JPH08301849A - Heteroring compound and its production - Google Patents

Abstract

PURPOSE: To obtain a heterocyclic compound excellent in tachykinin receptor antagonism, especially high in substance P receptor antagonism, low in toxicity and safe, useful as a tachykinin receptor antagonist, an improver for bladder emptying abnormality, etc. CONSTITUTION: This heterocyclic compound (salt) is shown by formula I (ring A is a homocyclic or heterocyclic; B is an amino group or hydroxyl; ring C is a homocyclic or heterocyclic; one of X and Y is NR<1> (R<1> is H or a hydrocarbon group) or O and the other is CO or CS, or one of X and Y is N and the other is CR<2> (R<2> is H, a halogen, etc.); R is H or a hydrocarbon group; (n) is an integer of 0-3] such as N-[3,5-bis(trifluoromethyl)benzyl]-1,2-dihydro--N,2- dimethy1-1-oxo-4-pyrrolidino-3-oxoquinolinecarboxamide. The compound of formula I, for example, is obtained by reacting a compound of formula II with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 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]

[Chemical 4] (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]

Embedded image Compounds represented by (3) EP-A-429,
366 has the following formula

[0008]

[Chemical 6] Compounds represented by are listed in (4) Journal of
Journal of Medicinal C
hemistry), 34, 1751 (published in 1991).

[0009]

[Chemical 7] Compounds represented by are disclosed.

Further, (5) WO91 / 09844 describes the formula

[0011]

Embedded image And the like are compounds (6) EP-A-522,
808 has the formula

[0012]

[Chemical 9] Compounds represented by are disclosed.

(7) WO93 / 01169 describes the formula

[0014]

[Chemical 10] Compounds represented by are (8) EP-A-532,
456 has the formula

[0015]

[Chemical 11] 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 12] The compound represented by is (10) European Journal of Pharmacology
armacology), 250, 403 pages (issued in 1993)
Has the following formula:

[0018]

[Chemical 13] The compound represented by: (11) EP-A-585,91
3 has the following formula:

[0019]

Embedded image [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]

[Chemical 15] D is a C _1-3 alkylene group optionally substituted with an oxo group or a thioxo group, or D and Y together form a 5- to 7-membered ring optionally 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. May 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) -XY-
O-CO- or -CO-O-, D is -CO- and E
Is —NR ⁵ —, (a) G is a 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 substituent. A hydrocarbon group which may have, and (ii) -XY- is-
When it is NH-CO-, D represents -CO-. ] 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]

Embedded image [In the formula, ring A is a homocycle or heterocycle which may have a substituent; B is an amino group which may have a substituent or a hydroxyl group which may have a substituent; X And Y, (1) one is —NR ¹ — (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent) or —O
-, the other is -CO- or -CS-, or (2) one is -N = and the other = CR ² - (R ² is a hydrogen atom, a halogen atom, may be substituted hydrocarbon group , An amino group which may have a substituent or a hydroxyl group which may have a substituent)]] is synthesized for the first time, and a heterocyclic compound having a partial chemical structure Based on the structure, the heterocyclic compound has unexpectedly excellent tachykinin receptor antagonism (particularly substance P receptor antagonism), and is sufficiently satisfactory as a drug based on this action. Headline,
The present invention has been completed based on these.

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

[0026]

[Chemical 17] [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; . The other symbols are the same as those defined above] or a salt thereof.

In the compound (I), the ring (2) A may be an aromatic homocycle which may have a substituent or a heterocycle which may have a substituent. (3) This aromatic heterocycle is a 5- or 6-membered aromatic heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. May be. B may be (4) a mono- or di-C _1-6 alkylamino group, a 4- to 9-membered cyclic amino group, an arylsulfonyloxy group, or the like, and (5) a 5- to 7-membered cyclic amino group. It may be a group. Further, the ring C may be (6) an aromatic homocycle which may have a substituent or an aromatic heterocycle which may have a substituent, and (7) has a substituent. 1 to 3 selected from an optionally benzene ring, (8) a halogen atom, an optionally halogenated C _1-6 alkyl group, and an optionally halogenated C _1-6 alkoxy group. It may be a benzene ring which may have a substituent. In the formula (I), (9) "-XY
“—” Is —CO—NR ¹ —, —NR ¹ —CO— (R ¹ is a hydrogen atom or a C _1-4 alkyl group) or —N═CR ² — (R ² is a hydrogen atom or a C _1-4 alkyl group) ), And (1
0) n may be 1.

In the compound represented by the above formula (I), for example, the ring (11) A has an aromatic heterocycle which may have a substituent or an aromatic heterocycle which may have a substituent. Elementary ring; B is a 5- to 7-membered cyclic amino group; C ring is a benzene ring which may have a substituent; -X-Y- is -CO-NR ^1- (R ¹ is a hydrogen atom or C _{1 -4 represents} an alkyl group); R is a hydrogen atom or a hydrocarbon group which may have a substituent; and n is a compound having an integer of 1 to 3, and the like.

(12) The compound represented by the above formula (I) is, for example, a compound represented by the general formula (II)

[0030]

Embedded image [The symbols in the formulas have the same meaning as in claim 1. ] Or a salt or reactive derivative thereof represented by the general formula (III)

[0031]

[Chemical 19] [The symbols in the formulas have the same meaning as in claim 1. ] It can manufacture by making it react with the compound represented by these, or its salt. (13) The preparation containing the compound represented by the general formula (I) or a salt thereof is useful as a tachykinin receptor antagonist.

The present invention will be described in detail below. General Description of A Ring and C Ring In the above general formula (I), A ring and C ring are each 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, it includes a 5- to 7-membered cyclic hydrocarbon, particularly a 5- or 6-membered homocyclic ring, and especially a 6-membered homocyclic ring (eg, benzene, cyclohexene, cyclohexane ring, etc.). Preferred homocyclic rings include, for example, benzene, C _5-6 cycloalkene (eg, cyclopentene, cyclohexene, etc.), C
_5-7 cycloalkane (eg, cyclohexane, cyclopentane, etc.) and the like are included, and a benzene ring is particularly 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.

