CN1471397A - 治疗偏头痛的方法 - Google Patents
治疗偏头痛的方法 Download PDFInfo
- Publication number
- CN1471397A CN1471397A CNA018177832A CN01817783A CN1471397A CN 1471397 A CN1471397 A CN 1471397A CN A018177832 A CNA018177832 A CN A018177832A CN 01817783 A CN01817783 A CN 01817783A CN 1471397 A CN1471397 A CN 1471397A
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- Prior art keywords
- pde5
- pde5 inhibitor
- hydrogen
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- methyl
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Abstract
公开了一种单独使用或与第二种PDE5抑制剂和/或其他抗偏头痛剂合用的使用PDE5抑制剂治疗偏头痛的方法。
Description
相关申请的相互参考
本申请要求于2000年8月30日提交的美国临时申请60/229083的权益。
发明领域
本发明涉及血管性头痛的治疗。特别是,本发明涉及类型5磷酸二酯酶(PDE5)抑制剂治疗偏头痛的应用。
发明背景
催化3’5’-环核苷酸如环鸟苷酸(cGMP)和环腺苷酸(cAMP)水解成相应的核苷5’-一磷酸的环核苷酸磷酸二酯酶(PDEs)组成复杂的酶家族。通过调节环核苷酸的细胞内浓度,所述PDE同工酶在包括环核苷酸第二信使的信号传导路径中起作用。
已确定了多个PDEs家庭。其命名体系包括指明PDEs家族的第一个数字。到目前为止,已知九个家族(PDE1-9),其分类如下:(i)一级结构;(ii)底物偏好;(iii)对不同调节剂的应答;(iv)特殊抑制剂的敏感性;和(v)调节模式(Loughney和Ferguson,in PhosphodiesteraseInhibitors,Schudt等,(Eds.),科学出版社:纽约,纽约(1996)1-19页)。指明家族的数字后面跟随一个大写字母,表示特定的基因,然后第二个数字跟在大写字母后面,表示特异性的剪接变体或者利用独特的转录起始位点的特异性转录物。
PDE1家族成员由钙-钙调蛋白激活。PDE1A和PDE1B优先水解cGMP,同时PDE1C对cAMP和cGMP显示出高的亲和力。PDE2家族的唯一成员,即PDE2A,是以通过cGMP(Loughney andFerguson,同上)特异性刺激为特征的。在PDE3家族中的酶,即PDE3A和PDE3B,是由cGMP特异性地抑制的。PDE4家族影响cAMP水解并包括四个基因,PDE4A、PDE4B、PDE4C和PDE4D。PDE5家族的唯一成员,即PDE5A,在非催化位点上结合cGMP并优先水解cGMP。光受体PDE6酶特异性地水解cGMP(Loughney and Ferguson,同上)。基因包括PDE6A、PDE6B和PDE6C。PDE7家族影响cAMP水解,但是,与PDE4家族相反,不被咯利普兰(Loughney and Ferguson,同上)抑制。PDE8家族显示水解cAMP和cGMP而对PDEs 1-5的特异性抑制剂不敏感。依据使用的命名法,PDE8也称作PDE10。PDE9家族优先水解cAMP并且对咯利普兰,一种PDE4-特异性抑制剂,或者对异丙基甲基黄嘌呤(IBMX),一种非特异性的PDE抑制剂不敏感。
PDE5抑制剂在化学结构上变化巨大。对各种PDE5抑制剂化合物的治疗价值的限制因素包括容易给药、效果和选择性。通常优选的抑制剂在低浓度下有效并能够口服给药。在另一方面,如果为了避免不利的生理学的副作用,化合物在其对PDE5的抑制效果方面具有高度选择性是重要的。
偏头痛是一种常见病,也是剧烈的、复发性头痛的最常见的原因。在任何指定年份中,大约15-20%的妇女和大约7-10%男士至少经历一次偏头痛的发作。
偏头痛可细分为典型的和普通型的。所有偏头痛的百分之八十是普通型的。典型的偏头痛存在三个阶段。其症状与最初的脑血管收缩和随后的脑血管舒张有关。最初的血管收缩称为前驱症状,紧接着就是血管舒张。普通型偏头痛不包括前驱症状的阶段。
典型的偏头痛的第一阶段主要包括视觉障碍,包括视线模糊或视觉浑浊、盲点和/或闪光。也可能发生眩晕、寒战、震颤、单侧麻木、失语、畏光或苍白。在第二个阶段,病人经历剧烈的、博动性头痛,它最初是单侧的。恶心、呕吐、腹泻、寒战、震颤和出汗也可能在这时发生。第三个阶段是恢复阶段。疼痛显著减轻,但是头还是触痛且病人筋疲力尽。普通型的偏头痛不包括前驱症状的阶段(阶段1),但是实际的头痛可能比典型的偏头痛持续的时间长(超过两小时)。
对一度广泛持有的偏头痛主要是身心失调病症的观点已产生怀疑。代替的观点是,实际的发作已被认为是由于脑和脑膜血管的原发性神经原性现象及继发性的后遗症所致。偏头痛原本是间歇性的,且从一个时期到另一个时期的频率可以不同。症状和剧烈程度在不同个体之间及在同一个体中可从偶然的温和发作到频繁剧烈的发作而不同。偏头痛似乎是遗传性疾病。
与偏头痛有关的病理生理学的理论由Graham等,和Wolff,在Arch,Neurol.Psychiatry,1938年39卷737-763页中的叙述所阐明。作者提出偏头痛的病因是颅外血管的血管舒张。这一观点由麦角生物碱和舒马普坦,一种5-HT激动剂,收缩头部血管平滑肌,及其在偏头痛的治疗中是有效的认识所支持。
虽然关于偏头痛的这种血管机制获得了广泛的认同,至于它的正确性却缺乏普遍一致的看法。例如,Moskowitz等,在Cephalalgia,1992年12卷5-7页中揭示了偏头痛的发生是不依赖于血管直径的变化。而且,Moskowitz等人提出从脉管系统上的轴突释放的血管活性神经肽引发一系列导致神经原性炎症的活动,其一种后果是疼痛。这种神经性炎症在人体中受到以类似于治疗人的急性偏头痛所需剂量的舒马普坦和麦角生物碱的阻断。
在偏头痛治疗中的主要障碍是缺乏清晰的关于疾病的处理原则。有限的有效抗偏头痛药物的数量已经确定,但是准确地预测它们在给定的个体中的效果是困难的。因此,偏头痛的治疗对于每一个病人经常是适应个体需要的。
偏头痛的治疗包括避免能够引起发作的因素,急性头痛的治疗,及有规律的药物的应用以预防发作。许多因素一直与个体偏头痛发作的诱因有关:禁食、酒精、口服避孕药和激素替代疗法、咖啡因和停用咖啡因、压力或解除压力、睡眠过少或过多、月经周期、疲劳、天气变化、头部外伤、暴露于强光下、噪音、烟雾、浓烈的气味、以及食物,包括巧克力、成熟干酪、含有亚硝酸盐的熏制和粗加工肉类、乳制品、含有谷氨酸氢钠或天冬甜素的食物、柑橘类水果及其它。
然而,一般而言,确定和避免偏头痛的诱因(triggers)并不是有效的治疗计划。第一,大多数偏头痛不是由确定的诱因引起的。第二,病人对诱因的反应不同,例如,禁食可能或不能诱发偏头痛,它减少病人的愿望以避免所有认识到的诱因。第三,许多偏头痛的诱因是不可避免的。
