CN1541093A - 联用的5-ht1a激动剂和选择性5-羟色胺再吸收抑制剂的新应用 - Google Patents
联用的5-ht1a激动剂和选择性5-羟色胺再吸收抑制剂的新应用 Download PDFInfo
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- CN1541093A CN1541093A CNA018191118A CN01819111A CN1541093A CN 1541093 A CN1541093 A CN 1541093A CN A018191118 A CNA018191118 A CN A018191118A CN 01819111 A CN01819111 A CN 01819111A CN 1541093 A CN1541093 A CN 1541093A
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Classifications
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- A—HUMAN NECESSITIES
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- 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
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Abstract
本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂的化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐在制备用于治疗慢性疼痛疾病或在治疗对疼痛信号、痛觉过敏、异常性疼痛、疼痛感觉增强和疼痛记忆增强存在致超敏作用的其它疾病以及用于治疗过敏性肠综合征(IBS)的药物中的应用。
Description
本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物在制备用于治疗慢性疼痛的药物中的应用。
本发明特别涉及联用的5-HT1A激动剂和选择性5-羟色胺再吸收抑制剂在制备用于治疗慢性疼痛的药物中的应用,其中所述的化合物选自1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐组成的组。
从美国专利US 5,532,241中得知了1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐(US 5,532,241,第7栏,第30-58行)及其制备方法(US5,532,241,实施例4)。在该专利中描述了作为联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的本文涉及的化合物。因此,本文公开了1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的酸加成的盐在制备用于治疗下列疾病的药物中的应用:抑郁性疾病,包括亚型疾病,主要是抑郁性疾病和忧郁性疾病;焦虑性疾病;精神性疾病,如精神病、精神分裂症或情感分裂症;脑梗塞,如中风和大脑局部缺血;CNS疾病,诸如紧张;治疗高血压中副作用的疗法(例如使用α-甲基多巴);且本文还公开了1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的酸加成的盐在制备用于预防和治疗大脑疾病的药物中的应用。另外,本文描述了这些化合物在内分泌学和妇科学中的应用,例如它们在治疗肢端肥大症、性腺机能减退、继发性闭经、月经前期综合征或不理想的产后哺乳中的应用。
从EP 0 736 525中得知了3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐(EP 0 736 525,第3页,第5、26行和第8页第28行-第9页第12行)及其制备方法(EP 0 736 525,实施例1)。它们特别表现出对中枢神经系统的作用、特别是5-HT1A-兴奋性和5-HT-再吸收抑制作用。因此,它们适合于治疗中枢神经系统疾病,诸如紧张状态、抑郁症和/或精神病和高血压治疗中的副作用。另外,本文描述了这些化合物在内分泌学和妇科学中的应用,例如在治疗肢端肥大症、性腺机能减退、继发性闭经、月经前期综合征或不理想的产后哺乳中的应用;且本文进一步描述了这些化合物在预防和治疗大脑疾病、特别是类似于某些麦角生物碱在老年病中和控制诸如中风和大脑局部缺血这样的脑梗塞(脑中风)后遗症中的应用。
本发明的主题是提供联用的5-HT1A激动剂和选择性5-羟色胺再吸收抑制剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪及其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈及其生理上可接受的盐的新应用。
