CN114306347A - 用于治疗性激素依赖性疾病的双重nk-1/nk-3受体拮抗剂 - Google Patents
用于治疗性激素依赖性疾病的双重nk-1/nk-3受体拮抗剂 Download PDFInfo
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- CN114306347A CN114306347A CN202210025860.5A CN202210025860A CN114306347A CN 114306347 A CN114306347 A CN 114306347A CN 202210025860 A CN202210025860 A CN 202210025860A CN 114306347 A CN114306347 A CN 114306347A
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Abstract
本发明涉及双重NK‑1/NK‑3受体拮抗剂或其药学上可接受的盐在治疗性激素依赖性疾病中的新用途。
Description
本申请是申请日为2016年5月16日,申请号为201680025842.X,发明名称为“用于治疗性激素依赖性疾病的双重NK-1/NK-3受体拮抗剂”的发明专利申请的分案申请。原申请对应国际申请PCT/EP2016/060945,优先权日为2015年5月18日。
发明领域
本发明涉及一种哺乳动物中的性激素依赖性疾病的治疗的方法,所述疾病的治疗期望***抑制和/或雄激素抑制。***和/或雄激素抑制根据本发明通过施用双重神经激肽-1(NK-1)受体拮抗剂和神经激肽-3(NK-3)受体拮抗剂(本文称为双重NK-1/NK-3受体拮抗剂)来实现。可用于本发明的合适的双重NK-1/NK-3受体拮抗剂由本文描述的化合物表示。
发明背景
雄激素通常被称为雄性性激素。雄激素性激素为类固醇,其在成年雄性中由睾丸产生且在成年雌性中由卵巢卵泡膜细胞产生;并且较少的量由肾上腺皮质产生,或者可以在实验室中合成。雄激素类固醇在许多生理过程中发挥重要作用,所述许多生理过程包括雄性性特征诸如肌肉和骨骼质量的发育和维持、***生长、***发生和雄性毛发分布。内源类固醇雄激素包括睾酮和双氢睾酮("DHT")。睾酮为由睾丸分泌的主要类固醇,并且为成年雄性血浆中发现的主要循环雄激素。在正常生理情况下,雄性比雌性产生多得多的睾酮。在许多外周组织中,睾酮被酶5-α-还原酶转化为DHT。因此认为,对于大多数雄激素作用而言,DHT起到胞内介质的作用。
***释放激素(GnRH),也称为促黄体生成激素释放激素(LHRH),为在人类生殖中发挥关键作用的十肽。该激素由下丘脑释放并对垂体起作用来刺激促黄体生成激素(LH)和促卵泡激素(FSH)的生物合成和分泌。由垂体释放的LH主要负责调节两种性别中的性腺类固醇的产生,而FSH在雄性中调节***发生并在雌性中调节卵泡的发育。
已经发现雄激素和/或***抑制或消除可以在雄性和雌性中的许多疾病和临床应用中产生有益效果。
在男性中,这些疾病或紊乱包括,但不限于,良性***增生(BPH)、转移性***癌、乳腺癌、睾丸癌、雄激素依赖性痤疮、全身性多毛症(hypertrichosis)、皮脂溢、雄性型秃发症和男孩性早熟。
在女性中,雄激素和/或***抑制或消除已被证明在临床环境中,诸如,例如在治疗以下中具有治疗性:***(PCOS)、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、局部多毛症(hirsutism)、雄激素依赖性痤疮、皮脂溢、雌性型雄激素性脱发和全身性多毛症、促性腺类固醇依赖性赘生物(乳腺癌、卵巢癌等)、***产生性垂体腺瘤、经前综合征和不育(例如辅助生殖技术诸如体外受精)。影响女性的其他相关状况为先兆子痫和妊娠预防(避孕),并且对于两种性别,为化脓性汗腺炎和热潮红。
然而,如在雄性和雌性受试者中的情况,***和雄激素抑制(也称为化学去势(androgen deprivation))伴随着多种不期望的临床状况和症状。对于接受***释放激素(GnRH)激动剂的雄性,这些最初引起增加的雄激素产生的突发,这在患有性激素敏感性癌症的患者中可以引起肿瘤生长的短期增加,并且如果癌症扩散至骨骼,它则可以导致疼痛。这些药剂也被注射,因此在注射部位可能存在酸痛、肿胀和发红。也与GnRH拮抗剂有关的其他副作用为例如降低或缺乏***、阳痿、睾丸和***收缩、热潮红、乳腺压痛或乳腺生长、骨质疏松症、贫血、认知降低(cognitive reduction)、肌肉质量损失、体重增加、疲倦、升高的胆固醇和沮丧。
对于施用5-α-还原酶抑制剂的雄性受试者,副作用在本质上为性的,例如***功能障碍、***减少、***量降低和***肿大或压痛。这些药物也可能降低***特异性抗原(PSA)的水平,从而干扰该分析物检测***癌的结果。雄性和雌性受试者也可能经历螺内酯乳腺压痛(spironolactone breast tenderness)、***(仅雌性)、疲倦、头晕、混乱、恶心和呕吐、头痛、低血压、腹泻和可能的高钾血症。乙酸环丙孕酮可以引起月经过少(仅雌性)、黑斑病、液体潴留、恶心和呕吐;在较罕见的情况下这种药物也与肝脏的肝毒性和凝血紊乱相关。氟他胺(Flutamide)施用可以导致乳腺压痛、胃肠不适、热潮红、和***减少;它具有严重的肝毒性潜在副作用。雌性服用组合口服避孕药可能经历子宫不规则出血、恶心、呕吐、乳腺压痛和头痛;且更少见的血块、心肌梗塞、中风、异常脂质指数、葡萄糖耐受不良和高血压。
在基础科学和临床水平两者上均迫切需要新的创新方法来开发组合物和治疗方案,其提供雄激素和/或***抑制或消除的有益作用,而没有与用于性激素依赖性疾病的当前治疗相关的有害的副作用。
