WO2000006571A1

WO2000006571A1 - Pyrroloquinoline derivatives and process for producing the same

Info

Publication number: WO2000006571A1
Application number: PCT/JP1999/004034
Authority: WO
Inventors: Yasumichi Fukuda; Asao Tanioka
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 1998-07-31
Filing date: 1999-07-28
Publication date: 2000-02-10
Also published as: AU4928499A; JP2000044561A

Abstract

Pyrroloquinoline derivatives having tachykinin antagonism, in particular, substance P receptor antagonism. Namely, pyrroloquinoline derivatives represented by general formula (1) and salts thereof and medicinal compositions containing these compounds or pharmaceutically useful salts thereof, wherein 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-pyromouth quinoline derivative and its production method

Technical field

TECHNICAL FIELD The present invention relates to a novel quinoline derivative having a stomatoquinone receptor antagonistic activity or a pharmacologically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition containing the quinoline derivative to a stoichiometric compound. ₍ Background technology

Tachykinins (substance Ρ, neurokinin A, neurokinin B) are a general term for neuropeptides, and their receptors in the body (neurokinin 1 (NKJ, neurokinin 2 (NK2), neurokinin 3) (NK 3)) is known to express various physiological activities by binding to it.In particular, substance P acts as a transmitter of central and peripheral primary sensory neurons, and has a diuretic effect. It has physiological activities such as nerve cell excitatory action, vascular hyperpermeability action, vasodilator action, smooth muscle contraction action, immunity action, etc., and various disease states (frequent urination, urinary incontinence, vomiting, inflammation, allergy, airway disease, pain) And central nervous system diseases), and are therefore excellent tachykinin receptors as preventive and therapeutic agents for the various disease states described above. Body antagonism, in particular a substance P receptor antagonistic activity, and excellent safety, the development of a compound having a sustained like desired.

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

R ¹ -AD-Trp (R ² ) -Ph9-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 And R ³ is an ar (lower) alkyl group, —N (R ⁴ ) (R ⁵ ) group, wherein R ⁴ and R ^{5 each} have a hydrogen, aryl group or an appropriate substituent. R ⁴ and R ⁵ are bonded to each other to form a benzene-condensed lower alkylene group, or —OR ⁶ group (where R ⁶ is hydrogen, aryl group) Or a lower alkyl group which may have a suitable substituent), wherein A represents a single bond or one or two amino acid residues, and A represents D— when mean one § Mi acid residue 1 of T rp is R ⁴ represents a non-hydrogen).) with the compounds and salts thereof disclosed represented It has been.

(2) E P — A — 4 2 9 3 6 6 Formula:

Are disclosed. (3) W〇 9 1/0 9 8 4 Formula in No. 4

Are disclosed.

(4) Ε Ρ— Α— 5 3 2 4 5 6 Formula

(5) EP—A—5 2 2 8 Q No. 8 discloses a compound represented by the formula

Are disclosed. 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 hetero ring; 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 a hydrocarbon residue) or — 0—, the other is — C〇 or — CS—, or one is N = and the other is CR ^2- (R ² is H, halogen, A hydrocarbon residue, an amino group or a hydroxy group); n represents 1 or 2.) or a salt thereof. (8) Japanese Patent Application Laid-Open No. 9-104646

(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. Alkyl groups including: carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, (4-phenylbiperazine-1-yl) methyl group, R ² is hydrogen atom, lower alkyl group, hydroxyl group A lower alkyl group, a lower alkanoyl group, or a lower alkoxy group, and the rings A and B each represent a benzene ring which may have a substituent.

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

(Wherein, the Μ ring is a heterocyclic ring having a partial structure of 1 N = C as 1Χ = Υ <, 1 C〇1 N <or 1 CS—N <; R ^a and R ^b are Forms a ring or is the same or different and has a hydrogen atom or M ring Ring A and ring B are all optionally substituted homo- or heterocyclic rings, at least one of which may have a substituent; heterocyclic ring; ring C is A homocyclic or heterocyclic ring which may have a substituent; a ring Z which may be substituted; and n is an integer of 1 or 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 to tachykinin receptor, particularly a substance P receptor antagonist, which has a different chemical structure from known compounds including the above-mentioned compounds, a tachykinin receptor antagonist, An object of the present invention is to provide an agent for preventing or treating dysuria, an agent for preventing or treating gastrointestinal disorders, and an agent for preventing or treating vomiting. Disclosure of the invention

The present inventors have 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 the ring A is independently selected from one to three substituents (adjacent two The substituents are bonded to each other to form a ring A homo- or heterocyclic ring which may have 1 or 5 substituents (optionally two adjacent substituents may be bonded to each other to form a ring) Optionally substituted benzene ring and C-ring may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) Shows a ring. The present invention provides a pyrroloquinoline derivative represented by the formula or a salt, hydrate and solvate thereof.

The present inventors have, A ring is a halogen atom, an alkyl group having or ~ C ₆ which may be substituted, substituted optionally may be Ariru group, human Doroki sills group, the optionally substituted C i C s alkoxy group, C ₃ ~ C i. A cycloalkoxy group, an optionally substituted C ₁ -C ₆ alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C ₃ -C i . A cycloalkanoyloxy group, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C i -C ₆ alkylsulfinyl group, an optionally substituted C i alkylsulfonyl group ~ C _6, amino group, mono- or di-substituted alkylamino amino group of C t~ C _6, 1~ 3 or may contain heteroatoms of 4-9 membered cyclic amino groups, C t Ce alkylcarbonylamino group, CtCe alkoxycarbonylamino group, CiCe alkylsulfonylamino group, optionally substituted arylsulfonylamino group, C i C e alkylcarbonyl group, a formyl group, a carboxyl group, include C i C s alkoxycarbonyl group, mono- or di-substituted Aruki carbamoyl group C i~ C _6, 1~ 3 or heteroatom 4 to 9-membered cyclic rubamoyl group 1 to 3 substituents each independently selected from a cyano group or a nitrogeno group (two adjacent substituents may be bonded to each other to form a ring) Represents a homo- or heterocyclic ring which may have B ring is a halogen atom, alkyl Le group optionally C i to C ₆ optionally substituted, C ₃ ~ C i. A cycloalkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C i -C ₆ alkoxy group, an optionally substituted (^ C e alkanoloxy group) group, optionally substituted § Li also be Roiruokishi group, substituted Moyoi § reel methyl O alkoxy group, C ₃ ~ C 1. cycloalkoxy group, C ₃ ~ C _1. cycloalkadienyl Noi Ruo alkoxy An optionally substituted C i Ce alkylthio group, an optionally substituted (, to C ₆ alkylsulfinyl group, an optionally substituted C i Ce alkylsulfonyl group, an amino group, mono- or alkylamino group C ~ C _e disubstituted from 1 to 3 may contain heteroatoms of 4-9 membered cyclic amino group, an alkylcarbonyl § amino group of C i to C ₆ , An alkoxycarbonylamino group of CiCe Alkyl Suruhoniruami amino group of C i C e, optionally substituted § Li one also be Rusuruhonirua amino group, an alkylcarbonyl group of C i to C _6, a carboxyl group, an alkoxycarbonyl group having C i to C _6, mono- or di-substituted Each independently represents a C i -C s alkyl group, a 4- to 9-membered cyclic group that may contain 1 to 3 heteroatoms, a cyano group or a nitro group. A benzene ring which may have 1 to 3 selected substituents (two adjacent substituents may be bonded to each other to form a ring),

