CN101534641A - 治疗高胆固醇血症和动脉粥样硬化的方法和组合物 - Google Patents
治疗高胆固醇血症和动脉粥样硬化的方法和组合物 Download PDFInfo
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- CN101534641A CN101534641A CNA2007800189793A CN200780018979A CN101534641A CN 101534641 A CN101534641 A CN 101534641A CN A2007800189793 A CNA2007800189793 A CN A2007800189793A CN 200780018979 A CN200780018979 A CN 200780018979A CN 101534641 A CN101534641 A CN 101534641A
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Abstract
本发明提供了可用于治疗或预防动脉粥样硬化、中风及其它缺血性血管疾病、血脂异常、高胆固醇血症以及预防这些病症的并发症的化合物和药物组合物。根据本发明的药剂包括:牛磺熊去氧胆酸(TUDCA)及其类似物和衍生物、4-苯基丁酸(PBA)及其类似物和衍生物、以及三甲胺N-氧化物(TMAO)及其类似物和衍生物。
Description
相关申请
本申请要求2006年3月22日提交的,与本申请名称相同的第60/785,156号美国临时专利申请的优先权。本申请也和2005年9月15日提交的第11/227,497号美国专利申请以及2005年9月15日提交的第11/227,543号美国专利申请的主题相关,所述申请的内容均通过引用并入本文。
政府支持
在本文中描述的工作部分得到国家卫生研究院(National Institutes ofHealth)的资助支持。美国政府可对本发明享有某些权利。
发明背景
高胆固醇血症遍及世界盛行并日益增长的健康问题。高胆固醇血症是指血液中存在高水平或过量水平的胆固醇。高胆固醇血症能够导致在动脉内形成动脉粥样硬化斑块,并且最终导致动脉粥样硬化、中风、缺血性血管疾病、血脂异常和高胆固醇血症以及这些病症(condition)的其它并发症。这些胆固醇相关疾病已经严重威胁到人类的健康。
高胆固醇血症可能与细胞应激(stress)信号传导途径的激活有关。细胞应激响应中的一个参与成分(player)为内质网(ER),它是在分泌性蛋白及膜蛋白的合成和加工中起作用的膜网络。ER负责真核细胞的大部分分泌蛋白和膜内在蛋白的加工和易位。ER腔为这些蛋白质的翻译后修饰和折叠提供了专门的环境。恰当折叠的蛋白质从ER清除出去并进入分泌途径,而未折叠或错折叠的蛋白质则通过ER相关蛋白降解结构(machinery)来处置。细胞加工的蛋白质载荷随着细胞类型和细胞的生理状态而发生相当大的变化。细胞通过调整其ER容量以适应加工蛋白质和合成蛋白质的载荷。ER载荷和折叠能力之间的不平衡称之为ER应激(Harding等人,Diabetes51(增刊3):S455,2002)。已表明ER应激是通过缺氧、血糖过低、暴露于干扰ER功能的天然毒素,以及影响客户蛋白质折叠能力的各种突变而触发的(Lee,TrendsBiochem.Sci.,26:504-510,2001;Lee,Curr.Opin.Cell.Biol.,4:267-273,1992)。
现已表明某些病理性病症可破坏ER稳态平衡,由此导致ER腔中未折叠和错折叠蛋白质的累积(Hampton,Curr.Biol.,10:R518,2000;Mori,Cell,101:451,2000;Harding等人,Annu.Rev.Cell Dev.Biol.,18:575,2002)。为应对ER应激,细胞激活连接ER腔与细胞质及细胞核的信号转导系统,称为解折叠蛋白效应(UPR)(Hampton,Curr.Biol.,10:R518,2000;Mori,Cell,101:451,2000;Harding等人,Annu.Rev.Cell Dev.Biol.,18:575,2002;其各自通过引用并入本文)。触发ER应激的情况包括葡萄糖和营养素丧失、病毒感染、分泌性蛋白合成的增加以及突变体或错折叠蛋白的表达(Ma等人,Cell,107:827,2001;Kaufman等人,Nat.Rev.Mol.Cell Biol.,3:411,2002)。
发明概述
发明人已经发现内质网应激是肥胖、胰岛素抵抗和2型糖尿病之间的关键联系(Ozcan等Science 313:1137-1140,2006)。胰岛素抵抗是肥胖和易患各种疾病的个体的常见特征,所述疾病包括高血压、血脂异常、心血管病和2型糖尿病。此外,肥胖和动脉粥样硬化都与炎症有关。Ozcan等(2006)描述了通过給予化学伴侣(chemical chaperones)减少内质网应激来恢复2型糖尿病小鼠模型的葡萄糖稳态并增强肝脏、肌肉和脂肪组织对胰岛素敏感度的方法。
本发明至少部分基于这样的发现:减少ER应激可以治疗高胆固醇血症和动脉粥样硬化。于是一方面,本发明提供治疗或预防受治疗者中高胆固醇血症和/或动脉粥样硬化的方法,其包括对有需要的受治疗者施用治疗有效剂量的式I的TUDCA化合物或其药学上可接受的盐或衍生物;或其混合物,由此治疗或预防所述受治疗者中高胆固醇血症和/或动脉粥样硬化:
其中R是-H或C1-C4烷基;
R1是-CH2-SO3R3,且R2是-H;或者R1是-COOH,且R2是-CH2-CH2-CONH2、-CH2-CONH2、-CH2-CH2-SCH3或-CH2-S-CH2-COOH;以及
R3是-H或碱性氨基酸残基。
另一方面中,本发明提供治疗或预防受治疗者中高胆固醇血症和/或动脉粥样硬化的方法,其包括对有需要的受治疗者施用治疗有效剂量的式II的PBA化合物及其药学上可接受的盐;或其混合物,由此治疗或预防所述受治疗者中高胆固醇血症和/或动脉粥样硬化:
其中n是1或2;
R0是芳基、杂芳基或苯氧基,所述芳基或苯氧基是未取代的或独立地被一个或多个卤素、羟基或低级烷基取代;
R1和R2独立地为H、低级烷氧基、羟基、低级烷基或卤素。
另一方面中,本发明提供治疗或预防受治疗者中高胆固醇血症和/或动脉粥样硬化的方法,其包括对有需要的受治疗者施用治疗有效剂量的式III的TMAO化合物或其药学上可接受的盐;或其混合物,由此治疗或预防所述受治疗者中高胆固醇血症和/或动脉粥样硬化:
其中,R1、R2和R3独立地为氢、卤素或C1-C6低级烷基。
