CN1764457A - 用于治疗阿尔茨海默病的联合疗法 - Google Patents
用于治疗阿尔茨海默病的联合疗法 Download PDFInfo
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- CN1764457A CN1764457A CNA2004800080354A CN200480008035A CN1764457A CN 1764457 A CN1764457 A CN 1764457A CN A2004800080354 A CNA2004800080354 A CN A2004800080354A CN 200480008035 A CN200480008035 A CN 200480008035A CN 1764457 A CN1764457 A CN 1764457A
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Abstract
本发明公开了与beta-淀粉在脑部沉积有关疾病,例如阿尔茨海默病,的治疗或预防,通过联合施用生长荷尔蒙促分泌素和PDE4抑制剂。
Description
本发明涉及用于人体治疗的方法和材料的用途。具体地是,本发明提供了与β-淀粉在脑中沉淀相关疾病的治疗方法,例如阿尔茨海默病(老年性痴呆),或提供了阻止或延缓与所述疾病相关的痴呆的发作的方法。
阿尔茨海默病(AD)是痴呆症中最普遍的形式。它的诊断描述在由美国精神病治疗协会(American Psychiatric Association)出版的精神病的诊断和统计手册第四版(the Diagnostic and StatisticalManual of Mental Disorders,4th ed.,DSM-IV)中。它是一种神经退化性疾病,在临床表现为记忆和一般认知功能的渐进退化,并且在病理学表现在大脑皮质和相关的脑部受损区域有细胞外蛋白质斑沉积。这些斑主要包含纤维聚合的β-淀粉样肽(β-amyloid peptide,Aβ),Aβ是由淀粉样蛋白前体(APP)经过包含β-分泌酶(β-secretase)和γ分泌酶(γ-secretase)的分裂细胞内蛋白水解作用而形成的。当分泌到细胞外介质中之后,最初可溶的Aβ形式聚集并最终形成不可溶的沉淀并且沉积成为神经炎斑,也就是AD的病理学特征。
其它的与Aβ在脑部沉积有关的发病症状包括脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementia pugilistica)和唐氏综合症(Down Syndrome)。
在斑块形成过程中的各种干涉均被建议用于治疗AD(见,例如,Hardy and Selkoe,Sience,297(2002),353-6),包括降低脑部的Aβ负担。例如,Carro等人,在Nature Medicine,8(2002),1390-7,公开了在皮下施予胰岛素样生长因子(Insulin-like Growth Factor1 IGF-1)可以减轻特定啮齿动物脑中Aβ负担。然而,一些作者质疑是否是Aβ的分泌导致神经元的损失而又直接导致了阿尔茨海默类型的痴呆症(见,例如,Robinson和Bishop,Neurobiology of Aging,23(2002),1051-72;以及New Scientist,Feb.12003,35-37)。
生长荷尔蒙(growth hormone)被建议用来治疗AD。如,US4,902,680建议在AD的晚期阶段对病人施于生长荷尔蒙,然而WO00/13650公开了脑部的增加水平的生长荷尔蒙能提供神经保护效果,并且尤其是能使神经元免于受损死亡例如由与神经退化性疾病如AD相关的疾病导致的受损。在脑部注射生长荷尔蒙可被考虑。
化合物生长荷尔蒙复合支持物(生长荷尔蒙促分泌素)(GHSs)是,当施加到动物体(例如人体),激活或提高动物体内在生长荷尔蒙的分泌。它们的作用方式和临床应用的评论在Ankersen et al,DrugDiscovery Today,4(1999),497-506;Casanueva 和Dieguez,TEM,10(1999),30-8;Smith et al,ibid.,10(1999)128-35;Betancourt 和Smith,J.Anti-Aging Med.,5(2002),63-72;和Ghigo et al,ibid.,5(2002),345-56,但是其中并没有提到治疗AD或任何神经退化症状。