CN101495183A - 治疗肌肉障碍和改善肌肉功能 - Google Patents
治疗肌肉障碍和改善肌肉功能 Download PDFInfo
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Abstract
本发明涉及如上文定义的通式Ia到Ie的化合物用作/用于组合物(特别是食物和膳食补剂、化妆品以及药物组合物)的用途,所述组合物用于预防和改善肌肉障碍和改善肌肉功能。其他应用领域是与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍,肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或治疗骨障碍如骨质疏松和骨质减少。该化合物还可被用于身体塑形,改善肌肉∶脂肪比例,或加速皮肤伤口愈合。本发明还涉及包含这类化合物的膳食组合物,如(强化)食品、饮料、(强化)饲料、食品添加剂、饮料添加剂、饲料添加剂、临床营养品、膳食补充剂、功能性食品、功能性饲料和营养品,并且涉及含有这类化合物的药物组合物,涉及在哺乳动物(包括人)中治疗上述障碍/疾病的方法,并且涉及式I的化合物自身。本发明的另一目的是这类化合物用于制造用于治疗上文所述的这类障碍/疾病的组合物的用途。
Description
本发明涉及用作药物(特别是用于治疗肌肉障碍和用于改善肌肉功能)的通式I或Ie的化合物,特别是如下文定义的通式Ia到Ig的化合物。
其他应用领域是与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍,肥胖症,超重病症,进食障碍如食欲过盛和神经性厌食症,心血管疾病,动脉粥样硬化,血管疾病,心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤和皮炎、变态反应,呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD),变应性疾病,和骨障碍如骨质疏松和骨质减少。该化合物还可被用于加速皮肤伤口愈合。
本发明还涉及包含这类化合物的膳食组合物如(强化)食品、饮料、(强化)饲料、食品添加剂、饮料添加剂、饲料添加剂、临床营养品、膳食补充剂、功能性食品、功能性饲料和营养品;并且涉及含有这类化合物的药物组合物和身体护理组合物;涉及在哺乳动物(包括人)中治疗肌肉障碍的方法;涉及改善肌肉功能的方法;涉及治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍的方法;涉及治疗下述其他病症的方法,所述病症如肥胖症,超重病症,进食障碍如食欲过盛和神经性厌食症,心血管疾病,动脉粥样硬化,血管疾病,心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤和皮炎,变态反应;涉及加速皮肤伤口愈合的方法;涉及治疗呼吸障碍如哮喘,慢性阻塞性肺疾病(COPD),变应性疾病的方法;涉及治疗骨障碍如骨质疏松和骨质减少的方法。
本发明的另一目的是这类化合物的下述用途:治疗肌肉障碍和改善肌肉功能,治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤,加速皮肤伤口愈合,治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)和变应性疾病,以及治疗骨障碍如骨质疏松和骨质减少,以及用于这些适应症/应用领域的在下文中更详细描述的(具有其中给定的优选级)化合物。
本发明的另一目的是这类化合物用于制造下述组合物的用途,所述组合物用于治疗肌肉障碍和改善肌肉功能,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘,慢性阻塞性肺疾病(COPD)和变应性疾病,以及用于治疗骨障碍如骨质疏松和骨质减少。
术语“治疗”在本文中也包括辅助治疗(co-treatment)、控制、预防和改善,以及维持健康状态。
属于“障碍”也包括疾病,以及目前状态需要被改善的个体主观意见。
我们目前发现通式I或Ie的化合物,特别是通式Ia、Ib、Ic、Id和Ie的化合物在预防、控制和/或治疗肌肉障碍和改善肌肉功能和其他使用领域中可以是有效的,所述其他使用领域例如治疗/预防与受损的脂质代谢相关的障碍、与受损的葡萄糖代谢和/或受损的胰岛素作用相关的障碍,治疗/预防肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,治疗/预防心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤和皮炎,变态反应,加速皮肤伤口愈合,治疗/预防呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD),治疗/预防变应性疾病,以及治疗/预防骨障碍如骨质疏松和骨质减少,所述通式I或Ie为
其中当L5为氢或R5时L为A或B任一,或
其中L和L5形成残基C或D,
且其中
L1为H、OH或R2;L2为H;L3为H、OH或R6;L4为H;
优选地当L为A时,L1为OH且L2、L3和L4为H;
优选地当L为B时,L1、L2和L4为H,L3为R6且L5为R5;
优选地当L和L5一起形成残基C时,L2、L4为H,L1为R2且L3为R6;
优选地当L和L5一起形成残基D时,L2、L4为H,L1为R2且L3为R6;
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8、R10为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6;
所述通式Ia、Ib、Ic、Id和Ie为
其中
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8和R10彼此独立地为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1- 6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
术语“改善肌肉功能”包括增强身体性能,特别是增强身体耐力和抗疲劳性。
骨骼肌纤维通常被分类为I型(氧化的/缓慢)或II型(糖酵解的/快速)纤维。它们在关于浓度、代谢和对疲劳的易感性方面显示显著的差异。I型纤维是富含线粒体的,并主要使用氧化的代谢用于能量生产,这提供了稳定并长效的ATP供应,从而是抗疲劳的。II型纤维包括三种亚型:IIa、IIx和IIb。IIb型纤维具有最低水平的线粒体含量和氧化酶,依赖于糖酵解代谢作为主要的能量来源,并且易于疲劳,而IIa和IIx型的氧化和收缩功能位于I型和IIb型之间。成年骨骼肌显示可塑性并可响应锻炼培训而在不同的纤维类型之间转化或调控运动神经元活性(PLOS Biology2004,2(10),e294)。
测定运动员中肌肉纤维的组成揭示了在受训练的肌肉系统中,耐力良好的运动员具有相对II型纤维来说更多的I型纤维。马拉松运动员也趋向于具有更多的I型纤维。一般认为I型纤维可能是支配身体耐久能力的一个因素。相反,衰老和身体不活动是与I型纤维减少、氧化容量和胰岛素敏感度降低相关的条件。似乎肌肉氧化容量是确定耐力和抗疲劳性的决定性因素。似乎存在骨骼肌通过控制氧化型肌纤维(I型纤维)的数量对耐力锻炼的适应性代谢应答。
IIb型骨骼肌向IIa型和I型骨骼肌的转化通过不同的信号转导途径调解。例如,Ras/促细胞分裂原-激活的蛋白质激酶(MAPK)、钙依赖磷酸镁、钙/钙调蛋白-依赖性的蛋白质激酶IV,和过氧化物酶体增殖子γ共活化物(PGC-1)。
上述化合物可调控这些途径,这可对骨骼肌纤维产生影响。
与肌肉障碍相关的这类“疾病”是肌肉消耗(muscle wasting)和相关的障碍,如老年性肌肉萎缩(sarcopenia)、恶病质、肌肉损伤,肌营养不良症和肌肉疲劳。术语“治疗肌肉障碍”还包括维持肌肉性能和/或强度和肌肉功能。此外,这类化合物可以在希望这样做的个体(也包括健康个体)中改善耐力,以及肌肉∶脂肪比例。
肌肉消耗的特征是肌肉量逐渐丧失,肌肉(特别是骨骼肌或随意肌和心肌)的削弱和退化。萎缩和肥大发生的过程在哺乳动物物种间是保守的。多种研究证明,在啮齿动物和人二者的萎缩期间发生相同的基本的分子、细胞和生理过程。
肌肉消耗归因于多种原因,并与多种病理、疾病和疾病相关。这包括但不限于由遗传性障碍造成的肌营养不良,所述遗传性障碍如Duchenne′s肌营养不良、进行性肌营养不良、Becker′s型肌营养不良、Dejerine-Landouzy肌营养不良、Erb′s肌营养不良、脊髓性肌萎缩、和婴儿神经轴肌营养不良。肌肉消耗也可能由各种慢性疾病和老龄化进程引起。随着身体的衰老,越来越多比例的骨骼肌被纤维组织取代。因此,正常的人体衰老与骨骼肌量和强度的逐步减少相关,这是称作老年性肌肉萎缩的病症,其促进脆弱(frailty)和塌陷(fall)的形成。
此外,年龄相关的障碍如高血压、葡萄糖耐受不良和糖尿病、肥胖症、血脂障碍、动脉粥样硬化和心血管疾病也与肌肉量损耗有关。
另外,其他病症如癌症、自身免疫疾病、传染病、HIV感染、AIDS、慢性炎症、关节炎、营养不良、肾脏疾病、慢性阻塞性肺疾病(COPD)、肺气肿、骨软化症、慢性腰背痛、外周神经损伤、脊髓损伤、化学损伤、中枢神经系统(CNS)损伤与肌肉消耗相关联或能够引起肌肉消耗。最后,导致肌肉消耗的病症可来源于废用性病症,如归因于病患或残疾的长期固定,如限制在轮椅中、长期的卧床休息、骨折或外伤。据估计外科手术后卧床休息引起每周约10%的骨骼肌量损耗。
未治疗的肌肉消耗障碍可造成严重的健康后果。在肌肉消耗期间发生的改变可导致削弱的身体状况,这导致身体性能差和有害的健康影响。
因此,肌肉萎缩可严重限制患者固定静养后的康复。归因于慢性疾病的肌肉消耗可导致过早丧失移动能力并且提高疾病相关发病率的风险。归因于废用性的肌肉消耗是老年人中特别严重的问题,所述老年人可能已经患有年龄相关的肌肉功能和量缺乏,这导致永久性残疾和过早死亡以及提高的骨折率。尽管该病症在临床上很重要,但是存在非常少的预防或反转该病症的疗法。
肌肉消耗通常被认为由能量或合成代谢和/或分解代谢途径中的紊乱引起,并伴随着循环炎性细胞因子、尤其是肿瘤坏死因子α(TNF-α)的慢性提高。提升的循环炎性介质(如TNF-α和白介素I(IL-I))水平被认为能触发引起肌肉消耗的事件。炎性介质通过降低或封闭卫星细胞融合或代替受损的肌纤维的能力来干扰卫星细胞的功能,该作用可最终导致骨骼肌组织的损耗。
本文所述的化合物具有抗炎活性并可适用于在哺乳动物(尤其是人)中预防和治疗导致肌肉损耗和肌肉萎缩的肌肉消耗及相关肌肉障碍,所述抗炎活性部分地由炎性介质如TNF-α生产的减少介导。
这类与受损的脂质代谢相关的疾病是异常脂肪血症(dyslipidemia)和相关的脂质异常,如高脂血症、高胆固醇血症、高甘油三酯血症、和混合性异常脂肪血症。
异常脂肪血症特征是由脂质代谢的改变导致的循环脂质水平异常。这些异常可包括任何一种或若干种不同的循环脂质级分(胆固醇、甘油三酯、脂蛋白)。异常脂肪血症包括高胆固醇血症,其为高于正常限度(人血中正常安全限度约在125-200mg/dl的范围内)的血清胆固醇提高,高甘油三酯血症,其为高于正常水平(人血中正常安全限度约在30-140mg/dl的范围内)的血清甘油三酯提高,和混合性脂质障碍。血胆固醇库通常依赖于来自肠的胆固醇膳食摄取,和来自于全身(特别是肝)的胆固醇生物合成。甘油三酯在我们的体内由膳食脂肪合成,特别是当热卡摄取量超过推荐的水平时。
在血浆中,胆固醇和甘油三酯由称作脂蛋白的蛋白质-脂质颗粒携带。已鉴定了不同种类的脂蛋白,如乳糜微粒、乳糜微粒残余物、极低密度脂蛋白(VLDL)、中密度脂质(IDL)、低密度脂蛋白(LDL)和高密度脂蛋白(HDL)。这些不同的类型在尺寸、密度和它们含有的胆固醇、甘油三酯、磷脂和载脂蛋白含量上彼此不同。LDL、HDL、VLDL和乳糜微粒最经常与异常脂肪血症相关。每种脂蛋白在其转运的脂质类型和它们被转运的位点方面发挥特异的功能。血浆中的大部分胆固醇在含载脂蛋白B的LDL和VLDL上携带。甘油三酯主要由乳糜微粒和VLDL携带。基于其功能,LDL和VLDL也被称作“不良胆固醇”,而HDL被称作“良好胆固醇”。因此,在对脂质代谢问题的做出诊断之前,在测量胆固醇时,测量其子级分(尤其是LDL、HDL和VLDL)是重要的。
异常脂肪血症包括高甘油三酯血症和混合性异常脂肪血症(高脂血症)。高甘油三酯血症涉及VLDL水平的提高,而混合性异常脂肪血症(高脂血症)涉及高甘油三酯血症和高胆固醇血症二者的组合,而且也通常伴随着HDL水平的下降。因此,异常脂肪血症也是脂蛋白代谢的障碍,其导致脂蛋白的超量生产或缺乏。异常脂肪血症典型地通过一项或多项以下内容表征:提升的血浆甘油三酯、提升的总血浆胆固醇、低高密度脂蛋白胆固醇(HDL-c)、提升的低密度脂蛋白胆固醇(LDL-c)水平。例如,异常脂肪血症可以是一种或多种以下的病症:低HDL-c(<35 or 40mg/dl)、高甘油三酯(>200mg/dl)、高LDL-c(>150mg/dl)、提升的胆固醇(>200mg/dl)。异常脂肪血症的表现通常也根据国家指导或专家推荐来定义。例如在美国,The Third Report of the National Cholesterol EducationProgram(NCEP)Expert Panel on Detection,Evaluation,and Treatment of HighBlood Cholesterol in Adults(Adult Treatment Panel III[ATP III])定义了甘露醇水平。根据ATP III规程,200-239mg/dL的总血清甘露醇水平被认为是“临界高”,大于或等于240mg/dL的水平被认为是“高”。