已经发现联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A激动剂、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐还对疼痛、尤其是对慢性疼痛具有活性。
美国专利US 5,532,241中公开了诸如1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪这样的哌嗪类及其生理上可接受的酸加成的盐具有止痛作用。然而,这类哌嗪在治疗疼痛、尤其是在治疗慢性疼痛中的应用尚未公开。
所公开的止痛作用不会必然产生对慢性疼痛的有效治疗。急性疼痛是神经系统中产生的使个体意识到可能的损伤的正常感觉。慢性疼痛是因最初损害或损伤消失后神经系统中持久疼痛信号持续发生而导致的。慢性疼痛可以在没有任何已往损伤存在或没有身体受损的证据情况下发生、即所谓的精神性疼痛。
本文所用的术语疼痛应指的是所有类型的疼痛。优选该术语指的是所有类型的慢性疼痛、包括伤害感受疼痛、神经病性疼痛、精神性疼痛和混合类疼痛(伤害感受疼痛和神经病性疼痛组成)。它特别包括但不限于糖尿病性神经病、神经原性疼痛、中枢性痛、躯体痛、内脏痛和癌症痛、炎症疼痛、术后疼痛、慢性后背疼痛、坐骨神经痛、颈和腰痛、紧张性头痛、丛集性头痛、每日慢性头痛、疱疹神经痛和疱疹后遗神经痛、面部和口腔神经痛以及肌筋膜痛综合征、假性肢痛、残肢痛和截瘫痛、牙痛、耐阿片样物质疼痛、包括心脏手术和乳房切除术在内的术后疼痛、劳累和分娩疼痛、分娩后疼痛、中风后疼痛、心绞痛、包括骨盆疼痛和膀胱炎以及阴道前庭炎和睾丸痛在内的泌尿生殖道疼痛、过敏性肠综合征、月经前期疼痛综合征、因烧伤和化学损伤或日晒导致的疼痛和骨损伤性疼痛。
伤害感受性疼痛的亚型是躯体痛和内脏痛。
躯体痛包括炎症疼痛、术后疼痛、慢性后背痛、颈和腰痛、丛集性疼痛、牙痛、劳累和分娩疼痛、分娩后疼痛、因烧伤和化学损伤或日晒导致的疼痛和骨损伤性疼痛。内脏痛包括癌症痛、包括心脏手术在内的术后疼痛、心绞痛、包括骨盆疼痛和膀胱炎以及阴道前庭炎和睾丸痛在内的泌尿生殖道疼痛和月经前期疼痛综合征。神经病性疼痛的亚型是糖尿病性神经病、癌症痛、神经原性疼痛、中枢性痛、坐骨神经痛、疱疹性神经痛、疱疹后遗神经痛、面部和口腔神经痛、假性肢痛、残肢痛和截瘫痛、耐阿片样物质疼痛、包括乳房切除术在内的术后疼痛和中风后疼痛。精神性疼痛的亚型是每日慢性头痛和紧张性头痛。混合类头痛的亚型是癌症痛、肌筋膜痛综合征和紧张性头痛(例如McCaffery M,Pasero C.《疼痛临床手册》(Pain:Clinical Manual)p19 St.Louis:Mosby 1999;Merskek H和Bogduk(编辑)《慢性疼痛分类》(Classification of chronicpain),第2版,IASP Task Force on Taxonomy,p 209-214,IASP Press,Seattle 1994;The Merck Manual,第14部分,167节,“疼痛”(Pain),第17版Merck & Co 1999)。
选择性5-羟色胺再吸收抑制剂(SSRIs)在各种疼痛适应症中的有效性已经在动物和人中得到了证实。
例如,已经证实SSRIs可增强传统阿片类止痛药的作用且它们本身对各种动物模型中的急性疼痛、炎症疼痛和神经病性疼痛有效(例如Messing等,《精神药理学通讯》(Psychopharmacol.Commun.)1975,1:511-521;Hynes等,《生命科学》(LifeSci.)1985,36:2317-2323;Larsen和Arnt,《药理学与毒理学综合学报》(Acta Pharmacol Toxicol.Copenh.)1985,57:345-351;Larsen和Hyttel,《药理学与毒理学综合学报》(ActaPharmacol Toxicol.Copenh.)1985,57:214-218;Yamamoto等,Nippon Yakurigaku Zasshi 1989,94:189-206;Fasmer等,《神经药理学》(Neuropharmacology)1989,28:1363-1366;Ardid等,《临床药理学基础》(Fundam.Clin.Pharmacol.)1992,6:75-82;Akunne和Soliman,《药理学和生物化学作用》(Pharmacol.Biochem.Behav.)1994,48:411-416;例如Schreiber等,《欧洲神经精神药理学》(Eur.Neuropsychopharmacol.)1996,6:281-284;Korzeniewska等,《药理学和生物化学作用》(Pharmacol.Biochem.Behav.)1998,59:331-338;Luger等,《(药理学与毒理学》(Pharmacol.Toxicol.)1999,85:263-268;Sawynok等,《疼痛》(Pain)1999,82:149-158;McCleane,《疼痛》(Pain)2000,85:311-312)。
