CN101466266A - 用于治疗代谢紊乱的化合物 - Google Patents
用于治疗代谢紊乱的化合物 Download PDFInfo
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- CN101466266A CN101466266A CNA2007800214615A CN200780021461A CN101466266A CN 101466266 A CN101466266 A CN 101466266A CN A2007800214615 A CNA2007800214615 A CN A2007800214615A CN 200780021461 A CN200780021461 A CN 200780021461A CN 101466266 A CN101466266 A CN 101466266A
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- diabetes
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- phenylacetic acid
- hyperlipidemia
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Abstract
本发明提供用于治疗代谢紊乱的化合物。3-(2,4-双(三氟甲基)苄氧基)苯基乙酸、4-(2,6-二甲基苄氧基)苯基乙酸及其可药用盐可用于治疗诸如胰岛素抵抗综合征、糖尿病、多囊卵巢综合征、高脂血症、脂肪性肝病、恶病质、肥胖症、动脉粥样硬化症和动脉硬化症等各种代谢紊乱。
Description
背景技术
糖尿病是发病和死亡的重要原因。慢性高血糖导致多种使人虚弱的并发症:肾病,通常必须进行透析或肾脏移植;周围神经病变;导致失明的视网膜病;导致截肢的腿足溃疡;脂肪性肝病,有时发展成肝硬化;并容易引发冠状动脉疾病和心肌梗塞。
糖尿病有两种主要类型。I型糖尿病(或胰岛素依赖型糖尿病(IDDM))是由于胰岛内产生胰岛素的β细胞的自身免疫性损伤所致。该病通常发作在儿童期或青春期。治疗方法主要包括每天多次注射胰岛素,并结合频繁检测血糖水平以指导对胰岛素剂量的调整,这是因为过量的胰岛素会导致低血糖症,并随之导致大脑损伤和其他功能损伤。
II型糖尿病(或非胰岛素依赖型糖尿病(NIDDM))通常在成人期发展。NIDDM与诸如脂肪组织、肌肉和肝脏等利用葡萄糖的组织对胰岛素作用的抵抗有关。起初,胰岛β细胞通过分泌过量的胰岛素进行补偿。最终胰岛衰竭,导致补偿不全和慢性高血糖症。相反,中度的胰岛机能不全可先于外周胰岛素抵抗而发生或与外周胰岛素抵抗同时发生。有几类药物可用于治疗NIDDM:1)胰岛素释放剂,它直接刺激胰岛素释放,有低血糖症的危险;2)膳食胰岛素释放剂,其加强葡萄糖诱导的胰岛素分泌,必须在每餐前服用;3)双胍类药物,包括二甲双胍,该类药物能削弱肝糖异生(在糖尿病中反常升高);4)胰岛素增敏剂,例如噻唑烷二酮衍生物罗格列酮和吡格列酮,胰岛素增敏剂能提高对胰岛素的外周响应,但有诸如体重增加、浮肿和偶发的肝脏毒性等副作用;5)胰岛素注射剂,在NIDDM的晚期,当胰岛在长期的过度刺激下已经衰竭时,经常需要该胰岛素注射剂。
在没有明显的高血糖症的情况下也会发生胰岛素抵抗,胰岛素抵抗通常与动脉粥样硬化症、肥胖症、高脂血症和原发性高血压有关。该类异常构成“代谢综合征”或“胰岛素抵抗综合征”。胰岛素抵抗还与脂肪肝有关,脂肪肝可发展成慢性肝炎(NASH;“非酒精性脂肪性肝炎”)、肝纤维化和肝硬化。总体而言,胰岛素抵抗综合症包括但不局限于糖尿病,年龄超过40岁的人发病和死亡的重要原因很多始于胰岛素抵抗综合症。
