JPH08301871A - Condensed heterocyclic compound and its production - Google Patents

Abstract

PURPOSE: To obtain a new condensed heterocyclic compound raised in tachykinin receptor antagonistic action, esp. substance P receptor antagonistic action. CONSTITUTION: This new condensed heterocyclic compound (salt) is expressed by formula I A ring is a (substituted) five- or six-membered ring; B ring and C ring are each a (substituted) homocyclic or heterocyclic ring; X-Y is N=CR<1> [R<1> is H, a (substituted) hydrocarbon, etc.] or NR<2> -CO [R<2> is H or a (substituted) hydrocarbon]; R is H or a (substituted) hydrocarbon; (n) is 0-3}, e.g. N-[3,5-bis(trifluoromethyl)benzyl]-N-7-dimethyl-5-phenylimidazo[1,2-a] pyrimidine-6- carboxamide. This new compound is obtained by reaction between a compound (salt) of formula II or a reactive derivative therefrom and a compound (salt) of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused heterocyclic compound having an excellent tachykinin receptor antagonistic activity, a process for producing the same, and a preparation containing the compound.

[0002]

BACKGROUND OF THE INVENTION Tachykinin is a general term for a group of neuropeptides, and in mammals, substance P, neurokinin-A and neurokinin-B are known, and these peptides are receptors for each of which are present in the living body. Body (Neurokinin-1, Neurokinin-2, Neurokinin-
It is known to exert various biological activities by binding to 3).

[0003] Among them, substance P has one of the longest history among neuropeptides and has been studied in detail. Its existence was confirmed in the extract of equine intestine in 1931, and its structure was determined in 1971. It is a peptide consisting of 11 amino acids. Substance P is known to play an important role as a signal transmitting substance in the peripheral and central regions, and also has various pathological states (eg, pain, inflammation, allergy, frequent urination, urinary incontinence, respiratory tract disease, psychosis). Etc.) are believed to be involved.

Currently, as a compound having a substance P receptor antagonistic action, (1) Japanese Patent Laid-Open No. 1-287095 discloses the following formula: R ¹ -A-D-Trp (R ² ) -Phe-R ³ [ In the formula, R ¹ is a hydrogen atom or an amino protecting group, R ² is a hydrogen atom, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R ³ is Ar (lower) alkyl group, formula:

[0005]

Embedded image (In the formula, R ⁴ and R ⁵ each represent a hydrogen atom, an aryl group or a lower alkyl group which may have a suitable substituent, or R ⁴ and R ⁵ are bonded to each other to form a benzene-fused lower alkylene group. A group represented by the formula) or a formula: —OR ⁶ (in the formula, R ⁶ represents a hydrogen atom, an aryl group or a lower alkyl group which may have a suitable substituent). Group, A means a single bond or one or two amino acid residues respectively, and when A means one amino acid residue of -D-Trp-, R ⁴ is not a hydrogen atom] Disclosed compounds and salts thereof are disclosed.

(2) EP-A-436,334 has the following formula

[0007]

[Chemical 6] Compounds represented by (3) EP-A-429,
366 has the following formula

[0008]

[Chemical 7] Compounds represented by are listed in (4) Journal of
Journal of Medicinal C
hemistry), 34, 1751 (published in 1991).

[0009]

Embedded image Compounds represented by are disclosed.

Further, (5) WO91 / 09844 describes the formula

[0011]

[Chemical 9] And the like are compounds (6) EP-A-522,
808 has the formula

[0012]

[Chemical 10] Compounds represented by are disclosed.

(7) WO93 / 01169 describes the formula

[0014]

[Chemical 11] Compounds represented by are (8) EP-A-532,
456 has the formula

[0015]

[Chemical 12] Compounds represented by are disclosed.

Further, (9) Bioorganic and Medicinal Chemistry Letters (Bioorganic
& Medicinal Chemistry Letters, Volume 4, page 1903 (published in 1994) has the following formula:

[0017]

[Chemical 13] The compound represented by is (10) European Journal of Pharmacology
armacology), 250, 403 pages (issued in 1993)
Has the following formula:

[0018]

Embedded image The compound represented by: (11) EP-A-585,91
3 has the following formula:

[0019]

[Chemical 15] [In the formula, the ring A may have a substituent; the ring B may have a substituent; a benzene ring which may have a substituent; either X or Y is -NR ^1- (R ¹ is A hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent), -O- or -S- , The other is -CO-, -C
S- or ^{-C (R 2) R 2a -} (R 2 and R ^2a represent, respectively, a hydrogen atom or a substituent optionally may hydrocarbon group having a), or one is -N =, the other = C
R ³ — (R ³ has a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an amino group which may have a substituent, a hydroxyl group which has a substituent or a substituent which has a substituent. Represents a mercapto group which may be substituted with an optionally substituted hydrocarbon group)

[0020]

Embedded image D is a C _1-3 alkylene group which may be substituted with an oxo group or a thioxo group, or D and Y together form a 5- to 7-membered ring which may be substituted with an oxo group or a thioxo group. E may be -NR ^5- (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent, or R ⁵ and Y together are substituted with an oxo group or a thioxo group. Optionally form a 5- to 7-membered ring), -O- or -S (O) _n- (n represents 0, 1 or 2) G is a bond or a C _1-3 alkylene group;
Ar represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent. However, (i)
-X-Y- is -O-CO- or -CO-O-, and D is-.
CO- and E is -NR ⁵ - when it is, (a) G is C
_1-3 alkylene group, Ar is a substituted aryl group or a substituted heterocyclic group, or (b) G is a bond and R ⁵
Is a hydrocarbon group which may have a substituent, and (ii)
When -X-Y- is -NH-CO-, D is -CO-
Indicates. ] The compound represented by these, its salt, etc. are described.

[0021]

At present, as a therapeutic drug for the various pathological conditions (particularly urinary frequency, urinary incontinence, etc.), it has an excellent tachykinin receptor antagonistic action (particularly substance P receptor antagonistic action) and is safe. A compound that is sufficiently satisfactory in terms of sex and durability has not yet been found. Therefore,
It is desired to develop a compound having a chemical structure different from that of the above-mentioned known compounds, having an excellent tachykinin receptor antagonistic action, and being sufficiently satisfactory as the therapeutic drug.

Accordingly, it is an object of the present invention to provide a novel compound having a high tachykinin receptor antagonistic action, particularly a substance P receptor antagonistic action, and a method for producing the same.

[0023]

Means for Solving the Problems As a result of intensive studies in view of the above circumstances, the present inventors have found that

[0024]

[Chemical 17] [In the formula, A ring is a 5- or 6-membered ring which may have a substituent; B ring is a homocyclic or heterocyclic ring which may have a substituent; CR ^1- (R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, an amino group which may have a substituent or a halogen atom. Shown) or -NR ² -CO-
(R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent). ] For the first time, a fused heterocyclic compound having a partial chemical structure represented by the above formula was synthesized. It has been found that the compound has a receptor antagonism) and has low toxicity, and therefore is sufficiently satisfactory as a medicine, and based on these, the present invention was completed.

That is, the present invention provides (1) the following general formula (I)

[0026]

Embedded image [In the formula, C ring is a homocyclic ring or a heterocyclic ring which may have a substituent; R is a hydrogen atom or a hydrocarbon group which may have a substituent; n is an integer of 0 to 3; . Other symbols are the same as those defined above] or a fused heterocyclic compound represented by the above] or a salt thereof.

In this compound (I), the ring A is
(2) In addition to a carbon atom and one nitrogen atom at the bridge head, a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and (3) other than a carbon atom. It may be a heterocycle containing 2 or 3 nitrogen atoms. Further, the ring B and the ring C may be (4) an aromatic homocyclic ring which may have a substituent or an aromatic heterocycle which may have a substituent, and (5) the substitution. It may be a benzene ring which may have a group. Furthermore, (6)
Ring B is a halogen atom, optionally halogenated C
_It may be a benzene ring optionally having 1 to 3 substituents selected from _1-6 alkyl group and optionally halogenated C _1-6 alkoxy group, and (7) C ring Is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group and an optionally halogenated C _1-6 alkoxy group. May be

In the compound (I), (8) R
¹ may be a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group or a mono- or di-C _1-6 alkylamino group, and (9) R ² may be a C _1-6 alkyl group. Often,
(10) —X—Y— may be —N═CR ¹ — (R ¹ is a hydrogen atom or a C _1-4 alkyl group), and (11) n may be 1.

