CN105764916A - 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 - Google Patents
鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法 Download PDFInfo
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- CN105764916A CN105764916A CN201480044341.7A CN201480044341A CN105764916A CN 105764916 A CN105764916 A CN 105764916A CN 201480044341 A CN201480044341 A CN 201480044341A CN 105764916 A CN105764916 A CN 105764916A
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Abstract
本发明提供纯化包括选自本文描述的SEQ ID NO:1?251的GCC激动剂序列的肽的方法。所述方法包括:溶剂交换步骤,然后冷冻干燥(冻干)步骤。
Description
相关申请
本申请要求提交于2013年6月5日的美国临时申请USSN 61/831,402的优先权和权益,其内容通过引用以其整体结合到本文中。
发明领域
本发明涉及纯化可用于制备治疗和预防各种疾病和病症的制剂的鸟苷酸环化酶C肽激动剂的方法。
发明背景
鸟苷酸环化酶C是鸟苷酸环化酶的跨膜形式,其表达在各种细胞包括胃肠道上皮细胞上(综述于Vaandrager 2002 Mol. Cell. Biochem. 230:73-83)。其最初作为由肠道细菌分泌且引起腹泻的热稳定毒素(ST)肽的肠道受体而被发现。ST肽与从肠粘膜和尿液中分离的两种肽鸟苷肽和尿鸟苷素(uroguanylin)共有相似的氨基酸一级结构(Currie等, Proc.Nat’l Acad. Sci. USA 89:947-951 (1992); Hamra等, Proc. Nat’l Acad. Sci. USA90:10464-10468 (1993); Forte, L., Reg. Pept. 81:25-39 (1999); Schulz等,Cell63:941-948 (1990); Guba等, Gastroenterology111:1558-1568 (1996); Joo等,Am. J. Physiol. 274:G633-G644 (1998))。
在肠道中,鸟苷肽和尿鸟苷素充当体液和电解质平衡的调节剂。响应于高口服盐摄入,这些肽释放进入肠腔,在肠腔中它们结合至定位于肠细胞(小肠和结肠的单层柱状上皮细胞)的管腔膜上的鸟苷酸环化酶C。鸟苷肽与鸟苷酸环化酶C的结合经由环单磷酸鸟苷(cGMP)的增加引发的复杂细胞内信号传递级联而诱导电解质和水排泄进入肠腔。
由鸟苷肽引发的cGMP介导的信号传递对于肠的正常运作是至关重要的。在这一过程中出现的任何异常现象都会导致胃肠功能病症,诸如肠易激综合症(IBS)和炎性肠病。炎性肠病是一组病症的统称,这种病症引起肠道发展成炎症,其特征在于组织发红和发肿。实例包括溃疡性结肠炎和克罗恩氏病。克罗恩氏病是一种严重的炎性疾病,这种疾病主要影响回肠和结肠,同时还可以发生在胃肠道的其他部分。溃疡性结肠炎特有地是结肠、大肠的炎性疾病。克罗恩氏病可以涉及肠道的所有层,并且在几片患病的肠道部分之间可以存在正常健康的肠,与克罗恩氏病不同,溃疡性结肠炎以一种连续的方式仅作用在结肠最里面的内衬(粘膜)。根据涉及胃肠道的何部分,克罗恩氏病可以称为回肠炎、局限性回肠炎、结肠炎等等。克罗恩氏病和溃疡性结肠炎与结肠痉挛综合症或者肠易激综合症不同,结肠痉挛综合症或者肠易激综合症是胃肠道的动力病症。肠胃炎症可以是慢性状况。据估计,多达1,000,000美国人都患有炎性肠病,其中男性患者和女性患者好像同样受影响。大多数病例在30岁之前被诊断出来,但更多疾病在六十、七十或者生命的更大的年龄阶段发生。
IBS和慢性特发性便秘是可引起极度肠不适和痛苦但与炎性肠病不同的病理状况,IBS不引起肠组织的严重炎症或改变,并且认为其不增加患结肠直肠癌的风险。过去,炎性肠病、乳糜泻和IBS被认为是完全独立的病症。现在,根据IBS中的炎症(虽然低度)以及IBS与乳糜泻之间重叠的症状的描述,该论点已遭到质疑。急性细菌性胃肠炎是迄今鉴定的随后发生感染后肠易激综合症的最强风险因素。临床风险因素包括延长的急性疾病和呕吐的不存在。遗传上确定的对炎性刺激的易感性也可以是患肠易激综合症的风险因素。潜在的病理生理学显示增加的肠通透性和低度炎症以及改变的动力和内脏敏感性(visceralsensitivity)。血清素(5-羟色胺[5-HT])是肠功能的关键调节剂,已知其在IBS的病理生理学中起着主要作用。5-HT的活性受cGMP调节。
尽管IBS和炎性肠病(IBD)的确切原因是未知的,但是胃肠粘膜的持续更新的过程的中断可能促进IBD的疾病病理和IBS加重。胃肠道内衬的更新过程是有效且动态的过程,该过程包括对不需要的受损细胞持续的增殖和补充。胃肠道粘膜内衬细胞的增殖速率非常高,仅次于造血系统。胃肠道体内平衡取决于肠道粘膜内衬上皮细胞的增殖和程序性细胞死亡(细胞凋亡)两者。细胞不断的从绒毛损失进入肠道内腔,并通过在隐窝处以基本上相等的速率通过细胞增殖,随后其向上移动到绒毛而进行补充。肠上皮的细胞增殖和细胞凋亡的速率可在许多环境中(例如响应于生理学刺激诸如衰老、炎性信号、激素、肽、生长因子、化学品和膳食习惯)增加或减小。此外,增加的增殖速率通常与周转时间的减少和增殖区域的扩大相关。增殖指数在病理状态诸如溃疡性结肠炎和其他肠胃病症中高得多。肠增生是胃肠炎症的主要促进因素。细胞凋亡和细胞增殖一起调节细胞数量且确定增殖指数。降低的细胞凋亡速率通常与异常生长、发炎、和赘生转化有关。因此,增殖增加和/或细胞死亡减少可以增加肠道组织的增殖指数,其进而可以导致胃肠道炎性疾病。
除了尿鸟苷素和鸟苷肽作为肠液和离子分泌的调节剂的作用外,这些肽还可通过维持增殖与细胞凋亡之间的平衡参与胃肠粘膜的持续更新。例如,尿鸟苷素和鸟苷肽似乎可以通过控制细胞离子流动而促进细胞凋亡。考虑到炎性状况在西方社会的流行率,存在改善炎性状况,特别是胃肠道的炎性状况治疗选择的需要。
鸟苷酸环化酶C激动剂(“GCC激动剂”)的肽激动剂描述于美国专利号7,041,786、7,799,897和美国专利申请公开号US2009/0048175、US 2010/0069306、US 2010/0120694、US 2010/0093635和US 2010/0221329以及WO2012/118972。然而,先前的用于药物应用的肽的合成呈现了大量的特定问题,例如总体低的得率(例如少于10%)和/或高水平的杂质(例如由在合成或纯化期间使用的有机溶剂导致的污染物,和在例如纯化期间产生的降解产物或拓扑异构体)。
发明简述
在一个方面,本发明源自解决在用于药物应用的肽GCC激动剂的纯化过程(例如描述于WO2012/118972的冻干过程和沉淀过程)期间遇到的各种意想不到的问题的努力。本文描述的方法提供对这些问题的解决方案。
在一个方面,本发明提供包含GCC激动剂序列的纯化的肽,所述序列选自SEQ IDNO: 1、9和104,其中所述纯化的肽具有以下特征:
a) 具有不大于0.1 g/mL的堆积密度;
b) 包含少于50 ppm乙酰胺;
c) 少于0.3% α-Asp-9-plenacanatide。
纯化的肽可具有一个或多个以下特征。
例如,所述肽在25℃下稳定至少3个月。
例如,当用液体分散剂通过光散射测量时,所述肽具有下述粒径分布:D10值为约2-15 µm;D50值为约15-50 µm;和D90值为约40-80 µm。
例如,纯化的肽包含不超过35 ppm乙酰胺(例如 ≤ 18 ppm)。
例如,纯化的肽包含少于0.15% α-Asp-9-plenacanatide (根据本文描述的超效液相色谱(UPLC)分析,其具有约1.33的相对保留时间(RRT))。
例如,纯化的肽具有不大于0.09 g/mL、不大于0.08 g/mL、不大于0.07 g/mL、不大于0.06 g/mL、不大于0.05 g/mL、不大于0.04 g/mL或不大于0.03 g/mL的堆积密度。
例如,纯化的肽基本上不含水(例如水含量不超过肽总重量的10%、9%、8%、7%、6%、5%、4%、3.5%、3%、2.5%、2%、1.5%、1%、0.5%、0.25%或0.1%)。
例如,纯化的肽具有不少于95%、不少于96%或不少于97%的色谱纯度。
例如,在纯化的肽中杂质的总含量为少于3% (例如 <2%或<1%)。
例如,纯化的肽另外基本上不含选自乙腈、醇、铵、乙酸盐和TFA的一种或多种杂质。
例如,纯化的肽包含少于300 ppm乙腈(例如 < 250 ppm)。
例如,纯化的肽包含少于0.2% TFA (例如 <0.15%、<0.1%、<400 ppm、< 300 ppm、<200 ppm、< 100 ppm或< 50 ppm)。
例如,纯化的肽包含少于0.2%异丙醇,即IPA (例如 <0.15%、< 0.1%、< 1000 ppm、< 900 ppm、< 800 ppm、< 700 ppm、< 600 ppm、< 500 ppm、< 400 ppm、< 300 ppm、< 200ppm、< 100 ppm、< 50 ppm或< 20 ppm)。
例如,纯化的肽包含少于0.25 %乙酸盐(例如 <0.2%或<0.1%)。
例如,纯化的肽基本上不含拓扑异构体(例如 <0.4%、<0.3%、<0.2%或<0.1%)。
例如,纯化的肽基本上不含异-Asp2-plecanatide (RRT 0.96-0.97) (例如 <0.4%、<0.3%、<0.2%或<0.1%)。
在另一方面,本发明还提供纯化/分离包含GCC激动剂序列的肽的方法,所述序列选自SEQ ID NO: 1-251。所述方法包括:
提供包含肽、水和乙腈的第一肽溶液,所述肽包含选自SEQ ID NO: 1-251的GCC激动剂序列;
用所述第一肽溶液上样C18或聚合物吸附柱,以将所述肽吸附到聚合物吸附柱上,
用醇的水溶液将所述肽从C18或聚合物吸附柱洗脱,以形成第二肽溶液,
减少在第二肽溶液中的醇的量;和
将第二肽溶液冻干,使得获得干燥的肽。
所述方法可包括一个或多个以下特征。
例如,所述醇的水溶液包含异丙醇(例如,在醇的水溶液中异丙醇含量为约40%)。
在另一实施方案中,所述醇的水溶液包含丙醇、叔丁醇、2-丁醇或乙醇。
例如,第一肽溶液还包含乙酰胺。
例如,第一肽溶液还包含乙酸(例如0.2%)或磷酸三乙胺(例如1%)。
例如,在第二肽溶液中醇(例如异丙醇)的量通过例如旋转蒸发减少至少于5%。
例如,所述方法还包括在冻干后在水中溶解干燥的肽以形成第三肽溶液。例如,第三肽溶液还包含乙酸铵或氢氧化铵(例如,使得第三溶液具有约5的pH值)。
例如,所述方法还包括冻干第三肽溶液使得获得纯化的肽。
例如,在第一肽溶液中的肽通过描述于WO2012/118972的片段缩合过程(即杂合溶液相和固相过程)制备。在一个实施方案中,第一肽溶液获自盐交换步骤,其中所述肽用包含磷酸三乙胺或乙酸的乙腈水溶液洗涤。
例如,所述聚合物吸附柱是制备型C18 RP-HPLC柱。在一个实施方案中,所述聚合物吸附柱包含聚苯乙烯树脂。具体而言,选择树脂使得被洗脱或被解吸附的纯化的肽为吸附到树脂上的肽量的不少于80%,例如不少于85%、不少于90%或不少于95%。在一个实施方案中,树脂由交联的聚苯乙烯形成,平均孔径大于5 nm,例如约6-8 nm、10-15 nm、15-20 nm或25-30 nm。
在又一个方面,本发明还提供通过本发明的纯化方法制备的纯化的肽。纯化的肽可具有一个或多个以下特征。
例如,纯化的肽包含选自SEQ ID NO: 1、9和104的GCC激动剂序列。
例如,纯化的肽具有不少于96%、不少于97%或不少于98%的色谱纯度。例如,GCC激动剂肽具有不大于4%、不大于3.5%、不大于3%、不大于2.5%、不大于2%、不大于1.5%或不大于1%的色谱杂质含量。色谱杂质含量通过HPLC测定为杂质的总面积百分比。色谱杂质含量包括拓扑异构体含量。杂质不包括用于药物制剂的任何药学上可接受的赋形剂。
例如,纯化的肽基本上不含由肽制备过程导致的污染物,例如用于所述过程的有机溶剂,例如铵、乙腈、乙酰胺、醇(例如甲醇、乙醇或异丙醇)、TFA、醚或其它污染物。在本文中,“基本上”不含污染物意指在纯化过程结束时肽的污染物含量优选为肽总重量的少于0.5%、少于0.3%、少于0.25%、少于0.1%、少于0.05%、少于0.04%、少于0.03%、少于0.02%、少于0.01%、少于0.005%、少于0.003%或少于0.001%。例如,纯化的肽包含 < 50 ppm乙酰胺(例如≤ 35 ppm或 ≤ 18 ppm)、< 300 ppm乙腈(例如 < 250 ppm)、< 1000 ppm TFA (例如 <400 ppm、< 300 ppm、< 200 ppm、< 100 ppm或< 50 ppm)、<2000 ppm异丙醇(例如 <1500ppm、<1000 ppm、<500 ppm、< 400 ppm、< 300 ppm、< 200 ppm、< 100 ppm、< 50 ppm或< 20ppm),和/或< 0.25 %乙酸盐(例如 <0.2%或<0.1%)。污染物含量可通过常规方法例如气相色谱测定。优选地,本发明的纯化的肽中的残留溶剂少于ICH指南,例如IMPURITIES:GUIDELINE FOR RESIDUAL SOLVENTS Q3C(R5) (杂质:残留溶剂指南Q3C(R5)) (可获自http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf)中设定的限度。
例如,纯化的肽包含少于0.3% (例如 < 0.15%) α-Asp-9-plenacanatide (RRT1.33)。
例如,纯化的肽具有不大于0.09 g/mL、不大于0.08 g/mL、不大于0.07 g/mL、不大于0.06 g/mL、不大于0.05 g/mL、不大于0.04 g/mL或不大于0.03 g/mL的堆积密度。
例如,纯化的肽基本上不含异-Asp2-plecanatide (RRT约0.96-0.97)。在本文中,“基本上”不含异-Asp2-plecanatide意指在纯化过程结束时肽的异-Asp2-plecanatide含量优选为肽总重量的少于2%、少于1.5%、少于1.25%、少于1%、少于0.9%、少于0.8%、少于0.7%、少于0.6%、少于0.5%、少于0.4%、少于0.3%、少于0.2%或少于0.1%。
例如,纯化的肽基本上不含拓扑异构体。在本文中,“基本上”不含拓扑异构体意指在纯化过程结束时肽的拓扑异构体含量优选为肽总重量的少于2%、少于1.5%、少于1.25%、少于1%、少于0.9%、少于0.8%、少于0.7%、少于0.6%、少于0.5%、少于0.4%、少于0.3%、少于0.2%或少于0.1%。
例如,纯化的肽基本上不含水。在本文中,“基本上”不含水意指在纯化过程结束时肽的水含量优选为肽总重量的少于10%、9%、8%、7%、少于6%、少于5%、少于4.5%、少于4.25%、少于4%、少于3.5%、少于3%、少于2.5%、少于2%、少于1.5%、少于1%、少于0.5%、少于0.25%或少于0.1%。
例如,当用液体分散剂通过光散射测量时,所述肽具有下述粒径分布:D10值为约2-15 µm;D50值为约15-50 µm;和D90值为约40-80 µm。
例如,当用空气分散剂通过光散射测量时,纯化的肽具有特征在于D50值为约600µm的粒径分布。比较而言,自描述于WO2012/118972的冻干和沉淀过程纯化的肽分别具有约180-250 µm和约300 µm的D50值。
例如,通过本发明的方法制备的纯化的肽具有用于药物制剂的合适的粒径分布。在一个实施方案中,肽(例如SP-304)具有与用于制剂的药用赋形剂(例如微晶纤维素)相当的粒径分布(例如平均粒径为80-120 µm),例如呈3 mg/天单位剂型。纯化的肽的粒径分布可基于单位剂量而改变。例如,当单位剂量为低于3 mg/天时,在药物制剂中纯化的肽具有比在3 mg/天剂量中的肽更小的平均粒径。例如,通过本发明的方法制备的纯化的肽经研磨以达到合适的粒径分布。
本发明的肽的粒径分布可通过传统方法例如分子筛分析、不透光度或动态光散射分析测定。
本发明还涉及包含通过本文所述的方法制备和/或纯化的肽的制剂(例如口服制剂),和具体而言,包含0.05-10 mg (例如0.1 mg、0.3 mg或0.5 mg)纯化的肽的低剂量制剂。低剂量制剂可进一步具有描述于WO2012/037380和US 2012-0237593中的一个或多个另外的特征,和可通过其中公开的方法例如干混来制备。
根据以下详述和权利要求,本发明的其它特征和益处将显而易见,并且包括在以下详述和权利要求中。
附图简述
图1是针对冻干的plecanatide和沉淀的plecanatide,通过分子筛分析,显示粒径分布的图。
图2是冻干的plecanatide的光学显微镜图像。
图3是沉淀的plecanatide的光学显微镜图像。
图4是通过本发明的纯化过程的一个实施方案分离的plecanatide的UPLC色谱图。
详述
在一个方面,本发明提供对在用于药物应用的肽GCC激动剂的纯化过程(例如描述于WO2012/118972中的冻干过程和沉淀过程)期间遇到的各种出人意料的问题的解决方案。
具体而言,发现描述于WO2012/118972的冻干过程,其涉及使用乙腈/水溶剂,出人意料地导致以高的乙酰胺含量(即,在测试的批次中范围为88-453 ppm,或平均约300 ppm)在冻干的plecanatide产物中富集残留的乙酰胺(乙腈中的痕量水平杂质),这阻碍了高于3mg/天的剂量的plecanatide的商业化。此外,冻干的plecanatide产物还具有高度变化的残留盐水平例如TFA、乙酸盐和铵盐。
另一方面,尽管经过描述于WO2012/118972中的沉淀过程纯化的plecanatide产物具有低的残留乙酰胺含量(<50 ppm)和比冻干产物更高的堆积密度或振实密度(即约10倍),但由于难以除去用于肽沉淀的溶剂,导致沉淀的plecanatide产物包含高水平的残留溶剂(例如,高至90,000 ppm的IPA)。此外,尽管在真空干燥期间低温度加热(45℃)有助于减少残留的异丙醇至低于5000 ppm的ICH限度的水平(例如1700 ppm),但然后以高至0.9 %的浓度在最终肽产物中形成热降解的α-Asp-9-plecanatide,其根据超效液相色谱(UPLC)分析具有约1.33的相对保留时间(RRT)。在室温贮存期间在plecanatide和其片剂中RRT1.33杂质的含量也增加。因此,在通过沉淀过程产生的plecanatide中起始高水平的该RRT1.33杂质导致较小的接受窗,因此缩短plecanatide药物产品的使用期限。
本发明的纯化过程通过例如交换乙腈/水溶剂为IPA/水溶剂接着旋转蒸发以减少IPA至临界低水平(例如 <5%),接着通过第一小批冷冻干燥(其产生低但不可接受水平的残留溶剂),然后接着在水中复溶和最终冷冻干燥,产生对于药物应用而言低且可接受水平的残留溶剂,解决了残留溶剂问题和降解问题。此外,本发明的纯化过程适合于按比例扩大肽的制备/纯化。
还出人意料地发现,最终冻干之前在用水(pH 5)复溶期间加入少量的乙酸铵缓冲液(例如0.5%至干燥的肽),改进最终产物的溶解性。此外,乙酸铵缓冲液(pH 5)减少在冻干期间在溶液中plecanatide拓扑异构化的速率。与描述于WO2012/118972中的冻干产物相比,乙酸铵缓冲液(pH 5)还以较低的变异性控制在最终产物中的残留盐水平。
在本发明的纯化或分离过程结束时肽具有低的残留乙酰胺水平(<50 ppm)和不大于0.1 g/mL的堆积密度,以及总体较低水平的残留溶剂(例如 <500 ppm IPA、<300 ppmACN)、低水平的降解杂质(例如 <0.1% α-Asp-9-plecanatide (RRT 1.33)降解物)和拓扑异构体(例如0.4%或更低)和低水平的残留盐(例如 <0.1% TFA、0.08-0.23%乙酸盐和0.11-0.17%铵)。通过不同方法分离的plenacanatide产物的比较提供在下文表XX中。
本发明提供纯化或分离肽、例如肽GCC激动剂、特别是经过杂合溶液相和固相过程(例如描述于WO2012/118972中,其通过引用以其整体予以结合)制备的肽的方法。杂合过程包括经过固相和/或溶液相合成提供两个或更多个目的肽片段,并经过溶液相合成将它们偶联以获得靶肽。如果需要,该过程可进一步包括通过片段偶联形成的线性肽的半胱氨酸氨基酸残基的氧化环化,以产生环化肽。
上文描述的片段可以通过标准溶液相肽合成或固相肽合成技术来制备,其中肽键通过第一个氨基酸的氨基(即,NH2)与第二个氨基酸的羧基(即,COOH)的直接缩合(消除一个水分子)而产生。在一个实施方案中,至少一个片段通过固相肽合成制备。
通过直接缩合进行的肽键合成(如上阐述的)需要抑制第一个氨基酸的氨基和第二个氨基酸的羧基的反应特征。掩蔽取代基(masking substituent) (即,保护基)必须能够容易地去除它们,而不诱导不稳定的肽分子的断裂。术语“保护的肽”或“保护的肽片段”是指一种肽或肽片段,其中其组成氨基酸上的所有反应性基团都被保护基团所掩蔽,除非另有规定。术语“脱保护的肽”或“脱保护的肽片段”是指一种肽或肽片段,其中其组成氨基酸上的所有反应性基团都没有被保护基团所掩蔽,除非另有规定。术语“反应性基团”是指形成肽键的基团和干扰肽键形成的基团,诸如氨基、羧基、羟基、和巯基(如在半胱氨酸中)基团。氨基的保护基团的实例包括但并不限于9-芴基甲氧基羰基(Fmoc)、叔丁氧基羰基(Boc)、苯甲酰基(Bz)、乙酰基(Ac)、和苄基(Bn)。羧基的保护基团的实例包括三苯甲基(三苯基甲基,Trt)和O-叔丁基(OtBu)。巯基的保护基团的实例包括乙酰胺基甲基(Acm)、叔丁基(tBu)、3-硝基-2-吡啶亚磺酰基(NPYS)、2 -吡啶-亚磺酰基(Pyr)、和三苯甲基(Trt)。其他保护基团的实例描述于Greene, T.W., Wuts, P.G. M., Protective Groups inOrganic Synthesis, 第3 版, John Wiley & Sons:New York, 1999,其上下文通过引用并入本文。
例如,杂合合成方法已经用于制备SP-304 (plecanatide)。具体地,如下制备三个肽片段A、B和C,然后通过片段A、B和C的缩合装配线性肽序列:通过来自2-氯-三苯甲基氯树脂的固相制备片段A,Boc-Asn(Trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-Leu-OH;通过来自2-氯三苯甲基氯树脂的固相制备片段B,Fmoc-Cys(Acm)-Val-Asn-Val-Ala-Cys(Trt)-Thr(tBu)-Gly-OH;通过溶液相合成制备片段C,Cys(Acm)-Leu-OtBu,在溶液相中偶联片段B和C以产生片段B-C和偶联片段A和B-C以产生线性肽A-B-C。
如下面方案1中所示,可以使用超强酸敏感的2-氯三苯甲基氯(2-ClTrt)树脂和Fmoc-保护的氨基酸衍生物通过Fmoc SPPS来制备侧链保护的片段A (BocAA1-6OH)和B(FmocAA7-14OH)。
片段C (HAA15-16OtBu)可通过溶液相合成制备,然后在溶液相中被偶联至片段B(FmocAA7-14OH),以得到片段B-C (FmocAA7-16OtBu)。如下面方案2中所示,然后Fmoc保护基团可以从片段B-C (FmocAA7-16OtBu)去除,以得到HAA7-16OtBu,然后将所述HAA7-16OtBu偶联至片段A (BocAA1-6OH),以得到侧链保护的线性SP-304 (BocAA1-16OtBu)。
侧链保护的线性SP-304 (BocAA1-16OtBu)可以用三氟乙酸/三异丙基硅烷/乙二硫醇(TFA/TIS/EDT)处理,以得到部分保护的SP-304 (HAA1-16OH),在所述SP-304 (HAA1-16OH)中,2 S-Acm基团(如上述方案2中所示)是完整的。如下面方案3和4中所示,部分保护的线性SP-304 (HAA1-16OH)可以被H2O2氧化,随后同时去除S-Acm基团和与碘形成二硫键,以得到粗双环SP-304。
然后,上述方案3中所示,通过将溶液上样至聚苯乙烯吸附树脂(例如,D101(Anhui Sanxing (China);交联的聚苯乙烯;表面积500-550 m2/g;平均孔径:9-10 nm;孔体积:1.18-1.24 ml/g;堆积密度:0.65-0.70 g/ml;比密度:1.03-1.07 g/ml;水分:67-75%;粒径:0.315~1.25 mm ≧95%;有效直径:0.4~0.7 mm;均匀系数:≤1.6%)、DA201C、DA201H、ADS-8、和ADS-5)柱,用洗脱剂(例如,90%乙醇水溶液)从柱中洗脱双环SP-304,在减压下浓缩收集的SP-304溶液,且用甲基叔丁基醚(MTBE)沉淀SP-304而纯化和浓缩粗双环SP-304的溶液。然后沉淀可以通过过滤或离心收集,高真空下干燥,以得到固体形式的SP-304。
