CN1152039C - 苯并噻庚因-1,1-二氧化物类衍生物、其制备方法、含有这些化合物的组合物及其应用 - Google Patents
苯并噻庚因-1,1-二氧化物类衍生物、其制备方法、含有这些化合物的组合物及其应用 Download PDFInfo
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- CN1152039C CN1152039C CNB998071722A CN99807172A CN1152039C CN 1152039 C CN1152039 C CN 1152039C CN B998071722 A CNB998071722 A CN B998071722A CN 99807172 A CN99807172 A CN 99807172A CN 1152039 C CN1152039 C CN 1152039C
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- ethyl
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- butyl
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Abstract
本发明涉及取代的苯并硫杂环庚三烯-1,1-二氧化物衍生物及其酸加成盐,和它们的生理相容盐和具有生理功能的衍生物,其中R1、R2、R3、R4、R5和Z如说明书中定义。本发明还涉及用于制备所述化合物的方法,所述化合物适合作为例如降血脂药。
Description
本发明涉及取代的苯并噻庚因-1,1-二氧化物类衍生物、其生理可接受盐和具有生理功能的衍生物。
苯并噻庚因-1,1-二氧化物类衍生物及其在治疗高脂血症以及动脉硬化和高胆固醇血症中的用途业已被公开[参见PCT申请号PCT/US97/04076,公开号WO 97/33882]。
本发明的目的是制备在治疗上表现出有利降血脂作用的、更有效的化合物。特别是,所述目的在于发现新的与现有化合物对比甚至在较低剂量下也可产生高排便胆酸分泌的化合物。ED200值的剂量比现有技术所述的化合物降低了至少5个因数尤其理想。
本发明涉及新的式I化合物:
其中
R1是甲基、乙基、丙基、丁基;
R2是H、OH、NH2、NH-(C1-C6)-烷基;
R3是糖基、二糖基、三糖基、四糖残基,所述糖基、二糖基、三糖基或四糖基任选被糖保护基单-或多取代;
R4是甲基、乙基、丙基、丁基;
R5是甲基、乙基、丙基、丁基;
Z是-(C=O)n-C0-C16-烷基、-(C=O)n-C0-C16-烷基-NH-、-(C=O)n-C0-C16-烷基-O-、-(C=O)n-C1-C16-烷基-(C=O)m、一个共价键;
n是0或1;
m是0或1;
及其药学上可接受的盐和具有生理功能的衍生物。
优选的式I化合物是其中一个或多个基团具有以下含义的那些:
R1是乙基、丙基、丁基;
R2是H、OH、NH2、NH-(C1-C6)-烷基;
R3是糖基、二糖基,所述糖基或二糖基任选被糖基保护基单-或多取代;
R4是甲基、乙基、丙基、丁基;
R5是甲基、乙基、丙基、丁基;
Z是-(C=O)n-C0-C16-烷基、-(C=O)n-C0-C16-烷基-NH-、-(C=O)n-C0-C16-烷基-O-、-(C=O)n-C1-C16-烷基-(C=O)m、一个共价键;
n式0或1;
m是0或1;
及其药学上可接受的盐。
特别优选的式I化合物是其中一个或多个基团具有以下含义的那些:
R1是乙基、丁基;
R2是OH;
R3是糖基,所述糖基任选被糖基保护基单-或多取代;
R4是甲基;
R5是甲基;
Z是-(C=O)-C0-C4-烷基、一个共价键;
及其药学上可接受的盐。
因其高于起始-或基础化合物的水溶性,药学上可接受的盐特别适于医药应用。这些盐必须具有药学上可接受的阴离子或阳离子。适用的本发明化合物的药学上可接受酸加成盐是:无机酸如盐酸、氢溴酸、磷酸、偏磷酸、硝酸、磺酸和硫酸的盐;和有机酸如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、葡糖酸、乙醇酸、异硫羰酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对-甲苯磺酸、酒石酸和三氟乙酸的盐。出于医药目的,特别优选采用盐酸盐。适用的药学上可接受碱性盐是铵盐、碱金属盐(例如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)。
另外,带有药学上不可接受阴离子的盐包括在本发明的范围内,如用作制备或纯化药学上可接受盐的中间体和/或用于非治疗如体外的用途。
本发明所用术语“具有生理功能的衍生物”是指本发明化合物的任何生理上可接受的衍生物,例如酯,其在对哺乳动物如人体给药时能够(直接或间接地)形成所述化合物或其活性代谢产物。
本发明的另一个方面是本发明化合物的前药。所述前药可以在体内代谢成为本发明的化合物。这些前药本身可以有活性或无活性。