The compound represented by the above formula (I) includes, for example, (12) a heterocycle in which ring A may have a substituent containing 2 or 3 nitrogen atoms in addition to carbon atoms; B The ring is a benzene ring which may have a substituent; C is a benzene ring which may have a substituent; -X-Y- is -N = CR ^1-.
(R ¹ represents a hydrogen atom or a C _1-4 alkyl group); R is a hydrogen atom or a hydrocarbon group optionally having a substituent; and a compound in which n is an integer of 1 to 3 is also included. .

The compound (I) has the general formula (I):
I)

[0031]

[Chemical 19] [Wherein the symbols in the formula are the same as the above] or a salt or reactive derivative thereof, and a compound represented by the general formula (III)

[0032]

Embedded image It can be produced by reacting with a compound represented by [the symbols in the formula are the same as above] or a salt thereof. In addition, (1
4) Among the compounds represented by the general formula (I), compounds in which R ¹ is a hydrogen atom or a hydrocarbon group which may have a substituent include compounds represented by the general formula (IV)

[0033]

[Chemical 21] [Wherein R ^1a represents a hydrogen atom or a hydrocarbon group which may have a substituent, and other symbols have the same meanings as defined in claim 1], or dehydrogenate the compound or salt thereof. It can be produced by subjecting it to a reaction. (15) The preparation containing the compound represented by the general formula (I) or a salt thereof is useful as a kykinin receptor antagonist.

The present invention will be described in detail below. Ring A In the general formula (I), ring A represents a 5- or 6-membered ring which may have a substituent. As is clear from the above formula (I), the “5- or 6-membered ring” contains at least one nitrogen atom (a nitrogen atom shared by the ring A and an adjacent ring) in addition to the carbon atom. Represents a heterocycle, and these rings may contain 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to the nitrogen atom at the bridge head.

The heterocycle containing at least one nitrogen atom in addition to the carbon atom is, for example, a 5- or 6-membered ring containing 1 to 4 nitrogen atoms, for example, pyrrole, imidazole, pyrazole, triazole, tetrazole, dihydropyrazole. A 5-membered ring such as dihydroimidazole and dihydrotriazole, and a 6-membered ring such as pyridine, pyridazine, pyrimidine, pyrazine, dihydropyridine, dihydropyrimidine, tetrahydropyridine and tetrahydropyrimidine. Examples of the heterocycle which may contain one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to the nitrogen atom include, for example, thiazole, isothiazole, oxazole and isoxazole ring. Is mentioned.

Preferred 5- or 6-membered rings are 5- or 6-membered heterocycles containing 2 or 3 nitrogen atoms, for example imidazole, pyrazole, triazole, dihydropyrazole, dihydroimidazole, dihydrotriazole, pyridine, pyridazine, Included are pyrimidines, dihydropyrimidines, tetrahydropyridines and the like. The 5- or 6-membered ring is often imidazole, dihydroimidazole, triazole, dihydrotriazole, pyridazine, pyrimidine, dihydropyrimidine and the like.

The 5- or 6-membered ring represented by A ring may have a substituent. Examples of the 5- or 6-membered ring substituent include a halogen atom (fluorine, chlorine, bromine and iodine atom), an optionally halogenated alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Linear or branched such as sec-butyl, tert-butyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-trifluoromethylethyl groups C _1-6 alkyl group, preferably a linear or branched C _1-4 alkyl group), an alkenyl group (eg, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and the like C _{2- 6} alkenyl groups, preferably C _2-4 alkenyl groups, alkynyl groups (eg ethynyl, propynyl, isopropynyl , Butynyl, isobutynyl, sec-butynyl and other C _2-6 alkynyl groups, preferably C _2-4 alkynyl groups), cycloalkyl groups (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups and other C _3-8 cyclo groups). Alkyl group, preferably C _3-6 cycloalkyl group), cycloalkylalkyl group (for example, C _3-6 cycloalkyl-C _1-4 alkyl group such as cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl group), aryl Group (for example, C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl group, preferably C _6-10 aryl group, especially phenyl group), nitro group, cyano group, hydroxyl group An optionally halogenated alkoxy group (eg, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, C, such as difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy group
_1-6 alkoxy group, preferably C _1-4 alkoxy group),
An optionally halogenated alkylthio group (for example,
C _1-6 such as methylthio, ethylthio and propylthio groups
An alkylthio group, preferably a C _1-4 alkylthio group),
Amino groups, mono- or di-alkylamino groups (eg,
Mono- or di-C such as methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups
_1-6 alkylamino group, preferably mono- or di-C
_1-4 alkylamino group), cyclic amino group (for example, in addition to nitrogen atom, 1 to 5 heteroatoms such as oxygen atom and sulfur atom)
A 5- to 9-membered cyclic amino group which may include three, specifically, for example, pyrrolidino, piperidino, morpholino group and the like), acyloxy group (for example, formyloxy, acetoxy, propionyloxy group and the like C _{1 -6} acyloxy group, preferably C _1-4 acyloxy group), alkylcarbonylamino group (eg, acetylamino,
C _1-6 alkyl-carbonylamino group such as propionylamino or butyrylamino group, preferably C _1-4 alkyl-carbonylamino group, alkylsulfonylamino group (eg, C _1- such as methylsulfonylamino or ethylsulfonylamino group) ₆ alkylsulfonylamino group,
Preferably C _1-4 alkylsulfonylamino group), alkoxycarbonyl group (eg, C such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group)
_1-6 alkoxy-carbonyl group, preferably C _1-4 alkoxy-carbonyl group), carboxyl group, alkylcarbonyl group (for example, C _1-6 alkyl-carbonyl group such as methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc., preferably Is a C _1-4 alkyl-carbonyl group), a carbamoyl group, a mono- or di-alkylcarbamoyl group (for example, a methyl-carbamoyl group, an ethylcarbamoyl group or other mono- or di-C _1-6 alkylcarbamoyl group, preferably a mono-) group. Or a di-C _1-4 alkylcarbamoyl group), an alkylsulfonyl group (for example, a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl group, preferably C _1-4
It may have a substituent selected from an alkylsulfonyl group), an oxo group, a thioxo group and the like. The number of these substituents is, for example, about 1 to 3, preferably 1 or 2 depending on the size of the A ring and the number of heteroatoms, and when the number of the substituents is 2 or more, May have the same or different substituents.

Preferred substituents which ring A may have include a halogen atom and an optionally halogenated C _1-4.
Alkyl group, optionally halogenated C _1-4 alkoxy group, optionally halogenated C _1-4 alkylthio group, hydroxyl group, amino group, mono- or di-C
_1-4 alkylamino group, cyano group, carboxyl group, C
_1-4 includes an alkoxycarbonyl group and an oxo group.

When the ring A has a nitrogen atom other than the nitrogen atom at the bridge head, it may form a quaternary ammonium salt, for example, a halogen ion (for example, Cl ⁻ , Br ⁻ ,
I ^−, etc.), anion such as sulfate ion, nitrate ion, and hydroxy ion may form a salt.

General Description of Ring B and Ring C In the above general formula (I), each of Ring B and Ring C is an homocycle or a heterocycle which may have a substituent. The "homocyclic ring" includes a cyclic hydrocarbon composed of carbon atoms, for example, an alicyclic hydrocarbon having about 5 to 8 carbon atoms, and 6 to 6 carbon atoms.
Approximately 10 aromatic hydrocarbons are included. Specifically, for example, C _5-8 cycloalkene (eg, cyclopentene, cyclohexene, etc.), C _5-8 cycloalkane (eg, cyclopentane, cyclohexane, cyclooctane, etc.), C _6-10 aryl (eg, benzene). Etc.) etc. are included. Preferred "cyclic hydrocarbons" include
For example, a 5- to 7-membered cyclic hydrocarbon, especially a 6-membered homocyclic ring (eg, benzene, cyclohexene, cyclohexane ring, etc.) is included. Preferred homocyclic rings include, for example, benzene, C _5-6 cycloalkenes (eg, cyclopentene, cyclohexene, etc.), C _5-7 cycloalkanes (eg, cyclohexane, cyclopentane, etc.), and particularly benzene rings. preferable.

The "heterocycle" is, for example, an aromatic heterocycle containing preferably 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. Included are rings or non-aromatic heterocycles. Examples of the “aromatic heterocycle” include, in addition to carbon atoms,
A 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene , Furan, thiazole, isothiazole, oxazole and isoxazole rings, etc.) and the like. Preferred aromatic heterocycles include, for example, pyridine, pyrazine, pyrrole, thiazole and thiophene rings. In particular, (i) a 6-membered nitrogen-containing heterocycle containing one or two nitrogen atoms in addition to the carbon atom (for example,
Pyridine, pyrazine ring, etc.) or (ii) a 5-membered aromatic heterocycle containing one sulfur atom in addition to the carbon atom (eg, thiophene ring) is preferable.

