JP2000044560A - Benzoquinolizine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having an excellent antagonism against a tachykinin receptor and useful as a medical composition, a preventing agent or treating agent of dysuria, gastrointestinal disease, emesis, etc., comprising a specific benzoquinolizine derivative. SOLUTION: This compound is expressed by formula I [R1-R3 are each H or a 1-6C alkyl; ring A is 1-3 pieces of (substituted) allotropic ring or the like; ring B is 1-5 pieces of (substituted) benzene ring; ring C is 1-3 pieces of (substituted) benzene ring], e.g. 7-(2,4-dichlorophenyl)-2,3-dihydro-5-ortho-1H,5H- benzo[(i),(j)] quinolizine-6-carboxylic acid ethyl ester. The compound of formula I is obtained by subjecting a benzoquinolizine derivative of formula II (R4 is OH, a 1-6C alkoxy or the like), etc., to condensation reaction with a compound of formula III, etc., at 20-80 deg.C. As the condensation agent, dicyclohexylcarbodiimide, etc., is exemplified and added as a solid-like or a solution dissolved in a solvent. As the base, sodium hydrogencarbonate, etc., is exemplified.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel benzoquinolidine derivative having a tachykinin receptor antagonistic activity or a pharmacologically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition containing the benzoquinolidine derivative. Things.

[0002]

2. Description of the Related Art Tachykinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors (neurokinin 1 (NK ₁ ), neurokinin 2 (NK) ₂ ) It is known that various physiological activities are expressed by binding to neurokinin 3 (NK ₃ )). Among them, substance P acts as a transmitter of central and peripheral primary sensory neurons, and has physiological functions such as a diuretic enhancing action, a nerve cell excitatory action, a vascular permeability enhancing action, a vasodilatory action, a smooth muscle contracting action, and an immune action. It has activity and is considered to be deeply involved in various disease states (frequent urination, urinary incontinence, vomiting, inflammation, allergy, airway disease, pain, central nervous system disease, etc.). Therefore, development of a compound having excellent tachykinin receptor antagonistic activity, particularly a substance P receptor antagonistic activity, as well as excellent safety and long-lasting properties, as preventive and therapeutic agents for the above-mentioned various disease states is expected. It is rare. At present, the following compounds and the like have been disclosed as compounds having a substance P receptor antagonistic action.

(1) Japanese Patent Application Laid-Open No. 1-287095 discloses a formula: (Wherein, R ¹ is hydrogen or an amino protecting group, R ² is hydrogen, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R ³ is (Lower) alkyl group, -N
An (R ⁴ ) (R ⁵ ) group, wherein R ⁴ and R ⁵ are each hydrogen,
An aryl group or a lower alkyl group which may have a suitable substituent, R ⁴ and R ⁵ are bonded to each other to form a benzene condensed lower alkylene group), or —OR
⁶ groups (wherein R ⁶ represents hydrogen, an aryl group or a lower alkyl group which may have a suitable substituent), wherein A is a single bond or one or two amino acid residues. R ⁴ is not hydrogen when A represents one amino acid residue of D-Trp). ) And salts thereof are disclosed.

(2) Formulas described in EP-A-429366: Are disclosed.

(3) In WO 91/09844, the formula is: Are disclosed.

(4) EP-A-532456 has the formula: Are disclosed.

(5) EP-A-522808 describes the formula: Are disclosed.

(6) In WO 93/01169, the formula is: Are disclosed.

(7) JP-A-8-67678 discloses a formula:(Wherein ring A and ring B are homo or heterocyclic,
At least one is a heterocyclic ring; the C ring is a benzene ring;
A hydrogen hydride residue; one of X and Y is -NR¹− (R ¹Is H
Is a hydrocarbon residue) or -O-, and the other is -CO- or -C
S-, or one is -N =, the other is = CR²− (R²
Is H, halogen, hydrocarbon residue, amino group or hydroxy
N represents 1 or 2. ) Or a compound represented by
Discloses its salts.

(8) Japanese Patent Application Laid-Open No. 9-104467 describes a formula: (Wherein, X represents a hydrogen atom or an oxygen atom, Y represents a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ contains a hydrogen atom, a lower alkyl group, a lower alkanoyl group, and a nitrogen atom. Alkyl group, carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, (4-phenylpiperazine-1
-Yl) methyl group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkyl group containing a hydroxyl group, a lower alkanoyl group, or a lower alkoxy group. Rings A and B represent a benzene ring which may have a substituent. ) Is disclosed.

(9) JP-A-9-263587 describes the formula: (Wherein the M ring has a partial structure -X = Y <, -N = C
A heterocyclic ring having <, -CO-N <or -CS-N <;
^a and R ^b are linked together to form ring A, or are the same or different and are a hydrogen atom or a substituent on ring M;
Ring and ring B are each an optionally substituted homo- or heterocyclic ring, at least one of which is an optionally substituted heterocyclic ring; ring C may have an optionally substituted substituent; A good homo or heterocyclic ring; a ring Z is an optionally substituted ring; and n is an integer of 1 to 6. ) Is disclosed.

[0012]

At present, as a prophylactic or therapeutic agent for the above-mentioned various pathological conditions, it has an excellent antagonism to tachykinin receptor (particularly a substance P receptor antagonism), and its safety, No compound has been found that can be a sufficiently satisfactory pharmaceutical from the viewpoint of sustainability and the like. An object of the present invention is to provide a pharmaceutical composition having a superior antagonism to tachykinin receptors, particularly a substance P receptor antagonism, a tachykinin receptor antagonist, and urination, which have a different chemical structure from known compounds including the aforementioned compounds. An object of the present invention is to provide an agent for preventing or treating disorders, an agent for preventing or treating digestive organ diseases, and an agent for preventing or treating vomiting.

[0013]

Means for Solving the Problems The present inventors have the following general formula (1): (Wherein, R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring which may have a plurality of substituents which may combine with each other to form a ring), and the ring B has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof.

The present inventors have found that ring A is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group, C ₃ -C ₁₀ cycloalkoxy group, optionally substituted C ₁ -C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted An arylmethyloxy group, a C ₃ -C ₁₀ cycloalkanoyloxy group, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C ₁ -C ₆ alkylsulfinyl group, alkylsulfonyl groups of C ₁ -C ₆ optionally, an amino group, mono- or di-substituted alkyl amino group of C ₁ -C _6, also contain one to three hetero atoms 4-9 membered cyclic amino _group, alkylcarbonylamino group of C 1 ~C _6, C 1 ~C alkoxycarbonylamino group _6, C 1 -C alkylsulfonylamino group _6, optionally substituted arylsulfonyl Amino group, C ₁
-C ₆ alkylcarbonyl group, formyl group, carboxyl group, C ₁ -C ₆ alkoxycarbonyl group, mono- or di-substituted C ₁ -C ₆ alkylcarbamoyl group,
1 to 3 substituents each independently selected from a 4- to 9-membered cyclic carbamoyl group, cyano group or nitro group which may contain three heteroatoms (two adjacent substituents May be bonded to each other to form a ring), the ring B may be a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, C
Cycloalkyl group ₃ -C _10, optionally substituted aryl group, a hydroxyl group, an optionally substituted C
_{1 to} C ₆ alkoxy group, optionally substituted C ₁ to C ₆
C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ -C ₁₀ cycloalkoxy group, C ₃
Cycloalkanoyl group having -C _10, optionally substituted _C 1 -C ₆ alkylthio group, a substituted alkylsulfinyl group of _C 1 -C ₆ optionally, an optionally substituted _C 1 -C ₆ alkylsulfonyl group, an amino group, mono- or alkylamino group _C 1 -C ₆ di-substituted, 1-3 cyclic amino group having 4 to 9-membered may contain a hetero _atom, C 1 -C ₆ alkylcarbonylamino _group, an alkoxycarbonylamino group of C 1 -C _6, C
Alkylsulfonylamino group ₁ -C _6, which may be substituted arylsulfonylamino _group, C 1 -C ₆ alkylcarbonyl group, a carboxyl _group, an alkoxycarbonyl group having C 1 -C _6, mono- or di-substituted C alkylcarbamoyl group ₁ -C _6, 1-3 amino cyclic carbamoyl groups 4-9 membered may contain a hetero atom, and are each independently selected from among cyano group or a nitro group 1-3
A benzene ring which may have two substituents (adjacent two substituents may be bonded to each other to form a ring), and the C ring may be substituted with a halogen atom C
Alkyl group of ₁ -C _6, a hydroxyl group, a substituted C ₁ optionally -C ₆ alkoxy group, optionally substituted C ₁ -C ₆ alkanoyloxy group, optionally substituted aryloyl oxy group, an optionally substituted arylmethyl _group, C 3 _-C cycloalkoxy group _10, cycloalkanoyl group of C 3 _{-C 10,} an amino group, an alkyl of _C 1 -C ₆ mono- or di-substituted An amino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkoxycarbonylamino group,
₁ to 3 substituents independently selected from an alkylsulfonylamino group of ₁ to ₆ carbon atoms, an arylsulfonylamino group which may be substituted, a cyano group or a nitro group (two adjacent substituents) The benzoquinolidine derivative according to claim 1, wherein the benzoquinolidine derivative represents a benzene ring which may have a group wherein the groups may be bonded to each other to form a ring.

