CN110430880A - 作为选择性bmp抑制剂的稠合杂环化合物 - Google Patents
作为选择性bmp抑制剂的稠合杂环化合物 Download PDFInfo
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- CN110430880A CN110430880A CN201880017935.7A CN201880017935A CN110430880A CN 110430880 A CN110430880 A CN 110430880A CN 201880017935 A CN201880017935 A CN 201880017935A CN 110430880 A CN110430880 A CN 110430880A
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- alkyl
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- aryl
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Abstract
本发明提供BMP信号传导的小分子抑制剂,其可用于治疗与BMP信号传导有关的疾病或病症,包括中枢神经系统的癌症。
Description
相关申请
本申请要求于2017年1月18日提交的美国临时专利申请62/447,830的优先权,其全部内容通过援引加入本文。
背景技术
涉及转化生长因子β(TGF-β)配体超家族的信号传导对于包括细胞生长、分化和凋亡在内的广泛的细胞过程是非常重要的。TGF-β信号传导涉及TGF-β配体与II型受体(丝氨酸/苏氨酸激酶)的结合,该II型受体募集并磷酸化I型受体。然后,I型受体磷酸化受体调节的SMAD(R-SMAD;例如,SMAD1、SMAD2、SMAD3、SMAD5、SMAD8或SMAD9),其与SMAD4结合,然后SMAD复合物进入细胞核,它在细胞核中在转录调节中发挥作用。TGF配体超家族包括两个主要分支,以TGF-β/激活素/Nodal和骨形态发生蛋白(BMP)为特征。
骨形态发生蛋白(BMP)配体介导的信号在脊椎动物的整个生命中起不同的作用。在胚胎形成期间,由配体、受体、共同受体和可溶性拮抗剂的协同表达所形成的BMP信号传导梯度建立了背腹轴。过度的BMP信号传导引起腹面发育(以背部结构为代价的腹部扩张),而减弱的BMP信号传导引起背部化(以腹部结构为代价的背部扩张)。BMP是原肠胚形成、中胚层诱导、器官形成和软骨内骨形成的关键调节因子,并调节多能细胞群的命运。BMP信号还在生理学和疾病中起关键作用,并且涉及例如原发性肺动脉高压、遗传性出血性毛细血管扩张综合征、进行性骨化性纤维发育不良以及幼年性息肉病综合征等。
BMP信号传导家族是TGF-β超家族的不同亚型。超过20个已知的BMP配体被三种不同的II型受体(BMPRII、ActRIIa和ActRIIb)和至少三种I型受体(ALK2、ALK3和ALK6)识别。二聚体配体促进受体异聚体的组装,从而允许组成性活性II型受体丝氨酸/苏氨酸激酶将I型受体丝氨酸/苏氨酸激酶磷酸化。激活的I型受体使BMP-响应性(BR-)SMAD效应物(SMAD1、5和8)磷酸化以促进与SMAD4(一种也促进TGF信号传导的协同SMAD)相关的核转位。此外,BMP信号可以以SMAD非依赖性方式激活诸如MAPK p38的细胞内效应物。可溶性BMP拮抗剂(诸如头蛋白、脊索发生素、gremlin和滤泡抑素)通过配体螯合限制BMP信号传导。
还提出了BMP信号在调节铁调素(一种肽激素,也是全身铁平衡重要调节因子)的表达中的作用。铁调素结合铁转运蛋白并促进铁转运蛋白的降解,铁转运蛋白是脊椎动物中唯一的铁转运体。铁转运蛋白活性的丧失防止铁从肠细胞、巨噬细胞和肝细胞中的细胞内储存移动到血流。BMP信号传导和铁代谢之间的联系代表治疗的潜在目标。
考虑到BMP和TGF-β超家族在配体(目前有>25种不同配体)和受体(识别BMP的3种I型受体和3种II型受体)水平的结构多样性以及受体结合的异四聚体方式,经由可溶性受体、内源性抑制剂或中和抗体来抑制BMP信号的传统方法是不实际或无效的。内源抑制剂(诸如头蛋白和滤泡抑素)对于配体亚类具有有限的特异性。单受体对配体具有有限的亲和力,而配体异四聚体对特定配体表现出相当精确的特异性。中和抗体对特定的配体或受体是特异性的,并且也受限于该信号传导系统的结构多样性。
因此,一直需要拮抗BMP信号传导通路并且在治疗或实验应用中可用于操纵这些通路的药剂。
发明内容
在一个方面,本发明涉及治疗或预防疾病或病症的方法,所述方法包括向个体施用具有式I所示结构的化合物或其药学上可接受的盐:
其中在本文中定义了A、D、E、M、G、W、X、Y和Z。
在一些实施方案中,所述疾病是癌症,诸如结肠直肠癌、偶发性结肠直肠癌、急性髓性白血病、慢性髓性白血病、非小细胞肺癌(NSCLC)、胰腺癌、卵巢癌、浆液性卵巢癌、上皮性卵巢癌、黑素瘤或头颈鳞状细胞癌(HNSCC)。在其他实施方案中,所述疾病是中枢神经系统癌症,诸如胶质瘤、星形胶质瘤、弥漫性内生性脑桥胶质瘤(DIPG)、高分化胶质瘤(HGG)、胚细胞瘤、多形性胶质母细胞瘤(GBM)、少突神经胶质瘤、垂体瘤或室管膜瘤。
在另外的其它实施方案中,所述疾病是贫血、铁难治性缺铁性贫血(IRIDA)、异位性骨化、非遗传性骨化性肌炎、创伤性骨化性肌炎、局限性骨化性肌炎。
在某些实施方案中,所述化合物以具有药学上可接受的载体的药物组合物形式施用。
具体实施方式
通过参考本发明的以下详细描述和其中包含的实施例可以更容易理解本发明。
在公开和描述本发明的化合物、组合物、制品、系统、装置和/或方法之前,应当理解,除非另外指明,它们不限于具体的合成方法,或者除非另外指明,他们不限于特定试剂,因此它们当然可以变化。还应当理解,本文使用的术语只用于描述特定方面的目的,而不旨在进行限制。尽管与本文描述的那些相似或等同的任何方法和材料都可用于实施或试验本发明,但现在将描述示例方法和材料。
本文所提及的所有出版物通过援引加入本文,用来公开和描述与所引用的出版物相关的方法和/或材料。本文论述的出版物仅是为其在本申请提出日期之前的公开而提供的。本文中的任何内容均不应被解释为承认本发明无权凭借在先发明而先于这些出版物。此外,本文提供的出版物的日期可能与实际出版日期有所不同,这需要单独予以核实。
A.定义
术语“酰基”是本领域公认的,并指由通式烃基C(O)-,优选烷基C(O)-表示的基团。
术语“酰氨基”是本领域公认的,指被酰基基团取代的氨基基团,并可例如由式烃基C(O)NH-表示。
术语“酰氧基”是本领域公认的,并指由通式烃基C(O)O-,优选烷基C(O)O-表示的基团。
术语“烷氧基”是指具有连接到其上的氧的烷基基团,优选低级烷基基团。代表性烷氧基基团包括甲氧基、-OCF3、乙氧基、丙氧基、叔丁氧基等。
术语“环烷基氧基”是指具有连接到其上的氧的环烷基基团。
术语“烷氧基烷基”是指被烷氧基基团取代的烷基基团,并可由通式烷基-O-烷基表示。
术语“烷基氨基烷基”是指被烷基氨基基团取代的烷基。
如本文所用的术语“烯基”是指包含至少一个双键的脂族基团,并旨在包括“未取代的烯基”和“取代的烯基”两者,后者是指具有替代烯基基团的一个或多个碳上的氢的取代基的烯基基团。此类取代基可存在于一个或多个包含在或不包含在一个或多个双键中的碳上。此外,除了稳定性禁止之外,此类取代基包括如下所讨论的针对烷基基团设想的所有那些取代基。例如,设想了通过一个或多个烷基、碳环基、芳基、杂环基或杂芳基基团来取代烯基基团。
“烷基”基团或“烷烃”是完全饱和的直链或支链非芳香性烃。通常,除非另外定义,否则直链或支链烷基基团具有1至约20个碳原子,优选1至约10个。直链烷基基团和支链烷基基团的例子包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、戊基和辛基。C1-C6直链或支链烷基基团也称为“低级烷基”基团。
此外,如贯穿说明书、实施例和权利要求书使用的术语“烷基”(或“低级烷基”)旨在包括“未取代的烷基”和“取代的烷基”两者,后者是指具有替代烃主链的一个或多个碳上的氢的取代基的烷基基团。若未另外指定,此类取代基可包括例如卤素、羟基、羰基(诸如羧基、烷氧羰基、甲酰基或酰基)、硫代羰基(诸如硫酯、硫代乙酸酯或硫代甲酸根)、烷氧基、磷酰基、磷酸根、膦酸根、亚膦酸根、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯氢基、烷硫基、硫酸根、磺酸根、氨磺酰基、磺酰氨基、磺酰基、杂环基、芳烷基或者芳族或杂芳族基团。本领域技术人员会理解,在适当时,在烃链上取代的基团自身可被取代。例如,取代的烷基的取代基可包括以下基团的取代和未取代形式:氨基、叠氮基、亚氨基、酰胺基、磷酰基(包括膦酸根和次膦酸根)、磺酰基(包括硫酸根、磺酰氨基、氨磺酰基和磺酸根)和甲硅烷基基团,以及醚、烷硫基、羰基(包括酮、醛、羧酸根和酯)、-CF3、-CN等。在下文描述示例性的取代烷基。环烷基可进一步被烷基、烯基、烷氧基、烷硫基、氨基烷基、羰基取代的烷基、-CF3、-CN等取代。
当与化学基团(诸如酰基、酰氧基、烷基、烯基、炔基或烷氧基)结合使用时,术语“Cx-y”意在包括在链中含有x至y个碳的基团。例如,术语“Cx-y烷基”是指取代或未取代的饱和烃基团,包括在链中含有x至y个碳的直链烷基和支链烷基基团,包括卤代烷基基团,诸如三氟甲基和2,2,2-三氟乙基等。当C0烷基处于末端位置时该基团表示氢,当其在内部时该基团表示键。术语“C2-y烯基”和“C2-y炔基”是指取代或未取代的不饱和脂族基团,其在长度和可能的取代方面与上述烷基相似,但分别包含至少一个双键或叁键。