可以获得许多种类的对偏头痛预防及其急性发作治疗的药物。常规有效的预防性药物包括:β-阻滞剂,例如,普萘洛尔、美托洛尔、阿替洛尔、噻吗洛尔和纳多洛尔;钙离子通道阻滞剂,例如,维拉帕米、硝苯地平、尼莫地平(nimopidine)和地尔硫;三环抗抑制剂,例如,阿米替林和去甲替林;抗惊厥剂,例如,双丙戊酸钠;5-HT激动剂,例如,舒马普坦、那拉曲坦,利扎曲普坦,唑咪曲普坦(zolmitriptan)和苯噻啶;及单胺氧化酶抑制剂,例如苯乙肼和异卡波肼。
上述药物的不利副作用是不同的。归因于使用β-阻滞剂治疗的不利的作用包括气喘的加重、心博徐缓、低血压、疲劳、抑郁和低血糖症状的掩盖。钙离子通道阻滞剂能引起低血压、便秘和外周水肿。三环抗抑制剂能引起镇静、口干、体重增加、震颤、心律失常、闭角型青光眼加重和排尿困难。双丙戊酸钠能引起恶心、疲劳、体重增加、脱发、震颤、肝功能障碍和胚胎发育中的神经管缺陷。5-HT激动剂能引起胸和颈压迫、以及心肌局部缺血。
对于大多数病人,偏头痛发作的早期治疗是治疗的主要部分。及时的治疗预期减少疼痛的剧烈程度,预防或减少相关症状,例如恶心和呕吐,以及缩短发作延续时间。可利用的药物包括OTC(非处方药)止痛剂,例如对乙酰氨基酚、阿司匹林、布洛芬、吲哚美辛和萘普生钠;同咖啡因合用的OTC止痛剂;麦角生物碱,如麦角胺和二氢麦角胺;和处方药止痛剂/抗偏头痛制剂,包括麻醉剂(例如,布他比妥(butalbitol))。这些药物的副作用包括胃肠道不适、反弹性头痛、肝中毒、镇静和依赖性。
因此,偏头痛预防性治疗的效果需要改进。例如,已有报道只有大约55%的治疗病人的发作频率减少50%或50%以上。然而,上述的不利副作用频繁发生,使这些预防性的治疗仅适合于有规律发作的病人。
综上所述,尽管目前可以获得各种治疗和预防偏头痛的药物,但是,本领域仍需要另外的具有改善功效和较少不利副作用的化合物。
发明概述
本发明涉及在哺乳动物中治疗典型的和普通的偏头痛及其它血管性头痛的方法。所述方法包含将抑制环鸟苷3’5’-一磷酸的药用有效量的特异性PDE5制剂,即PDE5抑制剂药物给予患有偏头痛的个体。PDE5抑制剂可在偏头痛发作前或发作后给予。PDE5抑制剂治疗偏头痛的能力在本领域是意想不到的,因为用包括PDE5抑制剂的PDE抑制剂治疗的典型副作用是头痛。
在优选的实施方案中,PDE5抑制剂给予个体的量是每日大约0.1mg至1000mg。更优选地,PDE5抑制剂给予的量是每日大约1mg至100mg。最优选PDE5抑制剂给予的量是每日大约2mg至20mg。
根据本发明的另一方面,所述方法包含联合给予有效量的第一种PDE5抑制剂与第二种PDE5抑制剂或与另一个已知的抗偏头痛制剂,优选止痛剂联合使用。
本发明的另一方面是给予个体药用有效量的具有(I)、(II)或(III)结构式的化合物,以治疗偏头痛或其他血管性头痛。
在式(I)中R1是甲基或乙基;R2是正丙基;R3是乙基、正丙基或烯丙基;R4是COCH2NR5R6、CONR5R6、SO2N9R10或1-甲基-2-咪唑基;R5和R6与它们相连的氮原子一起代表,吗啉代或4-N(R11)-哌嗪基基团;R9和R10与它们相连的氮原子一起代表4-N(R12)-哌嗪基;R11是甲基或乙酰基;及R12是氢、甲基、2-丙基或2-羟乙基;
在式(II)中R13选自氢、卤素和C1-6烷基基团;
R14选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、卤代C1-6烷基、C3-8环烷基、C3-8环烷基C1-3烷基和芳基C1-3烷基,其中芳基是苯基或由1-3个独立选自卤素、C1-6烷基、C1-6烷氧基和亚甲二氧基的取代基取代的苯基,以及杂芳基C1-3烷基,其中杂芳基是噻吩基、呋喃基或吡啶基,每个任选由1-3个独立选自卤素、C1-6烷基和C1-6烷氧基的取代基取代。
所述双环通过苯环碳原子中的一个连接于该分子的其余部分,并且其中稠环A是饱和的或部分的或完全不饱和的,并包含碳原子和任选一个或二个选自氧、硫和氮的杂原子的5-或6-元环;和
R16代表氢或C1-3烷基,或R1和R3一起代表3-或4-元烷基或5-或6-元环的链烯基成分;
及其盐和溶剂化物;
在式(III)中
R5是甲基或乙基,
R6是乙基或丙基,
R7和R8独立为具有最多可至5个碳原子的直链或支链烷基,任选独立由最多可至两个羟基或甲氧基取代,或
R7和R8与氮一起形成哌啶基、吗啉基、硫代吗啉基或下式的基团
其中R37是氢、甲酸基,或各自具有最多可至三个碳原子的直链或支链酰基或烷氧羰基,
或是具有最多可至三个碳原子的直链的或支链烷基,任选独立由一个或两个羟基、羧基,或各自具有最多可至三个碳原子的直链或支链烷氧基或烷氧基羰基,或者式-(D)fNR38R39或-P(O)(OR42)(OR43)的基团取代,
其中f是0或1,
D是式-CO的基团,
R38和R39独立地为氢或甲基,
R42和R43独立地为氢、甲基或乙基,或,
R37是环戊基,
和在R3和R4项下提及的与氮原子一起形成的杂环任选独立地由一个或二个,任选成对的(geminally),羟基、甲酰基、羧基和各自具有最多可至三个碳原子的直链或支链酰基或烷氧基羰基,或式-P(O)(OR46)(OR47)或-(CO)iNR49R50的基团取代,
其中R46和R47独立地为氢、甲基或乙基,
j是0或1,和
R49和R50独立地为氢或甲基和/或在R3和R4项下提及的与氮原子一起形成的杂环由具有最多可至三个碳原子的直链的或支链任选取代,它任选独立地由一个或两个羟基、羧基或式P(O)OR53OR54的基团取代,
其中R53和R54独立地为氢、甲基或乙基,和/或在R3和R4项下提及的与氮原子一起形成的杂环任选由经N-连接的哌啶基或吡咯烷基取代,
R9是氢,和
R10是乙氧基或丙氧基,
及其盐、水合物、N-氧化物,及其异构体形式。发明详述
本发明涉及在哺乳动物中治疗偏头痛及其它血管性头痛的方法。所述方法包括将抑制环鸟苷3’5’-一磷酸特异性PDE5的药用有效量的药物给予需要的个体。预期PDE5抑制剂可单独给予,可与第二种PDE5抑制剂合用,或与其它已知抗偏头痛疗法结合。
此处使用的“治疗”,定义为减少或消除偏头痛的临床症状和/或逐渐增加两次偏头痛发作的间隔和/或预防偏头痛的复发。偏头痛的“临床症状”包括头痛、恶心、呕吐、对光和/或声音的极度敏感、眩晕、寒战、震颤、苍白、失语、单侧麻木、腹泻和视觉障碍。
术语“IC50”定义为在单剂量反应实验中,产生50%酶抑制的化合物的浓度。因此IC50值是抑制包括PDE5的PDEs的化合物的效力的量度。测定化合物的IC50值可通过在Cheng等的Biochem.Pharmacology,22卷3099-3108页(1973年)中一般介绍的已知的体外方法容易地完成。
术语“抑制作用”或“抑制”是指阻碍PDE5的酶活性至足够的程度,以减少或消除偏头痛的临床症状和/或逐渐增加两次偏头痛发作的间隔,或预防偏头痛临床症状的复发。
术语“药用有效量”表示能够抑制PDE5,并产生偏头痛临床症状的改善和/或预防或减少偏头痛或其临床症状的复发的化合物的量。