The present inventors have the following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R₄Is a hydroxyl group, C₁~ C₆An alkoxy group, benzylo
A xy group or a reactive residue, wherein ring A is a halogen atom,
May be C₁~ C₆An alkyl group of which is substituted
Aryl group, hydroxyl group, even if substituted
Good C₁~ C₆An alkoxy group of C₃~ C₁₀The cyclo
An alkoxy group, an optionally substituted C₁~ C₆Al
Canoyloxy group, optionally substituted aryloylo
Xyl group, optionally substituted arylmethyloxy
Group, C₃~ C₁₀A cycloalkanoyloxy group, substituted
C that may be₁~ C₆Alkylthio group, substituted
C that may be₁~ C₆An alkylsulfinyl group of
Optionally substituted C₁~ C₆Alkylsulfonyl of
Group, amino group, mono- or di-substituted C₁~ C₆The alkyl of
An amino group, optionally containing 1 to 3 heteroatoms 4
A 9-membered cyclic amino group, C₁~ C₆Alkyl carboni
Ruamino group, C₁~ C₆Of the alkoxycarbonylamino
Group, C₁~ C₆Alkylsulfonylamino group, substituted
An optionally substituted arylsulfonylamino group, C₁~ C
₆Alkylcarbonyl group, formyl group, carboxyl
Group, C₁~ C₆An alkoxycarbonyl group, mono or di
Substitution C₁~ C₆Alkylcarbamoyl group of 1 to 3
4 to 9-membered cyclic carba optionally containing a heteroatom
Independent of moyl, cyano or nitro groups
1 to 3 substituents (adjacent two substituents
May be bonded to each other to form a ring)
Optionally a homo- or heterocyclic ring, the C ring is a halogen atom,
C that may be₁~ C₆Alkyl group, hydroxyl
Group, optionally substituted C₁~ C₆An alkoxy group of
Optionally substituted C₁~ C₆Alkanoyloxy
Group, an optionally substituted aryloyloxy group,
An optionally substituted arylmethyloxy group, C₃~ C₁₀
A cycloalkoxy group of C₃~ C₁₀The cycloalkano of
Yloxy group, amino group, mono- or di-substituted C₁~ C₆
Alkylamino groups containing 1 to 3 heteroatoms
A 4- to 9-membered cyclic amino group, C₁~ C₆Archi
Carbonylamino group, C₁~ C₆The alkoxy carb
Nylamino group, C₁~ C ₆Of alkylsulfonylamino
Group, optionally substituted arylsulfonylamino
Group, cyano group or nitro group
1 to 3 substituents (adjacent two substituents are
To form a ring).
Benzene ring. Benzoquinolidine derivative represented by)
Provided is a conductor or a salt, hydrate and solvate thereof.

The present inventors have the following general formula (3)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C is a halogen atom
Child, optionally substituted C₁~ C₆An alkyl group of
A droxyl group, an optionally substituted C₁~ C₆Al
Coxy group, optionally substituted C₁~ C₆No alkano
Yloxy group, optionally substituted aryloyloxy
Group, an optionally substituted arylmethyloxy group, C
₃~ C₁₀A cycloalkoxy group of C₃~ C₁₀No shiku
Lower alkanoyloxy group, amino group, mono- or di-substituted
C₁~ C₆Alkylamino group, 1-3 heteroatoms
A 4- to 9-membered cyclic amino group optionally containing ₁~ C
₆An alkylcarbonylamino group of C₁~ C₆Arco
Xycarbonylamino group, C₁~ C₆Alkylsulfo
Nylamino group, arylsulfonyl which may be substituted
Each independently from the amino, cyano or nitro groups.
1 to 3 substituents selected vertically (two adjacent substituents
Groups may be bonded to each other to form a ring)
Represents an optionally present benzene ring. Benzoquino represented by)
Provide lysine derivatives or salts, hydrates and solvates thereof
You.

The present inventors have the following general formula (4)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
Residue, C ring is a halogen atom, C
₁~ C₆Alkyl group, hydroxyl group, substituted
May be C₁~ C₆An alkoxy group, even if it is substituted
Good C₁~ C ₆Alkanoyloxy group, substituted
An aryloyloxy group, an optionally substituted
Reel methyloxy group, C₃~ C₁₀Cycloalkoxy
Si group, C₃~ C₁₀A cycloalkanoyloxy group,
Amino group, mono- or di-substituted C1-C6 alkylamino
Group, 4 to 9 members optionally containing 1 to 3 heteroatoms
A cyclic amino group of C₁~ C₆Alkylcarbonylamido
No group, C₁~ C₆An alkoxycarbonylamino group of C
₁~ C₆Alkylsulfonylamino group, substituted
An arylsulfonylamino group, a cyano group or a
1 to 3 positions independently selected from toro groups
A substituent (two adjacent substituents are bonded to each other to form a ring
Represents a benzene ring which may have
You. A benzoquinolidine derivative or a salt thereof,
Provides hydrates and solvates.

The present inventors have the following general formula (2) (Wherein, R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁴ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group or a reactive residue, and the ring A is independently selected from 1 to 3 substituents (two adjacent substituents are A homo- or heterocyclic ring, which may have a ring, which may combine to form a ring, is a C ring having 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have a benzene ring. And a salt, hydrate and solvate thereof represented by the following general formula (5): (In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring B has 1-5 substituents (a ring in which two adjacent substituents are bonded to each other Or a salt thereof, a hydrate and a solvate thereof, or a compound thereof or a salt thereof. Methods for producing salts, hydrates and solvates are provided.

The present inventors have made the following general formula (6)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁷Is a hydroxyl group, C₁~ C₆An alkoxy group, benzylo
A xyl group,(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C has 1 to 3
Substituents (two adjacent substituents are bonded to each other to form a ring
A benzene ring which may have
You. A benzoquinolidine derivative or a salt thereof,
Hydrates and solvates and the following general formula (7)(Where Y is a halogen atom, OSO₂R⁶(R⁶Is
), B (R⁸) ₂(R⁸Is a hydroxyl group, C₁~ C₆of
Alkyl group or C₁~ C₆Represents an alkoxy group. is there
Iha R⁸May combine with each other to form a ring
No. ), MgBr or ZnCl, and the A ring are each independently
1 to 3 substituents selected (adjacent two substituents
Which may combine with each other to form a ring)
Or a homocyclic or heterocyclic ring. )
4. The benzoquinol according to claim 1, wherein
Method for producing gin derivative or salt, hydrate and solvate thereof
I will provide a.

The present inventors provide a tachykinin receptor antagonist comprising a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. I do.

The present inventors have developed a substance P receptor antagonist comprising a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. provide.

The present inventors have found that the benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof is contained as a pharmaceutical composition, which is useful for pollakiuria and urinary incontinence. Provided is an agent for preventing or treating dysuria including a bladder dysfunction.

The present inventors have proposed a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition, which is characterized by ulcerative colitis and Crohn's disease And a prophylactic or therapeutic agent for gastrointestinal diseases comprising:

The present inventors have proposed an X-ray irradiation, chemotherapeutic agent comprising a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. And a prophylactic or therapeutic agent for vomiting induced by pregnancy, migraine, postoperative illness, gastrointestinal motility depression or side effects of drug administration.

The present inventors have ascertained tachykinin-related asthma, comprising a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. A therapeutic agent for cough, pain, migraine, toothache, rheumatoid arthritis and the like is provided.

Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. C ₁ -C ₆
The alkyl group is a methyl group, an ethyl group, a propyl group,
It means an isopropyl group, a t-butyl group, a hexyl group and the like. The C ₁ -C ₆ alkoxy group means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexyloxy group, or the like. The cycloalkoxy group of C ₃ -C _10, cyclopropyl group, cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like. The C ₃ -C ₁₀ cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclobutanoyloxy group, a cyclopentanoyloxy group, a cyclohexanoyloxy group, or the like. C
₁ The alkylcarbonyl group -C _6, means acetyl group, a propionyl group, a butyryl group. The C ₁ -C ₆ alkoxycarbonyl group is a methoxycarbonyl group,
Ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group,
It means a hexyloxycarbonyl group or the like. The mono- or di-substituted C _{1 to} C ₆ alkylcarbamoyl group means a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a t-butylcarbamoyl group, a hexylcarbamoyl group, a dimethylcarbamoyl group, or a diethylcarbamoyl group. , Dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, dihexylcarbamoyl and the like. 4 to which may contain 1 to 3 heteroatoms
The 9-membered cyclic carbamoyl group includes an azetidinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a 4-methylpiperidinylcarbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group,
It means piperazinylcarbonyl group, 4-methylpiperazinylcarbonyl group and the like. The C ₁ -C ₆ alkylthio group includes a methylthio group, an ethylthio group, a propylthio group,
It means an isopropylthio group, a t-butylthio group, a hexylthio group or the like. The C ₁ -C ₆ alkylamino group is
Methylamino group, ethylamino group, propylamino group,
It means isopropylamino group, t-butylamino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dihexylamino group and the like. A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms includes an azetidino group, a pyrrolidino group, a piperidino group,
-Methylpiperidino group, morpholino group, thiomorpholino group, piperazino group, 4-methylpiperazino group and the like. The C ₁ -C ₆ alkylcarbonylamino group means an acetylamino group, a propionylamino group, a butyrylamino group, or the like. The C ₁ -C ₆ alkoxycarbonylamino group means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group, or the like.
The C ₁ -C ₆ alkylsulfonylamino group means a methylsulfonylamino group, an ethylsulfonylamino group and the like. The arylsulfonylamino group means a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group, a naphthylsulfonylamino group, and the like. The homocyclic ring of the ring A means a benzene ring, a naphthalene ring or the like. The heterocyclic ring of the ring A is a group containing 1 to 3 hetero atoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Membered or 6-membered aromatic monocyclic heterocycle, or 9- or 1-membered
It means a 0-membered fused aromatic heterocycle. The optionally substituted C ₁ -C ₆ alkyl group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ alkyl group. _{1 to} C
₆ alkylamino group, 1-3 may contain a hetero atom 4-9 membered cyclic amino group, formylamino _group, alkylcarbonylamino group of _C 1 ~C _6, C 1 ~
1 to 5 selected from a C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like.
Means a C ₁ -C ₆ alkyl group which may have one or more substituents. The optionally substituted C ₁ -C ₆ alkoxy group means a halogen atom, a hydroxyl group, a C ₁ -C 6
₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, amino groups, mono- or di-substituted C ₁ -C ₆ alkylamino groups, 4- to 9-membered optionally containing 1 to 3 heteroatoms ₁ to 5 selected from a cyclic amino group, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like. It means a C ₁ -C ₆ alkoxy group which may have a substituent. The optionally substituted C ₁ -C ₆ alkanoyloxy group means a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted group. alkylamino groups C ₁ ~C _6, 1~3
4- to 9-membered cyclic amino group, formylamino group, C ₁ -C ₆ alkylcarbonylamino group, C ₁ -C ₆ alkylsulfonylamino group, which may be substituted C which may have 1 to 5 substituents selected from good arylsulfonylamino groups and the like
_{1 to} C ₆ alkanoyloxy group (acetyloxy group,
(Propionyloxy group, isopropionyloxy group, hexanoyloxy group, etc.). The aryloyloxy group which may be substituted is a halogen atom, C ₁ -C
₆ alkyl groups, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkylthio groups, amino groups, mono- or di-substituted C ₁ -C ₆ alkylamino groups, 1-3 hetero groups A 4- to 9-membered cyclic amino group which may contain an atom, a formylamino group, a C ₁ -C ₆ alkylcarbonylamino group, a C ₁ -C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonyl An aryloyloxy group which may have 1 to 5 substituents selected from an amino group and the like (benzoyloxy group, naphthyloxy group, pyridyloxy group, pyrimidyloxy group, quinolyloxy group, indolyloxy group, etc.) Means The optionally substituted arylmethyloxy group includes a halogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group,
Alkoxy groups of ₁ -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkylamino group of _C 1 -C ₆ mono- or di-substituted, may contain one to three hetero atoms 4
A 9-membered cyclic amino group, a formylamino group, C ₁ -C ₆
An arylmethyloxy group which may have 1 to 5 substituents selected from an alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like (Phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, quinolylmethyloxy group, indolylmethyloxy group, etc.). The optionally substituted arylsulfonylamino group includes a halogen atom, C ₁ -C ₆
Alkyl group, a hydroxyl _group, an alkoxy group of C 1 -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkylamino group of _C 1 -C ₆ mono- or di-substituted, 1-3 heteroatoms A 4- to 9-membered cyclic amino group, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino It means an arylsulfonylamino group optionally having 1 to 5 substituents selected from groups and the like. What is a ring in which two adjacent substituents may be bonded to each other to form And so on. The aryl group which may be substituted is
Halogen atom, C ₁ -C ₆ alkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylthio group, amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C ₁ to
An aryl group optionally having 1 to 5 substituents selected from a C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and the like; (Phenyl group, naphthyl group, etc.). The optionally substituted alkylthio group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ alkyl. Amino group,
A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a C _{1 to} C ₆ alkylcarbonylamino group, a C _{1 to} C ₆ alkylsulfonylamino group, And an alkylthio group which may have 1 to 5 substituents selected from an optionally substituted arylsulfonylamino group and the like. The alkylsulfinyl group which may be substituted includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ . Alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, formylamino group, C
_It may have 1 to 5 substituents selected from ₁ to ₆ alkylcarbonylamino groups, ₁ to ₆ alkylsulfonylamino groups, and optionally substituted arylsulfonylamino groups. It means an alkylsulfinyl group (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, etc.). The optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C ₁ -C ₆ . Alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, formylamino group, C ₁ to
Alkylcarbonylamino group C _6, C ₁ -C alkylsulfonylamino group _6, 1-5 substituents may alkylsulfonyl optionally having selected from optionally substituted arylsulfonylamino group Group (methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, etc.). The reactive residue is a halogen atom, 1-
It means an imidazolyl group, a 4-nitrophenoxy group, an imidoyloxy succinate group and the like. The C ₁ -C ₆ alkyl group which may be substituted with a halogen means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl which may be substituted with 1 to 13 fluorine atoms or chlorine atoms. Group, hexyl group and the like. The ring which may be formed by bonding to each other of R ⁸ includes —O (CH ₂ ) ₂ O— and —O
CH (Me) CH (Me) O -, - OC (Me) 2 C (Me) 2
Means O- or -O (CH _{2) 3} O- or the like.

As a preferred compound of the present invention, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-5-oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxamide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-7- (4-methoxyphenyl) -N
-Methyl-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- ( 3-methylcyphenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-dichlorophenyl) −
2,3-dihydro-N-methyl-5-oxo-1H, 5
H-benzo [ij] quinolidine-6-carboxamide,
N- [3,5-bis (trifluoromethyl) benzyl]
-9-chloro-7- (2,4-dichlorophenyl)-
2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,
5-bis (trifluoromethyl) benzyl] -2,3-
Dihydro-N-methyl-7- (1-naphthyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2, 3-dihydro-7- (4-fluorophenyl) -N-methyl-5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxamide, N-
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-5-oxo-7- (2
-Thiophene) -1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-7-
(3-Fluorophenyl) -N-methyl-5-oxo-
1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chlorophenyl) -2,3-dihydro-N-methyl-5 Oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,
5-bis (trifluoromethyl) benzyl] -2,3-
Dihydro-N-methyl-5-oxo-7- (3-trifluoromethylphenyl) -1H, 5H-benzo [ij]
Quinolizine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-1H, 5H-benzo [Ij] Quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-3, N-dimethyl-5-oxo-7-phenyl-1H, 5H-benzo [I
j] quinolidine-6-carboxamide, N- [3,5-
Bis (trifluoromethyl) benzyl] -2,3-dihydro-3, N-dimethyl-7- (3-methoxyphenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-dichlorophenyl) -2,3-dihydro-3, N-dimethyl-5
-Oxo-1H, 5H-benzo [ij] quinolidine-6
-Carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-3, N-dimethyl-9-fluoro-7- (3-methoxyphenyl)-
5-oxo-1H, 5H-benzo [ij] quinolidine-
6-carboxamide, 7- (3-aminophenyl) -N
-[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-N-methyl-5-oxo-1H, 5
H-benzo [ij] quinolidine-6-carboxamide and the like can be exemplified.

When the compound of the present invention forms a salt, hydrochloric acid,
Hydrobromic acid, sulfuric acid, inorganic acids such as nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,
Examples thereof include pharmacologically acceptable salts with organic acids such as citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid. The compound of the present invention or a salt thereof includes an optically active substance, a stereoisomer or a rotamer in addition to the racemic form. The compound of the present invention can be produced by various synthetic methods. Next, typical production steps of the compound of the present invention and a salt thereof will be described.

