WO2004029057A1

WO2004029057A1 - Medicinal composition for treatment for or prevention of visceral pain

Info

Publication number: WO2004029057A1
Application number: PCT/JP2003/012262
Authority: WO
Inventors: Keiichi Ito; Kazuya Kinoshita; Masahiko Hagihara; Nobuhiko Shibakawa
Original assignee: Sankyo Company, Limited; Ube Industries, Ltd.
Priority date: 2002-09-25
Filing date: 2003-09-25
Publication date: 2004-04-08
Also published as: AU2003266621A8; TW200418479A; AU2003266621A1

Abstract

A pyrrolopyridazine compound having a structure represented by the general formula (I) (wherein R1 represents alkenyl, halogenoalkenyl, alkynyl, cycloalkyl, or optionally substituted cycloalkylalkyl; R2 represents hydrogen or alkyl; R3 represents hydrogen, alkyl, or hydroxyalkyl; R4 represents hydrogen or alkyl; R5 represents optionally substituted phenyl; A represents alkylene; and X represents oxygen or sulfur), a pharmacologically acceptable salt of the compound, or a pharmacologically acceptable ester of the compound. They are useful as a medicine for treatments for or prevention of visceral pain.

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating or preventing visceral pain.

The present invention relates to a visceral pain containing, as an active ingredient, a pyro-oral pyridazine compound having a specific chemical structure, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof (particularly, visceral pain associated with ulcer disease). A pharmaceutical composition for the treatment or prevention (in particular, treatment) of

Pyro- mouth pyridazine compound having a specific chemical structure for producing a pharmaceutical composition for treating or preventing (especially treating) visceral pain (especially visceral pain associated with ulcer disease), and a pharmacologically acceptable compound thereof. Use of a salt or a pharmaceutically acceptable ester thereof; or

Visceral pain (particularly ulcer) comprising administering an effective amount of a pyrrolopyridazine compound having a specific chemical structure, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof to a warm-blooded animal (particularly, human). The present invention relates to a method for treating or preventing (particularly, treating) visceral pain associated with sexually transmitted diseases.

[Background technology]

Local anesthetics of the gastrointestinal mucosa such as oxesazin and antispasmodics such as butylscopolamine bromide have been used as drugs to control visceral pain (pain due to convulsions or hypermotor function). However, it is known that these remedies for visceral pain may have side effects such as constipation or headache. On the other hand, pyropyridazine compounds having a specific chemical structure are known to have a gastric acid secretion inhibitory action (for example, WO 95/19980, EP 0742218 WO 00Z77003, EP 1 186607, WO 0 lZ58901 etc.), it is not known to have a visceral pain inhibitory effect.

[Disclosure of the Invention]

The present inventors have reported that a pyrrodine pyridazine compound having a specific chemical structure has an excellent inhibitory effect on visceral pain associated with an increase in the internal pressure of the lower gastrointestinal tract or vasodilation, and side effects such as constipation or headache. The present inventors have found that the present invention is useful as a medicament for treating or preventing (particularly, treating) weak visceral pain (particularly, visceral pain associated with ulcer disease), and completed the present invention.

The present invention relates to a visceral pain containing a pyro-oral pyridazine compound having a specific chemical structure, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient (particularly, visceral pain associated with an ulcer disease). A) a pharmaceutical composition for the treatment or prevention (in particular, treatment) of

An internal organ comprising administering to a warm-blooded animal (particularly a human) an effective amount of a pyro-oral pyridazine compound having a specific chemical structure, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. Provide methods for the treatment or prevention (particularly treatment) of pain, especially visceral pain associated with ulcer disease. The pyrrodine compound of the present invention, which is an active ingredient,

General formula (I)

[In the formula, R ^1, C ₂ - C ₆ alkenyl group, a halogeno C ₂ -C ₆ alkenyl group, C ₂ - C ₆ Al Kiniru group, C ₃ - C ₇ cycloalkyl or C, one C ₄ alkyl Optionally substituted (C ₃ —c ₇ cycloalkyl) — represents a C, —C ₆ alkyl group,

R ² represents a hydrogen atom or a C, 1 C ₆ alkyl group,

R ³ represents a hydrogen atom, a C! —Ce alkyl group or a hydroxy C, — alkyl group; R ⁴ represents a hydrogen atom or a C ₆ alkyl group;

R ⁵ may be substituted with a substituent selected from the group consisting of C, —C ₆ alkyl, halogeno C, 1 C ₆ alkyl, C, —C ₆ alkoxy, halogeno, —C ₆ alkoxy, and halogen. Represents a phenyl group,

A represents C, one C ₃ alkylene group,

X represents an oxygen atom or a sulfur atom. ]

Having. '

In the general formula (I), C ₂ of R ¹ - C ₂ of C ₆ 7 Luque alkenyl group - - C ₆ alkenyl group or a halogeno C ₂ C ₆ alkenyl moiety, for example, pinyl, 1-Purobe alkenyl, 2 —Propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-Methyl-2-probenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-1 It may be a hexenyl, 21-hexenyl, propane-1,2-genyl, butane-1,1,2-genenyl, pentane-1,2-genenyl or hexane-1,1,2-genenyl group, preferably , C ₂ -C ₄ alkenyl groups (especially zenyl, 1-pro Benyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl group), more preferably a C ₃ -C ₄ alkenyl group, most preferably It is a 2-propenyl or 2-butenyl group.

The halogeno C ₂ -C ₆ alkenyl group for R ¹ is, for example, 2,2-difluorovinyl, 3-fluoro2-propenyl, 2-chloro-2-propenyl, 3-chloro-2-propenyl, 3 1-bromo-2-propionyl, 3-iodo-2-propionyl, 3,3-difluoro-2-propyl Rhodinil, 2,3-dichroic mouth, 2-propenyl, 3,3-diclochloro-2-propenyl, 2,3-dibutene, 2-propenyl, 3,3-dibromo-2 —Propenyl, 4,4,4-trifluoro-2-butenyl, 5-fluoro-2-pentenyl or 6-fluoro-2-hexenyl, preferably fluoro or C ₂ —C ₄ An alkenyl group, and more preferably, 2,2-difluorovinyl, 3-fluoro-2-probenyl, 3-chloro-2-propenyl, 2-chloro-'2-_propenyl, 3, A 3-difluoro-2-propenyl, 3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl group, most preferably a 3-chloro-2-propenyl group. Nyl, 3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl group.

The C ₂ -C ₆ alkynyl group for R ¹ can be, for example, a phenyl, 2-propynyl, 2-butynyl, 2-pentynyl or 2-hexynyl group, preferably a C ₂ -C ₄ alkynyl group. And most preferably a 2-propynyl group.

Of R ¹ C ₃ - C ₇ cycloalkyl or C, which may be substituted by one C ₄ alkyl (C ₃ - C ₇ cycloalkyl) C ₃ of -C, -C ₆ alkyl group - C ₇ cycloalkyl moiety May be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably C ₃ -C ₆ cycloalkyl, and more preferably cyclopropyl or cyclopropyl. A xyl group, most preferably a cyclopropyl group.

Of R ¹ C, - C ₄ can be substituted by alkyl (C ₃ -C ₇ cycloalkyl) - C, C single C ₆ Al kill group, one C ₄ alkyl moiety, for example, methyl, Echiru, propyl , Isopropyl, butyl, isobutyl or t-butyl group, preferably a methyl or ethyl group, most preferably a methyl group.