异常脂肪血症被广泛认为是心血管疾病(CVD)和动脉粥样硬化形成的主要危险因子之一。心血管障碍在全世界范围内属于残疾和死亡的主导原因。高血清胆固醇(尤其是与LDL和VLDL相关的胆固醇)是动脉粥样硬化的主要危险因子之一。高甘油三酯、提高的小LDL和降低的HDL水平均显示独立地致动脉粥样化。血浆HDL和CVD的风险之间存在强烈的逆关联(inverse association)。LDL胆固醇和CVD风险之间存在正关联(positive association)。因此,当LDL和VLDL水平提高时冠心病的风险提高,而HDL中携带的高水平的胆固醇则预防冠心病。甘油三酯也显示在CVD中起重要作用。高的空腹甘油三酯水平是老年人中缺血性心脏病的强危险因子,其与其他危险因子(包括HDL-胆固醇)无关。患有组合性高脂血症(特征是提升的胆固醇和甘油三酯二者的水平)的人群比仅具有高LDL胆固醇水平的人群具有更高的心脏病风险。因此,这两种水平都降低是一个想要的目标。
通常用他汀(statin)治疗高胆固醇血症,所述他汀通过抑制HMG-CoA还原酶降LDL-c的血浆浓度,但是对HDL-c几乎没有影响。使用非诺贝特(fibrate)治疗高甘油三酯血症。然而,需要相对高剂量的非诺贝特,这导致药物副作用。另外,它们仅诱导中度的HDL-c提升。
已经证明在一些患者、尤其是具有正常LDL-c水平的患者中,降低LDL-c水平不足以降低心血管疾病的风险。然而,不存在对降低LDL-c和提高HDL-c二者均有效的良好药物治疗。因此,存在对新治疗方法的需求,所述新治疗方法能够降低LDL-c和提高HDL-c。该需要被式I和If的化合物满足,特别是被本发明的式Ia到Ie的化合物满足。
这类与受损的葡萄糖代谢和受损的胰岛素作用相关的疾病为糖尿病,特别是1型和2型糖尿病,更特别的是(非自身免疫的)非胰岛素依赖性糖尿病(NIDDM;所谓的2型糖尿病)。另一种这类疾病是综合征X。
糖尿病定义了来自多种诱发因素的代谢疾病的联合体,其特征是受损的葡萄糖代谢,通常伴随着受损的蛋白质和脂肪代谢。这导致提升的空腹血糖和餐后血糖,所述提升的血糖如果不治疗的话会引起并发症。已知四种不同类型的糖尿病,(1)1型糖尿病,(2)2型糖尿病,(3)所谓的妊娠糖尿病,其在妊娠中第一次发生或被识别,和(4)主要基于遗传缺陷的一些其他形式。
术语“糖尿病”包括但不限于:代谢异常(如提高的血糖水平)、肥胖症相关的病理学、受损的葡萄糖耐受、提高的胰岛素抗性、高脂血症、异常脂肪血症、胆固醇提高(高胆固醇血症、高甘油三酯血症)、高胰岛素血症、高血压和微量白蛋白尿。受损的葡萄糖耐受和受损的空腹葡萄糖是被称作前驱糖尿病的两种症状。该阶段与所谓的胰岛素抗性相关,所述胰岛素抗性是被称作“综合征X”或“代谢综合征”的一组代谢疾病之一。因为2型糖尿病常伴随着来自综合征X的其他症状,如高甘油三酯血症或异常脂肪血症,所以根据本发明的化合物也适用于治疗或预防综合征X。
两种主要的糖尿病形式是1型和2型糖尿病,其中2型糖尿病是最主导的形式。1型和2型糖尿病伴随着高血糖症、高胆固醇血症和高脂血症。1型和2型糖尿病中对胰岛素的不敏感性和绝对的胰岛素缺乏导致肝、肌肉和脂肪组织对葡萄糖利用的降低和提高的血糖水平。不受控制的高血糖症伴随着多种器官如眼、心、血管、肾和神经的功能障碍和衰竭,导致提高的死亡率和过早的死亡,其归因于提高的微血管和大血管疾病风险,所述微血管和大血管疾病包括肾病、神经病、视网膜病变、腿和足溃疡、脂肪肝疾病、高血压、心血管疾病和脑血管疾病(中风),即所谓的糖尿病并发症。
最近的证据显示严格的血糖控制在1型和2型糖尿病二者中都是预防这些并发症的一个主要因素。因此,通过药物或治疗方案的最适血糖控制是治疗糖尿病的一个重要途径。
1型糖尿病是下述糖尿病形式,其通常在童年期或青春期开始,特征是产胰岛素的β-细胞的自身免疫破坏,导致胰岛素分泌的完全缺乏。
2型糖尿病是下述糖尿病形式,其主要在成人中发生,所述成人在疾病的早期阶段能够获得足够的胰岛素生产,但是存在胰岛素敏感性的缺陷,特别是周围组织中胰岛素介导的葡萄糖利用和代谢中存在缺陷。与2型糖尿病相关的多种组织中的改变甚至在检测出临床症状之前就存在。
高脂血症的治疗涉及膳食和生活方式的改变,随后是药理学治疗。主要的降血脂药物包括他汀类家族、烟酸(与他汀组合)、非诺贝特家族。他汀类家族的药物能够将LDL胆固醇减少60%,取决于特定的药物和剂量。他汀还能够减少甘油三酯和适当地提高HDL。尤其是在治疗开始时,大夫需要监测肝功能。他汀疗法的罕见并发症是肌肉损伤。因此,治疗期间发生肌肉疼痛时,应该通知大夫。美国目前使用的他汀的例子是立普妥(Lipitor)、辛伐他汀(Zocor)、普拉固(Pravachol)、来适可(Lescol)和Creston。烟酸可以被添加至他汀疗法中。高剂量的烟酸在提高HDL和降低甘油三酯中尤其有效。另一方面,其副作用可能是令人讨厌的。具体地,烟酸引起潮红。烟酸还引起血糖的提高,并且可能对肝是有毒的。非诺贝特家族在降低甘油三酯中尤其有效。一些大夫认为非诺贝特对于超过400mg/dl的甘油三酯水平而言是应选择的药物。当甘油三酯水平降低时,HDL通常提高。非诺贝特的毒性包括肝损伤和肌肉损伤(当与他汀组合时概率更高)。美国目前最广泛使用的非诺贝特是诺衡(Lopid)。若干种药剂减少从肠的脂肪吸收、降低血胆固醇。最常用的药剂为Zetia、Benecol、Welcol、考来烯胺(Cholestyramine)和考来替泊(Colestipol)。
因此,存在对下述具有最小副作用的化合物的需要,所述化合物用于预防、控制和/或治疗与受损的脂质代谢和高脂血症相关的障碍,和用于预防上述与之相关的身体并发症。许多患者对下述替代疗法感兴趣,所述替代疗法能够最小化与高剂量药物相关的副作用和药物抗性,并产生附加的临床益处。另外,处于发生代谢综合征的一些症状的高风险下的人群(如肥胖人群、具有2型糖尿病家族史的人群,和具有妊娠糖尿病史的妇女)需要早期预防措施。因此,对下述膳食补充剂的开发也存在越来越大的兴趣,所述膳食补充剂可被用于在处于风险下的人群(特别是老年人,以及肥胖儿童)中预防异常脂肪血症的发生。
我们目前发现通式I和Ie的化合物、特别是如上文定义的式Ia、Ib、Ic、Id和Ie的化合物,以及下文定义的式If和Ig的化合物可能是在预防、控制和/或治疗肌肉障碍,改善肌肉功能和肌肉性能,治疗与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍中的有效药剂。
这些化合物的治疗作用可包括但不限于以下所述。因此,本发明涉及通式I和Ie的化合物、特别是如上文定义的式Ia、Ib、Ic、Id和Ie的化合物和下文定义的式If和Ig的化合物(优选级:化合物4和11>化合物3、4、6和11>式If和Ig的化合物和化合物11>化合物1到6和11)用于以下的用途:
·提高健美度(fitness)、身体耐力和身体性能;即被施用了所述化合物的人或动物能够在比未施用该化合物的人或动物更长的时间内进行体力活动;
·改善骨骼肌耐力和抗疲劳性,该化合物是肌肉重塑剂,提高I型氧化性肌纤维的比例并刺激线粒体生物合成,从而提高肌肉氧化能力,这是肌肉耐力和肌肉抗疲劳性的关键因素;
·预防肌肉量损耗;抑制肌肉分解代谢并提高肌肉合成代谢,增强肌肉恢复,减少慢性疾病导致的蛋白质损耗,减少恶病质;
·预防老年性肌肉萎缩;在老年哺乳动物中预防由衰老导致的脆弱或年龄相关性功能减退,维持肌肉强度和功能;
·改善肌肉营养不良、改善由控制肌肉功能的一个或多个基因中的缺陷引起的肌肉障碍,减少骨骼肌的消耗;
·提高肌肉代谢以加强能量活动;
·通过刺激合成代谢途径,抑制分解代谢途径和在受损伤时加速肌肉再生从而增加骨骼肌量;
·降低血中的甘油三酯水平;通过调节/调整血脂水平来维持健康/正常的血脂平衡和健康/正常的血脂模式从而最优化血脂模式;通过代谢胆固醇和血脂来治疗高血脂水平和高血胆固醇水平;帮助降低高脂血症患者中的胆固醇水平;改善异常脂肪血症;即式I的化合物可以是降血脂剂;
·通过减少LDL和VLD胆固醇(“不良胆固醇”)和提高HDL胆固醇(“良好胆固醇”)改善血中的血胆固醇模式;
·是降血脂(hypolipemic)的,即通过调节血脂水平预防异常脂肪血症;
·帮助预防肥胖症;通过产生肥胖抗性的状态、抵抗膳食(脂肪)诱导的肥胖症、成为抗肥胖症的来维持最优的体重,抵抗体重增加;
·促进脂肪燃烧;作为脂肪燃烧的调节剂作用,通过脂肪酸氧化提高能量消耗,促进脂肪氧化并预防脂肪诱导的肥胖症,减少身体脂肪和增加肌肉量;
·通过提高身体的氧化能力来维持通过节食和锻炼达到的脂肪损耗;
·减少哺乳动物(特别是人)身体内的脂肪储存;
·帮助达到良好的轮廓(体形),减少身体脂肪和增加无脂肪肌肉量,预防或减轻超重;
·提高热生成;提高人或动物的代谢以燃烧更多的能量,预防肥胖症;
·减轻皮肤障碍,特别是在需要的病症中促进皮肤伤口愈合;
·减少炎症和相关的症状;
·维持能量内稳态和脂质内稳态,从而治疗或抑制例如异常脂肪血症的发展;
·帮助管理血糖水平,即通过平衡血糖水平帮助身体;帮助维持平衡的血糖水平,尤其是在患有糖尿病的人中;通过增强细胞的葡萄糖摄取和减少(循环)血糖水平来帮助,从而改善或重建葡萄糖耐受;降低血糖水平;最优化血糖应答;正常化葡萄糖耐受;即式I的化合物可以是α-葡糖苷酶抑制剂、高血糖症治疗剂和/或控制剂和血糖控制剂;
·降低对甜味的渴望;
·保持或改善胰腺β-细胞功能,从而促进健康的胰腺功能;即式I的化合物可以是胰腺β-细胞功能促进剂;
·通过例如帮助重建/增强外周组织(例如脂肪、肝和骨骼肌)中的胰岛素敏感性来治疗或控制胰岛素抗性/敏感性;即式I的化合物可以是胰岛素致敏剂;
·降低胰岛素抗性;
·延迟、预防或控制2型糖尿病(特别是NIDDM)和异常脂肪血症,从而也预防伴随着糖尿病的障碍/并发症,例如上文所述的障碍/并发症;即式I的化合物是2型糖尿病预防剂;
·激活脂肪细胞,从而提高胰岛素敏感性;
·将来自脂解内脏脂肪库(lipolytic visceral fat depot)的脂肪重新分配进皮下脂肪库中,从而降低肥胖症相关病理学如心血管疾病的风险;
·减少游离脂肪酸(FFA)的循环,从而改善肥胖人群中的胰岛素敏感性;
·维持内皮功能;
·改善骨健康和预防骨相关障碍,如骨质疏松和骨质减少。
因此,本发明涉及通式I和Ie的化合物,其用作药物,特别是用于治疗肌肉障碍、改善肌肉功能和肌肉性能,以及治疗与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍,所述通式I和Ie为
其中当L5为氢或R5时,L为A或B任一,或
其中L和L5形成残基C或D,
且其中
L1为H、OH或R2;L2为H;L3为H、OH或R6;L4为H;
优选地当L为A时,L1为OH且L2、L3和L4为H;
优选地当L为B时,L1、L2和L4为H,L3为R6且L5为R5;
优选地当L和L5一起形成残基C时,L2、L4为H,L1为R2且L3为R6;
优选地当L和L5一起形成残基D时,L2、L4为H,L1为R2且L3为R6;
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8、R10为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
优选地,本发明涉及通式Ia到Ie的化合物,其用作药物,特别是用于治疗肌肉障碍、改善肌肉功能和肌肉性能,以及治疗与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍,所述通式Ia到Ie为
其中
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8和R10彼此独立地为C1-6-烷氧基;
R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
另外,如上文定义的式I和Ie的化合物,特别是式Ia到If的化合物也可以是:
·抗动脉粥样硬化的,即帮助预防动脉粥样硬化;通过调控涉及动脉粥样硬化发生的多种过程而具有抗动脉粥样硬化作用,所述调控例如提高血浆HDL、降低细胞(特别是巨噬细胞)中脂质摄取和降低促炎症标记物;
·抗炎症的;即帮助预防炎症;
·促进皮肤健康,特别是预防和/或减弱银屑病、痤疮、肉赘、色素沉着、角化病、鱼鳞病、皮肤病损、白斑、酒渣鼻,加速/促进皮肤伤口愈合。
用于这些用途特别优选的是式Ia到Ie的化合物,其中
·R2为氢、羟基或甲氧基;和/或
·R3和R4彼此独立地为羟基或甲氧基;
·R6为羟基或甲氧基;和/或
·R5为氢或甲氧基;
·R7为氢;或
·R5和R7一起为-O-;
·R8和R10为甲氧基;和/或
·R9为氢、甲氧基或肉桂酰氧基;或
·R9和R10一起形成基团O-(CH2)x-O,其中x=1或2;和/或
·R17为N-乙酰基,N-甲基-2-氨乙基。
在本发明一个特别优选的实施方案中,使用选自以下的化合物或它们的混合物:
·通式Ia的化合物,其中R1=R3=R4=OH且R2=H(=化合物1;见图1);
·通式Ia的化合物,其中R1=OH、R2=R3=R4=甲氧基(=化合物2;见图1);
