor, 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). And Z or prevention methods for diseases derived from.

(28) A method for treating and / or preventing neuropathic pain, comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5). Law.

(29) 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).

(30) 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).

(31) 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).

(32) 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).

(33) Derived from hyperactivity of neurobeptide FF receptor, which comprises a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any of (6) to (12). And / or a method for treating and / or preventing a disease.

(34) 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.

(35) 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).

(36) 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).

(37) The indole derivative according to any of (6) to (12) or a pharmacologically acceptable A method for enhancing an analgesic action of an analgesic, comprising a step of administering an effective amount of a salt to be contained.

(38) 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).

(39) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) for the production of a neuropeptide FF receptor antagonist. .

(40) The indole derivative or the pharmacology thereof according to any of (1) to (5), for treating a disease derived from hyperactivity of a neuropeptide FF receptor and producing Z or a prophylactic agent. Use of chemically acceptable salts.

(41) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) for the manufacture of a therapeutic and / or prophylactic agent for neuropathic pain.

(42) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5) for the manufacture of an analgesic.

(43) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (5) for the manufacture of a drug for overcoming a narcotic analgesic resistance.

(44) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) for the production of an analgesic-enhancing agent for an analgesic.

(45) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5) for the manufacture of a drug for overcoming a narcotic analgesic dependence.

(46) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12) for the production of a neurobeptide FF receptor antagonist.

(47) The indole derivative or the pharmacology thereof according to any of (6) to (12), for treating a disease derived from hyperactivity of a neuropeptide FF receptor and producing Z or a prophylactic agent. Use of chemically acceptable salts.

(48) Use of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of (6) to (12) for the treatment of neuropathic pain and the manufacture of a Z or prophylactic agent.

(49) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12) for the manufacture of an analgesic.

(50) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12) for the manufacture of a drug for overcoming a narcotic analgesic resistance. (51) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12) for the production of an analgesic-enhancing agent for an analgesic.

(52) Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any of (6) to (12) for the manufacture of a drug for overcoming a narcotic analgesic dependence.

Hereinafter, the compounds represented by the general formulas (1), (IA), (IB) (IC), (ID) and (IE) are referred to as compounds (IX (IA), (IB), (IC), (IC) ID) and (IE) The same applies to compounds of other formula numbers.

In the definition of each group of the general formula (I),

(i) 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.

(ii) 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.

(iii) 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.

(iv) 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.

(V) 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.

(vi) aromatic heterocyclic group, aromatic heterocyclic oxy, monoaromatic heterocyclic amino and Or the 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. A heterocyclic group, a condensed aromatic heterocyclic group containing at least 0.1 atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a bicyclic or tricyclic ring condensed with a 3- to 8-membered ring, and the like. More specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pivalyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrazolyl Oxazolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, ben Thiazolyl, benzo O hexa benzisoxazolyl, purinyl and the like. The two aromatic heterocyclic groups in the diaromatic heterocyclic amino may be the same or different.

(vii> Examples of the alicyclic heterocyclic group include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least 原子 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. Includes pyrrolidinyl, piperidino, piperidinyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, homopiperidino, homopiridinyl, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl , Tetrahydrofuranyl, tetrahydroviranyl, dihydrobenzofuranyl and the like.

(viii) 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 (the condensed alicyclic heterocyclic group may contain another nitrogen atom, an oxygen atom or a sulfur atom), and the like; Specific examples include pyrrolidinyl, piperidino, piperazinyl, imidazolidinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetravidolinyl and the like. (ix) Halogen means each atom of fluorine, chlorine, bromine and iodine.

(X) 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. In the above (X), a halogen, a lower alkoxy and a lower alkyl portion of a mono- or di-lower alkylamino, an aryl, an aryloxy and an aryl portion of an arylamino, an aromatic heterocyclic group, an aromatic heterocyclic ring The oxy, aromatic heterocyclic amino and alicyclic heterocyclic groups are as defined above.

In the above (X), 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.

In the above (X), 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. Halogen, hydroxy, nitro, cyano, lower alkyl, lower alkenyl, lower alkynyl, alicyclic alkyl, lower alkoxy, amino, mono- or di-lower alkylamino of the formulas 1-3, where halogen, lower Alkyl, lower alkoxy and the lower alkyl portion of mono- or di-lower alkylamino, lower alkenyl, lower alkynyl and aliphatic alkyl are as defined above. (xi) Substituted aryl, substituted aryloxy, substituted monoarylamino, substituted mono or diarylamino, substituted aromatic heterocyclic group, substituted aromatic heterocyclic oxy, substituted monoaromatic heterocyclic amino and substituted mono or dimono Examples of the substituent in the aromatic heterocyclic amino include, for example, halogen, hydroxy, cyano, nitro, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl having the same or different 1 to 3 substituents. Substituted or unsubstituted lower alkynyl, substituted or unsubstituted aliphatic alkyl, substituted or unsubstituted lower alkoxy, methylenedioxy, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted lower alkanol, Substituted or unsubstituted lower aryloxy, substituted Or unsubstituted mono- or di-lower alkanoylamino, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted mono- or di-lower alkyl force, rubamoyl, substituted or unsubstituted mono- or di-lower alkyl force Rubamoyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted monoarylamino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted mono or diarylcarbamoyl, substituted or unsubstituted Substituted mono or diaryl rubamoyloxy, substituted or unsubstituted aroyl, substituted or unsubstituted aroyloxy or substituted or unsubstituted aroylamino, and the like.

In the above (xi), 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. Rubamoiruokishi, Aroiru, Ariru portion of Aroiruokishi and Aroirua Mino Ri it it previous remarks himself lower alkyl _(i)及Pi Ariru) synonymous der, two lower a in di-lower alk Noi Rua Mino Kanoiru, di-lower alkyl force component, and in Jiari one carbamoyl 及 Pi Jiariru force Rubamoiruokishi 2 The two reel parts may be identical or different.

In the above (xi), a substituted lower alkyl, a substituted lower alkenyl, a substituted lower alkynyl, a substituted alicyclic alkyl, a substituted lower alkoxy, a substituted mono- or di-lower alkylamino, a substituted lower alkyl, a substituted lower alkylyloxy, 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. Halogen, hydroxy, oxo, nitro, cyano, lower alkoxy, amino, mono- or di-lower alkylamino, aryl, alicyclic heterocyclic group, aromatic heterocyclic group, etc., wherein halogen, lower alkoxy And mono- or di-lower alkyla Lower alkyl moiety of Roh, § reel, alicyclic heterocyclic group, an aromatic heterocyclic group has the same meaning as it it the.

In the above (xi), a substituted aryl, a substituted aryloxy, a substituted monoarylamino, a substituted aromatic heterocyclic group, a substituted mono- or diarylcarbamoyl, a substituted mono- or diarylcarbamoyloxy, a substituted aryloyl, Examples of the 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, aryl And the aromatic heterocyclic group is as defined above.

(xii) Examples of the substituent in the substituted alicyclic heterocyclic group and the substituted alicyclic heterocyclic group formed together with the adjacent nitrogen atom include oxo and the like in addition to the groups described in (xi) above. can give.

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. Alkali metal salts, magnesium salts, calcium salts, etc. of alkaline earth metal salts, aluminum salts, zinc salts, etc., and pharmacologically acceptable ammonium salts include ammonium, tetramethylammonium, etc. And 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.

Manufacturing method

In compound (I), R ⁴ is

— (CH ₂ ) _P -R ¹²

Wherein p and R ¹² are each as defined above, and (IB) ヽ and E ⁴

— (CH ₂ ) _p -NR ³⁰ R ³¹

(Wherein p is as defined above, and 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. And 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.

(Wherein, 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)

(Process 1)

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 that can be used 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, Ν, Ν-dimethylacetamide , Ν-methylpyrrolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane and the like. These can be used alone or in combination, and among them, dimethoxyethane and the like are preferable.

Here, the starting compound (Ι-Α) 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.