尽管存在这些药物,糖尿病仍是一个重要的且日益严重的公众健康问题。糖尿病的晚期并发症消耗很大比例的国家卫生保健资源。需要能有效处理胰岛素抵抗和胰岛衰竭的主要缺陷、与已有药物相比副作用更少或更温和的新型口服活性治疗剂。
目前没有安全有效的治疗脂肪性肝病的方法。因此这样的治疗方法在治疗该病症方面将很有价值。
WO 04/073611(属于Wellstat Therapeutics Corp.)披露了在种类上涵盖本发明的化合物的一类化合物。
发明内容
本发明提供一种如下所述的生物活性剂。本发明提供如下所述的生物活性剂在制备用于治疗胰岛素抵抗综合征、糖尿病、恶病质、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化症或动脉硬化症的药物方面的应用。本发明提供治疗患有胰岛素抵抗综合征、糖尿病、恶病质、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化症或动脉硬化症的哺乳动物对象的方法,所述方法包括给对象施用有效量的如下所述的生物活性剂。本发明提供一种包含如下所述的生物活性剂和可药用载体的药物组合物。
经测试,本发明的生物活性剂在下述多种生物活性检测中显示活性,所述生物活性检测是人糖尿病和胰岛素抵抗综合征的公认动物模型。据信,本发明所有的生物活性剂也将在一种或多种这些检测中具有活性。因此,这样的制剂可用于治疗糖尿病和胰岛素抵抗综合征。
具体实施方式
此处所用的过渡术语“包含”是开放式的。使用该术语的权利要求可含有除该权利要求中所述的那些要素以外的要素。
本发明的化合物
本发明的生物活性剂选自由3-(2,4-双(三氟甲基)苄氧基)苯基乙酸;4-(2,6-二甲基苄氧基)苯基乙酸;及其可药用盐组成的组。
本文中用化学名或如下所示的双字母代码来表示某些化学化合物。化合物DN和DO包含在本发明的生物活性剂的范围内。
BI 4-(3-(2,6-二甲基苄氧基)苯基)-4-氧代丁酸
CF 3-(2,6-二甲基苄氧基)苯基乙酸
DN 3-(2,4-双(三氟甲基)苄氧基)苯基乙酸
DO 4-(2,6-二甲基苄氧基)苯基乙酸
在本发明的生物活性剂的优选实施方式中,所述活性剂基本上(至少98%)是纯态的。
本发明的生物活性剂可如WO 04/073611中所述,以及如下面的实施例中所述制备。在此通过参考引入WO 04/073611的内容。
在治疗方法中的应用
本发明提供一种对患有下述病症的哺乳动物对象进行治疗的方法,所述病症选自由胰岛素抵抗综合征、糖尿病(包括诸如I型糖尿病或II型糖尿病等原发性特发性糖尿病和继发性的非特发性糖尿病)和多囊卵巢综合征组成的组,所述方法包括给所述对象施用可有效治疗上述病症的量的如本文所述的生物活性剂。根据本发明的方法,可以减轻糖尿病的症状或减少糖尿病症状的发展机会,所述糖尿病症状是与糖尿病相关的以下症状:例如动脉粥样硬化、肥胖症、高血压、高脂血症、脂肪性肝病、肾病、神经病变、视网膜病变、足溃疡和白内障。本发明还提供一种治疗高脂血症的方法,所述方法包括给所述对象施用可有效治疗该病症的量的如本文所述的生物活性剂。化合物降低了高脂血症动物体内的血清甘油三酯和游离脂肪酸。本发明还提供了一种治疗恶病质的方法,所述方法包括给所述对象施用可有效治疗恶病质的量的如本文所述的生物活性剂。本发明还提供一种治疗肥胖症的方法,所述方法包括给所述对象施用可有效治疗该病症的量的如本文所述的生物活性剂。本发明还提供一种对选自动脉粥样硬化或动脉硬化的病症进行治疗的方法,所述方法包括给所述对象施用可有效治疗所述病症的量的如本文所述的生物活性剂。无论对象是否患有糖尿病或胰岛素抵抗综合征,本发明的活性剂都可以有效地治疗高脂血症、脂肪性肝病、恶病质、肥胖症、动脉粥样硬化症或动脉硬化症。可以通过全身性施用的任何常规途径来施用所述活性剂。该生物活性剂优选以口服给药。因此,优选的是将所述药物配制成用于口服给药的形式。可用于本发明的其他的给药途径包括直肠给药、胃肠外给药、注射给药(例如静脉内注射、皮下注射、肌内注射或腹腔内注射)或鼻腔给药。