如本文所用的术语“烷基氨基”是指被至少一个烷基基团取代的氨基基团。
如本文所用的术语“烷硫基”是指被烷基基团取代的巯基基团,并可由通式烷基S-表示。
如本文所用的术语“炔基”是指包含至少一个叁键的脂族基团,并旨在包括“未取代的炔基”和“取代的炔基”两者,后者是指具有替代炔基基团的一个或多个碳上的氢的取代基的炔基基团。此类取代基可存在于一个或多个包含在或不包含在一个或多个叁键中的碳上。此外,除了稳定性禁止之外,此类取代基包括如上文所讨论的针对烷基基团设想的所有那些取代基。例如,设想了通过一个或多个烷基、碳环基、芳基、杂环基或杂芳基基团来取代炔基基团。
如本文所用的术语“酰胺”是指以下基团:
其中每个R10独立地表示氢或烃基基团,或两个R10与它们所连接的N原子一起形成在环结构中具有4至8个原子的杂环。
术语“胺”和“氨基”是本领域公认的,并指未取代的胺和取代的胺两者及其盐,例如可通过下式表示的基团:
其中每个R10独立地表示氢或烃基基团,或两个R10与它们所连接的N原子一起形成在环结构中具有4至8个原子的杂环。
如本文所用的术语“氨基烷基”是指被氨基基团取代的烷基基团。
如本文所用的术语“芳烷基”是指被芳基基团取代的烷基基团。
如本文所用的术语“芳基”包括取代或未取代的单环芳香性基团,其中所述环的每个原子均为碳。优选地,所述环为5至7元环,更优选地为6元环。术语“芳基”还包括具有两个或更多个环的多环环系,其中两个或更多个碳为两个邻接的环所共有,其中至少一个环为芳香性的,其他的环可以为例如环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。芳基基团包括苯、萘、菲、苯酚、苯胺等。
术语“氨基甲酸根”是本领域公认的,并指以下基团:
其中R9和R10独立地表示氢或烃基基团,诸如烷基基团,或R9和R10与其间的原子一起形成在环结构中具有4至8个原子的杂环。
如本文所用的术语“碳环”或“碳环的”是指饱和或不饱和环,其中所述环的每个原子均为碳。术语碳环包括芳香性碳环和非芳性碳环两者。非芳香性碳环既包括所有碳原子均为饱和的环烷烃环,也包括包含至少一个双键的环烯烃环。“碳环”包括5-7元单环和8-12元双环。双环碳环的每个环可选自饱和环、不饱和环和芳香性环。碳环包括双环分子,其中在两个环之间共享一个、两个、三个或更多个原子。术语“稠合碳环”是指双环碳环,其中每一个环与另一个环共享两个相邻的原子。稠合碳环的每个环可选自饱和环、不饱和环和芳香性环。在一个示例性实施方案中,芳香性环(例如苯基)可稠合至饱和或不饱和环,例如环己烷、环戊烷或环己烯。饱和、不饱和和芳香性双环的任何组合在价态允许时均包含在碳环的定义中。示例性“碳环”包括环戊烷、环己烷、双环[2.2.1]庚烷、1,5-环辛二烯、1,2,3,4-四氢化萘、双环[4.2.0]辛-3-烯、萘和金刚烷。示例性稠合碳环包括十氢化萘、萘、1,2,3,4-四氢化萘、双环[4.2.0]辛烷、4,5,6,7-四氢-1H-茚和双环[4.1.0]庚-3-烯。“碳环”可在能够携带氢原子的任一个或多个位置被取代。
“环烷基”基团是完全饱和的环状烃。“环烷基”包括单环和双环。通常,除非另外定义,否则单环环烷基基团具有3至约10个碳原子,更通常具有3至8个碳原子。双环环烷基的第二个环可选自饱和环、不饱和环和芳香性环。环烷基包括双环分子,其中在两个环之间共享一个、两个、三个或更多个原子。术语“稠合环烷基”是指双环环烷基,其中每一个环与另一个环共享两个相邻的原子。稠合双环环烷基的第二个环可选自饱和环、不饱和环和芳香性环。“环烯基”基团是包含一个或多个双键的环状烃。
如本文所用的术语“碳环基烷基”是指被碳环基团取代的烷基基团。
术语“碳酸根”是本领域公认的,并指基团-OCO2-R10,其中R10表示烃基基团。
如本文所用的术语“羧基”是指由式-CO2H表示的基团。
如本文所用的术语“酯”是指基团-C(O)OR10,其中R10表示烃基基团。
如本文所用的术语“醚”是指通过氧连接到另一烃基基团的烃基基团。因此,烃基基团的醚取代基可以为烃基-O-。醚可以为对称的或不对称的。醚的例子包括但不限于杂环-O-杂环和芳基-O-杂环。醚包括“烷氧基烷基”基团,其可由通式烷基-O-烷基表示。
如本文所用的术语“卤代”和“卤素”意指卤素,并包括氯、氟、溴和碘。
如本文所用的术语“杂芳烷基(hetaralkyl)”和“杂芳烷基(heteroaralkyl)”是指被杂芳基(hetaryl)基团取代的烷基基团。
如本文所用的术语“杂烷基”是指碳原子和至少一个杂原子的饱和或不饱和链,其中没有两个杂原子是相邻的。
如本文所用的术语“杂烷基氨基”是指被杂烷基基团取代的氨基基团。
术语“杂芳基(heteroaryl)”和“杂芳基(hetaryl)”包括取代或未取代的芳香性单环结构,优选5至7元环,更优选5至6元环,其环结构包含至少1个杂原子,优选1至4个杂原子,更优选1或2个杂原子。术语“杂芳基(heteroaryl)”和“杂芳基(hetaryl)”还包括具有两个或更多个环的多环环系,其中两个或更多个碳为两个邻接的环所共有,其中至少一个环为杂芳族的,其他的环可以为例如环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂芳基基团包括例如吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡唑、吡啶、吡啶酮、苯并咪唑、喹啉、异喹啉、喹喔啉、喹唑啉、吲哚、异吲哚、吲唑、苯并噁唑、吡嗪、哒嗪、嘌呤和嘧啶等。
如本文所用的术语“杂原子”意指非碳或氢的任何元素的原子。优选的杂原子为氮、氧和硫。
术语“杂环基”、“杂环”和“杂环的”是指取代的或未取代的非芳香性环结构,优选3至10元环,更优选3至7元环,其环结构包含至少1个杂原子,优选1至4个杂原子,更优选1或2个杂原子。术语“杂环基”和“杂环的”还包括具有两个或更多个环的多环环系,其中两个或更多个碳为两个邻接的环所共有,其中至少一个环为杂环的,其他的环可以为例如环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基。杂环基基团包括例如哌啶、哌嗪、吡咯烷、吗啉、内酯、内酰胺等。杂环基基团还可以被氧代基取代。例如,“杂环基”包含吡咯烷和吡咯烷酮二者。
如本文所用的术语“杂环基烷基(heterocycloalkyl)”是指被杂环基团取代的烷基基团。
如本文所用的术语“杂环基烷基氨基(heterocycloalkylamino)”是指被杂环基烷基基团取代的氨基基团。
如本文所用的术语“烃基”是指通过不具有=O或=S取代基的碳原子连接的基团,并且通常具有至少一个碳-氢键和主要为碳的主链,但可以任选地包含杂原子。因此,出于本申请的目的,诸如甲基、乙氧基乙基、2-吡啶基和三氟甲基的基团被认为是烃基,但诸如乙酰基(其在连接碳上具有=O取代基)和乙氧基(其通过氧而非碳连接)的取代基则不被认为是烃基。烃基基团包括但不限于芳基、杂芳基、碳环、杂环基、烷基、烯基、炔基及其组合。
如本文所用的术语“羟基烷基”是指被羟基基团取代的烷基基团。
当与化学基团诸如酰基、酰氧基、烷基、烯基、炔基或烷氧基结合使用时,术语“低级”意在包括这样的基团,其中在取代基中存在十个或更少,优选六个或更少的非氢原子。例如,“低级烷基”是指含有十个或更少,优选六个或更少的碳原子的烷基基团。在某些实施方案中,本文定义的酰基、酰氧基、烷基、烯基、炔基或烷氧基取代基分别为低级酰基、低级酰氧基、低级烷基、低级烯基、低级炔基或低级烷氧基,不论它们是单独出现还是与其它取代基结合出现,诸如在羟基烷基和芳烷基的列举中(在该情况下,例如,当对烷基取代基中的碳原子计数时,芳基基团内的原子不计算在内)。
如本文所用的术语“氧代”是指羰基。当氧代取代基在其他方面饱和的基团上发生时,例如在氧代取代的环烷基基团(例如3-氧-环丁基)的情况下,被取代的基团仍旨在为饱和基团。当基团称为被“氧代”基团取代时,这可以表示羰基部分(即,-C(=O)-)替换亚甲基单元(即,-CH2-)。
术语“多环基”、“多环”和“多环的”是指两个或更多个环(例如,环烷基、环烯基、环炔基、芳基、杂芳基和/或杂环基),其中两个或更多个原子为两个邻接的环所共有,例如,环为“稠合环”。多环的环中的每一个可以为取代或未取代的。在某些实施方案中,多环的每个环在环中包含3至10个原子,优选5至7个。
术语“甲硅烷基”是指具有连接到其的三个烃基基团的硅基团。
术语“取代的”是指具有替代主链的一个或多个碳上的氢的取代基的基团。应当理解,“取代”或“被...取代”包括以下隐含的条件:此类取代是根据被取代的原子和取代基的允许价态,并且该取代产生稳定的化合物,例如,该化合物不会诸如通过重排、环化、消除等自发地发生转变。如本文所用,术语“取代的”期望包括有机化合物的所有可允许的取代基。在广泛的方面,可允许的取代基包括有机化合物的无环和环状的、支链和非支链的、碳环和杂环的、芳香性和非芳香性的取代基。针对合适的有机化合物,可允许的取代基可以是一个或多个并且可以是相同或不同的。出于本发明的目的,杂原子诸如氮可具有氢取代基和/或本文所述的有机化合物的任何可允许的取代基,该取代基满足杂原子的化合价。取代基可以包括本文所述的任何取代基,例如卤素、羟基、羰基(诸如羧基、烷氧羰基、甲酰基或酰基)、硫代羰基(诸如硫酯、硫代乙酸根或硫代甲酸根)、烷氧基、磷酰基、磷酸根、膦酸根、次膦酸根、氨基、酰胺基、脒、亚胺、氰基、硝基、叠氮基、巯氢基、烷硫基、硫酸根、磺酸根、氨磺酰基、磺酰氨基、磺酰基、杂环基、芳烷基、芳族或杂芳族基团。本领域技术人员会理解,在适当时,取代基自身可被取代。除非具体规定为“未取代的”,否则本文提及的化学基团应理解为包括取代的变体。例如,对“芳基”基团或部分的引用隐含地包括取代的变体和未取代的变体二者。
