JP2002338491A - Application of polypeptide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a polypeptide that has the ligand activity to sensory epithelium neuropeptide-like receptor(SENR) as a G protein conjugation type receptor protein and the use of the DNA encoding the polypeptide. SOLUTION: An anti-attention deficit disorder agent or an anti-narcolepsy agent bears an amino acid sequence identical or substantially identical to that represented by the sequence No.1 (refer to the specification) or an amide or ester thereof or salts thereof. A screening method for compounds having the anti-attention deficit disorder or an anti-narcolepsy activity or for compounds having antianxiety, antidepressant, antiinsomniac, antischizophrenic or antiphobic activities or their salts are characteristically carried out by using the polypeptides or their precursor proteins or salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a GPR14 [SENR (sensory e) which is a G protein-coupled receptor protein.
pithelium neuropeptide-like receptor)] and a use of DNA encoding the same.

[0002]

2. Description of the Related Art Many hormones and neurotransmitters regulate biological functions through specific receptors present on cell membranes. Many of these receptors are conjugated
It performs intracellular signal transduction through the activation of guanine nucleotide-binding protein (hereinafter sometimes abbreviated as G protein), and has a common structure with seven transmembrane domains. These are collectively called receptors or seven-transmembrane receptors. One of the reported orphan G protein-coupled receptors is SENR (Tal, M. et al., Bioch.
em. Biophys. Res. Commun., 209, 752-759, 1995). S
ENR has low homology to the somatostatin receptor (SSTR4), but it has not been known what its ligand is. GPR14 reported by Marche, A. et al. (Marchese, A., Genomics, 29, 335-
344, 1995) is the same receptor as SENR. Recently, the ligand for this receptor was urotensin II.
II) from several groups (Dave
nport, AP and Maguire, JJ, Trends Pharmacol Sc
i. 21, 80-82, 2000).

[0003]

SUMMARY OF THE INVENTION G, a G protein-coupled receptor expressed in the central nervous system, circulatory system, reproductive system, immune system, digestive system, urinary system, sensory system, etc.
Ligands for PR14 (SENR) are considered to be useful as pharmaceuticals. Its function has been reported on the circulatory system (Ames, RS, et al., Nature, 401, 2).
82-286, 1999), but no other effects have been reported.

[0004]

Means for Solving the Problems The present inventors have developed a GPR1
A ligand for 4 (SENR) is administered into the ventricle of the rat, and the receptor protein (GPR) is measured based on measurements of spontaneous activity, standing activity, elevated plus maze, and the like.
14 (SENR)) as a ligand. Furthermore, the present inventors have developed a compound having anti-attention deficit disorder or anti-narcoleptic activity or a compound having anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia or anti-phobic activity using the ligand as the activator. It has been found that screening can be performed.

That is, the present invention relates to (1) a polypeptide containing an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 1, an amide thereof, an ester thereof or a salt thereof; Attention deficit disorder or anti-narcoleptic agent, (2) the substantially identical amino acid sequence is SEQ ID NO: 2, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 24, sequence No. 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO: 29, the anti-attention deficit disorder or anti-narcoleptic agent according to the above (1), (3) the amino acid sequence according to the above (1) An anti-attention deficit disorder or an anti-narcoleptic agent comprising a DNA containing a nucleotide sequence encoding a polypeptide; (4) the DNA is SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 34, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32 or SEQ ID NO: 33 (3) the anti-attention deficit disorder or the anti-narcoleptic agent according to (3) above, which is a DNA containing the anti-attention deficit comprising the precursor protein of the polypeptide according to (1) or an amide or ester thereof or a salt thereof; A disorder or anti-narcoleptic agent, (6) SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 14,
The anti-attention deficit disorder or anti-narcoleptic agent according to the above (5), which comprises the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 17 or SEQ ID NO: 23; An antiattention deficit disorder characterized by using a polypeptide containing the same or substantially the same amino acid sequence as the represented amino acid sequence, its amide or its ester or its salt, or its precursor protein or its salt; A compound having anti-narcoleptic activity or a compound having anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia or anti-phobic activity,
Or a method for screening salts thereof, (8) a polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1, or an amide or ester thereof, or a salt thereof, or a precursor thereof. A compound comprising a protein or a salt thereof, which has an anti-attention deficit disorder or an anti-narcoleptic activity, or a compound which has an anxiolytic, antidepressant, anti-insomnia, anti-schizophrenia or anti-phobic activity, or a kit for screening the salts thereof (9) a compound having an anti-attention deficit disorder or an anti-narcoleptic activity, obtained using the screening method according to (7) or the screening kit according to (8), or anxiolytic, antidepressant, anti-insomnia, or antipsychotic Compounds having schizophrenia or anti-phobic activity, or those A salt, (10) an antiattention deficit disorder or an antinarcolepsy agent or an anxiolytic, antidepressant, antiinsomnia, antischizophrenic or antiphobic agent comprising the compound according to the above (9) or a salt thereof; (11) Attention deficit disorder or narcolepsy, characterized by using a polynucleotide comprising a nucleotide sequence complementary to a DNA comprising a nucleotide sequence encoding the polypeptide according to (1) or a part thereof. Or a method for diagnosing anxiety, depression, insomnia, schizophrenia or fear, (12) an antibody against the polypeptide according to (1) or the precursor protein according to (5) above, an amide thereof, an ester thereof, or a salt thereof. (13) an anxiolytic, anti-depressive, anti-insomnia, anti-schizophrenic or anti-phobic agent, characterized by containing No. 3 or an anti-attention deficit disorder or anti-narcoleptic or anti-anxiety characterized by containing an antibody against a protein containing the amino acid sequence represented by SEQ ID NO: 11, or an amide or ester or a salt thereof. , Antidepressant, anti-insomnia,
An anti-schizophrenia or anti-phobic agent, (14) an antibody against the polypeptide according to (1) or the precursor protein according to (5), an amide thereof, an ester thereof, or a salt thereof. A diagnostic agent for anxiety, depression, insomnia, schizophrenia or phobia; (15) a protein containing the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11, or an amide or ester thereof, or a protein thereof A diagnostic agent for attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia or phobia characterized by containing an antibody against a salt; (16) a DNA comprising a base sequence represented by SEQ ID NO: 34; Diagnostic agent comprising single nucleotide polymorphisms (SNPs), (17) attention deficit disorder or narcole The diagnostic agent according to the above (16), which is a diagnostic agent for psy or anxiety, depression, insomnia, schizophrenia or phobia, (18) a single nucleotide polymorphism of a DNA containing the nucleotide sequence represented by SEQ ID NO: 34 Attention deficit disorder or narcolepsy or a method of diagnosing anxiety, depression, insomnia, schizophrenia or phobia characterized by analyzing (SNPs); (19) an anti-attention deficit disorder or an anti-narcoleptic agent comprising a GPR14 agonist; A) an anxiolytic, anti-depressive, anti-insomnia, anti-schizophrenic or anti-phobic agent comprising a GPR14 antagonist, (21) a GPR14 antagonist having the formula (Ia):

Embedded image [In the formula, A ^a represents an optionally substituted benzene ring;
^a is a 5- to 8-membered ring which may be substituted, ^Xa is a divalent group having 1 to 4 atoms in ^a linear portion, R ^1a is an amino group which may be substituted, R ^2a Represents a cyclic group which may be substituted] or an anxiolytic, antidepressant, anti-insomnia, anti-schizophrenic or anti-phobic agent according to the above (20), or (22) GPR14. The antagonist has the formula (IIa):

Embedded image Wherein, A a ^'is a benzene ring which may further have a substituent other than the substituent R ^3a, B ^a is a good 5-8 membered ring optionally substituted, X ^a is a straight portion Is a divalent group having 1 to 4 atoms, R ^{1a ′} is a substituted amino group, R ^2a
Is a cyclic group which may be substituted, R ^3a is a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a nitro group, a halogen atom, an amino group which may be substituted or A group represented by R ^4a —Y ^a − (in the formula,
Y ^a represents an oxygen atom or ^a sulfur atom which may be oxidized, and R ^4a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted). (23) a GPR14 antagonist represented by the formula (Ib): wherein said salt is an anxiolytic, antidepressant, antiinsomnia, antischizophrenic or antiphobic agent according to the above (20).

Embedded image [Wherein, Ar represents an aryl group which may be substituted, X represents a spacer having 1 to 4 atoms constituting a straight-chain portion, n represents an integer of 1 to 10, and R represents hydrogen. An atom or a hydrocarbon group which may be substituted, wherein n may be the same or different, and R may be bonded to Ar or a substituent of Ar to form a ring; Y represents an amino group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted]] or a salt thereof, the anti-anxiety, antidepressant, anti-insomnia, (24) a GPR14 antagonist having the formula (IIb):

Embedded image [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group which may be substituted, ring A represents a benzene ring which may further have a substituent,
X represents a spacer having 1 to 4 atoms constituting the straight chain portion, n represents an integer of 1 to 10, R represents a hydrogen atom or a hydrocarbon group which may be substituted,
In the repetition of n, they may be the same or different,
R may be combined with ring A or a substituent of the ring A to form a ring, and Y represents an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic group]. The anxiolytic, antidepressant, anti-insomnia, anti-schizophrenic or anti-phobic agent according to the above (20), which is a compound represented by the formula or a salt thereof;

Embedded image[Wherein, R^1cIs a hydrogen atom or may be substituted
X represents a hydrocarbon group;^cIs the number of atoms constituting the straight chain part
Represents a spacer having 1 to 12;^1cAnd X ^cIs
May form a ring together,^cHas been replaced
Amino group or nitrogen-containing heterocyclic group which may be substituted
A ring group;^2cIs an optionally substituted hydrocarbon group
Or an amino group which may be substituted;^3cIs
A hydrocarbon group which may be substituted;^cRings and
C^cEach ring may be further substituted
Or a salt thereof.
(20) Anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia described in
Or (26) having a GRP14 agonist for mammals
Attention deficit disorder characterized by administering an effective amount or
Prevention and treatment of narcolepsy, (27) Prevention and cure of attention deficit disorder or narcolepsy
Use of a GPR14 agonist for producing a therapeutic agent, (28) a GPR14 antagonist for a mammal,
Anxiety, depression, or disability characterized by administering an effective amount of
Prevention and treatment of sleep, schizophrenia or phobia, (2
9) Prediction of anxiety, depression, insomnia, schizophrenia or phobia
GPR14 antagonist for producing an anti-therapeutic agent
About the use of

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, “substantially the same” means that the activity of a polypeptide or protein, for example, the binding activity between a ligand and a receptor (GPR14 (SENR)), physiological characteristics, etc. Means substantially the same. Amino acid substitutions, deletions, additions or insertions often do not result in a significant change in the physiological or chemical properties of the polypeptide or protein, in which case the substituted, deleted, added or inserted The peptides will be substantially identical to those without such substitutions, deletions, additions or insertions. Substantially identical substitutions of amino acids in the amino acid sequence may be selected, for example, from other amino acids of the class to which the amino acid belongs. Non-polar (hydrophobic) amino acids include alanine, leucine,
Isoleucine, valine, proline, phenylalanine,
Tryptophan, methionine and the like. Polar (neutral) amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine and the like. Examples of positively charged (basic) amino acids include arginine, lysine, histidine and the like. Examples of negatively charged (acidic) amino acids include aspartic acid and glutamic acid. The polypeptide of the present invention or its amide or its ester or its salt is a ligand for GRP14 (SENR), and specifically has the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1. Or an amide thereof, an ester thereof, or a salt thereof. Hereinafter, in the present specification, the polypeptide of the present invention is GRP14 (SE
NR) means a polypeptide that is a ligand for (NR).

[0007] The polypeptide of the present invention, its amide or its ester or its salt (hereinafter sometimes simply referred to as the polypeptide of the present invention), its production method and use will be described in more detail below. As the polypeptide of the present invention, warm-blooded animals (eg, human, guinea pig, rat, mouse, pig, sheep, cow, monkey, etc.)
Polypeptide from any tissue (eg, pituitary, pancreas, brain, kidney, liver, gonad, thyroid, gall bladder, bone marrow, adrenal gland, skin, muscle, lung, gastrointestinal tract, blood vessel, heart, etc.) or cells In addition, any polypeptide may be used as long as it has the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1. For example, the polypeptide of the present invention is substantially the same as the polypeptide containing the amino acid sequence represented by SEQ ID NO: 1 in addition to the polypeptide containing the amino acid sequence represented by SEQ ID NO: 1, and the like. (Eg, SEQ ID NOs: 2, 9, 10, 1)
8, 19, 24, 26, 27, 28 or 29). Examples of substantially equivalent activities include receptor binding activity, signal transduction activity, and the like. "Substantially the same quality" means that the receptor binding activity and the like are substantially the same. Therefore, quantitative factors such as strength and weakness of the receptor binding activity and the molecular weight of the polypeptide may be different. Examples of the amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 include, for example, about 50%
% Or more, preferably about 60% or more, more preferably about 7%.
An amino acid sequence having 0% or more, more preferably about 80% or more, particularly preferably about 90% or more, and most preferably about 95% or more homology is exemplified.

The amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 includes one or more amino acids (preferably about 1 to 5) in the amino acid sequence represented by SEQ ID NO: 1. More preferably about 1 to 3 amino acids, still more preferably 1 to 2 amino acids, and one or more (preferably 1 to 20) amino acids in the amino acid sequence represented by SEQ ID NO: 1. , More preferably about 1 to 12, more preferably several (1 to 5) amino acids, 1 or 2 or more (preferably , About 1 to 5, more preferably about 1 to 3, and still more preferably 1 to 2) amino acids substituted with other amino acids, or amino acids obtained by combining them. Such as proteins containing sequences may also be used. Specifically, the polypeptide containing the amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 is the third amino acid from the N-terminal of the polypeptide containing the amino acid sequence represented by SEQ ID NO: 1. Amino acid (Thr) is replaced with another amino acid (eg, Ala, Leu, Ile, V
al, Pro, Phe, Trp, Met, Gly, Ser, Cys, Tyr, Asn, G
(ln, Arg, Lys, His, Asp, Glu) and the like. Above all, the third amino acid from the N-terminus (Thr) of the polypeptide containing the amino acid sequence represented by SEQ ID NO: 1
Has been replaced with Pro (SEQ ID NO:
2) the amino acid sequence in which the third amino acid (Thr) from the N-terminus (Thr) is substituted with Ser (SEQ ID NO: 9), and the like. Are preferred examples.

[0009] In another embodiment, a polypeptide having an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 has (1) a glutamine residue or a pyroglutamic acid residue at the N-terminus, The amino acid sequence represented by SEQ ID NO: 18 from the 8th (Ala) to the 17th (Ile) from the N-terminus,
A polypeptide consisting of 14 to 17 amino acid residues or (2) an eighth amino acid (Ala) having an amino acid sequence represented by SEQ ID NO: 18 having a glutamine residue or a pyroglutamic acid residue at the N-terminus; ) To 17th (Ile)
Up to 3 to 1 at the N-terminus of the polypeptide comprising 14 to 17 amino acid residues.
A preferable example is a polypeptide to which 0 amino acid residues are added. In the present specification, the polypeptide has an N-terminus (amino terminus) at the left end and a C-terminus (carboxyl terminus) at the right end in accordance with the convention of peptide labeling.
(1) amino acid sequence represented by SEQ ID NO: 1, (2) amino acid sequence represented by SEQ ID NO: 2, (3) SEQ ID NO:
9, (4) an amino acid sequence represented by SEQ ID NO: 10, (5) an amino acid sequence represented by SEQ ID NO: 18, (6) an amino acid sequence represented by SEQ ID NO: 19, (7) an amino acid sequence represented by SEQ ID NO: 24, (8) an amino acid sequence represented by SEQ ID NO: 26,
(9) the amino acid sequence represented by SEQ ID NO: 27,
0) the amino acid sequence represented by SEQ ID NO: 28, (11)
SEQ ID NO: polypeptide containing such amino acid sequence represented by 29 C-terminal carboxyl group (-COOH), a carboxylate (-COO ^-), in either an amide (-CONH ₂₎ or an ester (-COOR) There may be. Examples of R in the ester include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl and n-butyl, C _3-8 cycloalkyl groups such as cyclopentyl and cyclohexyl, and C _3-8 such as phenyl and α-naphthyl. C- ₁₂ such as a _6-12 aryl group, phenyl- _C1-2 alkyl such as benzyl, phenethyl and benzhydryl, or α-naphthyl- _C1-2 alkyl such as α-naphthylmethyl.
_In addition to the _7-14 aralkyl group, a pivaloyloxymethyl group widely used as an oral ester and the like can be mentioned.

As a salt of the polypeptide of the present invention, a salt with a physiologically acceptable base (for example, an alkali metal or the like) or an acid (organic acid or inorganic acid) is used, and especially physiologically acceptable. Acid addition salts are preferred. Such salts include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid) And tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, and benzenesulfonic acid).

The polypeptide of the present invention is described in WO 00/32627, W
It can be produced according to the method described in O 00/31265, WO 99/35266 or Japanese Patent Application No. 2000-211996. Specifically, the polypeptide of the present invention can be produced by a method for purifying the polypeptide from tissues or cells of a warm-blooded animal, or can be produced according to the polypeptide synthesis method described later. . It can also be produced by culturing a transformant containing a DNA encoding the polypeptide described below. When producing from tissues or cells of a warm-blooded animal, after homogenizing the tissue or cells of the warm-blooded animal, extraction is performed with an acid, an organic solvent, or the like, and the extract is subjected to salting out, dialysis, gel filtration, reverse phase chromatography. It can be purified and isolated by combining chromatography such as chromatography, ion exchange chromatography, affinity chromatography and the like. As described above, the polypeptide of the present invention can be produced according to a polypeptide synthesis method known per se, or by cleaving a polypeptide containing the polypeptide of the present invention with an appropriate peptidase. As a method for synthesizing a peptide, for example, any of a solid phase synthesis method and a liquid phase synthesis method may be used. That is, the target peptide can be produced by condensing a partial peptide or amino acid capable of constituting the polypeptide of the present invention with the remaining portion and, when the product has a protecting group, removing the protecting group. Examples of the known condensation method and elimination of the protecting group include the following methods. M. Bodanszky and MA Ondetti, Peptide Synthesis, Interscience Publisher
s, New York (1966) Schroeder and Luebke, The Peptide,
Academic Press, New York (1965) Nobuo Izumiya et al., Fundamentals and experiments of peptide synthesis, Maruzen Co., Ltd.
(1975) Haruaki Yajima and Shunpei Sakakibara, Laboratory of Biochemistry 1, Protein Chemistry IV, 205, (1977) Supervised by Haruaki Yajima, Development of Continuing Drugs Volume 14 Peptide Synthesis Hirokawa Shoten The polypeptide of the present invention can be purified and isolated by a combination of purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, and recrystallization. When the polypeptide obtained by the above method is a free form, it can be converted to an appropriate salt by a known method. Can be.

As the amide of the polypeptide, a commercially available resin for peptide synthesis suitable for amide formation can be used. Examples of such a resin include chloromethyl resin, hydroxymethyl resin, benzhydrylamine resin, aminomethyl resin, 4-benzyloxybenzyl alcohol resin, 4-methylbenzhydrylamine resin,
PAM resin, 4-hydroxymethylmethylphenylacetamidomethyl resin, polyacrylamide resin, 4-
(2 ′, 4′-dimethoxyphenyl-hydroxymethyl) phenoxy resin, 4- (2 ′, 4′-dimethoxyphenyl-Fm
ocaminoethyl) phenoxy resin and the like. Using such a resin, an amino acid having an α-amino group and a side chain functional group appropriately protected is condensed on the resin in accordance with the sequence of the target peptide according to various condensation methods known per se. At the end of the reaction, the peptide is cleaved from the resin, and at the same time, various protecting groups are removed. If necessary, an intramolecular disulfide bond formation reaction is carried out in a highly diluted solution to obtain a target polypeptide.

For the condensation of the above protected amino acids, various activating reagents that can be used for peptide synthesis can be used, and carbodiimides are particularly preferable. Carbodiimides include DCC, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide and the like. Activation by these involves the addition of a protected amino acid directly to the resin along with a racemization inhibitor additive (eg, HOBt, HOOBt, etc.) or a symmetrical acid anhydride or HOBt ester or HO
It can be added to the resin after activation of the amino acid protected as a OBt ester beforehand. The solvent used for activating the protected amino acid or condensing with the resin can be appropriately selected from solvents known to be usable for the peptide condensation reaction. For example, N, N-dimethylformamide, N, N-dimethylacetamide,
Acid amides such as N-methylpyrrolidone; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as trifluoroethanol; sulfoxides such as dimethylsulfoxide; tertiary amines such as pyridine; dioxane; Ethers, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate and ethyl acetate, and appropriate mixtures thereof are used. The reaction temperature is appropriately selected from a range known to be usable for the peptide bond formation reaction, and is usually appropriately selected from a range of about -20 ° C to 50 ° C. The activated amino acid derivative is usually used in a 1.5 to 4-fold excess. As a result of the test using the ninhydrin reaction, when the condensation is insufficient, sufficient condensation can be performed by repeating the condensation reaction without removing the protecting group. When sufficient condensation cannot be obtained even by repeating the reaction, the unreacted amino acid can be acetylated using acetic anhydride or acetylimidazole so as not to affect the subsequent reaction.

Examples of the protecting group for the amino group of the starting amino acid include Z, Boc, tertiary pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, and adamantyloxycarbonyl. , Trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, Fmoc and the like. Examples of the carboxyl-protecting group include, for example, the above-mentioned C _1-6 alkyl group, C _3-8 cycloalkyl group, and C
_{In addition to the 7-14} aralkyl group, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl group, benzyloxycarbonyl hydrazide, tert-butoxycarbonyl hydrazide, trityl hydrazide and the like can be mentioned. The hydroxyl groups of serine and threonine can be protected, for example, by esterification or etherification. Examples of the group suitable for the esterification include a lower alkanoyl group such as an acetyl group, an aroyl group such as a benzoyl group, and a group derived from carbon such as a benzyloxycarbonyl group and an ethoxycarbonyl group. Examples of a group suitable for etherification include a benzyl group, a tetrahydropyranyl group, and a tertiary butyl group. Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, C
l ₂ -Bzl, 2-nitrobenzyl, Br-Z, t-butyl and the like. The protecting groups for histidine imidazole include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, DNP, benzyloxymethyl, Bum,
Boc, Trt, Fmoc and the like.

The activated carboxyl group in the raw material includes, for example, a corresponding acid anhydride, azide, active ester [alcohol (eg, pentachlorophenol,
2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, paranitrophenol,
HONB, N-hydroxysuccinimide, N-hydroxyphthalimide, ester with HOBt)]. The activated amino group of the raw material includes, for example, a corresponding phosphoric amide. As a method of removing (eliminating) the protecting group, for example, catalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd black or Pd carbon, hydrogen fluoride anhydride, methanesulfonic acid, trifluoromethanesulfonic acid Acid treatment with trifluoroacetic acid or a mixture thereof, or base treatment with diisopropylethylamine, triethylamine, piperidine, piperazine, etc.
In addition, reduction with sodium in liquid ammonia may be mentioned. The elimination reaction by the above acid treatment is generally performed at -20 ° C or higher.
It is carried out at a temperature of 40 ° C., but in the acid treatment, addition of a cation scavenger such as anisole, phenol, thioanisole, metacresol, paracresol, dimethylsulfide, 1,4-butanedithiol, 1,2-ethanedithiol. Is valid. In addition, the 2,4-dinitrophenyl group used as the imidazole protecting group of histidine is removed by thiophenol treatment, and the formyl group used as the indole protecting group of tryptophan is 1,2-ethanedithiol, 1,4-butane described above. In addition to deprotection by an acid treatment in the presence of dithiol or the like, it is also removed by an alkali treatment with dilute sodium hydroxide, dilute ammonia or the like. Protection and protection of functional groups that should not be involved in the reaction of the raw materials, elimination of the protected groups, activation of the functional groups involved in the reaction, and the like can be appropriately selected from known groups or known means.

As another method for obtaining an amide form of the polypeptide, first, after amidating the α-carboxyl group of the carboxyl terminal amino acid, the peptide chain is extended to a desired chain length on the amino group side, and Α at the N-terminus of the chain
-A peptide from which only the protecting group for the amino group is removed and a peptide (or amino acid) from which only the protecting group for the carboxyl group at the C-terminal is removed, and both peptides are condensed in a mixed solvent as described above. Details of the condensation reaction are the same as described above. After purifying the protected peptide obtained by the condensation, all the protecting groups are removed by the above-mentioned method to obtain a desired crude polypeptide. The crude polypeptide is purified using various known purification means, and the main fraction is freeze-dried to obtain an amide of the desired polypeptide. To obtain an ester of the polypeptide, after condensing the α-carboxyl group of the carboxy terminal amino acid with a desired alcohol to form an amino acid ester, obtain an ester of the desired polypeptide in the same manner as the amide of the polypeptide Can be. The polypeptide of the present invention contains the same or substantially the same amino acid sequence as the amino acid sequence represented by the above-mentioned SEQ ID NO: 1, and has the same action as the polypeptide, for example, anti-attention deficit disorder, anti-narcoleptic Any polypeptide may be used as long as it has an action or the like. Such polypeptides include, for example, SEQ ID NO:
Peptides having the amino acid sequence represented by 2, 9, 10, 18, 19, 24, 26, 27, 28 or 29 can be mentioned.

DNA encoding the polypeptide of the present invention
Any DNA may be used as long as it contains a DNA encoding a polypeptide having the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1. Also, genomic DNA, genomic DNA library, and the above-described tissue / cell-derived cD
NA, any of the above-described tissue / cell-derived cDNA libraries and synthetic DNAs may be used. The vector used for the library may be any of bacteriophage, plasmid, cosmid, phagemid and the like. Also,
Reverse Transcriptase Polymerase Chain Rea
ction (hereinafter, abbreviated as RT-PCR method). Here, as the polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1, as described above, SEQ ID NOs: 2, 9, 10, 18, 19, 24, 26, 27,
The amino acid sequence represented by SEQ ID NO: 28 or 29 is exemplified, and the DNA containing the DNA encoding the polypeptide having the amino acid sequence represented by SEQ ID NO: 2 is, for example, the DNA represented by SEQ ID NO: 12 DNA encoding the polypeptide containing the amino acid sequence represented by SEQ ID NO: 9
The DNA containing A includes, for example, SEQ ID NO: 13
And DNA containing a base sequence represented by
Examples of the DNA containing the DNA encoding the polypeptide containing the amino acid sequence represented by SEQ ID NO: 10 include a DNA containing the base sequence represented by SEQ ID NO: 34, and the like. DN encoding a polypeptide containing the amino acid sequence represented by 18
The DNA containing A includes, for example, SEQ ID NO: 20
And DNA containing a base sequence represented by
Examples of the DNA containing the DNA encoding the polypeptide containing the amino acid sequence represented by SEQ ID NO: 19 include a DNA containing the base sequence represented by SEQ ID NO: 21, and the like. DN encoding a polypeptide containing the amino acid sequence represented by SEQ ID NO: 24
The DNA containing A includes, for example, SEQ ID NO: 25
And DNA containing a base sequence represented by
Examples of the DNA containing the DNA encoding the polypeptide containing the amino acid sequence represented by SEQ ID NO: 26 include a DNA containing the base sequence represented by SEQ ID NO: 30, and the like. DN encoding a polypeptide containing the amino acid sequence represented by SEQ ID NO: 27
The DNA containing A includes, for example, SEQ ID NO: 31
And DNA containing a base sequence represented by
Examples of the DNA containing the DNA encoding the polypeptide containing the amino acid sequence represented by SEQ ID NO: 28 include a DNA containing the base sequence represented by SEQ ID NO: 32, and the like. DN encoding a polypeptide containing the amino acid sequence represented by No. 29
The DNA containing A includes, for example, SEQ ID NO: 33
And a DNA containing the base sequence represented by Examples of a DNA containing a DNA encoding a polypeptide having an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 include, for example, SEQ ID NO:
12, 13, 34, 20, 21, 25, 30, 31, 3,
About 80% or more, preferably about 90% or more, more preferably about 95% or more with the base sequence represented by 2 or 33;
More preferably, a DNA containing a base sequence having about 98% or more homology is exemplified.

The DNA containing a DNA encoding a polypeptide having an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 1 includes, for example, SEQ ID NOs: 12, 13, 34, 20, 21, 2
One, two or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 or 2) in the base sequence represented by 5, 30, 31, 32 or 33
SEQ ID NO: 12, 1)
One or more (preferably about 1 to 30, preferably about 1 to 10, more preferably about 1 to 30, in the base sequence represented by 3, 34, 20, 21, 25, 30, 31, 32, or 33) Is one or two), SEQ ID NO: 12, 13, 34, 20, 21, 2
One, two or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 or 2) in the base sequence represented by 5, 30, 31, 32 or 33
Base sequence), SEQ ID NO: 12,
13, 34, 20, 21, 25, 30, 31, 32 or 33 in the base sequence represented by 1 or 2 or more (preferably about 1 to 30, preferably about 1 to 10,
More preferably, DNAs containing a base sequence in which one or two bases have been replaced by other bases, or a base sequence obtained by combining the base sequences are also included. More specifically, (1) a DNA capable of binding to a DNA encoding a polypeptide containing an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 1 under stringent conditions (2) a polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1 due to the degeneracy of the genetic code; DN capable of binding to encoding DNA
DNA containing A and DNA specified in (1)
DNA that does not hybridize with, but encodes a polypeptide having the same amino acid sequence is used. Hybridization can be performed according to a method known per se or a method analogous thereto. The above stringent conditions include, for example, 42 ° C., 50% formamide, 4 × SSPE (1 × SSPE = 150 mM NaCl, 10 mM
_{M NaH 2 PO 4 · H 2} O, 1mM EDTA pH7.4), 5 × Denhardt's solution and 0.1% SDS. Examples of a DNA that hybridizes with a DNA containing a DNA encoding a polypeptide containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1 include, for example, SEQ ID NOs: 12, 13, 34, 20, 21, 25,
The nucleotide sequence represented by 30, 31, 32 or 33 and about 7
DNA containing a base sequence having a homology of 0% or more, preferably about 80% or more, more preferably about 90% or more, and most preferably about 95% or more is used.

DNA encoding the polypeptide of the present invention
Can also be produced by the following genetic engineering techniques. DNA completely encoding the polypeptide of the present invention
As a means for cloning, the target DNA is amplified from the above DNA library or the like by a PCR method known per se using a synthetic DNA primer having a partial nucleotide sequence of the nucleotide sequence of the DNA encoding the polypeptide of the present invention. Or DNA incorporated into an appropriate vector
Can be selected by, for example, hybridization with a DNA fragment having a partial or entire region of the polypeptide of the present invention or a fragment labeled with a synthetic DNA. The hybridization method is, for example, M
olecularCloning (2nd ed .; J. Sambrook et al., Col
d Spring Harbor Lab. Press, 1989). When a commercially available library is used, the procedure is performed according to the method described in the attached instruction manual.
D encoding the cloned polypeptide of the invention
NA can be used as it is depending on the purpose, or as desired, after digestion with a restriction enzyme or adding a linker. The DNA may have ATG as a translation initiation codon at the 5 'end and TAA, TGA or TAG as a translation stop codon at the 3' end. These translation start codon and translation stop codon
It can also be added using an appropriate synthetic DNA adapter. An expression vector for the polypeptide of the present invention may be prepared, for example, by (A) cutting out a DNA fragment of interest from DNA encoding the polypeptide of the present invention, and (B) placing the DNA fragment downstream of a promoter in an appropriate expression vector. It can be manufactured by connecting. As the vector, a plasmid derived from Escherichia coli (eg, pBR322, pB
R325, pUC12, pUC13) and plasmids derived from Bacillus subtilis (eg, pUB110, pTP5, pC19)
4), yeast-derived plasmids (eg, pSH19, pSH1
5), bacteriophages such as λ phage, and animal viruses such as retrovirus, vaccinia virus, and baculovirus are used. The promoter used in the present invention may be any promoter as long as it is appropriate for the host used for gene expression. When the host for transformation is an animal cell,
SV40-derived promoter, retrovirus promoter, metallothionein promoter, heat shock promoter, cytomegalovirus promoter,
An SRα promoter or the like can be used. When the host is a bacterium belonging to the genus Escherichia, the trp promoter, T7 promoter, lac promoter, recA promoter, λPL promoter, lpp promoter, etc.
When the host is a bacterium belonging to the genus Bacillus, an SPO1 promoter, an SPO2 promoter, a penP promoter, or the like, when the host is a yeast, a PHO5 promoter,
PGK promoter, GAP promoter, ADH1 promoter, GAL promoter and the like are preferable. If the host is an insect cell, a polyhedrin promoter,
P10 promoter and the like are preferred. In addition to the above, the expression vector may further include an enhancer, a splicing signal, a polyA addition signal, a selection marker,
Those containing V40 replication origin (hereinafter sometimes abbreviated as SV40 ori) or the like can be used. Examples of the selectable marker include a dihydrofolate reductase (hereinafter may be abbreviated as dhfr) gene [methotrexate (MTX) resistance], an ampicillin resistance gene (hereinafter may be abbreviated as Ampr), a neomycin resistance gene ( Hereinafter, G418 resistance, which may be abbreviated as Neo, may be used. In particular, CHO
When the DHFR gene is used as a selection marker using (dhfr ⁻ ) cells, selection can also be performed using a thymidine-free medium. If necessary, a signal sequence suitable for the host is added to the N-terminal side of the polypeptide or its partial peptide. When the host is a bacterium belonging to the genus Escherichia, a phoA signal sequence, an OmpA signal sequence, etc., and when the host is a bacterium belonging to the genus Bacillus, an α-amylase signal sequence, a subtilisin signal sequence, etc. In some cases, such as mating factor α (MFα) signal sequence, invertase signal sequence, etc., and when the host is an animal cell, for example, insulin signal sequence, α-interferon signal sequence, antibody molecule / signal sequence, etc. Are available respectively.

Using the vector containing the DNA encoding the polypeptide thus constructed, a transformant can be produced. As the host, for example, Escherichia, Bacillus, yeast, insects or insect cells, animal cells and the like are used. Examples of the genus Escherichia include Escherichia coli K1
2. DH1 [Procedings of the National Academy of Sciences of the USA (Proc. Natl. Acad. Sci. USA), 60]
Vol. 160 (1968)], JM103 [Nukuirek
Acids Research, 9
309 (1981)], JA 221 [Journal of Molecule
ar Biology)], 120, 517 (1978)], HB
101 [Journal of Molecular Biology, Vol. 41, 459 (1969)], C600 [Genetics, Vol. 39, 440 (1954)] and the like are used. Examples of the Bacillus genus include Bacillus subtilis MI114 [Gene, 24, 255 (1983)], 207-21 [Journal of Biochemistry.
emistry), Vol. 95, 87 (1984)]. Examples of yeast include Saccharomyces cerevisiae AH22 and AH22R.
^-, NA87-11A, DKD-5D, such as 20B-12 are used. As insects, for example, silkworm larvae are used [Maeda et al., Nature, 31
5, 592 (1985)]. As insect cells, for example, when the virus is AcNPV, a cell line derived from the larva of night-moth (Spodoptera frugiperda cell; Sf cell);
MG1 cells from Trichoplusia ni midgut, Trichoplusi
a ni egg-derived High Five ^TM cells, Mamestrabrassicae
Derived cells or cells derived from Estigmena acrea are used. When the virus is BmNPV, a silkworm-derived cell line (Bombyx mori N; BmN cell) or the like is used. As the Sf cells, for example, Sf9 cells (ATCC C
RL1711), Sf21 cells (Vaughn, JL et al., In Vitro, 13, 213-217 (1977)) and the like.

As animal cells, for example, monkey COS-7
Cell, Vero cell, Chinese hamster cell CH
O, DHFR gene deficient Chinese hamster cell C
HO (dhfr ^- CHO cells), mouse L cells, mouse 3T3 cells, mouse myeloma cells, human HEK293
Cells, human FL cells, 293 cells, C127 cells, BA
LB3T3 cells, Sp-2 / O cells and the like are used.
To transform Escherichia, for example, the Procesings of the National Academy of
Sciences of the USA (Proc. Nat)
l. Acad. Sci. USA), 69, 2110 (1972).
And Gene, Vol. 17, 107 (1982). For transformation of Bacillus sp., For example, Molecular and General
Genetics (Molecular & General Genetic
s), Vol. 168, 111 (1979). To transform yeast, for example, the Procesings of the National Academy of Sciences of the USA (Proc.
Natl. Acad. Sci. USA), 75, 1929 (197).
This is performed according to the method described in 8). Transformation of insect cells or insects is described, for example, in Bio / Technology, 6, 47-55 (1988).
Year). To transform animal cells, for example, Virology,
52, 456 (1973). Examples of a method for introducing an expression vector into cells include, for example, a lipofection method [Felgner, PL et al.
dings of the National Academy of Sciences of the U
nited States of America), 84, 7413 (1
987)], calcium phosphate method [Graham, FL an
d van der Eb, AJ Virology, 52
456-467 (1973)], electroporation [Nuemann, E. et al. Embo Journal (EMBO)
J.), 1, 841-845 (1982)]. Thus, a transformant transformed with the expression vector containing the DNA encoding the polypeptide of the present invention is obtained.

As a method for stably expressing the polypeptide of the present invention using animal cells, the above-mentioned method of selecting cells in which the expression vector introduced into the animal cells is integrated into the chromosome by clone selection is used. is there. Specifically, a transformant is selected using the above-mentioned selection marker as an index. Furthermore, a stable animal cell line having high expression ability of the polypeptide of the present invention can be obtained by repeatedly performing clonal selection on the animal cells obtained using the selection marker. When the dhfr gene was used as a selection marker, the dhfr concentration was gradually increased, and cultivation was carried out.
A DNA encoding the polypeptide of the present invention or a partial peptide thereof together with the fr gene can be amplified in a cell to obtain an animal cell strain with higher expression. The above transformant was transformed into D which encodes the polypeptide of the present invention.
The polypeptide of the present invention can be produced by culturing under conditions under which NA can be expressed to produce and accumulate the polypeptide of the present invention. When culturing a transformant whose host is a genus Escherichia or Bacillus, a liquid medium is suitable as a medium to be used for the culture. Nitrogen sources, inorganic substances, etc. are contained. As a carbon source, for example, glucose, dextrin, soluble starch, sucrose, etc., as a nitrogen source, for example, ammonium salts, nitrates, corn steep liquor, peptone, casein, meat extract, soybean meal, potato extract and the like Alternatively, examples of the organic substance and the inorganic substance include calcium chloride, sodium dihydrogen phosphate, and magnesium chloride. In addition, yeast extract, vitamins, growth promoting factors and the like may be added. The pH of the medium is preferably about 5 to 8.
As a medium for culturing the genus Escherichia, for example, an M9 medium containing glucose and casamino acid [Mill (Mill
er), Journal of Experimens in Molecular Genetics (Journal of Experimen)
ts in Molecular Genetics), 431-433, Cold S
Spring Harbor Laboratory, New York 1972]. If necessary, an agent such as 3β-indolylacrylic acid can be added in order to make the promoter work efficiently. When the host is a bacterium belonging to the genus Escherichia, the cultivation is usually carried out at about 15 to 43 ° C. for about 3 to 24 hours, and if necessary, aeration and stirring may be added. When the host is a bacterium belonging to the genus Bacillus, the cultivation is usually performed at about 30 to 40 ° C. for about 6 to 24 hours, and if necessary, aeration and stirring can be added. When culturing a transformant whose host is yeast, for example, Burkholder (Burkhold)
er) Minimal medium [Bostian, KL et al., Processings of the National Academy of Sciences of the USA (Proc. Natl. Acad.
Sci. USA), 77, 4505 (1980)] and 0.5
% Casamino acid SD medium [Bitter, GA et al.
Prossings of the National Academy of Sciences of the USA (Pr
Natl. Acad. Sci. USA), 81, 5330.
(1984)]. Preferably, the pH of the medium is adjusted to about 5-8. The cultivation is usually performed at about 20 ° C. to 35 ° C. for about 24 to 72 hours, and if necessary, aeration and stirring are added. When culturing a transformant whose host is an insect cell, Grace's Insect Medium (Grace, TCC,
Nature (195,788 (1962))
Those to which additives such as 0% bovine serum are appropriately added are used. Preferably, the pH of the medium is adjusted to about 6.2-6.4. Culture is usually performed at about 27 ° C. for about 3 to 5 days, and aeration and / or agitation are added as necessary. When culturing a transformant in which the host is an animal cell, for example, about 5 to 2
MEM medium containing 0% fetal bovine serum [Scie
nce, 122, 501 (1952)], DMEM medium [Virology, 8, 396 (195)
9)], RPMI 1640 medium [Journal of the American Medical Association (The Jo
urnal of the American Medical Association) 199
Volume, 519 (1967)], 199 medium [Proceeding of the Society for the Biological Medicine (Proceeding of the Society for the
Biological Medicine), 73, 1 (1950)]. Preferably, the pH is between about 6 and 8. The cultivation is usually carried out at about 30 ° C. to 40 ° C. for about 15 to 60 hours, and if necessary, aeration or stirring is added. Especially CHO (dhfr ⁻ )
When cells and the dhfr gene are used as selection markers, it is preferable to use a DMEM medium containing dialyzed fetal bovine serum containing almost no thymidine. The polypeptide of the present invention can be separated and purified from the above culture by, for example, the following method.

When the polypeptide of the present invention is extracted from cultured cells or cells, the cells or cells are collected by a known method after culturing and suspended in an appropriate buffer.
After disrupting the cells or cells by ultrasonication, lysozyme, and / or freeze-thawing, a method of obtaining a crude extract of the polypeptide by centrifugation or filtration may be used as appropriate. In a buffer solution, a protein denaturing agent such as urea or guanidine hydrochloride, or Triton X-100 (registered trademark, hereinafter referred to as T
M may be abbreviated. ) May be included. When the polypeptide is secreted into the culture solution, after completion of the culture, the supernatant is separated from the cells or cells by a method known per se, and the supernatant is collected. Purification of the polypeptide of the present invention contained in the thus obtained culture supernatant or extract can be carried out by appropriately combining known separation and purification methods. These known separation and purification methods include methods utilizing solubility such as salting out and solvent precipitation, dialysis, ultrafiltration, gel filtration, and SDS-polyacrylamide gel electrophoresis, and the like. Method using difference in charge, method using charge difference such as ion exchange chromatography, method using specific affinity such as affinity chromatography, and use of difference in hydrophobicity such as reverse phase high performance liquid chromatography A method utilizing a difference in isoelectric point such as isoelectric focusing or chromatofocusing is used. When the polypeptide of the present invention thus obtained is obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto, and conversely, when the polypeptide is obtained in a salt, a method known per se Alternatively, it can be converted into a free form or another salt by a method analogous thereto. The polypeptide of the present invention produced by the recombinant can be arbitrarily modified or partially removed by the action of an appropriate protein-modifying enzyme before or after purification. As the protein modifying enzyme, for example, trypsin, chymotrypsin, arginyl endopeptidase, protein kinase, glycosidase and the like are used. The presence of the polypeptide of the present invention thus produced can be measured by an enzyme immunoassay using a specific antibody or the like.

DNA encoding the polypeptide of the present invention
Alternatively, a polypeptide of the invention may be an anti-attention deficit disorder or anti-narcoleptic agent or anxiolytic, antidepressant, anti-insomnia,
It can be used for the development of drugs such as anti-schizophrenia or anti-phobic drugs, the development of a receptor binding assay system using a recombinant receptor protein expression system, the screening of drug candidate compounds, and gene therapy.

In particular, the recombinant GPR14 described below
GPR14 specific to warm-blooded animals such as humans was obtained by a receptor binding assay system using an expression system of (SENR).
(SENR) Agonists or antagonists can be screened, and the agonists or antagonists can be used as agents for preventing or treating various diseases. Furthermore, the polypeptide of the present invention or the DNA encoding the same may be expressed by GP expressed in the central nervous system, circulatory system, heart, kidney, urinary system or sensory system.
Since R14 (SENR) is recognized as a ligand, it is useful as a safe and low-toxic drug. The polypeptide of the present invention or a DNA encoding the polypeptide can be used as an agent for treating or preventing a disease such as attention deficit disorder or narcolepsy. When the polypeptide of the present invention or a DNA encoding the same is used as the above-mentioned medicament, it can be formulated according to a conventional method. For example, a sugar-coated or enteric-coated tablet as required, a capsule, a elixir, orally as a microcapsule, or a sterile solution with water or another pharmaceutically acceptable liquid, Alternatively, it can be used parenterally in the form of injections such as suspensions. For example, the compound or a salt thereof is mixed with a physiologically acceptable carrier, flavoring agent, excipient, vehicle, preservative, stabilizer, binder and the like in a unit dosage form generally required for the accepted pharmaceutical practice. Can be manufactured. The amount of the active ingredient in these preparations is such that a proper dosage in the specified range can be obtained.

When the DNA of the present invention is used, the DNA
Can be used alone or after insertion into a suitable vector such as a retrovirus vector, an adenovirus vector, an adenovirus associated virus vector, and the like, followed by conventional means. Examples of additives that can be incorporated into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth gum, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Swelling agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, reddish oil or cherry are used. When the preparation unit form is a capsule, the above type of material can further contain a liquid carrier such as oil and fat. Sterile compositions for injection can be formulated according to normal pharmaceutical practice such as dissolving or suspending the active substance in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like. . Aqueous liquids for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents. For example, alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), non-ionic surfactants (eg, polysorbate 80 ( ^TM ), HCO-
50) and the like. Sesame oil as the oily liquid,
Soybean oil and the like may be used, and may be used in combination with benzyl benzoate, benzyl alcohol and the like as a solubilizer. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride,
Procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.), antioxidants and the like may be added. The prepared injection is usually filled in a suitable ampoule.

Since the preparation thus obtained is safe and has low toxicity, it can be used for mammals (eg, human, mouse, rat, guinea pig, rabbit, sheep, pig, cow, cat, dog, monkey, etc.). Can be administered. The DNA encoding the polypeptide of the present invention or the polypeptide of the present invention may be administered to the central nervous system, circulatory system, heart,
G expressed in kidney, urinary system or sensory organ system
Since PR14 (SENR) is recognized as a ligand, it is useful as a safe and low-toxic drug. The DNA encoding the polypeptide of the present invention or the polypeptide of the present invention can be used as an agent for treating or preventing a disease such as attention deficit disorder or narcolepsy. The dosage of the polypeptide of the present invention or the DNA encoding the same may vary depending on the symptoms and the like.
Generally, in adults with attention deficit disorder (assuming a body weight of 60 kg), about 0.1 to 100 mg per day,
Preferably about 1.0 to 50 mg, more preferably about 1.0 to 20 mg. In the case of parenteral administration, the single dose varies depending on the administration subject, target organ, symptoms, administration method, and the like. In administration, about 0.01 to 30 mg per day,
It is convenient to administer preferably about 0.1 to 20 mg, more preferably about 0.1 to 10 mg by intravenous injection. In the case of other animals, the amount can be administered in terms of 60 kg.

The precursor protein of the polypeptide of the present invention or its salt, its production method and use will be described in more detail below. Examples of the precursor protein of the polypeptide of the present invention or a salt thereof (hereinafter, sometimes referred to as the precursor protein of the present invention) include, for example, 1 Or two or more, preferably about 1 to 200, more preferably about 1 to 120, and still more preferably 50 to 12
It is a protein or a salt thereof to which about 0 amino acids are bound. Specifically, a protein having the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 is used as the precursor protein of the present invention.

The precursor protein of the present invention can be used in any tissue (eg, pituitary, pancreas, brain, kidney) of warm-blooded animals (eg, human, guinea pig, rat, mouse, pig, sheep, cow, monkey, etc.). , Liver, gonads, thyroid,
Gall bladder, bone marrow, adrenal gland, skin, muscle, lung, digestive tract, blood vessels,
Heart, etc.) or cells derived from cells, etc., as long as they have the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23. It may be something. Examples of substantially equivalent activities include receptor binding activity, signal transduction activity, and the like. "Substantially the same quality" means that the receptor binding activity and the like are substantially the same. Therefore, quantitative factors such as strength and weakness of receptor binding activity and molecular weight of protein may be different. SEQ ID NOs: 7, 8, 14, 17
Or as an amino acid sequence substantially identical to the amino acid sequence represented by 23, specifically, SEQ ID NOs: 7, 8, 1
About 50% of the amino acid sequence represented by 4, 17 or 23
Or more, preferably about 60% or more, and more preferably about 7%.
It indicates an amino acid sequence having 0% or more, more preferably about 80% or more, particularly preferably about 90% or more, and most preferably about 95% or more homology.

The precursor protein of the present invention includes, for example, SEQ ID NO: 7, 8, 14, 17 or 2
1 or 2 or more (preferably about 1 to 30, preferably about 1 to 10 in the amino acid sequence represented by 3,
More preferably, 1 or 2 amino acids are deleted, and 1 or 2 or more (preferably about 1 to 30) in the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23. (Preferably about 1 to 10, more preferably 1 or 2) amino acids, and 1 or 2 amino acids in the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23. An amino acid sequence into which the above (preferably about 1 to 30, preferably about 1 to 10, and more preferably 1 or 2) amino acids have been inserted, SEQ ID NOS: 7, 8, 14, 1
1 or 2 or more (preferably about 1 to 30, preferably 1 to 1) in the amino acid sequence represented by 7 or 23
A protein containing an amino acid sequence in which about 0 (more preferably 1 or 2) amino acids are substituted with another amino acid, or an amino acid sequence obtained by combining them is also included. Specific examples of the precursor protein of the polypeptide of the present invention containing the amino acid sequence represented by SEQ ID NO: 2 include a protein containing the amino acid sequence represented by SEQ ID NO: 7 or SEQ ID NO: 8, and the like. Specific examples of the precursor protein of the polypeptide of the present invention containing the amino acid sequence represented by SEQ ID NO: 9 include a protein containing the amino acid sequence represented by SEQ ID NO: 14 and the like. . Specific examples of the precursor protein of the polypeptide of the present invention containing the amino acid sequence represented by SEQ ID NO: 10 include the precursor protein described in WO 99/35266 and the like. As a precursor protein of the polypeptide of the present invention containing the amino acid sequence represented by SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 26 or SEQ ID NO: 27, specifically,
And a protein containing the amino acid sequence represented by SEQ ID NO: 17. SEQ ID NO: 24, SEQ ID NO:
Specific examples of the precursor protein of the polypeptide of the present invention containing the amino acid sequence represented by SEQ ID NO: 28 or SEQ ID NO: 29 include a protein containing the amino acid sequence represented by SEQ ID NO: 23.

In the present specification, the precursor protein has an N-terminus (amino terminus) at the left end in accordance with the convention of peptide notation,
The right end is the C terminal (carboxyl terminal). For example, the precursor protein of the present invention containing the amino acid sequence represented by the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 has a carboxyl group at the C-terminus (-COO).
H), carboxylate (—COO ⁻ ), amide (—CONH ₂ ) or ester (—COOR). Examples of R in the ester include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl and n-butyl, C _3-8 cycloalkyl groups such as cyclopentyl and cyclohexyl, and C _3-8 such as phenyl and α-naphthyl.
_{A 6-12} aryl group, phenyl-C _1-2 alkyl such as benzyl, phenethyl, benzhydryl, or α
In addition to a C _7-14 aralkyl group such as α-naphthyl-C _1-2 alkyl such as -naphthylmethyl, a pivaloyloxymethyl group widely used as an oral ester and the like can be mentioned. Examples of the salt of the precursor protein of the present invention include those similar to the above-mentioned salts of the polypeptide of the present invention. The precursor proteins of the present invention are described in WO 00/32627, WO 00/31265, WO 99/35266.
Alternatively, it can be produced according to the method described in Japanese Patent Application No. 2000-211996. In addition, according to the above-described method for producing the polypeptide of the present invention, it can be produced by a method of purifying a protein from a tissue or a cell of a warm-blooded animal, or can be produced according to a protein synthesis method. Further, it can also be produced by culturing a transformant containing a DNA encoding the precursor protein of the present invention according to the above-described method for producing the polypeptide of the present invention. When producing from tissues or cells of a warm-blooded animal, after homogenizing the tissue or cells of the warm-blooded animal, extraction is performed with an acid, an organic solvent, or the like, and the extract is subjected to salting out, dialysis, gel filtration,
Purification and isolation can be performed by combining chromatography such as reverse phase chromatography, ion exchange chromatography, and affinity chromatography. As the amide of the precursor protein of the present invention, a commercially available resin for peptide synthesis suitable for amide formation can be used. As such a resin, for example, the above-mentioned resin for peptide synthesis or the like is used. Using such a resin, an amino acid having an α-amino group and a side chain functional group appropriately protected is condensed on the resin in accordance with the sequence of the target peptide according to various condensation methods known per se. At the end of the reaction, the peptide is cleaved from the resin and at the same time, various protecting groups are removed, and if necessary, an intramolecular disulfide bond formation reaction is carried out in a highly diluted solution to obtain the desired precursor protein of the present invention. The precursor protein of the present invention contains the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 above, and contains the polypeptide of the present invention. The precursor protein itself may have a similar action, for example, anti-attention deficit disorder, anti-narcoleptic action and the like.

D encoding the precursor protein of the present invention
As NA, SEQ ID NO: 7, 8, 14, 17 or 2
DNA encoding a protein containing the same or substantially the same amino acid sequence as the amino acid sequence represented by No. 3
Any DNA may be used as long as it contains A. Genomic DNA, genomic DNA library,
Any of the above-described tissue / cell-derived cDNA, the above-described tissue / cell-derived cDNA library, and synthetic DNA may be used. The vector used for the library may be any of bacteriophage, plasmid, cosmid, phagemid and the like. In addition, R
Using the prepared NA fraction directly for Reverse Transcri
ptase Polymerase Chain Reaction (hereinafter, RT-PCR
Method). Here, examples of the DNA containing the DNA encoding the protein having the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 include, for example, SEQ ID NO: : 4, 5, 6, 1
DN containing a base sequence represented by 5, 16 or 22
A and the like, and SEQ ID NOs: 4, 5, 6, 15,
About 50% or more, preferably about 60% or more, more preferably about 70% or more, more preferably about 80% or more, particularly preferably about 9% or more, of the nucleotide sequence represented by 16 or 22.
DNAs containing a base sequence having a homology of 0% or more, most preferably about 95% or more, may be mentioned.

The DNA containing a DNA encoding a protein containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 includes, for example, 1 or 2 or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 to 2) in the nucleotide sequence represented by SEQ ID NO: 4, 5, 6, 15, 16 or 22.
Or 2) base sequences in which the bases have been deleted, SEQ ID NO:
One, two or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 or 2) in the base sequence represented by 4, 5, 6, 15, 16 or 22 SEQ ID NO: 4, a base sequence to which the base of
One or two or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 or 2) in the base sequence represented by 5, 6, 15, 16 or 22
Base sequence), SEQ ID NO: 4,
One or two or more (preferably about 1 to 30, preferably about 1 to 10, more preferably 1 or 2) in the base sequence represented by 5, 6, 15, 16 or 22
DNA) containing an amino acid sequence in which one base is replaced by another base, or a base sequence obtained by combining them. More specifically, (1) encodes a protein containing an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23 under stringent conditions D from mammals that hybridize with DNA containing DNA
NA, (2) SEQ ID NO: 7, 8, due to degeneracy of the genetic code
The DNA does not hybridize with the DNA containing the DNA encoding the protein containing the same or substantially the same amino acid sequence as the amino acid sequence represented by 14, 17 or 23, and does not hybridize with the DNA specified in (1), A DNA encoding a protein having an amino acid sequence is used. Hybridization can be performed according to a method known per se or a method analogous thereto. The stringent conditions include, for example, 42
℃, 50% formamide, 4 × SSPE (1 × SSPE
= 150 mM NaCl, 10 mM NaH ₂ PO ₄ .H ₂ O, 1 mM EDTA pH7.
4) 5x Denhardt's solution, 0.1% SDS. DNA containing DNA encoding a protein containing the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 7, 8, 14, 17 or 23
As a DNA that hybridizes with, for example, about 70% or more, preferably about 80% or more, more preferably about 90% or more with the base sequence represented by SEQ ID NO: 4, 5, 6, 15, 16 or 22 And most preferably a DNA containing a base sequence having about 95% or more homology.

D encoding the precursor protein of the present invention
NA can also be produced by a genetic engineering technique in the same manner as the above-described polypeptide of the present invention. The DNA encoding the precursor protein of the present invention or the precursor protein of the present invention can be used as an antiattention deficit disorder or an anti-narcoleptic agent or a medicament such as an anxiolytic, antidepressant, antiinsomnia, antischizophrenic or antiphobic agent. It can be used for development of a receptor binding assay system using a recombinant receptor protein expression system, screening of drug candidate compounds, gene therapy and the like. In particular, a GPR14 (SENR) agonist or antagonist specific to a warm-blooded animal such as human can be screened by a receptor binding assay system using a recombinant GPR14 (SENR) expression system described later, Alternatively, an antagonist can be used as an agent for preventing or treating various diseases. Further, the precursor protein of the present invention or a DNA encoding the same is recognized by GPR14 (SENR) expressed in the central nervous system, circulatory system, heart, kidney, urinary system or sensory organ system as a ligand. Therefore, it is useful as a safe and low toxic drug. The precursor protein of the present invention or a DNA encoding the same can be used as an agent for treating or preventing a disease such as attention deficit disorder or narcolepsy.

When the precursor protein of the present invention or the DNA encoding the same is used as the above-mentioned medicine, it can be formulated according to a conventional method. For example, orally as tablets, capsules, elixirs, microcapsules, etc. coated with sugar coating or enteric coating as needed,
Alternatively, it can be used parenterally in the form of an injection such as a sterile solution with water or another pharmaceutically acceptable liquid, or a suspension. For example, the compound or a salt thereof is physiologically acceptable carrier, flavoring agent, excipient, vehicle,
It can be manufactured by mixing with preservatives, stabilizers, binders and the like in the unit dosage form required for generally accepted formulations. The amount of the active ingredient in these preparations is such that a proper dosage in the specified range can be obtained. As additives that can be mixed with tablets, capsules, and the like, the same additives as those described above can be used. As an aqueous liquid for injection, for example,
Physiological saline, isotonic solution containing glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, etc.) and the like.
For example, it may be used in combination with an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant (eg, polysorbate 80 ( ^TM ), HCO-50).
The oily liquid includes sesame oil, soybean oil and the like, and may be used in combination with a solubilizing agent such as benzyl benzoate and benzyl alcohol. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), storage Agents (eg, benzyl alcohol, phenol, etc.), antioxidants and the like. The prepared injection is usually filled in a suitable ampoule. The preparations thus obtained are safe and low toxic,
For example, it can be administered to mammals (eg, human, mouse, rat, guinea pig, rabbit, sheep, pig, cow, cat, dog, monkey, etc.).

The dosage of the precursor protein of the present invention or the DNA encoding the same may vary depending on the symptoms and the like. About 0.
1 to 100 mg, preferably about 1.0 to 50 mg,
More preferably, it is about 1.0 to 20 mg. In the case of parenteral administration, the single dose varies depending on the administration subject, target organ, symptoms, administration method, and the like. In administration, about 0.01 to 30 mg, preferably about 0.1 to 20 mg per day,
More preferably, about 0.1 to 10 mg is administered by intravenous injection. For other animals, 6
The amount converted per 0 kg can be administered.