如上述方案4中所示,粗双环SP-304的溶液也可以用各种缓冲系统中的乙腈(ACN)、甲醇和/或水直接在制备型HPLC C18柱上进行纯化。粗双环SP-304也可以经由本领域技术人员已知的其他方法进行纯化。
本领域普通技术人员将认识到,在固相合成中,脱保护和偶联反应必须要完成并且侧链封闭基团在整个合成中必须是稳定的。
N末端的乙酰化可通过在从树脂切割之前将最终的肽与醋酸酐反应来实现。C-酰胺化使用Boc技术,使用适当的树脂诸如甲基二苯甲基胺(methylbenzhydrylamine)树脂来实现。
在溶液相合成中,可使用多种偶联方法和保护基团(参见,Gross和Meienhofer,编,"The Peptides:Analysis, Synthesis, Biology,"第1-4卷(Academic Press,1979);Bodansky和Bodansky,"The Practice of Peptide Synthesis,"第2版(Springer Verlag,1994))。此外,中间的纯化和线性按比例放大是可能的。本领域普通技术人员将理解,溶液合成需要考虑主链和侧链保护基团和活化方法。此外,细心的片段选择是在片段缩合过程中使外消旋最小化所必需的。例如,当片段包含C末端Gly或Pro时,外消旋最小化。溶解性也是考虑因素。固相肽合成在有机合成过程中使用不溶性聚合物进行支持。聚合物支持的肽链允许使用简单的洗涤和过滤步骤而无需在中间步骤进行繁琐的纯化。固相肽合成通常可按照Merrifield等人,J. Am. Chem. Soc., 1963, 85:2149的方法来进行,其包括使用被保护的氨基酸在树脂载体上装配线性肽链。固相肽合成通常利用Boc或Fmoc策略,两者在本领域内是众所周知的。
用于杂合合成SP-353的总体策略包括固相和溶液相合成来产生合适的肽片段(参见下文方案5和6),随后区段缩合以形成线性粗肽(参见下文方案7),和天然氧化折叠以形成环化的最终产物(参见下文方案7)。同样的策略也可用于产生表II中所示的类似氨基酸序列的其他ST肽类似物(诸如SP-354、利那洛肽等)。
用于杂合合成SP-333的总体策略包括固相和溶液相合成来产生合适的肽片段(参见下文方案8和9),随后区段缩合以形成线性粗肽(参见下文方案9),氧化折叠以形成环化的最终产物,纯化,且冻干(参见下文方案10)。
纯化肽(包括通过本文公开的杂合方法合成的肽)的总体策略包括,例如,下文方案11中所示的步骤。据了解,方案11中的某些步骤可以重复(例如,用去离子水冲洗柱)或不存在(例如,脱水后的盐交换或醇去除)以优化纯化方法。
如方案11所示的沉淀过程提供纯化的肽,例如肽GCC激动剂。优选地,纯化的肽是SP-304 (SEQ ID NO:1)或SP-333 (SEQ ID NO:9)。在一个实施方案中,纯化的SP-304或SP-333具有不小于0.05 g/mL、不小于0.1 g/mL、不小于0.2 g/mL、不小于0.3 g/mL、不小于0.4g/mL、或不小于0.5 g/mL的堆积密度。在一个优选的实施方案中,纯化的SP-304或SP-333具有约0.05-2 g/mL、约0.2-0.7 g/mL、约0.3-0.6 g/mL、或约0.4-0.5 g/mL的堆积密度。在一个实施方案中,纯化的SP-304或SP-333具有不小于0.08 g/mL、不小于0.1 g/mL、不小于0.15 g/mL、不小于0.2 g/mL、不小于0.3 g/mL、不小于0.4 g/mL、不小于0.5 g/mL、或不小于0.6 g/mL的堆积密度。例如,纯化的SP-304或SP-333具有0.08-2 g/mL、约0.4-0.9 g/mL、约0.5-0.8 g/mL、或约0.6-0.7 g/mL的堆积密度。在一个实施方案中,纯化的肽SP-304或SP-333含有< 0.01%乙酰胺(例如,<28ppm)、<0.3%铵离子(例如,<0.25%)、<0.01%乙腈(例如,<20 ppm)、和/或< 0.1% TFA(例如,≤0.09%)。在一个实施方案中,纯化的肽SP-304或SP-333具有0.4-0.5 g/mL的堆积密度,具有0.6-0.7 g/mL的振实密度,且含有< 0.01%乙酰胺(例如,<28ppm)、<0.3%铵离子(例如,<0.25%)、<0.01%乙腈(例如,<20 ppm)、和/或< 0.1%TFA(例如,≤0.09%)。
在一些实施方案中,提供具有选自SEQ ID NO: 1、9和104的GCC激动剂序列的纯化的肽,其中纯化的肽具有以下特征:
a) 具有不大于0.1 g/mL的堆积密度;
b) 包含少于50 ppm乙酰胺;
c) 少于0.3% α-Asp-9-plenacanatide。
纯化的肽可具有一个或多个以下特征。
在一个实施方案中,所述肽在25℃下稳定至上3个月。
在一个实施方案中,当用液体分散剂通过光散射测量时,所述肽具有下述粒径分布:D10值为约2-15 µm;D50值为约15-50 µm;和D90值为约40-80 µm。
在一个实施方案中,纯化的肽包含不超过35 ppm乙酰胺(例如 ≤ 18 ppm)。
在一个实施方案中,纯化的肽包含少于0.15% α-Asp-9-plenacanatide (根据本文描述的超效液相色谱(UPLC)分析,其具有约1.33的相对保留时间(RRT))。
在一些实施方案中,纯化的肽具有不大于0.09 g/mL、不大于0.08 g/mL、不大于0.07 g/mL、不大于0.06 g/mL、不大于0.05 g/mL、不大于0.04 g/mL或不大于0.03 g/mL的堆积密度。
在一些实施方案中,纯化的肽基本上不含水(例如,水含量不超过肽总重量的10%、9%、8%、7%、6%、5%、4%、3.5%、3%、2.5%、2%、1.5%、1%、0.5%、0.25%或0.1%)。
在一些实施方案中,纯化的肽具有不少于95%、不少于96%或不少于97%的色谱纯度。
在一些实施方案中,在纯化的肽中杂质的总含量为少于3% (例如 <2%或<1%)。
在一些实施方案中,纯化的肽还基本上不含选自乙腈、醇、铵、乙酸盐和TFA的一种或多种杂质。
例如,纯化的肽包含少于300 ppm乙腈(例如 < 250 ppm)。
在一些实施方案中,纯化的肽包含少于0.2% TFA (例如 <0.15%、<0.1%、<400ppm、< 300 ppm、< 200 ppm、< 100 ppm或< 50 ppm)。
在一些实施方案中,纯化的肽包含少于0.2%异丙醇,即IPA (例如<0.15%、< 0.1%、< 1000 ppm、< 900 ppm< 800 ppm、< 700 ppm、< 600 ppm、< 500 ppm、< 400 ppm、< 300ppm、< 200 ppm、< 100 ppm、< 50 ppm或< 20 ppm)。
在一些实施方案中,纯化的肽包含少于0.25 %乙酸盐(例如 <0.2%或<0.1%)。
在一些实施方案中,纯化的肽基本上不含拓扑异构体(例如<0.4%、<0.3%、<0.2%或<0.1%)。
在一些实施方案中,纯化的肽基本上不含异-Asp2-plecanatide (RRT 0.96-0.97) (例如<0.4%、<0.3%、<0.2%或<0.1%)。
在一些实施方案中,纯化的肽具有不少于96%、不少于97%或不少于98%的色谱纯度。例如,GCC激动剂肽具有不大于4%、不大于3.5%、不大于3%、不大于2.5%、不大于2%、不大于1.5%或不大于1%的色谱杂质含量。色谱杂质含量通过HPLC测定为杂质的总面积百分比。色谱杂质含量包括拓扑异构体含量。杂质不包括用于药物制剂的任何药学上可接受的赋形剂。
在一些实施方案中,纯化的肽基本上不含自肽制备过程产生的污染物,例如用于该过程的有机溶剂,例如铵、乙腈、乙酰胺、醇(例如甲醇、乙醇或异丙醇)、TFA、醚或其它污染物。在该语境中,“基本上”不含污染物意指在纯化过程结束时肽的污染物含量优选为肽总重量的少于0.5%、少于0.3%、少于0.25%、少于0.1%、少于0.05%、少于0.04%、少于0.03%、少于0.02%、少于0.01%、少于0.005%、少于0.003%或少于0.001%。例如,纯化的肽包含< 50 ppm乙酰胺(例如 ≤ 35 ppm或≤ 18 ppm)、< 300 ppm乙腈(例如 < 250 ppm)、< 1000 ppmTFA (例如< 400 ppm、< 300 ppm、< 200 ppm、< 100 ppm或< 50 ppm)、<2000 ppm异丙醇(例如<1500 ppm、<1000 ppm、<500 ppm、< 400 ppm、< 300 ppm、< 200 ppm、< 100 ppm、<50 ppm或< 20 ppm)和/或< 0.25 %乙酸盐(例如<0.2%或<0.1%)。污染物含量可通过常规方法例如气相色谱测定。优选地,本发明的纯化的肽中的残留溶剂低于ICH指南例如IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS Q3C(R5) (杂质:残留溶剂指南Q3C(R5)) (可获自http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf)中设定的限度。
在一些实施方案中,纯化的肽包含少于0.3% (例如< 0.15%) α-Asp-9-plenacanatide (RRT 1.33)。
在一些实施方案中,纯化的肽具有不大于0.09 g/mL、不大于0.08 g/mL、不大于0.07 g/mL、不大于0.06 g/mL、不大于0.05 g/mL、不大于0.04 g/mL或不大于0.03 g/mL的堆积密度。
在一些实施方案中,纯化的肽基本上不含异-Asp2-plecanatide (RRT 约0.96-0.97)。在该语境中,“基本上”不含异-Asp2-plecanatide意指在纯化过程结束时肽的异-Asp2-plecanatide含量优选为肽总重量的少于2%、少于1.5%、少于1.25%、少于1%、少于0.9%、少于0.8%、少于0.7%、少于0.6%、少于0.5%、少于0.4%、少于0.3%、少于0.2%或少于0.1%。
在一些实施方案中,纯化的肽基本上不含拓扑异构体。在该语境中,“基本上”不含拓扑异构体意指在纯化过程结束时肽的拓扑异构体含量优选为肽总重量的少于2%、少于1.5%、少于1.25%、少于1%、少于0.9%、少于0.8%、少于0.7%、少于0.6%、少于0.5%、少于0.4%、少于0.3%、少于0.2%或少于0.1%。
在一些实施方案中,纯化的肽基本上不含水。在该语境中,“基本上”不含水意指在纯化过程结束时肽的水含量优选为肽总重量的少于10%、9%、8%、7%、少于6%、少于5%、少于4.5%、少于4.25%、少于4%、少于3.5%、少于3%、少于2.5%、少于2%、少于1.5%、少于1%、少于0.5%、少于0.25%或少于0.1%。
例如,当用空气分散剂通过光散射测量时,纯化的肽具有特征在于D50值为约600µm的粒径分布。相比之下,自描述于WO2012/118972的冻干和沉淀过程纯化的肽分别具有约180-250 µm和约300 µm的D50值。
例如,通过本发明的方法制备的纯化的肽具有用于药物制剂的合适的粒径分布。在一个实施方案中,肽(例如SP-304)具有与用于制剂的药用赋形剂(例如微晶纤维素)相当的粒径分布(例如平均粒径为80-120 µm),例如呈3 mg/天单位剂型。纯化的肽的粒径分布可基于单位剂量而改变。例如,当单位剂量低于3 mg/天时,在药物制剂中纯化的肽具有比在3 mg/天剂量中更小的平均粒径。例如,通过本发明的方法制备的纯化的肽经研磨以达到合适的粒径分布。
本发明的肽的粒径分布可通过传统方法例如分子筛分析、不透光度或动态光散射分析测定。
在一个实施方案中,本发明提供纯化肽的纯化方法,所述肽包括通过本文公开的杂合方法合成的那些。与描述于WO2012/118972的分离步骤(称为“分离过程1”)相比,所述方法包括例如下文方案12中所示的步骤(称为“分离过程2”)。
方案12
在一个实施方案中,本发明的纯化方法包括以下步骤:
线性粗肽的单环化:首先在8.0-8.5 pH下通过H2O2氧化在SP-304的Cys4和Cys12之间形成二硫键,以形成单环的粗肽。缓慢加入线性粗肽,并在含预添加的H2O2的水缓冲液中以肽的克数:H2O2 mL为100:9的比率溶于0.5%乙酸铵中,以产生大约1.0mg/mL的最终粗浓度。然后用NH4OH溶液将溶液pH调整至8.5,同时在开放空气中搅拌。监测氧化单环化反应,例如使用实施例8中描述的HPLC方法2。当线性粗肽的面积%为单环肽的面积%的≤5.0%时,通过使用TFA溶液调整肽溶液的pH至1.7-2以终止氧化反应。然后将肽溶液转移至用于形成双环肽的下一步骤。
单环肽的双环化:通过在乙腈溶液中的3.0% (w/v) I2在Cys7和Cys15之间形成二硫键。产生二硫桥,同时除去在剩余Cys残基上存在的Acm侧链保护基。监测氧化双环化反应,例如使用HPLC方法2。用在水溶液中的0.1M抗坏血酸猝灭过量的碘。在反应完成时,使用NH4OH溶液调整双环肽至pH 6.5-7,并且制备材料用于初步纯化。
双环粗肽的初步纯化:然后将自氧化步骤产生的双环粗肽溶液上样到填装有C18反相树脂的制备型RP-HPLC柱上,其通过制备型HPLC系统操作。在水pH7/ACN缓冲液系统中在1% TEAP中将肽洗脱。使用例如在实施例8中描述的HPLC方法1,以确定在初步纯化运行期间得到的各级分和各合并物的百分比纯度。
双环肽的循环合并物纯化:在初步纯化后,根据级分合并物的纯度使用在水pH7/ACN缓冲液系统中的1%TEAP或在水/ACN缓冲液系统中的0.2%乙酸将需要进一步纯化的级分纯化。然后将自氧化步骤产生的双环粗肽溶液上样至填装有C18反相树脂的制备型RP-HPLC柱上,其通过制备型HPLC系统操作。在水pH7/ACN缓冲液系统中在1%TEAP中将肽洗脱。使用例如实施例8中描述的HPLC方法1,以确定在循环纯化运行期间获得的各级分和各合并物的百分比纯度。
二级纯化和盐交换:在循环纯化后,根据级分合并物的纯度使用在水pH7/ACN缓冲液系统中的1%TEAP或在水/ ACN缓冲液系统中的0.2%乙酸将需要进一步纯化的级分纯化。使用例如实施例8中描述的HPLC方法1,以确定在二级纯化运行期间获得的各级分和各合并物的百分比纯度。使用例如实施例8中描述的UPLC方法1,以确定在所有纯化运行期间获得的主合并物的百分比纯度,然后移至下一步骤。
溶剂交换:以反方向在边缘末端上将满足主合并物标准的材料上样至制备型RP-HPLC柱上,用水/异丙醇溶液(例如,水与异丙醇比率为99:1)自反方向洗涤,并用水/异丙醇溶液(例如,水与异丙醇比率为60:40)以正方向洗脱。收集的肽溶液通过UPLC方法1测试,以确定纯度,然后将肽溶液过滤,经过旋转蒸发以除去过量的异丙醇(至例如低于5%),接着小批冻干例如不少于96小时。
复溶和最终冻干:小批冻干的干燥肽经过在水中复溶形成均质批次。将缓冲液例如乙酸铵(例如对干燥的肽为0.5% (w/w))加入至溶液中,并混合直至乙酸铵和肽溶解。可通过UPLC方法1分析材料以证实纯度。可将溶解的材料装到托盘冻干机上并保持在真空下例如不少于120小时,以构成最终的干燥肽材料。
1.1 GCC激动剂
通过本发明的方法制备的GCC激动剂可以结合至鸟苷酸环化酶C且刺激细胞内cGMP的产生。任选地,GCC激动剂诱导细胞凋亡且抑制上皮细胞增殖。术语“鸟苷酸环化酶C”是指鸟苷酸环化酶的跨膜形式,其充当由肠道细菌分泌的热稳定毒素(ST)肽的肠道受体。鸟苷酸环化酶C也是天然存在的肽鸟苷肽和尿鸟苷素的受体。尚未排除对于这些肽中的每一种存在不同受体的可能性。因此,术语“鸟苷酸环化酶C”也可包括一类在胃肠道粘膜内衬的上皮细胞上表达的跨膜鸟苷酸环化酶受体。
术语“GCC激动剂”是指肽和非肽化合物两者,诸如结合至肠道鸟苷酸环化酶C且刺激细胞内cGMP产生的化合物。当GCC激动剂是肽时,该术语包括这种结合至鸟苷酸环化酶C且刺激细胞内cGMP产生的肽和前肽(pro-peptide)的生物活性片段。
1.1.1 GCC激动剂肽
适合于本发明的方法的GCC激动剂优选为肽。在一些实施方案中,GCC激动剂肽是少于30个氨基酸长度。在具体实施方案中,GCC激动剂肽是少于或等于30、25、20、15、14、13、12、11、10、或5个氨基酸长度。用于本发明的制剂和方法中的GCC激动剂肽的实例包括美国专利号7,879,802和8,034,782和美国公开号US 2010-0069306和US 2010-0120694(其中每篇都通过引用整体并入本文)中描述的那些。
可通过本发明的方法纯化或制备的GCC激动剂肽的具体实例包括描述于下文表I-VII中的那些。如表I-VII中所用的,术语“PEG3”或“3PEG”是指聚乙二醇例如氨基乙氧基-乙氧基-乙酸(AeeA)和其聚合物。如本文使用的,术语“酰胺”意欲表示末端羧酸被酰胺基团置换,即末端COOH被CONH2置换。
术语“Xaa”指任意天然的或非天然的氨基酸或氨基酸类似物。术语“Maa”指半胱氨酸(Cys)、青霉胺(Pen)高半胱氨酸或3-巯基脯氨酸。术语“Xaan1”意指长度为1、2或3个残基的任意天然的或非天然的氨基酸或氨基酸类似物的氨基酸序列;Xaan2意指长度为0或1个残基的氨基酸序列;以及Xaan3意指长度为0、1、2、3、4、5或6个残基的氨基酸序列。此外,Xaa、Xaan1、Xaan2或Xaan3所示的任意氨基酸可以是L-氨基酸、D-氨基酸、甲基化的氨基酸或其任何组合。任选地,由表中式I-XX所示的任何GCC激动剂肽可在N末端、C末端或两者上包含一个或多个聚乙二醇残基。
在某些实施方案中,通过本发明的方法纯化或制备的GCC激动剂包括选自SEQ IDNO: 1-251的肽,其序列在下文表I-VII中阐明。在一个实施方案中,通过本发明的方法纯化的GCC激动剂包括由SEQ ID NO: 1、9或104指定的肽。
在某些实施方案中,通过本发明方法制备的GCC激动剂包含与选自SEQ ID NO:1-251的肽基本上等同的肽。术语“基本上等同”指具有与结合结构域的氨基酸序列等同的氨基酸序列的肽,其中某些残基可被缺失或被其他氨基酸替代,而不削弱肽结合肠鸟苷酸环化酶受体并且刺激流体和电解质运输的能力。
在某些实施方案中,通过本发明的方法制备的GCC激动剂包括作为选自SEQ IDNO: 1-251的肽的类似物的肽。特别地,这些类似物包含α-氨基己二酸(Aad),优选在自各肽的N-末端起第3位置上或在N-末端侧紧接第1个半胱氨酸(“Cys”)残基251的位置上。
在某些实施方案中,GCC激动剂肽是尿鸟苷素或细菌ST肽的类似物。尿鸟苷素是具有尿钠排泄活性的循环肽激素。ST肽是热稳定肠毒素家族(ST肽)的成员,其由大肠杆菌(E.coli)的致病性菌株和激活鸟苷酸环化酶受体并且引起分泌性腹泻的其他肠细菌分泌。与细菌ST肽不同,尿鸟苷素对鸟苷酸环化酶受体的结合依赖于肠的生理pH。因此,预期尿鸟苷素以pH依赖性的方式调节流体和电解质运输而不引起严重的腹泻。
通过本发明方法制备的GCC激动剂肽可以是L-氨基酸、D-氨基酸或两者的组合的聚合物。例如在多个实施方案中,所述肽为D逆-反肽(retro-inverso peptides)。术语“逆-反异构体(Retro-Inverso Isomer)”指其中序列的方向被反转并且每一个氨基酸残基的手性被倒转的线性肽的异构体。参见例如,Jameson等人,Nature, 368, 744-746 (1994);Brady等人,Nature, 368, 692-693 (1994)。组合D-对映体与逆向合成(reversesynthesis)的净结果是每一个酰胺键中的羰基和氨基基团的位置被交换,而每一个α碳上的侧链基团的位置得到保持。除非另外明确地指出,否则认为,可通过合成相应天然L-氨基酸序列的反向序列来将本发明的任何给定的L-氨基酸序列产生为D逆-反肽。
通过本发明方法制备的GCC 激动剂肽能够诱导表达鸟苷酸环化酶C的细胞和组织中的细胞内cGMP 产生。在某些实施方案中,与天然存在的GCC激动剂诸如尿鸟苷素、鸟苷肽或ST肽相比较,GCC激动剂肽刺激5%、10%、20%、30%、40%、50%、75%、90%或更多的细胞内cGMP。任选地,与SP-304(SEQ ID NO:1)相比较,GCC激动剂肽刺激5%、10%、20%、30%、40%、50%、75%、90%或更多细胞内cGMP。在进一步实施方案中,GCC激动剂肽刺激细胞凋亡,例如程序化细胞死亡或激活囊性纤维化跨膜传导调节蛋白(CFTR)。
在一些实施方案中,本发明的方法制备的GCC激动剂肽比天然存在的GCC激动剂和/或SP-304(SEQ ID NO:1)、SP-339 (利那洛肽) (SEQ ID NO:55)或SP-340 (SEQ ID NO:56)更稳定。例如,与天然存在的GCC激动剂和/或SP-304、SP-339 (利那洛肽)或SP-340相比,GCC激动剂肽降解2%、3%、5%、10%、15%、20%、30%、40%、50%、75%、90%或更少。在某些实施方案中,用于本发明的制剂和方法的GCC激动剂肽比天然存在的GCC激动剂和/或SP-304(SEQID NO:1)、SP-339 (利那洛肽) (SEQ ID NO:55)或SP-340 (SEQ ID NO:56)对于蛋白水解消化作用更稳定。在一个实施方案中,将GCC激动剂肽聚乙二醇化,以使得该肽对胃肠道酶的蛋白水解更耐受。在一个优选的实施方案中,用氨基乙氧基-乙氧基-乙酸(Aeea)基团在其C末端、在其N末端或两个末端将GCC激动剂肽聚乙二醇化。
通过本发明方法制备的GCC激动剂肽的具体实例包括选自SEQ ID NO:1-251的肽。
在一个实施方案中,GCC激动剂肽是具有式X- XVII (例如SEQ ID NO:87-98)中任一个的氨基酸序列的肽。
在一些实施方案中,GCC激动剂肽包括具有式I的氨基酸序列的肽,其中式I的至少一个氨基酸为D-氨基酸或甲基化的氨基酸和/或位置16上的氨基酸为丝氨酸。优选地,式I的位置16上的氨基酸为D-氨基酸或甲基化的氨基酸。例如,式I的位置16上的氨基酸为d-亮氨酸或d-丝氨酸。任选地,式I的位置1-3上的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸,或D-氨基酸或甲基化的氨基酸的组合。例如,式I的Asn1、Asp2或Glu3 (或其组合)为D-氨基酸或甲基化的氨基酸。优选地,式I的位置Xaa6上的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在可选择的实施方案中,GCC激动剂肽包括具有式II的氨基酸序列的肽,其中式II的至少一个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,由式II的Xaan2表示的氨基酸为D-氨基酸或甲基化的氨基酸。在一些实施方案中,由式II的Xaan2表示的氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选地,由式II的Xaan1表示的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,式II的位置Xaa6上的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在一些实施方案中,GCC激动剂肽包括具有式III的氨基酸序列的肽,其中式III的至少一个氨基酸为D-氨基酸或甲基化的氨基酸和/或Maa不是半胱氨酸。优选地,式III的Xaan2表示的氨基酸为D-氨基酸或甲基化的氨基酸。在一些实施方案中,由式III的Xaan2表示的氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选地,由式III的Xaan1表示的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,式III的位置Xaa6上的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在其他实施方案中,GCC激动剂肽包括具有式IV的氨基酸序列的肽,其中式IV的至少一个氨基酸为D-氨基酸或甲基化的氨基酸和/或Maa不是半胱氨酸。优选地,式IV的Xaan2为D-氨基酸或甲基化的氨基酸。在一些实施方案中,由式IV的Xaan2表示的氨基酸为亮氨酸、d-亮氨酸、丝氨酸或d-丝氨酸。优选地,由式IV的Xaan1表示的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,由式IV的Xaa6表示的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在进一步实施方案中,GCC激动剂肽包括具有式V的氨基酸序列的肽,其中式V的至少一个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,式V的位置16上的氨基酸为D-氨基酸或甲基化的氨基酸。例如,式V的位置16(即,Xaa16)上的氨基酸为d-亮氨酸或d-丝氨酸。任选地,式V的位置1-3上的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸或D-氨基酸或甲基化的氨基酸的组合。例如,式V的Asn1、Asp2或Glu3 (或其组合)为D-氨基酸或甲基化的氨基酸。优选地,式V的Xaa6表示的氨基酸为亮氨酸、丝氨酸或酪氨酸。
