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

Pharmaceutical compositions for the treatment or prevention of visceral pains Download PDF

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TW200418479A
TW200418479A TW092126426A TW92126426A TW200418479A TW 200418479 A TW200418479 A TW 200418479A TW 092126426 A TW092126426 A TW 092126426A TW 92126426 A TW92126426 A TW 92126426A TW 200418479 A TW200418479 A TW 200418479A
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pharmaceutically acceptable
group
compound
pharmaceutical composition
acceptable salt
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TW092126426A
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Chinese (zh)
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Keiichi Ito
Kazuya Kinoshita
Masahiko Hagihara
Nobuhiko Shibakawa
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Sankyo Co
Ube Industries
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 玖、發明說明： (一） 發明所屬之技術領域 本發明係關於治療或預防（特別是治療）內臟痛（特別是潰瘍性疾 病伴隨之內臟痛）之醫藥組成物，其包括具有特定化學構造之吡咯并 塔哄（pyrrolopyridazine)化合物，其醫藥可接受鹽或其醫藥可接受 酯爲有效成分；關於具有特定化學構造之吡咯并嗒畊化合物，其醫藥 可接受鹽或其醫藥可接受酯之使用，以製造可治療或預防（特別是治 療）內臟痛（特別是潰瘍性疾病伴隨之內臟痛）之醫藥組成物；或關於 治療或預防（特別是治療）內臟痛（特別是潰瘍性疾病伴隨之內臟痛）之 方法，其係對溫血動物（尤其是人類）投與有效量具有特定化學構造之 吡咯并嗒哄化合物，其醫藥可接受鹽或其醫藥可接受酯。 (二） 先前技術 歐克薩寧（oxethazame)類消化道黏膜局部麻醉劑、司可達明 丁基溴（s c 〇 p d a m i n e b u t y 1 b 1· 〇 m i d e)類鎭痙攣劑已知用於作爲抑制 內臟痛（內臟痙攣或運動機能亢進導致之疼痛）之藥劑。但已知這些內 臟痛治療藥會出現便秘或頭痛等副作用。另一方面，具有特定化學構 造之吡咯并嗒畊化合物，已知具有胃酸分泌抑制作用（例如 WO 9 5/ 1 99 80 ， EP07422 1 8 ， WO00/77 003 ， EP 1 1 86607 ， W0 0 1 /5 890 1等），但不知其具有內臟痛抑制作用。 (三） 發明內窓 發明之掲示 本案發明者發現具有特定化學構造之吡咯并嗒阱化合物，對於 下部消化道之內壓上升或管腔擴張伴隨之內臟痛具有優異的抑制作 用，故可作爲便秘或頭痛等副作用小之內臟痛（特別是潰瘍性疾病伴 200418479 隨之內臟痛）治療或預防用藥（特別是治療）而完成本發明。 本發明提供治療或預防（特別是治療）內臟痛（特別是潰瘍性疾病 伴隨之內臟痛）之醫藥組成物，其包括具有特定化學構造之啦咯并塔 哄化合物，其醫藥可接受鹽或其醫藥可接受酯爲有效成分；提供具有 特定化學構造之吡咯并嗒哄化合物，其醫藥可接受鹽或其醫藥可接受 酯之使用，以製造可治療或預防（特別是治療）內臟痛（特別是潰瘍性 疾病伴隨之內臟痛）之醫藥組成物；或提供治療或預防（特別是治療） 內臟痛（特別是潰瘍性疾病伴隨之內臟痛）之方法，其係對溫血動物（尤 其是人類）投與有效量具有特定化學構造之批略并塔哄化合物，其醫 藥可接受鹽或其醫藥可接受酯。 本發明之有效成分吡咯并嗒畊化合物具有一般式（I):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):

