CN108024974A - 含有dna烷化剂的氮丙啶 - Google Patents
含有dna烷化剂的氮丙啶 Download PDFInfo
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- CN108024974A CN108024974A CN201680036898.5A CN201680036898A CN108024974A CN 108024974 A CN108024974 A CN 108024974A CN 201680036898 A CN201680036898 A CN 201680036898A CN 108024974 A CN108024974 A CN 108024974A
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- Prior art keywords
- alkyl
- hydrogen
- compound according
- compound
- alkenyl
- Prior art date
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 38
- 201000011510 cancer Diseases 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 28
- -1 C2-C6Alkynes Base Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 23
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- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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Abstract
本发明提供式(I)‑式(VI)的化合物:其中变量定义于本文中;制备其的方法以及包含投与所述化合物的治疗癌症的方法。
Description
相关申请案的交叉参考
本申请案根据35U.S.C.§119(e)要求2015年6月24日申请的美国临时申请案第62/184,129号的优先权,其内容以全文引用的方式并入本文中。
技术领域
本发明提供适用作治疗剂的化合物、所述化合物的医药组合物和治疗癌症患者的癌症的方法,且因此涉及生物学、化学和医学的领域。
背景技术
癌症为人类发病和死亡的主要原因之一。因为难以在不损害或杀死正常细胞的情况下杀死癌细胞,所以癌症治疗具有挑战性。在癌症治疗期间损害或杀死正常细胞会在患者体内引起不良副作用且可限制投与癌症患者的抗癌药物的量。仍需要适用于治疗癌症患者的化合物。
发明内容
在一个方面中,本文提供选自以下的化合物:
其中变量定义且说明于以下本文中。如本文所提供的化合物包括立体异构体的混合物,例如对映异构体,和经分离的单独对映异构体,和其外消旋与非外消旋混合物。在不受理论束缚的情况下,在某些实施例中,本文所提供的化合物充当前药,所述前药可在肿瘤中或在肿瘤周围存在的低氧条件中或其周围活化。
在另一方面中,本文提供制备本文所提供的化合物的方法。
在另一方面中,本文提供医药组合物,其包含本文所提供的化合物和至少一种药学上可接受的赋形剂。
在另一方面中,本文提供治疗癌症的方法,其包含向有需要的患者投与治疗有效量的本文所提供的化合物或治疗有效量的本文所提供的组合物。
附图说明
在图1A-1C中以图形方式说明对某些化合物进行比较的肿瘤体积减少。
具体实施方式
定义
提供以下定义以辅助读者。除非另外定义,否则本文所使用的所有技术术语、符号以及其它科学或医学术语或术语集打算具有化学和医学领域中的技术人员通常所理解的含义。在一些情况下,为了清楚起见和/或为便于参考,在本文中定义具有通常所理解的含义的术语,且在本文中纳入所述定义不应视为表示在所属领域中通常理解的术语的定义上的实质性差异。
所有数字指示,例如pH值、温度、时间、浓度和重量,包括其各自的范围,均为近似值,适当时,所述近似值通常可通过0.1、1.0或10.0的增量来改变(+)或(-)。所有数字指示可理解为在之前加有术语“约”。本文所描述的试剂为示范性的且其等效物可为所属领域中已知的。
