CN102638983A - 用于治疗结肠炎的组合物和方法 - Google Patents
用于治疗结肠炎的组合物和方法 Download PDFInfo
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- CN102638983A CN102638983A CN2010800502120A CN201080050212A CN102638983A CN 102638983 A CN102638983 A CN 102638983A CN 2010800502120 A CN2010800502120 A CN 2010800502120A CN 201080050212 A CN201080050212 A CN 201080050212A CN 102638983 A CN102638983 A CN 102638983A
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- C07D211/96—Sulfur atom
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Abstract
本文公开了用于治疗结肠炎和其他炎症性肠病——尤其是未确定型结肠炎、克罗恩病、肠易激综合征和缺血性结肠炎——的组合物和方法。
Description
优先权
本申请要求均在2009年11月6日提交的第61/258,914号临时申请和第61/258,918号临时申请的优先权,两申请的全文通过引用的方式纳入本文。
技术领域
本发明公开了用于治疗结肠炎和其他炎性肠病尤其是溃疡性结肠炎、克罗恩病、肠易激综合征和缺血性结肠炎的组合物和方法。
发明内容
结肠炎是用于描述结肠炎症的术语。存在多种结肠炎的诱因,包括传染、血供弱和自身免疫反应。结肠壁有许多层。有包裹着外部并负责将未消化食物沿结肠的纵向挤压的平滑肌层。内层或粘膜与流体接触并使水和电解质吸收以帮助固化粪便。粘膜层是结肠炎症发生位置,并且承受结肠炎症状。
存在两种类型的炎性肠病。第一种为溃疡性结肠炎,被认为是一种自身免疫病,其中身体免疫系统攻击结肠并导致炎症。溃疡性结肠炎在直肠中开始并且可以逐渐地扩散到整个结肠。体征和症状通常是腹痛和带血的肠运动。
克罗恩病是第二种类型的炎性肠病,可能涉及从食管和胃至小肠和大肠的消化道的任何部分。它经常具有跳跃性损伤,即患病区域散布在健康组织区域中。
炎性肠病(IBD)、溃疡性结肠炎和克罗恩病如今由以分步方法使用的药物组合进行控制。最初使用抗炎药物,如果其不成功则可添加抑制免疫系统的药物。在大多数严重病例中,可能需要手术来除去全部或部分的结肠和小肠。对缺血性结肠炎的治疗最初是支持性的,使用静脉内流体来使肠稳定并防止脱水。如果未恢复对肠足够的血供,则可能需要手术来除去失去血供的部分肠。
所公开的组合物和方法除了包含患有结肠炎或其他炎性肠病的受试者的受损、耗尽或过度负荷的免疫系统中存在的其他因子外,还包含可以稳定HIF-1α和HIF-2α的化合物。照此,可以成功治疗结肠炎和结肠炎相关疾病的病因,而无需手术介入。
附图说明
图1示出由于以表VIII中公开的化合物预处理而预防患有TNBS诱导的结肠炎的小鼠体重降低。实心圆(●)表示的数据代表无诱导的结肠炎并以运载体预处理的对照动物,实心方框(■)代表有TNBS诱导的结肠炎并以运载体预处理的对照动物,实心三角(▲)代表以5mg/kg表VIII中公开的化合物预处理的无诱导的结肠炎的动物,实心倒三角代表以0.3mg/kg表VIII中公开的化合物预处理的有TNBS诱导的结肠炎的动物,实心菱形(◆)代表以1mg/kg表VIII中公开的化合物预处理的有TNBS诱导的结肠炎的动物,空心圆(○)代表以5mg/kg表VIII中公开的化合物预处理的有TNBS诱导的结肠炎的动物。
图2a示出以下处理组中出现的结肠长度百分数:(A)健康小鼠;(B)在疾病诱导前一天以5mg/kg表VIII中公开的化合物预处理的有TNBS诱导的结肠炎的小鼠;(C)在疾病诱导后两天以5mg/kg表VIII中公开的化合物后处理的有TNBS诱导的结肠炎的小鼠;和(D)仅接受运载体处理的有TNBS诱导的结肠炎的小鼠。
图2b示出如下小鼠的疾病活度值:(A)健康小鼠;(B)在疾病诱导前一天以5mg/kg表VIII中公开的化合物预处理的有TNBS诱导的结肠炎的小鼠;(C)在疾病诱导后两天以5mg/kg表VIII中公开的化合物后处理的有TNBS诱导的结肠炎的小鼠;和(D)仅接受运载体处理的有TNBS诱导的结肠炎的小鼠。
图2c示出如下动物的肠系膜淋巴结(MLN)总白细胞计数:接受运载体的动物(A)、仅接受乙醇载体的TNBS诱导的结肠炎动物(B)、接受10mg/kg表VIII中公开的化合物的无TNBS诱导的结肠炎动物和接受10mg/kg表VIII中公开的化合物且有TNBS诱导的结肠炎动物。
图3示出本研究的各组的血细胞比容水平变化。A组(健康对照)未患有TNBS诱导的结肠炎并且仅接受运载体预处理;B组患有TNBS诱导的结肠炎并且仅接受运载体预处理;C组未患有TNBS诱导的结肠炎并且接受5mg/kg表VIII中公开的化合物预处理;D组患有TNBS诱导的结肠炎并且接受0.3mg/kg表VIII中公开的化合物的预处理;E组患有TNBS诱导的结肠炎并且接受1mg/kg表VIII中公开的化合物预处理;F组患有TNBS诱导的结肠炎并且接受5mg/kg表VIII中公开的化合物预处理。
具体实施方式
在本说明书和所附的权利要求书中,将涉及多个术语,所述术语将被定义为具有以下含义:
在整个本说明书中,除非另外声明,否则词“包括”和该词的变形,例如“包含”或“含有”,应理解为是指包括陈述的整数或步骤或者整数或步骤的组,但不排除任何其他整数或步骤或者整数或步骤的组。
必需说明,除非文中另有明确指出,否则说明书和所附权利要求书中所用单数形式“a”、“an”和“the”包括复数个指示物。因此,例如提及“acarrier”时,包括两个或更多个这类载体的混合物,等等。
“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且该描述包括该事件或情况发生的情形及其不发生的情形。
“可药用”意指不是生物学不适或其他方面不适的物质,即所述物质可与相关的活性化合物一起给予个体,而不造成临床上不可接受的生物效应或以有害的方式与包含其的药学组合物的任何其他组分相互作用。在本文中范围可表示为自“约”一个具体值,和/或至“约”另一具体值。当表示所述范围时,另一方面包括自所述一个具体值和/或至所述另一具体值。类似地,当通过使用前缀“约”将数值表示为近似值时,应理解为所述具体值形成另一方面。还应理解,每个范围的端点在与另一端点相关和独立于另一端点时均是有意义的。
除非明确描述为相反,组分的重量百分数是基于包含所述组分的制剂或组合物的总重量计。
本文所使用的“有效量”意指“一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂在实现所需结果或治疗结果需要的剂量和时间周期下有效的量”。有效量可随本领域中已知的因素而变化,例如待治疗的人或动物的疾病状况、年龄、性别和重量。虽然具体的剂量方案可能在本文中的实施例中描述,但本领域技术人员应了解,所述剂量方案可改变以提供最佳的治疗响应。例如,可每日给予数个分开的剂量或可就治疗情形紧迫所表示的成比例减少剂量。此外,本公开的组合物可按所需的频率给予,以实现治疗量。
本文中通常使用的“混合物”或“掺合物”意指两种或多种不同组分的物理结合物。
本文所使用的“赋形剂”包括可包含在一种或多种所公开抑制剂中或与之结合的非治疗活性化合物或非生物活性化合物的任何其他化合物。因此,赋形剂应该是药学上或生物学上可接受的或相关的(例如,赋形剂通常应该对受试者是无毒的)。“赋形剂”包括单种这类化合物,也意欲包括多种赋形剂。
本文所使用的“受试者”意指个体。因此,所述“受试者”可包括家养动物(例如,猫、狗等)、家畜(例如,牛、马、猪、绵羊、山羊等)、实验动物(例如,小鼠、兔子、大鼠、豚鼠等),和禽类。“受试者”还可包括哺乳动物,例如灵长类或人。
“防止”或该词的其他形式如“阻止”或“预防”意指停止具体事件或特征,以稳定或推迟具体事件或特征的发展或进展,或者以使具体事件或特征将发生的几率最小化。防止不要求与对照相比,因为其通常比例如减少更绝对。如本文所使用的,某些事物可被减少但不可被防止,但被减少的某些事物也可被防止。同样,某些事物可被防止但不可被减少,但被防止的某些事物也可被减少。应理解,当使用减少或防止时,除非另外明确指出,否则也明确公开了使用另一词语。
“减少(reduce)”或该词的其他形式如“减少(reducing)”或“减少(reduction)”意指事件或特征(如,血管渗漏)的降低。应理解,这通常与一些标准值或预计值相关,换句话说它是相对的,但不必总是提及所述标准值或相对值。
本文使用的术语“治疗(treat)”或该词的其他形式如“治疗的(treated)”或“治疗(treatment)”意指给予本发明的化合物减轻宿主的疾病或病症,并且/或者减少、抑制或消除与病症相关的具体特征或事件(例如微生物引起的感染)。因此,术语“治疗”包括防止宿主发生病症,特别是当所述宿主容易患所述疾病、但尚未确诊所述疾病之时;抑制病症;以及/或者减轻或反转病症。只要本发明的方法涉及防止病症,就应理解术语“防止”不需要疾病状态完全被阻止。相反,本文使用的术语防止是指本领域技术人员的以下能力:鉴定易感病症的群体,使得可以在疾病发病前给予本发明的化合物。该术语并不意味着所述疾病状态被完全避免。
本文中范围可表示为从“约”一个具体值和/或至“约”另一个具体值。当表示这样的范围时,另一方面包括从一个具体值和/或至另一个具体值。类似地,当通过使用前缀“约”将数值表示为近似值时,应理解为是所述具体值形成另一方面。还应理解,每个范围的端点在与另一端点相关和独立于另一端点时均是有意义的。还应理解,本文公开了很多数值,并且每个数值在本文中也公开为除了所述数值本身之外的“约”该具体数值。例如,如果公开了数值“10”,那么也就公开了“约10”。还应理解,当一个数值被公开时,也就公开了“小于或等于”该数值,“大于或等于该数值”,以及数值之间的可能范围,这是为本领域技术人员所适当理解的。例如,如果公开了数值“10”,那么也就公开了“小于或等于10”和“大于或等于10”。还应理解,在整个申请中,数据以多种不同形式提供,并且该数据代表终点和起点以及所述数据点任意结合的范围。例如,如果公开了具体的数据点“10”和具体的数据点“15”,应理解认为公开了大于、大于或等于、小于、小于或等于、等于10和15以及10和15之间的数值。还应理解,还公开了两个具体单位之间的每个单位。例如,如果公开了10和15,那么也公开了11、12、13和14。“抗微生物”是指以任何浓度治疗或控制(例如减少、防止、抑制、瓦解或消除)微生物生长或存活的能力。类似地,术语“抗细菌”、“抗病毒”和“抗真菌”分别是指以任何浓度治疗或控制(例如减少、防止、抑制、瓦解或消除)细菌、病毒和真菌生长或存活的能力。
术语“阴离子”是一种类型的离子,包括在术语“离子”的意义范围内。“阴离子”是含净负电荷或者可以使其含净负电荷的任何分子、分子部分(例如两性离子)、分子簇、分子复合体、部分或原子。本文使用的术语“阴离子前体”具体指可以经化学反应(例如脱质子化)转化成阴离子的分子。
术语“阳离子”是一种类型的离子,包括在术语“离子”的意义范围内。“阳离子”是含净正电荷或者可以使其含净正电荷的任何分子、分子部分(例如两性离子)、分子簇、分子复合体、部分或原子。本文使用的术语“阳离子前体”具体指可以经化学反应(例如质子化或烷基化)转化成阳离子的分子。
本文使用的“化疗剂”包括可与所公开的HIF-1α脯氨酰羟化酶抑制剂结合使用的任何其他药用活性化合物,例如细胞毒性药物如6-羟基甲基酰基富烯、环磷酰胺、达卡巴嗪、卡莫司汀、多柔比星和氨甲蝶呤。其他化疗剂还包括消炎药,即非类固醇类消炎化合物(如阿司匹林)。
除非声明为相反,具有仅显示为实线而非楔形或虚线的化学键的式考虑每种可能的同分异构体,例如每种对映异构体、非对映异构体和内消旋化合物,以及同分异构体的混合物,例如外消旋混合物或部分消旋(scalemic)混合物。
以下化学体系在整个说明书中用于描述和充分公开本公开的范围,并且具体地指出并清楚地要求包含本公开化合物的单元,然而,除非另外明确定义,否则本文使用的术语与本领域普通技术人员所理解的相同。术语“烃基”表示任何基于碳原子的单元(有机分子),所述单元任选包含一个或多个有机官能团,包括含有无机原子的盐,尤其是羧酸盐、季铵盐。在术语“烃基”的广义含义中有“无环烃基”和“环烃基”类,所述术语用于将烃基单元分为有环类和无环类。
以下化学体系在整个说明书中用于描述和充分公开本公开的范围,并且以具体地指出并清楚地要求包含本公开化合物的单元,然而,除非另外明确定义,否则本文使用的术语与本领域普通技术人员所理解的相同。术语“烃基”表示任何基于碳原子的单元(有机分子),所述单元任选包含一个或多个有机官能团,包括含有无机原子的盐,尤其是羧酸盐、季铵盐。在术语“烃基”的广义含义中有“无环烃基”和“环烃基”类,所述术语用于将烃基单元分为有环类和无环类。
当“环烃基”单元涉及以下定义时,在其环上可仅包含碳原子(碳环和芳环),或者在其环上可包含一个或多个杂原子(杂环和杂芳基)。对于“碳环”,环中最少的碳原子数是3个碳原子;环丙基。对于“芳”环,环中最少的碳原子数是6个碳原子;苯基。对于“杂环”,环中最少的碳原子数是1个碳原子;二氮丙啶基(diazirinyl)。环氧乙烷包含2个碳原子,是C2杂环。对于“杂芳”环,环中最少的碳原子数是1个碳原子;1,2,3,4-四唑基。以下是本文所用的术语“无环烃基”和“环烃基”的非限制性描述。
A.被取代的和未被取代的无环烃基:
对于本公开的目的,术语“被取代的和未被取代的无环烃基”包括3类单元:
1)直链或支链烷基,其非限制性实例包括,甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)等;被取代的直链或支链烷基,其非限制性实例包括,羟基甲基(C1)、氯甲基(C1)、三氟甲基(C1)、氨基甲基(C1)、1-氯乙基(C2)、2-羟基乙基(C2)、1,2-二氟乙基(C2)、3-羧基丙基(C3)等。
2)直链或支链烯基,其非限制性实例包括,乙烯基(C2)、3-丙烯基(C3)、1-丙烯基(也称作2-甲基乙烯基)(C3)、异丙烯基(也称作2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)等;被取代的直链或支链烯基,其非限制性实例包括,2-氯乙烯基(也称作2-氯乙烯基)(C2)、4-羟基丁烯-1-基(C4)、7-羟基-7-甲基辛-4-烯-2-基(C9)、7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等。
3)直链或支链炔基,其非限制性实例包括,乙炔基(C2)、丙-2-炔基(也称作炔丙基)(C3)、丙炔-1-基(C3)和2-甲基-己-4-炔-1-基(C7);被取代的直链或支链炔基,其非限制性实例包括,5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等。
B.被取代的和未被取代的环烃基:
对于本公开的目的,术语“被取代的和未被取代的环烃基”包括5类单元:
1)术语“碳环的(carbocyclic)”在本文中定义为“包括含3至20个碳原子的环,其中构成所述环的原子限于碳原子,并且各个环还可独立地由能够代替一个或多个氢原子的一个或多个部分取代”。以下是“被取代的和未被取代的碳环”的非限制性实例,包括以下类单元:
i)具有单个被取代烃环或未被取代烃环的碳环,其非限制性实例包括,环丙基(C3)、2-甲基-环丙基(C3)、环丙烯基(C3)、环丁基(C4)、2,3-二羟基环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环戊二烯基(C5)、环己基(C6)、环己烯基(C6)、环庚基(C7)、环辛基(C8)、2,5-二甲基环戊基(C5)、3,5-二氯环己基(C6)、4-羟基环己基(C6)和3,3,5-三甲基环己-1-基(C6)。
ii)具有两个或多个被取代稠合烃环或未被取代稠合烃环的碳环,其非限制性实例包括,八氢环戊二烯基(C8)、八氢-1H-茚基(C9)、3a,4,5,6,7,7a-六氢-3H-茚-4-基(C9)、十氢萘基(C10)、十氢薁基(C10)。
iii)被取代双环烃环或未被取代双环烃环的碳环,其非限制性实例包括,双环-[2.1.1]己基、双环[2.2.1]庚基、双环[3.1.1]庚基、1,3-二甲基[2.2.1]庚-2-基、双环[2.2.2]辛基和双环[3.3.3]十一烷基。
2)术语“芳基”在本文中定义为“包含至少一个苯环或萘环的单元,其中不存在稠合于所述苯环或萘环的杂芳环或杂环,且各个环还可独立地由能够替代一个或多个氢原子的一个或多个部分取代”。以下是“被取代的和未被取代的芳环”的非限制性实例,包括以下类单元:
i)C6或C10被取代芳环或未被取代芳环;无论被取代或未被取代的苯环和萘环,其非限制性实例包括,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟基苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙基氨基)苯基(C6)、2-氰基苯基(C6)、2,6-二叔丁基苯基(C6)、3-甲氧基苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧基萘-1-基(C10)和6-氰基-萘-1-基(C10)。
ii)与1或2个饱和环稠合的C6或C10芳环,其非限制性实例包括,双环[4.2.0]辛-1,3,5-三烯基(C8)和二氢茚基(C9)。
3)术语“杂环的”和/或“杂环”在本文中定义为“包含一个或多个具有3至20个碳原子的环的单元,其中在至少一个环中的至少一个原子是选自氮(N)、氧(O)或硫(S)的杂原子或者N、O和S的混合物,并且另外其中包含杂原子的环也不是芳环”。以下是“被取代杂环和未被取代杂环”的非限制性实例,其包括以下类单元:
i)具有含一个或多个杂原子的单环的杂环单元,其非限制性实例包括,二氮丙啶基C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑烷基(C3)、噻唑烷基(C3)、异噻唑烷基(C3)、氧杂噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)、2,3,4,5-四氢-1H-氮杂基(azepinyl)(C6)、2,3-二氢-1H-吲哚(C8)、和1,2,3,4-四氢喹啉(C9)。
ii)具有其中之一为杂环的2个或多个环的杂环单元,其非限制性实例包括六氢-1H-吡咯烷基(C7)、3a,4,5,6,7,7a-六氢-1H-苯并[d]咪唑基(C7)、3a,4,5,6,7,7a-六氢-1H-吲哚基(C9)、1,2,3,4-四氢喹啉基(C9)和十氢-1H-环辛[b]吡咯基(C10)。
4)术语“杂芳基”在本文中定义为“包括一个或多个含5至20个原子的环,其中在至少一个环中的至少一个原子是选自氮(N)、氧(O)或硫(S)的杂原子或者N、O和S的混合物,并且另外其中至少包含杂原子的环之一是芳环”。以下是“被取代杂环和未被取代杂环”的非限制性实例,其包括以下类单元:
i)含单环的杂芳环,其非限制性实例包括,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、异噁唑基(C3)、异噻唑基(C3)、呋喃基(C4)、苯硫基(C4)、嘧啶基(C4)、2-苯基嘧啶基(C4)、吡啶基(C5)、3-甲基吡啶基(C5)和4-二甲基氨基吡啶基(C5)。
ii)含其中之一为杂芳环的2个或多个稠合环的杂芳环,其非限制性实例包括:7H-嘌呤基(C5)、9H-嘌呤基(C5)、6-氨基-9H-嘌呤基(C5)、5H-吡咯并[3,2-d]嘧啶基(C6)、7H-吡咯并[2,3-d]嘧啶基(C6)、吡啶并[2,3-d]嘧啶基(C7)、2-苯基苯并[d]噻唑基(C7)、1H-吲哚基(C8)、4,5,6,7-四氢-1-H-吲哚基(C8)、喹喔啉基(C8)、5-甲基喹喔啉基(C8)、喹唑啉基(C8)、喹啉基(C9)、8-羟基-喹啉基(C9)和异喹啉基(C9)。
5)C1-C6连接的(tethered)环烃基单元(无论是碳环单元、C6或C10芳基单元、杂环单元或杂芳基单元),其通过C1-C6亚烷基单元连接至所述分子的另一部分、单元或核心。连接的环烃基单元的非限制性实例包括具有下式的苄基C1-(C6):
其中Ra任选是一个或多个独立选择的对氢的取代基。其他实例包括其他芳基单元,尤其是(2-羟基苯基)己基C6-(C6);萘-2-基甲基C1-(C10)、4-氟苄基C1-(C6)、2-(3-羟基苯基)乙基C2-(C6),还有被取代的和未被取代的C3-C10亚烷基碳环单元,例如环丙基甲基C1-(C3)、环戊基乙基C2-(C5)、环己基甲基C1-(C6)。该类中包括被取代的和未被取代的C1-C10亚烷基-杂芳基单元,例如具有下式的2-吡啶甲基C1-(C6)单元:
其中Ra是与以上所定义的相同。另外,C1-C12连接的环烃基单元包括C1-C10亚烷基杂环单元和亚烷基-杂芳基单元,其非限制性实例包括,吖丙啶基甲基C1-(C2)和噁唑-2-基甲基C1-(C3)。
对于本公开的目的,碳环选自C3至C20;芳环选自C6或C10;杂环选自C1至C9;杂芳环选自C1至C9。
对于本公开的目的,并为提供对本公开定义中的一致性,包含单一杂原子的稠合环单元以及螺环、双环等在本文中将以与含杂原子的环对应的环家族表征并由其涵盖,但本领域技术人员可有另外的表征。例如,对于本公开的目的,具有下式的1,2,3,4-四氢喹啉:
被认为是杂环单元。对于本公开的目的,具有下式的6,7-二氢-5H-环戊并嘧啶:
被认为是杂芳基单元。当稠合环单元在饱和环(杂环)和芳环(杂芳环)二者中都包含杂原子时,对于描述本公开的目的,以芳环为主并且芳环决定所述环在本文中被分配的种类类型。例如,对于本公开的目的,具有下式的1,2,3,4-四氢-[1,8]二氮杂萘:
被认为是杂芳基单元。
术语“被取代的”在说明书中通篇使用。术语“被取代的”适用于这样的单元,即在本文中描述为“被取代的单元或部分是烃基单元或部分,无论是无环的还是环状的,其一个或多个氢原子被本文下文所定义的一个取代基或多个取代基替代”。当取代氢原子时,所述单元每次能够替代烃基部分的一个氢原子、两个氢原子或三个氢原子。另外,这些取代基可替代两个相邻碳上的两个氢原子从而形成所述取代基、新的部分或单元。例如,要求单一氢原子替代的被取代单元包括卤素、羟基等。两个氢原子替代包括羰基、肟基等。自相邻碳原子的两个氢原子替代包括环氧基等。三个氢原子取代包括氰基等。术语被取代的在本说明书中通篇使用以表明烃基部分(尤其是芳环、烷基链)可含有一个或多个被取代基替代的氢原子。当一个部分被描述为“被取代”时,任何数目的氢原子可被替代。例如,4-羟基苯基是“被取代的芳族碳环(芳环)”,(N,N-二甲基-5-氨基)辛基是“被取代的C8直链烷基单元”,3-胍基丙基是“被取代的C3直链烷基单元”,2-羧基吡啶基是“被取代的杂芳基单元”。
以下是可取代碳环、芳基、杂环或杂芳基单元上氢原子的单元的非限制性实例:
i)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环烷基;例如,甲基(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)、环己基(C6)等;
ii)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基(chlorovinyl))(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)和7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)被取代或未被取代的C2-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)被取代或未被取代的C6或C10芳基;例如,苯基、2-氯苯基、3-羟苯基、4-硝基苯基、2-氟-4-甲基苯基、3,5-二硝基苯基、8-羟基萘-1-基、6-磺酰基萘-2-基等;