SSRIs还对健康志愿者中的实验性疼痛有效(Coquoz等,Schweiz.Med.Wochenschr.1991,121:1843-1845;Coquoz等,《临床药物疗法》(Clin.Pharmacol.Ther.)1993,54:339-344)且更具体地说对患有各种慢性疼痛的患者有效,如头痛(紧张性头痛)、糖尿病性神经病、自发性疼痛、后背痛、假性肢痛、风湿性疼痛、过敏性肠综合征、月经前期疼痛综合征或弥漫性或混合性疼痛综合征(例如神经根疼痛、非典型胸痛)(例如Theesen和Marsh,DICP 1989,23:572-574;Sindrup等,《疼痛》(Pain)1990,42:135-144;Sindrup等,《药物疗法监测》(Ther.Drug Monit.)1991,13:408-414;Petitto等,《心身医学》(Psychosomatics)1992,33:338-341;Boyer,《国际临床精神药理学》(Int.Clin.Psychopharmacol.)1992,6(增刊5);5-12;Power-Smith和Turkington,《英国精神病学杂志》(Br.J.Psychiatry)1993,163:105-106;Manna等,《头痛》(Headache)1994,34:44-49;Langemark和Olesen,《头痛》(Headache)1994,34:20-24;最后,《药物疗法年鉴》(Ann.Pharmacother.)1994;28:1359-1369;Saper等,《头痛》(Headache)1994,34:497-502;Gruber等,《北美临床精神病学》(Psychiatr.Clin.NorthAm.)1996,19:351-369;Rani等,《麻醉止痛药》(Aneth.Analg.)1966,83:371-375;McQuay等,《疼痛》(Pain)1996,68:217-227;Jung等,《国际遗传药物杂志》(J.Gen.Intern.Med.)1997,12:384-389;Abramson和Garfin,《疼痛》(Pain)1999,83:137-145;Baraczka等,Orv.Hetil.1997,138:2605-2607;O’Mally 等,J.Fam.Pract.1999,48:80-990;Ciaramella等,Minerva Anestesiol.2000,66:55-61;Ansari,Harv.Rev.Psychiatry 2000,7:257-277)。
此外,SSRIs是抑郁性疾病中使用最频繁的药物,而对抑郁症和疼痛而言具有高合并发病率且甚至它们可能共有常见的病因学(例如Ekselius等,《斯堪地那维亚康复药物杂志》(Scand.J.Rehabil.Med.)1997,29:91-96;Max等,《新英格兰药物杂志》(N.Engl.J.Med.)1992,326:1250-1256;Gruber等,《北美临床精神病学》(Psychiatr.Clin.North Am.)1996,19:351-369)。
最后,选择性5-羟色胺5-HT1A受体激动剂减轻了在动物急性和慢性疼痛和炎症疼痛模型中的疼痛(例如Fasmer等,《药理学和生物化学作用》(Pharmacol.Biochem.Behav.)1986,25:883-888;Bragin等,《疼痛》(Pain)1989,36:257-261;Giordano和Rogers,《疼痛》(Pain)1989,39:109-113;Murphy和Zemlan,《神经药理学》(Neuropharmacology)1990,29:463-468;Crisp等,《遗传药理学》(Gen.Pharmacol.)1991,22:247-251;Danzebrink和Gebhart,《大脑研究》(Brain Res.)1991,538:64-75;Eide和Hole,《神经药理学》(Neuropharmacology)1991,30:727-731;Giordano和Rogers,《疼痛》(Pain)1992,50:365-372;Mjellem等,《神经学报告》(Neuroreport)1992,3:1061-1064;Eide和Hole,《头痛》(Cephalagia)1993,13:75-85;Korneyev和Seredenin,《生命科学》(LifeSci.)1993,52:997-1004;Cervo等,《欧洲药理学杂志》(Eur.J.Pharmacol.)1994,263:187-191;Xu等,《药理学实验疗法杂志》(J.Pharmacol.Exp.Ther.)1994,269:1182-1189;Sanchez等,《神经学报告》(Neuroreport)1995,6:2585-2588;Millan等,《大脑作用研究》(Behav.Brain Res.)1996,73:69-77;Robles等,《欧洲药理学杂志》(Eur.J.Pharmacol.)1996,295:181-188;Galeotti等,《药理学和生物化学作用》(Pharmacol.Biochem.Behav.)1997,57:835-841;Rouzade等,《消化疾病科学》(Digest.Dis.Sci.)1998,43:2048-2054;Jain和Kulkarni,《临床实验药理学方法探索》(Meth.Find.Exp.Clin.Pharmacol.)1999,21:161-165;Shannon和Lutz,《精神药理学》(Psychopharmacology)2000,149:93-97)。就我们的知识而言,因市场上缺乏选择性5-HT1A激动剂而尚未获得在疼痛患者中的临床效果。
