CN103596955A - Hsp90抑制剂 - Google Patents
Hsp90抑制剂 Download PDFInfo
- Publication number
- CN103596955A CN103596955A CN201280027360.XA CN201280027360A CN103596955A CN 103596955 A CN103596955 A CN 103596955A CN 201280027360 A CN201280027360 A CN 201280027360A CN 103596955 A CN103596955 A CN 103596955A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- pharmaceutically acceptable
- compound
- acceptable salt
- hsp90
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
本发明涉及式(1)化合物和其医药上可接受的盐,其中(a)Z1、Z2和Z3各自独立地为CH或N;(b)Y是S;(c)Xa和Xb是O;(d)Xc是-CH2-;(e)X2是-NR1R2,其中R1和R2各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、烷基芳基、芳基烷基、烷基杂芳基、杂芳基烷基或烷基杂芳基烷基;(f)X4是氢或卤素;且(g)R是R10-NH-R11,其中R10是亚乙基或亚丙基,且R11是具支链烷基。本发明还涉及包含有效量的式(1)化合物或其医药上可接受的盐的组合物,以及治疗或预防病况(例如过表达Her激酶的癌症)的方法,所述方法包含向有需要的患者投与治疗有效量的式(1)化合物或其医药上可接受的盐。
Description
相关申请案交叉参考
本申请案主张2011年4月5日提出申请的美国临时申请案第61/472,061号的权益和优先权,所述申请案的内容以引用的方式并入本文中。
技术领域
本申请案涉及抑制热激蛋白90(Hsp90)的化合物。
背景技术
Hsp90蛋白质家族在哺乳动物细胞中具有四个经识别的成员:Hsp90α和Hsp90β、Grp94和Trap-1。Hsp90α和Hsp90β与诸多其它蛋白质结合存在于胞质溶胶和细胞核中。呈多种形式的Hsp90是最丰富的细胞伴侣蛋白,且已在实验系统中显示为变性的或“解折叠的”蛋白质的ATP依赖性再折叠所需要。因此,已提出其作为对抗应激的细胞防御的一部分。当细胞暴露于热或其它环境应激时,催化解折叠的蛋白质再折叠或降解的路径阻止解折叠的蛋白质聚集。此过程依赖于解折叠的蛋白质以有序方式与多种伴侣蛋白(Hsp60、Hsp90、Hsp70和p23)的结合,从而形成“再折叠体(refoldosome)”且最终从再折叠蛋白质ATP依赖性地释放伴侣蛋白。
Hsp90还可在保持突变蛋白的稳定性和功能中起作用。突变p53和v-src的表达似乎比其野生型对应物的表达的需要程度更高。已表明,这是由Hsp90介导的对导致蛋白质解折叠的突变表型的抑制所致。
Hsp90还为若干种与细胞对细胞外因素的生长反应有关的重要蛋白质的构象成熟所需要。这些包括类固醇受体以及某些激酶(即,Raf丝氨酸激酶、v-src和Her2)。Hsp90影响这些蛋白质的机制尚未完全了解,但似乎与其在蛋白质再折叠中的作用类似。在孕酮受体的情况下,已显示,Hsp90与受体的结合和从受体的释放以循环方式与其它伴侣蛋白和亲免素的释放一致发生且为类固醇与受体的高亲和力结合所需要。因此,Hsp90甚至可在不存在应激下作为信号传导路径的生理学调节剂。
已显示Hsp90在多种肿瘤类型中过表达且随致癌性转化而变化。尚未知其是否在保持转化中起必需作用,但其在此方面具有至少三种功能。癌细胞在低氧、低pH和低营养物浓度的环境中生长。它们还快速地适应辐射和细胞毒性化学治疗剂或经选择变得对辐射和细胞毒性化学治疗剂具有抗性。因此,Hsp90在保持蛋白质在应激下的稳定性中的通常作用对于细胞在这些条件下的存活性可为必需的。第二,癌细胞含有突变的致癌蛋白质。这些中的一些是为经转化表型所需要的功能获得型(gain-of-function)突变。Hsp90可为这些蛋白质的折叠的功能活性构象的保持所需要。第三,由类固醇受体、Raf和其它Hsp90靶标介导的信号传导路径的激活对于许多肿瘤的生长和存活是必需的,因此所述肿瘤很可能也需要功能Hsp90。
Hsp90已经识别为治疗剂的可行靶标。Hsp90家族成员在其N端区中具有独特的袋,所述袋对Hsp90来说具有特异性且在从细菌到哺乳动物在内的所有Hsp90中保守,但其不存在于其它分子伴侣蛋白中。此袋的内源性配体未知,但其以低亲和力结合ATP和ADP且具有弱ATP酶活性。已显示,安沙霉素(ansamycin)抗生素格尔德霉素(geldanamycin)(GM)和除莠霉素(herbimycin)(HA)结合此保守袋,且已显示此结合亲和性针对Hsp90家族的所有成员。国际专利公开案第WO98/51702号揭示安沙霉素抗生素的用途,其偶合到靶标部分以提供安沙霉素的靶向递送,从而导致靶标细胞中的蛋白质降解和靶标细胞死亡。国际专利公开案第WO00/61578号涉及具有两个与伴侣蛋白Hsp90相互作用的部分的双功能分子,尤其包括安沙霉素抗生素的同二聚体和异二聚体。这些双功能分子用以促进HER家族酪氨酸激酶的降解和/或抑制且有效地治疗过表达Her激酶的癌症。
结合与ATP和安沙霉素抗生素相同的Hsp90结合袋的实例性小分子治疗剂揭示于PCT公开案第WO02/36075号、第WO2006/084030号、第WO2009/042646号、第WO2009/065035号和第WO2011/044394号;美国专利第7,834,181号;和美国专利公开案第2005/0113339号、第2005/0004026号、第2005/0049263号、第2005/0256183号、第2005/0119292号、第2005/0113340号、第2005/0107343号、第2008/0096903号、第2008/0234297号、第2008/0234314号、第2008/0253865号和第2009/0298857号中,所有案件均以引用的方式并入本文中。
具体来说,结合相同的Hsp90结合袋的某些小分子治疗剂可由以下一般结构式描述,其中Z1、Z2和Z3选自CH和N:
尽管这些化合物可作为Hsp90的抑制剂,但其活性水平变化极大,据报道,所测量的EC50和IC50值大概在微摩尔到毫微摩尔的范围内。
发明内容
在本发明的一个方面中,描述抑制Hsp90的新颖化合物。
一种式(1)化合物,
或其医药上可接受的盐,其中:
(a)Z1、Z2和Z3各自独立地为CH或N;
(b)Y是S;
(c)Xa和Xb是O;
(d)Xc是-CH2-;
(e)X2是-NR1R2,其中R1和R2各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、烷基芳基、芳基烷基、烷基杂芳基、杂芳基烷基或烷基杂芳基烷基;
(f)X4是氢或卤素;且
(g)R是R10-NH-R11,其中R10是亚乙基或亚丙基,且R11是具支链烷基。
所述化合物可借助其作为Hsp90抑制剂的活性用于治疗癌症和神经变性疾病的医药组合物中,且可用于治疗癌症或神经变性疾病的方法中。
附图说明
具体实施方式
本发明包括以下各项:
(1)式(1)化合物:
或其医药上可接受的盐,其中:
(a)Z1、Z2和Z3各自独立地为CH或N;
(b)Y是S;
(c)Xa和Xb是O;
(d)X係-CH2-;
(e)X2是-NR1R2,其中R1和R2各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、烷基芳基、芳基烷基、烷基杂芳基、杂芳基烷基或烷基杂芳基烷基,或其质子化形式;
(f)X4是氢或卤素;且
(g)R是R10-NH-R11,其中R10是亚乙基或亚丙基,且R11是具支链烷基。
(2)(1)的化合物,其中Z1、Z2和Z3全部为N,如式(2)中所示
或其医药上可接受的盐。
(3)(1)或(2)的化合物或其医药上可接受的盐,其中R11是新戊基、异丙基或叔丁基。
(4)以上(1)到(3)中的一者的化合物或其医药上可接受的盐,其中X2是二甲基胺。
(5)一种医药组合物,其包含以上(1)到(5)中的一者中的化合物或其医药上可接受的盐以及医药上可接受的载剂。
(6)一种治疗或预防癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的以上(1)到(5)中的一者中的化合物或其医药上可接受的盐。
(7)一种以上(1)到(5)中的一者中的化合物或其医药上可接受的盐的用途,其用于调配用以治疗或预防癌症或神经变性病症的医药组合物。
(8)一种抑制Hsp90的方法,其包含使Hsp90与Hsp90功能抑制量的以上(1)到(5)中的一者中的化合物或其医药上可接受的盐接触。
(9)一种以上(1)到(5)中的一者中的化合物或其医药上可接受的盐的用途,其用于调配用以抑制Hsp90的医药组合物。
如上文所述,本发明涵盖式(1)化合物:
或其医药上可接受的盐,其中:
(a)Z1、Z2和Z3各自独立地为CH或N;
(b)Y是S;
(c)Xa和Xb是O;
(d)Xc是-CH2-;
(e)X2是-NR1R2,其中R1和R2各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、环烷基、杂烷基、杂环烷基、芳基、杂芳基、烷基芳基、芳基烷基、烷基杂芳基、杂芳基烷基或烷基杂芳基烷基,或其质子化形式;
(f)X4是氢或卤素;且
(g)R是R10-NH-R11,其中R10是亚乙基或亚丙基,且R11是具支链烷基。
定义
如结合本发明所使用,本文中所用的术语具有以下含义:
除非另外特别说明,否则术语“烷基”和“经取代烷基”可互换,且是指经取代和未经取代的C1-C10直链饱和脂肪族烃基,即,具有1、2、3、4、5、6、7、8、9或10个碳原子的基团,以及经取代和未经取代的C3-C10具支链饱和脂肪族烃基,即,具有3、4、5、6、7、8、9或10个碳原子的基团。例如,“烷基”包括但不限于:甲基(Me)、乙基(Et)、丙基(Pr)、异丙基、丁基(Bu)、叔丁基、戊基、己基、庚基、辛基、壬基、癸基等。在一个实施例中,烷基是C1-C6烷基,即,具有1、2、3、4、5或6个碳原子的基团。烷基可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。经取代C1-C6烷基的例示性实例包括-CH2OH、-CF2OH、-CH2C(CH3)2C(O)OCH3、-CF3、-C(O)CF3、-C(O)CH3、-(CH2)4SCH3、-CH(C(O)OH)CH2CH2C(O)N(CH3)2、-(CH2)5NHC(O)NH2、-CH2CH2-(4-氟苯基)、-CH(OCH3)CH2CH3、-CH2SO2NH2和-CH(CH3)CH2CH2OC(O)CH3。术语“具支链烷基”涵盖为借助非末端碳原子附接的线性烷基的烷基以及包括界定分支点的烷基。因此,具支链烷基的例示性实例包括异丙基、异丁基、仲丁基、叔丁基、异戊基、仲戊基、叔戊基和新戊基。除非另外特别说明,否则术语“烯基”和“经取代烯基”可互换,且是指具有1、2或3个碳碳双键的经取代和未经取代的C2-C10直链脂肪族烃基,即,具有1、2、3、4、5、6、7、8、9或10个碳原子的基团,以及具有1、2或3个碳碳双键的经取代和未经取代的C3-C10具支链脂肪族烃基,即,具有3、4、5、6、7、8、9或10个碳原子的基团。例如,“烯基”包括但不限于:乙烯基、1-丙-1-烯基、1-丙-2-烯基、2-丙-1-烯基、1-丁-3-烯基、2-戊-2-烯基、1-己-6-烯基、1-庚-7-烯基、1-辛-8-烯基等。在一个实施例中,烯基是C2-C6烯基,即,具有2、3、4、5或6个碳原子和1或2个碳碳双键的基团。烯基可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。经取代C2-C6烯基的例示性实例包括-C(H)=CHCH2OH、-C(H)=CF2、-CH2C(H)=CH(CH2)2CF2OH、-CH2C(=CH2)C(O)OCH3、-C(H)=CHCF3、-CH2CH2C(H)=CHC(O)CH3、-C(H)=C(CH3)SCH3、-C(H)=CHC(H)=C(CH3)C(O)OCH3和-C(H)=C=CHOC(O)CH3。
除非另外特别说明,否则术语“炔基”和“经取代炔基”可互换,且是指具有1、2或3个碳碳三键的经取代和未经取代的C2-C10直链脂肪族烃基,即,具有1、2、3、4、5、6、7、8、9或10个碳原子的基团,以及具有1、2或3个碳碳三键的经取代和未经取代的C3-C10具支链脂肪族烃基,即,具有3、4、5、6、7、8、9或10个碳原子的基团。例如,“炔基”包括但不限于:乙炔基、1-丙-1-炔基、1-丙-2-炔基、2-丙-1-炔基、3-丙-1-炔基、1-丁-3-炔基、2-戊-2-炔基、1-己-6-炔基、1-庚-7-炔基、1-辛-8炔基等。在一个实施例中,炔基是C2-C6炔基,即,具有2、3、4、5或6个碳原子和1或2个碳碳三键的基团。炔基可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。经取代C2-C6炔基的例示性实例包括-C≡CCH2OH、-C≡CF、-CH2C≡C(CH2)2CF2OH、-C≡CCH2C(O)OCH3、-CH2C≡CCF3、-CH2CH2C≡CC(O)CH3、-C≡CSCH3和-C≡CC(O)OC(O)CH3。
除非另外特别说明,否则术语“环烷基”和“经取代环烷基”可互换,且是指单环状或多环状碳环,其中各环含有3、4、5、6、7、8、9或10个碳原子,且其中任一环可含有1、2或3个碳碳双键或三键。例如,“环烷基”包括但不限于:环丙基、环丁基、环戊基、环己基、环烯基、环炔基和环庚基。环烷基可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。
除非另外特别说明,否则术语“芳基”和“经取代芳基”可互换,且是指在任一能够形成稳定共价键的环位置处共价附接的单环状、多环状、联芳芳香族基团,某些优选附接点已为所属领域的技术人员所明了(例如,3-苯基、4-萘基等)。芳基可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。“芳基”的定义包括但不限于杂芳基。芳基的例示性实例包括苯基、联苯、萘基、二氢萘基、四氢萘基、茚基、茚满基、薁基、蒽基(anthryl)、菲基、芴基、芘基、蒽基(anthracenyl)、吡啶基、嘧啶基、哒嗪基、噻二唑基等。
