JP2003171380A - Method for producing tricyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a tricyclic compound having a tachykinin receptor antagonistic activity, substance P receptor antagonistic activity, or the like, and useful as a preventing and treating medicine of pollakiuria, urinary incontinence, or the like, simply and industrially advantageously. <P>SOLUTION: This method for producing the tricyclic compound expressed by formula (I) or its salt is characterized by performing a cyclization reaction of a compound expressed by formula (II) or its salt in a poor solvent. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic compound having excellent tachykinin receptor antagonism, substance P receptor antagonism and the like, which is useful as a medicament for the prevention / treatment of frequent urination / urinary incontinence. The present invention relates to a simple and industrially advantageous production method.

[0002]

2. Description of the Related Art A cyclization reaction in a process for producing a tricyclic compound having a tachykinin receptor antagonistic action, a substance P receptor antagonistic action and the like, which is useful as a medicament for the prevention / treatment of urinary frequency / urinary incontinence, etc. A method using tetrahydrofuran as a reaction solvent is known (for example, Patent Documents 1 and 2).
reference. ).

[0003]

[Patent Document 1] European Patent Application Publication No. 733632 (pages 27-28)

[Patent Document 2] Japanese Patent Laid-Open No. 9-263585 (No. 31
(See page 32)

[0004]

In the above prior art, the desired product is obtained through the steps of extraction, washing, concentration and crystallization after the reaction to obtain the tricyclic compound, which is industrially complicated and disadvantageous. there were. Therefore, a more convenient and industrially advantageous production method has been desired.

[0005]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that

[Chemical 4] [Wherein, M ring is a partial structure

[Chemical 5] As -N = C <, - CO- N < or -CS-N <heterocycle having; R ^a and R ^b or form a ring A bonded together, or the same or different and each represents a hydrogen atom or M
Substituent in the ring; A ring and B ring are the same or heterocycles each optionally having a substituent, at least one of which may have a substituent; C ring is a substituent A homocycle or a heterocycle which may have; n is an integer of 1 to 6; D and E are groups which form a Z ring with a nitrogen atom adjacent to E; and the Z ring includes an optionally substituted group. And nitrogen represents a leaving group. ] The compound or salt thereof represented by the formula

[Chemical 6] [The symbols in the formulas have the same meanings as described above. ] In the case of producing a compound represented by the following formula or a salt thereof, a solvent having a high solubility of a substrate has been used conventionally, but when a poor solvent is used as a reaction solvent, the reaction proceeds and the desired product is produced, resulting in crystallization. Can be converted into a precipitate, and industrially, extraction, separation,
It was found that the target product can be obtained in a simpler, higher yield, and higher quality by omitting post-treatment operations that had been carried out for concentration and crystallization, and enabling cost reduction of waste liquid and the like. Completed the invention.

That is, the present invention is based on the equation (1)

[Chemical 7] [Wherein, M ring is a partial structure

[Chemical 8] As -N = C <, - CO- N < or -CS-N <heterocycle having; R ^a and R ^b or form a ring A bonded together, or the same or different and each represents a hydrogen atom or M
Substituent in the ring; A ring and B ring are the same or heterocycles each optionally having a substituent, at least one of which may have a substituent; C ring is a substituent A homocycle or a heterocycle which may have; n is an integer of 1 to 6; D and E are groups which form a Z ring with a nitrogen atom adjacent to E; and the Z ring includes an optionally substituted group. And nitrogen represents a leaving group. ] The compound or its salt represented by this is subjected to a cyclization reaction in a poor solvent, the formula,

[Chemical 9] [The symbols in the formulas have the same meanings as described above. ] The manufacturing method of the compound represented by these, or its salt, (2) The manufacturing method as described in said (1) whose poor solvent is aromatic hydrocarbons, (3) The said (1) description that a poor solvent is toluene. Production method, (4) The production method according to (1) above, which is subjected to a cyclization reaction in the presence of a base, (5)
The production method according to the above (4), wherein the base is an alkoxide;
(6) (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7- [4- (4- Methylbenzenesulfonyloxy) -3-methylbutyl] -pyrido [3,4-b] pyridine-6-carboxamide is characterized by subjecting it to a cyclization reaction in a poor solvent (aR, 9R).
-7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2 , 1-g] [1,7] naphthyridine-6,1
Method for producing 3-dione, (7) (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-3-methylbutyl) -8-
Oxo-5- (4-methylphenyl) -pyrido [3,4
-B] Pyridine-6-carboxamide is reacted with p-toluenesulfonyl chloride (R)-
N- [3,5-bis (trifluoromethyl) benzyl]-
7,8-Dihydro-5- (4-methylphenyl) -8-
Oxo-7- [4- (4-methylbenzenesulfonyloxy) -3-methylbutyl] -pyrido [3,4-b] pyridine-6-carboxamide, (8) (R)-
N- [3,5-bis (trifluoromethyl) benzyl]-
7,8-Dihydro-5- (4-methylphenyl) -8-
Oxo-7- [4- (4-methylbenzenesulfonyloxy) -3-methylbutyl] -pyrido [3,4-b] pyridine-6-carboxamide, (9) (aR, 9R)-
7- [3,5-bis (trifluoromethyl) benzyl]
-8,9,10,11-tetrahydro-9-methyl-5
-(4-Methylphenyl) -7H- [1,4] diazocino [2,1-g] [1,7] naphthyridine-6,13-
It relates to dione toluene hydrate.

In the above formula, M ring is a partial structure

[Chemical 10] Shows a heterocycle having -N = C <, -CO-N <or -CS-N <. A preferred M ring has a partial structure -X =
It has -CO-N <or -N = C <as Y <. In the above formula, R ^a and R ^b are bonded together to form a ring A,
Alternatively, the same or different, a hydrogen atom or a substituent on the M ring is shown. Examples of the substituents R ^a and R ^b in the M ring include a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, and an alkylthio group which may be halogenated. , A cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (e.g., an oxygen atom other than a nitrogen atom, a sulfur atom) Such as a cyclic amino group which may contain a hetero atom), an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsulfonyl group. Group, oxo group and the like. The “halogen atom” includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine and bromine atoms. Examples of the “alkyl group which may have a substituent (s)” include, for example, a hydroxyl group, a C _1-6 alkoxy group (methoxy, ethoxy, propoxy, butoxy, isobutoxy, s-butoxy, t-butoxy and the like C _{1- 4} alkoxy groups), C _1-6 alkylthio groups (methylthio, ethylthio, propylthio, butylthio, isobutylthio,
C _1-4 alkylthio groups such as s-butylthio and t-butylthio), amino groups, C _1-7 acylamino groups (formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino groups, etc.), N-alkylamino groups , Carboxyl group, nitro group, mono- or di-C _1-6 alkylamino group (for example, mono- or di-C _1-4 such as methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino group)
Alkylamino group, etc.), which may have a substituent,
N-substituted amino groups substituted with 1 or 2 homocyclic rings (eg, mono- or di-C _3-8 cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclohexylamino groups; phenylamino groups, etc. C _{6 -10} arylamino group, etc.), or a heterocyclic group which may have a substituent [eg, may contain 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom 5 A 9-membered cyclic amino group (eg piperidino, 4-methylpiperidino, morpholino, thiomorpholino, piperazinyl, 4-
5- or 6-membered non-aromatic cyclic amino group such as methylpiperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; pyridyl, pyrazyl,
5- or 6-membered aromatic cyclic amino groups such as pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl and pyrazolyl), aromatic heterocyclic groups such as thiophenyl, furanyl, thiazole, isothiazole, oxazole and isoxazole groups, tetrahydropyridyl, dihydro Pyridyl, tetrahydropyrazyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
Dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrofuranyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxazolyl, dihydroisoxazolyl, hexahydropyrimidinyl, hexahydropyridazinyl, Non-aromatic heterocyclic group such as tetrahydropyranyl, pyrazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl group, etc.], alkylsulfonylamino group ( For example, methylsulfonylamino, ethylsulfonylamino group etc. C _1-4 alkylsulfonylamino group etc.), C
_1-6 alkyl-carbonyloxy group (for example, C _1-4 alkyl-group such as acetoxy, ethylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy group)
A carbonyloxy group, etc.) and a 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.

[0008] Preferred "optionally substituted alkyl
"Kill group" is substituted with about 1 to 4 halogen atoms.
May be C_1-6 Alkyl group [especially halogenated
May be C_1-4Alkyl groups (eg methyl, chloroform
Chill, fluoromethyl, difluoromethyl, trichloro
Methyl, trifluoromethyl, ethyl, 2-bromoethyl
2,2,2-trichloroethyl, 2,2,2-tri
Fluoroethyl, pentafluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 1
-(Trifluoromethyl) ethyl, butyl, 4,4,4
-Trifluorobutyl, isobutyl, sec-butyl, te
C such as rt-butyl group_1-4Alkyl groups and 1-5
C in which about 1 to 3 halogen atoms are substituted_1-4
Alkyl group, etc.)], C_1-6Alkoxy-C_1-6Alkyl
Groups (eg methoxymethyl, ethoxymethyl, isop
Ropoxymethyl, butoxymethyl, methoxyethyl, d
C such as toxyethyl_1-4Alkoxy-C_1-4Alkyl
Group), C_1-6Alkylthio-C_1-6Alkyl groups (eg,
Methylthiomethyl, ethylthiomethyl, butylthiomethy
C, such as phenyl, methylthioethyl, ethylthioethyl groups, etc.
_1-4Alkylthio-C_1-4Alkyl group), amino-C_1-6
Alkyl groups (eg aminomethyl, 2-aminoethyl
2-aminopropyl, 3-aminopropyl, 2-a
Minobutyl, 3-aminobutyl, 4-aminobutyl groups
Which amino-C_1-4Alkyl group), C_1-7Acylamino-
C_1-6Alkyl group (formylaminomethyl, acetyl
Minomethyl, propionylaminomethyl, formylami
Noethyl, acetylaminoethyl, propionylamino
Ethyl, butyrylaminoethyl, benzoylaminomethy
C such as ru radical_1-7Acylamino-C_1-4Alkyl group),
No or di-C_1-6Alkylamino-C_1-6Alkyl group
(For example, methylaminomethyl, ethylaminomethyl,
Butylaminomethyl, dimethylaminomethyl, diethyl
Aminomethyl, 2- (N-methylamino) ethyl, 2-
(N-ethylamino) ethyl, 2- (N-methylami)
No) propyl, 3- (N-methylamino) propyl, 3
-(N-methylamino) butyl, 4- (N-methylami)
No) butyl, 2- (N-dimethylamino) ethyl, 2-
Mono- or di- such as (N-diethylamino) ethyl group
C_1-4Alkylamino-C_1-4Alkyl group), C_3-10Shiku
Lowalkylamino-C_1-6Alkyl groups (eg cyclo
Propylaminomethyl, cyclobutylaminomethyl,
Chlohexylaminomethyl, cyclopropylaminoethyl
, Cyclobutylaminoethyl, cyclohexylamino
C such as ethyl group and phenylaminomethyl group_3-10Cyclo
Alkylamino-C_1-4Alkyl group),

A 5- or 6-membered cyclic amino-C _1-6 alkyl group which may contain 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom (for example, piperidinomethyl, 4-methylpiperidi) Nomethyl, morpholinomethyl,
Non-aromatic cyclic amino-C _1-4 alkyl groups such as thiomorpholinomethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, piperidinoethyl, morpholinoethyl, piperazinylethyl; pyridylmethyl, pyrimidinylmethyl, imidazolylmethyl, 5- or 6-membered aromatic cyclic amino-C _1-4 alkyl group such as pyridylethyl),
C _1-6 alkylsulfonylamino-C _1-6 alkyl group (for example, C _1-6 alkylsulfonylamino-C ₁ -such as methylsulfonylaminomethyl, ethylsulfonylaminomethyl, methylsulfonylaminoethyl, ethylsulfonylaminoethyl group, etc. ₆ alkyl groups), C _1-6 alkyl-carbonyloxy-C _1-6 alkyl groups (eg, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, butylcarbonyloxymethyl, methylcarbonyloxyethyl, ethylcarbonyloxyethyl groups, etc. C _1-4 alkyl-carbonyloxy-C _1-4 alkyl group)
Etc. are included.

The "optionally halogenated alkoxy group" is, for example, a C _1-6 alkoxy group or 1-
Examples thereof include C _1-6 alkoxy groups substituted by about 5 halogen atoms. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
Trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy. , Pentoxy, hexyloxy groups and the like. Preferred "optionally halogenated alkoxy group" is C _1-4 alkoxy group, or 1-
C _1-4 alkoxy group substituted with about 3 halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec-
A butoxy group and the like are included.