术语“硫酸根”是本领域公认的,并指基团-OSO3H或其药学上可接受的盐。
术语“磺酰胺”是本领域公认的,并指由以下通式表示的基团:
其中R9和R10独立地表示氢或烃基,诸如烷基,或R9和R10与其间的原子一起形成在环结构中具有4至8个原子的杂环。
术语“亚砜”是本领域公认的,并指基团S(O)-R10,其中R10表示烃基。
术语“磺酸根”是本领域公认的,并指基团SO3H或其药学上可接受的盐。
术语“砜”是本领域公认的,并指基团S(O)2-R10,其中R10表示烃基。
如本文所用的术语“硫烷基”是指被巯基基团取代的烷基基团。
如本文所用的术语“硫酯”是指基团-C(O)SR10或-SC(O)R10,其中R10表示烃基。
如本文所用的术语“硫醚”与醚等价,醚中的氧被硫替代。
术语“脲”是本领域公认的,并可由以下通式表示:
其中R9和R10独立地表示氢或烃基,诸如烷基,或R9的任一出现与R10和其间的原子一起形成在环结构中具有4至8个原子的杂环。
“保护基”是指这样的原子团,其在连接到分子中的反应性官能团上时掩蔽、降低或阻止该官能团的反应性。通常,在合成的过程中可根据需要选择性地移除保护基。保护基的例子可见于Greene and Wuts,Protective Groups in Organic Chemistry,3rd Ed.,1999,John Wiley&Sons,NY and Harrison et al.,Compendium of Synthetic OrganicMethods,Vols.1-8,1971-1996,John Wiley&Sons,NY。代表性的氮保护基包括但不限于甲酰基、乙酰基、三氟乙酰基、苄基、苄氧羰基(“CBZ”)、叔丁氧基羰基(“Boc”)、三甲基甲硅烷基(“TMS”)、2-三甲基甲硅烷基-乙磺酰基(“TES”)、三苯甲基和取代的三苯甲基基团、烯丙氧基羰基、9-芴基甲氧基羰基(“FMOC”)、硝基-藜芦基氧基羰基(“NVOC”)等。代表性的羟基保护基包括但不限于其中羟基基团被酰化(酯化)或烷基化的那些基团,诸如苄基醚和三苯甲基醚,以及烷基醚、四氢吡喃基醚、三烷基甲硅烷基醚(例如TMS或TIPS基团)、二醇醚(诸如乙二醇和丙二醇衍生物)和烯丙基醚。
如本文所用,“预防”病症或病状的治疗剂是指这样的化合物,其在统计样本中相对于未治疗的对照样本减少治疗样本中的该病症或病状的发生,或相对于未治疗的对照样本延缓该病症或病状的一种或多种症状的发作或降低其严重性。
术语“治疗”包括预防性和/或治疗性治疗。术语“预防性或治疗性”治疗是本领域公认的,并包括向宿主施用一种或多种本发明组合物。如果在不利病状(例如宿主动物的疾病或其它不利状态)临床显现之前施用,则治疗为预防性的(即,其防止宿主形成不利病状),而如果在不利病状显现之后施用,则治疗为治疗性的(即,其旨在减弱、改善或稳定现存的不利病状或其副作用)。
术语“前药”旨在涵盖在生理条件下转化成本发明的治疗活性剂(例如,式I的化合物)的化合物。制备前药的一般方法是要包括一个或多个选定的基团,所述基团在生理条件下水解而呈现出所需的分子。在其它实施方案中,前药通过宿主动物的酶活性转化。例如,酯或碳酸酯(例如,醇或羧酸的酯或碳酸酯)是本发明的优选前药。在某些实施方案中,在上文所示的制剂中的一些或全部式I的化合物可被相应的合适前药替代,例如,其中母体化合物中的羟基作为酯或碳酸酯呈现,或母体化合物中存在的羧酸作为酯呈现。
本文所述的化合物可以含有一个或多个双键,并且因此可能产生顺式/反式(E/Z)异构体,以及其它构象异构体。除非有相反的说明,本发明包括所有这些可能的异构体,以及这些异构体的混合物。
除非相反地说明,否则具有仅显示为实线而不是显示为楔形或虚线的化学键的式考虑了每种可能的异构体,例如每种对映体和非对映体,以及异构体的混合物,诸如外消旋混合物或非当量对应异构体混合物(scalemic mixture)。本文中描述的化合物可以含有一个或多个不对称中心,并因此可能产生非对映体和旋光异构体。除非有相反说明,本发明包括所有这些可能的非对映体以及它们的外消旋混合物、它们基本上纯的拆分的对映体、所有可能的几何异构体,及其药学上可接受的盐。也包括立体异构体的混合物以及分离的特定立体异构体。在用于制备此类化合物的合成过程中,或者在使用本领域技术人员已知的外消旋化或差向异构化过程中,这些过程的产物可以是立体异构体的混合物。
当然,当变量存在于多于一种情况中时,其在每次出现时可以是相同的或不同的。换句话说,每个变量彼此独立。在一些方面,化合物的结构可以由下式表示:
其被理解为等同于下式:
其中n通常是整数。也就是说,Rn被理解为表示五个独立的取代基Rn(a)、Rn(b)、Rn(c)、Rn(d)、Rn(e)。“独立的取代基”是指每个R取代基可以独立地定义。例如,如果在一种情况中,Rn (a)是卤素,那么在该情况下,Rn(b)不一定是卤素。同样,当基团R被定义为四个取代基时,R被理解为代表四个独立的取代基Ra、Rb、Rc和Rd。
除非有相反的说明,取代基不限于任何特定的顺序或排列。
本文使用以下缩写。DMF:二甲基甲酰胺。EtOAc:乙酸乙酯。THF:四氢呋喃。DIPEA或DIEA:二异丙基乙胺。HOBt:1-羟基苯并三唑。EDC:1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐。DMSO:二甲亚砜。DMAP:4-二甲基氨基吡啶。RT:室温。h:小时。Min:分钟。DCM:二氯甲烷。MeCN:乙腈。MeOH:甲醇。iPrOH:2-丙醇。n-BuOH:1-丁醇。
B.化合物
在一个方面,本发明涉及可用作BMP抑制剂的化合物或其药学上可接受的盐。例如,式I、II或III的化合物可用于治疗或预防疾病或病症。通常,预期每个公开的衍生物可以任选地被进一步取代。还预期任何一种或多种衍生物可以任选地从本发明中省略。应当理解,所公开的化合物可以通过所公开的方法提供。还应当理解,所公开的化合物可以用于所公开的使用方法中。
在本文公开的方法的某些实施方案中,所述化合物具有式I所示的结构:
其中:
W、X、Y和Z独立地为N或CH;
A为任选取代的环烷基、杂环基、芳基或杂芳基;
G选自CF3、卤素、CN、烷基、芳基、杂芳基、NR1R2、CHR3R4、S(O)NR1R2、S(O)2NR1R2、SR1、SOR1或SO2R1;
M为任选取代的芳基或杂芳基;
D选自键、O、CR3R4、NR1、NR1R2、SR1、SOR1或SO2R1;
E不存在或选自H、CF3、卤素、CN、烷基、芳基、杂芳基、C3-C12环烷基、C3-C12杂环烷基、C3-C12环烷基烷基或C3-C12杂环基烷基;
R1不存在或选自H、烷基、芳基或杂芳基;
R2选自H、烷基、芳基、杂芳基或COR1,或
R1和R2形成C3-C12环烷基或包含O、N和/或S的C3-C12杂环基;
R3选自H、烷基、芳基或杂芳基;且
R4选自H、烷基、芳基、杂芳基或COR1,或
R3和R4形成C3-C12环烷基或包含O、N和/或S的C3-C12杂环基;
或其药学上可接受的盐。
在一些实施方案中,W为CH。在一些实施方案中,Z为CH。在一些实施方案中,Z为N。在一些实施方案中,X为N。在一些实施方案中,Y为N。
在一些实施方案中,为:
其中A1独立地为O、CR3R4、NH或NR1,或者可以与另一A1连接以形成C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基。
在一些实施方案中,A选自以下:
在一些实施方案中,M任选地被一个或多个G取代,并且选自芳基或杂芳基。例如,在一些实施方案中,M是任选取代的苯基或吡啶。
还公开了这样的式I的化合物,其中M、D和E一起形成:
还公开了具有选自以下的结构的式(I)的化合物或其药学上可接受的盐:
在本文公开的方法的某些实施方案中,所述化合物具有式II表示的结构:
其中:
X1为N或CR5;
X2和X4独立地为N或CR5;
Y1、Y2和Y3独立地为N或CR5;
D为C或N;
W为N或O;
W1为N、O或C;
Cy被一个或多个G1取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基;
G1-G5不存在或独立地选自H,卤素,CN,CF3,C1-10烷基,C3-10环烷基;任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基,所述C3-8元环任选地被一个或多个R6取代;任选地被包含C、O、S或N的C3-8元环取代的NR6C1-10烷基,所述C3-8元环任选地被一个或多个R6取代;
R5和R6独立地选自H、卤素、CN、CF3、C1-10烷基、C3-10环烷基、任选被包含C、O、S或N的C3-8元环取代的OC1-10烷基;
Z任选地被一个或多个R5取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基;且
m为1或2。
在一些实施方案中,D为C且m为2。在一些实施方案中,W为N。
在一些实施方案中,为或者其中A1独立地为O、CR1R2、NH、NR1或NR1R2,或可与另一A1连接以形成C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基。