·通式Ib的化合物,其中R5=R6=R8=R10=甲氧基且R7=R9=R17=H(=化合物3;见图2);
·通式Ib的化合物,其中R5=R7=H,R6=R8=甲氧基,R9和R10一起形成-O-CH2-O-且R17=(N-酰基,N-甲基)-2-氨乙基(=化合物4;见图2);
·通式Ib的化合物,其中R5=R7=R8=R10=R17=H,R6=甲氧基且R9=肉桂酰氧(=化合物5;见图2);(CAS-No.619313-14-3)
·通式Ib的化合物,其中R5=R7=R8=R17=H,R6=R9=R10=甲氧基(=化合物6;见图2);
·通式Ib的化合物,其中R8=R9=R17=H,R6=OH,R5和R7一起为O,R10=甲氧基(=化合物7;见图2);(CAS-No.20727-61-1)
·通式Ib的化合物,其中R5=R7=R9=R17=H,R6=R8=R10=甲氧基(=化合物8;见图2);
·通式Ic的化合物,其中R3=R4=OH,且R2=R6=H(=化合物9;见图3);
·通式Ic的化合物,其中R2=R3=R6=OH,且R4=甲氧基(=化合物10;见图3);
·通式Id的化合物,其中R2=R3=H且R4=R6=甲氧基(=化合物11;见图4);
·通式Ie的化合物,其中R3=R4=甲氧基且两个氢彼此是顺式的(=化合物12;见图5)。
进一步更优选的是化合物1到8和11,然后是化合物1到6和11,然后是化合物11、下文定义的通式Ig的化合物和通式If的化合物(其中X1=H或CH3且X2=X3、X4或X5),然后是化合物3、4、6和11(落入通式If中的化合物,其中X1=H或CH3且X2=X3、X4或X5和落入通式Ig中的化合物)。最优选的是化合物4和11,特别是化合物11。
术语“式Ia/Ib/Ic/IáVIe/If/Ig的化合物”还包括含有式Ia/Ib/Ic/Id/Ie/If/Ig的这类化合物的任何植物材料或提取物,优选其含量以所述植物材料或提取物的总重为基础至少1wt-%(重量百分比) (除了在化合物1的情况下),更优选地其含量为至少50wt-%,进一步更优选地其含量为至少90wt-%。在本发明的上下文中使用的术语“植物的材料”和“植物材料”表示植物的任何部分。
化合物1(N-[3-(3,4-二羟苯基)-1-氧代-2-丙烯基]-2-羟基苯甲酰胺),2E或2Z或二者兼有,可分离自植物如Avena sativa(但不仅限于此)。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物1的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少50wt-%,更优选地含量为至少70wt-%,进一步更优选地含量为至少90wt-%。“化合物1”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物1。如果使用Avena sativa的提取物或部分作为化合物1自身的备选方案,则这些提取物或部分优选地本质上不含有任一种以下成分:生育酚、母育酚、黄酮、非黄酮类酚酸(例如avenanthramide、咖啡酸、阿魏酸)。
化合物2(2-羟基-N-[1-氧代-3-(3,4,5-三甲氧基苯基)-2-丙烯基苯甲酰胺]),2E或2Z或二者兼有,可以作为代谢产物从植物如Alstonialenormandii(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物2的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物2”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物2。
化合物3(3-(2,4-二甲氧基苯基)-1-(2,5-二甲氧基苯基)-2-丙烯-1-酮),2E或2Z或二者兼有,可以作为次要代谢产物从植物如Scutellariaindica(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物3的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物3”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物3。
化合物4,2E或2Z或二者兼有,可以作为痕量代谢产物从植物如Papaver pseudo orientale和罂粟植物(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物4的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物4”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物4。
化合物5(3-苯基-2-丙烯酸3-[3-(4-甲氧基苯基)-3-氧代-1-丙烯基]苯基酯),2E,1E或2Z,1Z或二者兼有,可以从植物如Glycyrrhiza glabra(甘草)(但不仅限于此)的培养的愈伤组织细胞中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物5的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物5”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物5。
化合物6(3-(3,4-二甲氧基苯基)-1-(4-甲氧基苯基)-2-丙烯-1-酮),2E或2Z或二者兼有,可以从植物如Glycyrrhiza glabra(甘草)(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物6的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物6”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物6。
化合物6的合成例如由Lin,Chun-Nan;Lee,Tai-Hua;Hsu,Mei-Feng;Wang,Jih-Pyang;Ko,Feng-Nien;Teng,Che-Ming在JPPMAB;J.Pharm.Pharmacol.;EN;49;5;1997;530-536中和由Patt,William C;Edmunds,Jeremy J.;Repine,Joseph T.;Berryman,Kent A.;Reisdorph,Billy R.;et al.在JMCMAR;J.Med.Chem.;EN;40;7;1997;1063-1074中描述。
化合物7(6-羟基-2-(4-甲氧基苯基)亚甲基)-3(2H)-苯并呋喃酮),2E或2Z或二者兼有,可以从植物如Glycine max和Lygos raetam(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物7的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物7”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物7。
化合物7的合成例如由Geissman and Harborne在JACSAT;J.Am.Chem.Soc;78;1956;832,837中描述。
化合物8(3-(2,4-二甲氧基苯基)-1-(4-甲氧基苯基)-2-丙烯-1-酮),2E或2Z或二者兼有,可以从植物如Prunus cerasus(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物8的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物8”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物8。
化合物8的合成例如由Kamat,,Vinayak S.;Graden,David W.;Lynn,David G.;Steffens,John C;Riopel,James L.;TELEAY在Tetrahedron Lett.;EN;23;15;1982;1541-1544中描述。
化合物9可从植物如Primula officinalis和大豆(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物9的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物9”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物9。
化合物9的合成例如由Journal of Organic Chemistry 1991,56(16),4884-7中的Nagarathnam,Dhanapalan;Cushman,Mark,″A short and facilesynthetic route to hydroxylated flavones.New syntheses of apigenin,tricin,andluteolin.″描述。
化合物10(香叶木素)可以从Valeriana spp.的地上部分、Digitalis spp.的叶、柠檬(Citrus limon)的果皮(但不仅限于此)中分离。因此,该术语也包括这些植物的任何材料或提取物或含有化合物10的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物10”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物10。
化合物10的合成例如由Bulletin de Ia Societe Chimique de France 1959,854-5中的Teoule,R.;Chopin,J.;Mentzer,C,″A new synthesis of diosmetinand some of its derivatives.″描述。
化合物11(4′,7-二甲氧基异黄酮)可从植物如Dalbergia violacea和Pterodon apparicioi心材(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物11的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物11”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物11。
化合物11的合成例如由Synthetic Communications 2000,30(3),469-484中的Balasubramanian,Sreenivasan;Nair,Muraleedharan G.,″An efficient″one pot″synthesis of isoflavones.″描述。
化合物12(美迪紫檀素)可从植物如Leguminosae subf.Papilionoideae、Osteophloeum platyspermum、Dalbergia spp.和Swartziamadagascariensis(但不仅限于此)中分离。
因此,该术语也包括这些植物的任何材料或提取物或含有化合物12的任何其他植物材料或提取物,优选以所述植物材料或提取物的总重为基础其含量为至少1wt-%,更优选地含量为50wt-%,进一步更优选地含量为至少90wt-%。“化合物12”既表示“天然的”(经分离的)也表示“合成的”(制造的)化合物12。
化合物12的合成例如由Indian Journal of Chemistry,Section B:OrganicChemistry Including Medicinal Chemistry 1990,29B(4),366-8中的Nabaei-Bidhendi,G.;Bannerjee,N.R.;″Convenient syntheses of 7-demethylhomopterocarpin and 7-demethylpterocarpin.″描述。
除了(纯净的)化合物1到12以外,优选的是植物材料和植物提取物,特别是以植物材料/提取物总重为基础含有至少10wt-%、优选地至少50wt-%、更优选地至少90wt-%这些化合物的植物材料/提取物。
本发明还涉及上文定义的式Ia/Ib/Ic/Id/Ie/If/Ig的化合物用于制造下述组合物的用途,所述组合物用于治疗肌肉障碍,改善肌肉功能和肌肉性能,治疗与受损的脂质代谢、受损的葡萄糖代谢和受损的胰岛素作用相关的障碍。
在本发明多个优选的实施方案中,该组合物被用作身体性能增强剂、耐性提高剂、肌肉损耗减少剂、HDL胆固醇增加剂、甘油三酯和胆固醇减少剂、血糖控制剂、胰岛素致敏剂、降血脂剂、胰腺β-细胞功能改善剂、2型糖尿病预防剂和/或综合征X预防剂。
本发明还涉及含有至少一种上文定义的式I或Ie的化合物的膳食组合物,特别是含有至少一种式Ia/Ib/Ic/Id/Ie/If/Ig的化合物的膳食组合物,
其中
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8和R10彼此独立地为C1-6-烷氧基;
R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