式中R1爲C2-C6M基’鹵C2-C6燒基，（1!2-06炔基，C3-C7環院基 或可經C「C4烷基取代之（C3-C7環烷基）-C「C6烷基； R2爲氫原子或C「C6院基； R3爲氫原子，C「C6烷基或羥基Ci-q烷基； R4爲氫原子或C「C6烷基； R5爲可經選自CVC6烷基，鹵CVC6烷基，CVC6烷氧基，鹵ίν(：6 院氧基以及鹵素之取代基取代之苯基； A爲C ! - C 3伸垸基； 200418479 x爲氧原子或硫原子。 上記一般式（I)中R1可爲C2-C6烯基或鹵c2-c6烯基之C2-C6 烯基部分，例如爲乙烯基，1 -丙烯基，2 -丙烯基，異丙烯基，1 - 丁 烯基，2-丁烯基，3-丁烯基，1-甲基-1-丙烯基，1-甲基-2-丙烯基， 2-甲基-1-丙烯基，2-甲基-2-丙烯基，1-戊烯基，2-戊烯基，3-戊 烯基，4-戊烯基，1-甲基-1-丁烯基，2-甲基-2-丁烯基，3-甲基-2-丁烯基，1-己烯基，2-己烯基，丙-1，2-二烯基，丁-1，2-二烯基，戊 -1,2-二烯基或己-1，2-二烯基；較佳爲C2-C4烯基（特別是乙烯基，卜 丙烯基，2-丙烯基，異丙烯基，1-丁烯基，2-丁烯基或3-丁烯基）； 更佳爲C3-C4烯基；最佳爲2-丙烯基或丁烯基。 R1爲鹵C2-C6烯基例如可爲2,2-二氟乙烯基，3-氟-2-丙烯基， 2-氯-2-丙烯基，3-氯-2-丙烯基，3-溴-2-丙烯基，3-碘-2-丙烯基， 3,3-二氟-2-丙烯基，2,3-二氯-2-丙烯基，3,3-二氯-2-丙烯基，2,3-二溴-2-丙烯基，3,3-二溴-2-丙烯基，4,4,4-三氟-2-丁烯基，5-氟-2-戊烯基或6-氟-2-己烯基；較佳爲氟或氯C2-C4烯基；更佳爲2,2-二氟乙烯基，3-氟-2-丙烯基，3-氯-2-丙烯基，2-氯-2-丙烯基，3，3-二氟-2-丙烯基，3,3-二氯-2-丙烯基，4,4,4-三氟-2-丁烯基；最佳 爲3-氯-2-丙烯基，3，3-二氯-2-丙烯基或4,4,4-三氟-2-丁烯基。 R1爲C2-C6炔基例如可爲乙炔基，2-丙炔基，2-丁炔基，2-戊 炔基或2-己炔基；較佳爲C2-C4炔基；最佳爲2-丙炔基。 R1爲C3-C7環烷基或可經烷基取代之（C3-C7環烷基）-烷基之C3-C7環烷基部分，例如可爲環丙基，環丁基，環戊基， 環己基或環庚基；較佳爲C3-C6環烷基，更佳爲環丙基或環己基； 最佳爲環丙基。 ’ 200418479 R]爲可經cvc4烷基取代之（c3-c7環烷基）-CVC6烷基之c「 04烷基部分，例如可爲甲基，乙基，丙基，異丙基，丁基，異丁基 或第三丁基；較佳爲甲基或乙基；最佳爲甲基。 R1爲可經CVC4烷基取代之（c3-c7環烷基）-CVC6烷基之（V C6烷基部分，R2、R3及R4之CVC6烷基，R3爲羥基CVC6烷基之 (：「(：6烷基部分，或R5爲可經選自CVC6烷基、鹵CVC6烷基、（：「(：6 烷氧基、鹵Ci-C^烷氧基以及鹵素之取代基取代之苯基之烷 基部分或鹵烷基之Ci-Ce烷基部分，例如可爲甲基，乙基， 丙基，異丙基，丁基，異丁基，第三丁基，戊基或己基；較佳爲C^ C4烷基；更佳爲甲基或乙基；最佳爲甲基。 R1爲可經烷基取代之（C3-C7環烷基ICi-q烷基，例如 可爲環丙基甲基，1-甲基環丙基甲基，2-甲基環丙基甲基，2-乙基 環丙基甲基，環丁基甲基，環戊基甲基，環己基甲基，甲基環己基甲 基，環庚基甲基，2-環丙基乙基，3-環丙基丙基，4-環丙基丁基，5-環丙基戊基或6-環丙基己基；較佳爲可經烷基取代之（C3-C7 環烷基烷基；更佳爲環丙基甲基，1-甲基環丙基甲基，2 -甲 基環丙基甲基，環丁基甲基，環戊基甲基，環己基甲基或2-環丙基 乙基；又更佳爲2 -甲基環丙基甲基；最佳爲（lS，2S)-2 -甲基環丙基 甲基。 R3爲羥基C ! - C 6院基例如可爲經甲基，經乙基，經丙基，經丁 基，羥戊基或羥己基；較佳爲羥基C ! - C 4烷基羥甲基；更佳爲羥甲 基或1 -經乙基；最佳爲經甲基。 R5爲可經選自CVC6院基、鹵院基、c「C6院氧基、鹵 C「C6烷氧基以及鹵素之取代基取代之苯基之烷氧基部分或鹵 -10- 200418479 C「c6烷氧基之c「c6烷氧基部分，例如可爲甲氧基，乙氧基，丙氧 基’異丙氧基，丁氧基，異丁氧基，第三丁氧基，戊氧基或己氧基； 較佳爲〔^匕烷氧基；更佳爲甲氧基或乙氧基；最佳爲甲氧基。 R5爲可經選自CVC6烷基、鹵CVC6烷基、c「c6烷氧基、鹵 烷氧基以及鹵素之取代基取代之苯基之鹵素，例如可爲氟，氯， 溴或碘；較佳爲氟或氯；最佳爲氟。 R5爲可經選自CVC6烷基、鹵CVC6烷基、c「c6烷氧基、鹵 C「c6烷氧基以及鹵素之取代基取代之苯基之鹵〔「匕烷基部分，例 如可爲氟甲基，氯甲基，二氟甲基，三氟甲基，2-氟乙基，2-氯乙 基，2-溴乙基，2-碘乙基，2,2,2-三氟乙基，3-氟丙基，4-氟丁基， 5-氟戊基或6-氟己基；較佳爲鹵CrG烷基；最佳爲三氟甲基。 R5爲可經選自CVC6烷基、鹵CVC6烷基、Κ6烷氧基、鹵 C「C6烷氧基以及鹵素之取代基取代之苯基之鹵C「C6烷氧基部分， 例如可爲氟甲氧基，二氟甲氧基，三氟甲氧基，2-氟乙氧基，2-氯 乙氧基，2-溴乙氧基，2-碘乙氧基，2,2,2-三氟乙氧基，3-氟丙氧基， 4-氟丁氧基，5-氟戊氧基或6-氟己氧基；較佳爲鹵Ci-C^烷氧基； 最佳爲二氟甲氧基。 R5之苯基的取代基數例如爲1至5個，較佳爲1至3個，更佳 爲1至2個，最佳爲1個。 R5之苯基的取代位置例如爲2至6位，較佳爲2、4或6位， 更佳爲2或4位，最佳爲4位。 