本发明所述化合物也可以以不同多晶型体存在,例如无定形和结晶多晶型物。本发明化合物的所有多晶型体包括在本发明的范围内且是本发明的另外方面。
本发明的化合物还适于预防或治疗胆结石。
下文中,所有“式(I)的化合物”均是指上文所述的式(I)化合物和它们的盐、溶剂化物和此处所述的具有生理功能的衍生物。
为获得预期生物效果所需要的式(I)化合物的量取决于多种因素,例如,所选择的具体化合物、预定用途、给药方式和患者的临床病症。通常,日剂量是在0.1mg至100mg(典型地自0.1mg至50mg)/天/kg体重的范围内,如0.1-10mg/kg/天。片剂或胶囊可以含有例如0.01至100mg,典型地是0.02至50mg。在药学上可接受盐的情况中,上述重量数据涉及衍生自盐的苯并硫杂环庚三烯离子的重量。为了预防或治疗上述病症,式(I)的化合物本身可以应用,但优选它们和可接受赋形剂以药物组合物的形式存在。显然,所述赋形剂必须是可接受的,也就是说与组合物的其他组分相容并且对患者的健康无损害。赋形剂可以是固体或液体或两者皆可,并且适宜将所述化合物配制为个体剂量,例如片剂,其可含有0.05至95%(重量)的活性化合物。除了包括式(I)的化合物以外,其他药学活性物质也可以存在。本发明的药物组合物可以通过一种已知的药学方法制备,其中主要包括将所述组分与药学上可接受的赋形剂和/或辅剂混合。
本发明的药物组合物是适合口服和经口(例如舌下)给药的那些,而最适用的给药方式在各种个体情况中取决于被治疗病症的性质和严重性以及各种情况中所用的式(I)化合物的种类。包衣制剂和包衣缓释制剂也属于本发明的范围内。优选耐酸和肠溶制剂。适用的肠溶包衣包括邻苯二甲酸乙酸纤维素、邻苯二甲酸乙酸聚乙烯、邻苯二甲酸羟丙基甲基纤维素以及甲基丙烯酸和甲基丙烯酸甲酯的阴离子聚合物。
适合口服给药的药学化合物可以以分开的单位存在,例如:胶囊、囊形片、锭剂或片剂,其在各种情况中含有特定量的式(I)化合物;粉末或颗粒剂;存在于水或非水液体中的溶液或混悬液;或水包油-或油包水乳液。如上文所述,这些组合物可以按照任何适当的药学方法制备,包括使其中的活性化合物与赋形剂(可以由一种或多种组分构成)相接触的步骤。一般地,所述组合物是通过将活性化合物与液体和/或微细固体赋形剂均匀且均相混合来制备,如果必要,随后可以将产物成形。譬如,片剂可以通过将所述化合物的粉末或颗粒压制或成形制备,如果适宜,可以采用一种或多种附加组分。通过将自由流动形式如粉末或颗粒的化合物压片可以制备压型片剂,如果适合,可以与粘合剂、润滑剂、惰性稀释剂和/或一种(多种)表面活性剂/分散剂在适当设备中混合。压型片剂可以通过在适当设备中将用惰性液体稀释剂湿润的粉状化合物成形而制备。
适合经口(舌下)给药的药物组合物包括:锭剂,其含有式(I)的化合物和矫味剂,通常为蔗糖和阿拉伯胶或黄芪胶;和软锭剂,其含有存在于惰性基质如明胶和甘油或蔗糖和阿拉伯胶中的化合物。
本发明进一步涉及式I的异构体混合物和式I的纯净立体异构体,以及式I的非对映异构体混合物和纯净非对映异构体。这些混合物的分离通过特别是色谱法进行。
式I的优选外消旋和对映体纯的混合物是具有以下结构的那些:
“糖基”应理解为衍生自具有3-7个碳原子的醛糖和酮糖的化合物,并且可以属于D或L系列;这些中包括氨基糖、糖醇或糖酸。可提及的实例是葡萄糖、甘露糖、果糖、半乳糖、核糖、赤藓糖、甘油醛、景天庚酮糖、葡糖胺、半乳糖胺、葡糖醛酸、半乳糖醛酸、葡糖酸、半乳糖酸、甘露糖酸、葡糖胺、3-氨基-1,2-丙二醇、葡糖二酸和半乳糖二酸。
优选的糖基是:
特别优选的糖基是:
二糖是指由两个糖单位组成的糖类。二-、三-或四糖是通过2个或多个糖的缩醛类键合而形成。在这种情况中,所述的建可以以α或β形式出现。可以提及的实例是乳糖、麦芽糖和纤维二糖。
若糖被取代,则取代反应优选发生在糖的羟基氢原子上。
糖羟基的可用保护基主要是:苄基、乙酰基、苯甲酰基、新戊酰基、三苯甲基、叔丁基二甲基甲硅烷基、亚苄基、亚环己基或亚异丙基保护基。
本发明进一步涉及一种制备式I的苯并硫杂环庚三烯-1,1-二氧化物类衍生物的方法:
一种用于式I化合物的方法包括,将式II的胺,其中R1、R2、R4和R5具有上述式I中的定义,与式III的化合物反应,其中R3和Z具有式I中的含义,脱除水生成式I的化合物,并且将式I化合物任选地转化为生理可接受盐或一种生理功能的衍生物。如果基团R3是一糖基,则该基团在与式II的胺键合后还可以任选地逐步加长,得到二糖基、三糖基或四糖基。
式I的化合物及其药学可接受盐和具有生理功能的衍生物是用于治疗脂质代谢性疾病、特别是高血脂症的理想药物。式I化合物还适当地影响血清胆固醇水平,由此适合用来预防和治疗动脉硬化症状。所述化合物也可以任选地以与他汀类药物的组合物给药,所述他汀类化合物例如是辛伐他汀、氟伐他汀、帕伐他汀、西立他汀(cerivastatin)、洛伐斯汀或阿托斯汀(atorvastin)。下列发现证实了本发明化合物的药理学效能。