The "optionally halogenated alkylthio group" includes, for example, a C _1-6 alkylthio group, and 1
A C _1-6 alkylthio group having about 5 to 5 halogen atoms is included, and examples of such an alkylthio group or a halogenated alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio. , Butylthio,
4,4,4-trifluorobutylthio, pentylthio,
Hexylthio group and the like can be mentioned. Preferred “optionally halogenated alkylthio group” is a C _1-4 alkylthio group or a C _1-4 alkylthio group substituted with about 1 to 3 halogen atoms, for example, methylthio, difluoromethylthio, trifluoro. Methylthio, ethylthio, propylthio, isopropylthio, butylthio,
A 4,4,4-trifluorobutylthio group and the like are included.

Further, "cycloalkyl group" means C
_3-10 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl groups, etc.) are included, and the “aryl group” is C
_{The 6-10} aryl group (eg, phenyl group) and the “acylamino group” include, for example, a C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group), etc. Be done. “Acyloxy group” includes, for example, C _1-3
An acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.) and the like are included. Examples of the “mono- or di-alkylamino group” include a mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, etc.) and the like. . Also,
The "cyclic amino group" includes, for example, a nitrogen atom, an oxygen atom, and a 5 to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as sulfur atom (for example, pyrrolidino, piperidino, morpholino, Thiomorpholino group) and the like. The "alkylcarbonylamino group" is, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the “alkylsulfonylamino group” is, for example, C _1-4 alkyl. A sulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino group, etc.), “alkoxycarbonyl group” includes, for example, C
_1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Butoxycarbonyl group etc.) and “alkylcarbonyl group” include, for example, C _1-6 alkyl-carbonyl group (eg formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl group etc.), “mono- or di-alkylcarbamoyl group”. Is, for example, mono- or di-
C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,
“Diethylcarbamoyl group etc.” and “alkylsulfonyl group” include, for example, C _1-6 alkylsulfonyl group (eg methylsulfonyl, ethylsulfonyl, propylsulfonyl group etc.) and the like.

In the above formula, A ring and B ring are respectively
A homocycle or a heterocycle which may have a substituent, at least one of which is a heterocycle which may have a substituent. The above-mentioned "homologous or heterocyclic ring" includes, for example, (i) one or two heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom, preferably 1 to 3 heteroatoms. Aromatic heterocycles or non-aromatic heterocycles, or (ii) cyclic hydrocarbons (homocycles) composed of carbon atoms are included. The “aromatic heterocycle” is, for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom (eg, 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 and thiophene rings, as well as pyrrole, thiazole rings and the like. 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 heterocycle containing one sulfur atom in addition to the carbon atom. Aromatic heterocycles (such as thiophene ring) and the like are preferable.

The "non-aromatic heterocycle" is, for example, a 5- to 9-membered non-aromatic ring containing, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. For example, for ring A, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydropyrazine. Examples of the B ring include an isoxazole ring and the like, and in addition to the above, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, Tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, te And La tetrahydroisoquinoline isoxazole ring. With respect to the ring A, for example, a 6-membered non-aromatic heterocycle containing 1 or 2 nitrogen atoms in addition to carbon atoms (eg, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring, etc.) is preferable, and a tetrahydropyridine ring is particularly preferable. Is used in general. With regard to the B ring, for example, a 6-membered non-aromatic heterocyclic ring containing 1 or 2 nitrogen atoms in addition to carbon atoms (eg, piperidine, piperazine ring, etc.) and the like are preferable, and particularly piperazine ring and the like are frequently used.

The above-mentioned "cyclic hydrocarbon (homocyclic ring)" includes, for example, a 3- to 10-membered (for example, 5- to 9-membered) cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. Be done. For example, for ring A, benzene, C
_3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and the like, and the cycloalkene includes C
_5-6 cycloalkene (eg, cyclopentene, cyclohexene, etc.) and the like are preferable. Regarding the B ring, in addition to the above, a C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane,
Cycloheptane, cyclooctane, etc.)
As the cycloalkane, C _5-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) and the like are preferable. Regarding the ring A, for example, a 6-membered homocyclic ring such as benzene or cyclohexene ring is preferable, and a benzene ring or the like is particularly preferable. Regarding ring B, for example, a 6-membered homocyclic ring such as benzene or cyclohexane ring is preferable, and a benzene ring is particularly preferable.

At least one of ring A and ring B is
It is composed of a heterocyclic ring which may have a substituent, and both the A ring and the B ring may be composed of a heterocyclic ring which may have a substituent. One of the A ring and the B ring is composed of an aromatic ring which may have a substituent, and the other is composed of a hetero ring which may have a substituent (particularly an aromatic heterocycle). Is preferred. Examples of the above-mentioned “aromatic ring” include (i) the “aromatic heterocycle”, that is, one or two heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to the carbon atom, Preferably 1 to 3 5- or 6-membered aromatic heterocycle optionally having a substituent (eg, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, Thiazole,
Isothiazole, oxazole and isoxazole rings, etc.) or (ii) a benzene ring which may have a substituent.

Examples of the substituent which the above-mentioned "aromatic ring" may have include the same substituents as those in the A ring and the B ring which will be described later. Examples of the "aromatic heterocycle" of "good aromatic heterocycle" include the same aromatic heterocycle as the above-mentioned "5- or 6-membered aromatic heterocycle". In addition, examples of the substituent that the “aromatic heterocycle that may have a substituent” may have include the same substituents as those in the A ring and the B ring described later. As the above-mentioned "5- or 6-membered aromatic heterocycle", the same heterocycles and the like as described in the above "Aromatic heterocycle" are preferable. More preferably, one of ring A and ring B is an aromatic heterocycle which may have a substituent (for example, a 5- or 6-membered aromatic heterocycle), and the other has a substituent. It may be a benzene ring.

"Homogeneous or heterocyclic ring", "aromatic heterocycle", "non-aromatic heterocycle", "cyclic hydrocarbon", "aromatic ring" and "benzene ring" represented by A ring and B ring are As the substituent which may have, for example, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, aryl Group, an acylamino group, an acyloxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (for example, in addition to a nitrogen atom, a hetero atom such as an oxygen atom or a sulfur atom is contained. Optionally cyclic amino group), alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoyl group Group, mono - or di - alkylcarbamoyl group, an alkylsulfonyl group, an oxo group. The “halogen atom” which ring A and ring B may have 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 "alkyl group which may have a substituent (s)" which ring A and ring B may have include, for example,
Hydroxyl group, amino group, carboxyl group, nitro group, mono- or di-C _1-6 alkylamino group (for example,
From methylamino, ethylamino, dimethylamino, diethylamino groups, etc., C _1-6 alkyl-carbonyloxy groups (eg, acetoxy, ethylcarbonyloxy groups, etc.) and halogen atoms (eg, fluorine, chlorine, bromine atoms, etc.) A selected C _1-6 alkyl group _optionally having 1 to 5 substituents (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl group, etc.) and the like.
Particularly, an alkyl group which may be halogenated, for example, a C _1-6 alkyl group, and a C _1-6 alkyl group substituted with about 1 to 4 halogen atoms are preferable. Examples of such an alkyl group or halogenated alkyl group include methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2, 2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 1- (trifluoromethyl) ethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,
Examples include 6,6-trifluorohexyl and 5-trifluoromethylpentyl groups.

The more preferable "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, pentafluoroethyl, propyl, 3,
C _1-4 alkyl group such as 3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl group or 1- Included are C _1-4 alkyl groups substituted with about 3 halogen atoms. Examples of the “optionally halogenated alkoxy group” which ring A and ring B may have include, for example, a C _1-6 alkoxy group or substituted with 1 to 5 halogen atoms as described above. Examples thereof include C _1-6 alkoxy groups. Such an alkoxy group or halogenated alkoxy group includes
For example, methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy group and the like are included. . Preferred "optionally halogenated alkoxy group", C _1-4 of C _1-4 alkoxy groups, or 1-3 about halogen atom has been substituted
Alkoxy group, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy group, etc. Is included.

The "optionally halogenated alkylthio group" which may be possessed by ring A and ring B is, for example, a C _1-6 alkylthio group and about 1 to 5 halogen atoms as described above. C _1-6 alkylthio groups having atoms are included, and examples of such alkylthio groups and halogenated alkylthio groups include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
Propylthio, isopropylthio, butylthio, 4,
4,4-trifluorobutylthio, pentylthio, hexylthio groups and the like can be mentioned. Preferred “optionally halogenated alkylthio group” is C _1-4 alkylthio group or C substituted with 1 to 3 halogen atoms.
_1-4 alkylthio groups such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4
A 4-trifluorobutylthio group and the like are included. Further, the aryl group as a substituent includes a C _6-10 aryl group (eg, phenyl group), and the acylamino group includes, for example, C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, Butyrylamino, benzoylamino groups, 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 a mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, etc.)
And so on. Further, the cyclic amino group, for example,
A 5- to 9-membered cyclic amino group (for example, pyrrolidino, piperidino, morpholino group, etc.) which may contain 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom is included. The alkylcarbonylamino group includes, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the alkylsulfonylamino group includes, for example, C
_1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino group, etc.), alkoxycarbonyl group includes, for example, C _1-4 alkoxy-
The carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and the alkylcarbonyl group include, for example, C
_{The 1-6} alkyl-carbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc.) and mono- or di-alkylcarbamoyl group include, for example, mono- or di-C _1-4 alkylcarbamoyl group ( For example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl groups, etc.), and alkylsulfonyl groups include, for example, C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl groups, etc.), etc. .

Hereinafter, when the term "optionally halogenated" is used in the present specification, the number of halogen atoms is 1
It means that the number is about 5, preferably about 1 to 3. Preferred substituents which ring A and ring B may have are a halogen atom and an optionally halogenated C.
_1-4 alkyl group, optionally halogenated C _1-4 alkoxy group, optionally halogenated C _1-4 alkylthio group, C _1-3 acyloxy group, hydroxyl group, amino group, mono- or Examples thereof include a di-C _1-4 alkylamino group, a carboxyl group, a C _1-4 alkoxy-carbonyl group and an oxo group. More preferred substituents that ring A and ring B may have include a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy, and hydroxyl. Group, amino group, mono- or di-C _1-4 alkylamino group, C _1-3 acyloxy group, oxo group and the like. In particular, a halogen atom, such as an optionally halogenated C _1-4 alkyl group and an optionally halogenated C ₁ even though _-4 alkoxy group.

The ring A and ring B substituents may be substituted at any substitutable position on 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 is preferably about 1 to 3.
When ring A and / or ring B has a nitrogen atom, it may form a quaternary ammonium salt, for example, halogen ion (for example, Cl ⁻ , Br ⁻ , I ^−, etc.), sulfate ion, hydroxy ion, etc. It may form a salt with the anion of.

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

[Chemical 11] [In the formula, A ¹ represents a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2 , 2,2-trifluoroethyl, pentafluoroethyl group, etc.) or an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- Trifluoroethoxy,
A pentafluoroethoxy group) or a formula (A-
2)

[0025]

[Chemical 12] [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,
Isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group, etc.), or an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy group) , Trichloromethoxy, ethoxy, 2,
2,2-trifluoroethoxy, pentafluoroethoxy group, etc.]]. More preferred homocycles include, for example, formula (A-3)

[Chemical 13] [In the formula, A ⁴ and A ⁵ are the same or different and are a halogen atom (eg, fluorine, chlorine atom, etc.), or an optionally halogenated C _1-4 alkyl group (eg,
A methyl group, a trifluoromethyl group, a trichloromethyl group, an ethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, an isopropyl group, and the like].

The homocyclic ring may be, for example, the following formula (A-4)

[Chemical 14] [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. The homocyclic ring represented by the above formula particularly preferably includes a homocyclic ring 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,
(2) A ² and A ³ are the same or different and optionally halogenated C _1-4 alkyl groups (for example, methyl, trifluoromethyl, ethyl, isopropyl groups, etc.) (eg, A methyl, trifluoromethyl, ethyl, isopropyl group, etc.) or an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, ethoxy group, etc.), a homocyclic ring,
(3) A ⁴ and A ⁵ are the same or different and are C _1-4
A homocyclic ring that is an 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 homocyclic rings which are the same or different and are C _1-4 alkoxy groups (eg, methoxy, ethoxy groups, etc.).

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.

[Chemical 15] Preferable 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.