Of R ¹ C, which may be substituted by one C ₄ alkyl (C ₃ - C ₇ cycloalkyl) - C, - C of C ₆ Al kill group, one C ₆ alkyl moiety, R ^2, R ³ and R ⁴ and C, one C ₆ alkyl group, a hydroxy C, -C ₆ alkyl group R ³ C, - C ₆ alkyl moiety, or R ⁵ C,, - C ₆ alkyl, halogeno C, - C ₆ alkyl, C, - C ₆ alkoxy, halogeno C, one C ₆ alkoxy and C of a phenyl group which may be substituted with a substituent selected from the group consisting of halogen, one C ₆ alkyl moiety or halogeno C, C single C ₆ alkyl moiety one C ₆ alkyl moiety, for example, methyl, Echiru be a cyclohexyl group flop port pills, isopropyl, butyl, Isopuchiru, t-butyl, pentyl, or to, preferably is one C ₄ alkyl group, more preferably Is a methyl or ethyl group, most preferably methyl It is.

(C ₃ -C ₇ cycloalkyl) —C, —C ₆ alkyl group which may be substituted by C ¹ , 1 C ₄ alkyl of R ¹ is, for example, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2- Methylcyclopropylmethyl, 2-ethylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methylcyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4 '- Shikuropuropi Rupuchiru be a cyclohexyl group 5-cyclopropylpentyl or 6-cyclopropyl, preferably, C, - C may be substituted by ₂ alkyl (C ₃ _C ₆ cycloalkyl) - C, - A C ₄ alkyl group, more preferably cyclopropylmethyl, 1-methylcyclopropyl A methyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl group, even more preferably a 2-methylcyclopropylmethyl group, most preferably , (IS, 2S) — is a 2-methylcyclopropylmethyl group.

The hydroxy C! -Ce alkyl group for R ³ can be, for example, a hydroxymethyl, hydroxyethyl, hydridipipropyl, hirogishivir, hydroxy'cypentyl or even a hydroxyhexyl group, preferably a hydroxy C, — A C ₄ alkyl group, more preferably a hydroxymethyl or 1-hydroxyethyl group, most preferably a hydroxymethyl group.

R ⁵ is a phenyl group which may be substituted with a substituent selected from the group consisting of C, 1 C ₆ alkyl, halogeno 1 C ₆ alkyl, C—C ₆ alkoxy, halogeno C, —C ₆ alkoxy and halogen. C) one C ₆ Arukikokishi moiety or halogeno C, - C ₆ alkoxy moiety of the C, - C ₆ § alkoxy moiety, for example, Kishiruokishi group methoxy, ethoxy, propoxy, Isopurobokishi, butoxy, isobutoxy, t-butoxy, pentoxy or to And preferably,

C, and an C ₄ alkoxy group, more preferably a methoxy or ethoxy group, and most preferably a methoxy group.

! D-Ce alkyl R ^5, halogeno C one C ₆ alkyl, C, - C ₆ alkoxy, halogeno C, - C ₆ A Kokishi and good Hue sulfonyl substituted with a substituent selected from the group consisting of halogen The halogen of the group can be, for example, fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, most preferably fluorine.

A phenyl optionally substituted with a substituent selected from the group consisting of C, —C ₆ alkyl, halogeno C, —C ₆ alkyl, C, _C ₆ alkoxy, halogeno C, —C ₆ alkoxy and halogen of R ⁵ The halogeno C, — C ₆ alkyl moiety of the group may be, for example, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-ethyl, 2,2,2- It may be a trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl or 6-fluorohexyl group, preferably a halogeno C, —C ₄ alkyl group, and most preferably a trifluorofuran. It is an orthomethyl group.

R ⁵ may be substituted with a substituent selected from the group consisting of C, —C ₆ alkyl, halogeno C, —C ₆ alkyl, C, —C ₆ alkoxy, halogeno C, 1 C ₆ alkoxy, and halogen. The halogeno C, 1 C ₆ alkoxy moiety of the nyl group may be, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-odoethoxy, 2,2,2 —Trifluoroethoxy, 3-Fluoropropoxy, 4-Fluorobutoxy, 5-Fluoropentoxy or 6-Fluorohexoxy group, preferably a halogeno C, —C ₄ alkoxy group, Most preferably, it is a difluoromethoxy group.

The number of substituents of the phenyl group for R ⁵ is, for example, 1 to 5, preferably 1 to 3, more preferably 1 to 2, and most preferably 1 to 2. Individual. The substitution position of the phenyl group of R ⁵ is, for example, the 2-6 position, preferably the 2, 4 or 6 position, more preferably the 2 or 4 position, and most preferably the 4 or 6 position. Rank.

A phenyl group which may be substituted with a substituent selected from the group consisting of C, one C ₆ alkyl, halogeno C, — C ₆ alkyl, — alkoxy, halogeno C, one C ₆ alkoxy and halogen of R ⁵ is Phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, difluoromethoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, It may be a trifluorophenyl or trifluoromethyl group, preferably C, -C ₄ alkyl, halogen C, — C ₄ alkyl, C, — C ₄ alkoxy, halogeno — C ₄ alkoxy, fluorine, chlorine and bromine A phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of More preferably, it is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine. And more preferably, 1 to 3 substituents selected from the group consisting of fluorine and chlorine, and 1 to 3 substituents selected from the group consisting of the 2-, 4- and 6-positions. Substituted phenyl groups (especially 2- or 4-fluorophenyl, 2- or 4-cyclophenyl, 2,4- or 2,6-difluorophenyl, 2,4- or 2,6-dichlorophenyl, 4 —Chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2,4,6-trifluorophenyl or 2,4,6-trichlorophenyl) Yes, and even more preferably, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2, -dichlorophenyl, 4-chloro-2-fluorophenyl or 2-chloro-4-fluoro. It is an olophenyl group, particularly preferably a 4-fluorophenyl, 4-chlorophenyl or a 2,4-difluorophenyl group, most preferably a 4-fluorophenyl group.

C of A, - C ₃ alkylene group such as methylene, ethylene, trimethylene, be a 1 Mechi Ruechiren or 2-methylethylene group, preferably a methylene group.

X is preferably an oxygen atom.

The pyro-pyridazine compound represented by the general formula (I), which is an active ingredient of the present invention, has a basic group and can be converted into a pharmacologically acceptable salt by treating with an acid. Various salts are also included in the present invention. Such salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates; perchlorates; sulfates; A carbonate; C, — which may be substituted with a fluorine atom such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate and propanesulfonate; C, - C _6, such as a benzenesulfonate, p- toluenesulfonic acid, naphthalenesulfonic acid salts; C ₆ alkyl sulfonate. Arylsulfonate; acetate, trifluoroacetate, propionate, butyrate, benzoate, oxalate, malonate, fumarate, maleate, cooctamate, citrate And carboxylates such as tartrate; or amino acid salts such as glutamate and aspartate; preferably, hydrogen halide, sulfate, C ₆ _ C, . Aryl sulfonate or carboxylate; More preferably, it is hydrochloride, sulfate, benzenesulfonate, P-toluenesulfonate, J3-naphthalenesulfonate or fumarate, most preferably p-toluenesulfonate or fumaric acid Salt.