术语“杂烷基”是指存在的一个或一个以上碳原子或氢原子独立地经氮、氧、硫或卤素杂原子替代的烷基。如果杂原子不具有与其替代的碳原子相同数量的化合价位点(valence site),那么键结到替代杂原子的氢的数量可能需要增加或减少以匹配杂原子的化合价位点的数量。例如,如果碳原子(四价)由氮原子(三价)替代,那么除去先前附接到被替代碳的氢原子中的一个氢原子。同样,如果碳原子由卤素原子(一价)替代,那么除去先前附接到被替代碳的氢原子中的三个氢原子。术语“杂烷基”还指(1)至少一个氢原子附接到碳的烷基或(2)至少一个氢原子附接到杂烷基的杂原子的杂烷基可经以下中的至少一者取代:烷基、芳基和杂烷基。
除非另外特别说明,否则术语“杂芳基”和“经取代杂芳基”可互换,且除非另外特别说明,否则术语“杂环”和“经取代杂环”可互换,且这些术语是指具有单个环或多个稠合环、环内具有1到8个碳原子和1到4个杂原子、各杂原子独立地选自氮、硫或氧的单价不饱和基团。在杂芳基或杂环中,与分子的附接点可在环内的杂原子或其它地方。杂芳基或杂环可经1、2或3个取代基取代或任选地经1、2或3个取代基取代。
杂芳基的例示性实例包括噻吩基、苯并噻吩基、异苯并噻吩基、2,3-二氢苯并噻吩基、呋喃基、吡喃基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、吡咯基、吡咯-3-基、吡咯-1-基、吲哚基、异吲哚基、3H-吲哚基、二氢吲哚基、吲嗪基、吲唑基、咪唑基、咪唑-4-基、2H-咪唑啉基、苯并咪唑基、吡啶基、吡嗪基、哒嗪基(pyradazinyl)、嘧啶基、嘧啶-2-基、三嗪基、喹啉基、异喹啉基、4H-喹嗪基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、1,8-萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、色满基、苯并间二氧杂环戊烯基、胡椒基、嘌呤基、吡唑基、吡唑-3-基、三唑基、1,2,4-三唑-1-基、四唑基、四唑-1-基、噻唑基、噻唑-4-基、异噻唑基、苯并噻唑基、噁唑基、噁唑-2-基、异噁唑基、异噁唑-3-基、苯并噁唑基、噁二唑基、1,2,4-噁二唑-3-基、噻二唑基、哒嗪-4-基、吡嗪-2-基、噻吩-2-基、呋喃-2-基、吡啶-2-基、吡啶-4-基、嘧啶-2-基等。
当任一基团经1、2或3个取代基取代或任选地经1、2或3个取代基取代时,各取代基独立地选自包含以下基团的群组:卤基、-OH、-SH、-CN、-NO2、-NH2、三卤基甲基、五卤基乙基、C1-C10烷基、芳基C0-C10烷基、C0-C10烷氧基C0-C10烷基、芳基C0-C10烷氧基C0-C10烷基、C0-C10烷基硫基C0-C10烷基、芳基C0-C10烷基硫基C0-C10烷基、C0-C10烷基氨基C0-C10烷基、芳基C0-C10烷基氨基C0-C10烷基、N-芳基-N-C0-C10烷基氨基C0-C10烷基、C1-C10烷基羰基C0-C10烷基、芳基C1-C10烷基羰基C0-C10烷基、C1-C10烷基羧基C0-C10烷基、芳基C1-C10烷基羧基C0-C10烷基、C1-C10烷基羰基氨基C0-C10烷基、芳基C1-C10烷基羰基氨基C0-C10烷基、-C0-C10烷基C(O)ORX和-C0-C10烷基C(O)NRYRZ,其中RX、RY和RZ独立地选自氢、烷基和芳基,或RY和RZ连同其所附接的氮一起形成具有3、4、5、6、7或8个碳原子与至少一个如上文所定义的取代基的饱和环状或不饱和环状系统。“C0烷基”在C0-C10烷基中是共价键。
术语“C0-C10烷氧基”是指具有指定数目的碳原子且借助氧原子附接到分子的烷基。在一个实施例中,C0-C10烷氧基是C1-C6烷氧基,即,具有1、2、3、4、5或6个碳原子的基团。烷氧基的例示性实例包括甲氧基、乙氧基、正丙氧基和异丙氧基。因此,术语“C0-C10烷氧基C0-C10烷基”是指借助氧原子附接到C0-C10烷基的C0-C10烷氧基,所述C0-C10烷基附接到分子。同样,术语“芳基C0-C10烷氧基C0-C10烷基”是指借助氧原子附接到C0-C10烷基的经芳基取代的C0-C10烷氧基,所述C0-C10烷基附接到分子。“C0烷氧基”是-OH。
术语“C0-C10烷基硫基”是指具有指定数目的碳原子且借助硫原子附接到分子的烷基。在一个实施例中,C0-C10烷基硫基是C1-C6烷基硫基,即,具有1、2、3、4、5或6个碳原子的基团。烷氧基的例示性实例包括甲基硫基、乙基硫基、正丙基硫基和异丙基硫基。因此,术语“C0-C10烷基硫基C0-C10烷基”是指借助硫原子附接到C0-C10烷基的C0-C10烷基硫基,所述C0-C10烷基附接到分子。同样,术语“芳基C0-C10烷基硫基C0-C10烷基”是指借助硫原子附接到C0-C10烷基的经芳基取代的C0-C10烷基硫基,所述C0-C10烷基附接到分子。“C0烷基硫基”是-SH。
术语“C1-C10烷基羰基”是指具有指定数目的碳原子且借助羰基的碳原子附接到分子的烷基。在一个实施例中,C1-C10烷基羰基是C1-C6烷基羰基,即,具有1、2、3、4、5或6个碳原子且包括羰基碳原子的基团。因此,术语“C1-C10烷基羰基C0-C10烷基”是指借助羰基的碳原子附接到C0-C10烷基的C1-C10烷基羰基,所述C0-C10烷基附接到分子。同样,术语“芳基C1-C10烷基羰基C0-C10烷基”是指借助羰基的碳原子附接到C0-C10烷基的经芳基取代的C1-C10烷基羰基,所述C0-C10烷基附接到分子。
术语“C1-C10烷基羧基”是指具有指定数目的碳原子(包括羧基的碳原子)且借助羧基附接到分子的烷基,其中羧基具有-C(=O)-O-或-O-C(=O)-定向。在一个实施例中,C1-C10烷基羧基是C1-C6烷基羧基,即,具有2、3、4、5或6个碳原子且包括羧基碳原子的基团。因此,术语“C1-C10烷基羧基C0-C10烷基”是指借助羧基附接到C0-C10烷基的C1-C10烷基羧基,所述C0-C10烷基附接到分子。同样,术语“芳基C1-C10烷基羧基C0-C10烷基”是指借助羧基附接到C0-C10烷基的经芳基取代的C1-C10烷基羧基,所述C0-C10烷基附接到分子。
术语“C0-C10烷基氨基”是指具有指定数目的碳原子且借助氨基-N(RW)-的氮原子附接到分子的烷基,其中RW是H、C1-C6烷基或芳基。“C0烷基氨基”是-NHRW。在一个实施例中,C0-C10烷基氨基是C1-C6烷基氨基,即,在烷基中具有1、2、3、4、5或6个碳原子且在RW基团中具有0、1、2、3、4、5或6个碳原子的基团。因此,术语“C0-C10烷基氨基C0-C10烷基”是指借助氨基的氮原子附接到C0-C10烷基的C0-C10烷基氨基,所述C0-C10烷基附接到分子。同样,术语“芳基C0-C10烷基氨基C0-C10烷基”是指借助氨基的氮原子附接到C0-C10烷基的经芳基取代的C0-C10烷基氨基,所述C0-C10烷基附接到分子。术语“N-芳基-N-C0-C10烷基氨基C0-C10烷基”是指经芳基和C0-C10烷基取代的胺氮原子,所述氮原子进一步附接到C0-C10烷基,所述C0-C10烷基附接到分子。
术语“C1-C10烷基羰基氨基”是指具有指定数目的碳原子(包括羰基氨基(即,酰胺)的碳原子)且借助酰胺基团附接到分子的烷基,其中酰胺基团具有-C(=O)N(RV)-或-N(RV)C(=O)-定向且其中RV是H或C1-C6烷基。在一个实施例中,C1-C10烷基羰基氨基是C1-C6烷基羰基氨基,即,在烷基中具有2、3、4、5或6个碳原子(包括酰胺的碳原子)且在RV基团中具有0、1、2、3、4、5或6个碳原子的基团。因此,术语“C1-C10烷基羰基氨基C0-C10烷基”是指借助酰胺基团附接到C0-C10烷基的C1-C10烷基羰基氨基,所述C0-C10烷基附接到分子。同样,术语“芳基C1-C10烷基羰基氨基C0-C10烷基”是指借助酰胺基团附接到C0-C10烷基的经芳基取代的C1-C10烷基羰基氨基,所述C0-C10烷基附接到分子。