(First Step) In this step, compound (I) (R
³ and C rings have the same meanings as defined above) with the compound (II) ^{(R 9} are the same or different alkyl group of _C 1 -C _6, by reacting a benzyl group), the compound ^{(III) (R 3, R} 9 and Ring C is the same as described above). This reaction is carried out at 100 to 300 ° C., preferably 150 to 150 equivalents using 1 to 20 equivalents, preferably 1 to 5 equivalents of compound (II) relative to compound (I).
Performed at 250 ° C. When a solvent is used, an inert solvent that does not participate in the reaction, for example, xylene, mesitylene,
Nitrobenzene, diphenyl ether, dautherm (a mixture of diphenyl ether and biphenyl) and the like are used.

(Second Step) In this step, compound (III) (R
³ , the ring R ⁹ and the ring C are the same as described above), and the hydroxyl group of the compound (IV) (X, R ³ , R ⁹
And ring C are the same as described above). In this step, for example, when X is a chlorine atom, a chlorinating agent such as triphenylphosphine, tributylphosphine or triphenoxyphosphine, and carbon tetrachloride, N-chlorosuccinimide or chlorine, thionyl chloride, phosphorus oxychloride, This is performed using phosphorus chloride or oxalyl chloride. When a solvent is used, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide,
Sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. This reaction proceeds smoothly at a temperature from room temperature to the boiling point of the chlorinating agent or, when a solvent is used, the boiling point of the solvent. When X is a bromine atom, the reaction can be carried out in the same manner as in the chlorination using the corresponding brominating agent. X
Is OSO ₂ R ⁶ (R ⁶ is as defined above), the sulfonating reagent used in this reaction includes methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trifluoromethane Sulfonyl chloride, N-phenyltrifluoromethanesulfonylimide and the like are used, and the reaction is carried out in a solvent in triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium,
The reaction is performed in the presence of a base such as lithium diisopropylamide. As the solvent, an inert solvent which does not participate in the reaction, preferably dichloromethane, tetrahydrofuran or the like is used. The reaction is carried out at -78 ° C to 100 ° C, preferably at -30 ° C to
80 ° C.

(Third Step) In this step, compound (IV)
(X, R ³ , R ⁹ and the C ring are the same as described above) and the compound (V) (the Y and A rings are the same as described above) by a cross-coupling reaction in the presence of a transition metal catalyst such as a palladium or nickel complex to give the compound (VI) A step of producing (R ³ , R ⁴ and Ring A are the same as described above). This reaction is preferably performed using an inert solvent not involved in the reaction,
For example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol, water and the like can be exemplified. These solvents are used alone or in a mixture at an arbitrary ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetylacetonato palladium, and tetrakis (triphenylphosphine) palladium. Examples of the nickel complex used in this reaction include bis (acetylacetonato) nickel, bis (1,5-cyclooctadiene) nickel, and tetrakis (triphenylphosphine) nickel. These palladium or nickel complexes are used in an amount of 0.001 to 1 equivalent, preferably 0.01 equivalent, relative to compound (IV).
It is used in the range of ０．１0.1 equivalent. When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri-o-tolylphosphine, tri-2-furylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,1′-bis ( Examples thereof include (diphenylphosphino) ferrocene and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl. These ligands are used in an amount of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex.
Used in the range of equivalents. X of compound (IV) is OSO ₂
In the case of R ⁶ , copper iodide or lithium chloride can be used together with the palladium or nickel complex, if necessary. This reaction is preferably performed in the presence of a suitable base, for example, organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, carbonate Examples thereof include inorganic bases such as calcium, cesium carbonate, and tripotassium phosphate. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (IV). The cross-coupling reaction in this step can be performed at room temperature to 150 ° C, preferably at 50 to 120 ° C. When a compound in which Y of compound (V) is not B (R ⁸ ) ₂ is used as a raw material in the cross-coupling reaction of this step, compound (IV) or compound (V) (where Y is B (R ⁸ ) Not ₂ ) and HB
Compound (IV) (X is B (R ⁸ ) ₂ ) or Compound (V) (Y is B (R ⁸ ) ₂ ) obtained by reacting (R ⁸ ) ₂ or (B (R ⁸ ) ₂ ) ₂ To compound (V) (where Y is not B (R ⁸ ) ₂ ) or compound (IV) to produce compound (VI). The compound (IV) (X is B (R ⁸ )
₂ ) or compound (V) (Y is B (R ⁸ ) ₂ ) and the A ring is the same as described above, and may be subjected to the next step without isolation or purification. It is also possible to provide.

(Fourth Step) In this step, compound (VI) (R
³ , R ⁴ and ring A are the same as described above) and compound (VII) (R
¹ , R ² and B are the same as described above) to produce a compound (VIII) (R ¹ , R ² , R ³ , A ring, B ring and C ring are the same). . As a condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction of this step, dicyclohexylcarbodiimide (DCC),
Examples thereof include ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and dimethylimidazolinium chloride (DMC), which are added in a solid state or as a solution in a suitable solvent. When a base is used in the present condensation reaction, an alkali carbonate such as sodium hydrogen carbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, Dimethylaminopyridine or 1,8
Examples include tertiary amines such as -bis (dimethylamino) naphthalene. As the solvent used in the present condensation reaction, an inert solvent not involved in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, Dichloromethane or the like is used. This condensation reaction is-
It proceeds smoothly at 20 ° C to 80 ° C. In the condensation reaction of this step, R ⁴ is a reactive residue (for example, a halogen atom, 1-
Carboxylic acid halides represented by imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc., imidazolides of carboxylic acids, active esters of carboxylic acids, mixed acid anhydrides of carboxylic acids (for example, with ethyl carbonate) Anhydrides, anhydrides with isobutyl carbonate, etc.) or symmetric acid anhydrides, in the presence of organic bases such as triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydrogen carbonate and potassium carbonate. Or in the absence of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, toluene, dichloromethane, etc.
It can be carried out by treating at 80 ° C. for 30 minutes to 48 hours. In the condensation reaction of this step, R ⁴ is C ₁
Alkoxy group -C _6, when the ester residue such as benzyl group, trimethylaluminum or tetraisopropoxytitanium in the presence of such titanium, or p- toluenesulfonic acid or the like acid catalyst, or sodium methoxide, potassium -t- Butoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile in the presence of a base such as sodium hydride,
30 ° C. in a solvent such as tetrahydrofuran, dioxane, toluene, xylene, dichloromethane at room temperature to 150 ° C.
It can be carried out by treating for from 48 minutes to 48 hours.

As shown in the fifth step, compound (XI) can also be produced from compound (IX) and compound (X). In this step, compound (X) is added to compound (IX) for 1
An acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium-t-butoxide,
N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran in the presence of a base such as sodium hydride,
50-1 in a solvent such as dioxane, toluene and xylene
It can be carried out by treating at 50 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (XI) according to the method described above.

As shown in the sixth step, compound (XIII)
Can also be produced from compound (XII) and compound (X). In this step, compound (X) is added to compound (XII)
An acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium-t-butoxide,
N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran in the presence of a base such as sodium hydride,
50-1 in a solvent such as dioxane, toluene and xylene
It can be carried out by treating at 50 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from compound (XIII) obtained according to the method described above.

The compound (1) of the present invention can be isolated and purified by usual separation means (eg, extraction, recrystallization, distillation, chromatography, etc.). When the obtained compound forms a salt, various salts can be produced by an ordinary method or a method analogous thereto (eg, neutralization). The compound (1) of the present invention or a salt thereof can be used alone or together with one or more pharmaceutically acceptable adjuvants as a pharmaceutical composition, and a pharmacologically acceptable carrier or excipient (for example, starch) , Lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg,
Magnesium stearate, calcium stearate talc, stearic acid, etc.), binders (eg, starch,
Crystalline cellulose, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc.), disintegrants (eg, talc, carboxymethylcellulose calcium, etc.), diluents (eg, physiological saline, aqueous solutions of glucose, mannitol, lactose, etc.) and the like. They can be mixed and administered orally or parenterally in the form of tablets, capsules, granules, powders, fine granules, ampoules, injections, or the like according to ordinary methods. The dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age and symptoms of the patient, and the like.
1-300 mg / kg / day. The administration is performed, for example, once or several times a day.

[0036]

The compounds of the present invention and salts thereof have excellent tachykinin receptor antagonism, have low toxicity, and are safe as pharmaceuticals. Therefore, the compounds of the present invention and salts thereof are useful as pharmaceutical compositions, tachykinin receptor antagonists, therapeutic agents for dysuria, and the like. The usefulness of the present invention is shown by the following experimental examples and examples, but the present invention is not limited to the experimental examples and examples.