因此,作为在1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪及其盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈及其盐中认识到的5-羟色胺再吸收抑制特性和5-羟色胺5-HT1A激动剂特性的组合在治疗慢性疼痛疾病或在治疗对疼痛信号、痛觉过敏、异常性疼痛、疼痛感觉增强和疼痛记忆增强存在致超敏作用的其它疾病中代表了超过单独SSRIs的优点。
因此,本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物在制备用于治疗慢性疼痛的药物中的应用。
因此,本发明涉及1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐在制备用于治疗慢性疼痛的药物中的应用。
本发明进一步涉及3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐在制备用于治疗慢性疼痛的药物中的应用。
1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的优选的盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐。
因此,本发明涉及制备治疗慢性疼痛的药物的应用,其中1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的生理上可接受的盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的盐酸盐。
3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的优选盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈盐酸盐。
因此,本发明涉及制备治疗慢性疼痛的药物的应用,其中3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的生理上可接受的盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的盐酸盐。
另外,本发明涉及含有至少一种联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐以及至少一种固体、液体或半固体赋形剂或辅助剂的药物组合物在治疗慢性疼痛中的应用。
因此,本发明提供了治疗疼痛的药物制剂,其特征在于它至少含有1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其药物上可接受的盐之一。
因此,本发明提供了治疗疼痛的药物制剂,其特征在于它至少含有3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其药物上可接受的盐之一。
优选以与其它已知商购治疗疼痛的制剂(例如度洛西汀(duloxetine))相似的方式给予本发明联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物。单位剂量一般含有0.1-1000mg、优选约0.1-500mg,特别是5、10、20、30、40、50、100、150、200、250和300mg。组合物可以给予一次或几次,例如每天2、3或4次。每日剂量约为0.01-50mg/kg体重。然而,对各患者而言的特定剂量取决于各种因素,例如取决于所用特定化合物的活性、体重、一般健康情况、性别、饮食、给药时间和给药途径、排泄率、药物物质的组合和疗法涉及的特定疾病的严重程度。优选口服给药,而且也可以使用非口服(peroral)给药途径(例如静脉内或经皮)。
优选用联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐治疗的慢性疼痛是伤害感受性疼痛。优选的伤害感受性疼痛适应症是炎症和术后疼痛。
因此,本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐在制备用于治疗伤害感受性疼痛的药物中的应用。
优选用联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐治疗的慢性疼痛是神经病性疼痛。优选的神经病性疼痛适应症是神经原性疼痛和面部和口腔神经痛。
因此,本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐在制备用于治疗神经原性疼痛的药物中的应用。
