TW200418479A - Pharmaceutical compositions for the treatment or prevention of visceral pains - Google Patents

Abstract

This invention relates to pyrrolopyridazine compounds of formula (I) and the pharmaceutical acceptable salt or pharmaceutical acceptable ester thereof, which is useful as medicines for the treatment or prevention of visceral pains. The pyrrolopyridazine compounds of formula (I), wherein R1 is alkenyl, halogenoalkenyl, alkynyl, cycloalkyl, or optionally substituted cycloalkyl-alkyl; R2 is hydrogen or alkyl; R3 is hydrogen, alkyl, or hydroxyalkyl; R4 is hydrogen or alkyl; R5 is optionally substituted phenyl; A is alkylene; X is O or S.

Description

200418479 (1) Description of the invention: (1) Technical field to which the invention belongs The present invention relates to a medicinal composition for treating or preventing (especially) visceral pain (especially visceral pain accompanied by ulcerative diseases), which includes a specific chemical structure A pyrrolopyrizazine compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is an active ingredient; and for a pyrrolopyridine compound having a specific chemical structure, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is used To produce a medicinal composition capable of treating or preventing (especially treating) visceral pain (especially visceral pain accompanied by ulcerative diseases); or regarding treating or preventing (especially treating) visceral pain (especially accompanied by ulcerative diseases) Visceral pain) method, which involves administering to a warm-blooded animal (especially a human) an effective amount of a pyrrolo compound having a specific chemical structure, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. (2) Prior art: Local anesthesia of oxethazame type digestive tract mucosa, scopolamine buty 1 b 1 · 〇mide type spasm agent is known to be used to inhibit visceral pain (viscera Pain caused by cramps or hyperkinesia). However, these visceral pain medications are known to cause side effects such as constipation or headache. On the other hand, pyrrolopyramine compounds with specific chemical structures are known to have gastric acid secretion inhibitory effects (for example, WO 9 5/1 99 80, EP07422 1 8, WO00 / 77 003, EP 1 1 86607, W0 0 1 / 5 890 1 etc.), but it is not known to have a visceral pain inhibitory effect. (3) Indications of the invention of the invention The invention of the present invention has found that the pyrrole and trap compounds with a specific chemical structure have an excellent inhibitory effect on the increase in internal pressure of the lower digestive tract or visceral pain accompanied by dilation of the lumen, so they can be used as constipation Visceral pain (especially ulcerative disease with 200418479 followed by visceral pain) with small side effects such as headache or headache is used to treat or prevent medication (especially treatment) to complete the present invention. The present invention provides a medicinal composition for treating or preventing (especially) visceral pain (especially visceral pain accompanied by ulcerative diseases), which includes a laropyral compound having a specific chemical structure, a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable ester is an active ingredient; the use of a pyrrolo compound with a specific chemical structure, the use of a pharmaceutically acceptable salt thereof, or the use of a pharmaceutically acceptable ester thereof for the manufacture or treatment (especially) of visceral pain (especially) Ulcerative disease accompanied by visceral pain); or a method for treating or preventing (especially treatment) visceral pain (especially visceral pain accompanied by ulcerative disease), which is for warm-blooded animals (especially humans) An effective amount of a compound having a specific chemical structure, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof is administered. The effective compound of the present invention, pyrrolopyrachidine, has the general formula (I):