术语“药剂”或“药物”是指适合于药学使用的化学化合物。
术语“PDE5抑制剂”是指抑制cGMP-特异性PDE5活性的药剂。用于本发明的PDE5抑制剂是抑制环鸟苷3’5’-一磷酸特异性PDE5和具有抑制人类重组细胞PDE5的IC50值约10nM或更少的药物。优选PDE5抑制剂的IC50值是约5nM或更少,更优选约3nM或更少,最优选约1nM或更少。最优选的PDE5抑制剂是选择性的PDE5抑制剂,即,抑制PDE5的化合物,但不能明显抑制其它PDE酶,即,PDE1至PDE4和PDE6至PDE9,特别是PDE6和PDE1c。因此,对于优选的抑制剂,对PDE5抑制的IC50值比对PDE1-PDE4和PDE6-PDE9抑制的IC50值少约100倍,特别是,对PDE6或PDE1c的抑制,更优选约少于500倍,及最优选约少于1000倍。
PDE5抑制剂可以全身给药,诸如,通过口服、静脉内、肌内或皮下途径给药。PDE3抑制剂可以作为气雾剂用于肺部给药、作为喷雾剂用于鼻部给药、心室内或鞘内给药至脑脊髓液中,或经连续的输注泵静脉给药。PDE抑制剂也可局部给药,诸如,经滴剂(特别是眼科滴剂)、软膏、贴剂,或经直肠或阴道,例如,通过栓剂或灌肠剂给药。对于联合治疗,第一个PDE5抑制剂和第二个PDE5抑制剂和/或其它抗偏头痛治疗剂可以同时或序贯给药。
PDE5抑制剂可以约0.1至约1000mg的剂量给药,优选每日约1至约100mg,及更优选在24小时内约2至约20mg。给药的剂量可视需要,每日一次,或在较长的或较短的时间间隔给予相等的剂量。本领域普通技术人员可以容易地通过由规范的药学实践和个体病人的临床病情确定最佳有效剂量和给药方案。
例如,合适的剂量可以通过应用建立的结合适当的剂量-反应数据确定血浓度剂量的分析来确定。最终的剂量方案由主治医生考虑了各种因素,例如,药物的比活性、病情的严重程度及病人的反应、病人的年龄、病情、体重、性别和饮食、临床症状的严重程度、给药比数、以及其他的临床因素确定。当联合用药时,所需的各药物发挥治疗效果的剂量可以少于单独使用单一PDE5抑制剂时所需的剂量。
本发明基于对患有偏头痛的病人PDE5的抑制提供有效治疗的发现。因此,用于本发明的PDE5抑制剂在化学结构上显著地不同并且用于本发明方法的PDE5抑制剂不依赖于特定的化学结构。但是,优选的具有抑制PDE5能力的化合物包括具有式(I)结构的化合物:
其中R1是甲基或乙基;R2是正丙基;R3是乙基、正丙基或烯丙基;R4是COCH2NR5R6、CONR5R6、SO2NR9R10或1-甲2-咪唑基;R5和R6与同它们相连的氮原子一起代表吗啉代或4-N(R11)-哌嗪基;R9和R10与同它们相连的氮原子一起代表4-N(R12)-哌嗪基;R11是甲基或乙酰基;和R12是氢、甲基、2-丙基或2-羟基-乙基;
式(I)结构的化合物及其制备公开于欧洲专利0702555,其公开内容结合于本文作为参考。优选的式(I)化合物包括:
5-(2-乙氧基-5-吗啉代乙酰基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(5-吗啉代乙酰基-2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(4-甲基-1-哌嗪基磺酰基)-苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;西地那非(sildenafil)
5-(2-烷氧基-5-(4-甲基-1-哌嗪基磺酰基)-苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-[4-(2-丙基)-1-哌嗪基磺酰基]-苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-[4-(2-羟基乙基)-1-哌嗪基磺酰基]苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(5-[4-(2-羟基乙基)-1-哌嗪基磺酰基]-2-正丙氧基苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(4-甲基-1-哌嗪基羰基)-苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(1-甲基-2-咪唑基)苯基)-1-甲基3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
及其混合物。
(西地那非)
另一类优选的化合物公开于Daugan的美国专利第5859006号和Daugan等的美国专利第5981527号,各专利都结合于本文作为参考。这类化合物,包括有效的和选择性的PDE5抑制剂,在治疗偏头痛上都是有用的并且具有以下结构式(II):
及其盐或溶剂化物。
其中R13选自氢、卤素和C1-6烷基;
R14选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、卤代C1-6烷基、C3-8环烷基、C3-8环烷基C1-3烷基和芳基C1-3烷基,其中芳基是苯基或由一到三个独立选自卤素、C1-6烷基、C1-6烷氧基和亚甲二氧基的取代基取代的苯基、以及杂芳基C1-3烷基,其中杂芳基是噻吩基、呋喃基或吡啶基,每个任选由一到三个独立选自卤素、C1-6烷基和C1-6烷氧基的取代基取代;
R15代表任选取代的单环芳环,它选自苯、噻吩、呋喃和吡啶,或通过苯环碳原子之一连接于分子的其余部分的任选取代的双环,其中稠环A是饱和或部分饱和或完全不饱和的,及包含碳原子和任选一个或二个选自氧、硫和氮的杂原子的5-或6-元环;和
R16代表氢或C1-3烷基,或R14和R16一起代表3-或4-元烷基或5-或6-元环的链烯基成分;
最优选的结构式(II)的化合物是其中R13是氢、卤素或C1-6烷基;R14是氢或C1-6烷基;R15是由一个或多个独立选自卤素和C1-3烷基的基团任选取代的双环;或
及R16是氢或C1-3烷基的化合物。
优选的结构式(II)的化合物包括:
顺-2,3,6,7,12,12a-六氢-2-(4-吡啶基甲基)-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
顺-2,3,6,7,12,12a-六氢-6-(2,3-二氢苯并[b]-呋喃-5-基)-2甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
顺-2,3,6,7,12,12a-六氢-6-(5-溴2-噻吩基)-2-甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