本发明的各种治疗用途和治疗方法的进一步的实施方式均包括施用如上所述的生物活性剂的任何一种实施方式。为了避免不必要的冗余,对各活性剂和活性剂组不进行重复,但如同对其进行重复一样,它们都包含在本说明书的治疗用途和治疗方法中。
通过本发明的化合物治疗的许多疾病或紊乱属于两大类:胰岛素抵抗综合征和慢性高血糖症的后果。在本身不存在糖尿病(持续的高血糖症)时也会出现物质代谢的调节异常,特别是胰岛素抵抗,这与多种症状有关,包括高脂血症、动脉粥样硬化症、肥胖症、特发性高血压、脂肪性肝病(NASH;非酒精性脂肪性肝炎),特别是在癌症或系统性炎性疾病、恶病质情况下。恶病质也会出现在I型糖尿病情况下或II型糖尿病晚期。通过改善组织物质代谢,本发明的活性剂可用于预防或改善与胰岛素抵抗有关的疾病或症状。虽然一系列与胰岛素抵抗相关的征兆和症状可能共存于一个患者,但在许多情况下只有一种症状处于主导地位,这是由于受胰岛素抵抗侵袭的许多生理系统在易感性方面存在个体差异。虽然如此,由于胰岛素抵抗是多种病症的主要原因,因此消除该细胞缺陷或分子缺陷的药物可用于预防或改善可能由胰岛素抵抗所导致或加剧的任何器官系统中的几乎任何症状。
当胰岛素抵抗和并发的由胰岛所产生的胰岛素不足十分严重时,出现慢性高血糖症,这表明II型糖尿病(NIDDM)的发作。除了与胰岛素抵抗相关的上述代谢紊乱外,在患有NIDDM的患者中也出现继发于高血糖症的疾病症状。这些疾病症状包括肾病、周围神经病变、视网膜病、微血管病变、四肢溃烂和蛋白质的非酶糖基化的后果,例如胶原质和其他结缔组织的损伤。高血糖症衰减可降低糖尿病的这些后果的发作率和严重性。由于本发明的活性剂和组合物有助于减少糖尿病中的高血糖症,所以它们可用于预防和改善慢性高血糖症的并发症。
人类和非人类哺乳动物对象都可根据本发明的治疗方法进行治疗。用于特定对象的本发明的特定活性剂的最佳剂量可由熟练的临床医师在临床应用中确定。在对人类口服给药以治疗与胰岛素抵抗相关的紊乱、糖尿病、高脂血症、脂肪性肝病、恶病质或肥胖症的情况下,通常以1mg~400mg的日剂量施用所述活性剂,每天给药一次或两次。在对小鼠口服给药的情况下,通常以1mg~300mg活性剂/千克体重的日剂量施用所述活性剂。本发明的活性剂可用作糖尿病或胰岛素抵抗综合征中的单一疗法,或者与一种或多种在这些类型的疾病中有疗效的其他药物(例如胰岛素释放剂、膳食胰岛素释放剂、双胍或胰岛素本身)组合使用。可根据标准临床实践施用这样的附加药物。在一些情况下,本发明的制剂将提高其他种类药物的效能,使得可向患者施用更低剂量(因此毒性更小)的这些制剂,并获得令人满意的治疗结果。对人类而言,公认的安全有效的代表性化合物的剂量范围是:二甲双胍500mg/天~2550mg/天;格列本脲1.25mg/天~20mg/天;GLUCOVANCE(二甲双胍和格列本脲的复方制剂)1.25mg/天~20mg/天的格列本脲和250mg/天~2000mg/天的二甲双胍;阿托伐他汀10mg/天~80mg/天;洛伐他汀10mg/天~80mg/天;普伐他汀10mg/天~40mg/天;和辛伐他汀5mg/天~80mg/天;氯贝丁酯2000mg/天;吉非罗齐1200mg/天~2400mg/天,罗格列酮4mg/天~8mg/天;吡格列酮15mg/天~45mg/天;阿卡波糖75mg/天~300mg/天;瑞格列奈0.5mg/天~16mg/天。
