CN102858340A - 伴有泌尿器官疼痛的疾病的预防剂或治疗剂 - Google Patents
伴有泌尿器官疼痛的疾病的预防剂或治疗剂 Download PDFInfo
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- CN102858340A CN102858340A CN2011800215031A CN201180021503A CN102858340A CN 102858340 A CN102858340 A CN 102858340A CN 2011800215031 A CN2011800215031 A CN 2011800215031A CN 201180021503 A CN201180021503 A CN 201180021503A CN 102858340 A CN102858340 A CN 102858340A
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- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
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Abstract
本发明提供伴有泌尿器官疼痛的疾病的预防剂或治疗剂。本发明人确认:非芳香族含氮杂环-1-羧酸吡啶基酯化合物或其盐基于FAAH抑制作用,不仅具有增大有效膀胱容量的作用,而且对膀胱疼痛和睾丸疼痛具有镇痛作用。因此,非芳香族含氮杂环-1-羧酸吡啶基酯化合物或其盐能够用于预防或治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征。
Description
技术领域
本发明涉及间质性膀胱炎/膀胱疼痛综合征、慢性非细菌性前列腺炎/慢性骨盆疼痛综合征这样伴有泌尿器官疼痛的疾病的预防剂或治疗剂。
背景技术
间质性膀胱炎/膀胱疼痛综合征以及慢性非细菌性前列腺炎/慢性骨盆疼痛综合征均为以尿频和膀胱疼痛为主要症状之一的疾病(Neurourology and Urodynamics,第21卷,第167-178页,2002年;The Journal of Urology,第168卷,第593-598页,2002年)。
间质性膀胱炎(interstitial cystitis)是多见于20~60岁女性的非感染性的膀胱炎,其为以耻骨上部疼痛、尿频、尿意急迫感为主要症状的疾病。但是,尚无共同的诊断标准、确定的治疗方法。1987年,由美国国立糖尿病、消化系统和肾脏疾病研究所(National Institute ofDiabetic,Digestive and Kidney Disease,NIDDK)公布了研究用的严格的入选标准,该标准目前多被视为临床诊断标准而用于诊断。但是,也有该标准的应用过于严格的批评。因此,尝试了更名为痛性膀胱综合征(painful bladder syndrome)或膀胱疼痛综合征(bladder pain syndrome)以通过症状来掌握该疾病,在2002年,由国际尿控协会(InternationalContinence Society)首次提出了“观察不到尿路感染症或其他明确疾病状态的、伴有白天尿频或夜间尿频等其他症状的、与膀胱充满相关的耻骨上部疼痛的主诉(“The complaint of suprapubic pain related tobladder filling,accompanied by other symptoms such as increased daytimeand night-time frequency,in the absence of proven urinary infection orother obvious pathology”)”的痛性膀胱综合征的疾病定义。目前,在2008年由美国尿动力学与女性泌尿外科学会(Society for Urodynamics andFemale Urology)提出了“观察不到感染症或其他能够鉴别的原因的、伴有6周以上的下部尿路症状的、认为与膀胱相关的不快感(疼痛、压迫感、不适感)(“An unpleasant sensation(pain,pressure,discomfort)perceived to be related to the urinary bladder,associated with lowerurinary tract symptoms ofmore than six weeks duration,in the absence ofinfection or other identifiable causes”)”的间质性膀胱炎/膀胱疼痛综合征的疾病定义。
