CN1474692A - 早泄的治疗 - Google Patents
早泄的治疗 Download PDFInfo
- Publication number
- CN1474692A CN1474692A CNA018189806A CN01818980A CN1474692A CN 1474692 A CN1474692 A CN 1474692A CN A018189806 A CNA018189806 A CN A018189806A CN 01818980 A CN01818980 A CN 01818980A CN 1474692 A CN1474692 A CN 1474692A
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- Prior art keywords
- pde5
- ethyl
- purposes
- inhibitor
- pyrazolo
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- Nitrogen Condensed Heterocyclic Rings (AREA)
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- Orthopedics, Nursing, And Contraception (AREA)
Abstract
本发明涉及环鸟苷3’,5’-一磷酸盐磷酸二酯酶五型抑制剂用途,特别是包括化合物西地那非(sildenafil)的用途,用于治疗具有正常勃起功能的患者的早泄。
Description
本发明涉及环鸟苷3’,5’-一磷酸盐磷酸二酯酶五型抑制剂(以下称为PDE5抑制剂)的用途,用于治疗早泄(PE)。特定的PDE5抑制剂是西地那非(sildenafil)、IC-351、瓦地那非(vardenafil)、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-酮和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮。
按照我们的国际专利申请WO 94/28902的说明书,我们已经探索了作为cGMP PDE5酶抑制剂的化合物是有力和有效的治疗男性勃起机能障碍(MED,阳痿)和女性性功能障碍的化合物。从这项发现而开发出化合物西地那非(5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)苯基]-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)(VIAGRA(万艾可)TM),作为第一种口服有效治疗MED的药物,它已被证实取得了极大成功。
PE是一种相当普遍的男性性机能障碍。它已经具有若干不同方式的定义,不过最广为接受的是Diagnostic and Statistical Manual of MentalDisorders IV,其中规定:“PE是在进入之前、之时或之后不久并且在患者需要之前,因微小的性刺激而持续或反复的射精。临床医师必须考虑影响兴奋期的持续时间的因素,例如年龄、性伴侣或刺激的新鲜感和性活动的频率。失调导致显著的痛苦或人际关系不和。”
国际疾病分类第10项定义规定:“不能延迟射精以充分享受性爱,表现为下列之一:(1)在性交之前或者在性交开始后很快发生射精(如果需要时间界限的话:在性交之前或者在性交开始15秒内);(2)射精发生在没有充分勃起使性交成为可能之时。此问题不是长期节制性活动的结果。”
其他已经用到的定义包括按下列标准的分类:
●涉及配偶的性欲高潮
●进入与射精之间的持续时间
●插入的次数和主动控制的能力
在PE中可能牵涉心理因素,关系问题、焦虑、抑郁、以前的性失败都起到一定作用。
据估计,PE的普遍性占男性人口的约22-38%;与MED不同,它与年龄没有确定的联系。假设平均普遍性为30%,也就是说在美国估计有两千四百万人患病(1995年,18-65岁的男性有八千万)。严格来讲没有关于普遍性的数据。据估计,可行的PE定义可能适用于5-10%的男性,不过接受治疗的不到0.2%。口服有效的疗法的可利用性极有可能改变这种情形。
泌尿科医师目前构成治疗PE的医师的主体(59%);GP构成治疗该疾病的医生的33%。性治疗医师、行为治疗医师和顾问也治疗PE患者。专家估计,50%的求诊者求诊是因为该疾病而对与配偶的关系造成了冲击。精神紧张、关系困难和/或对生活质量的影响是患者寻求PE治疗的关键动机。
射精取决于交感与副交感神经系统。传出神经冲动经由交感神经系统到达输精管和附睾,引起平滑肌收缩,移送精液进入后尿道。精囊、前列腺和尿道球腺类似的收缩,增加精液的容量和流体含量。精液的逼出受到发源于脊髓Onuf核的传出冲动的介导,该冲动通过副交感神经系统,导致球海绵体、坐骨海绵体和骨盆底肌肉的有节律的收缩。人类皮质对射精的控制仍在争论之中。在大鼠中,射精似乎牵涉下丘脑的内侧视前区和室旁核。
目前尚没有药物获准用于治疗PE。最常用的无标记(off-label)处方药物是抗抑郁剂(例如氯米帕明)和选择性血清素再摄取抑制剂(例如帕罗西汀和舍曲林)。这些药物经常不被患者所充分接受,因为它们被视为抗抑郁剂。它们是被“无标记”使用的,尽管在按需要使用时是有效的(即“prn”),不过由于它们的药动学Tmax(在口服给药后达到最大血浆药物浓度的时间)长,它们很可能起效缓慢。在长期使用中可以见到这类药物常有的副作用。行为疗法已经成为其他处置手段,但是还不是非常有效,并且中断和复发的比例高。因此需要新的更有效的疗法。