R2优选地为氢、羟基或甲氧基。
R3和R4彼此独立地优选地为羟基或甲氧基。
R6优选地为羟基或甲氧基。
R5优选地为氢或甲氧基。
R7优选地为氢。
R8和R10优选地为甲氧基。
R9优选地为氢、甲氧基或肉桂酰氧基。
还优选含有式Ib的化合物(其中R5和R7一起为-O-)的膳食组合物。
还优选含有式Ib的化合物(其中R9和R10一起形成基团O-(CH2)x-O,其中x=1或2;特别是其中R9和R10一起形成基团O-CH2-O)的膳食组合物。
R17优选地为N-乙酰基,N-甲基-2-氨乙基。
在本发明一个优选的实施方案中,膳食组合物含有至少一种选自下组的化合物,所述组由上文定义的化合物1到8和11组成,优选地由化合物1到6和11组成,更优选地由式If的化合物和化合物11组成,进一步更优选地由化合物3、4、6和11组成,最优选地由化合物4和11组成。
术语“膳食组合物”包括任何类型的(强化)食品、(强化的)(动物)饲料,和还包含临床营养品的饮料,膳食补充剂以及相应的添加剂:食品添加剂、饮料添加剂、饲料添加剂。还包括功能性食品/饲料,即用维生素、其他微量营养物或药物增强以提供特定的健康益处的食品/饲料,以及营养药物,即具有营养价值的药丸或其他药物制品。
根据本发明的膳食组合物可还含有保护性水胶体(例如树胶、蛋白质、变性淀粉)、粘合剂、成膜剂、包封剂/材料、臂/壳材料、基质化合物、包衣、乳化剂、表面活性剂、增溶剂(油、脂肪、蜡、卵磷脂等等)、吸附剂、载体、填充剂、辅助化合物、分散剂、湿润剂、加工助剂(溶剂)、流动剂、遮味剂、增重剂、啫喱化剂(jellyfying agents)、凝胶形成剂、抗氧化剂和抗微生物剂。
本发明还涉及含有至少一种式I或Ie或If的化合物的药物组合物,特别是下述药物组合物,其含有至少一种具有上文给定的R2到R17定义和优选级的式Ia、Ib、Ic、Id或Ie或If的化合物和常规的药物载体。
特别优选的是其中式Ia到Ie的化合物选自下组的药物组合物,所述组由上文定义的化合物1到8和11组成,优选地由化合物1到6和11组成,更优选地由通式If的化合物和化合物11组成,进一步更优选地由化合物3、4、6和11组成,最优选地由化合物4和11组成。
除了可药用的载体和至少一种式I或Ie的化合物、特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物或如上文定义的式If的化合物或如下文定义的式Ig的化合物以外,根据本发明的药物组合物可还含有常规的药物添加剂和佐剂、赋形剂或稀释剂,包括但不限于水、任何来源的明胶、植物胶、酸木质素磺酸盐、滑石、糖、淀粉、阿拉伯胶、植物油、聚亚烷基二醇、调味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、湿润剂、填充剂等等。载体材料可以是适用于口/肠胃外/注射施用的有机或无机惰性载体。
根据本发明的膳食和药物组合物可以是适用于对动物体(包括人体)施用的任何盖仑形式(galenic form),特别是对经口施用而言常规的任何形式,例如固体形式如食品或饲料(用于食品或饲料的添加剂/补充剂)、食品或饲料预混合物、强化的食品或饲料、片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制物如粉末和片剂,或液体形式如溶液、乳液或悬浮液,如例如饮料、糊剂和油悬浮液。糊剂可以被填充进硬壳或软壳胶囊中,藉此该胶囊具有(鱼、猪、家禽、牛)明胶、植物蛋白质或木质素磺酸盐基质。其他应用形式的例子是用于经皮、肠胃外或可注射施用的形式。膳食组合物和药物组合物可以是受控(延迟)释放配制物的形式。
强化食品的例子是谷物棒、烘焙物如蛋糕和曲奇。
饮料包括无醇饮品和含酒精的饮品,以及要添加进饮用水和液体食品中的液体制剂。无醇饮品为例如软饮、运动饮品、果汁、柠檬水、茶和基于乳的饮品。液体食品为例如汤和乳制品。
式I和Ie的化合物、特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物或如上文定义的式If的化合物或如下文定义的式Ig的化合物以及以下述含量含有它们的植物材料和植物提取物(的混合物)和含有它们的膳食/药物组合物因此适用于治疗哺乳动物(包括人),所述含量以植物材料或提取物的总重为基础优选地为至少1wt-%(化合物1例外),更优选地为至少50wt-%,进一步更优选地为至少90wt-%。
本发明还涉及身体护理组合物,其含有至少一种式I或Ie的化合物、特别是具有上文给定的R2到R17定义和优选级的式Ia、Ib、Ic、Id或Ie的化合物或一种如上文定义的式If的化合物或一种如下文定义的式Ig的化合物和常规的化妆品载体。身体护理组合物涵盖皮肤护理制剂、含有香味剂和/或香料的制剂、制剂、头发护理制剂、洁牙剂、除臭剂和止汗剂、修饰性制剂、光防护制剂和功能性制剂,以及促进/改善皮肤伤口愈合/或皮肤再生的制剂。
护肤制剂的例子特别是身体油、身体乳液、身体凝胶、修护霜、护肤软膏、剃须制剂(如剃须泡沫或凝胶)、爽肤粉、保湿凝胶、保湿喷雾、活肤身体喷雾和去死皮制剂。
含有气味和/或香料的制剂尤其是香水、花露水和剃须乳液(须后制剂)。
护发制剂的例子为例如人和动物用的香波、护发素、用于造型和处理头发的产品、定型剂、发用喷雾和发用光亮剂(lacquer)、发用凝胶、发用固定剂和染发剂或漂白剂。
洁牙剂的例子尤其是牙用霜剂、牙膏、口腔洗涤剂、漱口水、抗斑制剂和假牙清洁剂。
装饰性制剂的例子特别是唇膏、指甲油、眼影、睫毛膏、干的和湿的化妆品、腮红、散粉脱毛剂和美黑乳液。
功能性制剂的例子是含有活性成分(例如但不限于激素制剂、维生素制剂、植物提取物制剂和抗菌制剂)的化妆品或皮肤病学组合物。
本发明的身体护理制品如化妆品和皮肤病学组合物可以是液体、乳液、增稠的乳液、凝胶、霜、乳、软膏、粉末、化妆品或以固体管棒的形式提供,可任选地被包装为气溶胶,可以以摩丝、泡沫或喷雾泡沫、喷雾、棒或气溶胶或纸巾(wipe)的形式提供。
根据本发明的身体护理制品可以是溶剂或脂肪物质中悬浮液或分散体系的形式,或者是乳剂或微乳剂(尤其是O/W或W/O型,O/W/O或W/O/W型)的形式,如霜剂或乳、小泡分散体系,软膏、凝胶、固体管棒或气雾剂摩丝的形式。乳剂也可以含有阴离子的、非离子的、阳离子的或两性的表面活性剂。
根据本发明的身体护理制品或家居制品也可以含有常见的佐剂和添加剂,例如防腐剂/抗氧化剂,脂肪物质/油,水,有机溶剂,硅酮,增稠剂,软化剂,乳化剂,额外的遮光剂,消泡剂,增湿剂,香料,表面活性剂,填充剂,遮蔽剂,阴离子的、阳离子的、非离子的或两性的多聚物或其混合物,抛射剂,酸化或碱化剂,染料,着色剂,色素或纳米色素,光稳定剂,抗昆虫剂,皮肤美黑剂,皮肤美白剂,抗菌剂,防腐剂或通常配制进化妆品中的任何其它成分。化妆品和皮肤病佐剂和添加剂的必需量能够由本领域技术人员根据期望的产品容易地选择,并将在实施例中阐述而不仅限于此。
额外的遮光剂有利地选自下文所列化合物但不仅限于此:
考虑到与本发明化合物的组合,UV-B或广谱遮光剂(即具有约290和340nm之间吸收最大值的物质)的例子是例如以下的有机和无机化合物:
樟脑衍生物,例如4-甲基亚苄基樟脑(5000)、3-亚苄基樟脑、甲基硫酸樟脑苯甲烷铵(camphor benzalkonium methosulfate)、聚丙烯酰胺基甲基亚苄基樟脑、磺基亚苄基樟脑、磺基甲基亚苄基樟脑,和苯二亚甲基二樟脑酰胺磺酸;
对氨基苯甲酸衍生物,例如对氨基苯甲酸、对二甲基氨基苯甲酸2-乙基己基酯、N-氧丙烯化的对氨基苯甲酸乙酯和对氨基苯甲酸甘油酯;
二苯甲酮,例如二苯甲酮-3、二苯甲酮-4、2,2′,4,4′-四羟基-二苯甲酮和2,2′-二羟基-4,4′-二甲氧基二苯甲酮;
亚苄基丙二酸酯,例如4-甲氧基亚苄基丙二酸二-(2-乙基己基)酯;
2-(4-乙氧基-苯胺亚甲基)丙二酸酯,例如EP-A 0 895 776中所述的2-(4-乙氧基-苯胺亚甲基)丙二酸二乙酯;
如EP-A 0 358 584、EP-A 0 538 43 1和EP-A 0 709 080中所述的含有苯丙二酸基的有机硅氧烷化合物;
甲酚曲唑三硅氧烷(Drometrizole trisiloxane(Mexoryl XL));
色素,如微粒化的TiO2等等。术语“微粒化的”是指从约5nm到约200nm,尤其是从约15nm到约100nm的颗粒尺寸。TiO2颗粒也可用金属氧化物(例如氧化铝或氧化锆)或有机涂层(例如多元醇、甲基硅酮、硬脂酸铝、烷基甲硅烷)包覆。这类涂层为本领域熟知。
水杨酸酯衍生物,例如水杨酸异丙基苄酯、水杨酸苄酯、水杨酸丁酯、水杨酸乙基己基酯(NEO HELIOPAN OS)、水杨酸异辛酯或水杨酸高薄荷酯(homosalate,HELIOPAN)。
三嗪衍生物,例如辛基三嗪酮(UVINUL T-150)、二辛基丁酰胺基三嗪酮(UVASORB HEB)和二乙氧基苯酚甲氧苯基三嗪(Tinosorb S)。
考虑到与本发明化合物组合时,广谱的或UV A遮光剂(即在约320nm到400nm之间有最大吸收的物质)的实例例如是以下的有机和无机化合物:
苯并三唑衍生物,例如2,2′-亚甲基-二-(6-(2H-苯并三唑-2-基)-4-(1,1,3,3,-四甲基丁基)-苯酚)(TINOSORB M);
亚苯基-1,4-二-苯并咪唑磺酸或盐,例如2,2-(1,4-亚苯基)二-(1H-苯并咪唑-4,6-二磺酸)(Neoheliopan AP);
经氨基取代的羟基二苯甲酮,例如EP-A 1 046 391中所述的2-(4-二乙氨基-2-羟基-苯甲酰基)-苯甲酸己酯(Uvinul A plus);
色素,例如微粒化的ZnO或TiO2。术语“微粒化的”是指从约5nm到约200nm,尤其是从约15nm到约100nm的颗粒尺寸。颗粒也可用金属氧化物(例如氧化铝或氧化锆)或有机涂层(例如多元醇、甲基硅酮、硬脂酸铝、烷基甲硅烷)包覆。这类涂层为本领域熟知。
如EP-A 0 514 491和EP-A 0 780 119中描述的3,3-二苯基丙烯酸酯衍生物;
如US 5,605,680中描述的亚苄基樟脑;
如EP-A 0 358 584、EP-A 0 538 43 1和EP-A 0 70 9080中描述的含苯丙二酸酯基的有机硅氧烷。
以本发明为基础,可以使用通常被配制进身体护理、家居和香料产品的所有已知抗氧化剂。特别优选选自由以下物质组成的组的抗氧化剂:氨基酸(例如甘氨酸、组氨酸、酪氨酸、色氨酸)及其衍生物,咪唑(例如尿刊酸)和衍生物,肽例如D,L-肌肽、D-肌肽、L-肌肽和衍生物(例如鹅肌肽),类胡萝卜素,胡萝卜烯(例如α-胡萝卜烯、β-胡萝卜烯、番茄红素)和衍生物,氯原酸和衍生物,硫辛酸和衍生物(例如二氢硫辛酸),金硫代葡萄糖,丙基硫脲嘧啶和其他硫醇(例如硫氧还蛋白,谷胱甘肽,半胱氨酸,胱氨酸,胱胺及其糖酯、N-乙酰酯、甲酯、乙酯、丙酯、戊酯、丁酯、月桂酯、棕榈酯、油酯、y-亚油酯、胆固醇酯和甘油酯)及其盐,硫代二丙酸二月桂酯,硫代二丙酸二硬脂酯,硫代二丙酸及其衍生物(酯、醚、肽、脂质、核苷酸、核苷及盐)以及非常低剂量(例如pmol/kg到μmol/kg)的亚砜胺(sulfoximine)化合物(例如,丁硫氨酸亚砜胺(buthioninsulfoximine)、高半胱氨酸亚砜胺、丁硫氨酸砜(buthioninsulfone)、五、六、七硫堇亚砜胺),其它的(金属)螯合剂(例如α-羟基脂肪酸、棕榈酸、肌醇六磷酸、乳铁蛋白),β-羟酸(例如柠檬酸、乳酸、苹果酸),腐殖酸(huminic acid)、没食子酸,没食子提取物,胆红素,胆绿素,EDTA,EGTA及其衍生物,不饱和脂肪酸及其衍生物(例如γ-亚油酸、亚油酸、油酸),叶酸及其衍生物,泛醌和泛醌醇及其衍生物,维生素C和衍生物(例如棕榈酸抗坏血酸酯和四异棕榈酸抗坏血酸酯,抗坏血酸磷酸镁,抗坏血酸磷酸钠,抗坏血酸乙酸酯),生育酚和衍生物(例如维生素-E-乙酸酯),天然维生素E、维生素A和衍生物(维生素-A-棕榈酸酯和乙酸酯)的混合物以及苯甲酸松柏基酯(coniferylbenzoate),芸香亭酸和衍生物,α-糖基芸香苷,阿魏酸,亚糠基葡萄糖醇,肌肽,丁基羟基甲苯,丁基羟基苯甲醚,三羟基丁酰苯,脲及其衍生物,甘露糖和衍生物,锌和衍生物(例如ZnO、ZnSO4),硒和衍生物(例如硒代蛋氨酸),茋和衍生物(例如茋氧化物、反式茋氧化物)和所述活性成分的合适的衍生物(盐、酯、醚、糖、核苷酸、核苷、肽和脂质)。
一种或多种防腐剂/抗氧化剂可以占本发明组合物总重的至少0.01wt.%。优选以占本发明组合物总重的约0.01wt.%到约10wt.%。最优选地,一种或多种防腐剂/抗氧化剂以约0.1wt.%到约1wt.%的量存在。