[0037]

[Experimental method] NK1 receptor antagonism The method of Dion et al. (“Life Scie
vol. 41, p. 2269 (1987)). After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The removed ileum is placed in a Magnus tube.
g and suspended. Specimen responses were recorded isotonic. The nutrient solution uses Tyrode solution, O ₂ 95%,
A mixed gas of 5% CO ₂ was passed, and the liquid temperature was 32 ° C. The experiment started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration-response curve of substance P in the absence of the test compound was used as a control.

The NK1 receptor antagonism of the test compound was determined from a concentration-response curve of substance P, which was pretreated with at least three concentrations of the test compound for 10 minutes and then applied cumulatively. The pA2 value was determined according to the method of Schild ("Brit. J. Pharmacol.
Pharmacol.), Vol. 14, p. 48 (1959)), and the results are shown in Table 1.

The composition of the Tyrode solution was as follows. NaCl; 136.9, KCl; 2.7, CaCl
_{2 · 2H 2 O; 2.5,} MgCl 2 · 6H 2 O; 1.
_{0, NaH 2 PO 4 · 2H} 2 O; 0.4, NaHC
O ₃ ; 11.9, glucose; 11.1 (mM)

[0040]

【Example】Example No. pA ₂ value (nM)  18 11.3 19 5.20 29 24.1

Embodiment 1 Methanone- (1,2,3,4-tetrahydroquinoline-
8-yl) (2,4-dichlorophenyl) (918.6 mg, 3.
(0 mmol) in 10 ml of ethyl acetate to give 1.
25 ml, and ethylmalonyl chloride (0.96 ml,
7.5 mmol) was added dropwise and stirred for 2 hours. Methylene chloride was added to the reaction solution, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of tetrahydrofuran and potassium-t-butoxide (404.
0 mg, 3.6 mmol) was added little by little, and the mixture was stirred for 1 hour. The mixture was neutralized with 20 ml of a 1N hydrochloric acid aqueous solution, added with water, and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (methylene chloride) to give a colorless amorphous 7
-(2,4-dichlorophenyl) -2,3-dihydro-
5-oxo-1H, 5H-benzo [ij] quinolidine-
6-Carboxylic acid ethyl ester (1.34 g, 94%) was obtained. EIMS m / z: 401 (M ⁺ )

Embodiment 2 7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (427.1 mg, 1.06 mmol)
Then, palladium hydroxide on carbon (81.4 mg) was dissolved in ethanol (10 ml), triethylamine (0.3 ml) was added, and the mixture was stirred at 65 ° C for 6 hours under a hydrogen atmosphere (3.5 atm). The palladium hydroxide-on-carbon was removed by filtration through Celite, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography.
(Methylene chloride: ethyl acetate 20: 1). The crystals were washed with hexane to give colorless crystals of 2,3-dihydro-5-
Oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (187.7 g, 53
%). EIMS m / z: 333 (M ⁺ )

Embodiment 3 7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (402.3 mg, 1.0 mmol) and N-chlorosuccinimide (140.2 mg, 1.05 mmol) was dissolved in 5 ml of dimethylformamide and stirred at 80 ° C. N-
Add chlorosuccinimide (145.3mg, 1.09mmol),
Stir for 4 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed three times with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (methylene chloride) to give pale yellow amorphous 9-chloro-7- (2,4-dichlorophenyl). )-
2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (4
16.5 mg, 95%). EIMS m / z: 435 (M ⁺ )

Embodiment 4 7-chloro-2,3-dihydro-5-oxo-1H, 5
H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (291.7 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (46.2 mg, 0.04 mmol, 0.04 eq.)
Was dissolved in benzene (5 ml) and a 2M aqueous solution of sodium carbonate (1 ml), a solution of 3-methoxyphenylboric acid (303.9 mg, 2.0 mmol) in 1,4-dioxane (2 ml) was added, and the mixture was heated to reflux.
On the way, tetrakistriphenylphosphine palladium (2
(6.2 mg, 22.7 μmol) and heated under reflux for 10 hours. Water and methylene chloride were added to the reaction solution, and the mixture was extracted three times with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. -(3-Methoxyphenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (359.1 mg, 99%)
I got EIMS m / z: 363 (M ⁺ )

Embodiment 5 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (145.9 mg, 0.50
mmol) and 1-naphthyl boric acid (258.0 mg, 1.5 mmol) as a colorless oily substance, 2,3-dihydro-7- (1-naphthyl)
-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (202.6 mg, 100%) was obtained. EIMS m / z: 383 (M ⁺ )

Embodiment 6 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 4-fluorophenyl boric acid (167.9 mg, 1.2 mmo
From l), colorless crystalline 2,3-dihydro-7- (4-fluorophenyl) -5-oxo-1H, 5H-benzo [i
j] quinolidine-6-carboxylic acid ethyl ester (111.0
mg, 79%). EIMS m / z: 351 (M ⁺ )

Embodiment 7 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 2-thiophene boric acid (153.6 mg, 1.2 mmol) as colorless crystals of 2,3-dihydro-5-oxo-7- (2-
Thiophene) -1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (167.9 mg, 62%) was obtained. EIMS m / z: 339 (M ⁺ )

Embodiment 8 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 3-fluorophenyl boric acid (167.9 mg, 1.2 mmo
l) to 2,3-dihydro-7- (3-fluorophenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester as a colorless oily substance (1
08.8 mg, 77%). EIMS m / z: 351 (M ⁺ )

Embodiment 9 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 3-nitrophenyl boric acid (200.3 mg, 1.2 mmol)
To 2,3-dihydro-7- (3-
Nitrophenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (9
1.5 mg, 60%). EIMS m / z: 378 (M ⁺ )

Embodiment 10 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 3-chlorophenylboric acid (187.7 mg, 1.2 mmol)
To 7- (3-chlorophenyl) -2, a colorless oily substance from
3-dihydro-5-oxo-1H, 5H-benzo [i
j] quinolidine-6-carboxylic acid ethyl ester (119.4
mg, 81%). EIMS m / z: 367 (M ⁺ )

Embodiment 11 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 3-trifluoromethylphenyl boric acid (227.9m
g, 1.2 mmol) to give 2,3-dihydro-5 as a colorless oil.
-Oxo-7- (3-trifluoromethylphenyl)-
1H, 5H-Benzo [ij] quinolidine-6-carboxylic acid ethyl ester (136.0 mg, 85%) was obtained. EIMS m / z: 401 (M ⁺ )

Embodiment 12 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 4-methoxyphenyl boric acid (182.4 mg, 1.2 mmo
l) From colorless amorphous 2,3-dihydro-7- (4
-Methoxyphenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester
(99.2 mg, 68%). EIMS m / z: 363 (M ⁺ )

Embodiment 13 According to a method similar to that in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (116.7 mg, 0.40
mmol) and 3-methylphenyl boric acid (163.2 mg, 1.2 mmol)
To 2,3-dihydro-7- (3-methylphenyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester as colorless crystals (100.0 mg, 72
%). EIMS m / z: 363 (M ⁺ )

Embodiment 14 According to a method similar to that of Example 4, 7-chloro-2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (1
22.3mg, 0.40mmol) and phenylboric acid (146.3mg, 1.2mmo
From l), 2,3-dihydro-3-methyl-5 as colorless crystals
Oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (96.3 mg, 69
%). EIMS m / z: 347 (M ⁺ )

Embodiment 15 According to a method similar to that of Example 4, 7-chloro-2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (1
22.3 mg, 0.40 mmol) and 3-methoxyphenyl boric acid (182.
4 mg, 1.2 mmol) to 2,3-dihydro-
7- (3-Methoxyphenyl) -3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (80.7 mg, 53%) was obtained. EIMS m / z: 377 (M ⁺ )

Embodiment 16 According to a method similar to that of Example 4, 7-chloro-2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (1
22.3mg, 0.40mmol) and 2,4-dichlorophenyl boric acid
(286.2 mg, 1.5 mmol) from colorless amorphous 7- (2,
4-Dichlorophenyl) -2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (128.4 mg, 77%) was obtained. EIMS m / z: 415 (M ⁺ )

Embodiment 17 According to a method similar to that of Example 4, 7-chloro-2,3-dihydro-9-fluoro-3-methyl-5-oxo-1
From H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (112.9 mg, 0.40 mmol) and 3-methoxyphenyl boric acid (182.4 mg, 1.2 mmol) as a colorless oily substance, 2,3-dihydro-9-fluoro -7- (3-Methoxyphenyl) -3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (126.7 mg, 92%) was obtained. EIMS m / z: 395 (M ⁺ )