I型糖尿病:患有I型糖尿病的患者主要通过每天自已施用单剂量到多剂量的胰岛素来控制他们的疾病,同时时常监测血糖以对胰岛素施用的剂量和时机进行适当的调节。慢性高血糖症导致诸如肾病、神经病变、视网膜病、足溃疡和过早死亡等并发症;胰岛素施用过量导致的低血糖症可引起认知功能障碍或意识丧失。用1mg/天~400mg/天的本发明的活性剂单剂量或分剂量治疗患有I型糖尿病的患者,所述活性剂可以是片剂或胶囊形式。预期效果是将血糖维持在令人满意的范围内所需的胰岛素的施用剂量或施用频率降低,并降低低血糖症的发生率和严重性。通过测定血糖和糖基化血红蛋白(数月期间血糖控制的合适性的综合指标)以及糖尿病的典型并发症的发生率和严重性的降低来监控临床结果。本发明的生物活性剂的施用可结合胰岛移植来进行,以帮助维持胰岛移植的抗糖尿病功效。
II型糖尿病:患有II型糖尿病(NIDDM)的典型患者通过饮食规划和锻炼,以及通过服用诸如二甲双胍、格列本脲、瑞格列奈、罗格列酮或阿卡波糖等药物来控制他们的疾病,所有这些药物都能在一定程度上改善某些患者的血糖控制,但所有药物都具有副作用或会由于疾病的发展而导致最终治疗失败。随着时间推移,在患有NIDDM的患者中会出现胰岛衰竭,使得大部分患者必须进行胰岛素注射。预期本发明的活性剂(有或没有其他类型的抗糖尿病药物)的日常治疗将改善血糖控制、降低胰岛衰竭速率并减低糖尿病的典型症状的发生率和严重性。此外,本发明的活性剂将降低升高的血清甘油三酯和脂肪酸,因而降低心血管疾病的风险,心血管疾病是糖尿病患者死亡的一个重要原因。同所有其他糖尿病治疗药剂的情况一样,可根据需要、临床效果和对副作用的易感性在个体患者中进行剂量优化。
高脂血症:血液中升高的甘油三酯和游离脂肪酸水平影响相当大的一部分人群,是动脉粥样硬化和心肌梗塞的重要危险因素。本发明的活性剂可用于降低高脂血症患者中的循环甘油三酯和游离脂肪酸。高脂血症患者通常还具有升高的血胆固醇水平,它也增加了心血管疾病的风险。除了施用本发明的活性剂外,还可给高脂血症患者施用诸如HMG-CoA还原酶抑制剂(“他汀类”)等降胆固醇用药物,作为选择,可将所述还原酶抑制剂添加到同一药物组合物中。
脂肪性肝病:相当大一部分人群患有脂肪性肝病(也称之为非酒精性脂肪性肝炎(NASH));NASH通常与肥胖症和糖尿病有关。肝脂肪变性(即甘油三酯液滴与肝细胞共存)使肝易于得慢性炎症(在活组织切片样品中检测为炎症白细胞的浸润),该慢性炎症可导致肝纤维化和肝硬化。通常,通过观测诸如转氨酶ALT和AST等作为肝细胞损伤指标的肝特定酶的血清水平的升高,以及通过包括疲劳和肝区疼痛在内的症状的表现,可检测脂肪性肝病,虽然确诊通常需要进行活组织切片检查。预期的益处是肝部炎症的缓解和脂肪含量的减少,导致NASH向肝纤维化和肝硬化发展的衰减、停止或逆转。
药物组合物
本发明提供一种药物组合物,所述组合物包含此处所述的生物活性剂和可药用的载体。本发明的药物组合物的进一步的实施方式包含上述生物活性剂的任何一个实施方式。为了避免不必要的赘述,对各活性剂和活性剂组不进行重复,但如同对其进行重复一样,它们都包含在本说明书的药物组合物中。
优选的是所述组合物适于口服,例如是片剂、包衣片剂、糖衣丸、硬胶囊或软胶囊、溶液、乳液或悬浮液形式。所述口服组合物通常包含1mg~400mg的该活性剂。这样便于患者每天吞服一个或两个片剂、包衣片剂、糖衣丸或胶囊。然而,也可将所述组合物改成适用于通过全身用药的任何其他常规方式进行给药的形式,所述全身用药的方式包括直肠给药(例如栓剂形式)、胃肠外给药(例如注射溶液的形式)或鼻腔给药。