在其他实施方案中,GCC激动剂肽包括具有式VI、VII、VIII或IX的氨基酸序列的肽。优选地,式VI、VII、VIII或IX的位置6上的氨基酸为亮氨酸、丝氨酸或酪氨酸。在一些方面,式VI、VII、VIII或IX的位置16上的氨基酸为亮氨酸或丝氨酸。优选地,式V的位置16上的氨基酸为D-氨基酸或甲基化的氨基酸。
在其他实施方案中,GCC激动剂肽包括具有式X、XI、XII、XIII、XIV、XV、XVI或XVII的氨基酸序列的肽。任选地,式X、XI、XII、XIII、XIV、XV、XVI或XVII的一个或多个氨基酸为D-氨基酸或甲基化的氨基酸。优选地,根据式X、XI、XII、XIII、XIV、XV、XVI或XVII的肽的羧基端上的氨基酸为D-氨基酸或甲基化的氨基酸。例如,根据式X、XI、XII、XIII、XIV、XV、XVI或XVII的肽的羧基端上的氨基酸为D-酪氨酸。
优选地,由式XIV的Xaa6表示的氨基酸为酪氨酸、苯丙氨酸、或丝氨酸。最优选地,由式XIV的Xaa6表示的氨基酸为苯丙氨酸或丝氨酸。优选地,由式XV、XVI或XVII的Xaa4表示的氨基酸为酪氨酸、苯丙氨酸或丝氨酸。最优选地,式V、XVI或XVII的氨基酸位置Xaa4为苯丙氨酸或丝氨酸。
在一些实施方案中,GCRA肽包括包含式XVIII的氨基酸序列的肽。优选地,式XVIII的位置1上的氨基酸为谷氨酸、天冬氨酸、谷氨酰胺或赖氨酸。优选地,式XVIII的位置2和3上的氨基酸为谷氨酸或天冬氨酸。优选地,位置5上的氨基酸为谷氨酸。优选地,式XVIII的位置6上的氨基酸为异亮氨酸、缬氨酸、丝氨酸、苏氨酸或酪氨酸。优选地,式XVIII的位置8上的氨基酸为缬氨酸或异亮氨酸。优选地,式XVIII的位置9上的氨基酸为天冬酰胺。优选地,式XVIII的位置10上的氨基酸为缬氨酸或甲硫氨酸。优选地,式XVIII的位置11上的氨基酸为丙氨酸。优选地,式XVIII的位置13上的氨基酸为苏氨酸。优选地,式XVIII的位置14上的氨基酸为甘氨酸。优选地,式XVIII的位置16上的氨基酸为亮氨酸、丝氨酸或苏氨酸。
在可选择的实施方案中,GCRA肽包括包含式XIX的氨基酸序列的肽。优选地,式XIX的位置1上的氨基酸为丝氨酸或天冬酰胺。优选地,式XIX的位置2上的氨基酸为组氨酸或天冬氨酸。优选地,式XIX的位置3上的氨基酸为苏氨酸或谷氨酸。优选地,式XIX的位置5上的氨基酸为谷氨酸。优选地,式XIX的位置6上的氨基酸为异亮氨酸、亮氨酸、缬氨酸或酪氨酸。优选地,式XIX的位置8、10、11或13上的氨基酸为丙氨酸。优选地,式XIX的位置9上的氨基酸为天冬酰胺或苯丙氨酸。优选地,式XIX的位置14上的氨基酸为甘氨酸。
在进一步实施方案中,GCRA肽包括包含式XX的氨基酸序列的肽。优选地,式XX的位置1上的氨基酸为谷氨酰胺。优选地,式XX的位置2或3上的氨基酸为谷氨酸或天冬氨酸。优选地,式XX的位置5上的氨基酸为谷氨酸。优选地,式XX的位置6上的氨基酸为苏氨酸、谷氨酰胺、酪氨酸、异亮氨酸或亮氨酸。优选地,式XX的位置8上的氨基酸为异亮氨酸或缬氨酸。优选地,式XX的位置9上的氨基酸为天冬酰胺。优选地,式XX的位置10上的氨基酸为甲硫氨酸或缬氨酸。优选地,式XX的位置11上的氨基酸为丙氨酸。优选地,式XX的位置13上的氨基酸为苏氨酸。优选地,式XX的位置1上的氨基酸为甘氨酸。优选地,式XX的位置15上的氨基酸为酪氨酸。任选地,式XX的位置15上的氨基酸在长度上为2个氨基酸并且为半胱氨酸(Cys)、青霉胺(Pen)高半胱氨酸或3-巯基脯氨酸以及丝氨酸、亮氨酸或苏氨酸。
在某些实施方案中,GCC激动剂肽的一个或多个氨基酸被非天然存在的氨基酸或天然或非天然存在的氨基酸类似物替代。这样的氨基酸和氨基酸类似物在本领域内是已知的。参见例如,Hunt, “The Non-Protein Amino Acids,” Chemistry and Biochemistryof the Amino Acids, Barrett, Chapman, and Hall, 1985。在一些实施方案中,氨基酸被天然存在的、非必需氨基酸,例如,牛磺酸替代。可以被非蛋白氨基酸替代的天然存在的氨基酸的非限制性实例包括以下:(1) 芳香族氨基酸可被3,4-二羟基-L-苯丙氨酸、3-碘-L-酪氨酸、三碘甲状腺原氨酸、L-甲状腺素、苯基甘氨酸(Phg)或正-酪氨酸(norTyr)替代;(2) Phg和norTyr以及其他氨基酸包括Phe和Tyr可被例如卤素、-CH3、-OH、-CH2NH3、-C(O)H、-CH2CH3、-CN、-CH2CH2CH3、-SH或其他基团取代;(3) 谷氨酰胺残基可用γ-羟基-Glu或γ-羧基-Glu取代;(4) 酪氨酸残基可用α取代的氨基酸诸如L-α-甲基苯丙氨酸或用类似物诸如:3-氨基-Tyr;Tyr(CH3);Tyr(PO3(CH3)2);Tyr(SO3H);β-环己基-Ala;β-(1-环戊烯基)-Ala;β-环戊基-Ala;β-环丙基-Ala;β-喹啉基-Ala;β-(2-噻唑基)-Ala;β-(三唑-1-基)-Ala;β-(2-吡啶基)-Ala;β-(3-吡啶基)-Ala;氨基-Phe;氟-Phe;环己基-Gly;tBu-Gly;β-(3-苯并噻吩基)-Ala;β-(2-噻吩基)-Ala;5-甲基-Trp;和A-甲基-Trp取代;(5) 脯氨酸残基可用高脯氨酸(L哌可酸);羟基-Pro;3,4-脱氢-Pro;4-氟-Pro或α-甲基-Pro或N(α)-C(α)环化氨基酸类似物(具有结构:n=0,1,2,3)取代;以及(6) 丙氨酸残基可用α-取代或N-甲基化的氨基酸诸如α-氨基异丁酸(aib)、L/D-α-乙基丙氨酸(L/D-异缬氨酸)、L/D-甲基缬氨酸或L/D-α-甲基亮氨酸或非天然氨基酸诸如β-氟-Ala取代。丙氨酸还可用:n=0、1、2、3取代。甘氨酸残基可用α-氨基异丁酸(aib)或L/D-α-乙基丙氨酸(L/D-异缬氨酸)取代。
非天然氨基酸的进一步实例包括:酪氨酸的非天然类似物;谷氨酰胺的非天然类似物;苯丙氨酸的非天然类似物;丝氨酸的非天然类似物;苏氨酸的非天然类似物;烷基、芳基、酰基、叠氮基、氰基、卤素、肼、酰肼、羟基、烯基、炔基、醚、巯基、磺酰基、硒基、酯、硫代酸、硼酸盐(borate)、硼酸盐(boronate)、磷(phospho)、膦酰基、膦、杂环、烯酮、亚胺、醛、羟胺、酮或氨基取代的氨基酸或其任意组合;具有光激活交联剂的氨基酸;自旋标记的氨基酸;荧光氨基酸;具有新官能团的氨基酸;与另一种分子共价或非共价相互作用的氨基酸;结合金属的氨基酸;在非天然酰胺化的位置上被酰胺化的氨基酸、含金属的氨基酸;放射性氨基酸;photocaged和/或可光异构化(photoisomerizable)氨基酸;含生物素或生物素类似物的氨基酸;糖基化或碳水化合物修饰的氨基酸;含酮氨基酸;包含聚乙二醇或聚醚的氨基酸;重原子取代的氨基酸(例如,含氘、氚、13C、15N或18O的氨基酸);化学可切割或光可切割的氨基酸;具有长侧链的氨基酸;包含毒性基团的氨基酸;糖取代的氨基酸,例如糖取代的丝氨酸等;包含碳-连接的糖的氨基酸;氧化还原活性氨基酸;含α-羟基的酸;含氨基硫羰酸的氨基酸;α,α二取代的氨基酸;β-氨基酸;除脯氨酸外的环状氨基酸;O-甲基-L-酪氨酸;L-3-(2-萘基)丙氨酸;3-甲基-苯丙氨酸;对-乙酰基-L-苯丙氨酸;O-4-烯丙基-L-酪氨酸;4-丙基-L-酪氨酸;三-O-乙酰基-GlcNAc β-丝氨酸;L-多巴;氟化苯丙氨酸;异丙基-L-苯丙氨酸;对-叠氮基-L-苯丙氨酸;对-酰基-L-苯丙氨酸;对-苯甲酰基-L-苯丙氨酸;L-磷酸丝氨酸;膦酰基丝氨酸;膦酰基酪氨酸;对-碘-苯丙氨酸;4-氟苯基甘氨酸;对-溴苯丙氨酸;对-氨基-L-苯丙氨酸;异丙基-L-苯丙氨酸;L-3-(2-萘基)丙氨酸;D-3-(2-萘基)丙氨酸(dNal);含氨基-,异丙基-或O-烯丙基-的苯丙氨酸类似物;多巴,0-甲基-L-酪氨酸;糖基化氨基酸;对-(炔丙基氧基)苯丙氨酸;二甲基-赖氨酸;羟基-脯氨酸;巯基丙酸;甲基-赖氨酸;3-硝基-酪氨酸;正亮氨酸;焦谷氨酸;Z(苄氧羰基);ε-乙酰基-赖氨酸;β-丙氨酸;氨基苯甲酰基衍生物;氨基丁酸(Abu);瓜氨酸;氨基己酸;氨基异丁酸(AIB);环己基丙氨酸;d-环己基丙氨酸;羟脯氨酸;硝基-精氨酸;硝基-苯丙氨酸;硝基-酪氨酸;正缬氨酸;八氢吲哚羧酸;鸟氨酸(Orn);青霉胺(PEN);四氢异喹啉;乙酰氨基甲基保护的氨基酸和PEG化的氨基酸。非天然氨基酸和氨基酸类似物的进一步实例可见于U.S.20030108885、U.S.20030082575、US20060019347(第410-418段)和其中引用的参考文献中。本发明的多肽可包括进一步修饰,包括US20060019347,第589段中描述的修饰。包含非天然存在的氨基酸的示例性GCC激动剂肽包括,例如,SP-368和SP-369。
在一些实施方案中,GCC激动剂肽是环肽。GCC激动剂环肽可通过本领域已知的方法来制备。例如,大环化通常通过在肽N-和C-末端之间、在侧链与N-或C-末端之间[例如,利用K3Fe(CN)6,在pH 8.5下](Samson等人,Endocrinology, 137:5182-5185(1996))或在两个氨基酸侧链诸如半胱氨酸之间形成酰胺键来实现。参见例如,DeGrado, Adv ProteinChem, 39:51-124 (1988)。在多个实施方案中,GCC激动剂肽为[4,12; 7,15]双环。
在某些实施方案中,通常在GCC激动剂肽中形成二硫键的一个或两个Cys残基可被高半胱氨酸、青霉胺、3-巯基脯氨酸(Kolodziej等人1996 Int. J. Pept. Protein Res.48:274);β,β二甲基半胱氨酸(Hunt等人1993 Int. J. Pept. Protein Res. 42:249)或二氨基丙酸(Smith等人1978 J. Med. Chem. 2 1:117)替代,以在正常二硫键的位置上形成可选择的内部交联。
在某些实施方案中,在GCC激动剂肽中的一个或多个二硫键被可选择的共价交联替代,例如酰胺连接(-CH2CH(O)NHCH2-或- CH2NHCH(O)CH2-)、酯连接、硫酯连接、内酰胺桥、氨甲酰连接、脲连接(urea linkage)、硫脲连接、磷酸酯连接、烷基连接(-CH2CH2CH2CH2-)、烯基连接(-CH2CH=CHCH2-)、醚连接(-CH2CH2OCH2-或-CH2OCH2CH2-)、硫醚连接(-CH2CH2SCH2-或- CH2SCH2CH2-)、胺连接(-CH2CH2NHCH2-或-CH2NHCH2CH2-)或硫代酰胺连接(-CH2C(S)NHCH2-或-CH2NHC (S)CH2-)。例如,Ledu等人(Proc. Natl. Acad. Sci. 100:11263-78,2003)描述了用于制备内酰胺和酰胺交联的方法。包含内酰胺桥的示例性GCC激动剂肽包括例如SP-370。
在某些实施方案中,GCC激动剂肽的一个或多个常规多肽键被可选择的键替代。此类替代可增强多肽的稳定性。例如,用可选择的键替代残基氨基末端与芳香族残基(例如Tyr、Phe、Trp)之间的多肽键可减少被羧肽酶切割,并且可增加在消化道中的半衰期。可替代多肽键的键包括:逆-反键(retro-inverso bond)(C(O)-NH而非NH-C(O);还原的酰胺键(NH-CH2);硫亚甲基键(S-CH2或CH2-S);氧亚甲基键(O-CH2或CH2-O);乙烯键(CH2-CH2);硫代酰胺键(C(S)-NH);反式-烯键(CH=CH);氟取代的反式-烯键(CF=CH);酮亚甲基键(C(O)-CHR或CHR-C(O),其中R为H或CH3;和氟-酮亚甲基键(C(O)-CFR或CFR-C(O),其中R为H或F或CH3。
在某些实施方案中,使用标准修饰对GCC激动剂肽进行修饰。修饰可在氨基(N-)、羧基(C-)端、内部或任何上述位置的组合上进行。在本文描述的一个方面,在肽上可存在超过一种类型的修饰。修饰包括但不限于:乙酰化、酰胺化、生物素化、苯乙烯醛基化、法尼基化、甲酰化、豆蔻酰化、棕榈酰化、磷酸化(Ser、Tyr或Thr)、硬脂酰化、琥珀酰化、磺酰化和环化(通过二硫桥或酰胺环化)和通过Cys3或Cys5的修饰。本文中描述的GCC激动剂肽还可利用2,4-二硝基苯基(DNP)、DNP-赖氨酸来修饰,利用7-氨基-4-甲基-香豆素(AMC)、荧光素、NBD(7-硝基苯并-2-氧杂-1,3-二唑)、对硝基苯胺、罗丹明B、EDANS(5-((2-氨基乙基)氨基)萘-1-磺酸)、dabcyl、dabsyl、丹磺酰基、德克萨斯红、FMOC和Tamra(四甲基罗丹明)来进行修饰。还可将本文中描述的GCC激动剂肽缀合至例如聚乙二醇(PEG);烷基(例如,C1-C20直链或支链烷基);脂肪酸部分;PEG、烷基和脂肪酸部分的组合(参见,美国专利6,309,633;Soltero等人,2001 Innovations in Pharmaceutical Technology 106-110);BSA和KLH(钥孔血蓝蛋白)。PEG和可用于修饰本发明的多肽的其他聚合物的添加描述于US2006019347部分IX中。
GCC激动剂肽也可以是本文所述的GCC激动剂肽的衍生物。例如,衍生物包括其中某些氨基酸已被缺失或被替换的GCC激动剂肽的杂合体和修饰形式。修饰也可包括糖基化。优选地,当修饰是氨基酸取代时,它是在被预测为对于肽的生物活性非必需的氨基酸残基的一个或多个位置的保守取代。“保守取代”是其中氨基酸残基用具有相似侧链的氨基酸残基替代的取代。具有相似侧链的氨基酸残基的家族已在本领域进行了定义。这些家族包括具有下述的氨基酸:碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、酪氨酸)、β-分支侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。
在一个实施方案中,通过本文所述的方法制备的GCC激动剂肽进行随机诱变,以鉴定具有生物活性的突变体。
在一个实施方案中,本发明的方法可用于制备基本上与本文所述的GCC激动剂肽同源的GCC激动剂肽。这种基本上同源的肽可借助与针对本文所述的GCC激动剂肽的抗体的交叉反应而分离。
可以通过本发明的方法制备的GCC激动剂肽的进一步实例可见于下文表I-VII中。
1.1.2 GCC激动剂肽及其片段的可选择的制备方法
GCC激动剂肽和它们的片段可使用本领域公认的技术诸如分子克隆、肽合成或位点定向诱变来制备。
除上述常规的溶液或固相肽合成之外,GCC激动剂肽或它们的片段可通过现代克隆技术来产生。例如,在细菌(包括但不限于大肠杆菌)中或在用于多肽或蛋白质产生的其他现有系统(例如,枯草芽孢杆菌(Bacillus subtilis)、使用果蝇Sf9细胞的杆状病毒表达系统、酵母或丝状真菌表达系统、哺乳动物细胞表达系统)中产生GCC激动剂肽,或可化学合成它们。如果将在细菌例如大肠杆菌中产生GCC激动剂肽或变异肽,那么编码多肽的核酸分子还可编码允许成熟多肽从细胞分泌的前导序列。因此,编码多肽的序列可包括例如天然存在的细菌ST多肽的前序列(pre sequence)和前体序列(pro sequence)。可从培养基纯化分泌的成熟多肽。
可将编码本文中描述的GCC激动剂肽的序列插入能够在细菌细胞中递送和维持核酸分子的载体。可将DNA分子插入自主复制载体(适当的载体包括例如pGEM3Z和pcDNA3,及其衍生物)。载体核酸可以是细菌或噬菌体DNA,诸如λ噬菌体或M13及其衍生物。可构建包含本文中描述的核酸的载体,然后转化宿主细胞诸如细菌。适当的细菌宿主包括但不限于,大肠杆菌、枯草芽孢杆菌、假单胞菌属(Pseudomonas)、沙门氏菌属(Salmonella)。除编码核酸分子以外,基因构建体还包括允许表达的元件,诸如启动子和调控序列。表达载体可包含控制转录起始的转录控制序列,诸如启动子、增强子、操纵子和阻遏物序列。
各种转录控制序列对于本领域技术人员来说是众所周知的。表达载体还可包括翻译调控序列(例如,非翻译5′序列、非翻译3′序列或内部核糖体进入位点)。载体可以能够自主复制或其可整合入宿主DNA,以在多肽产生过程中确保稳定性。
还可将包括本文中描述的GCC激动剂肽的蛋白质编码序列融合至编码多肽亲和标签例如谷胱甘肽S-转移酶(GST)、麦芽糖E结合蛋白、蛋白A、FLAG标签、六组氨酸、myc标签或流感病毒HA标签的核酸,以帮助纯化。亲和标签或报告基因融合将目标多肽的读框与编码亲和标签的基因的读框连接,以便产生翻译融合物。融合基因的表达导致包含目标多肽和亲和标签的单个多肽的翻译。在一些使用亲和标签的情况下,在亲和标签与目标多肽的读框之间融合编码蛋白酶识别位点的DNA序列。
适用于在除细菌以外的蛋白质表达系统中产生本文中描述的GCC激动剂肽和变体的未成熟和成熟形式且本领域技术人员众所周知的基因构建体和方法可用于在生物系统中产生多肽。
本文中公开的肽可通过连接第二分子来进行修饰,所述第二分子赋予所述肽期望的性质诸如增加的体内半衰期,例如聚乙二醇化。此类修饰也落在本文使用的术语“变体”的范围内。
1.2 使用方法
本发明提供了用于在需要其的受试者中治疗或预防胃肠病症和增加胃肠蠕动的方法,其通过将有效量的GCC激动剂或其制剂施用于所述受试者而实现。可以根据本发明的方法治疗或预防的胃肠病症的非限制性实例包括肠易激综合症(IBS)、非溃疡性消化不良、幽门螺旋杆菌感染有关的溃疡、慢性假性肠梗塞、功能性消化不良、结肠假性梗阻、十二指肠胃反流、胃食管返流病(GERD)、肠梗阻(例如,术后肠梗阻)、胃肌轻瘫、胃灼热(GI道中的高酸性)、便秘(例如,与药物诸如阿片样物质、骨关节炎药物、或骨质疏松药物的使用相关的便秘);术后便秘、与神经性病症相关的便秘、克罗恩病和溃疡性结肠炎。
在一个实施方案中,本发明提供了用于治疗或预防胃肠蠕动病症、肠道易激综合症、功能性胃肠病、胃食管返流疾病、十二指肠胃反流、功能性胃灼热、消化不良、功能性消化不良、无溃疡性消化不良、胃轻瘫、慢性假性肠梗塞、假性结肠梗塞、肥胖症、充血性心力衰竭或良性前列腺增生的方法。
在一个实施方案中,本发明提供了用于在需要其的受试者中治疗或预防便秘和/或增加胃肠蠕动的方法,其通过将有效量的GCC激动剂或其制剂施用于所述受试者而实现。临床公认的定义便秘的标准是以肠运动的频率、排泄物的粘度和肠运动的轻松度进行定义。便秘的一个共同定义为每周少于三次肠运动。其他定义包括不规则的坚硬的粪便或者过度用力排便(Schiller 2001 Aliment Pharmacol Ther 15:749-763)。便秘可以是原发性的(功能性便秘或慢通过性便秘)或继发于包括神经系统、代谢或内分泌病症的其他因素。这些病症包括糖尿病、甲状腺功能减退、甲状腺功能亢进、低钙血症、多发性硬化症、帕金森病、脊髓损害、多发性神经纤维瘤、自主神经病、查加斯病、先天性巨结肠病和囊性纤维病。便秘也可能是由于手术的原因或由于使用诸如镇痛药(如阿片样物质)、抗高血压药、抗惊厥剂、抗抑郁药、解痉药和抗精神病药导致的。
在各个实施方案中,便秘和治疗药物的使用有关;便秘和神经病症有关;便秘是术后便秘;便秘和胃肠病有关;便秘是特发性的(功能性便秘或慢通过性便秘);便秘与神经系统、代谢或内分泌病症有关(例如,糖尿病、甲状腺功能减退、甲状腺功能亢进、低钙血症、多发性硬化症、帕金森病、脊髓损害、多发性神经纤维瘤、自主神经病、查加斯病、先天性巨结肠病或囊性纤维病)。便秘也可能是由于手术的原因或由于使用诸如镇痛药(如阿片样物质)、抗高血压药、抗惊厥剂、抗抑郁药、解痉药和抗精神病药导致的。
在一个实施方案中,本发明提供了用于在需要其的受试者中治疗或预防慢性特发性便秘和增加胃肠蠕动的方法,其通过将有效量的GCC激动剂或其制剂施用于所述受试者而实现。
本文使用的术语“治疗”是指与待治疗的胃肠病症相关的至少一种临床症状的减少、部分改善、减轻或缓解。术语“预防”是指与待预防的胃肠病症相关的至少一种临床症状的发作或进展的抑制或延迟。如本文使用的术语“有效量”是指为受试者提供一些改进或益处的量。在某些实施方案中,有效量是提供待治疗的胃肠病症的至少一种临床症状的一些减轻、缓解和/或下降的量。在其他实施方案中,有效量是提供与待预防的胃肠病症相关的至少一种临床症状的发作或进展的一些抑制或延迟的量。治疗效果不需要是彻底或治愈的,只要为受试者提供一些益处。术语“受试者”优选是指人受试者,但也可指优选选自小鼠、大鼠、狗、猫、牛、马或猪的非人灵长类动物或其他哺乳动物。
本发明还提供了用于在需要其的受试者中治疗胃肠癌症的方法,其通过将有效量的GCC激动剂或其制剂施用于所述受试者而实现。可以根据本发明的方法治疗的胃肠癌症的非限制性实例包括胃癌、食道癌、胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或结肠癌。
本发明也提供了用于治疗脂质代谢病症、胆的病症、炎性病症、肺病症、癌症、心脏病症包括心血管病症、眼病症、口腔病症、血液病症、肝病症、皮肤病症、前列腺病症、内分泌病症、和肥胖症的方法。
脂质代谢病症包括但不限于血脂异常、高脂血症、高胆固醇血症、高甘油三酯血症、谷固醇血症、家族性高胆固醇血症、黄瘤、组合高脂血症、卵磷脂胆固醇酰基转移酶缺乏症、丹吉尔病、无β脂蛋白血症、勃起功能病症、脂肪肝病和肝炎。
胆的病症包括胆囊病症诸如如胆结石、胆囊癌胆管炎或原发性硬化性胆管炎;或胆管病症诸如如胆囊炎、胆管癌或片形吸虫病。
炎性病症包括组织和器官炎症诸如肾炎症(例如,肾炎)、胃肠系统炎症(例如,克罗恩病和溃疡性结肠炎);坏死性小肠结肠炎(NEC);胰腺炎症(例如,胰腺炎)、胰功能不全、肺部炎症(例如,支气管炎或哮喘)或皮肤炎症(例如,银屑病、湿疹)。
肺病症包括例如慢性阻塞性肺病(COPD)和纤维化。
癌症包括组织和器官癌发生包括转移,诸如如胃肠癌,(例如,胃癌、食管癌、胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌或结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑色素瘤);口腔癌;尿道癌(例如膀胱癌或肾癌);血癌(例如骨髓瘤或白血病)或前列腺癌。
心脏病症包括例如充血性心力衰竭、气管心脏高血压、高胆固醇或高甘油三酯。心血管病症包括例如动脉瘤、心绞痛、动脉粥样硬化、脑血管意外(中风)、脑血管病、充血性心力衰竭、冠状动脉疾病、心肌梗塞(心脏病发作)或外周血管疾病。
肝病症包括例如肝硬化和纤维化。此外,GC-C激动剂还可用于促进肝移植患者的肝再生。眼病症包括例如升高的眼内压、青光眼、干眼、视网膜变性、泪腺的病症和眼炎。皮肤病症包括例如干燥病。口腔病症包括例如干口(口腔干燥症)、干燥综合症、齿龈疾病(例如,牙周病)或唾液腺管阻塞或机能病症。前列腺病症包括例如良性前列腺增生(BPH)。内分泌病症包括例如糖尿病、甲状腺功能亢进症、甲状腺功能减退症和囊性纤维化。
1.2.1 治疗有效剂量
通过给受试者例如哺乳动物诸如需要其的人施用治疗有效剂量的GCC激动剂肽来治疗、预防或缓解病症。本发明部分基于在人临床试验中意料之外的结果,所述结果表明,本发明的制剂在比基于动物研究预计的低得多的剂量是治疗有效的。根据本发明的一个方面,治疗有效剂量为0.01毫克(mg)至10 mg/每单位剂量。术语“单位剂量”指单次药物递送实体,例如片剂、胶囊、溶液、吸入制剂、控释或缓释制剂 (例如,Cosmo Pharmaceuticals的MMX®技术)。在一个实施方案中,有效剂量在0.01 mg和9 mg之间。在另一个实施方案中,有效剂量在0.01 mg和5 mg之间。在另一个实施方案中,有效剂量在0.01 mg和3 mg之间。在另一个实施方案中,有效剂量在0.10 mg和5 mg之间。在另一个实施方案中,有效剂量在0.10mg和3 mg之间。在一个实施方案中,单位剂量是 .01 mg、.05 mg、0.1 mg、0.2 mg、0.3 mg、0.5 mg、1.0 mg、1.5 mg、2.0 mg、2.5 mg、3.0 mg、5 mg、或10 mg。在一个实施方案中,单位剂量是0.3 mg、1.0 mg、3.0 mg、9.0 mg、或9.5 mg。
GCC激动剂肽可以以单位剂量形式与一种或多种药学可接受的赋形剂一起存在于药物组合物中。存在的肽的量应当在给患者施用时足以具有积极治疗效果。什么构成“积极治疗效果”将取决于待治疗的具体状况并且可包括易于被本领域技术人员认可的状况的任何显著改善。
优选口服施用上述方法中使用的GCC激动剂。剂型包括溶液、悬浮液、乳剂、片剂和胶囊。
可将总日剂量以单次剂量或以多次亚剂量给患者施用。通常,可每日2至6次,优选每日2至4次,甚至更优选每日2至3次施用亚剂量。优选地,每天施用单次剂量。
GCC激动剂可作为唯一的活性剂施用或可与一种或多种另外的活性剂组合来进行施用。在所有情况下,应当使用现有技术作为指导,以在治疗上有效的剂量施用其他活性剂。可以以单一组合物的形式施用GCC激动剂或相继地与一种或多种另外的活性剂施用GCC激动剂。在一个实施方案中,将GCC激动剂与一种或多种下述的抑制剂组合施用:cGMP依赖性磷酸二酯酶诸如舒林酸砜、扎普司特、莫他匹酮、伐地那非或西地那非。在另一个实施方案中,将GCC激动剂与一种或多种化学治疗剂组合施用。在另一个实施方案中,将GCC激动剂与一种或多种或抗炎药诸如甾体或非甾体抗炎药(NSAIDS)诸如阿司匹林组合施用。