(Process 2)

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. Among them, potassium hydroxide is preferable. Solvents inert to the reaction that can be used 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, Ν ,、-Dimethylformamide, Ν, Ν-Dimethylacetamide, Ν -Methylpyrrolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane, and the like. These can be used alone or as a mixture, and among them, dimethoxyethane and the like are preferable. (Process 3)

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. Examples of the reaction-inert solvents that can be used include water, methanol, ethanol, propanol, isopropyl alcohol, butyl alcohol, acetonitrile, nitromethane, methyl acetate, ethyl acetate, propyl acetate, getyl ether, and diisopropyl ether. , dimethoxy E Tan, tetrahydrofuran, Jiokisan, dichloro methane, black hole Holm, 1,2 Jikuroroetan, benzene, toluene, xylene, nits port benzene, _«3 alpha, - triflumizole Ruo Russia toluene, pentane, hexane, heptane, shea Chlorohexane, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν-methylvirolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane, and the like. Or mix It is possible to have. Suitable bases that can be used 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-

'Etc. Manufacturing method 2

In compound (I), R ² is

0

— CR ³²

(In the formula, 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);

-CH ₂ — R ³²

(Wherein I is as defined above) (I-F),.

OH

-CH-R ³²

(Wherein R ³² has the same meaning as described above).

(Wherein, 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.

(Wherein RR ³ _S R ⁴ , R ³² and R ³³ are as defined above, and M represents lithium or magnesium)

(Process 4)

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. and the boiling point of the solvent used, preferably at room temperature for 5 minutes to 24 hours. Suitable acids to be used include, for example, polyphosphoric acid, phosphoric acid and the like. Examples of 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. Form, 1,2-dichloroethane, benzene, toluene, xylene, double-ended benzene, hi, hi, hi-trifluorotoluene, pentane, hexane, heptane, cyclohexane, N, N-dimethylformami , Ν, Ν-dimethylacetamide, Ν-methylbirolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane and the like, and these can be used alone or in combination. (Step 5>

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. Examples of the silicate or boron compound used include triethylsilane, trichlorosilane, Examples thereof include dimethylphenylsilane and sodium borohydride, and preferably include triethylsilane.

Alternatively, 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. In this case, the compound (IF) can be produced. Examples of 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.

(Step 6)

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

(IG) can be manufactured. 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. Particularly preferably, 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.

(Step 7)

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. , HI, HI, a-Triphnoreo mouth Tofreen, pentane, hexane, heptane, cyclohexane and the like, and these can be used alone or as a mixture. 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. In particular, when 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).

Manufacturing method 3

Of compounds (IE) and (IF), R ⁴ is

— (CH ₂ ) _p -NR ³⁰ R ³¹

(Wherein R ³⁰ s R ³¹ and P are as defined above), and compounds (II) and (IJ) can also be produced by the following steps.

(l-l) (l-J)

Wherein R \ R ³² s X ² and p are as defined above.

(Step 8)

From compound (c) obtained by the method described in Production Method 1, Step 2, compound (g) is produced according to the method described in Production Method 2, Step 4, using compound (C-1) in which is can do.

(Step 9)

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.

(Process 10)

Compound (h) can be produced according to the method described in Production Method 2, Step 5, using Compound (g) obtained in Step 8 above.

(Step 11)

Compound (I-J) can be produced according to the method described in Production Method 1, Step 3, using compound () obtained in Step 10 above.

Manufacturing method 4

Among the compound (I), a compound wherein R ¹ is a 0H (I- L) and passing ¾ ⁶ (wherein, beta ⁵ and R ⁶ Waso are the same meanings as it above), Compound (141) it It can also be manufactured by the following steps. -

(i)

(Wherein, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each as defined above)

(Step 12)

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. Form, 1,2-dichloroethane, benzene, toluene, xylene, nitrobenzene,, a, a-trifluorotoluene, pentane, hexane, heptane, cyclohexane, N, N-dimethylformamide, Ν, Ν- Examples include dimethylacetamide, Ν-methylpyrrolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, and sulfolane. These can be used alone or in combination. Among them, it is preferable to use water in a mixture with the above-mentioned other solvents. 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 that can be used 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, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetoamide, Ν-methylpyrrolidone, Ν, Ν-dimethylimidazolidinone , Dimethylsulfoxide, sulfolane, pyridine and the like. Et a was or alone may be used as a mixture. 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. At this time, it is often good to use 1 to 5 equivalents of a suitable additive at the same time. Suitable additives to be used include, for example, Ν-hydroxysuccinimide, hydroxybenzotriazole, 3-hydroxy-4-oxo -3,4-dihydro-1,2,3-benzotriazine and the like.

Compound (Ι-Μ) can also be produced by the following steps.

(Step 14)

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 丄 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. As the solvent inert to the reaction which can be used at this time, 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, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, NJ-dimethylimidazolidinone, sulfolane, and the like. Alternatively, they can be used in combination. Examples of the chlorinating agent to be used include, for example, thionyl chloride, sulfuryl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, and the like.

(Process 15)

Compound (j) obtained in the above step 14, in a solvent or in a solvent inert to the reaction, 1 to 5 equivalents of the compound (i), usually at a temperature between -10 ° C. and the boiling point of the solvent used, The compound (IM) can be produced by reacting for 5 minutes to 24 hours. At this time, depending on the case, 1 to 10 equivalents of a suitable base can be used as an additive. Solvents inert to the reaction that can be used 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, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane, etc. , These Can be used alone or as a mixture. Suitable bases that can be used 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, Ν-methylmorpholine, 1,8-diazabicyclo [5.4.0]- 7-Pendecene, pyridine and the like. Manufacturing method 5

In the compound (I), 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.

(Wherein 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 ) (Step 15)

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 that can be used 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 , Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, Ν, Ν-dimethylimidazolidinone, dimethylsulfoxide, sulfolane and the like, and these can be used alone or in combination. Suitable bases that can be used 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, Ν-methylmorpholine, 1, 8-diazabicyclo [5.4.0]-7-pandene, pyridine and the like. Manufacturing method 6

Among the compounds (I), R ¹ is a NR¾ ^6, R ⁴ is

~ (CH ₂ ) _p -NR ³⁰ R ³¹

(Wherein ³⁰ R ³¹ and p are as defined above), respectively, can also be produced by the following steps.

(M) (m)

Process 1 9 HNR ³⁰ R ³¹

(d)

(l-O)

(Wherein, U \ R ³ , R ⁵ , R ⁶ , R ³ °, R ³¹ , p and X ² are as defined above)

(Step 17)

Production of compound (m) according to the method described in Production Method 5, Step 12 using a commercially available product or the compound (L) obtainable by the methods described in the above Production Methods 1 to 3 or according to them Can be.

(Step 18)

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.

(Step 19)

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.

Manufacturing method 7

In compound (I), R ² is

R ³⁵

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

In compound (I), R ² is

(In the formula, m is as defined above, and 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.

(Wherein, R \ R \ R ³⁷ s R ³⁸ and] n are as defined above)

(Step 20)

Using the method described in Production Method 1 or 4 to 6 or a compound (I-Q) obtainable according to them, and a dish ³⁷ E ³⁸ (wherein and R ³⁸ are as defined above), respectively. 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.

In each production method, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, the method for introducing and removing protecting groups commonly used in synthetic organic chemistry is used. [Eg Protective Groups ■ In-Organic Synthesis

(Protective Groups in Organic Synthesis), by T. W. Greene, John Wiley & Sons Inc., John Wiley & Sons Inc.

(1981)] can be used to obtain the desired compound. In addition, the order of reaction such as introduction of a substituent can be changed as required.

Above S 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 ΝΡΪΤ receptor antagonist of the present invention includes these. It is possible to use all possible isomers and mixtures thereof in any ratio.

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. Can be used for

Specific examples of the compound (I) used in the NPFF receptor antagonist of the present invention are shown in Tables 1, 2 and 3.

Table 1

Compound number FT

(Reference example 1 H

(Example 5) 2

(Example 6) 3

(Implemented Italy-4

(Example 8) 5

Table 1 continued

Compound number FT

(Example 9) 6

(Example 10) 7

(Example 11) 8

(Example 1 2) 9

(Example 13) 10

(Example 14) 11

(Example 15) 12

(Example 16) 13

(Example 17) 14

Table 1 continued

Compound number FT

(Example 18) 15

(Example 19) 16

-C ₃

: Example 20) 17

CH ₃

(Example 21) 18

(Example 22) 19

Table 2

Compound number R ¹

(Reference Example 2) 20 4

OH

(Reference Example 3) 21 4

(Example 23 22 4

(Example 24) 23 4

(Example 25) 24 4

(Example 26) 25 4

(Example 27 26 4

Table 2 continued

Compound number R ¹

(Example 28) 27 4

(Example 29) 28 4

(Reference Example 4) 29 3 ΟΗ

(Reference Example 5) 30 3

(Reference Example 6) 31 3

Table 3

Compound number R, FT

(Reference Example 7) 32

(Reference Example 8) 33

(Reference Example 9) 34

(Reference Example 10) 35

(Reference Example 11) 36

(Example 30) 37

Next, the pharmacological action of the representative compound (i) will be specifically described with reference to test examples.