典型地,配制品还含有表面活性成分,如乳化剂、增溶剂等等。乳化剂使两种或更多种不可溶合的成分均匀地组合。另外,乳化剂起稳定组合物的作用。可用于本发明从而形成O/W、W/O、O/W/O或W/O/W乳液/微乳液的乳化剂包括失水山梨糖醇油酸酯、失水山梨糖醇倍半油酸酯、失水山梨糖醇异硬脂酸酯、失水山梨糖醇三油酸酯、聚甘油-3-二异硬脂酸酯、油酸/异硬脂酸的聚甘油酯、聚甘油-6-六蓖麻醇酸酯、聚甘油-4-油酸酯、聚甘油-4-油酸酯/PEG-8丙二醇椰油酸酯、油酰胺DEA、TEA肉豆蔻酸酯、TEA硬脂酸酯、硬脂酸镁、硬脂酸钠、月桂酸钾、蓖麻醇酸钾、椰油酸钠、牛油酸钠、海狸香酸钾(potassium castorate)、油酸钠及其混合物。其他示范性的乳化剂为磷酸酯及其盐,例如磷酸十六烷基酯(A)、二乙醇胺磷酸十六烷基酯十六烷基磷酸钾(K)、油酸甘油酯磷酸钠、氢化植物甘油磷酸酯及其混合物。另外,一种或多种合成聚合物可以被用作乳化剂。例如,PVP二十碳烯共聚物、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、丙烯酸酯/steareth-20甲基丙烯酸酯共聚物、PEG-22/十二烷基二醇共聚物、PEG-45/十二烷基二醇共聚物及其混合物。优选的乳化剂是磷酸十六烷基酯(A)、二乙醇胺磷酸十六烷基酯十六烷基磷酸钾(K)、PVP二十碳烯共聚物、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、PEG-20失水山梨糖异硬脂酸酯、失水山梨糖异硬脂酸酯及其混合物。所述一种或多种乳化剂可以占组合物总重的至少0.01wt.%。优选用量为占本发明组合物总重的约0.01wt.%到约20wt.%。最优选地,使用约0.1wt.%到约10wt.%的乳化剂。
脂质相可有利地选自:
矿物油和矿物蜡;
油例如癸酸甘油三酯或辛酸甘油三酯,优选蓖麻油;
油或蜡和其他天然或合成的油,在优选的实施方案中,为脂肪酸与醇(例如异丙醇、丙二醇、丙三醇)的酯或脂肪醇与碳酸或脂肪酸的酯;
苯甲酸烷基酯;和/或
硅油,例如二甲基聚硅氧烷、二乙基聚硅氧烷、二苯基聚硅氧烷、环甲基硅酮;及其混合物。
可以被掺入本发明的乳液、微乳液、油啫哩、水分散体或脂分散体的油相中的示例性脂肪物质有利地选自具有3到30个碳原子饱和和/或不饱和的、线性或支化的烷基羧酸和/或具有3到30个碳原子的饱和和/或不饱和的、线性或支化醇的酯,以及芳香族羧酸与具有3到30个碳原子的饱和和/或不饱和的、线性或支化醇的酯。这种酯可有利地选自棕榈酸辛酯、椰油酸辛酯、异硬脂酸辛酯、辛基十二烷基肉豆蔻酸酯、异壬酸十六烷基酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、油酸异丙酯、硬脂酸正丁酯、月桂酸正己酯、油酸正癸酯、硬脂酸异辛酯、硬脂酸异壬酯、异壬酸异壬酯、棕榈酸2-乙基己基酯、月桂酸2-乙基己基酯、硬脂酸2-己基癸基酯、棕榈酸2-辛基十二烷基酯、庚酸硬脂基酯、油酸油基酯、芥酸油基酯、油酸瓢儿菜基酯、瓢儿菜酸瓢儿菜基酯、硬脂酸十三烷酯、十三烷基偏苯三酸酯,以及这些酯的合成、半合成或天然的混合物,例如霍霍巴油。
其他适用于在本发明配制品中使用的脂肪成分包括极性油,例如卵磷脂和脂肪酸甘油三酯,即具有8到24个碳原子(优选12到18个碳原子)的饱和和/或不饱和的、直链或支化的羧酸的甘油三酯,其中脂肪酸甘油三酯优选地选自合成、半合成或天然的油(例如椰油酸甘油酯、橄榄油、葵花子油、大豆油、花生油、油菜籽油、甜杏仁油、棕榈油、椰子油、蓖麻油、氢化蓖麻油、小麦油、葡萄籽油、澳洲坚果油和其它);非极性油,例如线性的和/或支化的烃和蜡,例如矿物油、凡士林(矿脂);石蜡、角鲨烷和角鲨烯、聚烯烃、氢化聚异丁烯和异十六烷,优选的聚烯烃为聚癸烯;二烷基醚,例如二辛醚;线性或环状的硅油,例如优选地环甲基硅酮(八甲基环四硅氧烷);十六烷基二甲基硅氧烷、六甲基环三硅氧烷、聚二甲基硅氧烷、聚(甲基苯基硅氧烷))及其混合物。
其他可有利地掺入本发明配制品中的脂肪成分为异二十烷;新戊二醇二庚酸酯;丙二醇-二辛酸酯/二癸酸酯;辛酸/癸酸/二甘油基琥珀酸酯;丁二醇辛酸酯/癸酸酯;C12-13-烷基乳酸酯;二-C12-13烷基酒石酸酯;三异硬脂精;二季戊四醇六辛酸酯/六癸酸酯;丙二醇单异硬脂酸酯;三辛精;二甲基异山梨糖醇酯。特别有益的是使用苯甲酸C12-15-烷基酯和异硬脂酸2-乙基己基酯的混合物、苯甲酸C12-15-烷基酯和异壬酸异十三烷基酯的混合物,以及苯甲酸C12-15-烷基酯、异硬脂酸2-乙基己基酯和异壬酸异十三烷基酯的混合物。
本发明配制品的油相也可含有天然的植物蜡或动物蜡,例如蜂蜡、中国蜡、熊蜂蜡和其他昆虫蜡,以及牛油树脂和可可脂。
可向本发明的产品中掺入湿润剂以保持皮肤水分或补水。通过提供防护层而阻止水分从皮肤蒸发的湿润剂称为柔润剂(emollient)。另外,柔润剂对皮肤表面提供软化或舒缓的效果,并通常被认为对局部使用是安全的。优选的柔润剂包括矿物油,羊毛脂,矿脂,癸酸/辛酸三甘油醛,胆固醇,硅酮(例如二甲基硅酮、环甲基硅酮),杏仁油,霍霍巴油,鳄梨油,蓖麻油,芝麻油,葵花子油,椰子油和葡萄籽油,可可脂,橄榄油,芦荟提取物,脂肪酸(例如油酸和硬脂酸),脂肪醇(例如鲸蜡醇和十六烷基醇(ENJAY)),己二酸二异丙基盐,羟基苯甲酸酯,C9-15-醇的苯甲酸酯,异壬酸异壬基酯,醚(例如聚氧化丙烯丁基醚和聚氧化丙烯十六烷基醚),和苯甲酸C12-15-烷基酯及其混合物。最优选的柔润剂是羟基苯甲酸酯、芦荟、苯甲酸C12-15-烷基酯及其混合物。
柔润剂以占产品总重量约1wt.%到约20wt.%的量存在。优选的柔润剂量为约2wt.%到约15wt.%,最优选约4wt.%到约10wt.%。
结合水从而将水留在皮肤表面的湿润剂称为致湿剂(humectant)。能够被掺入本发明产品中的致湿剂的例子为丙三醇、聚丙二醇、聚乙二醇、乳酸、吡咯烷酮羧酸、脲、磷脂、胶原、弹性蛋白、神经酰胺、卵磷脂山梨糖醇、PEG-4及其混合物。其他合适的湿润剂为下类可水溶和/或可溶胀和/或水啫哩多糖类的聚合湿润剂,例如透明质酸、壳聚糖和/或富含岩藻糖的多糖,所述富含岩藻糖的多糖可例如得自SOLABIA S产的1000(CAS-Nr.178463-23-5)。
一种或多种致湿剂以约0.5wt.%到约8wt.%,优选约1wt.%到约5wt.%任选地存在于本发明的产品中。
本发明产品的水相可含有常见的化妆品添加剂,例如醇(特别是低级醇,优选乙醇和/或异丙醇),低级二醇或多元醇及其醚(优选丙二醇、甘油、乙二醇、乙二醇单乙基或单丁基醚、丙二醇单甲基或单乙基或单丁基醚、二乙二醇单甲基或单乙基醚)和类似产品、聚合物、稳泡剂、电解质和特别是一种或多种增稠剂。可用于本发明配制品中以便利于获得合适产品稠度的增稠剂包括卡波姆(carbomer)、二氧化硅、硅酸镁和/或硅酸铝、蜂蜡、硬脂酸、硬脂醇多糖及其衍生物(例如黄原胶)、羟丙纤维素,聚丙烯酰胺、丙烯酸酯交联共聚物,优选卡波姆,例如单独的980、981、1382、2984、5984型或其混合物。可包含在本发明产品中以中和例如乳化剂或增泡剂/稳泡剂成分的中和剂的例子包括,但不限于,碱金属氢氧化物,例如氢氧化钠和氢氧化钾;有机碱,例如二乙醇胺(DEA)、三乙醇胺(TEA)、氨甲基丙醇及其混合物;氨基酸,例如精氨酸和赖氨酸,和任何前述物质的任何组合。
中和剂可以以约0.01wt.%到约8wt.%,优选1wt.%到约5wt.%的量存在于本发明的产品中。
可能需要向本发明产品中添加电解质可对改变疏水乳化剂的行为。因此,本发明的乳液/微乳液可优选地含有一种或若干种包含如下阴离子盐的电解质,例如氯离子、硫酸根、碳酸根、硼酸根和铝酸根,但不仅限于此。其他合适的电解质可以基于如下有机阴离子,所述有机阴离子例如,但不限于,乳酸根、乙酸根、苯甲酸根、丙酸根、酒石酸根和柠檬酸根。阳离子优选地选择铵离子、烷基铵离子、碱金属离子或碱土金属离子、镁离子、铁离子或锌离子。特别优选的盐是氯化钾和氯化钠、硫酸镁、硫酸锌及其混合物。
电解质可以以约0.01wt.%到约8wt.%的量存在于本发明的产品中。
其它光稳定剂的添加可能是期望的。这类光稳定剂是例如已知的受阻胺类光稳定剂(HALS),所述受阻胺类光稳定剂可以具有单体或多聚体的性质。它们例如选自由下述物质构成的组:N,N′-双甲酰基-N,N′-双-(2,2,6,6-四甲基-4-哌啶基)-己二胺(Uvinul 4050 H)、双-(2,2,6,6-四甲基-4-哌啶基)癸二酸酯(Uvinul 4077 H)、(双-(1,2,2,6,6-五甲基-4-哌啶基)-癸二酸酯+甲基·(1,2,2,6,6-五甲基-4-哌啶基)癸二酸酯。(Uvinul 4092 H),双(2,2,6,6-四甲基哌啶-4-基)癸二酸酯、双(2,2,6,6-四甲基哌啶-4-基)琥珀酸酯、双(1,2,2,6,6-五甲基哌啶-4-基)癸二酸酯、正丁基-3,5-二叔丁基-4-羟基苄基-丙二酸双(1,2,2,6,6-五甲基哌啶基)酯、1-羟乙基-2,2,6,6-四甲基-4-羟基哌啶和琥珀酸的缩合物、N,N′-双(2,2,6,6-四甲基-4-哌啶基)己二胺和4-叔辛基氨基-2,6-二氯-1,3,5-s-三嗪的缩合物、三(2,2,6,6-四甲基-4-哌啶基)次氮基三乙酸酯、四(2,2,6,6-四-甲基-4-哌啶基)-1,2,3,4-丁四酸酯、1,1′-(1,2-乙二基)-双(3,3,5,5-四甲基哌嗪酮)、4-苯甲酰-2,2,6,6-四甲基哌啶、4-十八烷氧-2,2,6,6-四甲基哌啶、双(1,2,2,6,6-五甲基哌啶基)-2-正丁基-2-(2-羟基-3,5-二-叔-丁基苄基)丙二酸酯、3-正辛基-7,7,9,9-四甲基-1,3,8-三氮杂螺[4.5]癸烷-2,4-二酮、N,N-双(2,2,6,6-四甲基-4-哌啶基)己二胺和4-吗啉代-2,6-二氯-1,3,5-三嗪的缩合物、2-氯-4,6-二(4-正丁基氨基-2,2,6,6-四-甲基哌啶基)-1,3,5-三嗪和1,2-双(3-氨基丙胺基)乙烷的缩合物、2-氯-4,6-二(4-正丁基氨基-1,2,2,6,6-五甲基哌啶基)-1,3,5-三嗪和1,2-双(3-氨基丙胺基)乙烷、8-乙酰基-3-十二烷基-7,7,9,9-四甲基-1,3,8-三氮杂螺[4.5]-癸烷-2,4-二酮、3-十二烷基-1-(2,2,6,6-四甲基-4-哌啶基)吡咯烷-2,5-二酮、3-十二烷基-1-(1,2,2,6,6-五甲基-4-哌啶基)-吡咯烷-2,5-二酮、4-十六烷氧基-和4-十八烷氧-2,2,6,6-四甲基哌啶的混合物、N,N′-双(2,2,6,6-四甲基-4-哌啶基)己二胺和4-环己基氨基-2,6-二氯-1,3,5-三嗪的缩合物、1,2-双(3-氨基丙胺基)乙烷和2,4,6-三氯-1,3,5-三嗪和4-丁基氨基-2,2,6,6-四甲基哌啶(CAS reg.No.[136504-96-6])的缩合物;(2,2,6,6-四甲基-4-哌啶基)-正十二烷基琥珀酰亚胺、(1,2,2,6,6-五甲基-4-哌啶基)-正十二烷基琥珀酰亚胺、2-十一烷基-7,7,9,9-四甲基-1-氧杂-3,8-二氮杂-4-氧代-螺[4,5]癸烷、7,7,9,9-四甲基-2-环十一烷基-1-氧杂-3,8-二氮杂-4-氧代螺[4,5]癸烷和环氧氯丙烷的反应产物,但不仅限于此。
可用于根据本发明的身体护理产品中的驱昆虫剂的例子为例如N,N-二乙基-间甲苯酰胺、1,2-戊二酮或驱昆虫剂3535。
自美黑成分的例子为例如二羟基丙酮和/或赤藓酮糖或二羟基丙酮和/或WO 01/85 124中所述的二羟基丙酮前体和/或赤藓酮糖。
皮肤美白成分的例子为例如维生素C、抗坏血酸磷酸钠和抗坏血酸磷酸镁。
考虑到的除臭活性成分的例子为止汗剂,如水合氯化铝、碱式乙酸铝和酸性铝/锆盐。可以添加酯酶抑制因子作为进一步除臭的活性成分。这类抑制因子优选为柠檬酸三烷基酯,如柠檬酸三甲基酯、柠檬酸三丙基酯、柠檬酸三异丙基酯、柠檬酸三丁基酯和特别是柠檬酸三乙基酯(HydagenCAT,Henkel),其抑制酶活性并从而减少臭味生成。作为酯酶抑制因子考虑的其它物质为固醇硫酸酯或磷酸酯(例如羊毛固醇、胆固醇、芸苔固醇、豆固醇和谷固醇的硫酸酯或磷酸酯)、二羧酸及其酯(例如戊二酸、戊二酸单乙酯、戊二酸二乙酯、己二酸、己二酸单乙酯、己二酸二乙酯、丙二酸和丙二酸二乙酯)和羟基羧酸及其酯(例如柠檬酸、苹果酸、酒石酸或酒石酸二乙酯)。影响微生物菌群并杀死或抑制汗分解细菌的生长的抗菌活性成分可类似地存在于制剂中(特别是棒状制剂中)。可存在的其它抗菌剂为壳聚糖、苯氧乙醇和葡萄糖酸氯己定-5-氯-2-(2,4-二氯苯氧基)-苯酚(Triclosan,Irgasan,Ciba Specialty Chemicals Inc.)。
可使用的去头屑剂的例子为地巴唑(dimbazole)、羟甲辛吡酮(octopirox)和硫氧吡啶锌(zinc pyrithione)。常规的成膜剂包括例如壳聚糖、微晶壳聚糖、季铵化的壳聚糖、聚乙烯吡咯烷酮、乙烯基吡咯烷酮/乙酸乙烯基酯共聚物、含高比例丙烯酸的四元纤维素衍生物的聚合物、胶原、透明质酸及其盐和类似的化合物。
防腐剂的例子包括对羟基苯甲酸甲酯、乙酯、丙酯、丁酯,氯扎苯铵,2-溴-2-硝基-丙烷-1,3-二醇,脱氢醋酸,重氮咪唑烷基脲(DiazolidinylUrea),2-二氯苯甲醇,DMDM乙内酰脲,甲醛溶液,甲基二溴戊二腈,苯氧乙醇,羟甲基谷氨酸钠,咪唑烷基脲(Imidazolidinyl Urea),三氯生(Triclosan)和以下参考文献中所列的其它物质种类:K.F.De Polo-A shorttextbook of cosmetology,Chapter 7,Table 7-2,7-3,7-4 & 7-5,p210-219。
细菌抑制剂的典型例子是对革兰氏阳性细菌具有特异作用的防腐剂,如2,4,4′-三氯-2′-羟基二苯醚、氯己定(1,6-二(4-氯苯基-双胍)己烷)或TCC(3,4,4′-三氯碳酰苯胺)。大量的芳香族物质和芳香油也具有抗微生物特性。典型的例子是丁香油、薄荷油和百里香油中的活性成分丁香油酚、薄荷醇和百里酚。感兴趣的天然除臭剂是萜醇法尼醇(3,7,11-三-甲基-2,6,10-十二碳三烯-1-醇),其存在于梨莓油(lime blossom oil)中。甘油单月桂酸酯也被证明是抑菌剂。
额外的细菌抑制剂的用量通常是以制剂固体含量为基础从0.1到2wt.%。
本稳定剂组合物特别适用于稳定身体护理产品,尤其是:
·皮肤护理制剂,例如片剂形式的皮肤洗涤和清洁制剂,或液体皂、无形去污剂或洗涤膏剂;