In the formula, R1 is a C2-C6M group, a halogen C2-C6 alkyl group, (1! 2-06 alkynyl group, C3-C7 cycloalkyl group or (C3-C7 cycloalkyl group) which may be substituted by C "C4 alkyl group- C "C6 alkyl; R2 is a hydrogen atom or C" C6 alkyl group; R3 is a hydrogen atom, C "C6 alkyl or hydroxy Ci-q alkyl group; R4 is a hydrogen atom or C" C6 alkyl group; R5 is a passable Selected from CVC6 alkyl, halo CVC6 alkyl, CVC6 alkoxy, halo (6 oxo and phenyl substituted with halogen substituents; A is C!-C 3 fluorenyl; 200418479 x is an oxygen atom Or sulfur atom. In the above general formula (I), R1 may be a C2-C6 alkenyl group or a C2-C6 alkenyl portion of a halo c2-c6 alkenyl group, for example, vinyl, 1-propenyl, 2-propenyl, iso Propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl , 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl 2-butenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, propan-1,2-dienyl, but-1,2-dienyl, Pent-1,2-dienyl or hexa-1,2-dienyl; preferably C2-C4 alkenyl Especially vinyl, propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl or 3-butenyl); more preferably C3-C4 alkenyl; most preferably 2 -Propenyl or butenyl. R1 is halo C2-C6 alkenyl may be 2,2-difluorovinyl, 3-fluoro-2-propenyl, 2-chloro-2-propenyl, 3-chloro- 2-propenyl, 3-bromo-2-propenyl, 3-iodo-2-propenyl, 3,3-difluoro-2-propenyl, 2,3-dichloro-2-propenyl, 3,3 -Dichloro-2-propenyl, 2,3-dibromo-2-propenyl, 3,3-dibromo-2-propenyl, 4,4,4-trifluoro-2-butenyl, 5- Fluoro-2-pentenyl or 6-fluoro-2-hexenyl; preferably fluorine or chloro C2-C4 alkenyl; more preferably 2,2-difluorovinyl, 3-fluoro-2-propenyl , 3-chloro-2-propenyl, 2-chloro-2-propenyl, 3,3-difluoro-2-propenyl, 3,3-dichloro-2-propenyl, 4,4,4-tri Fluoro-2-butenyl; preferably 3-chloro-2-propenyl, 3,3-dichloro-2-propenyl or 4,4,4-trifluoro-2-butenyl. R1 is C2 -C6 alkynyl may be, for example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl or 2-hexynyl; preferably C2-C4 alkynyl; most preferably 2-propynyl R1 is a C3-C7 cycloalkyl or an alkyl substituted (C3-C 7-Cycloalkyl) -C3-C7-Cycloalkyl moieties of alkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; preferably C3-C6 cycloalkyl, more Preferred is cyclopropyl or cyclohexyl; most preferred is cyclopropyl. '200418479 R] is a c 04 alkyl moiety of (c3-c7 cycloalkyl) -CVC6 alkyl which may be substituted by cvc4 alkyl, which may be, for example, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl or third butyl; methyl or ethyl is preferred; methyl is most preferred. R1 is (c3-c7 cycloalkyl) -CVC6 alkyl (V C6 Alkyl moiety, CVC6 alkyl of R2, R3 and R4, R3 is hydroxy CVC6 alkyl (: "(: 6 alkyl moiety, or R5 is a CVC6 alkyl which may be selected from CVC6 alkyl, halo CVC6 alkyl, (:" (: 6 alkoxy, halo Ci-C ^ alkoxy, and halogen-substituted phenyl-substituted alkyl group or Ci-Ce alkyl portion of haloalkyl group, for example, methyl, ethyl, propyl Group, isopropyl, butyl, isobutyl, third butyl, pentyl or hexyl; preferably C ^ C4 alkyl; more preferably methyl or ethyl; most preferably methyl. R1 is may Alkyl-substituted (C3-C7 cycloalkylICi-qalkyl, for example, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, 2-ethyl Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methylcyclohexylmethyl , Cycloheptylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl or 6-cyclopropylhexyl; more preferably Alkyl substituted (C3-C7 cycloalkylalkyl; more preferably cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentyl Methyl, cyclohexylmethyl or 2-cyclopropylethyl; still more preferably 2-methylcyclopropylmethyl; most preferably (1S, 2S) -2-methylcyclopropylmethyl. R3 is a hydroxy C! -C6 alkyl group, for example, may be methyl, ethyl, propyl, butyl, hydroxypentyl or hydroxyhexyl; preferably hydroxy C! -C4 alkylhydroxymethyl More preferably methylol or 1-Ethyl; most preferably Ethyl. R5 is selectable via CVC6 radical, halogen radical, c "C6 radical, halogen C" C6 alkoxy, and Halo substituent-substituted alkoxy moiety of phenyl or halogen-10-200418479 C "c6 alkoxy c" c6 alkoxy moiety, for example, may be methoxy, ethoxy, propoxy 'iso Propoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy or hexyloxy; preferably [^ alkaneoxy; Preferred is methoxy or ethoxy; most preferred is methoxy. R5 is substituted by a substituent selected from CVC6 alkyl, halo CVC6 alkyl, c6 alkoxy, haloalkoxy, and halogen. The halogen of phenyl can be, for example, fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine; most preferably fluorine. R5 can be selected from CVC6 alkyl, halo CVC6 alkyl, c, c6 alkoxy, Halo, C6 alkoxy and halogen-substituted phenyl halide ["alkyl group moiety, for example, may be fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl Methyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl or 6 -Fluorohexyl; preferably halogen CrG alkyl; most preferred is trifluoromethyl. R5 is a halogen C6 C6 alkoxy moiety of a phenyl group which may be substituted by a substituent selected from CVC6 alkyl, halo CVC6 alkyl, K6 alkoxy, halo C6 C6 alkoxy, and halogen substituents, and may be, for example, fluorine Methoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2- Trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5-fluoropentoxy or 6-fluorohexyloxy; preferably halogen Ci-C ^ alkoxy; most preferred is di Fluoromethoxy. The number of substituents of the phenyl group of R5 is, for example, 1 to 5, preferably 1 to 3, more preferably 1 to 2, and most preferably 1. The substitution position of the phenyl group of R5 is, for example, 2- to 6-position, preferably 2, 4- or 6-position, more preferably 2- or 4-position, and most preferably 4-position. R5 is a group that can be selected from CVC6 alkyl, halo CVC6 alkyl, and C "C6 alkoxy , Halogen CVC6 alkoxy and halogen-substituted phenyl, for example, phenyl, methylphenyl, trifluoromethylphenyl, methoxyphenyl, trifluoromethoxyphenyl, di Fluoromethoxyphenyl, -11-200418479 fluorophenyl, chlorophenyl, bromophenyl, difluorophenyl, chlorofluorophenyl, dichlorophenyl, trifluoro Or trichlorophenyl; preferably substituted with 1 to 3 substituents selected from alkyl, halo Ci-q alkyl, alkoxy, halo c, c4 alkoxy, fluorine, chlorine, and bromine Phenyl; more preferably phenyl which may be substituted by 1 to 3 substituents selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluorine, chlorine and bromine And more preferably phenyl (particularly 2- or 4-fluorobenzene) which can be substituted by 1 to 3 substitutions selected from fluorine and chlorine based on 1 to 3 substitutions selected from 2-, 4-, and 6-positions Methyl, 2- or 4-chlorophenyl, 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); still more preferably 4-fluoro Phenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chloro-2-fluorophenyl or 2-chloro-4-fluorophenyl; particularly preferred 4-fluorophenyl, 4-chlorophenyl or 2,4-difluorophenyl; preferably 4-fluorophenyl. A is an alkylene group such as methylene, ethylene, propyl, 1-Methylethene or 2-Methylethene; Methylene is preferred. X is preferably an oxygen atom. The active ingredient of the pyrrolopyridine compound represented by the general formula (I) has a basic group and can be treated with an acid to form a pharmaceutically acceptable salt. These salts are also included in the present invention. Such salts such as hydrofluoride, Hydrochlorides, nitrates, perchlorates, sulfates, phosphates, carbonates, mesylate, triflate, ethyl C6-C1Q of Cl_c6 alkyl sulfonate, benzene sulfonate, p-toluene sulfonate, naphthalene sulfonate, etc. which can be substituted by fluorine atom, such as sulfonate, pentafluoroethanesulfonate, propanesulfonate, etc. Aryl sulfonate, acetate, trifluoroacetate, propionate, butyrate, benzoate, oxalate, malonate, trans-butenedioate, cis-butenedi Carboxylate, succinate, citrate, tartrate, etc., or glutamate or aspartate amines, etc .; better than -12-200418479 is the hydrohalide, Sulfate, c 6-c! 