For in vitro evaluation, binding experiments to rat NPFF receptors were performed. For in vivo evaluation, a white plate test and a tilpinch test, which have long been widely used as test methods for judging the analgesic effect, were performed. Furthermore, as an evaluation of the effect on hyperalgesia during neuropathic pain, a thermal stimulation test using a neuropathic pain pathological model was performed. 'Test Example 1: Rat NPFF receptor binding experiment

Rat spinal meninges (final concentration 2 iDg-protein), [ ^{1 M} I] NP; FF {squirrel buffer [50 mmol / L Tris-HCl, 60 hi ol / L NaCl ヽ 1 orchid ol / L MgCl ₂ , 3 zg / ml aprotinin, 30 / mol / L base, 5 mg / mL ゥ serum albumin (pH = 7.4)] to a final concentration of 0.1 imol / L}, and a test compound (final concentration in Tris buffer). 30 nmol / L ~; diluted to LO mol / L) and incubated at 25 ° C for 60 minutes. 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 [ ^1¾i I] NPFF binding inhibition rate with respect to the specific binding of the test compound.

Table 4

'ヅ NPFF receptor

Inhibition rate (%)

Compound number 3 μηιοΙ /

42.5

3 74.9

4 57.2

5 59.1

6 61.4

8 43.8

9 81.1

10 58.6

11 48

12 59.2

13 48.5

15 70.4

17 46.3

19 54

21 100

22 93.6

23 61.1

28 88.8

30 93.8

31 41

46

36 71

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. Based on the measured latency and body weight, 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. The significance test is Using Student's t-test, the test was performed between the control group and the test compound administration group. The results are shown in Figure 1. Compound 30 significantly increased latency at 30 mg and 60 minutes after administration at a dose of 3 mg / k. This indicated that Compound 30 had an analgesic effect. 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. Based on the measured latency and weight, 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 result is shown in figure 2. On the first day of administration, in the second group (distilled water + morphine) and the third group (compound 30 + morphine), an increase in AUC relative to the first group (distilled water + saline), that is, an analgesic effect was confirmed. The analgesic effect of group 2 (distilled water + morphine) was reduced from day 2 of administration, whereas the analgesic effect of group 3 (compound 30 + morphine) was not reduced until day 5 of administration. This indicated that Compound 30 suppressed morphine tolerance. Test Example 4: Investigation of neuropathic pain suppression in rats with strangulated nerve injury

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. Based on the results, the 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.

The results are shown in Figure 3. 60 minutes after administration, Compound 30 significantly increased latency at a dose of 3 nig / k. The results showed that Compound 30 was also effective in a model of neuropathic pain due to nerve injury.

Based on the above, 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. . In addition, 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.

As 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. For example, in the case of an injection, 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.

■ In addition, these 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.

Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples. However, the scope of the present invention is not limited to these examples. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the analgesic effect of Compound 30 in a hot plate test. One hundred: one control mouth

-Hata-: Compound 30 administration group

FIG. 2 is a graph showing the inhibitory effect of compound 30 on morphine tolerance in tilpin titers.

110: distilled water + saline administration group

Ichinichi: distilled water + morphine administration group

— ▲ —: Compound 30 + morphine administration group

FIG. 3 is a graph showing the inhibitory effect of Compound 30 on neuropathic pain in rats with strangulated nerve injury.

一〇—: Control

-·-: Compound 30, 0.3 mg / kg dose group One-one: Compound 30, 1 nig / kg administration group

ー騸： Compound 30, 3 mg / kg dose group The best form for cold application of the invention Example 1: Tablet (Compound 30)

A tablet having the following composition is prepared by a conventional method.

40 g of Compound 30, 286.8 g of lactose and 60 of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine equipped with an 8 mm diameter punch (Kikusui RT15) to obtain tablets (20 mg of active ingredient per tablet). Containing) is obtained.

Formulation compound 30 20 mg

Lactose 143.3 mg

30K

Hydroxypropyl cellulose 6 mg

Magnesium stearate 1 Q-7

200 mg Example 2: Tablet (Compound 21)

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.

Prescription compound 21 20 mg

Lactose 143.3 mg

Potato starch 30 mg

Hydroxypropyl cell mouth 6 mg

Magnesium stearate 0. T mg

200 mg Example 3: Injection (Compound 3)

An injection having the following composition is prepared by a conventional method.

Dissolve 1 g of Compound 3 in purified soybean oil and add 12 g of purified egg yolk lecithin and 25 g of glycerin for injection. This mixture is kneaded and emulsified in a conventional manner with distilled water for injection to 1000 mL. The resulting dispersion is aseptically filtered using a 0.2 m disposable membrane filter, and aseptically filled into glass vials in 2 mL increments. Injection (containing 2 mg of active ingredient per vial) ).

Formulation compound 3 2 mg

Refined soybean oil 200 mg

Purified egg yolk lecithin 24 mg

Glycerin for injection-50 mg

1.72 mL of distilled water for injection

2.0 mL Example 4: Injection (Compound 22)

The title injection (containing 2 mg of active ingredient per vial) is obtained in the same manner as in Example 3 using 40 g of compound 22.

Formulation compound 22 2 mg

Refined soybean oil 200 mg

Purified egg yolk lecithin 24 mg

Glycerin for injection 50 mg

1.72 mL of distilled water for injection

The method for producing the compound will be specifically described below at 2.0 mL or less. In the proton nuclear magnetic resonance spectrum (-NMR) used herein, the notation of the multiplicity of a signal is a commonly used one, but indicates that the signal is apparently broad. Reference Example ί: Synthesis of Ν-cyclooctyl-tri [4- (topyrrolidinyl) butyl] indole-2-carboxamide (Compound 1)

Stage 1

A solution of シクロ -cyclooctylindole-2-carboxamide (500 mg 1.85 ol) in dimethoxyethane (10 L) obtained according to the method described in W097 / 03965 at room temperature at 10 mol / L hydroxylation power The aqueous solution (648β) and the bottle (320 L, 2.78 dishes ol) were added slowly with stirring. The reaction solution was heated to 70 ° C. and stirred for 3 hours. After completion of the reaction, the mixture was neutralized with 2 mol / L hydrochloric acid, and further added with water (100 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give 1- (4- (Butyl) -N-cyclooctylindole-2-carboxamide (compound aa) (300 mg ') was obtained as a white powder.

Stage 2

To a solution of the compound aa (260 mg, 0.722 orchid ol) obtained in the above step 1 in ethanol (20 ml) was added pyrrolidine (425 L, 5.06 ref), and the mixture was heated under reflux for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution, water and ethyl acetate were added to the residue for extraction. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel gel column chromatography (chloroform / methanol / aqueous ammonia = 100/10/1). Compound 1 (246 nigs 0.623 fan ol) was obtained as a white powder (total yield of two steps: 3950.

-Accessories ((Sppm, DMS0-d ₆ ): 8.32 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H) ₅ 7.52 (d, J = 8.1 Hz, III), 7.22 ( t, J = 8.1 Hz, 1H) ₃ 7.06 (t, J2 8.1 Hz, 1H), 7.01 (s, 1H), 4.53 (t, J = 7.3 Hz, 2H), 4.06-3.95 (m, 1H ), 2.35-2.30 (m, 4H), 1.82-1.28 (m, 24H)

Mass (m / z): 396 (M + H) ⁺

Example 5: Synthesis of 3-Penzol-N-cyclooctyl-1- [4- (topyrrolidinyl) butyl] indole-2-carboxamide (Compound 2)

Stage 1

Acetonitrile (20 mL) of polyphosphoric acid (470 mg) and benzoic acid (1.94 gJ5.86 nmol) To the solution was added trifluoroacetic anhydride (2.2 mL, 15.4 ol) at room temperature, and the mixture was stirred at room temperature for 5 minutes. Then, a solution of ethyl 2-indole-2-carboxylate (1.00 g, 5.29 mmol) in acetonitrile (10 mL) was added. Slowly and calorie, stirred at room temperature for another 2 hours. The reaction solution was poured into ice water, left at room temperature for 30 minutes, and extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (closure form) to give ethyl 3-benzoylindole-2-carboxylate (compound bb) (compound bb) ( 617 mg, 1.91 fractions ol) were obtained as white crystals (yield 36%).