Embodiment 18 2,3-dihydro-5-oxo-7-phenyl-1H,
5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (180.0 mg, 0.540 mmol) and potassium hydroxide (9
0.9 mg, 1.62 mmo) was dissolved in ethanol (4.5 ml) -water (0.5 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was ice-cooled, neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. 2,3-dihydro-
5-oxo-7-phenyl-1H, 5H-benzo [i
j] Quinolidine-6-carboxylic acid (153.8 mg, 93%) was obtained. 0.5 ml of thionyl chloride was added to the obtained 2,3-dihydro-5-oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid (149.3 mg, 0.489 mmol), and the mixture was added at room temperature for 1 hour. Stirred for hours. The residue obtained by distilling off thionyl chloride was dissolved in 5 ml of methylene chloride, and triethylamine was dissolved.
0.25 ml and 0.12 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine were added, and the mixture was stirred for 1 hour.
Water and methylene chloride are added to the reaction solution, and
Extracted times. After the extract was dried over anhydrous sodium sulfate, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1). The obtained crystals are washed with hexane to give colorless crystals of N.
-[3,5-bis (trifluoromethyl) benzyl]-
2,3-Dihydro-N-methyl-5-oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxamide (241.0 mg, 91%) was obtained. mp. 191.5-193 ° C EIMS m / z: 544 (M ⁺ )

Embodiment 19 In the same manner as in Example 18, 2,3-dihydro-7
-(3-methoxyphenyl) -5-oxo-1H, 5H
-Benzo [ij] quinolidine-6-carboxylic acid ethyl ester (352.8 mg, 0.971 mmol) and 0.25 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (485.7 mg, 87
%). mp. 168-172 ° C Anal: calculated as C ₂₉ H ₂₂ F ₆ N ₂ O ₃ C 62.72%, H 4.21%, N 4.88%; found C 62.64%, H 4.19%, N 4.89% EIMS m / z : 574 (M ⁺ )

Embodiment 20 In the same manner as in Example 18, 2,3-dihydro-7
-(4-methoxyphenyl) -5-oxo-1H, 5H
-Benzo [ij] quinolidine-6-carboxylic acid ethyl ester (95.3 mg, 0.262 mmol) and 0.065 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine gave N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-methoxyphenyl) -N-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (119.1 mg, 79
%). mp. 110-113 ° C EIMS m / z: 574 (M ⁺ )

Embodiment 21 In the same manner as in Example 18, 2,3-dihydro-7
-(3-methylcyphenyl) -5-oxo-1H, 5H
Colorless amorphous N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7
-(3-methylcyphenyl) -5-oxo-1H, 5H
-Benzo [ij] quinolidine-6-carboxamide (10
2.0 mg, 63%). FABMS m / z: 559 (M + H ⁺ )

Embodiment 22 According to a method similar to that in Example 18, 7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H,
7H of pale yellow crystals was obtained from 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (402.3 mg, 1.0 mmol).
(2,4-dichlorophenyl) -2,3-dihydro-5
-Oxo-1H, 5H-benzo [ij] quinolidine-6
-Carboxylic acid (326.6 mg, 87%) was obtained. 7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1
H, 5H-benzo [ij] quinolidine-6-carboxylic acid
(374.2 mg, 1.0 mmol) and 0.25 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl].
-7- (2,4-dichlorophenyl) -2,3-dihydro-N-methyl-5-oxo-1H, 5H-benzo [i
j] Quinolidine-6-carboxamide (586.1 mg, 96%) was obtained. EIMS m / z: 612 (M ⁺ )

Embodiment 23 According to a method similar to that in Example 18, 9-chloro-7-
(2,4-dichlorophenyl) -2,3-dihydro-5
-Oxo-1H, 5H-benzo [ij] quinolidine-6
-Carboxylic acid ethyl ester (409.2 mg, 0.937 mmol) to give 9-chloro-7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxylic acid (350.2 mg,
80%). 9-chloro-7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxylic acid (198.0 mg,
0.484 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine (146.6 mg, 0.570 mmol) were dissolved in 5 ml of methylene chloride, and N-ethyl-N ′-(3
-Dimethylaminopropyl) carbodiimide (111.4 mg,
0.581 mmol) and stirred for 1 hour. N-ethyl-N'-
(3-dimethylaminopropyl) carbodiimide (50.6m
g, 0.264 mmol) and further stirred for 1 hour. The reaction solution was brought to room temperature, methylene chloride was added, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1) to give a colorless amorphous N- [3,5- Bis (trifluoromethyl) benzyl] -9-chloro-7- (2,4-dichlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (47.4 mg,
15%). EIMS m / z: 646 (M ⁺ )

Embodiment 24 In the same manner as in Example 18, 2,3-dihydro-7
-(1-Naphthyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (2
02.6 mg, 0.528 mmol) and 0.15 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl].
This gave -2,3-dihydro-N-methyl-7- (1-naphthyl) -5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (117.9 mg, 38%). mp.
95.0-97.0 ° C EIMS m / z: 594 (M ⁺ )

Embodiment 25 In the same manner as in Example 18, 2,3-dihydro-7
-(4-Fluorophenyl) -5-oxo-1H, 5H
-Benzo [ij] quinolidine-6-carboxylic acid ethyl ester (103.7 mg, 0.295 mmol) and 0.07 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine gave N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (4-fluorophenyl) -N-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (158.6 mg, 96
%). mp. 152-155 ° C EIMS m / z: 562 (M ⁺ )

Embodiment 26 In the same manner as in Example 18, 2,3-dihydro-5
-Oxo-7- (2-thiophene) -1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester
(163.9 mg, 0.483 mmol) and 0.1 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] -2,3-. Dihydro-N-methyl-5-oxo-7
There was obtained-(2-thiophene) -1H, 5H-benzo [ij] quinolidine-6-carboxamide (211.5 mg, 80%).
mp. 100-102 ° C EIMS m / z: 550 (M ⁺ )

Embodiment 27 In the same manner as in Example 18, 2,3-dihydro-7
-(3-Fluorophenyl) -5-oxo-1H, 5H
A colorless amorphous N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-fluorophenyl) -N-methyl-5-oxo-1H, 5
H-benzo [ij] quinolidine-6-carboxamide (1
46.6 mg, 86%). EIMS m / z: 562 (M ⁺ )

Embodiment 28 According to a method similar to that in Example 18, 7- (3-chlorophenyl) -2,3-dihydro-5-oxo-1H, 5H-
Colorless amorphous N- [3,5-bis] from benzo [ij] quinolidine-6-carboxylic acid ethyl ester (112.3 mg, 0.305 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.076 ml (Trifluoromethyl) benzyl] -7- (3-chlorophenyl) -2,
3-dihydro-N-methyl-5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxamide (101.3
mg, 57%). EIMS m / z: 578 (M ⁺ )

Embodiment 29 In the same manner as in Example 18, 2,3-dihydro-5
-Oxo-7- (3-trifluoromethylphenyl)-
1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (131.3 mg, 0.327 mmol) and N-methyl-
3,5-bis (trifluoromethyl) benzylamine
Colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N
-Methyl-5-oxo-7- (3-trifluoromethylphenyl) -1H, 5H-benzo [ij] quinolidine-
6-carboxamide (128.4 mg, 64%) was obtained. EIMS m / z: 612 (M ⁺ )

Embodiment 30 In the same manner as in Example 18, 2,3-dihydro-7
-(3-nitrophenyl) -5-oxo-1H, 5H-
From benzo [ij] quinolidine-6-carboxylic acid ethyl ester (218.5 mg, 0.577 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.16 ml, pale yellow amorphous N- [3,5- Bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-7
-(3-nitrophenyl) -5-oxo-1H, 5H-
Benzo [ij] quinolidine-6-carboxamide (305.1
mg, 90%). EIMS m / z: 589 (M ⁺ )

Embodiment 31 According to a method similar to that in Example 18, 2,3-dihydro-3 was used.
-Methyl-5-oxo-7-phenyl-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (96.3 mg, 0.277 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzyl N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-3, N-dimethyl-5-oxo-7-phenyl-1H, 5H-benzo [ij ] Quinolizine-6-carboxamide (120.7 mg, 78%) was obtained. EIMS m / z: 558 (M ⁺ )

Embodiment 32 In the same manner as in Example 18, 2,3-dihydro-7
-(3-methoxyphenyl) -3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (80.7 mg, 0.214 mmol) and N-methyl-
3,5-bis (trifluoromethyl) benzylamine
From 055 ml, colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-
3, N-dimethyl-7- (3-methoxyphenyl) -5
-Oxo-1H, 5H-benzo [ij] quinolidine-6
-Carboxamide (90.8 mg, 72%) was obtained. EIMS m / z: 588 (M ⁺ )