速激肽属于广泛分布于哺乳动物中枢和外周神经***的短肽家族(Bertrand和Geppetti,Trends Pharmacol.Sci.17:255-259(1996))。它们共有共同的C-末端序列Phe-Xaa-Gly-Leu-Met-NH2。三种主要的速激肽为P物质(SP)、神经激肽A(NKA)和神经激肽B(NKB),他们分别对被称为NK-1、NK-2和NK-3的三种不同受体亚型具有优先的亲和力。
正在开发用于治疗精神***症和物质滥用紊乱两者的同时显示出对NK-1和NK-3受体两者的选择性亲和力的化合物,即双重NK-1/NK-3受体拮抗剂。
然而,在本发明之前,尚未公开或暗示根据本发明的双重NK-1/NK-3受体拮抗剂将可用于期望性激素依赖性疾病的治疗,该性激素依赖性疾病的治疗中减少水平的雄激素和***是期望的。
发明概述
本发明涉及双重NK-1/NK-3受体拮抗剂在哺乳动物中实现***和/或雄激素抑制的新用途。根据本发明,双重NK-1/NK-3受体拮抗剂被施用用于治疗由异常水平的雄激素,特别是睾酮引起的疾病。本文通过引用描述的化合物根据本发明是特别有用的。
因此,由本发明提供的方案为双重NK-1/NK-3受体拮抗剂在治疗性激素依赖性疾病中的用途。
具体地,在第一方面,本发明提供了一种治疗性激素依赖性疾病的方法,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐施用至有相应需要的人类。
在另外的方面,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于制备用于治疗性激素依赖性疾病的药物的用途。
又在另外的方面,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于在治疗性激素依赖性疾病中的用途。
又在本发明的另外的方面,本发明提供了一种用于提供口服避孕药的方法,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂施用至患者。
在本发明的另外的方面,提供了双重NK-1/NK-3受体拮抗剂用于制备用于口服避孕的药物的用途。
发明详述
出人意料地,现在已经发现,双重NK-1/NK-3受体拮抗剂有效抑制***和/或雄激素产生/分泌,特别地抑制哺乳动物中LH和/或睾酮的产生。抑制***产生/分泌导致雄激素产生/分泌的抑制。因此,本发明在于一种治疗受到升高的和/或异常水平的***和/或雄激素影响或加剧的性激素依赖性疾病的方法。具体地,本发明涉及通过施用有效量的双重NK-1/NK-3受体拮抗剂来抑制***和/或雄激素血液水平的方法。本文定义的化合物表现出抑制***和/或雄激素产生的能力,并且特别地,在可逆地降低LH和雄激素睾酮的血液水平中是有效的。
定义
在本说明书和权利要求书中使用的表示数量、百分比或比例的所有数字以及其他数值被理解为在所有情况下被术语“约”修饰。
应该理解,如本文使用的术语“一(a)”和“一(an)”指枚举的组分中的“一个或更多个”。本领域普通技术人员将清楚,除非另有特别说明,单数的使用包括复数。
如本文使用的术语“性激素依赖性疾病”意指由过度、不适当或不受调节的性激素产生而加重或引起的疾病。
在男性中此类疾病的实例包括,但不限于,良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、全身性多毛症、雄性型秃发症和男孩性早熟。女性中此类疾病的实例包括,但不限于,子宫内膜异位症,子宫腺肌病、***异常、子宫肌瘤、重度月经出血、激素依赖性癌症(卵巢癌,乳腺癌)、雄激素过多症、局部多毛症、全身性多毛症、雌性型雄激素性脱发、雄激素依赖性痤疮、皮脂溢、男性化、***(PCOS)、HAIR-AN综合征(雄激素过多症、胰岛素耐受和黑棘皮症)、卵巢卵泡膜细胞增生症(HAIR-AN伴随卵巢基质中黄体化卵泡膜细胞增生)、高卵巢内雄激素浓度的其他表现(例如卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育)和雄激素产生性肿瘤(男性化卵巢或肾上腺肿瘤)和骨质疏松症。在女性中,其他实例为先兆子痫且对于两种性别,为化脓性汗腺炎和热潮红。
如本文使用的,“双重NK-1/NK-3受体拮抗剂”指在单个分子中同时显示出对NK-1和NK-3受体两者的亲和力的化合物。
术语“雄激素”在本文中用于意指促进雄性性特征发育的类固醇,并包括雄甾烷的类固醇衍生物,包括睾酮、双氢睾酮、雄烯二酮和类似物。
如本文使用的,“***抑制”指一种或更多种天然存在的***(包括促黄体生成激素和促卵泡激素)的产生或合成的降低。
如本文使用的,“雄激素抑制”指有效量的双重NK-1/NK-3受体拮抗剂,当被给予患者用于预防或治疗由过度或不受调节雄激素产生而加重或引起的疾病状态时,将引起雄激素的体内水平减少至正常或亚正常水平。
如本文使用的,术语“热潮红(hot flushes)”可与术语“潮热(hot flashes)”和与术语“血管舒缩症状(vasomotor symptoms)”互换,并且意图具有相同的含义。
如本文使用的,术语“治疗(treatment)”、“治疗(treating)”等指获得期望的药理学、生理学、皮肤病学或美容效果。在完全地或部分地预防状况或疾病或紊乱或其症状方面该效果可以是预防性的,和/或在部分或完全治愈状况或疾病或紊乱和/或可归因于该状况或疾病或紊乱的不利症状或效果方面该效果可以是治疗性。
因此,例如,“治疗”涵盖哺乳动物,特别是人类,中的状况或疾病的任何治疗,并且包括:(a)预防来自发生于可能易患状况或疾病或紊乱但尚未被诊断为患有该状况或疾病或紊乱的受试者中的状况或疾病、紊乱或其症状;(b)抑制状况或疾病、紊乱或其症状,诸如阻止其发展;以及(c)缓解、减轻或改善状况或疾病或紊乱或其症状,诸如,例如,引起该状况或疾病或紊乱或其症状衰退。