在本文公开的方法的某些实施方案中,所述化合物具有由式III表示的结构:
其中:
X1、X2和X4独立地为N或CR5;
Y1、Y2和Y3独立地为N或CR5;
G1-G5不存在或独立地选自H,卤素,CN,CF3,C1-10烷基,C3-10环烷基;任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基,所述C3-8元环任选地被一个或多个R6取代;
R5和R6独立地选自H、卤素、CN、CF3、C1-10烷基、C3-10环烷基和任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基;且
Z任选被一个或多个G5取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基。
在本文公开的方法的某些实施方案中,所述化合物具有下式:
在一些实施方案中,i.X1为N,X4为N,且X2、X4、Y1、Y2和Y3独立地为C或CR5;
ii.X1为N,X2为N,Y1为N,且X4、Y2和Y3独立地为CR5;
iii.X1为N,X2为N,Y2为N,且X4、Y2和Y3独立地为CR5;或
iv.X1为N,且X2、X4、Y1、Y2和Y3独立地为CR5;
Y1、Y2和Y3独立地为N或CR1。
在一些实施方案中,X1为N,X4为N,且X2、X4、Y1、Y2和Y3为CH。在一些实施方案中,X1、X4和Y1为N,且X2、X4、Y2和Y3为CH。在一些实施方案中,X1、X4和Y2为N,且X2、X4、Y1和Y3为CH。
在一些实施方案中,G2不存在。在一些实施方案中,G3不存在。
本文公开的化合物可包括所有盐形式,例如碱性基团尤其是胺的盐,以及酸性基团尤其是羧酸的盐。以下是可与质子化的碱性基团形成盐的阴离子的非限制性例子:氯化物、溴化物、碘化物、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、甲酸根、乙酸根、丙酸根、丁酸根、丙酮酸根、乳酸根、草酸根、丙二酸根、马来酸根、琥珀酸根、酒石酸根、富马酸根、柠檬酸根等。以下是可形成酸性基团的盐的阳离子的非限制性例子:铵、钠、锂、钾、钙、镁、铋、赖氨酸等。
C.药物组合物
一方面,本发明涉及通过以药物组合物形式施用式I、II或III的化合物治疗疾病或病症的方法。也就是说,可以提供药物组合物,所述药物组合物包含治疗有效量的至少一种所公开的化合物或所公开方法的至少一种产品和药学上可接受的载体。
本发明的组合物和方法可以用于治疗有此需要的个体。在某些实施方案中,所述个体是哺乳动物诸如人或非人哺乳动物。当施用给动物诸如人时,所述组合物或化合物优选地作为药物组合物施用,所述药物组合物包含例如本发明的化合物和药学上可接受的载体。药学上可接受的载体是本领域众所周知的,且包括例如水溶液(诸如水或生理缓冲盐水)或者其它溶剂或媒介物(诸如二醇类、甘油、油(诸如橄榄油)或可注射的有机酯)。在优选的实施方案中,当此类药物组合物用于人类施用、特别是用于侵入性施用途径(即,避免穿过上皮屏障的运输或扩散的途径,诸如注射或植入)时,水溶液是无热原的或基本上无热原的。可以选择赋形剂,例如,以实现药剂的延迟释放或选择性地靶向一种或多种细胞、组织或器官。所述药物组合物可以是剂量单位形式诸如片剂、胶囊剂(包括撒布胶囊剂(sprinkle capsule)和明胶胶囊剂)、颗粒剂、用于重构的亲液物(lyophile)、粉剂、溶液剂、糖浆剂、栓剂、注射剂等。所述组合物还可以存在于透皮递送系统中,例如,皮肤贴剂。所述组合物还可以存在于适合用于局部施用的溶液中,诸如滴眼剂。
药学上可接受的载体可以含有生理上可接受的试剂,其用于例如稳定化合物(诸如本发明的化合物)、增加化合物的溶解度或增加化合物的吸收。此类生理上可接受的试剂包括,例如,碳水化合物(诸如葡萄糖、蔗糖或葡聚糖)、抗氧化剂(诸如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白或者其它稳定剂或赋形剂。药学上可接受的载体(包括生理上可接受的试剂)的选择取决于例如组合物的施用途径。制剂或药物组合物可以是自乳化的药物递送系统或自微乳化的药物递送系统。药物组合物(制剂)也可以是脂质体或其它聚合物基质,其可以在其中掺入例如本发明的化合物。例如,脂质体(其含有磷脂或其他脂质)是无毒的、生理学上可接受且可代谢的载体,其制造和施用都相对简便。
本文使用的短语“药学上可接受的”表示这样的化合物、材料、组合物和/或剂型:其在合理的医学判断范围内适合用于接触人类和动物的组织,而没有过度的毒性、刺激、变应性应答或者其它问题或并发症,与合理的收益/风险比相称。
本文中使用的短语“药学上可接受的载体”是指药学上可接受的材料、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。在与制剂中其他成分相容且对患者无害的意义上,每种载体应当是“可接受的”。可以充当药学上可接受的载体的材料的一些例子包括:(1)糖类,诸如乳糖、葡萄糖和蔗糖;(2)淀粉类,诸如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)粉末状黄芪胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,诸如可可脂和栓剂蜡;(9)油类,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇类,诸如丙二醇;(11)多元醇,诸如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯类,诸如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,诸如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲溶液;和(21)在药物制剂中采用的其它无毒的相容物质。
药物组合物(制剂)可以通过多种施用途径中的任一种施用给个体,包括例如口服(例如,顿服药剂(水性或非水性溶液或混悬剂的形式)、片剂、胶囊剂(包括散布胶囊剂和明胶胶囊剂)、大丸剂、粉剂、颗粒剂、施用到舌的糊剂);通过口腔粘膜吸收(例如舌下);肛门、直肠或阴道(例如,阴道栓、乳剂或泡沫的形式);胃肠外(包括肌肉内、静脉内、皮下或鞘内,例如以无菌溶液或混悬剂的形式);经鼻;腹膜内;皮下;经皮(例如作为施用到皮肤的贴剂);和局部施用(例如,作为施用到皮肤的乳剂、软膏或喷雾剂,或作为滴眼剂)。还可以配制化合物用于吸入。在某些实施方案中,可以将化合物简单地溶解或悬浮于无菌水中。适当的施用途径和适合用于它们的组合物的细节可以参见例如美国专利号6,110,973、5,731,000、5,541,231、5,427,798、5,358,970和4,172,896以及其中引用的专利。
制剂可以方便地以单位剂型提供,且可以通过药学领域众所周知的任意方法制备。可以与载体材料组合以产生单一剂型的活性成分的量会随正在治疗的个体、特定施用模式而变化。可以与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的化合物的量。通常,在100%中,该量会是约1%至约99%的活性成分,优选约5%至约70%,最优选约10%至约30%。
制备这些制剂或组合物的方法包括使活性化合物(诸如本发明的化合物)与载体和任选存在的一种或多种附加成分结合的步骤。一般而言,通过如下制备所述制剂:使本发明的化合物与液体载体或精细粉碎的固体载体或两者均匀地且密切地结合,然后,如果必要的话,使产品成形。
本发明的适合用于口服施用的制剂可以呈以下形式:胶囊剂(包括撒布胶囊剂和明胶胶囊剂)、扁囊剂、丸剂、片剂、锭剂(使用风味基质,通常是蔗糖和阿拉伯胶或黄芪胶)、亲液物、粉剂、颗粒剂,或者作为在水性或非水性液体中的溶液或混悬剂,或者作为水包油或油包水液体乳剂,或者作为酏剂或糖浆剂,或者作为软锭剂(使用惰性基质,诸如明胶和甘油、或蔗糖和阿拉伯胶)和/或作为口腔洗剂等,各自含有预定量的本发明化合物作为活性成分。组合物或化合物也可以作为大丸剂、药糖剂或糊剂来施用。
为了制备用于口服施用的固体剂型(胶囊剂(包括撒布胶囊剂和明胶胶囊剂)、片剂、丸剂、糖衣丸、粉剂、颗粒剂等),将活性成分与一种或多种药学上可接受的载体(诸如柠檬酸钠或磷酸二钙)和/或以下任一种混合:(1)填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,诸如,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)保湿剂,诸如甘油;(4)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)溶液阻滞剂,诸如石蜡;(6)吸收促进剂,诸如季铵化合物;(7)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(8)吸收剂,诸如高岭土和膨润土;(9)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;(10)络合剂,例如,改性和未改性的环糊精;和(11)着色剂。在胶囊剂(包括撒布胶囊剂和明胶胶囊剂)、片剂和丸剂的情况下,药物组合物也可以包含缓冲剂。相似类型的固体组合物也可用作利用赋形剂(如乳糖或奶糖以及高分子量聚乙二醇等)的软的和硬的填充明胶胶囊中的填料。
