WO2000006572A1 - Bensoquinolizine derivatives and process for producing the same - Google Patents

Abstract

Benzoquinolizine derivatives having tachykinin antagonism, in particular, substance P receptor antagonism. Namely, benzoquinolizine derivatives represented by general formula (1) and salts thereof and medicinal compositions containing these compounds or pharmaceutically useful salts thereof. In said formula, R?1, R2 and R3¿ are the same or different and each represents hydrogen or C¿1-6? alkyl; the ring A is a homocycle or a heterocycle optionally having 1 to 3 substituents selected independently (wherein 2 substituents adjacent to each other may be bonded together to form a ring); the ring B is a benzene ring optionally having 1 to 5 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring); and the ring C is a benzene ring optionally having 1 to 3 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring).

Description

 Satsuki Itoda β-benzoquinolidine derivative and its production method

 The present invention relates to a novel benzoquinolidine derivative having an inhibitory action on evening quinkinin receptor or a pharmacologically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition containing the benzoquinolidine derivative. Background art

Evening Kikinin (substance [rho, neurokinin A, Nyurokini emissions B) is a generic term for neuropeptide, it its receptors present in the body (neurokinin 1 (NKJ neurokinin 2 (NK _2), neurokinin 3 (NK3)) is known to exert various physiological activities, among which substance P acts as a transmitter of central and peripheral primary sensory neurons and diuresis. It has physiological activities such as hyperactivity, nerve cell excitability, vascular permeability enhancement, vasodilation, smooth muscle contraction, immunity, etc., and various disease states (frequent urination, urinary incontinence, vomiting, inflammation, allergy, airway Diseases, pain, central nervous system diseases, etc.). Therefore, tachykinin receptors are excellent as preventive and therapeutic agents for the above various conditions. There is a demand for the development of a compound that has an antagonistic effect, in particular, a substance P receptor antagonistic effect, and has excellent safety and long-lasting properties.

At present, the following compounds and the like are disclosed as compounds having a substance P receptor antagonistic action. (1) In Japanese Patent Application Laid-Open No. 1-28795, the formula is:

R -AD-Trp (R ² ) -Phe-R ³

(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; R ³ is an alk (lower) alkyl group, —N (R ⁴ ) (R ⁵ ) group (wherein R ⁴ and R ⁵ are each hydrogen. Aryl group or lower optionally having a suitable substituent) Represents an alkyl group, R ⁴ and R ⁵ are bonded to each other to form a benzene-condensed lower alkylene group, or an OR ⁶ group, wherein R ⁶ is hydrogen, an aryl group or an appropriate group. Wherein A represents a single bond or one or two amino acid residues, and A represents D-Trp. R ⁴ is not hydrogen when it means one amino acid residue). ing.

 (2) E P — A — 4 2 9 3 6 6 Formula:

Are disclosed. (3) W0 9 1/0 9 8 4 No.4 formula

Are disclosed.

(4) Ε Ρ— Α— 5 3 2 4 5 6 Formula

で表される化合物等が開示されている ( 5 ) E P— A— 5 2 2 8 0 8号に式

(5) EP—A— is a compound represented by the formula

で表される化合物等が開示されている で表される化合物等が開示されている。

Are disclosed. And the like are disclosed.

 (7) In Japanese Patent Application Laid-Open No. Hei 8-67676, the formula is as follows:

(Wherein, ring A and ring B are homo- or hetero-rings, at least one of which is a heterocycle; ring C is a benzene ring; R is H or a hydrocarbon residue; one of X and Y is —NR ¹ — (R ¹ is H or hydrocarbon residue) or — 0—, the other is —C〇 or —CS—, or one is N =, the other is = CR ² — (RH, halogen, hydrocarbon residue , An amino group or a hydroxyl group); n represents 1 or 2.) or a salt thereof is disclosed. (8) Japanese Patent Application Laid-Open No. Hei 9-11064674 formula

(In the formula, X is a hydrogen atom or an oxygen atom, Y is a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a nitrogen atom. R ² is a hydrogen atom, a lower alkyl group, a hydroxyl group, including an alkyl group, a carbamoyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a (4-phenylbiperazine-1-yl) methyl group. And a lower alkenyl group, a lower alkanol group and a lower alkoxy group, and the ring A and the ring B each represent a benzene ring which may have a substituent.

 (9) In Japanese Patent Application Laid-Open No. 9-2636587, the formula is as follows:

(Wherein, the M ring is a heterocyclic ring having a partial structure of X = Y and one N = C <, -CO—N <or one CS—N; R ^a and R ^b are bonded together to form the A ring Or the same or different hydrogen atom or M ring Ring A and ring B are all optionally substituted homo- or heterocyclic rings, at least one of which may be substituted with a heterocyclic ring; ring C is substituted A homocyclic or heterocyclic ring which may have a group; a ring Z which may be substituted; and n represents an integer of 1 to 6. ) Is disclosed.

 At present, it has an excellent antagonistic activity against tachykinin receptor (particularly, a substance P receptor antagonistic activity) as a preventive or therapeutic agent for the above-mentioned various disease states, and in view of safety, sustainability and the like. However, no compound has been found that can be a sufficiently satisfactory drug. An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism against the human kinkinin receptor, particularly a substance P receptor antagonism, which has a different chemical structure from known compounds including the above compounds, and a tachykinin receptor antagonist. Another object of the present invention is to provide a prophylactic or therapeutic agent for dysuria, a prophylactic or therapeutic agent for gastrointestinal disorders, and a prophylactic or therapeutic agent for vomiting. Disclosure of the invention

 The present inventors have the following general formula (1)

(Wherein, I ¹ , R ² and R ³ are the same or different and are each a hydrogen atom or a C i -C _fi alkyl group, and ring A is independently selected from one to three substituents (adjacent 2 Or substituents may be bonded to each other to form a ring), a homo- or heterocyclic ring which may have A benzene ring, which may have a substituent (two adjacent substituents may be bonded to each other to form a ring), and C ring has 1 to 3 substituents (two adjacent substituents). And the substituents may be bonded to each other to form a ring). The present invention provides a benzoquinolidine derivative represented by the following or a salt, hydrate and solvate thereof.

The present inventors have found that ring A is a halogen atom, an optionally substituted to C ₆ alkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i to C ₆ an alkoxy group, a cycloalkoxy group of C ₃ ~ C _{1 0} of optionally substituted C i C s of § Rukanoiruokishi group, optionally substituted § Li Roiruokishi group, an optionally substituted Arirumechiru Okishi group, C ₃ ~ C i. A cycloalkanoyloxy group, an optionally substituted C i C s alkylthio group, an optionally substituted C to C 6 alkylsulfinyl group, an optionally substituted C 1 to C ₆ An alkylsulfonyl group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, C1 alkylcarbonyl amino group ~ C _6, an alkoxycarbonyl amino group of C 1~ C _6, (~ alkylsulfonyl § Mi amino group of ^^, optionally substituted § Li one even if Le sulfonyl § amino groups, C alkylcarbonyl alkylsulfonyl group. 1 to C _6, a formyl group, a carboxyl group, C _t Arukokishikaru Boniru group-C _6, alkyl force Rubamoiru group C i to C ₆ mono- or di-substituted, 1-terrorism three of the 4- to 9-membered cyclic carba which may contain atoms 1 to 3 substituents each independently selected from a silyl group, a cyano group or a two-port group (two adjacent substituents may be bonded to each other to form a ring A) a homo- or heterocyclic ring which may have

B ring is a halogen atom, optionally substituted C ₁ to alkyl groups of _{C 6, C 3 ~ C i} . A cycloalkyl group, which may be substituted Group, hydroxy group, optionally substituted C ₁ -C ₆ alkoxy group, optionally substituted C! To C ₆ alkanoyloxy, optionally substituted aryloyloxy, optionally substituted arylmethyloxy, C ₃ to C i. Cycloalkoxy group, cycloalkadienyl Noi Ruo alkoxy group of C ₃ ~ C _{1 0,} optionally substituted C _t ~ alkylthio group C _6, optionally substituted C i to alkyl sulfinyl group C _6, alkylsulfonyl group optionally c ₁ to c ₆ may be substituted, amino group, alkylamino amino group of C t C s of mono- or di-substituted and may contain 1 to 3 heteroatom 4 1-9 membered cyclic § Mi amino group - C t C e alkylcarbonyl § Mi amino group, an alkoxy Karuboniruami Roh groups, C alkylsulfonyl § Mi amino group of - C _6, substitution which may be § reel sulfonyl Amino group, C i -C ₆ alkyl carbonyl group, carboxyl group, C i -C ₆ alkoxycarbonyl group, mono- or di-substituted C, -C ₆ alkyl rubamoyl groups, 1-3 4- to 9-membered ring which may contain a hetero atom 1 to 3 substituents independently selected from a rubamoyl group, a cyano group, or a nitro group (two adjacent substituents may be bonded to each other to form a ring) Represents a benzene ring which may have

Ring C is a halogen atom, an optionally substituted alkyl group of CC e, a hydroxyl group, an optionally substituted C i C alkoxy group, an optionally substituted C i C ₆ alkanol alkoxy group, an optionally substituted § Li Roiruokishi group, optionally substituted § Li Rumechiruokishi group, C ₃ ~ C i. A cycloalkoxy group of C ₃

(丄. Cycloalkanoyloxy group, amino group, mono- or di-substituted C t Ce alkylamino group, 4- to 9-membered cyclic group which may contain 1 to 3 hetero atoms Mi amino group, C! alkylcarbonyl § Mi amino group of ~ C _6, alkoxycarbonyl § Mi amino group of C ₁ ~ C _6, a C i C s 1 to 3 substituents each independently selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, a cyano group and a nitro group (two adjacent groups) The benzoquinolidine derivative according to claim 1, which represents a benzene ring which may have a benzene ring which may be bonded to each other to form a ring.

 The present inventors have the following general formula (2)

(In the formula, R ³ is a hydrogen atom or a C i Cs alkyl group, R ₄ is a hydroxyl group, a C i C alkoxy group, a benzyloxy group or a reactive residue, and ring A is a halogen atom or substituted. A C i -C ₆ alkyl group; an optionally substituted aryl group, a hydroxy group, an optionally substituted C i Cs alkoxy group, a C ₃ -C ₁₀ cycloalkoxy group, ! optionally substituted C for ~ C ₆ alkanoyloxy Noi Ruo alkoxy group, optionally substituted § Li also be Roiruokishi group, optionally substituted § Li - Rumechiruokishi group, Shikuroarukano of C ₃ -C _{1 0} Iruokishi group, optionally substituted C ₁ -C ₆ alkylthio group, a substituted alkylsulfinyl group which may C i to C ₆ optionally, alkylsulfonyl good C i to C _beta substituted Group, amino group, mono- or di-substituted CiCe alkyl Amino groups from 1 to 3 heteroatom to contain an be 4-9 membered cyclic § Mi amino group, an alkylcarbonyl § Mi amino group of _{C i~ C 6, C i C} e alkoxycarbonyl § Mino group, C i -C ₆ alkylsulfonylamino group, arylsulfyl which may be substituted Honylamino group, C i Ce alkylcarbonyl group, formyl group, carboxyl group, C! C ₆ -alkoxycarbonyl group, mono- or di-substituted C i -C ₆ alkyl rubamoyl group, 4- to 9-membered cyclic rubamoyl group optionally containing 1 to 3 hetero atoms, cyano group Or 1 to 3 substituents each independently selected from among the nitro groups (two adjacent substituents may be bonded to each other to form a ring) Good homo or heterocyclic ring, ring C is halogen atom, optionally substituted C i C (; alkyl group, hydroxy group, optionally substituted CCs alkoxy group, optionally substituted (! To C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylalkyloxy group, C ₃ to Cio cycloalkoxy group, C ₃ to C _{1 0} cycloalkadienyl Noi Ruo key sheet group, amino group, mono also Di-substituted alkyl amino group of C 1~ C _6, 1 ~ 3 or heteroatom to contain an be 4-9 membered cyclic § Mi amino group, C i C e alkylcarbonyl § Mi amino group of, alkoxy Karuboniruami amino group of, C i to alkylsulfonyl § amino group of C _6, selected replacement which may § Li one also be Rusuruhoniruami amino group, from among Shiano group or a filtrated group which it independently Represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring).