顺-2,3,6,7,12,12a-六氢-2-丁基-6-(4-甲基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-2-异丙基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-2-环戊基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-2-环丙基-甲基-6-(4-甲氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(3-氯-4-甲氧基苯基)-2-甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(5aR,12R,14aS)-1,2,3,5,6,11,12,14a-八氢-12-(3,4-亚甲二氧基苯基)吡咯并[1”,2”:4’,5’]-吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-5-1,4-二酮;
顺-2,3,6,7,12,12a-六氢-2-环丙基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(3S,6R,12aR)-2,3,6,7,12,12a-六氢-3-甲-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)-2-甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(3S,6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)-3-甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(3S,6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)-2,3-二甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)-2-异丙基-吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
其生理学上可接受的盐及溶剂化物;
以及其混合物。结构式(II)的化合物由于其抑制PDE5超过抑制其它PDE酶的选择性而特别有意义。
三个优选的结构式(II)的化合物是:
(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
(6R,12aR)-2,3,6,7,12,12a-六氢-6-(5-苯并呋喃基)-2-甲基吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;和
(3S,6R,12aR)-2,3,6,7,12,12a-六氢-2,3-二甲基-6-(3,4-亚甲二氧基苯基)吡嗪并[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮;
及其生理学上可接受的盐及溶剂化物(例如,水合物)。
另一类优选的化合物公开于WO 99/24433,结合于本文作为参考。所述化合物具有结构式(III):
其中
R5是甲基或乙基,
R6是乙基或丙基,
R7和R8独立为具有最多可至5个碳原子的直链或支链烷基,任选独立地由最多可至两个羟基或甲氧基取代,或
R7和R8与氮一起形成哌啶基、吗啉基、硫代吗啉基或下式的基团
其中R37是氢、甲酰基,或各自具有最多可至三个碳原子的直链或支链酰基或烷氧羰基,
或是具有最多可至三个碳原子的直链或支链烷基,任选独立地由一个或两个羟基、羧基,或各自具有最多可至三个碳原子的直链或支链烷氧基或烷氧基羰基,或者式-(D)fNR38R39或-P(O)(OR42)(OR43)的基团取代,
其中f是0或1,
D是式-CO的基团,
R38和R39独立是氢或甲基,
R42和R43独立是氢、甲基或乙基,或,
R37是环戊基,
和在R3和R4项下提及的与氮原子一起形成的杂环任选独立地由一个或二个,任选成对的,羟基、甲酰基、羧基和各自具有最多可至三个碳原子的直链或支链酰基或烷氧基羰基,或式-P(O)(OR46)(OR47)或-(CO)jNR49R50的基团取代,
其中R46和R47独立是氢、甲基或乙基,
j是0或1,和
R49和R50独立是氢或甲基和/或在R3和R4项下提及的与氮原子一起形成的杂环由具有最多可至三个碳原子的直链或支链任选取代,它任选独立由一个或两个羟基、羧基或式P(O)OR53OR54的基团取代,
其中R53和R54独立是氢、甲基或乙基,和/或在R3和R4项下提及的与氮原子一起形成的杂环任选由经N-连接的哌啶基或吡咯烷基取代,
R9是氢,和
R10是乙氧基或丙氧基,及其盐、水合物、N-氧化物,以及其异构体形式。
优选的结构式(III)的化合物是2-[2-乙氧基-5-(4-乙基哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮,也称为1-[[3-(3,4-二氢-5-甲基-4-氧代-7-丙基咪唑并[5,1-f]-砷-三嗪-2-基)-4-乙氧基苯基]磺酰基]-4-乙基哌嗪和具有下式的伐地那非:
(伐地那非)
还有其它用于本方法的示例性PDE5抑制剂公开于Daugan等的美国专利第6001847号、WO 93/07124、WO 93/07149、WO 93/12095、WO 94/05661、WO 94/00453、WO 96/26940、WO 97/43287、WO98/49166、WO 98/53819、WO 99/21831、WO 99/26946、WO 99/28319、WO 99/28325、WO 99/42452、WO 99/54284、WO 99/54333、WO00/15639、WO 00/27745、EP 0 463 756、EP 0 526 004和EP 0 995 750,各个专利都结合于本文作为参考。
其它的用于偏头痛治疗的PDE5抑制剂的实例包括,但并不局限于:
3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-正丙氧基苯基]-2-(吡啶-2-基)甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基乙氧基)吡啶-3-基]-2-(吡啶-2-基)-甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(pyrimidin-7-one);
(+)-3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-(2-甲氧基-1(R)-甲基乙氧基)吡啶-3-基]-2-甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,也称为3-乙基-5-(5-[4-乙基哌嗪-1-基磺酰基]-2-([(1R)-2-甲氧基-1-甲基乙基]氧基)吡啶-3-基)-2-甲基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,也称为1-(6-乙氧基-5-[3-乙基-6,8-二氢2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]3-吡啶基磺酰基)-4-乙基哌嗪;