通过任选地与一种或多种附加成分一起压缩或模塑,可以制备片剂。使用粘合剂(例如,明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,淀粉羟乙酸钠或交联羧甲基纤维素钠)、表面活性剂或分散剂,可以制备压制的片剂。通过在合适的机械中模塑用惰性液体稀释剂润湿的粉末状化合物的混合物,可以制备模塑的片剂。
药物组合物的片剂和其它固体剂型诸如糖衣丸、胶囊剂(包括撒布胶囊剂和明胶胶囊剂)、丸剂和颗粒剂可以任选地带刻痕,或者用包衣和壳(诸如肠溶包衣和药物配制领域中众所周知的其它包衣)制备。它们也可以配制成用来提供在其中的活性成分的缓慢或受控释放,例如,使用不同比例的羟丙基甲基纤维素(以提供所需的释放曲线)、其它聚合物基质、脂质体和/或微球。它们可以通过以下方式灭菌:例如,通过细菌截留滤器而过滤,或掺入无菌固体组合物形式的灭菌剂,所述无菌固体组合物可以在临使用前溶解在无菌水或一些其它无菌的可注射介质中。这些组合物也可以任选地含有遮光剂并且可以是仅释放活性成分或优选地在胃肠道的某些部分中,任选地以延迟方式释放的组合物。可以使用的埋植组合物的例子包括聚合物和蜡。活性成分也可以呈微囊形式,如果合适的话,其具有一种或多种上述赋形剂。
可用于口服施用的液体剂型包括药学上可接受的乳剂、用于重构的亲液物、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除活性成分以外,液体剂型可以含有本领域中常用的惰性稀释剂,诸如,例如水或其它溶剂、环糊精及其衍生物、增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯,及其混合物。
除了惰性稀释剂以外,口服组合物还可包括辅剂,诸如润湿剂、乳化剂和助悬剂、甜味剂、调味剂、着色剂、芳香剂和防腐剂。
除了活性化合物之外,混悬剂可以包含助悬剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇酯和聚氧乙烯脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、膨润土、琼脂和黄芪胶及其混合物。
用于直肠、阴道或尿道施用的药物组合物的制剂可呈现为栓剂,其可通过将一种或多种活性化合物与一种或多种合适的非刺激性赋形剂或载体混合来制备,所述赋形剂或载体包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯,其在室温下为固体,但在体温下为液体,因此会在直肠或阴道腔中融化并释放活性化合物。
用于施用至口腔的药物组合物的制剂可以呈现为漱口液、口腔喷雾剂或口腔软膏剂。
替代地或另外地,组合物可配制成经由导管、支架、线材或其它管腔内装置递送。经由此类装置的递送对于递送到膀胱、尿道、输尿管、直肠或肠尤其有用。
适于阴道施用的制剂还包括含有本领域已知适合的载体的阴道栓、棉球、霜剂、凝胶剂、糊剂、泡沫或喷雾制剂。
局部或经皮施用的剂型包括粉剂、喷雾剂、软膏剂、糊剂、乳膏、洗剂、凝胶剂、溶液剂、贴剂以及吸入剂。可以将活性化合物在无菌条件下与药学上可接受的载体以及与可能需要的任何防腐剂、缓冲剂或推进剂混合。
除了活性化合物之外,软膏剂、糊剂、乳膏和凝胶剂还可含有赋形剂,诸如动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌,或它们的混合物。
除了活性化合物以外,粉剂和喷雾剂可以含有赋形剂诸如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或者这些物质的混合物。喷雾剂可以另外含有常规推进剂,诸如氯氟烃和挥发性的未取代烃,诸如丁烷和丙烷。
透皮贴剂具有给身体提供本发明的化合物的受控递送的额外优点。此类剂型可以通过将活性化合物溶解或分散在适合的介质中来制备。还可以使用吸收增强剂来增加化合物穿过皮肤的通量。这样的通量速率可以通过提供控速膜或将化合物分散在聚合物基质或凝胶中来控制。
在本发明的范围内也设想眼用制剂、眼膏剂、粉剂、溶液剂等。示例性的眼用制剂描述在美国公开号2005/0080056、2005/0059744、2005/0031697和2005/004074以及美国专利号6,583,124中,其内容通过援引加入本文。如果需要的话,液体眼用制剂具有与泪液、眼房水或玻璃体液的性质类似的性质,或者与此类流体相容。优选的施用途径是局部施用(例如,局部施用,诸如滴眼剂,或经由植入物施用)。
本文中使用的短语“胃肠外施用”和“胃肠外地施用”是指通常通过注射进行的除了肠内和局部施用以外的施用模式,并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、椎管内和胸骨内注射和输注。
适合用于胃肠外施用的药物组合物包含与一种或多种药学上可接受的无菌等渗的水性或非水性溶液、分散体、混悬剂或乳剂、或无菌粉剂组合施用的一种或多种活性化合物,所述无菌粉剂可以在临用前重构成无菌的可注射溶液或分散体,其可含有抗氧化剂、缓冲剂、抑菌剂、使制剂与预定受体的血液等渗的溶质、或者助悬剂或增稠剂。
可以在本发明的药物组合物中应用的合适的水性和非水性载体的例子包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其适当的混合物,植物油诸如橄榄油,以及可注射的有机酯诸如油酸乙酯。可以维持适当的流动性,例如,通过使用包衣材料诸如卵磷脂、在分散体的情况下通过维持所需的粒度,以及通过使用表面活性剂。
这些组合物还可以含有辅剂,诸如防腐剂、润湿剂、乳化剂和分散剂。通过包含各种抗细菌剂和抗真菌剂,例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等,可以确保预防微生物的作用。也可能需要在组合物中包含等渗剂,诸如糖、氯化钠等。另外,通过包含延迟吸收的试剂诸如单硬脂酸铝和明胶,可以实现可注射药物形式的延长吸收。
在某些情况下,为了延长药物的作用,需要减慢来自皮下或肌肉内注射的药物的吸收。这可以通过使用具有差水溶性的结晶或无定形材料的液体混悬剂来完成。药物的吸收速率则取决于它的溶解速率,溶解速率又可以取决于晶体大小和晶型。或者,通过将药物溶解或悬浮在油媒介物中,实现胃肠外地施用的药物形式的延迟吸收。
通过形成本发明化合物在可生物降解的聚合物(诸如聚丙交酯-聚乙交酯)中的微囊化基质,制备可注射贮库形式。根据药物与聚合物的比率以及所应用的特定聚合物的性质,可以控制药物释放速率。其它可生物降解聚合物的例子包括聚(原酸酯)和聚(酸酐)。还通过将药物包封在与身体组织相容的脂质体或微乳剂中来制备贮库型可注射制剂。
为了用在本发明的方法中,活性化合物可以单独施用或作为药物组合物施用,所述药物组合物含有例如0.1-99.5%(更优选地,0.5-90%)的活性成分和药学上可接受的载体。
引入方法也可以由可再加载的或可生物降解的装置提供。近年来已经开发并在体内试验了多种缓释聚合物装置来用于药物(包括蛋白性生物药)的受控递送。多种生物相容的聚合物(包括水凝胶),包括可生物降解的和不可降解的聚合物,可以用于形成在特定靶位点持续释放化合物的植入物。
可以改变药物组合物中的活性成分的实际剂量水平,从而得到对于特定患者、组合物和施用模式而言在对患者无毒的情况下有效地实现期望的治疗应答的活性成分的量。
所选的剂量水平取决于多种因素,包括采用的特定化合物或化合物组合、或其酯、盐或酰胺的活性,施用途径,施用时间,采用的特定化合物的排泄速率,治疗的持续时间,与采用的特定化合物组合使用的其它药物、化合物和/或材料,正在治疗的患者的年龄、性别、重量、病状、一般健康和先前医疗史,以及医学领域中众所周知的类似因素。
本领域中有常规技术的医生或兽医可以容易地确定和处方治疗有效量的药物组合物。例如,医师或兽医可以用比实现期望的治疗效果所需的水平更低的水平的剂量开始给予药物组合物或化合物,并逐渐增加剂量直到实现期望的作用。“治疗有效量”是指足以引起期望的治疗效果的化合物的浓度。通常应当理解,化合物的有效量会随个体的重量、性别、年龄和医疗史而变化。影响有效量的其它因素可以包括但不限于:个体病状的严重程度、正在治疗的病症、化合物的稳定性,以及如果需要的话,与本发明的化合物一起施用的另一类治疗剂。通过药剂的多次施用,可以递送较大的总剂量。确定效力和剂量的方法是本领域技术人员已知的(Isselbacher et al.(1996)Harrison’s Principles of InternalMedicine 13ed.,1814-1882,通过援引加入本文)。
一般而言,在本发明的组合物和方法中使用的活性化合物的合适每日剂量会是这样的化合物的量:其为有效地产生治疗效果的最低剂量。这样的有效剂量通常取决于上述因素。
如果需要的话,活性化合物的有效每日剂量可以作为在一天中以适当间隔单独施用的1、2、3、4、5、6个或更多个亚剂量来施用,任选地,以单位剂量的形式。在本发明的某些实施方案中,活性化合物可以每天施用2或3次。在优选的实施方案中,活性化合物每天施用1次。
接受该治疗的患者是有此需要的任何动物,包括灵长类动物特别是人类,和其它哺乳动物诸如马、牛、猪和绵羊;以及一般的家禽和宠物。