A benzoquinolidine derivative represented by the formula: or a salt, hydrate and solvate thereof.

The present inventors have the following general formula (3)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(1 ¹ and 1 ² are the same over or different and each represents a hydrogen atom or a ₍₁ - ₍₆ Aruki Le group, B ring 1-5 substituents (and adjacent two substituents combined binding each other to form a ring forming a shows a benzene ring which may have a well may) have.) or a reactive residue, X is a halogen atom or a 0 S_〇 ₂ R ⁶ (R ⁶ is an optionally halogen-substituted C , To C ₆ alkyl group, optionally substituted aryl group), ring C is halogen atom, optionally substituted C i to C ₆ alkyl group, hydroxy group, optionally substituted CC e, an alkoxy group of e, an optionally substituted C! Ce alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C ₃ -C 1. Cyclic alkoxy group, C ₃ -Ci. Cycloalkanoyloxy group, amino group, mono or C 〖~ of disubstituted (6 alkylamino amino group of from 1 to three ring § Mi Roh group which may 4-9 membered contain a hetero atom, alkylcarbonyl § Mi C i to C ₆ Bruno Group, a C ₆ to C ₆ alkoxycarbonylamino group, a C i C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, a cyano group or a nitro group 1 to 3 independently selected substituents (two adjacent And the substituents may be bonded to each other to form a ring). The present invention provides a benzoquinolidine derivative represented by the following or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (4)

(Wherein, R ³ is a hydrogen atom or a C i Cs alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, the C ring is a halogen atom, an optionally substituted C i -C ₆ alkyl group, a hydroxy group, An optionally substituted C i Ce alkoxy group, an optionally substituted C i Ce alkanoloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyl Okishi group, C ₃ -C _{1 0} of consequent opening alkoxy group, C ₃ cycloalkadienyl Noi Ruo alkoxy group ~ C t _0, amino group, mono- or di-substituted alkylamino group C. 1 to C 6, 1 1-3 may also be 4-9 membered contain heteroatoms of the cyclic § Mi amino group, an alkyl Cal of C i to C ₆ Niruami amino group, C, alkoxycarbonyl Niruami amino group of ~ C _6, alkylsulfonyl § Mi amino group of C ~ C _6, optionally substituted One to three substituents independently selected from an arylsulfonylamino group, a cyano group or a nitro group which may be substituted (when two adjacent substituents are bonded to each other, Which may form a ring). The present invention provides a benzoquinolidine derivative represented by the formula or a salt, hydrate and solvate thereof.

The present inventors have the following general formula (2)

(In the formula, R ³ is a hydrogen atom or a C i C f; alkyl group, R ⁴ is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a benzyloxy group or a reactive residue, and the A ring is each independently. 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring) optionally having 1 to 3 substituents; Represents a benzene ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring).

Or a salt, hydrate or 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 i C s alkyl group, and the B ring has 1 to 5 substituents. A benzene ring which may be bonded to each other to form a ring). The present invention provides a method for producing a compound or a salt, hydrate or solvate thereof according to claim 1 by reacting the compound or a salt, hydrate or solvate thereof.

 The present inventors have the following general formula (6)

(Wherein, R ³ is a hydrogen atom or a C i C alkyl group, R ⁷ is a hydroxyl group, a C i -C ₆ alkoxy group, a benzyloxy group,

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, and X is a halogen atom or 0 S〇 ₂ R ⁶ (where R ⁶ is optionally substituted C) alkyl group i to C _6, substituted optionally may be Ariru group), C ring may 1-3 substituents (bonded two adjacent substituents together to be combined to form a ring) Represents a benzene ring which may have ) Or a salt, hydrate or solvate thereof and a benzoquinolidine derivative represented by the following general formula (7):

(A) -Y (7)

(Where Y is a halogen atom, OS〇 ₂ R ⁶ (RG is the same as above), B (R ⁸⁾ 2 (R ⁸ is a hydroxyl group, an alkoxy group an alkyl group or a C i C s of CC e. Or R ⁸ may be bonded to each other to form a ring.), M g B Each of the r or ZnCl and A rings independently has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). Represents an optionally homo- or heterocyclic ring. The present invention provides a method for producing a benzoquinolidine derivative or a salt, hydrate and solvate thereof according to claim 1 by reacting a compound represented by the formula:

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

 The present inventors provide a substance P receptor antagonist characterized by containing 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 bladder for pollakiuria, urinary incontinence, etc., characterized by containing a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is an agent for preventing or treating dysuria including a functional disorder.

 The present inventors have developed ulcerative colitis and Crohn's disease characterized by containing 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 gastrointestinal diseases, including:

The present inventors have proposed a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition, which is characterized by X-ray irradiation, a chemotherapeutic agent, Provided is a prophylactic or therapeutic agent for vomiting induced by pregnancy, migraine, postoperative illness, decreased gastrointestinal motility or side effects of drug administration. The present inventors have developed an asthma or cough involving tachykinin, which comprises a benzoquinolidine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. Provide therapeutic agents for pain, migraine, toothache, rheumatoid arthritis and the like.

Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group of c ₁ ~ c _6, means methyl group, E Ji group, a propyl group, an isopropyl group, t- butyl group, a hexyl group or the like. The C ^ Ce alkoxy group means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexoxy group and the like. The cycloalkoxy group of C ₃ ~ C i _0, cyclo propyl O alkoxy group, cyclobutyl O alkoxy group, means a Shikuropenchiruo alkoxy group, Kishiruokishi group cyclohexylene. C a C i. The cycloalkanoyloxy group means cyclopropanoyloxy group, cyclobutanoyloxy group, cyclopentanoyloxy group, cyclohexanoyloxy group and the like. The alkylcarbonyl group C t~ C _6, Asechiru group, a propionyl group, means an Puchiriru group. The C i C fj alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, a hexyloxycarbonyl group or the like. The mono- or di-substituted C ₆ -C ₆ alkyl rubamoyl group is a methylcarbamoyl group, an ethylcarbamoyl group, a tributyl rubamoyl group, an isobromovir group, a t-butyl group rubamoyl group, a hexylcarbamoyl group. A dimethylcarbamoyl group, a dimethylcarbamoyl group, a dipropylcarbamoyl group, a diisopropylcarbamoyl group, a dibutylcarbamoyl group, a dihexylcarbamoyl group, and the like. A 4- to 9-membered cyclic rubamoyl group which may contain 1 to 3 heteroatoms is azetidinylcarbonyl Group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, 4-methylbiperidinylcarbonyl group, morpholinylcarbonyl group, thiomorpholinylcarbonyl group, piperazinylcarbonyl group, 4-methylpipe It means a radinylcarbonyl group or the like. The C i -C ₆ alkylthio group means a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a t-butylthio group, a hexylthio group, and the like.

 C i Ce alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, t-butylamino, hexylamino, dimethylamino, getylamino, dipropylamino, dipropylamino It means a isopropylamino group, a dibutylamino group, a dihexylamino group and the like. The 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group, morpholino group, and thiomorpholino. Group, piperazino group, 4-methylbiperazino group and the like. The C i Ce alkylcarbonylamino group means an acetylamino group, a propionylamino group, a petyrylamino group, or the like.

The C i -C ₆ alkoxycarbonylamino group means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group, or the like. .

The C i Ce 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, or 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 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, or 9 Or a 10-membered fused aromatic heterocycle. The optionally substituted alkyl groups of ^ to ₆ include halogen atoms, hydroxy groups, and C! ~ C (; alkoxy group, an alkyl Chiomoto of C i~C _6, amino group, alkylamino group of C i C e of mono- or di-substituted - may contain from 1 to 3 heteroatom . 4-9 membered cyclic amino groups Horumiruami amino group, C i to C alkylcarbonyl § Mi amino group of _fi, alkylsulfonyl § amino group Ci -C _6, optionally substituted § Li - Rusuruhoniruami Bruno A C i C s alkyl group which may have 1 to 5 substituents selected from a group, etc. The optionally substituted C to C ₆ alkoxy group means a halogen atom , human Dorokishiru group, C, include alkoxy groups of ~ C _6, an alkylthio group having C! ~ C _6, an amino group, alkylamino amino group of C i C s of mono- or di-substituted, 1 to 3 heteroatom Idei and may 4-9 membered cyclic § Mi amino group, formylamino group, alkyl carbonyl C ₁ -C ₆ Which may have 1 to 5 substituents selected from an amino group, an alkylsulfonylamino group of CiCe, an optionally substituted arylsulfonylamino group, and the like. Means an alkoxy group of _6. An optionally substituted C _{1 to} C ₆ alkanoyloxy group is a halogen atom, a hydroxy group, a C 丄 to C ₆ alkoxy group, a C i to C ₆ An alkylthio group, an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, a formylamino group, 1 to 5 substituents selected from C t to C ₆ alkylcarbonylamino groups, CiCe alkylsulfonylamino groups, and optionally substituted arylsulfonylamino groups C i -C ₆ alkanoyloxy group which may have a group (acetyloxy group, A propionyloxy group, an isopropionyloxy group, a hexanoyloxy group, etc.) An optionally substituted aryloyloxy group includes a halogen atom, an alkyl group of € ^ 06, a hydroxyl group, C i C e An alkoxy group, a C 1 to C _fi alkylthio group, an amino group, a mono- or di-substituted C ₁ to C ₆ alkylamino group, a 4- to 9-membered group which may contain 1 to 3 heteroatoms Cyclic amino group, formyl amino group,

Alkylcarbonyl amino group of C _6, have a C i to alkyl sulfonyl Ruami amino group of C _6, optionally substituted § Li one also be Rusuruhoniruami Bruno 1-5 substituents selected from such groups Or an aryloxy group (a benzoyloxy group, a naphthyloxy group, a pyridyloxy group, a pyrimidyloxy group, a quinolyloxy group, an indyloxy group, etc.). The arylmethyloxy group which may be substituted includes a halogen atom, a C i C alkyl group, a hydroxy group, a (^ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, and an amino group. A mono- or di-substituted CiCs alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group, a CiCe alkyl Karuboniruami amino group, Arukirusu Ruhoniruami amino group, which may have 1 to 5 substituents selected from such optionally substituted § also be reel sulfonyl amino group Ariru Mechiruokishi of C ₁ ~ C ₆ (A phenylmethyloxy group, a naphthylmethyloxy group, a pyridylmethyloxy group, a quinolylmethyloxy group, an indylmethyloxy group, etc.) An optionally substituted arylsulfonylamino The halogen atom, an alkyl group of C ₁ -C _6, alkylamino arsenide Dorokishiru group, an alkoxy group of C ₁ ~ C _6, alkyl Chiomoto of CC e, amino group, mono- or di-substituted C i C e cyano group. 1 to 3 or heteroatom to contain an be 4-9 membered cyclic amino group, Horumiruami amino group, an alkylcarbonyl § Mi amino group of C! ~ C _6, a C i -C ₆ It means an arylsulfonylamino group optionally having 1 to 5 substituents selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group and the like. Two adjacent Is a ring in which the substituents may be combined with each other to form

ιΓ ο>

等を意味する。

And so on.