5-[2-异-丁氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-(1-甲基哌啶-4-基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-苯基-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮;
4-溴-5-(吡啶基甲基氨基)-6-[3-(4-氯代苯基)-丙氧基]-3(2H)哒嗪酮;
1-[4-[(1,3-苯并二氧杂环戊-5-基甲基)氨基]-6-氯-2-喹唑啉基(quinozolinyl)]4-哌啶-羧酸,一钠盐;
(+)-顺-5,6a,7,9,9,9a-六氢-2-[4-三氟甲基]-苯基甲基-5-甲基-环戊[4,5]咪唑并[2,1-b]嘌呤-4(3H)酮furazlocillin;
顺-2-己基-5-甲基-3,4,5,6a,7,8,9,9a-八氢环戊基[4,5]-咪唑并[2,1-b]嘌呤-4-酮;
3-乙酰基-1-(2-氯苄基)-2-丙基吲哚-6-羧酸酯;
4-溴-5-(3-吡啶基甲基氨基)-6-(3-(4-氯苯基)-丙氧基)-3-(2H)哒嗪酮;
1-甲基-5-(5-吗啉代乙酰基-2-正丙氧基苯基)-3-正丙基-1,6-二氢-7H-吡唑(4,3-d)嘧啶-7-酮;
1-[4-[(1,3-苯并二氧杂环戊-5-基甲基)氨基]-6-氯-2-喹唑啉基]-4-哌啶羧酸,一钠盐;
E-8010和E-4010(Eisai);和
Bay-38-3045和38-9456(Bayer)。
用于本发明的最优选的PDE5抑制剂是(a)有效的,即具有的对PDE5的IC50值小于10nM,(b)选择性的,即具有抑制人重组PDE5比抑制PDE6或PDE1c的IC50至少小100-倍,并(c)具有所希望的物理和生物学性质,例如,足够的水溶性,生物利用度,和代谢稳定性,以用于治疗偏头痛和其他血管性头痛。PDE5抑制剂治疗偏头痛的能力是未预料到的,因为已知PDE抑制剂的不利副作用是引起头痛。例如,报道用西地那非治疗的病人16%有不利副作用的头痛(与用安慰剂的4%相比)。
关于选择性,优选的PDE5抑制剂显示至少200的PDE6/PDE5和PDE1c/PDE5的IC50抑制系数(商)(quotient),并可至1000或更大的范围。PDE6/PDE5 IC50抑制系数是化合物对PDE6的IC50值与相同的化合物对PDE5的IC50值的比。PDE1c/PDE5抑制系数是对PDE1c和PDE5相同定义的。为了体现本发明的全部优势,所述化合物具有至少100的PDE6/PDE5和PDE1c/PDE5 IC50抑制系数及对于人重组PDE5的约5nM或更少,例如,约0.1至约5nM的IC50。
虽然可以将用于本发明方法的化合物不经任何配制直接给药,但PDE5抑制剂通常是以包括药学上可接受的赋形剂和至少一种活性成分的药物组合物的形式给药。这些组合物可以通过各种途径给药,包括口服、颊、舌下、直肠、经皮、皮下、静脉内、肌内及鼻内给药。许多用于本发明方法中的化合物作为注射的和口服的组合物都是有效的。此类组合物可以制药领域中熟知的方法制备并且包含至少一种活性化合物。
在本发明应用的组合物的制备中,PDE5抑制剂通常与赋形剂混合,用赋形剂稀释或包封在载体中,它可以是胶囊、小药囊、纸包(paper),或其他容器的形式。当赋形剂用作稀释剂时,可以是固体、半固体或液体物质,起PDE5抑制剂的溶媒、载体或介质的作用。这样,所述组合物可以是片剂、丸剂、散剂、糖锭剂、小药囊、扁囊剂、酏剂、悬浮剂、乳剂、溶液剂、糖浆剂、气雾剂(作为固体或在液体介质中)、包含例如最多可至10%重量PDE5抑制剂的软膏剂,软或硬明胶胶囊、栓剂、灭菌注射溶液剂和灭菌包装粉末剂。
在制备制剂时,在与其他成分混合前可以将PDE5抑制剂碾磨以提供合适的粒度。如果所述PDE5抑制剂是基本不溶的,通常将其碾磨成小于200目的粒度。如果所述PDE5抑制剂是基本水溶的,通常通过碾磨来调节粒度,例如,约40目以提供在制剂中的基本均匀分布。
通过使用本领域公知的方法,本发明使用的组合物可以配制成提供给予病人后的快速的,缓释的或延长释放的PDE5抑制剂。
所述组合物优选配制成单位剂型。术语“单位剂型”,是指适用于人类患者或其他哺乳动物的物理的不连续的单一剂量单位,每个单位含有经计算可产生所需治疗效果的,预定量的PDE5抑制剂,及任选的第二种活性剂,以及典型的合适的药用赋形剂。PDE5抑制剂在很宽的剂量范围通常是有效的。然而,应该理解实际给予的PDE5抑制剂及任选的第二种活性剂的量由医生根据相关情况的判断确定。
对于本领域技术人员而言,在考虑到下述非限定的实施方案后,本发明的许多其他方面和益处将是显然的。
实施例1
人PDE5的制备
人PDE5的重组生产除所用的酵母转化载体外,基本按照在结合于本文作为参考的美国专利第5702936号的实施例7描述的方法进行,该酵母转化载体衍生自结合酵母ADH2启动子和终止子序列(而不是ADH1启动子和终止子序列)的V.Price等在Methods inEnzymology,185,308-318(1990年)中描述的碱性ADH2质体,以及酿酒酵母(Saccharomyces cerevisiae)宿主为1998年8月31日保藏于美国典型培养物保藏中心(American Type Culture Collection),Manassas,Virginia的蛋白酶缺乏株BJ2-54,保藏号ATCC 74465。转化的宿主细胞在含有痕量金属和维生素的2X SC-leu培养基(pH 6.2)中生长,24小时后,将含有甘油的YEP培养基加入至最终浓度的2X YEP/3%甘油中。大约24小时后,收获细胞,洗涤,并于-70℃储存。
细胞小球(29g)用同等体积的溶胞缓冲液(25mM Tris-Cl,pH8,5mM MgCl2,0.25mM二硫苏糖醇,1mM苄脒,及10μM ZnSO4)在冰上解冻。细胞在微量流化器中用20000psi的N2溶胞。离心溶胞产物并经0.45μM的一次性过滤器过滤。将滤过物上样于150ml的Q琼脂糖快速流动(Sepharose Fast Flow)柱(Pharmacia)上。该柱用1.5体积的缓冲液A(20mM Bis-Tris丙烷,pH 6.8,1mM MgCl2,0.25mM二硫苏糖醇,10μM ZnSO4)洗涤并用在缓冲液A中的125mM NaCl分级梯度,接着用缓冲液A中的125-1000mM NaCl线性梯度洗脱。
将得自线性梯度的活性流份上样于缓冲液B(20mM Bis-Tris丙烷(PH 6.8),1mM MgCl2,0.25mM二硫苏糖醇,10μM ZnSO4和250mM KCl)中的180ml羟基磷灰石柱上。装载后,用2体积的缓冲液B洗柱,并用在缓冲液B中的0-125mM磷酸钾线性梯度洗脱。合并活性流份,用60%硫酸铵沉淀,并重悬浮于缓冲液C(20mM Bis-Tris丙烷,pH6.8,125mM NaCl,0.5mM二硫苏糖醇,和10μM ZnSO4)中。将合并物(pool)上样于140ml的Sephacryl S-300 HR柱上并用缓冲液C洗脱。活性流份被稀释至50%甘油中并于-20℃储存。所得的制备物经SDS-PAGE测定为约85%的纯度。
实施例2
PDE5活性分析