组合治疗可通过施用两种或更多种试剂(例如本文中描述的GCC激动剂肽和另一种化合物,配制所述试剂的每一种并将其单独施用)或以单一制剂施用两种或更多种试剂)来实现。组合治疗还可包括其他组合。例如,可将两种试剂配制在一起,将其与包含第三试剂的单独制剂结合施用。虽然可在组合治疗中同时施用两种或更多种试剂,但它们不必一定如此。例如,第一试剂(或试剂的组合)的施用可先于第二试剂(或试剂的组合)的施用数分钟、数小时、数天或数周。因此,可在彼此相隔数分钟内,或彼此相隔1、2、3、6、9、12、15、18或24小时内或彼此相隔1、2、3、4、5、6、7、8、9、10、12、14天内或彼此相隔2、3、4、5、6、7、8、9或10周内施用两种或更多种试剂。在一些情况下,甚至更长的间隔也是可能的。虽然在许多情况下,期望组合治疗中使用的两种或更多种试剂同时存在于患者体内,但不必一定如此。
可将本文中描述的GCC激动剂肽与磷酸二酯酶抑制剂例如舒林酸砜、扎普司特、西地那非、伐地那非或他达拉非组合以进一步增强靶组织或器官中的cGMP水平。
组合治疗还可包括组合使用的一种或多种试剂的两次或更多次施用。例如,如果组合使用试剂X和试剂Y,那么可以以任何组合相继地施用它们一次或多次,例如以顺序X-Y- X、X-X-Y、Y-X-Y、Y-Y-X、X-X-Y-Y等施用。
1.2.2 组合治疗的示例性药剂
本发明的GCC激动剂制剂可以单独施用或与作为治疗方案的部分的一种或多种另外治疗剂组合施用,用于治疗或预防胃肠疾病或病症。在一些实施方案中,GCC激动剂制剂包含一种或多种另外的治疗剂。在其他实施方案中,GCC激动剂与所述一种或多种另外的治疗剂分开配制。根据本实施方案,GCC激动剂与所述一种或多种另外的治疗剂同时施用,相继施用,或在不同时间施用。在一个实施方案中,GCC激动剂制剂与选自以下的一种或多种另外治疗剂组合施用:磷酸二酯酶抑制剂、环核苷酸(诸如cGMP和cAMP)、轻泻剂(诸如SENNA或METAMUCIL)、粪便软化剂、用于IBD的抗肿瘤坏死因子α的治疗剂(诸如REMICADE、ENBREL、或HUMIRA)、和抗炎药(诸如COX-2抑制剂、柳氮磺吡啶、5-ASA衍生物和NSAIDS)。在某些实施方案中,GCC激动剂制剂与有效剂量的cGMP特异性磷酸二酯酶(cGMP-PDE)抑制剂或同时或相继与所述GCC激动剂组合施用。cGMP-PDE抑制剂包括,例如,舒林酸砜、扎普司特、莫他匹酮、伐地那非、和西地那非。在另一个实施方案中,GCC激动剂制剂与环核苷酸转运蛋白抑制剂组合施用。可以与本发明的GCC激动剂制剂组合施用的治疗剂的进一步实例在下面部分中给出。
1.2.2.1 治疗胃肠癌症的药剂
本文描述的GCC激动剂制剂可以与一种或多种抗癌剂组合使用,所述抗癌剂包括但不限于,烷基化剂、表鬼臼毒素、硝基脲类药物、代谢拮抗剂、长春花生物碱、蒽环(anthracycline)抗生素、氮芥类试剂等。具体的抗癌剂包括他莫昔芬、红豆杉醇(taxol)、依托泊苷和5-氟代尿嘧啶。在一个实施方案中,GCC激动剂制剂与抗病毒剂或单克隆抗体组合使用。
可以与本发明的GCC激动剂制剂组合使用用于治疗结肠癌的抗癌剂的非限制性实例包括抗增殖剂、用于DNA修饰或修复的试剂、DNA合成抑制剂、DNA/RNA转录调节剂、RNA加工抑制剂、影响蛋白质表达、合成和稳定性的试剂、影响蛋白质定位或它们发挥它们的生理作用的能力的试剂、干扰蛋白质-蛋白质或蛋白质-核酸相互作用的试剂、通过RNA干扰起作用的试剂、任何化学性质的受体结合分子(包括小分子和抗体)、被靶向的毒素、酶激活剂、酶抑制剂、基因调节剂、HSP-90抑制剂、干扰微管或其他细胞骨架组分或细胞粘附和运动的分子、用于光线疗法的试剂和治疗辅助剂(therapy adjunct)。
代表性抗增殖剂包括N-乙酰基-D-鞘氨醇(C.sub.2神经酰胺)、芹菜配基、盐酸黄连素、二氯亚甲基二磷酸二钠盐(dichloromethylene diphosphonic acid disodiumsalt)、芦荟大黄素(loe-emodine)、大黄素、HA 14-1、N-己酰-D-鞘氨醇(C.sub.6神经酰胺)、7b-羟基胆固醇、25-羟基胆固醇、贯叶金丝桃素、小白菊内酯和雷帕霉素。用于DNA修饰和修复的代表性试剂包括阿非迪霉素、硫酸博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、环磷酰胺一水合物、环磷酰胺一水合物ISOPAC.RTM.、顺氯氨铂(cis-diammineplatinum(II)dichloride)(顺铂)、七叶亭(esculetin)、美法仑、甲氧胺盐酸盐、丝裂霉素C、米托蒽醌二盐酸盐、奥沙利铂和链脲菌素。
代表性DNA合成抑制剂包括(.+-.)甲氨蝶呤(氨甲蝶呤)、3-氨基-1,2,4-苯并三嗪1,4-二氧化物、氨喋呤、胞嘧啶b-D-呋喃阿拉伯糖苷(Ara-C)、胞嘧啶b-D-呋喃阿拉伯糖苷(Ara-C)盐酸盐、2-氟腺嘌呤-9-b-D-呋喃阿拉伯糖苷(脱磷酸氟达拉滨(Fludarabine des-phosphate)、F-ara-A)、5-氟-5′-脱氧尿苷、5-氟尿嘧啶、更昔洛韦、羟基脲、6-巯基嘌呤和6-硫鸟嘌呤。
代表性DNA/RNA转录调节剂包括放线菌素D、盐酸柔红霉素、5,6-二氯苯并咪唑1-b-D-呋喃型核糖苷、盐酸多柔比星、高三尖杉酯碱和盐酸伊达比星。
代表性酶激活剂和抑制剂包括弗司扣林、DL-氨鲁米特、apicidin、Bowman-Birk抑制剂、紫铆因、(S)-(+)-喜树碱、姜黄素、(-)-鱼藤素、(-)-depudecin、盐酸多西环素、依托泊苷、福美坦、福司曲星钠盐、硬毛素(hispidin)、2-亚氨基-1-咪唑啉醋酸(环肌酸)、oxamflatin、4-苯丁酸、roscovitine、丙戊酸钠、曲古抑菌素A、酪氨酸磷酸化抑制剂AG 34、酪氨酸磷酸化抑制剂AG 879、尿胰蛋白酶抑制剂片段、丙戊酸(2-丙戊酸)和XK469。
代表性基因调节剂包括5-氮杂-2′-脱氧胞苷、5-氮杂胞苷、维生素D3(VitaminD3)、ciglitizone、醋酸环丙孕酮、15-脱氧- D.sup.12,14-前列腺素J.sub.2、表睾酮、氟他胺、甘草酸铵盐(甘草皂苷)、4-羟泰米芬、米非司酮、盐酸普鲁卡因胺、盐酸雷洛昔芬、全-反视黄醛(维生素A醛)、视黄酸(维生素A酸)、9-顺-视黄酸、13-顺-视黄酸、视黄酸对-羟基苯胺(p-hydroxyanilide)、视黄醇(维生素A)、他莫昔芬、他莫昔芬柠檬酸盐、十四烷基硫代乙酸和曲格列酮。
代表性HSP-90抑制剂包括17-(烯丙基氨基)-17-去甲氧基格德霉素和格尔德霉素。
代表性微管抑制剂包括秋水仙素、多拉司他汀15、诺考达唑、紫杉烷类和特别地紫杉醇、鬼臼毒素、根霉素、长春碱硫酸盐、长春新碱硫酸盐以及长春地辛硫酸盐和长春瑞滨(诺维本)二酒石酸盐。
用于进行光线疗法的代表性试剂包括光敏卟啉环、金丝桃素、5-甲氧补骨脂素、8-甲氧补骨脂素、补骨脂素和熊脱氧胆酸。
用作治疗辅助剂的代表性试剂包括氨磷汀、4-氨基-1,8-萘二甲酰亚胺、布雷菲德菌素A、西咪替丁、磷霉素二钠盐(phosphomycin disodium salt)、亮丙瑞林(亮丙瑞林)醋酸盐、促黄体激素释放激素(LH-RH)醋酸盐、凝集素、盐酸罂粟碱、皮斐松-a(pifithrin-a)、(-)-氢溴酸东莨菪碱和毒胡萝卜素。
试剂还可以是抗VEGF(血管内皮生长因子)试剂,这样的试剂在本领域内是已知的。几种抗体和小分子目前用于临床试验中或已证明通过抑制VEGF起作用诸如阿瓦斯丁(Bevacizumab)、SU5416、SU11248和BAY 43-9006。所述试剂还可针对生长因子受体例如EGF/Erb-B家族的生长因子受体例如EGF受体(易瑞沙或吉非替尼,以及塔西法或厄洛替尼)、Erb-B2受体(赫赛汀或曲妥珠单抗)、其他受体(例如利妥昔单抗或Rituxan/美罗华)、酪氨酸激酶、非受体酪氨酸激酶、细胞丝氨酸/苏氨酸激酶(包括MAP激酶)和其病症促成肿瘤生成的各种其他蛋白质(例如小/Ras家族和大/异源三聚体G蛋白)。靶向那些分子的几种抗体和小分子目前在不同的开发阶段(包括批准用于治疗或临床试验)。
在一个优选的实施方案中,本发明提供了用于在需要其的受试者中治疗结肠癌的方法,其通过将GCC激动剂制剂与选自以下的一种或多种抗癌剂组合施用于所述受试者而实现:紫杉醇、多西他赛、他莫昔芬、长春瑞滨、吉西他滨、顺铂、依托泊苷、托泊替康、伊立替康、阿那曲唑、利妥昔单抗、曲妥珠单抗、氟达拉滨、环磷酰胺、吉妥珠单抗(gentuzumab)、卡铂、干扰素和多柔比星。在特定实施方案中,抗肿瘤剂是紫杉醇。在进一步的实施方案中,本方法还包含选自5-FU、多柔比星、长春瑞滨、环磷酰胺和顺铂的抗肿瘤剂。
1.2.2.2 治疗克罗恩病的试剂
在一个实施方案中,将本发明的GCC激动剂制剂作为与一种或多种另外的治疗剂的组合治疗的部分进行施用而用于治疗克罗恩病。一种或多种另外的治疗剂的非限制性实例包括柳氮磺吡啶和其他含氨水杨酸的药物,通常称为5-ASA试剂,诸如安萨科(Asacol)、奥柳氮钠、或颇得斯安、或英夫利昔单抗(REMICADE)。在某些实施方案中,一种或多种另外的试剂是皮质类固醇或免疫抑制试剂诸如6-巯基嘌呤或硫唑嘌呤。在另一个实施方案中,一种或多种另外的试剂是止泻药诸如地芬诺酯、洛哌丁胺或可待因。
1.2.2.3 治疗溃疡性结肠炎的试剂
在一个实施方案中,将本发明的GCC激动剂制剂作为与一种或多种另外的治疗剂的组合治疗的部分进行施用而用于治疗溃疡性结肠炎。用于治疗溃疡性结肠炎的试剂与用于治疗克罗恩病的试剂部分重叠。可以与本发明的GCC激动剂制剂组合使用的一种或多种另外治疗剂的非限制性实例包括氨基水杨酸酯/盐(aminosalicylates)(含有5-氨基水扬酸(5-ASA)的药物)诸如柳氮磺吡啶、奥沙拉秦、氨水杨酸和巴柳氮。其他可用的治疗剂包括皮质类固醇诸如泼尼松和氢化可的松,免疫调节剂诸如硫唑嘌呤、6-巯基-嘌呤(6-MP)、细胞因子、白细胞介素和淋巴因子,以及抗TNF-α试剂,包括噻唑烷二酮类或格列酮类(glitazones)诸如罗格列酮和吡格列酮。在一个实施方案中,一种或多种另外的治疗剂包括全部环孢霉素A和6-MP或硫唑嘌呤用来治疗活跃的严重溃疡性结肠炎。
1.2.2.4 治疗便秘/肠易激综合症的试剂
在一个实施方案中,将本发明的GCC激动剂制剂作为与一种或多种另外的治疗剂的组合治疗的部分进行施用而用于治疗便秘,诸如与肠易激综合症相关的便秘。一种或多种另外的治疗剂的非限制性实例包括轻泻剂诸如SENNA、MIRALAX、Lactulose、PEG或聚波卡非钙(calcium polycarbophil))、粪便软化剂(stool softener)(诸如矿物油或多库酯钠)、膨胀剂(诸如欧车前亲水胶(METAMUCIL)或麸)、试剂诸如ZELNORM (也称为替加色罗)、和抗胆碱药物诸如BENTYL和LEVSIN。
1.2.2.5 用于治疗术后肠阻塞的试剂
在一个实施方案中,将本发明的GCC激动剂制剂作为与一种或多种另外的治疗剂的组合治疗的部分进行施用而用于治疗术后肠阻塞。一种或多种另外的治疗剂的非限制性实例包括ENTEREG (爱维莫潘;以前称为ado lor/ ADL 8-2698)、考尼伐坦和US 6,645,959中描述的相关试剂。
1.2.2.6 抗肥胖剂
在一个实施方案中,将本发明的GCC激动剂制剂作为与一种或多种另外的治疗剂的组合治疗的部分进行施用而用于治疗肥胖。一种或多种另外的治疗剂的非限制性实例包括11βHSD-I(11-β羟基类固醇脱氢酶1型)抑制剂,诸如BVT 3498,BVT 2733,3-(1-金刚烷基)-4-乙基-5-(乙基硫)-4H-1,2,4-三唑,3-(1-金刚烷基)-5-(3,4,5-三甲氧基苯基)-4-甲基-4H-1,2,4-三唑,3-金刚烷基-4,5,6,7,8,9,10,11,12,3a-十氢-1,2,4-三唑并[4,3-a][11]轮烯和WO01/90091、WOO 1/90090、WOO 1/90092和WO02/072084中公开的那些化合物;5HT拮抗剂诸如WO03/037871、WO03/037887等中的那些;5HTIa调节剂诸如卡比多巴、苄丝肼以及US6207699、WO03/031439等中公开的那些;5HT2c(血清素受体2c)激动剂,诸如BVT933、DPCA37215、IK264、PNU 22394、WAY161503、R-1065、SB 243213(Glaxo Smith Kline)和YM348以及US3914250、WO00/77010、WO02/36596、WO02/48124、WO02/10169、WO01/66548、WO02/44152、WO02/51844、WO02/40456和WO02/40457中公开的那些;5HT6受体调节剂,诸如WO03/030901、WO03/035061、WO03/039547等中的那些;酰基-雌激素,诸如油酰基-雌酮,公开于del Mar-Grasa,M.等人,Obesity Research,9:202-9(2001)和日本专利申请号JP2000256190中;厌食双环化合物诸如1426(Aventis)和1954(Aventis),以及WO00/18749、WO01/32638、WO01/62746、WO01/62747和WO03/015769中公开的化合物;CB1(大麻素-1受体)拮抗剂/逆激动剂诸如利莫那班(Acomplia;Sanofi)、SR-147778(Sanofi)、SR-141716(Sanofi)、BAY 65-2520(Bayer)和SLV 319(Solvay),以及专利公开
中公开的那些;CCK-A(胆囊收缩素-A)激动剂,诸如AR-R15849、GI 181771(GSK)、JMV-180、A-71378、A-71623和SR146131(Sanofi),以及US5739106中公开的那些;CNTF(纤毛神经营养因子),诸如GI-181771(Glaxo-SmithKline)、SRl 46131(Sanofi Synthelabo)、butabindide、PD 170,292和PD 149164(Pfizer);CNTF衍生物,诸如Axokine®(Regeneron)以及WO94/09134、WO98/22128和WO99/43813中公开的那些;二肽基肽酶IV(DP-IV)抑制剂,诸如异亮氨酸噻唑烷、缬氨酸吡咯烷(pyrrolidide)、NVP-DPP728、LAF237、P93/01、P 3298、TSL 225(色氨酰-1,2,3,4-四氢异喹啉-3-羧酸;由Yamada等人,Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540公开)、TMC-2A/2B/2C、CD26抑制剂、FE999011、P9310/K364、VIP 0177、SDZ 274-444、2-氰基吡咯烷和4-氰基吡咯烷如由Ashworth等人,Bioorg. & Med. Chem. Lett.,第6卷,No.22,pp 1163-1166和2745-2748(1996)中公开的,以及专利公开
中公开的化合物;生长激素促泌素(secretagogue)受体激动剂/拮抗剂,诸如NN703、海沙瑞林、MK-0677(Merck)、SM-130686、CP-424391(Pfizer)、LY 444,711(Eli Lilly)、L-692,429和L-163,255、以及诸如USSN 09/662448、US临时申请60/203335、US6358951、US2002049196、US2002/022637、WO01/56592和WO02/32888中公开的那些;H3(组胺H3)拮抗剂/逆激动剂,诸如噻普酰胺、3-(1H-咪唑-4-基)丙基N-(4-戊烯基)氨基甲酸酯)、clobenpropit、iodophenpropit、imoproxifan、GT2394(Gliatech)和A331440、O-[3-(1H-咪唑-4-基)丙醇]氨基甲酸酯(Kiec-Kononowicz,K.等人.,Pharmazie,55:349-55(2000)),含哌啶组胺H3-受体拮抗剂(Lazewska,D.等人.,Pharmazie,56:927-32(2001),二苯甲酮衍生物和相关化合物(Sasse,A.等人,Arch.Pharm.(Weinheim)334:45-52(2001)),取代的N-苯基氨基甲酸酯(Reidemeister,S.等人.,Pharmazie,55:83-6(2000)),和proxifan衍生物(Sasse,A.等人.,J. Med. Chem. 43:3335-43 (2000))以及组胺H3受体调节剂诸如WO02/15905、WO03/024928和WO03/024929中公开的那些;瘦素衍生物,诸如
中公开的那些;瘦素,包括重组人瘦素(PEG-OB,Hoffman La Roche)和重组甲硫氨酰基人瘦素(Amgen);脂酶抑制剂,诸如四氢泥泊司它汀(奥利司他/ Xenical®)、Triton WR1 339、RHC80267、泥泊司它汀、茶皂素、磷酸二乙基伞酮、FL-386、WAY-121898、Bay-N-3176、缬氨内酯、esteracin、抑脂酶免疫酮A(ebelactone A)、抑脂酶免疫酮B和RHC 80267以及专利公开WO01/77094、US4598089、US4452813、USUS5512565、US5391571、US5602151、US4405644、US4189438和US4242453中公开的那些;脂类代谢调节剂诸如山楂酸、高根二醇(erythrodiol)、熊果酸乌发醇、白桦脂酸、桦木醇等以及WO03/011267中公开的化合物;Mc4r(黑皮质素4受体)激动剂,诸如CHIR86036(Chiron),ME-10142,ME-10145和HS-131(Melacure)以及PCT公开号
中公开的那些;Mc5r(黑皮质素5受体)调节剂,诸如WO97/19952,WO00/15826,WO00/15790,US20030092041中公开的那些;黑色素-浓缩激素1受体(MCHR)拮抗剂,诸如T-226296(Takeda),SB 568849,SNP-7941(Synaptic),以及专利公开
中公开的那些;mGluR5调节剂诸如
等中公开的那些;血清素能试剂(serotoninergic agents),诸如芬氟拉明(例如Pondimin®(苯乙胺,N-乙基-α-甲基-3-(三氟甲基)-,盐酸)、罗宾斯)、右芬氟拉明(诸如Redux®(苯乙胺,N-乙基-α-甲基-3-(三氟甲基)-,盐酸)、Interneuron)和西布曲明((Meridia®, Knoll/Reductil™)包括外消旋混合物,如光学纯异构体(+)和(-),以及其药学可接受的盐、溶剂、水合物、笼形包合物和药物前体,包括其盐酸西布曲明一水合物盐以及US4746680、US4806570和US5436272、US20020006964、WOO 1/27068和WOO 1/62341中公开的化合物;NE(去甲肾上腺素)转运抑制剂,诸如GW 320659、despiramine、他舒普仑和诺米芬辛;NPY 1拮抗剂、诸如BIBP3226、J-115814、BIBO 3304、LY-357897、CP-671906、GI- 264879A以及
中公开的那些;NPY5(神经肽Y Y5)拮抗剂,诸如
以及专利公开
等人,J. Med.Chem. 43:4288-4312 (2000)中公开的那些化合物;阿片样物质拮抗剂,诸如纳美芬(REVEX®)、3-甲氧基纳曲酮、甲基纳曲酮、纳洛酮和纳曲酮(例如PT901;Pain Therapeutics,Inc.)以及US20050004155和WO00/21509中公开的那些;阿立新拮抗剂,诸如SB-334867-A以及专利公开
中公开的那些;PDE抑制剂(例如通过抑制磷酸二酯酶减缓环AMP(cAMP)和/或环GMP(cGMP)的降解的化合物,其可导致cAMP和cGMP的细胞内浓度的相对增加;
可能的PDE抑制剂主要是在由PDE3抑制剂组成的种类、由PDE4抑制剂组成的种类和/或由PDE5抑制剂组成的种类中被编号的那些物质,特别是可称为PDE3/4抑制剂的混合类型或PDE3/4/5抑制剂的混合类型的那些物质),诸如专利公开
中公开的那些,以及PDE5抑制剂(诸如RX-RA-69、SCH-51866、KT-734、维司力农、扎普司特、SKF-96231、ER-21355、BF/GP-385、NM-702和西地那非(Viagra™))、PDE4抑制剂(诸如依他唑酯、ICI63197、RP73401、imazolidinone(RO-20-1724)、MEM 1414(R1533/R1500;Pharmacia Roche)、登布茶碱、咯利普兰、氧格雷酯、硝喹宗、Y-590、DH-6471、SKF-94120、莫他匹酮、利沙齐农、吲哚利旦、奥普力农、阿替唑仑、KS-506-G、dipamfylline、BMY-43351、阿替唑仑、阿罗茶碱、非明司特、PDB-093、UCB-29646、CDP-840、SKF-107806、吡拉米司特、RS-17597、RS-25344-000、SB-207499、TIBENELAST、SB-210667、SB-211572、SB-211600、SB-212066、SB-212179、GW-3600、CDP-840、莫哌达醇、阿那格雷、异丁司特、氨力农、匹莫苯、西洛他唑、喹齐酮和N-(3,5-二氯吡啶-4-基)-3-环丙基甲氧基4-二氟甲氧基苯甲酰胺、PDE3抑制剂(诸如ICI153,100,bemorandane(RWJ 22867)、MCI-154、UD-CG 212、硫马唑、ampizone、西洛酰胺、卡巴折伦、匹罗昔酮、伊马唑旦、CI-930、氰胍佐旦、阿地本旦、沙特力农、SKF-95654、SDZ-MKS-492、349-U-85、emoradan、EMD-53998、EMD-57033、NSP-306、NSP-307、瑞维齐农、NM-702、WIN-62582和WIN-63291、依诺昔酮和米力农、PDE3/4抑制剂( 诸如苯芬群、曲喹辛、ORG-30029、扎达维林、L-686398、SDZ-ISQ-844、ORG-20241、EMD-54622和托拉芬群)以及其他PDE抑制剂(诸如长春西丁(vinpocetin)、罂粟碱、恩丙茶碱、西洛司特、依诺昔酮、己酮可可碱、罗氟司特、他达拉非(Cialis®)、茶碱和伐地那非(Levitra®);神经肽Y2(NPY2)激动剂包括但不限于:多肽YY及其片段和变体(例如YY3-36(PYY3-36)(N.Engl.J.Med.349:941,2003;IKPEAPGEDASPEELNRY YASLRHYLNL VTRQRY (SEQ ID NO:XXX))以及PYY激动剂诸如WO02/47712、WO03/026591、WO03/057235和WO03/027637中公开的那些;血清素重摄取抑制剂,诸如,帕罗西汀、氟西汀(Prozac™)、氟伏沙明、舍曲林、西酞普兰和丙咪嗪以及US6162805、US6365633、WO03/00663、WOO 1/27060和WOO 1/162341中公开的那些;甲状腺激素β激动剂,诸如KB-2611(KaroBioBMS)以及WO02/15845、WO97/21993、WO99/00353、GB98/284425、美国临时申请号60/183,223和日本专利申请号JP 2000256190中公开的那些;UCP-I(解偶联蛋白-1)、2或3激活剂,诸如植烷酸,4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸(TTNPB),视黄酸以及WO99/00123中公开的那些;β3(β肾上腺素能受体3)激动剂,诸如