术语“烷基芳基”是指经1、2或3个如上文所定义的烷基取代的如上文所定义的芳基;甲苯基是实例性烷基芳基。在一个实施例中,烷基芳基是具有1、2或3个附接到芳基的烷基的“较低碳数烷基芳基”,各烷基独立地具有1、2、3、4、5或6个碳原子。
术语“芳基烷基”是指经1、2或3个如上文所定义的芳基取代的如上文所定义的烷基;苄基是实例性芳基烷基。在一个实施例中,芳基烷基是具有1、2或3个附接到烷基的芳基的“较低碳数芳基烷基”,所述烷基具有1、2、3、4、5或6个碳原子。
术语“杂环烷基”是指经1、2或3个如上文所定义的杂环基团取代的如上文所定义的烷基。在一个实施例中,杂环烷基是具有1、2或3个附接到烷基的杂环基团的“较低碳数杂环烷基”,所述烷基具有1、2、3、4、5或6个碳原子。
术语“烷基杂芳基”是指经1、2或3个如上文所定义的烷基取代的如上文所定义的杂芳基。在一个实施例中,烷基杂芳基是具有1、2或3个附接到杂芳基的烷基的“较低碳数烷基杂芳基”,各烷基独立地具有1、2、3、4、5或6个碳原子。
术语“杂芳基烷基”是指经1、2或3个如上文所定义的杂芳基取代的如上文所定义的烷基。在一个实施例中,杂芳基烷基是具有1、2或3个附接到烷基的杂芳基的“较低碳数杂芳基烷基”,所述烷基具有1、2、3、4、5或6个碳原子。
术语“烷基杂芳基烷基”是指经1、2或3个如上文所定义的烷基取代的如上文所定义的杂芳基烷基。在一个实施例中,烷基杂芳基烷基是“较低碳数烷基杂芳基烷基”,其中各烷基部分独立地具有1、2、3、4、5或6个碳原子。
术语“卤素”和“卤基”是指氟、氯、溴和碘。
对于所绘示的化学结构与化学名称的一致性具有疑问时,应以所绘示的化学结构为准。
术语“医药上可接受的盐”是指保留“游离”式(1)化合物的生物效力和性质的盐。医药上可接受的盐可从式(1)化合物的游离碱与无机酸(例如,盐酸、氢溴酸、硫酸、硝酸、磷酸等)或有机酸(例如,磺酸、羧酸、有机磷酸、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、富马酸、马来酸、琥珀酸、苯甲酸、水杨酸、乳酸、酒石酸(例如,(+)-酒石酸或(-)-酒石酸或其混合物)等)的反应获得。某些式(1)化合物具有酸性取代基且可作为与医药上可接受的碱的医药上可接受的盐存在。本发明包括所述盐。所述盐的实例包括金属抗衡离子盐,例如钠、钾、锂、镁、钙、铁、铜、锌、锡、银或铝盐,以及有机胺盐,例如甲基胺、二甲基胺、三甲基胺、二乙基胺、三乙基胺、正丙基胺、2-丙基胺或二甲基异丙基胺盐等。术语“医药上可接受的盐”包括单盐和存在多种盐的化合物,例如二盐和/或三盐。医药上可接受的盐可通过所属领域的技术人员已知的方法来制备。
某些式(1)化合物和/或其医药上可接受的盐可以一种以上晶体形式存在,且本发明涵盖每一种晶体形式和其混合物。这些晶体形式可通过所属领域的技术人员已知的方法来制备。
术语“溶剂合物”是指由一个或一个以上溶质分子(例如,式(1)化合物或其医药上可接受的盐)与一个或一个以上溶剂分子(其以化学计量或非化学计量量存在)形成的复合物或聚集体。适宜的溶剂包括但不限于水、乙酸、乙醇、甲醇、异丙醇和正丙醇。在溶剂是水的情况下,溶剂合物是水合物。实例性水合物包括但不限于半水合物、一水合物、二水合物、三水合物和四水合物。在一个实施例中,溶剂是医药上可接受的。在另一实施例中,复合物或聚集体呈结晶形式。在另一实施例中,复合物或聚集体呈非结晶形式。本发明涵盖每一种溶剂合物和其混合物。这些溶剂合物可通过所属领域的技术人员已知的方法来制备。
某些式(1)化合物可以不同互变异构形式或不同几何异构形式存在,且本发明包括式(1)化合物的每一种互变异构体和/或几何异构体和其混合物。
某些式(1)化合物可含有一个或一个以上手性中心且以不同光学活性形式存在,且本发明包括式(1)化合物的每一种光学活性形式和其混合物。当式(1)化合物含有一个手性中心时,化合物以两种对映异构形式存在,且本发明包括两种对映异构体和对映异构体的混合物,例如外消旋混合物。对映异构体可通过所属领域的技术人员已知的方法进行拆分,例如,通过形成非对映异构盐,所述盐可通过例如结晶或液相色谱加以分离。或者,可通过使用光学活性试剂、基质、催化剂或溶剂进行不对称合成或通过不对称转化将一种对映异构体转变成另一种对映异构体来合成具体的对映异构体。当式(1)化合物含有一个以上手性中心时,其可以非对映异构形式存在。非对映异构化合物可通过所属领域的技术人员已知的方法加以分离,例如,通过色谱或结晶,且个别对映异构体可如上文所述加以分离。本发明包括式(1)化合物的每一种非对映异构体和其混合物。
术语“同位素富集的”是指在构成式(1)化合物的一个或一个以上原子处含有非天然比例的同位素的化合物,且本发明包括式(1)化合物的每一种同位素富集形式和其混合物。在某些实施例中,同位素富集的化合物含有非天然比例的一种或一种以上同位素,包括但不限于氢(1H)、氘(2H)、氚(3H)、碳-11(11C)、碳-12(12C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-14(14N)、氮-15(15N)、氧-14(14O)、氧-15(15O)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、氟-18(18F)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-35(35S)、硫-36(36S)、氯-35(35Cl)、氯-36(36Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)、碘-123(123I)、碘-125(125I)、碘-127(127I)、碘-129(129I)和碘-131(131I)。在另一实施例中,同位素富集的化合物含有非天然比例的一种或一种以上同位素,包括但不限于1H、2H、12C、13C、14N、15N、16O、17O、18O、17F、32S、33S、34S、36S、35Cl、37Cl、79Br、81Br和127I。在另一实施例中,同位素富集的化合物是放射性的。在另一实施例中,同位素富集的化合物含有非天然比例的一种或一种以上同位素,包括但不限于3H、11C、4C、13N、14O、15O、18F、35S、36Cl、123I、125I、129I和131I。在另一实施例中,同位素富集的化合物含有非天然比例的123I、124I或131I以及选自3H、11C、4C、13N、14O、15O、18F、35S和36C1的另一种同位素。在另一实施例中,同位素富集的化合物含有非天然比例的123I、124I和/或131I。在另一实施例中,同位素富集的化合物含有非天然比例的123I。在另一实施例中,同位素富集的化合物含有非天然比例的124I。在另一实施例中,同位素富集的化合物含有非天然比例的131I。
术语“同位素富集的”是指在分子中的给定位置的元素的稀有同位素(例如,氢的氘)代替所述元素的常见同位素(例如,氢的1H)的掺入百分比。当将分子中特定位置的原子指定为特定的稀有同位素时,应了解,所述同位素在所述位置的丰度实质上大于其天然丰度。