本发明包括本发明的化合物的药学上可接受的盐在本发明的组合物和方法中的应用。本文中使用的术语“药学上可接受的盐”包括从无机或有机酸衍生出的盐,所述无机酸或有机酸包括例如盐酸、氢溴酸、硫酸、硝酸、高氯酸、磷酸、甲酸、乙酸、乳酸、马来酸、富马酸、琥珀酸、酒石酸、羟乙酸、水杨酸、柠檬酸、甲磺酸、苯磺酸、苯甲酸、丙二酸、三氟乙酸、三氯乙酸、萘-2-磺酸和其它酸。药学上可接受的盐形式可以包括这样的形式:其中包含盐的分子的比率不是1:1。例如,所述盐可以包含超过一个无机酸或有机酸分子/碱分子,诸如2个盐酸分子/式I或式II的化合物分子。作为另一例子,所述盐可以包含小于1个无机酸或有机酸分子/碱分子,诸如2个式I或式II的化合物分子/酒石酸分子。
在其它实施方案中,本发明考虑的盐包括但不限于烷基、二烷基、三烷基或四烷基铵盐。在某些实施方案中,本发明考虑的盐包括但不限于:L-精氨酸、苯乙苄胺(benenthamine)、苄星青霉素、甜菜碱、氢氧化钙、胆碱、地阿诺、二乙醇胺、二乙胺、2-(二乙基氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴胺(hydrabamine)、1H-咪唑、锂、L-赖氨酸、镁、4-(2-羟乙基)吗啉、哌嗪、钾、1-(2-羟乙基)吡咯烷、钠、三乙醇胺、氨丁三醇和锌盐。在某些实施方案中,本发明考虑的盐包括但不限于Na、Ca、K、Mg、Zn或其它金属盐。
药学上可接受的酸加成盐还可以作为各种溶剂化物存在,诸如具有水、甲醇、乙醇、二甲基甲酰胺等的溶剂化物。还可以制备此类溶剂化物的混合物。此类溶剂化物的来源可来自结晶的溶剂,在制剂或结晶的溶剂中固有的,或对于所述溶剂为外来的。
润湿剂、乳化剂和润滑剂(诸如月桂基硫酸钠和硬脂酸镁)以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。
药学上可接受的抗氧化剂的例子包括:(1)水溶性抗氧化剂,诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2)油溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3)金属螯合剂,诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
在这种组合中,本发明的化合物和其它活性试剂可以分开或者一起施用。另外,一种元素的施用可以在其它药剂施用之前、同时或之后。
因此,本发明化合物可以单独使用,或者与已知对目标适应症有益的其它药剂或者影响受体或酶的其它药物组合使用,所述受体或酶增加所公开化合物的效力、安全性、方便性、或者降低不良的副作用或毒性。本发明化合物和其它药剂可以同步疗法或以固定组合的形式共同施用。
在一个方面,所述化合物可以与具有调节BMP信号传导通路的已知副作用的第二化合物组合使用。
D.化合物和组合物的用途
在某些方面,本文提供治疗或预防疾病或病症的方法,所述方法包括向个体施用具有由式I、II或III表示的结构的化合物。
在某些实施方案中,疾病是癌症。在某些实施方案中,所述疾病是结肠直肠癌、幼年性息肉病综合征、散发性结肠直肠癌、白血病、急性髓性白血病、急性成巨核细胞白血病(AMKL)、非唐氏综合征AMKL、唐氏综合征AMKL、慢性髓性白血病、肺癌、非小细胞肺癌(NSCLC)、胰腺癌、卵巢癌、浆液性卵巢癌、上皮性卵巢癌、骨肉瘤、前列腺癌、骨癌、肾细胞癌、乳腺癌、黑素瘤或头颈鳞状细胞癌(HNSCC)。
在某些实施方案中,所述癌症是中枢神经系统的癌症。在某些实施方案中,所述癌症是胶质瘤、星形胶质瘤、弥漫性内生性脑桥胶质瘤(DIPG)、高分化胶质瘤(HGG)、胚细胞瘤、多形性胶质母细胞瘤(GBM)、少突神经胶质瘤、垂体瘤或室管膜瘤。
在其它实施方案中,所述疾病是贫血、铁难治性缺铁性贫血(IRIDA)、异位性骨化、非遗传性骨化性肌炎、创伤性骨化性肌炎或局限性骨化性肌炎。
在某些实施方案中,所述化合物或药物组合物按以下方式施用而非直接进入中枢神经系统:例如局部、口服、经鼻、静脉内、肌肉内、动脉内、囊内、眶内、心内、真皮内、腹膜内、经粘膜、经皮、肛门、直肠、阴道、经气管、皮下、表皮下、关节内或囊下施用。
E.药物的制备
在一个方面,本发明涉及制备用于治疗或预防有此需要的个体的疾病的药物的方法,所述方法包括使式I、II或者II的化合物与药物载体组合。
现已一般性地描述本发明,通过参考以下实施例会更容易理解本发明,所述实施例仅是为了说明本发明的某些方面和实施方案的目的而包括在本文中,而不是旨在限制本发明。
F.实验
阐述以下实施例以便提供给本领域普通技术人员如何制备和评价本文所要求保护的化合物、组合物、制品、装置和/或方法的完整公开和描述,并且旨在仅仅purely是本发明的示例,并且不旨在限制发明人所认为的他们的发明的范围。已经尽力确保有关数字(如量、温度等)的准确度,但是应考虑到会有某些误差和偏差。除非另外指出,否则份是重量份,温度按℃计或是环境温度,压力为大气压或接近大气压。
实施例1:化学合成
概述。在400MHz AMX Bruker NMR波谱仪上记录所有NMR波谱。以氘代溶剂为内标,以向低场方向位移ppm计的δ值来报告1H化学位移。数据报告如下:化学位移,峰裂数(s=单峰,d=双峰,t=三峰,q=四峰,br=宽峰,m=多峰),积分,耦合常数(Hz)。在具有电喷射离子化的Agilent 1200系列6130质谱仪上获得低分辨率质谱。在WatersQ-TOF API-US加Acquity系统上用电喷射离子化记录高分辨率质谱。(参见下表1)在EM Reagent 0.25mm硅胶60-F板上进行分析性薄层色谱。采用在215nm和254nm处的UV检测以及ELSD检测,在Agilent 1200系列上进行分析性HPLC。LC/MS:(Phenomenex-C18,2.1X 30mm,1min梯度,7%[0.1%TFA/CH3CN]:93%[0.1%TFA/H2O]至95%[0.1%TFA/CH3CN]。采用质量检测触发的收集,在定制HP1100纯化系统(参考16)上进行制备性纯化。用于萃取、洗涤和色谱的溶剂为HPLC级。所有试剂均购自Aldrich Chemical Co.并且未经纯化而使用。
一般路线I
7-氯咪唑并[1,2-a]吡啶。
向4-氯吡啶-2-胺(1.0g,7.78mmol,1.0当量)和NaHCO3(1.31g,15.56mmol,2.0当量)在EtOH(18mL)中的混合物中加入50wt%氯乙醛水溶液(1.48mL,11.67mmol,1.5当量)。将反应混合物加热回流。10h后,在减压下除去溶剂,并且在EtOAc:H2O(1:1,100mL)之间分配残留物。将有机层用盐水(50ml)冲洗、干燥(MgSO4)、过滤并浓缩。该材料无需进一步纯化即可通过。
LCMS:RT=0.123min,>98%@215和254nM,m/z=153.0[M+H]+。
7-氯-3-碘咪唑并[1,2-a]吡啶。
在室温下,向7-氯咪唑并[1,2-a]吡啶(7.78mmol,1.0当量)的DMF(12mL)溶液中加入N-碘代琥珀酰亚胺(1.84g,8.17mmol,1.05当量)。16h后,用H2O(100mL)和盐水(15mL)稀释棕色浆液。用EtOAc(100mL)萃取混合物。用EtOAc(100mL)再萃取水层,并将收集的有机层用H2O(2×20mL)、10%硫代硫酸钠(20mL)、盐水(20mL)洗涤并干燥(MgSO4)。过滤后,将溶液浓缩。将残留物用乙醚(15mL)研制并过滤,以得到灰白色固体(1.58g,2步收率73%)。
LCMS:RT=0.265min,>98%@215和254nM,m/z=279.0[M+H]+。
7-氯-3-苯基咪唑并[1,2-a]吡啶。
在μwave小瓶中,加入7-氯-3-碘咪唑并[1,2-a]吡啶(0.39g,1.38mmol,1.0当量)、苯基硼酸(0.18g,1.45mmol,1.05当量)和Pd(dppf)Cl2(50.5mg,0.07mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(6mL),然后加入K3PO4(0.59g,2.76mmol,2.0当量)的H2O(2.5mL)溶液。在微波辐射下将反应加热至120℃保持30分钟。将反应物加入到EtOAc:H2O(1:1,120mL)。将有机层分离,用H2O(2x 25mL)、盐水(25mL)冲洗,干燥(MgSO4),过滤并浓缩。通过反相HPLC(15-40%乙腈:H2O/0.1%TFA)纯化该材料,得到7-氯-3-苯基咪唑并[1,2-a]吡啶(0.30g,96%收率)。
LCMS:RT=0.458min,>98%@215和254nM,m/z=229.0[M+H]+。
7-(4-异丙氧基苯基)-3-苯基咪唑并[1,2-a]吡啶。
在μwave小瓶中,加入7-氯-3-苯基咪唑并[1,2-a]吡啶(5)(25.0mg,0.11mmol,1.0当量)、硼酸6(22.0mg,0.121mmol,1.1当量)和Pd(dppf)Cl2(4.0mg,0.006mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(2mL),然后加入K2CO3(30.0mg,0.22mmol,2.0当量)的H2O(1.0mL)溶液。在微波辐射下将反应加热至150℃保持30分钟。将反应物加入到EtOAc:H2O(1:1,20mL)。将有机层分离,用H2O(5mL)、盐水(5mL)冲洗,干燥(MgSO4),过滤并浓缩。通过反相HPLC(30-65%乙腈:H2O/0.1%TFA)纯化该材料,得到7-(4-异丙氧基苯基)-3-苯基咪唑并[1,2-a]吡啶(5.30mg,15%收率)。
LCMS:RT=0.714min,>98%@215和254nM,m/z=329.0[M+H]+。
