CN103601792A - 有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂 - Google Patents
有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂 Download PDFInfo
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Abstract
本发明提供了一种新型的鸟苷酸环化酶-C激动剂多肽及其在治疗人类疾病中的应用,所述人类疾病包括胃肠功能紊乱、炎症或者癌症(例如,胃肠道癌症)。所述多肽可以单独被给药,或者与cGMP依赖型磷酸二酯酶抑制剂结合给药。胃肠功能紊乱可分类为过敏性肠综合症、便秘、或酸度过量等。胃肠道疾病可被分类为发炎症性肠道疾病或其他胃肠道状况,包括克罗恩病和溃疡性结肠炎和癌症。
Description
本申请是2008年6月4日递交的申请号为200880101768.0,发明名称为“有效用于胃肠功能紊乱、炎症、癌症和其他疾病治疗的鸟苷酸环化酶激动剂”的分案申请。
相关申请
本申请要求2007年6月4日递交的美国临时申请第60/933,194号的优先权,该申请的内容通过引证全部并入本文。
发明领域
本发明涉及鸟苷酸环化酶(GC-C)激动剂的治疗剂应用,所述应用可以作为一种提高细胞内cGMP产量的方法。所述激动剂可以单独使用或者与cGMP特异性磷酸二酯酶抑制剂结合使用,从而防止或治疗炎症,癌症和其他疾病,特别是胃肠道和肺部的炎症,癌症和其他疾病。
背景技术
尿鸟苷素,鸟苷肽和细菌ST多肽是结构相关性多肽,这些多肽能够结合鸟苷酸环化酶受体并且刺激细胞内生产环鸟苷单磷酸(cGMP)的(1-6)。从而造成囊性纤维化跨膜转运调节因子(CFTR)的活化,所述囊性纤维化跨膜转运调节因子(CFTR)是一种顶端膜途径,允许氯从肠道细胞沿着肠道(1-6)流出。囊性纤维化跨膜转运调节因子(CFTR)的活化以及随后的氯经上皮分泌作用的提高会导致钠离子及水向肠道内腔分泌的刺激作用。因此,作为囊性纤维化跨膜转运调节因子(CFTR)活性的旁分泌调节,环鸟苷单磷酸(cGMP)受体激动剂调节流体和 电解液在胃肠(GI)道(1-6)的转移(美国专利第5,489,670号)。因此,环鸟苷单磷酸(cGMP)调节的囊性纤维化跨膜转运调节因子(CFTR)活化作用以及下游信号传导在使肠道生理机能正常化方面起到了十分重要的作用。因此,在这一过程中出现的任何异常现象都回潜在的导致胃肠功能紊乱,例如过敏性肠综合症、炎症性肠道疾病、酸度过度和癌症(25,26)。
上皮细胞的再生过程包括胃肠道细胞在所述内腔中的增殖、迁移、分化、衰老和最后的损失(7,8)。根据上皮细胞增殖指数,所述胃肠道(GI)粘膜可以被分成三个不同的区域。这三个区域中的一个叫做增殖区,增殖区由未分化的干细胞组成,负责提供稳定的新细胞。所述干细胞验证内腔向上迁徙,直到能将他们排出的位置。随着这种迁徙作用,所述细胞失去其分裂能力,成为分化细胞,能够在胃肠道(GI)粘膜内执行某些特定的功能(9)。胃肠道(GI)粘膜的更新是非常快的,可以再24-48小时时间内就完成完全的更新(9)。在这一过程中,突变细胞和不在需要的细胞被新细胞所替代。因此,通过不断的保持增殖和凋亡之间的平衡可以调节胃肠道(GI)粘膜的体内平衡(8)。
在肠道上皮上细胞增殖作用和凋亡作用的比率可以在各种各样的不同的环境下进行增加或者减少,例如,作为对生理学刺激的响应,所述生理学刺激例如,老化作用、炎症性信号传导、激素刺激、肽、生长因子、化学物质和饮食习惯。另外,增加的增殖作用比率通常与更新时间的减少和增殖区(10)的扩张有关。在溃疡性结肠炎及其他胃肠道(GI)功能性紊乱(11)等病理学情况下所观察得到的增殖作用指数都是非常高的。因此,肠增生作用是胃肠道炎症和致癌作用的主要助催化剂。
尿鸟苷素和鸟苷肽除了可以用作肠道液体和离子分泌调节剂之外,这些多肽还可以被用于胃肠道(GI)粘膜的持续更新中,该应用通过维持细胞沿着胃肠道(GI)粘膜的增殖作用和凋亡作 用的平衡来完成。因此,在这种更新过程中,由降低尿鸟苷素和/或鸟苷肽产生造成的任意失常情况都可以导致胃肠道(GI)发炎和癌症(25,26)。这种现象与之前公布的国际申请第WO01/25266中公开的数据一致,国际申请第WO01/25266教导了,具有尿鸟苷素活性区域的多肽可以在结肠中起到息肉发生抑制剂的作用,并且所述多肽可以作为结肠癌治疗的一部分。但是,目前的数据也建议尿鸟苷素还可以与一种当前位置的受体相结合,这种受体与鸟苷酸环化酶(GC-C)受体所不同(3,4)。缺乏这种鸟苷酸环化酶受体的基因敲除鼠在肠道中显示出对ST肽的抵抗力,尿鸟苷素和ST肽在体内肾脏中的作用并没有被破坏(3)。这些结果进一步支持了一个事实,这个事实是通过鸟苷肽诱导的薄膜去极化作用可以通过5,7,4-三羟基异黄酮、一种酪氨酸激酶抑制剂来阻断,相反,通过尿鸟甘素诱导的过超极化并没有起到作用(12,13)。因此,本领域普通技术人员并不清楚所述尿鸟苷素及其类似物的抗结肠癌活性和抗炎症性活性是否能够通过与这些受体中的一个或两个相结合来调节。
炎症性肠道疾病是一组紊乱的统称,这种紊乱是由肠道引起的,后来发展成炎症,具有组织发红和发肿等特征。胃肠道(GI)发炎可以是一种慢性病症并且经常导致胃肠道(GI)癌症(14)。这种炎症性肠道疾病(IBD)包括克罗恩氏病和溃疡性结肠炎(UC)。据估计,大约1,000,000美国人都患有炎症性肠道疾病(IBD),其中男性病人和女性病人好像具有相同的感染率。大多数病例可以在30岁之前被诊断出来,同时,更多的疾病发现在六十、七十或者更大的年龄阶段。
克罗恩氏病是一种严重的炎症性疾病,这种疾病主要作用在回肠和结肠中,同时还可以发生在胃肠道的其他部分,相反,溃疡性结肠炎(UC)是一种专有的炎症性疾病,专门发生在结肠、大部分肠道(15)上。克罗恩氏病可以涉及肠道的所有层面,并 且在几片患病的肠道部分之间可以存在正常健康的肠,与克罗恩氏病有所不同的是,溃疡性结肠炎(UC)只以一种连续的方式作用在结肠最里面的部分(粘膜)(16)。根据胃肠道患病的部分不同克罗恩氏病可以被认为是回肠炎、局限性回肠炎、结肠炎等等。克罗恩氏病和溃疡性结肠炎(UC)与结肠痉挛综合症或者过敏性肠综合症不同,结肠痉挛综合症或者过敏性肠综合症是一种可移动的胃肠道紊乱。
尽管炎症性肠道疾病(IBD)的精确原因仍然是位置的,但是本领域普通技术人员相信胃肠道(GI)粘膜的持续更新过程出现的失常情况可以被包括在疾病中(17,18)。胃肠道(GI)线路的更新过程是一种有效的并且有活力的过程,该过程包括对不需要的破坏细胞持续不带的增殖和补充。细胞沿着胃肠道(GI)粘膜的增殖比率是非常高的,仅次于造血系统的增殖比率。因此,增殖和凋亡过程的平衡在保持胃肠道(GI)粘膜体内平衡方面是重要的(19,20)。
胃肠道(GI)体内平衡取决于肠道粘膜上皮细胞的增殖作用和程序性细胞死亡(细胞凋亡)作用。因此,细胞不断的从绒毛部分损失进入肠道内腔,并通过在小囊处以基本上相等的速率发生细胞增殖作用,随后向上移动到绒毛处进行补充。日益明显的是,细胞死亡的控制作用是一种同等重要的或者是更加重要的细胞数目和增殖指数调节剂(19,20)。降低的细胞凋亡速率通过与异常生长、发炎、和赘生转化有关。因此,减少的增殖作用和/或增加的细胞死亡都可能会减少细胞数目,相反,增加的增殖作用和/或减少的细胞死亡作用会增加肠道组织的增殖指数(20),这会导致胃肠道(GI)的炎症性疾病和癌症。
通过对照细胞离子流动可以看出,尿鸟苷素和鸟苷肽似乎也可以促进细胞凋亡。在细胞凋亡过程中出现的改变与肿瘤的发展的转移性表型有关。尽管最初的胃肠道(GI)癌症局限于小肠、 结肠和直肠,但是这些癌症可以转移并波及其他区域,例如骨骼、淋巴结、肝脏、肺、腹膜、卵巢和脑部。通过增强K+的流出和Ca++的流入,尿鸟苷素和相关的肽可以促进转化细胞的死亡,并因此抑制转移。
过敏性肠综合症(IBS)和慢性先天性便秘是一种病理学病况,这种病况能够产生许多肠部不适和痛苦,但是与炎症性肠道疾病(IBD),例如溃疡性结肠炎和克罗恩氏病不同的是,过敏性肠综合症(IBS)不会造成严重的发炎或者改变肠道组织,并且,通常不认为过敏性肠综合症(IBS)能够增加结肠直肠癌的患病风险。过去,炎症性肠道疾病(IBD)、乳糜泻和过敏性肠综合症(IBS)被认为是完全无关的疾病。现在,根据发炎的描述,虽然对于过敏性肠综合症(IBS)是初步的,但是在过敏性肠综合症(IBS)和乳糜泻的症状之间有相同的部分,这一论点以及纳入考虑范围内。急性细菌性胃肠病是目前识别的在感染过敏性肠综合症之后的病况发展过程中具有最强的患病风险系数的疾病。临床上的风险系数包括延长的急性疾病和催吐药的缺失。对炎症性刺激的最初确定的敏感程度也可以是过敏性肠综合症的风险因素。基础病理生理学显示增加的肠部穿透性和低程度的发炎,以及改变的流动性和内脏灵敏度(27)。血清紧张素(5-羟基色胺[5-HT])是肠道功能的一种重要的调节因子,已知在过敏性肠综合症(IBS)的病理生理学中起到非常重要的作用。已经表明,5-羟基色氨(5-HT)的活性可以通过环鸟苷单磷酸(cGMP)来调节(28)。因此,根据观察结果以及环鸟苷单磷酸(cGMP)其他的作用,我们相信鸟苷酸环化酶(GC-C)激动剂可以有效用于治疗过敏性肠综合症(IBS)。
考虑到炎症性病况在西方社会的发病率以及伴随的从发炎的组织,特别是肠道组织发展成癌症性病变的风险,这里存在改善炎症性疾病,特别是胃肠道的炎症性疾病治疗方法的需要。
发明内容
本发明基于鸟苷酸环化酶受体激动剂的发展。所述激动剂是尿鸟苷素和细菌性ST多肽的类似物,具有某些高级性质,例如在N末端和C末端对羧肽酶和/或其他的蛋白水解酶降解作用的高抵抗力,所述其他的蛋白水解酶存在于刺激后的人类肠液和人类胃液中。
本发明的多肽可以用于治疗任何响应增强的环鸟苷单磷酸(cGMP)胞内水平的病况。通过增强细胞内环鸟苷单磷酸(cGMP)产量和/或通过抑制环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶的降解作用,可以增加环鸟苷单磷酸(cGMP)的细胞内水平。可以被治疗或者预防的具体的病况是胃肠功能紊乱、炎症性紊乱、肺紊乱、癌症、心脏功能紊乱、眼部功能紊乱、口腔紊乱、血液紊乱、肝脏功能紊乱、皮肤疾病、前列腺功能紊乱、内分泌紊乱、增加的胃肠道活动性和肥胖症。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假性梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻发炎(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸性)、便秘(例如,与使用药物有关的便秘,所述药物例如鸦片样物质、骨关节炎药、骨质疏松症药;手术后便秘;与神经性紊乱有关的便秘)。炎症性紊乱包括组织发炎和器官发炎,例如肾发炎(例如,肾炎)、胃肠系统发炎(例如,克罗恩氏病和溃疡性结肠炎);胰腺发炎(例如,胰腺炎)、肺部发炎(例如,支气管炎或者哮喘)或者皮肤发炎(例如,银屑病、湿疹)。肺部紊乱包括,例如,慢性阻塞性肺病(COPD)和纤维症。癌症包括组织致癌作用和器官致癌作用,包括转移性肿瘤,例如胃肠癌症(例如,胃癌、食道癌、胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或者结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑素瘤);口腔癌;泌尿道癌症(例如膀胱 癌或者肾癌);血液癌(例如髓细胞癌或者白血病)或者前列腺癌。心脏紊乱包括例如,充血性心力衰竭、气管贲门高血压、高胆固醇或者高甘油三酯。肝脏紊乱包括,例如,肝硬化和纤维症。另外,鸟苷酸环化酶(GC-C)激动剂还可以被用于促进肝脏移植病人体内肝脏再生。眼部紊乱包括,例如,增加的眼内压、青光眼、干眼症、视网膜变性、泪腺功能紊乱或者眼部发炎。皮肤紊乱包括,例如,干燥病。口腔紊乱包括,例如,口干燥(口腔干燥)、休格林氏症(Sjogren's syndrome)、牙龈疾病(例如,牙周病)、或者唾液腺管堵塞或者机能失调。前列腺紊乱包括,例如,良性前列腺肥大(BPH)。内分泌紊乱包括,例如,糖尿病、甲状腺机能亢进症、甲状腺机能减退症和囊肿性纤维化。
在一个方面,本发明涉及一种肽,该肽基本上由如下氨基酸序列:SEQ ID NOs:2-54和SEQ ID NOs57-98组成,本发明还涉及一种治疗剂组合物,该治疗剂组合物包括这些肽。优选的肽包括SEQ ID NO:8、9、10、58和59。术语“基本上由。。。组成”是指所述肽与序列识别号所代表的序列以及其他在结构和功能上与序列识别好所代表的序列没有本质区别的序列一致。为了实现本申请的目的,如果与SEQ ID NOs:2-54和57-98肽的结构相比一种肽结构的变化超过三个氨基酸,或者与参照多肽,例如SEQ ID NO:1、55或者56相比,一种肽对细胞内环鸟苷单磷酸(cGMP)产量的活化作用减少超过50%,就认为这种肽是基本上不同的肽。优选的,基本上相似的肽之间的区别不超过2个氨基酸并且其活化环鸟苷单磷酸(cGMP)产量的作用相差不超过大约25%。本发明肽序列包含至少12个氨基酸残基,优选长度在12到26个氨基酸之间。
所述多肽可以以单位剂量形式,与一种或一种以上药学上可接受的载体、赋形剂或者稀释剂一起存在于一种药物组合物中。术语“单位剂量形式”涉及一种单一的药物传递实体,例如,一 种片剂、胶囊剂、溶液或者吸入剂。在对患者给药时呈递的多肽的量应该足够实现阳性的治疗效果(一般地,在100微克到3克之间)。“阳性的治疗效果”由什么组成主要取决于接受治疗的具体状况,并且包括任意本领域技术人员能够识别的重要改善。例如,可以由减少的炎症、息肉或者肿瘤的缩小、转移性病变的减少等等组成。
在依旧另一个方面,本发明对所述病人给药一种治疗有效量的环鸟苷单磷酸-特异性磷酸二酯酶(cGMP-PDE)抑制剂和所述鸟苷酸环化酶受体激动剂,环鸟苷单磷酸-特异性磷酸二酯酶(cGMP-PDE)抑制剂和所述鸟苷酸环化酶受体激动剂可以同时给药或者顺序给药。所述环鸟苷单磷酸-特异性磷酸二酯酶(cGMP-PDE)抑制剂包括,例如,舒林砜(sulindae sulfone)、敏喘宁和莫他匹酮(motapizone)、vardenifil(伐地那非)、和西地那非(Sildenafil)。另外,鸟苷酸环化酶(GC-C)激动剂肽可以与环状核苷酸载体抑制剂结合使用。
选择性地,也可以给药消炎剂。消炎剂包括,例如,类固醇和非类固醇类消炎药(NSAIDS)。
通过下面的详细说明和权利要求书,本发明的其他特点和优点变得显而易见,本发明的其他特点和优点也包括在下面的详细说明和权利要求书中。
附图说明
图1A是一种条形图,显示了SP-304与人工胃液(SGF)一起培养指定的时间之后的生物活性。所述SP-304的生物活性可以通过测定其在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力来确定。在培养之后,使用样品测定其在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力。在与人工胃液(SGF)一起 培养的第0分钟,所述环鸟苷单磷酸(cGMP)在样品中的刺激活性认为是100%。样品在与人工胃液(SGF)一起培养的其他时间的活性以作为0分钟的样品活性的百分比来计算。所述数据是三个数值平均数±标准差。
图1B是一种示意图,显示了SP-304样品与人工胃液(SGF)一起培养指定时间之后的高效液相色谱分析。在与人工胃液(SGF)培养过程中,SP-304的主尖峰没有变化,这一结果显示了这种肽能够抵抗人工胃液(SGF)的消化作用。箭头表明了SP-304的洗提位置。
图2A是一种条形图,显示了在T84细胞中将SP304样品与人工肠液(SIF)一起培养指定时间之后环式鸟漂呤磷酸合成。在培养之后,使用样品测定其在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力。在与人工肠液(SIF)一起培养的第0分钟,所述环鸟苷单磷酸(cGMP)在样品中的刺激活性认为是100%。样品在与人工肠液(SIF)一起培养的其他时间的活性以作为0分钟的样品活性的百分比来计算。所述数据是三个数值平均数±标准差。
图2B是一种示意图,显示了SP-304样品与(A)加热失活的人工肠液(SIF)一起培养300分钟之后或者(B)与人工肠液(SIF)一起培养120分钟之后的高效液相色谱分析。在与人工肠液(SIF)培养过程中,SP-304完全转变为另一种肽,在9.4分钟时洗提出来,如*的显示。箭头表明了SP-304的位置。
图3是一种示意图,表示了SP-304可能的降解产物。
图4显示了通过SP-304截断肽在T84细胞内合成环鸟苷单磷酸(cGMP)的刺激作用。因此,SP-338与SP-304具有基本上一样的肽序列,区别仅在于SP-338缺失C末端的亮氨酸(Leu)。 相似的SP-327、SP-329和SP-331相对于其相应的母体SP-326、SP-328和SP-330相比具有C-末端亮氨酸(Leu)的缺失。评价这些多肽在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力。取得重复试验结果的平均数作为实验结果。
图5显示了通过SP-304和相似的肽在T84细胞中对环鸟苷单磷酸(cGMP)合成的刺激作用。将细胞暴露于肽类似物30分钟,使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。所述数据被表示为三个数值平均数±标准差。
图6显示了通过SP-339和其他的肽在T84细胞中对环鸟苷单磷酸(cGMP)合成的刺激作用。将T84细胞暴露于指定的肽中30分钟,使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。所述数据被表示为三个数值平均数±标准差。℃
图7A显示了SP-333在指定时间内抵抗人工肠液(SIF)消化作用的稳定性。通过将多肽与加热钝化的人工肠液(SIF)一起培养产生对照样品,将对照样品标记为C120。将样品从培养物中移出并在95℃条件下加热5分钟,钝化消化酶,然后用于刺激T84细胞中的环鸟苷单磷酸的合成。每个组中,将在0分钟时环鸟苷单磷酸(cGMP)刺激活性看做是100%。所得结果数据时三个值的平均数±标准差。
图7B显示了SP-332在指定时间内抵抗人工肠液(SIF)消化作用的稳定性。通过将多肽与加热钝化的人工肠液(SIF)一起培养产生对照样品,将对照样品标记为C120。将样品从培养物中移出并在95℃条件下加热5分钟,钝化消化酶,然后用于刺激T84细胞中的环鸟苷单磷酸的合成。每个组中,将在0分钟时环鸟苷单磷酸(cGMP)刺激活性看做是100%。所得结果数据时三个值的平均数±标准差。
图7C显示了SP-304在指定时间内抵抗人工肠液(SIF)消化作用的稳定性。通过将多肽与加热钝化的人工肠液(SIF)一起培养产生对照样品,将对照样品标记为C0和C60。将样品从消化液中移出并在95℃条件下加热5分钟,钝化消化酶,然后用于刺激T84细胞中的环鸟苷单磷酸的合成。每个组中,将在0分钟时环鸟苷单磷酸(cGMP)刺激活性看做是100%。所得结果数据时三个值的平均数±标准差。
图7D显示了SP-304样品在与人工肠液(SIF)一起培养0到60分钟之后的高效液相色谱分析。箭头显示了SP-304肽的洗提位置。这些数据清楚的显示了SP-304峰值在洗提14.3分钟之后完全不见,并且在7.4分钟和10.3分钟出现两个新的峰值。这些新出现的肽峰代表了SP-304可能的降解产物。
图7E显示了SP-332样品在与人工肠液(SIF)一起培养0到120分钟之后的高效液相色谱分析。箭头显示了SP-332肽的洗提位置。这些数据显示,在与人工肠液(SIF)一起培养之后,肽SP-332在洗提14.8分钟之后没有发生变化,显示了SP-332对人工肠液中存在的蛋白酶的水解作用不敏感。
图7F显示了SP-333样品在与人工肠液(SIF)一起培养0到120分钟之后的高效液相色谱分析。箭头显示了SP-333肽的洗提位置。这些数据显示,在与人工肠液(SIF)一起培养之后,肽SP-333在洗提14.8分钟之后没有发生变化,显示了SP-333在120分钟的培养时间内对人工肠液中存在的蛋白酶的水解作用不敏感。
图8显示了T84细胞中SP-333聚乙二醇化类似物对环鸟苷单磷酸(cGMP)合成的刺激作用。将T84细胞暴露于指定的多肽中30分钟,并使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。结果表示为三个数据的平均数±标准差。
图9显示了T84细胞中SP-304单独使用或者与磷酸二酯酶(PDE)抑制剂舒林砜(Sulindac Sulfone)(100微摩)或者敏喘宁(100微摩)结合使用对环鸟苷单磷酸(cGMP)合成的刺激作用。将T84细胞暴露于指定的多种处理方法中30分钟,并使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。结果表示为两个数据的平均数。
图10显示了T84细胞中SP-304(0.1微摩或者1.0微摩)单独使用或者与增加浓度的磷酸二酯酶(PDE)抑制剂结合使用对环鸟苷单磷酸(cGMP)合成的刺激作用,如图所示。将T84细胞暴露于指定的多种处理方法中30分钟,并使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。结果表示为两个数据的平均数。
图11显示了T84细胞中SP-333(0.1微摩或者1.0微摩)单独使用或者与增加浓度的敏喘宁结合使用对环鸟苷单磷酸(cGMP)合成的刺激作用,如图所示。将T84细胞暴露于指定的多种处理方法中30分钟,并使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。结果表示为两个数据的平均数。
图12显示了T84细胞中SP-333(0.1微摩)单独使用或者与增加浓度的舒林砜(Sulindac Sulfone)结合使用对环鸟苷单磷酸(cGMP)合成的刺激作用,如图所示。将T84细胞暴露于指定的多种处理方法中30分钟,并使用细胞溶解产物确定细胞内环鸟苷单磷酸(cGMP)水平。结果表示为两个数据的平均数。
图13显示了环鸟苷单磷酸(cGMP)水平细胞内浓度示意图。通过鸟苷酸环化酶(GC-C)活化作用刺激环鸟苷单磷酸(cGMP)合成或者通过抑制环鸟苷单磷酸(cGMP)-磷酸二酯酶(PDE)对环鸟苷单磷酸(cGMP)降解作用可疑斥为细胞内环鸟苷单磷酸(cGMP)水平。因此,将鸟苷酸环化酶(GC-C)激动剂与磷 酸二酯酶(PDE)抑制剂的结合可以产生一种协同效应,从而增强组织和器官中的环鸟苷单磷酸(cGMP)水平。
具体实施方式
本发明是以鸟苷酸环化酶(GC-C)激动剂的发展为基础的。所述激动剂是尿鸟苷素和细菌性的ST肽的类似物,这些激动剂具有一些高级性质,例如,在N末端和C末端对羧肽酶和/或其他的蛋白水解酶降解作用的高抵抗力,所述其他的蛋白水解酶存在于刺激后的人类肠液和人类胃液中。
所述鸟苷酸环化酶(GC-C)可以在不同的细胞中表达,包括在胃肠道上皮细胞上的表达,和在肠道外组织上的表达,所述肠道外组织包括肾脏、肺、胰脏、脑垂体、肾上腺、生长中的肝脏、心脏以及男性和女性的生殖组织(参见文献Vaandrager2002MoICell Biochem230:73-83)。所述鸟苷酸环化酶(GC-C)是肠道和肾脏中液体和电解质平衡的关键的调节因子。在肠道中,当收到刺激时,鸟苷酸环化酶(GC-C)会导致肠道上皮环鸟苷单磷酸(cGMP)的增加。所述环鸟苷单磷酸(cGMP)的增加会导致水吸收和那吸收的下降,以及氯离子和钾离子分泌的增加,从而导致肠道液体好电解液运输方面的变化和肠道活动性的增加。
根据本发明的鸟苷酸环化酶-C激动剂包括SEQ ID NO:2-54和SEQ ID NO:57-98,所述激动剂概括在下面的表I和表II中。本发明所述的鸟苷酸环化酶-C激动剂在这里统一表示为“GCRA多肽”。
在这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)能够结合鸟苷酸环化酶(GC-C)并刺激细胞内环鸟苷单磷酸(cGMP)的产生。选择性的,鸟苷酸环化酶-C激动剂(GCRA肽)会诱导细胞凋亡。在某些方面,鸟苷酸环化酶-C激动剂(GCRA肽)能够刺激细胞内环鸟苷单磷酸(cGMP)的产量比天然存在的鸟苷酸环化酶(GC-C)激动剂(例如,尿鸟苷素、鸟苷肽、和ST肽)和/或SP-304的产量要高。例如,与天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304相比,本发明的鸟苷酸环化酶-C激动剂(GCRA肽)能够刺激5%,10%,20%,30%,40%,50%,75%,90%或者更多的细胞内环鸟苷单磷酸(cGMP)的产生。术语“诱导”和“刺激”在本发明说明书中可以互换使用。在这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)比天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304更为稳定。所述“更为稳定”是指与天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304相比,所述肽在人工胃液和/或人工肠液中的降解量更少和/或降解作用更慢。例如,本发明鸟苷酸环化酶-C激动剂(GCRA肽)的降解与天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304的降解相比少2%,3%,5%,10%,15%,20%,30%,40%,50%,75%,90%或者更少。
这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)在多种紊乱和病况的治疗过程中具有治疗价值,所述紊乱和病况包括,例如,胃肠功能紊乱,炎症性疾病,肺部疾病,癌症,心脏疾病,眼部疾病,口腔疾病,血液病,肝脏疾病,皮肤疾病,前列腺疾病,内分泌失调,增加的肠胃蠕动和肥胖症。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸度)、便秘(例如,与使用药物有关的便秘, 所述药物例如,鸦片样物质、治疗骨关节炎的药物、治疗骨质疏松症的药物;与手术后有关的便秘;与神经性疾病有关的便秘)。炎症性疾病包括组织和器官发炎,例如肾脏发炎(例如,肾炎)、胃肠道系统炎症(例如,克罗恩病和溃疡性结肠炎);胰脏炎症(例如,胰腺炎)、肺部炎症(例如,支气管炎或哮喘)或者皮肤发炎(例如,牛皮癣,湿疹)。肺部疾病包括,例如慢性阻塞性肺疾病(COPD)和纤维症。癌症包括组织和器官癌变,包括转移性肿瘤,例如胃肠癌(例如,胃癌,食道癌,胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或者结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑色素瘤);口腔癌;尿道癌(例如,膀胱癌或者肾癌);血癌(例如,髓细胞癌或白血病)或前列腺癌。心脏疾病包括,例如,充血性心力衰竭、高血压气管贲门、高胆固醇或高甘油三酯。肝脏疾病包括,例如肝硬化和纤维症。眼部疾病包括,例如,增加的眼内压力、青光眼、干眼症、视网膜变性、泪腺分泌紊乱或者眼睛发炎。皮肤病包括,例如干燥症。口腔疾病包括,例如口干燥(口腔干燥)、干燥综合征(Sjogren'ssyndrome),齿龈疾病(例如,牙周疾病)、或唾液腺导管堵塞或机能失调。前列腺疾病包括,例如包括良性前列腺增生症(BPH)。内分泌疾病包括,例如糖尿病、甲状腺机能亢进症、甲状腺机能减退症和囊肿性纤维化。
如这里使用的术语“鸟苷酸环化酶(GC-C)”是指在任意细胞型中的一类鸟苷酸环化酶C受体,所述细胞型能够与本发明激动剂肽或者这里描述的天然激动剂相结合。如这里使用的“肠道鸟苷酸环化酶受体”仅仅发现在胃肠道(GI)粘膜上皮细胞线上。可以预计,尿鸟苷素、鸟苷肽和ST肽能够结合这些受体并导致细胞凋亡。但是并不排除每种激动剂多肽可能具有不同受体的可能性。因此,该术语涉及胃肠道(GI)粘膜的上皮细胞线上的一类鸟苷酸环化酶受体。
如这里所述的,术语“GCR激动剂”是指能够与肠内鸟苷酸环化酶C相结合的肽和/或其他化合物,所述激动剂能刺激液体和电解液的运输。该术语还包括能够结合鸟苷酸环化酶(GC-C)的片段和前肽,并且刺激液体和水的分泌。
如这里使用的,术语“基本上相同”是指一种多肽,这种多肽具有的氨基酸序列与结合区域相同,在所述结合区域上,某些残基可以被删除或者用其他氨基酸取代,同时不会损害多肽结合肠内鸟苷酸环化酶受体并刺激液体和电解液运输的能力。
本发明普通技术人员可以很好理解,可以向本发明组合物中加入载体(例如,磷酸盐缓冲盐水或者PBS)及其他组分。除了本发明化合物之外,本发明组合物还可以包括药学上可接受的载体及其他已知可以促进给药和/或加强吸收的成分。其他的制剂,例如,微球体、纳米颗粒、脂质体、和基于免疫学的系统也可以与本发明同时使用。其他的实施例包括带有聚合物(例如,20%w/v聚乙二醇)或者纤维素的制剂、或者肠溶制剂。
本发明是以许多方案为基础的,首先是存在一种环鸟苷单磷酸(cGMP)依赖型机制,该机制能够调节细胞增殖和细胞凋亡之间的平衡并且由于尿鸟苷素/鸟苷肽缺陷和/或由于环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶造成的环鸟苷单磷酸(cGMP)水平的减少,这种机制在赘生物转化过程中是早期的关键步骤。第二个方案是花生四烯酸从膜磷脂中的释放,从而导致细胞质磷脂酶A2(cPLA2)、环加氧酶-2(COX-2)和可能的5-脂肪氧合酶(5-LO)在发炎过程中的活化作用,通过环鸟苷单磷酸(cGMP)依赖型机制可以下调所述第二方案,从而导致前列腺素和白细胞三烯水平的降低,并且增加细胞内环鸟苷单磷酸(cGMP)水平,产生一种抗炎症性反应。此外,一种环鸟苷单磷酸(cGMP)依赖型机制也被认为包含在炎症前过程中。因此,细胞内环鸟苷单 磷酸(cGMP)水平的提高可以被用作治疗和控制胃肠功能紊乱、炎症性疾病,肺部疾病,癌症,心脏疾病,眼部疾病,口腔疾病,血液病,肝脏疾病,皮肤疾病,前列腺疾病,内分泌失调,增加的肠胃蠕动和肥胖症的方法。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸度)、便秘(例如,与使用药物有关的便秘,所述药物例如,鸦片样物质、治疗骨关节炎的药物、治疗骨质疏松症的药物;与手术后有关的便秘;与神经性疾病有关的便秘)。炎症性疾病包括组织和器官发炎,例如肾脏发炎(例如,肾炎)、胃肠道系统炎症(例如,克罗恩病和溃疡性结肠炎);胰脏炎症(例如,胰腺炎)、肺部炎症(例如,支气管炎或哮喘)或者皮肤发炎(例如,牛皮癣,湿疹)。肺部疾病包括,例如慢性阻塞性肺疾病(COPD)和纤维症。癌症包括组织和器官癌变,包括转移性肿瘤,例如胃肠癌(例如,胃癌,食道癌,胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或者结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑色素瘤);口腔癌;尿道癌(例如,膀胱癌或者肾癌);血癌(例如,髓细胞癌或白血病)或前列腺癌。心脏疾病包括,例如,充血性心力衰竭、高血压气管贲门、高胆固醇或高甘油三酯。肝脏疾病包括,例如肝硬化和纤维症。眼部疾病包括,例如,增加的眼内压力、青光眼、干眼症、视网膜变性、泪腺分泌紊乱或者眼睛发炎。皮肤病包括,例如干燥症。口腔疾病包括,例如口干燥(口腔干燥)、干燥综合征(Sjogren's syndrome),齿龈疾病(例如,牙周疾病)、或唾液腺导管堵塞或机能失调。前列腺疾病包括,例如包括良性前列腺增生症(BPH)。内分泌疾病包括,例如糖尿病、甲状腺机能亢进症、甲状腺机能减退症和囊肿性纤维化。
不希望被任何理论限制,本领域技术人员可以相信,离子通过质膜的运输是一种重要的细胞增殖和细胞凋亡平衡调节机制,通过制剂改变环鸟苷单磷酸(cGMP)浓度可以影响所述机制。尿鸟苷素已经表现出能够刺激K+流出和Ca++流入,以及水在胃肠道(3)的运输。此外,心房利钠多肽(ANP)也是一种能够与特异性鸟苷酸环化酶受体结合的肽,在鼠血管系膜细胞中,心房利钠多肽(ANP)表现出诱导细胞凋亡的能力,通过环鸟苷单磷酸(cGMP)机制(21-24)诱导心肌细胞的细胞凋亡。
本发明激动剂与一种鸟苷酸环化酶受体的结合能够刺激环鸟苷单磷酸(cGMP)的产生。通过活化环鸟苷单磷酸(cGMP)依赖性蛋白激酶级联和囊性纤维化跨膜转运调节因子(CFTR),这种配位体-受体之间的相互作用能够在目标细胞内诱导细胞凋亡。因此,给药由SEQ ID NO:2-54和SEQ ID NO:57-98定义的新型多肽,如表I和表II所示,或者给药尿鸟苷素、鸟苷肽或者大肠杆菌ST肽的多肽类似物可以有效的用于消除,或者至少延迟胃肠功能紊乱、炎症性紊乱、肺紊乱、癌症、心脏功能紊乱、眼部功能紊乱、口腔紊乱、血液紊乱、肝脏功能紊乱、皮肤疾病、前列腺功能紊乱、内分泌紊乱、增加的胃肠道活动性和肥胖症的发病。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸度)、便秘(例如,与使用药物有关的便秘,所述药物例如,鸦片样物质、治疗骨关节炎的药物、治疗骨质疏松症的药物;与手术后有关的便秘;与神经性疾病有关的便秘)。炎症性疾病包括组织和器官发炎,例如肾脏发炎(例如,肾炎)、胃肠道系统炎症(例如,克罗恩病和溃疡性结肠炎);胰脏炎症(例如,胰腺炎)、肺部炎症(例如,支气管炎或哮喘)或者皮肤发炎(例如,牛皮癣, 湿疹)。肺部疾病包括,例如慢性阻塞性肺疾病(COPD)和纤维症。癌症包括组织和器官癌变,包括转移性肿瘤,例如胃肠癌(例如,胃癌,食道癌,胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或者结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑色素瘤);口腔癌;尿道癌(例如,膀胱癌或者肾癌);血癌(例如,髓细胞癌或白血病)或前列腺癌。心脏疾病包括,例如,充血性心力衰竭、高血压气管贲门、高胆固醇或高甘油三酯。肝脏疾病包括,例如肝硬化和纤维症。眼部疾病包括,例如,增加的眼内压力、青光眼、干眼症、视网膜变性、泪腺分泌紊乱或者眼睛发炎。皮肤病包括,例如干燥症。口腔疾病包括,例如口干燥(口腔干燥)、干燥综合征(Sjogren's syndrome),齿龈疾病(例如,牙周疾病)、或唾液腺导管堵塞或机能失调。前列腺疾病包括,例如包括良性前列腺增生症(BPH)。内分泌疾病包括,例如糖尿病、甲状腺机能亢进症、甲状腺机能减退症和囊肿性纤维化。
尿鸟苷素是一种循环肽类激素,具有促尿钠排泄活性,并且发现能够以与另一种热稳定性肠毒素(ST肽)相似的方式刺激液体和电解液的运输,所述热稳定性肠毒素是由致病菌大肠杆菌及其他能够活化受体并产生分泌性腹泻的肠道细菌分泌的。与细菌性ST肽不同的是,尿鸟苷素与鸟苷酸环化酶受体的结合取决于肠道的生理pH值。因此,可以预计尿鸟苷素能够以一种pH依赖方式调节液体和电解液的运输并不会产生严重的腹泻。
GCRA肽
在一个方面,本发明提供了一种鸟苷酸环化酶-C激动剂(GCRA肽)。所述鸟苷酸环化酶-C激动剂(GCRA肽)是尿鸟苷素和细菌性ST肽的类似物。术语“肽”并不代表任何特定的长度。在某些实施方案中,鸟苷酸环化酶-C激动剂(GCRA肽) 的长度小于25个氨基酸,例如,长度小于或者等于20个氨基酸、15个氨基酸、14个氨基酸、13个氨基酸、12个氨基酸、11个氨基酸、10个氨基酸或者5个氨基酸。
所述鸟苷酸环化酶-C激动剂(GCRA肽)可以是L-氨基酸、D-氨基酸的聚合物或者两者的结合。例如,在不同的实施方案中,所述多肽是D逆反式肽。术语“逆反式异构体”是指一种线性肽的异构体,在此异构体中,序列的方向是反向的,并且每个氨基酸残基的手性是相反的。例如,参见Jameson et al.,Nature,368,744-746(1994);Brady et al,Nature,368,692-693(1994)。将D对性异构体与反向合成相结合的最后结果是每个胺键中的羰基和氨基的位置相互交换,同时保留每个α碳上的侧链位置。除非具体声明,假定本发明任意给定的L-氨基酸序列都可以通过合成相应天然L-氨基酸序列的反向序列制成一种D逆反式肽。例如,一种鸟苷酸环化酶-C激动剂(GCRA肽)包括SEQ ID NO:SEQ ID NO:2-54和SEQ ID NO:57-98的序列。在不同的实施方案中,鸟苷酸环化酶-C激动剂(GCRA肽)包括SEQ ID NO:45-54和SEQ ID NO:87-98氨基酸序列,其中SEQ ID NO:45-54和SEQ ID NO:87-98通过细胞诱导环鸟苷单磷酸(cGMP)产生。在不同的实施方案中,本发明的鸟苷酸环化酶-C激动剂(GCRA肽)包括式I-IX所示的氨基酸序列(例如,SEQ ID NO:45-54),条件是所述鸟苷酸环化酶-C激动剂(GCRA肽)不是SEQ ID NO:1。再进一步的实施方案中,本发明的鸟苷酸环化酶-C激动剂(GCRA肽)包括式X-XVII所示的氨基酸序列(例如,SEQ ID NO:87-98),条件是所述鸟苷酸环化酶-C激动剂(GCRA肽)不是SEQ ID NO:55或者SEQ ID NO:56。“诱导环鸟苷单磷酸(cGMP)产生”是指鸟苷酸环化酶-C激动剂(GCRA肽)能够诱导细胞内环鸟苷单磷酸(cGMP)的产生。细胞内环鸟苷单磷酸(cGMP)可以通过本领域已知的方法调节。例如,本发明的 鸟苷酸环化酶-C激动剂(GCRA肽)与天然存在的鸟苷酸环化酶(GC-C)激动剂相比能够刺激5%、10%、20%、30%、40%、50%、75%、90%或更多细胞内环鸟苷单磷酸(cGMP)的产生。选择性的,本发明的鸟苷酸环化酶-C激动剂(GCRA肽)与SP-304相比能够刺激5%、10%、20%、30%、40%、50%、75%、90%或更多细胞内环鸟苷单磷酸(cGMP)的产生。在进一步的实施方案中,鸟苷酸环化酶-C激动剂(GCRA肽)可以刺激细胞凋亡,例如,程序性细胞死亡,或者鸟苷酸环化酶-C激动剂(GCRA肽)可以活化囊性纤维化跨膜转运调节因子(CFTR)。在一些实施方案中,这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)比天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304(SEQ ID NO:1)、SP-339(SEQ ID NO:55)或者SP-340(SEQ ID NO:56)更加稳定。“更加稳定”的意思是指所述多肽与天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304相比,所述肽在人工胃液和/或人工肠液中的降解量更少和/或降解作用更慢。例如,本发明鸟苷酸环化酶-C激动剂(GCRA肽)的降解与天然存在的鸟苷酸环化酶(GC-C)激动剂和/或SP-304、SP-339或者SP-340的降解相比少2%,3%,5%,10%,15%,20%,30%,40%,50%,75%,90%或者更少。
如这里使用的“PEG3”、“3PEG”是指聚乙二醇,包括,例如氨基乙氧基-乙氧基-乙酸(AeeA)。如这里使用的(例如,式I-XVII,SEQ ID NO:45-54和SEQ ID NO:87-98),Xaa是指任意一种天然的、非天然的氨基酸或者氨基酸类似物;Maa是一种半胱氨酸(Cys)、青霉胺(Pen)同型半胱氨酸、或者3-mercaptoproline;Xaan1是指任意一种天然的、非天然的氨基酸或者氨基酸类似物的氨基酸序列,所述氨基酸或者氨基酸类似物的长度为1个氨基酸残基、2个氨基酸残基或者三个氨基酸残基;Xaab2是指任意一种天然的、非天然的氨基酸或者氨基酸类似物 的氨基酸序列,所述氨基酸或者氨基酸类似物的长度为0个氨基酸残基或者1个氨基酸残基;并且Xaan3是指任意一种天然的、非天然的氨基酸或者氨基酸类似物的氨基酸序列,所述氨基酸或者氨基酸类似物的长度为0个氨基酸残基、1个氨基酸残基、2个氨基酸残基、3个氨基酸残基、4个氨基酸残基、5个氨基酸残基或者6个氨基酸残基。另外,Xaa、Xaan1、Xaan2、或者Xaan3所代表的任一氨基酸都可以是L-氨基酸、D-氨基酸、甲基化的氨基酸或者他们的结合物。任选的,式I-VII所代表的任意GCRA肽可以在N-末端、C-末端或者两端包含一个或一个以上的聚乙二醇残基。实例性的聚乙二醇包括氨基乙氧基-乙氧基乙酸及其聚合物。
在某些实施方案中,GCRA肽包括含有式I氨基酸序列的肽,其中,至少一个式I氨基酸是D-氨基酸或者甲基化氨基酸和/或在位置16的氨基酸是丝氨酸。优选的,在式I第16位上的氨基酸是一种D-氨基酸或者甲基化的氨基酸。例如,在式I第16位上的氨基酸是D-亮氨酸或者D-丝氨酸。任选的,式I第1-3位的一种或一种以上的氨基酸是D-氨基酸或者甲基化的氨基酸,或者是D-氨基酸与甲基化氨基酸的结合物。例如,式I中的Asn1、Asp2或者Glu3(或其结合物)是D-氨基酸或者甲基化的氨基酸。优选的,式I第Xaa6位的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。
在一种作为选择的实施方案中,GCRA肽包括含有式II氨基酸序列的多肽,其中,式II中至少一个氨基酸是D-氨基酸或者甲基化氨基酸。优选的,式II中由Xaan2所表示的氨基酸是一种D-氨基酸或者甲基化的氨基酸。在某些实施方案中,式II中Xaan2所表示的氨基酸是一种亮氨酸、d-亮氨酸、丝氨酸或者d-丝氨酸。优选的,式II中Xaan1所表示的一种或者一种以上的氨基酸是一 种D-氨基酸或者一种甲基化的氨基酸。优选的,式II中第Xaa6位所表示的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。
在某些实施方案中,GCRA多肽包括含有式III所示氨基酸序列的肽,其中1)式I中的至少一个氨基酸是D-氨基酸或者甲基化的氨基酸,和/或2)Maa不是半胱氨酸。优选的,式III中Xaan2所表示的氨基酸是D氨基酸或者甲基化的氨基酸。在某些实施方案中,式III中Xaan2所表示的氨基酸是一种亮氨酸、d-亮氨酸、丝氨酸或者d-丝氨酸。优选的,式III中Xaan1所表示的一种或者一种以上的氨基酸是一种d-氨基酸或者甲基化的氨基酸,优选的,式III中第Xaa6位所表示的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。
在其他的实施方案中,GCRA多肽包括含有式IV所示氨基酸序列的肽,其中1)式IV中的至少一个氨基酸是D-氨基酸或者甲基化的氨基酸,和/或2)Maa不是半胱氨酸。优选的,式IV中Xaan2所表示的氨基酸是D氨基酸或者甲基化的氨基酸。在某些实施方案中,式IV中Xaan2所表示的氨基酸是一种亮氨酸、d-亮氨酸、丝氨酸或者d-丝氨酸。优选的,式IV中Xaan1所表示的一种或者一种以上的氨基酸是一种d-氨基酸或者甲基化的氨基酸,优选的,式IV中第Xaa6位所表示的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。在进一步的实施方案中,GCRA多肽包括含有式V所示氨基酸序列代表的肽,其中,式V中的至少一个氨基酸是D-氨基酸或者甲基化的氨基酸。优选的,在式V第16位的氨基酸是一种D-氨基酸或者甲基化的氨基酸。例如,在式V第16位的氨基酸(即,Xaa16)是一种d-亮氨酸或者d-丝氨酸。任选的,式V第1-3位的一种或一种以上的氨基酸是D-氨基酸或者甲基化的氨基酸,或者是D-氨基酸与甲基化氨基酸的结合物。例如,式V中的Asn1、Asp2或者Glu3(或其结合物) 是D-氨基酸或者甲基化的氨基酸。优选的,式V第Xaa6位的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。
在其他的实施方案中,GCRA多肽包括含有式VI、VII、VIII、IX所示氨基酸序列的肽。优选的,在式VI、VII、VIII、IX第6位上的氨基酸是一种亮氨酸、丝氨酸或者酪氨酸。在某些方面,式VI、VII、VIII、IX第16位上的氨基酸是一种亮氨酸或者丝氨酸。优选的,在式V第16位上的氨基酸是一种D-氨基酸或者一种甲基化的氨基酸。
在优选的实施方案中,GCRA多肽是SP-332(SEQ ID NO:8)、SP-333(SEQ ID NO:9)或SP-334(SEQ ID NO:10)。
在其他的实施方案中,GCRA多肽包括一种肽,所述肽含有式X、XI、XII、XIII、XIV、XV、XVI或者XVII所示氨基酸序列。任选的,在式X、XI、XII、XIII、XIV、XV、XVI或者XVII上一种或者一种以上的氨基酸序列是D-氨基酸或者甲基化的氨基酸。优选的,式X、XI、XII、XIII、XIV、XV、XVI或者XVII所示肽的羧基末端氨基酸是一种D-氨基酸或者甲基化的氨基酸。例如,式X、XI、XII、XIII、XIV、XV、XVI或者XVII所示肽羧基末端的氨基酸序列是D-酪氨酸。
优选的,式XIV的Xaa6位上的氨基酸是一种酪氨酸、苯基丙氨酸或者丝氨酸。更优选的,式XIV第Xaa6位上的氨基酸是一种苯基丙氨酸或者丝氨酸。优选的,在式XV、XVI或者XVII第Xaa4上的氨基酸是一种酪氨酸、苯基丙氨酸或者丝氨酸。更优选的,在式XV、XVI或者XVII第Xaa4上的氨基酸是一种苯基丙氨酸或者丝氨酸。
在优选的实施方案中,GCRA肽是SP-353(SEQ ID NO:58)或者SP-354(SEQ ID NO:59)。
在某些实施方案中,GCRA肽中一种或者一种以上的氨基酸可以被非天然存在的氨基酸、或者天然存在的氨基酸类似物或者非天然存在的氨基酸类似物所取代。在标准的20种氨基酸之外还有很多氨基酸(丙氨酸(Ala)、精氨酸(Arg)、蛋氨酸(Asn)、天门冬氨酸(Asp)、半胱氨酸(Cys)、谷胺酰胺(Gln)、谷氨酸(Glu)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、亮氨酸(Leu)、赖氨酸(Lys)、甲硫氨酸(Met)、苯基丙氨酸(Phe)、脯氨酸(Pro)、丝氨酸(Ser)、苏氨酸(Thr)、色氨酸(Trp)、酪氨酸(Tyr),和缬氨酸(VaI))。其中一些是天然存在的,其他的不是天然存在的(参见,例如,Hunt,The Non-Protein Amino Acids:In Chemistry and Biochemistry of the Amino Acids(菲蛋白质氨基酸:在氨基酸化学或者生物化学中),Barrett,Chapman and Hall,1985)。例如,一种芳香族氨基酸可以被3,4-二氢氧基-L-苯基丙氨酸,3-碘代-L-酪氨酸、三碘甲状腺氨酸,L-甲状腺素,苯基甘氨酸(PHG)或者非-酪氨酸(norTyr)所取代。苯基甘氨酸(PHG)和非-酪氨酸(norTyr)以及其他的包含Phe和Tyr的氨基酸可以被,例如,卤素、-CH3、-OH、-CH2NH3、-C(O)H、-CH2CH3、-CN、-CH2CH2CH3、-SH或者其他基团所取代。任意氨基酸都可以被其D-型氨基酸所取代。
对于本发明所描述的多肽和颉抗剂,关于非天然存在的氨基酸或者天然存在的氨基酸类似物或者非天然存在的氨基酸类似物方面可以存在多种替换,这些替换可以单独发生也可以结合发生。
例如,谷氨酸残基可以被γ-氢氧基-谷氨酸或者γ-羧基-谷氨酸所取代。酪氨酸残基可以被α取代的氨基酸或者类似物所取代,所述α取代的氨基酸例如,L-α-甲基苯基丙氨酸,所述类似物例如3-氨基-酪氨酸;Tyr(CH3);Tyr(PO3(CH3)2);Tyr(SO3H);β-环己基-丙氨酸;β-(1-环戊基)-丙氨酸;β-环戊基-丙氨酸;β-环丙基-丙氨酸;β-喹啉基-丙氨酸;β-环丙基-丙氨酸;β-喹啉基-丙氨酸;β-(2-噻唑基)-丙氨酸;β-(三唑基-1-基)-丙氨酸;β-(2-吡啶基)-丙氨酸;β-(3-吡啶基)-丙氨酸;氨基-苯基丙氨酸;氟代-苯基丙氨酸;环己基-甘氨酸;tBu-Gly;β-(3-苯甲基噻吩基)-丙氨酸;β-(2-噻吩基)-丙氨酸;5-甲基-色氨酸;和A-甲基-色氨酸。脯氨酸残基可以被高脯氨酸(L-哌啶酸);羟基脯氨酸;3,4-脱氢脯氨酸;4-氟代脯氨酸或α-甲基-弗氨酸或N(α)-C(α)环化氨基酸结构类似物所取代。N=0、1、2、3。丙氨酸残基可以被α取代的或者N-甲基化的氨基酸所取代,例如,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、或者L/D-α-甲基亮氨酸或者一种非天然氨基酸,例如,β-氟代-丙氨酸。丙氨酸残基也可以被取代:n=0、1、2、3。甘氨酸残基可以被α-氨基异丁酸(aib)、L/D-α-乙基丙氨酸(L/D-异缬氨酸)所取代。
非天然氨基酸进一步的例子包括: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,一种烷基,芳基,酰基,叠氮基,氰基,卤代物、联胺、酰肼、氢氧基、烯基、炔基、醚、硫醇、磺酰基、硒基、酯、硫代酸、硼酸盐、硼酸、磷酸基、膦酰基、三氢化磷、杂环基、烯酮、亚胺、醛、羟胺、酮基、或者氨取代的氨基酸、或者其任意结合物;含有光敏交联剂的氨基酸;一种自旋标记的氨基酸;一种有荧光性的氨基酸;一种有新型官 能团的氨基酸;能够与另一种分子发生共价或者非公价相互作用的氨基酸;一种结合金属的氨基酸;在非天然酰胺化位点发生酰胺化作用的氨基酸、一种包含金属的氨基酸;一种有放射性的氨基酸;一种photocaged和/或光敏异构的氨基酸;一种生物素或者包含氨基酸的生物素类似物;一种糖基化或者碳水化合物修饰的氨基酸;一种包含氨基酸的酮类物质;包括聚乙二醇或者聚醚的氨基酸;一种重分子取代的氨基酸(例如,包含氘、氚、13C,15N,或者18O的氨基酸);一种化学裂解或光裂解的氨基酸;一种具有延长的侧链的氨基酸;一种包含有毒基团的氨基酸;一种糖取代的氨基酸,例如,一种汤取代的丝氨酸等等;一种碳-连接的-包含糖的氨基酸;一种具有氧化还原活性的氨基酸;一种包含α-羟基的酸;一种包含氨基硫代酸的氨基酸;一种α,α双取代的氨基酸;一种β-氨基酸;一种除了脯氨酸之外的环状氨基酸;一种O-甲基-L-酪氨酸;一种L-3-(2-萘基)丙氨酸;一种3-甲基-苯基丙氨酸、一种p-乙酰基-L-苯基丙氨酸;一种O-4-烯丙基-L-酪氨酸;一种4-丙基-L-酪氨酸;一种三-O-乙酰氨基葡萄糖(GlcNAc)β-丝氨酸;一种左旋多巴;一种氟化苯丙氨酸;一种异丙基-L-苯基丙氨酸,一种P-叠氮基-L-苯基丙氨酸,一种P-酰基-L-苯基丙氨酸,一种P-苯甲酰基-L-苯基丙氨酸,一种L-磷酸丝氨酸,一种膦酰基丝氨酸,一种膦酰基酪氨酸,一种P-碘代-苯基丙氨酸,一种四氟苯甘氨酸,一种P-溴代苯基丙氨酸,一种P-氨基-L-苯基丙氨酸,一种异丙基-L-苯基丙氨酸;L-3-(2-萘基)丙氨酸;D-3-(2-萘基)丙氨酸(dNal);一种包含氨基、异丙基、或O-烯丙基的苯基丙氨酸类似物;一种多巴,O-甲基-L-酪氨酸;一种糖基化氨基酸;一种P-(氧化丙炔基)苯基丙氨酸;二甲基-赖氨酸;羟基脯氨酸;3巯基丙酸;甲基赖氨酸;3-硝基酪氨酸;正亮氨酸;焦谷氨酸;Z(下氧羰基);ε-乙酰-赖氨酸,β-丙氨酸;氨基苯甲酰衍生物;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-苯基丙氨酸;硝基酪氨酸;正缬氨酸;八氢吲哚羧酸酯;鸟氨酸(Orn);青霉胺(PEN);四氢基异喹啉;乙酰氨甲基保护的氨基酸和聚乙二醇化的氨基酸。非天然氨基酸和氨基酸类似物进一步的实施例可以在美国专利第20030108885号、美国专利第20030082575号、美国专利第20060019347号(410-418段)和这里引用的参考文献中发现。本发明的多肽可以进一步的包括一些修饰,所述修饰包括美国专利第20060019347号第589段的描述。包含非天然存在的氨基酸的示例性鸟苷酸环化酶-C激动剂(GCRA肽)包括,例如,SP-368和SP-369。