GPR14 (SENR) in the present invention is, as described above, Tal, M. et al., Biochem. Biop.
hys. Res. Commun., 209, 752-759, 1995, Marches, A., Genomics, 29, 335-344, 1995, EP 859052, etc. GPR14 (SEN), which contains an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11.
R) or a salt thereof, or an amino acid sequence or sequence in which 1 to 30 amino acids, preferably 1 to 10 amino acids in the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11 are deleted. An amino acid sequence obtained by adding (or inserting) 1 to 30 amino acids, preferably 1 to 10 amino acids to the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11, or SEQ ID NO: 3 or One or more 3 in the amino acid sequence represented by SEQ ID NO: 11
GPR14 (SENR), which is a protein containing an amino acid sequence in which 0 or less, preferably 1 to 10 amino acids are substituted with another amino acid, or a salt thereof, and the like. In addition, GPR14 (SE
NR) is a partial peptide of GPR14 of the present invention described above.
Any peptide may be used as long as it is a partial peptide of (SENR), for example, GPR14 (SENR) of the present invention.
Among the protein molecules, those that are exposed outside the cell membrane and have a binding activity to the polypeptide of the present invention are used. These GPR1s used in the present invention
4 (SENR) or a partial peptide thereof is described in Tal, M. et.
al., Biochem. Biophys. Res.Commun., 209, 752-75
9, March 1995, Marchese, A., Genomics, 29, 3
35-344, 1995, can be produced by the same method as that described in EP 859052 or a method analogous thereto, or can be produced by the same method as the above-described polypeptide of the present invention. it can. Examples of the salt of GPR14 (SENR) or a partial peptide thereof used in the present invention include those similar to the above-mentioned salts of the polypeptide of the present invention. GPR1 used in the present invention
4 (SENR) or its encoding partial peptide
The NA may be any DNA as long as it contains DNA encoding the above-mentioned GPR14 (SENR) or a partial peptide thereof. Genome DN
A, any of the genomic DNA library, the cDNA derived from the above-described tissue / cell, the cDNA library derived from the above-described tissue / cell, and the synthetic DNA may be used. The vector used for the library may be any of bacteriophage, plasmid, cosmid, phagemid and the like. Alternatively, amplification can be performed directly by RT-PCR using an RNA fraction prepared from the above-described tissue / cell. GPR14 (SEN) used in the present invention
DNA encoding R) or a partial peptide thereof is Ta
l, M. et al., Biochem. Biophys. Res. Commun., 209,
752-759, 1995, Marchese, A., Genomics,
29, 335-344, 1995, and the same or a method analogous to the method described in EP 859052.

A polynucleotide comprising a nucleotide sequence complementary to a DNA containing a nucleotide sequence encoding the polypeptide of the present invention or a part thereof is defined as a DNA of the present invention.
Is used to mean not only RNA but also RNA. The polynucleotide (nucleic acid) can hybridize with the RNA of the polypeptide gene of the present invention and inhibit the synthesis or function of the RNA, or interact with the polypeptide-related RNA of the present invention. Can regulate / control the expression of the polypeptide gene of the present invention. A polynucleotide complementary to the selected sequence of the polypeptide-related RNA of the invention,
And a polynucleotide capable of specifically hybridizing with the polypeptide-related RNA of the present invention is useful for regulating and controlling the expression of the polypeptide gene of the present invention in vivo and in vitro. It is useful for treating or diagnosing disorders or narcolepsy or diseases such as anxiety, depression, insomnia, schizophrenia or phobia.

With respect to the relationship between the target nucleic acid and the polynucleotide complementary to at least a part of the target region, the relationship between the target nucleic acid and the polynucleotide capable of hybridizing with the target can be said to be "antisense". The antisense polynucleotide is 2-deoxy-D-
Polydeoxynucleotides containing ribose, D
A polydeoxynucleotide containing ribose,
Other types of polynucleotides that are N-glycosides of purine or pyrimidine bases, or other polymers with non-nucleotide backbones (eg, commercially available protein nucleic acids and synthetic sequence-specific nucleic acid polymers) or others containing special linkages (However, the polymer contains a nucleotide having a configuration that allows base pairing and base attachment as found in DNA and RNA) and the like. They are double-stranded DN
A, which can be a single-stranded DNA, a double-stranded RNA, a single-stranded RNA, or a DNA: RNA hybrid, to which an unmodified polynucleotide (or an unmodified oligonucleotide) and further a known modification are added. Such as labeled, capped, methylated, substituted for one or more naturally occurring nucleotides with analogs, modified with intramolecular nucleotides, as known in the art, For example, those having an uncharged bond (for example, methylphosphonate, phosphotriester, phosphoramidate, carbamate, etc.), those having a charged bond or a sulfur-containing bond (for example, phosphorothioate, phosphorodithioate, etc.), for example, Proteins (nucleases, nuclease inhibitors, toxins, antibodies, signal probes) Plastid, poly -L- lysine, etc.)
Having side-chain groups such as sugars and sugars (eg, monosaccharides), those having interactive compounds (eg, acridine, psoralen, etc.), chelating compounds (eg, metals, radioactive metals, boron, etc.) , An oxidizing metal, etc.), an alkylating agent, or a compound having a modified bond (for example, α-anomeric nucleic acid). Here, "nucleoside", "nucleotide", and "nucleic acid" may include not only those containing purine and pyrimidine bases but also those having other modified heterocyclic bases. Such modifications may include methylated purines and pyrimidines, acylated purines and pyrimidines, or other heterocycles. Modified nucleotides and modified nucleotides may also be modified at the sugar moiety, for example, one or more hydroxyl groups are replaced with halogens, aliphatic groups, or the like,
Alternatively, it may be converted to a functional group such as ether or amine.

The antisense polynucleotide (nucleic acid) may be RNA, DNA, or a modified nucleic acid (R
NA, DNA). Specific examples of modified nucleic acids include, but are not limited to, sulfur derivatives and thiophosphate derivatives of nucleic acids, and those that are resistant to degradation of polynucleoside amides and oligonucleoside amides. The antisense nucleic acid can be preferably designed according to the following policy. That is, to make the antisense nucleic acid more stable in the cell, to make the antisense nucleic acid more cell permeable, to have a greater affinity for the target sense strand, and to be more toxic if it is toxic. Minimize the toxicity of sense nucleic acids.
Many such modifications are known in the art, for example
J. Kawakami et al., Pharm Tech Japan, Vol. 8, pp.2
47, 1992; Vol. 8, pp. 395, 1992; ST Crooke et a
l. ed., Antisense Research and Applications, CRC P
ress, 1993. The antisense nucleic acid may contain altered or modified sugars, bases, linkages, and may be provided in special forms such as liposomes, microspheres, applied or added by gene therapy. Can be given in a different form.
Thus, in the form of addition, polycations such as polylysine which acts to neutralize the charge of the phosphate skeleton, lipids which enhance the interaction with the cell membrane or increase the uptake of nucleic acids ( For example, hydrophobic substances such as phospholipid and cholesterol can be mentioned. Preferred lipids for addition include cholesterol and its derivatives (eg, cholesteryl chloroformate, cholic acid, etc.). These are
Can be attached to the 3 'end or 5' end of the nucleic acid,
It can be attached via bases, sugars, intramolecular nucleoside bonds. Other groups include cap groups specifically arranged at the 3 ′ end or 5 ′ end of the nucleic acid,
And those for preventing degradation by nucleases such as exonuclease and RNase. Examples of such capping groups include hydroxyl-protecting groups known in the art, including glycols such as polyethylene glycol and tetraethylene glycol.
It is not limited to that.

The preparation of an antibody against the polypeptide of the present invention, its precursor protein, an amide or ester thereof, or a salt thereof will be described below.

The antibody against the polypeptide of the present invention or its precursor protein or its amide or ester or a salt thereof recognizes the polypeptide of the present invention or its precursor protein or its amide or ester or its salt. Any antibody that can be obtained may be a polyclonal antibody or a monoclonal antibody. An antibody against the polypeptide of the present invention, its precursor protein, its amide or ester, or a salt thereof (hereinafter may be abbreviated as the polypeptide of the present invention) may use the polypeptide or the like of the present invention as an antigen. Can be produced according to a known method for producing an antibody or antiserum.

[Preparation of Monoclonal Antibody] (a) Preparation of Monoclonal Antibody-Producing Cell The polypeptide or the like of the present invention is administered to a mammal at a site where the antibody can be produced by administration to itself or together with a carrier and a diluent. Is done. Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered in order to enhance the antibody-producing ability upon administration. Administration is usually performed once every 2 to 6 weeks, for a total of about 2 to 10 times. Examples of the mammal used include monkeys, rabbits, dogs, guinea pigs, mice, rats, sheep, and goats, and mice and rats are preferably used. When preparing monoclonal antibody-producing cells, a warm-blooded animal immunized with an antigen, for example, an individual having an antibody titer is selected from a mouse, and the spleen or lymph node is collected 2 to 5 days after the final immunization. By fusing the contained antibody-producing cells with myeloma cells, a monoclonal antibody-producing hybridoma can be prepared. The antibody titer in the antiserum can be measured, for example, by reacting a labeled polypeptide or the like described below with the antiserum, and then measuring the activity of a labeling agent bound to the antibody. The fusion operation is performed by a known method, for example, the method of Kohler and Milstein [Nature, 256, 495 (197)].
5 years)]. Examples of the fusion promoter include polyethylene glycol (PEG) and Sendai virus.
Is used. As myeloma cells, for example, NS-
1, P3U1, SP2 / 0, etc., but P3U
1 is preferably used. The preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is 1: 1 to 1
20: 1 and PEG (preferably PEG10
00-PEG6000) at a concentration of about 10-80%, and incubating at about 20-40 ° C, preferably about 30-37 ° C for about 1-10 minutes, enables efficient cell fusion.

Various methods can be used for screening a monoclonal antibody-producing hybridoma. For example, a hybridoma culture supernatant is added to a solid phase (eg, a microplate) on which an antigen such as a polypeptide is adsorbed directly or together with a carrier. Then, an anti-immunoglobulin antibody labeled with a radioactive substance or an enzyme (an anti-mouse immunoglobulin antibody is used when the cells used for cell fusion are mice) or protein A is added, and the monoclonal antibody bound to the solid phase is added. Detection method, adding a hybridoma culture supernatant to a solid phase to which anti-immunoglobulin antibody or protein A is adsorbed, adding a polypeptide or the like labeled with a radioactive substance, an enzyme, or the like, and detecting a monoclonal antibody bound to the solid phase And the like. The selection of the monoclonal antibody can be carried out according to a method known per se or a method analogous thereto. Usually, it can be carried out in a medium for animal cells to which HAT (hypoxanthine, aminopterin, thymidine) is added. As a selection and breeding medium, any medium can be used as long as a hybridoma can grow. For example, RPMI 1 containing 1-20%, preferably 10-20% fetal calf serum
640 medium, GIT medium containing 1 to 10% fetal bovine serum (Wako Pure Chemical Industries, Ltd.) or serum-free medium for hybridoma culture (SFM-101, Nissui Pharmaceutical Co., Ltd.) can be used. The culturing temperature is usually 20 to 40 ° C, preferably about 37 ° C. The culturing time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. Culture is usually 5
% Carbon dioxide. The antibody titer of the hybridoma culture supernatant can be measured in the same manner as the measurement of the antibody titer in the antiserum described above.

(B) Purification of Monoclonal Antibody Separation and purification of monoclonal antibodies can be carried out in the same manner as in the separation and purification of normal polyclonal antibodies. , Electrophoresis, adsorption / desorption with an ion exchanger (eg, DEAE), ultracentrifugation, gel filtration, antigen-bound solid phase or an active adsorbent such as protein A or protein G to collect only antibodies and bind Specific Purification Method for Obtaining Antibody by Dissociation].

[Preparation of Polyclonal Antibody] The polyclonal antibody of the present invention can be produced according to a method known per se or a method analogous thereto. For example, a complex of an immunizing antigen (antigen such as the polypeptide of the present invention) and a carrier protein is formed, and a mammal is immunized in the same manner as in the above-described method for producing a monoclonal antibody. And the like. Regarding a complex of an immunizing antigen and a carrier protein used to immunize a mammal, the type of the carrier protein and the mixing ratio of the carrier and the hapten should be such that the antibody can be efficiently produced against the hapten immunized by crosslinking the carrier. Any kind may be cross-linked at any ratio. For example, bovine serum albumin, bovine thyroglobulin, keyhole limpet hemocyanin, etc. may be used in a weight ratio of about 0.1 to 20 with respect to 1 hapten. Preferably, a method of coupling at a ratio of about 1 to 5 is used.
Various coupling agents can be used for coupling the hapten and the carrier. For example, glutaraldehyde, carbodiimide, a maleimide active ester, an active ester reagent containing a thiol group or a dithioviridyl group, or the like is used. The condensation product is administered to a warm-blooded animal itself or together with a carrier or diluent at a site where antibody production is possible. In order to enhance antibody production ability at the time of administration,
Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered. The administration can usually be performed once every about 2 to 6 weeks, for a total of about 3 to 10 times. The polyclonal antibody can be collected from blood, ascites, or the like, preferably from blood, of the mammal immunized by the above method. The measurement of the polyclonal antibody titer in the antiserum can be performed in the same manner as the measurement of the antibody titer in the serum described above. The separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described separation and purification of the monoclonal antibody.

Preparation of an antibody against a protein containing GPR14 (SENR) (for example, the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11 of the present invention), an amide thereof, an ester thereof, or a salt thereof. This will be described below.

An antibody against a protein containing GPR14 (SENR) (for example, the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11 of the present invention), an amide thereof, an ester thereof, or a salt thereof is obtained by using GPR14 (SENR). An antibody capable of recognizing a protein containing (SENR) (for example, the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11 of the present invention), an amide thereof, an ester thereof, or a salt thereof, Any of a polyclonal antibody and a monoclonal antibody may be used. GPR14 (SENR) (for example, SEQ ID NO:
3 or an amino acid sequence represented by SEQ ID NO: 11 or an amide or ester thereof or a salt thereof (hereinafter, GPR14 (SPR
ENR) etc.) may be G
Using PR14 (SENR) or the like as an antigen, it can be produced according to a known method for producing an antibody or antiserum.

[Preparation of Monoclonal Antibody] (a) Preparation of Monoclonal Antibody-Producing Cell GPR14 (SENR) or the like is administered to a mammal at a site where the antibody can be produced by administration to itself or together with a carrier and a diluent. You. Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered in order to enhance the antibody-producing ability upon administration. Administration is usually 2-6
It is performed once a week, about 2 to 10 times in total. Examples of mammals used include monkeys, rabbits, dogs,
Guinea pigs, mice, rats, sheep and goats can be mentioned, and mice and rats are preferably used. When preparing monoclonal antibody-producing cells, a warm-blooded animal immunized with an antigen, for example, an individual having an antibody titer is selected from a mouse, and the spleen or lymph node is collected 2 to 5 days after the final immunization. By fusing the contained antibody-producing cells with myeloma cells, a monoclonal antibody-producing hybridoma can be prepared. The measurement of the antibody titer in the antiserum can be performed, for example, by using labeled GPR14 (SENR).
After reacting the antiserum with the antiserum, the activity can be measured by measuring the activity of the labeling agent bound to the antibody. The fusion operation is performed by a known method, for example, the method of Kohler and Milstein [Nature, 256, 495 (1)
975)]. Examples of the fusion promoter include polyethylene glycol (PEG)
And Sendai virus, but preferably P
EG is used. Examples of myeloma cells include NS
-1, P3U1, SP2 / 0, etc.
U1 is preferably used. The preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is 1:
PEG (preferably PEG
1000 to PEG 6000) at a concentration of about 10 to 80%, about 20 to 40 ° C., preferably about 30 to 37%.
Incubation at about 1 ° C. for about 1 to 10 minutes allows efficient cell fusion.

Various methods can be used to screen for a monoclonal antibody-producing hybridoma. For example, the hybridoma culture supernatant is applied to a solid phase (eg, a microplate) on which an antigen such as GPR14 (SENR) is adsorbed directly or together with a carrier. Then, an anti-immunoglobulin antibody (anti-mouse immunoglobulin antibody is used if the cell used for cell fusion is a mouse) or protein A labeled with a radioactive substance or an enzyme is added, and the monoclonal antibody bound to the solid phase is added. A method for detecting antibodies, adding a hybridoma culture supernatant to a solid phase to which an anti-immunoglobulin antibody or protein A is adsorbed, adding a polypeptide or the like labeled with a radioactive substance or an enzyme, etc., and forming a monoclonal antibody bound to the solid phase Detection method and the like can be mentioned. The selection of monoclonal antibodies can be performed according to a method known per se or a method analogous thereto.
(Hypoxanthine, aminopterin, thymidine) in a medium for animal cells or the like. As a selection and breeding medium, any medium can be used as long as a hybridoma can grow. For example, 1
RPMI 1640 medium containing 10-20%, preferably 10-20% fetal calf serum, GIT medium containing 1-10% fetal calf serum (Wako Pure Chemical Industries, Ltd.) or serum-free medium for hybridoma culture (SFM) -101, Nissui Pharmaceutical Co., Ltd.) can be used. The culturing temperature is usually 20 to 40 ° C, preferably about 37 ° C. The culturing time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. The culture can be usually performed under 5% carbon dioxide. The antibody titer of the hybridoma culture supernatant can be measured in the same manner as the measurement of the antibody titer in the antiserum described above.

(B) Purification of Monoclonal Antibody Separation and purification of monoclonal antibodies can be carried out by the same method as in the separation and purification of normal polyclonal antibodies, such as immunoglobulin separation and purification [eg, salting out, alcohol precipitation, isoelectric precipitation, etc. , Electrophoresis, adsorption / desorption with an ion exchanger (eg, DEAE), ultracentrifugation, gel filtration, antigen-bound solid phase or an active adsorbent such as protein A or protein G to collect only antibodies and bind Specific Purification Method for Obtaining Antibody by Dissociation].

[Preparation of Polyclonal Antibody] The polyclonal antibody of the present invention can be produced by a method known per se or a method analogous thereto. For example, a complex of an immunizing antigen (antigen such as the polypeptide of the present invention) and a carrier protein is formed, and a mammal is immunized in the same manner as in the above-described method for producing a monoclonal antibody. And the like. Regarding a complex of an immunizing antigen and a carrier protein used to immunize a mammal, the type of the carrier protein and the mixing ratio of the carrier and the hapten should be such that the antibody can be efficiently produced against the hapten immunized by crosslinking the carrier. Any kind may be cross-linked at any ratio. For example, bovine serum albumin, bovine thyroglobulin, keyhole limpet hemocyanin, etc. may be used in a weight ratio of about 0.1 to 20 with respect to 1 hapten. Preferably, a method of coupling at a ratio of about 1 to 5 is used.
Various coupling agents can be used for coupling the hapten and the carrier. For example, glutaraldehyde, carbodiimide, a maleimide active ester, an active ester reagent containing a thiol group or a dithioviridyl group, or the like is used. The condensation product is administered to a warm-blooded animal itself or together with a carrier or diluent at a site where antibody production is possible. In order to enhance antibody production ability at the time of administration,
Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered. The administration can usually be performed once every about 2 to 6 weeks, for a total of about 3 to 10 times. The polyclonal antibody can be collected from blood, ascites, or the like, preferably from blood, of the mammal immunized by the above method. The measurement of the polyclonal antibody titer in the antiserum can be performed in the same manner as the measurement of the antibody titer in the serum described above. The separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described separation and purification of the monoclonal antibody.

The following describes (1) GPR14 (SE) using the polypeptide of the present invention, its precursor protein, DNA encoding the polypeptide or precursor protein, and the like.
NR) and a method of screening for a compound (agonist, antagonist) that alters the binding of the polypeptide of the present invention or its precursor protein, (2) complementary to a DNA containing a nucleotide sequence encoding the polypeptide of the present invention (3) Diagnosis using an antibody against the polypeptide of the present invention, a precursor protein thereof, an amide thereof, an ester thereof, or a salt thereof. Method, (4) GPR14 (SENR)
Alternatively, a diagnostic method using an antibody against a salt thereof, (5) a genetic diagnostic method relating to the polypeptide of the present invention, and (6) a genetic diagnostic method relating to GPR14 (SENR) will be specifically described.

(1) The polypeptide of the present invention and its precursor
Protein, said polypeptide or precursor protein
GPR14 (SENR) using encoding DNA
And the polypeptide of the present invention or its precursor protein
Compounds that change the binding to (antagonists, antago
Nist) screening method using GPR14 (SENR) or a salt thereof, a partial peptide thereof or a salt thereof, or a recombinant GPR1 (SENR)
4 (SENR) expression system and a receptor binding assay system using the expression system, the polypeptide or its precursor protein and GPR14 (SE
Compounds (eg, peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, etc.) that alter the binding to NR) or salts thereof can be screened. Such compounds include GPR14 (SE
Via NR) cell stimulating activity (e.g., arachidonic acid release, acetylcholine release, intracellular ^{Ca 2+} release, intracellular cAMP production, intracellular cGMP production, inositol phosphate production, change in cell membrane potential, phosphorylation of intracellular proteins, a compound having an activity of promoting or suppressing c-fos activation, pH reduction, etc. (i.e., GP
R14 (SENR) agonists) and compounds not having the cell stimulating activity (ie, GPR14 (SENR) antagonists) and the like. The phrase "altering the binding to the ligand" includes both cases of inhibiting the binding to the ligand and promoting the binding to the ligand.

The present invention relates to (i) GPR14 (SENR)
Or the case where the polypeptide of the present invention or its precursor protein is brought into contact with the salt thereof or the partial peptide of GPR14 (SENR) or the salt thereof;
A polypeptide of the present invention or a precursor protein thereof characterized by comparing a partial peptide of PR14 (SENR) or a salt thereof with a polypeptide of the present invention or a precursor protein thereof and a test compound. And a method for screening a compound or a salt thereof that alters the binding property between the compound and GPR14 (SENR). In the screening method of the present invention, (i) GPR14 (SENR) or G
A case where the polypeptide of the present invention or its precursor protein is brought into contact with a partial peptide of PR14 (SENR); and (ii) GPR14 (SENR) or the aforementioned GP
When a polypeptide of the present invention or its precursor protein and a test compound are brought into contact with a partial peptide of R14 (SENR), for example, the GPR14 (SEN)
R) or the binding amount of the ligand to the partial peptide of GPR14 (SENR), cell stimulating activity and the like are measured and compared.

Specifically, the screening method of the present invention comprises contacting the labeled polypeptide of the present invention or its precursor protein with the aforementioned GPR14 (SENR) or a salt thereof or a partial peptide of GPR14 (SENR) or a salt thereof. And the labeled polypeptide of the present invention or its precursor protein and a test compound were GPR14 (SENR) or a salt thereof or GPR1
4 (SENR) when the polypeptide of the present invention or its precursor protein is brought into contact with the GRP14 (SENR) or its salt, or its partial peptide or its salt when contacted with the partial peptide of 4 (SENR) or its salt. Measuring and comparing the polypeptide of the present invention or its precursor protein with GPR
For screening a compound or a salt thereof that alters the binding property to 14 (SENR), contacting a labeled polypeptide of the present invention or its precursor protein with a cell containing GPR14 (SENR) or a membrane fraction of the cell And the labeled polypeptide of the present invention, when the labeled polypeptide of the present invention or its precursor protein and a test compound are brought into contact with cells containing GPR14 (SENR) or a membrane fraction of the cells. Or a compound that alters the binding between the polypeptide of the present invention or its precursor protein and GPR14 (SENR), wherein the amount of binding of the precursor protein to the cell or the membrane fraction is measured and compared. Or a method for screening a salt thereof, a labeled polypeptide of the present invention or a precursor thereof The proteins, DNA encoding GPR14 (SENR)
Culturing a transformant containing GPR14 (SENR), and contacting GPR14 (SENR) expressed on the cell membrane with a labeled polypeptide of the present invention or its precursor protein and a test compound. When a transformant containing DNA is cultured and brought into contact with GPR14 (SENR) expressed on the cell membrane, the labeled polypeptide of the present invention or its precursor protein GPR14 (SEN)
R) A method for screening for a compound or a salt thereof that alters the binding property between GPR14 (SENR) and the polypeptide of the present invention or its precursor protein, which comprises measuring and comparing the amount of binding to GPR14 (SENR). A compound that activates GPR14 (SENR) and a compound that activates GPR14 (SENR) and a test compound are contacted with a compound that activates GPR14 (SENR) (for example, a polypeptide or a precursor protein thereof). GPR14 (SNR) when contacted with cells containing
ENR) -mediated cell stimulating activity (eg, arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ release, intracellular cAMP production, intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorylation, binding to GPR14 (SENR) and the polypeptide of the present invention or its precursor protein, wherein the activity of promoting or suppressing c-fos, lowering of pH and the like is measured and compared. A method for screening a compound that alters sex or a salt thereof, and a method for activating a compound that activates GPR14 (SENR) (for example, a polypeptide of the present invention or a precursor protein thereof) containing DNA encoding GPR14 (SENR) GPR14 (expressed on the cell membrane by culturing the transformant) And when contacted with ENR),
A compound that activates GPR14 (SENR) and a test compound may be a DNA encoding GPR14 (SENR).
GPR14 (SENR) -mediated cell stimulating activity (eg, arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ ) in the case of contacting GPR14 (SENR) expressed on the cell membrane by culturing a transformant containing Release, intracellular cAMP generation, intracellular cGM
P production, inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorylation, activation of c-fos, pH
Of the present invention or a precursor protein thereof and GPR14 (SEN
And a method for screening a compound or a salt thereof that changes the binding property to R).

Specific description of the screening method of the present invention
The light is as follows. First, the screening method of the present invention
As GPR14 (SENR) to be used, the above GPR
Part 14 (SENR) or GPR14 (SENR)
Any substance containing a peptide
Although preferred, a membrane fraction of the organ of a warm-blooded animal is preferred. I
However, is it particularly difficult to obtain human-derived organs?
For screening, recombinant
GPR14 (SENR) expressed in large amounts using the body
Is suitable. To manufacture GPR14 (SENR)
The above method and the like are used. Screenini of the present invention
GPR14 (SENR)
When using cells or the cell membrane fraction, etc.
It is sufficient to follow the preparation method. Includes GPR14 (SENR)
When using cells having
Or formalin. The fixing method is
It can be carried out according to a method known per se. GPR
Cells containing 14 (SENR) include GPR1
4 (SENR) is expressed in the host cell.
As the vesicle, the above-mentioned Escherichia coli, Bacillus subtilis, yeast, insect cells,
Animal cells and the like. As a membrane fraction, cells are broken
After crushing, many cell membranes are obtained by a method known per se.
Refers to the fraction included. As a method for disrupting cells,
How to crush cells with a Potter-Elvehjem homogenizer
Method, waring blender and polytron (Kinematica
), Ultrasonic crushing, French press
Spouting cells from a narrow nozzle while applying pressure
Crushing and the like. Fractionation of cell membrane
Centrifugal force such as centrifugation or density gradient centrifugation
The painting method is mainly used. For example, slow cell lysate
(500 rpm to 3000 rpm) in a short time (usually about
(1 minute to 10 minutes), and centrifuged.
(rpm ~ 30,000 rpm) for 30 minutes ~ 2 hours
The resulting precipitate is used as a membrane fraction. In the membrane fraction,
GPR14 (SENR) and cell-derived phospholipids
It contains a lot of membrane components such as membrane proteins. The GPR1
GPR14 in cells and membrane fractions containing 4 (SENR)
The amount of (SENR) is 10 per cell³-10⁸molecule
Is preferably 10⁵-10 ⁷Preferably a molecule
Suitable. In addition, the higher the expression level, the more ligature per membrane fraction
High binding capacity (specific activity)
Not only enables the construction of a
Can measure a large amount of samples.

Screening for a compound that alters the binding between the polypeptide of the present invention or its precursor protein and GPR14 (SENR) In order to carry out the above-mentioned steps, an appropriate GPR14 (SENR) fraction and a label The polypeptide of the present invention or its precursor protein is used. The GPR14 (SENR) fraction may be a natural GPR14 (SENR) fraction or a recombinant GPR14 (SEN) having an activity equivalent thereto.
R) Fractions and the like are desirable. Here, the equivalent activity indicates an equivalent ligand binding activity and the like. As the labeled ligand, a labeled ligand, a labeled ligand analog compound, or the like is used. For example, [ ³ H],
Ligands labeled with [ ¹²⁵ I], [ ¹⁴ C], [ ³⁵ S] and the like can be used. In particular,
The polypeptide of the present invention or its precursor protein and G
In order to screen for a compound that alters the binding to PR14 (SENR), first, a GPR14 (SEN)
A receptor preparation is prepared by suspending the cells containing R) or the membrane fraction of the cells in a buffer suitable for screening. The buffer may be any buffer such as a phosphate buffer of pH 4 to 10 (preferably pH 6 to 8) or a buffer such as Tris-HCl buffer that does not inhibit the binding between the ligand and the receptor. Further, in order to reduce non-specific binding, CHAPS, Tween
Surfactants such as n-80 ^™ (Kao-Atlas), digitonin, deoxycholate and the like can also be added to the buffer. Furthermore, PMSF, for the purpose of suppressing the degradation of the receptor and the polypeptide of the present invention by protease,
Protease inhibitors such as leupeptin, E-64 (manufactured by Peptide Research Laboratories), and pepstatin can also be added. To 0.01 ml to 10 ml of the receptor solution, a fixed amount (5000 cpm to 500,000 cpm) of the labeled polypeptide of the present invention is added, and at the same time, 10 ^-10 to 1
^0-7M test compound is co-present. A reaction tube containing a large excess of the unlabeled polypeptide of the present invention is also prepared to determine the non-specific binding amount (NSB). Reaction is 0 ° C
To 50 ° C, preferably 4 to 37 ° C for 20 minutes to 2
It is performed for 4 hours, preferably for 30 minutes to 3 hours. After the reaction, the mixture is filtered with a glass fiber filter or the like, washed with an appropriate amount of the same buffer, and the radioactivity remaining on the glass fiber filter is measured with a liquid scintillation counter or a γ-counter. Count (B ₀ −NS) obtained by subtracting the non-specific binding amount (NSB) from the count (B ₀ ) when there is no antagonistic substance
Specific binding amount (B-NSB) assuming that B) is 100%
Is 50% or less, for example, can be selected as a candidate substance having competitive inhibitory ability.

In order to carry out the above-mentioned method for screening for a compound that alters the binding property between the polypeptide of the present invention or its precursor protein and GPR14 (SENR), a cell stimulating activity through GPR14 (SENR) is required. (Eg arachidonic acid release, acetylcholine release, intracellular Ca ²⁺ release, intracellular cAMP production,
Intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, intracellular protein phosphorylation, activation of c-fos, activity to promote or suppress pH reduction, etc.) by a known method or commercially available method It can be measured using a kit for use. Specifically, first, GPR
Cells containing 14 (SENR) are cultured in a multiwell plate or the like. Before performing screening, the cells were exchanged with a fresh medium or an appropriate buffer that is not toxic to cells, and a test compound was added and incubated for a certain period of time. The product is quantified according to the respective method. When the production of a substance (for example, arachidonic acid or the like) as an indicator of cell stimulating activity is difficult due to a degrading enzyme contained in a cell, an assay may be performed by adding an inhibitor against the degrading enzyme. In addition, the activity such as cAMP production suppression can be detected as a production suppression effect on cells whose basic production amount has been increased by forskolin or the like. To perform screening by measuring cell stimulating activity, an appropriate GPR14
(SENR) expressing cells are required. G of the present invention
As the cells expressing PR14 (SENR), the above-mentioned recombinant GPR14 (SENR) expressing cell line and the like are desirable. Test compounds include, for example, peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, cell extracts, plant extracts, animal tissue extracts, and the like.

A kit for screening a compound or a salt thereof that alters the binding property between the polypeptide of the present invention or its precursor protein and GPR14 (SENR) is provided by:
GPR14 (SENR) or a salt thereof, GPR14 (S
ENR) partial peptide or a salt thereof, GPR14 (S
ENR) -containing cells or GPR14 (SEN
R) -containing cell membrane fraction, and the polypeptide of the present invention or its precursor protein. Examples of the screening kit of the present invention include the following. 1. Screening reagent Measurement buffer and washing buffer Hanks' Balanced Salt Solution (manufactured by Gibco)
One containing 05% bovine serum albumin (manufactured by Sigma). Sterilized by filtration through a 0.45 μm filter, 4 ° C
Or may be prepared at the time of use. GPR14 (SENR) standard CHO cells expressing GPR14 (SENR) were
Passage into a 2-well plate at 5 × 10 ⁵ / well, 37 ° C., 5
Cultured at 2% CO ₂ , 95% air for 2 days. The polypeptide of the present invention or its precursor protein labeled with a labeled ligand [ ³ H], [ ¹²⁵ I], [ ¹⁴ C], [ ³⁵ S], or the like, dissolved in a suitable solvent or buffer at 4 ° C. or − Store at 20 ° C.
Dilute to μM. Ligand standard solution PB containing the polypeptide of the present invention or its precursor protein in 0.1% bovine serum albumin (Sigma)
Dissolve to 1 mM with S and store at -20 ° C. 2. GPR14 cultured on a 12-well tissue culture plate
(SENR) was expressed in 1 ml of a buffer solution for measurement.
After washing twice, 490 μl of measurement buffer is added to each well. After adding 5 μl of a 10 ⁻³ to 10 ⁻¹⁰ M test compound solution, 5 μl of the labeled polypeptide of the present invention or its precursor protein is added, and the mixture is reacted at room temperature for 1 hour. To determine the non-specific binding amount, 5 μl of 10 ⁻³ M of the polypeptide of the present invention or its precursor protein is added instead of the test compound. Remove the reaction solution and wash 3 times with 1 ml of washing buffer. The labeled ligand bound to the cells was 0.2N NaOH
1% SDS, 4 ml of liquid scintillator A
(Made by Wako Pure Chemical Industries). Liquid scintillation counter (Beckman)
Radioactivity was measured using Percent Maximum Binding
(PMB) is obtained by the following equation. Formula PMB = [(B−NSB) / (B ₀ −NSB)] × 10
0 PMB: Percent Maximum Binding B: Value when a sample is added NSB: Non-specific Binding (Non-specific binding amount) B ₀ : Maximum binding amount

The compound or a salt thereof obtained by using the screening method or the screening kit of the present invention alters the binding between the polypeptide of the present invention or its precursor protein and GPR14 (SENR) (inhibiting or promoting the binding). ), Specifically, G
A compound having a cell stimulating activity via PR14 (SENR) or a salt thereof (a so-called GPR14 (SENR) agonist) or a compound having no such stimulating activity (a so-called GPR14 (SENR) antagonist). Such compounds include peptides, proteins, non-peptidic compounds, synthetic compounds, fermentation products, and the like,
These compounds may be novel compounds or known compounds. A specific method for evaluating whether the compound is a GPR14 (SENR) agonist or antagonist may be in accordance with the following (i) or (ii). (I) A binding assay shown in the above screening methods (1) to (5) is carried out to obtain a compound that changes the binding property of GPR14 (SENR) to the polypeptide of the present invention or its precursor protein (particularly, inhibits the binding). After that, the compound is converted to GPR14 (SENR) as described above.
To determine whether it has cell-stimulating activity via
A compound having a cell stimulating activity or a salt thereof is GPR14.
A compound or a salt thereof that is a (SENR) agonist and does not have the activity is a GPR14 (SENR) antagonist. (Ii) (a) A test compound is brought into contact with cells containing GPR14 (SENR), and the above-mentioned GPR14 (SENR) -mediated cell stimulating activity is measured. The compound having a cell stimulating activity or a salt thereof is a GPR14 (SENR) agonist. (b) A compound that activates GPR14 (SENR) (for example, the polypeptide of the present invention, its precursor protein or SENR agonist, etc.) is converted to GPR14 (SNR).
ENR) and GPR1
GPR14 (SENR) -mediated cell stimulating activity when a compound that activates 4 (SENR) and a test compound are contacted with cells containing GPR14 (SENR) are measured and compared. A compound capable of decreasing the cell stimulating activity by a compound activating GPR14 (SENR) or a salt thereof is a GPR14 (SENR) antagonist.

The GPR14 (SENR) agonist is
Since it has an action similar to the physiological activity of the polypeptide of the present invention or its precursor protein to GPR14 (SENR), it is a safe and low toxic drug like the polypeptide of the present invention or its precursor protein. Useful. Conversely, GPR14 (SENR) antagonists can suppress the physiological activity of the polypeptide of the present invention against GPR14 (SENR), and are therefore useful as safe and low-toxic drugs for suppressing the receptor activity. Since the polypeptide of the present invention or its precursor protein is involved in an anxiety-promoting action, a GPR14 (SENR) agonist can be used as an agent for treating or preventing diseases such as attention deficit disorder and narcolepsy. GPR14 (SENR) antagonist can be used as a therapeutic / prophylactic agent for diseases such as anxiety, depression, insomnia, schizophrenia, and phobia.

Compounds useful as GPR14 (SENR) antagonists obtained by the screening method or screening kit of the present invention include, for example, compounds of the formula (I)
a):

Embedded image [In the formula, A ^a represents an optionally substituted benzene ring;
^a is a 5- to 8-membered ring which may be substituted, ^Xa is a divalent group having 1 to 4 atoms in ^a linear portion, R ^1a is an amino group which may be substituted, R ^2a Represents a cyclic group which may be substituted]] or a salt thereof.

[0064] In the above formula, the "benzene ring which may be substituted" represented by A ^a, as the substituent which may be possessed by the benzene ring, for example, may be substituted hydrocarbon group, optionally substituted heterocyclic group, a nitro group, a halogen atom, an optionally substituted amino group, wherein R ^4a -Y ^a - in a group represented by (wherein, Y ^a is is an oxygen atom or oxide R ^4a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), a cyano group, an optionally substituted acyl group, esterification or amidation A carboxyl group which may be used is used.

[0065] represented by A "optionally substituted hydrocarbon group" as the substituent which may be a benzene ring have the "substituted optionally also benzene ring" represented by ^a and R ^{4 a} "Optionally substituted hydrocarbon group"
Examples of the “hydrocarbon group” include: (1) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
(2) cycloalkyl (for example, C _1-10 alkyl such as tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably lower (C _1-6 ) alkyl); , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-8 cycloalkyl such as cycloheptyl); and, the cycloalkyl is condensed with the benzene ring, indane (e.g., indan-1-yl, indan -2
-Yl), tetrahydronaphthalene (eg, tetrahydronaphthalen-5-yl, tetrahydronaphthalene-
(Preferably indane and the like); and the cycloalkyl is cross-linked via a linear atom chain having 1 to 2 carbon atoms to form a bicyclo [2. 2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl and the like (preferably having 1 to 2 carbon atoms)
(3) a cyclohexyl having a bridge through a linear atom chain, and more preferably a bicyclic [2.2.1] heptyl and the like). Alkenyl (eg, vinyl, allyl,
C such as crotyl, 2-pentenyl and 3-hexenyl
_2-10 alkenyl, preferably lower _{(C 2-6)} such as alkenyl and the like); (4) cycloalkenyl (for example, 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenyl methyl, 2-cyclohexenyl methyl and the like _{C 3-8} cycloalkenyl, etc.); (5) alkynyl (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,
(6) Aryl (for example, C _2-10 alkynyl such as 3-hexynyl, preferably lower (C _2-6 ) alkynyl and the like);
_6-14 aryl, preferably _{C 6-10} aryl, more preferably like phenyl); (7) aralkyl (e.g., _{C 1-6} alkyl having 1-3 _{C 6-14} aryl, preferably phenyl _{-C 1-4} alkyl (e.g., benzyl, phenethyl, etc.)
Among them, alkyl is preferable, C _1-4 alkyl such as methyl and ethyl is more preferable, and methyl is particularly preferably used.

The hydrocarbon group may have a substituent. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, substituted and unsubstituted. Thiol group (eg, thiol, C _1-4 alkylthio, etc.), and optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, mono C _{2- 5-} alkanoylamino, tetrahydropyrrole, piperazine, piperidine, 5- or 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole, etc.), phenyl-lower (C _1-4 ) alkyl, C _3-7 cycloalkyl, ester reduction or a carboxyl group which (example be amidated, carboxyl, C _1-4 alkoxy - carbonyl, lower (C _-10) aralkyloxy - carbonyl, carbamoyl, _{mono-C 1-4} alkylcarbamoyl, and _{di-C 1-4} alkylcarbamoyl), a halogen atom or _{C 1-4} alkoxy optionally substituted _{C 1-4} alkyl (e.g. , Trifluoromethyl, methyl, ethyl, etc.), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy (eg,
Methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C _1-4 alkylenedioxy (eg, —O—CH ₂ —O—, —O—CH ₂ —CH ₂ —O
- etc.), _{formyl, C 2-4} alkanoyl (e.g., acetyl, propionyl, _{etc.), C 1-4} alkylsulfonyl (e.g., methanesulfonyl, etc. ethanesulfonyl)
C _1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl, etc.) and the like, and the number of substituents is preferably 1 to 3.

[0067] "optionally substituted heterocyclic group" as may be benzene ring optionally having in the "benzene ring which may be substituted" substituent represented by A ^a and R
^{As the} "heterocyclic group" in the "optionally substituted heterocyclic group" for ^4a , for example, 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like (preferably 1 to 3 hetero atoms) 5-8 membered aromatic heterocyclic ring, saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) containing at least one (preferably 1 to 4, more preferably 1 to 2) And the like, except for one hydrogen atom. Here, the “aromatic heterocycle” is a 5- to 8-membered (preferably 5 to 6-membered) aromatic monocyclic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole) , Pyrazole, 1,2,3-
Oxadiazole, 1,2,4-oxadiazole, 1,
3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, Pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.) and the like.
5-8 membered (preferably 5 to 6 membered) or saturated or imidazoline, pyrazolidine, pyrazoline, oxazine, oxadiazine, thiazine, thiadiazine, piperidine, morpholine, thiomorpholine, tetrahydropyran, piperazine, pyran, oxepin, thiepin, azepine and the like. Unsaturated monocyclic non-aromatic heterocycle (aliphatic heterocycle) or the like, or a 5- to 8-membered non-aromatic heterocycle in which a part or all of the above aromatic monocyclic heterocycle has a double bond saturated. And the like.

[0068] Also, it is shown in the "optionally substituted heterocyclic group" and R ^4a as may be benzene ring optionally having in the "benzene ring which may be substituted" substituent represented by A ^a Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” include the above-mentioned monocyclic heterocycle (monocyclic aromatic heterocycle and monocyclic non-aromatic heterocycle) and 5 to 8 5- to 8-membered (preferably 5 to 6-membered) saturated or unsaturated cycloaliphatic such as membered cyclic hydrocarbons ( _C5-8 cycloalkane, _C5-8 cycloalkene, _C5-8 cycloalkadiene, etc.) Hydrocarbons; 6-membered aromatic hydrocarbons such as benzene; etc.), and is formed by removing one hydrogen atom from a condensed ring formed by condensing two to three (preferably two) rings. These condensed rings may be saturated Fused ring, fused rings with partially unsaturated bond, may be any of the aromatic condensed ring. Preferred examples of such a condensed ring include two identical or different heterocyclic rings (preferably, one heterocyclic ring and one aromatic heterocyclic ring, more preferably, two identical or different two aromatic heterocyclic rings). One heterocyclic ring and one homocyclic ring (preferably one heterocyclic ring and one benzene ring, more preferably one aromatic heterocyclic ring and one And a ring in which a benzene ring is condensed. Specific examples of such a condensed ring include, for example, indole, benzothiophene, benzofuran, benzimidazole, imidazo
[1,2-a] pyridine, quinoline, isoquinoline, cinnoline and the like can be mentioned. Represented by A ^a "optionally substituted heterocyclic group" as may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent
And "heterocyclic group" in "optionally substituted heterocyclic group" represented by R ^4a may have a substituent, and examples of the substituent, for example, represented by A ^a described above " As the substituent that the benzene ring may have in the `` benzene ring which may be substituted '', the same group as the substituent which may be contained in the `` hydrocarbon group which may be substituted '' may be mentioned. .

[0069] Examples of "halogen atom" as a substituent which may be a benzene ring have the "substituted optionally also benzene ring" represented by A ^a is fluorine, chlorine, bromine, and iodine No.

[0070] As the "optionally substituted amino group" as it may be benzene ring optionally having in the "benzene ring which may be substituted" substituent represented by A ^a, in R ^1a below it may be mentioned those similar to the "optionally substituted amino group" represented, inter alia, "optionally substituted hydrocarbon group" (which may be "substituted represented by a ^a described above A group similar to the “optionally substituted hydrocarbon group” as a substituent that the benzene ring may have in the “benzene ring”), a “optionally substituted heterocyclic group” (the above-mentioned A ^a similar group as the “optionally substituted heterocyclic group” as a substituent that the benzene ring may have in the “optionally substituted benzene ring” represented by a) Acyl group which may be Selected from (such as similar to the "optionally substituted acyl group" as may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent group represented by A ^a, below) An amino group which may have 1 to 2 substituents is preferable, and an alkyl group which may be substituted (eg, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl group) , An optionally substituted thiol group (eg, thiol,
C _1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, _{mono-C 1-4} alkylamino, di _{C 1-4} alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole , 5- to 6-membered cyclic aminos such as imidazole, etc.), phenyl-lower (C _1-4 ) alkyl, C _3-7
Carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl, lower (C _7-10 ) aralkyloxy-carbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, dialkyl C _1-4 alkylcarbamoyl, etc.), optionally _{C 1-4} alkyl optionally substituted by halogen atom or _{C 1-4} alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.), a halogen atom or C
Good _{C 1-4} alkoxy optionally substituted by _C1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, _{etc.), C 1-4} alkylenedioxy (e.g., _-O-CH 2 -O -, - _O-CH 2 -C
H ₂ —O—, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C _1-4 alkylsulfinyl (eg, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, which may have 1 to 3 substituents selected from methanesulfinyl, ethanesulfinyl and the like.
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1- 6)} an amino group which may have one or two alkyl, etc.] preferred.

[0071] Also, "optionally substituted amino group" as may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent represented by A ^a
Is a group in which substituents of an amino group are bonded to each other to form a cyclic amino group (for example, a hydrogen atom from a ring-forming nitrogen atom of a 5- to 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, and imidazole). And a cyclic amino group having a bond on the nitrogen atom). The cyclic amino group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, thiol, amino, carboxyl and the like. , Optionally halogenated C
_1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally _{C 1 -4} alkoxy which may be halogenated (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), Examples include formyl, _C2-4 alkanoyl (eg, acetyl, propionyl, etc.), _C1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), and the number of substituents is preferably 1 to 3. .

[0072] As the "optionally substituted acyl group" as may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent represented by A ^a is hydrogen, "substituted optionally substituted hydrocarbon group "(" optionally substituted hydrocarbon group as the "optionally substituted benzene ring" substituent which may be a benzene ring optionally having in represented by a ^a described above ") And" optionally substituted heterocyclic group "(A
^a group as the “optionally substituted heterocyclic group” as a substituent that the benzene ring in the “optionally substituted benzene ring” represented by a) may have, for example, a carbonyl group or Examples thereof include those bonded to a sulfonyl group. Preferred examples thereof include (1) hydrogen, and (2) optionally substituted alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) , Tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1-6)} such as an alkyl and the like); (3) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (4) an optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 _C2-10 alkenyl such as _-hexenyl , preferably lower (C
_2-6) such as alkenyl and the like); (5) an optionally substituted cycloalkenyl (e.g., 2-cyclopentenyl, 2-cyclohexenyl, 2
And C _3-7 cycloalkenyl such as cyclopentenylmethyl and 2-cyclohexenylmethyl); (6) a 5- or 6-membered monocyclic aromatic group which may be substituted (for example, phenyl, pyridyl) And the like bonded to a carbonyl group or a sulfonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexane) Heptanecarbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.), and the above-mentioned (2) optionally substituted alkyl,
(3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5- to 6-membered Examples of the substituent which the monocyclic aromatic group may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol group (eg, thiol , C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, A 5- to 6-membered cyclic amino such as pyrrole or imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _{1) -4} alkoxycarbonyl, carbamoyl, mono _C1-4 alkylcarbamoyl, _diC1-4
Alkylcarbamoyl, etc.), halogen atom or C
C _1-4 alkyl optionally substituted with _1-4 alkoxy (eg, trifluoromethyl, methyl, ethyl and the like), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy ( E.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, _C2-4 alkanoyl (e.g., acetyl, propionyl, etc.), _C1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), C
_1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl and the like) and the like, and the number of substituents is preferably 1 to 3.

A^aThe "optionally substituted
Of benzene ring in benzene ring
Carboxyl which may be esterified as a group
Examples of the “group” include hydrogen, “optionally substituted hydrocarbon”
Group ”(A described above^aRepresented by "may be substituted
The benzene ring may have
Same as "optionally substituted hydrocarbon group"
Such as carbonyloxy)
Preferred examples include (1) hydrogen, (2) optionally substituted alkyl (for example, methyl
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, e
C such as cutyl, nonyl, and decyl_1-10Alkyl, good
Preferably low grade (C_1-6) Alkyl and the like
(3) optionally substituted cycloalkyl (for example,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclo
C such as rohexyl and cycloheptyl_3-7Cycloal
(4) alkenyl which may be substituted (for example,
Allyl, crotyl, 2-pentenyl, 3-hexenyl
C such as_2-10Alkenyl, preferably lower (C
_2-6) Alkenyl and the like); (5) optionally substituted cycloalkenyl (eg,
For example, 2-cyclopentenyl, 2-cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl
C such as_3-7Cycloalkenyl and the like.
(6) aryl which may be substituted (for example, phenyl
, Naphthyl, etc.)
, More preferably carboxyl, lower
(C _1-6) Alkoxycarbonyl, aryloxyca
Rubonyl (eg, methoxycarbonyl, ethoxycarbonyl
, Propoxycarbonyl, phenoxycarbonyl, na
And the like.
(2) optionally substituted alkyl, (3) substituted alkyl
Optionally substituted cycloalkyl, (4) optionally substituted
Good alkenyl, (5) optionally substituted cycloalkyl
Lucenyl, and (6) optionally substituted aryl
As a substituent which may be possessed, halogen (eg, fluorine)
Nitrogen, chlorine, bromine, iodine, etc.), nitro, cyano, water
Acid group, thiol group which may be substituted (eg, thio-
Le, C_1-4Alkylthio, etc.), may be substituted
Amino groups (eg, amino, mono C_1-4Alkylam
No, Di C _1-4Alkyl amino, tetrahydro pillow
, Piperazine, piperidine, morpholine, thiomorpho
5- to 6-membered cyclic amines such as phosphorus, pyrrole and imidazole
Mino), esterified or amidated
Carboxyl groups (eg, carboxyl, C_1-4Arco
Xycarbonyl, carbamoyl, mono C_1-4Alkyl
Carbamoyl, di C_1-4Alkyl carbamoyl
Etc.), halogen atom or C_1-4Substituted with alkoxy
C that may be_1-4Alkyl (eg, trifluoromethyl
Tyl, methyl, ethyl, etc.), a halogen atom or C
_1-4C optionally substituted with alkoxy_1-4Al
Coxy (eg, methoxy, ethoxy, trifluoromethoxy)
, Trifluoroethoxy, etc.), formyl, C_2-4
Alkanoyl (eg, acetyl, propionyl, etc.), C
_1-4Alkylsulfonyl (eg, methanesulfonyl,
Tansulfonyl), C_1-4Alkylsulfinyl
(Eg, methanesulfinyl, ethanesulfinyl, etc.)
And the like, and the number of substituents is preferably 1 to 3.
New

[0074] As "amidated carboxyl group which may be" as may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent represented by A ^a is (1) hydroxyl group (2) “optionally substituted amino group” (A
such as those similar to the "amino group which may be substituted" as it may have a benzene ring in the "unsubstituted or benzene ring optionally" substituent) represented by ^a; such that the group And the like.

[0075] A ^a substituent which may be a benzene ring have the "substituted optionally also benzene ring" represented by the 1-4 (preferably 1-2) the same or different ring May be substituted at any position. Also,
If the benzene ring in the "benzene ring which may be substituted" represented by A ^a has two or more substituents, among these, the two substituents bonded to each other, for example,
Lower (C _1-6 ) alkylene (eg, trimethylene, tetramethylene, etc.), lower (C _1-6 ) alkyleneoxy (eg, —CH ₂ —O—CH ₂ —, —O—CH ₂ —CH ₂
-Etc.), lower ( _C1-6 ) alkylenedioxy (eg,
—O—CH ₂ —O—, —O—CH ₂ —CH ₂ —O—, etc., lower (C _2-6 ) alkenylene (eg, —CH ₂ —
_{CH = CH -, - CH 2} -CH 2 -CH = CH -, - C
H ₂ —CHＣＨCH—CH ₂ —, etc.), lower (C _4-6 )
Alkadienylene (eg, -CH = CH-CH = CH-, etc.) may be formed.

A^aThe "optionally substituted
Of benzene ring in benzene ring
Examples of the group include an optionally substituted hydrocarbon group,
An optionally substituted heterocyclic group, nitro group, halogen atom,
An optionally substituted amino group, of the formula R^4a-Y^a−
A group represented by the formula:^aIs an oxygen atom or oxidized
A good sulfur atom, R^4aIs an optionally substituted carbonized
Represents a hydrogen group or an optionally substituted heterocyclic group)
Which are preferred, optionally substituted hydrocarbon group,
An optionally substituted heterocyclic group, a halogen atom,
Optionally an amino group, of the formula R^4a-Y^aGroup represented by-
(Where Y^aIs an oxygen atom or sulfur which may be oxidized
The yellow atom is represented by R^4aRepresents an optionally substituted hydrocarbon group.
Or an optionally substituted heterocyclic group).
, Especially low (C _1-4) Alkyl, ha
A logen atom is preferred.

[0077] Further, the "benzene ring which may be substituted" represented by A ^a has the formula:

Embedded image A benzene ring having at least one substituent at the position of "a" on the benzene ring represented by is preferable, and among them,
formula:

Embedded image Wherein, A a ^'is a benzene ring which may further have a substituent other than the substituent R ^3a, R ^3a may be substituted hydrocarbon group, an optionally substituted heterocyclic group , A nitro group, a halogen atom, an amino group which may be substituted or a group represented by the formula R ^4a -Y ^a-wherein Ya is an oxygen atom or ^a sulfur atom which may be oxidized;
^4a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and a benzene ring represented by the formula:

Embedded image [Wherein, R ^3a has the same meaning as described above]. Table with - in the above formula, as R ^3a is optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a halogen atom, an optionally substituted amino group or the formula R ^4a -Y ^a group (wherein is a Y ^a sulfur atom which may be the oxygen atom or oxide, R ^4a
Represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), among which an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and halogen An atom or the like is preferable, and a lower alkyl group or a halogen atom which may be substituted is particularly preferable.

[0078] In the above formula, the "optionally substituted 5- to 8-membered ring" represented by B ^a, for example, the formula:

Embedded image Wherein, Z ^a, Ring B ^a represents a divalent group of the saturated capable of forming a 5- to 8-membered saturated ring optionally substituted] represented by an arbitrary position substitutable Examples thereof include a saturated 5- to 8-membered ring which may have a substituent, and such a saturated 5- to 8-membered ring may partially have an unsaturated bond. It may be formed. As the ring B ^a, 5 to 8 membered saturated ring may be substituted is preferred. Here, "5- to 8-membered saturated ring" in the "5- to 8-membered saturated ring may be substituted" as the ring B ^a
Refers to "5- to 8-membered ring and ring B ^a quinoline ring is a single bond in all saturated bonds constituting the ring B ^a non-double bonds at the site to form a condensed ring (single bond)" Means
As the ring ^Ba , “optionally substituted unsaturated 5 to 8
The "5- to 8-membered unsaturated ring" in-membered ring "," ring B ^a
A quinoline ring and at least one of the bonds constituting the ring B ^a non-double bonds at the site to form a condensed ring means a 5- to 8-membered ring "is an unsaturated bond.

In the above formula, Z^aA saturated divalent group represented by
Is the ring B^aIs a 5- to 8-membered saturated ring which may be substituted
Any material that can be formed may be used. That is, Z^a
Is a saturated divalent group having 2 to 5 atoms in the straight chain portion
(Preferably, a saturated divalent group having 2 to 5 atoms in the straight chain portion)
Any hydrocarbon group), specific examples of which include
For example, for example, (1)-(CH_Two)_a1-(A1 is an integer of 2 to 5
Is shown. ), (2)-(CH_Two)_b1−Z^a1− (CH_Two)_b2− (B1
And b2 are the same or different and represent an integer of 0-4. However
However, the sum of b1 and b2 is 1-4. Z^a1Is NH, O, S, SO
Or SO _Two), (3)-(CH_Two)_d1−Z^a1− (CH_Two)_d2−
Z^a2− (CH_Two)_d3-(D1, d2 and d3 are the same or different
Represents an integer of 0 to 3. However, the sum of d1, d2 and d3 is 0
~ 3. Z ^a1And Z^a2Are NH, O, S, SO
Or SO_Two), (4)-(CH_Two)_e1−Z^a1− (CH_Two)_e2−Z
^a2− (CH_Two)_e3−Z^a3− (CH_Two)_e4− (E1, e2, e3 and e4
Are the same or different and represent an integer of 0 to 2. Where d1,
The sum of d2 and d3 is 0-2. Z^a1, Z^a2and^aZ^Three
Is NH, O, S, SO or SO respectively_TwoEtc.)
Or-(CH_Two)_a1-(A1 represents an integer of 2 to 5)]
And specifically, for example, -O- (CH_Two)_k1-(K1
Is an integer of 1-4),-(CH_Two)_k1-O- (k1 is an integer of 1-4
Number), -S- (CH_Two)_k1-(K1 is an integer of 1 to 4),-(CH_Two)_k1-
S- (k1 is an integer of 1 to 4), -NH- (CH_Two)_k1-(K1 is 1-4
Integer),-(CH_Two)_k1-NH- (k1 is an integer of 1 to 4),-(CH
_Two)_k2-(K2 is an integer of 2 to 5), -NH-NH-, -CH_Two-NH-NH
-, -NH-NH-CH_Two-, -NH-CH_TwoDivalent groups such as -NH-
You.

[0080] In the above formula, as "optionally substituted 5- to 8-membered ring" represented by B ^a, only the "5- to 8-membered saturated ring which may optionally be substituted" exemplified in this way Alternatively, it may be a "optionally substituted unsaturated 5- to 8-membered ring" having a partially unsaturated bond, or an "optionally substituted 5- to 8-membered aromatic ring", In such a case, the formula:

Embedded image In in represented by ring, Z ^a is a divalent part of binding in exemplified as the "divalent group of saturated atoms straight portion 2-5 'is converted to an unsaturated bond May be shown.

[0081] Further, said bivalent group may have a substituent group, the substituent may be any as long as it can bind to the divalent group said, for example, represented by the A ^a And the same oxo group as the "substituent" which the "optionally substituted benzene ring" may have. Such a substituent has 1-4 (preferably 1-2)
) May be the same or different and may be substituted at any position of the divalent group. Further, when the divalent group has two or more substituents, among these, two substituents bonded to each other, for example, lower (C _1-6) alkylene (e.g., trimethylene, tetramethylene ), Low grade (C
_1-6) alkyleneoxy (for _example, -CH 2 -O-CH _{2
-, - O-CH 2 -CH} 2 - , etc.), lower _{(C 1-6)}
Alkylenedioxy _{(e.g., -O-CH 2 -O -,} - O-
CH ₂ -CH ₂ -O-, etc.), lower _{(C 2-6)} alkenylene _{(e.g., -CH 2 -CH = CH -,} - CH 2 -CH
_{2 -CH = CH -, - CH} 2 -CH = CH-CH 2 - , etc.), lower _{(C 4-6)} alkadienylene (e.g., -CH
= CH-CH = CH-) or the like.