The "aromatic heterocycle" is, for example, a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom ( For example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole,
Isothiazole, oxazole, isoxazole ring and the like) 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 (eg, pyridine, pyrazine ring, etc.) or (ii)
A 5-membered aromatic heterocycle (for example, a thiophene ring) containing one sulfur atom in addition to the carbon atom is preferable.

The "non-aromatic heterocycle" includes, for example, 1 to 4 (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, for ring A, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole,
Dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole,
Examples thereof include dihydrooxazole and dihydroisoxazole rings. Regarding the C ring, in addition to the above, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydro. Examples thereof include oxazole and tetrahydroisoxazole rings. Regarding the ring A, for example, a 6-membered non-aromatic heterocycle containing 1 to 4, preferably 1 or 2, nitrogen atoms in addition to carbon atoms (eg, tetrahydropyridine, tetrahydropyrimidine,
Tetrahydropyridazine ring and the like) are preferable, and especially tetrahydropyridine ring and the like are widely used. Regarding the C ring, for example, 1 to 4 nitrogen atoms in addition to the carbon atom
A 6-membered non-aromatic heterocycle containing one, preferably one or two (eg, piperidine, piperazine ring, etc.) and the like are preferable.

Rings A and C each have (a) an aromatic ring which may have a substituent, (b) an aromatic homocyclic ring which may have a substituent or a substituent. It may be composed of an aromatic heterocycle.

More preferably, one of ring A 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 A is a benzene ring which may have a substituent or an aromatic heterocycle, and ring C is a benzene ring which may have a substituent.

Examples of the substituent which the ring A 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.) and the like 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.

Preferred "alkyl group optionally having substituent (s)" is 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-
C _1-4 alkyl groups such as butyl and tert-butyl groups and 1-
Included are C _1-4 alkyl groups substituted with about 3 halogen atoms.

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. Preferred "optionally halogenated alkoxy group" is C
_1-4 alkoxy group, or C _1-4 alkoxy group substituted with about 1 to 3 halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, 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 about 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. Preferred "optionally halogenated alkylthio group" includes C _1-4
An alkylthio group or a C _1-4 alkylthio group substituted with about 1 to 3 halogen atoms, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
A 4,4,4-trifluorobutylthio group and the like are included.

Further, the aryl group as the 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 A 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 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 that ring A 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 ring A and ring C substituents may be substituted at any substitutable position of the ring, and the substituent is 2
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 A 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 “A ring”, a preferable homocyclic ring in the A ring is a homocyclic ring composed of a carbon atom which may have a substituent, for example, a compound represented by the formula (A-
1)

[0050]

Embedded image [Wherein A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, trifluoromethyl group, etc.), or It represents a C _1-4 alkoxy group which may be halogenated (eg, methoxy, trifluoromethoxy, ethoxy group, etc.), or a formula (A-
2)

[0051]

[Chemical 21] [In the formula, A ² and A ³ are the same or different and each represents a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl,
Ethyl, isopropyl, trifluoromethyl group, etc.),
Or a homocyclic ring represented by an optionally halogenated C _1-4 alkoxy group (eg, a methoxy group, a trifluoromethoxy group, an ethoxy group).

More preferred homocycles include, for example, the formula (A-
3)

[0053]

[Chemical formula 22] [In the formula, A ⁴ and A ⁵ are the same or different and each is a halogen atom (eg, fluorine, chlorine, etc.) or an optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl). , Ethyl, isopropyl group, etc.)] and the like.

Examples of the homocyclic ring include those represented by the following formula (A-4)

[0055]

[Chemical formula 23] [Each symbol in the formulas has the same meaning as described above. ] The benzene ring which may have a substituent represented by] is also preferable.

Of the homocyclic rings represented by the above formula, particularly preferable are homocyclic rings having the following substituents.

(1) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.) or an optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, ethyl, isopropyl group, etc.) Is a homocyclic ring,
(2) A ² and A ³ are the same or different and are optionally halogenated C _1-4 alkyl groups (for example, methyl, trifluoromethyl, ethyl, isopropyl groups, etc.) or halogenated. A homocyclic ring which may be a C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, ethoxy group, etc.), (3) A ⁴ and A ⁵ are
The same or different, a homocyclic ring which is a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group, etc.),
(4) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.), (5) A ² and A ³ are the same or different and are a C _1-4 alkoxy group (eg, methoxy, ethoxy group, etc.) A homocyclic ring.

Preferred aromatic or non-aromatic heterocycles in ring A are 5- or 6-membered aromatic or non-aromatic heterocycles such as pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole, thiazole. Examples include rings. Specifically, for example, a heterocycle represented by formula (A-5) is preferable.

[0059]

[Chemical formula 24] Preferred examples of the aromatic or non-aromatic heterocyclic ring which may have a substituent include, for example, an oxo group and an alkyl group which may have a substituent (A ring and B ring may have). _Synonymous with those defined as good substituents), C _6-10
Pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole which may have 1 or 2 substituents selected from an aryl group (eg phenyl group) and a halogen atom (eg fluorine, chlorine, bromine atom etc.) , A thiazole ring, and the like. Specifically, for example, an aromatic or non-aromatic heterocycle represented by the following formula (A-6) is preferable.

[0060]

[Chemical 25] [In the formula, D represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), E represents a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), and (ii The compound having a partial structure represented by) forms a quaternary ammonium salt together with a halogen ion (for example, Cl ⁻ , Br ⁻ , I ^−, etc.), a sulfate ion, a nitrate ion or a hydroxy ion. G represents a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), J represents a hydrogen atom,
A C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.) or a C _6-10 aryl group (eg, phenyl group, etc.) is shown. A ring is a 5- or 6-membered nitrogen-containing heterocycle, for example, (i) a 6-membered aromatic nitrogen-containing heterocycle containing 1 or 2 nitrogen atoms in addition to the carbon atom (for example,
Pyridine, pyrazine ring, etc.), (ii) 6-membered non-aromatic heterocycle containing 1 or 2 nitrogen atoms in addition to carbon atom (eg, tetrahydropyridine, tetrahydropyrimidine,
Tetrahydropyridazine ring, etc.) are preferred. Particularly preferred ring A includes aromatic nitrogen-containing heterocycle, especially pyridine ring.