本发明第一方面提供PDE5抑制剂在药物制备中的用途,该药物用于治疗具有正常勃起功能的患者的早泄。
PDE5抑制剂是指这样一种化合物,它是cGMP PDE5同功酶的有效的选择性抑制剂。
按照本发明,具有正常勃起功能的患者能够实现勃起(无需任何药物或医学装置,例如真空泵)足以进入阴道,并且能够维持勃起直至射精。这些患者中的PE通常是原发性PE。
按照本发明,患有PE但具有正常勃起功能的患者在进入之后不久并且在其需要之前因微小的性刺激而持续或反复地射精。另外,这些患者中的PE不是处境性的或者继发于已知的器质性原因。通常,这些患者中的PE自他们的第一次性体验即已存在。
在本发明的优选实施方式中,具有正常勃起功能的患者关于勃起功能范围问卷(见下)的得分大于22(优选大于25)。
以下,术语“PDE5抑制剂”表示用于本发明的PDE5抑制剂。该术语包括用于本发明的PDE5抑制剂的药学上可接受的盐、溶剂化物和多晶型物。
PDE5抑制剂的适合性容易这样确定,利用文献方法评价它的效力和选择性,随后按照标准药学实践评价它的毒性、吸收、代谢、药动学等。
优选的是,PDE5抑制剂对PDE5酶的IC50小于100纳摩尔,更优选地小于50纳摩尔。
PDE5抑制剂的IC50值可以利用下文试验方法部分中的PDE5测定法加以测定。
优选的是,PDE5抑制剂对于PDE5酶是选择性的。优选的是,它们对PDE5的选择性比对PDE3的选择性高的倍数大于100,更优选地大于300倍。更优选的是,PDE5抑制剂的选择性比PDE3和PDE4的选择性高大于100倍,更优选大于300倍。
选择性之比值是技术人员容易确定的,可以根据与特定的酶相应的IC50之比来确定。关于PDE3和PDE4酶的IC50值可以利用已有的文献方法加以测定,参见S A Ballard等,Journal of Urology,1998,vol.159,p.2164-2171。
优选的是,PDE5抑制剂对PDE5的IC50小于100nM,选择性比PDE3的选择性高大于100倍。
用于本发明的PDE5抑制剂的实例是:
公开在EP-A-0463756中的吡唑并[4,3-d]嘧啶-7-酮;公开在EP-A-0526004中的吡唑并[4,3-d]嘧啶-7-酮;公开在已公开的国际专利申请WO93/06104中的吡唑并[4,3-d]嘧啶-7-酮;公开在已公开的国际专利申请WO93/07149中的异构的吡唑并[3,4-d]嘧啶-4-酮;公开在已公开的国际专利中请WO93/12095中的喹唑啉-4-酮;公开在已公开的国际专利申请WO94/05661中的吡啶并[3,2-d]嘧啶-4-酮;公开在已公开的国际专利申请WO94/00453中的嘌呤-6-酮;公开在已公开的国际专利申请WO98/49166中的吡唑并[4,3-d]嘧啶-7-酮;公开在已公开的国际专利申请WO99/54333中的吡唑并[4,3-d]嘧啶-7-酮;公开在EP-A-0995751中的吡唑并[4,3-d]嘧啶-4-酮;公开在已公开的国际专利申请WO00/24745中的吡唑并[4,3-d]嘧啶-7-酮;公开在EP-A-0995750中的吡唑并[4,3-d]嘧啶-4-酮;公开在已公开的国际专利申请WO95/19978中的化合物;公开在已公开的国际专利申请WO99/24433中的化合物;和公开在已公开的国际专利申请WO93/07124中的化合物;公开在已公开的国际专利申请WO01/27112中的吡唑并[4,3-d]嘧啶-7-酮;公开在已公开的国际专利申请WO01/27113中的吡唑并[4,3-d]嘧啶-7-酮;公开在EP-A-1092718中的化合物;和公开在EP-A-1092719中的化合物。
用于本发明的优选PDE5抑制剂:
5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)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),也已知为1-[[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯基]磺酰基]-4-甲基哌嗪(见EP-A-0463756);
5-(2-乙氧基-5-吗啉代乙酰苯基)-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(见EP-A-0526004);
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(见WO98/49166);
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(见WO99/54333);
(+)-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,也已知为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(见WO99/54333);
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,也已知为1-{6-乙氧基-5-[3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶磺酰基}-4-乙基哌嗪(见WO01/27113实施例8);