The "non-aromatic heterocycle" includes, for example, 1 to 4 heteroatoms, preferably 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom. Included are 5 or 6 membered non-aromatic heterocycles and the like. For example, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, Examples thereof include piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole and tetrahydroisoxazole ring.
The non-aromatic heterocycle includes, for example, 1 to 4 nitrogen atoms other than carbon atoms, preferably 1 or 2 nitrogen atoms.
Membered non-aromatic heterocycles (eg piperidine, piperazine ring, etc.) and the like are preferable.

More preferably, one of ring B and ring C has a benzene ring which may have a substituent or an aromatic heterocycle which may have a substituent (for example, 5 or 6).
Membered aromatic heterocycle), and the other is a benzene ring which may have a substituent. As the aromatic heterocycle,
The same heterocycle as described above can be exemplified, and a pyridine ring is often used. More preferable ring B and ring C are benzene rings each optionally having a substituent.

Examples of the substituent which ring B and ring C may have include, for example, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, and a halogenated group. An optionally substituted alkylthio group,
Aryl group, acylamino group, acyloxy group, hydroxyl group, nitro group, cyano group, amino group, mono- or di-alkylamino group, cyclic amino group (for example, in addition to nitrogen atom, hetero atoms such as oxygen atom, sulfur atom, etc. Cyclic amino group which may be included), alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoyl group, mono- or di-alkylcarbamoyl group, alkylsulfonyl group, oxo group, etc. Is mentioned.

The "halogen atom" includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine and bromine atoms (particularly fluorine and chlorine atoms).

Examples of the above-mentioned "alkyl group which may have a substituent (s)" include, for example, hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-C _1-6 alkylamino group (for example, methyl group). Amino, ethylamino, dimethylamino, diethylamino group, etc.), C _1-6 alkyl-carbonyloxy group (eg, acetoxy, ethylcarbonyloxy group, etc.) and halogen atom (eg, fluorine, chlorine, bromine atom, etc.) 1
~ C _1-6 alkyl group _optionally having 5 substituents (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl groups, etc.) and the like. In particular, an optionally halogenated alkyl group, such as a C _1-6 alkyl group, and 1
A C _1-6 alkyl group substituted with about 5 halogen atoms is preferable. Such alkyl groups or halogenated alkyl groups include, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, Propyl, 3,
3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5.
5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexyl,
A 5-trifluoromethylpentyl group and the like are included. Particularly preferred “alkyl group optionally having substituent (s)” is an optionally halogenated C _1-4 alkyl group, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl , 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4.
4-trifluorobutyl, isobutyl, sec-butyl, t
C _1-4 alkyl groups or one to three approximately halogen atoms such as ert- butyl group and the like C _1-4 alkyl group substituted.

Examples of the "optionally halogenated alkoxy group" include a C _1-6 alkoxy group or a C _1-6 alkoxy group substituted with about 1 to 5 halogen atoms. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,
It includes 2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy and hexyloxy groups. Particularly preferable "alkoxy group which may be halogenated" is a C _1-4 alkoxy group or a C _1-4 alkoxy group substituted with about 1 to 3 halogen atoms, for example, methoxy, difluoromethoxy and tri. Fluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy group and the like are included.

The "optionally halogenated alkylthio group" includes, for example, a C _1-6 alkylthio group and a C _1-6 alkylthio group having 1 to 5 halogen atoms. Examples of such alkylthio group and halogenated alkylthio group include, for example, methylthio,
Examples thereof include difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio groups. Particularly preferred “optionally halogenated alkylthio group” is a C _1-4 alkylthio group or a C _1-4 alkylthio group substituted with 1 to 3 halogen atoms, for example, methylthio, difluoromethylthio, tri Fluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio groups and the like are included.

Further, the aryl group as a substituent includes
Examples of the C _6-10 aryl group (eg, phenyl group) and the acylamino group include C _1-7 acylamino groups (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino groups, etc.).
_1-5 acylamino group, etc.) and the like. The acyloxy group includes, for example, a C _1-3 acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.) and the like. Examples of the mono- or di-alkylamino group include, for example, mono- or di-C _1-6 alkylamino groups (for example, mono- or di-C such as methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups). _1-4 alkylamino group) and the like. Further, the cyclic amino group, for example, in addition to the nitrogen atom, an oxygen atom, a 5 to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms such as sulfur atoms (for example, pyrrolidino, piperidino, Morpholino group, etc.) and the like. Examples of the alkylcarbonylamino group include a C _1-6 alkyl-carbonylamino group (for example, C _1-4 alkyl-carbonylamino group such as acetylamino, propionylamino, butyrylamino group, etc.), and an alkylsulfonylamino group, For example, a C _1-6 alkylsulfonylamino group (for example, a C _1-4 alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino group, etc.) and an alkoxycarbonyl group include, for example, a C _1-6 alkoxy-carbonyl group. (For example, a C _1-4 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group), an alkylcarbonyl group includes, for example, a C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, Ethylcarbonyl, propyi _C1-4 alkyl-carbonyl group such as lecarbonyl),
Mono- or di-alkylcarbamoyl groups include, for example:
A mono- or di-C _1-6 alkylcarbamoyl group (for example, a mono- or di-C _1-4 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), an alkylsulfonyl group includes, for example, , C _1-6 alkylsulfonyl groups (eg, C _1-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) and the like. Hereinafter, when the term "may be halogenated" is used in the present specification, it means that the number of halogen atoms is 1 to 5, preferably 1 to 3.

Preferred substituents which ring B and ring C may have include, for example, halogen atom, optionally halogenated C _1-6 alkyl group (especially C _1-4 alkyl group), halogen _Optionally substituted C _1-6 alkoxy group (especially C _1-4 alkoxy group), optionally halogenated C _1-6 alkylthio group (especially C _1-4 alkylthio group), C _1-3 acyloxy Group, hydroxyl group, amino group, mono- or di-C _1-6 alkylamino group (especially mono- or di-C _1-4 alkylamino group), carboxyl group, C _1-6 alkoxy-carbonyl group (especially C _1-4 alkoxy-carbonyl group), C _6-10 aryl group, oxo group and the like.

More preferred substituents which ring B and ring C may have are a halogen atom, an optionally halogenated C _1-6 alkyl group, and an optionally halogenated C.
_1-6 alkoxy groups and the like are included. Particularly, a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and the like are preferable.

The substituents on the B ring and the C ring may be substituted at any substitutable position in the ring.
When the number is one or more, the substituents may be the same or different, and the number thereof may be about 1 to 4. The number of substituents on the ring is preferably about 1 to 3.

When the ring B and / or the ring C has a nitrogen atom, it may form a quaternary ammonium salt, for example, a halogen ion (for example, Cl ⁻ , Br ⁻ , I ^−, etc.), a sulfate ion, A salt may be formed with an anion such as nitrate ion and hydroxy ion.

As for the ring B, a preferable homocyclic ring in the ring B is, for example, a homocyclic ring composed of a carbon atom which may have a substituent, for example, a compound represented by the formula (B-
1)

[0055]

[Chemical formula 22] [Wherein B ¹ , B ² , B ³ , B ⁴ , B ⁵ and B ⁶ are
The same or different, each represents a halogen atom, an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group] and the like. .

Further preferred homocyclic rings have the formula (B-2)

[0057]

[Chemical formula 23] The benzene ring which may have a substituent represented by [the symbols in the formula are as defined above] can be mentioned.

In the above formula, the halogen atom in B ^{1 to} B ⁶ includes, for example, fluorine, chlorine and bromine atoms,
Examples of the optionally halogenated C _1-6 alkyl group include methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, 1,
1,2,2-tetrafluoroethyl, propyl, 2,
Examples of the optionally halogenated C _1-6 alkoxy group which includes a C _1-4 alkyl group such as 2,3,3-tetrafluoropropyl and isopropyl group include methoxy, trifluoromethoxy and trichloro. Methoxy, ethoxy, 2,2,2-trifluoroethoxy, 1,1,
2,2-tetrafluoroethoxy, propoxy, 2,
It includes C _1-4 alkoxy groups such as 2,3,3-tetrafluoropropoxy and isopropoxy groups.