一方面中,本发明提供本发明TUDCA、PBA和TMAO化合物在制备治疗或预防高胆固醇血症和/或动脉粥样硬化的药物中的用途。
在本发明的一方面,还提供包含本发明中使用的TUDCA、PBA和TMAO化合物以及药学上可接受的赋形剂的本发明的药物组合物和药物。可将药物组合物配制用于口服、胃肠外或透皮传递。本发明化合物还可以与其他药剂联合使用。
一方面中,本发明提供包含本发明中使用的TUDCA、PBA和TMAO化合物的试剂盒。所述试剂盒还可以包含供医生和/或患者使用的说明书、注射器、针头、盒子、瓶子、小瓶等。
一方面中,本发明提供用于预防或治疗高胆固醇血症、动脉粥样硬化及相关疾病的方法和药剂。尤其,本发明提供可用于治疗或预防动脉粥样硬化、中风和其它缺血性血管疾病、血脂异常和高胆固醇血症,以及预防这些疾病的并发症的药剂或药物组合物。
本发明提供本发明组合物在制备预防或治疗高胆固醇血症、动脉粥样硬化及相关疾病的药物中的用途。
定义
“动物”:本文所用的术语动物指人以及非人动物,包括例如哺乳动物、鸟类、爬行类动物、两栖类动物和鱼类。非人动物优选为哺乳动物(例如啮齿类动物、小鼠、大鼠、兔子、猴子、狗、猫、灵长类动物或者猪)。在某些实施方案中,所述动物是人。
“化学伴侣”:“化学伴侣”是已知能抵抗蛋白质变性(例如化学变性、热变性)而使蛋白质构象稳定,从而保护蛋白质的结构和功能的化合物(Welch等.Cell Stress Chaperones 1:109-115,1996)。在某些实施方案中,“化学伴侣”是小分子或低分子量化合物。优选地,“化学伴侣”不是蛋白质。“化学伴侣”的实例包括甘油、重水(D2O)、二甲亚砜(DMSO)、三甲胺N-氧化物(TMAO)、甘氨酸甜菜碱(甜菜碱)、甘油磷酸胆碱(GPC)(Burg等.Am.J.Physiol.(Renal Physiol.43):F762-F765,1998)、4-苯基丁酸盐或4-苯基丁酸(PBA)、甲胺和牛磺熊去氧胆酸(TUDCA)。化学伴侣可用于影响细胞中的蛋白质折叠。已显示化学伴侣在某些情况下可以纠正诸如囊性纤维化(Fischer等,Am.J.Physiol.Lung Cell Mol.Physiol.281:L52-L57,2001)、朊病毒相关疾病、肾性尿崩症以及癌症(Bai等.Journal of Pharmacological and Toxicological Methods 40(1):39-45,July 1998)之类的疾病中观察到的折叠/运输缺陷。还发现化学伴侣用于减少ER应激,并可用于治疗高胆固醇血症、动脉粥样硬化及相关疾病。
“有效量”:通常,活性剂的“有效量”指引发所要求的生物反应的必需量。本领域普通技术人员将认识到,药剂的有效量可根据诸如所要求的生物终点(biological endpoint)、经传递的药剂、所治疗的疾病、被治疗的受治疗者等因素而变化。例如,用于治疗或预防高胆固醇血症或动脉粥样硬化的有效量是导致血胆固醇水平降低至少约10%、20%、30%、40%、或50%的量。
“高胆固醇血症”指血液中存在高水平或过量水平的胆固醇。高胆固醇血症能够导致在动脉内形成动脉粥样硬化斑块,并且最终导致动脉粥样硬化。本文中所使用的术语“高胆固醇血症”指空腹总胆固醇水平超过200mg/dL。
“肽”或“蛋白质”:根据本发明,“肽”或“蛋白质”包括一串由肽键连接在一起的至少三个氨基酸。术语“蛋白质”和“肽”可以互换使用。虽然可以做为选择地使用本领域已知的非天然氨基酸(即,不存在于自然界,但能并入多肽链中的化合物)和/或氨基酸类似物,但本发明的肽优选只包含天然氨基酸。还可以对本发明的肽中的一个或多个氨基酸进行修饰,例如通过加入化学实体(如碳水化合物基团、磷酸根、法尼基、异法尼基、脂肪酸基、结合用连接基(linkerfor conjugation))、官能化或其它修饰等。在一个优选实施方案中,肽的修饰形成更稳定的肽(例如更长的体内半衰期)。这些修饰可以包括肽的环化,D-氨基酸的引入等。所述修饰均不应实质上干扰肽的的预期生物活性。
“获得式I、式II或式III的化合物”中的术语“获得”指购买、合成或其它形式获得化合物。
“多核苷酸”或“寡核苷酸”指核苷酸聚合物。所述聚合物可包含天然核苷酸(即腺苷、胸苷、鸟苷、胞苷、尿苷、脱氧腺苷、脱氧胸苷、脱氧鸟苷及脱氧胞苷)、核苷酸类似物(例如2-硫代胸苷、肌苷、吡咯并嘧啶、3-甲基腺苷、5-甲基胞苷、2-氨基腺苷、C5-溴尿苷、C5-氟尿苷、C5-碘尿苷、C5-丙炔基尿苷、C5-丙炔基胞苷、C5-甲基胞苷、7-脱氮(deaza)腺苷、7-脱氮鸟苷、8-氧代腺苷、8-氧代鸟苷、O(6)-甲基鸟嘌呤、4-乙酰胞苷、5-(羧基羟基甲基)尿苷、二氢尿苷、甲基假尿苷、1-甲基腺苷、1-甲基鸟苷、N6-甲基腺苷和2-硫代胞苷)、化学修饰碱基(base)、生物修饰碱基(例如甲基化碱基)、嵌入的碱基、修饰的糖(例如2′-氟代核糖、核糖、2′-去氧核糖、2′-O-甲基胞苷、阿拉伯糖和己糖)或者修饰的磷酸根(例如硫代磷酸根(phosphorothioates)和5′-N-亚磷酰胺(phosphoramidite)键)
“小分子”:本文所使用的术语“小分子”指不论是天然存在或人工创造(例如通过化学合成)的有机化合物,其具有相对低的分子量并且不是蛋白质、多肽或核酸。小分子的分子量一般小于约1500g/mol。小分子还通常具有多个碳-碳键。已知的天然存在的小分子包括但不仅限于青霉素、红霉素、紫杉醇、环孢菌素和雷帕霉素。已知的合成小分子包括但不仅限于氨苄青霉素、甲氧苯青霉素、磺胺甲噁唑以及磺胺类。
附图简述
图1显示了经磷酸盐缓冲盐水(PBS)对照以及500mg/kg TUDCA治疗的高胆固醇血症小鼠的血胆固醇水平(mg/dl)。
图2a-2c显示了对高胆固醇血症小鼠的研究结果。图2(a)显示了经PBS(赋形剂对照)、50mg/kg TUDCA(TUD)、500mg/kg TUDCA或10mg/kg PBA治疗的高血胆固醇症小鼠的占每一主动脉全面积(per full aorta area)的损害面积百分比。图2(b)显示了经PBS(赋形剂对照)、50mg/kg TUDCA(TUD)、500mg/kgTUDCA或10mg/kg PBA治疗的高血胆固醇症小鼠的血清HPLC分析。显示了对应于VLDL、LDL和HDL的峰。图2(c)显示了经赋形剂对照(PBS)、50mg/kgTUDCA(TUD)、500mg/kg TUDCA或10mg/kg PBA治疗的高血胆固醇症小鼠的血胆固醇水平(mg/dl)。***表示p<0.001。(每组n=3-4)。
本发明某些优选实施方案详述