除非上下文另外清楚地规定,否则“一种(a/an)”和“所述”包括复数种参考物。因此,举例来说,提及一种化合物是指一或多种化合物或至少一种化合物。因此,术语“一种(a/an)”、“一或多种”和“至少一种”在本文中可互换地使用。
如本文中所用,术语“包含”打算意指组合物和方法包括所述要素,但不排除其它要素。当用于定义组合物和方法时,“主要由…组成”应意指排除对于所述组合物或方法具有任何基本意义的其它要素。“由…组成”应意指排除用于所主张的组合物和大体方法步骤中超过痕量要素的其它成分。由这些过渡术语中的每一者定义的实施例在本发明的范围内。因此,希望方法和组合物可包括另外的步骤和组分(包含),或者包括无意义的步骤和组合物(主要由…组成),或者希望仅包括所陈述的方法步骤或组合物(由…组成)。
在基团之前的“Cx-Cy”或“Cx-y”是指存在于所述基团中的碳原子数量范围。举例来说,C1-C6烷基是指具有至少1个且至多6个碳原子的烷基。
“烷氧基”是指-O-烷基。
“氨基”是指NRpRq,其中Rp和Rq独立地为氢或C1-C6烷基,或Rp和Rq与其所键接的氮原子一起形成4-15元杂环。
“烷基”是指具有1到10个碳原子且在一些实施例中具有1到6个碳原子的单价饱和脂肪族烃基。“Cx-y烷基”是指具有x到y个碳原子的烷基。举例来说,此术语包括直链和支链烃基,例如甲基(CH3-)、乙基(CH3CH2-)、正丙基(CH3CH2CH2-)、异丙基((CH3)2CH-)、正丁基(CH3CH2CH2CH2-)、异丁基((CH3)2CHCH2-)、仲丁基((CH3)CH3CH2)CH-)、叔丁基((CH3)3C-)、正戊基(CH3CH2CH2CH2CH2-)和新戊基((CH3)3CCH2-)。
“烯基”是指具有2到10个碳原子且在一些实施例中具有2到6个碳原子或2到4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基。举例来说,Cx-y烯基是指具有x到y个碳原子的烯基,且打算包括例如乙烯基、丙烯基、1,3-丁二烯基等。
“炔基”是指具有2到10个碳原子且在一些实施例中具有2到6碳原子或2到4个碳原子且含有至少一个三键的直链单价烃基或支链单价烃基。术语“炔基”还打算包括具有一个三键和一个双键的那些烃基。举例来说,C2-6炔基包括乙炔基、丙炔基等。
“芳基”是指具有6到14个碳原子且无环杂原子且具有单个环(例如苯基)或多个缩合(稠合)环(例如萘基或蒽基)的芳香族基团。对于多环系统(包括具有不含环杂原子的芳香族和非芳香族环的稠合、桥连和螺环系统),当连接点在芳香族碳原子处时,适用术语“芳基”或“Ar”(例如由于其连接点在芳香族苯基环的2位处,5,6,7,8四氢萘-2-基为芳基)。
“环烷基”是指具有3到14个碳原子且无环杂原子且具有单个环或多个环(包括稠合、桥连和螺环系统)的饱和或部分饱和环基。对于具有不含环杂原子的芳香族和非芳香族环的多环系统,当连接点在非芳香族碳原子处时,适用术语“环烷基”(例如5,6,7,8,-四氢萘-5-基)。术语“环烷基”包括环烯基。环烷基的实例包括例如金刚烷基、环丙基、环丁基、环戊基、环辛基和环己烯基。
“醚”是指经1-3个C1-C6烷氧基取代的C1-C6烷基,其中烷氧基是指-O-烷基。
“卤基”是指氟基、氯基、溴基和碘基中的一或多者。
“杂芳基”是指具有1到14个碳原子和1到6个选自由氧、氮和硫组成的群组的杂原子的芳香族基团,且包括单环系统(例如,咪唑基-2-基和咪唑5-基)和多环系统(例如,咪唑并吡啶基、苯并三唑基、苯并咪唑-2-基和苯并咪唑-6-基)。对于多环系统(包括具有芳香族和非芳香族环的稠合、桥连和螺环系统),如果存在至少一个环杂原子且附接点在芳香族环的原子处,那么适用术语“杂芳基”(例如1,2,3,4-四氢喹啉-6-基和5,6,7,8-四氢喹啉-3-基)。在一些实施例中,杂芳基的氮和/或硫环原子任选地经氧化以得到N-氧化物(N→O)、亚磺酰基或磺酰基部分。术语杂芳基包括(但不限于)吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并噻吩基、苯并咪唑啉基、咔唑基、NH-咔唑基、咔啉基、色满基、色烯基、噌啉基、二噻嗪基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑并吡啶基、咪唑基、吲唑基、吲哚烯基、吲哚啉基、吲哚嗪基、吲哚基、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基(isoquinolinyl)、异喹啉基(isoquinolyl)、异噻唑基、异噁唑基、萘啶基、八氢异喹啉基、噁二唑基、噁唑烷基、噁唑基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基和吨基。