Among the substituents in the above formula, particularly preferable substituents include, for example, (1) B ¹ , B ² , B ³ and
B ⁴ , B ⁵ and B ⁶ are the same or different and each is a halogen atom (eg fluorine, chlorine atom etc.) or an optionally halogenated C _1-6 alkyl group (eg methyl, trifluoromethyl, (C _1-4 alkyl groups such as ethyl and isopropyl groups), (2) B ¹ , B ² , B ³ ,
B ⁴ , B ⁵ and B ⁶ are the same or different and are optionally halogenated C _1-6 alkoxy groups (for example, C such as methoxy, trifluoromethoxy and ethoxy groups).
_1-4 alkoxy group etc.) and the like.

When ring B is a heterocycle (aromatic heterocycle or non-aromatic heterocycle), ring B is a 5- or 6-membered heterocycle, for example, nitrogen atom, oxygen atom, sulfur atom in addition to carbon atom. 5- or 6-membered aromatic nitrogen-containing heterocycle containing 1 or 2 heteroatoms selected from (for example, pyridine, thiophene, pyrazine ring, etc.) and non-aromatic heterocycles (eg, tetrahydropyridine, piperidine, tetrahydropyrimidine) , Tetrahydropyridazine ring, etc.) are preferred. Preferred ring B includes aromatic nitrogen-containing heterocycle. Ring B as a heterocycle may have the same preferable substituents as those exemplified above.

With respect to the C ring, preferred homocyclic rings in the C ring include a benzene ring which may have a substituent. When C ring is a heterocycle (aromatic heterocycle or non-aromatic heterocycle), C ring is a 5- or 6-membered heterocycle, for example, selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. An aromatic heterocycle (eg, pyridine, pyrazine, pyrrole, thiazole and thiophene ring) containing one or two heteroatoms, preferably one or two, or a non-aromatic heterocycle (eg, tetrahydropyridine) , Tetrahydropyrimidine,
Tetrahydropyridazine, piperidine, piperazine ring, etc.) are preferred. Preferred C-rings include aromatic nitrogen-containing heterocycles.

The substituent which ring C may have is
For example, a halogen atom (for example, fluorine, chlorine, bromine,
Iodine atom), optionally halogenated C _1-6 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl) , Perfluoroethyl, propyl, isopropyl,
3,3,3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl group, etc.), a C _1-6 alkyl group substituted with an amino group (eg, aminomethyl, 2-amino) Ethyl group, etc.),
C substituted with a mono- or di-C _1-6 alkylamino group
_1-6 alkyl group (eg, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl group, etc.), C _1-6 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxy) and ethyl group), C _1-6 alkoxy - carbonyl group substituted C _1-6 alkyl group (e.g., methoxycarbonylethyl, ethoxycarbonyl ethyl group), C _1-6 alkyl group substituted with a hydroxyl group ( For example,
Hydroxymethyl, hydroxyethyl group, etc.), C _1-6
C _1-6 alkyl group substituted with an alkoxy-carbonyl group (eg, methoxymethyl, methoxyethyl, ethoxyethyl group, etc.), C _3-6 cycloalkyl group (eg,
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group, etc.), nitro group, cyano group, hydroxyl group, optionally halogenated C _1-6 alkoxy group (eg, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy) , 2, 2,
2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
t-butoxy, perfluorobutoxy group, etc.), an optionally halogenated C _1-6 alkylthio group (eg,
Methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio group, etc.), amino group, mono- or di-C
_1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, etc.), cyclic amino group (for example, 1 to 3 heteroatoms such as oxygen atom and sulfur atom in addition to nitrogen atom) 5 to 9-membered cyclic amino group which may be contained, specifically,
For example, pyrrolidino, piperidino, morpholino groups, etc.), C _1-6 alkyl-carbonylamino groups (eg,
Acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C
_1-6 alkylaminocarbonyloxy group (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-6 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino) , Propylsulfonylamino group, etc.),
C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl group, etc.), aralkyloxycarbonyl group (eg, benzyloxycarbonyl group, etc.), carboxyl group, C _{1- 6}
An alkyl-carbonyl group (eg, methylcarbonyl,
Ethylcarbonyl, butylcarbonyl, etc.), C _1-6
Acyloxy group (eg acetoxy group), C _3-6
Cycloalkyl-carbonyl group (eg, cyclohexylcarbonyl group), carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl group) Etc.), a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.) and the like. C ring is
These substituents may have a substituent at a substitutable position, and the number of substituents can be appropriately selected within the substitutable range. The number of substituents that the C ring may have is about 1 to 5, preferably about 1 to 3. When the number of substituents is 2 or more, the types of the substituents may be the same or different.

Ring C is, for example, one C _6-10 aryl group (eg, phenyl group), a 5- or 6-membered aromatic monocyclic heterocyclic group (eg, furyl, thienyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,3 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
(Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl groups, etc.)
It may be replaced with. These aryl groups and / or aromatic monocyclic heterocyclic groups are optionally halogenated C _1-6 alkyl groups (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, C _1-4 alkyl group such as isopropyl group) and the like.

Preferable substituents which ring C may have include, for example, halogen atom (eg, fluorine, chlorine, bromine atom) and optionally halogenated C.
_1-6 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3 , 3-trifluoropropyl, butyl, s
C such as -butyl, t-butyl, perfluorobutyl group
_1-4 alkyl group), nitro group, hydroxyl group, optionally halogenated C _1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy) ,
Perfluoroethoxy, propoxy, isopropoxy,
3,3,3-trifluoro propoxy, etc. C _1-4 alkoxy group such as butoxy group), an amino group, a mono - or di -C _1-6 C _1-6 alkyl group substituted with an alkylamino group (e.g. , methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-mono-, such as dimethylaminoethyl group - or the like C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group), mono - Or di-C
_1-6 alkylamino group (eg, mono- or di-C _1-4 alkylamino group such as methylamino, ethylamino, dimethylamino, diethylamino group), C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) ,
Examples thereof include C _1-4 alkoxy-carbonyl group such as ethoxycarbonyl group), C _1-6 acyloxy group (for example, C _1-4 acyloxy group such as acetoxy group), carboxyl group and carbamoyl group. The number of these substituents is preferably, for example, about 1 to 3.

The preferred C ring is a benzene ring which may have a substituent (in particular, a benzene ring substituted by a substituent), for example, a halogen atom or an optionally halogenated C _1-4 alkyl. Group, optionally halogenated C _1-4 alkoxy group, di-C _1-4 alkylamino group, C
_1-3 include acyloxy groups and hydroxyl 1-3 benzene ring optionally substituted with a substituent selected from group (especially a benzene ring substituted with the substituent group).

Further preferred C ring includes a benzene ring which may have a substituent, particularly a benzene ring substituted with the above substituent. Specifically, the preferred C ring includes
For example, the following formula (C-1)

[0067]

[Chemical formula 24] [Wherein C ¹ , C ² and C ³ are the same or different,
Hydrogen atom, halogen atom (eg, fluorine, chlorine, bromine atom, etc.), optionally halogenated C _1-6 alkyl group (eg, methyl, trichloromethyl, trifluoromethyl, ethyl, 2,2,2-) Trifluoroethyl,
Perfluoroethyl, propyl, isopropyl, 3,
3,3-trifluoropropyl, butyl, s-butyl,
a C _1-4 alkyl group such as t-butyl group) and an optionally halogenated C _1-6 alkoxy group (eg, methoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoro) C _1-4 alkoxy groups such as ethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy groups), mono- or di-C
_1-6 alkylamino group (eg, mono- or di-C _1-4 alkylamino group such as methylamino, ethylamino, dimethylamino, diethylamino group etc.), C _1-3 acyloxy group (eg acetoxy group etc.) Or a hydroxyl group], or the following formula (C-2)

[0068]

[Chemical 25] [In the formula, C ⁴ and C ⁵ are the same or different and each is a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), or an optionally halogenated C _1-6 alkyl group (eg, Methyl, trichloromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, butyl, t
-A C _1-4 alkyl group such as a butyl group) and an optionally halogenated C _1-6 alkoxy group (eg, methoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy) , A C _1-4 alkoxy group such as propoxy, isopropoxy, butoxy, etc.)], which may be substituted.

More preferable C ring includes, for example, a benzene ring in which C ^{1 to} C ⁵ are the following substituents in the above formulas (C-1) and (C-2). (1) C ¹ , C ² and C ³ are the same or different,
A halogen atom, an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. (2) C ¹ , C ² and C ³ are the same or different,
Halogen atom or optionally halogenated C _1-6
Alkyl group. (3) C ¹ , C ² and C ³ are the same or different,
Halogen atom. (4) C ¹ , C ² and C ³ are the same or different,
An optionally halogenated C _1-6 alkyl group. (5) C ¹ , C ² and C ³ are the same or different,
An optionally halogenated C _1-6 alkoxyl group. (6) C ⁴ and C ⁵ are the same or different and are halogen atoms. (7) C ⁴ and C ⁵ are the same or different and are optionally halogenated C _1-6 alkyl groups. (8) C ⁴ and C ⁵ are the same or different and are optionally halogenated C _1-6 alkoxy groups. (9) C ⁴ and C ⁵ have a substituent at the 3 and 5 positions. (10) C ⁴ and C ⁵ have a substituent at the 2-position and the 5-position. (11) C ⁴ and C ⁵ have a substituent at the 2-position and the 6-position.