本发明提供可以用于治疗或预防动脉粥样硬化、中风及其它缺血性血管疾病、血脂异常、高胆固醇血症以及预防这些病症的并发症的药剂/化合物或药物组合物。对受治疗者施用有效治疗或预防动脉粥样硬化、中风及其它缺血性血管疾病的血脂异常、高胆固醇血症以及预防这些病症的并发症的剂量的此类药剂或包含此类药剂的联合治疗剂(therapy),可以治愈受治疗的疾病,缓解或降低受治疗疾病的至少一种征兆或症状,降低该疾病的短期后遗症,降低该疾病的长期后遗症,或对受治疗者提供一些其它的暂时的有益影响。
在某些实施方案中,本发明治疗降低了血胆固醇水平。在其它实施方案中,本发明治疗预防了高胆固醇血症的长期后遗症,包括动脉粥样硬化、中风、缺血性血管疾病和血脂异常。
在某些实施方案中,本发明治疗可以降低细胞(例如脂肪细胞、肝细胞)中ER应激标记的水平(例如XBP-1的剪接形式、PERK的磷酸化状态、eIF2α的磷酸化、GRP78/BIP的mRNA水平、GRP78/BIP的蛋白水平、JNK活性)。
在某些实施方案中,可能联合使用一种或多种化学伴侣。在某些实施方案中,以分剂量(例如一天两次、一天三次、一天四次、一天五次)给予药剂。在其它实施方案中,每日单剂量给予药剂。
所述药剂可以与一种或多种其它药剂(特别是传统用于治疗高胆固醇血症和/或动脉粥样硬化的药剂)联合。表1包括了与本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)联合使用的药剂清单。该清单包括通用名、商品名称和制造商。与本发明化合物联合使用的示例性药剂包括但不限于抗糖尿病药(例如胰岛素、降血糖药(例如口服降血糖药,如磺酰脲类、甲苯磺丁脲、二甲双胍、氯磺丙脲、醋磺己脲、妥拉磺脲、格列本脲等))、抗肥胖药、抗血脂异常药(anti-dyslipidemiaagent)或抗动脉粥样硬化药(例如降胆固醇药(如HMg-CoA还原酶抑制剂,如洛伐他汀、阿托伐他汀、辛伐他汀、普伐他汀、氟伐他汀等;阿司匹林)、抗肥胖药(如食欲抑制剂)、维生素、矿物质和抗高血压药。
在某些实施方案中,本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)与抗血脂异常药或抗动脉粥样硬化药联合使用。示例性抗血脂异常药或抗动脉粥样硬化药包括HMG-CoA还原酶抑制剂(如阿托伐他汀、普伐他汀、辛伐他汀、洛伐他汀、氟伐他汀、西立伐他汀、罗苏伐他汀、匹伐他汀)、贝特类(如环丙贝特、苯扎贝特、氯贝丁酯、非诺贝特、吉非贝齐)、胆汁酸螯合剂(如考来烯胺、考来替泊、考来维仑)、烟酸(速释和缓释)、抗血小板剂(如阿司匹林、氯吡格雷、噻氯匹定)、血管紧张素转换酶(ACE)抑制剂(如雷米普利、依那普利)、血管紧张素II受体拮抗剂(如氯沙坦钾)、脂酰辅酶A胆固醇乙酰转移酶(ACAT)抑制剂(如阿伐麦布、依鲁麦布(eflucimibe)、CS-505(Sankyo and Kyoto)、SW-797(Sumito))、胆固醇吸收抑制剂(如依泽替米贝、帕马苷)、烟酸衍生物(如烟酸)、胆固醇酯转移蛋白(CETP)抑制剂(如CP-529414(Pfizer)、JTT-705(Japan Tobacco)、CEIi-1、torcetrapib)、微粒体甘油三酯转移蛋白(MTTP)抑制剂(如英普他派、R-103757、CP-346086(Pfizer))、其它胆固醇调节剂(如NO-1886(Otsuka/TAPPharmaceutical)、CI-1027(Pfizer)、WAY-135433(Wyeth-Ayerst))、胆汁酸调节剂(如GT102-279(GelTex/Sankyo)、HBS-I07(HisamitsuBanyu)、BTG-511(British Technology Group)、BARI-1453(Aventis)、S-8921(Shionogi)、SD-5613(Pfizer)、AZD-7806(AstraZeneca))、过氧化物酶体增殖蛋白激活性受体(PPAR)激动剂(如替格列扎(Tesaglitazar)(AZ-242)(AstraZeneca)、萘格列酮(Netoglitazone)(MCC-555)(Mitsubishi/Johnson & Johnson)、GW-409544(LigandPharmaceuticals/GlaxoSmithKline)、GW-501516(LigandPharmaceuticals/GlaxoSmithKline)、LY-929(Ligand Pharmaceuticals and Eli Lilly)、LY-465608(Ligand Pharmaceuticals and Eli Lilly)、LY-518674(LigandPharmaceuticals and Eli Lilly)、MK-767(Merck and Kyorin))、基于基因的疗法(如AdGVVEGF121.10(GenVec)、ApoAl(UCB Pharma/GroupcFournier)、EG-004(Trinam)(Ark Therapeutics)、ATP-结合小盒转运蛋白-A1(ABCA1)(CVTherapeutics/Incyte、Aventis、Xenon))、复合血管保护剂(如AGI-1067((Atherogenics))、BO-653(Chugai)、糖蛋白IIb/IIIa抑制剂(如罗昔非班、(Bristol-Myers Squibb)、更托非班(Yamanouchi)、色满非班(Cromafiban)(Millennium Pharmaceuticals))、阿司匹林及其类似物(如Asacard、缓释阿司匹林、帕米格雷)、联合疗法(如烟酸/洛伐他汀、氨氯地平/阿托伐他汀、辛伐他汀/依泽替米贝)、IBAT抑制剂(如S-89-21(Shionogi))、角鲨烯合酶抑制剂(如,BMS-188494I(Bristol-Myers Squibb)、CP-210172(Pfizer)、CP-295697(Pfizer)、CP-294838(Pfizer)、TAK-475(Takeda))、单核细胞趋化蛋白(MCP-1)抑制剂(如RS-540393(RocheBioscience)、其它MCP-1抑制剂(GlaxoSmithKline,Teijin和Bristol-MyersSquibb))、肝X-受体激动剂(如GW-3965(GlaxoSmithKline)、TU-0901317(Tularik))和其它的新方法(如BMX-102(Metabolex)、NO-1886(Otsuka)、Gemcabene(Pfizer))。