In the above formula, X^a"The origin of the straight-chain portion
Examples of the divalent group having 1 to 4 children include (1)-(CH_Two)_f1−
(F1 represents an integer of 1 to 4.), (2)-(CH_Two)_g1−X^a1
− (CH_Two)_g2-(G1 and g2 are the same or different and each
Indicates an integer. However, the sum of g1 and g2 is 1-3. X
^a1Is NH, O, S, SO or SO _Two), (3)-(CH_Two)_h1
−X^a1− (CH_Two)_h2−X^a2− (CH_Two)_h3− (H1, h2 and h3 are
The same or different and the integer of 0-2 is shown. However, h1, h2
And the sum of h3 is 0-2. X ^a1And X^a2Each
Re NH, O, S, SO or SO_TwoIs shown. However, if h2 is 0
X^a1And X^a2At least one of which is preferably NH
Show. ) And some bonds are unsaturated.
And a divalent group converted into a sum bond.
Is, for example, -O- (CH_Two)_k3-(K3 is an integer of 1 to 3),-(CH
_Two)_k3-O- (k3 is an integer of 1 to 3), -S- (CH_Two)_k3-(K3 is 1
An integer of ~ 3),-(CH_Two)_k3-S- (k3 is an integer of 1 to 3), -NH
-(CH_Two)_k3-(K3 is an integer of 1 to 3),-(CH_Two)_k3-NH- (k3
Is an integer of 1 to 3),-(CH_Two)_k4-(K4 is an integer of 1 to 4),
-CH = CH-, -C≡C-, -CO-NH-, -SO
₂And a divalent group such as -NH-. X^aAs
Is -CO-O-CH₂A divalent group excluding-is preferable,
A straight-chain moiety having 1 to 4 carbon atoms 2
Valent groups are more preferred, with C_1-4Archire
N, C_2-4Alkenylene and the like are preferable, and C_1-4A
Luylene, especially methylene, is preferably used.

[0083] divalent group represented by X ^a is any position (preferably on a carbon atom) may have a substituent, and examples of the substituent include divalent constituting the straight chain moiety Any one that can bind to the chain may be used, for example,
Such similar groups and oxo groups and which may have "benzene ring which may be substituted" of "substituent" represented by the above A ^a and the like. Such substituents may be the same or different from one to four (preferably one to two), and may be substituted at any position of the divalent group. Examples of the divalent preferred substituents also groups have represented by X ^a, a lower (C _1-6) alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., lower (C _3-7 ) cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C _{2) -7} ) alkanoyl (eg, acetyl, propionyl, butyryl, etc.),
Lower (C _2-7 ) alkoxy-carbonyl, lower (C _2-7 ) alkoxy-carbonyl
_{1- 6)} alkoxy, hydroxyl, etc. oxo and the like.

In the above formula, R^1aIs replaced with
"Optionally substituted amino group"
Hydrocarbon group "(A^aIs replaced with
Benzene ring "
"Optionally substituted hydrocarbon as a substituent
Groups that are the same as the "substituent group"), "optionally substituted
Ring group ”(A described above^aThe "may be substituted
Benzene ring "may have a benzene ring
The same as the “optionally substituted heterocyclic group” as a substituent
And the like) and "optionally substituted acyl group"
(A described above^aRepresented by `` optionally substituted ben
Substituents on the benzene ring in the benzene ring
Group similar to the "optionally substituted acyl group"
Etc.) may have 1 to 2 substituents selected from
And an amino group. ^1aReplace with
An optionally substituted amino group ''
Is bonded to a cyclic amino group (eg, tetrahydropyrro
, Piperazine, piperidine, morpholine, thiomol
5- or 6-membered ring such as holin, pyrrole, imidazole
Nitrogen is formed by removing one hydrogen atom from the constituent nitrogen atoms.
To form a cyclic amino group with a bond on the atom)
It may be. The cyclic amino group may have a substituent
Often, such substituents include halogen (eg, fluorine,
Chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl,
Thiol group, amino group, carboxyl group, halogenated
C that may be_1-4Alkyl (eg, trifluoromethyl
Butyl, methyl, ethyl, etc.)
Good C_1-4Alkoxy (eg, methoxy, ethoxy,
Loxy, butoxy, trifluoromethoxy, triflu
Oloethoxy), formyl, C_2-4Alkanoyl
(Eg, acetyl, propionyl, etc.), C_1-4Archi
Rusulfonyl (eg, methanesulfonyl, ethanesulfonyl
And the like, and the number of substituents is from 1 to 3
Are preferred.

The substituent of the amino group in the “optionally substituted amino group” for R ^1a includes: (1) optionally substituted alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1-6)} such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyanooctyl, etc.
_3-8 cycloalkyl and the like); said cycloalkyl, condensed with the benzene ring, indane (e.g., indan-1-yl, indan-2-yl, etc.), tetrahydronaphthalene (e.g., tetrahydronaphthalen-5 Yl, tetrahydronaphthalen-6-yl and the like (preferably indane and the like); and further, the cycloalkyl is cross-linked through a linear atom chain having 1 to 2 carbon atoms. , Bicyclo [2.2.1] heptyl,
Bicyclo [2.2.2] octyl, bicyclo [3.2.
1] octyl, bicyclo [3.2.2] nonyl and the like (preferably cyclohexyl having a bridge through a linear atom chain having 1 to 2 carbon atoms, more preferably bicyclo [2.2.1] Heptyl or the like); (3) optionally substituted alkenyl (for example, C, such as allyl, crotyl, 2-pentenyl, and 3-hexenyl); _2-10 alkenyl, preferably lower (C
_2-6) such as alkenyl and the like); (4) optionally substituted cycloalkenyl (e.g., 2-cyclopentenyl, 2-cyclohexenyl, 2
- cyclopentenyl, 2- etc. _{C 3-7} cycloalkenyl such as cyclohexenyl methyl and the like); (5) an optionally substituted aralkyl (e.g., phenyl _{-C 1-4} alkyl (e.g., benzyl, phenethyl (6) formyl or an optionally substituted acyl (eg, _C2-4 alkanoyl (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), _C1-4 alkylsulfonyl (eg, (7) optionally substituted aryl (eg, phenyl, naphthyl, etc.); (8) optionally substituted heterocyclic group (eg, furan, thiophene) , Pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazo 5- or 6-membered aromatic containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, such as benzene, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole A group formed by removing one hydrogen atom from a heterocycle, tetrahydrofuran,
Nitrogen atom, sulfur atom and oxygen such as tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc. A group formed by removing one hydrogen atom from a 5- to 6-membered non-aromatic heterocycle containing from 1 to 2 heteroatoms selected from atoms, and from 1 to 4).

The above-mentioned (1) Al may be substituted
Kill, (2) an optionally substituted cycloalkyl,
(3) optionally substituted alkenyl, (4) substituted alkenyl
Optionally substituted cycloalkenyl, (5) substituted
Aralkyl, (6) optionally substituted
(7) optionally substituted aryl, and
(8) The heterocyclic group which may be substituted may have
Substituents include halogens (eg, fluorine, chlorine, odor
, Iodine, etc.), halogen atom or C_1-4Arco
C optionally substituted by xy_1-4Alkyl, halogen
Atom or C_1-4May be substituted with alkoxy
C_1-4Alkoxy (eg, methoxy, ethoxy, pro
Poxy, butoxy, trifluoromethoxy, trifluoro
Roethoxy etc.), C_1-4Alkylenedioxy (eg,
-O-CH₂-O-, -O-CH₂-CH ₂-O-
Etc.), Formyl, C_2-4Alkanoyl (eg, acetyl
, Propionyl, etc.), C_1-4Alkylsulfonyl
(E.g., methanesulfonyl, ethanesulfonyl, etc.)
Enyl-lower (C_1-4) Alkyl, C_3-7Cycloa
Alkyl, cyano, nitro, hydroxyl, optionally substituted
Thiol groups (eg, thiol, C _1-4Alkylthio
), An optionally substituted amino group (eg, amino,
No C_1-4Alkylamino, di-C_1-4Alkylam
, Tetrahydropyrrole, piperazine, piperidine,
Morpholine, thiomorpholine, pyrrole, imidazole
5-6 membered cyclic amino, etc.), carboxyl group,
Low grade (C_1-4) Alkoxy-carbonyl, lower (C
_7-10) Aralkyloxy-carbonyl, carbamoy
Le, Mono C_1-4Alkylcarbamoyl, di-C_1-4A
Rukycarbamoyl (preferably halogen, halogen
Low-grade (C_1-4) Alkyl, halogen
Low-grade (C_1-4) Alkoxy,
Enyl-lower (C_1-4) Alkyl, C_3-7Cycloa
Alkyl, cyano, hydroxyl, etc.)
Is preferably 1 to 3.

The “optionally substituted amino group” represented by R ^1a includes, among others, optionally substituted alkyl (eg, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, etc.). A hydroxyl group, an optionally substituted thiol group (eg, thiol, C _1-4 alkylthio, etc.), an optionally substituted amino group (eg,
Amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 5- to 6-membered cyclic amino such as imidazole, etc.), esterification or amidation Carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl,
Lower (C _7-10 ) aralkyloxy-carbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C
_1-4 etc. alkylcarbamoyl), optionally _{C 1-4} optionally substituted by halogen atom or _{C 1-4} alkoxy
Alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), optionally C _1-4 alkoxy optionally substituted by halogen atom or C _1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.) , C _1-4 alkylenedioxy (eg, -O-CH
_{2 -O -, - O-CH} 2 -CH 2 -O- , etc.), phenyl - lower _{(C 1-4) alkyl, C 3-7} cycloalkyl, _{formyl, C 2 -4} alkanoyl (e.g., acetyl,
Propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C
Methyl, ethyl each having from 1 to 3 substituents selected from _1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl, etc.),
Propyl, isopropyl, butyl, isobutyl, sec
- butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, have preferably having 1 or 2 lower _{(C 1-6)} alkyl, etc.] Amino groups which may be present are preferred.

In the above formula, the “cyclic group” of the “optionally substituted cyclic group” represented by R ^2a includes C _5-8 cycloalkane (eg, cyclopentane, cyclohexane,
Cycloheptane, etc.), C _5-8 cycloalkene (eg, 1
-Cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cyclohexene, 3-cyclohexene, etc., _C5-8 cycloalkadiene (eg, 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-
5-8 members (preferably 5 members) such as cyclohexadiene
To 6-membered) saturated or unsaturated alicyclic monocyclic hydrocarbons;
6-membered aromatic monocyclic hydrocarbon such as benzene; at least 1 (preferably 1 to 2) heteroatoms 1 to 3 (preferably 1 to 2) selected from oxygen, sulfur, nitrogen and the like A 5- to 8-membered aromatic monocyclic heterocyclic ring containing 4, more preferably 1 or 2), a saturated or unsaturated non-aromatic monocyclic heterocyclic ring (aliphatic heterocyclic ring) and the like;
And the same or different 2 selected from these single rings
A group formed by removing one hydrogen atom from a ring or the like in which 3 to 3 rings are fused, and the like.

Here, “aromatic monocyclic heterocycle” includes
A 5- to 8-membered (preferably 5- to 6-membered) aromatic monocyclic heterocycle (eg, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,
Imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,
Pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.), and examples of the "non-aromatic monocyclic heterocycle" include, for example, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiolane, dithiolane, oxathiolane, pyrroline, imidazolidine, imidazoline ,
5 such as pyrazolidine, pyrazoline, oxazine, oxadiazine, thiazine, thiadiazine, piperidine, morpholine, thiomorpholine, tetrahydropyran, piperazine, pyran, oxepin, thiepin, azepine, etc.
A saturated or unsaturated monocyclic non-aromatic heterocyclic ring (aliphatic heterocyclic ring) of 8 to 8 members (preferably 5 to 6 members), or a part or all of the above aromatic monocyclic heterocyclic ring; Examples thereof include a 5- to 8-membered non-aromatic heterocycle in which a heavy bond is saturated.

The “cyclic group” of the “optionally substituted cyclic group” represented by R ^2a is preferably 2 to 3 (preferably, monocyclic or heterocyclic) exemplified above. And 2) the same or different rings may be condensed to form a condensed ring with one hydrogen atom removed, and the condensed ring may be a saturated condensed ring or a partially condensed ring. Any of a condensed ring having an unsaturated bond and an aromatic condensed ring may be used. Preferred examples of such a condensed ring include two identical or different heterocyclic rings (preferably, one heterocyclic ring and one aromatic heterocyclic ring, more preferably, two identical or different two aromatic heterocyclic rings). One heterocyclic ring and one homocyclic ring (preferably one heterocyclic ring and one benzene ring, more preferably one aromatic heterocyclic ring and one Such as indole, benzothiophene, benzofuran, benzimidazole, imidazo [1,2-a] pyridine, quinoline, isoquinoline, and the like. Cinnoline and the like. As the "cyclic group" substituents which may be possessed by the "optionally substituted cyclic group optionally" represented by R ^2a, for example, "optionally substituted benzene ring represented by A ^a described above And the same substituents as the substituents that the "optionally substituted hydrocarbon group" may have as a substituent that the benzene ring may have.

As the “cyclic group” of the “optionally substituted cyclic group” for R ^2a , a 5- to 6-membered cyclic group is preferable, a 5- to 6-membered aromatic ring group is preferable, and phenyl, Furyl, thienyl, pyrrolyl, pyridyl (preferably a 6-membered ring) and the like are preferable, and phenyl is particularly preferable.

Among the compounds represented by the formula (Ia) or salts thereof, the compounds represented by the formula (IIa):

Embedded image Wherein, A a ^'is a benzene ring which may further have a substituent other than the substituent R ^3a, B ^a is a good 5-8 membered ring optionally substituted, X ^a is a straight portion Is a divalent group having 1 to 4 atoms, R ^{1a ′} is an amino group substituted with 1 to 2 lower alkyl groups which may be substituted, and R ^2a is a cyclic group which may be substituted. R ^3a represents a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a nitro group, a halogen atom, an amino group which may be substituted, or a group represented by the formula R ^4a —Y ^a −. is group (wherein the, the Y ^a represents an oxygen atom or an optionally oxidized sulfur atom, R
^4a represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), or a salt thereof; and formula (IIa ′):

Embedded image Wherein, A a ^'' substituent R ^{3a 'a} benzene ring which may further have a substituent other than, B ^a is a good 5-8 membered ring optionally substituted, X ^a straight 1 to 4 atoms in the chain
R ^1a represents an ^optionally substituted amino group, R ^2a represents an ^optionally substituted cyclic group, R ^{3a ′}
Is a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a halogen atom, an amino group which may be substituted or a group represented by the formula R ^4a —Y ^a − (wherein,
Ya represents an oxygen atom or ^a sulfur atom which may be oxidized, and R ^4a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted). Its salt is preferably used.

[0093] In the above formula, the "substituent represented by ^{A a} 'R
“Benzene ring optionally having a substituent other than ^3a ” ”and“ benzene ring ”represented by“ a benzene ring optionally having a substituent other than substituent R ^{3a ′} ”represented by A ^a ″ but, as the may have in addition to substituent R ^3a "substituent" optionally "benzene ring" has the "benzene ring which may be substituted" represented by the above a ^a " Substituents "are the same as those described above.

In the above formula, the “substituted amino group” represented by R ^{1a ′} is a group obtained by removing an unsubstituted amino group from the “optionally substituted amino group” represented by R ^1a ; That is, the same or different substituents as the substituents that may be possessed by the “amino group” in the “optionally substituted amino group” for R ^1a may be 1 to
Examples thereof include two amino groups, and among them,
"An amino group substituted with one or two optionally substituted lower alkyl groups" is preferred. Examples of the “amino group substituted by one or two lower alkyl groups which may be substituted” include (1) halogen (eg, fluorine, chlorine, bromine, iodine, etc.), (2) nitro, (3) ) Cyano,
(4) hydroxyl group, (5) thiol group which may be substituted (eg, thiol, C _1-4 alkylthio, etc.), (6)
Optionally substituted amino groups (eg, amino, mono C
_1-4 alkylamino, diC _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, 5- to 6-membered cyclic amino such as imidazole, etc.), (7) esterified or amidated Carboxyl group (eg, carboxyl, C _1-4 alkoxycarbonyl, lower (C
_7-10) aralkyloxy - carbonyl, carbamoyl, _{mono-C 1-4} alkylcarbamoyl, and _{di-C 1-4} alkylcarbamoyl), optionally substituted with (8) a halogen atom or a _{C 1-4} alkoxy _{C 1- 4} alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), (9) C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoro (10) C _1-4 alkylenedioxy (eg, —O—CH ₂ —O—, —O—CH ₂ —CH ₂ —O)
), (11) phenyl-lower (C _1-4 ) alkyl, (12) C _3-7 cycloalkyl, formyl, C
_2-4 alkanoyl (eg, acetyl, propionyl, etc.), (13) C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), (14) C
_1-4 alkylsulfinyl (e.g., methanesulfinyl and ethanesulfinyl) substituted lower (C 1 _-6) have a 1-3 substituents selected from an alkyl (e.g., methyl, ethyl, propyl, isopropyl , Butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, isopentyl, neopentyl, hexyl, etc.), and an amino group substituted with one or two amino acids. When the number of amino group substituents is two, they may be the same or different.

[0095] In the above formula, the "optionally substituted hydrocarbon group" represented by R ^3a and R ^{3a 'is} "a benzene ring in the" benzene ring optionally substituted "represented by the above A ^a And "a hydrocarbon group which may be substituted" which may have a substituent.

In the above formula, the “optionally substituted heterocyclic group” represented by R ^3a and R ^{3a ′} includes the above-mentioned A
^{The same} as the "optionally substituted heterocyclic group" which the "benzene ring" in the "optionally substituted benzene ring" represented by a may have as a substituent may be mentioned.

In the above formula, the “amino group which may be substituted” represented by R ^3a and R ^{3a ′} includes the above-mentioned A
And the same as the “optionally substituted amino group” which the “benzene ring” in the “optionally substituted benzene ring” may have as a substituent.

In the above formula, in the group represented by the formula R ^4a —Y ^a −, “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” represented by R ^4a
As is not "benzene ring" is "substituted and" hydrocarbon group which may be substituted "which may have a substituent group in the" benzene ring which may be substituted "represented by the above A ^a And the like. "

[0099] In the above formula, wherein R ^4a -Y ^a - In the group represented by the formula as "sulfur atom which may be oxidized" represented by ^{Y a,} for example, S, S (O), S ( O) _{2 and the} like.

The compound represented by the formula (Ia) or a salt thereof
Can be produced by a method known per se. Also, the formula (I
The compound represented by a) or a salt thereof is, for example,
Law or Tetrahedron Letters, Vol. 40, 564
3-5646 pages, JP-A-3-220189, Japanese Patent Publication
The method described in JP-A-48-30280 or the like
It can be manufactured by a method according to. Use in the following manufacturing methods
As long as the compound does not interfere with the reaction,
A salt similar to the product (Ia) may be formed. Also below
In each reaction, the starting compound is an amino group as a substituent.
Group, carboxyl group or hydroxyl group.
These groups are commonly used in peptide chemistry, etc.
May be introduced with a protective group.
The desired compound is obtained by removing the protecting group as necessary.
Can be Examples of the amino-protecting group include, for example,
C optionally having a substituent_1-6Alkylcarbonyl
(Eg, acetyl, propionyl, etc.), formyl,
Phenylcarbonyl, C_1-6Alkyloxycarboni
(For example, methoxycarbonyl, ethoxycarbonyl)
, T-butoxycarbonyl, etc.), phenyloxyca
Rubonyl (eg, benzyloxycarbonyl, etc.), C
_7-10Aralkyloxycarbonyl (eg, benzyl
Ruoxycarbonyl), trityl, phthaloyl, etc.
Is used. These substituents include a halogen atom
(Eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6Alkylcarbonyl (eg, acetyl, propyl
Onyl, butyryl, etc.), nitro group, etc.
The number of substituents is about 1 to 3. Carboxyl group
As the protecting group, for example, C 5 which may have a substituent
_1-6Alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, etc.), phenyl
, Trityl, silyl and the like are used. These substitutions
As the group, a halogen atom (for example, fluorine, chlorine,
Element, iodine, etc.), C_{1- 6}Alkylcarbonyl (eg,
Acetyl, propionyl, butyryl etc.), holmi
And nitro groups are used, and the number of substituents is 1 to 3
About one.

Examples of the protecting group for the hydroxy group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert.
- butyl, etc.), _{phenyl, C 7-10} aralkyl (e.g., _{benzyl), C 1 -6} alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl,
_{Phenyloxycarbonyl, C 7-10} aralkyloxycarbonyl (e.g., benzyloxycarbonyl), pyranyl, furanyl and silyl.
As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is 1 to There are about four. As a method for introducing and removing a protecting group, a method known per se or a method analogous thereto [for example, Protective Groups in Organic Chemistry (JFWMcOmie
Described in Plenum Press Co., Ltd.], but examples of the removal method include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, and acetic acid. A method of treating with palladium or the like is used.

Production Method Of the compound represented by the formula (Ia) or a salt thereof, R
^The compound represented by the formula (Iaa) or a salt thereof, wherein ^1a is an unsubstituted amino group, can be produced, for example, by the following scheme.

Embedded image [Wherein the symbols have the same meanings as described above]
No. 0189, JP-B-48-30280, or a method analogous thereto, the formula (II)
A compound represented by the formula (Va) or a salt thereof obtained by reacting a compound represented by the formula (Ia) or a salt thereof with a compound represented by the formula (IVa) or a salt thereof is subjected to a cyclization reaction. , A compound represented by the formula (Iaa) or a salt thereof.

The compound represented by the formula (Ia) or a salt thereof can also be produced, for example, by the following scheme.

Embedded image Wherein, Z ^al represents an alkali metal, and other symbols are as defined above] Tetrahedron Letters, 40
Vol., Pages 5643 to 5646, or a method analogous thereto, by reacting the compound represented by the formula (VIa) or a salt thereof with the compound represented by the formula (VIIa) or a salt thereof. by reacting a compound represented by the formula (VIIIa) or a compound represented by the salt thereof by the formula R ^1a Z ^al, it is possible to obtain a compound represented by the formula (Ia).

Z^alAs the alkali metal represented by
For example, lithium, sodium and the like can be mentioned. reaction
May be performed without a solvent or in a solvent. As a solvent
Is not particularly limited as long as it does not affect the reaction.
Ether solvents (eg, diethyl ether, tetra
Hydrofuran, dioxane, etc.), halogenated solvents (eg,
Dichloromethane, dichloroethane, chloroform,
Hydrocarbon solvents (eg, benzene, toluene)
Ene, hexane, heptane, etc.), amide solvents (dimethyl
Ruformamide, dimethylacetamide, N-methylpi
Lolidone, etc.), ester solvents (ethyl acetate, methyl acetate
), Acetonitrile, dimethyl sulfoxide, etc.
It is also possible to use a mixture of two or more of these.
No. The compound represented by the formula (VIIIa) or a salt thereof
Formula R used for^1aZ ^alThe amount of the compound represented by
Is about 0.5 to 20 molar equivalents, preferably about 0.8
To 10 molar equivalents, and the reaction temperature at this time is about -8.
0 ° C to 200 ° C, preferably about -80 ° C to 80 ° C
° C and a reaction time of about 0.1 to 96 hours, preferably
About 0.5 to 72 hours.

Further, among the compounds represented by the formula (Ia) or a salt thereof, a compound wherein R ^1a is not an unsubstituted amino group or a salt thereof can be produced according to a known method. Formula (Ia) synthesized by the above scheme
Using the compound represented by a) or a salt thereof as a raw material,
It can also be produced by various conversions according to the following reaction.

Embedded image [Wherein, R ^{1a ″} and R ^{1a ″ ′} each represent a substituent of an amino group (preferably, a lower alkyl group which may be substituted), and La represents ^a leaving group. ]

L^aAs the leaving group represented by, for example,
Halogen atoms such as chlorine, bromine and iodine
Or methanesulfonyl group, toluenesulfonyl group, etc.
And sulfonic acid esters. Reaction without solvent
Alternatively, it may be performed in a solvent. As a solvent,
There is no particular limitation as long as it has no effect, for example,
System solvents (eg, diethyl ether, tetrahydrofura
, Dioxane, etc.), halogenated solvents (eg, dichloro
Methane, dichloroethane, chloroform, carbon tetrachloride
), Hydrocarbon solvents (eg, benzene, toluene,
Hexane, heptane, etc.), amide solvents (dimethylform
Amide, dimethylacetamide, N-methylpyrrolidone
Etc.), ester solvents (ethyl acetate, methyl acetate, etc.),
Acetonitrile, dimethyl sulfoxide and the like are used,
Further, two or more of these may be used as a mixture. Also,
Optionally, a base (eg, triethylamine, 4
-(Dimethylamino) pyridine, 2-tert-butylimi
No-2-diethylamino-1,3-dimethylperhydro
-1,3,2-diazaphosphorin, sodium bicarbonate
, Potassium bicarbonate, sodium carbonate, potassium carbonate
, Sodium hydride, potassium hydride, etc.)
Is a phase transfer catalyst (eg, tetrabutylammonium bromide).
And benzyltriethylammonium chloride.
Ammonium salts and crowns such as 18-crown-6
Ethers) or the presence of a base and a phase transfer catalyst
You may go down. A compound represented by the formula (Iaa):
Is the formula R used for the salt^{1a ''}L ^aRepresented by
The amount of the compound and the compound of formula (Iab) or
Formula R used for the salt^{1a '''}L^aRepresented by
The amount of compound is from about 0.5 to 20 molar equivalents, preferably
Is about 0.8 to 10 molar equivalents, and the reaction temperature at this time is
The temperature is about -20 ° C to 200 ° C, preferably about 20 ° C.
The reaction temperature is about 0.1 to 96 hours
For about 0.5 to 72 hours. Used
The amount of the base to be used is usually the formula (Iaa) or the formula (Ia)
about 0.5 to 10 moles of the compound represented by b)
Equivalent, preferably about 1 to 5 molar equivalents. Further
A compound represented by the formulas (Iaa) to (Iad) or
In the salt, the ring A^aIs chlorine, bromine,
In the case of a halogen atom such as iodine, a known substitution
Response (Suzuki coupling reaction, Still reaction, Heck reaction
Etc.), various functional groups (ring A)^aIndicated by
To a substituent which the benzene ring may have).
Can be. Compound (Ia) thus obtained
Known separation and purification means, such as concentration, concentration under reduced pressure, solvent
For extraction, crystallization, recrystallization, phase transfer, chromatography, etc.
It can be more isolated and purified.

Further, GPR14 (SEN) obtained by the screening method or the screening kit of the present invention is used.
R) Compounds useful as antagonists include, for example, compounds of formula (Ib):

Embedded image [Wherein, Ar represents an aryl group which may be substituted, X represents a spacer having 1 to 4 atoms constituting a straight-chain portion, n represents an integer of 1 to 10, and R represents hydrogen. An atom or a hydrocarbon group which may be substituted, wherein n may be the same or different, and R may be bonded to Ar or a substituent of Ar to form a ring; Y represents an amino group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted]] or a salt thereof.

In the above formula, Ar represents “optionally substituted
Aryl group ". The "aryl which may be substituted"
Examples of the “substituent” of the “group” include (i) halogen
Optionally substituted lower alkyl group, (ii) halogen source
Children (eg, fluoro, chlor, bromide, iodine
And (iii) a lower alkylenedioxy group (for example,
C such as tylenedioxy and ethylenedioxy_1-3Al
(Iv) nitro group, (v) shea
(Vi) hydroxy group, (vii) halogenated
Lower alkoxy group which may be present, (viii) lower cycloal
A kill group (eg, cyclopropyl, cyclobutyl, cycloalkyl,
C such as lopentyl and cyclohexyl_3-6Cycloal
(Ix) a lower group which may be halogenated
Alkylthio group, (x) amino group, (xi) mono-lower
Alkylamino group (for example, methylamino, ethylamino
Mono-C such as_1-6Alkylam
And (xii) a di-lower alkylamino group (eg,
For example, di-C such as dimethylamino and diethylamino
_1-6Alkylamino group), (xiii) e.g.
In addition to nitrogen, nitrogen, oxygen, sulfur, etc.
May have 1 to 3 heteroatoms selected from
5- to 7-membered cyclic amino groups (for example, pyrrolidino,
Peridino, piperazino, morpholino, thiomorpholino
), (Xiv) lower alkyl-carbonylamino group (eg
For example, acetylamino, propionylamino, butyryl
C such as amino_1-6Alkyl-carbonylamino group
Etc.), (xv) aminocarbonyloxy group, (xvi) mono
A lower alkylamino-carbonyloxy group (e.g.,
Methylaminocarbonyloxy, ethylaminocarboni
Mono-C such as ruoxy_1-6Alkylamino-carbo
(Xvii) di-lower alkylamino
-Carbonyloxy group (for example, dimethylaminocarbo
Dioxy and diethylaminocarbonyloxy
-C_1-6Alkylamino-carbonyloxy group
), (Xviii) lower alkylsulfonylamino groups (eg
For example, methylsulfonylamino, ethylsulfonylamino
And C such as propylsulfonylamino_1-6Alkyl
Sulfonylamino group), (xix) lower alkoxy-
Carbonyl groups (eg, methoxycarbonyl, ethoxy
Carbonyl, propoxycarbonyl, isobutoxy
C such as Bonyl_1-6Alkoxy-carbonyl group
Etc.), (xx) carboxyl group, (xxi) lower alkyl-
Carbonyl groups (eg, methylcarbonyl, ethylcarboxyl)
C such as bonyl and butylcarbonyl_1-6Alkyl-ka
(Xxii) lower cycloalkyl-carbyl
Bonyl (eg, cyclopropylcarbonyl, cyclobut
Tylcarbonyl, cyclopentylcarbonyl, cyclohexyl
C such as xylcarbonyl_3-6Cycloalkyl-cal
Xxyl) carbamoyl group, (xxiv)
Mono-lower alkyl-carbamoyl groups (eg, methyl
Carbamoyl, ethyl carbamoyl, propyl carbamo
Mono-C such as yl and butylcarbamoyl_1-6Archi
(Xxv) di-lower alkyl-
Carbamoyl groups (eg, diethylcarbamoyl, dib
Di-C such as tylcarbamoyl_1-6Alkyl-carba
Moyl group), (xxvi) lower alkylsulfonyl group
(Eg, methylsulfonyl, ethylsulfonyl, pro
C such as pyrsulfonyl_1-6Alkylsulfonyl group
Etc.), (xxvii) lower cycloalkylsulfonyl (e.g.
For example, cyclopentylsulfonyl, cyclohexylsulfo
C such as nil_3-6Cycloalkylsulfonyl, etc.),
(Xxviii) phenyl group, (xxix) naphthyl group, (xxx)
Mono-phenyl-lower alkyl groups (e.g. benzyl, phenyl
Mono-phenyl-C such as phenylethyl _1-6Alkyl
Group), (xxxi) di-phenyl-lower alkyl group (eg,
For example, diphenylmethyl, diphenylethyl and the like
Phenyl-C_1-6Alkyl group etc.), (xxxii) mono
-Phenyl-lower alkyl-carbonyloxy group (eg,
Phenylmethylcarbonyloxy, phenylethylca
Mono-phenyl-C such as rubonyloxy_1-6Archi
(Xxxiii) di-phenyl
Ru-lower alkyl-carbonyloxy group (e.g. dif
Phenylmethylcarbonyloxy, diphenylethylcar
Di-phenyl-C such as bonyloxy_1-6Alkyl-
Carbonyloxy group), (xxxiv) phenoxy group,
(Xxxv) mono-phenyl-lower alkyl-carbonyl group
(For example, phenylmethylcarbonyl, phenylethylca
Mono-phenyl-C such as rubonyl_1-6Alkyl-ka
(Xxxvi) di-phenyl-lower alky!
A kill-carbonyl group (e.g., diphenylmethylcarbo)
Di-phenyl such as nyl and diphenylethylcarbonyl
-C_1-6Alkyl-carbonyl group, etc.), (xxxvii)
Benzoyl group, (xxxviii) phenoxycarbonyl group,
(Xxxix) phenyl-lower alkyl-carbamoyl group
(Eg, phenyl-methylcarbamoyl, phenyl-
Phenyl-C such as ethylcarbamoyl_1-6Alkyl
-Carbamoyl group), (xxxx) phenylcarbamoy
Group, (xxxxi) phenyl-lower alkyl-carbonyl
Amino group (for example, phenyl-methylcarbonylamido)
And phenyl such as phenyl-ethylcarbonylamino
-C_1-6Alkyl-carbonylamino, etc.), (xxxx
ii) phenyl-lower alkylamino (e.g. phenyl
-Phenyl, such as methylamino and phenyl-ethylamino
Le-C_1-6Alkylamino, etc.), (xxxxiii)
Nyl-lower alkylsulfonyl groups (e.g., phenyl-
Methylsulfonyl, phenyl-ethylsulfonyl and the like
Phenyl-C_1-6Alkylsulfonyl group), (xx
xxiv) phenylsulfonyl group, (xxxxv) phenyl-low
Primary alkylsulfinyl group (for example, phenyl-methyl
Sulfinyl, phenyl-ethylsulfinyl, etc.
Enyl-C_1-6Alkylsulfinyl group), (xx
xxvi) phenyl-lower alkylsulfonylamino group (eg
For example, phenyl-methylsulfonylamino, phenyl-
Phenyl-C such as ethylsulfonylamino_1-6Al
Killsulfonylamino group) and (xxxxvii)
Nylsulfonylamino group [the (xxviii) phenyl group,
(Xxix) naphthyl group, (xxx) mono-phenyl-lower
Alkyl group, (xxxi) di-phenyl-lower alkyl group,
(Xxxii) mono-phenyl-lower alkyl-carbonyl
An oxy group, (xxxiii) di-phenyl-lower alkyl-
Rubonyloxy group, (xxxiv) phenoxy group, (xxxv)
A mono-phenyl-lower alkyl-carbonyl group, (xxxv
i) di-phenyl-lower alkyl-carbonyl group, (xxx
vii) benzoyl group, (xxxviii) phenoxycarbonyl
Group, (xxxix) phenyl-lower alkyl-carbamoyl
Group, (xxxx) phenylcarbamoyl group, (xxxxi)
Nil-lower alkyl-carbonylamino group, (xxxxii)
Phenyl-lower alkylamino, (xxxxiii) phenyl
A lower alkylsulfonyl group, (xxxxiv) phenylsulfur
Honyl group, (xxxxv) phenyl-lower alkylsulfy
Nyl group, (xxxxvi) phenyl-lower alkylsulfonyl
Amino group and (xxxxvii) phenylsulfonylamino
The group further includes, for example, lower alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, sec-butyl
Tert-butyl, pentyl, hexyl, etc._1-6
Alkyl, etc.), lower alkoxy (eg, methoxy,
Ethoxy, propoxy, isopropoxy, n-butoxy
Si, isobutoxy, sec-butoxy, tert-butoxy, etc.
C_1-6Alkoxy, etc.), halogen atoms (for example,
Chloro, bromo, iodo, etc.), hydroxy, benzyl
Oxy, amino, mono-lower alkylamino (e.g.,
Models such as methylamino, ethylamino, and propylamino
No-C_1-6Alkylamino, etc.), di-lower alkyl
Amino (for example, dimethylamino, diethylamino, etc.)
The Di-C_1-6Alkylamino, etc.), nitro, lower
Alkyl-carbonyl (e.g., methylcarbonyl, ethyl
C such as carbonyl and butylcarbonyl_1-6Archi
1 selected from benzoyl, etc.
Or may have 4 to 4 substituents].
It is. The above "lower alkyl optionally halogenated"
Examples of "a group" include, for example, 1 to 3 halogen atoms
(Eg, chlor, brom, iodine, etc.)
Lower alkyl groups (eg, methyl, ethyl, pro
Pill, isopropyl, butyl, sec-butyl, tert-butyl
C such as le, pentyl and hexyl_1-6Alkyl group
And the like, and specific examples include methyl and chloro.
Methyl, difluoromethyl, trichloromethyl, trif
Fluoromethyl, ethyl, 2-bromoethyl, 2,2,2
-Trifluoroethyl, propyl, 3,3,3-trif
Fluoropropyl, isopropyl, butyl, 4,4,4-
Trifluorobutyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, isopentyl, neopentyl, 5,
5,5-trifluoropentyl, hexyl, 6,6,6
-Trifluorohexyl and the like.

The above-mentioned "optionally lower halogenated alkoxy group" includes, for example, a lower alkoxy group optionally having 1 to 3 halogen atoms (for example, chloro, bromo, iodo and the like). For example, methoxy,
Ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, C _1-6 alkoxy group such as tert-butoxy, etc.), and specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, Ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

The above-mentioned "optionally lower alkylthio group" includes, for example, a lower alkylthio group optionally having 1 to 3 halogen atoms (for example, chloro, bromo, iodo and the like). For example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
C _1-6 alkylthio group such as tert-butylthio etc.)
And the like, specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, 4,4,4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

The “substituent” of the “optionally substituted aryl group” is preferably (i) an amino group, (ii)
Mono-lower alkylamino groups (e.g., methylamino,
(Iii) a mono-C _1-6 alkylamino group such as ethylamino, propylamino, etc.), (iii) a di-lower alkylamino group (eg, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, etc.), iv) For example, 1
5- to 7-membered cyclic amino group which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to the nitrogen atoms (for example, pyrrolidino, piperidino, piperazino, morpholino, thiol Morpholino, etc.), (v) lower alkyl-carbonylamino group (eg, C _1-6 alkyl-carbonylamino group such as acetylamino, propionylamino, butyrylamino), (vi) aminocarbonyloxy group, (vii)
Mono - lower alkylamino - carbonyl group (e.g., mono--C _{1 -6} alkylamino such as methylamino carbonyloxy, ethylamino carbonyloxy - carbonyl group), (viii) di - lower alkylamino - carbonyl group (Eg, di-C _1-6 alkylamino-carbonyloxy group such as dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), (ix) lower alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino _{C 1-6,} such as alkylsulfonylamino group), (x) phenyl such as - lower alkylamino (e.g., phenyl - methylamino, phenyl - phenyl _{-C 1 -6} alkylamino such as ethylamino), (xi) off Sulfonyl - lower alkylsulfonylamino group (e.g., phenyl - methylsulfonylamino, phenyl - phenyl -C _1-6 alkyl, such as ethylsulfonylamino - such as sulfonylamino group), (xi
i) phenylsulfonylamino group, (xiii) halogen atom (eg, fluoro, chloro, etc.), (xiv) optionally halogenated lower (eg, C _1-6 ) alkyl group (eg, methyl, ethyl, isopropyl) Tert-butyl, trifluoromethyl, etc.) and (xv) optionally halogenated lower (eg, C _1-6 ) alkoxy groups (eg, methoxy, ethoxy, isopropoxy, tert.
-Butoxy, trifluoromethoxy, etc.), and especially a 5- to 7-membered member which may have 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur and the like in addition to one nitrogen atom Cyclic amino groups (eg,
Pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.).

In the above formula, the “aryl group” in the “optionally substituted aryl group” represented by Ar includes, for example, C _6-14 aryl such as phenyl and naphthyl, preferably C _6-10 aryl, More preferred are phenyl and the like. Here, the “aryl group which may be substituted” may be such that the substituents in the “aryl group” may be bonded to each other to form a condensed ring, and the aryl group (preferably a phenyl group) as Ar Examples of the condensed ring include, for example, (1) when condensed with a monocyclic heterocycle optionally having a substituent, (2) bicyclic heterocycle optionally having a substituent Condensed with two or three identical or different monocyclic rings (provided that at least one ring is a monocyclic heterocyclic ring), and (3) a tricyclic group optionally having a substituent For example, the case of condensing with a heterocyclic ring may be mentioned.

Specific examples of the case where the “aryl group” in the “optionally substituted aryl group” is condensed with a monocyclic heterocyclic ring which may have a substituent include, for example, those represented by the following formulas:

Embedded image [In the formula, ring B represents a heterocyclic ring which may have a substituent, and ring A represents a benzene ring which may have a substituent].

Examples of the substituent on the ring A include the same substituents as those described above for the “optionally substituted aryl group”. As the “heterocycle” of the “heterocycle optionally having substituent (s)” represented by ring B, for example, a 4- to 14-membered ring,
Preferably, a 5- to 9-membered ring or the like is used, and it may be aromatic or non-aromatic. As a hetero atom,
For example, one to three or four selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like are used. Specifically, for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, azepine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, Morpholine, thiomorpholine,
Pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, imidazoline and the like are used. In particular, a 5- to 9-membered non-aromatic heterocycle containing one heteroatom or two identical or different heteroatoms (eg, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, Piperazine, tetrahydrooxazepine, morpholine, thiomorpholine and the like). In particular, for example, a non-aromatic heterocyclic ring containing one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and one nitrogen atom and one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom Non-aromatic heterocycles containing atoms are frequently used.

The “substituent” of the “optionally substituted heterocycle” represented by ring B may be substituted on any carbon atom of ring B. Examples of the substituent on any carbon atom of ring B include (i) a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), (ii) a nitro group,
(Iii) cyano group, (iv) oxo group, (v) hydroxy group, (vi) lower alkyl group (for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, tert-
Butyl, C _1-6 alkyl groups such as sec-butyl, etc.)
(Vii) a lower alkoxy group (for example, a C _1-6 alkoxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, etc.), (vii
i) a lower alkylthio group (eg, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, etc.), (ix) an amino group, (x) a mono-lower alkylamino group (eg, methylamino, ethylamino, propylamino) Mono-C _1-6 alkylamino group, etc.),
(Xi) di-lower alkylamino groups (eg, di-C _1-6 alkylamino groups such as dimethylamino, diethylamino and the like), (xii) nitrogen atoms, oxygen atoms and the like in addition to carbon atoms and one nitrogen atom, for example. A 5- to 7-membered cyclic amino group optionally having 1 to 3 heteroatoms selected from a sulfur atom and the like (for example, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.);
(Xiii) a lower alkyl-carbonylamino group (for example,
C _1-6 alkyl-carbonylamino groups such as acetylamino, propionylamino and butyrylamino),
(Xiv) lower alkylsulfonylamino group (for example, C _1-6 alkyl-carbonylamino group such as methylsulfonylamino, ethylsulfonylamino, etc.), (xv)
Lower alkoxy-carbonyl groups (for example, C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like), (xv
i) carboxyl group, (xvii) lower alkyl-carbonyl group (for example, methylcarbonyl, ethylcarbonyl,
A C _1-6 alkyl-carbonyl group such as propylcarbonyl), (xviii) carbamoyl group, (xix) mono-
A lower alkylcarbamoyl group (eg, a mono-C _1-6 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.); (xx) a di-lower alkylcarbamoyl group (eg, di-C ₁₋ such as dimethylcarbamoyl, diethylcarbamoyl, etc.) ₆ such alkylcarbamoyl group), (xxi) lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, a C _1-6 alkylsulfonyl group such as propylsulfonyl) 1 to 5 selected from like are used. Above all,
Oxo group, lower alkyl group (for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, tert-
Butyl, sec-butyl and other C _1-6 alkyl groups) and the like, and oxo groups and the like are commonly used.

Further, when ring B has a nitrogen atom in the ring, it may have a substituent on the nitrogen atom. That is, in the ring B,> N—R ¹ [R ¹ is a hydrogen atom, a hydrocarbon group which may be substituted,
Represents an optionally substituted acyl group or an optionally substituted heterocyclic group]. The “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ¹ represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include an alkyl group and an alkenyl group. And a chain or cyclic hydrocarbon group such as an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Among them, a C _1-16 hydrocarbon group formed of a chain, a ring, or a combination thereof is preferably used.

As the chain or cyclic hydrocarbon group,
(1) Linear or branched lower alkyl groups (for example, C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, etc.) , (2)
Linear or branched lower alkenyl groups (for example, C _2-6 alkenyl groups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and the like);
(3) linear or branched lower alkynyl group (e.g., propargyl, ethynyl, butynyl, C _2-6 alkynyl groups such as 1-hexynyl), (4) a monocyclic lower cycloalkyl group (e.g., Monocyclic C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) bridged cyclic lower saturated hydrocarbon groups (eg, bicyclo [3.2.1] oct-2-yl) A bridged cyclic C _8-14 saturated hydrocarbon group such as bicyclo [3.3.1] non-2-yl and adamantan-1-yl; or (6) an aryl group (eg, phenyl, 1-naphthyl) , 2-naphthyl, biphenyl, 2
A C _6-14 aryl group such as -indenyl, 2-anthryl and the like, preferably a phenyl group),

The hydrocarbon group comprising a combination of a chain and a ring includes (1) a lower aralkyl group (for example,
Phenyl-C _1-10 alkyl (for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, etc.), naphthyl-
C _1-6 alkyl (for example, α-naphthylmethyl and the like)
Or (2) an aryl-alkenyl group (for example, styryl, cinnamyl, 4-phenyl-2-), or a _C7-16 aralkyl group such as diphenyl- _C1-3alkyl (for example, diphenylmethyl, diphenylethyl and the like). Phenyl-C such as butenyl, 4-phenyl-3-butenyl and the like
C _{6-14 aryl-} C such as _2-12 alkenyl
_2-12 alkenyl group), (3) aryl-C
_2-12 alkynyl group (for example, phenylethynyl, 3
Phenyl- _{2- C2-12} alkynyl, such as -phenyl-2-propynyl, 3-phenyl-1-propynyl;
_6-14 aryl-C _2-12 alkynyl group),
(4) lower cycloalkyl-lower alkyl group (for example,
Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl,
Cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutyl pentyl, cyclopentyl point pen chill, cyclohexyl pentyl, cycloheptyl pentyl, cyclopropyl hexyl, cyclo butyl hexyl, cyclopropyl pentylhexyl, C _3-7 cycloalkyl -C _1-6 alkyl group such as cyclohexyl hexyl), (5) aryl -C _1-10 alkyl group (e.g. biphenyl methyl, biphenyl _{-C 1-10} aralkyl, such as biphenyl ethyl Le) and the like are preferably used.

R¹Represented by the "may be substituted
Preferred as "hydrocarbon group" of "hydrocarbon group"
Is, for example, (1) a linear, branched or cyclic alkyl group, preferably
Or linear or branched C_1-6Alkyl groups (eg
For example, methyl, ethyl, propyl, isopropyl,
, Isobutyl, tert-butyl, sec-butyl, pliers
C, e.g. _1-6Alkyl group), cyclic C
_3-8Alkyl groups (eg, cyclopropyl, cyclobut
Tyl, cyclopentyl, cyclohexyl, etc.), or
C consisting of a combination of linear, branched or cyclic
_4-12Alkyl groups (eg, cyclopropylmethyl,
Cyclopentylmethyl, cyclohexylmethyl, cyclo
Hexylethyl, (4-methylcyclohexyl) methyl
Etc.) or (2) C_7-16Aralkyl groups (for example, phenyl-C
_1-10Alkyl (eg, benzyl, phenylethyl)
, Phenylpropyl, phenylbutyl, phenylpen
Tyl, phenylhexyl, etc.), naphthyl-C_1-6A
Alkyl (for example, α-naphthylmethyl, etc.) or diphth
Enyl-C_1-3Alkyl (eg diphenylmethyl,
Diphenylethyl, etc.), and more preferably C
_7-10Aralkyl groups (eg, benzyl, phenyl
Phenyl-C such as tyl and phenylpropyl _1-4Al
Kills etc.) are frequently used.

The “hydrocarbon group” represented by R ¹ may have a substituent, and as such a substituent, those generally used as a substituent of a hydrocarbon group can be appropriately used. Specifically, (i) a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), (i)
i) nitro, (iii) cyano, (iv) oxo,
(V) a hydroxy group, (vi) a lower alkyl group optionally substituted with halogen or phenyl (for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl and the like) (Vii) a lower alkoxy group optionally substituted by halogen or phenyl (for example, methoxy, ethoxy, n-propyloxy, i-propyloxy, n
A C _1-6 alkoxy group such as -butyloxy),
(Viii) a lower alkylthio group optionally substituted with halogen or phenyl (for example, a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, etc.), (ix) an amino group, and (x) a mono-lower alkylamino group (For example, mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, etc.),
(Xi) di-lower alkylamino groups (eg, di-C _1-6 alkylamino groups such as dimethylamino, diethylamino and the like), (xii) nitrogen atoms, oxygen atoms and the like in addition to carbon atoms and one nitrogen atom, for example. A 5- to 7-membered cyclic amino group optionally having 1 to 3 heteroatoms selected from a sulfur atom and the like (for example, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, etc.);
(Xiii) a lower alkyl-carbonylamino group (for example,
C _1-6 alkyl-carbonylamino groups such as acetylamino, propionylamino and butyrylamino),
(Xiv) lower alkylsulfonylamino group (for example, C _1-6 alkyl-sulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, etc.), (xv)
Lower alkoxy-carbonyl groups (for example, C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like), (xv
i) carboxyl group, (xvii) formyl, lower alkyl-carbonyl group (for example, C _1-6 alkyl-carbonyl group such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), (xviii) carbamoyl group, (x
ix) mono-lower alkyl-carbamoyl groups (eg, mono-C such as methylcarbamoyl, ethylcarbamoyl, etc.)
_1-6 alkyl - such as carbamoyl group), (xx) di - lower alkyl - carbamoyl group (e.g., dimethylcarbamoyl, -C _1-6 alkyl, such as diethylcarbamoyl - such as carbamoyl group), (xxi) lower alkylsulfonyl group (Eg, C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), (xxii) lower alkoxy-carbonyl-lower alkyl groups (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl) , methoxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonyl (dimethyl) methyl, ethoxycarbonyl (dimethyl) methyl, tert- butoxycarbonyl (dimethyl) _{C 1-6} alkoxy, such as methyl - carbonyl -C ₁ Such as ₆ alkyl group),
(Xxiii) a carboxyl-lower alkyl group (for example, a carboxyl-C _1-6 alkyl group such as carboxylmethyl, carboxylethyl, carboxyl (dimethyl) methyl and the like), and (xxiv) a heterocyclic group optionally having a substituent. , (Xxv) an alkyl group optionally having a substituent,
(Xxvi) an alkoxy group which may have a substituent, (xx
vii) an ureido group optionally having a substituent (for example,
Ureido, 3-methylureido, 3-ethylureido, 3-phenylureido, 3- (4-fluorophenyl) ureido, 3-
(2-methylphenyl) ureido, 3- (4-methoxyphenyl)
Ureido, 3- (2,4-difluorophenyl) ureido, 3-
[3,5-bis (trifluoromethyl) phenyl] ureido, 3-
Benzylureido, 3- (1-naphthyl) ureido, 3- (2-biphenylyl) ureido, etc.), (xxviii) a thioureido group optionally having a substituent (for example, thioureido,
3-methylthioureido, 3-ethylthioureido, 3-phenylthioureido, 3- (4-fluorophenyl) thioureido, 3- (4-methylphenyl) thioureido, 3- (4-methoxyphenyl) thioureido, 3- ( 2,4-dichlorophenyl)
Thioureido, 3-benzylthioureido, 3- (1-naphthyl) thioureido, etc.), (xxix) amidino group optionally having a substituent (for example, amidino, N ¹ -methylamidino, N ¹ -ethylamidino, N ¹ -Phenylamidino, N ¹ , N
¹ -dimethylamidino, N ¹ , N ² -dimethylamidino, N ¹ -methyl-N ¹ -ethylamidino, N ¹ , N ¹ -diethylamidino, N ¹
-Methyl-N ¹ -phenylamidino, N ¹ , N ¹ -di (4-nitrophenyl) amidino, etc.), (xxx) a guanidino group optionally having a substituent (for example, guanidino, 3-methylguanidino, 3,3-dimethylguanidino, 3,3-diethylguanidino, etc.), (xxxi) an optionally substituted cyclic aminocarbonyl group (eg, pyrrolidinocarbonyl, piperidinocarbonyl, (4-methylpiperidino) carbonyl ,
(4-phenylpiperidino) carbonyl, (4-benzylpiperidino) carbonyl, (4-benzoylpiperidino) carbonyl, [4- (4-fluorobenzoyl) piperidino] carbonyl, (4-methylpiperazino) carbonyl, (4-phenylpiperazino) carbonyl, [4- (4-nitrophenyl) piperazino] carbonyl, (4-benzylpiperazino) carbonyl,
Morpholinocarbonyl, thiomorpholinocarbonyl, etc.), (xxxii) optionally substituted aminothiocarbonyl group (eg, aminothiocarbonyl, methylaminothiocarbonyl, dimethylaminothiocarbonyl, etc.), (xxxiii) Optionally having aminosulfonyl (eg, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, etc.), (xxxi
v) optionally substituted phenylsulfonylamino (for example, phenylsulfonylamino, (4-methylphenyl) sulfonylamino, (4-chlorophenyl) sulfonylamino, (2,5-dichlorophenyl) sulfonylamino, (4 -Methoxyphenyl) sulfonylamino, (4-acetylaminophenyl) sulfonylamino, (4-nitrophenyl) phenylsulfonylamino, etc.), (xxxv) sulfo group, (xxxvi) sulfino group, (xxxvii) sulfeno group, (xxxviii) C _1-6 alkylsulfo group (for example,
Methylsulfo, ethylsulfo, propylsulfo, etc.),
_{(Xxxix) C 1-6} alkylsulfenyl fino group (e.g., methylsulfinyl Fino, ethylsulfamoyl Fino, etc. propylsulfanyl fino), _{(xxxx) C 1-6} alkylsulfenyl phenol group (e.g., methylsulfinyl phenolate, ethylsulfamoyl phenol, Propylsulfeno), (xxxxi) phosphono group, (xxxxii)
Di _{-C 1-6} alkoxy phosphoryl group (e.g., dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxy phosphoryl, _etc.), (xxxxiii) _{C 1-4} alkylenedioxy _{(e.g., -O-CH 2 -O -,} - O- CH ₂ -CH
_2- O-), (xxxxiv) 1 to 5 (preferably 1 to 3) selected from phenylthio optionally substituted with halogen, (xxxxv) phenoxy optionally substituted with halogen, and the like. Used. “Substituent” of “optionally substituted hydrocarbon group” for R ¹
Are preferably a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, a hydroxy group, a nitro group, a cyano group, a carboxyl group, and a C _1-6 alkoxycarbonyl Group, carbamoyl group, aminothiocarbonyl group, mono-lower alkyl-
A carbamoyl group, a di-lower alkyl-carbamoyl group,
Optionally substituted cyclic aminocarbonyl group, amino group, mono-lower alkylamino group, di-lower alkylamino group, nitrogen atom, oxygen atom and sulfur atom other than carbon atom and one nitrogen atom A 5- to 7-membered cyclic amino group optionally having 1 to 3 heteroatoms selected from the group _{consisting of} a C _1-6 alkylcarbonylamino group, an optionally substituted phenylsulfonylamino group,
_Examples thereof include a _1-6 alkylsulfonylamino group, an amidino group which may have a substituent, an ureido group which may have a substituent, and a heterocyclic group which may have a substituent. Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” include a monocyclic heterocyclic ring, a bicyclic heterocyclic ring, and a polycyclic ring such as a tricyclic ring or a tetracyclic ring. A group formed by removing one hydrogen atom from a heterocycle is used. The heterocyclic ring may be either aromatic or non-aromatic. As a hetero atom, for example, a nitrogen atom,
One to six atoms selected from oxygen atoms or sulfur atoms are used. Specifically, as the monocyclic heterocyclic group,
A group obtained by removing one hydrogen atom from the “heterocycle” of the “heterocycle optionally having substituent (s)” represented by the ring B is used. In addition, for example, a group formed by removing one hydrogen atom from a monocyclic heterocycle such as triazole, thiadiazole, oxadiazole, oxathiadiazole, triazine, and tetrazole is also used. Examples of the bicyclic heterocyclic group include indole, dihydroindole, isoindole, dihydroisoindole, benzofuran, dihydrobenzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, indazole,
Quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, tetrahydro-1H-1-benzazepine, tetrahydro-1H-2-benzazepine, tetrahydro-1H-3-benzazepine, tetrahydrobenzoxazepine, quinazoline, tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, Benzodioxane,
A group formed by removing one hydrogen atom from a bicyclic heterocycle such as benzodioxole, benzothiazine, imidazopyridine and the like is used. Examples of the polycyclic heterocyclic group such as tricyclic or tetracyclic include one hydrogen atom from a polycyclic heterocyclic ring such as acridine, tetrahydroacridine, pyrroloquinoline, pyrroloindole, cyclopentoindole, and isoindolobenzazepine. A group formed by individual removal is used. As the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)”, in particular, a group formed by removing one hydrogen atom from the above monocyclic heterocyclic ring or bicyclic heterocyclic ring, and the like Is frequently used. As the “substituent” of the “heterocyclic group which may have a substituent”, the “substituent” of the “heterocyclic ring which may have a substituent” represented by the ring B above (provided that
“Excluding a heterocyclic group which may have a substituent”). "Optionally substituted alkyl (preferably optionally substituted C _1-6 alkyl)" or "alkoxy optionally having substituent (preferably having a substituent the "substituent" also a C _1-6 alkoxy) "have, for example, as the" substituent "of the" optionally substituted hydrocarbon group "represented by R ¹ (i) To (xxiv) or (xxvi
The “substituents” shown in i) to (xxxxii) are used. "Optionally substituted ureido group", "optionally substituted thioureido group", "optionally substituted amidino group", "optionally substituted Guanidino group "," cyclic aminocarbonyl group optionally having substituent (s) "," aminothiocarbonyl group optionally having substituent (s) "" aminosulfonyl optionally having substituent (s) " Or as the `` substituent '' of the `` phenylsulfonylamino optionally having a substituent ''
For example, as the `` substituents '' of the `` optionally substituted hydrocarbon group '' represented by R ¹ (i) to (xxvi) or (xxxv) to `` substituent '' shown in (xxxxii) , C
_6-14 aryl group (the _{C 6-14} aryl group, organic _{halogen, C 1-6} alkyl, halo _{C 1-6} alkyl _group, a substituent selected from such _{C 1 -6} alkoxy group and a nitro group Or a C _7-16 aralkyl group. As the “optionally substituted hydrocarbon group” represented by R ¹ ,
(I) a C _1-6 alkyl group or (ii) a halogen atom,
Examples include a phenyl-C _1-6 alkyl group which may be substituted with a substituent such as nitro, C _1-6 alkyl, C _1-6 alkoxy, etc., and more preferably C _1-4 alkyl (eg, methyl). , Trihalogeno C _1-4 alkyl (such as methyl), halogen atom (such as fluoro and chloro), nitro, cyano, C _1-4 alkoxy (such as methoxy), trihalogeno C _1-4 alkoxy (such as methoxy), hydroxy, carbamoyl, (4-C _1-4 alkyl (such as methyl) -1-piperazinyl) carbonyl, aminothiocarbonyl, morpholinocarbonyl, carboxyl, C _1-4 alkoxy (such as methoxy) carbonyl,
C _1-4 alkoxy (such as ethoxy) carbonyl C
_1-4 alkoxy (such as methoxy), carboxyl C
_1-4 alkoxy (such as methoxy), C _1-4 alkoxy (such as ethoxy) carbonyl C _1-6 alkyl (such as isopropyl), carboxyl C _1-6 alkyl (such as isopropyl), amino, acetylamino, C _1-4 alkyl (such as methyl) sulfonylamino, _{(4-C 1-} 4
Alkyl (eg, methyl) phenyl) sulfonylamino,
Ureido, 3- _C1-4 alkyl (e.g., methyl) ureido, amidino, benzyl group optionally substituted by dihydrothiazolyl or dihydroimidazolyl. Among them, R ¹ is C _1-4 alkyl (such as methyl), trihalogeno (such as fluoro) C _1-4 alkyl (such as methyl), halogen atom (such as fluoro, chloro), nitro, cyano, carbamoyl, C _1-4 Alkoxy (such as methoxy) carbonyl, C _1-4 alkoxy (such as ethoxy) carbonyl C _1-4 alkoxy (such as methoxy), amino, acetylamino, C _1-4 alkyl (such as methyl) sulfonylamino, 3-C _1-4 Alkyl (e.g., methyl) ureido, amidino, benzyl group which may be substituted with dihydroimidazolyl is preferable,
Especially C _{1 -4} alkyl optionally substituted benzyl group, especially a benzyl group which may be substituted with methyl.