Among the pyridazine compounds of the general formula (I), which are -active ingredients of the present invention, compounds having a hydroxyl group can be converted into pharmacologically acceptable esters by conventional acylation. ¾Hide can: 'Such esters are also included in the present invention. Such esters are: for example, esters with aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, crotonic acid, propiolic acid; fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid Esters with aliphatic dicarboxylic acids such as benzoic acid, esters with aromatic carboxylic acids such as benzoic acid, methylbenzoic acid, methoxybenzoic acid, fluorobenzoic acid, and chlorobenzoic acid; methanesulfonic acid, trifluoromethanesulfonic acid Esters with sulfonic acids such as acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; esters with amino acids such as glutamic acid and aspartic acid; monomethyl carbonate, dimethyl carbonate, and monoethyl carbonate; Getyl ester carbonate, monopropyl carbonate Esters with esters such as ter, monobutyl carbonate, monophenyl carbonate, diphenyl carbonate; or phosphoric acid, monomethyl phosphate, dimethyl ester phosphate, monoethyl phosphate, phosphorus Esters with phosphoric acids such as acetic acid getyl ester, monophenyl phosphate, diphenyl phosphate and the like can be mentioned, and preferably, esters with aliphatic monocarboxylic acids, and aliphatic dicarboxylic acids. Or an ester with an aromatic carboxylic acid, most preferably C f C,. It is an ester with an aliphatic monocarboxylic acid.

The pyrolipid pyridazine compound represented by the general formula (I), which is an active ingredient of the present invention, can exist as a hydrate or a solvate, and each of them or a mixture thereof can be used in the present invention. Included.

An optical isomer and a Z or geometric isomer may be present in the pyro-opened pyridazine compound represented by the general formula (I), which is an active ingredient of the present invention, and each of them or a mixture thereof may be used. Included in the present invention.

In the present invention, visceral pain can be pain due to visceral convulsions or hypermobility accompanying various diseases, and diseases causing visceral pain include, for example, esophagitis, gastritis, enteritis, gastric ulcer, and duodenal ulcer. Irritable colitis, cholecystitis, cholangitis, cholelithiasis, urolithiasis, or cystitis. The active ingredient of the present invention, the pyro-oral pyridazine compound represented by the general formula (I) is useful for the treatment of visceral pain associated with these diseases (especially ulcer diseases such as esophagitis, gastritis, gastric ulcer, and duodenal ulcer). It can be used as a medicament for prevention or treatment (in particular, treatment).

The pyrrodazine compound of the present invention represented by the general formula (I), which is an active ingredient, is preferably a compound represented by the general formula (I):

(1) R ¹ is substituted with a C ₂ -C ₄ alkenyl group, a fluoro or cycloalkyl C ₂ -C ₄ alkenyl group, a 2-propynyl group, a C ₃ -C ₆ cycloalkyl group or a C, —C ₂ alkyl May

(C ₃ - C ₆ cycloalkyl) -C, compound of one C ₄ alkyl group, (2) R 'is vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3-fluoro-2-propenyl , 3-chloro-2-propyl, 2-chloro-2-propyl, 3,3-difluoro-2-propyl, 3,3-dichloro-2-propyl, 4,4,4- It is a trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-tylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl group Compound,

(3) a compound wherein R ¹ is a 2-methylcyclopropylmethyl group,

(4.) a compound, wherein R ¹ is (IS, 2 S) _2-methylcyclopropylmethyl group,

(5) compounds wherein R ² is a hydrogen atom or a C ₄ alkyl group,

(6) a compound wherein R ² is a methyl group,

(7) The compound wherein R ³ is a hydrogen atom, a C, mono C ₄ alkyl group or a hydroxy C, —C ₄ alkyl group,

(8) a compound wherein R ³ is a methyl or hydroxymethyl group,

(9) compounds wherein R ⁴ is a hydrogen atom,

(10) R5 is, C, -C ₄ alkyl, halogeno C, - C ₄ alkyl, C, - C ₄ alkoxy, Bruno, Rogeno C, one C ₄ alkoxy, fluorine, selected from the group consisting of chlorine及Pi bromine A compound which is a phenyl group optionally substituted with 1 to 3 substituents,

(11) R ⁵ is a phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine. A compound that is a group,

(12) R ⁵ is 1 or 2 substituents selected from the group consisting of fluorine and chlorine, and 1 or 2 substituents selected from the group consisting of 2-, 4- and 6-positions are substituted. A phenyl group,

(13) The compound wherein R ⁵ is one or two substituents selected from the group consisting of fluorine and chlorine, and the 4-position or the 2,4-position is a S-substituted phenyl group,

(14) a compound wherein A is a methylene group, or

(15) The compound wherein X is an oxygen atom

It is.

Also, R selected from (1) to (4), R ² selected from (5) to (6), R ³ selected from (7) to (8), and R selected from (9) ⁴ , compounds selected from any combination of R ⁵ selected from (10) to (13), A selected from (14), and Hiroko X selected from (15) are more preferable. Yes, for example, the following compounds are more preferred:

(16) R ¹ is, C ₂ - C ₄ alkenyl group, Furuoro or black port C ₂ - C ₄ alkenyl group, 2-propynyl group, C ₃ - C ₆ cycloalkyl group or C, substituted with one C ₂ alkyl (C ₃ -C ₆ cycloalkyl) is a C, —C ₄ alkyl group, R ² is a hydrogen atom or a C, C ₄ alkyl group, and is a hydrogen atom, C, —C ₄ alkyl group or hydroxy C, 1 C ₄ alkyl group, R ⁴ is a hydrogen atom, is, C, — C ₄ alkyl, halogeno 1 C ₄ Alkyl, o, -c, alkoxy, halogeno C, - c ₄ alkoxy, fluorine, from 1 to 3 substituents which may be substituted phenyl group by a group selected from the group consisting of chlorine and bromine, A is, A compound wherein m is a methylene group and X is an oxygen atom,

(17) R ¹ is pinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3_fluoro-2-pro Dinil, 3- ^ mouth low 2-probenyl, 2-chloro-1--2-propyl, 3,3-difluoro 2- propyl, 3,3-dichloro-2-propyl, 4, 4,4-trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropyl a Echiru group, R2 is a methyl group, R ³ is methyl or hydroxymethyl group, R ⁴ is, Ri Oh hydrogen atom, R ^5, methyl, triflusulfuron Ruo Russia methyl, main X is a phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of trifluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine, A is a methylene group, and X is A compound that is an oxygen atom,

(18) R ¹ is a 2-methylcyclopropylmethyl group, R ² is a methyl group, R ³ is a methyl or hydroxymethyl group, R ⁴ is a hydrogen atom, R ⁵ is 1 or 2 substituents selected from the group consisting of fluorine and chlorine, and phenyl substituted with 1 or 2 substituents selected from the group consisting of 2-, 4- and 6-positions A compound wherein A is a methylene group and X is an oxygen atom;

(19) R ¹ is a (1 S, 2 S) 12-methylcyclopropylmethyl group, R ² is a methyl group, R ³ is a methyl or hydroxymethyl group, and R ⁴ is A hydrogen atom, R ⁵ is a phenyl group substituted with one or two substituents selected from the group consisting of fluorine and chlorine and substituted at the 4-position or the 2,4-position, Is a methylene group and X is an oxygen atom,

(20) 71- (4-fluorobenzyloxy) —2,3-dimethyl-1-[(1 S, 2 S) — 2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (2,4-difluorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) 1-2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (4-chlorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) -2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (4-Fluorobenzyloxy) 1-3-hydroxymethyl-2-methyl-11 [(1 S, 2 S) -2-methylcyclopropylmethyl] Pyro [2,3-d] pyridazine,