在其它实施方案中,本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)与抗高血压药联合使用。抗高血压药的例子包括利尿剂(如氯噻酮、美托拉宗、吲达帕胺、布美他尼、依他尼酸、呋塞米、托塞米、盐酸阿米洛利、螺内酯、氨苯喋啶)、α-阻滞剂(如甲磺酸多沙唑嗪、盐酸哌唑嗪、盐酸特拉唑嗪)、β-阻滞剂(如醋丁洛尔、阿替洛尔、倍他洛尔、富马酸比索洛尔、盐酸卡替洛尔、酒石酸美托洛尔、琥珀酸美托洛尔、纳多洛尔、硫酸喷布洛尔、吲哚洛尔、盐酸普萘洛尔、马来酸噻吗洛尔,卡维地洛)、Ca2+通道阻滞剂(如苯磺酸氨氯地平、非洛地平、依拉地平、尼卡地平、硝苯地平、尼索地平、盐酸地尔硫、盐酸维拉帕米、阿折地平、普拉地平、分级(graded)地尔硫革制剂、(s)-氨氯地平、氯维地平)、血管紧张素转换酶(ACE)抑制剂(如盐酸贝那普利、卡托普利、马来酸依那普利、福辛普利钠、赖诺普利、莫昔普利、培哚普利、盐酸喹那普利、雷米普利、群多普利)、血管紧张素II(AT-II)拮抗剂(如氯沙坦、缬沙坦、伊贝沙坦、坎地沙坦、替米沙坦、依普沙坦、奥美沙坦(Olmesarta)、YM-358(Yamanouchi))、血管肽酶抑制剂(如奥马曲拉、吉马曲拉(Gemopatrilat)、法西多曲、山帕曲拉、AV37688(Aventis)、MI00240(Aventis)、Z13752A(Zambon/GSK)、796406(Zambon/GSK))、双重中性内肽酶和内皮肽转化酶(NEP/ECE)抑制剂(如SLV306(Solvay)、NEP抑制剂(如依卡曲尔)、醛固酮拮抗剂(如依普利酮)、肾素抑制剂(如阿利吉仑(Novartis)、SPP500(Roche/Speedel)、SPP600(Speedel)、SPP800(Locus/Speedel))、血管紧张素疫苗(如PMD-3117(Protherics))、ACE/NEP抑制剂(如AVE-7688(Aventis)、GW-66051 l(ZambonSpA))、Na+/K+ ATP酶调节剂(如PST-2238(Prassis-Sigma-Tau)、内皮素拮抗剂(如PD-156707(Pfizer))、血管扩张剂(如NCX-4016(NicOx)、LP-805(Pola/Wyeth))、利钠(naturetic)肽(如BDNP(Mayo Foundation))、血管紧张素受体阻滞剂(ARBs)(如普拉沙坦(pratosartan))、ACE交联破碎剂(如,阿拉氯胺(alagebrium chloride))、内皮素受体激动剂(如替唑生坦(Genentech)、安倍生坦(ambrisentan)(Myogen)、BMS 193884(BMS)、西他生坦(Encysive Pharmaceuticals))、SPP301(Rochel/Speedel)、达卢生坦(MyogenlAbbott)、J104132(Banyu/Merck &Co.)、TBC3711(Encysive Pharmaceuticals)、SB 234551(GSl/Shionogi))、联合疗法(例如盐酸贝那普利/氢氯噻嗪、卡托普利/氢氯噻嗪、马来酸依那普利/氢氯噻嗪、赖诺普利/氢氯噻嗪、氯沙坦/氢氯噻嗪、阿替洛尔/氯噻酮、富马酸比索洛尔/氢氯噻嗪、酒石酸美托洛尔/氢氯噻嗪、苯磺酸氨氯地平/盐酸贝那普利、非洛地平/马来酸依那普利、盐酸维拉帕米/群多普利、乐卡地平和依那普利、奥美沙坦/氢氯噻嗪、依普沙坦/氢氯噻嗪、苯磺酸氨氯地平/阿托伐他汀、尼群地平/依那普利)和MC4232(University ofManitoba/Medicure)。
在某些实施方案中,本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)与维生素、矿物质或其它营养补充剂联合使用。
在某些实施方案中,以亚适剂量(sub-optimal dose)(例如当不存在第二药剂下施用时,不能呈现可检测的治疗益处的量)给予本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)。在这样的情况下,联合施用该亚适剂量的本发明化合物与其它药剂,可产生协同效应。本发明化合物和其它药剂共同作用产生治疗益处。在其它实施方案中,以亚适剂量给予其它药剂(即,不是本发明化合物)。与本发明化合物联合,所述联合表现出治疗效果。在其它实施方案中,本发明化合物和其它药剂均以亚治疗(sub-therapeutic)剂量给予,并且在联合时产生治疗效果。其它药剂的剂量可低于在本领域使用的那些标准剂量。
用于抗糠尿病药、抗肥胖药、抗血脂异常药或抗动脉粥样硬化药、抗肥胖药、维生素,矿物质和抗高血压药(以上所列)的剂量、给药途径,制剂等是本领域已知的。治疗医师或卫生保健专业人员可以查阅诸如Physician′s Desk Reference(第59版,2005年),或Mosby′s Drug Consult and Interacations(2005)等文献以得到这些信息。可以理解的是,治疗医师将运用他的专业判断来确定针对具体患者的剂量方案。
本发明提供具有比单独施用本文所述化合物或其它的治疗方式(modality)更好的治疗概貌的治疗高胆固醇血症、动脉粥样硬化及相关病症的系统和方法。在某些实施方案中,治疗效果可以更好。在某些实施方案中,联合给药具有协同效应。在其它实施方案中,联合用药具有累加效应。联合治疗方案的施用可降低或甚至避免某些不想要的或有害的副作用。在某些实施方案中,联合给予的各药剂可以较低剂量给予,给药频率较低,或以较低频率且较低剂量给予。因此,具有上述益处的联合治疗可以提高患者的顺应性,改善治疗结果和/或降低不想要的或有害的副作用。
在某些实施方案中,根据本发明的小分子化合物包括4-苯基丁酸盐(4-phenylbutyrate)(PBA)、牛磺熊去氧胆酸(TUDCA)和三甲胺N-氧化物(TMAO)。PBA目前用来治疗α1-抗胰蛋白酶缺乏、尿素循环障碍、I型糖尿病和囊性纤维化。PBA、TUDCA或TMAO的衍生物、盐(例如钠、镁、钾、镁、铵等)、前药、酯、异构体和立体异构体也可以用于治疗高胆固醇血症、动脉粥样硬化及相关疾病。不愿受任何具体理论的束缚,认为这些化合物通过使内质网更好地处理错折叠和/或ER加工的突变蛋白质而起作用。
在某些实施方案中,本发明中使用的4-苯基丁酸盐的衍生物为下式的化合物或其药学上可接受的盐;或其混合物。
其中n是1或2;
R0是芳基、杂芳基或苯氧基,所述芳基或苯氧基是未取代的或独立地被一个或多个卤素、羟基或低级烷基(C1-C6)取代;以及
R1和R2独立地为H、低级烷氧基、羟基、低级烷基或卤素;以及