专利和专利申请公开的GHSs化合物包括US5,767,124,US5,536,716,WO94/13696,EP0615977B,US5,578,593;WO01/04119,WO98/25897,WO98/10653,WO97/36873,WO97/34604,WO97/15574,WO97/11697,WO96/32943,WO96/13265,WO96/02530,WO95/34311,WO95/14666,WO95/13069,WO94/19367,WO94/05634和WO92/16524(所有的归于Merck & Co.,Inc.);EP 1002802A,EP 0995748A,WO98/58948,WO98/58947和WO97/24369(所有的归于Pfizer Inc.);WO01/34593,WO00/26252,WO00/01726,WO99/64456,WO99/58501,WO99/36431,WO98/58950,WO98/08492,WO98/03473,WO97/40071,WO97/40023,WO97/23508,WO97/00894,WO96/24587,WO96/24580,WO96/22997,WO95/17423和WO95/17422(所有的归于Novo Nordisk A/S);WO96/15148(Genentech Inc.);WO97/22620(Deghenghi);WO02/32888,WO02/32878,WO00/49037,WO00/10565和WO99/08699(所有的归于Eli Lilly and Co.)WO02/057241和WO02/056873(两项归于BayerCorp.);并且WO01/85695,WO00/54729和WO00/24398(所有的归于Bridtol-Myers Squibb Co.)。化合物被推荐使用在提高食用动物的增长速度,并且用于人体治疗生理或医学症状特征为缺少生长荷尔蒙的分泌,以及可以用生长荷尔蒙的合成代谢效用改善的医学症状。在上面列出的某些公开中,治疗症状目录中包括AD。
上述US 5,767,124公开的化合物是在未涉及AD的治疗领域内一系列临床试验的目标物(见,例如,Murphy et al,J.Bone Miner.Res.,14,(1999),1182-8;Chapman et al,J.Clinical Endocrinology andMetabolism,81,(1996),4249-57;ibid.,82(1997),3455-63;和Svensson et al,ibid.,83,(1998),362-9)。
3’,5’-环核苷酸磷酸二酯酶(PDEs)是一类酶可以促进把3’,5’-环核苷酸转化为5’-核苷一磷酸。PDE4同工酶是它的亚级,特征在于对cAMP的高选择性和对咯利普兰(rolipram)抑制的敏感性。对PDE4的抑制会造成cAMP的升高水平,众多的PDE4抑制剂在本领域公知(见,例如,WO03/108579,WO02/060875,WO02/074726,W002/098878,WO01/46151,US5,449,686,US5,552,438,WO98/45268和WO99/20625)。主要的治疗目标是发炎和/或过敏症例如关节炎,气喘和其他的肺部疾病,但是cAMP水平的提高也会增加认知能力(见,例如,WO02/074726和WO02/098878)。一般认为咯利普兰(rolipram)和PDE4反应是通过高亲和性咯利普兰(rolipram)结合位置,该位置区别于催化位置,或PDE4以单独的异构形存在,该异构形对咯利普兰(rolipram)有相对高和低的亲和力,并且副反应例如呕吐,是特定的PDE4抑制剂与对咯利普兰(rolipram)高亲和力的所述位置或异构形发生反应导致的。鉴于它们的抗发炎和提高认知的效用,PDE4抑制剂被建议用于治疗阿尔茨海默病。本领域公开了PDE4抑制剂对AD后果的治疗(例如神经炎症和认知损伤),但却既没有公开也没有建议它们在AD的可能成因中的作用,成因例如不可溶的沉淀物Aβ在脑部的积累。
根据本发明,提供了生长荷尔蒙复合支持物(生长荷尔蒙促分泌素)和PDE4抑制剂作为制备治疗或预防与β-淀粉在脑部沉积有关疾病药剂的应用。所述疾病典型地是阿尔茨海默病,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementia pugilistica)和唐氏综合症(Down Syndrome),优选阿尔茨海默病。