在一些实施方案中,氨基酸可以被一种天然存在的、非必需氨基酸所取代,例如牛磺酸。
因此,GCRA肽是一种环状肽。通过本领域普通技术人员已知的方法可以制备GCRA环状肽。例如,通过在肽的N-末端和C-末端形成一种胺键,或者在N或C末端与一种侧链之间形成一种酰胺键[例如,在pH值为8.5的时候使用K3Fe(CN)6](Samson et al,Endocrinology,137:5182-5185(1996)),或者在两个氨基酸侧链,例如半胱氨酸之间形成一种胺键(参见,例如DeGrado,Adv Protein Chem,39:51-124(1988))的方法完成大环化合物的形成。在本发明的各个方面,GCRA肽是[4,12;7,15]双环的。
在某些GCRA多肽中,能够形成二硫键的半胱氨酸残基对中一个或两个成员都可以被同型半胱氨酸、青霉氨、3-mercaptoproline(Kolodziej et al.1996Int J Pept Protein Res48:274);β,β-二甲基半胱氨酸(Hunt et al.1993Int JPept Protein Res42:249)或者二氨基丙酸(Smith et al.1978J Med Chem2 1:117)所取代,从而在通常形成二硫键的位置形成一种作为替换的内交联。
另外,一个或者一个以上的二硫键可以被其他作为替换的共价交联方式所取代,例如,一种酰胺连接键(-CH2CH(O)NHCH2-或者-CH2NHCH(O)CH2-)、一种酯连接键、一种硫酯连接键、一种内酰胺桥、一种氨基甲酰连接键、一种脲连接键、一种硫脲连接键、一种磷酸酯连接键、一种烷基连接键(-CH2CH2CH2CH2-)、一种烯基连接键(-CH2CH=CHCH2-)、一种醚连接键(-CH2CH2OCH2-或者-CH2OCH2CH2-)、一种硫醚连接键(-CH2CH2SCH2-或者-CH2SCH2CH2-)、一种胺连接键(-CH2CH2NHCH2-或者-CH2NHCH2CH2-)或者一种硫代酰胺连接键(-CH2CH(S)HNHCH2-或者-CH2NHCH(S)CH2-)。例如,Ledu等人(Proc Nat’l Acad.Sci.100:11263-78,2003)描述的制备内酰胺或者酰胺交联方式的方法。包含内酰胺桥的示例性的GCRA肽包括SP-370。
在GCRA中,一种或一种以上的常见多肽键可以被其它的键所取代。这种取代可以增加所述多肽的稳定性。例如,用其他键取代残基氨基末端与一种芳香族残基(例如,Tyr、Phe、Trp)的多肽键会导致羧肽酶裂解作用的降低,并增加所得肽在消化道中的半衰期。能够取代多肽键的键包括:一种逆反式键(C(O)-NH代替NH-C(O);一种还原的酰胺键(NH-CH2);一种硫代甲基键(S-CH2或者CH2-S);一种氧甲基键(O-CH2或者CH2-O);一种乙基键(CH2-CH2);一种硫代酰胺键(C(S)-NH);一种反式-烯烃键(CH=CH);一种氟取代的反式烯烃键(CF=CH);一种酮甲基键(C(O)-CHR或者CHR-C(O),其中,R是氢或者CH3;一种氟-酮甲基键(C(O)-CFR或者CFR-C(O),其中R是H或者F或者CH3。
使用标准的修饰方法可以修饰本发明的鸟苷酸环化酶-C激动剂(GCRA肽)。修饰作用可以在前述序列的氨基(N-)末端、羧基(C-)末端、肽内部或其结合的任何位置发生。在这里描述的一个方面,多肽内部可以具有一种以上类型的修饰作用,所述修饰作用包括,但不局限于:乙酰化作用、酰胺化作用、生物酰化作用、cinnamoylation、法尼基化作用、甲酰化作用、豆蔻酰化作用、棕榈酰化作用、磷酸化作用(丝氨酸、酪氨酸或者苏氨酸)、硬脂酰化作用(stearoylation)、琥珀酰化作用、磺酰化作用和环化作用(通过二硫键环化作用或者酰胺环化作用)、以及通过Cys3或者Cys5实现的修饰作用。这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)也可以通过2,4-二硝基苯基(DNP)、2,4-二硝基苯基(DNP)-赖氨酸进行修饰,通过7-氨基-4-甲基香豆素(AMC)、荧光素、NBD(7-硝基苯-2-氧杂-1,3-二唑)、p-硝基-酰基苯胺、若丹明B、EDANS(5-((2-氨乙基)氨基)萘-1-磺酸)、dabcyl、dabsyl、1-二甲胺基萘-5-磺酰、texas red、FMOC、和Tamra(四甲基罗丹明)。这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)可以与例如,聚乙二醇(PEG);烷基(例如,C1-C20直链烷基或者含有支链的烷基);脂肪酸基团;聚乙二醇、烷基基团和脂肪酸基团的结合物(参见,美国专利第6,309,633号;Soltero et al,2001Innovations in Pharmaceutical Technology(制药技术革新2001年)106-110);牛血清白蛋白(BSA)和KLH(钥孔血蓝素)。聚乙二醇及其他可以用于修饰本发明所述多肽的聚合物在美国专利第2006019347号第IX节有所描述。与这里描述的多肽生物学等效或者功能等效的肽也包括在本发明范围内。这里所述的术语“生物学等效”或者“功能等效”是指本发明组合物能够显示某些或者全部环鸟苷单磷酸(cGMP)产生的调节作用。
鸟苷酸环化酶-C激动剂(GCRA肽)还可以包括鸟苷酸环化酶-C激动剂(GCRA肽)衍生物和修饰物,所述衍生物包括鸟苷酸环化酶-C激动剂(GCRA肽)的杂合物和修饰型,其中,某些氨基酸已经被删除或者被替换,所述修饰物例如肽中一种或者一种以上的氨基酸已经被转化为修饰过的氨基酸或罕见的氨基酸,修饰作用例如糖基化作用,例如能够保持鸟苷酸环化酶-C激动剂(GCRA肽)生物活性的修饰形式。“保持生物活性”是指通过鸟苷酸环化酶-C激动剂(GCRA肽)诱导环鸟苷单磷酸(cGMP)或者细胞凋亡,尽管不需要与天然存在的鸟苷酸环化酶-C激动剂(GCRA肽)具有相等程度的作用效果。
优选的变体是在一种或一种以上预定的非必须氨基酸残基上具有保守氨基酸取代作用的变体。所述“保守氨基酸取代作用”是指在肽中用具有相似侧链的氨基酸残基取代原有的氨基酸残基。本领域技术人员已经定义了具有相似侧链的氨基酸残基族。
这些氨基酸残基族包括具有碱性侧链的氨基酸(例如,赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(例如,天门冬氨酸、谷氨酸)、具有不带电的极性侧链的氨基酸(例如,甘氨酸、天门冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、具有非极性侧链的氨基酸(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯基丙氨酸、甲硫氨酸、色氨酸)、含有β-分支侧链的氨基酸(例如,苏氨酸、缬氨酸、异亮氨酸)和具有芳香族侧链的氨基酸(例如,酪氨酸、苯基丙氨酸、色氨酸、组氨酸)。因此,在GCRA多肽中存在的非必需氨基酸可以被术语同一侧链族的另外一种氨基酸残基所取代。作为选择,在另一种实施方案中,可以随机向所有GCRA编码序列或者GCRA编码序列的一部分中引入突变,例如,饱和突变,筛选所得突变体然后识别保持生物活性的突变体。
“基本上同源”的定义还包括任意可以通过与鸟苷酸环化酶-C激动剂(GCRA肽)抗体发生交叉反应性来分离的鸟苷酸环化酶-C激动剂(GCRA肽)。
GCRA肽的制备
鸟苷酸环化酶-C激动剂(GCRA肽)可以使用现有的克隆技术方便地制备,或者通过固态方法或者定点突变方法合成。一种鸟苷酸环化酶-C激动剂(GCRA肽)可以包括显性阴性形式的多肽。
使用标准液相或者固相肽合成技术可以进行化学合成,其中,通过定向冷凝,在一个氨基酸的氨基和另一个氨基酸的羧基之间形成一种肽键,同时伴随有水分子的消除。通过定向冷凝的肽键合成作用,如上面所示,需要抑制第一个氨基酸的氨基基团和第二个氨基酸的羧基基团的反应性特性。屏蔽取代基必须易于除去,同时不会导致不稳定的碳原子的分解。
在液相合成中,可以使用多种耦合方法和保护基团(参见,Gross and Meienhofer,eds.,″The Peptides:Analysis,Synthesis,Biology,″Vol.1-4(Academic Press,1979(Gross和Meienhofer编辑的“肽:分析、合成、生物研究”第1-4卷,学术出版社,1979);Bodansky and Bodansky,″The Practice of Peptide Synthesis,″2d ed.(Springer Verlag,1994)(Bodansky和Bodansky的“肽合成实践”第二版))。另外,中间产物的纯化和线性放大也是可行的。对于本发明所述领域普通技术人员来讲可以理解的是,溶液合成需要考虑主链和侧链保护基和活化方法。另外,在部分冷凝过程中也需要小心的进行部分选择,从而最小化外消旋作用。
溶解性同样也是需要考虑的因素。使用不可溶的聚合物在有机合成期间作为支持物进行固相肽合成。聚合物-支持的肽链允许使用简单的洗涤和过滤过程,代替中间步骤辛苦的纯化过程。根据Merrifield et al.,J.Am.Chem.Soc,1963,85:2149所述的方法通常可以进行固相肽合成,所述方法包括使用被保护的氨基酸在树脂支持物上集合直线肽链。固相肽合成通常使用Boc或者芴甲氧羰酰(Fmoc)策略,这些都是本发明所述领域已知的。
本领域普通技术人员可以认识到,在固相合成中,去保护和偶联反应必须完全完成,并且侧链封闭基团必须在整个合成过程中都保持稳定。另外,在小规模生产肽时通常固相合成最为合适。
在从树脂上裂解之前,N末端的乙酰化作用可以伴随有末端肽和乙酸酐之间的反应。使用适当的树脂,例如甲基二苯甲基胺树脂,通过Boc技术完成甲基苯C-酰胺化作用。作为选择,通过现代克隆技术可以生产鸟苷酸环化酶-C激动剂(GCRA肽)。例如,可以在细菌,包括但不仅限于大肠杆菌或者其他现有的用于多肽或蛋白质生产的系统(例如,枯草芽胞杆菌、利用果蝇Sf9细胞的杆状病毒表达系统、酵母或者丝状真菌表达系统、哺乳动物细胞表达系统)中生产鸟苷酸环化酶-C激动剂(GCRA肽),或者,鸟苷酸环化酶-C激动剂(GCRA肽)也可以化学合成。如果所述鸟苷酸环化酶-C激动剂(GCRA肽)或者变体肽是在细菌,例如大肠杆菌中产生的,择编码所述多肽的核酸分子可以同时编码一种前导序列,所述前导序列允许成熟多肽从细胞中分泌。因此,编码多肽的序列可以包括前(pre)序列和原(pro)序列,例如,天然存在的细菌性ST多肽的前(pre)序列和原(pro)序列。从培养基中可以纯化得到分泌出的成熟多肽。
可以像载体中插入能够编码这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)的序列,所述载体能够在细菌细胞中传递并维 持核酸分子。所述DNA分子可以被插入一种自动复制的载体(合适的载体包括,例如,pGEM3Z和pcDNA3,及其衍生物)中。所述载体核酸可以使一种细菌DNA或者细菌噬菌体DNA,例如,细菌噬菌体lambda或者M13及其衍生物。
在转化一种宿主细胞,例如转化细菌之后可以构建包括这里描述的核酸的载体。适当的细菌宿主包括,但不局限于,大肠杆菌、枯草杆菌、假单胞菌属、沙门氏菌。除了编码核酸分子之外,该基因构建物还包括允许表达的元素,例如,一种启动子和调节序列。所述表达载体可以包括可以控制转录开始的转录控制序列,例如,启动子、增强子、操纵子、和阻遏子序列。
各种转录控制序列对本领域普通技术人员来讲是已知的。这些表达载体还可以包括一种翻译调节序列(例如,一种未翻译的5’序列,一种未翻译的3’序列,或者一种内部核糖体入口位点)。这种载体可以自行复制或者能够整合入宿主DNA中,从而确保在多台产生过程中的稳定性。
包括这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)的蛋白质编码序列可以与编码多肽亲和标记的核酸相融合,所述多肽亲和标记,例如,谷胱甘肽S-转移酶(GST)、麦芽糖E结合蛋白、蛋白质A、FLAG标记、六-组氨酸、myc标记或者流行性感冒HA标记,从而促进纯化作用。所述亲和标记或者报道基因融合连接在多肽的阅读框处,从而影响编码亲和标记的基因的阅读框,因此发生翻译融合作用。
融合基因的表达导致单一多肽的表达,所述单一多肽既包括所关心的多肽和亲和标记。在使用亲和标记的情况下,编码蛋白酶识别部分的DNA序列融合在亲和标记阅读框和所关心的多肽之间。
适用于在除了细菌之外的蛋白表达系统中生产这里所描述的不成熟或成熟形式的鸟苷酸环化酶-C激动剂(GCRA肽)及其变体的基因构建物和方法对本领域技术人员来讲是已知的。所述基因构建物和方法可以在一种生物系统中生产多肽。
通过与一种第二分子相附着可以修饰这里所公开的多肽,所述第二分子可以赋予肽某些需要的性质,例如,增加体内半衰期,例如,聚乙二醇化。这些修饰作用也包含在这里使用的术语“变体”的范围内。
治疗方法
本发明提供了预防方法以及治疗方法,用于治疗有风险(或者易于)患有或者已经患有一种疾病的患者,所述疾病可以通过鸟苷酸环化酶受体激动剂调节。可以通过鸟苷酸环化酶受体激动剂调节的疾病包括胃肠功能紊乱、炎症性紊乱、肺紊乱、癌症、心脏功能紊乱、眼部功能紊乱、口腔紊乱、血液紊乱、肝脏功能紊乱、皮肤疾病、前列腺功能紊乱、内分泌紊乱、增加的胃肠道活动性和肥胖症。胃肠道紊乱包括,例如,过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假梗阻、十二指肠反流、胃食管反流疾病(GERD)、肠梗阻(例如,手术后肠梗阻)、胃轻瘫、胃灼热(在胃肠道中出现高酸度)、便秘(例如,与使用药物有关的便秘,所述药物例如,鸦片样物质、治疗骨关节炎的药物、治疗骨质疏松症的药物;与手术后有关的便秘;与神经性疾病有关的便秘)。炎症性疾病包括组织和器官发炎,例如肾脏发炎(例如,肾炎)、胃肠道系统炎症(例如,克罗恩病和溃疡性结肠炎);胰脏炎症(例如,胰腺炎)、肺部炎症(例如,支气管炎或哮喘)或者皮肤发炎(例如,牛皮癣,湿疹)。肺部疾病包括,例如慢性阻塞性肺疾病(COPD)和纤维症。癌症包括组织和器官癌变,包括转移性肿瘤,例如胃 肠癌(例如,胃癌,食道癌,胰腺癌、结肠直肠癌、肠癌、肛门癌、肝癌、胆囊癌、或者结肠癌;肺癌;甲状腺癌;皮肤癌(例如,黑色素瘤);口腔癌;尿道癌(例如,膀胱癌或者肾癌);血癌(例如,髓细胞癌或白血病)或前列腺癌。心脏疾病包括,例如,充血性心力衰竭、高血压气管贲门、高胆固醇或高甘油三酯。肝脏疾病包括,例如肝硬化和纤维症。眼部疾病包括,例如,增加的眼内压力、青光眼、干眼症、视网膜变性、泪腺分泌紊乱或者眼睛发炎。皮肤病包括,例如干燥症。口腔疾病包括,例如口干燥(口腔干燥)、干燥综合征(Sjogren's syndrome),齿龈疾病(例如,牙周疾病)、或唾液腺导管堵塞或机能失调。前列腺疾病包括,例如包括良性前列腺增生症(BPH)。内分泌疾病包括,例如糖尿病、甲状腺机能亢进症、甲状腺机能减退症和囊肿性纤维化。
术语“治疗”是指减少或者减轻主体的症状、预防症状恶化或者发展、和/或防止没有患病的主体染病。对于给定的主体,症状的改善、恶化、衰退或者发展可以通过任意主观或者客观的方法测定。治疗的效果可以根据改善发病率或者死亡率(例如,延长选择人群生存曲线)来测定。因此,有效的治疗应该包括对已经存在的基本的治疗、通过减缓或者停止疾病进程控制疾病、预防疾病发生、减少症状的数目或者严格程度,或其结合。在控制研究中,使用一种或一种以上统计上有显著意义标准显示治疗作用。通过将组织(例如,胃肠道组织)或者细胞暴露于GCRA激动剂中或者与GCRA激动剂相接触可以诱导细胞内环鸟苷单磷酸(cGMP)。鸟苷酸环化酶(GC-C)受体可以在整个胃肠道中表达,从食管开始,经十二指肠、小肠中段、肠骨、盲肠和结肠。人结肠癌细胞株(T81、CaCo-2和HT-29)也可以表达鸟苷酸环化酶(GC-C)受体。“诱导”是指与没有接触鸟苷酸环化酶-C激动剂(GCRA肽)或其变体的组织或者细胞相比,环鸟苷单磷 酸(cGMP)的产量增加。将组织或者细胞与鸟苷酸环化酶-C激动剂(GCRA肽)或其变体直接接触。作为选择,系统性给药鸟苷酸环化酶-C激动剂(GCRA肽)或其变体。以足够增加细胞内环鸟苷单磷酸(cGMP)浓度的量给药鸟苷酸环化酶-C激动剂(GCRA肽)或其变体。通过本领域内已知的基于细胞的试验(25)调节环鸟苷单磷酸(cGMP)的产生。
通过对需要的主体,例如一种哺乳动物,例如人,给药治疗有效量的鸟苷酸环化酶-C激动剂(GCRA肽)可以治疗、预防或者缓解疾病。所述鸟苷酸环化酶-C激动剂(GCRA肽)可以以单位剂量形式存在于药物组合物中,同时还包含一种或者一种以上药学上可接受的赋形剂。术语“单位剂量形式”是指一种单一药物传递实体,例如,一种片剂、胶囊剂、液剂或者吸入制剂。当对病人给药时,存在的肽的量应该具有阳性的治疗效果(通常,在10微克到3克之间)。“阳性治疗效果”的构成取决于被治疗的具体情况,并且包括任意本发明所述领域普通技术人员能够方便识别的重要的改进。
鸟苷酸环化酶-C激动剂(GCRA肽)可以单独给药或者与其他试剂结合给药。例如,所述鸟苷酸环化酶-C激动剂(GCRA肽)可以与环鸟苷单磷酸(cGMP)依赖型磷酸二酯酶抑制剂、一种或一种以上其他的化学治疗剂、或者抗炎药一起结合给药,所述环鸟苷单磷酸(cGMP)依赖型磷酸二酯酶抑制剂例如,舒林酸磺(sulindae sulfone)、敏喘宁莫他匹酮(motapizone)、伐地那非中间体(Vardenafil)或者西地那非(sildenifil);所述抗炎药例如,类固醇抗炎药或者非类固醇抗炎药(NSAIDS),例如阿司匹灵。
通过给药两种或者两种以上的试剂可以实现结合治疗,例如给药这里所描述的GCRA肽和另一种化合物,任意一种所述试剂 都可以单独配制、单独给药,或者将两种或者两种以上的试剂配制在单一制剂中给药。其他的结合方式也包括在结合治疗的范围内。例如,可以将两种试剂配制在一起,与包含第三试剂的单独的制剂联合给药。尽管结合治疗中两种或者两种以上的可以同时给药,但是这不是必需的。例如,第一试剂(或者试剂结合物)的给药可以在第二试剂(或者试剂结合物)的给药之前几分钟、几小时、几天或者几周进行。因此,两种或者两种以上的试剂可以在相隔几分钟的时间内给药,或者在相隔1、2、3、6、9、12、15、18或者24小时的时间内给药,或者在相隔1、2、3、4、5、6、7、8、9、10、12、14天的时间内给药、或者在相隔2、3、4、5、6、7、8、9或者10周的时间内给药。在某些情况下,间隔的时间可以更长。尽管在很多情况下结合治疗时需要让两种或者两种以上的试剂同时存在于病人体内,但是这里不需要这样。.
本发明的GCRA肽可以与磷酸二酯酶抑制剂结合使用从而进一步提高目标组织或者气管内的cGMP水平。所述磷酸二酯酶抑制剂例如,舒林酸磺(sulindae sulfone)、敏喘宁、西地那非、伐地那非和他达拉非。
结合治疗还包括将结合治疗中使用的一种或者一种以上的试剂给药两次或者两次以上。例如,如果结合治疗中使用了试剂X和试剂Y,则可以连续的给药任意结合形式一次或者一次以上,例如,以X-Y-X、X-X-Y、Y-X-Y、Y-Y-X、X-X-Y-Y等等的顺序给药。
结合治疗还包括通过不同的途径或者不同的位置给药两种或者两种以上的试剂。例如,(a)一种试剂可以口服给药,另一种试剂可以静脉内给药,或者(b)一种试剂口服给药,另一种试剂局部给药。在每种情况下,这些试剂可以同时给药或者顺序给药。这里描述一部分结合治疗试剂的大致剂量可以在国际申 请第WO01/76632,“BNF推荐剂量”一栏的表中(表中的数据归因于2000年3月的英国国家处方集)获得,或者可以在其他的标准处方集和其他药物处方词典中获得。对于这些药物,习惯上的处方剂量在各个国家之间是有区别的。
GCRA肽无论是单独给药还是结合给药,都可以与任意要学上可接受的载体或者媒介物相结合。因此,GCRA肽可以与不会对患者产生副作用、过敏性反应或者其他不希望的反应的材料结合使用。这里是用的载体或者媒介物包括溶剂,分散剂,涂料,吸收促进剂,控释剂,以及一种或者一种以上的惰性赋形剂(包括淀粉,多元醇,造粒剂,微晶纤维素(如微晶纤维素球形核粒子(Celphere),微晶纤维素球形核粒子(Celphere)珠),稀释剂,润滑剂,粘合剂,崩解剂,等)等,如果需要,可以使用标准液相技术或者非液相技术对本发明所公开的组合物的片剂剂型进行包衣。
配制本发明的药物组合物使其与计划的给药途径相兼容。给药途径的实施例包括胃肠外给药,例如,静脉给药,皮内给药,皮下给药,口服给药(如吸入),透皮给药(局部给药),透粘膜给药和直肠给药。用于肠胃外给药、皮内给药或皮下给药中的溶液或者悬浮液可以包括下列组成:无菌稀释剂,例如注射用无菌水稀释液,生理盐水悬浮液,不挥发性油,聚乙二醇,甘油,丙二醇或其他合成溶剂;抗菌剂,如苄酒精或甲基羟基苯甲酸;抗氧化剂,例如抗坏血酸和亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如醋酸缓冲剂、柠檬酸缓冲剂或磷酸盐缓冲剂,及调节渗透压的试剂,例如氯化钠或葡萄糖。可以用酸或者碱来调节pH值,例如盐酸或氢氧化钠。肠胃外给药制剂可以存放于安瓿、一次性注射器或由玻璃或塑料制成的多剂量瓶中。
适合于注射应用的药物组合物包括无菌水溶液(在水可溶的情况下)或者分散液以及适合于随时制备无菌可注射溶液或者分散液的无菌粉末。用于静脉给药的适当的载体包括生理盐水、具有抑菌作用的水、聚氧乙烯醚蓖麻油(Cremophor ELTM)(巴斯夫公司,Parsippany,N.J.)或者磷酸盐缓冲盐水(PBS)。在所有情况下,所述组合物必须是经过灭菌的,并且应该被液化到可注射的程度。该组合物必须在制造和储存条件下稳定,并且应该免于受到微生物,例如细菌和真菌的污染作用。所述载体可以是一种溶剂或者分散介质,包括,例如,水、乙醇、多元醇(例如,甘油、丙二醇和液态的聚乙二醇等等),及其适当的混合物。通过使用一种包衣来维持适当的流动性,所述包衣例如,卵磷脂。在分散液的情况下可以通过保持要求的颗粒粒径来维持适当的流动性,以及可以通过使用表面活性剂来维持适当的流动性。通过使用不同的抗菌剂和抗真菌剂可以防止微生物作用,所述抗菌剂和抗真菌剂,例如,对羟苯甲酸、氯代丁醇、石炭酸、抗坏血酸、乙基汞硫代水杨酸钠,等等。在很多情况下,组合物中优选包括等渗剂,例如,糖;多元醇例如木糖醇、山梨糖醇;氯化钠。通过向组合物中加入一种能够延迟吸收的试剂,例如,单硬脂酸铝和明胶,可以延长可注射组合物的吸收。
通过将要求量的生物活性化合物(例如,一种GCRA激动剂)整合到适当的溶剂中,可以制得无菌可注射溶液,所述适当的溶剂具有上面列举的一种或者一种以上的成分或其结合物,随后,按规定,随后进行过滤灭菌。通常,通过将活性化合物整合到无菌载体中来制备分散剂,所述无菌载体包括碱性分散介质和上面列举的其他成分。用于制备无菌可注射溶液的无菌粉末,其制备方法是真空干燥和冷冻干燥,通过对前述过滤后的无菌溶液进行真空干燥和冷冻干燥能够产生活性成分和任意其他理想成分的粉末。
口服组合物通常包括一种惰性稀释剂或者一种适合食用的载体。例如甘露糖醇、低聚果糖、聚乙二醇及其他赋形剂。他们可以被装入明教胶囊中或者被压制成片剂。为了实现口服治疗给药,本发明活性化合物可以与赋形剂整合在一起,以片剂、药片或者胶囊剂的形式被使用。口服组合物还可以使用一种液体载体来制备,作为一种洗口药而应用;其中在液体载体中的化合物被口服应用、swished、吐出或者吞咽。药学上相容的粘合剂和/或添加剂材料也可以被包括在组合物中作为组合物的一部分。所述片剂、药丸、胶囊剂、药片等等可以包括下列任意成分,或者相似性质的化合物:一种粘合剂,例如,微晶纤维素、黄蓍树胶或者明胶;一种赋形剂,例如淀粉或者乳糖;一种崩解剂,例如海藻酸;羧甲基淀粉钠;或者玉米淀粉;一种润滑剂,例如硬脂酸镁(Primogel)或者Sterotes;一种助流剂,例如胶体二氧化硅;一种甜味剂,例如蔗糖或者糖精;或者一种调味剂,例如胡椒薄荷、水杨酸甲酯、或者橙子调味剂。
通过吸入给药,本发明化合物以气雾剂喷雾形式从压缩气体容器或者分散混合器或者一种喷雾器中传递出去,所述分散混合器包括一种适当的推进剂,例如,一种气体,例如二氧化碳。
系统性给药也可以通过经粘膜或者透皮途径完成。对于经粘膜或者透皮给药,在制剂中使用适合于防止渗透的渗透剂。这种渗透剂在本发明所述领域中通常是已知的,并且包括,例如,用于经粘膜给药的清洁剂、胆汁盐和梭链孢酸衍生物。通过使用鼻喷入剂或者栓剂可以完成经粘膜给药。在透皮给药中,所述活性化合物被配制成本领域内已知的软膏剂、油膏剂、凝胶剂或者乳膏剂。
本发明还可以以用于直肠传递药物的栓剂(例如,常用的栓剂基质,例如,可可脂及其他甘油酯)或者保留灌肠剂的形式来 制备。在一个实施方案中,所述活性化合物与能够保护化合物不被身体快速清除的载体一起制备,制成,例如,控制释放制剂,包括植入剂和微囊传递系统。可以使用生物可降解的、具有生物相容性的聚合物,例如,乙烯-乙酸乙烯共聚物、聚酐、聚乙二醇酸、胶原蛋白、聚原酸酯、和聚乳酸。用于制备这种制剂的方法对本领域普通技术人员来讲是显而易见的。所述材料可以从Alza公司和Nova药物有限公司商业购得。脂质体栓剂(包括靶向受感染细胞的脂质体,所述受感染细胞含有针对病毒抗原的单克隆抗体)也可以作用药学上可接受的载体。这可以根据本领域普通技术人员已知的方法制备,例如美国专利第4,522,811号的记载,本专利通过引证全部并入本文。
为了方便给药并均一剂量,最适合配制成单一剂量形式的口头给药组合物或者肠胃外给药组合物。这里使用的“剂量单位形式”是指适合于对治疗主体给药的以单一剂量存在的物理离散单元;每个单位包含预先确定量的活性化合物和所需的药物载体,这里的预先确定量是指计算所得的能够产生所需治疗效果的量。本发明剂量单位形式的规格依照并直接取决于活性化合物的独特性质以及需要完成的具体治疗效果。
本发明药物组合物可以与给药说明书一起放入一种容器、包装或者分散混合器中。本发明的组合物还可以任选的包括其他治疗剂成分,包括,防结块剂、防腐剂、甜味剂、着色剂、香料、干燥剂、增塑剂、染料、助流剂、防粘剂,防静电剂、表面活性剂(润湿剂)、抗氧化剂、薄膜包衣剂、等等。这些任选成分的任意一种都必须与这里描述的化合物兼容,从而确保所得制剂的稳定性。如果需要的话,组合物还可以包括其他添加剂,包括,例如,乳糖、葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉籽糖(Raffnose)、麦芽糖醇、松三糖、水苏糖、乳糖醇、直 辉玄闪质岩、淀粉、木糖醇、甘露醇、肌醇、等等,及其水合物;组合物还可以包括氨基酸,如丙氨酸、甘氨酸和甘氨酸三甲基内盐,以及多肽和蛋白质,例如蛋白。适于用作药学上可接受载体和药学上可接受惰性载体及以上所述其他成分的赋形剂的实施例包括但不限于粘合剂、填充剂、崩解剂、润滑剂、抗微生物剂、和包覆剂,例如:粘合剂:玉米淀粉、马铃薯淀粉、其他淀粉、明胶、天然的或者合成的树胶,例如阿拉伯树胶、黄原胶、海藻酸钠、海藻酸、其他藻蛋白酸盐、粉状黄蓍胶、瓜尔豆胶、纤维素及其衍生物(如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯吡咯烷酮(例如,聚乙烯基吡咯烷酮,聚乙烯聚吡咯烷酮,共聚维酮等)、甲基纤维素、甲基纤维素(Methocel)、预糊化淀粉(例如,由卡乐康公司出售淀粉及淀粉)、羟丙基甲基纤维素、微晶纤维素(FMC公司,马库斯胡克,PA,美国)、或其混合物;填充剂:滑石粉、碳酸钙(例如,颗粒或粉末状的碳酸钙)、双磷酸钙、三元磷酸钙、硫酸钙(如颗粒或粉末状的硫酸钙)、微晶体纤维素、纤维素粉、葡萄糖结合剂、高岭土、甘露醇、硅酸、山梨醇、淀粉、预糊化淀粉、葡萄糖、果糖、蜂蜜、脱水乳糖、乳糖一水合物,乳糖和阿斯巴甜、乳糖和纤维素、乳糖和微晶纤维素、麦芽糊精、麦芽糖、甘露醇、微晶纤维素与腺苷一磷酸;瓜尔豆胶,糖浆、蔗糖或其混合物;崩解剂:琼脂、海藻酸、碳酸钙、微晶纤维素、交联羟甲基纤维素钠、聚乙烯聚吡咯烷酮,钾离子交换树脂、淀粉羟基乙酸钠、马铃薯或者木薯淀粉、其他淀粉、预糊化淀粉、粘土、其他褐藻胶、其他纤维素、树胶(比如结冷胶)、低取代羟基丙基纤维素、或其混合物;润滑剂:硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨醇、甘露醇、聚乙二醇、其他乙二醇、硬脂酸、十二烷基硫酸钠、硬脂富马酸钠、植物基脂肪酸润滑剂、滑石粉、氢化植物油(例如,花生油、棉籽油、葵花籽油、芝麻油、橄榄油、玉米油和大豆油)、硬脂酸锌、油酸乙 酯、十二烷酸乙酯、琼脂、消光粉(syloid)硅胶(AEROSIL200,购自格雷斯公司,马里兰州巴尔的摩,美国),合成硅凝结的气雾剂(购自Deaussa有限公司,Piano,得克萨斯州,美国)一种制热二氧化硅(CAB-O-SIL,购自Cabot公司,波士顿,MA,美国),或其混合物;抗结块剂:硅酸钙、硅酸镁、二氧化硅、胶体二氧化硅、滑石粉、或其混合物;抗微生物剂:氯化苯甲烃铵、氯化苄乙氧铵、苯甲酸、苯甲醇、对羟基苯甲酸丁酯、氯化十六烷基吡啶、甲酚、三氯叔丁醇、脱氢乙酸、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、苯酚、苯乙醇、苯氧基乙醇、醋酸苯汞酯、硝酸苯汞、山梨酸钾、对羟基苯甲酸丙酯、苯甲酸钠、脱氢醋酸钠、丙酸钠、2,4-已二烯酸、硫柳汞(thimersol)、胸腺,或其混合物;和包覆剂:羧甲基纤维素钠盐、,邻苯二甲酸醋酸纤维素、乙基纤维素、明胶、药物薄冰层、羟丙基纤维素、羟丙基甲基纤维素(hypromellose)、邻苯二甲酸羟丙基甲基纤维素、甲基纤维素、聚乙二醇、聚醋酸乙烯酯邻苯二甲酸盐、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、洁冷胶、麦芽糊精、甲基丙烯酸酯、微晶纤维素和卡拉胶或其混合物。
所述制剂也可以包括其他赋形剂及其同类物,包括但不限于,L-组氨酸、普卢兰尼克()、泊洛沙姆(例如,和泊洛沙姆188)、抗坏血酸、谷胱甘肽、渗透促进剂(例如,脂类、胆酸钠、酰肉碱、水杨酸盐、混合胆盐、脂肪酸胶束、螯合剂、脂肪酸、表面活性剂、中链甘油酯)、蛋白酶抑制剂(例如,大豆胰蛋白酶抑制剂、有机酸)、pH值降低剂和有效地促进生物利用度的吸收促进剂(包括但不限于美国专利第6086918和美国专利第5912014中描述的那些)、乳膏剂与乳液(如麦芽糖糊精和卡拉胶);用于咀嚼片的材料(例如,葡萄糖、果糖、乳糖一水合物、乳糖和阿斯巴甜、乳糖和纤维素、麦芽糖糊精、麦芽糖、甘露醇、微晶纤维素和瓜尔豆胶、山梨醇结晶);输液 (parenterals)(例如甘露醇,聚维酮);增塑剂(例如,癸二酸二丁酯、用于包衣的增塑剂、聚乙酸乙烯酯邻苯二甲酸盐);粉润滑剂(例如,甘油二十二酸甲酯)、软明胶胶囊(例如,山梨糖醇专用溶液);包衣球(例如,糖球);滚圆剂(例如,甘油二十二酸甲酯和微晶纤维素);悬浮剂/成胶剂(例如,角叉菜胶、结冷胶、甘露醇、微晶纤维素、聚乙烯基吡咯烷酮、淀粉羟基乙酸钠、黄原胶);甜味剂(例如,阿斯巴甜、阿斯巴甜和乳糖、葡萄糖、果糖、蜂蜜、麦芽糊精、麦芽糖、甘露醇、糖蜜、结晶山梨醇、山梨醇专门溶液、蔗糖);湿法制粒剂(例如,碳酸钙、无水乳糖、乳糖一水合物、麦芽糖糊精、甘露糖醇、微晶纤维素、聚乙烯基吡咯烷酮、淀粉)、焦糖、羧甲基纤维素钠,樱桃奶油增味剂和樱桃味增味剂、无水柠檬酸、柠檬酸、糖果糖、D&C Red No.33(药品和化妆品红第33号)、D&C Yellow#10(药品和化妆品黄第10号)铝色淀、二钠乙二胺四乙酸、乙醇15%、FD&CYellow No.6(药品和化妆品黄第6号)铝色淀、FD&C蓝色第1号铝色淀、FD&C蓝色1号、FD&C蓝色2号铝色淀、药品和化妆品绿色第3号、药品和化妆品红第40号、药品和化妆品黄色第6号铝色淀、药品和化妆品黄色第6号、药品和化妆品黄色第10号、硬脂酸棕榈酸甘油酯、硬脂酸单甘油酯、靛蓝、卵磷脂、甘露醇、甲基和丙基甲酸甲酯、甘草酸单铵、天然和人造桔位甜味剂、制药釉、泊洛沙姆188、聚葡萄糖、山梨醇酯20、吐温80、聚烯、预糊化玉米淀粉、预糊化淀粉、氧化铁红、糖精钠、羧甲基乙醚钠、氯化钠、柠檬酸钠、磷酸钠、草莓味甜味剂、合成的氧化铁黑、合成的氧化铁红、二氧化钛、和白蜡。
固体口服剂量形式可以选择性地被包衣系统处理(例如,欧巴代(Opadry)fx薄膜包衣系统,例如欧巴代(Opadry)蓝(OY-LS-20921)、欧巴代(Opadry)白(YS-2-7063),欧巴代(Opadry)白(YS-1-7040)和black ink(S-1-8106)。
所述试剂可以以其游离态或者盐形式与一种聚合物结合,从而产生一种持续释放试剂,所述聚合物例如,聚乳酸-羟基乙酸(PLGA)、聚(I)-乳酸-乙二醇-酒石酸(P(I)LGT)(国际申请第WO/12233号)、聚羟基乙酸(美国专利第3,773,919号)、聚乳酸(美国专利第4,767,628号)、聚(ε-羟基己酸内酯)和聚(氧化烯)(美国专利第20030068384)号。这种试剂可以用于一种移植物中,根据使用的聚合物、聚合物颗粒粒度、和移植物尺寸,所述移植物能够在几天、几周或者几个月的的时间内释放多肽或者其他试剂(参见,例如,美国专利第6,620,422号)。欧洲专利第0 467 389 A2,国际申请第WO93/24150号、美国专利第5,612,052号、国际申请第WO97/40085号、国际申请第WO03/075887号、国际申请第WO01/01964A2号、美国专利第5,922,356号、国际申请第WO94/155587号、国际申请第WO02/074247A2号、国际申请第WO98/25642号、美国专利第5,968,895号、美国专利第6,180,608号、美国专利第20030171296号、美国专利第20020176841号、美国专利第5,672,659号、美国专利第5,893,985号、美国专利第5,134,122号、美国专利第5,192,741号、美国专利第5,192,741号、美国专利第4,668,506号、美国专利第4,713,244号、美国专利第5,445,832美国专利第4,931,279号、美国专利第,5号、980,945号、国际申请第WO02/058672号、国际申请第WO9726015号、国际申请第WO97/04744号、和美国专利第20020019446号中描述了其他的持续释放制剂和可以使用的聚合物。在这种持续释放制剂中,多肽微粒(Delie and Blanco-Prieto2005Molecule10:65-80)与聚合物微粒结合。一种或者一种以上持续释放的移植物可以被放置在大肠、小肠、或者两者之中。美国专利第6,011,01号和国际申请WO94/06452号描述了一种持续释放制剂,这种持续释放制剂能够提供聚乙二醇(即,聚乙二醇300和聚乙二醇400)或者甘油三醋酸脂。国 际申请W003/053401描述了一种制剂,这种制剂既可以增强生物利用率也可以在胃肠道内控制试剂释放。其他的控制释放制剂描述在国际申请WO02/38129号、欧洲申请第326151号、美国申请第5,236,704号、国际申请WO02/30398号、国际申请WO98/13029;美国申请第20030064105号、美国申请第20030138488A1号、美国申请第20030216307A1号、美国申请第6,667,060号、国际申请WO01/49249号、国际申请WO01/49311号、国际申请WO01/49249号、国际申请WO01/49311号、和美国申请第5,877,224号,包括这些的材料描述在国际申请WO04041195号(包括其中描述的隔离层和肠溶衣)中。能够完成结肠传递的pH-敏感包衣包括美国专利第4,910,021号和国际申请WP9001329中描述的包衣。美国专利第4,910,021号描述了使用pH-敏感材料包覆一种胶囊剂。国际申请WP9001329号描述了在含酸颗粒上使用pH敏感材料,其中,在颗粒核心中的酸延长了pH敏感包衣的溶解。美国专利第5,175,003号描述了由pH敏感肠溶材料和成膜增塑剂组成的双重机制聚合物,所述聚合物能够赋予肠溶材料的渗透性,用于在药物传递系统中使用;由渗有药物的双重机制聚合物组成的基质丸剂,有些情况下,覆盖有一种药学上中性的核;一种薄膜包衣的丸剂,包括用双重机制聚合物包衣的基质丸剂,所述双重机制聚合物混合包裹相同的或者不同的组合物;和包括基质丸剂的药物剂量形式。所述基质丸剂通过在酸性pH值条件下的扩散作用和在大约5.0或者更高的pH水平下的崩解作用释放酸可溶的药物。在国际申请WO04052339号描述的pH引发的靶向控制释放系统中可以配制这里描述的GCRA肽。根据国际申请WO03105812中描述的工艺(挤出能水合的聚合物)、国际申请WO0243767(酶可裂解薄膜转位分子);国际申请WO03007913和国际申请WO03086297(粘膜粘附系统);国际申请WO02072075(包括pH降低剂和吸附增强子的双层分层制剂);国际申请WO04064769(酰胺化的 多肽);国际申请WO05063156(熔化后具有假性热能(pseudotropic)和/或触变性能固体脂类悬浮液);国际申请WO03035029和国际申请WO03035041(易侵蚀的、胃维持剂量形式);美国专利第5007790和美国专利第5972389(持续释放剂量形式);国际申请WO04112711(口服持续释放组合物);国际申请WO05027878、国际申请WO02072033、和国际申请WO02072034(具有天然或者合成树胶的延迟释放组合物);国际申请WO05030182(具有上升的释放速率的控制释放制剂);国际申请WO05048998(微囊化系统);美国专利第5,952,314号(生物聚合物);美国专利第5,108,758号(玻璃质直链淀粉基质传递);美国专利第5,840,860号(基于变性淀粉的传递)中描述的工艺可以配制这里所描述的试剂;日本专利第10324642号(包括脱乙酰壳多糖和胃耐腐蚀材料的传递系统,所述胃耐腐蚀材料例如小麦醇溶蛋白或者玉米醇溶蛋白);美国专利第5,866,619号和美国专利第6,368,629号(包括聚合物的糖类);美国专利第6,531,152号(描述了一种包括水溶型核心(果胶酸钙或者其他不溶于水的聚合物)和脉冲型外包衣(例如,疏水聚合物-优特奇(Eudragrit))的药物传递系统);美国专利第6,234,464号;美国专利第6,403,130号(包覆有包含酪蛋白和高甲氧基果胶的聚合物);国际申请WOO174175(美拉德反应产物);国际申请WO05063206(溶解性增加制剂);国际申请WO04019872(传递融合蛋白质)。
使用胃肠保留系统技术(GIRES;Merrion药物公司)可以制备这里描述的鸟苷酸环化酶-C激动剂(GCRA肽)。胃肠保留系统技术(GIRES)在膨胀带内部包括一种控制释放剂量形式,将其放置在药物胶囊中,口服给药。随着胶囊剂的溶解,气体发生系统在胃中将小袋膨胀,并在胃里维持16-24小时,并一直释放这里描述的试剂。
在一种渗透装置中配制这里描述的鸟苷酸环化酶-C激动剂(GCRA肽),所述渗透装置包括美国专利第4,503,030号、5,609,590号、和5,358,502号中描述的装置。美国专利第4,503,030号描述了用于将药物分配到胃肠道某些pH区域的渗透装置。更具体的,本发明涉及一种渗透装置,该装置包括由半渗透性pH敏感材料组成的外壁,外壁内部是一个分隔间,分隔间中含有一种药物,外壁中有通道穿过,将外部与分隔间相连接。该装置在胃肠道中以一种控制的速率传递药物,胃肠道的pH值小于3.5,在pH值大于3.5的胃肠道区域,该装置自毁并释放其中所有的药物,从而提供总的药物吸收有效性。美国专利第5,609,590号和5,609,590号、和5,358,502号公开了一种渗透成组装置,用于将有益制剂分配到水环境中。该装置包括一种有益试剂和具渗透压活性的亲水聚合物(osmagent),被至少一部分半透膜包围。所述有益试剂也可以起到具渗透压活性的亲水聚合物(osmagent)的作用。所述半透膜可以让水透过,但是不让有益试剂和具渗透压活性的亲水聚合物(osmagent)透过。引发方式附着于半透膜(例如,参与两个胶囊部分)。引发是指通过使pH值从3变化到9来活化,从而引发有益试剂最终快速释放。通过渗透破裂作用,该装置能够由pH引发释放有益试剂核心。
用于结合治疗的示范性的试剂
止痛剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与止痛剂一起用于结合治疗,所述止痛剂例如,一种止痛化合物或者一种止痛多肽,所述止痛化合物或者止痛多肽可以与这里所描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)一起给药(同时给药或者顺序给药)。他们也可以选择性地与这里描述的试剂共价连接或者 附着于这里所描述的试剂,从而产生治疗剂结合物。其中,有效的止痛剂是:Ca通路阻断剂、5HT受体拮抗剂(例如,5HT3受体拮抗剂、5HT4受体拮抗剂和5HT1受体拮抗剂)、鸦片样物质受体激动剂(洛哌丁胺(Loperamide)、非多托秦(Fedotozine)、和芬太尼)、NK1受体拮抗剂、CCK受体(例如,氯谷胺(Loxiglumide))、NK1受体拮抗剂、NK3受体拮抗剂、降肾上腺素-血清紧张素重摄取抑制剂(NSRI)、辣椒素受体激动剂和大麻素(cannabanoid)受体激动剂、和sialorphin。文献中描述了不同种类的止痛剂,其中,有效的止痛多肽是sialorphin有关的多肽,包括包含氨基酸序列QHNPR(SEQ ID NO:)的多肽、包括VQHNPR(SEQ ID NO:);VRQHNPR(SEQ ID NO:);VRGQHNPR(SEQ ID NO:);VRGPQHNPR(SEQ ID NO:);VRGPRQHNPR(SEQ ID NO:);VRGPRRQHNPR(SEQ ID NO:);和RQHNPR(SEQ ID NO:)的多肽。Sialorphin有关的多肽能够结合脑啡肽酶并且抑制脑啡肽酶-调节的P物质和Met-脑腓肽的分解。因此,已知脑啡肽酶的化合物和多肽也可以有效用作止痛剂,用于在共同疗法中与这里描述的多肽一起给药,或者通过例如共价键与这里描述多肽相连。Sialophin及其有关的多肽描述在美国专利第6,589,750号;美国专利20030078200A1;和国际申请02/051435A2中。
鸦片样物质受体拮抗剂和激动剂可以在共同治疗中与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)一起给药或者与这里描述的试剂通过例如共价键相连。鸦片样物质受体拮抗剂例如纳洛酮、纳曲酮、甲基纳洛酮、纳美芬、cypridime、β阿片μ受体拮抗剂、纳洛肼(naloxonazine)、纳曲吲哚、和nor-binaltorphimine,可以有效的用于过敏性肠综合症(IBS)的治疗中。这一类型的鸦片样物质拮抗剂可有效的被配制成一种延迟并且持续释放试剂因此,这种拮抗剂的最初释放开始于小肠中部或者末梢和/或升 结肠。国际申请WO01/32180A2中描述了这种拮抗剂。脑腓肽五肽(HOE825;酪氨酸-D-赖氨酸-甘氨酸-苯丙氨酸-L-高丝氨酸)是一种μ和△鸦片样物质受体激动剂,被认为能有效增加肠活动性(Eur.J.Pharm.219:445,1992),这种多肽可以被用于与这里所描述的多肽相结合。三甲丁酯也同样有效,普遍认为三甲丁酯能够结合μ/△/K鸦片样物质受体并且活化胃动素的释放和调节促胃液激素、血管活性肠多肽、促胃液素和胰高血糖素的释放。K鸦片样物质受体激动剂和在国际申请WO03/097051和国际申请WO05/007626中描述的化合物可以与这里描述的多肽一起使用或者与这里所描述的多肽相连,其中,所述K鸦片样物质受体激动剂例如非多托秦(Fedotozine)、阿西马朵林(asimadoline)和酮基环丫辛因(ketocyclazocine)。另外,可以使用μ鸦片样物质受体激动剂,例如,吗啡、diphenyloxylate、氟雷法胺(H-酪氨酸-D--苯丙氨酸(F)-苯丙氨酸-NH2;国际申请WO01/019849A1)和洛哌丁胺(Loperamide)。酪氨酸-精氨酸(京都啡肽)是一种二肽,能够通过刺激met-脑腓肽的释放起作用,实现止痛效果(J.Biol.Chem262:8165,1987)。京都啡肽可以与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)一起使用或者与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)相连。
嗜铬粒蛋白-衍生的多肽(CgA47-66;参见,例如,Ghia et al.2004Regulatory polypeptides119:199)可以与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)一起使用或者与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)相连。CCK受体激动剂,例如来自两栖动物及其他种类的雨蛙素,可以有效用作止痛剂,这种止痛剂可以与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)一起使用或者与这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)相连。
氨氯地平多肽代表一大类止痛多肽,这种止痛多肽可以驱动电压门控性钙通道、NMDA受体或者烟碱受体。这种多肽可以与这里描述的多肽一起使用或者相连。胸腺因子肽类似物(法国申请2830451号)具有止痛活性,可以与这里描述的多肽一起使用或者与这里描述的多肽相连。
CCK(CCKa或者CCKb)受体拮抗剂,包括氯谷胺(Loxiglumide)和右氯谷胺(氯谷胺(Loxiglumide)的R-异构体)(国际申请WO88/05774)具有止痛活性,可以与这里描述的多肽一起使用或者与这里描述的多肽相连。
其他有效的止痛剂包括5-HT4激动剂,例如,加色罗 莫沙必利,胃复安,扎考必利,西沙必利,伦扎必利,苯并咪唑酮衍生物,如BIMU1BIMU8和利沙必利。这种激动剂描述在:欧洲专利1321142A1,国际申请WO03/053432A1,欧洲专利505322A1,欧洲专利505322B1,美国专利第5,510,353,欧洲专利507672A1号、欧洲专利507672B1号、和美国专利第5,273,983号。
钙离子通道阻断剂例如齐考诺肽和描述在,例如,欧洲专利625162B1号、美国专利第5,364,842号、美国专利第5,587,454号、美国专利第5,824,645号、美国专利第5,859,186号、美国专利第5,994,305号、美国专利第6087,091号、美国专利第6,136,786号、国际申请WO93/13128A1号、欧洲专利1336409A1号、欧洲专利835126A1号、欧洲专利835126B1号、美国专利第5,795,864号、美国专利第5,891,849号、美国专利第6,054,429号、国际申请WO97/01351A1中的化合物,可以与这里描述的多肽一起使用或者相连。
不同的NK-I、NK-2、和NK-3受体拮抗剂(参见Giardina et al.2003.Drugs6:758)可以与这里描述的多肽一起使用或者与这里描述的多肽相连。NK1受体拮抗剂例如:阿瑞匹坦(默克公司),沃氟匹坦,依洛匹坦(辉瑞公司),R-673(罗氏公司)、SR-48968(赛诺菲),CP-122721(辉瑞公司)、GW679769(葛兰素史克)、TAK-637(Takeda/Abbot),SR-14033及在,例如,欧洲专利873753A1号、美国专利第20010006972A1号、美国专利第20030109417A1号、国际申请WO01/52844A1中描述的化合物,NK1受体拮抗剂可以与这里描述的多肽一起使用或者与这里描述的多肽相连。NK2受体拮抗剂例如,奈帕坦特(nepadutant)(Menarini Ricerche SpA公司),沙瑞度坦(赛诺菲圣德拉公司),GW597599(葛兰素史克),SR-144190(赛诺菲圣德拉公司)和UK-290795(辉瑞公司),NK2受体拮抗剂可以与这里描述的多肽一起使用或者与这里描述的多肽相连。NK3受体拮抗剂例如,奥沙奈坦(SR-142801;赛诺菲圣德拉公司)、SSR-241586、他奈坦和描述在例如国际申请WO02/094187A2号、欧洲专利876347A1号、国际申请WO97/21680A1号、美国专利第6,277,862号、国际申请WO98/11090号、国际申请WO95/28418号、国际申请WO97/19927号、和Boden等人的文献.(J Med Chem.39:1664-75,1996)中的化合物,NK3受体拮抗剂可以与这里描述的多肽一起使用或者与这里描述的多肽相连。
降肾上腺素-血清紧张素重摄取抑制剂(NSRI)例如米那普仑和国际申请WO03/077897A1号中描述的有关化合物可以这里描述的多肽一起使用或者与这里描述的多肽相连。
辣椒素受体拮抗剂例如arvanil和在国际申请WO01/64212A1中描述的有关化合物可以这里描述的多肽一起使用或者与这里描述的多肽相连。
止痛多肽和止痛化合物可以与这里描述的多肽和激动剂一起给药(同时给药或者顺序给药)。止痛剂还可以与这里描述的多肽和激动剂共价相连,从而产生治疗结合物。当止痛剂是多肽并与这里描述的一种试剂共价相连时,所得多肽还可以包括至少一个胰蛋白酶裂解地点。当存在于多肽内部时,止痛多肽可以在胰蛋白酶裂解位点之前(如果是在羧基末端)或者之后(如果在氨基末端),所述胰蛋白酶裂解位点造成止痛多肽的释放。
除了sialorphin有关的多肽,止痛多肽包括:AspPhe,吗啡肽-1,内吗啡-2,痛稳素,打拉净(dalargin)、利普安(lupron),齐考诺肽和P物质。
治疗肠胃功能紊乱的试剂