中公开的那些;去甲肾上腺素能试剂包括但不限于安非拉酮(诸如Tenuate®(1-丙酮,2-(二乙基氨基)-1-苯基-,盐酸),Merrell)、右苯丙胺(也称为硫酸右苯丙胺、右旋苯丙胺(dexamphetamine)、硫酸右旋苯丙胺(dexedrine)、Dexampex、Ferndex、Oxydess II、Robese,Spancap #1)、马吲哚((或5-(对氯苯基)-2,5-二氢-3H-咪唑并[2,1-a]异吲哚-5-醇)诸如Sanorex®,Novartis或Mazanor®,WyethAyerst)、苯基丙醇胺(或苯甲醇,α-(1-氨基乙基)-,盐酸)、芬特明((或苯酚,3-[[4,5-二氢-1H-咪唑-2-基)乙基](4-甲基苯基)氨基],一盐酸)诸如Adipex-P®,Lemmon,FASTIN®,Smith-Kline Beecham和Ionamin®,Medeva),苯甲曲秦((或(2S,3S)-3,4-二甲基-2苯基吗啉L-(+)-酒石酸盐(1∶1))诸如Metra® (Forest)、Plegine® (Wyeth- Ay erst)、Prelu-2® (Boehringer Ingelheim)和Statobex® (Lemmon)、酒石酸非那明(诸如Thephorin®(2,3,4,9-四氢-2-甲基-9-苯基-1H-茚酚[2,1-c]吡啶L-(+)-酒石酸盐(1∶1)),Hoffmann-LaRoche)、甲基苯丙胺(诸如Desoxyn®,Abbot((S)-N,(α)-二甲基苯乙胺盐酸))和酒石酸苯甲曲秦(诸如Bontril® Slow-Release Capsules,Amarin(-3,4-二甲基-2-苯基吗啉酒石酸盐);脂肪酸氧化正调节物/诱导物诸如Famoxin®(Genset);单胺氧化酶抑制剂包括但不限于贝氟沙通、吗氯贝胺、溴法罗明、phenoxathine、乙磺普隆、befol、托洛沙酮、坡尔吲哚(pirlindol)、阿米夫胺、sercloremine、巴嗪普令、拉扎贝胺、米拉醋胺、卡罗沙酮以及由WO01/12176公开的其他某些化合物;和其他抗-肥胖剂诸如5HT-2激动剂、ACC(乙酰基-CoA羧化酶)抑制剂诸如WO03/072197中公开的那些、α-硫辛酸(α-LA)、AOD9604、食欲抑制剂诸如WO03/40107中公开的那些、ATL-962(Alizyme PLC)、苯佐卡因、盐酸苄非他明(Didrex)、墨角藻(focus vesiculosus)、BRS3(铃蟾肽受体亚型3)激动剂、安非他酮、咖啡因、CCK激动剂、壳聚糖、铬、缀合亚油酸、促肾上腺皮质素释放激素激动剂、去氢表雄酮、DGAT1(二酰基甘油酰基转移酶1)抑制剂、DGAT2(二酰基甘油酰基转移酶2)抑制剂、二羧酸盐转运蛋白抑制剂、麻黄、艾塞那肽-4(glp-1的抑制剂)FAS(脂肪酸合酶)抑制剂( 诸如浅蓝菌素和C75)、脂肪吸收抑制剂(诸如WO03/053451等中的那些)、脂肪酸转运蛋白抑制剂、天然水溶性纤维(诸如蚤草、车前草(plantago)、古柯(guar)、燕麦、果胶)、加兰肽拮抗剂、山羊豆属(galega)(山羊芸香、法国紫丁香(French Lilac))、藤黄果、石蚕属植物(germander)(欧洲苦草(teucrium chamaedrys))、葛瑞林抗体和葛瑞林拮抗剂(诸如WO01/87335和WO02/08250中公开的那些)、影响胰岛细胞分泌的多肽激素及其变体、诸如胰泌素/肠抑胃肽(GIP)/血管活性肠肽(VIP)/垂体腺苷酸环化酶激活肽(PACAP)/胰高血糖素样多肽II(GLP-II)/肠高血糖素/胰高血糖素基因家族和/或肾上腺髓质素/淀粉不溶素(amylin)/降钙素基因相关肽(CGRP)基因家族的激素,包括GLP-1(胰高血糖素样多肽1)激动剂(例如(1)艾塞那肽-4、(2)US20050130891中描述的那些GLP-1分子,包括以其C末端羧化或酰胺化形式存在的或以经修饰的GLP-I多肽存在的GLP-1(7-34)、GLP-1(7-35)、GLP-1(7-36)或GLP-1(7-37)及其修饰,包括US20050130891的第17-44段中描述的那些,和衍生自GLP-1-(7-34)COOH的衍生物,其使用具有下列通式的相应酰胺:R-NH-HAEGTFTSDVSYLEGQAAKEFIAWLVK-CONH2,其中R=H或具有1至10个碳原子的有机化合物。优选地,R是羧酸的残基。特别优选的是下列羧酸残基:甲酰基、乙酰基、丙酰、异丙酰基、甲基、乙基、丙基、异丙基、n-丁基、仲-丁基、叔-丁基)和glp-1(胰高血糖素样多肽-1)、糖皮质激素拮抗剂、葡萄糖载体抑制剂、生长激素促泌素(诸如US5536716中公开的和明确描述的那些)、白细胞介素-6(IL-6)及其调节剂(如WO03/057237等中的)、L-肉碱、Mc3r(黑皮质素3受体)激动剂、MCH2R(黑色素浓缩激素2R)激动剂/拮抗剂、黑色素浓缩激素拮抗剂、黑皮质素激动剂(诸如Melanotan II或WO 99/64002和WO 00/74679中描述的那些)、nomame herba、磷酸盐转动蛋白抑制剂、phytopharm化合物57(CP 644,673)、丙酮酸盐、SCD-I(硬脂酰-CoA去饱和酶-1)抑制剂、T71(Tularik,Inc.,Boulder CO)、托吡酯(Topimax®,指定为已显示增加体重减轻的抗惊厥药)、转录因子调节剂(诸如WO03/026576中公开的那些)、β-羟基类固醇脱氢酶-1抑制剂(β-HSD-I)、β-羟基-β-甲基丁酸酯、p57(Pfizer)、唑尼沙胺(Zonegran™,指定为已显示导致体重减轻的抗-癫痫药),和US20030119428的第20-26段中公开的试剂。
1.2.2.7 磷酸二酯酶抑制剂
在某些实施方案中,组合治疗的治疗方案包括施用一种或多种磷酸二酯酶(“PDE”)抑制剂。PDE抑制剂通过抑制磷酸二酯酶而减缓环AMP (cAMP)和/或环GMP (cGMP)的降解,其可以导致cAMP和/或cGMP的细胞内浓度相对增加。可用于和本发明的GCC激动剂组合使用的PDE抑制剂的非限制性实例包括PDE3抑制剂、PDE4抑制剂和/或PDE5抑制剂,特别是可以被命名为混合型PDE3/4抑制剂或混合型PDE3/4/5抑制剂的那些物质。此类PDE抑制剂的非限制性实例在下列专利申请和专利中描述:
。可举例提及的PDE5抑制剂为RX-RA-69、SCH-51866、KT-734、维司力农、扎普司特、SKF-96231、ER-21355、BF/GP-385、NM-702和西地那非(Viagra®)。可举例提及的PDE4抑制剂为RO-20-1724、MEM 1414(R1533/R1500;Pharmacia Roche)、登布茶碱、咯利普兰、氧格雷酯、硝喹宗、Y-590、DH-6471、SKF-94120、莫他匹酮、利沙齐农、吲哚利旦、奥普力农、阿替唑仑、KS-506-G、DIPAMFYLLINE、BMY-43351、阿替唑仑、阿罗茶碱、非明司特、PDB-093、UCB-29646、CDP-840、SKF-107806、PICLAMILAST、RS-17597、RS-25344-000、SB-207499、硫苯司特、SB-210667、SB-211572、SB-211600、SB-212066、SB-212179、GW-3600、CDP-840、莫哌达醇、阿那格雷、异丁司特、氨力农、匹莫苯、西洛他唑、喹齐酮和N-(3,5-二氯吡啶-4-基)-3-环丙基甲氧基4-二氟甲氧基苯甲酰胺。可举例提及的PDE3抑制剂为硫马唑、AMPIZONE、西洛酰胺、卡巴折伦、匹罗昔酮、伊马唑旦、CI-930、氰胍佐旦、阿地本旦、沙特力农、SKF-95654、SDZ-MKS-492、349-U-85、EMORADAN、EMD-53998、EMD-57033、NSP-306、NSP-307、瑞维齐农、NM-702、WIN-62582和WIN-63291、依诺昔酮和米力农。可通过举例说明提及的PDE3/4抑制剂是苯芬群BENAFENTRINE、曲喹辛、ORG-30029、扎达维林、L-686398、SDZ-ISQ-844、ORG-20241、EMD-54622和托拉芬群。其他PDE抑制剂包括:西洛司特、己酮可可碱、罗氟司特、他达拉非(Cialis®)、茶碱和伐地那非(Levitra®)、扎普司特(PDE5特异性的)。GCC激动剂。
1.2.2.8 镇痛剂
在某些实施方案中,组合治疗的方案包括施用一种或多种镇痛剂,例如镇痛化合物或镇痛多肽。在一些实施方案中,GCC激动剂制剂与一种或多种镇痛剂同时或相继施用。在其他实施方案中,GCC激动剂共价连接或结合至镇痛剂以产生治疗性缀合物。可用的镇痛剂的非限制性实例包括钙通道阻断剂、5HT受体拮抗剂(例如5HT3、5HT4和5HT1受体拮抗剂)、阿片样物质受体激动剂(洛哌丁胺、非多托秦和芬太尼)、NK1受体拮抗剂、CCK受体激动剂(例如,氯谷胺),NK1受体拮抗剂、NK3受体拮抗剂、去甲肾上腺素-血清素重摄取抑制剂(NSRI)、辣椒素和大麻受体激动剂以及sialorphin。各个种类的镇痛剂的进一步实例在本领域中是已知的。
在一个实施方案中,镇痛剂是选自sialorphin-相关多肽的镇痛多肽,包括包含氨基酸序列QHNPR (SEQ ID NO:239)的那些,包括:
。Sialorphin-相关多肽结合脑啡肽酶并且抑制脑啡肽酶介导的物质P和Met-正脑啡肽的降解。因此,其为脑啡肽酶的抑制剂的化合物或多肽是有用的镇痛剂,可将其与本文中描述的GCC激动剂一起施用或共价连接至GCC激动剂以形成治疗性缀合物。Sialophin和相关多肽描述于美国专利6,589,750;U.S.20030078200 A1;和WO 02/051435 A2中。
在另一个实施方案中,将本发明的GCC激动剂制剂作为与阿片样物质受体拮抗剂或激动剂的组合治疗方案的部分进行施用。在一个实施方案中,GCC激动剂与阿片样物质受体拮抗剂或激动剂经由共价键连接在一起。阿片样物质受体拮抗剂的非限制性实例包括纳洛酮、纳曲酮、甲基纳洛酮、纳美芬、cypridime、β富纳曲胺、纳洛肼、纳曲吲哚、nor-binaltorphimine、正脑啡肽五肽(HOE825;Tyr-D-Lys-Gly-Phe-L-高丝氨酸)、三甲丁酯(trimebutine)、血管活性肠多肽、胃泌素、胰高血糖素。阿片样物质受体激动剂的非限制性实例包括非多托秦、阿西马朵林和酮基环佐辛,以及WO03/097051和WO05/007626中描述的化合物、吗啡、地芬诺酯、氟雷法胺(H-Tyr-D-Ala-Phe(F)-Phe-NH2;WO 01/019849 A1)和洛哌丁胺。
可以连同本发明的GCC激动剂制剂用于组合治疗中的镇痛剂的进一步非限制性实例包括二肽Tyr-Arg (京都啡肽); 嗜铬粒蛋白-来源的多肽(CgA 47-66;参见例如,Ghia等人2004 Regulatory polypeptides 119:199); CCK受体激动剂诸如雨蛙肽; 芋螺毒素多肽;胸腺素的肽类似物(FR申请2830451); CCK(CCKa或CCKb)受体拮抗剂,包括氯谷胺和右氯谷胺(氯谷胺的R-同分异构体)(WO 88/05774); 5-HT4激动剂诸如替加色罗(Zelnorm®),莫沙必利,甲氧氯普胺,扎考必利,西沙必利,伦扎必利,苯并咪唑酮衍生物诸如BIMU 1和BIMU 8以及利沙必利;钙通道阻断剂诸如齐考诺肽和例如
中描述的相关化合物;NK1受体拮抗剂诸如阿瑞匹坦(Merck & Co Inc)、沃氟匹坦(vofopitant)、依洛匹坦(Pfizer,Inc.)、R-673(Hoffmann-La Roche Ltd)、SR-48968(Sanofi Synthelabo)、CP-122,721(Pfizer,Inc.)、GW679769(Glaxo Smith Kline)、TAK-637(Takeda/Abbot)、SR-14033和例如EP 873753 A1、US 20010006972 A1、US20030109417 A1、WO 01/52844 A1中描述的相关化合物(综述参见Giardina等人2003.Drugs 6:758);NK-2受体拮抗剂诸如奈帕度坦(Menarini Ricerche SpA)、沙瑞度坦(Sanofι-Synthelabo)、GW597599(Glaxo Smith Kline)、SR-144190(Sanofι-Synthelabo)和UK-290795(Pfizer Inc);NK3受体拮抗剂诸如奥沙奈坦(SR-142801;Sanofι-Synthelabo)、SSR-241586、他奈坦和例如
中描述的相关化合物;去甲肾上腺素-血清素重摄取抑制剂(NSRI)诸如米那普仑和WO 03/077897中描述的相关化合物;以及辣椒素受体拮抗剂诸如arvanil和WO 01/64212 A1中描述的相关化合物。
除了sialorphin-相关多肽外,镇痛多肽包括:AspPhe、内吗啡肽-1、内吗啡肽-2、痛稳素、达拉根(dalargin)、醋酸亮丙瑞林、齐考诺肽和物质P。
1.2.2.9 胰岛素和胰岛素调节剂
本文中描述的GCC激动剂肽可与胰岛素和相关化合物(包括灵长类动物、啮齿类动物或兔胰岛素,包括其生物活性变体,包括等位基因变体,更优选可以以重组形式获得的人胰岛素)一起用于组合治疗。人胰岛素的来源包括药学可接受的和无菌的制剂,诸如可从EliLilly (Indianapolis, Ind. 46285)获得的制剂,如Humulin™ (人胰岛素rDNA源)。参见,THE PHYSICIAN'S DESK REFERENCE,55.sup.th Ed. (2001) Medical Economics,Thomson Healthcare (公开了其他适当的人胰岛素)。
本文中描述的GCC肽可以与在注射后增强受试者的胰岛素效应或水平的试剂例如格列吡嗪和/或罗格列酮一起用于组合治疗。本文中描述的多肽和激动剂可与SYMLIN®(醋酸普兰林肽)和Exenatide®(合成的艾塞那肽-4;39个氨基酸的多肽)一起用于组合治疗。
1.2.2.10 抗高血压药
本文中描述的GCC激动剂肽可与抗高血压药一起用于组合治疗,抗高血压药包括但不限于:(1)利尿剂,诸如噻嗪类,包括氯噻酮、氯噻嗪、二氯苯磺胺、氢氟噻嗪、吲达帕胺、泊利噻嗪和氢氯噻嗪;髓袢利尿剂,诸如布美他尼、依他尼酸、呋塞米和托拉塞米;保钾药、诸如阿米洛利和氨苯蝶啶;碳酸酐酶抑制剂、渗透剂(诸如甘油)和醛固酮拮抗剂,诸如螺内酯、依普利酮等;(2)β-肾上腺素阻断剂诸如醋丁洛尔、阿替洛尔、倍他洛尔、贝凡洛尔、比索洛尔、波吲洛尔、卡替洛尔、卡维地洛、塞利洛尔、艾司洛尔、茚诺洛尔、美托洛尔、纳多洛尔、奈必洛尔、喷布洛尔、吲哚洛尔、普萘洛尔、索他洛尔、特他洛尔、替利洛尔和噻吗洛尔等;(3)钙通道阻断剂诸如氨氯地平、阿雷地平、阿折地 平、巴尼地平、贝尼地平、苄普地尔、cinaldipine、氯维地平、地尔硫卓、依福地平、非洛地平、戈洛帕米、伊拉地平、拉西地平、来米地平、乐卡地平、尼卡地平、硝苯地平、尼伐地平、尼莫地平、尼索地平、尼群地平、马尼地平、普拉地平和维拉帕米等;(4)血管紧张素转换酶(ACE)抑制剂诸如贝那普利;卡托普利;西那普利;西拉普利;地拉普利;依那普利;enalopril;福辛普利;咪达普利;赖诺普利;losinopril;莫昔普利;喹那普利;喹普利拉;雷米普利;培哚普利;perindropril;quanipril;螺普利;tenocapril;群多普利和佐芬普利等;(5)中性肽链内切酶抑制剂诸如奥马曲拉、cadoxatril和依卡曲尔、fosidotril、山帕曲拉、AVE7688、ER4030等;(6)内皮缩血管肽拮抗剂诸如替唑生坦、A308165和YM62899等;(7)血管扩张剂诸如肼苯哒嗪、可乐定、米诺地尔和烟醇等;(8)血管紧张素II受体拮抗剂诸如aprosartan、坎地沙坦、依普罗沙坦、厄贝沙坦、氯沙坦、奥美沙坦、普拉沙坦、他索沙坦、替米沙坦、缬沙坦和EXP-3137、FI6828K和RNH6270等;(9)α/β肾上腺素阻断剂诸如尼普地洛、阿罗洛尔和氨磺洛尔等;(10)α1阻断剂诸如特拉唑嗪、乌拉地尔、哌唑嗪、坦洛新、布那唑嗪、曲马唑嗪、多沙唑嗪、萘哌地尔、吲哚拉明、WHP 164和XENOlO等;(11)α2激动剂诸如洛非西定、噻美尼定、莫索尼定、利美尼定和guanobenz等;(12)醛固酮抑制剂等;和(13)血管生成素-2-结合剂诸如WO03/030833中公开的那些。可与本文中描述的多肽和激动剂组合使用的具体抗高血压药包括但不限于:利尿剂,诸如噻嗪类(例如,氯噻酮、环噻嗪(CAS RN 2259-96-3)、氯噻嗪(CAS RN 72956-09-3,其可如US2809194中所公开的进行制备)、二氯苯磺胺、氢氟噻嗪、吲达帕胺、泊利噻嗪、bendroflumethazide、methyclothazide、泊利噻嗪、trichlormethazide、氯噻酮、吲达帕胺、美托拉宗、喹乙宗、阿尔噻嗪(CAS RN 5588-16-9,其可如英国专利号902,658中所公开的进行制备)、苄噻嗪(CAS RN 91-33-8,其可如US3108097中所公开的进行制备)、布噻嗪(其可如英国专利号861,367中所公开的进行制备)和氢氯噻嗪)、髓袢利尿剂(例如布美他尼、依他尼酸、呋塞米和托拉塞米)、保钾药(例如阿米洛利和氨苯蝶啶(CAS Number 396-01- O))和醛固酮拮抗剂(例如螺内酯(CAS Number 52-01-7)、依普利酮等);β-肾上腺素阻断剂诸如胺碘酮(可达龙、Pacerone)、盐酸丁萘酮心安(CAS RN 31969-05-8, Parke-Davis)、醋丁洛尔(±N-[3-乙酰基-4-[2-羟基-3-[(1甲基乙基)氨基]丙氧基]苯基-丁酰胺或(±)-3′-乙酰基-4′-[2-羟基-3-(异丙基氨基)丙氧基]丁酰苯胺)、盐酸醋丁洛尔(例如Sectral®,Wyeth-Ayerst)、盐酸阿普洛尔(CAS RN 13707-88-5参见荷兰专利申请No.6,605,692)、阿替洛尔(例如Tenormin®,AstraZeneca)、盐酸卡替洛尔(例如Cartrol®Filmtab®, Abbott )、盐酸塞利洛尔(CAS RN 57470-78-7,也参见US4034009)、盐酸塞他洛尔(CAS RN 77590-95-5,也参见US4059622)、盐酸拉贝洛尔(例如Normodyne®,Schering)、盐酸艾司洛尔(例如Brevibloc®, Baxter),盐酸左倍他洛尔(例如Betaxon™Ophthalmic Suspension, Alcon)、盐酸左布诺洛尔(例如Betagan® Liquifϊlm® 和CCAP® Compliance Cap, Allergan)、纳多洛尔(例如纳多洛尔,Mylan)、普拉洛尔(CAS RN6673-35-4,也参见US3408387)、盐酸普萘洛尔(CAS RN 318- 98-9)、盐酸索他洛尔(例如Betapace AF™,Berlex)、噻吗洛尔(2-丙醇,1-[(1,1-二甲基乙基)氨基]-3-[[4-4(4-吗啉基)-1,2,5-噻二唑-3-基]氧]-,半水化物,(S)-,CAS RN 91524-16-2),马来酸噻吗洛尔(S)-I-[(1,1-二甲基乙基)氨基]-3-[[4-(4-吗啉基)-1,2,5-噻二唑-3-基]氧]-2-丙醇(Z)-2-丁烯二酸(1∶1)盐,CAS RN 26921-17-5)、比索洛尔(2-丙醇,1-[4-[[2-(1-甲基乙氧基)乙氧基]-甲基]苯氧基]-3-[(1-甲基乙基)氨基]-,(±),CAS RN 66722-44-9),延胡索酸比索洛尔(诸如(±)-1-[4-[[2-(1-甲基乙氧基)乙氧基]甲基]苯氧基]-3-[(1-甲基乙基)氨基]-2-丙醇(E)-2-丁烯二酸(2∶1)(盐),例如,Zebeta™,Lederle Consumer)、nebivalol(2H-1-苯并吡喃-2-甲醇,αα′-[亚胺基二(亚甲基)]二[6-氟-3,4-二氢-,CAS RN99200-09-6,也参见美国专利No.4,654,362)、盐酸环丙洛尔,诸如2-丙醇,1-[4-[2-(环丙基甲氧基)乙氧基]苯氧基]-3-[1-甲基乙基)氨基]-,盐酸盐,A.A.S. RN 63686-79-3)、盐酸右旋心得安(2-丙醇,1-[1-甲基乙基)-氨基]-3-(1-奈氧基)-盐酸(CAS RN 13071-11-9)、盐酸二醋洛尔(乙酰胺,N-[3-乙酰基-4-[2-羟基-3-[(1-甲基-乙基)氨基]丙氧基][苯基]-,一盐酸CAS RN 69796-04-9)、盐酸地来洛尔(苯甲酰胺,2-羟基-5-[1-羟基-2-[1-甲基-3-苯基丙基)氨基]乙基]-,一盐酸,CAS RN 75659-08-4)、盐酸己丙洛尔(2-丙醇,1-(2-环己基苯氧 基)-3-[(1-甲基乙基)氨基]-,盐酸盐CAS RN 59333-90-3)、硫酸氟司洛尔(苯甲酸,2-氟-3-[[2-[氨基羰基)氨基]-二甲基乙基]氨基]-2-羟基丙基酯,(+)-硫酸盐(1∶1)(盐),CAS RN 88844-73-9;盐酸美他洛尔(甲基磺酰胺,N-[4-[1-羟基-2-(甲基氨基)丙基]苯基-,一盐酸CAS RN 7701-65-7)、美托洛尔2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[1-甲基乙基)氨基]-;CAS RN 37350-58-6)、酒石酸美托洛尔(诸如2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[(1-甲基乙基)氨基]-,例如,Lopressor®, Novartis )、硫酸帕马洛尔(氨基甲酸,[2-[4-[2-羟基-3-[(1-甲基乙基)氨基]丙氧基]苯基-乙基]-,甲酯,(±)硫酸盐(盐)(2∶1),CAS RN 59954-01-7)、硫酸喷布洛尔(2-丙醇,1-(2-环戊基苯氧基)-3-[1,1-二甲基乙基)氨基]1,(S)-,硫酸盐(2∶1)(盐),CAS RN 38363-32-5)、普拉洛尔(乙酰胺,N-[4-[2-羟基-3-[(1-甲基乙基)氨基]-丙氧基]苯基]-,CAS RN 6673-35-4);盐酸甲硫心安(丙醇,1-[(1-甲基乙基)氨基]-3-[2-(甲基硫)-苯氧基]-,盐酸,(±),CAS RN 39832-43-4)、妥拉洛尔(苯甲酰胺,4-[2-[[2-羟基-3-(2-甲基苯氧基)-丙基]氨基]乙氧基]-,CAS RN38103-61-6)、波吲洛尔,茚诺洛尔,吲哚洛尔,普萘洛尔,特他洛尔和替利洛尔等;钙通道阻断剂诸如氨氯地平的苯磺酸盐(诸如3-乙基-5-甲基-2-(2-氨基乙氧基甲基)-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸苯磺酸盐,例如Norvasc®, Pfizer)、马来酸克仑硫卓(1,5-苯并硫氮杂卓-4(5H)-酮,3-(乙酰基氧)-8-氯-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-(2S-顺)-,(Z)-2-丁烯二酸酯(1∶1),也参见US4567195)、伊拉地平(3,5-吡啶二羧酸,4-(4-苯并呋吖基)-1,4-二氢-2,6-二甲基-,甲基1-甲基乙基酯,(±)-4(4-苯并呋吖基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸盐,也参见US4466972);尼莫地平(诸如异丙基(2-甲氧基乙基)1,4-二氢-2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶-二羧酸,例如Nimotop®, Bayer)、非洛地平(诸如乙基甲基4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸-,例如Plendil® Extended-Release, AstraZeneca LP)、尼伐地平(3,5-吡啶二羧酸,2-氰基-1,4-二氢-6-甲基-4-(3-硝基苯基)-,3-甲基5-(1-甲基乙基)酯,也参见US3799934)、硝苯地平(诸如3,5-吡啶二羧酸,1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-,二甲基酯,例如Procardia XL® Extended Release Tablets, Pfizer)、盐酸地尔硫卓(诸如1,5-苯并硫氮杂卓-4(5H)-酮,3-(乙酰基氧)-5[2-(二甲基氨基)乙基]-2,-3-二氢-2(4-甲氧基苯基)-,一盐酸盐,(+)-顺式,例如Tiazac®, Forest)、盐酸维拉帕米(诸如苯乙腈,(α)-[[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-(α)-(1-甲基乙基)盐酸,例如,Isoptin® SR, Knoll Labs)、盐酸替鲁地平(3,5-吡啶二羧酸,2-[(二甲基氨基)甲基]4-[2-[(1E)-3-(1,1-二甲基乙氧基)-3-氧-1-丙烯基]苯基]-1,4-二氢-6-甲基-,二乙基酯,一盐酸) CAS RN 108700- 03-4)、贝磷地尔(膦酸,[2-(2-苯氧基乙基)-1,3-丙烷-二基]二-,四丁基酯CAS RN 103486-79-9)、福司地尔(膦酸,[[4-(2-苯并噻唑基)苯基]甲基]-,二乙酯CAS RN 75889-62-2)、阿雷地平、阿折地平、巴尼地平、贝尼地平、苄普地尔、cinaldipine、氯维地平、依福地平、戈洛帕米、拉西地平、来米地平、乐卡地平、马来酸莫那匹尔(1-哌嗪丁酰胺,N-(6,11-二氢二苯并(b,e)噻庚英-11-基)4-(4-氟苯基)-,(+)-,(Z)-2-丁烯二酸酯(1∶1)(±)-N-(6,11-二氢二苯并(b,e)噻庚英-11-基)-4-(p-氟苯基)-1-哌嗪丁酰胺马来酸盐(1∶1) CAS RN 132046-06-1)、尼卡地平、尼索地平、尼群地平、马尼地平、普拉地平等;T-通道钙拮抗剂诸如米贝拉地尔;血管紧张素转换酶(ACE)抑制剂诸如贝那普利、盐酸贝那普利(诸如3-[[1-(乙氧基羰基)-3-苯基-(1S)-丙基]氨基]-2,3,4,5-四氢-2-氧-1H-1-(3S)-苯并氮杂卓-1-乙酸一盐酸,例如,Lotrel®,Novartis)、卡托普利(诸如1-[(2S)-3-巯基-2-甲基丙酰基]-L-脯氨酸,例如,卡托普利,Mylan, CAS RN 62571-86-2和US4046889中公开的其他试剂)、西那普利(和US4452790中公开的其他试剂)、阿拉普利(cetapril)(阿拉普利(alacepril),Eur. Therap. Res. 39:671(1986); 40:543 (1986)中公开的Dainippon),J. Cardiovasc. Pharmacol. 