如本文使用的,术语“有效量”意指将引起正由例如研究人员、临床医师或兽医在寻求的组织、***、动物或人类的生物学或医学响应的药物或治疗剂或药剂的量。
如本文使用的,“药学上可接受的赋形剂”或“药学上可接受的载体”意指涉及给予药物组合物形式或相容性(consistency)的药学上可接受的材料、成分或媒介物。每一赋形剂当共混时必须与药物组合物的其他成分相容,以便避免将会实质上降低本发明的化合物当被施用至患者时的功效的相互作用和将会导致不是药学上可接受的药物组合物的相互作用。另外,每一赋形剂当然必须例如具有足够高的纯度以致使其药学上可接受。
本文使用的“药学上可接受的盐”意指具有药学上可接受的阴离子或阳离子的适用于医学应用的盐。
在一个实施方案中,本发明提供了一种治疗性激素依赖性疾病的方法,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、***异常、子宫肌瘤、卵巢癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、或肾上腺肿瘤、或骨质疏松症,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐施用至有相应需要的人类。
在一个实施方案中,本发明提供了一种治疗性激素依赖性疾病的方法,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、***异常、子宫肌瘤、重度月经出血、卵巢癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、肾上腺肿瘤、骨质疏松症或先兆子痫,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐施用至有相应需要的人类。
在另外的实施方案中,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于在治疗性激素依赖性疾病中的用途,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、***异常、子宫肌瘤、卵巢癌、乳腺癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、或肾上腺肿瘤、或骨质疏松症,所述用途包括将有效量的双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐施用至有相应需要的人类。
在另外的实施方案中,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于在治疗性激素依赖性疾病中的用途,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、***异常、子宫肌瘤、重度月经出血、卵巢癌、乳腺癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、肾上腺肿瘤、骨质疏松症或先兆子痫。
在本发明的另外的方面,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于制备用于治疗性激素依赖性疾病的药物的用途,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、***异常、子宫肌瘤、卵巢癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢或肾上腺肿瘤、或骨质疏松症。
在本发明的另外的方面,本发明提供了双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐用于制备用于治疗性激素依赖性疾病的药物的用途,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、***异常、子宫肌瘤、重度月经出血、卵巢癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、肾上腺肿瘤、骨质疏松症或先兆子痫。
在一个实施方案中,根据本发明的性激素依赖性疾病选自局部多毛症、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红。
用于本文使用的化合物包括双重NK-1/NK-3受体拮抗剂,如在以下中描述的,并且根据以下制备的:WO2004056799、WO2004056805、WO2005002577、WO2005097794、WO2006013050、WO2007028654、WO2008128891、WO2011131571或WO2011023733,其通过引用以其整体并入本文。
用于本文使用的WO2006013050的优选的吡啶衍生物如下:
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-苯基)-6-(2-羟基-乙氧基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-苯基)-6-(2-羟基-1-羟基甲基-乙氧基)-吡啶-3-基]-N-甲基-异丁酰胺;