7- (2,4-difluorobenzyloxy) -1-hydroxymethyl-2-methyl-1-[(1S, 2S) 1-2-methylcyclopropylmethyl] pyro [2,3-d] Pyridazine,

7— (4-chlorobenzoyloxy) -3-hydroxymethyl-2-methyl-1-[(1 S, 2S) —2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

1- (2-butenyl) -7- (4-fluorobenzyloxy) —2,3-dimethylpyro [2,3-d] pyridazine and 1- (2-butenyl) -7- (2,4-difluorobenzyloxy) —2,3-dimethylpyrrololo [2,3-d] pyridazine pyrrodazine compounds selected from the group consisting of pyridazines,

(21) 7- (4-Fluorobenzyloxy) -1,2,3-dimethyl-11-[(IS, 2S) -12-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7-1- (4-fluorobenzyloxy) -1-3-hydroxymethyl-12-methyl-11-[(1S, 2S) -12-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

1- (2-butenyl) -7- (4-fluorobenzyloxy) 1,2,3-dimethylpyro [2,3-d] pyridazine and

1- (2-butenyl) -7- (2,4-difluorobenzyloxy) —2,3-dimethylpyrrololo [2,3-d] pyridazine compounds selected from the group consisting of pyridazines, or ,

(22) 7- (4-Fluorobenzyloxy) -2,3-dimethyl-1-[(1 S, 2 S) — 2-methylcyclopropylmethyl] Pyrazine [2,3-d] pyridazine.

The present invention

(23) —A pyro-opened pyridazine compound represented by the general formula (I) [in particular, a compound according to any one of the above (1) to (22)], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. (24) A pharmaceutical composition according to (23), wherein the visceral pain is a visceral pain associated with an ulcer disease, the pharmaceutical composition comprising: And (25) a pyrolipid pyrimidine compound represented by the general formula (I) for producing a pharmaceutical composition for treating or preventing (particularly, treating) visceral pain: ) To (22), the use of a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof,

(26) The use according to (25), wherein the visceral pain is visceral pain associated with an ulcer disease.

(27)-a pyrrodine pyridazine compound represented by the general formula (I) [in particular, a compound according to any one of the above (1) to (22)], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A method for treating or preventing (particularly treating) visceral pain, comprising administering to a warm-blooded animal an effective amount of the desired ester.

(28) The method according to (27), wherein the visceral pain is visceral pain associated with an ulcer disease, or (29) the method according to any of (27) to (28), wherein the warm-blooded animal is a human. Provide a method. Among the pyrrodazine compounds of the formula (I) which are the active ingredients of the present invention, suitable compounds may be, for example, the compounds shown in Table 1, but the present invention is not limited to these compounds. Not something. The compounds described in Table 1 have a structure represented by the general formula (II).

[table 1]

Illustrative compounds

No.R ¹ R ² R ³ R ⁴ R ⁵ X

1 CH ₂ (2-MePr ^c ) Me Me H Ph 0

2 C¾ [(1S, 2S) - -2-MePr c] Me Me H Ph 0

3 Me Me H 4-FPh 0

5 Pr ^c Me Me H 4-FPh 0

6 CH ₂ Pr ^c Me Me H 4-FPh 0

7 CH ₂ Hx ^c Me Me H 4-FPh 0

8 CH ₂ (2-MePr ^c ) Me Me H 4-FPh 0

9 C¾ [(1S, 2S) - -2-MePr c] Me Me, H 4-FPh 0

10 CH ₂ CH ₂ Pr ^c Me Me H 4-FPh 0

11 C CH ⁼ C Me Me H 2,4-diFPh 0

12 C CH ⁼ CHCHs Me Me H 2,4-diFPh 0

13 CH ₂ Pr ^c Me Me H 2,4-diFPh 0

_{^{14 CH 2 (2-MePr c}} ) Me Me H 2,4-diFPh 0

_{15 CH 2 [(1S, 2S} ) - ■ 2-MePr c] Me Me H 2,4-diFPh 0

16 C¾ CH ⁼ C Me Me H 4-ClPh 0

17 CE ^ CH-CHCH ^ Me Me H 4-ClPh 0

18 CH ₂ Pr ^c Me Me H 4-ClPh 0

19 CH ₂ (2-MePr ^c ) Me Me H 4-ClPh 0

20 C¾ [(1S, 2S)-• 2-ePr ^c ] Me Me H 4-ClPh 0

21 C CH ⁼ C Me Me H 2,4-diClPh 0

22 C CH = CHC¾ Me Me H 2, -diClPh 0

23 CH ₂ Pr ^c Me Me H 2,4-diClPh 0

24 CH ₂ (2-MePr ^c ) Me Me H 2,4-diClPh 05 CH ₂ [(1S, 2S)-2-MePr ^c ] Me Me H 2,4-diClPh 06 CH ₂ (2-MePr ^c ) Me Me H 2-FPh 0 _{CH 2 [ClS, 2S) -2} -MePr c] Me Me H 2-FPh 0

CH ₂ (2-MePr ^c ) Me Me H 3-FPh 0

_{CH 2 [(lS, 2S)} -2-MePr c] Me Me H 3-FPh 0

CH ₂ (2-MePr ^c ) Me Me H 2-ClP 0 c¾ [(lS, 2S) -2-MePr ^c ] Me Me H 2-ClPh 0

CH ₂ (2-MePr ^c ) Me Me H 3-ClP 0

_{CH 2 [(IS, 2S)} -2-MePr c] Me Me H 3-ClPh 0

CH ₂ (2-MePr ^c ) Me Me H 4-MePh 0

_{CH 2 [(lS, 2S)} -2-MePr c] Me Me H 4-MeP 0

CH ₂ (2-MePr ^c ) Me Me H 4-OMePh 0

_{CH Z [(IS, 2S)} -2-MePr c] Me Me H 4-OMePh 0

CH ₂ (2-MePr ^c ) Me Me H 4-CF3PI1 0

_{CH 2 [(IS, 2S)} -2-MePr c] Me Me H 4-CF 3 Ph 0

CH ₂ (2-MePr ^c ) Me Me H 4-0CHF ₂ P 0 c¾ [(lS, 2S) -2- ePr ^c ] Me Me H 4-0CHF ₂ Ph 0

_{CH 2 [(lS, 2S)} -2-MePr c] Et Me H 4-FPh 0

_{CH 2 [(lS, 2S)} -2-MePr c] Pr Me H 4-FPh 0

_{CH 2 [(IS, 2S)} -2-MePr c] Pr i Me H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Bu Me H 4-FPh 0