慢性非细菌性前列腺炎/慢性骨盆疼痛综合征(chronic nonbacterialprostatitis/chronic pelvic pain syndrome)是代表性的泌尿器官疼痛疾病之一,作为1999年美国国立卫生研究所(NIH)提出的前列腺炎综合征的四种分类的类别III,被分类为以会阴部、睾丸部、阴茎部等骨盆部的疼痛/不适感和尿不净感、尿频等排尿症状为主要症状的一组疾病。但是,与类别I的急性细菌性前列腺炎和类别II的慢性细菌性前列腺炎不同,由于病因不明,因此未发现确定性的治疗方法。与前列腺肥大症、间质性膀胱炎、膀胱过度活动症等表现出下部尿路症状的其他疾病相比,慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的特征性的症状有包括睾丸在内的男性生殖器的疼痛,也可以列举NIH的慢性前列腺炎症状指数(NIH-CPSI)。
如上所述,对于间质性膀胱炎/膀胱疼痛综合征、慢性非细菌性前列腺炎/慢性骨盆疼痛综合征这样伴有泌尿器官疼痛的疾病,尚未发现确定性的治疗方法,迫切期望开发出有效性、安全性优良的治疗药。
已知脂肪酸酰胺水解酶(Fatty acid amide hydrolase;FAAH)通过将内源性大麻素水解而使其活性消失(Prostaglandins Leukotrienes andEssential Fatty Acids,第66卷,第143-160页,2002年;British Journalof Pharmacology,第141卷,第253-262页,2004年;Nature,第384卷,第83-87页,1996年;Biochemical Pharmacology,第62卷,第517-526页,2001年)。内源性大麻素(endocannabinoid)是作用于大麻素受体而发挥生理作用的生物体内物质的总称。作为代表性的内源性大麻素,有花生四烯酰乙醇胺、棕榈酰乙醇胺、油酸酰胺、2-花生四烯酸甘油酯,已知被FAAH水解而活性消失。另外,已知认为属于大麻的活性成分的Δ9-四氢大麻酚使大麻素受体(Currentmedicinal Chemistry,第6卷,第635-664页,1999年)活化。
迄今为止,在哺乳动物中已知两种大麻素受体CB1、CB2。CB1在中枢和周围神经系统中表达,通过其活化而产生精神作用及镇痛作用等。CB2在免疫系统组织中表达,通过其活化而产生抗炎作用及镇痛(炎性)作用等。
另一方面,在大鼠膀胱炎模型中,大麻素受体激动剂增大膀胱容量及排尿阈值(The Journal of Neuroscience,第22卷,第7147-7153页,2002年;Pain,第76卷,第189-199页,1998年),并且对动物施用大麻素受体激动剂时观察到的幻觉、妄想、心动过速、直立性低血压等副作用在施用FAAH抑制剂时观察不到(Naturemedicine,第9卷,第76-81页,2003年),因此,期待FAAH抑制剂作为副作用或常用性的担心少的、间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的治疗剂。
对于具有FAAH抑制活性的化合物有许多报道,例如已知以下的化合物。
在专利文献1中,公开了非芳香族含氮杂环-1-羧酸吡啶基酯化合物作为对治疗尿频、尿失禁、膀胱过度活动症、疼痛等有用的化合物。但是,并未具体公开对治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的有效性。
在专利文献2中,公开了非芳香族含氮杂环-1-羧酸吡啶基酯化合物作为对治疗神经源性疼痛有用的化合物。但是,并未具体公开对治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的有效性。
在专利文献3中,公开了芳基及杂芳基哌啶羧酸衍生物对治疗作为罗列的多种疾病的一种方式的尿失禁或膀胱炎有用。但是,并未公开具体显示出对治疗尿失禁或膀胱炎的有效性的数据。
在专利文献4中,公开了酰胺化合物对治疗作为罗列的多种疾病的一种方式的间质性膀胱炎有用。但是,并未公开具体显示出对治疗间质性膀胱炎的有效性的数据。
现有技术文献