Stage 2

In the same manner as in Reference Example 1, the compound bb (500 mg, 1.55 mol) obtained in the above Step 1 was used instead of N-cyclooctylindole-2-carboxamide to give 3-benzoyl- [4- (1-Pyrrolidinyl) butyl] indole-2-ethyl carboxylate (Compound cc) (238 mg, 0.569 tmol) was obtained as a colorless oil (total yield of two steps: 377).

Stage 3

To a solution of the compound cc (203 mg \ 0.486 thigh) obtained in the above step 2 in ethanol (3 mL) was added a 2 mol / L aqueous sodium hydroxide solution (730 lββ thigh) at room temperature, and the mixture was heated under reflux for 2 hours. After evaporating the solvent under reduced pressure, the solution is acidified with 2 mol / L hydrochloric acid, and the precipitated crystals are collected by filtration and dried under reduced pressure to give 3-pentyl-1- [4- (topyrrolidinyl) butyl] indole-2. -Carboxylic acid (compound dd) (9311, 0.238 01) was obtained as white crystals (yield 50%). Stage 4

The compound dd (80 mg _N 0.214 tmol) obtained in Step 3 above was suspended in dichloromethane (4 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide was suspended under ice cooling. Hydrochloride (hereinafter referred to as EDC) (82 mg, 0.428 mmol) and trihydroxybenzotriazole (76 mg, 0.428 mmol) were sequentially added, and the mixture was stirred for 30 minutes and then cyclooctylamine (44 L). , 0.321) and stirred overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (form: form / methanol = 10/1) to give Compound 2 (106 mg, 0.212 cafe ol) was obtained as a light brown solid (yield 99%).

_{¾ - NMR (dppm, CDC1 3} ): 8.32 (d, J = 7.8 Hz, 1H), 7.79 (d 3 J two _{7.6 Hz 3 2H), 7.58 (} t, J two 7.6 Hz, 1H), 7.45 ( t, J2 7.6 Hz, 2H), 7.42 (t, J = 7.0 Hz, IE), 7.31-7.21 (in, 2H), 7. 09 (t, J two _{7.0 Hz, 1H) 3 4.48 (} t, J two 7.3 Hz, 2H), 4.03-3. 92 (m 3 1H), 2.73-2.63 (m, 6H ), 1.96-1.53 (m, 22H)

Mass (m / z): 500 (M + H) ⁺

Example 6: Synthesis of N-cyclooctyl-3- (2-methoxybenzoyl)-[4- (topyrrolidinyl) butyl] indole-2-carboxamide (Compound 3)

Stage 1

In the same manner as in Step 1 of Reference Example 1, instead of N-cyclooctylindole-2-carboxamide, indole-2-ethyl carboxylate (3.00 g, 15.85 麵 ol) was used. N-butyl) indole-2-ethyl carboxylate (compound ee) (3.96, 14.19 t) was obtained as a white solid (yield 89.5%).

Stage 2

In the same manner as in Step 1 of Example 5, instead of indole-2-carboxylate and benzoic acid, the compound ee (156 mg, 0.56 marl ol) obtained in the above Step 1 and 2-methoxybenzoic acid ( Using 256 mg _N 1.68 mmol), 1- (4-chlorobutyl) -3- (2-methoxypentyl) indole-2-ethyl carboxylate (compound ff) (189 m, 0.458 inmol) as a colorless oil. Obtained (yield 82). '

Stage 3

In the same manner as in Step 3 of Example 5, compound ff (150 iDg, 0.363 ol) obtained in Step 2 was used instead of compound cc, and 1- (4-chlorobutyl) -3- (2- (Methoxybenzoyl) Indole-2-carboxylic acid (compound gg) (135 mg, 0.351 mmol) was obtained as a white solid (yield 97%).

Stage 4

In the same manner as in Step 4 of Example 5, compound gg (131 mg, 0.340 mmol) obtained in Step 3 above was used in place of compound dd, and 1- (4-clobutylbutyl) -N-cyclooctyl- 3- (2-Methoxybenzoyl) indole-2-carboxamide (compound hh) (120 mg, 0.245 mol) was obtained as a colorless oil (yield 72%).

Stage 5

Compound 3 (40 mg, 0.087 mmol) was converted to a colorless oil using the compound hh (60 mg, 0.13 mmol) obtained in Step 4 above in place of compound aa in the same manner as in Step 2 of Reference Example 1. Thing (Yield 67%).

¾-NM (d pm, DMS0 -d 6): 8.49 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.41 (t ₅ J = 7.3 Hz, 1H) ₃ 7.30 (t, J = 8.1 Hz, 1H), 7.25-7.17 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H) ₅ 4.17 (t, J = 7.3 Hz, 2H), 3.63 (s ₃ 3H) ₃ 3.51-3.37 (m, 1H), 2.43-2.35 (, 6H), 1.79-1.35 (m, 22H)

Mass (m / z): 531 (M + H) ⁺

Example 7: Synthesis of N-cyclooctyl-3- (3-methoxybenzoyl) -1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 4)

Compound 4 (64 m, 0.121 lmiiol) was obtained as a colorless oil by using 3-methoxybenzoic acid instead of 2-methoxybenzoic acid in Step 2 in the same manner as in Example 6. 16%).

¾-賺((5 ppm, discussions _{- d 6): 8.57 (d} , J = 7.8 Hz, 1H), 8.03 (d, J two 8.1 Hz, 1H), 7.68 ( d, J = 8.1 Hz, 1H), 7.66 -7.12 (m, 6H), 4.33 (t, J2 7.3 Hz, 2H), 3.78 (s, 3H), 3.53-3.42 (m, 1H), 2.45-2.35 (, 6H), 1.80-1.22 (m, 22H)

Mass (m / z): 531 (M + H) ⁺

Example 8: Synthesis of N-cyclooctyl-3- (4-methoxybenzoyl) -1- [4- (1-pyrrolidinyl) butyl} indole-2-carboxamide (Compound 5)

Compound 5 (76 mg, 0.121 mmol) was obtained as a colorless oil by using 4-methoxybenzoic acid instead of 2-methoxybenzoic acid in Step 2 in the same manner as in Example 6 (total yield). 27%). ,

] H - thigh _{(dppm, DMS0-d 6)} : 8.55 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 4.34 (t , J = 7.8 Hz, ZH), 3.82 (s, 3H), 3.58-3.50 (m, 1H), 2.42-2.33 (m, 6H), 1.75-1.14 (m, 22H) Mass (m / z): 530 (M ⁺ )

Example 9 Synthesis of 3- (2-cyclopentyl) -N-cyclooctyl-1- [4- (topyrrolidinyl) butyl] indole-2-carboxamide (Compound 6)

In the same manner as in Example 6, 2-methoxybenzoic acid was used instead of 2-methoxybenzoic acid in Step 2. Compound 6 (73 mg, 0.137 iMol) was obtained as a colorless oil by using an acid (total yield 21%).

Ή-Marauder (dppm, D S0-d _B ): 8.63 (d, J = 7.3 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.47 (m, 2H), 7.39-7.22 (m, 4H), 4.17 (t, J = 7.3 Hz, 2H), 3.42-3.33 (m, 1H), 2.42-2.33 (m, 6H), 1.79-1.33 (m ₃ 22H)

Mass (m / z): 534 (M + H) ⁺

Example 10: Synthesis of 3-cyclohexylcarbonyl-N-cyclooctyl-l- (4- (l-pyrrolidinyl) butyl) indole-2-carboxamide (Compound 7)

Stage 1

In the same manner as in Step 1 of Example 5, 1- (4-chlorobutyl) -3-cyclohexylcarbonyl-substituted with compound aa and cyclohexanecarboxylic acid instead of indole-2-ethyl carboxylate and benzoic acid N-Cyclooctylindole-2-carboxamide (Compound ii) (172 mg, 0.366 ex. 1) was obtained as a colorless oil (yield 65%).

Stage 2

Compound 7 (101ing, 0.20 mmol) was obtained as a colorless oil by using compound ii (107 mg, 0.228 iiimol) instead of compound aa in the same manner as in Step 2 of Reference Example 1 (yield 88 %).