·沐浴制剂,例如液体(泡沫沐浴、乳、淋浴制剂)或固体的沐浴制剂,例如沐浴块和沐浴盐;
·护肤制剂,例如皮肤乳液、多重乳液或皮肤油;身体油、身体乳液、身体啫哩;护肤软膏;
·化妆品个人护理制剂,例如日霜或粉底霜(powder cream)形式的面部彩妆、腮红或霜状彩妆,眼部护理制剂,例如眼影制剂、睫毛膏、眼线、眼霜或眼部修护霜(eye-fix cream);唇部护理制剂,例如唇膏、唇蜜、唇线笔,指甲护理制剂,例如指甲油、洗甲水、指甲强化剂(nail hardener)或去指皮水(cuticle remover);
·足部护理制剂,例如足浴、足粉、足霜或足脂(foot balsam),特别是除臭剂和止汗剂或去胼胝制剂;
·光保护制剂,如防晒乳、乳液、霜剂或油,隔离霜或彩油(tropicals)、晒黑前制剂或晒后制剂;
·皮肤美黑制剂,例如自身美黑霜;
·脱色制剂,例如用于漂白皮肤的制剂或皮肤美白制剂;
·驱虫水,例如驱虫油、乳液、喷雾或棒;
·除臭剂,例如除臭喷雾、泵作用喷雾、除臭啫哩、棒或滚擦剂(roll-on);
·止汗剂,例如止汗棒、霜或滚擦剂;
·用于清洁和护理受损皮肤的制剂,例如合成洗涤剂(固体或液体)、去死皮制剂或磨砂制剂或去死皮面膜;
·化学品形式的脱毛制剂(脱毛作用),例如脱毛粉、液体脱毛制剂、霜或膏形式的脱毛制剂、啫哩或气雾剂形式的脱毛制剂;
·剃须制剂,例如剃须皂、泡沫剃须霜、无泡沫剃须霜、泡沫和啫哩、用于干燥剃须的须前制剂、须后水或须后乳液;
·香味剂或香料制剂,例如含下述制剂的香味剂、香料和/或有香味的成分,所述制剂如香精、古龙水、淡香水、香水、淡香水、香精油或香精霜;
·化妆品头发护理制剂,例如香波和护发素形式的洗发制剂,头发护理制剂,例如预护理制剂,生发油,定型霜,定型啫哩,润发油,头发冲洗剂,护理套装(treatment pack),头发密集护理剂,发型造型(hair-structuring)制剂,例如用于持久卷发(热卷发、适中卷发、冷卷发)的卷发制剂,头发拉直制剂,液体头发定型制剂,头发泡沫,头发喷雾,漂白制剂,例如过氧化氢溶液、闪亮香波(lightening shampoo)、漂白霜、漂白粉、漂白膏或油,临时的、半永久性的或永久性的染发剂,含自身氧化染料的制剂,或天然染发剂如散沫花或甘菊;
·洁齿剂,尤其是牙霜、牙膏、口腔洗液、口腔冲洗液、抗斑制剂和假牙清洁剂;
·装饰制剂,尤其是唇膏、指甲油、眼影、睫毛膏、干和湿的彩妆、腮红、散粉、脱毛剂和美黑乳液。
·含活性成分的化妆品制剂,尤其是激素制剂、维生素制剂、植物提取物制剂和抗菌制剂。
所列的最终配制物可以以多种存在形式存在,例如以液体制剂的形式,如W/O、O/W、O/W/O、W/O/W或PIT乳液和所有微乳液种类,以啫哩的形式,以油、霜、乳或乳液的形式,以棒的形式,以喷雾(带有推进剂气体的喷雾或泵作用的喷雾)或气雾剂的形式,以泡沫的形式,或以膏剂的形式。
根据本发明作为皮肤化妆品制剂特别重要的是含着色剂、染料、活性成分、香味剂、香料或其混合物的制剂,所述制剂如防晒乳、乳液、霜、擦拭物、油、防晒隔离或彩油(tropicals),晒黑前制剂或晒后制剂,还有皮肤美黑制剂例如自身美黑霜。
作为头发化妆品制剂特别重要的是用于头发护理的上述制剂,特别是香波形式的头发洗涤制剂,护发素,头发护理制剂,例如预护理制剂,生发油,定型霜,定型啫哩,润发油,头发冲洗剂,护理套装,头发密集护理剂,头发拉直制剂,液体头发定型制剂,头发泡沫和头发喷雾。特别感兴趣的是香波形式的头发洗涤制剂。
式I和Ie的化合物、特别是具有上文和下文给定的取代基定义和优选级的式Ia到Ie的化合物以及以下述含量含有它们的植物材料和植物提取物(的混合物)和含有它们的身体护理组合物因此适用于局部治疗哺乳动物(包括人),所述含量以植物材料或提取物的总重为基础优选地为至少1wt-%,更优选地为至少50wt-%,进一步更优选地为至少90wt-%。
因此,本发明涉及在哺乳动物(包括人)中治疗与受损的葡萄糖代谢和受损的胰岛素作用相关的障碍的方法,所述方法包括对需要的哺乳动物(包括人)施用有效剂量的本文定义的式I或Ie的化合物,特别是式Ia、Ib、Ic、Id或Ie或If或Ig的化合物。
在本发明的上下文中,哺乳动物包括人。优选的“哺乳动物”是人和宠物如猫、犬、马、单峰驼和大象,特别是犬。
在本发明的上下文中,术语“治疗”还包括辅助治疗以及控制和预防。在本发明的上下文中,术语“障碍”还包括疾病。另外,术语“治疗”还包括健康个体的使用,所述健康个体寻求更好的健美度、体形或皮肤外观。在本发明的上下文中,术语“预防”也包括降低患本文所述某障碍/疾病的风险,或降低患本文所述某障碍/疾病的发病率。
对人而言,用于本发明目的的下述化合物的合适的每日剂量可在每天每kg体重0.01mg到每kg体重50mg的范围内,即对70kg的人而言0.7mg-3500mg,所述化合物为式I或Ie的化合物,特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物和如上文定义的式If的化合物或如下文定义的式Ig的化合物。更优选的是每kg体重0.1到25mg(即对70kg人而言为7mg-1750mg)的每日剂量,特别优选的是每kg体重0.3到15mg(即对70kg的人而言为21mg-1050mg)的每日剂量。可相应地计算含有式Ia到If的这类化合物的植物材料或植物提取物的用量。
在用于人的固体剂量单位制剂中,式I或Ie的化合物,特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物和如上文定义的式If的化合物或如下文定义的式Ig的化合物以下述用量适当地存在,所述用量为每剂量单位从0.25mg到1000mg,优选地从2mg到200mg。
在膳食组合物中,特别是在用于人的食品和饮料中,式I或Ie的化合物,特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物和如上文定义的式If的化合物或如下文定义的式Ig的化合物以下述用量适当地存在,所述用量为每份(份量大小可以是例如锭剂为500mg,面包为50g或饮料为250mL)从7mg到1750mg,优选地从20mg到1000mg。
在本发明的一个优选的实施方案中,食品和饮料中式I或Ie的化合物,特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物和如上文定义的式If的化合物或如下文定义的式Ig的化合物可以是每份20mg到1000mg。
对于犬而言,用于本发明目的的式I或Ie的化合物,特别是具有上文给定的R2到R17定义和优选级的式Ia到Ie的化合物和如上文定义的式If的化合物或如下文定义的式Ig的化合物可以在每天从每kg体重0.04mg到每kg体重500mg的范围内。更优选的是每kg体重从0.4mg到100mg的每日剂量范围,特别优选的是每kg体重从1mg到50mg的每日剂量。
本发明还涉及如上文定义的通式I和Ie的化合物作为药物的用途,特别是通式Ia到Ie的化合物或如上文定义的式If的化合物或如下文定义的式Ig的化合物作为药物的用途,所述通式为
其中
R2为H、OH或C1-6-烷氧基(优选地为甲氧基);R3、R4和R6彼此独立地为OH或C1-6-烷氧基(优选地为甲氧基);
R5为H或C1-6-烷氧基(优选地为H或甲氧基,更优选地为甲氧基);R7为H;或R5和R7一起为-O-;R8和R10彼此独立地为C1-6-烷氧基(优选地为甲氧基);
R9为H、C1-6-烷氧基(优选地为甲氧基)或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1- 6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6(优选地为(N-酰基,N-甲基)-2-氨乙基)。
本发明的最优选的实施方案
本发明的最优选的实施方案涉及通式Ig的化合物在哺乳动物(包括人)中用于治疗肌肉障碍(包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳)、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的用途;以及通式Ig的这类化合物用于制造组合物(如上文定义并具有上文给出的优选级的膳食、身体护理或药物组合物)的用途,所述组合物在哺乳动物(包括人)中用于治疗肌肉障碍(包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳)、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例,所述通式Ig为
其中X1为H或CH3,且
X2为X3、X4或X5;或X2和X6一起形成氧键(即-X6-X2-=-O-);且
X7为H或X8,
条件是如果X2=X3、X4或X5,则X6=X1且X7=H;且
另一条件是如果X2和X6一起形成氧键(即-X6-X2-=-O-),则X1=H且X7=X8。
对所述用途而言特别优选的是落入通式Ig内的化合物3、4、6和11(见图2和图4)。更优选的是化合物4和11,最优选的是化合物11。
所列的用途中特别优选以下的用途:
在哺乳动物(包括人)中增强肌肉功能,
在哺乳动物(包括人)中增强耐力,
改善哺乳动物(包括人)的体形,和
在哺乳动物(包括人)中改善肌肉∶脂肪比例。
本发明还最优选地涉及通式Ig的化合物,其用于在哺乳动物(包括人)中治疗肌肉障碍(包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳)、改善肌肉功能和耐力、增强身体性能、增强耐久能力、增加肌肉量、预防肌肉损耗、增强肌肉恢复、降低肌肉疲劳、改善能量平衡、维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或改善体形和/或改善肌肉∶脂肪比例,所述通式Ig为
其中X1为H或CH3,且
X2为X3、X4或X5;或X2和X6一起形成氧键(即-X6-X2-=-O-);且
X7为H或X8,
条件是如果X2=X3、X4或X5,则X6=X1且X7=H;且
另一条件是如果X2和X6一起形成氧键(即-X6-X2-=-O-),则X1=H且X7=X8。
本发明的另一最优选的实施方案是在本申请权利要求4和5中定义的组合物,特别是膳食组合物、身体护理组合物或药物组合物,根据权利要求6的这类组合物的用途和下述组合物的使用方法,所述组合物是具有上文给定的优选级的通式Ig的这类化合物或根据权利要求7和8在本发明上下文中的定义的含有它们的组合物。
本发明通过以下的实施例进一步阐述。
实施例
实施例1
软明胶胶囊
通过常规工序来制备软明胶胶囊,所述软明胶胶囊提供200mg式I或Ie的化合物剂量。合适的每日剂量为1到5粒胶囊。其它成分:甘油、水、明胶、植物油。对年龄60到75岁的男性或女性以该剂量施用两个月的周期时,这类人的行走距离可以被提高10%。
实施例2
硬明胶胶囊
通过常规工序来制备硬明胶胶囊,所述硬明胶胶囊提供100mg式I或Ie的化合物剂量。合适的每日剂量为1到5粒胶囊。对年龄30到40岁的男性或女性以该剂量施用两个月的周期时,这类人的奔跑距离可以被提高5%。
其它成分:
填料:适量的乳糖或纤维素或纤维素衍生物
润滑剂:如果需要的话,硬脂酸镁(0.5%)
实施例3
药片
通过常规工序来制备药片,每片提供80mg式I或Ie的化合物作为活性成分,且使用微晶纤维素、二氧化硅(SiO2)、硬脂酸镁、交聚维酮NF(一种崩解剂)总计500mg作为赋形剂。
实施例4:用30mg 10%CWS β-胡萝卜素着色的橙汁饮品
成分 | [g] |
糖浆64°白利糖度 | 156.2 |
苯甲酸钠 | 0.2 |
抗坏血酸,精细粉末 | 0.2 |
柠檬酸50%w/w | 5.0 |
果胶溶液2%w/w | 10.0 |
式I或Ie的化合物 | 0.5 |
果汁复合物* | 30.0 |
加水至 | 250.0 |
制备
将苯甲酸钠溶于水中同时搅拌;
持续搅拌并依次添加糖浆、抗坏血酸、柠檬酸、果胶溶液、果汁复合物。不要使用高速混合仪;
用(充二氧化碳的)水将瓶装糖浆稀释为一升饮料。
果汁复合物成分* | [g] |
橙汁浓缩物65°白利糖度 | 483.3 |
柠檬汁浓缩物45°白利糖度 | 173.3 |
油性橙味香料 | 5.0 |
作为10%储存液的10%CWSβ-胡萝卜素 | 10.0 |
去离子水 | 328.4 |
制备果汁复合物
向果汁浓缩物中添加去离子水,柔和搅拌并允许果汁浓缩物水合。
添加油性香料和10%CWSβ-胡萝卜素储存溶液,并在转子-定子-匀化器中预先乳化。
在高压匀化器中于200bar下匀化。
添加10%CWSβ-胡萝卜素
10%CWSβ-胡萝卜素应当作为去离子水中1-10%的储存溶液被添加进果汁复合物中。
橙汁饮品含有3ppm的β-胡萝卜素。
实施例5
4′,7-二甲氧基异黄酮(=化合物11)对小鼠的奔跑性能、身体组成和腓肠
肌-跖肌-比目鱼肌肌肉群的影响
从Jackson实验室(Bar Harbor,ME,USA)获得年龄为5周的20只雄性C57B1/6J小鼠。所有的小鼠被施用8周高脂肪膳食(Kliba#2154,ProvimiKliba AG,Kaiseraugst,瑞士)以诱导肥胖。之后将小鼠随机分配进两组:
第1组:对照(高脂肪膳食)
第2组:4′,7-二甲氧基异黄酮(补充有0.03%w/w 4′,7-二甲氧基异黄酮(Alfa Aesar)的高脂肪膳食)