另外,已经发现联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐进一步用于治疗对疼痛信号、痛觉过敏、异常性疼痛、疼痛感觉增强和疼痛记忆增强存在超致敏作用的其它疾病。优选的适应证是过敏性肠综合征。
过敏性肠综合征(IBS)是导致痉挛性疼痛、泛气、胃气胀和排便习惯改变的常见肠紊乱。IBS的原因尚不了解,但通常认为它是由情感冲突或压力造成的。IBS是所谓的功能性紊乱,因为当检查结肠时没有疾病的症候。患有IBS的人通常具有带有痛性便秘或腹泻的痉挛性腹痛。
因此,本发明涉及联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐在制备用于治疗炎症性肠综合征的药物中的应用。
1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的优选盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐。
因此,本发明涉及制备治疗过敏性肠综合征的药物的应用,其中1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的药物上可接受的盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的盐酸盐。
3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的优选盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的盐酸盐。
因此,本发明涉及制备治疗过敏性肠综合征的药物的应用,其中3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的药物上可接受的盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的盐酸盐。
另外,本发明涉及含有至少一种联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、特别是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐以及至少一种固体、液体或半固体赋形剂或辅助剂的药物组合物在治疗过敏性肠综合征中的应用。
因此,本发明提供了用于治疗过敏性肠综合征的药物制剂,其特征在于它至少含有1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其药物上可接受的盐之一。
因此,本发明提供了用于治疗过敏性肠综合征的药物制剂,其特征在于它至少含有3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其药物上可接受的盐之一。
优选以与其它已知商购治疗过敏性肠综合征(IBS)的制剂相似的方式给予本发明联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物。单位剂量一般含有0.1-1000mg、优选约0.1-500mg,特别是5、10和20mg。可以将该组合物每天给予一次。每日剂量约为0.01-10mg/kg体重。然而,对各患者而言的特定剂量取决于各种因素,例如取决于所用特定化合物的活性、体重、一般健康情况、性别、饮食、给药时间和给药途径、排泄率、药物物质的组合和疗法涉及的特定疾病的严重程度。优选口服给药,而且也可以使用非口服(peroral)给药途径(例如静脉内或经皮)。
可以将用于治疗疼痛或优选用于IBS的药物制剂用作人用或兽用医药中的药物。
用于治疗慢性疼痛的药物制剂的制备方法的特征在于将选自1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐组成的组的一种联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物转化成含有至少一种固体、液体或半固体或辅助剂的适宜剂型。
合适的赋形剂是适合于肠(例如经口腔)、非肠道或局部给药且不与1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪和/或其生物适合性盐之一发生反应的有机或无机物质,例如水、植物油、苄醇类、烷撑二醇类、聚乙二醇类、甘油三乙酸酯、明胶、诸如乳糖或淀粉这样的碳水化合物、硬脂酸镁、滑石、矿脂。用于口服给药的剂型特别是片剂、丸剂、包糖衣片、胶囊、粉剂、颗粒剂、糖浆剂、液体或滴剂;用于直肠给药的剂型特别是栓剂;用于非肠道给药的剂型特别是溶剂的溶液、优选油或水溶液、还有混悬剂、乳剂或植入物;且局部给药用剂型是经皮膏药、软膏、霜剂或粉剂。还可以将1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪和/其药物上可接受的盐之一冻干并且将所得冻干物用于例如制备可注射产品。上述制剂可以是无菌剂型和/或包括助剂,诸如助流剂、防腐剂、稳定剂和/或湿润剂、乳化剂、改变渗透压的盐、缓冲物质、着色剂、香料和/或其它活性物质、例如一种或多种维生素。