R5爲可經選自CVC6烷基、鹵CVC6烷基、C「C6烷氧基、鹵 CVC6烷氧基以及鹵素之取代基取代之苯基，例如可爲苯基，甲基苯 基，三氟甲基苯基，·甲氧基苯基，三氟甲氧基苯基，二氟甲氧基苯基， -11 - 200418479 氟苯基，氯苯基，溴苯基，二氟苯基，氯氟苯基，二氯苯基，三氟苯 基或三氯苯基；較佳爲可經1至3個選自烷基、鹵Ci-q烷 基、烷氧基、鹵c「c4烷氧基、氟、氯以及溴之取代基取代之 苯基；更佳爲可經1至3個選自甲基、三氟甲基、甲氧基、三氟甲 氧基、二氟甲氧基、氟、氯以及溴之取代基取代之苯基；又更佳爲可 經1至3個選自氟及氯之取代基於1至3個選自2位、4位及6位 之取代位取代之苯基（特別是2-或4-氟苯基，2-或4-氯苯基，2,4-或2,6-二氟苯基，2,4-或2,6-二氯苯基，4-氯-2-氟苯基，2-氯-4-氟苯基，2-氯-6-氟苯基，2,4,6-三氟苯基或2,4,6-三氯苯基）；又 進一步更佳爲4-氟苯基，4-氯苯基，2，4-二氟苯基，2，4-二氯苯基， 4-氯-2-氟苯基或2-氯-4-氟苯基；特佳爲4-氟苯基，4-氯苯基或2,4-二氟苯基；最佳爲4-氟苯基。 A爲伸烷基例如可爲亞甲基，伸乙基，伸丙基，1-甲基 伸乙基或2-甲基伸乙基；較佳爲亞甲基。 X較佳爲氧原子。 本發明之有效成分一般式（I)所示之吡咯并嗒畊化合物具有鹼性 基’與酸處理後可形成醫藥可接受鹽，此等鹽亦包含於本發明。此等 鹽例如氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽等之氫鹵酸鹽，硝酸 鹽，過氯酸鹽，硫酸鹽，磷酸鹽，碳酸鹽，甲磺酸鹽、三氟甲磺酸鹽、 乙磺酸鹽、五氟乙磺酸鹽、丙磺酸鹽等可經氟原子取代之Cl_c6烷 基磺酸鹽，苯磺酸鹽、對-甲苯磺酸鹽、萘磺酸鹽等之C6-C1Q芳基磺 酸鹽，醋酸鹽、三氟乙酸鹽、丙酸鹽、丁酸鹽、苯甲酸鹽、草酸鹽、、 丙二酸鹽、反-丁烯二酸鹽、順-丁烯二酸鹽、琥珀酸鹽、檸檬酸鹽、 酒石酸鹽等之羧酸鹽，或麩胺酸鹽或天冬胺酸鹽類之胺基酸鹽等；較 -12- 200418479 佳爲氫鹵酸鹽，硫酸鹽，c 6 - c! 〇芳基磺酸鹽或羧酸鹽；更佳爲鹽酸 鹽，硫酸鹽，苯磺酸鹽，對-甲苯磺酸鹽，Θ -萘磺酸鹽或反_ 丁烯二 酸鹽；最佳爲對-甲苯磺酸鹽或反-丁烯二酸鹽。 本發明之有效成分一般式（I)所不之壯咯并塔哄化合物中具有經 基之化合物，可依據常用方法經由醯基化可形成醫藥可接受酯，此等 酯亦包含於本發明。此等酯例如與甲酸、乙酸、丙酸、丁酸、丙條酸、 丁烯酸、丙炔酸等脂肪族單羧酸之酯，與反-丁烯二酸、順-丁烯二酸、 草酸、丙二酸、號珀酸等脂肪族二殘酸之醋，與苯甲酸、甲基苯甲酸、 甲氧基苯甲酸、氟苯甲酸、氯苯甲酸等芳香族羧酸之酯，與甲磺酸、 三氟甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等磺酸之酯，與麩胺酸、天 冬胺酸等胺基酸之酯，與碳酸單甲酯、碳酸二甲酯、碳酸單乙酯、碳 酸二乙酯、碳酸單丙酯、碳酸單丁酯、碳酸單苯酯、碳酸二苯酯等碳 酸酯類之酯，或與磷酸、磷酸單甲酯、磷酸二甲酯、磷酸單乙酯、憐 酸二乙酯、磷酸單苯酯、磷酸二苯酯等磷酸類之酯；較佳爲與脂肪族 單羧酸之酯，與脂肪族二羧酸之酯或與芳香族羧酸之酯；最佳爲與 。脂肪族單羧酸之酯。 本發明之有效成分一般式（I)所示之吡咯并嗒阱化合物，可以水 合物或溶劑合物存在，其個別或彼等之混合物皆包含於本發明。 本發明之有效成分一般式（I)所示之吡咯并嗒畊化合物，可存在 光學異構物或/及幾何異構物，其各別或彼等之混合物皆包含於本發 明。 本發明之內臟痛可爲各種疾病伴隨之內臟痙攣或運動機能亢進 導致之疼痛，引起內臟痛之疾病例如食道炎、胃炎、腸炎、胃潰瘍、 十二指腸潰瘍、過敏性大腸症、膽囊炎、膽管炎、膽結石、尿道結石、 200418479 或膀胱炎等等。本發明之有效成分—般式⑴所示之壯咯并塔哄化合 物，可使用作爲這些疾病（特別是食道炎、胃炎、胃潰瘍、十二指腸 潰瘍等潰瘍性疾病）伴隨之內臟痛的預防或治療用藥（特別是治療）。 本發明一般式（1)所示吡咯并嗒哄化合物，較佳爲上述一般式（1) 中·· (1) R1爲C2-C4烯基，氟或氯C2-C4烯基，2_丙炔基，C3_C6 環;)：兀基或可經Ci-C：2烷基取代之（C^C：6環烷基）_Ci_C4烷基之化合 物； (2) ν爲乙烯基，卜丙稀基，2 -丙烯基，異丙燃基，1_丁燦基， 2-丁烯基，3· 丁烯基，2,2-二氟乙烯基，3-氟-2-丙烯基，3-氯-2-丙烯基，2-氯-2-丙烯基，3，3-二氟-2-丙烯基，3,3 _二氯_2_丙烯基， 4,4,4 -二氟-2-丁烯基，環丙基，環己基，環丙基甲基，卜甲基環丙 基甲基，2 -甲基環丙基甲基，環丁基甲基，環戊基甲基，環己基甲基 或2 -環丙基乙基之化合物； (3) 111爲2-甲基環丙基甲基之化合物； (BR1爲（lS，2S)-2-甲基環丙基甲基之化合物； (5) R2爲氫原子或（^-匕烷基之化合物； (6) R2爲甲基之化合物； (7) R3爲氫原子，C「C4烷基或羥基C「C4烷基之化合物； (8) R3爲甲基或羥甲基之化合物； (9) R4爲氫原子之化合物； (10) R5爲可經1至3個選自C「C4烷基，鹵C「C4烷基，C「 C4烷氧基，鹵烷氧基，氟，氯及溴之取代基取代之苯基之化 合物； -14- 200418479 (11) R5爲可經1至3個選自甲基，三氟甲基，甲氧基，三氟甲 氧基，二氟甲氧基，氟，氯及溴之取代基取代之苯基之化合物； (12) R5爲可經1至2個選自氟及氯之取代基於1至2個選自2 位、4位及6位之取代位取代之苯基之化合物； (13) R5爲可經1至2個選自氟及氯之取代基於4位或2,4-位 之取代位取代之苯基之化合物； (14) A爲亞甲基之化合物； (15) X爲氧原子之化合物。 