The aryl group which may be substituted is a halogen atom, C! To C ₆ alkyl group, hydroxy group, C 1 to C ₆ alkoxy group, C i to

C ₆ alkylthio, amino, mono- or di-substituted C! -C ₆ alkylamino group, 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, formylamino group, C 1 -C ₆ alkylcarbonylamino group, C an aryl group optionally having 1 to 5 substituents selected from i-C6 alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. (phenyl group, naphthyl group Etc.). The alkylthio group which may be substituted includes a halogen atom, a hydroxyl group, a C i C alkoxy group, a C ₁ to C ₆ alkylthio group, an amino group, a mono- or di-substituted C! To C ₆ Alkylamino group, 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, formylamino group, C! To C6 alkylcarbonylamino group, CiCe alkylsulfonylamino group, optionally substituted arylsulfonylamino group, etc. It means an alkylthio group which may be possessed. The substituents on these alkylsulfinyl group, a halogen atom, human Dorokishi Le group, C. 1 to alkoxy groups of C _6, C 1~ C ₆ alkylthio group, § amino group, mono- or di-substituted C ~ C ₆ alkylamino groups, 4 to 9-membered cyclic amino groups which may contain 1 to 3 heteroatoms, formylamino groups, alkylcarbonylamino groups of (^ ~ (^; An alkylsulfenyl group which may have 1 to 5 substituents selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. (a methylsulfiel group, an ethylsulfyl group) Finyl group, propylsulfinyl group, etc.). The optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxy group, a C to C ₆ alkoxy group, a C i to C 6 alkylthio group, an amino group, a mono- or di-substituted C i Cs An alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, a formylamino group, an alkylcarbonylamino group, an alkyl group of C _{1 to} C ₆ An alkylsulfonyl group optionally having 1 to 5 substituents selected from a sulfonylamino group, an optionally substituted arylsulfonylamino group, etc. (a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, etc.) ) Means The reactive residue means a halogen atom, a 1-imidazolyl group, a 4-nitrophenoxy group, an imidoyloxy succinate group, or the like. The alkyl group of C which may be substituted with halogen includes a methyl group, an ethyl group, a propyl group, an isopropyl group, and a t-butyl group 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 R ⁸ to each other includes: 10 (CH ₂ ) ₂₀ —,-0 CH (Me) CH (Me) 0—, 100 ((] \ [6) ₂ ((] \ [6) ₂ 〇 one or ten (CH ₂₎ means ₃ 0 first class.

Preferred compounds of the present invention include N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-15-oxo 7-phenyl 1H, 5H —Benzo [ij] quino-lysine-1-61carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (3-methoxyphenyl) -1-N— Methyl-5-oxo-1H, 5H-benzo [ij] quinolidine 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7- (4-methoxyphenyl) -1-N-methyl-5-oxo-1H, 5H —Benzo [ij] quinolizine-1 6-carboxamide, N— [3,5_bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-7— (3-methylcyphenyl) -1 5— 1H, 5H-Benzo [ij] quinolidine_6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-dichlorophenyl) 1-2 N-methyl-1-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxamide, N- [3,5-bis (trifluoromethyl) Benzyl] — 9—chloro-1- 7— (2,4-dichlorophenyl) — 2, 3-dihydro-5-oxo-1 H, 5H-Benzo [ij] quinolidine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1N-methyl-1 7— (1— Naphthyl) 1-5-oxo-1H, 5H-benzo [ij] quinoline-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihidro 7 — (4-Fluorophenyl) — N-methyl-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl) ] — 2,3-Dihydro-1-N-methyl-1-oxo-1-7-1 (2-thiophene) 1-1H, 5H-benzo [ij] quinolizine-1-6-carboxamide, N— [3,5-— Bis (trifluoromethyl) benzyl] 1,2,3-dihydro-7_ (3-fluorophenyl) -N-methyl 1-5-oxo-1H, 5H-benzo [ij] quinolidine — 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) 1 2 , 3-Dihydro-1-N-methyl-1-5-oxo-1H, 5H-benzo [ij] quinolidine 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1N-methyl-5-oxo-1 7— (3—trifluoromethylphenyl) 1 1H, 5H-Benzo [ij] quinolidine 1-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1N-methyl-1 7- ( 3 12-Trophenyl) 1-5-oxo-1H, 5H-benzo [ij] quinolidine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihi Dro-3, N-dimethyl-15-oxo-7-phenyl-1-H, 5H-benzo [ij] quinolidine — 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 2,3-Dihydro 3, N-Dimethyl-17- (3-Methoxyphenyl) 1-5-Oxo 1 1H, 5H-Benzo [ij] quinolizine 1-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl]-7- (2,4-dichlorophenyl) 1-2, 3 dihydro-1, N-dimethyl-5-oxo 1H, 5H-benzo

[ij] Quinolidine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1,3, N-dimethyl-1-9-fluoro-7— (3-meth Toxifenyl) 1-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxamide,

7- (3-Aminophenyl) 1 N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-5-oxo-1H, 5H—benzo [ ij] quinolizine-1 6-carboxamide and the like.

When the compound of the present invention forms a salt, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, lingoic acid, tartaric acid, citrate, Organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid Can be exemplified.

 The compounds of the present invention or salts thereof include optically active isomers, stereoisomers and rotamers as well as racemic isomers.

 The compound of the present invention can be produced by various synthetic methods. Next, a typical production process of the compound of the present invention and a salt thereof will be described.o

(V)

 (VI) (VIII)

(First step)

In this step, the compound (I) (where R ³ and C ring are the same as described above) and the compound (II) (where R ⁹ is the same or different and an alkyl group or benzyl group of Ci to C ₆ ) are reacted to obtain a compound (III) (R ³ , R ⁹ and the C ring are the same as described above). In this reaction, the compound (当) is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents to the compound (I), at 100 to 300 ° C., preferably 150 to 25 ° C. Performed at 0 ° C. When a solvent is used, an inert solvent which does not participate in the reaction, for example, xylene, mesitylene, nitrobenesen, diphenyl ether, dautherm (a mixture of diphenyl ether and biphenyl) and the like are used.

 (Second step)

In this step, the water of compound (() (R ³ , R ⁹ and C ring are the same as above) In this step, the acid group is converted to X (X is the same as described above) to produce 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, the chlorinating agent is a phosphine such as triphenylphosphine, tributylphosphine, or triphenyloxyphosphine, and carbon tetrachloride, N-chlorosuccinimide. The reaction is carried out using chloride, chlorine, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride. When a solvent is used, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitril, 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, if 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 chlorination using a corresponding brominating agent. X is 0 S 〇 ₂ R ⁶

In the case of (R ⁶ is the same as above), the sulfonating reagents used in this reaction are methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and trifluoromethanesulfonic anhydride. , Trifluoromethanesulfonyl chloride, N-phenyl trifluoromethanesulfonylimide, etc. are used, and the reaction is carried out in a solvent in the form of triethylamine, triptylamine, diisopropylethylamine. The reaction is performed in the presence of a base such as N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisoproviramide. 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 a temperature of from 178 ° C to 100 ° C, preferably from 130 ° C to 80 ° C.

 (Third step)

In this step, compound (IV) (rings X, R ³ , R ⁹ and C are the same as described above) and compound (V) (rings Y and A are the same as described above) are treated with palladium or nickel. This is a step of producing a compound (VI) (R ³ , R ⁴ and the A ring are the same as above) by a cross-cutting reaction in the presence of a transition metal catalyst such as a Kel complex. This reaction is preferably performed using an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, Examples thereof include tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol, and water. These solvents are used alone or in a mixture at any ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetylacetonato palladium, and tetrax (triphenylphosphine) palladium. Examples of the nickel complex used in this reaction include bis (acetylacetonato) nickel, bis (1,5-cyclohexene) dienyl or tetrax (triphenylphosphine) nickel, and the like. These palladium or nickel complexes are used in the range of 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (IV). When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri10-tolylphosphine, tri2-furylphosphine, 1,2-bis (diphenylphosphino Examples thereof include ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) -11,1,1-binaphthyl. These ligands are used in a range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex. When the compound (IV) is 〇S 0 ₂ R ⁶ , a palladium or nickel complex may be used together with copper iodide or lithium chloride if necessary. The reaction is carried out in the presence of a suitable base. Preferably, for example, triethylamine, triptilamine, diisopropylethylamine, N —Organic bases such as methyl morpholine, pyridine, lutidine and collidine, sodium hydrogen carbonate, sodium carbonate, sodium carbonate, calcium carbonate, cesium carbonate or calcium phosphate, etc. The inorganic bases can be exemplified. 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 carried out at room temperature to 150 ° C., preferably at 50 to 120 ° C. In addition, in the cross-coupling reaction of this process, the compound

When a compound in which Y in (V) is not B (R ⁸ ) ₂ is used as a raw material for production, compound (IV) or compound (V) (where Y is not B (R ⁸ ) ₂ ) HB (R ⁸⁾ ₂ or _{^{(B (R 8) 2)}} 2 was reacted to give et compound (IV) (X is B (R ⁸⁾ 2) or the compound (V) (Y is B (R ⁸⁾ Compound (VI) can also be produced by reacting ₂ ) with compound (V) (where Y is not B (R ⁸ ) ₂ ) or compound (IV). The compound (IV) (where B (R ⁸ ) ₂ ) or compound (V) (Y is B (R ⁸ ) ₂ ) and the A ring is the same as the above, which is a production intermediate obtained at this time, is simply It can be subjected to the next step after isolation and purification, or can be continuously applied to the next step without isolation and purification.