The above R¹Represented by "may be substituted
Examples of the "acyl group" include-(C = O)-
R^2b, -SO₂-R^2b, -SO-R^2b,-(C =
O) NR^{3 b}R^2b,-(C = O) OR^2b,-(C
= S) OR^2bOr-(C = S) NR^3bR
^2b[R^2bAnd R^3bAre the same or different
(I) may have a hydrogen atom and (ii) a substituent
A hydrocarbon group or (iii) a compound which may have a substituent;
Represents a cyclic group;^2cAnd R^3cAre adjacent to each other
Nitrogen atom which may have a substituent together with the nitrogen atom
May form a sum heterocyclic group]. this
Preferably,-(C = O) -R^2b, -SO₂-R
^2b, -SO-R ^2b,-(C = O) NR^3bR^2bMa
Or-(C = O) OR^2b(R^2bAnd R^3bIs above
And-(C = O) -R^2bMa
Or-(C = O) NR^3bR^2b(R^2bAnd R^3b
Is the same as defined above). R^2bAnd R^3bso
Of the "hydrocarbon group which may have a substituent"
"Hydrocarbon group" refers to one hydrogen atom from a hydrocarbon compound
Indicates a removed group, for example, alkyl
Group, alkenyl group, alkynyl group, cycloalkyl group,
Chain or cyclic hydrocarbons such as aryl and aralkyl groups
Element group. Specifically, the above R¹Indicated by
"Hydrocarbon group" of "optionally substituted hydrocarbon group"
And the same groups as those mentioned above.
_1-16Hydrocarbon groups and the like are preferred, and particularly, lower (C
_1-6) Alkyl group, lower (C_2-6) Alkenyl groups,
C_7-16Aralkyl group or C_6-14Aryl group is
preferable. Especially low (C_1-6) Alkyl group, C
_7-16Aralkyl group or C_6-14Aryl group
Used. R^2bAnd R^3bWith a substituent
As the “heterocyclic group” of the “optionally substituted heterocyclic group”,
Cyclic heterocycle, bicyclic heterocycle, and tricyclic or tetracyclic
By removing one hydrogen atom from a polycyclic heterocycle such as
Groups are used. As the heterocyclic ring, aromatic, non-cyclic,
It may be either aromatic. As a hetero atom,
For example, select from nitrogen, oxygen, sulfur, etc.
1 to 6 pieces are used. Specifically, monocyclic
As the heterocyclic group, `` having a substituent represented by the ring B
One hydrogen atom from the "heterocycle" of the "optionally heterocycle"
A group formed by removal is used. In addition,
For example, triazole, thiadiazole, oxa
Diazole, oxathiadiazole, triazine, tet
Removing one hydrogen atom from a monocyclic heterocycle
Groups that can be used are also used. As a bicyclic heterocyclic group
Is, for example, indole, dihydroindole, isoi
Indole, dihydroisoindole, benzofuran, di
Hydrobenzofuran, benzimidazole, benzoki
Sazol, benzisoxazole, benzothiazole
, Indazole, quinoline, tetrahydroquinoline,
Isoquinoline, tetrahydroisoquinoline, tetrahydro
B-1H-1-benzazepine, tetrahydro-1H-2-benzau
Zepine, tetrahydro-1H-3-benzazepine, tetrahi
Drobenzoxazepine, quinazoline, tetrahydroxy
Nazoline, quinoxaline, tetrahydroquinoxaline,
Benzodioxane, benzodioxole, benzothiazi
Hydrogen atoms from bicyclic heterocycles such as
And a group formed by removing one. Tricyclic or
Is a polycyclic heterocyclic group such as tetracyclic, acridine,
Tetrahydroacridine, pyrroloquinoline, pyrroloin
Dole, cyclopentindole, isoindobenz
Remove one hydrogen atom from a polycyclic heterocycle such as azepine
And the like can be used. The "having a substituent
As the "heterocyclic group" of the "optionally heterocyclic group",
One hydrogen atom from a monocyclic heterocycle or bicyclic heterocycle
A group formed by removal is frequently used.

The “nitrogen-containing saturated heterocyclic group optionally having substituent (s)” which R ^2b and R ^3b may form together with an adjacent nitrogen atom includes, in addition to a carbon atom and one nitrogen atom, For example, a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom and a sulfur atom is used. As these nitrogen-containing saturated heterocyclic groups, groups having a bond at the ring-constituting nitrogen atom are preferred. As the group having a bond at the ring-constituting nitrogen atom, for example, a group represented by the formula:

Embedded image [Wherein the ring Q ^{1 is a} 5- to 9-membered nitrogen-containing ring which may contain, in addition to the carbon atom and one nitrogen atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. Which represents a saturated heterocyclic group]. More specifically, for example,

Embedded image Are frequently used.

R^2bAnd R^3b"Hydrocarbons
Group "or" heterocyclic group ", NR^3bR^2bIndicated by
Preferred positions that the “nitrogen-containing saturated heterocyclic group” may have
The substituent includes, for example, (i) a halogen atom (for example, full
Oro, chlor, brom, iodine, etc.), (ii) nitro
Group, (iii) cyano group, (iv) oxo group, (v) hydroxy
(Vi) a hydrocarbon group which may have a substituent,
(Vii) lower alcohol optionally substituted by a phenyl group
Xy groups (e.g., methoxy, ethoxy, n-propyl
C such as xy, i-propyloxy, n-butyloxy
_1-6(Vs) alkoxy group), (viii) phenyl group
An optionally substituted lower alkylthio group (eg, methyl
C such as thio, ethylthio, propylthio, etc._1-6Archi
(Ix) amino group, (x) mono-lower
Alkylamino group (for example, methylamino, ethylamino
Mono-C such as_1-6Alkylam
(Xi) di-lower alkylamino group (for example,
For example, di-C such as dimethylamino and diethylamino
_1-6Alkylamino group, etc.), (xii)
Nitrogen atom, oxygen atom and sulfur
Having 1 to 3 hetero atoms selected from yellow atoms, etc.
Optionally a 5- to 7-membered cyclic amino group (for example, pyro
Lysino, piperidino, piperazino, morpholino, chiomo
Ruholino), (xiii) lower alkyl-carbonyl
Amino groups (eg, acetylamino, propionylamido)
C, such as rho and butyrylamino_1-6Alkyl-carboni
), (Xiv) lower alkyl-sulfonyl
Amino groups (eg, methylsulfonylamino, ethyls
C such as rufonylamino_1-6Alkyl-sulfonylua
Amino group, etc.), (xv) lower alkoxy-carbonyl group
(Eg, methoxycarbonyl, ethoxycarbonyl,
C such as propoxycarbonyl_1-6Alkoxy-cal
Carbonyl group), (xvi) carboxyl group, (xvii) low
Lower alkyl-carbonyl groups (e.g., methyl carbonyl
C such as ethyl, ethylcarbonyl and propylcarbonyl
_1-6Alkyl-carbonyl group, etc.), (xviii)
Bamoyl group, (xix) mono-lower alkyl-carbamoy
(Eg, methylcarbamoyl, ethylcarbamoy)
Mono-C such as_1-6Alkyl-carbamoyl group
And (xx) di-lower alkyl-carbamoyl groups (eg,
For example, dimethylcarbamoyl, diethylcarbamoyl, etc.
The Di-C_1-6Alkyl-carbamoyl group), (xx
i) a lower alkylsulfonyl group (for example, methylsulfo
C such as nil, ethylsulfonyl and propylsulfonyl
_1-6(Xxii) lower alcohol
A xy-carbonyl-lower alkyl group (e.g., methoxy
Carbonylmethyl, ethoxycarbonylmethyl, tert-
Butoxycarbonylmethyl, methoxycarbonylethyl
Methoxycarbonylmethyl, methoxycarbonyl
(Dimethyl) methyl, ethoxycarbonyl (dimethyl)
Methyl, tert-butoxycarbonyl (dimethyl) methyl
Such as C _1-6Alkoxy-carbonyl-C_1-6Al
(Xxiii) carboxyl-lower alkyl
Groups (eg, carboxymethyl, carboxyethyl
Carboxyl (dimethyl) methyl
Le-C_1-6Alkyl group, etc.), (xxiv)
An optionally substituted heterocyclic group, substituted by (xxv) halogen
Optionally substituted with phenylthio, (xxvi) halogen
1 to 5 selected from phenoxy, etc.
(Preferably 1 to 3) is used. The "lower class
"Lucoxy" and "lower alkylthio" are phenyl
It may have a group as a substituent. The "having a substituent
"Substituent" and "hydrocarbon"
The "substituent"¹"Replaced
Substituents "and" hydrocarbons "
And the like. The “optionally substituted compound”
The “heterocyclic group” of the “ring group” is represented by the above B ring
From the "heterocycle" of the "optionally substituted heterocycle"
A group formed by removing one hydrogen atom is used. Ma
In addition, the "substitution" of the "optionally substituted heterocyclic group"
As the “group”, “having a substituent represented by the ring B”
May be a heterocyclic ring, a “substituent (provided that“ substituted
Heterocyclic group which may be optionally used)) and the like. R
^2b, R^3bAnd preferably C_1-4Alkyl
(Methyl, ethyl, etc.) or C_1-4Alkoxy (me
Phenyl which may be substituted with ethoxy, ethoxy, etc.)
Le, C_1-4Alkyl (methyl, ethyl, etc.), halo
Geno (fluoro, chloro, etc.) C_1-4Alkyl (meth
Benzyl, naphthyl, pyridyl, thi
An enyl, furyl or hydrogen atom is exemplified. the above
R¹Represented by the "optionally substituted acyl group"
And preferably formyl, acetyl, trihalogeno
(Fluoro, etc.) acetyl, pyridylcarbonyl, thie
Nilcarbonyl, furylcarbonyl, phenacyl, ben
Zoil, C_{1 -4}Alkyl (such as methyl) benzoyl,
C_1-4Alkoxy (such as methoxy) benzoyl, ben
Zensulfonyl, naphthylsulfonyl, thienylsulfo
And more preferably,-(C = O)-
R^2b[Wherein, R^2bIs C_{1- 6}Alkyl group, C_1-6
A phenyl group optionally substituted with an alkoxy group or
Phenyl-C_1-6Represents an alkyl group].
You.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ¹ includes a monocyclic heterocyclic group,
A group formed by removing one hydrogen atom from a cyclic heterocyclic ring and a polycyclic heterocyclic ring such as a tricyclic ring or a tetracyclic ring is used. The heterocyclic ring may be either aromatic or non-aromatic. As the hetero atom, for example, 1 to 6 atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like are used. Specifically, as the monocyclic heterocyclic group, a group formed by removing one hydrogen atom from the “heterocycle” of the “heterocycle optionally having substituent (s)” represented by ring B above Are used. Also, in addition to them, for example,
Groups formed by removing one hydrogen atom from a monocyclic heterocycle such as triazole, thiadiazole, oxadiazole, oxathiadiazole, triazine, and tetrazole are also used. Examples of the bicyclic heterocyclic group include indole, dihydroindole, isoindole, dihydroisoindole, benzofuran, dihydrobenzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, indazole,
Quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, tetrahydro-1H-1-benzazepine, tetrahydro-1H-2-benzazepine, tetrahydro-1H-3-benzazepine, tetrahydrobenzoxazepine, quinazoline, tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, Benzodioxane,
A group formed by removing one hydrogen atom from a bicyclic heterocycle such as benzodioxole, benzothiazine, imidazopyridine and the like is used. Examples of the polycyclic heterocyclic group such as tricyclic or tetracyclic include one hydrogen atom from a polycyclic heterocyclic ring such as acridine, tetrahydroacridine, pyrroloquinoline, pyrroloindole, cyclopentoindole, and isoindolobenzazepine. A group formed by individual removal is used. As the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)”, in particular, a group formed by removing one hydrogen atom from the above monocyclic heterocyclic ring or bicyclic heterocyclic ring and the like Are frequently used, and among them, a pyridyl group is preferable. Also,
As the “substituent” of the “heterocyclic group which may have a substituent”, the “substituent” of the “heterocyclic ring which may have a substituent” represented by the above-mentioned ring B (however, and "substituent" of the "optionally substituted hydrocarbon group" may have a group represented by good excluding heterocyclic group ")" and the R ¹ is used. Preferably, R ¹ may be substituted with, for example, (i) a hydrogen atom, (ii) a C _1-6 alkyl group, (iii) a halogen atom, nitro, C _1-6 alkyl or C _1-6 alkoxy. A phenyl-C _1-6 alkyl group or (iv)-(C ＝ O) —R ^{2b wherein} R ^2b is a phenyl group which may be substituted with a C _1-6 alkyl group or a C _1-6 alkoxy group Or a phenyl-C _1-6 alkyl group].

More specific examples of the case where the “aryl group” of the “optionally substituted aryl group” is condensed with a monocyclic heterocyclic ring which may have a substituent include the following:

Embedded image As a phenyl group fused to a monocyclic heterocycle represented by
For example, 2,3-dihydrobenzofuran; 3,4-dihydro-2H-1-benzothiopyran; 2,3-dihydro-1H-indole; 1,2,3,4-tetrahydroquinoline; 2,3-dihydro-1H- Isoindole; 1,
2,3,4-tetrahydroisoquinoline; 2,3,4,5-
Tetrahydro-1H-1-benzazepine, 2,3,4,
5-tetrahydro-1H-2-benzazepine, 2,3,
Benzazepines such as 4,5-tetrahydro-1H-3-benzazepine; 1,2,3,4,5,6-hexahydro-
1-benzazocine, 1,2,3,4,5,6-hexahydro-2-benzazocine, benzazocin such as 1,2,3,4,5,6-hexahydro-3-benzazocine;
2,3,4,5,6,7-hexahydro-1H-1-benzazonin, 2,3,4,5,6,7-hexahydro-1H-
2-benzazonin, 2,3,4,5,6,7-hexahydro-1H-3-benzazonin, 2,3,4,5,6,7-
Benzazonin such as hexahydro-1H-4-benzazonin; benzoxazole such as 2,3-dihydrobenzoxazole; benzothiazole such as 2,3-dihydrobenzothiazole; benzimidazole such as 2,3-dihydro-1H-benzimidazole; 3,4-dihydro-1H-2,1-benzoxazine, 3,4-dihydro-1H-2,3-benzoxazine, 3,4-dihydro-2H-1,2-benzoxazine, 3,4-dihydro Benzoxazines such as -2H-1,4-benzoxazine, 3,4-dihydro-2H-1,3-benzoxazine and 3,4-dihydro-2H-3,1-benzoxazine; 3,4-dihydro- 1H-2,1-benzothiazine, 3,4-dihydro-1H-2,3-benzothiazine, 3,4-dihi B-2H-1,2-benzothiazine, 3,4-dihydro-2H-1,4-benzothiazine, 3,4-dihydro-2H-1,3-benzothiazine, 3,4-dihydro-2H-3,1- Benzothiazine such as benzothiazine; 1,2,3,4-tetrahydrocinnoline, 1,2,3,4-tetrahydrophthalazine,
1,2,3,4-tetrahydroquinazoline, 1,2,2
Benzodiazines such as 3,4-tetrahydroquinoxaline; 3,4-dihydro-1,2-benzoxatiin;
3,4-dihydro-2,1-benzoxatiin, 2,
3-dihydro-1,4-benzoxatiin, 1,4-
Dihydro-2,3-benzoxatiin, 4H-1,3
Benzoxatiins such as benzoxatiin, 4H-3,1-benzoxatiin; 3,4-dihydro-1,
Benzodioxins such as 2-benzodioxin, 2,3-dihydro-1,4-benzodioxin, 1,4-dihydro-2,3-benzodioxin, 4H-1,3-benzodioxin; 3,4-dihydro- 1,2-benzdithiin, 2,3-dihydro-1,4-benzdithiin, 1,
4-dihydro-2,3-benzdithiin, 4H-1,3
-Benzdithiin such as benzdithiin; 2,3,4,5
-Tetrahydro-1,2-benzoxazepine, 2,
3,4,5-tetrahydro-1,3-benzoxazepine, 2,3,4,5-tetrahydro-1,4-benzoxazepine, 2,3,4,5-tetrahydro-1,5-
Benzoxazepine, 1,3,4,5-tetrahydro-
2,1-benzoxazepine, 1,3,4,5-tetrahydro-2,3-benzoxazepine, 1,3,4,5
-Tetrahydro-2,4-benzoxazepine, 1,
2,4,5-tetrahydro-3,1-benzoxazepine, 1,2,4,5-tetrahydro-3,2-benzoxazepine, 1,2,3,5-tetrahydro-4,1-
Benzoxazepines such as benzoxazepine; 2,3
4,5-tetrahydro-1,2-benzothiazepine,
2,3,4,5-tetrahydro-1,4-benzothiazepine, 2,3,4,5-tetrahydro-1,5-benzothiazepine, 1,3,4,5-tetrahydro-2,1-
Benzothiazepine, 1,3,4,5-tetrahydro-
2,4-benzothiazepine, 1,2,4,5-tetrahydro-3,1-benzothiazepine, 1,2,4,5-tetrahydro-3,2-benzothiazepine, 1,2,3
Benzothiazepines such as 5-tetrahydro-4,1-benzothiazepine; 2,3,4,5-tetrahydro-1H-
1,2-benzodiazepine, 2,3,4,5-tetrahydro-1H-1,3-benzodiazepine, 2,3,4
5-tetrahydro-1H-1,4-benzodiazepine,
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, 2,3,4,5-tetrahydro-1H-
Benzodiazepines such as 2,3-benzodiazepine and 2,3,4,5-tetrahydro-1H-2,4-benzodiazepine; 4,5-dihydro-1,3-benzodioxepin, 4,5-dihydro-3H- 1,2-benzodioxepin, 2,3-dihydro-5H-1,4-benzodioxepin, 3,4-dihydro-2H-1,5-benzodioxepin, 4,5-dihydro-1H Benzodioxepins such as -2,3-benzodioxepin and 1,5-dihydro-2,4-benzodioxepin; 4,5-dihydro-1
H-2,3-benzothiepine, 1,5-dihydro-2,
4-benzodithiepine, 3,4-dihydro-2H-1,
5-benzodithiepine, 2,3-dihydro-5H-1,
Benzodithiepine such as 4-benzodithiepine;
5,6-tetrahydro-2H-1,5-benzoxazosin, 3,4,5,6-tetrahydro-2H-1,6-
Benzoxazosins such as benzoxazosin; 3,4
Benzothiazocins such as 5,6-tetrahydro-2H-1,5-benzothiazocine and 3,4,5,6-tetrahydro-2H-1,6-benzothiazocine;
Benzodiazocine such as 4,5,6-hexahydro-1,6-benzodiazocine; benzooxathiocin such as 2,3,4,5-tetrahydro-1,6-benzooxathiocin; 2,3 Benzodioxocins such as 4,5-tetrahydro-1,6-benzodioxosin; benzotrioxepins such as 1,3,5-benzotrioxepin and 5H-1,3,4-benzotrioxepin 3,4-dihydro-1H-5,2,1-benzoxathiazepine, 3,4;
-Dihydro-2H-5,1,2-benzoxthiazepine, 4,5-dihydro-3,1,4-benzoxathiazepine, 4,5-dihydro-3H-1,2,5-benzoxathi Benzoxatiazepines such as azepine; 2,
Benzoxadiazepines such as 3,4,5-tetrahydro-1,3,4-benzoxadiazepine;
Benzthiadiazepines such as 5-tetrahydro-1,3,5-benzthiadiazepine; benzotriazepines such as 2,3,4,5-tetrahydro-1H-1,2,5-benzotriazepine; 5-dihydro-1,3,2-benzoxathiepine, 4,5-dihydro-1H-2,3-
Benzoxathiepine, 3,4-dihydro-2H-1,
5-benzoxathiepine, 4,5-dihydro-3H-
1,2-benzoxathiepine, 4,5-dihydro-3
H-2,1-benzoxathiepine, 2,3-dihydro-5H-1,4-benzoxathiepine, 2,3-dihydro-5H-4,1-benzoxathiepine, especially 2,3 , 4,5-Tetrahydro-1H-3-benzazepine, 2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3-dihydro-1H-indole, 2,
Examples include groups formed by removing one hydrogen atom from a bicyclic fused benzene ring such as 3,4,5-tetrahydro-1,4-benzoxazepine.

Preferred examples of the case where the “aryl group” of the “optionally substituted aryl group” is condensed with a monocyclic heterocyclic ring which may have a substituent include, for example, those represented by the following formulas:

Embedded image Wherein the ring B ′ represents a 5- to 9-membered nitrogen-containing heterocyclic ring which may be substituted with an oxo group other than R ¹ , wherein the ring A and R ¹ are as defined above. And the like. Said "5 to 9 optionally substituted with an oxo group"
"5- to 9-membered nitrogen-containing heterocycle" of "Membered nitrogen-containing heterocycle"
A 5- to 9-membered nitrogen-containing heterocyclic group which may contain 1 to 3 heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and one nitrogen atom, etc. And a 5- to 9-membered non-aromatic nitrogen-containing heterocyclic ring (eg, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine, etc.) are preferable. Used. More preferred examples of the case where the `` aryl group '' of the `` aryl group which may be substituted '' condenses with the monocyclic heterocyclic ring which may have a substituent include:

Embedded image [Wherein, A ring and R ¹ have the same meanings as above, k and m each independently represent an integer of 0 to 5, and 1 <k
+ M <5. In addition to the group represented by

Embedded image Wherein R ¹ is as defined above. And the like, and particularly preferred examples include

Embedded image [Wherein, A ring and R ¹ are as defined above. In addition to the group represented by

Embedded image Wherein R ¹ is as defined above. And the like.

When the "aryl group" of the "optionally substituted aryl group" for Ar is condensed with a bicyclic heterocyclic ring which may have a substituent, or two identical or different monocyclic rings (However, at least one of the rings is a monocyclic heterocycle), a specific example of the case of condensing

Embedded image [In the formula, ring A has the same meaning as described above, and ring C and ring D are one or more heterocycles which may have a substituent, and the other may have a substituent, and Represents a 5- to 9-membered ring which may be contained].

The “heterocycle” of the “heterocycle optionally having substituent (s)” represented by ring C and ring D is, for example, 4
A to 14-membered heterocyclic ring, preferably a 5- to 9-membered heterocyclic ring is used. As the heteroatom, for example, one to three selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like are used. Further, it may be either aromatic or non-aromatic. Specifically, for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, Thiomorpholine and the like are used. The “substituent” of the “optionally substituted heterocycle” has the same meaning as the “substituent” of the “optionally substituted heterocycle” represented by the ring B. “5- to 9-membered ring optionally having a substituent and optionally containing a hetero atom” represented by ring C and ring D
Examples of the “5- to 9-membered ring optionally containing a hetero atom” include a 5- to 9-membered heterocyclic ring (for example, pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene,
Saturated or unsaturated 5- to 9-membered heterocycles such as dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine) or 5 Or a 9-membered carbocycle is used. The "5
The “9-membered carbocycle” may be a saturated or unsaturated ring, and for example, benzene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene and the like are used. Among them, benzene or cyclohexane is preferred.

As the “substituent” of the “5- to 9-membered ring optionally having a substituent and containing a hetero atom”, the above “substituent having a substituent represented by the ring B” And "substituent on any carbon atom of ring B" of "good heterocycle". More specific examples of the case where the “aryl group” of the “optionally substituted aryl group” represented by Ar is condensed with an optionally substituted bicyclic heterocycle include (1) formula:

Embedded image As a phenyl group fused to a bicyclic heterocycle represented by
For example, carbazole, 1,2,3,4,4a, 9a-hexahydrocarbazole, 9,10-dihydroacridine,
1,2,3,4-tetrahydroacridine, 10,11-dihydro-5H-dibenz [b, f] azepine, 5,6,7,1
2-tetrahydrodibenz [b, g] azocine, 6,11-
Dihydro-5H-dibenz [b, e] azepine, 6,7-dihydro-5H-dibenz [c, e] azepine, 5,6,11,
12-tetrahydrodibenz [b, f] azocine, dibenzofuran, 9H-xanthen, 10,11-dihydrodibenz [b, f] oxepin, 6,11-dihydrodibenz [b, e] oxepin, 6,7- Dihydro-5H-dibenz [b, g] oxocin, dibenzothiophene, 9H-thioxanthene, 10,11-dihydrodibenzo [b, f] thiepin, 6,11-dihydrodibenzo [b, e] thiepin,
6,7-dihydro-5H-dibenzo [b, g] thiocin,
0H-phenothiazine, 10H-phenoxazine, 5,
10-dihydrophenazine, 10,11-dibenzo [b,
f] [1,4] thiazepine, 10,11-dihydrodibenz [b, f] [1,4] oxazepine, 2,3,5,6,11,
11a-Hexahydro-1H-pyrrolo [2,1-b]
[3] benzazepine, 10,11-dihydro-5H-
Dibenzo [b, e] [1,4] diazepine, 5,11-dihydrodibenz [b, e] [1,4] oxazepine, 5,11
-Dihydrodibenzo [b, f] [1,4] thiazepine, 1
0,11-dihydro-5H-dibenzo [b, e] [1,4]
A group formed by removing one hydrogen atom from a tricyclic fused benzene ring such as diazepine, 1,2,3,3a, 8,8a-hexahydropyrrolo [2,3-b] indole,

Formula (2):

Embedded image As a phenyl group fused to a bicyclic heterocycle represented by
For example, 1H, 3H-naphtho [1,8-cd] [1,2] oxazine, naphtho [1,8-de] -1,3-oxazine, naphtho [1,8-de] -1,2-oxazine, 1,2,2a,
3,4,5-hexahydrobenz [cd] indole, 2,
3,3a, 4,5,6-hexahydro-1H-benzo [de]
Quinoline, 4H-pyrrolo [3,2,1-ij] quinoline,
1,2,5,6-tetrahydro-4H-pyrrolo [3,2,1
-Ij] quinoline, 5,6-dihydro-4H-pyrrolo [3,
2,1-ij] quinoline, 1H, 5H-benzo [ij] quinolidine, azepino [3,2,1-hi] indole, 1,2,
4,5,6,7-hexahydroazepino [3,2,1-hi]
Indole, 1H-pyrido [3,2,1-jk] [1] benzazepine, 5,6,7,8-tetrahydro-1H-pyrido [3,2,1-jk] [1] benzazepine, 1,2, 5,
6,7,8-hexahydro-1H-pyrido [3,2,1-j
k] [1] benzazepine, 2,3-dihydro-1H-benz [de] isoquinoline, 1, 2, 3, 4, 4a, 5, 6, 7
-Octahydronaphtho [1,8-bc] azepine, 2,3,
5,6,7,8-Hexahydro-1H-pyrido [3,2,1
-Jk] [1] a group formed by removing one hydrogen atom from a tricyclic fused benzene ring such as benzazepine,

Equation (3):

Embedded image As a phenyl group condensed with two identical or different monocyclic rings represented by the formula (where at least one ring is a monocyclic heterocyclic ring), for example, 1,2,3,5,6,7-hexahydrobenzo [1,2-b: 4,5-b '] dipyrrole, 1,
A group formed by removing one hydrogen atom from a tricyclic fused benzene ring such as 2,3,5,6,7-hexahydrocyclopent [f] indole; or formula (4):

Embedded image As a phenyl group fused to two identical or different rings represented by the formula (where at least one ring is a monocyclic heterocyclic ring), for example, 1,2,3,6,7,8-hexahydrocyclo A group formed by removing one hydrogen atom from a tricyclic fused benzene ring such as pent [e] indole, 2,3,4,7,8,9-hexahydro-1H-cyclopenta [f] quinoline; .

Preferred examples of the case where the “aryl group” of the “optionally substituted aryl group” represented by Ar is condensed with a bicyclic heterocyclic ring which may have a substituent include:
For example, the formula:

Embedded image [Wherein, the ring C ′ and the ring D ′ each represent a 5- to 9-membered nitrogen-containing heterocyclic ring which may be substituted with an oxo group other than R ¹ , wherein A ring, D ring and R ¹ are as defined above. And a group represented by the following: Examples of the “5- to 9-membered nitrogen-containing heterocycle” of the “5- to 9-membered nitrogen-containing heterocycle optionally substituted with an oxo group” include, besides a carbon atom and one nitrogen atom, a nitrogen atom A 5- to 9-membered nitrogen-containing heterocyclic group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom;
A 5- to 9-membered non-aromatic nitrogen-containing heterocycle (for example, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine, etc.) is preferably used. More preferred examples of the case where the “aryl group” of the “optionally substituted aryl group” represented by Ar is condensed with an optionally substituted bicyclic heterocyclic ring are those represented by the formula:

Embedded image [Wherein, R ¹ has the same meaning as described above].

Specific examples of the case where the “phenyl group” of the “phenyl group which may have a substituent and may be condensed” condenses with the tricyclic heterocyclic ring which may have a substituent As an example, the formula:

Embedded image [Wherein, ring A has the same meaning as described above, and at least one of ring E, ring F and ring G is a heterocyclic ring which may have a substituent, and the other rings are substituents. And a 5- to 9-membered ring which may contain a heteroatom].

The “heterocycle” and “substituent” of the “optionally substituted heterocycle” represented by ring E, ring F and ring G are those represented by ring C and ring D described above. "Heterocycle" and "substituent" of "heterocycle optionally having substituent (s)"
Are used. "5- to 9-membered ring optionally having a substituent and optionally containing a hetero atom" represented by "5 to 9 optionally containing a hetero atom" represented by ring E, ring F and ring G. As the “membered ring” and “substituent”, the “heteroatom” of the “5- to 9-membered ring optionally having a substituent and optionally containing a hetero atom” represented by the above-mentioned ring C or ring D And a "5- to 9-membered ring optionally containing" and "substituent".

More specific examples of the case where the “phenyl group” of the “phenyl group which may have a substituent and may be condensed” is condensed with a tricyclic heterocyclic ring which may have a substituent. A typical example is equation (1):

Embedded image A phenyl group [E ′ fused to a tricyclic heterocycle represented by
The definition of the ring and the F ′ ring will be described later], for example, 2H-isoindolo [2,1-e] purine, 1H-pyrazolo [4 ′, 3 ′: 3,4] pyrido [2,1-a] iso Indole, 1H-pyrido [2 ', 3': 4, 5] imidazo [2,
1-a] isoindole, 2H, 6H-pyrido [1 ',
2 ': 3,4] imidazo [5,1-a] isoindole,
1H-isoindolo [2,1-a] benzimidazole,
1H-pyrido [3 ', 4': 4,5] pyrrolo [2,1-a]
Isoindole, 2H-pyrido [4 ', 3': 4,5] pyrrolo [2,1-a] isoindole, 1H-isoindolo [2,1-a] indole, 2H-isoindolo [1,2
-A] isoindole, 1H-cyclopenta [4,5]
Pyrimido [2,1-a] isoindole, 2H, 4H-pyrano [4 ', 3': 4,5] [1,3] oxazino [2,3
-A] isoindole, 2H-isoindolo [2,1-
a] [3,1] benzoxazine, 7H-isoindolo [1,2-b] [1,3] benzoxazine, 2H-pyrido [2 ′, 1 ′: 3,4] pyrazino [2,1-a] Isoindole, pyrido [2 ', 3': 4,5] pyrimido [2,1
-A] isoindole, pyrido [3 ', 2': 5,6] pyrimido [2,1-a] isoindole, 1H-pyrido [1 ', 2': 3,4] pyrimido [2,1-a ] Isoindole, isoindolo [2,1-a] quinazoline, isoindolo [2,1-a] quinoxaline, isoindolo [1,2
-A] isoquinoline, isoindolo [2,1-b] isoquinoline, isoindolo [2,1-a] quinoline, 6H-oxazino [3 ', 4': 3,4] [1,4] diazepino [2,1- a] Isoindole, azepino [2 ', 1':
3,4] pyrazino [2,1-a] isoindole, 2H,
6H-pyrido [2 ', 1': 3,4] [1,4] diazepino [2,1-a] isoindole, 1H-isoindolo [1,2-b] [1,3,4] benzotriazepine , 2H-
Isoindolo [2,1-a] [1,3,4] benzotriazepine, isoindolo [2,1-d] [1,4] benzoxazepine, 1H-isoindolo [2,1-b] [2, 4]
Benzodiazepine, 1H-isoindolo [2,1-c]
[2,3] benzodiazepine, 2H-isoindolo [1,
2-a] [2,4] benzodiazepine, 2H-isoindolo [2,1-d] [1,4] benzodiazepine, 5H-indolo [2,1-b] [3] benzazepine, 2H-isoindolo [1,2 -A] [2] benzazepine, 2H-isoindolo [1,2-b] [3] benzazepine, 2H-
Isoindolo [2,1-b] [2] benzazepine, 2H
-Isoindolo [1,2-b] [1,3,4] benzooxadiazosin, isoindolo [2,1-b] [1,2,6] benzotriazosin, 5H-4,8-methano-1H- [1,
5] a group formed by removing one hydrogen atom from a tetracyclic fused benzene ring such as diazacycloundecino [1,11-a] indole;

Equation (2):

Embedded image In 3 heterocycle fused phenyl group represented [- - -
Represents a single bond or a double bond. The definitions of the E ′ ring and the G ′ ring will be described later], for example, 1H, 4H-pyrrolo [3 ′,
2 ′: 4,5] pyrrolo [3,2,1-ij] quinoline, pyrrolo [3,2,1-jk] carbazole, 1H-furo [2 ′,
3 ': 4,5] pyrrolo [3,2,1-ij] quinoline, 1H,
4H-cyclopenta [4,5] pyrrolo [1,2,3-de]
Quinoxaline, 1H, 4H-cyclopenta [4,5] pyrrolo [3,2,1-ij] quinoline, pyrido [3 ', 4':
4,5] pyrrolo [1,2,3-de] benzoxazine,
[1,4] oxazino [2,3,4-jk] carbazole,
1H, 3H- [1,3] oxazino [5,4,3-jk] carbazole, pyrido [3 ′, 4 ′: 4,5] pyrrolo [1,
2,3-de] [1,4] benzothiazine, 4H-pyrrolo [3,2,1-de] phenanthridine, 4H, 5H-pyrido [3,2,1-de] phenanthridine, 1H, 4H -3
a, 6a-Diazafluoroanthene, 1-oxa-4,6a
-Diazafluoroanthene, 4-oxa-2,10b-
Diazafluoroanthene, 1-thia-4,6a-diazafluoroanthene, 1H-pyrazino [3,2,1-jk] carbazole, 1H-indolo [3,2,1-de] [1,
5] naphthyridine, benzo [b] pyrano [2,3,4-h
i] indolizine, 1H, 3H-benzo [b] pyrano [3,4,5-hi] indolizine, 1H, 4H-pyrano [2 ', 3': 4,5] pyrrolo [3,2,1- ij] quinoline, 1H, 3H-benzo [b] thiopyrano [3,4,5-h
i] indolizine, 1H-pyrido [3,2,1-jk] carbazole, 4H-3-oxa-11b-azacyclohepta [jk] fluorene, 2H-azepino [1 ′, 2 ′: 1,
2] pyrimidino [4,5-b] indole, 1H, 4H-
Cyclohepta [4,5] pyrrolo [1,2,3-de] quinoxaline, 5H-pyrido [3 ′, 4 ′: 4,5] pyrrolo [1,
2,3-ef] [1,5] benzoxazepine, 4H-pyrido [3 ′, 4 ′: 4,5] pyrrolo [3,2,1-jk] [4,
1] benzothiazepine, 5H-pyrido [3 ', 4': 4,
5] pyrrolo [1,2,3-ef] [1,5] benzothiazepine, 5H-pyrido [4 ′, 3 ′: 4,5] pyrrolo [1,2,
3-ef] [1,5] benzothiazepine, [1,2,4] triazepino [6,5,4-jk] carbazole, [1,2,
4] triazepino [6,7,1-jk] carbazole,
[1,2,5] triazepino [3,4,5-jk] carbazole, 5H- [1,4] oxazepino [2,3,4-jk] carbazole, 5H- [1,4] thiazepino [2,3 , 4-j
k] carbazole, [1,4] diazepino [3,2,1-j
k] carbazole, [1,4] diazepino [6,7,1-j
k] carbazole, azepino [3,2,1-jk] carbazole, 1H-cycloocta [4,5] pyrrolo [1,2,3
-De] quinoxaline, a group formed by removing one hydrogen atom from a tetracyclic fused benzene ring such as 1H-cycloocta [4,5] pyrrolo [3,2,1-ij] quinoline,

Equation (3):

Embedded image In 3 heterocycle fused phenyl group represented [- - -
Represents a single bond or a double bond. The definitions of the E ′ ring and F ′ ring will be described later], for example, as 1H-indolo [1,2-a]
Benzimidazole, 1H-indolo [1,2-b] indazole, pyrrolo [2 ′, 1 ′: 3,4] pyrazino [1,2
-A] indole, 1H, 5H-pyrrolo [1 ', 2': 4,
5] pyrazino [1,2-a] indole, 2H-pyrido [2 ', 3': 3,4] pyrrolo [1,2-a] indole,
1H-pyrrolo [2 ', 3': 3,4] pyrido [1,2-a]
Indole, 1H-indolo [1,2-a] indole,
6H-isoindolo [2,1-a] indole, 6H-indolo [1,2-c] [1,3] benzoxazine, 1H
-Indolo [1,2-b] [1,2] benzothiazine, pyrimido [4 ', 5': 4,5] pyrimido [1,6-a] indole, pyrazino [2 ', 3': 3,4] Pyrido [1,2-
a] indole, 6H-pyrido [1 ', 2': 3,4] pyrimido [1,6-a] indole, indolo [1,2-b] cinnoline, indolo [1,2-a] quinazoline, indolo [ 1,2-c] quinazoline, indolo [2,1-b] quinazoline, indolo [1,2-a] quinoxaline, indolo [1,2-a] [1,8] naphthyridine, indolo [1,2
-B] -2,6-naphthyridine, indolo [1,2-b]
[2,7] naphthyridine, indolo [1,2-h] -1,7
-Naphthyridine, indolo [1,2-b] isoquinoline,
Indolo [2,1-a] isoquinoline, Indolo [1,2
-A] quinoline, 2H, 6H-pyrido [2 ', 1': 3,
4] [1,4] diazepino [1,2-a] indole, 1
H-indolo [2,1-c] [1,4] benzodiazepine, 2H-indolo [1,2-d] [1,4] benzodiazepine, 2H-indolo [2,1-a] [2,3] benzodiazepine , 2H-indolo [2,1-b] [1,3] benzodiazepine, 1H-indolo [1,2-b] [2] benzazepine, 2H-indolo [1,2-a] [1] benzazepine, 2H- 4-cyclic fused benzene rings such as indolo [2,1-a] [2] benzazepine, indolo [1,2-e] [1,5] benzodiazocine, indolo [2,1-b] [3] benzazosin A group formed by removing one hydrogen atom from

Equation (4):

Embedded image In 3 heterocycle fused phenyl group represented [- - -
Represents a single bond or a double bond. The definition of the E 'ring will be described later]
For example, 1H-imidazo [1 ′, 2 ′: 1,
2] pyrido [3,4-b] indole, 1H-imidazo [1 ′, 2 ′: 1,6] pyrido [4,3-b] indole,
1H-imidazo [1 ', 5': 1,2] pyrido [3,4-
b] indole, 1H-imidazo [1 ', 5': 1,6] pyrido [4,3-b] indole, 1H-pyrido [2 ',
1 ': 2,3] imidazo [4,5-b] indole, imidazo [4,5-a] carbazole, imidazo [4,5-c] carbazole, pyrazolo [3,4-c] carbazole, 2H
-Pyrazino [1 ', 2': 1,5] pyrrolo [2,3-b] indole, 1H-pyrrolo [1 ', 2': 1,2] pyrimido [4,5-b] indole, 1H-indolizino [6,7
-B] indole, 1H-indolizino [8,7-b] indole, indolo [2,3-b] indole, indolo [3,2-b] indole, pyrrolo [2,3-a] carbazole, pyrrolo [2 , 3-b] carbazole, pyrrolo [2,
3-c] carbazole, pyrrolo [3,2-a] carbazole, pyrrolo [3,2-b] carbazole, pyrrolo [3,2
-C] carbazole, pyrrolo [3,4-a] carbazole, pyrrolo [3,4-b] carbazole, pyrrolo [3,4
-C] carbazole, 1H-pyrido [3 ', 4': 4,5]
Flow [3,2-b] indole, 1H-Flow [3,4-a]
Carbazole, 1H-furo [3,4-b] carbazole,
1H-furo [3,4-c] carbazole, 2H-furo [2,3-a] carbazole, 2H-furo [2,3-c] carbazole, 2H-furo [3,2-a] carbazole, 2
H-furo [3,2-c] carbazole, 1H-pyrido [3 ', 4': 4,5] thieno [2,3-b] indole,
Thieno [3 ', 2': 5,6] thiopyrano [4,3-b] indole, Thieno [3 ', 4': 5,6] thiopyrano [4,
3-b] indole, 1H- [1] benzothieno [2,3
-B] indole, 1H- [1] benzothieno [3,2-
b] indole, 1H-thieno [3,4-a] carbazole, 2H-thieno [2,3-b] carbazole, 2H-thieno [3,2-a] carbazole, 2H-thieno [3,2
−b] carbazole, cyclopenta [4,5] pyrrolo [2,3-f] quinoxaline, cyclopenta [5,6] pyrido [2,3-b] indole, pyrido [2 ′, 3 ′: 3,
4] cyclopenta [1,2-b] indole, pyrido [2 ′, 3 ′: 4.5] cyclopenta [1,2-b] indole, pyrido [3 ′, 4 ′: 3,4] cyclopenta [1, 2
-B] indole, pyrido [3 ', 4': 4,5] cyclopenta [1,2-b] indole, pyrido [4 ', 3': 4,
5] cyclopenta [1,2-b] indole, 1H-cyclopenta [5,6] pyrano [2,3-b] indole, 1
H-cyclopenta [5,6] thiopyrano [4,3-b] indole, cyclopenta [a] carbazole, cyclopenta [c] carbazole, indeno [1,2-b] indole, indeno [2,1-b] indole, [1,2,4]
Triazino [4 ', 3': 1,2] pyrido [3,4-b] indole, 1,3,5-triazino [1 ', 2': 1,1]
Pyrido [3,4-b] indole, 1H- [1,4] oxazino [4 ', 3': 1,2] pyrido [3,4-b] indole, 1H- [1,4] oxazino [4 ' , 3 ': 1,6]
Pyrido [3,4-b] indole, 4H- [1,3] oxazino [3 ', 4': 1,2] pyrido [3,4-b] indole, indolo [3,2-b] [1, 4] benzoxazine, 1,3-oxazino [6,5-b] carbazole, 2
H-pyrimido [2 ', 1': 2,3] [1,3] thiazino [5,6-b] indole, 2H- [1,3] thiazino [3 ', 2': 1,2] pyrido [ 3,4-b] indole,
4H- [1,3] thiazino [3 ', 4': 1,2] pyrido [3,4-b] indole, indolo [2,3-b] [1,
4] benzothiazine, indolo [3,2-b] [1, 4]
Benzothiazine, indolo [3,2-c] [2,1] benzothiazine, 1,4-thiazino [2,3-a] carbazole, [1,4] thiazino [2,3-b] carbazole,
[1,4] thiazino [2,3-c] carbazole, 1,4-
Thiazino [3,2-b] carbazole, 1,4-thiazino [3,2-c] carbazole, 1H-indolo [2,3-
g] pteridine, 1H-indolo [3,2-g] pteridine, pyrazino [1 ′, 2 ′: 1,2] pyrido [3,4-b]
Indole, pyrazino [1 ', 2': 1, 2] pyrido [4,
3-b] Indole, 1H-pyrido [2 ', 3': 5, 6]
Pyrazino [2,3-b] indole, 1H-pyrido [3 ', 2': 5.6] pyrazino [2,3-b] indole, 1H-pyrido [3 ', 4': 5.6] pyrazino [ A few
-B] indole, pyrido [1 ', 2': 1,2] pyrimido [4,5-b] indole, pyrido [1 ', 2': 1,2]
Pyrimido [5,4-b] indole, pyrido [2 ', 1':
2,3] pyrimido [4,5-b] indole, pyrimido [1 ′, 2 ′: 1,2] pyrido [3,4-b] indole,
Pyrimido [1 ', 2': 1,6] pyrido [3,4-b] indole, pyrimido [5 ', 4': 5,6] pyrano [2,3-
b] indole, pyridazino [4 ', 5': 5, 6] thiopyrano [4, 5-b] indole, 1H-indolo [3,2
-C] cinnoline, 1H-indolo [2,3-b] quinoxaline, 1H-pyrazino [2,3-a] carbazole, 1
H-pyrazino [2,3-b] carbazole, 1H-pyrazino [2,3-c] carbazole, 1H-pyridazino [3,
4-c] carbazole, 1H-pyridazino [4,5-b]
Carbazole, 1H-pyrimido [4,5-a] carbazole, 1H-pyrimido [4,5-c] carbazole, 1H-
Pyrimido [5,4-a] carbazole, 1H-pyrimido [5,4-b] carbazole, 1H-pyrimido [5,4-
c] carbazole, 7H-1,4-dioxino [2 ′,
3 ': 5,6] [1,2] dioxino [3,4-b] indole, 6H- [1,4] benzodioxino [2,3-b]
Indole, 6H- [1,4] benzodithiino [2,3-
b] indole, 1H-indolo [2,3-b] -1,5-
Naphthyridine, 1H-indolo [2,3-b] [1,6]
Naphthyridine, 1H-indolo [2,3-b] [1,8]
Naphthyridine, 1H-indolo [2,3-c] -1,5-
Naphthyridine, 1H-indolo [2,3-c] [1,6]
Naphthyridine, 1H-indolo [2,3-c] [1,7]
Naphthyridine, 1H-indolo [2,3-c] [1,8]
Naphthyridine, 1H-indolo [3,2-b] -1,5-
Naphthyridine, 1H-indolo [3,2-b] [1,7]
Naphthyridine, 1H-indolo [3,2-b] [1,8]
Naphthyridine, 1H-indolo [3,2-c] [1,8]
Naphthyridine, indolo [2,3-a] quinolidine, indolo [2,3-b] quinolizine, indolo [3,2-a] quinolizine, indolo [3,2-b] quinolizine, pyrano [4 ′, 3 ′]: 5,6] pyrido [3,4-b] indole,
Pyrido [4 ', 3': 4,5] pyrano [3,2-b] indole, pyrido [4 ', 3': 5,6] pyrano [2,3-b]
Indole, pyrido [4 ', 3': 5, 6] pyrano [3, 4
-B] indole, 1H-indolo [2,3-c] isoquinoline, 1H-indolo [3,2-c] isoquinoline, 1
H-indolo [2,3-c] quinoline, 1H-indolo [3,2-c] quinoline, 1H-pyrido [2,3-a] carbazole, 1H-pyrido [2,3-b] carbazole, 1
H-pyrido [2,3-c] carbazole, 1H-pyrido [3,2-a] carbazole, 1H-pyrido [3,2-b]
Carbazole, 1H-pyrido [3,2-c] carbazole, 1H-pyrido [3,4-a] carbazole, 1H-pyrido [3,4-b] carbazole, 1H-pyrido [3,4
-C] carbazole, 1H-pyrido [4,3-a] carbazole, 1H-pyrido [4,3-b] carbazole, 1H
-Pyrido [4,3-c] carbazole, 1H-kindrin, 1H-quinindrin, 1H-pyrano [3 ', 4':
5,6] pyrano [4,3-b] indole, [1] benzopyrano [2,3-b] indole, [1] benzopyrano [3,2-b] indole, [1] benzopyrano [3,4
-B] indole, [1] benzopyrano [4,3-b] indole, [2] benzopyrano [4,3-b] indole, pyrano [2,3-a] carbazole, pyrano [2,3
-B] carbazole, pyrano [2,3-c] carbazole, pyrano [3,2-a] carbazole, pyrano [3,2
-C] carbazole, pyrano [3,4-a] carbazole, 1H-phosphinolino [4,3-b] indole,
[1] benzothiopyrano [2,3-b] indole,
[1] benzothiopyrano [3,2-b] indole,
[1] benzothiopyrano [3,4-b] indole,
[1] benzothiopyrano [4,3-b] indole,
[2] Benzothiopyrano [4,3-b] indole, 1H
-Benzo [a] carbazole, 1H-benzo [b] carbazole, 1H-benzo [c] carbazole, [1,6,
2] oxathiazepino [2 ', 3': 1, 2] pyrido [3,
4-b] indole, 1H-azepino [1 ′, 2 ′: 1,
2] pyrido [3,4-b] indole, 1H-pyrido [1 ', 2': 1,2] azepino [4,5-b] indole, 2H-pyrido [1 ', 2': 1,2] Azepino [3,4
-B] indole, 1H-pyrido [3 ', 2': 5,6] oxepino [3,2-b] indole, 1H-pyrido [4 ', 3': 5,6] oxepino [3,2-b ] Indole, 2H-pyrido [2 ', 3': 5, 6] oxepino [2,
3-b] Indole, 2H-pyrido [2 ', 3': 5, 6]
Oxepino [3,2-b] indole, 2H-pyrido [3 ', 4': 5.6] oxepino [3,2-b] indole, pyrido [2 ', 3': 4.5] cyclohepta [1, 2-
b] indole, pyrido [3 ', 2': 3, 4] cyclohepta [1, 2-b] indole, pyrido [3 ', 4': 4,
5] cyclohepta [1,2-b] indole, pyrido [3 ′, 4 ′: 5.6] cyclohepta [1,2-b] indole, 2H-pyrano [3 ′, 2 ′: 2,3] azepino [ Four,
5-b] indole, 1H-indolo [3,2-b] [1,
5] benzoxazepine, 1H-indolo [3,2-d]
[1,2] benzoxazepine, 1H-indolo [2,3
−c] [1,5] benzothiazepine, [1,4] diazepino [2,3-a] carbazole, indolo [2,3-b]
[1,5] benzodiazepine, indolo [2,3-d]
[1,3] benzodiazepine, indolo [3,2-b]
[1,4] benzodiazepine, indolo [3,2-b]
[1,5] benzodiazepine, indolo [3,2-d]
[1,3] benzodiazepine, indolo [3,2-d]
[2,3] benzodiazepine, indolo [2,3-a]
[3] Benzazepine, indolo [2,3-c] [1] Benzazepine, indolo [2,3-d] [1] Benzazepine, indolo [2,3-d] [2] Benzazepine, indolo [3,2- b] [1] Benzazepine, indolo [3,2-c] [1] Benzazepine, indolo [3,2
-D] [1] benzazepine, 1H-indolo [2,1-
b] [3] benzazepine, 1H- [1] benzoxepino [5,4-b] indole, 1H- [2] benzoxepino [4,3-b] indole, 1H- [1] benzothiepino [4,5-b] Indole, 1H- [1] benzothiepino [5,4-b] indole, benzo [3,4] cyclohepta [1,2-b] indole, benzo [4,5] cyclohepta [1,2-b] indole, benzo [5,6]
Cyclohepta [1,2-b] indole, benzo [6,
7] cyclohepta [1,2-b] indole, cyclohepta [b] carbazole, 4H- [1,5] oxazocino [5 ′, 4 ′: 1,6] pyrido [3,4-b] indole,
Azocino [1 ', 2': 1,2] pyrido [3,4-b] indole, 2,6-methano-2H-azecino [4,3-b]
Indole, 3,7-methano-3H-azecino [5,4-
b] indole, pyrido [1 ', 2': 1,8] azosino [5,4-b] indole, pyrido [4 ', 3': 6, 7]
Oxosino [2,3-b] indole, pyrido [4 ',
3 ′: 6,7] oxono [4,3-b] indole, 1,
5-methano-1H-azecino [3,4-b] indole,
2,6-methano-1H-azecino [5,4-b] indole, 1H-pyrido [3 ', 4': 5.6] cycloocta [1,2-b] indole, 1,4-ethanooxocino [3, 4-b] Indole, pyrano [3 ', 4': 5, 6]
Cycloocta [1,2-b] indole, 1H-indolo [2,3-c] [1,2,5,6] benzotetrazocine, 1
H-indolo [2,3-c] [1,6] benzodiazocine, 6,13b-methano-13bH-azecino [5,4-
b] indole, oxocino [3,2-a] carbazole, 1H-benzo [g] cycloocta [b] indole,
6,3- (iminomethano) -2H-1,4-thiazono [9,8-b] indole, 1H, 3H- [1,4] oxazonino [4 ', 3': 1,2] pyrido [3,4 -B] indole, 2H-3,6-ethanoazonino [5,4-b] indole, 2H-3,7-methanoazacycloundesino [5,4-b] indole, 1H-6,12b-ethanoazonino [5 , 4-b] indole, indolo [3,2-e]
[2] benzazonin, 5,9-methanoazacycloundecino [5,4-b] indole, 3,6-ethano-3H
-Azecino [5,4-b] indole, 3,7-methano-
3H-azacycloundecino [5,4-b] indole,
Pyrano [4 ', 3': 8,9] azezino [5,4-b] indole, 1H-indolo [2,3-c] [1,7] benzodiazecin, 1H-indolo [3,2-e] [ 2] Benzazecin or the like is used.

Further, benzo [e] pyrrolo [3,2-b]
Indole, benzo [e] pyrrolo [3,2-g] indole, benzo [e] pyrrolo [3,2,1-hi] indole,
Benzo [e] pyrrolo [3,4-b] indole, benzo [g] pyrrolo [3,4-b] indole, 1H-benzo [f] pyrrolo [1,2-a] indole, 1H-benzo [g] Pyrrolo [1,2-a] indole, 2H-benzo [e] pyrrolo [1,2-a] indole, 1H-benzo [f] pyrrolo [2,1-a] isoindole, 1H-benzo [g] pyrrolo [2,1-a] isoindole, 2H-benzo [e] pyrrolo [2,1-a] isoindole, isoindolo [6,7,1-cde] indole, spiro [cyclohexane-1,5 ′-[5H ] Pyrrolo [2,1-a] isoindole], isoindolo [7,1,2-hij] quinoline, 7,11-methanoazosino [1,2-a] indole, 7,11-methanoazosino [2,1-a ] Indole, dibenz [cd, f] Indole, dibenz [cd, g]
Indole, dibenz [d, f] indole, 1H-dibenz [e, g] indole, 1H-dibenz [e, g] isoindole, naphtho [1,2,3-cd] indole, naphtho [1,8-ef Indole, naphtho [1,8-fg] indole, naphtho [3,2,1-cd] indole, 1H-naphtho [1,2-e] indole, 1H-naphtho [1,2-f]
Indole, 1H-naphtho [1,2-g] indole, 1
H-naphtho [2,1-e] indole, 1H-naphtho [2,3-e] indole, 1H-naphtho [1,2-f] isoindole, 1H-naphtho [2,3-e] isoindole, Spiro [1H-carbazole-1,1′-cyclohexane], spiro [2H-carbazole-2,1′-cyclohexane], spiro [3H-carbazole-3,1′-cyclohexane], cyclohepta [4,5] pyrrolo [ 3,2
-F] quinoline, cyclohepta [4,5] pyrrolo [3,2
-H] quinoline, azepino [4,5-b] benz [e] indole, 1H-azepino [1,2-a] benz [f] indole, 1H-azepino [2,1-a] benz [f] iso 4 such as indole, benzo [e] cyclohepta [b] indole, benzo [g] cyclohepta [b] indole
A group formed by removing one hydrogen atom from a cyclic fused benzene ring, or

Formula (5):

Embedded image In 3 heterocycle fused phenyl group represented [- - -
Represents a single bond or a double bond. The definitions of the E ′ ring and the F ′ ring will be described later], for example, as 1H-dipyrrolo [2,3-
b: 3 ', 2', 1'-hi] indole, spiro [cyclopentane-1,2 '(1'H) -pyrrolo [3,2,1-
hi] indole], spiro [imidazolidine-4,
1 '(2'H)-[4H] pyrrolo [3,2,1-ij] quinoline], pyrido [2,3-b] pyrrolo [3,2,1-
hi] indole, pyrido [4,3-b] pyrrolo [3
2,1-hi] indole, benzo [de] pyrrolo [3,2,1-ij] quinoline, 3H-pyrrolo [3,
2,1-de] acridine, 1H-pyrrolo [3,2,1
-De] phenanthridine, spiro [cyclohexane-
1,6 ′-[6H] pyrrolo [3,2,1-ij] quinoline], 4,9-methanopyrrolo [3,2,1-lm]
[1] Benzoazosin, spiro [cycloheptane-1,
6 '-[6H] pyrrolo [3,2,1-ij] quinoline], 1H-pyrano [3,4-d] pyrrolo [3,2,1
-Jk] [1] benzazepine, 3H-benzo [b] pyrrolo [3,2,1-jk] [4,1] benzoxazepine, 7H-indolo [1,7-ab] [4,1] benz Oxazepine, benzo [b] pyrrolo [3,2,1-j
k] [1,4] benzodiazepine, indolo [1,7-
ab] [1,4] benzodiazepine, indolo [1,7
-Ab] [1] benzazepine, indolo [7, 1-a
b] [3] benzazepine, 1H-cyclohepta [d]
[3,2,1-jk] [1] benzazepine, spiro [azepino [3,2,1-hi] indole-7 (4
H), 1'-cycloheptane], 4H-5,11-methanopyrrolo [3,2,1-no] [1] benzazacycloundesine, spiro [azepino [3,2,1-hi] indole-7 (4H), 1′-cyclooctane], and the like, which can be obtained by removing one hydrogen atom from a tetracyclic fused benzene ring.

The “phenyl group condensed with a tricyclic heterocycle” includes, in addition to the phenyl group condensed with a tricyclic heterocycle containing an optionally hydrogenated indole ring or isoindole ring, A phenyl group condensed with a tricyclic heterocycle exemplified below and a dihydro form, tetrahydro form, hexahydro form, octahydro form, and decahydro form thereof are used. Specifically, for example, fluoranthene,
Acephenanthrylene, aceanthrylene, triphenylene, pyrene, chrysene, naphthacene, pleiaden,
Benzo [a] anthracene, indeno [1,2-a] indene, cyclopenta [a] phenanthrene, pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-b] quinoxaline, 1H-2-oxapyrene, Spiro [piperidine-4.9′-xanthene] and the like.

Preferred examples of the case where the "phenyl group" of the "phenyl group which may have a substituent and may be condensed" is condensed with a tricyclic heterocyclic ring which may have a substituent As an example, the formula:

Embedded image [Wherein the ring E ′, the ring F ′ and the ring G ′ each represent a 5- to 9-membered nitrogen-containing heterocyclic ring which may be substituted with an oxo group other than R ¹ , and include ring A, ring F, ring G and R ¹ is as defined above. And the like. Among them, the formula:

Embedded image And the like are particularly preferred. The “5- to 9-membered nitrogen-containing heterocycle” of the “5- to 9-membered nitrogen-containing heterocycle optionally substituted by an oxo group” includes the above-mentioned C ′ ring and D ′
A “5- to 9-membered nitrogen-containing heterocycle” represented by a ring is used. The “optionally substituted aryl group” represented by Ar is condensed with (2) a bicyclic heterocyclic ring which may have a substituent, or two identical or different monocyclic rings (however, at least one of Preferred examples of the case where the ring is condensed with (3) a tricyclic heterocyclic ring which may have a substituent,
r is the formula:

Embedded image Wherein each symbol is as defined above. And the like.