v)被取代或未被取代的C1-C9杂环;例如,如本文进一步定义的;
vi)被取代或未被取代的C1-C11杂芳基;例如,如本文进一步定义的;
vii)卤素;例如,氟、氯、溴和碘;
viii)-[C(R23a)(R23b)]xOR10;
R10选自:
a)-H;
b)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环烷基;
c)C6或C10被取代或未被取代的芳基或亚烷基芳基;
d)C1-C9被取代或未被取代的杂环;
e)C1-C11被取代或未被取代的杂芳基;
ix)-[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b各自独立地选自:
a)-H;
b)-OR12;
R12为氢或C1-C4直链烷基;
c)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环烷基;
d)C6或C10被取代或未被取代的芳基;
e)C1-C9被取代或未被取代的杂环;
f)C1-C11被取代或未被取代的杂芳基;或
g)R11a和R11b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
x)-[C(R23a)(R23b)]xC(O)R13;
R13为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-OR14;
R14为氢、被取代或未被取代的C1-C4直链烷基、C6或C10被取代或未被取代的芳基、C1-C9被取代或未被取代的杂环、C1-C11被取代或未被取代的杂芳基;
c)-N(R15a)(R15b);
R15a和R15b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或被未取代的杂环;C1-C11被取代或未被取代的杂芳基;或者R15a和R15b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xi)-[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环烷基;
b)-N(R17a)(R17b);
R17a和R17b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或R17a和R17b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)-[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)-H;或
b)被取代或未被取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R19为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R20a)(R20b);
R20a和R20b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或R20a和R20b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xiii)-[C(R23a)(R23b)]xCN;
xiv)-[C(R23a)(R23b)]xNO2;
xv)-[C(R23a)(R23b)]xR21;
R21为被1-21个选自-F、-Cl、-Br或-I的卤素原子取代的C1-C10直链、C3-C10支链或C3-C10环状烷基;
xvi)-[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、被取代或未被取代的C1-C4直链或C3-C4支链烷基;被取代或未被取代的C6、C10或C14芳基;C7-C15亚烷基芳基;C1-C9取代或未取代的杂环;或C1-C11取代或未取代的杂芳基;
R23a和R23b各自独立地为氢或C1-C4烷基;并且
指数x为0至5的整数。
本文公开的化合物包括所有盐形式,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。以下是可与碱性基团形成盐的阴离子的非限制性实例:氯离子、溴离子、碘离子、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、延胡索酸根、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实例:钠离子、锂离子、钾离子、钙离子、镁离子、铋离子等。
对于本公开的目的,术语“化合物”、“类似物”和“物质的组合物”可同样地彼此替代,包括所有对映异构体形式、非对映体形式、盐等,以及术语“化合物”、“类似物”和“物质的组合物”。
HIF-1α脯氨酰羟化酶抑制剂
所公开的化合物具有下式:
其中L选自CH2或SO2,从而得到N-取代的苄基或N-取代的磺酰基芳基-3-羟基吡啶-2-(1H)-酮。Y、R1和R2在下文中进一步定义。
本文公开了N-取代的苄基和N-取代的磺酰基芳基-4-氨基亚甲基-3-羟基吡啶-2-(1H)-酮,其是具有下式的HIF-1α脯氨酰羟化酶抑制剂:
其中R1和R2在下文中进一步定义。
哌嗪-1-甲酸烷基酯
这些化合物的一个类别涉及具有下式的4-{[(1-N-(氯-或氟-取代的)-苄基]-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基}哌嗪-1-甲酸C1-C4直链或支链烷基酯:
其中Z为被1-5个选自氯和氟的卤素原子取代的苯基,R1和R2一起形成一个被烷基羧基单元取代的哌嗪环,其中R4选自C1-C4直链或C3-C4支链烷基,例如,具有下式的4{[1-(4氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯:
R4单元的一方面涉及其中R4为叔丁基(C4)的化合物。R4单元的另一方面涉及其中R4为甲基(C1)的化合物。R4单元的又一方面涉及其中R4为乙基(C2)的化合物。R4单元的再一方面涉及其中R4选自正丙基(C3)、异丙基(C3)、正丁基(C4)、仲丁基(C4)和异丁基(C4)的化合物。R4不为氢,因此,具有式:-CO2H的羧化物单元明确排除在该类别之外,但可以包括在下文描述的其他类别中。
Z为被1-5个选自氟和氯的卤素取代的苯基。Z单元的一个方面涉及其中Z为4-氯苯基的化合物。Z单元的另一个方面涉及其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基的化合物。Z单元的又一个方面涉及其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯的化合物。
以下是该类别化合物的非限制性实例:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸甲酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸乙酯:
具有下式的4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯:
具有下式的4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯:
另一化合物类别涉及具有下式的N-未被取代的-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮,其中Z为未被取代的苯基基团:
其中R1和R2一起形成一个被取代或未被取代的杂环或杂芳环。
该类别的第一方面涉及具有下式的化合物:
其中R1和R2一起形成一个被取代或未被取代的具有2-20个碳原子和1-7个杂原子的环A表示的杂环或杂芳环;R200表示0-40个氢的取代基。指数w为0-40的整数。所述环的非限制性实例包括二氮丙啶基(C1)、1,2,3,4-四唑基(C1)、吖丙啶基(C2)、尿唑基(C2)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、1H-咪唑基(C3)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、哌啶-2-酮基(戊内酰胺)(C5)、7H-嘌呤基(C5)、9H-嘌呤基(C5)、6-氨基-9H-嘌呤基(C5)、2,3,4,5-四氢-1H-氮杂基(C6)、5H-吡咯并[3,2-d]嘧啶基(C6)、7H-吡咯并[2,3-d]嘧啶基(C6)和1,2,3,4-四氢喹啉(C9)。
每个R200单元独立地选自:
i)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)和7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)被取代或未被取代的C1-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)被取代或未被取代的C6或C10芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)被取代或未被取代的C1-C9杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基、(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)被取代或未被取代的C1-C11杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如,-F、-Cl、-Br或-I;
viii)-[C(R37a)(R37b)]yOR24;
R24选自:
a)-H;
b)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
c)被取代或未被取代的C6或C10芳基或C7或C10亚烷基芳基;例如,苯基或苄基
d)被取代或未被取代的C1-C9杂环;
e)被取代或未被取代的C1-C11杂芳基;
例如,-OH、-CH2OH、-OCH3、-CH2OCH3、-OCH2CH3、-CH2OCH2CH3、-OCH2CH2CH3和-CH2OCH2CH2CH3;
ix)-[C(R37a)(R37b)]yN(R25a)(R25b);
R25a和R25b各自独立地选自:
a)-H;
b)-OR26;
R26为氢或C1-C4直链烷基;
c)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
d)被取代或未被取代的C6或C10芳基;
e)被取代或未被取代的C1-C9杂环;
f)被取代或未被取代的C1-C11杂芳基;或者
g)R25a和R25b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、-CH2NH(CH2CH3)等;
x)-[C(R37a)(R37b)]yC(O)R27;
R27为:
a)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
b)-OR28;
R28为氢、被取代或未被取代的C1-C4直链烷基、被取代或未被取代的C6或C10芳基、被取代或未被取代的C1-C9杂环、被取代或未被取代的C1-C11杂芳基;
c)-N(R29a)(R29b);
R29a和R29b各自独立地为氢、被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基、被取代或未被取代的C1-C9杂环、被取代或未被取代的C1-C11杂芳基;或R29a和R29b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)-[C(R37a)(R37b)]yOC(O)R30;
R30为:
a)C1-C12被取代或未被取代的直链、支链或环状烷基;
b)-N(R31a)(R31b);
R31a和R31b各自独立地为氢、被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基、被取代或未被取代的C1-C9杂环、被取代或未被取代的C1-C11杂芳基;或R31a和R31b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-OC(O)CH3、-CH2OC(O)CH3、-OC(O)NH2、-CH2OC(O)NH2、-OC(O)NHCH3、-CH2OC(O)NHCH3、-OC(O)N(CH3)2、-CH2OC(O)N(CH3)2等;
xii)-[C(R37a)(R37b)]yNR32C(O)R33;
R32为:
a)-H;或者
b)被取代或未被取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R33为:
a)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R34a)(R34b);
R34a和R34b各自独立地为氢、被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基、被取代或未被取代的C1-C9杂环、被取代或未被取代的C1-C11杂芳基;C1-C11取代或未取代的杂芳基;或R34a和R34b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)-[C(R37a)(R37b)]yCN;例如,-CN、-CH2CN和-CH2CH2CN;
xiv)-[C(R37a)(R37b)]yNO2;例如,-NO2、-CH2NO2和-CH2CH2NO2;
xv)-[C(R37a)(R37b)]yR35;例如,-CH2F、-CHF2、-CF3、-CCl3或-CBr3;
R35为被1-21个选自-F、-Cl、-Br或-I的卤素原子取代的C1-C10直链、C3-C10支链或C3-C10环状烷基;
xvi)-[C(R37a)(R37b)]ySO2R36;
R36为氢、羟基、被取代或未被取代的C1-C4直链或C3-C4支链烷基;被取代或未被取代的C6、C10或C14芳基;C7-C15亚烷基芳基;被取代或未被取代的C1-C9杂环;或被取代或未被取代的C1-C11杂芳基;
例如,-SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和-CH2SO2C6H5;并且
xvii)环碳原子上的两个氢原子可以被取代以形成=O、=S或=NH单元;
R37a和R37b各自独立地为氢或C1-C4烷基;并且
指数y为0至5的整数。
该方面的第一实施方案涉及其中R1和R2一起形成一个5元被取代或未被取代的C1-C4杂环或者被取代或未被取代的C1-C4杂芳环的化合物,其非限制性实例包括选自如下结构的环:
该实施方案的第一迭代方案涉及具有下式的HIF-1α脯氨酰羟化酶抑制剂:
R200代表环氢的0-2个取代基,其中所述氢的取代基独立地选自:
i)C1-C4直链或C3-C4支链烷基;
ii)C1-C4直链或C3-C4支链烷氧基;
iii)羟基;
iv)氰基;
v)硝基;
vi)氨基、甲基氨基或二甲基氨基;
vii)羧基、甲基羧基;或乙基羧基;
viii)甲酰基、乙酰基或丙酰基;
ix)酰胺基、甲基酰胺基或二甲基酰胺基;
x)卤素;
xi)杂环;或
xii)杂芳基。
该迭代方案的非限制性实例包括具有下式的HIF-1α脯氨酰羟化酶抑制剂:
该实施方案的另一个迭代方案涉及其中R1和R2一起形成一个环中具有多于一个杂原子的5元被取代或未被取代的杂环或杂芳环的HIF-1α脯氨酰羟化酶抑制剂。非限制性实例包括:
该方面的另一实施方案涉及其中R1和R2一起形成一个被取代或未被取代的C4-C11杂环或者被取代或未被取代的C4-C11杂芳环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例选自:
该实施方案的非限制性实例包括:
另一类别的化合物具有下式:
其中R200和指数w与上文定义相同。R代表0-5个氢的取代基,其中每个R独立地选自:
i)C1-C12被取代或被未取代的直链、支链或环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)C2-C12被取代或未被取代的直链、支链或环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)和7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)C2-C12被取代或未被取代的直链或支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)C6或C10被取代或未被取代的芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)C1-C9被取代或未被取代的杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)C1-C11被取代或未被取代的杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如、-F、-Cl、-Br或-I;
viii)-[C(R23a)(R23b)]xOR10;
R10选自:
a)-H;
b)C1-C12被取代或未被取代的直链、支链或环状烷基;
c)C6或C10被取代或未被取代的芳基或亚烷基芳基;
d)C1-C9被取代或未被取代的杂环;
e)C1-C11被取代或未被取代的杂芳基;
例如,-OH、-CH2OH、-OCH3、-CH2OCH3、-OCH2CH3、-CH2OCH2CH3、-OCH2CH2CH3和-CH2OCH2CH2CH3;
ix)-[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b各自独立地选自:
a)-H;
b)-OR12;
R12为氢或C1-C4直链烷基;
c)C1-C12被取代或未被取代的直链、支链或环状烷基;
d)C6或C10被取代或未被取代的芳基;
e)C1-C9被取代或未被取代的杂环;
f)C1-C11被取代或未被取代的杂芳基;或者
g)R11a和R11b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、-CH2NH(CH2CH3)等;
x)-[C(R23a)(R23b)]xC(O)R13;
R13为:
a)C1-C12被取代或未被取代的直链、支链或环状烷基;
b)-OR14;
R14为氢、被取代或未被取代的C1-C4直链烷基、C6或C10被取代或未被取代的芳基、C1-C9被取代或未被取代的杂环、C1-C11被取代或未被取代的杂芳基;
c)-N(R15a)(R15b);
R15a和R15b各自独立地为氢、C1-C12被取代或未被取代的直链、支链或环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或者R15a和R15b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)-[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)C1-C12被取代或未被取代的直链、支链或环状烷基;
b)-N(R17a)(R17b);
R17a和R17b各自独立地为氢、C1-C12被取代或未被取代的直链、支链或环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或者R17a和R17b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)-[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)-H;或者
b)C1-C4被取代或未被取代的直链、支链或环状烷基;
R19为:
a)C1-C12被取代或未被取代的直链、支链或环状烷基;
b)-N(R20a)(R20b);
R20a和R20b各自独立地为氢、C1-C12被取代或未被取代的直链、支链或环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或者R20a和R20b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)-[C(R23a)(R23b)]xCN;例如,-CN、-CH2CN和-CH2CH2CN;
xiv)-[C(R23a)(R23b)]xNO2;例如,-NO2、-CH2NO2和-CH2CH2NO2;
xv)-[C(R23a)(R23b)]xR21;例如,-CH2F、-CHF2、-CF3、-CCl3或-CBr3;
R21为被1-21个选自-F、-Cl、-Br或-I的卤素原子取代的C1-C10直链、支链或环状烷基;
xvi)-[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、被取代或未被取代的C1-C4直链或支链烷基;被取代或未被取代的C6、C10或C14芳基;C7-C15亚烷基芳基;C1-C9被取代或未被取代的杂环;或C1-C11被取代或未被取代的杂芳基;例如,-SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和-CH2SO2C6H5;
R23a和R23b各自独立地为氢或C1-C4烷基;并且
指数x为0至5的整数。
该类别的非限制性实例包括具有下式的化合物:
另一类别的化合物涉及具有下式的未被取代的N-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮:
其中R1和R2各自独立地选自:
i)氢;
ii)被取代或未被取代的C1-C10直链、支链或环状烷基;
iii)被取代或未被取代的C2-C10直链、支链或环状烯基;
iv)被取代或未被取代的C2-C10直链或支链炔基;
v)被取代或未被取代的C6或C10芳基;
vi)被取代或未被取代的C1-C9杂环;或
vii)被取代或未被取代的C1-C9杂芳基。
该类别的第一方面涉及其中R2为氢且R1为被取代或未被取代的C1-C9杂环或C1-C9杂芳基的HIF-1α脯氨酰羟化酶抑制剂。在第一个实施方案中,R1为被取代的杂环基团,其非限制性实例包括吖丙啶基(C2)、氮杂环丁基(C3)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、哌啶-2-酮基(戊内酰胺)(C5)和氮杂环庚-2-酮基(己内酰胺)(C6),其中所述R1单元可以结合于所述环中任意位置处的氮原子。另外,所述C1-C9杂环或C1-C9杂芳环可以在无论环碳或环杂原子(例如环氮)的任意位置被取代。该实施方案的非限制性实例包括:
在另一个实施方案中,R2为氢且R1为被取代或未被取代的C3-C12环烷基,其中所述环烷基环可以在任意环位置处被取代。该实施方案的非限制性实例包括:
又一化合物类别涉及具有下式的未被取代的N-苄基-4-氨基甲基-3-羟基吡啶-2-(1H)-酮:
R1和R2各自独立地为氢或者被取代或未被取代的C1-C10直链或支链烷基,其中所述烷基单元可以被一个或多个独立选自如下基团的单元取代:
i)C1-C8直链、支链或环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)-SR40;R40为氢或C1-C4直链或支链烷基;
vii)被取代或未被取代的C6或C10芳基;
viii)被取代或未被取代的C1-C9杂环;或
ix)被取代或未被取代的C1-C9杂芳基。
该类别的非限制性实例包括:
再一类别的所公开化合物具有下式:
其中R200和指数w与上文定义相同。R代表0-5个氢的取代基、其中每个R独立地选自:
i)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;例如,甲基(C1)、(C1)、氯甲基(C1)、三氟甲基(C1)、氨甲基(C1)、乙基(C2)、羟甲基1-氯乙基(C2)、2-羟乙基(C2)、1,2-二氟乙基(C2)、正丙基(C3)、异丙基(C3)、3-羧丙基(C3)、环丙基(C3)、2-甲基-环丙基(C3)、正丁基(C4)、仲丁基(C4)、异丁基(C4)、叔丁基(C4)、环丁基(C4)、2,3-二羟基环丁基(C4)、戊基(C5)、环戊基(C5)、己基(C6)和环己基(C6)等;
ii)被取代或未被取代的C2-C12直链、C3-C12支链或C3-C12环状烯基;例如,乙烯基(C2)、2-氯乙烯基(也称为2-氯乙烯基)(C2)、3-丙烯基(C3)、1-丙烯基(也称为2-甲基乙烯基)(C3)、异丙烯基(也称为2-甲基乙烯-2-基)(C3)、丁烯-4-基(C4)、4-羟丁烯-1-基(C4)、环丁烯基(C4)、环戊烯基(C5)、环戊二烯基(C5)、环己烯基(C6)、7-羟基-7-甲基辛-4-烯-2-基(C9)和7-羟基-7-甲基辛-3,5-二烯-2-基(C9)等;
iii)被取代或未被取代的C2-C12直链或C3-C12支链炔基;例如,乙炔基(C2)、丙-2-炔基(也称为炔丙基)(C3)、丙炔-1-基(C3)、2-甲基-己-4-炔-1-基(C7);5-羟基-5-甲基己-3-炔基(C7)、6-羟基-6-甲基庚-3-炔-2-基(C8)、5-羟基-5-乙基庚-3-炔基(C9)等;
iv)被取代或未被取代的C6或C10芳基;例如,苯基(C6)、萘-1-基(C10)、萘-2-基(C10)、4-氟苯基(C6)、2-羟苯基(C6)、3-甲基苯基(C6)、2-氨基-4-氟苯基(C6)、2-(N,N-二乙氨基)苯基(C6)、2-氰苯基(C6)、2,6-二-叔丁基苯基(C6)、3-甲氧苯基(C6)、8-羟基萘-2-基(C10)、4,5-二甲氧萘-1-基(C10)、6-氰-萘-1-基(C10)等;
v)被取代或未被取代的C1-C9杂环;例如,二氮丙啶基(C1)、吖丙啶基(C2)、尿唑基(C2)、氮杂环丁基(C3)、吡唑烷基(C3)、咪唑烷基(C3)、噁唑烷基(C3)、异噁唑啉基(C3)、异噁唑基(C3)、噻唑烷基(C3)、异噻唑基(C3)、异噻唑啉基(C3)、噁噻唑烷酮基(C3)、噁唑烷酮基(C3)、乙内酰脲基(C3)、四氢呋喃基(C4)、吡咯烷基(C4)、吗啉基(C4)、哌嗪基(C4)、哌啶基(C4)、二氢吡喃基(C5)、四氢吡喃基(C5)、哌啶-2-酮基(戊内酰胺)(C5)等;
vi)被取代或未被取代的C1-C11杂芳基;例如,1,2,3,4-四唑基(C1)、[1,2,3]三唑基(C2)、[1,2,4]三唑基(C2)、三嗪基(C3)、噻唑基(C3)、1H-咪唑基(C3)、噁唑基(C3)、呋喃基(C4)、噻吩基(C4)、嘧啶基(C4)、吡啶基(C5)等;
vii)卤素;例如、-F、-Cl、-Br或-I;
viii)-[C(R23a)(R23b)]xOR10;
R10选自:
a)-H;
b)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
c)被取代或未被取代的C6或C10芳基或C7或C10亚烷基芳基;
d)被取代或未被取代的C1-C9杂环;
e)被取代或未被取代的C1-C11杂芳基;
例如,-OH、-CH2OH、-OCH3、-CH2OCH3、-OCH2CH3、-CH2OCH2CH3、-OCH2CH2CH3和-CH2OCH2CH2CH3;
ix)-[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b各自独立地选自:
a)-H;
b)-OR12;
R12为氢或C1-C4直链烷基;
c)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
d)被取代或未被取代的C6或C10芳基;
e)被取代或未被取代的C1-C9杂环;
f)被取代或未被取代的C1-C11杂芳基;或
g)R11a和R11b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NH2、-CH2NH2、-NHCH3、-N(CH3)2、-NHOH、-NHOCH3、-NH(CH2CH3)、-CH2NHCH3、-CH2N(CH3)2、-CH2NH(CH2CH3)等;
x)-[C(R23a)(R23b)]xC(O)R13;
R13为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-OR14;
R14为氢、被取代或未被取代的C1-C4直链烷基、被取代或未被取代的C6或C10芳基、被取代或未被取代的C1-C9杂环、被取代或未被取代的C1-C11杂芳基;
c)-N(R15a)(R15b);
R15a和R15b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基;被取代或未被取代的C1-C9杂环;被取代或未被取代的C1-C11杂芳基;或R15a和R15b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-COCH3、-CH2COCH3、-OCH2CH3、-CH2COCH2CH3、-COCH2CH2CH3、-CH2COCH2CH2CH3等;
xi)-[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R17a)(R17b);
R17a和R17b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基;被取代或未被取代的C1-C9杂环;被取代或未被取代的C1-C11杂芳基;或者R17a和R17b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)-[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)-H;或
b)被取代或未被取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R19为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R20a)(R20b);
R20a和R20b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;被取代或未被取代的C6或C10芳基;被取代或未被取代的C1-C9杂环;被取代或未被取代的C1-C11杂芳基;或者R20a和R20b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
例如,-NHC(O)CH3、-CH2NHC(O)CH3、-NHC(O)NH2、-CH2NHC(O)NH2、-NHC(O)NHCH3、-CH2NHC(O)NHCH3、-OC(O)N(CH3)2、-CH2NHC(O)N(CH3)2等;
xiii)-[C(R23a)(R23b)]xCN;例如,-CN、-CH2CN和-CH2CH2CN;
xiv)-[C(R23a)(R23b)]xNO2;例如,-NO2、-CH2NO2和-CH2CH2NO2;
xv)-[C(R23a)(R23b)]xR21;例如,-CH2F、-CHF2、-CF3、-CCl3或-CBr3;
R21为被1-21个选自-F、-Cl、-Br或-I的卤素原子取代的C1-C10直链、支链或环状烷基;
xvi)-[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、被取代或未被取代的C1-C4直链或C3-C4支链烷基;被取代或未被取代的C6、C10或C14芳基;C7-C15亚烷基芳基;被取代或未被取代的C1-C9杂环;或被取代或未被取代的C1-C11杂芳基;例如,-SO2H、-CH2SO2H、-SO2CH3、-CH2SO2CH3、-SO2C6H5和-CH2SO2C6H5;
R23a和R23b各自独立地为氢或C1-C4烷基;并且
指数x为0至5的整数。
该类别的一方面实施方案涉及其中R1和R2一起形成一个5元被取代或未被取代的C1-C4杂环或者被取代或未被取代的C1-C4杂芳环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例包括选自如下的环:
该类别的另一方面涉及其中R1和R2一起形成一个被取代或未被取代的C4-C11杂环或者被取代或未被取代的C4-C11杂芳环的HIF-1α脯氨酰羟化酶抑制剂,其非限制性实例选自:
该类别的非限制性实例包括具有下式的化合物:
又一类所公开的化合物具有下式:
其中R代表1至5个苯环氢原子的可选取代基,R1和R2各自独立地为氢或者被取代或未被取代的C1-C10直链或支链烷基,其中所述烷基单元可以被一个或多个独立选自如下基团的单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)-SR40;R40为氢或C1-C4直链或支链烷基;
vii)被取代或未被取代的C6或C10芳基;
viii)被取代或未被取代的C1-C9杂环;或
ix)被取代或未被取代的C1-C9杂芳基。
该类别的非限制性实例包括:
再一类所公开的HIF-1α脯氨酰羟化酶抑制剂涉及具有下式的化合物:
其中R1和R2一起形成一个被取代或未被取代的哌嗪环,所述环上的取代基如上文对R200所定义。
再一类所公开的HIF-1α脯氨酰羟化酶抑制剂具有下式:
本文还公开了具有下式的N-取代的苄基或N-取代的磺酰基芳基-3-羟基吡啶-2-(1H)-酮:
其可用于刺激受试者中的细胞免疫应答。对于这些化合物,Z和L与上文公开相同。这些化合物的非限制性实例包括:
具有下式的1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮:
具有下式的1-(3-氯苄基)-3-羟基吡啶-2(1H)-酮:
具有下式的1-(2-氯苄基)-3-羟基吡啶-2(1H)-酮:
本文还公开了具有下式的N-取代的苄基或N-取代的磺酰基芳基-5-取代的-3-羟基吡啶-2-(1H)-酮:
其中Y为被取代或未被取代的苯基,Z和L与上文的定义相同。
Y的一个方面涉及被1-5个卤素原子取代的苯基,例如,Y选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。Y单元的又一方面涉及其中Y选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基的化合物。
该类别化合物的非限制性实例包括具有下式的1-(4-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)酮:
另外的非限制性实例包括:
1-(2-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(2-氯苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(3-氯苯基)-3-羟基吡啶-2(1H)-酮
1-(4-氟苄基)-5-(4-氯苯基)-3-羟基吡啶-2(1H)-酮
1-(2-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氯苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氯苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氯苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮
1-(2-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(2-氟苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(3-氟苄基)-5-(4-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(2-氟苯基)-3-羟基吡啶-2(1H)-酮;
1-(4-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮;和
1-(4-氟苄基)-5-(3-氟苯基)-3-羟基吡啶-2(1H)-酮。
为严格地以非限制性方式描述制备本文未进行明确示例的化合物范围内亚属化合物的合成策略的替换方案之目的,可将所公开的化合物分成几种类别。这种主观分类不意味着任何本文所述化合物或物质的组合物的生物功效的任何增加或降低。
所公开的HIF-1α脯氨酰羟化酶抑制剂的类别I涉及具有下式的化合物:
其中A为具有2-20个碳原子和1-7个杂原子的被取代或未被取代的杂环或杂芳环,R200表示0-40个氢的取代基,R代表上文定义的1-5个氢的取代基,指数n为1-5。表I提供了该类别化合物的代表性实例。
表I
编号 | R | A环 |
A1 | 3-甲氧基 | 吡咯烷-1-基 |
A2 | 3-甲氧基 | 3-羟基吡咯烷-1-基 |
A3 | 3-甲氧基 | 2-(吡啶-2-基)吡咯烷-1-基 |
A4 | 3-甲氧基 | 2-甲基羧基吡咯烷-1-基 |
A5 | 3-甲氧基 | 2-(甲氧甲基)吡咯烷-1-基 |
A6 | 3-甲氧基 | 噻唑烷-3-基 |
A7 | 3-甲氧基 | 1H-咪唑-1-基 |
A8 | 3-甲氧基 | 哌啶-1-基 |
A9 | 3-甲氧基 | 4-苄基哌啶-1-基 |
A10 | 3-甲氧基 | 1,4’-联哌啶基-1’-基 |
A11 | 3-甲氧基 | 哌嗪-1-基 |
A12 | 3-甲氧基 | 4-苄基哌嗪-1-基 |
A13 | 3-甲氧基 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
A14 | 3-甲氧基 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
A15 | 3-甲氧基 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
编号 | R | A环 |
A16 | 3-甲氧基 | 吗啉-4-基 |
A17 | 3-甲氧基 | 硫代吗啉-4-基 |
A18 | 3-甲氧基 | 氮杂环庚-1-基 |
A19 | 3-甲氧基 | 氮杂环辛-1-基 |
A20 | 3-甲氧基 | 3,4-二氢喹啉-1(2H)-基 |
A21 | 4-氯 | 吡咯烷-1-基 |
A22 | 4-氯 | 3-羟基吡咯烷-1-基 |
A23 | 4-氯 | 2-(吡啶-2-基)吡咯烷-1-基 |
A24 | 4-氯 | 2-甲基羧基吡咯烷-1-基 |
A25 | 4-氯 | 2-(甲氧甲基)吡咯烷-1-基 |
A26 | 4-氯 | 噻唑烷-3-基 |
A27 | 4-氯 | 1H-咪唑-1-基 |
A28 | 4-氯 | 哌啶-1-基 |
A29 | 4-氯 | 4-苄基哌啶-1-基 |
A30 | 4-氯 | 1,4’-联哌啶基-1’-基 |
A31 | 4-氯 | 哌嗪-1-基 |
A32 | 4-氯 | 4-苄基哌嗪-1-基 |
A33 | 4-氯 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
A34 | 4-氯 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
A35 | 4-氯 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
A36 | 4-氯 | 吗啉-4-基 |
A37 | 4-氯 | 硫代吗啉-4-基 |
A38 | 4-氯 | 氮杂环庚-1-基 |
A39 | 4-氯 | 氮杂环辛-1-基 |
A40 | 4-氯 | 3,4-二氢喹啉-1(2H)-基 |
A41 | 4-氯 | 4-叔丁氧羰基哌嗪-1-基 |
该类别所公开的化合物可以通过下文路线I中列出且在实施例1中描述的步骤制备。
路线I
试剂和条件:(a)TBDMSCl,咪唑,DMF:室温,30分钟。
试剂和条件:(b)(4-氯)苄基氯,Cs2CO3,THF;室温。
试剂和条件:(c)5M HCl,EtOH;30分钟。
试剂和条件:(d)(i)H2CHO,AcOH,t-Boc-哌嗪,EtOH;3天。
实施例1
{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(4)
制备3-(叔丁基二甲基硅氧)-1H-吡啶-2-酮(1):将3-羟基吡啶-2(1H)-酮(15g,135mmol)和咪唑(23g,338mmol)在惰性气氛下悬浮于二甲基甲酰胺(200mL)中。在室温下,经30分钟的时间将叔丁基二甲基氯硅烷(20.5g,136mmol)在二甲基甲酰胺(200mL)中的溶液逐滴加入。然后使所述反应系搅拌过夜。然后将所得到的溶液倒入水(300mL),以叔丁基甲基醚(3×500mL)萃取所述混合物。将合并的有机层用水(300mL)和盐水(300mL)洗涤并经Na2SO4干燥。在减压下除去溶剂,从庚烷结晶粗产物,得到16.3g(53%产率)所需产品。
1H NMR(250MHz,CDCl3)δppm 12.98(1H,m);6.9l(1H,dd,J=l.Hz,J =6.8Hz);6.81(1H,dd,J=1.8Hz,J=7.2Hz);6.02-6.007(1H,m);0.90(9H,s),和0.17(6H,s).
制备3-(叔丁基二甲基硅氧)-1-(3-氯苄基)-1H-吡啶-2-酮(2):在0℃下,在惰性气氛下将4-氯苄基氯(4.44mmol)在THF(10mL)中的溶液逐滴加入3-(叔丁基二甲基硅氧)-1H-吡啶-2-酮,1,(1g,4,44mmol)和CsCO3(2.17g,6.66mmol)在THF(10mL)的溶液中。使所述反应溶液升至室温,并连续搅拌过夜。将所得到的溶液用水(40mL)稀释,然后以EtOAc(3×30mL)萃取。将合并的有机层用盐水(30mL)洗涤并经Na2SO4干燥。在减压下除去溶剂,经二氧化硅(EtOAc∶庚烷4∶1)纯化粗产物,得到白色固体的所需产品。
制备1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮(3):在室温下,向3-(叔丁基二甲基硅氧)-1-(3-氯苄基)-1H-吡啶-2-酮,2,(2.36g,10mmol)在EtOAc(25mL)中的溶液剧烈搅拌加入5M HCl(25mL)。对所述反应通过TLC监测原料的消失,并在30分钟内完成。将有机层倒出,以二氯甲烷(2×50mL)萃取水层。将合并的有机层经Na2SO4干燥并在减压下除去溶剂。从二氯甲烷重结晶粗产物。产率几乎是定量的。
1H NMR(360MHz,DMSO-d6)δppm 5.12(2H,s);6.13(1H,t,J=7.04);6.71(1H,dd,J=7.04,1.59);7.23-7.28(2H,m);7.36-7.43(2H,m);9.10(1H,br.s).
制备{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢-吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(4):将哌嗪-1-甲酸叔丁酯(97.6mmol)、甲醛(8mL 37%溶液(soln.),97.6mmol)和乙酸(8mL)溶解于乙醇(350mL)中并在室温下将所述溶液搅拌1小时。经30分钟将1-(4-氯苄基)-3-羟基吡啶-2(1H)-酮,3,(48.8mmol)在乙醇(350mL)中的溶液逐滴加入。在搅拌3天后,加入甲醛(3mL)并将所述反应系加热至50℃,其后在减压下浓缩所述反应溶液至大约500mL。通过结晶从乙醇得到所需的产物。
1H NMR(250MHz,CDCl3)d ppm 1.46(s,9H);2.38-2.57(m,4H);3.40-3.49(m,4H);3.51(s,2H);5.13(s,2H);6.13(d,J=7.16Hz),1H);6.79(d,J=7.16Hz,1H);7.20-7.41(m,4H);8.33-8.85(m,1H).所公开的生物数据涉及A41。
所公开的脯氨酰羟化酶抑制剂的类别II涉及具有下式的化合物:
其中A为一个具有2-20个碳原子和1-7个杂原子的被取代或未被取代的杂环或杂芳环,R200表示0-40个氢的取代基。表II提供了该类别化合物的代表性实例。
表II
编号 | A环 |
B1 | 吡咯烷-1-基 |
B2 | 3-羟基吡咯烷-1-基 |
B3 | 2-(吡啶-2-基)吡咯烷-1-基 |
B4 | 2-甲基羧基吡咯烷-1-基 |
B5 | 2-(甲氧甲基)吡咯烷-1-基 |
B6 | 噻唑烷-3-基 |
B7 | 1H-咪唑-1-基 |
B8 | 哌啶-1-基 |
B9 | 4-苄基哌啶-1-基 |
B10 | 1,4’-联哌啶基-1’-基 |
B11 | 哌嗪-1-基 |
B12 | 4-苄基哌嗪-1-基 |
B13 | 4-(2-甲氧苯基)哌嗪-1-基甲基 |
B14 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
编号 | A环 |
B15 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
B16 | 吗啉-4-基 |
B17 | 硫代吗啉-4-基 |
B18 | 氮杂环庚-1-基 |
B19 | 氮杂环辛-1-基 |
B20 | 3,4-二氢喹啉-1(2H)-基 |
类别II的化合物可以依照路线I中列出且在实施例1中公开的步骤制备。以下是类别II的抑制剂的另外的实例。
1-苄其-3-羟其-4-(哌啶-1-其甲基)吡啶-2(1H)-酮.
1HNMR(300MHz,CD3OD)δ1.81(m,6H),3.07(m,2H),3.51(m,2H),4.23(s,2H),5.24(s,2H),6.31(d,J=6.9Hz,1H),7.35(m,6H);19F NMR(252MHz,CD3OD)δ85.5;13C NMR(75MHz,DMSO)δ21.3,22.7,51.8,52.5,53.1,106.4,117.4,127.7,128.0,128.2,128.9,137.3,147.4,158.0;ES MS(M+1)299.12;HRMS Calcd.For C18H22N2O2,298.38.Found(M+1)299.17.
1-苄基-3-羟基-4-(吗啉-4-基甲基)吡啶-2(1H)-酮:
1HNMR (300MHz,DMSO)δ3.25(m,4H),3.81(m,4H),4.18(s,2H),5.17(s,2H),6.31(d,J=6.9Hz,1H),7.35(m,6H);19FNMR(300MHz,DMSO)δ88.5;13C NMR(300MHz,DMSO)δ51.6,51.8,53.4,63.5,107.9,119.1,127.8,128.0,128.2,128.9,137.3,147.5,158.3;ESMS(M+1)301.12;HRMS Calcd.For C17H20N2O3,300.35.
1-苄基-3-羟基-4-(硫代吗啉-4-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ2.92(m,4H),3.38(m,4H),4.17(s,2H),5.16(s,2H),6.29(d,J=7.5Hz,1H),7.34(m,6H),9.97(s,1H);19F NMR(300MHz,DMSO)δ88.4;13CNMR(75MHz,DMSO)δ24.3,51.9,53.4,53.7,107.9,110.9,127.8,128.0,128.2,128.8,137.2,147.6,157.6;ES MS(M+1)317.14;HRMS Calcd.For C17H20N2O2S,316.42.Found:(M+1)317.13.