可将所述生物活性剂与药学上无活性的无机或有机载体一起进行加工以制备药物组合物。例如,乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等可用作片剂、包衣片剂、糖衣丸和硬胶囊用的所述载体。合适的软胶囊用载体是,例如植物油、蜡、脂肪、半固体和液体多元醇等。然而,取决于活性成分的性质,在软胶囊的情况下除了软明胶本身之外通常不需要载体。合适的溶液剂和糖浆剂制备用载体是,例如水、多元醇、甘油、植物油等。合适的栓剂用载体是,例如天然油或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,所述药物组合物可包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、芳香剂、用于改变渗透压的盐、缓冲物、包衣剂或抗氧化剂。所述药物组合物还可包含其他有治疗价值的物质,特别是作用机理与本发明的化合物的起效机理不同的那些抗糖尿病药剂或降血脂药剂。可在单一制剂中与本发明的化合物有利地结合的制剂包括但不局限于:诸如二甲双胍等双胍类药物;诸如磺酰脲胰岛素释放剂格列本脲和其他磺酰脲胰岛素释放剂等胰岛素释放剂;诸如“他汀”HMG-CoA还原酶抑制剂等降胆固醇用药物,例如阿托伐他汀、洛伐他汀、普伐他汀和辛伐他汀;诸如氯贝丁酯和吉非罗齐等PPAR-α激动剂;诸如噻唑烷二酮(例如罗格列酮和吡格列酮)等PPAR-γ激动剂;诸如阿卡波糖等α-糖苷酶抑制剂(能抑制淀粉消化);和诸如瑞格列奈等膳食胰岛素释放剂。在单一制剂中与本发明的化合物组合使用的互补药剂的量与标准临床实践中所用的剂量一致。某些代表性化合物的公认安全有效的剂量范围如上所述。
通过参考下述实施例将更好地理解本发明,此处所述的实施例对本发明进行描述而不限制本发明。
实施例
实施例1
3-(2,4-双(三氟甲基)苄氧基)苯基乙酸
步骤A:3-羟基苯基乙酸乙酯的制备
将3-羟基苯基乙酸(25g,164.31mmol)和对甲苯磺酸一水合物(3.49g,18.3mmol)在无水乙醇(250ml)中的溶液回流4小时,或回流到所有的原料耗尽为止。将反应混合物浓缩,用乙酸乙酯稀释并用水洗涤。将有机层用Na2SO4干燥,过滤,浓缩,并通过在硅胶柱上快速层析(己烷:乙酸乙酯=2:1)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):1.2(t,3H);3.5(s,2H);4.1(q,2H);6.6-7.2(m,4H)。
步骤B:3-(2,4-双(三氟甲基)苄氧基)苯基乙酸乙酯的制备
在3-羟基苯基乙酸乙酯(3.22g,17.9mmol)和碳酸钾(2.92g,21.2mmol)在干燥的N,N-二甲基甲酰胺(15ml)中的溶液中加入2,4-双(三氟甲基)苄基溴(5g,16.3mmol)。反应混合物在室温搅拌5小时,用水淬灭反应,并在真空中进行浓缩。将粗残余物溶解在乙酸乙酯中,并用水和盐水洗涤。水层用乙酸乙酯提取两次。将合并的有机层用Na2SO4干燥,过滤,浓缩,并通过在硅胶柱上快速层析(己烷:乙醚=5:1)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):1.2(t,3H);3.6(s,2H);4.1(q,2H);5.3(s,2H);6.8-7.0(m,3H);7.3(m,1H);7.8(d,1H);7.9-8.0(m,2H)。
步骤C:3-(2,4-双(三氟甲基)苄氧基)苯基乙酸的制备