C ring is a halogen atom, alkyl Le group optionally substituted C i to C _6, human Dorokishiru group, alkoxy group optionally C ~ C ₆ optionally substituted, an optionally substituted C, ~ Arca Noi Ruo carboxymethyl group C _e, it may also be substituted I § Li Roiruokishi group, optionally substituted § reel also be methyl O alkoxy group, C ₃ ~ C. A cycloalkoxy group, C ₃ -C,. Cycloalkanoyloxy group, amino group, mono or di Alkylamino amino group of conversion of C i C e, 1~ 3 pieces may Idei contain heteroatoms of 4-9 membered cyclic § Mi amino group, an alkyl Cal Boniruami amino group of C 1~ C _6, C i alkoxycarbonyl § Mi amino group of ~C _6, C i C t; alkylsulfonyl amino group, an optionally substituted § Li one also be Rusuruhoniruami amino group, it then independently from the Shiano group or a preparative port group 2. The benzene ring according to claim 1, which represents a benzene ring which may have 1 to 3 substituents selected from the above (two adjacent substituents may be bonded to each other to form a ring). Provide a quinoline derivative having a pyro opening.

The present inventors have the following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i -C ₆ alkyl group, R ⁴ is a hydroxyl group, a C i -C ₆ alkoxy group, a benzyloxy group or a reactive residue, ring A is a halogen atom, Optionally substituted C i -C ₆ alkyl group, optionally substituted aryl group, hydroxy group, optionally substituted C i Ce alkoxy group, C ₃ -C i ₀ cycloalkoxy group, Arca Noi Ruo alkoxy groups optionally substituted C i to C _6, optionally substituted § Li Roiruokishi group, optionally substituted § reel methyl O alkoxy group, C ₃ ~ C _{1 0} cycloalkadienyl Noi Le Okishi group, an optionally substituted C. 1 to C ₆ alkylthio group, alkyl sulfide alkenyl group may be substitution, optionally substituted C, of ~ C _fi Alkylsulfonyl group, amino group, Di- or di-substituted CiCe alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, CtCs alkylcarbonylamino group A C i -C ₆ alkoxycarbonylamino group, a C i -C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, a C ₁ -C ₆ alkyl radical Boniru group, formyl group, carboxyl group, alkoxy carbonyl group, mono- or alkyl force Rubamoi Le group di-substituted C i to C _G,. 1 to three of also be 4-9 membered contain heteroatoms 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 A) a homo- or heterocyclic ring which may have a C ring, a halogen atom, Which may be C i C e alkyl group, human Dorokishiru group, an optionally substituted C, alkoxy group ~ C _6, alk Noi Ruo alkoxy group optionally C! C e may be substituted, it is substituted which may § Li Roiruokishi group optionally, optionally substituted § Li one also be Rumechiruokishi group, C ₃ ~ 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, C T～ alkylcarbonyl Niruami amino group of C _6, alkoxycarbonyl § Mi amino group of C ₁ ~ C _e, alkylsulfonyl § amino group ~ C _6, substituted I § Li one good even if Rusuruhoniruami amino group, Shiano 1 to 3 substituents independently selected from a group or a nitro group (adjacent two substituents may be bonded to each other to form a ring) Shows a good benzene ring. And 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 t C s alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C! To C ₆ alkyl group, and ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 0 S 0 ₂ R ⁶

(Where R ^G is an optionally substituted C 1, -C _β alkyl group or an optionally substituted aryl group), the C ring is a halogen atom, an optionally substituted C i -C ₆ alkyl An optionally substituted C i Ce alkoxy group, an optionally substituted C i Ce alkanoloxy group, an optionally substituted aryloxy group, An optionally substituted arylmethyloxy group, C

₃ ~ C _{1 0} cycloalkoxy group, C g C i. Of Shikuroarukanoi Ruokishi group, an amino group, mono- or di-substituted Arukirua amino groups of C i~ C _6, 1~ 3 or may contain heteroatoms of 4-9 membered cyclic amino groups, C ₁ -C ₆ alkylcarbonyl § amino groups, C i to alkoxycarbonyl amino group of C _6, C. 1 to alkylsulfonylamino group C _6, optionally substituted § also be reel sulfonyl § Mi amino group, shea It has 1 to 3 substituents independently selected from an ano group or a nitrogeno group (adjacent two substituents may be bonded to each other to form a ring) Represents an optionally substituted benzene ring. The present invention provides a pyroquinoline derivative represented by the formula 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 are the same or different and each is a hydrogen atom or a C i C s alkyl group; ring B is 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, optionally substituted C丄-alkoxy group C _6, alk Noi Ruo alkoxy group-C ₆ optionally C ₁ be substituted, may be substituted also good § Li Roiruokishi group optionally substituted § reel methyl O alkoxy group, C ₃ ~ C. A cycloalkoxy group, C g C i. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted C 丄 -C ₆ alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C i -C ₆ alkylcarbonylamino group, C i -C ₆ alkoxycarbonylamino group, C t Ce alkylsulfonylamino group, optionally substituted arylsulfonylamino group, cyano 1 to 3 substituents each independently selected from a group or a nitro group (adjacent two substituents may be bonded to each other to form a ring) Shows a good benzene ring. And a salt, hydrate and solvate thereof.

The present inventors have the following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, R ⁴ is a hydroxyl group, a C! -C ₆ alkoxy group, a benzyloxy group or a reactive residue, and the A ring is independently A homo- or heterocyclic ring optionally having 1-3 selected substituents (adjacent two substituents may be bonded to each other to form a ring); Represents a benzene ring which may have three substituents (two adjacent substituents may be bonded to each other to form a ring). Or its salts, hydrates and solvates

The following general formula (5)

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom or a C i C s alkyl group; ring B has 1 to 5 substituents (when two adjacent substituents are bonded to each other, A benzene ring which may have a) or a salt, a hydrate and a solvate thereof. Provided are methods for producing a compound or a salt, hydrate and solvate thereof.

The present inventors have the following general formula (6)

(Wherein, R ³ is a hydrogen atom or a C i Cs alkyl group, R ⁷ is a hydroxyl group, a C-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 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 Or a reactive residue, X is a halogen atom or 0 S 0 ₂ R ⁶

(R ⁶ is an alkyl group of C i -C ₆ which may be substituted with halogen, an aryl group which may be substituted), and the C ring has 1 to 3 substituents (two adjacent substituents are A benzene ring which may have a bond. ) Pyro-mouth quinoline represented by) Derivatives or their salts, hydrates and solvates and the following general formula (7)

(A Y (7)

(Wherein Y is a halogen atom, 〇S 0 ₂ R ^fi (R ⁶ is the same as above), B (R ⁸ ) 2 (R ⁸ is a hydroxyl group, a C i C s alkyl group or a C i C s alkoxy group. 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 a process for producing a pyro-mouth quinoline derivative or a salt, hydrate and solvate thereof according to item 3.