¾-NMR (5 ppm, DMSO-d ₆ ): 9.14 (d, J 7.8 Hz, 1H), 8.23 (d, J 7.6 Hz, 1H), 7.60 (d, J 7.6 Hz, 1H) ₅ 7.30 ( t, J = 7.6 Hz, 1H), 7.23 (t ₃ J = 7.6 Hz, 1H), 4.16 (t, J = 7.3 Hz, 2H), 4.21-4.05 (m, 1H) ₅ 3.08-2.97 (m, IE ), 2.45-2.33 (m, 6H), 1.98-1.23 (m, 32H)

Mass (m / z): 506 (M + H) ⁺

Example 11: Synthesis of N-cyclooctyl-1- [4- (1-piperidinyl) butyl] -3- (2,2,2-trifluoroacetyl) indole-2-carboxamide (Compound 8)

By using trifluoroacetic acid instead of cyclohexanecarboxylic acid in the same manner as in Example 10, compound 8 (12 mg, 0.024 mol) was obtained as a colorless oil (total yield 9%).

¾-謹 ((5ppm ₅ DMS0-d ₆ ): 8.97 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H) ₃ 7.45 -7.36 (m, 2H), 4.26 (t, J = 7.6 Hz, 2H) 5 4.09-4.03 (m, 1H), 2.40-2.33 (m 5 6H) 3 1.92-1.42 (m, 22H)

Mass (m / z): 492 (M + H) ⁺ Example 12: Synthesis of N-cyclooctyl-3- (1-hydroxy-1-phenylmethyl) -1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 9)

To a solution of compound 2 (40 mg, 0.08 mmol) obtained in Example 5 in methanol (0.4 mL) was slowly added an aqueous solution (2 mL) of sodium borohydride (19 mg, 0.51 mmol) at room temperature. And stirred at 60 ° C for 15 minutes. After cooling to room temperature, a saturated aqueous solution of ammonium chloride (2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (form: form / methanol / aqueous ammonia = 100/10/1) to give compound 9 ( 30 mg, 0.06 tmol) was obtained as a colorless oil (yield: 75¾).

ΐ-ΝΜ (άρρπι, CDGlg): 8.08 (d, J = 7.3 Hz, 1H) ₅ 7.42-7.21 (m, 8H), 7.00 (t, J2 7.3 Hz, 1H), 6.38 (s, 1H), 4.52 (dt, J2 14.5, 7.2 Hz, 1H), 4.41 (dt, J = 14.5, 7.2 Hz, 1H), 4.06-3.95 (m, 1H), 2.35 (t, J2 7.6 Hz, 2H), 1.88- 1.18 (m,

26H).

Mass (m / z): 503 (M + H) ⁺

Example 13: N-cyclooctyl-3- [hydroxy-1- (2-methoxyphenyl) methyl] -1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (compound 10 )

Compound 10 (13 iDg, 0.024 mmol) was obtained as a colorless oil by using compound 3 obtained in Example 6 instead of compound 2 in the same manner as in Example 12. (Yield 28) ¾-NMR (dppm, DMS0- d c): 8.36 (d, J two 7.6 Hz, 1H), 7.80 ( d, J two 7.6 Hz, 1H), 7.42 ( d, J = 7.6 Hz, 2H), 7.21- 7.07 (m, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.90-6.81 (m, 2H), 6.31 (d, J two 4.1 Hz, 1H), 5.71 (d, J = 4.1 Hz, 1H ), 4.37-4.26 (m, 2H), 4.17-4.08 (m, 1H), 3.56 (s, 3H), 2.47-2.32 (m, 6H), 1.86-1.75 (m, 22H) Mass (m / z) : 532 (M + H) ⁺

Example 14: Synthesis of N-cyclooctyl-3- [1-hydroxy-1- (3-methoxyphenyl) methyl] -l- [4-U-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 11) Synthesis

Compound 11 (36 mg, 0.068 mmol) was obtained as a colorless oil by using compound 4 obtained in Example 7 instead of compound 2 in the same manner as in Example 12. Ή-Ν (dppm, DMSO- d 6): 8.61 (d, J two 7.6 Hz, IH), 7.50 ( t 3 J two 7.6 Hz, 2H), 7.20-7.12 ( m, 2H), 6.98-6.93 (m , 2H) ₃ 6.84 (d, J2 7.6 Hz, IH), 6.73 (d, J = 7.6 Hz, IH), 6.14-6.10 (m, 2H), 4.42-4.30 (m, 2H) ₃ 4.05-3.93 ( m, IH), 3.69 (s , 3H), 2.35-2.30 (m, 6H), 1.82-1.35 (m 3 22H)

Mass (m / z): 532 (M + H) ⁺

Example 15: Preparation of N-cyclooctyl-3- [trihydroxy-1- (4-methoxyphenyl) methyl] -tri [4- (tropyrolidinyl) butyl] indole-2-carboxamide (Compound 12) Synthesis

Compound 12 (30 m, 0.056 mmol) was obtained as a colorless oil by using compound 5 obtained in Example 8 instead of compound 2 in the same manner as in Example 12 (yield: 41%). . Ή-thigh (dppm, DMSO-d ₆ ): 8.64 (d ₅ J = 7.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 7.17 ( t, J = 7.8 Hz, IH), 6.94 (d, J = 7.8 Hz, 1H), 6.80 (d, J 8.6 Hz, 2H), 6.13 (d, J = 3.8 Hz, IH), 6.06 (d, J = 3.8 Hz, IH), 4.40-4.30 (m, 2H), 4.03-3.92 (m, IH), 3.69 (s, 3H), 2.45-2.38 (m, 6H), 1.90-1.38 (m 3 22H)

Mass (m / z): 532 (M + H) ⁺

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. %). Ή-Job (δρρη, DMS0-d ₆ ): 8.38 (d, J = 7.6 Hz, IH), 8.03 (d, J-7.6 Hz, 1H), 7.48-7.38 (m, 2H), 7.29-7.20 (m , 3H), 7.12 (t, J = 7.6 Hz, IH), 6.87 (t, J = 7.6 Hz, IH), 6.26 (d, J = 3.8 Hz, 1H) ₅ 6.03 (d, J = 3.8 Hz, IH ), 4.46-4.35 (m, IH), 4.29-4.18 (m, IH), 4.13-4.03 (m, IH), 2.40-2.34 (m, 6H), 1.90-1.36 (m, 22H) Mass (m / z): 537 (M + H) ⁺

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).

Thigh _{(dpprn, DMS0 - d 6)} : 8.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, IE), 7.41 (s, 1H) ₅ 7.31-7.16 (m, 4H), 6.98 (t ₃ J = 7.8 Hz, 1H), 6.27 (d, J = 4.0 Hz, 1H), 6.17 (J = 4.0 Hz, 1H), 4.40-4.27 ( m, 2H), 4.08-3.92 (m, 1H), 2.34-2.29 (m, 6H), 1.76-1.31 (m, 22H)

Mass (m / z): 537 (M + H) ⁺

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. ). _{Ή- NMR (dppm, CDC1 3)} : 7.69 (d, J two 7.8 Hz, 1H), 7.28-7.12 ( m, 4H), 5.40 (dd, J = 12.1, 7.3 Hz, 1H), 4.33-4.09 (m , 4H), 2.33 (t, J2 7.6 Hz, 2H), 1.83-1.23 (m, 26H)

Mass (m / z): 495 (M + H) ⁺

Example 19: 3-Cyclohexylmethyl-N-cyclooctyl-1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 16)

Stage 1

To a solution of compound ϋ (49 mg, 0.104 referred to) obtained in Step 1 of Example 10 in trifluoracetic acid (0.2 fflL) was slowly added triethylsilane (64 L 0.396 mmol) at room temperature, and the mixture was stirred overnight. . Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue obtained is purified by silica gel column chromatography to give 1- (4-chlorobutyl) -3-cyclohexylmethyl- N-Cyclooctylindole-2-carboxamide (compound) (45 mg, 0.099 mmol) was obtained as a white solid (yield 95%).