In the above embodiments (1) to (8), "optionally halogenated C _1-6 alkyl group", "optionally halogenated C _1-6 alkoxy group" and "halogen atom" Can be exemplified by the same groups or atoms as described above.

More preferable C ring is, for example, a benzene ring in which C ⁴ and C ⁵ are the following substituents in the above formula (C-2). (A) one of C ⁴ and C ⁵ is a hydrogen atom, the other is a methoxy group, (b) one of C ⁴ and C ⁵ is a hydrogen atom, the other is a chlorine atom, and (c) of C ⁴ and C ⁵ One is a methoxy group, the other is an isopropyl group, (d) one of C ⁴ and C ⁵ is a methoxy group, and the other is 1-methoxy-
1-methylethyl group, (d) C ⁴ and C ⁵ are trifluoromethyl groups.

“About X and Y” In the above formula, “—X
-Y- ^{"is, -N = CR 1 - (R} 1 is a hydrogen atom or may be an optionally substituted hydrocarbon group, hydroxyl group which may have a substituent, substituted Optionally represents an amino group or a halogen atom) or —NR ² —CO—
(R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent).

The "hydrocarbon group optionally having substituent (s)" represented by R ¹ is the same "carbon atom optionally having substituent (s)" as will be described later in the section "R". And "hydrogen group". Examples of the “hydroxyl group which may have a substituent” represented by R ¹ include, for example, a hydroxyl group and an optionally halogenated C _1-6 alkoxy group (eg, methoxy, difluoromethoxy, trichloromethoxy). , Trifluoromethoxy, ethoxy, 2,2
C such as 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy group
_1-4 alkoxy groups, etc.), aralkyloxy groups (eg, C _7-11 aralkyloxy groups such as benzyloxy groups, etc.) and the like. Incidentally, when R ¹ is a hydroxyl group, - -N as "X-Y-" = C (OH)
-Also exists as -NH-CO- (group in which R ² is a hydrogen atom) having a tautomeric relationship.

The "optionally substituted amino group" represented by R ¹ includes, for example, an amino group, a mono- or di-C _1-6 alkylamino group (eg, methylamino,
Ethylamino, propylamino, methylethylamino,
A mono- or di-C _1-4 alkylamino group such as dimethylamino or diethylamino group), a cyclic amino group (for example, containing about 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom) 5-8-membered cyclic amino group which may be present, specifically, for example, pyrrolidino, piperidino, 4-methylpiperazino, morpholino group, etc.),
C _1-6 alkylcarbonylamino group (for example, acetylamino, propionylamino, butyrylamino group, etc. C
_1-4 alkylcarbonylamino group) and the like. Examples of the “halogen atom” represented by R ¹ include a fluorine, chlorine, bromine atom and the like.

Preferred R ¹ includes a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group or a mono- or di-C _1-6 alkylamino group, a 5- to 7-membered cyclic amino group and the like. More preferred R ¹ is a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl group), a hydroxyl group, a C _1-4 alkoxy group (eg, methoxy). , Ethoxy, propoxy, isopropoxy, butoxy group), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino group, etc.) Cyclic amino groups (eg, pyrrolidino, piperidino, 4-methylpiperazino, morpholino groups, etc.) are included.

The "hydrocarbon group optionally having substituent (s)" represented by R ² is the same "carbon atom optionally having substituent (s)" as described in the section "R" below. And "hydrogen group". R ² is a C _1-6 alkyl group (for example,
C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl and isobutyl groups), C _7-11 aralkyl groups (eg benzyl, phenethyl group etc.), C _3-6 cycloalkyl-C _{A 1-3} alkyl group (eg, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl group, etc.) and the like are preferable. More preferred R ² is C _1-6 alkyl group, especially C
_1-4 alkyl groups.

Preferred "-X-Y-" is -N = CR ¹
-(R ¹ is a hydrogen atom or a C _1-4 alkyl group).

Regarding “R” In the above formula, R represents a hydrogen atom or a hydrocarbon group which may have a substituent. The “hydrocarbon group” represented by R includes
For example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group and an aralkyl group are included, and an alkyl group is often used.

The "alkyl group" is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-). Butyl, pentyl, hexyl groups, etc.) are included, and a linear or branched alkyl group having about 1 to 4 carbon atoms is preferable. "Alkenyl group"
Includes, for example, an alkenyl group having 2 to 6 carbon atoms (for example,
Ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl group, etc.) and the like.
The "alkynyl group" includes, for example, an alkynyl group having 2 to 6 carbon atoms (eg, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl group, etc.).
Is included.

Examples of the above-mentioned “cycloalkyl group” include cycloalkyl groups having 3 to 8 carbon atoms (for example, C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups). . As the “cycloalkylalkyl group”, for example, a C _3-6 cycloalkyl-C _1-6 alkyl group (eg,
C _3-6 such as cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl and cyclohexylethyl groups
Cycloalkyl-C _1-3 alkyl group etc.) and the like. The “aryl group” includes, for example, an aryl group having 6 to 14 carbon atoms (eg, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl group, etc.) and the like. Preferred aryl groups include, for example, phenyl groups. Examples of the aralkyl group include C
_{And 7-11} aralkyl groups (eg, C _7-10 aralkyl groups such as benzyl and phenethyl groups). R
Is often a hydrogen atom or an alkyl group having about 1 to 3 carbon atoms, particularly a hydrogen atom or an alkyl group having about 1 or 2 carbon atoms.

The substituent which the “hydrocarbon group” may have is, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine atom), a nitro group, a cyano group, a hydroxyl group, C _1-6. Alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl group, etc.), C _1-6
Alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio group, etc.), amino group, mono-, di- Or a tri-C _1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, trimethylamino, triethylamino group, etc.), a cyclic amino group (for example, oxygen atom other than nitrogen atom, sulfur) A 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as atoms, for example, pyrrolidino, piperidino, morpholino group, etc., C _1-6 alkyl-carbonylamino group (for example, acetylamino , Propionylamino, butyrylamino groups, etc.), C _1-6 alkyl Sulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.), C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.), C _{1- 6} alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), carbamoyl group, mono- or di-C
_1-6 alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, diethylcarbamoyl group, etc.), C _1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl,
And a C _6-10 aryl group (eg, a phenyl group) and the like. The number of these substituents is not particularly limited and is, for example, about 1 to 5, preferably about 1 or 2. When the number of substituents is 2 or more, the types of the substituents may be the same or different.

“N” In the above formula, n represents an integer of 0 to 3. n (that is, the number of repeating methylene chains) can be appropriately selected, but is particularly 1
Alternatively, 2 is preferable, and 1 is particularly preferable.

Preferred Embodiments of Compounds Among the compounds represented by the above general formula (I), preferred compounds include the following compounds and pharmaceutically acceptable salts. (1) A ring which may have a substituent containing 2 or 3 nitrogen atoms including the nitrogen atom of the bridge head in addition to carbon atoms; B ring having a substituent Benzene ring which may be present; benzene ring in which C ring may have a substituent; -X
-Y- is -N = CR ^1- (R ¹ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a mono- or di-C _1-4 alkylamino group) or -NR ² -CO- (R ² represents a hydrogen atom or a C _1-4 alkyl group); R is a hydrogen atom or a C _1-4 alkyl group; and n is 1, or a pharmaceutically acceptable salt thereof.

(2) A heterocycle in which the ring A contains, in addition to carbon atoms, 2 or 3 nitrogen atoms including the nitrogen atom at the bridge head; B
Ring is a halogen atom, optionally halogenated C _1-4
A benzene ring optionally having 1 or 2 substituents selected from an alkyl group and an optionally halogenated C _1-4 alkoxy group; C ring may be a halogen atom or halogenated C _1-4 alkyl groups, one to three selected from optionally C _1-4 alkoxy group which may be halogenated (e.g., one or three) a benzene ring which may have a substituent; -X-Y- is -N = CR ^1- (R ¹ is a hydrogen atom, C
_1-4 alkyl group, C _1-4 alkoxy group, mono- or di-C
_{1-4 represents} an alkylamino group) or —NR ² —CO—
(R ² represents a hydrogen atom or a C _1-4 alkyl group); R is a hydrogen atom or a C _1-4 alkyl group; and n is 1 or 2
Or a pharmaceutically acceptable salt thereof.