〇 Aryl sulfonate or carboxylate; more preferably hydrochloride, sulfate, benzenesulfonate, p-toluenesulfonate, Θ-naphthalenesulfonate or trans- Butenoate ; The most preferred is p-toluenesulfonate or trans-butenedioate. The active ingredient of the present invention, which is a compound having a base in the strong pyrrole compound which is not represented by the general formula (I), can be formed into a pharmaceutically acceptable ester through amidation according to a common method, and these esters are also included in the present invention. These esters are, for example, esters of aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, propionic acid, butenoic acid, and propargylic acid, and trans-butenedioic acid, maleic acid, Esters of aliphatic di-residual acids such as oxalic acid, malonic acid, and berberic acid, and esters of aromatic carboxylic acids such as benzoic acid, methylbenzoic acid, methoxybenzoic acid, fluorobenzoic acid, and chlorobenzoic acid, and Esters of sulfonic acids such as sulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc., and esters of amino acids such as glutamic acid, aspartic acid, and monomethyl carbonate, dicarbonate Methyl ester, monoethyl carbonate, diethyl carbonate, monopropyl carbonate, monobutyl carbonate, monophenyl carbonate, diphenyl carbonate, and other carbonate esters, or with phosphoric acid, monomethyl phosphate, and diphosphate Methyl esters, monoethyl phosphate, diethyl phosphonate, monophenyl phosphate, diphenyl phosphate and other phosphoric acid esters; preferably esters with aliphatic monocarboxylic acids, esters with aliphatic dicarboxylic acids or Esters with aromatic carboxylic acids; best with. Esters of aliphatic monocarboxylic acids. The pyrrole trap compounds represented by the general formula (I) as the active ingredient of the present invention may exist as hydrates or solvates, and individual or mixtures thereof are included in the present invention. The active compounds of the present invention as pyrrolophenyl compounds represented by general formula (I) may exist as optical isomers and / or geometric isomers, and each or a mixture thereof is included in the present invention. Visceral pain of the present invention may be pain caused by visceral spasm or hyperkinesis accompanied by various diseases, such as esophagitis, gastritis, enteritis, gastric ulcer, duodenal ulcer, allergic colitis, cholecystitis, cholangitis, Gallstones, urethral stones, 200418479 or cystitis, etc. The active ingredient of the present invention, the strong pyrrolatum compound shown in General Formula (I), can be used as a preventive or therapeutic agent for visceral pain accompanied by these diseases (especially ulcerative diseases such as esophagitis, gastritis, gastric ulcer, duodenal ulcer). (Especially treatment). The pyrrolo compound shown in the general formula (1) of the present invention is preferably the above-mentioned general formula (1) (1) R1 is a C2-C4 alkenyl group, fluorine or chlorine C2-C4 alkenyl group, 2-propene Alkynyl, C3_C6 ring;): Carboxyl or a compound (C ^ C: 6 cycloalkyl) _Ci_C4 alkyl which may be substituted by Ci-C: 2 alkyl; (2) ν is vinyl, propylene , 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2 -Propenyl, 2-chloro-2-propenyl, 3,3-difluoro-2-propenyl, 3,3_dichloro_2_propenyl, 4,4,4-difluoro-2-butene Group, cyclopropyl, cyclohexyl, cyclopropylmethyl, methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclo Propylethyl compounds; (3) 111 is a 2-methylcyclopropylmethyl compound; (BR1 is (1S, 2S) -2-methylcyclopropylmethyl compound; (5) R2 is A hydrogen atom or a ^ -alkyl compound; (6) a compound in which R2 is a methyl group; (7) a compound in which R3 is a hydrogen atom, a compound of "C4 alkyl group or a hydroxyl group of" C4 alkyl group "; (8) R3 is Methyl or hydroxy (9) R4 is a compound of hydrogen atom; (10) R5 is a compound selected from C, C4 alkyl, halo C, C4 alkyl, C, C4 alkoxy, haloalkoxy Phenyl, fluoro, chloro and bromo substituted phenyl compounds; -14-200418479 (11) R5 can be selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy through 1 to 3 Phenyl, difluoromethoxy, fluorine, chlorine and bromine substituted phenyl compounds; (12) R5 can be substituted by 1 to 2 selected from fluorine and chlorine based on 1 to 2 selected from the 2-position Compounds of phenyl substituted at the 4, 4, and 6 substitution positions; (13) R5 is a phenyl group that can be substituted with 1 or 2 substitutions selected from fluorine and chlorine based on the 4 or 2,4-position substitution positions. (14) A is a methylene compound; (15) X is an oxygen atom. Furthermore, any combination is selected from R1 of (1) to (4), and is selected from (5) to (6) R2 is selected from R7 of (7) to (8), R4 is selected from (9), R5 is selected from (10) to (13), A is selected from (14), and The compound obtained by X is more preferable, for example, the following compounds are more preferable: (16) 111 is C2-C4 alkenyl, fluorine or chlorine C2-C4 alkenyl, 2 -Propynyl, C3-C6 cycloalkyl or (C3-C6 cycloalkylalkyl may be substituted by (^-(: 2 alkyl; R2 is a hydrogen atom or C4C alkyl; R3 is a hydrogen atom, Alkyl or hydroxy C4 alkyl; R4 is a hydrogen atom; R5 is an alkyl group selected from CVC4 alkyl, halo CVC4 alkyl, alkoxy, halo Ci-G alkoxy, fluorine, chlorine And bromine substituted phenyl; A is methylene; X is an oxygen atom; (17) ν is vinyl, propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-difluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2-propenyl, 2-chloro-2-propenyl, 3, 3-difluoro-2-propenyl, 3,3-dichloro-2-propenyl, 4,4,4-trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl; R2 is methyl; R3 Is methyl or hydroxymethyl; R4 is hydrogen atom 200418479; R5 is one or three selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, fluorine , Chlorine and bromine substituents Substituted phenyl; A is methylene; X is an oxygen atom; (18) 111 is 2-methylcyclopropylmethyl; R2 is methyl; R3 is methyl or hydroxymethyl; R4 is hydrogen Atom; R5 is a phenyl group which can be substituted by 1 to 2 substitutions selected from fluorine and chlorine based on 1 to 2 substitution positions selected from the 2-, 4- and 6-positions; A is a methylene group; X is an oxygen atom (19) 111 is a compound of (1S, 2S) -2-methylcyclopropylmethyl; R2 is methyl; R3 is methyl or hydroxymethyl; R4 is hydrogen atom; R5 is To 2 substituted phenyl groups selected from fluorine and chlorine based on substitution at the 4- or 2,4-position; A is a methylene group; X is an oxygen atom; (20) pyrrole Compound: 7- (4-fluorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] Dagen; 7- (2,4-difluorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3 -d] Dagen; 7- (4-chlorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3 -d] Da Geng; 7- (4-fluorobenzyloxy) -3-hydroxymethyl-2 -methyl-l-[(lS, 2S) -2 -methylcyclopropylmethyl] Pyrrolo [2,3-d] da-crop; 7- (2,4-difluorobenzyloxy) -3-hydroxymethyl-2-methyl-l-[(lS, 2S) -2-methyl Cyclopropylmethyl] pyrrolo [2,3-d] Dagon; 7- (4-chlorobenzyloxy) -3-hydroxymethyl-2 -methyl-l-[(lS, 2S) -2 -Methylcyclopropylmethyl] pyrrolo [2,3-d] da-peng; -16- 200418479 1- (2-butenyl) -7- (4-fluorobenzyloxy) -2,3- Dimethylpyrrolo [2,3-d] datra; and 1- (2-butenyl) -7- (2,4-—fluoropingoxy) -2,3-monomethyl ratio [2,3-d] Mouth trap; (2 1) selected from the following pyrrolopyridine compounds: 7_ (4_fluorobenzyloxy) -2,3-dimethyl-M (lS, 2S ) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] Daqin; 7- (4-fluorobenzyloxy) -3-hydroxymethyl-2-methyl-l-[( lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] taoxin; 1- (2-butenyl) -7- (4-fluorobenzyloxy) -2, 3-dimethylpyrrolo [2,3-d] daquin; and 1- (2-butenyl) -7- (2,4-difluorobenzyloxy) -2,3-dimethylpyrrole Ac [2,3-d] da-crop; or (22) a pyrrolo-da-crop compound selected from the group consisting of 7- (4-fluorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2 -methylcyclopropylmethyl] pyrrolo [2,3-d] Farming. The present invention provides: (23) A medicinal composition for treating or preventing (especially) visceral pain, which comprises a pirocta compound represented by the general formula (I) [especially (1) to (2 2 above) A compound according to any one of the above], wherein a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is an active ingredient; (24) The pharmaceutical composition described in (23), wherein visceral pain is visceral pain accompanied by ulcerative disease; ( 25) A pyrrolo-drag trap compound represented by general formula (I) [especially the compound described in any one of (1) to [22) above], its pharmaceutically acceptable salt or its pharmaceutically acceptable ester makes -17 -200418479 for the manufacture of a medicinal composition that can treat or prevent (especially) visceral pain; (2 6) the use described in (2 5), where visceral pain is visceral pain accompanied by ulcerative diseases; (27) A method for treating or preventing (especially) visceral pain, which comprises administering an effective amount of a pyrrolopyramine compound of general formula (I) to a warm-blooded animal [especially in the above (i) to (22) A compound as described in any one], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof; (28 ) The method described in (27), wherein the visceral pain is visceral pain accompanied by ulcerative diseases; (29) The method described in any one of (27) to (28), wherein the warm-blooded animal is a human #. Among the pyrrolopyridine compounds represented by the general formula (I) as the active ingredient of the present invention, preferred compounds are those shown in Table 1, but the present invention is not limited to these compounds. The compounds described in Table 1 have a structure represented by general formula (II). [Table 1 ]