The “optionally substituted aryl group” represented by Ar is particularly preferably a group represented by the formula:

Embedded image Wherein R ¹ is as defined above. A group represented by the formula:

Embedded image Wherein R ¹ is as defined above. ] Is preferable.

In the above formula, n represents an integer of 1 to 10. Preferred n is an integer of 1 to 6, particularly preferably 1 to 5, more preferably 2 to 5, particularly preferably 3, 4 or 5. In the above formula, R represents a hydrogen atom or a hydrocarbon group which may be substituted, and may be different in repeating n. The “hydrocarbon group” and “substituent” of the “optionally substituted hydrocarbon group” represented by R include the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ¹ above. "And" substituent ". R may be bonded to Ar or a substituent of Ar.

Examples of the compound represented by the formula (Ib) wherein R is bonded to Ar or a substituent of Ar include, for example, a compound represented by the formula:

Embedded image [Wherein, R ¹ , n, X, and Y have the same meanings as described above. Or a compound represented by the formula:

Embedded image [Wherein, n, X and Y have the same meanings as above. A compound represented by the formula:

Embedded image [Wherein, n, X and Y have the same meanings as above. And the like. R is preferably a hydrogen atom.

In the above formula, Y is an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic group (preferably a nitrogen-containing saturated heterocyclic group) [Y is preferably substituted or unsubstituted. Good amino group]. Examples of the “optionally substituted amino group” for Y include, for example, those represented by the formula:

Embedded image [Wherein, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted acyl group, and R ⁴ and R ⁵ combine to form a ring And the like may be used.

As the “substituent” and “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ⁴ and R ⁵ , for example, the “optionally substituted hydrocarbon group” described above for R ¹ “Substituent” and “hydrocarbon group” of “hydrocarbon group” are used. Preferred examples of the optionally substituted hydrocarbon group represented by R ⁴ and R ⁵ include:
For example, (i) a halogen atom (for example, fluoro, chloro, bromo, iodo, etc.), (ii) a lower alkoxy group (for example, methoxy, ethoxy, n-propyloxy,
C _1-6 such as i-propyloxy and n-butyloxy
(Iii) a linear or branched lower alkyl group which may have 1 to 3 substituents selected from (iii) a hydroxy group and the like (for example, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, te
C such as rt-butyl, sec-butyl, pentyl, hexyl, etc.
_{(I.e., a 1-6} alkyl group) or (i) a halogen atom (e.g., fluoro, chloro, bromo, iodo, etc.),
(Ii) a lower alkoxy group (for example, a C _1-6 alkoxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, etc.), (ii)
i) 1 to 3 substituents selected from a hydroxy group, etc.
Optionally, a lower aralkyl group (for example, phenyl-C _1-10 alkyl (for example, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, etc.), naphthyl-C
_1-6 alkyl (e.g., alpha-naphthylmethyl, etc.) or diphenyl _{-C 1-3} alkyl (e.g., diphenylmethyl, diphenyl ethyl) and the like _{C 7-16} aralkyl group such as.

More preferably, unsubstituted linear or branched lower alkyl groups (for example, C _1- such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl and the like) ₆
An unsubstituted lower aralkyl group (eg, phenyl-C _1-10 alkyl (eg, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, etc.)),
Examples thereof include a C _7-16 aralkyl group such as naphthyl-C _1-6 alkyl (for example, α-naphthylmethyl) or diphenyl-C _1-3 alkyl (for example, diphenylmethyl, diphenylethyl and the like). As the “optionally substituted acyl group” represented by R ⁴ and R ⁵ , for example, the “optionally substituted acyl group” described above for R ¹ and the like are used. In the “optionally substituted amino group” represented by Y, when R ⁴ and R ⁵ combine to form a ring, ie, the “optionally substituted amino group” represented by Y is Specific examples of the “optionally substituted cyclic amino group” include those represented by the formula:

Embedded image [Wherein the ring Q ^{1 is a} 5- to 9-membered nitrogen-containing ring which may contain, in addition to the carbon atom and one nitrogen atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. A heterocyclic group (preferably a nitrogen-containing saturated heterocyclic group)]. More specifically, for example,

Embedded image Are frequently used. The “substituent” of the “optionally substituted cyclic amino group” as the “optionally substituted amino group” represented by Y includes, for example, R ^2b and R
"Substituent" of "nitrogen-containing heterocycle optionally having substituent (s)" which ^3b may form together with an adjacent nitrogen atom,
Represented by R ¹ 'which may be substituted hydrocarbon group, an optionally substituted acyl group or an optionally substituted heterocyclic group "and the like are used. The “optionally substituted amino group” represented by Y includes (1)
formula:

Embedded image [In the formula, R ² represents a hydrogen atom, an optionally substituted acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and p represents an integer of 1 to 3. ,
R ′ and R ″ each represent a hydrogen atom or an optionally substituted alkyl group, and R ′ and R ″ may be bonded to form a ring]; ) An optionally substituted piperidino group; and the like, and among others, a formula (1a):

Embedded image [In the formula, R ² represents a hydrogen atom, an optionally substituted acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ′ and R ″ each represent a hydrogen atom Which represents an atom or an optionally substituted alkyl group]; (1b) a formula:

Embedded image Wherein R ² represents a hydrogen atom, an optionally substituted acyl group, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; and the like; Used. Here, the "optionally substituted acyl group" represented by R ^2, the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group" in R ¹ described above Examples include the same as the above-mentioned "optionally substituted acyl group", "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group". As the “alkyl group” in the “optionally substituted alkyl group” for R ′ and R ″,
_1-6 such as an alkyl group. Examples of the "substituent" of the "alkyl group", those similar to the "substituent" of the "optionally substituted hydrocarbon group" represented by R ¹ described above Is mentioned. When R ′ and R ″ are bonded to each other to form a ring, in the “nitrogen-containing heterocyclic group” exemplified as the aforementioned ring Q ¹ , a nitrogen atom other than a carbon atom and two nitrogen atoms And a 5- to 9-membered nitrogen-containing heterocyclic group (preferably nitrogen-containing saturated heterocyclic group) which may contain one heteroatom selected from an oxygen atom and a sulfur atom. The ring is preferably a 5- to 9-membered nitrogen-containing heterocyclic ring (preferably nitrogen-containing saturated heterocyclic ring) composed of a carbon atom and two nitrogen atoms,
These rings may further have a Q ¹ ring similar substituents as defined above. The optionally substituted piperidino group as Y is the “optionally substituted acyl group”, the “optionally substituted hydrocarbon group” or the “optionally substituted hydrocarbon group” for R ¹ described above. A heterocyclic group "or the like as a substituent.

The “nitrogen-containing heterocyclic group” of the “optionally substituted nitrogen-containing heterocyclic group” represented by Y includes, in addition to a carbon atom and one nitrogen atom, for example, a nitrogen atom, an oxygen atom and a sulfur atom. A 5- to 9-membered nitrogen-containing heterocyclic group (preferably a nitrogen-containing saturated heterocyclic group) which may contain 1 to 3 heteroatoms such as atoms is used. These nitrogen-containing heterocyclic groups may be groups having a bond at a ring-forming nitrogen atom or groups having a bond at a ring-forming carbon atom. As the group having a bond at the ring-constituting nitrogen atom, for example, a group represented by the formula:

Embedded image [Wherein the ring Q ^{1 is a} 5- to 9-membered nitrogen-containing ring which may contain, in addition to the carbon atom and one nitrogen atom, one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. A heterocyclic group (preferably a nitrogen-containing saturated heterocyclic group)]. More specifically, for example,

Embedded image Are frequently used.

Examples of the group having a bond at a ring-constituting carbon atom include, for example, those represented by the formula:

Embedded image [Wherein the ring Q ^{2 is a} 5- to 9-membered nitrogen-containing ring which may contain, in addition to the carbon atom and one nitrogen atom, one or two heteroatoms selected from nitrogen, oxygen and sulfur, etc. A heterocyclic group (preferably a nitrogen-containing saturated heterocyclic group)]. More specifically, for example,

Embedded image Are frequently used.

The “substituent” of the “optionally substituted nitrogen-containing heterocyclic group (preferably nitrogen-containing saturated heterocyclic group)” represented by Y is, for example, a nitrogen atom in which the above R ^2b and R ^3b are adjacent to each other. A "substituent" of the "nitrogen-containing heterocyclic ring optionally having substituent (s)" which may be formed together with the "optionally substituted hydrocarbon group represented by R ¹ , And an optionally substituted heterocyclic group or the like. A “optionally substituted cyclic amino group” as the “optionally substituted amino group” represented by Y; and a “optionally substituted nitrogen-containing heterocyclic group” represented by Y When it has two or more substituents, the substituents may be bonded to each other to form a ring. Specific examples of such a ring include a benzene ring,
To an 8-membered (preferably 5 to 6-membered) aromatic monocyclic heterocycle (e.g., pyrrole, oxazole, isoxazole,
Thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2 , 4-thiadiazole, 1,3,4-
Thiadiazole, 1,2,3-triazole, 1,2,4-
Triazole, tetrazole, pyridine, pyridazine,
Pyrimidine, pyrazine, triazine, etc.), and rings in which some or all of the unsaturated bonds in these rings have been converted to saturated bonds. Further, the “optionally substituted cyclic amino group” as the “optionally substituted amino group” represented by Y; and the “optionally substituted nitrogen-containing heterocyclic group” represented by Y When two or more substituents are present on one carbon atom, the substituents may be bonded to each other to form a spiro ring. Specific examples of the case of forming such a spiro ring include, for example, spiro ( 1H-
Indene-1,4'-piperidinyl) ring and the like.

The “nitrogen-containing heterocyclic group” of the “optionally substituted nitrogen-containing heterocyclic group” represented by Y is preferably a 4-piperidinyl group, a 1-piperidinyl group or a 1-piperidinyl group.
-Piperazinyl group and the like. That is, for Y, the formula:

Embedded image [Wherein, R ⁶ has the same meaning as R ¹ ]. More preferably as Y, for example, the formula:

Embedded image Wherein R ⁶ is (i) C _1-6 alkyl, C _1-6 alkoxy, a halogen atom, nitro, mono- or di-C
_6alkyl - carbamoyloxy, hydroxy, cyano, _{carboxyl, C 1-6} alkoxycarbonyl,
Carbamoyl, cyclic aminocarbonyl, amino, C
_1-6 alkylcarbonylamino, phenyl _{sulfonylamino, C 1-6} alkylsulfonylamino, amidino, ureido or heterocyclic ring optionally substituted phenyl _{-C 1-6} alkyl (said _{C 1-6} alkyl and _{C 1- The 6} alkoxy, carbamoyl, cyclic aminocarbonyl, amino, phenylsulfonylamino, amidino, ureido, and heterocyclic ring may further have a substituent. Examples of the “substituent” include “substituted” represented by R ¹ it is optionally may hydrocarbon group "of the" such substituent "is used), (ii) a hydrogen atom, (iii) a halogen atom, hydroxy, C _1-6 alkoxy, amino, mono - or di -C _{1- 6} alkylamino, carboxyl, cyano or _{C 1-6} alkoxy - a _{C 1-6} alkyl optionally substituted by a carbonyl Or (iv) mono or di
-C _1-6 alkylamino or _{C 1-6} alkoxy - a substituted which do be a _{C 1-6} alkylcarbonyl group with a carbonyl, _{preferably, C 1-4} alkyl (such as methyl), trihalogeno _{C 1-4} Alkyl (eg, methyl), halogen atom (eg, fluoro, chloro), nitro, cyano, C _1-4 alkoxy (eg, methoxy), hydroxy, carbamoyl, (4-C _1-4 alkyl (eg, methyl) -1-piperazinyl) Carbonyl, aminothiocarbonyl, morpholinocarbonyl, carboxyl, C
_1-4 alkoxy (such as methoxy) carbonyl, C
_1-4 alkoxy (such as ethoxy) carbonyl C _1-4
Alkoxy (such as methoxy), carboxyl C _1-4 alkoxy (such as methoxy), C _1-4 alkoxy (such as ethoxy) carbonyl C _1-6 alkyl (such as isopropyl), carboxyl C _1-6 alkyl (such as isopropyl), amino, Acetylamino, _C1-4alkyl (methyl etc.) sulfonylamino, (4- _C1-4alkyl (methyl) phenyl) sulfonylamino, ureido, 3- _C1-4alkyl (methyl etc.) ureido, amidino, dihydro A benzyl group which may be substituted with thiazolyl or dihydroimidazolyl], wherein R ⁶ is C _1-4 alkyl (methyl or the like), trihalogeno (fluoro or the like)
_A benzyl group which may be substituted by _1-4 alkyl (such as methyl), a halogen atom (such as fluoro or chloro), nitro, hydroxy, carbamoyl, amino, amidino, or dihydroimidazolyl is preferable. As Y, in particular, a 1-benzyl-4-piperidinyl group, a 4-benzyl-1-piperidinyl group or a 4-benzyl-1-
Piperazinyl group, 1-acetyl-4-piperidinyl group,
1-[(2-methylphenyl) methyl] -4-piperidinyl group, 1-[(3-chlorophenyl) methyl] -4-
Piperidinyl group, 1-[(2-chlorophenyl) methyl] -4-piperidinyl group, 1-[(3-nitrophenyl) methyl] -4-piperidinyl group, 1-[[3- (trifluoromethyl) phenyl] methyl 4-piperidinyl group and the like are preferable, and 1-benzyl-4-piperidinyl group, 1-acetyl-4-piperidinyl group, 1-
[(2-methylphenyl) methyl] -4-piperidinyl group, 1-[(3-chlorophenyl) methyl] -4-piperidinyl group, 1-[(2-chlorophenyl) methyl]-
A 4-piperidinyl group, 1-[(3-nitrophenyl) methyl] -4-piperidinyl group, 1-[[3- (trifluoromethyl) phenyl] methyl] -4-piperidinyl group and the like are widely used.

In the above formula, a “straight-chain portion represented by X”
The spacer having 1 to 4 atoms to be used is (1)-
(CH_Two)_q1-(Q1 represents an integer of 1 to 4), (2)-(C
H_Two)_r1−X¹− (CH_Two)_r2-(R1 and r2 are the same or different
Represents an integer of 0 to 3. However, the sum of r1 and r2 is 1-3
is there. X¹Is NH, O, S, SO or SO_Two), (3)-(C
H_Two)_s1−X¹− (CH_Two)_s2−X^Two− (CH_Two)_s3-(S1, s2, and s3
Are the same or different and represent an integer of 0 to 2. Where s1,
The sum of s2 and s3 is 0-2. X¹And X^TwoAre each
NH, O, S, SO or SO_TwoIs shown. However, when s2 is 0, X
¹And X ^TwoAt least one preferably denotes NH. )
Saturated divalent groups and some bonds become unsaturated bonds
A converted divalent group or the like; or -CO-, -O
-, -NR^3ba-, -S-, -SO-, -SO₂−,
-SO₂NR^3ba-, -SO₂NHCONR
^3ba-, -SO₂NHC (= NH) NR^3ba−, −
CS-, -CR^3ba(R^3bb)-, -C (= CR
^3ba(R^3bb))-, -C (= NR^3ba)-,-
CONR^3ba− (Where R^3baAnd R^3bbIs
Each independently represents a hydrogen atom, a cyano group,
Group, amino group, C_1-6Alkyl group or C_1-6Al
Shows a coxy group. ), Etc.
Examples thereof include a divalent group having 1 to 4 divalent groups. As X
Is -CO-, -O-, -NR^3ba-, -S-, -S
O-, -SO ₂-, -SO₂NR^3ba-, -SO₂N
HCONR^3ba-, -SO₂NHC (= NH) NR
^3ba-, -CS-, -CR^3ba(R^3bb)-,-
C (= CR^3ba(R^3bb))-, -C (= NR
^3ba)-, -CONR^3ba− (Where R^3baYou
And R^3bbAre each independently a hydrogen atom, a cyano
Group, hydroxy group, amino group, C_1-6Alkyl group
Is C_1-6Shows an alkoxy group. ) Is more preferred
Especially, -CO-, -O-, -SO₂-, -SO
₂NR^3ba-, -CR^3ba(R^3bb)-, -CO
NR^3ba-And the like are preferable, and especially -SO₂NR
^3ba-, -CONR^3ba-, -CR^3ba(R^3
bb)-And the like are preferably used. Divalent represented by X
Is a substituent at any position (preferably on a carbon atom)
May be included as such a substituent, for example,
Low grade (C_1-6) Alkyl (eg, methyl, ethyl, pro
Pill, isopropyl, butyl, isobutyl, sec-butyl
Chill, tert-butyl, pentyl, isopentyl, ne
Pentyl, hexyl, etc.), low grade (C_3-7) Cyclo
Alkyl (eg, cyclopropyl, cyclobutyl, cyclo
Pentyl, cyclohexyl, cycloheptyl, etc.), e
Lumil, low grade (C_2-7) Alkanoyl (eg, acetyl
, Propionyl, butyryl, etc.), lower (C_1-6)
Alkoxy-carbonyl, lower (C_1-6) Alkoki
And hydroxy, oxo and the like.

Among the compounds represented by the formula (Ib) or salts thereof, the compounds represented by the formula (IIb):

Embedded image [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group which may be substituted, ring A represents a benzene ring which may further have a substituent,
X represents a spacer having 1 to 4 atoms constituting the straight-chain portion, n represents an integer of 1 to 10, R represents a hydrogen atom or a hydrocarbon group which may be substituted, In the repetition, they may be the same or different, R may be bonded to ring A or a substituent of ring A to form a ring, and Y may be an optionally substituted amino group or a substituted And a nitrogen-containing heterocyclic group. Or a salt thereof is preferably used.

The compounds represented by formulas (Ib) and (IIb) or salts thereof can be produced, for example, by the following synthesis methods. Also, Japanese Patent Application Laid-Open No.
6, JP-A-11-310532, EP-A-48707
1, EP-A-560235, WO98 / 46590,
It can also be produced by a method described in WO 00/23437 or a method analogous thereto. Formulas (Ib) and (Ib)
When the compound represented by Ib) and the compound (raw material compound or synthetic intermediate) in each step in its production are free forms, they can be converted into salts according to a conventional method. It can be converted to a free form or another salt according to the method. Formulas (Ib) and (II)
The compound represented by b) and each starting compound or synthetic intermediate may be an optical isomer, a stereoisomer, a positional isomer or a rotamer, or a mixture thereof,
These are also included in the compounds represented by the formulas (Ib) and (IIb) and the starting compounds or synthetic intermediates of the present invention. For example, compound (Ib) may be a racemate or an optical isomer separated from the racemate. These can be isolated and purified according to a separation method known per se. The optical isomer can be produced according to a method known per se. Specifically, an optical isomer can be produced by using an optically active starting compound or a synthetic intermediate, or by optically resolving a racemic form of the final compound according to a conventional method. As the optical resolution method, a method known per se, for example, a fractional recrystallization method, an optically active column method, a diastereomer method and the like can be applied. Stereoisomers, positional isomers, and rotamers can also be produced by applying a method known per se.

The following reactions can be carried out without using a solvent or, if necessary, using an appropriate solvent. As the solvent, any solvent that can be generally used for a chemical reaction can be used as long as the reaction is not hindered. For example, hydrocarbon solvents (eg, hexane, toluene, etc.), ether solvents (eg, , Ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane), amide solvents (eg, formamide, N, N-
Dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, etc.), urea-based solvents (eg, 1,3-dimethyl-2-imidazolidinone), sulfoxide-based solvents (eg, dimethylsulfoxide), An alcohol solvent (eg, methanol, ethanol, isopropanol, t-butanol, etc.), a nitrile solvent (eg, acetonitrile, propionitrile, etc.), an organic solvent such as pyridine, or water is used. The amount of the solvent to be used is generally about 0.5 ml to about 100 ml, preferably about 3 ml to about 30 ml, per 1 mmol of compound. The reaction temperature varies depending on the type of the solvent used, but is usually about -30 ° C to about 180 ° C.
And preferably about 0 ° C to about 120 ° C. The reaction time varies depending on the reaction temperature, but is usually about 0.5 hour to about 72 hours, preferably about 1 hour to about 24 hours. The reaction is usually carried out at normal pressure,
If necessary, the reaction may be performed under a pressurized condition of about 1 atm to about 100 atm.

The compound obtained in each of the following steps can be obtained by a known method, for example, concentration, liquid conversion, phase transfer, solvent extraction, fractionation,
It is isolated and purified by distillation, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc., and used as a raw material for the next reaction, but is used as a raw material in the reaction mixture without isolation or purification. You may. In the following description, the “condensation reaction” can be performed in the presence of a base, if necessary. Examples of the base include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, sodium methoxide, potassium t-butoxide, and pyridine; Lutidine,
Organic bases such as collidine and triethylamine are used. The amount of the base to be used is generally equimolar to excess, preferably about 1 molar equivalent to about 5 molar equivalents, relative to the compound. Further, this reaction may be promoted in the presence of a catalytic amount of an iodide compound such as sodium iodide, potassium iodide, 4-dimethylaminopyridine or the like, if necessary.

In the compound (IIb), -X- is -O-
The compound (IIba) or a salt thereof can be produced by the following reaction formula 1-1. Reaction formula 1-1

Embedded image In the step (aa), a compound represented by the formula (IIIba) (wherein each symbol has the same meaning as described above) (hereinafter sometimes abbreviated as compound (IIIba)) and a compound represented by the formula (IVba) [formula Wherein Z ¹ represents a leaving group, and other symbols have the same meanings as described above.] (Hereinafter sometimes abbreviated as compound (IVba)) to give compound (IIba) Can be manufactured. The leaving group represented by Z ¹ includes:
For example, a halogen atom (eg, chloro, bromo, iodo, etc.), a C _1-6 alkylsulfonyloxy group (eg,
For example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, and the like, a C _6-10 arylsulfonyloxy group (for example, benzenesulfonyloxy, p-toluenesulfonyloxy, and the like) are used. In particular, for example, a halogen atom (eg, bromo, iodine, etc.) is preferably used. In the condensation reaction between the compound (IIIba) and the compound (IVba), as the solvent, for example, an alcohol solvent such as ethanol or a nitrile solvent such as acetonitrile is preferably used. The reaction temperature depends on the type of the solvent used, but is preferably about 0
C. to about 120.degree. The reaction time varies depending on the reaction temperature, but is preferably about 1 hour to about 24 hours. As the base, for example, sodium carbonate, potassium carbonate, triethylamine and the like are preferably used. The amount of the base to be used is about 1 to compound (IVba).
Equivalents to about 3 equivalents are preferred. Further, if necessary, a catalytic amount of the iodide compound (eg, sodium iodide, potassium iodide, etc.) or 4-
This reaction may be promoted in the presence of dimethylaminopyridine or the like. Specifically, in a solvent such as N, N-dimethylformamide, for example, potassium carbonate,
It can be performed in the presence of sodium hydride or the like. The amount of the base to be used is preferably about 1 equivalent to about 3 equivalents relative to compound (IVba). Compound (IVba) can be produced by a method known per se or a method analogous thereto. In addition, the starting compound (II) in step (aa)
Iba) or a salt thereof is described, for example, in WO 00/23437.
Can be produced according to the method described in (1).

In the compound (IIb), -X- is -NR
^3ba -, compound (IIbb) or a salt thereof can be prepared by the reaction equation 2-1 below. Reaction formula 2-1

Embedded image In the step (ba), condensation of a compound represented by the formula (IIIbb) (wherein each symbol has the same meaning as described above) (hereinafter may be abbreviated as the compound (IIIbb)) and the compound (IVba) By the reaction, compound (IIbb) can be produced. The condensation reaction between compound (IIIbb) and compound (IVba)
For example, the reaction can be performed in a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate or sodium hydride. The amount of the base to be used is preferably about 1 equivalent to about 3 equivalents relative to compound (IVba). The starting compound (IIIbb) or a salt thereof in the step (ba) can be produced by the following reaction formula 2-2. That is, step (bb): a nitration reaction of a compound represented by the formula (Vbb) (wherein each symbol has the same meaning as described above) (hereinafter sometimes abbreviated as compound (Vbb)), (Bc): a reduction reaction of a compound represented by the formula (VIbb) [wherein each symbol has the same meaning as described above] (hereinafter, sometimes abbreviated as compound (VIbb)), and step (bd) A compound represented by the formula (VIIbb) wherein each symbol is as defined above (hereinafter, compound (VIIbb)
) And a compound represented by the formula (IXbb) (wherein each symbol has the same meaning as described above) (hereinafter sometimes abbreviated as compound (IXbb)): The compound (IIIbb) can be produced by performing the steps sequentially.

Reaction formula 2-2

Embedded image The compound (VIbb) can be produced by nitrating the compound (Vbb) in the step (bb). This reaction is performed using an appropriate nitrating reagent (for example, nitric acid, nitric acid-sulfuric acid, nitronium trifluoroborate, etc.)
Known methods (eg, Synthesis, 217-238)
(1977), Chemistry of the Nitro and
Nitroso Groups (Chemistry of the Nitro and Nitr
oso Groups), p.1-48 Wiley (1970), etc.)
Alternatively, it can be performed by a method corresponding thereto. Compound (Vbb) can be produced by a method known per se or a method analogous thereto. For example, Journal of the Organic Chemistry (J.Org. Chem.),
34, 2235 (1969), Journal of the Organic Chemistry (J. Org. Chem.), 54,
5574 (1989), Tetrahedron Letters (Tetr
ahedron Lett.), 35, 3023 (1977), Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.), 56, 2300 (19)
83), Indian Journal of Chemistry (Indian. J. Chem.), 2, 211 (1964), Indian Journal of Chemistry (Indian. J. Che.)
m.), 12, 247 (1974), Bulletin of the Chemical Society of Japan (Bull. Chem. So
c., Jpn.), 43, 1824 (1970), Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.), 20,
1328 (1972), Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.), 27, 1982 (1979),
Helvetica Himika Acta (Helv. Chem. Acta), 4
6, 1696 (1963), Synthesis, 541 (197)
9), US 3,682,962, US 3,911,126., Ger. Offen.
2,314,392, Ger.1,545,805, Journal of Chemical Society (J. Chem. Soc.), 1381 (194
9), Canadian Journal of Chemistry (Can. J. Chem.), 42, 2904 (1964), Journal of Organic Chemistry (J. Org. Chem.), 2
8, 3058 (1963), Journal of American Chemical Society (J. Am. Chem. Soc.), 76, 319
4 (1954), 87, 1397 (1965), 88, 4061 (1966),
It can be produced according to the method described in 9-41539 or the like or a method analogous thereto.

In the step (bc), the compound (VIIbb) can be produced by a reduction reaction of the compound (VIbb). This reaction can be performed using an appropriate reduction reaction (for example, a catalytic reduction reaction using a transition metal catalyst, a reduction reaction using a metal such as tin in an acidic solvent, and the like). Specifically, known methods, for example, organic synthesis (O
rganic Synthesis), Coll. Vol. 5, 829-833 (1973),
Organic Synthesis, Coll.
Vol. 1, 455 (1941), Journal of the American Chemical Society (J. Am. Chem. Soc.),
66, 1781 (1944) or a method analogous thereto.

In the step (bd), the compound (VIIbb)
And the compound (IIIbb) by a condensation reaction of the compound (IIIbb)
b) can be manufactured. The condensation reaction between compound (VIIbb) and compound (IXbb) can be performed, for example, in the same manner as the condensation reaction between compound (IIIba) and compound (IVba). Further, the compound (IIIbb) can be obtained by using the compound (VIIbb) as a starting material, for example, by a reductive alkylation method (eg, Journal of the American Chemical Society (J. Am. Chem. Soc.), 87, 2767 (1965)). , Organic Synthesis, Coll. Vol.
4, 283-285 (1963)) or a method by Michael addition reaction (for example, Helvetica Himika Acta (Helv. Chem. Acta), 43, 1898 (1960), Journal of Organic Chemistry (J. Org. Chem.)
, 39, 2044 (1974); Synthesis, 5, 375
(1981)) or a method analogous thereto.

In the compound (IIb), -X- is -NR
Compound (IIbc) which is ^3ba CO— or a salt thereof can be produced according to the following reaction formula 3. Reaction formula 3

Embedded image In the step (ca), the compound (IIIbb) and the compound of the formula (IVbc)
[Wherein Z ² represents a leaving group, and other symbols have the same meanings as described above] (hereinafter sometimes abbreviated as compound (IVbc)). II
bc) can be manufactured. As the leaving group for Z ² , for example, a halogen atom (for example, chloro, bromo,
Iodine), a C _1-6 alkyloxy group (eg, methoxy, ethoxy, benzyloxy), a C _6-10 aryloxy group (eg, phenoxy, p-nitrophenoxy), a hydroxyl group, and the like. Particularly, for example, a halogen atom (for example, chloro or the like), a hydroxyl group or the like is preferably used. Compound (IIIbb) and Compound (IVb
The amidation reaction of c) can also be performed using a suitable condensing agent or base. For example, if Z ² is a hydroxyl group, a suitable condensing agent, condensing agent commonly used in the field of for example peptide chemistry, in particular, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) such carbodiimide The amidation reaction can be carried out using phosphodines such as carbodiimides, diphenylphosphoryl azide and diethyl cyanophosphonate, and phosgene equivalents such as 1-1′-carbonylbis-1H-imidazole. The amount of the condensing agent used is the same as that of the compound (IIIb
b) about 1 equivalent to about 5 equivalents per 1 mmol,
Preferably about 1 to about 1.5 equivalents. Also,
For example, if Z ² is a halogen atom, a suitable base, such as sodium carbonate, potassium carbonate, with triethylamine or the like, preferably to carry out the reaction. The amount of the base to be used is generally about 1 equivalent to about 1 equivalent relative to compound (IIIbb).
0 equivalent, preferably about 1 equivalent to about 2 equivalents.

In the compound (IIb), -X- is -S-,
Compound (IIbd), which is —SO— or —SO ₂ —, or a salt thereof can be produced by the following reaction formula 4-1. Reaction formula 4-1

Embedded image In step (da), compound (IIIbd) and compound (IVb
Compound (IIbd) can be produced by carrying out the condensation reaction of a) and, if necessary, subsequently carrying out the oxidation reaction. [Wherein, ^Xd represents -S-, -SO- or -S
O ₂ — and other symbols are as defined above.] The condensation reaction between compound (IIIbd) and compound (IVba) is, for example, N,
The reaction can be carried out in a solvent such as N-dimethylformamide in the presence of a base such as potassium carbonate, sodium hydride or the like. The amount of the base used may be a compound (IVb
About 1 equivalent to about 3 equivalents to a) are preferred. X
^The compound (IIbd) in which ^d is -S- is optionally subjected to an oxidation reaction, whereby ^Xd is -SO- or -SO-
_2- (Compound (IIbd)). As the oxidizing agent, any one can be used as long as it is used as an oxidizing agent for sulfide.
For example, metachloroperbenzoic acid, peracetic acid, hydrogen peroxide, alkali metal periodate and the like are used. Particularly preferably, metachloroperbenzoic acid, hydrogen peroxide and the like are used. The amount of the oxidizing agent to be used is, in the case of oxidation of S to SO, about 1 equivalent to about 1.1 equivalents relative to compound (IIbd).
Equivalents are particularly preferred. In the case of oxidizing S to SO ₂ , about 2 equivalents to 2.5 equivalents is particularly preferred based on compound (IVbd). As a solvent for this reaction, for example, dichloromethane, chloroform, acetic acid, ethyl acetate and the like are preferable. The starting compound (IIIbd) or a salt thereof in the step (da) can be produced by the following reaction formula 4-2.
That is, step (db): chlorosulfonylation reaction of compound (Vbb), and step (dc): formula (VIbd) wherein each symbol has the same meaning as described above. (Hereinafter sometimes abbreviated as compound (VIbd)) by the reduction reaction of the compound (II
Ibd) can be manufactured.

Reaction formula 4-2

Embedded image In the step (db), the compound (VIbd) can be produced by subjecting the compound (Vbb) to chlorosulfonylation. Examples of the reagent for the chlorosulfonylation reaction include chlorosulfonic acid, sulfuryl chloride, sulfur dioxide
Copper chloride or the like can be used. Particularly, chlorosulfonic acid and the like are preferable. The amount of the chlorosulfonylating reagent to be used is about 1 equivalent to a large excess. This reaction can be performed without a solvent or using a solvent. As a solvent used in the case of using a solvent, for example, dichloromethane, 1,2-dichloroethane, carbon disulfide and the like are preferable. Reactions without solvent are particularly preferred. The reaction temperature is preferably from about -20C to about 100C. The chlorosulfonyl group is introduced into any of the reactable positions. For example, when the ring A is unsubstituted, the chlorosulfonyl group is mainly substituted at the 7-position. However, a compound having a chlorosulfonylation at the 6-position can also be formed and separated.

In the step (dc), the compound (IIIbd) can be produced by reducing the compound (VIbd). This reduction reaction can be performed under appropriate reduction conditions, for example, a combination of a metal and an acid such as zinc-acetic acid, tin-hydrochloric acid, a catalytic reduction reaction using a transition metal catalyst, or a metal hydride such as lithium aluminum hydride. . Particularly preferred is a reduction reaction using zinc-acetic acid. Among the compounds (IIb), -X- is _-SO 2 NR ^3ba -, Compound (IIbe) or a salt thereof can be prepared by the reaction equation 5 below. Reaction formula 5

Embedded image In the step (ea), condensation of the compound (VIbd) with a compound represented by the formula (IVbe) (wherein each symbol has the same meaning as described above) (hereinafter, sometimes abbreviated as compound (IVbe)) Compound (IIbe) can be produced by the reaction. The condensation reaction between the compound (VIbd) and the compound (IVbe) can be performed, for example, in the same manner as the amidation reaction between the compound (IIIbb) and the compound (IVbc). Compound (IVbe) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, Journal of the Medicinal Chemistry (J. Med. Chem.),
33, 1880 (1990) and the like, or by a method analogous thereto.

In the compound (IIb), -X- is -SO ₂
NHCONR ^3ba - Compound (IIbf) or a salt thereof can be prepared by the reaction equation 6 below. Reaction formula 6

Embedded image In the step (fa), the compound (VIbd) is reacted with an alkali metal isocyanate (MOCN; M represents an alkali metal) and then reacted with the compound (IVbe) to give the compound (IIbf). Can be manufactured.
This reaction can be produced, for example, by the method described in European Patent (EP-759431), JP-A-7-118267, or the like or a method analogous thereto. The reaction between the compound (VIbd) and the alkali metal isocyanate is performed in the presence of a base, if necessary. As the base used, in particular, pyridine,
Triethylamine and the like are preferred. The amount of the base to be used is preferably about 1 equivalent to about 5 equivalents relative to compound (VIbd). Acetonitrile and the like are particularly preferably used as the reaction solvent. As the alkali metal, for example, potassium or the like is preferably used.

In the compound (IIb), -X- is -SO ₂
The compound (IIbg) or a salt thereof which is NHC (= NH) NR ^3ba- can be produced by the following reaction formula 7. Reaction formula 7

Embedded image In the step (ga), condensation of the compound (VIbd) with a compound represented by the formula (IVbg) [wherein each symbol has the same meaning as described above] (hereinafter, sometimes abbreviated as compound (IVbg)) Compound (IIbg) can be produced by the reaction. The condensation reaction between the compound (VIbd) and the compound (IVbg) can be performed, for example, in the same manner as the amidation reaction between the compound (IIIbb) and the compound (IVbc). Compound (IVbg) can be produced using compound (IVbe) by a method known per se or a method analogous thereto. For example, compound (IVbe)
(For example, the method described in Journal of the Organic Chemistry (J. Org. Chem.) 13, 924 (1948), etc.),
Method of reacting cyanamide (for example, Helvetica Chem. Acta), 29, 324 (1946)
And 1,3-bis (t-butoxycarbonyl) -2-methyl-2-thiopsoidurea
(1,3-Bis (tert-butoxycarbonyl) -2-methyl-2-thiopseud
ourea) (eg tetrahedron
Letters (Tetrahedron Lett.), 33, 6541-6542 (199
2), the compound (IVbg) can be produced by the method described in Journal of Organic Chemistry (J. Org. Chem.), 52, 1700-1703 (1987) and the like.

In the compound (IIb), -X- is -CR
Compound (IIbh) or a salt thereof, which is ^3ba (R ^3bb )-, can be produced according to the following reaction formula 8. Reaction formula 8

Embedded image In the step (ha), a compound represented by the formula (IIIbh): wherein each symbol is as defined above. (Hereinafter sometimes abbreviated as compound (IIIbh)) with an appropriate reagent to convert the carbonyl group to produce compound (IIbh). Examples of the reagent used for the conversion reaction of the carbonyl group include, for example, reducing agents such as sodium borohydride, lithium aluminum hydride, and triethylsilane; organometallic reagents such as alkyllithium and alkylmagnesium halide; and others, such as hydrogen cyanide Are used. Specifically, -CH carbonyl group (OH) - or -CH 2 _- Conversion to, for example using sodium borohydride, lithium aluminum hydride, a reducing agent such as triethylsilane, suitable reducing conditions (For example, a combination of triethylsilane-trifluoroacetic acid, lithium aluminum hydride-aluminum chloride, zinc-hydrochloric acid, etc.). This reaction is performed, for example, with reduction with
Complex Metal Hydridos (Reduction wit
h Complex Metal Hydrides) Interscience, New Yor
k (1956), Chemical Society Reviews (C
hem. Soc. Rev.), 5, 23 (1976), Synthesis (Synthesi
s), 633 (1974), Journal of the American Chemical Society (J. Am. Chem. Soc.) 91,
2967 (1969), Journal of Organic Chemistry (J. Org. Chem.), 29, 121 (1964), Organic Reactions (Org. Reactions), 1, 155 (194)
2), Angew. Chem., 71, 726 (1
956), Synthesis, 633 (1974), Journal of the American Chemical Society
(J. Am. Chem. Soc.), 80, 2896 (1958), Organic Reactions (Org. Reactions), 4, 378 (1948),
The method can be carried out by a method described in Journal of the American Chemical Society (J. Am. Chem. Soc.), 108, 3385 (1986) or a method analogous thereto.
The ^{conversion of} the carbonyl group to —CR ^3bc (OH) — (where R ^3bc represents a C _1-6 alkyl group) is performed by using an organometallic reagent such as alkyllithium and alkylmagnesium halide. For example, Grignard Reactions of Nonmetallic Substances, P
rentice-Hall: Englewood Cliffs, NJ, 1954, pp. 138-
528, Organolithium Meths
ods), Academic Press: New York, 1988, pp. 67-75 and the like, or a method analogous thereto. Also, besides, Advanced Organic Chemistry, 5th ed. W
The conversion of the carbonyl group can be performed by a method described in iley-Interscience: New York, 1992, pp. 879-981 or the like, or the like. Compound (IIIbh) can be obtained by a method known per se or a method analogous thereto, for example, JP-A-5-1401
49, JP-A-6-206875, Journal of Medicinal Chemistry (J. Med. Chem.), 37, 2292
(1994) or the like, or a method analogous thereto.

In the compound (IIb), -X- is -C (=
Compound (IIbi) or a salt thereof, which is CR ^3ba (R ^3bb )) —, can be produced according to the following reaction formula 9. Reaction formula 9

Embedded image In the step (ia), the compound (IIb) can be produced by reacting the compound (IIIbh) with an appropriate reagent to convert the carbonyl group. Examples of the carbonyl group conversion reaction include, for example, a Wittig reaction,
Horner-Wadsworth-Em
mons) reaction, Peterson olefination reaction, Knoevenagel reaction, and the like, and common reagents used in these reactions are used as reagents. This reaction is performed, for example, by using Advanced Organic Chemistr
y), 5th ed. Wiley-Interscience: New York, 1992, p
p. 879-981, Organic Synth
esis), coll. vol. 5, 751 (1973), Organic Synthesis, coll. vol. 5, 509 (1973)
3), Synthesis, 384 (1984), Organic Reactions (Org. Reactions), 15, 204 (1967)
And the like, or a method similar thereto.

In the compound (IIb), -X- is -C (=
The compound (IIbj) or a salt thereof, which is NR ^3ba ) —
It can be produced by the following reaction formula 10. Reaction formula 10

Embedded image In step (ja), compound (IIbj) can be produced by reacting compound (IIIbh) with an appropriate reagent to convert the carbonyl group. Examples of the reagent used for the carbonyl group conversion reaction include hydrazine which may be substituted, hydroxylamine which may be substituted, and the like. As the substituent, C
_{A 1-6} alkyl group or the like is used. The reaction is, for example,
Advanced Organic Chemistry
Organic Chemistry), 5th ed.Wiley-Interscience: N
ew York, 1992, pp. 904-907, Organic Functional Group Preparations (OrganicFunc
National Group Preparations), vol. III, Academic (198
3), Rodd's Chemistry of Carbon Compounds, vo
l.1, part C, Elsevier Publishing co. (1965), etc., or a method based thereon.

In the compound (IIb), -X- is -CS-
The compound (IIbk) or a salt thereof is represented by the following reaction formula 1.
1 can be manufactured. Reaction formula 11

Embedded image In the step (ka), the compound (IIIbh) is reacted with an appropriate reagent to convert a carbonyl group into a thiocarbonyl group, whereby (IIbk) can be produced. Examples of the reagent used for converting a carbonyl group to a thiocarbonyl group include general sulfurizing reagents such as Lawesson's reagent, diphosphorus pentasulfide, and hydrogen sulfide-hydrochloric acid. This reaction is described in Synthesis, 7, 543 (199
1), Journal of the American Chemical Society (J. Am. Chem. Soc.), 106, 934 (1984),
It can be carried out by a method described in Journal of the American Chemical Society (J. Am. Chem. Soc.) 68, 769 (1946) or a method analogous thereto.

In the compound (IIb), -X- is -CON
The compound (IIbm) or a salt thereof represented by R ^3ba — can be produced by the following reaction formula 12-1. Reaction formula 12-1

Embedded image In the step (ma), condensation of the compound (IVbe) with a compound represented by the formula (IIIbm) (wherein the symbols have the same meanings as described above) (hereinafter, sometimes abbreviated as compound (IIIbm)) Compound (IIbm) can be produced by the reaction. The reaction between compound (IIIbm) and compound (IVbe) can be carried out, for example, in the same manner as in the amidation reaction between compound (IIIbb) and compound (IVbc). Further, the starting compound (IIIbm) in the step (ma) can be produced by the following reaction formula 12-2. That is, step (mb): Compound (Vb
Acetylation reaction of b), and step (mc): Formula (VIbm)
Wherein each symbol is as defined above. (Hereinafter, sometimes abbreviated as compound (VIbm)), and the functional group conversion as required, whereby compound (IIIbm) can be produced.

Reaction formula 12-2

Embedded image In the step (mb), the compound (VIbm) can be produced by acetylating the compound (Vbb).
This reaction is a general reaction of Friedel-Crafts.
fts) It can be carried out depending on the conditions of the reaction. As a reagent for acetylation, acetyl chloride, acetic anhydride and the like are used. Specifically, for example, it can be produced by a method described in JP-A-5-140149, JP-A-6-206875, Journal of Medicinal Chemistry (J. Med. Chem.), 37, 2292 (1994), or a method based thereon. Can be. By oxidizing the compound (VIbm) in the step (mc), a compound (IIIbm), particularly a compound in which Z ² is a hydroxyl group, can be produced. As the oxidizing agent used in this reaction, for example, hypochlorite, hypobromite, or a simple halogen (eg, bromine, iodine, etc.) in the presence of an appropriate base (eg, sodium hydroxide, etc.) ) And the like. This reaction is specifically performed, for example, in Organic Synthesis (Org. Synthesis), Coll.
2, 428 (1943), Journal of the American
Chemical Society (J. Am. Chem. Soc.), 66, 8
94 (1944), etc., or a method similar thereto. If necessary, the hydroxyl group of the compound (IIIbm) in which Z ² is a hydroxyl group is subjected to a functional group conversion, whereby Z ² is converted to a halogen atom (eg, chloro, bromo, iodo), a C _1-6 alkyloxy group. (E.g., methoxy, ethoxy, benzyloxy, etc.), or a _C6-10 aryloxy group (e.g., phenoxy, p
-Nitrophenoxy and the like). The method of functional group conversion is described in, for example, Advanced Organic Chemistry (Advanced Org
anic Chemistry), 5th ed. Wiley-Interscience: New Y
ork, 1992, pp. 393-396, 437-438, Comprehensive
Organic Transformations (Comprehe
nsive Organic Transformations), VCH Publishers I
nc. (1989) and the like, or a method similar thereto. The compound (II) thus obtained
b) is a known separation and purification means, for example, concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

GPR14 (SENR) obtained by the screening method or the screening kit of the present invention.
Compounds useful as antagonists include, for example, compounds of formula (Ic):

Embedded image[Wherein, R^1cIs a hydrogen atom or may be substituted
X represents a hydrocarbon group;^cIs the number of atoms constituting the straight chain part
Represents a spacer having 1 to 12;^1cAnd X ^cIs
May form a ring together,^cHas been replaced
Amino group or nitrogen-containing heterocyclic group which may be substituted
A ring group;^2cIs an optionally substituted hydrocarbon group
Or an amino group which may be substituted;^3cIs
A hydrocarbon group which may be substituted;^cRings and
C^cEach ring may be further substituted
Which shows a ring] or a salt thereof.
You.

In the above formula (Ic), the “optionally substituted benzene ring” represented by B ^c or C ^c is
Indicates that the benzene ring may further have a substituent other than the substituent specified in the formula (Ic), and such a substituent (a substituent other than the substituent specified in the formula (Ic)) Is, for example, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a nitro group,
A halogen atom, an optionally substituted amino group,
^6c -Y ^c - group (wherein represented by, ^{Y c} represents an oxygen atom or an optionally oxidized sulfur atom (e.g., S, S
(O), S (O) _{2 and the} like, and R ^6c represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), a cyano group, an optionally substituted acyl group And a carboxyl group which may be esterified or amidated.

In the “optionally substituted benzene ring” for B ^c or C ^c , “optionally substituted hydrocarbon group” as a substituent which the benzene ring may have, and R ^6c Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by (1) include (1) alkyl (for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
(2) cycloalkyl (for example, C _1-10 alkyl such as tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably lower (C _1-6 ) alkyl); , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-8 cycloalkyl such as cycloheptyl); and, the cycloalkyl is condensed with the benzene ring, indane (e.g., indan-1-yl, indan -2
-Yl), tetrahydronaphthalene (eg, tetrahydronaphthalen-5-yl, tetrahydronaphthalene-
(Preferably indane and the like); and the cycloalkyl is cross-linked via a linear atom chain having 1 to 2 carbon atoms to form a bicyclo [2. 2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl and the like (preferably having 1 to 2 carbon atoms)
(3) a cyclohexyl having a bridge through a linear atom chain, and more preferably a bicyclic [2.2.1] heptyl and the like). Alkenyl (eg, vinyl, allyl,
Crotyl, 2-pentenyl, 3-hexenyl alkenyl having 2 to 10 carbon atoms such as, preferably a lower _{(C 2 -6)}
(4) cycloalkenyl (for example, cycloalkenyl having 3 to 8 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl); (5) alkynyl (for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,
Alkynyl having 2 to 10 carbon atoms such as 3-hexynyl, preferably lower _{(C 2-6)} an alkynyl and the like); (6) aryl (e.g., phenyl, C, such as naphthyl
_6-14 aryl, preferably _{C 6-10} aryl, more preferably like phenyl); (7) aralkyl (e.g., _{C 1-6} alkyl having 1-3 _{C 6-14} aryl, preferably phenyl _{-C 1-4} alkyl (e.g., benzyl, phenethyl, etc.)
Among them, alkyl is preferable, C _1-4 alkyl such as methyl and ethyl is more preferable, and methyl is particularly preferably used.

The hydrocarbon group may have a substituent. Examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, oxo, hydroxyl, substituted and unsubstituted. Thiol group (eg,
Thiol, C _1-4 alkylthio, etc., optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine A 5- to 6-membered cyclic amino such as pyrrole, imidazole, etc.), phenyl-lower (C _1-4 ) alkyl,
C _3-7 cycloalkyl, a carboxyl group which may be esterified or amidated (eg, carboxyl, C
_1-4 alkoxy-carbonyl, lower (C _7-10 ) aralkyloxy-carbonyl, carbamoyl, mono-C
_1-4 alkylcarbamoyl, and _{di-C 1 -4} alkylcarbamoyl), optionally _{C 1-4} alkyl optionally substituted by halogen atom or _{C 1-4} alkoxy (e.g., trifluoromethyl, methyl, ethyl, etc.), halogen It may be substituted with atoms or _{C 1-4} alkoxy _{C 1
-4} alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, _{etc.), C 1-4} alkylenedioxy _{(e.g., -O-CH 2 -O -,} - O-C
H ₂ —CH ₂ —O—, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4
Alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C _1-4 alkylsulfinyl (eg,
Methanesulfinyl, ethanesulfinyl and the like), and the number of substituents is preferably 1 to 3.

[0179] B ^c or a benzene ring in the "optionally further substituted also benzene ring optionally" is as the substituent which may have the "optionally substituted heterocyclic group" represented by C ^c and R ^6c As the "heterocyclic group" in the "optionally substituted heterocyclic group" represented by, for example,
Containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from oxygen, sulfur and nitrogen Examples thereof include groups formed by removing one hydrogen atom from an 8-membered aromatic heterocycle, a saturated or unsaturated non-aromatic heterocycle (aliphatic heterocycle), and the like. Here, the “aromatic heterocycle” is a 5- to 8-membered (preferably 5- to 6-membered) aromatic monocyclic heterocycle (for example, furan, thiophene, pyrrole, oxazole, isoxazole,
Thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2 , 4-thiadiazole, 1,3,4-
Thiadiazole, 1,2,3-triazole, 1,2,4-
Triazole, tetrazole, pyridine, pyridazine,
Pyrimidine, pyrazine, triazine, etc.) and the like. 5-8 members (preferably 5-6 members) such as oxadiazine, thiazine, thiadiazine, piperidine, morpholine, thiomorpholine, tetrahydropyran, piperazine, pyran, oxepin, thiepin, azepine and the like.
Or a saturated or unsaturated monocyclic non-aromatic heterocycle (aliphatic heterocycle), or a 5- to 8-membered aromatic monocyclic heterocycle in which part or all of the double bonds are saturated. And the like.

In the “optionally substituted benzene ring” for B ^c or C ^c , an “optionally substituted heterocyclic group” as a substituent which the benzene ring may have, and As the “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^6c , the above-mentioned monocyclic heterocyclic ring (monocyclic aromatic heterocyclic ring and monocyclic non-aromatic heterocyclic ring) And a 5- to 8-membered cyclic hydrocarbon (C
_5-8 cycloalkane, C _5-8 cycloalkene, C
_{A 5-8} -membered (preferably 5-6-membered) saturated or unsaturated alicyclic hydrocarbon such as _5-8 cycloalkadiene; a 6-membered aromatic hydrocarbon such as benzene;
And a group formed by removing one hydrogen atom from a condensed ring formed by condensing two to three (preferably two) rings, and these condensed rings may be a saturated condensed ring, Any of a condensed ring having an unsaturated bond and an aromatic condensed ring may be used. Preferred examples of such a condensed ring include two identical or different heterocycles (preferably, one heterocycle and one heterocycle).
Aromatic heterocycles, more preferably two identical or different aromatic heterocycles) condensed; one heterocycle and one homocycle (preferably one heterocycle) One benzene ring, more preferably one aromatic heterocycle and one
And condensed benzene rings). Specific examples of such a condensed ring include indole and
Benzothiophene, benzofuran, benzimidazole, imidazo [1,2-a] pyridine, quinoline, isoquinoline, cinnoline and the like can be mentioned. “Optionally substituted heterocyclic group” as a substituent which the benzene ring in the “optionally substituted benzene ring” for B ^c or C ^c may have, and R ^6c The “heterocyclic group” in the “optionally substituted heterocyclic group” may have a substituent, and examples of such a substituent include the above-mentioned “ ^Bc or ^Cc ” And the benzene ring in the "optionally substituted benzene ring" may be the same as the substituent which the "optionally substituted hydrocarbon group" may have.

[0181] Examples of "halogen atom" as a B ^c or substituent which may be a benzene ring have the "further substituted optionally also benzene ring" represented by C ^c is fluorine, chlorine, bromine , Iodine and the like.

In the “optionally substituted benzene ring” for B ^c or C ^c , the “optionally substituted amino group” as a substituent that the benzene ring may have is described later. it may be mentioned those similar to the "optionally substituted amino group" represented by wherein is a ^c, among others, "optionally substituted hydrocarbon group"
(Similar to the “optionally substituted hydrocarbon group” as a substituent that the benzene ring in the “optionally substituted benzene ring” represented by B ^c or C ^c above may have) group, etc.), as the "optionally substituted heterocyclic group" (the above-mentioned B ^c or may have a benzene ring in the "optionally further substituted also benzene ring optionally" substituent represented by C ^c And the like, and the like. The “optionally substituted heterocyclic group” described above, and the “optionally substituted acyl group” (the “optionally substituted benzene” represented by B ^c or C ^c described later) And an amino group optionally having one or two substituent (s) selected from the same groups as the “optionally substituted acyl group” as a substituent that the benzene ring in the ring may have Is preferred, Only, alkyl may be substituted [for example, halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxyl, optionally substituted thiol group (e.g., thiol, C _1-4 alkylthio An optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine,
5- or 6-membered cyclic amino such as morpholine, thiomorpholine, pyrrole, imidazole, etc.), phenyl-lower (C _1-4 ) alkyl, C _3-7 cycloalkyl, a carboxyl group which may be esterified or amidated (Eg, carboxyl, C _1-4 alkoxycarbonyl,
Lower (C _7-10 ) aralkyloxy-carbonyl, carbamoyl, mono C _1-4 alkylcarbamoyl, di C
_1-4 etc. alkylcarbamoyl), optionally _{C 1-4} optionally substituted with a halogen atom or _{C 1-4} alkoxy
Alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.) , _{C 1-4} alkylenedioxy (e.g., -O-CH
_{2 -O -, - O-CH} 2 -CH 2 -O- , etc.), _{formyl, C 2-4} alkanoyl (e.g., acetyl, propionyl, _{etc.), C 1-4} alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc. ), C _1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl, etc.) and the like, each of which may have 1 to 3 substituents, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, ter
t-butyl, pentyl, isopentyl, neopentyl,
Hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1 -6)} amino group which may have one or two alkyl, etc.] preferred.

The “optionally substituted amino group” as a substituent that the benzene ring in the “optionally substituted benzene ring” for B ^c or C ^c may have, Amino group substituents are bonded to each other,
Cyclic amino group (for example, formed by removing one hydrogen atom from the ring-constituting nitrogen atom of a 5- to 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc. And the like).
The cyclic amino group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine,
Iodine), nitro, cyano, hydroxyl, thiol,
Amino group, a carboxyl group, a C _1-4 alkyl which may be halogenated (for example, trifluoromethyl, methyl, ethyl, etc.), a C may be halogenated
_1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), _{formyl, C 2-4} alkanoyl (e.g.,
Acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like, and the number of substituents is preferably 1 to 3.

In the “optionally substituted benzene ring” for B ^c or C ^c , the “optionally substituted acyl group” as a substituent that the benzene ring may have is hydrogen. , "an optionally substituted hydrocarbon group" ( "substitution as the B ^c or may have a benzene ring in the" optionally further substituted also benzene ring optionally "substituent represented by C ^c above such same groups as also substituted hydrocarbon group "have been), in the" optionally substituted heterocyclic group "(benzene ring which may be" further substituted represented by B ^c or C ^c above " Examples of the substituent which the benzene ring may have include a group similar to the "optionally substituted heterocyclic group" or the like) bonded to a carbonyl group or a sulfonyl group. As an example, (1) hydrogen, (2) alkyl optionally substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1-6)} such as an alkyl and the like); (3) optionally substituted cycloalkyl (e.g. ,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-7 cycloalkyl such as cycloheptyl); (4) an optionally substituted alkenyl (e.g., allyl (allyl), crotyl, 2-pentenyl, 3 Alkenyl having 2 to 10 carbon atoms such as -hexenyl, preferably lower ( _C2-6 ) alkenyl and the like); (5) cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, 2-cyclohexenyl) , 2
-Cyclopentenylmethyl, cycloalkenyl having 3 to 7 carbon atoms such as 2-cyclohexenylmethyl); (6) a 5- or 6-membered monocyclic aromatic group which may be substituted (for example, phenyl, And the like bonded to a carbonyl group or a sulfonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, Cycloheptanecarbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.), and the above-mentioned (2) optionally substituted alkyl,
(3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5- to 6-membered Examples of the substituent which the monocyclic aromatic group may have include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, and optionally substituted thiol group (eg, thiol , C _1-4 alkylthio, etc.), an optionally substituted amino group (eg, amino, mono C _1-4 alkylamino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, A 5- to 6-membered cyclic amino such as pyrrole or imidazole, etc., a carboxyl group which may be esterified or amidated (eg, carboxyl, C _{1) -4} alkoxycarbonyl, carbamoyl, mono _C1-4 alkylcarbamoyl, _diC1-4
Alkylcarbamoyl, etc.), halogen atom or C
C _1-4 alkyl optionally substituted with _1-4 alkoxy (eg, trifluoromethyl, methyl, ethyl and the like), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy ( E.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, _C2-4 alkanoyl (e.g., acetyl, propionyl, etc.), _C1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), C
_1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl and the like) and the like, and the number of substituents is preferably 1 to 3.

B^cOr C^cIs indicated by "
Benzene ring "
As a substituent which may be
Good carboxyl groups include hydrogen, "substituted
Or a hydrocarbon group which may be^cOr C^cIndicated by
In the "optionally substituted benzene ring"
As a substituent which the benzene ring optionally has
And the like hydrocarbon groups which may be substituted))
And those bonded to a carbonyloxy group.
Preferred examples include (1) hydrogen, (2) optionally substituted alkyl (for example, methyl
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, e
C such as cutyl, nonyl, and decyl_1-10Alkyl, good
Preferably low grade (C_1-6) Alkyl and the like
(3) optionally substituted cycloalkyl (for example,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclo
C such as rohexyl and cycloheptyl_3-7Cycloal
(4) alkenyl which may be substituted (for example,
Allyl, crotyl, 2-pentenyl, 3-hexenyl
Alkenyl having 2 to 10 carbon atoms, such as
(C_2-6) Alkenyl and the like); (5) optionally substituted cycloalkenyl (eg,
For example, 2-cyclopentenyl, 2-cyclohexenyl, 2
-Cyclopentenylmethyl, 2-cyclohexenylmethyl
And cycloalkenyl having 3 to 7 carbon atoms such as
(6) aryl which may be substituted (for example, phenyl
, Naphthyl, etc.)
, More preferably carboxyl, lower
(C _1-6) Alkoxycarbonyl, aryloxyca
Rubonyl (eg, methoxycarbonyl, ethoxycarbonyl
, Propoxycarbonyl, phenoxycarbonyl, na
And the like.
(2) optionally substituted alkyl, (3) substituted alkyl
Optionally substituted cycloalkyl, (4) optionally substituted
Good alkenyl, (5) optionally substituted cycloalkyl
Lucenyl, and (6) optionally substituted aryl
As a substituent which may be possessed, halogen (eg, fluorine)
Nitrogen, chlorine, bromine, iodine, etc.), nitro, cyano, water
Acid group, thiol group which may be substituted (eg, thio-
Le, C_1-4Alkylthio, etc.), may be substituted
Amino groups (eg, amino, mono C_1-4Alkylam
No, Di C _1-4Alkyl amino, tetrahydro pillow
, Piperazine, piperidine, morpholine, thiomorpho
5- to 6-membered cyclic amines such as phosphorus, pyrrole and imidazole
Mino), esterified or amidated
Carboxyl groups (eg, carboxyl, C_1-4Arco
Xycarbonyl, carbamoyl, mono C_1-4Alkyl
Carbamoyl, di C_1-4Alkyl carbamoyl
Etc.), halogen atom or C_1-4Substituted with alkoxy
C that may be_1-4Alkyl (eg, trifluoromethyl
Tyl, methyl, ethyl, etc.), a halogen atom or C
_1-4C optionally substituted with alkoxy_1-4Al
Coxy (eg, methoxy, ethoxy, trifluoromethoxy)
, Trifluoroethoxy, etc.), formyl, C_2-4
Alkanoyl (eg, acetyl, propionyl, etc.), C
_1-4Alkylsulfonyl (eg, methanesulfonyl,
Tansulfonyl), C_1-4Alkylsulfinyl
(Eg, methanesulfinyl, ethanesulfinyl, etc.)
And the like, and the number of substituents is preferably 1 to 3.
New

In the “optionally substituted benzene ring” for B ^c or C ^c , the “optionally amidated carboxyl group” as a substituent which the benzene ring may have includes: (1) hydroxyl group; (2) "optionally substituted amino group" (B
^{and the same} as the “optionally substituted amino group” as a substituent that the benzene ring may have in the “optionally substituted benzene ring” for ^c or C ^c ); Is bonded to a carbonyl group.

