TW201206440A - Prophylactic or therapeutic agent for diseases associated with pains in urinary organs - Google Patents
Prophylactic or therapeutic agent for diseases associated with pains in urinary organs Download PDFInfo
- Publication number
- TW201206440A TW201206440A TW100114442A TW100114442A TW201206440A TW 201206440 A TW201206440 A TW 201206440A TW 100114442 A TW100114442 A TW 100114442A TW 100114442 A TW100114442 A TW 100114442A TW 201206440 A TW201206440 A TW 201206440A
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- TW
- Taiwan
- Prior art keywords
- piperidine
- compound
- carboxylate
- group
- pyridin
- Prior art date
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- 150000003180 prostaglandins Chemical class 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Communicable Diseases (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
201206440 六、發明說明: 【發明所屬之技術領域】 本發明係有關間質性膀胱炎/膀胱痛症候群,及/或 慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群之伴隨泌尿 器疼痛之預防或治療。 【先前技術】 間質性膀腕炎/膀胱痛症候群,以及慢性非細菌性攝 護腺炎/慢性骨盆疼痛症候群主要症狀均爲頻尿同時出現 膀肤:痛之疾病(Neurourology and Urodynamics,第 21 期 ,第 1 67- 1 78 頁 ’ 2002 年;The Journal of Urology,第 168 期,第 593 -598 頁,2002 )。 間質性膀胱炎(interstitial cystitis)係常見於20〜 60歲女性之非感染性膀胱炎,主要症狀爲恥骨上疼痛及 頻尿、尿急。然而目前尙未建立共通的診斷標準及決定性 的治療方法。1987 年 National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)訂立硏究用之嚴 格的診斷標準,目前將其掌握爲臨床診斷標準,常使用於 診斷。然而,亦有該標準是否過於嚴格之批判,因而嘗試 將其更名爲疼痛性膀腕症候群(painful bladder syndrome )或膀胱疼痛症候群(bladder pain syndrome),以症狀 來掌握該疾病,並於2002年於國際尿禁制協會( International Continence Society)上,首度提倡「未發現 尿路感染及其他明顯的疾病狀態,伴隨日間頻尿或夜間頻 -5- 201206440 尿等其他症狀,主訴與膀胱滿漲有關之恥骨上疼痛(“The complaint of suprapublic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology”)」之疼痛 性膀胱症候群之疾病定義。目前,則於2008年之美國尿 流動力及婦女泌尿學醫學會(Society for Urodynamics and Female Urology)上提倡「未發現感染症及其他可鑑 別的原因,伴隨6周以上之下尿路症狀,認爲有與膀胱有 關的不適感(疼痛、壓迫感、不快感)(“An unpleasant sensation ( pain, pressure, discomfort ) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes”) 」之間質性膀胱炎/膀胱疼痛症候群之疾病定義。 慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群( chronic nonbacterial prostatitis/chronic pelvic pain syndrome)係具代表性的泌尿器官疼痛疾病之一,1999 年美國國家衛生硏究院(NIH)所提倡之攝護腺炎症候群 4個分類的類別m,將主要症狀爲會陰部、睪九、陰莖部 等骨盤部之疼痛/不快感與殘尿感、頻尿等排尿症狀分類 爲同一群的疾病。