根据本发明的第二个方面,提供了生长荷尔蒙复合支持物(生长荷尔蒙促分泌素)和PDE4抑制剂作为制备治疗,预防或延缓痴呆症发病药剂的应用,所述痴呆症是与阿尔茨海默病,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementia pugilistica)和唐氏综合症(Down Syndrome)相关的。
本发明也提供治疗或预防与β-淀粉在脑部沉积有关疾病的方法包含施予所需主体治疗有效剂量的荷尔蒙复合支持物(生长荷尔蒙促分泌素)并联合有效剂量的PDE4抑制剂。所述疾病通常是是阿尔茨海默病,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementiapugilistica)和唐氏综合症(Down Syndrome),优选阿尔茨海默病。
本发明进一步提供了治疗,预防或延缓痴呆症发病的方法,所述痴呆症是与阿尔茨海默病,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementia pugilistica)和唐氏综合症(Down Syndrome)相关的,包含施予所需病人治疗有效剂量的荷尔蒙复合支持物(生长荷尔蒙促分泌素)并联合有效剂量的PDE4抑制剂。
在这里所用的,措词“联合”要求治疗有效剂量的GHS和PDE4抑制剂两者都被施给所需主体,但却对如何完成这一给药的方式不作限制。也就是,两者可以结合在单一药剂量形式中同时施药给主体,或分别制成独立药剂同时或先后施药给主体。先后给药可以是在时间上衔接的或隔一段时间,例如,一种在早晨给药并且另一种在晚上给药。不同的药剂可以以相同的频率给药也可以以不同的频率给药,例如一种药剂一天一次而另一种药剂一天二次或更多次。不同的药剂可以以相同的途径给药也可以通过不同的路径给药,例如一种药剂口服而另一种通过肠胃外给药,虽然对于两种药剂口服均为优选的。
本发明的又一方面是提供了GHS和PDE4抑制剂的联合体用于治疗或预防与β-淀粉在脑部沉积有关疾病,尤其是阿尔茨海默病。所述的应用涉及对需要此种治疗或预防的病人同时或先后施予每一种治疗剂,并且治疗剂可以制成一种药剂量形式或分开独立的药剂量形式。
GHS和PDE4抑制剂被认为可以协同作用促进Aβ从脑部的清除。一般假设GHS引起生长荷尔蒙循环水平的提高,这又会增加胰岛素样生长因子(IGF-1)浆液水平,当其穿过血脑屏障时这能够促进β-淀粉从脑部清除。而PDE4抑制剂被认为会进一步协助这一穿过过程。
因此,本发明又一方面是提供了延迟,阻拦或预防Aβ在脑部累积的方法包含施予所需主体治疗有效剂量的荷尔蒙复合支持物(生长荷尔蒙促分泌素)并联合治疗有效剂量的PDE4抑制剂。施予相关的化合物后Aβ从脑部的清除可由可溶性Aβ在脑脊髓液和/或血浆中的改变水平所观测到。相应地(或附加地),成像技术例如磁共振成像,正电子衍射成像,单光子衍射和多光子显微技术可以用来监测Aβ在脑部沉积的程度(见,例如,Bacskai et al.,J.Cereb.Blood Flow Metab.,22(2002),1035-41)。
本发明的一个实施方案,是将GHS和PDE4抑制剂施药给患AD,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementiapugilistica)和唐氏综合症(Down Syndrome)的病人。
本发明另一个替代的实施方案,将GHS和PDE4抑制剂施药给遭受轻度认知功能损伤或增龄相关认知功能减退(Age-Related CognitiveDecline)的病人。此种治疗的有益结果是预防或延缓AD的发生。增龄相关认知功能减退和轻度认知功能损伤(MCI)的症状是出现了记忆缺失,但是缺少其他的痴呆症的诊断标准(Santacruz and Swagerty,American Family Physician,63(2001),703-13)。(见“The ICD-10Classification of Mental and Behavioural Disorders”,日内瓦:世界卫生组织,1992,64-5)。在这里所用的增龄相关认知功能减退是指至少为期六个月的在至少下述一个方面的衰退:记忆力和学习能力;注意力和集中力;思维;语言;和视觉功能和多于一项的标准偏差值低于正常值在标准化的神经心理学测试中例如MMSE。特别地,出现了记忆力的渐进下降。在更严重的状况MCI,记忆损伤度对于该年龄的病人是超出正常值的单AD症状并未出现。MCI和轻度AD的诊断区别在Ptersen et al.,Arch Neurol.,56(1999),303-8.中有描述。