The present inventors have proposed a quinokinin receptor antagonist characterized by containing a pyromouth quinone derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide the agent.

The present inventors have proposed a substance P receptor antagonist comprising a pyro-mouth quinoline derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide the agent.

DISCLOSURE OF THE INVENTION The present inventors have found that a pyrroloquinoline derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition is characterized by containing a urinary frequency, urinary incontinence, etc. Provided is an agent for preventing or treating dysuria including bladder dysfunction.

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

The present inventors have proposed a pyrroloquinoline derivative represented by the general formula (1) or a derivative thereof. X-ray irradiation, chemotherapeutic agents, pregnancy, migraine, postoperative illness, reduced gastrointestinal motility or side effects of drug administration characterized by containing a salt, hydrate, and solvate of the drug as a pharmaceutical composition And vice versa.

The present inventors are concerned with tachykinin, which is characterized by containing a pyro-mouth quinoline derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide therapeutic agents for asthma, cough, 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 C ₆ alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group and the like. The alkoxy group of c ₁ to c ₆ means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexoxy group, or the like. c ₃ ~ c _1. The cycloalkoxy group in the above means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group or the like. The CsC, 0 cycloalkanoyloxy group means a cyclobronoyloxy group, a cyclobutanoyloxy group, a cyclopentanoyloxy group, a cyclohexanoyloxy group, or the like. The alkyl force luponyl group of c ₁ to c ₆ means an acetyl group, a propionyl group, a butyryl group or the like. The C i -C ₆ alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, a hexoxycarbonyl group, or the like. The § Ruki carbamoyl group C i ~ C ₆ mono or di-substituted, methylcarbamoyl group, Echirukaruba sulfamoyl group, a propyl force Rubamoiru group, Lee an isopropyl force Rubamoiru group, t - butylcarbamoyl group, the alkoxy carbamoyl group, Jimechiruka It means a rubamoyl group, a getylcarbamoyl group, a rubamoyl group having a dibutyl pill, a rubamoyl group having a diisopropyl group, a dibutylcarbamoyl group, a dihexylcarbamoyl group, and the like. A 4- to 9-membered cyclic rubamoyl group which may contain 1 to 3 hetero atoms includes azetidinyl carbonyl group, pyrrolidinylcarbonyl group, piperidinyl carbonyl group, and 4-methylbiperidinyl group. It means a carbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, a 4-methylbiperazinylcarbonyl 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. The C i -C ₆ alkylamino group includes a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a t-butylamino group, a hexylamino group, a dimethylamino group, and a ethylamino group. , A jib mouth bilamino group, a diisopropylamino group, a dibutylamino group, a dihexylamino group and the like. A 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, It means a thiomorpholino group, a piperazino group, a 4-methylpyrazino group or the like. The CiCe alkylcarbonylamino group means an acetylamino group, a propionylamino group, a petyrylamino group, or the like. C ₁ and alkoxycarbonyl § Mi amino group of ~ C _6, main butoxycarbonyl § Mi amino group, e butoxycarbonyl § Mi amino group, refers to t- butoxycarbonyl amino group, a hexyl O alkoxycarbonyl amino group I do. The C i C 6 alkylsulfonylamino group means a methylsulfonylamino group, an ethylsulfonylamino group, and the like. An arylsulfonylamino group is 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 naphthylene 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 aromatic fused heterocyclic ring. The alkyl group which may be substituted (^ to (^ (; is a halogen atom, a hydroxyl group, a C i Ce alkoxy group, a C ₆ alkylthio group, an amino group, a mono- or di-substituted C i C s alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, formyl amino group, C i C s alkyl carbonyl amino group, C i A C _{1 to} C ₆ alkyl group which may have 1 to 5 substituents selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. The optionally substituted C 1 to C ₆ alkoxy group includes, for example,, a halogen atom, a hydroxy group, a C i C alkoxy group, a C i to C ₆ alkylthio group, an amino group, and a mono group. Or a disubstituted CiCe alkylamino group, containing 1-3 heteroatoms 4- to 9-membered cyclic amino group, formylamino group, C i Ce alkyl alkylonylamino group, C to C ₆ alkylsulfonylamino group, optionally substituted aryl It means a C ₁ -C ₆ alkoxy group which may have 1 to 5 substituents selected from a sulfonylamino group, etc. An optionally substituted C i -C _e alkanoy Roxy group means halogen atom, hydroxy group, C 1 to C ₆ alkoxy group, C i C fj alkylthio group, amino group, mono- or di-substituted (! To C ₆ alkylamino group, 1 1-3 of the but it may also contain a hetero atom 4-9 membered cyclic amino group, Horumiruami amino group, Al kill carbonyl amino group of C ₁ ~ C _6, alkylsulfonyl C i~C ₆ amino Selected from an optionally substituted arylsulfonylamino group, etc. C 1 to C ₆ alkanoyloxy group (acetyloxy, propionyloxy, isopropionyloxy, hexanoyloxy, etc.) which may have 1 to 5 substituents. The optionally substituted aryloxy group includes a halogen atom, a C i -C ₆ alkyl group, a hydroxy group, a C -C ₆ alkoxy group, and a C! A C ₆ -C ₆ alkylthio group, an amino group, a mono- or di-substituted C -C ₆ -alkyl amino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, Horumiruami amino group, C i C e Al kill carbonyl amino group, C i to C alkylsulfonyl amino groups of _6, optionally substituted selected from good § reel sulfonylamino group 1-5 substituents It means an aryloxy group which may have a group (a benzoyloxy group, a naphthyloxy group, a pyridyloxy group, a pyrimidyloxy group, a quinolyloxy group, an indyloxy group, etc.). The optionally substituted arylmethyloxy group includes a halogen atom, a C i C fj alkyl group, a hydroxy group, a C i Ce alkoxy group, a C i -C ₆ alkylthio group, and an amino group. amino group, mono- or alkylamino amino group of C ₁ -C ₆ di-substituted from 1 to 3 hetero atoms may be free Ndei to the 4-9 membered cyclic amino group, Horumiruami amino group, a ~ C ₆ alkylcarbonyl amino group, C i to alkylsulfinyl Honiruami amino group of C _6, which may have 1 to 5 substituents selected from good substituted I § reel sulfonyl § amino group It means an arylmethyloxy group (phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, quinolylmethyloxy group, indolylmethyloxy group, etc.). The arylsulfonylamino group which may be substituted includes a halogen atom, a C i C alkyl group, a hydroxy group, a C t -C ₆ alkoxy group, a C i C alkyl group, and an amino group. group, mono- or di-substituted alkylamino group C i to C _6, 1-3 pieces may also be 4-9 membered contain heteroatoms of the cyclic § Mi cyano group. Horumiruami amino group, an alkylcarbonyl § Mi amino group of C i to C _6, alkylsulfonyl C ₁ ~ C ₆ An arylsulfonylamino group which may have 1 to 5 substituents selected from an amino group, an optionally substituted arylsulfonylamino group and the like. 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 includes a halogen atom, C i-