[Chemical 16] [In the formula, D ¹ represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), E ¹ represents a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), The compound having the partial structure represented by (ii) is a halogen ion (for example, Cl ⁻ , Br ⁻ , I ^−).
Etc.), sulfate ion or hydroxy ion, etc. to form a quaternary ammonium salt. G is a hydrogen atom or C
_1-4 alkyl group (for example, methyl, ethyl, propyl,
Isopropyl group) and J represents a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group) or a C _6-10 aryl group (eg, phenyl group). A ring is a 5- or 6-membered nitrogen-containing heterocycle, for example, (i) 1 or 2 nitrogen atoms in addition to carbon atom.
6-membered aromatic nitrogen-containing heterocycles (eg, pyridine,
Pyrazine ring, etc.), (ii) In addition to carbon atom, 1 nitrogen atom
Alternatively, it is preferably a 6-membered non-aromatic heterocyclic ring containing two (eg, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring, etc.) and the like. Particularly preferred ring A includes aromatic nitrogen-containing heterocycle, especially pyridine ring.

The preferred homocycle in ring B is a homocycle consisting of carbon atoms which may have a substituent, for example, the formula (B-1)

[Chemical 17] [Wherein B ¹ is a halogen atom, a C _1-4 alkyl group which may be substituted with hydroxy or is halogenated, a C _1-4 alkoxy group which may be halogenated, a C _1-6 alkyl-carbonyl group Or a carboxyl group], formula (B-2)

[Chemical 18] [In the formula, B ² and B ³ are the same or different and each represents a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group] , Or formula (B-3)

[Chemical 19] [In the formula, B ⁴ , B ⁵ and B ⁶ are the same or different and each is a halogen atom or an optionally halogenated C _1-4.
An alkyl group and an optionally halogenated C _1-4 alkoxy group].

Further preferred homocyclic rings have the formula (B-4)

[Chemical 20] [Wherein B ⁷ , B ⁸ and B ⁹ are the same or different,
A halogen atom, an optionally halogenated C _1-4 alkyl group, or an optionally halogenated C _1-4 alkoxy group] and the like. A particularly preferred homocycle is represented by the following formula (B-5)

[Chemical 21] Wherein, B ¹⁰ is a halogen atom, an optionally substituted or halogenated hydroxy C _1-4 alkyl group, halogenated which may be C _1-4 alkoxy group, C _1-6 alkyl - carbonyl A group or a carboxyl group].

In the above formula, the halogen atom in B ^{1 to} B ¹⁰ includes, for example, fluorine, chlorine, bromine atom and the like, and the optionally halogenated C _1-4 alkyl group includes, for example, methyl group. , Trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,
2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl,
C _{1, 4} optionally containing halogen, including 2,2,3,3-tetrafluoropropyl, isopropyl group, etc.
Alkoxy groups include, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-
Includes trifluoroethoxy, 2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, propoxy, 2,2,3,3-tetrafluoropropoxy, isopropoxy groups, etc. . In the above formula, the C _1-6 alkyl-carbonyl group represented by B ¹ or B ¹⁰ includes formyl, acetyl and the like.

It is also preferable that the B ring is a benzene ring which may have a substituent. Such a benzene ring has, for example, the formula (B-6)

[Chemical formula 22] Are preferred, more preferably formula (B-7)

[Chemical formula 23] In particular, the formula (B-8)

[Chemical formula 24] A benzene ring and the like represented by [the symbols in the formula are as defined above] are included.

Among the substituents in the above formula, particularly preferred positions are
As the substituent, (1) B¹ , B² , B³ , B^Four , B^Five Oh
And B⁶Are the same or different and are halogen atoms (for example,
Fluorine, chlorine atom, etc.), even if halogenated
Good C _1-4Alkyl groups (eg methyl, trifluoro
(Methyl, ethyl, isopropyl, etc.), (2) B¹ ,
B² , B³ , B^Four , B^Five And B⁶Are the same or different
And optionally halogenated C_1-4Alkoxy group
(For example, methoxy, trifluoromethoxy, ethoxy
Group), (3) B⁷ , B⁸ And B⁹ But the halogen source
Child (eg, fluorine, chlorine atom, etc.), (4) B^TenIs
Fluorine atom, (5) B^TenIs C_1-4Alkyl groups (for example,
(Eg, chill group), (6) B¹Or B^TenSet with hydroxy
C that may be replaced_1-6Alkyl groups (eg, hydro
Xymethyl, etc.), C_1-6Alkyl-carbonyl (eg
Formyl, acetyl, etc.), carboxyl groups, etc.
Can be mentioned. More preferable substituents may have a substituent.
As the Nzen ring, the following formula (B-9)

[Chemical 25] A phenyl group represented by

Preferred aromatic or non-aromatic heterocycles in ring B include, for example, 5- or 6-membered aromatic or non-aromatic heterocycles such as pyridine, thiophene and piperidine rings. The ring may have the same preferable substituents as those exemplified in the item of the ring A. When the ring B is an aromatic heterocycle or a non-aromatic heterocycle, particularly preferable aromatic heterocycles or non-aromatic heterocycles include, for example, compounds of the formula (B-10)

[Chemical formula 26] Heterocycles represented by are included. When both or one of A ring and B ring is a heterocycle, an unsubstituted heterocycle is also preferable as this heterocycle.

A preferred combination (1) of ring A and ring B is as follows. (1) One of ring A and ring B: selected from a nitrogen atom and a sulfur atom in addition to a carbon atom which may be substituted with a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group). A 5- or 6-membered heterocycle containing 1 or 2 heteroatoms (eg, pyridine, pyrazine,
Thiophene, tetrahydropyridine, piperidine, piperazine ring, etc.), the other of A ring and B ring: halogen atom (for example, fluorine, chlorine, bromine atom, etc.), optionally halogenated C _1-4 alkyl group (for example, Methyl,
Trifluoromethyl, trichloromethyl, ethyl, 2,
2,2-trifluoroethyl, pentafluoroethyl,
2,2,2-trichloroethyl, propyl, isopropyl group, etc.) and an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-tri) Fluoroethoxy, pentafluoroethoxy, 2,2
A benzene ring optionally substituted with 1 to 3 substituents selected from 2-trichloroethoxy, propoxy, isopropoxy groups and the like).

More preferred combination (2) of A ring and B ring is as follows. (2) One of ring A and ring B: a 5- or 6-membered aromatic heterocycle containing one or two heteroatoms selected from nitrogen atom and sulfur atom in addition to carbon atom (for example,
Pyridine, pyrazine, thiophene ring, etc.) and the other of A ring and B ring: halogen atom (eg, fluorine, chlorine,
Bromine atom etc.), optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2 2-trichloroethyl, propyl, isopropyl group and the like and optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, penta 1 to 3 selected from fluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy group, etc.)
A benzene ring optionally substituted with one substituent. In particular,
The aromatic heterocycle in which ring A may have a substituent (for example, a 5- or 6-membered aromatic heterocycle, especially a pyridine ring), and the benzene ring in which ring B may have a substituent. Is preferred.

In the above formula, ring C represents a homocyclic ring which may have a substituent or a heterocyclic ring which may have a substituent.
The homocyclic ring or the heterocyclic ring may have the same or different substituents.
It may have about 5 to about 3, preferably about 1 to 3. Moreover, those substituents may be substituted at any position of the homocyclic ring or the heterocyclic ring. For the homocycle, the same “cyclic hydrocarbon (homocycle)” as described in the section “A ring and B ring”, for example, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C _{3- 10} cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, 3 to 10-membered cyclic hydrocarbon, such as cyclooctane, etc.), preferably 5 or 6-membered Included are cyclic hydrocarbons and the like. Preferred homocyclic rings include 6-membered homocyclic rings such as benzene, cyclohexene, and cyclohexane rings, with the benzene ring being particularly preferred.

Examples of the substituent on the above-mentioned homocyclic ring such as a benzene ring are, for example, halogen atoms (for example, fluorine, chlorine,
Bromine, iodine atom), optionally halogenated C
_1-10 alkyl group (for example, 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, octyl and decyl groups), a C _1-4 alkyl group substituted with an amino group (for example, aminomethyl,
A 2-aminoethyl group), mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group (e.g.,
Methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl group, etc.),
C _1-4 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl group, etc.), C
C _1-4 alkyl group substituted with _1-4 alkoxy-carbonyl group (eg, methoxycarbonylethyl, ethoxycarbonylethyl group, etc.), C _1-4 alkyl group substituted with hydroxyl group (eg, hydroxymethyl, hydroxy) ethyl group, etc.), C _1-4 alkoxy - C _1-4 alkyl group substituted with a carbonyl group (e.g., methoxymethyl, methoxyethyl, etc. ethoxyethyl group), C _3-10
Cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.), nitro group, cyano group, hydroxyl group, optionally halogenated C _1-10 alkoxy group (eg, methoxy group , Difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, octyloxy, decyloxy groups, etc.), halogenated which may C _1-4 alkylthio group (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, etc. butylthio group), an amino group, a mono - or di -C _1-4 alkylamino group (e.g.,
Methylamino, ethylamino, propylamino, dimethylamino, diethylamino groups, etc., cyclic amino groups (for example, 5 to 9 members which may contain 1 to 3 heteroatoms such as oxygen atom and sulfur atom in addition to nitrogen atom) Cyclic amino groups such as, for example, pyrrolidino, piperidino, morpholino groups, etc.), C _1-4 alkyl-carbonylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy groups, mono -Or di-C _1-4 alkylaminocarbonyloxy group (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C
_1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxy) Carbonyl group), aralkyloxycarbonyl group (eg, C _7-19 aralkyloxycarbonyl group such as phenyl-C _1-4 alkyloxy-carbonyl (eg, benzyloxycarbonyl group, etc.)), carboxyl group, C _1-6 Alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), C _3-6 cycloalkyl-carbonyl group (eg,
Cyclohexylcarbonyl group), carbamoyl group,
Mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl group, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethyl Sulfonyl, propylsulfonyl group, etc.) and the like.

Further, the homocyclic ring as the C ring is, for example,
One 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, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl groups, etc.), and these aromatic monocyclic heterocyclic groups are It may be substituted with about _{1 to 4 optionally} halogenated C _1-4 alkyl groups (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, isopropyl groups, etc.) and the like.

Preferable substituents for substituting the homocyclic ring as C ring (such as benzene ring) are, for example, halogen atom (for example, fluorine, chlorine and bromine atom) and optionally halogenated C _{1- 6} alkyl groups (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, s-butyl, t-butyl, perfluorobutyl group, etc.), nitro group, hydroxyl group An optionally halogenated C _1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
Perfluoroethoxy, propoxy, isopropoxy,
3,3,3-trifluoro propoxy and butoxy group), an amino group, a mono - or di -C _1-4 alkylamino C _1-4 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl , 2-methylaminoethyl, 2-dimethylaminoethyl group, etc.), mono- or di-C _1-4 alkylamino group (eg, methylamino,
Examples thereof include an ethylamino group, a dimethylamino group, a diethylamino group and the like), a C _1-4 alkoxy-carbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group and the like), a carboxyl group and a carbamoyl group.

Among them, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl,
Difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t-butyl group, etc.), And an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy,
Ethoxy, 2,2,2-trichloroethoxy, 2,2
2-trifluoroethoxy, perfluoroethoxy, propoxy group, etc.), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.), C _1-3
An acyloxy group (eg, acetoxy group) and a hydroxyl group are preferable. The number of these substituents is
For example, it is preferable that the number is 1 to 3. In particular, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg,
Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t- Butyl group), an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, perfluoro) Ethoxy, propoxy groups, etc.) are suitable.

The “heterocycle” of the “heterocycle optionally having substituent (s)” includes, for example, nitrogen atom,
A 5- to 10-membered heterocycle containing 1 to 4 1 or 2 heteroatoms such as oxygen atom and sulfur atom is included.
Specific examples of the heterocycle include (1) furyl,
Thienyl, pyrrolyl, 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, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
5- or 6-membered aromatic monocyclic heterocycle such as pyrazinyl and triazinyl;

(2) Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2- Benzisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxalinyl. , Thianthrenyl, phenatridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
A 9 or 10-membered fused aromatic heterocycle such as 1,2,4-triazolo [4,3-b] pyridazinyl; or

(3) 5- to 10-membered non-aromatic heterocycles such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and pyrazinyl. The heterocycle (1)
Among (3), for example, 5- or 6-membered heterocycles containing 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, and sulfur atom in addition to carbon atom are widely used. Such heterocycles include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl and the like. As the substituent which the heterocycle may have,
The same substituents as those described in the above-mentioned “homocyclic ring which may have a substituent (s)” can be mentioned.