·(S)-2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-6-(吡咯烷-2-基甲氧基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-6-(2-羟基-乙基硫烷基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-[2,3']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1'-氧基-[2,3']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-6-(3-羟基甲基-苯基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-5'-羟基甲基-[2,3']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-2'-羟基甲基-[2,4']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1’-甲磺酰基-1’,2',3',6'-四氢-[2)4']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1’-甲磺酰基-1’,2',3',4',5',6'-六氢-[2)4']联吡啶基-5-基]-N-甲基-异丁酰胺;
·(RS)-2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1’-甲磺酰基-1’,2',3',4',5',6'-六氢-[2,3']联吡啶基-5-基]-N-甲基-异丁酰胺;
·(RS)-N-[1'-乙酰基-4-(4-氟-2-甲基-苯基)-1',2',3',4',5',6'-六氢-[2,3']联吡啶-5-基]-2-(3,5-双-三氟甲基-苯基)-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[6-(3,6-二氢-2H-噻喃-4-基)-4-(4-氟-2-甲基-苯基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[6-(1,1-二氧代-1,2,3,6-四氢-1λ6噻喃-4-基)-4-(4-氟-2-甲基-苯基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[6-(1,1-二氧代-六氢-1λ6噻喃-4-基)-4-(4-氟-2-甲基-苯基)-吡啶-3-基]-N-甲基-异丁酰胺;
或其药学上可接受的盐。
用于本文使用的WO2008128891的优选的吡咯烷衍生物如下:
·外消旋-2-(3,5-双-三氟甲基-苯基)-N-[(3S,4R)-4-(4-氯-苯基)-1-(吗啉-4-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-2-(3,5-二氯-苯基)-N-[(3S,4R)-4-(4-氟-苯基)-1-(吗啉-4-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-2-(3,5-双-三氟甲基-苯基)-N-[(3S,4R)-4-(4-氟-2-甲基-苯基)-1-(吗啉-4-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-2-(3,5-双-三氟甲基-苯基)-N-[(3S,4R)-4-(4-氟-苯基)-1-(4-甲磺酰基-哌嗪-1-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-N-[(3S,4R)-1-(4-乙酰基-哌嗪-1-羰基)-4-(4-氟-苯基)-吡咯烷-3基]-2-(3,5-双-三氟甲基-苯基)-N-甲基-异丁酰胺;
·外消旋-2-(3,5-双-三氟甲基-苯基)-N-[(3S,4R)-1-(4-甲磺酰基-哌嗪-1-羰基)-4-苯基-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-2-(3,5-二氯-苯基)-N-[(3S,4R)-4-(4-氟-苯基)-1-(4-甲磺酰基-哌嗪-1-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-2-(3,5-双-三氟甲基-苯基)-N-[(3S,4R)-4-(4-氟-2-甲基-苯基)-1-(4-甲磺酰基-哌嗪-1-羰基)-吡咯烷-3-基]-N-甲基-异丁酰胺;
·外消旋-N-[(3S,4R)-4-(4-氯-苯基)-1-(4-甲磺酰基-哌嗪-1-羰基)-吡咯烷-3-基]-2-(3,5-二氯-苯基)-N-甲基-异丁酰胺;
·外消旋-(3S,4R)-3-{[2-(3,5-双-三氟甲基-苯基)-2-甲基-丙酰基]-甲基-氨基}-4-(4-氟-苯基)-吡咯烷-1-羧酸双-(2-羟基-乙基)–酰胺;
·外消旋-(3S,4R)-3-{[2-(3,5-双-三氟甲基-苯基)-2-甲基-丙酰基]-甲基-氨基}-4-(4-氟-苯基)-吡咯烷-1-羧酸-(2-羟基-乙基)–酰胺;
或其药学上可接受的盐。
用于本文使用的WO2011131571的优选的吡唑并吡啶衍生物如下:
·2-(3,5-双-三氟甲基-苯基)-N-(1-乙基-4-邻-甲苯基-1H-吡唑并[3,4-b]吡啶-5-基)-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-乙基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-苯基)-1-乙基-1-H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(3,4-二氯-苯基)-1-乙基-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-(2,2-二氟-乙基)-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1-甲基-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·N-[1-苄基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-2-(3,5-双-三氟甲基-苯基)-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-乙基-4-(4-氟-2-甲氧基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-3-氟-苯基)-1-乙基-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2,3-二氯-苯基)-1-乙基-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-4-氟-苯基)-1-乙基-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-5-羟基甲基-苯基)-1-乙基-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·N-[1-乙酰基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-2-(3,5-双-三氟甲基-苯基)-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1-(2-甲氧基-乙酰基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-环丙烷羰基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1-甲磺酰基-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-二甲基氨磺酰基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1-甲磺酰基甲基-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-乙基-4-(4-甲基-噻吩-3-基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(2-氯-噻吩-3-基)-1-乙基-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3-氟-5-三氟甲基-苯基)-N-[1-乙基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;或
·2-(3,5-二氯-苯基)-N-[1-乙基-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]-吡啶-5-基]-N-甲基-异丁酰胺;
或其药学上可接受的盐。
用于本文使用的特别优选的化合物为
·2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺;
·(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1’-甲磺酰基-1’,2',3',6'-四氢-[2)4']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1’-甲磺酰基-1’,2',3',4',5',6'-六氢-[2)4']联吡啶基-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[6-(1,1-二氧代-1,2,3,6-四氢-1λ6噻喃-4-基)-4-(4-氟-2-甲基-苯基)-吡啶-3-基]-N-甲基-异丁酰胺;
·外消旋-N-[(3S,4R)-4-(4-氯-苯基)-1-(4-甲磺酰基-哌嗪-1-羰基)-吡咯烷-3-基]-2-(3,5-二氯-苯基)-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[1-(2,2-二氟-乙基)-4-(4-氟-2-甲基-苯基)-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;
·2-(3,5-双-三氟甲基-苯基)-N-[4-(4-氟-2-甲基-苯基)-1-甲磺酰基甲基-1H-吡唑并[3,4-b]吡啶-5-基]-N-甲基-异丁酰胺;或其药学上可接受的盐。
根据本发明的特别优选的化合物为
·2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺(式A);
·(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺(式B);
或其药学上可接受的盐或其结晶形式。
用于制备式A化合物、其盐及其结晶形式的方法分别描述于WO2007028654和WO2011023733中,该方法通过引用并入本文。
具体地,WO2011023733公开了呈结晶无水物形式(形式1)的式A的化合物,其具有在4.3±0.1、7.9±0.1、9.8±0.1、10.7±0.1、10.8±0.1、13.3±0.1、14.0±0.1、15.1±0.1度发生的某些特征2θ角,这些分别对应于在20.4、11.1、9.0、8.3、8.2、6.6、6.3和的d间距(d-spacing)。