Regarding “B” In the above formula (I), B represents an amino group which may have a substituent or a hydroxyl group which may have a substituent. Examples of the amino group which may have a substituent include an amino group, a mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, butylamino, dimethylamino, methyl Mono- or di-C _1-4 alkylamino groups such as ethylamino, diethylamino, dipropropylamino, dibutylamino groups, etc., cyclic amino groups (for example, in addition to nitrogen atoms, 1 hetero atom such as oxygen atom, sulfur atom, etc.) To 4 to 9-membered cyclic amino groups, which may contain 3 to 3, specifically, for example, pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino group, etc.), C _1-6 alkyl-carbonylamino group ( For example, C _1-4 alkyl-, such as acetylamino, propionylamino and butyrylamino groups.
Carbonylamino group, etc., C _6-14 aryl-carbonylamino group (eg, C such as benzoylamino group)
_6-10 arylcarbonylamino group), C _1-6 alkylsulfonylamino group (for example, C _1-4 alkylsulfonylamino group such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.),
C _6-14 arylsulfonylamino group (for example, benzenesulfonylamino, toluenesulfonylamino group, etc.
_6-10 arylsulfonylamino group) and the like.

Examples of the hydroxyl group which may have a substituent include a hydroxyl group and an optionally halogenated C _1-10 alkoxy group (eg, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, C _1-10 alkoxy groups such as ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, octyloxy, decyloxy groups, etc. ), A C _7-11 aralkyloxy group (for example, a C _7-10 aralkyloxy group such as benzyloxy or phenethyloxy group), an aminocarbonyloxy group, a mono- or di-C _1-6 alkylaminocarbonyloxy group ( For example, methylaminocarbonyloxy, ethi Aminocarbonyloxy, dimethylaminocarbonyloxy, mono diethylamino carbonyl group - or and di -C _1-4 alkylaminocarbonyl group), C _1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethyl sulfonyloxy , C such as propylsulfonyloxy group
_1-4 alkylsulfonyloxy group etc.), C _6-14 arylsulfonyloxy group (for example, C _6-10 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy group etc.) and the like.

As B, a di-C _1-4 alkylamino group, a 5- to 7-membered cyclic amino group, a C _6-10 arylsulfonyloxy group and the like are preferable, and a cyclic amino group is particularly preferable. When B has a nitrogen atom, it may form a quaternary ammonium salt, for example, an anion such as a halogen ion (for example, Cl ⁻ , Br ⁻ , I ⁻ ), a sulfate ion, a nitrate ion, a hydroxy ion or the like. And may form a salt.

Regarding “C ring”, preferable homocyclic ring in C ring includes 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 (particularly, 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)

[0070]

[Chemical formula 26] [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)

[0071]

[Chemical 27] [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 preferred C ring is, for example, a benzene ring in the above formula (C-2), wherein C ⁴ and C ⁵ are the following substituents. (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, (e) C ⁴ and C ⁵ are trifluoromethyl groups.

“X and Y” In the above formula, X and Y are (1) One of —NR ¹ — (R ¹
Represents a hydrogen atom or a hydrocarbon group which may have a substituent) or -O-, and the other is -CO- or -CS.
-, or (2) one is -N =, the other = CR ² -
(R ² represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an amino group which may have a substituent or a hydroxyl group which may have a substituent) Show. Preferred "-X-Y-" is, for example,
(1a) -NR ¹ -CO-, -CO-NR ^1- (R ¹ has the same meaning as above), -O-CO-, -CO-O-, or (2a) -N = C (R ² )-(R ² has the same meaning as above)
And the like, and more preferable "-XY-" includes-
NR ¹ —CO—, —CO—NR ¹ — (R ¹ has the same meaning as above), —N═C (R ² ) —, especially —CO—NR ¹ —
(R ¹ has the same meaning as described above) and the like. R ¹ , R
"A hydrocarbon group which may have a substituent" represented by ²
Examples thereof include the same "hydrocarbon group optionally having substituent (s)" as described in the section "R" described later. R
"Halogen atom" for ^2, fluorine, chlorine, bromine and iodine atoms. Of these, fluorine and chlorine atoms are preferred. The "substituent" of the "optionally substituted amino group" represented by R ² includes (i) C
_1-6 alkyl groups (eg, methyl, ethyl, propyl,
(C _1-4 alkyl groups such as isopropyl, butyl and isobutyl groups), (ii) C _1-6 alkyl-carbonyl groups (eg C such as acetyl, propionyl and butyryl groups)
_1-4 alkyl-carbonyl group), (iii) C _1-6 alkoxy-carbonyl group (for example, C such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group)
_1-4 alkoxy-carbonyl group), (iv) halogen atom such as fluorine or chlorine atom, C _1-6 alkyl group such as methyl, ethyl, isopropyl, butyl group or methoxy,
C _6-14 aryl group which may have a substituent such as C _1-6 alkoxy group such as ethoxy and isopropoxy group (for example, 2-methylphenyl, 3-methylphenyl, 4-
C _1-6 alkyl-phenyl group such as methylphenyl, 2-ethylphenyl, 4-tert-butylphenyl group; for example, halogenated phenyl such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl group Group; 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-isobutoxyphenyl group and the like C _1-6 alkoxy-phenyl group) and the like. The number of these substituents is about 1 to 3. Preferred “amino group optionally having substituent (s)” include amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc. Mono- or di-C _1-4 alkylamino group) and the like.