再者，任意組合選自（1)至（4)之R1，選自（5)至（6)之R2，選 自（7)至（8)之R3，選自（9)之R4，選自（10)至（13)之R5，選自（14) 之A，以及選自（15)之X所得之化合物更佳，例如以下之化合物更 佳： (16) 111爲C2-C4烯基，氟或氯C2-C4烯基，2-丙炔基，C3-C6 環烷基或可經（^-(：2烷基取代之（C3-C6環烷基烷基；R2爲 氫原子或C「C4烷基；R3爲氫原子，烷基或羥基C「C4烷基； R4爲氫原子；R5爲可經1至3個選自CVC4烷基，鹵CVC4烷基， 烷氧基，·鹵Ci-G烷氧基，氟，氯及溴之取代基取代之苯基； A爲亞甲基；X爲氧原子之化合物； (17)ν爲乙烯基，卜丙烯基，2-丙烯基，異丙烯基，1-丁烯 基，2-丁烯基，3-丁烯基，2,2-二氟乙烯基，3-氟-2-丙烯基，3-氯-2-丙烯基，2-氯-2-丙烯基，3,3-二氟-2-丙烯基，3,3-二氯-2-丙烯 基，4,4,4 -三氟-2-丁稀基，環丙基，環己基，環丙基甲基，1-甲基 環丙基甲基，2-甲基環丙基甲基，環丁基甲基，環戊基甲基，環己基 甲基或_ 2-環丙基乙基；R2爲甲基；R3爲甲基或羥甲基；R4爲氫原 200418479 子；R5爲可經1至3個選自甲基，三氟甲基，甲氧基，三氟甲氧基， 二氟甲氧基，氟，氯及溴之取代基取代之苯基；A爲亞甲基；X爲氧 原子之化合物； (18) 111爲2-甲基環丙基甲基；R2爲甲基；R3爲甲基或羥甲基； R4爲氫原子；R5爲可經1至2個選自氟及氯之取代基於1至2個選 自2位、4位及6位之取代位取代之苯基；A爲亞甲基；X爲氧原子 之化合物； (19) 111爲（lS，2S)-2-甲基環丙基甲基之化合物；R2爲甲基；R3 爲甲基或羥甲基；R4爲氫原子；R5爲可經1至2個選自氟及氯之取 代基於4位或2,4-位之取代位取代之苯基；A爲亞甲基；X爲氧原 子之化合物； (20) 選自下列之吡咯并嗒哄化合物： 7-(4-氟苄氧基）-2,3-二甲基-l-[(lS,2S)-2-甲基環丙基甲基]吡咯并 [2,3-d]嗒畊； 7-(2,4-二氟苄氧基）-2,3-二甲基-l-[(lS，2S)-2-甲基環丙基甲基]吡 咯并[2,3-d]嗒畊； 7-(4-氯苄氧基）-2,3-二甲基-l-[(lS,2S)-2-甲基環丙基甲基]吡咯并 [2,3-d]嗒畊； 7-(4-氟苄氧基）-3-羥甲基-2 -甲基-l-[(lS,2S)-2 -甲基環丙基甲基] 吡咯并[2,3-d]嗒畊； 7-(2,4-二氟苄氧基）-3-羥甲基-2-甲基-l-[(lS，2S)-2-甲基環丙基甲 基]吡咯并[2,3-d]嗒畊； 7-(4-氯苄氧基）-3-羥甲基-2 -甲基-l-[(lS,2S)-2-甲基環丙基甲基] 吡咯并[2,3-d]嗒畊； -16- 200418479 1-(2-丁烯基）-7-(4-氟苄氧基）-2,3-二甲基吡略并[2,3-d]嗒阱；以 及 1-(2 -丁烯基）-7-(2,4 - —氟平氧基）-2,3 - 一甲基口比略并[2,3-d] 口荅 阱； (2 1)選自下列之吡咯并嗒畊化合物： 7_(4_氟苄氧基）-2,3-二甲基-M(lS，2S)-2-甲基環丙基甲基]吡咯并 [2,3-d]嗒畊； 7-(4-氟苄氧基）-3-羥甲基-2-甲基-l-[(lS,2S)-2-甲基環丙基甲基] 吡咯并[2,3-d]嗒哄； 1-(2-丁烯基）-7-(4-氟苄氧基）-2,3-二甲基吡咯并[2,3-d]嗒畊；以 及 1-(2-丁烯基）-7-(2,4 -二氟苄氧基）-2,3-二甲基吡咯并[2,3-d]嗒 畊；或 (22) 選自下列之吡咯并嗒畊化合物： 7-(4-氟苄氧基）-2,3-二甲基-l-[(lS，2S)-2 -甲基環丙基甲基]吡咯并 [2,3-d]嗒畊。 本發明提供： (23) —種治療或預防（特別是治療）內臟痛之醫藥組成物，其包 括一般式（I)所示吡略并嗒哄化合物[特別是上述（1)至（2 2)中任一記 載之化合物]，其醫藥可接受鹽或其醫藥可接受酯爲有效成分； (24) 記載於（23)之醫藥組成物，其中內臟痛爲潰瘍性疾病伴隨 之內臟痛； (25 ) —種一般式（I)所示吡咯并嗒阱化合物[特別是上述（1)至 〔22)中任一記載之化合物]，其醫藥可接受鹽或其醫藥可接受酯之使 -17- 200418479 用，以製造可治療或預防（特別是治療）內臟痛之醫藥組成物； (2 6)記載於（2 5 )之使用，其中內臟痛爲潰瘍性疾病伴隨之內臟 痛； (27) —種治療或預防（特別是治療）內臟痛之方法，其係對溫血 動物投與有效量之一般式（I)所示吡咯并嗒畊化合物[特別是上述（i) 至（22)中任一記載之化合物]，其醫藥可接受鹽或其醫藥可接受酯； (28) 記載於（27)之方法，其中內臟痛爲潰瘍性疾病伴隨之內臟 痛； (29) 記載於（27)至（28)中任一項之方法，其中溫血動物爲人# 類。 本發明有效成分一般式（I)所示吡咯并嗒畊化合物中，較佳化合 物可如表1所示之化合物，但本發明不限定於這些化合物。此外， 表1記載之化合物具有一般式（II)所示結構。 [表1 ]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- 200418479-18- 200418479