1-苄基-3-羟基-4-(噻唑烷-3-基甲基)吡啶-2(1H)-酮:
1HNMR (300MHz,DMSO)δ3.09(t,J=6.3Hz,2H),3.42(t,J=6.3Hz,2H),4.03(s,2H),4.29(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),10.48(broad s,1H);19FNMR(300MHz,DMSO)δ87.9;13CNMR(75MHz,DMSO)δ28.3,48.3,50.1,56.3,57.0,107.4,122.1,127.8,128.2,128.8,137.4,146.3,157.6;ES MS(M+1)303.08;Anal.Calcd forC18H19N2O4SF,C,51.92;H,4.60;N,6.73;S,7.70.Found:C,51.67;H,4.48;N,6.69;S,765
1-苄基-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.96(s,4H),3.16(s,2H),3.43(s,2H),4.23(s,4H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ22.8,50.9,51.8,53.7,107.3,118.0,128.0,128.2,128.9,137.3,146.7,157.6;ESMS(M+1)285.13;Anal.Calcd.For C19H21F3N2O4,C,57.28;H,5.31;N,7.03.Found:C,57.10;H,5.11,N,7.02.
1-苄基-3-羟基-4-(4-苄基哌啶-1-基甲基)吡啶-2(1H)-酮:
1HNMR(DMSO)δ1.43(m,2H),1.72(m,4H),2.96(m,2H),3.41(m,3H),4.09(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.35(m,11H);19F NMR(252MHz,DMSO)δ88.8;13CNMR(75MHz,DMSO)δ;ES MS(M+1)389.21;HRMS Calcd.For C25H28N2O2,388.50.Found(M+1)389.22.
1-苄基-3-羟基-4-(4-苄基哌嗪-1-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.11(broad s,4H),3.81(s,2H),4.18(s,2H),5.15(s,2H),6.24(d,J=7.2Hz,1H),7.34(m,6H),7.46(m,5H);19F NMR(252MHz,DMSO)δ88.2;13C(75MHz,DMSO)δ;ES MS(M+1)390.21;HRMS Calcd.For C24H27N3O2,389.49.Found(M+1)390.21.
1-苄基-3-羟基-4-[(3-羟基吡咯烷-1-基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.90(m,1H),3.18(m,2H),3.47(m,3H),4.24(s,2H),4.43(s,1H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ89.0;13C NMR(75MHz,DMSO)δ51.8,52.6,61.3,68.6,107.4,117.9,128.0,128.2,128.9,137.3,146.7,157.6;ES MS(M+1)301.13;HRMS Calcd.For C17H20N2O3,300.35.Found:(M+1)301.15.
1-苄基-3-羟基-4-(1,4-二氧杂-8-氮杂螺[4,5]癸-8-基甲基)吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.90(m,4H),3.11(m,2H),3.43(m,2H),3.93(s,4H),4.19(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),10.01(broad s,1H);19FNMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ31.7,50.7,51.9,52.5,64.5,101.1,108.0,116.5,127.8,128.0,128.3,128.9,137.3,147.5157.6;ES MS(M+1)357.19;HRMS Calcd.For C20H24N4O2,356.42.Found(M+1)357.18.
1-苄基-3-羟基-4-氮杂环庚-1-基甲基吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.61(m,4H),1.80(m,4H),3.20(m,4H),4.17(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ22.8,26.4,51.8,53.4,54.4,107.6,117.2,127.9,128.0,18.2,128.9,137.3,147.2,157.6;ES MS(M+1)313.18;HRMS Calcd.For C19H24N2O4,312.41.Found(M+1)313.19.
1-苄基-3-羟基-4-(氮杂环辛-1-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.59(m,10H),3.18(m,2H),3.38(m,2H),4.17(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ;ES MS(M+1)327.2;HRMS Calcd.For C20H26N2O2,326.43.Found(M+1)327.20.
1-苄基-3-羟基-(1,4’-联哌啶基-1’-基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.43-1.98(m,10H),2.21(m,2H),3.01(m,4H),3.43(m,3H),4.12(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),9.85(broad s,1H);19FNMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.6,22.9,23.8,49.6,50.5,51.8,53.0,59.5,108.0,127.8,128.0,128.2,128.9,137.3,147.5,157.6;ES MS(M+1)382.4;HRMS Calcd.For C23H31N3O2,383.51.Found(M+1)382.25.
1-苄基-3-羟基-4-[(3,4-二氢喹啉-1(2H)-基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.13(t,J=6.3Hz,2H),3.52(m,2H),4.28(s,2H),4.41(s,2H),5.18(s,2H),6.34(d,J=7.2Hz,1H),7.23-7.41(m,10H),10.15(broad s,1H);19F NMR(252MHz,DMSO)δ88.9;13C NMR(75MHz,DMSO)δ25.4;49.3,51.8,52.7,52.9,107.6,11.6,116.8,126.9,127.0,127.9,128.0,128.1,128.2,128.8,128.9,131.7,137.3,147.3,157.6;ES MS(M+1)347.40;HRMS Calcd.For C22H22N2O2,346.42.Found(M+1)347.17.
1-[(1-苄基-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基]吡咯烷-2-甲酸甲酯:
1H NMR(300MHz,.DMSO)δ2.01(m,3H),2.45(m,1H),3.26(m,1H),3.53(m,1H),3.69(s,3H),4.30(m,3H),5.17(s,2H),6.27(d,6.9Hz,1H),7.35(m,6H),19F NMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ;ES MS(M+1)343.20;HRMS Calcd.For C19H22N2O4,342.39.Found(M+1)
1-苄基-3-羟基-4-{[2-(甲氧甲基)吡咯烷-1-基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.71(m,1H),1.84(m,1H),1.99(m,1H),2.15(m,1H),3.19(m,1H),3.30(s,3H),3.41(m,1H),3.62(m,2H),3.77(m,1H),4.15(m,1H),4.39(m,1H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);9.60(broad s,1H);19F NMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ;ES MS(M+1)329.2;HRMS Calcd.For C19H24N2O3,328.41.Found(M+1)
1-苄基-3-羟基-4-{[2-(吡啶-2-基)吡咯烷-1-基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.12(m,4H),3.39(m,1H),3.63(m,1H),4.07(m,2H),4.60(m,.1H),5.10(m,2H),6.15(d,J=6.9Hz,1H),7.33(m,6H),7.44(m,1H),8.05(d,J=8.1Hz,1H),8.59(d,J=4.8Hz,1H),8.74(s,1H);19F NMR(252MHz,DMSO)δ88.0;ES MS(M+1)362.22;HRMS Calcd.For C22H23N3O2,361.44.Found(M+1).
1-苄基-3-羟基-4-[4-(6-氯哒嗪-3-基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.18(m,2H),3.48(m,4H),4.19(s,2H),4.46(m,2H),5.16(s,2H),6.62(d,J=7.2Hz,1H),7.35(m,6H),7.48(m,1H),7.68(m,1H),11.5(broad s,1H);13C NMR(75MHz,DMSO)δ42.1,50.3,51.9,52.5,108.2,116.2;118.0,128.0,128.2,128.9,129.8,137.3,147.4,.157.6,158.8;ES MS(M+1)476.09.HRMS Calcd.For C21H22ClN5N3O2,411.88.Found(M+1)412.76.
1-苄基-3-羟基-4-[4-(2-甲氧苯基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.95(m,2H),3.30(m,2H),3.48(m,4H),3.80(s,3H),4.25(s,2H),5.18(s,2H),6.34(d,J=7.2Hz,1H),6.93(m,2H),7.01(m,2H),7.34(m,6H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ47.2,51.8,53.0,55.3,108.1,112.2,114.8,116.2,118.6,121.2,123.8,127.8,128.0,128.9,137.3,139.6,147.5,152.2,157.6;ES MS(M+1)405.82;HRMS Calcd.For C24H27N3O3,405.49.Found(M+1)406.21.
所公开的脯氨酰羟化酶抑制剂类别III涉及具有下式的化合物:
R1和R2各自独立地为氢或者被取代或未被取代的C1-C10直链或支链烷基,其中所述烷基单元可以被一个或多个独立选自如下基团的单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)-SR40;R40为氢或C1-C4直链或C3-C4支链烷基;
vii)被取代或未被取代的C6或C10芳基;
viii)被取代或未被取代的C1-C9杂环;或
ix)被取代或未被取代的C1-C9杂芳基。
本文下表III提供了该类别包含的化合物的非限制性实例。
表III
编号 | R1 | R2 |
C1 | 苄基 | 氢 |
C2 | 4-甲氧苄基 | 氢 |
C3 | 4-氟苄基 | 氢 |
C4 | 4-氯苄基 | 氢 |
C5 | 4-甲基苄基 | 氢 |
C6 | 2-(吡啶-2-基)乙基 | 氢 |
C7 | [1,3]二氧戊环-2-基甲基 | 氢 |
C8 | 四氢呋喃-2-基甲基 | 氢 |
C9 | 2-甲氧乙基 | 氢 |
C10 | 1-羟基-2-甲基丙-2-基 | 氢 |
C11 | 吡啶-4-基甲基 | 氢 |
编号 | R1 | R2 |
C12 | 呋喃-2-基甲基 | 氢 |
C13 | 2-(甲基硫)乙基 | 氢 |
C14 | 1-苯乙基 | 氢 |
C15 | 3-咪唑-1-基丙基 | 氢 |
C16 | 环庚基 | 氢 |
C17 | 4-甲基环己基 | 氢 |
C18 | 1-苄基哌啶-4-基 | 氢 |
C19 | 氮杂环庚-2-酮-3-基 | 氢 |
C20 | 1-苄基吡咯烷-3-基 | 氢 |
C21 | 苄基 | 甲基 |
C22 | 4-甲氧苄基 | 甲基 |
C23 | 4-氟苄基 | 甲基 |
C24 | 4-氯苄基 | 甲基 |
C25 | 4-甲基苄基 | 甲基 |
C26 | 2-(吡啶-2-基)乙基 | 甲基 |
C27 | [1,3]二氧戊环-2-基甲基 | 甲基 |
C28 | 四氢呋喃-2-基甲基 | 甲基 |
C29 | 2-甲氧乙基 | 甲基 |
C30 | 1-羟基-2-甲基丙-2-基 | 甲基 |
C31 | 吡啶-4-基甲基 | 甲基 |
C32 | 呋喃-2-基甲基 | 甲基 |
C33 | 2-(甲基硫)乙基 | 甲基 |
C34 | 1-苯乙基 | 甲基 |
C35 | 3-(1H-咪唑-1-基)丙基 | 甲基 |
C36 | 环庚基 | 甲基 |
C37 | 4-甲基环己基 | 甲基 |
C38 | 1-苄基哌啶-4-基 | 甲基 |
C39 | 氮杂环庚-2-酮-3-基 | 甲基 |
C40 | 1-苄基吡咯烷-3-基 | 甲基 |
所公开的该类别的化合物可以通过下文路线II中列出且在实施例2中描述的步骤制备。
路线II
试剂和条件:(a)(i)HCHO,EtOH;0.5小时(ii)3-(1-H-咪唑-1-基)丙-1-胺;2小时。
实施例2
1-苄基-3-羟基-4-{[3-(1-H-咪唑-1-基)丙基氨基]甲基}-吡啶-2(1H)-酮(6)
N-苄基-3-羟基吡啶-2(1H)-酮(5)可以依照实施例1通过将苄基溴或苄基氯替代步骤(b)中的(4-氯)苄基氯而制备。
1-苄基-3-羟基-4-{[3-(1-H-咪唑-1-基)丙基氨基]甲基}吡啶-2(1H)-酮(6):将N-苄基-3-羟基吡啶-2(1H)-酮(5)(250mg,1.23mmol)和甲醛(200mg,273当量)在乙醇水溶液(10mL)中合并搅拌30分钟。然后加入3-(1-H-咪唑-1-基)丙-1-胺(340mg,2.7mmol)并使所述反应系搅拌12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(2mL)中并经制备型HPLC以水/乙腈洗脱进行纯化,得到三氟乙酸盐形式的所需产物。
1H NMR(300MHz,DMSO)δ2.19(m,2H),2.97(m,2H),4.02(s,2H),4.30(t,J=6.6Hz,2H);5.17(s,2H),6.30(d,J=6.9Hz,1H),7.36(m,6H),7.26(s,1H),7.76(s,1H),9.03(s,1H),9.11(s,1H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ26.5,44.0,46.0,51.8,106.8,118.7,120.5,122.2,127.9,128.2,128.9,135.8,137.4,146.0,158.2;ES MS(M+1)339.05;HRMSCalcd.For C19H22N4O2,338.44.Found(M+1)339.18.
以下是该方面所公开HIF-1α脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-苄基-3-羟基-4-(苄基氨基甲基)吡啶-2(1H)-酮:
1HNMR (300MHz,DMSO)δ4.01(s,2H),4.20(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.36(m,11H),9.16(broad s,1H);19FNMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ;ES MS(M+1)321.16;Anal.Calcd.For C22H21F3N2O4,C,60.83;H,4.87;N,6.45.Found:C,60.75;H,4.56;N,6.34.
1-苄基-3-羟基-4-{[(2-(吡啶-2-基)乙氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ3.26(m,2H),3.37(m,2H),4.08(s,2H),5.17(s,2H);6.34(d,J=7.2Hz,1H),7.38(m,6H),7.86(d,J=5.7Hz,2H),8.84(m,2H),9.32(broad s,1H);19FNMR(252MHz,DMSO)δ88.6;13C NMR (75MHz,DMSO)δ31.5,44.1,46.3,51.8,106.9,114.8,127.1,128.1,128.8,137.4,143.8,146.1,155.3,157.5,158.4;ES MS(M+1)336.18;HRMS Calcd For C20H21N3O2,335.40.Found:336.16.
1-苄基-3-羟基-4-{[(四氢呋喃-2-基甲基)氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.56(m,1H),1.86(m,2H),1.99(m,1H),2.92(m,1H),3.05(m,1H),3.80(m,2H),4.09(m,3H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);8.91(broad s,1H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ;ES MS(M+1)315.16;HRMS.Calcd.For C18H22N2O3,314.38.Found(M+1)31516.
1-苄基-3-羟基-4-[(2-甲氧乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.13(broad s,2H),3.30(s,3H),3.59(t,J=5.4Hz,2H),4.02(s,2H),5.16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),8.91(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(252MHz,DMSO)δ;ES MS(M+1)289.13;HRMSCalcd.For C16H20N2O3,288.34.Found(M+1)289.15.
1-苄基-3-羟基-4-[(1-羟基-2-甲基丙-2-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.27(s,6H),3.49(s,2H),3.95(s,2H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),8.47(broad s,2H),9.94(broad s,1H);19FNMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ;ES MS(M+1)303.19;HRMS Calcd.For C17H22N2O3,302.37.Found(M+1)303.17.
1-苄基-3-羟基-4-[(吡啶-4-基甲基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ4.07(s,2H),4.32(s,2H),5,16(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H);7.62(d,J=5.7Hz,2H),8.71(d,J=4.5Hz,2H);19F NMR(252MHz,DMSO)δ88.0;13C NMR(75MHz,DMSO)δ;ES MS(M+1)322.17;HRMS Calcd.ForC19H19N3O2,321.37.Found (M+1)322.15.
1-苄基-3-羟基4-{[(呋喃-2-基甲基)氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ4.00(s,2H),4.28(s,2H),5.16(s,2H),6.27(d,J=6.9Hz,1H),6.54(m,1H),6.65(m,1H),7.34(m,6H),7.80(m,1H),9.27(broad s,1H);19F NMR(252MHz,DMSO)δ88.3;13C NMR(75MHz,DMSO)δ;ES MS(M+1)323.15;HRMSCalcd.For C18H18N2O3,310.35.Found(M+1)
1-苄基-3-羟基-4-{[2-(甲基硫)乙氨基]甲基}吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.10(s,3H),2.74(t,J=6.9Hz,2H),3.16(t,J=8.1Hz,2H),4.05(s,2H),5.17(s,2H),6.34(d,J=7.2Hz,1H),7.34(m,6H),19F NMR(252MHz,DMSO)δ89.0;ES MS(M+1)305.14,HRMS Calcd.For C16H20N2O2S,304.41.Found(M+1)
1-苄基-3-羟基-4-[(4-甲氧苄基氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ3.70(s,3H),3.98(s,2H),4.13(s,2H),5.16(s,2H),6.28(d,J=7.5Hz,1H),7.00(d,J=9.0Hz,4H),7.34(m,6H);9.07(broad s,1H);19F NMR(252MHz,DMSO)δ89.0;ES MS(M+1)351.10;HRMS Calcd.For C21H22N2O3,350.41.Found(M+1)351.17.
1-苄基-3-羟基-4-[(1-苯乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.59(d,J=7.2Hz,3H),3.71-3.93(m,2H),4.45(m,1H),5.15(s,2H),6.28(d,J=7.5Hz,1H),7.34(m,11H);19F NMR(252MHz,DMSO)δ88.9;13CNMR(75MHz,DMSO)δ19.6,42.5,51.7,58.0,106.8,119.3,128.0,128.1,128.2,128.9,129.3,129.4,137.3,145.9,158.3;ES MS(M+1)335.13;HRMS Calcd.For C21H22N2O2,334.41.Found (M+1)335.17.
1-苄基-3-羟基-4-(环庚基氨基甲基)吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.55(m,10H),2.03(m,2H),3.18(s,1H),3.99(m,2H),5.17(s,2H),6.32(d,J=6.9Hz,1H),7.35(m,6H),8.65(broad s,2H),9.98(broad s,1H);19F NMR(252MHz,DMSO)δ88.6;13C NMR(75MHz,DMSO)δ23.0,27.2,30.4,41.6,51.7,58.9,107.0,111.7,127.9,128.0,128.2,128.8,137.4,146.0,157.5;ES MS(M+1)327.13;HRMSCalcd.For C20H26N2O2,326.43.Found(M+1)327.20.
1-苄基-3-羟基-4-[(4-甲基环己基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ0.93(d,J=6.9Hz,3H),1.38(m,4H),1.74(m,4H),2.05(m,1H),3.10(m,1H),4.01(s,2H),5.17(s,2H),6.31(m,1H),7.34(m,6H),8.05(broad s,2H),9.98(broad s,1H);19F NMR(252MHz,DMSO)δ88.9;ES MS(M+1)327.14;HRMSCalcd.For C20H26N2O2,326.43;Found(M+1)372.20.
1-苄基-3-羟基-4-[(1-苄基哌啶-4-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.77(m,2H),2.31(m,2H),2.98(m,2H),3.30(m,3H),3.46(m,2H),4.03(s,2H),.29(s,2H),5.16(s,2H),6.30(d,J=7.5Hz,1H),7.34(m,6H),7.49(s,5H),9.12(broad s,1H),10.05(broad s,1H);19F NMR(252MHz,DMSO)δ88.8;13C NMR(75MHz,DMSO)δ27.1,43.4,51.8,52.1,54.2,54.7,57.6,106.9,118.5,128.0,128.1,128.8,129.3,129.8,130.7,131.3,137.3,146.2,157.4;ES MS(M+1)404.56;HRMS Calcd.For C25H28N3O2,403.52.Found(M+1)404.23.
3-[(1-苄基-3-羟基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基]氮杂环庚-2-酮:
1H NMR(300MHz,DMSO)δ1.25(m,1H),1.59(m,2H),1.74(m,1H),1.92(m,1H),2.10(m,1H),3.18(m,3H),4.03(s,2H),4.2(m,1H),5.17(s,2H),6.33(d,J=7.5Hz,1H),7.34(m,6H),8.31(t,J=5.4Hz,1H),9.07(broad s,2H),9.90(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(75MHz,DMSO)δ27.0,27.2,28.4,43.4,51.7,59.3,107.1,118.9,127.8,127.9,128.1,128.9,137.4,146.0,157.5,166.3;ES MS(M+1)342.01;HRMS Calcd.For C19H23N3O3,341.40.Found(M+1)342.18.
1-苄基-3-羟基-4-[(1-苄基吡咯烷-3-基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.22(m,2H),2.42(m,1H),3.39(m,3H),3.68(m,1H),4.06(s,2H),4.39(s,2H),5.17(s,2H),6.33(d,J=7.5Hz,1H),7.30-7.52(m,11H);19F NMR (252MHz,DMSO)δ88.5;13C NMR (75MHz,DMSO)δ27.1,43.4,51.8,52.1,54.2,54.7,57.5,106.9,118.5,128.0,128.8,129.3,129.8,130.7,131.3,137.3,146.2,157.5;ES MS(M+1)390.14;HRMS Calcd.For C24H27N3O2,389.49.Found(M+1)390.21.