专利文献
专利文献1:国际公开小册子WO2006/088075号
专利文献2:国际公开小册子WO2010/007966号
专利文献3:国际公开小册子WO2005/090347号
专利文献4:国际公开小册子WO2006/054652号
发明内容
发明所要解决的问题
本发明的课题在于提供间质性膀胱炎/膀胱疼痛综合征、慢性非细菌性前列腺炎/慢性骨盆疼痛综合征这样伴有泌尿器官疼痛的疾病的预防剂或治疗剂。
用于解决问题的手段
本发明人对具有FAAH抑制活性的化合物进行了深入的研究,结果发现,式(I)的非芳香族含氮杂环-1-羧酸吡啶基酯化合物(以下有时记作“式(I)的化合物”)或其盐基于FAAH抑制作用,不仅具有增大有效膀胱容量的作用,而且对膀胱疼痛和睾丸疼痛具有镇痛作用,从而对预防或治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征有用,从而完成了本发明。
即,本发明涉及间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂,即间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防或治疗用医药组合物,其以式(I)的化合物或其盐作为有效成分,
式(I)中,
A为苯环、5~7元环烷烃环或5~7元含氮杂环;
L为单键、低级亚烷基、低级亚烯基、-N(R8)-CO-、-CO-N(R8)-、-低级亚烯基-CO-、-O-或-CO-;
R8为H或低级烷基;
X为CH或N;
R1、R2和R3相同或不同地为H、卤素、-CN、-CF3、低级烷基、-O-低级烷基、可由选自下述G组的基团取代的芳基、可由选自下述G组的基团取代的含氮杂芳基、R9-低级亚烷基-O-、R9-低级亚烷基-N(R8)-或R10R11N-CO-;
R9为可由选自下述G组的基团取代的芳基、可由选自下述G组的基团取代的含氮杂芳基或5~7元环烷基;
R10和R11相同或不同地为H或低级烷基,或者与所键合的N原子成为一体而形成5~7元含氮杂环;
G组由卤素、-CN、-CF3、低级烷基和-O-低级烷基组成;
R4为H或低级烷基;
R5、R6和R7相同或不同地为H、低级烷基、-CO-O-低级烷基、-CO2H或-CONH2。
另外,本发明涉及间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防或治疗方法,其包括对哺乳动物施用有效量的式(I)的化合物或其盐。另外,本发明涉及:式(I)的化合物或其盐在制造间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂中的应用;式(I)的化合物或其盐在预防或治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征中的应用;以及用于在间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防或治疗中使用的式(I)的化合物或其盐。
发明效果
作为本发明的有效成分的式(I)的非芳香族含氮杂环-1-羧酸吡啶基酯化合物或其盐能够作为间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂使用。
具体实施方式
以下,对本发明进行详细说明。
本发明的间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂的有效成分即式(I)的化合物或其盐为上述的专利文献1和2中公开的化合物,可以根据该专利文献的记载来制造。
本说明书中,“低级烷基”是指直链或支链的碳原子数为1~6(以下简记为C1-6)的烷基,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。另一方式为C1-4烷基,又一方式为甲基或乙基。
“低级亚烷基”是指直链或支链的C1-6的亚烷基,例如为亚甲基、亚乙基、三亚甲基、四亚甲基、五亚甲基、六亚甲基、亚丙基、甲基亚甲基、乙基亚乙基、1,2-二甲基亚乙基、1,1,2,2-四甲基亚乙基等。另一方式为亚甲基、亚乙基、三亚甲基或五亚甲基。
“低级亚烯基”是指直链或支链的C2-6的亚烯基,例如为亚乙烯基、乙烯叉基、亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基、亚1,3-丁二烯基、亚1,3-戊二烯基等。另一方式为C2-4亚烯基,又一方式为亚乙烯基。