Stage 2

Similarly to 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%). ¾ -賺_{(dppm, DMS0 - d 6)} ': 8.34 (d, J two _{8.4 Hz, 1H) 3 7.53 (} d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 8.4 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 4.23 (t, J = 7.3 Hz, 2H), 4.08-4.01 (m, 1H), 2.69 (d, J = _{6.2 Hz, 2H) 3 2.40-2.30 (} m, 6H), 1.75-1.52 (m, 29H), 1.38-1.30 (m, 2H), 1.17-1.02 (m 5 1H), 0.92-0.80 (m, 1H)

Mass (m / z): 492 (M + H) ⁺

Example 20: N-cyclooctyl-3-isobutyl-1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 17)

Stage 1

In the same manner as in Step 1 of Example 10, using isobutyric acid instead of cyclohexanecarboxylic acid, 1- (4-octylbutyl) -N-cyclooctyl-3-isobutyrylindole-2 -Carboxamide (compound kk) (107 mg, 0.25 mol) was obtained as a white solid (yield 45%). Stage 2

In the same manner as in Step 1 of Example 19, the compound kk (74 mg, 0.174 mmol ol) obtained in the above Step 1 was used in place of Compound 、, to give 1- (4-clobutylbutyl) -N -Cyclooctyl-3-isobutylindole-2-carboxamide (Compound 11) (46 m, 0.116 mmol) was obtained as a white solid (yield 67).

Stage 3

Compound 17 (39 mg, 0.086 mmol) was obtained in the same manner as in Step 2 of Reference Example 1 by using Compound 11 (43 mg, 0.106 OH) obtained in Step 2 instead of Compound aa. Obtained as an oil (82% yield).

¾ NMR (dppm, DMS0-d ₆ ): 8.34 (d, J = 7.8 Hz, 1H), 7.54 (d ₃ J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.17 (t , J2 7.8 Hz, 1H), 7.02 (t, J2 7.8 Hz, 1H), 4.25 (t, J = 7.3 Hz, 2H), 4.08-4.00 (m, 1H), 2.69 (d, J = 7.3 Hz , 2H), 2.33-2.28 (m, 6H), 1.74-1.53 (m, 22H), 1.36-1.30 (m, 1H) ₃ 0.82 (d, J = 6.5 Hz, 6H) Mass (m / z): 452 (则 +

Example 21: N-cyclooctyl-3-phenyl-l- [4- (l-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 18)

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顺) (387 mg, 1.12 mmol) was obtained as a white solid (total yield 62%). Stage 2

In the same manner as in Reference Example '1, the compound obtained in the above Step 1] m (300 mg, 0.867 mmol) was used in place of N-cyclooctylindole-2-carboxamide to give Compound 18. mg, 0.224 mmol) as a white solid (total yield 37%).

¾ NMR (dppm, DMS0-d B): 8.20 (d, J two 8.1 Hz, 1H), 7.66 ( d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.51-7.40 (m, 4H), 7.31-7.24 ( m, 2H), 7.12 (t, J two 7.8 Hz, 2H), 4.27 ( t, J = 7.3 Hz, 2H), 4.07-3.92 (m 5 1H) 5 2.48- 2.41 (m, 6H), 1.78-1.47 (m, 22H)

Mass (m / z): 472 (M + H) ⁺

Example 22: 3-Benzyl-N-cyclooctyl-1- [4- (1-piperidinyl) butyl] indole-2-carboxamide / 1 maleate (Compound 19)

In the same manner as in Example 20, 3-benzyl-N-cyclooctyl-1- [4- (topyrrolidinyl) butyl] indole-2-carboxamide (84 mg, 0.221 mmol) as a colorless oil (total yield 3%).

Then, the obtained compound (48 m, 0.099 mmol) and maleic acid (11.5 mg, 0.099 mol) were heated under reflux in ethanol (1 mL) for 15 minutes, and the solvent was distilled off. The compound 19 (33 Dig, 0.054 mol) was obtained as white crystals by recrystallization from alcohol diisopropyl ether (yield 55%).

Compound 19 (as free base)

_{¾ NMR (dppm, CDC1 3)} : 7.54 (d, J = 8.1 Hz, 1H), 7.40-7.10 (m, 8E), 5.90 (brs, 1H), 4.42 (t, J = 7.6 Hz, 2H), 4.30 (s, 2H), 4.12-4.05 (m, IH), 2.74-2.56 (m, 6H), 1.94-1.25 (m, 22H)

Mass (m / z): 486 (M + H) ⁺

Reference example: 3- (l, l-diphenylmethyl) -1- [4- (topyrrolidinyl) butyl] indole -2-carboxylic acid (compound 20)

Compound 20 was obtained according to Example 89 described in W097 / 03965.

Reference Example 3: N-cyclooctyl-3- (1,1-diphenylmethyl)-[4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 21)

Compound 21 was obtained according to Example 92 described in W097 / 03965.

Example 23: N-cycloheptyl-3- (1,1-diphenylmethyl)-[4- (1-pyrrolidinyl) butyl] indole-2-carboxamide.1 maleate (Compound 22)

Compound 20 (200 mg 0.442 Lotus ol) was suspended in dichloromethane (8 mL), and the suspension was added with ice-cooling to give 3- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (169 mg, 0.884 mL). 1) Hydroxybenzotriazole (135 mg, 0.884 mmol) was sequentially added, and the mixture was stirred for 30 minutes. Then, cycloheptylamine (84 ju O.663 ol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain N-cycloheptyl-3- (1,1-diphenylmethyl)- 1- [4- (1-Pyrrolidinyl) butyl] indole-2-carboxamide (180 mg \ 0.33 Dimol) was obtained (yield: 75%).

The obtained compound (180 mg, 0.33 tmol) and maleic acid (38 mg, 0.33 nunol) were heated under reflux in ethanol (5 mL) for 15 minutes, the solvent was distilled off, and the residue was concentrated in isopropyl alcohol. The compound 22 (163 in, 0.24 orchid ol) was obtained as white crystals by recrystallizing from 1-ludiisopropyl ether (yield 73%).

Compound 22 (as free base)

Ή賺_{(] n, CDC1 3):} 7.34-7.15 (m, 12H), 6.88-6.80 (m, 2H), 5.92 (s, 1H), 5.77 (d, J = 8.1 Hz, 1H), 4.30 (t , J = 6.5 Hz, 2H), 4.07-3.99 (m, 1H) ₅ 2.89 (t, J = 8.1 Hz, 2H), 2.05-1.90 (m, 12H), 1.58-1.44 (m, 10H), 1.30- 1.20 (m, 2H) Mass (m / z): 548 (M + H) ⁺

Example 24: N-cyclohexyl-3- (1,1-diphenylmethyl'tyl) -1- [4- (l-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 23)

Compound 20 (200 mg, 0.442 awake ol) was suspended in dichloromethane (8 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (169 mg) was added under ice cooling. , 0.884 tmol) and 1-hydroxybenzotriazole (135 mg, 0.884 imol) were added sequentially, and stirred for 30 minutes. After stirring, cyclohexylamine (76 zL, 0.663 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (form: chloroform / methanol / aqueous ammonia = 100/10/1) to give Compound 23 (160 mg, 0.30 mmol) was obtained (68% yield).

¾ NMR (dppm ₃ D S0-d ₆ ): 8.27 (d, J = 8.4 Hz, 1H), 7.52 (d, J'2 8.4 Hz, 1H) ₃

7.29- 7.11 (m, 11H), 6.93 (d, J = 7.6 Hz, 1H), 6.85 (t, J two _{7.6 Hz 3 1H), 5.88 (} s, m), 4.23 (t, J = 6.5 Hz, 2H ), 3.83-3.72 (m, 1H) , 3.18-2.97 (m, 2H), 2.92 (t, J = 6.5 Hz, 2H), 1.90-1.56 (m 3 18H), 1.33-1.23 (m, 2H)

Mass (m / z): 534 (thigh) +

Example 25: 3- (1,1-didiphenylmethyl) -2- (morpholinocarbonyl) -tri [4- (1-pyrrolidinyl) butyl] indole (Compound 24)

Compound 24 (30 mg, 0.06 mmol) was obtained in the same manner as in Example 24, except that morpholine was used instead of cyclohexylamine (yield: 26%).

_{_{¾ NMR (dppm 5 CDG1 3)}} : 7.36-7.13 (m 3 13H), 6.98 (t, J two 7.8 Hz, 1H), 5.71 ( s, 1H), 4.36-4.30 (m, 1H), 3.89-3.83 ( _{m 5 1H), 3.72-3.55 (m} 3 6H), 3.49-3.40 (m, 1H) 5

3.30- 3.21 (m, 1H), 3.09-2.97 (m, 1H) ₅ 2.86-2.63 (m, 5H), Z.18-1.65 (m, 8H)

Mass (m / z): 522 (M + H) ⁺

Example 26: 3- (1, Todiphenylmethyl) -2- (piperidinocarbonyl) -1- [4-"" pyrrolidinyl) butyl] indole.1 Maleate (Compound 25)

In the same manner as in Example 23, piperidin was used in place of cycloheptylamine to obtain a conjugate 25 (66 mg, 0.13 mmol) (yield 47%).