于室温向搅拌中的3-(2,4-双(三氟甲基)苄氧基)苯基乙酸乙酯(来自步骤B,3.88g,9.5mmol)在无水乙醇(50ml)中的溶液中添加1N NaOH(20ml)。反应混合物搅拌3小时,用1N HCl将其酸化至pH3-4,并浓缩。将残余物溶解在氯仿中并用1N HCl洗涤,用Na2SO4干燥,过滤、浓缩,并通过在硅胶柱上快速层析(氯仿:甲醇(95:5),添加有乙酸)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):3.7(s,2H);5.3(s,2H);6.8-7.0(m,3H);7.3(m,1H);7.8(d,1H);7.9-8.0(m,2H)。
实施例2
4-(2,6-二甲基苄氧基)苯基乙酸
步骤A:4-羟基苯基乙酸乙酯的制备
将4-羟基苯基乙酸(25g,164.31mmol)和对甲苯磺酸一水合物(3.49g,18.3mmol)在无水乙醇(250ml)中的溶液回流4小时,或回流到所有的原料耗尽为止。将反应混合物浓缩,用乙酸乙酯稀释并用水洗涤。将有机层用Na2SO4干燥,过滤,浓缩,并通过在硅胶柱上快速层析(己烷:乙酸乙酯=2:1)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):1.2(t,3H);3.6(s,2H);4.1(q,2H);7.0(d,2H);7.1(d,2H)。
步骤B:4-(2,6-二甲基苄氧基)苯基乙酸乙酯的制备
于0℃将2,6-二甲基苄醇(3g,22.0mmol)和偶氮二甲酸二异丙酯(DIAD,4.86g,24mmol)在THF(20ml)中的溶液逐滴加入4-羟基苯基乙酸乙酯(来自步骤A,4.36g,24.2mmol)和三苯基膦(6.30g,24mmol)在THF(100ml)中的溶液中。于相同的温度将反应混合物搅拌4小时,用乙醚稀释并用水洗涤。将有机层用Na2SO4干燥,过滤,浓缩,并通过在硅胶柱上快速层析(己烷:乙酸乙酯=4:1)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):1.2(t,3H);2.4(s,6H);3.6(s,2H);4.1(q,2H);5.0(s,2H);7.0(d,2H);7.1(d,2H);7.2-7.3(m,3H)。
步骤C:4-(2,6-二甲基苄氧基)苯基乙酸的制备
于室温向搅拌中的4-(2,6-二甲基苄氧基)苯基乙酸乙酯(来自步骤B,6.67g,22.4mmol)在无水乙醇(100ml)中的溶液中添加1N NaOH(50ml)。将反应混合物搅拌3小时,用1N HCl将其酸化至pH3-4,并浓缩。将残余物溶解在氯仿中并用1N HCl洗涤,用Na2SO4干燥,过滤,浓缩,并通过在硅胶柱上快速层析(氯仿:甲醇(95:5),添加有乙酸)来进行纯化,以得到目标化合物。
1H NMR(270MHz,CDCl3):2.4(s,6H);3.6(s,2H);5.0(s,2H);7.0(d,2H);7.1(d,2H);7.2-7.3(m,3H)。
实施例3:口服化合物DN在雄性db/db小鼠中的抗糖尿病效果
雄性db/db小鼠在用于食欲调节的蛋白质瘦素(leptin)的受体方面存在缺陷,因而发展出食欲过盛、肥胖症、胰岛素抵抗、高血糖症和高甘油三酯血症。此外,雄性db/db小鼠经历进行性胰岛衰竭,导致从高胰岛素血症变为胰岛素不足。
将雄性db/db小鼠(10周龄)分至重量匹配的小组,每组5只小鼠。年龄匹配的雄性C57BL/6小鼠用作瘦型对照组。小鼠每天摄入一次口服(管饲)剂量的载体(1%的水中的羟基丙基甲基纤维素)、化合物BI、化合物CF或化合物DN,持续两周。治疗组和药物剂量如下。
1.载体
2.化合物BI100mg/kg/天
3.化合物CF100mg/kg/天
4.化合物DN100mg/kg/天