R3和R4独立地为H、低级烷基、低级烷氧基或卤素。在某些实施方案中,R0是取代或未取代的苯环。在某些实施方案中,R0是未取代的苯环。在其它实施案中,R0是单取代的苯环。在另外实施方案中,R0是双取代的苯环。在又一些其它实施方案中,R0是三取代的苯环。在某些实施方案中,R0是被1、2、3或4个卤素原子取代的苯环。在某些实施方案中,R0是取代或未取代的杂芳环。在某些实施方案中,R0是萘环(naphthyl ring)。在某些实施方案中,R0是五或六元环,优选是六元环。在某些实施方案中,R1和R2都是氢。在某些实施方案中,n是1。在其它实施方案中,n是2。在某些实施方案中,R3和R4都是氢。在其它实施方案中,R3或R4至少一个是氢。在某些实施方案中,化合物以盐的形式(例如钠盐、钾盐、镁盐、铵盐等)来使用。第5,710,178号美国专利中描述了用于本发明的其它衍生物。4-苯基丁酸盐或其衍生物可以通过商业来源得到,或者通过全合成或半合成制备。
在某些实施方案中,所述化合物是PBA。
在某些实施方案中,本发明中使用的TUDCA衍生物是下式的化合物其药学上可接受的盐:
其中R是-H或C1-C4烷基;
R1是-CH2-SO3R3,且R2是-H;或者R1是-COOH,且R2是-CH2-CH2-CONH2、-CH2-CONH2、-CH2-CH2-SCH3或-CH2-S-CH2-COOH;以及
R3是-H或碱性氨基酸残基。在某些实施方案中,所述衍生物的立体化学根据以下结构所示定义:
在某些实施方案中,R是H。在其它实施方案中,R是甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基。在某些实施方案中,R1或R2是氢。在某些实施方案中,R1是-CH2-SO3R3,且R2是-H。在其它实施方案中,R1是-COOH,且R2是-CH2-CH2-CONH2、-CH2-CONH2、-CH2-CH2-SCH3或-CH2-S-CH2-COOH。在某些实施方案中,R3是氢。在某些实施方案中,R3是赖氨酸、精氨酸、鸟氨酸或组氨酸。TUDCA和乌索脱氧胆酸的衍生物可以通过商业来源得到,由全合成制备,或用半合成获得。在某些实施方案中,例如美国专利5,550,421和4,865,765中描述了通过半合成来制备衍生物。
在某些实施方案中,本发明中使用的三甲胺N-氧化物衍生物是下式的化合物其药学上可接受的盐;或其混合物:
其中R1、R2和R3独立地为氢、卤素或C1-C6低级烷基。在某些实施方案中,R1、R2和R3是相同的。在其它实施方案中,R1、R2和R3中至少一个是不同的。在另一些其它实施方案中,R1、R2和R3都不同。在某些实施方案中,R1、R2和R3独立地为氢或者C1-C6低级烷基。在另一些其它实施方案中,R1、R2和R3独立地为C1-C6低级烷基。在另外实施方案中,R1、R2和R3独立地为甲基、乙基或丙基。在某些实施方案中,R1、R2和R3是乙基。TMAO的衍生物可通过商业来源得到,或通过全合成或半合成来制备。
在某些实施方案中,本发明方法进一步包括获得式I、II和/或III的化合物。在其它实施方案中,本发明方法进一步包括鉴定需要预防或治疗高胆固醇血症和/或动脉粥样硬化的受治疗者。
根据本发明的某些实施方案,可通过达到期望的生物学结果的任何途径对受治疗者施用治疗有效量的本发明化合物。可使用的任何途径包括口服、胃肠外、静脉内、动脉内、肌内、皮下、直肠、阴道、经皮、腹膜内和鞘内途径。在某些实施方案中,通过胃肠外给予化合物。在其它实施方案中,口服给予化合物。在使用PBA、TUDCA或TMAO中,优选口服给予化合物;然而,也可以使用上面列出的任何给药途径。在某些实施方案中,经胃肠外给予PBA、TUDCA或TMAO。在某些实施方案中,以分剂量(例如一天两次、一天三次、一天四次、一天五次)给予化合物。在其它实施方案中,每日单剂量给予化合物。
药物组合物
本发明的药物组合物和根据本发明使用的药物组合物可以包含药学上可接受的赋形剂或载体。这样,可将本发明组合物联合药学上可接受的载体用于配制药物。本文所使用的术语“药学上可接受的载体”是指无毒的、惰性固体、半固体或液体填充剂、稀释剂、包胶囊材料或任何类型的制剂辅剂。可用作药学上可接受的载体的材料的一些例子为:糖,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素、乙酸纤维素;黄蓍胶粉;麦芽;明胶;滑石粉;赋形剂,如可可脂和栓剂蜡;油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,如丙二醇;酯,如油酸乙酯和月桂酸乙酯;琼脂;去垢剂,如吐温80;缓冲剂,如氢氧化镁和氢氧化铝;褐藻酸;无热原水;等渗盐水;林格氏溶液;乙醇;人工脑脊髓液(CSF);和磷酸盐缓冲溶液;以及其它非毒性相容性润滑剂,如十二烷基硫酸钠和硬脂酸镁;以及。着色剂、释放剂、包衣材料、甜味剂、矫味剂和香料,根据配制者的判断,组合物中也可存在防腐剂和抗氧化剂。可通过以下途径对人和/或动物使用本发明药物组合物:口服、直肠、胃肠外、脑池内、阴道内、鼻内、腹膜内、局部(例如通过粉剂、霜剂、软膏剂或滴剂)、经皮、皮下、经颊或口腔或鼻腔喷雾。
可以根据已知技术,使用合适的分散剂或湿润剂以及悬浮剂来配制注射制剂(例如无菌可注射水性或油性悬浮剂)。无菌注射剂也可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射溶液、混悬剂或乳剂,例如在1,3-丁二醇中的溶液。可使用的所述可接受的赋形剂或溶剂为水、林格氏溶液、U.S.P.和等渗氯化钠溶液。另外,通常使用无菌的不挥发性油作为溶剂或悬浮介质。为此可以使用包括合成的甘油单酯或甘油二酯的任何温和的不挥发性油。另外,诸如油酸之类的脂肪酸也用于制备注射剂。
可通过以下方式对注射制剂灭菌:例如通过截菌过滤器过滤,或通过将灭菌剂加入无菌固体组合物中,可在使用前将该组合物溶于或分散于无菌水中或其它无菌的可注射介质中。
本发明的药物组合物可以和其它用于治疗或预防高胆固醇血症和/或动脉粥样硬化的药剂一起以试剂盒形式提供。所述试剂盒可以包含供治疗医生和/或患者使用的说明书,该说明可包括剂量信息、安全信息、副作用目录、药物的化学式、作用机理等。在某些实施方案中,试剂盒可以包含用于施用药物组合物的材料。例如,试剂盒可以包含供给予注射制剂的注射器、针头、酒精药签等。在某些实施方案中,当试剂盒中提供两种或更多种药剂时,可将活性药物成分单独配制或配制在一起。例如,试剂盒可以包含容纳本发明化合物(例如PBA、TUDCA、TMAO或其衍生物)的第一个容器和容纳用于治疗高胆固醇血症和相关疾病的第二种药剂的第二个容器。在某些实施方案中,活性药物成分是单独配制的。在其它实施方案中,将活性药物成分配制在一起。
实施例
实施例1
TUCA和PBA对高胆固醇血症小鼠的影响