9:39 (1987)中公开的西拉普利(Hoffman-LaRoche)、地拉普利(地拉普利盐酸(2H-1,2,4-苯并噻二嗪-7-氨苯磺胺,3-二环[2.2.1]庚-5-烯-2-基-6-氯-3,4-二氢-,1,1-二氧化物CAS RN 2259-96-3);公开于US4385051)、依那普利(US4374829中公开的其他试剂)、enalopril、enaloprilat、福辛普利((诸如L-脯氨酸,4-环己基-1-[[[2-甲基-1-(1-氧丙氧基)丙氧基](4-苯基丁基)亚膦酰]乙酰基]-,钠盐,例如,Monopril, Bristol-Myers Squibb和US4168267中公开的其他试剂)、福辛普利钠(L-脯氨酸,4-环己基-1-[[(R)-[(1S)-2-甲基-1-(1-氧-丙氧基)丙氧基)、咪达普利、吲哚普利(Schering,J. Cardiovasc. Pharmacol.5:643, 655 (1983)中公开的)、赖诺普利(Merck)、losinopril、莫昔普利、盐酸莫昔普利(3-异喹啉羧酸,2-[(2S)-2-[[(1S)-1-(乙氧基羰基)-3-苯基丙基]氨基]-1-氧丙基]-1,2,3,4-四氢-6,7-二甲氧基-,一盐酸,(3S)- CAS RN 82586-52-5,喹那普利,喹普利拉,EP79022和Curr. Ther. Res. 40:74 (1986)中公开的雷米普利(Hoechsst)、培哚普利特丁胺(诸如2S,3aS,7aS-1-[(S)-N-[(S)-1-羧基丁基]丙氨酰]六氢-二氢吲哚羧酸,1-乙酯,具有叔-丁基胺(1∶1)的化合物,例如,Aceon®, Solvay)、培哚普利(Servier, Eur. J. clin.Pharmacol. 31 :519 (1987)中公开的)、quanipril(US4344949中公开的)、螺普利(Schering,Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986)中公开的)、tenocapril、群多普利、佐芬普利(和US4316906中描述的其他试剂)、伦唑普利(芬替普利,Clin. Exp. Pharmacol. Physiol. 10:131 (1983)中公开的)、匹伏普利、YS980、替普罗肽(缓激肽增强剂BPP9a CAS RN 35115-60-7)、BRL 36,378(Smith Kline Beecham,参见EP80822和EP60668)、MC-838(Chugai,参见CA. 102:72588v和Jap. J. Pharmacol. 40:373(1986), CGS 14824 (Ciba-Geigy,3-([1-乙氧基羰基-3-苯基-(1S)-丙基]氨基)-2,3,4,5-四氢-2-氧-1-(3S)-苯并氮杂卓-1乙酸HCl,参见英国专利No.2103614),CGS 16,617(Ciba-Geigy,3(S)-[[(1S)-5-氨基-1-羧基戊基]氨基]-2,3,4,5-四氢-2-氧-1H-1-苯并氮杂卓-1-乙酸,参见US4473575),Ru 44570(Hoechst,参见Arzneimittelforschung 34:1254(1985)),R 31-2201(Hoffman-LaRoche,参见FEBS Lett.165:201(1984))、CI925(Pharmacologist 26:243, 266 (1984))、WY-44221(Wyeth,参见J. Med. Chem. 26:394(1983)),和US2003006922(第28段落,US4337201,US4432971(膦酰胺酯)中公开的那些;中性肽链内切酶抑制剂诸如奥马曲拉(Vanlev®)、CGS 30440、cadoxatril和依卡曲尔、法西多曲(也称为aladotril或alatriopril)、山帕曲拉、mixanpril和格莫曲拉、AVE7688、ER4030和US5362727、US5366973、US5225401、US4722810、US5223516、US4749688、US5552397、US5504080、US5612359、US5525723、EP0599444、EP0481522、EP0599444、EP0595610、EP0534363、EP534396、EP534492、EP0629627中公开的那些;内皮缩血管肽拮抗剂诸如替唑生坦、A308165和YM62899等;血管扩张剂诸如肼苯哒嗪(阿普利素灵),可乐定(盐酸可乐定(1H-咪唑-2-胺,N-(2,6-二氯苯基)4,5-二氢-,一盐酸CAS RN 4205-91-8)、氯压定、米诺地尔(loniten)、烟醇(roniacol)、盐酸地尔硫卓(诸如1,5-苯并硫氮杂卓-4(5H)-酮,3-(乙酰基氧)-5[2-(二甲基氨基)乙基]-2,-3-二氢-2(4-甲氧基苯基)-,一盐酸,(+)-顺,例如Tiazac®, Forest)、二硝酸异山梨酯(诸如1,4:3,6-二酐-D-葡萄糖醇2,5-二硝酸盐例如,Isordil® Titradose®, Wyeth- Ayerst)、单硝酸异山梨酯(诸如1,4:3,6-二酐-D-葡萄糖醇-1,5-硝酸盐,有机硝酸盐,例如,Ismo®, Wyeth-Ayerst),硝酸甘油(诸如2,3丙烷三醇三硝酸盐,例如,Nitrostat® Parke- Davis)、盐酸维拉帕米(诸如苯乙腈,(±)-(α)[3-[[2-(3,4二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-(α)-(1-甲基乙基)盐酸,例如,Covera HS® Extended-Release, Searle)、卡波罗孟(其可如US3282938中所公开的制备)、clonitate(Annalen 1870 155)、氢普拉明(其可如DE2521113中所公开的制备)、利多氟嗪(其可如US3267104中所公开的制备);普尼拉明(其可如US3152173中所公开的制备)、丙帕硝酯(其可如法国专利No. 1,103,113中所公开的制备)、盐酸米氟嗪(1-哌嗪乙酰胺,3-(氨基羰基)4-[4,4-二(4-氟苯基)丁基]-N-(2,6-二氯苯基)-,二氢氯化物CAS RN 83898-67-3)、米克昔定(苯乙胺,3,4-二甲氧基-N-(1-甲基-2-吡咯烷亚基)-吡咯烷,2-[(3,4-二甲氧基苯乙基)亚胺基]-1-甲基-1-甲基-2-[(3,4-二甲氧基苯乙基)亚胺基]吡咯烷CAS RN 27737-38-8)、吗多明(1,2,3-噁二唑,5-[(乙氧基羰基)氨基]-3-(4-吗啉基)-,内盐CAS RN 25717-80-0)、单硝酸异山梨酯(D-葡糖醇,1,4:3,6-二酐-,5-硝酸盐CAS RN 16051-77-7)、丁四硝酯(1,2,3,4-丁烷四醇,四硝酸盐,(2R,3S)-rel-CAS RN 7297-25-8)、氯硝甘油(1,2-丙二醇,3-氯-,二硝酸盐(7CI, 8CI, 9CI) CASRN 2612-33-1)、双嘧达莫,2,2',2",2'"-[(4,8-二-1-哌啶基嘧啶并[5,4-d]嘧啶-2,6-二基)二氮川]四-CAS RN 58-32-2)、尼可地尔(CAS RN 65141-46-03-)、吡啶甲酰胺(N-[2-(硝氧)乙基]-尼索地平3,5-吡啶二羧酸,1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-,甲基2-甲基丙基酯CAS RN 63675-72-9)、硝苯地平3,5-吡啶二羧酸,1,4-二氢-2,6-二甲基-4-(2-硝基苯基)-,二甲基酯CAS RN 21829-25-4)、马来酸哌克昔林(哌啶,2-(2,2-二环己基乙基)-,(2Z)-2-丁烯二酸酯(1 :1) CAS RN 6724-53-4)、盐酸氧烯洛尔(2-丙醇,1-[(1-甲基乙基)氨基]-3-[2-(2-丙烯基氧)苯氧基]-,盐酸盐CAS RN 6452-73-9)、戊硝醇(1,3-丙二醇,2,2-二[(硝氧)甲基]-,一硝酸盐(酯)CAS RN 1607-17-6)、维拉帕米(苯乙腈,α-[3-[[2-(3,4-二甲氧基苯基)乙基]-甲基氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)- CASRN 52-53-9)等;血管紧张素II受体拮抗剂诸如,aprosartan、佐拉沙坦、奥美沙坦、普拉沙坦、FI6828K、RNH6270、坎地沙坦(1H-苯并咪唑-7-羧酸,2-乙氧基-1-[[2′-(1H-四唑-5-基)[1,1′-二苯基]4-基]甲基]- CAS RN 139481-59-7)、坎地沙坦环庚塞((+/-)-1-(环己基羰基氧)乙基-2-乙氧基-1-[[2′-(1H-四唑-5-基)二苯基-4-基]-1H-苯并咪唑羧酸盐,CAS RN145040-37-5,US5703110和US5196444)、依普罗沙坦(3-[1-4-羧基苯基甲基)-2-n-丁基-咪唑-5-基]-(2-噻吩基甲基)丙烯酸,US5185351和US5650650)、厄贝沙坦(2-n-丁基-3-[[2′-(1h-四唑-5-基)二苯基-4-基]甲基]1,3-二氮杂螺[4,4]壬-1-烯-4-酮,US5270317和US5352788)、氯沙坦(2-N-丁基-4-氯-5-羟基甲基-1-[(2′-(1H-四唑-5-基)二苯基-4-基)-甲基]咪唑,钾盐,US5138069,US5153197和US5128355)、他索沙坦(5,8-二氢-2,4-二甲基-8-[(2′-(1H-四唑-5-基)[1,r-二苯基]4-基)甲基]-吡啶并[2,3-d]嘧啶-7(6H)-酮,US5149699)、替米沙坦(4′-[(1,4-二甲基-2′-丙基-(2,6′-二-1H-苯并咪唑)-r-基)]-[1,1′-二苯基]-2-羧酸,CAS RN 144701-48-4, US5591762)、米法沙坦、阿比沙坦、缬沙坦(Diovan® (Novartis),(S)-N-戊酰-N-[[2′-(1H-四唑-5-基)二苯基-4-基)甲基]缬氨酸,US5399578)、EXP-3137(2-N-丁基-4-氯-1-[(2′-(1H-四唑-5-基)二苯基-4-基)-甲基]咪唑-5-羧酸,US5138069,US5153197和US5128355)、3-(2′-(四唑-5-基)-1,r-联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶,4′[2-乙基-4-甲基-6-(5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基]-苯并咪唑-1-基]-甲基]-1,r-二苯基]-2-羧酸,2-丁基-6-(1-甲氧基-1-甲基乙基)-2-[2′-)IH-四唑-5-基)二苯基-4-基甲基]guinazolin-4(3H)-酮,3-[2′-羧基二苯基-4-基)甲基]-2-环丙基-7-甲基-3H-咪唑并[4,5-b]吡啶,2-丁基-4-氯-1-[(2′-四唑-5-基)二苯基-4-基)甲基]咪唑-羧酸,2-丁基-4-氯-1-[[2′-(1H-四唑-5-基)[1,1′-二苯基]-4-基]甲基]-1H-咪唑-5-羧酸-1-(乙氧基羰基-氧)乙酯钾盐,2-丁基-4-(甲基硫)-1-[[2-[[[(丙基氨基)羰基]氨基]-磺酰](1,1′-二苯基)-4-基]甲基]-1H-咪唑-5-羧酸二钾盐,甲基-2-[[4-丁基-2-甲基-6-氧-5-[[2′-(1H-四唑-5-基)-[1,1′-二苯基]-4-基]甲基]-1-(6H)-嘧啶基]甲基]-3-噻吩羧酸酯,5-[(3,5-二丁基-1H-1,2,4-三唑-1-基)甲基]-2-[2-(1H-四唑-5-基苯基)]吡啶,6-丁基-2-(2-苯基乙基)-5[[2′-(1H-四唑-5-基)[1,1′-二苯基]-4-甲基]嘧啶-4-(3H)-酮D,L赖氨酸盐,5-甲基-7-n-丙基-8-[[2′-(1H-四唑-5-基)二苯基-4-基]甲基]-[1,2,4]-三唑并[1,5-c]嘧啶-2(3H)-酮,2,7-二乙基-5-[[2′-(5-四唑)二苯基-4-基]甲基]-5H-吡唑并[1,5-b][1,2,4]三唑钾盐,2-[2-丁基-4,5-二氢-4-氧-3-[2′-(1H-四唑-5-基)-4-二苯基甲基]-3H-咪唑[4,5-c]吡啶-5-基甲基]苯甲酸,乙酯,钾盐,3-甲氧基-2,6-二甲基-4-[[2′(1H-四唑-5-基)-1,1′-二苯基-4-基]甲氧基]吡啶,2-乙氧基-1-[[2′-(5-氧-2,5-二氢-1,2,4-恶二唑-3-基)二苯基-4-基]甲基]-1H-苯并咪唑-7-羧酸,1-[N-(2’-(1H-四唑-5-基)二苯基-4-基-甲基)-N-戊酰氨基甲基)环戊烷-1-羧酸,7-甲基-2n-丙基-3-[[2′1H-四唑-5-基)二苯基-4-基]甲基]-3H-咪唑并[4,5-6]吡啶,2-[5-[(2-乙基-5,7-二甲基-3H-咪唑并[4,5-b]吡啶-3-基)甲基]-2-喹啉基]苯甲酸钠,2-丁基-6-氯-4-羟基甲基-5-甲基-3-[[2′-(1H-四唑-5-基)二苯基-4-基]甲基]吡啶,2-[[[2-丁基-1-[(4-羧基苯基)甲基]-1H-咪唑-5-基]甲基]氨基]苯甲酸四唑-5-基)二苯基-4-基]甲基]嘧啶-6-酮,4(S)-[4-(羧基甲基)苯氧基]-N-[2(R)-[4-(2-磺胺苯酰)咪唑-1-基]辛酰基]-L-脯氨酸,1-(2,6-二甲基苯基)-4-丁基-1,3-二氢-3-[[6-[2-(1H-四唑-5-基)苯基]-3-吡啶基]甲基]-2H-咪唑-2-酮,5,8-桥亚乙基-5,8-二甲基-2-n-丙基-5,6,7,8-四氢-1-[[2′(1H-四唑-5-基)二苯基-4-基]甲基]-1H,4H-1,3,4a,8a-四氮杂环戊烯萘-9-酮,4-[1-[2′-(1,2,3,4-四唑-5-基)二苯-4-基)甲基氨基]-5,6,7,8-四氢-2-三氟甲磺酰基喹唑啉,2-(2-氯苯甲酰)亚胺基-5-乙基-3-[2′-(1H-四唑-5-基)二苯基-4-基)甲基-1,3,4-噻二唑啉,2-[5-乙基-3-[2-(1H-四唑-5-基)二苯基-4-基]甲基-1,3,4-噻唑啉-2-亚基]氨基羰基-1-环戊烯羧酸二钾盐,和2-丁基-4-[N-甲基-N-(3-甲基巴豆酰)氨基]-1-[[2’-(1H-四唑-5-基)二苯基-4-基]甲基]-1H-咪唑-5-羧酸1-乙氧基羰基氧乙基酯,专利公开
中公开的那些,以及其药学可接受的盐和酯;α/β肾上腺素阻断剂(adrenergic blockers)诸如尼普地洛、阿罗洛尔、氨磺洛尔、溴苄铵托西酸盐(CAS RN:61-75-6),甲磺酸双氢麦角胺(诸如ergotaman-3′,6′,18-三酮,9,-10-二氢-12′-羟基-2′-甲基-5′-(苯基甲基)-,(5′(α))-,单甲磺酸酯,例如,DHE 45® Injection, Novartis)、卡维地洛(诸如(±)-1-(咔唑-4-基氧)-3-[[2-(o-甲氧基苯氧基)乙基]氨基]-2-丙醇,例如,Coreg®, SmithKline Beecham)、拉贝洛尔(诸如5-[1-羟基-2-[(1-甲基-3-苯基丙基)氨基]乙基]水杨酰基酰胺一盐酸,例如,Normodyne®, Schering)、溴苄铵托西酸盐(Benzenemethanaminium,2-溴-N-乙基-N,N-二甲基-,与4-甲基苯磺酸的盐(1∶1) CAS RN 61-75-6)、甲磺酸酚妥拉明(苯酚,3-[[(4,5-二氢-1H-咪唑-2-基)甲基](4-甲基苯基)氨基]-,单甲磺酸(盐) CAS RN 65-28-1)、酒石酸苯哌乙噁哚(5H-1,3-二氧基[4,5-f]吲哚,7-[2-[4-(2-甲氧基苯基)-1-哌嗪]乙基]-,(2R,3R)-2,3-二羟基丁二酸(1∶1) CAS RN 5591-43-5)、盐酸佐勒汀(哌嗪,1-苯基4-[2-(1H-四唑-5-基)乙基]-,一盐酸(8Cl,9Cl)CAS RN 7241-94-3)等;α肾上腺素能受体阻断剂,诸如阿夫唑嗪(CAS RN:81403-68-1)、特拉唑嗪、乌拉地尔、哌唑嗪(Minipress®)、坦洛新、布那唑嗪、曲马唑嗪、多沙唑嗪、萘哌地尔、吲哚拉明、WHP 164、XENOlO、盐酸苯螺旋酮(其可如US3399192中所公开的制备)、proroxan(CAS RN 33743-96-3)和盐酸拉贝洛尔及其组合;α2激动剂诸如甲基多巴、甲基多巴HCL、洛非西定、噻美尼定、莫索尼定、利美尼定、guanobenz等;醛固酮抑制剂等;肾素抑制剂包括阿利吉仑(SPPlOO;Novartis/Speedel);血管生成素-2-结合剂诸如WO03/030833中公开的那些;抗-心绞痛剂诸如雷诺嗪(盐酸1-哌嗪乙酰胺,N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-,二盐酸CAS RN 95635- 56-6)、盐酸倍他洛尔(2-丙醇,1-[4-[2(环丙基甲氧基)乙基]苯氧基]-3-[(1-甲基乙基)氨基]-,盐酸CAS RN 63659-19-8)、盐酸布托丙茚(甲酮,[4-[3(二丁基氨基)丙氧基]苯基(2-乙基-3-吲嗪基)-,一盐酸CAS RN 62134-34-3)、马来酸盐1-哌嗪乙酸桂哌酯cinepazetmaleatel-Piperazine乙酸,4-[1-氧-3-(3,4,5-三甲氧基苯基)-2-丙烯基]-,乙基酯,(2Z)-2-丁烯二酸酯(1∶1) CAS RN 50679-07-7)、托西芬(苯磺酰胺,4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]- CAS RN 32295-184)、盐酸维拉帕米(苯乙腈,α-[3-[[2-(3,4-二甲氧基苯基)乙基]甲基氨基]丙基]-3,4-二甲氧基-α-(1-甲基乙基)-,一盐酸CASRN 152-114),吗多明(1,2,3-噁二唑,5-[(乙氧基羰基)氨基]-3-(4-吗啉基)-,内盐CAS RN25717-80-0)和盐酸雷诺嗪(1-哌嗪乙酰胺,N-(2,6-二甲基苯基)4-[2-羟基-3-(2-甲氧基苯氧基)丙基]-,二盐酸CAS RN 95635-56-6);托西芬(苯磺酰胺,4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]- CAS RN 32295-184);肾上腺素能兴奋剂诸如盐酸胍法辛(诸如N-脒基-2-(2,6-二氯苯基)乙酰胺盐酸盐,例如可获自Robins的Tenex®片剂);与氢氯噻嗪(诸如6-氯-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺酰胺1,1-二氧化物组合的甲基多巴-氢氯噻嗪(诸如左旋-3-(3,4-二羟基苯基)-2-甲基丙氨酸),例如,组合例如,可获自Merck的Aldoril®片剂)、甲基多巴-氯噻嗪(诸如6-氯-2H-1,2,4-苯并噻二嗪-7-磺酰胺1,1-二氧化物和如上所述的甲基多巴,例如,Aldoclor®, Merck)、盐酸可乐定(诸如2-(2,6-二氯苯基氨基)-2-咪唑啉盐酸和氯噻酮(诸如2-氯-5-(1-羟基-3-氧-1-异吲哚啉基)苯磺酰胺),例如,Combipres®, Boehringer Ingelheim)、盐酸可乐定(诸如2-(2,6-二氯苯基氨基)-2-咪唑啉盐酸,例如,Catapres®, Boehringer Ingelheim)、可乐定(1H-咪唑-2-胺,N-(2,6-二氯苯基)4,5-二氢- CAS RN 4205-90-7)、Hyzaar (Merck;氯沙坦和氢氯噻嗪的组合)、Co-Diovan(Novartis;缬沙坦和氢氯噻嗪的组合,Lotrel(Novartis;贝那普利和氨氯地平的组合)和Caduet(Pfizer;氨氯地平和阿托伐他汀的组合),和US20030069221中公开的那些试剂。
1.2.2.11 用于治疗呼吸病症的试剂
本文中描述的GCC激动剂肽可与用于治疗呼吸和其他病症的一种或多种下列试剂一起用于组合治疗,所述试剂包括但不限于:(1)β-激动剂包括但不限于:沙丁胺醇(PRO VENTIL®、S ALBUT AMOl®、VENTOLIN®)、班布特罗、比托特罗、克仑特罗、非诺特罗、福莫特罗、异他林(BRONKOSOL®、BRONKOMETER®)、奥西那林(ALUPENT®、METAPREL®)、吡布特罗(MAXAIR®)、瑞普特罗、利米特罗、沙美特罗、特布他林(BRETHAIRE®、BRETHINE®、BRICANYL®)、肾上腺素、异丙肾上腺素(ISUPREL®)、肾上腺素酒石酸氢盐(PRIMATENE®)、麻黄素、奥西那林、非诺特罗和异他林;(2)类固醇(steroids),包括但不限于倍氯米松、丙酸倍氯米松、倍他米松、布地奈德、bunedoside、布替可特、地塞米松、氟尼缩松、氟可丁、氟替卡松、氢化可的松、甲基泼尼松、莫米松、泼尼松龙、泼尼松、替泼尼旦、tixocortal、曲安西龙和醋酸曲安西龙;(3)β2-激动剂-皮质类固醇组合[例如,沙美特罗-氟替卡松(AD VAIR®)、福莫特罗-布地奈德(S YMBICORT®)];(4)白三烯D4受体拮抗剂/白三烯拮抗剂/LTD4拮抗剂(即,能够阻断、抑制、减少或另外地中断白三烯与Cys LTI受体之间的相互作用的任何化合物)包括但不限于:zafhiukast、孟鲁司特、孟鲁司特钠(SINGULAIR®)、普仑司特、伊拉司特、泊比司特、SKB-106,203和美国专利No.5,565,473中描述的被描述为具有LTD4拮抗活性的化合物; (5)5-脂氧合酶抑制剂和/或白三烯生物合成抑制剂[例如,齐留通和BAY1005(CA registry 128253-31-6)];(6)组胺H1受体拮抗剂/抗组胺剂(即,能够阻断、抑制、减少或另外地中断组胺与其受体之间的相互作用的任何化合物)包括但不限于:阿司咪唑、阿伐斯汀、安他唑啉、阿扎他定、氮卓斯汀、astamizole、溴苯那敏、马来酸溴苯那敏、卡比沙明、卡瑞斯汀、西替利嗪、氯苯那敏、马来酸氯苯那敏、西咪替丁氯马斯汀、赛克力嗪、赛庚啶、去羧乙氧基氯雷他定、右氯苯那敏、二甲茚定、苯海拉明、二苯拉林、琥珀酸多西拉敏、多西拉敏、依巴斯汀、乙氟利嗪、依匹斯汀、法莫替丁、非索非那定、羟嗪、羟嗪、酮替芬、左卡巴斯汀、左西替利嗪、左西替利嗪、氯雷他定、美克洛嗪、美吡拉敏、美喹他嗪、甲地嗪、米安色林、咪唑斯汀、诺柏斯汀、去甲阿司咪唑、noraztemizole、苯茚胺、非尼拉敏、哌香豆司特、异丙嗪、pynlamine、美吡拉敏、雷尼替丁、替美斯汀、特非那定、异丁嗪、曲吡那敏和曲普利啶;(7)抗胆碱能药包括但不限于:阿托品、苯扎托品、比哌立登、flutropium、莨菪碱(例如Levsin®; Levbid®; Levsin/SL®、Anaspaz®、Levsinex timecaps®、NuLev®)、ilutropium、异丙托铵、异丙托溴铵、甲基东莨菪碱、奥昔布宁、利喷西平、东莨菪碱和噻托溴铵;(8)抗咳嗽药,包括但不限于:右美沙芬、可待因和氢吗啡酮;(9)解充血药包括但不限于:假麻黄素和苯丙醇胺;(10)祛痰药包括但不限于:guafenesin、guaicolsulfate、萜二醇(terpin)、氯化铵、甘油guaicolate和碘化甘油;(11)支气管扩张药包括但不限于:茶碱和氨茶碱;(12)抗炎药包括但不限于:氟比洛芬,双氯芬酸、吲哚美辛、酮洛芬、S-酮洛酚、替诺昔康;(13)PDE(磷酸二酯酶)抑制剂包括但不限于本文中公开的那些; (14)重组人源化单克隆抗体[例如奥马珠单抗(也称为奥马佐单抗),rhuMab和他利珠单抗];(15)人源化肺表面活性剂包括表面活性蛋白SP-B、SP-C或SP-D的重组形式[例如SURFAXIN®,以前称为dsc-104(Discovery Laboratories)],(16)抑制上皮钠通道(ENaC)的试剂诸如阿米洛利和相关化合物;(17)用于治疗肺部感染的抗微生物剂诸如阿昔洛韦,阿米卡星、阿莫西林、多西环素、三甲氧苄二氨嘧啶磺胺甲基异恶唑、两性霉素B、阿奇霉素、克拉霉素、罗红霉素、克拉霉素、头孢菌素类(头孢西丁、头孢美唑等)、环丙沙星、乙胺丁醇、庆大霉素、更昔洛韦、亚胺培南、异烟肼、伊曲康唑、青霉素、利巴韦林、利福平、利福布汀、金刚烷胺、金刚乙胺、链霉素、妥布霉素和万古霉素;(18)通过Ca++依赖性氯通道激活氯分泌的试剂(诸如嘌呤型受体(P2Y(2)激动剂);(19)降低痰粘度的试剂,诸如人重组DNA酶1,(Pulmozyme®);(20)非类固醇抗炎药(阿西美辛、对乙酰氨基酚、乙酰水杨酸、阿氯芬酸、阿明洛芬、阿扎丙宗、阿司匹林、苯噁洛芬、bezpiperylon、布氯酸、卡洛芬、环氯茚酸、双氯芬酸、双氯芬酸、二氟尼柳、diflusinal、依托度酸、芬布芬、芬布芬、芬氯酸、芬克洛酸、非诺洛芬、芬替酸、非普拉宗、氟芬那酸、氟苯柳、氟苯柳、氟洛芬、氟比洛芬、氟比洛芬、呋罗芬酸、异丁芬酸、布洛芬、吲哚美辛、吲哚美辛、吲哚洛芬、伊索克酸、伊索昔康、酮洛芬、酮洛芬、酮咯酸、甲氯芬那酸、甲氯芬那酸、甲芬那酸、甲芬那酸、咪洛芬、莫非布宗、萘丁美酮奥沙普秦、萘普生、萘普生、尼氟酸、奥沙普秦、oxpinac、羟布宗、非那西丁、保泰松、保泰松、吡罗昔康、吡罗昔康、吡洛芬、普拉洛芬、舒多昔康、替诺昔康、柳氮磺吡啶、舒林酸、舒林酸、舒洛芬、噻洛芬酸、硫平酸、硫噁洛芬、托芬那酸、托美丁、托美丁、齐多美辛、佐美酸和佐美酸;和(21)雾化抗氧化剂治疗剂诸如S-亚硝基谷胱甘肽。