In the “optionally substituted benzene ring” for B ^c or C ^c , the benzene ring may have 1 to 4 substituents (preferably 1 to 2
) May be the same or different and may be substituted at any position of the ring. When the benzene ring in the “optionally further substituted benzene ring” represented by B ^c or C ^c has two or more substituents, two of these substituents are bonded to each other, For example, lower (C _1-6 ) alkylene (eg, trimethylene, tetramethylene, etc.),
Lower (C _1-6 ) alkyleneoxy (eg, —CH ₂ —O
—CH ₂ —, —O—CH ₂ —CH ₂ —, etc.), lower (C
_1-6) alkylenedioxy (e.g., _-O-CH 2 -O
_{-, - O-CH 2 -CH} 2 -O- , etc.), lower (C
_2-6) alkenylene _(e.g., -CH 2 -CH = _{CH-,
-CH 2 -CH 2 -CH = CH -} , - CH 2 -CH = C
H-CH _2-, etc.) and lower (C _4-6 ) alkadienylene (eg, -CH = CH-CH = CH-, etc.) may be formed.

In the “optionally substituted benzene ring” for B ^c or C ^c , the substituent which the benzene ring may have may be an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon group. A heterocyclic group, a nitro group,
A halogen atom, an optionally substituted amino group,
^6c -Y ^c - in the group represented by (wherein, Y ^c is an oxygen atom or an optionally oxidized sulfur atom, R ^6c is an optionally hydrocarbon group or a substituted may be substituted heterocycle And a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocyclic group, a halogen atom, a substituted or unsubstituted amino group, a compound represented by the formula R ^6c −
Y ^c - group (wherein represented by, Y ^c represents an oxygen atom or oxidized to sulfur atom which may be, R ^6c are optionally substituted hydrocarbon group or an optionally substituted heterocyclic group Are more preferable, and especially, lower (C
_1-4 ) Alkyl, halogen atom and the like are preferable. B ^{c
Alternatively} , the “optionally substituted benzene ring” represented by C ^c is preferably a benzene ring having no substituent other than the substituents specified.

In the above formula (Ic), R^1c, R^2cand
R^3cRepresented by the "optionally substituted hydrocarbon group"
Examples of the “hydrocarbon group” include: (1) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, hexyl, heptyl, octyl, nonyl, decyl
Such as C_1-10Alkyl, preferably lower
(C_1-6) Alkyl and the like); (2) cycloalkyl (eg, cyclopropyl, cycloalkyl)
Robutyl, cyclopentyl, cyclohexyl, cyclohexyl
C such as Petil_3-8Cycloalkyl and the like
The cycloalkyl is condensed with a benzene ring
And indan (eg, indan-1-yl, indan-2
-Yl, etc.), tetrahydronaphthalene (eg, tetrahi
Dronaphthalen-5-yl, tetrahydronaphthalene-
(Preferably, indane, etc.)
Further wherein the cycloalkyl is carbon
Bridged through a linear atom chain of the formulas 1 and 2,
[2.2.1] heptyl, bicyclo [2.2.2] oct
Tyl, bicyclo [3.2.1] octyl, bicyclo
[3.2.2] nonyl and the like (preferably having 1 to 2 carbon atoms)
Having a cross-link through a linear atom chain
And more preferably bicyclo [2.2.1] hep
Tyl) may form a crosslinked cyclic hydrocarbon residue
(3) alkenyl (eg, vinyl, allyl,
Carbon such as crotyl, 2-pentenyl and 3-hexenyl
Alkenyl of number 2 to 10, preferably lower (C_{2 -6})
(4) cycloalkenyl (for example, 2-cyclopentenyl);
, 2-cyclohexenyl, 2-cyclopentenylmethyl
And C3-C8 cycloalkyl such as 2-cyclohexenylmethyl
(5) alkynyl (eg, ethynyl, 1-propynyl)
, 2-propynyl, 1-butynyl, 2-pentynyl,
C2-C10 alkynyl such as 3-hexynyl;
Preferably low grade (C_2-6) Alkynyl and the like
(6) aryl (eg, C such as phenyl, naphthyl, etc.)
_6-14Aryl, preferably C_6-10Aryl,
(7) aralkyl (for example, 1 to 3 carbon atoms)_6-14Ants
C with_1-6Alkyl, preferably phenyl
-C_1-4Alkyl (eg, benzyl, phenethyl, etc.)
(8) Formula -X^c'' '-G^c-(CH_Two)_n-J^c [Where X^c'' 'Is C_1-4Alkylene group or C_2-4
An alkenylene group;^cIs a bond, -O-, -S-, -CO-N
H- or -NH-CO-; n represents an integer of 0 to 3;^c
Represents an optionally substituted aromatic ring group]
Or (9) expression -X^c'' '' -L^c-(CH_Two)_n-M^c [Where X^c'' '' Is a bond, C_1-4Indicates an alkylene group
Then L^cAre (a) a bond, (b) an optionally substituted aromatic ring
Represents a group, (c) -O-, (d) -S-, (e) -CO-NH- or (f) -NH-CO-.
And n represents an integer of 0 to 3;^cIs amino group, guanidi
Group, sulfamoyl group, carbamoyl group or hydroxyl group
And a group represented by the following: In the above formula,
J^cAnd L^cOptionally substituted aromatic ring group represented by
Represents an optionally substituted aryl group,
And an optionally substituted aromatic heterocyclic group. J^cYou
And L^c"Aryl group which may be substituted" represented by
Examples of the "aryl group" include, for example, phenyl,
C such as naphthyl_6-14Aryl, preferably C
_6-10Aryl, more preferably phenyl and the like.
I can do it. J^cAnd L^c"Even if it is substituted
"Aromatic heterocyclic group" in "good aromatic heterocyclic group"
For example, R^6c"Even if it is substituted
"Optionally substituted aromatic" in "good heterocyclic group"
Heterocyclic group '' and the like, among which
And a 5- or 6-membered aromatic monocyclic ring which may have a substituent
Heterocyclic groups are preferred, where 5-6 membered aromatic monocyclic
As the heterocyclic group, for example, furan, thiophene, pillow
, Oxazole, isoxazole, thiazole,
Sothiazole, imidazole, pyrazole, 1,2,3-
Oxadiazole, 1,2,4-oxadiazole, 1,
3,4-oxadiazole, 1,2,3-thiadiazo
1,2,4-thiadiazole, 1,3,4-thiadiazole
, 1,2,3-triazole, 1,2,4-triazole
, Tetrazole, pyridine, pyridazine, pyrimidi
, Pyrazine, triazine and the like. J^cAnd
And L^cIn the “optionally substituted aromatic ring group”
The “aromatic ring group” may have a substituent,
Examples of the substituent include halogen (eg, fluorine, salt
, Bromine, iodine, etc.), nitro, cyano, hydroxyl,
Optionally substituted thiol groups (eg, thiol, C
_1-4Alkylthio), an optionally substituted amino
No group (eg, amino, mono C_1-4Alkylamino, di-C
_1-4Alkylamino, tetrahydropyrrole, pipera
Gin, piperidine, morpholine, thiomorpholine, pyro
, Imidazole, 2-oxo-1-pyrrolidinyl, 2-
5- or 6-membered cyclic amino such as xo-1-piperidinyl
), Phenyl-lower (C _1-4) Alkyl, C_3-7
Cycloalkyl, esterified or amidated
Carboxyl groups (eg, carboxyl, C_1-4A
Lucoxy-carbonyl, lower (C_7-10) Aralkyl
Oxy-carbonyl, carbamoyl, mono-C _1-4Al
Kircarbamoyl, Di C_1-4Alkyl carbamoyl
Etc.), halogen atom or C_1-4Substituted with alkoxy
C that may be_1-4Alkyl (eg, trifluoromethyl
Tyl, methyl, ethyl, etc.), a halogen atom or C
_1-4C optionally substituted with alkoxy_1-4Al
Coxy (eg, methoxy, ethoxy, trifluoromethoxy)
C, trifluoroethoxy, etc.), C_1-4Alkylene
Dioxy (eg, -O-CH₂-O-, -O-CH₂-C
H₂-O-), formyl, C_2-4Alkanoyl
(Eg, acetyl, propionyl, etc.), C_1-4Archi
Rusulfonyl (eg, methanesulfonyl, ethanesulfonyl
), C_1-4Alkylsulfinyl (eg, methane
Sulfinyl, ethanesulfinyl, etc.)
Sulfamoyl groups (eg, sulfamoyl,
No C_1-4Alkylsulfamoyl, di-C_1-4Archi
Rusulfamoyl, etc.), optionally substituted aryl
And a heterocyclic group which may be substituted, and the like.
The number of substituents is preferably 1 to 3.

The "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by R ^1c , R ^2c and R ^3c may have a substituent. Examples of such a substituent include, for example, Halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, oxo, hydroxyl, optionally substituted thiol group (eg, thiol, C _1-4 alkylthio, etc.), optionally substituted amino Groups (eg, amino, mono C _1-4 alkylamino, di C
_1-4- alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl), phenyl Lower (C _1-4 ) alkyl, C _3-7
Cycloalkyl, esterified or amidated carboxyl group which may be (for example, _{carboxyl, C 1 -4} alkoxy - carbonyl, lower _{(C 7-10)} aralkyloxy - carbonyl, carbamoyl, _{mono-C 1-4} alkylcarbamoyl, di _{C 1-4} alkylcarbamoyl, etc.), optionally _{C 1-4} alkyl (e.g. optionally substituted with halogen atom or _{C 1-4} alkoxy, trifluoromethyl, methyl, ethyl, etc.), a halogen atom or C
Good _{C 1-4} alkoxy optionally substituted by _C1-4 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, _{etc.), C 1-4} alkylenedioxy (e.g., _-O-CH 2 -O -, - _O-CH 2 -C
H ₂ —O—, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C _1-4 alkylsulfinyl (eg, Methanesulfinyl, ethanesulfinyl, etc.), an optionally substituted sulfamoyl group (eg, sulfamoyl, mono C _1-4 alkyl sulfamoyl, di C _1-4 alkyl sulfamoyl, etc.), optionally substituted aryl Group, an optionally substituted heterocyclic group and the like,
The number of substituents is preferably 1 to 3.

R^1c, R^2cAnd R^3cIndicated by
As a substituent of the “optionally substituted hydrocarbon group”
"Aryl" in the "optionally substituted aryl group"
And the like are, for example, C.sub.2 such as phenyl and naphthyl.
_6-14Aryl, preferably C_6-10Aryl,
More preferably, phenyl and the like can be mentioned. The "Ally
Substituents which the `` aryl group '' may have, for example,
Rogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitrite
B, cyano, hydroxyl group, thiol group which may be substituted
(Eg, thiol, C_1-4Alkylthio), substituted
Optionally substituted amino groups (eg, amino, mono C_1-4A
Lucylamino, Di C_1-4Alkylamino, tetrahydride
Lopyrrole, piperazine, piperidine, morpholine, thi
5 or 6 members such as omorpholine, pyrrole, imidazole
Phenyl-lower (C_1-4) Al
Kill, C_3-7Cycloalkyl, esterified or amido
Carboxyl group which may be
Le, C_1-4Alkoxy-carbonyl, lower (C
_7-10) Aralkyloxy-carbonyl, carbamoy
Le, Mono C_1-4Alkylcarbamoyl, di-C_1-4A
Alkylcarbamoyl), a halogen atom or C
_1-4C optionally substituted with alkoxy _1-4Al
Kill (eg, trifluoromethyl, methyl, ethyl
Etc.), halogen atom or C_1-4Substituted with alkoxy
C that may be_1-4Alkoxy (eg, methoxy, d
Toxic, trifluoromethoxy, trifluoroethoxy
Etc.), C _1-4Alkylenedioxy (eg, -O-CH
₂-O-, -O-CH₂-CH₂-O-), Holmi
Le, C_2-4Alkanoyl (eg, acetyl, propioni
), C_1-4Alkylsulfonyl (eg, methanes
Ruphonyl, ethanesulfonyl, etc.), C_1-4Alkyl
Sulfinyl (eg, methanesulfinyl, ethanesulfin
), An optionally substituted sulfamoyl group
(Eg, Sulfamoyl, Mono C_1-4Alkyl sulfa
Moyle, C_1-4Alkylsulfamoyl, etc.), 5
To 6-membered aromatic monocyclic heterocycles (eg, furan, thiophene
, Pyrrole, oxazole, isoxazole, thia
Sol, isothiazole, imidazole, pyrazole,
1,2,3-oxadiazole, 1,2,4-oxadiazo
, 1,3,4-oxadiazole, 1,2,3-thiazi
Azole, 1,2,4-thiadiazole, 1,3,4-thia
Diazole, 1,2,3-triazole, 1,2,4-tri
Azole, tetrazole, pyridine, pyridazine, pyri
Midine, pyrazine, triazine, etc.)
The number of substituents is preferably 1 to 3. R^1c, R
^2cAnd R^3cRepresented by the "optionally substituted charcoal
"Optionally substituted compound" as a substituent of "hydrogen group"
Examples of the "ring group" include, for example, R^6cIndicated by
The same as “optionally substituted heterocyclic group”
No.

In the above formula (Ic), examples of the substituent of the “amino group” in the “optionally substituted amino group” for R ^2c include, for example, an optionally substituted hydrocarbon group and a heterocyclic group. A ring group, an acyl group and the like are preferable. When the “amino group” is substituted, the number of substituents is 1
Or two.

The hydrocarbon group as a substituent of the “optionally substituted amino group” for R ^2c includes, for example, (1) alkyl (for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
(2) cycloalkyl (for example, C _1-10 alkyl such as tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably lower (C _1-6 ) alkyl); , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C _3-8 cycloalkyl such as cycloheptyl); and, the cycloalkyl is condensed with the benzene ring, indane (e.g., indan-1-yl, indan -2
-Yl), tetrahydronaphthalene (eg, tetrahydronaphthalen-5-yl, tetrahydronaphthalene-
(Preferably indane and the like); and the cycloalkyl is cross-linked via a linear atom chain having 1 to 2 carbon atoms to form a bicyclo [2. 2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl and the like (preferably having 1 to 2 carbon atoms)
(3) a cyclohexyl having a bridge through a linear atom chain, and more preferably a bicyclic [2.2.1] heptyl and the like). Alkenyl (eg, vinyl, allyl,
Crotyl, 2-pentenyl, 3-hexenyl alkenyl having 2 to 10 carbon atoms such as, preferably a lower _{(C 2 -6)}
(4) cycloalkenyl (for example, cycloalkenyl having 3 to 8 carbon atoms such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, and 2-cyclohexenylmethyl); (5) alkynyl (for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,
Alkynyl having 2 to 10 carbon atoms such as 3-hexynyl, preferably lower _{(C 2-6)} an alkynyl and the like); (6) aryl (e.g., phenyl, C, such as naphthyl
_6-14 aryl, preferably _{C 6-10} aryl, more preferably like phenyl); (7) aralkyl (e.g., _{C 1-6} alkyl having 1-3 _{C 6-14} aryl, preferably phenyl _{-C 1-4} alkyl (e.g., benzyl, phenethyl, etc.)
And the like); and the like.

[0194] The heterocyclic group as the substituent of the "amino group which may be substituted" represented by the R ^2c, for example, "may be further substituted represented by B ^c or C ^c above “Optionally substituted heterocyclic group” as a substituent that the benzene ring in the “benzene ring” may have and “heterocyclic group” in the “optionally substituted heterocyclic group” for R ^6c And the like.

[0195] The acyl group as the substituent of the "optionally substituted amino group" represented by the R ^2c, for example, be "substituted represented by R ^2c that (1) hydrogen or a hydrocarbon group (the such same groups as the hydrocarbon group as the substituent also an amino group "have) is linked to a carbonyl group or a sulfonyl group, a" substituted represented by (2) a Hajime Tamaki (R ^2c described above And the like, as the substituent of the "optionally substituted heterocyclic group", is bonded to a carbonyl group or a sulfonyl group.

“Optionally substituted hydrocarbon group” as a substituent of the “optionally substituted amino group”;
Examples of the substituents of the “optionally substituted heterocyclic group” and the “optionally substituted acyl group” include, for example, the aforementioned “optionally substituted benzene ring” represented by B ^c or C ^c Of the "optionally substituted hydrocarbon group" as a substituent which the benzene ring may have, and the "hydrocarbon group" of the " ^optionally substituted hydrocarbon group" for R ^6c Examples of the substituent include the same as those described above. The number of the substituent is preferably 1 to 3.

In the above formula (Ic), R^1cAs hydrogen
Atom or optionally substituted C _1-6Alkyl is good
More preferably, a hydrogen atom or C_1-4Alkyl is more preferred
In particular, a hydrogen atom is preferably used. the above
In the formula (Ic), R^2cThe "may be substituted
Hydrocarbon group '' has the formula -X^c'' '-G^c-(CH_Two)_n-J^c[formula
Medium, X^c'' 'Is C_1-4Alkylene group or C_2-4Al
G represents a kenylene group;^cIs a bond, -O-, -S-, -CO-NH- or
Or -NH-CO-, n represents an integer of 0 to 3,^cIs
Represents an aromatic ring group which may be substituted]
Is the formula -X^c'' '' -L^c-(CH_Two)_n-M^c[Where X^c'' '' Is a bond,
C_{1 -4}Represents an alkylene group; L^cAre (a) a bond, and (b)
Optionally substituted aromatic ring group, (c) -O-, (d) -S-, (e) -CO
-NH- or (f) -NH-CO-, and n represents an integer of 0 to 3.
Then M^cIs an amino group, a guanidino group, a sulfamoyl group,
Represents a carbamoyl group or a hydroxyl group].
Best, J^cAnd L^cMay be substituted represented by
As the aromatic ring group, phenyl which may be substituted,
5 to 6-membered aromatic monocyclic heterocyclic group which may be
Which is preferred. In the above formula (Ic), R^3cIndicated by
As the "optionally substituted hydrocarbon group",
C that may be_1-6Alkyl is preferred, among which
Also the formula-(CH_Two)_p-T^cWherein p represents an integer of 1 to 6,
^cRepresents an optionally substituted aromatic ring group]
Groups are preferred. Where T^cIs replaced with
And the aromatic ring group which may be^cIndicated by
Examples of the same group as the “optionally substituted aromatic ring group” include
But an "optionally substituted aromatic ring represented by T"
As the “aromatic ring group” in the “group”, a phenyl group is preferable.
Shit, T^cRepresented by the "optionally substituted aromatic ring"
A substituent which the “aromatic ring group” in the “group” may have
A hydroxyl group, an optionally substituted sulfamoyl
Groups (eg, sulfamoyl, mono C_1-4Alkylsulf
Amoyl, Di C_1-4Alkylsulfamoyl, etc.)
Which is preferred.

In the above formula (Ic), R ^1c and X
The "ring" in the case where ^c is bonded to form a ring may be a saturated ring or an unsaturated ring as long as it is a nitrogen-containing heterocyclic ring, and the size of the ring is not limited. Preferred is a 3- to 8-membered nitrogen-containing heterocycle, especially a saturated 3- to 8-membered nitrogen-containing heterocycle, ie, a compound represented by the formula:

Embedded image Wherein, ^{D c} ring represents a 3 to 8-membered nitrogen-containing heterocyclic ring saturated]
Is preferably represented by Examples of the “3- to 8-membered nitrogen-containing heterocycle” include, for example, one nitrogen atom, and one to three heteroatoms (preferably one to two) selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. 1)
And a 3- to 8-membered nitrogen-containing heterocyclic ring which may contain from 4 to 4 (preferably from 1 to 2), and more specifically, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline and oxazine. , Oxadiazine, thiazine, thiadiazine, piperidine, morpholine, thiomorpholine, piperazine, azepine, etc., a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) monocyclic non-aromatic heterocyclic ring (Aliphatic heterocycle) and the like. Further, the "3- to 8-membered nitrogen-containing heterocyclic ring" may have a substituent, and examples of the substituent, for example, be "further substituted represented by B ^c or C ^c above As the substituent which the benzene ring in the "good benzene ring" may have, there may be mentioned the same groups as the substituents which the "optionally substituted hydrocarbon group" may have. Further, in the above formula (Ic), R
^1c may form a ring with the "optionally substituted amino group" represented by A ^c, such "ring"
May be any of a saturated ring and an unsaturated ring as long as it is a heterocyclic ring containing at least two nitrogen atoms,
Although the size of the ring is not limited, a 3- to 8-membered nitrogen-containing heterocyclic ring is preferable, and a saturated 3- to 8-membered nitrogen-containing heterocyclic ring is particularly preferable.

Embedded image Wherein, A c ^'represents a nitrogen atom which may be substituted, F ^c ring represents a 3 to 8-membered nitrogen-containing heterocyclic ring saturated] preferably represented by. In the above formula, ^{examples of the} substituent which the “nitrogen atom” in the “optionally substituted nitrogen atom” represented by Ac ′ may have include “substituted and substituted” represented by ^Ac described below. And the same substituents as the "amino group" of the "good amino group" may have. Examples of the “3- to 8-membered nitrogen-containing heterocyclic ring” include, for example, two nitrogen atoms and one to three heteroatoms (preferably one to two) selected from oxygen, sulfur, nitrogen and the like. Seeds) 1 to 4
(Preferably 1 or 2) 3 to 8
And more specifically 3-8 membered (preferably 5 to 6 membered) saturated or imidazolidin, imidazoline, pyrazolidine, pyrazoline, oxadiazine, thiadiazine, piperazine, diazepine and the like. An unsaturated (preferably saturated) monocyclic non-aromatic heterocycle (aliphatic heterocycle) is exemplified. In addition, the “3 to 8”
Membered nitrogen-containing heterocyclic ring "may have a substituent, such substituents include for example, benzene ring in the" further optionally substituted benzene ring "represented by B ^c or C ^c above And the same substituents as the substituents that the “optionally substituted hydrocarbon group” may have.

In the above formula, X^cThe “straight-chain portion”
As a spacer having 1 to 12 atoms, "
"Divalent group having 1 to 12 atoms in the straight chain portion"
Any one may be used, for example, (1)-(CH_Two)_t1− (T1 is 1 to
An integer of 12, preferably an integer of 1 to 8, more preferably
Represents an integer of 1 to 6, particularly preferably an integer of 1 to 4
You. ), (2)-(CH_Two)_u1−X^c1− (CH_Two)_u2− (U1 and u2
Are the same or different and represent an integer of 0 to 11. Where u1
And the sum of u2 is 0 to 11. X^c1Is NH, O, S, SO or
Is SO_Two), (3)-(CH_Two)_v1−X^c1− (CH_Two)_v2−X^c2−
(CH_Two)_v3-(V1, v2 and v3 are the same or different
Indicates an integer of 10. However, the sum of v1, v2 and v3 is 0-1
0. X^c1And X^c2Is NH, O, S, SO or
SO_TwoIs shown. However, when v2 is 0, X ¹And X^TwoLess of
Both preferably represent NH. )
Divalent group in which the group and some bonds have been converted to unsaturated bonds
And specifically, for example, -O- (CH_Two)_w3-(W
3 is an integer from 0 to 11),-(CH_Two)_w3-O- (w3 is an integer from 0 to 11
Number), -S- (CH_Two)_w3-(W3 is an integer of 0 to 11),-(CH_Two)_w3-
S- (w3 is an integer of 0 to 11), -NH- (CH_Two)_w3-(W3 is 0-1
An integer of 1),-(CH_Two)_w3-NH- (w3 is an integer of 0 to 11),-
(CH_Two)_w4-(W4 is an integer of 1 to 12), -CH = CH-,-
C≡C-, -CO-NH-, -SO₂2 such as -NH-
And valence groups. X^cIs composed of a straight chain
A divalent group having 1 to 4 carbon atoms is further formed.
And particularly, C_1-4Alkylene, C_2-4
Alkenylene and the like are preferred, and especially C_1-4Archi
Len is preferably used.

The divalent group represented by ^Xc may have a substituent at an arbitrary position (preferably on a carbon atom). May be any as long as it can be combined with, for example, B
^{In the} “benzene ring which may be further substituted” represented by ^c or C ^c , the same oxo group as the substituent which the benzene ring may have and an oxo group may be mentioned. Such substituents may be the same or different from one to four (preferably one to two), and may be substituted at any position of the divalent group. Further, the substituents of the divalent group represented by ^Xc may be bonded to each other to form a ring. Examples of such a “ring” include C _5-7 cycloalkane such as cyclopentane, cyclohexane, and cycloheptane; Benzene is exemplified. Examples of the divalent group is preferred substituents that have as X ^c, a lower _{(C 1-6)} alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl,
Pentyl, isopentyl, neopentyl, hexyl, etc., lower (C _3-7 ) cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C _2-7 ) alkanoyl (eg, acetyl) , Propionyl, butyryl, etc.), lower ( _C1-6 ) alkoxy-carbonyl, lower ( _C1-6 ) alkoxy, hydroxyl group, oxo and the like.

[0201] In the above formula, the "optionally substituted amino group" represented by A ^c, the "optionally substituted hydrocarbon group" ( "further substituted represented by B ^c or C ^c above In the optionally substituted benzene ring, a group similar to the "optionally substituted hydrocarbon group" as a substituent which the benzene ring may have), and the "optionally substituted heterocyclic group" (The same as the “optionally substituted heterocyclic group” as a substituent that the benzene ring may have in the “optionally substituted benzene ring” for B ^c or C ^c described above. as a group, etc.) and the "optionally substituted acyl group optionally" (above-mentioned B ^c or may have a benzene ring in the "optionally further substituted also benzene ring optionally" substituent represented by C ^c The "replaced Although the like amino group which may have 1-2 substituents selected from the same, etc. groups) and also acyl group "have been shown by A ^c" may be substituted The “amino group” is a group in which substituents of an amino group are bonded to each other to form a cyclic amino group (for example, from a nitrogen atom constituting a 5- to 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, and imidazole). (A cyclic amino group formed by removing one hydrogen atom and having a bond on a nitrogen atom). The cyclic amino group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxyl, thiol, amino, carboxyl and the like. , Optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, Fluoromethoxy, trifluoroethoxy, etc.), formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like. As 1-3
Are preferred.

[0202] The substituent for the amino group in the "optionally substituted amino group" represented by A ^c, (1) alkyl which may be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, preferably lower _{(C 1-6)} such as an alkyl and the like); (2) optionally substituted cycloalkyl (e.g. ,
C such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyanooctyl, etc.
_3-8 cycloalkyl and the like); said cycloalkyl, condensed with the benzene ring, indane (e.g., indan-1-yl, indan-2-yl, etc.), tetrahydronaphthalene (e.g., tetrahydronaphthalen-5 Yl, tetrahydronaphthalen-6-yl and the like (preferably indane and the like); and further, the cycloalkyl is cross-linked through a linear atom chain having 1 to 2 carbon atoms. , Bicyclo [2.2.1] heptyl,
Bicyclo [2.2.2] octyl, bicyclo [3.2.
1] octyl, bicyclo [3.2.2] nonyl and the like (preferably cyclohexyl having a bridge through a linear atom chain having 1 to 2 carbon atoms, more preferably bicyclo [2.2.1] Heptyl or the like); (3) optionally substituted alkenyl (eg, allyl, crotyl, 2-pentenyl, 3-hexenyl, etc.) (4) cycloalkenyl which may be substituted (for example, 2-cyclopentenyl, 2-cyclohexenyl, 2-10 alkenyl, preferably lower (C _2-6 ) alkenyl, etc.);
- cyclopentenyl, 2- cyclohexenyl methyl, etc. cycloalkenyl having 3 to 7 carbon atoms and the like); (5) an optionally substituted aralkyl (e.g., phenyl _{-C 1-4} alkyl (e.g., benzyl, (6) Formyl or an optionally substituted acyl (for example, alkanoyl having 2 to 4 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, etc.), 1 carbon atom)
And (4) alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.); (7) optionally substituted aryl (eg, phenyl, naphthyl, etc.); (8) optionally substituted complex A ring group (for example, one selected from a nitrogen atom, a sulfur atom, and an oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazole; A group formed by removing one hydrogen atom from a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 hetero atoms, tetrahydrofuran,
Nitrogen atom, sulfur atom and oxygen such as tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc. A group formed by removing one hydrogen atom from a 5- to 6-membered non-aromatic heterocycle containing from 1 to 2 heteroatoms selected from atoms, and from 1 to 4).

The above (1) optionally substituted al
Kill, (2) an optionally substituted cycloalkyl,
(3) optionally substituted alkenyl, (4) substituted alkenyl
Optionally substituted cycloalkenyl, (5) substituted
Aralkyl, (6) optionally substituted
(7) optionally substituted aryl, and
(8) The heterocyclic group which may be substituted may have
Substituents include halogens (eg, fluorine, chlorine, odor
, Iodine, etc.), halogen atom or C_1-4Arco
C optionally substituted by xy_1-4Alkyl, halogen
Atom or C_1-4May be substituted with alkoxy
C_1-4Alkoxy (eg, methoxy, ethoxy, pro
Poxy, butoxy, trifluoromethoxy, trifluoro
Roethoxy etc.), C_1-4Alkylenedioxy (eg,
-O-CH₂-O-, -O-CH₂-CH ₂-O-
Etc.), Formyl, C_2-4Alkanoyl (eg, acetyl
, Propionyl, etc.), C_1-4Alkylsulfonyl
(E.g., methanesulfonyl, ethanesulfonyl, etc.)
Enyl-lower (C_1-4) Alkyl, C_3-7Cycloa
Alkyl, cyano, nitro, hydroxyl, optionally substituted
Thiol groups (eg, thiol, C _1-4Alkylthio
), An optionally substituted amino group (eg, amino,
No C_1-4Alkylamino, di-C_1-4Alkylam
, Tetrahydropyrrole, piperazine, piperidine,
Morpholine, thiomorpholine, pyrrole, imidazole
5-6 membered cyclic amino, etc.), carboxyl group,
Low grade (C_1-4) Alkoxy-carbonyl, lower (C
_7-10) Aralkyloxy-carbonyl, carbamoy
Le, Mono C_1-4Alkylcarbamoyl, di-C_1-4A
Rukycarbamoyl (preferably halogen, halogen
Low-grade (C_1-4) Alkyl, halogen
Low-grade (C_1-4) Alkoxy,
Enyl-lower (C_1-4) Alkyl, C_3-7Cycloa
Alkyl, cyano, hydroxyl, etc.)
Is preferably 1 to 3.

[0204] As the "optionally substituted amino group" represented by A ^c, inter alia, alkyl optionally substituted [for example, halogen (e.g., fluorine, chlorine, bromine,
Iodine, etc.), nitro, cyano, hydroxyl, optionally substituted thiol (eg, thiol, C _1-4 alkylthio), optionally substituted amino (eg, amino, mono C _1-4 alkyl) amino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated carboxyl group which may be ( For example, carboxyl, C _1-4 alkoxycarbonyl, lower (C
_7-10 ) aralkyloxy-carbonyl, carbamoyl, mono-C _1-4 alkylcarbamoyl, di-C _1-4 alkylcarbamoyl, etc.), halogen atom or C
C _1-4 alkyl optionally substituted with _1-4 alkoxy (eg, trifluoromethyl, methyl, ethyl and the like), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy ( E.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), _C1-4 alkylenedioxy (e.g., -O-CH
_{2 -O -, - O-CH} 2 -CH 2 -O- , etc.), phenyl - lower _{(C 1-4) alkyl, C 3-7} cycloalkyl, _{formyl, C 2-4} alkanoyl (e.g., acetyl,
Propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C
Methyl, ethyl each having from 1 to 3 substituents selected from _1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl, etc.),
Propyl, isopropyl, butyl, isobutyl, sec
- butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, _{C 1-10} alkyl such as decyl, have preferably having 1 or 2 lower _{(C 1-6)} alkyl, etc.] Amino groups which may be present are preferred.

[0205] In the above formula, the "nitrogen-containing heterocyclic group" of the "optionally substituted nitrogen-containing heterocyclic group" represented by A ^c comprises one nitrogen atom, further oxygen atom, sulfur atom and 5- to 8-membered aromatic monocyclic heterocyclic group which may contain 1 to 4 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from nitrogen and the like A ring, a saturated or unsaturated non-aromatic monocyclic heterocycle (aliphatic heterocycle), and the like; and a hydrogen atom from a ring or the like in which two or three same or different rings selected from these monocycles are condensed. And groups formed excluding the individual.
Further, "optionally substituted nitrogen-containing heterocyclic group" represented by A ^c, via either a nitrogen atom or a carbon atom X
^It may be bonded to ^c , but is preferably bonded to ^Xc via a carbon atom.

Here, “aromatic monocyclic heterocycle” includes
5- to 8-membered (preferably 5- to 6-membered) aromatic monocyclic heterocycles (eg, pyrrole, oxazole, isoxazole,
Thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2 , 4-thiadiazole, 1,3,4-
Thiadiazole, 1,2,3-triazole, 1,2,4-
Triazole, tetrazole, pyridine, pyridazine,
Pyrimidine, pyrazine, triazine, etc.), and the like. 5 to 5 such as morpholine, thiomorpholine, piperazine, azepine
An 8-membered (preferably 5 to 6-membered) saturated or unsaturated monocyclic non-aromatic heterocyclic ring (aliphatic heterocyclic ring), or a part or all of the above aromatic monocyclic heterocyclic ring Examples thereof include a 5- to 8-membered non-aromatic heterocyclic ring having a saturated bond.

[0207] As the "optionally substituted nitrogen-containing heterocyclic group optionally" in the "nitrogen-containing heterocyclic group" substituent optionally possessed represented by A ^c, for example, B and the ^c or C ^c The same as the substituent which the "optionally substituted hydrocarbon group" may have as a substituent which the benzene ring in the "optionally substituted benzene ring" may have Groups. As the "nitrogen-containing heterocyclic group" of the "optionally substituted nitrogen-containing heterocyclic group" represented by A ^c, preferably nitrogen-containing heterocyclic group 5-6 membered,
Saturated 5- to 6-membered nitrogen-containing heterocyclic groups are more preferable, and among them, pyrrolidine, piperidine, piperazine (preferably, saturated 5- to 6-membered nitrogen-containing heterocyclic group containing one nitrogen atom) and the like are preferable. preferable.

In the above formula, the formula:

Embedded image The group represented by the formula:

Embedded image [Wherein, R ^1c has the same meaning as described above, X ^c ′ represents an optionally substituted C _1-6 alkylene group, and R ^4c and R ^5c each represent a hydrogen atom or an optionally substituted C _1-6 an alkyl ^group, group ^{R 4c} and ^{R 5c} is represented by may be linked to form a ring]; formula:

Embedded image [Wherein, X ^c ″ represents a bond or an optionally substituted C _1-4 alkylene group, and each of the D ^c ring and the E ^c ring represents a saturated 3- to 8-membered nitrogen-containing heterocyclic ring]. Group to be performed;
And the like are preferably used. In the above formula, the “C _1-6 alkylene group (preferably, C _1-4 alkylene group)” in the “ _optionally substituted C _1-6 alkylene group” represented by X ^c ′ may have Good substituents include X
^{The same} substituents as the substituents that the divalent group as ^c may have may be mentioned. In the above formula, the “ ^optionally substituted C _1-6 alkyl group” represented by R ^4c and R ^5c includes, for example, halogen (eg, fluorine, chlorine, bromine,
Iodine, etc.), nitro, cyano, hydroxyl, optionally substituted thiol (eg, thiol, C _1-4 alkylthio), optionally substituted amino (eg, amino, mono C _1-4 alkyl) amino, di C _1-4 alkylamino, tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, cyclic amino such as 5- or 6-membered, such as imidazole), esterified or amidated carboxyl group which may be ( For example, carboxyl, C _1-4 alkoxycarbonyl, lower (C
_7-10) aralkyloxy - carbonyl, carbamoyl, _{mono-C 1-4} alkylcarbamoyl, _{di-C 1-4} alkylcarbamoyl, etc.), a halogen atom or C
C _1-4 alkyl optionally substituted with _1-4 alkoxy (eg, trifluoromethyl, methyl, ethyl and the like), C _1-4 alkoxy optionally substituted with a halogen atom or C _1-4 alkoxy ( E.g., methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), _C1-4 alkylenedioxy (e.g., -O-CH
_{2 -O -, - O-CH} 2 -CH 2 -O- , etc.), phenyl - lower _{(C 1-4) alkyl, C 3-7} cycloalkyl, _{formyl, C 2-4} alkanoyl (e.g., acetyl,
Propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.), C
Methyl, ethyl each having from 1 to 3 substituents selected from _1-4 alkylsulfinyl (eg, methanesulfinyl, ethanesulfinyl, etc.),
Propyl, isopropyl, butyl, isobutyl, sec
-Butyl, tert-butyl, pentyl, isopentyl, neopentyl, lower (C _1-6 ) alkyl such as hexyl, and the like.

In the above formula, R ^4c and R ^5c are bonded to form a ring, and a cyclic amino group (eg, tetrahydropyrrole, piperazine, piperidine,
A cyclic amino group formed by removing one hydrogen atom from a ring-constituting nitrogen atom of a 5- to 6-membered ring such as morpholine, thiomorpholine, pyrrole, imidazole and the like, and having a bond on the nitrogen atom; preferably pyrrolidino, piperazino , A saturated 5- or 6-membered cyclic amino group such as piperidino; and more preferably a pyrrolidino).
The cyclic amino group may have a substituent, and examples of the substituent include halogen (eg, fluorine, chlorine, bromine,
Iodine), nitro, cyano, hydroxyl, thiol,
Amino group, carboxyl group, optionally halogenated C _1-4 alkyl (eg, trifluoromethyl, methyl, ethyl, etc.), optionally halogenated C _1-4
1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, _C2-4 alkanoyl (eg,
Acetyl, propionyl, etc.), C _1-4 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like, and the number of substituents is preferably 1 to 3. In the above formula, “C _1-4 ” in the “ _optionally substituted C _1-4 alkylene group” for X ^c ″
Examples of the substituent which the “alkylene group” may have include X
^{The same} substituents as the substituents that the divalent group as ^c may have may be mentioned. In the above formula, the “saturated 3- to 8-membered nitrogen-containing heterocyclic ring” represented by the D ^c ring and the E ^c ring includes, for example, one nitrogen atom and is further selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. And 3 to 8 membered nitrogen-containing heterocycles which may contain 1 to 4 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms. Specifically, 3- to 8-membered (preferably 5- to 6-membered) such as pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, oxazine, oxadiazine, thiazine, thiadiazine, piperidine, morpholine, thiomorpholine, piperazine, azepine and the like. Saturated or unsaturated (preferably saturated)
And a monocyclic non-aromatic heterocycle (aliphatic heterocycle). Further, the "3- to 8-membered nitrogen-containing heterocyclic ring" may have a substituent, and examples of the substituent, for example, be "further substituted represented by B ^c or C ^c above As the substituent which the benzene ring in the "good benzene ring" may have, there may be mentioned the same groups as the substituents which the "optionally substituted hydrocarbon group" may have. The “3- to 8-membered nitrogen-containing heterocyclic group” represented by the D ^c ring and the E ^c ring may be bonded to X ^c ″ via any of a nitrogen atom and a carbon atom. It is preferable to bond to X ^c ″ via an atom.

In the above formula (Ic), the groups specified as substituents on the ^Bc ring and the ^Cc ring may be substituted at any substitutable position, and are represented by the formula (Ic). Or a salt thereof, has the formula:

Embedded image Wherein each symbol is as defined above. ] Is preferable. Among them, the formula:

Embedded image It is preferable to have a structure represented by

The compound represented by the formula (Ic) or a salt thereof can be produced, for example, according to Scheme 1c. Scheme 1c

Embedded image [Wherein each symbol has the same meaning as described above] The compound represented by the formula (Ic) or a salt thereof is a compound represented by the formula (IIc) and a carboxylic acid represented by the formula R ^2c COOH, The reactive derivative or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. Reactive derivatives of carboxylic acids include acid anhydrides,
Active esters (e.g., p-nitrophenyl ester,
N-hydroxysuccinimide ester, pentafluorophenyl ester, 1-hydroxybenzotriazole ester, etc.), acid halide (eg, acid chloride, acid bromide, etc.), imidazolide or mixed acid anhydride (eg, anhydride with methyl carbonate, ethyl) Anhydride with carbonic acid, etc.). As a specific example, for example, a group represented by the formula -COOH is represented by the formula -COQ ^c [wherein Q ^c is a leaving group [eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine), methanesulfonyloxy] Benzenesulfonyloxy, p-toluenesulfonyloxy, etc.]]. Examples of the solvent to be used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), and halogen solvents (eg, dichloromethane, dichloroethane, chloroform, Carbon tetrachloride), acetonitrile, N, N-dimethylformamide and the like. As the base to be used, triethylamine,
Organic bases such as 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine or alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metals or alkaline earths Metal-like hydrogencarbonates (eg, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.) and hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, etc.). Examples of the condensing agent used include condensing agents used for peptide synthesis, and specifically, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide and its hydrochloride, benzotriazole -1-yl-tris (dimethylamino) phosphonium hexafluorophosphide, benzotriazol-1-yl-trispirolidinophosphonium hexafluorophosphide, diethyl cyanophosphate, diphenylphosphoryl azide, N-hydroxy-5 Norbornene-2,3-
Carboximide and the like. These may be used alone or in combination with 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole and the like. At this time, the carboxylic acid represented by the formula R ^2c COOH or a salt thereof is used in an amount of 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of the compound represented by the formula (IIc) or a salt thereof. The condensing agent is used in an amount of 0.5 to 10 molar equivalents, preferably 1 to 6 molar equivalents. At this time, the reaction temperature is −50 to 200 ° C.,
The reaction temperature is preferably -20 to 100 ° C, and the reaction time is 0.5 to 96 hours, preferably 0.5 to 72 hours, more preferably 1 to 24 hours.

The compound represented by the formula (Ic) or a salt thereof can also be produced, for example, according to Scheme 2c. Scheme 2c

Embedded image [Wherein the symbols have the same meanings as described above] The compound represented by the formula (Ic) or a salt thereof is a compound represented by the formula (IIIc), a reactive derivative thereof or a salt thereof, and a compound represented by the formula (Ic): I
The compound represented by Vc) or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. As the reactive derivative of the compound represented by the formula (IIIc), acid anhydrides, active esters (for example, p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester,
Examples thereof include 1-hydroxybenzotriazole ester, acid halides (eg, acid chloride, acid bromide, etc.), imidazolide, and mixed acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, etc.), and the like. .
As a specific example, for example, a group represented by the formula -COOH of the compound represented by the formula (III) is represented by the formula -COQ ^c [wherein Q ^c is a leaving group [eg, a halogen atom (fluorine, chlorine , Bromine, iodine, etc.), methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.]. Examples of the solvent to be used include ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.),
Examples include hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), acetonitrile, N, N-dimethylformamide and the like. As the base to be used, triethylamine,
Organic bases such as 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine or alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metals or alkaline earths Metal-like hydrogencarbonates (eg, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.) and hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, etc.). Examples of the condensing agent used include condensing agents used for peptide synthesis, and specifically, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide and its hydrochloride, benzotriazole -1-yl-tris (dimethylamino) phosphonium hexafluorophosphide, benzotriazol-1-yl-trispirolidinophosphonium hexafluorophosphide, diethyl cyanophosphate, diphenylphosphoryl azide and the like. These may be used alone or 1-
Hydroxybenzotriazole, 1-hydroxy-7-
It may be used in combination with azabenzotriazole or the like. At this time, the compound represented by the formula (IVc) or a salt thereof is 0.5 to 10 molar equivalents, preferably 1 to 1 mol of the compound represented by the formula (IIIc) or a salt thereof.
To 5 molar equivalents, and 0.5 to 10
It is used in molar equivalents, preferably 1 to 6 molar equivalents.
At this time, the reaction temperature is −50 to 200 ° C., preferably −20 to 100 ° C., and the reaction time is 0.5 to 96 hours, preferably 0.5 to 72 hours, more preferably 1 to 24 hours. .

The compound represented by the formula (IIc) or a salt thereof can be produced, for example, according to Scheme 3c. Scheme 3c

Embedded image [Wherein, W ^c represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as described above]. Formula (VIc) The compound or a salt thereof has the formula (V
It can be produced by reacting a compound represented by c), a reactive derivative thereof or a salt thereof with a compound represented by the formula (IVc) or a salt thereof. This reaction employs the same conditions and the like as the condensation reaction exemplified in the above scheme 2c. The compound represented by the formula (VIIc) or a salt thereof is
The compound represented by the formula (VIc) or a salt thereof can be produced by reacting with formylbenzeneboronic acid or its ester or anhydride in a solvent under basic conditions in the presence of a transition metal catalyst. Examples of the solvent to be used include water, alcohol solvents (eg, methanol,
Ethanol, n-propanol, isopropanol, etc.),
Examples include ether solvents (eg, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), and N, N-dimethylformamide. These solvents may be used alone or, if necessary, in a mixture of two or more kinds in an appropriate ratio. As the base to be used, for example, an alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, etc.),
Alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.), hydroxide of alkali metal or alkaline earth metal (eg,
Sodium hydroxide, potassium hydroxide, etc.), triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine and the like. Examples of the transition metal catalyst used include a palladium catalyst [eg, tetrakis (triphenylphosphine) palladium, 1,1-bis (diphenylphosphino) ferrocenedichloropalladium, dichlorobis (triphenylphosphine) palladium, etc.]. At this time, formylbenzeneboronic acid or an ester or an anhydride thereof is 0.5 to 10 mol per mol of the compound represented by the formula (VIc) or a salt thereof.
The molar equivalent is used, preferably 1 to 5 molar equivalents, and the transition metal catalyst is used in 0.01 to 1 molar equivalent, preferably 0.05 to 0.2 molar equivalent. At this time, the reaction temperature is 0 to 200 ° C, preferably 50 to 1 ° C.
00 ° C. and the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. The compound represented by the formula (IIc) or a salt thereof is reductively aminated using a compound represented by the formula (VIIc) or a salt thereof and an amine represented by the formula R ^3c NH ₂ or a salt thereof. It can be produced according to the conditions of the reaction. In the reductive amination reaction, for example, ether solvents (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), hydrocarbon solvents (eg, benzene, toluene, hexane, heptane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, etc.) Chloroform, carbon tetrachloride, etc.), alcohol solvents (eg,
Methanol, ethanol, n-propanol, isopropanol, etc.) in a solvent such as acetonitrile, N, N-dimethylformamide, acetic acid or a mixture thereof, the compound of the formula (VII)
A compound represented by c) or a salt thereof and an amine represented by the formula R ^3c NH ₂ or a salt thereof are reacted with a metal hydride complex compound (eg, sodium borohydride, sodium cyanoborohydride, triacetoxy hydride). (Sodium borohydride, etc.). At this time, the amine represented by the formula R ^3c NH ₂ or the salt thereof was added in an amount of 0.1 mol per mol of the compound represented by the formula (VIIc) or the salt thereof.
5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, and the metal hydride complex compound is used in 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents. At this time, the reaction temperature is 0 to 200 ° C., preferably 20 to 100 ° C., and the reaction time is 0.5 to 96 hours, preferably 1 to 24 hours.

The compound represented by the formula (IIc) or a salt thereof can also be produced, for example, according to Scheme 4c. Scheme 4c

Embedded image [Wherein, R ^5c represents a C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl,
Other symbols representing silyl and the like have the same meanings as described above.] The compound represented by the formula (IXc) or a salt thereof is represented by the formula (VI
The compound represented by IIc) or a salt thereof can be produced by reacting with formylbenzeneboronic acid or an ester or anhydride thereof in a solvent under basic conditions in the presence of a transition metal catalyst. This reaction is carried out from the compound represented by the formula (VIc) in the above scheme 3c or a salt thereof to the formula (V
The same conditions and the like as those exemplified for the reaction with the compound represented by IIc) or a salt thereof are used. The compound represented by the formula (Xc) or a salt thereof is obtained by subjecting a compound represented by the formula (IXc) or a salt thereof to an amine represented by the formula R ^3c NH ₂ or a salt thereof under conditions for reductive amination reaction. Can be manufactured. In this reaction, the same conditions and the like as those exemplified for the reaction from the compound represented by the formula (VIIc) or a salt thereof to the compound represented by the formula (IIc) or a salt thereof in the above scheme 3c are used. The compound represented by the formula (XIc) or a salt thereof can be produced by treating the compound represented by the formula (Xc) or a salt thereof with an acid or a base. That is, the compound represented by the formula (Xc) or a salt thereof is converted into, for example, water, an ether solvent (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), an alcohol solvent (eg, methanol, ethanol, n-propanol, isopropanol, etc.). ) Or a mixed solvent thereof, a mineral acid (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or a hydroxide of an alkali metal (eg, sodium hydroxide, potassium hydroxide, 0 to 150 ° C., preferably 2
It can be produced by reacting at 0 to 50 ° C. At this time, the strength of the acid and the base is 0.1
The reaction time is 1 to 72 hours. The compound represented by the formula (IIc) or a salt thereof,
It can be produced by reacting a compound represented by the formula (XIc), a reactive derivative thereof or a salt thereof with a compound represented by the formula (IVc) or a salt thereof. This reaction employs the same conditions and the like as the condensation reaction exemplified in the above scheme 2c.

The compound represented by the formula (IIIc) or a salt thereof can be produced, for example, according to Scheme 5c. Scheme 5c

Embedded image Wherein each symbol is as defined above. The compound represented by the formula (XIIc) or a salt thereof is obtained by combining a compound represented by the formula (Xc) whose production method is illustrated in the above scheme 4c with a compound represented by the formula R ^2c CO 2
The carboxylic acid represented by OH, a reactive derivative thereof or a salt thereof can be produced by using a condensing agent in a solvent, if necessary, in the presence of a base. For this reaction, the same conditions and the like as those for the condensation reaction exemplified in the above scheme 1c are used. The compound represented by the formula (IIIc) or a salt thereof can be produced by treating the compound represented by the formula (XIIc) or a salt thereof with an acid or a base. In this reaction, the same conditions and the like as those exemplified for the reaction from the compound represented by the formula (Xc) or a salt thereof to the compound represented by the formula (XIc) or a salt thereof in the above scheme 4c are used.

Compound (Ic) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound used in each of the above production methods may form a salt similar to the compound (Ic) as long as the reaction is not hindered. In each of the above reactions, when the raw material compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 alkylcarbonyl optionally having a substituent (eg, acetyl, propionyl, etc.), formyl,
Phenylcarbonyl, C _1-6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like), phenyloxycarbonyl (for example, benzooxycarbonyl and the like), C
_7-10 aralkyloxycarbonyl (for example, benzyloxycarbonyl and the like), trityl, phthaloyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6 alkylcarbonyl (for example, acetyl, propionyl, butyryl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the carboxyl-protecting group include, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like. Examples of these substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, butyryl, and the like), formyl, and nitro groups, substituents Number of 1 to 3
About one.

Examples of the hydroxy-protecting group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert.
- butyl, etc.), _{phenyl, C 7-10} aralkyl (e.g., _{benzyl), C 1 -6} alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl,
_{Phenyloxycarbonyl, C 7-10} aralkyloxycarbonyl (e.g., benzyloxycarbonyl), pyranyl, furanyl and silyl.
As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is 1 to There are about four. As a method for introducing and removing a protecting group, a method known per se or a method analogous thereto [for example, Protective Groups in Organic Chemistry (JFWMcOmie
Described in Plenum Press Co., Ltd.], but examples of the removal method include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, and acetic acid. A method of treating with palladium or the like is used.

The salts of the compounds obtained by using the above-mentioned screening method or screening kit include:
For example, pharmaceutically acceptable salts and the like are used. For example, salts with inorganic bases, salts with organic bases, salts with inorganic acids,
Salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine And the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid And the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ortin, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like.

When the above-mentioned GPR14 (SENR) antagonist is used as an anxiolytic, anti-depressive, anti-insomnia, anti-schizophrenic or anti-phobic agent, it can be formulated according to a conventional method. For example, a sugar-coated or enteric-coated tablet as required, a capsule, a elixir, orally as a microcapsule, or a sterile solution with water or another pharmaceutically acceptable liquid, Alternatively, it can be used parenterally in the form of injections such as suspensions.
For example, the compound or a salt thereof is mixed with a physiologically acceptable carrier, flavoring agent, excipient, vehicle, preservative, stabilizer, binder and the like in a unit dosage form generally required for the accepted pharmaceutical practice. Can be manufactured. The amount of the active ingredient in these preparations is such that a proper dosage in the specified range can be obtained.

Examples of additives that can be mixed with tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth gum, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. And a lubricating agent such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint, reddish oil or cherry, and the like. When the preparation unit form is a capsule, the above type of material can further contain a liquid carrier such as oil and fat. Sterile compositions for injection can be formulated according to normal pharmaceutical practice such as dissolving or suspending the active substance in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like. . Aqueous liquids for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents. For example, alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, Polysorbate 80 ( ^TM ), HCO-5)
0) and the like. The oily liquid includes sesame oil, soybean oil and the like, and may be used in combination with a solubilizing agent such as benzyl benzoate and benzyl alcohol. Also,
Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives ( For example,
Benzyl alcohol, phenol, etc.), antioxidants and the like. The prepared injection is usually filled in a suitable ampoule.

The preparations thus obtained are safe and have low toxicity, and thus are useful for mammals (eg, humans, mice, rats, guinea pigs, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.). Can be administered. The dosage of the GPR14 (SENR) antagonist of the present invention varies depending on symptoms and the like, but in the case of oral administration, generally, in an adult (with a body weight of 60 kg), about 0.1 to 100 mg, preferably, 100 mg / day is preferable. About 1.0 to 50 mg, more preferably about 1.0 to 20 mg
mg. In the case of parenteral administration, the single dose varies depending on the administration subject, target organ, symptoms, administration method and the like.
g) as about 0.01 mg / day.
It is convenient to administer intravenously about from about 30 mg, preferably about 0.1 to about 20 mg, more preferably about 0.1 to about 10 mg. In the case of other animals, the amount can be administered in terms of 60 kg.

(2) Encodes the polypeptide of the present invention
A base sequence complementary to the DNA containing the base sequence or
For diagnosis using polynucleotides containing a part of DNA
Law polynucleotide polypeptide as the DNA containing the base sequence encoding the comprising a complementary base sequence or a portion thereof of the present invention contains a nucleotide sequence encoding a polypeptide of the present invention in vivo Since it can suppress the function of DNA or the protein encoded thereby, it can be used as an agent for treating or preventing attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia or phobia. For example,
The polynucleotide can be administered alone or after insertion into an appropriate vector such as a retrovirus vector, an adenovirus vector, an adenovirus associated virus vector, or the like, and then administered in a conventional manner. The antisense DNA can be administered as it is or in the form of a formulation together with a physiologically acceptable carrier such as an adjuvant for promoting uptake, and then administered using a gene gun or a catheter such as a hydrogel catheter. Alternatively, it can be aerosolized and administered into the trachea as an inhalant. Further, the antisense DNA is used as a diagnostic oligonucleotide probe for examining the presence or expression of the DNA of the present invention in tissues or cells, that is, attention deficit disorder or narcolepsy or anxiety, depression, insomnia,
It can also be used as a diagnostic agent for schizophrenia.

(3) The polypeptide of the present invention or before it
Antagonist proteins or their amides or their
Using antibodies to esters or their salts
Method The antibody against the polypeptide of the present invention or its precursor protein or their amide or their ester or their salts can be used in vivo to obtain the polypeptide of the present invention or its precursor protein or their amide or their ester or their esters Because it can suppress the function of the salt of, for example, anxiety, depression,
It can be used as a therapeutic / prophylactic agent for insomnia, schizophrenia or phobia. Also, antibodies against the polypeptide of the present invention or its precursor protein or their amides or their esters or their salts may be used for the diagnosis of diseases such as attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia. Can be used. Using these antibodies, the polypeptide of the present invention, its precursor protein, their amides, their esters, or their salts can be quantified, and detection by tissue staining or the like can also be performed. For these purposes, the antibody molecule itself may be used, or F (ab ') ₂ , Fab', or Fab fraction of the antibody molecule may be used. Antibodies are monoclonal antibodies, polyclonal antibodies, human-mouse chimeric antibodies,
A human antibody or a human antibody prepared by genetic engineering may be used. Human antibodies can be prepared by a cell fusion method using human myeloma cells or by immunizing a mouse into which a human immunoglobulin gene has been introduced, and fusing the immunocompetent cells of the mouse with myeloma cells (K. Tomizuka e).
t. Al. Proc. Natl. Acad. Sci. 97, 722-727, 200
0). The genetically engineered human antibodies, single chain antibodies crosslink the V _H and V _L regions are also included. Quantification of the polypeptide of the present invention or its precursor protein or their amides or their esters or their salts using an antibody against the polypeptide of the present invention or its precursor proteins or their amides or their esters or their salts The method is not particularly limited, and the amount of the antigen in the test solution (for example,
Detecting the amount of the antibody, antigen or antibody-antigen complex corresponding to the polypeptide of the present invention or its precursor protein or its amide or their ester or their salts) by chemical or physical means,
Any measurement method may be used as long as it is calculated from a standard curve prepared using a standard solution containing a known amount of antigen. For example, nephelometry, a competitive method, an immunometric method, and a sandwich method are suitably used. In applying these individual immunoassays to the quantification method of the present invention, no special conditions, operations, and the like need to be set. What is necessary is just to construct the measuring system of the polypeptide of this invention, adding the usual technical consideration of those skilled in the art to the usual conditions and operation methods in each method. For details of these general technical means, reference can be made to reviews and books.

For example, "Radioimmunoassay" edited by Hiroshi Irie (Kodansha, published in 1974), "Radioimmunoassay" edited by Hiroshi Irie (published in Kodansha, 1979), "enzyme immunoassay" edited by Eiji Ishikawa et al. Shoin, published in 1978), Eiji Ishikawa et al., “Enzyme Immunoassay” (2nd edition) (Medical Shoin, published in 1982), Eiji Ishikawa, et al., “Enzyme Immunoassay” (3rd edition) (Medical) Shoin, published in 1987), "Me
thods in ENZYMOLOGY ”Vol. 70 (Immunochemical Techn
iques (Part A)), ibid.Vol. 73 (Immunochemical Techn.
iques (Part B)), Ibid.Vol. 74 (Immunochemical Techn)
iques (Part C)), ibid.Vol. 84 (Immunochemical Techn)
iques (Part D: Selected Immunoassays)), ibid.Vol. 9
2 (Immunochemical Techniques (Part E: Monoclonal Anti
bodies and General Immunoassay Methods)), ibid.
l. 121 (Immunochemical Techniques (Part I: Hybridoma
Technology and Monoclonal Antibodies)) (above, published by Academic Press).