C ₆ alkyl group, hydroxy group, C i -C ₆ alkoxy group,

C i -C ₆ alkylthio group, amino group, mono- or di-substituted 〇! ~

C ₆ alkyl amino group, 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, formyl amino group, C ₁ to C ₆ alkylcarbonyl amino group, C an aryl group optionally having 1 to 5 substituents selected from i to C ₆ alkylsulfonylamino groups, an optionally substituted arylsulfonylamino group, etc. (phenyl Group, naphthyl group, etc.). The alkylthio group which may be substituted, a halogen atom, arsenic Dorokishiru group, C! ~ Alkoxy group C _6, the Arukiruchio group, amino group, mono- or di-substituted. Alkylamino of丄~ C ₆ amino group from 1 to 3 good not 4-9 membered also contain heteroatoms of the cyclic amino group, Horumiruami amino group, C i C e Al Kill carbonyl amino group, Means an alkylthio group optionally having 1 to 5 substituents selected from C i to C ₆ alkylsulfonylamino groups, optionally substituted arylsulfonylamino groups, etc. You. The optionally substituted alkylsulfinyl group includes a halogen atom, a hydroxyl group, a C i -C ₆ alkoxy group, a C t Ce alkylthio group, an amino group, a mono- or di-substituted C i -C ₆ alkyl amino group of from 1 to 3 of the a or 4-9 membered optionally contain heteroatoms ring-shaped § Mi amino group, Horumiruami amino group, an alkylcarbonyl amino group, the C I～C ₆ An alkylsulfinyl group optionally having 1 to 5 substituents selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. (a methylsulfinyl group, an ethylsulfinyl group) Group, propylsulfinyl group, etc.). The alkylsulfonyl group which may be substituted includes a halogen atom, a hydroxyl group and a C! -C ₆ alkoxy, C ₁ -C ₆ alkylthio, amino, mono- or di-substituted C! C ₆ -C ₆ alkylamino group, 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, formylamino group, C i -C ₆ alkylcarbonylamino group, C! To C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and an optionally substituted alkylsulfonyl group (methylsulfonylamino group) Honyl group, ethylsulfonyl group, propylsulfonyl group, etc.). The reactive residue means a halogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidyloxy succinate group or the like. Halogen substituted the alkyl group which may C i~ C _6, 1~ 1 3 single full Tsu atom or an optionally substituted methyl group with a chlorine atom, Echiru group, propyl group, i an isopropyl group , T-butyl group, hexyl group and the like. The rings that may be formed by bonding R ⁸ to each other are —〇 (CH ₂ ) ₂₀ —, — 0 CH (M e) CH (M e) 0—, — OC (M e) ₂ C (Me) ₂₀ — or 10 (CH ₂ ) ₃₀ — and the like.

Preferred compounds of the present invention include N- [3,5-bis (trifur O-methyl) benzyl] 1,1,2-dihydro-1-N-methyl-1-oxo-6-phenyl-14H-pyrro [3,2,1-ij] quinoline—5-carboxamide, N — [3,5-bis (trifluoromethyl) benzyl] 1-1,2-dihydro-6- (3-methoxyphenyl) -1-N-methyl-14-oxo-4H—pyro mouth [3, 2,1, -ij] quinolin-5-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —6- (2,4-dichlorophenyl) one

1,2-dihydro-1-N-methyl-1-oxo-4 H-pyro [3,2,1—ij] quinolin-5-carboxamide, N— [3,5-bis (trifluoromethyl Benzyl] — 1,2, -Dihydro-1,2, N—Dimethyl-1,4-oxo-1,6-Huenyl-4H—Pyro mouth [3,2,

1 — i j] quinoline—5-carboxamide, N— [3,5-bis

(Trifluoromethyl) benzyl] — 1,2-dihydro-1,2, N-dimethyl-16- (3-methoxyphenyl) -14-oxo-4H-pyrrolo [3,2,1-ij] Quinolin-1 5—Carboxamide, N—

[3,5-bis (trifluoromethyl) benzyl] — 6— (2,4—dichlorophenyl) 1,1,2-dihydro-1,2, N—dimethyl-14—oxo-4H—pyromouth [3 , 2,1-ij] quinolin-5-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, Examples thereof include pharmacologically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

The compound of the present invention or a salt thereof includes 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, typical production steps of the compound of the present invention and a salt thereof will be described.

(II) (R ⁹ is the same or different and Ci-C ₆ alkyl group, benzyl group) is reacted to produce compound (ΠΙ) (R ³ , R ⁹ and C ring are as defined above) It is a process. In this reaction, the compound (II) 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 2 ° C. Performed at 50 ° C. When a solvent is used, an inert solvent which does not participate in the reaction, for example, xylene, mesitylene, nitrobenzene, diphenyl ether, dausam (diphenyl)

—A mixture of ter and biphenyl).

(Second step)

In this step, the hydroxyl group of the compound (ΠΙ) (R ³ , R ⁹ and the C ring are the same as described above) is converted to X (X is the same as the above), and 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, salt The reaction is carried out using thionyl chloride, oxychloride, pentachloride or oxalyl chloride. When a solvent is used, use an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethan, toluene, pyridine, etc. Can be This reaction proceeds smoothly at a temperature from room temperature to the boiling point of the chlorinating agent or the boiling point of the solvent when a solvent is used. When X is a bromine atom, the reaction can be carried out in the same manner as in chlorination using the corresponding brominating agent. But

In the case of 0 S 0 2 R ⁶ (R ⁶ is the same as above), the sulfonating reagent used in this reaction is methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride , Trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonylimide, etc. are used, and the reaction is carried out in a solvent in the form of triethylamine, triptylamin, diisoprom. The reaction is performed in the presence of a base such as pyrethylamin, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamine. 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 170 ° C. (: 〜100 ° C., preferably 130 ° C. to 80 ° C.).

(Third step)

In this step, the compound (IV) (X, R ³ , R ⁹ and C rings are the same as described above) and the compound (V) (Y and A rings are the same as described above) are treated with a transition metal such as palladium or nickel complex. This is a step of producing compound (VI) (R ³ , R ⁴ and ring A are the same as above) by a cross-coupling reaction under a catalyst. 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 , Tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol or 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, acetylacetonatopalladium, tetrakis (triphenylphosphine) palladium and the like. Examples of the nickel complex used in this reaction include bis (acetylacetonato) nickel, bis (1,5-cyclooctadiene) nickel, and tetrax (triphenylphosphine) nickel. These palladium or nickel complexes are used in an amount of 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, based on the compound (IV).

Used in the range of one equivalent. When a ligand for palladium or a nickel complex is used in this reaction, triphenylphosphine, tri-10-tolylphosphine, tri-12-furylphosphine, 1,2-bis (diphenylphosphine) is used. No.) ethane, 1,1,1-bis (diphenylphosphino) phenene or 2,2,1-bis (diphenylphosphino) -11,1, -binaphthyl and the like can be exemplified. 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. If X in the compound (IV) is 0 S 0 ₂ R ^6, together with the palladium or nickel complex, can also be used ® © copper or lithium chloride Lai de like if necessary. This reaction is preferably performed in the presence of a suitable base. For example, organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and hydrogencarbonate Examples thereof include inorganic bases such as sodium, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, and potassium triphosphate. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (IV). Cross force of this process The priming reaction 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 in this step, compound (IV) or compound (V) (where Y is B and (R ⁸⁾ not _2), HB (R ⁸⁾ ₂ or (B (R ⁸⁾ ₂₎ ₂ is reacted with a compound obtained (IV) (X is B (R ⁸⁾ ₂₎ or of focus Compound (V) (丫 is 8 (1 ^ ⁸ ) ₂ ) and compound (V) (where Y is

B (not R ⁸ ) ₂ ) or compound (IV) to produce compound (VI). The compound (IV) (X is B ( ⁸ ) ₂ ) or compound (V) (Y is B (R ⁸ ) ₂ ) and the A ring is the same as the production intermediate obtained at this time is isolated. It can be used for the next step after purification or it can be continuously used for the next step without isolation and purification.