When the compound represented by the above formula (I) forms a salt and it is used as a medicine, the salt is preferably a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid, or acetic acid, malic acid, maleic acid, Fumaric acid, tartaric acid,
Examples thereof include salts with organic acids such as succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid and stearic acid.

Method for producing compound or salt thereof Compound (I) or a salt thereof of the present invention can be prepared, for example, by a compound represented by the general formula (II) or a salt or a reactive derivative thereof, and a compound represented by the general formula: It can be produced by reacting the compound represented by (III) or a salt thereof to form an amide bond.

[0087]

[Chemical formula 26] [Symbols in the Formula are the Same as Above] Examples of the amide bond-forming reaction include (a) compound (I
I) or a salt thereof and a compound (III) or a salt thereof are reacted using a suitable condensing agent, or (b) the compound (II) or a salt thereof is introduced into a reactive derivative and then the compound ( It can be carried out by a method of reacting with III) or a salt thereof. Examples of the salt of compound (II) include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as magnesium, and ammonium salts. The salt of compound (III) includes salts with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,
Examples thereof include salts with organic acids such as acetic acid, oxalic acid, fumaric acid, and maleic acid.

In the above method (a), the condensing agent may be a conventional condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide and the like. Can be mentioned. The reaction is usually
It is carried out in a solvent inert to the reaction. Examples of the solvent include ethers such as tetrahydrofuran, dioxane and dimethoxyethane; esters such as ethyl acetate; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane; hydrocarbons such as benzene and toluene; N, N-dimethylformamide. Examples thereof include amides such as; and sulfoxides such as dimethyl sulfoxide. Compound (III)
Alternatively, the amount of the salt and the condensing agent used is, for example, about 1 to 5 equivalents, preferably about 1 to 3 equivalents, relative to 1 mol of the compound (II) or a salt thereof. The reaction may be carried out in the presence of a base to accelerate the reaction. Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine, and basic nitrogen-containing heterocyclic compounds such as pyridine.
The amount of the base used is, for example, compound (II) or its salt 1
It is about 1 to 5 mol, preferably about 1 to 3 mol per mol. The reaction temperature is, for example, -10 ° C to 100 ° C, preferably about 0 to 60 ° C, and the reaction is usually 1 to 9 ° C.
It takes about 6 hours, preferably about 1 to 72 hours.

In the method (b), the compound (II)
As the reactive derivative of, for example, a corresponding acid halide (for example, chloride, bromide, etc.), an acid anhydride, a mixed acid anhydride (for example, an anhydride with methyl carbonic acid, an anhydride with ethyl carbonic acid, and isobutyl carbonic acid) Anhydride, etc.), active ester (for example, ester with hydroxysuccinimide, ester with 1-hydroxybenzotriazole,
Examples thereof include N-hydroxy-5-norbornene-2,3-dicarboximide ester, p-nitrophenol ester, 8-oxyquinoline ester, and the like. Reactive derivative of compound (II) and compound (II
The reaction with I) or a salt thereof is usually carried out in a solvent inert to the reaction. As the solvent, the same solvent as in the above method (a) can be used, and a basic solvent such as pyridine may be used as the solvent. The amount of compound (III) or a salt thereof used is, for example, usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the reactive derivative of compound (II).
It is about molar. In order to accelerate the reaction, it is advantageous to react in the presence of a base. As the base, in addition to the base in the method (a), aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline; alkali metal carbonates such as sodium carbonate and potassium carbonate; hydrogen carbonate. Alkali metal hydrogencarbonates such as sodium and potassium hydrogencarbonate can also be preferably used.
The amount of the base used is, for example, about 1 to 5 mol, preferably about 1 to 3 mol, relative to 1 mol of the reactive derivative of the compound (II). The reaction temperature is usually, for example, -10 ° C to 12 ° C.
It is 0 ° C., preferably about 0 ° C. to 100 ° C., and the reaction time is usually 1 to 48 hours, preferably about 1 to 24 hours. When a solvent immiscible with water is used in this reaction, water may be added to the reaction system and the reaction may be carried out in a two-phase system.

Of the compounds represented by the above general formula (I), compounds in which R ¹ is a hydrogen atom or a hydrocarbon group which may have a substituent include compounds represented by the general formula (IV)

[0091]

[Chemical 27] [Wherein R ^1a represents a hydrogen atom or a hydrocarbon group which may have a substituent, and other symbols have the same meanings as defined in claim 1], or dehydrogenate the compound or salt thereof. It can be produced by subjecting it to a reaction.

The dehydrogenation (oxidation) reaction is usually carried out in a solvent inert to the reaction. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone. And organic acids such as acetic acid and propionic acid, and aprotic polar solvents such as dimethylformamide and dimethylsulfoxide. The dehydrogenation reaction proceeds also by air (oxygen), light, etc., but it proceeds more favorably in the presence of a dehydrogenating agent. Examples of the dehydrogenating agent (oxidizing agent) include nitrites such as sodium nitrite (under acidic conditions), peroxides such as hydrogen peroxide and persulfuric acid, halogens such as chlorine, bromine and iodine, silver nitrate, Nitric acid such as nitric acid, manganese dioxide, oxides such as silver oxide, iron trichloride,
Halides such as sodium hypochlorite, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (D
Examples thereof include quinones such as DQ). In the dehydrogenation reaction, using a nitrite such as sodium nitrite,
In many cases, a method of reacting in a solvent such as acetic acid or nitric acid is preferably used, and when a peroxide such as hydrogen peroxide coexists in this reaction system, the reaction may proceed advantageously.
The reaction temperature is, for example, about −50 ° C. to 200 ° C., preferably about −20 ° C. to 110 ° C., and the reaction time varies depending on the type of compound (II) or its salt, the type of oxidizing agent, the reaction temperature, etc. For example, it is about 30 minutes to 72 hours, preferably about 1 to 24 hours.

When the compound (I) is obtained as a free compound by these methods, for example, an inorganic acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (eg, methanesulfonic acid, Benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid,
Tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium, potassium, alkaline earth metals such as calcium, magnesium, aluminum or ammonium) or organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine). , Triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine) etc.
When compound (I) is obtained in the form of a salt, it can be converted to a free compound or another salt according to a conventional method. The target compound (I) or a salt thereof produced by these methods can be separated and purified by using a conventional separation and purification means (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).

Production Method of Starting Compound or Salt Thereof The starting compound (II) or a salt thereof and a part of the compound having a reactive derivative at the carboxyl group thereof are known, for example, in JP-A-59-95289. It can be produced by the method described. In addition, the reduced form of a part of the raw material compound (II) is a bioorganic & medicinal chemistry letters (Bioorganic & Medici).
nal Chemistry Letters), Volume 1, pp. 291-294 (published in 1991), and reduction of these compounds in the same manner as the reaction for producing compound (I) by dehydrogenation reaction of compound (II). Compound (II) can be obtained by subjecting the body to a dehydrogenation reaction. Moreover, various compounds (II) or salts thereof, or reactive derivatives at the carboxyl group thereof can be produced by utilizing methods similar to these methods and known chemical conversion methods.

The starting compound (IV) can be produced, for example, by condensing a compound represented by the general formula (V) with a compound represented by the general formula (VI) as shown in the following reaction formula. Can be manufactured.

[0096]

[Chemical 28] [Wherein the symbols have the same meanings as defined above] The condensation reaction is usually carried out in a solvent inert to the reaction. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethyne, tetrahydrofuran and dioxone, alcohols such as methanol, ethanol and isopropanol, acetic acid, propionic acid and the like. Examples thereof include organic acids, aprotic polar solvents such as dimethylformamide, and dimethylsulfoxide. The reaction between the compound (V) and the compound (VI) is preferably carried out directly without using a solvent. The reaction temperature is, for example, about 0 to 200 ° C., preferably about 20 to 160 ° C., and the reaction time varies depending on the types of the compound (V) and the compound (VI) and the reaction temperature, for example, 1 to 72 hours, It is preferably about 1 to 24 hours.

The compounds (II), (III), (IV), (V) and (VI) may form salts, and examples of these salts include inorganic acids (eg hydrochloric acid, phosphoric acid). , Salts with hydrobromic acid, sulfuric acid, etc., organic acids (eg acetic acid, formic acid,
Examples thereof include salts with propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like. Further, when the compound (II) has an acidic group such as a carboxyl group, an inorganic base (for example, an alkali metal such as sodium or potassium,
A salt may be formed with an alkaline earth metal such as calcium or magnesium, ammonia or the like) or an organic base (eg, tri-C _1-3 alkylamine such as trimethylamine or triethylamine).