术语“治疗有效量”是指式(1)化合物或两种或两种以上所述化合物的组合抑制(完全或部分)所治疗病况的进展或至少部分减轻所述病况的一种或一种以上症状的量。治疗有效量也可为预防有效量。治疗有效量取决于患者的性别和体格、所治疗的病况、病况的严重程度和所寻求的结果。对于给定患者,治疗有效量可通过所属领域的技术人员已知的方法来确定。
术语“患者”是指动物,包括(但不限于)哺乳动物、灵长类动物(例如,人类)、牛、猪、绵羊、山羊、马、狗、猫、兔、大鼠或小鼠。
术语“癌症”或“赘生性病症(neoplastic disorder)”是指由异常或不受控的细胞生长引起的肿瘤。癌症的实例包括但不限于乳癌、结肠癌、结肠直肠癌、前列腺癌、卵巢癌、胰腺癌、肺癌、胃癌、食管癌、胶质瘤和血液恶性肿瘤。赘生性病症的实例包括但不限于造血病症,例如骨髓增殖性病症、原发性血小板增多、血小板增多症、血管生成性髓样化生、真性红细胞增多症、骨髓纤维化、骨髓纤维化伴髓样化生、慢性特发性骨髓纤维化、血细胞减少和恶变前脊髓发育不良综合症。
术语“血液恶性肿瘤”是指骨髓和淋巴组织-身体的血液形成系统和免疫系统的癌症。血液恶性肿瘤的实例包括但不限于脊髓发育不良、淋巴瘤、白血病、淋巴瘤(非霍奇金氏淋巴瘤(non-Hodgkin′s lymphoma))、霍奇金氏病(Hodgkin′s disease)(也称为霍奇金氏淋巴瘤(Hodgkin′s lymphoma))和骨髓瘤,例如急性淋巴细胞白血病(ALL)、成人T细胞ALL、急性髓样白血病(AML)、三谱系脊髓发育不良相关性AML、急性早幼粒细胞白血病、急性未分化性白血病、间变性大细胞淋巴瘤、慢性淋巴细胞白血病、慢性髓样白血病、慢性嗜中性白细胞白血病、幼年型粒单核细胞白血病、混合谱系白血病、骨髓增殖性病症、脊髓发育不良综合症、多发性骨髓瘤和幼淋巴细胞白血病。
术语“白血病”是指血液形成组织的恶性肿瘤,包括但不限于急性淋巴母细胞白血病、急性髓样白血病、急性髓母细胞白血病、慢性淋巴细胞白血病和慢性粒细胞白血病。白血病可为复发性的、难治性的或对常用疗法有抗性。
术语“神经变性病症”是指在周围神经系统或中枢神经系统中发生神经元的进行性损失的病症。神经变性病症的实例包括但不限于慢性神经变性疾病,例如糖尿病性周围神经病变、阿兹海默氏症(Alzheimer′s disease)、皮克氏病(Pick′s disease)、弥漫性路易体病(diffuse Lewy body disease)、进行性核上麻痹(斯-理二氏综合症(Steel-Richardsonsyndrome))、多系统变性(夏伊-德雷格综合症(Shy-Drager syndrome))、运动神经元病,包括肌萎缩侧索硬化(“ALS”)、变性共济失调、皮质基底变性、关岛ALS-帕金森氏症-痴呆症候群(ALS-Parkinson′s-Dementia complex of Guam)、亚急性硬化性全脑炎、亨廷顿氏症(Huntington′s disease)、帕金森氏症(Parkinson′s disease)、多发性硬化、共核蛋白病、原发进行性失语、纹状体黑质变性、马查多-约瑟夫病(Machado-Joseph disease)/脊髓小脑共济失调3型和橄榄体脑桥小脑变性、日拉斯德拉图拉泰病(Gilles De La Tourette′sdisease)、延髓麻痹和假性延髓麻痹、脊髓性和脊髓延髓性肌萎缩(肯尼迪氏病(Kennedy′sdisease))、原发性侧索硬化、家族性痉挛性截瘫、威涅克-柯萨可夫相关性痴呆(Wernicke-Korsakoff′s related dementia)(酒精诱发的痴呆)、韦尼印-霍夫曼病(Werdnig-Hoffmann disease)、库格尔贝格-韦兰德病(Kugelberg-Welander disease)、泰萨二氏病(Tay-Sach′s disease)、桑德霍夫病(Sandhoff disease)、家族性痉挛性疾病、沃-库-韦三氏病(Wohifart-Kugelberg-Welander disease)、痉挛性轻截瘫、进行性多病灶脑白质病和朊病毒病(包括克雅二氏病(Creutzfeldt-Jakob)、格斯特曼-施特劳斯纳综合症(Gerstmann-Straussler-Scheinker disease)、库鲁病(Kuru)和致命性家族性失眠症(fatalfamilial insomnia))。其它还包括在本发明方法以内的病况包括老年痴呆和其它痴呆,以及具有记忆损失的病况,包括血管性痴呆、弥漫性白质病(宾斯旺格病(Binswanger′sdisease))、内分泌或代谢来源的痴呆、头损伤和弥漫性脑损害引起的痴呆、拳击员痴呆和额叶痴呆。还包括由以下疾病引起的其它神经变性病症:大脑缺血或梗塞,包括栓子性闭塞(embolic occlusion)和血栓性闭塞(thrombotic occlusion),以及任一类型的颅内出血(包括但不限于硬膜外、硬膜下、蛛网膜下和大脑内),以及颅内和脊柱内损伤(包括但不限于挫伤、穿刺、剪切、挤压和撕裂伤)。因此,术语“神经变性病症”还涵盖急性神经变性病症,例如与以下疾病有关的那些:中风、外伤性脑损伤、精神分裂症、周围神经损害、低血糖症、脊髓损伤、癫痫、缺养症和低氧症。
在某些实施例中,神经变性病症选自阿兹海默氏症、帕金森氏症、肌萎缩侧索硬化、年龄相关性记忆损失、衰老和老年痴呆。在另一实施例中,神经变性病症是阿兹海默氏症,也描述为淀粉样变性。因此,本发明的其它实施例涉及治疗或预防其它共享特征的淀粉样变性病症,包括(但不限于)遗传性大脑血管病、神经病变性遗传性淀粉样变性、唐氏综合症(Down′s syndrome)、巨球蛋白血症、继发性家族性地中海热(secondary familialMediterranean fever)、穆-韦二氏综合症(Muckle-Wells syndrome)、多发性骨髓瘤、胰腺和心脏相关性淀粉样变性、慢性血液透析关节病、芬兰型淀粉样变性(Finnish amyloidosis)和爱荷华型淀粉样变性(Iowa amyloidosis)。
术语“医药上可接受的载剂”是指医药上可接受的材料、组合物或媒剂,例如液体填充剂或固体填充剂、稀释剂、溶剂或囊封材料。在一个实施例中,各组份在以下意义上是“医药上可接受的”:与医药调配物的其它成份相容,且适用于与患者的组织或器官接触而不会产生过度毒性、刺激、过敏性反应、免疫原性或其它问题或并发症,与合理的效益/风险比相称。医药上可接受的载剂已为所属领域的技术人员已知;参见例如,医药处方设计前工作和调配(Pharmaceutical Preformulation and Formulation)(吉卜森(Gibson)编辑,第2版,CRC出版社(CRC Press),伯克莱屯(Boca Raton),佛罗里达州(FL),2009);医药添加剂手册(Handbook of Pharmaceutical Additives)(阿什(Ash)和阿什(Ash)编辑,第3版,高尔出版公司(Gower Publishing Co.),奥尔德肖特(Aldershot),英国,2007);雷明顿医药科学(Remington′s Pharmaceutical Sciences)(加那诺(Gennaro)编辑,第19版,迈克出版公司(Mack Publishing),伊斯顿(Easton),宾夕法尼亚州(PA),1995);和医药赋形剂手册(Handbook of Pharmaceutical Excipients)(美国药学协会(Amer.PharmaceuticalAss′n),华盛顿哥伦比亚特区(Washington,DC),1986)。