B '

(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 ring B are the same as described above) are condensed to obtain compound (VIII) (R ¹ R ² , R ³ , ring A, ring B and ring C are as defined above). Examples of the condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction in this step include dicyclohexyl carpoimide (DCC) and 3-ethyl-1- (3-dimethylaminopropyl) carboxide. Examples thereof include amide hydrochloride (EDCI) and dimethylimidazo dimethyl chloride (DMC), which are added in a solid state or as a solution dissolved in an appropriate solvent. When a base is used in the present condensation reaction, an alkali carbonate such as sodium hydrogencarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5 4.0] — 7-Pendecene, pyridine, 4-dimethylaminoviridine or 1,8-bis (Dimethylamino) Tertiary amines such as naphthalene can be 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, acetonitrile, Trahydrofuran, dioxane, 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 reactive residue (for example, a halogen atom, an 11-imidazolyl group, a 4- 12-tropinoxy group, an imidyloxy succinate group), or a carboxylic acid halide or carboxylic acid. In the case of acid imidazolides, active esters of carboxylic acids, mixed anhydrides of carboxylic acids (for example, anhydrides with ethyl carbonate, anhydrides with isobutyl carbonate, etc.) or, in the case of symmetric acid anhydrides, triethylamine, N, N-dimethylform in the presence or absence of organic bases such as diisopropylethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydrogencarbonate and potassium carbonate Amid, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran, dioxane, ethylate , Dimethyl Toki Shetan, acetic Echiru, toluene, in a solvent such as dichloromethane, One

It can be carried out by treating at 20 to 80 ° C for 30 minutes to 48 hours. In the condensation reaction of this step, when R ⁴ is an ester residue such as a C ₆ -C ₆ alkoxy group or benzyloxy group, in the presence of trimethylaluminum or tetraisopropoxytitanium, or p-toluenesulfone N, N-dimethylformamide, N, N-dimethylacetamide in the presence of an acid catalyst such as an acid or a base such as sodium methoxide, potassium-t-butoxide, sodium hydride and the like , Dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxan, toluene, xylene, dichloromethane, etc. 5 days. It can be carried out by treating with C for 30 minutes to 48 hours.

(XII) (III)

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 butoxide, hydrogen N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, etc. in the presence of a base such as sodium fluoride It can be carried out by treating in a solvent of 50 to 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from compound (XI) obtained 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, the compound (X) is used in an amount of 1 to 10 equivalents of the compound (X), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide or potassium t-butoxide is used. N, N — dimethylformamide, N, N — dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, and toluene in the presence of bases such as sodium chloride and sodium hydride This can be carried out by treating in a solvent such as xylene or the like at 50 to 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (XIII) 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 together with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition, and a pharmacologically acceptable carrier, excipient ( For example, starch, lactose, calcium phosphate, calcium carbonate, etc., lubricants (eg, magnesium stearate, calcium talc, stearate, etc.), binders (eg, starch, crystalline cellulose, Carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, calcium carboxymethylcellulose, etc.), diluents (eg, aqueous solutions of saline, glucose, mannitol, lactose, etc.) Etc.) and tablets, capsules, granules, , Fine granules, can be administered orally or parenterally in forms such as ampoules or injection. The dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, symptoms, and the like. 0.0000 to 30 mg / kg / day. 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% was bubbled through C 02 5% of the mixed gas, liquid temperature and 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. p A ₂ value method S child ( "Pretty Mesh Journal 'O Bed' files one Makoroji (Brit. J Pharmacol.)" 1 Volume 4, 4 8 pages (1 9 5 9 years)) determined by its binding 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 aH 2 P 0 _{_{4 - 2 H 2 0; 0.}} 4,

N a H C 0a; 11.9, glucose; 11.1 (mM)

〔table 1〕

Example No. P A "Direct (nM)

1 0 4 2. 1

1 1 2 5.2 Example 1

Dissolve Methanone (2,3-Dihydro 1 H-indole-17-yl) (3-Methoxyphenyl) (3.33 g, 13.1 mmol) in 30 ml of ethyl acetate and 5.5 ml of triethylamine Was added dropwise under ice cooling, and ethyl ethyl malonylk mouth ride (4.2 ml, 32.9 mmol) was added dropwise, followed by stirring 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 30 ml of tetrahydrofuran, and 1 t-butoxide (1.91 g, 17.0 mmol) of potassium 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 extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (methylene chloride: hexane 1: 1) to give colorless crystals. 2—Dihydro 6— (3—Methoxyphenyl) 1-4—oxo 4 H—Pyro mouth [3,2,1—ij] quinolin-5—Carboxylic acid ethyl ester (4.11 g, 89%) ).

EIMS m / z: 349iM Example 2

6-1,2-Dihydro-4-oxo-4H-pyro [3: 2,1-ij] quinolin-5-Ethyl ruvonate (lll.lmg, 0.40mmol) and te Dissolved tristriphenylphosphinoradium (18.5 mg, 16.0 imol, 0.04 eq.) In 5 ml of benzene and 1 ml of 2M sodium carbonate aqueous solution and phenylboric acid (146.3 mg, 1.2 mmol) A solution of dimethylformamide (2 ml) was added, and the mixture was heated to reflux. On the way, texturyl phenylphosphinoradium (18.5 mg, 16.0 μmol, 0.04 eq.) Was added, and the mixture was heated and refluxed for 8 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. The resulting residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1) to give pale brown crystals. 1, 2-dihydro-4-oxo-1-6-fenil-4 H-pyro [3, 2, 1-ij] quinoline-1 5-ethyl acetyl ester (77.9 mg, 61%) was obtained. Was.

EIMS m / z: 319 (M ⁺ ) Example 3

According to a method similar to that of Example 2, 6-chloro-1,4-dioxo-4-oxo-4 ピロ -pyro [3,2,1—ij] quinoline-5-potassium ethyl rubonate (Lll.lmg, 0.40mmol) and 2,4-dichlorophenylboric acid (229.0mg, 1.2mmo to 6- (2,4-dichloromouth phenyl) as pale yellow oily substance) 1,1,2-dihydro-1-4-oxo One 4 H-pyro-mouth [3,2,1-ij] quinoline 15-potassium ester ethyl ester (98.6 mg, 63%) was obtained.

