CN103534250A - 用于治疗免疫障碍的被取代的吲哚衍生物 - Google Patents
用于治疗免疫障碍的被取代的吲哚衍生物 Download PDFInfo
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Abstract
Description
本发明涉及被取代的吲哚衍生物、它们的制备方法、它们作为药物的用途和包含它们的药物组合物。
发明背景
药物产品的生物利用度差常常是药学有效成分的局限因素。现在在特定的吲哚衍生物领域通过将相应的母体药物转化成其衍生物而解决了这一问题,与其母体化合物相比,所述衍生物显然具有预料不到的有利作用。
发明概述
具体地,本发明涉及式(I)的化合物或其药学上可接受的盐或水合物,
其中
X是CH或N;
R是H或PO3H2;
R1是H;或C1-4烷基;
R2是H;或C1-4烷基;
R3是H;C1-4烷基;CN;Hal;或OH;且
R4和R5彼此独立地是H或C1-4烷基;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐或水合物,
其中X是CH;
R是PO3H2;
R1是H;
R2是H;或C1-4烷基;
R3是H;或C1-4烷基;且
R4和R5彼此独立地是H;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐或水合物,
其中X是CH;
R是H;
R1是H;
R2是H;或C1-4烷基;
R3是H;或C1-4烷基;且
R4和R5彼此独立地是H;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐或水合物,
其中X是N;
R是PO3H2;
R1是H;
R2是H;或C1-4烷基;
R3是H;且
R4和R5彼此独立地是H;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
在另一个实施方案中,本发明涉及式(I)的化合物或其药学上可接受的盐或水合物,
其中X是N;
R是PO3H2;
R1是H;
R2是H;或C1-4烷基;
R3是H;且
R4和R5彼此独立地是H;或C1-4烷基。
在另一个实施方案中,本发明涉及式(II)的化合物
或其药学上可接受的盐。
在另一个实施方案中,本发明涉及式(III)的化合物
或其药学上可接受的盐或水合物。
在另一个实施方案中,本发明涉及式(IV)的化合物
或其药学上可接受的盐。
附图简要说明
图1显示了磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯的结晶性一水合物(实施例1的一水合物)的X-射线衍射图。
图2显示了实施例1的结晶性一水合物的吸水概况[在50%RH下平衡6h,然后是以10%RH的步进从50%RH-90%RH-0%RH-90%RH-0%RH-50%RH的2个RH循环]。RH=相对湿度。
现有技术
N.Fotouhi等人(EP1,224,181)描述了被取代的吡咯衍生物,其中所述吡咯环上的化学修饰由大量的变量组成,并且还可以含有亚甲基羟基或亚甲基磷酸酯基。
定义
本文所用的术语“卤素“(或卤代)是指氟、溴、氯或碘,特别是氟、氯。
本文所用的术语“烷基”是指具有至多4个碳原子的完全饱和的支链或无支链的烃基。烷基的代表性实例包括、但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等。
本文所用的术语“烷氧基”是指烷基-O-,其中烷基如上文所定义。烷氧基的代表性实例包括、但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基、环丙氧基-、环己氧基等。典型地,烷氧基具有1-4个碳原子。
本文所用的术语“环烃基”是指3-6个碳原子、特别是3-5个碳原子、尤其是3-4个或3个碳原子的饱和或不饱和的单环烃基。
本文所用的术语“盐”是指本发明的化合物的酸加成盐或碱加成盐。“盐”特别地包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留了本发明的化合物的生物学有效性和性质且典型地在生物学上或其它方面不具有不希望的性质的盐。在许多情况中,本发明的化合物能通过存在氨基和/或羧基或与其类似的基团形成酸和/或碱盐。
药学上可接受的酸加成盐可以用无机酸和有机酸形成,例如,乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、chlortheophyllonate、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以自其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以自其衍生得到盐的有机酸包括例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸和磺基水杨酸等。药学上可接受的碱加成盐可以用无机碱和有机碱形成。
可以自其衍生得到盐的无机碱包括例如铵盐和来自元素周期表I-XII族的金属。在某些实施方案中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别适合的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以自其衍生得到盐的有机碱包括例如伯、仲和叔胺、被取代的胺(包括天然存在的被取代的胺)、环状胺、碱性离子交换树脂等。某些有机胺包括异丙基胺、苄星盐(benzathine)、胆碱酸盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
本发明的药学上可接受的盐可以通过常规化学方法由母体化合物、碱性或酸性部分制备。一般而言,可以通过使这些化合物的游离酸形式与化学计量的适宜的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或通过使这些化合物的游离碱形式与化学计量的适宜的酸反应来制备这类盐。这类反应典型地在水中或在有机溶剂中或在两者的混合物中进行。一般而言,如果可行,则非水性介质例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈的使用是合乎需要的。另外的适合的盐的列表可以例如在“Remington's Pharmaceutical Sciences”,第20版,Mack PublishingCompany,Easton,Pa.,(1985)中;以及在Stahl和Wermuth的“Handbook ofPharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,Weinheim,德国,2002)中找到。
本文给出的任何结构式也代表化合物的未标记的形式以及同位素标记的形式。同位素标记的化合物具有本文所给出的结构式所描绘的结构,不同之处是一个或多个原子被具有所选择的原子质量或原子数的原子所代替。可被掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。本发明包括各种同位素标记的本文所定义的化合物,例如,其中掺入了放射性同位素例如3H和14C的那些,或者其中掺入了非放射性同位素例如2H和13C的那些。这类同位素标记的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成象技术如正电子发射断层成象术(PET)或单光子发射计算机断层成象术(SPECT),包括药物或底物组织分布测定法,或者可用于患者的放射性治疗中。特定地,18F或标记的化合物对于PET或SPECT研究而言是特别合乎需要的。同位素标记的本发明的化合物及其前药一般可通过进行流程图中或下文所述的实施例和制备例中所公开的操作、通过用易于得到的同位素标记的试剂替代非同位素标记的试剂来制备。