在另一实施例中,医药组合物是通过此项技术中已知的方法从式(1)化合物和医药上可接受的载剂形成。因此,另一实施例涉及包含式(1)化合物和医药上可接受的载剂的医药组合物。所述组合物可用于治疗或预防例如有需要的患者的癌症或神经变性病症。
另一实施例涉及治疗或预防癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的式(1)化合物。另一实施例涉及治疗或预防癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的包含式(1)化合物的医药组合物。另一实施例涉及治疗癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的式(1)化合物。另一实施例涉及治疗癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的包含式(1)化合物的医药组合物。另一实施例涉及预防癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的式(1)化合物。另一实施例涉及预防癌症或神经变性病症的方法,其包含向有需要的患者投与治疗有效量的包含式(1)化合物的医药组合物。另一实施例涉及式(1)化合物的用途,其用于制造可用于治疗癌症或神经变性病症或者预防癌症或神经变性病症的药物。
另一实施例涉及抑制Hsp90的方法,其包含使Hsp90与Hsp90功能抑制量的式(1)化合物接触。下文标题为“Hsp90结合分析”的实例中提供Hsp90功能抑制量的例示性测定。在一个实施例中,通过本文中提供的“Hsp90结合分析”测定的IC50小于10μM。在另一实施例中,通过本文中提供的“Hsp90结合分析”测定的IC50小于1μM。在另一实施例中,通过本文中提供的“Hsp90结合分析”测定的IC50≤0.1μM。另一实施例涉及式(1)化合物的用途,其用于调配用以抑制Hsp90的医药组合物。
给出以下实例以帮助理解本发明,且不应视为对如本文中所描述和主张的本发明的具体限制。在所属领域的技术人员所知的范围内的本发明的变化形式,包括现在已知的或以后发展的所有等效形式的取代,以及配方的变化或实验设计的变化视为并入本文中在本发明的范围以内。
4.实例
下文的某些实例涉及本发明例示性化合物的合成。
方案1.DZ4-132、DZ4-134、DZ4-135和相关化合物的合成
试剂和条件:(a)Ac2O、AcOH,室温;(b)ICl、CH2Cl2、AcOH,室温;(c)NaOH、EtOH、H2O,回流;(d)多聚甲醛、NaBH3CN、MeOH,50℃;(e)8-巯基腺嘌呤、新亚铜试剂、CuI、NaOtBu、DMF,115℃;(f)1,2-二溴乙烷/1,3-二溴丙烷或对应溴化物、Cs2CO3、DMF,室温;(g)胺、DMF,室温
N-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙酰胺(B):
向3,4-(亚甲基二氧基)苯胺(5.0g,36.5mmol)存于AcOH(75mL)中的溶液中添加乙酸酐(30mL)。将反应混合物在约25℃的温度下搅拌约16小时,随后倾倒到饱和NaHCO3溶液中并过滤。用乙酸乙酯萃取滤液,以定量产率提供B,其未经进一步纯化即使用。
1H NMR(500MHz,DMSO-d6,δ):9.82(s,1H),7.29(d,J=1.4Hz,1H),6.93(dd,J=8.3,1.4Hz,1H),6.83(d,J=8.3Hz,1H),5.97(s,2H),1.99(s,3H)。
MS(ESI):m/z=180.1[M+H]+。
N-(6-碘苯并[d][1,3]间二氧杂环戊烯-5-基)乙酰胺(C):
将一氯化碘存于二氯甲烷(46.5mL)中的1.0M溶液逐滴添加到B(6.4g,35.8mmol)存于二氯甲烷(42mL)和乙酸(7mL)中的溶液中。将反应混合物搅拌约16小时,随后用饱和硫代硫酸钠和盐水洗涤。二氯甲烷溶液经MgSO4干燥,过滤并在减压下浓缩以提供残留物,通过色谱(CH2Cl2:EtOAc,20:1)进行纯化以提供C(6.0g,55%产率)。
1H NMR(500MHz,DMSO-d6,δ):9.33(s,1H),7.37(s,1H),6.96(s,1H),6.07(s,2H),2.01(s,3H)。
MS(ESI):m/z=328.0[M+Na]+。
6-碘苯并[d][1,3]间二氧杂环戊烯-5-胺(D):
将C(3.2g,10.5mmol)和NaOH(21g,525mmol)存于乙醇(420mL)和水(96mL)中的溶液回流4h。冷却反应混合物并在减压下浓缩以提供残留物,将其分配于二氯甲烷与水之间。有机层用水洗涤,经MgSO4干燥,过滤并在减压下浓缩以提供残留物,通过色谱(己烷:CH2Cl2,7:3)进行纯化以提供D(2.1g,76%产率)。
1H NMR(500MHz,CDCl3,δ):7.05(s,1H),6.38(s,1H),5.87(s,2H),3.85(br s,2H)。
MS(ESI):m/z=264.0[M+H]+。
6-碘-N,N-二甲基苯并[d][1,3]间二氧杂环戊烯-5-胺(E):
向D(200mg,0.7604mmol)、多聚甲醛(228mg,7.604mmol)和分子筛(2g)存于二氯甲烷(4ml)和AcOH(0.435mL,7.604mmol)中的混合物中添加NaBH3CN。将混合物加热到50℃,保持2h。向反应混合物中添加水,并分离有机层,并且水性层进一步用二氯甲烷萃取数次。合并有机层并用盐水洗涤,经MgSO4干燥,过滤并在减压下浓缩以提供E(181mg,82%产率),其未经进一步纯化即使用。
1H NMR(500MHz,CDCl3,δ):7.25(s,1H),6.74(s,1H),5.95(s,2H),2.65(s,6H)。
MS(ESI):m/z=292.1[M+H]+。
8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9H-嘌呤-6-胺(F):
将8-巯基腺嘌呤(160mg,0.978mmol)、新亚铜试剂水合物(40.7mg,0.196mmol)、CuI(36.4mg,0.196mmol)、叔丁醇钠(0.184mg,1.91mmol)、E(370mg,1.27mmol)和DMF(4mL)的混合物在115℃下加热32h。在减压下移除溶剂,并通过制备型TLC(CH2Cl2:MeOH-NH3(7N),10:1)纯化残留物以提供F(123mg,39%产率)。
1H NMR(500MHz,CDCl3/MeOH-d4,δ):8.15(s,1H),6.86(s,1H),6.81(s,1H),5.97(s,2H),2.72(s,6H)。
MS(ESI):m/z=331.3[M+H]+。
9-(2-溴乙基)-8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9H-嘌呤-6-胺(G):
将存于DMF(0.6mL)中的F(29mg,0.0878mmol)、Cs2CO3(42.9mg,0.1317mmol)、1,2-二溴乙烷(82.5mg,37.8μL,0.439mmol)在约25℃的温度下搅拌1.5h。随后添加额外的Cs2CO3(14mg,0.043mmol),并将混合物再搅拌20min。将混合物在减压下干燥,并通过制备型TLC(CH2Cl2:MeOH:AcOH,15:1:0.5)纯化残留物以提供G(24mg,63%产率)。