用于制备式B的化合物或其盐的方法描述于WO2005002577中,该方法通过引用并入本文。
在另外的实施方案中,本发明提供了
·2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺或
·(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺;其药学上可接受的盐或结晶形式用于治疗性激素依赖性疾病的用途,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、***异常、子宫肌瘤、重度月经出血、卵巢癌、乳腺癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、肾上腺肿瘤、骨质疏松症或先兆子痫。
在另外的实施方案中,本发明提供了一种治疗性激素依赖性疾病的方法,所述性激素依赖性疾病选自由以下组成的组:良性***增生(BPH)、转移性***癌、睾丸癌、乳腺癌、雄激素依赖性痤疮、皮脂溢、局部多毛症、全身性多毛症、雄性型秃发症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、***异常、子宫肌瘤、重度月经出血、卵巢癌、乳腺癌、雄激素过多症、男性化、***(PCOS)、HAIR-AN综合征、卵巢卵泡膜细胞增生症、化脓性汗腺炎、热潮红和男孩性早熟、卵泡成熟阻滞、闭锁、***停止、痛经、功能失调性子宫出血、不育男性化卵巢、肾上腺肿瘤、骨质疏松症或先兆子痫,所述方法包括将有效量的以下所述化合物施用至有相应需要的人类:
·2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺;
·(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺;或其药学上可接受的盐或结晶形式。
在另外的实施方案中,本发明提供了一种治疗性激素依赖性疾病的方法,所述性激素依赖性疾病选自由以下组成的组:雄激素依赖性局部多毛症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐施用至有相应需要的人类。
在另外的实施方案中,本发明提供了一种治疗性激素依赖性疾病的方法,所述性激素依赖性疾病选自由以下组成的组:雄激素依赖性局部多毛症、雌性型雄激素性脱发、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红,所述方法包括将有效量的2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺;
(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺;或其药学上可接受的盐施用至有相应需要的人类。
在一个实施方案中,根据本发明的化合物为2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺或其结晶无水物形式用于在治疗局部多毛症、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红中的用途。
又在另外的实施方案中,根据本发明的化合物为作为无水结晶形式1的2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺用于在治疗子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红中的用途。
又在另外的实施方案中,根据本发明的化合物为作为无水结晶形式1的2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺用于在治疗热潮红中的用途。
由于双重NK-1/NK-3受体拮抗剂对***释放激素(GnRH)途径的活性,双重NK-1/NK-3受体拮抗剂可以单独或与***和孕激素组合使用作为避孕药。
因此,在另外的方面,本发明提供了一种用于提供口服避孕药的方法,所述方法包括将有效量的双重NK-1/NK-3受体拮抗剂施用至患者。
在本发明的另外的方面,提供了双重NK-1/NK-3受体拮抗剂用于制备用于口服避孕的药物的用途。
用于口服避孕使用的化合物包括双重NK-1/NK-3受体拮抗剂,如在以下中描述的,并且根据以下来制备:WO2004056799、WO2004056805、WO2005002577、WO2005097794、WO2006013050、WO2007028654、WO2008128891、WO2011131571、WO2011023733,其通过引用以其整体并入本文。
用于口服避孕使用的WO2006013050的优选的吡啶衍生物为分别在本说明书的第8页第28行-第10页第5行中公开的那些。
用于口服避孕使用的WO2008128891的优选的吡啶衍生物为在本说明书的第10页第6行-第11页第2行中公开的那些。
用于口服避孕使用的WO201131571的优选的吡唑并吡啶衍生物为本说明书的从第11页第3行至第12页第25行公开的那些。
用于口服避孕使用的特别优选的化合物为
·2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺(式A);
·(2R,3S)-2-(3,5-双-三氟甲基苯基)-N-[4-(4-氟-2-甲基-苯基)-6–(3-羟基-2-羟基甲基-吡咯烷-1-基)-吡啶-3-基]-N-甲基-异丁酰胺(式B);
或其药学上可接受的盐或结晶形式。
本发明还提供了一种药物组合物,所述药物组合物包含双重NK-1/NK-3受体拮抗剂或以上描述的化合物、其药学上可接受的盐或结晶形式和药学上可接受的载体。