“杂环的”或“杂环”或“杂环烷基”或“杂环基”是指具有1到14个碳原子和1到6个选自由氮、硫或氧组成的群组的杂原子的饱和或部分饱和环状基团,且包括单环系统和包括稠合、桥连和螺环系统的多环系统。对于具有芳香族和/或非芳香族环的多环系统,当存在至少一个环杂原子且连接点在非芳香族环原子处时,适用术语“杂环的”、“杂环”、“杂环烷基”或“杂环基”(例如1,2,3,4-四氢喹啉-3-基、5,6,7,8-四氢喹啉-6-基和十氢喹啉-6-基)。在一些实施例中,本文中的杂环基团为3-15元、4-14元、5-13元、7-12元或5-7元杂环。在一些其它实施例中,杂环含有4个杂原子。在一些其它实施例中,杂环含有3个杂原子。在另一实施例中,杂环含有最多2个杂原子。在一些实施例中,杂环基团的氮和/或硫原子任选地经氧化以得到N-氧化物、亚磺酰基或磺酰基部分。杂环基包括(但不限于)四氢吡喃基、哌啶基、N-甲基哌啶-3-基、哌嗪基、N-甲基吡咯烷-3-基、3-吡咯烷基、2-吡咯烷酮-1-基、吗啉基和吡咯烷基。指示碳原子数目的前缀(例如C3-10)是指杂环基团部分中除杂原子数目以外的碳原子总数。二价杂环基团应具有适当调整的氢含量。
术语“任选地经取代”是指经取代或未经取代的基团。所述基团可经一或多个取代基,例如1、2、3、4或5个取代基取代。所述取代基优选地选自由以下组成的群组:氧代、卤基、-CN、NO2、-N2+、-CO2R100、-OR100、-SR100、-SOR100、-SO2R100、-NR100SO2R100、-NR101R102、-CONR101R102、-SO2NR101R102、C1-C6烷基、C1-C6烷氧基、-CR100=C(R100)2、-CCR100、C3-C10环烷基、C3-C10杂环基、C6-C12芳基和C2-C12杂芳基,或二价取代基,例如-O-(CH2)-O-、-O-(CH2)2-O-和其经1-4个甲基取代的形式,其中R100、R101和R102各自独立地为氢或C1-C8烷基;C3-C12环烷基;C3-C10杂环基;C6-C12芳基;或C2-C12杂芳基;或R101和R102与其连接的氮原子一起形成5-7元杂环;其中烷基、环烷基、杂环基、芳基或杂芳基各自任选地经1-3个卤基、1-3个C1-C6烷基、1-3个C1-C6卤烷基或1-3个C1-C6烷氧基取代。所述取代基优选地选自由以下组成的群组:氯基、包括三氟基的氟基、-OCH3、甲基、乙基、异丙基、环丙基、OH、OAc、含有1-3个杂原子(例如任选地经1-3个C1-C6烷基或C6-C10芳基取代的氮和氧)的5-6元杂环基、含有1-3个杂原子(例如任选地经1-3个C1-C6烷基取代的氮和氧)的5-6元杂芳基、-CO2H和其盐和C1-C6烷基酯、CONMe2、CONHMe、CONH2、-SO2Me、-SO2NH2、-SO2NMe2、-SO2NHMe、-NHSO2Me、-NHSO2CF3、-NHSO2CH2Cl、-NO2、-NH2、-NMe2、-OCF3、-CF3和-OCHF2。其它任选的取代基包括在本文以下表中说明的那些。
“前药”是指一种化合物,其在投与之后代谢或以其它方式转化为关于至少一种特性的生物活性或更具活性的化合物(或药物)。相对于药物,前药以使其相对于药物活性较低或无活性的方式经化学改性,然而化学改性使得在投与所述前药之后,通过代谢或其它生物过程产生相应药物。相对于活性药物,前药可具有改变的代谢稳定性或转运特征、更少副作用或更低毒性,或改进的香味(例如,参见参考文献诺格拉迪(Nogrady),1985,药物化学-生物化学方法(Medicinal Chemistry A Biochemical Approach),牛津大学出版社(Oxford University Press),纽约(New York),第388-392页,以引用的方式并入本文中)。前药可使用除相应药物外的反应物合成。
向患者“投与(administering)”药物或向患者的药物“的投与(administrationof)”(和此短语的文法等效者)是指直接投与,此可为由医学专业人员向患者投与或可为自投药;和/或间接投与,此可为开具药物处方的行为。举例来说,教导患者自投药和/或向患者提供药物处方的医师向患者投与药物。