1H NMR(500MHz,CDCl3/MeOH-d4,δ):8.24(s,1H),6.81(s,1H),6.68(s,1H),5.96(s,2H),4.62(t,J=6.9Hz,2H),3.68(t,J=6.9Hz,2H),2.70(s,6H)。
MS(ESI):m/z=437.2/439.1[M+H]+。
8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9-(2-(新戊基氨基)乙基)-9H-嘌呤-6-胺(DZ4-132):
将存于DMF(0.50mL)中的G(24mg,0.0549mmol)和新戊基胺(239mg,2.7mmol)在约25℃的温度下搅拌约16小时。在减压下移除溶剂,并通过制备型TLC(CH2Cl2:MeOH-NH3(7N),20:1)纯化所得残留物以提供20.6mg(85%产率)DZ4-132。
1H NMR(500MHz,CDCl3/MeOH-d4,δ):8.16(s,1H),6.73(s,1H),6.55(s,1H),5.88(s,2H),4.27(t,J=6.4Hz,2H),2.91(t,J=6.4Hz,2H),2.61(s,6H),2.28(s,2H),0.79(s,9H)。
13C NMR(125MHz,CDCl3/MeOH-d4,δ):154.8,152.9,151.8,149.4,149.2,148.7,145.2,120.0,118.7,111.6,102.9,102.3,62.4,50.1,45.7,44.1,31.9,28.1。
MS(ESI):m/z=444.3[M+H]+。
9-(3-溴丙基)-8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9H-嘌呤-6-胺(H):
将存于DMF(2mL)中的F(60mg,0.1818mmol)、Cs2CO3(88.8mg,0.2727mmol)、1,3-二溴丙烷(184mg,93μL,0.909mmol)在约25℃的温度下搅拌40min。将混合物在减压下干燥,并通过制备型TLC(CH2Cl2:MeOH:AcOH,15:1:0.5)纯化残留物以提供H(60mg,73%产率)。
1H NMR(500MHz,CDCl3,δ):8.26(s,1H),6.84(br s,2H),6.77(s,1H),6.50(s,1H),5.92(s,2H),4.35(t,J=7.0Hz,2H),3.37(t,J=6.6Hz,2H),2.68(s,6H),2.34(m,2H)。
MS(ESI):m/z=451.1/453.1[M+H]+。
8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9-(3-(异丙基氨基)丙基)-9H-嘌呤-6-胺(DZ4-134):
将存于DMF(1mL)中的H(30mg,0.0665mmol)和异丙基胺(196mg,283μL,3.3mmol)在约25℃的温度下搅拌约16小时。在减压下移除溶剂,并通过制备型TLC(CH2Cl2:MeOH-NH3(7N),20:1)纯化所得残留物以提供21.8mg(78%产率)DZ4-134。
1H NMR(500MHz,CDCl3,δ):8.24(s,1H),6.69(s,1H),6.39(s,1H),5.98(br s,2H),5.83(s,2H),4.23(t,J=6.9Hz,2H),2.68(septet,J=6.3Hz,1H),2.61(s,6H),2.48(t,J=6.8Hz,2H),1.95(m,2H),0.99(d,J=6.3Hz,6H)。
13C NMR(125MHz,CDCl3,δ):155.3,153.6,152.3,148.7,147.7,147.0,145.4,121.1,120.8,109.7,103.1,102.3,49.6,45.9,44.2,42.1,30.5,23.1。
MS(ESI):m/z=430.2[M+H]+。
9-(3-(叔丁基氨基)丙基)-8-(6-(二甲基氨基)苯并[d][1,3]间二氧杂环戊烯-5-基硫基)-9H-嘌呤-6-胺(DZ4-135):
将存于DMF(1mL)中的H(30mg,0.0665mmol)和叔丁基胺(243mg,350μL,3.3mmol)在约25℃的温度下搅拌约16小时。在减压下移除溶剂,并通过制备型TLC(CH2Cl2:MeOH-NH3(7N),20:1)纯化所得残留物以提供18.5mg(63%产率)DZ4-135。
1H NMR(500MHz,CDCl3,δ):8.25(s,1H),6.69(s,1H),6.40(s,1H),5.88(br s,2H),5.83(s,2H),4.23(t,J=7.0Hz,2H),2.62(s,6H),2.43(t,J=6.8Hz,2H),1.91(m,2H),0.98(s,9H)。
MS(ESI):m/z=444.2[M+H]+。
Hsp90结合分析:
对于结合研究,如先前所报道类似地实施荧光偏振(FP)分析[杜(Du)等人(2007)“肿瘤特异性Hsp90的高通量筛选荧光偏振分析(High-throughput screening fluorescencepolarization assay for tumor-specific Hsp90)”,生物分子筛选杂志(J.Biomol.Screen)12:915-924]。简单来说,在分析家(Analyst)GT仪器(分子装置(Molecular Devices),桑尼维尔(Sunnyvale),加利福尼亚州(CA))上实施FP测量。在黑色96孔微量滴定板(康宁(Corning)编号3650)中实施测量,其中激发和发射二者均从孔的顶部发生。在DMSO中制备10μM cy3B-GM的储备溶液,并用HFB缓冲液(20mM Hepes(K),pH7.3,50mMKCl、2mM DTT、5mM MgCl2、20mM Na2MoO4和0.01%NP40,含有0.1mg/mL BGG)稀释。将测试化合物溶解于DMSO中,并以若干个浓度添加到含有6nM cy3B-GM和转基因小鼠脑溶解产物(6μg JNPL3溶解产物)或人类癌细胞溶解产物(3μg SKBr3溶解产物)的HFB分析缓冲液中,最终体积为100μL。将药物添加到三个相同的孔中。在各板中包括仅含有游离的cy3B-GM(6nM cy3B-GM)、结合的cy3B-GM(6nM cy3B-GM+溶解产物,如上文所指示)和缓冲液的孔(背景)作为对照。将板在振荡器上在4℃下培育,并在24h时测量偏振值。如下计算抑制百分比:(对照%)=100-((mPc-mPf)/(mPb-mPf))×100,其中mPc是从化合物孔记录的mP,mPf是从仅含有cy3B-GM的孔记录的mP的平均值,且mPb是从含有cy3B-GM和溶解产物的孔记录的mP的平均值,并相对于竞争剂的浓度值绘制曲线。通过使用非线性回归分析如Prism4.0(GraphPad软件)中所执行拟合数据,获得50%的结合的cy3B-GM被替换时抑制剂的浓度。
在这些分析中,对于C50,使用以下简化的Hsp90结合等级:I≥10μM;10μM>II>1μM;1μM>III>0.1μM;IV≤0.1μM。如所示,各测试化合物显示小于或等于0.1μM的IC50,这是高活性水平。
表1显示化合物DZ4-132、DZ4-134和DZ4-135以及下式的比较化合物(PU-H71)的测试结果