Further, in each reaction of the target compound and the raw material synthesis, when the raw material compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are protected by those generally used in peptide chemistry and the like. It may be protected with a group. In this case, the target compound can be obtained by removing the protecting group after the reaction, if necessary. As the amino-protecting group, for example,
C _1-6 alkylcarbonyl group (eg formyl, methylcarbonyl, ethylcarbonyl group etc.), phenylcarbonyl group, C _1-6 alkyl-oxycarbonyl group (eg methoxycarbonyl, ethoxycarbonyl group etc.), phenyloxycarbonyl group (Eg, a benzoxycarbonyl group), a C _7-10 aralkyl-carbonyl group (eg, a benzyloxycarbonyl group), a trityl group, a phthaloyl group, and the like, and these protecting groups have a substituent. Good. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine atom), a C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), a nitro group, etc. And the number of substituents is about 1 to 3. Examples of the protective group for the carboxyl group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.
-Butyl group), a phenyl group, a trityl group, a silyl group and the like, and these protecting groups may have a substituent. Examples of these substituents include a halogen atom (fluorine, chlorine, bromine, iodine atom), a C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), a nitro group, etc. The number of substituents is about 1 to 3. Examples of the protecting group for the hydroxyl group include C _1-6
Alkyl groups (eg methyl, ethyl, n-propyl,
i-propyl, n-butyl, tert-butyl group, etc.), phenyl group, C _7-10 aralkyl group (eg, benzyl group), C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl group) Etc.), a phenyloxycarbonyl group (eg, a benzoxycarbonyl group), a C _7-10 aralkyl-carbonyl group (eg, a benzyloxycarbonyl group), a pyranyl group, a furanyl group, a silyl group, and the like. The protecting group may have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms), C _1-6 alkyl groups, phenyl groups, C _7-10 aralkyl groups, nitro groups, and the like. Is 1
It is about 4 pieces.

The protecting group can be removed by a known method or a modification thereof, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method of treating with palladium acetate or the like can be used.

The compound (I) produced by such a method can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. When the compound (I) thus obtained is a free compound, it can be converted into a salt by a known method or a method analogous thereto (for example, neutralization etc.), and vice versa. When (I) is obtained in the form of a salt, by a known method or a method analogous thereto,
It can be converted into the educt or other salt.

The compound (I) of the present invention or a salt thereof has a capsaicin-induced activity of suppressing the increase in tracheal vascular permeability. Capsaicin is the main stimulant component of capsicum, and among the primary sensory nerves, substance P (hereinafter sometimes simply referred to as SP) and neurokinin A
(NKA), calcitonin gene-related peptide (CGR
It is known as a substance that selectively stimulates C-fibers containing P) and the like to release their endogenous neuropeptides. It is considered that this inhibitory action on vascular hyperpermeability of compound (I) is based on the tachykinin receptor antagonistic action.

Substance P is widely distributed in the central and peripheral nervous systems and functions as a messenger of primary sensory neurons, as well as vasodilatory action, vascular permeability enhancing action,
It has physiological activities such as smooth muscle contraction action, nerve cell excitatory action, salivary secretion action, diuretic enhancement action, and immune action. In particular,
S released from the end of the dorsal horn of the spinal cord by a pain impulse
It is known that P transmits pain information to secondary neurons and that SP released from peripheral terminals induces an inflammatory reaction in its receptive field. SP is also considered to be involved in Alzheimer's dementia [Review: Physiological Reviews, 73].
Volume 229-308 (Published in 1993), Journal of Autonomic Pharmacology (Journal
of Autonomic Pharmacology, 13: 23-93 (published in 1993)]. In addition, the compound (I) of the present invention
Has low toxicity.

Thus, the compound (I) of the present invention or a salt thereof having an excellent SP receptor antagonistic activity and low toxicity is a mammal (eg, mouse, rat, hamster,
Rabbit, cat, dog, cow, sheep, monkey, human etc.)
For inflammatory or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis) ,pain,
Migraine, neuralgia, pruritus, cough, and diseases of the central nervous system [eg, schizophrenia, Parkinson's disease, psychosomatic disease, dementia (eg, Alzheimer's disease etc.)], digestive system diseases (eg, irritable bowel disease, ulcer) Colitis, Crohn's disease, etc.), vomiting, dysuria (eg, frequent urination, urinary incontinence, etc.),
It is expected to be useful as a preventive or therapeutic drug for cardiovascular diseases (eg, angina, hypertension, heart failure, thrombosis, etc.) and immune disorders. In particular, the compound (I) of the present invention or a salt thereof is useful as a tachykinin receptor antagonist, an agent for improving urination abnormality such as urination, urinary incontinence or a therapeutic agent.

When the compound (I) of the present invention or a salt thereof is used as the above-mentioned medicinal product, a suitable pharmacologically acceptable carrier or excipient (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.) , Binders (eg starch, arabic gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone etc.), lubricants (eg stearic acid, magnesium stearate, calcium stearate, talc etc.), disintegrating agents (Eg, calcium carboxymethyl cellulose, talc, etc.), diluent (eg, saline solution, etc.)
It can be administered orally or parenterally in the form of powder, fine granules, granules, tablets, capsules, injections and the like by mixing with the above. Although the dose varies depending on the type of Compound (I) or a pharmaceutically acceptable salt thereof, administration route, symptoms, age of the patient, etc., for example, when orally administered to an adult patient with dysuria, per day About 0.005 to 50 mg, preferably about 0.05 to 1, as Compound (I) or a salt thereof per 1 kg of body weight
0 mg, more preferably about 0.2-4 mg daily
It can be divided into three doses.

[0105]

The compound (I) of the present invention or a salt thereof comprises
It has a high tachykinin receptor antagonism, especially a substance P receptor antagonism, has low toxicity and is safe as a medicine.

[0106]

The present invention will be further described in detail in the following reference examples and examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change with.

Elution by column chromatography in Reference Examples and Examples was carried out by TLC (Thin Lay) unless otherwise specified.
er Chromatography, thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method.
As silica gel for column chromatography, silica gel 60 (70-230 mesh) manufactured by Merck was used.
Room temperature usually means about 10 ° C to 35 ° C. Sodium sulfate or magnesium sulfate was used for drying the extract.

Abbreviations in Examples and Reference Examples mean the following.

NMR: Nuclear magnetic resonance spectrum EI-MS: Electron impact mass spectrometry spectrum SI-MS: Secondary electron ion mass spectrometry spectrum DMF: Dimethylformamide, THF: Tetrahydrofuran, DMSO: Dimethylsulfoxide, Hz: Hertz, J: Cup Ring constant, m: multiplet, q:
Quartet, t: triplet, d: doublet,
s: singlet, b: broad, like: approximation.

Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-N, 7-dimethyl-5-phenylimidazo [1,2-
a] Pyrimidine-6-carboxamide N- [3,5-bis (trifluoromethyl) benzyl]
To a solution of -5,8-dihydro-N, 7-dimethyl-5-phenylimidazo [1,2-a] pyrimidine-6-carboxamide (Reference Example 1) (50 mg) in nitric acid (3 ml),
Sodium nitrite (500 mg) was added under cooling, and the mixture was stirred for 1 hour. The mixture was made alkaline with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried, and the solvent was evaporated to give the title compound as colorless crystals (36 mg). Mp 180-182 ° C. (acetone - isopropyl recrystallized from _{ether) NMR (200MHz, CDCl 3)} ppm: 2.65 (3H, s), 2.68 (3H, s),
4.45 (1H, d, J = 14.6Hz), 4.83 (1H, d, J = 14.6Hz), 7.2
0-7.80 (10H, m) Elemental analysis C ₂₄ H ₁₈ N ₄ Calculated C as _{OF 6, 58.54; H, 3.68} ; N, 11.38 Found C, 58.35; H, 3.67; N, 11.69.

Reference Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-5,8-Dihydro-N, 7-dimethyl-5-phenylimidazo [1,2-a] pyrimidine-6-carboxamide (Step 1) N- [3,5-bis (trifluoromethyl)
Diketene (3.4 ml) was added to a solution of benzyl] methylamine (12.5 g) in ethyl ether (100 ml) under cooling with stirring. The mixture was stirred at room temperature for 15 minutes, and the solvent was evaporated to give N- [3,5-bis (trifluoromethyl) benzyl] -N-methyl-3-oxobutanamide as a yellow oil (16.5 g). Was given. NMR (200MHz, CDCl ₃ ) ppm: 2.01 (3H × 1/5, s), 2.31 (3H
× 4/5, s), 2.98 (3H, s), 3.63 (2H × 1/5, s), 3.71 (2H ×
4/5, s), 4.67 (2H × 1/5, s), 4.74 (2H × 4/5, s), 7.62-
7.90 (3H, m).