因此,在一个实施方案中,本发明提供了包含双重NK-1/NK-3受体拮抗剂或其药学上可接受的盐和药学上可接受的载体的药物组合物用于在治疗性激素依赖性疾病中的用途。
在另外的实施方案中,本发明提供了包含2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺或其结晶无水物形式和药学上可接受的载体的药物组合物用于在治疗性激素依赖性疾病中的用途。
在另外的实施方案中,本发明提供了包含2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺或其结晶无水物形式和药学上可接受的载体的药物组合物用于在治疗局部多毛症、子宫内膜异位症、子宫腺肌病、子宫肌瘤、重度月经出血、***(PCOS)和热潮红中的用途。
在另外的实施方案中,本发明提供了一种药物,所述药物包含双重NK-1/NK-3受体拮抗剂和药学上可接受的载体。
又在另外的实施方案中,本发明提供了一种药物,所述药物包含2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)基]-3-吡啶基}-N,2-二甲基丙酰胺或其药学上可接受的盐和药学上可接受的载体。
本发明的此类药物和组合物可以通过将本发明的化合物与适当的药学上可接受的载体混合来制备。它可以以常规方式包含稀释剂、结合剂、填充剂、崩解剂、调味剂、着色剂、润滑剂或防腐剂。
可以例如,如在制备用于治疗状况的已知剂的组合物中一样利用这些常规赋形剂。
优选地,本发明的药物组合物呈单位剂型并且呈适于在医学或兽医领域中使用的形式。例如,此类制剂可以呈包装形式,其附有剂在治疗状况时的书面或印刷的使用说明。
用于本发明的化合物的合适剂量范围取决于待采用的化合物和患者的状况。除此以外,这还将取决于效力与吸收能力的关系以及施用的频率和途径。
本发明的化合物或组合物可以被配制为通过任何途径施用,并且优选地呈单位剂型或呈人类患者可以以单一剂量施用至自身的形式。
有利地,该组合物适用于口服、直肠、局部、肠胃外、静脉内或肌内施用。制剂可以被设计为给予缓慢释放活性成分。
组合物可以例如呈片剂、胶囊、小袋(sachets)、小瓶、粉末、颗粒、锭剂、可重构粉末或液体制剂,例如溶液或悬浮液或栓剂。
组合物,例如适用于口服施用的那些组合物可以包含常规赋形剂,诸如结合剂,例如糖浆、***胶、明胶、山梨糖醇、黄蓍胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;压片润滑剂,例如硬脂酸镁;崩解剂,例如淀粉,聚乙烯吡咯烷酮、羧甲基淀粉钠或微晶纤维素;或药学上可接受的硬化剂,诸如十二烷基硫酸钠。
固体组合物可以通过共混、填充、压片等的常规方法获得。可以使用重复共混操作将活性剂分布在采用大量填充剂的那些组合物中。
当组合物呈片剂、粉末或锭剂的形式时,可以使用适用于配制固体药物组合物的任何载体,实例为硬脂酸镁、淀粉、葡萄糖、乳糖、蔗糖、米粉和白垩(chalk)。
片剂可以根据标准药学实践中熟知的方法,特别地用肠溶衣来包被。组合物还可以呈可摄入胶囊的形式,例如包含化合物的明胶,如果需要,具有载体或其他赋形剂。
作为液体用于口服施用的组合物可以呈例如乳液、糖浆或酏剂的形式,或者可以作为用于在使用前用水或其他合适的媒介物重构的干燥产品呈现。此类液体组合物可以包含常规添加剂,诸如悬浮剂,例如山梨糖醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶、氢化可食用脂肪;乳化剂,例如卵磷脂、失水山梨醇单油酸酯或***胶;水性或非水性媒介物,其包括可食用油,例如杏仁油,分级的椰子油,油性酯,例如甘油或丙二醇或乙醇的酯,甘油,水或生理盐水;防腐剂,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸;以及在需要时的常规调味剂或着色剂。
本发明的化合物也可以通过非口服途径施用。根据常规药物程序,组合物可以被配制为,例如作为栓剂直肠施用。它们也可以被配制为呈现于药学上可接受的液体中的水性或非水性溶液、悬浮液或乳液的可注射形式,例如无菌的无热原水或肠胃外可接受的油或液体混合物。液体可以包含抑菌剂、抗氧化剂或其他防腐剂、缓冲液或使溶液与血液等渗的溶质、增稠剂、悬浮剂或其他药学上可接受的添加剂。
此类形式将呈现于单位剂量形式,诸如安瓿或一次性可注射装置,或呈多剂量形式,诸如可从其中取出适当剂量的瓶或可用于制备可注射制剂的固体形式或浓缩物。
本发明的化合物也可以通过经由鼻或口服途径的吸入施用。此类施用可以用喷雾制剂进行,所述喷雾制剂包含本发明的化合物和合适的载体,它们任选地悬浮于例如烃推进剂中。
优选的喷雾制剂包括微粉化化合物颗粒,其与表面活性剂、溶剂或用于防止悬浮颗粒沉降的分散剂组合。优选地,化合物的粒径为从约2微米至10微米。
本发明的化合物的另外施用方式包括利用皮肤贴片制剂的经皮递送。优选的制剂包括分散于粘附至皮肤的压敏粘合剂中的本发明的化合物,从而允许化合物从粘合剂扩散通过皮肤递送至患者。为了恒定的经皮吸收速率,可使用本领域已知的压敏粘合剂诸如天然橡胶或硅酮。
根据本发明主题的药物组合物的制备可以根据本领域已知的方法进行。可以使用通常已知和使用的药学上可接受的助剂以及另外合适的稀释剂、调味剂、甜味剂、着色剂等,这取决于预期的施用方式以及待使用的活性化合物的具体特征,诸如溶解度、生物可利用度等。
任何无毒、惰性和有效的局部、口服等药学上可接受的载体可以用于配制本文描述的组合物。