7-氯-3-(吡啶-4-基)咪唑并[1,2-a]吡啶。
在μwave小瓶中,加入7-氯-3-碘咪唑并[1,2-a]吡啶(3)(0.31g,1.13mmol,1.0当量)、4-吡啶基硼酸(0.15g,1.24mmol,1.1当量)和Pd(dppf)Cl2(41.0mg,0.06mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(5mL),然后加入K3PO4(0.48g,2.26mmol,2.0当量)的H2O(2.0mL)溶液。在微波辐射下将反应加热至120℃保持30分钟。将反应物加入到EtOAc:H2O(1:1,120mL)。将有机层分离,用H2O(2x25mL)、盐水(25mL)冲洗,干燥(MgSO4),过滤并浓缩。该材料无需进一步纯化即可通过。
LCMS:RT=0.147min,>98%@215和254nM,m/z=230.0[M+H]+。
4-(3-(吡啶-4-基)咪唑并[1,2-a]吡啶-7-基)苯酚。
在μwave小瓶中,加入7-氯-3-(吡啶-4-基)咪唑并[1,2-a]吡啶(0.28g,1.23mmol,1.0当量)、4-羟苯基硼酸(0.19g,1.35mmol,1.1当量)和Pd(dppf)Cl2(45.0mg,0.06mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(5mL),然后加入K2CO3(0.34g,2.46mmol,2.0当量)的H2O(2.0mL)溶液。在微波辐射下将反应加热至150℃保持30分钟。将反应物加入到EtOAc:H2O(1:1,20mL)。将有机层分离,用H2O(5mL)、盐水(5mL)冲洗,干燥(MgSO4),过滤并浓缩。通过反相HPLC(5-35%乙腈:H2O/0.1%TFA)纯化该材料,得到4-(3-(吡啶-4-基)咪唑并[1,2-a]吡啶-7-基)苯酚(53.0mg,15%收率)。
LCMS:RT=0.343min,>98%@215和254nM,m/z=288.0[M+H]+。
7-(4-(2-(哌啶-1-基)乙氧基)苯基)-3-(吡啶-4-基)咪唑并[1,2-a]吡啶。
向μwave小瓶中加入4-(3-(吡啶-4-基)咪唑并[1,2-a]吡啶-7-基)苯酚(29.5mg,0.10mmol,1.0当量)、Cs2CO3(134.0mg,0.411mmol,4.0当量)、KI(16.6mg,0.10mmol,1.0当量)、1-(2-氯乙基)哌啶盐酸盐(20.3mg,0.11mmol,1.1当量)和DMF(1.5mL)。将反应混合物(rxn)在120℃下接受微波辐射10分钟。通过硅藻土塞过滤反应物,并通过反相HPLC(5-35%乙腈:H2O/0.1%TFA)纯化溶液,得到7-(4-(2-(哌啶-1-基)乙氧基)苯基)-3-(吡啶-4-基)咪唑并[1,2-a]吡啶(15.02mg,38%收率)。
LCMS:RT=0.404min,>98%@215和254nM,m/z=399.0[M+H]+。
一般路线II
4-(4-(4-甲基哌嗪-1-基)苯基)吡啶-2-胺。
在μwave小瓶中,加入4-溴吡啶-2-胺(0.50g,2.89mmol,1.0当量)、硼酸酯(0.92g,3.03mmol,1.05当量)和Pd(dppf)Cl2(106mg,0.15mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(12mL),然后加入K3PO4(1.23g,5.78mmol,2.0当量)的H2O(5.0mL)溶液。在微波辐射下将反应加热至120℃保持30分钟。向反应物中加入EtOAc(15mL)并过滤反应混合物。用冷EtOAc(2mL)冲洗固体。该材料无需进一步纯化即可通过。
LCMS:RT=0.285min,>98%@215nM和ELSD,m/z=269.1[M+H]+.
7-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶。
向4-(4-(4-甲基哌嗪-1-基)苯基)吡啶-2-胺(2.89mmol,1.0当量)和NaHCO3(0.49g,5.78mmol,2.0当量)在EtOH(30mL)中的混合物中加入50wt%氯乙醛水溶液(0.56mL,4.34mmol,1.5当量)。将反应混合物加热回流。18h后,在减压下除去溶剂,并且在EtOAc:H2O(1:1,100mL)之间分配残留物。将有机层用盐水(50mL)冲洗,干燥(MgSO4),过滤并浓缩。该材料无需进一步纯化即可通过。
LCMS:RT=0.343min,>90%@215nM和ELSD,m/z=293.1[M+H]+.
7-(7-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶-3-基)噻吩并[3,2-b]吡啶。
在μwave小瓶中,加入7-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶(23mg,0.08mmol,1.1当量)、7-氯噻吩并[3,2-b]吡啶(8μL,0.071mmol,1.0当量)、KOAc(14.0mg,0.143mmol,2.0当量)和Pd(OAc)2(~1mg,0.001当量),然后加入DMA(1.5mL)。在微波辐射下将反应加热至200℃保持30分钟。向反应中加入DMSO(0.5mL),且在通过硅藻土塞过滤后,通过反相HPLC(20-55%乙腈:H2O w/0.1%TFA)纯化该溶液,得到7-(7-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶-3-基)噻吩并[3,2-b]吡啶(14.0mg,47%收率)。
LCMS:RT=0.361min,>98%@215nM和ELSD,m/z=370.1[M+H]+。
7-(4-异丙氧基苯基)咪唑并[1,2-a]吡啶。
以与7-(4-(4-甲基哌嗪-1-基)苯基)咪唑并[1,2-a]吡啶类似的方式制备化合物7-(4-异丙氧基苯基)咪唑并[1,2-a]吡啶。
LCMS:RT=0.578min,>98%@220和254nM,m/z=253.1[M+H]+。
3-碘-7-(4-异丙氧基苯基)咪唑并[1,2-a]吡啶。
在室温下,向7-(4-异丙氧基苯基)咪唑并[1,2-a]吡啶(2.89mmol,1.0当量)的DMF(20mL)溶液中加入N-碘代琥珀酰亚胺(0.68g,3.03mmol,1.05当量)。16h后,用H2O(100mL)和盐水(15mL)稀释棕色浆液。用EtOAc(100mL)萃取混合物。用EtOAc(100mL)再萃取水层,并将收集的有机层用H2O(2×20mL)、10%硫代硫酸钠(20mL),盐水(20mL)洗涤并干燥(MgSO4)。过滤后,浓缩该溶液,并且该材料无需进一步纯化即可通过。
LCMS:RT=0.640min,>95%@220nM和ELSD,m/z=378.9[M+H]+。
7-(4-异丙氧基苯基)-3-(2-甲基吡啶-4-基)咪唑并[1,2-a]吡啶。
在μwave小瓶中,加入3-碘-7-(4-异丙氧基苯基)咪唑并[1,2-a]吡啶(35mg,0.093mmol,1.0当量)、(2-甲基吡啶-4-基)硼酸(15mg,0.11mmol,1.2当量)和Pd(dppf)Cl2(4.0mg,0.005mmol,0.05当量)。将固体混合物在真空下抽空并用氩气吹扫(3x)。向混合物中加入1,4-二氧六环(2mL),然后加入K3PO4(40mg,0.19mmol,2.0当量)的H2O(0.5mL)溶液。在微波辐射下将反应加热至120℃保持30分钟。将反应物加入到EtOAc:H2O(1:1,20mL)。将有机层分离,用H2O(2x 25mL)、盐水(25mL)冲洗,干燥(MgSO4),过滤并浓缩。通过反相HPLC(20-55%乙腈:H2O w/0.1%TFA)纯化残留物,得到7-(4-异丙氧基苯基)-3-(2-甲基吡啶-4-基)咪唑并[1,2-a]吡啶(4.3mg,14%收率)。
LCMS:RT=0.544min,>98%@215nM和ELSD,m/z=344.1[M+H]+。
表1:质谱数据
实施例2:生物测定
表2-4总结了用于鉴定和评估本发明的实施方案的测定结果。
表2
表3
表4
援引加入
本文提及的所有出版物和专利通过援引整体加入本文,就好像每个单独的出版物或专利被具体地和单独地指出以通过援引加入一样。在冲突的情况下,以本申请(包括本文中的任何定义)为准。
等同
虽然已经讨论了本发明的具体实施方案,但是上述说明书是说明性的而非限制性的。在阅读本说明书和下面的权利要求时,本发明的许多变化对于本领域技术人员将变得显而易见。本发明的全部范围应通过参考权利要求以及它们的等同的全部范围以及说明书连同这样的变化来确定。
Claims (31)
1.治疗或预防疾病或病症的方法,所述方法包括向个体施用具有式I所示结构的化合物或其药学上可接受的盐:
其中:
W、X、Y和Z独立地为N或CH;
A为任选取代的环烷基、杂环基、芳基或杂芳基;
G选自H、CF3、卤素、CN、烷基、芳基、杂芳基、NR1R2、CHR3R4、S(O)NR1R2、S(O)2NR1R2、SR1、SOR1或SO2R1;
M为任选取代的芳基或杂芳基;
D选自键、O、CR3R4、NR1、NR1R2、SR1、SOR1或SO2R1;
E不存在或选自H、CF3、卤素、CN、烷基、芳基、杂芳基、C3-C12环烷基、C3-C12杂环烷基、C3-C12环烷基烷基或C3-C12杂环基烷基;
R1不存在或选自H、烷基、芳基或杂芳基;