“5~7元环烷基”是指C5-7的饱和烃环基,具体而言为环戊基、环己基或环庚基。另一方式为环己基。另外,“5~7元环烷烃环”是指构成“5~7元环烷基”的环,具体而言为环戊烷环、环己烷环或环庚烷环。
“卤素”是指F、Cl、Br、I。
“芳基”是指C6-14的单环式芳香族烃环基至三环式芳香族烃环基,例如为苯基、萘基等。另一方式为苯基。
“5~7元含氮杂环”是指含有1~4个选自O、S和N中的杂原子且必须含有至少一个以上N的5~7元单环式的饱和环或不饱和环。不饱和环包括芳香族杂环。另外,作为环原子的S或O可以被氧化而形成氧化物或二氧化物。具体而言为吡咯烷、咪唑烷、吡唑烷、唑烷、噻唑烷、哌啶、哌嗪、吗啉、硫代吗啉、氮杂环庚烷(アゼパン)、二氮杂环庚烷、吡咯啉、二氢吡啶、四氢吡啶、氮杂环庚三烯(アゼピン)、吡咯、咪唑、吡唑、三唑、四唑、唑、异唑、噻唑、异噻唑、二唑、噻二唑、吡啶、嘧啶、哒嗪、吡嗪、三嗪等。
“含氮杂芳基”是指含有1~4个选自O、S和N中的杂原子且必须含有至少一个以上N的5~10元单环式或双环式的芳香族环基。具体而言为吡咯基、咪唑基、吡唑基、三唑基、四唑基、唑基、异唑基、噻唑基、异噻唑基、二唑基、噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、异吲哚基、苯并咪唑基、吲唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、酞嗪基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基等。
本说明书中,“可被取代”是指未取代或者具有1~5个取代基。另外,在具有多个取代基的情况下,这些取代基可以相同也可以彼此不同。
另外,本说明书中,“泌尿器官疼痛”是指包括膀胱在内的耻骨上部的疼痛/压迫感/不适感、以及会阴部、睾丸部、阴茎部等骨盆部的疼痛/不适感等。
本发明的间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂的有效成分即式(I)的化合物或其盐的某些方式为选自由下述化合物组成的组中的化合物或其盐:
4-{4-[(3-氟苄基)氧基]苯氧基}哌啶-1-羧酸吡啶-3-基酯(以下称为“化合物A”)、
5-{[(4-{4-[(3-氟苄基)氧基]苯氧基}哌啶-1-基)羰基]氧基}烟酸(以下称为“化合物B”)、
5-({[4-(2-苯基乙基)哌啶-1-基]羰基}氧基)烟酸(以下称为“化合物C”)、
5-[({4-[4-(2-环己基乙氧基)苯氧基]哌啶-1-基}羰基)氧基]烟酸(以下称为“化合物D”)、
5-[({4-[(E)-2-苯基乙烯基]哌啶-1-基}羰基)氧基]烟酸(以下称为“化合物E”)、
5-{[(4-{3-[1-(6-甲基吡啶-2-基)哌啶-4-基]丙基}哌啶-1-基)羰基]氧基}烟酸(以下称为“化合物F”)、
4-{2-[3-(氨基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物G”)、
4-(2-{3-[(二甲基氨基)羰基]苯基}乙基)哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物H”)、
4-{2-[3-(哌啶-1-基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物I”)、
4-{2-[3-(吡咯烷-1-基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物J”)、
4-[(2E)-3-苯基丙-2-烯酰基]哌嗪-1-羧酸吡啶-3-基酯(以下称为“化合物K”)、
4-(苯胺基羰基)哌啶-1-羧酸吡啶-3-基酯(以下称为“化合物L”)、
4-(2-苯基乙基)哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物M”)、
4-(2-苯基乙基)哌嗪-1-羧酸吡啶-3-基酯(以下称为“化合物N”)、
4-(2-苯基乙基)哌嗪-1-羧酸5-(甲氧基羰基)吡啶-3-基酯(以下称为“化合物O”)、
4-[2-(3-氟苯基)乙基]哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物P”)、
4-[2-(3-氰基苯基)乙基]哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物Q”)、