-18- 200418479

Exemplified compound numbers R1 R, R2 R4 R5 X 1 Me Me H Ph 0 2 CH2 [(iS, 2S) -2-MePrc] Me Me H Ph 0 3 C% CH = CH! Me Me H 4, PPh 0 4 CH2CH ^ CHCH3 Me Me H 4-FPh 0 5 Frc Me Me H 4-FPh 0 6 CH2Prc Me Me H 4-FPh 0 7 CH2Hxe ^ Me Me H 4-FPh 0 8 CH2 (2-MePrc) Me Me H 4-FPh 0 9 CH2 [(1S, 2S) -2 " MePrc3 Me Me 4 H 4-FPh 0 10 CH2CH2Prc Me Me H 4-FPh 0 U CH2CH = CH2 Me Me H 2,4-diFPh 0 12 CH2CH = CHCHs Me Me H 2,4-diFPh 0 13 CH2Prc Me Me H 2,4-diFPh 0 Η CH2 (2-MePrO Me Me r 2,4-diFPh 0 15 CH2 [(lS, 2S) -2-MePrc] Me Me H 2, 4-diFPh 0 16 CH2CH < H2 Me Me H 4-ClPh 0 17 ch5ch ^ chch3 Me Me H 4-CIPh 0 18 CH, Pr? Me Me H 4-CiPh 0 19 CH2 (2nMePrc) Me Me H 4-ClPli 0 20 CHjtasJ ^ -S-MePr ^ Me Me H 4-C! Ph 0 21 CH, CH-CHZ Me Me H 2,4-diClPl »0 22 CHjCH-CHCH ^ Me Me H 2,4-diClPii 0 23 CH, Prc Me Me H 2,4-diCIPh 0 24 CH, (2-MePrc) Me Me H 2,4-diClPh 0 25 CH2 [(! S, 2S) -2-MePrc] Me Me H 2.4-diCtPh 0 26 CH2 (2-MePrc) Me Me -19- H 2-FPh 0