例示化合物 編號 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 0Exemplified 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] H M€ H 4-FPh 0 52 αΗ5[(Ι5,2$)-2-Μ6ΡΓ€] Me H H 4-FPh 0 53 CB2[(IS,2S)-2-M€Prc] Me Me H 4-BrPli 0 54 CH2[(lS,2S)-2，ePre] Me Me H 4~0CF3Ph 0 55 CH2[(lS,2S)-2-MePrc] Me Me H 2,6-diFPh 0 56 CH2[(lS,2S)-2-MePrc] Me Me H 2,6-diClPh 0 57 CHddSJS)-2-MePrc] Me Me H 2,4,6-triFPh 0 5S CHjdS^SJ^-MePr^ Me Me H 2,4,6-triClPh 0 59 CHi[(lS,2S)+MePrc] Me Me H 2-a+FPh 0 60 CHjUlS^S 卜 2-MePre] Me Me H 2一c卜4-pph 0 61 CHjtilS, 2S)-2-MePr^] Me Me H 4-Cl-2-FPh 0 62 CH“2_MePrc) Me Me H 4-FPh s 63 CH,[(lS,2S)-2-MePr€] Me Me H 4~FPh s 64 CH2[{!S,2S)-2~MeP:rc3 Me Me H 2,4-diFPli s -20- 200418479 65 CH2[(lS,2S)-2-MePrc] Me Me H 4-C!Ph 66 CH3[(iS,2S)~2-M€Prc] Me Me H 2,4-diClPh 6? CH2[(iS，2S)+MePrc] Me ch2oh H 2-FPh 68 CH“2_MePrc) Me ch2oh H 4-FPli 69 CH^iOS, 2S)-2-MePrc] Me ch2oh H 4_FPh 70 CH2[(lS,2S)-2-M€Pr€] Me ch2oh H 2,4-diFPh 71 CHjtdS, 2S)-2-MePrJ] Me CH^OH H 2-CiPh 72 CH2[(lS,2S)-2-MePrc3 Me C_ H 4-ClPh 73 CH:[(lS,2S)-2-MePrc] Me ch2oh H 2,4-diClPh 74 ouasjsM.PKi Me CH20Ac H 2-FPh 75 CH2(2-MePrc) Me CH20Ac H 4-FPh 76 CH2[(lSt2S)-2-MePrc3 Me CH20Ac H 4-FPh 77 CH】[as,2S>—2-MePre] Me CH20Ac H 2,4-dIFPh 78 CH2[(IS,2S)-2-MePrc] Me CH20Ac H 4-ClPh 79 CH2[(lS,2S)-2-MePrc] Me CH20Ac H 2,4-diCIPh 80 CHdas,2S)+MePTl Me CHiOPrp H 4-FPh 81 CHjtdS, 2θ) -2-ΜβΡ^] Me C_ur H 4-FPh 82 CHj(2~MePrc) Me CHjOCOPh H 4-FPh 83 CH2t(lS,2S)-2-MePrc] Me CH:0C0Ph H 4-FPh 84 CHjaS, 2$)-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-CF3Ph 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 偶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-财”] 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 s200418479 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