本发明化合物的生物学实验是通过测定ED200排泄作用来进行的。该实验研究了在大鼠每天给药2次后本发明化合物对回肠中的胆酸运送和粪便排泄胆酸的影响。测试了所述化合物的非对映体混合物。试验进行如下:
1)试验的制剂和参照物
下列方案用于制备水溶液:将活性物质溶解在足够量的水溶液中,该水溶液含有Solutol(=聚乙二醇600羟基硬脂酸酯;BASF,Ludwigshafen,德国;批号1763),使Solutol在该水溶液中的终浓度是5%。该溶液/混悬液的口服给药剂量为5ml/kg。
2)试验条件
维持雄性Wistar大鼠(Kastengrund,Hoechst AG体重25-350)为每组6只动物,且在治疗开始(第1天)之前接受标准混合饲料(Altromin,Lage,德国)和白天/黑夜循环节律(4:00-16:00黑夜,16:00-4:00光照)共10天。试验开始前三天(第0天),将动物分成每组4只动物。
动物分为治疗组:
组的编号 | 动物号/试验号 | 试验物质1 | 剂量(mg/kg/天) |
1 | 1-4 | 阴性对照 | 赋形剂 |
2 | 5-8 | 试验物质剂量1 | 2×0.008 |
3 | 9-12 | 试验物质剂量2 | 2×0.02 |
4 | 13-16 | 试验物质剂量3 | 2×0.1 |
5 | 17-20 | 试验物质剂量4 | 2×0.5 |
1溶解/悬浮在5% Solutol HS 15/0.4%淀粉胶浆中
3)试验过程
在对每只大鼠静脉内或皮下给予5μCi的14C-牛磺胆酸盐(第0天)后,在随后1天(第1天)的7.00-8.00和15.00-16.00时给予赋形剂或试验化合物(处理1天)。
自清晨给药后每24小时采集粪样用于分析14C-牛磺胆酸盐。称重粪便,保藏在-18℃下且随后悬浮在100ml软化水中并均质(UltraTurrax,Janke & Kunkel,IKA-Werk)。称量等份试样(0.5g)且在燃烧装置(Tri Carb307燃具堪培拉Packard GmbH,Frankfurt am Main,德国)内的燃烧罩(Combusto Cones,堪培拉Packard)上燃烧。用Carbo-Sorb(堪培拉Packard)吸收所得的14CO2。加入闪烁器(Perma-Fluor完全闪烁混合液,编号6013187,Packard)后通过液体闪烁计数(LSC)测定样本的14C放射性。粪便排泄的14C-牛磺胆酸被计算为累积和/或百分残余放射性(参见下文)。
4)观察和测量
以24小时的间隔测定燃烧粪样的等份试样中粪便排泄的14C-TCA,将其计算为给药作用的“累积百分数”且表示为残余活性(=剩余活性,即给药活性减去已排泄的活性)的百分数。为了计算剂量-反应曲线,将排泄的14牛磺胆酸表示作对照组(用赋形剂处理)的相应数值的百分比。ED200是指使排泄的14C键合胆酸增高为对照组的200%时的剂量,由S形或线性剂量反应曲线通过内推法计算出ED200。计算出的ED200相当于使粪便排泄的胆酸成双倍的剂量。
5)结果
表1表示ED200排泄的测量结果
表1:
实施例的化合物(非对映异构体混合物) | ED200排泄(mg/kg/天)口服 |
1 | 0.009 |
2 | 0.008 |
3 | 0.04 |
5 | 0.03 |
6 | 0.04 |
7 | 0.04 |
8 | 0.007 |
9 | 0.007 |
10 | 0.04 |
3(纯的结构11a) | 0.008 |
对照实施例 | |
1 | 0.8 |
2 | 1.0 |
3 | 0.9 |
6)讨论
由测量数据可以推断,本发明的式I化合物具有比现有技术的化合物更好20至100个因数的作用。
以下实施例的作用是更详细地举例说明本发明,但不限制在实施例1中的产物和实施方案。
实施例1
C30H44N2O9S(608.76).MS(M+H)+=609.3
实施例2
C40H54N2O14S(818.40),MS(M+H)+=819.3
实施例3
C35H55N3O9S(693.91).MS(M+H)+=694.4
实施例4
C37H59N3O9S(721.96).MS(M+H)+=722.3
实施例5
C41H65N3O10S(792.05).MS(M+H)+=792.5
实施例6
C42H58N2O14S(846.97),MS(M+H)+=847.4
实施例7
C32H48N2O9S(636.80).MS(M+H)+=637.4
实施例8
C45H63N3O15S(918.06).MS(M+H)+=918.6
实施例9
C35H53N3O10S(707.88).MS(M+H)+=708.4
实施例10
C47H67N3O15S(946.12).MS(M+H)+=946.5
得自PCT/US97/04076的对照实施例。
对照实施例1
对照实施例2
对照实施例3
本发明实施例和对照实施例按照以下方法制备(制备中只给出了α-非对映异构体的合成):
反应路线1:
反应路线2:
反应路线3:
作为非对映异构体混合物的化合物3的合成