The more preferable 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. An alkyl group, an optionally halogenated C _1-4 alkoxy group, a di-C _1-4 alkylamino group,
A benzene ring optionally substituted with 1 to 3 substituents selected from a C _1-3 acyloxy group and a hydroxyl group (in particular, a benzene ring substituted with the above-mentioned substituents) is included. Specifically, a preferred C ring includes, for example, the following formula (C-1)

[Chemical 27] [Wherein C ¹ , C ² and C ³ are the same or different and are a hydrogen atom, a halogen atom, an optionally halogenated C _1-4 alkyl group, or an optionally halogenated C
_1-4 alkoxy group, mono- or di-C _1-4 alkylamino group, C _1-3 acyloxy group or hydroxyl group], or the following formula (C-2)

[Chemical 28] [In the formula, C ⁴ and C ⁵ are the same or different and are a hydrogen atom, a halogen atom, or an optionally halogenated C.
_1-4 alkyl group or optionally halogenated C _1-4
And an optionally substituted benzene ring represented by [showing an alkoxy group].

Here, C ¹ , C ² , C ³ , C ⁴ or C ⁵
The halogen atom, the optionally halogenated C _1-4 alkyl group, the optionally halogenated C _1-4 alkoxy group and the mono- or di-C _1-4 alkylamino group represented by Halogen atom, optionally halogenated C _1-4 alkyl group, optionally halogenated C
_{The same} groups as the _1-4 alkoxy group and the mono- or di-C _1-4 alkylamino group are used. More preferred C ring, for example, the formula (C-1) and in (C-2), C ¹
Includes a benzene ring in which C ⁵ is the following substituent. (1) C ¹ , C ² and C ³ are the same or different,
A halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, (2) C ¹ , C ² and C ³ are the same or different, A halogen atom or an optionally halogenated C _1-4 alkyl group, (3) C ¹ , C ² and C ³ are the same or different, and a halogen atom, (4) C ¹ , C ² and C ³ Are the same or different, optionally halogenated C _1-4 alkyl groups,

(5) C ¹ , C ² and C ³ are the same or different and optionally halogenated C _1-4 alkoxyl group, (6) C ⁴ and C ⁵ are the same or different. A halogen atom, (7) C ⁴ and C ⁵ are the same or different, and an optionally halogenated C _1-4 alkyl group, or (8) C ⁴ and C ⁵ are the same or different. And an optionally halogenated C _1-4 alkoxy group. In the above aspects (1) to (8), the "optionally halogenated C _1-4 alkyl group", the "optionally halogenated C _1-4 alkoxy group" and the "halogen atom" include The same groups or atoms as described above can be exemplified.

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) C ⁴ and C ⁵ are chlorine atoms, and (c) C
^{One of 4} and C ⁵ is a methoxy group, the other is an isopropyl group, (d) one of C ⁴ and C ⁵ is a methoxy group, the other is a 1-methoxy-1-methylethyl group, or (e) C ⁴ and C ⁵ is a trifluoromethyl group.

In the above formula, the Z ring represents an optionally substituted nitrogen-containing heterocycle. Examples of the substituent on the Z ring include various substituents, for example, an alkyl group (eg, a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group). Carbon such as straight or branched alkyl group, preferably linear or branched alkyl group having 1 to 4 carbon atoms, alkenyl group (eg, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl group, etc. C2-C6 alkenyl groups, preferably C2-C4 alkenyl groups, alkynyl groups (eg ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl groups and other alkynyl groups). , Preferably 2 to 2 carbon atoms
4 alkynyl group), cycloalkyl group (eg, C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group, preferably C _3-8
3-6 cycloalkyl group), cycloalkyl-alkyl group (for example, C _3-6 cycloalkyl-C _1-4 alkyl group such as cyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl group), aryl group (for example, phenyl) , 1-naphthyl, 2-naphthyl, anthryl, phenanthryl groups and other aryl groups having 6 to 14 carbon atoms, preferably aryl groups having 6 to 10 carbon atoms, especially phenyl group),
Nitro group, cyano group, hydroxyl group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio group, etc.), Amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, etc.), cyclic amino group (eg, oxygen atom, sulfur atom other than nitrogen atom) Such as 5 to 9 membered cyclic amino group which may contain 1 to 3 hetero atoms, specifically, for example, pyrrolidino, piperidino, morpholino, thiomorpholino group, etc.), C _1-4 alkyl-carbonyl Amino groups (eg,
Acetylamino, propionylamino, butyrylamino groups, etc.), C _1-4 alkylsulfonylamino groups (eg, methylsulfonylamino, ethylsulfonylamino groups, etc.), C _1-4 alkoxy-carbonyl groups (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg methylcarbonyl, ethylcarbonyl, propylcarbonyl group etc.), carbamoyl group, mono- or di-C _1-4 Examples thereof include an alkylcarbamoyl group (eg, methylcarbamoyl group, ethylcarbamoyl group, etc.), a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.), an oxo group, a thioxo group and the like. The number of these substituents depends on the size of the Z ring, for example, 1 to
The number is about 5, preferably about 1 or 2.

Ring Z may be a heterocycle which may contain, in addition to Y and nitrogen atom N, at least one heteroatom selected from nitrogen atom, oxygen atom and sulfur atom, but is oxolated. It is preferably an optional ring. The Z ring has the following formula (Z-1)

[Chemical 29] (In the formula, D and E represent a group that forms the Z ring together with the nitrogen atom adjacent to E). Examples of D and E forming the Z ring include an alkylene group, at least one of which may be oxo, an oxyalkylene group, an iminoalkylene group, and the like. Desirable D and E are often an alkylene group and an oxyalkylene group which may be oxoated, respectively. The optionally oxo alkylene group, oxyalkylene group, and iminoalkylene group represented by D and E have a carbon number such that Z ring forms a 5 to 12-membered ring, preferably a 5 to 9-membered ring. Is preferred. Note that D and E
The carbon numbers of the alkylene groups represented by may be the same or different.

Preferred D includes, for example, an optionally oxo- _treated C _1-7 alkylene group (particularly an optionally-oxo C _1-5 alkylene group), a C _1-7 oxyalkylene group (particularly C _1-5 oxyalkylene group) and C _1-7 iminoalkylene group (particularly C _1-5 iminoalkylene group). More preferred D, the formula - (CH _{2) m} - (wherein, m is 1-7) alkylene group represented by the formula -O-
(CH _{2) p} - (wherein, p is an integer of 1 to 7) oxyalkylene group represented by the formula -NH- (CH _{2) q} - (wherein,
(q is an integer of 1 to 7) includes an iminoalkylene group. In the above formula, m and p are each 1 to
It is preferably 5, especially 2-5. Preferred E includes
For example, it includes a C _1-3 alkylene group which may be oxo, particularly an alkylene group having 1 or 2 carbon atoms which may be oxo, and a methylene group which may be oxo. The number of oxo groups that can be substituted on the Z ring is not particularly limited, and can be selected from the range of about 1 to 3 depending on the size of the Z ring. The number is about 1 or 2. The oxo group may be substituted on at least one of D and / or E. In the preferred Z ring, the oxo group is substituted with E.

In a preferred Z ring, D has 1 to 1 carbon atoms.
5 is an alkylene group having 2 to 5 carbon atoms or an oxyalkylene group, and E is an oxo group having 1 or 2 carbon atoms, particularly> C═O. Preferred Z rings include
For example, the following formula (Z-2)

[Chemical 30] (In the formula, m and p each represent an integer of 1 to 5) and a 5- to 9-membered nitrogen-containing heterocycle is included.

In the above formula, n represents an integer of 1 to 6,
It is preferably an integer of 1 to 3, particularly 1 or 2. More preferably, n is 1. In the compound represented by the general formula (I), the "M ring"

[Chemical 31] The combination is not particularly limited, and the compounds (I) and (Ia) can be constructed by an appropriate combination. Preferred compound (I) is the “M ring” of the above preferred embodiment.

[Chemical 32] Constructed by combining. Examples of the leaving group L include a halogen atom (eg, chlorine, bromine, iodine atom, etc.), a C _1-4 alkanesulfonyloxy group (eg, methanesulfonyloxy group, ethanesulfonyloxy group, etc.), C _6-10 An arylsulfonyloxy group (for example, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, etc.) and the like can be mentioned.

Among the compounds represented by the above general formula (I), the preferred compound (1) includes the following compounds and pharmaceutically acceptable salts. 5 or 6 in which one of ring A and ring B contains 1 or 2 heteroatoms selected from nitrogen atom and sulfur atom in addition to carbon atom
Membered heterocycle, the other is a benzene ring, and A ring and B ring each have 1 or 2 substituents selected from a halogen atom and an optionally halogenated C _1-4 alkyl group. C ring is a halogen atom or an optionally halogenated C _1-6 alkyl group (preferably C _1-4
Alkyl group) and optionally halogenated C _1-6
A benzene ring optionally having 1 to 3 substituents selected from an alkoxy group (preferably a C _1-4 alkoxy group); D constituting the Z ring is-(CH ₂ ) _m- (m is 1-7 of an integer), or _{-O- (CH 2) p - (} p is an integer of 1-7);

E constituting the Z ring is> C═O;

[Chemical 33] A compound wherein n is 1, or a pharmaceutically acceptable salt thereof. Examples of the above-mentioned "5- or 6-membered heterocycle" include pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine, etc. Specifically, as the A ring, the above formula (A-5) And a ring represented by the formula (B-7) (B-
8), especially a benzene ring represented by the above formula (B-10). The “halogen atom” includes, for example, a fluorine, chlorine, bromine atom, etc., and the “optionally halogenated C _1-4 alkyl group” includes, for example, methyl, chloromethyl, difluoromethyl, trichloro. Methyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,
4,4,4-trifluorobutyl, isobutyl, sec-
Examples thereof include a butyl group and a tert-butyl group, and the “optionally halogenated C _1-6 alkyl group” includes, in addition to the above alkyl group or halogenated alkyl group, a pentyl group, a hexyl group, and the like.

The "optionally halogenated C _1-4 alkoxy group" is, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2.
-Trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, te
Examples thereof include rt-butoxy group, and the “optionally halogenated C _1-6 alkoxy group” includes pentyloxy, hexyloxy group and the like in addition to the above alkoxy group or halogenated alkoxy group. Among the compounds represented by the general formula (I), preferred compound (2)
Also includes the following compounds or pharmaceutically acceptable salts. Ring A has one nitrogen atom or one other than carbon atom
5- or 6-membered heterocycle containing 1 sulfur atom, for example, a heterocycle represented by the following formula (A-7);

[Chemical 34] Ring B is a benzene ring which may have 1 to 3 substituents selected from a halogen atom and an optionally halogenated C _1-4 alkyl group; A benzene ring which may be substituted with 1 to 3 substituents selected from an optionally substituted C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group; D to the - (CH _{2) m} - (indicating represents an integer of 1-7 p) - (m is an integer of 1 to 7) or -O- (CH _{2) p;}

E constituting the Z ring is> C═O;

[Chemical 35] A compound wherein n is 1, or a pharmaceutically acceptable salt thereof.
“Halogen atom”, “C which may be halogenated
_1-4 alkyl group ”and“ optionally halogenated C ”
Examples of the " _1-4 alkoxy group" include the same atom or group as described in the section of the compound (1). More preferably, R ^a and R ^b are the same or different and each is a hydrogen atom or a C _1-6 alkoxy group, a C _1-6 alkylthio group, an amino group, a C _1-7 acylamino group, a mono- or di-C _1-6. alkylamino group, C _3-10 cyclic amino group, C _1-6 alkyl which may be substituted 5 or optionally 6-membered cyclic amino group with a group, C _1-6 alkylsulfonylamino group or a C _1-6 alkylcarbonyloxy C optionally substituted with a group
_1-6 alkyl group, or R ^a and R ^b are bonded together to form a pyridine ring which may have 1 to 3 substituents selected from halogen atom or C _1-4 alkyl group,
Ring B is a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C
_A benzene ring which may have 1 to 3 substituents selected from _1-4 alkoxy groups, wherein C ring is a halogen atom, an optionally halogenated C _1-4 alkyl group, a halogenated group 1 to 3 substituents selected from an optionally substituted C _1-4 alkoxy group, an amino group optionally substituted by a C _1-4 alkyl group, a C _1-3 acyloxy group or a hydroxyl group. A benzene ring which may optionally be present, and a 5- to 10-membered nitrogen-containing heterocyclic group in which Z ring may be substituted with a C _1-4 alkyl group or a hydroxyl group and may be oxo-ized,

[Chemical 36] A compound in which n is 1 or a salt thereof is included.

Preferred compounds among the compounds (I) are
For example, a compound represented by the following general formula or a salt thereof is included.