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(见WO01/27113实施例15);
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(见WO01/27113实施例66);
5-(5-乙酰基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-异丙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(见WO01/27112实施例124);
5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(见WO01/27112实施例132);
(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(IC-351),即已公开的国际申请WO95/19978实施例78和95化合物以及实施例1、3、7和8化合物;
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(vardenafil),也已知为1-[[3-(3,4-二氢-5-甲基-4-氧代-7-丙基咪唑并[5,1-f]-as-三嗪-2-基)-4-乙氧基苯基]磺酰基]-4-乙基哌嗪,即已公开的国际申请WO99/24433实施例20、19、337和336;
已公开的国际申请WO93/07124实施例11化合物(EISAI);和Rotella D P,J.Med.Chem.,2000,43,1257中的化合物3和14。
还有另一种用于本发明的PDE5抑制剂包括:4-溴-5-(吡啶基甲氨基)-6-[3-(4-氯苯基)丙氧基]-3(2H)哒嗪酮;1-[4-[(1,3-苯并二氧戊环-5-基甲基)氨基]-6-氯-2-喹唑啉基]-4-哌啶羧酸,一钠盐;(+)-顺式-5,6a,7,9,9,9a-六氢-2-[4-(三氟甲基)苯甲基-5-甲基环戊二烯并[4,5]咪唑并[2,1-b]嘌呤-4(3H)-酮;furazlocillin;顺式-2-己基-5-甲基-3,4,5,6a,7,8,9,9a-八氢环戊二烯并[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-吡唑并[4,3-d]嘧啶-7-酮;1-[4-[(1,3-苯并二氧戊环-5-基甲基)氨基]-6-氯-2-喹唑啉基]-4-哌啶羧酸,一钠盐;Pharmaprojects No.4516(Glaxo Wellcome);Pharmaprojects No.5051(Bayer);Pharmaprojects No.5064(Kyowa Hakko;WO 96/26940);Pharmaprojects No.5069(Schering Plough);GF-196960(Glaxo Wellcome);E-8010和E-4010(Eisai);Bay-38-3045 & 38-9456(Bayer)和Sch-51866。
已公布的专利申请和杂志文章的内容、确切为其中权利要求的治疗活性化合物的通式和举例的化合物全部引用在此作为参考。
更优选用于本发明的PDE5抑制剂选自下组:
5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)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);
(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(IC-351);
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(瓦地那非);
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;和
5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮,及其药学上可接受的盐。
特别优选的PDE5抑制剂是5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)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)(也已知为1-[[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯基]磺酰基]-4-甲基哌嗪)及其药学上可接受的盐。西地那非柠檬酸盐是优选的盐。
口服生物利用度是指口服给药的药物到达全身循环的比例。决定药物口服生物利用度的因素是溶解性、膜渗透性和代谢稳定性。通常,首先在体外进行级联筛选,然后采用体内技术,以测定口服生物利用度。
溶解性是胃肠道(GIT)水性内容物对药物的增溶作用,可以从体外溶解度实验预知,该实验是在适当pH下进行的,以模拟GIT。优选地,PDE5抑制剂的最低溶解度为50mcg/ml。溶解度可以通过本领域已知的标准方法加以测定,例如Adv.Drug Deliv.Rev.23,3-25,1997所述。