将300mg(0.69mmol)的1a/b(按照类似于PCT/US 97/04076)和700mg(1.7mmol)五-O-乙酰基-D-葡糖酸(《有机合成》5卷,887)溶解在10ml DMF中。依次加入700mg(2.0mmol)TOTU、250mg(1.7mmol)肟(羟基亚氨基氰基乙酸乙酯;Fluka)和0.7ml(5.5mmol)NEM。室温下1小时后,用100ml乙酸乙酯稀释且用水洗涤3次。有机相用硫酸镁干燥,过滤且浓缩。残余物通过闪蒸式色谱(乙酸乙酯/正庚烷2∶1)的方式纯化,得到502mg(88%)3a/b,其为无定形固体。DC(乙酸乙酯/正己烷2∶1),Rr=0.3。产物3a/b在相同反应中作为离析物1a/b,但不同的是用2M硫酸染色。
C40H54N2O14S(818.40)。MS(M+H)+=819.3。
作为非对映异构体混合物的化合物4的合成
将455mg(0.55mmol)的3a/b溶解在20ml甲醇中。加入0.3ml的1M甲醇钠的甲醇溶液后,令混合物在室温下放置1小时。随后用HCl甲醇溶液中和并浓缩。残余物利用闪蒸式色谱(二氯甲烷/甲醇/浓氨水30/5/1)纯化,得到280mg(83%)4a/b,其为无定形固体。DC(二氯甲烷/甲醇/浓氨水30/5/1),Rf=0.2。
C30H44N2O9S(608.76)。MS(M+H)+=609.3。
作为非对映异构体混合物的化合物11的合成
将77mg(0.013mmol)的9a/b(按照类似于PCT/US 97/04076制备)溶解在4mlDMF中。加入150mg(0.082mmol)的10(葡糖胺,Fluka)后,将混合物在80℃加热2小时。随后用50ml乙酸乙酯稀释且用水洗涤3次。有机相用硫酸镁干燥,过滤且浓缩。在室温下放置1小时。随后用HCl甲醇溶液中和并浓缩。残余物通过闪蒸式色谱(二氯甲烷/甲醇/浓氨水30/5/1)的方式纯化,得到55mg(61%)11a/b,其为无定形固体。DC(二氯甲烷/甲醇/浓氨水30/5/1),Rf=0.3。
C35H55N3O9S(693.91)。MS(M+H)+=694.4。
化合物14的合成
将8.0g(18.8mmol)12(五-O-乙酰基-D-葡糖酰氯;《有机合成》第5卷,887)加入到8.0g(40mmol)13(Fluka)在150ml无水DMF中的悬浮液内。室温下将该悬浮液剧烈搅拌20小时。加入500ml乙酸乙酯和200ml水。再用250ml的乙酸乙酯提取该水相。合并的有机相用氯化钠溶液洗涤3次,用硫酸镁干燥,过滤且浓缩。生成9.5g(86%)14,其为无色油状物。DC(二氯甲烷/甲醇/浓氨水30/10/3),Rf=0.8。
C27H43NO13(589.64)。MS(M+H)+=590.4。
作为非对映异构体混合物的化合物15的合成
将200mg(0.34mmol)的14、78mg(0.18mmol)1a/b、240mg的TOTU、80mg肟和0.3ml NEM在4mlDMF中按照类似于化合物4的方法反应。通过闪蒸式色谱(二氯甲烷/甲醇/浓氨水30/5/1)后,得到47mg(33%,经2个步骤)的15a/b,其为无定形固体。DC(二氯甲烷/甲醇/浓氨水30/5/1),Rf=0.2。
C41H65N3O10S(792.05)。MS(M+H)+=792.5。
Claims (12)
2.如权利要求1所述的式I化合物,其中,
R1是乙基、丙基、丁基;
R2是OH;
R3是单糖基,所述单糖基未被取代或被糖基保护基单-或多取代;
R4是甲基、乙基、丙基、丁基;
R5是甲基、乙基、丙基、丁基;
Z是-(C=O)n-C0-C16-烷基、-(C=O)n-C0-C16-烷基-NH-、一个共价键;
n是0或1;
m是0或1;
或其药学上可接受的盐。
3.如权利要求1或2所述的式I化合物,其中,
R1是乙基、丁基;
R2是OH;
R3是单糖基,所述单糖基任选被糖基保护基单-或多取代;
R4是甲基;
R5是甲基;
Z是-(C=O)-C0-C4-烷基、一个共价键;
或其药学上可接受的盐。
5.如权利要求1或2所述的式I化合物,其中所述化合物具有下列结构:
或其药学上可接受的盐。
6.用于制备权利要求1中一或多个式I化合物的方法,该方法包括,按照以下反应式:
使其中R1、R2、R4和R5具有权利要求1式I中所述含义的式II的胺与其中R3和Z具有权利要求1所述含义的式III化合物反应,脱除水,得到式I化合物,并且将或不将式I化合物转化为生理可接受盐。
7.一种药物,其中含有一或多个如权利要求1中所述的化合物。
8.一种药物,其中含有一或多个如权利要求1中所述的化合物和一种或多种他汀类药物。
9.用于制备含有一或多个权利要求1中所述化合物的药物的方法,其中包括,将活性化合物与药学上适用的赋形剂混合,且使该混合物制成适合的给药形式。
10.如权利要求1所述的一或多个化合物在制备用于治疗高脂血症的药物中的应用。
11.如权利要求1所述的一或多个化合物在制备作用于血清胆固醇水平的药物中的应用。
12.权利要求1所述的一或多个化合物在制备用于预防动脉硬化症状的药物中的应用。