[Chemical 37] (In the formula, D and E are alkylene groups which may be oxo, and other symbols have the same meanings as described above.) D and E are each C _1-3 which may be substituted with one oxo group. It is preferably an alkylene group. Among the compounds (I), more preferable compounds include, for example, compounds represented by the following general formula or salts thereof.

[Chemical 38] (In the formula, m is an integer of 1 to 7, and other symbols have the same meanings as described above.) M is preferably an integer of 2 to 5. In the above formula, R ^a and R ^b are each a hydrogen atom or a (I) halogen atom, (I
I) (i) hydroxy group, (ii) C _1-6 alkoxy group, (iii) C
_1-6 alkylthio group, (iv) amino group, (v) C _1-7 acylamino group, (vi) mono- or di-C _1-6 alkylamino group,
(vii) mono- or di-C _3-8 cycloalkylamino group, (v
iii) A 5- to 9-membered cyclic amino group which may be substituted with C _1-6 alkyl and may contain 1 to 3 heteroatoms selected from the group consisting of oxygen atom and sulfur atom in addition to the nitrogen atom. , (Ix) C _1-4 alkylsulfonylamino group, (x) C
_1-6 alkyl-carbonyloxy group and (xi) a C _1-6 alkyl group _optionally having 1 to 5 substituents selected from the group consisting of halogen atoms, (III) C _1-6 alkyl 5 to 9 optionally containing 1 to 3 (preferably 1 or 2) heteroatoms selected from the group consisting of oxygen and sulfur atoms in addition to the nitrogen atom, which may be substituted.
Member (preferably 6-membered) cyclic amino group, (IV) carboxyl group, (V) carbamoyl group and (VI) mono- or di-
Represents a substituent selected from the group consisting of a C _1-6 alkylcarbamoyl group; R ^a and R ^b bond together to form an A ring, and the A ring may be substituted with a C _1-6 alkyl group A 5- to 9-membered aromatic heterocycle (preferably a pyridine ring) containing 1 to 3 1 or 2 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom ) indicates; B ring is (i) hydroxy group optionally substituted by a C _1-6 alkyl group, including (ii) C _1-6 alkylcarbonyl group (formyl) and (iii) the group consisting of carboxyl group _{Represents a} C _6-14 aryl group (preferably a benzene ring) which may be substituted with a substituent selected from the group _consisting of (i) a halogen atom and (ii) an optionally halogenated C _{1- 10} alkyl groups and (iii) C _1-10
A C _6-14 aryl group (preferably a benzene ring) which may be substituted with 1 to 3 substituents selected from the group consisting of alkoxy groups; and Z ring is (i) a C _1-6 alkyl group , (Ii) hydroxy group, and (iii) oxo group, which may be substituted with 1 to 3 substituents, may be a nitrogen atom, an oxygen atom, and a sulfur atom in addition to Y and the nitrogen atom. Preferred is the case where it represents a 5- to 12-membered heterocycle optionally containing at least one heteroatom selected from the group. The compound represented by the above formula (I) may form a salt, and when it is used as a medicine, the salt is preferably a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid, or acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, Succinic acid, citric acid, lactic acid, methanesulfonic acid,
Examples thereof include salts with organic acids such as p-toluenesulfonic acid, palmitic acid, salicylic acid and stearic acid.

The compound (I) or a salt thereof includes stereoisomers such as cis and trans isomers, racemates, and optically active forms such as R and S isomers. Further, depending on the size of the ring such as Z ring, an isomer due to conformation may be produced, and such an isomer is also included in the compound (I) or a salt thereof. The compound (I) or its salt may be a hydrate or a solvate.

[0059]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, the above formula (I
The compound represented by formula (I) or a salt thereof is produced by subjecting the compound represented by I) or a salt thereof to a cyclization reaction in a poor solvent. As the poor solvent used in the present invention, a solvent having a low solubility in the compound (I) as a product or a salt thereof, specifically, a solubility at 20 ° C. of about 0 to 15% (w / v), Preferably about 0.01-10
% (W / v) solvent is used. Examples of such a solvent include ethers such as diethyl ether, diisopropyl ether, dipropyl ether, dibutyl ether, tert-butyl methyl ether and diisopropyl methyl ether, and C such as pentane, hexane, cyclohexane, methylcyclohexane, heptane and dimethylcyclohexane. _2-8 non-aromatic hydrocarbons, C _6-8 aromatic hydrocarbons such as benzene, toluene, xylene and the like can be mentioned. Particularly, C _6-8 aromatic hydrocarbons such as toluene are preferable. The amount of the solvent used is, relative to compound (II),
The amount is about 1 to about 20 times (v / w), preferably about 1 to about 10 times (v / w). Addition of a base favors the reaction. Examples of such bases include inorganic bases (alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metals such as sodium carbonate and potassium carbonate). Alkali metal hydrides such as metal carbonates, sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide. Etc.) organic bases (trimethylamine, triethylamine, diisopropylethylamine,
Diazabicyclo- [2,2,2] -octane, quinuclidine, amines such as 1,8-diazabicyclo [5,4,0] -7-undecene, and pyridines). Especially for systems using aromatic hydrocarbons as solvent, the above alkoxides give suitable results. The amount of the base used is about 0.1 to about 3.0 molar equivalent, preferably about 0.8 to about 2.0 molar equivalent. The reaction temperature is about 0 ° C to the boiling point of the solvent, preferably room temperature (about 20 ° C. The same applies hereinafter) to about 70 ° C. Further, the reaction temperature may be raised stepwise. The target product can be directly obtained as crystals from the reaction solution. Alternatively, a solvent or water may be added for crystallization. The solvent to be added may be any solvent as long as it reduces the solubility and facilitates crystallization. The addition amount is about 0.1 to about 10 times (v / w), preferably about 0.1 to about 5 times (v / w), with respect to the solvent used. By separating the target substance in this manner, complicated operations such as extraction, washing, and concentration, which are general methods, are unnecessary. In addition, among compound (I) or a salt thereof, (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,1
1-Tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-g]
[1,7] naphthyridine-6,13-dione (Example 1
Compound) is usually added as a recrystallization solvent from a general solvent, and a small amount of crystals (A type crystal and B type crystal) having different crystal forms are added by a method known per se before the crystals are precipitated. It is possible to produce crystals having different crystal forms (A-type crystal and B-type crystal). Examples of such a crystallization method include crystallization from a solution. As the method of "crystallization from solution",
For example, a concentration method, a cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a flux method and the like can be mentioned. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane etc.), nitriles (eg acetonitrile etc.), ketones (eg acetone etc.), sulfoxides (eg dimethyl sulfoxide etc.), acid amides Examples thereof (eg, N, N-dimethylformamide etc.), esters (eg ethyl acetate etc.), alcohols (eg methanol, ethanol, isopropyl alcohol etc.), water etc. are used. These solvents may be used alone or in an appropriate ratio of two or more kinds (eg, 1: 1 to 1:10).
0) and mixed. Preferably ethanol,
Methanol, isopropyl alcohol, hexane, heptane, diisopropyl ether, ethyl acetate, water, etc. are used, and these solvents may be used alone or in admixture of two or more kinds at an appropriate ratio (eg, 1: 1 to 1: 100). Used. As a method for analyzing two types of crystal forms, X
Crystal analysis and thermal analysis methods by line diffraction are common.
The A-type crystal was analyzed by powder X-ray crystal diffraction to obtain a diffraction angle (2θ).
(°)) About 9.5, about 9.7, about 12.0, about 12.6,
About 12.9, about 13.4, about 14.0, about 15.0, about 16.3, about 16.6, about 17.3, about 17.9, about 1
9.2, about 20.6, about 22.4, about 23.1, about 2
3.3, about 23.6, about 25.5, about 28.0, about 2
It shows a diffraction pattern having a characteristic peak at 8.3 °. By thermal analysis, the DSC curve shows an endothermic peak due to melting at around 234 ° C, and the TG curve shows no weight change up to around 250 ° C. The data of powder X-ray crystal diffraction of the A-type crystal are shown in Table 1, and the powder X-ray crystal diffraction pattern is shown in FIG.

[Table 1] The B-type crystal was analyzed by powder X-ray diffraction to obtain a diffraction angle (2θ).
(°)) About 10.7, about 11.6, about 13.8, about 15.
0, about 17.0, about 17.4, about 17.7, about 18.
9, about 19.0, about 20.1, about 20.6, about 21.
4, about 22.3, about 23.0, about 23.2, about 23.
6 shows a diffraction pattern having characteristic peaks at 6, about 24.6, about 27.3, and about 31.8 °. According to the thermal analysis, the DSC curve shows an endothermic peak near 207 ° C. and then an endothermic peak due to melting around 234 ° C.
The curve shows no weight change up to around 250 ° C. The data of powder X-ray crystal diffraction of the B-type crystal are shown in Table 2, and the powder X-ray crystal diffraction pattern is shown in FIG.

[Table 2] Crystals separated directly from the reaction solution may form a solvate. In particular, when toluene is used as a solvent, it becomes a toluene solvate, and related substances can be advantageously removed. The solvate crystals can be desolvated by drying under heating and reduced pressure, and can be easily purified by a general recrystallization method.

The compound (II) to be subjected to the ring closure reaction is described in JP-A-9-
-263585 (European Patent Application Publication No. 73363)
Although it can be produced by the production method described in No. 2),

[Chemical Formula 39] Is -CO-N- and the ring A is a heterocycle (II
The a) can also be produced by the method shown in the following reaction scheme.

[Chemical 40] [In the formula, R ¹ represents a hydrocarbon group which may have a substituent,
Other symbols have the same meanings as described above. ]

Step 1 is a step in which compound (IV) is produced by subjecting compound (III) to a dehydration reaction.
The compound (IV) can be produced by dehydrating the compound (III) by heating, but an acid may be added to accelerate the reaction. It can also be produced by way of a mixed acid anhydride or acid halide.
Examples of the acid to be added include general mineral acids and organic acids. Method via mixed acid anhydride, trifluoroacetic anhydride,
Carboxylic anhydrides such as acetic anhydride, ethyl chlorocarbonate,
There is a method of adding a halocarbonic acid ester such as benzyl chlorocarbonate and tert-butyl chlorocarbonate. The solvent is not particularly limited as long as it does not react with the acid anhydride that is the product. For example, non-aromatic hydrocarbons, aromatic hydrocarbons, ethers or carboxylic acids, carboxylic acid anhydrides and the like are used. As the non-aromatic hydrocarbons, aromatic hydrocarbons and ethers, the above-mentioned compound (I)
Examples of the solvent that can be used in the production of Examples of the carboxylic acids include C1 to C4 versatile carboxylic acids such as formic acid, acetic acid, propionic acid, and butyric acid. Examples of carboxylic acid anhydrides include acetic anhydride and propionic anhydride. The amount of solvent used is about 1 to about 10 times (v / w) of the starting material. Especially about 1 to about 5
Double amount (v / w) is preferred. The reaction temperature is from room temperature to about 1
It is 50 ° C, preferably about 60 to about 110 ° C. The reaction time is about 0.5 to about 24 hours, preferably about 0.5 to
It is about 10 hours.

Step 2 is the step of reacting the compound (IV) with the formula

[Chemical 41] [The symbols in the formulas have the same meanings as described above. ] The compound (V) is produced by subjecting a compound represented by the formula [1] to a Friedel-Crafts reaction in the presence of a Lewis acid under a catalyst of a Lewis acid. Or the expression

[Chemical 42] [In the formula, X represents a halogen atom (for example, chlorine, bromine, iodine, etc.), and B represents the same meaning as described above. ] It is the process of manufacturing the compound (V) by reacting a halide represented by the above formula with metallic magnesium to obtain a Grignard reagent, and subjecting this to a general Grineer reaction with the compound (IV). As a solvent for the Grineer reaction, diethyl ether, diisopropyl ether, tert-butyl methyl ether,
Ethers such as tetrahydrofuran are used. The amount of the solvent used is about 1 to about 15 with respect to compound (IV).
Double amount (v / w), preferably about 2 to about 10 times amount (v
/ W). It is preferable to add organic amines to the Grignard reagent or the substrate solution. Examples of organic amines include trimethylamine, triethylamine, diisopropylmethylamine, N-methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N,
N, N ', N'-tetramethylethylenediamine, diazabicyclo- [2,2,2] -octane, quinuclidine,
Chain-like or cyclic tertiary amines such as 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine, 4
-Pyridines such as dimethylaminopyridine and the like. The amount of organic amines used is about 0.1 with respect to the substrate.
To about 5 molar equivalents, preferably about 0.1 to about 3 molar equivalents. The Grineer reaction temperature is about 10 ° C or less, preferably about -5 to about 10 ° C. To the reaction-completed liquid, water is added, and the desired product is obtained by a method such as extraction and washing, crystallization and the like. Generally, the solvent is concentrated, the extraction solvent is added and dissolved,
The target product can be obtained by subjecting the extract to a concentration crystallization operation. The extraction efficiency can also be adjusted by adjusting the pH.
The pH depends on the compound, but is around 0 to 7. The extraction solvent is
Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane are preferred, but C4 to C8 alcohols or ketones give similar results.