此外,被更重的同位素、特别是氘(即2H或D)取代可因更大的代谢稳定性而提供某些治疗优势,例如增加的体内半衰期或降低的剂量需求或治疗指数的改善。应当理解的是,在本文的上下文中氘被视为本发明的化合物的取代基。这类更重的同位素、特别是氘的浓度可以用同位素富集因子来定义。本文所用的术语“同位素富集因子”意指给定的同位素的同位素丰度与天然丰度之间的比。如果本发明的化合物上的取代基是所示的氘,则这类化合物对每个指定的氘原子而言具有至少3500(在每个指定的氘原子上52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)或至少6633.3(99.5%氘掺入)的同位素富集因子。
同位素标记的本发明的化合物一般可通过本领域技术人员已知的常规技术或通过与所附的实施例和制备例中所述的方法类似的方法、使用适宜的同位素标记的试剂代替之前使用的非标记的试剂来制备。
本发明的药学上可接受的溶剂合物包括其中结晶溶剂可以被同位素取代、例如D2O、d6-丙酮、d6-DMSO的那些。
本发明的化合物、例如含有能作为氢键供体和/或受体起作用的基团的式(I)的化合物能与适合的共结晶(co-crystal)形成剂一起形成共结晶。这些共结晶可以通过已知的共结晶形成操作由式(I)的化合物制备。这类操作包括研磨、加热、共升华、共熔或使式(I)的化合物在溶液中在结晶条件下与共结晶形成剂接触并分离由此形成的共结晶。适合的共结晶形成剂包括WO2004/078163中所述的那些。因此,本发明还提供了包含式(I)的化合物的共结晶。
如本领域技术人员已知的那样,本文所用的术语“药学上可接受的载体”包括任意和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如,抗细菌剂、抗真菌剂)、等张剂(isotonic agent)、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等以及它们的组合(参见例如Remington's PharmaceuticalSciences,第18版,Mack Printing Company,1990,第1289-1329页)。除非任何常规载体与活性成分不相容,否则其在治疗或药物组合物中的应用将被考虑。
术语本发明的化合物的“治疗有效量”是指将引起个体的生物学或医药响应的本发明化合物的量,所述响应例如是降低或抑制酶或蛋白质活性,或者改善症状、缓解病症、减慢或延迟疾病进展,或者预防疾病等。在一个非限制性实施方案中,术语“治疗有效量”是指当施用于个体时有效地(1)至少部分缓解、抑制、预防和/或改善(i)由蛋白激酶C介导的或(ii)与蛋白激酶C活性相关的或(iii)以蛋白激酶C的(正常的或异常的)活性为特征的病症或障碍或疾病、或者(2)降低或抑制蛋白激酶C活性、或者(3)减少或抑制蛋白激酶C表达的本发明的化合物的量。在另一个非限制性实施方案中,术语“治疗有效量”是指当施用于细胞或组织或非细胞生物学材料或培养基时有效地至少部分降低或抑制蛋白激酶C活性、或者至少部分减少或抑制蛋白激酶C表达的本发明的化合物的量。
本文所用的术语“个体”是指动物。典型地,所述动物是哺乳动物。个体还指例如灵长类动物(例如,人,男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述个体是灵长类动物。在另一些实施方案中,所述个体是人。
本文所用的术语“抑制”是指减轻或抑制给定的病症、症状、或障碍、或疾病,或者显著减少生物学活性或过程的基线活性。
本文所用的术语“治疗”任何疾病或障碍或者任何疾病或障碍的“治疗”在一个实施方案中是指改善所述疾病或障碍(即,减慢或阻止或减轻疾病或其至少一种临床症状的发展)。在另一个实施方案中,“治疗”是指缓解或改善至少一种物理参数,包括可能不是患者可辨别的那些物理参数。在又一个实施方案中,“治疗”是指在身体上(例如可辨别的症状的稳定)、生理上(例如物理参数的稳定)或者这两个方面对所述疾病或障碍进行调节。在又一个实施方案中,“治疗”是指预防或延迟所述疾病或障碍的发作或发生或进展。
如本文所用的那样,如果个体会在生物学上、医学上或生活质量方面从这类治疗中获益,那么该个体是“需要”治疗的。
除非本文另有说明或者上下文清楚地有相反含义,否则本文所用的术语“一个”、“一种”、“该/所述”以及本发明的上下文中(尤其是在权利要求书的上下文中)所使用的类似术语应理解为既包括单数,又包括复数。
除非本文另有说明或者上下文清楚地有相反含义,否则本文所述的所有方法可以以任意适合的顺序进行。本文提供的任意和所有实施例或举例性语言(例如,“例如”、“如”)的使用仅仅旨在更好地举例说明本发明,不对在另外部分请求保护的本发明的范围构成限制。
制备方法
本发明的化合物可以通过下面提供的方法制备,例如通过以下方法制备:将式(Va)的马来酰亚胺转化成式(Vb)的醇,例如使用甲醛,在存在或不存在溶剂或碱例如碳酸钾的情况下,并且任选地在该反应前根据现有技术的反应引入保护基例如叔丁氧基羰基,例如当式(Va)的化合物中存在游离的和反应性的氨基时,其中变量X、R、R1、R2、R3、R4和R5具有针对式(I)所提供的含义。
式(Vb)的醇可以任选地被转化成反应性酯,例如使用三氯甲基乙腈和适宜的碱例如DBU转化成反应性酯,然后可以与适宜的磷酸化试剂例如磷酸二叔丁酯在存在或不存在适宜的溶剂例如非质子溶剂例如乙腈的情况下反应,然后可以被水解,例如用三氟乙酸、例如在二氯甲烷或1,2-二氯乙烷中水解,得到终产物Vc。
或者,式(Vb)的醇可以直接与磷酸酯、例如与磷酸二叔丁酯、例如在Mitsunobu反应条件下反应,得到磷酸酯,然后可以将其水解,例如用三氟乙酸、例如在二氯甲烷中水解,得到终产物Vc。
实验部分:
就未具体描述的原料的制备而言,所述化合物是已知的或可以类似于本领域已知的方法或如下文所述制备。
下面的实施例用于举例说明本发明,不对本发明具有任何限制作用。
缩写:
bs 宽单峰
d 双峰
DMSO 二甲亚砜
d.n. 归一化的剂量
EtOAc 乙酸乙酯
Et2O 乙醚
FCC 闪柱色谱法
MeOH 甲醇
MS 质谱法
m 多重峰
NMR 核磁共振
p.o. 口服
r.t. 室温
s 单峰(singulet)
t 三重峰
TFA 三氟乙酸
TLC 薄层色谱法
UPLC 超高压液相色谱法
NMR光谱是用BrukerAvance DPX400光谱仪在室温下记录的。
所用的LCMS方法:
LC方法1(Rt (1) ):保留时间(Rt)是用连接Waters ZQ2000质谱仪、采用Waters BEH C181.7μm2.1×50mm柱的Waters Acquity UPLC系统获得的(流速=0.7ml/min;检测240-350nm;DAD),应用梯度(溶剂A:水+0.1%甲酸,溶剂B:乙腈;t=0min:99%A,1%B;t=1min98%A,2%B;t=2.25min1%A,99%B;t=4.5min0%A,100%B)。
LC方法2(Rt (2) ):保留时间(Rt)是用带有Express柱C182.7μm,30×2.1mm(Supelco)的Agilent HPLC系统获得的,应用梯度(H2O+0.05%甲酸+3.75mM乙酸铵)/(CH3CN+0.04%甲酸)90/10-5/95,1.7min,溶剂流速1.2mL/min,然后5/95,0.7min,溶剂流速1.4mL/min,烘箱温度40℃。检测方法UV214-350nm–MS。