本实施例说明了TUDCA在以下方面是有效的:(1)减轻分离自高胆固醇血症小鼠的主动脉组织上的动脉粥样硬化损害;和(2)降低得自高胆固醇血症小鼠的血样中的血胆固醇水平。
apoE-/-小鼠(高胆固醇血症和动脉粥样硬化的常用模型)购自Jackson Labs。6周龄时,用western饲粮(diet)喂养小鼠(以进一步增加胆固醇水平和血管损害)并开始用磷酸盐缓冲盐水(PBS)(赋形剂)或TUDCA(500mg/kg/日,单剂量,腹腔注射)治疗。
经western饲粮喂养并治疗3个月后,将小鼠处死并解剖主动脉,用10%缓冲福尔马林固定并用对脂质染色的油红O进行染色。相比于经TUDCA治疗的小鼠,得自经PBS治疗的动物的主动脉的油红O着色明显多,这说明TUDCA有用于预防和治疗动脉粥样硬化斑块的形成。
从上述动物获得血样,并用Picolo自动血脂分析仪(Piccolo automated devicewith lipid panel)(Abaxis,CA)测定血清胆固醇水平。图1显示TUDCA治疗显著(p<0.001)降低上述动物的胆固醇水平。这些结果说明TUDCA对降低血清胆固醇以及预防和治疗高胆固醇血症有用。
在相似条件下对PBA进行试验,发现相对于经对照物治疗的动物,约10mg/kg/日的剂量有效降低动脉粥样硬化损害量。
实施例2
TUCA和PBA对高胆固醇血症小鼠的影响
本实施例说明了TUDCA和PBA均在以下方面是有效的:(1)减轻分离自高胆固醇血症小鼠的主动脉组织上的动脉粥样硬化损害;(2)所述动脉粥样硬化的减轻不依赖于总胆固醇或超低密度脂蛋白(VLDL)水平的降低。本实施例进一步说明500mg/kg剂量的TUDCA在以下方面是有效的:(1)降低得自高胆固醇血症小鼠的血样中的总血胆固醇水平;和(2)在增加高密度脂蛋白(HDL)水平的同时,降低VLDL和低密度脂蛋白(LDL)水平。
从Jackson Labs购买apoE-/-老鼠。在6周大的时候,用西方食谱喂养老鼠并开始用磷酸缓冲盐(PBS)(载体);TUDCA(50mg/kg/日或500mg/kg/日,单剂量,腹膜内)治疗。apoE-/-小鼠购自Jackson Labs。6周龄时,用western饲粮喂养小鼠并开始用磷酸盐缓冲盐水(PBS)(赋形剂)或TUDCA(50mg/kg/日或500mg/kg/日,单剂量,腹腔注射)或4-PBA(10mg/kg/日、200mg/kg/日或1g/kg/日,单剂量,口服强饲)治疗。
经western饲粮喂养并治疗3个月后,将小鼠处死并解剖主动脉,用10%缓冲福尔马林固定并用油红O进行染色。测定每一主动脉全面积的动脉粥样硬化损害面积量,如图2(a)中所示其以百分比表示。接受赋形剂(PBS)的小鼠在主动脉弓和胸腹部主动脉中都形成了强劲的(robust)动脉粥样硬化损害(0.25%±0.06)。给予50mg/kg/日或500mg/kg/日的TUDCA完全阻止了动物中动脉粥样硬化的发展(分别为0.03%±0.01和0.01%±0.01,每组n=3,对比于对照组p<0.05)。还发现,给予10mg/kg/日剂量的PBA有效减少动脉粥样硬化损害的形成(0.09%±0.03,n=4,对比于对照组p<0.05)。然而,在更高的剂量下没有观察到类似的减少效果。
从上述动物获取血样。用HPLC进行脂蛋白谱(图2b)和总胆固醇水平(图2c)分析。总脂蛋白分析显示,用500mg/kg/日的TUDCA治疗显著降低总胆固醇、VLDL和LDL,并显著提高HDL。令人惊讶的是,虽然用50mg/kg/日的TUDCA或4-PBA治疗改变了动脉粥样硬化损害的存在量,但是总胆固醇或具体脂蛋白水平并没有观察到有显著变化。这些数据说明,化合物的抗动脉粥样硬化影响与其降低胆固醇的影响是可分离(separable)的。另外,化合物降低动脉粥样硬化损害发展的能力不依赖于其降低胆固醇的能力。
表I
与本发明的化合物联合使用的药物
抗动脉粥样硬化药
HMG-CoA还原酶抑制剂(他汀类)
阿托伐他汀(Warner-Lambert/Pfizer’s Lipitor)
普伐他汀(Bristol-Myers Squibb’s Pravachol/Sankyo’s Mevalotin)
辛伐他汀(Merck & Co.’s Zocor)
洛伐他汀(Merck & Co.’s Mevacor)
氟伐他汀(Novartis’s Lescol)
西立伐他汀(Bayer’s Lipobay/GlaxoSmithKline’s Baycol)
罗苏伐他汀(AstraZeneca’s Crestor)
匹伐他汀(伊伐他汀/risivastatin)(Nissan/Kowa/Sankyo/Novartis)
贝特类
苯扎贝特(Boehringer Mannheim/Roche’s Bezalip,Kissci’s Bezatol)
氯贝丁酯(Wyeth-Ayerst’s Atromid-S,非专利药(generics))
非诺贝特(Fournier’s Lipidil,Abbott’s Tricor,Takeda’s Lipantil,generics)
吉非贝齐(Pfizer’s Lopid,非专利药)
胆汁酸螯合剂
考来烯胺(Bristol-Myers Squibb’s Questran and Questran Light,非专利药)
考来替泊(Pharmacia’s Colestid)
烟酸
烟酸—速释型(Aventis’s Nicobid,Upsher-Smith’s Niacor,Aventis’s Nicolar,Sanwakagaku’s Perycit,非专利药)
烟酸—缓释型(Kos Pharmaceuticals’Niaspan,Upsher-Smith’s Slo-Niacin)抗血小板药
阿司匹林(Bayer’s Aspirin,非专利药)
氯吡格雷(Sanofi-Synthélabo/Bristol-Myers Squibb’s Plavix)
噻氯匹啶(Sanofi-Synthélabo’s Ticlid,Daiichi’s Panaldine,非专利药)血管紧张素转化酶抑制剂
雷米普利(Aventis’s Altace)
依那普利(Merck & Co.’s Vasotec)
血管紧张素II受体拮抗剂
氯沙坦钾(Merck & Co.’s Cozaar)
脂酰辅酶A-胆固醇乙酰转移酶(ACAT)抑制剂
阿伐麦布(Pfizer)
依鲁麦布(BioMérieux Pierre Fabre/Eli Lilly)
CS-505(Sankyo和Kyoto)
SMP-797(Sumito)
胆固醇吸收抑制剂
依泽替米贝(Schering-Plough/Merck & Co.)