Examples of the “hydroxyl group which may have a substituent” represented by R ² 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 group etc.), C _6-14 aryloxy group (eg phenyloxy, naphthyloxy group etc. C _6-10
Aryloxy group), C _7-11 aralkyloxy group (eg C _7-10 aralkyloxy group such as benzyloxy group), C _1-6 alkyl-carbonyloxy group (eg formyloxy, acetoxy, propionyloxy) Groups such as C _1-4 alkyl-carbonyloxy groups) and C _6-14 aryl-carbonyloxy groups (eg, C _6-10 aryl-carbonyloxy groups such as benzoyloxy and naphthylcarbonyloxy groups). it can. When R ² is a hydroxyl group,
-N = C (OH)-or-as "-X-Y-"
C (OH) = N- is in a tautomeric relationship-
It also exists as NH—CO— or —CO—NH— (group in which R ¹ is a hydrogen atom). Preferable “hydroxyl group optionally having substituent (s)” includes C _1-6 alkoxy group (eg, C _1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy group, etc.) and the like.

R ¹ is a C _1-6 alkyl group which may be substituted with a halogen atom or a hydroxy group (eg, methyl, ethyl, propyl, isopropyl, 2-
(C _1-4 alkyl groups such as hydroxyethyl, 3-chloropropyl, 3-bromopropyl groups) and the like are preferable. More preferable R ² includes, for example, a C _1-6 alkyl group, particularly a C _1-3 alkyl group (eg, methyl group, ethyl group, etc.), and especially a methyl group. R ² is preferably a C _1-6 alkyl group (for example, a C _1-4 alkyl group such as methyl, ethyl, propyl or isopropyl group) and a hydrogen atom, and particularly preferably a hydrogen atom.

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 n is 1
It is preferable that it is -3, especially 1 or 2, and especially 1.

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) Ring A is an aromatic heterocycle which may have a substituent or an aromatic homocycle which may have a substituent; B is 5 to 7
Member cyclic amino group; benzene ring in which C ring may have a substituent; -X-Y- is -CO-NR ^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 a compound wherein n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof. Etc. are included.

(2) A ring is a benzene ring or a 5- or 6-membered aromatic heterocycle containing 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom; B is 5- or 6-membered cyclic amino group; C ring is a halogen atom, an optionally halogenated C _1-6 alkyl group (particularly a C _1-4 alkyl group), an optionally halogenated C
_A benzene ring optionally having 1 to 3 (for example, 1 or 3) substituents selected from a _1-6 alkoxy group (particularly a C _1-4 alkoxy group); -CO-NR ¹
-(R ¹ represents a hydrogen atom or a C _1-3 alkyl group (especially a methyl group)); R is a hydrogen atom or a C _1-3 alkyl group (especially a methyl group); and n is a compound or a medicine of 1 or 2. Its acceptable salt.

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 The compound (I) or salt thereof of the present invention is, for example, a compound (carboxylic acid) represented by the general formula (II) or a salt or reactive derivative thereof according to the following reaction formula. And the general formula (II
It can be produced by reacting with a compound (amine) represented by I) or a salt thereof to form an amide bond.

[0087]

[Chemical 28] [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 and sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid,
Examples thereof include salts with organic acids such as 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 solvents as in the method (a) (for example, halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ethers such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, Esters such as ethyl acetate, hydrocarbons such as benzene and toluene, amides such as N, N-dimethylformamide) 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). 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 used in the method (a), N, N-dimethylaniline, N, N
Aromatic amines such as diethylaniline; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; 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 120 ° C, preferably about 0 ° C to 100 ° C, and the reaction time is usually 1
It is about 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.

Further, among the compounds (I), "-XY
-"Is -CO-NR ^1- (R ¹ has the same meaning as above)
The compound (I-1) represented by or a salt thereof is subjected to a ring closure reaction of the compound represented by the following general formula (IV) to produce a compound represented by the general formula (I-2), Then, if desired, it can be produced by introducing a desired substituent into the amino group or hydroxyl group.

[0091]

[Chemical 29] [In the formula, Z represents —CN or —CO ₂ R ³ (R ³ represents a protective group for a carboxyl group), and represents a B ⁰ amino group or a hydroxyl group. Other symbols have the same meanings as above] The ring-closing reaction of compound (IV) is usually performed under basic conditions. Examples of the base used in this reaction include organic bases (for example, 1,5-diasabicyclo [4.3.
0] Non-5-ene (DBN), 1,8-diasabicyclo [5.4.0] undec-7-ene (DBU), N-
Benzyltrimethylammonium hydroxide (Trit
on B)), an inorganic base (for example, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, and potassium t-butoxide, sodium hydride,
Alkali metal hydrides such as potassium hydride, n-butyllithium, lithium diisopropylamide, etc.) can be used. Furthermore, for example, tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine, aromatic amines such as pyridine, picoline and N, N-dimethylaniline may be used. The amount of base used is usually 0.5 to 20 equivalents, preferably about 1 to 5 equivalents, relative to 1 mol of compound (IV).

The reaction is usually carried out in a solvent. Any solvent can be used as long as it does not interfere with the reaction, for example, ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) , Alcohols (eg, methanol, ethanol, isopropanol, etc.), amides (eg, N, N-dimethylformamide, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.) and the like. In particular, in the ring-closing reaction, it is advantageous to combine an alcohol (eg, methanol, ethanol, etc.) as a solvent and an alkali metal alkoxide (eg, sodium alkoxide such as sodium methoxide, sodium ethoxide) as a base. The reaction temperature will differ depending on the amount of base used, but is usually -80 ° C to 200 ° C, preferably -50 ° C.
The reaction time varies depending on the starting materials used, the base, the reaction time, and the type of solvent, but usually about 1
It is about 0 minutes to 24 hours.