_{¾ NMR (dppm, CDC1 3)} : 7.34-7.11 (m, 13H), 6.94 (t, J = 7.8 Hz, 1H) 3 5.68 (s, m), 4.29-4.21 (m, IE), 3.96-3.83 ( m, 1H), 3.73-3.53 (m , 2E), 3.00-2.92 (m, 1H), 2.78-2.63 (m 5 5H) 5 2.54-2.48 (m, 2H), 2.17-1.43 (m, 12H), 1.23-1.12 (m, IE), 1.00-0.91 (m, 1H)

Mass (m / z): 520 (M + H) ⁺

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%).

Compound 26 (as the free _{base), NMR (Sppm, CDC1 3} ): 7.34-7.11 (m 3 13H), 6.94 (t, J = 7.0 Hz; IH), 5.73 (s, IH), 4.32-4.19 (m, IH), 3.94-3.83 (m, IH), 3.59-3.30 (m, 2H), 2.97-2.83 (m, 1H) ₃ 2.62-2.43 (m, 7H), 2.17-1.55 (m, 11H), 1.55- 1.39 (m, IH)

Mass (m / z): 506 (M + H) ⁺

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 °).

_{¾NMR ((5ppm, CDC1 3)} : 7.33-7.17 (m, 12H), 6.91-6.82 (m, 2H), 6.47-6.42 (m, IH), 5.92 (s, 1H), 4.31 (t, J = 7.0 Hz, 2H), 3.47-3.34 (m, 5H), 2.89 (t, J 7.3 Hz, 4H), 2.69 (t, J 7.9 Hz, 2H), 2.22 (t, J = 7.9 Hz, 2H), 2.00-1.65 (m, 11H) Example 9: 3- (1,2-diphenylmethyl) -N- (2-pyridinoethyl) -1- [4- (1-pyrrolidinyl) butyl] indole-2-carboxamide (Compound 28)

Compound 28 (360 mg, 0.64 orchid ol) was obtained in the same manner as in Example by using 2-piridinoethylamine instead of cyclohexylamine (yield 26%).

_{_{¾ NMR ((5ppm 3 CDC1 3}} ): 7.42-7.13 (m 3 12H) 3 6.94 (d 5 J two _{8.1 Hz, 1H) 3 6.85 (} dd, J = 8.1, 7.0 Hz, 1H), 6.16 (t, J = 4.9 Hz, IH), 6.00 (s, 1H), 4.35 (t, J2 7.3 Hz, 2H), 3.44 (dt, J2 6.1, .9 Hz, 2H), 2.37 (t, J = 6.1 Hz, 2H), 2.5 2.21 (m, 12H), 1.91-1.22 (m, 12H).

Reference Example 4: 3- (1,1-diphenylmethyl) -1- [3- (1-pyrrolidinyl) propyl] indole-2-carboxylic acid (Compound 29)

Compound 29 was obtained according to Example 74 described in W097 / 03965.

Reference Example 5: 3- (1, didiphenylmethyl) -N- (2-piberidinoethyl) -tri [3- (topyrrolidinyl) propyl) indole-2-carboxamide dihydrochloride (Compound 30)

Using the synthesis method of Example 78 described in W097 / 03965, Ν- (2-pyridinoethyl) -3- (1,1-diphenylmethyl) -tri [3- (topyrrolidinyl) propyl] indole-2 -Carboxamide (2.13 g, 3.89 mmol) was obtained (yield 43%). In the same manner as in the maleate synthesis method described in Example 23, using this compound and using 2.5 mL (10 mmol) of a 4 mol / L hydrochloric acid / ethyl acetate solution instead of maleic acid, compound 30 (1.18 g, 1.90 mmol) was obtained (yield 53%). Compound 30 (as free base)

_{¾ NM (5ppm, CDC1 3)} : 7.39-7.15 (m, 12H), 6.98-6.83 {, 2H), 6.71 {t, J two 5.3 Hz, 1H), 6.04 ( s, 1H), 4.42 (t, J _{= 6.9 Hz, 2H) 3 3.43} (dt, J two _{6.3, 5.9 Hz, 2H) 5} 2.50-2.40 (m 5 6H), 2.39 (t, J: 6.3 Hz, 2H), Z.35-2.25 (m 5 4H), 2.12-2.04 (m, 2H), 1.80-1.70 (m, 4H) ₅ 1.45-1.30 (m, 6H)

Mass (m / z): 548 (M) ⁺

Reference Example 6: N-cyclooctyl-3- (1,1-diphenylmethyl) -1- [3- (1-pyrrolidinyl) propylpyr] indole-2-carboxamide (Compound 31)

Compound 31 was obtained according to Example 77 described in W097 / 03965.

Reference Example 7: N-cycloheptyl-1- (2-dimethylaminoethyl) -3- (1,1-diphenylmethyl) indole-2-carboxamide (Compound 32)

Compound 32 was obtained according to Example 11 described in W097 / 03965.

Reference Example 8: N-cyclooctyl-1- (3-dimethylaminopropyl) -3- (1,1-diphenylmethyl) indole-2-carboxamide (Compound 33)

Compound 33 was obtained according to Example 69 described in W097 / 03965.

Reference Example 9: N-cyclooctyl-1- (4-dimethylaminobutyl) -3- (1,1-diphenylmethyl) indole-2-carboxamide (Compound 34)

Compound 34 was obtained according to Example 85 described in Volume 97/03965.

Reference Example 10: (2-Dimethylaminoethyl) -3- (1,1-diphenylmethyl) -N- (2-piperidinoethyl) indole-2-carboxamide (Compound 35)

Compound 35 was obtained according to Example 19 described in W097 / 03965.

Reference Example 11: 1- (3-Dimethylaminopropyl) -3- (1,1-diphenylmethyl) -N- (2-pyridinoethyl) indole-2-carboxamide (Compound 36)

Compound 36 was obtained according to Example 70 described in W097 / 03965.

Example 30: N-cyclooctyl-3- (1, didiphenylmethyl) -tri (pyridine-4-ylmethyl) indole-2-carboxamide (Compound 37) Stage 1

3- (1,1-diphenylmethyl) indole-2 obtained by the method described in the literature [Journal of the 'Ob' Medicinal 'Chemistry, 1974, Vol. 17, P.1298] -Carboxylic acid (750 mg, 2.29 ol) was suspended in dichloromethane (8 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimid hydrochloride (880 mg, 4.59 mmol) and trihydroxybenzotriazole (815 mg, 5.32 thigh ol) were added sequentially, and the mixture was stirred for 30 minutes. . Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate 1/1) to give N-cyclooctyl-3-. (1,1, didiphenylmethyl) indole-2-carboxamide (compound nn) (627 mg, 1.4 tmol) was obtained (yield 63%). Stage 2

To a dimethoxetane solution of the compound nn (61 mg \ 0.1 t ol) obtained in the above step 1 was added a 10 mol / L aqueous hydroxide aqueous solution (63 L, 0.63 t ol) under ice-cooling, followed by stirring for 30 minutes. Then, under ice-cooling, 4-picolyl chloride hydrochloride (36 mg, 0.21 mol) was added, and the mixture was heated to room temperature and stirred at 70 ° C for 4 hours. After the reaction was completed, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (form-form / methanol / aqueous ammonia = 100/10/1) to give Compound 37. (27 mg, 0.05 w / ol) was obtained (36% yield). ¾ NMR (dppm, DMS0-d ₆ ): 8.45 (d, J two 6.2 Hz, 2H), 8.24 (d, J two 8.1 Hz, 1H), 7.40 (d, J two 8.6 Hz, 1H), 7.32-7.17 (m, 1011), 7.12-7.06 (m, 1H), 7.02 (d, J = 6.2 Hz, 2H), 6.90-6.81 (m, 2H), 5.97 (s, III), 5.49 (s, 2H), 3.90-3.83 (m, 1H), 1.65-1.40 (m, 14H)

Mass (m / z): 528 (M + H) ⁺ Industrial applicability

According to the present invention, various diseases derived from NPFF receptor hyperactivity (eg, hyperalgesia at the time of neuropathic pain, arodinia, morphine) containing an indole derivative or a pharmacologically acceptable salt thereof as an active ingredient. And molar tolerance to narcotic analgesics represented by NPFF receptor antagonists useful for treatment and / or prevention of narcotic analgesics such as chicks) are provided. Further, the present invention provides a novel indole derivative having the above-mentioned characteristics or a pharmaceutically acceptable salt thereof.