4-(5-苯基戊基)哌嗪-1-羧酸5-(氨基羰基)吡啶-3-基酯(以下称为“化合物R”)、
4-(3-苯基-1H-1,2,4-三唑-5-基)哌啶-1-羧酸吡啶-3-基酯(以下称为“化合物S”)、
4-[3-(4-氟苯基)-1H-1,2,4-三唑-5-基]哌啶-1-羧酸6-甲基吡啶-3-基酯(以下称为“化合物T”)、
4-[3-(2-氟苯基)-1H-1,2,4-三唑-5-基]哌啶-1-羧酸2-甲基吡啶-3-基酯(以下称为“化合物W”)和
4-(3-苯基-1H-吡唑-1-基)哌啶-1-羧酸6-甲基吡啶-3-基酯(以下称为“化合物X”)。
需要说明的是,化合物A~化合物R为上述专利文献1中记载的化合物,化合物S~化合物X为上述专利文献2中记载的化合物。
式(I)的化合物中,根据取代基的种类,可能存在互变异构体或几何异构体。本说明书中,式(I)的化合物有时仅以异构体的一种形式记载,但本发明也包括除此以外的异构体,还包括异构体的分离产物或者它们的混合物。
另外,式(I)的化合物中有时存在不对称碳原子或轴不对称,可能存在基于此的光学异构体。本发明也包括式(I)的化合物的光学异构体的分离产物或者它们的混合物。
另外,式(I)的化合物的盐是指式(I)的化合物的制药学上容许的盐,根据取代基的种类,有时形成酸加成盐或与碱的盐。具体而言,可以列举:与盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、扁桃酸、酒石酸、二苯甲酰酒石酸、二甲苯甲酰酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、天冬氨酸、谷氨酸等有机酸的酸加成盐;与钠、钾、镁、钙、铝等无机碱、甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等有机碱的盐;与乙酰亮氨酸等各种氨基酸及氨基酸衍生物的盐;铵盐等。
另外,本发明的有效成分也包括式(I)的化合物及其盐的各种水合物或溶剂化物以及多晶型物。另外,本发明还包括用各种放射性或者非放射性同位素标记的化合物。
含有式(I)的化合物或其盐中的一种或两种以上作为有效成分的药物组合物可以通过使用本领域通常使用的赋形剂即药剂用赋形剂或药剂用载体等并利用通常使用的方法来制备。
施用可以为片剂、丸剂、胶囊剂、颗粒剂、散剂、液剂等的经口施用或者关节内、静脉内、肌肉内等的注射剂、栓剂、滴眼剂、眼软膏、经皮用液剂、软膏剂、经皮用贴剂、经粘膜液剂、经粘膜贴剂、吸入剂等的非经口施用中的任意一种形式。
作为用于经口施用的固体组合物,可以使用片剂、散剂、颗粒剂等。在这样的固体组合物中,将一种或两种以上有效成分与至少一种惰性赋形剂例如乳糖、甘露糖、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮和/或偏硅酸铝镁等混合。组合物可以根据常规方法含有惰性添加剂,例如硬脂酸镁等润滑剂、羧甲基淀粉钠等崩解剂、稳定剂、助溶剂。片剂或丸剂可以根据需要由糖衣包覆或者由胃溶性或肠溶性物质的薄膜包覆。
用于经口施用的液体组合物包括药剂学上容许的乳浊剂、溶液剂、悬浊剂、糖浆剂或酏剂等,其含有通常使用的惰性稀释剂例如纯化水或乙醇。该液体组合物除了含有惰性稀释剂以外,还可以含有增溶剂、润湿剂、助悬剂等助剂、甜味剂、风味剂、芳香剂、防腐剂。
用于非经口施用的注射剂含有无菌的水性或非水性的溶液剂、悬浊剂或者乳浊剂。作为水性的溶剂,包含例如注射用蒸馏水或生理盐水。作为非水性的溶剂,有例如丙二醇、聚乙二醇或橄榄油等植物油、乙醇等醇类或者聚山梨酯80(药典名)等。这样的组合物可以进一步含有等渗剂、防腐剂、润湿剂、乳化剂、分散剂、稳定剂或助溶剂。这些组合物可以通过例如从除菌过滤器中通过进行过滤、配合杀菌剂或者照射而进行无菌化。另外,这些组合物可以制成无菌的固体组合物并在使用前溶解或悬浊到无菌水或无菌注射用溶剂中来使用。
作为外用剂,包括软膏剂、硬膏剂、霜剂、胶浆剂、巴布剂、喷雾剂、洗剂、滴眼剂、眼软膏等。上述外用剂含有通常使用的软膏基剂、洗剂基剂、水性或非水性的液剂、悬浊剂、乳剂等。作为软膏或洗剂基剂,可以列举例如:聚乙二醇、丙二醇、白色凡士林、白蜂蜡、聚氧乙烯氢化蓖麻油、单硬脂酸甘油酯、硬脂醇、鲸蜡醇、聚桂醇、倍半油酸失水山梨醇等。