EIMS m / z: 367 (M ⁺ ) Example 4

In the same manner as in Example 2, 6-chloro-1,2-dimethyl-2-methyl-4-oxo-4H-pyro [3,2,1—ij] quinoline-5—caprolubone Acid ethyl ester (116.7mg, 0.40mmol) 1,2-Dihydro-12-methyl-4-oxo-6-phenylu-4H-pyro [3,2,1-ij] quinoline as colorless crystals from ruboric acid (146.3 mg, 1.2 mmol) 5-Ethyl carboxylate (49.1 mg, 37%) was obtained.

EIMS m / z: 333 (M ⁺ ) Example 5

In the same manner as in Example 2, 6-chloro-1,2, dihydro-2, methyl-1,4-oxo-4H-pyro [3,2,1—ij] quinolin-5 —Colorless amorphous 1,2-dihydro-1 6 — (3—methoxyphenyl) 1-2 from carboxylic acid ethyl ester (116.7 mg, 0.40 mmol) and 3-methoxyphenylboric acid (182.4 mg, 1.2 mmol) —Methyl-4-oxo-4H—pyro-mouth [3,2,1—ij] quinolin-5-carboxyethyl ester (101.0 mg, 69%) was obtained.

EIMS m / z: 363 (M ⁺ ) Example 6

According to the same method as in Example 2, 6-chloro-1,2-dihydro-1-methyl-4-oxo-4H-pyro [3,2,1-i] quinolin-5- Colorless crystalline 6- (2,4-dichlorophenyl) from 1,4-dichlorophenylboronic acid (229.0mg, 1.2mmol) with 1,7-dichlorophenyl ether ester (116.7mg, 0.40mmo) —Methyl-1-oxo-4H—pyro-mouth [3,2,1-ij] quinolin-5-force Ethyl ribonate (37.9 mg, 24%) was obtained.

EIMS m / z: 401 (M ⁺ ) Example 7

1, 2-dihydro 4-1-6-feneru 4 H-pyro [3,2,1-ij] quinoline 1 5-carboxylic acid ethyl ester (74.4 mg, 0.233 mmol) and water Oxidizing power i65.4mg, 1.16mmol, 5eq.) Was dissolved in ethanol (4.5 ml) -water (0.5 ml) and heated under reflux for 3 hours. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. 0.5 ml of thionyl chloride was added to the obtained residue and stirred at room temperature for 0.5 hour. The residue obtained by distilling off the thionyl chloride was dissolved in 3 ml of methylene chloride, and 0.2 ml of triethylamine and 0.05 ml of N-methyl-13,5-bis (trifluoromethyl) benzylamine were added, followed by stirring for 0.5 hour. did. Water and methylene chloride were added to the reaction solution, and extracted three times with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue obtained was subjected to silica gel column chromatography (methylene chloride: ethyl acetate 10: 1 → 5: 1 → 2: 1). ). Hexane is added to the obtained oil to crystallize it, and colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] —1,2-dihydro N-methyl-14-oxo-6- There was obtained phenyl-4H-pyro [3,2,1-ij] quinolin-5-carboxamide (72.9 mg, 59%). mp. 183-185 ° C

Anal: As C _{2 8} H _{2 0} F ₆ N ₂ O ₂

Calculated values C 63.40%, H 3.80%, N 5.28%;

Found C 63.30%, H 3.85%, N 5.18%

EIMS m / z: 530rM ⁺ )

Example 8

According to a method similar to that of Example 7, 1,2-dihydro-6- (3-methoxyphenyl) 14-oxo-1-4H-pyro [3,2,1—ij] Norin — 5 — Potassium ethyl ester (129.4 mg, 0.370 mmol) and 0.09 ml of N-methyl-1,3,5-bis (trifluoromethyl) benzylamine from colorless N — [3,5—Bis (trifluoromethyl) benzyl] —1,2-dihydro-6- (3-methoxyphenyl) 1-N-methyl-14-oxo-4H—pyromouth [3 [2,1-ij] quinolin-5-carboxamide (170.7 mg, 82%). mp. 194-196 ° C

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

Calculated values C 62.14%, H 3.96%, N 5.00%;

Measured value C 61.89%, H 4.06%, N 4.92%

EIMS m / z: 560 (M ⁺ ) Example 9

According to the same method as in Example 7, 6— (2,4—dichlorobenzene) 1 1,2—dihydro-4-4-oxo-1 4H—pyromouth [3,2,1−ij ] Colorless crystalline N- [3,5] -quinolinine-5-potassium ester (98.6mg, 0.254mmol) and N-methyl13,5-bis (trifluoromethyl) benzylamine 0.065ml 5-bis (trifluoromethyl) benzyl] — 6 — (2,4-dichlorophenyl) 1-1,2-dihydro N-methyl-4-oxo-1 4H-pyro [3,2,1—ij] Quinolin-5-carboxamide (95.7 mg, 63%) was obtained. mp. 190-193 ° C

Anal: as a _{_{_{C 2 8 H t 8 C t}}} 2 F fi N 2 O 2

Calculated values C 56.11%, H 3.03%, N 4.67%;

Measured value C 56.26%, H 3.00%, N 4.70%

EIMS m / z: 598 (M +) Example i_g „

By the same method as in Example 7, 1,2-dihydro-2-methyl-4-oxo-1-6-phenyl-4H-pyro [3,2,1-ij] quinoline-5-caprolubone Acid-ethyl ester (49.lmg, 0.147mmol) and N-methyl-1,3,5-bis (trifleolomethyl) benzylamine 0.035ml from N- [3,5-bis (trifluoromethyl) as colorless crystals ) Benzyl] -1,2—dihydro-1,2, N-dimethyl-14-oxo-6-phenyl-4H-pyro [3,2, l—ij] quinolin-5-carboxamide (50.1 mg, 62%). mp. 182-184 ° C

EIMS m / z: 544 (M ⁺ )

In the same manner as in Example 7, 1,2-dihydro-6- (3-me Toxiphenyl) 2-Methyl-14-oxo-4H-pyrro [3,2,1-ij] quinolin-5-carboxylic acid ethyl ester (98.5 mg, 0.271 mmol) and N_methyl-1,3 Colorless crystalline N- [3,5-bis (trifluoromethyl) benzyl] 1-1,2-dihydro-1-2, N-dimethyl from 0.07 ml of 5-bis (trifluoromethyl) benzylamine 3-Methoxyphenyl) 1-4-oxo-1 4H-pyro [32,1-ij] quinolin-5-carboxamide (117.3 mg, 75%) was obtained. mp.159-161.5 ° C

Anal: As C _{3 0} H _{2 4} F _G N ₂ O ₃

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

Measured value C 62.45%, H 4.17%, N 4.86%

EIMS m / z: 574 (M ⁺ )

According to the same method as in Example 7, 6- (2,4-dichlorophenyl) 1-1,2-dihydro-12-methyl-14-oxo-14H-pyromouth [3,2] , 1 — ij] quinoline _ 5-potassium ethyl ester (37.9 mg, 0.0942 mmol) and N-methyl-1,3,5-bis (trifluoro N- [3,5-bis (trifluoromethyl) benzyl] —6— (2,4-dichlorophenyl) 1-1,2-dihydro-2, N-dimethyl mono-methyl-benzylamine from 0.025 ml 4-oxo-4H-pyrro [3,2,1-ij] quinolin-5-carboxamide (22.7 mg, 39%) was obtained. mp.166-170 ° C

EIMS m / z: 612 (M ⁺ ) Reference example 1

2-Methylindolin (1.33 g, 10 mmol) and triethyl methane tricarboxylate (4.70 g, 20 mmol) were stirred at 220 ° C for 30 minutes. The product is purified by silica gel column chromatography (methylene chloride), and the resulting crystals are washed with hexane to give pale yellow crystals of 1,2-dihydro-6-hydroxy-12-methyl-4-oxo. One 4 H-pyro [3,2,1-ij] quinoline-5-potassium ethyl ester (1.13 g, 41%) was obtained.