 (Fourth step)

In this step, compound (VII) (R ³ , R ⁴ and ring A are the same as described above) and compound (VII) (RR ² and ring B are the same as described above) are condensed to form compound (VIII (R ¹ R ² , R ³ , ring A, ring B and ring C are the same as described above). Examples of the condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction of this step include dicyclohexylcarpoimide (DCC), 3-ethyl-1- (3-dimethylaminoprobiol) and carbodiimide hydrochloride ( EDCI) or dimethylimidazolinium chloride (DMC), etc., which are added in solid form or as a solution dissolved in a suitable solvent. Use of base in this condensation reaction If present, alkaline carbonates such as sodium hydrogen carbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5.4.0] — Tertiary amines such as 7-indene, pyridine, 4-dimethylamino pyridine or 1,8-bis (dimethylamino) naphthalene are exemplified. As the solvent used in the present condensation reaction, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran, dioxane San, ethyl ether, dimethoxetane, ethyl acetate, dichloromethane and the like are used. This condensation reaction proceeds smoothly at a temperature of 120 ° C to 80 ° C. In the condensation reaction of this step, R ⁴ is a carboxylic acid halide represented by a reactive residue (eg, a halogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc.) In the case of imidazolides of carboxylic acids, active esters of carboxylic acids, mixed anhydrides of carboxylic acids (for example, anhydrides with ethylcarbonate, anhydrides with isobutylcarbonate, etc.) or, in the case of symmetric acid anhydrides, triethylamido N, N in the presence or absence of an organic base, such as benzene, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or an inorganic base, such as sodium hydrogencarbonate or potassium carbonate. —Dimethylformamide, N, N —Dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethylethyl Le, dimethyl Tokishe Tan, acetic Echiru, toluene, in a solvent such as dichloromethane, can be carried Ri by the treating 3 0 minutes to 48 hours in one 2 0 ~ 8 0 ° C. In the condensation reaction in this step, R ⁴ is an alkoxy group of CiCs. When an ester residue such as a benzyloxy group is used, in the presence of trimethylaluminum or tetraisopropoxytitanium, or p-toluene Acid catalyst such as sulfonic acid or sodium methoxide, calcium -N, N-Dimethylformamide, N, N-Dimethylacetamide, Dimethyl sulfoxide, Acetonitrile, Tetrahydrofuran in the presence of bases such as t-butoxide and hydrogenated sodium It can be carried out by treating the mixture in a solvent such as dioxane, toluene, xylene, or dichloromethane at room temperature to 150 ° C. for 30 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, the compound (X) is used in an amount of 1 to 10 equivalents with respect to the compound (IX), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium-t-butoxide, water N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene in the presence of base such as hydrogenated sodium It can be carried out by treating in a solvent such as these at 50 to 150 ° 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) is compounded with compound (XII) It can also be manufactured from product (X). In this step, the compound (X) is used in an amount of 1 to 10 equivalents to the compound (XII), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium 1-butoxide, N, N—dimethylformamide, N, N—dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, in the presence of a base such as hydrogenated sodium It can be carried out by treating in a solvent such as xylene at 50 to 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (II) 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 a usual method or a method analogous thereto (eg, neutralization).

The compound (1) or a salt thereof of the present invention can be used alone or in combination with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition. Agents (eg, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc, stearic acid, etc.), binders (eg, starch, crystals) Cellulose, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose, calcium, etc.), diluents (eg, saline, glucose, mannitol, lactose, etc.) Solution, etc.) and tablets, capsules, granules, It can be administered orally or parenterally in the form of powders, fine granules, ampules or injections. The dose depends on the type of the compound (1) or a salt thereof, the administration route, the age of the patient, For example, the compound (1) of the present invention or a salt thereof is 0.0001 to 30 mg / kg / day for mammals including humans, although it varies depending on symptoms and the like. For example, administration is performed once or several times a day. BEST MODE FOR CARRYING OUT THE INVENTION

 experimental method

NK1 receptor antagonism

 The method of S. Dion et al. (“Life Sciences”, Vol. 41, pp. 2269 (1989)) was partially modified.

After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The removed ileum was suspended in a Magnus tube with a load of 1 g. Specimen responses were recorded isotonic. Nutrient solution, using a T Yrode solution, 0 ₂ 9 5% bubbled C_〇 _25% of the mixed gas, the liquid temperature was set to 3 2 ° C. The experiment was 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 PA 2 value was determined by the method of Schi 1 d (“Brit. J. Pharmaceuticals, Vol. 14, p. 48, p. Year)), and the results are shown in Table 1.

The composition of the Tyrode solution was as follows. N a C l; 1 3 6. 9, KC 1; 2. 7, C a C l 2 - 2 H 2 0; 2. 5, Mg C l 2 - 6 H 20; 1. 0, N a H 2 P_〇 _{4 '2 H 2 O; 0.} 4, N a HC_〇 _{3; 1 1. 9, glucose 1} 1. 1 (mM) 〔table 1〕

Example number ― J) A 2 ifin nMl

 1 8 1 1.3

 1 9 5.2 0

 2 9 2 4.1 Example 1

Methanone (1,2,3,4-tetrahydroquinolin-18-yl) (2,4-dichlorophenyl) (918.6 mg, 3.0 mmol) is dissolved in 10 ml of ethyl acetate and triethylamine 1.25 ml was added thereto, and ethylmalonyl chloride (0.96 ml, 7.5 mmol) was added dropwise under ice cooling, and the mixture was stirred for 2 hours. Methylene chloride was added to the reaction solution, which was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was dissolved in tetrahydrofuran (10 ml), and water-t-butoxide (404.0 mg, 3.6 mmol) was added little by little under ice-cooling, followed by stirring for 1 hour. Neutralized with 20 ml of 1N aqueous hydrochloric acid, water was added, and the mixture was extracted three times with ethyl acetate. The extract 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 a colorless amorphous 7- (2, 4). 1,2-Dihydroxy-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxylic acid ethyl ester (1.34g, 94%).

EIMS m / z: 401 (M ⁺ ) Example 2

 7- (2,4-dichlorophenyl) -1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylic acid ethyl ester (427.1mg, 1.06mmol) and Palladium hydroxide carbonate (81.4 mg) was dissolved in ethanol (10 ml), triethylamine (0.3 ml) was added, and the mixture was stirred under a hydrogen atmosphere (3.5 atm) at 65 for 6 hours. The palladium hydroxide was removed by filtration through celite, and the residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1). The crystals are washed with hexane to give colorless crystals of 2,3-dihydro-5-oxo-17-phenyl-1H, 5H-benzo [ij] quinolidine-16-carboxylic acid ethyl ester (187.7g , 53%) 7 o

EIMS m / z: 333CM ⁺ ) Example 3

 7- (2,4-Dichlorophenyl) -1,2,3-dihydro-5-oxo1H, 5H-benzo [ij] quinolizine-16-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-chloro succinic acid imid (145.3 mg, 1.09 mmol) was added, and the mixture was stirred for 4 hours. Ethyl acetate was added to the reaction solution, which 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 chromatography (methylene chloride) to obtain a pale yellow amorphous solid. 1 7— (2,4—dichlorophenyl) 1-2,3-dihydro-5-oxo-1H, 5H—benzo [ij] quinolinidine-16—carboxylic acid ethyl ester (416.5 mg, 95%) Obtained.

EIMS m / z: 435 (M ⁺ ) Example 4

 7-Chloro-2,3-dihydro-5-oxo-1H, 5H-Benzo [ij] quinolizine-16-Ethyl carboxylate (291.7mg, l.Ommol) and tetrakistri Phenylphosphinoradium (46.2 mg, 0.04 mmol, 0.04 eq.) Was dissolved in 5 ml of benzene and 1 ml of a 2M aqueous solution of sodium carbonate to give 3-methoxyethoxyboronic acid (303.9 mg, 2.0 mmol) of 1,4-dioxane (2 m solution) was added, and the mixture was heated to reflux. Tetrataxiphenylphenylphosphine palladium (26.2 mg, 22.7 mol) was added in the middle, and the mixture was heated to reflux for 10 hours. Water and methylene chloride were added to the mixture, and the mixture was extracted three times with methylene chloride.The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (chloroform chromatography). Methylene: Purified with ethyl acetate 20: 1) to give colorless crystals of 2,3-di Draw 7- (3 - Main Tokishifueniru) one 5 - O Kiso one 1 H, 5 H - benzo [i j] quinoline-lysine one 6 - Power carboxylic acid E Ji glycol ester (359.1mg, 99%) was obtained.

EIMS m / z: 363 (M ⁺ ) Example 5

 According to the same method as in Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizin-16-carboxylate ethyl ester (145.9 mg , 0.50 mmol) and 1-naphthyl boric acid (258. Omg, 1.5 mmol) as colorless oils of 2,3-dihydro-17- (1-naphthyl) -15-oxo-1H, 5H-benzo [ij The quinolizine-6-potassium rubonic acid ethyl ester (202.6 mg, 100%) was obtained.

EIMS m / z: 383 (M ⁺ ) Example 6

According to a method similar to that of Example 4, 7-clo mouth_2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylate ethyl ester (116.7 mg, 0.40 mmol) and 4-fluorophenyl 2,3-Dihydro-1- 7- (4-fluorofurnyl) -l- 5-Hydroxyl 1H, 5H-benzo [ij] quinolidine 16- from colorless crystals of oxalic acid (167.9mg, 1.2mmol) The carboxylic acid ethyl ester (111.0 mg, 79%) was obtained. EIMS m / z: 351 (M ⁺ )

実施例 4 と同様の方法によ り、 7—クロ口一 2， 3 —ジヒ ドロ一 5 —ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リジン一 6 —カルボ ン酸ェチルエステル（116.7mg， 0.40mmol)と 2 —チォフ ェンほう酸 (153.6mg, 1.2mmol)から無色結晶の 2 , 3 —ジヒ ドロ一 5 —ォキソ一 7— （ 2 —チォフェン） 一 1 H , 5 H—ベンゾ [ i j ] キノ リジン — 6 —力ルボン酸ェチルエステル（167.9mg， 62%)を得た。

According to the same method as that of Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylate ethyl ester (116.7 mg, 0.40 mmol) and 2-thiophenic boric acid (153.6 mg, 1.2 mmol) in the form of colorless crystals of 2,3-dihydro-1-5-oxo-7-(2-thiophene)-1 H, 5 H-benzo [ij] Quinolysine-6-potassium ethyl ester (167.9 mg, 62%) was obtained.

EIMS m / z: 339 (M ⁺ )

Example 8

実施例 4 と同様の方法によ り、 7—クロ口一 2， 3 —ジヒ ドロー 5 —ォキソ一 1 H， 5 H—べンゾ [ i j ] キノ リジン一 6—カルボ ン酸ェチルエステル（116.7mg， 0.40mmol)と 3 -フルォロフェニルほ う酸（167.9mg, 1.2mmol)から無色油状物質の 2 , 3—ジヒ ドロー 7— ( 3—フルオロフェニル） 一 5 —ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リジン一 6 —力ルボン酸ェチルエステル（108.8mg， 77%)を 得た。

According to the same method as that of Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxyethyl ester (116.7 mg) , 0.40 mmol) and 3-fluorophenylboronic acid (167.9 mg, 1.2 mmol) as a colorless oily substance, 2,3-dihydro 7- (3-fluorophenyl) -1-5-oxo-1H, 5H-benzo [ ij] Quinolysine 6-potassium ethyl ester (108.8 mg, 77%) was obtained.