补充给药的时间是9周。在该周期内,所有的小鼠随意取用食品和水。在补充给药周期结束时,在啮齿动物跑步机(Technical & ScientificEquipment GmbH,Bad Homburg,Germany)上测定最大奔跑性能。通过在有知觉的动物中进行定量磁共振(Minispec MQ10,Bruker Optics GmbH,Faellanden,瑞士)测量身体组成。在研究结束时处死动物,取血,切除腓肠肌-跖肌-比目鱼肌肌肉群并称重。
与对照组中的小鼠相比,用4′,7-二甲氧基异黄酮对小鼠补充给药降低了体重和身体脂肪量百分比,同时其提高了无脂肪体重百分比(表1)。另外,腓肠肌-跖肌-比目鱼肌肌肉群的重量相对于体重的比例被4′,7-二甲氧基异黄酮的消耗提高,并且最大奔跑距离提高了6%(表1)。
表1:对照小鼠和用4′,7-二甲氧基异黄酮补充给药的小鼠的体重、身体脂肪量、无脂肪体重、腓肠肌-跖肌-比目鱼肌重量和最大奔跑距离。
对照 | 4′,7-二甲氧基异黄酮 | |
体重(g) | 33.1 | 30.5 |
身体脂肪量(占体重的百分比%) | 22.7 | 15.6 |
无脂肪体重(占体重的百分比%) | 69.7 | 75.0 |
腓肠肌-跖肌-比目鱼肌重量(mg/g体重) | 6.06 | 6.74 |
最大奔跑距离(m) | 2081 | 2201 |
跑步机测试中提高的最大奔跑距离证明了增强的耐力,其表明4′,7-二甲氧基异黄酮消耗引起了骨骼肌中提高的氧化能力。从解剖学角度看来,这由提高的I型和IIa型肌纤维比例反映。另外,与对照动物相比,4′,7-二甲氧基异黄酮的消耗降低了身体脂肪量并提高了无脂肪体重,从而缓解了高脂肪膳食的有害影响。该作用可以由骨骼肌中提高的脂肪氧化引起,所述提高的脂肪氧化归因于氧化性I型和IIa型肌纤维的更大比例。
因此,用4′,7-二甲氧基异黄酮补充给药在哺乳动物中增强肌肉功能和耐力,并改善体形以及肌肉∶脂肪比例。
实施例6
化合物1-8对脂肪代谢(包括脂肪燃烧)的影响
细胞培养
C2C12亚克隆细胞得自Dr.Grimaldi,University of Nice,法国。将C2C12PPd细胞播种于24孔平板中(0.1×106到0.15×106)并在维持培养基(DMEM#41965调节至10%FBS、2mM L-谷氨酰胺、1mM丙酮酸钠、100IU/ml青霉素和100μg/ml链霉素)中在37℃下保持。在90-95%的融合下,用1x PBS洗涤细胞并换至分化培养基(DMEM #41965调节至3%FBS、2mM谷氨酰胺和1mM丙酮酸钠)。分化4天后,用1x PBS洗涤细胞并在处理培养基(DMEM #41965调节至2%BSA、2mM谷氨酰胺和100IU/ml青霉素和100μg/ml链霉素)中用测试化合物处理。DMSO含量被调节至0.5%终浓度。与测试化合物孵育24小时后,用1x PBS洗涤细胞,用300μl RLT缓冲液(Qiagen RNeasy Mini Kit #74106)将细胞收集在QIAshredder(Qiagen 79656)中并储存于-20℃。
RNA分离和分析
使用Qiagen RNeasy Mini Kit提取总RNA,其中包括根据制造商方案的柱内DNase步骤(Qiagen #79254)。使用RNA定量测定法(Molecular Probes#R11490,Eugene,USA)根据制造商方案测定RNA浓度。使用OmniscriptTM RT-kit(Qiagen#205113,Basel,CH),根据制造商的说明,用10μM随机引物(Promega#C1181)通过反转录对200ng总RNA进行第一链cDNA合成。用DEPC处理过的水(Ambion,Austin,TX,USA)将终体积调节至400μl并储存于-20℃。
基因表达分析
使用基于多元方法(multiplex method)的定量实时TaqMan RT-PCR来定量所选择的基因的表达水平。在定量的TaqMan RT-PCR中,向20μl反应混合物中添加5μl经稀释的cDNA,所述反应混合物由12.5μl TaqMan 2xMaster Mix(PE biosystems,Rotkreuz,CH)、300nM PCR引物(正向和反向)和针对感兴趣的基因的100nM TaqMan探针组成。使用的参考基因是18S rRNA,引物和探针分别为50nM和100nM。针对感兴趣的基因的探针在5′端用FAM标记,在3′端用Tamra标记。18S rRNA探针在5′端用VIC标记,在3′端用Tamra标记。引物和探针的寡核苷酸序列在表2中展示。使用Abi-Prism 7700 Sequence Detector(PE Biosystems,Foster City,CA,USA)在MicroAmp Optical 96-孔反应板(PE Biosystems,Foster City,CA,USA)中进行扩增。PCR程序由50℃2分钟、95℃10分钟和40个循环的95℃15秒和60℃60秒组成。CT阈值被设定为0.05。感兴趣的基因的基线起始值和终止值分别被设定为3和15,参考基因(18S rRNA)的基线起始值和终止值分别被设定为3和7。使用ΔCT方法根据制造商的方案测定mRNA丰度。简言之,感兴趣的基因的ΔCT被测定为参考基因和感兴趣的基因的CT之间的差异。然后,ΔΔCT被测定为未处理的对照组和每个处理组之间的dCT差异。感兴趣的基因的诱导倍数(即感兴趣的基因的mRNA量,其针对内源参考和相对于校准器被标准化)被测定为2-ΔΔCT。图中的数据表示为百分比。
结果
使用实时RT-PCR检验涉及脂肪酸β-氧化和脂质代谢的基因。与DMSO对照相比的诱导倍数在下表3中展示。
表3
化合物 | mCD36 | mUCP2 | mCPT1b | mUCP3* | mACO1 | mLPL | mFABP3 |
1 | 2.93 | 2.46 | 1.33 | 1.98 | 1.11 | 1.35 | |
2 | 3.2 | 3.27 | 1.05 | 1.81 | 1.91 | 1.63 | |
3 | 10.16 | 4.25 | 3.64 | 4.73 | 1.54 | 3.5 | 4.76 |
4 | 15.56 | 7.55 | 5.08 | 5.95 | 1.74 | 3.31 | 6.29 |
5 | 1.91 | 2.33 | 4.19 | 1.03 | 1.84 | 1.88 | |
6 | 22.66 | 6.1 | 1.62 | 1.92 | 1.09 | 2.44 | 5.02 |
7 | 2.95 | 2.33 | 1.12 | 1.03 | 1.06 | 2.16 | |
8 | 9.49 | 4.68 | 1.29 | 1.15 | 1.88 | 3.36 |
*仅针对具有表中给定值的化合物测定。
外周组织(如脂肪、骨骼肌和肝)中的脂肪过剩导致胰岛素抗性、肥胖症、异常脂肪血症和这些器官的功能障碍。骨骼肌是葡萄糖和脂质代谢的一个主要位点。肌肉中的长期脂质累积不仅导致下降的性能,而且导致慢性炎症,所述慢性炎症伴随着肌肉蛋白质降解和年龄相关的老年性肌肉萎缩。与异常脂质代谢相关的疾病(如肥胖症和糖尿病)通常导致肌肉消耗。甘油三酯的分解代谢产物脂肪酸在线粒体中被进一步氧化,该过程称作TCA循环,其产生ATP作为生物的能量来源。因此,肌肉中提高的脂肪酸氧化会导致提高的脂质消耗、减少的脂肪储存、改善的胰岛素敏感性和改善的肌肉功能。
使用小鼠骨骼肌细胞模型研究上述天然化合物对脂质分解代谢的关键调节器表达的影响。
脂蛋白脂肪酶(LPL)水解其运载体脂蛋白上的脂质,并将其释放用于进一步的分解代谢。化合物3、4和6适度地提高该酶的表达。其他的脂肪酸运载体和储存酶如CD36和FABP3(肌肉特异形式)被所测试的大部分化合物诱导,使其中用化合物6、4和3时观察到最显著的作用。长链脂肪酸的线粒体氧化由肉毒碱棕榈酰基转移酶I(外膜的,并且在洗涤剂中不稳定)和肉毒碱棕榈酰基转移酶II(内膜)的顺序作用来启始。CPT I是跨越线粒体内膜的肉毒碱依赖性转运中的关键酶。该酶的肌肉特异形式CPTIb由肌细胞中的化合物4、5和3诱导。酰基CoA羧化酶(ACO1)是极长链脂肪酸β-氧化通路的第一个酶,其催化酰基CoA到2-反式-烯酰-CoA的去饱和作用。其对分子氧直接供给电子,从而产生过氧化氢。化合物1、4和2将ACO1的表达提高~2倍,而其他测试化合物显示无作用。最后但并非最不重要的是,线粒体解偶联蛋白(UCP)是较大的线粒体阴离子载体蛋白家族的成员,并在热产生中起重要作用。UCP有助于阴离子从线粒体内膜到外膜的转移和质子从线粒体外膜到内膜的回路转移。骨骼肌具有最高的UCP表达水平。我们观察到所有测试的化合物对YCP2有正面影响和由化合物4、6和3引起的提高的UCP3表达。
总而言之,化合物1-8显示了选择性激活涉及肌细胞中脂肪酸氧化和线粒体解偶联的一组基因,这表明它们在调控脂质代谢和肌肉功能中的功能。
Claims (33)
1.通式Ig的化合物在哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能、和/或用于改善体形和/或用于改善肌肉∶脂肪比例的用途,其中所述哺乳动物包括人,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳,所述通式Ig为:
其中X1为H或CH3,且
X2为X3、X4或X5;或X2和X6一起形成氧键;且
X7为H或X8,
条件是如果X2=X3、X4或X5,则X6=X1且X7=H;且
另一条件是如果X2和X6一起形成氧键,则X1=H且X7=X8。
3.根据权利要求1的用途,特征是所述通式Ig的化合物是化合物11。
4.包含至少一种根据权利要求1到3中任一项的通式Ig的化合物的组合物,优选膳食组合物、身体护理组合物或药物组合物。
5.根据权利要求4的组合物,其中所述组合物是膳食组合物,其为食品形式如乳制品(例如酸乳),强化食品形式如谷物棒和烘焙物如蛋糕和曲奇,膳食补充剂形式如片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制物,无醇饮品形式如软饮、运动饮品、果汁、柠檬水、茶和基于乳的饮品,液体食品形式如汤和乳制品(麦芯饮品)。
6.根据权利要求4或5的组合物在哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的用途,所述哺乳动物包括人,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
7.在包括人的哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的方法,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳,其中所述方法包括对需要的哺乳动物施用有效剂量的如权利要求1到3中任一项中定义的通式Ig的化合物。
8.根据权利要求7的方法,其中所述哺乳动物为人、宠物动物或农场动物。
9.通式I或Ie的化合物用于治疗肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少的用途,其中所述通式I或Ie为:
其中当L5为氢或R5时,L为A或B任一,或
其中L和L5形成残基C或D,
且其中
L1为H、OH或R2;L2为H;L3为H、OH或R6;L4为H;
优选地当L为A时,L1为OH且L2、L3和L4为H;
优选地当L为B时,L1、L2和L4为H,L3为R6且L5为R5;
优选地当L和L5一起形成残基C时,L2、L4为H,L1为R2且L3为R6;
优选地当L和L5一起形成残基D时,L2、L4为H,L1为R2且L3为R6;
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8、R10为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
11.根据权利要求9或10的用途,其中所述化合物的取代基如下:R2为H、OH或甲氧基;和/或R3、R4和R6彼此独立地为OH或甲氧基;和/或R5为H或甲氧基;或R7为H;或R5和R7一起为-O-;R8和/或R10为甲氧基;或R9为H、甲氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2;和/或R17为(N-酰基,N-甲基)-2-氨乙基。
12.根据权利要求9的用途,其中所述通式I的化合物选自由化合物1-12组成的组,其中所述化合物1是通式Ia的化合物,其中R1=R3=R4=OH且R2=H;化合物2是通式Ia的化合物,其中R1=OH、R2=R3=R4=甲氧基;化合物3是通式Ib的化合物,其中R5=R6=R8=R10=甲氧基且R7=R9=R17=H;化合物4是通式Ib的化合物,其中R5=R7=H,R6=R8=甲氧基,R9和R10一起形成-O-CH2-O-且R17=(N-酰基,N-甲基)-2-氨乙基;化合物5是通式Ib的化合物,其中R5=R7=R8=R10=R17=H,R6=甲氧基且R9=肉桂酰氧基;化合物6是通式Ib的化合物,其中R5=R7=R8=R17=H,R6=R9=R10=甲氧基;化合物7是通式Ib的化合物,其中R8=R9=R17=H,R6=OH,R5和R7一起为O,R10=甲氧基;化合物8是通式Ib的化合物,其中R5=R7=R9=R17=H,R6=R8=R10=甲氧基;化合物9是通式Ic的化合物,其中R3=R4=OH,且R2=R6=H;化合物10是通式Ic的化合物,其中R2=R3=R6=OH,且R4=甲氧基;化合物11是通式Id的化合物,其中R2=R3=H且R4=R6=甲氧基;和化合物12是通式Ie的化合物,其中R3=R4=甲氧基且两个氢彼此是顺式的。