200418479 27 CH-Las ^ SJ ^ iePr0] Me Me H 2-FPh 0 28 mt (2-MePrc) Me Me H 3-FPh 0 29 CH, [(iS, 2S) -2-MePrc] Me Me H S- FPh 0 30 CH2 (2-MePrc) Me Me H 2-ClPh 0 3i CH2 [(lS, 2S) -2-MePrc] Me Me H 2-CiPli 0 32 CH2 (2-MePrc) Ide Me H 3-C! Ph 0 33 CHiEdSjSi ^ -MePr ^] Me Me H 3-CiPh 0 34 CH2 (2, MePrc) Me Me H 4-MePh 0 35 CHj (IS, 2S) -2-MePrc3 Me Me H 4-MePh 0 36 CH , (2-MePrc) Me Me H 4-OMePh 0 37 CHl [as, 2S) -2-MePrt] Me Me H 4-OMePh 0 38 CHt < 2-MePrc) Me Me H 4-CF3P1i 0 39 CH2 [( iS, 2S) + MePre] Me Me H 4-CF3Ph 0 40 CE ^ Ue? ^) Me Me H 4-0CHF, Ph 0 41 CH! [(iS, 2S) -2, MePrc] Me Me H 4-0CHF : Ph 0 42 CH2 [(lSf 28) -2 ^ 1 ^] Ei Me H 4 ^ FPti 0 43 CHg [{lS, 2S) -2-MePrfi] Pr Me H 4-FPh 0 44 CHJ (IS, 2S > -24! EPrc] Pr1 Me H 4-FPh 0 45 CH2C (lS, 2S) -2- «ePrc3 Bu Me H 4-FPh 0 46 2S) -2-MePrc] Bu 'Me H 4 ^ FPh 0 4? CI2 [(lS, 2S) -2-MePrc] Bu5 Me H 4-FPh 0 48 Bu1 Me H 4-FPh 0 49 CH1 (2-MePrc) Me Me Me 4-FPh 0 50 CH2 [(lS, 2S) -2 -MePrc] Me Me Me 4-F? H 0 51 CH! [(1S, 2S) -2-MePrc] HM € H 4-FPh 0 52 αΗ5 [(Ι5,2 $)-2-Μ6 ΡΓ €] Me HH 4-FPh 0 53 CB2 [(IS, 2S) -2-M € Prc] Me Me H 4-BrPli 0 54 CH2 [(lS, 2S) -2, ePre] Me Me H 4 ~ 0CF3Ph 0 55 CH2 [(lS, 2S) -2-MePrc] Me Me H 2,6-diFPh 0 56 CH2 [(lS, 2S) -2-MePrc] Me Me H 2,6-diClPh 0 57 CHddSJS) -2 -MePrc] Me Me H 2,4,6-triFPh 0 5S CHjdS ^ SJ ^ -MePr ^ Me Me H 2,4,6-triClPh 0 59 CHi [(lS, 2S) + MePrc] Me Me H 2-a + FPh 0 60 CHjUlS ^ S BU 2-MePre] Me Me H 2 -c BU 4-pph 0 61 CHjtilS, 2S) -2-MePr ^] Me Me H 4-Cl-2-FPh 0 62 CH "2_MePrc) Me Me H 4-FPh s 63 CH, [(lS, 2S) -2-MePr €] Me Me H 4 ~ FPh s 64 CH2 [(! S, 2S) -2 ~ MeP: rc3 Me Me H 2,4 -diFPli s -20- 200418479 65 CH2 [(lS, 2S) -2-MePrc] Me Me H 4-C! Ph 66 CH3 [(iS, 2S) ~ 2-M € Prc] Me Me H 2,4- diClPh 6? CH2 [(iS, 2S) + MePrc] Me ch2oh H 2-FPh 68 CH “2_MePrc) Me ch2oh H 4-FPli 69 CH ^ iOS, 2S) -2-MePrc] Me ch2oh H 4_FPh 70 CH2 [( lS, 2S) -2-M € Pr €] Me ch2oh H 2,4-diFPh 71 CHjtdS, 2S) -2-MePrJ] Me CH ^ OH H 2-CiPh 72 CH2 [(lS, 2S) -2-MePrc3 Me C_ H 4-ClPh 73 CH: [(lS, 2S) -2-MePrc] Me ch2oh H 2,4-diClPh 74 ouasjsM.PKi Me CH20Ac H 2-FPh 75 CH2 (2- MePrc) Me CH20Ac H 4-FPh 76 CH2 [(lSt2S) -2-MePrc3 Me CH20Ac H 4-FPh 77 CH] [as, 2S > —2-MePre] Me CH20Ac H 2,4-dIFPh 78 CH2 [(IS , 2S) -2-MePrc] Me CH20Ac H 4-ClPh 79 CH2 [(lS, 2S) -2-MePrc] Me CH20Ac H 2,4-diCIPh 80 CHdas, 2S) + MePTl Me CHiOPrp H 4-FPh 81 CHjtdS , 2θ) -2-ΜβΡ ^) Me C_ur H 4-FPh 82 CHj (2 ~ MePrc) Me CHjOCOPh H 4-FPh 83 CH2t (lS, 2S) -2-MePrc] Me CH: 0C0Ph H 4-FPh 84 CHjaS , 2 $)-2-MePr <] Me CH2OCO (4-MePh) H; 4-FPh 85 CHjaSJSid-MePrl Me CB5OCO (4-OMePb) H 4-FFh 86 CH2 [(iS, 2S) -2-MePrc] Me _C0 (4-FPh) H 4-FPh 87 CHjas ^ Si ^ -MeP ^] Me C02O € O (4-C) Ph) H 4-FPh 8S CH2 (2-MePrc) Me CEjOCOiMe H 4-FPh 89 CH2 [(lS, 2S) ~ 2-MePrc] Me CHjOCOjMe H 4-FPh 90 CHl [(lS > 2S) -2-MePrc3 Me CHjOCOjEt H 4-FPh 91 CHsUiS, 2S) + MePrc] Me € H20C02Pr H 4_FPh 92 CH2 [(iS, 2S) -2-MePre] Me CHjOCOjBu H 4-FPh 93 CH.EOS, 2S) -2-MePrc] Me CH2OC02Ph H 4-FPh 94 CH2 [(iS, 2S) -2-MePrc] Et _H H 4-FPh 95 CHsEOS, 2S) -2-MePxc] Et CHjOAc H 4-FPh 96 CHjas, Me CHjOH H 4-MePh 97 CH ^ CdS, 2S) -2-MePrc] Ue C_ H 4-CF3 Ph 98 Me CHjOH H 4-OMePh 99 CH2C {lS, 2S} -2-MePrc] Me CHjOH H 4-OCHFjPh 100 CH: [US, 2S) -24! EPrc] Me C_ H 4-0CF3Ph 101 CH2 [(1S , 2S) ~ 2-MePrc3 Me ch2oh H 4-BrPh 102 CH: [(1 $, 2S) -2-MePic] Me CHjOAc H 4-MePh -21-200418479 103 CH2 [(lS, 2S) -2-MePrc3 Ue C_c H 4-CF3Ph 0 104 CH2 [(lSJS) -2-MePrc] Me CH20Ac H 4-OMePh 0 105 CH2 [(lS, 2S) -2-MePrc] Me CH20Ac H 4-0CHF2Ph 0 106 CH2 [(lS , 2S) -2, ePrc] Me CH20Ac H 4-0CF3Ph 0 107 CH2 [(lS, 2S) + MePrc] Me Even OAc H 4-BrPh 0 108 CHjUSJSJ + MePrc] Me CH20H H 4-FPh s 109 CH2 [( lS ， 2S) + MePKl Me ch2oh H 2,4_d_ s 110 CH2 [〇S > 2S) -2-MePrc] Me CHjOH H 4-ClPb s 1Π CB2C (IS, 2S) -2-MePrc] Me CH20H H 2, 4-diCiPh s 112 CHJOSJS)-2 -MePre] Me CH.OAc H 4-FPh s 113 CH2 [US, 2S)-2 -MePrc] Me CH ^ OCOPh H 4-FPh s 114 Me CH20C02Me H 4-FPh s 115 CH, [(iS, Me CH20C02Ei H 4 ~ FPh s 116 CH2Cas, 2S) -2-MePrc] Me Et 4-FPh 0 1Π Oit [(\ St2S) -2-UeM Me Pr H 4-FPh 0 118 CH : [(lS, 2S) -2, rfrt Me Pr1 H 4-FPh 0 119 CH2 [(lS, 2S) + MePrc] Me Bu H 4-FPh 0 120 CHJ (IS, 2S) -2-Finance "] Me Bu1 H 4-FFh 0 121 CH: [(iS, 2S) -2-MePrc] Me Bus H 4-F? H 0 122 CHr [(lS, 2S) -2-MePrc] Me By1 H 4-FPh 0 123 CH2 [(lSJS) -2-MePrc] Me Pn H 4-FFh 0 124 CH2 [(iS, 2S) -2-MePr1 Me CH (0H) CH5 H 4-FPh 0 125 CH3 [(IS, 2S)- 2-MePrc] Me CH2CHt0H H 4-FPh 0 126 CHj [(IS, 2S) -24iePrc3 Me CH (0Ac) CH3 H 4-FPh 0 127 CHr [(lS > 2S) -2-MePrc] Me CH (OH) CHtCH3 H 4-FPh 0 128 C, [(lS, 2S) -2-MePKI Me CH (OH) (CHj) j € H3 H 4-FPh 0 129 CH2 [(IS, 2S) -2-MePrc] Me CH (OH) (CH2) aCH3 H 4-FPh 0 130 CH2 [(IS, 2S) -2-MePrc3 Me CH (OH) (CH2), CH3 H 4 ”FPh 0 131 € H2 [(iS, 2S) -2 -MePr £ 3 Me CH (0H) CH3 H 4-FPh s

The abbreviations in Table 1 above indicate the following bases. Ac: Ethyl butyl B u. Butyl Bu1: Isobutyl