治疗14天后收集空腹血样,用于测定血清葡萄糖、甘油三酯和游离脂肪酸。
治疗2周后,用载体治疗的小鼠严重高血糖,而且血清甘油三酯的水平升高。
如表1和表2所示,相对于在经载体治疗的小鼠中所观察到的值,化合物BI、化合物CF或化合物DN中的任何一种的施用均明显降低空腹血清葡萄糖和甘油三酯。
表1:用化合物BI、化合物CF或化合物DN治疗2周的db/db小鼠中的血清葡萄糖
N=5小鼠/组 | 葡萄糖(mg/dL)平均值±SD |
载体 | 735.0±66.0 |
化合物BI | 257.0±57.0* |
化合物CF | 441.0±162.0* |
化合物DN | 396.0±84.0* |
*与载体比较,p<0.05[学生T检验(student’s T-test)]
表2:治疗2周的db/db小鼠中的血清甘油三酯
N=5小鼠/group | 甘油三酯(mg/dL)平均值±SEM |
载体 | 220.8±62.1 |
化合物BI | 85.8±13.0* |
化合物CF | 90.5±17.4* |
化合物DN | 157.2±40.3 |
*低于载体组,p<0.05(学生T检验)
Claims (11)
1.一种生物活性剂在药物制造中的应用,所述药物用于治疗选自由胰岛素抵抗综合征、包括I型糖尿病和II型糖尿病的糖尿病和多囊卵巢综合征组成的组中的一种或多种病症;或用于治疗与糖尿病相关的动脉粥样硬化症、动脉硬化症、肥胖症、高血压症、高脂血症、脂肪性肝病、肾病、神经病、视网膜病、足溃疡或白内障或者减少这些病症的发展机会;或用于治疗选自由高脂血症、恶病质和肥胖症组成的组中的一种或多种病症;
其中,所述活性剂选自由3-(2,4-双(三氟甲基)苄氧基)苯基乙酸、4-(2,6-二甲基苄氧基)苯基乙酸及它们的可药用盐组成的组。
2.如权利要求1所述的应用,其中,将所述药物配制用于口服。
3.一种治疗患有选自由胰岛素抵抗综合征、糖尿病、多囊卵巢综合征、高脂血症、脂肪性肝病、恶病质、肥胖症、动脉粥样硬化症和动脉硬化症组成的组中的一种或多种病症的哺乳动物对象的方法,所述方法包括给所述对象施用一定量的生物活性剂,
其中,所述生物活性剂选自由3-(2,4-双(三氟甲基)苄氧基)苯基乙酸、4-(2,6-二甲基苄氧基)苯基乙酸及它们的可药用盐组成的组。
4.如权利要求3所述的方法,其中,所述对象是人。
5.如权利要求4所述的方法,其中,以1mg/天~400mg/天的量口服所述活性剂。
6.如权利要求3所述的方法,其中,所述病症是胰岛素抵抗综合征或II型糖尿病。
7.如权利要求3所述的方法,其中,所述治疗缓解糖尿病的症状或减少糖尿病症状的发展机会,其中所述症状是选自由与糖尿病相关的动脉粥样硬化症、肥胖症、高血压症、高脂血症、脂肪性肝病、肾病、神经病、视网膜病、足溃疡和白内障组成的组中的一种或多种症状。
8.一种药物组合物,所述药物组合物用于治疗选自由胰岛素抵抗综合征、糖尿病、多囊卵巢综合征、高脂血症、脂肪性肝病、恶病质、肥胖症、动脉粥样硬化、动脉硬化组成的组中的一种或多种病症,并适合口服,所述药物组合物包含可药用的载体和1mg~400mg的生物活性剂,
其中,所述活性剂选自由3-(2,4-双(三氟甲基)苄氧基)苯基乙酸、4-(2,6-二甲基苄氧基)苯基乙酸及它们的可药用盐组成的组。
9.如权利要求8所述的药物组合物,其中,所述药物组合物是口服剂型。
10.一种化合物或其可药用盐,所述化合物是3-(2,4-双(三氟甲基)苄氧基)苯基乙酸。
11.一种化合物或其可药用盐,所述化合物是4-(2,6-二甲基苄氧基)苯基乙酸。
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