EIMS m / z: 351 (M ⁺ )

実施例 4 と同様の方法によ り、 7—クロロー 2， 3 —ジヒ ドロー 5 —ォキソ一 1 H， 5 H—ベンゾ [ i j ] キノ リジン一 6 —カルボ ン酸ェチルエステル（116.7mg, 0.40mmol)と 3 —ニ トロフエニルほう 酸（200.3mg， 1.2mmol)から無色アモルフ ァスの 2， 3—ジヒ ドロ一 7 - ( 3 —二 ト ロフエニル） 一 5 —ォキソ一 1 H , 5 H—べンゾ [ i j ] キノ リ ジン一 6 —力ルボン酸ェチルエステル（91.5mg, 60%)を得 た。

In the same manner as in Example 4, 7-chloro-2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carbo Ethyl ester (116.7 mg, 0.40 mmol) and 3-nitrophenyl boric acid (200.3 mg, 1.2 mmol) to give colorless amorphous 2,3-dihydro-17- (3-diphenyl) -1-5-oxo One 1H, 5H-benzo [ij] quinoidine 16-potassium ethyl ester (91.5 mg, 60%) was obtained.

EIMS m / z: 378 (M ⁺ ) Example 10

実施例 4 と同様の方法によ り、 7—クロ口一 2， 3 —ジヒ ドロ一 5 —ォキソ一 1 H， 5 H—べンゾ [ i j ] キノ リ ジン一 6 —カルボ ン酸ェチルエステル（116.7mg， 0.40mmol)と 3 —クロ口フエニルほう 酸（187.7mg， 1.2mmoりから無色油状物質の 7 — ( 3 —クロ口フ エ二 ル） 一 2 , 3 —ジヒ ドロ一 5 —ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リ ジン一 6 —力ルボン酸ェチルエステル（119.4mg， 81%)を得た。

According to a method similar to that of Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxylate ethyl ester ( 116.7mg, 0.40mmol) and 7- (3-chlorophenyl) both (187.7mg, 1.2mmo) as colorless oily substance 7- (3-chlorophenyl) 1-2,3-dihydro-5-oxo-1 1H, 5H-Benzo [ij] quinolidine-16-potassium ethulyl ester (119.4mg, 81%) was obtained.

EIMS m / z: 367 (M ⁺ ) Example 1 1

 According to the same method as in Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxyethyl ester (116.7 mg) , 0.40 mmol) and 3-trifluoromethylphenylboronic acid (227.9 mg, 1.2 mmo to 2,3-dihydro-15-oxo-17- (3-trifluoromethylphenyl) 1-1H as a colorless oily substance , 5H-Venzo [ij] quinolidine-l-6-ethyl carboxylate (136. () Mg, 85%) was obtained.

EIMS m / z: 401 (M ⁺ ) Example 1 2

In the same manner as in Example 4, 7-black 5—oxo 1 H, 5 H—benzo [ij] quinolizine 16—carboxyethyl ester (116.7 mg, 0.40 mmol) and 4—methoxyphenylboronic acid (182.4 mg, 1.2 mmol) colorless 2,3-Dihydro-7- (4-methoxyphenyl) -1-5-H-benzo-1H, 5H-benzo [ij] quino-lysine-16-amorphous Ethyl ester of ruvonic acid (99.2 mg, 68%) I got

EIMS m / z: 363 (M ⁺ ) Example 13

 According to the same method as in Example 4, 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylate ethyl ester (116.7 mg, 0.40 mmol) and 3-Methynolephenyl borate (163.2 mg, 1.2 mmol) ^ colorless crystals of 2,3-dihydro-17- (3-methylphenyl) -15-oxo-1H, 5H-benzo [ij] quino There was obtained lysine 16-potassium ethyl ester (100.0 mg, 72%).

EIMS m / z: 363 (M ⁺ ) Example 14

 In the same manner as in Example 4, 7-chloro-1,2,3-dihydro-3-methyl-5-year-old 1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (122.3 mg, 0.40 mmol) and phenylboronic acid (146.3 mg, 1.2 mmol) as colorless crystals of 2,3-dihydro-1-methyl-5-oxo-17-phenyl-1-H, 5H-benzo [ij] Quinolysine 1-6-ruthenic acid ethyl ester (96.3 mg, 69%) was obtained.

EIMS m / z: 347 (M ⁺ )

In the same manner as in Example 4, 7-chloro-1,2,3-dihydro-13-methyl-5-oxo-1H, 5H-benzo [ij] quinoidine-6-carboxylic acid ethyl ester ( 122.3 mg, 0.40 mmol) and 3-methoxydiboronic acid (182.4 mg, 1.2 mmol) as colorless oils of 2,3 -dihydro-1 7-(3- methoxyphenyl) 1-3 -methyl-1 5 —Oxo — 1H, 5H-Benzo [ij] quinolinidine-16-carboxylate ethyl ester (80.7mg, 53%) was obtained.

EIMS m / z: 377 (M ⁺ ) Example 16

In the same manner as in Example 4, 7-chloro-2,3-dihydro-3-methyl-1-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (122.3 mg, 0.40 mmol) and 2,4-dichloroporous phenylboric acid (286.2 mg, 1.5 mmol) to give colorless amorphous 7- (2,4-dichlorophenyl) 1-2,3-dihydro-3-methyl was obtained Lou 5- Okiso one 1 H, 5 H- base emission zone [ij] quinoline-lysine one 6-force carboxylic acid Echiruesuteru ^{(128. 4 mg, 77%)} .

EIMS m / z: 415 (M ⁺ )

CO _z Et

In the same manner as in Example 4, 7-chloro-1,2,3-dihydro 9-fluoro-3-methyl-5-oxo-1 H, 5H-benzo [ij] quinoline-16- Ethyl ester carboxylate (112.9 mg, 0.40 mmol) and 3-methoxyphenyl boric acid (182.4 mg, 1.2 mmol) were used to form the colorless oily substance 2,3-dihydro-1-9-fluoro-7- (3-methoxy). (Ciphenyl) 1-3-methyl-1-5-oxo-1H, 5H-benzo [ij] quinolinidine-16-potassium ethyl ester (126.7 mg, 92%) was obtained.

EIMS m / z: 395 (M ⁺ ) Example 1-8

2,3-dihydro-5-oxo-1 7-phenyl-1H, 5H-benzo [ij] quinolinidine-6-potassium ruethyl acrylate (180.0mg, 0.540mmol) and hydroxylamine Use a room (90.9mg, 1.62mmo) with ethanol (4.5 ml)-Dissolved in water (0.5 ml) and heated under reflux for 3 hours. The reaction solution was cooled on ice and neutralized with IN hydrochloric acid, and the precipitated crystals were collected by filtration. 2,3-Dihydro-5-oxo-7-phenyl-2H, 5H-benzo [ij] quinolizine-6 monocarboxylic acid (153.8 mg, 93%) was obtained. The resulting 2,3—dihydroquinone 5 —oxo 17 —phenyl 1 H, 5 H—benzo [ij] quino lysine 6 —thionyl chloride in 149.3 mg (0.489 mmol) 0.5 ml was added, and the mixture was stirred at room temperature for 1 hour. The residue obtained by distilling off thionyl chloride was dissolved in 5 ml of methylene chloride, 0.25 ml of triethylamine and 0.12 ml of N-methyl-1,3-bis (trifluoromethyl) benzylamine were added, and the mixture was stirred for 1 hour. 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. The resulting residue 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-1-N-methyl-5-oxo—7-phen Two-loop 1H, 5H-benzo [ij] quinolinidine-16-potassium (241.0 mg, 91%) was obtained. mp. 191.5-193 ° C

EIMS m / z: 544 (M ⁺ ) Example 19

According to the same method as in Example 18, 2,3-dihydro-7— (3 Methoxyphenyl) 1-5-oxo-1H, 5H-benzo [ij] quinolinidine-16-carboxylic acid ethyl ester (352.8mg, 0.971mmol) and N-methyl-3,5-bis (trifluoromethyl ) From 0.25 ml of benzylamine, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7- (3-methoxyphenyl) N-methyl-5-oxo-1 H, 5H-Venzo [ij] quinolidine-6-carboxamide (485.7 mg, 87%) was obtained. mp.168-172 ° C

Anal: As C _{2 9} H _{2 2} F ₆ N ₂ O ₃

 Calculated values C 62.72%, H 4.21%, N 4.88%;

 Measured value C 62.64%, H 4.19%, N 4.89%

EIMS m / z: 574 (M ⁺ ) Example 20

By a method similar to that in Example 18, 2,3-dihydro-7- (4-methoxyphenyl) -15-oxo-1H, 5H-benzo [ij] quinolidine-16-caprolubone Colorless crystalline N- [3,5-bis (trifluoromethyl) benzyl] from 0.065 ml of acid ethyl ester (95.3 mg, 0.262 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 1,2,3 —Dihydro-7- (4-Methoxyphenyl) -1-N-methyl-5-oxo-1H, 5H-benzo [ij] quino lysine — 6-Carboxamide (119.1 mg, 79%) was obtained. mp.110-113 ° C

EIMS m / z: 574 (M ⁺ )

 In the same manner as in Example 18, 2,3-dihydro-1 7- (3-methylcyphenyl) -5-oxo-1 11, 5H-benzo [ij] quinolidine-1-6- Ethyl carboxylate (100.0mg, 0.288mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.07ml from colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] — 2,3-Dihydro N-methyl-17- (3-methylcyphenyl) -1-5-oxo-1H, 5H-benzo [ij] quinolidine-16-carboxamide (102.0mg, 63%) I got

FABMS ηι / ζ: 559ΓΜ + Η ⁺ )

Example 22

 In the same manner as in Example 18, 8- (2,4-dichlorophenyl) -12,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylic acid 7- (2,4-dichlorophenyl) -1,2,3-dihydro-15-oxo-1H, 5H-benzo [ij] quinolizine as pale yellow crystals from ethyl ester (402.3mg, l.Ommol) One 6-carboxylic acid (326.6 mg, 87%) was obtained. Ί- (2,4-dichlorophenyl) -1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylic acid (374.2 mg, l.Ommol) and N —Methyl-1,3,5-bis (trifluoromethyl) benzylamine 0.25 ml of colorless crystalline N— [3,5—bis (trifluoromethyl) benzyl] 17—

(2,4-Dichlorophenyl) -1,2,3-dihydro-1-N-methyl-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxamide (586.1mg, 96%) I got

EIMS m / z: 612 (M ⁺ ) Example 2 3

 In the same manner as in Example 18, 9-chloro-1- (2-, 4-dichlorophenyl) -12,3-dihydro-5-oxo-1H, 5H-benzo [ij] quino 9-chloro-17- (2,4-dichlorophenyl) -12,3-dihydro-5-oxo-1H, pale yellow crystals of 9-chloro-1-ethyl H-lysine ester (409.2 mg, 0.937 mmol) 5 H—benzo

[ij] Quinolysine 1-6-carboxylic acid (350.2 _mg , 80%) was obtained. 9 _ 1- (2,4-dichlorophenyl) -1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxylate (198.0 mg, 0.484) mmol) and N-methyl-1,5-bis (trifluoromethyl) benzylamine (146.6 mg, 0.570 mmol) were dissolved in 5 ml of methylene chloride, and N-ethyl-1-N,-(3-dimethylamino) was dissolved under ice-cooling. Propinole (11.4 mg, 0.581 mmol) was stirred and stirred for 1 hour N-ethyl-1-N, 1- (3-dimethylaminopropyl) carpoimide (50.6 mg, 0.264 mmol) was added and further added. The reaction mixture was stirred at room temperature, the reaction mixture 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. Gel power Purified by ram chromatography (methylene chloride: ethyl acetate 10: 1) and colorless Amorphous of N-[3, 5-bis (g Rifuruoromechiru) benzyl] - 9 one black opening one 7- (2, 4-dichloro port phenyl) one 2, 3-Dihydro-5-oxo-1H, 5-dibenzo [ij] quinolizin-1 6-carboxamide (47.4 mg, 15%) was obtained.