然而,與類別I之急性細菌性攝護腺炎 及類別π之慢性細菌性攝護皞炎不同的是,由於病因不明 而無法建議決定性的治療方法。與前列腺肥大及間質性膀 -6- 201206440 胱炎、膀胱過動症等呈現下尿路症狀的其他疾病相比,慢 性非細菌性攝護腺炎/慢性骨盆疼痛症候群特徵性的症狀 爲包含睪九之男性生殖器的疼痛,NIH亦列舉於慢性前列 腺炎症狀附錄(NIH-CPSI)中。 如上所述,目前尙未發現對於間質性膀胱炎/膀胱痛 症候群,以及慢性非細菌性攝護腺炎/慢性骨盆疼痛症候 群等伴隨泌尿器官疼痛之疾病,有決定性的治療法,而正 迫切期望開發具優異有效性、安全性之治療藥物》 已知脂肪酸胺基水解酶(Fatty acid amide hydrolase ;FAAH )係藉由水解內生性大麻鹼(endocannabinoid ) ,使其活性消失(Prostaglandins Leukotrinenes and Essential Fatty Acids,第 66 期,第 1 43 - 1 60 頁,2002 年 ;British Journal of Pharmacology,第 141 期,第 25 3 -262 頁,2004 年;Nature,第 3 84 期,第 8 3 -8 7 頁,1996 年;Biochemical Pharmacο 1 ogy,第 62 期,第 5 1 7-526 頁 ,2001年)。內生性大麻驗(endocannabinoid)係作用 於大麻鹼的受器而發揮生理作用之生體內物質的總稱。具 代表性的內生性大麻鹼有花生四烯酸乙醇醯胺、PEA、油 酸胺、2-花生四烯酸甘油酯,已知因FAAH,受水解而使 活性消失。另外,目前已知被認爲是大麻活性成分之△ 9-四氫大麻酚,可活化大麻鹼受器(Current Medicinal Chemistry,第 6 期,第 653-664 頁,1 999 年)。 目前已知哺乳動物存在2種大麻鹼受器CB1、CB2。 CB1係表現於中樞及末梢神經系,.藉由其之活性化可引起 201206440 精神作用及鎭痛作用等。CB2則表現於免疫組織,藉由其 之活性化可引起抗發炎作用及鎭痛(發炎性)作用等。 另一方面,於小鼠膀胱炎模型中,發現大麻鹼受器拮 抗劑可增大膀胱容量及排尿閥値(The Journal of Neuroscience,第 22 期,第 7 1 47-7 1 5 3 頁,2002 年;Pain ,第76期,第189-199頁,1998年),以及對動物投以 大麻鹼受器拮抗劑時雖然觀察到幻覺、妄想、頻脈、姿勢 性低血壓等副作用,但由於投以FAAH抑制劑時並未觀察 到(Nature Medicine,第 9 期,第 76-81 頁,2003 年), 而降低對FAAH抑制劑的副作用及常用性的擔憂,並期待 可作爲間質性膀胱炎/膀胱痛症候群,以及/或慢性非細 菌性攝護腺炎/慢性骨盆疼痛症候群之治療劑。 已有許多針對具有FAAH抑制活性之化合物的報告, 例如已知有下述化合物。 專利文件1中揭示有將吡啶非芳香族含氮雜環-1 -羧 酸酯化合物做爲頻尿、尿失禁、膀胱過動症、疼痛等有效 的治療化合物。然而,對於間質性膀胱炎/膀胱痛症候群 ,以及/或慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群 治療的有效性並無具體的揭示。 專利文件2中,揭不有對神經因性疼痛有效的治療化 合物之吡啶非芳香族含氮雜環-1-羧酸酯化合物。然而, 對於間質性膀胱炎/膀胱痛症候群,以及/或慢性非細菌 性攝護腺炎/慢性骨盆疼痛症候群治療的有效性並無具體 的揭示。 -8- 201206440 專利文件3中揭示有將芳基以及雜環芳基哌啶羧酸衍 生物,做爲多數羅列之疾病,如尿失禁及膀胱炎有效的治 療。然而,並未具體揭示對尿失禁及膀胱炎治療有效性之 數據。 專利文件4中揭示有將醯胺化合物,做爲多數羅列之 疾病,如間質性膀胱炎有效的治療。然而,並未具體揭示 對間質性膀胱炎治療有效性之數據。 專利文件1 :國際公開W02006/088075號公報 專利文件2 :國際公開W〇2010/0〇7966號公報 專利文件3 :國際公開W02005/090347號公報 專利文件4 :國際公開W02006/〇54652號公報 【發明內容】 [發明欲解決之課題] 本發明之課題係提供間質性膀胱炎/膀胱痛症候群、 慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群等伴隨泌尿 器官疼痛之疾病之預防或治療劑。 [解決課題之手段] 本發明團隊針對具有FAAH抑制活性之化合物進行專 心檢討後,發現式(I )之吡啶非芳香族含氮雜環-1 -羧酸 酯化合物(以下有時記作「式(I)之化合物」)或其鹽 ’以FAAH阻礙作用爲基礎,且經確認不僅具有有效膀胱 201206440 容量增大作用,亦具有對膀胱痛及睪九痛之鎭痛作用,可 使用於間質性膀胱炎/膀胱痛症候群,以及/或慢性非細 菌性攝護腺炎/慢性骨盆疼痛症候群之預防或治療,遂完 成本發明。 亦即’本發明係一種預防或治療劑,其係間質性膀胱 炎/膀胱痛症候群’以及/或慢性非細菌性攝護腺炎/慢 性骨盆疼痛症候群之預防或治療劑,亦即與間質性膀胱炎 /膀胱痛症候群’以及/或慢性非細菌性攝護腺炎/慢性 骨盆疼痛症候群的預防或治療用的醫藥組成物有關,其係 以式(I)所示之化合物或其鹽爲有效成分, 【化1】 R1