如果需要,可以将制剂设计成1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生物相容性盐的缓释制剂。
下列实施例涉及用于解释联用的5-HT1A激动剂和5-羟色胺再吸收抑制剂有效性的动物模型。
实施例1:小鼠和大鼠中用于测试疼痛缓解的急性止痛特性的步骤
1.按照Eddy和Leimbach所述的对小鼠或大鼠的热板试验(《药理学实验疗法杂志》(J.Pharmacol.Exp.Ther.)1953,107:385-393):
将小鼠或大鼠置于对小鼠而言维持在54℃下的热金属平板或对大鼠而言维持在52℃的热金属平板上,热金属平板上包围有有机玻璃圆筒(高:13cm;直径:19cm)。测定第一次舔足的潜伏期(最大值:30秒)。
2.按照D’Amour和Smith所述对小鼠或大鼠进行的甩尾试验(《药理学实验疗法杂志》(J.Pharmacol.Exp.Ther.)1941,72:74-79):
通过热光源加热动物的尾部。测定动物抽回尾部前的潜伏期(最大值:对小鼠而言为15秒,对大鼠而言为30秒)。
3.由Escalier等描述的对小鼠或大鼠进行的电击敏感性试验(《欧洲药理学杂志》(Eur.J.Pharmacol.)1981,74:1-7):
将每只动物置于与给动物爪传输短暂电休克的电休克发生器连接的栅极底板上。在1mA电流强度下给予3次电击,每次持续0.5秒的期限。
电击间隔30秒。使用引入3种参数的等级标准对电休克的反应进行定量:跳、发声和逃逸(各参数的得分为0、1或2)。取获自3次电击的所有3种参数的总得分作为对电休克敏感性的测定值。
4.按照Weiss和Laties所述进行的电击滴定试验(ShockTitration Test)(《欧洲药理学杂志》(Eur.J.Pharmacol.)1961,131:120-129):
装置由安装了家用光源的声音减弱的标准剥皮箱(Skinner)(23×21×18cm)、一个杠杆和与程控施加电击发生器(Imetronic)连接的栅极底板组成。该剥皮箱与控制实验的MED.PC操作系统连接且自动采集数据。首先在实验室内训练大鼠压杠杆以便终止间隔5秒给予的电击休克(0.8mA)(逃逸训练)。然后训练它们通过压杠杆控制电休克强度(30个分级阶梯:0.03-0.9mA)。当大鼠在有电击的情况下压杠杆时,终止电击并在5秒后返回到下一个较低的强度。如果大鼠在电击存在过程中不起反应,那么在5秒后自动终止电击并在5秒后返回到下一个较高的强度(电击滴定)。在电击之间的压杠杆(试验内反应)没有结果。每次训练期限持续15分钟并在第10个电流强度水平(0.3mA)开始。在每次期限前60分钟动物接受给予测试化合物的载体。取两次行为的测定值:将每只大鼠的中值电击水平(伤害感受阈值)定义为动物接受50%电击上下的电流强度并将内部试验反应定义为电击存在之间发生的压杠杆的次数。对连续两周内达到稳定基线情况的动物进行药物测试。每周给予两次药物测试期限,其中在药物测试期限之间至少一次训练期限中不使用药物。每周对动物测试(训练和试验期限)5天(周一至周五)。如上所述,15分钟后终止期限。将每只动物用作其自身的对照并在各自测试期限中接受所有选择的治疗和对照品(载体)。通过确保不同治疗时间上的平均分布的步骤确定治疗的顺序。始终在同一剥皮箱中按照相同的顺序和一天当中相同的时间测试每只动物。
5.按照Hendershot等描述的方法对小鼠进行的苯基苯醌和乙酸扭动试验(《药理学实验疗法杂志》(J.Pharmacol.Exp.Ther.)1959,125:237-240):
给小鼠注射苯基苯醌(PBQ)(1.25mg/kg腹膜内)或乙酸(0.5%腹膜内)。这种治疗方法在对照动物中诱发可识别的扭动反应。从注射PBQ或乙酸后5分钟开始对扭动的次数计数10分钟。
口服给予30mg/kg 1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐使扭动次数减少了82%。
实施例2:小鼠和大鼠中用于测试与抗炎过程相关的疼痛缓解特性的步骤
1.按照Wheeler-Aceto等所述对小鼠或大鼠进行的福尔马林爪试验(《精神药理学》(Psychopharmacology)1991,104:35-44):
将5%福尔马林(对小鼠而言为25ul,对大鼠而言为50ul)经足底内注入动物后左爪。这种治疗方法在对照动物中诱发可识别的退缩反应。在小鼠中从注射福尔马林后立即开始(早期)对退缩的次数计数10分钟并且再次计数5分钟或在注射后20分钟开始在大鼠中计数15分钟。
口服给予30mg/kg 1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐使福尔马林诱发的疼痛反应减少了79%。
实施例3:小鼠和大鼠中用于测试与抗炎过程相关的疼痛缓解的特性和抗炎/解热特性的步骤
1.按照Winter等描述在大鼠中进行的角叉菜胶水肿试验(《国家实验生物药物协会》(Proc.Soc.Exp.Biol.Med.)1962,111:544-547):