EIMS m / z: 646 (M ⁺ ) Example 24

実施例 1 8 と同様の方法により、 2， 3—ジヒ ドロ - 7— ( 1 — ナフチル） 一 5 —ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リジン - 6 —カルボン酸ェチルエステル（202.6mg, 0.528mmol)と N—メチ ル一 3 , 5 —ビス （ ト リ フルォロメチル） ベンジルァミ ン 0.15ml から無色結晶の N - [ 3 , 5 —ビス （ ト リ フルォロメチル） ベンジ ル] — 2 , 3 —ジヒ ドロ— N—メチルー 7— ( 1 —ナフチル） 一 5 一才キソー 1 H , 5 H—べンゾ [ i j ] キノ リ ジン一 6—カルボキ サミ ド（117.9mg， 38%)を得た。 mp.95.0-97.0°C

According to the same method as that of Example 18, 2,3-dihydro-7- (1-naphthyl) -15-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxylic acid ethyl ester (202.6 mg) , 0.528 mmol) and 0.15 ml of N-methyl-1,3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dithiol D-N-methyl-7- (1-naphthyl) -1.5-year-old kiso 1H, 5H-benzo [ij] quinolinidine-6-carboxamide (117.9 mg, 38%) was obtained. mp.95.0-97.0 ° C

EIMS m / z: 594 (M ⁺ ) Example 2 5

実施例 1 8 と同様の方法により、 2， 3—ジヒ ドロー 7— ( 4— フルオロフヱニル） 一 5—ォキソ _ 1 H， 5 H—ベンゾ [ i j ] キ ノ リ ジン一 6—カルボン酸ェチルエステル（103.7mg, 0.295mmol)と N—メチル一 3， 5—ビス （ ト リフルォロメチル） ベンジルァミ ン 0.07ml から無色結晶の N— [ 3 , 5—ビス （ ト リ フルォロメチル） ベンジル] 一 2 , 3—ジヒ ドロ一 7— ( 4—フルオロフヱニル） 一 N—メチル一 5—ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リジン — 6—カルボキサミ ド（158.6mg， 96%)を得た。 mp.152-155°C

In the same manner as in Example 18, 2,3-dihydro 7- (4-fluorophenyl) -15-oxo_1H, 5H-benzo [ij] quinolinidine-16-carboxylic acid ethyl ester (103.7 mg, 0.295 mmol) and 0.07 ml of N-methyl-1,3,5-bis (trifluoromethyl) benzylamine from N— [3,5-bis (trifluoromethyl) benzyl] colorless crystals from 1,2,3-dihydrobenzene 7- (4-Fluorophenyl) -1-N-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-6-carboxamide (158.6 mg, 96%) was obtained. mp.152-155 ° C

EIMS m / z: 562 (M ⁺ ) Example 26

実施例 1 8 と同様の方法により、 2， 3—ジヒ ドロー 5—ォキソ — 7— （ 2—チオフヱン） 一 1 H, 5 H—べンゾ [ i j ] キノ リジ ンー 6—力ルボン酸ェチルエステル（163.9mg， 0.483mmol)と N—メ チルー 3， 5—ビス （ ト リ フルォロメチル） ベンジルァミ ン 0.1ml から無色結晶の N— [ 3 , 5—ビス （ ト リ フルォロメチル） ベンジ ル] — 2， 3—ジヒ ドロ一 N—メチルー 5—ォキソ一 7— ( 2—チ ォフェン） 一 1 H , 5 H—ベンゾ [ i j ] キノ リジン一 6 カルボ キサミ ド（211.5mg， 80%)を得た。 mp.100-102°C

In the same manner as in Example 18, 2,3-dihydroxy 5-oxo-7- (2-thiophene) 1-1H, 5H-benzo [ij] quino lysine-6-ethyl rubonate ( 163.9 mg, 0.483 mmol) and 0.1 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine from N- [3,5-bis (trifluoromethyl) benzyl] as colorless crystals — 2,3- Dihydro-1-N-methyl-5-oxo-17- (2-thiophene) -11H, 5H-benzo [ij] quinolizine-16-carboxamide (211.5 mg, 80%) was obtained. mp.100-102 ° C

EIMS m / z: 550 (M ⁺ ) Example 2 7

実施例 1 8 と同様の方法によ り、 2， 3—ジヒ ドロ一 7— ( 3 - フルオロフェニル） 一 5—ォキソ _ 1 H, 5 H—べンゾ [ i j ] キ ノ リ ジン— 6—カルボン酸ェチルエステル（106.3mg， 0.303mmol)と N—メチルー 3， 5—ビス （ ト リ フルォロメチル） ベンジルァミ ン 0.075ml から無色ァモルファスの N— [ 3， 5 _ビス （ ト リ フルォ ロメチル） ベンジル] — 2 , 3—ジヒ ドロ一 7— ( 3—フルオロフ ェニル） 一 N—メチル一 5—ォキソ一 1 H， 5 H—べンゾ [ i j ] キノ リジン一 6—カルボキサミ ド（146.6mg, 86%)を得た。

According to the same method as in Example 18, 2,3-dihydro-17- (3-fluorophenyl) -15-oxo_1H, 5H-benzo [ij] quinoidine-6 —Ethyl carboxylate (106.3mg, 0.303mmol) and 0.075ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine from colorless amorphous N— [3,5_bis (trifluoromethyl) benzyl] — 2,3-Dihydro-7- (3-fluorophenyl) -1-N-methyl-5-oxo-1H, 5H-benzo [ij] quinolizine-6-carboxamide (146.6mg, 86%) I got

EIMS m / z: 562 (M ⁺ )

実施例 1 8と同様の方法により、 7— ( 3—クロロフヱ二

In the same manner as in Example 18, 7- (3-chlorophenyl

2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-16-carboxylic acid ethyl ester (112.3mg, 0.305mmol) and N-methyl-3,5-bis (tri Colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) 1-2,3-dihydro N-methyl-5-oxo from 0.076 ml of fluoromethyl) benzylamine One 1H, 5H-benzo [ij] quinolinidine 16-carboxamide (101.3 mg, 57%) was obtained.

EIMS m / z: 578 (M ⁺ ) Example 29

実施例 1 8と同様の方法により、 2， 3—ジヒ ドロー 5—ォキソ - 7 - ( 3 — ト リ フルォロメチルフエニル） 一 1 H， 5 H—ベンゾ [ i j ] キノ リ ジン一 6 —カルボン酸ェチルエステル（131.3mg，

In the same manner as in Example 18, 2,3-dihydro 5-oxo -7-(3-Trifluoromethylphenyl) 1H, 5H-benzo [ij] quinolizine 16-carboxylic acid ethyl ester (131.3mg,

0.327 mmol) and N-methyl-1,3,5-bis (trifluoromethyl) benzylamine from 0.082 ml of colorless amorphous N— [3,5—bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1- N—methyl 5 —oxo 1 7— (3—trifluoromethylphenyl) 1 1 H,

5 H-benzo [ij] quinolizine-1 6-carboxamide (128.4 mg,

64%).

EIMS m / z: 612 (M ⁺ ) Example 30

実施例 1 8 と同様の方法により、 2， 3—ジヒ ドロ一 7 - ( 3 — ニ トロフエニル） 一 5 —ォキソ一 1 H， 5 H—ベンゾ [ i j ] キノ リジン一 6 —力ルボン酸ェチルエステル（218.5mg， 0.577mmol)と N —メチルー 3， 5 —ビス （ ト リ フルォロメチル） ベンジルァミ ン 0.16mlから淡黄色アモルファスの N— [ 3 , 5 —ビス （ ト リ フルォ ロメチル） ベンジル] — 2 , 3—ジヒ ドロー N—メチル一 7— ( 3 —ニ トロフエニル） 一 5 —ォキソ一 1 H , 5 H—べンゾ [ i j ] キ ノ リ ジン一 6 —カルボキサミ ド（305.1mg, 90%)を得た。

According to a method similar to that in Example 18, 2,3-dihydro-1- 7- (3-nitrotropenyl) -1-5-oxo-1H, 5H-benzo [ij] quinolizine-16-potassium ethyl ester 218.5 mg, 0.577 mmol) and 0.16 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine to pale yellow amorphous N— [3,5-bis (trifluoromethyl) benzyl] —2,3— Dihidro N-methyl-1 7- (3-nitrotropenyl) -1-5-oxo-1H, 5H-benzo [ij] quinolinidine-6-carboxamide (305.1 mg, 90%) was obtained. .

EIMS m / z: 589 (M ⁺ ) Example 3 1

実施例 1 8と同様の方法により、 2， 3—ジヒ ドロー 3—メチル — 5—ォキソ一 7—フエ二ルー 1 H, 5 H—ベンゾ [ i j ] キノ リ ジン一 6 —力ルボン酸ェチルエステル（96.3mg， 0.277mmol)と N—メ チル一 3， 5—ビス （ ト リ フルォロメチル） ベンジルァミ ン 0.071ml から無色結晶の N— [ 3 , 5—ビス （ ト リ フルォロメチル） ベンジ ル] — 2， 3—ジヒ ドロー 3 , N—ジメチル一 5—ォキソ一 7—フ ェニル一 1 H , 5 H—ベンゾ [ i j ] キノ リジン一 6—カルボキサ ミ ド（120.7mg， 78%)を得た。

In the same manner as in Example 18, 2,3-dihydroxy 3-methyl-5-oxo-17-phenyl-2H, 5H-benzo [ij] quinolizine-16-potassium oleate 96.3 mg, 0.277 mmol) and 0.071 ml of N-methyl-1,3,5-bis (trifluoromethyl) benzylamine as colorless crystals of N— [3,5-bis (trifluoromethyl) benzyl] — 2,3 —Dihydro-3, N-dimethyl-15-oxo-17-phenyl-1H, 5H-benzo [ij] quinolidine-16-carboxamide (120.7 mg, 78%) was obtained.