吸入剂、经鼻剂等经粘膜剂可以使用固态、液态或半固态的制剂,可以通过现有公知的方法制造。例如,可以适当添加公知的赋形剂、以及pH调节剂、防腐剂、表面活性剂、润滑剂、稳定剂或增稠剂等。施用可以使用适当的用于吸入或吹送的器具。例如,可以使用计量施用吸入器具等公知的器具或喷雾器,将化合物单独以粉末的形式施用或以配制好的混合物的粉末的形式施用,或者与医药上可容许的载体组合以溶液或悬浊液形式施用。干燥粉末吸入器等可以用于单次或多次施用,可以使用干燥粉末或含有粉末的胶囊。或者,可以是使用适当的喷射剂(駆出剤)例如氯氟烃、氢氟烃或二氧化碳等适当气体的加压气溶胶喷雾剂等形式。
通常,在经口施用的情况下,每天的施用量按体重计为约0.001mg/kg~约100mg/kg、优选约0.1mg/kg~约30mg/kg、更优选约0.1mg/kg~约10mg/kg是适当的,该施用量可以一次施用或分2次~4次施用。在静脉内施用的情况下,每天的施用量按体重计为约0.0001mg/kg~约10mg/kg是适当的,一天施用一次或分多次施用。另外,作为经粘膜剂,将按体重计约0.001mg/kg~约100mg/kg的量一天施用一次或分多次施用。施用量考虑症状、年龄、性别等根据各自的情况适当确定。
式(I)的化合物或其盐可以与各种间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂并用。该并用可以同时施用,或者连续地或空出期望的时间间隔来分开施用。同时施用制剂可以是配合剂,也可以分别形成制剂。
实施例
以下,基于实施例来具体说明本发明。另外,本发明不限于下述实施例中记载的范围。
实施例1
使用人膀胱上皮癌来源的细胞进行抑制FAAH活性的物质的筛选
(1)抑制FAAH活性的物质的筛选
使用含有10%胎牛血清(HyClone公司)的RPMI1640培养基(Invitrogen公司),将人膀胱上皮癌来源的细胞株5637细胞(HTB-9;ATCC)以每孔1×105个接种到48孔的细胞培养板中。在37℃下培养12小时以上,然后,用每孔400μl的缓冲液(汉克平衡盐溶液(Hank’sBalanced Salt Solution),20mM Hepes-NaOH(pH 7.4))清洗细胞。向底物液(含有3μCi/ml放射标记的花生四烯酰乙醇胺(Anandamide[ethanolamine 1-3H])、10μM花生四烯酰乙醇胺的上述缓冲液)中添加溶解在DMSO中的试验物质,使其达到0.003nM~30nM。作为对照,仅添加DMSO。向上述细胞中添加每孔100μl的底物液,并在CO2孵育箱内在37℃下孵育30分钟。然后,将细胞培养板转移到冰上,抽吸除去底物液,每孔加入75μl的冰冷却后的细胞溶解用溶液(含有0.5%TritonX-100、10μM的具有FAAH抑制活性的化合物环己基氨基甲酸3’-氨基甲酰基联苯-3-基酯(URB597;Cayman chemical公司;Kathuria等,Nature Med.,第9卷,第76-81页,2003年)的上述缓冲液)并搅拌。将所得到的细胞溶解液与孔一起转移到1.5ml容量的样品管中,添加150μl的氯仿与甲醇的1:1(体积比)溶液并搅拌。离心分离(15000转/分钟、2分钟)时,上层(水/甲醇层)分离出分解产物乙醇胺(ethanolamine 1-3H),下层(氯仿层)分离出未反应的放射标记的花生四烯酰乙醇胺。将上层的25μl转移到96孔的耐有机溶剂性白色微孔板(PicoPlate-96;PerkinElmer公司)中,添加150μl的マイクロシンチ20(PerkinElmer公司),并利用微孔板闪烁计数器(TopCountTM;Beckman公司)进行测定。筛选出与对照相比使测定值减少的物质作为抑制FAAH活性的物质。
(2)FAAH活性抑制物质的IC50值的测定
将以达到10mM的方式溶解在DMSO中的受试化合物添加到底物液中,使其达到0.003nM~30nM,通过上述中记载的方法考察给FAAH活性带来的影响。将作为阴性对照的DMSO、作为阳性对照的URB597以达到10μM的方式添加到底物液中,将阳性对照的测定值设为0%并将阴性对照的测定值设为100%,求出IC50值。结果示于表1中。
[表1]
受试化台物 | IC50(nM) | 受试化台物 | IC50(nM) |
化合物A | 0.11 | 化台物M | 0.081 |
化台物B | 0.44 | 化台物N | 0.18 |
化台物C | 0.89 | 化台物O | 1.4 |
化台物D | 0.22 | 化台物P | 0.058 |
化台物E | 1.5 | 化台物Q | 0.062 |