治疗肠胃及其他紊乱的其他治疗剂的实施例包括治疗便秘的试剂(例如,一种氯离子通道活化剂,例如,双环脂肪酸、鲁比前列酮(Lubiprostone)(之前成为SPI-0211;Sucampo药物股份有限公司;马里兰州贝塞斯达);一种缓泻药(例如,块状缓泻药(例如非淀粉多肽、Colonel片剂(聚卡波菲钙)、Plantago Ovata(洋车前子纤维)(聚卡波菲钙));纤维(例如(聚卡波菲钙);一种渗透性缓泻药、一种刺激剂缓泻药(例如二苯甲烷(例如双乙酰氧苯基甲基吡啶)、蒽醌(例如用其树皮制成的缓泻剂(cascara)、番泻叶)、和表面活性缓泻药(例如蓖麻油、多库酯类(Docusates))、软化剂/润滑剂(例如矿物油、甘油和多库酯类(Docusates))、MiraLax(布伦特里实验室,布伦特里马)、右氯谷胺(森林实验室,又名CR2017Rottapharm(Rotta Research Laboratorium SpA公司))、缓泻药盐水、灌肠剂、栓剂和CR3700(Rottapharm(Rotta Research Laboratorium SpA公司));酸性还原剂,例如质子泵抑制剂(例如,奥梅普拉佐耳()、埃索美拉唑()、兰 索拉唑泮托拉唑和雷贝拉唑 )和组胺H2受体拮抗剂(也称为H2受体阻断剂,包括甲腈咪胍、甲胺呋硫、法莫替丁和尼扎替丁);促动力试剂,包括伊托必利、奥曲肽、甲氨酰甲基胆碱、胃复安多潘立酮红霉素(及其衍生物)或西沙必利 前动力多肽同系相似物、变体及其嵌合体包括美国专利第7,052,674号中的描述,其可以与这里描述的多肽一起使用或者与这里描述的多肽相连;前活动性试剂例如血管抑制因子(vasostatin)-衍生多肽、嗜铬粒蛋白A(4-16)(参见,例如,Ghia et al.2004Regulatory polypeptides(调节性多肽)121:31)或者胃动素激动剂(例如,GM-611或者米坦西诺延胡索酸盐)或者nociceptm/孤啡肽FQ受体调节剂(US20050169917);可以结合/活化鸟苷酸环化酶(GC-C)的其他肽包括US20050287067中描述的肽;完全的或者部分的5HT(例如5HT1、5HT2、5HT3、5HT4)受体激动剂或者拮抗剂(包括5HT1A拮抗剂(例如AGI-OO1(AGI治疗齐)、5HT2B拮抗齐(例如PGN1091和PGN1164(Pharmagene实验室有限公司)、和5HT4受体激动剂(例如加色罗普鲁卡罗酰胺(Prucalopride)、莫沙必利、胃复安、扎考必利、西沙必利、伦扎必利,苯并咪唑酮衍生物,例如BIMU1和BIMU8,和利沙必利(Lirexapride)。这些激动剂/调节剂描述在欧洲专利1321142A1号、国际申请WO03/053432A1、欧洲专利505322A1号、欧洲专利505322B1号、美国专利第5,510,353号、欧洲专利507672A1号、欧洲专利507672B1号、美国专利第5,273,983号、和美国专利第6,951,867中);5HT3受体激动剂,例如MKC-733;和5HT3受体拮抗剂,例如DDP-225(MCI-225;Dynogen制药公司),西兰司琼阿洛司琼盐酸昂丹司琼 多拉司帕洛诺司琼格拉司琼YM060(雷莫司琼;阿斯特拉制药公司;雷 莫司琼可以以0.002至0.02毫克的日给药剂量给药,如欧洲专利第01588707号的描述)和ATI-7000(Aryx治疗剂公司,加利福尼亚州圣克拉拉);毒蕈碱受体激动剂;抗消炎药;抗痉挛药,包括但不限于抗胆碱能药物(如双环胺(例如 ),莨菪碱(如(硫酸莨菪碱), 液体儿科 ),Donnatal(如 ),克利铵(如Quarzan与利眠宁一起形成Librax),乙胺大林(例如,本辛(Banthine)),美喷酯(例如,坎蒂尔)、后马托品(如重酒石酸二氢可待因酮,溴甲)、溴丙胺大林(例如,普鲁本辛)、胃长宁(如),东莨菪碱(例如,),东莨菪碱-氮-丁溴(如),哌仑西平(如)、溴丙胺大林(例如,),双环维林(例如,)、格隆溴铵(例如),天仙子碱溴氢酸盐、甲溴天仙子碱、methanthelinium和辛托品),薄荷油;和指导平滑肌弛缓药样西托溴铵,美贝弗林( ),奥替溴铵(octilonium),匹维铵(如 (匹维溴铵;Solvay S.A.)),(水合苯三酚和三甲基间苯三酚)和三甲丁酯(包括三甲丁酯顺丁烯二酸 抗抑郁药,包括但不限于这里所列举的,以及三环抗忧郁药,例如,阿密曲替林去甲丙咪嗪(盐酸去甲丙咪嗪),丙咪嗪(盐酸丙咪嗪),阿莫沙平去甲替林;选择性血清素再摄取抑制剂(SSRTs),例如帕罗西汀氟苯氧丙胺 舍曲林和citralopram及其他试剂,例如多塞平(多塞平)和曲唑酮);集中作用止痛剂,例如,鸦片样物质受体激动剂、鸦片样物质受体拮抗剂(例如纳曲酮),用于炎症性肠病治疗的试剂;用于治疗克罗恩氏病和/或溃疡性结肠炎的试剂(例如,alequel(恩佐生化公司;Farmingsale,纽约州)、抗炎症性多肽RDP58(Genzyme公司,剑桥,MA),和(ChemoCentryx公司;圣卡洛斯,加利福尼亚州);治疗肠胃痛或内脏痛的试剂;增加环鸟苷单磷酸(cGMP)水平的试剂(例如美国专利第20040121994号中描述的试剂),例如肾上腺素能受体拮抗剂、多巴胺受体激动剂和PDE(磷酸二酯酶)抑制剂,所述PDE(磷酸二酯酶)抑制剂包括但不限于本文所公开的;在肠道内控制流体的止泻剂(例如磷酸二氢钠一水合物和无水磷酸二氢钠的组合物);促肾上腺皮质激素释放因子(CRF)受体拮抗剂(包括NBI-34041(Neurocrine Biosciences公司,圣地亚哥,加利福尼亚州)、CRH9-41、astressin、R121919(杨森制药)、CP154,526、NBI-27914,Antalarmin、DMP696(百时美施贵宝公司)、CP-316311(辉瑞公司)、SB723620(葛兰素史克)、GW876008(Neurocrine公司/葛兰素史克)、ONO-2333Ms(Ono药物公司)、TS-041(西安杨森)、AAG561(诺华公司)和美国专利第5063245号、美国专利第5,861,398号、美国专利第20040224964号、美国专利第20040198726号、美国专利第20040176400号、美国专利第20040171607号、美国专利第20040110815号、美国专利第20040006066号以及美国专利第20050209253号中公开的试剂);胰高血糖素样多肽(GLP-1)和及其类似物(包括exendin-4和GTP-OlO(Gastrotech Pharma A公司))和DPP-IV抑制剂(DPP-IV能够调节glp-1的失活);托非索洋(tofisopam),光学纯R-托非索洋(tofisopam),和药学上可接受盐(美国专利第20040229867号);二苯硫氮卓类三环抗忧郁药包括但不限于 (Vela制药公司),噻奈普汀和美国专利第6683072号所描述的其他试剂;(E)-4(1,3双(环己基甲基)-1,2,3,4,-四氢化-2,6-二ONO-9H-嘌呤-8-基)肉桂酸九聚乙二醇甲基醚酯和国际申请WO02/067942中描述的相关化合物;益生菌(BioBalance公司,纽约州纽约),其中包括对胃肠功能紊乱有治疗效果的微生物。止泻药,包括但不限于洛哌丁胺(Loperamide)(易蒙停,胨腹泻)、含有阿托品的氰苯哌酯(止泻宁,Lomocot)、消胆胺(降胆敏(Questran),Cholybar)、阿托品(Co-Phenotrope,止泻宁,氰苯哌酯,Lofene,Logen,Lonox,Vi-Atro、硫酸阿托品注射液)和(利福昔明;Salix制药有限公司)、TZP-201(Tranzyme制药公司)、神经元乙酰胆碱受体(nAChR)阻断剂AGI-004(AGItherapeutics公司),以及碱式水杨酸铋(Pepto-bismol公司);抗焦虑药物,包括但不限于Ativan(氯羟去甲安定),阿普唑仑 甲氨二氮卓/克利铵氯硝西泮二钾氯氮艹卓(clorazepate)苯甲二氮卓艾司唑仑氟西泮 去甲羟基安定环丙二氮卓替马西泮三唑苯二氮(蒙脱土beidellitic;易普森公司)、Solvay SLV332(ArQuIe公司)、YKP(SK制药)、阿西马朵林(asimadoline)(Tioga药物公司/默克公司)、AGI-003(AGI Therapeutics公司);神经肽拮抗剂,包括美国专利第20060040950号中描述的试剂;钾通路调制器,包括在美国专利第7,002,015号中的描述;血清紧张素调节剂AZD7371(AstraZeneca PIc公司);M3毒蕈碱型受体拮抗剂,例如达非那新(Enablex;诺华公司和扎非那新(Zamifenacin)(辉瑞公司);草本和自然治疗剂,包括但不限于嗜酸试剂、甘菊茶、月见草油、茴香籽、艾草、紫草根和保济丸(Bao-Ji-Wan)化合物(木兰醇、和厚朴酚、白茅苷和异英波拉托林),如美国 专利第6923992号中的描述;和包括赖氨酸和抗应激剂的组合物,如欧洲专利第1550443号中的描述,所述组合物能够治疗肠易激综合症。
胰岛素和胰岛素调节剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可与胰岛素和相关化合物一起用于结合治疗,所述胰岛素和相关化合物包括灵长类动物、啮齿动物或者兔类的胰岛素,及其包括等位基因的生物活性变体,更优选的,包括以重组方式使用的人类胰岛素。人类胰岛素的来源包括药学上可接受的制剂和无菌制剂,例如,可以从礼莱制药公司(印第安纳州印第安纳波利斯46285)获得的优泌林(HumulinTM)(rDNA的人胰岛素来源)。参见“医生桌上参考手册”55.sup.th版(2001)医药经济学,Thomson保健公司(公开了其他适当的人胰岛素)。这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)还可以与其他试剂一起用于结合治疗,所述其他试剂在对主体给药后能够促进主体胰岛素作用或者水平,例如,格列甲嗪和/或罗格列酮。这里描述的多肽和激动剂可以与 (醋酸普兰林肽(Pramlintide))和(合成的exendin-4;一种长度为39个氨基酸的多肽)一期用于结合治疗。
用于治疗手术后肠梗阻的试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)还可以与其他试剂(例如,EnteregTM(爱维莫潘(alvimopan);也叫做ado lor/ADL8-2698)、考尼伐坦(conivaptan)和美国专利第6,645,959号中描述的有关试剂)一起用于结合治疗中,从而治疗手术后肠梗阻及其他疾病。
抗高血压试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种抗高血压药一起用于结合治疗,所述抗高血压要包括但不局限于:(1)利尿剂,例如噻嗪类,包括氯噻酮、克尿塞、二氯苯磺胺、氢氟甲噻嗪、、吲达帕胺、泊利噻嗪、和双氢氯噻嗪;髓袢利尿药,例如丁苯氧酸、利尿酸、利尿磺胺和托拉塞米;留钾剂,例如阿米洛利和氨苯喋啶;碳酸酐酶抑制剂、渗透性拮抗剂(如甘油)和醛固酮拮抗剂,例如螺旋内酯固醇、epirenone,等等;(2)β-肾上腺素受体阻断剂,例如醋丁洛尔、阿替洛尔、倍他索洛尔、贝凡洛尔、比索洛尔(bisoprolol)、波引咯尔(bopindolol)、卡替洛尔(carteolol)、卡维地洛、塞利洛尔、艾司洛尔、茚诺洛尔(Indenolol)、美托洛尔、萘羟心安、奈必洛尔、喷布洛尔(Penbutolol)、吲哚洛尔、心得安、甲磺胺心定、特他洛尔(Tertatolol)、替利洛尔(Tilisolol)和噻吗洛尔等等;(3)钙离子通道阻断剂,例如氨氯地平、阿雷地平(Aranidipine)、阿折地平、巴尼地平、贝尼地平、苄普地尔、cinaldipine,氯维地平(clevidipine)、地尔硫卓、依福地平、非洛地平、戈洛帕米(Gallopamil)、伊拉地平、拉西地平、来米地平(Lemildipine)、乐卡地平、硝吡胺甲酯、硝苯吡啶、尼伐地平、尼莫地平(Nimodepine)、尼索地平、尼群地平、马尼地平、普拉地平(Pranidipine)和维拉帕米,等等;(4)血管紧张素转换酶(ACE),例如苯那普利抑制剂、甲巯丙脯酸;塞兰普利(Ceranapril);西拉普利;拉普利;依那普利(Enalopril);西拉普利(enalopril);福辛普利;咪达普利(Imidapril);赖诺普利(lisinopril);赖诺普利(losinopril);莫西普利、喹普利拉(quinaprilat);雷米普利;培哚普利;培哚普利(perindropril);quanipril;螺普利(Spirapril);tenocapril;群多普利(trandolapril)和佐芬普利,等等;(5)中性肽链内切酶抑制剂,例如奥马曲拉、cadoxatril和依卡曲尔 (Ecadotril)、fosidotril、山帕曲拉、AVE7688、ER4030等等(6)内皮素拮抗剂,例如唑生坦,A308165和YM62899,等等;(7)血管扩张剂,例如肼苯哒嗪、可乐定、米诺地尔和烟醇,等等;(8)血管紧张素II受体拮抗剂,例如依普罗沙坦(aprosartan)、坎地沙坦、依普沙坦、伊贝沙坦、氯沙坦(Losartan)、奥美沙坦(Olmesartan)、普拉沙坦(pratosartan)、他索沙坦(Tasosartan)、替米沙坦、缬沙坦、和EXP-3137、FI6828K和RNH6270,等等;(9)α/β肾上腺素受体阻断剂,例如尼普地洛(nipradilol)、阿罗洛尔和氨磺洛尔(Amosulalol),等等;(10)α1阻滞剂,例如特拉唑嗪、呱胺甲尿啶、哌唑嗪、坦索罗辛、布那唑嗪(Bunazosin)、三甲氧唑啉、多沙唑、萘哌地尔、吲哚哌胺、WHP164、和XENOlO,等等;(11)α2激动剂,例如洛非西定、噻美尼定(Tiamenidine)、莫索尼定、利美尼定和guanobenz,等等;(12)醛甾酮抑制剂等;及(13)血管生成素-2粘合剂,例如国际申请WO03/030833号中的公开。可以与这里所描述的多肽和激动剂联合使用的特异性抗-高血压试剂包括但不限于:例如,利尿剂,例如噻嗪类(如氯噻酮,环噻嗪(CAS登记号2259-96-3)、氯噻嗪(CAS登录号72956-09-3,可以根据美国专利第2809194号的中公开的方法制备)、二氯苯磺胺、氢氟甲噻嗪、吲达帕胺、泊利噻嗪、苄氟噻嗪(bendroflumethazide)、甲氯噻嗪,泊利噻嗪、三氯噻嗪(trichlormethazide)、氯噻酮、吲达帕胺、甲苯喹唑磺胺、喹噻酮、阿尔噻嗪(althiazide)(CAS登记号5588-16-9,可以根据英国专利第902,658号的公开制备)、苯噻嗪(Benzthiazide)(CAS登记号91-33-8,可以根据美国专利第3108097号的公开制备),异丁双氢氯噻嗪(可以根据英国专利第861,367号的公开制备)和氢氯噻嗪)、髓袢利尿药(例如布美他尼、利尿酸、利尿磺胺和托拉塞米)、留钾剂(例如氨氯吡脒和氨苯喋啶(CAS编号396-01-O))和醛甾酮拮抗剂(如螺旋内酯固醇(CAS编号52-01-7),依普利酮,等等);β-肾 上腺素受体阻断剂,例如乙胺碘呋酮(胺碘酮,Pacerone),丁萘酮心安氢氯化物(CAS登记号31969-05-8,Parke-Davis),醋丁洛尔(±N-[3-乙酰基-4-[2-氢氧基-3-[(1甲基乙基)ammo]丙氧基]苯基]-丁酰胺,或者(±)-3’-乙酰基-4’-[2-氢氧基-3-(异丙基氨基)丙氧基]丁酰苯胺),醋丁洛尔盐酸盐(例如,惠氏制药公司),烯丙心安盐酸盐(CAS登记号13707-88-5,参见荷兰专利申请第6,605,692号)、阿替洛尔(例如阿斯利康公司)、盐酸卡替洛尔(如雅培制药公司)、盐酸塞利洛尔(CAS登记号57470-78-7,同时参见美国专利第4034009号)、塞他洛尔盐酸盐(CAS登记号77590-95-5,同时参见美国专利第4059622号)、盐酸拉贝洛尔(例如, 先灵公司)、盐酸艾司洛尔(例如巴克斯特公司)、醋丁洛尔(±N-[3-乙酰基-4-[2-氢氧基-3-[(1甲基乙基)ammo]丙氧基]苯基]-丁酰胺,或者(±)-3’-乙酰基-4’-[2-氢氧基-3-(异丙基氨基)丙氧基]丁酰苯胺),醋丁洛尔盐酸盐(例如,惠氏制药公司),烯丙心安盐酸盐(CAS登记号13707-88-5,参见荷兰专利申请第6,605,692号)、阿替洛尔(例如阿斯利康公司)、盐酸卡替洛尔(如 雅培制药公司)、盐酸塞利洛尔(CAS登记号57470-78-7,同时参见美国专利第4034009号)、塞他洛尔盐酸盐(CAS登记号77590-95-5,同时参见美国专利第4059622号)、盐酸拉贝洛尔(例如,先灵公司)、盐酸艾司洛尔(例如巴克斯特公司)、左倍他洛尔盐酸盐(例如,Betaxon眼用悬浮剂,阿尔康公司),左布诺洛尔(Levobunolol)盐酸盐(例如,具有合格帽,艾尔建公司)、纳多洛尔(如纳多洛尔,Mylan公司)、普拉洛尔(CAS登记号6673-35-4,还可以参见美国专利第3408387号)、盐酸普萘洛尔(CAS登记号318-98-9)、盐酸索他洛尔(如Betapace AFTM,伯莱克斯公司)、噻吗(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]-,半水合物,(S)-,CAS登记号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登记号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-剂-乙基)氨基]-,(±),CAS登记号66722-44-9),富马酸比索洛尔(例如,(±)-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公司)、nebivalol(2H-1-苯并吡喃-2-甲醇,αα’-[亚氨基二(亚甲基)]二[6-氟代-3,4-二氢-,CAS登记号99200-09-6还可以参见美国专利第4,654,362号),环丙洛尔盐酸盐,例如,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,(C.A.S.登记号63686-79-3),右普萘洛尔盐酸盐(2-丙醇,1-[1-甲基乙基)-氨基]-3-(1-萘氧基)-盐酸盐(CAS登记号13071-11-9),二醋洛尔盐酸盐(乙酰胺,N-[3-乙酰基-4-[2-氢氧基-3-[(1-甲基-乙基)氨基]丙氧基][苯基]-、单盐酸盐CAS登记号69796-04-9),地来洛尔盐酸盐(苯甲酰胺,2-氢氧基-5-[1-氢氧基-2-[1-甲基-3-苯基丙基)氨基]乙基]-,单盐酸盐,CAS登记号75659-08-4),己丙洛尔盐酸盐(2-丙醇,1-(2-环己基苯氧基)-3-[(1-甲基乙基)氨基]-,盐酸盐CAS登记号59333-90-3),氟司洛尔(安息香酸,2-fhiro-,3-[[2-[氨基羰基)氨基]-二甲基乙基]氨基]-2-氢氧基丙基酯,(+)-硫酸盐(1:1)(盐),CAS登记号88844-73-9;美他洛尔盐酸盐(甲基磺酰胺,N-[4-[1-氢氧基-2-(甲基氨基)丙基]苯基]-,单盐酸盐,CAS登记号7701-65-7),美多洛尔2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[1-甲基乙基)氨基]-;CAS登记号37350-58-6),美多洛尔酒石酸盐(例如2-丙醇,1-[4-(2-甲氧基乙基)苯氧基]-3-[(1-甲基乙基)氨基]-,例如,诺华公司),帕马洛尔硫酸盐(氨基甲酸,[2-[4-[2-氢氧基-3-[(1- 甲基乙基)氨基]丙氧基]苯基]-乙基]-,甲酯,(±)硫酸盐(盐)(2:1),CAS登记号59954-01-7),喷布洛尔硫酸盐(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登记号38363-32-5),普拉洛尔(乙酰胺,N-[4-[2-氢氧基-3-[(1-甲基乙基)氨基]-丙氧基]苯基]-,CAS登记号6673-35-4;)替普洛尔盐酸盐(丙醇,1-[(1-甲基乙基)氨基]-3-[2-(甲基硫代)-苯氧基]-,盐酸盐,(±),CAS登记号39832-43-4),胺甲苯心安(苯甲酰胺,4-[2-[[2-氢氧基-3-(2-甲基苯氧基)-丙基]氨基]乙氧基]-,CAS登记号38103-61-6)、波引咯尔、茚诺洛尔(Indenolol)、心得静、恩特来、特他洛尔(Tertatolol)和替利洛尔(Tilisolol)、等等;钙离子通道阻断剂,例如,氨氯地平的苯磺酸盐(例如,3-乙基-5-甲基-2-(2-氨基乙氧基甲基)-4-(2-氯代苯基)-1,4-二氢-6-甲基-3,5-吡啶二羧酸苯磺酸盐、例如, 辉瑞公司)、克仑硫卓马来酸盐(1,5-苯并噻庚因-4(5H)-酮,3-(乙酰氧基)-8-氯代-5-[2-(二甲基氨基)乙基]-2,3-二氢-2-(4-甲氧基苯基)-(2S-顺式)-,(Z)-2-丁烯二酸(1:1),也可以参见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,也可以参见US4466972);尼莫地平(例如,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-二羧酸盐,例如,拜耳公司),非洛地平(Felodipine)(例如,乙基甲基4-(2,3-二氯代苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸盐-,例如,延迟释放制剂,AstraZeneca LP公司),尼伐地平(Nilvadipine)(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,还可以参见美国专利第US3799934号),硝苯地平(例如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,例如延迟释放片剂,辉瑞公司),地尔硫 卓盐酸盐(例如1,5-苯并噻庚因-4(5H)-酮,3-(乙酰氧基)-5[2-(二甲基氨基)乙基]-2,-3-二氢-2(4-甲氧基苯基)-,单盐酸盐,(+)-顺式,例如Forest公司),维拉帕米(Verapamil)盐酸盐(例如苯并乙腈,(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)盐酸盐,例如SR,Knoll实验室),替鲁地平(Teludipine)盐酸盐(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,单盐酸盐)CAS登记号108700-03-4),贝磷地尔(膦酸,[2-(2-苯氧基乙基)-1,3-丙烷-二基]双-,四丁基酯CAS登记号103486-79-9),福司地尔(膦酸,[[4-(2-苯并噻唑基)苯基]甲基]-,二乙基酯CAS登记号75889-62-2),阿雷地平(Aranidipine),阿折地平,巴尼地平(baraidipine),贝尼地平(Benidipine),苄普地尔(bepridil),西尼地平(cinaldipine),氯维地平(clevidipine),依福地平,戈洛帕米(Gallopamil),拉西地平,来米地平(Lemildipine),乐卡地平,莫那匹尔马来酸盐(1-哌嗪丁酰胺,N-(6,11-二氢二苯并(b,e)硫杂(艹卓)-11基)4-(4-氟代苯基)-,(+)-,(Z)-2-丁烯二酸(1:1)(±)-N-(6,11-二氢二苯并(b,e)硫杂(艹卓)-11-基)-4-(p-氟代苯基)-1-哌嗪丁酰胺马来酸盐(1:1)CAS登记号132046-06-1)、硝吡胺甲酯,尼索地平(Nisoldipine),尼群地平(Nitrendipine),马尼地平,普拉地平(Pranidipine),等等;T-通路钙拮抗剂,例如,米贝拉地尔(mibefradil);血管紧张素转换酶(ACE)抑制剂,例如,贝那普利(benazepril)、贝那普利盐酸盐(例如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)-苯骈吖庚因(benzazepine)-1-乙酸单盐酸盐,例如诺华公司),卡托普利(例如1-[(2S)-3-氢硫基-2-甲基丙酰基]-L-脯氨酸,例如卡托普利,Mylan公司,CAS登记号62571-86-2及其他在美国专利第US4046889号中公 开的试剂),塞兰普利(Ceranapril)(及其他在美国专利第US4452790号中公开的试剂),阿拉普利(cetapril)(阿拉普利(alacepril),Dainippon在Eur.Therap.Res.(欧洲治疗剂研究)39:671(1986);40:543(1986)上公开的文献),西拉普利(Hoffman-LaRoche公司)在J.Cardiovasc.Pharmacol.9:39(1987)中公开的文献,地拉普利(indalapril)(地拉普利(delapril)盐酸盐(2H-1,2,4-苯并噻二嗪-7-磺胺,3-双环[2.2.1]庚-5-烯-2-基-6-氯代-3,4-二氢-,1,1-二氧化物CAS登记号2259-96-3);如美国专利第4385051号的公开),依拉普利(Enalapril)(及其他试剂如在美国专利第US4374829号中的公开),西拉普利(Enalopril)、enaloprilat、福辛普利,((例如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)氧膦基]乙酰基]-,钠盐,例如福辛普利,百时美施贵宝公司公司及其他在美国专利第US4168267号中公开的试剂)、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公司,如在文献J.Cardiovasc.Pharmacol.5:643,655(1983)中的公开)、赖诺普利(默克公司),赖诺普利(losinopril),莫昔普利,莫昔普利盐酸盐(3-异喹啉基羧酸,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-,单盐酸盐,(3S)-CAS登记号82586-52-5),喹那普利、喹普利拉、雷米普利(Hoechsst)如欧洲专利第79022号和Curr.Ther.Res.40:74(1986)中的公开,培哚普利(例如2S,3aS,7aS-1-[(S)-N-[(S)-1-羰基丁基丁基]氨基]丙酰基]八氢-1H-吲哚-2-羧酸叔丁胺盐,1-乙基酯,具有叔丁基胺的化合物(1:1),例如Solvay公司),培哚普利(施维亚,如Eur.J.clin.Pharmacol.31:519(1987)中的公开),quanipril(如美国专利第US4344949号中的公开),螺普利(Spirapril)(Schering,如文献Acta.Pharmacol.Toxicol.59(Supp.5):173(1986)中的公开),tenocapril,群多普利,佐芬普利(以 及其他试剂,如在美国专利第US4316906号中的公开),伦唑普利(芬替普利(Fentiapril),如文献Clin.Exp.Pharmacol.Physiol.10:131(1983)中的公开),匹伏普利、YS980、替普罗肽(Bradykinin potentiator BPP9a CAS登记号35115-60-7),BRL36,378(Smith Kline Beecham公司,参见欧洲专利第80822号和欧洲专利第EP60668号)、MC-838(Chugai制药公司,参见CA.102:72588v以及Jap.J.Pharmacol.40:373(1986)中的公开,CGS14824(Ciba-Geigy公司,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)-苯骈吖庚因(苯并氮杂卓)-1乙酸盐酸盐,参见英国专利第2103614号),CGS16,617(Ciba-Geigy公司,3(S)-[[(1S)-5-氨基-1-羰基戊基]氨基]-2,3,4,-5-四氢-2-氧-1H-1-苯骈吖庚因(苯并氮杂卓)-1-乙酸,参见美国专利第US4473575号),Ru44570(Hoechst公司,参见see Arzneimittelforschung34:1254(1985)中的描述),R31-2201(Hoffman-LaRoche公司,参见FEBS Lett.165:201(1984)中的描述),CI925(参见Pharmacologist(制药学)26:243,266(1984)中的描述),WY-44221(惠氏制药公司,参见,J.Med.Chem.(药物化学杂质)26:394(1983)中的公开),以及美国专利第US2003006922号(第28段)、US4337201、US4432971(膦酸单体)的公开;中性肽链内切酶抑制剂,例如奥帕曲拉CGS30440,cadoxatril和依卡曲尔,法西多曲(也叫做aladotril或者alatriopril),山帕曲拉(sampatrilat)、mixanpril和格莫曲拉,AVE7688,ER4030和在美国专利第5362727号、美国专利第5366973号、美国专利第5225401号、美国专利第4722810号、美国专利第5223516号、美国专利第4749688号、美国专利第5552397号、美国专利第5504080号、美国专利第5612359号、美国专利第5525723号、欧洲专利第0599444号、欧洲专利第0481522号、欧洲专利第0599444号、欧洲专利第0595610号、欧洲专利第0534363号、欧洲专利第534396号、欧洲专利第 534492号、欧洲专利第0629627号中的公开,内皮素拮抗剂例如替唑生坦、A308165和YM62899,等等;血管扩张药例如肼苯达嗪(阿普利素宁),可乐定(可乐定盐酸盐(1H-咪唑-2-胺,N-(2,6-二氯代苯基)4,5-二氢-,单盐酸盐CAS登记号4205-91-8),可乐宁、米诺地尔(loniten),烟醇(roniacol),地尔硫卓盐酸盐(例如1,5-苯并噻庚因-4(5H)-酮,3-(乙酰氧基)-5[2-(二甲基氨基)乙基]-2,3-二氢-2(4-甲氧基苯基)-,单盐酸盐,(+)-顺式,例如Forest公司),硝酸异山梨酯(例如1,4:3,6-双脱水-D-葡糖胺2,5-硝酸,例如 Wyeth-Ayerst公司),异山梨醇单硝酸盐(例如1,4:3,6-双脱水-D-葡糖胺-1,5-硝酸盐,一种有机硝酸盐,例如 Wyeth-Ayerst公司),硝基甘油(例如2,3甘油三硝酸盐,例如硝基Parke-Davis公司),维拉帕米(维拉帕米(Verapamil))盐酸盐(例如苯并乙腈,(±)-(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)盐酸盐,例如延迟释放试剂,Searle公司),乙胺香豆素盐酸盐(可以根据美国专利第3282938号的公开制备),clonitate(Annalen1870155),氢普拉明(可以根据DE2521113的公开制备)、利多氟嗪(可以根据美国专利第3267104号的公开制备);普尼拉明(Prenylamine)(可以根据美国专利第3152173号的公开制备),硝二羟甲丁醇(可以根据法国专利第1,103,113号的公开制备),米氟嗪盐酸盐(1-哌嗪乙酰胺,3-(氨基羰基)-[4,4-双(4-氟代苯基)丁基]-N-(2,6-二氯代苯基)-,二盐酸盐CAS登记号83898-67-3),米克西定(苯并乙胺,3,4-二甲氧基-N-(1-甲基-2-吡咯烷基idene)-吡咯烷基,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]吡咯烷基CAS登记号27737-38-8),吗多明(1,2,3-恶二唑鎓、5-[(乙氧基羰基)氨基]-3-(4-吗啉)-,内盐CAS登记号25717-80-0),异山梨醇单硝酸盐(D- 葡糖胺,1,4:3,6-双脱水-,5-硝酸盐,CAS登记号16051-77-7),赤藓醇酯四硝酸盐(1,2,3,4-丁四醇,四硝酸盐,(2R,3S)-rel-CAS登记号7297-25-8),氯硝酯(1,2-丙二醇,3-氯代-,二硝酸盐(7CI,8CI,9CI)CAS登记号2612-33-1),双嘧达莫乙醇2,2’,2″,21″-[(4,8-二-1-哌啶基嘧啶并[5,4-d]嘧啶-2,6-二基)二次氮基]四-CAS登记号58-32-2),尼可地尔(CAS登记号65141-46-03-),吡啶甲酰胺(N-[2-(硝基氧基)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登记号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登记号21829-25-4),双环己哌啶马来酸盐(哌啶,2-(2,2-二环己基乙基)-,(2Z)-2-丁烯二酸(1:1)CAS登记号6724-53-4),氧烯洛尔(Oxprenolol)盐酸盐(2-丙醇,1-[(1-甲基乙基)氨基]-3-[2-(2-丙烯基氧基)苯氧基]-,盐酸盐CAS登记号6452-73-9),戊硝醇(1,3-丙二醇,2,2-双[(硝基氧基)甲基]-,单硝酸盐(酯)CAS登记号1607-17-6),维拉帕米(Verapamil)(苯并乙腈,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)-CAS登记号52-53-9)等等;血管紧缩素II受体拮抗剂,例如,依普罗沙坦(aprosartan),佐拉沙坦,奥美沙坦(Olmesartan),普拉沙坦(pratosartan),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,r-二苯基]4-基]甲基]-CAS登记号139481-59-7),坎地沙坦西来替昔酯((+/-)-1-(环己基羰基氧基)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,CAS登记号145040-37-5,美国专利第5703110号和美国专利第5196444号],依普罗沙坦(Eprosartan)(3-[1-4-羰基苯基甲基)-2-n-丁基-咪唑-5-基]-(2-噻嗯基甲基)丙烯酸,美国专利第5185351号和美国专利第5650650号),厄贝沙坦(2-n-丁基-3-[[2’-(1h-四唑-5-基)二苯基-4-基]甲基]1,3-二氮杂螺环 [4,4]non-1-en-4-酮,美国专利第5270317号和美国专利第5352788号),科素亚(2-N-丁基-4-氯代-5-氢氧基甲基-1-[(2’-(1H-四唑-5-基)二苯基-4-基)-甲基]咪唑,钾盐,美国专利第5138069号、美国专利第5153197号和美国专利第5128355号),他索沙坦(tasosartan)(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,美国专利第5149699号),泰米沙坦(Telmisartan)(4’-[(1,4-二甲基-2’-丙基-(2,6’-双-1H-苯并咪唑)-r-基)]-[1,1’-二苯基]-2-羧酸,CAS登记号144701-48-4,美国专利第5591762)、米法沙坦、阿比沙坦、缬沙坦((诺华公司),(S)-N-戊酰基-N-[[2’-(1H-四唑-5-基)二苯基-4-基)甲基]缬氨酸,美国专利第5399578号),EXP-3137(2-N-丁基-4-氯代-1-[(2’-(1H-四唑-5-基)二苯基-4-基)-甲基]咪唑-5-羧酸,美国专利第5138069号,美国专利第5153197号和美国专利第5128355号),3-(2’-(四唑-5-基)-1,r-二苯-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’-)1H-四唑-5-基)二苯基-4-基甲基]喹唑啉(guinazolin)-4(3H)-酮,3-[2’-羰基二苯基-4-基)甲基]-2-环丙基-7-甲基-3H-咪唑并[4,5-b]吡啶,2-丁基-4-氯代-1-[(2’-四唑-5-基)二苯基-4-基)甲基]咪唑e-羧酸,2-丁基-4-氯代-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-氧基)乙酯钾盐,二钾2-丁基-4-(甲基硫代)-1-[[2-[[[(丙基氨基)羰基]氨基]-磺酰基](1,1’-二苯基)-4-基]甲基]-1H-咪唑-5-羧酸盐,甲基-2-[[4-丁基-2-甲基-6-o-5-[[2’-(1H-四唑-5-基)-[1,1′-二苯]-4基]甲基1-(6H)-嘧啶基]甲基]-3-硫代苯基羧酸盐,5-[(3,5-二丁基-1H-1,2,4-三唑基-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’-(IH-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]-三唑基[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]三唑基钾盐,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]安息香酸乙基酯,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-氧二唑-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-缬草油酮基氨基甲基)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]苯甲酸钠,2-丁基-6-氯代-4-氢氧基甲基-5-甲基-3-[[2’-(IH-四唑-5-基)二苯基-4-基]甲基]吡啶,2-[[[2-丁基-1-[(4-羰基苯基)甲基]-1H-咪唑-5-基]甲基]氨基]安息香酸四唑-5-基)二苯基-4-基]甲基]嘧啶-6-酮,4(S)-[4-(羰基甲基)苯氧基]-N-[2(R)-[4-(2-硫磺苯甲酰胺)咪唑-1-基]辛酰]-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-乙酸-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-四环戊烷十氢化萘-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-2-三苯甲游基喹唑啉,2-(2-氯代苯甲酰)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,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-ylidene]氨基羰基-1-环戊烯羧酸二钾盐,和2-丁基-4-[N-甲基-N-(3-甲基丁烯酰)氨基]-1-[[2’-(1H-四唑-5-基)二苯基-4-基]甲基]-1H-咪唑-5-羧酸1-乙氧基羰基氧基乙基酯,以及在欧洲专利第475206号、欧洲专利第497150号、欧洲专利第539086号、欧洲专利第539713号、欧洲专利第535463号、欧洲专利第 535465号、欧洲专利第542059号、欧洲专利第497121号、欧洲专利第535420号、欧洲专利第407342号、欧洲专利第415886号、欧洲专利第424317号、欧洲专利第435827号、欧洲专利第433983号、欧洲专利第475898号、欧洲专利第490820号、欧洲专利第528762号、欧洲专利第324377号、欧洲专利第323841号、欧洲专利第420237号、欧洲专利第500297号、欧洲专利第426021号、欧洲专利第480204号、欧洲专利第429257号、欧洲专利第430709号、欧洲专利第434249号、欧洲专利第446062号、欧洲专利第505954号、欧洲专利第524217号、欧洲专利第514197号、欧洲专利第514198号、欧洲专利第514193号、欧洲专利第514192号、欧洲专利第450566号、欧洲专利第468372号、欧洲专利第485929号、欧洲专利第503162号、欧洲专利第533058号、欧洲专利第467207欧洲专利第399731号、欧洲专利第399732号、欧洲专利第412848号、欧洲专利第453210号、欧洲专利第456442号、欧洲专利第470794号、欧洲专利第470795号、欧洲专利第495626号、欧洲专利第495627号、欧洲专利第499414号、欧洲专利第499416号、欧洲专利第499415号、欧洲专利第511791号、欧洲专利第516392号、欧洲专利第520723号、欧洲专利第520724号、欧洲专利第539066号、欧洲专利第438869号、欧洲专利第505893号、欧洲专利第530702号、欧洲专利第400835号、欧洲专利第400974号、欧洲专利第401030号、欧洲专利第407102号、欧洲专利第411766号、欧洲专利第409332号、欧洲专利第412594号、欧洲专利第419048号、欧洲专利第480659号、欧洲专利第481614号、欧洲专利第490587号、欧洲专利第467715号、欧洲专利第479479号、欧洲专利第502725号、欧洲专利第503838号、欧洲专利第505098号、欧洲专利第505111欧洲专利第513,979欧洲专利第507594号、欧洲专利第510812号、欧洲专利第511767号、欧洲专利第512675号、欧洲专利第512676号、欧洲专利第512870号、欧洲专利第 517357号、欧洲专利第537937号、欧洲专利第534706号、欧洲专利第527534号、欧洲专利第540356号、欧洲专利第461040号、欧洲专利第540039号、欧洲专利第465368号、欧洲专利第498723号、欧洲专利第498722号、欧洲专利第498721号、欧洲专利第515265号、欧洲专利第503785号、欧洲专利第501892号、欧洲专利第519831号、欧洲专利第532410号、欧洲专利第498361号、欧洲专利第432737号、欧洲专利第504888号、欧洲专利第508393号、欧洲专利第508445号、欧洲专利第403159号、欧洲专利第403158号、欧洲专利第425211号、欧洲专利第427463号、欧洲专利第437103号、欧洲专利第481448号、欧洲专利第488532号、欧洲专利第501269号、欧洲专利第500409号、欧洲专利第540400号、欧洲专利第005528号、欧洲专利第028834号、欧洲专利第028833号、欧洲专利第411507号、欧洲专利第425921号、欧洲专利第430300号、欧洲专利第434038号、欧洲专利第442473号、欧洲专利第443568号、欧洲专利第445811号、欧洲专利第459136号、欧洲专利第483683号、欧洲专利第518033号、欧洲专利第520423号、欧洲专利第531876号、欧洲专利第531874号、欧洲专利第392317号、欧洲专利第468470号、欧洲专利第470543号、欧洲专利第502314号、欧洲专利第529253号、欧洲专利第543263号、欧洲专利第540209号、欧洲专利第449699号、欧洲专利第465323号、欧洲专利第521768号、欧洲专利第415594号、国际申请第WO92/14468号、国际申请第WO93/08171号、国际申请第WO93/08169号、国际申请第WO91/00277号、国际申请第WO91/00281号、国际申请第WO91/14367号、国际申请第WO92/00067号、国际申请第WO92/00977号、国际申请第WO92/20342号、国际申请第WO93/04045号、国际申请第WO93/04046号、国际申请第WO91/15206号、国际申请第WO92/14714号、国际申请第WO92/09600号、国际申请第WO92/16552号、国际申请第 WO93/05025号、国际申请第WO93/03018号、国际申请第WO91/07404号、国际申请第WO92/02508号、国际申请第WO92/13853号、国际申请第WO91/19697号、国际申请第WO91/11909号、国际申请第WO91/12001号、国际申请第WO91/11999号、国际申请第WO91/15209号、国际申请第WO91/15479号、国际申请第WO92/20687号、国际申请第WO92/20662号、国际申请第WO92/20661号、国际申请第WO93/01177号、国际申请第WO91/14679号、国际申请第WO91/13063号、国际申请第WO92/13564号、国际申请第WO91/17148号、国际申请第WO91/18888号、国际申请第WO91/19715号、国际申请第WO92/02257号、国际申请第WO92/04335号、国际申请第WO92/05161号、国际申请第WO92/07852号、国际申请第WO92/15577号、国际申请第WO93/03033号、国际申请第WO91/16313号、国际申请第WO92/00068号、国际申请第WO92/02510号、国际申请第WO92/09278号、国际申请第WO9210179号、国际申请第WO92/10180号、国际申请第WO92/10186号、国际申请第WO92/10181号、国际申请第WO92/10097号、国际申请第WO92/10183号、国际申请第WO92/10182号、国际申请第WO92/10187号、国际申请第WO92/10184号、国际申请第WO92/10188号、国际申请第WO92/10180号、国际申请第WO92/10185号、国际申请第WO92/20651号、国际申请第WO93/03722号、国际申请第WO93/06828号、国际申请第WO93/03040号、国际申请第WO92/19211号、国际申请第WO92/22533号、国际申请第WO92/06081号、国际申请第WO92/05784号、国际申请第WO93/00341号、国际申请第WO92/04343号、国际申请第WO92/04059号、美国专利第5104877号、美国专利第5187168号、美国专利第5149699号、美国专利第5185340号、美国专利第4880804号、美国专利第 5138069号、美国专利第4916129号、美国专利第5153197号、美国专利第5173494号、美国专利第5137906号、美国专利第5155126号、美国专利第5140037号、美国专利第5137902号、美国专利第5157026号、美国专利第5053329号、美国专利第5132216号、美国专利第5057522号、美国专利第5066586号、美国专利第5089626号、美国专利第5049565号、美国专利第5087702号、美国专利第5124335号、美国专利第5102880号、美国专利第5128327号、美国专利第5151435号、美国专利第5202322号、美国专利第5187159号、美国专利第5198438号、美国专利第5182288号、美国专利第5036048号、美国专利第5140036号、美国专利第5087634号、美国专利第5196537号、美国专利第5153347号、美国专利第5191086号、美国专利第5190942号、美国专利第5177097号、美国专利第5212177号、美国专利第5208234号、美国专利第5208235号、美国专利第5212195号、美国专利第5130439号、美国专利第5045540号、美国专利第5041152号、和美国专利第5210204号中公开的化合物及其药学上可接受的盐和酯;α/β肾上腺素能阻断剂,例如,尼普地洛(Nipradilol),阿罗洛尔,氨磺洛尔(Amosulalol),溴下胺甲苯磺酸盐(CAS登记号61-75-6),dihydroergtamine甲磺酸盐(例如麦角它曼-3’,61,18三醇,9,-10-二氢-12’-氢氧基-2’-甲基-5’(苯基甲基)-,(5’(α)),单甲烷磺酸盐,例如DHE注射液,诺华公司),卡维地洛(Carvedilol)(例如(±)-1-(咔唑-4-基氧基)-3-[[2-(o-甲氧基苯氧基)乙基]氨基]-2-丙醇,例如,SmithKline Beecham公司),柳安羟胺(Labetalol)(例如5-[1-氢氧基-2-[(1-甲基-3-苯基丙基)氨基]乙基水杨酰胺单盐酸盐,例如,Schering公司),溴苄铵托西酸盐(苯并甜菜碱,2-溴代-N-乙基-N,N-二甲基-,盐含有4-甲基苯并硫酸(1:1)CAS登记号61-75-6),酚胺唑啉甲磺酸(酚,3-[[(4,5-二氢-1H-咪唑-2-y1)甲基](4-甲基苯基)氨基]-,单甲烷磺酸 (盐)CAS登记号65-28-1),索立哌汀酒石酸盐(5H-1,3-二氧代并[4,5-f]吲哚,7-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-,(2R,3R)-2,3-二氢氧基丁二酸盐(1:1)CAS登记号5591-43-5),佐勒汀盐酸盐(哌嗪,1-苯基4-[2-(1H-四唑-5-基)乙基]-,单盐酸盐(8C1,9C1)CAS登记号7241-94-3)等等;α肾上腺素能受体阻断剂,例如阿夫唑嗪(Alfuzosin)(CAS RN:81403-68-1),特拉唑嗪、呱胺甲尿啶、派唑嗪坦索罗辛,布那唑嗪(Bunazosin)、三甲氧唑啉、多沙唑、萘哌地尔、吲哚哌胺、WHP164、XENOlO、螺癸酮喘通(Fenspiride)盐酸盐(可以根据美国专利第3399192号的公开制备)、普罗克生(cas登记号33743-96-3),和柳安羟胺(柳胺苄心定)及其结合物;α2激动剂,例如爱道美(Methyldopa)、爱道美(Methyldopa)盐酸盐、洛非西定、噻美尼定(Tiamenidine)、莫索尼定、利美尼定、,guanobenz,等等;醛甾酮抑制剂,等等;肾素抑制剂包括阿力克伦(SPPlOO;诺华公司/speedel公司);血管生成素-2结合剂,例如在国际申请第WO03/030833号中公开的试剂;抗心绞痛药物,例如,雷诺嗪(盐酸盐1-哌嗪乙酰胺,N-(2,6-二甲基苯基)-4-[2-氢氧基-3-(2-甲氧基苯氧基)丙基]-,二盐酸盐,CAS登记号95635-56-6),倍他洛尔盐酸盐(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]-,盐酸盐CAS登记号63659-19-8),布托丙茚盐酸盐(甲酮,[4-[3(二丁基氨基)丙氧基]苯基](2-乙基-3-indolizinyl)-,单盐酸盐CAS登记号62134-34-3),桂哌酸马来酸盐1-哌嗪乙酸,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(1:1)CAS登记号50679-07-7),托西芬(苯并磺胺,4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]-CAS登记号32295-184),维拉帕米(Verapamil)盐酸盐(苯并乙腈,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)-,单盐酸盐CAS登记号152-114),吗多明(1,2,3-恶二唑鎓, 5-[(乙氧基羰基)氨基]-3-(4-吗啉基)-,内盐CAS登记号25717-80-0),和雷诺嗪盐酸盐(1-哌嗪乙酰胺,N-(2,6-二甲基苯基)4-[2-氢氧基-3-(2-甲氧基苯氧基)丙基]-,二盐酸盐CAS登记号95635-56-6);托西芬(苯并磺胺;4-甲基-N-[[[(1S)-1-甲基-2-苯基乙基]氨基]羰基]-CAS登记号32295-184);肾上腺素兴奋剂,例如,胍法辛盐酸盐(例如N-脒-2-(2,6-二氯代苯基)乙酰胺盐酸盐,例如可从Robins公司购买得到的片剂);爱道美(Methyldopa)-盐酸噻嗪(例如左旋-3-(3,4-二氢氧基苯基)-2-甲基丙氨酸)与盐酸噻嗪相结合(例如6-氯代-3,4-二氢-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物,例如结合为,例如可以从默克公司购买得到的片剂),爱道美(Methyldopa)-氯代噻嗪(例如6-氯代-2H-1,2,4-苯并噻二嗪-7-磺胺1,1-二氧化物和上面描述的爱道美(Methyldopa),例如 默克公司),可乐定盐酸盐(例如2-(2,6-二氯代苯基氨基)-2-咪唑盐酸盐和氯噻酮(例如2-氯代-5-(1-氢氧基-3-氧-1-异丁吲哚)苯并磺胺),例如Boehringer Ingelheim公司),可乐定盐酸盐(例如2-(2,6-二氯代苯基氨基)-2-咪唑盐酸盐,例如Boehringer Ingelheim公司),可乐定(1H-咪唑-2-胺,N-(2,6-二氯代苯基)4,5-二氢-CAS登记号4205-90-7),海捷亚(默克公司,洛沙坦和氢氯代噻嗪的结合物),可得安稳(诺华公司;缬沙坦和氢氯代噻嗪的结合物),Lotrel(诺华公司;苯那普利和氨氯地平的结合物)和Caduet(辉瑞公司;氨氯地平与阿托伐他汀的结合物),及其他在美国专利第20030069221中公开的试剂。