在这个实施方案中,GHS和PDE4抑制剂更有优势的是给药于遭受记忆功能损伤的患者但是又没有出现痴呆。这样的记忆功能损伤通常不是归于系统或大脑疾病,例如中风或由垂体功能紊乱引起的代谢疾病。这样的病人尤其是那些55岁或以上的人,尤其是60岁或以上的人,尤其是65岁或以上的人。这样的病人有他们年龄段正常的生长荷尔蒙促分泌素的式样和水平。然而,这样的病人有一种或多种额外的风险因素导致阿尔茨海默病。所述的因素包括该疾病的家庭史;对该病遗传的易患病体质;升高的血清胆固醇;和成年发病的糖尿病。另外,Grundman et al(J.Mol.Neurosci.,19(2002),23-28)报道了MCI患者的下降基线海马体积(lower baseline hippocampal volume)是随后AD的预兆指示。同样地,Andreasen et al(Acta Neurol.Scand,107(2003)47-51)报道了整体微管相关蛋白(tau)的高CSF水平,磷酸化微管相关蛋白(phospho-tau)的高CSF水平和Aβ42的降低的CSF水平与增加MCI转化成AD的风险相关。
在本发明一个具体的实施方案中,GHS和PDE4抑制剂施药给遭受增龄相关认知功能减退或轻度认知功能损伤的患者并且所述患者还具有一种或多种会导致发展成AD风险因素,这些因素选自:该疾病的家庭史;对该病遗传的易患病体质;升高的血清胆固醇;和成年发病的糖尿病;下降基线海马体积;整体微管相关蛋白的高CSF水平,磷酸化微管相关蛋白的高CSF水平和Aβ42的降低的CSF水平。
遗传的易患病体质(尤其是针对早期发病的AD)能起源于一种或多种一定数量基因的点突变,包括APP,早老素(presenilin)-1和早老素-2。同时,那些是载脂蛋白E基因的ε4异构形的纯合子具有更大的导致AD的风险。
病人的认知能力减退或损伤度应该在根据本发明的治疗之前,治疗中和/或治疗后作定期评定,以至于可以检测到其中的变化,例如,减缓了或制止了认知能力的减退。已知的本领域的各种的神经心理学检验都可以用来做评定,例如细微精神状态检查(MMSE)并且根据年龄和教育程度校正均值(Folstern et al.,J.Psych.Res.,12(1975),196-198,Anthony et al.,Psychological Med.,12(1982),397-408;Cockrell et al.,Psychopharmacology,24(1988),689-692;Crum et al.,J.Am.Med.Assoc’n.18(1993),2386-2391)。MMSE是成年人认知状况的主要的定量方法。它可以用来检测认知的减退和损伤,来评定在给定时间点上认知减退和损伤的严重性,在一段时间内描述个体的认知变化过程,以及记录个体对治疗的反应。另一个合适的检验是老年性痴呆评定量表(ADAS),尤其是它的认知部分(ADAS-cog)(见Rosen et al.,Am.J.Psychiatry,141(1984),1356-64)。
本发明进一步提供了一个治疗组合包括第一药剂包含GHS和第二药剂包含PDE4抑制剂,以及所述药剂的先后或同时给药的说明,将所述药剂施于患有AD,增龄相关认知功能减退,MIC,脑淀粉样血管病变,多发性脑梗死性痴呆,拳击员痴呆(dementia pugilistica)或唐氏综合症(Down Syndrome)。
本发明所用的GHS可以是任何施于个体后具有刺激和提高内在生长荷尔蒙的分泌的功能的化合物,例如任何上述专利和专利申请所公开的化合物。然而,优选的化合物是那些适合于口服的。
第一类适合于用于本发明的GHS公开在WO94/13696中,尤其是它的子集公开在EP 0615977B中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式I化合物:
命名为N-[1(R)-[(1,2-二氢-1-甲磺酰螺[3H-吲哚-3,4’-哌啶]-1’-基)羰基]-2-(苯甲氧基)乙基]-2-氨基-2-甲丙基酰胺,和它的药物可接受盐,尤其是它的甲基磺酸盐,它的制备在US5,767,124中有描述。
第二类适合于用于本发明的GHS公开在US5,578,593中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式II化合物:
和它的药物可接受盐,它的制备在US5,578,593中有描述。
第三类适合于用于本发明的GHS公开在WO92/16524中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式III和IV的化合物:
和它们的药物可接受盐,尤其是它的三氟乙酸盐,它的制备在WO92/16524中有描述。
第四类适合于用于本发明的GHS公开在WO97/23508中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式V化合物,又为NN703:
和它的药物可接受盐,它的制备在WO99/64456中有描述。
第五类适合于用于本发明的GHS公开在WO 97/24369中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式VI化合物:
命名为2-氨基-N-[2-(3a-(R)-苄基-2-甲基-3-氧基-2,3,3a,4,6,7-六氢-吡唑并[4,3-c]吡啶-5-基)-1-(R)-苄氧甲基-2-氧基-乙基]-异丁酰胺,和它的药物可接受盐,尤其是它的L-酒石酸盐,又为capromorelin,它的制备在WO97/24369和Carpino et al,Bioorg.Med.Chem.,11(2003),581-90中有描述。
第六类适合于用于本发明的GHS公开在WO 98/58947中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式VII化合物:
和它的药物可接受盐,它的制备在WO98/58947中有描述。
第七类适合于用于本发明的GHS公开在WO99/08699中,通过引用在此纳入本发明。在这一类中优选的GHS例子包括式VIII化合物:
和它的药物可接受盐,它的制备在WO99/08699和WO02/32878中有描述。
进一步适合于用于本发明的GHS包括式IX化合物:
和它的药物可接受盐,它的制备在De Vita et al,J.Med.Chem.,41(1998),1716-28中有描述,和式X化合物:
和它的药物可接受盐,它的制备在Yang et al,J.Med.Chem.,41(1998),2439-41中有描述。
优选地,GHS选自上述描述的式I,II,V,VI,VIII和IX化合物,以及它们的药物可接受盐。最优选地,用在本发明的GHS是式I化合物的甲基磺酸盐,它是US 5,767,124描述的多晶型之一。
本发明所用的PDE4抑制剂可以是任何已知的抑制PDE4酶的化合物,或被发现有此功能的化合物。测量PDE4抑制活性的化验在WO01/46151中给出。优选的PDE4抑制剂是在抑制PDE4到治疗有效范围的浓度水平上时不会抑制其它PDE族成分到一定范围。优选适合口服的PDE4抑制剂。优选的PDE4抑制剂具有对位置(异构形)相对较低的亲和力,该位置以高亲和力与咯利普兰(rolipram)连接,并因此(或其他方法)在治疗有效药剂量上减少呕吐。对该位置或异构形的PDE4抑制剂的相对亲和力评定在US 5,998,428中有描述。一般认为PDE4抑制剂在本发明的实践中能起到有益作用而不用通过血脑屏障,并因此化合物有低的在脑对在血浆比例,例如0.1或0.05或更少,或者在脑中并未出现,都适合用于本发明。
合适的PDE4抑制剂包括化合物公开在上述的WO03/018579,WO02/060875,WO02/074726,WO02/098878,WO01/46151,WOUS5,449,686,US5,552,438,WO98/45268和WO99/20625。
优选用于本发明的PDE4抑制剂是N-环丙基-1-[3-(1-氧化(oxido)-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺,和它的药物可接受盐,公开在WO03/018579。
优选用于本发明的PDE4抑制剂也包括WO01/46151公开的那类化合物,尤其是式XI化合物:
名为6-[1-甲基-1-(甲磺酰)乙基]-8-[3-[(E)-2-[3-甲基-1,2,4-oxadiazol-5-基]-2-[4-(甲磺酰)苯基]乙炔基]苯基]喹啉,和它们的药物可接受盐,特别是苯磺酸盐,它们的制备在WO 01/46151中有描述。
优选用于本发明的PDE4抑制剂也包括US 5,552,438公开的那类化合物,尤其是式XII化合物:
名为顺-[4-氰基-4-(3-环戊氧基-4-甲氧苯基)环己烷-1-羧酸],和它们的药物可接受盐,也已知为SB-207499或cilomilast或Ariflo,它们的制备在US 5,552,438中有描述。进一步该类中的有用的化合物包括2-甲酯基-4-氰基-4-(3-环丙甲氧基-4-二氟甲氧苯基)环己基-1-酮和顺-[4-氰基-4-(3-环丙甲氧基-4-二氟甲氧苯基)环己基-1-醇。