When the ring A is a heterocyclic ring containing a nitrogen atom, it can be easily isolated as an acid salt from the extract by omitting the concentrated crystallization operation. Examples of the acid include halogen acids such as hydrochloric acid, chlorous acid, chloric acid, perchloric acid and hydrobromic acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and mineral acids such as sulfuric acid and nitric acid. . The acid is used in an amount of about 0.5 to about 5 molar equivalents relative to the substrate, preferably about 1 to about 2
Used in molar equivalents. The acid salt thus obtained can be reacted with a base to obtain a free form. The base is
Hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate,
Trimethylamine, triethylamine, diisopropylmethylamine, N-methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N, N, N ',
Examples thereof include tertiary amines such as N′-tetramethylethylenediamine, diazabicyclo- [2,2,2] -octane and quinuclidine, and pyridines such as pyridine and substituted pyridines.

Step 3 is a step of reacting the compound (V) with the formula

[Chemical 43] [The symbols in the formulas have the same meanings as described above. ] Is a step of producing a compound (VI) by reacting the compound represented by the above or a salt thereof in the presence of a base to undergo an esterification reaction. Any general solvent may be used. Further, the base includes hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, trimethylamine, triethylamine, diisopropylmethylamine, N. -Methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N,
Examples thereof include tertiary amines such as N, N ′, N′-tetramethylethylenediamine, diazabicyclo- [2,2,2] -octane and quinuclidine, and pyridines such as pyridine and substituted pyridines. The compound (VI) thus obtained may be isolated by a general method, but can also be used in the next step without isolation.

Alternatively, the step 3 comprises the step of reacting the compound (V) with the formula

[Chemical 44] [The symbols in the formulas have the same meanings as described above. The compound (VI) can also be produced by reacting the compound represented by the above formula or a salt thereof with an esterification reaction. Any general solvent may be used. In this case, the compound (VI) can be obtained by using a general condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Alternatively,
Compound (V) is converted to an acid halide using thionyl chloride or oxalyl chloride, and then compound 2 represented by the formula
It can also be produced by a condensation reaction with a hydroxymalonic acid diester. For esterification from the acid halide, this reaction proceeds predominantly if a base is added. The acid halide of compound (V) can be prepared by a general method. At this time, as the solvent, an alkyl halide is generally used, but hydrocarbons such as hexane, cyclohexane, methylcyclohexane and heptane or aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, It can also be adjusted by using ethers such as tetrahydropyran. As the base, sodium hydroxide, potassium hydroxide, hydroxides such as calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, carbonates such as potassium hydrogen carbonate, trimethylamine, triethylamine,
Diisopropylmethylamine, N-methylpyrrolidine,
Tertiary amines such as N-methylpiperidine, N, N'-dimethylpiperazine, N, N, N ', N'-tetramethylethylenediamine, diazabicyclo- [2,2,2] -octane and quinuclidine, pyridine, substituted pyridine Examples include pyridines and the like. The compound (VI) thus obtained may be isolated by a general method, but can also be used in the next step without isolation.

Step 4 is a step of producing compound (VII) by subjecting compound (VI) to a ring closure reaction in the presence of a base. Any general solvent may be used.
Examples of the base include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, trimethylamine, triethylamine, diisopropylmethylamine and N-methyl. Pyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N,
N, N ', N'-tetramethylethylenediamine, diazabicyclo- [2,2,2] -octane, quinuclidine,
Chain-like or cyclic tertiary amines such as 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine, 4
-Pyridines such as dimethylaminopyridine and the like. The amount of the base used is approximately 0.1 to approximately 6 molar equivalents, preferably approximately 0.5 to approximately 3.5 molar equivalents, with respect to compound (VI). The reaction temperature is about -10 ° C to the boiling point of the solvent, preferably about 10 to about 40 ° C. The reaction time is about 0.5 to about 10 hours, preferably about 1 hour to about 6 hours.
It's time.

Step 5 is a step of producing compound (VIII) by hydrolyzing and decarboxylating compound (VII). Any general solvent may be used. In particular, it is preferable to use carboxylic acids such as acetic acid, aromatic hydrocarbons such as benzene, toluene and xylene, and C6-C8 hydrocarbons such as hexane, cyclohexane, heptane and methylcyclohexane. The amount of the solvent used is about 1 to about 20 times (v / w) the substrate, preferably about 1
Is about 10 times (v / w). The reaction temperature is about 80-
It is about 110 ° C. The reaction time is about 1 hour to about 24 hours. Furthermore, the reaction is accelerated when a mixed solution with a mineral acid such as hydrochloric acid or sulfuric acid is used. The mineral acid used is about 0.1 to about 3 times the amount of acetic acid (v / w), especially about 0.5 to about 1.5.
Double amount (v / w) is preferred.

In step 6, compound (VIII) and the formula H ₂ N-D-L [wherein the symbols have the same meanings as described above]. ] It is the process of reacting with the compound represented by these, and manufacturing a compound (IX). Any general solvent may be used. Particularly, halogenated hydrocarbons, ethers, aromatic hydrocarbons and alcohols are preferable. The solvents may be mixed and used. The amount of the solvent used is about 1 to 20 times (v / w), preferably about 5 to 10 times (v / w) the substrate. Good results are obtained by adding a base to the reaction. Examples of the base to be added include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, trimethylamine, triethylamine and diisopropyl. Chain-like or cyclic tertiary amines such as methylamine, methylpyrrolidine, methylpiperidine, dimethylpiperazine, tetramethylethylenediamine, 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine, 4-dimethylamino Examples include pyridines such as pyridine. The reaction temperature is
About 0 ° C. to about 70 ° C., preferably about 10 ° C. to about 40 ° C.
℃. The reaction time is about 0.5 to about 24 hours, preferably about 0.5 to about 6 hours. The reaction solution is concentrated,
Although depending on the target compound, the target product can be obtained by adjusting the pH.

Step 7 is a step of converting compound (VIII) to a compound of formula (III) via thionyl chloride, oxalyl chloride, etc.

[Chemical formula 45] [The symbols in the formulas have the same meanings as described above. ] It is the process of manufacturing a compound (X) by carrying out a condensation reaction with the amine compound represented by these. As the solvent for acid halogenation, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and the like are generally used, but aromatic hydrocarbons such as benzene, toluene and xylene, diisopropyl ether, tetrahydrofuran and tetrahydropyran. Ethers such as can also be used. The amount of the solvent used is about 1 to about 15 with respect to compound (VIII).
Double amount (v / w), preferably about 5 to about 10 times amount (v
/ W). The reaction temperature is room temperature to about 150 ° C, preferably about 80 to about 130 ° C. The reaction time is about 30
Minutes to about 10 hours, preferably about 1 to about 5 hours. After completion of the reaction, the solvent is concentrated to obtain an acid halide of compound (VIII). This is the formula

[Chemical formula 46] [The symbols in the formulas have the same meanings as described above. ] The compound (X) is obtained by reacting with an amine compound represented by Adding a base to the reaction can drive the reaction predominantly. Examples of the base include trimethylamine, triethylamine, diisopropylmethylamine, N-methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N, N, N ', N'-tetramethylethylenediamine, 1,8-diazabicyclo [ Examples thereof include linear or cyclic tertiary amines such as 5,4,0] -7-undecene and pyridines such as pyridine and substituted pyridines.
The amount of the base used is approximately 0.1 to approximately 6 molar equivalents, preferably approximately 0.5 to approximately 3.5 molar equivalents, relative to compound (VIII). The compound (X) can also be produced by using a general active esterification method and a condensing agent.

Step 8 is a step of reacting the compound (IX) with the formula

[Chemical 47] [The symbols in the formulas have the same meanings as described above. ] It is the process of manufacturing a compound (IIa) by making it react with the amine compound represented by this. The solvent, reaction temperature, and reaction time are the same as in step 7.

In step 9, compound (X) and formula H ₂ N-D-L [wherein the symbols have the same meanings as described above]. ] The compound (IIa) is produced in two steps by reacting with a compound represented by A common solvent is used. In particular, ethers and aromatic hydrocarbons are preferable. The reaction temperature in the first step is about 10 to about 70 ° C., preferably room temperature to about 60 ° C. The reaction time is about 0.5 to about 4
8 hours, preferably about 1 to about 24 hours. The adduct thus obtained can be isolated and purified, but can be subjected to the next reaction without isolation. The second step reacts in the presence of a base. Examples of the base include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, trimethylamine, triethylamine, diisopropylmethylamine, N- Methylpyrrolidine, N-methylpiperidine,
Chain-like or cyclic tertiary amines such as N, N'-dimethylpiperazine, N, N, N ', N'-tetramethylethylenediamine and 1,8-diazabicyclo [5,4,0] -7-undecene, Pyridines such as pyridine and 4-dimethylaminopyridine are exemplified.

[Chemical 48] [G in the formula represents a protecting group. Other symbols have the same meanings as described above. Steps 10 to 12 are methods for producing IIa by deprotecting the IIa precursor, the protecting group G, and introducing the leaving group L.

In step 10, compound (VIII) and the formula H ₂ N-D-O-G [wherein G represents a protecting group. Other symbols have the same meanings as described above. ] By reacting with a compound represented by the formula

[Chemical 49] [G in the formula represents a protecting group. Other symbols have the same meanings as described above. ] It is the process of manufacturing the IIa precursor represented by these. The solvent, reaction temperature, and reaction time are the same as in step 9.

Step 11 comprises the step of deprotecting the protecting group G of the IIa precursor by the formula

[Chemical 50] [The symbols in the formulas have the same meanings as described above. ] Is a process of manufacturing. The deprotection method is performed according to the deprotection method of the protecting group.

Step 12 is a step of introducing the leaving group L into the OH group of the compound (XII) by a conventional method.
This is a step of manufacturing a. As the leaving group L, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoroacetoxy and the like are common. Any solvent may be used as long as it is usually used, but halogenated hydrocarbons, ethers, pyridines, esters and the like are particularly used. The reaction proceeds predominantly if a base is added to the system. Examples of the base include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, trimethylamine, triethylamine, diisopropylmethylamine, N- Methylpyrrolidine, N-methylpiperidine, N, N'-dimethylpiperazine, N, N, N ', N'-tetramethylethylenediamine, 1,8-diazabicyclo [5,4,0]-
Examples thereof include linear or cyclic tertiary amines such as 7-undecene, pyridines such as pyridine and 4-dimethylaminopyridine. The amount of the solvent used is about 1 to about 20 times (v / w), preferably about 1 to about 10 times (v / w) the substrate. The reaction temperature is about 0 ° C to the boiling point of the solvent, preferably about 0 ° C to about 50 ° C. The reaction time is about 0.5 hour to about 48 hours, preferably about 0.5 hour to about 12 hours. The product of each step described above can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[0075]

EXAMPLES The present invention will be described below with reference to reference examples and examples, but the present invention is not limited thereto. Reference example 1

[Chemical 51] Kolben was charged with 280 g of 2,3-pyridinedicarboxylic acid, 205 g of acetic anhydride and 420 g of acetic acid, and the mixture was stirred at an internal temperature of about 85 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure and the solvent was distilled off. After adding 600 g of toluene to the concentrated residue, the mixture was stirred at an internal temperature of about 5 ° C for 1 hour. The crystals were filtered and then washed with 120 g of toluene. Wet crystals were dried at 60-70 ℃ under reduced pressure to give the desired product 231.6g Yield 9
Obtained at 2.7%.

Reference Example 2 Kolven was charged with 280 g of 2,3-pyridinedicarboxylic acid, 180 g of acetic anhydride [1.05 eq] and 364 g of toluene, and the internal temperature was about 95.
The reaction was carried out at ℃ for about 5 hours. The reaction solution was concentrated under reduced pressure and the solvent was distilled off. After adding toluene 242 g [1.0 v / w] to the concentrated residue,
The mixture was stirred at an internal temperature of about 5 ° C for 1 hour. After filtering the crystals, toluene 1
It was washed with 20 g [0.5 v / w]. The wet crystals were dried under reduced pressure at about 65 ° C. to obtain 234.8 g of the desired product in 94% yield.