用于治疗呼吸紊乱的试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种或一种以上试剂用于结合治疗中,所述试剂能够有效的治疗呼吸 紊乱及其他紊乱,这些试剂包括但不局限于:(1)β-激动剂,包括但不局限于:舒喘宁 班布特罗、比托特罗、氨哮素、非诺特罗、福莫特罗、异丙乙基去甲肾上腺素 二羟苯基异丙氨基乙醇 吡布特罗茶丙喘宁、羟苯哌啶甲醇、沙美特罗、间羟叔丁肾上腺素 肾上腺素、异丙基肾上腺素 肾上腺素二酒石酸盐麻黄素、奥西那林(orciprenline)、非诺特罗和异丙乙基去甲肾上腺素;(2)甾簇化合物,包括但不局限于,beclomethasono,倍氯米松二丙酸盐、betamethasono、布地奈德、bunedoside、布替可特、氟美松、氟尼缩松、氟可丁、fluticasono,hydrocortisono,甲基强的松,莫美他松,氢化泼尼松,泼尼松,替泼尼旦、巯氢可的松、去炎舒松(triamcinolono)和氟羟脱氢皮醇丙酮化合物。(3)β2-激动剂-糖皮质激素结合物,[例如,沙美特罗-氟替卡松 福莫特罗-布地奈德];(4)白细胞三烯D4受体拮抗剂/白细胞三烯拮抗剂/LTD4拮抗剂(即,任何能够阻断、抑制、减少或者反向终端白细胞三烯和半胱氨酸LTI受体之间相互作用的化合物),包括但不限于:zafhiukast、孟鲁司特、孟鲁司特钠普鲁司特、伊拉司特、泊比司特,SKB-106203和美国专利第5,565,473号中描述的具有LTD4对抗活性的化合物;(5)5-脂肪氧合酶抑制剂和/或白细胞三烯生物合成抑制剂,[例如齐留通和BAY1005(CA登记号128253-31-6)];(6)组胺H1受体拮抗剂/抗组胺药(即任意能够阻断、抑制、减少或者反向终端组合及其受体之间相互作用的化合物),包括但不限于:能息斯敏、阿伐斯汀、安他唑啉,阿扎他定,盐酸氮卓斯汀,阿司咪唑,溴代非尼拉敏,溴代非尼拉敏马来酸盐,吡氯下氧胺,卡瑞斯汀,西替利嗪,扑尔敏,氯代非 尼拉敏马来酸盐,西咪替丁马斯汀,新止吐嗪,盐酸二苯环庚啶,去羧乙氧基氯雷他定,右氯敏锭,二甲吡茚,苯海拉明,二苯基吡拉啉,琥珀酸杜克西拉明,doxylarnine,依巴斯汀,乙氟利嗪,依匹斯汀,法莫替丁,非索非那定,氢氧基锌,氢氧基锌,甲哌噻庚酮,卡巴斯汀,左西替利,左西替利,氯雷他定,氯苯甲嗪,新安替根,美喹他嗪,甲吡咯烷基甲吩噻嗪,米安色林,咪唑斯汀、诺柏斯汀,norasternizole,noraztemizole,苯茚胺,非尼拉敏,哌香豆司特,异丙嗪,甲氧苄二胺,新安替根,雷尼替丁,替美斯汀,特非那丁,10γ二甲胺异丁基吩噻嗪,曲吡那敏和吡咯烷甲苯基丙烯吡啶;(7)一种抗胆碱能药,包括但不限于:阿托品,苯扎托品,安克痉,氟托溴铵(flutropium),天仙子胺(例如 ),ilutropium,异丙托,异丙托溴铵,甲东莨菪碱,奥昔布宁,利喷西平,东莨菪碱和噻托溴铵(8)一种抗咳嗽药,包括但不限于:右美沙芬,可待因和吗啡;(9)一种解充血药,包括但不限于:伪麻黄素和苯基丙醇胺;(10)一种祛痰药,包括但不限于:愈创木酚甘油醚(guafenesin),愈创木醇硫酸盐、松油二醇,氯化铵,愈创木酚甘油醚和碘化甘油;(11)支气管扩张剂,包括但不限于:茶碱和氨基氨茶碱;(12)一种抗炎药,包括但不限于:氟比洛芬,双氯芬酸,吲哚美辛,酮基布洛芬,S-ketroprophen,替诺昔康;(13)一种磷酸二酯酶(PDE)抑制剂,包括但不限于这里公开的抑制剂;(14)重组人性单克隆抗体,[例如索雷尔(也称为奥马珠单抗),rhuMab和talizumab];(15)一种人源化肺表面活化剂,包括重组形式的界面活性剂蛋白质SP-B、SP-C或者SP-D[例如也叫做dsc-104(Discovery实验室)];(16)抑制上皮细胞钠离子通道(ENaC)的试剂,例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,例如阿昔洛韦,氨基羟丁基卡那霉素A,羟氨苄青霉素,强力霉素,三甲氧苄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(头孢西丁,头孢美唑等等),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)能够活化氯通过Ca++依赖性氯通道分泌的试剂(例如嘌呤受体(P2Y嘌呤(2)激动剂);(19)能够减少痰粘度的试剂,例如重组人DNA酶1,(20)非甾体类抗炎药(阿西美辛,乙酰氨基啉,乙酰基水杨酸,阿氯芬酸,阿明洛芬,apazono,阿司匹林,苯恶洛芬,bezpiperylon,布氯酸,卡洛芬,环氯茚酸,双氯芬酸,双氯芬酸,二氟苯水杨酸,二氟尼柳,依托度酸,联苯丁酮酸,芬布芬,芬氯酸,芬克洛酸,苯氧基氢化阿托酸,芬替酸,非普拉宗,氟灭酸,氟苯沙酸,氟苯沙酸,氟洛芬,比洛芬,布洛芬,呋罗芬酸,对异丁基苯乙酸,布洛芬,抗炎吲哚酸,吲哚美辛,吲哚洛芬,伊索克酸,异恶噻酰胺,酮洛芬,酮洛芬,酮咯酸,甲氯灭酸,抗炎酸,甲灭酸,甲芬那酸,咪洛芬,mofebutazono,萘丁美酮、奥沙普秦,萘普生,萘普生,尼氟灭酸,奥沙普秦,oxpinac,羟基保泰松,非那西丁,苯基保泰松,苯基保泰松,罗昔康,吡罗昔康,吡丙芬,普拉洛芬,苏多西卡,替诺昔康,柳氮磺胺吡啶,舒林酸,舒林酸,舒洛芬,噻洛芬酸,二氢氧二苯并硫杂,硫恶洛芬,托灭酸,甲苯酰吡啶乙酸,甲苯酰吡啶乙酸,齐多美辛,氯苯酰二甲基吡咯乙酸,和氯苯酰二甲基吡咯乙酸)和(21)雾化的抗氧化治疗剂,例如,s-亚硝基谷胱甘肽。
抗肥胖症试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种抗肥胖症试剂一起用于结合治疗。适当的这种试剂包括,但不局限于:11βHSD-I(11-β氢氧基类固醇脱氢酶1型)抑制剂,例如 BVT3498、BVT2733、3-(1-金剛烷)-4-乙基-5-(乙基硫代)-4H-1,2,4-三唑基、3-(1-金剛烷)-5-(3,4,5-三甲氧基苯基)-4-甲基-4H-1,2,4-三唑基、3-adamantany1-4,5,6,7,8,9,10,11,12,3a-十二氢-1,2,4-三唑基[4,3-a][11]轮烯,和在国际申请第WOO1/90091号、国际申请第WOO1/90090号、国际申请第WOO1/90092号、和国际申请第WO02/072084号中公开的试剂;5HT拮抗剂,例如在国际申请第WO03/037871号、国际申请第WO03/037887号、等等中公开的试剂;5HTIa调节剂,例如卡别多巴、羟下丝肼和在美国专利第6207699号、国际申请第WO03/031439号、等等中公开的试剂;5HT2c(血清紧张素受体2c)激动剂,例如BVT933,DPCA37215,IK264,PNU22394,WAY161503,R-1065,SB243213(Glaxo Smith Kline公司)和YM348,以及在美国专利第3914250号、国际申请第WOOO/77010号、国际申请第WO02/36596号、国际申请第WO02/48124号、国际申请第WO02/10169号、国际申请第WO01/66548号、国际申请第WO02/44152号、国际申请第WO02/51844号、国际申请第WO02/40456号、和国际申请第WO02/40457号中公开的试剂;5HT6受体调节剂,例如在国际申请第WO03/030901号、国际申请第WO03/035061号、国际申请第WO03/039547号、等待中公开的试剂;酰基雌激素,例如油酰雌酮,在文献del Mar-Grasa,M.et al,Obesity Research,9:202-9(2001)中和日本专利申请第JP2000256190号中公开的试剂;减食欲的二环化合物,例如1426(Aventis)和1954(Aventis),以及在国际申请第WO00/18749号、国际申请第WO01/32638号、国际申请第WO01/62746号、国际申请第WO01/62747号、和国际申请第WO03/015769号中所描述的化合物;CB1(大麻类-1受体)拮抗剂/反向激动剂,例如,利莫那班(Rimonabant)(Acomplia;Sanofi公司),SR-147778(Sanofi公司),SR-141716(Sanofi),BAY65-2520(拜耳公司),和SLV319(Solvay公 司),和在美国专利第4973587号、美国专利第5013837号、美国专利第5081122号、美国专利第5112820号、美国专利第5292736号、美国专利第5532237号、美国专利第5624941号、美国专利第6028084号、美国专利第6509367号、美国专利第6509367号、国际申请第WO96/33159号、国际申请第WO97/29079号、国际申请第WO98/31227号、国际申请第WO98/33765号、国际申请第WO98/37061号、国际申请第WO98/41519号、国际申请第WO98/43635号、国际申请第WO98/43636号、国际申请第WO99/02499号、国际申请第WO00/10967号、国际申请第WOOO/10968号、国际申请第WO01/09120号、国际申请第WO01/58869号、国际申请第WO01/64632号、国际申请第WO01/64633号、国际申请第WO01/64634号、国际申请第WO01/70700号、国际申请第WO01/96330号、国际申请第WO02/076949号、国际申请第WO03/006007号、国际申请第WO03/007887号、国际申请第WO03/020217号、国际申请第WO03/026647号、国际申请第WO03/026648号、国际申请第WO03/027069号、国际申请第WO03/027076号、国际申请第WO03/027114号、国际申请第WO03/037332号、国际申请第WO03/040107号、国际申请第WO03/086940号、国际申请第WO03/084943号和欧洲专利第658546号中公开的试剂;CCK-A(胆囊收缩素-A)激动剂,例如AR-R15849,GI181771(葛兰素史克公司),JMV-180,A-71378,A-71623和SR146131(Sanofi公司),和在美国专利第5739106号中公开的试剂;CNTF(睫状神经营养因子),例如,GI-181771(葛兰素史克公司),SR146131(Sanofi Synthelabo公司),butabindide,PD170,292,和PD149164(辉瑞公司);CNTF(睫状神经营养因子)衍生物,例如(Regeneron公司)和在国际申请第WO94/09134号、国际申请第WO98/22128号、和国际申请第WO99/43813号中公开的试剂;二肽基肽酶IV (DP-IV)抑制剂,例如,异亮氨酸噻唑烷,缬氨酸pyrrolidide,NVP-DPP728,LAF237,P93/01,P3298,TSL225(色氨酰-1,2,3,4四氢异喹啉-3-羧酸;Yamada et al,Bioorg.&Med.Chem.Lett.8(1998)1537-1540)中公开的试剂,TMC-2A/2B/2C,CD26抑制剂,FE999011,P9310/K364,VIP0177,SDZ274-444,2-氰甲基吡咯烷和4-氰甲基吡咯烷,如文献Ash国际申请第WOWOrth et al,Bioorg.&Med.Chem.Lett.,Vol.6,No.22,pp1163-1166和2745-2748(1996)中的公开,以及专利出版物中公开的化合物。国际申请第WO99/38501号、国际申请第WO99/46272号、国际申请第WO99/67279(前体生物药物)号、国际申请第WO99/67278号(前体生物药物)、国际申请第WO99/61431号(前体生物药物)、国际申请第WO02/083128号、国际申请第WO02/062764号、国际申请第WO03/000180号、国际申请第WO03/000181号、国际申请第WO03/000250号、国际申请第WO03/002530号、国际申请第WO03/002531号、国际申请第WO03/002553号、国际申请第WO03/002593号、国际申请第WO03/004498号、国际申请第WO03/004496号/国际申请第WO03/017936号、国际申请第WO03/024942号、国际申请第WO03/024965号、国际申请第WO03/033524号、国际申请第WO03/037327和欧洲专利第1258476号;生长激素分泌受体激动剂/拮抗剂,例如,NN703,海沙瑞林(hexarelin),MK-0677(默克公司),SM-130686,CP-424391(辉瑞公司),LY444,711(Eli Lilly公司),L-692,429和L-163,255和例如在USSN09/662448、美国临时专利申请第60/203335号,美国专利第6358951号,美国专利第2002049196号,美国专利第2002/022637号,国际申请第WO01/56592号和国际申请第WO02/32888号中公开的试剂;H3(组氨酸H3)拮抗剂/反向激动剂,例如,硫丙咪胺,3-(1H-咪唑-4-基)丙基N-(4-戊烯基)氨基甲酸盐),丙酸倍氯松,iodophenpropit,imoproxifan,GT2394(Gliatech公 司)和A331440,O-[3-(1H-咪唑-4-基)丙醇]氨基甲酸酯(Kiec-Kononowicz,K.et al.,Pharmazie,55:349-55(2000)),包含哌啶的组胺H3-受体拮抗剂(Lazewska,D.et al.,Pharmazie,56:927-32(2001),二苯甲酮衍生物及相关化合物(Sasse,A.et al.,Arch.Pharm.(Weinheim)334:45-52(2001)),取代的N-苯基氨基甲酸酯(Reidemeister,S.et al.,Pharmazie,55:83-6(2000)),和proxifan衍生物(Sasse,A.et al.,J.Med.Chem..43:3335-43(2000))和组胺H3受体调节剂,例如在国际申请第WO02/15905号、国际申请第WO03/024928号、和国际申请第WO03/024929号中公开的试剂;瘦素(leptin)衍生物,例如在美国专利第5552524号、美国专利第5552523号、美国专利第5552522号、美国专利第5521283号、国际申请第WO96/23513号、国际申请第WO96/23514号、国际申请第WO96/23515号、国际申请第WO96/23516号、国际申请第WO96/23517号、国际申请第WO96/23518号、国际申请第WO96/23519号、和国际申请第WO96/23520号中公开的衍生物;瘦素包括重组的人类瘦素(PEG-OB,Hoffman La Roche公司)和重组甲硫氨酰人类瘦素(Amgen);脂肪酶抑制剂,例如,四氢利泼斯汀(Tetrahydrolipstatin)氚核WRl339,RHC80267,泥泊司他汀(Lipstatin),茶皂素,二乙基伞形花内酯磷酸盐(diethylumbelliferyl phosphate),FL-386,WAY-121898,Bay-N-3176,缬氨内酯,esteracin,厄比内酯A,厄比内酯B,和RHC80267,以及在国际申请第WO01/77094号,美国专利第4598089号,美国专利第4452813号,美国专利第5512565号,美国专利第5391571号,美国专利第5602151号,美国专利第4405644号,美国专利第4189438号和美国专利第4242453号中公开的试剂;脂质代谢调节剂,例如山楂酸、高根二醇、熊果酸熊果醇,桦木酸,白桦脂醇,等等和在国际申请第WO03/011267号中公开的化合物;Mc4r(黑皮素4受体)激动剂,例如, CHIR86036(Chiron公司),ME-10142,ME-10145和HS-131(Melacure公司)和在PCT国际申请第WO99/64002号、国际申请第WO00/74679号、国际申请第WOO1/991752号、国际申请第WOO1/25192号、国际申请第WOO1/52880号、国际申请第WOO1/74844号、国际申请第WOO1/70708号、国际申请第WO01/70337号、国际申请第WO01/91752号、国际申请第WO02/059095号、国际申请第WO02/059107号、国际申请第WO02/059108号、国际申请第WO02/059117号、国际申请第WO02/06276号、国际申请第WO02/12166号、国际申请第W002/11715号、国际申请第WO02/12178号、国际申请第W002/15909号、国际申请第WO02/38544号、国际申请第W002/068387号、国际申请第WO02/068388号、国际申请第WO02/067869号、国际申请第WO02/081430号、国际申请第WO03/06604号、国际申请第WO03/007949号、国际申请第WO03/009847号、国际申请第WO03/009850号、国际申请第WO03/013509号、和国际申请第WO03/031410号中公开的化合物;Mc5r(黑皮素5受体)调节剂,例如在国际申请第WO97/19952号、国际申请第WO00/15826号、国际申请第WO00/15790号、美国专利第20030092041号中公开的试剂;黑色素聚集素1受体(MCHR)拮抗剂,例如,T-226296(Takeda公司),SB568849,SNP-7941(Synaptic),和在国际申请第WOO1/21169号、国际申请第WO01/82925号、国际申请第WO01/87834号、国际申请第WO02/051809号、国际申请第WO02/06245号、国际申请第WO02/076929号、国际申请第WO02/076947号、国际申请第WO02/04433号、国际申请第WO02/51809号、国际申请第WO02/083134号、国际申请第WO02/094799号、国际申请第WO03/004027号、国际申请第WO03/13574号、国际申请第W003/15769号、国际申请第WO03/028641号、国际申请第WO03/035624号、国际申请第WO03/033476号、国际申请第 WO03/033480号、日本专利第13226269号、和日本专利第437059号中公开的试剂;mGluR5调节剂,例如,在国际申请第WO03/029210号、国际申请第WO03/047581号、国际申请第WO03/048137号、国际申请第WO03/051315号、国际申请第WO03/051833号、国际申请第WO03/053922号、国际申请第WO03/059904号中公开的试剂,等等;羟色胺剂,例如,芬氟拉明(例如,(苯乙胺,N-乙基-α-甲基-3-(三氟代甲基)-,盐酸盐),Robbins),右芬氟拉明(例如,(苯乙胺,N-乙基-α-甲基-3-(三氟代甲基)-,盐酸盐),Interneuron公司)和包括曲美(Sibutramine)((Knoll/ReductilTM)的外销旋混合物,例如光学纯异构体(+)和(-),及其药学上可接收的盐、溶剂、水合物、包合物和前体药物,包括其including西布曲明盐酸盐单水合盐;和在美国专利第4746680号、美国专利第4806570号、和美国专利第5436272号、美国专利第20020006964号、国际申请第WOO1/27068号、和国际申请第WOO1/62341号中公开的化合物;NE(去甲肾上腺素)输送抑制剂,例如,GW320659,despiramine,他舒普仑,和诺米芬新;NPY1拮抗剂;例如,BIBP3226,J-115814,BIBO3304,LY-357897,CP-671906,GI-264879A和在美国专利第6001836号、国际申请第WO96/14307号、国际申请第WO01/23387号、国际申请第WO99/51600号、国际申请第WO01/85690号、国际申请第WO01/85098号、国际申请第WO01/85173号、和国际申请第WO01/89528号中公开的试剂;NPY5(神经肽Y Y5)拮抗剂,例如,152,804,GW-569180A,GW-594884A,GW-58708IX,GW-548118X,FR235208,FR226928,FR240662,FR252384,1229U91,GI-264879A,CGP71683A,LY-377897,LY-366377,PD-160170,SR-120562A,SR-120819A,JCF-104和H409/22以及在美国专利第6140354号、美国专利第6191160号、美国专利第6218408号、美国专利第6258837号、美国专利第6313298号、 美国专利第6326375号、美国专利第6329395号、美国专利第6335345号、美国专利第6337332号、美国专利第6329395号、美国专利第6340683号、EP01010691号、EP-01044970号、国际申请第WO97/19682号、国际申请第WO97/20820号、国际申请第WO97/20821号、国际申请第WO97/20822号、国际申请第WO97/20823号、国际申请第WO98/27063号、国际申请第WO00/107409号、国际申请第WO00/185714号、国际申请第WO00/185730号、国际申请第WO00/64880号、国际申请第WO00/68197号、国际申请第WO00/69849号、国际申请第WO/0113917号、国际申请第WO01/09120号、国际申请第WO01/14376号、国际申请第WO01/85714号、国际申请第WO01/85730号、国际申请第WO01/07409号、国际申请第WO01/02379号、国际申请第WO01/23388号、国际申请第WO01/23389号、国际申请第WOO1/44201号、国际申请第WO01/62737号、国际申请第WO01/62738号、国际申请第WO01/09120号、国际申请第WO02/20488号、国际申请第WO02/22592号、国际申请第WO02/48152号、国际申请第WO02/49648号、国际申请第WO02/051806号、国际申请第WO02/094789号、国际申请第WO03/009845号、国际申请第WO03/014083号、国际申请第WO03/022849号、国际申请第WO03/028726号和文献Norman et al,J.Med.Chem.43:4288-4312(2000)中公开的化合物;鸦片样物拮抗剂,例如,纳美芬( ),3-甲氧基钠曲酮,甲基钠曲酮,钠曲酮,和纳曲酮(例如,PT901;Pain Therapeutics有限公司)和在美国专利第US20050004155号和国际申请第WO00/21509号中公开的试剂;增食因子拮抗剂,例如,SB-334867-A和在国际申请第WO01/96302号、国际申请第WO01/68609号、国际申请第WO02/44172号、国际申请第WO02/51232号、国际申请第WO02/51838号、国际申请第WO02/089800号、国际申请第 WO02/090355号、国际申请第WO03/023561号、国际申请第WO03/032991号、和国际申请第WO03/037847号中公开的试剂;PDE抑制剂(例如,通过抑制磷酸二酯酶减缓环化单磷酸腺苷(cAMP)和/或环化单磷酸鸟苷(cGMP)的降解作用的化合物,这回导致单磷酸腺苷(cAMP)和/或环化单磷酸鸟苷(cGMP)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编号命名的物质,尤其是可以作为PDE3/4抑制剂混合型命名的物质,或者作为PDE3/4/5抑制剂混合型命名的物质),例如,在德国专利第1470341号、德国专利第2108438号、德国专利第2123328号、德国专利第2305339号、德国专利第2305575号、德国专利第2315801号、德国专利第2402908号、德国专利第2413935号、德国专利第2451417号、德国专利第2459090号、德国专利第2646469号、德国专利第2727481号、德国专利第2825048号、德国专利第2837161号、德国专利第2845220号、德国专利第2847621号、德国专利第2934747号、德国专利第3021792号、德国专利第3038166号、德国专利第3044568号、欧洲专利第000718号、欧洲专利第0008408号、欧洲专利第0010759号、欧洲专利第0059948号、欧洲专利第0075436号、欧洲专利第0096517号、欧洲专利第O112987号、欧洲专利第O116948号、欧洲专利第0150937号、欧洲专利第0158380号、欧洲专利第0161632号、欧洲专利第0161918号、欧洲专利第0167121号、欧洲专利第0199127号、欧洲专利第0220044号、欧洲专利第0247725号、欧洲专利第0258191号、欧洲专利第0272910号、欧洲专利第0272914号、欧洲专利第0294647号、欧洲专利第0300726号、欧洲专利第0335386号、欧洲专利第0357788号、欧洲专利第0389282号、欧洲专利第0406958号、欧洲专利第0426180号、欧洲专利第0428302号、欧洲专利第0435811号、欧洲专利第0470805号、欧洲专利第 0482208号、欧洲专利第0490823号、欧洲专利第0506194号、欧洲专利第0511865号、欧洲专利第0527117号、欧洲专利第0626939号、欧洲专利第0664289号、欧洲专利第0671389号、欧洲专利第0685474号、欧洲专利第0685475号、欧洲专利第0685479号、日本专利第92234389号、日本专利第94329652号、日本专利第95010875号、美国专利第4963561号、美国专利第5141931号、W09117991号、国际申请第WO9200968号、国际申请第WO9212961号、国际申请第WO9307146号、国际申请第WO9315044号、国际申请第WO9315045号、国际申请第WO9318024号、国际申请第WO9319068号、国际申请第WO9319720号、国际申请第WO9319747号、国际申请第WO9319749号、国际申请第WO9319751号、国际申请第WO9325517号、国际申请第WO9402465号、国际申请第WO9406423号、国际申请第WO9412461号、国际申请第WO9420455号、国际申请第WO9422852号、国际申请第WO9425437号、国际申请第WO9427947号、国际申请第WO9500516号、国际申请第WO9501980号、国际申请第WO9503794号、国际申请第WO9504045号、国际申请第WO9504046号、国际申请第WO9505386号、国际申请第WO9508534号、国际申请第WO9509623号、国际申请第WO9509624号、国际申请第WO9509627号、国际申请第WO9509836号、国际申请第WO9514667号、国际申请第WO9514680号、国际申请第WO9514681号、国际申请第WO9517392号、国际申请第WO9517399号、国际申请第WO9519362号、国际申请第WO9522520号、国际申请第WO9524381号、国际申请第WO9527692号、国际申请第WO9528926号、国际申请第WO9535281号、国际申请第WO9535282号、国际申请第WO9600218号、国际申请第WO9601825号、国际申请第WO9602541号、国际申请第 WO9611917号、德国专利第3142982号、德国专利第1116676号、德国专利第2162096号、欧洲专利第0293063号、欧洲专利第0463756号、欧洲专利第0482208号、欧洲专利第0579496号、欧洲专利第0667345美国专利第6331543号、美国专利第20050004222号(包括式I-XIII表示的化合物和在37-39、85-0545和557-577段公开的化合物)、国际申请第WO9307124号、欧洲专利第0163965号、欧洲专利第0393500号、欧洲专利第0510562号、欧洲专利第0553174号、国际申请第WO9501338and国际申请第WO9603399号中公开的试剂;以及PDE5抑制剂,(例如,Rx-RA-69、SCH-51866、KT-734、维司力农、扎普司托(zaprinast)、SKF-96231、ER-21355、BF/GP-385、NM-702和西地那非(ViagraTM)),PDE4抑制剂(例如,依他唑酯(Etazolate),ICI63197,RP73401,咪唑烷酮(RO-20-1724),MEM1414(R1533/R1500;Pharmacia Roche公司),登布茶,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(Indolidan),奥普力农(Olprinone),阿替唑仑(atizoram),KS-506-G,dipamfylline,BMY-43351,阿替唑仑(atizoram),阿罗茶碱(Arofylline),非明司特,PDB-093,UCB-29646,CDP-840,SKF-107806,吡拉米特(piclamilast),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(Ibudilast),氨力农,匹莫苯丹,西洛他唑,喹齐酮和N-(3,5-二氯代吡啶-4-基)-3-环丙基甲氧基4-二氟甲氧基苯甲酰胺,PDE3抑制剂(例如,ICI153,100,bemorandane(RWJ22867),MCI-154,UD-CG212,硫马唑(Sulmazole),ampizone,西洛酰胺(Cilostamide),卡巴折伦,匹罗昔酮,伊马唑旦(Imazodan),CI-930,氰胍佐旦(Siguazodan),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(例如,苯芬群,曲喹辛,ORG-30029,扎达维林(Zardaverine),L-686398,SDZ-ISQ-844,ORG-20241,EMD-54622,和托拉芬群)及其它磷酸二酯酶(PDE)抑制剂(例如,长春西汀(Vinpocetin),罂粟碱,恩丙茶碱(Enprofylline),西洛司特,依诺苷酮,己酮可可碱,罗氟司特,他达拉非茶碱和伐地那非神经原肽Y2(NPY2)激动剂包括但不局限于:多肽YY及其片段和变体(例如,YY3-36(PYY3-36)(N.Engl.J.Med.349:941,2003;IKPEAPGE DASPEELNRY YASLRHYLNL VTRQRY(SEQ ID NO:XXX))和PYY激动剂,例如在国际申请第WO02/47712号、国际申请第WO03/026591号、国际申请第WO03/057235号和国际申请第WO03/027637号中公开的激动剂;羟色胺再摄取抑制剂,例如帕罗西汀,氟西汀(百忧解TM),氟伏沙明,舍曲林,西酞普兰,和丙咪嗪,以及在美国专利第6162805号、美国专利第6365633号、国际申请第WO03/00663号、国际申请第WOO1/27060号和国际申请第WOO1/162341号中公开的试剂;甲状腺激素β激动剂,例如,KB-2611(KaroBioBMS)以及在国际申请第WO02/15845号、国际申请第WO97/21993号、国际申请第WO99/00353号、GB98/284425、美国临时专利申请第60/183,223号、和日本专利申请第JP2000256190号中记载的试剂;UCP-I(解偶联蛋白-1)、UCP-2(解偶联蛋白-2)或者UCP-3(解偶联蛋白-3)活化剂,例如,植烷酸,4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-石脑油烯基)-1-丙烯基]苯甲酸(TTNPB),维甲酸,以及在国际申请第WO99/00123号中公开的试剂;β3(β肾上腺素受体3)激动剂,例如,AJ9677/TAK677(Dainippon/Takeda),L750355(默克公司),CP331648(辉瑞公司),CL-316,243,SB418790,BRL-37344,L-796568,BMS-196085,BRI-35135A,CGP12177A,BTA-243,GW427353, 曲卡君(Trecadrine),捷利康D7114,N-5984(Nisshin Kyorin公司),LY-377604(Lilly公司),SR59119A,以及在美国专利第US5541204号、美国专利第US5770615号、美国专利第US5491134号、美国专利第US5776983号、美国专利第US488064号、美国专利第US5705515号、美国专利第US5451677号、国际申请第WO94/18161号、国际申请第WO95/29159号、国际申请第WO97/46556号、国际申请第WO98/04526号和国际申请第WO98/32753号、国际申请第WO01/74782号、国际申请第WO02/32897号、国际申请第WO03/014113号、国际申请第WO03/016276号、国际申请第WO03/016307号、国际申请第WO03/024948号、国际申请第WO03/024953号和国际申请第WO03/037881号中公开的试剂;去甲肾上腺素能药物,包括但不限于,二乙胺苯酮(例如,(1-丙酮,2-(二乙胺)-1-苯基-,盐酸),Merrell公司),右旋安非他命(也称为右旋安非他命硫酸盐,右旋苯丙胺,苯丙胺,右旋安非他明,右旋苯丙胺(Ferndex),Oxydess II,Robese,Spancap#1),马吲哚((或者5-(p-氯代苯基)-2,5-二氢-3H-咪唑并[2,1-a]异氮茚基-5-o1)例如诺华公司的或者惠氏-艾尔斯特制药有限公司的 ),苯丙醇胺(或苯甲醇,α-(1-氨乙基)-盐酸盐),芬特明((或苯酚,3-[[4,5-二氢-1H-咪唑-2-基)乙基](4-甲基苯基-1)氨基],单盐酸盐)例如,Lemmon公司的Smith-Kline Beecham公司的和Medeva公司的 ),苯甲曲秦((或者(2S,3S)-3,4-二甲基-2苯基吗啉L-(+)-酒石酸盐(1:1)),例如(Forest公司), (惠氏-艾尔斯特制药有限公司),(勃林格殷格翰公司)和(Lemmon公司),Dhendamine酒石酸盐(例如,(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公司),甲基安非他命(例如,Abbot((S)-N,(α)-二甲 基苯乙胺盐酸盐)),和酒石酸苯甲曲秦(例如,缓释胶囊,Amarin(-3,4-二甲基-2苯基吗啉酒石酸盐);脂肪酸氧化作用上调节剂/诱导剂,例如,(Genset公司);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(Toloxatone),pirlindol,阿米夫胺,sercloremine,巴嗪普今(Bazinaprine),拉扎贝胺(Lazabemide),米拉醋胺,卡罗沙酮及其它在国际申请第WOO1/12176号中公开的某些化合物;及其它抗肥胖试剂,例如,5HT-2激动剂,ACC(乙酰CoA脱羧酶)抑制剂,例如在国际申请第WO03/072197号中的公开;硫辛酸(α-LA),AOD9604,食欲抑制剂,例如在国际申请第WO03/40107号中公开的试剂,ATL-962(Alizyme PLC),苯佐卡因,苄非他明(Benzphetamine)烟酸盐(Didrex),黑角菜藻提取液(bladderwrack)(墨角藻精华(focus vesiculosus)),BRS3(蛙皮素受体亚型-3)激动剂,安非他酮,咖啡因,胆囊收缩素激动剂,壳聚糖,铬,共轭亚油酸,促肾上腺皮质激素释放激素激动剂,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,二羧酸转运抑制剂,麻黄,exendin-4(一种glp-1抑制剂),FAS(要求脂肪酸合成酶)抑制剂(如浅蓝菌素和C75),脂肪吸收抑制剂(例如,国际申请第WO03/053451号中的公开,等等),脂肪酸转运抑制剂,天然水溶性纤维(如欧车前,车前子,瓜尔豆,燕麦,果胶),甘丙拮抗剂,山羊(galega)(羊的名称,French Lilac),藤黄果,石蚕属植物(草药石蚕香科(Teucrium chamaedrys)),人生长激素释放多肽(ghrelin)抗体和人生长激素释放多肽(ghrelin)拮抗剂(例如在国际申请第WOO1/87335号和国际申请第WO02/08250号中的公开),能够影响内部细胞分泌的多肽激素及其受体,例如,分泌/胃抑制性多肽(GIP)/血管活性肠肽(VIP)/垂体腺苷酸环化酶活性肽(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/或包含GLP-1(胰高血糖素样多肽1)激动剂的肾上腺髓质素/淀素/降钙素基因相关多肽(CGRP)的基因族(例如,(1)exendin-4,(2)在US20050130891中描述的包括胰高血糖素样多肽-1(7-34),胰高血糖素样多肽-1(7-35),胰高血糖素样多肽-1(7-36)或者胰高血糖素样多肽-1(7-37)的胰高血糖素样多肽-I分子,其中所述胰高血糖素样多肽-1(7-34),胰高血糖素样多肽-1(7-35),胰高血糖素样多肽-1(7-36)或者GLP-1(7-37)以其C-末端羧酸化或者酰胺化的形式存在,或者作为修饰的胰高糖素样多肽-1多肽的形式及其修饰型存在,包括在US20050130891第17-44段中描述的修饰型,并且,使用从胰高血糖素养肽-1-(7-34)COOH及其相应的酸胺中衍生的衍生物,所述衍生物具有下列通式:R-NH-HAEGTFTSDVSYLEGQAAKEFIAWLVK-CONH2,其中,R=H或者一种具有1到10个碳原子的有机化合物。优选的,R是一种羧酸残基。特别优选的,是下列羧酸残基:酰基羧酸,乙酰羧酸,丙酰羧酸,异丙酰羧酸,甲基羧酸,乙基羧酸,丙基羧酸,异丙基羧酸,丁基羧酸,仲丁基羧酸,叔丁基羧酸)和glp-1(胰高糖素样肽-1),糖皮质激素(glucocorticoid)拮抗剂,葡萄糖转运抑制剂,生长激素分泌促进剂(例如在US5536716中描述的试剂),白细胞介素-6(IL-6)及其调节剂(参见国际申请第WO03/057237号等等),L-肉碱,Mc3r(黑素皮质素3受体)激动剂,MCH2R(黑色素聚集激素2受体)激动剂/拮抗剂,黑色素聚集激素拮抗剂,黑素皮质素激动剂(如拉诺坦II或者在国际申请第WO99/64002号和国际申请第WO00/74679号中公开的试剂),nomame herba,磷转运抑制剂,phytopharm化合物57(CP644,673),丙酮酸(pyruvate),SCD-I(硬脂酰基-CoA脱氢酶-1)抑制剂,T71(Tularik有限公司,Boulder CO),托吡酯(可以被用作抗惊厥药,能够显示增加的体重下降),转录因子调节剂(例如,在国际申请第WO03/026576中 公开的试剂),β-羟基类固醇脱氢酶-1抑制剂(β-HSD-I),β-氢氧基-β-甲基丁酸,p57(辉瑞公司),唑尼沙胺(ZonegranTM,作为一种一种抗痫药物,同时会导致体重下降),以及在US20030119428第20-26段中公开的试剂。
糖尿病治疗剂
这里描述的GCRA肽可以与一种或者一种以上的糖尿病治疗剂一起用于结合治疗,所述糖尿病治疗剂包括,但是不局限于:PPARγ激动剂,例如,格列酮类(例如,WAY-120744,AD5075,巴格列酮(balaglitazone),格列酮,达格列酮(CP-86325,辉瑞公司),恩格列酮(CP-68722,辉瑞公司),isaglitazone(麻省理工学院/强生公司),MCC-555(在US5594016公开的Mitsibishi),吡格列酮(例如的ActosTM吡格列酮;Takeda公司),罗格列酮(文迪雅TM;史克必成),马来酸罗格列酮,曲格列酮(如US4572912中的公开),利格列酮(CS-Ol1,Sankyo公司),GL-262570(Glaxo Welcome公司),BRL49653(如国际申请第WO98/05331中公开的内容),CLX-0921,5-BTZD,GW-0207,LG-100641,JJT-501(JPNT/P&U),L-895645(默克公司),R-119702(Sankyo/辉瑞公司),NN-2344(Dr.Reddy/NN),YM-440(Yamanouchi),LY-300512,LY-519818,R483(Roche),T131(Tularik),等等,以及在美国专利第US4687777号、美国专利第US5002953号、美国专利第US5741803号、美国专利第US5965584号、美国专利第US6150383号、美国专利第US6150384号、美国专利第US6166042号、美国专利第US6166043号、美国专利第US6172090号、美国专利第US6211205号、美国专利第US6271243号、美国专利第US6288095号、美国专利第US6303640号、美国专利第US6329404号、美国专利第US5994554号、W097/10813号、国际申请第 WO97/27857号、国际申请第WO97/28115号、国际申请第WO97/28137,国际申请第WO97/27847号、国际申请第WOOO/76488号、国际申请第WO03/000685,国际申请第WO03/027112,国际申请第WO03/035602号、国际申请第WO03/048130号、国际申请第WO03/055867号中所描述的试剂及其药学上可接受的盐;双胍类,例如,盐酸二甲双胍(N,N-二甲基酰亚胺缩二脲盐酸盐,例如,百时美施贵宝的格华止TM);含有格列本脲的二甲双胍(例如百时美施贵宝的GlucovanceTM),丁双胍(酰亚胺缩二脲,N-丁基-);依托福明(1-丁基-2-乙级双胍,先灵公司);其他二甲双胍盐形式(包括,其中所述盐选自下列盐所组成的组中:醋酸盐,苯甲酸盐,柠檬酸盐,ftimarate,双羟萘酸盐,氯苯氧基醋酸盐,乙醇酯,palmoate,天门冬氨酸,甲烷磺酸,马来酸盐,对氯代苯氧基异酪酸盐,甲酸盐,乳酸盐,琥珀酸盐,硫酸盐,酒石酸盐,环己烷羧酸盐,己酸,辛酸,癸酸,棕榈酸盐,八葵酸盐(octodecanoate),苯并磺酸盐,三甲氧基苯甲酸盐,对甲苯基磺酸盐,金刚烷羧酸盐,乙醛酸盐,谷氨酸盐,吡咯烷酮羧酸盐,萘磺酸盐,1-葡糖磷酸盐,硝酸盐,亚硫酸盐,二硫代硫酸盐和磷酸盐),和苯乙双胍;蛋白酪氨酸磷酸酶-IB(PTP-IB)抑制剂,例如,A-401,674,KR61639,OC-060062,OC-83839,OC-297962,MC52445,MC52453,ISIS113715,和在国际申请第WO99/585521号、国际申请第WO99/58518号、国际申请第WO99/58522号、国际申请第WO99/61435号、国际申请第WO03/032916号、国际申请第WO03/032982号、国际申请第WO03/041729号、国际申请第WO03/055883号、国际申请第WO02/26707号、国际申请第WO02/26743号、日本专利第JP2002114768号中公开的试剂,及其药学上可接受的盐河酯;磺脲类药物,例如,醋磺己脲(例如,Dymelor,礼来公司),磺胺丁脲,氯磺丙脲(例如,辉瑞公司),格列胺脲(辉瑞公司),格列齐特(例如,达美康, Servier加拿大公司),格列美脲(例如,在美国专利第US4379785中公开的试剂,例如亚莫利,安万特),格列戊脲,格列吡嗪(例如格列吡嗪(Glucotrol)或格列吡嗪(Glucotrol)XL缓释制剂,辉瑞公司),格列喹酮,格列索脲,格列本脲/格列本脲(例如Micronase或格列本脲(Glynase Prestab),法玛西亚普和Diaβ,安万特公司),妥拉磺脲(如Tolinase)和磺丁脲(如Orinase)及其药学上可接受的盐类和酯类;meglitinides类药物,例如瑞格列奈(例如诺和诺德),KAD的1229(PF/Kissei公司)和格列奈(如诺华公司),以及其药学上可接受的盐及酯;α糖苷酶抑制剂(或葡萄糖苷酶抑制剂),例如阿卡波糖(例如PrecoseTM,拜耳在US4904769中公开的试剂),米格列醇(如GLYSETTM,Pharmacia & Upjohn公司在US4639436中公开的试剂),卡格列波糖(甲基6-脱氧-6-[(2R,3R,4R,5S)-3,4,5-三氢氧基-2-(氢氧基甲基哌啶)-α-D吡喃葡萄糖苷,Marion Merrell Dow公司),格列波糖(takeda公司),脂解素,乙格列酯,帕地霉素(pradimicin)-Q,salbostatin,CKD-711,MDL-25,637,MDL-73,945,和MOR14,和在美国专利第us4062950号,美国专利第us4174439号,美国专利第us4254256号,美国专利第us4701559号,美国专利第us4639436号,美国专利第us5192772号,美国专利第us4634765号,美国专利第us5157116号,美国专利第us5504078号,美国专利第us5091418号,美国专利第us5217877号,美国专利第us51091号和国际申请WO01/47528号(多胺)中公开的化合物;α-淀粉酶抑制剂,例如淀粉酶抑肽,萃他丁(trestatin),和A1-3688,和在美国专利第US4451455号、美国专利第US4623714号和美国专利第us4273765中公开的化合物;SGLT2抑制剂,包括那公开在美国专利第us6414126号和美国专利第us6515117号中的化合物;一种ap2抑制剂,例如公开在美国专利第us6548529号中的化合物;胰岛素secreatagogues例如利诺格列,A-4166, forskilin,dibutyrl cAMP,异丁基甲基黄嘌呤(IBMX)及其药学上可接受的盐和酯;脂肪酸氧化抑制剂,例如氯莫克舍,和乙莫克舍,及其药学上可接受的盐和酯;A2拮抗剂,例如,咪格列唑,伊格列哚,德格列哚,亚达唑散,earoxan,和氟洛克生,和药学上可接受的盐和酯;胰岛素和有关化合物(例如,胰岛素类似物),例如biota,LP-100,novarapid,胰岛素诺和平(insulin detemir),赖脯胰岛素,甘精胰岛素,胰岛素锌混悬液(长效的和超长效的),赖氨酸-脯氨酸-胰岛素,GLP-1(1-36)酰胺,GLP-1(73-7)(insulintropin,如us5614492中的公开),LY-315902(礼来公司),GLP-1(7-36)-NH2),AL-401(Autoimmune),以及在美国专利第us4579730,美国专利第us4849405,美国专利第us4963526号、美国专利第us5642868号、美国专利第us5763396号、美国专利第us5824638号、美国专利第us5843866号、美国专利第us6153632号、美国专利第us6191105号和国际申请第WO85/05029中公开的某些组合物,和包含生物活性变体或等位基因的灵长类动物,啮齿动物,或兔子胰岛素,更优选的,以重组形势可利用的人胰岛素(人胰岛素源包括药学上可接受的制剂和无菌制剂,例如从礼来公司(印第安纳州印第安纳波利斯46285)购得的律草素(人胰岛素rDNA源),参见医生桌上参考手册”55.sup.th版(2001)医药经济学,Thomson保健公司(公开了其他适当的人胰岛素);非噻唑烷二酮类化合物,例如JT-501和法格列酮(Farglitazar)(GW-2570/GI-262579)及其药学上可接受的盐和酯;PPARα/γ双重激动剂,例如AR-H039242(阿斯利康公司),GW-409544(葛兰素威康公司)的BVT-142,CLX-0940,GW-1536,GW-1929,GW-2433,KRP-297(杏林默克公司,5-[(2,4-二氧噻唑烷基)甲基]甲氧基-N-[[4-(三氟代甲基)苯基]甲基]苯甲酰胺),L-796449,LR-90,MK-0767(默克/Kyorin/Banyu公司)的SB219994,muraglitazar(BMS公司),tesaglitzar(阿斯利康),reglitazar(JTT-501)和国际 申请第WO99/16758,国际申请第WO99/19313,国际申请第WO99/20614,国际申请第WO99/38850,国际申请第WO00/23415,国际申请第WO00/23417,国际申请第WO00/23445号,国际申请第WO00/50414号,国际申请第WO01/00579号,国际申请第WO01/79150号,国际申请第WO02/062799号,国际申请第WO03/004458号,国际申请第WO03/016265号,国际申请第WO03/018010号,国际申请第WO03/033481号,国际申请第WO03/033450号,国际申请第WO03/033453号,国际申请第WO03/043985号,国际申请第031053976号,2000年9月18日递交的美国申请系列号09/664,598,文献Murakami et al.Diabetes47,1841-1847(1998)中公开的试剂,及其药学上可接受的盐和酯;其他胰岛素增敏药物;VPAC2受体激动剂;GLK的调节剂,例如在国际申请第WO03/015774号公开的试剂,类视黄醇调节剂,例如在国际申请第WO03/000249号中公开的试剂;GSK3β/GSK3抑制剂,例如4-[2-(2-溴代苯基)-4-(4-氟代苯基-1H-咪唑-5-基]吡啶和在国际申请WO03/024447号,国际申请WO03/037869号,国际申请WO03/037877号,国际申请WO03/037891号,国际申请WO03/068773号,欧洲专利ep1295884号,欧洲专利ep1295885号等等中公开的化合物;糖原磷酸化酶(HGLPa)抑制剂,例如CP-368,296上,CP-316,819,BAYR3401和在国际申请WO01/94300号,国际申请WO02/20530号,国际申请WO03/037864号中公开的化合物及其药学上可接受的盐或酯;三磷酸腺苷消耗促进剂,例如在国际申请WO03/007990中公开的试剂;TRB3抑制剂;辣椒素受体配位体,例如在国际申请WO03/049702中公开的化合物;降血糖药,例如在国际申请WO03/015781和国际申请WO03/040114中公开的化合物;糖原合成酶激酶3抑制剂,例如在国际申请WO03/035663中公开的试剂,以及在国际申请WO99/51225、us20030134890、国际申请WO01/24786和国际申请WO03/059870中公开的化合物;胰岛素 响应性DNA结合蛋白-1(IRDBP-I),如在国际申请WO03/057827中的公开,等等;腺苷酸A2拮抗剂,例如在国际申请WO03/035639、国际申请WO03/035640等等之中的公开;PPARδ激动剂,例如GW501516、GW590735和在JP10237049和WO02/14291中公开的化合物;二肽基肽酶IV(DP-IV)抑制剂,例如,异亮氨酸噻唑烷,NVP-DPP728A(1-[[[2-[(5-氰基吡啶-2-基)氨基]乙基]氨基]乙酰基]-2-氰基-(S)-吡咯烷基,如Hughes et al,Biochemistry,38(36),11597-11603,1999的公开),P32/98,NVP-LAF-237,P3298,TSL225(色氨酰-1,2,3,4-四氢-异喹啉基-3-羧酸,如文献Yamada et al,Bioorg.&Med.Chem.Lett.8(1998)1537-1540)中的公开,缬氨酸pyrrolidide,TMC-2A/2B/2C,CD-26抑制剂,FE999011,P9310/K364,VIP0177,DPP4,SDZ274-444,2-氰基pyrrolidides和4-氰基pyrrolidides,如文献Ashworth et al,Bioorg.&Med.Chem.Lett.,Vo1.6,No.22,pp1163-1166and2745-2748(1996)中的公开,以及在美国专利第us6395767号,美国专利第us6573287号,美国专利第us6395767号(其中公开的化合物包括BMS-477118,BMS-471211和BMS538305),国际申请WO99/38501,国际申请WO99/46272,国际申请WO99/67279,国际申请WO99/67278,国际申请WO99/61431,国际申请WO03/004498,国际申请WO03/004496,欧洲专利第ep1258476号,国际申请WO02/083128,国际申请WO02/062764,国际申请WO03/000250,国际申请WO03/002530,国际申请WO03/002531,国际申请WO03/002553,国际申请WO03/002593,国际申请WO03/000180和国际申请WO03/000181中公开的化合物;GLP-1激动剂,例如exendin-3和exendin-4(包括长度为39个氨基酸的多肽合成的exendin-4,叫做),以及在us2003087821和NZ504256中公开的化合物,及其药学上可接受的盐和酯;肽包括安林肽和(普兰林肽(Pramlintide)醋酸盐);和甘氨酸激酶(glycokinase) 活化剂,例如在us2002103199(融合的芳香杂环化合物)和WO02/48106(异吲哚-1-酮-取代丙酰胺化合物)中公开的试剂。