(R)-1-苄基-3-羟基-4-[(1-苯乙氨基)甲基]吡啶-2(1H)-酮:
1HNMR(300MHz,DMSO)δ1.58(d,J=6.9Hz,3H),3.74(m,2H),4.44(m,1H),5.14(s,2H),6.23(d,J=7.2Hz,1H),7.35(m,6H);19F NMR(252MHz,DMSO)δ89.4;13C NMR(75MHz,DMSO)δ19.6,42.6,51.7,58.0,106.9,18.7,128.0,128.1,128.8,129.3,129.4,137.2,137.4,145.9,157.5;ES MS(M+1)335.13;Anal.Calcd.For C21H22N2O2,334.41.Found (M+1)335.31.
1-苄基-3-羟基-4-[([1,3]二氧戊环-2-基甲基甲基氨基)甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.81(s,3H),3.35(d,J=3.9Hz,2H),3.89(m,2H),4.01(m,2H),4.21(m,2H),5.17(s,2H);5.27(t,J=3.9Hz,1H),6.34(d,J=7.2Hz,1H),7.35(m,6H);19F NMR(252MHz,DMSO)δ88.5;13C NMR(75MHz,DMSO)δ;ES MS(M+1)331.18;HRMS Calcd.For C18H22N2O4,330.38.Found(M+1)331.16.
所公开的脯氨酰羟化酶抑制剂的类别IV涉及具有下式的化合物:
其中A代表任选被一个或多个R200单元取代的环。表IV提供了该类别的非限制性实例。
表IV
编号 | A环 |
D1 | 吡咯烷-1-基 |
D2 | 3-羟基吡咯烷-1-基 |
D3 | 2-(吡啶-2-基)吡咯烷-1-基 |
D4 | 2-甲基羧基吡咯烷-1-基 |
D5 | 2-(甲氧甲基)吡咯烷-1-基 |
D6 | 噻唑烷-3-基 |
D7 | 1H-咪唑-1-基 |
D8 | 哌啶-1-基 |
D9 | 4-苄基哌啶-1-基 |
D10 | 1,4’-联哌啶基-1’-基 |
D11 | 哌嗪-1-基 |
D12 | 4-苄基哌嗪-1-基 |
D13 | 4-(2-甲氧苯)哌嗪-1-基甲基 |
D14 | 4-(6-氯哒嗪-3-基)哌嗪-1-基 |
D15 | 1,4-二氧杂-8-氮杂螺[4,5]癸-8-基 |
D16 | 吗啉-4-基 |
D17 | 硫代吗啉-4-基 |
D18 | 氮杂环庚-1-基 |
D19 | 氮杂环辛-1-基 |
D20 | 3,4-二氢喹啉-1(2H)-基 |
所公开的该类别的化合物可以通过下文路线III中列出且在实施例3中描述的步骤制备。
路线III
试剂和条件:(a)(i)n-BuLi,TsCl,THF;-78℃至室温,1小时;
(ii)HCl,MeOH;室温,1小时。
试剂和条件:(b)吡咯烷,HCHO,H2O/EtOH;室温,12小时。
实施例3
1-(4’-甲基苯磺酰基)-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮(8)
1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7):向在干燥氮气气氛下保持于-78℃下的3-[(叔丁基二甲基硅基)氧]吡啶-2(1H)-酮(1)(4.66g,20.7mmol)在干燥THF(150mL)中的溶液搅拌加入正丁基锂(1.6M的乙烷溶液,21.0mmol)。在20分钟后,4-甲基-苯磺酰氯(3.95g,20.7mmol)作为THF溶液加入。使所述溶液经一小时升温至室温,加入水(10mL),将所述反应容器的内容物以EtOAc(3x)萃取,用盐水(1x)洗涤,经Na2SO4干燥并浓缩。将合并的有机层经Na2SO4干燥并浓缩。将残留物收集在乙醇(10mL)中,并以浓HCl(2mL)处理。将所述混合物搅拌1小时,在减压下除去溶剂,得到白色固体形式的所需化合物。
1H NMR(300MHz,DMSO)δ2.43(s,3H),6.14(t,J=6.9Hz,1H),6.76(dd,J=7.65Hz,1.5Hz,1H),7.18(dd,J=6.6Hz,1.8Hz,1H),7.32(d,J=7.3Hz,2H),7.98(d,J=7.9Hz,2H).
1-(4’-甲基苯磺酰基)-3-羟基-4-(吡咯烷-1-基甲基)吡啶-2(1H)-酮(8):
将1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7)(250mg,0.94mmol)和甲醛(200mg,2.07mmol)在乙醇水溶液(10mL)中合并,并搅拌30分钟。然后加入吡咯烷(149mg,2.07mmol)并将所述反应系搅拌12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(5mL)中,经制备型HPLC以水/乙腈洗脱进行纯化,得到所需产物。
1H NMR(300MHz,DMSO)δ1.87(m,2H),1.99(m,2H),2.44(s,3H),3.09(m,2H),3.40(m,2H),4.19(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),9.93(broad s,1H);19F NMR(252MHz,DMSO)δ88.4;13C NMR(75MHz,DMSO)δ21.5,22.7,50.5,53.7,108.7,118.6,119.4,128.4,129.7,130.1,133.1,146.8,147.7,156.2;ES MS(M+1)349.25;HRMSCalcd.For C17H20N2O4S,348.42.Found(M+1)349.42.
以下是该类别脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-(4’-甲基苯磺酰基)-3-羟基-4-噻唑烷-3-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.43(s,3H),2.94(t,J=6.6MHz,2H),3.18(t,J=6.0Hz,2H),3.66(s,2H),4.12(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz,1H),19F NMR(252MHz,DMSO)δ87.9;13C NMR(75MHz,DMSO)δ21.5,21.9,24.6,25.8,50.3,51.6,108.7,118.6,120.8,129.7,130.1,133.1,146.9,148.1,156.1,158.4,158.8;ES MS(M+1)367.18;HRMS Calcd.For C16H18N2O4S2,366.46.Found(M+1)367.43.
1-(4’-甲基苯磺酰基)-3-羟基-4-氮杂环辛-1-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.59(m,10H),2.44(s,3H),3.17(m,2H),3.32(m,2H),4.15(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.5,21.9,23.7,24.6,25.8,50.3,51.6,108.7,118.9,120.8,129.8,130.1,133.1,146.9,148.2,156.1;ES MS(M+1)391.18;HRMS Calcd.For C20H26N2O4S,390.18.Found(M+1)391.23.
1-(4’-甲基苯磺酰基)-3-羟基-4-(4-苯基哌嗪-1-基甲基)-吡啶-2(1H)-酮:
1H NMR(300MHz,.DMSO)δ2.43(s,3H),3.13(m,8H),3.43(s,2H),6.47(d,J=7.5Hz,1H),6.78(t,J=7.2Hz,1H),7.219m,2H),7.50(d,J=8.1Hz,2H),7.67(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,2H);13C NMR(75MHz,DMSO)δ21.5,42.6,45.6,46.2,50.8,51.9,109.6,116.4,116.8,117.7,120.6,121.1,129.5,129.6,129.8,130.1,133.2,146.8,149.5,156.1;ES MS(M+1)440.15;HRMS Calcd.For C23H25N3O5S,439.53.Found (M+1)440.16.
1-(4’-甲基苯磺酰基)-3-羟基-4-[1,4’]联哌啶基-1’-基甲基吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ1.43(m,1h),1.67(m,2H),1.82(m,4H),2.19(m,2H),2.44(s,3H),2.94(m,4H),3.39(m,2H),3.54(m,3H),4.06(s,2H),6.47(d,J=8.1Hz,1H),7.51(d,J=8.1Hz,2H),7.73(d,7.8Hz,1H),7.99(d,J=8.4Hz,2H);19F NMR(252MHz,DMSO)δ88.7;13C NMR(75MHz,DMSO)δ21.4,22.9,23.6,48.4,49.5,59.4,109.3,114.8,117.6,120.5,122.7,129.7,130.1,133.1,146.9,148.6,156.2;ES MS(M+1)446.19;HRMS Calcd.For C23H31N3O4S,445.58.Found(M+1)44621.
1-(4’-甲基苯磺酰基)-3-羟基-4-[4-(6-氯哒嗪-3-基)哌嗪-1-基甲基]吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.44(s,3H),3.17(m,2H),3.46(m,4H),4.17(s,2H),4.45(m,2H),6.77(d,J=7.8Hz,1H),7.04(m,1H),7.53(m 2H),7.68(m,2H),7.98(m,2H),11.3(broad s,1H),ES MS(M+1)476.92.HRMS Calcd.For C21H25CIN5O4S,475.95.Found (M+1)476.11.
HIF-1α脯氨酰羟化酶抑制剂的类别V涉及具有下式的化合物:
R代表1-5个对苯环氢原子的任选取代基,R1和R2各自独立地为氢或者被取代或未被取代的C1-C10直链或支链烷基,其中所述烷基单元可以被一个或多个独立选自如下基团的单元取代:
i)C1-C8直链、C3-C8支链或C3-C8环状烷氧基;
ii)羟基;
iii)卤素;
iv)氰基;
v)氨基、C1-C8单-烷基氨基、C1-C8二-烷基氨基;
vi)-SR40;R40为氢或C1-C4直链或C3-C4支链烷基;
vii)被取代或未被取代的C6或C10芳基;
viii)被取代或未被取代的C1-C9杂环;或
ix)被取代或未被取代的C1-C9杂芳基。
表V提供了该类别HIF-1α脯氨酰羟化酶抑制剂的非限制性实例。
表V
编号 | R | R1 | R2 |
E1 | 4-甲基 | 苄基 | 氢 |
E2 | 4-甲基 | 4-甲氧苄基 | 氢 |
E3 | 4-甲基 | 4-氟苄基 | 氢 |
E4 | 4-甲基 | 4-氯苄基 | 氢 |
E5 | 4-甲基 | 4-甲基苄基 | 氢 |
E6 | 4-甲基 | 2-(吡啶-2-基)乙基 | 氢 |
E7 | 4-甲基 | [1,3]二氧戊环-2-基甲基 | 氢 |
E8 | 4-甲基 | 四氢呋喃-2-基甲基 | 氢 |
E9 | 4-甲基 | 2-甲氧乙基 | 氢 |
E10 | 4-甲基 | 1-羟基-2-甲基丙-2-基 | 氢 |
E11 | 4-甲基 | 吡啶-4-基甲基 | 氢 |
编号 | R | R1 | R2 |
E12 | 4-甲基 | 呋喃-2-基甲基 | 氢 |
E13 | 4-甲基 | 2-(甲基硫)乙基 | 氢 |
E14 | 4-甲基 | 1-苯乙基 | 氢 |
E15 | 4-甲基 | 3-咪唑-1-基丙基 | 氢 |
E16 | 4-甲基 | 环庚基 | 氢 |
E17 | 4-甲基 | 4-甲基环己基 | 氢 |
E18 | 4-甲基 | 1-苄基哌啶-4-基 | 氢 |
E19 | 4-甲基 | 氮杂环庚-2-酮-3-基 | 氢 |
E20 | 4-甲基 | 1-苄基吡咯烷-3-基 | 氢 |
E21 | 4-甲基 | 苄基 | 甲基 |
E22 | 4-甲基 | 4-甲氧苄基 | 甲基 |
E23 | 4-甲基 | 4-氟苄基 | 甲基 |
E24 | 4-甲基 | 4-氯苄基 | 甲基 |
E25 | 4-甲基 | 4-甲基苄基 | 甲基 |
E26 | 4-甲基 | 2-(吡啶-2-基)乙基 | 甲基 |
E27 | 4-甲基 | [1,3]二氧戊环-2-基甲基 | 甲基 |
E28 | 4-甲基 | 四氢呋喃-2-基甲基 | 甲基 |
E29 | 4-甲基 | 2-甲氧乙基 | 甲基 |
E30 | 4-甲基 | 1-羟基-2-甲基丙-2-基 | 甲基 |
E31 | 4-甲基 | 吡啶-4-基甲基 | 甲基 |
E32 | 4-甲基 | 呋喃-2-基甲基 | 甲基 |
E33 | 4-甲基 | 羧基甲基 | 甲基 |
E34 | 4-甲基 | 2-(甲基硫)乙基 | 甲基 |
E35 | 4-甲基 | 1-苯乙基 | 甲基 |
E36 | 4-甲基 | 3-咪唑-1-基丙基 | 甲基 |
E37 | 4-甲基 | 环庚基 | 甲基 |
E38 | 4-甲基 | 4-甲基环己基 | 甲基 |
E39 | 4-甲基 | 1-苄基哌啶-4-基 | 甲基 |
E40 | 4-甲基 | 氮杂环庚-2-酮-3-基 | 甲基 |
E41 | 4-甲基 | 1-苄基吡咯烷-3-基 | 甲基 |
所公开的该类别的化合物可以通过下文路线IV中列出且在实施例4中描述的步骤制备。
路线IV
试剂和条件:(a)苄基溴,HCHO,H2O/EtOH;室温,12小时。
实施例4
1-(4’-甲基苯磺酰基)-3-羟基-4-[(苄基氨基)甲基]-吡啶-2(1H)-酮(9)
1-(4’-甲基苯磺酰基)-3-羟基-4-(苄基氨基甲基)吡啶-2(1H)-酮(9):将1-(4’-甲基苯磺酰基)-3-羟基吡啶-2(1H)-酮(7)(250mg,0.94mmol)和甲醛(200mg,2.07mmol)在乙醇水溶液(10mL)中合并并搅拌30分钟。然后加入苄基胺(229mg,2.07mmol),并将所述反应系搅拌12小时。通过蒸发除去溶剂,将残留物溶解于甲醇(5mL)中,经制备型HPLC以水/乙腈洗脱进行纯化,得到三氟乙酸盐形式的所需产物。
1H NMR(300MHz,DMSO)d 2.44(s,3H),3.96(s,2H),4.16(s,2H),6.69(d,J=8.1Hz),7.40(m,7H),7.52(m,1H),7.73(d,J=8.1Hz,1H),7.97(d,J=8.1Hz,1H),9.71(broad s,2H),10.44(broad s,1H);ES MS(M+1)396.67;HRMS Calcd.For C20H20N2O4S,384.45.Found(M+1)385.12.
以下是该类别HIF-1α脯氨酰羟化酶抑制剂的另外的非限制性实例。
1-(4’-甲基苯磺酰基)-3-羟基-4-[(2-甲氧乙氨基)甲基]-吡啶-2(1H)-酮:
1H NMR(300MHz,DMSO)δ2.43(s,3H),3.12(m,2H),3.29(s,3H),3.56(t,J=5.1Hz,2H),3.99(s,2H),6.51(d,J=7.5Hz,1H),7.51(d,J=8.4Hz,1H),7.76(d,J=7.5Hz,1H),7.98(d,J=8.1Hz);19F NMR(252MHz,DMSO)δ88.6;13CNMR(75MHz,DMSO)δ21.5,43.8,46.2,46.5,58.5,67.2,106.7,119.2,120.2,123.9,128.4,129.7,130.1,133.1,146.8,147.0,156.0;ES MS(M+1)353.12.HRMS Calcd.ForC16H20N2O5S,352.41.Found(M+1)353.11.