优选用于本发明的PDE4抑制剂包括WO02/074726和WO02/098878公开的化合物;已知为MEM-1414(Memory Pharmaceuticals Corp.)的化合物;化合物R-[+]-4-[2-(3-环戊氧基-4-甲氧苯基)-2-苯乙基]吡啶,也已知为CDP840(Alexander et al,Bioorg.Med.Chem.Lett.,12(2002),1451-6)和它的药物可接受盐;化合物N-(3,5-二氯吡啶基-4-基)-3-环戊氧基-4-甲氧基苯酰胺,也已知为吡拉米司特(piclamilast)或RP73401(Raeburn et al,Br.J.Pharmacol.,113(1994),1423-31);化合物已知为CP-80,633或atizoram(Wrightet al,Can.J.Physiol.Pharmacol.,75(1997),1001-8);化合物1-丙基-3-(4-氯苯基)-黄嘌呤,也已知为LAS31025或阿罗茶碱(arofylline)(见Wright et al,Br.J.Physiol.Pharmacol.,126(1999),1863-71);化合物3-(3-环戊氧基-4-甲氧苄基)-6-乙基氨-8-异丙基-3H-嘌呤氯化氢,也已知为V1129A(Gale et al,Br.J.Clin.Pharmacol.,54(2002),478-84);化合物已知为D4418和D4396(Chiroscience and Schering-Plough);化合物N-(3,5-二氯吡啶基-4-基)-[1-(4-氟苄基)-5-羟基吲哚-3-基]-乙醛酸酰胺,也已知为AWD-12-281(Baumer et al,Eur.H.Pharmacol.,446(2002),195-200);化合物N-(3,5-二氯吡啶基-4-基)-3-环丙甲氧基-4-二氟甲氧基苯酰胺,也已知为罗氟司特(roflumilast)(Reid,Curr.Opin.Investig.Drugs,3(2002),1165-70);9-苄基腺嘌呤衍生物标记为NCS613,NCS675,NCS728,NCS700和NCS706(Raboisson et al,Eu.J.Med.Chem.,38(2003),199-214);化合物已知为CC-3052和其它的酞胺哌啶酮类似物公开在Guckian et al,Clin.Exp.Immunol.121(2000),472-9和Muller et al,Bioorg.Med.Chem.Lett.,8(1998),2669-74;和化合物已知为T440和T2585和类似化合物公开在Ukita et al,J.Med.Chem.,42(1999),10/88-99。
最优选地,用于本发明的PDE4抑制剂是式XI化合物的苯磺酸盐或N-环丙基-1-[3-(1-氧化(oxido)-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺,或它的药物可接受盐。
在本发明特别优选的实施方案中,GHS是N-[1(R)-[(1,2-二氢-1-甲磺酰螺[3H-吲哚-3,4’-哌啶]-1’-基)羰基]-2-(苯甲氧基)乙基]-2-氨基-2-甲丙基酰胺的甲基磺酸盐以及PDE4抑制剂是6-[1-甲基-1-(甲磺酰)乙基]-8-[3-[(E)-2-[3-甲基-1,2,4-oxadiazol-5-基]-2-[4-(甲磺酰)苯基]乙炔基]苯基]喹啉或N-环丙基-1-[3-(1-氧化(oxido)-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺,或它的药物可接受盐。
根据是否是同时给药还是单独给药,GHSP和DE4抑制剂通常提供为单一或多药物组合物包含活性成分和药物可接受载体。优选这些组合物制成单元药剂量形式例如片剂,药丸,胶囊,粉末,颗粒,灭菌肠胃外溶液或悬浮液,定量喷雾液或液体喷雾,液滴,一次性针剂,经皮贴片,自动注射装置或栓剂;用于口服,肠胃外,鼻内,舌下或直肠给药,或通过吸入或吹入给药。主要的活性成分通常与药物载体混合,例如,传统的成片剂成分例如玉米淀粉,乳糖,蔗糖,山梨糖醇,滑石粉,硬脂酸,硬脂酸镁和磷酸二钙,或树脂,分散剂,悬浮剂或表面活性剂例如脱水山梨糖醇单油酸酯和聚乙二醇,和其它药物稀释剂,例如水,形成均相制剂前组合物包含一种或全部两种活性物质,或它们药物可接受盐。称这些制剂前组合物时均相的是指活性物质均匀地分散在组合物中,以至组合物可以被预备分成等效用单位剂量形式例如片剂,药丸和胶囊。