磷酸二酯酶抑制剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种磷酸二酯酶抑制剂一起用于结合治疗。所述磷酸二酯酶(PDE)抑制剂是能够通过移植磷酸二酯酶(PDE)减缓环腺苷酸(cAMP)和/或环鸟苷单磷酸(cGMP)降解作用的化合物,这会导致细胞内环腺苷酸和/或环鸟苷单磷酸(cGMP)的浓度相对增加。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编号命名的物质,尤其是可以作为PDE3/4抑制剂混合型命名的物质,或者作为PDE3/4/5抑制剂混合型命名的物质。例如,所述磷酸二酯酶(PDE)抑制剂可以包括下面专利申请和专利中描述和/或要求保护的化合物:例如,在德国专利第1470341号、德国专利第2108438号、德国专利第2123328号、德国专利第2305339号、德国专利第2305575号、德国专利第2315801号、德国专利第2402908号、德国专利第2413935号、德国专利第2451417号、德国专利第2459090号、德国专利第2646469号、德国专利第2727481号、德国专利第2825048号、德国专利第2837161号、德国专利第2845220号、德国专利第2847621号、德国专利第2934747号、德国专利第3021792号、德国专利第3038166号、德国专利第3044568号、欧洲专利第000718号、欧洲专利第0008408号、欧洲专利第0010759号、欧洲专利第0059948号、欧洲专利第0075436号、欧洲专利第0096517号、欧洲专利第0112987号、欧洲专利第0116948号、欧洲专利第0150937号、欧洲专利第0158380号、欧洲专利第0161632号、欧洲专利第0161918号、欧洲专利第0167121号、欧洲专利第0199127号、 欧洲专利第0220044号、欧洲专利第0247725号、欧洲专利第0258191号、欧洲专利第0272910号、欧洲专利第0272914号、欧洲专利第0294647号、欧洲专利第0300726号、欧洲专利第0335386号、欧洲专利第0357788号、欧洲专利第0389282号、欧洲专利第0406958号、欧洲专利第0426180号、欧洲专利第0428302号、欧洲专利第0435811号、欧洲专利第0470805号、欧洲专利第0482208号、欧洲专利第0490823号、欧洲专利第0506194号、欧洲专利第0511865号、欧洲专利第0527117号、欧洲专利第0626939号、欧洲专利第0664289号、欧洲专利第0671389号、欧洲专利第0685474号、欧洲专利第0685475号、欧洲专利第0685479号、日本专利第92234389号、日本专利第94329652号、日本专利第95010875号、美国专利第4963561号、美国专利第5141931号、国际申请第W09117991号、国际申请第WO9200968号、国际申请第WO9212961号、国际申请第WO9307146号、国际申请第WO9315044号、国际申请第WO9315045号、国际申请第WO9318024号、国际申请第WO9319068号、国际申请第WO9319720号、国际申请第WO9319747号、国际申请第WO9319749号、国际申请第WO9319751号、国际申请第WO9325517号、国际申请第WO9402465号、国际申请第WO9406423号、国际申请第WO9412461号、国际申请第WO9420455号、国际申请第WO9422852号、国际申请第WO9425437号、国际申请第WO9427947号、国际申请第WO9500516号、国际申请第WO9501980号、国际申请第WO9503794号、国际申请第WO9504045号、国际申请第WO9504046号、国际申请第WO9505386号、国际申请第WO9508534号、国际申请第WO9509623号、国际申请第WO9509624号、国际申请第WO9509627号、国际申请第WO9509836号、国际申请第WO9514667号、国际申请第WO9514680号、国际申请第 WO9514681号、国际申请第WO9517392号、国际申请第WO9517399号、国际申请第WO9519362号、国际申请第WO9522520号、国际申请第WO9524381号、国际申请第WO9527692号、国际申请第WO9528926号、国际申请第WO9535281号、国际申请第WO9535282号、国际申请第WO9600218号、国际申请第WO9601825号、国际申请第WO9602541号、国际申请第WO9611917号、德国专利第3142982号、德国专利第1116676号、德国专利第2162096号、欧洲专利第0293063号、欧洲专利第0463756号、欧洲专利第0482208号、欧洲专利第0579496号、欧洲专利第0667345美国专利第6331543号、美国专利第20050004222号(包括式I-XIII表示的化合物和在37-39、85-0545和557-577段公开的化合物)、国际申请第WO9307124号、欧洲专利第0163965号、欧洲专利第0393500号、欧洲专利第0510562号、欧洲专利第0553174号、国际申请第WO9501338and国际申请第WO9603399号中公开的试剂;可以使用PDE5抑制剂,例如,RX-RA-69、SCH-51866、KT-734、维司力农、扎普司托(zaprinast)、SKF-96231、ER-21355、BF/GP-385、NM-702和西地那非(ViagraTM))。可以使用PDE4抑制剂,例如,RO-20-1724,MEM1414(R1533/R1500;Pharmacia Roche公司),登布茶,ROLIPRAM、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(Indolidan),奥普力农(Olprinone),阿替唑仑(atizoram),KS-506-G,dipamfylline,BMY-43351,阿替唑仑(atizoram),阿罗茶碱(Arofylline),非明司特,PDB-093,UCB-29646,CDP-840,SKF-107806,吡拉米特(piclamilast),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(Ibudilast),氨力农,匹莫苯丹,西洛他唑,喹齐酮和N-(3,5-二氯代吡啶-4-基)-3-环丙基甲氧基4-二氟甲 氧基苯甲酰胺。可以使用PDE3抑制剂,例如,硫马唑(Sulmazole),ampizone,西洛酰胺(Cilostamide),卡巴折伦,匹罗昔酮,伊马唑旦(Imazodan),CI-930,氰胍佐旦(Siguazodan),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。可以使用PDE3/4抑制剂,例如,苯芬群,曲喹辛,ORG-30029,扎达维林(Zardaverine),L-686398,SDZ-ISQ-844,ORG-20241,EMD-54622,和托拉芬群。其它磷酸二酯酶(PDE)抑制剂包括,西洛司特,己酮可可碱,罗氟司特,他达拉非 茶碱和伐地那非敏喘宁(PDE5特异性)。
抗子宫收缩试剂
这里所述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种抗分娩试剂一起用于结合治疗(例如,用于减少或者抑制子宫收缩),所述抗分娩试剂包括但不局限于β-肾上腺素能试剂、硫酸镁、前列腺素抑制剂和钙离子通道阻断剂。
抗赘生物试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种抗赘生物试剂一起用于结合治疗中,所述抗赘生物试剂包括但不局限于,烷基化剂、表鬼臼毒素、亚硝腮类药物、代谢拮抗剂、长春花生物碱、蒽环(anthracycline)抗生素、氮芥类试剂、等等。具体的抗赘生物试剂可以包括枸橼酸他莫昔芬(tamoxifen)、红豆杉醇、依托泊甙和5-氟代尿嘧啶。
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与一种抗病毒抗体或者单克隆抗体治疗剂一起被用于结合治疗(例如,作为一种化学治疗组合物)。
治疗充血性心力衰竭的试剂
这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)可以与孤菲肽受体ORL1部分激动剂一起用于结合治疗(例如,在防止/治疗充血性心力衰竭的方法中或者这里描述的其他方法中),所述孤菲肽受体ORL1部分激动剂参见Dooley等人的描述(The Journal of Pharmacology and Experimental Therapeutics(药理学与实验医疗学报),283(2):735-741,1997)。这种激动剂是一种六胜肽(hexapeptide),其氨基酸序列为Ac-RYY(RK)(WI)(RK)-NH2(“Dooley多肽”),其中,括号中表示的是容许变异的氨基酸残基。因此,Dooley多肽可以包括,但不局限于KYYRWR、RYYRWR、KWRYYR、RYYRWK、RYYRWK(全D氨基酸)、RYYRIK、RYYRIR、RYYKIK、RYYKIR、RYYKWR、RYYKWK、RYYRWR、RYYRWK、RYYRIK、RYYKWR、RYYKWK、RYYRWK和KYYRWK,其中,除非另有规定,所有的氨基酸残基都以L-形式存在。这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)还可以与国际申请WOO1/98324中描述的Dooley多肽的多肽结合修饰物一起用于结合治疗中。
剂量
在药物组合物中,活性成分的剂量水平也可以使变化的,从而是化合物在主体中,尤其是在发炎位点或者疾病区域附近达到一种瞬时或者持续浓度,并到产生需要的反应。本领域技术人员已知,开始时,对患者给药比实现理想效果所需要的更少的化合物剂量,然后逐渐增加所述剂量直到达到理想的效果。本领域技 术人员应当理解,对于具体主体使用的具体剂量取决于很多因素,包括,体重、总体健康程度、饮食、病史、给药的途径和时间、与一种或一种以上其他药物结合使用,和疾病的严重程度。组合物的有效剂量通常在大约1微克和大约10毫克每千克体重,优选在大约10微克到5毫克化合物每千克体重。使用本领域的常规方法可以进行计量调整,同时要考虑使用的具体组合物和临床应用。上述方法中使用的鸟苷酸环化酶受体激动剂可以被口服给药、全身性给药或者局部给药。剂量形式包括吸入制剂、注射制剂、溶液、悬浮液、乳剂、片剂、胶囊剂、局部油膏剂和洗液、透皮组合物,其他已知的肽制剂和聚乙二醇化肽类似物。激动剂可以作为单一活性试剂给药或者与其他药物结合给药,所述其他药物例如环鸟苷单磷酸(cGMP)-依赖性磷酸二酯酶抑制剂和抗炎症性药物。在任何情况下,参考存在的现有技术,其他药物应该以治疗有效剂量被给药。药物可以在单一组合物中给药,或者顺序给药。本发明方法中使用的GCR激动剂的剂量水平通常在每日大约0.001毫克到大约10,000毫克10,000/75毫克/千克范围内,优选在每日大约0.005毫克到大约1,000毫克范围内。以毫克/千克日剂量为单位,或者以单一剂量给药或者以分开的剂量给药,给药剂量通常在大约0.001/75毫克/千克到大约10,000/75毫克/千克范围内,优选从大约0.005/75毫克/千克到大约1,000/75毫克/千克范围内。
每种抑制剂的总日剂量可以在单一剂量中对患者给药,或者在多个分剂量中对患者给药。通常分剂量每日可以给药2-6次,优选每日给药2-4次,更有选每日给药2-3次。剂量可以以立即释放形式或者持续释放形式给药,所述剂量形式能够有效获得对医学状况理想的控制作用。
预防、治疗、减轻或者改善医学病况或者紊乱的给药方案,或者与本发明结合物和组合物一起用于预防或者治疗一种医学状况的给药方案应该参照多种因素进行选择。这些因素包括,但不局限于,主体的类型、年龄、重量、性别、日常饮食和医学情况、疾病的严重程度、给药途径、药理学方面需要考虑的事情,例如,使用的具体抑制剂的活性、功效、药物动力学和毒性曲线,是否使用了药物传递系统和治疗剂是否与其他活性成分一起给药。因此,实际使用的给药方案是有很大变化的,从而超出这里描述的优选的给药方案的范围。
实施例
实施例1:鸟苷酸环化酶-C拮抗剂(GCRA肽)的合成和纯化
使用标准的固相肽合成方法合成鸟苷酸环化酶-C拮抗剂(GCRA肽)。根据生产的多肽的规模选择Boc/Bzl或者芴甲氧羰酰(Fmoc)/tBu保护基团策略。在产量较小的情况下,使用芴甲氧羰酰(Fmoc)/tBu方案更可能得到理想的产品,但是对于产量较大的情况(1克或者更多),Boc/Bzl更好。
在各种情况下,对于具有C末端亮氨酸、芴甲氧羰酰(Fmoc)-亮氨酸-Wang(D-1115)或者Boc-亮氨酸-Pam树脂(D-1230)或者Boc-亮氨酸-Merrifield(D-1030)的产物,使用预先装载的Wang(芴甲氧羰酰(Fmoc))或者Merrifield(Boc)或者Pam(Boc)树脂开始制备鸟苷酸环化酶-C拮抗剂(GCRA肽)。因此,对于包括C末端d-亮氨酸的肽,使用的树脂是芴甲氧羰酰(Fmoc)-d-亮氨酸-Wang树脂(D-2535)和Boc-d-亮氨酸-Merrifield、Boc-d-亮氨酸-Pam-树脂(分别是Bachem产物D-1230和D-1590)(SP-332和有关类似物)。对于作为C末端酰胺的 肽,使用具有Ramage连接体(Bachem产物D-2200)(Fmoc)或者mBHA(Boc)(Bachem产物D-1210)的树脂,并在第一合成步骤装载C末端残基。
Fmoc-tBu概述
每个合成循环包括去保护作用,所述去保护作用有在DMF中20%的哌啶完成。交替使用二甲基甲酰胺和IpOH完成树脂洗涤,从而分别使树脂膨胀和缩小。多肽合成作用从C末端到N末端延长链。用过量4倍的HBTU/DIEA活化氨基酸45分钟。在自动化化学过程中,每种氨基酸两两耦合从而实现最优的耦合效果。为了确保二硫键的正确位置,在位置15和位置7引入半胱氨酸残基,作为Cys(Acm)。将Cys(Trt)放置于Cys4和Cys12。这种保护基团策略产生正确的拓扑学异构体,作为显性产物(75:25)。(对于肠毒素类似物,使用一种第三二硫键保护基团(Mob))。
对于包含C末端Aeea(氨基乙基氧基乙基氧基乙酰基)基团的肽,通过使用Fmoc-保护的Aeea衍生物,利用与上述相同的活化作用化学将肽与Ramage酰胺连接体耦合在一起。在这种情况下,半胱氨酸计数保持一致并且保护基团的位置也保持一致。对于包含N末端Aeea延长链的多肽,半胱氨酸参见的编号增加三位,Cys4变成Cys7,Cys12变成Cys15;Cys7变成Cys10并且Cys15变成Cys18。后面的一对用Acm进行保护,前面的一对用Trt基团保护。对于包含D-氨基酸取代作用的类似物,通过本文中描述的相同的活化作用将正确保护的衍生物整合到合适的位置,可以直接引入所述D-氨基酸取代作用。对于Fmoc策略,使用Fmoc-dAsn(Trt)-OH、Fmoc-dAsn(Xan)-OH、Fmoc-dAsp(tBu)-OH、Fmoc-dGlu(tBu)-OH,对于Boc策略,使用Boc- dAsn(Xan)-OH,Boc-dAsn(Trt)-OH,Boc-dAsp(Chx),Boc-dAsp(Bzl)-OH,Boc-dGlu(Chx)-OH和Boc-dGlu(Bzl)-OH。
在室温条件下,使用树脂TFA:H2O:三异丙基硅烷(8.5:0.75:0.75)毫升/克裂解混合物处理2小时将每种肽从固相支持物中裂解下来。过滤粗品去保护肽,去掉废树脂颗粒并沉淀出冷冻的二乙酯。垂直引入各个二硫键。简单来说,将粗品合成产物溶于含有NH4OH的水中,将pH值增加到9.在产物完全溶解之后,通过使用双氧水滴定,在Trt去保护的半胱氨酸参见之间产生二硫键。通过反相高效液相色谱(RP-HPLC)纯化单环产物。随后用碘溶液处理纯化后的单环产物,同时去掉Acm保护基团并引入第二二硫键。对于肠毒素类似物,在室温条件下,通过用含有10%二甲亚砜和5%的茴香硫醚的三氟乙酸85%处理所述双环产物2小时,从而去掉Mob基团。
使用TEAP在H2O和乙腈(MeCN)中的结合缓冲系统通过反向高效液相色谱纯化每种产物,随后使用在水和乙腈(MeCN)中的三氟乙酸纯化。结合高纯度的馏分并冷冻干燥,使用离子交换或者反向高效液相色谱的方法将最终产物转化为一种醋酸盐,所述离子交换含有装载有醋酸盐的Dow-Ex树脂,所述反向高效液相色谱使用NH4OAc进行碱性洗涤步骤,随后用1%乙酸在水和乙腈(MeCN)中的溶液进行洗涤。
使用在以Fmoc形式存在的半胱氨酸(Trt)或者以Boc形式存在的半胱氨酸(MeB)进行随机氧化作用可以产生肠毒素类似物。在裂解之后,使用二硫化物互换氧化还原对可以形成二硫键,所述二硫化物互换氧化还原对例如,谷胱甘肽(red/ox)和/或半胱氨酸/胱氨酸。这一过程会产生成倍的产物,其中必须确定二硫化物对,这是由于二硫化物对的位置没有办法可以直接知晓。
Boc-Bzl过程
在Merrifield或者Pam预装载树脂上开始肽合成,或者使用mBHA作为C末端酰胺进行肽生产。每种合成的环由去保护步骤组成,所述去保护步骤使用在二氯甲烷中含量为50%的三氟乙酸进行。反复用二氯甲烷和甲醇洗涤树脂。用碱性洗液中和三氟乙酸盐形式,所述碱性洗液为在二氯甲烷中含量为50%的三氟乙酸。在耦合步骤之前,用二氯甲烷和甲醇洗涤树脂,最后用二甲基甲酰胺洗涤树脂。进行比色试验确保去保护作用的进行。用含有HOBT的二异丙基碳化二亚胺调节每个耦合过程,从而形成活性酯。每种耦合过程在室温条件下延续2小时或者对于困难的耦合过程,反应过夜。使用铀或者磷试剂进行再耦合作用,直到对有利一元胺呈现阴性比色试验。。然后用二甲基甲酰胺、二氯甲烷和甲醇洗涤树脂,并为下一个固相步骤做准备。利用半胱氨酸(Acm)在位置7和位置15进行半胱氨酸保护,利用半胱氨酸(MeB)在Cys4和Cys12进行半胱氨酸保护。
通过使用甲氧基苯作为清除剂(9:1:1)毫升:毫升:克(树脂)用HF在0℃下处理60分钟进行裂解和去保护作用。随后从树脂中提取肽,并沉淀在冰冷却的醚中。对于Fmoc-产生的产物进行的二硫键引入和纯化过程所采用的方案与上述方案完全相同。
实施例2:使用人工胃液(SGF)消化进行的体外蛋白水解作用的稳定性
确定存在人工胃液(SGF)的情况下SP-304的稳定性。在人工胃液(SGF)(朊蛋白胨(8.3克/升;Difco公司)、右旋葡萄糖(3.5克/升;西格马公司)、NaCl(2.05克/升;西格马公司)、KH2PO4(0.6克/升;西格马公司)、CaCl2(0.11克/升)、KCl(0.37克/升;西格马公司)、猪胆汁(终浓度为0.05 克/升;西格马公司)在磷酸盐缓冲盐水中的溶液,溶菌酶(最后1x浓度0.10克/升;西格马公司)在磷酸盐缓冲盐水中的溶液,胃蛋白酶(最终1x浓度为0.0133克/升;西格马公司)在磷酸盐缓冲盐水中的溶液)中培养SP-304(终浓度为8.5毫克/毫升)。在进行试验的当天制备人工胃液(SGF),如果需要的话,使用盐酸或者NaOH将其pH值调节到2.0±0.1。在调整pH值之后,用0.22微米的薄膜过滤器过滤消毒人工胃液(SGF)。在三等分溶液中,37℃条件下在人工胃液(SGF)中分别培养SP-304(终浓度为8.5毫克/毫升)0、15、30、45、60、120分钟。培养之后,将样品快速冻干在干冰中,然后储存在-80℃的冰箱中直到实验,一式两份。
图1A是一种条形图,显示了SP-304与人工胃液(SGF)一起培养指定的时间之后的生物活性。将0时刻的活性看做100%,每个数据点是三个测定值的平均数±标准差。数据显示SP-304对人工胃液(SGF)的消化作用不敏感。另外,这些数据还说明,即使暴露于人工胃液(SGF)的酸性pH值条件下,SP-304的活性不受影响。
在用人工胃液(SGF)进行消化之后,使用高效液相色谱法分析所得样品进一步说明这些结果。在这里,使用高效液相色谱对从消化过程中获得的样品的一个等份进行分析,按照之前开发的方法对SP-304进行分析。稀释经过人工胃液(SGF)消化的样品,产生终浓度为0.17毫克/毫升的SP-304。图1B显示了SP-304样品与人工胃液(SGF)一起培养指定时间之后的高效液相色谱分析。在与人工胃液(SGF)培养过程中,SP-304的主尖峰没有变化,这一结果显示了这种肽能够抵抗人工胃液(SGF)的消化作用。
实施例3:使用人工肠液(SIF)消化进行的体外蛋白水解作用的稳定性
这里还评价了与人工肠液(SIF)一起培养之后SP-304的稳定性。通过美国药典第23版第2236页描述地方法制备人工肠液(SIF)溶液。制备人工肠液(SIF)溶液的配方如下所述。人工肠液(SIF)溶液包括NaCl(2.05克/升;西格玛公司),KH2PO4(0.6克/升;西格玛公司),CaCl2(0.11克/升),KCl(0.37克/升;西格玛公司)和胰酶(Pacreatin)10毫克/毫升。将pH值调节到6,然后对溶液进行过滤消毒。在三等分溶液中,37℃条件下在人工胃液(SGF)中分别培养SP-304(终浓度为8.5毫克/毫升)0、30、60、120、150和300分钟。培养之后,将样品快速冻干在干冰中,然后储存在-80℃的冰箱中直到实验,一式两份。
图2A是一种条形图,显示了在T84细胞中将SP304样品与人工肠液(SIF)一起培养指定时间之后SP-304刺激环鸟苷单磷酸(cGMP)合成的能力。在与人工肠液(SIF)一起培养的第0分钟,所述环鸟苷单磷酸(cGMP)在样品中的刺激活性认为是100%。所述数据是三个数值平均数±标准差。
数据表明,在使用人工肠液(SIF)进行消化之后,SP-304的生物活性减少了30%。这可以归结于肽的降解作用。因此,在使用人工肠液(SIF)消化之后的样品可以进一步使用高效液相色谱进行分析。
使用专用与人工胃液(SGF)消化的方法,通过高效液相色谱进一步分析SP-304肽暴露于人工肠液(SIF)之后的完整性。图2B是一种示意图,分别显示了SP-304样品与加热失活的人工肠液(SIF)一起培养300分钟之后或者与人工肠液(SIF)一起 培养120分钟之后的高效液相色谱分析。Sp-304的主峰应该在16.2分钟洗提出来,但是该峰却转化为在9.4分钟时洗提出来以及几个次要肽峰。因此,确定出使用人工肠液(SIF)消化之后SP-304的代谢产物结构是十分重要的。与人工肠液(SIF)一起培养SP-304肽不同的时间,分离所述消化产物并通过MS分析确定构造。
图3是一种示意图,表示了SP-304可能的降解产物。主要降解产物包括从SP304N-末端剪下的N和D以及从C末端剪下的L。然而,生物活性只减少了30%,这说明一种或者一种以上的降解产物也是具有生物活性的。为了证明这种可能性,合成并评价若干截断肽在T84细胞中促进环鸟苷单磷酸(cGMP)合成的能力。
图4显示了不同的肽在T84细胞环鸟苷单磷酸(cGMP)刺激试验(基本上如文献Shailubhai,et ah,Cancer Research(癌症研究)60,5151-5157(2000))中的分析数据。简单来讲,在24孔板上用250微升包括50mM HepES(pH7.4)的DMEM洗涤汇流的单层T-84细胞两次,并与250微升包括50mM HepES(pH7.4)的DMEM和1mM异丁基甲基黄嘌呤(IBMX)一起在37℃条件下预培养10分钟。然后,将单层T84细胞与250微升DMEM一起培养30分钟,所述DMEM中包括50mM HepES(pH7.4)和浓度为1.0微摩的图4所示的一种肽。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并加入氢氧化钠(0.1N)中和pH值,使用环鸟苷单磷酸(cGMP)酶联免疫吸附测定试剂盒(产品目录号581021;Cayman Chemical公司,密歇根州安阿伯市)测定溶解产物中细胞内环鸟苷单磷酸(cGMP)水平。培养过程一式两份进行,产生两种样品,每种样品一式两份进行酶联免疫吸附测定试验。
这些数据显示,在SP-304羧基末端的亮氨酸(L)残基有助于肽的生物学效应。例如,当亮氨酸(L)从SP-304中删除时,例如从SP-338中删除时,其生物学效应有显著的降低。相似的,羧基末端不含有亮氨酸(L)的肽SP-327、SP-329和SP-331的生物学效应相对于在羧基末端含有亮氨酸(L)的对应肽,例如SP-326、SP-328和SP-330肽来讲,也显示出20-25%的减少。另外,这些结果也说明,在氨基末端的氨基酸残基也可能对台的稳定性和/或效应十分重要。根据这些结果,在肽的羧基末端和氨基末端,可以用D-形式的氨基酸取代相应的L-型氨基酸。图5显示了通过这些台在T84细胞中刺激环鸟苷单磷酸(cGMP)合成能力。
图5显示的结果说明在肽的羧基末端和氨基末端用D-氨基酸取代L-氨基酸不会显著的改变他们的效应。在T84细胞中,肽SP-332、SP-333和SP-335显示了类似的刺激环鸟苷单磷酸(cGMP)合成的能力。在另一个方面,在SP-337的位置6用D-亮氨酸取代L-亮氨酸导致其在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力完全损失。这些结果建议在氨基末端的天冬酰胺、天冬氨酸和谷氨酸残基和羧基末端的亮氨酸残基可以被他们各自的D-型氨基酸取代。但是,在第6位置上的亮氨酸不能被其D-型氨基酸取代。
图7(A-F)显示了在与人工肠液(SIF)一起培养2小时候肽SP-332、SP-333和SP-304的稳定性。这一结果显示在氨基末端具有D-天冬酰胺在羧基末端具有D-亮氨酸的肽SP-333对人工肠液(SIF)的消化作用具有完全的耐受性(图7F),并在与人工肠液(SIF)一起培养2小时之后保持基本上100%的生物活性(图7A)。在羧基末端具有D-亮氨酸的肽SP-332与人工肠液(SIF)一起培养120分钟之后其效应有所减少(图7B)。然后,SP-332 的高效液相色谱分析没有显示所述肽有任何降解作用(图7E),这说明这些肽对人工肠液中存在的蛋白酶的水解作用有耐受力。在另一个方面,SP-304在与人工肠液(SIF)一起培养仅仅一个小时之后,其效应损失大约30%(图7C)。在与人工肠液(SIF)一起培养之后对SP-304进行高效液相色谱分析也证实了它的降解作用(图7D)。这一结果说明,肽SP-304在与人工肠液(SIF)之后经历了蛋白水解作用,而在氨基末端用D-天冬酰胺取代L-天冬酰胺并在羧基末端用D-亮氨酸取代L-亮氨酸,能够保护SP-333不被人工肠液(SIF)消化。因此,肽SP-333表现出更为稳定有效的性质,可以作为药物候补物。
实施例4:环状环鸟苷单磷酸(cGMP)刺激作用试验
通过使用T84人结肠癌细胞株测试鸟苷酸环化酶-C拮抗剂(GCRA肽)结合并活化肠鸟苷酸环化酶(GC-C)受体的能力。人T84结肠癌细胞从美国菌种保藏中心获得。在Ham's F-12培养基和补充有10%胎牛血清、100U青霉素/毫升和100微克/毫升链霉素的Dulbecco's修饰的伊格尔培养基(DMEM)的1:1混合物中培养细胞。每三天用新鲜培养基培养细胞并在汇合了大约80%之后停止补充。按照之前报道的方法(Shailubhai,et al.,Cancer Research(癌症研究)60,5151-5157(2000))测试鸟苷酸环化酶-C拮抗剂(GCRA肽)的生物活性。简单来讲,在24孔板上用250微升包括50mM HepES(pH7.4)的DMEM洗涤汇流的单层T-84细胞两次,并与250微升包括50mM HepES(pH7.4)的DMEM和1mM异丁基甲基黄嘌呤(IBMX)一起在37℃条件下预培养10分钟。然后,将单层T84细胞与鸟苷酸环化酶-C拮抗剂(GCRA肽)(0.1nM到10.mu.M)一起培养30分钟。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并加入氢氧化钠(0.1N)中和pH值,直接使用上清液, 使用酶联免疫吸附测定试剂盒(Cayman Chemical公司,密歇根州安阿伯市)测定环鸟苷单磷酸(cGMP)。
图6显示了在评价与大肠杆菌肠毒素ST肽类似的肽的环鸟苷单磷酸(cGMP)刺激作用试验(如上)中的实验结果。在这些肽中,SP=353和SP-354在T84细胞中刺激环鸟苷单磷酸(cGMP)合成相当有效。特别的,在第6位点具有丝氨酸残基的肽SP-353在所有测试的肽中被发现时最为有效的。在羧基末端具有D-酪氨酸的肽SP-355显示的效应远远小于其他的肽。
实施例5:聚乙二醇化肽
使肽对消化蛋白酶更具抵抗力的另一种策略是在氨基末端或者羧基末端进行聚乙二醇化。用氨基乙基氧基-乙氧基-乙酸(Aeea)基团在肽SP-333的羧基末端进行聚乙二醇化(SP-347)、用氨基乙基氧基-乙氧基-乙酸(Aeea)基团在肽SP-333的氨基末端进行聚乙二醇化(SP-350)或者用氨基乙基氧基-乙氧基-乙酸(Aeea)基团在肽SP-333的羧基和氨基末端进行聚乙二醇化(SP-343)。按照如上所述的方法对T84细胞中的环式鸟漂呤磷酸合成方法进行调节。
肽SP-347和SP-350在T84细胞中刺激环鸟苷单磷酸(cGMP)合成的能力与SP-333的能力相类似。然而,与测试的其他肽相比,肽SP-343的能力相对较少。SP-343较差的活性可能是归因于有大氨基乙基氧基-乙氧基-乙酸(Aeea)基团在两个波段产生的重要的位阻作用。
实施例6:鸟苷酸环化酶激动剂与磷酸二酯酶抑制剂的结合
环状核苷酸(即,环化腺苷酸和环鸟苷单磷酸(cGMP))的细胞内浓度调节作用和通过第二信使进行的信号传递已经通常被认为取决于他们的产生和细胞内破坏作用的比率。因此,在组织和器官中的环鸟苷单磷酸(cGMP)水平还可以通过环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)的表达水平来调节,所述环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)通常在癌症和炎症性疾病中过表达。因此,由鸟苷酸环化酶(GC-C)激动剂和环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)抑制剂组成的结合物可以对靶组织和器官中的环鸟苷单磷酸(cGMP)水平实现协同效应。
舒林砜(SS)和敏喘宁(ZAP)是两种已知的环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)抑制剂,并且已经显示能够通过环鸟苷单磷酸(cGMP)依赖型机制诱导癌细胞的细胞凋亡。将舒林砜(SS)和敏喘宁(ZAP)与SP-304和SP-333相结合进行评价,观察这些磷酸二酯酶(PDE)抑制剂在环鸟苷单磷酸(cGMP)细胞内蓄积作用方面是否具有协同效应(图9-12)。如数据显示,舒林砜在浓度为100微摩时不会加强环鸟苷单磷酸(cGMP)的细胞内蓄积作用。然而,与单独使用SP304相比,将舒林砜与SP304相结合,会刺激环鸟苷单磷酸(cGMP)的产量成倍增加。当SP304的使用浓度为0.1微摩时,这种关于环鸟苷单磷酸(cGMP)水平的协同效应更加明显(图10)。当将SP304或者SP333与敏喘宁结合使用时,可以观察到相似情况(图10、图11和图12)。这一结果说明细胞内环鸟苷单磷酸(cGMP)水平是稳定的,由于舒林砜抑制负责消耗细胞内环鸟苷单磷酸(cGMP)的环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)。因此,使用鸟苷酸环化 酶(GC-C)激动剂与环鸟苷单磷酸(cGMP)-特异性磷酸二酯酶(PDE)(cGMP-PDE)抑制剂的结合物的方法是有吸引力的。
对于图9中显示的结果,使用基本上如文献Shailubhai et al.,Cancer Research(癌症研究)60,5151-5157(2000)中描述的方式评价在T84细胞中进行的环式鸟漂呤磷酸合成。简单来讲,在24孔板上用250微升包括50mM HepES(pH7.4)的DMEM洗涤汇流的单层T-84细胞两次,并与250微升包括50mM HepES(pH7.4)的DMEM和1mM异丁基甲基黄嘌呤(IBMX)一起在37℃条件下预培养10分钟。然后,将单层T84细胞与250微升DMEM一起培养30分钟,所述DMEM中包括50mM HepES(pH7.4)和SP-304或者磷酸二酯酶(PDE)抑制剂的一种或两种,实验组如下所述:1)对照;2)SP-304(0.1微摩);3)舒林砜(100微摩);4)敏喘宁(100微摩);5)SP-304(0.1微摩)+舒林砜(100微摩);和6)SP-304(0.1微摩)+敏喘宁(100微摩)。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并加入氢氧化钠(0.1N)中和pH值,使用环鸟苷单磷酸(cGMP)酶联免疫吸附测定试剂盒(产品目录号581021;Cayman Chemical公司,密歇根州安阿伯市)测定溶解产物中细胞内环鸟苷单磷酸(cGMP)水平。培养过程一式两份进行,产生两种样品,每种样品一式两份进行酶联免疫吸附测定试验。
对于图10中显示的结果,使用的方法与图9中使用的基本上相同,区别仅在单层T84细胞与500微升DMEM一起培养,所述DMEM包含50mM的HepES(pH7.4)和SP-304(0.1或者1.0微摩)或者增加浓度的磷酸二酯酶(PDE)抑制剂(0到750微摩),单独使用或者与SP-304相结合。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并 加入氢氧化钠(0.1N)中和pH值,使用环鸟苷单磷酸(cGMP)酶联免疫吸附测定试剂盒(产品目录号581021;Cayman Chemical公司,密歇根州安阿伯市)测定溶解产物中细胞内环鸟苷单磷酸(cGMP)水平。培养过程一式两份进行,产生两种样品,每种样品一式两份进行酶联免疫吸附测定试验。
对于图11中显示的结果,使用的方法与图10中使用的基本上相同,区别仅在单层T84细胞与500微升DMEM一起培养,所述DMEM包含50mM的HepES(pH7.4)和SP-333(0.1或者1.0微摩)或者增加浓度的敏喘宁(0到500微摩),单独使用或者与SP-333相结合。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并加入氢氧化钠(0.1N)中和pH值,使用环鸟苷单磷酸(cGMP)酶联免疫吸附测定试剂盒(产品目录号581021;Cayman Chemical公司,密歇根州安阿伯市)测定溶解产物中细胞内环鸟苷单磷酸(cGMP)水平。每种样品一式三份进行酶联免疫吸附测定试验。
对于图12中显示的结果,使用的方法与图10中使用的基本上相同,区别仅在单层T84细胞与500微升DMEM一起培养,所述DMEM包含50mM的HepES(pH7.4)和SP-333(0.1或者1.0微摩)或者增加浓度的舒林砜(0到500微摩),单独使用或者与SP-333相结合。在培养30分钟之后,吸出培养基并通过加入3%的高氯酸终止反应。随后离心并加入氢氧化钠(0.1N)中和pH值,使用环鸟苷单磷酸(cGMP)酶联免疫吸附测定试剂盒(产品目录号581021;Cayman Chemical公司,密歇根州安阿伯市)测定溶解产物中细胞内环鸟苷单磷酸(cGMP)水平。每种样品一式三份进行酶联免疫吸附测定试验。
实施例7:口服范围-在猕猴体内进行的发现性毒性研究
进行客观试验,对猕猴进行单一口服喂养给药确定本发明所属GRCA肽的毒性,并允许评价最少7天的观察/冲洗期内任意变化的可逆性。本发明的每种GRCA肽会以两种不同的剂量水平给药。
试验设计
在最少7天的观察期内在分离的三相中给药试验物(例如本发明GRCA肽)和参照/媒介物。每一相由单一向雌性猕猴口服喂养给药法组成,如下表所指出的:
相1:
八只成年雌性猕猴从ITR备用猴聚居地转移出来并分配给4个如下剂量组:
在相1剂量完成之后,观察所有的猴子33天。在观察期结束之后,所有的猴子被送回ITR备用猴聚居地。
相2:如之前相1中使用的相同的8只成年雌性猕猴从ITR备用猴聚居地转移出来并分配给4个如下剂量组:
在相2剂量完成之后,观察所有的猴子7天。
给药途径
选择口服给药途径,这是由于口服给药时人治疗的优选途径。
试验物和对照/媒介物的制备
在给药当天,在冷却的蒸馏水(维持冰水浴)中制备新鲜的试验物和对照/媒介物。向适当的蒸馏水中加入足够量的试验物品粉末,从而达到所需的浓度。剂量制剂通过简单的变型被混合。
剂量制剂中试验物品浓度和稳定性的分析
为了合理确定试验物品在制剂中的浓度和稳定性,从每个浓度的中间值选取代表性样品,包括在向每组给药的第一天给药对照/媒介物,如下所述。在制备第一天立即收集样品,并在给药完成后当天再次收集样品,在20毫升有螺帽的试管中冷冻储存(在大约-80℃)。因此,在给药完成后,保存有剂量制剂的试管应立刻送回配药部。
组1:从第一天中得到1.5毫升,一式两份(在给药前和给药后)。
组2:从第一天中得到1.5毫升,一式两份(在给药前和给药后)。
组3:从第一天中得到1.5毫升,一式两份(在给药前和给药后)。
组4:从第一天中得到1.5毫升,一式两份(在给药前和给药后)。
在整个制样过程中,在冰水浴中维持制剂冷却状态。在制样前,用搅拌棒连续搅拌制剂至少15分钟。
在ITR中保持样品冷冻状态(大约-80℃)直到主管人员要求运往指定的实验室用于分析。一旦分析人员和研究部门经理认为不再需要这些样品时,可以将样品丢弃。这些样品的处置应记载在原始数据中。
如果进行了分析,主要研究人员应该制备一种剂量制剂报告(制剂分析)并提供给ITR总结在最终报告中。
试验系统
实际年龄和体重范围在最终报告中记录。
测试化合物和参照/媒介物的给药
在最少7天的观察期/冲洗期内,在分离的三相中,使用连接有注射器的饲料管通过口服喂养给药的方法给药测试化合物和参照/媒介物。每个给药过程由单一口服喂养给药方法组成。在给药剂量组合物之后用反渗透水立即刷洗饲料管从而确保整个剂量体积被传递给动物。对于所有动物,给药的剂量体积是10毫升/千克,包括参照物。在每相中第一天对每个猴子给药的实际体积通过每个相的第一天体重计算。
在剂量给药期间,通过将剂量制剂放置在冰水浴中维持剂量制剂的冷却。
在开始给药之前,剂量制剂必须放置到搅拌平板上至少15分钟,并在整个给药过程中保持在搅拌平板上。剂量制剂必须在制备完成后2小时内使用。
临床观察
按照如下所示记录笼边的临床症状(生病,行为变化等等),除了详细临床检查期之外,在详细临床检查期,上午的笼边的临床症状被详细的临床检查(DCE)所取代。在常规笼边的临床症状和详细检查期间,应该特别注意大便的状态,例如产生的大便量、大便的形状等等。
按照如下所述方式进行笼测临床征象:
在预处理期间和7-日(最少)观察期:每日三次,每次最少间隔3小时。
在相1给药期间:预给药,给药后2、4、6、8和24小时。
在相2给药期间:预给药,给药后前4个小时和给药后第6、8、24小时。
在相3给药期间:预给药,给药后前4个小时和给药后第6、8、24小时。
在动物传递时要对每一只猴子进行一次详细的临床检查,在此后每一周都要进行一次。
判断动物的健康状况是否允许其他评价,兽医或者技师在兽医的监督下对通过判断的动物进行检查。只有经过研究部门经理的同意,才能进行兽医推荐的治疗。在可能的情况下,在给药治疗药物之前应该咨询主管人员。
在运输的当天开始到研究结束为止,每天都应该记录一次所有动物的体重。
在运输的当天开始到研究结束为止,每天都应该记录一次所有动物的饮食量。在开始食品喂养之前应该首先打扫干净笼子,从而确保没有食物保留到笼子中。在12点之前喂给猴子7个点心,在12点之后再给猴子喂7个点心。记录每天喂给猴子的点心的总量。
第二日早上,对猴子进行视觉检查,观察多少点心被剩在笼子中。记录所有剩余在食物槽或者托盘中的点心总数。用喂给猴子的点心总数减去剩余的点心总数可以计算猴子吃掉的点心数。
实施例8:小肠分泌的乳鼠模型(SUMI试验)
使用小肠分泌乳鼠模型检测这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)增加小肠分泌作用的能力。在这种模型中,对7-9天大的乳鼠给药鸟苷酸环化酶-C拮抗剂(GCRA肽)。随后杀死小鼠,解剖胃到盲肠的胃肠道(“肠道(guts)”)。承重剩余的部分(“尸体”)以及肠道,计算肠道与尸体重量比。如果比例在0.09以上,就可以得到检测化合物增加小肠分泌的结论。这种实验的参照物包括野生型SP-304,ST多肽和替加色罗
苯基苯醌诱导的扭体模型
苯基苯醌诱导的扭体模型可用于评价这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)的疼痛控制活性。Siegmund等人描述了这种模型(1957Proc.Soc.Exp.Bio.Med.95:729-731)。简单的说,在口服给药试验化合物一小时之后,例如在给药鸟苷酸环化酶-C拮抗剂(GCRA肽)、吗啡或者媒介物一小时之后,向小鼠腹膜内注射0.02%的苯基苯醌(PBQ)溶液(12.5毫升/千克)。在苯基苯醌(PBQ)注射后第5到第10分钟,记录伸展 和扭体次数,并在第35分钟到第40分钟之间计数,在第60到65分钟计数,从而提供一种动力评价。结果表示为伸展和扭体的数目(平均数±标准差)和有媒介物治疗组平均值计算出的疼痛阈值变化百分比。治疗组和参照组之间的任意统计学显著性差异可以通过Dunnett实验确定,使用SigmaStat软件在单向方差分析(P<0.05)之后使用剩余方差确定。
实施例9:鸟苷酸环化酶-C拮抗剂(GCRA肽)的药代动力学性质确定
从暴露小鼠(口服给药或者静脉给药鸟苷酸环化酶-C拮抗剂(GCRA肽)的小鼠)和参照小鼠的全血中提取血清样品,然后不需要进一步处理直接注射到(10毫升)一种串联固相提取(SPE)柱(沃特斯Oasis公司,HLB25微米柱,2.0x15mm直接接合)用5%的甲酸、95%的dH2O溶液洗涤串联固相提取(SPE)柱(2.1毫升/分,1.0分钟),然后使用阀开关装载在一种0分析柱上,所述阀开关将串联固相提取(SPE)柱以一种反流向方向放置在分析柱上(沃特斯Xterra MS C85微米IS柱,2.1x20mm)。试用反向梯度从分析柱上洗提样品(流动相A:在dH2O中的10mM氢氧化铵,流动相B:在80%乙腈和20%甲酸中的10mM氢氧化铵;先用20%B洗脱3分钟,然后在4分钟内将浓度均匀变化到95%B,维持25分钟,所有情况下,流速为0.4毫升/分钟)。在9.1分钟,梯度回到20%B的初始条件,维持1分钟。从分析柱从将多肽洗提出来,并用三-四磁极质谱检测(MRM,764(+2电荷状态)>182(+1电荷状态)Da;恒压=30V;collision=20eV;parent resolution=2Da at base peak;daughter resolution=2Da at base peak)。使用相同的方法,将制备所得的已知量的化学合成肽注射到小鼠血浆中,获得标准曲线,将仪器响应转变为浓度单位与此标准曲线相比较。
相似的,使用LCMS方法学确定老鼠体内的药代动力学性质。使用沃特斯Oasis MAX96孔固相提取(SPE)板提取包含鸟苷酸环化酶-C拮抗剂(GCRA肽)的鼠血浆样品。在制备的SPE板的孔中,将200微升体积的鼠血浆与200微升13Cg、15N-标记的多肽混合。使用15毫米汞柱真空度将样品从静止相吸出。用200微升的在水中的2%氢氧化铵洗涤所有样品,随后用在水中浓度为20%的甲酸洗涤所有样品。用连续的100微升的5/20/75蚁酸/水/甲醇和100微升5/15/80蚁酸/水/甲醇洗提样品。在氮环境下干燥样品并再悬浮在100微升在水中浓度为20%的甲醇中。通过与沃特斯1525二元泵连接在一起并装有沃特斯2777自动取样器的沃特斯quattro的微型质谱仪分析样品。将40微升体积的每种样品注射在Thermo Hypersil GOLD Cl(热色谱柱金氯)8柱(2.1x50毫米,5um)上。通过一种梯度在三分钟内用乙腈和包括0.05%三氟代醋酸的水洗提多肽。在多重反应监控(MRM)模式下运行沃特斯quattro的微型质谱仪,使用例如764>182或者682>136的质量转移。使用这种工艺,多肽以10毫克/公斤的剂量对小鼠进行口服给药或者静脉注射给药。包括曲线下面积的药代动力学性质和生物相容性被确定。
实施例10:对利尿和尿钠排泄有作用的利尿有关实验
使用国际申请WO06/001931中描述的相似的工艺(实施例6(第42页)和实施例8(第45页))可以确定这里描述的鸟苷酸环化酶-C拮抗剂(GCRA肽)对利尿和尿钠排泄的作用。简要的,将这里描述的多肽/激动剂(180-pmol)注射入5只麻醉的老鼠或者灵长类动物体内60分钟。据估计,老鼠血浆体积为10毫升,输液速率大约是3pmol/毫升/分钟。在输液前大约40分钟、输液期间和树叶之后大约50分钟的时间内监控老鼠的血压、尿产生、和纳排泄,从而测定鸟苷酸环化酶-C拮抗剂(GCRA肽) 对利尿和尿钠排泄的作用。为了比较,向参照组的老鼠输入常用的盐水。可以评价尿和钠排泄。还可以确定剂量反应。在60分钟的时间内将这里描述的多肽/鸟苷酸环化酶(GC-C)激动剂输入老鼠或者灵长类动物的经脉中。每隔30分钟收集尿,直到终止输入多肽/鸟苷酸环化酶(GC-C)激动剂180分钟之后,测定每个收集间隔中的尿量、钠排泄、和钾排泄。持续监测血液。对于每个剂量,可以确定对于尿量、钠和钾排泄的剂量反应关系。在静脉输液之前和之后还可以测定多肽/鸟苷酸环化酶(GC-C)激动剂的血浆浓度。
小鼠或者灵长类动物利尿实验:一旦达到适当的麻醉水平,将一种聚氨基甲酸乙脂导管插入到尿道中并在尿道/导管结合处使用1-2滴兽医用粘合胶进行固定。然后,通过静脉或者腹膜内途径对动物给药媒介物或者检测物。允许动物恢复知觉,并定期记录每只老鼠在1-5小时的时间内分泌的尿体积。
参考文献
1.Currie,et al,Proc.Nat’I Acad.ScL usA89:941-951(1992).
2.Hamra,et al,Proc.Nat’I Acad.ScL usA90:10464-10468(1993).
3.Forte,L.,Reg.Pept.81:25-39(1999).
4.Schulz,et al,Cell65:941-948(1990).
5.Guba,et al,Gastroenterology(胃肠病学)777:1558-1568(1996).
6.Joo,et al,Am.J.Physiol.274:G633-G644(1998).
7.Evan,et al,Nature(London)411:342-348(2001).
8.Eastwood,G.,J.Clin.Gastroenterol(临床胃肠病学).14:^,29-33(1992).
9.Lipkin,M.Arch.Fr.MaI Appl Dig.61:691-693(1972).
10.Wong,et al,Gut50:212-217(2002).
11.Potten,et al,Stem Cells75:82-93.
12.Basoglu,et al,in:Proceedings of the Second FepS Congress,June 29-July 4,1999,Prague,Czech REPublic,If2.cuni.cz/physiolres/feps/basoglu
13.Sindic,et al.,J.Biol.Chem.March11,2002,manuscript Ml10627200(in press).
14.Askling,J.,Dickman,P.W.,Karlen,P.,Brostrom,O.,Lapidus,A.,Lofberg,R.,and Ekbom,A.Colorectal cancer rates among first-degree relatives of patients with inflammatory bowel disease(患有炎症性肠病的第一相关程度病人之中患有大肠癌的比率):a population-based cohort study(以人口为基础的队列研究).Lancet,357:262-266,
15.Provenzale,D.and Onken,J.Surveillance issues in inflammatory bowel disease:Ulcerative colitis(炎症性肠病:溃疡性结肠炎的检测问题).J Clin Gastroenterol(胃肠道疾病临床杂志),32:99-105,2001.
16.Ettorre,G.M,Pescatori,M.,Panis,Y.,Nemeth,J.,Crescenzi,A.,and Valleur,P.Mucosal changes in ileal pouches after restorative proctocolectomy for ulcerative and Crohn's colitis(对溃疡和克罗恩结肠炎进行恢复性直肠切除术后回肠袋中的黏膜改变).Dis Colon Rectum(结肠直肠研究),43:1743-1748,2000.
17.Shinozaki M,Watababe T,KubotaY,Sawada T,Nagawa H,Muto T.High proliferative activity is associated with dysplasia in ulcerative colitis(与溃疡性结肠炎发育不良有关的高增殖活性).Dis Colon Rectum(结肠直肠研究),43:S34-S39,2000.
18.Deschner,E.E.,Winawer,S.J.,Katz,S.,Katzka,L,and Kahn,E.Proliferative defects in ulcerative colitis patients(溃疡性结肠炎患者增生性缺陷).Cancer Invest(癌症观察),1:41-47,1983.