上記表1中之簡寫符號代表以下各基。 Ac :乙醯基 B u . 丁基 Bu1 :異丁基The abbreviations in Table 1 above indicate the following bases. Ac: Ethyl butyl B u. Butyl Bu1: Isobutyl

Bur : 丁醯基 .22 - 200418479Bur: Ding Yingji .22-200418479

Bus :第二丁基Bus: Second butyl

Bul ••第三丁基Bul •• Third butyl

Et :乙基Et: ethyl

Hxe :環己基Hxe: cyclohexyl

Me :甲基Me: methyl

Ph :苯基 Ρ η ·戊基 P r :丙基Ph: Phenyl PηPentyl Pr: Propyl

Pre :環丙基Pre: Cyclopropyl

Prj :異丙基，以及Prj: isopropyl, and

Prρ :丙醯基。 上記表1中較佳之化合物爲例示化合物編號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 之 化合物。 更佳爲例示化合物編號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 之化合物。 進一步更佳爲例示化合物編號4、9、12、15、20、25、27、 31、55、56、60、61、63、69、70、72、73、76、77、78、108 -23 - 200418479 之化合物。 進一步更佳之化合物爲： 例示化合物編號4 : 1-(2-丁烯基）-7-(4-氟苄氧基）_2,3-二甲基P比略 并[2,3-d]嗒哄； 例示化合物編號9 : 7-(4-氟苄氧基）-2,3-二甲基-l-[(lS，2S)-2-甲 基環丙基甲基]吡咯并[2,3-d]嗒畊； 例示化合物編號12 : 1-(2-丁烯基）-7-(2,4-二氟；氧基）_2,3_二甲 基吡咯并[2,3-d]嗒阱； 例示化合物編號15 : 7-(2,4-二氟苄氧基）-2,3-二甲基-M(1S，2S)-2-甲基環丙基甲基]吡咯并[2,3-d]嗒哄； 例示化合物編號20 : 7-(4-氯苄氧基）-2,3-二甲基-M(lS，2S)-2-甲 基環丙基甲基]吡咯并[2,3-d]嗒畊； 例示化合物編號69 : 7-(4-氟苄氧基）-3-羥甲基-2-甲基-1-[(lS，2S)-2-甲基環丙基甲基]吡咯并[2,3-d]嗒畊； 例示化合物編號70 : 7-(2,4 -二氟苄氧基）-3 -羥甲基-2-甲基-卜 [(lS，2S)-2 -甲基環丙基甲基]吡咯并[2,3-d]嗒阱；或 例示化合物編號72 : 7-(4-氯苄氧基）-3-羥甲基-2-甲基-卜 [(13,23)-2-甲基環丙基甲基]吡咯并[2,3-(1]嗒哄。 特佳之化合物爲： 例示化合物編號4 : 1-(2-丁烯基）-7-(4-氟苄氧基）-2,3-二甲基吡咯 并[2，3 - d ]嗒畊； 例示化合物編號9 : 7-(4-氟苄氧基）-2,3-二甲基-M(lS,2S)-2-甲 基環丙基甲基]吡咯并[2,3-d]嗒阱； 例示化合物編號1 2 : 1 - (2 - 丁烯基）-7 - (2，4 -二氟苄氧基）-2,3 -二甲 -24 - 200418479 基吡咯并[2,3-d]嗒畊；或 例示化合物編號69 : 7-(4-氟苄氧基）-3-羥甲基-2-甲基-1_ [(1 S，2 S ) - 2 -甲基環丙基甲基]吡咯并[2，3 - d ]嗒阱。 最佳之化合物爲： 例示化合物編號9 : 7-(4-氟苄氧基）-2,3-二甲基-M(lS，2S)-2-甲 基環丙基甲基]D比略并[2,3-d]塔哄。 本發明之有效成分一般式（I)所示之吡咯并嗒哄化合物可依照公 知 之方法[例如 WO9 5/ 1 99 80( = EP-07422 1 8A)， W〇00/77003( = EP-1 1 86607A)]或按照此等方法輕易地製造。 本發明之有效成分一般式（I)所示之吡咯并嗒畊化合物中具有羥 基之化合物，可如前述依據常用方法經由醯基化製造其醫藥可接受 酯。亦即可於惰性溶劑中將具有羥基之化合物與相當之醯基鹵或酸酐 在鹼基存在下依據常用方法反應，製造其醫藥可接受酯（例如 W0 01/58901 公報等）。 使用本發明之有效成分一般式（I)所示吡咯并嗒畊化合物，其醫 藥可接受鹽或其醫藥可接受酯作爲藥劑時，可以其自體（原始狀態）形 式投與有效成分，或與醫藥可接受賦形劑、稀釋劑等混合爲可經口投 與之錠劑、膠囊劑、顆粒劑、散劑或糖漿劑等製劑，或可非經口投與 之注射劑或坐劑等製劑（較佳爲經口投與）。 這些製劑是使用賦形劑、結合劑、崩散劑、潤滑劑、乳化劑、 安定劑、矯味矯臭劑、稀釋劑、注射劑用溶劑等添加劑，經由周知之 方法製造。 賦形劑例如乳糖、白糖、葡萄糖、甘露醇、山梨糖醇類之糖衍 生物；玉米澱粉、馬鈴薯澱粉、α澱粉、糊精、羧甲基澱粉類之澱粉 -25 - 200418479 衍生物；結晶纖維素、低取代程度之羥丙基纖維素、羥丙基甲基纖維 素、羧甲基纖維素、羧甲基纖維素鈣、交叉羧甲基纖維素鈉類之纖維 素衍生物；***膠樹；葡聚糖；桂櫻苷（Pluran);輕質無水矽酸、 合成矽酸鋁、矽酸鈣、矽酸鋁酸鎂類之矽酸鹽衍生物；磷酸鈣類之磷 酸鹽衍生物；碳酸鈣類之碳酸鹽衍生物；或硫酸鈣類之硫酸鹽衍生物 等等。 崩散劑可例如上述之賦形劑；交叉羧甲醚纖維素鈉 (croscarmelose sodium)、羧甲基澱粉鈉類經化學修飾之澱粉或纖 維衍生物；或交叉聚乙烯吡咯烷酮等等。 潤滑劑例如滑石；硬脂酸；硬脂酸鈣、硬脂酸鎂類之硬脂酸金 屬鹽；二氧化砂膠體；蜂膠（b e e g u m)、鯨織等之蠟類；硼酸；乙二 醇；D，L -白胺酸；己二酸類之羧酸類；安息香酸鈉類之羧酸鈉鹽； 硫酸鈉類之硫酸鹽；月桂基硫酸鈉、月桂基硫酸鎂類之月桂基硫酸鹽； 無水矽酸、矽酸水合物類之矽酸鹽；以及上記賦形劑中之澱粉衍生物 等等。 乳化劑例如皂土、蜂膠類之膠體性黏土；氫氧化鎂、氫氧化鋁 類之金屬氫氧化物；月桂基硫酸鈉、硬脂酸鈣類之陰離子界面活性劑； 氯化烷銨類之陽離子界面活性劑；以及聚羥乙烯烷基醚、聚羥乙燦山 梨糖醇酐脂肪酸酯、蔗糖脂肪酸酯類之非離子界面活性劑等等。 安定劑例如對-羥基苯甲酸甲酯、對-羥基苯甲酸丙酯類之對_經 基苯甲酸酯類·，氯丁醇、苄醇、苯乙醇類之醇類；氯化院錢；_、甲 酚類之酚類；乙基汞硫代水楊酸鈉；無水醋酸；或山梨酸等等。 矯味矯臭劑例如常使用之甘味料、酸味料或香料等等。 稀釋劑例如水，乙醇’丙二醇，乙氧化異硬脂醇或聚氧乙烯山 -26- 200418479 梨糖醇酐脂肪酸酯類等等。 注射用溶劑例如水，乙醇，甘油等等。 本發明一般式（I)所示吡咯并嗒哄化合物，其醫藥可接受鹽或其 醫藥可接受酯可投與到溫血動物（尤其是人類），投與量依據各個藥劑 的活性、患者症狀、年齡、體重等種種條件變化得到。 此投與量因症狀、年齡等不同而經口投與時，對成人投與每次 下限爲O.lmg(較佳0.5mg)，上限爲lOOOmg(較佳500mg)，非經 口投與時每次下限爲O.Olmg(較佳0.05mg)，上限爲l〇〇mg(較佳 5 Omg)，可視症狀每曰投與1至6次。 再者，本發明之有效成分一般式（I)所示吡咯并嗒畊化合物，其 醫藥可接受鹽或其醫藥可接受酯，由於具有自體胃酸分泌抑制作用， 因此用於作爲食道炎、胃炎、胃潰瘍、十二指腸潰瘍等潰瘍性疾病伴 隨之內臟痛的治療或預防用醫藥組成物時，可期待同時具有內臟痛的 治療或預防效果，以及潰瘍性疾病的治療或預防效果。 本發明之有效成分一般式（I)所示之Pit咯并塔哄化合物，其醫藥 可接受鹽或其醫藥可接受酯，對於下部消化道之內壓上升或管腔擴張 伴隨之內臟痛具有優異的抑制作用，故可作爲便秘或頭痛等副作用小 之溫血動物用（特別是人類用）之內臟痛（特別是食道炎、胃炎、胃潰 瘍、十二指腸潰瘍等潰瘍性疾病伴隨之內臟痛）的預防或治療用藥。 LB)實施方式 [實施本發明之最佳態樣] 以下以試驗例及製劑例更進一步詳細舉例說明本發明，但本胃 明範圍不因此限定於此。 1)內臟痛評僭試驗 200418479 改變 Banner 等人之方法（Br. J. Pharmacol.，1995 年第 114 卷，P.5 5 8 )實施本試驗。一組6至7隻大鼠禁食一晚後，以戊巴比 妥鈉麻醉，切開腹部正中部位的皮膚，將用於觀察腹直肌收縮運動之 強度轉換器縫附於腹直肌。從肛門1公分內側的直腸***接連於內 壓偵測用轉換器的氣球，然後固定此位置。將大鼠放入固定氣球之籠 內。大鼠從麻醉覺醒後，以〇.〇8ml/min的速度注入水到氣球內，同 時觀察氣球內壓及腹直肌的收縮。氣球內壓上升伴隨直腸擴張時，看 到之最初腹直肌的收縮之氣球內壓閾値作爲內臟痛的指標。 以每1公斤體重平均經口投與2ml之7-(4-氟苄氧基）-2,3-二 β 甲基-1-[(13,23)-2-甲基環丙基甲基]吡咯并[2,3-(1]嗒哄懸浮液〔例 示化合物編號9之化合物：W〇00/77003 ( = EP- 1 1 86607A)實施例1 記載之化合物：以下稱爲化合物（III)〕懸浮於0.5%羧甲基纖維素鈉 鹽及0.4%聚山梨酸酯80水溶液而成爲1.5至5mg/kg濃度之懸浮 液’ 1、2及3小時後測定氣球內壓。使用懸浮介質作爲對照組。以 杜納特法（Dunnett)檢討投與前後內壓閾値之有意義差異。 表2顯示化合物（III)及投與介質投與後之氣球內壓閾値推移。 φ 如表2所示，對照組未看到投與後之氣球內壓閾値變化，而化合物（ΠΙ) 投與組看到投與後用量依賴性之有意義的內壓閾値上升。 -28- 200418479 [表2] 內壓閾値（mmHg) 例數 投與前 1小時後 2小時後 3小時後 對照組 7 7.04 9.5 1 9.66 6.29 化合物（III)投與 6 7.62 13.1 14.1 11.8 組 3mg/kg 化合物（III)投與 6 7.20 16.3 23.0 19.3 組 1 0 m g / k g 依據以上結果，化合物（III)對於下部消化道之內壓上升、管腔 擴張伴隨之內臟痛具有優異的抑制作用，因此本發明之有效成分p比咯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