(4) GPR14 (SENR) or its
Antibody to amide or its ester or its salt
The antibody against GPR14 (SENR) or its amide or its ester or its salt can inhibit the function of GPR14 (SENR) or its amide or its ester or its salt in a living body. , Attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia or phobia. GPR
Antibodies against 14 (SENR) or its amide or its ester or its salt can be used for the diagnosis of diseases such as attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia. In addition, GPR14 (SENR) or its amide, its ester or its salt can be quantified using the antibody, and detection by tissue staining or the like can also be performed. For these purposes, the antibody molecule itself may be used,
F (ab ') ₂ , Fab', or Fab fractions of antibody molecules may be used. The antibody may be a monoclonal antibody, a polyclonal antibody, a human-mouse chimeric antibody, a human antibody, or a genetically engineered human antibody. Human antibodies can be prepared by a cell fusion method using human myeloma cells or by immunizing a mouse into which a human immunoglobulin gene has been introduced, and fusing the immunocompetent cells of the mouse with myeloma cells (K. Tomizukaet. . Proc. Nat
l. Acad. Sci. 97, 722-727, 2000). The genetically engineered human antibodies, single chain antibodies crosslink the V _H and V _L regions are also included. The method for quantifying GPR14 (SENR) or its amide or its ester or its salt using an antibody against GPR14 (SENR) or its amide or its ester or its salt is not particularly limited. The amount of the antibody, antigen or antibody-antigen complex corresponding to the amount (for example, the amount of GPR14 (SENR) or its amide or its ester or its salt) is detected by chemical or physical means, and the amount is determined by a known amount. Any measurement method may be used as long as it is a measurement method calculated from a standard curve prepared using a standard solution containing an antigen. For example, nephelometry, a competitive method, an immunometric method, and a sandwich method are suitably used. In applying these individual immunoassays to the quantification method of the present invention, special conditions,
No settings such as operation are required. What is necessary is just to construct the measuring system of the polypeptide of this invention, adding the usual technical consideration of those skilled in the art to the usual conditions and operation methods in each method.
For details of these general technical means, reference can be made to reviews and books.

For example, “Radio immunoassay” edited by Hiroshi Irie (Kodansha, published in 1974), “Radio Immunoassay” continued by Hiroshi Irie (published in 1954), “Enzyme immunoassay” (ed.) Edited by Eiji Ishikawa et al. Shoin, published in 1978), Eiji Ishikawa et al., “Enzyme Immunoassay” (2nd edition) (Medical Shoin, published in 1982), Eiji Ishikawa, et al., “Enzyme Immunoassay” (3rd edition) (Medical) Shoin, published in 1987), "Me
thods in ENZYMOLOGY ”Vol. 70 (Immunochemical Techn
iques (Part A)), ibid.Vol. 73 (Immunochemical Techn.
iques (Part B)), Ibid.Vol. 74 (Immunochemical Techn)
iques (Part C)), ibid.Vol. 84 (Immunochemical Techn)
iques (Part D: Selected Immunoassays)), ibid.Vol. 9
2 (Immunochemical Techniques (Part E: Monoclonal Anti
bodies and General Immunoassay Methods)), ibid.
l. 121 (Immunochemical Techniques (Part I: Hybridoma
Technology and Monoclonal Antibodies)) (above, published by Academic Press).

(5) Remains related to the polypeptide of the present invention
Gene diagnostic method the DNA encoding the polypeptides of the present invention (the promoter region, exons, introns) or mRNA
The information on the properties of the DNA may include, for example, damage to the DNA or the mRNA associated with attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or fear, or suddenness if the abnormality (gene abnormality) is found. It is useful for performing genetic diagnosis, because it can realize the detection of abnormalities such as mutation, decreased expression, increased copy number, and excessive expression. For mRNA, increase or decrease of splice variant expression, or mRNA editing (C.
M. Niswender et. Al. Ann. NY Acad. Sci. 861, 38
-48, 1998) is also considered. In addition, information on loci on the chromosome can also be used for research on genetic diseases involving the DNA of the present invention. The above-described genetic diagnosis using a DNA encoding the polypeptide of the present invention can be performed, for example, by the known Northern hybridization or PCR-S
SCP method (Genomics, Vol. 5, 874)
879 (1989), The Prossings of
The National Academy of Sciences
Proceedings of the National Ac
ademy ofSciences of the United States of Americ
a), Vol. 86, pp. 2766-2770 (1989)
Year), DNA microarray (Scienc
e), Vol. 270, pp. 467-470 (1995),
Or other methods (Experimental Medicine Vol. 18, No. 14, 1894)
-1906, 2000). When an increase or decrease in the expression of the gene or a mutation in the DNA is detected by any of the methods described above, the disease may be associated with various diseases, particularly attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia. It is possible to make a diagnosis such as easy, attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia. In particular, in recent years, SNP has become a very important tool in searching for disease-related genes.
s (single nucleotide polymorphisms, single nucleotide polymorphism)
The emergence of a polymorphic marker called, which defines the likelihood of becoming a disease (difficulty of becoming a disease), and is attracting attention as a factor that affects differences in responsiveness and side effects to drugs. Depending on the specific purpose, SNPs can be typed directly by sequencing, Invade
r method, Sniper method, MALDI-TOF / MS method, oligo SNP chip method, etc. (Experimental Medicine Vol. 18, No. 12, 2000)
Year). DNA encoding the protein of the present invention (promoter region, exon,
(Including introns) can be SNPs by themselves or on other genes or the DNA of the present invention.
By analyzing in conjunction with this, it is possible to judge the susceptibility to attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia, and predict the onset time, or attention deficit disorder, narcolepsy, anxiety, depression, insomnia It is useful for diagnosis of schizophrenia or phobia.

(6) Related to GPR14 (SENR)
Genetic diagnosis method GPR14 (SENR) (for example, SEQ ID NO:
No. 3 or amino acid sequence represented by SEQ ID NO: 11), information relating to the properties of the DNA (including the promoter region, exons and introns) or the mRNA encoding the protein contains those abnormalities (genetical abnormalities). Damage, mutation, decreased expression of the DNA or mRNA associated with, for example, attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or fear,
It is useful for performing a genetic diagnosis, because it can realize detection of an abnormality such as an increase in copy number and excessive expression. For mRNA, increase or decrease of splice variant expression or mRNA editing (CM Ni
swender et. Al. Ann. NY Acad. Sci. 861, 38-48,
1998) is also considered. In addition, information on loci on the chromosome can also be used for research on genetic diseases involving the DNA of the present invention. GPR14 (SENR) (for example,
DN encoding a protein comprising the amino acid sequence of the present invention represented by SEQ ID NO: 3 or SEQ ID NO: 11)
The above-mentioned genetic diagnosis using A can be performed, for example, by Northern hybridization or PCR-SSCP method (Genomics, Vol. 5, 874-879) known per se.
Page (1989), Proceedings of the National Academy of Sciences of USA
Sciences of the UnitedStates of America), 86th
Volume, 2766-2770 (1989), DNA microarray (Science, 270, 4)
67-470 (1995), or other methods (Experimental Medicine 18:14, 1894-1906, 20)
2000) or the like. Increase or decrease the expression of the gene by any of the above methods,
If the mutation is detected, it is susceptible to various diseases, especially attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia, or attention deficit disorder, narcolepsy, anxiety, depression, insomnia, mental disorders Diagnosis such as schizophrenia or phobia is highly possible. GPR14 (SENR) (for example,
DN encoding a protein comprising the amino acid sequence of the present invention represented by SEQ ID NO: 3 or SEQ ID NO: 11)
A (including promoter region, exons and introns)
Are analyzed by themselves or alone or in combination with the DNA of the present invention for attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia. It is useful for determining the susceptibility and predicting the onset time, or for diagnosing attention deficit disorder, narcolepsy, anxiety, depression, insomnia, schizophrenia or phobia.

In the present specification and drawings, when bases, amino acids and the like are represented by abbreviations, IUPAC-IUB
It is based on the abbreviation by the Commission on Biochemical Nomenclature or the abbreviation commonly used in the relevant field. When an amino acid can have an optical isomer, the L-form is indicated unless otherwise specified. DNA: deoxyribonucleic acid cDNA: complementary deoxyribonucleic acid A: adenine T: thymine G: guanine C: cytosine Y: thymine or cytosine N: thymine, cytosine, adenine or guanine R: adenine or guanine M: cytosine or adenine W: thymine or adenine Adenine S: cytosine or guanine RNA: ribonucleic acid mRNA: messenger ribonucleic acid dATP: deoxyadenosine triphosphate dTTP: deoxythymidine triphosphate dGTP: deoxyguanosine triphosphate dCTP: deoxycytidine triphosphate ATP: adenosine triphosphate EDTA : Ethylenediaminetetraacetic acid SDS: Sodium dodecyl sulfate TFA: Trifluoroacetic acid EIA: Enzyme immunoassay Gly or G: Glycine Ala Or A: Alanine Val or V: Valine Leu or L: Leucine Ile or I: Isoleucine Ser or S: Serine Thr or T: Threonine Cys or C: Cysteine Met or M: Methionine Glu or E: Glutamate Asp or D: Asparagine Acid Lys or K: lysine Arg or R: arginine His or H: histidine Phe or F: phenylalanine Tyr or Y: tyrosine Trp or W: tryptophan Pro or P: proline Asn or N: asparagine Gln or Q: glutamine pGuglutamine Me: methyl group Et: ethyl group Bu: butyl group Ph: phenyl group TC: thiazolidine-4 (R) -carboxamide group Bom: benzyl Oxymethyl NMP: N-methylpyrrolidone PAM: phenylacetamidomethyl

The substituents, protecting groups and reagents frequently used in the present specification are represented by the following symbols. Tos: p-toluenesulfonyl HONB: N-hydroxy-5-norbornene-2,3
-Dicarboximide Bzl: benzyl Z: benzyloxycarbonyl Br-Z: 2-bromobenzyloxycarbonyl Cl-Z: 2-chlorobenzyloxycarbonyl Boc: t-butyloxycarbonyl HOBt: 1-hydroxybenztriazole DCC: N, N'-dicyclohexylcarbodiimide TFA: trifluoroacetic acid Fmoc: N-9-fluorenylmethoxycarbonyl DNP: dinitrophenyl Bum: tert-butoxymethyl Trt: trityl MeBzl: 4-methylbenzyl CHO: formyl NMP: N-methylpyrrolidone OcHex : Cyclohexyl ester

[0231] The sequence numbers in the sequence listing in the present specification indicate the following sequences. [SEQ ID NO: 1] This shows the amino acid sequence of porcine SENR ligand peptide (porcine ligand 1). [SEQ ID NO: 2] This shows the amino acid sequence of porcine SENR ligand peptide (porcine ligand 2). [SEQ ID NO: 3] This shows the amino acid sequence of rat SENR protein. [SEQ ID NO: 4] Porcine SENR ligand precursor protein cD
Shows the entire nucleotide sequence of NA. [SEQ ID NO: 5] Porcine SENR ligand precursor protein cD
Shows the entire nucleotide sequence of NA. [SEQ ID NO: 6] Porcine SENR ligand precursor protein cD
Shows the entire nucleotide sequence of NA. [SEQ ID NO: 7] This shows the entire amino acid sequence of porcine SENR ligand precursor protein. [SEQ ID NO: 8] This shows the entire amino acid sequence of porcine SENR ligand precursor protein. [SEQ ID NO: 9] This shows the amino acid sequence of bovine SENR ligand peptide. [SEQ ID NO: 10] This shows the amino acid sequence of human SENR ligand polypeptide (human urotensin II). [SEQ ID NO: 11] This shows the entire amino acid sequence of human SENR protein. [SEQ ID NO: 12] This shows the DNA sequence of SEQ ID NO: 2 (porcine ligand 2). [SEQ ID NO: 13] D of SEQ ID NO: 9 (bovine ligand)
Shows the NA sequence. [SEQ ID NO: 14] This shows the entire amino acid sequence of bovine SENR ligand precursor protein. [SEQ ID NO: 15] Bovine SENR ligand precursor protein
1 shows the entire nucleotide sequence of cDNA. [SEQ ID NO: 16] rat urotensin II like peptide
1 shows the entire nucleotide sequence of a precursor protein cDNA. [SEQ ID NO: 17] rat urotensin II like peptide
2 shows the entire amino acid sequence of the precursor protein. [SEQ ID NO: 18] rat urotensin II like peptide-
1 shows the amino acid sequence of 1. [SEQ ID NO: 19] rat urotensin II like peptide-
2 shows the amino acid sequence of 2. [SEQ ID NO: 20] SEQ ID NO: 18 (rat urotensin
2 shows the DNA sequence of II like peptide-1). [SEQ ID NO: 21] SEQ ID NO: 19 (rat urotensin
2 shows the DNA sequence of II like peptide-2). [SEQ ID NO: 22] mouse urotensin II like peptide
1 shows the entire nucleotide sequence of a precursor protein cDNA. [SEQ ID NO: 23] mouse urotensin II like peptide
2 shows the entire amino acid sequence of the precursor protein. [SEQ ID NO: 24] mouse urotensin II like peptide
1 shows the amino acid sequence of [SEQ ID NO: 25] SEQ ID NO: 24 (mouse urotensin
2 shows the DNA sequence of II like peptide). [SEQ ID NO: 26] This shows the amino acid sequence of mature rat urotensin II like peptide deduced from the amino acid sequence of precursor protein. [SEQ ID NO: 27] This shows the amino acid sequence of mature rat urotensin II like peptide deduced from the amino acid sequence of precursor protein. [SEQ ID NO: 28] This shows the amino acid sequence of mature mouse urotensin II like peptide deduced from the amino acid sequence of precursor protein. [SEQ ID NO: 29] This shows the amino acid sequence of mature mouse urotensin II like peptide deduced from the amino acid sequence of precursor protein. [SEQ ID NO: 30] SEQ ID NO: 26 (rat urotensin
2 shows the DNA sequence of II like peptide (mature peptide). [SEQ ID NO: 31] SEQ ID NO: 27 (rat urotensin
2 shows the DNA sequence of II like peptide (mature peptide). [SEQ ID NO: 32] SEQ ID NO: 28 (mouse urotensin
2 shows the DNA sequence of II like peptide (mature peptide). [SEQ ID NO: 33] SEQ ID NO: 29 (mouse urotensin
2 shows the DNA sequence of II like peptide (mature peptide). [SEQ ID NO: 34] human SENR ligand (SEQ ID NO:
10 shows the DNA sequence of 10).

[0232]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto.

In the following Reference Examples, mass spectra (MS)
Was measured under the following conditions. Measurement equipment: Micromass Platform II Ionization method: Atmospheric pressure chemical ionization method (Atmospheric Pr
essure Chemical Ionization: APCI) or Electron Impact Ionization (Electron Spray Ionization: ESI)

Reference Example 1 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine N-benzylpyrrolidone (1.8 g, 10.4 mmol) was dissolved in 4 ml of chloroform, phosphorus oxychloride (1.8 g, 11.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. . 4-Bromo-2-cyanoaniline (2.0 g, 10 mmol) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water and neutralized with a 20% aqueous sodium hydroxide solution. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in 10 ml of nitrobenzene, 2 g of zinc chloride was added, and the mixture was heated at 160 ° C. for 3 hours. A 20% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 50 g, ethyl acetate / hexane = 1/2). The target fraction was concentrated under reduced pressure, ethanol was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to give the title compound (1.2 g, 3.4 mmo
l) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (2H, t, J = 8.0 Hz), 3.41 (2
(H, t, J = 8.0Hz), 4.59 (2H, s), 7.24-7.33 (6H, m),
7.42 (1H, dd, J = 9.2, 2.2Hz), 8.12 (1H, d, J = 2.2H
z). Mass (ESI +); 354 (M + H), 356

Reference Example 2 1-benzyl-6- (4-methylphenyl) -2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2, 3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (70 mg, 0.
2 mmol) was suspended in 0.5 ml of toluene, and Pd (Ph ₃ P) ₄ (6 mg) and 2
A 0.2 M aqueous solution of sodium carbonate and a solution of 4-methylphenylboronic acid (30 mg) in ethanol (0.25 ml) were added, and the mixture was reacted at 90 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
(2 g of silica gel, ethyl acetate / hexane = 1/2).
After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (15 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.92 (2H, t, J = 8.0H
z), 3.50 (2H, t, J = 8.0Hz), 4.75 (2H, s), 7.24-7.38
(7H, m), 7.57 (2H, d), 7.69 (3H, m) .Mass (ESI +);
366 (M + H)

Reference Example 3 1-benzyl-6- (3-thienyl) -2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo-2 , 3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (140 mg,
0.4 mmol) was suspended in 1 ml of toluene, and a solution of Pd (Ph ₃ P) ₄ (12 mg), a 2 M aqueous solution of sodium carbonate (0.4 ml) and 3-thiophenboronic acid (56 mg) in ethanol (0.5 ml) was added.
The reaction was performed for 6 hours. Water and ethyl acetate were added to the reaction solution, the layers were separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1/2). did. After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (52 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.01 (2H, t, J = 8.0Hz), 3.73 (2
(H, t, J = 8.0Hz), 4.92 (2H, s), 7.40 (5H, bs), 7.70-
7.88 (3H, m), 8.02-8.09 (2H, m), 8.54 (1H, s) .Mass (ESI +); 358 (M + H)

Reference Example 4 N-benzyl-1-benzyl-6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2,3 -Dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (70 mg, 0.
2 mmol) was dissolved in 1 ml of dimethylformamide, and 2-tert-
Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (0.24 ml) and benzyl bromide (0.095 ml) were added and reacted at 80 ° C. for 1 hour.
Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated.
Purification was performed by HPLC (YMC CombiPrep ODS, 20 × 50 mm). The desired fraction was dried under reduced pressure to give the title compound (44 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.13 (2H, t, J = 8.0 Hz), 3.54 (2H,
t, J = 8.0Hz), 4.72 (2H, s), 4.82 (2H, s), 7.22-7.37
(10H, m), 7.50 (1H, dd, J = 9.0, 2.0Hz), 7.69 (1H, d,
J = 9.0Hz), 8.00 (1H, d, J = 2.0Hz) .Mass (ESI +); 444 (M + H), 446

Reference Example 5 N, N-dibenzyl-1-benzyl-6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2 , 3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (70 mg, 0.
2 mmol) was dissolved in 1 ml of dimethylformamide, and 2-tert-
Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (0.24 ml) and benzyl bromide (0.095 ml) were added and reacted at 80 ° C. for 1 hour.
Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated.
Purification was performed by HPLC (YMC CombiPrep ODS, 20 × 50 mm). The desired fraction was dried under reduced pressure to obtain the title compound (32 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.61 (2H, t, J = 8.0 Hz), 3.49 (2H,
t, J = 8.0Hz), 4.27 (4H, s), 4.99 (2H, s), 7.17-7.38
(15H, m), 7.74 (1H, dd, J = 8.8, 2.0Hz), 7.97 (1H, d,
J = 8.8Hz), 8.16 (1H, d, J = 2.0Hz) .Mass (ESI +); 534 (M + H), 536

Reference Example 6 N-allyl-1-benzyl-6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo- 2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (70 mg, 0.
2 mmol) was dissolved in 1 ml of dimethylformamide, and 2-tert-
Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (0.24 ml) and allyl bromide (0.07 ml) were added and reacted at 80 ° C. for 1 hour. Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by HPLC.
(YMC CombiPrep ODS, 20 × 50 mm). The target fraction was dried under reduced pressure to obtain the title compound (26 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.23 (2H, t, J = 8.0Hz), 3.62 (2H,
t, J = 8.0Hz), 4.07 (2H, bs), 4.83 (2H, s), 5.12-5.24
(2H, m), 5.91-6.00 (1H, m), 7.35 (5H, bs), 7.44 (1
H, dd, J = 8.8, 2.0Hz), 7.61 (1H, d, J = 8.8Hz), 8.03
(1H, d, J = 2.0Hz). Mass (ESI +); 394 (M + H), 396

Reference Example 7 N, N-diallyl-1-benzyl-6-bromo-
2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (70 mg, 0.
2 mmol) was dissolved in 1 ml of dimethylformamide, and 2-tert-
Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin (0.24 ml) and allyl bromide (0.07 ml) were added and reacted at 80 ° C. for 1 hour. Water and ethyl acetate were added to the reaction solution, and after separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by HPLC.
(YMC CombiPrep ODS, 20 × 50 mm). The desired fraction was dried under reduced pressure to obtain the title compound (12 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.20 (2H, t, J = 8.0Hz), 3.70 (2H,
t, J = 8.0Hz), 3.88 (4H, d), 5.01 (2H, s), 5.20-5.2
9 (4H, m), 5.68-5.89 (2H, m), 7.36 (5H, bs), 7.67
(1H, dd, J = 9.0, 2.0Hz), 7.90 (1H, d, J = 9.0Hz), 7.9
7 (1H, d, J = 2.0Hz) .Mass (ESI +); 434 (M + H), 436

Reference Example 8 N-methyl-1-benzyl-6-bromo-2,3-dihydro-
1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (50 mg) was dissolved in 0.5 ml of dimethylformamide, 0.05 ml of diisopropylethylamine and 0.5 ml of methyl iodide were added, and the mixture was reacted at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure and the residue was collected.
Purification was performed by HPLC (YMC CombiPrep ODS, 20 × 50 mm). The desired fraction was dried under reduced pressure to obtain the title compound (8 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.19 (3H, s), 3.39 (2H, t, J = 8.0
Hz), 3.66 (2H, t, J = 8.0Hz), 4.81 (2H, s), 7.28-7.5
7 (7H, m), 7.97 (1H, s) .Mass (ESI +); 368 (M + H), 370

Reference Example 9 N, N-dimethyl-1-benzyl-6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine 1-benzyl-6-bromo-2 , 3-Dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (50 mg) was dissolved in 0.5 ml of dimethylformamide, 0.05 ml of diisopropylethylamine and 0.5 ml of methyl iodide were added, and the mixture was reacted at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure and the residue was collected.
Purification was performed by HPLC (YMC CombiPrep ODS, 20 × 50 mm). The desired fraction was dried under reduced pressure to obtain the title compound (5 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.14 (6H, s), 3.37 (2H, t, J = 8.0
Hz), 3.74 (2H, t, J = 8.0Hz), 4.94 (2H, s), 7.38 (5
H, bs), 7.67 (1H, dd, J = 9.0, 2.0Hz), 7.77 (1H, d,
J = 9.0Hz), 7.95 (1H, d, J = 2.0Hz) .Mass (ESI +); 382 (M + H), 384

Reference Example 10 6-bromo-1- (4-fluorobenzyl) -2,3-
Dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine sodium hydride (60% mineral oil suspension) (4
To a suspension of 40 mg) in N, N-dimethylformamide (10 ml) was added 2-pyrrolidone (0.76 ml), and the mixture was stirred at room temperature for 15 minutes, and then 4-fluorobenzyl bromide (1.37 ml).
Was added. After the reaction mixture was stirred at room temperature for 15 hours, water was added and extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n-
Purification with hexane / ethyl acetate = 1/2) gave 1- (4-fluorobenzyl) -2-pyrrolidone (1.28 g). Phosphorus oxychloride (0.30 ml) was added to a solution of 1- (4-fluorobenzyl) -2-pyrrolidone (600 mg) in chloroform (3 ml), and the mixture was stirred at room temperature for 30 minutes, then 2-amino-5-bromobenzonitrile (583 mg) ) Was added. After heating and refluxing the reaction mixture for 3 hours, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 5-bromo-2-{(1- (4-fluorobenzyl) -2-pyrrolidinylidene) amino} benzonitrile (1. 01g). Under a nitrogen atmosphere, 5-bromo-2-｛(1- (4-
Fluorobenzyl) -2-pyrrolidinylidene) amino
A solution of benzonitrile (1.01 g) in tetrahydrofuran (8 ml) was cooled to -40 ° C. Under stirring at the same temperature, lithium diisopropylpropylamide (2.0 M heptane / tetrahydrofuran / ethylbenzene solution; 1.63 ml) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred for 1 hour. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 2/1) to obtain the title compound (347 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (2H, t, J = 8.0Hz), 3.42
(2H, t, J = 8.0Hz), 4.58 (2H, s), 7.14 (2H, d, J = 8.8H
z), 7.29-7.46 (4H, m), 8.13 (1H, d, J = 2.2Hz) Mass (APCI +); 372 (M + H), 374

Reference Example 11 6-Bromo-1- (2-phenethyl) -2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride Sodium hydride (60% mineral oil suspension) Turbid liquid) (4
To a suspension of 40 mg) in N, N-dimethylformamide (10 ml) was added 2-pyrrolidone (0.76 ml), and the mixture was stirred at room temperature for 15 minutes, and then (2-bromoethyl) benzene (1.50 ml).
Was added. After the reaction mixture was stirred at room temperature for 15 hours, water was added and extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n-
Purification with hexane / ethyl acetate = 1/2) gave 1- (2-phenethyl) -2-pyrrolidone (0.438 g). 1
-Phosphorus oxychloride (0.23) was added to a solution of-(2-phenethyl) -2-pyrrolidone (438 mg) in chloroform (3 ml).
ml) and the mixture was stirred at room temperature for 30 minutes, and then 2-amino-5-bromobenzonitrile (435 mg) was added. After heating and refluxing the reaction mixture for 3 hours, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2-｛(1-
(2-phenethyl) -2-pyrrolidinylidene) amino}
Benzonitrile (736 mg) was obtained. Under nitrogen atmosphere, 5
A solution of -bromo-2-{(1- (2-phenethyl) -2-pyrrolidinylidene) amino} benzonitrile (736 mg) in tetrahydrofuran (6 ml) was cooled to -40 ° C. Under stirring at the same temperature, lithium diisopropylpropylamide (2.0 M heptane / tetrahydrofuran / ethylbenzene solution; 1.20 ml) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred for 1 hour. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 2/1), and further treated with 4N hydrochloric acid in ethyl acetate to give the title compound (254 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.80-3.00 (2H, m), 3.15-3.30
(2H, m), 3.83 (2H, t, J = 8.0Hz), 3.93 (2H, t, J = 8.0
Hz), 7.15-7.45 (5H, m), 7.75-7.90 (2H, m), 8.39 (1
H, s)

Reference Example 12 6-Bromo-1- (3-pyridinylmethyl) -2,3-
Dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine dihydrochloride Sodium hydride (60% mineral oil suspension) (8
2-pyrrolidone (0.76 ml) was added to a suspension of 80 mg) in N, N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 15 minutes, and then 3- (chloromethyl) pyridine hydrochloride (1.8).
0 g) was added. After stirring the reaction mixture at room temperature for 15 hours,
Water was added and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was treated with a 4N solution of hydrochloric acid in ethyl acetate to give 1- (3-pyridinylmethyl) -2-pyrrolidone hydrochloride (2.02 g). Phosphorus oxychloride (0.31 ml) was added to a solution of 1- (3-pyridinylmethyl) -2-pyrrolidone hydrochloride (600 mg) in chloroform (3 ml), and the mixture was stirred at room temperature for 30 minutes, and then 2-amino-5-bromobenzonitrile ( 530 mg). After heating and refluxing the reaction mixture for 3 hours, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2-{(1- (3-pyridinylmethyl) -2-pyrrolidinylidene) amino} benzonitrile (736 mg). Obtained. Under nitrogen atmosphere
Bromo-2-{(1- (3-pyridinylmethyl) -2-
Pyrrolidinylidene) amino @ benzonitrile (940m
A solution of g) in tetrahydrofuran (10 ml) was cooled to -40 ° C. Under stirring at the same temperature, lithium diisopropylpropylamide (2.0 M heptane / tetrahydrofuran / ethylbenzene solution; 1.99 ml) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred for 1 hour. Ice water is added to the reaction solution,
Extracted with ethyl acetate. Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n-hexane /
The residue was purified with ethyl acetate (2/1) and further treated with 4N hydrochloric acid in ethyl acetate to give the title compound (198 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.00 (2H, t, J = 8.0Hz), 3.79 (2
H, t, J = 8.0Hz), 5.28 (2H, s), 7.56 (2H, m), 7.83 (1
(H, d, J = 8.0Hz), 7.90-8.10 (2H, m), 8.46 (1H, s), 8.
54 (1H, d, J = 8.0Hz), 8.85 (1H, d, J = 5.8Hz), 9.05
(1H, s) Mass (APCI +); 355 (M + H), 357

Reference Example 13 1-benzyl-6-fluoro-2,3-dihydro-1H
-Pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride To a solution of 1-benzyl-2-pyrrolidone (0.84 ml) in chloroform (3 ml) was added phosphorus oxychloride (0.51 ml) and the mixture was stirred at room temperature for 30 minutes. Thereafter, 2-amino-5-fluorobenzonitrile (0.65 ml) was added. Add 3 reaction mixtures
After heating under reflux for an hour, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform.
The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-fluoro-2-{(1-benzyl-2-pyrrolidinylidene) amino} benzonitrile (1.68 g). . A solution of 5-fluoro-2-{(1-benzyl-2-pyrrolidinylidene) amino} benzonitrile (500 mg) in tetrahydrofuran (2 ml) was prepared by adding-
It was added to a solution of sodium hexamethyldisilazane (3.91 ml) cooled to 78 ° C. in tetrahydrofuran (3 ml). After stirring at the same temperature for 15 minutes, the reaction solution was gradually heated to -20 ° C and stirred for 2 hours. Further raise the temperature to 40 ° C and
After stirring for an hour, saturated saline was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (n-hexane / ethyl acetate = 2 /
Purification in 1) and further treatment with 4N hydrochloric acid in ethyl acetate solution gave the title compound (60 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (2H, t, J = 8.0Hz), 3.72 (2
(H, t, J = 8.0Hz), 4.95 (2H, s), 7.25-7.65 (6H, m), 7.
95-8.15 (2H, m) Mass (APCI +); 294 (M + H)

Reference Example 14 1-benzyl-7-bromo-1,2,3,4-tetrahydrobenzo [b] [1,8] naphthyridin-5-ylamine hydrochloride sodium hydride (60% mineral oil suspension ) (4
To a suspension of 40 mg) in N, N-dimethylformamide (10 ml) was added 2-piperidone (991 mg), and after stirring at room temperature for 15 minutes, benzyl bromide (1.31 ml) was added. After stirring the reaction mixture at room temperature for 4 hours, water was added and extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 1/1) to obtain 1-benzyl-2-piperidone (1.30 g). Phosphorus oxychloride (0.29 ml) was added to a solution of 1-benzyl-2-piperidone (567 mg) in chloroform (3 ml). After heating and refluxing the reaction mixture for 3 hours, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2-{(1-benzyl-2-).
Piperidinylidene) amino @ benzonitrile (1.05
g) was obtained. 5-bromo-2-｛(1-benzyl-2-
Piperidinylidene) amino @ benzonitrile (1.01
g) was dissolved in nitrobenzene (5 ml) and zinc chloride (4 ml) was added.
After adding 66 mg), the mixture was stirred at 155 ° C. for 1 hour. After cooling, a 20% aqueous sodium hydroxide solution was added to adjust the pH to 10, followed by extraction with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n
-Hexane / ethyl acetate = 9/1 → 3/2) and further treated with 4N hydrochloric acid in ethyl acetate to give the title compound (5.
51 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.00 (2H, m), 2.59 (2H,
t, J = 6.0Hz), 3.10-3.50 (2H, m), 5.12 (2H, s), 7.25-
7.45 (5H, m), 7.80 (1H, dd, J = 1.8Hz, 8.8Hz), 8.03
(1H, d, J = 8.8Hz), 8.54 (1H, d, J = 1.8Hz) Mass (APCI +); 368 (M + H), 370

Reference Example 15 1-benzyl-7-bromo-2,2,4,5-tetrahydro-1H-azepino [2,3-b] quinolin-6-ylamine hydrochloride Sodium hydride (60% mineral oil suspension) Turbid liquid) (4
Ε-caprolactam (1.13 g) was added to a suspension of N, N-dimethylformamide (40 ml) in 40 ml), and the mixture was added at room temperature.
After stirring for 5 minutes, benzyl bromide (1.31 ml) was added. After stirring the reaction mixture at room temperature for 4 hours, water was added and extracted with diethyl ether. Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n-hexane /
Purification with ethyl acetate (1/1) gave N-benzyl-ε-caprolactam (1.72 g). Phosphorus oxychloride (0.29 ml) was added to a solution of N-benzyl-ε-caprolactam (607 mg) in chloroform (3 ml). Add 3 reaction mixtures
After heating under reflux for an hour, ice water was added. Further, the mixture was neutralized by adding a 20% aqueous sodium hydroxide solution, and extracted with chloroform.
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-benzyl-2-{(4-bromo-2-cyanophenyl) imino} hexahydro-1.
H-azepine (1.08 g) was obtained. 1-benzyl-2-
{(4-Bromo-2-cyanophenyl) imino} hexahydro-1H-azepine (1.08 g) was dissolved in nitrobenzene (5 ml), and zinc chloride (463 mg) was added.
Stirred at 155 ° C. for 1 hour. After cooling, aqueous ammonia was added to adjust the pH to 10, followed by extraction with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography (n-hexane / ethyl acetate = 9/1 → 3/2).
The residue was treated with 4N hydrochloric acid in ethyl acetate to give the title compound (475 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.85 (4H, m), 2.71 (2H,
m), 3.51 (2H, m), 4.94 (2H, s), 7.30-7.50 (5H, m), 7.
84 (1H, dd, J = 2.0Hz, 8.8Hz), 8.07 (1H, d, J = 8.8H
z), 8.60 (1H, d, J = 2.0Hz) Mass (APCI +); 382 (M + H), 384

Reference Example 16 1-benzyl-6- (benzofuran-2-yl) -2,3
-Dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (140 mg,
0.4 mmol) was suspended in 1 ml of toluene, Pd (Ph ₃ P) ₄ (12 mg) and 0.4 ml of a 2 M aqueous sodium carbonate solution,
Add a solution of ilboronic acid (72 mg) in ethanol (0.5 ml) and add 9
The reaction was performed at 0 ° C. for 16 hours. Water and ethyl acetate were added to the reaction solution, the layers were separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1/2). did. After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (63 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.01 (2H, t, J = 8.0 Hz), 3.74 (2
(H, t, J = 8.0Hz), 4.95 (2H, s), 7.26-7.74 (12H, m),
7.97 (1H, d, J = 8.4Hz), 8.19 (1H, d, J = 8.4Hz), 8.75
(1H, s). Mass (ESI +); 392 (M + H)

Reference Example 17 1-benzyl-6- (3-acetaminophenyl) -2,
3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (140 mg,
0.4 mmol) was suspended in 1 ml of toluene, and a solution of Pd (Ph ₃ P) ₄ (12 mg) and a 2 M aqueous solution of sodium carbonate 0.4 ml, and a solution of 3-acetoaminophenylboronic acid (79 mg) in ethanol (0.5 ml) were added. The reaction was performed for 16 hours. Water and ethyl acetate were added to the reaction solution, the layers were separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1/2). did. After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (17 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.09 (3H, s), 3.00 (2H, t, J =
8.0Hz), 3.73 (2H, t, J = 8.0Hz), 4.98 (2H, s), 7.35-
7.64 (9H, m), 7.88 (1H, d, J = 8.4Hz), 7.99 (2H, b
s), 8.01 (1H, d, J = 8.4Hz), 8.44 (1H, s) .Mass (ESI +); 409 (M + H)

Reference Example 18 1- (4-tert-butylbenzyl) -6-bromo-
2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (350 mg, 1
mmol) was suspended in 2 ml of dichloromethane, and BBr ₃ (1.4 ml) was added dropwise. After stirring at room temperature for 8 hours, ice water was added,
The mixture was made alkaline with a 10% aqueous sodium hydroxide solution and extracted with dichloromethane containing ethanol. After concentration under reduced pressure, the residue was crystallized from dichloromethane to give 6-bromo-
50 mg of 2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine were obtained. This was dissolved in 1 ml of N, N-dimethylformamide, and 0.088 ml of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin and 0.060 ml of 4-tert-butylbenzylbromide were dissolved. Was added and reacted at room temperature for 40 hours. After adding ice water and dichloromethane, the organic layer is washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate).
/ Hexane = 1/2). After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (20 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (9H, s), 2.98 (2H, t, J =
8.0Hz), 3.73 (2H, t, J = 8.0Hz), 4.87 (2H, s), 7.29
(1H, d, J = 8.2Hz), 7.42 (1H, d, J = 8.2Hz), 7.48 (2H,
bs), 7.81 (2H, s), 8.43 (1H, s). Mass (ESI +); 410 (M + H)

Reference Example 19 1- (4-Cyanobenzyl) -6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo- 2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (350 mg, 1
mmol) was suspended in 2 ml of dichloromethane, and BBr ₃ (1.4 ml) was added dropwise. After stirring at room temperature for 8 hours, ice water was added,
The mixture was made alkaline with a 10% aqueous sodium hydroxide solution and extracted with dichloromethane containing ethanol. After concentration under reduced pressure, the residue was crystallized from dichloromethane to give 6-bromo-
50 mg of 2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine were obtained. This was dissolved in 1 ml of N, N-dimethylformamide, and 0.088 ml of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin, 4-cyanobenzyl bromide 6
6 mg was added and reacted at room temperature for 40 hours. Ice water and dichloromethane were added, and after the liquid separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1).
/ 2). After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. After washing the precipitate with ethanol,
Drying under reduced pressure gave the title compound (20 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.00 (2H, t, J = 8.0Hz), 3.74 (2
H, t, J = 8.0Hz), 5.06 (2H, s), 7.50-7.62 (4H, m),
7.82-7.90 (6H, m), 8.45 (1H, s) .Mass (ESI +); 379 (M + H)

Reference Example 20 1- (3,5-dimethoxybenzyl) -6-bromo-2,
3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo-2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (350 mg, 1
mmol) was suspended in 2 ml of dichloromethane, and BBr ₃ (1.4 ml) was added dropwise. After stirring at room temperature for 8 hours, ice water was added,
The mixture was made alkaline with a 10% aqueous sodium hydroxide solution and extracted with dichloromethane containing ethanol. After concentration under reduced pressure, the residue was crystallized from dichloromethane to give 6-bromo-
50 mg of 2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine were obtained. This was dissolved in 1 ml of N, N-dimethylformamide, and 0.088 ml of 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin and 75 mg of 3,5-dimethoxybenzyl bromide were added. In addition, the reaction was performed at room temperature for 40 hours. Ice water and dichloromethane were added. After liquid separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1/2). After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (17 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (2H, t, J = 8.0 Hz), 3.70-3.
74 (8H, m), 6.42-6.54 (3H, m), 7.48 (2H, bs), 7.80
(2H, s), 8.43 (1H, s). Mass (ESI +); 414 (M + H)

Reference Example 21 1- (4-methoxybenzyl) -6-bromo-2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine hydrochloride 1-benzyl-6-bromo- 2,3-dihydro-1H-
Pyrrolo [2,3-b] quinolin-4-ylamine (350 mg, 1
mmol) was suspended in 2 ml of dichloromethane, and BBr ₃ (1.4 ml) was added dropwise. After stirring at room temperature for 8 hours, ice water was added,
The mixture was made alkaline with a 10% aqueous sodium hydroxide solution and extracted with dichloromethane containing ethanol. After concentration under reduced pressure, the residue was crystallized from dichloromethane to give 6-bromo-
50 mg of 2,3-dihydro-1H-pyrrolo [2,3-b] quinolin-4-ylamine were obtained. This was dissolved in 1 ml of N, N-dimethylformamide, and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin 0.088 ml, 4-methoxybenzyl bromide
0.045 ml was added and reacted at room temperature for 40 hours. Ice water and dichloromethane were added. After liquid separation, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (silica gel 2 g, ethyl acetate / hexane = 1/2). After the target fraction was concentrated, hydrochloric acid in ethanol was added, and the precipitate was collected by filtration. The precipitate was washed with ethanol and dried under reduced pressure to obtain the title compound (17 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.95 (2H, t, J = 8.0 Hz), 3.69 (2
(H, t, J = 8.0Hz), 3.75 (3H, s), 4.85 (2H, s), 6.95
(2H, d, J = 8.8Hz), 7.33 (2H, d, J = 8.8Hz), 7.45 (2H,
bs), 7.84 (2H, bs), 8.43 (1H, s).

Reference Example 22 4- (4-phenyl-1-piperazinyl) -1- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) -1-butanone trihydrochloride 1) 2,2,2-trifluoro-1- (1,2,4,5-tetrahydro-3H-
3-benzazepin-3-yl) -1-ethanone 2,3,4,5-tetrahydro-1H-3-benzazepine (15 g) and triethylamine (51 ml) in tetrahydrofuran (THF;
To the solution (100 ml) was added trifluoroacetic anhydride (31 g) under ice-cooling. After stirring the reaction mixture at room temperature for 15 hours, 1N hydrochloric acid was added to stop the reaction, and the mixture was extracted with ethyl acetate.
The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (normal hexane / ethyl acetate = 4/1)
Purification afforded the title compound (25 g). ¹ H-NMR (CDCl ₃ ) δ: 2.95-3.05 (4H, m), 3.65-3.85 (4
H, m), 7.10-7.30 (4H, m) 2) 4-bromo-1- [3- (2,2,2-trifluoroacetyl) -2,
3,4,5-tetrahydro-1H-3-benzazepin-7-yl] -1-
Butanone 2,2,2-trifluoro-1- (1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl) -1-ethanone (10 g) was added to a dichloromethane (70 ml) solution. -Bromobutyryl chloride (4.
8 ml) and aluminum chloride (8.2 g) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with dichloromethane. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (normal hexane /
Purification with ethyl acetate (4/1) gave the title compound (5.9 g). ¹ H-NMR (CDCl ₃ ) δ: 2.20-2.40 (2H, m), 2.95-3.10 (4
H, m), 3.17 (2H, t, J = 7.0 Hz), 3.56 (2H, t, J = 6.4
Hz), 3.65-3.85 (4H, m), 7.20-7.30 (1H, m), 7.75-7.
85 (2H, m) 3) 4- (4-phenyl-1-piperazinyl) -1- [3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3 -Benzazepin-7-yl] -1-butanone 4-bromo-1- [3- (2,2,2-trifluoroacetyl) -2,3,4,5
-Tetrahydro-1H-3-benzazepin-7-yl] -1-butanone (100 mg), 1-phenylpiperazine (0.043 ml), potassium carbonate (35 mg) and N, N-dimethylformamide (D
MF; 3 ml) was stirred at 80 ° C. for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane / ethyl acetate = 1/3) to give the title compound (72 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.91-2.05 (2H, m), 2.47 (2H, t,
J = 6.8 Hz), 2.55-2.65 (4H, m), 2.95-3.05 (6H, m),
3.10-3.20 (4H, m), 3.60-3.80 (4H, m), 6.80-6.95 (3
H, m), 7.20-7.30 (3H, m), 7.75-7.85 (2H, m) MS (APCI +): 474 (M + H) 4) 4- (4-phenyl-1-piperazinyl) -1- ( 2,3,4,5-tetrahydro-1H-3-benzazepine-
7-yl) -1-butanone trihydrochloride 4- (4-phenyl-1-piperazinyl) -1- [3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- 1H-3-Benzazepin-7-yl] -1-butanone (58 mg) in methanol (1 m
l) A 1M aqueous solution of potassium carbonate (0.24 ml) was added to the solution, and the mixture was stirred at room temperature for 1.5 hours. After methanol was distilled off under reduced pressure, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 4- (4-phenyl-1-piperazinyl) -1- (2,3,4,5-tetrahydro- 1H-3-Benzazepin-7-yl) -1-butanone was obtained. This was treated with a 1N solution of hydrogen chloride in ethyl acetate to obtain the desired compound (22 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.20 (2H, m), 3.10-3.40
(16H, m), 3.50-3.65 (2H, m), 3.70-3.90 (2H, m), 6.
87 (1H, t, J = 8.0 Hz), 7.00 (2H, d, J = 8.0 Hz), 7.27
(2H, t, J = 8.0 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.80-
7.85 (2H, m) MS (APCI +): 378 (M + H)

The following compounds were produced in the same manner as in Reference Example 22. Reference Example 23 4- [4- (1,3-benzodioxy-5-ylmethyl) -1-piperazinyl] -1- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl ) -1-butanone trihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.15 (2H, m), 3.00-3.20
(12H, m), 3.25-3.80 (10H, m), 6.07 (2H, s), 6.98
(1H, d, J = 8.0 Hz), 7.05-7.15 (1H, m), 7.27 (1H, m),
7.37 (1H, d, J = 8.0 Hz), 7.75-7.85 (2H, m) MS (ESI +): 436 (M + H) Reference Example 24 4- (4-benzhydryl-1-piperazinyl) -1- (2 , 3,4,5-tetrahydro-1H-3-benzazepin-7-yl) -1-butanone ¹ H-NMR (CDCl ₃ ) δ: 1.55 (4H, m), 2.20-2.60 (12H,
m), 2.80-2.30 (8H, m), 4.21 (1H, s), 6.85-7.60 (13
H, m) MS (ESI +): 454 (M + H) Reference Example 25 4- (4-benzhydryl-1-piperazinyl) -1- (2,3,4,5-tetrahydro-1H-3-benzazepine-7 -Yl) -1-butanone trihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.80 (4H, m), 3.00-3.40
(12H, m), 3.50-4.00 (9H, m), 7.00-7.80 (13H, m) MS (ESI +): 454 (M + H) Reference Example 26 4- {4- [bis (4-fluorophenyl) Methyl] -1-piperazinyl} -1- (2,3,4,5-tetrahydro-1H-3-benzazepine-7-
Yl) -1-butanone ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.00 (2H, m), 2.25-2.55 (1
0H, m), 3.90-4.00 (10H, m), 4.18 (1H, s), 6.90-7.0
0 (4H, m), 7.15 (1H, d, J = 8.2 Hz), 7.25-7.50 (4H, m
m), 7.50-7.80 (2H, m) MS (ESI +): 504 (M + H) Reference Example 27 4- {4- [bis (4-fluorophenyl) methyl] -1-piperazinyl} -1- (2 , 3,4,5-tetrahydro-1H-3-benzazepine-7-
Yl) -1-butanone trihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.15 (2H, m), 2.60-3.80
(21H, m), 7.10-7.30 (4H, m), 7.37 (1H, d, J = 8.4
z), 7.40-7.95 (6H, m) MS (ESI +): 504 (M + H) Reference Example 28 4- {4- (4-chlorobenzyl) -1-piperazinyl} -1- (2,3,4 ,Five
-Tetrahydro-1H-3-benzazepin-7-yl) -1-butanone ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.00 (2H, m), 2.30-2.55
(10H, m), 2.85-3.00 (10H, m), 3.45 (2H, s), 7.10-
7.30 (5H, m), 7.65-7.75 (2H, m) MS (ESI +): 426 (M + H) Reference Example 29 4- {4- (4-chlorobenzyl) -1-piperazinyl} -1- (2 , 3,4,5
-Tetrahydro-1H-3-benzazepin-7-yl) -1-butanone trihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.95-2.10 (2H, m), 3.00-3.95
(20H, m), 4.20-4.40 (2H, m), 7.38 (1H, d, J = 8.4H
z), 7.53 (2H, d, J = 8.4 Hz), 7.68 (2H, d, J = 8.4 Hz),
7.75-7.85 (2H, m) MS (APCI +): 426 (M + H) Reference Example 30 4- {4- (1-naphthylmethyl) -1-piperazinyl} -1- (2,3,4,5
-Tetrahydro-1H-3-benzazepin-7-yl) -1-butanone ¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.00 (2H, m), 2.21 (2H,
m), 2.35-2.60 (8H, m), 2.80-3.00 (10H, m), 3.88 (2
H, s), 7.14-7.19 (1H, m), 7.40-7.55 (4H, m), 7.65
7.90 (4H, m), 8.25-8.35 (1H, m) MS (APCI +): 442 (M + H) Reference Example 31 4- {4- (1-naphthylmethyl) -1-piperazinyl} -1- (2 , 3,4,5
-Tetrahydro-1H-3-benzazepin-7-yl) -1-butanone trihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.10 (2H,
m), 3.00-4.00 (22H, m), 7.30-7.40 (1H, m), 7.50-7.
70 (2H, m), 7.75-8.15 (6H, m), 8.35-8.45 (1H, m) MS (APCI +): 442 (M + H)

Reference Example 32 N- [2- (4-benzylpiperazin-1-yl) ethyl] -2,3,4,5-
Tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride 1) 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carbaldehyde Acetic anhydride (18 ml) was added to formic acid (54 ml), Stirred at room temperature for 1 hour. 2,3,4,5-tetrahydro-
1H-3-Benzazepine (9.5g) in ethyl acetate (5ml)
Was added dropwise under ice cooling. After stirring at room temperature for 30 minutes, the solvent was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (9.37 g). ¹ H-NMR (CDCl ₃ ) δ: 2.85-3.00 (4H, m), 3.45-3.50 (2
H, m), 3.64-3.70 (2H, m), 7.10-7.20 (4H, m), 8.15
(1H, s) 2) 7-acetyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carbaldehyde 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carbo Aldehyde (4.50 g) and acetyl chloride (2.01 ml)
To a solution of the above in dichloroethane (25 ml) was added aluminum chloride (12.0 g). After stirring the reaction mixture at room temperature for 15 hours, it was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (3.26
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H, s), 2.90-3.05 (4H,
m), 3.45-3.55 (2H, m), 3.65-3.75 (2H, m), 7.20-7.3
0 (1H, m), 7.50-7.80 (2H, m), 8.16 (1H, s) 3) 3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid hydroxylation An aqueous solution (70 ml) of sodium (4.78 g)
Acetyl-1,2,4,5-tetrahydro-3H-3-benzazepine-
3-Carboxaldehyde (3.24g) in dioxane (50ml)
After adding the solution, bromine (2.31 ml) was added dropwise under ice cooling.
After stirring the reaction mixture under ice cooling for 30 minutes, acetone was added to stop the reaction. After the solvent was concentrated under reduced pressure, the aqueous layer was extracted with ethyl acetate, and 5N hydrochloric acid was added to the extract. The precipitated crystals were collected by filtration, washed sequentially with water and ether to give the title compound (2.
11 g) were obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 2.85-3.00 (4H, m), 3.45-3.60
(4H, m), 7.32 (1H, dd, J = 2.2, 7.6Hz), 7.72-7.80 (2
H, m), 8.12 (1H, s) 4) 2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid 3-formyl-2,3,4,5-tetrahydro-1H-3 A solution of -benzazepine-7-carboxylic acid (1.0 g) in concentrated hydrochloric acid (50 ml) was stirred at 100 ° C for 12 hours. After concentrating the solvent under reduced pressure, the obtained solid was collected by filtration and washed with water and ether sequentially to give the title compound (990 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.18 (4H, m), 3.46 (4H, m), 7.3
3 (1H, d, J = 7.8Hz), 7.76 (1H, d, J = 7.8Hz), 7.78 (1
H, s) 5) 3- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid 2,3,4,5-tetrahydro-1H-3-benzazepine -7-Carboxylic acid (300 mg) was added to a 1N aqueous sodium hydroxide solution (2.6
4 ml), water (2.5 ml) and tetrahydrofuran (2.5 ml), and then di-tert-butyl dicarbonate (0.33
ml) and stirred at room temperature for 2 hours. After the tetrahydrofuran was concentrated under reduced pressure, the aqueous layer was made acidic with a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (344 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.95-3.00 (4H,
m), 3.55-3.60 (4H, m), 7.23 (1H, d, J = 8.4Hz), 7.86
(1H, s), 7.89 (1H, d, J = 8.4 Hz) 6) tert-butyl 7-({[2- (4-benzylpiperazin-1-yl) ethyl] amino} carbonyl) -1,2, 4,5-tetrahydro-
3H-3-Benzazepine-3-carboxylate Diethyl cyanophosphate (0.086 ml) was converted to 3- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxylic acid (150 mg) , 2- (4-benzylpiperazin-1-yl) ethylamine (124 mg) and triethylamine (0.079 ml) were added to a DMF (5 ml) solution. The reaction mixture was stirred at room temperature for 15 hours and diluted with water. After extraction with ethyl acetate, the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to give the title compound (199 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.50-2.65 (8H,
m), 2.59 (2H, t, J = 6.0Hz), 2.90-3.00 (4H, m), 3.53
(2H, s), 3.45-3.60 (6H, m), 6.81 (1H, m), 7.15-7.
35 (6H, m), 7.45-7.60 (2H, m) MS (ESI +): 493 (M + H) 7) N- [2- (4-benzylpiperazin-1-yl) ethyl] -2,3,
4,5-tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride tert-butyl 7-({[2- (4-benzylpiperazin-1-yl) ethyl] amino} carbonyl) -1,2,4 , 5-tetrahydro-3H-3-
Benzazepine-3-carboxylate (199 mg) was treated with a 1N solution of hydrogen chloride in ethyl acetate to give the desired compound (126
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.00-4.00 (20H, m), 4.35 (2H,
m), 7.30 (1H, d, J = 7.8Hz), 7.40-7.50 (3H, m), 7.6
0-7.70 (2H, m), 7.70-7.80 (2H, m), 8.84 (1H, m) MS (ESI +): 393 (M + H)

In the same manner as in Reference Example 32, Reference Examples 33 to 39
Was prepared. Reference Example 33 N- [2- (4-benzhydrylpiperazin-1-yl) ethyl] -2,
3,4,5-tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride Yield: 238 mg ¹ H-NMR (DMSO-d ₆ ) δ: 3.00-4.00 (21H, m), 7.25-7.40
(8H, m), 7.60-7.90 (5H, m), 8.89 (1H, m) MS (APCI +): 469 (M + H) Reference Example 34 N- [2- [4- (4-chlorobenzyl) Piperazin-1-yl] ethyl] -2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride Yield: 198 mg ¹ H-NMR (DMSO-d ₆ ) δ: 3.00-4.00 ( 20H, m), 4.31 (2H,
m), 7.30 (1H, d, J = 7.8Hz), 7.45-7.80 (6H, m), 8.8
5 (1H, m) MS (APCII +): 427 (M + H) Reference Example 35 N- (2- {4- [bis (4-fluorophenyl) methyl] piperazine
-1-yl} ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride Yield: 148 mg ¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.45 (16H , m), 3.50-3.80
(5H, m), 7.15-7.40 (5H, m), 7.50-8.00 (6H, m), 8.
90 (1H, m) MS (APCI +): 505 (M + H) Reference Example 36 N- [2- (4-benzylpiperazin-1-yl) ethyl] -2,3,4,5-
Tetrahydro-1H-2-benzazepine-8-carboxamide trihydrochloride Yield: 139 mg ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.00 (2H, m), 3.00-4.20
(18H, m), 4.37 (2H, m), 7.30-7.80 (6H, m), 7.80-8.
05 (2H, m), 8.95 (1H, m) MS (ESI +): 393 (M + H) Reference Example 37 N- [2- (4-benzhydrylpiperazin-1-yl) ethyl] -2,
3,4,5-tetrahydro-1H-2-benzazepine-8-carboxamide trihydrochloride Yield: 201 mg ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.95 (2H, m), 2.95-4.20
(18H, m), 4.35 (1H, s), 7.30-7.45 (7H, m), 7.60-8.
00 (6H, m), 8.97 (1H, m) MS (ESI +): 469 (M + H) Reference Example 38 N- [2- [4- (4-chlorobenzyl) piperazin-1-yl] ethyl] -2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxamide trihydrochloride Yield: 205 mg ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.00 (2H,
m), 3.00-4.00 (18H, m), 4.36 (2H, s), 7.36 (1H, d,
J = 8.0Hz), 7.52 (1H, d, J = 8.4Hz), 7.69 (1H, d, J =
8.4Hz), 7.89 (1H, d, J = 8.0Hz), 8.00 (1H, s), 8.94
(1H, m) MS (ESI +): 427 (M + H) Reference Example 39 N- (2- {4- [bis (4-fluorophenyl) methyl] piperazine
-1-yl} ethyl) -2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxamide trihydrochloride Yield: 325 mg ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.00 (2H , m), 3.00-4.50
(19H, m), 7.20-7.40 (5H, m), 7.60-8.10 (5H, m), 8.
97 (1H, m) MS (ESI +): 505 (M + H)

Reference Example 40 2-benzyl-N- (2- {4- [bis (4-fluorophenyl) methyl] piperazin-1-yl} ethyl) -2,3,4,5-tetrahydro-
1H-2-benzazepine-8-carboxamide trihydrochloride 2,3,4,5-tetrahydro-1H-2-benzazepine-8-synthesized in the same manner as described in 1) to 4) of Reference Example 32.
Carboxylic acid (200mg) and benzyl bromide (0.23m
l), a mixture of potassium carbonate (267 mg) and DMF (10 ml) was stirred at room temperature for 24 hours and diluted with water. The aqueous layer was washed with ethyl acetate, acidified with 1N hydrochloric acid, and extracted with dichloromethane. After washing the extract with saturated saline,
After drying over anhydrous magnesium sulfate and concentrating the solvent under reduced pressure, 2-benzyl-2,3,4,5-tetrahydro-1H-2-benzazepine-8-carboxylic acid (89 mg) was obtained. From this, the title compound (104 mg) was synthesized in the same manner as described in 6) and 7) of Reference Example 32. ¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.05 (2H, m), 3.00-4.70
(21H, m), 7.23 (4H, m), 7.35-7.50 (4H, m), 7.60-7.
80 (6H, m), 7.90-8.00 (2H, m), 8.97 (1H, m) MS (ESI +): 595 (M + H)

Reference Example 41 N- [2- (4-benzhydrylpiperazin-1-yl) ethyl] -N-
Benzyl-2,3,4,5-tetrahydro-1H-3-benzazepine-
7-carboxamide trihydrochloride A mixture of 2- (4-benzhydrylpiperazin-1-yl) ethylamine (275 mg), benzaldehyde (0.15 ml), molecular sieve (1 g) and methanol (5 ml) was stirred at room temperature for 2 hours. . After removing the molecular sieve by filtration, the filtrate was concentrated under reduced pressure. Methanol of the residue obtained
To a solution of -THF (3: 2; 5 ml) was added sodium tetrahydroborate (56 mg), and the mixture was stirred at room temperature for 17 hours. After the solvent was concentrated under reduced pressure, brine was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. When the solvent is concentrated under reduced pressure, N
-[2- (4-Benzhydrylpiperazin-1-yl) ethyl] -N-
Benzylamine (245 mg) was obtained. From this, the title compound (154 mg) was synthesized in the same manner as described in 6) and 7) of Reference Example 32. ¹ H-NMR (DMSO-d ₆ ) δ: 2.90-4.00 (21H, m), 4.58 (2H,
m), 7.10-7.50 (12H, m), 7.50-7.90 (3H, m), MS (ESI +): 559 (M + H)

Reference Example 42 N-benzyl-N- {2- [4- (4-chlorobenzyl) piperazine-1
-Yl] ethyl} -2,3,4,5-tetrahydro-1H-3-benzazepine-7-carboxamide trihydrochloride It was produced in the same manner as in Reference Example 41. ¹ H-NMR (DMSO-d ₆ ) δ: 3.00-3.80 (20H, m), 4.37 (2H,
m), 4.59 (2H, m), 7.10-7.50 (5H, m), 7.53 (2H, d,
J = 8.0Hz), 7.70 (2H, d, J = 8.0Hz) MS (ESI +): 517 (M + H)