“癌症”是指可通过侵袭局部扩大且通过转移全身性地扩大来潜在地无限生长的白血病、淋巴瘤、癌瘤和其它恶性肿瘤,包括实体肿瘤。癌症的实例包括(但不限于)肾上腺癌、骨癌、脑癌、乳癌、支气管癌、结肠癌和/或直肠癌、胆囊癌、头颈癌、肾癌、喉癌、肝癌、肺癌、神经组织癌症、胰脏癌、前列腺癌、副甲状腺癌、皮肤癌、胃癌和甲状腺癌。癌症的某些其它实例包括急性和慢性淋巴细胞瘤和颗粒细胞瘤、腺癌、腺瘤、基底细胞癌、子宫颈发育不良和原位癌、尤文氏肉瘤(Ewing's sarcoma)、表皮样癌、巨细胞瘤、多形性成胶质细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西氏肉瘤(Kaposi'ssarcoma)、平滑肌瘤、白血病、淋巴瘤、恶性类癌、恶性黑色素瘤、恶性高钙血症、类马方氏症体型肿瘤(marfanoid habitus tumor)、髓性癌、转移性皮肤癌、粘膜神经瘤、骨髓瘤、蕈样真菌病、成神经细胞瘤、骨肉瘤、成骨肉瘤和其它肉瘤、卵巢肿瘤、嗜铬细胞瘤、真性红血球过多症、原发性脑肿瘤、小细胞肺肿瘤、溃疡型和乳头型鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、成视网膜细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病变、网状细胞肉瘤和威尔姆氏肿瘤(Wilm's tumor)。
“患者”与“个体”可互换地使用,用以指代需要癌症治疗的哺乳动物。患者通常为人类。患者通常为经诊断患有癌症的人类。在某些实施例中,“患者”或“个体”可指代用于筛选、表征和评价药物和疗法的非人类哺乳动物,例如非人类灵长类动物、犬、猫、兔、猪、小鼠或大鼠。
“实体肿瘤”是指实体肿瘤,包括(但不限于)骨骼、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤和软组织(肉瘤)中的转移性肿瘤。
药物的“治疗有效量”是指当投与癌症患者时,应具有预期治疗效果,例如缓解、改善、缓和或消除在患者体内的癌症的一或多种表现的药物的量。治疗效果在投与一次剂量时未必会发生,且可能仅在投与一系列剂量之后发生。因此,可在一或多次投与中投与治疗有效量。
“治疗”病况或患者、病况或患者“的治疗”或“的疗法”是指采取步骤以获得有益的或所需的结果,包括临床结果。出于本发明的目的,有益的或所需的临床结果包括(但不限于)癌症的一或多种症状的缓解或改善;疾病程度的减轻;疾病进展的延迟或减缓;疾病病况的改善、缓和或稳定;或其它有益的结果。在一些情况下,癌症的治疗可引起部分反应或稳定疾病。
化合物
在一个方面中,本文提供选自以下的化合物:
或其药学上可接受的盐或其各自的药学上可接受的溶剂合物,其中
R1为:氢、-N3、CN、卤基、NR21R22、-OR23、-SO2(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基或醚;
R21和R22各自独立地为氢、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基或-SO2(C1-C6烷基);或R21和R22与其所键接的氮原子一起形成4-15元杂环或5-15元杂芳基;
R23为氢、C1-C6烷基或C6-C10芳基;
R2和R3独立地为氢或卤基;
R4为氢、卤基、C1-C6烷氧基、C1-C6烷基或C6-C10芳基,
R5、R7、R9、R12和R15独立地为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基;或R4和R5与其之间的介入碳原子一起形成C5-C6环烷基环;
R6和R10独立地为氢或卤基;
R8为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基或5-15元杂芳基;
R11各自独立地为C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基或C6-C10芳基;
R13、R14、R16和R17独立地为氢、卤基、C1-C6烷基、C2-C6烯基、C2-C6炔基或C1-C6烷氧基;
其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、烷氧基和醚基团任选地经取代。
在一个实施例中,提供的化合物具有下式:
在另一实施例中,R1为非氢取代基。在另一实施例中,R2和R3为氢。在另一实施例中,R4为氢或卤基。在另一实施例中,R4为氢。在另一实施例中,R4为卤基。在另一实施例中,R4为氟基。在另一实施例中,R4与R5一起形成5元环烷基。在另一实施例中,R1为非氢取代基,R2和R3为氢且R4为氢或卤基或R4与R5一起形成5元环烷基。在另一实施例中,R5为非氢取代基。在另一实施例中,R1为NR21R22。
在另一实施例中,所提供的化合物具有下式:
在另一实施例中,R8为氢。在另一实施例中,R8为C1-C6烷基、C2-C6烯基或C2-C6炔基。在另一实施例中,R9为任选地经取代的C1-C6烷基。
在另一实施例中,所提供的化合物具有下式:
在另一实施例中,R7为任选地经取代的C1-C6烷基。
在另一实施例中,所提供的化合物具有下式:
在另一实施例中,R12为任选地经取代的C1-C6烷基。
在另一实施例中,所提供的化合物具有下式:
在另一实施例中,R15为任选地经取代的C1-C6烷基。
在另一实施例中,所提供的化合物具有下式:
在另一实施例中,R7为任选地经取代的C1-C6烷基。
本文所提供和/或使用的某些非限制性和示范性化合物与其在氮气下和在空气下的抗癌能力一起列表如下。
实例
实例1.TH 2565和2566的合成
流程1
化合物B
在室温下,将NaBH4(0.38g)添加到化合物A(1.65g)于15mL甲醇中的溶液中。搅拌溶液30min。溶液以水(50mL)稀释且以DCM萃取。以Na2SO4干燥有机层。去除溶剂以获得化合物B(1.6g)。
化合物D
在氩气下,在0℃下将DIAD(2.5mL)添加到化合物B(1.36g)、化合物C(3.7g)、和PPh3(3.2g)于THF(40mL)中的悬浮液中。从0℃到室温搅拌混合物2小时。在真空下去除溶剂后,通过硅胶快速色谱法(Hex:AcOEt=100:70(v/v))分离残余物以产生1.3g化合物D。
TH 2937
在50℃下搅拌化合物D(1.3g)、Ag2O(2.5g)、DIEA(2mL)于THL(30mL)中的混合物5小时。在真空下去除溶剂后,通过硅胶快速色谱法(AcOEt:20%MeOH/DCM=70:30(v/v))分离残余物以产生0.7g轻质液态TH 2937。
TH 2565和TH 2566
通过手性柱分离1.0g TH 2937以获得0.48g TH 2565和0.47g TH 2566。TH2565和TH2566的1HNMR(CDCl3)。1.65(d,J=6.4Hz,3H),2.02-2.22(m,8H),5.70-5.75(m,1H),7.57(d,J=8.4Hz,2H),8.23(d,J=8.4Hz,2H)。
1.化合物2的合成
在氩气下在-40℃下,将LiHMDS(1.0M THF溶液,24mL,24mmol)添加到化合物1(2.9g,22.83mmol)于THF(35mL)中的溶液中。在-40℃下搅拌混合物15分钟。
在保持内部温度低于-30℃的情况下缓慢添加醛。
在-40℃下搅拌混合物75分钟,随后以饱和NH4Cl水溶液(10mL)淬灭。
反应混合物以EtOAc(40mL×3)萃取,以盐水(50mL)洗涤,经Na2SO4干燥。
在减压下去除溶剂且通过快速柱纯化残余物以得到澄清油状物(1.5g,产率33%)。
1HNMR(CDCl3,400MHz)δ:7.97(s,1H),4.22(m,1H),4.00(s,3H),2.24-2.14(m,1H),1.06(d,J=6.4Hz,3H),0.93(dd,J=1.2,6.4Hz,3H)
2.化合物3的合成
在氩气下在-78℃下,将LiHMDS(1.0M THF溶液,8.3mL,8.3mmol)添加到化合物2(1.5g,7.54mmol)于THF(60mL)中的混合物中。
在-78℃下搅拌混合物10分钟且随后缓慢添加溴化合物(3.7g,11.31mmol)的溶液。
在-78℃下搅拌混合物且随后在室温下搅拌过夜。
在减压下去除溶剂且通过快速柱纯化残余物以得到浅黄色油状物(1.8g,49%产率)
1HNMR(CDCl3,400MHz)δ:8.01(s,1H),5.18(t,J=6.4Hz,1H),4.07(s,3H),3.59-3.02(m,8H),2.41-2.36(m,1H),1.83(d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H)。
3.TH 2567/2568的合成