(式中, A係苯環、碳數爲5〜7之環烷環或碳數爲5〜7之含氮雜 壊, L係單鍵、低級亞垸基 '低級伸烧基、_ N (R 8) _ c 〇 _、 -CO-N-(R8)-、-低級伸烯基 _c〇_、-〇j_c〇·; R8係Η或低級烷基; X係CH或Ν ; R1、R2及R3係相同或相異之Η、鹵素、_CN、_CF3、低級 烷基、-〇-低級烷基、可以選自下述G群之基取代之芳基 、可以選自下述G群之基取代之含鉍雜環芳基、R9_低級 -10- 201206440 亞烷基- Ο-、R9-低級亞烷基-N(R8)-或R1GRnN-CO-; R9係可以選自下述G群之基取代之芳基、可以選自下述 G群之基取代之含氮雜環芳基或碳數爲5〜7之環烷基: R1Q及R11係相同或相異之Η或低級烷基,或爲與鍵結之 Ν原子形成一體’形成碳數爲5〜7之含氮雜環; G群係由鹵素、_ C Ν、- C F 3、低級烷基以及-Ο -低級烷基所 構成; R4係Η或低級烷基; R5、R6及R7係相同或相異之Η、低級烷基、-C0-0-低級烷基、-C02H或-CONH2)。 另外,本發明係有關一種方法,其係預防或治療間質 性膀胱炎/膀胱痛症候群,以及/或慢性非細菌性攝護腺 炎/慢性骨盆疼痛症候群之方法,其係由將式(I )所示 之化合物或其鹽之有效量對哺乳動物投藥所構成。進而, 本發明亦有關爲製造間質性膀胱炎/膀胱痛症候群,及/ 或慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群之預防或 治療劑之式(I)之化合物或其鹽之使用、用以預防或治 療間質性膀胱炎/膀胱痛症候群,及/或慢性非細菌性攝 護腺炎/慢性骨盆疼痛症候群之式(I)之化合物或其鹽 之使用’以及式(I)所示之化合物或其鹽,其係用以於 預防或治療間質性膀胱炎/膀胱痛症候群,及/或慢性非 細菌性攝護腺炎/慢性骨盆疼痛症候群時使用。 [發明的效果] -11 - 201206440 本發明之有效成分之式(I)吡啶非芳香族含氮 1-羧酸酯化合物或其鹽,可使用爲間質性膀胱炎/隹 症候群’以及/或慢性非細菌性攝護腺炎/慢性骨玄 症候群之預防或治療劑。 實施發明之形態 以下詳細說明本發明。 本發明之間質性膀胱炎/膀胱痛症候群,以及/ 性非細菌性攝護腺炎/慢性骨盆疼痛症候群之預防或 劑的有效成分之式(I)之化合物或其鹽,爲上述專 件1及2揭示之化合物,可根據該專利文件之記載而 〇 本說明書中,「低級烷基」係直鏈或支鏈狀碳數 至6 (以下略記作C, .6 )之烷基,例如甲基、乙基、 基、異丙基、正丁基、異丁基、第二丁基、第三丁基 戊基、正己基等。其他之方式爲Ci -4烷基,進而另 方式爲甲基或乙基。 「低級亞烷基」係直鏈或支鏈狀Ci_6的亞烷基 如亞甲基、亞乙基、三亞甲基、四亞甲基、五亞甲基 亞甲基、亞丙基、甲基亞甲基、乙基亞乙基、1,2_二 亞乙基、1,1,2,2-四甲基亞乙基等。其他之方式爲亞 、亞乙基、三亞甲基或五亞甲基9 「低級伸烯基」係直鏈或支鏈狀的伸烯基 如亞乙烯基、亞乙基、亞丙烯基、亞丁烯基、亞戊烯 雜環_ i胱痛 :疼痛 或慢 治療 利文 製造 爲1 正丙 、正 一個 ,例 、六 甲基 甲基 ,例 基、 -12- 201206440 亞己烯基、1,3 -丁二烯基、1,3 -戊二烯 式係C2_4的伸烯基,進而其他的實施方 「5〜7個碳的環烷基」係C 5-7的 爲環戊基、環己基或環庚基。另一實施 外,「5〜7個碳的環烷環」係構成「5 」之環,具體而言爲環戊環、環己環或 「鹵素」係F、 Cl、 Br、 I。 「芳基」係C6-14的單環〜三環式 如苯基、萘基等。另一實施方式係苯基 「5〜7個碳的含氮雜環」係意指名 、S以及N的雜環原子,且必須至少含 5〜7個碳的單環式、飽和環或不飽和 有芳香族雜環。另外,環原子之S或 成氧化物及二氧化物。具體而言有吡略 烷、噁唑烷、噻唑烷、哌啶、哌嗪、嗎 雜環庚三烯、雙氮雜環庚三烯、吡咯啉 吡啶、氮雜環庚烷、吡咯、咪唑、吡哇 唑、異噁唑、噻唑、異噻唑、噁二唑、 陡、塔肼、耻嚷、三嗪等。 「含氮雜環芳基」係意指含有1〜 及N的雜環原子,且必須至少含有1個 個碳的單環式或二環式的芳香族環基。 唑基、吡唑基、三哩基、四唑基、噁哩 唑基、異噻唑基、噁二唑基、噻二唑基 基等。另一實施方 式爲亞乙烯基。 飽和烴環基,具體 方式係環己基。