CN102076344A - 用于治疗疾病的NF-κB的非激素甾体调节剂 - Google Patents
用于治疗疾病的NF-κB的非激素甾体调节剂 Download PDFInfo
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Abstract
本发明涉及可用于治疗诸如肌营养不良症的神经肌肉疾病的化合物和方法,所述化合物可作为NF-κB抑制剂以治疗或预防包括肌营养不良症在内的肌萎缩疾病。
Description
本发明是在美国政府的支持下,根据第DOD 05118004号合同和NIH第1U54HD053177-01Al号完成的。美国政府对本发明享有一定权利。
本发明要求2008年5月28日提交的美国临时专利申请第61/056,715号的优先权,其公开内容援引加入本文。
本文公开了新的非激素甾体化合物和组合物以及它们作为药物用于治疗疾病的用途。本文还提供了在人类或动物个体中调节NF-κB活性的方法,其用于治疗NF-κB介导的疾病。
诸如肌营养不良症的肌萎缩疾病(muscular wasting diseases)是一类最终导致进行性骨骼肌萎缩(progressive skeletal muscle wasting)的变性性疾病,其导致肌无力、高骨折发生率、轮椅依赖(wheelchair dependence),并且在某些情况下导致死亡。在肌营养不良症中,最严重且最为人熟知的是杜氏肌营养不良症。另一种表现出类似症状的肌萎缩疾病为贝克肌营养不良症,但其没有杜氏肌营养不良症严重。尽管引起杜氏肌营养不良症和贝克肌营养不良症二者的缺陷性肌营养不良蛋白基因已经为人们所知20余年,然而目前仍然缺乏相应的治疗方法。
已识别出数种在恶病质过程中破坏宿主组织的分解代谢因子(catabolicfactor)。看来炎性细胞因子(特别是肿瘤坏死因子-α(TNF-α))的过度分泌是恶病质的最可能的原因之一。具体而言,TNF-α可以模拟在恶病质中发生的大多数异常情况,例如体重减轻、厌食症、产热增加(increasedthermogenesis)、脂代谢变化、胰岛素抗药性和肌萎缩。
肌营养不良症也可能是由肌肉组织丧失神经支配(loss of innervation)或神经支配受损(damage to innervation)所引起的。诸如慢性神经病和运动神经元病的疾病可能导致神经支配受损。对神经的物理伤害也可能导致肌肉组织的神经支配受损。或者,肌营养不良症可能是由环境条件(例如在航天期间)所致或者由衰老或长期卧床休息所致。在这些环境条件下,肌肉不能承受通常的负重,从而导致废用性肌萎缩(muscle atrophy from disuse)。具体而言,在肌肉废用期间,主要通过ATP依赖性泛素蛋白酶体通路激活细胞内过程以诱导蛋白酶解,这调控了NF-κB通路。
已知NF-κB介导负责诱导参与促炎症反应的基因的胞外信号。通过与几种已知作为κ-β(IκBs)抑制剂的蛋白的非共价相互作用,NF-κB存在于大多数非刺激细胞的细胞质中(May & Ghosh,(1997)Semin.Cancer.Biol.8,63-73;May & Ghosh,(1998)Immunol.Today 19,80-88;Ghosh等人,(1998)Annu.Rev.Immunol.16,225-260)。与促炎症反应相关的细胞刺激素(例如TNF-α活化激酶)再通过磷酸化IκBs激活NF-κB。对IκBs进行磷酸化的激酶被称为IκB激酶(IKK)。
磷酸化针对IκBs进行随后的遍在蛋白化和降解。IκBs的降解揭示了对NF-κB的核定位信号,使得活化的核积聚,这导致了DNA的结合以及对特异性基因表达的控制。因此,NF-κB的磷酸化是调控多种刺激素的NF-κB下游中的一个重要步骤,但其它机制可能导致功能化NF-κB的活化。
对磷酸化IκBs的激酶的识别和表征使人们对参与NF-κB活化的信号通路有了更好的理解。迄今为止已识别了几种不同的IKK亚型。IKKα最初在海拉细胞中被识别为通过TNF-α刺激诱导的IκB激酶(DiDonato等人,(1997)Nature 388,548-554)。人们还识别出另一种与IKKα同源的IκB激酶,其被称为IKKβ,并且被确定为TNFα刺激后诱导的主要IκB激酶(Takeda等人,(1999)Science 284,313-316;Pots等人,美国专利6,030,834(2000);Woronicz等人,美国专利5,939,302(1999))。IKKα和IKKβ的整体同源性为52%,在激酶结构域方面的同源性为65%(Zandi等人,(1997)Cell 91,243-252)。
IκB蛋白激酶(IKK)在特定的丝氨酸残基上磷酸化IκBs。具体而言,它们磷酸化IκBζ的丝氨酸32和36位(Traenckner等人,(1995)EMBO J.14,2876-2883;DiDonato等人,(1996)MoI.Cell.Biol.16,1295-1304)。对这两个位点的磷酸化对于有效针对IκBα进行降解是必需的。此外,IκKα和IκKβ的活化通常是响应NF-κB激活剂,所述NF-κB激活剂包括佛波醇12-肉豆蔻酸酯13-乙酸酯(PMA)、脂多糖(LPS)、白细胞介素-1(IL-1)、TNF-α、活性氧和DNA损试剂。无催化活性的突变体IKKα和IKKβ可用来阻断NF-κB刺激。因此,IκB激酶在调控炎性刺激素NF-κB下游的活化过程中是必需的。在其它通路中,IκB激酶可能并不重要。
IKKα和IKKβ具有截然不同的结构基序,包括通过亮氨酸拉链结构域从羧基近端的螺旋-环-螺旋结构域分离的氨基端丝氨酸-苏氨酸激酶结构域。这些结构特征不同于其它激酶,并且非催化结构域被认为参与蛋白质-蛋白质相互作用。因此,与IKK结合的蛋白应当能够调节NF-κB的活性,并能够潜在地调节下游事件(例如诱导NF-κB)。例如,NEMO(NF-κB必需调节剂)是已被识别为与IKK结合并促进激酶活性的蛋白(Yamaoke等人,(1998)Cell 93,1231-1240;Rothwarf等人,(1998)Nature 395,287-300)。
体内研究表明,慢性NF-κB活化与诸如杜氏肌营养不良症的肌萎缩疾病有关,US 2007/0225315(2007年3月15日)对此进行了进一步阐述。具体而言,在对p65/RelA NF-κB亚单元杂合的个体中大多预防了肌萎缩。据发现,注射NF-κB活化抑制剂肽在被感染的小鼠个体中抑制营养不良表型。抛开具体理论的束缚,看来NF-κB的慢性活化对于杜氏肌营养不良症的肌萎缩症状是必需的。因此,针对NF-κB的以药物为基础的治疗对于治疗杜氏肌营养不良症以及其它形式的肌萎缩疾病而言,可能是一种有效的策略。
通常,可以根据本发明的记载,用NF-κB的直接或间接调节剂来治疗肌萎缩疾病。NF-κB的间接调节剂包括例如IκB激酶(IKK)抑制剂(如IKKα抑制剂和IKKβ抑制剂)以及在信号通路中从IKK上游直接起作用的抑制剂(如磷酸肌醇依赖性激酶(PDK)抑制剂和Akt(也称为PKB)抑制剂)。
如上所述,用于调节NF-κB通路的一种合适的方法是通过与IκB蛋白激酶(IKK)中的一种结合。通过与IKK结合,阻断了IκBs的磷酸化,并且无法激活NF-κB。在一实施方案中,为了阻断NF-κB通路并抑制肌萎缩疾病,可以将直接抑制IKK催化活性的化合物给药。具体而言,为了抑制肌萎缩疾病,可以向个体给药IKKα抑制剂或其对映体、类似物、前药、活性代谢产物、盐和/或水合物。
发明人发现新的化合物和药物组合物,发现其中的一些能够调节NF-κB,同时也发现合成和使用这些化合物的方法,包括通过给药这些化合物来治疗患者的NF-κB介导的疾病的方法。
在一些实施方案中,本文公开了具有结构式I的化合物或其盐:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基(thiol);
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基(hydrazinyl)、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基。
在另一实施方案中,R7和R8独立地选自氢、未取代C2-3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
在另一实施方案中,R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基。
在另一实施方案中,R1和R3各自为氢;R2和R4各自独立地选自氢、甲基和氟;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R2和R4各自为氢;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R5选自氢、甲基和乙基;R6选自氢、羟基和甲基;以及R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
在另一实施方案中,R5选自未取代C2-C6烷基和苯基;R6选自氢、羟基和甲基;以及R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
在另一实施方案中,R5为乙基。
在另一实施方案中,所述虚线表示任选的双键;R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;如果R1、R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为-C(O)CH2CH2CO2H;如果所述虚线不表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为-C(O)CH2CH2CO2H;如果所述虚线表示双键,R1为甲基,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为-C(O)CH2CH2CO2H;如果R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢或乙酰基;如果所述虚线不表示双键,R1为氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢或乙酰基;以及如果所述虚线不表示双键,R1为甲基,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为乙酰基。
在另一实施方案中,R7和R8独立地选自氢、未取代C2-3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
在另一实施方案中,R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基。
在另一实施方案中,R1和R3各自为氢;R2和R4各自独立地选自氢、甲基和氟;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R2和R4各自为氢;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R5选自氢、甲基和乙基;R6选自氢、羟基和甲基;以及R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
在另一实施方案中,R5选自未取代C2-C6烷基和苯基;R6选自氢、羟基和甲基;以及R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
在另一实施方案中,R5为乙基。
在另一实施方案中,所述虚线表示任选的双键;R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;R7和R8独立地选自氢、未取代C2-3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
在另一实施方案中,R1和R3各自为氢;R2和R4各自独立地选自氢、甲基和氟;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
在另一实施方案中,R2和R4各自为氢;R5选自氢、未取代低级烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
在另一实施方案中,R5选自氢、甲基和乙基;R6选自氢、羟基和甲基;以及R9选自氢和乙酰基。
在另一实施方案中,所述虚线表示任选的双键;R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基。
在另一实施方案中,R1和R3各自为氢;R2和R4各自独立地选自氢、甲基和氟;R5选自未取代C2-C6烷基和苯基;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R2和R4各自为氢;R6选自氢、羟基和甲基;R7和R8各自为氢;以及R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
在另一实施方案中,R6选自氢、羟基和甲基;以及R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
在另一实施方案中,R5为乙基。
本文公开的某些化合物可能具有有用的NF-κB调节活性,并且可用于治疗或预防NF-κB在其中起活性作用的的疾病或病状。因此,从广义上来看,某些实施方案还提供了包含本文公开的一种或多种化合物和药学可接受的载体的药物组合物,以及制备和使用所述化合物和组合物的方法。某些实施方案提供了调节NF-κB的方法。另一些实施方案提供了在需要这样的治疗的患者中治疗NF-κB介导的病症的方法,其包括向所述患者给药治疗有效量的本发明的化合物或组合物。本发明还提供了本文公开的某些化合物在制备用于治疗通过调节NF-κB而得以改善的疾病或病状的药物中的用途。
在一些实施方案中,所述NF-κB介导的疾病选自:肌营养不良症、关节炎、外伤性脑损伤、脊髓损伤、脓毒症、风湿性疾病、癌症、动脉粥样硬化、1型糖尿病、2型糖尿病、钩端螺旋体肾病(leptospiriosis renal disease)、青光眼、视网膜疾病、衰老、头痛、疼痛、复合性局部疼痛综合征、心脏肥大、肌萎缩、分解代谢紊乱(catabolic disorder)、肥胖症、胎儿生长迟缓、高胆固醇血症、心脏病、慢性心力衰竭、缺血/再灌注、中风、脑动脉瘤、心绞痛、肺疾病、囊性纤维化、酸致肺损伤(acid-induced lung injury)、肺性高血压、哮喘、慢性阻塞性肺病、干燥综合征(Sjogren’s syndrome)、透明膜病、肾疾病、肾小球疾病、酒精性肝病、肠道疾病(gut diseases)、腹膜子宫内膜异位症(peritoneal endometriosis)、皮肤病、鼻窦炎、间皮瘤、无汗性外胚层发育不良-ID、白塞氏病、色素失调症、结核病、哮喘、局限性肠炎(crohn′sdisease)、结肠炎、眼变应性、阑尾炎、佩吉特氏病、胰腺炎、牙周病(periodonitis)、子宫内膜异位症、炎性肠疾病、炎性肺疾病、硅致疾病(silica-induced diseases)、睡眠呼吸暂停、艾滋病、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮性肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激疾病(psychosocial stress diseases)、神经病理疾病、家族性淀粉样多神经病、炎症性神经病、帕金森氏病、多发性硬化、阿尔茨海默氏症、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、白内障和听力损失。
在另一实施方案中,所述NF-κB介导的疾病为哮喘或慢性阻塞性肺病。
在另一实施方案中,所述NF-κB介导的疾病为干燥综合征。
在另一实施方案中,所述NF-κB介导的疾病为关节炎。
在另一实施方案中,所述NF-κB介导的疾病为肌萎缩。
在另一实施方案中,所述肌萎缩疾病为肌营养不良症。
在另一实施方案中,所述肌营养不良症选自:杜氏肌营养不良症、贝克肌营养不良症、肢带型肌营养不良症、先天性肌营养不良症、面肩肱型肌营养不良症、强直性肌营养不良症、眼咽肌营养不良症、远端肌营养不良症、和Emery-Dreifuss肌营养不良症。
在另一实施方案中,所述肌营养不良症为杜氏肌营养不良症。
当公开数值范围且使用表述“从n1...至n2”(其中,n1和n2为数值)时,则除非另有规定,该表述意图包括这些数值本身和它们之间的范围。该范围可以是整数或连续区间,并包括端值。例如,范围“2至6个碳”意图包括2、3、4、5和6个碳,因为碳以整数单位存在。作为比较,例如范围“1μM至3μM(微摩尔)”意图包括1μM、3μM以及1μM和3μM之间的具有任意个有效数字的任意值(例如1.255μM、2.1μM、2.9999μM等)。
本文使用的术语“约”意图限定改变的数值,表示在误差范围内作为变量的值。当并未列出具体误差范围(例如在数据图或数据表中给出的平均值的标准偏差)时,应当理解术语“约”意味着包括所列值的范围,以及包括通过将该数字向上或向下舍入的范围(考虑有效数字)。
本文单独使用或组合使用的术语“酰基”是指与烯基、烷基、芳基、环烷基、杂芳基、杂环或任意其它基团相连的羰基,其中与所述羰基相连的原子是碳。“乙酰基”基团是指-C(O)CH3基团。“烷基羰基”或“烷酰基”基团是指通过羰基基团与母体分子基团相连的烷基基团。这样的基团的实例包括甲基羰基和乙基羰基。酰基基团的实例包括甲酰基、烷酰基和芳酰基。
本文单独使用或组合使用的术语“烯基”是指具有一个或多个双键且含有2至20个碳原子的直链或支链烃基。在一些实施方案中,所述烯基包括2至6个碳原子。术语“亚烯基(alkenylene)”是指在两个或多个位点连接的碳-碳双键体系,例如亚乙烯基[(-CH=CH-),(-C::C-)]。合适的烯基基团的实例包括乙烯基、丙烯基、2-甲基丙烯基、1,4-丁二烯基等。除非另有规定,术语“烯基”可包括“亚烯基”基团。
本文单独使用或组合使用的术语“烷氧基”是指烷基醚基团,其中术语烷基定义如下。合适的烷基醚基团的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
本文单独使用或组合使用的术语“烷基”是指含有1至20个碳原子的直链或支链烷基基团。在一些实施方案中,所述烷基包括1至10个碳原子。在另一些实施方案中,所述烷基包括1至6个碳原子。如本文所定义,烷基基团可以任选地被取代。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、辛基、壬基(noyl)等。本文单独使用或组合使用的术语“亚烷基(alkylene)”是指衍生自在两个或多个位点连接的直链或支链饱和烃的饱和脂肪基,例如亚甲基(-CH2-)。除非另有规定,术语“烷基”可包括“亚烷基”基团。
本文单独使用或组合使用的术语“烷氨基”是指通过氨基基团与母体分子基团相连的烷基基团。合适的烷氨基基团的实例可以是单烷基化或双烷基化的,形成诸如N-甲氨基、N-乙氨基、N,N-二甲氨基、N,N-乙基甲基氨基等基团。
本文单独使用或组合使用的术语“亚烷基(alkylidene)”是指烯基基团,其中碳-碳双键的一个碳原子属于与烯基基团相连的基团。
本文单独使用或组合使用的术语“烷硫基”是指烷基硫醚(R-S-)基团,其中术语烷基定义如上,并且其中硫可被单氧化或双氧化。合适的烷基硫醚基团的实例包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、甲磺酰基、乙基亚磺酰基(ethanesulfinyl)等。
本文单独使用或组合使用的术语“炔基”是指具有一个或多个三键且含有2至20个碳原子的直链或支链烃基。在一些实施方案中,所述炔基含有2至6个碳原子。在另一些实施方案中,所述炔基含有2至4个碳原子。术语“亚炔基”是指在两个位点连接的碳-碳三键,例如亚乙炔基(-C:::C-,-C≡C-)。炔基基团的实例包括乙炔基、丙炔基、羟基丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、3-甲基丁炔-1-基、己炔-2-基等。除非另有规定,术语“炔基”可包括“亚炔基”基团。
本文单独使用或组合使用的术语“酰氨基(amido)”和“氨基甲酰基”是指如下所述通过羰基基团与母体分子基团相连的氨基基团,反之亦然。本文单独使用或组合使用的术语“C-酰氨基”是指-C(=O)-NR2基团,其中R如本文所定义。本文单独使用或组合使用的术语“N-酰氨基”是指RC(=O)NH-基团,其中R如本文所定义。本文单独使用或组合使用的术语“酰氨基(acylamino)”包含通过氨基与母体基团相连的酰基。“酰氨基”基团的实例为乙酰氨基(CH3C(O)NH-)。
本文单独使用或组合使用的术语“氨基”是指NRR’,其中R和R’独立地选自氢、烷基、酰基、杂烷基、芳基、环烷基、杂芳基和杂环烷基,其中的任一个本身可被任选取代。此外,R和R’可结合形成杂环烷基,其中的任一个可被任选取代。
本文单独使用或组合使用的术语“芳基”意指含有1个、2个或3个环的碳环芳族体系,其中这样的多元环体系稠和在一起。术语“芳基”包括芳族基,例如苯基、萘基、蒽基和菲基。
本文单独使用或组合使用的术语“芳基烯基”或“芳烯基”是指通过烯基基团与母体分子基团相连的芳基基团。
本文单独使用或组合使用的术语“芳基烷氧基”或“芳烷氧基”是指通过烷氧基基团与母体分子基团相连的芳基基团。
本文单独使用或组合使用的术语“芳基烷基”或“芳烷基”是指通过烷基基团与母体分子基团相连的芳基基团。
本文单独使用或组合使用的术语“芳基炔基”或“芳炔基”是指通过炔基基团与母体分子基团相连的芳基基团。
本文单独使用或组合使用的术语“芳基烷酰基”或“芳烷酰基”是指衍生自芳基取代的烷基羧酸的酰基基团,例如苯甲酰基、萘甲酰基、苯乙酰基、3-苯基丙酰基(氢化肉桂酰基)、4-苯基丁酰基、(2-萘基)乙酰基、4-氯代氢化肉桂酰基等。
本文单独使用或组合使用的术语芳氧基是指通过氧基与母体分子基团相连的芳基基团。
本文单独使用或组合使用的术语“苯并”是指衍生自苯的二价基团C6H4=。其实例包括苯并噻吩和苯并咪唑。
本文单独使用或组合使用的术语“氨基甲酸酯”是指氨基甲酸的酯(-NHCOO-),其可以从氮端或酸端与母体分子基团相连,并且可以如本文所定义的那样任选地被取代。
本文单独使用或组合使用的术语“O-氨基甲酰基”是指-OC(O)NRR’基团,其中R和R’如本文所定义。
本文单独使用或组合使用的术语“N-氨基甲酰基”是指ROC(O)NR′-基团,其中R和R’如本文所定义。
本发明使用的术语“羰基”,当其单独使用时包括甲酰基[-C(O)H],而组合使用时为-C(O)-基团。
本文单独使用或组合使用的术语“羧基”是指-C(O)OH或相应的“羧酸根”阴离子,例如羧酸盐形式。“O-羧基”基团是指RC(O)O-基团,其中,R如本文所定义。“C-羧基”基团是指-C(O)OR基团,其中,R如本文所定义。
本文单独使用或组合使用的术语“氰基”是指-CN。
本文单独使用或组合使用的术语“环烷基”或“碳环”是指饱和或部分饱和的一元环烷基、二元环烷基或三元环烷基基团,其中各环基团含有3至12个碳原子环成员,并且其可以任选地为苯并稠环体系,所述苯并稠环体系可以如本文所定义那样被任选取代。在一些实施方案中,所述环烷基含有3至7个碳原子。在一些实施方案中,所述环烷基含有5-7个碳原子。这样的环烷基基团的实例包括环丙基、环丁基、环戊基、环己基、环庚基、四氢萘基、茚满基、八氢萘基、2,3-二氢-1H-茚基、金刚烷基等。本文使用的“二环”和“三环”意图包括稠环体系(例如十氢萘、八氢萘)以及多环(多中心)的饱和或部分不饱和类型。一般而言,后一类型的异构体例如二环[1,1,1]戊烷、樟脑、金刚烷和二环[3,2,1]辛烷。
本文单独使用或组合使用的术语“酯”是指桥连两个基团(在碳原子上连接)的羧基基团。
本文单独使用或组合使用的术语“醚”是指桥连两个基团(在碳原子上连接)的氧基基团。
本文单独使用或组合使用的术语“卤代”或“卤素”是指氟、氯、溴或碘。
本文单独使用或组合使用的术语“卤代烷氧基”是指通过氧原子与母体分子基团相连的卤代烷基基团。
本文单独使用或组合使用的术语“卤代烷基”是指具有如上述定义的含义的烷基基团,其中一个或多个氢被卤素替代。其具体包括单卤代烷基、而卤代烷基和多卤代烷基基团。例如单卤代烷基基团可在基团中含有一个碘、溴、氯或氟原子。二卤代和多卤代烷基基团可含有两个或更多个相同的卤原子或不同卤代基团的组合。卤代烷基基团的实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。“卤代亚烷基”是指在两个或多个位点连接的卤代烷基基团。其实例包括氟代亚甲基(-CFH-)、二氟亚甲基(-CF2-)、氯代亚甲基(-CHCl-)等。
本文单独使用或组合使用的术语“杂烷基”是指稳定的直链或支链或环状烃基或其组合,其为完全饱和的或具有1至3的不饱和度,由所述数目的碳原子和1至3个选自O、N和S的杂原子组成,其中所述氮原子和硫原子可任选被氧化,并且所述氮原子可任选被季铵化。所述杂原子O、N和S可置于杂烷基基团的任意内部位点。至多2个杂原子可以是连续的,例如-CH2-NH-OCH3。
本文单独使用或组合使用的术语“杂芳基”是指3至7元不饱和单杂环或者稠和单环、二环或三环体系,其中至少一个稠环为芳环,所述杂芳基含有至少一个选自O、S和N的原子。在一些实施方案中,所述杂芳基含有5至7个碳原子。该术语还包括稠和多环基团,其中杂环与芳环稠和、其中杂芳环与其它杂芳环稠和、其中杂芳环与杂环烷基环稠和或者其中杂芳环与环烷基环稠和。杂芳基基团的实例包括吡咯基、吡咯啉基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、吡喃基、呋喃基、噻吩基、噁唑基、异噁唑基、噁二唑基、噻唑基、噻二唑基、异噻唑基、吲哚基、异吲哚基、中氮茚基(indolizinyl)、苯并咪唑基、喹啉基、异喹啉基、喹噁啉基、喹唑啉基、吲唑基、苯并三唑基、苯并间二氧杂环戊烷基(benzodioxolyl)、苯并吡喃基、苯并噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、苯并噻吩基、色酮基(chromonyl)、香豆素基(coumarinyl)、苯并吡喃基、四氢喹啉基、四唑并哒嗪基、四氢异喹啉基、噻吩并吡啶基、呋喃并吡啶基、吡咯并吡啶基等。示例性的三元杂环基团包括咔唑基、苯并吲哚基、菲咯啉基、二苯并呋喃基、吖啶基、啡啶基、呫吨基等。
本文单独使用或组合使用的术语“杂环烷基”和“杂环”可以互换,各自是指含有至少一个作为环成员的杂原子的饱和、部分不饱和或完全不饱和的单环、二环或三环杂环基团,其中各所述杂原子可独立地选自氮、氧和硫。在一些实施方案中,所述杂环烷基含有1至4个作为环成员的杂原子。在另一些实施方案中,所述杂环烷基含有1至2个作为环成员的杂原子。在一些实施方案中,所述杂环烷基在每个环中含有3至8个环成员。在另一些实施方案中,所述杂环烷基在每个环中含有3至7个环成员。在又一些实施方案中,所述杂环烷基在每个环中含有5至6个环成员。“杂环烷基”和“杂环”意图包括砜、亚砜、含有叔氮(tertiary nitrogen)环成员的N-氧化物以及碳环稠环和苯并稠环体系;另外,这两个术语还包括这样的体系,其中如本文所定义的,杂环与芳基基团或其它杂环基团稠和。杂环基团的实例包括氮丙啶基、氮杂环丁烷基、1,3-苯并间二氧杂环戊烷基、二氢异吲哚基、二氢异喹啉基、二氢噌啉基、二氢苯并二噁英基(dihydrobenzodioxinyl)、二氢[1,3]噁唑并[4,5-b]吡啶基、苯并噻唑基、二氢吲哚基、二氢吡啶基、1,3-二噁烷基、1,4-二噁烷基、1,3-二氧戊环基、异吲哚啉基、吗啉基、哌嗪基、吡咯烷基、四氢吡啶基、哌啶基、硫代吗啉基等。除非明确禁止,杂环基可任选地被取代。
本文单独使用或组合使用的术语“肼基”是指通过单键连接的两个氨基基团,即-N-N-。
本文单独使用或组合使用的术语“羟基”是指-OH。
本文单独使用或组合使用的术语“羟基烷基”是指通过烷基基团与母体分子基团相连的羟基基团。
本文单独使用或组合使用的术语“亚氨基”是指=N-。
本文单独使用或组合使用的术语“亚氨基羟基”是指=N(OH)和=N-O-。
本文单独使用或组合使用的短语“在主链中”是指起从基团与本文所公开的任意一种分子式的化合物的连接点起始的碳原子的最长邻近或邻接链。
术语“异氰酸基”是指-NCO基团。
术语“异硫氰酸基”是指-NCS基团。
短语“原子的直链”是指独立地选自碳、氮、氧和硫的原子的最长直链。
在没有其它具体限定的情况下,本文单独使用或组合使用的术语“低级”意味着含有1至6(包括6)个碳原子。
本文单独使用或组合使用的术语“低级芳基”意指苯基或萘基,其可按照规定被任选地取代。
本文单独使用或组合使用的术语“低级杂芳基”意指下述两者之一:1)含有5或6个环成员的单环杂芳基,其中1至4个所述环成员可以是选自O、S和N的杂原子,或者2)二环杂芳基,其中各稠环含有5或6个环成员,在所述环成员中含有1至4个选自O、S和N的杂原子。
本文单独使用或组合使用的术语“低级环烷基”意指具有3至6个环成员的单环烷基。低级环烷基可以是不饱和的。低级环烷基的实例包括环丙基、环丁基、环戊基和环己基。
本文单独使用或组合使用的术语“低级杂环烷基”是指具有3至6个环成员的单杂环烷基,其中1至4个所述环成员可以是选自O、S和N的杂原子。低级杂环烷基的实例包括吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基和吗啉基。低级杂环烷基可以是不饱和的。
本文单独使用或组合使用的术语“低级氨基”是指-NRR’,其中R和R’独立地选自氢、低级烷基和低级杂烷基,其中的任一个可被任选地取代。另外,低级氨基基团的R和R’可结合形成5元或6元杂环烷基,其中的任一个可被任选地取代。
本文单独使用或组合使用的术语“mercaptyl”是指RS-基团,其中R如本文所定义。
本文单独使用或组合使用的术语“硝基”是指-NO2。
本文单独使用或组合使用的术语或“氧基”或“氧杂”是指-O-。
本文单独使用或组合使用的术语“氧代”是指=O。
术语“全卤代烷氧基”是指其中所有氢原子均被卤素原子取代的烷氧基基团。
本文单独使用或组合使用的术语“全卤代烷基”是指其中所有氢原子均被卤素原子取代的烷基基团。
本文单独使用或组合使用的术语“磺酸酯”、“磺酸”和“磺酸基”是指-SO3H基团,其作为磺酸的阴离子用于成盐。
本文单独使用或组合使用的术语“硫烷基(sulfanyl)”是指-S-。
本文单独使用或组合使用的术语“亚磺酰基”是指-S(O)-。
本文单独使用或组合使用的术语“磺酰基”是指-S(O)2-。
术语“N-磺酰氨基”是指RS(=O)2NR′-基团,其中R和R′如本文所定义。
术语“S-磺酰氨基”是指-S(=O)2NRR′-基团,其中R和R′如本文所定义。
本文单独使用或组合使用的术语“硫代”是指-S-基团或者其中用硫取代氧的醚。硫代基团的氧化衍生物(即亚磺酰基和磺酰基)包括在硫代的定义中。
本文单独使用或组合使用的术语“巯基”是指-SH基团。
本文使用的术语“硫代羰基”,当其单独使用时包括硫代甲酰基-C(S)H,而当其组合使用时为-C(S)-基团。
术语“N-硫代氨甲酰基”是指ROC(S)NR′-基团,其中R和R′如本文所定义。
术语“O-硫代氨甲酰基”是指-OC(S)NRR′基团,其中R和R′如本文所定义。
术语“硫氰酸基”是指-CNS基团。
术语“三卤代甲磺酰氨基”是指X3CS(O)2NR-基团,其中X为卤素且R如本文所定义。
术语“三卤代甲磺酰基”是指X3CS(O)2-基团,其中X为卤素。
术语“三卤代甲氧基”是指X3CO-基团,其中X为卤素。
本文单独使用或组合使用的术语“三取代甲硅烷基”是指按照取代氨基的定义,在其三个自由价上被本文所列的基团取代的硅酮基团。其实例包括三甲基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基等。
本发明中的任何定义可与任何其它定义结合使用以描述复合结构基团。按照惯例,任何这样的定义的后随元素(trailing element)是与母体基团相连的元素。例如,复合基团烷基酰氨基表示通过酰氨基基团与母体分子相连的烷基基团,而术语烷氧基烷基表示通过烷基基团与母体分子相连的烷氧基基团。
当一个基团被定义为“无(null)”时,其意味着所述基团不存在。
术语“任选取代”是指所述基团可以是取代的或未取代的。当其被取代时,“任选取代”的基团的取代基可以非限定性地包括一个或多个选自单独的下述基团或特定基团组或其组合的取代基:低级烷基、低级烯基、低级炔基、低级烷酰基、低级杂烷基、低级杂环烷基、低级卤代烷基、低级卤代烯基、低级卤代炔基、低级全卤代烷基、低级全卤代烷氧基、低级环烷基、苯基、芳基、芳氧基、低级烷氧基、低级卤代烷氧基、氧代、低级酰氧基、羰基、羧基、低级烷基羰基、低级羧酸酯(carboxyester)、低级甲酰氨基、氰基、氢、卤素、羟基、氨基、低级烷氨基、芳氨基、酰氨基、硝基、巯基、低级烷硫基、低级卤代烷硫基、低级全卤代烷硫基、芳硫基、磺酸酯、磺酸、三取代甲硅烷基、N3、SH、SCH3、C(O)CH3、CO2CH3、CO2H、吡啶基、噻吩、呋喃基、低级氨基甲酸酯和低级脲。可以将两个取代基相连以形成由0至3个杂原子组成的稠和五元、六元或七元碳环或杂环,例如形成亚甲二氧基或亚乙二氧基。任选取代的基团可以是未取代的(例如-CH2CH3)、完全取代的(例如-CF2CF3)、单取代的(例如-CH2CH2F)或以完全取代和单取代之间的任意水平取代的(例如-CH2CF3)。在未对所列取代基的取代进行限定的情况下,取代或未取代形式均包含在内。在取代基被限定为“取代的”的情况下,特定意指取代形式。另外,可以按照需要对特定基团的任选取代基的不同集合进行定义;在这些情况下,通常紧随在短语“被...任选取代”之后对任选取代进行定义。
除非另有规定,单独出现且无数量限定的术语R或术语R’是指选自下述基团的基团:氢、烷基、环烷基、杂烷基、芳基、杂芳基和杂环烷基,其中的任一个可被任选地取代。这样的R或R’基团应被理解为如本文所定义的那样被任选地取代。无论基团是否进行了数目限定,应当理解每个R基团(包括R、R’和Rn(其中n=1,2,3..n))、每个取代基和每个术语在基团的选择上彼此独立。如果任何变量、取代基或术语(例如芳基、杂环、R等)在一个分子式或通式结构(generic structure)中出现超过一次,则其每次出现时的定义与在其它次出现时的定义无关。本领域技术人员会进一步认识到某些基团可以与母体分子连接,或者可以从任一端点在元素链中占据位置。因此,仅举例而言,诸如-C(O)N(R)-的非对称基团可以在碳或氮中的任一位点上与母体分子相连。
本文所公开的化合物存在非对称中心。这些中心取决于手性碳原子周围的取代基的构型而用符号“R”或“S”标明。应当理解,本发明包括所有立体化学异构形式,包括非对映异构、对映异构和差向异构形式以及d-异构体和l-异构体,以及它们的混合物。可以从含有手性中心的商购原料合成制备化合物的单个立体异构体;或者可以通过以下方法制备化合物的单个立体异构体:制备对映异构产物的混合物,然后(例如通过转化)分离非对映异构体的混合物,然后进行分离或重结晶、色谱技术、在手性色谱柱上直接分离对映异构体或者本领域已知的任意其它适用的方法。具有特定立体化学的起始化合物是可商购的,或者可以通过本领域已知的技术进行制备和拆分。另外,本文所公开的化合物可能以几何异构体的形式存在。本发明包括所有的顺式(cis)、反式(trans)、顺(syn)、反(anti)、异侧(entgegen,E)和同侧(zusammen,Z)异构体以及它们的适合的混合物。另外,化合物可以以互变异构体形式存在;本发明提供所有的互变异构体。此外,本文所公开的化合物可以以未溶剂化形式或者以药学可接受的溶剂(例如水、乙醇等)的溶剂化形式存在。通常,溶剂化形式被视为与未溶剂化形式等效。
术语“键”是指两个原子或两个基团之间的共价连接,此时被键连接的原子被视为是较大亚结构的部分。除非另有说明,键可以为单键、双键或三键。分子式中的两个原子间的虚线表示在该位置上可存在或不存在另外的键。
一般而言,本文使用的术语“疾病”意图与术语“病症”和“病状”(如在医学病状中)同义并可互换使用,因为它们全都反映损害正常功能的人体或动物体或其部分的的异常状况,疾病通常通过区别体征和症状表现出来,并导致人类或动物的寿命缩短或生命质量降低。
术语“NF-κB介导的疾病”是指在疾病病理方面,NF-κB在其中起活性作用的疾病。NF-κB介导的疾病包括这样的疾病,其中除了NF-κB介导的过程之外还有多个生物学通路和/或过程对疾病病理起作用。可以通过调节NF-κB的活性或量来完全或部分地介导NF-κB介导的疾病。具体而言,NF-κB介导的疾病是这样的疾病,其中调节NF-κB对潜在的疾病起一定作用,例如给药NF-κB调节剂在至少一些接受治疗的患者中引起某些程度的改善。即使本文公开的化合物通过不同于NF-κB的生物学通路和/或过程发挥作用,术语“NF-κB介导的疾病”也指下述疾病:肌营养不良症、关节炎、外伤性脑损伤、脊髓损伤、脓毒症、风湿性疾病、癌症、动脉粥样硬化、1型糖尿病、2型糖尿病、钩端螺旋体肾病、青光眼、视网膜疾病、衰老、头痛、疼痛、复合性局部疼痛综合征、心脏肥大、肌营养不良、分解代谢紊乱、肥胖症、胎儿生长迟缓、高胆固醇血症、心脏病、慢性心力衰竭、缺血/再灌注、中风、脑动脉瘤、心绞痛、肺疾病、囊性纤维化、酸致肺损伤、肺性高血压、哮喘、慢性阻塞性肺病、干燥综合征、透明膜病、肾疾病、肾小球疾病、酒精性肝病、肠道疾病、腹膜子宫内膜异位症、皮肤病、鼻窦炎、间皮瘤、无汗性外胚层发育不良-ID、白塞氏病、色素失调症、结核病、哮喘、局限性肠炎、结肠炎、眼变应性、阑尾炎、佩吉特氏病、胰腺炎、牙周病、子宫内膜异位症、炎性肠疾病、炎性肺疾病、硅致疾病、睡眠呼吸暂停、艾滋病、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮性肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激疾病、神经病理疾病、家族性淀粉样多神经病、炎症性神经病、帕金森氏病、多发性硬化、阿尔茨海默氏症、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、白内障和听力损失。
术语“联合治疗”意指给药两种或多种治疗剂以治疗本发明所述的治疗性病状或病症。这样的给药包括以基本同时的方式将这些治疗剂同时给药,例如以含有固定比例的活性成分的单胶囊形式或者以各活性成分的多个分别的胶囊形式给药。此外,这样的给药还包括以连续方式使用每种治疗剂。在每种情况中,所述治疗方案会在治疗本文所述的病状或病症中提供药物联合的有益效果。
本发明使用的“NF-κB调节剂”是指这样的化合物,其通常如下述NF-κB抑制剂测定所测量的,对NF-κB活性表现的EC50不超过约100μM,更典型地不超过50μM。“EC50”是指将酶(例如(NF-κB))激活或者降低其活性或者增加或降低其量至半数最大水平的调节剂的浓度。已发现本文所公开的某些化合物对NF-κB表现出调节活性。如在本文所述的NF-κB测定中所测量的,在一些实施方案中,化合物对NF-κB活性表现出不超过约10μM的EC50值;在另一些实施方案中,化合物对NF-κB活性表现出不超过约5μM的EC50值;在又一些实施方案中,化合物对NF-κB活性表现出不超过约1μM的EC50值;在进一步的实施方案中,化合物对NF-κB活性表现出不超过约20nM的EC50值。
短语“治疗有效的”意图限定在疾病或病症的治疗中所使用的活性成分的量。所述量可以实现减轻或消除所述疾病或病症的目的。
术语“治疗上可接受的”是指适用于与患者的组织接触而不产生过度的毒性、刺激和过敏反应,符合合理的益处/风险比,并且对它们的预期用途有效的那些化合物(或盐、前药、互变异构体、两性离子形式)。
如本文所用,提及对患者的“治疗”意图包括预防。术语“患者”意指包括人类在内的所有哺乳动物。患者的实例包括人类、母牛、狗、猫、山羊、绵羊和兔。优选地,患者为人类。
术语“前药”是指制成在体内具有更高活性的化合物。如Hydrolysis inDrug and Prodrug Metabolism:Chemistry,Biochemistry,and Enzymology(Testa,Bemard and Mayer,Joachim M.Wiley-VHCA,Zurich,Switzerland2003)中所述,本文所公开的某些化合物也可以前药的形式存在。本文所述的化合物的前药是该化合物的结构修饰形式,其在生理条件下容易发生化学变化以提供所述化合物。另外,前药可以通过化学或生物化学的方法在体外环境中转化为所述化合物。例如,当将前药置于含有适合的酶或化学试剂的透皮贴剂储库(reservoir)中时,其可缓慢转化为化合物。前药通常是有用的,因为在某些情况下,它们比化合物或母体药物更易给药。例如,它们经口服给药时可具有生物利用度,而母体药物则不具有。在药物组合物中的前药具有比母体药物改善的溶解度。本领域中已知有多种前药衍生物,例如依赖前药的水解分裂(hydrolytic cleavage)或氧化激活的那些前药衍生物。前药的非限定性实例是这样的化合物,其以酯的形式(“前药”)给药,然后代谢水解成活性体羧酸。其它实例包括化合物的肽基衍生物。
本文所公开的化合物可以治疗上可接受的盐的形式存在。本发明包括盐(包括酸加成盐)的形式的以上所列化合物。适合的盐包括那些与有机酸或无机酸形成的盐。这样的酸加成盐通常是药学可接受的。然而,非药学可接受的盐可用于制备或纯化上述化合物。也可以形成碱加成盐,并且其是药学可接受的。为了更完整的讨论盐的制备和选择,可参考PharmaceuticalSalts:Properties,Selection,and Use(Stahl,P.Heinrich.Wiley-VCHA,Zurich,Switzerland,2002)。
本文使用的术语“治疗上可接受的盐”或“盐”表示本文所公开的化合物的盐或两性离子形式,如本文所定义,其为水溶性或油溶性或可分散的以及治疗上可接受的。可以在化合物的最后分离和纯化过程中制备所述盐,或者可以通过使游离碱形式的适合的化合物与适合的酸反应来分别制备所述盐。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、L-抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、丁酸盐、樟脑酸盐、柠檬酸盐、二葡糖酸盐、甲酸盐、富马酸盐、龙胆酸盐、戊二酸盐、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(羟乙基磺酸盐)、乳酸盐、马来酸盐、丙二酸盐、DL-扁桃酸盐、均三甲基苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、膦酸盐、苦味酸盐、新戊酸盐、丙酸盐、焦谷氨酸盐、琥珀酸盐、磺酸盐、酒石酸盐、L-酒石酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐(p-tosylate)和十一酸盐。此外,本文所公开的化合物中的碱性基团可用以下物质季铵化:甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二甲基、二乙基、二丁基和二戊基硫酸盐;癸基、十二烷基、十四烷基和十八烷基(steryl)氯化物、溴化物和碘化物;以及苄基和苯乙基溴化物。可用于形成治疗上可接受的酸加成盐的酸的实例包括无机酸(例如盐酸、氢溴酸、硫酸和磷酸)以及有机酸(例如草酸、马来酸、琥珀酸和柠檬酸)。也可以通过将化合物与碱金属和碱土金属离子配位来形成盐。因此,本发明包括本文所公开的化合物的钠盐、钾盐、镁盐和钙盐等。
可以在化合物的最后分离和纯化过程中通过使羧基与适合的碱(例如金属阳离子的氢氧化物、碳酸盐或碳氢酸盐)或者与氨或有机伯胺、仲胺或叔胺反应来制备碱加成盐。治疗上可接受的盐的阳离子包括锂、钠、钾、钙、镁和铝以及无毒叔胺阳离子(例如铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺和N,N’-二苄基乙二胺)。用于形成碱加成盐的其它代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。
在一些实施方案中,盐可包括本文所公开化合物的盐酸盐、氢溴酸盐、磺酸盐、柠檬酸盐、酒石酸盐、膦酸盐、乳酸盐、丙酮酸盐、乙酸盐、琥珀酸盐、草酸盐、富马酸盐、苹果酸盐、草酰乙酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、苯磺酸盐和羟乙基磺酸盐。可以通过使游离碱形式的适合化合物与适合的酸反应来制备化合物的盐。
虽然本发明的化合物可以以原料化学品的形式给药,但也可以将它们以药物制剂的形式提供。因此,本文提供了药物制剂,其包含一种或多种本文公开的特定化合物或者一种或多种其药学可接受的盐、酯、前药、酰胺或溶剂化物,以及一种或多种其药学可接受的载体和任选存在的一种或多种其它治疗成分。从与所述制剂的其它成分相容且对其接受者无害的意义上说,所述载体必须是“可接受的”。适宜的制剂取决于所选的给药途径。可以使用任何适合且本领域可理解的公知技术、载体和赋形剂,例如那些在Remington′s Pharmaceutical Sciences中所记载的。可以通过本领域已知的任何方式制备本文公开的药物组合物,例如,通过常规混合、溶解、制粒、制糖衣(dragee-making)、研磨、乳化、装胶囊、包埋(entrapping)或压制工艺。
所述制剂包括那些适于口服、胃肠外(包括皮下、皮内、肌内、静脉内、关节内和髓内)、腹膜内、跨粘膜、透皮、直肠和局部(包括皮肤、含服、舌下及眼内)给药的制剂,但最适合的途径可能取决于例如接受者的病状和病症。所述制剂可以方便地以单位剂型提供,并可以通过任何药学领域公知的方法制备。通常,这些方法包括将本发明的化合物或其药学可接受的盐、酯、酰胺、前药或溶剂化物(“活性成分”)与由一种或多种助剂构成的载体混合的步骤。通常,通过将活性成分与液体载体或粉碎的固体载体或二者均匀且紧密地混合来制备所述制剂,视需要将产品定型成期望的制剂。
可以以下述形式提供适于口服的本文公开化合物的制剂:离散单位(例如各含有预定量的活性成分的胶囊剂、扁囊剂或片剂);散剂或胶囊剂;在水性液体或非水性液体中的溶液剂或混悬剂;或者水包油液体乳剂或油包水液体乳剂。也可以大丸剂、煎膏剂或糊剂的形式提供所述活性成分。
可以口服施用的药物制剂包括片剂、由明胶制成的推入式(push-fit)胶囊剂以及由明胶和增塑剂(例如甘油或山梨醇)制成的密封软胶囊剂。可以通过任选地与一种或多种助剂进行压制或模制来制备片剂。可以通过在合适的机器中将任选地与粘结剂、惰性稀释剂或润滑剂、表面活性剂或分散剂混合的自由流动形式(例如粉末或颗粒)的活性成分进行压制来制备压制片剂。可以通过在合适的机器中将用惰性液体稀释剂润湿的粉状化合物的混合物模制来制备模制片剂。所述片剂可以任选地被包衣或刻痕,并可以进行配制以提供其中活性成分的缓释或控释。所有用于口服给药的制剂的剂量应当适于这样的给药。所述推入式胶囊剂可以包含与填充剂(例如乳糖)、粘结剂(例如淀粉)和/或润滑剂(例如滑石或硬脂酸镁)以及任选存在的稳定剂混合的活性成分。在软胶囊剂中,活性化合物可以溶于或悬浮于适合的液体(例如脂肪油、液体石蜡或液体聚乙二醇)中。此外,可以加入稳定剂。所述糖锭剂芯提供有适合的包衣。为此,可以使用浓缩糖溶液,所述浓缩糖溶液可任选地包含阿拉伯树胶、滑石、聚乙烯基吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、漆溶液(lacquer solution)以及适合的有机溶剂或溶剂混合物。可以向所述片剂或糖锭剂包衣中加入染料或颜料用以识别或表征活性化合物剂量的不同组合。
可以配制所述化合物以供通过注射(例如通过弹丸注射或持续输注)进行胃肠外给药。可以以单位剂型(例如安瓿或在多剂量容器)提供注射用制剂,其中添加有防腐剂。所述组合物可以采用诸如在油性或水性载体中的混悬剂、溶液剂或乳剂的形式,并且可以含有诸如助悬剂、稳定剂和/或分散剂的配方剂(formulatory agent)。所述制剂可以在单剂量或多剂量容器(例如密封的安瓿瓶和小瓶)中提供,并可以以散剂形式或在冻干(冷冻干燥)条件下保存,其仅需在即将使用前加入无菌液体载体(例如盐水或无菌无热原水)。可以由前述无菌散剂、颗粒剂和片剂制备临时注射溶液剂和混悬剂。
用于胃肠外给药的制剂包括所述活性化合物的水性和非水性(油性)无菌注射溶液剂,其可含有抗氧化剂、缓冲剂、抑菌剂和使所述制剂与预期接受者的血液等渗的溶质;以及可含有助悬剂和增稠剂的水性和非水性无菌混悬剂。合适的亲脂性溶剂或载体包括脂肪油(例如芝麻油)或合成脂肪酸酯(例如油酸乙酯或甘油三酯)或脂质体。水性注射混悬剂可含有提高混悬剂粘度的物质,例如羧甲基纤维素钠、山梨醇或葡聚糖。任选地,所述混悬剂还可含有适合的稳定剂或提高所述化合物的溶解度以制备高浓缩溶液的试剂。
对于口服或胃肠外施用,可以将所述化合物配制为纳米颗粒制剂。这样的纳米颗粒制剂可包括:例如活性化合物的纳米球包囊、可将活性化合物束缚于其中的无活性纳米颗粒或活性化合物的纳米级散剂。纳米颗粒制剂可用于提高活性化合物的生物利用度、控制活性化合物的释放速率或将活性化合物递送至身体内的特定部位。参见A.Dove,″An Easy Pill toSwallow″,Drug Discovery & Development Magazine:11(11),November,2008,pp.22-24。
除前述制剂之外,还可以将所述化合物配制为缓释剂。这样的长效制剂可以通过(例如皮下或肌内)植入或通过肌内注射给药。因此,例如,可以将所述化合物用适合的聚合材料或疏水材料(例如作为在可接受的油中的乳液)或离子交换树脂进行配制,或者将其配制为略溶的衍生物(例如略溶的盐)。
对于含服或舌下给药,所述组合物可以采用以常规方式配制的片剂、锭剂、软锭剂或凝胶剂的形式。这样的组合物可以在矫味基质(例如蔗糖和阿拉伯树胶或黄蓍胶)中包含所述活性成分。
还可以将所述化合物配制为直肠用组合物,例如栓剂或保留灌肠剂,其例如含有常规的栓剂基质(例如可可脂、聚乙二醇或其它甘油酯)。
本文公开的一些化合物可以局部给药,即非全身给药。这包括将本文公开的化合物外用到表皮上或口腔中,以及将这样的化合物滴注到耳朵、眼睛和鼻子中,以使所述化合物不会大量进入血流中。相比而言,全身给药是指口服、静脉内、腹膜内和肌内给药。
适于局部给药的制剂包括适于透过皮肤到达发炎部位的液体或半液体制剂,例如凝胶剂、搽剂、洗剂、乳膏剂、软膏剂或糊剂,以及适于向眼睛、耳朵或鼻子给药的滴剂。用于局部给药的活性成分可以占例如所述制剂重量的0.001%至10%w/w。在一些实施方案中,所述活性成分可以占多达10%w/w。在一些实施方案中,其可以占少于5%w/w。在一些实施方案中,所述活性成分可以占2%w/w至5%w/w。在其它实施方案中,其可以占所述制剂的0.1%至1%w/w。
用于在口腔中(例如含服或舌下)局部给药的制剂包括在矫味基质(例如蔗糖和阿拉伯树胶或黄蓍胶)中包含所述活性成分的锭剂,以及在基质(例如明胶和甘油或蔗糖和阿拉伯树胶)中包含所述活性成分的软锭剂。
对于吸入给药,可以从吹入器、喷雾器增压包(nebulizer pressurizedpacks)或其它递送喷气雾喷雾剂的便利装置中方便地递送化合物。增压包可含有合适的抛射剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适宜气体。对于增压气雾剂,可以通过提供用于递送固定量的阀来确定剂量单位。或者,对于吸入或吹入给药,本发明的化合物可以采用干粉组合物的形式,例如所述化合物和适合的粉末基质(例如乳糖或淀粉)的粉末混合物。所述粉末组合物可以以在例如胶囊、药盒(cartridge)、明胶或可以借助于吸入器或吹入器从其中给药粉末的泡罩包装(blister packs)中的单位剂型提供。
优选的单位剂量制剂为含有如下所述的有效剂量或其适当部分的活性成分的那些制剂。
应当理解,除了以上具体提及的成分之外,上述制剂还可以根据所讨论的制剂类型含有本领域常规的其它药剂,例如那些适于口服给药的制剂可以包含矫味剂。
可以将化合物按每日0.1mg/kg至500mg/kg的剂量通过口服或注射给药。成人的剂量范围通常为每日5mg至2g。以离散单位提供的片剂或其它形式可以方便地含有一定量的一种或多种化合物,其在这样的剂量下有效或在多个这样的剂量下有效,例如含有5mg至500mg(通常约10mg至200mg)的单位。
可以与载体物质结合以制备单一剂型的活性成分的量取决于所治疗主体和具体给药方式而变化。
可以将化合物以多种方式给药,例如口服、局部或注射给药。向患者给药的化合物的确切量由医生决定。对任何特定患者的特定剂量水平会取决于多种因素,包括所用特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄速率、药物联合、所治疗的确切病症以及所治疗的适应症或病状的严重性。此外,给药途径可以取决于病状和其严重性而变化。
在一些情况下,可以将至少一种本文所述的化合物(或其药学可接受的盐、酯或前药)与另一种治疗剂联合给药。仅举例而言,如果患者在接受一种本文的化合物时所经受的副作用之一是高血压,则可以将抗高血压剂与初始治疗剂联合给药。或者,仅举例而言,一种本文所述的化合物的治疗有效性可以通过给药佐剂而得以增强(也就是说,佐剂本身可能仅具有最小疗效(therapeutic benefit),但与另一种治疗剂联用时增强对患者的总体疗效)。或者,仅举例而言,通过将一种本文所述的化合物与另一种也具有疗效的治疗剂(也包括治疗方案)联合给药,可以增强患者所感受的疗效。仅举例而言,在涉及将本文所述的化合物给药的糖尿病的治疗中,通过向患者提供另一种糖尿病治疗剂可以导致疗效增强。在任何情况下,不论所治疗的是什么疾病、病症或病状,患者所体验的总体疗效可能仅仅是这两种治疗剂的简单加和,或者患者也可能感受到协同效果。
在任何情况下,可以将多种治疗剂(其中至少一种是本文公开的化合物)以任意顺序给药或者同时给药。如果同时给药,则可以将多种治疗剂以单一统一(unified)形式或以多种形式(仅举例而言,作为单一丸剂或两种分别的丸剂)提供。可以将一种治疗剂以多剂量的形式提供,或者可以将两种均以多剂量的形式提供。如果不是同时给药,则多剂量之间的时间间隔可能是几分钟至四周的任意持续时间。
因此,另一方面,一些实施方案提供在需要这样的治疗的人类或动物个体中治疗NF-κB介导的病症的方法,其包括将一定量的在所述个体中有效减轻或预防所述病症的本文公开的化合物以及至少一种本领域已知的用于治疗所述疾病的其它药剂向所述个体联合给药。在相关方面,一些实施方案提供了治疗组合物,其包含与一种或多种用于治疗NF-κB介导的病症的其它药剂组合的至少一种本文公开的化合物。
本文公开的化合物、组合物和方法所要治疗的具体疾病包括衰老、头痛、疼痛、复合性局部疼痛综合征、心脏肥大、肌营养不良、肌萎缩、分解代谢紊乱、1型糖尿病、2型糖尿病、肥胖症、胎儿生长迟缓、高胆固醇血症、动脉粥样硬化、心脏病、慢性心力衰竭、缺血/再灌注、中风、脑动脉瘤、心绞痛、肺疾病、囊性纤维化、酸致肺损伤、肺性高血压、慢性阻塞性肺病、透明膜病、肾疾病、肾小球疾病、酒精性肝病、钩端螺旋体肾病、肠道疾病、腹膜子宫内膜异位症、皮肤病、鼻窦炎、间皮瘤、无汗性外胚层发育不良-ID、白塞氏病、色素失调症、结核病、哮喘、关节炎、局限性肠炎、结肠炎、眼变应性、青光眼、阑尾炎、佩吉特氏病、胰腺炎、牙周病、子宫内膜异位症、炎性肠疾病、炎性肺疾病、脓毒症、硅致疾病、睡眠呼吸暂停、艾滋病、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮性肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激疾病、神经病理疾病、家族性淀粉样多神经病、炎症性神经病、外伤性脑损伤、脊髓损伤、帕金森氏病、多发性硬化、风湿性疾病、阿尔茨海默氏症、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、视网膜疾病、白内障、听力损失和癌症。
除了用于人的治疗外,本发明公开的某些化合物和制剂也可用于宠物、野生动物(exotic animals)和耕作动物(包括哺乳类、啮齿类等)的兽用治疗。更优选的动物包括马、狗和猫。
本文引用的所有参考文献、专利或申请(无论其是美国的或外国的)均援引加入本文,如同以其整体写入本文。凡出现任何不一致,则以本文字面上披露的内容为准。
制备化合物的一般合成方法
下述路线可用于实施本发明。
路线I
可以根据路线I合成实施例6-7、23和28。
路线II
可以根据路线II合成实施例8和24-25。
路线III
可以根据路线III合成实施例15、22和27。
路线IV
可以根据路线IV合成实施例19、21和26。
路线V
可以根据路线V合成实施例32。
路线VI
可以根据路线VI合成实施例1-3。
路线VII
可以根据路线VII合成制备例1。
路线VIII
可以根据路线VIII合成实施例16。
通过下列实施例进一步阐述本发明。所有的IUPAC命名均使用CambridgeSoft′s ChemDraw 10.0生成。
制备例1
2-氧代-2-((6S,10R,13S)-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15-八氢-3H-环戊[a]菲-17-基)乙基乙酸酯
步骤1
2-((6S,10R,13S)-17-羟基-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯:(参见Tetrahedron Letters,2001,42(14):2639-2642)。或者,将甲泼尼龙21-乙酸酯溶解于二甲基甲酰胺和四氢呋喃的混合物中,并在冰浴中冷却。将SO2通入到甲磺酰氯中,并将混合物滴加到含有甲泼尼龙21-乙酸酯的溶液中。然后可以通过标准水处理(standard aqueous workup)分离标题产物。
步骤2
(2′R,4′R,6S,10R,13S)-2′-乙酰基-2′,6,10,13-四甲基-7,8,10,12,13,14,15,16-八氢螺[环戊[a]菲-17,4′-[1,3]二氧六环]-3,5′(6H)-二酮:将2-((6S,10R,13S)-17-羟基-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯溶于甲苯中,并与1.5当量的原乙酸乙酯和微量的吡啶盐酸盐一起加热。从反应混合物中蒸出乙醇以完成反应。
步骤3
(6S,10R,13S)-17-(2-羟乙酰基)-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基乙酸酯:将步骤3得到的反应混合物进行浓缩,溶于四氢呋喃中,并用稀盐酸处理。通过标准水处理得到标题化合物。
步骤4
2-氧代-2-((6S,10R,13S)-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15-八氢-3H-环戊烷[a]菲-17-基)乙基乙酸酯:将(6S,10R,13S)-17-(2-羟乙酰基)-6,10,13-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基乙酸酯与2当量的碳酸钾在二甲基甲酰胺中加热。通过标准水处理得到标题化合物。
实施例1
(10S,13S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
步骤1
(10S,13S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮:作为乙酸阿奈可他商购。可以根据实施例8的步骤2的操作,通过将2-((10S,13S,17R)-17-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯取代为2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯来合成标题化合物。
实施例2
(10S,13S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
(10S,13S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮:可以根据实施例3的步骤1和实施例1的步骤1的操作,通过将乙酸泼尼松龙取代为乙酸氢化可的松来合成标题化合物。
实施例3
2-((10S,13S,17R)-17-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯
步骤1
2-((10S,13S,17R)-17-羟基-10,13-二甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯:可以根据EP 0097328中所公开的操作,由乙酸氢化可的松来合成标题化合物。将405g(1mol)乙酸氢化可的松加入到2升N,N-二甲基甲酰胺和350ml吡啶的混合物中,并在室温搅拌下加入260g甲磺酰氯。将反应混合物加热,在80-85℃下维持1小时,然后冷却至室温。加入甲醇(7升)。通过过滤分离析出的晶体,用甲醇和水洗涤,并减压干燥得到标题化合物。
实施例6
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
步骤1
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮:将实施例7的步骤2所得产物在二氯甲烷和甲醇(1∶3二氯甲烷/甲醇)中的溶液在惰性气氛下搅拌,并在冰浴中冷却。用注射器加入碳酸钾水溶液。将反应在5℃下搅拌2小时。然后用1N HCl中和反应,并浓缩。在水和二氯甲烷之间分配,然后将产物溶液用无水硫酸镁干燥,经过滤和蒸发得到标题化合物。
实施例7
2-氧代-2-((10S,13S,16R)-10,13,16-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)乙基乙酸酯
步骤1
2-((10S,13S,16R)-10,13,16-三甲基-3-氧代-7,8,12,13,15,16-六氢-3H-环戊[a]菲-17(6H,10H,14H)-亚基)-2-(三甲基甲硅烷氧基)乙基乙酸酯:(参见K.P.Shephard,US 4,975,536;Dec.4,1990;Preparation 1,col.8)向预干燥的反应器1中加入36.64g(100mmole)2-((10S,13S)-10,13-二甲基-3-氧代-6,7,8,10,12,13,14,15-八氢-3H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯(商购自Pfizer)。将原料溶于200ml无水四氢呋喃和200ml无水二氯甲烷中。加入三甲基甲硅烷基咪唑(20.0ml,136mmole)。将溶液在小量氮气流下冷却至-50℃。
向预干燥的反应器2中加入丙酸酮II(2.10克,10.0mmole)、150ml无水四氢呋喃和无水1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮。将混合物冷却至-50℃,并在约5分钟内滴加甲基氯化镁(3M,10.0ml)。将混合物搅拌约10分钟。将反应器2的内容物经由套管迅速转移至反应器1中(约30sec),用10ml无水四氢呋喃冲洗反应器2,并将冲洗液也引入反应器1中。将甲基氯化镁(3M,45.0ml)装入泵中,并在45min内泵入反应器1中(泵设定值1.0ml/min)。将反应器1在-50℃下进一步搅拌1小时,然后升温至-30℃,持续过夜。
加入甲苯(1L),并升温至0℃。先后用2×500ml的5%乙酸(冷)和200ml的25%氯化钠萃取混合物。将水相用300ml甲苯反萃取。将合并的甲苯提取物用硫酸镁干燥,过滤并浓缩成粘性油。产量为57.8克。
步骤2
2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)乙基乙酸酯:将步骤1得到的粗产物溶于乙酸乙酯中,并与1N HCl水溶液混合成浆状物直至水解完成。用碳酸氢钾水溶液中和酸的水溶液,并将乙酸乙酯相干燥,过滤,并浓缩成半固体。
实施例8
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
步骤1
2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯:将3.3g(8.6mM)2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)乙基乙酸酯、氯代三(三苯基膦)铑(I)(Wilkinson催化剂,480mg,0.52mM)、三乙基硅烷(1.4mL,1.0g,8.8mM)和二氯甲烷(15mL)的混合物升温至40℃,搅拌直至大部分原料耗尽(由薄层色谱测定)。将反应真空蒸发,并进行细硅胶(600g)层析,洗脱液为含有10-15%乙酸乙酯的二氯甲烷。收集700mL部分,然后收集12份200mL部分。通过蒸发第6-12部分来获得1.0g期望产物(30%产率)。(从第13部分中获得0.7g原料,20%回收率)。NMR(500MHz,CDCl3,TMS):δ0.68(s,3H),0.98(d,3H,J=6.5Hz),1.12(m,1H),1.33(s,3H),1.47(m,1H),1.57(m,1H),1.69(m,1H),1.99(m,1H),2.18(s,3H),2.07-2.29(m,6H),2.36(d,1H),2.50(m,3H),2.79(m,1H),4.48(d,1H,J=17Hz),4.73(d,1H,J=17Hz),5.50(s,1H),5.75(s,1H)。
步骤2
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮:将2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯(1.0g,2.6mM)在二氯甲烷(5mL)和甲醇(15mL)中的溶液置于惰性气氛中,并在冰浴中冷却。用注射器加入l mL的1M碳酸钾水溶液。将反应在5℃下搅拌2h。然后用1N HCl中和反应,并浓缩。在水和二氯甲烷间分配,然后将产物溶液用无水硫酸镁干燥,过滤并蒸发。从乙酸乙酯中结晶得到0.33g第一批产物。NMR(500MHz,CDCl3,TMS):δ0.67(s,3H),1.01(d,3H,J=7Hz),1.13(m,1H),1.33(s,3H),1.47-1.80(m,3H),2.00(m,1H),2.06-2.24(m,6H),2.37(d,1H),2.45-2.60(m,3H),2.82(m,1H),3.30(m,1H),4.20(m,2H),5.50(d,1H,J=5Hz),5.76(s,1H)。
实施例15
(10S,13S,16R,17R)-17-羟基-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
步骤1
2-((10S,13S,16R,17R)-17-羟基-10,13,16-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯:将(Z)-2-((10S,13S,16R)-10,13,16-三甲基-3-氧代-7,8,12,13,15,16-六氢-3H-环戊[a]菲-17(6H,10H,14H)-亚基)-2-(三甲基甲硅烷氧基)乙基乙酸酯溶于二氯甲烷中,并将混合物冷却至0摄氏度。滴加间氯过氧苯甲酸在二氯甲烷中的溶液,并将混合物搅拌4小时。先后用乙酸水溶液和亚硫酸氢盐水溶液洗涤有机相。浓缩有机相,经硅胶层析得到标题化合物。
步骤2
(10S,13S,16R,17R)-17-羟基-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮:根据实施例8的步骤2,通过将2-((10S,13S,16R,17R)-17-羟基-10,13,16-三甲基-3-氧代-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯取代为2-氧代-2-((10S,13S,16R,17S)-10,13,16-三甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯进行制备。
实施例16
(10S,13S,16S,17R)-17-羟基-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例19
(10S,13S,16R,17R)-17-羟基-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例20
(10S,13S,16S,17R)-17-羟基-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例21
(10S,13S,16R,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-16-丙基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例22
(10S,13S,16R,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-16-丙基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例23
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13-二甲基-16-丙基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例24
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13-二甲基-16-丙基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例25
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13-二甲基-16-苯基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例26
(10S,13S,16S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-16-苯基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例27
(10S,13S,16S,17R)-17-羟基-17-(2-羟乙酰基)-10,13-二甲基-16-苯基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例28
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13-二甲基-16-苯基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例29
(10S,13S,16S,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-3H-环戊[a]菲-3-酮
实施例30
(10S,13S,16S,17S)-17-(2-羟乙酰基)-10,13,16-三甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
实施例31
2-氧代-2-((10S,13S,16S,17S)-10,13,16-三甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯
实施例32
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16,17-四甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮
步骤1
2-氧代-2-((10S,13S,16R,17S)-10,13,16,17-四甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯:将2-((10S,13S)-10,13-二甲基-3-氧代-2,3,6,7,8,10,12,13,14,15-十氢-1H-环戊[a]菲-17-基)-2-氧代乙基乙酸酯(150g)和丙酸酮(1.9M在THF(90ml)中)的混合物在冰丙酮浴中冷却。在30分钟内滴加甲基氯化镁(1.96M在240ml THF中)。1小时后,用在200ml THF中的碘甲烷(100g)终止反应。然后将反应混合物用水和甲苯分配。将分离的有机相用水洗涤,用硫酸钠干燥,并浓缩。将残留物从乙醚和己烷中结晶得到标题化合物。
步骤2
(10S,13S,16R,17S)-17-(2-羟乙酰基)-10,13,16,17-四甲基-6,7,8,10,12,13,14,15,16,17-十氢-1H-环戊[a]菲-3(2H)-酮:将2-氧代-2-((10S,13S,16R,17S)-10,13,16,17-四甲基-3-氧代-2,3,6,7,8,10,12,13,14,15,16,17-十二氢-1H-环戊[a]菲-17-基)乙基乙酸酯(144g)在1500ml甲醇中进行搅拌,并用甲醇钠(25%,5ml)处理30分钟。使混合物在二氯甲烷和碳酸氢钠间分配。分离出有机相,并用碳酸氢钠洗涤,用硫酸钠干燥,并浓缩得到标题化合物。
通常可以采用上述方法制备下列化合物。预期制得的这些化合物会具有与已制备和测试的化合物相似的活性。
在下述测定中说明实施例1-7和15-16的化合物作为NF-κB调节剂的活性。预期尚未制备和/或测试的以上所列的其它化合物在这些测定中也具有活性。
生物活性测定
体内NF-κB抑制剂筛选测定
使用用在多拷贝NF-κB应答元件(Panomics,Fremont,CA)下调控的荧光素酶报告基因构建体(luciferase reporter construct)稳定转染的C2C12骨骼肌细胞来筛选NF-κB抑制剂。在37℃下用5%CO2将这些细胞保存在含有达尔伯克改良伊格尔培养基(Dulbecco′s modified Eagle′s medium,DMEM)的组织培养箱内,所述DMEM含有10%胎牛血清(FBS)(ATCC,Manassas,VA)、100U/ml青霉素、100μg/ml链霉素和100μg/ml潮霉素B(Roche,Indianapolis,IN)。在双份96孔板中的成肌细胞(在含有10%FBS的培养基中生长)中,以每孔(容积100μl)5×104个细胞的细胞浓度进行筛选测定。将细胞用不同浓度(0.01μg/ml至10μg/ml)的化合物预处理24小时,然后再用肿瘤坏死因子-α(TNF-α)(10ng/ml)刺激24小时。每块测试板中均包含作为阳性对照的泼尼松龙。完成细胞培养后,用PBS洗两次,并用细胞溶解缓冲液溶解,以使用Centro LB 960光度计(Berthold technologies,GmbH &Co,Bad Wildbad,Germany)测量荧光素酶的活性。将在不存在药物的情况下用TNF-α刺激的相对发光单位当作100%,并将数据表示为相对于TNF-α诱导的NF-κB活化的抑制%。
表1:NF-κB在C2C12骨骼肌细胞荧光酶素试验中的剂量依赖性抑制
实施例# | 0.01ug/mL | 0.1ug/mL | 1ug/mL | 10ug/mL |
1 | ++ | ++ | ++ | +++* |
2 | ++ | ++ | ++* | +++* |
3 | + | + | ++* | +++* |
4 | - | - | - | + |
5 | - | - | + | + |
6 | ++ | ++* | +++* | ++++* |
7 | + | ++* | +++* | ++++* |
15 | ++ | ++* | +++* | ++++* |
16 | + | ++* | ++* | +++* |
-表示≥100%抑制
+表示80-100%抑制
++表示60-80%抑制
+++表示40-60%抑制
++++表示20-40%抑制
*表示p<0.01
按照制造商的方法,用MTT(3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴化物)(Sigma,Saint Louis,Missouri)测定双份板上的细胞存活率。相对于未处理的细胞计算细胞存活百分比。对于以任意剂量(0.01μg/ml、0.1μg/ml、1μg/ml和10μg/ml)测定的实施例1-7和15-16中的任一种,其细胞存活率未发生明显降低(<80%)。
对NF-κB核转运的抑制
通过核转运免疫荧光测定证实对TNF-α诱导的NF-κB活化的抑制。使C2C12细胞在盖玻片上生长,并用上述最佳浓度的TNF-α和化合物进行处理。将细胞用丙酮固定,并用兔抗-NF-κB(p60)抗体/抗兔得克萨斯红(SantaCruz Biotech Inc,Santa Cruz和CA)染色,然后用4’,6-二脒基-苯基吲哚盐酸盐(DAPI)复染色以使细胞核显影。
表2:实施例化合物与已知的NF-κB抑制剂在成肌细胞中对TNF-α诱导的NF-κB荧光素酶活性抑制的比较
实施例# | 核转运抑制剂(成肌细胞) |
1 | + |
2 | + |
泼尼松 | + |
+表示化合物阻断TNF-α诱导的NF-κB核转运
营养不良症的体内mdx小鼠模型
用泼尼松龙(5mg/kg/日;口服,掺在饲料中)、实施例1(20mg/kg/日和40mg/kg/日;口服,掺在饲料中)和实施例2(20mg/kg/日和40mg/kg/日;口服,掺在饲料中)治疗不同组(n=12-14)的mdx小鼠,持续3个月。在治疗期间,所有的小鼠每两周进行一次30分钟的跑台运动,以暴露mdx小鼠模型的轻度疾病表型。
对体重(RW)的影响
表3:实施例化合物对体重和腓肠肌肌肉质量的影响
治疗 | 体重(g) | 腓肠肌肌肉质量(mg) |
未治疗 | 26.58+1.24 | 142.2±15.83 |
泼尼松龙(5mg/kg) | 25.44±1.06* | 136.2±10.94* |
实施例1(20mg/kg) | 28.18±1.25* | 152.2±13.53* |
实施例1(40mg/kg) | 27.3+1.56 | 151.2±11.15 |
实施例2(20mg/kg) | 27.44±2.12 | 148.5+16.86 |
实施例2(40mg/kg) | 27.42+1.73 | 15.1±15.23 |
*表示P<0.05
对体内运动协调和力量的影响
使用转棒(Rota-rod)(Ugo Basile,VA,Italy)测试来评价运动协调和力量。简言之,将老鼠在转棒上训练两天,然后收集数据。每个驯化(acclimatization)过程由四个训练过程组成,每天2个,每个过程以5rpm的速度持续120秒。每个试验由以下步骤组成:将小鼠在转速为10rpm的棒上放置60秒(稳定期),然后在第一个25秒内从10rpm加速到40rpm,直至该动物从棒上掉下来或者时间达到180秒。如果动物在稳定期掉下来,则将它们放回棒上以完成该过程。总的测试时间为240秒(60秒的稳定时间和180秒的测试时间)。每个试验一天进行两次(过程之间有2小时的间隔),持续三天。记录掉落的等待时间(秒),对每只小鼠的全部六个分数求平均值。该平均值表示为三个年龄组的每组小鼠的掉落等待时间(以秒计)。未治疗小鼠逗留在棒上的能力未随时间发生显著变化。
表4:实施例1对在转棒上的动作协调和力量的影响
对体外收缩力(force contraction)的影响:
将指长伸肌(EDL)肌肉的远端肌腱(distal tendon)牢固地固定到伺服电机/力传感器(型号305B,Aurora Scientific,Richmond Hill,ON,Canada)的杠杆臂上,并将近端肌腱(proximal tendon)固定到组织镊上。在两个铂电极之间刺激肌肉。通过使用单一0.2-ms方波刺激脉冲对EDL肌肉的超高级刺激来将肌肉长度调节至引起最大颤搐张力的长度(L0)。使用30Hz、50Hz、80Hz、100Hz、120Hz和150Hz的刺激频率使肌肉保持在L0,记录在一系列300ms刺激脉冲期间对EDL肌肉产生的最大等长强直性张力(P0)。然后用测径器测量肌肉长度,并在从浴中移去肌肉之后测定肌肉质量。对每块肌肉,通过将L0乘以先前测量的Lf/L0的比值0.45来计算最佳纤维长度(Lf)。通过将湿重除以Lf和哺乳动物骨骼肌密度(1.06mg/mm3)的乘积来测定总的肌纤维横截面积。通过将P0除以总的肌纤维横截面积来测定最大等长比力(maximum isometric specific force,sP0)。未治疗组与泼尼松龙组在比力方面并无统计学显著差异(P<0.05)。
表5:用泼尼松龙和实施例化合物长期治疗对体外EDL肌肉收缩力的影响
治疗 | 比力(kN/m2) |
未治疗 | 150.3±13.0 |
泼尼松龙 5mg/kg | 159.8±10.4 |
实施例1 20mg/kg | 167.3±6.8* |
实施例1 40mg/kg | 143.7±14.2 |
实施例2 20mg/kg | 165.7±13.7* |
实施例2 40mg/kg | 175.0±12.1* |
*表示P<0.05
组织学评价
对未治疗mdx小鼠腓肠肌的苏木素和曙红染色显示出明显的变性和炎症。与未治疗的和用泼尼松龙治疗的小鼠相比,用实施例1和实施例2治疗的小鼠的骨骼肌显示炎症、变性的明显减轻,以及再生中的肌纤维的明显增加。持续给药泼尼松龙显示出变性的增加以及营养不良骨骼肌再生的减少。
糖皮质激素受体结合测定
为了测定实施例化合物与糖皮质激素受体(GR)的受体结合亲和性,采用cDNA表达克隆(杆状病毒群)对人类和小鼠的糖皮质激素受体-α进行配体结合测定。在测定缓冲液(10mM Tris-HCl,1.5mM EDTA,10%甘油,1mM二硫苏糖醇和20mM钼酸钠,pH 7.6)中,用放射性标记的3H-地塞米松(Amersham Pharmacia Biotech)和测试化合物培养含有不同GR构建体的肝提取物。用闪烁板读数仪(scintillation plate reader)测量放射性的量。在微摩尔浓度下,地塞米松显示与3H-地塞米松的竞争性结合。
表6:3H地塞米松特异性结合的百分比
浓度(mol/L) | 地塞米松 | 实施例1 | 实施例2 | 实施例3 |
1.67x10-5 | 0.0 | 90.9 | 88.3 | 92.5 |
1.67x10-6 | 0.0 | 94.2 | 97.0 | 103.1 |
6.67x10-7 | 7.2 | 95.7 | 99.6 | 91.1 |
1.67x10-7 | 25.4 | 95.2 | 96.7 | 94.8 |
6.67x10-8 | 46.0 | 93.7 | 99.9 | 94.7 |
1.67x10-8 | 75.8 | 92.4 | 77.6 | 94.6 |
6.67x10-9 | 87.0 | 93.5 | 100.5 | 92.4 |
1.67x10-9 | 102.4 | 92.2 | 98.5 | 94.1 |
6.67x10-10 | 97.9 | 91.4 | 98.0 | 92.6 |
1.67x10-10 | 95.8 | 97.6 | 93.0 | 92.3 |
通过以上描述,本领域技术人员能够容易地确定本发明的必要特征,并能够在不背离本发明的精神和范围的情况下对本发明做出各种变化和修改以使其适应不同的用途和条件。
Claims (54)
1.化合物或其盐,所述化合物用于制备用于减轻肌营养不良症的症状的药物,其中所述化合物具有结构式I:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基。
2.如权利要求1所述的用途,其中
R7和R8独立地选自氢、未取代C2-3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;
如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;
如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;
如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及
如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
3.如权利要求1所述的用途,其中R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基。
4.如权利要求1所述的用途,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
5.如权利要求4所述的用途,其中
R2和R4各自为氢;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
6.如权利要求5所述的用途,其中
R5选自氢、甲基和乙基;
R6选自氢、羟基和甲基;以及
R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
7.如权利要求5所述的用途,其中
R5选自未取代C2-C6烷基和苯基;
R6选自氢、羟基和甲基;以及
R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
8.如权利要求5所述的用途,其中R5为乙基。
9.如权利要求1所述的用途,其中所述肌营养不良症选自:杜氏肌营养不良症、贝克肌营养不良症、肢带型肌营养不良症、先天性肌营养不良症、面肩肱型肌营养不良症、强直性肌营养不良症、眼咽肌营养不良症、远端肌营养不良症、和Emery-Dreifuss肌营养不良症。
10.如权利要求1所述的用途,其中所述肌营养不良症为杜氏肌营养不良症。
11.如权利要求1所述的用途,其包括给药另一种治疗剂。
12.化合物或其盐,所述化合物用于制备用于减轻关节炎的症状的药物,其中所述化合物具有结构式I:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;
如果R1、R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为-C(O)CH2CH2CO2H;
如果所述虚线不表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,R6为羟基,则R9不为-C(O)CH2CH2CO2H;
如果所述虚线表示双键,R1为甲基,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为-C(O)CH2CH2CO2H;
如果R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢或乙酰基;
如果所述虚线不表示双键,R1为氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢或乙酰基;以及
如果所述虚线不表示双键,R1为甲基,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为乙酰基。
13.如权利要求12所述的用途,其中
R7和R8独立地选自氢、未取代C2-3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;
如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;
如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;
如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及
如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
14.如权利要求12所述的用途,其中R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基。
15.如权利要求12所述的用途,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
16.如权利要求15所述的用途,其中
R2和R4各自为氢;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
17.如权利要求16所述的用途,其中
R5选自氢、甲基和乙基;
R6选自氢、羟基和甲基;以及
R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
18.如权利要求16所述的用途,其中
R5选自未取代C2-C6烷基和苯基;
R6选自氢、羟基和甲基;以及
R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
19.如权利要求18所述的用途,其中R5为乙基。
20.如权利要求12所述的用途,其包括给药另一种治疗剂。
21.化合物或其盐,所述化合物用于制备用于减轻NF-κB介导的疾病的症状的药物,其中所述化合物具有结构式I:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C2·3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;
如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;
如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;
如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及
如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
22.如权利要求21所述的用途,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
23.如权利要求22所述的用途,其中
R2和R4各自为氢;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
24.如权利要求23所述的用途,其中
R5选自氢、甲基和乙基;
R6选自氢、羟基和甲基;以及
R9选自氢和乙酰基。
25.如权利要求21所述的用途,其中所述NF-κB介导的疾病选自:肌营养不良症、关节炎、外伤性脑损伤、脊髓损伤、脓毒症、风湿性疾病、癌症、动脉粥样硬化、1型糖尿病、2型糖尿病、钩端螺旋体肾病、青光眼、视网膜疾病、衰老、头痛、疼痛、复合性局部疼痛综合征、心脏肥大、肌萎缩、分解代谢紊乱、肥胖症、胎儿生长迟缓、高胆固醇血症、心脏病、慢性心力衰竭、缺血/再灌注、中风、脑动脉瘤、心绞痛、肺疾病、囊性纤维化、酸致肺损伤、肺性高血压、哮喘、慢性阻塞性肺病、干燥综合征、透明膜病、肾疾病、肾小球疾病、酒精性肝病、肠道疾病、腹膜子宫内膜异位症、皮肤病、鼻窦炎、间皮瘤、无汗性外胚层发育不良-ID、白塞氏病、色素失调症、结核病、哮喘、局限性肠炎、结肠炎、眼变应性、阑尾炎、佩吉特氏病、胰腺炎、牙周病、子宫内膜异位症、炎性肠疾病、炎性肺疾病、硅致疾病、睡眠呼吸暂停、艾滋病、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮性肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激疾病、神经病理疾病、家族性淀粉样多神经病、炎症性神经病、帕金森氏病、多发性硬化、阿尔茨海默氏症、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、白内障和听力损失。
26.如权利要求21所述的用途,其中所述NF-κB介导的疾病为哮喘或慢性阻塞性肺病。
27.如权利要求21所述的用途,其中所述NF-κB介导的疾病为干燥综合征。
28.如权利要求24所述的用途,其中所述NF-κB介导的疾病为哮喘或慢性阻塞性肺病。
29.如权利要求24所述的用途,其中所述NF-κB介导的疾病为干燥综合征。
30.如权利要求21所述的用途,其包括给药另一种治疗剂。
31.化合物或其盐,其用于制备用于减轻NF-κB介导的疾病的症状的药物,其中所述化合物具有结构式I:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基。
32.如权利要求31所述的用途,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R5选自未取代C2-C6烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
33.如权利要求32所述的用途,其中
R2和R4各自为氢;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基、羟基和羧基所取代。
34.如权利要求33所述的用途,其中
R6选自氢、羟基和甲基;以及
R9选自氢、乙酰基和-C(O)CH2CH2CO2H。
35.如权利要求34所述的用途,其中R5为乙基。
36.如权利要求31所述的用途,其中所述NF-κB介导的疾病选自:肌营养不良症、关节炎、外伤性脑损伤、脊髓损伤、脓毒症、风湿性疾病、癌症、动脉粥样硬化、1型糖尿病、2型糖尿病、钩端螺旋体肾病、青光眼、视网膜疾病、衰老、头痛、疼痛、复合性局部疼痛综合征、心脏肥大、肌萎缩、分解代谢紊乱、肥胖症、胎儿生长迟缓、高胆固醇血症、心脏病、慢性心力衰竭、缺血/再灌注、中风、脑动脉瘤、心绞痛、肺疾病、囊性纤维化、酸致肺损伤、肺性高血压、哮喘、慢性阻塞性肺病、干燥综合征、透明膜病、肾疾病、肾小球疾病、酒精性肝病、肠道疾病、腹膜子宫内膜异位症、皮肤病、鼻窦炎、间皮瘤、无汗性外胚层发育不良-ID、白塞氏病、色素失调症、结核病、哮喘、局限性肠炎、结肠炎、眼变应性、阑尾炎、佩吉特氏病、胰腺炎、牙周病、子宫内膜异位症、炎性肠疾病、炎性肺疾病、硅致疾病、睡眠呼吸暂停、艾滋病、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮性肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激疾病、神经病理疾病、家族性淀粉样多神经病、炎症性神经病、帕金森氏病、多发性硬化、阿尔茨海默氏症、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、白内障和听力损失。
37.如权利要求31所述的用途,其中所述NF-κB介导的疾病为哮喘或慢性阻塞性肺病。
38.如权利要求31所述的用途,其中所述NF-κB介导的疾病为干燥综合征。
39.如权利要求35所述的用途,其中所述NF-κB介导的疾病为哮喘或慢性阻塞性肺病。
40.如权利要求35所述的用途,其中所述NF-κB介导的疾病为干燥综合征。
41.如权利要求31所述的用途,其包括给药另一种治疗剂。
42.结构式I的化合物或其盐:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自氢、低级烷基、芳基、环烷基、杂环烷基和杂芳基,所述低级烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C2·3烷基,或者R7和R8可以共同形成C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R5、R7和R8各自为氢,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;
如果R1为氢、甲基、-CH2F或氟,R2、R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基、三氟乙酰基、-C(O)-金刚烷基或苯甲酰基;
如果R1为氢、甲基、氟或氯,R2、R3、R4、R6、R7和R8各自为氢,且R5为甲基,则R9不为氢、未取代C1-C5烷酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R7和R8各自为氢,且R5和R6各自为甲基,则R9不为氢、乙酰基或苯甲酰基;
如果所述虚线表示双键,R1、R2、R3、R4、R5、R7和R8各自为氢,且R6为乙基,则R9不为乙酰基;
如果所述虚线不表示双键,R1为氢或氟,且R2、R3、R4、R5、R6、R7和R8各自为氢,则R9不为氢或乙酰基;
如果R1、R2、R4、R5、R7和R8各自为氢,R3为甲基,且R6为羟基,则R9不为氢、甲酰基、未取代C1-C5烷酰基或苯甲酰基;以及
如果R1和R2各自为氟,R3、R4、R7和R8各自为氢,R5为甲基,且R6为羟基,则R9不为乙酰基。
43.如权利要求42所述的化合物,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
44.如权利要求43所述的化合物,其中
R2和R4各自为氢;
R5选自氢、未取代低级烷基和苯基;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
45.如权利要求43所述的化合物,其中
R5选自氢、甲基和乙基;
R6选自氢、羟基和甲基;以及
R9选自氢和乙酰基。
46.如权利要求45所述的化合物,其中R5为乙基。
47.如权利要求42所述的化合物,其用作药物。
48.具有结构式I的化合物或其盐:
其中:
所述虚线表示任选的双键;
R1、R2、R3和R4各自独立地选自氢、未取代低级烷基、低级卤代烷基和卤素;
R5选自C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基,所述C2-C8烷基、芳基、环烷基、杂环烷基和杂芳基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、炔基、酰氨基、氨基、芳基、芳氧基、环烷基、卤代烷氧基、卤代烷基、杂烷基、杂芳基、羟基、全卤代烷氧基和巯基;
R6选自氢、羟基和低级烷基,所述低级烷基任选地被选自下组的一个或多个取代基所取代:烯基、烷氧基、烷基、炔基、芳基、芳氧基、卤代烷氧基、卤代烷基、杂烷基、羟基和巯基;
R7和R8独立地选自氢、未取代C1-3烷基,或者R7和R8可以共同形成氧代或C3-6饱和环烷基;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被选自下组的一个或多个取代基所取代:酰基、烯基、烷氧基、烷基、烷氨基、烷硫基、炔基、酰氨基、氨基、芳基、芳氧基、芳酰基、氨基甲酸酯、羧基、氰基、环烷基、卤素、卤代烷氧基、卤代烷基、杂烷基、杂环烷基、杂芳基、肼基、羟基、mercaptyl、硝基、氧代、全卤代烷氧基、磺酸酯、烷基磺酰基、N-磺酰氨基、S-磺酰氨基和巯基。
49.如权利要求48所述的化合物,其中R5选自未取代C2-C6烷基和苯基。
50.如权利要求49所述的化合物,其中
R1和R3各自为氢;
R2和R4各自独立地选自氢、甲基和氟;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
51.如权利要求50所述的化合物,其中
R2和R4各自为氢;
R6选自氢、羟基和甲基;
R7和R8各自为氢;以及
R9选自氢、酰基和烷基,所述酰基和烷基任选地被氨基和羟基所取代。
52.如权利要求51所述的化合物,其中
R5为乙基或苯基;
R6选自氢、羟基和甲基;以及
R9选自氢和乙酰基。
53.如权利要求52所述的化合物,其中R5为乙基。
54.如权利要求48所述的化合物,其用作药物。
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CN108135911A (zh) * | 2015-07-06 | 2018-06-08 | 萨奇治疗股份有限公司 | 氧甾醇及其使用方法 |
CN108135911B (zh) * | 2015-07-06 | 2021-06-25 | 萨奇治疗股份有限公司 | 氧甾醇及其使用方法 |
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