并嗒畊化合物可作爲內臟痛之預防或治療用藥。 (製劑例Π綻劑 將化合物（111)(30.〇1112)，乳糖（144.〇111£)，玉米源粉 (2 5 · 0 m g)，以及硬脂酸鎂（1 · 〇 m g)混合，經由打錠機打錠爲1錠 200mg之錠劑。此錠劑可視需要施予塗覆（較佳爲糖衣）。 產業上可利用件 本發明之有效成分一般式（I)所示之吡咯并嗒阱化合物，其醫藥 可接受鹽或其醫藥可接受酯，對於下部消化道之內壓上升或管腔擴張 伴隨之內臟痛具有優異的抑制作用，故可作爲便秘或頭痛等副作用小 之溫血動物用（特別是人類用）之內臟痛（特別是食道炎、胃炎、胃潰 瘍、十二指腸潰瘍等潰瘍性疾病伴隨之內臟痛）的預防或治療用藥。 (五）圖式簡單說明：無 -29-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 拾、申請專利範圍： 1.一種治療或預防內臟痛之醫藥組成物，其含有一般式（1)之啦略并 嗒哄化合物，其醫藥可接受鹽或其醫藥可接受酯作爲有效成分，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, 式中R1爲C2-C6條基’鹵C2-C6嫌基’（]2-(1!6炔基，c3-C7環院 基或可經（：「(：4烷基取代之（C3-C7環烷基）-C「C6烷基； R2爲氫原子或C「C6烷基； R3爲氫原子，0「(：6烷基或羥基C「C6烷基； R4爲氫原子或C「C6烷基； R5爲可經選自C「C6院基，鹵CrC^院基’CrC^;!：完氧基，鹵 烷氧基以及鹵素之取代基取代之苯基； A爲CVC3伸烷基； X爲氧原子或硫原子。 2.如申請專利範圍第丨項之醫藥組成物，其係以爲c2-(：4烯基， 氟或氯C2_C4儲基，2 -丙炔基，C3-C6環院基或可經院基 取代之（CrC6環烷基）-Cl_c4烷基之吡咯并嗒哄化合物，其醫藥 可接受鹽或其醫藥可接受酯作爲有效成分。 3·如申請專利範圍第1項之醫藥組成物，其係以R1爲乙烯基，丨_丙 稀基，2-丙烯基，異丙烯基，丁烯基，2-丁烯基，3-丁烯基，2,2-二氟乙烯基，3-氟-2-丙烯基，3 -氯-2-丙烯基，2-氯-2-丙烯基， -30- 200418479 3,3 -二氟-2-丙烯基，3, 3 -二氯-2-丙烯基，4，4,4 -三氟-2 -丁烯基， 環丙基，環己基，環丙基甲基，1-甲基環丙基甲基，2 -甲基環丙 基甲基，環丁基甲基，環戊基甲基，環己基甲基或2 -環丙基乙基 之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受醋作爲有 效成分。 4. 如申請專利範圍第1項之醫藥組成物，其係以Ri爲2-甲基環丙基 甲基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受酯作 爲有效成分。 5. 如申請專利範圍第1項之醫藥組成物，其係以Ri爲（1S,2S)_2_甲 基環丙基甲基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可 接受酯作爲有效成分。 6. 如申請專利範圍第1至5項中任一項之醫藥組成物，其係以R2爲 氫原子或CrC4烷基之吡咯并嗒畊化合物，其醫藥可接受鹽或其 醫藥可接受酯作爲有效成分。 7 .如申請專利範圍第1至5項中任一項之醫藥組成物，其係以r 2爲 甲基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受酯作 爲有效成分。 8. 如申請專利範圍第1至7項中任一項之醫藥組成物，其係以R3爲 氫原子，烷基或羥基烷基之吡咯并嗒畊化合物，其 醫藥可接受鹽或其醫藥可接受酯作爲有效成分。 9. 如申請專利範圍第丨至7項中任一項之醫藥組成物，其係以r3爲 甲基或經甲基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可 接受酯作爲有效成分。 10. 如申請專利範圍第丨至9項中任一項之醫藥組成物，其係以R4 200418479 爲氫原子之吡咯并嗒阱化合物，其醫藥可接受鹽或其醫藥可接受 酯作爲有效成分。 11.如申請專利範圍第1至10項中任一項之醫藥組成物，其係以R5 爲可經1至3個選自（VC4烷基，鹵C「C4烷基，匕-匕烷氧基， 鹵烷氧基，氟，氯及溴之取代基取代之苯基之吡咯并嗒哄 化合物，其醫藥可接受鹽或其醫藥可接受酯作爲有效成分。 12·如申請專利範圍第1至1〇項中任一項之醫藥組成物，其係以R5 爲可經1至3個選自甲基，三氟甲基，甲氧基，三氟甲氧基，二 氟甲氧基，氟，氯及溴之取代基取代之苯基之吡咯并嗒阱化合物， 其醫藥可接受鹽或其醫藥可接受酯作爲有效成分。 13·如申請專利範圍第1至1〇項中任一項之醫藥組成物，其係以R5 爲可經1至3個選自氟及氯之取代基於1至3個選自2位、4位 及6位之取代位取代之苯基之吡咯并嗒畊化合物，其醫藥可接受 鹽或其醫藥可接受酯作爲有效成分。 14. 如申請專利範圍第1至1〇項中任一項之醫藥組成物，其係以R5 爲可經1至2個選自氟及氯之取代基於4位或2，4-位之取代位取 代之苯基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受 酯作爲有效成分。 15. 如申請專利範圍第1至14項中任一項之醫藥組成物，其係以A 爲亞甲基之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受 酯作爲有效成分。 16. 如申請專利範圍第1至15項中任一項之醫藥組成物，其係以X 爲氧原子之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受 酯作爲有效成分。 -32- 200418479 如申請專利範圍第丨項之醫藥組成物，其係以Ri爲C2_c4烯基， 氟或氯C2-C4烯基，2-丙炔基，C3-C6環烷基或可經C「C2烷基 取代之（CVC6環烷基）-CVC4烷基；R2爲氫原子或（VC4烷基； R3爲氫原子，烷基或羥基Ci-q烷基；R4爲氫原子；R5爲 可經1至3個選自院基，鹵C「C4院基，院氧基， IS 烷氧基，氟，氯及溴之取代基取代之苯基；A爲亞甲基； X爲氧原子之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接 受酯作爲有效成分。 W·如申請專利範圍第1項之醫藥組成物，其係以Rl爲乙烯基，^ 丙烯基，2 -丙烯基，異丙烯基，1-丁烯基，2-丁烯基，3 -丁烯基， 2,2 -一氟乙燃基，3 -氟-2-丙嫌基，3 -氯-2-丙嫌基，2 -氯-2-丙燒 基，3,3-二氟-2-丙烯基，3,3-二氯-2-丙烯基，4,4,4-三氟-2-丁 烯基，環丙基，環己基，環丙基甲基，1-甲基環丙基甲基，2-甲 基環丙基甲基，環丁基甲基，環戊基甲基，環己基甲基或2-環丙 基乙基；R2爲甲基；R3爲甲基或羥甲基；R4爲氫原子；R5爲可 經1至3個選自甲基，三氟甲基，甲氧基，三氟甲氧基，二氟甲 氧基’氟，氯及溴之取代基取代之苯基；A爲亞甲基；X爲氧原 子之吡咯并嗒阱化合物，其醫藥可接受鹽或其醫藥可接受酯作爲 有效成分。 1 9 ·如申請專利範圍第1項之醫藥組成物，其係以R1爲2 _甲基環丙 基甲基；R2爲甲基；R3爲甲基或羥甲基；R4爲氫原子；R5爲可 經1至2個运:自親及氣之取代基於1至2個選自2位、4位及6 位之取代位取代之苯基；A爲亞甲基；X爲氧原子之吡咯并嗒哄 化合物，其醫藥可接受鹽或其醫藥可接受酯作爲有效成分。 -33 - 200418479 2 〇 .如申請專利範圍第1項之醫藥組成物，其係以R 1爲（1 S，2 S ) - 2 -甲基環丙基甲基之化合物；R2爲甲基；R3爲甲基或羥甲基；R4 爲氫原子；R5爲可經1至2個選自氟及氯之取代基於4位或2,4 -位之取代位取代之苯基；A爲亞甲基；X爲氧原子之吡咯并嗒阱 化合物，其醫藥可接受鹽或其醫藥可接受酯作爲有效成分。 21.如申請專利範圍第1項之醫藥組成物，其係以選自： 7-(4-氟苄氧基）-2,3-二甲基-l-[(lS，2S)-2-甲基環丙基甲基]吡 咯并[2,3-d]嗒畊， 7-(2,4-二氟苄氧基）-2,3-二甲基-l-[(lS,2S)-2-甲基環丙基甲基] 吡咯并[2,3-d]嗒畊， 7-(4-氯苄氧基）-2,3-二甲基-l-[(lS,2S)-2-甲基環丙基甲基]吡 咯并[2,3-d]嗒哄， 7-(4-氟苄氧基）-3-羥甲基-2 -甲基-l-[(lS，2S)-2 -甲基環丙基甲 基]吡咯并[2,3-d]嗒阱， 7-(2,4-二氟苄氧基）-3-羥甲基-2 -甲基-l-[(lS，2S)-2 -甲基環丙 基甲基]吡咯并[2,3-d]嗒畊， 7-(4-氯苄氧基）-3-羥甲基-2 -甲基-l-[(lS,2S)-2 -甲基環丙基甲 基]吡咯并[2,3-d]嗒畊， 1-(2-丁烯基）-7-(4-氟苄氧基）-2,3-二甲基吡咯并[2,3-d]嗒畊， 以及 1-(2 -丁烯基）-7-(2,4 -二氟苄氧基）-2,3 -二甲基吡略并[2,3-d]嗒 阱之吡咯并嗒阱化合物，其醫藥可接受鹽或其醫藥可接受酯作爲 有效成分。 22·如申請專利範圍第1項之醫藥組成物，其係以選自： - 34- 200418479 7-(4 -氟苄氧基）-2,3 -二甲基- l- [(lS，2S)-2 -甲基環丙基甲基;]口比 咯并[2,3-d]嗒哄， 7-(4 -氟苄氧基）-3 -羥甲基-2-甲基- l- [(lS，2S)-2 -甲基環丙基甲 基]吡咯并[2,3-d]嗒阱， 1-(2 -丁；(¾基）-7-(4 -氟韦氧基）-2,3-二甲基B比略并[2,3-d]塔哄， 以及 1-(2 -丁燒基）-7-(2,4-二_平氧基）-2,3-二甲基壯略并[2,3-(1]嗜 畊之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受酯作爲 有效成分。 23.如申請專利範圍第1項之醫藥組成物，其係以7-(4-氟苄氧基）_ 2,3-二甲基-1-[(13,23)-2-甲基環丙基甲基]吡咯并[2,3-(1]嗒哄 之吡咯并嗒畊化合物，其醫藥可接受鹽或其醫藥可接受酯作爲有 效成分。 24·如申請專利範圍第1至23項中任一項之醫藥組成物，其中內臟 痛爲潰瘍性疾病伴隨之內臟痛。 25·—種申請專利範圍第1至23項中任一項記載之吡略并嗒畊化合 物、其醫藥可接受鹽或其醫藥可接受酯之使用，其係用於製造可 治療或預防內臟痛之醫藥組成物。 26. 如申請專利範圍第25項之使用，其中內臟痛爲潰瘍性疾病伴隨 之內臟痛。 27. —種治療或預防內臟痛之方法，其係對溫血動物投與有效量之如 申請專利範圍第1至23項中任一項記載之吡咯并嗒畊化合物，其 醫藥可接受鹽或其醫藥可接受酯。 28. 如申請專利範圍第27項之方法，其中內臟痛爲潰瘍性疾病伴隨 -35 - 200418479 之內臟痛。 29.如申請專利範圍第27至28項中任一項之方法，其中溫血動物爲 人類。 -36- 200418479 柒、指定代表圖：無 (一） 本案指定代表圖為：第（ ）圖。 (二） 本代表圖之元件代表符號簡單說明: 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式: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:
TW092126426A 2002-09-25 2003-09-25 Pharmaceutical compositions for the treatment or prevention of visceral pains TW200418479A (en)