If desired, desired substituents can be introduced into the amino group and hydroxyl group of the compound (I-2) by alkylation, acylation, sulfonylation or the like. The alkylation reaction can be carried out by reacting an alkylating agent in a solvent in the presence of a base. Examples of the solvent include alcohols such as methanol, ethanol and propanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran, ketones such as acetone, and amides such as N, N-dimethylformamide. Examples of the base include organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline and N, N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. . Further, the alkylating agent includes, for example, an alkane halide which may have a substituent (for example, chloride, bromide, iodide, etc.), a sulfate ester or a sulfonate ester (for example, methanesulfonate, p-toluenesulfonate, Benzene sulfonate, etc. Among compounds (I-2), in the alkylation reaction of a compound in which B ⁰ is an amino group, an alkane dihalide (eg, 1,3-dibromopropane, etc.) is used as an alkylating agent.
1,4-dibromobutane, 1,4-dichlorobutane,
When 1,5-dibromopentane, 1,5-dichloropentane, 1,6-dibromohexane, 1,7-dipromoheptane, etc.) is used, a compound in which B is a cyclic amino group (eg, pyrrolidino, piperidino group, etc.) ) Can be obtained. As the alkane dihalide, an alkane dichloride or dibromide having a carbon number corresponding to the cyclic amino group can be used. The amount of the alkylating agent used is, for example, about 1 to 1 mol of the compound (I-2).
It is about 5 mol, preferably about 1 to 3 mol. The reaction temperature is generally -10 ° C to 100 ° C, preferably about 0 ° C to 8 ° C.
It is about 0 ° C. The reaction time is usually 15 minutes to 24 hours,
It is preferably about 30 minutes to 12 hours.

The acylation reaction is carried out by reacting the desired carboxylic acid or its reactive derivative. Although this reaction varies depending on the type of acylating agent and the type of compound (I-2), it is generally carried out in a solvent, and an appropriate base may be added to accelerate the reaction. Examples of the solvent include hydrocarbons such as benzene and toluene, ethers such as ethyl ether, dioxane and tetrahydrofuran, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, N, N-dimethylformamide. Examples thereof include halogenated hydrocarbons such as and aromatic amines such as pyridine. Examples of the base include hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, carbonates such as sodium carbonate and potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and aromatics such as pyridine. Examples include group amines. As the reactive derivative of carboxylic acid as an acylating agent, for example, acid anhydride, mixed acid anhydride, acid halide (eg chloride, bromide) and the like can be used. The amount of these acylating agents used is, for example, 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of compound (I-2). The reaction temperature is usually 0
C. to 150.degree. C., preferably about 10.degree. C. to 100.degree. C., and the reaction time is usually 15 minutes to 12 hours, preferably 30 minutes to 6 hours. The sulfonylation reaction is
Instead of carboxylic acid or its reactive derivative in the acylation reaction, sulfonic acid or its reactive derivative can be used in the same manner.

Among the compounds (I) of the present invention, a compound in which the A ring is a tetrahydropyridine ring can be produced by subjecting a compound in which the A ring is a pyridine ring to a reduction reaction. This reduction reaction can be carried out by various methods, and for example, a method of reducing in the presence of a metal catalyst for catalytic reduction is preferable. Examples of the catalyst used in the catalytic reduction method include:
Examples thereof include platinum catalysts such as platinum black, platinum oxide and platinum carbon, palladium catalysts such as palladium black, palladium oxide, palladium barium sulfate and palladium carbon, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel and lacquer nickel. The amount of the catalyst used varies depending on the type of the catalyst, and is usually 0.1 to 10 relative to the compound (I).
% (W / w).

The reduction reaction is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, and isopropanol, ethers such as tetrahydrofuran and dioxane, and esters such as ethyl acetate. The reaction temperature is, for example, 0 ° C. to 200 ° C., preferably about 20 ° C. to 110 ° C., and the reaction time is usually 0.5 to 48 hours, preferably about 1 to 16 hours. The reaction is usually carried out under normal pressure in many cases, but if necessary, under pressure (for example, 3 times).
It is carried out at about 10 atm). Such a reduction reaction can also be applied to a method of converting another aromatic heterocycle into a non-aromatic heterocycle.

Further, the compound in which the A ring is a tetrahydropyridine ring is a compound represented by the formula:
A quaternary salt was formed by reacting with an alkylating agent represented by Q-L (wherein Q represents an alkyl group which may have a substituent and L represents a leaving group), and then formed. It can also be produced by subjecting a quaternary salt to a reduction reaction. Examples of the leaving group L include a halogen atom (eg, chlorine, bromine,
Examples thereof include an iodine atom) and a substituted sulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.). Examples of the alkylating agent QL used for conversion into a quaternary salt include alkane halides (for example, chloride, bromide, iodide, etc.), sulfates, or sulfonates (for example, methanesulfonate, p-toluenesulfonate, and the like).
Benzene sulfonate, etc.) and the like, and particularly alkyl halides are preferably used. The amount of the alkylating agent used is, for example, 1 to 100 equivalents, preferably 1 to 30 equivalents, relative to 1 mol of the substrate. The reaction with the alkylating agent is usually performed in a solvent. As the solvent, for example, methanol, ethanol, propanol,
Alcohols such as isopropanol, tetrahydrofuran, ethers such as dioxane, esters such as ethyl acetate, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane can be used, and the alkylating agent itself can be used as a solvent. Good. The reaction temperature is, for example, 10 ° C. to 200 ° C., preferably about 20 ° C. to 110 ° C., and the reaction time is usually 0.5 to 24 hours, preferably about 1 to 16 hours.

The reduction reaction of the produced quaternary salt to the tetrahydropyridine ring can be carried out in the presence of a reducing agent such as a metal hydride in an inert solvent. Examples of the metal hydride as the reducing agent include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium aluminum hydride and the like. Preferred metal hydrides include sodium borohydride and the like.
The amount of the reducing agent used is, for example, about 1 to 10 equivalents, preferably about 1 to 2 equivalents, relative to the quaternary salt. Examples of the reaction solvent include lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, hydrocarbons such as benzene and toluene, and these solvents may be used alone or in combination. Can be used. The reaction temperature is usually about -100 ° C to 40 ° C,
It is preferably about -80 ° C to 25 ° C, and the reaction time is generally 5 minutes to 10 hours, preferably 10 minutes to 5
It's about time. In the reduction reaction of the quaternary salt, a compound having a dihydropyridine ring, which is one of the compounds of the present invention, may be produced depending on the kind of the compound. This dihydropyridine ring can be converted to a further reduced tetrahydropyridine ring by, for example, the above-mentioned catalytic reduction method. Further, when the A ring is a tetrahydropyridine ring and the nitrogen atom thereof has a hydrogen atom,
A compound in which a Q group is introduced into a nitrogen atom can be obtained by using an alkylating agent represented by QL (the symbols in the formula have the same meanings as described above).