PDE5的活性可通过本领域的标准分析测定。例如,任一PDE的比活性可以如下确定。应用活性炭分离技术的PDE分析基本按照Loughney等在J.Biol.Chem.,271,796-806页(1996年)中描述的进行。在此分析中,PDE5的活性按照存在的PDE5活性的量成比例地将[32P]cGMP转化为[32P]5’GMP。然后通过蛇毒5’-核苷酸酶的作用,将[32P]5’GMP定量地转化成游离的[32P]磷酸盐和未标记的腺苷。因此,释放的[32P]磷酸盐的量与酶活性成比例。该分析于30℃在100μL含有(最终浓度)40mM Tris-Cl(pH8.0)、lμM ZnSO4、5mM MgCl2和0.1mg/ml的小牛血清白蛋白的反应混合物中进行。PDE5以产生<30%的底物全部水解(线性分析情况)的量存在。该分析由加入底物(1mM[32P]cGMP)引发,并且培养混合物12分钟。然后加入75μg大响尾蛇(Crotalus atrox)蛇毒,并再继续培养3分钟(一共15分钟)。通过加入200μL活性炭(25mg/ml在0.1M NaH2PO4中的悬浮液,pH4)终止反应。离心(750Xg,3分钟)沉淀活性炭后,取上清液样品在闪烁计数器上进行放射性检测,并计算PDE5活性。
实施例3
测定PDE5抑制剂的作用的分析
本发明的抑制剂对PDE5制剂的酶活性的作用可以通过两种在尺度上彼此基本不同的分析方法来确定,但两者提供基本目同的IC50值的结果。两种分析都包括对Wells等,Biochim.Biophys.Acta,384,430页(1975年)的方法的改进。第一种分析方法是在含有50mM TrispH7.5、3mM乙酸镁、1mM EGTA、50μg/ml蛇毒核苷酸酶和50nM[3H]-cGMP(Amersham)的总体积200μL中进行。将本发明化合物溶于DMSO中,使最终以2%存在于分析液中。将分析液于30℃培养30分钟,并经加入800μL的10mM Tris pH7.5、10mM EDTA、10mM茶碱、0.1mM腺苷,及0.1mM鸟苷终止。将该混合物装载在0.5mlQAE Sephadex柱上,并用2ml的0.1M甲酸盐(pH7.4)洗脱。洗脱物通过在Optiphase Hisafe3上闪烁计数测定放射性。
第二种方法,微量培养板(microplate)PDE分析使用多筛板(Multi-screen plates)和真空歧管(vacuum manifold)。分析液(100μL)中含有50mM Tris pH7.5、5mM乙酸镁、1mM EGTA、250μg/ml蛇毒核苷酸酶。反应混合物中的其他成分如上所述。在培养结束后,将全部体积的分析物经过滤装载在QAE Sephadex微柱板上。游离放射性用200μL水洗脱,从中取50μL等分液并通过上述的闪烁计数进行分析。
实施例4
PDE5抑制剂在偏头痛上的生理学作用的评估
抑制PDE5的化合物对治疗偏头痛的用途在评价所述化合物在减少偏头痛的临床症状和/或减少或预防偏头痛临床症状的复发的生理学作用的临床研究中得到证明。这项研究也是在健康的患者中进行的双盲、安慰剂对照的交叉研究。患者以1至20mg的剂量,或者接受试验化合物,或者接受安慰剂。研究的终点通过使用专门设计的评价临床症状减弱的问卷方式来确定。另外的终点是测定至下一次偏头痛发作前所经历的时间。
实施例5
硬脑脊膜蛋白外渗的动物模型
许多临床前实验室动物模型已有介绍。所用的常规模型是Phebus等在Life Sci.,61(21),2117-2126页(1997年)描述的硬脑脊膜外渗物模型,它可以用于评价本发明化合物。
在该模型中,用戊巴比妥钠腹腔注射(65mg/kg)麻醉HarlanSprague-Dawley大鼠(250至350g)并固定在带有-3.5mm切齿(incisor)棍的脑立体定位框架(David KopfInstruments)中,经中线矢状皮下切口后,穿过头骨钻通两对双侧的孔(6mm后向的,2.0和4.0mm侧面的,全部都参照前囱的坐标定位)。不锈钢刺激电极对,除在末端绝缘外(Rhodes Medical Systems,Inc.),向下插进大脑两个半球的深度9mm的洞中。
暴露股静脉,并以1mL/kg的体积剂量静脉注射试验化合物,或者以2mL/kg体积的试验化合物经管饲法口服给药。大约静脉注射8分钟后,将50mg/kg剂量的Evans Blue,一种荧光染料,也经静脉注射到体内。Evans Blue与蛋白质在血液中结合,并起蛋白外渗物的标记物的作用。在注射试验化合物后10分钟,准时用273型稳压器/galvanostat(Eg&G Princeton Applied Research),以1.0mA的电流强度(5Hz,4msec持续时间(duration))刺激左侧三叉神经的神经节3分钟。
刺激15分钟后,将动物处死并用40mL生理盐水放血。除去头骨顶部以方便收集硬脑脊膜层。从两个大脑半球移出膜样品,用水漂洗,并在显微镜载物片上展平。干燥后,组织用70%的甘油/水溶液浸没(cover-slipped)。
使用配有光栅单色器和分光光度计的荧光显微镜(Zeiss)定量各个样品的Evans Blue染料的量,使用大约535nm的激发波长及测定600nm的发射强度。所述显微镜配有机动镜台,并有接口与个人计算机连接。这便利了计算机-控制的荧光测定的镜台在各个硬脑脊膜样品的25个点(500mm间距)的移动。测定的平均和标准误差通过计算机确定。
通过电刺激三叉神经的神经节诱导的外渗是同侧效应的(即,仅发生在刺激的三叉神经的神经节的一侧的硬脑脊膜)。这样可以使另一半(未刺激的)硬脑脊膜用作对照。计算硬脑脊膜从刺激侧外渗的量与在未刺激侧的硬脑脊膜外渗的量的比率。对照动物仅给予生理盐水,得到大约1.9的比率。作为对照,可以有效防止在刺激侧的硬脑脊膜外渗的化合物将得到大约1.0的比率。
使用上述的硬脑脊膜外渗模型在大鼠中对化合物(IIc)进行试验。化合物(IIc)具有对人重组PDE5的2.4nM的IC50值。化合物(IIc)对于PDE5的最低选择性是对于PDEs 1-4和7-10的2800倍。对大鼠静注20mg/kg剂量的化合物(IIc)提供大约1500ng/mL的化合物(IIc)的总血浆浓度,其半衰期(t1/2)为3.8小时。这相当于化合物(IIc)的约375nM的最大浓度(Cmax)的游离浓度。这种量的化合物(IIc)抑制PDE5,但不抑制PDEs1-4和7-10。
在用于偏头痛的特殊大鼠血浆蛋白外渗(PPE)模型中,化合物(IIc)是静注给药的。3和10ng/kg剂量的化合物(IIc)给予10分钟后最大地抑制PPE麻醉大鼠,即,外渗物比率分别是1.2和1.0。大约1的外渗物比率显示对外渗的完全抑制。0.3ng/kg剂量的化合物(IIc)显示约2的外渗物比率,其中对照样品(即,仅给予溶媒)显示约1.8的外渗物比率。作为比较,对照化合物,那拉曲坦,在同样的实验中以0.1ng/kg抑制PPE。本实施例说明给予PDE5抑制剂对于治疗偏头痛是有效的。
实施例6
临床实验