Embodiment 33 According to a method similar to that in Example 18, 7- (2,4-dichlorophenyl) -2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester ( 117.7 mg, 0.283 mmol) and 0.073 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine to give N- [3,5-bis (trifluoromethyl) benzyl] -7- (2, 4-
Dichlorophenyl) -2,3-dihydro-3, N-dimethyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (154.8 mg, 87%) was obtained. EIMS m / z: 626 (M ⁺ )

Embodiment 34 In the same manner as in Example 18, 2,3-dihydro-9
-Fluoro-7- (3-methoxyphenyl) -3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (121.7 mg, 0.308 mmol
l) and N-methyl-3,5-bis (trifluoromethyl)
Colorless amorphous N- from 0.079 ml of benzylamine
[3,5-bis (trifluoromethyl) benzyl]-
2,3-dihydro-3, N-dimethyl-9-fluoro-
7- (3-methoxyphenyl) -5-oxo-1H, 5
H-benzo [ij] quinolidine-6-carboxamide (1
82.3 mg, 98%). EIMS m / z: 606 (M ⁺ )

Embodiment 35 N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-Dihydro-N-methyl-7- (3-nitrophenyl) -5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxamide (211.2 mg, 0.358 mmol) and 29.3 mg of palladium carbon. It was dissolved in 5 ml of ethanol and stirred under a hydrogen atmosphere for 25 hours. The palladium carbon was removed by filtration through celite, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 5: 1 → 1: 1). Hexane was added to the purified product to crystallize it, and colorless crystals of 7- (3-aminophenyl)-
N- [3,5-bis (trifluoromethyl) benzyl]
-2,3-dihydro-N-methyl-5-oxo-1H,
5H-benzo [ij] quinolidine-6-carboxamide
(111.2 mg, 55%). mp. 132-136 ° C EIMS m / z: 559 (M ⁺ )

Reference Example 1 2-methyl-1,2,3,4-tetrahydroquinoline
(1.47 g, 10 mmol) and triethyl methanetricarboxylate
(4.70 g, 20 mmol) was stirred at 220 ° C. for 5 hours. Hexane and diethyl ether were added to the reaction solution, and the mixture was cooled in a dry ice-acetone bath. The precipitated crystals were collected by filtration, washed with hexane, and light yellow crystals of 2,3-dihydro-7-hydroxy-3-methyl- 5-oxo-1H, 5H-benzo [i
j] quinolidine-6-carboxylic acid ethyl ester (1.31
g, 46%). EIMS m / z: 287 (M ⁺ )

Reference Example 2 In the same manner as in Reference Example 1, 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.65 g, 10
mmol) and triethyl methanetricarboxylate (4.70 g, 20m
mol) from light yellow crystalline 2,3-dihydro-9-fluoro-7-hydroxy-3-methyl-5-oxo-1H,
5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (1.13 g, 37%) was obtained. EIMS m / z: 305 (M ⁺ )

Reference Example 3 2,3-dihydro-7-hydroxy-3-methyl-5-
Oxo-1H, 5H-benzo [ij] quinolidine-6
Ethyl carboxylate (1.30 g, 4.52 mmol) and triphenylphosphine (2.37 g, 9.04 mmol) were dissolved in 10 ml of acetonitrile, carbon tetrachloride (2.70 ml, 27.1 mmol) was added, and the mixture was heated under reflux for 3 hours. Triphenylphosphine (2.37 g,
9.04 mmol) and carbon tetrachloride (2.70 ml, 27.1 mmol) were added, and the mixture was heated under reflux for 2 hours, and triphenylphosphine (237
mg, 0.904 mmol) and carbon tetrachloride (0.27 ml, 2.71 mmol), and the mixture was heated under reflux for 2 hours. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained product was crystallized by adding hexane to give 7-chloro-2,3-dihydro-3- pale yellow crystals. Methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (853.5 mg, 62%) was obtained. EIMS m / z: 305 (M ⁺ )

Reference Example 4 In the same manner as in Reference Example 3, 2,3-dihydro-7-
Hydroxy-5-oxo-1H, 5H-benzo [ij]
Quinolizine-6-carboxylic acid ethyl ester (1.09 g, 4.
0 mmol) to give ethyl 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylate (1.29 g, 89%) as colorless crystals. EIMS m / z: 291 (M ⁺ )

Reference Example 5 In the same manner as in Reference Example 3, 2,3-dihydro-9-
Fluoro-7-hydroxy-3-methyl-5-oxo-
From 1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (1.11 g, 3.64 mmol), 7-chloro-2,3-dihydro-9-fluoro- as a pale yellow oily substance was obtained.
3-methyl-5-oxo-1H, 5H-benzo [ij]
Quinolizine-6-carboxylic acid ethyl ester (843.4 g, 7
2%). EIMS m / z: 323 (M ⁺ )

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K31 / 435 ACD A61K31 / 435 ACD ACJ ACJ ACK ACK ACL ACL ACP ACP ACV ACV AED AED FED term (reference) 4C065 AA07 BB09 CC09 DD01 EE02 HH08 JJ04 KK01 LL01 PP03 PP06 QQ02 QQ04 QQ05 4C086 AA01 AA02 AA03 AA04 CB18 MA01 MA04 NA07 NA14 ZA08 ZA59 ZA66 ZA68 ZA71 ZA81 ZB15 ZC42

Claims (13)

