CN102753544A - 具有治疗性能的1,4-苯并二氮杂*-2,5-二酮和相关化合物 - Google Patents
具有治疗性能的1,4-苯并二氮杂*-2,5-二酮和相关化合物 Download PDFInfo
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Abstract
本发明提供了以Rho激酶(ROCK)抑制剂为特征的新的化合物、发现它们的方法和它们的治疗、研究和诊断用途。尤其是,本发明提供了具有ROCK抑制活性的1,4-苯并二氮杂
Description
相关申请的交叉引用
本申请要求待定的美国临时专利申请61/262,017(2009年11月17日申请)的优先权,本文以引证的方式结合其全部内容。
关于联邦资助的研究或研发的陈述:
没有。
本发明的领域
本发明的背景
在1981年发现Ras之后,已经确定了许多相关的小分子GTP结合蛋白(小分子GTP酶),并且广泛地研究了它们的生理功能。这些小分子GTP酶(分子量20-30kDa)在非活性的GDP结合状态和活性GTP结合状态之间转换,这种过程主要通过鸟嘌呤转换因子(GEFs)和GTP酶激活蛋白(GAPs)来高度调节(参见,例如,Hall,A.,Science(1990)249:635-640;Bourne,H.R.等人,Nature(1991)349:117-127;本文以引证的方式结合每一个的全部内容)。
迄今为止,已经从酵母至哺乳动物中确定了50种以上的编码小分子GTP酶的基因,形成Ras超家族。按照原始氨基酸序列和功能相似性,这些小分子GTP酶主要分为Ras、Rho、Rab、Arf和Ran五个家族。这些当中,Rho(Ras同源物)编码与Ras具有大约35%同源性的多肽(参见,例如,Madaule,P.,Cell(1985)41:31-40,本文以引证的方式结合其全部内容)。基于原始氨基酸序列、结构基元和生物功能,Rho家族本身可以被分成六个亚族,包括:RhoA相关的亚族、Cdc42相关的亚族、Rac相关的亚族以及Rnd、RhoBTB和Miro亚族。已经利用一些方法研究了Rho的细胞活性,包括:Rho的活性GTP结合形式的超表达或显微注射(可以确定Rho活化的表型)。辅助的(second)称赞的方法是用肉毒素(botulinum)C3外酶处理细胞,其特异性地ADP-核糖基化,并且使内原性的Rho失活,由此确定Rho失活的表型(Narumiya,S.J Biochem(1996)120:215-228)。因此,已经将Rho GTP酶确定为肌动蛋白重构的关键调节剂,并且涉及细胞极性、迁移、细胞形状、粘附性、收缩以及胞吞作用和胞吐作用的调节(参见,例如Ridley,A.J.,Trends Cell Biol(2001)11:471-477)。
涉及肌动蛋白细胞骨架重构的Rho GTP酶的下游靶向包括citron激酶、p140mDia、蛋白激酶N(PKN)、p21激活的蛋白激酶(PAK)、rhophillen和rhotekin。Rho相关的卷曲螺旋形成蛋白激酶(ROCKs)(首先由T.Ishizaki和合作者在20世纪90年代中期分离)是RhoA的第一种和充分表征的效应子,并且最初通过它们对肌球蛋白轻链的磷酸化的影响,表征它们在介导RhoA诱导的紧张纤维和粘着斑的形成中的作用(Matsui,T.,等人,EMBO J(1996)15:2208-2216;Leung,T.,等人,Mol.Cell Biol.(1996)16:5315-5327)。随后证明了ROCKs在许多关键的细胞功能(例如,细胞运动,侵入,收缩,分化,迁移和存活)中起一定作用(Riento,K.,Ridley,A.,Nature Rev.Mol.CellBiol.(2003)4:446-456)。
ROCKs是具有大约160kDa分子质量的丝氨酸/苏氨酸蛋白激酶。已经确定了被两种不同基因编码的两种异构型:ROCKI(亦称ROKβ或p160ROCK)和ROCKII(或ROKα)。该异构型在它们的激酶域中享有65%的总体氨基酸序列同一性和92%序列同一性。ROCKs与AGC激酶的成员(例如,萎缩性肌强直激酶(DMPK),DMPK相关的细胞分裂控制蛋白42(Cdc42)-结合激酶(MRCK)和citron激酶(CK))最具同源性。通常,此激酶家族由下列组成:氨基端激酶域,后面是卷曲螺旋形成域,然后是普列克底物蛋白-同源(PH)域,其具有在羧基端的内部半胱氨酸富集的重复部分。另外,ROCKs在它们的卷曲螺旋域内还含有Rho结合域(RBD)。在非活性状态下,羧基端域与氨基端域结合,形成自动抑制环。激活的GTP结合的Rho与ROCK的RBD结合,导致激酶的开放构象,由此释放催化活性。ROCKs还可以被结合PH域的脂质(例如,花生四烯酸和神经鞘氨醇磷酸胆碱)激活。由于半胱天冬酶3可以使ROCKI的自动抑制环断裂,所以,还可以在细胞凋亡亡期间引发ROCK活性,而粒酶B和半胱天冬酶2以类似的方式断裂ROCKII,所以,这两者都可以导致结构性地活性ROCK。
在对Rho的活化剂(例如,溶血磷脂酸(LPA)或鞘胺醇-1磷酸酯(S1P),其刺激Rho GEFs,并且导致活性GTP结合的Rho的形成)的响应过程中,通过各种细胞靶向的磷酸化,ROCKs介导与肌动蛋白细胞骨架有关的大量细胞反应。例如,发动(motor)蛋白肌球蛋白II的磷酸化在调节肌动球蛋白收缩性方面具有重要的作用。ROCK可以直接磷酸化肌球蛋白轻链(MLC),这随后导致肌球蛋白-肌动蛋白相互作用,并且提高细胞收缩性。通过肌球蛋白轻链磷酸酶(MLCP)的磷酸化(和失活),ROCK还可以间接地调节MLC磷酸化水平。ROCK的另一个下游靶向是LIM激酶1和2,它的磷酸化可以抑制cofilin介导的肌动蛋白丝分解,并因此增加肌动蛋白丝的数量。ROCK的其它细胞靶向包括:埃兹蛋白/根蛋白/膜突蛋白(ERM)蛋白复合物,中间丝蛋白(例如波形蛋白)和丝状(F)肌动蛋白结合蛋白内收蛋白(Riento,K.,Ridley,A.,Nature Rev.Mol.Cell Biol.(2003)4:446-456)。
虽然具有类似的激酶域,但ROCK1和ROCK2可以具有不同的细胞功能,并且可以具有不同的下游靶向。例如,已经证明,体外ROCK1可以磷酸化LIM激酶1和2,而ROCK 2磷酸化MLC、内收蛋白、平滑肌特异性碱性调宁蛋白(calponin)和崩溃反应介质蛋白-2(CRMP2)、涉及LPA引发的生长锥崩溃的神经元蛋白(Riento,K.,Ridley,A.,Nature Rev.Mol.Cell Biol.(2003)4:446-456)。此外,siRNA实验已经证明了ROCK1和ROCK2在大鼠胚胎成纤维细胞中的独特作用,在这种成纤维细胞中,ROCK1对于应力纤维形成和粘着斑部位的稳定性是重要的,而ROCK2活性与基质涂渍的微粒的吞噬作用有关(Yoneda,A.,等人,J..Cell Biol.(2005)170:443-453)。还在各种细胞类型中观察到了差异表达和调节。例如,只有ROCK1是在细胞凋亡亡期间通过半胱天冬酶3断裂的,而ROCK2是通过粒酶B和半胱天冬酶2断裂的。另外,ROCK1表达倾向于更普遍存在,而ROCK2在肌肉和脑组织中最高度表达,表明该蛋白在这些细胞类型中可以具有特殊作用(Nakagawa,O.,等人,FEBS Lett.(1996)392:189-193)。然而,还缺乏有关ROCK1和ROCK2异构型对于不同功能的体内数据。
已经表明,Rho/ROCK途径的异常活化在许多疾病(包括与异常平滑肌弹性或平滑肌高反应性有关的那些疾病)中以及在与非平滑肌细胞有关的病理过程起作用。例如,已经证明,Rho/ROCK介导的信号与高血压症的病理、导致血管收缩和缺血的血管痉挛(大脑和冠状动脉)、支气管性哮喘、早产、勃起功能障碍和青光眼有关(Werrschureck,N.,Offermanns,S.,J Mol Med.(2002)80:629-638和其中的参考文献)。还证明血管疾病(例如高血压症,动脉粥样硬化,血管成形术后的再狭窄和移植动脉硬化,其特点在于异常的血管平滑肌细胞(VSMC)增殖和迁移)与Rho/ROCK信号提高相关。Rho/ROCK介导的信号还与非平滑肌细胞的疾病相关,例如心肌肥大。已经在各种中枢神经系统病症中观察到Rho/ROCK途径的异常活化(CNS;Mueller,B.K.等人,Nature Rev.Drug Discovery(2005)4:387-398和其中的参考文献)。成年脊椎动物的脑和脊髓的损伤可以激活ROCK,由此抑制轴突生长和萌发。因此,ROCK抑制剂在治疗各种神经障碍(包括脊髓损伤,阿尔海默氏疾病,中风,多发性脑硬化和神经性疼痛)方面具有显著的潜在治疗用途。此外,肿瘤细胞迁移和侵入与Rho介导的过程有关,并且已经表明,RhoA或ROCK的活化可以使培养的大鼠肝癌细胞的侵入增加(Itoh,K.,等人,Nat Med.(1999)5:221-225)。另外,许多癌基因编码Rho的转换因子,说明Rho/ROCK途径是新的抗癌策略的有吸引力的候选物。
考虑到Rho/ROCK途径广泛涉及许多疾病状态,在过去20多年中,已对ROCK抑制剂的研发产生了相当大的兴趣。法舒地尔是发现的第一种小分子ROCK抑制剂(Uehata,M.等人Nature(1997)389:990-994)。随后,已经又研发了很多抑制剂,并且按照它们的铰链结合骨架通常可以归成四类:异喹啉类(例如,法舒地尔),4-氨基吡啶类(例如,Y-27632),吲唑类和酰胺和脲衍生物。据迄今报道,ROCK抑制剂通过在ATP结合位点的竞争性相互作用来起作用。然而,由于在ATP结合位点之间具有高序列同源性,所以,研发ROCK的特异性抑制剂遇到挑战。虽然通常很少报道ROCK抑制剂的效果,但对Y-27632和法舒地尔报告的试验数据表明了这些抑制剂对其它激酶的一些交叉反应性。例如,Y-27632针对所试验的25种激酶中的21种具有选择性,但等效能地抑制蛋白激酶N(PKN或PRK2),并且相对于丝裂原和应激诱导的激酶1(MSK1)、促分裂原活化蛋白激酶激活的蛋白激酶1b(MAPKAPK1b)、citron激酶和磷酸化酶激酶(PHK),其只有10-50倍的选择性(Davies,S.P.,等人Biochem J(2000)351:95-105)。在相同研究中,法舒地尔显示了更小的选择性,Y-27632只对所试验的27种激酶中的19种具有选择性。此外,Y-27632和法舒地尔(与其它报道的ROCK抑制剂相似)没有显示任何ROCK异构型选择性,对ROCK1和ROCK2的抑制几乎相同。虽然涉及ROCK1和ROCK2敲除的小鼠的动物研究表明了两种ROCK异构型的独特的生理作用,但还缺乏数据。然而,现行的ROCK抑制剂在细胞信号或底物识别方面不能用于区分ROCK1相对于ROCK2的作用,或更重要的是,不能用于区分每个异构型在疾病中的特定作用。
从1995年以来,法舒地尔已经在日本销售,用于治疗蜘蛛膜下腔出血之后的血管痉挛,安全特性的数据表明其在人中具有较好的耐受性。其在许多心血管疾病中已经显示了有益效果,包括:心绞痛,高血压症,冠状动脉痉挛,经皮冠状动脉介入治疗之后的再狭窄和动脉硬化(Hirooka,Y.,Shimokawa,H.,Am.J.Cardiovasc.Drugs(2005)5:31-39和其中的参考文献)。对Y-27632进行了很少的体内研究,但有限的研究已经表明(与法舒地尔相似),它快速地代谢,并且脑渗透太低,从而不能实现CNS疾病的治疗水平。另外,同由于与胞内微摩尔的ATP浓度竞争所产生的体外活性相比,在细胞试验中,两种抑制剂(与其它ATP-竞争性抑制剂类似)的活性降低了100-1,000倍。在这种高细胞浓度下,它们对于PKN、citron激酶、MSK1和MAPKAPK1b的低至中等的激酶选择性可以导致额外的脱靶效果。因此,研发新结构类别的ROCK抑制剂不但可以提供针对其它激酶更具选择性的ROCK抑制剂,而且可以开发ROCK异构型特异性抑制剂。由于从ROCK涉及侵入、转移病变、神经再生和平滑肌细胞收缩的动物研究中获得证据,所以,这种抑制剂对癌症和心脏病具有治疗潜能。
所需要的是:在患有与异常Rho激酶活性相关的疾病和病症的患者中,改进的抑制Rho激酶活性的组合物和方法。
概述
Rho激酶(ROCK)是丝氨酸-苏氨酸蛋白激酶家族的成员。ROCK存在两种异构型:ROCK1和ROCK2(参见,例如,T.Ishizaki等人,EMBO J.,1996,15,1885-1893,本文以引证的方式结合其全部内容)。本发明提供了以选择性的ROCK抑制剂(例如,ROCK1和/或ROCK2的抑制剂)为特征的新的化合物、发现它们的方法和它们的治疗、研究和诊断用途。尤其是,本发明提供了具有选择性的ROCK抑制活性的1,4-苯并二氮杂-2,5-二酮化合物和相关化合物、使用这种化合物作为治疗剂治疗许多与ROCK活性相关的病症的的方法。本申请通篇描述了这样的化合物和用途,并且代表了组合物和应用的各种集合。某些优选的组合物和用途描述如下。本发明不局限于这些具体组合物和用途。本发明提供了贯穿本申请所描述的许多有用的组合物。
在某些实施方案中,本发明提供了具有选择性ROCK抑制活性的化合物。本发明不局限于选择性ROCK抑制剂的具体类型或种类。在开展本发明实施方案期间进行的实验确定了能够抑制ROCK活性(例如,抑制ROCK1和/或ROCK2活性)的化合物。另外,在开展本发明实施方案期间进行的实验确定了作为选择性ROCK抑制剂的化合物(例如,相对于ROCK2活性,选择性地抑制ROCK1活性的化合物)(例如,相对于ROCK1活性,选择性地抑制ROCK2活性的化合物)。
在一些实施方案中,R1是含有至少两个碳分子的化学基团。在一些实施方案中,R1不是吡啶。
在一些实施方案中,R2选自H,烷基,取代的烷基和R1。
在一些实施方案中,R3选自H,烷基(例如,甲基,乙基,己基,异丙基)和取代的烷基。
在一些实施方案中,R3选自氢;H;CH3;乙基;己基;异丙基;卤素(例如,氟,氯,溴,碘,砹);OH;含有芳基次级基团的化学部分;含有取代的芳基次级基团的化学部分;含有环脂族次级基团的化学部分;含有取代的环脂族次级基团的化学部分;含有杂环次级基团的化学部分;含有取代的杂环次级基团的化学部分;含有至少一个酯次级基团的化学部分;含有至少一个醚次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和的、取代的或非取代的脂肪链;含有硫的化学部分;含有氮的化学部分;-OR-,其中R选自:包含芳基次级基团的化学部分;包含取代的芳基次级基团的化学部分;包含环脂族次级基团的化学部分;包含取代的环脂族次级基团的化学部分;包含杂环次级基团的化学部分;包含取代的杂环次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和、取代或非取代的脂肪链;包含至少一个酯次级基团的化学部分;包含至少一个醚次级基团的化学部分;包含硫的化学部分;包含氮的化学部分。
在一些实施方案中,R1和R3基团可以互换(例如,在一些实施方案中,R1基团位于苯并二氮杂环的第一个位置,R3基团位于苯并二氮杂环的第三个位置;在一些实施方案中,R1基团位于苯并二氮杂环的第三个位置,R3基团位于苯并二氮杂环的第一个位置)。
在一些实施方案中,R4选自C,N,S和O。
在一些实施方案中,R5选自H,烷基,取代的烷基,单取代的芳基,二取代的芳基和三取代的芳基。
在一些实施方案中,R6选自C,N,S和O。
在一些实施方案中,R7、R8、R9和R10独立地选自由下列构成的组:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R28,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7′选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂族,单取代的环脂族,二取代的环脂族和三取代的环脂族。
在一些实施方案中,R11、R12、R13和R14独立地选自:H,烷基(例如,取代的烷基)(例如,未取代的烷基),氟烷基,(例如,取代的烷基)(例如,未取代的烷基),氨基烷基,(例如,取代的烷基)(例如,未取代的烷基), 和其取代的和未取代的,和其衍生物。
在一些实施方案中,R15、R16、R17和R18独立地选自:C,N,O和S。
在一些实施方案中,R19选自H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基)。
在一些实施方案中,R20选自H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基)。
在一些实施方案中,R21、R22、R23和R24独立地选自:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R7’,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7′选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂肪族,单取代的环脂肪族,二取代的环脂肪族和三取代的环脂肪族;其中R21、R22、R23和R24中的至多两个可以是氢。
在一些实施方案中,R25、R26、R27和R28独立地选自:氢,烷基(例如,取代的烷基)(例如,未取代的烷基),氟烷基,(例如,取代的烷基)(例如,未取代的烷基),氨基烷基,(例如,取代的烷基)(例如,未取代的烷基), 和其取代的和未取代的,和其衍生物;其中R25、R26、R27和R28中的至多三个可以是氢。
在某些实施方案中,本发明提供了包含一个或多个本发明的抑制Rho激酶活性的化合物的药物制剂。
在某些实施方案中,本发明提供了治疗病症的方法:该方法包括:给予患有该病症的患者有效量的药物制剂,其中该病症与异常Rho激酶活性有关,并且其中该药物制剂包含一个或多个本发明的抑制Rho激酶活性的化合物。在一些实施方案中,该化合物是选择性的Rho激酶抑制剂(例如,抑制ROCK1超过抑制ROCK2)(例如,抑制ROCK2超过抑制ROCK1)。在一些实施方案中,该化合物对ROCK2的选择性抑制活性高于对ROCK1(参见,例如,表1所示的化合物1-5和实施例II)。在一些实施方案中,患者是人患者(例如,患有该病症的人患者)。
这些化合物中的任何一个或多个可用于治疗与Rho激酶活性相关的各种病症,包括但不限于:心血管病症(例如,绞痛(例如,心绞痛),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围性血管疾病,狭窄症(例如,冠状动脉狭窄症,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,大脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统性高动脉压)),平滑肌相关病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿)和急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征)。
在一些实施方案中,病症是自身免疫病症。自身免疫病症的例子包括但不局限于:类风湿性关节炎,牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,多发性脑硬化,系统性红斑狼疮,乳糜泻,自发的血小板减少性血栓性紫癜,重症肌无力,干燥综合症,硬皮病或牛皮癣的表皮增生。在某些其它实施方案中,该自身免疫病症是牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,系统性红斑狼疮或牛皮癣的表皮增生。在一些实施方案中,自身免疫病症是选自下列的牛皮癣类型:斑块型牛皮癣,滴状牛皮癣,皮褶牛皮癣,脓疱性牛皮癣和红皮病型牛皮癣。在一些实施方案中,免疫病症是炎症性肠病或溃疡性结肠炎。在一些实施方案中,免疫病症是与致病性胸腺依赖性细胞的活性相关或由其引起的免疫病症。在一些实施方案中,免疫病症是对给予患有免疫病症的患者可抑制线粒体呼吸的活性剂敏感的免疫病症。
在一些实施方案中,该自身免疫病症是关节炎,幼年关节炎,幼年型类风湿关节炎,少关节幼年型类风湿关节炎,多关节幼年型类风湿关节炎,全身发病型幼年型类风湿关节炎,幼年强直性脊柱炎,幼年肠病性关节炎,幼年反应性关节炎,幼年赖透氏综合症,关节病综合症,少年型皮肌炎,幼年牛皮癣关节炎,幼年硬皮病,幼年系统性红斑狼疮,幼年血管炎,少关节类风湿性关节炎,多关节类风湿性关节炎,全身发病型类风湿性关节炎,强直性脊柱炎,肠病性关节炎,反应性关节炎,葡萄膜炎,赖透氏综合症,皮肤肌炎,牛皮癣关节炎,血管炎,脊髓炎,多发性肌炎,皮肌炎,骨关节炎,结节性多动脉炎,眶坏死性肉芽肿病,动脉炎,风湿性多肌痛,结节病,硬化症,原发性胆道硬化症,硬化性胆管炎,皮炎,特异性皮炎,斯提耳病,慢性阻塞性肺病,吉兰-巴雷综合征,格雷夫斯氏病,阿狄森氏病,雷诺氏现象或自身免疫性肝炎。
另外,这些化合物中的任何一个或多个可以在治疗中与至少一种其它治疗剂联合使用。
在一些实施方案中,病症与促炎细胞因子(例如,IL-17和/或IL-21)表达(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))有关。例如,已经证明,抑制ROCK2可抑制促炎细胞因子(例如,IL-17和/或IL-21)的表达(参见,例如,Biswas等人,J.Clin.Inv.2010,120(9),3280-3295,本文以引证的方式结合其全部内容)。相应地,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))抑制是通过使用任何本发明的化合物(其对ROCK2的选择性抑制活性高于ROCK1)(参见,例如,表1所示的化合物1-5和实施例II)来实现的。该方法不局限于促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))抑制的具体方式。例如,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)抑制是通过抑制ROCK2实现的,这由此(例如)抑制IRF4表达(例如,通过防止IRF4磷酸化),从而(例如)抑制IL 17和/或IL-21表达。
该方法不局限于与促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))有关的病症。在一些实施方案中,病症是炎性病症。炎性病症包括但不局限于:关节炎,类风湿性关节炎,牛皮癣关节炎,骨关节炎,变性关节炎,多肌痛风湿症,强直性脊柱炎,反应性关节炎,痛风,软骨钙质沉着病,炎性关节病,系统性红斑狼疮,多肌炎和肌纤维痛。关节炎的其它类型包括:跟腱炎,软骨发育不全,肢端肥大性关节病,肩关节冻结症,成人斯蒂尔病,鹅足滑囊炎,无血管形成性坏死,Behcet综合症,二头肌腱炎,Blount′s疾病,布鲁杆菌脊椎炎,滑囊炎,跟部滑囊炎,焦磷酸钙二水合物沉积性疾病(CPPD),晶体沉积疾病,Caplan′s综合症,腕管综合征,软骨钙质沉着病,髌骨软化症,慢性滑膜炎,慢性复发性多灶性骨髓炎,Churg-Strauss综合症,Cogan′s综合症,皮质类甾醇诱导的骨质疏松症,肋胸综合症,CREST综合症,冷球蛋白血症,变性性关节病,皮肤肌炎,糖尿病性指硬化症,广泛性特发性骨质增生(DISH),关节盘炎,盘状红斑狼疮,药物诱导的狼疮,Duchenne′s肌肉营养不良,Dupuytren′s挛缩,埃-当二氏综合征,肠病性关节炎,上髁炎,糜烂性炎症性骨关节炎,锻炼诱导的腔隙综合症,Fabry′s疾病,家族性地中海热,Farber′s脂肪肉芽肿病,Felty′s综合症,Fifth′s疾病,平足,异物滑膜炎,Freiberg′s疾病,真菌性关节炎,Gaucher′s疾病,巨细胞性动脉炎,淋病性关节炎,Goodpasture′s综合症,肉芽肿性动脉炎,关节积血,血色沉着病,亨-舍二氏紫癜,乙型肝炎表面抗原疾病,髋发育异常,投手综合症,过度活动综合征,超敏反应血管炎,肥大性骨关节病,免疫复合物型血清病,撞击综合症,Jaccoud′s关节病,幼年强直性脊柱炎,少年型皮肌炎,幼年型类风湿关节炎,川崎氏病,Kienbock′s疾病,股骨头骨骺骨软骨病,莱纳二氏综合症,带状硬皮病,脂肪性皮肤病关节炎,Lofgren′s综合症,Lyme疾病,恶性滑膜瘤,Marfan′s综合症,内侧滑膜皱襞综合征,转移性的癌性关节炎,混合结缔组织病(MCTD),混合的冷球蛋白血症,粘多糖病,多中心的网状组织细胞增生症,多发性骨骺发育不良,支原体性关节炎,肌筋膜疼痛综合症,初生儿狼疮,夏科氏关节,结节性脂膜炎,褐黄病,鹰嘴突滑囊炎,Osgood-Schlatter′s疾病,骨关节炎,骨软骨瘤病,成骨不全,骨软化症,骨髓炎,骨坏死,骨质疏松症,重叠综合征,骨的厚皮性Paget′s疾病,汉-罗二氏综合征,膑骨股骨疼痛综合症,Pellegrini-Stieda综合症,色素沉着绒毛结节性滑膜炎,梨状肌综合症,足底筋膜炎,结节性多动脉炎,多肌痛风湿症,多肌炎,腘窝囊肿,胫后肌腱炎,Pott′s疾病,髌前粘液囊炎,人工关节感染,假性弹力性黄色瘤,牛皮癣关节炎,Raynaud′s现象,反应性关节炎/Reiter′s综合症,反射性交感神经营养不良综合征,复发性多软骨炎,足跟部滑囊炎,风湿热,类风湿病性血管炎,肩轴肌腱炎,骶髂关节炎,沙门氏菌性骨髓炎,结节病,铅中毒性痛风,Scheuermann′s骨软骨炎,硬皮病,脓毒性关节炎,血清阴性关节炎,志贺菌性关节炎,肩手综合症,镰状细胞关节病,干燥综合症,股骨头骨骺滑脱,脊椎狭窄症,椎骨脱离,葡萄球菌性关节炎,Stickler综合症,亚急性皮肤狼疮,Sweet′s综合症,Sydenham′s舞蹈病,梅毒性关节炎,系统性红斑狼疮(SLE),Takayasu′s动脉炎,踝管综合征,网球肘,Tietse′s综合症,一过性骨质疏松症,外伤性关节炎,大转子滑囊炎,结核性关节炎,溃疡性结肠炎的关节炎,未分化型结缔组织综合症(UCTS),荨麻疹性血管炎,病毒关节炎,Wegener′s肉芽肿病,Whipple′s疾病,Wilson′s疾病和耶尔森菌关节炎。
在某些实施方案中,本发明提供了抑制Rho激酶活性的方法。该方法不局限于具体技术。在一些实施方案中,该方法包括:使靶细胞与包含一或多种本发明的Rho激酶活性抑制化合物的组合物接触。在一些实施方案中,该组合物与靶细胞结合,以便在靶细胞内抑制Rho激酶活性。该方法不局限于具体类型的细胞。在一些实施方案中,该细胞是,例如,体外细胞,体内细胞,体表外细胞和/或癌细胞。
在某些实施方案中,本发明提供了抑制促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))的方法。该方法不局限于具体技术。在一些实施方案中,该方法包括:使靶细胞与包含一或多种本发明的Rho激酶活性抑制化合物(相对于ROCK1,其选择性地抑制ROCK2活性)(参见,例如,表1所示的化合物1-5和实施例II)的组合物接触。在一些实施方案中,该组合物与靶细胞结合,以便在靶细胞内抑制促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))。该方法不局限于具体类型的细胞。在一些实施方案中,该细胞是,例如,体外细胞,体内细胞,体表外细胞和/或癌细胞。该方法不局限于促炎细胞因子表达(例如,IL-17和/或IL-21)抑制的具体方式。例如,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)抑制是通过抑制ROCK2实现的,这由此(例如)抑制IRF4表达(例如,通过防止IRF4磷酸化),从而(例如)抑制IL17和/或IL-21表达。
在某些实施方案中,本发明提供了治疗炎性病症的方法:该方法包括:给予患有炎性病症的患者有效量的药物制剂(例如,包含设计为抑制ROCK2活性的化合物)。本发明不局限于设计为抑制ROCK2活性的具体化合物。设计为抑制ROCK2活性的化合物的例子包括但不局限于:
在一些实施方案中,炎性病症与异常促炎细胞因子活性(例如,异常IL-17和/或IL-21和/或IRF4活性)有关。在一些实施方案中,患者是人。
该方法不局限于具体炎性病症。实际上,炎性病症的例子包括但不局限于:关节炎,类风湿性关节炎,牛皮癣关节炎,骨关节炎,变性关节炎,多肌痛风湿症,强直性脊柱炎,反应性关节炎,痛风,软骨钙质沉着病,炎性关节病,系统性红斑狼疮,多肌炎和肌纤维痛。关节炎的其它类型包括:跟腱炎,软骨发育不全,肢端肥大性关节病,肩关节冻结症,成人斯蒂尔病,鹅足滑囊炎,无血管形成性坏死,Behcet综合症,二头肌腱炎,Blount′s疾病,布鲁杆菌脊椎炎,滑囊炎,跟部滑囊炎,焦磷酸钙二水合物沉积性疾病(CPPD),晶体沉积疾病,Caplan′s综合症,腕管综合征,软骨钙质沉着病,髌骨软化症,慢性滑膜炎,慢性复发性多灶性骨髓炎,Churg-Strauss综合症,Cogan′s综合症,皮质类甾醇诱导的骨质疏松症,肋胸综合症,CREST综合症,冷球蛋白血症,变性性关节病,皮肤肌炎,糖尿病性指硬化症,广泛性特发性骨质增生(DISH),关节盘炎,盘状红斑狼疮,药物诱导的狼疮,Duchenne′s肌肉营养不良,Dupuytren′s挛缩,埃-当二氏综合征,肠病性关节炎,上髁炎,糜烂性炎症性骨关节炎,锻炼诱导的腔隙综合症,Fabry′s疾病,家族性地中海热,Farber′s脂肪肉芽肿病,Felty′s综合症,Fifth′s疾病,平足,异物滑膜炎,Freiberg′s疾病,真菌性关节炎,Gaucher′s疾病,巨细胞性动脉炎,淋病性关节炎,Goodpasture′s综合症,肉芽肿性动脉炎,关节积血,血色沉着病,亨-舍二氏紫癜,乙型肝炎表面抗原疾病,髋发育异常,投手综合症,过度活动综合征,超敏反应血管炎,肥大性骨关节病,免疫复合物型血清病,撞击综合症,Jaccoud′s关节病,幼年强直性脊柱炎,少年型皮肌炎,幼年型类风湿关节炎,川崎氏病,Kienbock′s疾病,股骨头骨骺骨软骨病,莱纳二氏综合症,带状硬皮病,脂肪性皮肤病关节炎,Lofgren′s综合症,Lyme疾病,恶性滑膜瘤,Marfan′s综合症,内侧滑膜皱襞综合征,转移性的癌性关节炎,混合结缔组织病(MCTD),混合的冷球蛋白血症,粘多糖病,多中心的网状组织细胞增生症,多发性骨骺发育不良,支原体性关节炎,肌筋膜疼痛综合症,初生儿狼疮,夏科氏关节,结节性脂膜炎,褐黄病,鹰嘴突滑囊炎,Osgood-Schlatter′s疾病,骨关节炎,骨软骨瘤病,成骨不全,骨软化症,骨髓炎,骨坏死,骨质疏松症,重叠综合征,骨的厚皮性Paget′s疾病,汉-罗二氏综合征,膑骨股骨疼痛综合症,Pellegrini-Stieda综合症,色素沉着绒毛结节性滑膜炎,梨状肌综合症,足底筋膜炎,结节性多动脉炎,多肌痛风湿症,多肌炎,腘窝囊肿,胫后肌腱炎,Pott′s疾病,髌前粘液囊炎,人工关节感染,假性弹力性黄色瘤,牛皮癣关节炎,Raynaud′s现象,反应性关节炎/Reiter′s综合症,反射性交感神经营养不良综合征,复发性多软骨炎,足跟部滑囊炎,风湿热,类风湿病性血管炎,肩轴肌腱炎,骶髂关节炎,沙门氏菌性骨髓炎,结节病,铅中毒性痛风,Scheuermann′s骨软骨炎,硬皮病,脓毒性关节炎,血清阴性关节炎,志贺菌性关节炎,肩手综合症,镰状细胞关节病,干燥综合症,股骨头骨骺滑脱,脊椎狭窄症,椎骨脱离,葡萄球菌性关节炎,Stickler综合症,亚急性皮肤狼疮,Sweet′s综合症,Sydenham′s舞蹈病,梅毒性关节炎,系统性红斑狼疮(SLE),Takayasu′s动脉炎,踝管综合征,网球肘,Tietse′s综合症,一过性骨质疏松症,外伤性关节炎,大转子滑囊炎,结核性关节炎,溃疡性结肠炎的关节炎,未分化型结缔组织综合症(UCTS),荨麻疹性血管炎,病毒关节炎,Wegener′s肉芽肿病,Whipple′s疾病,Wilson′s疾病和耶尔森菌关节炎。
在一些实施方案中,该方法包括:共同给予患者用于治疗所述炎性病症的治疗剂。这种药剂的例子包括但不局限于:改善疾病的抗风湿药物(例如,来氟米特,氨甲喋呤,柳氮磺吡啶,羟氯奎),生物药剂(例如,美罗华,因福利美,依那西普,阿达木单抗,戈利木单抗(golimumab)),非甾体抗炎症的药物(例如,布洛芬,西乐葆,酮洛芬,萘普生,吡罗昔康,双氯芬酸),镇痛药(例如,醋氨酚,反胺苯环醇),免疫调节剂(例如,阿那白滞素,阿巴西普(abatacept))和糖皮质激素(例如,脱氢可的松,甲基强的松),IL-1抑制剂,IL-17抑制剂,IL-21抑制剂和金属蛋白酶抑制剂。
定义
为了有助于理解本发明,如下所述,限定一些术语和短语。
本文使用的术语“ROCK”、“Rho激酶”或类似的术语指的是具有大约160kDa分子质量的丝氨酸/苏氨酸蛋白激酶。已经确定了两种由不同基因编码的两种异构型:ROCKI(亦称ROKβ或p160ROCK)和ROCKII(或ROKα)。
本文使用的术语“选择性的ROCK抑制剂”、“选择性的ROCK抑制化合物”或类似的术语指的是天然或合成的本发明化合物,其选择性地抑制ROCK1和/或ROCK2活性和/或与ROCK1和/或ROCK2活性有关的途径(例如,促炎细胞因子表达(例如,IL-17和/或IL-21和/或相关的途径(例如,与IL-17和/或IL-21表达有关的途径(例如,IRF4))。选择性的ROCK抑制化合物不局限于选择性的ROCK抑制的具体方式。例如,在一些实施方案中,一或多种选择性的ROCK抑制化合物相对于ROCK2活性选择性地抑制ROCK1活性。例如,在一些实施方案中,一或多种选择性的ROCK抑制化合物,相对于ROCK1活性,选择性地抑制ROCK2活性(参见,例如,表1所述的化合物1-5和实施例II)。此外,在一些实施方案中,一或多种选择性的ROCK抑制化合物选择性地抑制ROCK1活性和ROCK2活性,抑制能力类似。
本文使用的术语“苯并二氮杂”是指与苯基环稠合的七元非芳香杂环,其中该七元环具有两个氮原子作为杂环的部分。在一些方面,两个氮原子在下面通用结构所示的1和4位或1和5位:
术语“比苯大”是指含有7个或更多个非氢原子的任何化学基团。
术语“化学部分”是指含有至少一个碳原子的任何化合物。化学部分的例子包括但不局限于:芳香化学部分,包含硫的化学部分,包含氮的化学部分,亲水性的化学部分和疏水性的化学部分。
本文使用的术语“脂族基团“表示下列基团,包括但不限于:烷基,烯基,炔基和无环的(acyclic)基团。
本文使用的术语“芳基”表示单芳香环,例如苯基环,或两个或多个芳香环(例如,联苯,萘,蒽),或一个芳香环和一个或多个非芳香环。芳基可以任选被低级脂族基(例如,烷基,烯基,炔基或无环的基团)取代。另外,脂族基团和芳基可以进一步被一个或多个官能团取代,包括但不限于:包含N、S、O、-NH2、-NHCOCH3、-OH、低级烷氧基(C1-C4)和卤代基(-F、-Cl、-Br或-I)的化学部分。
本文使用的术语“取代的脂族基团”是指烷烃,烯烃,炔烃或脂环(alcyclic)部分,其中至少一个脂族基团的氢原子已经被例如卤素、氨基、羟基、醚、硝基、硫基、酮、砜、磺酰胺、醛、酯、酰胺、低级脂族基团、取代的低级脂族基团或环(芳基,取代的芳基,环脂族基团或取代的环脂族基团,等等)取代。这种基团的例子包括但不局限于:1-氯乙基等等。
本文使用的术语“取代的芳基”是指由至少一个芳香环组成的芳香环或稠合的芳香环系统,其中环碳上的至少一个氢原子被例如卤素、氨基、羟基、硝基、硫基、酮、醛、醚、酯、酰胺、砜、磺酰胺、低级脂族基团、取代的低级脂族基团或环(芳基,取代的芳基,环脂族基团或取代的环脂族基团)取代。这种基团的例子包括但不局限于:羟基苯基等等。
本文使用的“环脂族”是指含有稠合环系统的脂肪族结构。这种基团的例子包括但不局限于:十氢化萘等等。
本文使用的术语“取代的环脂族”是指环脂族结构,其中至少一个脂族基团的氢原子被卤素、杂原子、硝基、硫基、氨基、羟基、酮、醛、酯、酰胺、低级脂族基团、取代的低级脂族基团或环(芳基,取代的芳基,环脂族基团或取代的环脂族基团)取代。这种的例子包括但不局限于:1-氯癸基(1-chlorodecalyl),二环庚烷,辛烷和壬烷(例如,nonrbornyl)等等。
本文使用的术语“杂环”表示例如含有一个或多个杂原子的芳香或非芳香环。杂原子可以彼此相同或不同。杂原子的例子包括但不局限于:氮、氧和硫。芳香和非芳香杂环在本领域是众所周知的。芳香杂环的一些非限制性例子包括:吡啶,嘧啶,吲哚,嘌呤,喹啉和异喹啉。非芳香杂环化合物的非限制性例子包括:哌啶,哌嗪,吗啉,吡咯烷和吡唑烷。含氧杂环的例子包括但不限于:呋喃,氧杂环丙烷,2H-吡喃,4H-吡喃,2H-苯并吡喃和苯并呋喃。含硫杂环的例子包括但不局限于:噻吩,苯并噻吩和对噻嗪。含氮环的例子包括但不限于:吡咯,吡咯烷,吡唑,吡唑烷,咪唑,咪唑啉,咪唑烷,吡啶,哌啶,吡嗪,哌嗪,嘧啶,吲哚,嘌呤,苯并咪唑,喹啉,异喹啉,三唑和三嗪。含有两个不同杂原子的杂环的非限制性例子包括但不局限于:吩噻嗪,吗啉,对噻嗪,噁嗪,噁唑,噻嗪和噻唑。杂环任选进一步被一个或多个选自下列的基团取代:脂族基团,硝基,乙酰基(即,-C(=O)-CH3)或芳基。
本文使用的术语“取代的杂环”是指杂环结构,其中至少一个环氢原子被氧、氮或硫替代,且其中至少一个脂族基团的氢原子被卤素、羟基、硫基、硝基、氨基、醚、砜、磺酰胺、酮、醛、酯、酰胺、低级脂族基团、取代的低级脂族基团或环(芳基,取代的芳基,环脂族基团或取代的环脂族基团)取代。这种基团的例子包括但不局限于:2-氯吡喃基。
本文使用的术语“电子富集杂环”是指其中一个或多个环原子是杂原子(例如,氧、氮或硫)的环状化合物,并且杂原子具有未成对电子,这种未成对电子有助于6-π电子系统。示范性的电子富集杂环包括但不局限于:吡咯,吲哚,呋喃,苯并呋喃,噻吩,苯并噻吩及其它类似的结构。
本文使用的术语“连接基”是指含有至多(并且包括)八个连续原子的链,其连接两个不同结构部分,其中这种原子是例如碳、氮、氧或硫。乙二醇是一个非限制性实例。
本文使用的术语“低级烷基取代的氨基”是指含有至多(并且包括)八个碳原子的任何烷基单元,其中一个脂族基团的氢原子被氨基取代。这种基团的例子包括但不局限于:乙胺基等等。
本文使用的术语“低级烷基取代的卤素”是指含有至多(并且包括)八个碳原子的任何烷基链,其中一个脂族基团的氢原子被卤素取代。这种基团的例子包括但不局限于:氯乙基等等。
本文使用的术语“乙酰氨基”是指被乙酰化的任何伯或仲氨基。这种基团的例子包括但不局限于:乙酰胺等等。
本文使用的术语“参与氢键合的部分”表示可以为了形成氢键而接受或提供质子的基团。参与氢键合的部分的一些特定非限制性例子包括:本领域众所周知的氟、含氧和含氮基团。参与氢键合的含氧基团的一些例子包括:羟基,低级烷氧基,低级羰基,低级羧基,低级醚和酚基。本文使用的限定词“低级”是指相应的含氧官能团连接的低级脂族基团(C1-C4)。由此,例如,术语“低级羰基”尤其是指甲醛,乙醛。参与氢键形成的含氮基团的一些非限制性例子包括氨基和酰胺基。另外,含有氧和氮两种原子的基团也可以参与氢键形成。这种基团的例子包括硝基、N-羟基和亚硝基。还可能的是,在本发明中,氢键受体可以是芳香环的π电子。
本文使用的术语化合物的“衍生物”是指化学修饰的化合物,其中该化学修饰在化合物的官能团(例如,芳香环)或苯并二氮杂骨架上进行。这种衍生物包括但不局限于:含有醇的化合物的酯,含有羧基的化合物的酯,含有胺的化合物的酰胺,含有羧基的化合物的酰胺,含有氨基的化合物的亚胺,含有醛的化合物的缩醛,含有羰基的化合物的缩酮,等等。
本文使用的术语“免疫病症”是指任何病症,在这种病症中,有机体产生能够辨别有机体的固有分子、细胞或组织的抗体或免疫细胞。免疫病症的非限制性例子包括:自身免疫病症,免疫性溶血性贫血,免疫性肝炎,Berger′s疾病或IgA肾病,乳糜泻,慢性疲劳综合症,克罗恩病,皮肤肌炎,肌纤维痛,移植物抗宿主疾病,Grave′s疾病,桥本甲状腺炎,自发性血小板减少性紫癜,扁平苔癣,多发性脑硬化,重症肌无力,牛皮癣,风湿热,风湿性关节炎,硬皮病,Sjorgren综合症,系统性红斑狼疮,I型糖尿病,溃疡性结肠炎,白斑,肺结核,等等。
本文使用的“炎性病症”是指以炎症为特征、由其所引起、起因于其或受其影响的病症。炎性病症可以由例如促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))相关的生物和病理过程所引起或与其有关。炎性疾病或病症的例子包括但不局限于:急性和慢性炎性病症,例如哮喘,牛皮癣,类风湿性关节炎,骨关节炎,牛皮癣关节炎,炎症性肠病(克罗恩氏病,溃疡性结肠炎),强直性脊柱炎,败血症,血管炎和滑囊炎,自身免疫疾病,例如狼疮,风湿性多肌痛,硬皮病,眶坏死性肉芽肿病,颞动脉炎,冷球蛋白血症和多发性脑硬化,移植物排斥,骨质疏松症,癌症,包括实质固态瘤(例如,肺癌,CNS,结肠癌,肾癌和胰腺癌),阿尔茨海默氏病,动脉粥样硬化,病毒(例如,HIV或流感)感染和慢性病毒(例如,Epstein-Barr,巨细胞病毒,单纯疱疹病毒)感染。
本文使用的术语“患者”是指通过本发明方法要治疗的有机体。这种有机体优选包括但不局限于:哺乳动物(例如,鼠,猴,马,牛,猪,犬,猫,等等),最优选包括人。在本发明背景下,术语“患者”泛指将要接受或已经接受与异常Rho激酶活性相关的病症的治疗(例如,给予本发明的化合物和任选一或多种其它药剂)的个体。
本文使用的术语“诊断”是指通过疾病的体征和症状(例如,对常规治疗的抗性)或基因分析、病理学分析、组织学分析等等来认识疾病。
本文使用的术语“体外”是指人造环境和在人造环境内出现的过程或反应。体外环境包括但不局限于:试管和细胞培养物。术语“体内”是指自然环境(例如,动物或细胞)和在自然环境内出现的过程或反应。
本文使用的术语“宿主细胞”是指任何真核或原核细胞(例如,哺乳动物细胞,鸟类细胞,两栖动物细胞,植物细胞,鱼细胞和昆虫细胞),无论位于体外或体内。
本文使用的术语“细胞培养物”是指细胞的任何体外培养物。包括在该术语内的是连续细胞系(例如,具有无限生长分化的的表型),原代细胞培养物,有限细胞系(例如,非转化细胞)和体外保持的任何其它细胞群体,包括卵细胞和胚胎。
在优选实施方案中,本发明组合物和方法的“靶细胞”包括但不局限于:具有异常或非异常Rho激酶活性的细胞。
本文使用的术语“有效量”是指足以实现有益或目标效果的化合物(例如,本发明的化合物)的数量。可以在一或多次给药中、一或多次应用中或一个或多个剂量中给予有效量,并且有效量不会用来限制将其限于具体制剂或给药途径。
本文使用的术语“共同给药”是指给予患者至少两种药剂(例如,本发明的化合物)或疗法。在一些实施方案中,共同给予两种或多种药剂/疗法是并行的。在其它实施方案中,首先给予第一种药剂/疗法,而后给予第二种药剂/疗法。本领域技术人员可以理解,所使用的各种药剂/疗法的制剂和/或给药途径可以变化。本领域技术人员可以容易地确定共同给药的合适剂量。在一些实施方案中,当共同给予药剂/疗法时,相应的药剂/疗法的给予剂量比单独给予它们时的合适剂量低。由此,在共同给予药剂/疗法可以降低已知的潜在有害(例如毒性)药剂的需要剂量的实施方案中,共同给药是特别合乎需要的。
本文使用的术语“毒性”是指对细胞或组织的任何不利或有害影响(与给予毒性药剂之前的相同细胞或组织相比)。
本文使用的术语“药物组合物”是指活性剂与载体(惰性或活性)的组合物,使得该组合物特别适合于体内、体内或离体诊断或治疗使用。
本文使用的术语“可药用载体”是指任何标准药物载体,例如磷酸盐缓冲盐水溶液,水,乳化液(例如,油/水或水/油乳化液)和各种型式的湿润剂。组合物还可以包括稳定剂和防腐剂。对于载体、稳定剂和佐剂的例子(参见,例如,Martin,Remington′s Pharmaceutical Sciences,15th Ed.,Mack Publ.Co.,Easton,PA[1975])。
本文使用的术语“可药用盐”是指本发明化合物的任何可药用盐(例如,酸或碱盐),一旦将其给予患者,能够提供本发明的化合物或其活性代谢产物或残余物。正如本领域技术人员已知的那样,本发明化合物的“盐”可以衍生自无机或有机酸和碱。酸的例子包括但不局限于:盐酸,氢溴酸,硫酸,硝酸,高氯酸,富马酸,马来酸,磷酸,乙二醇酸,乳酸,水杨酸,琥珀酸,对甲苯磺酸,酒石酸,乙酸,柠檬酸,甲磺酸,乙磺酸,甲酸,苯甲酸,丙二酸,萘-2-磺酸,苯磺酸,等等。其它酸,例如草酸,尽管本身不是可药用的,但可以在得到本发明化合物和其可药用酸加成盐的过程中用作中间体的盐的制备中使用。
碱的例子包括但不局限于:碱金属(例如,钠)氢氧化物,碱土金属(例如,镁),氢氧化物,氨和式NW4 +的化合物,其中W是C1-4烷基,等等
盐的例子包括但不局限于:乙酸盐,己二酸盐,海藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,环戊烷丙酸盐,二葡糖酸盐,十二烷基硫酸盐,乙磺酸盐,富马酸盐,flucoheptanoate,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙磺酸盐,乳酸盐,马来酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,草酸盐,棕榈酸盐,果胶酯酸盐,过硫酸盐,苯丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐,十一烷酸盐,等等。盐的其它例子包括:与合适阳离子例如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等等化合的本发明化合物的阴离子。
对于治疗使用,本发明化合物是可药用盐。然而,也可以使用非可药用的酸和碱的盐,例如,在可药用化合物的制备或纯化过程中。
本文使用的术语“调节”是指化合物(例如,本发明的化合物)的活性影响(例如,促进或阻滞)细胞功能的方面,包括但不限于:抑制Rho激酶活性。
本发明的详细说明
Rho激酶(ROCK)是丝氨酸-苏氨酸蛋白激酶家族的成员。ROCK存在两种异构型:ROCK1和ROCK2(参见,例如,T.Ishizaki等人,EMBO J.,1996,15,1885-1893,本文以引证的方式结合其全部内容)。ROCK已经被确定为RhoA的效应分子,其是在许多细胞信号途径中起到关键作用的小分子GTP-结合蛋白(G蛋白)。ROCK和RhoA是在整个组织中普遍表达的。RhoA/ROCK信号途径涉及许多细胞功能,例如激励组织、细胞粘附、细胞迁移和胞质分裂(参见,例如,K.Rientoand A.J.Ridley,Nat Rev Mol Cell Biol,2003,4,446-56,本文以引证的方式结合其全部内容)。它还直接参与调节平滑肌收缩(参见,例如,A.P.Somlyo,Nature,1997,389,908-911,本文以引证的方式结合其全部内容)。它的受体一旦活化,RhoA被激活,随后它激活ROCK。激活的ROCK将肌球蛋白轻链磷酸酶的肌球蛋白-结合亚单位磷酸化,其抑制磷酸酶的活性,并引起收缩。在血管系统中,平滑肌的收缩提高血压,引起高血压症。另外,激活的ROCK(例如ROCK2)已表明可以抑制IRF4的磷酸化,随后降低促炎细胞因子(例如,IL-17和/或IL-21)表达(参见,例如,Biswas等人,J.Clin.Inv.2010,120(9),3280-3295,本文以引证的方式结合其全部内容)。
文献中有大量的证据表明,RhoA/ROCK信号途径在一些血管活性因子(例如血管紧张素II,尾加压素II,内皮素-1,血清素,去甲肾上腺素和血小板生长因子(PDGF))引发的信号转导中起重要作用。这些因子中的许多因子涉及心血管疾病的病理。
在文献的其它研究中,使用已知的ROCK抑制剂法舒地尔(参见,e.g,T.Asano等人,J.Pharmacol.Exp.Ther.,1987,24,1033-1040;本文以引证的方式结合其全部内容)或Y-27632(参见,例如,M.Uehata等人,Nature,1997,389,990-994;本文以引证的方式结合其全部内容)的一些研究进一步说明了在ROCK和心血管疾病之间的联系。例如,已经证明,在自发性高血压大鼠中,ROCK表达和活性升高,表明了与这些动物中高血压症的发展的联系。ROCK抑制剂Y-27632(参见,例如,M.Uehata等人,Nature,1997,389,990-994;本文以引证的方式结合其全部内容)在三个高血压症的大鼠模型(包括自发性高血压白鼠、肾高血压大鼠和醋酸去氧皮质酮高血压大鼠模型)中可显著地降低血压,同时在对照大鼠中对血压只有次要影响,这强化了在ROCK和高血压症之间的联系。
其它研究表明了在ROCK和动脉粥样硬化之间的联系。例如,ROCK的显性阴性形式的基因转移可以在猪股动脉的球囊损伤之后抑制新内膜形成。在类似的模型中,ROCK抑制剂Y-27632还在大鼠中抑制新内膜形成。在IL-1β诱导的冠状动脉狭窄的猪模型中,用ROCK抑制剂法舒地尔进行长期治疗可逐渐地降低冠状动脉狭窄,并且促进冠状动脉收缩性重塑的衰退。已经证明了在ROCK和促炎细胞因子表达(例如,IL-17和/或IL-21)之间的联系。例如,已经证明,抑制ROCK2可以抑制促炎细胞因子(例如,IL-17和/或IL-21)的表达(参见,例如,Biswas等人,J.Clin.Inv.2010,120(9),3280-3295;本文以引证的方式结合其全部内容)(例如已表明激活的ROCK(例如,ROCK2)可以抑制IRF4的磷酸化,随后导致促炎细胞因子(例如,IL-17和/或IL-21)表达降低)。相应地,通过使用本发明的化合物,本发明提供了抑制促炎细胞因子表达(例如,IL-17和/或IL-21)和/或与这种促炎细胞因子表达有关的病症的方法。
其它研究说明,ROCK抑制剂可用于治疗其它心血管疾病。例如,在大鼠中风模型中表明,法舒地尔可减少梗塞面积和神经缺陷。在Dahl盐敏性大鼠的充血性心力衰竭模型中表明,ROCK抑制剂Y-27632可改善心室肥厚和功能。
其它动物或临床研究表明ROCK与其它疾病有关,包括冠状动脉痉挛,脑血管痉挛,缺血/再灌注损伤,肺高血压症,绞痛,肾病和勃起功能障碍。
上述研究提供了在ROCK和心血管疾病之间存在联系的证据,包括高血压症,动脉粥样硬化(参见,例如,Retzer等人FEBS Lett 2000,466,70;本文以引证的方式结合其全部内容),再狭窄(参见,例如,Eto等人Am J Physiol Heart Circ Physiol 2000,278,H 1744;Negoro等人Biochem Biophys Res Commun 1999,262,211;本文以引证的方式结合每个的全部内容),中风,心力衰竭,冠状动脉痉挛,脑血管痉挛,缺血/再灌注损伤(参见,例如,Uehata等人Nature 1997,389,990;Seasholtz等人Circ Res 1999,84,1186;Hitomi等人Life Sci 2000,67,1929;Yamamoto等人J Cardiovasc Pharmacol 2000,35,203;;本文以引证的方式结合每个的全部内容),肺高血压症和绞痛,以及肾病和勃起功能障碍(参见,例如,Chitaley等人Nat Med 2001,7,119,本文以引证的方式结合其全部内容)。由于证明了ROCK对平滑肌的影响,所以,ROCK抑制剂还可有效用于涉及平滑肌高反应性的其它疾病,包括哮喘和青光眼。此外,已经表明Rho激酶可作为治疗各种其它疾病的药物靶向(例如,脑血管痉挛(参见,例如,Sato等人Circ Res 2000,87,195;Kim等人Neurosurgery 2000,46,440;本文以引证的方式结合其全部内容),中枢神经系统病症,例如神经元变性和脊髓损伤(参见,例如,Hara等人J Neurosurg 2000,93,94;Toshima等人Stroke 2000,31,2245;本文以引证的方式结合每个的全部内容),瘤形成(在这种瘤形成中,已经表明抑制Rho激酶可抑制肿瘤细胞生长和转移病变)(参见,例如,Itoh等人Nat Med 1999,5,221;Somlyo等人Biochem BiophysRes Commun 2000,269,652;本文以引证的方式结合它们的全部内容),血管生成(参见,例如,Uchida等人Biochem Biophys Res Commun2000,269,633;Gingras等人Biochem J 2000,348 Pt 2,273;本文以引证的方式结合它们的全部内容),动脉血栓性病症例如血小板凝聚(参见,例如,Klages等人J Cell Biol 1999,144,745;Retzer等人Cell Signal2000,12,645;本文以引证的方式结合它们的全部内容),白细胞聚集(参见,例如,Kawaguchi等人Eur J Pharmacol 2000,403,203;Sanchez-Madrid等人Embo J 1999,18,501;本文以引证的方式结合它们的全部内容),哮喘(参见,例如,Setoguchi等人Br J Pharmacol 2001,132,111;Nakahara等人Eur J Pharmacol 2000,389,103;本文以引证的方式结合它们的全部内容),调节眼内压力(参见,例如,Honjo等人Invest Opthalmol V is Sci 2001,42,137;本文以引证的方式结合其全部内容)和骨吸收(参见,例如,Chellaiah等人J Biol Chem 2000,275,11993;Zhang等人J Cell Sci 1995,108,2285;本文以引证的方式结合每一个的全部内容))。
虽然有许多关于ROCK抑制剂的研究报告(参见,例如,E.Hu和D.Lee,Expert Opin.Ther.Targets,2005,9,715-736;本文以引证的方式结合其全部内容),但迄今为止,法舒地尔是唯一上市的ROCK抑制剂。相应地,还需要新的疗法,包括ROCK抑制剂,用于治疗与ROCK活性有关的病症(例如,心血管病症(例如,绞痛(例如,心绞痛),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围性血管疾病,狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,大脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统高动脉压)),平滑肌相关的病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿),急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征),和自身免疫病症(例如,类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化))。
本发明提供了以Rho激酶(ROCK)抑制剂为特征的新的化合物、发现它们的方法和它们的治疗、研究和诊断用途。尤其是,本发明提供了具有ROCK抑制活性的1,4-苯并二氮杂-2,5-二酮化合物和相关化合物、使用这种化合物作为治疗剂治疗许多与ROCK活性相关的病症的方法(例如,心血管病症(例如,绞痛(例如,心绞痛),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围性血管疾病,狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,大脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统高动脉压)),平滑肌相关的病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿),急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征),和自身免疫病症(例如,类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化))。
在一些实施方案中,病症是自身免疫病症。自身免疫病症的例子包括但不局限于:类风湿性关节炎,牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,多发性脑硬化,系统性红斑狼疮,乳糜泻,自发的血小板减少性血栓性紫癜,重症肌无力,干燥综合症,硬皮病或牛皮癣的表皮增生。在某些其它实施方案中,该自身免疫病症是牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,系统性红斑狼疮或牛皮癣的表皮增生。在一些实施方案中,自身免疫病症是选自下列的牛皮癣类型:斑块型牛皮癣,滴状牛皮癣,皮褶牛皮癣,脓疱性牛皮癣和红皮病型牛皮癣。在一些实施方案中,免疫病症是炎症性肠病或溃疡性结肠炎。在一些实施方案中,免疫病症是与致病性胸腺依赖性细胞(pathogenic lymphocytes)的活性相关或由其引起的免疫病症。在一些实施方案中,免疫病症是对给予患有免疫病症的患者可抑制线粒体呼吸的活性剂敏感的免疫病症。
在一些实施方案中,该自身免疫病症是关节炎,幼年关节炎,幼年型类风湿关节炎,少关节幼年型类风湿关节炎,多关节幼年型类风湿关节炎,全身发病型幼年型类风湿关节炎,幼年强直性脊柱炎,幼年肠病性关节炎,幼年反应性关节炎,幼年赖透氏综合症,关节病综合症,少年型皮肌炎,幼年牛皮癣关节炎,幼年硬皮病,幼年系统性红斑狼疮,幼年血管炎,少关节类风湿性关节炎,多关节类风湿性关节炎,全身发病型类风湿性关节炎,强直性脊柱炎,肠病性关节炎,反应性关节炎,葡萄膜炎,赖透氏综合症,皮肤肌炎,牛皮癣关节炎,血管炎,脊髓炎,多发性肌炎,皮肌炎,骨关节炎,结节性多动脉炎,眶坏死性肉芽肿病,动脉炎,风湿性多肌痛,结节病,硬化症,原发性胆道硬化症,硬化性胆管炎,皮炎,特异性皮炎,斯提耳病,慢性阻塞性肺病,吉兰-巴雷综合征,格雷夫斯氏病,阿狄森氏病,雷诺氏现象或自身免疫性肝炎。
在某些实施方案中,本发明提供了抑制促炎细胞因子表达(例如,IL-17和/或IL-21)和/或与促炎细胞因子表达(例如,与IL-17和/或IL-21)有关的病症(例如,炎性病症)的方法。本发明不局限于具体技术。该方法不局限于促炎细胞因子表达(例如,IL-17和/或IL-21)抑制的具体方式。例如,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)抑制是通过下述过程实现的,抑制ROCK2,这由此(例如)抑制IRF4表达(例如,通过防止IRF4磷酸化),从而(例如)抑制IL 17和/或IL-21表达。
在下面部分中更详细地描述本发明的示范性组合物和方法:I.示范性的化合物;II.药物组合物、制剂和示范性的给药途径和给药考虑因素;III.药物筛选;和IV.治疗应用。
除非另有陈述,否则,本发明的实践使用有机化学、药理学、分子生物学(包括重组技术)、细胞生物学、生物化学和免疫学的常规技术,这在本领域技术人员的知识范围之内。这种技术在文献中得到了充分解释,例如,“Molecular cloning:a laboratory manual”第二版(Sambrook等人,1989);“Oligonucleotide synthesis”(M.J.Gait,ed.,1984);“Animal cell culture”(R.I.Freshney,ed.,1987);系列“Methodsin enzymology”(Academic Press,Inc.);“Handbook of experimentalimmunology”(D.M.Weir & C.C.Blackwell,eds.);“Gene transfervectors for mammalian cells”(J.M.Miller & M.P.Calos,eds.,1987);“Current protocols in molecular biology”(F.M.Ausubel等人,eds.,1987,和定期更新);“PCR:the polymerase chain reaction”(Mullis等人,eds.,1994);和“Current protocols in immunology”(J.E.Coligan等人,eds.,1991),本文以引证的方式结合每个的全部内容。
I.示范性的化合物;
下面提供了本发明的示范性化合物。某些1,4-苯并二氮杂-2,5-二酮衍生物已经得到了描述(参见,例如,美国专利申请09/700,101;美国专利6,506,744;Kamal等人,2004Synlett 14:2533-2535;Hulme等人,1998 J.Org.Chem.63:8021-8022;Raboisson等人,2005 Bioorg.Med.Chem.Lett.15:1857-1861;Raboisson等人,2005 Bioorg.Med.Chem.Lett.15:765-770;Rabiosson等人,2005 J.Med.Chem.48:909-912;美国专利申请公开2007/0111994;本文以引证的方式结合每一个的全部内容)。本发明提供了新的1,4-苯并二氮杂-2,5-二酮化合物和相关化合物和这种化合物的用途。
在某些实施方案中,本发明提供了设计为抑制Rho激酶活性的化合物。本发明不局限于Rho激酶抑制剂的具体类型或种类。在开展本发明实施方案期间进行的实验确定了能够抑制ROCK活性(例如,抑制ROCK1和/或ROCK2活性)的化合物。另外,在开展本发明实施方案期间进行的实验确定了作为选择性ROCK抑制剂的化合物(例如,相对于ROCK2活性,选择性地抑制ROCK1活性的化合物)(例如,相对于ROCK1活性,选择性地抑制ROCK2活性的化合物;参见,例如,表1所述的化合物1-5和实施例II)。尽管不局限于具体化合物,但本发明提供了选自下式所描述的Rho激酶活性抑制化合物:
在一些实施方案中,R1是含有至少两个碳分子的化学基团。在一些实施方案中,R1不是吡啶。
在一些实施方案中,R1选自:
在一些实施方案中,R2选自H,烷基,取代的烷基和R1。
在一些实施方案中,R3选自H,烷基(例如,甲基,乙基,己基,异丙基)和取代的烷基。
在一些实施方案中,R3选自氢;H;CH3;乙基;己基;异丙基;卤素(例如,氟,氯,溴,碘,砹);OH;含有芳基次级基团的化学部分;含有取代的芳基次级基团的化学部分;含有环脂族次级基团的化学部分;含有取代的环脂族次级基团的化学部分;含有杂环次级基团的化学部分;含有取代的杂环次级基团的化学部分;含有至少一个酯次级基团的化学部分;含有至少一个醚次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和的、取代的或非取代的脂肪链;含有硫的化学部分;含有氮的化学部分;-OR-,其中R选自:包含芳基次级基团的化学部分;包含取代的芳基次级基团的化学部分;包含环脂族次级基团的化学部分;包含取代的环脂族次级基团的化学部分;包含杂环次级基团的化学部分;包含取代的杂环次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和、取代或非取代的脂肪链;包含至少一个酯次级基团的化学部分;包含至少一个醚次级基团的化学部分;包含硫的化学部分;包含氮的化学部分。
在一些实施方案中,R1和R3基团可以互换(例如,在一些实施方案中,R1基团位于苯并二氮杂环的第一个位置,R3基团位于苯并二氮杂环的第三个位置;在一些实施方案中,R1基团位于苯并二氮杂环的第三个位置,R3基团位于苯并二氮杂环的第一个位置)。
在一些实施方案中,R4选自C,N,S和O。
在一些实施方案中,R5选自H,烷基,取代的烷基,单取代的芳基,二取代的芳基和三取代的芳基。
在一些实施方案中,R6选自C,N,S和O。
在一些实施方案中,R7、R8、R9和R10独立地选自由下列构成的组:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R28,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7′选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂族,单取代的环脂族,二取代的环脂族和三取代的环脂族。
在一些实施方案中,R11、R12、R13和R14独立地选自:H,烷基(例如,取代的烷基)(例如,未取代的烷基),氟烷基,(例如,取代的烷基)(例如,未取代的烷基),氨基烷基,(例如,取代的烷基)(例如,未取代的烷基), 和其取代的和未取代的,和其衍生物。
在一些实施方案中,R15、R16、R17和R18独立地选自:C,N,O和S。
在一些实施方案中,R19选自H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基)。
在一些实施方案中,R20选自H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基)。
在一些实施方案中,R21、R22、R23和R24独立地选自:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R7’,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7′选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂肪族,单取代的环脂肪族,二取代的环脂肪族和三取代的环脂肪族;其中R21、R22、R23和R24中的至多两个可以是氢。
在一些实施方案中,R25、R26、R27和R28独立地选自:氢,烷基(例如,取代的烷基)(例如,未取代的烷基),氟烷基,(例如,取代的烷基)(例如,未取代的烷基),氨基烷基,(例如,取代的烷基)(例如,未取代的烷基), 和其取代的和未取代的,和其衍生物;其中R25、R26、R27和R28中的至多三个可以是氢。
从上面说明书可知,许多具体实施例由上面提供的通式代表。通过选择每个取代基位置上的具体基团所产生的各种子组合是可能的,并且所有这种组合在本发明范围之内。下面提供的实验实施例描述了这些化合物的生物活性,并且提供了评价衍生物或其它相关化合物的活性的试验。
总之,本文提供了大量化合物。这些化合物中的任何一个或多个可用于治疗本文其它地方所描述的与ROCK活性有关的各种病症(例如,心血管病症(例如,绞痛(例如,心绞痛),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围性血管疾病,狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,大脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统高动脉压)),平滑肌相关的病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿),急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征),和自身免疫病症(例如,类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化))。另外,这些化合物中的任何一个或多个可以在药物组合物中与至少一种其它治疗治疗剂以及可药用载体或稀释剂联合使用(例如,钾通道开放剂,钙通道阻断剂,钠氢交换抑制剂,抗心律失常药剂,抗动脉粥样硬化药剂,抗凝血剂,抗血栓形成药剂,prothrombolytic剂,纤维蛋白原拮抗剂,利尿剂,抗高血压药剂,ATP酶抑制剂,盐皮质激素受体拮抗剂,磷酸二脂酶抑制剂,抗糖尿病药药剂,消炎药,抗氧化剂,血管生成调节剂,抗骨质疏松药剂,激素替代疗法,激素受体调节剂,口服避孕药,抗肥胖药剂,抗抑郁剂,抗焦虑剂,抗精神病药剂,抗增殖药剂,抗肿瘤剂,抗溃疡和胃食管反流病药剂,生长激素药剂和/或生长激素促泌剂,甲状腺模拟物,抗感染药剂,抗病毒剂,抗菌剂,抗真菌药剂,胆固醇/脂质降低药剂和脂质特性(profile)疗法,和模拟缺血预处理和/或心肌顿抑的药剂,抗动脉粥样硬化药剂,抗凝血剂,抗血栓形成药剂,抗高血压药,抗糖尿病药剂,和选自ACE抑制剂、AT-1受体拮抗剂、ET受体拮抗剂、双重ET/AII受体拮抗剂和血管肽酶抑制剂的抗高血压药剂,或选自GPIIb/IIIa阻断剂、P2Y1和P2Y12拮抗剂、血栓烷受体拮抗剂和阿司匹林的抗血小板药剂)。上述化合物还可以在药物筛选试验及其它诊断和研究方法中使用。
III.药物组合物、制剂和示范性的给药途径和给药考虑因素
下面提供了各种药物和药物组合物的示范性实施方案。
A.制备药物
本发明的化合物可有效用于制备治疗与ROCK活性相关的各种病症(例如,心血管疾病,癌症,神经疾病,肾疾病,支气管性哮喘,勃起功能障碍和青光眼)的药物。另外,该化合物还可用于制备治疗其它病症的药物,在这种病症中,已知或预测该化合物是有效的。制备本发明化合物的药物的方法和技术在本领域是众所周知的。示范性的药物制剂和递送途径描述如下。
本领域技术人员可以理解,任何一个或多个本文所描述的化合物,包括许多具体实施方案,是使用标准药物制备方法来制备的。可以使用药物领域众所周知的递送方法,将这种药物给予患者。
B.示范性的药物组合物和制剂
在本发明的一些实施方案中,单独给予组合物,而在一些其它的实施方案中,组合物优选存在于药物制剂中,该制剂包含至少一种上述的活性组分/药剂以及固体载体或者一或多种可药用载体和任选的其它治疗剂。从与制剂的其它组分的相容性来说,每个载体应该是“可接受的”,并且对患者无害。
所涵盖的制剂包括适合于口服、直肠、鼻、局部(包括透皮、口腔和舌下)、阴道、肠胃外(包括皮下,肌肉,静脉注射和皮内)和肺部给药的那些制剂。在一些实施方案中,制剂方便地存在于单位剂型中,并且可以利用药学领域众所周知的任何方法来制备。这种方法包括下列步骤:使活性组分与构成一或多种助剂成分的载体结合。通常,如下制备制剂:使活性组分与液体载体或细碎的固体载体或两者均匀和密切地结合(例如,混合),而后,如有必要,使产品成型。
适合于口服给药的本发明制剂可以以下列形式存在:离散单位形式,例如胶囊剂、扁囊剂或片剂,其中每个优选含有预定数量的活性组分;粉剂或颗粒剂形式;在水或非水液体中的溶液剂或混悬剂形式;或水包油型液体乳剂或油包水型液体乳剂形式。在其它实施方案中,活性组分以丸剂(bolus)、膏剂或糊剂等等形式存在。
在一些实施方案中,包含至少一种活性组分和任选一或多种助剂/载体的片剂是通过压制或模制相应的药剂来制备的。在优选实施方案中,压制片是如下制备的:在合适的机械中,压制自由流动形式的活性组分,例如粉末或颗粒,任选与粘合剂(例如,聚维酮,明胶,羟基丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟乙酸(glycolate)淀粉钠,交联聚维酮,交联羧甲基纤维素钠)、表面活性剂或分散剂混合。模制片可以如下制备:在合适的机械中,将湿润的粉末化合物(例如,活性组分)与惰性液体稀释剂的混合物一起模制。可以任选将片剂包衣或刻痕,并且可以使用例如变化比例的羟基丙基甲基纤维素配制,以便使其中的活性组分缓慢或控制释放,从而提供目标释放特性。片剂可以任选拥有肠溶衣,以便在胃以外的肠管部分中释放。
适合于口腔局部给药的制剂包括:含有活性组分(在调味基质中,通常是蔗糖和阿拉伯胶或黄芪胶)的糖锭;包含活性组分(在惰性基质中,例如凝胶和丙三醇,或蔗糖和阿拉伯胶)的软锭剂;和包含活性组分(在合适的液体载体中)的漱口药。
可以任选将按照本发明的局部给药的药物组合物配制为软膏剂,乳膏剂,混悬剂,洗剂,粉剂,溶液剂,糊剂,凝胶剂,喷雾剂,气雾剂或油剂。在替代性实施方案中,局部制剂包括浸入活性组分和任选一或多种赋形剂或稀释剂的贴片或敷料(例如绷带或橡皮膏)。在优选实施方案中,局部制剂包括可提高活性剂通过皮肤或其它受影响区吸收或渗透的化合物。这种表皮渗透增强剂的例子包括二甲亚砜(DMSO)和相关类似物。
如果需要的话,乳膏剂基质的水相包括,例如,至少大约30%w/w的多元醇,即,具有两个或多个羟基的醇,例如丙二醇,丁-1,3-二醇,甘露醇,山梨糖醇,甘油和聚乙二醇和其混合物。
在一些实施方案中,本发明的油相乳状液是用已知的方式、由已知的组分构成的。该相典型地含有单独的乳化剂(emulsifier)(或者称为乳化剂(emulgent)),在该相的一些实施方案中,其进一步含有至少一种乳化剂与油脂或油或与油脂和油两者的混合物也是合乎需要的。
优选,包括亲水性乳化剂以及亲脂性乳化剂,以充当稳定剂。在一些实施方案中,还优选包括油和油脂两者。乳化剂与稳定剂一起(或没有稳定剂)构成所谓的乳化蜡,并且该蜡与油和/或油脂一起构成所谓的乳化软膏基质,其形成乳膏剂的油性分散相。
适合在本发明制剂中使用的乳化剂和乳剂稳定剂包括:Tween60,Span 80,十六醇十八醇混合物,十四烷醇,单硬脂酸甘油酯和月桂基硫酸钠。
由于活性化合物/药剂在药物乳化制剂中可能使用的大部分油中的溶解度极低,所以,制剂所用的合适的油或油脂是基于实现目标性能(例如,美容性能)来选择的。由此,乳膏剂应该优选具有合适稠度(从而避免从管或其它容器中渗漏出来)的非油性、不污染和可洗的产品。可以使用直链或支链的单或二元烷基酯,例如二异己二酸酯(di-isoadipate),硬脂酸异十六烷基酯,椰油脂肪酸的丙二醇二酯,十四烷酸异丙酯,油酸癸基酯,棕榈酸异丙酯,硬脂酸丁酯,2-乙基己基棕榈酸酯或被称为Crodamol CAP的支链酯的混合物,最后三个是优选的酯。根据需要的性能,这些可以单独或组合使用。或者,可以使用高熔点的脂,例如白色软石蜡和/或液体石蜡或其它矿物油。
适合于局部给予眼睛的制剂还包括滴眼剂,其中活性组分溶解或悬浮在合适载体中,特别是悬浮在药剂的水溶剂中。
直肠给药制剂可以以含有合适基质(包括,例如,可可脂或水杨酸酯)的栓剂形式存在。
适合于阴道给药的制剂可以以阴道栓、乳膏剂、凝胶剂、糊剂、泡沫体或喷雾制剂形式提供,除了药剂之外,其还含有本领域已知的合适载体。
适合于鼻部给药的制剂(其中载体是固体)包括粗粉末,其具有例如在大约20至大约500微米范围内的粒径,采用鼻吸的方式给药,即,通过鼻腔从保持接近鼻子的粉末容器中快速吸入(例如,施加压力)。用于给药的其它合适的制剂(其中载体是液体)包括但不局限于:鼻喷雾剂、滴剂或气雾剂(利用雾化器),其包括药剂的水或油溶液。
适合于肠胃外给药的制剂包括水和非水等渗无菌注射溶液剂,其可以含有抗氧化剂,缓冲剂,抑菌剂和能够使该制剂与目标接受者的血液等渗的溶质;和水和非水的无菌混悬剂,其可以包含悬浮剂和增稠剂、和脂质体或其它微粒系统,可以对其进行设计,使化合物靶向血液组分或一个或多个器官。在一些实施方案中,可以将制剂提供于/配制在单位剂量或多剂量密封容器中,例如,小瓶和管瓶,并且可以保存在冷冻干燥(冻干)条件下,在临近使用之前,只需要加入无菌的液体载体,例如注射用水。可以用先前所描述种类的无菌粉剂、颗粒剂和片剂来制备临时注射溶液剂和混悬剂。
优选的单位剂量制剂是含有本文上面列举的药剂的日剂量或单位、日亚剂量或其合适部分的那些制剂。
应该理解,根据所述制剂的类型,除了上面具体提及的组分之外,本发明的制剂还可以包含本领域的其它常规药剂,例如,适合于口服给药的那些制剂可以进一步包含例如甜味剂、增稠剂和调味剂。本发明的药剂、组合物和方法还可以与其它合适的组合物和疗法相结合。其它制剂还可以任选包含食品添加剂(合适的甜味剂,调味剂,着色剂等等),植物营养素(phytonutrients)(例如,亚麻油),矿物质(例如,Ca,Fe,K,等等),维生素及其它可接受的组合物(例如,共轭的(conjugated)亚油酸),扩充剂和稳定剂,等等。
C.示范性的给药途径和给药考虑因素
各种递送系统是已知的,并且可用于给予本发明的治疗剂(例如,上面I部分所述的示范性的化合物),例如,包封在脂质体、微颗粒、微胶囊中,受体介导的胞吞等等。递送方法包括但不局限于:动脉内、肌原纤维内、静脉内、鼻内和口服途径。在具体实施方案中,合乎需要的是,局部给予需要治疗的区域本发明的药物组合物;这可以通过例如(但不局限于)在手术期间局部输液、注射或借助于导管来实现。
可以给予对靶细胞的发展中的病态生长和相关病症敏感或处于其危险之中的患者或个体经过鉴定的药剂。当给予患者例如小鼠、大鼠或人患者药剂时,可以将药剂加入到可药用载体中,并系统或局部地给予患者。为了确定可以有利治疗的患者,从患者中取出组织样品,并检验细胞对药剂的敏感性。可以凭经验确定治疗数量,并且随所治疗的病变、所治疗的患者和药剂的效果和毒性而变化。
在一些实施方案中,体内给药用单剂量进行,在整个疗程中连续或周期性地进行。确定给药的最有效手段和剂量的方法对于本领域技术人员是众所周知的,并且随疗法所使用的组合物、疗法的目的、所治疗的靶细胞和所治疗的患者而变化。通过治疗医生所选择的剂量水平和模式来进行单一或多次给药。
本领域技术人员可以容易地确定合适的剂量制剂和给予药剂的方法。优选,给予大约0.01mg/kg至大约200mg/kg的化合物,更优选大约0.1mg/kg至大约100mg/kg,甚至更加优选大约0.5mg/kg至大约50mg/kg。当本文所描述的化合物与另一个药剂(例如,敏化剂)共同给予时,有效量可以低于该药剂单独使用时的数量。
可以口服、鼻内、胃肠外或通过吸入疗法来给予药物组合物,并且可以采取片剂、糖锭、颗粒剂、胶囊剂、丸剂、安瓿剂、栓剂或气雾剂的形式。它们还可以采取活性组分在水或非水稀释剂中的混悬剂、溶液剂和乳剂的形式、糖浆剂、颗粒剂或粉剂形式。除了本发明的药剂之外,药物组合物还可以含有其它药学活性化合物或多个本发明的化合物。
更具体地说,在本文中,本发明的药剂还指的是活性组分,可以通过任何合适的途径给予(用于治疗),包括但不限于:口服,直肠,鼻部,局部(包括但不限于:透皮,气雾剂,口腔和舌下),阴道,parental(包括但不限于:皮下,肌内,静脉内和皮内)和肺部。还应理解,优选的途径可以随接受者的条件和年龄和所治疗的疾病而变化。
理想地,应该将药剂给予以至在疾病的位点获得活性化合物的最大浓度。这可以如下实现:例如,静脉注射药剂,任选在盐水中,或口服给予药剂,例如,作为含有活性组分的片剂、胶囊剂或糖浆剂。
可以通过连续输液,从而在疾病组织内提供治疗数量的活性组分,来保持药剂的合乎需要的血液水平。有效的联用药的使用是在考虑范围内的,以提供需要比在单独使用每个单一治疗化合物或药物时可能需要的量低的各个抗病毒剂组分总剂量的治疗联用药,由此降低副作用。
D.示范性的共同给药途径和给药考虑因素
本发明还包括与共同给予本文所描述化合物与一或多种其它活性剂有关的方法。实际上,通过共同给予本发明的化合物,本发明的进一步方面提供了提高现有技术治疗和/或药物组合物的方法。在共同给药方法中,可以同时或顺序地给予药剂。在一个实施方案中,在给予其它活性剂之前给予本文所描述的化合物。药物制剂和给药模式可以是上述那些中的任一项。另外,两种或多种共同给予的化学药剂、生物制剂或辐射可以使用不同模式或不同制剂来各自给予。
共同给予的药剂取决于所治疗的病症的类型。例如,当所治疗的病症是癌症时,其它药剂可以是化学治疗剂或辐射。当所治疗的病症是自身免疫病症时,其它药剂可以是免疫抑制剂或消炎剂。当所治疗的病症是慢性炎症时,其它药剂可以是消炎剂。共同给予的其它药剂,例如抗癌剂、免疫抑制剂、抗炎剂,可以是本领域众所周知的任何药剂,包括但不限于目前临床上使用的那些药剂。确定辐射治疗的合适类型和剂量也在本领域技术人员的知识范围之内,或可以相对容易地确定。
III.药物筛选
在本发明的一些实施方案中,筛选本发明的化合物及其它潜在有用的化合物的ROCK调节(例如,激活,抑制)活性。在本发明的一些实施方案中,通过评价促炎细胞因子活性(例如,IL-17和/或IL-21,和/或与促炎细胞因子活性有关的途径(例如,IRF-4)),筛选本发明的化合物及其它潜在有用的化合物的ROCK调节(例如,激活,抑制)活性。
测定药物及其它小分子与受体的结合亲合性的许多合适筛选方法在本领域是已知的。在一些实施方案中,结合亲合性筛选在体外系统中进行。在其它实施方案中,这些筛选在体内或体表外系统中进行。
IV.治疗应用
在特别优选实施方案中,预计本发明的组合物通过在受到影响的细胞或组织中调节(例如,抑制或促进)ROCK活性,可以给患者提供治疗益处,该患者患有与ROCK活性相关的许多病症中的任何一或多种病症(例如,心血管疾病,癌症,神经疾病,肾疾病,支气管性哮喘,勃起功能障碍和青光眼)。在进一步优选实施方案中,本发明的组合物用于治疗与ROCK活性相关的病症和/或障碍(例如,心血管疾病,癌症,神经疾病,肾疾病,支气管性哮喘,勃起功能障碍和青光眼)。
在某些实施方案中,本发明提供了调节抑制Rho激酶活性的方法(例如,治疗应用),该方法包括:a)提供:i.具有Rho激酶活性的靶细胞;和ii.组合物(例如,上面I部分所述的示范性的化合物);和b)在暴露导致抑制(例如,降低,终止)Rho激酶活性的条件下,使靶细胞暴露于该组合物。本发明的方法不局限于具体靶细胞。在一些实施方案中,靶细胞选自体外细胞,体内细胞,体表外细胞,平滑肌细胞,非平滑肌细胞和癌细胞。本发明不局限于具体治疗应用。
在一些实施方案中,预计本发明的组合物通过在受到影响的细胞或组织中调节(例如,抑制或促进)ROCK的活性而为患有与异常ROCK活性相关的许多病症中的任何一或多种病症的患者提供治疗益处(例如,心血管病症(例如,绞痛(例如,心绞痛),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围性血管疾病,狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,大脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统高动脉压)),平滑肌相关的病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿),急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征),和自身免疫病症(例如,类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化))。
在一些实施方案中,与异常ROCK活性相关的病症与促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))有关(例如,炎性病症)。例如,已经证明,抑制ROCK2可抑制促炎细胞因子(例如,IL-17和/或IL-21)的表达(参见,例如,Biswas等人,J.Clin.Inv.2010,120(9),3280-3295,本文以引证的方式结合其全部内容)。相应地,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))抑制是通过使用任何本发明的化合物(其对ROCK2的选择性抑制活性高于对ROCK1)(参见,例如,表1所示的化合物1-5和实施例II)来实现的。该方法不局限于促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))抑制的具体方式。例如,在一些实施方案中,促炎细胞因子表达(例如,IL-17和/或IL-21)抑制是通过下述过程实现的,抑制ROCK2,这由此(例如)抑制IRF4表达(例如,通过防止IRF4磷酸化),从而(例如)抑制IL17和/或IL-21表达。
在一些实施方案中,本发明的组合物提供了治疗患有与异常ROCK活性相关的障碍和/或病症的患者的方法。在一些实施方案中,该方法包括:在调节ROCK活性的条件下(例如,提高或降低),给予患有与异常ROCK活性相关的障碍和/或病症的患者本发明的ROCK抑制剂(例如,I部分所描述的化合物)。
本发明不局限于治疗与异常ROCK活性相关的具体障碍和/或病症。在某些实施方案中,所述化合物用于治疗急性和慢性疼痛和炎症。例如,本发明的化合物用于治疗患有下列病症的患者:神经病,神经性疼痛或炎性疼痛,例如反射交感性营养不良/灼痛(神经损伤),周围神经病(包括糖尿病性神经病变),难治的癌症疼痛,复杂区域疼痛综合症和卡陷性神经病变(腕管综合症)。该化合物也可有效用于治疗与急性带状疱疹(shingles)相关的疼痛、带状疱疹神经痛(PHN)和相关的疼痛综合症,例如眼睛疼痛。该化合物可以进一步在治疗疼痛的过程中用作镇痛药(例如手术镇痛),或作为治疗发热的退热剂。疼痛适应症包括但不局限于:各种手术过程的手术后疼痛(包括心脏手术后的疼痛),牙齿疼痛/拔牙,起因于癌症的疼痛,肌肉疼痛,乳腺痛,起因于表皮损伤的疼痛,下背(腰)疼痛,各种病源的头痛,包括偏头痛,等等。该化合物也可有效用于治疗疼痛相关的病症,例如触诱发痛和痛觉过敏。疼痛可以是体因性的(感受性或神经性疼痛)、急性和/或慢性疼痛。本发明的化合物也可有效用于传统上给予NSAIDs、吗啡或芬太尼阿片剂和/或其它阿片样镇痛药的病症。
在一些实施方案中,本发明的化合物在需要的患者中用于治疗或预防阿片(例如长效阿片镇痛药)耐受性,和治疗或预防摄取苯并二氮杂的患者的苯并二氮杂耐受性,及其它上瘾行为,例如,烟碱成瘾性、酒精中毒和进食障碍。此外,本发明的化合物和方法用于治疗或预防药物戒断症状,例如,治疗或预防戒除阿片剂、洒精或烟草瘾的症状。
在一些实施方案中,本发明的化合物用于治疗抗胰岛素性及其它代谢失调,例如典型地与放大的炎性信号相关的动脉粥样硬化。
在一些实施方案中,本发明的化合物用于治疗或预防呼吸系统疾病或病症,包括在预防和治疗下列呼吸系统疾病或病症的药物中使用的治疗方法:哮喘病症,包括过敏原诱导的哮喘,运动诱发的哮喘,污染诱导的哮喘,寒冷诱导的哮喘和病毒诱导的哮喘;哮喘相关的疾病,例如呼吸道高反应性和小呼吸道疾病;慢性阻塞性肺疾病,包括具有正常空气流的慢性支气管炎,具有气道阻塞的慢性支气管炎(慢性阻塞性支气管炎),肺气肿,气喘性支气管炎和大疱疾病;及其它肺疾病,包括炎症,包括细支气管炎,支气管扩张症,囊性纤维化,鸽“爱好者”病,农民肺,急性呼吸困难综合征,肺炎,局部急性肺炎,吸入性损伤,肺脂肪栓,肺的酸中毒性炎症,急性肺水肿,急性高山病,急性肺高血压症,新生儿的持久性的肺部高血压症,围产期吸入综合征,透明膜病,急性肺血栓栓塞,肝素-精蛋白反应,败血症,哮喘持续状态,低氧,气喘,呼吸过度,充气过度,低氧血和咳嗽。进一步的,本发明的化合物可用于治疗变应性紊乱,例如迟发型超敏反应,变应性接触性皮炎,过敏性鼻炎和慢性窦炎。
可以用本发明化合物治疗的其它障碍或病症包括炎症和相关的病症。例如,该化合物可用于治疗关节炎,包括但不局限于:类风湿性关节炎,脊椎关节病变,痛风性关节炎,骨关节炎,幼年关节炎,急性风湿性关节炎,肠病性关节炎,神经病性关节炎,牛皮癣关节炎,反应性关节炎(瑞特氏综合症)和化脓性关节炎,和自身免疫疾病,包括系统性红斑狼疮,溶血综合症,自身免疫性肝炎,自身免疫性神经病,白斑病(vitiglio)(自身免疫性甲状腺炎),桥本氏甲状腺炎,贫血,肌炎包括多肌炎,脱发,古德帕斯彻氏综合征,垂体炎(hypophytis)和肺纤维化。
在一些实施方案中,该化合物用于治疗骨质疏松症及其它相关的骨病症。
在一些实施方案中,本发明的化合物用于治疗胃肠病症,例如反流性食管炎,腹泻,炎症性肠病,克罗恩氏病,胃炎,过敏性肠综合症,格雷夫斯氏病(甲状腺机能亢进),坏死性小肠结肠炎和溃疡性结肠炎。该化合物也可以用于治疗肺部的炎症,例如,与病毒感染和囊性纤维化相关的肺部炎症。
在一些实施方案中,本发明的化合物用于治疗器官移植患者,其可以单独使用或与常规免疫调节剂联合使用。所治疗的所述患者的病症的例子包括:移植物抗宿主反应(即,移植物抗宿主疾病),同种异体移植排斥(例如,急性的同种异体移植排斥和慢性同种异体移植排斥),移植物再灌注损伤和初期移植排斥(例如,急性的同种异体移植排斥)。
在一些实施方案中,本发明的化合物用于治疗搔痒症和白斑病(vitaligo)。
在一些实施方案中,本发明的化合物用于治疗下述疾病中的组织损伤,例如,血管疾病,偏头痛,结节性动脉周围炎,甲状腺炎,再生障碍性贫血,淋巴肉芽肿病,硬皮病(sclerodoma),风湿热,I型糖尿病,肌神经接点疾病,包括重症肌无力,脑白质病,包括多发性脑硬化,结节病,肾炎,肾病综合症,郎格汉斯细胞组织细胞增生症,肾小球肾炎,再灌注损伤,胰腺炎,间质性膀胱炎,白塞氏综合征,多肌炎,牙龈炎,牙周炎,超敏反应,损伤之后出现的肿胀,缺血,包括心肌缺血、心血管缺血和缺血性继发性心跳骤停(second to cardiacarrest),肝硬化,脓毒性休克,内毒素性休克,格兰氏阴性败血症,中毒性休克综合症,中风,缺血性再灌注损伤,多器官功能障碍,再狭窄,包括冠状动脉旁路手术之后的再狭窄,等等。
在一些实施方案中,本发明的化合物用于治疗神经系统的某些疾病和病症。中枢神经系统病症(在这种病症中,抑制Rho激酶是有效的)包括:皮层痴呆,包括阿尔茨海默氏病和轻微的认知损害(MCI),起因于中风的中枢神经系统损伤,缺血,包括脑缺血(局灶性缺血、血栓性中风和全脑缺血(例如,继发性的心跳骤停(second to cardiacarrest)))和创伤。神经变性病症(在这种病症中,抑制Rho激酶是有效的)包括:在例如低氧、血糖过低症、癫痫病症中和在中枢神经系统(CNS)创伤(例如脊髓和颅脑损伤)、高压氧惊厥和中毒情况下的神经变性或神经坏死,痴呆(例如早老性痴呆)和AIDS相关的痴呆,恶病体质,西登哈姆氏舞蹈病,亨丁顿舞蹈症,帕金森氏症,肌萎缩性侧索硬化(ALS),多发性脑硬化,遗忘性虚谈综合征和与脑血管病症有关的愚钝。其中抑制Rho激酶可能证明有用的其它病症包括:中枢和周围神经系统的神经病(包括,例如,IgA神经病,膜神经病和自发性神经病),慢性炎性脱髓鞘多发性神经病,横贯性脊髓炎,Gullain-Barre疾病,脑炎和神经系统的癌症。可以使用Rho激酶抑制剂的CNS功能病症包括:睡眠障碍,精神分裂症,抑郁症,与经前期综合征(PMS)相关的抑郁症或其它症状,和焦虑症。
此外,使用本发明的化合物来抑制Rho激酶活性,用于改善系统病症,包括各种各样药剂诱导的败血和/或毒性出血性休克;作为与细胞因子例如TNF、IL-1和IL-2一起使用的疗法;和在移植物治疗中作为短期免疫抑制的辅助药。
可以用本发明化合物治疗的其它障碍或病症包括:癌症的预防或治疗,例如结肠直肠癌和乳癌,肺癌,前列腺癌,膀胱癌,宫颈癌和皮肤癌。本发明的化合物可以用于治疗和预防瘤形成,包括但不局限于:脑癌,骨癌,白血病,淋巴瘤,上皮细胞衍生的瘤形成(上皮癌),例如基底细胞癌,腺癌,胃肠癌,例如唇癌,口腔癌,食道癌,小肠癌和胃癌,结肠癌,肝癌,膀胱癌,胰腺癌,卵巢癌,子宫颈癌,肺癌,乳腺癌和皮肤癌,例如鳞状细胞和基底细胞癌,前列腺癌,肾细胞癌,及影响整个身体上皮细胞的其它已知的癌。瘤形成可以选自:胃肠癌,肝癌,膀胱癌,胰腺癌,卵巢癌,前列腺癌,子宫颈癌,肺癌,乳腺癌和皮肤癌,例如鳞状细胞和基底细胞癌。本发明化合物和方法也可以用于治疗放射治疗所出现的纤维化。本发明化合物和方法可以用于治疗患有腺瘤息肉的患者,包括患有家族性多发性腺癌(FAP)的那些患者。另外,本发明化合物和方法可以用于防止处于FAP危险之中的患者形成息肉。
在一些实施方案中,本发明的化合物用于治疗眼睛疾病,例如干眼症,青光眼,角膜新血管化,视神经炎,Sjogren′s综合症,视网膜神经节变性,眼睛缺血,视网膜炎,视网膜病,葡萄膜炎,眼睛恐光症和与眼睛组织急性损伤相关的炎症和疼痛。在一些实施方案中,该化合物用于治疗青光眼性视网膜病和/或糖尿病性视网膜病。在一些实施方案中,该化合物用于治疗手术后的炎症或从眼睛手术引起的疼痛,例如白内障手术和屈光手术。
在一些实施方案中,本发明的化合物用于治疗月经痛,痛经,早产,子宫内膜异位,腱炎,滑囊炎,皮肤相关的病症,例如牛皮癣,湿疹,灼伤,晒斑,皮炎,胰腺炎,肝炎,扁平苔癣,巩膜炎,硬皮病,皮肤肌炎,等等。可以使用本发明化合物的其它病症包括糖尿病(I型或II型),心肌炎,病理性血管生成和主动脉瘤。
此外,本发明的化合物用于治疗心血管疾病,例如绞痛,冠状动脉血管痉挛,心肌梗塞,冠状动脉缺血,充血性心力衰竭,心脏异体移植血管病变,静脉移植疾病和血管再狭窄,缺血性再灌注损伤,脑动脉血管痉挛,中风,脑缺血,原发性高血压,肺高血压症,肾性高血压及其它继发性的高血压病症,动脉粥样硬化和勃起功能障碍。
在一些实施方案中,本发明的化合物用于治疗自身免疫病症。自身免疫病症的例子包括但不局限于:类风湿性关节炎,牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,多发性脑硬化,系统性红斑狼疮,乳糜泻,自发的血小板减少性血栓性紫癜,重症肌无力,干燥综合症,硬皮病或牛皮癣的表皮增生。在某些其它实施方案中,该自身免疫病症是牛皮癣,慢性移植物抗宿主病,急性移植物抗宿主病,克罗恩病,系统性红斑狼疮或牛皮癣的表皮增生。在一些实施方案中,自身免疫病症是选自下列的牛皮癣类型:斑块型牛皮癣,滴状牛皮癣,皮褶牛皮癣,脓疱性牛皮癣和红皮病型牛皮癣。在一些实施方案中,免疫病症是炎症性肠病或溃疡性结肠炎。在一些实施方案中,免疫病症是与致病性胸腺依赖性细胞的活性相关或由其引起的免疫病症。在一些实施方案中,免疫病症是对给予患有免疫病症的患者可抑制线粒体呼吸的活性剂治疗敏感的免疫病症。
在一些实施方案中,该自身免疫病症是关节炎,幼年关节炎,幼年型类风湿关节炎,少关节幼年型类风湿关节炎,多关节幼年型类风湿关节炎,全身发病型幼年型类风湿关节炎,幼年强直性脊柱炎,幼年肠病性关节炎,幼年反应性关节炎,幼年赖透氏综合症,关节病综合症,少年型皮肌炎,幼年牛皮癣关节炎,幼年硬皮病,幼年系统性红斑狼疮,幼年血管炎,少关节类风湿性关节炎,多关节类风湿性关节炎,全身发病型类风湿性关节炎,强直性脊柱炎,肠病性关节炎,反应性关节炎,葡萄膜炎,赖透氏综合症,皮肤肌炎,牛皮癣关节炎,血管炎,脊髓炎,多发性肌炎,皮肌炎,骨关节炎,结节性多动脉炎,眶坏死性肉芽肿病,动脉炎,风湿性多肌痛,结节病,硬化症,原发性胆道硬化症,硬化性胆管炎,皮炎,特异性皮炎,斯提耳病,慢性阻塞性肺病,吉兰-巴雷综合征,格雷夫斯氏病,阿狄森氏病,雷诺氏现象或自身免疫性肝炎。
在一些实施方案中,本发明的化合物用于治疗与促炎细胞因子表达(例如,IL-17和/或IL-21)(例如,与IL-17和/或IL-21表达相关的途径(例如,IRF4))有关的病症。在一些实施方案中,病症是炎性病症。炎性病症包括但不局限于:关节炎,类风湿性关节炎,牛皮癣关节炎,骨关节炎,变性关节炎,多肌痛风湿症,强直性脊柱炎,反应性关节炎,痛风,软骨钙质沉着病,炎性关节病,系统性红斑狼疮,多肌炎和肌纤维痛。关节炎的其它类型包括:跟腱炎,软骨发育不全,肢端肥大性关节病,肩关节冻结症,成人斯蒂尔病,鹅足滑囊炎,无血管形成性坏死,Behcet综合症,二头肌腱炎,Blount′s疾病,布鲁杆菌脊椎炎,滑囊炎,跟部滑囊炎,焦磷酸钙二水合物沉积性疾病(CPPD),晶体沉积疾病,Caplan′s综合症,腕管综合征,软骨钙质沉着病,髌骨软化症,慢性滑膜炎,慢性复发性多灶性骨髓炎,Churg-Strauss综合症,Cogan′s综合症,皮质类甾醇诱导的骨质疏松症,肋胸综合症,CREST综合症,冷球蛋白血症,变性性关节病,皮肤肌炎,糖尿病性指硬化症,广泛性特发性骨质增生(DISH),关节盘炎,盘状红斑狼疮,药物诱导的狼疮,Duchenne′s肌肉营养不良,Dupuytren′s挛缩,埃-当二氏综合征,肠病性关节炎,上髁炎,糜烂性炎症性骨关节炎,锻炼诱导的腔隙综合症,Fabry′s疾病,家族性地中海热,Farber′s脂肪肉芽肿病,Felty′s综合症,Fifth′s疾病,平足,异物滑膜炎,Freiberg′s疾病,真菌性关节炎,Gaucher′s疾病,巨细胞性动脉炎,淋病性关节炎,Goodpasture′s综合症,肉芽肿性动脉炎,关节积血,血色沉着病,亨-舍二氏紫癜,乙型肝炎表面抗原疾病,髋发育异常,投手综合症,过度活动综合征,超敏反应血管炎,肥大性骨关节病,免疫复合物型血清病,撞击综合症,Jaccoud′s关节病,幼年强直性脊柱炎,少年型皮肌炎,幼年型类风湿关节炎,川崎氏病,Kienbock′s疾病,股骨头骨骺骨软骨病,莱纳二氏综合症,带状硬皮病,脂肪性皮肤病关节炎,Lofgren′s综合症,Lyme疾病,恶性滑膜瘤,Marfan′s综合症,内侧滑膜皱襞综合征,转移性的癌性关节炎,混合结缔组织病(MCTD),混合的冷球蛋白血症,粘多糖病,多中心的网状组织细胞增生症,多发性骨骺发育不良,支原体性关节炎,肌筋膜疼痛综合症,初生儿狼疮,夏科氏关节,结节性脂膜炎,褐黄病,鹰嘴突滑囊炎,Osgood-Schlatter′s疾病,骨关节炎,骨软骨瘤病,成骨不全,骨软化症,骨髓炎,骨坏死,骨质疏松症,重叠综合征,骨的厚皮性Paget′s疾病,汉-罗二氏综合征,膑骨股骨疼痛综合症,Pellegrini-Stieda综合症,色素沉着绒毛结节性滑膜炎,梨状肌综合症,足底筋膜炎,结节性多动脉炎,多肌痛风湿症,多肌炎,腘窝囊肿,胫后肌腱炎,Pott′s疾病,髌前粘液囊炎,人工关节感染,假性弹力性黄色瘤,牛皮癣关节炎,Raynaud′s现象,反应性关节炎/Reiter′s综合症,反射性交感神经营养不良综合征,复发性多软骨炎,足跟部滑囊炎,风湿热,类风湿病性血管炎,肩轴肌腱炎,骶髂关节炎,沙门氏菌性骨髓炎,结节病,铅中毒性痛风,Scheuermann′s骨软骨炎,硬皮病,脓毒性关节炎,血清阴性关节炎,志贺菌性关节炎,肩手综合症,镰状细胞关节病,干燥综合症,股骨头骨骺滑脱,脊椎狭窄症,椎骨脱离,葡萄球菌性关节炎,Stickler综合症,亚急性皮肤狼疮,Sweet′s综合症,Sydenham′s舞蹈病,梅毒性关节炎,系统性红斑狼疮(SLE),Takayasu′s动脉炎,踝管综合征,网球肘,Tietse′s综合症,一过性骨质疏松症,外伤性关节炎,大转子滑囊炎,结核性关节炎,溃疡性结肠炎的关节炎,未分化型结缔组织综合症(UCTS),荨麻疹性血管炎,病毒关节炎,Wegener′s肉芽肿病,Whipple′s疾病,Wilson′s疾病和耶尔森菌关节炎。在某些实施方案中,与异常ROCK活性相关的障碍和/或病症包括但不局限于:心血管病症(例如,心绞痛(例如,狭心症),动脉粥样硬化,中风,脑血管疾病(例如,脑血栓形成,脑栓塞和脑出血),充血性心力衰竭,冠状动脉病,心肌梗塞,周围血管疾病,狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄),血管痉挛(例如,脑动脉血管痉挛,冠状动脉血管痉挛),高血压症(例如,肺动脉高压,系统高动脉压)),平滑肌相关病症(例如,青光眼,勃起功能障碍,支气管性哮喘),肉芽肿病症(例如,结节病,韦格氏肉芽肿),急性巨噬细胞介导的疾病(例如,成人呼吸窘迫综合征)和自身免疫病症(例如,类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化)。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗绞痛的药剂(例如,抗血小板药剂(例如,阿司匹林,噻氯匹定,氯吡格雷),β-肾上腺素阻断剂(例如,美托洛尔,卡维地洛,普奈洛尔,阿替洛尔),钙通道阻断剂(例如,氨氯地平,地尔硫维拉帕米),短效硝化甘油(例如,硝化甘油),长效的硝化甘油(例如,异山梨醇),血管紧张素-转化酶抑制剂(例如,雷米普利),抗缺血的药剂(例如,雷诺嗪(ranolazine)),If抑制剂(例如,伊伐布雷定(ivabradine))和他汀类(statin)(例如,罗苏伐他汀,阿托伐他汀,西立伐他汀,氟伐他汀,洛伐他汀,美伐他汀,匹伐他汀,西伐他汀和其任何联用药))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗自身免疫病症和/或炎性病症(例如,类风湿性关节炎)的药剂共同给药。这种药剂的例子包括但不局限于:改善疾病的抗风湿药物(例如,来氟米特,氨甲喋呤,柳氮磺吡啶,羟氯奎),生物药剂(例如,美罗华,因福利美,依那西普,阿达木单抗,戈利木单抗(golimumab)),非甾体抗炎症的药物(例如,布洛芬,西乐葆,酮洛芬,萘普生,吡罗昔康,双氯芬酸),镇痛药(例如,醋氨酚,反胺苯环醇),免疫调节剂(例如,阿那白滞素,阿巴西普(abatacept))和糖皮质激素(例如,脱氢可的松,甲基强的松),IL-1抑制剂和金属蛋白酶抑制剂。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗动脉粥样硬化的药剂(例如,他汀类(statin)(例如,罗苏伐他汀,阿托伐他汀,西立伐他汀,氟伐他汀,洛伐他汀,美伐他汀,匹伐他汀,西伐他汀和其任何联用药),纤维酸衍生物(例如,非诺贝特,吉非贝齐(gemfibrozil)),胆汁酸螯合剂(例如,考来烯胺,考来替泊),抗氧化剂(例如,维生素E)和烟酸衍生物(例如,烟碱酸))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗中风的药剂(例如,抗凝药剂(例如,肝素,华法林,依诺肝素,达肝素钠,亭扎肝素(tinzaparin),未分级肝素),再灌注药剂(例如,溶栓剂(例如,阿替普酶,尿激酶,链激酶)),纤维蛋白溶解剂(例如,阿替普酶,瑞替普酶(reteplase),尿激酶,链激酶)和抗血小板药剂(例如,阿司匹林,噻氯匹定,氯吡格雷))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗脑血栓形成的药剂(例如,抗凝血药剂(例如,肝素,华法林,依诺肝素,达肝素钠,亭扎肝素(tinzaparin),未分级肝素)和溶栓剂(例如,阿替普酶,瑞替普酶(reteplase),尿激酶,链激酶))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗脑栓塞的药剂(例如,纤维蛋白溶解剂(例如,阿替普酶,瑞替普酶(reteplase),尿激酶,链激酶),抗凝血药剂(例如,肝素,华法林,依诺肝素,达肝素钠,亭扎肝素(tinzaparin),未分级肝素))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗脑出血的药剂(例如,抗高血压药(例如,柳胺苄心定,尼卡地平),渗透利尿剂(例如,甘露醇),清热药/镇痛药(例如,醋氨酚),抗惊厥剂(例如,磷苯妥英(fosphenytoin)),解毒剂(例如,植物甲萘醌,维生素K,硫酸鱼精蛋白),抗酸剂(例如,法莫替丁))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗充血性心力衰竭的药剂(例如,利尿剂(例如,利尿磺胺,美托拉宗),硝酸盐(例如,硝化甘油,硝普钠),镇痛药(例如,硫酸吗啡),影响收缩的药剂(例如,多巴胺,多巴酚丁胺),人B型利钠肽(例如,奈西立肽(nesiritide)))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗冠状动脉病的药剂(例如,他汀类(statin)(例如,瑞舒伐他汀,阿托伐他汀,西立伐他汀,氟伐他汀,洛伐他汀,美伐他汀,匹伐他汀,西伐他汀和其任何联用药),纤维酸衍生物(例如,非诺贝特,吉非贝齐(gemfibrozil)),胆汁酸螯合剂(例如,考来烯胺,考来替泊),抗氧化剂(例如,维生素E)和烟酸衍生物(例如,烟碱酸))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗心肌梗塞的药剂(例如,抗血栓形成药剂(例如,阿司匹林,肝素,依诺肝素),血管扩张剂(例如,硝化甘油),β-肾上腺素阻断剂(例如,美托洛尔,艾司洛尔),溶解血栓的药剂(例如,阿替普酶,替奈普酶(tenecteplase),阿尼普酶,链激酶,瑞替普酶(reteplase)),血小板聚集抑制剂(例如,氯吡格雷,埃替非巴肽(eptifibatide),替罗非班(tirofiban),阿昔单抗),镇痛药(例如,硫酸吗啡),血管紧张素-转化酶(ACE)抑制剂(例如,卡托普利))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗周围性血管疾病的药剂(例如,抗凝血剂(例如,肝素,华法林,依诺肝素,达肝素钠,亭扎肝素(tinzaparin),未分级肝素))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗狭窄(例如,冠状动脉狭窄,主动脉瓣狭窄,再狭窄,肺动脉狭窄)的药剂(例如,前列腺素(例如,前列地尔),β-阻断剂(例如,阿替洛尔,艾司洛尔,普奈洛尔))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗血管痉挛(例如,脑动脉血管痉挛,冠状动脉血管痉挛)的药剂(例如,硝酸盐(例如,硝化甘油,二硝酸异山梨酯,单硝酸异山梨醇),钙通道阻断剂(例如,硝苯地平,氨氯地平,维拉帕米,地尔硫))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗高血压症的药剂(例如,肺动脉高压,系统的高动脉压)(例如,肠胃外血管扩张剂(例如,依前列醇,曲前列尼尔(treprostinil)),磷酸二酯酶(5型)酶抑制剂(例如,西地那非),吸入式血管扩张剂(例如,伊洛前列素(iloprost)),口服肺高血压症药剂(例如,波生坦,安立生坦(ambrisentan)),利尿剂(例如,双氢克尿噻,螺甾内酯,阿米洛利,利尿磺胺),α-1-肾上腺素能阻断剂(例如,哌唑嗪,特拉唑嗪),β-肾上腺素能阻滞剂(例如,阿替洛尔,美托洛尔,普奈洛尔,奈比洛尔(nebivolol)),α/β-肾上腺素能阻滞剂(例如,柳胺苄心定,卡维地洛),外周(periperhal)血管扩张剂(例如,肼苯哒嗪,米诺地尔),钙通道阻断剂(例如,地尔硫维拉帕米,硝苯地平),血管紧张素-转化酶(ACE)抑制剂(例如,卡托普利,依那普利,赖诺普利,雷米普利),血管紧张素II受体拮抗剂(例如,氯沙坦,丙戊沙坦,依普罗沙坦,奥美沙坦),醛甾酮拮抗剂(例如,依普利酮),α-肾上腺素能激动剂(例如,甲基多巴,可乐定(clonodine)),肾素抑制剂(例如,阿利吉仑(aliskiren)))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗青光眼的药剂(例如,碳酸酐酶抑制药(例如,乙酰唑胺,甲醋唑胺),β-肾上腺素能阻断剂(例如,噻吗洛尔(tomolol),卡替洛尔,左倍他洛尔(Levobetaxolol),左旋布诺洛尔(levobunolol)),α-肾上腺素激动剂(例如,阿普可乐定(apraclonidine),溴莫尼定),皮质类甾醇(例如,脱氢可的松),眼用药剂(例如,毛果碱),高渗药剂(例如,丙三醇,异山梨醇,甘露醇))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗勃起功能障碍的药剂(例如,磷酸二酯酶抑制剂(例如,西地那非,伐地那非,他达拉非(tadalafil)),注射药剂(例如,前列地尔,罂粟碱,酚妥拉明,前列地尔),雄激素(例如,睾酮))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗支气管性哮喘的药剂(例如,β2-肾上腺素能激动剂(例如,左沙丁胺醇(levalbuterol),沙美特罗,福莫特罗,沙丁胺醇),皮质类甾醇(例如,氟替卡松,氟羟脱氢皮醇,倍氯米松,脱氢可的松,布地奈德),支气管扩张药(例如,异丙托品,茶碱),β2-激动剂/皮质类甾醇药剂的联用药(例如,沙美特罗/氟替卡松,布地奈德/福莫特罗),白细胞三烯受体拮抗剂(例如,孟鲁司特,扎鲁司特),柱状细胞稳定剂(例如,可玛林),5-脂氧合酶抑制剂(例如,弃白通),单克隆抗体(例如,奥马珠单抗))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗结节病的药剂(例如,皮质类甾醇(例如,脱氢可的松),细胞毒素药剂(例如,氨甲喋呤,硫唑嘌呤),抗疟药(例如,羟氯奎),免疫调节药剂(例如,反应停),肿瘤坏死因子抑制剂(例如,因福利美))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗韦格氏肉芽肿的药剂(例如,抗肿瘤药(例如,环磷酰胺,氨甲喋呤),皮质类甾醇(例如,脱氢可的松),抗生素(例如,三甲氧苄二氨嘧啶,磺胺甲基异噁唑),抗甲状腺药剂(例如,碘化钾),生物制剂/TNF-α抑制剂(例如,因福利美,硫唑嘌呤,美罗华))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗成人呼吸窘迫综合征的药剂(例如,皮质类甾醇(例如,甲基强的松))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗系统性红斑狼疮的药剂(例如,非乙酰化水杨酸盐(例如,三水杨酸胆碱镁),非甾体抗炎症的药物(NSAID)(例如,布洛芬),抗疟药(例如,羟氯奎),糖皮质激素(例如,脱氢可的松,甲基强的松),免疫抑制/细胞毒素药剂(例如,环磷酰胺,硫唑嘌呤))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗多发性脑硬化的药剂(例如,皮质类甾醇(例如,甲基强的松,地塞米松),免疫调节剂(例如,干扰素β-1a,干扰素β-1b,醋酸格拉默,那他珠单抗(natalizumab)),免疫抑制剂(例如,米托蒽醌,环磷酰胺,硫唑嘌呤,氨甲喋呤),抗病毒剂/抗帕金森药剂(例如,二盐酸金刚烷胺),中枢神经系统兴奋剂(例如,莫达非尼(modafinil)))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗过敏性肠综合症的药剂(例如,抗胆碱能药(例如,盐酸双环胺),硫酸莨菪碱),止泻药(例如,盐酸地芬诺酯与硫酸阿托品,洛哌丁胺),三环抗抑郁药(例如,丙咪嗪,阿米替林),促进肠胃蠕动(例如,西沙必利一水合物,替加色罗),血清素(5-HT3)受体拮抗剂(例如,阿洛司琼),氯离子通道活化剂(例如,鲁比前列酮(lubiprostone)),容积性泻药(例如,甲基纤维素,车前草))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗系统性硬化的药剂(例如,免疫调节药剂(例如,脱氢可的松,氨甲喋呤,苯丁酸氮芥,环孢灵,他克莫司,环磷酰胺),抗纤维化药剂(例如,3-巯基缬氨酸,秋水仙碱),血管活性药剂(例如,硝苯地平),抗血小板药剂(例如,阿司匹林),抗高血压药(例如,利血平,甲基多巴))共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗类风湿性关节炎的药剂(例如,非甾体消炎药(NSAID)(例如,萘丁美酮,阿司匹林,西乐葆,布洛芬),金色化合物(例如,金诺芬),免疫抑制剂(例如,氨甲喋呤),抗疟药药剂(例如,羟氯喹),消炎药(例如,柳氮磺吡啶),皮质类甾醇(例如,倍他米松),疾病-调节剂(例如,3-巯基缬氨酸,阿达木单抗),免疫调节剂(例如,阿巴西普(abatacept)))共同给药。
在一些实施方案中,ROCK抑制剂(参见,例如,I部分-示范性化合物)用于治疗患有与异常血管生成有关的疾病的患者。在一些实施方案中,一个以上的本发明化合物通过在进行异常血管生成的受到影响的细胞或组织中调节(例如,抑制或促进)Rho激酶(ROCK)的活性,用于治疗与异常血管生成有关的疾病。本发明不局限于与异常血管生成有关的疾病的类型。与异常血管生成有关的疾病的例子包括但不局限于:癌(例如,与实质固态瘤有关的癌),牛皮癣,糖尿病性视网膜病,黄斑变性,动脉粥样硬化和类风湿性关节炎。
在一些实施方案中,含有本发明ROCK抑制剂的组合物与设计为治疗与异常血管生成有关的疾病的药剂(例如,达肝素钠,ABT-510,CNGRC肽TNF α共轭物(NGR-TNF),康普瑞汀A4磷酸盐,乙酸二甲基呫吨酮,来那度胺(Lenalidomide),LY317615,PPI-2458,大豆异黄酮(染料木素;大豆蛋白质分离物),枸橼酸它莫西芬,反应停,ADH-1,AG-013736,AMG-706,抗VEGF抗体,AZD2171,Bay 43-9006,GW786034,CHIR-265,PI-88,PTK787/ZK 222584,RAD001,苏拉明,SU 11248,XL 184,ZD6474,ATN-161,EMD 121974和西乐葆)共同给药。
在一些实施方案中,含有本发明的ROCK抑制剂的组合物与设计为治疗癌症的下述药剂共同给药(例如,阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;多柔比星;阿地白介素;阿利维甲酸(Alitretinoin);别嘌醇钠;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;番荔枝内酯;安曲霉素;巴婆(双呋)内酯(Asimicin);门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;贝沙罗汀(Bexarotene);比卡鲁胺;盐酸比生群;甲磺酸双奈法德(Bisnafide Dimesylate);比折来新;硫酸博来霉素;布喹那钠;溴匹立明;布拉他辛(Bullatacin);白消安;卡麦角林;放线菌素C;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;西乐葆;苯丁酸氮芥;西罗霉素;顺铂;克拉屈滨;甲磺酸克雷斯托(Crisnatol);环磷酰胺;阿糖胞苷;达卡巴嗪;DACA(N-[2-(二甲基-氨基)乙基]吖啶-4-甲酰胺);放线菌素;盐酸柔红霉素;柔毛霉素;地西他滨;白介素融合毒素(Denileukin Diftitox);右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;多西他赛;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;依氟鸟氨酸盐酸盐;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;乙碘油I 131;依托泊苷;磷酸依托泊苷;艾托卜宁(Etoprine);盐酸法屈唑;法扎拉滨;芬维A胺(Fenretinide);氮尿苷;氟达拉滨磷酸盐;氟尿嘧啶;5-FdUMP;氟西他滨;磷喹酮;磷曲星钠;FK-317;FK-973;FR-66979;FR-900482;吉西他滨;盐酸吉西他滨;吉妥珠单抗奥唑米星(Gemtuzumab Ozogamicin);Gold Au198;醋酸性瑞林;Guanacone;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;干扰素Alfa-2a;干扰素Alfa-2b;干扰素Alfa-n1;干扰素Alfa-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸依立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;环己亚硝脲;盐酸洛索蒽醌;马索罗酚;美登素;盐酸二氯甲二乙胺;醋酸甲地孕酮;十六次甲基甲地孕酮;米尔法兰;美诺立尔;巯基嘌呤;氨甲喋呤;氨甲喋呤钠;补骨脂素;氯苯氨啶(Metoprine);美乌替派;米丁度胺;米托卡星(Mitocarcin);丝裂红素;丝林霉素;丝裂马菌素;丝裂霉素;丝裂霉素C;米托司培;米托坦;盐酸米托蒽醌;霉酚酸;噻氨酯达唑;诺加霉素;Oprelvekin;奥马铂;亚磺酰吡啶;太平洋紫杉醇;帕米膦酸二钠;培加帕酶;佩里霉素;戊氮芥;硫酸培洛霉素;培磷酰胺;双溴丙基哌嗪;保释芬;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;波福霉素;松龙苯芥;盐酸甲基苄肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;美罗华;洛太米特(Rogletimide);Rolliniastatin;沙芬戈;沙芬戈盐酸盐;来昔决南钐(Samarium/Lexidronam);赛氮芥;二甲二苯四氮烯;磷乙酰天冬氨酸钠(Sparfosate Sodium);稀疏霉素;盐酸锗螺胺;螺莫司汀;螺铂;Squamocin;Squamotacin;链黑菌素;链脲霉素;氯化锶Sr 89;磺氯苯脲;他利霉素;紫杉烷(taxane);Taxoid;替可加兰钠(TecogalanSodium);替加氟;盐酸替洛蒽醌;替莫卟吩;表鬼臼毒噻吩糖苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;硫替派;Thymitaq;噻唑呋啉;替拉扎明;拓优得(Tomudex);TOP-53;盐酸托泊替康;柠檬酸托瑞米芬;曲妥珠单抗;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;尿嘧啶氮芥;尿烷亚胺;戊柔比星(Valrubicin);伐普肽;维替泊芬;长春碱;硫酸长春碱;长春花新碱;硫酸醛基长春碱;去乙酰长春酰胺;硫酸去乙酰长春酰胺;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞宾;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼拉汀;净司他丁;盐酸佐柔比星;2-氯脱氧腺苷;2′-脱氧间型霉素;9-氨基喜树碱;雷替曲塞(raltitrexed);N-炔丙基-5,8-dideazafolic acid;2-氯-2′-阿糖基-氟-2′-脱氧腺苷;2-氯-2′-脱氧腺苷;茴香霉素;曲古抑菌素(trichostatin)A;hPRL-G129R;CEP-751;三羧氨基喹啉;硫芥子气;氮芥(二氯甲二乙胺);环磷酰胺;米尔法兰;苯丁酸氮芥;异环磷酰胺;白消安;N-甲基-N-亚硝基脲(MNU);N,N′-二(2-氯乙基)-N-亚硝基脲(BCNU);N-(2-氯乙基)-N′-环己-基-N-亚硝基脲(环己亚硝脲);N-(2-氯乙基)-N′-(反式-4-甲基环己基-N--亚硝基脲(甲基氯乙环己亚硝脲);N-(2-氯乙基)-N′-(二乙基)乙基磷酸酯-N-亚硝基脲(福莫司汀);链脲佐菌素;达卡巴嗪(diacarbazine)(DTIC);米托唑胺(mitozolomide);替莫唑胺;硫替派;丝裂霉素C;AZQ;阿多来新;顺铂;卡铂;奥马铂;奥沙利铂;C 1-973;DWA 2114R;JM216;JM335;二(铂);拓优得(tomudex);阿扎胞苷;阿糖胞苷;吉西他滨;6-巯基嘌呤;6-硫代鸟嘌呤;次黄嘌呤;表鬼臼毒噻吩糖苷;9-氨基喜树碱;托泊替康;CPT-11;多柔比星;柔毛霉素;表柔比星;依达比星(darubicin);米托蒽醌;洛索蒽醌;放线菌素(放线菌素D);安吖啶;吡唑并吖啶;全-反式视黄醇;14-羟基-逆-视黄醇;全-反式视黄酸;N-(4-羟基苯基)维甲胺;13-顺式视黄酸;3-甲基TTNEB;9-顺式视黄酸;氟达拉滨(2-F-ara-AMP);和2-氯脱氧腺苷(2-N-环己基十二烷基胺)。其它抗癌症药剂包括但不局限于:抗增殖药剂(例如,吡曲克辛硫代硫酸盐),抗前列腺肥大药剂(例如,西托糖苷(Sitogluside)),良性前列腺肥大治疗药剂(例如,盐酸坦洛新),前列腺生长抑制剂(例如,喷托孟(Pentomone))和放射性药剂:纤维蛋白原1 125;氟[18F]脱氧葡糖;氟[18F]多巴;胰岛素I 125;胰岛素I 131;硫酸碘苄胍I 123;已乌洛康(胆影酸,Iodipamide)钠I 131;碘安替比林(Iodoantipyrine)I 131;碘胆甾醇I 131;碘马尿酸钠I 123;碘马尿酸钠I 125;碘马尿酸钠I 131;碘吡啦啥I 125;碘吡啦啥I 131;盐酸碘非他胺I 123;碘双胺喹(Iomethin)I 125;碘双胺喹(Iomethin)I131;碘酞酸钠I 125;碘酞酸钠I 131;碘酪氨酸I 131;三碘甲腺原氨酸I 125;三碘甲腺原氨酸I 131;放射性汞丙醇醋酸酯Hg 197;放射性汞丙醇醋酸酯Hg 203;放射性汞丙醇Hg 197;硒代蛋氨酸Se 75;锝Tc 99m三硫化二锑胶体;锝Tc 99m比西酸盐;锝Tc 99m地索苯宁;锝Tc 99m依替膦酸盐;锝Tc 99m依沙美肟;锝Tc 99m呋膦(Furifosmin);锝Tc 99m葡庚糖酸盐;锝Tc 99m利多苯宁(Lidofenin);锝Tc 99m甲溴苯宁(Mebrofenin);锝Tc 99m亚甲基二磷酸(Medronate);锝Tc 99m亚甲基二磷酸(Medronate)二钠;锝Tc 99m巯替肽(Mertiatide);锝Tc 99m羟亚甲基二膦酸盐(Oxidronate);锝Tc 99m三胺五乙酸盐(Pentetate);锝Tc 99m三胺五乙酸(Pentetate)钙三钠;锝Tc 99m Sestamibi;锝Tc 99m西硼肟(Siboroxime);锝Tc 99m琥巯酸(Succimer);锝Tc 99m硫胶体;锝Tc 99m替肟(Teboroxime);锝Tc 99m替曲膦(Tetrofosmin);锝Tc 99m Tiatide;甲状腺素I 125;甲状腺素I131;碘下聚乙烯吡咯烷酮I 131;三油精I 125;三油精I 131。其它的抗癌症药剂包括但不局限于:抗癌辅助增效剂:三环兴奋剂(例如,丙咪嗪,地昔帕明,阿密替林(amitryptyline),氯米帕明,三甲丙咪嗪,多塞平,去甲替林,普罗替林,阿莫沙平和马普替林);非三环兴奋剂(例如,舍曲林,曲唑酮和西酞普兰);Ca++拮抗剂(例如,维拉帕米,硝苯地平,尼群地平和卡罗维林);钙调素抑制剂(例如,心可定,三氟拉嗪(trifluoroperazine)和氯米帕明);两性霉素B;三苯乙醇类似物(例如,三苯氧胺);抗心律失常药(例如,奎尼丁);抗高血压药(例如,利血平);Thiol depleters(例如,丁硫氨酸(buthionine)和磺基肟)和多耐药性降低药剂,例如Cremaphor EL。还有其它抗癌剂是选自下列的那些抗癌剂:番荔枝内酯;巴婆(双呋)内酯(asimicin);rolliniastatin;guanacone,squamocin,布拉他辛(bullatacin);squamotacin;紫杉烷(taxane);太平洋紫杉醇;吉西他滨;氨甲喋呤FR-900482;FK-973;FR-66979;FK-317;5-FU;FUDR;FdUMP;羟基脲;多西他赛;discodermolide;埃坡霉素;长春花新碱;长春碱;长春瑞宾;meta-pac;依立替康;SN-38;10-OH campto;托泊替康;依托泊苷;多柔比星;夫拉平度(flavopiridol);顺铂;碳铂;博来霉素;丝裂霉素C;光神霉素;卡培他滨;阿糖胞苷;2-C1-2′脱氧腺苷;氟达拉滨-PO4;米托蒽醌;米托唑胺(mitozolomide);喷司他丁;和拓优得(Tomudex)。一种特别优选的抗癌剂是紫杉烷(taxane)(例如,太平洋紫杉醇和多西他赛)。抗癌剂的另一个重要类型是番荔枝内酯。
在一些实施方案中,ROCK抑制剂(参见,例如,I部分的示范性化合物)用于调节患者的血压。在一些实施方案中,一种以上的本发明化合物用于调节患者的血压(例如,保持患者的血压在目标范围之内)。在一些实施方案中,本发明的化合物通过在受到影响的细胞或组织中调节(例如,抑制或促进)Rho激酶(ROCK)的活性来调节血压。在一些实施方案中,本发明的化合物与至少一种调节患者血压的其它药剂共同给药(例如,噻嗪和相关利尿剂(例如,双氢氯噻嗪,氯噻酮),α/β-肾上腺素能阻滞剂(例如,卡维地洛),β-肾上腺素能阻滞剂(例如,比索洛尔,阿替洛尔,美托洛尔),血管紧张素-转化酶抑制剂(例如,卡托普利,福辛普利,贝那普利,喹那普利,雷米普利),血管紧张素II受体拮抗剂(例如,氯沙坦,丙戊沙坦,坎地沙坦,伊贝沙坦,依普罗沙坦,和奥美沙坦),钙通道阻断剂-非二氢吡啶类(例如,地尔硫和维拉帕米),钙通道阻断剂-二氢吡啶类(例如,氨氯地平,硝苯地平,非洛地平),周围血管扩张剂(例如,肼苯哒嗪),醛甾酮拮抗剂(例如,螺甾内酯))。
在一些实施方案中,ROCK抑制剂(参见,例如,I部分的示范性化合物)用于调节患者的HDL/LDL水平。在一些实施方案中,一种以上的本发明化合物用于治疗调节患者的HDL/LDL水平(例如,降低患者的LDL水平,提高患者的HDL水平)。在一些实施方案中,本发明的化合物通过在受到影响的细胞或组织中调节(例如,抑制或促进)Rho激酶(ROCK)的活性来调节HDL/LDL水平。在一些实施方案中,本发明的化合物与至少一种用于调节患者HDL/LDL水平目的的药剂共同给药。用于调节患者HDL/LDL水平目的的其它药剂的例子包括但不局限于:抗血脂药剂(例如,烟酸,尼克酸,吉非贝齐(gemfibrozil),非诺贝特)和HMG-CoA还原酶抑制剂(例如,阿托伐他汀,西伐他汀,普伐他汀,洛伐他汀,氟伐他汀和罗苏伐他汀)。
实施例
提供下列实施例,以便表明和进一步说明本发明的某些优选实施方案,不应该将其理解为限制本发明的范围。
实施例1。
化合物1的制备:
向500-mL圆底烧瓶中加入溶于乙腈/水(1∶1,150mL)中的4-碘代-D-苯丙氨酸(2g,0.007mol)。将三乙胺(0.94mL,0.007mol,1当量)加入到该溶液中,并将该混合物在室温下搅拌30min。将5-氯-靛红酸酐(isatoic anhydride)(1.45g,0.007mol,1当量)加入到该搅拌溶液中,并将该反应在80℃加热,搅拌过夜。将该反应混合物冷却,并用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂。向黄色固体中加入冰醋酸(300mL)。将该搅拌溶液在130℃下加热过夜。冷却至室温后,将该反应混合物再次用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂,对残余物进行硅胶快速色谱(6英寸x 150mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到白色固体(1.2g,44%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.5。旋光度(丙酮,0.998dm)=-164.9°。
1H NMR(DMSO,500MHz):δ(ppm)2.79-2.82(1H,dd,J=9.3,14.2Hz),3.04-3.08(1H,dd,J=5.2,14.2Hz),3.93-3.95(1H,m),7.10-7.15(3H,m),7.56-7.61(4H,m),8.66(1H,dd,J=6.0Hz),10.50(1H,s)。
向250-mL圆底烧瓶中加入溶于二甲基甲酰胺(100mL)中的中间体A(1.2g,3.00mmol),并冷却至0℃。将氢化钠(60%,分散在矿物油中,0.120g,3.00mmol,1当量)加入到该溶液中,并将该混合物在0℃下搅拌30min。加入碘甲烷(0.19mL,3.00mmol,1当量),并将该溶液搅拌4小时,并升温至室温。通过加入水(30mL)来猝灭该反应。将该溶液倒入乙酸乙酯(30mL)中,并将有机层和水层分离。用乙酸乙酯(3x 30mL)提取水层,用水(2x 20mL)和盐水(1x 20mL)洗涤,用硫酸镁干燥。真空除去溶剂,得到黄色油。对残余物进行硅胶快速色谱(6英寸x 150mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色/白色固体(0.877g,66%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.61。旋光度(丙酮,0.998dm)=-143.8°。
1H NMR(丙酮,400MHz):δ(ppm)3.05-3.09(1H,dd,J=8.5,14.4Hz),3.33-3.37(4H,m),4.22-4.25(1H,m),7.20-7.21(2H,d,J=8.1Hz),7.42-7.43(1H,d,J=8.8Hz),7.59-7.63(3H,m),7.69(1H,d,J=2.4Hz),7.97(1H,bs)。
向溶于二甲基甲酰胺(25mL)中的中间体B(0.197g,0.45mmol)的溶液中加入4-吡唑硼酸频哪醇酯(boronic acid pinnacle ester,0.174g,0.90mmol,2当量)、[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)(0.037g,0.045mmol,0.1当量)和碳酸钠(1.80mL 2M水溶液,3.60mmol,8当量)。将该溶液在130℃下加热30min,然后冷却至室温。将该混合物倒入水(15mL)中,用二氯甲烷(3x 15mL)提取。收集有机层,用水(2x 15mL)、盐水(1x 15mL)洗涤,用硫酸镁干燥。浓缩该溶液,用硅胶快速色谱纯化残余物(2英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(23mg,11%)。TLC(硅胶,二氯甲烷-甲醇(90∶10))Rf=0.38。在Chiracel OJ-H分析柱上进行HPLC探测,用100%MeOH作为洗脱液(在20℃),在26.1min和27.9min处得到两个峰(95.0∶5.0,R∶S)。
1H NMR(丙酮,500MHz):δ(ppm)3.06-3.10(1H,dd,J=8.6,14.4Hz),3.35-3.41(4H,m),4.20-4.24(1H,m),7.35-7.37(2H,d,J=8.1Hz),7.45-7.52(3H,m),7.59-7.62(1H,dd,J=2.7,8.8Hz),7.66(1H,dd,J=2.4Hz),7.67(1H,d,J=2.7Hz),7.81(bd,1H),7.97(bs,2H)。
13C NMR(500MHz,丙酮):δ(ppm)34.0,34.7,53.9,69.4,121.7,124.0,125.3,129.2,129.9,130.5,131.6,131.9,135.4,136.2,140.2,154.8,166.4,170.1。
化合物2的制备:
向溶于二甲基甲酰胺(50mL)中的中间体B(0.200g,0.44mmol)的溶液中加入3-氨基-4-吡啶硼酸频哪醇酯(0.200g,0.88mmol,2当量)、[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)(0.036g,0.044mmol,0.1当量)和碳酸钠(1.76mL 2M水溶液,3.52mmol,8当量)。将该溶液在130℃下加热30min,然后冷却至室温。将该混合物倒入水(15mL)中,用二氯甲烷(3x 15mL)提取。收集有机层,用水(2x 15mL)、盐水(1x15mL)洗涤,用硫酸镁干燥。浓缩该溶液,用硅胶快速色谱纯化残余物(4英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(25.7mg,14%)。TLC(硅胶,二氯甲烷-甲醇(90∶10))Rf=0.22。旋光度(丙酮,0.998dm)=-214°。在Chiracel OJ-H分析柱上进行HPLC探测,用100%MeOH作为洗脱液(在10℃),在54.8min和58.3min处得到两个峰(1.5∶98.5,S∶R)。
1H NMR(500MHz,丙酮):δ(ppm)3.14-3.17(1H,dd,J=8.5Hz),3.41-3.45(4H,m),4.26-4.28(1H,ABq),5.46(2H,bs),6.80-8.62(2H,m),7.44-7.47(3H,m),7.55-7.56(2H,dd,J=1.7,6.6Hz),7.55-7.56(1H,dd,J=2.7,8.8Hz),7.67(1H,d,J=2.7Hz),8.00(2H,m)。
13C NMR(500MHz,丙酮):δ(ppm)34.0,34.8,61.5,69.4,105.2,110.8,124.0,126.7,129.3,129.9,130.5,131.9,137.3,138.3,140.1,148.6,148.8,160.5,166.5,170.0。
化合物3的制备:
中间体C:6-甲氧基-1H-苯并[d][1,3]噁嗪-2,4-二酮
向2-氨基-5-甲氧基苯甲酸(9g,0.054mmol)的乙腈(60mL,1M)搅拌溶液中加入吡啶(8.7mL,0.108mmol,2当量)和三光气(15.9g,0.054mmol,1当量)(在二氯甲烷(85mL,0.7M)中)。将该橙色反应溶液在50℃下加热两小时,而后冷却至室温。将该溶液用水(50mL)稀释,并将有机层和水层分离。用二氯甲烷(3x 50mL)洗涤水层,并将合并的有机层用盐水(50mL)洗涤一次,用硫酸镁干燥。真空除去溶剂,剩余黄色固体。用己烷研制(titrate)该固体,得到8-氯-1H-苯并[d][1,3]噁嗪-2,4-二酮(8.3g,80%)白色固体。
1H NMR(丙酮,500MHz):δ(ppm)3.80(3H,s),7.09-7.11(1H,t,J=9.0Hz),7.33(1H,s),7.37-7.39(1H,dd,J=2.9,8.7Hz),11.60(1H,bs)。
中间体D:(S)-3-(4-碘代苄基)-7-甲氧基-3,4-二氢-1H-苯并[e][1,4]
向500-mL圆底烧瓶中加入溶于乙腈/水(1∶1,150mL)中的4-碘代-L-苯丙氨酸(2g,0.007mol)。将三乙胺(0.94mL,0.007mol,1当量)加入到该溶液中,并将该混合物在室温下搅拌30min。将中间体C(1.31g,0.007mol,1当量)加入到该搅拌溶液中,并将该反应在80℃加热,搅拌过夜。将该反应混合物冷却,并用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂。向黄色固体中加入冰醋酸(300mL)。将该搅拌溶液在130℃下加热过夜。冷却至室温后,将该反应混合物再次用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂,对残余物进行硅胶快速色谱(6英寸x 150mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(0.42g,13%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.53。旋光度(DMSO,0.998dm)=+122.3°。
1H NMR(DMSO,500MHz):δ(ppm)2.76-2.80(1H,dd,J=9.5,14.2Hz),3.04-3.08(1H,dd,J=5.1,14.1Hz),3.32(3H,s),3.83-3.85(1H,m),7.01-7.02(1H,d,J=8.7Hz),7.09-7.15(4H,m),7.59-7.61(2H,d,J=8.3Hz),8.52-8.54(1H,bd,J=6.1Hz),10.23(1H,bs)。
向100-mL圆底烧瓶中加入溶于二甲基甲酰胺(50mL)中的中间体D(0.42g,0.99mmol),并冷却至0℃。将氢化钠(60%,分散在矿物油中,0.024g,0.99mmol,1当量)加入到该溶液中,并将该混合物在0℃下搅拌30min。加入碘甲烷(0.06mL,0.99mmol,1当量),将该溶液搅拌4小时,并升温至室温。通过加入水(10mL)来猝灭该反应。将该溶液倒入乙酸乙酯(10mL)中,并将有机层和水层分离。用乙酸乙酯(3x 10mL)提取水层,用水(2x 10mL)和盐水(1x 10mL)洗涤,用硫酸镁干燥。将溶剂置于真空中(除去),得到黄色油。对残余物进行硅胶快速色谱(2英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到褐色固体(0.317g,70.7%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.66。旋光度(丙酮,0.998dm)=+129.5°。
1H NMR(DMSO,500MHz):δ(ppm)2.76-2.80(1H,dd,J=9.5,14.2Hz),3.04-3.15(4H,m),3.31-3.32(3H,s),3.86-3.89(1H,m),7.01-7.03(1H,d,J=8.7Hz),7.06-7.15(4H,m),7.59-7.61(2H,d,J=8.3Hz),8.52-8.54(1H,bd,J=6.1Hz)。
化合物3:(S)-3-(4-(2-氨基吡啶-4-基)苄基)-7-甲氧基-1-甲基-3,4-
向溶于二甲基甲酰胺(25mL)中的中间体E(0.120g,0.28mmol)的溶液中加入3-氨基-4-吡啶硼酸频哪醇酯(0.123g,0.55mmol,2当量)、[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)(0.023g,0.028mmol,0.1当量)和碳酸钠(1.1mL 2M水溶液,2.24mmol,8当量)。将该溶液在130℃下加热30min,然后冷却至室温。将该混合物倒入水(15mL)中,用二氯甲烷(3x 15mL)提取。收集有机层,用水(2x 15mL)、盐水(1x15mL)洗涤,用硫酸镁干燥。浓缩该溶液,用硅胶快速色谱纯化残余物(2英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到浅棕色固体(10.8mg,7.2%)。TLC(硅胶,二氯甲烷-甲醇(90∶10))Rf=0.28。旋光度(丙酮,0.998dm)=+118.0°。
1H NMR(500MHz,丙酮):δ(ppm)3.09-3.14(1H,dd,J=8.5,14.4Hz),3.37-3.43(4H,m),3.85(3H,s),4.17-4.19(1H,m),5.41(2H,bs),6.79-6.82(2H,m),7.14-7.19(2H,m),7.34-7.36(1H,d,J=8.8Hz),7.46-7.49(2H,d,J=8.3Hz),7.55-7.57(2H,d,J=8.0Hz),7.71(1H,bd,J=5.4Hz)8.00(1H,d,J=5.4Hz)。
13C NMR(500MHz,丙酮):δ(ppm)34.1,34.8,54.0,55.0,69.4,105.1,110.8,112.9,118.7,123.6,126.6,130.1,134.5,137.3,138.7,147.3,148.6,148.9,156.8,170.1。
化合物4的制备:
向500-mL圆底烧瓶中加入溶于乙腈/水(1∶1,150mL)中的4-碘代-L-苯丙氨酸(2g,0.007mol)。将三乙胺(0.94mL,0.007mol,1当量)加入到该溶液中,并将该混合物在室温下搅拌30min。将5-氯-靛红酸酐(1.5g,0.007mol,1当量)加入到该搅拌溶液中,并将该反应在80℃加热,搅拌过夜。将该反应混合物冷却,并用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂。向黄色固体中加入冰醋酸(300mL)。将该搅拌溶液在130℃下加热过夜。冷却至室温后,将该反应混合物再次用乙酸乙酯(300mL)稀释,用水(2x 200mL)洗涤。真空除去溶剂,对残余物进行硅胶快速色谱(6英寸x 150mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(1.2g,41%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.5。旋光度(丙酮,0.998dm)=+161.2°。
1H NMR(DMSO,500MHz):δ(ppm)2.78-2.81(1H,dd,J=9.2,14.2Hz),3.04-3.08(1H,dd,J=5.2,14.2Hz),3.94-3.95(1H,m),7.10-7.15(3H,m),7.56-7.61(4H,m),8.66(1H,dd,J=6.1Hz),10.50(1H,s)。
向250-mL圆底烧瓶中加入溶于二甲基甲酰胺(100mL)中的中间体F(1.2g,2.8mmol),并冷却至0℃。将氢化钠(60%,分散在矿物油中,0.112g,2.8mmol,1当量)加入到该溶液中,并将该混合物在0℃下搅拌30min。加入碘甲烷(0.17mL,2.8mmol,1当量),将该溶液搅拌4小时,并升温至室温。通过加入水(20mL)来猝灭该反应。将该溶液倒入乙酸乙酯(40mL)中,并将有机层和水层分离。用乙酸乙酯(3x 30mL)提取水层,用水(2x 20mL)和盐水(1x 20mL)洗涤,用硫酸镁干燥。将溶剂置于真空中(除去),得到黄色油。对残余物进行硅胶快速色谱(6英寸x 150mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(0.747g,60%)。TLC(硅胶,己烷-乙酸乙酯(50∶50))Rf=0.61。旋光度(丙酮,0.998dm)=+148.0°。
1H NMR(丙酮,400MHz):δ(ppm)3.05-3.09(1H,dd,J=8.5,14.4Hz),3.33-3.37(4H,m),4.22-4.25(1H,m),7.20-7.21(2H,d,J=8.1Hz),7.42-7.43(1H,d,J=8.8Hz),7.59-7.63(3H,m),7.69(1H,d,J=2.4Hz),7.97(1H,bs)。
向溶于二甲基甲酰胺(25mL)中的中间体G(0.200g,0.45mmol)的溶液中加入4-(1,5-二甲基-2,4-二氧杂-3-硼二环[3.1.0]己-3-基)-1H-吡咯并[2,3-b]吡啶(0.215g,0.90mmol,2当量)、[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)(0.037g,0.045mmol,0.1当量)和碳酸钠(1.8mL 2M水溶液,3.60mmol,8当量)。将该溶液在130℃下加热30min,然后冷却至室温。将该混合物倒入水(15mL)中,用二氯甲烷(3x 15mL)提取。收集有机层,用水(2x 15mL)、盐水(1x 15mL)洗涤,用硫酸镁干燥。浓缩该溶液,用硅胶快速色谱纯化残余物(2英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到黄色固体(33.1mg,16%)。TLC(硅胶,二氯甲烷-甲醇(90∶10))Rf=0.33。旋光度(丙酮,0.998dm)=+150.0°。在Chiracel OJ-H分析柱上进行HPLC探测,用100%MeOH作为洗脱液(在45℃),在41.5min和42.0min处得到两个峰(95.0∶5.0,S∶R)。
1H NMR(500MHz,丙酮):δ(ppm)3.19-3.24(1H,dd,J=8.2,14.4Hz),3.43(3H,s),3.47-3.52(3H,dd,J=5.9,14.4Hz),4.33-4.35(1H,m),6.65(1H,d,J=3.4Hz),7.16-7.17(1H,d,J=4.9Hz),7.45-7.46(1H,d,J=8.7Hz),7.53-7.56(3H,m),7.60-7.62(1H,dd,J=2.6,8.1Hz),7.69-7.71(2H,d,J=2.6,8.1Hz),8.15(1H,bd,J=5.8Hz)8.31(1H,d,J=4.9Hz),11.00(1H,bs)。
13C NMR(500MHz,丙酮):δ(ppm)34.1,34.8,53.8,69.3,99.5,109.3,114.3,117.8,124.1,125.7,128.3,129.3,129.9,130.5,131.9,137.3,138.0,140.2,140.8,143.1,166.7,170.0。
化合物5的制备:
向溶于二甲基甲酰胺(25mL)中的中间体E(0.120g,0.28mmol)的溶液中加入4-(1,5-二甲基-2,4-二氧杂-3-硼杂二环[3.1.0]己-3-基)-1H-吡咯并[2,3-b]吡啶(0.134g,0.55mmol,2当量)、[1,1′-二(二苯基膦基)二茂铁]二氯钯(II)(0.023g,0.028mmol,0.1当量)和碳酸钠(1.1mL 2M水溶液,2.24mmol,8当量)。将该溶液在130℃下加热30min,然后冷却至室温。将该混合物倒入水(15mL)中,用二氯甲烷(3x 15mL)提取。收集有机层,用水(2x 15mL)、盐水(1x 15mL)洗涤,用硫酸镁干燥。浓缩该溶液,用硅胶快速色谱纯化残余物(2英寸x 20mm,己烷至己烷-乙酸乙酯(50∶50)的分级梯度作为洗脱液(每增加1个柱体积,增加5%乙酸乙酯)),得到褐色结晶固体(14.2mg,10.7%)。TLC(硅胶,二氯甲烷-甲醇(90∶10))Rf=0.33。旋光度(丙酮,0.998dm)=+116.5°。在Chiracel OJ-H分析柱上进行HPLC探测,用100%MeOH作为洗脱液(在40℃),在41.3min和50.1min处得到两个峰(96.2∶3.8,S∶R)。
1H NMR(500MHz,丙酮):δ(ppm)3.16-3.21(1H,dd,J=8.5,14.4Hz),3.38(3H,s),3.46-3.50(1H,dd..J=5.9,14.4Hz),3.85(3H,s),4.23-4.26(1H,m),6.65(1H,d,J=3.6Hz),7.15-7.17(2H,m),7.23(1H,d,J=3.0Hz),7.35-7.37(1H,d,J=8.8Hz),7.53-7.57(3H,m),7.70-7.71(2H,d,J=8.0Hz),7.96(1H,bd,J=5.8Hz)8.31(1H,d,J=4.9Hz),11.01(1H,bs)。
13C NMR(500MHz,丙酮):δ(ppm)34.2,34.8,53.9,55.1,69.4,99.5,109.3,113.0,114.4,118.8,123.6,125.8,128.3,129.9,130.1,133.8,137.3,138.3,140.8,143.2,156.8,167.6,170.1.
实施例II。
该实施例描述了用本发明的化合物1、2、3、4和5(参见实施例I)来抑制ROCK1和ROCK2活性。
ROCK-I(h)抑制试验:在25μL的最终反应体积中,用8mMMOPS(pH7.0)、0.2mM EDTA、30μMKEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK、10mM乙酸镁和[γ-32P-ATP](比活性大约为500cpm/pmol,浓度根据需要来定)培养ROCK-I(h,氨基酸17-535)(5-10mU)。通过加入MgATP混合物来引发反应。在室温下培养40分钟之后,通过加入5μL 3%磷酸溶液来终止该反应。然后将10μL反应物点到P30滤垫(filtermat)上,在75mM磷酸中洗涤三次(5分钟),在甲醇中洗涤一次,而后干燥,并闪烁计数。
ROCK-II(h)抑制试验:在25μL的最终反应体积中,用50mMTris(pH7.5)、0.1mM EGTA、30μMKEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK、10mM乙酸镁和[γ-32P-ATP](比活性大约为500cpm/pmol,浓度根据需要来定)培养ROCK-II(h,氨基酸11-552)(5-10mU)。通过加入MgATP混合物来引发反应。在室温下培养40分钟之后,通过加入5μL 3%磷酸溶液来终止该反应。然后将10μL反应物点到P30过滤垫上,在75mM磷酸中洗涤三次(5分钟),在甲醇中洗涤一次,而后干燥,并闪烁计数。
表1显示了用相应的ROCK1和ROCK2抑制试验测定的本发明化合物1、2、3、4和5(参见实施例I)的ROCK1和ROCK2抑制活性(IC50值)。
表1
在上述说明书中提到的所有出版物和专利以引证的方式结合到本文中。尽管本发明已经结合具体优选实施方案加以描述,应该理解请求保护的本发明不应该过度地局限于这样的具体实施方案。实际上,进行本发明所描述的方式的各种修饰都意图包括在下列权利要求的范围之内,这些修饰对相关领域的技术人员是显而易见的。
Claims (35)
其中R1是含有至少两个碳分子的化学基团,其中含有至少两个碳分子的所述化学基团不是吡啶;
其中R2选自H,烷基,取代的烷基和R1;
其中R3选自H,烷基(例如,甲基,乙基,己基,异丙基)和取代的烷基;H;CH3;乙基;己基;异丙基;卤素(例如,氟,氯,溴,碘,砹);OH;含有芳基次级基团的化学部分;含有取代的芳基次级基团的化学部分;含有环脂族次级基团的化学部分;含有取代的环脂族次级基团的化学部分;含有杂环次级基团的化学部分;含有取代的杂环次级基团的化学部分;含有至少一个酯次级基团的化学部分;含有至少一个醚次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和、取代或非取代的脂肪链;含有硫的化学部分;含有氮的化学部分;-OR-,其中R选自:包含芳基次级基团的化学部分;包含取代的芳基次级基团的化学部分;包含环脂族次级基团的化学部分;包含取代的环脂族次级基团的化学部分;包含杂环次级基团的化学部分;包含取代的杂环次级基团的化学部分;具有至少2个碳的直链或支链、饱和或不饱和、取代或非取代的脂肪链;包含至少一个酯次级基团的化学部分;包含至少一个醚次级基团的化学部分;包含硫的化学部分;和包含氮的化学部分;
其中R4选自C,N,S和O;
其中R5选自H,烷基,取代的烷基,单取代的芳基,二取代的芳基和三取代的芳基;
其中R6选自C,N,S和O;
其中R7、R8、R9和R10独立地选自:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R28,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7’选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂肪族,单取代的环脂肪族,二取代的环脂肪族和三取代的环脂肪族;
其中R11、R12、R13和R14独立地选自:H,烷基(例如,取代的烷基)(例如,未取代的烷基),氟烷基,(例如,取代的烷基)(例如,未取代的烷基),氨基烷基,(例如,取代的烷基)(例如,未取代的烷基), 和其取代的和未取代的,和其衍生物;
其中R15、R16、R17和R18独立地选自:C,N,O和S;
其中R19选自:H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基);
其中R20选自:H,烷基(例如,取代的烷基)(未取代的烷基),酮,包含氮的化学部分(例如,取代的烷基)(未取代的烷基),包含氧的化学部分(例如,取代的烷基)(未取代的烷基)和包含硫的化学部分(例如,取代的烷基)(未取代的烷基);
其中R21、R22、R23和R24独立地选自:不存在,H,卤素,CF3,(例如,取代的烷基)(例如,未取代的烷基),(例如,取代的烷基)(例如,未取代的烷基),OH,氟烷基,磺酰胺,砜,OCH3,CH3,SO2R7’,SO2N(R7’)2,OR7’,N(R7’)2,CON(R7’)2,NHCOR7’,NHSO2R7’,烷基,单取代的烷基,二取代的烷基,三取代的烷基;其中R7′选自卤素,H,烷基,单取代的烷基,二取代的烷基,三取代的烷基,芳基,单取代的芳基,二取代的芳基,三取代的芳基,环脂肪族,单取代的环脂肪族,二取代的环脂肪族和三取代的环脂肪族;其中R21、R22、R23和R24中的至多两个可以是氢;和
5.含有一或多种权利要求1所描述化合物的药物制剂。
6.治疗病症的方法,该方法包括:给予患有所述病症的患者有效量的药物制剂,其中所述病症与异常Rho激酶活性有关,其中所述药物制剂含有设计为抑制Rho激酶活性的化合物,其中所述化合物由选自权利要求1所列化合物的化学式来描述。
7.权利要求6的方法,其中所述病症选自:心血管病症,平滑肌相关的病症,肉芽肿病症,急性巨噬细胞介导的疾病和自身免疫病症。
8.权利要求7的方法,其中所述心血管病症选自:绞痛,动脉粥样硬化,中风,脑血管疾病,充血性心力衰竭,冠状动脉病,心肌梗塞,周围血管疾病,狭窄,血管痉挛和高血压症。
9.权利要求8的方法,其中所述脑血管疾病选自:脑血栓形成,脑栓塞和脑出血。
10.权利要求8的方法,其中所述狭窄选自:冠状动脉狭窄,主动脉瓣狭窄,再狭窄和肺动脉狭窄。
11.权利要求8的方法,其中所述血管痉挛选自:脑动脉血管痉挛和冠状动脉血管痉挛。
12.权利要求8的方法,其中所述高血压症选自:肺动脉高压和系统高动脉压。
13.权利要求7的方法,其中所述平滑肌相关的病症选自:青光眼,勃起功能障碍和支气管性哮喘。
14.权利要求7的方法,其中所述肉芽肿病症选自:结节病和韦格氏肉芽肿。
15.权利要求7的方法,其中所述急性巨噬细胞介导的疾病是成人呼吸窘迫综合征。
16.权利要求7的方法,其中所述自身免疫病症选自:类风湿性关节炎,系统性红斑狼疮,多发性脑硬化,过敏性肠综合症和系统性硬化。
17.权利要求7的方法,进一步包括给予治疗所述病症的其它药剂。
18.权利要求6的方法,其中所述患者是人。
19.抑制Rho激酶活性的方法,包括
a.提供靶细胞和包含权利要求1所描述化合物的组合物;和
b.在所述组合物与所述靶细胞结合、从而在所述靶细胞内抑制Rho激酶活性的条件下,将所述靶细胞暴露于所述组合物。
20.权利要求19的方法,其中所述靶细胞是体外细胞。
21.权利要求19的方法,其中所述靶细胞是体内细胞。
22.权利要求19的方法,其中所述靶细胞是体表外细胞。
23.权利要求19的方法,其中所述靶细胞是癌细胞。
26.权利要求25的方法,其中所述靶细胞选自体外细胞、体内细胞、体表外细胞和癌细胞。
28.权利要求27的方法,其中所述炎性病症与异常促炎细胞因子活性有关。
29.权利要求28的方法,其中所述异常促炎细胞因子活性包括IL-17活性。
30.权利要求28的方法,其中所述异常促炎细胞因子活性包括IL-21活性。
31.权利要求28的方法,其中所述异常促炎细胞因子活性包括IRF4活性。
32.权利要求27的方法,其中所述炎性病症选自:关节炎,类风湿性关节炎,牛皮癣关节炎,骨关节炎,变性关节炎,多肌痛风湿症,强直性脊柱炎,反应性关节炎,痛风,软骨钙质沉着病,炎症性关节病,系统性红斑狼疮,多肌炎和肌纤维痛;关节炎的其它类型包括:跟腱炎,软骨发育不全,肢端肥大性关节病,肩关节冻结症,成人斯蒂尔病,鹅足滑囊炎,无血管形成性坏死,Behcet综合症,二头肌腱炎,Blount′s疾病,布鲁杆菌脊椎炎,滑囊炎,跟部滑囊炎,焦磷酸钙二水合物沉积性疾病(CPPD),晶体沉积疾病,Caplan′s综合症,腕管综合征,软骨钙质沉着病,髌骨软化症,慢性滑膜炎,慢性复发性多灶性骨髓炎,Churg-Strauss综合症,Cogan′s综合症,皮质类甾醇诱导的骨质疏松症,肋胸综合症,CREST综合症,冷球蛋白血症,变性性关节病,皮肤肌炎,糖尿病性指硬化症,广泛性特发性骨质增生(DISH),关节盘炎,盘状红斑狼疮,药物诱导的狼疮,Duchenne′s肌肉营养不良,Dupuytren′s挛缩,埃-当二氏综合征,肠病性关节炎,上髁炎,糜烂性炎症性骨关节炎,锻炼诱导的腔隙综合症,Fabry′s疾病,家族性地中海热,Farber′s脂肪肉芽肿病,Felty′s综合症,Fifth′s疾病,平足,异物滑膜炎,Freiberg′s疾病,真菌性关节炎,Gaucher′s疾病,巨细胞性动脉炎,淋病性关节炎,Goodpasture′s综合症,肉芽肿性动脉炎,关节积血,血色沉着病,亨-舍二氏紫癜,乙型肝炎表面抗原疾病,髋发育异常,投手综合症,过度活动综合征,超敏反应血管炎,肥大性骨关节病,免疫复合物型血清病,撞击综合症,Jaccoud′s关节病,幼年强直性脊柱炎,少年型皮肌炎,幼年型类风湿关节炎,川崎氏病,Kienbock′s疾病,股骨头骨骺骨软骨病,莱纳二氏综合症,带状硬皮病,脂肪性皮肤病关节炎,Lofgren′s综合症,Lyme疾病,恶性滑膜瘤,Marfan′s综合症,内侧滑膜皱襞综合征,转移性的癌性关节炎,混合结缔组织病(MCTD),混合的冷球蛋白血症,粘多糖病,多中心的网状组织细胞增生症,多发性骨骺发育不良,支原体性关节炎,肌筋膜疼痛综合症,初生儿狼疮,夏科氏关节,结节性脂膜炎,褐黄病,鹰嘴突滑囊炎,Osgood-Schlatter′s疾病,骨关节炎,骨软骨瘤病,成骨不全,骨软化症,骨髓炎,骨坏死,骨质疏松症,重叠综合征,骨的厚皮性Paget′s疾病,汉-罗二氏综合征,膑骨股骨疼痛综合症,Pellegrini-Stieda综合症,色素沉着绒毛结节性滑膜炎,梨状肌综合症,足底筋膜炎,结节性多动脉炎,多肌痛风湿症,多肌炎,腘窝囊肿,胫后肌腱炎,Pott′s疾病,髌前粘液囊炎,人工关节感染,假性弹力性黄色瘤,牛皮癣关节炎,Raynaud′s现象,反应性关节炎/Reiter′s综合症,反射性交感神经营养不良综合征,复发性多软骨炎,足跟部滑囊炎,风湿热,类风湿病性血管炎,肩轴肌腱炎,骶髂关节炎,沙门氏菌性骨髓炎,结节病,铅中毒性痛风,Scheuermann′s骨软骨炎,硬皮病,脓毒性关节炎,血清阴性关节炎,志贺菌性关节炎,肩手综合症,镰状细胞关节病,干燥综合症,股骨头骨骺滑脱,脊椎狭窄症,椎骨脱离,葡萄球菌性关节炎,Stickler综合症,亚急性皮肤狼疮,Sweet′s综合症,Sydenham′s舞蹈病,梅毒性关节炎,系统性红斑狼疮(SLE),Takayasu′s动脉炎,踝管综合征,网球肘,Tietse′s综合症,一过性骨质疏松症,外伤性关节炎,大转子滑囊炎,结核性关节炎,溃疡性结肠炎的关节炎,未分化型结缔组织综合症(UCTS),荨麻疹性血管炎,病毒关节炎,Wegener′s肉芽肿病,Whipple′s疾病,Wilson′s疾病和耶尔森菌关节炎。
33.权利要求27的方法,其中所述患者是人。
34.权利要求27的方法,进一步包括:共同给予所述患者用于治疗所述炎性病症的治疗剂。
35.权利要求34的方法,其中所述治疗剂选自:改善疾病的抗风湿药物,生物药剂,非甾体抗炎症药物,止痛剂,免疫调节剂,糖皮质激素,IL-1抑制剂,IL-17抑制剂,IL-21抑制剂和金属蛋白酶抑制剂。
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CN109206428A (zh) * | 2017-07-05 | 2019-01-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 吡嗪并二氮*类衍生物及其医药用途 |
CN112972479A (zh) * | 2021-03-08 | 2021-06-18 | 天津医科大学 | Rho抑制剂盐酸法舒地尔的新用途 |
WO2023093787A1 (zh) * | 2021-11-24 | 2023-06-01 | 成都奥睿药业有限公司 | 苯并二氮杂䓬类化合物及其作为Rho激酶抑制剂的应用 |
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CA2780333C (en) | 2009-11-17 | 2016-05-24 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties |
EP2501695B1 (en) * | 2009-11-17 | 2018-08-29 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties |
TW201416354A (zh) * | 2012-07-17 | 2014-05-01 | Boehringer Ingelheim Int | 白三烯生成抑制劑 |
ES2924915T3 (es) | 2012-10-05 | 2022-10-11 | Kadmon Corp Llc | Inhibidores de RHO cinasa |
EP3016950B1 (en) | 2013-07-02 | 2017-06-07 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
ES2633987T3 (es) | 2013-07-02 | 2017-09-26 | Bristol-Myers Squibb Company | Derivados de pirido-carboxamidas tricíclicas como inhibidores de ROCK |
CN103751804B (zh) * | 2014-01-23 | 2015-09-30 | 武汉大学 | 干扰素调节因子4(irf4)基因在冠状动脉粥样硬化性心脏病中的应用 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109206428A (zh) * | 2017-07-05 | 2019-01-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 吡嗪并二氮*类衍生物及其医药用途 |
CN109206428B (zh) * | 2017-07-05 | 2020-11-03 | 中国人民解放军军事科学院军事医学研究院 | 吡嗪并二氮*类衍生物及其医药用途 |
CN112972479A (zh) * | 2021-03-08 | 2021-06-18 | 天津医科大学 | Rho抑制剂盐酸法舒地尔的新用途 |
WO2023093787A1 (zh) * | 2021-11-24 | 2023-06-01 | 成都奥睿药业有限公司 | 苯并二氮杂䓬类化合物及其作为Rho激酶抑制剂的应用 |
Also Published As
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CA2780287C (en) | 2015-03-17 |
EP2501695A2 (en) | 2012-09-26 |
JP5856064B2 (ja) | 2016-02-09 |
JP2016041726A (ja) | 2016-03-31 |
CA2780287A1 (en) | 2011-05-26 |
JP6158891B2 (ja) | 2017-07-05 |
JP2013510903A (ja) | 2013-03-28 |
WO2011062766A2 (en) | 2011-05-26 |
US20120270862A1 (en) | 2012-10-25 |
WO2011062766A3 (en) | 2011-09-29 |
AU2010322287B2 (en) | 2014-04-03 |
AU2010322287A1 (en) | 2012-05-31 |
US8815845B2 (en) | 2014-08-26 |
EP2501695A4 (en) | 2013-04-17 |
ES2703752T3 (es) | 2019-03-12 |
EP2501695B1 (en) | 2018-08-29 |
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