另 ;〜7個碳的環烷基 環庚環。 芳香族烴環基,例 〇 ί有1〜4個選自0 有1個以上的Ν之 環。不飽和環中含 〇亦可被氧化,形 啶、咪唑啉、吡唑 啉、硫嗎啉、雙氮 、二氫吡啶、四氫 、三哩、四哩、嚼 噻二唑、吡啶、嘧 4個選自 Ο、S以 丨以上的Ν之5〜1 〇 具體爲吡咯基、咪 基、異噁唑基、噻 、吡啶基、嘧啶基 -13- 201206440 、嗒肼基、三嗪基、吲哚基、異吲哚基、苯並咪唑、吲唑 基、喹啉基、異喹啉基、喹唑啉基、喹喔啉基、酞嗪基、 苯並噻唑基、苯並異噻唑基、苯並噁唑基、苯並異噁唑基 等。 本說明書中,「亦可被取代」係指並無取代,或具有 1〜5個取代基。且具有複數個取代基之情況,該等取代 基可爲同一種,亦可爲相異者。 本說明書中’ 「泌尿器官疼痛」係指包含膀胱的恥骨 上部位的疼痛/壓迫感/不快感,以及會陰部、睪九、陰 莖部等骨盤部之疼痛/不快感等。 本發明之間質性膀胱炎/膀胱痛症候群,及/或慢性 非細菌性攝護腺炎/慢性骨盆疼痛症候群之預防或治療劑 之有效成分之式(I)所示之化合物或其鹽的實施方式, 係選自 啦陡-3-¾ 4-{4、[(3_氟节基)氧基]苯氧基}哌陡小 化合物A」)、
羧酸酯(以下稱作「 5-{[ ( 4-彳 羰基]氧基}菸j 5- ( {[4-(以下稱作「
苯基乙烯基]哌啶- l-基}羰基)氧基 5-[ ( {4-[4 基)氧基]薛驗 5-[ ( {4-[ ( e )、
]薛鹼酸(以 -14- 201206440
-2-基)哌啶-4-基]丙基}
(以下稱作「化合物F 5-(月安基羰基)D比啶、3、基 4_{2_[3-(胺基羰基)苯
化合物G 基]乙基}哌啶-1-羧酸酯(以下稱作 5-(胺基羰基)耻啶4_ 羰基]苯基}乙基)哌啶-1-羧酸醋( 4- ( 2-{3[(二甲基胺基) (以下稱作「化合物Η 5-(胺基羰基)吡啶-3 -基4-{2-[3-(哌啶-1-基羰基 )苯基]乙基}哌啶-1 -羧酸酯(以下稱作「化合物I」)、 5-(胺基羰基)吡啶-3 -基4-{2-[3·(吡咯啶-1-基羰 基)苯基]乙基}哌啶-1 -羧酸酯(以下稱作「化合物j」) 、 啦啶-3-基 4-[ ( 2Ε ) -3·苯基丙烷-2-烯醇醯基]哌啶-1 _殘酸酯(以下稱作「化合物Κ」)、 啦啶-3-基4-(苯胺基羰基)哌啶-1-羧酸酯(以下稱 作「化合物L」)、 5·(胺基羰基)吡啶-3-基 4- ( 苯乙基)峨啶-1-羧 酸醋(以下稱作「化合物Μ」)、 耻唆-3-基4- ( 2-苯乙基)哌啶-1-羧酸酯(以下稱作 「化合物Ν」)、 5·(甲氧基羰基)吡啶·3_基 4-(2-苯乙基)哌啶-1-、以下稱作「化合物〇」)、 (月安基毅基)卩比D定-3-基 4-[2_(3_氟节基)乙基] -15- 201206440 哌啶-1 -羧酸酯(以下稱作「化合物P」)、 5-(胺基羰基)吡啶-3-基 4-[2- ( 3-氰基苯基)乙基 ]哌啶-1-羧酸酯(以下稱作「化合物Q」)、 5- (胺基羰基)吡啶-3-基 4- ( 5-苯基戊基)哌啶-1-羧酸酯(以下稱作「化合物R」)、 吡啶-3-基 4- ( 3-苯基-1H-1,2,4-三唑-5-基)哌啶-1-羧酸酯(以下稱作「化合物S」)、 6- 甲基吡啶-3·基 4-[3- ( 4-氟苄基)-1H-1,2,4-三唑-5-基]哌啶-1-羧酸酯(以下稱作「化合物T」)、 6-甲基吡啶-3-基 4-[5- ( 4-氟苄基)-1,3-噁唑-2-基] 哌啶-1 -羧酸酯(以下稱作「化合物U」)、 2,6-二甲基吡啶-3-基 4-[5-(3,4-二氟苄基)-1,2,4-噁唑-3-基]哌啶-1-羧酸酯(以下稱作「化合物V」)、 2-甲基吡啶-3-基 4-[3- ( 2-氟苄基)-1H-1,2,4-三唑-5-基)哌啶-1-羧酸酯(以下稱作「化合物W」)、以及 6·甲基吡啶-3 -基 4- ( 3 -苯基-1H -吡唑-1-基]哌啶-1- 羧酸酯(以下稱作「化合物X」)所成群之化合物或其鹽 〇 化合物A〜化合物R係前述專利文件1記載之化合物 ,化合物S〜化合物X係前述專利文件2記載之化合物。 式(Ο所示之化合物依取代基的種類,可存在互變 異構體及幾何異構體。本說明書中,式(I)之化合物僅 以一種異構物之型態表示,但本發明亦包含其以外的異構 物,以及包含異構物經分離者,或該等之混合物。 -16- 201206440 另外,式(I)之化合物中有時具有不對稱碳原子及 軸向手性’且可存在以此爲基礎之光學異構物。本發明亦 包含式(I)之化合物之光學異構物經分離者,或該等之 混合物。 式(I)之化合物之鹽係式(I)之化合物於藥學上許 可之鹽,依取代基的種類,有時形成與酸加成鹽或鹼基之 鹽。舉體可舉出與鹽酸、溴化氫酸、碘化氫酸、硫酸、硝 酸、磷酸等無機酸、及蟻酸、醋酸、丙酸、草酸、丙二酸 、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、杏仁酸、酒 石酸、二苯甲酒石酸、二對甲苯甲醯酒石酸、檸檬酸、甲 基磺酸、乙基磺酸、苄基磺酸、對-甲苯磺酸、天門冬胺 酸、麩胺酸等有機酸之酸加成鹽,與鈉、鉀、鎂、鈣、鋁 等之無機鹼基,與甲基胺、乙基胺、乙醇胺、離胺酸、鳥 胺酸等有機鹼基之鹽,與乙醯亮胺酸等各種胺基酸以及胺 基酸衍生物之鹽及銨鹽等。 