CH ₂ ; (1S, 2S) -2- ePr ^c ] Bu 'Me H 4-FPh 0

_{CH 2; (1S, 2S)} -2-MePr c] Bu s Me H 4-FPh 0

CH ₂ ! (1S, 2S) -2-MePr ^c ] Bu ¹ Me H 4-FPh 0

CH ₂ [2-MePr ^c ) Me Me Me 4-FPh 0 c¾; (1S, 2S) -2-MePr ^c ] Me Me Me 4-FPh 0

_{CH 2! (1S, 2S)} -2-MePr c] H Me H 4-FPh 0

_{CH 2! (1S, 2S)} -2-MePr c] Me HH 4-FPh 0

CH ₂ ; (lS, 2S) -2-MePr ^c ] Me Me H 4-BrPh 0

CH ₂ ; (1S, 2S) -2-MePr ^c ] Me Me H 4-OCFgPh 0

CH ₂ ; (lS, 2S) -2- ePr ^c ] Me Me H 2,6-diFPh 0

CH ₂ ; (1S, 2S) -2-MePr ^c ] Me Me H 2,6-diClPh 0

C¾ [: (lS, 2S) -2-MePr c] Me Me H 2,4, 6-triFPh 0

C¾ [: (1S, 2S) - 2- MePr c] Me Me H 2,4, 6-triClPh 0

_{CH 2 [; (lS, 2S} ) -2- ePr c] Me Me H 2-Cl-6-FPh 0

_{CH 2 [; (1S, 2S} ) -2-MePr c] Me Me H 2-C1 -4-FPh 0

C¾ [(lS, 2S) -2- ePr ^c ] Me Me H 4-C1 -2-FPh 0

CH ₂ (2-MePr ^c ) Me Me H 4-FPh s

C¾ [(IS, 2S) -2-MePr ^c ] Me Me H 4-FPh s

C¾ [(lS, 2S) -2- ePr ^c ] Me Me H 2,4-diFPh s _{CH 2 [(1S, 2S)} -2-MePr c] Me Me H 4-ClP S

C¾ [(1S, 2S) -2 -MePr c] Me Me H 2,4-diClPh S

C [(1S, 2S)-2-MePr ^c ] Me C¾OH H 2-FPh 0

CH ₂ (2-MePr ^c ) Me C¾OH H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me C¾OH H 4-FPh 0

_{CH 2 [(lS, 2S)} -2-MePr c] Me CH 2 OH H 2,4-diFPh 0

CH ₂ [(1S, 2S) -2-MePr ^c ] Me CH _z OH H 2-ClPh 0

_{CH 2 [(1S, 2S)} -2-MePr c] Me CH 2 OH H 4-ClPh 0

CH ₂ [(1S, 2S) -2-MePr ^c ] Me C OH H 2,4-diClPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me C¾OAc H 2-FPh 0

CH ₂ (2-MePr ^c ) Me CH ₂ OAc H 4-FPh 0

_{CH 2 [(1S, 2S)} - 2 - MePr c] Me CH 2 OAc H 4-FPh 0

_{CH z [(lS, 2S)} -2- ePr c] Me CH z OAc H 2,4-diFPh 0

C¾ [(lS, 2S) -2-MePr ^c ] Me CH ₂ OAc H 4-ClPh 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me CH ₂ OAc H 2,4-diClPh 0

_{CH 2 [(lS, 2S)} -2-MePr c] Me CH 2 OPrp H 4-FPh 0

CH ₂ [(lS, 2S) -2- ePr ^c ] Me C¾OBur H 4-FPh 0

_{^{CH 2 (2-MePr c)}} Me CH 2 OCOPh H 4-FPh 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me C¾OCOPh H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ OCO (4-MePh) H 4-FPh 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me CH ₂ OCO (4-OMePh) H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ 0C0 (4-FPh) H 4-FPh 0

CH ₂ [(1S, 2S) -2-MePr ^c ] Me C¾0C0 (4-ClPh) H 4-FPh 0

CH ₂ (2-MePr ^c ) Me C¾OC0 ₂ Me H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me C¾OC0 ₂ Me H 4-FPh 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me C¾OC0 ₂ Et H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ OC0 ₂ Pr H 4-FPh 0

C¾ [(1S, 2S) -2- ePr ^c ] Me C¾OC0 ₂ Bu H 4-FPh 0

_{CH 2 [(lS, 2S)} -2- MePr c] Me CH 2 OC0 2 Ph H 4-FPh 0

_{CH 2 [(1S, 2S)} -2-MePr c] Et CH 2 OH H 4-FPh 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Et CH ₂ OAc H 4-FPh 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me CH ₂ OH H 4-MePh 0

C¾ [(1S, 2S) - 2- MePr c] Me CH 2 OH H 4-CF 3 Ph 0

CH ₂ [(1S, 2S) -2- ePr ^c ] Me CH ₂ OH H 4-OMePh 0

C¾ [(1S, 2S) -2-MePr ^c ] Me CH ₂ 0H H 4-0CHF ₂ Ph 0

_{CH 2 [(lS, 2S)} -2-MePr c] Me CH 2 0H H 4-OCF3PI1 0

CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ 0H H 4-BrPh 0

C¾ [(lS, 2S) -2-MePr ^c ] Me CH ₂ 0Ac H 4-MePh 0 103 CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ 0Ac H 4-CF3PI10

104 CH _z [(lS, 2S) -2-MePr ^c ] Me CH ₂ OAc H 4-OMeP 0

_{105 CH 2 [(1S, 2S} ) -2- ePr c] Me CH 2 OAc H 4-0CHF 2 Ph 0

106 C¾ [(1S, 2S) -2-MePr ^c ] Me C¾OAc H 4-OCFgPh 0

107 CH ₂ [(lS, 2S) -2-MePr ^c ] Me C¾OAc H 4-BrPh 0

108 CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH ₂ OH H 4-FPh s

109 CH ₂ [(lS, 2S) -2- ePr ^c ] Me CH ₂ OH H 2,4-diFPh s

110 CH ₂ [(lS, 2S) -2-MePr ^c ] Me C¾OH H 4-ClPh s

111 C¾ [(lS, 2S) -2- ePr ^c ] Me CH ₂ OH H 2, 4-diClPh s

112 CH, [(lS, 2S) -2- ePr ^c ] Me CH ₂ OAc H 4-FPh s

113 C¾ [(lS, 2S) -2- ePr ^c ] Me CH ₂ OCOPh H 4-FPh s

114 CH ₂ [(1S, 2S) -2-MePr ^c ] Me CH ₂ OC0 ₂ Me H 4-FPh s

115 C¾ [(lS, 2S) -2-MePr ^c ] Me CH ₂ OC0 ₂ Et H 4-FPh s

_{116 CH 2 [(1S, 2S} ) -2-MePr c] Me Et H 4-FPh 0

_{117 CH 2 [(1S, 2S} ) -2-MePr c] Me Pr H 4-FPh 0

_{118 CH 2 [(1S, 2S} ) -2-MePr c] Me Pr 1 H 4-FPh 0

_{119 CH 2 [(1S, 2S} ) -2-MePr c] Me. Bu H 4-FPh 0

120 CH ₂ [(1S, 2S) -2- ePr ^c ] Me Bu 'H 4-FPh 0

121 CH ₂ [(lS, 2S) -2-MePr ^c ] Me Bu ^s H 4-FPh 0

122 C¾ [(1S, 2S) -2-MePr ^c ] Me Bu ¹ H 4-FPh 0

123 CH ₂ [(lS, 2S) -2-MePr ^c ] Me Pn H 4-FPh 0

124 CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH (OH) C¾ H 4-FPh 0

_{125 CH 2 [(lS, 2S} ) -2-MePr c] Me CHoCHoOH H 4-FPh 0

126 CH ₂ [(1S, 2S) -2-MePr ^c ] Me CH (0Ac) C¾ H 4-FPh 0

127 C¾ [(1S, 2S) -2-MePr ^c ] Me CH (0H) CH ₂ C¾ H 4-FPh 0

128 CH ₂ [(lS, 2S) -2-MePr ^c ] Me CH (OH) (CH ₂ ) ₂ CH ₃ H 4-FPh 0

129 C¾ [(1S, 2S) -2- ePr ^c ] 'Me CH (OH) (CH ₂ ) ₃ CH ₃ H 4-FPh 0

130 C¾ [(lS, 2S) -2-MePr ^c ] Me CH (OH) (CH ₂ ) ₄ CH ₃ H 4-FPh 0

In _{131 CH 2 [(1S, 2S} ) -2- ePr c] Me CH (0H) CH 3 H 4-FPh s Table 1, abbreviations indicate the following groups.