Reference Example 43 3- (4-benzylpiperazin-1-yl) -N- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) propionamide
Trihydrochloride 1) 7-nitro-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine 3- (trifluoroacetyl) -2,3,4,5-tetrahydro- 1H-
Potassium nitrate (229 mg) was added to a solution of 3-benzazepine (500 mg) in sulfuric acid (3 ml) under ice-cooling. After stirring for 3 hours under ice cooling, the mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain the title compound (295 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.05-3.15 (4H, m), 3.70-3.86 (4
H, m), 7.30-7.38 (1H, m), 8.02-8.10 (2H, m) MS (APCI-): 287 (MH) 2) 3- (trifluoroacetyl) -2,3,4,5- Tetrahydro
-1H-3-benzazepine-7-amine 7-nitro-3- (trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (100 mg), tin chloride (I
I) A mixture of dihydrate (391 mg) and DMF (2 ml) was stirred at room temperature for 5 hours. After dilution with water, the mixture was extracted with ethyl acetate. After washing the extract with saturated aqueous sodium bicarbonate and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure to obtain the title compound (85 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.80-3.00 (4H, m), 3.60-3.80 (6
H, m), 6.45-6.52 (2H, m), 6.85-6.98 (1H, m) MS (APCI +): 259 (M + H) 3) 3- (4-benzylpiperazin-1-yl) -N- [3- (Trifluoroacetyl) -2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl] propionamide diethyl cyanophosphate (0.050 ml) was added to 3- (trifluoroacetyl) -2,3, 4,5-tetrahydro-1H-3-benzazepin-7-amine (77 mg), 3- (4-benzylpiperazine-1-
Yl) propionic acid (105 mg), triethylamine (0.
137 ml) to a DMF (3 ml) solution. The reaction mixture was stirred at room temperature for 15 hours and diluted with water. After extraction with ethyl acetate, the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate =
Purification by 2/3) gave the title compound (71 mg). ¹ H-NMR (CDC
l ₃ ) δ: 2.40-2.80 (12H, m), 2.90-3.00 (4H, m), 3.9
5 (2H, s), 3.65-3.85 (4H, m), 7.00-7.50 (8H, m) MS (APCI +): 489 (M + H) 4) 3- (4-benzylpiperazin-1-yl)- N- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) propionamide 3- (4-benzylpiperazin-1-yl) -N- [3- (trifluoroacetyl) -2, 3,4,5-tetrahydro-1H-3-benzazepine
-7-yl] propionamide (64 mg) in methanol (1 ml)
To the solution was added a 1M aqueous solution of potassium carbonate (0.39 ml), and the mixture was stirred at room temperature for 1.5 hours. After methanol was distilled off under reduced pressure, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (31 mg). ¹ H-NMR (CDCl ₃ ) δ: 2.35-2.80 (12H, m), 2.85-3.00
(8H, m), 3.51 (2H, s), 7.03 (1H, d, J = 8.0Hz), 7.15-
7.35 (7H, m) MS (APCI +): 393 (M + H) 5) 3- (4-benzylpiperazin-1-yl) -N- (2,3,4,5-tetrahydro-1H-3-benzazepine -7-yl) propionamide trihydrochloride 3- (4-benzylpiperazin-1-yl) -N- (2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl) propionamide (27 mg) Treatment with a 1N solution of hydrogen chloride in ethyl acetate gave the target compound (4.0 mg). MS (APCI +): 393 (M + H)

In the same manner as in Reference Example 43, the compounds of Reference Examples 44 and 45 were produced. Reference Example 44 3- (4-benzhydrylpiperazin-1-yl) -N- (2,3,4,5-
Tetrahydro-1H-3-benzazepin-7-yl) propionamide trihydrochloride Yield: 24 mg ¹ H-NMR (DMSO-d ₆ ) δ: 2.80-3.80 (21H, m), 7.10-7.70
(13H, m), 10.30 (1H, m) MS (ESI +): 469 (M + H) Reference Example 45 3- [4- (4-chlorobenzyl) piperazin-1-yl] -N- (2,3 ,
4,5-tetrahydro-1H-3-benzazepin-7-yl) propionamide trihydrochloride Yield: 73 mg ¹ H-NMR (DMSO-d ₆ ) δ: 2.80-4.00 (20H, m), 4.33 (2H,
m), 7.12 (1H, d, J = 8.0Hz), 7.35-7.60 (4H, m), 7.6
0-7.75 (2H, m), 10.36 (1H, m) MS (ESI +): 427 (M + H)

Reference Example 46 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [(E)-
3-phenyl-2-propenoyl] amino) methyl} -N- [2- (1-
Pyrrolidinyl) ethyl] [1,1'-biphenyl] -3-carboxamide 1) 3-Bromo-N- [2- (1-pyrrolidinyl) ethyl] phenylcarboxamide N, N- of 3-bromobenzoic acid (5.00 g) To a solution of dimethylformamide (DMF; 60 ml) were added 1- (2-aminoethyl) pyrrolidine (4.34 g), diethyl cyanophosphate (5.57 ml) and triethylamine (10.4 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with diethyl ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Hexane was added to the residue for crystallization to give the title compound (6.31 g). ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.90 (4H, m), 2.50-2.60 (4
H, m), 2.70 (2H, t, J = 6.0 Hz), 3.45-3.60 (2H, m),
6.86 (1H, s), 7.30 (1H, t, J = 8.0 Hz), 7.60 (1H, d
m, J = 8.0 Hz), 7.70 (1H, dm, 8.0 Hz), 7.93 (1H, t,
J = 1.6 Hz). 2) 3'-formyl-N- [2- (1-pyrrolidinyl) ethyl] [1,1'-
Biphenyl] -3-carboxamide 3-Bromo-N- [2- (1-pyrrolidinyl) ethyl] phenylcarboxamide (6.31 g) in toluene (50 ml) solution palladium tetrakistriphenylphosphine (735 mg) and 2M aqueous sodium carbonate solution (21.2 ml), and 3-formylboronic acid (3.49 g) in ethanol (15 m
l) The solution was added and the mixture was stirred at 90 ° C for 15 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain the title compound (6.83 g). ¹ H-NMR (CDCl ₃ ) δ: 1.95-2.35 (4H, m), 2.95 (2H,
m), 3.30-3.50 (2H, m), 3.80-3.40 (4H, m), 7.40-7.6
0 (2H, m), 7.76 (1H, dm, J = 8.0Hz), 7.85 (1H, dm, J
= 8.0Hz), 8.00 (1H, dm, 8.0Hz), 8.09 (1H, dm, J = 8.0
Hz), 8.25 (1H, bs), 8.40 (1H, bs), 8.41 (1H, m), 1
0.10 (1H, s). 3) 3 '-[{2- [4- (aminosulfonyl) phenyl] ethyl} aminomethyl] -N- [2- (1-pyrrolidinyl) ethyl]-[1,1'- Biphenyl] -3-carboxamide 3'-formyl-N- [2- (1-pyrrolidinyl) ethyl] [1,1'-biphenyl] -3-carboxamide (3.81 g) in methanol (50
4- (2-aminoethyl) benzenesulfonamide (2.37 g) and molecular sieves 3A (4.0 g)
After stirring, the mixture was stirred at room temperature for 1.5 hours. After diluting the reaction mixture with tetrahydrofuran (THF), the molecular sieves were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol-THF (1: 1) (100 ml), and sodium borohydride (0.89 g) was added.
After stirring the reaction mixture at room temperature for 5 hours, the solvent was distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. Hexane was added to the residue for crystallization to obtain the desired compound (3.71 g). ¹ H-NMR (CDCl ₃ ) δ: 1.75-1.85 (4H, m), 2.55-2.65 (4
H, m), 2.78 (2H, t, J = 6.0Hz), 2.85-3.00 (4H, m),
3.60-3.65 (2H, m), 3.87 (2H, s), 7.05-7.15 (1H,
m), 7.20-7.60 (6H, m), 7.65-7.85 3H, m), 7.84 (2H,
d, J = 8.4Hz), 8.05 (1H, s). 4) 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl}
[(E) -3-phenyl-2-propenoyl] amino) methyl} -N- [2
-(1-Pyrrolidinyl) ethyl] [1,1'-biphenyl] -3-carboxamide 3 '-[{2- [4- (aminosulfonyl) phenyl] ethyl} aminomethyl] -N- [2- (1- Pyrrolidinyl) ethyl]-[1,1'-biphenyl] -3-carboxamide (506 mg), trans-cinnamic acid (1
63 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCIHCl; 211 mg), 1-hydroxybenzotriazole (HOBT; 149 mg) in dichloromethane
(15 ml) and a mixed solvent of DMF (7 ml) and stirred at room temperature for 18 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98/2) to obtain the desired compound (284 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.73 (4H, m), 2.52 (4H, m), 2.6
9 (2H, t, J = 6.0Hz), 2.85-3.00 (2H, m), 3.50-3.60
(2H, m), 3.66 (2H, t, J = 7.0Hz), 4.60 (2H, s), 6.57
(1H, d, J = 15.6Hz), 6.85 (1H, d, J = 15.6Hz), 7.10-7.
90 (16H, m), 8.05 (1H, s). MS (APCI +): 637 (M + H)

Reference Example 47 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [(E)-
3-phenyl-2-propenoyl] amino) methyl} -N- [2- (1-
Pyrrolidinyl) ethyl] [1,1'-biphenyl] -3-carboxamide hydrochloride 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [(E)-
3-phenyl-2-propenoyl] amino) methyl} -N- [2- (1-
Pyrrolidinyl) ethyl] [1,1′-biphenyl] -3-carboxamide (200 mg) was treated with a 4N solution of hydrogen chloride in ethyl acetate to obtain the desired compound (198 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.10 (4H, m), 2.90-3.10
(4H, m), 3.30-3.50 (2H, m), 3.55-3.90 (6H, m), 4.7
3 (2H, s), 7.05-8.00 (18H, m), 8.25 (1H, s), 9.03 (1
H, m). Elemental analysis (molecular formula C ₃₇ H ₄₀ N ₄ O ₄ S · HCl · 1.5H ₂ O): Calculated, C: 63.46; H: 6.33; N: 8.00; Cl: 5.08 Experimental, C: 63.65; H: 6.51; N: 7.86; Cl: 5.25

Reference Example 48 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [4-phenylbutanoyl] amino) methyl} -N- [2- (1-pyrrolidinyl) ethyl] [ 1,1′-Biphenyl] -3-carboxamide In the same manner as in Reference Example 46, the target compound (277 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.85 (8H, m), 2.20-2.40
(2H, m), 2.45-2.60 (2H, m), 2.60-2.95 (4H, m), 3.2
0-3.60 (6H, m), 4.62 (2H, s), 7.05-7.95 (18H, m), 8.
13 (1H, s), 8.71 (1H, m). MS (ESI +): 653 (M + H)

Reference Example 49 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [4-phenylbutanoyl] amino) methyl} -N- [2- (1-pyrrolidinyl) ethyl] [ 1,1′-Biphenyl] -3-carboxamide hydrochloride The target compound (185 mg) was obtained in the same manner as in Reference Example 47. ¹ H-NMR (DMSO-d ₆ ) δ: 1.75-2.10 (8H, m), 2.25-2.45
(2H, m), 2.45-2.60 (2H, m), 2.80-2.90 (2H, m), 2.9
5-3.10 (2H, m), 3.20-3.50 (2H, m), 3.50-3.75 (4H, m
m), 4.61 (2H, s), 7.05-8.00 (18H, m), 8.23 (1H, s),
9.02 (1H, m). Elemental analysis (molecular formula C ₃₈ H ₄₄ N ₄ O ₄ S.HCl.H ₂ O): Calculated, C: 64.53; H: 6.70; N: 7.92; Cl: 5.01 Experimental, C : 64.39; H: 6.82; N: 7.86; Cl: 5.20

Reference Example 50 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [(benzyloxy) acetyl] amino) methyl} -N- [2- (1-pyrrolidinyl) ethyl] [ 1,1'-biphenyl] -3-carboxamide 3 '-[{2- [4- (aminosulfonyl) phenyl] ethyl} aminomethyl] -N- [2- (1-pyrrolidinyl) ethyl]-[1,1 To a solution of '-biphenyl] -3-carboxamide (506 mg) in DMF (10 ml) was added pyridine (0.16 ml) and benzyloxyacetyl chloride (0.16 ml). Bring the reaction mixture to room temperature for 1 hour.
After stirring for 6 hours, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane / methanol = 98
/ 2) to give the desired compound (257 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.74 (4H, m), 2.60-2.80 (4H,
m), 2.88 (2H, m), 3.20-3.40 (8H, m), 4.17 (2H, s),
4.47 (2H, s), 4.62 (2H, s), 6.57 (1H, d, J = 15.6H
z), 7.20-7.90 (18H, m), 8.11 (1H, s), 8.65 (1H,
m). MS (ESI +): 655 (M + H)

Reference Example 51 3 '-{({2- [4- (aminosulfonyl) phenyl] ethyl} [(benzyloxy) acetyl] amino) methyl} -N- [2- (1-pyrrolidinyl) ethyl] [ [1,1'-biphenyl] -3-carboxamide hydrochloride The target compound (155 mg) was obtained in the same manner as in Reference Example 47. ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.10 (4H, m), 2.80-3.15
(6H, m), 3.20-3.50 (2H, m), 3.60-3.75 (4H, m), 4.1
9 (2H, s), 4.48 (2H, s), 4.62 (2H, s), 7.20-7.90
(18H, m), 8.11 (1H, s), 8.65 (1H, m). Elemental analysis (molecular formula C ₃₇ H ₄₂ N ₄ O ₅ S.HCl.1.5H ₂ O): Calculated, C: 61.87; H : 6.45; N: 7.80; Cl: 4.94 experimental, C: 61.76; H: 6.31; N: 7.73; Cl: 5.25

Example 1 Measurement of Locomotion Male Wistar rats (9 weeks old) were guided into the lateral ventricle (AP: +8.1 mm, L: 1.8 mm, H: +7.1 mm) under pentobarbital anesthesia (AG). -8, Acom). After recovering for at least one week, the experiment was performed. During the recovery period, daily handling was performed to reduce stress during intraventricular administration. From the day before the experiment, the rats were placed in a locomotion measuring device and acclimated. Attach the microinjection cannula to the guide cannula under anaesthesia and unrestrained conditions, and add the polypeptide (SEQ ID NO: 9) (10 nmol) or PBS alone dissolved in phosphate buffered saline (PBS) 5 times.
Administration was performed at 2 μl / min for 2 minutes. Immediately thereafter, the rats were returned to the locomotion measuring device (Supermex, Muromachi Kikai), and the spontaneous locomotion and the number of times of standing up were measured (FIG. 1). Intraventricular administration after acclimation of the rat to the locomotion measuring device stimulates handling associated with the administration, and the spontaneous locomotor activity transiently increases and then rapidly decreases. Under these conditions, the polypeptide represented by SEQ ID NO: 9 (10 nmo
Immediately after administration of l), a tendency of a decrease in spontaneous activity was observed as compared with the control, and thereafter an increase in the activity was observed. The same effect as the amount of spontaneous activity was observed for the number of times of standing up.

Example 2 Measurement of Activity A lateral ventricle of a Wistar male rat (9 weeks old) (AP: 8.1 mm, L:
At 1.8 mm, H: 7.1 mm), a guide cannula (AG-8, Acom) was inserted under pentobarbital anesthesia. After recovering for at least one week, the experiment was performed. During the recovery period, daily handling was performed to reduce stress during intraventricular administration. From the day before the experiment, the rats were placed in a locomotion measuring device and acclimated. Attach the microinjection cannula to the guide cannula under no anesthesia, unrestrained,
Polypeptide (SEQ ID NO: 9) dissolved in PBS (1 nmo
l) or 10 μl of PBS alone (2 μl at 5 μl / min). Immediately thereafter, the rats were returned to a locomotion measuring device (Supermex, Muromachi Kikai), and spontaneous locomotion and the number of times of standing up were measured (FIG. 2). When the polypeptide represented by SEQ ID NO: 9 (1 nmol) was administered, an increase in the amount of activity was observed immediately after the administration. However, no temporary suppression of the amount of behavior observed at the time of 10 nmol administration was observed. From this, it was found that the polypeptide represented by SEQ ID NO: 9 exhibited a locomotor activity suppressing action at a high dose.

Example 3 Measurement of Activity A male Wistar rat (8 weeks old) was anesthetized with pentobarbital and fixed on a stereotaxic apparatus. Guide cannula (AG-8, Acom) into the lateral ventricle (AP: +8.1 mm, L: 1.8
mm, H: +7.1 mm). After recovering for one week or more, it was used for the experiment. Handling was performed daily during the recovery period to reduce stress during intraventricular administration. The cannulated rats were placed in a locomotion device (Supermex, Muromachi Kikai) and acclimated overnight. Rats are taken out from the locomotion measuring device and the polypeptide (SEQ ID NO: 9) (1 nmol or 10 nmo) dissolved in phosphate buffered saline (PBS)
l) or PBS alone was administered to the lateral ventricle at a flow rate of 2.5 μl / min for 4 minutes. Immediately after the administration, the rat was returned to the measuring device, and the spontaneous activity and the number of standing actions were measured. When 10 nmol of the polypeptide (SEQ ID NO: 9) was administered to the lateral ventricle of the rat, a decrease in the amount of activity and the number of times of standing up were observed immediately after the administration (FIG. 3). These behavioral changes lasted about 10 minutes. In addition, an increase in the amount of action was observed following the temporary decrease in the amount of action (FIG. 3). The increase in the amount of action lasted for about one hour. Cumulative activity up to 90 minutes after administration was significantly increased (PBS: 1612.7 ± 130.4 counts / 9
0 min, n = 27; 10 nmol of polypeptide (SEQ ID NO: 9):
2759.3 ± 422.5 counts / 90 min, n = 10, * p <0.05, D
unnett). The number of standing actions was not significant but increased (PBS: 35.1 ± 3.8 times / 90 mi
n, polypeptide (SEQ ID NO: 9) 10 nmol: 51.0 ± 1
3.4 times / 90 min). Polypeptide (SEQ ID NO: 9) 1 n
When mol was administered, the decrease in the amount of activity observed immediately after the administration of 10 nmol disappeared, and an increase in the amount of activity and rising behavior was observed immediately after the administration (FIG. 3). 90 immediately after administration
Minutes later, the cumulative activity increased significantly (PBS:
1612.7 ± 130.4 counts / 90 min, 1 nmol of polypeptide (SEQ ID NO: 9): 3741.0 ** ± 378.5 counts / 90 min,
n = 9, ** p <0.01, Dunnett). The number of standing actions also showed a significant increase (PBS: 35.1 ± 3.8 times / 90 min,
1 nmol of polypeptide (SEQ ID NO: 9): 75.3 ** ± 12.
5 times / 90 min, ** p <0.01, Dunnett).

Example 4 Measurement of Activity A male Wistar rat (8 weeks old) was anesthetized with pentobarbital and fixed on a stereotaxic apparatus. Guide cannula (AG-8, Acom) into the lateral ventricle (AP: +8.1 mm, L: 1.8
mm, H: +7.1 mm). After recovering for one week or more, it was used for the experiment. Handling was performed daily during the recovery period to reduce stress during intraventricular administration. The cannulated rats were placed in a locomotion device (Supermex, Muromachi Kikai) and acclimated overnight. The rats were taken out from the locomotion measuring device, and diazepam (1 mg / kg) was subcutaneously administered. 1
After hours, the polypeptide (SEQ ID NO: 9) (10 nmol) or PACAP38 dissolved in phosphate buffered saline (PBS)
(3 nmol) was administered to the lateral ventricle at a flow rate of 2.5 μl / min for 4 minutes. Immediately after the administration, the rat was returned to the measuring device, and the spontaneous activity and the amount were measured (FIG. 4). Polypeptide (SEQ ID NO:
The increase in the amount of action caused by 9) is significantly suppressed by diazepam, but PA which is known to have an action-enhancing effect
The increase in CAP38 activity was not affected by diazepam (Figure 4). These results suggest that the polypeptide (SEQ ID NO: 9) may have enhanced stress.

Example 5 Elevated Plus Maze Test Male Wistar rats (9 weeks old) were inserted with a guide cannula in the lateral ventricle under pentobarbital anesthesia. Then 1
The experiment was performed after recovering for at least a week. 10 nmo for rats
30 minutes after administration of the polypeptide or PBS represented by SEQ ID NO: 9 (intraventricular administration), an elevated plus maze (acrylic in which four arms each having a length of 25 cm and a width of 8 cm are arranged in a cross shape) A wall was installed on two opposing arms of a maze and a cross maze (closed arm), and no wall was installed on the other two (open arm) (FIG. 5).
On the open and closed arm for 5 minutes,
Openarm stay time was measured. FIG. 6 shows the results.

Example 6 Elevated Cross Maze Test An acrylic maze (elevated cross maze) in which four arms each having a length of 25 cm and a width of 8 cm were arranged in a cruciform shape was illuminated with low illumination (0.5 m).
lux) soundproof room. Walls were installed on two opposing arms of the elevated plus maze (closed arm).
No walls were installed on the other two (open arms). The maze was set 25 cm above the floor (Figure 5). C57BL /
After acclimating 6N mice to the measurement room, 2
5 μl of PBS containing the polypeptide (SEQ ID NO: 9) (1 nmol or 3 nmol) or PBS alone was administered into the lateral ventricle using a step needle (Matsumoto Seisakusho). Thirty minutes after administration, the mouse was placed in an elevated 10 o'clock maze, and the number of times of entering each arm for 5 minutes and the stay time in the open arm were measured. The results are shown in [Table 1].

[Table 1] Administration of the polypeptide (SEQ ID NO: 9) reduced open arm selectivity.

Example 7 Hole Board Test A box made of vinyl chloride having four holes with a diameter of 3.8 cm at the bottom was used as a hole board. The amount of activity on the hole board was measured with a Supermex sensor (Muromachi Kikai). To measure the number of peeping times, the MRS-
110RX infrared-scanning sensors (Muromachi Kikai) were used. After acclimating the C57BL / 6N mouse to the measurement room, the polypeptide (SEQ ID NO: 9) (0.1 nmol, 0.3 nmol or 3 nmol) was injected into the lateral ventricle using a two-stage needle (Matsumoto Seisakusho) under ether anesthesia. 5 μl of PBS or PBS alone was administered. Thirty minutes after the administration, the mouse was placed in the center of the hole board, and the amount of activity for five minutes and the number of peepings were measured. FIG. 7 shows the results. No change in the amount of activity was observed by administration of the polypeptide (SEQ ID NO: 9), but the number of peeping was significantly reduced. These results suggest that the polypeptide (SEQ ID NO: 9) may be involved in anxiety in the brain.

Example 8 Measurement of Activity A male Wistar rat (8 weeks old) was anesthetized with pentobarbital and fixed on a stereotaxic apparatus. Guide cannula (AG-8, Acom) into the lateral ventricle (AP: +8.1 mm, L: 1.8
mm, H: +7.1 mm). After recovering for one week or more, it was used for the experiment. Handling was performed daily during the recovery period to reduce stress during intraventricular administration. Polypeptide (SEQ ID NO: 9) dissolved in phosphate buffered saline (PBS) (10 nmol) or CRF (1 nmol) known to have an anxiety / stress-inducing effect, or PBS alone .
It was administered to the lateral ventricle at a flow rate of 5 μl / min for 4 minutes. Decapitation was performed 15 minutes after administration, and blood was collected. Radioimm ACTH in plasma
Measured with the unoassay system (Yuka Medias).
FIG. 8 shows the results.

[0278]

Industrial Applicability DN encoding the polypeptide of the present invention
A, The polypeptide of the present invention or its precursor protein may be used as an anti-attention deficit disorder or an anti-narcoleptic agent or a medicament such as an anxiety, antidepressant, anti-insomnia, anti-schizophrenia or anti-phobic agent, a recombinant receptor It can be used for development of a receptor binding assay system using a protein expression system, screening of drug candidate compounds, gene therapy, and the like. Since the polypeptide of the present invention or the precursor protein thereof is involved in an anxiety-like action, a compound obtained by a screening method using the polypeptide of the present invention, which changes the binding property between the polypeptide and SENR Is useful as a medicament and SEN
R agonists can be used as agents for treating or preventing diseases such as attention deficit disorder and narcolepsy,
SENR antagonists can be used as agents for treating or preventing diseases such as anxiety, depression, insomnia, schizophrenia, and phobia.

(Sequence Listing Free Text) SEQ ID NO: 1 Other information on sequence: 6th and 11th 2
Two Cys residues form an intramolecular disulfide bond. SEQ ID NO: 2 Other sequence information: 6th and 11th 2
Two Cys residues form an intramolecular disulfide bond. SEQ ID NO: 9 Other information on sequence: 6th and 11th 2
Two Cys residues form an intramolecular disulfide bond. SEQ ID NO: 10 Additional sequence information: 5th and 10th 2
Two Cys residues form an intramolecular disulfide bond. SEQ ID NO: 18 Other sequence information: two eleventh and sixteenth Cys residues form an intramolecular disulfide bond. SEQ ID NO: 19 Other information on the sequence: the 8th and 13th Cys residues form an intramolecular disulfide bond. SEQ ID NO: 24 Other sequence information: Two 11th and 16th Cys residues form an intramolecular disulfide bond. SEQ ID NO: 26 Other sequence information: two Cys residues at positions 14 and 19 form an intramolecular disulfide bond. SEQ ID NO: 27 Other sequence information: Two Cys residues at positions 18 and 23 form an intramolecular disulfide bond. SEQ ID NO: 28 Other sequence information: Two Cys residues at 14th and 19th form an intramolecular disulfide bond. SEQ ID NO: 29 Other sequence information: Two Cys residues at positions 18 and 23 form an intramolecular disulfide bond.

[0280]

[Sequence List] [Sequence Listing] <110> Takeda Chemical Industries, Ltd. <120> Polypeptide and Its Use <130> 179385 <150> JP 2000-247968 <151> 2000-08-10 <160> 34 <210> 1 <211> 12 <212> PRT <213> Pig <223> The 6th cystein residue binds with the 11th cystein residue to for ma intra-molecular disulfide-bond. <400> 1 Gly Pro Thr Ser Glu Cys Phe Trp Lys Tyr Cys Val 1 5 10 12 <210> 2 <211> 12 <212> PRT <213> Pig <223> The 6th cystein residue binds with the 11th cystein residue to for ma intra-molecular disulfide-bond. <400> 2 Gly Pro Pro Ser Glu Cys Phe Trp Lys Tyr Cys Val 1 5 10 12 <210> 3 <211> 386 <212> PRT <213> Rat <400> 3 Met Ala Leu Ser Leu Glu Ser Thr Thr Ser Phe His Met Leu Thr Val 1 5 10 15 Ser Gly Ser Thr Val Thr Glu Leu Pro Glu Asp Ser Asn Val Ser Leu 20 25 30 Asn Ser Ser Trp Ser Gly Pro Thr Asp Pro Ser Ser Leu Lys Asp Leu 35 40 45 Val Ala Thr Gly Val Ile Gly Ala Val Leu Ser Ala Met Gly Val Val 50 55 60 Gly Met Val Gly Asn Val Tyr Thr Leu Val Val Met Cys Arg Phe Leu 65 70 75 80 Arg Ala Ser Ala Ser Met Tyr Val Tyr Val Val Asn Leu Ala Leu Ala 85 90 95 Asp Leu Leu Tyr Leu Leu Ser Ile Pro Phe Ile Ile Ala Thr Tyr Val 100 105 110 Thr Lys Asp Trp His Phe Gly Asp Val Gly Cys Arg Val Leu Phe Ser 115 120 125 Leu Asp Phe Leu Thr Met His Ala Ser Ile Phe Thr Leu Thr Ile Met 130 135 140 Ser Ser Glu Arg Tyr Ala Ala Val Leu Arg Pro Leu Asp Thr Val Gln 145 150 155 160 Arg Ser Lys Gly Tyr Arg Lys Leu Leu Val Leu Gly Thr Trp Leu Leu 165 170 175 Ala Leu Leu Leu Thr Leu Pro Met Met Leu Ala Ile Gln Leu Val Arg 180 185 190 Arg Gly Ser Lys Ser Leu Cys Leu Pro Ala Trp Gly Pro Arg Ala His 195 200 205 Arg Thr Tyr Leu Thr Leu Leu Phe Gly Thr Ser Ile Val Gly Pro Gly 210 215 220 Leu Val Ile Gly Leu Leu Tyr Val Arg Leu Ala Arg Ala Tyr Trp Leu 225 230 235 240 Ser Gln Gln Ala Ser Phe Lys Gln Thr Arg Arg Leu Pro Asn Pro Arg 245 250 255 Val Leu Tyr Leu Ile Leu Gly Ile Val Leu Leu Phe Trp Ala Cys Phe 260 265 270 270 Leu Pro Phe Trp Leu Trp Gln Leu Leu Ala Gln Tyr His Glu Ala Met 275 280 285 Pro Leu Thr Pro Glu Thr Ala Arg Ile Val Asn Tyr Leu Thr Thr Cys 290 295 300 Leu Thr Tyr Gly Asn Ser Cys Ile Asn Pro Leu Leu Tyr Thr Leu Leu 305 310 315 320 Thr Lys Asn Tyr Arg Glu Tyr Leu Arg Gly Arg Gln Arg Ser Leu Gly 325 330 335 Ser Ser Cys His Ser Pro Gly Ser Pro Gly Ser Phe Leu Pro Ser Arg 340 345 350 Val His Leu Gln Gln Asp Ser Gly Arg Ser Leu Ser Ser Ser Ser Gln 355 360 365 Gln Ala Thr Glu Thr Leu Met Leu Ser Pro Val Pro Arg Asn Gly Ala 370 375 380 Leu Leu 385 <210> 4 <211> 638 <212> DNA <213> Pig <220> <223> <400> 4 cggaccaaca gaagccagga aggaagtgtc ctgcctcctg ccagtcatgt ccaagctggt 60 cccctgcttg ctcctcctag gatgcttagg tctcctcttc gctcttcccg tccctgactc 120 caggaaagag cccctgccct tctcagcacc tgaagatgtc agatcagctt gggatgagct 180 ggaaagagcc tcccttcttc agatgctgcc agagacgcca ggtgcagagg caggagagga 240 tctcagggaa gcagatgccg gaatggacat tttttaccca agaggagaaa tgagaaaggc 300 tttctctgga caagatccta acatttttct gagtcacctt ttggccagaa tcaagaaacc 360 atacaagaaa cgtgggcccc cctctgaatg cttctggaaa tactgtgtct gaagtcacct 420 caacaacaac catcttagaa aatgtaaaaa aagtgcttga cttgacagca gtgcagatga 480 aaaaccaggc aaaccctact ctgttcacta ttatctggaa aataaaccct ttgtgtttgg 540 ccaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 600 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 638 <210> 5 <211> 583 <212> DNA <213> Pig <400> 5 gaccaacaga agccaggaag gaagtgtcct gcctcctgcc agtcatgtcc aagctggtcc 60 cctgcttgct cctcctagga tgcttaggtc tcctcttcgc tcttcccgtc cctgactcca 120 ggaaagagcc cctgcccttc tcagcacctg aagatgtcag atcagcttgg gacgagctgg 180 aaagagcctc ccttcttcag atgctgccag agacgccagg tgcagaggca ggagaggatc 240 tcagggaagc agatgccgga atggacattt tttacccaag aggagaaatg agaaaggctt 300 tctctggaca agatcctaac atttttctga gtcacctttt ggccagaatc aagaaaccat 360 acaagaaacg tgggcccccc tctgaatgct tctggaaata ctgtgtctga agtcacctca 420 acaacaacca tcttagaaaa tgtaaaaaaa gtgcttgact tgacagcagt gcagatgaaa 480 aaccaggcaa accctactct gttcactatt atctggaaaa taaacccttt gtgtttggca 540 agttaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 583 < 210> 6 <211> 522 <212> DNA <213> Pig <400> 6 agttgaggct tcggaccaac agaagccagg aaggaagtgt cctgcctcct gccagtcatg 60 tccaagctgg tcccctgctt gctcctccta ggatgcttag gtctcctctt cgctcttccc 120 gtccctgact ccaggaaaga gcccctgccc ttctcagatg ccggaatgga cattttttac 180 ccaagaggag aaatgagaaa ggctttctct ggacaagatc ctaacatttt tctgagtcac 240 cttttggcca gaatcaagaa accatacaag aaacgtgggc ccccctctga atgcttctgg 300 aaatactgtg tctgaagtca cctcaacaac aaccatctta gaaaatgtaa aaaaagtgct 360 tgacttgaca gcagtgcaga tgaaaaacca ggcaaaccct actctgttca ctattatctg 420 gaaaataaac cctttgtgtt tggcaagtta aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 480 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa 522 <210> 7 <211> 121 <212> PRT <213> Pig <400> 7 Met Ser Lys Leu Val Pro Cys Leu Leu Leu Leu Gly Cys Leu Gly Leu 1 5 10 15 Leu Phe Ala Leu Pro Val Pro Asp Ser Arg Lys Glu Pro Leu Pro Phe 20 25 30 Ser Ala Pro Glu Asp Val Arg Ser Ala Trp Asp Glu Leu Glu Arg Ala 35 40 45 Ser Leu Leu Gln Met Leu Pro Glu Thr Pro Gly Ala Glu Ala Gly Glu 50 55 60 Asp Le u Arg Glu Ala Asp Ala Gly Met Asp Ile Phe Tyr Pro Arg Gly 65 70 75 80 Glu Met Arg Lys Ala Phe Ser Gly Gln Asp Pro Asn Ile Phe Leu Ser 85 90 95 His Leu Leu Ala Arg Ile Lys Lys Pro Tyr Lys Lys Arg Gly Pro Pro 100 105 110 Ser Glu Cys Phe Trp Lys Tyr Cys Val 115 120 <210> 8 <211> 85 <212> PRT <213> Pig <400> 8 Met Ser Lys Leu Val Pro Cys Leu Leu Leu Leu Gly Cys Leu Gly Leu 1 5 10 15 Leu Phe Ala Leu Pro Val Pro Asp Ser Arg Lys Glu Pro Leu Pro Phe 20 25 30 Ser Asp Ala Gly Met Asp Ile Phe Tyr Pro Arg Gly Glu Met Arg Lys 35 40 45 Ala Phe Ser Gly Gln Asp Pro Asn Ile Phe Leu Ser His Leu Leu Ala 50 55 60 Arg Ile Lys Lys Pro Tyr Lys Lys Arg Gly Pro Pro Ser Glu Cys Phe 65 70 75 80 Trp Lys Tyr Cys Val 85 <210> 9 <211> 12 < 212> PRT <213> Bovine <223> The 6th cystein residue binds with the 11th cystein residue to for ma intra-molecular disulfide-bond. <400> 9 Gly Pro Ser Ser Glu Cys Phe Trp Lys Tyr Cys Val 1 5 10 12 <210> 10 <211> 11 <212> PRT <213> Human <223> The 5th cystein residue binds with the 10th cystein residue to for ma intra-molecular disulfide-bond. <400> 10 Glu Thr Pro Asp Cys Phe Trp Lys Tyr Cys Val 1 5 10 11 <210> 11 <211> 389 <212> PRT <213> Human <400 > 11 Met Ala Leu Thr Pro Glu Ser Pro Ser Ser Phe Pro Gly Leu Ala Ala 1 5 10 15 Thr Gly Ser Ser Val Pro Glu Pro Pro Gly Gly Pro Asn Ala Thr Leu 20 25 30 Asn Ser Ser Trp Ala Ser Pro Thr Glu Pro Ser Ser Leu Glu Asp Leu 35 40 45 Val Ala Thr Gly Thr Ile Gly Thr Leu Leu Ser Ala Met Gly Val Val 50 55 60 Gly Val Val Gly Asn Ala Tyr Thr Leu Val Val Thr Cys Arg Ser Leu 65 70 75 80 Arg Ala Val Ala Ser Met Tyr Val Tyr Val Val Asn Leu Ala Leu Ala 85 90 95 Asp Leu Leu Tyr Leu Leu Ser Ile Pro Phe Ile Val Ala Thr Tyr Val 100 105 110 Thr Lys Glu Trp His Phe Gly Asp Val Gly Cys Arg Val Leu Phe Gly 115 120 125 Leu Asp Phe Leu Thr Met His Ala Ser Ile Phe Thr Leu Thr Val Met 130 135 140 Ser Ser Glu Arg Tyr Ala Ala Val Leu Arg Pro Leu Asp Thr Val Gln 145 150 155 160 Arg Pro Lys Gly Tyr Arg Lys Leu Leu Ala Leu Gly Thr Trp Leu Leu 165 170 1 75 Ala Leu Leu Leu Thr Leu Pro Val Met Leu Ala Met Arg Leu Val Arg 180 185 190 Arg Gly Pro Lys Ser Leu Cys Leu Pro Ala Trp Gly Pro Arg Ala His 195 200 205 Arg Ala Tyr Leu Thr Leu Leu Phe Ala Thr Ser Ile Ala Gly Pro Gly 210 215 220 Leu Leu Ile Gly Leu Leu Tyr Ala Arg Leu Ala Arg Ala Tyr Arg Arg 225 230 235 240 Ser Gln Arg Ala Ser Phe Lys Arg Ala Arg Arg Pro Gly Ala Arg Ala 245 250 255 Leu Arg Leu Val Leu Gly Ile Val Leu Leu Phe Trp Ala Cys Phe Leu 260 265 270 Pro Phe Trp Leu Trp Gln Leu Leu Ala Gln Tyr His Gln Ala Pro Leu 275 280 285 Ala Pro Arg Thr Ala Arg Ile Val Asn Tyr Leu Thr Thr Cys Leu Thr 290 295 300 Tyr Gly Asn Ser Cys Ala Asn Pro Phe Leu Tyr Thr Leu Leu Thr Arg 305 310 315 320 Asn Tyr Arg Asp His Leu Arg Gly Arg Val Arg Gly Pro Gly Ser Gly 325 330 335 Gly Gly Arg Gly Pro Val Pro Ser Leu Gln Pro Arg Ala Arg Phe Gln 340 345 350 Arg Cys Ser Gly Arg Ser Leu Ser Ser Cys Ser Pro Gln Pro Thr Asp 355 360 365 Ser Leu Val Leu Ala Pro Ala Ala Pro Ala Arg Pro Ala Pro Glu Gly 370 375 380 P ro Arg Ala Pro Ala 385 <210> 12 <211> 36 <212> DNA <213> Pig <400> 12 gggcccccct ctgaatgctt ctggaaatac tgtgtc 36 <210> 13 <211> 36 <212> DNA <213> Bovine <400> 13 ggaccttcct ctgaatgctt ctggaaatac tgtgtc 36 <210> 14 <211> 122 <212> PRT <213> Bovine <400> 14 Met Tyr Lys Leu Val Ser Cys Cys Leu Leu Phe Ile Gly Ser Leu Asn 1 5 10 15 Pro Leu Leu Ser Leu Pro Val Leu Asp Ser Arg Gln Glu Ser Leu Gln 20 25 30 Leu Leu Ala Pro Glu Asp Val Arg Ser Thr Leu Asp Glu Leu Glu Arg 35 40 45 Ala Ser Leu Leu Gln Met Leu Pro Glu Met Ser Gly Ala Glu Thr Gly 50 55 60 Glu Gly Leu Arg Asn Thr Asp Pro Ile Thr Asn Ile Phe Tyr Pro Arg 65 70 75 80 Gly Asn Met Arg Lys Ala Phe Ser Gly Gln Asp Pro Lys Leu Phe Leu 85 90 95 Ser Asp Leu Leu Ser Arg Ile Arg Lys Gln Ser Lys Lys Arg Gly Pro 100 105 110 Ser Ser Glu Cys Phe Trp Lys Tyr Cys Val 115 120 <210> 15 <211> 431 <212> DNA <213> Bovine <400> 15 atgtataagc tggtctcctg ctgtttgctt ttcataggat ccttaaatcc gctcctgtct 60 cttcctgtcc ttgactccag gcaagagtcc ctgcagctct tagcacctga ag atgtcaga 120 tcaactctgg atgagctgga aagagcgtct cttctgcaga tgctgccaga gatgtcaggc 180 gcagagacag gagagggtct taggaacaca gatcccatta ccaacatttt ttacccaaga 240 ggaaacatga gaaaggcctt ctctgggcaa gatcctaagc ttttcctgag tgaccttttg 300 tccagaatta ggaaacaatc taagaaacgt ggaccttcct ctgaatgctt ctggaaatac 360 tgtgtctgaa gcaaaatgac cctctactag ttacctccaa gacgaccatc tgagaaaatg 420 taaaataaag a 431 <210> 16 <211> 405 <212 > DNA <213> Rat <400> 16 tcttcccgtc gtcatggaca gggtgccctt ctgctgcctg ctcttcgtag gactcctgaa 60 tccactcctg tcttttcccg tcacggacac tggtgaaatg tctcttcagc ttccagtgct 120 tgaggaaaat gctcttcggg ctctggagga gctggagagg actgccctcc tgcagacgct 180 gcgccagacc gtgggcacag aagcagaggg aagccttggc caggcagatc ccagtgccga 240 gactcccact ccaaggggaa gcttgaggaa ggctctcact gggcaagatt ctaacactgt 300 actgagccgt cttttggcga gaaccaggaa acaacgtaag caacacggga ctgccccaga 360 atgcttctgg aagtactgca tttgaagaga gacgtctcct cagaa 405 <210> 17 <211> 123 <212> PRT <213> Rat <400> 17 Met Asp Arg Val Pro Phe Cys Cys Leu Leu Phe Val Gly Leu Leu Asn 1 5 10 15 Pro Leu Leu Ser Phe Pro Val Thr Asp Thr Gly Glu Met Ser Leu Gln 20 25 30 Leu Pro Val Leu Glu Glu Asn Ala Leu Arg Ala Leu Glu Glu Leu Glu 35 40 45 Arg Thr Ala Leu Leu Gln Thr Leu Arg Gln Thr Val Gly Thr Glu Ala 50 55 60 Glu Gly Ser Leu Gly Gln Ala Asp Pro Ser Ala Glu Thr Pro Thr Pro 65 70 75 80 Arg Gly Ser Leu Arg Lys Ala Leu Thr Gly Gln Asp Ser Asn Thr Val 85 90 95 Leu Ser Arg Leu Leu Ala Arg Thr Arg Lys Gln Arg Lys Gln His Gly 100 105 110 Thr Ala Pro Glu Cys Phe Trp Lys Tyr Cys Ile 115 120 <210> 18 <211> 17 <212> PRT <213> Rat <223> Xaa shows pyroglutamic acid or glutamine <400> 18 Xaa Arg Lys Gln His Gly Thr Ala Pro Glu Cys Phe Trp Lys Tyr Cys Ile 1 5 10 15 17 <210> 19 <211> 14 <212> PRT <213 > Rat <223> Xaa shows pyroglutamic acid or glutamine <400> 19 Xaa His Gly Thr Ala Pro Glu Cys Phe Trp Lys Tyr Cys Ile 1 5 10 14 <210> 20 <211> 51 <212> DNA <213> Rat < 400> 20 caacgtaagc aacacgggact gccccagaa tgcttctgga agtactgcat t 51 <210> 21 <211> 42 <212> DNA <213> Rat <400> 21 caacacggga ctgccccaga atgcttctgg aagtactgca tt 42 <210> 22 <211> 403 <212> DNA <213> Mouse <400> 22 atggacaggg tgcccttctg ctgcctgctc ttcataggac ttctgaatcc actgctgtcc 60 cttcccgtca cggacactgg tgagaggact cttcagcttc cagtgcttga ggaagacgct 120 cttcgggctc tggaggagct ggagaggatg gccctcctgc agaccctgcg tcagaccatg 180 ggcacggaag caggggagag ccctggagaa gcaggtccca gcactgagac tcccactcca 240 cggggaagca tgaggaaggc tttcgctggg caaaattcta acactgtact gagtcgtctc 300 ttggcaagaa ccaggaaaca acataagcaa cacggggctg ccccagagtg cttctggaaa 360 tactgcattt gaggagacac aagcgcccgt tggtctctca gaa 403 <210> 23 <211> 123 <212> PRT <213> Mouse <400> 23 Met Asp Arg Val Pro Phe Cys Cys Leu Leu Phe Ile Gly Leu Leu Asn 1 5 10 15 Pro Leu Leu Ser Leu Pro Val Thr Asp Thr Gly Glu Arg Thr Leu Gln 20 25 30 Leu Pro Val Leu Glu Glu Asp Ala Leu Arg Ala Leu Glu Glu Leu Glu 35 40 45 Arg Met Ala Leu Leu Gln Thr Leu Arg Gln Thr Met Gly Thr Glu Ala 50 55 60 Gly Glu Ser Pro Gly Glu Ala Gly Pro Ser Thr Glu Thr Pro Thr Pro 65 70 75 80 A rg Gly Ser Met Arg Lys Ala Phe Ala Gly Gln Asn Ser Asn Thr Val 85 90 95 Leu Ser Arg Leu Leu Ala Arg Thr Arg Lys Gln His Lys Gln His Gly 100 105 110 Ala Ala Pro Glu Cys Phe Trp Lys Tyr Cys Ile 115 120 <210> 24 <211> 17 <212> PRT <213> Mouse <223> Xaa shows pyroglutamic acid or glutamine <400> 24 Xaa His Lys Gln His Gly Ala Ala Pro Glu Cys Phe Trp Lys Tyr Cys Ile 5 10 15 17 <210> 25 <211> 51 <212> DNA <213> Mouse <400> 25 caacataagc aacacggggc tgccccagag tgcttctgga aatactgcat t 51 <210> 26 <211> 20 <212> PRT <213> Rat <400> 26 Thr Arg Lys Gln Arg Lys Gln His Gly Thr Ala Pro Glu Cys Phe Trp 1 5 10 15 Lys Tyr Cys Ile 20 <210> 27 <211> 24 <212> PRT <213> Rat <400> 27 Leu Leu Ala Arg Thr Arg Lys Gln Arg Lys Gln His Gly Thr Ala Pro 1 5 10 15 Glu Cys Phe Trp Lys Tyr Cys Ile 20 24 <210> 28 <211> 20 <212> PRT <213> Mouse <400> 28 Thr Arg Lys Gln His Lys Gln His Gly Ala Ala Pro Glu Cys Phe Trp 1 5 10 15 Lys Tyr Cys Ile 20 <210> 29 <211> 24 <212> PRT <213> Mouse <400> 29 Leu Leu Ala Arg Thr Arg L ys Gln His Lys Gln His Gly Ala Ala Pro 1 5 10 15 Glu Cys Phe Trp Lys Tyr Cys Ile 20 24 <210> 30 <211> 60 <212> DNA <213> Rat <400> 30 accaggaaac aacgtaagca acacgggact gccccagaat gcttctggaa gtactgcatt 60 <210> 31 <211> 72 <212> DNA <213> Rat <400> 31 cttttggcga gaaccaggaa acaacgtaag caacacggga ctgccccaga atgcttctgg 60 aagtactgca tt 72 <210> 32 <211> 60 <212> DNA <213> Mouse <400> 32 accaggaaac aacataagca acacggggct gccccagagt gcttctggaa atactgcatt 60 <210> 33 <211> 72 <212> DNA <213> Mouse <400> 33 ctcttggcaa gaaccaggaa acaacataag caacacgggg ctgccccaga gtgcttctgg 60 aaatactca 34 <213> Human <400> 34 gagactcctg attgcttctg gaaatactgt gtc 33

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the change in spontaneous activity by the intraventricular injection of the polypeptide represented by 10 nmol SEQ ID NO: 9 in Example 1. A) shows the change in spontaneous activity, and B) shows the change in the number of standing actions (PBS: n = 10, polypeptide represented by SEQ ID NO: 9: n = 10).

FIG. 2 shows the polypeptide of Example 2 (SEQ ID NO:
9) Changes in spontaneous behavior by intraventricular administration of (1 nmol). A) shows the change in the spontaneous action amount, and B) shows the change in the number of standing actions. Each value indicates an average value ± SEM (PBS: n = 17, polypeptide represented by SEQ ID NO: 9: n
= 10).

FIG. 3 shows the polypeptide of Example 3 (SEQ ID NO:
9) Changes in spontaneous behavior due to intracerebroventricular administration of (1 nmol or 10 nmol). A) Figure shows spontaneous behavior change,
B) shows the change in the number of times of standing action. Each value represents an average value ± SEM (PBS: n = 27, polypeptide represented by SEQ ID NO: 9 (1 nmol): n = 9, polypeptide represented by SEQ ID NO: 9 (10 nmol): n = Ten).

FIG. 4 shows the polypeptide (SEQ ID NO:
9) Effect of diazepam (1 mg / kg) on intraventricular administration of (10 nmol) and PACAP38 (3 nmol). A) The figure shows diazepam (1 mg / l) in spontaneous behavioral change by intracerebroventricular administration of the polypeptide (SEQ ID NO: 9) (10 nmol).
kg). B) The figure shows the polypeptide (SEQ ID NO:
9) shows the effect of diazepam (1 mg / kg) on cumulative locomotor activity by intraventricular administration of (10 nmol) and PACAP38 (3 nmol). Each value represents an average value ± SEM (polypeptide (SEQ ID NO: 9): n = 10, diazepam + polypeptide (SEQ ID NO: 9): n = 10, PACAP38: n = 8, diazepam + PA
CAP38: n = 8). * P <0.05, Dunnett

FIG. 5 is a schematic view of an elevated plus maze used in the test of Example 5.

FIG. 6 shows the results of an elevated plus maze test using 10 nmol polypeptide (SEQ ID NO: 9) in Example 5 by intraventricular administration (FIG. 6A): number of entries into the closed arm; FIG.
The length of stay in the arm, and C) shows the number of times of entry into the open arm). Each value indicates an average value ± SEM (n = 9-10). * P
<0.05, Dunnett

FIG. 7 shows a polypeptide (SEQ ID NO:
9) shows the results of a whole board test by intraventricular administration of (0.1 nmol, 0.3 nmol or 3 nmol). A) shows the cumulative spontaneous activity (5 minutes). B) shows the number of peeping (5 minutes). Each value represents the mean ± SEM (PBS: n
= 18, polypeptide (SEQ ID NO: 9) 0.1 nmol: n = 10, polypeptide (SEQ ID NO: 9) 0.3 nmol: n = 17, polypeptide (SEQ ID NO: 9) 3 nmol: n = 8). * P <0.05,
** p <0.01, Dunnett

FIG. 8 shows the polypeptide of Example 8 (SEQ ID NO:
9) shows the effect of (10 nmol) and CRF (1 nmol) on the amount of ACTH in plasma (PBS: n = 8, polypeptide (SEQ ID NO: 9) 10 nmol: n = 7, CRF 1 nmol: n = 8) ). ** p <
0.01, Dunnett

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 39/395 A61K 39/395 M 4H045 45/00 45/00 48/00 48/00 A61P 25/00 A61P 25/00 25/18 25/18 25/20 25/20 25/22 25/22 25/24 25/24 25/28 25/28 C07K 14/47 C07K 14/47 G01N 33/15 Z C12N 15/09 ZNA 33/50 Z G01N 33/15 33/53 D 33/50 M 33/53 A61K 37/02 C12N 15/00 ZNAA (72) Inventor Masaaki Mori 3-8-8 Kasuga, Tsukuba, Ibaraki 5F term (reference ) 2G045 AA40 DA12 DA13 DA36 FB02 FB03 4B024 AA01 BA44 BA80 GA11 HA01 HA12 HA15 4C084 AA02 AA13 AA17 BA01 BA08 BA18 BA19 BA21 BA22 BA23 MA01 NA14 ZA012 ZA052 ZA122 ZA152 ZA182 ZC412 4C085 AA31 DD33 DDA DD DD DD AA01 AA02 BC0 7 BC32 CB05 CB09 CB11 EA16 MA01 MA04 NA14 ZA01 ZA05 ZA12 ZA15 ZA18 ZC41 4H045 AA30 BA10 CA40 DA76 DA86 EA21 EA50 FA74

Claims (29)

[Claims] 1. An anti-attention deficit disorder or an anti-narcoleptic agent comprising a polypeptide having the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1, or an amide or an ester or a salt thereof. . 2. The substantially identical amino acid sequence is SEQ ID NO: 2, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1.
8, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 2
6, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO:
The anti-attention deficit disorder or anti-narcoleptic agent according to claim 1, which is an amino acid sequence represented by 29. 3. An anti-attention deficit disorder or anti-narcoleptic agent comprising a DNA containing the nucleotide sequence encoding the polypeptide according to claim 1. 4. The DNA is SEQ ID NO: 12, SEQ ID NO: 1.
3, SEQ ID NO: 34, SEQ ID NO: 20, SEQ ID NO: 2
1, SEQ ID NO: 25, SEQ ID NO: 30, SEQ ID NO: 3
The anti-attention deficit disorder or anti-narcoleptic agent according to claim 3, which is a DNA containing the nucleotide sequence represented by 1, SEQ ID NO: 32 or SEQ ID NO: 33. 5. An anti-attention deficit disorder or anti-narcoleptic agent comprising the precursor protein of the polypeptide according to claim 1, or an amide or ester thereof or a salt thereof. 6. The method according to claim 5, which comprises an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 14, SEQ ID NO: 17 or SEQ ID NO: 23. The anti-attention deficit disorder or the anti-narcoleptic agent described. 7. Use of a polypeptide having the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 1, its amide or its ester or its salt, or its precursor protein or its salt A method for screening a compound having anti-attention deficit disorder or anti-narcoleptic activity, a compound having anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia or anti-phobic activity, or a salt thereof. 8. A polypeptide comprising an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 1, or an amide or ester thereof or a salt thereof, or a precursor protein or a salt thereof. A compound having anti-attention deficit disorder or anti-narcoleptic activity or a compound having anti-anxiety, antidepressant, anti-insomnia, anti-schizophrenia or anti-phobic activity,
Or a kit for screening their salts. 9. A compound having an anti-attention deficit disorder or an anti-narcoleptic activity obtained by using the screening method according to claim 7 or the screening kit according to claim 8, or an anxiolytic, antidepressant, antiinsomnia, or antipsychotic. Compounds having symptomatic or anti-phobic activity, or salts thereof. 10. An anti-attention deficit disorder or an anti-narcoleptic agent or an anti-anxiety, an antidepressant, an anti-insomnia, an anti-schizophrenia or an anti-phobic agent comprising the compound according to claim 9 or a salt thereof. (11) a method comprising using a polynucleotide comprising a nucleotide sequence complementary to a DNA comprising a nucleotide sequence encoding the polypeptide according to (1) or a part thereof; Narcolepsy or a method of diagnosing anxiety, depression, insomnia, schizophrenia or fear. [12] An anxiolytic, antidepressant, anti-anxiety agent comprising an antibody against the polypeptide according to the above [1] or the precursor protein according to the above [5], an amide thereof, an ester thereof or a salt thereof. Insomnia, anti-schizophrenia or anti-phobic drugs. 13. An anti-attention deficit disorder comprising an antibody against a protein containing the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11, or an amide or ester or salt thereof. Or anti-narcoleptic or anti-anxiety, antidepressant,
Anti-insomnia, anti-schizophrenia or anti-phobic drugs. 14. Anxiety, depression, insomnia, mental disorders comprising an antibody against the polypeptide according to claim 1 or the precursor protein according to claim 5, or an amide or ester or salt thereof. Diagnosis agent for schizophrenia or phobia. 15. An attention-deficit disorder or an attention-deficit disorder characterized by containing an antibody against a protein containing the amino acid sequence represented by SEQ ID NO: 3 or SEQ ID NO: 11, or an amide or ester or a salt thereof. Diagnostic agent for narcolepsy or anxiety, depression, insomnia, schizophrenia or phobia. 16. A diagnostic agent comprising a single nucleotide polymorphism (SNPs) of a DNA containing the nucleotide sequence represented by SEQ ID NO: 34. 17. The diagnostic agent according to claim 16, which is a diagnostic agent for attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia or phobia. 18. Attention deficit disorder or narcolepsy or anxiety, depression, insomnia, schizophrenia characterized by analyzing single nucleotide polymorphisms (SNPs) of DNA containing the nucleotide sequence represented by SEQ ID NO: 34 Or phobia diagnosis method. 19. An anti-attention deficit disorder or anti-narcoleptic agent comprising a GPR14 agonist. 20. An anxiolytic, anti-depressive, anti-insomnia, anti-schizophrenic or anti-phobic agent comprising a GPR14 antagonist. 21. A GPR14 antagonist having the formula (I)
a): embedded image [In the formula, A ^a represents an optionally substituted benzene ring;
^a is a 5- to 8-membered ring which may be substituted, ^Xa is a divalent group having 1 to 4 atoms in ^a linear portion, R ^1a is an amino group which may be substituted, R ^2a Represents a cyclic group which may be substituted] or a salt thereof. 22. A GPR14 antagonist having the formula (I)
Ia): embedded image Wherein, A a ^'is a benzene ring which may further have a substituent other than the substituent R ^3a, B ^a is a good 5-8 membered ring optionally substituted, X ^a is a straight portion Is a divalent group having 1 to 4 atoms, R ^{1a ′} is a substituted amino group, R ^2a
Is a cyclic group which may be substituted, R ^3a is a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, a nitro group, a halogen atom, an amino group which may be substituted or A group represented by R ^4a —Y ^a − (in the formula,
Y ^a represents an oxygen atom or ^a sulfur atom which may be oxidized, and R ^4a represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted). The anti-anxiety according to claim 20, which is a salt thereof,
Anti-depressant, anti-insomnia, anti-schizophrenia or anti-phobic agents. 23. A GPR14 antagonist having the formula (I)
b): embedded image [Wherein, Ar represents an aryl group which may be substituted, X represents a spacer having 1 to 4 atoms constituting a straight-chain portion, n represents an integer of 1 to 10, and R represents hydrogen. An atom or a hydrocarbon group which may be substituted, wherein n may be the same or different, and R may be bonded to Ar or a substituent of Ar to form a ring; Y represents an amino group which may be substituted or a nitrogen-containing heterocyclic group which may be substituted. ]
21. The anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia or anti-phobic agent according to claim 20, which is a compound represented by the formula: or a salt thereof. 24. A GPR14 antagonist having the formula (I)
Ib): embedded image [Wherein, R ¹ represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group which may be substituted, ring A represents a benzene ring which may further have a substituent,
X represents a spacer having 1 to 4 atoms constituting the straight chain portion, n represents an integer of 1 to 10, R represents a hydrogen atom or a hydrocarbon group which may be substituted,
In the repetition of n, they may be the same or different,
R may be combined with ring A or a substituent of ring A to form a ring, and Y represents an optionally substituted amino group or an optionally substituted nitrogen-containing heterocyclic group]. The anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia or anti-phobic agent according to claim 20, which is a compound represented by the formula or a salt thereof. 25. A GPR14 antagonist having the formula (I)
c): embedded image[Wherein, R^1cIs a hydrogen atom or may be substituted
X represents a hydrocarbon group;^cIs the number of atoms constituting the straight chain part
Represents a spacer having 1 to 12;^1cAnd X ^cIs
May form a ring together,^cHas been replaced
Amino group or nitrogen-containing heterocyclic group which may be substituted
A ring group;^2cIs an optionally substituted hydrocarbon group
Or an amino group which may be substituted;^3cIs
A hydrocarbon group which may be substituted;^cRings and
C^cEach ring may be further substituted
Or a salt thereof.
20 Anti-anxiety, anti-depression, anti-insomnia, anti-schizophrenia if described
Or anti-fear. 26. A method for preventing or treating attention deficit disorder or narcolepsy, which comprises administering an effective amount of a GRP14 agonist to a mammal. 27. Use of a GPR14 agonist for producing a prophylactic / therapeutic agent for attention deficit disorder or narcolepsy. 28. A method for preventing or treating anxiety, depression, insomnia, schizophrenia or phobia, which comprises administering to a mammal an effective amount of a GPR14 antagonist. 29. Use of a GPR14 antagonist for producing a prophylactic / therapeutic agent for anxiety, depression, insomnia, schizophrenia or phobia.