在氩气下在65℃下,搅拌化合物3(1.8g,3.67mmol)、DIPEA (3mL)、Ag2O(10g)于THF(45mL)中的混合物4小时。过滤固体且浓缩滤液到干燥,通过快速柱纯化以得到澄清油状物(1.02g,81%产率)。
1HNMR(CDCl3,400MHz)δ:8.04(s,1H),5.16(t,J=6.8Hz,1H),4.10(s,3H),2.50-2.41(m,1H),2.24-2.01(m,8H),1.19(d,J=6.4Hz,3H),0.81(d,J 6.4Hz,3H)。
通过手性HPLC分离此混合物以得到TH 2567和TH 2568
1.化合物5的合成
在0℃下将NaBH4(775mg,20mmol)逐份添加到酮1(3.52g,19.03mmol)于MeOH(35mL)中的溶液中。
在0℃下搅拌混合物1h,且随后以丙酮(5mL)淬灭反应。
反应混合物通过旋蒸仪浓缩到初始体积的一半,残余物以EtOAc(400mL)稀释,以盐水(50mL×3)洗涤,经Na2SO4干燥。
在减压下去除溶剂且通过快速柱纯化残余物以得到澄清油状物(3.5g,产率99%)。
1H NMR(CDCl3,400MHz)δ:8.06(t,J=8.4Hz,1H),7.35(d,J=11.6Hz,1H),7.30(d,J=11.6Hz,1H),5.01-4.99(m,1H),1.52(d,J=6.4Hz,3H)。
2.化合物6的合成
在氩气下在0℃下,依序将Br-IPM(6.99g,22.70mmol)、PPh3(7.44g,28.38mmol)和DIAD(5.73g,28.38mmol)添加到化合物4(3.5g,18.92mmol)于THF(100mL)中的混合物中。
在0℃下搅拌混合物2h且随后在搅拌时升温到室温过夜。
在减压下去除溶剂且通过快速柱纯化残余物以得到浅黄色油(4.28g,47%产率)
1H NMR(CDCl3,400MHz)δ:8.09(t,J=8.0Hz,1H),8.31(dd,J=2.4,13.6Hz,2H),5.52-5.60(m,1H),3.54-3.19(m,8H),1.63(d,J=6.4Hz,3H)。
3.化合物7的合成
在氩气下在50℃下,将化合物6(3.95g,8.28mmol)、Ag2O(12g)于THF(100mL)中的混合物搅拌过夜。过滤固体且浓缩滤液到干燥,通过快速柱纯化以得到黄色固体(2.28g,87%产率)。
1H NMR(CDCl3,400MHz)δ:8.08(t,J=8.0Hz,1H),7.36(d,J=11.6Hz,1H),7.31(d,J=8.4Hz,1H),5.70-5.67(m,1H),2.25-2.08(m,8H),1.64(d,J=6.4Hz,3H)。
4.TH 2803/2804的合成
在0℃下将K2CO3(230mg,1.66mmol)添加到咪唑(62mg,0.91mmol)和化合物7(260mg,0.83mmol)于DMF(5mL)中的混合物中。将混合物在室温下搅拌过夜。
通过半制备型HPLC纯化以得到澄清油状物。
1H NMR(CDCl3,400MHz)δ:8.02(d,J=8.4Hz,1H),7.65-7.2(m,2H),7.50(d,J=1.6Hz,1H),7.24(s,1H),7.08(s,1H),5.81-5.75(m,1H),2.22-2.02(m,8H),1.68(d,J=6.4Hz,3H)。
通过手性HPLC分离此混合物以得到TH 2803和TH 2804。
本文所提供的其它化合物遵循此方法在适当取代起始材料时制备,所述起始材料为市售的或根据公认方法从市售的起始材料制备。参见例如参见美国专利申请公开案第2005/0256191号、第2007/0032455号和第2009/0136521号,和PCT公开案第2000/064864号、第2004/087075号和第2007/002931号,其各自以引用的方式并入本文中。
实例2.体外人类肿瘤细胞系细胞毒性分析
关于H460非细胞肺癌人类肿瘤细胞系的体外增殖数据报道于以上表中。IC50数值以微摩尔为单位报道且由以下引起:暴露于各种浓度的化合物2小时,随后进行洗涤步骤且添加新鲜培养基,随后生长和细胞活力染色且与仅培养基处理的对照比较。