化合物F | 0.89 | 化合物R | 0.083 |
化台物G | 0.50 | 化台物S | 0.35 |
化台物H | 0.54 | 化合物T | 1.8 |
化合物I | 0.16 | 化台物U | 0.56 |
化合物J | 0.52 | 化合物V | 2.6 |
化台物K | 0.58 | 化合物W | 0.38 |
化台物L | 0.69 | 化台物X | 0.11 |
实施例2
化合物对环磷酰胺(CPA)诱发的尿频大鼠的作用
使用病态模型对化合物改善膀胱刺激症状的作用进行研究。已知环磷酰胺(CPA)通过全身施用而转变为代谢物丙烯醛,从尿中损害膀胱粘膜。对于大鼠,通过施用CPA来诱发出血性膀胱炎所伴有的膀胱疼痛或尿频状态,因此,能够评价对这些症状的药效。实验中使用9周龄的Wistar系雌性大鼠(日本チヤ一ルス·リバ一株式会社)。腹腔内施用CPA(100mg/kg),两天后进行实验。使用0.5%甲基纤维素作为溶剂来经口施用受试化合物,15分钟后,强制性地经口施用蒸馏水(30ml/kg)。将大鼠放入代谢笼中,连续测定一小时的排尿重量。通过用总排尿量除以总排尿次数而计算出有效膀胱容量。结果,溶剂施用组中,有效膀胱容量减少,确认为尿频状态。另一方面,化合物A和化合物B的有效经口施用量为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H、化合物J、化合物L和化合物X的有效经口施用量为1mg/kg,这些化合物使减少的有效膀胱容量增加而改善尿频状态。
实施例3
化合物对膀胱疼痛模型大鼠的作用
使用病态模型研究化合物对膀胱疼痛的镇痛作用。用环磷酰胺(150mg/kg)进行腹腔内处理,两天后,在非束缚条件下,通过经尿道插入到膀胱内的导管以45ml/小时的流速注入生理盐水,由此使膀胱快速扩张。通过使膀胱快速扩张,观察到伴有疼痛相关行为的腹外斜肌肌电图的尖锋增强。可以将该时刻的注入量视为膀胱疼痛阈值,因此能够评价对膀胱疼痛阈值的药效。实验中使用7周龄的SD系雌性大鼠(日本チヤ一ルス·リバ一株式会社)(n=3-6)。对于进行了环磷酰胺预处理的大鼠,测定施用受试化合物前和施用受试化合物后的膀胱疼痛阈值,考察其变化量(Δml)。对于施用前的值,进行膀胱扩张直到得到三次连续稳定的膀胱疼痛阈值,将最后三次的膀胱疼痛阈值的平均值作为测定值。使用0.5%甲基纤维素作为溶剂来经口施用受试化合物(3mg/5ml/kg),60分钟或120分钟后开始测定膀胱疼痛阈值,将连续三次的膀胱疼痛阈值的平均值作为施用后的测定值。结果示于表2中。化合物施用组与溶剂施用组相比,膀胱疼痛阈值显著增加(全部p<0.05,检验方法:学生t检验(Student’s t-test)),从而确认化合物对膀胱疼痛的镇痛作用。
表2
实施例4
化合物对睾丸疼痛模型大鼠的作用
使用病态模型研究化合物对睾丸疼痛的镇痛作用。使用注射针向大鼠左右睾丸中以各为1ml/kg的量注射1%乙酸来进行处理时,观察到睾丸疼痛所伴有的疼痛行为(writhing),因此能够评价对该疼痛行为的药效。实验中,使用3-4周龄的Wistar系雄性大鼠(日本チヤ一ルス·リバ一株式会社)(n=9-13)。使用0.5%甲基纤维素作为溶剂来经口施用受试化合物(3mg/5ml/kg),55分钟后或115分钟后用乙酸进行睾丸内处理,将大鼠转移到直径为30cm、高度为50cm的丙烯酸圆筒状笼中,测定乙酸处置后5分钟至15分钟的疼痛行为的次数。结果示于表3中。化合物施用组与溶剂施用组相比,疼痛行为的次数显著减少(全部p<0.01,检验方法:学生t检验(Student’s t-test)),从而确认化合物对睾丸疼痛的镇痛作用。
表3
由上述各试验的结果确认,这些化合物基于FAAH抑制作用,不仅具有增大有效膀胱容量的作用,而且对膀胱疼痛和睾丸疼痛具有镇痛作用。因此,式(I)的化合物或其盐能够用于预防或治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征。
产业实用性
本发明的有效成分即式(I)的非芳香族含氮杂环-1-羧酸吡啶基酯化合物或其盐能够作为间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂使用。
Claims (6)
1.一种间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂,其以式(I)的化合物或其盐作为有效成分,
式(I)中,