膜渗透性是指化合物通过GIT细胞的程度。亲脂性是预测该参数的一个关键性能,由使用有机溶剂和缓冲液进行的体外Log D7.4测量所定义。优选地,PDE5抑制剂的Log D7.4为-2至+4,更优选为-1至+3。Log D可以通过本领域已知的标准工艺加以测定,例如J.Pharm.Pharmacol.1990,42:144所述。
细胞单层测定法、例如CaCO3另外可以在溢出转运蛋白例如p-糖蛋白的存在下,预测合适的膜渗透性,即所谓的caco-2流量。优选PDE5抑制剂的caco-2流量大于2×10-6cms-1,更优选大于5×10-6cms-1。caco流量值可以通过本领域已知的标准方法加以测定,例如J.Pharm.Sci.,1990,79,595-600所述。
代谢稳定性是指GIT或肝脏在吸收过程中代谢化合物的能力:首过效应(the first pass effect)。测定系统例如微粒体、肝细胞等,有代谢倾向的预兆。优选地,PDE5抑制剂在与肝提取物等价的测定系统中的代谢稳定性小于0.5。测定系统和数据处理的实例描述在Curr.Opin.Drug Disc.Devel.,201,4,36-44,Drug Met.Disp.,2000,28,1518-1523。
由于上述过程的相互作用通过动物体内实验进一步支持了口服药物在人体中能够获得生物可利用性。绝对生物利用度在这些研究中是这样测定的,通过口服途径服用单独的化合物或混合物。关于绝对测定(吸收%),也采用静脉内途径。动物口服生物利用度评估的实例可以参见Drug Met.Disp.,2001,29,82-87;J.Med.Chem.,1997,40,827-829,DrugMet.Disp.,1999,27,221-226。
PDE5抑制剂可以单独给药,但是一般将与适合的药物赋形剂、稀释剂或载体混合给药,根据预定给药途径和标准药学实践加以选择。
例如,PDE5抑制剂可以口服、颊部或舌下给药,剂型为片剂、胶囊剂、多颗粒剂、凝胶剂、膜剂、卵状体剂、酏剂、溶液或混悬液,其中可以含有矫味剂或着色剂,用于立即、延迟、缓释、持续、脉冲或受控释放的应用。PDE5抑制剂还可以作为快速分散或快速溶解的剂型给药,或者以高能分散系或包衣颗粒的形式给药。适合的制剂可以是包衣或未包衣的形式,视需要而定。
这类固体药物组合物、例如片剂可以含有赋形剂,例如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘氨酸和淀粉(优选玉米、马铃薯或木薯淀粉),崩解剂,例如淀粉羟乙酸钠、交联羧甲基纤维素钠和某些复合硅酸盐,和造粒粘合剂,例如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯胶。另外,可以包括润滑剂,例如硬脂酸镁、硬脂酸、山萮酸甘油酯和滑石。
下列制剂例仅为举例说明,并不是要限制本发明的范围。活性成分是表示PDE5抑制剂。
制剂1:
利用下列成分制备片剂:
将活性成分(50mg)与纤维素(微晶纤维素)、二氧化硅、硬脂酸(发烟)共混,将混合物压制成片。
制剂2:
将活性成分(100mg)与等渗盐水(1000ml)混合,可以制成静脉内制剂。
片剂是通过标准方法制备的,例如直接压制或者湿法或干法造粒过程。片芯可以包以适当的包衣。
还可以采用相似类型的固体组合物作为明胶或HPMC胶囊中的填充物。在这一点上优选的赋形剂包括乳糖、淀粉、纤维素、奶糖或高分子聚乙二醇。关于水悬液和/或酏剂,可以将PDE5抑制剂与各种甜味剂或矫味剂、着色物或染剂混合,以及与乳化剂和/或悬浮剂和稀释剂混合,例如与水、乙醇、丙二醇和甘油及它们的组合物相混合。
缓慢释放和脉冲释放的剂型可以含有赋形剂,例如立即释放剂型所述那些,以及另外加充当释放速率调节剂的赋形剂,它们被包涂在剂型上和/或包含在器件内。释放速率调节剂包括但不仅限于羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素、乙酸纤维素、聚氧乙烯、黄原胶、Carbomer、异丁烯酸铵共聚物、氢化蓖麻油、巴西棕榈蜡、石蜡、乙酸纤维素邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、异丁烯酸共聚物及其混合物。缓慢释放和脉冲释放的剂型可以含有释放速率调节性赋形剂中的一种或几种组合。释放速率调节性赋形剂可以存在于剂型内部,也就是基料内,和/或存在于剂型上,也就是表面或包衣。
快速分散或溶解的剂型(FDDF)可以含有下列成分:阿司帕坦、乙酰舒泛钾、柠檬酸、交联羧甲基纤维素钠、交联聚维酮、二抗坏血酸、丙烯酸乙酯、乙基纤维素、明胶、羟丙基甲基纤维素、硬脂酸镁、甘露糖醇、异丁烯酸甲酯、薄荷调味剂、聚乙二醇、发烟硅石、二氧化硅、淀粉羟乙酸钠、硬脂酰富马酸钠、山梨糖醇、木糖醇。这里用于描述FDDF的术语分散或溶解是取决于所用药物物质的溶解度,也就是说,若药物物质是不溶性的,则可以制备快速分散的剂型,若药物物质是可溶性的,则可以制备快速溶解的剂型。
PDE5抑制剂还可以被肠胃外给药,例如腔内、静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内或皮下,或者可以利用输注或无针注射技术给药。关于这类肠胃外给药,最好使用无菌水溶液的形式,其中可以含有其他物质,例如足够的盐或葡萄糖,使溶液与血液等渗。如果必要的话,水溶液应当被适当地缓冲(优选至pH为3至9)。利用本领域技术人员熟知的标准药学技术容易实现适合的肠胃外制剂在无菌条件下的制备。