R2选自H、烷基、芳基、杂芳基或COR1,或
R1和R2形成C3-C12环烷基或包含O、N和/或S的C3-C12杂环基;
R3选自H、烷基、芳基或杂芳基;且
R4选自H、烷基、芳基、杂芳基或COR1,或
R3和R4形成C3-C12环烷基或包含O、N和/或S的C3-C12杂环基。
2.权利要求1的方法,其中W为CH。
3.任一前述权利要求的方法,其中Z为CH。
4.权利要求1或2的方法,其中Z为N。
5.任一前述权利要求的方法,其中X为N。
6.任一前述权利要求的方法,其中Y为N。
7.任一前述权利要求的方法,其中
为:
其中A1各自独立地为O、CR3R4、NH或NR1,或者可以与另一A1连接以形成C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基。
8.权利要求1至7中任一项的方法,其中A选自以下:
9.任一前述权利要求的方法,其中M任选地被一个或多个G取代,并且选自芳基或杂芳基。
10.权利要求9的方法,其中M是任选取代的苯基或吡啶。
11.任一前述权利要求的方法,其中M、D和E一起形成:
12.权利要求1的方法,其中所述化合物具有以下结构:
或其药学上可接受的盐。
13.治疗或预防疾病或病症的方法,所述方法包括向个体施用具有式II所示结构的化合物:
其中:
X1为N或CR5;
X2和X4独立地为N或CR5;
Y1、Y2和Y3独立地为N或CR5;
D为C或N;
W为N或O;
W1为N、O或C;
Cy被一个或多个R1取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基;
G1-G4不存在或独立地选自H,卤素,CN,CF3,C1-10烷基,C3-10环烷基;任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基,所述C3-8元环任选地被一个或多个R6取代;或者任选地被包含C、O、S或N的C3-8元环取代的NR6C1-10烷基,所述C3-8元环任选地被一个或多个R6取代;
R5和R6独立地选自H、卤素、CN、CF3、C1-10烷基、C3-10环烷基、任选被包含C、O、S或N的C3-8元环取代的OC1-10烷基;
Z任选地被一个或多个R5取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基;且
m为1或2。
14.权利要求13的方法,其中D为C且m为2。
15.权利要求13或14中任一项的方法,其中W为N。
16.治疗或预防疾病或病症的方法,所述方法包括向个体施用具有式III所示结构的化合物:
其中:
X1、X2和X4独立地为N或CR5;
Y1、Y2和Y3独立地为N或CR5;
G1-G5不存在或独立地选自H,卤素,CN,CF3,C1-10烷基,C3-10环烷基;或者任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基,所述C3-8元环任选地被一个或多个R6取代;
R5和R6独立地选自H、卤素、CN、CF3、C1-10烷基、C3-10环烷基、或者任选地被包含C、O、S或N的C3-8元环取代的OC1-10烷基;且
Z任选被一个或多个G5取代,并且选自C3-C12环烷基、C3-C12环烯基、芳基、杂芳基或C3-C12杂环基。
17.权利要求16的方法,其中所述化合物具有下式:
18.权利要求16或17的方法,其中:
i.X1为N,X4为N,且X2、X4、Y1、Y2和Y3独立地为CR5;
ii.X1为N,X2为N,Y1为N,且X4、Y2和Y3独立地为CR5;
iii.X1为N,X2为N,Y2为N,且X4、Y2和Y3独立地为CR5;或
iv.X1为N,且X2、X3、X4、Y1、Y2和Y3独立地为CR5;
Y1、Y2和Y3独立地为N或CR5。
19.权利要求18的方法,其中X1为N,X4为N,且X2、X4、Y1、Y2和Y3为CH。
20.权利要求16至18中任一项的方法,其中X1、X4和Y1为N,且X2、X4、Y2和Y3为CH。
21.权利要求16至18中任一项的方法,其中X1、X4和Y2为N,且X2、X4、Y1和Y3为CH。
22.权利要求16至21中任一项的方法,其中G2不存在。
23.权利要求16至22中任一项的方法,其中G3不存在。
24.任一前述权利要求的方法,其中所述疾病是选自结肠直肠癌、散发性结肠直肠癌、急性髓性白血病、慢性髓性白血病、非小细胞肺癌(NSCLC)、胰腺癌、卵巢癌、浆液性卵巢癌、上皮性卵巢癌、黑素瘤或头颈鳞状细胞癌(HNSCC)的癌症。
25.权利要求1至23中任一项的方法,其中所述疾病是中枢神经系统的癌症。
26.权利要求25的方法,其中所述癌症是胶质瘤、星形胶质瘤、弥漫性内生性脑桥胶质瘤(DIPG)、高分化胶质瘤(HGG)、胚细胞瘤、多形性胶质母细胞瘤(GBM)、少突神经胶质瘤、垂体瘤或室管膜瘤。
27.权利要求1至23中任一项的方法,其中所述疾病是铁难治性缺铁性贫血(IRIDA)、异位性骨化、非遗传性骨化性肌炎、创伤性骨化性肌炎或局限性骨化性肌炎。
28.任一前述权利要求的方法,其中所述化合物以具有药学上可接受的载体的药物组合物形式施用。
29.权利要求1至28中任一项的方法,其中局部、口服、经鼻、静脉内、肌肉内、动脉内、囊内、眶内、心内、真皮内、腹膜内、经粘膜、经皮、肛门、直肠、阴道、经气管、皮下、表皮下、关节内或囊下施用所述化合物。
30.权利要求29的方法,其中静脉内施用所述化合物。
31.权利要求29的方法,其中口服施用所述药物组合物。
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EP3105226B1 (en) | 2014-02-13 | 2019-09-04 | Incyte Corporation | Cyclopropylamines as lsd1 inhibitors |
US9527835B2 (en) | 2014-02-13 | 2016-12-27 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
CR20200199A (es) | 2014-02-13 | 2020-06-19 | Incyte Corp | CICLOPROPILAMINA COMO INHIBIDOR DE LA LSD1 (Divisional 2016-0396) |
WO2016007722A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Triazolopyridines and triazolopyrazines as lsd1 inhibitors |
WO2016007736A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Imidazopyrazines as lsd1 inhibitors |
WO2016007731A1 (en) | 2014-07-10 | 2016-01-14 | Incyte Corporation | Imidazopyridines and imidazopyrazines as lsd1 inhibitors |
AU2016243939B2 (en) | 2015-04-03 | 2020-09-03 | Incyte Holdings Corporation | Heterocyclic compounds as LSD1 inhibitors |
TWI765860B (zh) | 2015-08-12 | 2022-06-01 | 美商英塞特公司 | Lsd1抑制劑之鹽 |
US20190218214A1 (en) * | 2016-09-14 | 2019-07-18 | Vanderbilt University | Inhibition of BMP Signaling Compounds, Compositions and Uses Thereof |
US10745400B2 (en) | 2018-03-14 | 2020-08-18 | Vanderbuilt University | Inhibition of BMP signaling, compounds, compositions and uses thereof |
US10968200B2 (en) | 2018-08-31 | 2021-04-06 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
AU2019401649A1 (en) | 2018-12-20 | 2021-07-08 | Incyte Corporation | Imidazopyridazine and imidazopyridine compounds as inhibitors of activin receptor-like kinase-2 |
KR20230025434A (ko) * | 2020-06-12 | 2023-02-21 | 인사이트 코포레이션 | 이미다조피리다진 화합물 및 이의 용도 |
CN113304151B (zh) * | 2021-04-15 | 2022-05-03 | 中山大学 | 一种硝基呋喃类小分子化合物在制备诱导铁死亡和/或减缓胃癌化疗耐药药物中的应用 |
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