19.Wong,W.M.,and Wright,N.A.Cell proliferation and gastrointestinal mucosa(细胞增殖和肠胃道粘膜).J Clin Pathol(临床病理学杂质),52:321-333.
20.Potten,C.S.,Wilson,J.W.,and Booth,C.Regulation and significance of apoptosis in the stem cells(干细胞调节和细胞凋亡重要性).Stem Cells(干细胞),15:82-93.
21.Bhakdi,et al,Infect.Immun.(感染免疫学)57:3512-3519(1989).
22.Hughes,et ah,J.Biol.Chem(生物化学杂志).272:30567-30576(1997).
23.Cermak,et al,Pflugers Arch.43:511-511(1996).
24.Wu,et al,J.Biol.Chem(生物化学杂志).272:14860-14866(1997).
25.Shailubhai et al,Cancer Research(癌症研究)60,5151-5157(2000)
26.Shailubhai et al.,Curr.Opin.Drug Disc.Dev.5(2):261-268,2002.
27.Collins,SM.J Clin Gastroenterol(胃肠道疾病临床杂志).41Suppl 1:S30-32(2007).
28.Ramamoorthy S et al.,J Biol Chem(生物化学杂志).282(16):11639-11647(2007).
Claims (14)
1.一种肽,该肽由氨基酸序列:SEQ ID NO:8组成,其中所述肽是一种[4,12;7,15]双环肽。
2.一种单位剂量的药物组合物,包括一种鸟苷酸环化酶受体激动剂肽,这种鸟苷酸环化酶受体激动剂肽由氨基酸序列:SEQID NO:8组成,并以治疗有效量存在于一种药物载体、赋形剂或稀释剂中,其中所述肽是一种[4,12;7,15]双环肽。
3.根据权利要求1所述的肽,其中,所述肽能够增加细胞中环鸟苷单磷酸(cGMP)的产生。
4.根据权利要求2所述的药物组合物,其中所述肽能够增加细胞中环鸟苷单磷酸(cGMP)的产生。
5.根据权利要求2或者4所述的药物组合物,其中单位剂量形式选自由片剂、胶囊剂、溶液以及吸入剂所组成的组中。
6.一种鸟苷酸环化酶受体激动剂在制备用于在需要的病人中预防或者治疗一种病况的药物中的应用,其中,所述病况选自由溃疡性结肠炎、过敏性肠综合症(IBS)、非溃疡性消化不良、慢性肠假性梗阻、机能性消化不良、结肠假梗阻、十二指肠反流、与麻醉止痛药使用有关的便秘、胃食管反流疾病(GERD)、手术后便秘、胃轻瘫、与神经性疾病有关的便秘、胃灼热、缺少肠胃活动性、充血性心力衰竭、高血压、良性前列腺肥大(BPH)、结肠癌、肺癌、膀胱癌、肝癌、唾液腺癌或者皮肤癌、支气管炎、组织发炎、器官发炎、呼吸道发炎、哮喘、慢性阻塞性肺病(COPD)所组成的组中,所述鸟苷酸环化酶受体激动剂由氨基酸序列:SEQ ID NO:8组成,其中所述肽是一种[4,12;7,15]双环肽。
7.根据权利要求6所述的应用,进一步包括有效剂量的环鸟苷单磷酸(cGMP)-依赖性磷酸二酯酶抑制剂在制备有效剂量的所述药物中的应用。
8.根据权利要求7所述的应用,其中,包括同时或者顺序应用有效剂量的环鸟苷单磷酸(cGMP)-依赖性磷酸二酯酶抑制剂与鸟苷酸环化酶受体激动剂。
9.根据权利要求7所述的应用,其中,所述环鸟苷单磷酸(cGMP)-依赖型磷酸二酯酶抑制剂选自由舒林砜、敏喘宁、莫他匹酮(motapizone)、伐地那非、和西地那非所组成的组中。
10.根据权利要求7所述的应用,进一步包括有效剂量的至少一种消炎剂在制备有效剂量的所述药物制剂的应用。
11.根据权利要求10所述的应用,其中,所述消炎剂是一种类固醇或非类固醇类消炎药(NSAIDS)。
12.一种体外增加细胞中环鸟苷单磷酸(cGMP)产量的方法,包括将所述细胞与一种肽相接触,所述肽由SEQ ID NO:8所示的氨基酸序列所组成,其中所述肽是一种[4,12;7,15]双环肽。
13.根据权利要求12所述的方法,进一步包括将所述细胞与一种环鸟苷单磷酸(cGMP)-依赖型磷酸二酯酶抑制剂相接触。
14.根据权利要求13所述的方法,其中,所述环鸟苷单磷酸(cGMP)-依赖型磷酸二酯酶抑制剂选自由舒林砜、敏喘宁、莫他匹酮、伐地那非、和西地那非所组成的组中。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10493011B2 (en) | 2017-08-03 | 2019-12-03 | ALASTIN Skincare, Inc. | Peptide compositions and methods for ameliorating skin laxity and body contour |
US10688147B2 (en) | 2016-02-04 | 2020-06-23 | ALASTIN Skincare, Inc. | Compositions and methods for invasive and non-invasive procedural skincare |
US11103455B2 (en) | 2018-08-02 | 2021-08-31 | ALASTIN Skincare, Inc. | Liposomal compositions and methods of use |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2944648B1 (en) | 2001-03-29 | 2019-11-13 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists for the treatment of organ inflammation |
ES2668551T3 (es) * | 2005-09-26 | 2018-05-18 | Lifecell Corporation | Composición seca de plaquetas |
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US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
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WO2009149278A1 (en) * | 2008-06-04 | 2009-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2009148623A2 (en) | 2008-06-05 | 2009-12-10 | Stc.Unm | Methods and related compositions for the treatment of cancer |
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CA2732892C (en) | 2008-08-15 | 2020-12-15 | Forest Laboratories Holdings Limited | Stable solid formulation of a gc-c receptor agonist polypeptide suitable for oral administration |
US20120039949A1 (en) * | 2008-09-04 | 2012-02-16 | Ironwood Pharmaceuticals, Inc. | Stable Solid Formulations of GC-C Receptor Agonist Polypeptides Suitable for Oral Administration |
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US8748573B2 (en) | 2009-08-06 | 2014-06-10 | Ironwood Pharmaceuticals, Inc. | Formulations comprising linaclotide |
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AU2011218009B2 (en) * | 2010-02-17 | 2016-11-03 | Ironwood Pharmaceuticals, Inc | Treatments for gastrointestinal disorders |
PL2603232T3 (pl) | 2010-08-11 | 2020-05-18 | Ironwood Pharmaceuticals, Inc. | Stabilne formulacje linaklotydu |
CA2810243C (en) | 2010-09-15 | 2021-04-20 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
CN108676076A (zh) * | 2011-03-01 | 2018-10-19 | 辛纳吉制药公司 | 制备鸟苷酸环化酶c激动剂的方法 |
US20160213739A1 (en) * | 2011-05-11 | 2016-07-28 | Ironwood Pharmaceuticals, Inc | Treatments for disorders using guanylate cyclase c agonists |
CA2835624A1 (en) | 2011-05-11 | 2012-11-15 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
US9303066B2 (en) * | 2011-05-11 | 2016-04-05 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
US20140213534A1 (en) * | 2011-05-23 | 2014-07-31 | Thomas Jefferson University | Intestinal hyperpermeability and prevention of systemic disease |
US9527887B2 (en) | 2011-06-08 | 2016-12-27 | Ironwood Pharmaceutical, Inc. | Treatments for gastrointestinal disorders |
US9617305B2 (en) | 2011-06-08 | 2017-04-11 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
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EP2776055B1 (en) | 2011-08-17 | 2016-12-14 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
US20130123264A1 (en) * | 2011-10-17 | 2013-05-16 | Darren D. Browning | Compositions and methods for treatment of inflammatory bowel disorders and intestinal cancers |
PE20142322A1 (es) | 2012-04-27 | 2015-01-25 | Millennium Pharm Inc | Moleculas de anticuerpo anti-gcc y uso de las mismas para probar la susceptibilidad a la terapia dirigida a gcc |
WO2014131024A2 (en) * | 2013-02-25 | 2014-08-28 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
CN104211777A (zh) * | 2013-05-30 | 2014-12-17 | 深圳翰宇药业股份有限公司 | 一种皮卡那肽的制备方法 |
JP6606491B2 (ja) | 2013-06-05 | 2019-11-13 | シナジー ファーマシューティカルズ インコーポレイテッド | グアニル酸シクラーゼcの超高純度アゴニスト、その作成および使用方法 |
MX2016001714A (es) | 2013-08-09 | 2016-10-03 | Ardelyx Inc | Compuestos y metodos para inhibir el transporte de fosfato. |
US20160367622A1 (en) * | 2013-10-10 | 2016-12-22 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions |
EP3054969B1 (en) * | 2013-10-10 | 2021-03-10 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of opioid induced dysfunctions |
US20160317542A1 (en) | 2013-12-09 | 2016-11-03 | Respira Therapeutics, Inc. | Pde5 inhibitor powder formulations and methods relating thereto |
JP6667526B2 (ja) | 2014-08-13 | 2020-03-18 | シーダーズ−サイナイ メディカル センター | 抗メタン生成組成物及びその使用 |
EP3277274A4 (en) | 2015-04-01 | 2018-12-05 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
US10188645B2 (en) | 2015-08-26 | 2019-01-29 | Ian Cain Smith | Methods and compositions for ameliorating symptoms of termination of opioid pain therapy |
JP2018534317A (ja) * | 2015-11-18 | 2018-11-22 | シナジー ファーマシューティカルズ インコーポレイテッド | 結腸がんの処置および検出のための組成物および方法 |
CN108884130B (zh) * | 2016-01-11 | 2022-09-13 | 博士医疗爱尔兰有限公司 | 用于治疗溃疡性结肠炎的制剂和方法 |
CN106994145B (zh) | 2016-01-26 | 2022-05-03 | 财团法人工业技术研究院 | 用于治疗或减缓自体免疫疾病、其并发症和/或肾炎的医药组合物以及其有效成分之用途 |
CN107349417A (zh) * | 2017-04-01 | 2017-11-17 | 南阳市中心医院 | 一种治疗食管鳞癌的ecm复合物以及其在制备治疗食管鳞癌的药物中的用途 |
WO2020237096A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
BR112021024938A2 (pt) | 2019-06-12 | 2022-01-25 | Novartis Ag | Anticorpos de receptor 1 de peptídeo natriurético e métodos de uso |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1551760A (zh) * | 2001-03-29 | 2004-12-01 | ҩ��Э��˾ | 用于治疗组织炎症和癌变的鸟苷酸环化酶受体拮抗剂 |
WO2006086653A2 (en) * | 2005-02-08 | 2006-08-17 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
WO2007022531A2 (en) * | 2005-08-19 | 2007-02-22 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
Family Cites Families (962)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3108097A (en) | 1963-10-22 | Ehnojs | ||
US2809194A (en) | 1957-10-08 | Thiadiazine type natriuretic agents | ||
US488064A (en) | 1892-12-13 | Magnetic separator | ||
DE1116676B (de) | 1955-03-14 | 1961-11-09 | Thomae Gmbh Dr K | Verfahren zur Herstellung von Pyrimido [5, 4-d] pyrimidinen |
FR1217929A (fr) | 1958-03-03 | 1960-05-06 | Ciba Geigy | Procédé de préparation du 1,1-dioxyde de la 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine et de ses sels |
BE578515A (zh) | 1958-05-07 | |||
DE1302648B (zh) | 1960-09-27 | |||
NL281975A (zh) | 1961-08-12 | |||
GB1051218A (zh) | 1963-03-09 | |||
NL127065C (zh) | 1964-04-22 | |||
NL137318C (zh) | 1964-06-09 | |||
GB1078852A (en) | 1964-09-30 | 1967-08-09 | Ici Ltd | Alkanolamine derivatives |
US3466325A (en) | 1965-04-30 | 1969-09-09 | Haessle Ab | 1-(ortho-alkenyl phenoxy) - 2-hydroxy-3-isopropylaminopropanes and the salts thereof |
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US3636039A (en) | 1970-02-24 | 1972-01-18 | Hoffmann La Roche | Substituted benzylimidazolidinones |
GB1361441A (en) | 1970-05-13 | 1974-07-24 | Sandoz Ltd | Benzonaphthyridine derivatives |
US4059622A (en) | 1970-05-27 | 1977-11-22 | Imperial Chemical Industries Limited | Alkanolamine derivatives |
GB1338235A (en) | 1970-12-15 | 1973-11-21 | May & Baker Ltd | Azapurinones |
DE2117571C3 (de) | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Unsymmetrische 1,4-Dihydropyridin-33-dicarbonsäureester, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel |
BE794964A (fr) | 1972-02-04 | 1973-08-02 | Bristol Myers Co | Nouveaux agents hypotenseurs et procede pour les preparer |
JPS5229318B2 (zh) | 1972-03-30 | 1977-08-01 | ||
DE2305339C3 (de) | 1973-02-03 | 1980-05-08 | Dr. Karl Thomae Gmbh, 7950 Biberach | Imidazo [4,5-b] pyridine, ihre Herstellung und ihre Verwendung als Cardiötonica |
US4062950A (en) | 1973-09-22 | 1977-12-13 | Bayer Aktiengesellschaft | Amino sugar derivatives |
AR205004A1 (es) | 1973-10-30 | 1976-03-31 | Ishikawa M | Procedimiento para preparar derivados de 6,8-dialquil-7-alcoxi-carbonil-4-hidroximetil-1-ftalazona y la 7,8-lactona |
GB1491510A (en) | 1973-12-14 | 1977-11-09 | Hisamitsu Pharmaceutical Co | 1-nitrophenylquinazoline-2,4(1h,3h)-diones |
AT334385B (de) | 1973-12-20 | 1976-01-10 | Chemie Linz Ag | Verfahren zur herstellung von neuen phenoxypropylaminderivaten und deren salzen |
DE2462367A1 (de) | 1974-01-22 | 1976-11-11 | Wuelfing J A Fa | 7-(oxoalkyl)-1,3-dialkylxanthine enthaltende arzneimittelzubereitungen |
DE2413935A1 (de) | 1974-03-20 | 1975-10-16 | Schering Ag | 4-(polyalkoxy-phenyl)-2-pyrrolidone |
DE2521113A1 (de) | 1974-05-15 | 1976-03-18 | Maggioni & C Spa | Cycloaliphatische derivate von 3.3-diphenylpropylamin |
US3914250A (en) | 1974-08-01 | 1975-10-21 | American Home Prod | 1,4-Diazepino{8 6,5,4-jk{9 carbazoles |
US4072746A (en) | 1975-10-14 | 1978-02-07 | Sterling Drug Inc. | 3-Amino-5-(pyridinyl)-2(1H)-pyridinones |
US4046889A (en) | 1976-02-13 | 1977-09-06 | E. R. Squibb & Sons, Inc. | Azetidine-2-carboxylic acid derivatives |
JPS608117B2 (ja) | 1977-02-08 | 1985-02-28 | 財団法人微生物化学研究会 | 新生理活性物質エステラスチンおよびその製造法 |
DE2719912C3 (de) | 1977-05-04 | 1979-12-06 | Bayer Ag, 5090 Leverkusen | Verfahren zur Isolierung von 0- |4,6-Dideoxy-4- [JJl S-O,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2cyclohexen-1-yl] -amino] - a -D-glucopyranosyl} -(I Pfeil nach rechts 4)-0- a D-glucopyranosyl-(l Pfeil nach rechts 4)-D-glucopyranose aus Kulturbrühen |
IE46852B1 (en) | 1977-06-10 | 1983-10-05 | Otsuka Pharma Co Ltd | Novel carbostyril derivatives |
DE2727481A1 (de) | 1977-06-18 | 1979-01-11 | Basf Ag | Dihydropyridazone und dihydropyridazone enthaltende therapeutische mittel |
US4466972A (en) | 1977-06-20 | 1984-08-21 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
NL7807507A (nl) | 1977-07-25 | 1979-01-29 | Hoffmann La Roche | Tricyclische verbindingen. |
NO154918C (no) | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
CA1114379A (en) | 1977-11-03 | 1981-12-15 | Pfizer Corporation | Piperidino-phthalazines |
JPS5953920B2 (ja) | 1977-12-28 | 1984-12-27 | 東洋醸造株式会社 | 新規なアミノ糖化合物およびその製法 |
CA1121290A (en) | 1978-02-14 | 1982-04-06 | Yasuji Suhara | Amino sugar derivatives |
JPS54148788A (en) | 1978-05-15 | 1979-11-21 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative and its preparation |
JPS5527105A (en) | 1978-08-11 | 1980-02-27 | Dai Ichi Seiyaku Co Ltd | Imidazothienopyrimidinones compound |
US4316906A (en) | 1978-08-11 | 1982-02-23 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of substituted prolines |
DE2837161A1 (de) | 1978-08-25 | 1980-03-06 | Thomae Gmbh Dr K | Neue benzimidazole und deren verwendung |
JPS5535019A (en) | 1978-09-01 | 1980-03-11 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
DE2845220A1 (de) | 1978-10-17 | 1980-04-30 | Yoshitomi Pharmaceutical | Pyridazinon-derivate, ihre salze mit saeuren, verfahren zu ihrer herstellung und ihre verwendung bei der behandlung von thrombosen und hypertonie |
US4168267A (en) | 1978-10-23 | 1979-09-18 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl prolines |
DE2847693A1 (de) | 1978-11-03 | 1980-05-22 | Hoechst Ag | Verfahren zur herstellung von pyrimido-(6,1-a)-isochinolin-2-onen |
IL58849A (en) | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
NZ193935A (en) | 1979-06-18 | 1985-05-31 | Richardson Merrell Inc | 4-aroyl-imidazol-2-one derivatives;pharmaceutical compositions |
DE2928485A1 (de) | 1979-07-14 | 1981-01-29 | Bayer Ag | Verwendung von harnstoffderivaten als arzneimittel bei der behandlung von fettstoffwechselstoerungen |
GB2063249A (en) | 1979-10-09 | 1981-06-03 | Mitsubishi Yuka Pharma | 4-Phenylphthalazine derivatives |
JPS5671073A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | Imidazole derivative |
JPS5671074A (en) | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
NZ195564A (en) | 1979-11-26 | 1983-09-30 | Sterling Drug Inc | 5-pyridinyl-2(1h)-pyridinones pharmaceutical compositions intermediate pyridine compounds |
DE2951135A1 (de) | 1979-12-19 | 1981-06-25 | Hoechst Ag, 6230 Frankfurt | Sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung |
US4344949A (en) | 1980-10-03 | 1982-08-17 | Warner-Lambert Company | Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
ES505959A0 (es) | 1980-10-09 | 1982-09-01 | Hoechst Ag | Procedimiento para la preparacion de un inactivador de alfa-amilasa |
JPS5777676A (en) | 1980-10-31 | 1982-05-15 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
US4337201A (en) | 1980-12-04 | 1982-06-29 | E. R. Squibb & Sons, Inc. | Phosphinylalkanoyl substituted prolines |
EP0056194B1 (en) | 1981-01-05 | 1984-09-12 | Takeda Chemical Industries, Ltd. | N-substituted pseudo-aminosugars, their production and use |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
DE3107100A1 (de) | 1981-02-20 | 1982-09-09 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Azaprostacycline, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
US4405628A (en) | 1981-03-05 | 1983-09-20 | Merrell Dow Pharmaceuticals Inc. | 4-Pyridylimidazolones and method of use |
DE3266746D1 (en) | 1981-03-12 | 1985-11-14 | Beecham Group Plc | N-carboxyalkyl dipeptide derivatives and pharmaceutical compositions thereof |
ZA821577B (en) | 1981-04-06 | 1983-03-30 | Boots Co Plc | Therapeutic agents |
US4452813A (en) | 1981-05-22 | 1984-06-05 | Taiho Pharmaceutical Company Limited | Sulfonate derivatives, process for preparing same and antilipemic compositions containing the derivative |
US4432971A (en) | 1981-08-03 | 1984-02-21 | E. R. Squibb & Sons, Inc. | Phosphonamidate compounds |
GB2103614B (en) | 1981-08-11 | 1984-11-21 | Ciba Geigy Ag | Benzazepin-2-ones |
HU190412B (en) | 1981-09-17 | 1986-09-29 | Warner-Lambert Co,Us | Process for producing substituted 4,5-dihiydro-6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones and 6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones |
DE3226768A1 (de) | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | Derivate der cis, endo-2-azabicyclo-(3.3.0)-octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung |
EP0080822A1 (en) | 1981-11-27 | 1983-06-08 | Beecham Group Plc | Anti-hypertensive prolinol-based peptides |
EP0096517A3 (en) | 1982-06-05 | 1985-04-03 | Smith Kline & French Laboratories Limited | Aryl pyrazinones |
US4452790A (en) | 1982-06-23 | 1984-06-05 | E. R. Squibb & Sons, Inc. | Phosphonyl hydroxyacyl amino acid derivatives as antihypertensives |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4473575A (en) | 1982-07-19 | 1984-09-25 | Ciba-Geigy Corporation | 3-Amino-(1)-benzazepin-2-one-1-alkanoic acids |
DE3241102A1 (de) | 1982-11-06 | 1984-05-10 | A. Nattermann & Cie GmbH, 5000 Köln | Imidazolylalkylthienyl-tetrahydropyridazine und verfahren zu ihrer herstellung |
US4490371A (en) | 1983-02-16 | 1984-12-25 | Syntex (U.S.A.) Inc. | N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides |
IL68769A (en) | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
US4503030A (en) | 1983-06-06 | 1985-03-05 | Alza Corporation | Device for delivering drug to certain pH environments |
CA1247547A (en) | 1983-06-22 | 1988-12-28 | Paul Hadvary | Leucine derivatives |
JPS6051189A (ja) | 1983-08-30 | 1985-03-22 | Sankyo Co Ltd | チアゾリジン誘導体およびその製造法 |
US4722810A (en) | 1984-08-16 | 1988-02-02 | E. R. Squibb & Sons, Inc. | Enkephalinase inhibitors |
US4654362A (en) | 1983-12-05 | 1987-03-31 | Janssen Pharmaceutica, N.V. | Derivatives of 2,2'-iminobisethanol |
GB8400863D0 (en) | 1984-01-13 | 1984-02-15 | Smith Kline French Lab | Chemical compounds |
DK520784A (da) | 1984-01-21 | 1985-07-22 | Hoechst Ag | Cycliske polypeptider, deres fremstilling og anvendelse |
NL8400924A (nl) | 1984-03-23 | 1985-10-16 | Philips Nv | Gelijkstroom-wisselstroomomzetter voor het ontsteken en voeden van een gas-en/of dampontladingsbuis. |
US4849405A (en) | 1984-05-09 | 1989-07-18 | Synthetic Blood Corporation | Oral insulin and a method of making the same |
US4963526A (en) | 1984-05-09 | 1990-10-16 | Synthetic Blood Corporation | Oral insulin and a method of making the same |
WO1985005029A1 (en) | 1984-05-09 | 1985-11-21 | Medaphore Inc. | Oral insulin and a method of making the same |
DK159431C (da) | 1984-05-10 | 1991-03-18 | Byk Gulden Lomberg Chem Fab | 6-phenyl-3(2h)-pyridazinoner, fremgangsmaade til fremstilling deraf, laegemidler indeholdende disse samt anvendelse af forbindelserne til fremstilling af laegemidler |
PL147842B1 (en) | 1984-05-12 | 1989-08-31 | Method of obtaining novel pyroisobenzimidazoles | |
IL75122A (en) | 1984-05-14 | 1989-02-28 | Lilly Co Eli | 3-methyl-5-(tetrahydro-6-oxopyridazin-3-yl)indoline derivatives,their preparation and use |
DE3424685A1 (de) | 1984-07-05 | 1986-02-06 | Beiersdorf Ag, 2000 Hamburg | Neue substituierte phenylpiperazinyl-propanole, verfahren zu ihrer herstellung und ihre verwendung sowie diese verbindungen enthaltende zubereitungen |
US4634765A (en) | 1984-12-18 | 1987-01-06 | Merrell Dow Pharmaceuticals Inc. | Homodisaccharide hypoglycemic agents |
AR240698A1 (es) | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales |
JPS61218589A (ja) | 1985-03-26 | 1986-09-29 | Eisai Co Ltd | 5―(6―イミダゾ〔1,2―a〕ピリジニル)ピリジン誘導体 |
US4713244A (en) | 1985-08-16 | 1987-12-15 | Bausch & Lomb Incorporated | Sustained-release formulation containing an amino acid polymer with a lower alkyl (C1 -C4) polar solvent |
US4668506A (en) | 1985-08-16 | 1987-05-26 | Bausch & Lomb Incorporated | Sustained-release formulation containing and amino acid polymer |
US4931279A (en) | 1985-08-16 | 1990-06-05 | Bausch & Lomb Incorporated | Sustained release formulation containing an ion-exchange resin |
ZW20586A1 (en) | 1985-10-17 | 1988-05-25 | Smith Kline French Lab | Chemical compounds |
IL77186A0 (en) | 1985-11-29 | 1986-04-29 | Touitou Elka | Pharmaceutical insulin composition |
DE3543999A1 (de) | 1985-12-13 | 1987-06-19 | Bayer Ag | Hochreine acarbose |
US5036048A (en) | 1986-03-07 | 1991-07-30 | Schering Corporation | Angiotensin II receptor blockers as antiglaucoma agents |
WO1987006576A1 (en) | 1986-04-29 | 1987-11-05 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US4749688A (en) | 1986-06-20 | 1988-06-07 | Schering Corporation | Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension |
US5138069A (en) | 1986-07-11 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
ES2033922T3 (es) | 1986-08-28 | 1993-04-01 | Sandoz Ag | Procedimiento para preparar nuevos derivados de xantina. |
NZ222843A (en) | 1986-12-22 | 1989-10-27 | Ortho Pharma Corp | Benzoxazinyl- and benzothiazinyl-tetrahydropyridazinones and intermediates, and medicaments |
GB8630702D0 (en) | 1986-12-23 | 1987-02-04 | Wellcome Found | Quinoline compound |
DE3856401D1 (de) | 1987-01-23 | 2000-05-04 | Gen Hospital Corp | Hydralazin zur topischen Behandlung von Glaukom |
CA1303037C (en) | 1987-02-02 | 1992-06-09 | Smith Kline & French Laboratories Limited | Purinone derivatives as bronchodilators vasodilators and anti-allergic agents |
IT1217123B (it) | 1987-02-05 | 1990-03-14 | Rotta Research Lab | Derivati otticamente attivi dell acido 5 pentilammino 5 oxo pentanoico r ad attivita antagonista della colecistochinina e procedimento per la loro preparazione |
US5041152A (en) | 1987-03-26 | 1991-08-20 | Kabushiki Kaisha Toshiba | Apparatus for bending tubular glass |
AU614965B2 (en) | 1987-06-06 | 1991-09-19 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Thiadiazinones |
IL87149A (en) | 1987-07-20 | 1994-05-30 | Merck & Co Inc | 6-Piperazinyl derivatives of purine and its 3- and 9-deaza isosteres, their preparation and pharmaceutical compositions containing them |
EP0842925A1 (en) | 1987-09-04 | 1998-05-20 | Beecham Group Plc | Substituted thiazolidinedione derivatives |
US6288095B1 (en) | 1987-09-04 | 2001-09-11 | Beecham Group P.L.C. | Compounds |
GB2209937B (en) | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
US5192772A (en) | 1987-12-09 | 1993-03-09 | Nippon Shinyaku Co. Ltd. | Therapeutic agents |
US5015651A (en) | 1988-01-07 | 1991-05-14 | E. I. Du Pont De Nemours And Company | Treatment of hypertension with 1,2,4-angiotensin II antagonists |
US4880804A (en) | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
CA1338238C (en) | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
US5236704A (en) | 1988-01-28 | 1993-08-17 | Sumitomo Pharmaceuticals Co., Ltd. | Controlled release formulation |
JP2717687B2 (ja) | 1988-02-13 | 1998-02-18 | 日本曹達株式会社 | ピリダジノン誘導体及びその製造方法 |
US5142096A (en) | 1988-03-31 | 1992-08-25 | Kyowa Hakko Kogyo Co., Ltd. | 2,4-dihydroxy-3,5,6-trimethylbenzoic acid compounds |
GB8812490D0 (en) | 1988-05-26 | 1988-06-29 | Agricultural & Food Res | Delayed release formulations |
EP0344383A1 (en) | 1988-06-02 | 1989-12-06 | Merrell Dow Pharmaceuticals Inc. | Novel alpha-Glucosidase inhibitors |
JP2792862B2 (ja) | 1988-07-30 | 1998-09-03 | 寛治 高田 | 経口腸溶製剤 |
IE61928B1 (en) | 1988-11-29 | 1994-11-30 | Boots Co Plc | Treatment of obesity |
US5106834A (en) | 1988-12-27 | 1992-04-21 | G. D. Searle & Co. | Linear free-sulfhydryl-containing oligopeptide derivatives as antihypertensive agents |
US4916129A (en) | 1989-01-19 | 1990-04-10 | E. I. Du Pont De Nemours And Company | Combination β-blocking/angiotensin II blocking antihypertensives |
GB8906792D0 (en) | 1989-03-23 | 1989-05-10 | Beecham Wuelfing Gmbh & Co Kg | Treatment and compounds |
DE3928177A1 (de) | 1989-04-08 | 1991-02-28 | Thomae Gmbh Dr K | Benzimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
US5007790A (en) | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
ES2075202T3 (es) | 1989-04-17 | 1995-10-01 | Byk Gulden Lomberg Chem Fab | Nuevas arilpiridazinas, su preparacion, su utilizacion, y medicamentos que las contienen. |
CA2016710A1 (en) | 1989-05-15 | 1990-11-15 | Prasun K. Chakravarty | Substituted benzimidazoles as angiotensin ii antagonists |
IE64514B1 (en) | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
GB8911854D0 (en) | 1989-05-23 | 1989-07-12 | Ici Plc | Heterocyclic compounds |
US5157026A (en) | 1989-05-30 | 1992-10-20 | Merck & Co., Inc. | Oxo-purines as angiotensin II antagonists |
IL94390A (en) | 1989-05-30 | 1996-03-31 | Merck & Co Inc | The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them |
US5102880A (en) | 1989-05-30 | 1992-04-07 | Merck & Co., Inc. | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
US5064825A (en) | 1989-06-01 | 1991-11-12 | Merck & Co., Inc. | Angiotensin ii antagonists |
ATE190051T1 (de) | 1989-06-14 | 2000-03-15 | Smithkline Beecham Corp | Imidazoalkensäure |
US5185351A (en) | 1989-06-14 | 1993-02-09 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists |
CA2018443A1 (en) | 1989-06-14 | 1990-12-14 | Joseph A. Finkelstein | Imidazolyl-alkenoic acids |
JP2550442B2 (ja) | 1989-06-30 | 1996-11-06 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | 置換イミダゾール |
JP2568315B2 (ja) | 1989-06-30 | 1997-01-08 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | 縮合環アリール置換イミダゾール |
CA2020073A1 (en) | 1989-07-03 | 1991-01-04 | Eric E. Allen | Substituted quinazolinones as angiotensin ii antagonists |
US5164407A (en) | 1989-07-03 | 1992-11-17 | Merck & Co., Inc. | Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists |
EP0407342A3 (en) | 1989-07-06 | 1991-07-10 | Ciba-Geigy Ag | Pyrimidine derivatives |
NZ234186A (en) | 1989-07-07 | 1991-10-25 | Janssen Pharmaceutica Nv | Imidazo quinazolin-one derivatives and pharmaceutical compositions |
GB9413975D0 (en) | 1994-07-11 | 1994-08-31 | Fujisawa Pharmaceutical Co | New heterobicyclic derivatives |
EP0409332A3 (en) | 1989-07-19 | 1991-08-07 | Merck & Co. Inc. | Substituted triazoles as angiotensin ii antagonists |
CH679207A5 (zh) | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
EP0412594B1 (en) | 1989-07-28 | 1996-01-03 | Merck & Co. Inc. | Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists |
DE69013607T2 (de) | 1989-08-02 | 1995-03-02 | Takeda Chemical Industries Ltd | Pyrazol-Derivate, Verfahren zu deren Herstellung und Anwendung. |
NO903525L (no) | 1989-08-11 | 1991-02-12 | Ici Plc | Nitrogenforbindelser. |
JP2862576B2 (ja) | 1989-08-14 | 1999-03-03 | 日産自動車株式会社 | カチオン電着塗料組成物 |
US5100897A (en) | 1989-08-28 | 1992-03-31 | Merck & Co., Inc. | Substituted pyrimidinones as angiotensin ii antagonists |
EP0415886A3 (en) | 1989-08-30 | 1991-10-23 | Ciba-Geigy Ag | Aza compounds |
IE70593B1 (en) | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
EP0424317A3 (en) | 1989-10-19 | 1991-09-25 | Ciba-Geigy Ag | Pyrimidines |
IL95975A (en) | 1989-10-24 | 1997-06-10 | Takeda Chemical Industries Ltd | N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them |
AU640417B2 (en) | 1989-10-25 | 1993-08-26 | Smithkline Beecham Corporation | Substituted 5-((tetrazolyl)alkenyl)imidazoles |
IL96019A0 (en) | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
US4943573A (en) | 1989-11-01 | 1990-07-24 | Bristol-Myers Squibb Company | Imidazo[4,5-b]quinolinyloxyalkanoic acid amides with enhanced water solubility |
CA2028925A1 (en) | 1989-11-06 | 1991-05-07 | Gerald R. Girard | Substituted n-(imidazolyl)alkyl alanine derivatives |
RU2104306C1 (ru) | 1989-11-13 | 1998-02-10 | Пфайзер Инк. | Способ получения оптически активного (2s)- или (2r)-эндо-бицикло[2.2.1]гептан-2-ола, способ получения 5-(3-[(2r)-экзо-бицикло[2.2.1]гепт-2-илокси]-4-метоксифенил)-3,4,5,6-тетрагидропиримидин-2(1н)-она, оптически активный 5-(3-[экзо-бицикло[2.2.1]гепт-2-илокси]4-метоксифенил)-3,4,5,6-тетрагидропиримидин-2(1н)-он, оптически активные промежуточные соединения и способ их получения |
US5391571A (en) | 1989-11-15 | 1995-02-21 | American Home Products Corporation | Cholesterol ester hydrolase inhibitors |
PT95899A (pt) | 1989-11-17 | 1991-09-13 | Glaxo Group Ltd | Processo para a preparacao de derivados indole |
IE903911A1 (en) | 1989-11-20 | 1991-05-22 | Ici Plc | Diazine derivatives |
US5073566A (en) | 1989-11-30 | 1991-12-17 | Eli Lilly And Company | Angiotensin ii antagonist 1,3-imidazoles and use thereas |
EP0430300A3 (en) | 1989-12-01 | 1992-03-25 | Takeda Chemical Industries, Ltd. | Xanthine derivatives, their production and use |
EP0430709A3 (en) | 1989-12-01 | 1992-02-12 | Glaxo Group Limited | Benzthiophen derivatives |
GB8927277D0 (en) | 1989-12-01 | 1990-01-31 | Glaxo Group Ltd | Chemical compounds |
US5104891A (en) | 1989-12-11 | 1992-04-14 | G. D. Searle & Co. | Cycloheptimidazolone compounds as angiotensin ii antagonists for control of hypertension |
EP0433983B1 (en) | 1989-12-20 | 1998-03-04 | Texas Instruments Incorporated | Copper etch process using halides |
EP0434038A1 (en) | 1989-12-22 | 1991-06-26 | Takeda Chemical Industries, Ltd. | Fused imidazole derivatives, their production and use |
GB8929208D0 (en) | 1989-12-27 | 1990-02-28 | Almirall Lab | New xanthine derivatives |
EP0435827A3 (en) | 1989-12-28 | 1991-11-13 | Ciba-Geigy Ag | Diaza compounds |
CA2032289A1 (en) | 1989-12-29 | 1991-06-30 | Joseph A. Finkelstein | Substituted 5-(alkyl) carboxamide imidazoles |
JP2726563B2 (ja) | 1990-02-13 | 1998-03-11 | メルク・エンド・カムパニー・インコーポレーテツド | 置換ベンジル要素を含むトリアゾールアンギオテンシン▲ii▼拮抗物質 |
JPH05503530A (ja) | 1990-02-13 | 1993-06-10 | メルク・エンド・カムパニー・インコーポレーテツド | 置換ベンジル成分を含むアンギオテンシン2拮抗物質 |
US5162326A (en) | 1990-02-15 | 1992-11-10 | Takeda Chemical Industries, Ltd. | Pyrimidinedione derivatives, their production and use |
ES2084801T3 (es) | 1990-02-19 | 1996-05-16 | Ciba Geigy Ag | Acil compuestos. |
CA2036618C (en) | 1990-02-22 | 2002-10-29 | Akira Morimoto | Fused thiophene derivatives, their production and use |
US4963561A (en) | 1990-02-28 | 1990-10-16 | Sterling Drug Inc. | Imidazopyridines, their preparation and use |
DE4006693A1 (de) | 1990-03-01 | 1991-09-05 | Schering Ag | Neue benzimidazolderivate, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung |
US5081122A (en) | 1990-03-05 | 1992-01-14 | Sterling Drug Inc. | Antiglaucoma compositions containing 4-arylcarbonyl-1-(4-morpholinyl)-lower-alkyl)-1H-indoles and method of use thereof |
US5112820A (en) | 1990-03-05 | 1992-05-12 | Sterling Drug Inc. | Anti-glaucoma compositions containing 2- and 3-aminomethyl-6-arylcarbonyl- or 6-phenylthio-2,3-dihydropyrrolo-(1,2,3-de)-1,4-benzoxazines and method of use thereof |
CA2037630C (en) | 1990-03-07 | 2001-07-03 | Akira Morimoto | Nitrogen-containing heterocylic compounds, their production and use |
US5013837A (en) | 1990-03-08 | 1991-05-07 | Sterling Drug Inc. | 3-Arylcarbonyl-1H-indole-containing compounds |
US4973587A (en) | 1990-03-08 | 1990-11-27 | Sterling Drug Inc. | 3-arylcarbonyl-1-aminoalkyl-1H-indole-containing antiglaucoma method |
GB9005354D0 (en) | 1990-03-09 | 1990-05-02 | Glaxo Group Ltd | Chemical compounds |
US5287273A (en) | 1990-03-15 | 1994-02-15 | Mount Sinai School Of Medicine | Functional organ images |
FR2659655B1 (fr) | 1990-03-19 | 1992-07-24 | Union Pharma Scient Appl | Nouveaux derives d'oxypyrazole antagonistes des recepteurs a l'angiotensine ii ; leurs procedes de preparation, compositions pharmaceutiques les contenant. |
FR2681067B1 (fr) | 1991-09-10 | 1993-12-17 | Elf Sanofi | Derives heterocycliques n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
US5155126A (en) | 1990-03-20 | 1992-10-13 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with pyrazole, pyrrole and triazole angiotensin-II receptor antagonists |
US5137906A (en) | 1990-03-20 | 1992-08-11 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with benzimidazole angiotensin-II receptor antagonists |
IE910913A1 (en) | 1990-03-20 | 1991-09-25 | Sanofi Sa | N-substituted heterocyclic derivates, their preparation¹and pharmaceutical compositions containing them |
US5140037A (en) | 1990-03-20 | 1992-08-18 | E. I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
US5173494A (en) | 1990-03-20 | 1992-12-22 | E. I. Du Pont De Nemours And Company | Specific inhibition of angiotensin-II binding to angiotensin-II receptor subtype-2 |
US5270317A (en) | 1990-03-20 | 1993-12-14 | Elf Sanofi | N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present |
US5223516A (en) | 1990-03-22 | 1993-06-29 | E. R. Squibb & Sons, Inc. | 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same |
US5063245A (en) | 1990-03-28 | 1991-11-05 | Nova Pharmaceutical Corporation | Corticotropin-releasing factor antagonism compounds |
WO1991015479A1 (en) | 1990-03-30 | 1991-10-17 | Merck & Co., Inc. | Substituted pyrazoles, isoxazoles and isothiazoles |
JPH05505609A (ja) | 1990-03-30 | 1993-08-19 | メルク・エンド・カムパニー・インコーポレーテツド | 置換ピリミジン、ピリミジノンおよびピリドリミジン |
DE4010797A1 (de) | 1990-04-04 | 1991-10-10 | Hoechst Ag | Substituierte azole, verfahren zu deren herstellung, diese enthaltende mittel und deren verwendung |
WO1991015206A1 (en) | 1990-04-05 | 1991-10-17 | E.I. Du Pont De Nemours And Company | Treatment of glaucoma and ocular hypertension with imidazole angiotensin-ii receptor antagonists |
US5175003A (en) | 1990-04-06 | 1992-12-29 | Biosytes Usa, Inc. | Dual mechanism controlled release system for drug dosage forms |
WO1991016313A1 (en) | 1990-04-13 | 1991-10-31 | Smithkline Beecham Corporation | Substituted benzimidazoles |
EP0453210A3 (en) | 1990-04-19 | 1993-01-13 | Imperial Chemical Industries Plc | Pyridine derivatives |
US5196444A (en) | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
JPH07107055B1 (zh) | 1990-04-25 | 1995-11-15 | ||
US5703110A (en) | 1990-04-27 | 1997-12-30 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives, their production and use |
US5642868A (en) | 1990-05-02 | 1997-07-01 | The United States Of America As Represented By The Secretary Of The Navy | Ceramic material |
US5098920A (en) | 1990-05-04 | 1992-03-24 | G. D. Searle & Co. | 1h-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders |
IL98087A (en) | 1990-05-04 | 1996-11-14 | Perio Prod Ltd | Preparation for dispensing drugs in the colon |
GB9010394D0 (en) | 1990-05-09 | 1990-06-27 | Ici Plc | Heterocyclic compounds |
MY105344A (en) | 1990-05-16 | 1994-09-30 | Byk Gulden Lomberg Chemische Fabrik | New sulphonyl compounds |
WO1991018888A1 (en) | 1990-05-25 | 1991-12-12 | G.D. Searle & Co. | N-substituted-1,2,4-triazolone compounds for treatment of cardiovascular disorders |
US5045540A (en) | 1990-05-25 | 1991-09-03 | Warner-Lambert Co. | Amino acid derivatives with angiotensin II antagonist properties |
US5504078A (en) | 1990-06-08 | 1996-04-02 | Merrell Dow Pharmaceuticals Inc. | α-glucosidase inhibitors |
AU653524B2 (en) | 1990-06-08 | 1994-10-06 | Roussel-Uclaf | New imidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them |
AU7983691A (en) | 1990-06-15 | 1992-01-07 | G.D. Searle & Co. | 1h-substituted-imidazo{4,5-d}pyridazine compounds for treatment of cardiovascular disorders |
WO1991019697A1 (en) | 1990-06-19 | 1991-12-26 | Meiji Seika Kabushiki Kaisha | Pyridine derivative with angiotensin ii antagonism |
GB9013750D0 (en) | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
EP0533840B1 (en) | 1990-06-22 | 1996-12-11 | E.I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists |
NZ238688A (en) | 1990-06-28 | 1992-05-26 | Smithkline Beecham Corp | Substituted histidines: pharmaceutical compositions, preparation and uses thereof |
IE912114A1 (en) | 1990-07-02 | 1992-01-15 | Union Pharma Scient Appl | Novel pyrimidine derivatives which are angiotensin ii¹receptor antagonists, their methods of preparation and¹pharmaceutical compositions in which they are present |
US5053329A (en) | 1990-07-05 | 1991-10-01 | Merck & Co., Inc. | Process for preparation of novel angiotensin II antagonists |
IL98319A (en) | 1990-07-05 | 1997-04-15 | Roussel Uclaf | Sulphurous derivatives of imidazole, their preparation process, and pharmaceutical compositions containing them |
HUT65903A (en) | 1990-07-10 | 1994-07-28 | Smithkline Beecham Corp | Oxamides, process for preparing them and pharmaceutical compositions containing them |
US5137902A (en) | 1990-07-13 | 1992-08-11 | E. I. Du Pont De Nemours And Company | 4-alkylimidazole derivatives and anti-hypertensive use thereof |
CA2044806A1 (en) | 1990-07-18 | 1992-01-19 | Roland Jaunin | Purine derivatives |
CA2047029A1 (en) | 1990-07-19 | 1992-01-20 | Shieh-Shung T. Chen | Microbial transformation process for antihypertensive products |
US5132216A (en) | 1990-07-19 | 1992-07-21 | Merck & Co., Inc. | Microbial transformation process for antihypertensive products |
US5057522A (en) | 1990-07-19 | 1991-10-15 | Merck & Co., Inc. | Anti-hypersensitive N2-tetrazole-β-glucuronide analog |
CA2046830C (en) | 1990-07-19 | 1999-12-14 | Patrick P. Deluca | Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer |
DE4023215A1 (de) | 1990-07-21 | 1992-01-23 | Hoechst Ag | Substituierte azole, verfahren zu deren herstellung, sie enthaltende mittel und deren verwendung |
RU1836357C (ru) | 1990-07-23 | 1993-08-23 | Др.Карл Томэ ГмбХ | Производные бензимидазола, их изомеры, смеси изомеров, гидраты или их физиологически переносимые соли, обладающие антагонистическими в отношении ангиотензина свойствами |
NZ239161A (en) | 1990-07-31 | 1994-01-26 | Smithkline Beecham Corp | Substituted [1h-imidazol-5-yl] alkanoic acid derivatives; medicaments, |
US5124455A (en) | 1990-08-08 | 1992-06-23 | American Home Products Corporation | Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents |
GB9017479D0 (en) | 1990-08-09 | 1990-09-26 | Ici Plc | Process |
GB9017482D0 (en) | 1990-08-09 | 1990-09-26 | Ici Plc | Manufacturing process |
GB9017480D0 (en) | 1990-08-09 | 1990-09-26 | Ici Plc | Chemical process |
EP0470543A1 (de) | 1990-08-10 | 1992-02-12 | Dr. Karl Thomae GmbH | Heterocyclische Imidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zur ihrer Herstellung |
WO1992002257A2 (en) | 1990-08-10 | 1992-02-20 | G.D. Searle & Co. | Renal-selective angiotensin ii antagonists for treatment of hypertension |
US5066586A (en) | 1990-08-20 | 1991-11-19 | Merck & Co., Inc. | Process for preparation of novel angiotensin II antagonists |
US5089626A (en) | 1990-08-23 | 1992-02-18 | Merck & Co., Inc. | Process for preparing an angiotensin II antagonist |
US5217985A (en) | 1990-08-28 | 1993-06-08 | G. D. Searle & Co. | Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension |
AU8405691A (en) | 1990-09-04 | 1992-03-30 | Yamanouchi Pharmaceutical Co., Ltd. | Novel tetrahydrobenzazole derivative |
IL99372A0 (en) | 1990-09-10 | 1992-08-18 | Ciba Geigy Ag | Azacyclic compounds |
IL99246A0 (en) | 1990-09-10 | 1992-07-15 | Abbott Lab | Angiotensin ii receptor antagonists and pharmaceutical compositions containing them |
WO1992004059A1 (en) | 1990-09-11 | 1992-03-19 | Mectra Labs, Inc. | Disposable lavage |
US5140036A (en) | 1990-09-19 | 1992-08-18 | G. D. Searle & Co. | 1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders |
US5210092A (en) | 1990-09-25 | 1993-05-11 | Fujisawa Pharmaceutical Co., Ltd. | Angiotensin ii antagonizing heterocyclic derivatives |
US5091418A (en) | 1990-09-28 | 1992-02-25 | Bristol-Myers Squibb Company | Novel alpha-glucosidase inhibitor, pradimicin Q |
US5242939A (en) | 1990-09-28 | 1993-09-07 | Warner-Lambert Company | Anilide derivatives with angiotensin ii antagonist properties |
US5217877A (en) | 1990-09-28 | 1993-06-08 | Bristol-Myers Squibb Company | Process for the preparation of α-glucosidase inhibitor, pradimicin Q |
EP0481614A1 (en) | 1990-10-01 | 1992-04-22 | Merck & Co. Inc. | Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists |
US5126342A (en) | 1990-10-01 | 1992-06-30 | Merck & Co., Inc. | Imidazole angiotensin ii antagonists incorporating acidic functional groups |
JP3208139B2 (ja) | 1990-10-02 | 2001-09-10 | ワーナー−ランバート・コンパニー | アンギオテンシン▲ii▼アンタゴニスト |
US5260322A (en) | 1990-10-08 | 1993-11-09 | Merck & Co., Inc. | Angiotension II antagonists in the treatment of hyperuricemia |
IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
US5565473A (en) | 1990-10-12 | 1996-10-15 | Merck Frosst Canada, Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
ATE168101T1 (de) | 1990-10-16 | 1998-07-15 | Byk Gulden Lomberg Chem Fab | Arylpyridazinone |
CA2053148A1 (en) | 1990-10-16 | 1992-04-17 | Karnail Atwal | Dihydropyrimidine derivatives |
CA2053340C (en) | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
US5130333A (en) | 1990-10-19 | 1992-07-14 | E. R. Squibb & Sons, Inc. | Method for treating type II diabetes employing a cholesterol lowering drug |
AU9024591A (en) | 1990-10-25 | 1992-05-26 | G.D. Searle & Co. | Biphenylalkyl xanthine compounds for treatment of cardiovascular disorders |
AU636066B2 (en) | 1990-10-30 | 1993-04-08 | Takeda Chemical Industries Ltd. | Thienoimidazole derivatives, their production and use |
PH31175A (en) | 1990-10-31 | 1998-03-20 | Squibb & Sons Inc | Indole and benzimi-dazole-substituted imidazole and benzimidazole derivatives. |
US5087634A (en) | 1990-10-31 | 1992-02-11 | G. D. Searle & Co. | N-substituted imidazol-2-one compounds for treatment of circulatory disorders |
DE4036645A1 (de) | 1990-11-16 | 1992-05-21 | Hoechst Ag | Substituierte azole, verfahren zu deren herstellung, deren enthaltende mittel und deren verwendung |
GB9026006D0 (en) | 1990-11-29 | 1991-01-16 | Glaxo Group Ltd | Chemical compounds |
EP0559755A1 (en) | 1990-11-30 | 1993-09-15 | Smithkline Beecham Corporation | Substituted 5-aryl imidazoles |
CA2057089A1 (en) | 1990-12-07 | 1992-06-08 | Eric E. Allen | Substituted pyrazolopyrimidines and imidazopyridazines as angiotensin ii antagonists |
US5049565A (en) | 1990-12-07 | 1991-09-17 | Merck & Co., Inc. | Microbial transformation process for preparing anti-hypertensive products |
GB9027197D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027055D0 (en) | 1990-12-13 | 1991-02-06 | Sandoz Ltd | Organic compounds |
GB9027201D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027199D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
AU657498B2 (en) | 1990-12-14 | 1995-03-16 | Novartis Ag | Biphenylyl compounds |
CA2098176C (en) | 1990-12-14 | 2006-12-12 | Joseph Weinstock | Angiotensin ii receptor blocking compositions |
GB9027209D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027212D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027200D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027208D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027210D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027198D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
GB9027211D0 (en) | 1990-12-14 | 1991-02-06 | Smithkline Beecham Plc | Medicaments |
JPH04234389A (ja) | 1990-12-28 | 1992-08-24 | Sapporo Breweries Ltd | ナフチリジン誘導体及びそれを有効成分とする抗潰瘍剤 |