帕马苷(Pfizer)
胆固醇酯转移蛋白(CETP)抑制剂
CP-529414(Pfizer)
JTT-705(Japan Tobacco)
CETi-1(Avant Immunotherapeutics)
微粒体甘油三酯转移蛋白(MTTP)抑制剂
英普他派(Bayer)
R-103757(Janssen)
其它胆固醇调节剂
NO-1886(Otsuka/TAP Pharmaceutical)
CI-1027(Pfizer)
WAY-135433(Wyeth-Ayerst))
胆汁酸调节剂
GT102-279(GelTex/Sankyo)
HBS-107(Hisamitsu/Banyu)
过氧化物酶体增殖蛋白激活性受体(PPAR)激动剂
替格列扎(AZ-242)(AstraZeneca)
萘格列酮(MCC-555)(Mitsubishi/Johnson & Johnson)
GW-409544(Ligand Pharmaceuticals/GlaxoSmithKline)
GW-501516(Ligand Pharmaceuticals/GlaxoSmithKline
基于基因的疗法
AdGVVEGF121.10(GenVec)
ApoA1(UCB Pharma/Groupe Fournier)
EG-004(Trinam)(Ark Therapeutics)
ATP-结合小盒转运蛋白-A1(ABCA1)(CV Therapeutics/lncyte,Aventis,Xenon)
复合血管保护剂
AGI-1067(Atherogenics)
其它抗动脉粥样硬化药
BO-653(Chugai Pharmaceuticals)
糖蛋白IIb/IIIa抑制剂
罗昔非班(Bristol-Myers Squibb)
更托非班(Yamanouchi)
色满非班(Millennium Pharmaceuticals)
阿司匹林及阿司匹林样化合物
Asacard(缓释阿司匹林)(Pharmacia)
帕米格雷(Kanebo/Angelini Ricerche/CEPA)
联合疗法
Advicor(烟酸/洛伐他汀)(Kos Pharmaceuticals)
氨氯地平/阿托伐他汀(Pfizer)
辛伐他汀/依泽替米贝(Merck & Co./Schering-Plough)
IBAT抑制剂
S-89-21(Shionogi)
角鲨烯合酶抑制剂
BMS-188494I(Bristol-Myers Squibb)
CP-210172(Pfizer)
CP-295697(Pfizer)
CP-294838(Pfizer)
单核细胞趋化蛋白(MCP)-1抑制剂
RS-504393(Roche Bioscience)
其它MCP-1抑制剂(GlaxoSmithKline、Teijin和Bristol-Myers Squibb)
PDR中的其它药物
适应症=高胆固醇血症
Advicor片(Kos)
洛伐他汀、烟酸
Altoprev缓释片(Andrx Labs)
洛伐他汀
Caduet片(Pfizer)
苯磺酸氨氯地平、阿托伐他汀钙
Crestor片(AstraZeneca)
罗苏伐他汀钙
Lescol胶囊(Novartis)
氟伐他汀钠
Lescol胶囊(Reliant)
氟伐他汀钠
Lescol XL片(Novartis)
氟伐他汀钠
Lescol XL片(Reliant)
氟伐他汀钠
Lipitor片(Parke-Davis)
阿托伐他汀钙
Lofibra胶囊(Gate)
非诺贝特
Mevacor片(Merck)
洛伐他汀
Niaspan缓释片(Kos)
烟酸
Pravachol片(Bristol-Myers Squibb)
普伐他汀钠
Tricor片(Abbott)
非诺贝特
Vytorin 10/10片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/10片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/20片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/20片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/40片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/40片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/80片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/80片(Schering)
依泽替米贝、辛伐他汀
WelChol片(Sankyo)
盐酸考来维仑
Zetia片(Schering)
依泽替米贝
Zetia片(Merck/Schering Plough)
依泽替米贝
Zocor片(Merck)
辛伐他汀
抗血脂异常药
HMg-CoA还原酶抑制剂
阿托伐他汀(Pfizer’s Lipitor/Tahor/Sortis/Torvast/Cardyl)
辛伐他汀(Merck’s Zocor/Sinvacor,Boehringer Ingelheim’s Denan,Banyu’sLipovas)
普伐他汀(Bristol-Myers Squibb’s Pravachol,Sankyo’s Mevalotin/Sanaprav)
氟伐他汀(Novartis’s Lescol/Locol/Lochol,Fujisawa’s Cranoc,Solvay’sDigaril)
洛伐他汀(Merck’s Mevacor/Mevinacor,Bexal’s Lovastatina,Cepa;SchwarzPharma’s Liposcler)
罗苏伐他汀(AstraZeneca’s Crestor)
匹伐他汀(Nissan Chemical,Kowa Kogyo,Sankyo,and Novartis)
HMg-CoA还原酶抑制剂联合疗法
辛伐他汀/依泽替米贝(Merck and Schering-Plough)
贝特类
非诺贝特(Abbott’s Tricor,Fournier’s Lipidil/Lipantil)
苯扎贝特(Roche’s Béfizal/Cedur/Bezalip,Kissei’s Bezatol,generics)
吉非贝齐(Pfizer’s Lopid/Lipur,generics)
氯贝丁酯(Wyeth’s Atromid-S,generics)
环丙贝特(Sanofi-Synthélabo’s Modalim)
胆汁酸螯合剂
考来烯胺(Bristol-Myers Squibb’s Questran)
考来替泊(Pfizer’s Colestid)
考来维仑(Genzyme/Sankyo’s Welchol)
胆固醇吸收抑制剂
依泽替米贝(Merck and Schering-Plough’s Zetia)
帕马苷(Pfizer)
烟酸衍生物
烟酸(Kos’s Niaspan,Yamanouchi’s Nyclin)
脂酰辅酶A-胆固醇乙酰转移酶(ACAT)抑制剂
阿伐麦布(Pfizer)
依鲁麦布(EliLilly)
胆固醇酯转移蛋白抑制剂
Torcetrapib(Pfizer)
JTT-705(Japan Tobacco)
CETi-1(Avant Immunotherapeutics)
微粒体甘油三酯转移蛋白抑制剂
英普他派(Bayer)
CP-346086(Pfizer)
过氧化物酶体增殖蛋白激活性受体激动剂
GW-501516(Ligand Pharmaceuticals/GlaxoSmithKline)
替格列扎(AstraZeneca)
LY-929(Ligand Pharmaceuticals和Eli Lilly)
LY-465608(Ligand Pharmaceuticals和Eli Lilly)
LY-518674(Ligand Pharmaceuticals和Eli Lilly)
MK-767(Merck和Kyorin)
角鲨烯合酶抑制剂
TAK-475(Takeda)
其它新方法
MBX-102(Metabolex)
NO-1886(Otsuka)
Gemcabene(Pfizer)
肝X受体激动剂
GW-3965(GlaxoSmithKline)
TU-0901317(Tularik)
胆汁酸调节剂
BTG-511(British Technology Group)
HBS-107(Hisamitsu/Banyu)
BARI-1453(Aventis)
S-8921(Shionogi)
SD-5613(Pfizer)
AZD-7806(AstraZeneca)
PDR中的其它药物
适应症=高胆固醇血症
Advicor片(Kos)
洛伐他汀、烟酸
Altoprev缓释片(Andrx Labs)
洛伐他汀
Caduet片(Pfizer)
苯磺酸氨氯地平、阿托伐他汀钙