Claims

The scope of the claims

1. General formula (I)

Wherein R ¹ is hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aromatic heterocyclic oxy or -NR ⁶ (wherein R ⁵ and R ^s are Same or different, hydrogen or

One H ^ k One R

Wherein R ⁷ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted alicyclic alkyl, an amino, a 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 (where R ⁷ is R ⁷ When it is bonded to (C¾) _k via a nitrogen atom in the formula, it represents an integer of 2 to 6)], or R ⁵ and R ⁶ are substituted or unsubstituted together with the adjacent nitrogen atom. Which forms an alicyclic heterocyclic group of the formula

R ² is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group,

0

I I o

One (^ H ₂ Fir ^ -R

Wherein R ⁸ is hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloaliphatic 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 Formula represents a heterocyclic group, an amino, a substituted or unsubstituted mono- or di-lower alkylamino, a substituted or unsubstituted mono- or diarylamino, or a substituted or unsubstituted mono- or di-aromatic heteroamino, wherein m is an integer of 0 to 6. ), Or

(Wherein represents hydrogen or hydroxy, β ^ω and R ¹¹ are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted cycloaliphatic alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted mono- or di-lower alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted aryl Unsubstituted monoarylamino, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted monoaromatic heterocyclic amino or substituted or unsubstituted alicyclic Represents a formula heterocyclic group, and η represents an integer of 0 to 6)

R ³ represents hydrogen, halo.gen, nitro, cyano, hydroxy, substituted or unsubstituted lower alkoxy, amino or substituted or unsubstituted mono- or di-lower alkylamino;

R ⁴ is hydrogen or

One (cny ^ R ¹²

Wherein R ¹² 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 arylamino, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted mono or diaromatic represents heterocycle Amino, substituted or unsubstituted Ariru, a substituted or unsubstituted Kaoru aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group, P is 1-6 (provided that, R ¹² is R ¹² through a nitrogen atom in (CH ₂₎ when joining the _P is an integer of representative representing the> indole derivative or a pharmacologically acceptable represented by 2-6) Neuro base peptide FF receptor antagonists containing a salt as an active ingredient.

2. beta ¹ is - 1¾¾ ⁶ (wherein, R ⁵ and it it the same meaning as defined above) neuro base peptide FF receptor antagonist according to claim 1, wherein a.

3. R ² 0

— CR ⁸

3. The neurobeptide FF receptor antagonist according to claim 1, wherein: has the same meaning as defined above.

4. R ²

The neurobeptide FF receptor antagonist c according to claim 1 or 2,

5. R ⁴

(Wherein is as defined above). The dual-mouth FF receptor antagonist according to any one of claims 1 to 4, wherein

6. —General formula (IA)

(IA)

[Wherein, R ^1A is -NR ^5A R ^6A (wherein, R ^5A and R ^6A are the same or different and each represent hydrogen or an aliphatic 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 ^ has the same meaning as R ³ above. Derivatives or pharmacologically acceptable salts thereof.

7. General formula (IB)

(IB)

(Wherein, R ^13B represents a substituted or unsubstituted alicyclic heterocyclic group, and R ^3B has the same meaning as R ³ ) or a pharmacologically acceptable salt thereof.

8. General formula (IC)

( I C )

(Wherein, R ^5C represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic alkyl, R ^12G represents a substituted or unsubstituted aromatic heterocyclic group, and R ^3G represents the above R ³ Or a pharmacologically acceptable salt thereof.

9. General formula (ID)

(ID)

(Wherein, R ^5D represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic alkyl,

R ^9D represents hydrogen or hydroxy,

R ^lffl) represents hydrogen, or R ^9D and R ¹ ™ represent oxo,

R ^11D is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted alicyclic alkyl, Represents a substituted or unsubstituted aryl,

R ^3D has the same meaning as R ³ ,

r represents an integer of 2 to 6,

_R WD and j ^ D are the same or different and each represents a substituted or unsubstituted lower alkyl, or R ^14D and together with an adjacent nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic group. Formed) or a pharmacologically acceptable salt thereof.

10. The indole derivative or the pharmaceutically acceptable salt thereof according to claim 9, wherein R ^5D is alicyclic alkyl.

11. r is 3 or 4, R ^{1 D} and R ^15D if substitution together with the adjacent nitrogen atom clause of claims 9 or 10 wherein the forming the unsubstituted alicyclic heterocyclic group Indole derivative or a pharmacologically acceptable salt thereof.

12. —General formula (IE)

(IE)

(Wherein, R ^2E represents a substituted or unsubstituted aryl, R ^5E represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted alicyclic alkyl, and R ^3E has the same meaning as the above R ^:! And s represents an integer of 2 to 6, and R ^14E and R ^15E are the same or different and represent a substituted or unsubstituted lower alkyl, or R ^14E and R ^15E are substituted together with an adjacent nitrogen atom. Or an unsubstituted aliphatic heterocyclic group) or a pharmacologically acceptable salt thereof. .

13. A medicament comprising the indole derivative according to any one of claims 6 to 12 or a pharmacologically acceptable salt thereof as an active ingredient.

14. A neurobeptide FF receptor antagonist comprising the indole derivative according to any one of claims 6 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

15. Treatment of a disease caused by hyperactivity of a neuropeptide FF receptor containing the indole derivative according to any one of claims 6 to 12 or a pharmacologically acceptable salt thereof as an active ingredient, and Z Or prophylactic agents.

16. Treatment of diseases caused by hyperactivity of neurobeptide ΪΤ receptor containing the indole derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient, and Z Or prophylactic agents.

17. A therapeutic and / or prophylactic agent for neuropathic pain comprising the indole derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

18. An analgesic comprising the indole derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

19. A drug for overcoming a narcotic analgesic resistance, comprising the indole derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.

20. An analgesic potentiator comprising an indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient.

21. A therapeutic and / or preventive agent for neuropathic pain comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 as an active ingredient.

22. An analgesic comprising the indole derivative according to any one of claims 6 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.

23. A drug for overcoming a narcotic analgesic resistance comprising the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 as an active ingredient.

24. An analgesic potentiator comprising an indole derivative or a pharmacologically acceptable salt thereof according to any one of claims 6 to 12 as an active ingredient.

25. A disease derived from hyperfunction of neuropeptide FF receptor, comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5. Treatment and / or prevention method.

26. A method for treating and / or preventing or treating neuropathic pain, comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

27. An analgesic method comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

28. 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 one of claims 1 to 5.

29. 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 claims 1 to 5.

30. Derived from enhanced function of neurobeptide FF receptor, comprising a step of administering an effective amount of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 A method for treating and / or preventing a disease.

31. A method for treating and / or preventing or treating neuropathic pain, comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 12.

32. 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 claims 6 to 12. .

33. A method for overcoming a narcotic analgesic resistance, comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 12.

34. A method for enhancing an analgesic action of an analgesic, comprising a step of administering an effective amount of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 12.

35. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the production of a neurobeptide FF receptor antagonist.

36. The indole derivative according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof, for the manufacture of a therapeutic and / or prophylactic agent for a disease derived from hyperactivity of a neuropeptide FF receptor. Use of salt.

37. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a therapeutic and / or prophylactic agent for neuropathic pain.

38. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of an analgesic.

39. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a drug for overcoming a narcotic analgesic resistance.

40. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of an analgesic-enhancing agent for an analgesic.

41. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 for the production of a neuropeptide II receptor antagonist.

42. The indole derivative according to any one of claims 6 to 2 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease derived from hyperactivity of neurobeptide FF receptor. Use of salt.

43. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 for the manufacture of a therapeutic and / or prophylactic agent for neuropathic pain.

44. Use of the indole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 for the manufacture of an analgesic.

45. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to 12 for the manufacture of a drug for overcoming a narcotic analgesic resistance.

46. Use of the indole derivative or the pharmaceutically acceptable salt thereof according to any one of claims 6 to L2 for the production of an analgesic-enhancing agent for an analgesic.