CN1305469A - 苯并(b)硫杂环庚三烯-1,1-二氧化物类衍生物、其制备方法、含有这些化合物的药物组合物及其应用 - Google Patents
苯并(b)硫杂环庚三烯-1,1-二氧化物类衍生物、其制备方法、含有这些化合物的药物组合物及其应用 Download PDFInfo
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Abstract
本发明涉及取代的苯并(b)硫杂环庚三烯-1,1-二氧化物衍生物及其酸加成盐。本发明涉及式(Ⅰ)的化合物,其中R1、R2、R3、R4、R5和Z如说明书中定义,还涉及生理相容盐、具有生理功能的衍生物,还涉及其制备方法。所述化合物适合作为例如降脂血药。
Description
本发明涉及取代的苯并(b)硫杂环庚三烯-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(b)硫杂环庚三烯-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WO97/33882]。
本发明的目的是制备在治疗上表现出有用的降血脂作用的、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泄胆酸分泌的化合物。ED200值的剂量比现有技术所述的化合物降低至少5个因数是特别理想的。
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是氨基酸残基、二氨基酸残基、三氨基酸残基、四氨基酸残基,所述氨基酸残基、二氨基酸残基、三氨基酸残基或四氨基酸残基任选被氨基酸保护基单-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化合物是这些,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是氨基酸残基、二氨基酸残基,所述氨基酸残基或二氨基酸残基任选被氨基酸保护基单-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是二氨基酸残基,所述二氨基酸残基任选被氨基酸保护基单-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合于医药应用。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)生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。这些前药自身可以有活性或无活性。
本发明所述化合物也可以以不同的多晶型体存在,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。
下文中,所有“式(Ⅰ)的化合物”均是指上文所述的式(Ⅰ)的化合物和它们的盐、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必需的式(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0.1mg至50mg)/天/kg体重的范围内,如0.1-10mg/kg/天。片剂或胶囊可含有例如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(b)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,但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,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所述组合物,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色谱法进行。
术语“多种-或一种氨基酸残基”是指例如下列化合物的立体异构体形式,即D-或L-形式:丙氨酸 甘氨酸 脯氨酸半胱氨酸 组氨酸 谷酰胺天门冬氨酸 异亮氨酸 精氨酸谷氨酸 赖氨酸 丝氨酸苯丙氨酸 亮氨酸 苏氨酸色氨酸 甲硫氨酸 缬氨酸酪氨酸 天冬酰胺2-氨基己二酸 2-氨基异丁酸3-氨基己二酸 3-氨基异丁酸β-丙氨酸 2-氨基庚二酸2-氨基丁酸 2,4-二氨基丁酸4-氨基丁酸 锁链(赖氨)素哌啶酸(piperidinic acid) 2,2-二氨基庚二酸6-氨基己酸 2,3-二氨基丙酸2-氨基庚酸 N-乙基甘氨酸2-(2-噻吩基)甘氨酸 3-(2-噻吩基)丙氨酸青霉胺 肌氨酸N-乙基天冬酰胺 N-甲基异亮氨酸羟基赖氨酸 6-N-甲基赖氨酸别-羟基赖氨酸 N-甲基缬氨酸3-羟基脯氨酸 正缬氨酸4-羟基脯氨酸 正亮氨酸异锁链赖氨素 鸟氨酸别-异亮氨酸N-甲基甘氨酸
氨基酸的简写符号按照一般的常用符号(参见,Schrder,Lübke,《肽类化合物》,1卷,纽约,1965,ⅩⅫ-ⅩⅩⅢ页;Houben-Weyl,《有机化学方法》,ⅩⅤ/1和2卷,斯图加特,1974)。氨基酸pGlu是指pyroglytamyl,Nal是3-(2-萘基)丙氨酸,azagly-NH2是指式NH2-HN-CONH2的化合物和D-Asp是D型的天冬氨酸。按照其化学性质,肽是氨基酸类化合物且在水解时分解为氨基酸。
二氨基酸残基、三氨基酸残基、四氨基酸残基应理解为是由2至4个上述氨基酸合成的肽类化合物。
适用于氨基酸的保护基(参见,例如T.W.Greene,“有机合成中的保护基”)主要是:Arg(Tos),Arg(Mts),Arg(PMV),Asp(OBzl),Asp(OBut),Cys(4-MeBzl),Cys(Acm),Cys(SBut),Glu(Obzl),Glu(OBut),His(Tos),His(Fmoc),His(Dnp),His(Trt),Lys(Cl-Z),Lys(Boc),Met(O),Ser(Bzl),Ser(But),Thr(Bzl),Thr(But),Trp(Mts),Trp(CHO),Tyr(Br-Z),Tyr(Bzl)或Tyr(But)。
所用氨基保护基优选是可通过催化氢化脱除的苄氧基羰基(Z)残基,可通过弱酸断裂的2-(3,5-二甲基氧基-苯基)丙-2-基氧基羰基(Ddz-)或三苯甲基(Trt)基团和用仲胺类化合物脱除的9-芴基甲氧基羰基(Fmoc)。
本发明进一步涉及一种制备式Ⅰ的苯并(b)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是一氨基酸,则该基团在与式Ⅱ的胺键合后还可以任选地逐步加长,得到二氨基酸残基、三氨基酸残基或四氨基酸残基。
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是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:
1溶解/悬浮在5% Solutol HS15/0.4%淀粉胶浆中3)试验过程
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 |
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时的剂量。5)结果表1表示ED200排泄的测量结果表1:
6)讨论
实施例的化合物 | ED200排泄(mg/kg/天)口服 |
4 | 0.04 |
对照实施例 | |
1 | 0.8 |
2 | 1.0 |
3 | 0.9 |
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。C46H74N6O9S(887.20),MS(M+H)+=887.5得自PCT/US97/04076的对照实施例。 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):作为非对映异构体混合物的化合物6的合成
令150mg(0.35mmol)的1a/b和245mg(0.52mmol)Fmoc-D-Lys(Boc)-OH5(Fluka)在6ml DMF中与169mg TOTU、74mg肟和0.5ml NEM按照类似于化合物3的合成反应。生成290mg(94%)6a/b无定形固体。DC(乙酸乙酯/正己烷2∶1),Rf=0.6。C50H64N4O8S(881.15)。MS(M+H)+=881.5。作为非对映异构体混合物的化合物7的合成
将285mg(0.32mmol)6a/b溶解在5ml DMF中。加入0.6ml二乙胺后,令该混合物放置30分钟。按照类似于化合物3的合成处理。生成173mg(81%)的7a/b,其为无定形固体。DC(二氯甲烷/甲醇15∶1),Rf=0.2,离析物:6a/b Rf=0.4,C35H54N4O6S(658.91)。MS(M+H)+=659.4。作为非对映异构体混合物的化合物8的合成
令168mg(0.25mmol)7a/b按照类似于化合物6和7的合成法反应,得到169mg(75%,经两步)的8a/b无定形固体。DC(二氯甲烷/甲醇9∶1),Rf=0.3,C46H74N6O9S(887.20)。MS(M+H)+=887.5。
Claims (11)
2.如权利要求1所述的式Ⅰ化合物,其中一个或多个基团具有以下含义:
R1是乙基、丙基、丁基;
R2是H、OH、NH2、NH-(C1-C6)-烷基;
R3是氨基酸残基、二氨基酸残基,所述氨基酸残基或二氨基酸残基
任选被氨基酸保护基单-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;
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,其中一个或多个基团具有以下含义:
R1是乙基、丁基;
R2是OH;
R3是二氨基酸残基,所述二氨基酸残基任选被氨基酸保护基单-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;
其药学上可接受的盐。
4.一种用于制备权利要求1-3的一个或多个权利要求中所述式Ⅰ化合物的方法,该方法包括,按照以下反应式:
令其中R1、R2、R4和R5具有式Ⅰ所述含义的式Ⅱ的胺与其中R3和Z有所述含义的式Ⅲ化合物反应,脱除水得到式Ⅰ的化合物,且任选地,将式Ⅰ的化合物转化为生理可接受盐或具有生理功能的衍生物。
5.一种药物,其中含有一种或多种如权利要求1-3中一个或多个权利要求中所述的化合物。
6.一种药物,其中含有一种或多种如权利要求1-3中一个或多个权利要求中所述的化合物和一种或多种他汀类药物。
7.用作治疗脂质代谢疾病的药物的、如权利要求1-3中一个或多个权利要求中所述的化合物。
8.一种用于制备含有一种或多种如权利要求1-3中一个或多个权利要求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给药的形式。
9.如权利要求1-3中一个或多个权利要求所述的化合物在制备用于治疗高脂血症的药物中的应用。
10.如权利要求1-3中一个或多个权利要求所述的化合物在制备作用于血清胆固醇水平的药物中的应用。
11.权利要求1-3中一个或多个权利要求所述的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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DE19825804A DE19825804C2 (de) | 1998-06-10 | 1998-06-10 | 1,4-Benzothiepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
DE19825804.6 | 1998-06-10 |
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CNB998071722A Expired - Lifetime CN1152039C (zh) | 1998-06-10 | 1999-05-29 | 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 |
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EP (2) | EP1086092B1 (zh) |
JP (2) | JP4374426B2 (zh) |
KR (2) | KR100681721B1 (zh) |
CN (2) | CN1127497C (zh) |
AR (2) | AR018634A1 (zh) |
AT (2) | ATE227715T1 (zh) |
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BR (2) | BR9912188B1 (zh) |
CA (2) | CA2334775C (zh) |
CZ (2) | CZ297989B6 (zh) |
DE (3) | DE19825804C2 (zh) |
DK (2) | DK1086092T3 (zh) |
ES (2) | ES2182535T3 (zh) |
HK (2) | HK1039490A1 (zh) |
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PL (2) | PL196074B1 (zh) |
PT (2) | PT1086092E (zh) |
RU (2) | RU2215001C2 (zh) |
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GB0121337D0 (en) | 2001-09-04 | 2001-10-24 | Astrazeneca Ab | Chemical compounds |
GB0121621D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
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GB0213669D0 (en) | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
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