US5141931A (en) | 1991-01-03 | 1992-08-25 | Sterling Winthrop Inc. | 5-Quinolinylpyridinones, cardiotonic compositions and methods |
CA2058198A1 (en) | 1991-01-04 | 1992-07-05 | Adalbert Wagner | Azole derivatives, process for their preparation, and their use |
IE914572A1 (en) | 1991-01-17 | 1992-07-29 | Zeneca Ltd | Chemical process |
IE914573A1 (en) | 1991-01-17 | 1992-07-29 | Ici Plc | Boron compounds |
IE71647B1 (en) | 1991-01-28 | 1997-02-26 | Rhone Poulenc Rorer Ltd | Benzamide derivatives |
US5124335A (en) | 1991-01-30 | 1992-06-23 | Merck & Co., Inc. | Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists |
US5087702A (en) | 1991-01-30 | 1992-02-11 | Merck & Co., Inc. | Microbial transformation process for producing an antihypertensive product |
US5290780A (en) | 1991-01-30 | 1994-03-01 | American Cyanamid Co. | Angiotensin II receptor blocking 2,3,6 substituted quinazolinones |
AT395853B (de) | 1991-01-31 | 1993-03-25 | Chem Pharm Forsch Gmbh | Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung |
US5153347A (en) | 1991-01-31 | 1992-10-06 | E. R. Squibb & Sons, Inc. | Phosphonate, phosphinate derivatives useful as antihypertensive agents |
SI9210098B (sl) | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo |
US5614519A (en) | 1991-02-06 | 1997-03-25 | Karl Thomae Gmbh | (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists |
AU1256692A (en) | 1991-02-06 | 1992-09-07 | Schering Corporation | Combination of an angiotensin II antagonist or renin inhibitor with a neutral endopeptidase inhibitor |
DE69221175T2 (de) | 1991-02-07 | 1998-01-15 | Roussel Uclaf | Bizyklische Stickstoffverbindungen, ihre Herstellung, erhaltene Zwischenprodukte, ihre Verwendung als Arzneimittel und diese enthaltende pharmazeutische Zusammensetzungen |
MX9200299A (es) | 1991-02-07 | 1992-12-01 | Roussel Uclaf | Nuevos derivados biciclicos nitrogenados, su procedimiento de preparacion los nuevos compuestos intermedios obtenidos su aplicacion como medicamentos y las composiciones farmaceuticas que los contienen. |
IL100555A (en) | 1991-02-07 | 2000-08-31 | Hoechst Marion Roussel Inc | N-substituted quinoline derivatives their preparation their use for the preparation of medicaments and the pharmaceutical compositions containing them |
GB9102727D0 (en) | 1991-02-08 | 1991-03-27 | Ici Plc | Pharmaceutical agent |
GB9102804D0 (en) | 1991-02-11 | 1991-03-27 | Ici Plc | Heterocyclic derivatives |
GB9102803D0 (en) | 1991-02-11 | 1991-03-27 | Ici Plc | Pyridine compounds |
IE920175A1 (en) | 1991-02-11 | 1992-08-12 | Zeneca Ltd | Nitrogen heterocycles |
IL100917A0 (en) | 1991-02-16 | 1992-11-15 | Fisons Plc | Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them |
FR2672892B1 (fr) | 1991-02-20 | 1994-01-14 | Synthelabo | Derives de 4-pyrimidinones, leur preparation et leur application en therapeutique. |
IE920540A1 (en) | 1991-02-21 | 1992-08-26 | Sankyo Co | 1-biphenylmethylimidazole derivatives, their preparation and¹their therapetuic use |
US5104877A (en) | 1991-02-25 | 1992-04-14 | Abbott Laboratories | Psoriasis treatment |
CA2061159A1 (en) | 1991-02-26 | 1992-08-27 | Michael A. Poss | Imidazole and benzimidazole derivatives |
US5187271A (en) | 1991-02-28 | 1993-02-16 | G. D. Searle & Co. | N-substituted (α-imidazolyl-toluyl) pyrrole compounds for treatment of circulatory disorders |
FR2673427B1 (fr) | 1991-03-01 | 1993-06-18 | Sanofi Elf | Derives heterocycliques diazotes n-substitues par un groupement biphenylmethyle, leur preparation, les compositions pharmaceutiques en contenant. |
US5202328A (en) | 1991-03-06 | 1993-04-13 | Merck & Co., Inc. | Substituted fused pyrimidinones |
EP0503838A3 (en) | 1991-03-08 | 1992-10-07 | Merck & Co. Inc. | Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists |
US5191086A (en) | 1991-03-19 | 1993-03-02 | E.R. Squibb & Sons, Inc. | Imidazole and benzimidazole derivatives |
EP0505098A1 (en) | 1991-03-19 | 1992-09-23 | Merck & Co. Inc. | Imidazole derivatives bearing acidic functional groups as angiotensin II antagonists |
US5196537A (en) | 1991-03-21 | 1993-03-23 | G. D. Searle & Co. | 5-apylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders |
US5187179A (en) | 1991-03-22 | 1993-02-16 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted imidazo [1,2-b][1,2,4]triazole |
HUT64023A (en) | 1991-03-22 | 1993-11-29 | Sandoz Ag | Process for producing aminoguanidine derivatives and pharmaceutical compositions comprising such compounds |
IE73235B1 (en) | 1991-03-25 | 1997-05-21 | Akzo Nv | 4-aryl-thiazole or imidazole derivatives |
US5128327A (en) | 1991-03-25 | 1992-07-07 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle |
AU1417092A (en) | 1991-03-25 | 1992-10-21 | Glaxo Group Limited | 1-imidazolgemethyl benzofuran derivatives as inhibitors of angiotensin ii activity |
US5177074A (en) | 1991-03-26 | 1993-01-05 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted thiophene or furan |
DE4110019C2 (de) | 1991-03-27 | 2000-04-13 | Merck Patent Gmbh | Imidazopyridine, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen |
FR2674849B1 (fr) | 1991-04-02 | 1994-12-23 | Logeais Labor Jacques | Nouveaux derives de n-cyclohexyl benzamides ou thiobenzamides, leurs preparations et leurs applications en therapeutique. |
US5157040A (en) | 1991-04-05 | 1992-10-20 | Merck & Co., Inc. | Substituted quinolines as angiotensin ii antagonists |
US5164403A (en) | 1991-04-05 | 1992-11-17 | G. D. Searle & Co. | N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders |
US5151435A (en) | 1991-04-08 | 1992-09-29 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating an indole or dihydroindole |
US5155117A (en) | 1991-04-12 | 1992-10-13 | G. D. Searle & Co. | 1-arylheteroarylalkyl substituted-1h-1,2,4-triazole compounds for treatment of circulatory disorders |
TW274551B (zh) | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
US5190942A (en) | 1991-04-22 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Benzoxazole and related heterocyclic substituted imidazole and benzimidazole derivatives |
US5252574A (en) | 1991-04-26 | 1993-10-12 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted thiophene or furan |
WO1992019602A1 (de) | 1991-04-26 | 1992-11-12 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Neue pyridazine |
EP0511767A1 (en) | 1991-04-29 | 1992-11-04 | Merck & Co. Inc. | Tablets containing compound DUP753 |
GB9109246D0 (en) | 1991-04-30 | 1991-06-19 | Ici Plc | Nitrogen derivatives |
US5191084A (en) | 1991-05-01 | 1993-03-02 | American Home Products Corporation | Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents |
US5198438A (en) | 1991-05-07 | 1993-03-30 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted thiophene or furan |
US5162325A (en) | 1991-05-07 | 1992-11-10 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted benzyl element |
JPH05112533A (ja) | 1991-05-08 | 1993-05-07 | Upjohn Co:The | イミダゾベンゾキノン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤 |
US5238942A (en) | 1991-05-10 | 1993-08-24 | Merck & Co., Inc. | Substituted quinazolinones bearing acidic functional groups as angiotensin ii antagonists |
CA2109524A1 (en) | 1991-05-10 | 1992-11-11 | Prasun K. Chakravarty | Acidic aralkyl triazole derivatives active as angiotensin ii antagonists |
US5223501A (en) | 1991-05-10 | 1993-06-29 | Merck & Co., Inc. | Substituted pyrimidinones bearing acidic functional groups as angiotensin ii antagonists |
NZ242724A (en) | 1991-05-15 | 1994-09-27 | Du Pont | Synergistic composition comprising an angiotensin-ii receptor antagonist and a calcium channel blocker |
GB9110532D0 (en) | 1991-05-15 | 1991-07-03 | Smithkline Beecham Corp | Chemical compounds |
EP0514192A1 (en) | 1991-05-16 | 1992-11-19 | Glaxo Group Limited | Antihypertensive benzofuran derivatives, substituted by varied N-pyrimidinyl- or N-imidazolyl-methyl groups |
CA2068756A1 (en) | 1991-05-16 | 1992-11-17 | Barry C. Ross | Benzofuran derivatives |
GB9110636D0 (en) | 1991-05-16 | 1991-07-03 | Glaxo Group Ltd | Chemical compounds |
GB9110625D0 (en) | 1991-05-16 | 1991-07-03 | Glaxo Group Ltd | Chemical compounds |
WO1992020661A1 (en) | 1991-05-22 | 1992-11-26 | Merck & Co., Inc. | N, n-diacylpiperazines |
FR2676734B1 (fr) | 1991-05-23 | 1995-05-19 | Roussel Uclaf | Nouveaux derives de la pyrimidine, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant. |
AU1625192A (en) | 1991-05-31 | 1992-12-03 | Zeneca Limited | Heterocyclic derivatives |
US5175164A (en) | 1991-06-05 | 1992-12-29 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted indole or dihydroindole |
JPH05213884A (ja) | 1991-06-14 | 1993-08-24 | Upjohn Co:The | 新規な4−アミノキノリン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤 |
US5210211A (en) | 1991-06-21 | 1993-05-11 | Warner-Lambert Company | 4-(1h-pyrrol-1-yl) imidazoles with angiotension ii antagonist activity |
FR2677984B1 (fr) | 1991-06-21 | 1994-02-25 | Elf Sanofi | Derives d'imidazoline n-substitues, leur preparation, les compositions pharmaceutiques en contenant. |
GB9113628D0 (en) | 1991-06-25 | 1991-08-14 | Ici Plc | Heterocyclic derivatives |
GB9113626D0 (en) | 1991-06-25 | 1991-08-14 | Ici Plc | Heterocyclic compounds |
IL102183A (en) | 1991-06-27 | 1999-11-30 | Takeda Chemical Industries Ltd | The heterocyclic compounds are converted into biphenyl groups, their production and the pharmaceutical compositions containing them |
WO1993001177A1 (en) | 1991-07-03 | 1993-01-21 | Merck & Co., Inc. | Substituted triazolinones |
FR2678618B1 (fr) | 1991-07-05 | 1993-11-05 | Upsa Laboratoires | Nouveaux derives de triazolo pyrimidine antagonistes des recepteurs a l'angiotensine ii; leurs procedes de preparation, compositions pharmaceutiques les contenant. |
DE4123341A1 (de) | 1991-07-15 | 1993-01-21 | Thomae Gmbh Dr K | Phenylalkylderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
CH683149A5 (fr) | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Procédé pour la préparation de microsphères en matériau polymère biodégradable. |
US5177097A (en) | 1991-07-24 | 1993-01-05 | E. R. Squibb & Sons, Inc. | Acyl amidine and acyl, guanidine substituted biphenyl derivatives |
GB9116039D0 (en) | 1991-07-25 | 1991-09-11 | Ucb Sa | Substituted cyclopropylamino-1,3,5-triazines |
WO1993003033A1 (en) | 1991-07-26 | 1993-02-18 | G. D. Searle & Co. | CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS |
IT1250749B (it) | 1991-08-02 | 1995-04-21 | Luso Farmaco Inst | Composti eterociclici ad attivita' a ii antagonista |
WO1993003040A1 (en) | 1991-08-05 | 1993-02-18 | Taisho Pharmaceutical Co., Ltd. | Thienopyrimidin-4-one derivative |
US5225401A (en) | 1991-08-12 | 1993-07-06 | E. R. Squibb & Sons, Inc. | Treatment of congestive heart failure |
US5246944A (en) | 1991-08-13 | 1993-09-21 | Merck & Co., Inc. | Quinoline angiotensin ii antagonists incorporating a substituted benzyl element |
ATE152718T1 (de) | 1991-08-15 | 1997-05-15 | Ciba Geigy Ag | N-acyl-n-heterocyclyl- oder naphthylalkyl- aminosäuren als angiotensin ii antagonisten |
AU2496492A (en) | 1991-08-19 | 1993-03-16 | E.I. Du Pont De Nemours And Company | Angiotensin ii receptor blocking imidazolinone derivatives |
CZ36394A3 (en) | 1991-08-19 | 1994-07-13 | Du Pont | Substituted imidazilonone derivatives and pharmaceutical preparations based thereon |
DE4129340A1 (de) | 1991-09-04 | 1993-03-11 | Merck Patent Gmbh | 1,2-dihydro-2-oxopyridine |
WO1993005025A1 (en) | 1991-09-06 | 1993-03-18 | Glaxo Group Limited | C-linked pyrazole derivatives |
AU644539B2 (en) | 1991-09-10 | 1993-12-09 | Tanabe Seiyaku Co., Ltd. | Imidazoindolizine derivatives and process for preparation thereof |
SG42942A1 (en) | 1991-09-10 | 1997-10-17 | Tanabe Seiyaku Co | Imidazopyridine derivatives and process for preparation thereof |
TW300219B (zh) | 1991-09-14 | 1997-03-11 | Hoechst Ag | |
US5256667A (en) | 1991-09-25 | 1993-10-26 | Merck & Co., Inc. | Quinazolinones and pyridopyrimidinones |
US5202322A (en) | 1991-09-25 | 1993-04-13 | Merck & Co., Inc. | Quinazolinone and pyridopyrimidine a-II antagonists |
CA2078759C (en) | 1991-09-27 | 2003-09-16 | Alan M. Warshawsky | Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace |
AU657793B2 (en) | 1991-09-27 | 1995-03-23 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
CA2078758C (en) | 1991-09-27 | 2003-12-09 | Alan M. Warshawsky | 2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
PT100905A (pt) | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem |
DE4132631A1 (de) | 1991-10-01 | 1993-04-08 | Bayer Ag | Imidazolyl-propensaeurederivate |
DE4132632A1 (de) | 1991-10-01 | 1993-04-08 | Bayer Ag | Substituierte imidazolyl-propensaeurederivate |
DE4132633A1 (de) | 1991-10-01 | 1993-04-08 | Bayer Ag | Cyclisch substituierte imidazolyl-propensaeurederivate |
AT398202B (de) | 1991-10-04 | 1994-10-25 | Chem Pharm Forsch Gmbh | Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung |
US5187159A (en) | 1991-10-07 | 1993-02-16 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted 1,3-benzodioxole or 1,3-benzodithiole |
CA2079982A1 (en) | 1991-10-07 | 1993-04-08 | Stephen E. De Laszlo | Substituted pyrazino (2,3-d)-pyrimidinones as angiotensin ii antagonists |
EP0612321B1 (en) | 1991-10-09 | 1999-08-25 | Syntex (U.S.A.) Inc. | Pyrido pyridazinone and pyridazinthione compounds with pde iv inhibiting activity |
GB9121463D0 (en) | 1991-10-10 | 1991-11-27 | Smithkline Beecham Corp | Medicament |
GB9121727D0 (en) | 1991-10-14 | 1991-11-27 | Ici Plc | Heterocyclic compounds |
US5234936A (en) | 1991-10-24 | 1993-08-10 | American Home Products Corporation | Pyrimidocycloalkanes as a ii antagonists |
US5149699A (en) | 1991-10-24 | 1992-09-22 | American Home Products Corporation | Substituted pyridopyrimidines useful as antgiotensin II antagonists |
JPH06107661A (ja) | 1991-10-24 | 1994-04-19 | Upjohn Co:The | イミダゾール誘導体およびこれを有効成分とする医薬組成物 |
US5336677A (en) | 1991-10-24 | 1994-08-09 | American Home Products Corporation | Substituted aminopyrimidines as antihypertensives |
TW226375B (zh) | 1991-10-24 | 1994-07-11 | American Home Prod | |
US5187168A (en) | 1991-10-24 | 1993-02-16 | American Home Products Corporation | Substituted quinazolines as angiotensin II antagonists |
FR2683819B1 (fr) | 1991-10-28 | 1994-02-11 | Synthelabo | Derives de quinoleine, leur procede de preparation et leur application en therapeutique. |
JP3221894B2 (ja) | 1991-10-31 | 2001-10-22 | ダウ・コ−ニング・コ−ポレ−ション | 分岐オルガノポリシロキサンの製造方法 |
US5252753A (en) | 1991-11-01 | 1993-10-12 | Ortho Pharmaceutical Corporation | Process for the preparation of certain substituted biphenyl tetrazoles and compounds thereof |
DE4221583A1 (de) | 1991-11-12 | 1993-05-13 | Bayer Ag | Substituierte biphenylpyridone |
US5182288A (en) | 1991-11-13 | 1993-01-26 | Ortho Pharmaceutical Corporation | Substituted n-biphenylyl lactams |
EP0543263A3 (en) | 1991-11-16 | 1993-08-25 | Dr. Karl Thomae Gmbh | Benziimidazoles, pharmaceuticals containing them and process for their preparation |
US5130439A (en) | 1991-11-18 | 1992-07-14 | Lo Young S | Tetrazolylphenylboronic acid intermediates for the synthesis of AII receptor antagonists |
WO1993012068A1 (en) | 1991-12-11 | 1993-06-24 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
US5212177A (en) | 1991-12-16 | 1993-05-18 | E. R. Squibb & Sons, Inc. | Indole and benzimidazole-substituted dihydropyrimidine derivatives |
CA2151741C (en) | 1991-12-30 | 2001-12-11 | Alan Justice | Methods of producing analgesia and enhancing opiate analgesia |
US5824645A (en) | 1991-12-30 | 1998-10-20 | Neurex Corporation | Method of treating inflammation |
WO1993015045A1 (en) | 1992-01-29 | 1993-08-05 | Smithkline Beecham Corporation | N-(3-phenylpropyl)oxamic acid, oxamate, and oxamide derivatives |
WO1993015044A1 (en) | 1992-01-29 | 1993-08-05 | Smithkline Beecham Corporation | N-benzyloxamic acid, oxamate, and oxamide derivatives and their use as tnf and pde iv inhibitors |
GB9204808D0 (en) | 1992-03-04 | 1992-04-15 | Rhone Poulenc Rorer Ltd | Novel compositions of matter |
US5208235A (en) | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole derivatives |
US5208234A (en) | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Substituted imidazole phosphonic and phosphinic acid derivatives |
US5264437A (en) | 1992-03-20 | 1993-11-23 | Syntex (U.S.A.) Inc. | Optionally substituted pyrido[2,3-d]pyridine-2,4(1H,3H)-diones and pyrido[2,]pyrimidine-2(1H,3H)-ones |
US5605923A (en) | 1992-04-02 | 1997-02-25 | Smithkline Beecham Corporation | Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor |
MX9301943A (es) | 1992-04-02 | 1994-08-31 | Smithkline Beecham Corp | Compuestos. |
WO1993019720A2 (en) | 1992-04-02 | 1993-10-14 | Smithkline Beecham Corporation | Compounds |
US5602173A (en) | 1992-04-02 | 1997-02-11 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
US5552397A (en) | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
US5212195A (en) | 1992-05-13 | 1993-05-18 | Syntex (U.S.A.) Inc. | Substituted indole antagonists derivatives which are angiotensin II |
JP3360079B2 (ja) | 1992-05-15 | 2002-12-24 | メレルダウファーマスーティカルズ インコーポレイテッド | エンケファリナーゼ及びACEの阻害剤として有用な新規なメルカプトアセチルアミドピリダゾ[1,2]ピリダジン、ピラゾロ[1,2]ピリダジン、ピリダゾ[1,2‐a][1,2]ジアゼピン、及びピラゾロ[1,2‐a][1,2]ジアゼピン誘導体類 |
RU2124503C1 (ru) | 1992-05-18 | 1999-01-10 | И.Р.Сквибб энд Санз, Инк. | Гетероциклические азотсодержащие производные карбоновой кислоты, способ их получения и фармацевтическая композиция |
GB9211268D0 (en) | 1992-05-28 | 1992-07-15 | Ici Plc | Salts of basic peptides with carboxyterminated polyesters |
ES2102036T3 (es) | 1992-06-15 | 1997-07-16 | Celltech Therapeutics Ltd | Derivados con grupo fenilo trisustituido utilizados como inhibidores selectivos de la fosfodiesterasa iv. |
US5210204A (en) | 1992-06-16 | 1993-05-11 | Warner-Lambert Company | Biphenyl oxadiazoles and thiadiazoles as angiothesin II antagonists |
FR2692575B1 (fr) | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
US5969097A (en) * | 1992-06-23 | 1999-10-19 | G. D. Searle & Co. | Human guanylin |
JP2657760B2 (ja) | 1992-07-15 | 1997-09-24 | 小野薬品工業株式会社 | 4−アミノキナゾリン誘導体およびそれを含有する医薬品 |
DK0652868T3 (da) | 1992-07-28 | 2005-02-14 | Aventis Pharma Ltd | Hæmmere af c-AMP-phosphodiesterase |
US5185340A (en) | 1992-08-04 | 1993-02-09 | American Home Products Corporation | Pyrimidinyl arylalkyl ethers with antihypertensive activity |
US5741803A (en) | 1992-09-05 | 1998-04-21 | Smithkline Beecham Plc | Substituted thiazolidinedionle derivatives |
DE59309490D1 (de) | 1992-09-14 | 1999-05-06 | Forssmann Wolf Georg Prof Dr | Neue verwendung von inhibitoren der phosphodiesterase iv |
AU5018693A (en) | 1992-09-21 | 1994-04-12 | Upjohn Company, The | Sustained-release protein formulations |
US6472178B1 (en) | 1998-02-27 | 2002-10-29 | Regeneron Pharmaceuticals, Inc. | Nucleic acids encoding a modified ciliary neurotrophic factor and method of making thereof |
US5349056A (en) | 1992-10-09 | 1994-09-20 | Regeneron Pharmaceuticals | Modified ciliary neurotrophic factors |
US5504080A (en) | 1992-10-28 | 1996-04-02 | Bristol-Myers Squibb Co. | Benzo-fused lactams |
CA2400368A1 (en) | 1992-12-02 | 1994-06-09 | Allen J. Duplantier | Catechol diethers as selective pde iv inhibitors |
US5578593A (en) | 1992-12-11 | 1996-11-26 | Merck & Co., Inc. | Spiro piperidines and homologs promote release of growth hormone |
TW263495B (zh) | 1992-12-23 | 1995-11-21 | Celltech Ltd | |
JP3339730B2 (ja) | 1992-12-24 | 2002-10-28 | 忠弘 大見 | 半導体装置 |
US5594016A (en) | 1992-12-28 | 1997-01-14 | Mitsubishi Chemical Corporation | Naphthalene derivatives |
US5672659A (en) | 1993-01-06 | 1997-09-30 | Kinerton Limited | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
PL174772B1 (pl) | 1993-01-06 | 1998-09-30 | Kinerton Ltd | Kompozycja farmaceutyczna zawierająca jonowy konjugat cząsteczkowy |
US5451677A (en) | 1993-02-09 | 1995-09-19 | Merck & Co., Inc. | Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity |
US5358502A (en) | 1993-02-25 | 1994-10-25 | Pfizer Inc | PH-triggered osmotic bursting delivery devices |
US5292736A (en) | 1993-02-26 | 1994-03-08 | Sterling Winthrop Inc. | Morpholinoalkylindenes as antiglaucoma agents |
ATE258685T1 (de) * | 1993-03-09 | 2004-02-15 | Baxter Int | Makromolekulare mikropartikel und verfahren zur ihrer herstellung |
GB9304919D0 (en) | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
US5455252A (en) | 1993-03-31 | 1995-10-03 | Syntex (U.S.A.) Inc. | Optionally substituted 6,8-quinolines |
US5459151A (en) | 1993-04-30 | 1995-10-17 | American Home Products Corporation | N-acyl substituted phenyl piperidines as bronchodilators and antiinflammatory agents |
GB9309324D0 (en) | 1993-05-06 | 1993-06-16 | Bayer Ag | Venzofuranyl-and-thiophenyl-alkanecarboxyclic acids derivatives |
US6191105B1 (en) | 1993-05-10 | 2001-02-20 | Protein Delivery, Inc. | Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin |
GB9311282D0 (en) | 1993-06-01 | 1993-07-21 | Rhone Poulenc Rorer Ltd | New compositions of matter |
US5508272A (en) | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
JPH0710875A (ja) | 1993-06-21 | 1995-01-13 | Green Cross Corp:The | 選択的ホスホジエステラーゼiv阻害剤 |
GB9312853D0 (en) | 1993-06-22 | 1993-08-04 | Euro Celtique Sa | Chemical compounds |
EP0706513B1 (de) | 1993-07-02 | 2002-05-15 | Byk Gulden Lomberg Chemische Fabrik GmbH | Fluoralkoxy substituierte benzamide und ihre verwendung als zyklisch-nukleotid phosphodiesterase-inhibitoren |
CZ3696A3 (en) | 1993-07-06 | 1997-06-11 | Pfizer | Bicyclic tetrahydropyrazolepyridines per se and for treating diseases, and pharmaceutical compositions based thereon |
US5362727A (en) | 1993-07-26 | 1994-11-08 | Bristol-Myers Squibb | Substituted azepino[2,1-a]isoquinoline compounds |
EP0711282B1 (en) | 1993-07-28 | 2002-06-05 | Aventis Pharma Limited | Compounds as pde iv and tnf inhibitors |
GB9315595D0 (en) | 1993-07-28 | 1993-09-08 | Res Inst Medicine Chem | New compounds |
EP0714293A4 (en) | 1993-07-30 | 1999-04-07 | Smithkline Beecham Corp | 3-CYANO-3- (3,4-DISUBSTITUTED) PHENYLCYCLOHEXYL-1-CARBOXYLATE |
JPH09502170A (ja) | 1993-08-19 | 1997-03-04 | スミスクライン・ビーチャム・コーポレイション | フェネチルアミン化合物 |
US5665754A (en) | 1993-09-20 | 1997-09-09 | Glaxo Wellcome Inc. | Substituted pyrrolidines |
AU7957794A (en) | 1993-10-01 | 1995-05-01 | Smithkline Beecham Corporation | Anti-allergic, anti-inflammatory compounds, compositions and uses |
AU7957894A (en) | 1993-10-01 | 1995-05-01 | Smithkline Beecham Corporation | Compounds, compositions and treatment of allergies and inflammation therewith |
WO1995009836A1 (en) | 1993-10-01 | 1995-04-13 | Smithkline Beecham Corporation | Cyanocyclohexane compounds, compositions, and uses thereof |
DE69427485T2 (de) | 1993-10-01 | 2002-04-25 | Smithkline Beecham Corp | Verbindungen, zubereitungen und behandlung von allergien und entzündungen |
US5601990A (en) * | 1994-09-13 | 1997-02-11 | Thomas Jefferson University | Methods of diagnosing colorectal tumors and metastasis thereof |
US5879656A (en) * | 1993-10-26 | 1999-03-09 | Thomas Jefferson University | Methods of treating metastatic colorectal cancer with ST receptor binding compounds |
US5518888A (en) * | 1993-10-26 | 1996-05-21 | Thomas Jefferson University | ST receptor binding compounds and methods of using the same |
CA2174928C (en) * | 1993-10-26 | 2011-08-16 | Scott A. Waldman | Compositions that specifically bind to colorectal cancer cells and methods of using the same |
US5489670A (en) * | 1993-10-29 | 1996-02-06 | G. D. Searle & Co. | Human uroguanylin |
GB9322828D0 (en) | 1993-11-05 | 1993-12-22 | Sandoz Ltd | Organic compounds |
WO1995013801A1 (en) | 1993-11-17 | 1995-05-26 | Commonwealth Scientific And Industrial Research Organisation | Fatty acid delivery system |
US5525723A (en) | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
US5502072A (en) | 1993-11-26 | 1996-03-26 | Pfizer Inc. | Substituted oxindoles |
ATE154932T1 (de) | 1993-11-26 | 1997-07-15 | Pfizer | Isoxazolinverbindungen als entzündungshemmende mittel |
EP0730587B1 (en) | 1993-11-26 | 1999-12-08 | Pfizer Inc. | 3-phenyl-2-isoxazolines as antiinflammatory agents |
FR2714057B1 (fr) | 1993-12-17 | 1996-03-08 | Sanofi Elf | Nouveaux dérivés du 3-pyrazolecarboxamide, procédé pour leur préparation et compositions pharmaceutiques les contenant. |
US5776983A (en) | 1993-12-21 | 1998-07-07 | Bristol-Myers Squibb Company | Catecholamine surrogates useful as β3 agonists |
GB9326600D0 (en) | 1993-12-22 | 1994-03-02 | Celltech Ltd | Chemical compounds |
ATE260911T1 (de) | 1993-12-22 | 2004-03-15 | Celltech R&D Ltd | Trisubstituierte phenyl-derivate, verfahren zu deren herstellung und deren verwendung als phosphodiesterase (typ iv) hemmstoffe |
US5508300A (en) | 1994-01-14 | 1996-04-16 | Pfizer Inc. | Dihydro pyrazolopyrroles, compositions and use |
JP2928079B2 (ja) | 1994-02-14 | 1999-07-28 | 永信薬品工業股▲ふん▼有限公司 | 1−(置換ベンジル)−3−(置換アリール)縮合ピラゾール類、その製造法及びその用途 |
NZ279689A (en) | 1994-02-17 | 1997-08-22 | American Home Prod | Substituted biphenyl derivatives, preparation and pharmaceutical compositions thereof |
CA2143143A1 (en) | 1994-03-08 | 1995-09-09 | Toshihiko Tanaka | 3-phenylpyrrolidine derivatives |
GB9404706D0 (en) | 1994-03-11 | 1994-04-27 | Smithkline Beecham Corp | Compounds |
US5952314A (en) | 1994-04-01 | 1999-09-14 | Demichele; Stephen Joseph | Nutritional product for a person having ulcerative colitis |
WO1995027692A1 (en) | 1994-04-08 | 1995-10-19 | Smithkline Beecham Corporation | Subtituted biphenyl tnf inhibitors |
US5610145A (en) | 1994-04-15 | 1997-03-11 | Warner-Lambert Company | Tachykinin antagonists |
CA2188269A1 (en) | 1994-04-21 | 1995-11-02 | Helmut Wachtel | Pde iv inhibitors for treating multiple sclerosis |
DE69535432T2 (de) | 1994-04-22 | 2007-12-06 | Astellas Pharma Inc. | Kolon-spezifisches Arzneistofffreisetzungssystem |
US5705515A (en) | 1994-04-26 | 1998-01-06 | Merck & Co., Inc. | Substituted sulfonamides as selective β-3 agonists for the treatment of diabetes and obesity |
IL113410A (en) | 1994-04-26 | 1999-11-30 | Merck & Co Inc | Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them |
ES2127966T3 (es) | 1994-05-31 | 1999-05-01 | Bayer Ag | Derivados de amino-benzofurilo y -benzotienilo. |
GB9410877D0 (en) | 1994-05-31 | 1994-07-20 | Bayer Ag | Heterocyclycarbonyl substituted benzoduranyl-and-thiophenyl-alkanecarboxyclic acid derivatives |
HRP950288A2 (en) | 1994-05-31 | 1997-08-31 | Bayer Ag | Oxalylamino-benzofuran- and benzothienyl-derivatives |
GB9412383D0 (en) | 1994-06-21 | 1994-08-10 | Celltech Ltd | Chemical compound |
US5786354A (en) | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
MX9700068A (es) | 1994-06-24 | 1997-12-31 | Euro Celtique Sa | Compuestos y metodo para inhibir a la fosfodiesterasa iv. |
US5466697A (en) | 1994-07-13 | 1995-11-14 | Syntex (U.S.A.) Inc. | 8-phenyl-1,6-naphthyridin-5-ones |
US6121274A (en) | 1994-07-22 | 2000-09-19 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Dihydrobenzofurane |
US5612359A (en) | 1994-08-26 | 1997-03-18 | Bristol-Myers Squibb Company | Substituted biphenyl isoxazole sulfonamides |
US5491134A (en) | 1994-09-16 | 1996-02-13 | Bristol-Myers Squibb Company | Sulfonic, phosphonic or phosphiniic acid β3 agonist derivatives |
WO1996011917A1 (en) | 1994-10-12 | 1996-04-25 | Euro-Celtique, S.A. | Novel benzoxazoles |
BR9509610A (pt) | 1994-11-07 | 1997-10-28 | Pfizer | Ligandos específicos de neuropeptideo Y1 |
US5541204A (en) | 1994-12-02 | 1996-07-30 | Bristol-Myers Squibb Company | Aryloxypropanolamine β 3 adrenergic agonists |
US5902726A (en) | 1994-12-23 | 1999-05-11 | Glaxo Wellcome Inc. | Activators of the nuclear orphan receptor peroxisome proliferator-activated receptor gamma |
US5843866A (en) | 1994-12-30 | 1998-12-01 | Hampshire Chemical Corp. | Pesticidal compositions comprising solutions of polyurea and/or polyurethane |
DE19501481A1 (de) | 1995-01-19 | 1996-07-25 | Bayer Ag | 2,8-Disubstituierte Chinazolinone |
US5559208A (en) | 1995-01-31 | 1996-09-24 | Eli Lilly And Company | Anti-obesity proteins |
CA2211656A1 (en) | 1995-01-31 | 1996-08-08 | Margret B. Basinski | Anti-obesity proteins |
WO1996023515A1 (en) | 1995-01-31 | 1996-08-08 | Eli Lilly And Company | Anti-obesity proteins |
US5521283A (en) | 1995-01-31 | 1996-05-28 | Eli Lilly And Company | Anti-obesity proteins |
US5554727A (en) | 1995-01-31 | 1996-09-10 | Eli Lilly And Company | Anti-obesity proteins |
US5552524A (en) | 1995-01-31 | 1996-09-03 | Eli Lilly And Company | Anti-obesity proteins |
US5552523A (en) | 1995-01-31 | 1996-09-03 | Eli Lilly And Company | Anti-obesity proteins |
US5552522A (en) | 1995-01-31 | 1996-09-03 | Eli Lilly And Company | Anti-obesity proteins |
US5605886A (en) | 1995-01-31 | 1997-02-25 | Eli Lilly And Company | Anti-obesity proteins |
US5532237A (en) | 1995-02-15 | 1996-07-02 | Merck Frosst Canada, Inc. | Indole derivatives with affinity for the cannabinoid receptor |
US5612052A (en) | 1995-04-13 | 1997-03-18 | Poly-Med, Inc. | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
US5831115A (en) | 1995-04-21 | 1998-11-03 | Abbott Laboratories | Inhibitors of squalene synthase and protein farnesyltransferase |
US20020006964A1 (en) | 1995-05-16 | 2002-01-17 | Young James W. | Methods of using and compositions comprising (+) sibutramine optionally in combination with other pharmacologically active compounds |
US5824638A (en) | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
US5739106A (en) | 1995-06-07 | 1998-04-14 | Rink; Timothy J. | Appetite regulating compositions |
TW438587B (en) | 1995-06-20 | 2001-06-07 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
US5795864A (en) | 1995-06-27 | 1998-08-18 | Neurex Corporation | Stable omega conopetide formulations |
US6054429A (en) | 1996-03-08 | 2000-04-25 | Elan Pharmaceuticals, Inc. | Epidural method of producing analgesia |
PT835126E (pt) | 1995-06-27 | 2003-07-31 | Elan Pharm Inc | Composicoes e formulacoes para a producao de analgesia e para a inibicao de patologias dolorosas neuropaticas |
US5877224A (en) | 1995-07-28 | 1999-03-02 | Rutgers, The State University Of New Jersey | Polymeric drug formulations |
WO1997010813A1 (en) | 1995-09-18 | 1997-03-27 | Ligand Pharmaceuticals Incorporated | Ppar gamma antagonists for treating obesity |
AUPN634595A0 (en) | 1995-11-03 | 1995-11-30 | Borody, Thomas Julius | Improved method for colonic evacuation |
FR2741621B1 (fr) | 1995-11-23 | 1998-02-13 | Sanofi Sa | Nouveaux derives de pyrazole, procede pour leur preparation et compositions pharmaceutiques en contenant |
US6277862B1 (en) | 1995-11-24 | 2001-08-21 | Smithkline Beecham S.P.A. | Quinoline derivatives |
GB9524104D0 (en) | 1995-11-24 | 1996-01-24 | Smithkline Beecham Spa | Novel compounds |
US6482927B1 (en) | 1995-11-27 | 2002-11-19 | Millennium Pharmaceuticals, Inc. | Chimeric proteins comprising the extracellular domain of murine Ob receptor |
WO1997020823A2 (en) | 1995-12-01 | 1997-06-12 | Novartis Ag | 2-amino quinazoline derivatives as npy receptor antagonists |
WO1997020821A1 (en) | 1995-12-01 | 1997-06-12 | Novartis Ag | Heteroaryl derivatives |
AU7626496A (en) | 1995-12-01 | 1997-06-27 | Ciba-Geigy Ag | Heteroaryl compounds |
AU7692896A (en) | 1995-12-01 | 1997-06-27 | Novartis Ag | Quinazolin-2,4-diazirines as NPY receptor antagonist |
WO1997019682A1 (en) | 1995-12-01 | 1997-06-05 | Synaptic Pharmaceutical Corporation | Aryl sulfonamide and sulfamide derivatives and uses thereof |
US6236946B1 (en) | 1995-12-13 | 2001-05-22 | Thomas S. Scanlan | Nuclear receptor ligands and ligand binding domains |
TW432073B (en) | 1995-12-28 | 2001-05-01 | Pfizer | Pyrazolopyridine compounds |
US5980945A (en) | 1996-01-16 | 1999-11-09 | Societe De Conseils De Recherches Et D'applications Scientifique S.A. | Sustained release drug formulations |
AU721452B2 (en) | 1996-02-02 | 2000-07-06 | Merck & Co., Inc. | Antidiabetic agents |
EP0904079B1 (en) | 1996-02-02 | 2004-03-24 | Merck & Co., Inc. | Antidiabetic agents |
ES2241036T3 (es) | 1996-02-02 | 2005-10-16 | MERCK & CO., INC. | Procedimiento de tratamiento de diabetes y estados patologicos asociados. |
AU708055B2 (en) | 1996-02-02 | 1999-07-29 | Merck & Co., Inc. | Heterocyclic derivatives as antidiabetic and antiobesity agents |
KR19990082330A (ko) | 1996-02-06 | 1999-11-25 | 미즈노 마사루 | 신규 화합물 및 이의 의약 용도 |
US5912014A (en) | 1996-03-15 | 1999-06-15 | Unigene Laboratories, Inc. | Oral salmon calcitonin pharmaceutical products |
US5770615A (en) | 1996-04-04 | 1998-06-23 | Bristol-Myers Squibb Company | Catecholamine surrogates useful as β3 agonists |
CA2250981C (en) | 1996-04-23 | 2002-07-02 | Kinerton Limited | Acidic polylactic polymers |
AU712057B2 (en) | 1996-06-07 | 1999-10-28 | Merck & Co., Inc. | Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity |
WO1998005331A2 (en) | 1996-08-02 | 1998-02-12 | Ligand Pharmaceuticals Incorporated | Prevention or treatment of type 2 diabetes or cardiovascular disease with ppar modulators |
US5861398A (en) | 1996-08-26 | 1999-01-19 | Alanex Corporation | Benzoperimidine-carboxylic acids and derivatives thereof |
AU717633B2 (en) | 1996-09-09 | 2000-03-30 | Kiwitech Limited | Acid casein or a non-toxic soluble salt thereof and high-methoxyl pectin polymer |
AU4176997A (en) | 1996-09-16 | 1998-04-02 | Warner-Lambert Company | 3-alkyl-3-phenyl-piperidines |
US5972389A (en) | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
HRP970493A2 (en) | 1996-09-23 | 1998-08-31 | Wienman E. Phlips | Oral delayed immediate release medical formulation and method for preparing the same |
CA2217134A1 (en) | 1996-10-09 | 1998-04-09 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release formulation |
US6331543B1 (en) | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
IT1288388B1 (it) | 1996-11-19 | 1998-09-22 | Angeletti P Ist Richerche Bio | Uso di sostanze che attivano il recettore del cntf ( fattore neurotrofico ciliare) per la preparazione di farmaci per la terapia |
US5968895A (en) | 1996-12-11 | 1999-10-19 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
CA2274594C (en) | 1996-12-16 | 2006-10-10 | Banyu Pharmaceutical Co., Ltd. | Aminopyrazole derivatives |
EP0971588B1 (en) | 1997-01-21 | 2004-03-17 | Smithkline Beecham Corporation | Novel cannabinoid receptor modulators |
BR9807096A (pt) | 1997-01-28 | 2000-04-18 | Merck & Co Inc | Composto, processos para o tratamento do diabetes, da obesidade em um mamìfero, para reduzir nìveis de triglicerìdeos e nìveis de colesterol ou elevar nìveis de lipoproteìnas de alta densidade, para diminuir a motilidade do intestino, para reduzir inflamação neurogênica das vias aéreas e a depressão e para tratar distúrbios gastrintestinais, e, composições para o tratamento dos distúrbios acima e farmacêutica |
CN1982290A (zh) | 1997-02-04 | 2007-06-20 | 阿肯色大学评议会 | 杀菌的羧酰胺 |
US6589750B2 (en) | 1997-02-20 | 2003-07-08 | Institut Pasteur | Therapeutic use of the SMR1 protein, the SMR1 maturation products, specifically the QHNPR pentapeptide as well as its biologically active derivatives |
DK0966436T3 (da) | 1997-02-21 | 2003-03-31 | Bayer Ag | Arylsulfonamider og analoger deraf og anvendelse deraf til behandling af neurodegenerative lidelser |
US6153632A (en) | 1997-02-24 | 2000-11-28 | Rieveley; Robert B. | Method and composition for the treatment of diabetes |
US5893985A (en) | 1997-03-14 | 1999-04-13 | The Lincoln Electric Company | Plasma arc torch |
WO1998041519A1 (en) | 1997-03-18 | 1998-09-24 | Smithkline Beecham Corporation | Novel cannabinoid receptor agonists |
JPH10324642A (ja) | 1997-03-26 | 1998-12-08 | Meiji Seika Kaisha Ltd | 大腸送達性構造体 |
FR2761265B1 (fr) | 1997-03-28 | 1999-07-02 | Sanofi Sa | Composition pharmaceutique pour l'administration orale d'un derive du n-piperidino-3-pyrazolecarboxamide, de ses sels et de leurs solvates |
FR2761266B1 (fr) | 1997-03-28 | 1999-07-02 | Sanofi Sa | Composition pharmaceutique formee par granulation humide pour l'administration orale d'un derive du n-piperidino-3- pyrazolecarboxamide, de ses sels et de leurs solvates |
NZ329807A (en) | 1997-04-23 | 2000-07-28 | Pfizer | NK-1 receptor antagonists and P receptor antagonists 2-Diarylmethyl-3-amino-1-azabicyclo[2.2.2]octane derivatives and amino substituted N-containing rings as agents for treating irritable bowel syndrome |
CA2288122C (en) | 1997-04-23 | 2006-09-26 | Banyu Pharmaceutical Co., Ltd. | Neuropeptide y receptor antagonist |
JP2001523245A (ja) | 1997-04-24 | 2001-11-20 | メルク シヤープ エンド ドーム リミテツド | 肥満を治療するためのnk−1受容体拮抗薬およびssriの使用 |
US6001836A (en) | 1997-05-28 | 1999-12-14 | Bristol-Myers Squibb Company | Dihydropyridine NPY antagonists: cyanoguanidine derivatives |
SE9702457D0 (sv) | 1997-06-26 | 1997-06-26 | Pharmacia & Upjohn Ab | Screening |
GB9713739D0 (en) | 1997-06-27 | 1997-09-03 | Karobio Ab | Thyroid receptor ligands |
KR20010021696A (ko) | 1997-07-11 | 2001-03-15 | 미즈노 마사루 | 퀴놀린 화합물 및 그의 의약용도 |
EP1012188B1 (de) | 1997-09-12 | 2004-08-18 | Pharis Biotec GmbH | Zusammensetzung zur therapie von diabetes mellitus und fettsucht |
DE19744027A1 (de) | 1997-10-06 | 1999-04-08 | Hoechst Marion Roussel De Gmbh | Substituierte Pyrazolo[3,4-b]pyridine, ihre Herstellung und Verwendung in Arzneimitteln |
US6440961B1 (en) | 1997-10-27 | 2002-08-27 | Dr. Reddy's Research Foundation | Tricyclic compounds and their use in medicine: process for their preparation and pharmaceutical compositions containing them |
WO1999019313A1 (en) | 1997-10-27 | 1999-04-22 | Dr. Reddy's Research Foundation | Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them |
AU1198699A (en) | 1997-10-27 | 1999-04-23 | Dr. Reddy's Research Foundation | Novel heterocyclic compounds and their use in medicine, process for their reparation and pharmaceutical compositions containing them |
US6203513B1 (en) | 1997-11-20 | 2001-03-20 | Optonol Ltd. | Flow regulating implant, method of manufacture, and delivery device |
EP1051403A1 (en) | 1998-01-29 | 2000-11-15 | Dr. Reddy's Research Foundation | Novel alkanoic acids and their use in medicine, process for their preparation and pharmaceutical compositions containing them |
AU766219B2 (en) | 1998-02-02 | 2003-10-09 | 1149336 Ontario Inc. | Method of regulating glucose metabolism, and reagents related thereto |
JP2002506075A (ja) | 1998-03-09 | 2002-02-26 | フォンダテッヒ・ベネルクス・ナムローゼ・フェンノートシャップ | セリンペプチダーゼ調節剤 |
AU3464599A (en) | 1998-04-02 | 1999-10-25 | Neurogen Corporation | Aminoalkyl substituted 9h-pyridino(2,3-b)indole and 9h-pyrimidino(4,5-b)indole derivatives |
US20010006972A1 (en) | 1998-04-21 | 2001-07-05 | Stephen A. Williams | Nk-1 receptor antagonists for the treatment of symptoms of irritable bowel syndrome |
JP2004503462A (ja) | 1998-04-29 | 2004-02-05 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | 肥満症及び他の障害の処置において有用な神経ペプチドyy5レセプターのためのリガンドとしてのn−置換アミノテトラリン |
JP2002514639A (ja) | 1998-05-12 | 2002-05-21 | アメリカン・ホーム・プロダクツ・コーポレイション | ナフト[2,3−b]ヘテロアリー−4−イル誘導体 |
JP2002514635A (ja) | 1998-05-12 | 2002-05-21 | アメリカン・ホーム・プロダクツ・コーポレイション | インスリン耐性および高血糖の処置に有用なビフェニルオキソ−酢酸 |
CN1308627A (zh) | 1998-05-12 | 2001-08-15 | 美国家用产品公司 | 可用于治疗胰岛素抗性和高血糖的11-芳基-苯并[b]萘并[2,3-d]呋喃和11-芳基-苯并[b]萘并[2,3-d]噻吩 |
PL344081A1 (en) | 1998-05-12 | 2001-09-24 | American Home Prod | Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia |
EP1082313A1 (en) | 1998-05-27 | 2001-03-14 | Dr. Reddy's Research Foundation | Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them |
DE19823831A1 (de) | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
US6329395B1 (en) | 1998-06-08 | 2001-12-11 | Schering Corporation | Neuropeptide Y5 receptor antagonists |
CA2334551A1 (en) | 1998-06-11 | 1999-12-16 | Merck & Co., Inc. | Spiropiperidine derivatives as melanocortin receptor agonists |
DE19828113A1 (de) | 1998-06-24 | 2000-01-05 | Probiodrug Ges Fuer Arzneim | Prodrugs von Inhibitoren der Dipeptidyl Peptidase IV |
DE19828114A1 (de) | 1998-06-24 | 2000-01-27 | Probiodrug Ges Fuer Arzneim | Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV |
DE19830375A1 (de) | 1998-07-08 | 2000-01-13 | K D Pharma Bexbach Gmbh | Mikroverkapselte ungesättigte Fettsäure oder Fettsäureverbindung oder Mischung aus Fettsäuren und/oder Fettsäureverbindungen |
DE19837627A1 (de) | 1998-08-19 | 2000-02-24 | Bayer Ag | Neue Aminosäureester von Arylsulfonamiden und Analoga |
HN1998000027A (es) | 1998-08-19 | 1999-06-02 | Bayer Ip Gmbh | Arilsulfonamidas y analagos |
US6358951B1 (en) | 1998-08-21 | 2002-03-19 | Pfizer Inc. | Growth hormone secretagogues |
DE69926764T2 (de) | 1998-09-10 | 2006-06-29 | Millennium Pharmaceuticals, Inc., Cambridge | Methoden zur bestimmung von komponenten zur modulation des körpergewichts |
US6337332B1 (en) | 1998-09-17 | 2002-01-08 | Pfizer Inc. | Neuropeptide Y receptor antagonists |
DE19844547C2 (de) | 1998-09-29 | 2002-11-07 | Aventis Pharma Gmbh | Polycyclische Dihydrothiazole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US6531152B1 (en) | 1998-09-30 | 2003-03-11 | Dexcel Pharma Technologies Ltd. | Immediate release gastrointestinal drug delivery system |
DK1121111T3 (da) | 1998-10-15 | 2010-05-31 | Imp Innovations Ltd | Forbindelser til behandling af vægttab |
AU6325599A (en) | 1998-10-21 | 2000-05-08 | Dr. Reddy's Research Foundation | New compounds, their preparation and use |
US6353018B1 (en) | 1998-10-21 | 2002-03-05 | Novo Nordisk A/S | Compounds, their preparation and use |
EP1123269A1 (en) | 1998-10-21 | 2001-08-16 | Novo Nordisk A/S | New compounds, their preparation and use |
DE69929235T2 (de) | 1998-11-10 | 2006-08-24 | Merck & Co., Inc. | Spiro-indole als y5-rezeptor antagonisten |
US6235782B1 (en) * | 1998-11-12 | 2001-05-22 | Rifat Pamukcu | Method for treating a patient with neoplasia by treatment with a platinum coordination complex |
IT1304152B1 (it) | 1998-12-10 | 2001-03-08 | Mediolanum Farmaceutici Srl | Composizioni comprendenti un peptide ed acido polilattico-glicolicoatte alla preparazione di impianti sottocutanei aventi un prolungato |
ES2161594B1 (es) | 1998-12-17 | 2003-04-01 | Servier Lab | Nuevos derivados de la hidrazida, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen. |