Bur: Ding Yingji .22-200418479

Bus: Second butyl

Bul •• Third butyl

Et: ethyl

Hxe: cyclohexyl

Me: methyl

Ph: Phenyl PηPentyl Pr: Propyl

Pre: Cyclopropyl

Prj: isopropyl, and

Prρ: propionyl. The preferred compounds in Table 1 above are exemplified compound numbers 1, 2, 3, 4, 6, 8, 9, 12, 14, 15, 19, 20, 24, 25, 27, 29, 31, 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, 111, 112, 113, 114 , 115, 124, 125 compounds. More preferably, it is exemplified by compound number 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, 1 0 9, 1 1 0, 1 1 1, 1 1 2 It is even more preferable to exemplify compound numbers 4, 9, 12, 15, 20, 25, 27, 31, 55, 56, 60, 61, 63, 69, 70, 72, 73, 76, 77, 78, 108 -23 -200418479 compounds. A further more preferred compound is: Exemplified Compound No. 4: 1- (2-butenyl) -7- (4-fluorobenzyloxy) _2,3-dimethyl P slightly less than [2,3-d] Coax; Exemplary Compound No. 9: 7- (4-fluorobenzyloxy) -2,3-dimethyl-1-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2, 3-d] Da-Chang; Exemplified Compound No. 12: 1- (2-butenyl) -7- (2,4-difluoro; oxy) _2,3_dimethylpyrrolo [2,3-d ] Datra; Exemplified Compound No. 15: 7- (2,4-difluorobenzyloxy) -2,3-dimethyl-M (1S, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] Coco; Exemplified Compound No. 20: 7- (4-chlorobenzyloxy) -2,3-dimethyl-M (1S, 2S) -2-methylcyclopropylmethyl ] Pyrrolo [2,3-d] Da Teng; Exemplary Compound No. 69: 7- (4-fluorobenzyloxy) -3-hydroxymethyl-2-methyl-1-[(lS, 2S) -2 -Methylcyclopropylmethyl] pyrrolo [2,3-d] Da-Chang; Exemplified Compound Number 70: 7- (2,4-difluorobenzyloxy) -3 -hydroxymethyl-2-methyl -[[LS, 2S) -2 -methylcyclopropylmethyl] pyrrolo [2,3-d] datra; or exemplified compound number 72: 7- (4-chlorobenzyloxy) -3- Hydroxymethyl-2-methyl-bu [(13,23) -2-methylcyclopropylmethyl ] Pyrrolo [2,3- (1] oxo. Particularly preferred compounds are: Exemplified compound number 4: 1- (2-butenyl) -7- (4-fluorobenzyloxy) -2,3-di Methylpyrrolo [2,3-d] Daqin; Exemplified Compound No. 9: 7- (4-fluorobenzyloxy) -2,3-dimethyl-M (lS, 2S) -2-methyl ring Propylmethyl] pyrrolo [2,3-d] datra; exemplified compound number 1 2: 1-(2-butenyl) -7-(2,4-difluorobenzyloxy) -2,3 -Dimethyl-24-200418479 ylpyrrolo [2,3-d] DAKO; or exemplified compound number 69: 7- (4-fluorobenzyloxy) -3-hydroxymethyl-2-methyl-1_ [ (1 S, 2 S)-2 -methylcyclopropylmethyl] pyrrolo [2,3-d] trap. The best compounds are: Exemplified compound number 9: 7- (4-fluorobenzyloxy ) -2,3-dimethyl-M (lS, 2S) -2-methylcyclopropylmethyl] D is slightly less than [2,3-d]. The active ingredient of the present invention is represented by the general formula (I The pyrrolopyridine compound shown in) may be in accordance with a known method [for example, WO 9 5/1 99 80 (= EP-07422 1 8A), W00 / 77003 (= EP-1 1 86607A)] or according to these methods Easily made. The compound having a hydroxy group in the pyrrolopyridine compound represented by the general formula (I) as the active ingredient of the present invention can be used to produce a pharmaceutically acceptable ester thereof through amidation according to a conventional method. That is to say, a compound having a hydroxyl group and an equivalent fluorenyl halide or an acid anhydride can be reacted in the presence of a base in accordance with a common method in an inert solvent to produce a pharmaceutically acceptable ester (for example, WO 01/58901 Gazette, etc.). When the pyrrolodocazone compound represented by the general formula (I) of the active ingredient of the present invention is used as a pharmaceutical with a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, the active ingredient may be administered in its native (original state) form, or Pharmaceutically acceptable excipients, diluents, etc. are mixed into preparations such as lozenges, capsules, granules, powders, or syrups, which can be administered orally, or preparations such as injections or seaters, which can be administered orally (more Preferably administered orally). These preparations are manufactured by known methods using additives such as excipients, binders, disintegrating agents, lubricants, emulsifiers, stabilizers, flavor correctors, diluents, and solvents for injections. Excipients such as sugar derivatives of lactose, white sugar, glucose, mannitol, sorbitol; corn starch, potato starch, alpha starch, dextrin, starch of carboxymethyl starch-25-200418479 derivatives; crystalline fiber Cellulose, low degree of substitution of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, cellulose derivatives of sodium cross carboxymethyl cellulose; acacia Glucan; Pluran; light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminosilicate silicate derivatives; calcium phosphate phosphate derivatives; carbonic acid Carbonate derivatives of calcium; or sulfate derivatives of calcium sulfate, etc. Examples of disintegrating agents include the above-mentioned excipients; croscarmelose sodium, chemically modified starches or cellulose derivatives of sodium carboxymethyl starch; or cross-polyvinylpyrrolidone. Lubricants such as talc; stearic acid; metal stearate salts of calcium stearate and magnesium stearate; colloidal sand colloids; waxes of beeum and cetacean; boric acid; ethylene glycol; D , L-leucine; carboxylic acids of adipic acid; sodium carboxylic acid salts of sodium benzoate; sulfates of sodium sulfate; sodium lauryl sulfate, lauryl sulfate of magnesium lauryl sulfate; anhydrous silicic acid , Silicates of silicic acid hydrates; starch derivatives in the excipients mentioned above, and so on. Emulsifiers such as bentonite and propolis colloidal clays; magnesium hydroxide and aluminum hydroxide metal hydroxides; sodium lauryl sulfate and calcium stearate anionic surfactants; alkylammonium chloride cations Surfactants; and nonionic surfactants such as polyhydroxyvinyl alkyl ethers, polyhydroxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters. Stabilizers such as methyl para-hydroxybenzoate, propyl para-hydroxybenzoate, etc.-Parabens, chlorobutanol, benzyl alcohol, phenethyl alcohols; chlorinated compounds; , Phenols of cresols; ethylmercury sodium thiosalicylate; anhydrous acetic acid; or sorbic acid, etc. Flavoring and deodorizing agents are, for example, sweeteners, sour agents, or flavors that are commonly used. Diluents such as water, ethanol 'propylene glycol, ethoxylated isostearyl alcohol or polyoxyethylene hill -26-200418479 sorbitan fatty acid esters and the like. Solvents for injection such as water, ethanol, glycerol and the like. In the present invention, the pyrrolopyridine compound of the general formula (I) can be administered to warm-blooded animals (especially humans) in a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, and the administration amount depends on the activity of each agent and the symptoms of the patient. Changes in various conditions such as age, weight, etc. When this dosage is administered orally due to different symptoms, age, etc., the lower limit for adult administration is 0.1 mg (preferably 0.5 mg), and the upper limit is 1,000 mg (preferably 500 mg). When administered orally, The lower limit of each time is 0.01 mg (preferably 0.05 mg), and the upper limit is 100 mg (preferably 50 mg), and it can be administered 1 to 6 times per day depending on symptoms. In addition, the active ingredient of the present invention is a pyrrolopyridine compound represented by general formula (I), a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, and has an autogastric acid secretion suppressing effect, and thus is used as esophagitis and gastritis. In the case of a pharmaceutical composition for the treatment or prevention of visceral pain accompanied by ulcerative diseases such as gastric ulcer, duodenal ulcer, etc., it is expected that the treatment or prevention effect of visceral pain and the treatment or prevention effect of ulcerative disease may be simultaneously achieved. The pharmaceutically acceptable salt or pharmaceutically acceptable ester of the Pit-pyrrole tower copious compound represented by the general formula (I) as the active ingredient of the present invention is excellent for the internal pressure of the lower gastrointestinal tract or the visceral pain accompanied by dilation of the lumen. It can be used for the prevention of visceral pain (especially esophageal inflammation, gastritis, gastric ulcer, duodenal ulcer and other visceral pain) in warm-blooded animals (especially for human use) with small side effects such as constipation or headache. Or therapeutic medication. LB) Embodiment [Best Mode for Carrying Out the Invention] The present invention will be described in more detail by way of test examples and preparation examples, but the scope of the present invention is not limited thereto. 1) Visceral pain evaluation test 200418479 This method was changed by changing the method of Banner et al. (Br. J. Pharmacol., 1995, Vol. 114, P.5 58). A group of 6 to 7 rats were fasted overnight, anesthetized with sodium pentobarbital, the skin in the middle of the abdomen was cut, and an intensity converter for observing the contraction movement of the rectus abdominis was sewn to the rectus abdominis. A balloon connected to the transducer for detecting the internal pressure was inserted from the rectum 1 cm inside the anus, and the position was fixed. The rats were placed in a balloon cage. After awakening from anesthesia, rats were injected with water into the balloon at a rate of 0.08 ml / min. At the same time, the balloon pressure and rectus abdominis contraction were observed. When balloon internal pressure rises with rectal dilatation, the threshold value of balloon internal pressure, which is the initial contraction of rectus abdominis, is seen as an indicator of visceral pain. Oral administration of 2 ml of 7- (4-fluorobenzyloxy) -2,3-diβ methyl-1-[(13,23) -2-methylcyclopropylmethyl per 1 kg of body weight ] Pyrrolop [2,3- (1] Tazo suspension [Exemplified compound of compound No. 9: WO00 / 77003 (= EP-1 1 86607A) The compound described in Example 1: hereinafter referred to as compound (III) ] Suspension in 0.5% carboxymethyl cellulose sodium salt and 0.4% polysorbate 80 aqueous solution to form a suspension with a concentration of 1.5 to 5 mg / kg '1, 2 and 3 hours after the measurement of the balloon internal pressure. The suspension medium was used as a control Group. Dunnett method was used to review the significant difference in the internal pressure threshold before and after the administration. Table 2 shows the transition of the internal pressure threshold of the balloon after the compound (III) and the administration medium. Φ As shown in Table 2, comparison The group did not see a change in the balloon internal pressure threshold 后 after administration, while the compound (ΠΙ) administration group saw a significant increase in the internal pressure threshold 用量 after dose administration. -28- 200418479 [Table 2] Internal pressure threshold 値 ( mmHg) Number of cases 1 hour before administration 2 hours after administration 3 hours later 3 hours after the control group 7 7.04 9.5 1 9.66 6.29 Compound (III) administration 6 7.62 13.1 14.1 11.8 Group 3 mg / kg Administration of Compound (III) 6 7.20 16.3 23.0 19.3 Group 10 mg / kg Based on the above results, Compound (III) has an excellent inhibitory effect on the increase in internal pressure of the lower digestive tract and visceral pain accompanied by dilation of the lumen. The effective ingredient of the invention