Reference Example 3 3- (4-methylbenzoyl)
-2-Pyridinecarboxylic acid

[Chemical 52] Magnesium in Kolben under nitrogen atmosphere 45.3 g [1.2 e
q], tetrahydrofuran 1334 g, iodine 54.4 mg,
Stir at an internal temperature of 30-40 ° C. A mixture of 318.8 g [1.2 eq] of p-bromotoluene and 51 g of tetrahydrofuran was added dropwise at an internal temperature of 35 to 45 ° C. After the completion of dropping, the mixture was stirred at an internal temperature of 35 to 45 ° C for about 1 hour. In another Kolben under a nitrogen atmosphere, 231.6 g of anhydrous pyridinedicarboxylic acid, 824 g of tetrahydrofuran [4 v / w PA
N], N, N, N ', N'-tetramethylethylenediamine
216.6 g [1.2 eq] was added and stirred. After cooling to an internal temperature of 0 ° C or lower, drop the previously prepared Grineer reagent while maintaining the internal temperature of 5 ° C or lower, and stir at an internal temperature of 0-5 ° C for about 1 hour, then water 463
g [2 v / w PAN] was added dropwise. The solvent was distilled off under reduced pressure. 2-Butanone (746 g [4 v / w PAN]) was added to the residue and stirred to dissolve, then 307 g of water and concentrated hydrochloric acid were added to adjust the pH to 1.7, and the mixture was stirred. did. The water layer is 2-butanone 373g [2
v / w PAN] three times. Combine the organic layers and water 232 g [1 v
/ w PAN] and washed twice. The organic layer was concentrated under reduced pressure. 2-butanone 186 g [1 v / w PAN] and toluene 802 g [4 v / w in the concentrate
PAN] and isopropyl ether 1007 g [6 v / w PAN] were added and precipitated, and then dispersed at an internal temperature of about 5 ° C for 1 hour. The crystals were collected by filtration and washed with 115 g of isopropyl ether. The target product is obtained by drying the wet crystals under reduced pressure at an internal temperature of 60 ° C or lower.122.
2 g was obtained with a yield of 32.6%.

Reference Example 4 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid 45.3 g [1.2 e of magnesium in colben under nitrogen atmosphere
q], tetrahydrofuran 453g [2.2v / w PAN], iodine 54.4
mg was added, and the mixture was stirred at an internal temperature of about 35 ° C. P- at an internal temperature of about 40 ° C
Bromotoluene 318.8 g [1.2 eq] and tetrahydrofuran 6
A mixed solution of 2 g [0.3 v / w PAN] was added dropwise. After completion of dropping, the mixture was stirred at an internal temperature of about 45 ° C for about 1 hour. N, N, N ', N'-tetramethylethylenediamine 10 at an internal temperature of about 35 ° C with slow cooling
8.3 g [0.6 eq] was added. Under a nitrogen atmosphere, add another pyridine to anhydrous pyridinedicarboxylic acid 231.6 g, tetrahydrofuran
824 g [4 v / w PAN], N, N, N ', N'-tetramethylethylenediamine 108.3 g [0.6 eq] are added and stirred, and the internal temperature is 0 ° C.
After cooling to below, the previously prepared Grineer reagent was added dropwise while being kept at 5 ° C or lower. After stirring at an internal temperature of 0-5 ° C for about 1 hour, 463 g of water [2 v / w PAN] was added. Internal temperature of reaction liquid 40 ℃
It concentrated under reduced pressure below. (The content is about 1246g). 2-Butanone (746 g [4 v / w PAN]) was added to the residue and stirred to dissolve it. Then, 307 g (1.3 v / w PAN) of water and concentrated hydrochloric acid were added to adjust the pH to around 1.7, and the mixture was left to stand to separate liquids. After that, the organic layer was separated. Water layer
2-butanone was extracted with 373 g [2 v / w PAN], and further extracted with 2-butanone 187 g [1 v / w PAN] twice. After collecting the collected organic layers and cooling the internal temperature to 10 ° C or lower, concentrated sulfuric acid 152.4g [1.0eq
PAN] was added dropwise at an internal temperature of 20 ° C or lower. After confirming crystal precipitation,
The mixture was stirred at room temperature for about 1 hour and aged at an internal temperature of 5 ± 5 ° C for about 1 hour.
The crystals were collected by filtration and washed with 2-butanone [0.5 v / w PAN] to obtain the desired sulfate. A part of this crystal was taken, dried, and then subjected to elemental analysis to confirm that it corresponded to a 1: 1 compound. C ₁₄ H ₁₃ NO ₇ S: Calcd. C49.55, H3.86, N4.13, S9.4
5 Found C49.26, H3.80, N4.09, S9.74. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 2.38 (3H, s), 7.34 (2
H, d, J = 8.0Hz), 7.56 (2H, d, J = 8.1Hz), 7.74 (1H, m),
7.93 (1H, m), 8.82 (1H, m) Water 1390g [6v / w PAN] was added to the target sulfate, and the internal temperature was 15-25.
A sodium hydroxide aqueous solution (solution having a ratio of NaOH 52.8 g and water 463 g) was added dropwise at 0 ° C. to adjust the pH of the crystallized liquid to 2.9, and after completion of the dropwise addition, the mixture was stirred at room temperature for about 1 hour. The crystals were collected by filtration, the crystallized liquid was filtered, and the crystals were washed with 463 g of water [2 v / w PAN]. Internal temperature of wet crystals
143.2g Yield 3
Obtained at 8.2%.

Reference Example 5 2-hydroxy-2- [5-
(4-Methylphenyl) -7-oxo-5,7-dihydrofuro [3,4-b] pyridin-5-yl] malonic acid
Diethyl ester

[Chemical 53] In Kolven, 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid 122.2g, tetrahydrofuran 543g [5 v /
w MPA], 1.2 g of N, N-dimethylformamide was added and stirred, and 90.4 g of thionyl chloride was added at an internal temperature of 40 ° C or lower.
Was added dropwise, the mixture was stirred at an internal temperature of 55-60 ° C., reacted for about 1 hour, and then the reaction solution was concentrated under reduced pressure. 220 g of ethyl acetate [2
v / w MPA] was added, and the mixture was concentrated to dryness under reduced pressure again. Acetonitrile 288 g [3 v / w MPA] was added to the concentrated residue, and diethyl hydroxymalonate (107.09 g (pure amount)) and pyridine 108.2 g were added at an internal temperature of 30 ° C. or lower. The mixture was stirred at an internal temperature of 25-30 ° C and reacted for about 2 hours. Cool to an internal temperature of 10 ° C or lower, and add triethylamine 15
3.8 g [3.0 eq] was added at an internal temperature of 20 ° C or lower. The mixture was stirred at an internal temperature of 15-30 ° C and reacted for about 3 hours. Cool down to below 15 ℃, 90%
158.6 g of acetic acid was added at an internal temperature of 20 ° C or lower. The mixture was concentrated under reduced pressure at an internal temperature of 50 ° C or lower, and the solvent was distilled off. The residue was dissolved in 242 g of methanol, and 306 g of water [2.5 v / w MPA] was added dropwise to cause precipitation. Inner temperature 5
The mixture was cooled to ± 5 ° C and stirred for 1 hour. The crystals were collected by filtration and washed with 112 g of cold 50% water-containing methanol. The wet crystals were dried under reduced pressure at 60 ° C. or lower to obtain 158.8 g of the desired product in a yield of 78.5%.

Reference Example 6 2-hydroxy-2- [5-
(4-Methylphenyl) -7-oxo-5,7-dihydrofuro [3,4-b] pyridin-5-yl] malonic acid
Diethyl ester Kolben with 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid 122.2 g, toluene 317 g [3 v / w MPA], N,
When 1.2 g of N-dimethylformamide was added and stirred, 72.3 g of thionyl chloride was added dropwise at an internal temperature of 40 ° C or lower. The internal temperature was stirred at 55-60 ° C and the reaction was performed for about 1 hour. The reaction solution was concentrated under reduced pressure. 220 g [2 v / w MPA] of ethyl acetate was added to the residue, and the mixture was concentrated to dryness under reduced pressure. 288 g of acetonitrile in the concentrated residue
[3 v / w MPA] was added, and diethyl hydroxymalonate (107.09 g (pure amount)) and pyridine (108.2 g) were added at an internal temperature of 30 ° C or lower. The mixture was stirred at an internal temperature of 25-30 ° C and reacted for about 2 hours. Cool the internal temperature to 10 ℃ or below and add 153.8 g [3.0 eq] of triethylamine to the internal temperature of 20
Added below ℃. The mixture was stirred at an internal temperature of 15-30 ° C and reacted for about 3 hours. Cool to an internal temperature of 15 ° C or below and add 158.6 g of 90% acetic acid to an internal temperature of 20
Added below ℃. The mixture was concentrated under reduced pressure at an internal temperature of 50 ° C or lower. Dissolve the residue in 145 g [1.5 v / w MPA] of methanol and 183 g of water [1.5
v / w MPA] was added dropwise to deposit. The internal temperature was cooled to 5 ± 5 ° C, and the mixture was stirred for about 1 hour. The crystals were collected by filtration, and 50% cold water-containing methanol 1
The crystals were washed with 12 g [1 v / w]. The wet crystals were dried under reduced pressure at 60 ° C. or lower to obtain 174.4 g of the desired product in a yield of 86.2%.

Reference Example 7 5- (4-methylphenyl)-
8-oxo-8H-pyrano [3,4-b] pyridine-6
-Carboxylic acid

[Chemical 54] In Kolben, 2-hydroxy-2- [5- (4-methylphenyl) -7-oxo-5,7-dihydrofuro [3,
4-b] Pyridin-5-yl] malonic acid diethyl ester 158.8 g, acetic acid 167 g [1 v / w MPD] and concentrated hydrochloric acid 189 g were charged, and the mixture was stirred at an internal temperature of 90 to 105 ° C. and reacted for about 7 hours. The reaction solution was concentrated under reduced pressure. Isopropyl alcohol 12 in concentrated residue
After adding 5 g [1 v / w MPD], drop 159 g of water and adjust the internal temperature to 5 ± 5
The mixture was cooled to ℃ and stirred for 1 hour. Crystals are collected by filtration and water 80g [0.5
The crystals were washed 3 times with v / w MPD]. The crystals were further washed with 48 g of 40% hydrous isopropyl alcohol. External temperature of wet crystals 50 ℃
The product was dried under reduced pressure at 105.3 g to give 95.3% of the desired product.

Reference Example 8 N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-methylphenyl)
-8-oxo-8H-pyrano [3,4-b] pyridine-
6-carboxamide

[Chemical 55] In Kolben, 5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxylic acid 105.3 g, toluene 842 g [8 w / w MPC], N, N-dimethyl Formamide 0.5g and thionyl chloride 89.1g [2.0 eq] were added and stirred. The mixture was stirred at an internal temperature of 100 ± 10 ° C and reacted for about 2 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. Toluene 365 g [4 v / w MPC] was added to the residue, and the mixture was concentrated under reduced pressure to dryness. 1400 g of ethyl acetate was added to the concentrated residue, and the mixture was cooled to 5 ° C or lower. At an internal temperature of 3 ± 5 ° C, 100.0 g of 3,5-bis (trifluoromethyl) benzylamine was added, and triethylamine 4
1.7 g [1.1 eq] was added dropwise. The mixture was stirred at an internal temperature of 3 ± 5 ° C. About 1
Reacted for hours. After confirming the completion of the reaction, concentrated hydrochloric acid 85.5 g and water 394 g
The mixed solution of was dropped. Next, tetrahydrofuran 936g [10
v / w MPC] was added. Stir for about 5 minutes at an internal temperature of 30 ± 10 ℃,
After the stationary separation, the aqueous layer was removed. 42 g of normal salt and 396 g of water in the organic layer
Was added and the mixture was stirred for about 5 minutes, and after standing to perform liquid separation, the aqueous layer was removed. Water (396 g) was added to the organic layer, and the mixture was stirred for about 5 minutes. The organic layer was concentrated under reduced pressure at an internal temperature of 50 ° C or lower,
Acetonitrile 497g [6 v / w MPC] and water 158g [1.5
v / w MPC] was added and dissolved by heating, and then slowly cooled to crystallize. After sufficient crystallization, isopropyl ether 76
g [1 v / w MPC] was added dropwise. Then, at an internal temperature of 30 ± 10 ℃, water 474g
[4.5 v / w MPC] was added dropwise. Cool the crystallized solution to an internal temperature of 5 ± 10
The mixture was aged by stirring for 1 hour or more at ° C. The crystals are collected by filtration, 50
Crystals were washed with 188 g of cold hydrated acetonitrile (188 g [2 v / w MPC]). The wet crystals were dried under reduced pressure at an internal temperature of 60 ° C. or lower to obtain 167.6 g of the desired product in a yield of 88.4%.