Further, a compound in which the A ring is a pyridone ring can be produced by subjecting a compound in which the A ring is a quaternary salt of a pyridine ring to an oxidation reaction. This oxidation reaction is carried out, for example, by a known method (E.A.
A. Prill) et al., Organic S
Syntheses), Vol. 2, p. 419 (published in 1957)] or a method similar thereto.

When 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 and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium) or It is also possible to form a salt with an organic base (for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine), and the compound (I) But If obtained in the form according to a conventional method, it can also be converted free compound or into another salt.

The object compound (I) or a salt thereof produced by these methods can be isolated and purified by a conventional separation and purification means (for example,
Separation and purification can be performed by using concentration, solvent extraction, column chromatography, recrystallization, etc.).

Production Method of Starting Compound or Salt Thereof Among the starting compounds (II) for producing the compound (I) of the present invention or a salt thereof, for example, “—X—Y—” is —CO
Compound (II-1) in which -NR ^1- (R ¹ has the same meaning as described above), A ring is a benzene ring, and B is a hydroxyl group is prepared according to, for example, the method described in JP-B-1-28012. Compound (II-2) in which -X-Y- is -CO-NR ^1- (R ¹ has the same meaning as above), A ring is a benzene ring, and B is an amino group can be produced by N- (2-methoxycarbonyl) used in JP-A 1-28012
Instead of benzoylsarcosine methyl ester, N-
It can be prepared by the same method using (2-cyano) benzoylsarcosine methyl ester.

Of the starting compound (II), for example,
Compound (II-3) in which —X—Y— is —NR ¹ —CO— (R ¹ has the same meaning as described above), A ring is a benzene ring, and B is a hydroxyl group is, for example, the chemistry of・ Heterocyclic compound (The Chemistry of Het
erocyclic Compunds), Volume 32, Volume 1, 197 pages (Published in 1977) [John Willie & Sons (Jo
hn Wiley & Sons Inc.) issued]. The hydroxyl group of this compound is converted to an amino group via a halogen group or the like to obtain a compound (II-4) in which B is an amino group. Using these compounds (II-1) to (II-4), an alkylation reaction,
A raw material compound (II-5) having a hydroxyl group or an amino group having a desired substituent can be produced by performing an acylation reaction, a sulfonylation reaction, or the like. These reactions can be carried out by the same method as the method of introducing a substituent into the amino group or the hydroxyl group in the compound (I-2). Further, among the raw material compounds (II), -X-
Y- is -CR ² = N-or -N = CR ² - (R ² is as defined above), Compound A ring is a benzene ring, for example, the compound (II-1) ~ (II -5) out of -XY
Using a compound in which-is -CO-NH- or -NH-CO-, -XY- is converted to -CM by a known method (for example, halogenation reaction by reaction with phosphorus oxychloride).
= N- or -N = CM- (M represents a halogen atom), and if necessary, the halogen atom can be converted to R ² .

The synthesis of the starting material compound in which the A ring is a benzene ring has been described above, but compounds in which the A ring is an allocyclic ring or a heterocyclic ring other than the benzene ring can also be produced according to these methods.

The starting compound (IV) can be produced, for example, by reacting the compound represented by the general formula (V) or a salt or reactive derivative thereof with the compound represented by the general formula (VI) or a salt thereof. .

[0106]

Embedded image [The symbols in the formulas have the same meanings as described above. The reaction between the compound (V) and the compound (VI) can be carried out by the same method as the amide bond type reaction between the compound (II) and the compound (III). Compounds (II) and (IV)
In the above, the compound in which the ring A is a non-aromatic ring (for example, a non-aromatic nitrogen-containing heterocyclic ring) can be produced by subjecting the corresponding aromatic ring to the above-mentioned reduction reaction.

The compounds (II) and (IV) may form salts, and examples of these salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.). , Organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid,
Maleic acid, succinic acid, tartaric acid, citric acid, malic acid,
Examples thereof include salts with 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 and potassium, an alkaline earth metal such as calcium and magnesium, ammonia, etc.) or an organic base (for example, , A tri-C _1-3 alkylamine such as trimethylamine and triethylamine), and a salt may be formed. 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 a protecting group generally used in peptide chemistry and the like. It may have been done. In this case, the target compound can be obtained by removing the protecting group after the reaction, if necessary.

Examples of the amino-protecting group include 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 ( Examples thereof include 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 may 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 protecting group for the carboxyl group include a C _1-6 alkyl group (eg, methyl, ethyl, n-).
Propyl group, i-propyl group, n-butyl group, tert-butyl group, etc.), phenyl group, trityl group, 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.

The hydroxyl-protecting group is, for example, a C _1-6 alkyl group (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, ethyl) Carbonyl group), phenyloxycarbonyl group (eg, benzoxycarbonyl group), C _7-10 aralkyl-carbonyl group (eg, benzyloxycarbonyl group),
Examples thereof include a pyranyl group, a furanyl group and a silyl group, and these protecting groups may have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine,
Bromine, iodine atom), C _1-6 alkyl group, phenyl group,
C _7-10 aralkyl group, nitro group and the like can be mentioned, and the number of substituents is about 1 to 4.

The protecting group can be removed by a known method or a method analogous thereto, 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 form, 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 its salt, it can be converted into a free form or another salt by a known method or a method analogous thereto.

The compound (I) of the present invention or a salt thereof has a capsaicin-induced action 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 and 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)].

The compound (I) of the present invention or a salt thereof has low toxicity and is safe. Therefore, the compound (I) of the present invention or a salt thereof having an excellent SP receptor antagonistic activity is used in mammals (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. Particularly, the compound (I) of the present invention or a salt thereof is useful as a tachykinin receptor antagonist, an agent for improving urinary dysfunction such as urination and urinary incontinence, and a drug for treating urinary dysfunction such as urination and urinary incontinence.

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, carboxymethylcellulose calcium, 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.