1.2.2.12 抗-糖尿病剂
可将本文中描述的GCC激动剂肽与一种或多种抗-糖尿病剂一起用于组合治疗,所述抗-糖尿病剂包括但不限于:PPARγ激动剂诸如格列酮类(例如,WAY-120,744、AD 5075、巴格列酮、环格列酮、达格列酮(CP-86325、Pfizer)、恩格列酮(CP-68722、Pfizer)、isaglitazone(MIT/J&J)、MCC-555(US5594016中公开的Mitsibishi)、吡格列酮(诸如Actos™吡格列酮;Takeda)、罗格列酮(Avandia™;Smith Kline Beecham)、马来酸罗格列酮、曲格列酮(Rezulin®,于US4572912中公开的)、利格列酮(CS-O11,Sankyo)、GL-262570(Glaxo Welcome)、BRL49653(于WO98/05331中公开的)、
中公开的化合物及其药学可接受的盐;双胍类诸如盐酸二甲双胍(N,N-二甲基亚胺基二碳酸亚胺二酰胺盐酸盐,诸如Glucophage™,Bristol-Myers Squibb);盐酸二甲双胍和格列本脲,诸如Glucophage™,Bristol-Myers Squibb);丁福明(亚胺基二碳酸亚胺二酰胺,N-丁基-);etoformine(1-丁基-2-乙基双胍,ScheringA.G.);其他二甲双胍盐形式(包括其中盐选自醋酸盐、苯甲酸盐、柠檬酸盐、ftimarate、双羟萘酸盐、氯苯氧乙酸盐、羟乙酸盐、palmoate、天冬氨酸、甲磺酸盐(methanesulphonate)、马来酸盐、对氯苯氧异丁酸盐、甲酸盐(formate)、乳酸盐、琥珀酸盐、硫酸盐、酒石酸盐、环己烷羧酸盐、己酸盐、辛酸盐、癸酸盐、十六酸盐、十八酸盐、苯磺酸盐、三甲基苯甲酸盐、对甲苯磺酸盐、金刚烷甲酸盐、乙醛酸、谷氨酸盐、吡咯烷酮羧酸盐、萘磺酸盐、1-葡萄糖磷酸盐、硝酸盐、亚硫酸盐、连二硫酸盐和磷酸盐)和苯乙双胍;蛋白酪氨酸磷酸酶-IB(PTP-IB)抑制剂,诸如
中描述的那些,及其药学可接受的盐和酯;磺酰脲例如醋酸己脲(例如醋磺己脲,Eli Lilly)、磺胺丁脲、氯磺丙脲(例如Diabinese®,Pfizer)、格列胺脲(Pfizer)、格列齐特(例如Diamcron,Servier Canada Inc)、格列美脲(例如US4379785中公开的,诸如Amaryl,Aventis)、格列戊脲、格列吡嗪(例如Glucotrol或Glucotrol XL Extended Release,Pfizer)、格列喹酮、格列索脲、格列本脲/优降糖(glibenclamide)(例如Micronase或Glynase Prestab,Pharmacia & Upjohn和Diabeta,Aventis)、妥拉磺脲(例如Tolinase)和甲苯磺丁脲(例如Orinase)及其药学可接受的盐和酯;氯茴苯酸类(meglitinides)诸如瑞格列奈(例如Pranidin®, Novo Nordisk)、KAD1229(PF/Kissei)和那格列胺(例如Starlix®, Novartis)及其药学可接受的盐和酯;α葡糖苷水解酶抑制剂(或葡糖苷抑制剂)诸如阿卡波糖(例如US4904769中公开的Precose™,Bayer)、米格列醇(诸如US4639436中公开的GLYSET™,Pharmacia & Upjohn)、卡格列波糖(甲基6-脱氧-6-[(2R,3R,4R,5S)-3,4,5-三羟基-2-(羟基甲基)哌啶基]-α-D-吡喃葡萄糖苷,Marion Merrell Dow)、伏格列波糖(Takeda)、脂解素、乙格列酯、普那米星-Q、salbostatin、
(聚胺)中公开的化合物;α-淀粉酶抑制剂诸如淀粉酶抑肽、萃他丁和A1-3688以及US4451455、US4623714和US4273765中公开的化合物;SGLT2抑制剂,包括US6414126和US6515117中公开的那些;aP2抑制剂诸如US6548529中公开的那些;胰岛素促泌剂诸如利诺格列、A-4166、毛喉素、二丁基cAMP、异丁基甲基黄嘌呤(IBMX),及其药学可接受的盐和酯;脂肪酸氧化抑制剂,诸如氯莫克舍和乙莫克舍,及其药学可接受的盐和酯;A2拮抗剂,诸如咪格列唑、伊格列哚、德格列哚、咪唑克生、earoxan和氟洛克生,及其药学可接受的盐和酯;胰岛素和相关化合物(例如胰岛素模拟物)诸如biota、LP-100、novarapid、地特胰岛素、赖脯胰岛素、甘精胰岛素、锌胰岛素注射液(缓慢的和超缓慢的)、Lys-Pro胰岛素、GLP-I(1-36)酰胺、GLP-I(73-7)(insulintropin,公开于US5614492)、LY-315902(Lilly)、GLP-I(7-36)-NH2)、AL-401(Autoimmune)、US4579730、US4849405、US4963526、US5642868、US5763396、US5824638、US5843866、US6153632、US6191105和WO 85/05029中公开的某些化合物以及灵长类动物、啮齿类动物或兔胰岛素包括其生物活性变体,包括等位基因变体,更优选可以以重组形式获得的人胰岛素(人胰岛素的来源包括药学可接受的和无菌的制剂诸如可从Eli Lilly(Indianapolis, Ind. 46285)获得的人胰岛素如Humulin™ (人胰岛素rDNA来源),也参见THE PHYSICIAN'S DESKREFERENCE, 55.sup.th Ed. (2001) Medical Economics, Thomson Healthcare (公开了其他适当的人胰岛素);非-噻唑啉二酮类诸如JT-501和法格立他扎(GW-2570/GI-262579)及其药学可接受的盐和酯;PPARα/γ双激动剂诸如AR-HO39242 (Aztrazeneca)、GW-409544(Glaxo-Wellcome)、BVT-142、CLX-0940、GW-1536、GW-1929、GW-2433、KRP-297 (Kyorin Merck;5-[(2,4-二氧噻唑烷基)甲基]甲氧基-N-[[4-(三氟甲基)苯基]甲基]苯甲酰胺)、L-796449、LR-90、MK-0767(Merck/Kyorin/Banyu)、SB 219994、莫格列他(BMS)、替格列扎(Astrazeneca)、瑞格列扎(JTT-501)以及
2000年9月18日提交的美国申请系列No.09/664,598、Murakami等人Diabetes 47, 1841-1847 (1998)中公开的那些,及其药学可接受的盐和酯;其他胰岛素增敏药物;VPAC2受体激动剂;GLK调节剂,诸如WO03/015774中公开的那些;类视色素调节剂诸如WO03/000249中公开的那些;GSK 3β/GSK 3抑制剂诸如4-[2-(2-溴苯基)-4-(4-氟苯基-1H-咪唑-5-基]吡啶和WO03/024447、WO03/037869、WO03/037877、WO03/037891、WO03/068773、EP1295884、EP1295885等中公开的那些化合物等;糖原磷酸化酶(HGLPa)抑制剂诸如CP-368,296、CP-316,819、BAYR3401和WOO 1/94300、WO02/20530、WO03/037864中公开的化合物以及其药学可接受的盐或酯;ATP消耗促进剂诸如WO03/007990中公开的那些;TRB3抑制剂;辣椒素受体配体诸如WO03/049702中公开的那些;降血糖试剂诸如WO03/015781和WO03/040114中公开的那些;糖原合酶激酶3抑制剂诸如WO03/035663中公开的那些,试剂例如WO99/51225、US20030134890、WO01/24786和WO03/059870公开的那些;胰岛素-反应DNA结合蛋白-1(IRDBP-I),如WO03/057827等中公开的;腺苷A2拮抗剂诸如WO03/035639、WO03/035640等中公开的那些;PPARδ激动剂诸如GW 501516、GW 590735以及JP10237049和WO02/14291中公开的化合物;二肽基肽酶IV(DP-IV)抑制剂,诸如异亮氨酸噻唑烷、NVP-DPP728A (1-[[[2-[(5-氰基嘧啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷,由Hughes等人,Biochemistry, 38(36), 11597-11603, 1999公开的)、P32/98、NVP-LAF-237、P3298、TSL225(色氨酰-1,2,3,4-四氢-异喹啉-3-羧酸,由Yamada等人,Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540公开的),缬氨酸吡咯烷、TMC-2A/2B/2C、CD-26抑制剂、FE999011、P9310/K364、VIP 0177、DPP4、SDZ 274-444、2-氰基吡咯啶和4-氰基吡咯啶,如由Ashworth等人,Bioorg. & Med. Chem. Lett.,第6卷,No.22,pp 1163-1166和2745-2748(1996)公开的,和 (公开的化合物包括
中公开的化合物;GLP-I激动剂诸如艾塞那肽-3和艾塞那肽-4(包括称为Exenatide®的39个氨基酸多肽的合成的艾塞那肽-4),和US2003087821和NZ 504256中公开的化合物,及其药学可接受的盐和酯;肽包括安林肽和Symlin®(醋酸普兰林肽)的肽;和糖激酶激活剂诸如US2002103199(稠合的杂芳族化合物)和WO02/48106(异吲哚啉-1-酮-取代的丙酰胺化合物)中公开的那些。
本文提到的所有专利、专利申请和出版物通过引用完整地并入本文。然而,当含有明确定义的专利、专利申请或出版物通过引用并入时,应当理解,那些明确定义适用于它们存在于其中的并入的专利、专利申请或出版物,且不适用于该申请文本的其他部分。在冲突的情况下,以本说明书(包括定义)为准。不承认本文引用的参考文献是本发明的现有技术。
应当理解,尽管本发明结合其优选具体实施方案已进行描述,但前述描述意在说明而非限制本发明的范围。本领域技术人员将理解,可以进行各种变化,且对应物在不脱离本发明范围的情况下可以进行取代,且进一步地,其他方面、优点和改变对于本发明涉及领域的技术人员而言是显而易见的。
实施例
实施例1:SP-304的侧链保护的片段的制备(如WO 2012/118972)
Fmoc-AA-OH连接至2-ClTrt树脂
将2-ClTrt树脂(10 g,取代率(substitution) =1.0 mmol/g树脂)悬浮在100 mL二氯甲烷(DCM)中持续5分钟,然后排空。使用在80 mL DCM中的1.5当量的Fmoc-氨基酸和1.7当量的二异丙基乙胺(DIEA)(用最小量的二甲基甲酰胺(DMF)来完全溶解氨基酸)进行酯化反应,持续2小时。用60 mL DCM洗涤得到的树脂,且用60 mL DIEA /甲醇(1:9,v/v)溶液进行封端,持续30分钟。然后将负载的树脂用DCM (6倍体积)洗涤2次,用DMF(6倍体积)洗涤3次且用甲基叔丁基醚(MTBE)(6倍体积)洗涤3次,且在高真空下干燥。通过Fmoc释放试验确定Fmoc-保护树脂的取代率。最后,将Fmoc基团用在DMF (10倍体积)中5%哌啶、1% 1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)和1% N-羟基苯并三唑(HOBt)的混合物进行脱保护2次,洗涤树脂,且在高真空下干燥以得到用于肽合成的最终树脂。实验结果列于下表VIII中。
表VIII. H-Gly-2ClTrt和H-Leu-2ClTrt树脂的制备
。侧链保护的片段A和B的合成
将H-Gly-2-ClTrt树脂或H-Leu-2-ClTrt树脂悬浮在DMF (10倍体积)中持续20分钟,然后排空。得到的树脂用DMF洗涤(10倍体积),持续5分钟。使用标准Fmoc化学进行链装配。通常,将1.5当量的Fmoc氨基酸和1.5当量的HOBt溶解在DMF(4.5倍体积)中,随后添加1.5当量的DIEA。然后,用冰水浴将得到的溶液冷却至低于5℃,且通过添加1.5当量的HBTU活化。将DCM(1.5倍体积)添加至树脂,然后添加活化的Fmoc氨基酸溶液。将得到的混合物在室温下搅拌2小时,且通过Kaiser试验监测酰化反应的完成。如果Kaiser试验表明2小时后存在未反应的胺,那么需要以相同方案使用1.0当量的Fmoc氨基酸、1.0当量的HOBt和1.0当量的DIEA进行重新偶联。通常通过用乙酸酐/吡啶/ DMF溶液的混合物乙酰化未反应的胺而实现封端。通过以从C到N-末端的顺序用对应的Fmoc氨基酸衍生物重复上述封端程序而装配肽序列。通过以DCM/DMF方案使用2.0当量的Fmoc-Cys(Trt)-OH或Fmoc-Cys(Acm)-OH、2.0当量的HOBt和2.0当量的DIC原位活化而实现Fmoc-Cys(Trt)-OH或Fmoc-Cys(Acm)-OH残基的偶联以使得半胱氨酸的外消旋作用最小化。
合成步骤完成之后,用DMF(10倍体积)、MTBE(10倍体积)、DMF(10体积,3次)和MTBE(10体积,3次)彻底洗涤肽树脂,且随后在真空烘箱中干燥至恒重。
使用1%TFA/DCM (10倍体积)从树脂上裂解侧链保护的肽,持续3次,每次5分钟,且每次将裂解级分收集到吡啶上(在每个裂解级分中与TFA 1:1体积比)。肽树脂用DCM(7.5倍体积)洗涤。组合级分,且在真空下浓缩至初始体积的10%,且将得到的溶液用乙醇(3倍体积)重构,且浓缩至初始体积的50%。最后,通过添加水(1倍体积)沉淀肽。通过真空过或离心收集固体,且用水洗涤两次。将产物在真空中干燥至恒重,且进行HPLC和ES-MS分析。实验结果提供于下表IX中。
表IX. A和B片段的制备
*计算值=平均分子质量;实测值=通过ES-MS测量的单一同位素质量。
实施例2:SP-304的片段在溶液中的缩合(如WO 2012/118972)
片段C:H-AA15-16OtBu (1-1)的合成
将Fmoc-Cys(Acm)-OH (124.38克, 0.3 mol)、H-Leu-OtBu.HCl (67.12克, 0.3 mol)、和HOBt (40.54克, 0.3 mol)在DMF (600 mL)中的溶液冷却至-5℃。添加2-[1H-苯并三唑-1-基]-1,1,3,3-四甲基脲六氟磷酸酯(HBTU) (113.79克, 0.3 mol),且完全溶解。在良好搅拌下在相同温度经105分钟期间逐滴添加DIEA (183.1 mL, 1.05 mol),将混合物的pH保持在6和7之间。在0℃继续搅拌15分钟,且用TLC监测反应。用乙酸乙酯(EtOAc)(600 mL)和5% H3PO4 (300 mL)稀释反应混合物。分出有机层,且用EtOAc(600 mL)萃取水层。用5%H3PO4 (2次)、H2O (1次)、饱和的NaHCO3 (3次)、H2O (2次)、和盐水(2次)洗涤组合的萃取液。溶液用无水MgSO4干燥,过滤,且在真空中蒸发至干燥。将产物从石油醚/EtOAc (3:1)重结晶且干燥:166.75克(得率95.0%,纯度99.0%)。
在搅拌下将Fmoc-Cys(Acm)-Leu-OtBu (166.75克, 0.277 mol)溶解在10%哌啶/DCM溶液(810 mL)中。用TLC监测反应。在3小时内完成反应后,使用旋转蒸发仪去除溶剂和挥发性物质。获得的油状物质用石油醚研磨,以通过倾析以去除副产物。将残留物糖浆投入EtOAc中,用NaH2PO4/Na2HPO4 (pH=6)的混合溶液、然后饱和的NaHCO3、纯H2O和盐水洗涤。用无水MgSO4干燥有机层。溶剂和挥发性物质的蒸发得到油状产物H-Cys(Acm)-Leu-OtBu (1-1) (73.23克,得率73.1%,纯度:98.0%)。
片段B-C:HAA7-16OtBu (2-3)的合成
将Fmoc-AA7-14OH (1׳) (198.3克,124.0 mmol)、H-AA15-16OtBu (1-1) (52.3克,148.8 mmol)和Cl-HOBt (21.0克,124.0 mmol)在DMF (2500 mL)中的溶液冷却至-5℃。添加HBTU (51.7克,136.4 mmol),且完全溶解。然后在搅拌下添加DIEA (54.1 mL, 310mmol),将混合物的pH保持在6和7之间。在0-5℃继续搅拌30分钟。使反应混合物缓慢升温至20-27℃且继续搅拌1个半小时。然后,将混合物倒入预冷(10-20℃)的0.5 N HCl水溶液(20L)。悬浮液在20-25℃下储存45分钟。通过将悬浮液过滤通过中间孔隙率的烧结玻璃漏斗且随后用0.5N HCl水溶液(3500 mL,2次)、纯水(3500 mL)、饱和的NaHCO3水溶液(3500 mL,2次)和纯水(3500 mL,2次)和二乙醚(2000 mL,2次)洗涤而收集固体。最后,在高真空下在室温在干燥器中干燥湿的粗肽FmocAA7-16OtBu,得到产物238.22克(纯度85.27%,得率98.9%)。
向FmocAA7-16OtBu (234.88 gm, 120.9 mmol)的DMF (2350 mL)溶液中加入哌啶(123 mL, 1245.2mmol)。将反应混合物在25℃搅拌2.5小时,然而将混合物倾入n-己烷(20.0L)中。得到的粘性沉淀物用n-己烷(3500mL, 7次)研磨。将粘性沉淀物溶于最少量的DMF (2000mL),然而倾入0.5N HCl aq. (10 vol.)中。通过过滤收集固体,用纯水洗涤(3次),然而用乙醚(3000mL, 3次)洗涤,在空气中干燥过夜,然而真空干燥得到产物(2-3)(HAA7-16OtBu) (183.67gm, 纯度: 68.4%,得率%: 88.33%, ES-MS, MW: 计算值=1721.2,实测值=1719.84)。
完全保护的A-B-C:BocAA1-16OtBu (3-3)的合成
将HAA7-16OtBu (2-3) (183.67克,106.71 mmol)、BocAA1-6-OH (2׳) (157.65克,106.71 mmol)、和6-Cl-HOBt (18.141克,106.71 mmol)在DMF (3 L)中的溶液冷却至-3至0℃。添加HBTU (44.523克,117.38 mmol),且完全溶解。然后在搅拌下添加DIEA(55.8 mL,320.13 mmol),将混合物的pH保持在6。在-5至0℃继续搅拌20分钟。使反应混合物缓慢升温至25 ℃且继续搅拌2.5小时,随后进一步添加HBTU (4.048克,10.671 mmol)和DIEA (2mL)。再继续搅拌1.5小时。将得到的混合物倒入MeOH (15 L)中,收集沉淀物,且用MeOH/DMF混合物(5:1, v/v) (2次,3 L)、0.1N HCl (3 L,2次)、饱和的NaHCO3 (2次)、纯水(3次)、二乙醚(2次)洗涤,且在真空下干燥,得到产物BocAA1-16OtBu(3-3) (278.0克,得率82.0%。注:在脱保护后测定纯度)。
部分保护的线性SP-304:HAA1-16OH (4-4)的合成
在氮气下将TFA/TIS/EDT (8:1:1, 2400 mL)的混合物冷却至(0-5℃),且分份添加Boc-AA1-16OtBu (3-3) (201克)。在0 - 10℃下将得到的悬浮液搅拌30分钟,然后用水浴使反应溶液升温至20-25℃(10分钟),且在相同温度下继续搅拌另外1小时50分钟。将反应混合物倒入预冷却(10℃)的MTBE(18L)中。在添加肽/TFA溶液过程中提供一些热量,内部温度上升至25℃。然后将得到的悬浮液储存在冰-水浴(5-10℃)中40分钟。通过过滤收集沉淀物,用MTBE (2000 mL,4次)洗涤,且用P2O5在真空中干燥,得到148.37克的灰白色产物,HAA1-16OH (4-4)(纯度:62.23%,ES -MS,MW:计算值= 1828.07,实测值=1826.67)。
实施例3:氧化环化反应和通过聚苯乙烯吸附树脂纯化SP-304 (如WO 2012/118972)
将HAA1-16OH (4-4) (0.58克)溶解在5 mL乙腈中,且用575 mL纯水稀释。用25%氨水溶液将溶液调节至pH 8-9,添加3%过氧化氢(0.58 mL),然后将反应混合物保持一小时,通过HPLC监测二硫键形成。然后将氮气通过反应混合物,且用乙酸将溶液酸化至pH 3-4(71.8% HPLC,从峰面积估算的回收率为98.5%)。在良好搅拌下经10分钟期间将1%碘/ACN逐滴添加至得到的混合物中,直至黄色的碘持续存在。在17-20℃继续搅拌30分钟。通过添加0.5M抗坏血酸水溶液猝灭碘,直至黄色消失。然后,用25%氨水溶液将混合物的pH调节至6-7(51.0% HPLC,从峰面积估算的回收率为50%)。
将聚苯乙烯吸附树脂(D101)填充至3(ID) × 9(L) CM柱中,且以3 CV/小时的流速用6个柱体积(CV)的乙醇、4 CV的纯水、2 CV的5% HCl水溶液、4 CV的纯水、2 CV 的2%NaOH水溶液和4 CV的纯水充分平衡。然后以2 CV/h将氧化的肽溶液上样至柱中。上样后,用2 CV纯水以2 CV/h洗柱。通过将80%乙醇水溶液以2 CV/h上样至柱进行洗脱。收集且组合在215 nm具有UV吸收的级分(125 mL)。然后将组合的级分在真空下蒸发至初始体积的10%,且用125 mL冷MTBE(10倍体积)沉淀悬浮液。通过过滤收集固体且真空干燥,得到粗SP-304(0.282克,55.0%HPLC)。
实施例4:氧化环化反应和通过RP-HPLC纯化SP-304 (如WO 2012/118972)
在连续搅拌下经由机械搅拌器将如实施例2中所述制备的粗肽(4-4)溶解在10% ACN水溶液中至约1.25 g/L的浓度。用20%氨水将肽溶液的pH调节至8.5-9.0,且将得到的溶液剧烈搅拌,向大气开放。添加过氧化氢 (3%,0.25当量),且在室温下继续搅拌60分钟。HPLC分析显示线性肽的完全消耗。然后,用10% AcOH水溶液将溶液酸化至pH 3-4。用纯水将得到的溶液稀释至约1 g/L的浓度。在剧烈搅拌下经10分钟的期间添加碘(ACN中1.3%),直至黄色的碘持续存在。以约半小时的时间间隔,样品取自混合物且通过RP-HPLC进行分析。单环的肽峰逐渐降低,出现一个新的峰(双环的肽)。当单环的肽峰消失时,氧化反应完成。通过少量的抗坏血酸中和过量的碘。将得到的溶液上样至填充Kromasil 100Å, 10µm硅胶的C18RP-HPLC柱上。将双环的肽溶液上样后,将3倍柱体积的90%流动相A(H2O中1.0%TEA、0.5%H3PO4,pH=7)和10%流动相B(乙腈)的溶液上样以洗出线(lines)。然后,在80分钟内从10%B到30%B操作梯度。当主峰开始洗脱时,以记录的时间间隔收集级分。通过分析型RP-HPLC监测各级分的纯度。相应地合并纯度≤95%(不符合主要合并标准)的级分,且使用上述相同的缓冲系统和梯度洗脱参数向前处理。合并所有纯度≥95%的级分,且贮存于2-8℃。用纯水将纯化的肽溶液以1:1比例稀释,然后上样到相同的RP-HPLC柱。通过用2-3倍柱体积的0.5M乙酸铵水溶液洗柱、随后在50分钟内从90% C (0.2% AcOH水溶液)和10%流动相D(ACN)至50%流动相C和50%流动相D的梯度洗脱完成反离子交换。以记录的时间间隔收集级分且通过分析型RP-HPLC进行监测。收集级分(≥95%)且冻干,以获得最终的干燥肽68.0g (96.1%纯)。
实施例5:通过RP-HPLC纯化后SP-304的脱盐和分离(如WO 2012/118972)
如实施例4中所述通过RP-HPLC纯化plecanatide后,将其进行脱盐和分离。简而言之,将乙酸铵/乙腈/水缓冲液中纯化的plecanatide上样到填充聚合吸附剂(大孔吸附树脂)的柱上,且然后通过醇/水的混合物进行洗脱。最后,在减压下浓缩肽醇溶液,用醚(例如,二乙醚或MTBE)沉淀,且在真空下干燥,以得到最终产物。
树脂(聚合吸附剂)筛选