HIF-1α脯氨酰羟化酶抑制剂的类别VI涉及具有下式的化合物:
其中L选自CH2或SO2,Z为被取代或未被取代的苯基。该类别抑制剂的非限制性实例公开于下表VI。
表VI
编号 | L | Z |
F1 | CH2 | 2-氯苯基 |
F2 | CH2 | 3-氯苯基 |
F3 | CH2 | 4-氯苯基 |
F4 | CH2 | 2-氟苯基 |
F5 | CH2 | 3-氟苯基 |
F6 | CH2 | 4-氟苯基 |
F7 | CH2 | 2,3-二氯苯基 |
F8 | CH2 | 2,4-二氯苯基 |
F9 | CH2 | 2,5-二氯苯基 |
F10 | CH2 | 2,6-二氯苯基 |
F11 | CH2 | 3,4-二氯苯基 |
F12 | CH2 | 3,5-二氯苯基 |
F13 | CH2 | 2,3-二氟苯基 |
F14 | CH2 | 2,4-二氟苯基 |
F15 | CH2 | 2,5-二氟苯基 |
F16 | CH2 | 2,6-二氟苯基 |
F17 | CH2 | 3,4-二氟苯基 |
F18 | CH2 | 3,5-二氟苯基 |
编号 | L | Z |
F19 | CH2 | 2-氰苯基 |
F20 | CH2 | 3-氰苯基 |
F21 | CH2 | 4-氰苯基 |
F22 | SO2 | 2-氯苯基 |
F23 | SO2 | 3-氯苯基 |
F24 | SO2 | 4-氯苯基 |
F25 | SO2 | 2-氟苯基 |
F26 | SO2 | 3-氟苯基 |
F27 | SO2 | 4-氟苯基 |
F28 | SO2 | 2,3-二氯苯基 |
F29 | SO2 | 2,4-二氯苯基 |
F30 | SO2 | 2,5-二氯苯基 |
F31 | SO2 | 2,6-二氯苯基 |
F32 | SO2 | 3,4-二氯苯基 |
F33 | SO2 | 3,5-二氯苯基 |
F34 | SO2 | 2,3-二氟苯基 |
F35 | SO2 | 2,4-二氟苯基 |
F36 | SO2 | 2,5-二氟苯基 |
F37 | SO2 | 2,6-二氟苯基 |
F38 | SO2 | 3,4-二氟苯基 |
F39 | SO2 | 3,5-二氟苯基 |
F40 | SO2 | 2-氰苯基 |
F41 | SO2 | 3-氰苯基 |
F42 | SO2 | 4-氰苯基 |
该类别包括的化合物对于Z等于CH2可以依照路线I制备,对于Z等于SO2可以依照路线III制备。
可药用盐
用于治疗结肠炎和其他炎性肠病和症状的所公开化合物可以为可药用盐的形式。可药用盐可以由配方者用于提供一种所公开抑制剂的形式,所述形式更适合所述抑制剂至受试者的拟定送递方式或者出于所述制剂的相容性的目的。
以下是用于制备所公开抑制剂——{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯——的可药用盐的步骤实例。
将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(242mg,0.56mmol)在MeOH(15mL)中的悬浮液加热回流直至得到均匀溶液。停止加热,在仍然热时加入0.1N HCl(6.7mL,1.2当量),将所述溶液冷却至室温。在减压下蒸发挥发物,在丙酮(5mL)中结晶无定型残留物。通过过滤收集所述固体。
将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯(217mg,0.5mmol)在MeOH(15mL)中的悬浮液加热回流直至得到均匀溶液。停止加热,在仍然热时加入甲磺酸(115.2mg,1.2当量),将所述溶液冷却至室温。在减压下蒸发挥发物,在丙酮(5mL)中结晶无定型残留物。通过过滤收集所述固体。
下文表VII提供了从有机酸和无机酸形成的{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯的可药用盐实例。
表VII
酸 | 产率 | 纯度* | M.P.(℃) | 颜色 |
游离碱 | -- | 99.3% | 183-184 | 粉红 |
HCl | 90% | 99.7% | 185-186 | 白色 |
H2SO4 | 93% | 99.7% | 175(dec.) | 浅粉红 |
对甲苯磺酸 | 74% | 99.8% | 185-186 | 白色 |
甲磺酸 | 79% | 99.9% | 155-157 | 白色 |
*通过HPLC分析确定
1H NMR分析用于确定盐形式,例如,上文形成的甲磺酸盐具有下式:
1H NMR分析用于确定盐形成发生在所述分子中的哪个位置。桥接哌嗪和吡啶酮环的亚甲基上的质子的化学位移从游离碱中的3.59ppm移至盐中的4.31ppm。另外,邻接叔胺的哌嗪亚甲基从2.50ppm移至大约3.60ppm。剩余质子的化学位移大多数未变。这些数据表明,哌嗪环的叔胺氮被质子化成盐形式。另外,相对于核心化合物整合甲磺酰基单元的甲基质子表明存在一个当量的酸。
配方者可以通过任何所需的方法确定所公开抑制剂的可药用盐的溶解度。如下是用于评估所公开抑制剂的盐的溶解度步骤的非限制性实例。在水浴温度低于25℃下,将{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯甲磺酸盐(26.6mg)在去离子蒸馏水(3.0mL)中的悬浮液超声处理20分钟。将所述悬浮液过滤以除去任何不溶性盐。将所述澄清滤液(200μL)以去离子蒸馏水(800μL)稀释,并进行HPLC分析。如下是上文表VII中列出的可药用盐的结果。
*通过HPLC分析确定
如下是可以用于形成所公开抑制剂的可药用盐的其他酸的非限制性实例:乙酸根、柠檬酸根、马来酸根、琥珀酸根、乳酸根、乙醇酸根、酒石酸根、溴离子、碘离子、硫酸根、硫酸氢根、碳酸根、碳酸氢根、磷酸根、甲酸根、丙酸根、丁酸根、丙酮酸根、草酸根、丙二酸根、延胡索酸根等。
肠的急性和慢性炎症由多种疾病引起。一般而言,粘膜组织表面的上皮细胞由于存在炎症而具有诱导的缺氧状态。身体对该缺氧状态的反应是缺氧诱导因子-1α(HIF-1α)的存在增加,HIF-1α驱动下游HIF-1靶基因(尤其是红细胞生成素)的表达。因此,HIF-1α是身体对炎性反应的重要介质。HIF-1α的细胞浓度受脯氨酰羟化酶的调节,该酶在常氧期间中负责使HIF-1α失稳定,导致该蛋白破坏。
抑制HIF-1α脯氨酰羟化酶因此可导致HIF-1α的稳定性增加,导致可使得对炎性反应相应增加的HIF-1的上调。在患有一种或多种炎性上皮疾病的受试者中,以一种或多种有效HIF-1α脯氨酰羟化酶抑制剂治疗可增加身体细胞炎性反应的水平。另外,在慢性疾病情形中的低炎症期间,相对于身体正常会产生的量,HIF-1α脯氨酰羟化酶抑制剂可以增加上皮细胞康复的量。因此,向患有炎性疾病(例如克罗恩病)的受试者或者被诊断有炎性疾病的受试者给予一种或多种HIF-1α脯氨酰羟化酶抑制剂提供了一种治愈、控制、介导、减少或者以其他方式影响所述病症严重度的方法。
方法
本文公开了用于治疗具有或患有一种或多种影响肠上皮组织的疾病或病症的受试者的方法。在一个方面,本文公开了用于治疗患有炎性肠病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。炎性肠病的非限制性实例包括克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎(diversion colitis)、白塞综合征(Behcet’ssyndrome)和未确定型结肠炎(indetermiante colitis)。因此,公开了如下的方法。所公开的方法还涉及用于治疗被诊断有一种或多种如下病症、综合征、疾病、病理、病、疾病等的受试者的方法。
一种用于治疗受试者的克罗恩病的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有克罗恩病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有克罗恩病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的溃疡性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有溃疡性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有溃疡性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的胶原性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有胶原性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有胶原性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的淋巴细胞性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有淋巴细胞性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有淋巴细胞性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的缺血性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有缺血性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有缺血性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的改道性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有转向性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有转向性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的溃疡性结肠炎的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有溃疡性结肠炎的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有溃疡性结肠炎的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
一种用于治疗受试者的白塞综合征的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有白塞综合征的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有白塞综合征的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
本文还公开了用于治疗具有或患有一种或多种炎性上皮疾病、病症、综合征、疾病、病理、病等的受试者的方法。在一个方面中,本文公开了一种用于治疗患有呼吸道的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有呼吸道的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有呼吸道的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
在另一方面中,本文公开了一种用于治疗患有粘膜的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有粘膜的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有粘膜的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
在又一方面中,本文公开了一种用于治疗患有皮肤的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有皮肤的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有皮肤的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
在再一方面中,本文公开了一种用于治疗患有GI道的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有GI道的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有GI道的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
在还一方面中,本文公开了一种用于治疗患有一个或多个主器官和/或内分泌腺内层的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有一个或多个主器官和/或内分泌腺内层的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有一个或多个主器官和/或内分泌腺内层的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
在又一方面中,本文公开了一种用于治疗患有脉管组织的炎性上皮疾病的受试者的方法,包括向所述受试者给予有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。该方法的一个实施方案涉及向患有脉管组织的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物。该方法的另一实施方案涉及向患有脉管组织的炎性上皮疾病的受试者给予有效量的本文公开的药物组合物,所述药物组合物包含与有效量的一种或多种其他药剂结合的有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
本文还公开了有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐用于制备治疗肠上皮组织炎性疾病例如炎性肠病——包括克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎、白塞综合征和未确定型结肠炎——的药物的用途。本文还公开了有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐用于制备治疗炎性上皮疾病——包括呼吸道、粘膜、皮肤、GI道、主器官和内分泌腺的内层和脉管组织疾病——的药物的用途。
制剂
药物和药物组合物
本公开还涉及可以作为用于治疗一种或多种所公开的疾病的方法使用的药物组合物。另外,所公开的制剂可以用于制备用于治疗一种或多种所公开的疾病、病症、病、综合征等的药物或药物组合物。所公开的药物或药物组合物包含有效量的一种或多种本公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐。
所公开的组合物的一个方面包含:
a)有效量的一种或多种所公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种赋形剂。
对于本公开的目的,术语“赋形剂”和“载体”在本公开的整个说明书中可互换使用,并且所述术语在本文中定义为“用于配制安全有效的药用组合物的成分”。
配方者应理解,赋形剂主要用于在送递安全、稳定且功能性药物中发挥作用,其不仅作为用于送递的整体运载体(vehicle)的一部分,而且作为接受者实现有效吸收活性成分的工具。赋形剂可如惰性填充剂那样简单且直接地起作用,或者本文使用的赋形剂可为pH稳定体系或确保成分被安全送递至胃中的涂层的一部分。配方者还可利用这样的事实,即本公开的化合物具有改善的细胞潜能、药物代谢动力学性质以及改善的口服生物利用度。
本公开的组合物的非限制性实例包括:
a)约0.001mg至约1000mg的一种或多种公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种赋形剂。
本公开的另一实例涉及如下组合物:
a)约0.01mg至约100mg的一种或多种公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种赋形剂。
本公开的又一实例涉及如下组合物:
a)约0.1mg至约10mg的一种或多种公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种赋形剂。
本公开的组合物的再一实例包含:
a)有效量的一种或多种公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种本文中进一步描述的化疗剂或化疗化合物。
化疗剂或化疗化合物的一个类别包括细胞毒性药物,例如6-羟甲基酰基富烯、环磷酰胺、达卡巴嗪、卡莫司汀、多柔比星和氨甲蝶呤。
化疗剂或化疗化合物的另一类别包括但不限于:阿西维辛(acivicin);阿柔比星(aclarubicin);盐酸阿考达唑(acodazolehydrochloride);阿克罗宁(acronine);阿多来新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波霉素(ambomycin);乙酸阿美蒽醌(ametantrone acetate);氨鲁米特(aminoglutethimide);氨吖啶(amsacrine);阿那曲唑(anastrozole);安曲霉素(anthramycin);天冬酰胺酶(asparaginase);曲林菌素(asperlin);阿扎胞苷(azacitidine);阿扎替派(azetepa);阿佐霉素(azotomycin);巴马司他(batimastat);苯佐替派(benzodepa);比卡鲁胺(bicalutamide);盐酸比生群(bisantrenehydrochloride);甲磺酸双奈法德(bisnafide dimesylate);比折来新(bizelesin);硫酸博来霉素(bleomycin sulfate);布喹那钠(brequinarsodium);溴匹立明(bropirimine);白消安(busulfan);放线菌素C(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡贝替姆(carbetimer);卡铂(carboplatin);卡莫司汀(carmustine);盐酸卡柔比星(carubicin hydrochloride);卡折来新(carzelesin);西地芬戈(cedefingol);苯丁酸氮芥(chlorambucil);西罗霉素(cirolemycin);顺铂(cisplatin);克拉屈滨(cladribine);甲磺酸克立那托(crisnatolmesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D(dactinomycin);盐酸柔红霉素(daunorubicin hydrochloride);地西他滨(decitabine);右奥马铂(dexormaplatin);地扎胍宁(dezaguanine);甲磺酸地扎胍宁(dezaguanine mesylate);地吖醌(diaziquone);多西他赛(docetaxel);多柔比星;盐酸多柔比星(doxorubicin hydrochloride);屈洛昔芬(droloxifene);柠檬酸屈洛昔芬柠(droloxifene citrate);丙酸屈他雄酮(dromostanolone propionate);达佐霉素(duazomycin);依达曲沙(edatrexate);盐酸依氟鸟氨酸(eflornithine hydrochloride);依沙芦星(elsamitrucin);恩洛铂(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);厄布洛唑(erbulozole);盐酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸酯钠(estramustine phosphate sodium);依他硝唑(etanidazole);依托泊苷(etoposide);磷酸依托泊苷(etoposidephosphate);氯苯乙嘧胺(etoprine);盐酸法倔唑(fadrozolehydrochloride);法扎拉宾(fazarabine);芬维A胺(fenretinide);氟尿苷(floxuridine);磷酸氟达拉滨(fludarabine phosphate);氟尿嘧啶(fluorouracil);氟西他滨(flurocitabine);磷喹酮(fosquidone);福司曲星钠(fostriecin sodium);吉西他滨(gemcitabine);盐酸吉西他滨(gemcitabine hydrochloride);羟基脲(hydroxyurea);盐酸伊达比星(idarubicin hydrochloride);异环磷酰胺(ifosfamide);伊莫福新(ilmofosine);白细胞介素II(interleukin II)(包括重组白细胞介素II或rIL2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-Ia;干扰素γ-Ib;异丙铂(iproplatin);盐酸伊立替康(irinotecanhydrochloride);醋酸兰瑞肽(lanreotide acetate);来曲唑(letrozole);醋酸亮丙立德(leuprolide acetate);盐酸利阿唑(liarozole hydrochloride);洛美曲索钠(lometrexol sodium);洛莫司汀(lomustine);盐酸洛索蒽醌(losoxantrone hydrochloride);马索罗酚(masoprocol);美登素(maytansine);盐酸氮芥(mechlorethamine hydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美仑孕酮(melengestrol acetate);美法仑(melphalan);美诺立尔(menogaril);巯嘌呤(mercaptopurine);氨甲喋呤methotrexate);氨甲喋呤钠(methotrexate sodium);氯苯氨啶(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);丝裂红素(mitocromin);米托洁林(mitogillin);米托马星(mitomalcin);丝裂霉素(mitomycin);米托司培(mitosper);米托坦(mitotane);盐酸米托蒽醌(mitoxantrone hydrochloride);麦考酚酸(mycophenolic acid);诺考达唑(nocodazole);诺拉霉素(nogalamycin);奥马铂(ormaplatin);奥昔舒仑(oxisuran);紫杉醇(paclitaxel);培门冬酶(pegaspargase);培利霉素(peliomycin);萘莫司汀(pentamustine);硫酸培洛霉素(peplomycin sulfate);培磷酰胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);盐酸吡罗蒽醌(piroxantronehydrochloride);普卡霉素(plicamycin);普洛美坦(plomestane);卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼莫司汀(prednimustine);盐酸丙卡巴肼(procarbazine hydrochloride);嘌呤霉素(puromycin);盐酸嘌呤霉素(puromycin hydrochloride);吡唑呋林(pyrazofurin);利波腺苷(riboprine);罗谷亚胺(rogletimide);沙芬戈(safingol);盐酸沙芬戈(safingol hydrochloride);司莫司汀(semustine);辛曲秦(simtrazene);磷乙酰天冬氨酸钠(sparfosate sodium);司帕霉素(sparsomycin);盐酸锗螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺铂(spiroplatin);链黑霉素(streptonigrin);链佐星(streptozocin);磺氯苯脲(sulofenur);他利霉素(talisomycin);替可加兰钠(tecogalan sodium);替加氟(tegafur);盐酸替洛蒽醌(teloxantronehydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替罗昔隆(teroxirone);睾内酯(testolactone);硫咪嘌呤(thiamiprine);硫鸟嘌呤(thioguanine);塞替派(thiotepa);噻唑呋林(tiazofurin);替拉扎明(tirapazamine);柠檬酸托瑞米芬(toremifene citrate);醋酸曲托龙(trestolone acetate);磷酸曲西立滨(triciribine phosphate);三甲曲沙(trimetrexate);三甲曲沙葡糖醛酸(trimetrexate glucuronate);曲普瑞林(triptorelin);盐酸妥布氯唑(tubulozole hydrochloride);乌拉莫司汀(uracilmustard);乌瑞替派(uredepa);伐普肽(vapreotide);维替泊芬(verteporfin);硫酸长春碱(vinblastine sulfate);硫酸长春新碱(vincristinesulfate);长春地辛(vindesine);硫酸长春地辛(vindesine sulfate);硫酸长春匹定(vinepidine sulfate);硫酸长春甘酯(vinglycinate sulfate);硫酸长春罗辛(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbine tartrate);硫酸长春罗定(vinrosidine sulfate);硫酸长春利定(vinzolidine sulfate);伏氯唑(vorozole);折尼泊(zeniplatin);净司他丁(zinostatin);盐酸佐柔比星(zorubicin hydrochloride)。