Ac: acetyl group

Bu: butyl group

Bu ^! Isobutyl group

Bur: Putyryl group

Bu ^s s-butyl group

Bu ¹ : t-butyl group

Et: ethyl group Hx ^c

Me: methyl group

P: phenyl group

Pn: pentyl group

Pr: propyl group

Pr ^c : cyclopropyl group

Pr ¹ : isopropyl group, and

Prp: propionyl group.

In Table 1 above, suitable compounds are

Exemplified compound numbers 1, 2, 3, 4, 6, 8, 9, 12, 14, 15, 19, 20, 24, 25, 27, 29, 31 1, 33, 35, 37, 39, 41, 42 , 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 108, 109, 110, 1 1 1, 1 12, 113, 1 14 , 115, 124, 125, more preferably

Exemplified compound numbers 2, 4, 9, 12, 15, 20, 25, 27, 31, 35, 37, 39, 41, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 66, 69, 70, 72, 73, 76, 77, 78, 79, 83, 89, 108, 109, 110, 111, 112, and more preferably,

Exemplified Compound No. 4, 9, 12, 15, 20, 25, 27, 31, 55, 56, 60, 61, 63, 69, 70, 72, 76, 77, 78, 108 Preferably,

Exemplified Compound No. 4: 1- (2-butenyl) -7- (4-fluorobenzyloxy) -2,3-dimethylbirolo [2,3-d] pyridazine,

Exemplified Compound No. 9: 7- (4-Fluorobenzyloxy) -2,3-dimethyl-11-[(1 S, 2S) -1-2-methylcyclopropylmethyl] Pyro mouth [2,3-d] Pyridazine, Exemplified Compound No. 12: 1- (2-butenyl) -7- (2,4-difluorobenzoyloxy) -2,3-dimethylbirrolo [2,3-d] pyridazine,

Exemplified Compound No. 15: 7- (2,4-difluorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) _2-methylcyclopropylmethyl] -d] pyridazine,

Exemplified Compound No. 20: 7- (4-chlorobenzyloxy) -2,3-dimethyl-11-[(1S, 2S) _2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine, Exemplified Compound No. 69: 7- (4-Fluorobenzyloxy) 1-3-hydroxymethyl-2-methyl-11-[(1S, 2S) -12-methylcyclopropylmethyl] d] pyridazine,

Exemplified Compound No. 70: 7- (2,4-difluorobenzyloxy) -1-hydroxy Cyl-2-methyl-11-[(1 S, 2 S) -1-2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine or

Illustrative Compound No. 72: 7- (4-cyclobenzyloxy) -1-hydroxymethyl-2-methyl-1-[(1S, 2S) _2-methylcyclopropylmethyl] pyro [2,3-d] A compound of pyridazine, particularly preferably

Exemplified compound number 4: 1— (2-butenyl) —7— (4-fluorobenzyloxy) —2,3-dimethylbirolo [2,3-d] pyridazine,

Exemplified Compound No. 9: 7- (4-Fluorobenzyloxy) _2,3-dimethyl-1-[(1S, 2S) -1-Methylcyclopropylmethyl] Pyro [2,3-d] pyridazine Exemplified Compound No. 12: 1- (2-butenyl) 1 7- (2,4-difluorobenzoyl) 1,2,3-dimethylpyro [2,3-d] pyridazine or

Illustrative Compound No. 69: 7- (4-Fluorobenzyloxy) -3-hydroxymethyl-2-methyl-11-[(1S, 2S) -12-methylcyclopropylmethyl] d] compounds of pyridazine, most preferably

Exemplified Compound No. 9: 7-1- (4-fluorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) -1-2-methylcyclopropylmethyl] Pyro [2,3-d] It is a compound of pyridazine. The pyrrodazine compound of the formula (I), which is an active ingredient of the present invention, may be prepared by a known method [for example, WO95Z19980 (= EP-0742218A), WO 00/77003].

(= 'EP-1 186607 A), WO 01/58901, etc.] or a method analogous thereto, and can be easily produced.

As described above, the compound having a hydroxyl group among the pyrrolic pyridazine compounds represented by the general formula (I), which is the active ingredient of the present invention, is acylated by a conventional method, and is pharmacologically acceptable. Esters can be produced. That is, a pharmacologically acceptable ester can be produced by reacting a compound having a hydroxyl group with a corresponding acid halide or acid anhydride in an inert solvent according to a conventional method in the presence of a base. (For example, WO01 / 58901, etc.).

When the pyrolipid pyridazine compound represented by the general formula (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, is used as a medicament, the active ingredient is It can be administered as it is (as is) or mixed with appropriate pharmacologically acceptable excipients, diluents, etc. to produce tablets, capsules, granules, powders or syrups Or parenterally (preferably orally) as a preparation such as an injection or a suppository.

These preparations are manufactured by known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, and injections. You.

Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, α-starch, dextrin, carpoxy. Starch derivatives such as cimethyl starch; crystalline cellulose, cellulose derivatives such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium propyloxymethylcellulose calcium, internally cross-linked carboxymethylcellulose sodium; gum arabic; Dextran; pullulan; silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium metasilicate silicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; or calcium sulfate And the like.

The binder can be, for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone;

Disintegrants can be, for example, the excipients described above; chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium; or crosslinked polypinylpyrrolidone, and the like.

Lubricants include, for example, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as pea gum and gay wax; boric acid; Sulfonic acids such as fumaric acid and adipic acid; sodium carboxylate such as sodium benzoate; sulfate such as sodium sulfate; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride; Silicic acids such as silicic acid hydrate; or starch derivatives in the above-mentioned excipients.

Emulsifiers include, for example, colloidal clays such as bentonite and pea gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; benzalkonium chloride Or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, or sucrose fatty acid ester.

Stabilizers include, for example, parahydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol And thimerosal; anhydrous acid; 'or sorbic acid.

Flavoring agents may be, for example, commonly used sweetening, sour or flavoring agents. The diluent may be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol or polyoxyethylene sorbin fatty acid esters. The injection solvent may be, for example, water, ethanol, glycerin and the like.

The pyrolipid pyridazine compound represented by the general formula (I), a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof, which is an active ingredient of the present invention, is administered to a warm-blooded animal (particularly a human). The dosage may vary depending on various conditions such as the activity of the particular drug, the condition of the patient, age, weight and the like.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 100 mg (preferably, 50 O mg) for parenteral administration In some cases, the lower limit of 0.1 mg (preferably 0.05 mg) and the upper limit of 10 rag (preferably 5 mg) per adult should be 1 to 6 times a day, depending on the symptoms. Can be administered.

The active ingredient of the present invention, which is a pyrrodazine compound of the general formula (I), its pharmacologically acceptable salt or its pharmacologically acceptable ester, itself has a gastric acid secretion inhibitory action. When these are used as a pharmaceutical composition for the treatment or prevention of visceral pain associated with ulcerative diseases such as esophagitis, gastritis, gastric ulcer, and duodenal ulcer, the ulcerative and ulcerative effects are also exhibited. The effect of treating or preventing a disease can be expected.