[0117]

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.

[0118]

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.

The 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: Dimethyl sulfoxide, Hz: Hertz, J: Coupling constant, m: multiplet, q:
Quartet, t: triplet, d: doublet,
s: singlet, b: broad, like: approximation.

Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-1,2-dihydro-N, 2-dimethyl-1-oxo-
4-Pyrrolidino-3-isoquinolinecarboxamide 1,2-dihydro-N, 2-dimethyl-1-oxo-4
-Pyrrolidino-3-isoquinolinecarboxylic acid (Reference Example 1) (440 mg) in dichloromethane (25 ml) was added with oxalyl chloride (0.55 ml) and DMF.
(1 drop) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane (20 ml).
To this solution was added N- [3,5-bis (trifluoromethyl) benzyl] methylamine hydrochloride (520 mg) and triethylamine (1.2 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, ethyl acetate was added to the residue, and the mixture was washed successively with water, aqueous sodium hydrogen carbonate and water, and dried. The solvent was evaporated to give the title compound as colorless crystals (270 mg). Melting point 194-195 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.96 (4H, m), 2.96 (3H, s),
3.13 (2H, m), 3.30 (2H, m), 3.50 (3H, s), 4.39 (1H,
d, J = 15.0Hz), 5.37 (1H, d, J = 15.0Hz), 7.45-7.71 (3H,
m), 7.89 (3H, s), 8.52 (1H, dd, J = 1.2, 8.2Hz) Elemental analysis value Calculated as C ₂₅ H ₂₃ N ₃ O ₂ F ₆ C, 58.71; H, 4.53; N, 8.22 Found C, 58.66; H, 4.50; N, 8.23.

Example 2 5-Amino-N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-N, 7-dimethyl-8-oxo-6-pyrido [3,4- b] Pyridinecarboxamide N- {N- [3,5-bis (trifluoromethyl) benzyl] -N-methylaminocarbonylmethyl} -3-cyano-N-methyl-2-pyridinecarboxamide (Reference Example 2) (590 mg) Was added to an ethanol (20 ml) solution of (1) in ethanol (prepared from sodium ethoxide (250 mg) and ethanol (5 ml)), and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to give the title compound as yellow crystals (365 mg). Mp 170-172 ° C. (ethyl acetate - recrystallized from ethyl _{ether) NMR (200MHz, CDCl 3)} ppm: 2.98 (3H × 7/10, s), 3.10 (3
H × 3/10, s), 3.41 (2H, b), 3.58 (3H, s), 4.40 (1H × 3 /
10, d, J = 15.2Hz), 4.89 (1H, d, J = 15.2Hz), 5.19 (1H ×
7/10, d, J = 15.2Hz), 7.30-8.20 (5H, m), 8.99 (1H,
m).

Example 3 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-Dihydro-N, 7-dimethyl-8-oxo-
5-Pyrrolidino-6-pyrido [3,4-b] pyridinecarboxamide The compound (200 mg) obtained in Example 2 in anhydrous DMF (1
0 ml) at room temperature with stirring 1,4-dibromobutane (0.078 ml) and lithium bis (trimethylsilyl) amide (1M hexane solution) (0.16 m
1) was added and stirred for 20 minutes at room temperature. Evaporate the solvent,
Ethyl acetate and water were added to the residue. After adjusting the pH of the aqueous layer to about 8 using 2N hydrochloric acid, the ethyl acetate layer was separated, washed with water and dried. The solvent was evaporated, and the residue was separated and purified by column chromatography using silica gel (30 g) (eluted with ethyl acetate: methanol = 9: 1 → 4: 1) to give the title compound as colorless crystals (26 mg). It was Mp 203-204 ° C. (decomposition) (ethyl acetate - recrystallized from ethyl _{ether) NMR (200MHz, CDCl 3)} ppm: 1.96 (4H, m), 2.98 (3H, s),
3.09 (2H, m), 3.28 (2H, m), 3.57 (3H, s), 3.39 (1H,
d, J = 14.6Hz), 5.41 (1H, d, J = 14.6Hz), 7.58 (1H, dd,
J = 4.4, 8.4Hz), 7.90 (4H, s-like), 8.93 (1H, m).

Reference Example 1 1,2-Dihydro-2-dimethyl-1-oxo-4-pyrrolidino-3-isoquinolinecarboxylic acid (Step 1) 2-cyanobenzoic acid (15.4 g) in THF
(300 ml) solution with oxalyl chloride (11.4 m
1) and DMF (1 drop) were added and stirred for 0.5 hours at room temperature. The solvent was distilled off, and the residue was THF (100 ml).
Dissolved in. This solution was stirred under cooling with sarcosine ethyl ester hydrochloride (12.2 g) and triethylamine (33.3 ml) and THF (100 m).
It was added to the mixture of l) and stirred at room temperature for 2 hours. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogen carbonate, and water in this order, and dried. The solvent was evaporated to give N-ethoxycarbonylmethyl-N-methyl-2-cyanobenzenecarboxamide as a pale yellow oil (16.3 g). NMR (200MHz, CDCl ₃ ) ppm: 1.26 (3H × 1/4, t, J = 7.2H
z), 1.33 (3H × 3/4, t, J = 7.2Hz), 3.01 (3H × 3/4, s),
3.19 (3H × 1/4, s), 3.93 (2H × 1/4, s), 4.16 (2H × 1/4,
q, J = 7.2Hz), 4.27 (2H × 3/4, q, J = 7.2Hz), 4.32 (2H × 3
/ 4, s), 7.42-7.80 (4H, m).

(Step 2) The compound (15.9) obtained in Step 1 was used.
Sodium ethoxide (9.4 g) was added to a solution of g) in absolute ethanol (400 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, water was added to the residue, and the pH was adjusted to about 8 with 2N hydrochloric acid. This mixture was extracted with ethyl acetate, and the extract was washed with water, aqueous sodium hydrogencarbonate, and water in this order, and dried. When the solvent was distilled off, 4-amino-1,2-dihydro-2-methyl-1-oxo-3-
Isoquinolinecarboxylic acid ethyl ester was obtained as yellow crystals (6.3 g). Melting point 102-104 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.41 (3H, t, J = 7.4Hz), 3.5
9 (3H, s), 4.41 (2H, q, J = 7.4Hz), 5.61 (2H, b), 7.60-
7.90 (4H, m), 7.51 (1H, dd, J = 1.4, 7.6Hz).