13.包含至少一种通式I或Ie的化合物的组合物,优选膳食组合物、身体护理组合物或药物组合物,所述通式I或Ie为:
其中当L5为氢或R5时,L为A或B任一,或
其中L和L5形成残基C或D,
且其中
L1为H、OH或R2;L2为H;L3为H、OH或R6;L4为H;
优选地当L为A时,L1为OH且L2、L3和L4为H;
优选地当L为B时,L1、L2和L4为H,L3为R6且L5为R5;
优选地当L和L5一起形成残基C时,L2、L4为H,L1为R2且L3为R6;
优选地当L和L5一起形成残基D时,L2、L4为H,L1为R2且L3为R6;
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8、R10为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
15.根据权利要求13或14的组合物,优选地为膳食组合物、身体护理组合物或药物组合物,其中R2为H、OH或甲氧基;和/或R3、R4和R6彼此独立地为OH或甲氧基;和/或R5为H或甲氧基;或R7为H;或R5和R7一起为-O-;R8和/或R10为甲氧基;或R9为H、甲氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2;和/或R17为(N-酰基,N-甲基)-2-氨乙基。
16.根据权利要求13或14的组合物,优选地为膳食组合物、身体护理组合物或药物组合物,其特征是所述通式I的的化合物选自由以下组成的组:通式Ia的化合物,其中R1=R3=R4=OH且R2=H(=化合物1);通式Ia的化合物,其中R1=OH、R2=R3=R4=甲氧基(=化合物2);通式Ib的化合物,其中R5=R6=R8=R10=甲氧基且R7=R9=R17=H(=化合物3);通式Ib的化合物,其中R5=R7=H,R6=R8=甲氧基,R9和R10一起形成-O-CH2-O-且R17=(N-酰基,N-甲基)-2-氨乙基(=化合物4);通式Ib的化合物,其中R5=R7=R8=R10=R17=H,R6=甲氧基且R9=肉桂酰氧(=化合物5);通式Ib的化合物,其中R5=R7=R8=R17=H,R6=R9=R10=甲氧基(=化合物6);通式Ib的化合物,其中R8=R9=R17=H,R6=OH,R5和R7一起为O,R10=甲氧基(=化合物7);通式Ib的化合物,其中R5=R7=R9=R17=H,R6=R8=R10=甲氧基(=化合物8);通式Ic的化合物,其中R3=R4=OH,且R2=R6=H(=化合物9);通式Ic的化合物,其中R2=R3=R6=OH,且R4=甲氧基(=化合物10);通式Id的化合物,其中R2=R3=H且R4=R6=甲氧基(=化合物11);和通式Ie的化合物,其中R3=R4=甲氧基且两个氢彼此是顺式的(=化合物12)。
17.根据权利要求13到16中任一项的组合物,其为以下形式的膳食组合物:食品形式如乳制品(例如酸乳),强化食品形式如谷物棒和烘焙物如蛋糕和曲奇,膳食补充剂形式如片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制物,无醇饮品形式如软饮、运动饮品、果汁、柠檬水、茶和基于乳的饮品,液体食品形式如汤和乳制品(麦芯饮品)。
18.根据权利要求13到17中任一项的所述膳食或药物组合物用于治疗肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少的用途,其中所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
19.用作药物的如权利要求9中定义的所述通式I或Ie的化合物。
20.根据权利要求19的用作药物的所述化合物,其特征是所述通式I的化合物选自由以下组成的组:通式Ia的化合物,其中R1=R3=R4=OH且R2=H(=化合物I);通式Ia的化合物,其中R1=OH、R2=R3=R4=甲氧基(=化合物2);通式Ib的化合物,其中R5=R6=R8=R10=甲氧基且R7=R9=R17=H(=化合物3);通式Ib的化合物,其中R5=R7=H,R6=R8=甲氧基,R9和R10一起形成-O-CH2-O-且R17=(N-酰基,N-甲基)-2-氨乙基(=化合物4);通式Ib的化合物,其中R5=R7=R8=R10=R17=H,R6=甲氧基且R9=肉桂酰氧(=化合物5);通式Ib的化合物,其中R5=R7=R8=R17=H,R6=R9=R10=甲氧基(=化合物6);通式Ib的化合物,其中R8=R9=R17=H,R6=OH,R5和R7一起为O,R10=甲氧基(=化合物7);通式Ib的化合物,其中R5=R7=R9=R17=H,R6=R8=R10=甲氧基(=化合物8);通式Ic的化合物,其中R3=R4=OH,且R2=R6=H(=化合物9);通式Ic的化合物,其中R2=R3=R6=OH,且R4=甲氧基(=化合物10);通式Id的化合物,其中R2=R3=H且R4=R6=甲氧基(=化合物11);和通式Ie的化合物,其中R3=R4=甲氧基且两个氢彼此是顺式的(=化合物12)。
21.用作药物的根据权利要求19或20的所述化合物,其中所述药物被用于治疗肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
22.如权利要求9中定义的所述通式I或Ie的化合物用于制造下述组合物的用途,优选地权利要求10到12中任一项定义的化合物用于制造下述组合物的用途,所述组合物用于治疗肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
23.根据权利要求19的化合物或根据权利要求22的用途,其中所述药物和所述组合物分别被用于增强身体性能、增强耐久能力、增加肌肉量、维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能、改善骨健康和功能、预防肌肉损耗、增强肌肉恢复、降低肌肉疲劳、提高脂肪氧化、改善能量平衡、改善血脂模式、减少不良胆固醇(LDL)和增加良好胆固醇(HDL)、防止肥胖症、促进脂肪氧化、维持健康的葡萄糖和胆固醇水平、预防心血管疾病、改善胰岛素敏感性、维持内皮功能,和/或改善关节功能、减轻关节炎疼痛和肿胀、加速皮肤伤口愈合,和/或改善炎性皮肤病症。
24.在包括人的哺乳动物中用于治疗和/或预防肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少的方法,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳,所述方法包括对需要的哺乳动物施用有效剂量的如权利要求9中定义的通式I或Ie的化合物,优选地如权利要求10到12中任一项中定义的化合物。
25.根据权利要求24的方法,其中所述哺乳动物是人、宠物动物或农场动物。
26.用于治疗包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳的肌肉障碍,用于改善肌肉功能和耐力,用于治疗与受损的脂质代谢、受损的葡萄糖代谢、受损的胰岛素作用相关的障碍,和用于治疗肥胖症、超重病症、进食障碍如食欲过盛和神经性厌食症,用于身体塑形,用于改善肌肉∶脂肪比例,用于治疗心血管疾病、动脉粥样硬化、血管疾病、心力衰竭,炎性病症如关节炎、类风湿性关节炎、骨关节炎、痛风,胃肠道障碍如炎性肠综合征、Crohn′s疾病、胃炎、肠易激综合征和溃疡性结肠炎,皮肤相关病症如银屑病、湿疹、烧伤、皮炎和变态反应,用于加速皮肤伤口愈合,用于治疗呼吸障碍如哮喘、慢性阻塞性肺疾病(COPD)、变应性疾病和/或用于治疗骨障碍如骨质疏松和骨质减少的通式I或Ie的化合物,
其中当L5为氢或R5时L为A或B任一,或
其中L和L5形成残基C或D,
且其中
L1为H、OH或R2;L2为H;L3为H、OH或R6;L4为H;
优选地当L为A时L1为OH且L2、L3和L4为H;
优选地当L为B时L1、L2和L4为H,L3为R6且L5为R5;
优选地当L和L5一起形成残基C时,L2、L4为H,L1为R2且L3为R6;
优选地当L和L5一起形成残基D时,L2、L4为H,L1为R2且L3为R6;
R2为H、OH或C1-6-烷氧基;R3、R4和R6彼此独立地为OH或C1-6-烷氧基;
R5为H或C1-6-烷氧基;R7为H;或R5和R7一起为-O-;R8、R10为C1-6-烷氧基;R9为H、C1-6-烷氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2、3;R17为(N-C1-6-酰氧基,N-C1-6-烷氧基)-y-氨基-Cy-烷基,其中y=1-6。
28.根据权利要求26或27的化合物,其中所述化合物的取代基如下:R2为H、OH或甲氧基;和/或R3、R4和R6彼此独立地为OH或甲氧基;和/或R5为H或甲氧基;或R7为H;或R5和R7一起为-O-;R8和/或R10为甲氧基;或R9为H、甲氧基或肉桂酰氧基;或R9和R10一起形成基团O-(CH2)x-O,其中x=1、2;和/或R17为(N-酰基,N-甲基)-2-氨乙基。
29.根据权利要求26的化合物,其中所述通式I的化合物选自由所述化合物1-12组成的组,其中所述化合物1是通式Ia的化合物,其中R1=R3=R4=OH且R2=H;化合物2是通式Ia的化合物,其中R1=OH、R2=R3=R4=甲氧基;化合物3是通式Ib的化合物,其中R5=R6=R8=R10=甲氧基且R7=R9=R17=H;化合物4是通式Ib的化合物,其中R5=R7=H,R6=R8=甲氧基,R9和R10一起形成-O-CH2-O-且R17=(N-酰基,N-甲基)-2-氨乙基;化合物5是通式Ib的化合物,其中R5=R7=R8=R10=R17=H,R6=甲氧基且R9=肉桂酰氧;化合物6是通式Ib的化合物,其中R5=R7=R8=R17=H,R6=R9=R10=甲氧基;化合物7是通式Ib的化合物,其中R8=R9=R17=H,R6=OH,R5和R7一起为O,R10=甲氧基;化合物8是通式Ib的化合物,其中R5=R7=R9=R17=H,R6=R8=R10=甲氧基;化合物9是通式Ic的化合物,其中R3=R4=OH,且R2=R6=H;化合物10是通式Ic的化合物,其中R2=R3=R6=OH,且R4=甲氧基;化合物11是通式Id的化合物,其中R2=R3=H且R4=R6=甲氧基;和化合物12是通式Ie的化合物,其中R3=R4=甲氧基且两个氢彼此是顺式的。
30.4′,7-二甲氧基异黄酮在哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的用途,其中所述哺乳动物包括人,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
31.在哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的4′,7-二甲氧基异黄酮,其中所述哺乳动物包括人,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
32.4′,7-二甲氧基异黄酮用于制造下述组合物的用途,所述组合物在哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例,所述哺乳动物包括人,所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳。
33.在包括人的哺乳动物中用于治疗肌肉障碍、用于改善肌肉功能和耐力、用于增强身体性能、用于增强耐久能力、用于增加肌肉量、用于预防肌肉损耗、用于增强肌肉恢复、用于降低肌肉疲劳、用于改善能量平衡、用于维持肌肉性能和/或肌肉强度和/或肌肉量和/或肌肉功能,和/或用于改善体形和/或用于改善肌肉∶脂肪比例的方法,其中所述肌肉障碍包括肌肉消耗和相关的障碍,如老年性肌肉萎缩、恶病质、肌肉损伤、肌营养不良症和肌肉疲劳,所述方法包括对需要的哺乳动物施用有效剂量的4′,7-二甲氧基异黄酮。
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CA2762351A1 (en) | 2009-05-18 | 2010-11-25 | Ottawa Hospital Research Institute | Treatment of muscle disease characterized by insulin resistance |
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EP2580967A1 (en) * | 2011-10-11 | 2013-04-17 | Nestec S.A. | Accelerating muscle recovery after immobilization-induced muscle atrophy |
US10899727B2 (en) | 2016-04-11 | 2021-01-26 | Middle Tennessee State University | Therapeutic aurones |
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