EIMS m / z: 273 (M ⁺ ) Reference example 2

1,2-dihydroxy-6-hydroxy-4-oxo-4H-pyro [3,2,1—ij] quinolin-5-carboxylic acid ethyl ester (1.55 g, 5.95 mmol) and triphene Nilphosphine (3.14 g, 12.0 mmol) was dissolved in 10 ml of acetonitrile, carbon tetrachloride (3.61111, 35.911111101) was added, and the mixture was heated under reflux for 2 hours. Triphenylphosphine (1.57 g, 6.0 mmol) and carbon tetrachloride (1.8 ml, 18.0 mmol) were added, and the mixture was refluxed for 2 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained crystals were washed with hexane to give pale yellow crystals of 6-chloro-1,6-dihydro. A 14-oxo-4H-pyrro [3,2,1-ij] quinolin-5-carboxylic acid ethyl ester (1.82g, 100%) was obtained.

EIMS m / z: 277 (M ⁺ ) Reference example 3

C0 ₂ Et In the same manner as in Reference Example 2, 1,2-dihydro 6-hydroxy-1-methyl 4-oxo-4 H-pyro [3,2,1-ij] quinolin-5-force From ethyl ribonate (1.10 g, 4.03 mmol), colorless crystals of 6-chloro-1,2-dihydro-1,2-methyl-4-oxo-1 4 H-pyro [3,2,1-ij] quino There was obtained ethyl 5-carboxylate (647.4 mg, 55%).

EIMS m / z: 291 (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 R 〖, 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 ring A is independently selected from one to three substituents (adjacent 2 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) May be bonded to each other to form a ring) The optionally substituted benzene ring and C ring have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring A pyrroloquinoline derivative represented by the formula 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 hydroxyl group, an optionally substituted C t C s alkoxy group. A C ₃ -C ₁₀ cycloalkoxy group, an optionally substituted C alkanoloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C ₃ ~ C i. Of Shikuroarukano Iruokishi group, an optionally substituted C ~ alkylthio group C _6, Optionally substituted C i C ^ Arukirusurufu I alkylsulfonyl group, an alkylsulfonyl group optionally C ₁ -C ₆ substituted, amino group, alkylamino amino group of C i~C ₆ mono- or di-substituted A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a C ₁ to C ₆ alkylcarbonyl amino group, a C> to C ₆ alkoxycarbonyl amino group, C i -C ₆ alkylsulfonylamino group, optionally substituted arylsulfonylamino group, C i C e alkyl force reportanol group, formyl group, carboxyl group, C i C e of an alkoxy carbonyl group, mono- or di-substituted C ^ ~ alkyl carba model I le group C _6,. 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic forces Rubamoiru group, Shiano group Or 1 to 3 substituents independently selected from nitro groups Two adjacent substituents represents a bond and may have a good) also form a ring homo- or heterocyclic each other,

Ring B is a halogen atom, an optionally substituted CiCe alkyl group, or CsCi. A cycloalkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C! To C 6 alkoxy group, optionally substituted C i Ce alkanoloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ to C i. A cycloalkoxy group, C g C i. A cycloalkanoyloxy group, an optionally substituted CiCe alkylthio group, an optionally substituted

C ₆ alkylsulfinyl group, which may be substituted

Alkylsulfonyl group, amino group, mono- or di-substituted C i to alkylamino group C _6,. 1 to 3 or may contain heteroatoms of 4-9 membered cyclic § Mi Roh groups, C alkylcarbonyl § Mi amino group of i to C _6, an alkoxycarbonyl amino group of C ₁ ~ C _6, alkyl of C i C e Sulfonylamino group, optionally substituted arylsulfonylamino group, C i -C ₆ alkylcarbonyl group, carboxyl group, C i -C ₆ alkoxycarbonyl group, mono- or di-substituted C i C s Alkyl group, a 4- to 9-membered cyclic group optionally containing 1 to 3 heteroatoms, a cyano group or a 2-nitro group, each independently selected from 1 to 3 A benzene ring which may have one or more substituents (adjacent two substituents may be bonded to each other to form a ring),

C ring is a halogen atom, an optionally substituted C t C e alkylene group, human Dorokishiru group, alkoxy group optionally C i to C ₆ optionally substituted, which may C ₁ ~ be substituted C ₆ alkanoyloxy, optionally substituted aryloyloxy, optionally substituted arylmethyloxy, C ₃ -C 基. Cycloalkoxy group, C _3. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted alkylamino group of CC fj, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C i C s alkylcarbonylamino group, C i Ce alkoxycarbonylamino group, C i Ce alkylsulfonylamino group, optionally substituted arylsulfonylamino group, cyano group or It may have 1 to 3 substituents independently selected from the nitro group (two adjacent substituents may be bonded to each other to form a ring) 2. The quinoline derivative of claim 1, wherein the quinoline derivative has a benzene ring.

3. The following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i -C ₆ alkyl group, R ⁴ is a hydroxyl group, an alkoxy group of CC e, a benzyloxy group or a reactive residue, a ring A is a halogen atom, C ₁ -C ₆ alkyl group, optionally substituted aryl group, hydroxy group, optionally substituted alkoxy group, C ₃ -C ₁₀ cycloalkoxy group, substituted and Arukanoiruoki sheet group which may C _t ~ C _6, optionally substituted Ariroiruokishi group, substituted Moyoi § reel methyl O alkoxy group, C s C i. of Shikuroarukano i Ruokishi groups, substituted Optionally substituted alkylthio group; an optionally substituted C i -C ₆ alkylsulfinyl group, an optionally substituted C i -C ₆ alkylsulfonyl group, an amino group , Mono- or di-substituted C i C s al Kiruami amino group from 1 to 3 may include a terrorist atom to the 4-9 membered cyclic amino group, an alkylcarbonyl amino group of C! C e, alkoxycarbonyl amino of C i to C ₆ group, C t C e alkylsulfonyl § Mi amino group of, optionally substituted § Li one also be Rusuruhoniruami amino group, an alkyl force carbonyl group C. 1 to C _6, a formyl group, a carboxyl group, C ₁ ~ C ₆ an alkoxy carbonyl group, mono- or di-substituted alkyl carba model I le group C ~ C _6,. 1 to 3 pieces of it 4-9 membered also contain heteroatoms in the cyclic 1 to 3 substituents each independently selected from the group consisting of a carbamoyl group, a cyano group or a nitro group (two adjacent substituents may be bonded to each other to form a ring) A homo- or heterocyclic ring optionally having

C ring is a halogen atom, alkyl Le group optionally C i to C ₆ substituted, human Dorokishiru group, alkoxy group optionally C to C ₆ optionally substituted, optionally C ₁ substituted Arca Noi Ruo alkoxy group ~ C _G, an optionally substituted § Li Roiruokishi group, optionally substituted § reel also be methyl O alkoxy group, C g C i. A cycloalkoxy group of C ₃

. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted CiC alkyl amino group, and a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms A group, a C i -C ₆ alkylcarbonylamino group, a C ₁ -C ₆ alkoxycarbonylamino group, a C ₁ -C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group 1 to 3 substituents independently selected from a group, a cyano group or a nitrogen group (two adjacent substituents may be bonded to each other to form a ring) A benzene ring that may be used. ) Or a salt, hydrate or solvate thereof.