将角叉菜胶溶液注入动物右后爪的下表面(溶于0.05ml生理盐水的0.75mg/爪)。2小时后连续给大鼠的未红肿发炎和红肿发炎的后爪均进行热和触觉刺激。就热刺激而言,装置(Ugo Basile,Reference:7371)由置于升起的玻璃板上的6个独立的有机玻璃盒(plexiglas box)(17×11×13cm)组成。将大鼠置于盒中并保持自由习惯10分钟。然后使活动的红外线光源(设定在20)聚焦在未红肿发炎和红肿发炎的后爪中并自动记录爪退缩的潜伏期。爪的退缩阻断了反射光并切断了计数器和光源。为了防止组织损害,如果没有观察到反应,那么在45秒后终止该试验。为了进行触觉刺激,将动物置于栅极底板上的倒置有机玻璃盒(17×11×13cm)下。然后将带有增加压力的电Von Frey探头顶端施加给未红肿发炎和红肿发炎的后爪并自动记录诱发爪退缩所需的力。将该步骤进行3次并计算平均力/爪而得到每只动物的基础得分。3.5小时后通过脱颈椎处死动物并给后爪切片且称重。爪重量增加(水肿)指示炎症。也可以将后一个步骤用于小鼠。
2.按照Teotino等所述对小鼠或大鼠进行的酵母体温过高(Yeast Hyperthermia)试验(《药物化学杂志》(J.Med.Chem.)1963,6:248):
首先使用直肠探测器测定动物的直肠温度。然后给它们注射酵母混悬液(512mg/kg皮下)。8小时后给予测试物质。在给予测试物质前立即测定小鼠的直肠温度且在60分钟和120分钟后再次测定直肠温度。
实施例4:在大鼠中用于测试慢性疼痛和炎症中疼痛缓解特性的步骤
1.按照Whiteley所述对大鼠进行的慢性炎症疼痛试验(弗氏佐剂试验)(《最新药理学方案》(Current Protocols inPharmacology),Wiley,New York,5.5,1999):
给大鼠注射弗氏佐剂诱发带有疼痛的多关节炎的慢性临床症候。在第1天时给大鼠称重并将丁酸分枝杆菌(Mycobacteriumbutyricum)混悬液(弗氏佐剂)经真皮内注入尾部的近端四分之一处(1mg溶于0.1ml矿物油)。假饲对照组接受类似注射的矿物油。在第18天,当慢性状态完全建立时,再次给大鼠称重并评价炎症的临床症状。然后对它们的两个后爪进行连续的热和触觉刺激。就临床症候而言,按照5点等级(0-4)给每只爪的炎症进行评分并按照4-点等级(0-3)给尾部评分,即每只动物的最高得分为19。就热刺激而言,装置(Ugo Basile,Reference:7371)由置于升起的玻璃板上的6个独立的有机玻璃盒(17×11×13cm)组成。将大鼠置于盒中并保持自由习惯10分钟。然后使活动的红外线光源(设定在20)聚焦在每一后爪中并自动记录爪退缩的潜伏期。爪的退缩阻断了反射光并切断了计数器和光源。为了防止组织损害,如果没有观察到反应,那么在45秒后终止该试验。为了进行触觉刺激,将动物置于在栅极底板上的倒置有机玻璃盒(17×11×13cm)下。然后将带有增加压力的电Von Frey探头(Bioseb,Model 1610)顶端施加给每一后爪并自动记录诱发爪退缩所需的力。将该步骤进行3次并计算平均力/爪而得到每只动物的基础得分。在接受药物治疗前对所有动物进行触觉刺激并将其分配到基于其疼痛反应相匹配的治疗组。
2.按照Kim和Chung所述对大鼠进行的神经病性疼痛试验(Chung氏试验)(《疼痛》(Pain)1992,50:355-363):
扎紧大鼠体内的脊神经与痛觉过敏、异常性疼痛和自发性疼痛相关且由此构成了用于人体内外周神经病性疼痛的模型。抗痛觉增敏药缓解了疼痛超敏反应的这些慢性症候。麻醉(戊巴比妥钠40mg/kg腹膜内)大鼠(180-220g)并作L4-S2水平的切口以暴露左侧L5和L6脊神经。用结扎线围绕扎紧每条神经。然后缝合伤口。大鼠接受肌内注射的50 000 IU青霉素并使之恢复。手术后至少2周,当慢性状态完全建立时,对大鼠未受损害和受损害的后爪均进行热和触觉刺激。就热刺激而言,装置(Ugo Basile,Reference:7371)由置于升起的玻璃板上的6个独立的有机玻璃盒(17×11×13cm)组成。将大鼠置于盒中并保持自由习惯10分钟。然后使活动的红外线光源(设定在20)聚焦在未受损害和受损害的后爪中并自动记录爪退缩的潜伏期。爪的退缩阻断了反射光并切断了计数器和光源。为了防止组织损害,如果没有观察到反应,那么在45秒后终止该试验。为了进行触觉刺激,将动物置于在栅极底板上倒置的有机玻璃盒(17×11×13cm)中。然后带有增加压力的电Von Frey探头顶端施加给未受损害和受损害的后爪并自动记录诱发爪退缩所需的力。将该步骤进行3次并计算平均力/爪而得到每只动物的基础得分。在接受药物治疗前对所有动物进行触觉刺激并将其分配到基于其疼痛反应相匹配的治疗组。
下列实施例涉及药物产品:
实施例A:小瓶
用2N盐酸将100g联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物和5g磷酸氢二钠溶于3升双蒸水所得到的溶液调节至pH6.5、进行无菌过滤、过滤入小瓶、在无菌条件下冻干并密封成无菌剂型。各小瓶中包括5mg活性组分。
实施例B:栓剂
将20g联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物的混合物与100g大豆卵磷脂和1400g可可脂一起熔化并将该混合物倾入塑模且保持冷却。每一个栓剂包括20mg活性组分。