用于配制用于施用至人类的其他局部治疗组合物的熟知的载体可用于这些组合物中。本领域技术人员熟知的这些组分的实例描述于以下中:The Merck Index,第13版,Budavari等,编著,Merck&Co.,Inc.,Rahway,N.J.(2001);the CTFA(Cosmetic,Toiletry,and Fragrance Association)International Cosmetic Ingredient Dictionary andHandbook,第10版(2004);以及the“Inactive Ingredient Guide”,美国食品和药物管理局(FDA)药物中心(U.S.Food and Drug Administration(FDA)Center for Drug)。
如以上提及的,化合物的有效剂量取决于采用的具体化合物、患者的状况以及施用的频率和途径。有效剂量将通常包含从1mg至250mg,并且优选地将包含从10mg至220mg,特别地30mg至200mg。
组合物可以每天施用一次或更多次,例如每天2次、3次或4次,并且对于70kg成年人的总每日剂量通常将在30mg至200mg的范围内。
可选地,单位剂量将包含从10mg至100mg的活性成分,并且如果需要,以多次施用,以给予前述每日剂量。
当根据本发明被施用时预期本发明的化合物不存在不可接受的毒理作用。
本发明的化合物或其药学上可接受的盐和其他药学活性剂可以以固定组合一起或单独地(即非固定组合)被施用。
当单独地施用时,这可以以任何顺序单独地或依次地发生,并且也可以存在其中剂不一定通过相同施用途径施用的治疗方案。为了达到期望的组合治疗作用,将选择本发明的化合物或其药学上可接受的盐和其他药学活性剂的量和施用的相对时间安排。
可以与本发明的化合物或其药学上可接受的盐组合使用的合适的治疗剂的实例包括***释放激素(GnRH)的激动剂,诸如那法瑞林(nafarelin)、布舍瑞林(buserelin)、戈舍瑞林(goserelin)和亮丙瑞林(leuprorelin);***释放激素(GnRH)的拮抗剂,诸如地加瑞克(degarelix)、加尼瑞克(ganirelix)、西曲瑞克(cetrorelix)、阿巴瑞克(abarelix)和恶拉戈利(elagolix);5-α-还原酶抑制剂,诸如度他雄胺(dutasteride)和非那雄胺(finasteride);组合的雄激素受体拮抗剂/5-α-还原酶抑制剂诸如螺内酯(spironolactone);抗雄激素诸如乙酸环丙孕酮和氟他胺(flutamide);组合(***与孕激素)口服避孕药诸如***与诺孕酯(norgestimate)、或与炔诺酮(norethindrone)或与屈螺酮(drospirenone);孕酮(progesterone)受体调节剂诸如乙酸乌利司他(ulipristal acetate)。
生物学数据
可用于本文的化合物的抗雄激素作用通过表现出降低睾酮的作用对人类志愿者的以下临床研究来确定。
实施例1
2-[3,5-双(三氟甲基)苯基]-N-{4-(4-氟-2-甲基苯基)-6-[(7S,9aS)-7-(羟基甲基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-基]-3-吡啶基}-N,2-二甲基丙酰胺(下文称为化合物A)以单次或重复递增剂量两者在男性人类志愿者(HV)中被施用,并且评价了化合物A对睾酮水平的影响。
1.单次递增剂量研究
雄性HV以单盲、随机方式接受作为悬浮液的范围为从10mg至250mg的单次递增口服剂量的安慰剂或化合物A。
在第-1天,然后在每一个剂量之后24小时和在随访时(化合物A剂量之后7至14天)测量游离睾酮和总睾酮血清水平。如表1中描述确定所得的HV血清睾酮水平(游离的和总的)。
表1.来自单次递增剂量研究中的HV的游离睾酮和总睾酮水平
说明:SD=标准差
如表1中示出的,在施用化合物A之后24h内,游离睾酮和总睾酮水平的临床相关的降低是明显的。在≥160mg的剂量,减少范围为在35%和43%之间。在随访时(在化合物A的最后剂量之后7至14天),睾酮水平恢复至基线水平。
2.重复递增剂量的化合物A
该研究的A部分包括3个组群,研究化合物A的递增的多个每日剂量的安全性、耐受性和PK。这些群组的信息如下:
·组群1和2持续14天接受化合物A;在他们的最后剂量之后7至14天进行随访。两个组群中的睾酮水平均在第1天剂量前、第15天和随访时进行测量。
·组群3在14天的重复治疗时间内也接受化合物A;在他们的最后剂量之后7至14天进行随访。将该群组中的睾酮水平在第-1天剂量前和第14天剂量前及在随访时进行测量。
如表2中描述确定所得的HV血清睾酮水平(游离的和总的)。
表2.来自重复剂量研究的HV的游离睾酮和总睾酮水平
说明:SD=标准差;*90mg剂量组中的两个受试者在基线和第5天之间剂量降低,并从分析中去除,以避免混淆数据;**在200mg剂量组中的两个受试者在基线和第14天之间剂量降低(数据被去除)
PD=剂量前(Pre-dose)
在重复给药化合物A之后,游离睾酮和总睾酮水平的临床相关降低仍然是明显的。在200mg的剂量,在第14天之后;减少范围为在43%和45%之间;与单次递增剂量研究中24小时之后观察到的值一致。在随访时(在200mg化合物A的最后剂量之后7-14天),睾酮水平恢复至基线水平。
以上描述充分公开了本发明,包括其优选的实施方案。本文具体公开的实施方案的修改和改进在所附权利要求的范围内。无需进一步详尽说明,认为本领域的技术人员可以使用前述描述,利用本发明至其最大程度。因此,本文的实施例将被解释为仅说明性的,并不以任何方式限制本发明的范围。其中要求保护独占的特性或特权的本发明的实施方案定义如下。
Claims (4)
3.根据权利要求1或2所述的用途,其中所述式(A)的化合物为结晶无水物形式。
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