纯化方法:
制备型反相Gilson HPLC
柱SunFire制备型C18OBD5μm,30×100mm,来自Waters,流动相H2O+0.1%TFA和乙腈+0.1%TFA。检测方法UV220-400nm
实施例1:磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯
在0℃、氩气下,向7-{1-[1-(二叔丁氧基-磷酰基氧基甲基)-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯(1.90g,2.42mmol)在1,2-二氯乙烷(50mL)中的溶液中加入TFA(8.27g,72.5mmol)。将反应混合物在0℃、氩气下搅拌3.5h,直到UPLC-MS显示原料已经完全转化。用1,2-二氯乙烷(50mL)稀释反应混合物,减压浓缩,得到粗产物,为红色固体。将粗反应产物溶于MeOH,缓慢地减压浓缩,直到开始出现结晶。加入戊烷,过滤出固体,用Et2O洗涤。通过将粗产物混悬于DMSO进一步纯化,然后声处理30min。过滤出固体,用Et2O洗涤,在高真空下干燥(<1mm Hg),得到标题化合物,为深红色固体。1H-NMR(400MHz,DMSO-d6):12.10(s,1H),8.08(d,1H),7.65-7.61(m,2H),7.44(t,1H),7.20(s,1H),7.06(t,1H),6.74(d,1H),6.43(t,1H),6.00(d,1H),5.29(d,2H),3.87-3.01(m,6H),2.37(s,3H),0.97-0.62(m,4H)。31P-NMR(162MHz,DMSO-d6):-6.0。LCMS:[M+1]+=574.0,Rt(1)=1.77min.,Rt(2)=0.71min。
7-{1-[4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯的制备
在r.t.、氩气下,向7-{1-[1-羟基甲基-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯(7.30g,12.30mmol)在乙腈(60mL)中的溶液中滴加DBU(0.374g,0.371mL,2.46mmol)在三氯乙腈(17.8g,12.3mL,123mmol)中的溶液。将反应混合物在r.t.搅拌5h,直到TLC(SiO2,EtOAc/环己烷6:4)显示完全转化。减压蒸发反应混合物至干,将残余物混悬于乙腈(60mL)。加入磷酸二叔丁酯(3.36g,15.99mmol),将反应混合物在r.t.、氩气下搅拌约3.5h,直到TLC(SiO2,EtOAc/环己烷6:4)显示反应完全。减压浓缩反应混合物,使残余物在EtOAc与水之间分配。分离各层,用水洗涤有机相(5次)。用Na2SO4干燥有机相,减压浓缩,得到红色固体。通过FCC(Biotage SP4TM系统,SiO2,环己烷/EtOAc20:80)纯化粗产物,得到标题化合物,为红色固体。1H-NMR(400MHz,DMSO-d6):12.03(s,1H),8.08(d,1H),7.70-7.65(m,2H),7.47(t,1H),7.11(s,1H),7.11-7.07(m,1H),6.77(d,1H),6.44(t,1H),5.97(d,1H),5.39(d,1H),3.49-3.08(m,6H),2.39(s,3H),1.45(s,18H),1.41(s,9H),0.87-0.56(m,4H)。31P-NMR(162MHz,DMSO-d6):-12.1。LCMS:[M+1]+=786.4,Rt(1)=2.53min.,Rt(2)=1.62min。
7-{1-[1-羟基甲基-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯的制备
在r.t.、氩气下,向7-{1-[4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯(3.00g,5.32mmol)在MeOH(25mL)中的溶液中加入37%甲醛水溶液(9.5g,8.72mL,117mmol)。将反应混合物加热至85℃,搅拌4h。将反应混合物在持续搅拌下冷却至r.t.,过滤。用冰-水洗涤固体,在高真空下干燥(<1mmHg),得到标题化合物,为深红色晶体。1H-NMR(400MHz,DMSO-d6):11.96(s,1H),8.05(s,1H),7.69-7.64(m,2H),7.47(t,1H),7.12-7.06(m,2H),6.76(d,1H),6.42(t,1H),6.01(d,1H),5.00(d,2H),3.49-3.10(m,6H),2.39(s,3H),1.41(s,9H),0.89-0.57(m,4H)。LCMS:[M]+=593.7,Rt(1)=2.34min。
7-{1-[4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯的制备
在r.t.、氩气下,将二碳酸二叔丁酯(2.77g,10.8mmol)和三乙胺(2.18g,21.6mmol)加入到3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-吡咯-2,5-二酮(5.0g,10.8mmol)在THF(50mL)中的溶液中。将反应混合物搅拌16h,减压浓缩。使残余物在饱和NH4Cl水溶液与CH2Cl2之间分配。分配各层,用CH2Cl2萃取水层。用饱和NaHCO3水溶液和盐水洗涤合并的有机层,用无水Na2SO4干燥,减压浓缩,得到标题化合物,为橙色固体。1H-NMR(400MHz,DMSO-d6):11.88(s,1H),11.15(s,1H),8.00(d,1H),7.68-7.65(m,2H),7.46(t,1H),7.09(t,1H),7.06(s,1H),6.73(d,1H),6.41(t,1H),6.01(d,1H),3.48-3.16(m,6H),2.38(s,3H),1.40(s,9H),0.87-0.54(m,4H)。LCMS:[M+1]+=563.9,Rt(1)=3.51min,Rt(1)=2.36min.,Rt(2)=1.37min.
实施例2:3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-1-羟基甲基-4-(7-甲基-1H-吲哚-3-基)-吡咯-2,5-二酮
在0℃、氩气下,向7-{1-[1-羟基甲基-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-1H-吡咯-3-基]-异喹啉-3-基}-4,7-二氮杂-螺[2.5]辛烷-4-甲酸叔丁酯(500mg,0.842mmol)在1,2-二氯乙烷(5mL)中的溶液中加入TFA(1.44g,0.973mL,12.7mmol)。将反应混合物在0℃、氩气下搅拌1h,之后加入另外的TFA(0.768g,0.52mL,6.74mmol)。在0℃下持续搅拌1.5h。减压蒸发反应混合物至干,使粗产物从MeOH中结晶,得到标题化合物,为红色固体(TFA盐),为深红色固体。1H-NMR(400MHz,DMSO-d6):12.01(d,1H),9.06(bs,2H),8.11(d,1H),7.71-7.66(m,2H),7.51(t,1H),7.27(s,1H),7.14(t,1H),6.77(d,1H),6.45-6.39(m,2H),5.92(d,1H),5.00(d,2H),3.84-3.54(m,6H),2.39(s,3H),0.96-0.67(m,4H).LCMS:[M+1]+=493.7,Rt(1)=1.84min.
实施例3:3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-吡咯-2,5-二酮
标题化合物的合成已经在WO03082859中的实施例69中描述。
实施例4:磷酸单{3-(1H-吲哚-3-基)-4-[2-(4-甲基-哌嗪-1-基)-喹唑啉-4-基]-2,5-二氧代-2,5-二氢-吡咯-1-基甲基}酯
在氩气下,将磷酸二叔丁酯氯甲酯(1.24g,4.81mmol)和Cs2CO3(3.14g,9.63mmol)加入到3-(1H-吲哚-3-基)-4-[2-(4-甲基-哌嗪-1-基)-喹唑啉-4-基]-吡咯-2,5-二酮(2.0g,4.01mmol)在丙酮(40mL)中的溶液中。将反应混合物在50℃下在氩气下搅拌16h,然后减压浓缩。使残余物在EtOAc与饱和NH4Cl水溶液之间分配,分离各层,用无水Na2SO4干燥有机层。减压浓缩,得到粗产物,为红色泡沫。如上文所述通过反相Gilson HPLC纯化粗产物。真空浓缩所需的级分后,得到红色固体。UPLC-MS显示叔丁酯基已经部分裂解。将由此得到的混合物(280mg)溶于1,2-二氯乙烷(4mL)和乙腈(2.0mL)的混合物。加入TFA(145mg,98μL,1.27mmol),将得到的溶液在0℃、氩气下搅拌3h,此时UPLC-MS显示原料已经全部转化。用1,2-二氯乙烷(4.0mL)稀释反应混合物,减压浓缩,得到粗产物,为红色固体。将粗反应产物溶于MeOH(3mL),缓慢地减压浓缩,直到开始出现结晶。过滤出晶体,用Et2O和戊烷洗涤,得到标题化合物,为橙色固体。1H-NMR(400MHz,DMSO-d6):12.27(s,1H),8.21(s,1H),7.72-7.66(m,2H),7.58(d,1H),7.40(d,1H),7.14(t,1H),7.02(t,1H),6.65(t,1H),6.24(d,1H),5.34(d,2H),4.14-3.72(bs,4H),3.00-2.73(bs,4H),2.60(s,3H)。31P-NMR(162MHz,DMSO-d6):-2.7。LCMS:[M]+=548.6,Rt(1)=1.72min.,Rt(2)=0.73min.
实施例1的化合物的结晶性物质的制备:
将2克磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯(实施例1)分散于800ml乙醇和200ml水的混合物中。将混悬液在室温下搅拌3天。此后,通过烧结玻璃滤器过滤所述混悬液,在标准大气流中干燥得到的晶体。向1克这些晶体中加入4ml80%乙醇/20%水(体积/体积)溶液,在大气压下将得到的混合物蒸发至干,得到实施例1的一水合物。
图1
上述结晶性一水合物的X-射线衍射图如图1中所示,在表1中对2θ角记录峰。
表1.实施例1的结晶性一水合物的X-射线衍射图的主要峰
因此,在另一个实施方案中,本发明提供了磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯、尤其是一水合物的晶形,其优选具有X-射线粉末衍射图,该衍射图具有至少1个、优选2个、更优选3个、甚至更优选4个、尤其是5个、最优选所有折射角2θ如下的峰:9.525、16.356、17.091、18.005、20.859(各自±0.2),尤其是如图1中所示的峰。
表2.无定形和结晶性的实施例1化合物的化学稳定性
表概述了用DSC(差示扫描量热法)和TGA(热重分析)观察到的热事件。
温度范围[℃] | 事件 |
30-125 | 失水 |
225-265 | 降解 |
图2
实施例1的结晶性一水合物的吸水概况如图2所示。应用下列湿度暴露:在50%RH平衡6h,然后是以10%RH的步进从50%RH-90%RH-0%RH-90%RH-0%RH-50%RH的2个RH循环。(RH=相对湿度)。
生物药剂学部分
游离形式或药学上可接受的盐或水合物形式的本发明的化合物例如式(I)、(II)、(III)或(IV)的化合物等在下面的试验、例如体外和体内试验中显示出有价值的药理学性质,因此适合用于疗法。
A.体外
1.蛋白激酶Cα和θ测定法
根据下列方法测试了本发明的化合物对不同PKC同种型的活性。所有测定均在384孔微量滴定板中进行。每个测定板含有40种测试化合物的8-点系列稀释液以及作为参比化合物的星孢素的两个16点系列稀释液+16个高-和16个低的对照。液体处理和孵育步骤是在装配有InnovadyneNanodrop Express的自动化工作站上进行的。
测定法是如下制备的:加入50nL/孔的在90%DMSO中的化合物溶液。通过逐步添加4.5μl/孔的2x肽/ATP-溶液和4.5μl/孔的2x酶溶液启动激酶反应。在激酶反应过程中试剂的终浓度为:50mM HEPES,pH7.5,1mM DTT,0.02%Tween20,0.02%BSA,0.6%DMSO,10mMβ-磷酸甘油和10μM原钒酸钠。PKC-α和PKC-θ测定中所用的肽底物是Dy495-X5-ME-Mpr-RFARKGSLRQKNV-COOH。两种酶都是在昆虫细胞中表达的人重组蛋白(Invitrogen AG,Basel,瑞士)。特别针对各激酶测定调整了其它组分:PKC-α:12pM酶,17μM ATP,1μM肽底物,7mM MgCl2,0.2mM CaCl2。PKC-θ:29pM酶,70μM ATP,1μM肽底物,7mM MgCl2,0.2mM CaCl2。
将激酶反应在30℃下孵育60分钟,随后通过添加16μl/孔的终止溶液(100mM HEPES pH7.5、5%DMSO、0.1%Caliper包被试剂、10mMEDTA和0.015%Brij35)终止激酶反应。
将具有终止的激酶反应的板转入Caliper LC3000工作站以便读取。使用Caliper微流体泳动率变动技术(Caliper microfluidic mobility shifttechnology)分离磷酸化的和未磷酸化的肽,并且根据形成的磷酸-肽的量计算激酶活性。
测定 | 实施例1 | 实施例3 |
PKCα(以nM计的IC50) | 1677 | 0.4 |
PKCθ(以nM计的IC50) | 462 | 0.2 |
上下文中所示的试验结果可以支持本发明的化合物的前药概念。
2.骨髓细胞增殖(BM)测定法
将来自CBA小鼠的骨髓细胞(在平底组织培养微量滴定板中2.5×104个细胞/孔)在100μL含有10%FCS、100U/mL青霉素、100μg/mL链霉素(Gibco BRL,Basel瑞士)、50μM2-巯基乙醇(Fluka,Buchs,瑞士)、WEHI-3条件培养基(7.5%v/v)和L929条件培养基(3%v/v)(作为生长因子来源)和系列稀释的化合物的RPMI培养基中孵育。对每种测试化合物一式两份地进行7个3-倍稀释步骤。孵育4天后,加入1μCi3H-胸苷。在另外的5-小时孵育期后,收获细胞,根据标准操作测定掺入的3H-胸苷。如下制备条件培养基。使WEHI-3细胞(ATCC TIB68)和L929细胞(ATCC CCL1)在RPMI培养基中分别生长至汇合达4天和1周。收获细胞,在相同的培养烧瓶中重新混悬在含有1%FCS(Schreier和Tess1981)的培养基C中(对于WEHI-3细胞)和RPMI培养基中(对于L929细胞),孵育2天(WEHI-3)或1周(L929)。收集上清液,通过0.2μm过滤,以等分试样贮存在-80℃下。将不具有测试化合物并且不具有WEHI-3和L929上清液的培养物用作低对照值。从所有的值中减去低对照值。不具有任何样品的高对照值被用作100%增殖。计算样品的抑制百分比,并且测定50%抑制所需的浓度(IC50值)。
实施例1 | 实施例3 | |
以nM计的IC50 | 6741±1117 | 1672±256 |
B.体内:
实施例1的化合物的施用
将单剂量的实施例1的化合物(3.0mg/kg)口服施用于3只雄性比格(Beagle)犬。将化合物1以结晶性一水合物形式在甲基纤维素(0.5%):Tween80(1%)(90:10)中的水性混悬液的形式给予。通过静脉穿刺以规律的时间间隔采血,对样片进行分析达至多24小时的时间。随时间推移定量评价实施例1、2和3的化合物,结果列表如下:
时间(h) | 化合物1(nM) | 化合物2(nM) | 化合物3(nM) |
0 | - | - | - |
0.083 | - | 10.0 | 15.0 |
0.25 | 3.1 | 39.6 | 166.7 |
0.5 | 1.1 | 31.3 | 757.4 |
0.75 | - | 19.1 | 1198.0 |
1 | - | 6.3 | 1308.3 |
2 | - | 7.7 | 1118.6 |
3 | - | 1.0 | 958.9 |
4 | - | - | 762.0 |
7 | - | - | 403.1 |
24 | - | - | 67.9 |
在口服给予实施例1的化合物后化合物1、2和3的关键药动学参数(平均值±标准差(n=3))。
参数 | 化合物1 | 化合物2 | 化合物3 |
Cmaxd.n.(nM) | - | 15±8 | 441±165 |
Tmax(h) | - | 0.4±0.1 | 0.9±0.1 |
AUC d.n.(nM·h) | - | 低 | 3350±1402 |
实施例3的化合物的施用
将实施例3的化合物以在硬胶囊中的单乙酸盐的形式口服施用于6只禁食的雄性比格犬。给予100mg/犬的标称剂量,得到8.9–11.3mg/kg的剂量(犬的体重在8.9–11.3kg范围内)。通过静脉穿刺采血,进行采样长达32h。针对化合物3进行了生物分析测定,并且将其列表如下:
时间(h) | 化合物3(nM) |
0 | - |
0.25 | 177 |
0.5 | 936 |
1 | 2155 |
2 | 2548 |
3 | 2000 |
4 | 1898 |
6 | 1486 |
8 | 1238 |
24 | 276 |
32 | 116 |
在如上所述的口服给药后化合物3的关键药动学参数(平均值或范围)。
参数 | 化合物3 |
Cmaxd.n.(nM) | 323 |
Tmax(h) | 0.5-2 |
AUC d.n.(nM·h) | 2790 |
物理化学部分
溶解度评价
在室温下实施例1化合物在模拟胃液和模拟肠液中的溶解度
实施例3的化合物(游离形式/乙酸盐形式)在模拟胃液中的溶解度:
稳定性评价
在37℃下实施例1的化合物在胃和肠模拟液中的稳定性:
在37℃下实施例3的化合物(游离形式/乙酸盐形式)在胃和肠模拟液中的稳定性:
效用部分
本发明的化合物典型地用于预防或治疗PKC、或其它激酶的介体(mediator)在其中发挥作用的障碍或疾病,例如由T淋巴细胞、B淋巴细胞、肥大细胞、嗜酸性粒细胞或心肌细胞(cardiomyocyte)介导的疾病或障碍,因此典型地适用于器官或组织的同种异体移植物或异种移植物的急性或慢性排斥反应、移植物抗宿主病、宿主抗移植物病(host-versus-graftdisease)、动脉粥样硬化、脑梗死、由血管损伤如血管成形术引起的血管闭塞、再狭窄、纤维化(尤其是肺纤维化,还有其它类型的纤维化,例如肾纤维化)、血管生成、高血压、心力衰竭、慢性阻塞性肺疾病、CNS疾病如阿尔茨海默病或肌萎缩性侧索硬化、癌症、感染性疾病如AIDS、败血症性休克或成人型呼吸窘迫综合征、缺血/再灌注损伤例如心肌梗死、中风、肠缺血(gut ischemia)、肾衰竭或失血性休克(hermorrhage shock),或外伤性休克。
本发明的化合物还用于治疗和/或预防急性或慢性炎性疾病或障碍或者自身免疫性疾病例如结节病、纤维化肺、特发性间质性肺炎、阻塞性气道疾病,包括诸如哮喘、内源性哮喘、外源性哮喘、粉尘性哮喘、特别是慢性或慢性顽固性哮喘(例如迟发性哮喘(late asthma)和气道高反应性(airway hyperreponsiveness))等病症、支气管炎,包括支气管哮喘、小儿哮喘(infantile asthma)、类风湿性关节炎、骨关节炎、系统性红斑狼疮、肾病综合征狼疮、桥本甲状腺炎、多发性硬化、重症肌无力、I型糖尿病和与其相关的并发症、II型成年型糖尿病、眼色素层炎、肾病综合征、类固醇依赖性(steroid dependent)和类固醇抗性(steroid-resistant)肾病、掌跖脓疱病、变应性脑脊髓炎、肾小球肾炎、银屑病、银屑病关节炎、特应性湿疹(特应性皮炎)、变应性接触性皮炎、刺激性接触性皮炎和另外的湿疹性皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、红斑、皮肤嗜酸粒细胞增多(cutaneouseosinophilias)、痤疮、斑形脱发、嗜酸细胞性筋膜炎(eosinophilic fasciitis)、动脉粥样硬化、结膜炎、角膜结膜炎、角膜炎、春季结膜炎、与贝赫切特病相关的眼色素层炎、疱疹性角膜炎、圆锥形角膜、舍格伦综合征(Sjoegren’s syndrome)、角膜上皮营养不良(dystorphia epithelialiscorneae)、角膜白斑、眼天疱疮、莫伦溃疡、巩膜炎、格雷夫斯眼病、重度眼内炎症、粘膜或血管的炎症例如白三烯B4-介导的疾病、胃溃疡、由局部缺血性疾病和血栓形成导致的血管损伤、心脏肥大、缺血性肠病、炎症性肠病(例如局限性回肠炎或溃疡性结肠炎)、坏死性小肠结肠炎、肾脏疾病,包括间质性肾炎、古德帕斯丘综合征、溶血性尿毒症综合征和糖尿病肾病、选自多发性肌炎、吉-巴综合征、梅尼埃病和神经根病的神经疾病、胶原疾病,包括硬皮病、韦格纳肉芽肿(Wegener's granuloma)和舍格伦综合征、慢性自身免疫性肝疾病,包括自身免疫性肝炎、原发性胆汁性肝硬化和硬化性胆管炎)、部分肝切除(partial liver resection)、急性肝坏死(例如由毒素、病毒性肝炎、休克或缺氧导致的坏死)、肝硬化、暴发型肝炎、脓疱性银屑病、贝赫切特病、慢性活动性肝炎(active chronic hepatitis)、埃文斯综合征、花粉症、特发性甲状旁腺功能减退、艾迪生病、自身免疫性萎缩性胃炎、类狼疮肝炎、肾小管间质性肾炎(tubulointerstitial nephritis)、膜性肾炎或风湿热。
本发明的化合物还可用于治疗肿瘤,例如乳癌、泌尿生殖系统癌症、肺癌、胃肠癌、表皮样癌、黑素瘤、卵巢癌、胰腺癌、神经母细胞瘤、头和/或颈癌或膀胱癌,或者更广的含义的肾癌、脑癌或胃癌;特别是(i)乳癌;表皮样瘤,例如表皮样头和/或颈肿瘤或口腔肿瘤;肺肿瘤,例如小细胞或非小细胞肺肿瘤;胃肠肿瘤,例如结肠直肠肿瘤;或泌尿生殖系统肿瘤,例如前列腺肿瘤(尤其是激素-难治性前列腺肿瘤);或(ii)使用其它化疗剂的治疗难治的增殖性疾病;或(iii)由于多药抗药性导致的使用其它化疗剂的治疗难治的肿瘤。
本发明的化合物还可用于治疗血液和淋巴系统的肿瘤(例如霍奇金病、非霍奇金淋巴瘤、伯基特淋巴瘤、与AIDS有关的淋巴瘤、恶性免疫增殖性疾病(malignant immunoproliferative disease)、多发性骨髓瘤和恶性浆细胞瘤(malignant plasma cell neoplasm)、淋巴性白血病、急性或慢性髓性白血病、急性或慢性淋巴细胞白血病、单核细胞白血病、其它指定细胞类型的白血病、未指定细胞类型的白血病、其它的和未指定的淋巴样组织、造血组织和相关组织的恶性瘤,例如弥漫型大细胞性淋巴瘤、T-细胞淋巴瘤或皮肤T-细胞淋巴瘤)。骨髓癌(myeloid cancer)包括例如急性或慢性髓性白血病。
当提到肿瘤、肿瘤疾病、癌或癌症时,也作为替代选择地或另外地指起始器官或组织中和/或任意其它部位中的转移灶(metastasis),无论肿瘤和/或转移灶的部位如何。
优选地,本发明的化合物特别用于预防和/或治疗由T淋巴细胞介导的疾病或障碍,例如器官或组织的同种异体移植物或异种移植物的急性或慢性排斥反应、移植物抗宿主病、宿主抗移植物病、多发性硬化、银屑病或类风湿性关节炎。
药物产品的生物利用度差常常是药学活性成分的限制因素。此外,生物利用度可能是种属依赖性的。例如,在小鼠、大鼠或狗等中良好吸收的药物可能无法转化成在人中的恰当生物利用度。本发明提供了式(I)的前药化合物,其产生就其母体化合物而言良好的生物利用度,特别是在人中。例如,如实验部分中所示(体内部分B),实施例1的化合物例如被转化成实施例3的化合物,其在施用后短时间内(例如在约1小时后)可以在血液中作为主要组分被检测到,从而证明了向母体化合物的有效的和有利的转化。
就上述用途而言,所需的剂量当然将取决于施用方式、待治疗的具体病症和所需的效果。一般而言,表明以约0.02-25mg/kg体重的日剂量全身性施用时获得了令人满意的结果。在较大的哺乳动物例如人中,适用的日剂量可以在约0.2mg至约2g范围内,该日剂量可以方便地例如以每天不超过4次的分剂量施用或以缓释形式施用。对于口服施用而言,适合的单位剂型可以包含约0.1-500mg活性成分。
本发明的化合物可以通过任何常规途径施用,特别是肠胃外施用,例如以可注射的溶液或混悬剂的形式肠胃外施用;肠道施用,例如口服施用,例如以片剂或胶囊剂的形式肠道施用;局部施用,例如以洗剂、凝胶剂、软膏剂或乳膏剂的形式局部施用;或以鼻用形式或栓剂形式施用。局部施用可以例如是施用于皮肤。另外的局部施用形式可以是施用于眼。包含本发明的化合物以及至少一种药学上可接受的载体或稀释剂的药物组合物可以用常规方法通过与药学上可接受的载体或稀释剂混合来制备。
本发明的化合物可以以游离形式或以药学上可接受的盐形式或以水合物形式(例如上文所示的那些)施用。这类盐或水合物可以用常规方式制备,并且可以典型地显示出与游离化合物相同等级的活性。
根据上文所述的内容,本发明还提供了:
(1)本发明的化合物或其药学上可接受的盐或水合物,其用作药物;
(2)本发明的化合物或其药学上可接受的盐或水合物,其用作PKC抑制剂,例如用于上文所述的特定适应症中的任意一种;
(3)药物组合物,例如其用于上文所述的特定适应症中的任意一种,包含本发明的化合物或其药学上可接受的盐或水合物,以及一种或多种药学上可接受的稀释剂或载体;
(4)在需要其的个体中治疗或预防PKC活化在其中发挥作用或牵涉于其中的疾病或病症、例如治疗上文所述的特定适应症中的任意一种的方法,其包括给所述个体施用有效量的本发明的化合物或其药学上可接受的盐或水合物;
(5)本发明的化合物或其药学上可接受的盐或水合物在制备药剂中的用途,所述药剂用于治疗或预防PKC活化在其中发挥作用或牵涉于其中的疾病或病症;例如上文所述的那些。
组合
本发明的化合物可以作为单独的活性成分施用或者与例如作为佐剂的其它药物(例如在免疫抑制或免疫调节方案中)或其它抗炎剂(例如用于治疗或预防同种异体移植物或异种移植物的急性或慢性排斥反应或者炎性或自身免疫性障碍)、化疗剂或抗感染药例如抗病毒药、例如抗逆转录病毒药或抗生素联合施用。
例如,本发明的化合物可以与以下物质组合使用:钙调磷酸酶抑制剂,例如环孢素A、ISA247或FK506;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟基乙基)-雷帕霉素、CCI779、ABT578、TAFA-93、AP23573、AP23464、AP23841、biolimus-7或biolimus-9;具有免疫抑制性质的子囊霉素,例如ABT-281、ASM981等;皮质类固醇;环磷酰胺;硫唑嘌呤;甲氨蝶呤;来氟米特;咪唑立宾;麦考酚酸或其盐;麦考酚酸吗乙酯;15-脱氧精胍菌素或其免疫抑制同系物、类似物或衍生物;PKC抑制剂,例如WO02/38561或WO03/82859中所公开的那些,例如实施例56或70的化合物;S1P受体激动剂或调节剂,例如任选磷酸化的FTY720或其类似物,例如任选磷酸化的2-氨基-2-[4-(3-苄基氧基苯基硫基)-2-氯苯基]乙基-1,3-丙二醇或1-{4-[1-(4-环己基-3-三氟甲基-苄基氧基亚氨基)-乙基]-2-乙基-苄基}-氮杂环丁烷-3-甲酸或其药学上可接受的盐;免疫抑制单克隆抗体,例如针对白细胞受体的单克隆抗体,例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD52、CD58、CD80、CD86或它们的配体;其它免疫调节化合物,例如具有至少一部分CTLA4胞外结构域的重组结合分子或其突变体,例如与非CTLA4蛋白序列结合的至少CTLA4的胞外部分或其突变体,例如CTLA4Ig(例如,命名为ATCC68629)或其突变体,例如LEA29Y;粘着分子抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂,例如那他珠单抗或抗趋化因子抗体或抗趋化因子受体抗体,或低分子量趋化因子受体拮抗剂,例如抗MCP-1抗体。
本发明的化合物还可以与其它抗增殖剂组合使用。这类抗增殖剂包括、但不限于:
(i)芳香酶抑制剂,例如类固醇,尤其是依西美坦和福美司坦,和特别是非类固醇,尤其是氨鲁米特、伏罗唑、法曲唑、阿那曲唑,和特别尤其是来曲唑;
(ii)雄激素药,例如他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬;
(iii)拓扑异构酶I抑制剂,例如拓扑替康、伊立替康、9-硝基喜树碱和大分子喜树碱轭合物PNU-166148(WO99/17804中的化合物A1);
(iv)拓扑异构酶II抑制剂,例如蒽环类多柔比星(包括脂质体制剂,例如CAELYXTM)、表柔比星、伊达比星和奈莫柔比星、蒽醌类米托蒽醌和洛索蒽醌,以及鬼臼毒素类依托泊苷和替尼泊苷;
(v)微管活性剂,例如紫杉烷类紫杉醇和多西他赛、长春花生物碱例如长春碱、尤其是硫酸长春碱、长春新碱、尤其是硫酸长春新碱和长春烯碱、淅皮海绵内酯和埃坡霉素类,例如埃坡霉素B和D;
(vi)烷化剂,例如环磷酰胺、异环磷酰胺和美法仑;
(vii)组蛋白脱乙酰酶抑制剂;
(viii)法尼基转移酶抑制剂;
(x)MMP抑制剂;
(xi)mTOR抑制剂;
(xii)抗肿瘤抗代谢物,例如5-氟尿嘧啶、替加氟、卡培他滨、克拉屈滨、阿糖胞苷、磷酸氟达拉滨、氟尿苷(fluorouridine)、吉西他滨、6-巯基嘌呤、羟基脲、甲氨蝶呤、依达曲沙和这些化合物的盐,还有ZD1694(RALTITREXEDTM)、LY231514(ALIMTATM)、LY264618(LOMOTREXOLTM)和OGT719;
(xiii)铂化合物,例如卡铂、顺铂和奥沙利铂;
(xiv)降低蛋白激酶活性的化合物和另外的抗血管生成化合物,例如(i)降低血管内皮生长因子(VEGF)、(b)表皮生长因子(EGF)、c-Src、蛋白激酶C、血小板衍生生长因子(PDGF)、Bcr-Abl酪氨酸激酶、c-kit、Flt-3和胰岛素样生长因子I受体(IGF-IR)和细胞周期蛋白依赖性激酶(CDK)活性的化合物;(ii)伊马替尼、米哚妥林、IressaTM(ZD1839)、CGP75166、伐他拉尼、ZD6474、GW2016、CHIR-200131、CEP-7055/CEP-5214、CP-547632和KRN-633;(iii)沙立度胺(THALOMID)、塞来考昔(Celebrex)、SU5416和ZD6126;
(xv)戈那瑞林(gonadorelin)激动剂,例如阿巴瑞克、性瑞林和醋酸性瑞林;
(xvi)抗雄激素药,例如比卡鲁胺(CASODEXTM);
(xvii)bengamides;
(xviii)二膦酸类,例如依曲膦酸(etridonic acid)、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸;
(xix)抗增殖抗体,例如曲妥珠单抗(HerceptinTM)、曲妥珠单抗-DM1、厄洛替尼(TarcevaTM)、贝伐珠单抗(AvastinTM)、利妥昔单抗PRO64553(抗-CD40)和2C4抗体;
(xxi)他汀类药物(statins)。
可以从现行版本的标准目录“默克索引(The Merck Index)”或从数据库例如Patents International(例如IMS World Publications)得到由代码号、通用名或商品名确定的活性剂的结构。
根据上文,本发明还提供了:
(6)上文所定义的方法,其包括共同施用、例如同时和相继施用治疗有效量的a)式I的化合物或其药学上可接受的盐或水合物和b)第二药物物质,所述第二药物物质例如用于上文所述的特定适应征中的任意一种;
(7)组合产品,例如药盒,其包含治疗有效量的式I的化合物或其药学上可接受的盐或水合物和第二药物物质,所述第二药物物质例如如上文所述。
如果本发明的化合物与其它免疫抑制剂/免疫调节剂、抗炎剂或抗肿瘤剂、例如上文所公开的那些联合施用,则所述的共同施用的药物或活性剂的剂量当然将根据所使用的共用药物或共同活性剂的类型、或者所用的具体药物或活性剂、或者所治疗的病症等而改变。
在另一个实施方案中,提供了制备式(I)的化合物的方法,
其中X是CH或N;R是H或PO3H2;R1是H或C1-4烷基;R2是H或C1-4烷基;R3是H、C1-4烷基、CN、Hal或OH;且R4和R5彼此独立地是H或C1-4烷基;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基,
所述方法包括:
(a)任选地,对于其中R1和/或R2是氢的化合物而言,将式(Va)的马来酰亚胺例如用二碳酸二叔丁酯在存在或不存在溶剂例如THF或二氯甲烷和/或碱例如三乙胺的情况下处理,由此得到式(Va)的马来酰亚胺,在适宜的情况下,其在R1和/或R2上包含叔丁氧基羰基,而不是氢;
(b)将任选地被保护的式(Va)的马来酰亚胺例如用甲醛在存在或不存在溶剂和/或碱例如碳酸钾的情况下处理,由此得到式(Vb)的醇,其中R=H;
(c)任选地,将式(Vb)的醇例如用三氯乙腈典型地在存在碱例如DBU或三甲胺的情况下处理,形成反应性酯,然后用磷酸化试剂、例如用磷酸酯、例如用磷酸二叔丁酯典型地在存在碱例如DBU或三甲胺的情况下处理,届时将所得的中间体酯用适宜的酸例如盐酸或TFA在不存在或存在溶剂例如THF、二氯甲烷、二氯乙烷等的情况下处理,得到通式(I)的终产物,或者作为供替代选择的步骤(c),
可以使式(Vb)的醇直接与磷酸酯、例如磷酸二叔丁酯、例如在Mitsunobu反应条件下反应,得到磷酸酯,然后可以将其水解,例如用三氟乙酸、例如在二氯甲烷中水解,得到式(I)的终产物。
Claims (14)
2.根据权利要求1所述的式(I)的化合物或其药学上可接受的盐或水合物,
其中X是CH;
R是H;
R1是H;
R2是H;或C1-4烷基;
R3是H;或C1-4烷基;且
R4和R5彼此独立地是H;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
3.根据权利要求1所述的式(I)的化合物或其药学上可接受的盐或水合物,
其中X是N;
R是PO3H2;
R1是H;
R2是H;或C1-4烷基;
R3是H;且
R4和R5彼此独立地是H;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基。
5.根据权利要求1或4所述的化合物,其是磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯一水合物。
6.根据权利要求1或2中任意一项所述的化合物或其药学上可接受的盐,所述化合物是3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-1-羟基甲基-4-(7-甲基-1H-吲哚-3-基)-吡咯-2,5-二酮。
7.根据权利要求1或3中任意一项所述的化合物或其药学上可接受的盐,所述化合物是磷酸单{3-(1H-吲哚-3-基)-4-[2-(4-甲基-哌嗪-1-基)-喹唑啉-4-基]-2,5-二氧代-2,5-二氢-吡咯-1-基甲基}酯。
8.根据以上权利要求1至7中任意一项所述的化合物或其药学上可接受的盐或水合物,用作药物,特别是用于治疗PKC、或其它激酶的介体在其中发挥作用的障碍或疾病。
9.治疗或预防PKC活化在其中发挥作用或牵涉于其中的疾病或病症的方法,特别是在需要其的个体中治疗或预防PKC活化在其中发挥作用或牵涉于其中的疾病或病症的方法,该方法包括给所述个体施用有效量的以上权利要求1至7中任意一项的化合物或其药学上可接受的盐或水合物。
10.根据权利要求8所述的用于所述用途的化合物或根据权利要求9所述的治疗方法,其中所述的治疗或预防可以由T淋巴细胞、B淋巴细胞、肥大细胞、嗜酸性粒细胞或心肌细胞介导,因此可以适用于器官或组织的同种异体移植物或异种移植物的急性或慢性排斥反应、移植物抗宿主病、宿主抗移植物病、动脉粥样硬化、脑梗死、由血管损伤如血管成形术引起的血管闭塞、再狭窄、纤维化(尤其是肺纤维化,还有其它类型的纤维化,例如肾纤维化)、血管生成、高血压、心力衰竭、慢性阻塞性肺疾病、CNS疾病如阿尔茨海默病或肌萎缩性侧索硬化、癌症、感染性疾病如AIDS、败血症性休克或成人型呼吸窘迫综合征、缺血/再灌注损伤例如心肌梗死、中风、肠缺血、肾衰竭或失血性休克,或外伤性休克。
11.根据权利要求8所述的用于所述用途的化合物或根据权利要求9所述的治疗方法,其中所述的治疗或预防针对器官或组织的同种异体移植物或异种移植物的急性或慢性排斥反应、移植物抗宿主病、宿主抗移植物病、多发性硬化、银屑病或类风湿性关节炎。
12.组合产品,例如药盒,其包含治疗有效量的以上权利要求1至7中任意一项的化合物或其药学上可接受的盐或水合物,和第二药物物质。
13.磷酸单[3-[3-(4,7-二氮杂-螺[2.5]辛-7-基)-异喹啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二氧代-2,5-二氢-吡咯-1-基甲基]酯、尤其是一水合物的晶形,其优选具有X-射线粉末衍射图,该衍射图具有至少1个、优选2个、更优选3个、甚至更优选4个、尤其是5个、最优选所有折射角2θ如下的峰:9.525±0.2、16.356±0.2、17.091±0.2、18.005±0.2、20.859±0.2,尤其是如图1和/或表1中所示的峰。
14.制备权利要求1中所定义的式(I)的化合物的方法,
其中X是CH或N;
R是H或PO3H2;
R1是H;或C1-4烷基;
R2是H;或C1-4烷基;
R3是H;C1-4烷基;CN;Hal;或OH;且
R4和R5彼此独立地是H或C1-4烷基;或者R4和R5与它们所连接的碳原子一起形成3–6元环烃基,
所述方法包括:
(a)任选地,对于其中R1和/或R2是氢的化合物而言,将式(Va)的马来酰亚胺例如用二碳酸二叔丁酯在存在或不存在溶剂例如THF或二氯甲烷和/或碱例如三乙胺的情况下处理,由此得到式(Va)的马来酰亚胺,在适宜的情况下,其在R1和/或R2上包含叔丁氧基羰基,而不是氢;
(b)将任选地被保护的式(Va)的马来酰亚胺例如用甲醛在存在或不存在溶剂和/或碱例如碳酸钾的情况下处理,由此得到式(Vb)的醇,其中R=H;
(c)任选地,将式(Vb)的醇例如用三氯乙腈典型地在存在碱例如DBU或三甲胺的情况下处理,形成反应性酯,然后用磷酸化试剂、例如用磷酸酯、例如用磷酸二叔丁酯典型地在存在碱例如DBU或三甲胺的情况下处理,届时将所得的中间体酯用适宜的酸例如盐酸或TFA在不存在或存在溶剂例如THF、二氯甲烷、二氯乙烷等的情况下处理,得到通式(I)的终产物,或者作为供替代选择的步骤(c),
可以使式(Vb)的醇直接与磷酸酯、例如磷酸二叔丁酯、例如在Mitsunobu反应条件下反应,得到磷酸酯,然后可以将其水解,例如用三氟乙酸、例如在二氯甲烷中水解,得到式(I)的终产物。
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