下列剂量水平和本文其他剂量水平是针对体重约65至70kg的普通受治疗人而言的。技术人员能够容易地确定体重超出该范围的受治疗者所需的剂量水平,例如儿童和老人。
PDE5抑制剂在这类制剂中的剂量将取决于它的效力,但是可以预期在1至500mg的范围内,每天给药至多三次。在西地那非的情况下,优选的剂量在10至100mg的范围内(例如10、25、50和100mg),每天可以给药一次、两次或三次(优选一次)。不过,精确的剂量将由主治医师决定,并将取决于患者的年龄与体重和症状的严重性。
关于对人类患者口服和肠胃外给药,PDE5抑制剂的每日剂量水平通常将从5至500mg/kg(单独或分开剂量)。
因而,PDE5抑制剂的片剂或胶囊剂可以含有5mg至250mg(优选10至100mg)活性化合物,用于在一定时间给药一次或两次或多次,视情况而定。无论如何,医师都将决定实际剂量,该剂量将最适合于任意个别患者,并将因特定患者的年龄、体重和反应而异。上述剂量是一般情况的举例。当然可以存在个别的情形,其中比这更高或更低的剂量范围也是恰当的,也属于本发明的范围。技术人员将领会到,PDE5抑制剂可以根据必要或需要(即prn)而以单剂服用。需要意识到的是本文所有涉及治疗的提法包括急性治疗(根据需要采取)和慢性治疗(长期的连续的治疗)。
PDE5抑制剂还可以被鼻内给药或者通过吸入给药,适宜以干粉吸入剂或气雾剂的形式从加压容器、泵、喷雾器、雾化器(atomiser)或喷洒器(nebuliser)内释放出来,其中使用或者不用适合的推进剂,例如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、氢氟烷(例如1,1,2,2-四氟乙烷(HFA 134ATM)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EATM))、二氧化碳或其它适合的气体。在加压气雾剂的情况下,该剂量单位可以通过提供释放计量的阀门加以确定。加压容器、泵、喷雾器、雾化器或喷洒器可以含有活性化合物的溶液或混悬液,例如使用乙醇与推进剂的混合物作为溶剂,还可以另外含有润滑剂,例如脱水山梨醇三油酸酯。用在吸入器或吹入器内的胶囊和药筒(例如由明胶制成)可以被配制成含有PDE5抑制剂与适合的粉末基质例如乳糖或淀粉的粉末混合物。
气雾剂或干粉制剂优选的是这样用法,使之每计量单位的剂量或“每揿一下”含有1至50mg PDE5抑制剂释放给患者。气雾剂的每日总剂量将在1至50mg的范围内,可以在全天内一次给药,或者更通常地分多次给药。
或者,PDE5抑制剂可以以栓剂或阴道栓的形式给药,或者它们可以以凝胶剂、水凝胶剂、洗剂、溶液、霜剂、软膏剂或撒布粉剂的形式局部用药。PDE5抑制剂还可以经皮或透皮给药,例如利用皮肤贴剂。它们还可以通过肺或直肠途径给药。
关于皮肤局部用药,可以将PDE5抑制剂配制成适合的软膏剂,其中含有悬浮或溶解在例如下列一种或更多试剂的混合物中的活性化合物:矿物油、液体矿脂、白矿脂、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡和水。或者,可以配制成适合的洗剂或霜剂,悬浮或溶解在例如下列一种或更多试剂的混合物中:矿物油、脱水山梨醇单硬脂酸酯、聚乙二醇、液体石蜡、聚山梨醇酯60、鲸蜡基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。
PDE5抑制剂还可以与环糊精结合使用。已知环糊精与药物分子形成包埋和非包埋的复合物。药物-环糊精复合物的形成可以改变药物分子的溶解度、溶解速率、生物利用度和/或稳定性性质。药物-环糊精复合物一般可用于大多数剂型和给药途径。作为直接与药物复合的替代选择,环糊精还可以用作辅助添加剂,例如载体、稀释剂或增溶剂。α-、β-和γ-环糊精是最常用的,适合的实例描述在WO-A-91/11172、WO-A-94/02518和WO-A-98/55148中。
一般对人类而言,PDE5抑制剂的口服给药是优选的途径,也是最方便的。在受体患有吞咽障碍或者口服给药后药物吸收少的情况下,该药物也可以通过肠胃外、舌下或颊部给药。
进一步优选的途径是经由皮肤局部给药,优选局部给药至男性生殖器。
在本发明的实施方式中,PDE5抑制剂还可以与另外一种或多种活性药物结合用于治疗具有正常勃起功能的患者的PE,该活性药物选自下列:
1)一种或多种天然存在或合成的前列腺素或其酯;适用于此的前列腺素例如包括前列地尔、前列腺素E1、前列腺素E0、13,14-二氢前列腺素E1、前列腺素E2、eprostinol、天然、合成与半合成的前列腺素及其衍生物(包括WO-00033825和/或2000年3月14日公布的US6,037,346所述那些,全部引用在此作为参考)、PGE0、PGE1、PGA1、PGB1、PGF1α、19-羟基PGA1、19-羟基PGB1、PGE2、PGB2、19-羟基PGA2、19-羟基PGB2、PGE3α、卡前列素氨丁三醇、地诺前列素氨丁三醇、地诺前列酮、lipoprost、吉美前列素、甲烯前列素、硫前列酮、噻前列素和莫西赛利;