4. General formula (3) below

(3)

(Wherein, R ³ is a hydrogen atom or a C 〖-( ₆ alkyl group, R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group; ring B has 1 to 5 substituents (even if two adjacent 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 ^ϋ (R ⁶ is a C 3 -C _G alkyl group which may be halogen-substituted.) , An optionally substituted aryl group), the C ring is a halogen atom, an optionally substituted C ₆ -C ₆ alkyl group, a hydroxyl group, an optionally substituted C! Ce alkoxy group, (（-C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ -C ₁₀ cycloalkyl group) alkoxy group, cycloalkadienyl Noi Ruo alkoxy group of C ₃ ~ C _{1 0,} amino group, mono also The alkylamino amino group of _C 1~ C ΰ disubstituted from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic § Mi amino group, an alkylcarbonyl § Mi C ₁ ~ C ₆ Bruno Group, an alkoxycarbonylamino group of CiCs, an alkylsulfonylamino group of CiC, an arylsulfonylamino group, a cyano group or a nitrate group which may be substituted Represents 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. ) Or a salt, hydrate or solvate thereof.

5 · General formula (4)

(Wherein, R ³ is a hydrogen atom or a C t C s alkyl group, and R ⁵ is

(R ¹ and R ² are the same or different and are a hydrogen atom or a C i C s 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, the C ring is a halogen atom, an optionally substituted C i -C ₆ alkyl group, a hydroxy group, Optionally substituted C i -C ₆ alkoxy group, optionally substituted C i -C 6 alkanoyloxy group, optionally substituted aryloyloxy group-optionally substituted § reel methyl O carboxymethyl group, C ₃ ~ C! . A cycloalkoxy group, C ₃ -C ₁ . A cycloalkanoyloxy group, an amino group, a mono- or di-substituted CiCe alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, C alkylcarbonyl amino group of i to C _6, C alkoxy carbonyl amino group i~ C _6, C i C fj alkylsulfonyl amino group, optionally substituted § Li one even if Le sulfonyl § amino group, Shiano Group or A benzene ring which may have 1 to 3 substituents independently selected from among nitro groups (two adjacent substituents may be bonded to each other to form a ring) Is shown. And a salt, hydrate and solvate thereof.

6. The following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Cs 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 independently 1 to 3 selected substituents (adjacent two substituents may be bonded to each other to form a ring), optionally a homo- or heterocyclic ring, 1 to 3 ring (s). Represents a benzene ring which may have three substituents (two adjacent substituents may be bonded to each other to form a ring). Or a salt, hydrate and solvate thereof and the following general formula (5)

R ²

(Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom or C i C e The ring B 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). 2. The method for producing a compound or a salt, hydrate and solvate thereof according to claim 1, wherein the compound or a salt, hydrate and solvate thereof are reacted with each other.

7 · 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 a C i C s alkyl group, and the B ring has 1 to 5 substituents. Or a reactive residue, X is a halogen atom or 0 S〇 ₂ R ⁶

(R ⁶ is an alkyl group of C i -C ₆ which may be halogen-substituted, an aryl group which may be substituted), and the C ring has 1 to 3 substituents (two adjacent substituents are May combine to form a ring) The benzene ring which may be possessed is shown. ) Or a salt, hydrate and solvate thereof, and a quinoline derivative represented by the following general formula (7):

(In the formula, Y is a halogen atom, 0 S_〇 ₂ R ^fi (R ⁶ are the ^{_{same), B (R 8) 2}} (R 8 is a hydroxyl group, an alkyl group or a C i to C ₆ of the C i~C ₆ Or 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 A homocyclic or heterocyclic ring which may have a group (two adjacent substituents may be bonded to each other to form a ring). Item 4. The method for producing a pyro-mouth quinoline derivative or a salt, hydrate and solvate thereof according to Item 1 or 3.

8. The following general formula (1)

(Wherein RR 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 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 A benzene ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring), and the C ring may have one to three substituents (two adjacent substituents). And the substituents may be bonded to each other to form a ring). A tachykinin receptor antagonist comprising a pyrroloquinoline derivative represented by the formula or a salt, hydrate or solvate thereof as a pharmaceutical composition.

9. General formula (1) below

(Wherein 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 (adjacent 2 May be bonded to each other to form a ring.) A homo- or heterocyclic ring optionally having 1 to 5 substituents (where two adjacent substituents A benzene ring, which may have a ring, which may be bonded to each other, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring; A pyrroquinoline derivative represented by the formula or a salt, hydrate or solvate thereof as a pharmaceutical composition. Substance P receptor antagonist.

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 i -C ₆ alkyl group, and the A ring is independently selected from one to three substituents (adjacent two substituents A homo- or heterocyclic ring, which may have a ring which may be bonded to each other), and the ring B has 1 to 5 substituents (two adjacent substituents are bonded to each other) A benzene ring or C ring which may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring, A pyrroquinoline derivative represented by the formula: or a salt, hydrate or solvate thereof as a pharmaceutical composition. For preventing or treating dysuria 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! To C ₆ alkyl group, and the A ring is independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring.) A homo- or heterocyclic ring which may have 1 to 5 substituents (where two adjacent substituents A benzene ring, which may have a ring, which may be bonded to each other, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring; A pyrroquinoline derivative represented by the formula or a salt, hydrate or solvate thereof as a pharmaceutical composition. A preventive or therapeutic agent for digestive diseases including ulcerative colitis and Crohn's disease.

1 2. 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 the A ring is independently selected from one to three substituents (adjacent two substituents A homo- or heterocyclic ring, which may have a ring which may be bonded to each other), and the ring B has 1 to 5 substituents (two adjacent substituents are bonded to each other) A benzene ring or C ring which may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring, A pyrroquinoline derivative represented by the formula: or a salt, hydrate or solvate thereof as a pharmaceutical composition. To prevent vomiting induced by X-ray irradiation, chemotherapeutics, pregnancy, migraine, postoperative illness, gastrointestinal motility depression or side effects of drug administration. The 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 i -C ₆ alkyl group, and the A ring is independently selected from one to three substituents (adjacent two substituents A homo- or heterocyclic ring, which may have a ring which may be bonded to each other), and the ring B has 1 to 5 substituents (two adjacent substituents are bonded to each other) A benzene ring or C ring which may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring, A pyrroquinoline derivative represented by the formula: or a salt, hydrate or solvate thereof as a pharmaceutical composition. Remedies for asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc. involving evening kikinin.