A为苯环、5~7元环烷烃环或5~7元含氮杂环;
L为单键、低级亚烷基、低级亚烯基、-N(R8)-CO-、-CO-N(R8)-、-低级亚烯基-CO-、-O-或-CO-;
R8为H或低级烷基;
X为CH或N;
R1、R2和R3相同或不同地为H、卤素、-CN、-CF3、低级烷基、-O-低级烷基、可由选自下述G组的基团取代的芳基、可由选自下述G组的基团取代的含氮杂芳基、R9-低级亚烷基-O-、R9-低级亚烷基-N(R8)-或R10R11N-CO-;
R9为可由选自下述G组的基团取代的芳基、可由选自下述G组的基团取代的含氮杂芳基或5~7元环烷基;
R10和R11相同或不同地为H或低级烷基,或者与所键合的N原子成为一体而形成5~7元含氮杂环;
G组由卤素、-CN、-CF3、低级烷基和-O-低级烷基组成;
R4为H或低级烷基;
R5、R6和R7相同或不同地为H、低级烷基、-CO-O-低级烷基、-CO2H或-CONH2。
2.如权利要求1所述的预防剂或治疗剂,其中,
式(I)的化合物或其盐为选自由下述化合物组成的组中的化合物或其盐:
4-{4-[(3-氟苄基)氧基]苯氧基}哌啶-1-羧酸吡啶-3-基酯、
5-{[(4-{4-[(3-氟苄基)氧基]苯氧基}哌啶-1-基)羰基]氧基}烟酸、
5-({[4-(2-苯基乙基)哌啶-1-基]羰基}氧基)烟酸、
5-[({4-[4-(2-环己基乙氧基)苯氧基]哌啶-1-基}羰基)氧基]烟酸、
5-[({4-[(E)-2-苯基乙烯基]哌啶-1-基}羰基)氧基]烟酸、
5-{[(4-{3-[1-(6-甲基吡啶-2-基)哌啶-4-基]丙基}哌啶-1-基)羰基]氧基}烟酸、
4-{2-[3-(氨基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-(2-{3-[(二甲基氨基)羰基]苯基}乙基)哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-{2-[3-(哌啶-1-基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-{2-[3-(吡咯烷-1-基羰基)苯基]乙基}哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-[(2E)-3-苯基丙-2-烯酰基]哌嗪-1-羧酸吡啶-3-基酯、
4-(苯胺基羰基)哌啶-1-羧酸吡啶-3-基酯、
4-(2-苯基乙基)哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-(2-苯基乙基)哌嗪-1-羧酸吡啶-3-基酯、
4-(2-苯基乙基)哌嗪-1-羧酸5-(甲氧基羰基)吡啶-3-基酯、
4-[2-(3-氟苯基)乙基]哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-[2-(3-氰基苯基)乙基]哌啶-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-(5-苯基戊基)哌嗪-1-羧酸5-(氨基羰基)吡啶-3-基酯、
4-(3-苯基-1H-1,2,4-三唑-5-基)哌啶-1-羧酸吡啶-3-基酯、
4-[3-(4-氟苯基)-1H-1,2,4-三唑-5-基]哌啶-1-羧酸6-甲基吡啶-3-基酯、
4-[3-(2-氟苯基)-1H-1,2,4-三唑-5-基]哌啶-1-羧酸2-甲基吡啶-3-基酯和
4-(3-苯基-1H-吡唑-1-基)哌啶-1-羧酸6-甲基吡啶-3-基酯。
3.权利要求1所述的式(I)的化合物或其盐在制造间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防剂或治疗剂中的应用。
4.权利要求1所述的式(I)的化合物或其盐在预防或治疗间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征中的应用。
5.用于在间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防或治疗中使用的权利要求1所述的式(I)的化合物或其盐。
6.一种间质性膀胱炎/膀胱疼痛综合征和/或慢性非细菌性前列腺炎/慢性骨盆疼痛综合征的预防或治疗方法,其包括对哺乳动物施用有效量的权利要求1所述的式(I)的化合物或其盐。
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