(Step 3) The compound (1.0
g), DM of 1,4-dibromobutane (0.58 ml)
Sodium hydride (60% oil) in F (15 ml) solution
(650 mg) was added, and the mixture was stirred at room temperature for 0.5 hr. The solvent was evaporated, and ethyl acetate and water were added to the residue. Two
After adjusting the pH of the aqueous layer to about 8 using N hydrochloric acid, the ethyl acetate layer was separated, washed with water and dried. When the solvent is distilled off,
1,2-Dihydro-2-methyl-1-oxo-4-pyrrolidino-3-isoquinolinecarboxylic acid ethyl ester was obtained as colorless crystals (0.83 g). Mp 155-157 ° C (recrystallized from dichloromethane-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.41 (3H, t, J = 7.4Hz), 2.0
2 (4H, m), 3.25 (4H, m), 3.51 (3H, s), 4.42 (2H, q, J =
7.4Hz), 7.45-7.70 (3H, m), 8.50 (1H, m).

(Step 4) Step 3 Compound obtained (760 m
A mixture of g), ethanol (30 ml) and 4N sodium hydroxide (30 ml) was stirred with heating under reflux for 4.5 hours. Ethanol was distilled off, and hydrochloric acid was used to p
The H was adjusted to about 3. The mixture was saturated with sodium chloride, ethyl acetate and ethyl acetate-THF (5:
Sequential extraction was performed in 1). The extract was washed with saturated aqueous sodium chloride, dried, the solvent was distilled off, and the precipitated crystals were collected by filtration.
The compound was washed with ethyl ether to give colorless crystals (5
60 mg). Melting point 151-152 ° C (decomposition) (recrystallized from methanol-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.53 (4H, m), 3.56 (4H, m),
3.92 (3H, s), 7.50-7.82 (3H, m), 8.61 (1H, dd, J = 1.
4, calcd 7.8 Hz) Elemental analysis _{C 15 H 16 N 2 O 3} C, 66.16; H, 5.92; N, 10.29 Found C, 65.80; H, 5.99; N, 10.25.

Reference Example 2 N- {N- [3,5-bis (trifluoromethyl) benzyl] -N-methylaminocarbonylmethyl} -3-cyano-N-methyl-2-pyridinecarboxamide 3-cyano-2 -Pyridinecarboxylic acid [Luc IM Spie
ssens et al., Bulletin des Societes Chimiques Belg
es, 89 , 205-231 (1980)]] (578 mg)
In THF (30 ml) solution of thionyl chloride (1.0 m
1) and DMF (1 drop) were added, and the mixture was heated under reflux for 2 hours with stirring. The solvent was evaporated, the residue was THF (30 ml)
Dissolved in. This solution was mixed with N '-[3,5-bis (trifluoromethyl) benzyl] -N, N'-dimethylglycinamide hydrochloride (1.42 g), triethylamine (2.7 ml) and TMF (30 ml). Was stirred for 2 hours at room temperature. In addition, N '-[3,
5-bis (trifluoromethyl) benzyl] -N, N '
-Dimethylglycinamide was prepared by amidating t-butoxycarbonyl sarcosine with N- [3,5-bis (trifluoromethyl) benzyl] -N-methylamine, followed by deprotection. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogen carbonate, and water in this order, and dried. When the solvent was distilled off, the title compound was obtained as a pale yellow oil (59
0 mg). This compound was used in the reaction of Example 2 without purification.

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 6 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.

Claims (13)

[Claims] 1. A compound of the general formula [In the formula, A ring is a homocyclic ring or a heterocyclic ring which may have a substituent; B is an amino group which may have a substituent or a hydroxyl group which may have a substituent; C The ring is an allocyclic ring or a heterocyclic ring which may have a substituent; in X and Y, (1) one is -NR ^1- (R ¹ is a hydrogen atom or a carbon atom which may have a substituent. Hydrogen group) or -O
-, the other is -CO- or -CS-, or (2) one is -N = and the other = CR ² - (R ² is a hydrogen atom, a halogen atom, may be substituted hydrocarbon group Represents an amino group which may have a substituent or a hydroxyl group which may have a substituent); R represents a hydrogen atom or a hydrocarbon group which may have a substituent; Indicates an integer of 3. ] The heterocyclic compound or its salt represented by these. 2. The compound according to claim 1, wherein ring A is an aromatic homocycle which may have a substituent or an aromatic heterocycle which may have a substituent. 3. The aromatic heterocycle is a 5- or 6-membered aromatic heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. A compound according to claim 2. 4. The compound according to claim 1, wherein B is a mono- or di-C _1-6 alkylamino group, a 4- to 9-membered cyclic amino group or an arylsulfonyloxy group. 5. The compound according to claim 1, wherein B is a 5- to 7-membered cyclic amino group. 6. The compound according to claim 1, wherein the ring C is an aromatic homocycle which may have a substituent or an aromatic heterocycle which may have a substituent. 7. The compound according to claim 1, wherein ring C is a benzene ring which may have a substituent. 8. 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 a benzene ring which may have. 9. --X--Y-- is --CO--NR ^1- , --NR ¹
-CO- (R ¹ is a hydrogen atom or a C _1-4 alkyl group) or-
The compound according to claim 1, wherein N = CR ^2- (R ² is a hydrogen atom or a C _1-4 alkyl group). 10. The compound according to claim 1, wherein n is 1. 11. A ring A is an aromatic heterocycle which may have a substituent or an aromatic homocycle which may have a substituent;
B is a 5- to 7-membered cyclic amino group; C ring is a benzene ring which may have a substituent; -X-Y- is -CO-NR ^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. Compound of. 12. 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. 13. A tachykinin receptor antagonist comprising the compound according to claim 1.