[Claims] 1. The following general formula (1) (Wherein, R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring which may have a plurality of substituents which may combine with each other to form a ring), and the ring B has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof. 2. A ring may be substituted with a halogen atom.
C₁~ C₆An alkyl group of which may be substituted
A hydroxyl group, an optionally substituted C₁~
C₆An alkoxy group of C₃~ C₁₀Cycloalkoxy
Group, optionally substituted C ₁~ C₆The alkanoylo
An xyl group, an optionally substituted aryloyloxy group,
An optionally substituted arylmethyloxy group, C₃~ C
₁₀Cycloalkanoyloxy group, even when substituted
Good C₁~ C₆Alkylthio group, which may be substituted
C₁~ C₆Alkylsulfinyl group of
May be C₁~ C₆An alkylsulfonyl group, amino
Group, mono- or di-substituted C₁~ C₆An alkylamino group of
4- to 9-membered ring optionally containing 1 to 3 heteroatoms
Amino group, C₁~ C₆The alkylcarbonylamino of
Group, C₁~ C₆An alkoxycarbonylamino group of C₁
~ C₆An alkylsulfonylamino group of
Arylsulfonylamino group, C₁~ C₆Al
Kill carbonyl group, formyl group, carboxyl group, C₁
~ C₆An alkoxycarbonyl group, a mono- or di-substituted C
₁~ C₆Alkylcarbamoyl group, 1-3 hetero groups
4- to 9-membered cyclic carbamoyl optionally containing atoms
Group, cyano group or nitro group
1 to 3 substituents (adjacent two substituents are
To form a ring).
Ring B is a halogen atom, optionally substituted C₁~ C₆
An alkyl group of C₃~ C₁₀Cycloalkyl group, substitution
Optionally substituted aryl, hydroxyl, substituted
C that may be₁~ C₆An alkoxy group, which is substituted
May be C₁~ C₆Alkanoyloxy group, substituted
An aryloyloxy group which may be substituted,
Good arylmethyloxy group, C₃~ C₁₀Cycloa
Lucoxy group, C₃~ C₁₀Cycloalkanoyloxy
Group, optionally substituted C₁~ C₆The alkylthio
Group, optionally substituted C₁~ C₆Alkylsulf
Ynyl group, optionally substituted C₁~ C₆The alkyl of
Sulfonyl group, amino group, mono- or di-substituted C₁~ C₆
Alkylamino groups containing 1 to 3 heteroatoms
A 4- to 9-membered cyclic amino group, C₁~ C₆Archi
Carbonylamino group, C₁~ C₆The alkoxy carb
Nylamino group, C₁~ C₆Of alkylsulfonylamino
Group, optionally substituted arylsulfonylamino
Group, C₁~ C₆Alkylcarbonyl group, carboxyl
Group, C₁~ C₆An alkoxycarbonyl group, mono or di
Substitution C₁~ C₆Alkylcarbamoyl group of 1 to 3
4 to 9-membered cyclic carba optionally containing a heteroatom
Independent of moyl, cyano or nitro groups
1 to 3 substituents (adjacent two substituents
May be bonded to each other to form a ring)
A benzene ring, wherein the ring C is a halogen atom,
C that may be₁~ C₆An alkyl group of hydroxy
Group, optionally substituted C₁~ C₆The alkoxy of
Group, optionally substituted C₁~ C₆The alkanoylo
An xyl group, an optionally substituted aryloyloxy group,
An optionally substituted arylmethyloxy group, C₃~ C
₁₀A cycloalkoxy group of C₃~ C₁₀The cycloal
Canoyloxy group, amino group, mono- or di-substituted C₁~
C₆Alkylamino group containing 1 to 3 heteroatoms
A 4- to 9-membered cyclic amino group, which may be₁~ C₆No
Alkylcarbonylamino group, C₁~ C₆Alkoxyka
Rubonylamino group, C₁~ C₆Alkylsulfonyluas
Amino group, arylsulfonylamyl which may be substituted
, Cyano or nitro groups each independently
1 to 3 selected substituents (two adjacent substituents are
May be bonded to form a ring)
The benzoquinolidine according to claim 1, which exhibits a good benzene ring.
Derivatives. 3. The following general formula (2)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁴Is a hydroxyl group, C₁~ C₆An alkoxy group, benzylo
A xy group or a reactive residue, a ring A having a halogen atom, an optionally substituted C₁~ C₆
An alkyl group, an optionally substituted aryl group,
Roxyl group, optionally substituted C₁~ C₆Arco
Xy group, C₃~ C₁₀A cycloalkoxy group, substituted
May be C ₁~ C₆Alkanoyloxy group, substituted
An aryloyloxy group, which may be substituted
Arylmethyloxy group, C₃~ C₁₀The cyclo
Alkanoyloxy group, optionally substituted C₁~ C
₆An alkylthio group of the formula₁~ C₆
An alkylsulfinyl group of an optionally substituted C₁
~ C₆Alkylsulfonyl group, amino group, mono or di
Substitution C₁~ C₆Alkylamino group, 1 to 3
A 4- to 9-membered cyclic amino group optionally containing
₁~ C₆An alkylcarbonylamino group of C₁~ C₆of
Alkoxycarbonylamino group, C₁~ C₆The alkyl of
Sulfonylamino group, aryls which may be substituted
Rufonylamino group, C₁~ C₆Alkyl carbonyl
Group, formyl group, carboxyl group, C₁~ C₆Arco
Xycarbonyl group, mono- or di-substituted C ₁~ C₆Al
Quilcarbamoyl group, containing 1 to 3 heteroatoms
4 to 9-membered cyclic carbamoyl group, cyano group or
1 to 3 independently selected from nitro groups
Substituents (two adjacent substituents are bonded to each other to form a ring
Allomorphic or complex
Ring, ring C is a halogen atom, optionally substituted C₁~ C₆
Alkyl group, hydroxyl group, which may be substituted
C₁~ C₆An alkoxy group, optionally substituted C₁
~ C₆Alkanoyloxy group, which may be substituted
Aryloyloxy group, aryl group which may be substituted
Tyloxy group, C₃~ C₁₀A cycloalkoxy group of C
₃~ C₁₀A cycloalkanoyloxy group, an amino group,
Mono- or di-substituted C₁~ C₆An alkylamino group of 1 to
A 4- to 9-membered cyclic amine optionally containing three heteroatoms
Mino group, C₁~ C₆An alkylcarbonylamino group of C
₁~ C₆An alkoxycarbonylamino group of C₁~ C₆
Alkylsulfonylamino group, which may be substituted
Arylsulfonylamino, cyano or nitro group
1 to 3 substituents each independently selected from
Two contacting substituents are bonded to each other to form a ring,
A benzene ring which may have a benzene ring. )
Benzoquinolidine derivatives or their salts, hydrates and
Solvate. 4. The following general formula (3)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
X is a halogen atom or OSO₂R⁶(R⁶Ha
C which may be substituted with a logene₁~ C₆An alkyl group of
An aryl group which may be substituted), and ring C is a halogen atom
Child, optionally substituted C₁~ C₆An alkyl group of
A droxyl group, an optionally substituted C₁~ C₆Al
Coxy group, optionally substituted C₁~ C₆No alkano
Yloxy group, optionally substituted aryloyloxy
Group, an optionally substituted arylmethyloxy group, C
₃~ C₁₀A cycloalkoxy group of C₃~ C₁₀No shiku
Lower alkanoyloxy group, amino group, mono- or di-substituted
C₁~ C₆Alkylamino group, 1-3 heteroatoms
A 4- to 9-membered cyclic amino group optionally containing ₁~ C
₆An alkylcarbonylamino group of C₁~ C₆Arco
Xycarbonylamino group, C₁~ C₆Alkylsulfo
Nylamino group, arylsulfonyl which may be substituted
Each independently from the amino, cyano or nitro groups.
1 to 3 substituents selected vertically (two adjacent substituents
Groups may be bonded to each other to form a ring)
Represents an optionally present benzene ring. Benzoquino represented by)
Lysine derivatives or salts, hydrates and solvates thereof. 5. The following general formula (4)(Where R³Is a hydrogen atom or C₁~ C₆An alkyl group of
R⁵Is(R¹And R²Are the same or different and represent a hydrogen atom or C₁~
C₆Alkyl group and B ring have 1 to 5 substituents (adjacent
Two substituents may combine with each other to form a ring
Benzene ring). ) Or reaction
Residue, C ring is a halogen atom, C
₁~ C₆Alkyl group, hydroxyl group, substituted
May be C₁~ C₆An alkoxy group, even if it is substituted
Good C₁~ C ₆Alkanoyloxy group, substituted
An aryloyloxy group, an optionally substituted
Reel methyloxy group, C₃~ C₁₀Cycloalkoxy
Si group, C₃~ C₁₀A cycloalkanoyloxy group,
Amino group, mono- or di-substituted C₁~ C₆The alkylamino
Group, 4 to 9 members optionally containing 1 to 3 heteroatoms
A cyclic amino group of C₁~ C₆Alkylcarbonylamido
No group, C₁~ C₆An alkoxycarbonylamino group of C
₁~ C₆Alkylsulfonylamino group, substituted
An arylsulfonylamino group, a cyano group or a
1 to 3 positions independently selected from toro groups
A substituent (two adjacent substituents are bonded to each other to form a ring
Represents a benzene ring which may have
You. A benzoquinolidine derivative or a salt thereof,
Hydrates and solvates. 6. The following general formula (2) (Wherein, R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁴ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group or a reactive residue, and the ring A is independently selected from 1 to 3 substituents (two adjacent substituents are A homo- or heterocyclic ring, which may have a ring, which may combine to form a ring, is a C ring having 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have a benzene ring. And a salt, hydrate and solvate thereof represented by the following general formula (5): (In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring B has 1-5 substituents (a ring in which two adjacent substituents are bonded to each other. Or a salt thereof, a hydrate and a solvate thereof, or the compound represented by the formula (1) or a salt thereof. Method for producing salt, hydrate and solvate. 7. The following general formula (6) (Wherein, R ³ is a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁷ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group, (R ¹ and R ² may be the same or different and each represent a hydrogen atom or C _1-
The C ₆ alkyl group and the ring B represent a benzene ring which may have 1 to 5 substituents (two adjacent substituents may be bonded to each other to form a ring). ) Or a reactive residue, X is a halogen atom or OSO ₂ R ⁶ (R ⁶ is a C ₁ -C ₆ alkyl group which may be halogen-substituted,
A benzene which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring), and the ring C may be a substituted or unsubstituted aryl group. Shows a ring. A benzoquinolidine derivative or a salt thereof,
Hydrates and solvates and the following general formula (7) (Wherein, Y is a halogen atom, OSO ₂ R ⁶ (R ⁶ is the same as above), B (R ⁸ ) 2 (R ⁸ is a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy) Or R ⁸ may be mutually bonded to form a ring), MgBr or ZnCl, and the A ring are each independently selected from one to three substituents (two adjacent substituents) A benzo group according to claim 1 or 3 by reacting a compound represented by the formula (1): wherein the substituents may be mutually bonded to form a ring. A method for producing a quinolidine derivative or a salt, hydrate or solvate thereof. 8. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Receptor antagonist. 9. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. P receptor antagonist. 10. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. An agent for preventing or treating dysuria including urinary bladder dysfunction such as urine and urinary incontinence. 11. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). Wherein the benzoquinolidine derivative represented by the formula (1) or a salt, hydrate or solvate thereof is contained as a pharmaceutical composition. For preventing or treating gastrointestinal diseases including ulcerative colitis and Crohn's disease. 12. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Radiation, chemotherapeutics, pregnancy, migraine,
An agent for preventing or treating vomiting induced by postoperative disease, gastrointestinal motility, side effects of drug administration, and the like. 13. The following general formula (1) (Wherein R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 Or a heterocyclic ring, which may have a substituent (s), which may combine with each other to form a ring), and the B ring has 1 to 5 substituents (when two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other to form a ring by forming 1 to 3 substituents (adjacent two substituents are bonded to each other). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate and solvate thereof as a pharmaceutical composition. A therapeutic agent for asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc. in which tachykinin is involved.