本發明之有效成分亦包含式(I)之化合物及其鹽之 各種水和物及溶媒和物,以及多晶型之物質。另外,本發 明亦包含以各種放射性或非放射性的同位素標幟之化合物 0 含有1種或2種以上之式(I)之化合物或其鹽爲有 效成分之醫藥組成物,可使用常用於該領域中之賦形劑, 亦即可使用藥劑用賦形劑及藥劑用載體等,以一般使用之 方法而調製。 投藥可藉由錠劑、九劑、膠囊劑、顆粒劑、散劑、液 -17- 201206440 劑等經口投藥,或經關節內、靜脈內、肌肉內等之注 、坐劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經 貼劑、經黏膜液劑、經黏膜貼劑、吸入劑等非經口投 任一種型態。 用於經口投藥的固體組成物,可使用錠劑、散劑 粒劑等。該等固體組成物中之1種或2種以上有效成 與至少一種的惰性賦形劑,例如乳糖' 甘露糖、葡萄 羥丙基纖維素、微結晶纖維素、澱粉、聚丙烯吡咯烷 /或鎂鋁矽酸鹽等進行混合。組成物可遵循常用方法 可含有惰性添加劑,例如硬酯酸鎂等滑澤劑及羧甲基 鈉等崩解劑、安定劑、溶解輔助劑。錠劑或九劑可依 要被膜糖衣或具有胃溶性,或腸溶性物質之薄膜。 用於經口投藥之液體組成物,可含有藥劑上許可 濁劑、溶液劑、懸濁劑、糖漿劑或酏劑等,亦可含有 所使用之惰性稀釋劑例如純水或乙醇。該液體組成物 性稀釋劑外亦可含有可溶化劑、濕潤劑、懸濁劑等輔 、甘味劑、風味劑、芳香劑、防腐劑。 用於非經口投藥之注射劑,可含有無菌的水性或 性溶液劑、懸濁劑或乳濁劑。水性溶劑係包含例如注 蒸餾水或生理食鹽水。非水性溶劑有例如丙二醇、聚 醇或橄欖油等植物油、乙醇等醇類、或Tween 80 ( 名)等。該等組成物可進而含有等張化劑、防腐劑、 劑、乳化劑、分散劑、安定化劑或溶解輔助劑。可將 液體以例如可濾過細菌之過濾器進行過漉,摻混殺菌 射劑 皮用 藥之 、顆 分, 糖、 酮及 ,亦 澱粉 據需 之乳 一般 除惰 助劑 非水 射用 乙二 局方 濕潤 該等 劑或 -18- 201206440 藉由放射線照射使其無菌化。另外,製造該等無菌之固體 組成物,於使用前以無菌水或無菌注射用溶媒溶解或懸濁 後再加以使用。 外用劑包含軟膏劑、硬膏劑、乳霜劑、凝膠劑、泥劑 、噴霧劑、水劑、點眼劑、眼軟膏等。含有一般使用之軟 膏基劑、水劑基劑、水性或非水性之液劑、懸濁劑、乳劑 等。軟膏或水劑基劑可舉出聚乙二醇、丙二醇、白色凡士 林、蜜蠟、聚氧乙烯氫化蓖麻油、單硬酯酸甘油酯、硬酯 醇、鯨蠟醇、聚桂醇、倍半油酸山梨糖醇等。 吸入劑及經鼻劑等經黏膜劑可使用固體、液體或半固 體狀物,可遵循先前已知之方法而製造。例如周知的賦形 劑,進而亦可適當地添加pH調整劑、防腐劑、界面活性 劑、滑澤劑、安定劑及增黏劑等。投藥可適當地使用用於 吸入或吹送的裝置。例如使用計量投藥吸入裝置等周知的 裝置及噴霧器,可將化合物以單獨或經配方之混合物的粉 末,或與醫藥上許可之載體組合後,以溶液或懸濁液的方 式進行投藥。乾燥粉末吸入器等,若爲單次或數次投藥用 者即可,可利用乾燥粉末或含有粉末的膠囊。或可使用適 當的噴出劑,例如使用氯氟烷烴、羥氟烷烴或二氧化碳等 適合的氣體的加壓氣膠噴霧器等形態。 經口投藥時1日投藥量係體重之0.001〜100 mg/kg ’以0.1〜30 mg/kg爲佳,0.1〜10 mg/kg更佳’可將 其以1次或分成2〜4次進行投藥。經靜脈內投藥時1日 投藥量係體重之0.0001〜10 mg/kg爲較恰當,以1日1 -19" 201206440 次〜分作數次進行投藥。另外,經黏膜劑以體重之0.001 〜100 mg/ kg’以1日〜分作數次進行投藥。投藥量 可考慮症狀、年齡、性別等因應各種場合適當地加以決定 〇 式(I)之化合物可與各種間質性膀胱炎/膀胱痛症 候群’以及/或慢性非細菌性攝護腺炎/慢性骨盆疼痛症 候群之預防或治療劑倂用。倂用時可同時投藥,或個別地 連續進行’或可依據期望的時間間隔而進行投藥。同時投 藥的製劑可爲混合劑液可爲分別經製劑化者。 【實施方式】 [實施例] 以下以實施例爲基礎具體說明本發明。且本發明並未 被限定於下述實施例所記載之範圍。 實施例1 使用來自人類膀胱上皮細胞癌之細胞篩選具有阻礙FAAH 活性之物質 (1 )篩選具有阻礙FAAH活性之物質 將來自人類膀胱上皮細胞癌之細胞株5 63 7細胞( HTB-9 : ATCC )播種於48孔細胞培费盤中,每孔細胞爲 lxl 〇5個,及使用含10%牛胎兒血清(HyC lone公司)之 RPMI1640培養基(Invitrogen公司)。於37°C培養12小 時以上後,將每孔之細胞以 400 // 1之緩衝液(Hank’s -20- 201206440