DE19903087A1 (de) * | 1999-01-27 | 2000-08-10 | Forssmann Wolf Georg | Behandlung von erektilen Dysfunktionen mit C-Typ Natriuretischem Polypeptid (CNP) als Monotherapie oder in Kombination mit Phosphodiesterasehemmern |
US6344481B1 (en) | 1999-03-01 | 2002-02-05 | Pfizer Inc. | Thyromimetic antiobesity agents |
EP1178789B1 (en) | 1999-03-19 | 2008-07-16 | Abbott GmbH & Co. KG | Method of treating eating disorders |
IL145661A0 (en) | 1999-03-31 | 2002-06-30 | Janssen Pharmaceutica Nv | Pregelatinized starch in a controlled release formulation |
US6548529B1 (en) | 1999-04-05 | 2003-04-15 | Bristol-Myers Squibb Company | Heterocyclic containing biphenyl aP2 inhibitors and method |
FR2792314B1 (fr) | 1999-04-15 | 2001-06-01 | Adir | Nouveaux composes aminotriazoles, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US6218408B1 (en) | 1999-06-30 | 2001-04-17 | Synaptic Pharmaceutical Corporation | Selective NPY (Y5) antagonists (bicyclics) |
DK1183245T3 (da) | 1999-04-22 | 2007-09-24 | Lundbeck & Co As H | Selektive NPY(Y5)-antagonister |
US6340683B1 (en) | 1999-04-22 | 2002-01-22 | Synaptic Pharmaceutical Corporation | Selective NPY (Y5) antagonists (triazines) |
MXPA01011321A (es) | 1999-05-05 | 2003-08-01 | Johnson & Johnson | Neuropeptidos y ligandos de receptores 3a, 4, 5, 9b-tetrahidro-1h-benz(e)indol-2-il amino derivados utiles en el tratamiento de obesidad y otros trastornos. |
DE60023128T2 (de) | 1999-05-12 | 2006-07-06 | Ortho-Mcneil Pharmaceutical, Inc. | Pyrazolcarboxamide zur behandlung von fettleibigkeit und anderen erkrankungen |
EP1187614A4 (en) | 1999-06-04 | 2005-06-22 | Merck & Co Inc | SUBSTITUTED PIPERIDINES THAN MELANOCORTIN-4 RECEPTOR AGONISTS |
GB9913782D0 (en) | 1999-06-14 | 1999-08-11 | Smithkline Beecham Plc | Novel compounds |
US6552017B1 (en) | 1999-06-15 | 2003-04-22 | Bristol-Myers Squibb Pharma Company | Substituted heterocycle fused gamma-carbolines |
US6207699B1 (en) | 1999-06-18 | 2001-03-27 | Richard Brian Rothman | Pharmaceutical combinations for treating obesity and food craving |
US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
PT1593387E (pt) | 1999-06-23 | 2009-03-18 | Pasteur Institut | Composições para o tratamento de desordens comportamentais e deficiências interpessoais. |
AU1186401A (en) | 1999-06-23 | 2001-01-22 | Sedum Laboratories, Inc. | Ionically formulated biomolecule microcarriers |
CA2380866A1 (en) | 1999-06-30 | 2001-01-11 | Synaptic Pharmaceutical Corporation | Selective npy (y5) antagonists |
ES2437103T3 (es) | 1999-06-30 | 2014-01-08 | Amgen Inc. | Compuestos para la modulacion de la actividad de PPAR gamma |
WO2001007409A1 (en) | 1999-07-23 | 2001-02-01 | Astrazeneca Uk Limited | Carbazole derivatives and their use as neuropeptide y5 receptor ligands |
US6380224B1 (en) | 1999-07-28 | 2002-04-30 | Ortho-Mcneil Pharmaceutical, Inc. | Amine and amide derivatives as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders |
WO2001012233A2 (en) | 1999-08-18 | 2001-02-22 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Sustained release formulation of a peptide |
TWI279402B (en) | 1999-08-20 | 2007-04-21 | Banyu Pharma Co Ltd | Spiro compounds having NPY antagonistic activities and agents containing the same |
EP1206262A4 (en) | 1999-08-26 | 2003-01-02 | Bristol Myers Squibb Co | Y NEUROPEPTID ANTAGONISTS: SPIROISOQUINOLINONE DERIVATIVES |
EP1227134B1 (en) | 1999-08-31 | 2006-10-04 | Daikin Industries, Ltd. | Polymer composition crosslinkable with ultraviolet |
SE9903291D0 (sv) | 1999-09-15 | 1999-09-15 | Astra Ab | New process |
EP1219294A4 (en) | 1999-09-20 | 2005-01-26 | ANTAGONISTS OF THE MELANIN CONCENTRATING HORMON | |
CZ20021089A3 (cs) | 1999-09-30 | 2002-11-13 | Neurogen Corporation | Aminosustituované pyrazolo[1,5-a]-1,5-pyrimidiny a pyrazolo[1,5-a]-1,3,5-triaziny |
EA200200424A1 (ru) | 1999-09-30 | 2002-12-26 | Ньюроджен Корпорейшн | Некоторые гетероциклы, замещенные алкилендиамином |
HUP0202678A3 (en) | 1999-09-30 | 2004-06-28 | Pfizer | Certain alkylene diamine-substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines, pharmaceutical compositions containing them and their use |
JP2003516316A (ja) | 1999-10-06 | 2003-05-13 | ファルマシア コーポレイション | 腸癌阻止剤としてのウログアニリン |
AU7802700A (en) | 1999-10-06 | 2001-05-10 | Melacure Therapeutics Ab | Guanidine derivatives and their use in the production of a medicament for blocking xanthine oxidase/dehydrogenase |
PH12000002657B1 (en) | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
US6515117B2 (en) | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
DE19949319A1 (de) | 1999-10-13 | 2001-06-13 | Ruetgers Vft Ag | Verfahren zur Herstellung von Arylalkylethern |
AU769430B2 (en) | 1999-10-13 | 2004-01-29 | Pfizer Products Inc. | Biaryl ether derivatives useful as monoamine reuptake inhibitors |
DE60013630T2 (de) | 1999-11-01 | 2005-09-15 | John Cardiff Rhodes | Arzneimittel zur behandlung von darmverstopfung und reizkolon |
DK1230230T3 (da) | 1999-11-05 | 2003-12-15 | Aventis Pharma Gmbh | Derivater af indeno-dihydrothiazol, fremstilling deraf og anvendelse som anorektiske lægemidler |
US6444687B1 (en) | 1999-12-16 | 2002-09-03 | Schering Corporation | Substituted imidazole neuropeptide Y Y5 receptor antagonists |
FR2802817B1 (fr) | 1999-12-23 | 2002-10-11 | Centre Nat Rech Scient | Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete |
JP4917726B2 (ja) | 1999-12-31 | 2012-04-18 | ルトガーズ、ザ ステイト ユニバーシティ オブ ニュージャージー | ポリマー混合物および活性化合物からなる徐放用医薬製剤 |
AU784226B2 (en) | 1999-12-31 | 2006-02-23 | Rutgers, The State University | Pharmaceutical formulation for regulating the timed release of biologically active compounds based on a polymer matrix |
US7521061B2 (en) | 1999-12-31 | 2009-04-21 | Rutgers, The State University Of New Jersey | Pharmaceutical formulation for regulating the timed release of biologically active compounds based on a polymer matrix |
US20030064105A1 (en) | 2000-08-25 | 2003-04-03 | Myung-Jin Kim | Lipophilic-coated microparticle containing a protein drug and formulation comprising same |
AUPQ514600A0 (en) | 2000-01-18 | 2000-02-10 | James Cook University | Brain injury treatment |
WO2001052880A1 (en) | 2000-01-18 | 2001-07-26 | Merck & Co., Inc. | Cyclic peptides as potent and selective melanocortin-4 receptor antagonists |
US6645959B1 (en) | 2000-01-26 | 2003-11-11 | Warner-Lambert Company | Method for treating postoperative ileus |
AU2001228325A1 (en) | 2000-02-01 | 2001-08-14 | Novo-Nordisk A/S | Use of compounds for the regulation of food intake |
JP2004502642A (ja) | 2000-02-11 | 2004-01-29 | ブリストル−マイヤーズ スクイブ カンパニー | カンナビノイドレセプターモジュレーター、それらの製造方法、および呼吸系および非呼吸系疾患の処置のためのカンナビノイドレセプターモジュレーターの使用 |
JP2001226269A (ja) | 2000-02-18 | 2001-08-21 | Takeda Chem Ind Ltd | メラニン凝集ホルモン拮抗剤 |
AU2001234128B2 (en) | 2000-02-22 | 2004-11-11 | Banyu Pharmaceutical Co., Ltd. | Novel imidazoline compounds |
GB0004003D0 (en) | 2000-02-22 | 2000-04-12 | Knoll Ag | Therapeutic agents |
AU781003B2 (en) | 2000-02-23 | 2005-04-28 | Aventis Pharma Deutschland Gmbh | 8,8A-dihydro-indeno(1,2-D)thiazole derivatives, substituted in position 8A, a method for their production and their use as medicaments, e.g. anorectic agents |
US6531478B2 (en) | 2000-02-24 | 2003-03-11 | Cheryl P. Kordik | Amino pyrazole derivatives useful for the treatment of obesity and other disorders |
RS49933B (sr) | 2000-02-26 | 2008-09-29 | Sanofi-Aventis Deutschland Gmbh., | Derivati 8,8a-dihidro-indeno/1,2-d/tiazola,koji sadrže u 2 položaju supstituent sa sulfonamidnom ili sulfonskom strukturom, postupak za njihovu proizvodnju i njihova primena kao medikamenata |
AU3580001A (en) | 2000-03-01 | 2001-09-12 | University College London | Modulators of the endocannabinoid uptake and of the vallinoid receptors |
FR2805817B1 (fr) | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Compositions pharmaceutiques contenant des derives d'azetidine, les nouveaux derives d'azetidine et leur preparation |
FR2805818B1 (fr) | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant |
FR2805810B1 (fr) | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Compositions pharmaceutiques contenant des derives de 3- amino-azetidine, les nouveaux derives et leur preparation |
EP1132389A1 (en) | 2000-03-06 | 2001-09-12 | Vernalis Research Limited | New aza-indolyl derivatives for the treatment of obesity |
US6703392B2 (en) | 2000-03-14 | 2004-03-09 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
JP2003527444A (ja) | 2000-03-23 | 2003-09-16 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン受容体アゴニストとして作用するスピロピペリジン誘導体 |
EP1268449A4 (en) | 2000-03-23 | 2004-09-15 | Merck & Co Inc | SUBSTITUTED PIPERIDINE AS MELANOCORTIN RECEPTOR AGONISTS |
CN1205188C (zh) | 2000-03-23 | 2005-06-08 | 索尔瓦药物有限公司 | 具有cb1-拮抗活性的4,5-二氢-1h-吡唑衍生物 |
US6600015B2 (en) | 2000-04-04 | 2003-07-29 | Hoffmann-La Roche Inc. | Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity |
PH12001000675B1 (en) | 2000-04-04 | 2009-09-22 | Australian Food Ind Sci Ct | Encapsulation of food ingredients |
EP1142886A1 (en) | 2000-04-07 | 2001-10-10 | Aventis Pharma Deutschland GmbH | Percyquinnin, a process for its production and its use as a pharmaceutical |
ES2263604T5 (es) | 2000-04-10 | 2017-02-07 | Nicholas John Wald | Formulación para la Prevención de Enfermedad Cardiovascular |
AU2001248279A1 (en) | 2000-04-17 | 2001-10-30 | Novo-Nordisk A/S | New compounds, their preparation and use |
AU2001257146B2 (en) | 2000-04-19 | 2006-11-30 | Johns Hopkins University | Methods for prevention and treatment of gastrointestinal disorders |
WO2001082925A1 (fr) | 2000-04-28 | 2001-11-08 | Takeda Chemical Industries, Ltd. | Antagonistes de l'hormone concentrant la melanine |
GB0010757D0 (en) | 2000-05-05 | 2000-06-28 | Astrazeneca Ab | Chemical compounds |
GB0011013D0 (en) | 2000-05-09 | 2000-06-28 | Astrazeneca Ab | Chemical compounds |
US6432960B2 (en) | 2000-05-10 | 2002-08-13 | Bristol-Myers Squibb Company | Squarate derivatives of dihydropyridine NPY antagonists |
AU2001263021A1 (en) | 2000-05-10 | 2001-11-20 | Bristol-Myers Squibb Company | Alkylamine derivatives of dihydropyridine npy antagonists |
US6444675B2 (en) | 2000-05-10 | 2002-09-03 | Bristol-Myers Squibb Company | 4-alkyl and 4-cycloalkyl derivatives of dihydropyridine NPY antagonists |
ES2252230T3 (es) | 2000-05-11 | 2006-05-16 | Bristol-Myers Squibb Company | Analogos de tetrahidroisoquinolina utiles como secretores de la hormona del crecimiento. |
US7229986B2 (en) | 2000-05-16 | 2007-06-12 | Takeda Pharmaceutical Company Ltd. | Melanin-concentrating hormone antagonist |
AU2001259056A1 (en) | 2000-05-17 | 2001-11-26 | Eli Lilly And Company | Method for selectively inhibiting ghrelin action |
US6391881B2 (en) | 2000-05-19 | 2002-05-21 | Bristol-Myers Squibb Company | Thiourea derivatives of dihydropyridine NPY antagonists |
SE0001899D0 (sv) | 2000-05-22 | 2000-05-22 | Pharmacia & Upjohn Ab | New compounds |
AU6497701A (en) | 2000-05-30 | 2001-12-11 | Merck & Co Inc | Melanocortin receptor agonists |
SK287026B6 (sk) | 2000-06-15 | 2009-10-07 | Schering Corporation | Nor-seko-himbacínové deriváty, farmaceutický prostriedok s ich obsahom a ich použitie |
JP4611608B2 (ja) | 2000-06-16 | 2011-01-12 | スミスクライン ビーチャム ピー エル シー | オレキシン受容体アンタゴニストとして使用するためのピペリジン |
AU783403B2 (en) | 2000-07-05 | 2005-10-20 | H. Lundbeck A/S | Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof |
JP2004516239A (ja) | 2000-07-06 | 2004-06-03 | ニューロジェン コーポレイション | メラニン凝集ホルモン受容体リガンド |
GB0019357D0 (en) | 2000-08-07 | 2000-09-27 | Melacure Therapeutics Ab | Novel phenyl guanidines |
MXPA03000308A (es) | 2000-07-13 | 2003-06-06 | Lilly Co Eli | Agonistas beta3 adrenergicos. |
AU2001283938A1 (en) | 2000-07-24 | 2002-02-05 | Ardana Bioscience Limited | Ghrelin antagonists |
AU2001283955B2 (en) | 2000-07-31 | 2006-05-18 | F. Hoffmann-La Roche Ag | Piperazine derivatives |
US6768024B1 (en) | 2000-08-04 | 2004-07-27 | Lion Bioscience Ag | Triamine derivative melanocortin receptor ligands and methods of using same |
GB0019359D0 (en) | 2000-08-07 | 2000-09-27 | Melacure Therapeutics Ab | Novel guanidines |
WO2003024953A1 (fr) | 2000-08-10 | 2003-03-27 | Nisshin Pharma Inc. | Derive de propanolamine a noyau 1,4-benzodioxane |
US6680340B2 (en) | 2000-08-21 | 2004-01-20 | Merck & Co., Inc. | Anti-hypercholesterolemic drug combination |
EP1320364A1 (en) | 2000-08-21 | 2003-06-25 | Gliatech, Inc. | The use of histamine h3-receptor inverse agonists for the control of appetite and treatment of obesity |
JP2004506687A (ja) | 2000-08-23 | 2004-03-04 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン受容体作働薬としての置換ピペリジン類 |
US20020037829A1 (en) | 2000-08-23 | 2002-03-28 | Aronson Peter S. | Use of DPPIV inhibitors as diuretic and anti-hypertensive agents |
US6900226B2 (en) | 2000-09-06 | 2005-05-31 | Hoffman-La Roche Inc. | Neuropeptide Y antagonists |
JP2004509108A (ja) | 2000-09-14 | 2004-03-25 | シェーリング コーポレイション | 置換尿素神経ペプチドyy5受容体アンタゴニスト |
WO2002026707A1 (en) | 2000-09-26 | 2002-04-04 | Biovitrum Ab | Novel compounds |
WO2002026743A1 (en) | 2000-09-26 | 2002-04-04 | Biovitrum Ab | Novel pyridazine compounds for the treatment of diabetes |
JP2002114768A (ja) | 2000-10-11 | 2002-04-16 | Japan Tobacco Inc | 2−(2,5−ジハロゲン−3,4−ジヒドロキシフェニル)アゾール化合物及びそれを含有してなる医薬組成物 |
JP2004511552A (ja) | 2000-10-13 | 2004-04-15 | イーライ・リリー・アンド・カンパニー | 成長ホルモン分泌促進薬としての置換ジペプチド |
GB0025208D0 (en) | 2000-10-13 | 2000-11-29 | Euro Celtique Sa | Delayed release pharmaceutical formulations |
CN100334076C (zh) | 2000-10-16 | 2007-08-29 | 霍夫曼-拉罗奇有限公司 | 二氢吲哚衍生物及其作为5-ht2受体配体的用途 |
AP2001002307A0 (en) | 2000-10-20 | 2001-12-31 | Pfizer Prod Inc | B3 adrenergic receptor agonists and uses thereof. |
MXPA03003902A (es) | 2000-11-03 | 2004-04-02 | Univ California | Polipeptidos de proquineticina, composiciones relacionadas y metodos. |
AU2002227170A1 (en) | 2000-11-03 | 2002-05-15 | Wyeth | Cycloalkyl(b)(1,4)diazepino(6,7,1-hi)indoles and derivatives |
DE10055857A1 (de) | 2000-11-10 | 2002-08-22 | Creative Peptides Sweden Ab Dj | Neue pharmazeutische Depotformulierung |
DE60120748T2 (de) | 2000-11-10 | 2007-05-16 | Eli Lilly And Co., Indianapolis | 3-substituierte oxindolderivate als beta-3-agonisten |
NZ525700A (en) | 2000-11-20 | 2004-12-24 | Biovitrum Ab | Piperazinylpyrazine compounds as agonist or antagonist of serotonin 5HT-2 receptor |
PL360982A1 (en) | 2000-11-20 | 2004-09-20 | Biovitrum Ab | Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor |
DE60108420T2 (de) | 2000-11-28 | 2005-12-22 | Smithkline Beecham P.L.C., Brentford | Morpholinderivate als antagonisten an orexinrezeptoren |
US6673574B2 (en) | 2000-11-30 | 2004-01-06 | Unigene Laboratories Inc. | Oral delivery of peptides using enzyme-cleavable membrane translocators |
MXPA03004245A (es) | 2000-12-12 | 2003-09-22 | Neurogen Corp | Espiro[isobenzofuran-1,4'piperidin]-3-onas y 3h-espiroisobenzofuran-1,4'-piperidinas. |
BR0116206A (pt) | 2000-12-14 | 2003-12-23 | Amylin Pharmaceuticals Inc | Peptìdeo yy e agonistas de peptìdeo yy para tratamento de distúrbios metabólicos |
GB0030710D0 (en) | 2000-12-15 | 2001-01-31 | Hoffmann La Roche | Piperazine derivatives |
IL156157A0 (en) | 2000-12-21 | 2003-12-23 | Schering Corp | Heteroaryl urea neuropeptide y y5 receptor antagonists |
DE60018085T2 (de) | 2000-12-22 | 2005-07-07 | Institut Pasteur | Prozess zum Screening von Molekülen, die spezifisch an die NEP-Bindungsstelle des QHNPR-pentapeptides binden |
MXPA03005648A (es) | 2000-12-22 | 2003-10-06 | Astrazeneca Ab | Derivados de carbazol y su uso, como ligandos de receptor del neuropeptido y5. |
ES2243588T3 (es) | 2000-12-22 | 2005-12-01 | Schering Corporation | Antagonistas piperidinicos de la mch y su uso en el tratamientyo de la obesidad. |
JP4088412B2 (ja) * | 2000-12-26 | 2008-05-21 | トヨタ自動車株式会社 | 内燃機関の空燃比制御装置 |
CA2432085C (en) | 2000-12-27 | 2009-02-24 | F. Hoffmann-La Roche Ag | Indole derivatives and their use as 5-ht2b and 5-ht2c receptor ligands |
WO2002051232A2 (en) | 2000-12-27 | 2002-07-04 | Actelion Pharmaceuticals Ltd. | Novel benzazepines and related heterocyclic derivatives |
US7169777B2 (en) | 2001-01-23 | 2007-01-30 | Eli Lilly And Company | Melanocortin receptor agonists |
CA2433025A1 (en) | 2001-01-23 | 2002-08-01 | Chaoyu Xie | Substituted piperidines/piperazines as melanocortin receptor agonists |
EP1368340B1 (en) | 2001-01-23 | 2005-08-10 | Eli Lilly And Company | Piperazine derivatives as melanocortin receptor agonists |
CA2435415A1 (en) | 2001-01-26 | 2002-08-01 | Debio Recherche Pharmaceutique S.A. | Microparticles of biodegradable polymer encapsulating a biologically active substance |
CZ20032031A3 (cs) | 2001-01-26 | 2003-12-17 | Schering Corporation | Farmaceutický prostředek |
AU2002235520A1 (en) | 2001-02-02 | 2002-08-19 | Pharmacia Corporation | Uroguanylin and cyclooxygenase-2 inhibitor combinations for inhibition of intestinal cancer |
PL364221A1 (en) | 2001-02-02 | 2004-12-13 | Takeda Chemical Industries, Ltd. | Fused heterocyclic compounds |
AU2002226633A1 (en) | 2001-02-02 | 2002-08-12 | Pfizer Limited | Treatment of diabetes mellitus using vardenafil |
JP2004534733A (ja) | 2001-02-05 | 2004-11-18 | ドクター・レディーズ・ラボラトリーズ・リミテッド | 血中コレステロール低下剤剤としてのアリール置換アルキルカルボン酸 |
DE60219295T2 (de) | 2001-02-28 | 2008-01-03 | Merck & Co., Inc. | Acylierte piperidinderivate als melanocortin-4-rezeptoragonisten |
WO2002068387A2 (en) | 2001-02-28 | 2002-09-06 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor agonists |
EP1385506B1 (en) | 2001-02-28 | 2009-05-06 | Merck & Co., Inc. | Acylated piperidine derivates as melanocortin-4 receptor agonists |
AU2002252134A1 (en) | 2001-02-28 | 2002-09-12 | Smithkline Beecham Corporation | Methods of treating irritable bowel syndrome and functional dyspepsia |
US7316819B2 (en) | 2001-03-08 | 2008-01-08 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
GB0105772D0 (en) | 2001-03-08 | 2001-04-25 | Sterix Ltd | Use |
US20030190360A1 (en) | 2001-03-13 | 2003-10-09 | Baichwal Anand R. | Chronotherapeutic dosage forms containing glucocorticosteroid and methods of treatment |
US20020133168A1 (en) | 2001-03-16 | 2002-09-19 | Smedley Gregory T. | Applicator and methods for placing a trabecular shunt for glaucoma treatment |
EP1383376A4 (en) | 2001-03-19 | 2006-03-08 | Praecis Pharm Inc | PHARMACEUTICAL FORMULATIONS WITH PROLONGED RELEASE |
CN100537527C (zh) | 2001-03-21 | 2009-09-09 | 法马科皮亚公司 | 具有mch调节活性的芳基和二芳基化合物 |
US6900329B2 (en) | 2001-03-21 | 2005-05-31 | Schering Corporation | MCH antagonists and their use in the treatment of obesity |
RU2281941C2 (ru) | 2001-03-22 | 2006-08-20 | Солвей Фармасьютикалс Б.В. | Производные 4,5-дигидро-1h-пиразола, обладающие cb1-антагонистической активностью |
EP1373212A4 (en) | 2001-03-29 | 2004-06-23 | Molecular Design Int | ADRENERGIC-BETA-3 RECEPTOR AGONISTS, AGONIST COMPOSITIONS AND METHODS OF PREPARING AND USING THE SAME |
GB0108631D0 (en) | 2001-04-05 | 2001-05-30 | Melacure Therapeutics Ab | Novel benzylideneamino guanidines and their uses as ligands to the melanocortin receptors |
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
JP4280073B2 (ja) | 2001-04-12 | 2009-06-17 | ファーマコペイア ドラッグ ディスカバリー, インコーポレイテッド | Mchアンタゴニストとして使用されるアリールピペリジンおよびビアリールピペリジン |
US6573287B2 (en) | 2001-04-12 | 2003-06-03 | Bristo-Myers Squibb Company | 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method |
JP2005502322A (ja) | 2001-04-19 | 2005-01-27 | ザ スクリップス リサーチ インスティテュート | 非天然アミノ酸のインビボ組込み |
CN1649848A (zh) | 2001-04-30 | 2005-08-03 | 葛兰素集团有限公司 | 作为促肾上腺皮质激素释放因子(crf)拮抗剂的稠合嘧啶衍生物 |
AU2002341123A1 (en) | 2001-05-05 | 2002-11-18 | Smithkline Beecham P.L.C. | N-aroyl cyclic amine derivatives as orexin receptor antagonists |
CZ20032990A3 (cs) | 2001-05-05 | 2004-04-14 | Smithkline Beecham P. L. C. | N-aroylové cyklické aminy |
FR2824825B1 (fr) | 2001-05-15 | 2005-05-06 | Servier Lab | Nouveaux derives d'alpha-amino-acides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
MY134211A (en) | 2001-05-18 | 2007-11-30 | Smithkline Beecham Corp | Novel use |
ES2300478T3 (es) | 2001-05-21 | 2008-06-16 | F. Hoffmann-La Roche Ag | Derivados de quinolina como ligandos para el receptor de neuropeptido y. |
HUP0400854A2 (hu) | 2001-05-21 | 2004-08-30 | Neurocrine Inc. | Tri- és tetraaza-acenaftilén-származékok mint CRF receptor antagonisták és ezeket tartalmazó gyógyszerkészítmények |
MXPA03010612A (es) | 2001-05-22 | 2004-04-02 | Neurogen Corp | Ligandos receptores de la hormona concentradora de melanina: analogos de 1-bencil-4-aril piperazina substiruidos. |
WO2002098912A2 (de) | 2001-06-05 | 2002-12-12 | Yalcin Cetin | Luftseitig verabreichte guanylat cyclase c liganden für atemwegserkrankungen |
JP2005500308A (ja) | 2001-06-20 | 2005-01-06 | メルク エンド カムパニー インコーポレーテッド | 糖尿病を治療するためのジペプチジルペプチダーゼ阻害剤 |
WO2003000685A1 (en) | 2001-06-20 | 2003-01-03 | Takeda Chemical Industries, Ltd. | 5-membered heterocycle derivatives |
CA2450579A1 (en) | 2001-06-20 | 2003-01-03 | Merck & Co., Inc. | Dipeptidyl peptidase inhibitors for the treatment of diabetes |
US6825198B2 (en) | 2001-06-21 | 2004-11-30 | Pfizer Inc | 5-HT receptor ligands and uses thereof |
GB0115517D0 (en) | 2001-06-25 | 2001-08-15 | Ferring Bv | Novel antidiabetic agents |
CA2419888A1 (en) | 2001-06-27 | 2003-01-09 | Probiodrug Ag | Peptide structures useful for competitive modulation of dipeptidyl peptidase iv catalysis |
IL158923A0 (en) | 2001-06-27 | 2004-05-12 | Smithkline Beecham Corp | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
ATE370943T1 (de) | 2001-06-27 | 2007-09-15 | Smithkline Beecham Corp | Fluoropyrrolidine als dipeptidyl-peptidase inhibitoren |
JP4300108B2 (ja) | 2001-06-27 | 2009-07-22 | スミスクライン ビーチャム コーポレーション | ジペプチジルペプチダーゼ阻害剤としてのピロリジン類 |
DE10150203A1 (de) | 2001-10-12 | 2003-04-17 | Probiodrug Ag | Peptidylketone als Inhibitoren der DPIV |
JP2003018009A (ja) | 2001-06-29 | 2003-01-17 | Mitsubishi Electric Corp | デジタルアナログコンバータ |
EP1404675B1 (en) | 2001-07-03 | 2008-03-12 | Novo Nordisk A/S | Dpp-iv-inhibiting purine derivatives for the treatment of diabetes |
WO2003004458A1 (en) | 2001-07-03 | 2003-01-16 | Biovitrum Ab | New compounds |
HUP0401880A2 (hu) | 2001-07-05 | 2005-01-28 | Synaptic Pharmaceutical Corporation | Helyettesített anilin-piperidinek mint MCH-szelektív antagonisták, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk |
UA74912C2 (en) | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
ITMI20011483A1 (it) | 2001-07-11 | 2003-01-11 | Res & Innovation Soc Coop A R | Uso di composti come antagonisti funzionali ai recettori centrali deicannabinoidi |
US6960646B2 (en) | 2001-07-12 | 2005-11-01 | Merck & Co., Inc. | Cyclic peptides as potent and selective melanocortin-4 receptors agonists |
GB0117396D0 (en) | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
JP4336196B2 (ja) | 2001-07-18 | 2009-09-30 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン受容体作動薬としての架橋ピペリジン誘導体 |
US20030017195A1 (en) | 2001-07-20 | 2003-01-23 | Samir Mitragotri | Method for oral drug delivery |
AU2002319627A1 (en) | 2001-07-20 | 2003-03-03 | Merck And Co., Inc. | Substituted imidazoles as cannabinoid receptor modulators |
US6977264B2 (en) | 2001-07-25 | 2005-12-20 | Amgen Inc. | Substituted piperidines and methods of use |
US7115607B2 (en) | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
CN1911913A (zh) | 2001-07-26 | 2007-02-14 | 先灵公司 | 取代脲类神经肽y y5受体拮抗剂 |
JP4301940B2 (ja) | 2001-07-31 | 2009-07-22 | 日清オイリオグループ株式会社 | 抗肥満剤およびその原料 |
WO2003014113A1 (en) | 2001-08-06 | 2003-02-20 | Glenmark Pharmaceuticals Limited | Novel benzopyran compounds and process for their preparation and use |
GB0119172D0 (en) | 2001-08-06 | 2001-09-26 | Melacure Therapeutics Ab | Phenyl pyrrole derivatives |
CN1538956A (zh) | 2001-08-07 | 2004-10-20 | ������ҩ��ʽ���� | 螺环化合物 |
JP2004537581A (ja) | 2001-08-08 | 2004-12-16 | メルク エンド カムパニー インコーポレーテッド | メラニン濃縮ホルモン拮抗物質 |
EP1421078B1 (en) | 2001-08-14 | 2006-09-27 | Eli Lilly And Company | Indole derivatives as beta-3 adrenergic agonists for the treatment of type 2 diabetes |
EP1444224B1 (en) | 2001-08-14 | 2006-05-03 | Eli Lilly And Company | 3-substituted oxindole beta-3 agonists |
DE10139416A1 (de) | 2001-08-17 | 2003-03-06 | Aventis Pharma Gmbh | Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US7371777B2 (en) | 2001-08-17 | 2008-05-13 | Eisai Co., Ltd. | Cyclic compound and PPAR agonist |
US20030092041A1 (en) | 2001-08-23 | 2003-05-15 | Millennium Pharmaceuticals, Inc. | Novel use for muscarinic receptor M5 in the diagnosis and treatment of metabolic disorders |
JPWO2003018010A1 (ja) | 2001-08-23 | 2004-12-09 | 三菱ウェルファーマ株式会社 | 動脈硬化作用に基づく疾患の予防及び/または治療薬 |
AU2002331766A1 (en) | 2001-08-31 | 2003-03-18 | University Of Connecticut | Novel pyrazole analogs acting on cannabinoid receptors |
GB0121941D0 (en) | 2001-09-11 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
US6915444B2 (en) | 2001-09-12 | 2005-07-05 | Rockwell Automation Technologies, Inc. | Network independent safety protocol for industrial controller using data manipulation techniques |
TWI246510B (en) | 2001-09-14 | 2006-01-01 | Mitsubishi Pharma Corp | Thiazolidine derivatives and pharmaceutical uses thereof |
ATE479655T1 (de) | 2001-09-14 | 2010-09-15 | High Point Pharmaceuticals Llc | Neue aminoazetidin-, aminopyrrolidin- und aminopiperidinderivative |
JP2005526696A (ja) | 2001-09-14 | 2005-09-08 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | ベータ−3アドレナリン受容体アゴニストとして有用なベンゾフランおよびジヒドロベンゾフラン誘導体 |
DE60234616D1 (de) | 2001-09-14 | 2010-01-14 | High Point Pharmaceuticals Llc | Substituierte piperidinen mit selektiver bindungsfähigkeit zu histamin h3-rezeptoren |
WO2003024965A2 (en) | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
MXPA03009439A (es) | 2001-09-21 | 2004-02-12 | Solvay Pharm Bv | Derivados de 4,5-dihidro-1h-pirazol que tienen una potente actividad antagonistica de cb1. |
TWI231757B (en) | 2001-09-21 | 2005-05-01 | Solvay Pharm Bv | 1H-Imidazole derivatives having CB1 agonistic, CB1 partial agonistic or CB1-antagonistic activity |
CA2456606C (en) | 2001-09-21 | 2010-01-26 | Solvay Pharmaceuticals B.V. | 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
US6509367B1 (en) | 2001-09-22 | 2003-01-21 | Virginia Commonwealth University | Pyrazole cannabinoid agonist and antagonists |
JP2005532982A (ja) | 2001-09-24 | 2005-11-04 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | 肥満の処置のためのピロール誘導体の製造及び使用 |
EP2050460A1 (en) | 2001-09-24 | 2009-04-22 | Imperial Innovations Limited | PYY and agonists thereof for modification of feeding behaviour |
WO2003027114A1 (en) | 2001-09-24 | 2003-04-03 | Bayer Pharmaceuticals Corporation | Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine derivatives for treatment of obesity |
WO2003026576A2 (en) | 2001-09-24 | 2003-04-03 | Board Of Supervisors Of Louisiana State Universityand Agricultural And Mechanical College | Induction of brown adipocytes by transcription factor nfe2l2 |
CA2461454A1 (en) | 2001-09-24 | 2003-04-03 | Oregon Health And Science University | Assessment of neurons in the arcuate nucleus to screen for agents that modify feeding behavior |
AR036608A1 (es) | 2001-09-24 | 2004-09-22 | Bayer Corp | Derivados de imidazol, composiciones farmaceuticas y el uso de dichos derivados para la fabricacion de un medicamento para el tratamiento de la obesidad |
MXPA04002136A (es) | 2001-09-26 | 2005-03-07 | Bayer Pharmaceuticals Corp | Derivados de 1,6-naftiridina y su uso para el tratamiento de la diabetes y trastornos relacionados. |
US20040191926A1 (en) | 2001-09-26 | 2004-09-30 | Zhong-Yin Zhang | Ptp1b inhibitors and ligands |
US6787558B2 (en) | 2001-09-28 | 2004-09-07 | Hoffmann-La Roche Inc. | Quinoline derivatives |
WO2003028641A2 (en) | 2001-10-01 | 2003-04-10 | Taisho Pharmaceutical Co., Ltd. | Mch receptor antagonists |
AU2002341921B2 (en) | 2001-10-04 | 2007-05-31 | Merck Sharp & Dohme Corp. | Heteroaryl substituted tetrazole modulators of metabotropic glutamate receptor-5 |
US6667322B2 (en) | 2001-10-05 | 2003-12-23 | Wyeth | Antidepressant chroman and chromene derivatives of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole |
FR2830451B1 (fr) | 2001-10-09 | 2004-04-30 | Inst Nat Sante Rech Med | Utilisation de peptides analogues de la thymuline(pat)pour la fabrication de medicaments contre la douleur |
WO2003031410A1 (en) | 2001-10-09 | 2003-04-17 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
US6727274B2 (en) | 2001-10-09 | 2004-04-27 | Pharmacia & Upjohn Company | Arylsulphonyl substituted-tetrahydro- and hexahydro-carbazoles |
GB0124463D0 (en) | 2001-10-11 | 2001-12-05 | Smithkline Beecham Plc | Compounds |
US7521053B2 (en) | 2001-10-11 | 2009-04-21 | Amgen Inc. | Angiopoietin-2 specific binding agents |
US6573396B2 (en) | 2001-10-12 | 2003-06-03 | Exxonmobil Chemical Patents Inc. | Co-production of dialkyl carbonates and diols with treatment of hydroxy alkyl carbonate |
DE60208815T2 (de) | 2001-10-12 | 2006-07-20 | Bayer Pharmaceuticals Corp., West Haven | Phenyl substituierte 5-gliedrige stickstoff enthaltende heterocyclen zur behandlung von fettleibigkeit |
GB0124627D0 (en) | 2001-10-15 | 2001-12-05 | Smithkline Beecham Plc | Novel compounds |
PL369732A1 (en) | 2001-10-16 | 2005-05-02 | Dr.Reddy's Laboratories Ltd. | Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them |
US20050065118A1 (en) | 2001-10-16 | 2005-03-24 | Jing Wang | Organosulfur inhibitors of tyrosine phosphatases |
KR20050036876A (ko) | 2001-10-17 | 2005-04-20 | 노보 노르디스크 에이/에스 | 디카르복실산 유도체, 그것의 제제 및 치료에의 사용 |
US7022730B2 (en) | 2001-10-19 | 2006-04-04 | Transtech Pharma, Inc. | Bis-heteroaryl alkanes as therapeutic agents |
PT1438045E (pt) | 2001-10-23 | 2007-05-31 | Biovitrum Ab | Utilização de derivados de indole e indolina para o tratamento da obesidade ou para a redução de ingestão de alimentos |
US20030091630A1 (en) | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
WO2003035602A1 (fr) | 2001-10-25 | 2003-05-01 | Sankyo Company, Limited | Modulateurs lipidiques |
CA2409552A1 (en) | 2001-10-25 | 2003-04-25 | Depomed, Inc. | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
CA2464981A1 (en) | 2001-10-25 | 2003-05-01 | Takeda Chemical Industries, Ltd. | Quinoline compound |
US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
US7342117B2 (en) | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
GB0126292D0 (en) | 2001-11-01 | 2002-01-02 | Smithkline Beecham Plc | Compounds |
SE0103644D0 (sv) | 2001-11-01 | 2001-11-01 | Astrazeneca Ab | Therapeutic isoquinoline compounds |
SE0103648D0 (sv) | 2001-11-01 | 2001-11-01 | Astrazeneca Ab | Therapeutic quinolone compounds |
JP2005511594A (ja) | 2001-11-09 | 2005-04-28 | ビオヴィトルム・アクチボラゲット | 肥満の治療における、もしくは摂食量の減少のためのスルホンアミド誘導体の使用 |
TW200303742A (en) | 2001-11-21 | 2003-09-16 | Novartis Ag | Organic compounds |
EP1453815A4 (en) | 2001-11-30 | 2005-04-06 | Merck & Co Inc | METABOTROPIC GLUTAMATE RECEPTOR-5 MODULATORS |
BR0214437A (pt) | 2001-11-30 | 2004-10-13 | Lilly Co Eli | Composto, composição farmacêutica, métodos de modular um receptor ativado por proliferador de peroxissoma, de tratar e de prevenir a diabete melito, e de tratar a sìndrome x, e doenças cardiovasculares em um mamìfero, e, uso de um composto |
GB0128996D0 (en) | 2001-12-04 | 2002-01-23 | Novartis Ag | Organic compounds |
DE60213851T2 (de) | 2001-12-04 | 2007-09-13 | F. Hoffmann-La Roche Ag | Ringannelierte pyrazolderivate |
DE10160409A1 (de) | 2001-12-10 | 2003-06-18 | Guenther Beisel | Verwendung von ionischen und nichtionischen Celluloseethern zur Herstellung eines gelartigen Mittels zur Verhinderung der Resorption von Fetten aus dem Magen-Darm-Trakt |
US6923992B2 (en) | 2001-12-17 | 2005-08-02 | The Chinese University Of Hong Kong | Active compounds of Bao-Ji-Wan for anti-diarrhea and relieving gastrointestinal symptoms |
WO2003051833A2 (en) | 2001-12-18 | 2003-06-26 | Merck & Co., Inc. | Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5 |
ES2292854T3 (es) | 2001-12-18 | 2008-03-16 | MERCK & CO., INC. | Moduladores triazol sustituidos con heteroarilo del receptor-5 metabotropico de glumatamato. |
WO2003053922A2 (en) | 2001-12-19 | 2003-07-03 | Merck & Co., Inc. | Heteroaryl substituted imidazole modulators of metabotropic glutamate receptor-5 |
IL162293A0 (en) | 2001-12-19 | 2005-11-20 | Alza Corp | Formulation and dosage form for increasing oral bioavailability of hydrophilic macromolecules |
WO2003053976A1 (en) | 2001-12-20 | 2003-07-03 | Biovitrum Ab | PIPAZOLO [1,5-a] PYRIMIDINE DERIVATIVES AS MODULATORS OF PPAR |
FR2833949B1 (fr) | 2001-12-21 | 2005-08-05 | Galderma Res & Dev | NOUVEAUX LIGANDS ACTIVATEURS DES RECEPTEURS PPARy, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION EN MEDECINE HUMAINE AINSI QU'EN COSMETIQUE |
CA2470519C (en) | 2001-12-21 | 2009-11-17 | Merck & Co., Inc. | Heteroaryl substituted pyrrole modulators of metabotropic glutamate receptor-5 |
EP1321142A1 (en) | 2001-12-21 | 2003-06-25 | Novartis AG | Solid pharmaceutical composition for oral administration of Tegaserod |
US6642381B2 (en) | 2001-12-27 | 2003-11-04 | Hoffman-La Roche Inc. | Pyrimido[5,4-e][1,2,4]triazine-5,7-diamine compounds as protein tyrosine phosphatase inhibitors |
US20030129160A1 (en) | 2002-01-09 | 2003-07-10 | John-Olov Jansson | Use of Interleukin-6 |
JP4733922B2 (ja) | 2002-01-10 | 2011-07-27 | インペリアル・イノベ−ションズ・リミテッド | 摂食行動の修正 |
KR20040095239A (ko) | 2002-02-27 | 2004-11-12 | 화이자 프로덕츠 인코포레이티드 | Acc 억제제 |
JP2005525374A (ja) | 2002-03-04 | 2005-08-25 | ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス | 担体ペプチドを含有する持続放出ドラッグ製剤 |
WO2003077897A1 (en) | 2002-03-15 | 2003-09-25 | Cypress Bioscience, Inc. | Ne and 5-ht reuptake inhibitors for treating visceral pain syndromes |
AU2003226041A1 (en) | 2002-04-08 | 2003-10-27 | Lavipharm Laboratories, Inc. | Multi-layer mucoadhesive drug delivery device with bursting release layer |
FR2838439B1 (fr) | 2002-04-11 | 2005-05-20 | Sanofi Synthelabo | Derives de terphenyle, leur preparation, les compositions pharmaceutqiues en contenant |
SE0201175L (sv) | 2002-04-18 | 2003-10-19 | Jonsered Cranes Ab | Kranarrangemangstillhörig hållarenhet |
PL371596A1 (en) | 2002-05-17 | 2005-06-27 | Merck Patent Gmbh | Use of compounds that are effective as selective opiate receptor modulators |
GB0214013D0 (en) | 2002-06-18 | 2002-07-31 | Euro Celtique Sa | Pharmaceutical product |
US6991726B2 (en) * | 2002-07-01 | 2006-01-31 | Usfilter Corporation | Filter having a media retaining plate |
CN100591372C (zh) | 2002-07-19 | 2010-02-24 | 耶鲁大学 | 色素层巩膜引流装置 |
AU2003270009A1 (en) | 2002-08-30 | 2004-03-19 | Biorexis Pharmaceutical Corporation | Oral delivery of modified transferrin fusion proteins |
AU2003264431A1 (en) | 2002-09-18 | 2004-04-08 | Ajinomoto Co., Inc. | Composition against stress-related diseases |
AU2003259482A1 (en) | 2002-09-20 | 2004-04-08 | Pfizer Japan Inc. | N-substituted piperidinyl-imidazopyridine compounds as 5-ht4 receptor modulators |
WO2004041195A2 (en) | 2002-10-31 | 2004-05-21 | Supergen, Inc. | Pharmaceutical formulations targeting specific regions of the gastrointestinal tract |
JP4401298B2 (ja) | 2002-12-02 | 2010-01-20 | エフ.ホフマン−ラ ロシュ アーゲー | Crfアンタゴニストとしてのインダゾール誘導体 |
US7670627B2 (en) | 2002-12-09 | 2010-03-02 | Salvona Ip Llc | pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients |
US20040121994A1 (en) | 2002-12-20 | 2004-06-24 | Anderson Steven N. | Novel amides that activate soluble guanylate cyclase |
JO2696B1 (en) | 2002-12-23 | 2013-03-03 | شركة جانسين فارماسوتيكا ان. في | Derivatives of 1-piperdine-4-yl-4-biprolidine-3-yl-piperazine substituted and used as quinine antagonists |
AR042667A1 (es) | 2002-12-26 | 2005-06-29 | Taisho Pharmaceutical Co Ltd | Derivados de pirrolopirimidina y pirrolopiridina sustituidos con un grupo amino ciclico |
WO2004064769A2 (en) | 2003-01-21 | 2004-08-05 | Hector Herrera | Methods for making and using topical delivery agents |
MXPA05008097A (es) | 2003-01-28 | 2006-02-08 | Microbia Inc | Metodos y composiciones para el tratamiento de desordenes gastrointestinales. |
US20060281682A1 (en) * | 2003-01-28 | 2006-12-14 | Currie Mark G | Methods and compositions for the treatment of gastrointestinal disorders |
US7304036B2 (en) | 2003-01-28 | 2007-12-04 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
ZA200409537B (en) | 2003-01-31 | 2006-10-25 | Yamanouchi Pharma Co Ltd | Stable solid medicinal composition for oral administration |
US6683072B1 (en) | 2003-02-04 | 2004-01-27 | Vela Pharmaceuticals, Inc. | Compositions and methods for treatment of irritable bowel syndrome and nonulcer dyspepsia |
WO2004081199A2 (en) | 2003-03-11 | 2004-09-23 | Genentech, Inc. | Novel compositions and methods for the treatment of immune related disease |
US20050004155A1 (en) | 2003-04-08 | 2005-01-06 | Boyd Thomas A. | Use of methylnaltrexone to treat irritable bowel syndrome |
EP1622910A1 (en) | 2003-05-05 | 2006-02-08 | F. Hoffmann-La Roche Ag | Fused pyrimidine derivatives with crf activity |
EP1624875A4 (en) | 2003-05-16 | 2010-01-20 | Vela Acquisition Corp | TREATMENT OF GASTROINTESTINAL DYSFUNCTION AND RELATED LOADS WITH ENANTIOMERIC PURE (R) 2,3-BENZODIAZEPINE |
US7173010B2 (en) | 2003-05-19 | 2007-02-06 | Regents Of The University Of Michigan | Orphanin FQ receptor |
US7073363B2 (en) * | 2003-05-20 | 2006-07-11 | Schumag Ag | Method for processing drawn material and drawn material production installation |
DK1644021T3 (da) | 2003-06-13 | 2012-10-29 | Ironwood Pharmaceuticals Inc | Fremgangsmåder og sammensætninger til behandlingen af gastrointestinale sygdomme |
EP2529730A1 (en) | 2003-06-16 | 2012-12-05 | ANDRX Pharmaceuticals LLC. | Oral sustained-release composition |
DE10331723A1 (de) | 2003-07-11 | 2005-06-16 | Merck Patent Gmbh | Kappa-Agonisten |
NZ545921A (en) | 2003-09-19 | 2009-09-25 | Penwest Pharmaceuticals Co | Delayed released dosage forms |
NZ546183A (en) | 2003-09-26 | 2011-04-29 | Alza Corp | Controlled release formulations exhibiting an ascending rate of release |
EP1675555A4 (en) | 2003-09-30 | 2011-03-09 | Shire Llc | PHARMACEUTICAL COMPOSITIONS FOR PREVENTING EXCESSIVE DOSE OR ABUSE |
US7002015B2 (en) | 2003-10-14 | 2006-02-21 | Bristol-Myers Squibb Company | 3-Thia-4-arylquinolin-2-one derivatives as smooth muscle relaxants |
US7291125B2 (en) | 2003-11-14 | 2007-11-06 | Transcend Medical, Inc. | Ocular pressure regulation |
WO2005048998A1 (en) | 2003-11-21 | 2005-06-02 | Commonwealth Scientific & Industrial Research Organisation | G i tract delivery systems |
WO2005063156A1 (en) | 2003-12-22 | 2005-07-14 | Shear/Kershman Laboratories, Inc. | Oral peptide delivery system with improved bioavailability |
WO2005063206A1 (en) | 2003-12-23 | 2005-07-14 | Alza Corporation | Methods and dosage forms for increasing solubility of drug compositions for controlled delivery |
US20050267197A1 (en) | 2004-05-25 | 2005-12-01 | Roger Berlin | Compositions containing policosanol and HMG-Co-A reductase inhibitor and their pharmaceutical uses |
EP1781339B1 (en) | 2004-06-25 | 2013-12-25 | Thomas Jefferson University | Guanylyl cyclase C ligands |
US20060013889A1 (en) | 2004-07-16 | 2006-01-19 | Playford Raymond J | Colostrum-based treatment for irritable bowel syndrome |
MX2007000728A (es) | 2004-07-21 | 2007-03-15 | Ambrx Inc | Polipeptidos biosinteticos que utilizan amino acidos no naturalmente codificados. |
TWI393170B (zh) * | 2004-11-18 | 2013-04-11 | 尼康股份有限公司 | A position measuring method, a position control method, a measuring method, a loading method, an exposure method, an exposure apparatus, and a device manufacturing method |
US20070101158A1 (en) * | 2005-10-28 | 2007-05-03 | Elliott Robert C | Security region in a non-volatile memory |
US20090192083A1 (en) | 2006-02-24 | 2009-07-30 | Currie Mark G | Methods and compositions for the treatment of gastrointestinal disorders |
US7692307B2 (en) * | 2006-12-08 | 2010-04-06 | Intel Corporation | Compliant structure for an electronic device, method of manufacturing same, and system containing same |
WO2008106429A2 (en) | 2007-02-26 | 2008-09-04 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of heart failure and other disorders |
MX2009011898A (es) | 2007-05-04 | 2009-11-18 | Ironwood Pharmaceuticals Inc | Composiciones y metodos para tratar trastornos asociados con retencion de sal o fluido. |
CA2688161C (en) | 2007-06-04 | 2020-10-20 | Kunwar Shailubhai | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
ES2522968T3 (es) | 2008-06-04 | 2014-11-19 | Synergy Pharmaceuticals Inc. | Agonistas de guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos |
WO2009149278A1 (en) | 2008-06-04 | 2009-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
ES2624828T3 (es) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros |
ES2608050T3 (es) | 2008-12-03 | 2017-04-05 | Synergy Pharmaceuticals Inc. | Formulaciones de agonistas de guanilato ciclasa C y métodos de uso |
EP2499154B1 (en) | 2009-11-09 | 2016-12-21 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
KR20120103689A (ko) | 2009-12-07 | 2012-09-19 | 아이언우드 파마슈티컬스, 인코포레이티드 | 위장 장애의 치료 |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
CA2810243C (en) | 2010-09-15 | 2021-04-20 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
US9486494B2 (en) * | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
JP6606491B2 (ja) * | 2013-06-05 | 2019-11-13 | シナジー ファーマシューティカルズ インコーポレイテッド | グアニル酸シクラーゼcの超高純度アゴニスト、その作成および使用方法 |
-
2008
- 2008-06-04 CA CA2688161A patent/CA2688161C/en active Active
- 2008-06-04 WO PCT/US2008/065824 patent/WO2008151257A2/en active Application Filing
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1551760A (zh) * | 2001-03-29 | 2004-12-01 | ҩ��Э��˾ | 用于治疗组织炎症和癌变的鸟苷酸环化酶受体拮抗剂 |
WO2006086653A2 (en) * | 2005-02-08 | 2006-08-17 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
WO2007022531A2 (en) * | 2005-08-19 | 2007-02-22 | Microbia, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
Non-Patent Citations (1)
Title |
---|
何炳林 等,: "对一环胺甲基苯丙氨酸的合成、拆分及保护", 《科学通报》 * |
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