将1名患有偏头痛30年的54岁男性作为研究的对象,该患者每月有三至四次偏头痛发作,每次持续12至24小时,并伴有恶心偶尔有呕吐。在研究之前的时间里,患者在偏头痛发作时,需要固定的药物,特别是含有舒马普坦的药物。患者还患有轻度的糖尿病和勃起功能障碍。患者使用VIAGRA(即,活性成分是西地那非),以50或100mg的剂量每周服药约2至3次。患者对其偏头痛的正性作用感到满意,并开始以25或50mg的剂量每周服用VIAGRA3至4次。当开始采用VIAGRA治疗方案时,患者保持完全不受偏头痛发作的影响超过一年和一年半。当患者停止VIAGRA治疗方案时,严重的偏头痛也立即重新发生。在患者重新使用VIAGRA的短的时间后,偏头痛发作完全中止。
实施例7
用于本发明方法的制剂的实例包括,但不限于下述:
用于口服给药的片剂
A.
直接压片
Mg/片 | |
活性成分 | 50.0 |
胶体二氧化硅 | 0.5 |
聚乙烯聚吡咯烷酮 | 8.0 |
十二烷基硫酸钠 | 1.0 |
硬脂酸镁Ph Eur | 1.0 |
微晶纤维素USNF | 139.5 |
将活性成分过筛并与赋形剂混合。将所得混合物压制成片剂。
B.
湿法制粒
Mg/片 | |
活性成分 | 50.0 |
聚乙烯吡咯烷酮 | 150.0 |
聚乙二醇 | 50.0 |
聚山梨醇酯80 | 10.0 |
硬脂酸镁Ph Eur | 2.5 |
交联羧甲基纤维素钠 | 25.0 |
胶体二氧化硅 | 2.5 |
微晶纤维素USNF | 210.0 |
将聚乙烯吡咯烷酮、聚乙二醇,及聚山梨醇酯80溶于水中。用所得溶液与活性成分一起制粒。干燥后,将所得颗粒过筛,然后在升温和加压下挤压制粒。将挤压的颗粒研磨和/或过筛,然后与微晶纤维素、交联羧甲基纤维素钠、胶体二氧化硅,及硬脂酸镁混合。将所得混合物压制成片剂。
其他规格的片剂可以通过改变活性成分与其他赋形剂的比率制备。
薄膜衣片
对前述片剂进行薄膜包衣。
包衣悬浮液 | %w/w |
Opadry白+ | 13.2 |
纯水Ph Eur | 至100.0* |
*在最终产物中不出现水。在包衣过程中使用的固体的最大理论重量是20mg/片。
+Opadry白是得自Colorcon Limited,UK专有物质,该物质包含羟丙基甲基纤维素,二氧化钛,及甘油酯三乙酸。
所述片剂用包衣悬浮液在常规薄膜包衣设备中进行薄膜包衣。
胶囊
Mg/片 | |
活性成分 | 50.0 |
乳糖 | 148.5 |
聚乙烯吡咯烷酮 | 100.0 |
硬脂酸镁 | 1.5 |
将活性成分过筛并与赋形剂混合。使用合适的设备将所得混合物填充到1号硬明胶胶囊中。
基于前述对本发明优选的实施方案的描述的考虑,对于本领域技术人员来说,本发明的实践中的许多改进及变化是可以预料的。因此,在本发明的范围内仅有的限制应该是在所附权利要求书中出现的内容。
Claims (21)
1.一种治疗偏头痛的方法,它包括给予需要的个体减少或消除偏头痛的临床症状的有效量的PDE5抑制剂。
2.一种治疗偏头痛的方法,它包括给予需要的个体减少或消除偏头痛的临床症状的有效量的(a)第一种PDE5抑制剂和(b)第二种PDE抑制剂,一种抗偏头痛剂,或其混合物。
3.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的IC50值比对于PDE1至PDE4及PDE6至PDE9的IC50值小约100倍。
4.权利要求1或2的方法,其中PDE5抑制剂在偏头痛发作时给予。
5.权利要求1或2的方法,其中PDE5抑制剂是在偏头痛发作后给予。
其中R1是甲基或乙基;R2是正丙基;R3是乙基、正丙基或烯丙基;R4是COCH2NR5R6、CONR5R6、SO2NR9R10或1-甲基-2-咪唑基;R5和R6与它们相连的氮原子一起代表吗啉代或4-N(R11)-哌嗪基基团;R9和R10与它们相连的氮原子一起代表4-N(R12)-哌嗪基基团;R11是甲基或乙酰基;和R12是氢、甲基、2-丙基或2-羟乙基;
其中R13选自氢、卤素和C1-6烷基;
R14选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、卤代C1-6烷基、C3-8环烷基、C3-8环烷基C1-3烷基和芳基C1-3烷基,其中芳基是苯基或由一到三独立选自卤素、C1-6烷基、C1-6烷氧基和亚甲二氧基的取代基取代的苯基,以及杂芳基C1-3烷基,其中杂芳基是噻吩基、呋喃基或吡啶基,每个任选由一到三个独立选自卤素、C1-6烷基和C1-6烷氧基的取代基取代。
所述双环通过苯环碳原子中的一个连接到所述分子的其余部分,并且其中稠环A是饱和的或部分或完全不饱和的,且包含碳原子和任选一个或二个选自氧、硫和氮的杂原子的5-或6-元环;和
R16代表氢或C1-3烷基,或R1和R3一起代表5-或6-元环的3-或4-个原子的烷基或烯基的链的成分;
以及其盐和其溶剂化物;
其中
R5是甲基或乙基,
R6是乙基或丙基,
R7和R8独立为具有最多可至5个碳原子的直链或支链烷基,任选独立由最多可至两个羟基或甲氧基取代,或
其中R37是氢、甲酰基或各自具有最多可至三个碳原子的直链或支链酰基或烷氧羰基,
或是具有最多可至三个碳原子的直链或支链烷基,任选独立由一个或两个羟基、羧基,或各自具有最多可至三个碳原子的直链或支链烷氧基或烷氧基羰基,或者式-(D)fNR38R39或-P(O)(OR42)(OR43)的基团取代,
其中f是0或1,
D是式-CO的基团,
R38和R39独立是氢或甲基,
R42和R43独立是氢、甲基或乙基,或,
R37是环戊基,
和在R3和R4项下提及的与氮原子一起形成的杂环任选独立由一个或二个,任选成对的,羟基、甲酰基、羧基和各自具有最多可至三个碳原子的直链或支链酰基或烷氧基羰基,或式-P(O)(OR46)(OR47)或-(CO)jNR49R50的基团取代,
其中R46和R47独立是氢、甲基或乙基,
j是0或1,和
R49和R50独立是氢或甲基和/或在R3和R4项下提及的与氮原子一起形成的杂环由具有最多可至三个碳原子的直链或支链任选取代,它任选独自由一个或两个羟基、羧基或式P(O)OR53OR54的基团取代,
其中R53和R54独立是氢、甲基或乙基,和/或在R3和R4项下提及的与氮原子一起形成的杂环任选由经N-连接的哌啶基或吡咯烷基取代,
R9是氢,和
R10是乙氧基或丙氧基,
及其盐、水合物、N-氧化物,及其异构体形式。
9.权利要求1或2的方法,其中所述PDE5抑制剂在24小时的时间内以约1mg至约100mg的量给予。
10.权利要求2的方法,其中(a)第一个PDE5抑制剂和(b)第二个PDE5抑制剂,抗偏头痛剂,或其混合物被同时给予。
11.权利要求2的方法,其中(a)第一个PDE5抑制剂和(b)第二个PDE5抑制剂,抗偏头痛剂,或其混合物按顺序给予。
12.权利要求2的方法,其中抗偏头痛剂选自麦角生物碱、止痛剂、镇静剂、β-阻滞剂、钙通道阻滞剂、三环类抗抑郁剂、抗惊厥剂、单氨氧化酶抑制剂和5-HT激动剂。
13.权利要求2的方法,其中抗偏头痛剂选自普萘洛尔、美托洛尔、阿替洛尔、噻吗洛尔、纳多洛尔、维拉帕米、地尔硫、硝苯地平、尼莫地平、阿米替林、去甲替林、双丙戊酸钠、舒马普坦、那拉曲坦、利扎曲普坦、唑咪曲普坦、苯噻啶、对乙酰氨基酚、阿司匹林、布洛芬、吲哚美辛、麦角胺、二氢麦角胺、布他比妥、苯乙肼和异卡波肼。