这种制剂前组合物接着被分成如上所述的单位剂量形式,通常包含从0.01到约500mg的活性物质。代表性的单位剂量形式包含0.05到100mg,例如0.05,0.1,0.5,1,2,5,10,25,50或100mg的活性物质。药物组合物的片剂或药丸可以被涂外衣或以其它方法复合来制成药剂形式以达到可以延长使用的目的。例如,片剂或药丸可以包含内部药剂和外部药剂成分,后者制成包含前者的形式。两种成分用肠衣层分隔达到防止在胃部的分解并保持内部成分完整的进入十二指肠或延迟释放。各种物质都可以用于所述的肠衣层或外衣层,这样的材料包括一系列的聚合酸和聚和酸与材料如虫胶,鲸蜡醇,纤维素乙酸酯的混合物。
用于本发明的药物组合物的液体形式可以用于口服给药或注射包括水溶液,液体-或胶体-填充的胶囊,适合的加香糖浆,水或油悬浮液,和加香乳剂用可食用油例如棉籽油,芝麻油,椰子油和花生油,以及西也剂和类似的药物媒介物。用于水悬浮液的适合的分散剂或悬浮剂包括合成的和天然的树脂例如黄芪胶,阿拉伯树胶,藻酸盐,右旋糖苷,羧甲基纤维素钠,甲基纤维素,聚乙二醇,聚乙烯吡咯烷酮和白明胶。
适于口服的药物组合物是优选的。
为了治疗或预防AD,GHS和PDE4抑制剂的药剂量水平应达到单独化合物为了有效达到最初目的而具备的水平。也就是GHS通常的药剂量已知是提高目标人体内在生长荷尔蒙的分泌,并且PDE4抑制剂的药剂量已知是在人体内起到足够的抑制PDE4酶的作用。在许多情况下,这些药剂量水平可从公开的文献中获得,否则可从标准化的临床方法中确定。
相关化合物的给药频率(例如每天一次,两次,三次或四次)可根据所涉及化合物的药物代谢动力学选择。
在优选GHS是式I的情况下,可考虑的药剂量是约0.01到5.0mg/kg每天,优选约0.05到2.5mg/kg每天,更优选约0.1到1.0mg/kg人体重量每天,特别地是,药剂量相当于5mg,10mg或25mg的自由物质(free base),可以每天给患者口服一次。
在优选PDE4抑制剂是式XI的情况下,可考虑的药剂量是约0.001到0.5mg/kg每天,优选约0.005到0.1mg/kg每天。特别地是,药剂量相当于约0.1mg,0.5mg或5.0mg的自由物质(free base),可以每天给患者口服一次。
在化合物是式XII(Ariflo)的情况下,可考虑的药剂量是每人约5mg,10mg或15mg,每天给药两次。在化合物是CDP840的情况下,可考虑的药剂量是每人约15mg或30mg,每天给药一次。在化合物是V-11294A的情况下,可考虑的药剂量是约300mg每人,每天给药一次。
在又一方面,本发明提供了药物组合物包含,药物可接受载体,式I化合物或它的药物可接受盐以及式XI化合物或它的药物可接受盐。优选的式I化合物是甲基磺酸盐形式。优选的式XI化合物是苯基磺酸盐形式。优选的药物组合物是适合口服的单位药剂量形式,例如片剂或胶囊。在具体的实施方案中,所述的单位剂量形式包含相当于5,10或25mg式I化合物的自由物质(free base)和相当于0.1,0.5或5.0mg的式XI化合物自由物质(free base)。
在又一方面,本发明提供了药物组合物包含,药物可接受载体,式I化合物或它的药物可接受盐,以及N-环丙基-1-[3-(1-氧化(oxido)-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺,或它的药物可接受盐。优选的式I化合物是甲基磺酸盐形式。优选的药物组合物是适合口服的单位药剂量形式,例如片剂或胶囊。在具体的实施方案中,所述的单位剂量形式包含相当于5,10或25mg式I化合物的自由物质(free base)。
Claims (10)
1.生长荷尔蒙促分泌素和PDE4抑制剂在制备治疗或预防与β-淀粉在脑部沉积有关疾病的药物中的用途。
2.根据权利要求1的用途,其中所述疾病是阿尔茨海默病。
3.生长荷尔蒙促分泌素和PDE4抑制剂在制备治疗、预防或延缓痴呆症发病的药物中的用途,所述痴呆症是与阿尔茨海默病、脑淀粉样血管病变、多发性脑梗死性痴呆、拳击员痴呆(dementiapugilistica)和唐氏综合症(Down Syndrome)相关的。
4.根据上述任何一项权利要求的用途,其中所述的药物是施药给患MC1的患者的。
5.根据权利要求4的用途,其中所述患者具有一种或多种会导致发展成阿尔茨海默病的额外风险因素,这些因素选自:该疾病的家庭史、对该病遗传的易患病体质、升高的血清胆固醇、和成年发病的糖尿病、下降的基线海马体积、整体微管相关蛋白的高CSF水平、磷酸化微管相关蛋白的高CSF水平、和Aβ42的降低的CSF水平。