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ZA (2) | ZA200007060B (zh) |
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SE0000772D0 (sv) | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | Chemical compounds |
EP1345895B1 (de) * | 2000-12-21 | 2006-12-27 | Sanofi-Aventis Deutschland GmbH | Neue diphenzylazetidinone, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung zur behandlung von lipidstoffwechselstörungen |
EG26979A (en) | 2000-12-21 | 2015-03-01 | Astrazeneca Ab | Chemical compounds |
ATE411802T1 (de) * | 2001-08-22 | 2008-11-15 | Sanofi Aventis Deutschland | Kombinationspräparate von 1,4- benzothiepin-1,1- dioxidderivaten mit weiteren wirkstoffen und deren verwendung |
GB0121337D0 (en) | 2001-09-04 | 2001-10-24 | Astrazeneca Ab | Chemical compounds |
GB0121621D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
GB0121622D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
EP1427423B9 (en) | 2001-09-08 | 2017-12-20 | AstraZeneca AB | Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia |
GB0209467D0 (en) | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
GB0213669D0 (en) | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
SE0201937D0 (sv) | 2002-06-20 | 2002-06-20 | Astrazeneca Ab | Therapeutic agents |
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US20040138145A1 (en) * | 2002-12-12 | 2004-07-15 | Aventis Pharma S.A. | Application of intestinal biliary acid reuptake inhibitors for the prevention and treatment of alzheimer's disease |
GB0304194D0 (en) | 2003-02-25 | 2003-03-26 | Astrazeneca Ab | Chemical compounds |
GB0307918D0 (en) | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
DE102006053635B4 (de) * | 2006-11-14 | 2011-06-30 | Sanofi-Aventis Deutschland GmbH, 65929 | Neue mit Benzylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
DE102006053636B4 (de) * | 2006-11-14 | 2008-09-18 | Sanofi-Aventis Deutschland Gmbh | Neue mit Cyclohexylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate und deren Verwendung |
US20100221513A1 (en) * | 2008-09-05 | 2010-09-02 | Wisconsin Alumni Research Foundation | Self sintering transparent nanoporous thin-films for use in self-cleaning, anti-fogging, anti-corrosion, anti-erosion electronic and optical applications |