2)一种或多种α-肾上腺素能受体拮抗剂(也已知为α-肾上腺受体阻滞剂、α-受体阻滞剂或α-阻滞剂);适合的α1-肾上腺素能受体拮抗剂包括酚妥拉明、哌唑嗪、甲磺酸酚妥拉明、曲唑酮、阿夫唑嗪、吲哚拉明、萘哌地尔、坦洛新、苯氧苄胺、萝芙木生物碱、Recordati15/2739、SNAP1069、SNAP5089、RS17053、SL89.0591、多沙唑嗪、特拉唑嗪和阿巴诺喹;适合的α2-肾上腺素能受体拮抗剂包括地苯那明、妥拉唑林、曲马唑嗪、依法克生、育亨宾、咪唑克生、可乐定和氯乙双苄胺;适合的非选择性α-肾上腺素能受体拮抗剂包括达哌唑;另外的α-肾上腺素能受体拮抗剂描述在1998年6月14日公开的PCT申请WO99/30697和下列美国专利中:4,188,390、4,026,894、3,511,836、4,315,007、3,527,761、3,997,666、2,503,059、4,703,063、3,381,009、4,252,721和2,599,000,各自引用在此作为参考;
3)一种或多种血管舒张剂;适用于此的血管舒张剂包括尼莫地平、吡那地尔、环扁桃酯、异克舒令、chloroprumazine、氟哌啶醇、Rec15/2739和曲唑酮;
4)一种或多种麦角生物碱;适合的麦角生物碱描述在2000年3月14日公布的美国专利6,037,346中,包括乙酰麦角胺、溴麦角林、溴麦角脲、氰麦角林、delorgotrile、地舒勒近、马来酸麦角新碱、酒石酸麦角胺、乙舒麦角、麦角腈、麦角二乙胺、美舒麦角、甲麦角林、甲麦角胺(metergotamine)、尼麦角林、培高利特、普罗麦角、丙麦角脲、特麦角脲;
5)一种或多种血管紧张素受体拮抗剂,例如洛沙坦;
6)一种或多种钙通道阻滞剂,例如氨氯地平;
7)一种或多种内皮缩血管肽受体拮抗剂和内皮缩血管肽转化酶抑制剂;
8)一种或多种胆固醇降低剂,例如他汀类(例如atorvastatin/LipitorTM)和贝特类;
9)一种或多种乙酰胆碱酯酶抑制剂,例如donezipil;
10)一种或多种雌激素受体调节剂和/或雌激素激动剂和/或雌激素拮抗剂,优选雷洛昔芬或lasofoxifene、(-)-顺式-6-苯基-5-[4-(2-吡咯烷-1-基乙氧基)苯基]-5,6,7,8-四氢萘-2-酚及其药学上可接受的盐,其制备详见WO96/21656;
11)一种或多种其他PDE抑制剂,特别是PDE2、7或8抑制剂,优选PDE2抑制剂,所述抑制剂对各酶的IC50小于100nM;
12)一种或多种NPY(神经肽Y)抑制剂,特别是NPY1或NPY5抑制剂,优选NPY1抑制剂,优选地所述NPY抑制剂(包括NPY Y1和NPY Y5)的IC50小于100nM,更优选地小于50nM;关于鉴别NPY抑制剂的测定法列在WO-A-98/52890中(见96页2至28行);
13)一种或多种作用于血管的肠蛋白(VIP)、VIP模拟物、VIP类似物,特别是受一种或多种VIP受体亚型VPAC1、VPAC或PACAP的介导(垂体腺苷酸环化酶活化性肽),和一种或多种VIP受体激动剂或VIP类似物(例如Ro-125-1553)或VIP片断,一种或多种α-肾上腺受体拮抗剂与VIP的组合(例如invicorp、aviptadil);
14)一种或多种黑皮质素(melanocortin)受体激动剂或调节剂或黑皮质素增强剂,例如melanotan II、PT-14、PT-141或WO-09964002、WO-00074679、WO-09955679、WO-00105401、WO-00058361、WO-00114879、WO-00113112、WO-09954358所要求保护的化合物;
15)一种或多种5-HT3拮抗剂(优选巴他必利、格拉司琼、昂丹司琼、托烷司琼或MDL-73147EF);
16)一种或多种5-HT4拮抗剂(优选西沙必利和D-麦角酸二乙酰胺);
17)一种或多种睾酮、睾酮替代剂(例如脱氢雄甾烯二酮)、testosternone(Tostrelle)、二氢睾酮或睾酮植入物;
18)一种或多种雌二醇、雌激素、雌激素与甲羟孕酮或乙酸甲羟孕酮(MPA)(也就是作为组合)、或雌激素与甲基睾酮激素替代治疗剂(例如HRT,尤其是Premarin、Cenestin、Oestrofeminal、Equin、Estrace、Estrofem、Elleste Solo、Estring、Eastraderm TTS、Eastraderm Matrix、Dermestril、Premphase、Preempro、Prempak、Premique、Estratest、Estratest HS、替勃龙);
19)一种或多种去甲肾上腺素、多巴胺和/或血清素的转运蛋白调节剂,例如安非他酮和GW-320659;
20)一种或多种嘌呤能受体激动剂和/或调节剂;
21)一种或多种神经激肽(NK)受体拮抗剂,包括WO-09964008所述那些;
22)一种或多种类阿片受体激动剂、拮抗剂或调节剂;
23)一种或多种类大麻酚受体调节剂;
24)加巴喷丁;
25)一种或多种血管紧张素转化酶(ACE)抑制剂,例如喹那普利;和
26)一种或多种抗抑郁剂;例如选择性血清素再摄取抑制剂(舍曲林、氟西汀、氟伏沙明、帕罗西汀、西酞普兰、文拉法辛、米氮平、奈法唑酮、曲唑酮);三环抗抑郁剂(TCA、与心血管副作用有关)(氯米帕明、地昔帕明、米帕明、阿米替林、多塞平、阿莫沙平、马普替林、去甲替林、普罗替林、曲米帕明、安非他酮);和单胺氧化酶抑制剂苯乙肼、反苯环丙胺。优选的另外与PDE5抑制剂(优选西地那非、vardenafil、IC-351、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-酮和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮)联合用于本发明的活性药物选自下列:
a)一种或多种α-肾上腺素能受体拮抗剂(优选哌唑嗪、曲唑酮、阿夫唑嗪、吲哚拉明、坦洛新、苯氧苄胺、育亨宾、多沙唑嗪、特拉唑嗪、可乐定、Recordati 15/2739、SNAP1069、SNAP5089和RS17053);
b)一种或多种5-HT3拮抗剂(优选巴他必利、格拉司琼、昂丹司琼、托烷司琼或MDL-73147EF);
c)一种或多种去甲肾上腺素、多巴胺和/或血清素的转运蛋白调节剂,例如安非他酮和GW-320659;和
d)抗抑郁剂(优选舍曲林、氟西汀、氟伏沙明、帕罗西汀、西酞普兰、文拉法辛、氯米帕明)。
特别优选的另外与西地那非联合用于本发明的活性药物选自下列:舍曲林、氟西汀、帕罗西汀、氯米帕明、昂丹司琼、苯氧苄胺、阿夫唑嗪和特拉唑嗪。
特别优选的另外与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-酮联合用于本发明的活性药物选自下列:舍曲林、氟西汀、帕罗西汀、氯米帕明、昂丹司琼、苯氧苄胺、阿夫唑嗪和特拉唑嗪。
特别优选的另外与5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮联合用于本发明的活性药物选自下列:舍曲林、氟西汀、帕罗西汀、氯米帕明、昂丹司琼、苯氧苄胺、阿夫唑嗪和特拉唑嗪。
这里所有提及的治疗均将其理解为包括治愈、减轻和预防性处置。
如果联合服用几种活性药物,那么它们可以被同时、分开或先后服用。
本发明将被理解为是基于下列另外几个方面,并且上文关于第一方面特定的实施方式也延及这些方面:i)用于治疗具有正常勃起功能的患者的早泄的PDE5抑制剂;ii)用于治疗具有正常勃起功能的患者的早泄的药物组合物,包含PDE5抑制剂和另外如上文所定义的活性药物;iii)药物组合物在药物制备中的用途,该药物用于治疗具有正常勃起功能的患者的早泄,包含PDE5抑制剂和另外如上文所定义的活性药物;iv)用于治疗具有正常勃起功能的患者的早泄的试剂盒,该试剂盒包含:a)包含PDE5抑制剂的第一药物组合物;b)包含另外如上文所定义的活性药物的第二药物组合物;和c)该第一和第二组合物的容器;v)试剂盒在药物制备中的用途,该药物用于治疗具有正常勃起功能的患者的早泄,该试剂盒包含:a)包含PDE5抑制剂的第一药物组合物;b)包含另外如上文所定义的活性药物的第二药物组合物;和c)该第一和第二组合物的容器;vi)治疗具有正常勃起功能的早泄患者的方法,包括用有效量PDE5抑制剂治疗所述患者;和vii)治疗具有正常勃起功能的早泄患者的方法,包括用药物组合物治疗所述患者,该药物组合物包含PDE5抑制剂和另外如上文所定义的活性药物。
为了调查PDE5抑制剂在具有正常勃起功能的患者PE治疗中的用途,进行下列研究。
本研究是利用西地那非(万艾可)进行的,但该研究应被理解为还可以利用其他PDE5抑制剂进行,例如上文列举的一种或多种优选的PDE5抑制剂。
该研究包含II期安慰剂对照研究,以评估患有早泄但具有正常勃起功能的患者(也就是根据勃起功能范围问卷(见下)得分大于22的患者)在性交前一小时口服西地那非(万艾可)的功效。
使用下列功效变量(分析结果)评价该研究。
i)
阴道内射精潜伏期(IELT)-这构成主要的功效变量。比较万艾可组与安慰剂组的基线IELT变化。IELT是用计时表测定的,由患者记录在日志中。患者记录每次性事的IELT。嘱咐患者收集在任意单一性事期间第一次进入阴道内的IELT数据。另外,日志搜集了关于剂量和相应性交尝试的信息,当患者已经接受研究药物治疗和/或进行性活动时完成日志。
ii)
早泄指数(IPE)-该指数记录患者性生活问题的效果。该指数包含一系列问询。这构成本研究的二级功效分析结果。
iii)
性生活质量(男性)问卷(SQoL-M)-该问卷评估治疗前后的性生活质量。这构成本研究的二级功效分析结果。
iv)
综合功效问询(GEQ)-该问询记录在治疗期间性交的总体满意水平的提高。这构成本研究的二级功效分析结果。
v)阴茎受振动刺激射精的时间-嘱咐一定数量患者记录他们阴茎受振动刺激射精的时间。这是一种可靠的测量射精潜伏期的方法。阴茎振动器是市场上可得到的,例如“FERTICAREpersonal”(
www.multicept.com/ferticare.html,Multicept A/S,Lyngso Alle 3,2970Horsholm,Denmark)。
结果
该研究的初步结果证明了PDE5抑制剂在治疗具有正常勃起功能的患者PE中的功效。
GEQ
表1显示GEQ的初步结果。结果证明服用西地那非与服用安慰剂相比,患者在性交期间总体满意水平在统计学上有显著的提高。
表1:GEQ:你所接受的治疗是否提高性交期间的总体满意水平?
患者数量 | 体验到提高的数量 | 体验到提高的% | |
安慰剂 | 56 | 11 | 19.64 |
万艾可 | 72 | 27 | 37.50 |
IPE
IPE的初步结果证明患者在回答大量问询时的性问题有统计学上显著的提高。确切而言,服用西地那非与服用安慰剂相比可见,患者在回答下列问询时在统计学上有显著的提高。
●多少时间一次在你做好准备之前就射精?
●你在控制射精上有多大把握?
●你对性欲高潮的质量有怎样的满意程度?