The pyrolipid pyridazine compound represented by the general formula (I), its pharmacologically acceptable salt or its pharmacologically acceptable ester, which is an active ingredient of the present invention, accompanies an increase in the internal pressure of the lower gastrointestinal tract or luminal expansion It has an excellent inhibitory effect on visceral pain and has weak side effects such as constipation or headache. Visceral pain for warm-blooded animals (especially for humans) (ulcers such as esophagitis, gastritis, gastric ulcer, and duodenal ulcer) It is useful as a medicament for treating or preventing (particularly, treating) visceral pain associated with sexual diseases.

[Best Mode for Carrying Out the Invention]

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

(Test Example 1) Visceral pain evaluation test

This test was carried out by modifying the method of Banner et al. (Br. J. Pharma Co., 1995, Vol. 114, p. 558). Groups 6-7 After fasting one rat overnight, it was anaesthetized with bentobarbital sodium, the median abdominal skin was incised, and a force transducer for observing contractile movements of the rectus abdominal muscle was attached to the rectus abdominal muscle. A balloon connected to a transducer for internal pressure monitoring was inserted into the rectum 1 cm inside the anus to fix the position, and the rat was placed in a Paulman cage. Water was injected at a rate of 0.08 m 1 in at the same time, and the balloon's internal pressure and contraction of the rectus abdominal muscles were observed simultaneously. The internal pressure threshold was used as an index of visceral pain.

7— (4-Fluorobenzyloxy) -1,2,3-dimethyl-1-[(1S, 2S) 1-2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine [Exemplary Compound No. Compound No. 9: Compound described in Example 1 of WO 00/77003 (= EP-1186607A): hereinafter referred to as compound (III)] was replaced with 0.5% carboxymethylcellulose sodium salt. In addition, a suspension of 1.5 to 5 mg Zkg in a 0.4% polysorbate 80 aqueous solution was orally administered at a dose of 2 ml per kg of body weight, and the balloon internal pressure threshold was measured 1, 2, and 3 hours later. The suspension medium was used as a control. Significant differences in the internal pressure threshold before and after administration were examined by the Dunnett's method.

Table 2 shows the transition of the threshold value of the internal pressure of the plant after the administration of the compound (III) and the administration vehicle. As shown in Table 2, In the control group, no change was observed in the balloon internal pressure threshold after administration, but in the compound (III) administration group, a significant dose-dependent increase in internal pressure threshold was observed after administration. Ho 2] Internal pressure threshold (marauder)

No. of subjects 1 hour 2 hours 3 hours after administration Control group 7 7.04 9.51 9.66 6.29 Compound (III) administration group 6 7.62 13.1 14.1 11.8

3 mg / kg Compound a ID administration group 6 7.20 16.3 23.0 19.3

10 mg / kg

From the above results, compound (III) has an excellent inhibitory effect on the internal pressure of the lower gastrointestinal tract and visceral pain associated with luminal dilatation, and the active ingredient of the present invention, It is useful as a medicament for treating or preventing visceral pain.

(Formulation Example 1) Tablet

A mixture of (III) (30. Omg), lactose (144. Omg), corn starch (25. Omg), and magnesium stearate (1. Omg) was mixed with a tableting machine and compressed into a tablet. | ¾20 Omg tablets. The tablets can be coated (preferably sugar-coated) as necessary.

[Industrial applicability]

The active ingredient of the present invention, a pyro-oral pyridazine compound represented by the general formula (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof increases the internal pressure of the lower gastrointestinal tract or expands the lumen. It has an excellent inhibitory effect on accompanying visceral pain and has weak side effects such as constipation or headache. Visceral pain for warm-blooded animals (especially for humans) (especially esophagitis, gastritis, gastric ulcer, duodenal ulcer, etc.) It is useful as a medicament for the treatment or prevention (particularly, treatment) of visceral pain associated with ulcer disease.

Claims

The scope of the claims

1.-General formula

(I)

Wherein R ¹ is a C ₂ —C ₆ alkenyl group, a halogeno C ₂ —C ₆ alkenyl group, a C ₂ —C ₆ alkynyl group, a C ₃ —C ₇ cycloalkyl group or a C, 1C ₄ alkyl Optionally substituted (c ₃ —c ₇ cycloalkyl) represents a C, —c ₆ alkyl group,

R ² represents a hydrogen atom or a C, 1 C ₆ alkyl group,

R ³ represents a hydrogen atom, a C, C ₆ alkyl group or a hydroxy C, 1 C ₆ alkyl group, R ⁴ represents a hydrogen atom or a C, 1 C ₆ alkyl group,

R ⁵ may be substituted with a substituent selected from the group consisting of C, —C ₆ alkyl, halogeno C, —C ₆ alkyl, C, —C ₆ alkoxy, halogeno C, 1 C ₆ alkoxy, and halogen. Represents a phenyl group,

A represents C, one C ₃ alkylene group,

Represents an oxygen atom or a sulfur atom. ]

A pharmaceutical composition for treating or preventing visceral pain, comprising a pyrrolopyridazine compound having the following formula: a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient.

2. R ¹ is substituted by a C ₂ -C ₄ alkenyl group, a fluoro or cyclo C ₂ -C ₄ alkenyl group, a 2-propynyl group, a C ₃ -C ₆ cycloalkyl group or a C, 1 C ₂ alkyl Claim 1 containing a pyrrodazine compound having a pyro-opening that is a (C ₃ -〇 ₆ cycloalkyl) 1 c ₄ alkyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient. 8. The pharmaceutical composition according to item 1.

3. R ¹ is pier, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3-fluoro-2-propenyl 1, 3-chloro-2-propyl, 2,3-chloro-2-propyl, 3,3-difluoro-2-propyl, 3,3-dichloro-2-propyl, 4,4 4-Trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl group Pyrrolopyrida 2. The pharmaceutical composition according to claim 1, comprising a gin compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof as an active ingredient.

4. The method according to claim ¹ , wherein R1 is a 2-methylcyclopropylmethyl group, a pyro-opened pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. Pharmaceutical composition.

. 5 R ¹ is, (1 S, 2 S) - containing as the 2-methyl-cyclopropylmethyl group pyromellitic port Piridaji emission compound, a pharmacologically acceptable salt thereof or an active ingredient a pharmacologically acceptable ester The pharmaceutical composition according to claim 1, wherein .

6. The first claim, wherein R ² is a hydrogen atom or a C, C ₄ alkyl group, a pyro-opened pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. Item 6. The pharmaceutical composition according to any one of Items 5 to 5.

7. R ² is pyro port pyridazine compound is a methyl group, a pharmacologically acceptable There deviation range of paragraphs 1 through 5 of Claims containing salt or its pharmacologically acceptable esters as active ingredient A pharmaceutical composition according to any one of the above. '

8. R ³ is a hydrogen atom, a C 1, 1 C ₄ alkyl group or a C, —C ₄ alkyl group, a pyro-opened pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is contained as:

9. R ³ is methyl or pyro port pyridazine compound is hydroxymethyl group, a pharmacologically acceptable salt thereof or range囲第1 Section to seventh preceding claims containing a pharmacologically acceptable ester as an active ingredient The pharmaceutical composition according to any one of the above.

10. Any one of claims 1 to 9, wherein R ⁴ contains a hydrogen atom as a pyrolipid pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. 8. The pharmaceutical composition according to item 1.