6.根据权利要求1-5的任何一项权利要求的用途,其中生长荷尔蒙促分泌素是N-[1(R)-[(1,2-二氢-1-甲磺酰基螺[3H-吲哚-3,4’-哌啶]-1’-基)羰基]-2-(苯甲氧基)乙基]-2-氨基-甲基丙酰胺的甲磺酸盐。
7.根据权利要求1-6的任何一项权利要求的用途,其中PDE4抑制剂是6-[1-甲基-1-(甲磺酰)乙基]-8-[3-[(E)-2-[3-甲基-1,2,4-噁二唑-5-基]-2-[4-(甲磺酰基)苯基]乙炔基]苯基]喹啉或N-环丙基-1-[3-(1-氧基-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺的苯磺酸盐,或它们的药学上可接受的盐。
8.一种生长荷尔蒙促分泌素和PDE4抑制剂的组合,用于治疗或预防与β-淀粉在脑部沉积有关疾病,尤其是阿尔茨海默病。
9.一种药物组合物,包含:药学上可接的受载体,式I化合物或其药学上可接受的盐,
以及N-环丙基-1-[3-(1-氧基-3-吡啶乙炔基)苯基]-1,4-二氢[1,8]二氮杂萘-4-酮-3-甲酰胺或其药学上可接受的盐。
10.一种组合药物盒,包括:含有GHS的第一种药物,含有PDE4抑制剂的第二种药物,以及所述药物的说明书;所述药物先后或同时给药给患有AD、增龄相关的认知功能减退、MIC、脑淀粉样血管病变、多发性脑梗死性痴呆、拳击员痴呆(dementia pugilistica)或唐氏综合症(Down Syndrome)的病人。
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CN102300582A (zh) * | 2009-01-30 | 2011-12-28 | 阿尔法贝塔公司 | 用于治疗阿尔茨海默病的化合物和方法 |
RU2574918C2 (ru) * | 2010-11-19 | 2016-02-10 | Бейджинг Речсэнд Сайенс энд Текнолоджи Групп Ко., Лтд | Устройство для разделения нефти и воды и система для сбора плавающей нефти, включающая это устройство |
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US20100099609A1 (en) * | 2008-07-28 | 2010-04-22 | Buck Institute For Age Research | eAPP AND DERIVATIVES FOR TREATMENT OF ALZHEIMER'S DISEASE |
WO2019147824A1 (en) | 2018-01-26 | 2019-08-01 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a pde4 inhibitor |
WO2020106754A1 (en) | 2018-11-19 | 2020-05-28 | Progenity, Inc. | Methods and devices for treating a disease with biotherapeutics |
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CN102300582A (zh) * | 2009-01-30 | 2011-12-28 | 阿尔法贝塔公司 | 用于治疗阿尔茨海默病的化合物和方法 |
RU2574918C2 (ru) * | 2010-11-19 | 2016-02-10 | Бейджинг Речсэнд Сайенс энд Текнолоджи Групп Ко., Лтд | Устройство для разделения нефти и воды и система для сбора плавающей нефти, включающая это устройство |
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GB0307863D0 (en) | 2003-05-14 |
WO2004087157A3 (en) | 2004-11-18 |
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