Reference Example 9 N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-methylphenyl)
-8-oxo-8H-pyrano [3,4-b] pyridine-
5- (4-methylphenyl) -8-oxo-to 6-carboxamide colben
8H-Pyrano [3,4-b] pyridine-6-carboxylic acid
105.3 g, toluene 448 g [4.25 w / w MPC], N, N-dimethylformamide 0.5 g, thionyl chloride 57.9 g [1.3 e
q] was added and the mixture was stirred. The mixture was stirred at an internal temperature of 100 ± 10 ° C and reacted for about 3 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate (927 g) was added to the concentrated residue, and the mixture was cooled to 5 ° C or lower. Internal temperature 3 ± 5 ℃ 3,
5-bis (trifluoromethyl) benzylamine 100.0
g was added, and triethylamine 41.7 g [1.1 eq] was added dropwise.
The mixture was stirred at an internal temperature of 3 ± 5 ° C for about 1 hour. Concentrated hydrochloric acid 60 g and water 276 g
Was added dropwise, and then tetrahydrofuran 655 g [7 v /
w MPC] was added. The mixture was stirred at an internal temperature of 35 ± 5 ° C for about 5 minutes, and after standing to perform liquid separation, the aqueous layer was removed. Water (263 g) was added to the organic layer and the mixture was stirred for about 5 minutes. Water (263 g) was added to the organic layer and the mixture was stirred for about 5 minutes. The organic layer was concentrated under reduced pressure at an internal temperature of 50 ° C or lower. Acetonitrile 497 g [6 v / w MPC] and water 158 g [1.5 v / w MPC] were added to the residue, and the mixture was heated and dissolved, and then slowly cooled to crystallize. After sufficient crystallization, 76 g [1 v / w MPC] of isopropyl ether was added dropwise, and then 474 g [4.5 v / w MPC] of water was added dropwise at an internal temperature of 30 ± 10 ° C. The crystallized liquid was cooled and stirred at an internal temperature of 5 ± 10 ° C for about 1 hour. The crystals were collected by filtration, and 188 g of 50% cold water-containing acetonitrile [2 v /
w MPC] and the crystals were washed. The wet crystals were dried under reduced pressure at an internal temperature of 60 ° C. or lower to obtain 167.6 g of the desired product in a yield of 88.4%.

Reference Example 10 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-3-methylbutyl) -8-oxo-5- (4-Methylphenyl) -pyrido [3,4-
b] Pyridine-6-carboxamide

[Chemical 56] In Kolben, 167.6 g of N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide, Toluene 1160 g [8 v / w BMPC], (R) -3-methyl-4-tetrahydropyranyloxybutylamine 80.6 g (pure amount) prepared by reacting 3,4-dihydro-2H-pyran with a corresponding amino alcohol. ) Was added. The mixture was stirred at an internal temperature of 50-60 ° C for about 1 hour. 1,8-diazabicyclo [5,4.0] -7-undecene 65.5 g [1.3
eq] was added. The mixture was stirred at an internal temperature of 75-85 ° C for about 2 hours. Inner temperature 1
Cool the reaction mixture to 0 ° C or below, and add 298g of concentrated hydrochloric acid and 5m of methanol.
Added 30 g [4 v / w BMPC]. The mixture was stirred at an internal temperature of 50-60 ° C for about 2 hours. The inner temperature was cooled to about 30 ° C., the mixture was allowed to stand until the two layers were separated, and the hydrochloric acid / methanol layer was separated. To the toluene layer, 60 g of concentrated hydrochloric acid and 160 g of methanol [1.2 v / w BMPC] were added, and the mixture was stirred for about 5 minutes and then allowed to stand and separate to separate the toluene layer and the hydrochloric acid / methanol layer. The hydrochloric acid / methanol layers were combined and cooled to 5 ° C or lower with stirring, and while maintaining the internal temperature at 30 ° C or lower, an aqueous sodium hydroxide solution (NaOH 120 g / water 8 g
A solution (00 g ratio) was added dropwise to adjust the pH to 4.5-6.0. Methanol was distilled off under reduced pressure at an external temperature of 60 ° C or lower. 151g of ethyl acetate [1 v / w BMPC], 365g of isopropyl ether
[3 v / w BMPC] was added in that order and stirred at room temperature for 1 hour. The crystallized liquid was cooled and aged by stirring at an internal temperature of 0-10 ° C for 2 hours or more. The crystals were collected by filtration and 122 g of isopropyl ether [1 v / w B
The crystals were washed in the order of MPC] and 503 g of water [3 v / w BMPC]. Wet crystals were dried under reduced pressure at an internal temperature of 60 ° C or less to yield the desired product in an amount of 173.5g.
Obtained in a yield of 88.6%.

Reference Example 11 (R) -N- [3,5-bis
(Trifluoromethyl) benzyl] -7,8-dihydro-
5- (4-methylphenyl) -8-oxo-7- [4-
(4-Methylbenzenesulfonyloxy) -3-methylbutyl] -pyrido [3,4-b] pyridine-6-carboxamide

[Chemical 57] In Kolben, (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-
Hydroxy-3-methylbutyl) -8-oxo-5-
173.5 g of (4-methylphenyl) -pyrido [3,4-b] pyridine-6-carboxamide and 347 g of pyridine were added and stirred. P-toluenesulfonyl chloride 95.1 at an internal temperature of 0-10 ° C
After adding g [1.7 eq], the internal temperature was raised to 20-30 ° C, and the mixture was stirred for about 3 hours. 30 g of water was added dropwise at an internal temperature of 10 ° C or lower, and ethyl acetate 187
Add 0 g [12 v / w BHMP], then wash the organic layer 3 times with a mixture of 72 g of concentrated hydrochloric acid and 650 g of water [4 v / w BHMP] and twice with 694 g of water [4 v / w BHMP]. I went. The washed organic layer is filtered,
The filtrate was concentrated under reduced pressure. 620g ethyl acetate [4 v
/ w BHMP] was added and reconcentrated. Ethyl acetate was added to the concentrated residue to adjust the weight to about 540 g, and the mixture was stirred at room temperature. After confirming crystallization, 500 g of isopropyl ether [4 v / w BHMP] was added and stirred for about 30 minutes. Cool the crystallized solution to an internal temperature of 0-10 ° C and
The mixture was aged with stirring for an hour. The crystals were collected by filtration and washed with 250 g of isopropyl ether [2 v / w BHMP]. Wet crystal inside temperature 60
After drying under reduced pressure below ℃, the target product is 198.4g Yield 90.7%
Got with. ¹ H-NMR (300MHz, CDCl ₃ ) δ: 0.90 (3H, d, J = 6.5),
1.61-1.65 (2H, m), 1.70-1.90 (2H, m), 2.31 (3H, s), 2.
46 (3H, s), 3.70-3.90 (4H, m), 4.52 (2H, d, J = 5.99),
7.05-7.11 (2H, m), 7.20-7.25 (2H, m), 7.30-7.35 (2H,
m), 7.44-7.50 (1H, m), 7.55-7.66 (1H, m), 7.77-7.90 (6
H, m), 8,77-8.81 (1H, m)

Example 1 (aR, 9R) -7- [3,5
-Bis (trifluoromethyl) benzyl] -8,9,1
0,11-Tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-
g] [1,7] naphthyridine-6,13-dione

[Chemical 58] In Kolben, 130 mL of toluene and (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7- [4
60 g of-(4-methylbenzenesulfonyloxy) -3-methylbutyl] -pyrido [3,4-b] pyridine-6-carboxamide was charged and washed with 30 mL of toluene. Charge 9.28 g of sodium tert-butoxide and add 20 mL of toluene.
I washed it in. The reaction was performed at an internal temperature of about 50 ° C for about 1 hour. The mixture was further heated and stirred at an internal temperature of about 65 ° C for about 1 hour. After 18 mL of water was charged and the internal temperature was stirred at about 65 ° C for about 30 minutes, heating was stopped. Water (342 mL) was charged and cooled, and crystallization was performed at an internal temperature of 10 ° C or lower. After cooling to 7 ± 5 ° C and confirming crystal crystallization, 30 at the same temperature
Stirred for more than a minute. The crystals were collected by filtration, and ethanol-water (2:
The crystals were washed with 90 mL of the mixed solution of 8) to obtain wet crystals. (A part of this crystal was taken and dried, and then elemental analysis was conducted to confirm that the target substance: toluene corresponded to a 1: 1 compound. C ₃₇ H ₃₃ N ₃ O ₂ F ₆ : Calcd. C66 .76, H5.00, N6.
31, F17.12 Found C66.59, H4.81, N6.14, F17.28. ) The wet crystals were dried under reduced pressure at about 90 ° C to obtain 40.0 g of the desired product in a yield of 86.8%. (The elemental analysis of the target substance after drying was C ₃₀ H ₂₅ N ₃ O ₂ F ₆ : Calcd. C62.83, H4.39, N7.
33, F19.88 Found C63.81, H4.48, N7.29, F19.86. ) 40 g of crude crystals and 220 ml of ethanol were charged into Kolben, and the crystals were dissolved by heating to an internal temperature of about 35 ° C. with stirring. While stirring, 208 ml of purified water was added dropwise over about 50 minutes at an internal temperature of about 25 ° C. Then, crystals were precipitated. The crystallized liquid was cooled to about 5 ° C. and kept in that state for 1 hour. The crystals were collected by filtration and washed with 60 ml of a mixed solution of ethanol: water (2: 8). The obtained wet crystals were dried under reduced pressure by heating at 55 ° C to obtain the target product. Yield 36g Yield 90%

[0087]

INDUSTRIAL APPLICABILITY By the production method of the present invention, a tricyclic compound having a tachykinin receptor antagonistic action, a substance P receptor antagonistic action and the like and useful as a medicament for the prevention / treatment of frequent urination / urinary incontinence, etc. It can be produced simply and industrially advantageously.

[0088]

[Brief description of drawings]

1 is a powder X of a type A crystal of the compound obtained in Example 1. FIG.
The line crystal diffraction pattern is shown.

2 is a powder X of a B-type crystal of the compound obtained in Example 1. FIG.
The line crystal diffraction pattern is shown.

Claims (9)

[Claims] 1. The formula: [In the formula, M ring is a partial structure: As -N = C <, - CO- N < or -CS-N <heterocycle having; R ^a and R ^b or form a ring A bonded together, or the same or different and each represents a hydrogen atom or M
Substituent in the ring; A ring and B ring are the same or heterocycles each optionally having a substituent, at least one of which may have a substituent; C ring is a substituent A homocycle or a heterocycle which may have; n is an integer of 1 to 6; D and E are groups which form a Z ring with a nitrogen atom adjacent to E; and the Z ring includes an optionally substituted group. And nitrogen represents a leaving group. ] The compound represented by the formula or a salt thereof is subjected to a cyclization reaction in a poor solvent, and is represented by the formula: [The symbols in the formulas have the same meanings as described above. ] The manufacturing method of the compound or its salt represented by these. 2. The poor solvent is an aromatic hydrocarbon.
The manufacturing method described. 3. The method according to claim 1, wherein the poor solvent is toluene. 4. The method according to claim 1, wherein the cyclization reaction is carried out in the presence of a base. 5. The method according to claim 4, wherein the base is an alkoxide. 6. (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-5- (4-
Methylphenyl) -8-oxo-7- [4- (4-methylbenzenesulfonyloxy) -3-methylbutyl]-
The pyrido [3,4-b] pyridine-6-carboxamide is characterized by subjecting it to a cyclization reaction in a poor solvent (a
R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-
9-methyl-5- (4-methylphenyl) -7H-
Process for producing [1,4] diazocino [2,1-g] [1,7] naphthyridine-6,13-dione. 7. (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-
Hydroxy-3-methylbutyl) -8-oxo-5-
(R) -N- [3,5, characterized by reacting (4-methylphenyl) -pyrido [3,4-b] pyridine-6-carboxamide with p-toluenesulfonyl chloride.
-Bis (trifluoromethyl) benzyl] -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7-
[4- (4-methylbenzenesulfonyloxy) -3-
Methylbutyl] -pyrido [3,4-b] pyridine-6-
Method for producing carboxamide. 8. (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-5- (4-
Methylphenyl) -8-oxo-7- [4- (4-methylbenzenesulfonyloxy) -3-methylbutyl]-
Pyrido [3,4-b] pyridine-6-carboxamide. 9. (aR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-
Tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-g]
[1,7] naphthyridine-6,13-dione toluene solvate.