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JP2016514684A (ja) | 2013-03-15 | 2016-05-23 | ルメナ ファーマシューティカルズ エルエルシー | 原発性硬化性胆管炎および炎症性腸疾患の処置のための胆汁酸再循環阻害剤 |
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KR102560954B1 (ko) | 2014-06-25 | 2023-07-31 | 이에이 파마 가부시키가이샤 | 고형 제제 및 그의 착색 방지 또는 착색 감소 방법 |
EP3012252A1 (en) | 2014-10-24 | 2016-04-27 | Ferring BV | Crystal modifications of elobixibat |
US10441604B2 (en) | 2016-02-09 | 2019-10-15 | Albireo Ab | Cholestyramine pellets and methods for preparation thereof |
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US10786529B2 (en) | 2016-02-09 | 2020-09-29 | Albireo Ab | Oral cholestyramine formulation and use thereof |
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ES2874669T3 (es) | 2016-02-09 | 2021-11-05 | Albireo Ab | Formulación oral de colestiramina y uso de la misma |
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JP2020530448A (ja) | 2017-08-09 | 2020-10-22 | アルビレオ・アクチボラグ | コレスチラミン顆粒、経口コレスチラミン製剤、及びそれらの使用 |
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US11801226B2 (en) | 2018-06-20 | 2023-10-31 | Albireo Ab | Pharmaceutical formulation of odevixibat |
US11007142B2 (en) | 2018-08-09 | 2021-05-18 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US10722457B2 (en) | 2018-08-09 | 2020-07-28 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US11549878B2 (en) | 2018-08-09 | 2023-01-10 | Albireo Ab | In vitro method for determining the adsorbing capacity of an insoluble adsorbant |
US10975045B2 (en) | 2019-02-06 | 2021-04-13 | Aibireo AB | Benzothiazepine compounds and their use as bile acid modulators |
FI3921028T3 (fi) | 2019-02-06 | 2023-01-31 | Bentsotiadiatsepiinin yhdisteet ja niiden käyttö sappihapon modulaattoreina | |
EP3921027B1 (en) | 2019-02-06 | 2023-07-19 | Albireo AB | Benzothiazepine compounds and their use as bile acid modulators |
US10941127B2 (en) | 2019-02-06 | 2021-03-09 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
KR20210137046A (ko) | 2019-02-12 | 2021-11-17 | 미룸 파마슈티컬스, 인크. | 담즙정체의 치료 방법 |