Balanced Salt Solution, 20mM Hepes-NaOH ( pH 7.4)) 洗淨。於基質液(3 Ci/ ml放射性標幟之花生四烯酸乙 醇醯胺(Anandamide[ethanolamine 1-3H])、含有 Μ 花生四烯酸乙醇醯胺之前述緩衝液)中,將溶解於DM SO 之試驗物質,以 0.00 3 nM〜3 OnM之濃度添加。控制組僅 添加DMSO。於前述細胞,每孔添加100"1之基質液, 並於C02培養箱內,於37°C培養30分鐘。其後,將細胞 培養盤移至冰上,吸去基質液後,再於每孔中加入冰涼的 75//1之細胞溶解用溶液(0.5%TritonX-100,10//M之 含有 FAAH阻礙活性之化合物 cyclohexylcarbamic acid 3 ’ - c ar b am o y 1 b i p h en y 1 - 3 - y 1 ester ( URB5 97 ; Cayman chemical 公司;Kathuria 等氏,Nature Med.第 9 期,第 76-81頁,2003年)之前述緩衝溶液)並攪拌。將每孔所 得之細胞溶解液轉移至容量1.5 ml的檢體管內’再加入 150"1的氯仿與甲醇之1: 1 (容量比)溶液並攪拌。進 行離心分離( 15000 rpm /分鐘’ 2分鐘)時’上層(水/ 甲醇量)爲分解產物乙醇胺(ethanolamine ’下層 (氯仿層)爲被分離之未反應之放射性標幟之花生四烯酸 乙醇醯胺。將上層之25//1移至96孔之具有機溶媒耐性 的白色微孔盤中(pic〇piate-96; PerkinEimer公司)’加 入 150/z 1 之 MicroScint-20 ( PerkinElmer 公司),並以微 孔盤閃爍計數器(Top Count™ ; Beckman )測定。將與控 制組比較使測定値減少之物質,選擇爲具有阻礙FA AH活 性之物質。 -21 - 201206440 (2 )測定具有阻礙FAAH活性物質之ICso値 將溶解於DMSO成爲濃度i〇mM之受試化合物,加入 基質液使其成爲 0.003nM〜30nM,並以上述方法調查對 FAAH活性之影響。以DMSO作爲陰性控制組’並將作爲 陽性控制組之URB597,以成爲10/zM之濃度添加於基質 液中,以陽性控制組之測定値爲0 %,陰性控制組之測定 値爲100%求出IC5〇値。結果示於表1。 表1 受試化合物 IC5〇(nM) 受試化合物 IC5〇(nM) 化合物A 0.11 化合物Μ 0.081 化合物B 0.44 化合物Ν 0.18 化合物C 0.89 化合物。 1.4 化合物D 0.22 化合物Ρ 0.058 化合物E 1.5 化合物Q 0.062 化合物F 0.89 化合物R 0.083 化合物G 0.50 化合物S 0.35 化合物Η 0.54 化合物Τ 1.8 化合物I 0.16 化合物ϋ 0.56 化合物J 0.52 化合物V 2.6 化合物Κ 0.58 化合物W 0.38 化合物L 0.69 化合物X 0.11 實施例2 環磷醯胺(CPA)對於誘發頻尿之小鼠之化合物作用 檢討使用病態小鼠模型之化合物的膀胱刺激症狀改善 作用。已知以環磷醯胺(CP A )進行全身投藥會被轉換爲 -22- 201206440 代謝物之丙烯醛(acrolein ),自尿液傷害膀胱黏膜。由 於在小鼠模型中藉由投藥CPA而誘發出血性膀胱炎並伴 隨膀胱痛或頻尿狀態,而可進行對該等症狀之藥效評價。 實驗係採用 9周齡之 Wistar系雌小鼠(日本Charles River)。經由腹腔投藥CPA(100mg/kg),並於2日 後進行實驗。溶媒使用0.5%甲基纖維素並於受試化合物 經口投藥15分鐘後,強制經口投以蒸餾水(30ml/ kg) 。將小鼠放入觀察代謝飼育籠內,連續測定1小時之排尿 重量。藉由將總排尿量除以總排尿次數,可算出有效膀胱 容量。其結果,在溶媒投藥群中有效膀胱容量減少,發現 頻尿之狀態。另一方面,化合物A及化合物B有效經口 投藥量爲3mg/kg,化合物C、化合物D、化合物E、化 合物F、化合物G、化合物Η、化合物〗、化合物L以及 化合物X有效經口投藥量爲lmg/kg,該等化合物可使減 少的有效膀胱容量增加並改善頻尿狀態。 實施例3 對於膀胱疼痛小鼠模型之化合物作用 使用病態小鼠模型檢討化合物對於膀胱疼痛的鎭痛作 用。自腹腔投藥環磷醯胺(150 mg/ kg),並於2日後小 鼠之非拘束條件下,由經尿道插入膀胱內之導管,藉由以 4 5ml/ hr之流速注入生理食鹽水使膀胱急速擴張。藉由 使膀胱急速擴張,可發現伴隨疼痛相關行爲的腹外斜肌肌 電圖尖峰電位的增幅。由於可將該時點之注入量掌握爲膀 -23- 201206440 胱疼痛閥値,而可進行對膀胱疼痛閥値之藥效評價。實驗 係採用7周齡之SD系雌小鼠(日本Charles River)( n = 3 -6 )。對經環磷醯胺前處理之小鼠,測定受試化合物 投藥前後之膀胱疼痛閥値,並調查其變化量(△ ml )。