EIMS m / z: 558 (M ⁺ ) Example 3 2

実施例 1 8と同様の方法により、 2， 3—ジヒ ドロ一 7— ( 3— メ トキシフエ二ル） 一 3—メチル一 5—ォキソ一 1 H , 5 H—ベン ゾ [ i j ] キノ リ ジン一 6 —カルボン酸ェチルエステル（80.7mg， 0.214mmol)と N—メチルー 3 , 5—ビス （ ト リ フル才ロメチル） ベ ンジルァミ ン 0.055ml から無色アモルファスの N— [ 3 , 5—ビス ( ト リ フルォロメチル） ベンジル] — 2 , 3—ジヒ ドロー 3， N— ジメチル一 7— ( 3—メ トキシフエ二ル） 一 5—ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リ ジン一 6—カルボキサミ ド（90.8mg， 72%) を得た。

By a method similar to that in Example 18, 2,3-dihydro-17- (3-methoxyphenyl) -13-methyl-15-oxo-1H, 5H-benzine The colorless amorphous N— [3, [3-, 3-]-[3-, 3-ethylcarboxylate] ester (80.7 mg, 0.214 mmol) and N-methyl-3,5-bis (trifluromethylmethyl) benzylamine were obtained from 0.055 ml. 5-bis (trifluoromethyl) benzyl] —2,3-dihydro-3, N-dimethyl-17- (3-methoxyphenyl) -1-5-oxo-1H, 5H-benzo [ij] quinolin Gin-6-carboxamide (90.8 mg, 72%) was obtained.

EIMS m / z: 588 (M ⁺ ) Example 3 3

実施例 1 8 と同様の方法により、 7— ( 2， 4—ジクロロフエ二 ル） 一 2， 3—ジヒ ドロー 3—メチル一 5 _ォキソ一 1 H， 5 H - ベンゾ [ i j ]キノ リ ジン一 6—力ルボン酸ェチルエステル（117.7mg, 0.283mmol)と N—メチル一 3 , 5 _ビス （ ト リ フルォロメチル） ベ ンジルァミ ン 0.073ml から無色アモルファスの N— [ 3 , 5—ビス ( ト リ フルォロメチル） ベンジル] — 7— （ 2， 4ージクロ口フエ ニル） 一 2， 3—ジヒ ドロ一 3， N—ジメチルー 5—ォキソ一 1 H, 5 H—ベンゾ [ i j ] キノ リ ジン一 6 —カルボキサ ミ ド（154.8mg， 87%)を得た。 EIMS m/z:626(M ⁺ ) 実施例 34

According to a method similar to that in Example 18, 7- (2,4-dichlorophenyl) -1,2,3-dihydro-3-methyl-5-oxo-1H, 5H-benzo [ij] quinoidine-1 Colorless amorphous N- [3,5-bis (trifluoromethyl) from 6-potassium rubonic acid ester (117.7 mg, 0.283 mmol) and 0.073 ml of N-methyl-1,3-bis (trifluoromethyl) benzylamine Benzyl] — 7— (2,4-dichloromethyl) 1,2,3-dihydro-13, N-dimethyl-5-oxo-1H, 5H-benzo [ij] quinolinidine-16—carboxamide (154.8 mg, 87%). EIMS m / z: 626 (M ⁺ ) Example 34

実施例 1 8と同様の方法により、 2， 3—ジヒ ドロー 9 _フルォ 口一 7— ( 3—メ トキシフエ二ル） 一 3—メチル一 5—ォキソ一 1 H， 5 H—ベンゾ [ i j ] キノ リジン一 6—カルボン酸ェチルエス テル（121.7mg, 0.308mmol)と N—メチル一 3， 5 —ビス （ ト リフルォ ロメチル）ベンジルアミ ン 0.079mlから無色アモルファスの N— [ 3 5 —ビス （ ト リ フルォロメチル） ベンジル] — 2， 3 —ジヒ ドロー 3， N—ジメチル一 9—フルオロー 7— （ 3—メ トキシフエ二ル） ー 5—ォキソ一 111, 5 H—ベンゾ [ i j ] キノ リ ジン一 6—カル ボキサミ ド（182.3mg， 98%)を得た。

In the same manner as in Example 18, 2,3-dihydro 9 _fluoro 1-7- (3-methoxyphenyl) -13-methyl-15-oxo-1 H, 5H-benzo [ij] A colorless amorphous N- [35-bis (trifluoromethyl) is obtained from quinolidine-1-ethyl carboxylate (121.7 mg, 0.308 mmol) and 0.079 ml of N-methyl-1,5-bis (trifluoromethyl) benzylamine. Benzyl) —2,3-dihydro-3, N-dimethyl-1-9-fluoro-7— (3-methoxyphenyl) -5-oxo111,5H-benzo [ij] quinolinidine-6-cal Boxamide (182.3 mg, 98%) was obtained.

EIMS m / z: 606 (M ⁺ )

Example 3 5

N- [3,5—Bis (trifluoromethyl) benzyl] —2,3—dihydro-1N—methyl-1 7— (3-nitrophenyl) -1 5—oxo-1H, 5H—B Nzo [ij] quinolizine-16-carboxamide (211.2 mg, 0.358 mmol) and 29.3 mg of palladium carbon were dissolved in 5 ml of ethanol and stirred under a hydrogen atmosphere for 25 hours. The palladium carbonate was filtered off through celite, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 5: 1 1: 1). Hexane is added to the purified product to crystallize it and colorless crystals of 7- (3-aminophosphinyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-5 —Oxo-1H, 5H-benzo [ij] quinolizine-16-carboxamide (111.2 mg, 55%) was obtained. mp.132-136 ° C

EIMS m / z: 559 (M ⁺ ) Reference example 1

 2—Methyl-1,2,3,4—Tetrahydroquinoline (1.47 g, lOmmol) and triethyl methane tricarboxylate (4.70 g, 20 mmol) at 220 ° C for 5 hours Stirred. Hexane and Jethyl ether were added to the reaction mixture, and the mixture was cooled in a dry ice-acetone bath. The precipitated crystals were collected by filtration, washed with hexane, and washed with light yellow crystals to give 2,3-dihydro-1-ethyl-7. —Hydroxy-1 3 —methyl-5 —oxo-1 H, 5 H —benzo [ij] quinolinidine 16 —potassium ethyl ester (1.31 g, 46%) was obtained.

EIMS m / z: 287 (M ⁺ ) Reference example 2

According to the same method as in Reference Example 1, 6-fluoro-2-methyl-1,2,3,4—tetrahydroquinoline (1.65 g, lOmmol) and triethyl methanetricarboxylate (4.70 g, 20 mmol) ) From light yellow crystals of 2,3-dihydro-9-fluoro-7-hydroxy-3-methyl-5-oxo-1H, 5H-benzo [ij] quinolidine-16-carboxylic acid Jet Yield (1.13 g, 37%)

EIMS m / z: 305 (M ⁺ ) Reference example 3

CI

C0 ₂ Et

Me

2,3-Dihydroxy-7-hydroxy-1-methyl-5-oxo-1H, 5H-benzo [ij] quinolizine-6-potassium ester ester (1.30 g, 4.52 mmol) Rephenylphosphine (2.37 g, 9.04 mmol) was 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 then triphenylphosphine (237 mg, 0.904 mmol) and carbon tetrachloride ( (0.27 ml, 2.71 mmol) was added, and the mixture was heated under reflux for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained product was crystallized by adding hexane. 2, 3 dihydric mud one 3- methyl-5-O Kiso one 1 H, 5 H- benzo [ij] quinoline lysine one 6- force carboxylic Sane Chiruesuteru ^{(8 5 3. 5 mg, 62} %) was obtained .

EIMS m / z: 305 (M ⁺ ) Reference example 4

参考例 3と同様の方法によ り、 2 , 3—ジヒ ドロー 7—ヒ ドロキ シ一 5—ォキソ一 1 H , 5 H—ベンゾ [ i j ] キノ リジン一 6—力 ルボン酸ェチルエステル（1.09g， 4.0mmol)から、 無色結晶の 7—クロ 口一 2 , 3—ジヒ ドロー 5—ォキソ一 1 H， 5 H—べンゾ [ i j ] キノ リジン一 6—力ルボン酸ェチルエステル（1.29g， 89%)を得た。 EIMS m/z:291(M⁺) 参考例 5

According to the same method as in Reference Example 3, 2,3-dihydroxy 7-hydroxy-5-oxo-1H, 5H-benzo [ij] quinolizine-1-6-force ethyl ester of rubonate (1.09 g, 4.0 mmol) from the colorless crystalline 7-chloro-1,2,3-dihydro-5-oxo-1H, 5H-benzo [ij] quinolizine-6-potassium ethyl ester (1.29 g, 89% ). EIMS m / z: 291 (M ⁺ ) Reference example 5

In the same manner as in Reference Example 3, 2,3-dihydroxy 9-fluoro-7-hydroxy-13-methyl-5-oxo_1H, 5H-benzo [ij] quinoline-1 6 — From ethyl carboxylate (l.llg, 3.64 mmol), 7-chloro-1,2,3-dihydro-1,9-fluoro-3-methyl-1,5-oxo-1 H, 5 H— Benzo [ij] quinolizine-6-potassium ethyl ester (843.4 g, 72% yield) Was.

EIMS m / z: 323 (M ⁺ ) Industrial applicability

 The compound of the present invention and a salt thereof have an excellent kinkinin receptor antagonistic activity, 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.

Claims

Scope of word blue 1. The following general formula (1)