TW202134220A (zh) | 2019-12-04 | 2021-09-16 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
US11014898B1 (en) | 2020-12-04 | 2021-05-25 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
CR20220315A (es) | 2019-12-04 | 2022-10-26 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como moduladores del ácido biliar |
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EP4069247A1 (en) | 2019-12-04 | 2022-10-12 | Albireo AB | Benzothiadiazepine compounds and their use as bile acid modulators |
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ES2973355T3 (es) | 2019-12-04 | 2024-06-19 | Albireo Ab | Compuestos de benzotia(di)azepina y su uso como moduladores del ácido biliar |
TW202134223A (zh) | 2019-12-04 | 2021-09-16 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
EP4069359B1 (en) | 2019-12-04 | 2024-01-03 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
WO2021110887A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
WO2022029101A1 (en) | 2020-08-03 | 2022-02-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
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KR20230106651A (ko) | 2020-11-12 | 2023-07-13 | 알비레오 에이비 | 진행성 가족성 간내 담즙정체증(pfic)을 치료하기 위한 오데빅시바트 |
AU2021390172A1 (en) | 2020-12-04 | 2023-06-22 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
TW202313579A (zh) | 2021-06-03 | 2023-04-01 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
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US5994391A (en) * | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
PT781278E (pt) * | 1994-09-13 | 2001-08-30 | Monsanto Co | Novas benzotiepinas com actividade inibidora do transporte de acido biliar ileal e da remocao do taurocolato |
DE69734100D1 (de) * | 1996-03-11 | 2005-10-06 | G D Searle Llc St Louis | Benzothiepinen mit wirkung als inhibitoren des ileumgallensäuretransports und der taurocholate-aufnahme |
US6221897B1 (en) * | 1998-06-10 | 2001-04-24 | Aventis Pharma Deutschland Gmbh | Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use |
AU5301599A (en) * | 1998-08-20 | 2000-03-14 | Takeda Chemical Industries Ltd. | Quaternary ammonium salts and their use |
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