The compound of pectinate can be used as a preventive or therapeutic agent for visceral pain. (Preparation Example II) The compound (111) (30.01112), lactose (144.〇111 £), corn-based flour (25.0 mg), and magnesium stearate (1.0 mg) were mixed. A tablet of 200 mg is tableted through a tabletting machine. This tablet can be coated (preferably sugar-coated) as needed. Industrially available pieces of pyrrole shown by the general formula (I), the active ingredient of the present invention The palladium compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, has an excellent inhibitory effect on the internal pressure of the lower gastrointestinal tract or visceral pain accompanied by dilation of the lumen, so it can be used as a mild side effect such as constipation or headache Blood or animal (especially human) visceral pain (especially esophageal inflammation, gastritis, gastric ulcer, duodenal ulcer and other visceral pain accompanied by visceral pain) preventive or therapeutic drugs. (V) Schematic description: None-29 -

Claims (1)

200418479 The scope of patent application: 1. A pharmaceutical composition for treating or preventing visceral pain, which contains a slightly succinct compound of general formula (1), a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient, In the formula, R1 is a C2-C6 strip group 'halo-C2-C6 alkynyl' () 2- (1! 6 alkynyl, c3-C7 cycloalkyl or may be substituted by (: "(: 4 alkyl substituted (C3- C7 cycloalkyl) -C "C6 alkyl; R2 is a hydrogen atom or C" C6 alkyl; R3 is a hydrogen atom, 0 "(: 6 alkyl or hydroxy C" C6 alkyl; R4 is a hydrogen atom or C " C6 alkyl; R5 is a phenyl group which can be substituted by a substituent selected from the group consisting of C, C6, halo, CrC ^, and 'CrC ^;!: Oxy, haloalkoxy, and halogen substituents; A is CVC3 butane X is an oxygen atom or a sulfur atom. 2. The pharmaceutical composition according to item 丨 of the patent application scope is c2-(: 4 alkenyl, fluorine or chlorine C2-C4 storage group, 2-propynyl group, C3- C6 cyclosynthetic or pyrrolopyramine compounds (CrC6 cycloalkyl) -Cl_c4 alkyl substituted by academy, the pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof are used as active ingredients. 3. If the scope of patent application is the first The pharmaceutical composition of this item, wherein R1 is a vinyl group, a propylene group, a 2-propenyl group, an isopropenyl group, a butenyl group, a 2-butenyl group, a 3-butenyl group, and a 2-2-diene group. Fluorovinyl, 3-fluoro-2-propenyl, 3-chloro-2-propenyl, 2-chloro-2-propenyl, -30- 200418479 3,3-difluoro-2-propenyl, 3, 3-dichloro-2-propenyl, 4,4,4-trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropyl Methyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl The compound, its pharmaceutically acceptable salt or its pharmaceutically acceptable vinegar as an active ingredient. 4. For the pharmaceutical composition of item 1 of the scope of patent application, it is pyrrolopyramine with Ri being 2-methylcyclopropylmethyl. A compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof as an active ingredient. 5. If the pharmaceutical composition of item 1 of the scope of patent application, Ri is (1S, 2S) _2_methylcyclopropylmethyl The pyrrolopyridine compound has a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 6. For a pharmaceutical composition according to any one of claims 1 to 5, the R 2 is a hydrogen atom or CrC4 alkyl pyrrolopyridine compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 7. If any of the scope of claims 1 to 5 of the patent application The pharmaceutical composition according to item 1, which is a pyrrolopyramine compound having r 2 as a methyl group, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. The pharmaceutical composition of this item is a pyrrolopyridine compound having R3 as a hydrogen atom, an alkyl group or a hydroxyalkyl group, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. The pharmaceutical composition according to any one of items 7 to 7, which is a pyrrolopyramine compound having r3 as a methyl group or a methyl group, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 10. The pharmaceutical composition according to any one of claims 1 to 9 of the scope of application for a patent, which is a pyrrole trap compound having R4 200418479 as a hydrogen atom, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 11. The pharmaceutical composition according to any one of claims 1 to 10 in the scope of patent application, which is based on R5 and can be selected from 1 to 3 selected from (VC4 alkyl, halogen C, C4 alkyl, dagger-doxyloxy Pyrrolo compounds of phenyl substituted with phenyl, haloalkoxy, fluorine, chlorine and bromine substituents, and the pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof are used as the active ingredients. The pharmaceutical composition according to any one of 10, wherein R5 is selected from 1 to 3 selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, and fluorine The pyrrolopyridine compounds of phenyl substituted by chloro and bromine substituents, and the pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof are used as active ingredients. 13. As described in any one of claims 1 to 10 A pharmaceutical composition, which is a pyrrolopyridine compound having R5 as a phenyl group which can be substituted by 1 to 3 substituents selected from fluorine and chlorine based on 1 to 3 substituents selected from substitution positions of 2, 4, and 6 , A pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 14. For a pharmaceutical composition according to any one of claims 1 to 10 of the scope of patent application, R5 is a pyrrolopyridine compound which can be substituted by 1 to 2 substituents selected from fluorine and chlorine based on a phenyl group substituted at the 4- or 2,4-position, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof As an active ingredient 15. The pharmaceutical composition according to any one of claims 1 to 14, which is a pyrrolopyridine compound having A as a methylene group, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof As an active ingredient 16. The pharmaceutical composition according to any one of claims 1 to 15 of the scope of application for a patent, which is a pyrrolopyridine