树脂预处理:将聚合吸附剂,DA201-C(来自Jiangsu Suqing, China;交联聚苯乙烯;表面积1200-1400 m2/g;平均孔径:3-4 nm;孔体积:1.1-1.2 ml/g;堆积密度:0.68-0.75 g/ml;比密度:1.03-1.1 g/ml;湿度:50-60%;粒径:0.315~1.25 mm ≧95%;有效直径:0.4~0.7mm;均匀系数:≤1.6%),DA201-H(来自Jiangsu Suqing, China;交联聚苯乙烯;表面积≥800 m2/g;平均孔径:6-8 nm;孔体积:1.5-1.8 ml/g;堆积密度:0.65-0.70 g/ml;比密度:1.02-1.07 g/ml;湿度:55%-65%,粒径:0.315~1.25 mm ≧95%;有效直径:0.4~0.7 mm;均匀系数:≤1.6% ),ADS-5(来自Nankai Hecheng, China;交联聚苯乙烯;表面积:520-600m2/g;平均孔径:25-30 nm;堆积密度:0.7-0.8 g/ml;湿度:60-70%;粒径:0.315~1.25 mm≧95%;均匀系数:≤1.6%),和ADS-8(来自Nankai Hecheng, China;交联聚苯乙烯;表面积:450-500 m2/g;平均孔径:12-16 nm;堆积密度:0.65-0.75 g/ml;湿度:60-70%;粒径:0.315~1.25 mm ≧95%;均匀系数:≤1.6%)悬浮在4-6倍体积的乙醇中过夜。从沉降的树脂倾析或吸去上清液。添加6-8倍体积的去离子水且以轻微高处(overhead)搅拌下悬浮树脂。再次,从沉降的树脂倾析或吸去上清液。重复上述水处理和倾析步骤直到细粉出现最少。
柱填充和再生:分别通过使用温和搅拌用1-2倍体积的去离子水重悬上述预处理的树脂以形成树脂浆料。将树脂浆料缓慢倒入柱内侧以防止空气滞留。树脂浆料已完全转入柱中后,使用含去离子水的喷瓶冲洗柱内部。打开柱的出口以形成沉降的树脂床(ID=4cm, H=10cm)。然后通过4 CV的去离子水、2CV的5% HCl水溶液、4 CV的去离子水、2CV的2%NaOH水溶液和最后4 CV的去离子水以3CV/每小时的流速依次洗涤树脂床,直到洗脱液的pH为约7。
上样样品的制备:将2000mg冻干plecanatide溶解在60mL ACN和150mL 0.2% AcOH水溶液的混合物中(用10%氨水溶液将AcOH水溶液的pH调节至4)。用1.2 µm尼龙膜过滤后,用0.2% AcOH水溶液(pH4)将过滤液稀释至250 mL,且分成4份(各62.5 mL)用于上样。
将样品上样至柱:分别以2CV/h的流速将62.5 mL上述肽溶液上样至上述4个柱上。收集上样洗脱液,且通过RP-HPLC检测以评价各树脂的吸附容量。各树脂的吸附容量结果显示在下表X中。
表X
HPLC方法:HPLC仪器:Shimadzu LC-10AD vp;柱:Kromasil, C18, 4.6x250mm;流动相A:0.1%TFA/水;流动相B:0.1%TFA/ACN;检测在:215nm;柱温度:40℃;流速:1.0mL/min;梯度:30 min内25%B到45%B。
吸附容量计算:通过上样到各柱上的肽的吸附率(其通过吸附至各树脂柱上的肽的量除以各上样样品中的肽量(500mg)来计算)显示各树脂的吸附容量。通过下式计算各柱中吸附的肽量:
吸附的肽量=上样样品中的肽量-上样洗脱液中的肽量= 500mg- 62.5mLx (1.6mg/mLx 洗脱液的HPLC峰面积/肽标准溶液的HPLC峰面积)
用去离子水洗涤柱:然后以2CV/h用2CV的去离子水洗涤上述上样柱以去除盐。收集洗涤的洗脱液,且通过RP-HPLC分析以确定使用上述相同方法通过水解吸的肽量。各树脂的肽解吸率列在下表XI中。
表XI
用90%乙醇/水解吸肽:2CV的水洗涤后,然后以2 CV/h通过1-2CV的90%乙醇/水洗脱各柱中吸附的肽。收集洗脱液,且通过RP-HPLC分析以确定使用上述相同方法通过90%乙醇解吸的肽量。各树脂的肽解吸率列在下表XII中。
表XII
从乙醇溶液分离肽:在减压下浓缩从各柱收集的肽/乙醇/水溶液,用MTBE沉淀,过滤且在真空下干燥,以得到最终产物。通过各柱处理的肽的总得率显示在下表XIII中。
表XIII
。树脂筛选结论:从上面的数据(表X至表XIII),在实验中的树脂间,对于plecanatide,DA201-H树脂给出了最佳的吸附容量和最佳的解吸(通过乙醇)性能。
脱盐和分离过程优化
洗脱溶剂选择:异丙醇和乙醇是用于从聚合吸附剂洗脱肽的两种常用溶剂。表XIV显示根据v/v % 异丙醇(或乙醇):水能够溶解在乙醇或异丙醇水溶液中的plecanatide的量。
表XIV
肽/醇溶液中的水可通过共沸蒸馏去除。表XV显示乙醇/水和异丙醇/水的二元共沸物的特性。
表XV
。
Plecanatide的降解将发生在肽/醇/水溶液的长期储存和浓缩过程期间。表XVI表明在23℃下plecanatide在75% IPA/水溶液和90% EtOH/水中的稳定性数据。
表XVI
* HPLC方法:HPLC仪器:Shimadzu LC-10AD vp:柱:Kromasil, C18, 4.6x250mm;流动相A:0.1%TFA/水;流动相B:0.1%TFA/ACN;检测在:215nm;柱温度:40℃;流速:1.0mL/min;梯度:30 min内25%B到45%B。
根据获得的测试数据,plecanatide在23℃下在6小时内在醇/水溶液中是相当稳定的。
使用不同v/v %的异丙醇/水混合物进行洗脱实验。肽洗脱液的解吸率和水含量列在下表XVII中。
表XVII
v/v % IPA/水 | 75% IPA/水 | 95% IPA/水 | 100% IPA/水 |
肽中的水含量* | 65.9% | 53.0% | 49.8% |
解吸率 | 100% | 100% | 90% |
。75%异丙醇/水作为洗脱溶液:将500mg plecanatide(98.1%纯)溶解在16 mL ACN和49 mL 0.2% AcOH水溶液的混合物中(通过添加10% NH4OH水溶液将0.2%AcOH溶液的pH调节至4.0)。通过1.2 µm尼龙膜过滤后,以2CV/h将肽溶液上样至填充DA201-H 树脂(ID=4cm,H=10cm,通过上述程序填充和预处理)的柱上。上样后,以2CV/h用2 CV去离子水洗涤柱。然后,以2CV/h通过1.5CV 75% IPA/水洗脱肽。通过RP-HPLC监测洗脱。收集洗脱液(124mL,98.3%纯)。Karl Fisher分析表明水(65.9% wt. %)。将上面收集的124mL肽/IPA/水洗脱液(97.6%纯,在2-8℃下储存2天过程中发生略微降解)置于1-颈500 mL圆底烧瓶中。然后将烧瓶在减压下(60 Pa)下置于旋转蒸发器上,且部分地浸在23℃水浴中。通过在2小时内将约622mL异丙醇减料(feed-stripping)至溶液初始体积的约1/3而形成带白色的悬浮液(97.7%纯)。Karl Fisher分析表明水(0.17% wt. %)。向浓缩物中添加350 mL预冷二乙醚,通过以3500 rpm离心3分钟而收集固体,且在真空下干燥,得到333 mg的最终产物(得率66.6%,97.2% HPLC纯)。
95%异丙醇/水作为洗脱溶液I:将500mg plecanatide(98.1%纯)溶解在16 mLACN和49 mL 0.2% AcOH水溶液的混合物中(通过添加10% NH4OH水溶液将0.2%AcOH溶液的pH调节至4.0)。通过1.2 µm尼龙膜过滤后,以2CV/h将肽溶液上样至填充DA201-H 树脂(ID=4cm,H=10cm,通过上述程序预处理)的柱上。上样后,以2CV/h用2 CV去离子水洗涤柱。然后,以2CV/h通过1.5CV 95% IPA/水洗脱肽。通过RP-HPLC监测洗脱。收集洗脱液(117mL,98.1%纯)。Karl Fisher分析表明水(52% wt. %)。将上面收集的117mL肽/IPA/水洗脱液置于1-颈500 mL圆底烧瓶中。然后将烧瓶在减压下(50 Pa)下置于旋转蒸发器上,且部分地浸在23℃水浴中。通过在130min内减料(feed-stripping)约470mL异丙醇而形成带白色的固体(97.9%纯)。向上述固体添加50 mL预冷二乙醚以形成悬浮液,且在23℃下在减压(50Pa)下在旋转蒸发器下蒸发至干燥。产率为430mg的终产物(86%)。HPLC纯度为97.9%。
95%异丙醇/水作为洗脱溶液II:将500 mg plecanatide(98.1%纯)溶解在16 mLACN和49 mL 0.2% AcOH水溶液的混合物中(通过添加10% NH4OH水溶液将0.2%AcOH溶液的pH调节至4.0)。通过1.2 µm尼龙膜过滤后,以2CV/h将肽溶液上样至填充DA201-H 树脂(ID=4cm,H=10cm,通过上述程序填充和预处理)的柱上。上样后,以2CV/h用2 CV去离子水洗涤柱。然后,以2CV/h通过1.5CV 95% IPA/水洗脱肽。通过RP-HPLC监测洗脱。收集洗脱液(118mL,98.2%纯)。Karl Fisher分析表明水(53% wt. %)。将上面收集的118mL肽/IPA/水洗脱液置于1-颈500 mL圆底烧瓶中。然后将烧瓶在减压下(50 Pa)下置于旋转蒸发器上,且部分地浸在23℃水浴中。通过在100min内减料(feed-stripping)约330mL异丙醇而形成带白色的悬浮液(~40mL)(97.7%纯)。向上述悬浮液添加400 mL预冷二乙醚以形成悬浮液。在室温静置1小时后,通过以3500 rpm离心3分钟而收集固体,且在真空下干燥,得到370 mg的最终产物。产率为74%。HPLC纯度为97.9%。
95%异丙醇/水作为洗脱溶液III:以与上述类似的方式将10g plecanatide脱盐且沉淀。有趣的是,沉淀产率改善到93%,这是显著的产率增加。沉淀后的HPLC纯度为98.47%。
实施例6:冻干的SP-304和沉淀的SP-304的表征(如WO 2012/118972)
分析如实施例4中所述通过冻干纯化的plecanatide和如实施例5中所述通过沉淀纯化的plecanatide,以确定显著的化学杂质值,如乙酰胺、TFA、铵离子和乙腈的水平。结果列于下表中。
。
如以上结果表明,沉淀过程提供了不期望的过程杂质的水平的显著降低。
测量如实施例4中所述通过冻干纯化的plecanatide和如实施例5中所述通过沉淀纯化的plecanatide,以获得其堆积密度、振实密度、粒径分布和形状。
设备:(1)振实密度测试仪型号TD-1020;(2)声频筛分离器型号L3P;(3)光学显微镜LINITRON 2850。
方法:
1) 堆积密度和振实密度测量:改良的USP 1方法
a. 100.0 mL量筒用于冻干的plecanatide
b. 10.0 mL量筒用于沉淀的plecanatide
2) 粒径分布分析
a. 使用的筛:200、140、100、60、40 和30目。
b. 样品量:2g冻干的plecanatide和6.4g沉淀的plecanatide
3) 光学显微分析:粒径和形状
a. 将干燥粉末手工分散到微观板上
b. 放大倍数:100 x
c. 在正常光条件下(没有偏振滤光片)。
结果:
(1) 物理外观:冻干的plecanatide是轻的蓬松的白色粉末。沉淀的plecanatide是略微灰白色粉末。
(2) 堆积密度和振实密度:表XVIII提供冻干和沉淀的Plecanatide样品二者的堆积和振实密度数据:
表XVIII
。
如从数据可以看出,沉淀的plecanatide出乎意外地明显比冻干的plecanatide更加致密。沉淀的plecanatide在加工过程中具有更低生成粉尘的趋势,这提供了增加的安全性和降低的加工损失的优点。
(3) 粒径分布:表XIX总结了粒径分布分析。图1图示提供了数据。
表XIX
。
如表XIX和图1所表明,对于两种类型的plecanatide,粒径分布是不同的。在分析过程中,观察到,沉淀的plecanatide含有一些较大的颗粒,这可能容易粉碎。还注意到,冻干的plecanatide似乎是薄片状的且粘附到筛的顶部和底部,而对于沉淀的plecanatide则没有观察到粘附。这表明沉淀的plecanatide的更好的加工特性。
(4) 粒径和形状:图2和3分别提供了冻干的和沉淀的plecanatide样品的光学显微镜分析。如在图2中可以看到,冻干的plecanatide是无定形形式,且具有不规则形状的颗粒。它们与躺在彼此顶部的颗粒形成物理聚集物。在图3中,沉淀的plecanatide显示可辨别的个别颗粒。根据颗粒外观和形状,沉淀的plecanatide将具有更好的流动特性,且因此可以促进制造过程中的固体加工。
冻干和沉淀形式的plecanatide已经显示通过密度、粒径分布和形状分析可辨别的物理外观和特性。在减少粉尘生成、更少粘附到加工设备上和可能更少的加工损失的方面,沉淀形式更适合用于在制造过程中的固体剂型加工。
沉淀形式更适合用于在制造过程中加工固体剂型(例如,低剂量的固体剂型)。更高密度的沉淀物质将减少称重、转移和掺合过程中的气溶胶或“粉尘”损失。已经显示不同的颗粒形状减少由粘附到筛(screen)或筛(seive)引起的损失。更高的密度应改善含量均匀度,因为药物颗粒的大小和密度更紧密地匹配赋形剂的大小和密度。
实施例7:沉淀的SP-304的低剂量制剂(如WO 2012/118972)
如下文所述,进一步加工如实施例5中所述通过沉淀纯化的plecanatide以制备低剂量制剂。
干掺合批次的组成
。
掺合
将Avicel PH 102筛选通过60目筛。然后通过过筛的Avicel PH 102将V型掺合器(1Qt、4Qt、和16 Qt)粉尘化。SP-304过筛通过200目筛网,且上样至1-Qt V型掺合器。然后,将约80 g Avicel PH 102添加到1-Qt掺合器,且将混合物以25 rpm掺合10分钟。然后将混合物转移到4-Qt V型混合器(其由过筛的Avicel PH 102预粉尘化)。用Avicel冲洗1-Qt掺合器且将冲洗材料转移到4-Qt掺合器。重复冲洗,直至将所有SP-304转移到4-Qt掺合器。将约200g Avicel添加到4-Qt V型掺合器,且将混合物掺合10分钟。然后将得到的掺合物过筛通过60目筛网,且然后转移到预粉尘化的16-Qt掺合器(用1500g Avicel粉尘化)。用Avicel冲洗4-Qt掺合器且将冲洗材料转移到16-Qt掺合器。将剩余的Avicel添加到16-Qt V型掺合器,且将混合物掺合10分钟。将得到的掺合物通过Comil,用过量的Avicel冲洗,且然后返回至16-Qt掺合器,且进一步掺合5分钟。称取适当量的硬脂酸镁,过筛通过60目筛网,且添加至16-Qt掺合器中。将得到的混合物掺合2分钟。然后将得到的混合物或封装在胶囊中或压缩以形成片剂。
封装
设置MG2 Planeta胶囊填充器。确定空胶囊壳的平均重量,且计算目标胶囊填充重量(±5%)。将来自从上面过程的掺合物添加至胶囊填充器的料斗且开始封装。手工调整运行重量参数。然后根据目标填充重量分选得到的胶囊。
压缩
设置Fette压片机。然后将掺合混合物上样至粉末料斗且安装工具作业。各片剂的重量设定为100 mg±5%,硬度设定为4-6 Kp。测量片剂的重量、硬度、和厚度且每隔5至10分钟进行记录。还进行脆度测量以确保满意的产品。
实施例8:通过溶剂交换-冻干来合成和纯化SP-304
线性粗肽的单环化:首先在8.0-8.5 pH下通过H2O2氧化在Cys4和Cys12之间形成二硫键,以形成单环粗肽。缓慢加入线性粗肽,并以肽克数:H2O2 mL为100:9的比率在含预添加的H2O2的水缓冲液中溶于0.5%乙酸铵,以产生大约1.0 mg/mL的最终粗浓度。然后用NH4OH溶液调整溶液pH至8.5,同时在开放空气中搅拌。使用HPLC方法2监测氧化单环反应。当线性粗肽的面积%为单环肽的面积%的≤5.0%时,通过使用TFA溶液调整肽溶液的pH至1.7-2以终止氧化反应。然后将肽溶液转移至用于形成双环肽的下一步骤。
单环肽的双环化:通过含3.0% (w/v) I2的乙腈溶液在Cys7和Cys15之间形成二硫键。产生二硫桥,同时除去在剩余Cys残基上存在的Acm侧链保护基。使用HPLC方法2监测氧化双环化反应。用0.1 M抗坏血酸的水溶液猝灭过量的碘。当反应完成时,使用NH4OH溶液将双环肽调整至pH 6.5-7,并制备材料用于初步纯化。
双环粗肽的初步纯化:然后将自氧化步骤产生的双环粗肽溶液上样到填装有C18反相树脂的制备型RP-HPLC柱上,其通过制备型HPLC系统操作。在水pH7/ACN缓冲液系统中在1%磷酸三乙胺(TEAP)中将肽洗脱。使用HPLC方法1以确定在初步纯化运行期间获得的各级分和各合并物的百分比纯度。
双环肽的循环合并物纯化:在初步纯化后,根据级分合并物的纯度使用在水pH7/ACN缓冲液系统中的1%TEAP或在水/ACN缓冲液系统中的0.2%乙酸将需要进一步纯化的级分纯化。然后将自氧化步骤产生的双环粗肽溶液上样到填装有C18反相树脂的制备型RP-HPLC柱上,其通过制备型HPLC系统操作。在水pH7/ACN缓冲液系统中在1%TEAP中将肽洗脱。使用HPLC方法1以确定在循环纯化运行期间获得的各级分和各合并物的百分比纯度。
二级纯化和盐交换:在循环纯化后,根据级分合并物的纯度使用在水pH7/ACN缓冲液系统中的1%TEAP或在水/ACN缓冲液系统中的0.2%乙酸将需要进一步纯化的级分纯化。使用HPLC方法1以确定在二级纯化运行期间获得的各级分和各合并物的百分比纯度。使用UPLC方法1以确定在所有纯化运行期间获得的主合并物的百分比纯度,然后移至下一步骤。
溶剂交换:在边缘末端上以反方向,将满足主合并物标准的材料上样至制备型RP-HPLC柱上,用99:1的水与异丙醇溶液自反方向洗涤,并用40:60异丙醇:水溶液以正方向洗脱。收集的肽溶液通过UPLC方法1测试,以确定纯度,然后过滤肽溶液,经过旋转蒸发以除去过量的异丙醇至低于5%,接着小批冻干不少于96小时。
复溶和最终冻干:小批冻干的干燥肽经过在水中复溶,形成均质批次。加入对干燥肽为0.5% (w/w)的量的乙酸铵至溶液中,并混合直至乙酸铵/肽溶解。材料经过UPLC方法1分析以证实纯度。将溶解的材料装到托盘冻干机上并保持真空下不少于120小时,以构成最终的干燥肽材料。
过程中试验方法
HPLC方法1:以下RP-HPLC分析方法将用于证实初步和循环纯化步骤或指示的批次记录的HPLC百分比纯度。
HPLC参数:
柱:Waters SunFireTM C8, 3.5µm, 4.6 x 150mm或等效物
波长:215 nm
流动相A:含0.02M TEAP的水pH 6.5 (分析缓冲液BA)
流动相B:100% ACN
注射体积:5-50 µL
柱温度:40℃
梯度洗脱参数:
HPLC方法2:以下RP-HPLC分析方法将用于证实线性粗肽的HPLC百分比纯度和监测氧化环化步骤的进展。
HPLC参数:
柱:Kromasil C18 5µ 100Å 4.5 x 250mm或等效物
波长:215 nm
流动相A:含0.02M TEAP的水pH 6.5 (分析缓冲液BA)
流动相B:100% ACN
注射体积:5-50 µL
柱温度:40℃
梯度洗脱参数:
UPLC方法1:以下RP-UPLC分析方法将用于在冻干前证实主合并物百分比纯度和最终产物肽材料。
UPLC参数:
柱:Waters Acquity BEH C18, 1.7µm, 150 x 2.1mm, P/N 186002353,具有WatersAcquity柱在线过滤器装置, 0.2µm, P/N 205000343
波长:215 nm
流动相A:48/ 52/ 0.16 – MeOH/水/ TFA
注射体积:5µL
柱温度:10℃
等度洗脱参数:
通过实施例中描述的方法制备两个批次:批次大小为50 g的lot#121026 IPA2,和批次大小为930 g的lot#121026 B。如图4所示的,lot#121026 IPA2肽具有约98%的UPLC色谱纯度。与通过描述于WO 2012/118972的方法制备的批次相比,这两个批次的其它特征概述在下文表XX中。
表XXI. Plecanatide药物Lot 121026B在25℃下贮存的稳定性
Claims (28)
1. 纯化的肽,其包含选自SEQ ID NO: 1、9和104的GCC激动剂序列,其中所述纯化的肽具有以下特征:
a) 具有不大于0.1 g/mL的堆积密度;
b) 包含少于50 ppm乙酰胺;和
d) 少于0.3% α-Asp-9-plenacanatide (RRT 1.33)。
2.权利要求1的纯化的肽,其中所述肽在25℃下稳定至少3个月。
3. 权利要求1的纯化的肽,其中所述肽具有特征为以下的粒径分布:
当用液体分散剂通过光散射测量时
a) D10值为约2 -15 µm;
b) D50值为约15-50 µm;和
c) D90值为约40-80 µm。
4. 权利要求1的纯化的肽,其中所述肽具有不大于0.06 g/mL、不大于0.05 g/mL或不大于0.04 g/mL的堆积密度。
5.权利要求1或2的纯化的肽,其中所述肽具有不少于95%、不少于96%或不少于97%的色谱纯度。
6.权利要求1-5中任一项的纯化的肽,其中所述肽基本上不含水。
7.权利要求6的纯化的肽,其中所述水不大于10%、不大于9%、不大于8%、不大于7%、不大于6%或不大于5%。
8.权利要求1-7中任一项的纯化的肽,其中所述肽还基本上不含选自乙腈、醇、铵、乙酸盐和TFA的一种或多种杂质。
9. 权利要求8的纯化的肽,其中所述肽包含少于300 ppm乙腈。
10. 权利要求8或9的纯化的肽,其中所述肽包含少于0.1% TFA。
11. 权利要求8-10中任一项的纯化的肽,其中所述肽包含少于1000 ppm异丙醇。
12. 权利要求8-11中任一项的纯化的肽,其中所述肽包含少于600 ppm异丙醇。
13. 权利要求8-12中任一项的纯化的肽,其中所述肽包含少于0.25 %乙酸盐。
14.权利要求1-13中任一项的纯化的肽,其中所述肽还基本上不含拓扑异构体。
15. 权利要求1-14中任一项的纯化的肽,其中所述肽还基本上不含异-Asp2-plecanatide (RTT 0.96-0.97)。
16. 纯化包含选自SEQ ID NO: 1-251的GCC激动剂序列的肽的方法,所述方法包括:
提供包含肽、水和乙腈的第一肽溶液,所述肽包含选自SEQ ID NO: 1-251的GCC激动剂序列;
用所述第一肽溶液上样C18或聚合物吸附柱,以将所述肽吸附至C19或聚合物吸附柱;
用醇的水溶液将所述肽从C18或聚合物吸附柱洗脱,形成第二肽溶液;
减少在第二肽溶液中的醇的量;和
冻干第二肽溶液,使得获得干燥的肽。
17.权利要求16的方法,其中所述醇的水溶液包含异丙醇。
18.权利要求17的方法,其中在醇的水溶液中异丙醇含量为约40%。
19.权利要求16的方法,其中第一肽溶液还包含乙酰胺。
20.权利要求16的方法,其中第一肽溶液还包含0.2%乙酸或1%磷酸三乙胺。
21.权利要求16的方法,其中在第二肽溶液中醇的量通过旋转蒸发而减少。
22.权利要求16的方法,其中在第二肽溶液中的醇减少至少于5%。
23.权利要求22的方法,其中在第二肽溶液中的醇为异丙醇。
24.权利要求17-23中任一项的方法,还包括在冻干后将干燥的肽溶解在水中,形成第三肽溶液。
25.权利要求24的方法,其中第三肽溶液还包含氢氧化铵或乙酸铵。
26.权利要求24或25的方法,还包括将第三肽溶液冻干,使得获得纯化的肽。
27.通过权利要求16-26中任一项的方法制备的纯化的肽。
28. 权利要求27的纯化的肽,其中所述肽包含选自SEQ ID NO: 1、9和104的GCC激动剂序列。
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CN117538461A (zh) * | 2024-01-10 | 2024-02-09 | 地奥集团成都药业股份有限公司 | 一种盐酸贝那普利片有关物质的检测方法 |
CN117538461B (zh) * | 2024-01-10 | 2024-03-26 | 地奥集团成都药业股份有限公司 | 一种盐酸贝那普利片有关物质的检测方法 |
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CN113388007A (zh) | 2021-09-14 |
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US11319346B2 (en) | 2022-05-03 |
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CN105764916B (zh) | 2021-05-18 |
AU2018226473A1 (en) | 2018-09-27 |
JP6606491B2 (ja) | 2019-11-13 |
BR112015030326A2 (pt) | 2017-08-29 |
AU2020205349B2 (en) | 2021-12-09 |
US10011637B2 (en) | 2018-07-03 |
EP3004138A2 (en) | 2016-04-13 |
JP2016522216A (ja) | 2016-07-28 |
HK1221959A1 (zh) | 2017-06-16 |
CA2913737A1 (en) | 2014-12-11 |
US10745441B2 (en) | 2020-08-18 |
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US20160145307A1 (en) | 2016-05-26 |
AU2014274812A1 (en) | 2015-12-17 |
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