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WO1991017164A1 (en) * 1990-04-27 1991-11-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyridazines
WO1992006979A1 (en) * 1990-10-15 1992-04-30 Byk Gulden Lomberg Chemische Fabrik Gmbh New diazines
DE59209687D1 (en) * 1991-10-25 1999-06-02 Byk Gulden Lomberg Chem Fab PYRROLO-PYRIDAZINE WITH STOMACH AND COLON PROTECTIVE EFFECTS
EP0742218B1 (en) * 1994-01-19 2002-12-04 Sankyo Company Limited Pyrrolopyridazine derivative
SE9704404D0 (en) * 1997-11-28 1997-11-28 Astra Ab New compounds
DE19859231A1 (en) * 1998-12-21 2000-06-29 Kurt Heinz Bauer Foaming antacid suspension tablets
TWI287014B (en) * 1999-06-15 2007-09-21 Sankyo Co Optically active pyrrolopyridazine compound
TWI237695B (en) * 1999-12-14 2005-08-11 Joy Biomedical Corp Helicobacter pylori antigens in blood
AU2001230585B2 (en) * 2000-02-10 2005-01-06 Sankyo Company, Limited Pyrrolopyridazine compound
JP2002068992A (en) * 2000-08-25 2002-03-08 Ito En Ltd Eradicating agent for helicobacter pylori, and food, beverage or food additive having this eradicating effect
JP3387066B2 (en) * 2000-12-14 2003-03-17 三共株式会社 Anti-ulcer agent containing pyrrolopyridazine compound
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