具体地说,将指数生长细胞以4×103个细胞/孔的密度接种于96孔板中且在37℃下于5%CO2、95%空气和100%相对湿度中培育24小时,随后添加测试化合物。将化合物以200倍所需最终测试浓度溶解于100%DMSO中。在药物添加时,用完全培养基将化合物进一步稀释到4倍所需最终浓度。将50μl指定浓度的化合物的等分试样添加到已含有150μl培养基的微量滴定孔中,产生所报道的最终药物浓度。在添加药物之后,在37℃下于5%CO2、95%空气和100%相对湿度中将板再培育2小时,随后洗去药物且添加新鲜培养基,且在37℃下于5%CO2、95%空气和100%相对湿度中将板再培育70小时。此培育结束时,使用阿尔玛蓝分析法(AlamarBlue assay)对活细胞进行定量。使用Prism软件(加利福尼亚尔湾(Irvine,CA))计算导致50%的生长抑制的药物浓度(IC50),且结果列举于表中。
以上H460数据表明与在空气下相比,在氮气下观测到实质性抗肿瘤效果和增强的抗肿瘤功效。
基于对这些化合物有利的体外数据,评估其在H460(NSCLC)人类肿瘤异种移植模型中的抗肿瘤活性。将H460细胞(1×106个)皮下植入无病原体的纯合雌性裸小鼠(nu/nu,查尔斯河实验室(Charles River Laboratories))的侧腹。当肿瘤尺寸达到100-150mm3时,动物随机分为每处理组10只小鼠。所有测试化合物以5%DMSO、5%Tween 80于D5W中调配。基于初步研究选择所有化合物的剂量以定义每一化合物在每日投与持续5日时的MTD。基于重量损失和行为迹象,TH2565和TH2566的MTD经测定分别为2mg/kg。在图1A-1C中以图形方式说明对某些化合物进行比较的肿瘤体积减少。
应了解,尽管已通过某些方面、实施例和任选的特征具体地公开本发明,但所属领域的技术人员可对所述方面、实施例和任选的特征作出修改、改进和变化,且认为所述修改、改进和变化在本发明的范围内。
本发明已大致上且一般性地描述于本文中。处于通用公开内容内的较狭义类型和亚属组中的每一者也形成本发明的一部分。此外,在本发明的特征或方面以马库西组(Markush group)的方式进行描述的情况下,所属领域的技术人员将认识到本发明也因此以马库西组的任何个别成员或成员子组的形式进行描述。
Claims (22)
1.一种化合物,其选自:
或其药学上可接受的盐或其各自的药学上可接受的溶剂合物,其中
R1为:氢、-N3、CN、卤基、NR21R22、-OR23、-SO2(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基或醚;
R21和R22各自独立地为氢、羟基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基或-SO2(C1-C6烷基);或R21和R22与其所键接的氮原子一起形成4-15元杂环或5-15元杂芳基;
R23为氢、C1-C6烷基或C6-C10芳基;
R2和R3独立地为氢或卤基;
R4为氢、卤基、C1-C6烷氧基、C1-C6烷基或C6-C10芳基,
R5、R7、R9、R12和R15独立地为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C6-C10芳基、4-15元杂环、5-15元杂芳基;或R4和R5与其之间的介入碳原子一起形成C5-C6环烷基环;
R6和R10独立地为氢或卤基;
R8为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基或5-15元杂芳基;
R11各自独立地为C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基或C6-C10芳基;
R13、R14、R16和R17独立地为氢、卤基、C1-C6烷基、C2-C6烯基、C2-C6炔基或C1-C6烷氧基;
其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、烷氧基和醚基团任选地经取代。
2.根据权利要求1所述的化合物,其具有下式:
3.根据权利要求2所述的化合物,其中R1为非氢取代基,R2和R3为氢且R4为氢或卤基或R4与R5一起形成5元环烷基。
4.根据权利要求3所述的化合物,其中R4为氢。
5.根据权利要求3所述的化合物,其中R4为卤基。
6.根据权利要求3所述的化合物,其中R4为氟基。
7.根据权利要求3所述的化合物,其中R1为NR21R22,其中R21和R22根据权利要求1所定义。
8.根据权利要求1所述的化合物,其具有下式:
9.根据权利要求1所述的化合物,其具有下式:
10.根据权利要求1所述的化合物,其具有下式:
11.根据权利要求1所述的化合物,其具有下式:
12.根据权利要求1所述的化合物,其具有下式:
13.根据权利要求8所述的化合物,其中R8为氢。
14.根据权利要求8所述的化合物,其中R8为C1-C6烷基、C2-C6烯基或C2-C6炔基。
15.根据权利要求8所述的化合物,其中R9为任选地经取代的C1-C6烷基。
16.根据权利要求9所述的化合物,其中R7为任选地经取代的C1-C6烷基。
17.根据权利要求10所述的化合物,其中R12为任选地经取代的C1-C6烷基。
18.根据权利要求11所述的化合物,其中R15为任选地经取代的C1-C6烷基。
19.根据权利要求3所述的化合物,其中R5为非氢取代基。
20.根据权利要求3所述的化合物,其中R1为非氢取代基;R2和R3为氢,且R4为氢或卤基,且R5为任选地经取代的C1-C6烷基。
21.一种医药组合物,其包含根据权利要求1到20中任一权利要求所述的化合物和至少一种药学上可接受的赋形剂。
22.一种治疗癌症的方法,其包含向有需要的患者投与治疗有效量的根据权利要求1到20中任一权利要求所述的化合物或治疗有效量的根据权利要求21所述的组合物。
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2021120717A1 (zh) | 2019-12-20 | 2021-06-24 | 深圳艾欣达伟医药科技有限公司 | 抗癌化合物及其医药用途 |
WO2022052564A1 (zh) | 2019-12-20 | 2022-03-17 | 深圳艾欣达伟医药科技有限公司 | 乏氧活化的dna烷化剂及其医药用途 |
TWI833055B (zh) * | 2019-12-20 | 2024-02-21 | 大陸商深圳艾欣達偉醫藥科技有限公司 | 抗癌化合物及其醫藥用途 |
TWI837402B (zh) | 2019-12-20 | 2024-04-01 | 大陸商深圳艾欣達偉醫藥科技有限公司 | 含氟化合物、含氟化合物之製備方法及其抗癌醫藥用途 |
CN114106042A (zh) * | 2021-11-12 | 2022-03-01 | 深圳艾欣达伟医药科技有限公司 | 一种氘代化合物及其制备方法和应用 |
WO2023082354A1 (zh) | 2021-11-12 | 2023-05-19 | 深圳艾欣达伟医药科技有限公司 | 一种氘代化合物及其制备方法和应用 |
WO2023174319A1 (zh) * | 2022-03-15 | 2023-09-21 | 深圳艾欣达伟医药科技有限公司 | 治疗brca突变癌症患者的方法 |
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EP3313385A4 (en) | 2019-01-23 |
EP3313385B1 (en) | 2021-03-03 |
JP7327900B2 (ja) | 2023-08-16 |
AU2021229128A1 (en) | 2021-09-30 |
EP3313385B8 (en) | 2021-04-21 |
US10668047B2 (en) | 2020-06-02 |
CN108024974B (zh) | 2023-11-14 |
US20180169064A1 (en) | 2018-06-21 |
US20200085786A1 (en) | 2020-03-19 |
AU2016282785A1 (en) | 2018-02-15 |
JP2023089109A (ja) | 2023-06-27 |
TW201713646A (zh) | 2017-04-16 |
EP3313385A1 (en) | 2018-05-02 |
JP7317059B2 (ja) | 2023-07-28 |
AU2021229128B2 (en) | 2023-08-17 |
ES2872533T3 (es) | 2021-11-02 |
CA2990665A1 (en) | 2016-12-29 |
TWI772263B (zh) | 2022-08-01 |
JP2018527301A (ja) | 2018-09-20 |
JP2021091722A (ja) | 2021-06-17 |
WO2016210175A1 (en) | 2016-12-29 |
EP3854798A1 (en) | 2021-07-28 |
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