(Wherein RR ² and R ³ are the same or different and are each a hydrogen atom or a C i -C ₆ alkyl group, and ring A is independently selected from one to three substituents (adjacent two May be bonded to each other to form a ring) may be a homo- or heterocyclic ring, and ring B is 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 and have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have a benzoquinolizine derivative or a salt, hydrate or solvate thereof. 2. Ring A is a halogen atom, an optionally substituted C i -C ₆ alkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i C s alkoxy group, c ₃ to c _{1 0} a a cycloalkyl Kokishi groups, alkanoyloxy Noi Ruo alkoxy group optionally C i to C ₆ substituted - optionally substituted § Li Roiruokishi group, optionally substituted good § reel methyl O alkoxy group, c ₃ ~c _1. Cycloalkadienyl Noi Ruo alkoxy group, an optionally substituted c ₁ to c ₆ alkylthio group, alkylsulfinyl group optionally C t C e be substituted, may be substituted Alkylsulfonyl group optionally C t~ C _6, amino group, mono- or alkylamino amino group of C t C e disubstituted from 1 to 3 of may 4-9 membered also contain heteroatoms in the cyclic § Mi Roh groups, C alkylcarbonyl amino group i~ C _6, C i C e alkoxycarbonyl § Mi Roh groups, C i to C alkylsulfonyl amino groups of _6, optionally substituted § Li one Rusulfonylamino group, C i-C ₆ alkylcarbonyl group, formyl group, carboxyl group, C i-C ₆ alkoxycarbonyl group, mono- or di-substituted c-C ₆ alkyl group rubamoyl group, 1-3 1 to 3 substituents independently selected from a 4- to 9-membered cyclic rubamoyl group, a cyano group or a nitro group which may contain a heteroatom (two adjacent substituents May be bonded to each other to form a ring) Also indicate a good homo- or heterocyclic, Ring B is a halogen atom, an optionally substituted C i -C ₆ alkyl group, C ₃ -C i. A cycloalkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted C i -C ₆ alkano An aryloxy group, an optionally substituted aryloxy group, an optionally substituted arylmethyloxy group, C ₃ -C i. Cycloalkoxy group, C ₃ ~ C i. An optionally substituted C j -C ₆ alkylthio group, an optionally substituted C i Ce alkyl sulfinyl group, an optionally substituted C -C ₆ alkyl A sulfonyl group, an amino group, a mono- or di-substituted CiC alkyl amino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, C ₁ to alkylcarbonyl § Mi amino group of C _6, C i C e alkoxy Karuboniruami amino group, C i to alkylsulfonyl § amino group of C _6, replacement is good § Li one also be Rusuruhoniruami amino group, C 1 -C ₆ alkylcarbonyl group, carboxyl group, C i -C ₆ alkoxycarbo Group, a mono- or alkyl force Rubamoiru group C i to C ₆ disubstituted, 1-3 may also be 4-9 membered contain heteroatoms of the cyclic forces Rubamoi group, Shiano group or two preparative port A benzene ring which may have 1 to 3 substituents (each of which may be bonded to two adjacent substituents to form a ring) independently selected from the groups Show, Ring C is a halogen atom, an optionally substituted C i -C ₆ alkyl group, a hydroxyl group, an optionally substituted C! C e alkoxy group, an optionally substituted C, -C ₆ Alkanoyloxy group, optionally substituted aryloxy group, optionally substituted arylmethyloxy group, C ₃ -C! . Cycloalkoxy group, C ₃ ~ C丄. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted C i Ce alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C ~ alkylcarbonyl § Mi amino group of C _6, C i C e alkoxycarbonyl § Mi amino group, C i C s alkylsulfonyl § amino group, optionally substituted § Li one also be Rusuru Honiruami amino group of Shiano group Or one to three substituents independently selected from a nitro group (two adjacent substituents may be bonded to each other to form a ring) The benzoquinolidine derivative according to claim 1, which shows a good benzene ring. 3. The following general formula (2) (2)

(Wherein, R ³ is a hydrogen atom or a C alkyl group, R ⁴ is a hydroxyl group, a C i Ce alkoxy group, a benzyloxy group or a reactive residue, Ring A is a halogen atom, an optionally substituted C i -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C ₁ -C ₆ alkoxy group, ₃ ~ C _{1 0} of Shikuroaruko alkoxy group, alkanoyloxy Noi Ruo alkoxy group optionally C. 1 to C ₆ optionally substituted, optionally substituted § Li Roiruokishi groups, unsubstituted or optionally § Li have one Rumechiruokishi group (:.. ~ cycloalkadienyl Noi Ruo alkoxy group, an optionally substituted alkylthio group C i~C _6, alkylsulfides alkylsulfonyl group optionally C i to C 6 substituted, substituted alkylsulfonyl group which may C ~ C _6, amino group, mono- or alkylamino amino group of C i C e disubstituted, 1 three of 4 may contain a hetero atom 9- cyclic § Mi amino group, an alkylcarbonyl authors C t~ C ₆ Amino group, C! C s alkoxycarbonyl § Mi amino group, (^ - (^ alkylsulfonyl § amino group, optionally substituted § Li one also be Luz Ruhoniruami amino group, an alkylcarbonyl group of C i to C ₆ , A formyl group, a carboxyl group, a C i -C ₆ alkoxycarbonyl group, a mono- or di-substituted C -C ₆ alkyl group rubamoyl group, 4 to 9 members optionally containing 1 to 3 hetero atoms 1 to 3 substituents independently selected from the group consisting of a rubamoyl group, a cyano group and a nitrogen group (even if two adjacent substituents are bonded to each other to form a ring) A) a homo- or heterocyclic ring which may have Ring C is a halogen atom, optionally substituted C! To C ₆ alkyl group, hydroxy group, optionally substituted C i C alkoxy group, optionally substituted C! C ₆ to C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted aryloxy group, C ₃ to C i. A cycloalkoxy group of C ₃ C! . A cycloalkanoyloxy group, an amino group, a mono- or di-substituted CiCe alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms Group, C 1 to C _G alkylcarbonylamino group, C i Cs alkoxycarbonylamino group, C i to C ₆ alkylsulfonylamino group, optionally substituted arylsulfur 1 to 3 substituents independently selected from a phonylamino group, a cyano group, or a nitro group (two adjacent substituents may be bonded to each other to form a ring) Represents a benzene ring which may have ) A benzoquinolidine derivative represented by or a salt, hydrate and solvate thereof.

(Wherein, R ³ is a hydrogen atom or an alkyl group of C to ( ₆ , R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C ₁ to C ₆ alkyl group; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring; Or a reactive residue, and X is a halogen atom or 0 S 0 ₂ R ⁶ (R ⁶ Is an optionally substituted C 1 to C ₆ alkyl group, an optionally substituted aryl group), the C ring is a halogen atom, an optionally substituted c _{1 to} c ₆ alkyl group, hydroxyl Group, an optionally substituted C i Ce alkoxy group, an optionally substituted C i Ce alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted § reel methyl O alkoxy group, C ₃ ~ C 1 Q of consequent opening alkoxy group, C ₃ -C _{1 0} cycloalkadienyl Noi Ruo alkoxy group, amino group, alkylamino C i to C ₆ mono- or di-substituted group from 1 to three ring § Mi Roh group which may 4-9 membered contain a hetero atom, an alkylcarbonyl amino group of C i to C _6, an alkoxycarbonylamino group of C i to C 6, C ! Ce alkylsulfonylamino group, which may be substituted 1 to 3 substituents each independently selected from a arylsulfonylamino group, a cyano group, and a nitro group (when two adjacent substituents are bonded to each other to form a ring, Represents a benzene ring which may have. ) A benzoquinolidine derivative represented by or a salt, hydrate and solvate thereof. 5. The following general formula (4)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(R ^l and R ² form the same or different alkyl Le group hydrogen atom or a C i C s, B ring 1 to 5 substituents (and adjacent two substituents combined binding each other to form a ring Or a reactive residue, the C ring is a halogen atom, an optionally substituted C t -C ₆ alkyl group, a hydroxy group, alkoxy group but it may also be substituted C! C e, which may be substituted C i~ C ₆ of § Rukanoiruokishi group, which may be substituted § Li Roiruokishi group, which may be substituted Yoia reel methyl O alkoxy group, C ₃ ~ C i. The alkoxy group of the mouth, C3-Ci. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted CCG alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, C to C ₆ alkylcarbonyl amino group, C i to alkoxycarbonylamino group C _6, C i~C alkylsulfonyl § Mi amino group of _6, optionally substituted § Li one even if Le sulfonyl § amino group, Shiano group or It may have from 1 to 3 substituents independently selected from two groups (two adjacent substituents may be bonded to each other to form a ring) Shows a benzene ring. ) A benzoquinolidine derivative represented by or a salt, hydrate and solvate thereof. 6. The following general formula (2

(Wherein, R ³ is a hydrogen atom or a C t Ce alkyl group, and R ⁴ is a hydroxyl group. C t Ce alkoxy, benzyloxy or reactive residue, and ring A are each independently selected from 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring A homo- or heterocyclic ring which may have 1 to 3 substituents (two or more adjacent substituents may be bonded to each other to form a ring) Represents a benzene ring which may have ) Or a salt, hydrate or solvate thereof represented by the following general formula (5) R ¹  (Five) (Wherein R ¹ and R ² are the same or different and are each a hydrogen atom or a C i -C ₆ alkyl group, and ring B has 1 to 5 substituents (two adjacent substituents are bonded to each other A benzene ring which may have a) or a salt, hydrate, or solvate thereof represented by the formula: Or a salt, hydrate and solvate thereof. 7. The following general formula (6)

(Wherein, R ³ is a hydrogen atom or an alkyl group of CiCs, R ⁷ is a hydroxyl group, C i -C ₆ alkoxy, benzyloxy, R ¹ (R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C i -C ₆ alkyl group; ring B has 1-5 substituents (adjacent two substituents are bonded to each other to form a ring have also may) to form showing a benzene ring.) or a reactive residue, X is a halogen atom or 〇 S_〇 ₂ R ⁶ (R ⁶ is an optionally halogen-substituted C i A C ₆ alkyl group, an aryl group which may be substituted), and the C ring has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). It represents a benzene ring which may be possessed. Or a salt, hydrate or solvate thereof represented by the following general formula (7):

(In the formula, Y is a halogen ^{_{atom, OS 0 2 R 6 (R}} 6 is the ^{same), B (R 8) 2} (R 8 is a hydroxyl group, an alkoxy group of C t C e alkyl or C i C s of Alternatively, R ⁸ may be bonded to each other to form a ring.), MgBr or ZnCl, and the A ring are each independently selected from 1 to 3 substituents ( Two adjacent substituents may be bonded to each other to form a ring), or a homocyclic or heterocyclic ring which may have the following formula: 1. The compound represented by the formula: Or the process for producing a benzoquinolidine derivative or a salt, hydrate and solvate thereof according to item 3. 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 ₆ -C ₆ alkyl group, and the A ring is independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Evening kikinin receptor antagonist. 9. General formula (1) below

(In the formula, R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C i -C ₆ alkyl group, and the A ring is each independently selected from 1 to 3 substituents. A homo- or heterocyclic ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring); the ring B has 1 to 5 substituents (adjacent A benzene ring, which may have two substituents which may combine with each other to form a ring), and a C-ring, which has 1 to 3 substituents (two adjacent substituents are A benzene ring which may be bonded to a benzene ring. ) A substance P receptor antagonist comprising a benzoquinolidine derivative represented by the formula or a salt, hydrate and solvate thereof as a pharmaceutical composition. 10. The following general formula (1)

(Wherein RR ² and R ³ are the same or different and are each a hydrogen atom or a C t -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent two A substituent may be bonded to each other to form a ring) a homo- or heterocyclic ring which may have 1 to 5 substituents (two adjacent substituents are bonded to each other) The benzene ring and C ring which may have a ring may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. A preventive or therapeutic agent for urinary dysfunction including urinary frequency, urinary incontinence and other bladder dysfunctions. 1 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 i -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) A benzene ring which may have a benzoquinolidine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. For preventing or treating gastrointestinal diseases including ulcerative colitis and Crohn's disease. 1 2. 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 i -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) A benzene ring which may have a benzoquinolizine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. Prevention of vomiting induced by X-ray irradiation, chemotherapeutic agents, pregnancy, migraine, postoperative illness, gastrointestinal motility or side effects of drug administration Or therapeutic agent. 1 3. The following general formula (1)

(Wherein RR ² and R ³ are the same or different and are each a hydrogen atom or a C t -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent two A substituent may be bonded to each other to form a ring) a homo- or heterocyclic ring which may have 1 to 5 substituents (two adjacent substituents are bonded to each other) The benzene ring and C ring which may have a ring may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). May be) The benzene ring which may be possessed is shown. ), Or a salt, hydrate or solvate thereof as a pharmaceutical composition, wherein tachykinin provides asthma, cough, pain, migraine, toothache A therapeutic agent for rheumatoid arthritis.