在解释这些测试结果中,应了解,对于治疗癌症或神经变性病症的活性来说,期望结合Hsp90。相反,通常不期望结合hERG,这是因为结合hERG可导致不期望的心脏副作用。因此,期望具有较低的结合Hsp90的值和较高的结合hERG的值,记住,两种测量的单位是不同的。
表1
化合物 | SKBr3结合亲和力(nM) | hERG结合(uM) |
DZ4-132 | 10.0 | 5.5 |
DZ4-134 | 55.3 | 11.0 |
DZ4-135 | 45.4 | 14.0 |
PU-H71 | 20 | 1 |
本发明的范围并不受实例中所揭示的具体实施例所限制,所述实例打算作为本发明数个方面的例示,且功能等效的任何实施例均在本发明的范围内。实际上,除那些本文所示和所描述的实施例以外,本发明的各种修改对所属领域的技术人员将显而易见,而且这些修改打算落入所附权利要求书的范围内。已提及诸多参考文献,其全部揭示内容出于所有目的以引用的方式并入本文中。
Claims (13)
2.根据权利要求1所述的化合物或其医药上可接受的盐,其中X2是二甲基胺。
3.根据权利要求1或2所述的化合物或其医药上可接受的盐,其中R11是新戊基。
4.根据权利要求1到3中任一权利要求所述的化合物或其医药上可接受的盐,其中R11是异丙基。
5.根据权利要求1到3中任一权利要求所述的化合物或其医药上可接受的盐,其中R11是叔丁基。
6.根据权利要求1所述的化合物或其医药上可接受的盐,其中X2是二甲基胺,Y是S,R10是亚乙基,R11是新戊基,且X4是H。
7.根据权利要求1所述的化合物或其医药上可接受的盐,其中Z1、Z2和Z3各自为N,X2是二甲基胺,Y是S,R10是亚丙基,R11是异丙基,且X4是H。
8.根据权利要求1所述的化合物或其医药上可接受的盐,其中Z1、Z2和Z3各自为N,X2是二甲基胺,Y是S,R10是亚丙基,R11是叔丁基,且X4是H。
9.一种医药组合物,其包含根据权利要求1到8中任一权利要求所述的化合物或其医药上可接受的盐以及医药上可接受的载剂。
10.一种治疗或预防癌症或神经变性病症的方法,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8中任一权利要求所述的化合物。
11.一种根据权利要求1到8中任一权利要求所述的化合物的用途,其用于调配用以治疗或预防癌症或神经变性病症的医药组合物。
12.一种抑制Hsp90的方法,其包含使Hsp90与Hsp90功能抑制量的根据权利要求1到8中任一权利要求所述的化合物接触。
13.一种根据权利要求1到8中任一权利要求所述的化合物的用途,其用于调配用以抑制Hsp90的医药组合物。
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US9546170B2 (en) | 2011-04-05 | 2017-01-17 | Sloan-Kettering Institute For Cancer Research | Hsp90 inhibitors |
JP6266506B2 (ja) | 2011-04-05 | 2018-01-24 | スローン − ケッタリング インスティチュート フォー キャンサー リサーチ | Hsp90阻害物質 |
JP6539275B2 (ja) | 2013-08-16 | 2019-07-03 | メモリアル スローン ケタリング キャンサー センター | 選択的grp94阻害剤およびその使用 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10590157B2 (en) | 2012-02-09 | 2020-03-17 | University Of Kansas | C-terminal HSP90 inhibitors |
US10882881B2 (en) | 2012-02-09 | 2021-01-05 | University Of Kansas | C-terminal Hsp90 inhibitors |
US11390640B2 (en) | 2012-02-09 | 2022-07-19 | University Of Kansas | C-terminal Hsp90 inhibitors |
CN106536498A (zh) * | 2014-06-24 | 2017-03-22 | 堪萨斯大学 | 作为hsp90抑制剂和hsp70诱导剂的具有经修饰醚基的联苯酰胺 |
US10590065B2 (en) | 2014-06-24 | 2020-03-17 | University Of Kansas | Biphenyl amides with modified ether groups as HSP90 inhibitors and HSP70 inducers |
US11098008B2 (en) | 2014-06-24 | 2021-08-24 | University Of Kansas | Biphenyl amides with modified ether groups as Hsp90 inhibitors and Hsp70 inducers |
US11708319B2 (en) | 2014-06-24 | 2023-07-25 | University Of Kansas | Biphenyl amides with modified ether groups as HSP90 inhibitors and HSP70 inducers |
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WO2012138896A1 (en) | 2012-10-11 |
CA2832099C (en) | 2019-07-09 |
MX2013011531A (es) | 2014-08-22 |
NZ616890A (en) | 2016-01-29 |
KR20140073464A (ko) | 2014-06-16 |
MX354215B (es) | 2018-02-19 |
AU2012240079B2 (en) | 2017-05-18 |
JP2014510149A (ja) | 2014-04-24 |
ES2647889T3 (es) | 2017-12-27 |
EP2694506A1 (en) | 2014-02-12 |
US20140045867A1 (en) | 2014-02-13 |
EA201391337A1 (ru) | 2014-05-30 |
US10064867B2 (en) | 2018-09-04 |
BR112013025761A2 (pt) | 2018-05-29 |
AU2012240079A1 (en) | 2013-11-07 |
EA024647B1 (ru) | 2016-10-31 |
EP2694506B1 (en) | 2017-09-20 |
US20170151247A1 (en) | 2017-06-01 |
JP5961683B2 (ja) | 2016-08-02 |
US9546170B2 (en) | 2017-01-17 |
CN103596955B (zh) | 2016-11-16 |
CA2832099A1 (en) | 2012-10-11 |
KR101984480B1 (ko) | 2019-05-31 |
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