Crestor片(AstraZeneca)
罗苏伐他汀钙
Lescol胶囊(Novartis)
氟伐他汀钠
Lescol胶囊(Reliant)
氟伐他汀钠
Lescol XL片(Novartis)
氟伐他汀钠
Lescol XL片(Reliant)
氟伐他汀钠
Lipitor片(Parke-Davis)
阿托伐他汀钙
Lofibra胶囊(Gate)
非诺贝特
Mevacor片(Merck)
洛伐他汀
Niaspan缓释片(Kos)
烟酸
Pravachol片(Bristol-Myers Squibb)
普伐他汀钠
Tricor片(Abbott)
非诺贝特
Vytorin 10/10片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/10片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/20片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/20片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/40片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/40片(Schering)
依泽替米贝、辛伐他汀
Vytorin 10/80片(Merck/Schering Plough)
依泽替米贝、辛伐他汀
Vytorin 10/80片(Schering)
依泽替米贝、辛伐他汀
WelChol片(Sankyo)
盐酸考来维仑
Zetia片(Schering)
依泽替米贝
Zetia片(Merck/Schering Plough)
依泽替米贝
Zocor片(Merck)
辛伐他汀
通过引用并入
贯穿本专利申请所引用的所有参考文献(包括参考文献、公告的专利、公开的专利申请和共同未决专利申请)的内容,通过引用将其整体特意并入本文。
等价物
本领域技术人员将认识到,或仅使用常规试验能够确定本文所述的本发明具体实施方案的许多等价物。此类等价物有意包括在随附的权利要求中。
Claims (39)
2.如权利要求1所述的方法,其中式I化合物中,R1是-CH2-SO3H且R2是-H。
3.如权利要求2所述的方法,其中R是-H。
4.如权利要求1所述的方法,其中式I化合物是牛磺熊去氧胆酸(TUDCA)。
5.如权利要求1所述的方法,其中以约10mg/kg/日~约500mg/kg/日的剂量施用式I化合物。
6.如权利要求1所述的方法,其中以约50mg/kg/日的剂量施用式I化合物。
7.如权利要求1所述的方法,其中以约低于10mg/kg/日的剂量施用式I化合物。
8.如权利要求1~7中任一项所述的方法,其中所述化合物是TUDCA的衍生物、盐或异构体。
10.如权利要求9所述的方法,其中式II化合物中,R0是苯基、萘基或苯氧基,所述苯基、萘基或苯氧基是未取代的或独立地被一个或多个卤素、羟基或低级烷基取代。
11.如权利要求9所述的方法,其中式II化合物中,
R0是苯基、萘基或苯氧基,所述苯基、萘基或苯氧基是未取代的或独立地被1~4个卤素、羟基或1~4个碳原子的低级烷基取代;
R1和R2独立地为H、羟基、1~2个碳原子的低级烷氧基、1~4个碳原子的低级直链或支链烷基或卤素;以及
R3和R4独立地为H、1~2个碳原子的低级烷氧基、1~4个碳原子的低级直链或支链烷基或卤素。
12.如权利要求9所述的方法,其中式II化合物中,n是1。
13.如权利要求9所述的方法,其中式II化合物中,n是2。
14.如权利要求9所述的方法,其中式II化合物中,R0是苯基。
15.如权利要求9所述的方法,其中式II化合物中,R0是取代的苯基。
16.如权利要求9所述的方法,其中式II化合物中,R0处苯基上的取代基是1~4个卤素部分。
17.如权利要求9所述的方法,其中式II化合物中,R3和R4都是-H。
18.如权利要求9所述的方法,其中式II化合物是4-苯基丁酸(PBA)。
19.如权利要求9所述的方法,其中以约1mg/kg/日~约少于1000mg/kg/日的剂量施用式II化合物。
20.如权利要求9所述的方法,其中以约200mg/kg/日的剂量施用式II化合物。
21.如权利要求9所述的方法,其中以约10mg/kg/日的剂量施用式II化合物。
22.如权利要求9~21中任一项所述的方法,其中所述化合物是PBA的衍生物、盐或异构体。
24.如权利要求23所述的方法,其中式III化合物中,R1、R2和R3独立地为C1-C6低级烷基。
25.如权利要求23所述的方法,其中式III化合物是三甲胺N-氧化物(TMAO)。
26.如权利要求23~25中任一项所述的方法,其中所述化合物是TMAO的衍生物、盐或异构体。
27.如权利要求1~26中任一项所述的方法,其中所述受治疗者是哺乳动物。
28.如权利要求1~27中任一项所述的方法,其中所述受治疗者是人。
29.如权利要求1~28中任一项所述的方法,其中所述施用步骤包括口服给予所述化合物。
30.如权利要求1~28中任一项所述的方法,其中所述施用步骤包括胃肠外给予所述化合物。
31.如权利要求30所述的方法,其中所述施用步骤包括化合物的静脉内给予所述化合物。
32.如权利要求1~31中任一项所述的方法,其进一步包括鉴定需要预防或治疗高胆固醇血症和/或动脉粥样硬化的受治疗者。
33.如权利要求1~32中任一项所述的方法,其进一步包括获得式I、式II和式III的化合物。
34.如权利要求1~33中任一项所述的方法,其包括进一步施用选自以下的化合物:抗动脉粥样硬化药、抗血脂异常药和治疗高胆固醇血症的药。
35.一种药物组合物,其包含权利要求1~34中任一项所述的用于治疗或预防高胆固醇血症和/或动脉粥样硬化的治疗有效量的化合物以及药学上可接受的稀释剂或载体。
36.权利要求1~35中任一项所述的化合物作为治疗或预防高胆固醇血症和/或动脉粥样硬化的药物的用途。
37.权利要求1~35中任一项所述的化合物在制备治疗或预防高胆固醇血症和/或动脉粥样硬化的药物中的用途。
38.一种试剂盒,其包含权利要求1~35中任一项所述的化合物和指导使用所述化合物按照权利要求1~31中任一项所述的方法来治疗或预防高胆固醇血症和/或动脉粥样硬化的说明书。
39.如权利要求38所述的试剂盒,其中将所述化合物配制为药物组合物,其包含用于治疗或预防高胆固醇血症和/或动脉粥样硬化的治疗有效量的化合物和药学上可接受的稀释剂和载体。
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CN110559303A (zh) * | 2019-09-24 | 2019-12-13 | 江西天元药业有限公司 | 降血脂预防治疗心脑血管病和动脉粥样硬化的精制熊胆粉 |
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IT1213390B (it) * | 1986-11-28 | 1989-12-20 | Gipharmex Spa | Composizioni farmaceutiche ad uso orale del tipo a cessione controllata nel tempo contenenti composti a struttura steroidea attivi nelle alterazioni del metabolismo del colesterolo. |
CA2167537A1 (en) * | 1993-07-19 | 1995-02-02 | Tsuneo Ozeki | Hepatitis c virus proliferation inhibitor |
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2007
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- 2007-03-22 CN CNA2007800189793A patent/CN101534641A/zh active Pending
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WO2007111992A3 (en) | 2008-11-06 |
US20090312297A1 (en) | 2009-12-17 |
AU2007230989A1 (en) | 2007-10-04 |
EP2001484A4 (en) | 2010-04-21 |
CA2679608A1 (en) | 2007-10-04 |
JP2009530398A (ja) | 2009-08-27 |
EP2001484A2 (en) | 2008-12-17 |
WO2007111992A2 (en) | 2007-10-04 |
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