其他抗癌药物包括但不局限于:20-表-1,25二羟基维生素D3;5-乙炔尿嘧啶;阿比特龙(abiraterone);阿柔比星;酰基富烯;腺环戊醇(adecypenol);阿多来新(adozelesin);阿地白介素(aldesleukin);ALL-TK拮抗剂;六甲蜜胺(altretamine);氨莫司汀(ambamustine);2,4-二氯苯氧乙酸(amidox);氨磷汀(amifostine);5-氨基酮戊酸(aminolevulinic acid);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑(anastrozole);穿心莲内酯(andrographolide);血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背侧形态发生蛋白1(anti-dorsalizing morphogeneticprotein-1);抗雄激素(antiandrogen)、前列腺癌物质(prostaticcarcinoma)、抗雌激素物质(antiestrogen);抗瘤酮(antineoplaston);反义寡核苷酸;蚜肠菌素甘氨酸(aphidicolin glycinate);细胞凋亡基因调节物质(apoptosis gene modulators);细胞凋亡调节物(apoptosis regulators);脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨基酶;asulacrine;阿他美坦(atamestane);阿莫司汀(atrimustine);海洋环肽1(axinastatin 1);海洋环肽2(axinastatin 2);海洋环肽3(axinastatin 3);偶氮丝氨酸(azasetron);阿扎毒素(azatoxin);重氮酪氨酸(azatyrosine);浆果赤霉素III(baccatin III)衍生物;balanol;巴马司他(batimastat);BCR/ABL拮抗剂;苯并二氢卟吩(benzochlorin);苯酰星孢素(benzoylstaurosporine);β-内酰胺衍生物(beta lactam derivatives);beta-alethine;betaclamycin B;桦木酸(betulinic acid);bFGF抑制剂;比卡鲁胺(bicalutamide);比生群(bisantrene);双氮丙啶基精胺(bisaziridinylspermine);双奈法德(bisnafide);bistratene A;比折来新(bizelesin);breflate;溴匹立明(bropirimine);布度钛(budotitane);丁胱亚磺酰亚胺(buthionine sulfoximine);卡泊三醇(calcipotriol);calphostinC;喜树碱衍生物;canarypox IL-2;卡培他滨(capecitabine);酰胺-氨基-三唑(carboxamide-amino-triazole);羧基酰胺三唑(carboxyamidotriazole);CaRest M3;CARN 700;软骨衍生的抑制剂(cartilage derived inhibitor);卡折来新(carzelesin);酪蛋白激酶抑制剂(casein kinase inhibitors (ICOS));粟精胺(castanospermine);杀菌肽B(cecropin B);西曲瑞克(cetrorelix);chlorlns;磺胺氯喹(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);顺式-卟啉(cis-porphyrin);克拉屈滨(cladribine);氯米芬类似物(clomifeneanalogues);克霉唑(clotrimazole);collismycin A;collismycin B;考布他汀A4(combretastatin A4);考布他汀类似物;conagenin;crambescidin816;克立那托(crisnatol);cryptophycin 8;cryptophycin A衍生物;curacin A;cyclopent anthraquinones;cycloplatam;cypemycin;阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate);溶细胞因子(cytolytic factor);cytostatin;达昔单抗(dacliximab);地西他滨(decitabine);dehydrodidemnin B;地洛瑞林(deslorelin);地塞米松(dexamethasone);右异环磷酰胺(dexifosfamide);右雷佐生(dexrazoxane);右维拉帕米(dexverapamil);地吖醌(diaziquone);didemnin B;didox;diethylnorspermine;二氢-5-氮胞苷;9-二氢紫杉醇(dihydrotaxol,9-);dioxamycin;联苯螺莫司汀(diphenyl spiromustine);多西他赛(docetaxel);二十二醇(docosanol);多拉司琼(dolasetron);去氧氟尿苷(doxifluridine);屈洛昔芬(droloxifene);屈大麻酚(dronabinol);duocarmycin SA;依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依决可单抗(edrecolomab);依氟鸟氨酸(eflornithine);榄香烯(elemene);乙嘧替氟(emitefur);表柔比星;依立雄胺(epristeride);雌氮芥类似物;雌激素激动剂(estrogen agonists);雌激素拮抗剂(estrogen antagonists);依他硝唑(etanidazole);磷酸表鬼臼毒素吡喃葡糖苷;依西美坦(exemestane);法倔唑(fadrozole);法扎拉宾(fazarabine);芬维A胺(fenretinide);非格司亭(filgrastim);非那雄胺(finasteride);flavopiridol;氟卓司汀(flezelastine);fluasterone;氟达拉滨(fludarabine);fluorodaunorunicinhydrochloride;福酚美克(forfenimex);福美坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);钆替沙林(gadolinium texaphyrin);硝酸镓;加洛他滨(galocitabine);加尼瑞克(ganirelix);明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;调蛋白(heregulin);六亚甲基二乙酰胺(hexamethylene bisacetamide);金丝桃素(hypericin);依班膦酸盐(ibandronic acid);伊达比星(idarubicin);艾多昔芬(idoxifene);伊决孟酮(idramantone);伊莫福新(ilmofosine);伊洛马司他(ilomastat);咪唑并吖啶酮(imidazoacridone);咪喹莫特(imiquimod);免疫刺激肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白细胞介素;碘苄胍(iobenguane);碘阿霉素(iododoxorubicin);依波米醇、4-(ipomeanol,4-);伊罗普拉(iroplact);伊索拉定(irsogladine);isobengazole;isohomohalicondrin B;依他司琼(itasetron);促微丝聚合剂(jasplakinolide);kahalalide F;片螺素(lamellarin)-N triacetate;兰瑞肽(lanreotide);leinamycin;来格斯汀(lenograstim);硫酸香菇多糖(lentinan sulfate);leptolstatin;来曲唑(letrozole);白血病抑制因子;白细胞α干扰素;亮丙立德+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);直链多胺类似物(linear polyamineanalogue);亲脂二糖肽;亲脂铂化合物;lissoclinamide 7;洛铂(lobaplatin);蚯蚓磷脂(lombricine);洛美曲索(lometrexol);氯尼达明(lonidamine);洛索蒽醌(losoxantrone);洛伐他汀(lovastatin);洛索立滨(loxoribine);勒托替康(lurtotecan);lutetium texaphyrin;lysofylline;裂解肽(lytic peptide);美坦辛(maitansine);抑甘露糖苷酶素A(mannostatin A);马立马司他(marimastat);马索罗芬(masoprocol);乳腺丝抑蛋白(maspin);溶基质蛋白抑制剂(matrilysin inhibitor);基质金属蛋白酶抑制剂(matrixmetalloproteinase inhibitor);美诺立尔(menogaril);merbarone;美替瑞林(meterelin);蛋氨酸酶(methioninase);甲氧氯普胺(metoclopramide);MIF抑制剂;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);错配双链RNA;米托胍腙(mitoguazone);二溴卫矛醇(mitolactol);丝裂霉素类似物;米托萘胺(mitonafide);mitotoxinfibroblastgrowth factor-saporin;米托蒽醌;莫法罗汀(mofarotene);莫拉司亭(molgramostim);人绒毛膜促性腺激素单克隆抗体;单磷酰脂质A+分枝杆菌细胞壁sk;莫哌达醇(mopidamol);多抗药基因抑制剂;基于多肿瘤抑制剂-1的疗法(multiple tumor suppressor 1-based therapy);芥抗癌试剂(mustard anticancer agent);印度洋海绵B(mycaperoxide B);分枝杆菌细胞壁提取物(mycobacterial cell wall extract);myriaporone;N-乙酰地那林(N-acetyldinaline);N-取代苯酰胺;那法瑞林(nafarelin);nagrestip;纳洛酮+喷他佐新(naloxone+pentazocine);napavin;naphterpin;那托司亭(nartograstim);奈达铂(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);中性内肽酶(neutralendopeptidase);尼鲁米特(nilutamide);nisamycin;一氧化氮调节剂;一氧化二氮抗氧化剂(nitroxide antioxidant);nitrullyn;O6-苄基鸟嘌呤;奥曲肽(octreotide);okicenone;寡核苷酸;奥那司酮(onapristone);昂丹司琼(ondansetron);昂丹司琼;oracin;口服细胞因子诱导剂(oral cytokineinducer);奥马铂;奥沙特隆(osaterone);奥沙利铂(oxaliplatin);oxaunomycin;紫杉醇(paclitaxel);紫杉醇类似物;紫杉醇衍生物;六环二胍抗生素(palauamine);棕榈酰根霉素(palmitoyl rhizoxin);帕米膦酸(pamidronic acid);人参三醇(panaxytriol);帕诺米芬(panomifene);副球菌素(parabactin);帕折普汀(pazelliptine);培门冬酶(pegaspargase);培得星(peldesine);戊聚硫钠(pentosan polysulfate sodium);喷司他丁(pentostatin);pentrozole;全氟溴烷(perflubron);培磷酰胺(perfosfamide);紫苏子醇(perillyl alcohol);phenazinomycin;苯乙酸;磷酸酶抑制剂;溶血性链球菌制剂(picibanil);盐酸毛果芸香碱(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);placetin A;placetin B;血纤蛋白溶酶原激活物抑制剂;铂复合物;铂化合物;铂-三胺复合物;卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼松(prednisone);丙基双吖啶酮(propyl bis-acridone);前列腺素J2(prostaglandin J2);蛋白酶体抑制剂(proteasome inhibitor);基于蛋白A的免疫调节剂(protein A-based immune modulator);蛋白激酶C抑制剂(protein kinase C inhibitor);微藻蛋白激酶C抑制剂(protein kinase Cinhibitors,microalgal);蛋白酪氨酸磷酸酶抑制剂(protein tyrosinephosphatase inhibitors);嘌呤核苷磷酸化酶抑制剂(purine nucleosidephosphorylase inhibitors);羟基茜草素(purpurins);吡唑啉吖啶(pyrazoloacridine);pyridoxylated hemoglobin polyoxyethylene conjugate;raf拮抗剂;雷替曲塞(raltitrexed);雷莫司琼(ramosetron);ras法尼基转移酶抑制剂(ras farnesyl protein transferase inhibitor);ras抑制剂(rasinhibitor);ras-GAP抑制剂;脱甲基瑞提普汀(retelliptine demethylated);铼Re 186依替膦酸(rhenium Re 186etidronate);根霉素(rhizoxin);核酶(ribozyme);RII异维A酰胺(RII retinamide);罗谷亚胺(rogletimide);罗希吐碱(rohitukine);罗莫肽(romurtide);罗喹美克(roquinimex);rubiginone B 1;ruboxyl;沙芬戈(safmgol);saintopin;SarCNU;sarcophytol A;沙格司亭(sargramostim);Sdi 1模拟物(Sdi 1 mimetic);司莫司汀(semustine);衰老衍生抑制剂1(senescence derived inhibitor 1);有义寡核苷酸;信号转导抑制剂;信号传导调节剂;单链抗原结合蛋白;西佐喃(sizoffran);索布佐生(sobuzoxane);硼卡钠(sodium borocaptate);苯乙酸钠;solverol;生长调节素结合蛋白;索钠明(sonermin);膦门冬酸(sparfosic acid);spicamycin D;螺莫司汀(spiromustine);splenopentin;海绵抑制素1(spongistatin 1);角鲨胺(squalamine);干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂(stromelysin inhibitor);sulfmosine;超活性血管活性肠肽拮抗剂(superactive vasoactive intestinalpeptide antagonist);suradista;苏拉明(suramin);八氢吲嗪三醇(swainsonine);合成糖胺聚糖;他莫司汀(tallimustine);甲碘他莫昔芬(tamoxifen methiodide);牛磺莫司汀(tauromustine);他扎罗汀(tazarotene);替可加兰钠(tecogalan sodium);替加氟(tegafur);tellurapyrylium;端粒酶抑制剂;替莫泊芬(temoporfin);替莫唑胺(temozolomide);替尼泊苷;tetrachlorodecaoxide;tetrazomine;thaliblastine;噻可拉林(thiocoraline);血小板生成素(thrombopoietin);血小板生成素模拟物(thrombopoietin mimetic);胸腺法新(thymalfasin);胸腺生成素受体激动剂(thymopoietin receptor agonist);胸腺曲南(thymotrinan);促甲状腺素;tin ethyl etiopurpurin;替拉扎明(tirapazamine);二氯化二茂钛(titanocene bichloride);topsentin;托瑞米芬(toremifene);全能干细胞因子;转录抑制剂;维生素A酸(tretinoin);三乙酰胆碱(triacetyluridine);曲西立滨(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司琼(tropisetron);妥罗雄脲(turosteride);酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂(tyrphostin);UBC抑制剂;乌苯美司(ubenimex);源自泌尿生殖窦的生长抑制因子(urogenitalsinus-derived growth inhibitory factor);尿激酶受体拮抗剂(urokinasereceptor antagonist);伐普肽(vapreotide);variolin B;载体系统,红细胞基因治疗(vector system,erythrocytegene therapy);维拉雷琐(velaresol);藜芦明(veramine);verdin;维替泊芬(verteporfin);长春瑞滨(vinorelbine);vinxaltine;vitaxin;伏氯唑(vorozole);扎诺特隆(zanoterone);折尼铂(zeniplatin);亚苄维C(zilascorb)和净司他丁斯酯(zinostatin stimalamer)。在一个实施方案中,所述抗癌药是5-氟尿嘧啶、紫杉醇或甲酰四氢叶酸(leucovorin)。
可以与所公开的HIF-1α抑制剂结合使用的其他化疗剂包括但不限于有丝分裂抑制剂(长春花生物碱)。这些化疗剂包括长春新碱、长春碱(vinblastine)、长春地辛(vindesine)和NavelbineTM(脱水长春花碱-5′-noranhydroblastine)。在其他实施方案中,癌症化疗剂包括拓扑异构酶I抑制剂,例如喜树碱化合物。本文使用的“喜树碱化合物”包括CamptosarTM(盐酸伊立替康)、HycamtinTM(盐酸托泊替康(topotecanHCL))和其他从喜树碱及其类似物得到的化合物。可用于本文公开的方法和组合物中的另一类癌症化疗剂是鬼臼毒素(podophyllotoxin)衍生物,例如依托泊苷(etoposide)、替尼泊苷(teniposide)和米托肼(mitopodozide)。本发明的公开内容还包括其他已知为烷化剂的癌症化疗剂,其将肿瘤细胞中的遗传物质烷基化。这些癌症化疗剂包括但不局限于顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、氮芥(nitrogen mustard)、三亚甲基硫磷酰胺(trimethylene thiophosphoramide)、卡莫司汀(carmustine)、白消安(busulfan)、苯丁酸氮芥(chlorambucil)、belustine、乌拉莫司汀(uracil mustard)、chlomaphazin和达卡巴嗪(dacarbazine)。本公开包括作为化疗剂的抗代谢物。这些类型治疗剂的实例包括胞嘧啶阿拉伯糖苷(cytosine arabinoside)、氟尿嘧啶(fluorouracil)、氨甲喋呤(methotrexate)、巯嘌呤(mercaptopurine)、硫唑嘌呤(azathioprime)和丙卡巴肼(procarbazine)。可用于本文公开的方法和组合物的另一类癌症化疗剂包括抗生素。非限制性实例包括多柔比星(doxorubicin)、博来霉素(bleomycin)、放线菌素D(dactinomycin)、红比霉素(daunorubicin)、光神霉素(mithramycin)、丝裂霉素(mitomycin)、丝裂霉素C和道诺霉素(daunomycin)。这些化合物有市售的各种脂质体制剂。本发明的公开内容还包括其他癌症化疗剂,其包括但不局限于抗肿瘤抗体、达卡巴嗪(dacarbazine)、5-氮杂胞苷(azacytidine)、安吖啶(amsacrine)、美法仑(melphalan)、异环磷酰胺(ifosfamide)和米托蒽醌(mitoxantrone)。
本文公开的HIF-1α脯氨酰羟化酶抑制剂可与其他抗肿瘤剂结合给予,所述其他抗肿瘤剂包括细胞毒性剂/抗肿瘤剂和抗血管生成剂。细胞毒性剂/抗肿瘤剂被定义为攻击并杀死癌细胞的药剂。一些细胞毒性剂/抗肿瘤剂是烷化剂,其使肿瘤细胞中的遗传物质烷基化,例如顺铂、环磷酰胺、氮芥、三亚甲基硫磷酰胺、亚硝基脲氮芥、白消安、苯丁酸氮芥、belustine、乌拉莫司汀、chlomaphazin和达卡巴嗪。其他细胞毒性剂/抗肿瘤试剂是肿瘤细胞的抗代谢物,例如胞嘧啶阿拉伯糖苷、氟尿嘧啶、氨甲喋呤、巯嘌呤、硫唑嘌呤和丙卡巴肼。其他细胞毒性剂/抗肿瘤剂是抗生素,例如多柔比星、博来霉素、放线菌素D、红比霉素、光神霉素、丝裂霉素、丝裂霉素C和道诺霉素。这些化合物有多种市售脂质体制剂。其他细胞毒性剂/抗肿瘤剂是有丝分裂抑制剂(长春花生物碱)。这些包括长春新碱、长春碱和依托泊苷。多种细胞毒性剂/抗肿瘤剂包括紫杉醇及其衍生物、L-天冬酰胺酶、抗肿瘤抗体、达卡巴嗪、5-氮杂胞苷、安吖啶、美法仑、VM-26、异环磷酰胺、米托蒽醌和长春地辛。
本公开的组合物的再一实例包含:
a)有效量的一种或多种公开的HIF-1α脯氨酰羟化酶抑制剂或其可药用盐;和
b)一种或多种用于治疗感染疾病的疫苗。
包含用于治疗结肠炎和其他炎性肠病和症状的化合物自身或者与另一药物或其他治疗剂(尤其是化疗剂或化疗化合物)相结合的所公开的组合物和药物制剂形式可以根据希望的给药途径而变化。
口服给药的制剂可以为固体剂、液体剂、乳剂、悬浮剂或凝胶剂的形式,或者为单位剂型,例如为片剂或胶囊剂。片剂可以与其他常用的成分(例如滑石(tale)、植物油、多元醇、树胶、明胶、淀粉和其他载体)结合而复合。所述用于治疗结肠炎和其他炎性肠病和症状的化合物可以以合适的液体载体分散或者与之结合成为液体、悬液或乳液。
预期用于注射(皮下注射、肌内注射或静脉注射)的肠胃外组合物可以配制为液体或在注射前溶解于液体的固体形式,或者为乳剂。这类制剂是无菌的,且待静脉注射的液体应是等渗的。合适的赋形剂有例如水、右旋糖、盐水和甘油。
给予本文描述的物质的可药用盐包括在本公开的范围内。这类盐可以从无毒可药用碱包括有机碱和无机碱制备。来自无机碱的盐包括钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。来自无毒可药用有机碱的盐包括伯胺、仲胺、叔胺、碱性氨基酸等的盐。关于制药用盐的有益讨论参见S.M.Berge et al,Journal of Pharmaceutical Sciences 66:1-19(1977),其公开内容通过引用纳入本文。
用于注射的物质可以配制成在安瓿中或者在多剂量容器中的单位剂型。待送递的所述用于治疗结肠炎和其他炎性肠病和症状的化合物或者包含一种或多种用于治疗结肠炎和其他炎性肠病和症状的化合物的组合物可以呈现为例如油性或优选水性运载体中的悬浮剂、溶液剂或乳剂的形式。或者,所述HIF-1α脯氨酰羟化酶抑制剂的盐可以为冻干形式,用于在送递时用合适的运载体例如无菌无热原水进行再配制。液体以及待再配制的冻干形式二者都包含适合调节所注射溶液pH所需量的药剂,优选缓冲物。对于任何肠胃外使用,特别是如果所述制剂待静脉内给药,应控制溶质的总浓度以使得所述制剂等渗、低渗或弱高渗。非离子物质(例如糖)优选用于调节张度,特别优选蔗糖。任一这些形式还可包含合适的配制试剂,例如淀粉或糖、甘油或盐水。不管是液体还是固体,单位剂量的所述组合物可以包含0.1%至99%的多核苷酸物质。
步骤
EGLN-1活性测定
EGLN-1(或EGLN-3)酶活性使用质谱(基质辅助的激光解吸电离、飞行时间MS、MALDI-TOF MS)进行确定。重组人EGLN-1-179/426如上文和补充数据中所述进行制备。全长重组人EGLN-3以类似方式进行制备,但由于切割的蛋白的不稳定性所述测定需要使用His-MBP-TVMV-EGLN-3融合物而进行。对于两种酶,与残基556-574对应的HIF-1α肽被用作底物。所述反应以包含TrisCl(5mM,pH 7.5)、抗坏血酸(120μM)、2-酮戊二酸(oxoglutarate)(3.2μM)、HIF-1α(8.6μM)和牛血清白蛋白(0.01%)的总体积50μL而进行。加入预先确定在20分钟中羟基化20%底物的用量的酶以起动所述反应。如果使用抑制剂,则将化合物在二甲基亚砜中以终测定浓度的10倍进行制备。在室温下20分钟后,通过将10μL反应混合物转移至50μL质谱基质溶液(50%乙腈/0.1%TFA、5mM NH4PO4中5mg/mL的α-氰基-4-羟基肉桂酸)中来终止所述反应。将两微升所述混合物点到MALDI-TOF MS靶板上,以装配有Nd:YAG激光器(355nm,3ns脉冲宽度,200Hz重现率)的Applied Biosystems(Foster City,CA)4700Proteomics Analyzer MALDI-TOF MS进行分析。通过16Da的增益从底物中鉴定羟基化的肽产物。在GraphPad Prism 4中分析定义为底物向产物转化百分数的数据,以计算IC50值。
VEGF ELISA测定
将DMEM(10%FBS,1%NEAA,0.1%谷氨酰胺)中的HEK293细胞以每孔20,000个细胞接种在多赖氨酸涂敷的96孔板。过夜孵育后,将所述细胞以100μL的Opti-MEM(Gibco,Carlsbad,CA)洗涤以除去血清。将DMSO中的化合物以Opti-MEM系列稀释(起始为100μM),并加入细胞。以Quantikine人VEGF免疫测定试剂盒(R&D Systems,Minneapolis,MN)分析所述VEGF的条件化培养基。使用Spectra Max250(Molecular Devices,Sunnyvale,CA)记录450nm下的光密度测量值。定义为DFO刺激%的数据被用于以GraphPad Prism 4软件(SanDiego,CA)计算EC50值。