投 藥前之値,係於獲得3次連續之安定的膀胱疼痛閥値爲止 ,進行膀胱擴張,將最後3次之膀胱疼痛閥値之平均値作 爲測定値。溶媒使用0.5%甲基纖維素,並將受試化合物 (30 mg/5ml/kg)經口投藥,於60分鐘或120分鐘後 開始測定膀胱疼痛閥値,並將連續3次的膀胱疼痛閥値的 平均作爲投藥後之測定値。結果示於表2。化合物投藥群 與溶媒投藥群相比,有意義的增加膀胱疼痛閥値(均爲 p<0.05,Student’s t-test),確認化合物對於膀眺疼痛的 鎭痛作用。 表2 受試化合物 化合物投藥 膀胱痛閾値(生理食鹽水注入量(Ami) 溶媒投藥群 化合物投藥群 化合物C 測定60分前 0.011 0.145 化合物J 測定60分前 0.011 0.150 化合物L· 測定120分前 -0.003 0.173 化合物X 測定120分前 0.017 0.138 實施例4 對於睪九疼痛小鼠模型之化合物作用 使用病態小鼠模型檢討化合物對於睪九疼痛的鎭痛作 用。於小鼠左右的睪九上,以注射針分別注入1 m 1 / k g之 -24- 201206440 1%醋酸,由於可觀察伴隨睪九之疼痛行爲(writhing), 而可進行對該疼痛之藥效評價。實驗係採用3-4周齡之 Wistar 系雄小鼠(日本 Charles River) (n = 9-13) ^ 溶媒 使用0.5%甲基纖維素,並於將受試化合物(3 mg/5ml / kg)經口投藥後之55分鐘或1 15分鐘後,以醋酸處置 睪九,並將小鼠移至直徑30cm,高度50cm的壓克力圓桶 狀籠中,測定於醋酸處置後5分鐘至15分鐘之間疼痛行 爲的次數。結果示於表3。化合物投藥群與溶媒投藥群相 比,有意義的減少疼痛行爲次數(均爲 p<0.01, Student’s t-test),確認化合物對於睪九疼痛的鎭痛作用 表3 受試化合物 化合物投藥 疼痛行動之次數 溶媒投藥群 化合物投藥群 化合物C 測定60分前 23.9 10.4 化合物J 測定60分前 22.7 9.5 化合物L 測定120分前 22.0 6.7 化合物X 測定120分前 25.6 13.3 由上述實驗結果,確認該等化合物以F A A Η阻礙作用 爲基礎,不僅具有有效膀胱容量增大作用,亦具有對膀胱 痛及睪九痛之鎭痛作用。因此可將式(I)所示之化合物 或其鹽,使用於間質性膀胱炎/膀胱痛症候群,以及/或 慢性非細菌性攝護腺炎/慢性骨盆疼痛症候群之預防或治 療。 -25- 201206440 [產業上之可利用性] 本發明之有效成分之式(I)之吡啶非芳香族含氮雜 環-1-羧酸酯化合物或其鹽,可使用爲間質性膀胱炎/膀 胱痛症候群,以及/或慢性非細菌性攝護腺炎/慢性骨盆 疼痛症候群之預防或治療劑。 -26-
Claims (1)
- 201206440 七、申請專利範圍: 1. 一種預防或治療劑,其係間質性膀胱炎/膀胱痛 症候群,以及/或慢性非細菌性攝護腺炎/慢性骨盆疼痛 症候群之預防或治療劑,其係以式(I)所示之化合物或 其鹽爲有效成分, 【化2】(式中, A係苯環、碳數爲5〜7之環烷環或碳數爲5〜7之含氮雜 L係單鍵、低級亞烷基、低級伸烯基、-N(R8)-CO-、 -CO-N-(R8)-、-低級伸烯基-CO-、-Ο-或-CO-; R8係Η或低級烷基; X係CH或Ν ; R1、R2及R3係相同或相異之Η、鹵素、-CN、-CF3、低級 烷基、-〇-低級烷基、可以選自下述G群之基取代之芳基 、可以選自下述G群之基取代之含氮雜環芳基、R9-低級 亞烷基- 〇-、R9 -低級亞烷基- N(R8) -或rMr^N-CO-; R9係可以選自下述G群之基取代之芳基、可以選自下述 G群之基取代之含氮雜環芳基或碳數爲5〜7之環烷基; R1()及R11係相同或相異之Η或低級烷基,或爲與鍵結之 Ν原子形成一體’形成碳數爲5〜7之含氮雜環; 201206440 G群係由鹵素、-CN、-CF3、低級烷基以及-Ο-低級烷基所 構成; R4係Η或低級烷基; R5、R6及R7係相同或相異之Η、低級烷基、-C0-0-低級烷基、-co2H或-CONH2)。 2.如申請專利範圍第1項之預防或治療劑,其中式 (I)所示之化合物或其鹽係選自 吡啶-3-基 4-{4-[ ( 3-氟苄基)氧基]苯氧基}哌啶-1-羧酸酯、 5-{[(4-{4-[(3-氟苄基)氧基]苯氧基}哌啶-1-基) 羰基]氧基}菸鹼酸、 5-( {[4-(2-苯乙基)哌啶-1-基]羰基}氧基)菸鹼酸 、 5-[ ( {4-[4- (2-環己基乙氧基)苯氧基]哌啶- l-基}羰· 基)氧基]菸鹼酸、 5-[ ( M_[ ( E) -2 -苯基乙嫌基]峨D定基}碳基)氧基 ]菸鹼酸、 5-{[ ( 4-{3-[1- ( 6 -甲基卩比陡-2-基)峨D定-4-基]丙基} 哌啶-1-基)羰基]氧基}菸鹼酸、 5-(胺基羰基)吡啶-3-基 4-{2-[3-(胺基羰基)苯 基]乙基}哌啶-1-羧酸酯、 5-(胺基羰基)吡啶-3-基 4-(2-{3[(二甲基胺基) 