compound having X as an oxygen atom, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as Active ingredients. -32- 200418479 The pharmaceutical composition according to item 丨 of the patent application scope, which is based on Ri as C2_c4 alkenyl, fluorine or chlorine C2-C4 alkenyl, 2-propynyl, C3-C6 cycloalkyl or (CVC6 cycloalkyl) -CVC4 alkyl group which may be substituted by C2C2 alkyl group; R2 is a hydrogen atom or (VC4 alkyl group; R3 is a hydrogen atom, an alkyl group or a hydroxy Ci-q alkyl group; R4 is a hydrogen atom; R5 is one or three substituents selected from the group consisting of halogen, C, C4, halogen, oxygen, IS alkoxy, fluorine, chlorine and bromine. Substituted phenyl group; A is methylene group; X is an pyrrodocacol compound of oxygen atom, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is used as an active ingredient. , Which is based on R1 as a vinyl group, ^ propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,2-monofluoroethenyl, 3-fluoro-2-propanyl, 3-chloro-2-propanyl, 2-chloro-2-propanyl, 3,3-difluoro-2-propenyl, 3,3-dichloro-2 -Propenyl, 4,4,4-trifluoro-2-butenyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 2-methylcyclopropylmethyl Group, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or 2-cyclopropylethyl; R2 is methyl; R3 is methyl or hydroxymethyl; R4 is a hydrogen atom; R5 is a hydrogen atom 3 phenyl substituted with substituents selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy'fluoro, chlorine and bromine; A is methylene; X is oxygen An atomic pyrrole trap compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof as an active ingredient. 19 · The pharmaceutical composition according to item 1 of the scope of patent application, wherein R1 is a 2-methylcyclopropylmethyl group; R2 is a methyl group; R3 is a methyl group or a hydroxymethyl group; R4 is a hydrogen atom; R5 For 1 to 2 substitutions: Self-affinity substitution is based on 1 to 2 phenyl groups substituted at substitution positions selected from the 2-, 4-, and 6-positions; A is a methylene group; X is a pyrrole of an oxygen atom As the active ingredient, a dada compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof is used. -33-200418479 2 0. The pharmaceutical composition according to item 1 of the scope of patent application, which is a compound in which R 1 is (1 S, 2 S)-2-methylcyclopropylmethyl; R2 is methyl; R3 is a methyl group or a hydroxymethyl group; R4 is a hydrogen atom; R5 is a phenyl group which can be substituted by 1 or 2 substitutions selected from fluorine and chlorine based on a 4-position or a 2,4-position; A is a methylene group Group; X is a pyrrole trap compound of oxygen atom, and a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is used as an active ingredient. 21. The pharmaceutical composition according to item 1 of the scope of patent application, which is selected from the group consisting of: 7- (4-fluorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2- Methylcyclopropylmethyl] pyrrolo [2,3-d] Daqin, 7- (2,4-difluorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] Da-tung, 7- (4-chlorobenzyloxy) -2,3-dimethyl-l-[(lS, 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] daco, 7- (4-fluorobenzyloxy) -3-hydroxymethyl-2 -methyl-l-[(lS , 2S) -2-methylcyclopropylmethyl] pyrrolo [2,3-d] datrap, 7- (2,4-difluorobenzyloxy) -3-hydroxymethyl-2 -methyl -l-[(lS, 2S) -2 -methylcyclopropylmethyl] pyrrolo [2,3-d] daquin, 7- (4-chlorobenzyloxy) -3-hydroxymethyl-2 -Methyl-l-[(lS, 2S) -2 -methylcyclopropylmethyl] pyrrolo [2,3-d] dacro, 1- (2-butenyl) -7- (4- Fluorobenzyloxy) -2,3-dimethylpyrrolo [2,3-d] Dagon, and 1- (2-butenyl) -7- (2,4-difluorobenzyloxy)- As a active ingredient, a pyrrolopyraganium compound of 2,3 -dimethylpyrrolo [2,3-d] datrapeptide is a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof. 22. The pharmaceutical composition according to item 1 of the scope of patent application, which is selected from the group consisting of:-34- 200418479 7- (4-fluorobenzyloxy) -2,3-dimethyl- l-[(lS, 2S ) -2 -Methylcyclopropylmethyl;] Homopyrolo [2,3-d] Da, 7- (4-fluorobenzyloxy) -3 -hydroxymethyl-2-methyl-1 -[(lS, 2S) -2 -methylcyclopropylmethyl] pyrrolo [2,3-d] datrap, 1- (2-butane; (¾yl) -7- (4-fluvaloxo ) -2,3-dimethyl B than the benzo [2,3-d] column, and 1- (2-butanyl) -7- (2,4-di_pentoxy) -2 2,3-Dimethylzhuang and [2,3- (1] cultivating pyrrolopyrachidine compound, its pharmaceutically acceptable salt or its pharmaceutically acceptable ester as the active ingredient. 23. As the first item in the scope of patent application The pharmaceutical composition is 7- (4-fluorobenzyloxy) _2,3-dimethyl-1-[(13,23) -2-methylcyclopropylmethyl] pyrrolo [2 , 3- (1) pyrrolopyrrolo compound, its pharmaceutically acceptable salt or its pharmaceutically acceptable ester as an active ingredient. 24. If a pharmaceutical composition according to any one of claims 1 to 23, Visceral pain is visceral pain accompanied by ulcerative diseases. 25 · —Applicable patent scopes 1 to The use of the piraclopidine compound, the pharmaceutically acceptable salt thereof, or the pharmaceutically acceptable ester thereof according to any one of 23 items, which is used for manufacturing a pharmaceutical composition capable of treating or preventing visceral pain. Use of item 25 of the scope, in which visceral pain is visceral pain accompanied by ulcerative diseases. 27. A method for treating or preventing visceral pain, which is to administer an effective amount of warm-blooded animals such as those in the scope of patent applications 1 to 23 The pyrrolopyrachidine compound according to any one of the above items, a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof. 28. The method according to item 27 of the patent application, wherein the visceral pain is accompanied by ulcerative disease -35-200418479 Visceral pain. 29. The method according to any one of items 27 to 28 of the scope of patent application, wherein the warm-blooded animal is a human. -36- 200418479 柒, designated representative map: none (1) The designated representative map in this case is: ( ). (II) Brief description of the representative symbols of the components in this representative diagram: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: