CN106458981B - 用于治疗补体介导的疾病的化合物 - Google Patents
用于治疗补体介导的疾病的化合物 Download PDFInfo
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- CN106458981B CN106458981B CN201580010598.5A CN201580010598A CN106458981B CN 106458981 B CN106458981 B CN 106458981B CN 201580010598 A CN201580010598 A CN 201580010598A CN 106458981 B CN106458981 B CN 106458981B
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Classifications
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Abstract
本发明提供了包含式I或其药学可接受的盐的补体因子D抑制剂化合物、其使用方法及制备方法或组合物。本文描述的抑制剂靶向因子D,并在替代补体途径中在早期和必需位点处抑制或调节补体级联,并降低因子D调节经典和凝集素补体途径的能力。本文描述的因子D的抑制剂能够降低补体的过度活化,所述过度活化与某些自身免疫、炎性和神经变性疾病以及缺血‑再灌注损伤和癌症相关。
Description
相关申请的交叉引用
本申请要求2014年2月25日提交的美国临时申请第61/944,189号、2014年7月10日提交的美国临时申请第62/022,916临时和2014年9月5日提交的美国临时申请第62/046,783号的权益。每个这些申请的全部内容全部以引用方式并入本文。
背景技术
补体系统是先天免疫系统的一部分,其不随宿主生命过程中的变化而变化,但被适应性免疫系统所募集(recruit)和使用。例如,其协助或补充抗体和吞噬细胞清除病原体的能力。此复杂的调节途径能够实现对病原有机体的快速反应,同时保护宿主细胞不受破坏。超过三十种蛋白和蛋白片断组成补体系统。这些蛋白通过调理(增强抗原的吞噬作用)、趋化(吸引巨噬细胞和中性粒细胞)、细胞裂解(破坏外源细胞的膜)和凝集(簇集和将病原体在结合一起)起作用。
补体系统有三个途径:经典、替代和凝集素。补体因子D在补体级联的替代途径的活化中起着早期和核心作用。替代补体途径的活化由C3内的硫酯键的自发水解以产生C3(H2O)来引发,C3(H2O)与因子B缔合形成C3(H2O)B复合物。补体因子D的作用是断裂C3(H2O)B复合物内的因子B以形成Ba和Bb。Bb片段保持与C3(H2O)缔合以形成替代途径C3转化酶C3(H2O)Bb。另外,由任何C3转化酶生成的C3b也与因子B缔合以形成C3bB,因子D将其断裂以生成后期替代途径C3转化酶C3bBb。替代途径C3转化酶的此后一形式可在所有三种所定义的补体途径内提供重要的下游放大,最终导致补体级联途径中其它因子的募集和组装,包括C5断裂为C5a和C5b。C5b在因子C6、C7、C8和C9组装为膜攻击复合物中起作用,所述复合物可通过裂解细胞来破坏病原细胞。
补体的功能障碍或过度活化已经与某些自身免疫、炎性、和神经变性疾病以及缺血-再灌注损伤和癌症联系起来。例如,补体级联的替代途径的活化有助于C3a和C5a(二者均为强效过敏毒素)的产生,C3a和C5a也在许多炎性疾病中起作用。因此,在一些情况下,期望减少补体途径的响应,包括替代补体途径。由补体途径介导的疾病的一些实例包括年龄相关性黄斑变性(AMD)、阵发性睡眠性血红蛋白尿症(PNH)、多发性硬化症和类风湿性关节炎。
年龄相关性黄斑变性(AMD)是工业化国家中视力丧失的主要原因。基于许多遗传研究,存在补体级联与黄斑变性之间的联系的证据。在编码补体因子H的基因中有突变的个体具有五倍的增加的黄斑变性风险,在其它补体因子基因中有突变的个体也具有增加的AMD风险。具有突变因子H的个体也有着增高的C-反应蛋白水平,C-反应蛋白是炎症的标志物。没有适当的功能因子H,补体级联的替代途径将过度活化,导致细胞损伤。因此期望抑制替代途径。
阵发性睡眠性血红蛋白尿症(PNH)是非恶性血液性疾病,其特征为缺乏一些表面蛋白的造血干细胞和子代成熟血细胞的扩增。PNH红细胞不能够调节它们的表面补体活化,这导致PNH的典型标志——补体介导的血管性贫血的慢性活化。目前,仅一种产品:抗-C5单克隆抗体依库珠单抗,已在美国批准用于PNH的治疗。然而,许多经用依库珠单抗治疗的病人仍然贫血,并且许多病人继续需要输血。另外,用依库珠单抗的治疗需要终身静脉注射。因此,存在对开发补体途径新型抑制剂的未满足的需要。
由于在替代补体途径中的早期和重要作用及其在经典和凝集素补体途径内信号放大中的潜在作用,因子D是用于抑制或调节补体级联的有吸引力的靶点。因子D的抑制有效地中断所述途径并削弱膜攻击复合物的形成。
虽然已进行初步尝试来开发因子D的抑制剂,但目前在临床试验中没有小分子因子D抑制剂。因子D抑制剂或脯氨酰化合物的实例在以下公开内容中有述。
Biocryst Pharmaceuticals的标题为“Compounds useful in the complement,coagulat and kallikrein pathways and method for their preparation(可用于补体、凝聚体和激肽释放酶途径的化合物及其制备方法)”的美国专利6653340描述了作为因子D的强效抑制剂的稠合双环化合物。因子D抑制剂BCX 1470的开发由于该化合物缺乏特异性并且半衰期短而中断。
Novartis的标题为“Indole compounds or analogues thereof useful for thetreatment of age-related macular degeneration(用于治疗年龄相关的黄斑变性的吲哚化合物或其类似物)”的PCT专利公布WO2012/093101描述了某些因子D抑制剂。
Novartis的标题为“pyrrolidine derivatives and their use as complementpathway modulators(吡咯烷衍生物及其用作补体途径调节剂的用途)”的PCT专利公布WO2014/002057和标题为“Complement pathway modulators and uses thereof(补体途径调节剂及其用途)”的WO2014/009833描述了具有杂环取代基的其它因子D抑制剂。其它因子D抑制剂描述在Novartis的PCT专利公开WO2014/002051、WO2014/002052、WO2014/002053、WO2014/002054、WO2014/002058、WO2014/002059和WO2014/005150。
Bristol-Myers Squibb的标题为“Open chain prolyl urea-relatedmodulators of androgen receptor function(与开链脯氨酰脲相关的雄激素受体功能调节剂)”的PCT专利公开WO2004/045518描述了用于治疗雄激素受体相关病症如年龄相关疾病例如少肌症的开链脯氨酰脲和硫脲相关化合物。
日本Tobacco Inc.的标题为“Amide derivatives and nociceptin antagonists(酰胺衍生物及孤啡肽拮抗剂)”的PCT专利公开WO1999/048492描述了可用于治疗疼痛的具有脯氨酸类核和通过酰胺键连接到脯氨酸核的芳族取代基的化合物。
Ferring B.V.和Yamanouchi Pharmaceutical Co.LTD.的标题为“CCK and/orgastrin receptor ligands(CCK和/或胃泌素受体配体)”的PCT专利公开WO 1993/020099描述了用于治疗例如胃部疾病或疼痛的具有脯氨酸类核和通过酰胺键连接到脯氨酸核的杂环取代基的化合物。
Alexion Pharmaceuticals的标题为“Methods and compositions for thetreatment of glomerulonephritis and other inflammatory diseases(用于治疗肾小球肾炎和其他炎性疾病的方法和组合物)”的PCT专利公开WO 1995/029697公开了针对补体途径的C5的抗体,用于治疗涉及补体系统的病理性活化的肾小球肾炎和炎性病症。AlexionPharmaceutical的抗-C5抗体依库珠单抗()是目前市场上唯一的补体特异性抗体,并且是第一个也是唯一一个批准的用于阵发性睡眠性血红蛋白尿症(PNH)的治疗剂。
需要介导补体途径并例如充当因子D抑制剂的化合物来治疗宿主包括人类中与补体级联的误调节相关的疾病。
发明内容
本发明提供了式I的化合物:
以及其药学上可接受的盐和组合物。式I可认为具有中心核、L-B取代基,和(C=O)A取代基。已发现式I的化合物或其药学可接受的盐或组合物是优异的补体因子D的抑制剂,并因此可以有效量用于治疗需要补体因子D调节的宿主。如下面所描述的,本发明提供了式I的化合物,其中X2为氮或存在如下所定义的(d)、(e)、(g)、(i)、(l)、(n)、(p)、(s)、(v)、(x)和(y)中的至少一者。还公开了包含式I的化合物或盐以及药学可接受的载体的药物组合物。
在一个实施方案中,本发明提供了用于治疗与补体途径的功能障碍包括增加的活性相关的疾病的方法,所述方法包括施用任选存在于药学可接受的载体中的有效量的式I化合物或其药学可接受的盐,这将在下文更详细地描述。
在一个实施方案中,所述疾病与替代补体级联途径相关。在又一个实施方案中,所述疾病与补体经典途径相关。在再一个实施方案中,所述疾病与补体凝集素途径相关。通过以合适的方式向需要其的宿主施用有效的量,本文提供的因子D抑制剂可因此减弱或抑制宿主中有害的补体活性。
本发明的具体实施方案涉及某些疾病适应症。在一个实施方案中,提供了用于治疗阵发性睡眠性血红蛋白尿症(PNH)的方法,其包括施用任选存在于药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗年龄相关性黄斑变性(AMD)的方法,其包括施用任选存在于药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗类风湿性关节炎的方法,其包括施用任选存在于药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗多发性硬化症的方法,其包括施用任选存在于药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。
在本发明的其它实施方案中,可使用本文提供的活性化合物来治疗或预防宿主中由补体因子D、或由过度或有害量的补体途径的C3放大回路介导的疾病。作为实例,本发明包括治疗或预防由抗体-抗原相互作用、免疫或自身免疫疾病的组成部分或由缺血性损伤诱导的补体相关疾病的方法。本发明还提供了减少由因子D介导或影响的炎症或免疫应答、包括自身免疫应答的方法。
式I具有变量,例如,A、B、L、X1、X2、Q1、Q2和Q3,并具有下面的定义。
Q1为N(R1)或C(R1R1’);
Q2为C(R2R2’)、C(R2R2’)-C(R2R2’)、S、O、N(R2)或C(R2R2’)O;
Q3为N(R3)、S或C(R3R3’);
(a)X1和X2独立地为N、CH或CZ,或者(b)X1和X2一起为C=C;和
Q1、Q2、Q3、X1和X2选择为使得产生稳定的化合物。
环的非限制性实例在下面示例(其任何一者可另外被R1、R1’、R2、R2’、R3和R3’所取代),这将在下文更详细地描述。
其中q为0、1、2或3并且r为1、2或3。
R和R’独立地选自H、其中每一个基团可任选地被取代的烷基、环烷基、烷基环烷基、环烷基烷基、杂环、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基或本文中提供所需性质的任何其它取代基。在一些实施方案中,环包含一个或多个手性碳原子。本发明包括其中手性碳可作为对映体、或对映体的混合物包括外消旋混合物提供的实施方案。当环包含超过一个立体中心时,所有对映体和非对映异构体均作为单独的种类包含在本发明中。
Z为F、Cl、NH2、CH3、CH2D、CHD2或CD3。
R1、R1’、R2、R2’、R3和R3’在每一次出现时独立地选自(c)和(d):
(c)氢、卤素、羟基、硝基、氰基、氨基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C2-C6炔基、C2-C6烷酰基、C1-C6硫代烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C4烷基NR9R10、-C(O)OR9、-OC(O)R9、-NR9C(O)R10、-C(O)NR9R10、-OC(O)NR9R10、-O(杂芳基)、-NR9C(O)OR10、C1-C2卤代烷基和C1-C2卤代烷氧基,其中R9和R10在每一次出现时独立地选自氢、C1-C6烷基、和(C3-C7环烷基)C0-C4烷基;
(d)-C0-C4烷基(C3-C7环烷基)和-O-C0-C4烷基(C3-C7环烷基)。
在另一种实施方案中,可存在下面的环(e)、(f)、(g)、(h)、(i)或(j)中任一者:
(e)R1和R1’或R3和R3’可一起形成3-至6-元碳环螺环或含1或2个独立地选自N、O或S的杂原子的3-至6-元杂环螺环;
(f)R2和R2’可一起形成3-至6-元碳环螺环;
(g)R2和R2’可一起形成3-至6-元杂环螺环;
螺环(e)、(f)和(g)中的每一者可以是未取代的或被1个或多个取代基所取代,所述取代基独立地选自卤素(特别是F)、羟基、氰基、-COOH、C1-C4烷基(包括特别是甲基)、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C2-C4烷酰基、羟基C1-C4烷基、(单-和二-C1-C4烷基氨基)C0-C4烷基、-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
(h)R1和R2可一起形成3-元碳环;
(i)R1和R2可一起形成4-至6-元碳环或者含1或2个独立地选自N、O和S的杂原子的4-至6-元杂环;
(j)R2和R3,如果键合到相邻的碳原子,可一起形成3-至6-元碳环或者3-至6-元杂环;所述环(h)、(i)和(j)中的每一者可以是未取代的或被1个或多个取代基所取代,所述取代基独立地选自卤素(特别是F)、羟基、氰基、-COOH、C1-C4烷基(包括特别是甲基)、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C2-C4烷酰基、羟基C1-C4烷基、(单-和二-C1-C4烷基氨基)C0-C4烷基、-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
在另一种实施方案中,R1和R1’、R2和R2’或者R3和R3’可一起形成羰基基团。在另一种实施方案中,R1和R2或者R2和R3可一起形成碳-碳双键。
A为选自(k)和(1)的基团,其中(k)为
且(1)为
X4为B(OH)且Y为CHR9;或X4为CHR9且Y为B(OH)。
R101为氢、烷基、羧基。
R4为(m)或(n):
(m)-CHO、-CONH2、或C2-C6烷酰基,包括C(O)C3-C7环烷基;
(n)氢、-S02NH2、-C(CH2)2F、-CH(CF3)NH2、C1-C6烷基、-C0-C4烷基(C3-C7环烷基)、-C(O)C0-C2烷基(C3-C7环烷基)、
除氢、-CHO和-CONH2外的每一个所述R4是未取代的或被氨基、亚氨基、卤素、羟基、氰基、氰基亚氨基、C1-C2烷基、C1-C2烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C2卤代烷基和C1-C2卤代烷氧基中的一种或多种所取代。
R5和R6独立地选自(o)和(p):
(o)-CHO、-C(O)NH2、-C(O)NH(CH3)、或C2-C6烷酰基;
(p)氢、羟基、卤素、氰基、硝基、-COOH、-SO2NH2、-C(NH2)C1-C3烷基、-C(NH2)C1-C3卤代烷基、-CF(C=CH2)、-C(=NCN)C1-C6烷基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、-C0-C4烷基(C3-C7环烷基)、-C(O)C0-C4烷基(C3-C7环烷基)、-P(O)(OR9)2、-OC(O)R9、-C(O)OR9、-C(O)N(CH2CH2R9)(R10)、-NR9C(O)R10、苯基或5-至6-元杂芳基。
除氢、羟基、氰基和-COOH外的每一个R5和R6是未取代的或任选地被取代。例如,除氢、羟基、氰基和-COOH外的R5和R6可被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、亚氨基、氰基、氰基亚氨基、C1-C2烷基、C1-C4烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C2卤代烷基、C1-C2卤代烷氧基、C(O)烷基、C(O)环烷基、C(O)芳基、C(O)杂环基和C(O)杂芳基。
R6’为氢、卤素、羟基、C1-C4烷基、或C1-C4烷氧基;或者R6和R6’可一起形成氧代、乙烯基或亚氨基基团。
R7为氢、C1-C6烷基或-C0-C4烷基(C3-C7环烷基)。
在另一个实施方案中,两个A基团可通过合适的连接基团一起形成达到期望目的的二聚体。连接基团的实例包括但不限于脲、酰胺、-C(O)-C(O)-、氨基甲酸酯和酮。在一个实施方案中,两个杂芳基环,例如两个吲哚环通过脲连接形成二聚体。
R8和R8’独立地选自氢、卤素、羟基、C1-C6烷基、C1-C6烷氧基和(C1-C4烷基氨基)C0-C2烷基;或者R8和R8’一起形成氧代基团,或者可与它们所键合至的碳一起形成3-元碳环。
R16为0或1个或多个取代基,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
R19为氢、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、-SO2C1-C6烷基、(单-和二-C1-C6烷基氨基)C1-C4烷基、-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(C3-C7杂环烷基)、C0-C4烷基(芳基)、C0-C4烷基(杂芳基)和-C(O)(CH2)1-2C(O)OR9,并且除氢外的R19的每一个被0个或一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、-COOH和-C(O)OC1-C4烷基。
X11为N或CR11。
X12为N或CR12。
X13为N或CR13。
X14为N或CR14。
X11、X12、X13和X14中不超过2者为N。
R11、R14和R15在每次出现时独立地选自氢、卤素、羟基、硝基、氰基、-NR9C(O)R10、C(O)NR9R10、-O(PO)(OR9)2、-(PO)(OR9)2、C1-C6烷基、C2-C6烯基、C2-C6烯基(芳基)、C2-C6烯基(环烷基)、C2-C6烯基(杂环基)、C2-C6烯基(杂芳基)、C2-C6炔基、C2-C6炔基(芳基)、C2-C6炔基(环烷基)、C2-C6炔基(杂环基)、C2-C6炔基(杂芳基)、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、(苯基)C0-C4烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基、和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和杂环基或杂芳基)C0-C4烷基、-C0-C4烷氧基(C3-C7环烷基)、C1-C2卤代烷基、和C1-C2卤代烷氧基。
或者,R13和R14可一起形成可被任选取代的环烷基、杂环基或杂芳环的桥。
R12和R13在每次出现时独立地选自(q)、(r)和(s)。
(q)氢、卤素、羟基、硝基、氰基、氨基、-COOH、C1-C2卤代烷基、C1-C2卤代烷氧基;
(r)C1-C6烷基、-C0-C4烷基(C3-C7环烷基)、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C2-C6烯氧基、-C(O)OR9、C1-C6硫代烷基、-C0-C4烷基NR9R10、-C(O)NR9R10、-SO2R9、-SO2NR9R10、-OC(O)R9和-C(NR9)NR9R10,每一个所述(r)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、氨基、-COOH、-CONH2、C1-C2卤代烷基和C1-C2卤代烷氧基,并且每一个所述(r)还任选地被一个取代基所取代,所述取代基选自苯基和含1、2或3个独立地选自N、O和S的杂原子的4-至7-元杂环;所述苯基或4-至7-元杂环是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基;
(s)-C(CH2)2R30。
R30为-NR9C(O)R31或R32。
R31和R32各自独立地选自C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、(C3-C7环烷基)C0-C4烷基、(芳基)C0-C4烷基、(杂环基)C0-C4烷基和(杂芳基)C0-C4烷基,其中每个基团可任选地被取代;或每个所述(s)可以是未取代的或被一个或多个取代基取代,所述取代基独立地选自但不限于卤素、羟基、硝基、氰基、氨基、氧代基、-B(OH)2、-Si(CH3)3、-COOH、-CONH2、-P(O)(OH)2、C1-C6烷基、C1-C6烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C6烷基酯、C1-C4烷基氨基、C1-C4羟基烷基、C1-C2卤代烷基、和C1-C2卤代烷氧基。
L为(t)、(u)或(v):
(t)为式的基团,其中R17为氢或C1-C6烷基且R18和R18’独立地选自氢、卤素、羟甲基和甲基;且是0、1、2或3;
(u)为键;
(v)或直接连接任选取代的烷基、烷基(杂芳基)、杂环基芳基、杂芳基、包括但不限于以下的部分:
B为单环、双环碳环或碳环-氧基基团或具有1、2、3或4个独立地选自N、O和S的杂原子且每个环有4-7个环原子的单环、双环、或三环杂环基团、或B为C2-C6烯基或C2-C6炔基、或B为-(C0-C4烷基)(芳基)、-(C0-C4烷基)(杂芳基)、或-(C0-C4烷基)(联苯基).
每一个所述B是未取代的或被一个或多个取代基取代,所述取代基独立地选自(w)和(x)且0或1个取代基选自(y)和(z):
(w)卤素、羟基、-COOH、氰基、C1-C6烷基、C2-C6烷酰基、C1-C6烷氧基、-C0-C4烷基NR9R10、-SO2R9、C1-C2卤代烷基和C1-C2卤代烷氧基;
(x)硝基、C2-C6烯基、C2-C6炔基、C1-C6硫代烷基、-JC3-C7环烷基、-B(OH)2、-JC(O)NR9R23、-JOSO2OR21、-C(O)(CH2)1-4S(O)R21、SR9、-O(CH2)1-4S(O)NR21R22、-JOP(O)(OR21)(OR22)、-JP(O)(OR21)(OR22)、-JOP(O)(OR21)R22、-JP(O)(OR21)R22、-JOP(O)R21R22、-JP(O)R21R22、-JSP(O)(OR21)(OR22)、-JSP(O)(OR21)(R22)、-JSP(O)(R21)(R22)、-JNR9P(O)(NHR21)(NHR22)、-JNR9P(O)(OR21)(NHR22)、-JNR9P(O)(OR21)(OR22)、-JC(S)R21、-JNR21SO2R22、-JNR9S(O)NR10R22、-JNR9SO2NR10R22、-JSO2NR9COR22、-JSO2NR9CONR21R22、-JNR21SO2R22、-JC(O)NR21SO2R22、-JC(NH2)NR22、-JC(NH2)NR9S(O)2R22、-JOC(O)NR21R22、-JNR21C(O)OR22、-JNR21OC(O)R22、-(CH2)1-4C(O)NR21R22、-JC(O)R24R25、-JNR9C(O)R21、-JC(O)R21、-JNR9C(O)NR10R22、-CCR21、-(CH2)1-4OC(O)R21和-JC(O)OR23;每个所述(x)可以是未取代的或被一个或多个取代基取代,所述取代基独立地选自卤素、羟基、硝基、氰基、氨基、氧代基、-B(OH)2、-Si(CH3)3、-COOH、-CONH2、-P(O)(OH)2、C1-C6烷基、C1-C6烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C6烷基酯、C1-C4烷基氨基、C1-C4羟基烷基、C1-C2卤代烷基和C1-C2卤代烷氧基;
(y)萘基、萘氧基、茚满基、含1或2个选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基、和含1、2或3个独立地选自N、O和S的杂原子并且在每环中含4-至7-个环原子的双环杂环;每一个所述(y)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、-SO2R9、C1-C2卤代烷基和C1-C2卤代烷氧基;和
(z)四唑基、(苯基)C0-C2烷基、(苯基)C1-C2烷氧基、苯氧基、和含1、2或3个独立地选自N、O、B和S的杂原子的5-或6-元杂芳基,每一个所述(z)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、-SO2R9、-OSi(CH3)2C(CH3)3、-Si(CH3)2C(CH3)3、C1-C2卤代烷基和C1-C2卤代烷氧基。
J在每次出现时独立地选自共价键、C1-C4亚烷基亚、-OC1-C4亚烷基、C2-C4亚烯基、和C2-C4亚炔基。
R21和R22在每一次出现时独立地选自氢、羟基、氰基、氨基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、(C3-C7环烷基)C0-C4烷基、(苯基)C0-C4烷基、-C1-C4烷基OC(O)OC1-C6烷基、C1-C4烷基OC(O)C1-C6烷基、-C1-C4烷基C(O)OC1-C6烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和或芳族杂环)C0-C4烷基。
R23在每一次出现时独立地选自(C3-C7环烷基)C0-C4烷基、(苯基)C0-C4烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基,和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和或芳族杂环基)C0-C4烷基。
R24和R25与它们所连接至的氮一起形成4-至7-元单环杂环烷基基团、或具有稠环、螺环或桥环的6-至10-元双环杂环基团。
要么X2是氮,要么存在(d)、(e)、(g)、(i)、(1)、(n)、(p)、(s)、(v)、(x)和(y)中的至少一个。还公开了包含式I的化合物或盐以及药学可接受的载体的药物组合物。
还公开了治疗或预防由补体级联因子D介导的疾病的方法,所述疾病包括但不限于年龄相关性黄斑变性(AMD)、视网膜变性、其它眼科疾病(例如,地图状萎缩)、阵发性睡眠性血红蛋白尿症(PNH)、多发性硬化症(MS)、关节炎包括类风湿性关节炎(RA)、呼吸道疾病或心血管疾病,所述方法包括向需要此类治疗的宿主(包括人)施用治疗有效量的式I化合物或盐。
在另一个实施方案中,提供有效量的活性因子D抑制化合物来治疗由因子D介导或影响的炎性或免疫疾病,包括自身免疫疾病。在一个替代的实施方案中,可使用式I的化合物来治疗由补体途径介导的疾病,而不管其是否通过因子D起作用。
本发明包括至少以下特征:
(a)如本文所述的式I化合物、及其药学可接受的盐和前药(其每一者及其所有亚组和种类被认为是单独且具体描述的);
(b)如本文所述的式I、及其药学可接受的盐和前药,用于治疗或预防由补体途径例如级联因子D介导的疾病,包括年龄相关性黄斑变性(AMD)、视网膜变性、阵发性睡眠性血红蛋白尿症(PNH)、多发性硬化症(MS)和类风湿性关节炎(RA)及本文中进一步描述的其它疾病;
(c)式I及其药学可接受的盐和前药在用于治疗或预防由补体级联因子D介导的疾病的药物的制造中的用途,所述疾病包括年龄相关性黄斑变性(AMD)、视网膜变性、阵发性睡眠性血红蛋白尿症(PNH)、多发性硬化症(MS)和类风湿性关节炎(RA)及本文中进一步描述的其它疾病;
(d)制造用于治疗或预防由补体级联因子D介导的疾病的治疗用药物的方法,所述疾病包括年龄相关性黄斑变性(AMD)、视网膜变性、阵发性睡眠性血红蛋白尿症(PNH)、多发性硬化症(MS)和类风湿性关节炎(RA)及本文中进一步描述的其它疾病,所述方法的特征在于在制造中使用如本文所述的式I;
(e)包含治疗宿主有效量的式I或其药学可接受的盐或前药以及药学可接受的载体或稀释剂的药学制剂;
(f)基本上纯形式的本文所述式I,包括基本上与其它化学个体分离(例如,至少90或95%);
(g)制造式I的化合物及其盐、组合物、剂型的方法;和
(h)制备含有效量的如本文所述式I的治疗产品的方法。
具体实施方式
I.术语
使用标准命名法描述化合物。除非另有定义,否则本文中使用的所有技术和科学术语具有与本发明所属领域技术人员通常所理解的相同的含义。
本文中描述的任何式的化合物包括对映体、对映体的混合物、非对映异构体、互变异构体、外消旋体和其它异构体,如旋转异构体,好像每一个被明确述及一样。“式I”包括式I的所有亚组,如式IA和式IB,并还包括式I化合物的药学可接受的盐,除非其中使用该表述的上下文明显矛盾。“式I”还包括式I的所有亚组,如式IC-ID和式II-XXX,并还包括式I的所有亚组如式IA-ID和式II-XXX的药学可接受的盐,除非其中使用该表述的上下文矛盾。
术语“一个”和“一种”不表示量的限制,而是表示所提及项目中至少之一的存在。术语“或”指“和/或”。值的范围的叙述仅意在起到单独地提及落在该范围内的每一个单独的值的述及方法的作用,本文中另有指出除外,并且每一个单独的值并入本说明书中就好像其在本文中被单独地陈述一样。所有范围的端点均包括在所述范围内并可独立地合并。本文描述的所有方法可以合适的顺序执行,本文中另有指出或上下文明显矛盾除外。实例或示例性语言(例如,“例如”)的使用仅意在更好地示意本发明而不对本发明的范围提出限制,另有要求除外。除非另有定义,否则本文中使用的技术和科学术语具有与本发明所属领域技术人员通常所理解的相同的含义。
本发明包括式I化合物及某原子被至少一种所需的同位素以高于该同位素的天然丰度的量取代即富含该同位素的化合物的用途。同位素为具有相同的原子序数但不同的质量数即相同的质子数但不同的中子数的原子。
可引入到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,分别如2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本发明包括如本文所定义的各种同位素标记的化合物,例如其中存在例如3H,13C和14C的放射性同位素的那些。这样的同位素标记的化合物用于代谢研究(用14C)、反应动力学研究(用例如2H或3H)、检测或成像技术如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)包括药物或底物组织分布测定中或在病人的放射治疗中使用同位素标记的化合物。特别地,18F标记的化合物对于PET或SPECT研究来说可能特别理想。本发明的同位素标记化合物及其前药通常可通过进行方案中或实施例中公开的程序和下文描述的制备通过用易得的同位素标记试剂代替非同位素标记试剂来制备。
作为一般实例并且非限制性地,可在所述结构中任何地方使用氢的同位素如氘(2H)和氚(3H)。可替代地或此外,可使用碳的同位素如13C和14C。典型的同位素取代为用氘取代分子上一个或多个位置处的氢以改善药物的性能,例如药效学、药动学、生物分布、半衰期、稳定性、AUC、Tmax、Cmax等。例如,氘可键合到代谢过程中键断裂的位置处(α-氘动力学同位素效应)或紧邻键断裂的位点或键断裂的位点附近(β-氘动力学同位素效应)的碳。
同位素取代,例如氘取代,可以是部分的或完全的。部分氘取代指至少一个氢被氘所取代。在某些实施方案中,在任何感兴趣的位置处同位素占90、95或99%或更丰富。在一个实施方案中,在所需的位置处富含90、95或99%的氘。除非另有指出,否则在任何点处的富集度均高于天然丰度并足以改变药物在人中的可检测性。
在一个实施方案中,氘原子对氢原子的取代发生在L-B部分区域上R基团取代基内。在一个实施方案中,氘原子对氢原子的取代发生在选自R18、R18’、R33、R34、R35和/或R36中任何一者的R基团内。在一个实施方案中,氘原子对氢原子的取代发生在A-羰基部分区域内R基团取代基内。在一个实施方案中,氘原子对氢原子的取代发生在R4、R5、R6、R6’、R7、R8、R8’、R11、R12、R13、R14、R15、R16、R19、R21、R22、R23和R30处。在其它实施方案中,脯氨酸环上的某些取代基被选择性地氘化。例如,在一个实施方案中,氘原子对氢原子的取代发生在R、R’、R1、R1’、R2、R2’、R3和/或R3’处。在一个实施方案中,例如当脯氨酸环上的任何R取代基为甲基或甲氧基时,烷基残基被任选地氘化,例如CD3或OCD3。在某些其它实施方案中,当脯氨酸环的两个取代基合并形成环丙基环时,未取代的亚甲基碳被氘化。
在一个实施方案中,当R基团内的至少一个变量为氢(例如,2H或D)或烷基(例如,CD3)时,氘原子对氢原子的取代发生在R基团内。例如,当任何R基团是甲基或乙基,或例如通过取代包含甲基或乙基时,烷基残基通常被氘化,例如,CD3、CH2CD3或CD2CD3。在某些其他实施方案中,当上述R基团是氢时,氢可被同位素富集为氘(即,2H)。
本发明的化合物可与溶剂(包括水)形成溶剂化物。术语“溶剂化物”指本发明的化合物(包括其盐)与一种或多种溶剂分子的分子复合物。溶剂包括水、乙醇、二甲亚砜、丙酮和其它常见有机溶剂。术语“水合物”指包含本发明的化合物和水的分子复合物。根据本发明的药学可接受的溶剂化物包括其中结晶的溶剂可被同位素取代的那些,例如,D2O、d6-丙酮、d6-DMSO。溶剂化物可呈液体或固体形式。
不在两个字母或符号之间的短线“-”用来指示取代基的连接点。例如,-(C=O)NH2通过酮(C=O)基团的碳连接。
如本文所用,术语“取代的”指所指定的原子或基团上的任何一个或多个氢被选自所指示基团的部分所代替,前提条件是不超过所指定的原子的正常价态。例如,当取代基为氧代(即=O)时,则原子上的两个氢被代替。当氧代基团代替芳族部分中的两个氢时,相应的部分不饱和环将代替芳环。例如,被氧代取代的吡啶基团为吡啶酮。仅在取代基和/或变量的组合产生稳定的化合物或有用的合成中间体警方,此类组合才是允许的。
稳定的化合物或稳定的结构指产生可被分离并可配制成具有至少一个月的货架寿命的剂型的化合物的那些化合物。
任何合适的基团均可存在于“取代的”或“任选地取代的”位置上,其形成稳定的分子并推进本发明的预期目的并且包括但不限于例如卤素(其可独立地为F、Cl、Br或I);氰基;羟基;硝基;叠氮基;烷酰基(如C2-C6烷酰基基团);甲酰胺;烷基、环烷基、烯基、炔基、烷氧基、芳氧基如苯氧基;烷硫基,包括具有一个或多个硫醚键的那些;烷基亚硫酰基;烷基磺酰基团,包括具有一个或多个磺酰键的那些;氨基烷基基团,包括具有一个或多个N原子的基团;芳基(例如,苯基、联苯基、萘基等,各个环或为被取代或为未被取代的芳族环);具有例如1至3个单独的或稠合的环和6至约14或18个环碳原子的芳基烷基,苄基为示例性的芳基烷基基团;芳基烷氧基,例如具有1至3个单独的或稠合的环,苄氧基为示例性的芳基烷氧基基团;或者具有1至3个单独的或稠合的环、具有一个或多个N、O或S原子的饱和、不饱和或芳族杂环基团,例如香豆素基、喹啉基、异喹啉基、喹唑啉基、吡啶基、吡嗪基、嘧啶基、呋喃基、吡咯基、噻吩基、噻唑基、三嗪基、噁唑基、异噁唑基、咪唑基、吲哚基、苯并呋喃基、苯并噻唑基、四氢呋喃基、四氢吡喃基、哌啶基、吗啉代、哌嗪基和吡咯烷基。此类杂环基团可被进一步取代,例如被羟基、烷基、烷氧基、卤素和氨基所取代。在某些实施方案中,“任选地被取代的”包括一个或多个取代基,所述取代基独立地选自卤素、羟基、氨基、氰基、-CHO、-COOH、-CONH2、C1-C6烷基、C2-C6烯基、C2-C6炔基、-C1-C6烷氧基、C2-C6烷酰基、C1-C6烷基酯、(单-和二-C1-C6烷基氨基)C0-C2烷基、C1-C2卤代烷基、羟基C1-C6烷基、酯、氨基甲酸酯、脲、磺酰胺、-C1-C6烷基(杂环)、C1-C6烷基(杂芳基)、-C1-C6烷基(C3-C7环烷基)、O-C1-C6烷基(C3-C7环烷基)、B(OH)2、磷酸基、膦酸基和C1-C2卤代烷氧基。
“烷基”为支链或直链饱和脂族烃基团。在一个实施方案中,烷基含1至约12个碳原子,更通常1至约6个碳原子或1至约4个碳原子。在一个实施方案中,烷基含1至约8个碳原子。在某些实施方案中,烷基为C1-C2、C1-C3或C1-C6。如本文所用,指定的范围指所述范围的每一个成员作为独立的种类的烷基基团。例如,如本文所用,术语C1-C6烷基指具有1、2、3、4、5或6个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。例如,如本文所用,术语C1-C4烷基指具有1、2、3或4个碳原子的直链或支链烷基基团并意在指这些中的每一者作为独立的种类描述。当C0-Cn烷基在本文中结合另一基团使用时,例如(C3-C7环烷基)C0-C4烷基或-C0-C4烷基(C3-C7环烷基),所指示的基团——在此情况下环烷基,或通过单一共价键(C0烷基)直接键合或通过烷基链(在此情况下1、2、3或4个碳原子)连接。烷基也可经由其它基团如杂原子连接,如在-O-C0-C4烷基(C3-C7环烷基)中。烷基的实例包括但不限于甲基、乙基、正-丙基、异丙基、正-丁基、异丁基、仲-丁基、叔-丁基、正-戊基、异戊基、叔-戊基、新戊基、正-己基、2-甲基戊烷、3-甲基戊烷、2,2-二甲基丁烷和2,3-二甲基丁烷。在一个实施方案中,烷基基团任选地被如上所述取代。
“烯基”为具有一个或多个碳-碳双键的支链或直链脂族烃基团,所述双键可发生在链上的稳定点处。非限制性实例有C2-C8烯基、C2-C6烯基和C2-C4烯基。如本文所用,指定的范围指所述范围的每一个成员作为独立的种类的烯基基团,如上面针对烷基部分所述。烯基的实例包括但不限于乙烯基和丙烯基。在一个实施方案中,烯基基团任选地被如上所述取代。
“炔基”为具有一个或多个碳-碳三键的支链或直链脂族烃基团,所述三键可发生在链上的任何稳定点处,例如C2-C8炔基或C2-C6炔基。如本文所用,指定的范围指所述范围的每一个成员作为独立的种类的炔基基团,如上面针对烷基部分所述。炔基的实例包括但不限于乙炔基、丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基和5-己炔基。在一个实施方案中,炔基基团任选地被如上所述取代。
“亚烷基”为二价饱和烃。亚烷基可例如为1至8个碳部分、1至6个碳部分或指定数量的碳原子,例如C1-C4亚烷基、C1-C3亚烷基或C1-C2亚烷基。
“亚烯基”为具有至少一个碳-碳双键的二价烃。亚烯基可例如为2至8个碳部分、2至6个碳部分或指定数量的碳原子,例如C2-C4亚烯基。
“亚炔基”为具有至少一个碳-碳三键的二价烃。亚炔基可例如为2至8个碳部分、2至6个碳部分或指定数量的碳原子,例如C2-C4亚炔基。
“烷氧基”为通过氧桥(-O-)共价键合的如上所述烷基基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正-丙氧基、异-丙氧基、正-丁氧基、2-丁氧基、叔-丁氧基、正-戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正-己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。类似地,“烷硫基”或“硫代烷基”基团为通过硫桥(-S-)共价键合的具有指定数量的碳原子的如上所述烷基基团。在一个实施方案中,烷氧基基团任选地被如上所述取代。
“烯氧基”为通过氧桥(-O-)共价键合到其取代的基团的所述烯基基团。
“烷酰基”为通过羰基(C=O)桥共价键合的如上所述烷基基团。羰基碳包括在碳数中,即C2烷酰基为CH3(C=O)-基团。在一个实施方案中,烷酰基基团任选地被如上所述取代。
“烷基酯”为通过酯键共价键合的如本文所述烷基基团。酯键可在任一方向上,例如式-O(C=O)烷基的基团或式-(C=O)O烷基的基团。
“酰胺”或“甲酰胺”为-C(O)NRaRb,其中Ra和Rb各自独立地选自氢、烷基如C1-C6烷基、烯基如C2-C6烯基、炔基如C2-C6炔基、-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(C3-C7杂环烷基)、-C0-C4烷基(芳基)和-C0-C4烷基(杂芳基);或Ra和Rb可与其所键合至的氮一起形成C3-C7杂环。在一个实施方案中,Ra和Rb基团各自独立地任选地被如上所述取代。
“碳环基团”“碳环环”或“环烷基”为包含所有碳环原子的饱和或部分不饱和(即,非芳族)基团。碳环基团通常含3至7个碳原子的1个环或各含3至7个碳原子的2个稠环。在一个实施方案中,碳环可被稠合为芳环。环烷基取代基可以是自取代的氮或碳原子的侧基,或者可具有两个取代基的取代碳原子可具有环烷基基团,其作为螺环基团连接。碳环的实例包括环己烯基、环己基、环戊烯基、环戊基、环丁烯基、环丁基和环丙基环。在一个实施方案中,碳环任选地被如上所述取代。在一个实施方案中,环烷基为含所有碳环原子的部分不饱和(即非芳族)基团。在另一个实施方案,环烷基为包含全部碳环原子的饱和基团。
“碳环-氧基基团”为经由氧连接基(-O-)连接到其取代的基团的如上所述单环碳环或者单-或二-环碳环基团。
“卤代烷基”指被1个或多个卤素原子、至多最大许可数量的卤素原子所取代的支链和直链烷基基团。卤代烷基的实例包括但不限于三氟甲基、单氟甲基、二氟甲基、2-氟乙基和五氟乙基。
“卤代烷氧基”指通过氧桥(羟基基团的氧)连接的如本文所述卤代烷基基团。
“羟烷基”为被至少一个羟基取代基所取代的如前所述烷基基团。
“氨基烷基”为被至少一个氨基取代基所取代的如前所述烷基基团。
“卤素”独立地指氟、氯、溴和碘中的任何一者。
“芳基”指在芳族环或环中仅含碳的芳族基团。在一个实施方案中,芳基基团含1至3个单独的或稠合的环并且具有6至约14或18个环原子,无杂原子作为环成员。在指出时,这样的芳基基团可进一步被碳或非碳原子或基团所取代。此类取代可包括稠合到5至7-元饱和环基团,所述饱和环基团任选地含1或2个独立地选自N、O和S的杂原子,以形成例如3,4-亚甲基二氧苯基基团。芳基基团包括例如苯基和萘基,包括1-萘基和2-萘基。在一个实施方案中,芳基基团是侧基。侧基环实例为被苯基基团所取代的苯基基团。在一个实施方案中,芳基基团任选地被如上所述取代。
如本文所用,术语“杂环”指具有3至约12、更通常3、5、6、7至10个环原子的饱和或部分不饱和(即,在环内具有一个或多个双键和/或三键而无芳香性)碳环原子团,其中至少一个环原子为选自氮、氧、磷和硫的杂原子,其余的环原子为C,其中一个或多个环原子任选地被一个或多个上述取代基独立地取代。杂环可为具有3至7个环成员(2至6个碳原子和1至4个选自N、O、P和S的杂原子)的单环或具有6至10个环成员(4至9个碳原子和1至6个选自N、O、P和S的杂原子)的双环,例如:双环[4,5]、[5,5]、[5,6]或[6,6]系。在一个实施方案中,唯一的杂原子为氮。在一个实施方案中,唯一的杂原子为氧。在一个实施方案中,唯一的杂原子为硫。杂环描述在Paquette,Leo A.;“Principles of Modern HeterocyclicChemistry”(W.A.Benjamin,New York,1968)特别是第1、3、4、6、7和9章;“The Chemistryof Heterocyclic Compounds,A series of Monographs”(John Wiley&Sons,New York,1950至现在)特别是第13、14、16、19和28章;和J.Am.Chem.Soc.(1960)82:5566中。杂环的实例包括但不限于吡咯烷基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、哌啶酮基、吗啉代、硫代吗啉代、氧硫杂环己烷基(thioxanyl)、哌嗪基、高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、氧杂环庚基(oxepanyl)、硫杂环庚基(thiepanyl)、氧氮杂环基(oxazepinyl)、二氮杂环基(diazepinyl)、硫氮杂环基(thiazepinyl)、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧杂环戊基、吡唑啉基、二噻烷基、二硫戊环基、二氢吡喃基、二氢噻吩基、二氢呋喃基、二氢异喹啉基、四氢异喹啉基、吡唑烷基咪唑啉基、咪唑烷基、2-氧杂-5-氮杂双环[2.2.2]辛烷、3-氧杂-8-氮杂双环[3.2.1]辛烷、8-氧杂-3-氮杂双环[3.2.1]辛烷、6-氧杂-3-氮杂双环[3.1.1]庚烷、2-氧杂5-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[4.1.0]庚烷基、氮杂双环[2.2.2]己烷基、3H-吲哚基、喹嗪基、N-吡啶基脲和吡咯并嘧啶。螺部分也包括在本定义的范围内。其中1或2个环碳原子被氧代(=O)部分所取代的杂环基团的实例有嘧啶酮基和1,1-二氧代-硫代吗啉代。本文中的杂环基团任选地被一个或多个本文所述的取代基独立地取代。
“杂环氧基团”为经由氧连接基(-O-)连接到其取代的基团的如前所述单环杂环或双环杂环基团。
“杂芳基”指含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的稳定单环芳族环,或者含至少一个其中含1至3个或在一些实施方案中1至2个选自N、O和S的杂原子、其余环原子为碳的5-至7-元芳族环的稳定双环或三环系。在一个实施方案中,唯一的杂原子为氮。在一个实施方案中,唯一的杂原子为氧。在一个实施方案中,唯一的杂原子为硫。单环杂芳基基团通常具有5至7个环原子。在一些实施方案中,双环杂芳基基团为9-至10-元杂芳基基团,即含9或10个环原子的基团,其中一个5-至7-元芳族环稠合到第二个芳族或非芳族环。当杂芳基基团中S和O原子的总数超过1时,这些杂原子不彼此相邻。在一个实施方案中,杂芳基基团中S和O原子的总数不超过2。在另一个实施方案中,芳族杂环中S和O原子的总数不超过1。杂芳基基团的实例包括但不限于吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、四氢呋喃基和呋喃并吡啶基。杂芳基基团任选地被一个或多个本文所述取代基独立地取代。“杂芳氧基”为经由氧连接基(-O-)键合到其取代的基团的所述杂芳基基团。
“杂环烷基”为饱和环基团。其可具有例如1、2、3或4个独立地选自N、S和O的杂原子,其余环原子为碳。在一个典型的实施方案中,氮为杂原子。单环杂环烷基基团通常具有3至约8个环原子或4至6个环原子。杂环烷基基团的实例包括吗啉代、哌嗪基、哌啶基和吡咯啉基。
术语“单-和/或二-烷基氨基”指仲或叔烷基氨基基团,其中烷基基团独立地选自如本文所定义的烷基基团。烷基氨基基团的连接点在氮上。单-和二-烷基氨基基团的实例包括乙基氨基、二甲基氨基和甲基-丙基-氨基。
“剂型”指活性剂的施用单元。剂型的实例包括片剂、胶囊剂、注射剂、混悬剂、液体剂、乳剂、植入物、颗粒、球体、乳膏剂、软膏剂、栓剂、可吸入形式、透皮形式、口腔剂、舌下剂、局部剂、凝胶剂、粘膜剂等。“剂型”可还包括植入物,例如光学植入物。
“药物组合物”为包含至少一种活性剂,如式I的化合物或盐和至少一种其它物质如载体的组合物。“药物组合”为至少两种活性剂的组合,所述至少两种活性剂可组合成单一剂型或以分开的剂型并与说明这些活性剂一起使用来治疗本文描述的任何疾病的说明书一起提供。
“药学可接受的盐”包括所公开化合物的衍生物,其中母体化合物通过制备其无机和有机、无毒、酸或碱加成盐来改性。本化合物的盐可自含酸性或碱性部分的母体化合物通过常规化学方法合成。通常,此类盐可通过使这些化合物的游离酸形式与化学计量量的适宜的碱(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量的适宜的酸反应来制备。这样的反应通常在水中或在有机溶剂中或在这两者的混合物中进行。通常,在可行的情况下,非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是典型的。本化合物的盐还包括化合物和化合物盐的溶剂化物。
药学可接受的盐的实例包括但不限于碱性残基如胺的无机或有机酸盐;酸性残基如羧酸的碱金属或有机盐;等。药学可接受的盐包括自例如无毒无机或有机酸形成的母体化合物的常规无毒盐和季铵盐。例如,常规无毒酸盐包括衍生自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的那些;和自有机酸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸、羟基乙磺酸、HOOC-(CH2)n-COOH(其中n为0-4)等制得的盐。其它合适的盐的列表可见于例如Remington′s Pharmaceutical Sciences,17th ed.,MackPublishing Company,Easton,Pa.,p.1418(1985)中。
应用于本发明的药物组合物/组合的术语“载体”指活性化合物与之一起提供的稀释剂、赋形剂或媒介物。
“药学可接受的赋形剂”指可用于制备通常安全、无毒并且既不在生物学上也不在其它方面不宜施用于宿主的药物组合物/组合的赋形剂,并且在一个实施方案中包括对于兽医用途以及人药用途而言可接受的赋形剂。如本申请中所用,“药学可接受的赋形剂”包括一种和超过一种此类赋形剂。
“病人”或“宿主”或“患者”为需要调节补体因子D途径的人或非人类动物。通常,所述宿主为人。“病人”或“宿主”或“患者”还指例如哺乳动物、灵长类(例如人)、奶牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。
如本文所用,“前药”指当体内施用于宿主时转化为母体药物的化合物。如本文所用,术语“母体药物”指任何目前描述的可用于治疗任何本文所述疾病、或者控制或改善宿主通常是人中与本文所述任何生理或病理疾病相关的潜在原因或症状的化学化合物。可使用前药来取得任何期望的效果,包括增强母体药物的性质或者改善母体的药物或药代动力学性质。存在前药策略,其在对母体药物的体内生成的条件的调节中提供选择,所有这些均视为包括在本文中。前药策略的非限制性实例包括可移除基团、或基团的可移除部分的共价连接,例如但不限于酰化、磷酸化、膦酸化、氨基磷酸酯衍生物、酰胺化、还原、氧化、酯化、烷基化、其它羧基衍生物、亚砜或砜衍生物、羰基化或酐等。
“与至少一种其它活性剂一起提供式I的化合物”指式I的化合物和其它一种或多种活性剂以单一剂型同时提供、以分开的剂型相伴地提供、或以分开的剂型隔开一定时间量地施用来提供,其中所述时间量在其中式I的化合物和所述至少一种其它活性剂均在病人的血流内的时间内。在某些实施方案中,式I的化合物和所述其它活性剂不必由同一医疗保健工作者开处方给病人。在某些实施方案中,所述一种或多种其它活性剂不必需要处方。式I的化合物或所述至少一种其它活性剂的施用可经由任何适宜的途径进行,例如口服片剂、口服胶囊剂、口服液体剂、吸入、注射剂、栓剂或局部接触。
本发明的药物组合物/组合的“治疗有效量”指当施用于病人时有效地提供治疗学有益效果如症状改善的量,例如有效地减少黄斑变性的症状的量。在一个实施方案中,治疗有效量为足以防止病人的血液、血清或组织中补体因子D的可检测水平的显著增加或将显著降低病人的血液、血清或组织中补体因子D的可检测水平的量。
II.活性化合物的详细描述
本发明提供了式I的化合物:
以及其药学可接受的盐和组合物。可以认为式I具有中心核、L-B取代基和(C=O)A取代基。已发现式I化合物或者其药学可接受的盐或组合物是优异的补体因子D抑制剂,并因此可以有效量使用来治疗需要补体因子D调节的宿主。
下面示出了落在式I内的在变量例如A、B、R1-R3’和L方面变动的化合物的非限制性实例。本发明涵盖这些定义的所有组合,只要产生稳定的化合物即可。
式II-XXX
在一个方面,本公开涉及式II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX和XXX的化合物和盐,其在式I的范围内。式II-XXX中示出的变量具有发明内容部分中针对式I给出的定义或本公开中给出的任何定义。
m为0或1。式XXIX m为0或1。式XXX
另外,本公开包括式I的化合物和盐及其药学可接受的组合物,以及下述实施方案中其中满足以下条件中的至少之一的任何其子式(II-XXX)。
R12和R13取代基
已发现式I化合物、其药学可接受的盐或组合物是优异的补体因子D抑制剂。
在一个实施方案中,R12和R13在每次出现时独立地选自(q)、(r)和(s):
(q)氢、卤素、羟基、硝基、氰基、氨基、-COOH、C1-C2卤代烷基、C1-C2卤代烷氧基;
(r)C1-C6烷基、-C0-C4烷基(C3-C7环烷基)、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C2-C6烯氧基、-C(O)OR9、C1-C6硫代烷基、-C0-C4烷基NR9R10、-C(O)NR9R10、-SO2R9、-SO2NR9R10、-OC(O)R9和-C(NR9)NR9R10,每一个所述(r)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、氨基、-COOH、-CONH2、C1-C2卤代烷基和C1-C2卤代烷氧基,并且每一个所述(r)还任选地被一个取代基所取代,所述取代基选自苯基和含1、2或3个独立地选自N、O和S的杂原子的4-至7-元杂环;所述苯基或4-至7-元杂环是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基;
(s)-C(CH2)2-4R30。
R30为-NR9C(O)R31或R32。
R31和R32为C1-C6烷基、C1-C6卤代烷基、(C3-C7环烷基)C0-C4烷基、(苯基)C0-C4烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基、和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和或芳族杂环基)C0-C4烷基。
每一个所述(s)可以是未取代的或被一个多个取代基取代,所述取代基独立地选自卤素、羟基、硝基、氰基、氨基、氧代基、-B(OH)2、-Si(CH3)3、-COOH、-CONH2、-P(O)(OH)2、C1-C6烷基、C1-C6烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C6烷基酯、C1-C4烷基氨基、C1-C4羟基烷基、C1-C2卤代烷基、和C1-C2卤代烷氧基。
在某些实施方案中,R12或R13独立地选自:
非限制性R12/R13实施方案
在一个实施方案中,本公开提供了式I的化合物,其中:R12和R13中的一者为H而R12和R13中的另一者选自(s):
(s)-C(CH2)2R30;
其中R30为如上面发明内容部分中所定义。
在另一个实施方案中,本公开提供了式I的化合物,其中:
R1、R1’、R2和R3’均为氢;
R2为氟并且R3为氢、-C0-C4烷基(C3-C7环烷基)或-O-C0-C4烷基(C3-C7环烷基);
R5为氢、卤素或C1-C2烷基;
R11、R13、R14和R15(如果存在)在每一次出现时独立地选自氢、卤素、羟基、氨基、C1-C4烷基、C1-C4烷氧基、-C0-C2烷基(单-和二-C1-C2烷基氨基)、三氟甲基和三氟甲氧基;
X12为CR12;且
R12选自(s):
(s)-C(CH2)2R30;
其中R30为如上面发明内容部分中所定义。
在一个实施方案中,本公开提供了式I的化合物,其中:
m为0或1;
R2为卤素,R2’为氢或卤素,且R3为氢、卤素、-C0-C4烷基(C3-C7环烷基),或-O-C0-C4烷基(C3-C7环烷基);
R6为-C(O)C1-C4烷基、-C(O)NH2、-C(O)CF3、-C(O)(C3-C7环烷基)、或-乙基(氰基亚氨基);
R12和R13中之一选自氢、卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基和三氟甲氧基;R12和R13中的另一者选自(s):
(s)-C(CH2)2R30;
其中R30为如上面发明内容部分中所定义。
在一个实施方案中,本公开提供了式I的化合物,其中:
R12和R13中之一为氢、羟基、卤素、甲基或甲氧基;R12和R13中的另一者选自(s):
(s)-C(CH2)2R30;
其中R30为如上面发明内容部分中所定义。
中心核部分
式I中的中心核部分在下面示意:
其中:
Q1为N(R1)或C(R1R1’);
Q2为C(R2R2’)、C(R2R2’)-C(R2R2’)、S、O、N(R2)或C(R2R2’)O;
Q3为N(R3)、S或C(R3R3’);
(a)X1和X2独立地为N、CH或CZ,或者(b)X1和X2一起为C=C;
Q1、Q2、Q3、X1和X2选择为使得产生稳定的化合物。
环的非限制性实例示意在下面(其任何一者可另外被R1、R1’、R2、R2’、R3和R3’所取代),这将在下文更详细地描述。 其中q为0、1、2或3并且r为1、2或3。
R和R’独立地选自H、烷基、环烷基、烷基环烷基、环烷基烷基、杂环、杂环烷基、芳基、芳烷基、杂芳基、杂芳基烷基(其中每一个基团可任选地被取代),或本文中提供所需性质的任何其它取代基基团。在一些实施方案中,环包含一个或多个手性碳原子。本发明包括其中手性碳可作为对映体或对映体的混合物包括外消旋混合物提供的实施方案。当环包含不止一个立体中心时,所有对映体和非对映异构体均作为单独的种类包含在本发明中。
Z为F、Cl、NH2、CH3、CH2D、CHD2或CD3。
R1、R1’、R2、R2’、R3和R3’在每一次出现时独立地选自(c)和(d):
(c)氢、卤素、羟基、硝基、氰基、氨基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、C2-C6炔基、C2-C6烷酰基、C1-C6硫代烷基、羟基C1-C6烷基、氨基C1-C6烷基、-C0-C4烷基NR9R10、-C(O)OR9、-OC(O)R9、-NR9C(O)R10、-C(O)NR9R10、-OC(O)NR9R10、-O(杂芳基)、-NR9C(O)OR10、C1-C2卤代烷基和C1-C2卤代烷氧基,其中R9和R10在每一次出现时独立地选自氢、C1-C6烷基和(C3-C7环烷基)C0-C4烷基;
(d)-C0-C4烷基(C3-C7环烷基)和-O-C0-C4烷基(C3-C7环烷基)。
非限制性中心核实施方案
在替代的实施方案中,可存在下面的环(e)、(f)、(g)、(h)、(i)或(j)中的任一者:
(e)R1和R1’或R3和R3’可一起形成3-至6-元碳环螺环或含1或2个独立地选自N、O或S的杂原子的3-至6-元杂环螺环;
(f)R2和R2’可一起形成3-至6-元碳环螺环;
(g)R2和R2’可一起形成3-至6-元杂环螺环;每一个所述螺环(e)、(f)和(g)可以是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素(特别是F)、羟基、氰基、-COOH、C1-C4烷基(包括特别是甲基)、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C2-C4烷酰基、羟基C1-C4烷基、(单-和二-C1-C4烷基氨基)C0-C4烷基、-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
(h)R1和R2可一起形成3-元碳环;
(i)R1和R2可一起形成4-至6-元碳环或者含1或2个独立地选自N、O和S的杂原子的4-至6-元杂环;
(j)R2和R3,如果键合到相邻的碳原子,可一起形成3-至6-元碳环或者3-至6-元杂环;
每一个所述环(h)、(i)和(j)可以是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素(特别是F)、羟基、氰基、-COOH、C1-C4烷基(包括特别是甲基)、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C2-C4烷酰基、羟基C1-C4烷基、(单-和二-C1-C4烷基氨基)C0-C4烷基、-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
在一个实施方案中,中心核部分为脯氨酸。
在一个实施方案中,中心核部分为4-氟脯氨酸。
在一个实施方案中,R1、R1’、R2’、R3和R3’,如果存在,均为氢;R2为氟。
在一个实施方案中,R1、R1’、R2’和R3’,如果存在,均为氢;且R2为氟并且R3为-C0-C4烷基(C3-C7环烷基)或-O-C0-C4烷基(C3-C7环烷基)。
在一个实施方案中,R1和R2一起形成3-至6-元环烷基基团,并且R1’、R2’、R3和R3’,当存在时,均为氢。
在一个实施方案中,R1、R1’、R3和R3’,如果存在,均为氢,并且R2和R2’一起形成具有1或2个氧原子的5-或6-元杂环烷基基团。
在一个实施方案中,R1为氢并且R2为氟。
在一个实施方案中,R1和R2接合形成3元环。
本公开包括其中中心吡咯烷被乙烯基取代的式I化合物,例如:
在一个实施方案中,式I的化合物具有结构:
在一个实施方案中,中心吡咯烷通过向吡咯烷环加入第二杂原子如N、O、S或Si来改性,例如:
本发明的范围内的另一改性为将中心吡咯烷环上的取代基结合到R7或R8以形成5-至6-元杂环,例如:
具有上面公开的改性的实例化合物包括:
中心核L-B取代基
式I中的中心核L-B取代基示意在下面:
L为(t)、(u)或(v):
(t)为下式的基团:
其中R17为氢或C1-C6烷基,且R18和R18’独立地选自氢、卤素、羟甲基和甲基;并且m为0、1、2或3。
(u)为键,
(v)或直接连接的任选取代的烷基、烷基(杂芳基)、杂环芳基、杂芳基、包括但不限于下式的部分:
B为单环、双环碳环或碳环氧基基团或具有1、2、3或4个独立地选自N、O和S的杂原子并且每环具有4至7个环原子的单环、双环或三环杂环基团;或B是C2-C6烯基或C2-C6炔基,或B为-(C0-C4烷基)(芳基);-(C0-C4烷基)(杂芳基);或-(C0-C4烷基)(联苯基)。
每一个所述B是未取代的或被一个或多个取代基所取代,所述取代基独立地选自(w)和(x),并且0或1个取代基选自(y)和(z):
(w)卤素、羟基、-COOH、氰基、C1-C6烷基、C2-C6烷酰基、C1-C6烷氧基、-C0-C4烷基NR9R10、-SO2R9、C1-C2卤代烷基和C1-C2卤代烷氧基;
(x)硝基、C2-C6烯基、C2-C6炔基、C1-C6硫代烷基、-JC3-C7环烷基、-B(OH)2、-JC(O)NR9R23、-JOSO2OR21、-C(O)(CH2)1-4S(O)R21、SR9、-O(CH2)1-4S(O)NR21R22、-JOP(O)(OR21)(OR22)、-JP(O)(OR21)(OR22)、-JOP(O)(OR21)R22、-JP(O)(OR21)R22、-JOP(O)R21R22、-JP(O)R21R22、-JSP(O)(OR21)(OR22)、-JSP(O)(OR21)(R22)、-JSP(O)(R21)(R22)、-JNR9P(O)(NHR21)(NHR22)、-JNR9P(O)(OR21)(NHR22)、-JNR9P(O)(OR21)(OR22)、-JC(S)R21、-JNR21SO2R22、JNR9S(O)NR10R22、-JNR9SO2NR10R22、-JSO2NR9COR22、-JSO2NR9CONR21R22、-JNR21SO2R22、-JC(O)NR21SO2R22、-JC(NH2)NR22、-JC(NH2)NR9S(O)2R22、-JOC(O)NR21R22、-JNR21C(O)OR22、-JNR21OC(O)R22、-(CH2)1-4C(O)NR21R22、-JC(O)R24R25、-JNR9C(O)R21、-JC(O)R21、-JNR9C(O)NR10R22、-CCR21、-(CH2)1-4OC(O)R21和-JC(O)OR23;每一个所述(x)可以是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、氨基、氧代、-B(OH)2、-Si(CH3)3、-COOH、-CONH2、-P(O)(OH)2、C1-C6烷基、C1-C6烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C6烷基酯、C1-C4烷基氨基、C1-C4羟烷基、C1-C2卤代烷基和C1-C2卤代烷氧基;
(y)萘基、萘氧基、茚满基、含1或2个选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基和含1、2或3个独立地选自N、O和S的杂原子并且在每环中含4-至7-个环原子的双环杂环;每一个所述(y)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、-SO2R9、C1-C2卤代烷基和C1-C2卤代烷氧基;和
(z)四唑基、(苯基)C0-C2烷基、(苯基)C1-C2烷氧基、苯氧基、和含1、2或3个独立地选自N、O、B和S的杂原子的5-或6-元杂芳基,每一个所述(z)是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、(单-和二-C1-C6烷基氨基)C0-C4烷基、C1-C6烷基酯、-C0-C4烷基(C3-C7环烷基)、-SO2R9、-OSi(CH3)2C(CH3)3、-Si(CH3)2C(CH3)3、C1-C2卤代烷基和C1-C2卤代烷氧基。
在一个实施方案中,-L-B-为
其中
R26和R27独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、-C0-C4烷氧基(C3-C7环烷基)、C1-C2卤代烷基、C1-C2卤代烷氧基和C1-C2卤代烷硫基。
非限制性L-B实施方案
在另一个实施方案中,-L-B-为
其中
R18和R18’独立地选自氢、卤素、羟甲基和甲基;m为0或1;并且
R26、R27和R28独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、(单-和二-C1-C6烷基氨基)C0-C4烷基、(C3-C7环烷基)C0-C4烷基、(芳基)C0-C4烷基-、(杂芳基)C0-C4烷基-和-C0-C4烷氧基(C3-C7环烷基);除氢、卤素、羟基、硝基、氰基外的每一个所述R26、R27和R28是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、C1-C2烷氧基、C1-C2卤代烷基、(C3-C7环烷基)C0-C4烷基-和C1-C2卤代烷氧基;和
R29为氢、C1-C2烷基、C1C2卤代烷基或-Si(CH3)2C(CH3)3。
在一个实施方案中,m为0。
在一个实施方案中,本发明还包括其中B为2-氟-3-氯苯基的式I的化合物和盐。在另一个实施方案中,使用另一碳环、芳基、杂环、或杂芳基基团如2-溴-吡啶-6-基、1-(2,2,2-三氟乙基)-1H-吡唑-3-基、2,2-二氯环丙基甲基、或2-氟-3-三甲基甲硅烷基苯基。
在另一个实施方案中,B为苯基、吡啶基或茚满基,其每一个是未取代的或被一个或多个取代基所取代,所述取代基独立地选自氢、卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、(单-和二-C1-C6烷基氨基)C0-C4烷基、(C3-C7环烷基)C0-C4烷基、-C0-C4烷氧基(C3-C7环烷基)、(苯基)C0-C2烷基、(吡啶基)C0-C2烷基;除氢、卤素、羟基、硝基、氰基外的每一个所述取代基是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、C1-C2烷基、C1-C2烷氧基、-OSi(CH3)2C(CH3)3、-Si(CH3)2C(CH3)3、C1-C2卤代烷基和C1-C2卤代烷氧基。
在另一个实施方案中,B为被1、2或3个取代基所取代的苯基或吡啶基,所述取代基选自氯、溴、羟基、-SCF3、C1-C2烷基、C1-C2烷氧基、三氟甲基、苯基和三氟甲氧基,除氯、溴、羟基、-SCF3外的每一个所述取代基可任选地被取代。
在某些实施方案中,B为2-氟-3-氯苯基或2-氟-3-三氟甲氧基苯基基团。
在一个实施方案中,B为吡啶基,其任选地被卤素、C1-C2烷氧基和三氟甲基所取代。
在一个实施方案中,B为苯基,其被1、2或3个取代基所取代,所述取代基独立地选自卤素、C1-C2烷基、C1-C2烷氧基、三氟甲基和任选地被取代的苯基。
在一个实施方案中,R23在每一次出现时独立地选自(C3-C7环烷基)C0-C4烷基、(苯基)C0-C4烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基、和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和或芳族杂环)C0-C4烷基。
在一个实施方案中,B选自
其中,R27为氢、甲基或三氟甲基;R28为氢或卤素;R29为氢、甲基、三氟甲基或-Si(CH3)2C(CH3)3。
中心核(C=O)A取代基
式I中的中心核(C=O)A取代基示意在下面:
A为选自(k)和(1)的基团,其中(k)为:
且(1)为
X4为B(OH)且Y为CHR9;或X4为CHR9且Y为B(OH)。
R101为氢、烷基、羧基。
R4为(m)或(n):
(m)-CHO、-CONH2或C2-C6烷酰基,包括C(O)C3-C7环烷基;
(n)氢、-SO2NH2、-C(CH2)2F、-CH(CF3)NH2、C1-C6烷基、-C0-C4烷基(C3-C7环烷基)、-C(O)C0-C2烷基(C3-C7环烷基)、
除氢、-CHO和-CONH2外的每一个所述R4是未取代的或被氨基、亚氨基、卤素、羟基、氰基、氰基亚氨基、C1-C2烷基、C1-C2烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C2卤代烷基和C1-C2卤代烷氧基中的一种或多种所取代。
R5和R6独立地选自(o)和(p):
(o)-CHO、-C(O)NH2、-C(O)NH(CH3)或C2-C6烷酰基;
(p)氢、羟基、卤素、氰基、硝基、-COOH、-SO2NH2、-C(NH2)C1-C3烷基、-C(NH2)C1-C3卤代烷基、-CF(C=CH2)、-C(=NCN)C1-C6烷基、C1-C6烷基、C2-C6烯基、C1-C6烷氧基、-C0-C4烷基(C3-C7环烷基)、-C(O)C0-C4烷基(C3-C7环烷基)、-P(O)(OR9)2、-OC(O)R9、-C(O)OR9、-C(O)N(CH2CH2R9)(R10)、-NR9C(O)R10、苯基或5-至6-元杂芳基。
除氢、羟基、氰基和-COOH外的每一个R5和R6是未取代的或任选地被取代的。例如,除氢、羟基、氰基和-COOH外的R5和R6可被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、亚氨基、氰基、氰基亚氨基、C1-C2烷基、C1-C4烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C2卤代烷基、C1-C2卤代烷氧基、C(O)烷基、C(O)环烷基、C(O)芳基、C(O)杂环基和C(O)杂芳基。
R6’为氢、卤素、羟基、C1-C4烷基、或C1-C4烷氧基;或者R6和R6’可一起形成氧代、乙烯基或亚氨基基团。
R7为氢、C1-C6烷基或-C0-C4烷基(C3-C7环烷基)。
R8和R8’独立地选自氢、卤素、羟基、C1-C6烷基、C1-C6烷氧基和(C1-C4烷基氨基)C0-C2烷基;或者R8和R8’一起形成氧代基团;或者R8和R8’可与其所键合至的碳一起形成3-元碳环。
R16为0或1个或多个取代基,所述取代基独立地选自卤素、羟基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
R19为氢、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、-SO2C1-C6烷基、(单-和二-C1-C6烷基氨基)C1-C4烷基、-C0-C4烷基(C3-C7环烷基)、-C0-C4烷基(C3-C7杂环烷基)、-C0-C4烷基(芳基)、C0-C4烷基(杂芳基),每一个除氢外的所述R19被0个或1个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、-COOH和-C(O)OC1-C4烷基。
X11为N或CR11。
X12为N或CR12。
X13为N或CR13。
X14为N或CR14。
X11、X12、X13和X14中不超过2个为N。
R11、R14和R15在每次出现时独立地选自氢、卤素、羟基、硝基、氰基、-NR9C(O)R10、C(O)NR9R10、-O(PO)(OR9)2、-(PO)(OR9)2、C1-C6烷基、C2-C6烯基、C2-C6烯基(芳基)、C2-C6烯基(环烷基)、C2-C6烯基(杂环基)、C2-C6烯基(杂芳基)、C2-C6炔基、C2-C6炔基(芳基)、C2-C6炔基(环烷基)、C2-C6炔基(杂环基)、C2-C6炔基(杂芳基)、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、(苯基)C0-C4烷基、具有1、2或3个独立地选自N、O和S的杂原子的(4-至7-元杂环烷基)C0-C4烷基、和具有1、2或3个独立地选自N、O和S的杂原子的(5-或6-元不饱和的或芳族杂环基)C0-C4烷基、-C0-C4烷氧基(C3-C7环烷基)、C1-C2卤代烷基、和C1-C2卤代烷氧基。可替代地,R13和R14可一起形成可以是任选取代的环烷基、杂环基或杂芳环的桥。
在一个实施方案中,R5和R6独立地选自-CHO、-C(O)NH2、-C(O)NH(CH3)、C2-C6烷酰基和氢。
在一个实施方案中,除氢、羟基、氰基和-COOH外的每一个R5和R6是未取代的或被一个或多个取代基所取代,所述取代基独立地选自卤素、羟基、氨基、亚氨基、氰基、氰基亚氨基、C1-C2烷基、C1-C4烷氧基、-C0-C2烷基(单-和二-C1-C4烷基氨基)、C1-C2卤代烷基、C1-C2卤代烷氧基、C(O)烷基、C(O)环烷基、C(O)芳基、C(O)杂环基和C(O)杂芳基。
在一个实施方案中,R8和R8’独立地为氢或甲基。
在一个实施方案中,R8和R8’为氢。
在一个实施方案中,R7为氢或甲基。
在一个实施方案中,R7为氢。
在一个实施方案中,两个A基团可通过合适的连接基团一起形成达到期望目的的二聚体。连接基团的实例包括但不限于脲、酰胺、-C(O)-C(O)-、氨基甲酸酯和酮。在一个实施方案中,两个杂芳基环,例如两个吲哚环通过脲连接形成吲哚-NHC(O)NH-吲哚。
式IA、IB、IC和ID的实施方案
为进一步说明本发明,提供了式IA、IB、IC和ID的多种实施方案。这些实施方案以实例呈现来示出本发明内呈现的化合物的一些变型并可适用于式I-XXX中的任何一者。
在一个方面,本发明包括式IA的化合物和盐:
其中R6、R13和B可具有本文中针对该变量给出的任何定义。
在另一个方面,本发明包括式IB、IC和ID的化合物和盐。
在式IA、IB、IC和ID中,变量可包括本文中给出的产生稳定化合物的任何定义。
式VII的实施方案
为进一步说明本发明,提供了式VII的多种实施方案。在一个方面,本公开包括式VII的化合物和盐:
其中:
R1、R2、R2’和R3独立地选自氢、卤素、C1-C4烷基、C1-C4烷氧基、-C0-C2烷基NR9R10、-C0-C4烷基(C3-C7环烷基)、-O-C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基、和C1-C2卤代烷氧基;
R8和R8’独立地选自氢、卤素和甲基;
R5为氢、羟基、氰基、-COOH、C1-C6烷基、C1-C6烷氧基、C2-C6烷酰基、-C0-C4烷基(C3-C7环烷基)、-C(O)C0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基或C1-C2卤代烷氧基;
R6为-C(O)CH3、-C(O)NH2、-C(O)CF3、-C(O)(环丙基)或-乙基(氰基亚氨基);并且
R11和R14独立地选自氢、卤素、羟基、氨基、硝基、氰基、C1-C6烷基、C2-C6烯基、C2-C6烷酰基、C1-C6烷氧基、C1-C6硫代烷基、-C0-C4烷基(单-和二-C1-C6烷基氨基)、-C0-C4烷基(C3-C7环烷基)、-OC0-C4烷基(C3-C7环烷基)、C1-C2卤代烷基和C1-C2卤代烷氧基。
式I的前药也在本发明的范围内。
III.药物制剂
本文公开的化合物可作为纯化学品施用,但也可作为药物组合物施用,所述药物组合物包含对于需要治疗的宿主有效量的如本文所述的选定的式I化合物。相应地,本发明提供了药物组合物,其包含有效量的式I的化合物或药学可接受的盐、以及至少一种药学可接受的载体。药物组合物可含式I的化合物或盐作为唯一的活性剂,或者在一个替代的实施方案中,式I和至少一种另外的活性剂。在某些实施方案中,药物组合物呈这样的剂型,其在单位剂型中含约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的式I化合物和任选地约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的另外的活性剂。实例为具有至少25、50、100、200、250、300、400、500、600、700或750mg活性化合物或其盐的剂型。药物组合物可还包含一定摩尔比的式I化合物和另外的活性剂。例如,药物组合物可含约0.5∶1、约1∶1、约2∶1、约3∶1或从约1.5∶1至约4∶1的摩尔比的另一抗炎剂。
本文公开的化合物可以以包含常规药学可接受的载体的单位剂量制剂通过口服、局部、肠道外、通过吸入或喷雾、舌下、经由植入物(包括眼植入物)、经皮、经由口腔含化、直肠给药、作为眼用溶液、注射(包括眼部注射)、静脉内、动脉内、颅内或通过其它方式施用。药物组合物可配制为任何药学可用的形式,例如配制为气雾剂、乳膏剂、凝胶剂、丸剂、胶囊剂、片剂、糖浆剂、透皮贴剂或眼用溶液。一些剂型如片剂和胶囊剂被细分为合适规格的单位剂量,其含适宜量的活性组分,例如获得期望目的的有效量。
载体包括赋形剂和稀释剂并且必须是足够高纯度且足够低的毒性以使得它们适于施用于被治疗的病人。载体可以是惰性的或者其可具有其自身的药学有益效果。与所述化合物一起采用的载体的量应足以为施用每单位剂量的化合物提供实际的材料量。
载体的类别包括但不限于粘结剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、润滑剂、防腐剂、稳定剂、表面活性剂、压片剂和润湿剂。一些载体可能被列在超过一个类别中,例如植物油在一些制剂中可用作润滑剂而在其它中用作稀释剂。示例性的药学可接受载体包括糖、淀粉、纤维素、黄芪胶粉末、麦芽、明胶;滑石,和植物油。可在药物组合物中包含任选的活性剂,其不实质性地干扰本发明的化合物的活性。
药物组合物/组合可针对口服给药配制。这些组合物可包含达到期望结果的任何量的式I的活性化合物,例如0.1和99重量%(wt%)之间的式I化合物,通常至少约5重量%的式I化合物。一些实施方案包含约25重量%至约50重量%或约5重量%至约75重量%的式I化合物。
本发明的补体因子D抑制剂可例如全身性地或局部地施用。全身施用包括例如口服、经皮、真皮下、腹膜内、皮下、经鼻、舌下或经直肠。对于眼部给药的局部施用包括:局部、玻璃体内、眼周、经巩膜、眼球后、巩膜旁、筋膜(tenon)下或经由眼内装置。所述抑制剂可经由玻璃体内或经巩膜植入的持续递送装置、或通过其它已知的局部眼部递送措施递送。
IV.治疗方法
本文公开的化合物和药物组合物可用于治疗或预防由补体途径、特别是由补体因子D调节的途径介导的疾病。在某些实施方案中,所述疾病为宿主中的炎性疾病、免疫疾病、自身免疫疾病或补体因子D相关疾病。在一个实施方案中,所述疾病为眼部疾病。可由本发明的化合物和组合物治疗或预防的补体介导疾病包括但不限于脓毒症的炎性效应、全身性炎症反应综合征(SIRS)、缺血/再灌注损伤(I/R损伤)、银屑病、重症肌无力、系统性红斑狼疮(SLE)、阵发性睡眠性血红蛋白尿症(PNH)、遗传性血管性水肿、多发性硬化症、创伤、烧伤、毛细血管渗漏综合征、肥胖症、糖尿病、阿耳茨海默氏老年痴呆症、中风、精神分裂症、癫痫症、年龄相关性黄斑变性、青光眼、糖尿病性视网膜病、哮喘、过敏症、急性呼吸窘迫综合征(ARDS)、非典型溶血性尿毒症综合征(aHUS)、溶血性尿毒症综合征(HUS)、囊性纤维化、心肌梗塞、狼疮性肾炎、克罗恩氏病、类风湿性关节炎、动脉粥样硬化、移植排斥、预防胎儿流产、生物材料反应(例如,在血液透析、植入物中)、C3肾小球肾炎、腹主动脉瘤、视神经脊髓炎(NMO)、血管炎、神经系统疾病、格林-巴利综合征、外伤性脑损伤、帕金森氏病、不适当或不希望的补体活化的疾病、血液透析并发症、超急性同种异体移植物排斥、异种移植排斥、IL-2疗法过程中自细胞介素-2诱导的毒性、炎性疾病、自身免疫疾病的炎症、成人呼吸窘迫综合征、热损伤(包括烧伤或冻伤)、心肌炎、缺血后再灌注病状、气囊血管成形术、心肺转流术或肾旁路中泵后综合征、血液透析、肾缺血、主动脉重建后肠系膜动脉灌注、免疫复合物病和自身免疫疾病、SLE肾炎、增生性肾炎、肝纤维化、溶血性贫血、组织再生和神经再生。另外,其它已知的补体相关疾病有肺病和疾病如呼吸困难、咳血、慢性阻塞性肺病(COPD)、肺气肿、肺栓塞和梗塞、肺炎、纤维化粉尘疾病、惰性粉尘和矿物质(例如,硅,煤尘、铍和石棉)、肺纤维化、有机粉尘疾病、化学损伤(由于刺激性气体和化学品,例如,氯、光气、二氧化硫、硫化氢、二氧化氮、氨和盐酸)、烟雾损伤、热损伤(例如,烧伤,冻伤)、支气管收缩、过敏性肺炎、寄生虫病、肺出血肾炎综合征、肺血管炎、寡免疫性血管炎、免疫复合物相关炎症、葡萄膜炎(包括贝切特氏病和其它葡萄膜炎的子类型)、抗磷脂综合征、关节炎、自身免疫性心脏病、炎性肠病、缺血-再灌注损伤、Barraquer-Simons综合征、血液透析、系统性红斑狼疮、红斑狼疮、移植、中枢神经系统疾病和其它神经变性病症、肾小球肾炎(包括膜增生性肾小球肾炎)、起泡性皮肤病(包括大疱性类天疱疮、天疱疮和大疱性表皮松解)、眼部瘢痕性类天疱疮、MPGN II、葡萄膜炎、成人黄斑变性、糖尿病性视网膜病、色素性视网膜炎、黄斑水肿、贝切特氏葡萄膜炎、多灶性脉络膜炎、Vogt-Koyangi-Harada综合征、中间葡萄膜炎、鸟枪弹样网膜脉络膜病变、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮、非动脉炎性缺血性视神经病变、术后炎症和视网膜静脉阻塞。
在一些实施方案中,补体介导的疾病包括眼科疾病(包括早期或新生血管性年龄相关性黄斑变性和地图状萎缩)、自身免疫疾病(包括关节炎、类风湿性关节炎)、呼吸系统疾病、心血管疾病。在其它实施方案中,本发明的化合物适于用在与脂肪酸代谢相关的疾病和紊乱的治疗中,包括肥胖症和其它代谢性疾病。
在一个实施方案中,提供了治疗阵发性睡眠性血红蛋白尿症(PNH)的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗年龄相关性黄斑变性(AMD)的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗类风湿性关节炎的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗多发性硬化症的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗重症肌无力的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗非典型溶血性尿毒症综合征(aHUS)的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗C3肾小球肾炎的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗腹主动脉瘤的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在另一个实施方案中,提供了治疗视神经脊髓炎(NMO)的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。
在一些实施方案中,本发明提供了通过向需要其的宿主施用有效量的本发明式I化合物来治疗或预防炎性疾病或补体相关疾病的方法。在一些实施方案中,本发明提供了通过向患有因子D介导的炎性疾病的病人提供有效量的式I化合物或药学可接受的盐来治疗或预防炎性疾病、更通常是免疫疾病、自身免疫疾病或补体因子D相关疾病的方法。式I的化合物或盐可作为唯一的活性剂提供或可与一种或多种另外的活性剂一起提供。
在一个实施方案中,提供了治疗与补体级联中功能障碍相关的疾病的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在一个实施方案中,提供了抑制患者中替代补体途径的活化的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。在一个实施方案中,提供了调节患者中因子D活性的方法,其包括施用任选地在药学可接受的载体中的有效量的式I化合物或其药学可接受的盐。
如本公开中所用,“预防”指相比于未施用化合物的病人中症状出现的可能性,预防性地施用化合物的病人中症状出现的可能性减小,或者与患疾病或病症但未施用化合物的病人经历的症状的严重性相比,预防性地施用化合物的病人中症状的严重性减小。在一个替代的实施方案中,使用有效量的式I化合物来防止或预防补体因子D相关疾病。
本发明的药物组合物/组合的有效量可为足以(a)抑制补体途径介导的疾病包括炎性疾病、免疫(包括自身免疫)疾病或补体因子D相关疾病的发展;(b)导致炎性疾病、免疫(包括自身免疫)疾病或补体因子D相关疾病的消退;或(c)导致炎性疾病、免疫(包括自身免疫)疾病或补体因子D相关疾病的治愈的量。
当施用于病人以提供临床有益效果时,有效量的本文所述化合物或药物组合物还将提供足够的量的活性剂。这样的量可通过实验确定,例如通过测定试剂的血液浓度或者通过从理论上计算生物利用度。
V.联合治疗
在一个实施方案中,式I的化合物或盐可与至少一种另外的补体系统抑制剂或具有不同的生物作用机制的第二活性化合物组合或交替地提供。在一个实施方案中,式I的化合物或盐可与补体C5抑制剂或C5转化酶抑制剂组合地提供。在另一个实施方案中,式I的化合物或盐可与依库珠单抗组合地提供。在一个实施方案中,式I的化合物或盐可与另外的因子D的抑制剂组合地提供。
在一个实施方案中,式I的化合物或盐可与抑制代谢蛋白酶抑制剂的酶的化合物一起提供。在一个实施方案中,式I的化合物或盐可与利托那韦一起提供。
在非限制性的实施方案中,式I的化合物或盐可与蛋白酶抑制剂、可溶性补体调节剂、治疗性抗体(单克隆或多克隆)、补体组分抑制剂、受体激动剂或siRNA一起提供。
在这些类别中,活性剂的非限制性实例有:
蛋白酶抑制剂:血浆来源的C1-INH浓缩物,例如(Sanquin)、(CSL Behring,Lev Pharma)和和重组人CI-抑制剂,例如
可溶性补体调节剂:可溶性补体受体1(TP10)(Avant Immunotherapeutics);sCRl-sLeX/TP-20(Avant Immunotherapeutics);MLN-2222/CAB-2(MilleniumPharmaceuticals);Mirococept(Inflazyme Pharmaceuticals);
治疗性抗体:依库珠单抗/Soliris(Alexion Pharmaceuticals);培克珠单抗(Alexion Pharmaceuticals);奥法木单抗(Genmab A/S);TNX-234(Tanox);TNX-558(Tanox);TA106(Taligen Therapeutics);Neutrazumab(G2 Therapies);Anti-properdin(Novelmed Therapeutics);HuMax-CD38(Genmab A/S);
补体组分抑制剂:Compstatin/POT-4(Potentia Pharmaceuticals);ARC 1905(Archemix);
受体激动剂:PMX-53(Peptech Ltd.);JPE-137(Jerini);JSM-7717(Jerini);
其它:重组人MBL(rhMBL;Enzon Pharmaceuticals)。
在一个实施方案中,本发明提供了通过向需要其的患者施用有效量的包含本发明化合物的组合物来治疗或预防年龄相关性黄斑变性(AMD)的方法。在一个实施方案中,本发明的组合物与抗-VEGF剂组合地施用。抗-VEGF剂的非限制性实例包括但不限于阿柏西普(Regeneron Pharmaceuticals);兰尼单抗(Genentech和Novartis);和哌加他尼(OSI Pharmaceuticals和Pfizer);贝伐单抗(Avastin;Genentech/Roche);醋酸阿奈可他、乳酸角鲨胺和皮质类固醇,包括但不限于曲安奈德。
在另一个实施方案中,可将式I的化合物与第二试剂联用来治疗眼病。
可联用于眼部应用的治疗剂的类型的实例包括抗炎药、抗微生物剂、抗血管生成剂、免疫抑制剂、抗体、类固醇、降眼压药以及它们的组合。治疗剂的实例包括阿米卡星、醋酸阿奈可他、蒽二酮、蒽环类抗生素、唑类、两性霉素B、贝伐珠单抗、喜树碱、头孢呋辛钠、氯霉素、双氯苯双胍己烷、葡萄糖酸氯己定、克霉唑、克霉唑头孢菌素、糖皮质激素、地塞米松、氟美松(desamethazone)、益康唑、头孢他啶、表鬼臼毒素、氟康唑、氟胞嘧啶、氟尿嘧啶、氟喹诺酮类、加替沙星、糖肽类、咪唑类、伊曲康唑、双氢除虫菌素、酮康唑、左氧氟沙星、大环内酯类、咪康唑、硝酸咪康唑、莫西沙星、纳他霉素、新霉素、制霉菌素、氧氟沙星、聚六亚甲基双胍、泼尼松龙、醋酸泼尼松龙、哌加他尼钠、铂类似物、多粘菌素B、丙烷脒羟乙磺酸盐、嘧啶核苷、兰尼单抗、乳酸角鲨胺、磺胺类、去炎松、曲安奈德、三唑类、万古霉素、抗血管内皮生长因子(VEGF)剂、VEGF抗体、VEGF抗体片段、长春花生物碱、噻吗洛尔、倍他洛尔、曲伏前列素、拉坦前列素、比马前列素、溴莫尼定、多佐胺、乙酰唑胺、毛果芸香碱、环丙沙星、阿奇霉素、庆大霉素、托普霉素、头孢唑啉、伏立康唑、更昔洛韦、西多福韦膦甲酸钠、双氯芬酸、奈帕芬胺、酮咯酸、布洛芬、吲哚美辛、氟米龙、瑞美松龙、阿奈可他、环孢菌素、氨甲喋呤、他克莫司以及它们的组合。可根据本文公开的组合物和方法治疗的眼病的实例包括阿米巴角膜炎、真菌性角膜炎、细菌性角膜炎、病毒性角膜炎、盘状角膜炎(onchorcercalkeratitis)、细菌性角结膜炎、病毒性角结膜炎、角膜营养不良性疾病、Fuchs内皮营养不良、Sjogren综合征、Stevens-Johnson综合征、自身免疫性干眼病、环境性干眼病、角膜新血管形成疾病、角膜移植后排斥反应的预防和治疗、自身免疫性葡萄膜炎、传染性葡萄膜炎、前葡萄膜炎、后葡萄膜炎(包括弓形体病)、泛葡萄膜炎、玻璃体或视网膜的炎性疾病、眼内炎的预防和治疗、黄斑水肿、黄斑变性、年龄相关性黄斑变性、增生性和非增生性糖尿病性视网膜病变、高血压性视网膜病变、视网膜自身免疫疾病、原发性和转移性眼内黑色素瘤、其它眼内转移性肿瘤、开角型青光眼、闭角型青光眼、色素性青光眼以及它们的组合。
可经由向玻璃体腔、视网膜下空间、脉络膜下空间、巩膜外层、结膜、巩膜、前房以及角膜和其中的隔室(例如,上皮下、基质内、内皮)中注射来向眼区室中施用式I的化合物或式I与另一活性剂的组合。
在一个替代的实施方案中,可通过粘结到粘膜穿透颗粒来向眼区室中施用式I的化合物或式I与另一活性剂的组合以治疗位于玻璃体腔、视网膜下空间、脉络膜下空间、巩膜外层、结膜、巩膜或前房以及角膜和其中的隔室(例如,上皮下、基质内、内皮)中的病症。粘膜穿透颗粒是本领域已知的,并描述在例如授予Kala Pharmaceuticals的PCT公开申请WO 2013166436中,该公开申请以全文引用并入本文。
在其它实施方案中,提供了适于局部施用于眼的包含式I化合物的组合物。所述药物组合物包含多个涂布颗粒,所述涂布颗粒包含核颗粒和涂层,所述核颗粒包含式I的化合物,其中式I构成核颗粒的至少约80重量%,所述涂层包含一种或多种表面改变剂,其中所述一种或多种表面改变剂包含泊洛沙姆、聚(乙烯醇)或聚山梨醇酯中的至少一种。所述一种或多种表面改变剂以至少0.01个分子/nm的密度存在于核颗粒的外表面上。所述一种或多种表面改变剂以约0.001重量%至约5重量%之间的量存在于药物组合物中。所述多个涂布颗粒具有小于约1微米的平均最小横截面尺寸。所述药物组合物还包含一种或多种眼科学可接受的载体、添加剂和/或稀释剂。
本领域普通技术人员将理解,适于用本文公开的方法使用的颗粒可以各种形状存在,包括但不限于球状体、棒、盘、角锥体、立方体、圆柱体、纳米螺旋结构、纳米弹簧、纳米环、棒状颗粒、箭头状颗粒、泪滴状颗粒、四角锥体状颗粒、棱柱状颗粒以及多种其它几何和非几何形状。在一些实施方案中,本文公开的颗粒具有球形形状。
在一个实施方案中,本发明提供了通过向需要其的患者施用有效量的包含本发明化合物的组合物来治疗或预防阵发性睡眠性血红蛋白尿症(PNH)的方法。在一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与另外的补体系统抑制剂或具有不同的生物作用机制的另一活性化合物组合地或交替地施用于需要其的患者来治疗或预防阵发性睡眠性血红蛋白尿症(PNH)的方法。在另一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与依库珠单抗组合地或交替地施用于需要其的患者来治疗或预防阵发性睡眠性血红蛋白尿症(PNH)的方法。
在一个实施方案中,本发明提供了通过向需要其的患者施用有效量的包含本发明化合物的组合物来治疗或预防类风湿性关节炎的方法。在一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与另外的补体系统抑制剂组合地或交替地施用于需要其的患者来治疗或预防类风湿性关节炎的方法。在另一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与氨甲喋呤组合地或交替地施用于需要其的患者来治疗或预防类风湿性关节炎的方法。
在某些实施方案中,式I的化合物与选自以下的至少一种抗类风湿性关节炎药组合地或交替地施用:水杨酸盐,包括阿司匹林(Anacin、Ascriptin、Bayer Aspirin、Ecotrin)和双水杨酸酯(Mono-Gesic、Salgesic);非甾类抗炎药(NSAID);环加氧酶(COX-1和COX-2)酶的非选择性抑制剂,包括双氯芬酸(Cataflam、Voltaren)、布洛芬(Advil、Motrin)、酮洛芬(Orudis)、萘普生(Aleve、Naprosyn)、吡罗昔康(Feldene)、依托度酸(Lodine)、吲哚美辛、奥沙普秦(Daypro)、萘丁美酮(Relafen)和美洛昔康(Mobic);选择性环加氧酶-2(COX-2)抑制剂,包括塞来昔布(Celebrex);疾病调修抗风湿药(DMARD),包括硫唑嘌呤(Imuran)、环胞霉素(Sandimmune、Neoral)、金盐类(Ridaura、Solganal、Aurolate、Myochrysine)、羟化氯喹(Plaquenil)、来氟米特(Arava)、氨甲喋呤(Rheumatrex)、青霉胺(Cuprimine)和柳氮磺胺吡啶(Azulfidine);生物药物,包括阿巴西普(Orencia)、依那西普(Enbrel)、英夫利昔单抗(Remicade)、阿达木单抗(Humira)和阿那白滞素(Kineret);糖皮质激素,包括倍他米松(Celestone Soluspan)、可的松(Cortone)、地塞米松(Decadron)、甲基强的松龙(SoluMedrol、DepoMedrol)、强的松龙(Delta-Cortef)、泼尼松(Deltasone、Orasone)和曲安奈德(Aristocort);金盐,包括金诺芬(Ridaura);硫代葡萄糖金(Solganal);金硫代苹果酸钠注射剂;硫代苹果酸金钠;或它们的任何组合。
在一个实施方案中,本发明提供了通过向需要其的患者施用有效量的包含本发明化合物的组合物来治疗或预防多发性硬化症的方法。在一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与另外的补体系统抑制剂组合地或交替地施用于需要其的患者来治疗或预防多发性硬化症的方法。在另一个实施方案中,本发明提供了通过将有效量的包含本发明化合物的组合物与皮质类固醇组合地或交替地施用于需要其的患者来治疗或预防多发性硬化症的方法。皮质类固醇的实例包括但不限于泼尼松、地塞米松、甲强龙和甲基强的松龙。
在一个实施方案中,将式I的化合物与选自以下的至少一种抗多发性硬化症药联用:Aubagio(特立氟胺)、Avonex(干扰素β-1a)、Betaseron(干扰素β-1b)、Copaxone(醋酸格拉替雷)、Extavia(干扰素β-1b)、Gilenya(芬戈莫德)、Lemtrada(阿仑珠单抗)、Novantrone(米托蒽醌)、Plegridy(聚乙二醇干扰素β-1a)、Rebif(干扰素β-1a)、Tecfidera(富马酸二甲酯)、Tysabri(那他珠单抗)、Solu-Medrol(甲基强的松龙)、High-dose oral Deltasone(泼尼松)、H.P.Acthar Gel(ACTH)以及它们的组合。
在一个方面,式I的化合物或盐可与免疫抑制剂或抗炎剂组合地或交替地提供。
在本发明的一个实施方案中,本文描述的化合物可与至少一种免疫抑制剂组合地或交替地施用。作为非限制性实例,免疫抑制剂可为钙调神经磷酸酶抑制剂,例如,环孢菌素或子囊霉素,如环孢菌素AFK506(他克莫司)、吡美莫司;mTOR抑制剂,例如,雷帕霉素或其衍生物,如西罗莫司依维莫司坦罗莫司、佐他莫司、百奥莫司(biolimus)-7、百奥莫司-9;雷帕类似物,例如ridaforolimus、硫唑嘌呤、阿仑单抗1H;S1P受体调节剂,例如,芬戈莫德或其类似物;抗IL-8抗体、霉酚酸或其盐,例如,其钠盐或前药,如霉酚酸酯OKT3(ORTHOCLONE)、强的松、 布喹那钠、OKT4、T10B9.A-3A、33B3.1、15-脱氧精胍菌素、曲培莫司、来氟米特CTLAI-Ig、抗-CD25、抗-IL2R、巴利昔单抗达利珠单抗咪唑立宾、甲氨蝶呤、地塞米松、ISAtx-247、SDZ ASM 981(吡美莫司,)、CTLA41g(阿巴西普)、贝拉西普、LFA31g、依那西普(由Immunex以出售)、阿达木单抗英夫利昔单抗抗-LFA-1抗体、那他珠单抗恩莫单抗、加维莫单抗、抗胸腺细胞免疫球蛋白、西利珠单抗、阿来塞普依法珠单抗、颇得斯安、美沙拉嗪、亚沙可(asacol)、磷酸可待因、贝诺酯、芬布芬、萘普生、双氯芬酸、依托度酸和吲哚美辛、阿司匹林和布洛芬。
抗炎剂的实例包括甲氨蝶呤、地塞米松、地塞米松醇、地塞米松磷酸钠、醋酸氟米龙、氟米龙醇、氯替泼诺、甲羟松、醋酸泼尼松龙、强的松龙磷酸钠、醋丁二氟龙、利美索龙、氢化可的松、醋酸氢化可的松、洛度沙胺氨丁三醇、阿司匹林、布洛芬、舒洛芬、吡罗昔康、美洛昔康、氟比洛芬、萘普生、酮洛芬、替诺昔康、双氯芬酸钠、富马酸酮替芬、双氯芬酸钠、奈帕芬胺、溴芬酸、氟比洛芬钠、舒洛芬、塞来考昔、萘普生、罗非考昔、糖皮质激素、双氯芬酸和它们的任何组合。在一个实施方案中,将式I的化合物与选自以下的一种或多种非甾体抗炎药(NSAID)联用:萘普生钠(Anaprox)、塞来昔布(Celebrex)、舒林酸(Clinoril)、奥沙普秦(Daypro)、双水杨酯(Disalcid)、二氟尼柳(Dolobid)、吡罗昔康(Feldene)、吲哚美辛(Indocin)、依托度酸(Lodine)、美洛昔康(Mobic)、萘普生(Naprosyn)、萘丁美酮(Relafen)、酮咯酸氨丁三醇(Toradol)、萘普生/艾美拉唑(Vimovo)和双氯芬酸(Voltaren)以及它们的组合。
VI.制备式I化合物的方法
缩略语
(Boc)2O 二碳酸二叔丁酯
ACN 乙腈
AcOEt,EtOAc 乙酸乙酯
CH3OH,MeOH 甲醇
CsF 氟化铯
CuI 碘化亚铜
DCM,CH2Cl2 二氯甲烷
DIEA,DIPEA N,N-二异丙基乙胺
DMA N,N-二甲基乙酰胺
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
DPPA 二苯基磷酰基叠氮化物
Et3N,TEA 三乙胺
EtOAc 乙酸乙酯
EtOH 乙醇
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑
并[4,5-b]吡啶3-氧化物六氟磷酸盐
HCl 盐酸
iPr2Net N,N-二异丙基乙胺
K2CO3 碳酸钾
LiOH 氢氧化锂
MTBE 甲基叔丁基醚
Na2SO4 硫酸钠
NaCl 氯化钠
NaH 氢化钠
NaHCO3 碳酸氢钠
NEt3,TEA 三乙胺
Pd(OAc)2 醋酸钯
Pd(dppf)Cl2 [1,1’-双(二苯基膦)二茂铁]二氯钯(II)
Pd(PPh3)2Cl2 双(三苯基膦)钯(II)二氯化物
Pd(PPh3)4 四(三苯基膦)钯(0)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
PPh3 三苯基膦
RT 室温
TBTU O-苯并三唑基四甲基异脲四氟硼酸盐
tBuOK 叔丁醇钾
Tf2O 三氟甲磺酸酐
TFA 三氟乙酸
THF 四氢呋喃
TMSBr 溴代三甲基硅烷
tR 保留时间
Zn(CN)2 氰化锌
一般方法
所有非水反应均在干燥氩气或氮气气氛下使用无水溶剂进行。反应的进度和目标化合物的纯度使用下面列出的两种液相色谱(LC)方法中之一确定。起始材料、中间体和最终产物的结构通过包括NMR光谱和质谱法在内的标准分析技术确认。
LC方法A
仪器:Waters Acquity Ultra Performance LC
柱子:ACQUITY UPLC BEH C 18 2.1×50mm,1.7μm
柱温:40℃
流动相:溶剂A:H2O+0.05%FA;溶剂B:CH3CN+0.05%FA
流率:0.8mL/min
梯度:0.24min@15%B,3.26min梯度(15-85%B),然后0.5min@85%B
检测:UV(PDA)、ELS和MS(SQ在EI模式下)
LC方法B
仪器:Shimadzu LC-2010A HT
柱子:Athena,C18-WP,50×4.6mm,5μm
柱温:40℃
流动相:溶剂A:H2O/CH3OH/FA=90/10/0.1;溶剂B:H2O/CH3OH/FA=10/90/0.1
流率:3mL/min
梯度:0.4min@30%B,3.4min梯度(30-100%B),然后0.8min@100%B
检测:UV(220/254nm)
实施例1:一般合成路线
自例如中心核制备本发明的化合物。在一个实施方案中,中心核结构1为例如N-保护氨基酸,其中X1为氮并且PG=保护基团。在一个实施方案中,中心核偶联到胺以生成结构2的酰胺(其中L-B包括C(O)N部分)。结构2然后可被去保护以生成结构3。结构3偶联到结构4(A-COOH)以生成第二酰胺键,从而形成式I内的化合物。此化学以路线1示意。
路线1
在一个替代的实施方案中,中心核结构5与杂环或杂芳基化合物反应以生成结构6的化合物。在一个实施方案中,结构6被去保护以生成羧酸(结构7)。在一个实施方案中,结构7被偶联到胺以生成式I的化合物。此化学以路线2示意。
路线2
在一个替代的实施方案中,结构8被去保护以生成胺,其为结构9。结构9然后被偶联以生成酰胺,其为结构6。结构6然后被去保护以生成羧酸,其为结构7。结构7然后被偶联以形成酰胺,其落在式I内。此化学以路线3示意。
路线3
在一个替代实施方案中,杂芳基或芳基部分4-1偶联至中心核以生成4-2。保护的酸4-2被解封以形成羧酸4-3。羧酸然后被偶联以形成酰胺(L-B),其为4-4。杂芳基或芳基部分A′可然后被进一步衍生化以在X11、X12、X13和X14位置处添加取代基以生成式I的化合物。该化学示意在路线4中。
路线4
在一个替代实施方案中,结构5-1偶联至酸,结构5-2,以生成结构5-3。羧酸结构5-3,被解封以生成结构5-4的羧羧。羧酸结构5-4被偶联至胺以形成为式I内化合物的产物酰胺(L-B)。该化学示意在路线5中。
路线5
在一个替代的实施方案中,结构6-1被偶联至胺以生成酰胺(L-B),其为结构6-2。结构6-2被偶联至胺生成式I内的化合物,该化学示意在路线6中。
路线6
在另一个实施方案中,杂芳基化合物例如结构7-1被碘化以在R6位置引入碘化物基团。本领域技术人员也可引入其它R6基团。例如,结构7-1可被乙酰化以在R6位置处引入乙酰基。结构7-2被偶联至活化的酯,结构7-3,以生成结构7-4。在一些实施方案中,离去基团LG为卤化物。结构7-4用无机氰化物和两种有机金属催化剂处理以在R6位置处生成氰基。在一些实施方案中,无机氰化物为氰化锌。在一些实施方案中,有机金属催化剂为Pd(dppf)2和Pd2(dba)3。结构7-4用有机酸处理以生成结构7-5。在一些实施方案中,有机酸为三氟乙酸。结构7-5被偶联至来自路线1的结构3以生成式I的化合物。该化学示意在路线7中。
路线7
在另一实施方案中,杂芳基化合物例如结构8-1被偶联至活化酯,结构8-2以生成结构8-3。在一些实施方案中,R6为C(O)OEt。在一些实施方案中,离去LG为卤化物。结构8-3用有机酸处理以生成结构8-4。在一些实施方案中,有机酸为三氟乙酸。结构8-4被偶联至来自路线1的结构3以生成式I化合物。在R6为C(O)OEt的一些实施方案中,酯可被水解且用酸在R6位置处生成酰胺-C(O)NH2。该化学示意在路线8中。
路线8
在另一实施方案中,杂芳基化合物,结构9-1,被偶联至活化酯,结构9-2以生成结构9-3。在一些实施方案中,离去基团LG1为卤化物。在一些实施方案中,LG为卤化物。在一些实施方案中,结构9-3用无机氰化物和两种有机金属催化剂处理以生成结构9-4。在一些实施方案中,无机氰化物为氰化锌。在一些实施方案中,所述两种有机金属催化剂为Pd2(dba)3和Pd(dppf)Cl2。结构9-4用有机酸处理以生成结构9-5。在一些实施方案中,有机酸为三氟乙酸。结构9-5被偶联至来自路线1的结构3以生成式I内的化合物。该化学示意在路线9中。
路线9
在另一实施方案中,杂芳基化合物,结构10-1,被偶联至活化酯,结构10-2,以生成结构10-3。在一些实施方案中,离去基团LG1为卤化物。在一些实施方案中,LG为卤化物。在一些实施方案中,结构10-3用无机氰化物和两种有机金属催化剂处理以生成结构10-4。在一些实施方案中,无机氰化物为氰化锌。在一些实施方案中,所述两种有机金属催化剂为Pd2(dba)3和Pd(dppf)Cl2。结构10-4用有机酸处理以生成结构10-5。在一些实施方案中,有机酸为三氟乙酸。结构10-5被偶联至来自路线1的结构3以生成式I的化合物。该化学示意在路线10中。
路线10
直接连接到芳基或杂芳基以替代L-B区域的中心核可根据已知方法制备。例如,中心核被烷基化以生成中心核,包含羧酸的化合物被还原为醇并用于生成烷基卤化物。烷基卤化物用杂芳基化合物处理以生成式I的化合物。该化学可被有机化学领域的技术人员实施。参见例如Advanced Organic Chemistry:Reactions,Mechanisms and Structure byJ.March。
在一个实施方案中,吡咯烷化合物被烷基化以生成吡咯烷-C(O)-A化合物。产物被在吡咯烷的α位氯化并用碱处理以生成亚胺。亚胺产物用杂芳基化合物处理以生成式I的化合物。该化学可被有机化学领域的技术人员进行。参见例如Advanced Organic Chemistry:Reactions,Mechanisms and Structure by J.March。
在一个实施方案中,氨基吲哚用光气或光气等效物处理以生成式I的化合物。该化学可被有机化学领域的技术人员进行。参见例如Advanced Organic Chemistry:Reactions,Mechanisms and Structure by J.March。
实施例2:中心合成子的实例
ZA为卤素。
在一个实施方案中,公开了氘化L-脯氨酸合成子。氘化合成子包括但不限于例如以下化合物:
结构A可用氧化氘处理以生成结构B。参见Barraclough,P.et al.TetrahedronLett.2005,46,4653-4655;Barraclough,P.et al.Org.Biomol.Chem.2006,4,1483-1491和WO 2014/037480(p.103)。结构B可被还原以生成结构C。参见Barraclough,P.etal.Tetrahedron Lett.2005,46,4653-4655;Barraclough,P.etal.Org.Biomol.Chem.2006,4,1483-1491。结构C可用Mitsunobu反应条件处理以生成结构D。结构B可用DAST处理以生成结构E。参见WO 2014/037480。结构A可用硼氘化钠处理以生成结构F。参见Dormoy,J.-R.;Castro,B.Synthesis 1986,81-82。化合物F可以用于生成结构K。参见Dormoy,J.-R.;Castro,B.Synthesis 1986,81-82。结构B可用氘化还原剂例如硼氘化钠处理以生成结构G。结构G可用DAST处理以生成结构H。结构F可用来生成结构K。参见Dormoy,J.-R.;Castro,B.Synthesis 1986,81-82。结构G可用来生成结构I。结构J可根据Hruby,V.J.et al.J.Am.Chem.Soc.1979,101,202-212制备。结构A-J可用来制备式I的化合物。
实施例3:中心-L-B合成子的制备
路线1a、1b和1c
在路线1a中,(4S)-5-氮杂螺[2.4]庚烷-4,5-二羧酸、5-(1,1-二甲基乙基)酯(CAS209269-08-9)可如Tandon,M.et al.Bioorg.Med.Chem.Lett.1998,8,1139-1144中所述制备。在步骤2中,被保护的氮杂螺[2.4]庚烷在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤3中,保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
在路线1b中,(4S)4-噁唑烷羧酸盐酸盐用胺保护试剂处理。在一个实施方案中,胺保护试剂为二碳酸二叔丁酯。在另一个实施方案中,(4S)-3,4-噁唑烷二羧酸3-(1,1-二甲基乙基)酯可自JPM2Pharmaceuticals商购获得。在一个实施方案中,反应在有机溶剂中于碱的存在下进行。在一个实施方案中,有机溶剂为乙腈。在一个实施方案中,碱为4-二甲基氨基吡啶(DMAP)。在步骤2中,被保护的4-噁唑烷羧酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤3中,保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
在路线1c中,(S)-5-(叔丁氧基羰基)-5-氮杂螺[2.4]庚烷-6-羧酸(CAS 1129634-44-1)可自Ark Pharm商购获得。在步骤2中,羧酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤3中,保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
路线2a、2b、2c和2d
在路线2a中,市售Boc-L-脯氨酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤2中,Boc保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
在路线2b中,来自Enamine的市售(1R,3S,5R)-2-[(叔丁氧基)羰基]-2-氮杂双环[3.1.0]庚烷-3-羧酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤2中,Boc保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
在路线2c中,来自Manchester Organics的市售(2S,4R)-1-(叔丁氧基羰基)-4-氟吡咯烷-2-羧酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤2中,Boc保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。
在路线2d中,来自Chem-Impex的市售(S)-1-(叔丁氧基羰基)吲哚啉-2-羧酸在有机溶剂、碱和偶联试剂的存在下被偶联到胺以生成酰胺键:L-B部分。在一个实施方案中,胺为(3-氯-2-氟苯基)甲胺。在一个实施方案中,有机溶剂为DMF。在一个实施方案中,碱为二异丙基乙胺。在一个实施方案中,偶联试剂为HATU。在步骤2中,Boc保护基团被移除。在一个实施方案中,使起始材料与酸在有机溶剂的存在下反应。在一个实施方案中,酸为4N盐酸。在一个实施方案中,有机溶剂为二氧六环。此化学在方案2中说明。
可易于转化为中心-L-B-合成子的其它起始材料包括但不限于:可得自Ark Pharm的(S)-1-(叔丁氧基羰基)-2,3-二氢-1H-吡咯-2-羧酸(CAS 90104-21-5);购自Ark Pharm的环戊-1-烯-1,2-二羧酸(CAS 3128-15-2);可自FCH Group商购获得的咪唑:1H-咪唑-1,2-二羧酸1-(1,1-二甲基乙基)2-乙酯(CAS 553650-00-3);Boc-L-八氢吲哚-2-羧酸可购自Chem Impex。
化合物可根据WO 2004/111041中公开的程序制备;(S)-Boc-5-氧代吡咯烷-2-羧酸可得自Aldrich Chemical Co.;(1S,2S,5R)-3-(叔丁氧基羰基)-3-氮杂双环[3.3.0]庚烷-2-羧酸可得自Ark Pharm;(S)-3-Boc-噻唑烷-2-羧酸可得自AlfaAesar;(2S,4R)-1-(叔丁氧基羰基)-4-氯吡咯烷-2-羧酸可得自Arch Bioscience;(1S,3aR,6aS)-2-(叔丁氧基羰基)八氢环戊[c]吡咯-1-羧酸可得自Ark Pharm;1,2-吡咯烷二羧酸,3-[[(苯基甲氧基)羰基]氨基]-1-(1,1-二甲基乙基)酯,(2S,3R)可如WO 2004/007501中所公开制备。Cbz基团可被移除并且氨基基团可被烷基化以生成本发明的中心核化合物。
化合物可如Braun,J.V.;Heymons,Albrecht Berichte derDeutschen Chemischen Gesellschaft[Abteilung]B:Abhandlungen(1930)63B,502-7所公开制备。
化合物(2S,3S,4S)-4-氟-3-甲氧基-吡咯烷-1,2-二羧酸1-叔丁酯和(2R,3R,4R)-3-氟-4-甲氧基-吡咯烷-1,2-二羧酸1-叔丁酯可根据Novartis的WO 2012/093101制备为混合物并且区域异构体可在偶联以生成中心-L-B合成子后被最终分离。化合物(S)-Boc-5-氧代吡咯烷-2-羧酸可得自Aldrich Chemical Co.。
实施例4.A-C(O)-部分的制备
A-C(O)-部分的制备的实例可见实施例1和下文。
在一个替代实施方案中,结构1-1的杂芳基化合物被乙酰化以生成结构1-2。在一个替代实施方案中,结构1-1用无机氰化物和有机金属催化剂处理以生成其中R6=氰基的化合物。该氰基化合物可用肟处理以在R6位置处生成酰胺,-C(O)NH2。结构1-2被偶联至结构1-3的活化酯以生成结构1-4。在一些实施方案中,离去基团LG为卤化物。酯被水解以生成酸结构1-5。该化学示意在路线4a中。
路线4a
在一个替代实施方案中,结构2-1的杂芳基化合物被乙酰化以生成结构2-2。在一个替代实施方案中,结构2-1用无机氰化物和有机金属催化剂处理以生成其中R6=氰基的化合物。氰基化合物可用肟处理以在R6位置处生成酰胺,-C(O)NH2。结构2-2被偶联至结构2-3的活化酯以生成结构2-4。在一些实施方案中,离去基团LG为卤化物。结构2-4的酯被水解以生成酸结构2-5。该化学示意在路线4b中。
路线4b
在一个替代实施方案中,结构3-1的杂芳基化合物被乙酰化以生成结构3-2。在一个替代实施方案中,结构3-1用无机氰化物和有机金属催化剂处理以生成其中R6=氰基的化合物。该氰基化合物可用肟处理以在R6位置处生成酰胺,-C(O)NH2。结构3-2被偶联至结构3-3的活化酯以生成结构3-4。在一些实施方案中,离去基团LG为卤化物。酯被水解以生成酸,其为结构3-5。该化学示意在路线4c中。
路线4c
实施例5.中心-L-B-合成子偶联至A-C(O)-部分
中心-L-B-合成子偶联至A-C(O)-部分的实例可见于实施例1和下文。
在一个实施方案中,来自实施例4路线4a的结构1-5被偶联至来自路线1的结构3以生成式I的化合物。该化学示意在路线5a中。
路线5a
在一个实施方案中,来自实施例4路线4b的结构2-5被偶联至中心核-L-B以生成式I的化合物。该化学示意在路线5b中。
路线5b
在一个实施方案中,来自实施例4路线4c的结构3-5被偶联至来自路线1的结构3以生成式I的化合物。该化学示意在路线5c中。
路线5c
实施例6.式I化合物的非限制性实例的合成
方案1.(2S,4R)-N-(2′-氯-2-氟-[1,1′-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(Int-1)的合成
步骤1:2′-氯-2-氟-[1,1′-联苯基]-3-胺盐酸盐(SM3)
SM1(30g)、SM2(60g)K2CO3(91g)和Pd(dppf)2Cl2(19.25g)在溶剂(二氧六环400mL,H2O 100mL)中的混合物在压力容器中用氩气吹扫5分钟并在100℃下搅拌15小时。减压除去溶剂且剩余的残余物通过柱色谱纯化。纯化的材料然后溶解在MeOH中并用HCl/MeOH处理。溶剂被减压除去且剩余固体用IPA-庚烷(1/1)洗涤得到SM3。
步骤2:(2S,4R)-叔丁基2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯(SM5)
向SM4(530mg)在DCM(20mL)中的冰冷溶液中在搅拌下逐滴加入1-氯-N,N,2-三甲基-1-丙烯胺(0.333mL,1.1当量)。在该温度下搅拌继续3小时,并然后加入固体SM3(640mg,1.1当量),接着加入DIEA(1.12mL,3当量)。移除冷却浴且反应混合物在室温下搅拌过夜。反应混合物然后加入水(20mL)中并用DCM(2x25mL)萃取。有机层相继用碳酸氢钠水溶液(20mL)、水(20mL)和盐水(20mL)洗涤,然后在硫酸钠上干燥并减压浓缩。剩余残余物通过柱色谱(用己烷/EtOAc洗脱)纯化得到SM5。
步骤3:(2S,4R)-N-(2′-氯-2-氟-[1,1′-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(Int-1)
(2S,4R)-叔丁基2-((2’-氯-2-氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯SM5(700mg)被溶入4N HCl的二氧六环溶液(25mL)中且所得反应混合物在室温下搅拌3小时。然后减压除去溶剂且剩余残余物Int-1不用进一步纯化而直接使用。
方案2.(2S,4R)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺TFA盐(Int-2)的合成
步骤1:(2S,4R)-叔丁基2-((6-溴吡啶-2-基)氨甲酰)-4-氟吡咯烷-1-羧酸酯(SM8)
向SM6(30g)在DCM(600mL)中的冰冷溶液中在搅拌下逐滴加入1-氯-N,N,2-三甲基-1-丙烯胺(18.7mL,1.1当量)。在该温度下搅拌继续3小时。然后加入固体SM7(24.48g,1.1当量),接着加入DIEA(67.2mL,3当量)。移除冷却浴且反应混合物在室温下搅拌过夜。溶剂与甲醇(30mL)共蒸发。残余物然后溶解在氯仿(300mL)中,并相继用冷的1N HCl水溶液(3×200mL)、水(300mL)和饱和碳酸氢钠水溶液(300mL)洗涤。有机层被干燥(硫酸钠)并减压浓缩。剩余残余物在1∶1的DCM和庚烷的溶液(150mL)中搅拌。通过过滤分离白色固体并高真空度下干燥以得到SM8(37.3g)。
步骤2:(2S,4R)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺TFA盐(Int-2)
SM8被溶解在DCM中并加入等体积的TFA。混合物在室温下搅拌30分钟。减压除去挥发物且残余Int-2不进一步纯化而使用。
方案3:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(99)的合成
步骤1:1H-噻吩并[3,2-c]吡唑(99b)
根据文献(Airey,J.et al.Synthesis 2014,96-100),从3-溴噻吩-2-甲醛99a制备标题化合物99b(310mg)。1H NMR(400MHz,CDCl3,300K):δ7.11(s,1H),7.60(s,1H),7.76+8.03(1H),13.33+13.0(1H)。
步骤2:3-碘-1H-噻吩并[3,2-c]吡唑(99c)
在DMF(10mL)中的1H-噻吩并[3,2-c]吡唑99b(310mg,2.5mmol)用碘(954mg,3.76mmol)、接着用粉末状KOH(421mg,7.5mmol)处理。混合物在室温下搅拌过夜。混合物用水(50mL)稀释,接着加入10%Na2S2O3溶液(5mL)。混合物用乙酸乙酯(3×50mL)萃取。合并的有机萃取物用盐水洗涤并在硫酸镁上干燥。溶液被过滤并浓缩,残余物99c不用纯化被用于下一步骤中。
步骤3:2-(3-碘-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(99d)
来自步骤2的残余物99c溶解在CH3CN(50mL)中。向该溶液中加入2-溴乙酸叔丁酯(634mg,0.48mL,3.25mmol)和固体碳酸钾(1.03g,7.5mmol)。混合物在氩气气氛下回流过夜。反应混合物被冷却至室温并通过垫过滤。固体饼用CH3CN(20mL)洗涤,且合并的溶液在减压下浓缩。剩余的残余物通过柱色谱纯化得到纯的化合物99d(610mg)和不纯的异构体2-(3-碘-2H-噻吩并[3,2-c]吡唑-2-基)乙酸叔丁酯(130mg)。1H NMR(400MHz,CDCl3):δ1.45(s,9H),4.93(s,2H),6.93(d,J=5.2Hz,1H),7.42(d,J=5.2Hz,1H).LC/MS(EI)m/z:[M+H]+365。
步骤4:2-(3-氰基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(99e)
在氩气气氛下向2-(3-碘-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯99d(610mg,1.67mmol)在共溶剂DMF(14mL)和水(2mL)中的脱气的溶夜中加入Zn(CN)2(235mg,2.0mmol),Pd(dppf)2(125mg,0.17mmol)和Pd2(dba)3(156mg,0.17mmol)。混合物在110℃下加热6小时。反应混合物冷却至室温并减压除去挥发物。剩余残余物用乙酸乙酯(50mL)稀释并通过垫过滤。固体用乙酸乙酯(30mL)洗涤。合并的有机溶液减压浓缩且剩余的残余物通过柱色谱纯化得到标题化合物99e(290mg)。1H NMR(400MHz,CDCl3,300K):δ1.47(s,9H),5.0(s,2H),6.93(d,J=5.2Hz,1H),7.52(d,J=5.2Hz,1H).LC/MS(EI)m/z:[M+H]+264。
步骤5:2-(3-氨甲酰基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸(99f)
2-(3-氰基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(59mg,0.22mmol)在TFA(2mL)中的溶液在140℃下经受微波照射30分钟。混合物减压浓缩,且残余物与甲苯(10mL)共蒸发两次。干燥的残余物99f直接用于下一步骤中。LC/MS(EI)m/z:226。
步骤6:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(99)
在室温下向来自步骤5的剩余物99f(0.22mmol)的溶液中加入在DMF(2mL)中的(2S,4R)-N-(2′-氯-2-氟-[1,1′-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐Int-1(90mg,0.24mmol),接着加入HATU(109mg,0.29mmol),并逐滴加入DIEA(0.3mL)。反应混合物在室温下搅拌1小时,并减压除去挥发物。残余物用20mL的10%的碳酸钠稀释并用乙酸乙酯(3×20mL)萃取。合并的有机溶液用水和盐水洗涤,并然后在硫酸镁上干燥。溶液被过滤并减压除去溶剂。剩余的残余物通过柱色谱纯化得到99(50.7mg).1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ2.00-2.19(m,1H),2.47-2.53(m,1H),3.75-3.88(m,1H),4.02-4.11(m,1H),4.70(t,J=8.8Hz,1H),5.26(d,J=17.2Hz,1H),5.38-5.49(m,2H),6.97-7.01(m,1H),7.05(d,J=5.2Hz,1H),7.15(t,J=7.6Hz,1H),7.30-7.41(m,4H),7.51-7.54(m,2H),7.60-7.62(m,1H),7.89-7.93(m,1H),9.92(s,1H);19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.8,-175.8.LC(方法A):tR=1.94min.LC/MS(EI)m/z:[M+H]+544。
方案4:1-(2-((2S,4R)-2-((6-溴吡啶-2-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(106)的合成
向2-(3-氨甲酰基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸99f(0.193mmol)的溶液中加入在DMF(1.5mL)中的(2S,4R)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(0.212mmol)、接着加入TBTU(93mg,0.29mmol),并逐滴加入DIEA(0.21mL,1.2mmol)。反应混合物在室温下搅拌0.5小时,然后通过碳酸氢钠水溶液(5mL)淬灭。通过过滤收集沉淀,并通过柱色谱(洗脱液:5%MeOH,在DCM中)纯化得到106(68mg)。1H NMR(400MHz,CDCl3-CD3OD,300K):(主要旋转异构体)δ2.37(m,1H),2.39-2.41(m,1H),2.59-2.70(m,1H),3.65(dd,J=36.0,12.4Hz,1H),3.90-3.98(dd,J=20.0,12.0Hz,1H),4.80(t,J=8.0Hz,1H),5.18(d,J=8.0Hz,1H),5.4(m,1H),6.96(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),7.50(d,J=4.0Hz,1H),7.55(t,J=8.0Hz,1H),8.14(d,J=8.0Hz,1H).31F NMR(376MHz,CDCl3-CD3OD,300K):(主要旋转异构体)δ-177.0.LC(方法A):tR=1.33min.LC/MS(EI)m/z:[M+H]+497。
方案5:1-(2-((1R,3S,5R)-3-((3-氯-2-氟苄基)氨甲酰基)-2-氮杂双环[3.1.0]己-2-基)-2-氧代乙基)-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(109)的合成
向2-(3-氨甲酰基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸99f(0.287mmol)的溶液中加入在DMF(1.5mL)中的(1R,3S,5R)-N-(3-氯-2-氟苄基)-2-氮杂双环[3.1.0]己烷-3-甲酰胺盐酸盐(48mg,0.158mmol)、接着加入TBTU(69mg,0.216mmol),并逐滴加入DIEA(0.13mL,0.75mmol)。反应混合物在室温下搅拌0.5小时,然后通过碳酸氢钠水溶液(5mL)淬灭。混合物用EtOAc(30mL)萃取且有机层用水和盐水洗涤。减压除去溶剂且剩余残余物通过柱色谱(洗脱液:5%MeOH,在DCM中)纯化得到109(57mg)。1H NMR(400MHz,CDCl3,300K):(主要旋转异构体)δ0.59-0.61(m,1H),1.08-1.12(m,1H),1.95-2.06(m,3H),2.70-2.72(m,1H),3.34-3.62(m,1H),4.41(s,2H),4.57-4.60(m,1H),5.21-5.32(m,2H),6.00(s,1H),6.70(s,1H),6.84-6.85(m,1H),6.92-6.94(m,1H),7.11-7.13(m,1H),7.21-7.26(m,1H),7.36-7.38(m,1H),7.43(m,1H).13C NMR(100MHz,CDCl3,300K):(主要旋转异构体)δ19.40,20.74,29.97,37.14,37.52,53.43,65.54,108.95,120.76,120.94,123.07,124.58,124.63,126.83,126.98,127.93,129.56,134.78,137.27,150.91,154.84,157.30,163.16,167.60,170.45.31F NMR(376MHz,CDCl3,300K):(主要旋转异构体)δ-120.9.LC(方法A):tR=1.49min.LC/MS(EI)m/z:[M+H]+476。
方案6:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-5-甲基-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(113)的合成
步骤1:3-溴-5-甲基噻吩-2-甲醛(113b)
在氩气气氛下向冷却至-78℃的4-溴-2-甲基噻吩113a(11g,62mmol)在无水THF(100mL)中的溶液中逐滴加入2M LDA-THF溶液(34mL,68mmol)。混合物在-78℃下搅拌2小时并然后加入无水DMF(9.6mL,124mmol)。反应混合物在-78℃下保持1小时并用10%柠檬酸水溶液(10mL)淬灭。减压除去挥发物且剩余残余物用乙酸乙酯(150mL)稀释。有机层相继用5%柠檬酸水溶液(80mL)、水(100mL)和盐水(50mL)洗涤并然后在硫酸镁上干燥。溶液被过滤并减压浓缩得到浅黄色油的113b(12.3g),其不进一步纯化用于下一步骤中。
步骤2:5-甲基-1H-噻吩并[3,2-c]吡唑(113c)
以类似于文献(Airey,J.et al.Synthesis 2014,96-100)报告的方式从3-溴-5-甲基噻吩-2-甲醛113b(12.2g)制备标题化合物113c(3.0g).1H NMR(400MHz,CDCl3,300K):δ2.49(s,3H),6.86(s,1H),7.65+7.89(1H),12.83+13.10(1H).LC/MS(EI)m/z:[M+H]+139。
步骤3:3-碘-5-甲基-1H-噻吩并[3,2-c]吡唑(113d)
以类似于方案3的步骤2中所述的方式从5-甲基-1H-噻吩并[3,2-c]吡唑(1.0g)制备标题化合物113d。
步骤4:2-(3-碘-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(113e)
以类似于方案3的步骤3中所述的方式从3-碘-5-甲基-1H-噻吩并[3,2-c]吡唑制备标题化合物113e。1H NMR(400MHz,CDCl3):1.46(s,9H),2.53(s,3H),4.87(s,2H),6.64(s,1H)ppm.MH+379.09。少量产物为2-(3-碘-5-甲基-2H-噻吩并[3,2-c]吡唑-2-基)乙酸叔丁酯。1H NMR(400MHz,CDCl3,300K):δ1.47(s,9H),2.51(s,3H),4.98(s,2H),6.80(s,1H).LC/MS(EI)m/z:[M+H]+379。
步骤5:2-(3-氰基-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(113f)
以类似于方案3的步骤4中所述的方式从2-(3-碘-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(823mg,2.15mmol)制备标题化合物113f。1H NMR(400MHz,CDCl3,300K):δ1.47(s,9H),2.56(s,3H),4.93(s,2H),6.65(s,1H).LC/MS(EI)m/z:[M+H]+278。
步骤6:2-(3-氨甲酰基-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸(113g)
以类似于方案3的步骤5中所述的方式从2-(3-氰基-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸叔丁酯(143mg)制备标题化合物113g。LC/MS(EI)m/z:[M+H]+240。
步骤7:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-5-甲基-1H-噻吩并[3,2-c]吡唑-3-甲酰胺(113)
以类似于方案3的步骤6中所述的方式从2-(3-氨甲酰基-5-甲基-1H-噻吩并[3,2-c]吡唑-1-基)乙酸(105mg,0.3mmol)制备标题化合物113(86.9mg)。1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ2.06-2.19(m,1H),2.39(s,3H),2.40-2.55(m,1H),3.74-3.87(m,1H),4.02-4.10(m,1H),4.69(t,J=8.8Hz,1H),5.18(d,J=17.2Hz,1H),5.31-5.51(m,2H),6.79(s,1H),7.0(t,J=7.2Hz,1H),7.15(t,J=8.0Hz,1H),7.24-7.46(m,4H),7.50-7.53(m,2H),7.87-7.92(m,1H),9.92(s,1H);19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.71,-175.87.LC(方法A):tR=2.10min.LC/MS(EI)m/z:[M+H]+558。
方案7:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(104)的合成
步骤1:1-(2-(叔丁氧基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯(104b)
向4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯104a(1.03g,5.35mmol)在CH3CN(50mL)中的溶液中加入2-溴乙酸叔丁酯(1.17g,0.89mL,6.0mmol)和碳酸钾(1.5g,10.6mmol)。混合物在氩气气氛下回流过夜。LC-MS分析指示形成了比率为4∶1的两种异构体。反应混合物冷却至室温并通过垫过滤。固体饼用CH3CN(20mL)洗涤,且合并的溶液减压浓缩。剩余物通过柱色谱纯化得到主要的异构体1-(2-(叔丁氧基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯104b(1.37g)和次要异构体2-(2-(叔丁氧基)-2-氧代乙基)-4,5,6,7-四氢-2H-吲唑-3-羧酸乙酯104c(0.28g)。1H NMR(400MHz,CDCl3,300K):(主要异构体)δ1.38(t,J=7.2Hz,3H),1.45(s,9H),1.75(m,2H),1.82(m,2H),2.52(t,J=5.2Hz,2H),2.75(t,J=5.2Hz,2H),4.37(q,J=7.2Hz,2H),4.77(s,2H).LC/MS(EI)m/z:309.1H NMR(400MHz,CDCl3,300K):(次要异构体)δ1.35(t,J=7.2Hz,3H),1.47(s,9H),1.74-1.80(m,4H),2.67(t,J=5.2Hz,2H),2.75(t,J=5.2Hz,2H),4.30(q,J=7.2Hz,2H),5.11(s,2H).LC/MS(EI)m/z:[M+H]+309。
步骤2:2-(3-(乙氧基羰基)-4,5,6,7-四氢-1H-吲唑-1-基)乙酸(104d)
l-(2-(叔丁氧基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯104b(1.35g,4.38mmol)用TFA(5mL)和DCM(5mL)处理并在室温下搅拌过夜。减压除去挥发物且剩余的残余物与甲苯(10mL)共蒸发两次。干燥残余物104d直接用于下一步骤中。
步骤3:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-羧酸乙酯(104e)
向来自步骤2的剩余物104d(375mg,1.5mmol)的溶液中加入在DMF(2mL)中的(2S,4R)-N-(2′-氯-2-氟-[1,1′-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(560mg,1.5mm0l)、接着加入HATU(741mg,1.95mmol),并逐滴加入DIEA(4.5mmol,0.78mL)。混合物在室温下搅拌1小时,并减压除去挥发物。剩余残余物用10%的碳酸钠水溶液(20mL)和水(50mL)稀释,然后用乙酸乙酯(3×50mL)萃取。合并的有机萃取物用水和盐水洗涤,然后在硫酸镁上干燥。溶液被过滤且溶剂在减压下除去。剩余残余物通过柱色谱纯化得到标题化合物104e(608mg).LC/MS(EI)m/z:[M+H]+571.
步骤4:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-羧酸(104f)
来自步骤3的化合物104e(608mg,1.06mmol)溶解在MeOH-THF-H2O(3mL-3mL-3mL)的混合物中并用LiOH(100mg,4.25mmol)处理。反应混合物在室温下搅拌过夜。减压除去挥发物且剩余残余物用10%的柠檬酸水溶液(10mL)酸化。固体104f通过过滤收集,用水洗涤,并真空干燥用于下一步骤。LC/MS(EI)m/z:[M+H]+543。
步骤5:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4,5,6,7-四氢-1H-吲唑-3-甲酰胺(104)
来自步骤4的酸104f(252mg,0.46mmol)与在DMF(3mL)中的NH4Cl(125mg,2.32mmol)混合。向该溶液中加入HATU(262mg,0.69mmol)、接着逐滴加入DIEA(1.38mmol,0.24mL)。混合物在室温下搅拌3小时,并减压除去挥发物。剩余残余物用10%的碳酸钠水溶液(15mL)和水(15mL)稀释,并然后用乙酸乙酯(3×25mL)萃取。合并的有机溶液用水和盐水洗涤,并然后在硫酸镁上干燥。混合物被过滤且滤液减压浓缩。剩余残余物通过柱色谱纯化得到标题化合物104(160mg)。1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ1.53-1.61(m,4H),1.99-2.16(m,1H),2.38-2.41(m,3H),2.54-2.56(m,2H),3.40-3.53(m,1H),3.93-4.07(m,1H),4.68(t,J=8.8Hz,1H),4.90-5.14(m,2H),5.36-5.49(1H),6.93-7.19(m,4H),7.32-7.43(m,3H),7.52-7.54(m,1H),7.92(t,J=6.8Hz,1H),9.90(s,1H);19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.8,-176.06.LC(方法A):tR=2.02min.LC/MS(EI)m/z:[M+H]+542。
方案8:(2S,4R)-1-(2-(3-乙酰基-8-(3-氯苯基)-1H-咪唑并[1,2-a]吡唑并[3,4-c]吡啶-1-基)乙酰基)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺(105)的合成
步骤1:2-(3-乙酰基-8-(3-氯苯基)-1H-吡唑并[4,3-g]吲哚嗪-1-基)乙酸甲酯(105c)
将1-(1-叠氮乙烯基)-3-氯苯105a(0.05g)(如根据Donthiri等.J.Org.Chem2014,79,11277-11284报告的制备)、2-(3-乙酰基-1H-吡唑并[3,4-c]吡啶-1-基)乙酸甲酯105b(0.195g),CuI(1mg)和分子筛的混合物置于小瓶中并加入无水乙腈(3mL)。密封小瓶在65℃下加热24小时。使反应混合物冷却至室温且减压除去溶剂。剩余的残余物通过柱色谱(洗脱液:DCM)纯化得到浅橙色固体的105c(20mg)。
步骤2:2-(3-乙酰基-8-(3-氯苯基)-1H-吡唑并[4,3-g]吲哚嗪-1-基)乙酸(105d)
来自步骤1的固体105c(20mg,0.052mmol)溶入THF(3mL),水(0.3mL),和MeOH(1mL)中,并然后加入1N NaOH水溶液(1mL)。所得混合物在室温下搅拌过夜并减压浓缩。剩余残余物用乙酸乙酯和水稀释。有机层被分离且水层用乙酸乙酯反复萃取。合并的有机层被干燥并浓缩得到浅黄色固体105d,其原样用于下一步骤中。
步骤3:(2S,4R)-1-(2-(3-乙酰基-8-(3-氯苯基)-1H-咪唑并[1,2-a]吡唑并[3,4-c]吡啶-1-基)乙酰基)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺(105)
向冷却至0-5℃的2-(3-乙酰基-8-(3-氯苯基)-1H-吡唑并[4,3-g]吲哚嗪-1-基)乙酸105d(0.052mmol)和(2S,4R)-N-(6-溴吡啶-2-基)-4-氟吡咯烷-2-甲酰胺TFA盐(0.05mmol)在DMF(1mL)中的溶液中加入DIEA(47μl)。然后向该冷却的溶液中加入HATU(24mg),并移除冷却浴。反应混合物在室温下搅拌30分钟并倒入水(10mL)中,并搅拌。固体通过过滤分离并通过柱色谱(洗脱液:0-1.5%MeOH,在DCM中)纯化得到浅黄色固体105(10mg)。1H NMR(400MHz,CDCl3,300K):(主要旋转异构体)δ2.48-2.52(m,1H),2.73(s,3H),2.78-2.94(m,1H),4.04-4.27(m,2H),4.95(t,J=7.6Hz,1H),5.51(d,J=52.4Hz,1H),5.77(d,J=16Hz,1H),5.88(d,J=16Hz,1H),6.99(d,J=8.4Hz,1H),7.19-7.23(m,2H),7.54-7.56(m,1H),7.69-7.71(m,2H),7.75(d,J=8Hz,1H),7.85(s,1H),7.87(d,J=7.2Hz,1H),8.97(br s,1H);31F NMR(376MHz,CDCl3,300K):(主要旋转异构体)δ-176.04;LC(方法A):tR=2.60min.LC/MS(EI)m/z:[M+H]+640。
方案9:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰)-4-氟吡咯烷-1-基)-2-氧代乙基)-7-氰基-1H-吲唑-3-甲酰胺(111)的合成
步骤1:7-溴-1H-吲唑-3-甲酰胺(111b)
向溴吲唑111a(3g)在DMF(30mL)中的溶液中加入氯化铵(1.8g)和DIEA(10.38mL)。反应混合物在冰浴中冷却并然后加入HATU(5.7g)。反应混合物加温至室温并搅拌过夜。反应混合物倒入包含LiOH(630mg)的水(300mL)中。产物通过过滤分离并用水洗涤。棕褐色固体在高真空度下干燥得到111b(2.15g)。
步骤2:2-(7-溴-3-氨甲酰-1H-吲唑-1-基)乙酸叔丁酯(111c)
7-溴-1H-吲唑-3-甲酰胺111b(2.15g)、溴乙酸叔丁酯(1.45mL)和碳酸钾(1.36g)在无水乙腈(40mL)中的混合物被回流2小时。反应混合物然后冷却至室温且溶剂被减压除去。剩余残余物用水(40mL)超声并过滤。获得的固体用水充分洗涤并进一步用2∶1的叔丁基甲基醚和庚烷的混合物(30mL)洗涤并在高真空度下干燥得到111c(2.5g)。
步骤3:2-(3-氨甲酰-7-氰基-1H-吲唑-1-基)乙酸叔丁酯(111d)
2-(7-溴-3-氨甲酰基-1H-吲唑-1-基)乙酸叔丁酯111c(0.5g)、氰化锌(0.198g),Pd(dppf)Cl2(0.115g)和Pd2(dba)3(0.129g)在DMF(5mL)和水(1mL)中的混合物用氩气鼓泡5分钟。然后密封小瓶并在80℃下加热3小时。将反应混合物冷却至室温后,其用乙酸乙酯稀释。混合物然后用水和饱和的碳酸氢钠水溶液洗涤。分离的有机层被干燥(硫酸钠)并浓缩。剩余残余物通过柱色谱(0-2%MeOH,在DCM中)纯化得到浅黄色固体(0.3g)。固体然后用醚(3mL)洗涤以得到无色固体的111d(0.23g)。
步骤4:2-(3-氨甲酰基-7-氰基-1H-吲唑-1-基)乙酸(111e)
以类似于方案7的步骤2中所述的方式从2-(3-氨甲酰基-7-氰基-1H-吲唑-1-基)乙酸叔丁酯(50mg)制备标题化合物111e,并不用进一步纯化用于下一步骤中。
步骤5:1-(2-((2S,4R)-2-((2′-氯-2-氟-[1,1′-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-7-氰基-1H-吲唑-3-甲酰胺(111)
使用方案3的步骤6中所述的程序将来自上述步骤4的2-(3-氨甲酰基-7-氰基-1H-吲唑-1-基)乙酸111e与(2S,4R)-N-(2′-氯-2-氟-[1,1′-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐偶联。粗产物通过柱色谱(0-2%MeOH,在DCM中)纯化得到标题化合物111(50mg)。1H NMR(400MHz,CD3OD,300K):(主要旋转异构体)δ2.65-2.75(m,1H),4.1-4.14(m,1H),4.16-4.24(m,1H),4.89(t,J=8.4Hz,1H),5.52(d,J=52.8Hz,1H),5.73(d,J=17.6Hz,1H),5.89(d,J=17.6Hz,1H),7.07(t,J=7.2Hz,1H),7.19(t,J=8Hz,1H),7.28-7.44(m,5H),7.49-7.59(m,1H),7.87(d,J=7.2Hz,1H),7.91(s,1H),7.97(t,J=7.2Hz,1H),8.59(d,J=8Hz,1H).).31F NMR(376MHz,CD3OD,300K):(主要旋转异构体)δ-178.5,-128.8.LC(方法A):tR=2.09min.LC/MS(EI)m/z:[M+H]+563。
方案10:1-(2-((2S,4R)-2-((5’-乙酰基-2'-氯-2-氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-吲唑-3-甲酰胺(117)
步骤1:1-(3'-氨基-6-氯-2'-氟-[1,1'-联苯基]-3-基)乙酮(117c)
在氩气气氛下,向3-溴-2-氟苯胺117a(1.0g)、(5-乙酰基-2-氯苯基)硼酸117b(3.132g)、Pd(dppf)Cl2(0.860g)和K2CO3(3.64g)的混合物中加入二氧六环(40mL)和水(10mL)。混合物用氩气鼓泡5分钟并在100℃下搅拌过夜。反应混合物然后通过垫过滤且滤液在减压下浓缩。剩余残余物通过柱色谱(0-0.5%MeOH,在DCM中)纯化得到橙-黄色油状的117c(0.9g)。
步骤2:(2S,4R)-叔丁基2-((5'-乙酰基-2’-氯-2-氟-[1,1'-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯(117d)
在搅拌下向(2S,4R)-1-(叔丁氧基羰基)-4-氟吡咯烷-2-羧酸(0.25g,1.07mmol)在DCM(15mL)中的冰冷溶液中逐滴加入1-氯-N,N,2-三甲基丙-1-烯-1-胺(1.2mmol,0.16mL,1.1当量)。在该温度下搅拌继续3小时。然后加入固体1-(3'-氨基-6-氯-2'-氟-[1,1’-联苯基]-3-基)乙酮117c(256mg,0.97mmol)、接着加入DIEA(0.56mL,3.6mmol,3当量)。移除冷却浴且反应混合物在室温下搅拌过夜。溶剂与MeOH(3mL)共蒸发。剩余残余物然后溶解在氯仿(30mL)中并相继用1N的HCl水溶液(3×20mL)、水(30mL)和饱和的碳酸氢钠水溶液(30mL)洗涤。有机层被干燥(硫酸钠)并减压浓缩。最后,残余物用1∶1的DCM和庚烷的溶液(15mL)搅拌。产物通过过滤分离并在高真空度下干燥得到白色固体117d(0.2g)。
步骤3:(2S,4R)-N-(5'-乙酰基-2'-氯-2-氟-[1,1'-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺TFA盐(117e)
(2S,4R)-叔丁基2-((5’-乙酰基-2'-氯-2-氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯117d(110mg)在DCM(2mL)和TFA(2mL)中搅拌30min。减压除去挥发物,所得残余物117e原样用于下一步骤中。
步骤4:1-(2-((2S,4R)-2-((5'-乙酰基-2'-氯-2-氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-吲唑-3-甲酰胺(117)
以类似于方案8的步骤3的方式制备标题化合物117。因此,(2S,4R)-N-(5’-乙酰基-2’-氯-2-氟-[1,1’-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺TFA盐117e(获自步骤3)与2-(3-氨甲酰基-1H-吲唑-1-基)乙酸(0.05g)使用在DMF(1.5mL)中的HATU(0.104g)和DIEA(0.2mL)进行偶联。通过柱色谱(0-2%MeOH,在DCM中)纯化粗产物得到117(60mg)。1H NMR(400MHz,CD3OD,300K):(主要旋转异构体)δ2.65-2.75(m,1H),3.91-4.04(m,1H),4.20-4.29(m,1H),4.84(t,J=8Hz,1H),5.48(d,J=52Hz,1H),5.42(d,J=17.2Hz,1H),5.57(d,J=17.2Hz,1H),7.12(t,J=6.8Hz,1H),7.21-7.32(m,2H),7.43(t,J=7.2Hz,1H),7.59(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.89(s,1H),7.93(s,1H),7.96-8.02(m,2H),8.22(d,J=8Hz,1H).31F NMR(376MHz,CD3OD,300K):(主要旋转异构体)δ-128.5,-178.6ppm.LC(方法A):tR=1.92min.LC/MS(EI)m/z:[M+H]+580。
方案11:1-(2-((2S,4R)-2-((2'-氯-2-氟-[1,1'-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-3-甲酰胺(110)的合成
步骤1:2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸叔丁酯(110b)
将4-溴-1H-吡唑-3-甲酰胺110a(1.0g,5.26mmol)、溴乙酸叔丁酯(1.13g,0.84mL5.78mmol)和碳酸钾(798mg,5.78mmol)在无水乙腈(20mL)中的混合物回流5小时。反应混合物然后冷却至室温且溶剂在减压下除去。残余物溶入1∶1的DCM和水(100mL∶100mL)的混合物中。分离两层且有机层用水(2×100mL)洗涤。最后,有机层被干燥(硫酸钠)并浓缩。所得残余物通过柱色谱纯化得到2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸叔丁酯110b。
步骤2:2-(3-氨甲酰基-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-1-基)乙酸叔丁酯(110c)
在压力容器中用氩气吹扫2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸叔丁酯110b(150mg,0.49mmol)、(2-甲氧基嘧啶-5-基)硼酸(154mg,1mmol)、碳酸铯(380mg,1.17mmol)和DMF(2mL)的混合物5分钟。然后在氩气下加入四(三苯基膦)钯(0)(30mg,0.025mmol)并密封压力容器并用微波在90℃下照射30分钟。反应混合物被冷却至室温并减压除去溶剂。剩余残余物通过柱色谱纯化得到110c。
步骤3:2-(3-氨甲酰基-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-1-基)乙酸(110d)
在DCM(5mL)中的2-(3-氨甲酰基-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-1-基)乙酸叔丁酯110c(120mg,0.36mmol)用TFA(5mL)处理。反应完成(如根据LC-MS分析判断)后,减压除去溶剂。剩余物质110d直接用于下一步骤中。
步骤4:1-(2-((2S,4R)-2-((2'-氯-2-氟-[1,1'-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-3-甲酰胺(110)
在5℃下将来自步骤3的2-(3-氨甲酰基-4-(2-甲氧基嘧啶-5-基)-1H-吡唑-1-基)乙酸110d(0.36mmol)溶解在DMF(4mL)中并加入DIEA(1.8mmol),然后加入(2S,4R)-N-(2'-氯-2-氟-[1,1’-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(120mg,0.32mmol)。然后在该温度下缓慢添加HATU(287mg,0.76mmol)且反应混合物在室温下搅拌3小时。反应混合物然后加入水(50mL+10g固体NaCl)中并用DCM(2×25mL)萃取。有机层相继用碳酸氢钠的水溶液(20mL)、水(20mL)和盐水(20mL)洗涤,然后在硫酸钠上干燥并减压浓缩。剩余残余物通过柱色谱(用DCM/CH3OH洗脱)纯化得到标题化合物110。1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ2.20-2.26(m,1H),2.51-2.62(m,1H),3.79-3.91(m,1H),3.94(s,3H),4.09-4.17(m,1H),4.80(t,J=8.0Hz,1H),5.17-5.41(m,2H),5.50(d,J=7Hz,1H),7.08(t,J=7.2Hz,1H),7.24(t,J=8.0Hz,1H),7.30(s,1H),7.39-7.47(m,4H),7.58-7.61(m,1H),7.96-8.13(m,2H),8.74(s,2H),10.05(s,1H);19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.84,-175.97ppm.LC(方法A):tR=1.85min.LC/MS(EI)m/z:[M+H]+596。
方案12:(1R,3S,5R)-2-(2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酰基)-N-(2'-氯-2-氟-[1,1'-联苯基]-3-基)-2-氮杂双环[3.1.0]己烷-3-甲酰胺(77)的合成
步骤1:2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸(77a)
以与方案7的步骤2中所述相似的方式用TFA(5mL)处理在DCM(5mL)中的2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸叔丁酯110b(120mg,0.40mmol)。减压除去挥发物且剩余的物质直接用于下一合成步骤中。
步骤2:(1R,3S,5R)-2-(2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酰基)-N-(2'-氯-2-氟-[1,1'-联苯基]-3-基)-2-氮杂双环[3.1.0]己烷-3-甲酰胺(77)
以与方案5中所述的类似方式从2-(4-溴-3-氨甲酰基-1H-吡唑-1-基)乙酸77a和(1R,3S,5R)-N-(2’-氯-2-氟-[1,1’-联苯基]-3-基)-2-氮杂双环[3.1.0]己烷-3-甲酰胺盐酸盐(131mg)制备标题化合物77(50mg)。1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ0.65(d,J=1.6Hz,1H),0.97-1.02(m,1H),1.86-1.88(m,1H),2.24-2.29(m,2H),3.66(t,J=5.2Hz,1H),4.52-4.56(m,1H),5.19-5.47(m,2H),7.09(t,J=7.2Hz,1H),7.24(t,J=8.0Hz,1H),7.28(s,1H),7.39-7.47(m,4H),7.59-7.61(m,1H),7.94(t,J=7.2Hz,1H),7.99(s,1H),9.79(s,1H);19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.64.LC(方法A):tR=1.97min.LC/MS(EI)m/z:[M+H]+560。
方案13:1-(2-((2S,4R)-2-((2’-氯-2,4’,5’-三氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-吲唑-3-甲酰胺(80)的合成
步骤1:2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(80b)
3-溴-2-氟苯胺(0.5g,2.63mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂环戊硼烷)(1.67g,6.6mmol)和KOAc(0.77g)在二氧六环(10mL)中的溶液被脱气并用氩气再填充两次。向该溶液中在氩气气氛下加入Pd(dppf)2Cl2(289mg)。溶液在90℃下加热15小时。反应混合物被冷却至室温并减压除去挥发物。剩余残余物通过柱色谱纯化得到80b(803mg)。
步骤2:2’-氯-2,4'-5’-三氟-[1,1'-联苯基]-3-胺盐酸盐(80c)
将2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺80b(26.0g,110mmol)、1-溴-2,4,5-三氟苯(12.5g,60mmol)和K2CO3(38g,275mmol)在二氧六环(250mL)和水(63mL)的共溶剂中的溶液脱气并用氩气再填充两次。向该溶液中在氩气气氛下加入Pd(dppf)2Cl2(8.04g)。溶液回流15小时。反应混合物被冷却至室温并减压除去挥发物。剩余残余物通过柱色谱纯化。收集期望的产物馏分并浓缩,然后通过用HCl/MeOH处理制得HCl盐80c。获得13.1g的80c。
步骤3:(2S,4R)-叔丁基2-((2’-氯-2,4'-5’-三氟-[1,1'-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯(80d)
在搅拌下向(2S,4R)-1-(叔丁氧基羰基)-4-氟吡咯烷-2-羧酸(9.5g,40.7mmol)在DCM(200mL)的冰冷溶液中逐滴加入1-氯-N,N,2-三甲基-1-丙烯胺(5.92mL,1.1当量)。在该温度下继续搅拌3小时,并然后加入固体2'-氯-2,4',5'-三氟-[1,1’-联苯基]-3-胺盐酸盐80c(13.1g,44.5mmol),接着加入DIEA(21.3mL)。移除冷却浴且反应混合物在室温下搅拌过夜。反应混合物然后加入水(120mL)中并用DCM(2×120mL)萃取。有机层相继用NaHCO3的水溶液(20mL)、水(20mL)和盐水(20mL)洗涤,并然后在Na2SO4上干燥并减压浓缩。剩余残余物通过柱色谱(用己烷/EtOAc洗脱)纯化得到14.1g的期望的标题化合物80d。
步骤4:(2S,4R)-N-(2'-氯-2,4',5,-三氟-[1,1’-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐(80e)
将(2S,4R)-叔丁基2-((2’-氯-2,4’,5’-三氟-[1,1’-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-羧酸酯80d(1.0g)溶入4N HCl/二氧六环(10mL)中且所得反应混合物在室温下搅拌2小时。然后减压除去溶剂且剩余残余物80e不用进一步纯化直接使用。
步骤5:2-(3-氨甲酰基-1H-吲唑-1-基)乙酸叔丁酯(80g)
将1H-吲唑-3-甲酰胺80f(56g,347mmol)溶解在CH3CN(500mL)中。向该溶液中加入2-溴乙酸叔丁酯(82g,61.5mL)和碳酸钾(77.4g,560mmol)。在氩气气氛下将混合物在90℃下加热3小时。反应混合物冷却至室温并通过垫过滤。固体饼用CH3CN(120mL)洗涤,且合并的滤液减压浓缩。剩余残余物通过柱色谱纯化得到标题化合物80g(70g)。
步骤6:2-(3-氨甲酰基-1H-吲唑-1-基)乙酸(80h)
将2-(3-氨甲酰基-1H-吲唑-1-基)乙酸叔丁酯80g(1.0g)加入位于二氧六环(10mL)中的4N HCl中,所得的反应混合物在室温下搅拌2小时。之后减压下除去溶剂,所得剩余的残余物80h直接使用,无需进一步纯化。
步骤7:1-(2-((2S,4R)-2-((2’-氯-2,4'-5’-三氟-[1,1'-联苯基]-3-基)氨甲酰基)-4-氟吡咯烷-1-基)-2-氧代乙基)-1H-吲唑-3-甲酰胺(80)
在室温下向2-(3-氨甲酰基-1H-吲唑-1-基)乙酸80h(5.3g,24.2mmol)、(2S,4R)-N-(2'-氯-2,4',5'-三氟-[1,1'-联苯基]-3-基)-4-氟吡咯烷-2-甲酰胺盐酸盐80e(9.0g,22.0mmol)在DMF(50mL)中的溶液中加入HATU(10g)、接着逐滴加入DIEA(18.0mL)。混合物在室温下搅拌1小时并减压除去挥发物。剩余残余物用10%的碳酸钠水溶液(50mL)稀释并用乙酸乙酯萃取。有机萃取物用水和盐水洗涤,然后在硫酸镁上干燥。溶液被过滤且滤液被减压蒸发。剩余残余物通过柱色谱纯化得到标题化合物80(10.0g)。1H NMR(400MHz,DMSO-d6,300K):(主要旋转异构体)δ2.13-2.26(m,1H),2.45-2.57(m,1H),3.88-4.00(m,1H),4.18-4.27(m,1H),4.76(t,J=8.4Hz,1H),5.43-5.68(m,3H),7.07-7.09(m,1H),7.20-7.27(m,2H),7.35-7.42(m,2H),7.59-7.64(m,2H),7.85-7.89(m,1H),7.91-7.99(m,1H),8.17(d,J=8.4Hz,1H),10.00(s,1H).19F NMR(376MHz,DMSO-d6,300K):(主要旋转异构体)δ-126.7,-135.8,-139.4,-175.9.LC(方法A):tR=2.28min.LC/MS(EI)m/z:[M+H]+574。
实施例7:式I化合物的非限制性实例
表1示出了式I的示意性化合物和表征数据。采用实施例8的测试来确定化合物的IC50。也可利用其它标准的因子D抑制试验。使用三个星号(***)来表示IC50低于1微摩尔的化合物,两个星号(**)表示IC50介于1微摩尔和10微摩尔之间的化合物,一个星号(*)表示IC50大于10微摩尔的化合物。
表1
实施例8:人因子D试验
将80nM最终浓度的人因子D(自人血清纯化,Complement Technology,Inc.)用不同浓度下的试验化合物于室温下在50mM Tris、1M NaCl中于pH 7.5下培育5分钟。加入合成底物Z-L-Lys-SBzl和DTNB(Ellman试剂)至各100μM的最终浓度。在分光荧光剂中以30秒时间点在30分钟内在微板中以运动模式记录OD405nm下的颜色增加。IC50值根据补体因子D活性抑制百分数随试验化合物浓度的变化通过非线性回归计算。
实施例9:溶血试验
溶血试验之前在G.Ruiz-Gomez,et al,J.Med.Chem.(2009)52:6042-6052中有述。此试验中使用GVB缓冲剂(0.1%明胶、5mM Veconal、145mM NaCl、0.025%NaN3,pH 7.3)加10mM最终的Mg-EGTA洗涤红血细胞(RBC):兔红细胞(购自Complement Technologies)。细胞在1×108个细胞/mL的浓度下使用。在溶血试验前,通过滴定法确定获得兔红细胞的100%溶解所需的正常人血清(NHS)的最佳浓度。将NHS(Complement Technologies)用抑制剂于37℃下培育15分钟,加入在缓冲剂中的兔红细胞并于37℃下再培育30分钟。阳性对照(100%溶解)由血清和RBC组成,而阴性对照(0%溶解)仅由Mg-EGTA缓冲剂和RBC组成。样品于2000g下离心5分钟,并收集上清液。使用UV/vis分光光度计于405nm下监测上清液的光学密度。相对于阳性对照(100%溶解)计算每一样品中的溶解百分数。
本说明书结合本发明的实施方案进行了描述。然而,本领域普通技术人员应理解,可作各种修改和变化而不偏离本发明在下面的权利要求书中给出的范围。因此,本说明书被认为是说明性的而非限制性的意义,并且所有这样的修改旨在包括在本发明的范围内。
Claims (15)
1.化合物或其药学可接受的盐,其中所述化合物是:
2.根据权利要求1所述的化合物或其药学可接受的盐在制备用于治疗由补体途径介导的疾病的药物中的用途。
3.根据权利要求2所述的用途,其中所述疾病为由补体因子D介导的疾病。
4.根据权利要求2或3所述的用途,其中所述疾病为年龄相关性黄斑变性(AMD)。
5.根据权利要求2或3所述的用途,其中所述疾病为阵发性睡眠性血红蛋白尿症(PNH)。
6.根据权利要求2或3所述的用途,其中所述疾病为多发性硬化症、关节炎或COPD。
7.根据权利要求2或3所述的用途,其中所述疾病为眼科疾病。
8.根据权利要求2或3所述的用途,其中所述疾病为呼吸系统疾病。
9.根据权利要求2或3所述的用途,其中所述疾病为心血管疾病。
10.根据权利要求2或3所述的用途,其中所述疾病为非典型或典型溶血性尿毒症综合征。
11.根据权利要求2或3所述的用途,其中所述疾病为类风湿性关节炎。
12.根据权利要求2或3所述的用途,其中所述疾病为C3肾小球肾炎。
13.根据权利要求7所述的用途,其中所述药物适于经由玻璃体内或脉络膜下递送。
14.根据权利要求2或3所述的用途,其中所述药物用于与有效量的其它活性剂联合施用。
15.药物组合物,其包含在药学可接受的载体中的有效量的权利要求1的化合物或其药学可接受的盐。
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