14.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的约10nM或更少的IC50值。
15.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的约5nM或更少的IC50值。
16.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的约3nM或更少的IC50值。
17.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的IC50值比其对PDE6和PDE1c的IC50值小约100倍。
18.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的IC50值比其对PDE6和PDE1c的IC50值小约500倍。
19.权利要求1或2的方法,其中PDE5抑制剂具有对人重组PDE5的IC50值比其对PDE6和PDE1c的IC50值小约1000倍。
20.一种治疗偏头痛的方法,它包括给予需要的个体减少或消除偏头痛的临床症状的有效量的PDE5抑制剂,所述PDE5抑制剂在偏头痛的临床症状发作时给予。
21.PDE5抑制剂在制备用于治疗偏头痛的药物中的用途。
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DE10135815A1 (de) * | 2001-07-23 | 2003-02-06 | Bayer Ag | Verwendung von 2-Alkoxyphenyl-substituierten Imidazotriazinonen |
GB0219024D0 (en) * | 2002-08-15 | 2002-09-25 | Pfizer Ltd | Synergistic combinations |
DE10325813B4 (de) | 2003-06-06 | 2007-12-20 | Universitätsklinikum Freiburg | Prophylaxe und/oder Therapie bei der portalen Hypertonie |
ES2538082T3 (es) | 2007-02-11 | 2015-06-17 | Map Pharmaceuticals Inc | Método de administración terapéutica de DHE para permitir el rápido alivio de migraña mientras que se minimiza el perfil de efectos secundarios |
ES2533206T3 (es) | 2007-03-27 | 2015-04-08 | Omeros Corporation | Inhibidores de PDE7 para uso en el tratamiento de trastornos del movimiento |
ES2527448T3 (es) | 2008-04-28 | 2015-01-23 | Zogenix, Inc. | Nuevas formulaciones para el tratamiento de la migraña |
US9415048B2 (en) | 2010-07-08 | 2016-08-16 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
US10010514B2 (en) | 2010-07-08 | 2018-07-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
US20130323288A1 (en) | 2010-07-08 | 2013-12-05 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for bedwetting and method of use thereof |
US9532959B2 (en) | 2010-07-08 | 2017-01-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
US10105330B2 (en) | 2012-01-04 | 2018-10-23 | Wellesley Pharmaceuticals, Llc | Extended, delayed and immediate release formulation method of manufacturing and use thereof |
WO2013103389A1 (en) | 2012-01-04 | 2013-07-11 | Wellesley Pharmaceuticals, Llc | Delayed-release formulation for reducing the frequency of urination and method of use thereof |
US10278925B2 (en) | 2012-01-04 | 2019-05-07 | Wellesley Pharmaceuticals, Llc | Delayed-release formulations, methods of making and use thereof |
BR112015001627A2 (pt) * | 2012-07-27 | 2017-07-04 | A Dill David | composição farmacêutica, respectivos usos e método para diminuir a frequência de micção |
EP2935280A4 (en) | 2012-12-21 | 2016-05-25 | Map Pharmaceuticals Inc | 8'-HYDROXY-DIHYDROERGOTAMINE COMPOUNDS AND COMPOSITIONS |
US10792326B2 (en) | 2013-06-28 | 2020-10-06 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for bedwetting and method of use thereof |
JP2017114764A (ja) * | 2014-04-25 | 2017-06-29 | 武田薬品工業株式会社 | 片頭痛治療剤 |
US10105328B2 (en) | 2014-06-06 | 2018-10-23 | Wellesley Pharmaceuticals, Llc | Composition for reducing frequency of urination, method of making and use thereof |
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