●你对总体的性生活有了怎样的满意程度?
另外,服用西地那非与服用安慰剂相比,患者在回答下列问询时也见到提高。
●你从事性交多少次?
●多少时间一次你限制了你所进行的前戏数量?
●你对控制射精的感觉有怎样的满意程度?
勃起功能范围问卷的内容
问询 | 回答选项 |
Q1:在过去4周,你能够在性活动期间获得勃起多少次?Q2:在过去4周有多少次当你已经因性刺激而勃起时,勃起维持足以进入的硬度? | 0=没有性活动1=几乎从不/从不2=次数少(少于一半时间)3=有时(大约一半时间)4=次数多(多于一半时间)5=几乎总是/总是 |
Q3:在过去4周,当你尝试性交时,你能够进入你的伴侣多少次?Q4:在过去4周有多少次在性交期间你能够在已经进入你的伴侣之后维持勃起? | 0=没有尝试性交1=几乎从不/从不2=次数少(少于一半时间)3=有时(大约一半时间)4=次数多(多于一半时间)5=几乎总是/总是 |
Q5:在过去4周,在性交期间,维持勃起以完成性交有多难? | 0=没有尝试性交1=极其困难2=非常困难3=困难4=略微困难5=不难 |
Q15:在过去4周,你怎样评价你能够获得并保持勃起的信心? | 1=非常低2=低3=中等4=高5=非常高 |
测定法
这里所述的PDE效力值是通过下列测定法测定的。
本发明适用的优选的PDE化合物是有力的和选择性PDE5抑制剂。对抗环鸟苷3’,5’-一磷酸盐(cGMP)和环腺苷3’,5’-一磷酸盐(cAMP)磷酸二酯酶的体外PDE抑制活性可以通过测量它们的IC50值(抑制50%酶活性所需的化合物浓度)加以测定。
所需的PDE酶可以从各种来源分离,包括人阴茎海绵体、人与兔血小板、人心室、人骨骼肌和牛视网膜,基本上采用W.J.Thompson and M.M.Appleman(Biochem.,1971,10,311)的方法。具体而言,cGMP特异性PDE(PDE5)和抑制cGMP的cAMP PDE(PDE3)可以从人阴茎海绵体组织、人血小板或兔血小板中获得;刺激cGMP的PDE(PDE2)是从人阴茎海绵体中获得的;钙/钙调蛋白(Ca/CAM)依赖性PDE(PDE1)是从人心室中获得的;cAMP特异性PDE(PDE4)是从人骨骼肌中获得的;光感受器PDE(PDE6)是从牛视网膜中获得的。磷酸二酯酶7-11可以从转染到SF9细胞中的全长人重组克隆生成。
测定可以这样进行,利用改进的W.J.Thompson等(Biochem.,1979,18,5228)的“批量”方法,或者利用闪烁近似测定法,用于直接检测AMP/GMP,用改进的Amersham plc所述方案,产品代码TRKQ7090/7100。总之,PDE抑制剂的效果是这样调查的,在不同抑制剂浓度和少量底物(cGMP或cAMP,未标记与[3H]-标记之比为3∶1,浓度~1/3Km)的存在下,测定固定量的酶,从而使IC50≈Ki。用测定缓冲液(20mMTris-HCl pH7.4,5mM MgCl2,1mg/ml牛血清白蛋白)将最终测定体积加至100μl。用酶引发反应,在30℃下培育30-60分钟,得到<30%的底物周转率,再用50μl硅酸钇SPA珠粒(关于PDE9和11,含有3mM各自未标记的环核苷酸)终止反应。将平板重新密封,摇动20分钟,然后使珠粒在黑暗中沉降30分钟,然后在TopCount平板读数器(Packard,Meriden,CT)上计数。将放射性单位转化为未受抑制的对照物(100%)的活性%,对抑制剂浓度作图,利用“适配曲线”Microsoft Excel扩展得到抑制剂的IC50值。
Claims (10)
1.PDE5抑制剂在药物制备中的用途,该药物用于治疗具有正常勃起功能的患者的早泄。
2.根据权利要求1的用途,其中该患者关于勃起功能范围问卷的得分大于22。
3.根据权利要求1或权利要求2的用途,其中该PDE5抑制剂对PDE5酶的IC50小于100纳摩尔。
4.根据权利要求3的用途,其中该PDE5抑制剂的选择性比PDE3的选择性高的倍数大于100。
5.根据权利要求4的用途,其中该PDE5抑制剂的选择性比PDE3和PDE4的选择性高的倍数大于100。
6.根据权利要求5的用途,其中该PDE5抑制剂对PDE5的IC50小于100nM,并且其选择性比PDE3高的倍数大于100。
7.根据权利要求6的用途,其中该PDE5抑制剂选自下组:5-[2-乙氧基-5-(4-甲基-1-哌嗪磺酰基)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),(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(IC-351),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(瓦地那非),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,和5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮及其药学上可接受的盐。
8.根据前述任一权利要求的用途,其中该抑制剂是口服给药的。
9.根据权利要求8的用途,其中每日剂量是5至500mg。
10.根据权利要求9的用途,其中每日剂量是10至100mg。
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