11. R ⁵ is selected from the group consisting of C, C ₄ alkyl, octogeno C, 1 C ₄ alkyl, C, C ₄ alkoxy, halogeno C, C ₄ alkoxy, fluorine, chlorine and bromine Claims 1 to 4 which contain, as an active ingredient, a pyrrolic pyridazine compound which is a phenyl group which may be substituted with 1 to 3 substituents, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof. Item 10. The pharmaceutical composition according to any one of Items 10 to 10.

1 2. R ⁵ is methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluro Pyrrodazine compound, which is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of fluoromethoxy, fluorine, chlorine, and bromine; a pharmacologically acceptable salt thereof; or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 10, further comprising an ester as an active ingredient.

13. R ⁵ is 1 to 3 substituents selected from the group consisting of fluorine and nitrogen, and 1 to 3 substituents selected from the group consisting of 2, 4 and 6 are substituted 11. The pharmaceutical composition according to any one of claims 1 to 10, comprising a pyrropyridazine compound which is a phenyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof as an active ingredient.

14. R ⁵ is a pyrrodazine compound having 1 or 2 substituents selected from the group consisting of fluorine and chlorine, and a phenyl group substituted at the 4-position or the 2,4-position; The pharmaceutical composition according to any one of claims 1 to 10, comprising a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof as an active ingredient.

15. The method according to any one of Claims 1 to 14, wherein A is a methylene group, a pyro-opened pyridazine compound, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof as an active ingredient. The pharmaceutical composition according to any one of the preceding claims.

16. Any one of claims 1 to 15, wherein X is an oxygen atom, which contains a pyrrolic pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. 8. The pharmaceutical composition according to item 1.

17. is, C ₂ - C ₄ alkenyl group, Furuoro or black port C ₂ -C ₄ alkenyl group, 2-propynyl group, C ₃ - C ₆ cycloalkyl group or a C, - be substituted by C ₂ alkyl (C ₃ -C ₆ -alkyl) —C, — alkyl group, R ² is a hydrogen atom or C, —C ₄ alkyl group, and R ³ is a hydrogen atom, C, —C ₄ alkyl group Or a hydroxy C, —C ₄ alkyl group, R ⁴ is a hydrogen atom, and R ⁵ is C, —C ₄ alkyl, halogeno C ₄ alkyl, CC ₄ alkoxy, halogeno alkoxy, fluorine, chlorine and bromine. Is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of: wherein A is a methylene group; and is an oxygen atom. Salt or its pharmacologically acceptable ester as the active ingredient The pharmaceutical composition according to claim 1 containing Te.

18. R ¹ is vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2-propyl, 2-chloro-2-propenyl, 3,3-difluoro-2-propyl, 3,3-dichloro-2-propyl, 4,4,4-trifluoro Low 2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl group; R ² is a methyl group, R ³ is a methyl or hydroxymethyl group, R ⁴ is a hydrogen atom, and R ⁵ is methyl, trifluoromethyl, methoxy, trifluoromethoxy Is a phenyl group which may be substituted with 1 to 3 S substituents selected from the group consisting of, difluoromethoxy, *, and bromine; A is a methylene group; and X is an oxygen atom Claims containing a pyrolipid pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. 2. The pharmaceutical composition according to item 1 above.

19. R ¹ is a 2-methylcyclopropylmethyl group, R ² is a methyl group, R ³ is a methyl or hydroxymethyl group, R ⁴ is a hydrogen atom, and R ⁵ is A phenyl group in which one or two substituents selected from the group consisting of fluorine and chlorine are substituted with one or two substituents selected from the group consisting of the 2-, 4- and 6-positions; A claim 1 wherein A is a methylene group and X is an oxygen atom, which comprises a pyro-opened pyridazine compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. Pharmaceutical composition.

20. R ¹ is a (1 S, 2 S) .— 2-methylcyclopropylmethyl group, R ² is a methyl group, R ³ is a methyl or hydroxymethyl group, and R ⁴ is A hydrogen atom, R ⁵ is a phenyl group substituted with one or two substituents selected from the group consisting of fluorine and chlorine and substituted at the 4-position or the 2,4-position, Is a methylene group, and is an oxygen atom. 4. The pharmaceutical according to claim 1, which comprises a pyrrodine compound having a mouth, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof as an active ingredient. Composition.

21. 7— (4-Fluorobenzyloxy) —2,3-dimethyl-1-([1S, 2S) -12-methylcyclopropylmethyl] pyrro [2,3-d] pyridazine,

7- (2,4-difluorobenzyloxy) —2,3-dimethyl—1-1 [(IS, 2S) 1-2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (4-cyclobenzyloxy) —2,3-dimethyl-1-[(1 S, 2S) -12-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (4-Fluorobenzyloxy) 1-3-Hydroxymethyl-2-methyl-1 [(1S, 2S) 1-2-Methylcyclopropylmethyl] Pyro- [2,3-d] pyridazine ,

7- (2,4-Difluorobenzyloxy) -1-3-hydroxymethyl-12-methyl-1-[(1S, 2S) —2-Methylcyclopropylmethyl] Pyro [2,3-d] Pyridazine,

7- (4-chlorobenzyloxy) -1-hydroxymethyl-2-methyl-1-[(1S, 2S) -1-methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

1- (2-butenyl) 1 7_ (4-fluorobenzyloxy) 1,2,3-dimethylpyrro [2,3-d] pyridazine and 1- (2-butenyl) -7- (2,4-difluorobenzyloxy) —2,3-dimethylpyrrololo [2,3-d] pyridazine pyrrodazine compounds selected from the group consisting of pyridazines, 2. The pharmaceutical composition according to claim 1, comprising a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof as an active ingredient.

22. 7-(4-Fluorobenzyloxy) 1,2,3-dimethyl- 11 [(1 S, 2 S) 12-Methylcyclopropylmethyl] pyro [2,3-d] pyridazine,

7- (4-Fluorobenzyloxy) — 3-hydroxymethyl-2-methylene 11 [(1 S, 2 S) 1-2-methylcyclopropylmethyl] Pyro mouth [2, 3-d] Pyridazine,

1- (2-butenyl) -7- (4-fluorobenzyloxy) -2,3-dimethylpyro [2,3-d] pyridazine and

'1- (2-butenyl) —7— (2,4-difluoro-p-benzyloxy) —2,3-dimethylpyrrololo [2,3-d] pyridazine Pyrodazine compound selected from the group consisting of pyridazines; 2. The pharmaceutical composition according to claim 1, comprising an acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient.

23. 7- (4-Fluorobenzyloxy) -2,3-dimethyl-1-[(1S, 2S) 1-2-methylcyclopropylmethyl] pyro [2,3-d] pyridazine The pharmaceutical composition according to claim 1, comprising a pharmacologically acceptable salt or a pharmacologically acceptable ester thereof as an active ingredient. ,

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the visceral pain is visceral pain associated with an ulcer disease.

25. A pyro-oral pyridazine compound according to any one of claims 1 to 23, a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for treating or preventing visceral pain. Is the use of its pharmacologically acceptable esters.

26. The use according to claim 25, wherein the visceral pain is visceral pain associated with an ulcer disease.

27. administering to a warm-blooded animal, an effective amount of the pyrolipid pyridazine compound according to any one of claims 1 to 23, a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof. A method for the treatment or prevention of visceral pain.

28. The method according to claim 27, wherein the visceral pain is visceral pain associated with an ulcer disease.

29. The method according to any one of claims 27 to 28, wherein the warm-blooded animal is a human.