(Step 2) The compound (17.9) obtained in Step 1 was used.
A mixture of 4 g), benzaldecht (6.14 g), piperidine acetate (100 mg) and benzene (200 ml) was heated to reflux using a reactor equipped with a water separator. Water was added to this mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, 1N hydrochloric acid, water, aqueous potassium carbonate, water and saturated aqueous sodium chloride and dried, and the solvent was evaporated to give N- [3,5-bis (trifluoromethyl) benzyl] -N. -Methyl-3-oxo-2-phenylmethylenebutanamide was obtained as colorless crystals (12.27g). Melting point 86-87 ° C (recrystallized from isopropyl ether-hexane) NMR (200MHz, CDCl ₃ ) ppm: 2.50 (3H, s), 2.74 (3H × 6 /
7, s), 3.00 (3H × 1/7, s), 4.29 (1H × 1/7, d, J = 16.0H
z), 4.46 (1H × 1/7, d, J = 16.0Hz), 4.69 (1H × 6/7, d, J
= 15.0Hz), 5.01 (1H × 6/7, d, J = 15.0Hz), 7.25-7.85 (2
H, m) calcd Elemental analysis _{C 21 H 17 NO 2 F 6} C, 58.75; H, 3.99; N, 3.26 Found C, 58.61; H, 4.00; N, 3.23.

(Step 3) Compound obtained in Step 2 (500 m
g) and 2-aminoimidazole (1.0 g) in DM
The F (2 ml) solution was heated at 120 ° C. for 40 minutes. After cooling the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with water, 1N hydrochloric acid, water, aqueous potassium carbonate, water and saturated aqueous sodium chloride, dried and evaporated to give N- [3,5-bis (trifluoromethyl) benzyl] -5. , 8-Dihydro-N, 7-dimethyl-5-phenylimidazo [1,2-a] pyrimidine-6-carboxamide (title compound) and N- [3,5-bis (trifluoromethyl) benzyl] -N, A mixture of 7-dimethyl-5-phenylimidazo [1,2-a] pyrimidine-6-carboxamide (compound of Example 1) was crystallized (350 m).
Obtained as g). Further, crystals of the compound of Example 1 were obtained as colorless crystals (116 mg) from this mother liquor. The crystals of the above mixture were subjected to column chromatography using silica gel (30 g) (eluted with ethyl acetate), separated and purified to give the title compound as colorless crystals (145
mg). Melting point 195-197 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.03 (3H, s), 2.57 (3H, s),
4.03 (1H, b), 4.89 (1H, b), 6.23 (1H, s), 6.33 (1H,
s), 6.71 (1H, s), 7.18 (6H, s), 7.61 (1H, b), 7.79 (1H,
s), 11.61 (1H, b).

Pharmacological Test [Radioligand Receptor Binding Inhibitory Activity] A receptor from human lymphoblastoid cells (IM-9) was used.
Binding inhibitory activity MA Cascieri [Molecular Pharmacology] 42
Volume, p. 458 (published in 1992)] and the like. Receptors were prepared from human lymphoblast cells (IM-9). IM-9 cells (2 × 10 ⁵ cells / ml) were inoculated and cultured for 3 days (1 liter), followed by centrifugation at 500 × G for 5 minutes to obtain a cell pellet. The obtained pellets were treated with a phosphate buffer (Flow Laboratory, CAT. No. 2
After washing once with 8-103-05), 30 ml of 120
mM sodium chloride, 5 mM potassium chloride, 2 μg / m
l chymostatin, 40 μg / ml bacitracin, 5 μg
/ Ml phosphoramidon, 0.5 mM phenylmethylsulfonylfluoride, 1 mM ethylenediaminetetraacetic acid in 50 mM Tris-HCl buffer (pH 7.4) Polytron homogenizer [Kinematika (Kinematika)
(Germany, Germany), and the mixture was centrifuged at 40,000 × G for 20 minutes. The separated product was washed twice with 30 ml of the above-mentioned buffer and then stored frozen (-80 ° C) as a receptor standard.

This preparation was added to a reaction buffer solution [50 mM Tris / HCl buffer solution (pH 7.4), 0.02% bovine serum albumin, 1 m so that the protein concentration was 0.5 mg / ml.
M Phenylmethylsulfonyl fluoride, 2μg / m
l chymostatin, 40 μg / ml bacitracin, 3 mM
Manganese chloride] and 100 μl volume was used for the reaction. Sample, ¹²⁵ I-BHSP (0.46KBq)
Was added to 0.2 ml of reaction buffer at 25 ° C for 30
It was made to react for minutes. The amount of non-specific binding was determined by adding substance P so as to be 2 × 10 ⁻⁶ M.

After the reaction, the cell harvester [290PH
D, Cambridge Technology, Inc., USA] using a glass filter [GF / B, Whatman (Whatma
n), USA)] to stop the reaction by rapid filtration.
The plate was washed 3 times with 0 μl of 50 mM Tris-HCl buffer (pH 7.4) containing 0.02% bovine serum albumin, and the radioactivity remaining on the filter was measured with a gamma counter. The filter was immersed in 0.1% polyethyleneimine for one day before use, and then air-dried for use.

Under the above conditions, Example 1 which is a test drug
The antagonistic activity of the compound obtained in 1. was determined as the drug concentration (IC ₅₀ value) required to exhibit 50% inhibition.
It was 8 nM. (Radio ligand refers to substance P labeled with ¹²⁵ I.) From this fact, the compound P of the present invention (I) or its salt is superior to substance P.
It can be seen that it has a receptor antagonism.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 471/04 117 C07D 471/04 117A

Claims (15)

[Claims] 1. A compound of the general formula [Wherein, A ring is a 5- or 6-membered ring which may have a substituent; B ring and C ring may be a homocycle or a heterocycle which may have a substituent; -X-Y- Is -N = CR ^1- (R ¹
Represents a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent, an amino group which may have a substituent or a halogen atom) or -NR ² -CO- (R ² represents a hydrogen atom or an optionally substituted hydrocarbon group); R is a hydrogen atom or an optionally substituted hydrocarbon group; n is 0 to 3 Indicates an integer. ] The condensed heterocyclic compound represented by these, or its salt. 2. The ring A is a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, in addition to a carbon atom and one nitrogen atom at the bridge head. The compound according to claim 1. 3. The compound according to claim 1, wherein ring A is a heterocycle containing 2 or 3 nitrogen atoms in addition to carbon atoms. 4. The compound according to claim 1, wherein ring B and ring C are an aromatic homocycle which may have a substituent or an aromatic heterocycle which may have a substituent. 5. The compound according to claim 1, wherein each of ring B and ring C is a benzene ring which may have a substituent. 6. The ring B has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group, and an optionally halogenated C _1-6 alkoxy group. The compound according to claim 1, which is a benzene ring which may be possessed. 7. The C ring has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group, and an optionally halogenated C _1-6 alkoxy group. The compound according to claim 1, which is an optionally substituted benzene ring. 8. The compound according to claim 1, wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group or a mono- or di-C _1-6 alkylamino group. 9. R ¹ is a C _1-6 alkyl group.
A compound as described. 10. The compound according to claim 1, wherein —X—Y— is —N═CR ¹ — (R ¹ is a hydrogen atom or a C _1-4 alkyl group). 11. The compound according to claim 1, wherein n is 1. 12. A ring A is a heterocycle which may have a substituent containing 2 or 3 nitrogen atoms in addition to carbon atoms; B is a benzene ring which may have a substituent; A benzene ring which may have a substituent; -X-Y- is -N = CR ¹
-(R ¹ represents a hydrogen atom or a C _1-4 alkyl group); R is a hydrogen atom or a hydrocarbon group which may have a substituent; and n is an integer of 1 to 3. The described compound. 13. A general formula: [The symbols in the formulas have the same meaning as in claim 1. ] Or a salt or reactive derivative thereof represented by the following general formula: [The symbols in the formulas have the same meaning as in claim 1. ] The compound of Claim 1 or its salt is made to react, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 14. A general formula: [Wherein R ^1a represents a hydrogen atom or a hydrocarbon group which may have a substituent, and other symbols have the same meanings as defined in claim 1] or a salt thereof is dehydrogenated. The method for producing the compound according to claim 1, which is used for the reaction. 15. A tachykinin receptor antagonist comprising the compound according to claim 1.