实施例C:溶液
由1g联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂化合物、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵溶于940ml双蒸水制备溶液。将pH调节至6.8并将该溶液制成1升且通过照射灭菌。该溶液可以滴眼液形式使用。
实施例D:软膏
在无菌条件下将500mg联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的化合物与99.5g矿脂混合。
实施例E:片剂
按照常规方式将1kg联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的化合物、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物压片,使得每片含有10mg活性组分。
实施例F:包糖衣片
按照与实施例E类似的方式对混合物压片且随后按照常规方式给片剂包上诸如蔗糖、马铃薯淀粉、滑石、黄蓍胶和着色剂这样的包衣材料。
实施例G:胶囊
按照常规方式将2kg联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的化合物填入硬胶囊,使得每一个胶囊含有20mg活性组分。
实施例H:安瓿
将1kg联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的化合物溶于60升双蒸水所得到的溶液进行无菌过滤、装入安瓿、在无菌条件下冻干并密封成无菌剂型。每个安瓿中包括10mg活性组分。
实施例I:吸入喷雾剂
将14g联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂的化合物溶于10升等渗NaCl溶液并将该溶液装入商购的泵操作喷雾容器中。将该溶液喷入口腔或鼻部。一次启动(约0.1ml)相当于约0.14mg。
Claims (10)
1.联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物在制备用于治疗慢性疼痛的药物中的应用。
2.权利要求1的应用,其中联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物选自1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐组成的组。
3.权利要求2的应用,其中所述1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的生理上可接受的盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐。
4.权利要求2的应用,其中所述3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的生理上可接受的盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈盐酸盐。
5.用于治疗慢性疼痛的药物制剂,其特征在于它含有联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂中的至少一种化合物。
6.联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物在制备用于治疗过敏性肠综合征的药物中的应用。
7.权利要求6的应用,其中联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRIs)和5-HT1A受体激动剂化合物选自1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪或其生理上可接受的盐或3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈或其生理上可接受的盐组成的组。
8.权利要求7的应用,其中所述1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪的生理上可接受的盐是1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基-苯并呋喃-5-基)-哌嗪盐酸盐。
9.权利要求7的应用,其中所述3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈的生理上可接受的盐是3-{4-[4-(4-氰基-苯基)-哌嗪-1-基]-丁基}-1H-吲哚-5-腈盐酸盐。
10.用于治疗过敏性肠综合征的药物制剂,其特征在于它含有联用的选择性5-羟色胺(5-HT)再吸收抑制剂(SSRI)和5-HT1A受体激动剂中的至少一种化合物。
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