小鼠缺血性后肢研究
所有动物研究依照Guide for the Care and Use of LaboratoryAnimals (National Academy of Sciences;Copyright1996)进行。这些实验使用了来自Charles River Laboratory(Portage,MI)的9-10周龄雄性C57Bl/6小鼠。所述小鼠以运载体(碳酸盐水缓冲液,50mM;pH 9.0)、或50mg/kg或100mg/kg在运载体中的待测试化合物口服给药。对小鼠给药三次:在第1天的8AM和5PM,第2天的8AM。在第一次给药后1小时,在使用异氟烷麻醉下进行单侧动脉结扎。在接近腘动脉起源处结扎股动脉。对对侧肢进行假手术操作。结扎在左右后肢之间以交替的方式进行。第2天的8AM给药后两小时,在小鼠以异氟烷麻醉下通过心室穿刺获得血。使用凝胶块血清分离管获得血清样品用于EPO分析。将心脏、肝和腓肠肌收集、快速冷冻在液氮中,并在-80℃下保存至使用。
小鼠血清EPO测定
使用购自R&D Systems的Mouse Quantikine Erythropoietin ELISA试剂盒依照制造商的说明书检测小鼠血清EPO。
小鼠组织HIF蛋白质印迹分析
将在-80℃下保存的小鼠组织以液氮冷却的研钵和研棒磨成粉。使用NE-PER试剂盒(Pierce Biotechnology)制备核提取物。为进行免疫沉淀,以200∶1的组织与抗体比将核提取物加入针对HIF-1α的单克隆抗体(Novus,Littleton,CO)中。在4℃下,将所述悬浮液在锥形微量离心管中孵育4小时。然后将蛋白A/G-偶联的琼脂糖珠(40μL的50%悬浮液)加入所述管中。在4℃下过夜翻转后,将所述珠以冰冷的磷酸盐缓冲盐水洗涤3次。然后用40μL的Laemmli样品缓冲液对所述珠进行制备用于SDS-PAGE。将在SDS-PAGE上分离的蛋白质用XCell-II Blot Module系统(Invitrogen,Carlsbad,CA)转移至硝酸纤维素膜上。以5%BSA封闭所述印迹物,然后用以1∶100稀释的针对HIF-1α的兔抗体(Novus)孵育。然后,将所述印迹物以Tris-缓冲盐水/Tween-20缓冲液洗涤,并与辣根过氧化物酶缀合的山羊抗兔二抗(Pierce,Rockford,IL)孵育。将印迹物用ECL试剂(Amersham,Piscataway,NJ)显色。以EpsonExpression 1600扫描仪捕获印迹物图像。
下表VIII提供了对本公开化合物体内反应的非限制性实例,例如HIFPH2(EGLN1)抑制和VEGF刺激。
表VIII
将化合物F2在上文描述的小鼠血清EPO测定中进一步进行测试,发现具有EPO EC50=14μM。
所公开的化合物、组合物和方法可稳定HIF-1α和HIF-2α,以及存在于受损免疫系统中或由于存在疾病状态和呈现疾病状态(尤其是腹泻和肠痛)而耗尽或负荷过度的其他因子。所公开的化合物可以用于治疗结肠炎和其他炎性肠病,尤其是未确定型不定性结肠炎、克罗恩病、肠易激综合征和缺血性结肠炎,并且可以与其他肠疾病治疗药物共给药。
诱导的结肠炎研究
如Karhausen JO,et al.“Epithelial hypoxia inducible factor-1 isprotective in murine experimental colitis.”’J.Clin.Invest.2004;114:1098-1106中所述,在受试者动物中使用2,4,6-三硝基苯磺酸(TNBS)诱导结肠炎。简而言之,通过如下方式致敏小鼠:在第1-7天表皮(epicutaneous)施用1%TNBS(Sigma-Aldrich)在100%乙醇中的溶液,然后在第+7天直肠内给予5μL/g体重的2.5%TNBS溶液在50%乙醇中的溶液。运载体对照小鼠仅接受相应体积的50%乙醇。仅对处理显示初始反应的动物被包括在所述研究中;该反应定义为诱导结肠炎后体重减轻5%。作为另一个参数,结肠长度通过测量从盲肠最远面至直肠最末面的距离进行确定。
化合物A41经100mL皮下注射每日给予至颈背。将动物以0.3、1.0或5.0mg/kg的表VIII中公开的化合物或100μL环糊精运载体处理。观察所有组的注射部位的脱毛和光秃情况。在验尸过程中还观察到了轻微纤维化,这是由于在颈背部位重复注射和运载体积累所致。
从疾病诱导前一天(第-1天)开始在实验过程中每24小时测量动物体重。在处死时,测量结肠长度以评估纤维化和变短。将结肠切下进行分析。取样并将其固定在4%福尔马林中,用于组织学分析。通过心脏穿刺取血用于血细胞比容分析,将剩余部分保存用于血清分析。
图1示出了该研究的结果。对照组未接受TNSB诱导的结肠炎并且仅接受运载体,以实心圆(●)标识的线显示。该线平坦,显示该组基本没有体重降低。实心方框(■)代表的数据表示有TNBS诱导的结肠炎并只以运载体预处理的对照动物。因此,对于未接受表VIII中公开的化合物的预处理剂量的两组动物,实心圆(●)代表健康动物,而实心方框(■)代表有TNBS诱导的结肠炎的动物。比较这两条线,证实TNSB诱导的结肠炎导致未治疗的患有诱导疾病的动物至少约20%的体重减轻。
以5mg/kg表VIII中公开的化合物预处理的患有TNSB诱导的结肠炎的动物(空心圆(○))在该研究过程中保持其体重。以5mg/kg表VIII中公开的化合物预处理的无TNSB诱导的结肠炎的动物(实心三角(▲))体重在该研究过程中稍微减轻,但体重返回接近正常。
以1mg/kg表VIII中公开的化合物预处理的患有TNSB诱导的结肠炎的动物(实心菱形(◆))到第1天体重减轻约10%,但在该研究的剩余时间中开始恢复体重。以0.3mg/kg表VIII中公开的化合物预处理的患有TNSB诱导的结肠炎的动物(实心倒三角)到第3天以更低速度减轻体重。
图2a、2b和2c示出所述研究4天内动物的三种临床疾病指示物的反转。结肠长度是结肠炎症的标记物,表现为长度缩短由于炎症相关的纤维变性的增加而增大。
图2a示出以下处理组中出现的结肠长度百分数:(A)健康小鼠;(B)在从第-1天以5mg/kg表VIII中公开的化合物处理的有TNBS诱导的结肠炎的小鼠;(C)在从第+2天以5mg/kg表VIII中公开的化合物处理的有TNBS诱导的结肠炎的小鼠;和(D)仅接受运载体的有TNBS诱导的结肠炎的小鼠。
图2b示出该研究中处理的动物的疾病活度值。炎症的严重度通过肉眼记录,考虑体重和全身外观(毛发、活泼性)的变化。开腹后立即记录大便和直肠出血以及结肠的颜色、膨胀和浆膜表观。最大肉眼观测值给12分,依照下述:由于青年小鼠每周体重增加至少5%,体重变化超过5%记0分,增加0-5%=1,体重减轻=2。毛发为正常(0)或暗淡(1);小鼠活泼(0)或不爱动(1)。大便正常(0)、半流体(1)或流体(2)。直肠出血给1分。结肠颜色正常(0)或发红(1);膨胀无(0)或显著(1)。浆膜方面正常(0)或增厚(1)。图2b中示出的组如下:(A)健康小鼠;(B)在第-1天以5mg/kg表VIII中公开的化合物处理的有TNBS诱导的结肠炎的小鼠;(C)在第+2天以5mg/kg表VIII中公开的化合物处理的有TNBS诱导的结肠炎的小鼠;和(D)仅接受运载体的有TNBS诱导的结肠炎的小鼠。
参见Cooper HS et al.“Clinicopathologic study of dextran sulfatesodium experimental murine colitis.”’Lab Invest.1993Aug;69(2):238-249。
图2c示出如下动物的肠系膜淋巴结(MLN)总白细胞计数:接受运载体的动物(A)、仅接受乙醇运载体的患有TNBS诱导的结肠炎动物(B)、接受10mg/kg表VIII中公开的化合物的无TNBS诱导的结肠炎动物(C)和接受10mg/kg表VIII中公开的化合物且患有TNBS诱导的结肠炎动物(D)。从这些数据可以看出,接受表VIII中公开的化合物处理的动物与未接受药物的患有诱导结肠炎的动物相比具有更低的白细胞计数。
图3示出本研究的各组的血细胞比容水平变化。A组(健康对照)未患有TNBS诱导的结肠炎并且仅接受运载体预处理;B组患有TNBS诱导的结肠炎并且仅接受运载体预处理;C组未患有TNBS诱导的结肠炎但接受5mg/kg表VIII中公开的化合物预处理;D组患有TNBS诱导的结肠炎并且接受0.3mg/kg表VIII中公开的化合物的预处理;E组患有TNBS诱导的结肠炎并且接受1mg/kg表VIII中公开的化合物预处理;F组患有TNBS诱导的结肠炎并且接受5mg/kg表VIII中公开的化合物预处理。如这些数据显示,对于以表VIII中公开的化合物预处理的动物,血细胞比容水平未发生变化。
异种移植模型:小鼠结肠26癌
对裸鼠(Harlan Sprague Dawley,Inc.,Indianapolis IN)以0.1mL包含小鼠结肠26肿瘤细胞的0.9%NaCl混合物(大约1×106细胞/小鼠)在右胁腹进行皮下接种。在接种后9天,使用游标卡尺测量所形成的肿瘤,并使用下式计算肿瘤重量:
其中可以取宽作为所述肿瘤的最小直径,可以取长作为所述肿瘤的最大直径。然后,选择24只具有在75-144mg范围内的肿瘤的小鼠。将所述小鼠随机分配至3组中,每组8只小鼠。在第1天将所述小鼠配对时测每只小鼠的体重,并记录。之后每周测2次体重,并结合肿瘤测量。参见Britten C.D. et al.,“Enhanced antitumor activity of6-hydroxymethyl-acylfulvene in combination with irinotecan and5-fluorouracil in the HT29human colon tumor xenograft model.”’Cancer Res 1999;59:1049-53,其全文通过引用的方式纳入本文。
从第1天开始,将5-氟尿嘧啶(5-FU)静脉内给予每只动物,每天一次持续5天(第1-3组)。从第2天开始,将表VIII中公开的化合物以5mg/kg(第2组)或10mg/kg(第3组)的剂量隔日皮下给予3个剂量(第2、4和6天)。在第27天对照组肿瘤重量平均值达到1926.9mg时终止研究。将所述小鼠处死,从所有小鼠收集肿瘤。所有动物在该研究全程中都存活。记录每个肿瘤的实际重量。下表IX显示了该研究的结果。
表IX
*抑制剂为表VIII中公开的化合物
如表IX所表明,在接受与5-氟尿嘧啶结合的表VIII中公开的化合物的两组中肿瘤总重量都比仅接受5-氟尿嘧啶的第1组显著减轻。第3组中动物的平均肿瘤收缩率是87%,一只动物的肿瘤完全收缩。
试剂盒
本文还公开了包含所述HIF-1α脯氨酰羟化酶抑制剂的试剂盒,所述HIF-1α脯氨酰羟化酶抑制剂拟被送递至患有或者诊断有一种或多种影响肠上皮组织的疾病或病症的人或哺乳动物中,所述疾病或病症尤其是克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、转向改道性结肠炎、白塞综合征和未确定型不定性结肠炎。所述试剂盒可以包含:一个或多个包装的单位剂量的包含一种或多种待送递至人或哺乳动物中的HIF-1α脯氨酰羟化酶抑制剂的组合物。所述单位剂量安瓿或多剂量容器在使用之前包装有待送递的HIF-1α脯氨酰羟化酶抑制剂,其可以包含熔封容器,所述熔封容器封装一个量的多核苷酸或者包含适合其药物有效剂量或多个有效剂量的物质的溶液。所述HIF-1α脯氨酰羟化酶抑制剂可以包装为无菌制剂,所述熔封容器可设计成保持所述制剂无菌至使用。
所公开的HIF-1α脯氨酰羟化酶抑制剂还可以用于将气雾剂形式的活性治疗剂送递至体腔(例如鼻、喉或支气管道)的液体剂、乳剂或悬浮剂形式存在。在这些制品中,所述HIF-1α脯氨酰羟化酶抑制剂与其他复合剂的比例将随剂型的要求变化。
根据预计的给药方式,药学组合物可以为固体、半固体或液体剂型,例如片剂、栓剂、丸剂、胶囊剂、粉剂、液体剂、悬浮剂、洗剂、霜剂、凝胶剂等,优选适合用于单次精确给药的单位剂型。如上所述,所述组合物将包括与可药用载体结合的有效量的所述HIF-1α脯氨酰羟化酶抑制剂,并且另外可包括其他医学剂、药剂、载体、助剂、稀释剂等。
对于固体组合物,常规无毒固体载体包括,例如,医药级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。可作为药物给药的液体组合物可通过例如以下方式制备:将本文所述的活性化合物和任选的药学助剂在赋形剂(例如水、右旋糖盐水溶液、甘油、乙醇等)中溶解、分散等,从而形成溶液或悬浮液。如果需要,待给药的药学组合物还可包含微量的无毒辅助物质(例如润湿剂或乳化剂、pH缓冲剂等,例如乙酸钠、脱水山梨醇单月桂酸酯、三乙醇胺乙酸钠、三乙醇胺油酸盐等)。制备所述剂型的实际方法是已知的,或者对本领域技术人员是显而易见的;例如参见以上参考的Remington′sPharmaceutical Sciences。
如果使用肠胃外给药,其特征通常是注射。注射剂可以制备为常规形式,液体溶液剂或悬浮剂形式、适合在注射之前溶于或悬浮于液体的固体形式,或乳剂形式。肠胃外给药的最近修改的方法包括使用缓释或持续释放体系,使得保持恒定剂量水平。参见,例如美国专利3,710,795,其通过引用的方式纳入本文。
当HIF-1α脯氨酰羟化酶抑制剂待送递至哺乳动物中时,所述哺乳动物可为非人类灵长类、马、猪、兔、狗、绵羊、山羊、牛、猫、豚鼠或啮齿目动物。术语人和哺乳动物不表示特定年龄或性别。因此,成年和新生受试者,以及胎儿,无论是雌雄或者男女,均意欲被涵盖在内。患者、受试者、人或哺乳动物指患有疾病或病症的受试者。术语“患者”包括人和兽医受试者。
尽管已举例说明并描述了本公开的具体实施方案,但是对于本领域技术人员来说显而易见的是,可在不背离本公开的主旨和范围的情况下做出多种其他变化和修改。因此,所附的权利要求书意欲包括本公开范围内的所有这些变化和修改。
Claims (43)
1.一种用于治疗有炎症上皮疾病的受试者的方法,包括对受试者给予有效量的一种或多种具有下式的化合物或其可药用盐:
其中L选自CH2或SO2;
R代表0-5个氢的取代基;
指数n为0-5的整数;
R1和R2各自独立地选自:
i)氢;
ii)被取代或未被取代的C1-C10直链、支链或环状烷基;
iii)被取代或未被取代的C2-C10直链、支链或环状烯基;
iv)被取代或未被取代的C2-C10直链或支链炔基;
v)被取代或未被取代的C6或C10芳基;
vi)被取代或未被取代的C1-C9杂环;
vii)被取代或未被取代的C1-C9杂芳基;或
viii)R1和R2可以一起形成一个具有2-20个碳原子和1-7个杂原子的被取代或未被取代的杂环或被取代或未被取代的杂芳环。
2.根据权利要求1的方法,其中所述一种或多种化合物为选自如下的可药用盐的形式:盐酸盐、硫酸氢盐、硫酸盐、对甲苯磺酸盐、甲磺酸盐和其混合物。
3.根据权利要求1或2的方法,其中L为CH2。
4.根据权利要求1或2的方法,其中L为SO2。
5.根据权利要求1-4任一项的方法,其中每个R为独立选自如下基团的氢的取代基:
i)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
ii)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烯基;
iii)被取代或未被取代的C2-C12直链或C3-C12支链炔基;
iv)C6或C10被取代或未被取代的芳基;
v)C1-C9被取代或未被取代的杂环;
vi)C1-C11被取代或未被取代的杂芳基;
vii)卤素;
viii)-[C(R23a)(R23b)]xOR10;
R10选自:
a)-H;
b)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
c)C6或C10被取代或未被取代的芳基或亚烷基芳基;
d)C1-C9被取代或未被取代的杂环;
e)C1-C11被取代或未被取代的杂芳基;
ix)-[C(R23a)(R23b)]xN(R11a)(R11b);
R11a和R11b各自独立地选自:
a)-H;
b)-OR12;
R12为氢或C1-C4直链烷基;
c)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
d)C6或C10被取代或未被取代的芳基;
e)C1-C9被取代或未被取代的杂环;
f)C1-C11被取代或未被取代的杂芳基;或
g)R11a和R11b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
x)-[C(R23a)(R23b)]xC(O)R13;
R13为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-OR14;
R14为氢、被取代或未被取代的C1-C4直链烷基、C6或C10被取代或未被取代的芳基、C1-C9被取代或未被取代的杂环、C1-C11被取代或未被取代的杂芳基;
c)-N(R15a)(R15b);
R15a和R15b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或R15a和R15b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xi)-[C(R23a)(R23b)]xOC(O)R16;
R16为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R17a)(R17b);
R17a和R17b各自独立地为氢、被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或R17a和R17b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xii)-[C(R23a)(R23b)]xNR18C(O)R19;
R18为:
a)-H;或
b)被取代或未被取代的C1-C4直链、C3-C4支链或C3-C4环状烷基;
R19为:
a)被取代或未被取代的C1-C12直链、C3-C12支链或C3-C12环状烷基;
b)-N(R20a)(R20b);
R20a和R20b各自独立地为氢、被取代或未被取代的C1-C4直链或C2-C4支链烷基;C6或C10被取代或未被取代的芳基;C1-C9被取代或未被取代的杂环;C1-C11被取代或未被取代的杂芳基;或R20a和R20b可以一起形成一个被取代或未被取代的具有3-10个碳原子和0-3个选自氧、氮和硫的杂原子的环;
xiii)-[C(R23a)(R23b)]xCN;
xiv)-[C(R23a)(R23b)]xNO2;
xv)-[C(R23a)(R23b)]xR21;
R21为被1-21个选自-F、-Cl、-Br或-I的卤素原子取代的C1-C10直链、支链或环状烷基;
xvi)-[C(R23a)(R23b)]xSO2R22;
R22为氢、羟基、被取代或未被取代的C1-C4直链或C2-C4支链烷基;被取代或未被取代的C6、C10或C14芳基;C7-C15亚烷基芳基;C1-C9被取代或未被取代的杂环;或C1-C11被取代或未被取代的杂芳基;
R23a和R23b各自独立地为氢或C1-C4烷基;并且
指数x为0-5的整数。
6.根据权利要求1-5任一项的方法,其中R1和R2一起形成一个5元被取代或未被取代的C1-C4杂环或被取代或未被取代的C1-C4杂芳环。
8.根据权利要求1-7任一项的方法,其中R1和R2一起形成一个被取代或未被取代的C4-C11杂环或被取代或未被取代的C4-C11杂芳环。
10.根据权利要求1-5和9任一项的方法,其中R1和R2一起形成一个选自如下基团的环:吡咯烷-1-基、3-羟基吡咯烷-1-基、2-(吡啶-2-基)吡咯烷-1-基、2-甲基羧基吡咯烷-1-基、2-(甲氧基甲基)吡咯烷-1-基、噻唑烷-3-基、1H-咪唑-1-基、哌啶-1-基、4-苄基哌啶-1-基、1,4’-联哌啶基-1’-基、哌嗪-1-基、4-苄基哌嗪-1-基、4-(2-甲氧基苯基)-哌嗪-1-基甲基、4-(6-氯哒嗪-3-基)哌嗪-1-基、1,4-二氧杂-8-氮杂螺[4,5]癸-8-基、吗啉-4-基、硫代吗啉-4-基、氮杂环庚-1-基、氮杂环辛-1-基和3,4-二氢喹啉-1(2H)-基。
11.根据权利要求1-5任一项的方法,其中R2为氢和R1选自苄基、4-甲氧苄基、4-氟苄基、4-氯苄基、4-甲基苄基、2-(吡啶-2-基)乙基、[1,3]二氧戊环-2-基甲基、四氢呋喃-2-基甲基、2-甲氧乙基、1-羟基-2-甲基丙-2-基、吡啶-4-基甲基、呋喃-2-基甲基、2-(甲基硫)乙基、1-苯乙基、3-咪唑-1-基丙基、环庚基、4-甲基环己基、1-苄基哌啶-4-基、氮杂环庚-2-酮-3-基和1-苄基-吡咯烷-3-基。
13.根据权利要求12的方法,其中R4为甲基。
14.根据权利要求12的方法,其中R4为乙基。
15.根据权利要求12的方法,其中R4为叔丁基。
16.根据权利要求12-15任一项的方法,其中Z为4-氯苯基。
17.根据权利要求12-15任一项的方法,其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。
18.根据权利要求12-15任一项的方法,其中Z选自2,3-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、2,6-二氟苯基、2,3-二氯苯基、2,4-二氯苯基、2,5-二氯苯基和2,6-二氯苯基。
19.根据权利要求1的方法,其中所述一种或多种化合物为4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯或选自以下盐的可药用盐:盐酸盐、硫酸氢盐、硫酸盐、对甲苯磺酸盐、甲磺酸盐和其混合物。
20.根据权利要求1的方法,其中所述一种或多种化合物选自:
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(2-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸甲酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸乙酯;
4-{[1-(4-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;
4-{[1-(3-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯;和
4-{[1-(2-氟苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}哌嗪-1-甲酸叔丁酯。
21.根据权利要求1-20任一项的方法,其中所述炎症上皮疾病为影响肠上皮组织的疾病。
22.根据权利要求1-20任一项的方法,其中所述疾病为克罗恩病。
23.根据权利要求1-20任一项的方法,其中所述疾病为溃疡性结肠炎。
24.根据权利要求1-20任一项的方法,其中所述疾病为胶原性结肠炎。
25.根据权利要求1-20任一项的方法,其中所述疾病为淋巴细胞性结肠炎。
26.根据权利要求1-20任一项的方法,其中所述疾病为缺血性结肠炎。
27.根据权利要求1-20任一项的方法,其中所述疾病为改道性结肠炎。
28.根据权利要求1-20任一项的方法,其中所述疾病为白塞综合征。
29.根据权利要求1-20任一项的方法,其中所述疾病为未确定型结肠炎。
30.根据权利要求1-20任一项的方法,其中所述炎症上皮疾病选自影响呼吸道、粘膜、皮肤、GI道、主器官和内分泌腺内层、脉管组织和其结合的疾病。
31.一种用于治疗有炎症上皮疾病的受试者的组合物,包含
a)有效量的一种或多种具有下式的化合物或其可药用盐:
其中L选自CH2或SO2;
R代表0-5个氢的取代基;
指数n为0-5的整数;
R1和R2各自独立地选自:
i)氢;
ii)被取代或未被取代的C1-C10直链、支链或环状烷基;
iii)被取代或未被取代的C2-C10直链、支链或环状烯基;
iv)被取代或未被取代的C2-C10直链或支链炔基;
v)被取代或未被取代的C6或C10芳基;
vi)被取代或未被取代的C1-C9杂环;
vii)被取代或未被取代的C1-C9杂芳基;或
viii)R1和R2可以一起形成一个具有2-20个碳原子和1-7个杂原子的被取代或未被取代的杂环或被取代或未被取代的杂芳环;
和
b)一种或多种赋形剂。
32.根据权利要求31的组合物,其中所述一种或多种化合物为选自如下盐的可药用盐的形式:盐酸盐、硫酸氢盐、硫酸盐、对甲苯磺酸盐、甲磺酸盐和其混合物。
34.根据权利要求31-33任一项的组合物,其中R4为甲基。
35.根据权利要求31-33任一项的组合物,其中R4为乙基。
36.根据权利要求31-33任一项的组合物,其中R4为叔丁基。
37.根据权利要求31-33任一项的组合物,其中Z为4-氯苯基。
38.根据权利要求31-33任一项的组合物,其中Z选自2-氯苯基、3-氯苯基、2-氟苯基、3-氟苯基或4-氟苯基。
39.根据权利要求31-33任一项的组合物,其中所述一种或多种化合物为4-{[1-(4-氯苄基)-3-羟基-2-氧代-1,2-二氢吡啶-4-基]甲基}-哌嗪-1-甲酸叔丁酯或选自以下盐的可药用盐:盐酸盐、硫酸氢盐、硫酸盐、对甲苯磺酸盐、甲磺酸盐和其混合物。
40.根据权利要求31-39任一项的组合物,还包含一种或多种化疗化合物。
41.根据权利要求41的组合物,其中所述一种或多种化疗化合物选自6-羟基甲基酰基富烯、环磷酰胺、达卡巴嗪、卡莫司汀、多柔比星和氨甲蝶呤。
42.根据权利要求32的组合物,其中所述炎症上皮疾病选自克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、改道性结肠炎、白塞综合征和未确定型结肠炎。
43.一种治疗患结肠炎的受试者的组合物,包含
a)有效量的一种或多种具有下式的化合物或其可药用盐:
其中L选自CH2或SO2;
R代表0-5个氢的取代基;
指数n为0-5的整数;
R1和R2各自独立地选自:
i)氢;
ii)被取代或未被取代的C1-C10直链、支链或环状烷基;
iii)被取代或未被取代的C2-C10直链、支链或环状烯基;
iv)被取代或未被取代的C2-C10直链或支链炔基;
v)被取代或未被取代的C6或C10芳基;
vi)被取代或未被取代的C1-C9杂环;
vii)被取代或未被取代的C1-C9杂芳基;或
viii)R1和R2可以一起形成具有2-20个碳原子和1-7个杂原子的被取代或未被取代的杂环或被取代或未被取代的杂芳环;
R4为C1-C4直链或C3-C4支链烷基;
和
b)一种或多种赋形剂。
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