羰基]苯基}乙基)哌啶-1-羧酸酯、 5-(胺基羰菽)吡啶-3-基 4-{2-[3-(哌啶-1-基羰基 -28- 201206440 )苯基]乙基}哌啶-1-羧酸酯、 5-(胺基羰基)吡啶-3-基 4-{2-[3-(吡咯啶-1-基羰 基)苯基]乙基}哌啶-1-羧酸酯、 吡啶-3-基 4-[ ( 2E ) -3-苯基丙烷-2-烯醇醯基]哌啶-1-羧酸酯、 吡啶-3-基 4-(苯胺基羰基)哌啶-1-羧酸酯、 5-(胺基羰基)吡啶-3-基 4-(2-苯乙基)哌啶-1-羧 酸酯、 吡啶-3-基 4- ( 2-苯乙基)哌啶-1-羧酸酯、 5* (甲氧基羰基)吡啶-3-基 4- (2-苯乙基)哌啶-1-羧酸酯、 5-(胺基羰基)吡啶-3-基 4-[2- ( 3-氟苄基)乙基] 哌啶-1-羧酸酯、 5-(胺基羰基)吡啶-3-基 4-[2- ( 3-氰基苯基)乙基 ]哌啶-1-羧酸酯、 5- (胺基羰基)吡啶-3-基 4- ( 5-苯基戊基)哌啶-1· 羧酸酯、 吡啶-3 -基 4 - ( 3 -苯基-1 Η -1,2,4 -三唑-5 -基)哌啶-1 -羧酸酯、 6- 甲基吡啶-3-基 4-[3- ( 4-氟苄基)-1Η-1,2,4-三唑-5-基]哌啶-1-羧酸酯、 6-甲基吡啶-3-基 4-[5- ( 4-氟苄基)-1,3-噁唑-2-基] 哌啶-1-羧酸酯、 2,6-二甲基吡啶-3-基 4-[5-(3,4-二氟苄基)-1,2,4- -29 - 201206440 噁唑-3-基]哌啶-1-羧酸酯、 2-甲基吡啶-3-基4-[3- ( 2-氟苄基)-11·1-1,2,4-三唑_ 5-基)哌啶-1-羧酸酯、以及 6-甲基吡啶-3 -基4- ( 3 -苯基·1Η-_哩— I-基]哌淀-1_ 羧酸酯所成群之化合物或其鹽。 3 . —種如申請專利範圍第1項之式(1 )所示之化合 物或其鹽之使用,其係用以製造間質性膀腕炎/膀腕痛症 候群,及/或慢性非細菌性攝護腺炎/慢性骨盆疼痛症候 群之預防或治療劑。· 4 · 一種如申請專利範圍第1項之式(1 )所示之化合 物或其鹽之使用,其係用以預防或治療間質性膀胱炎/膀 胱痛症候群,及/或慢性非細菌性攝護腺炎/慢性骨盆疼 痛症候群。 5. —種如申請專利範圍第1項之式(1)所示之化合 物或其鹽,其係用以於預防或治療間質性膀胱炎/膀胱痛 症候群,及/或慢性非細菌性攝護腺炎/慢性骨盆疼痛症 候群時使用。 6. —種方法,其係預防或治療間質性膀胱炎/膀胱 痛症候群’以及/或慢性非細菌性攝護腺炎/慢性骨盆疼 痛症候群之方法,其係由將如申請專利範圍第1項之式( I)所示之化合物或其鹽之有效量對哺乳動物投藥所構成 -30- 201206440 四 指定代表圓: (一) 本案指定代表圖為:無 (二) 本代表圖之元件符號簡單說明:無 201206440 五 本案若有化學式時,請揭示最能顯示發明特徵的化學 式:無
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- 2011-04-27 EA EA201291122A patent/EA201291122A1/ru unknown
- 2011-04-27 WO PCT/JP2011/060332 patent/WO2011136308A1/ja active Application Filing
- 2011-04-27 EP EP11775089.3A patent/EP2564849A4/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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EP2564849A4 (en) | 2013-11-06 |
AU2011246111B2 (en) | 2014-07-17 |
EA201291122A1 (ru) | 2013-04-30 |
CA2797420A1 (en) | 2011-11-03 |
KR20130061684A (ko) | 2013-06-11 |
WO2011136308A1 (ja) | 2011-11-03 |
AU2011246111A1 (en) | 2012-10-18 |
UA106131C2 (uk) | 2014-07-25 |
BR112012026876A2 (pt) | 2016-07-19 |
US20130030006A1 (en) | 2013-01-31 |
EP2564849A1 (en) | 2013-03-06 |
MX2012012378A (es) | 2012-11-16 |
CN102858340A (zh) | 2013-01-02 |
JPWO2011136308A1 (ja) | 2013-07-22 |
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