CN107846898B - 用于管理低氧诱导因子相关病症的二苯基甲醇衍生物 - Google Patents
用于管理低氧诱导因子相关病症的二苯基甲醇衍生物 Download PDFInfo
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- CN107846898B CN107846898B CN201680034730.0A CN201680034730A CN107846898B CN 107846898 B CN107846898 B CN 107846898B CN 201680034730 A CN201680034730 A CN 201680034730A CN 107846898 B CN107846898 B CN 107846898B
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- 206010021143 Hypoxia Diseases 0.000 title abstract description 23
- 230000007954 hypoxia Effects 0.000 title abstract description 16
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical class C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 title abstract description 8
- 230000001939 inductive effect Effects 0.000 title abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- -1 nitro, cyano, hydroxy, amino, mercapto, formyl Chemical group 0.000 claims description 119
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 238000006467 substitution reaction Methods 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 20
- 125000004001 thioalkyl group Chemical group 0.000 claims description 20
- 125000001589 carboacyl group Chemical group 0.000 claims description 19
- 125000004414 alkyl thio group Chemical group 0.000 claims description 17
- 125000003282 alkyl amino group Chemical group 0.000 claims description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 15
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 14
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 4
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- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本公开涉及用于管理与低氧诱导因子(HIF)途径相关的病症的二苯基甲醇衍生物,例如用于治疗癌症。在某些实施方案中,本公开涉及化合物和药物组合物。在某些实施方案中,本公开涉及本文公开的化合物,作为前药,任选被一个或多个取代基取代,其衍生物或盐。
Description
关于联邦资助研究的声明
本发明是由美国国家卫生研究院授予的资助号CA116804和CA180805的政府支持下进行的。政府对本发明具有一定的权利。
背景
癌症的有效治疗是研究人员面临的主要挑战,需要靶向异常增生性疾病的新疗法。实体癌中低氧区的存在已经与抗化疗和放射治疗相关。低氧诱导因子(HIF)是激活基因控制机制的转录因子,如糖酵解,红细胞生成,血管发生,上皮与间质转化,细胞运动和可有利于癌细胞的存活的侵袭/转移。HIF是由HIF1-α和HIF1-β亚单位组成的异二聚体蛋白复合物,然后与辅因子如p300和CBP结合形成活性转录因子。HIF的调节主要发生在蛋白质水平,并且依赖于HIF1-α亚单位的合成和稳定性。在正常氧条件下,HIF1-α亚单位通过氧依赖性脯氨酰羟化酶(PHD)在脯氨酸残基处羟化,其介导Von Hippel-Lindau(VHL)E3泛素连接酶复合物的识别和通过蛋白酶体的快速降解。在低氧条件下,HIF1-α亚单位由于抑制脯氨酸羟化而稳定,功能性HIF转录复合体组装,转运到细胞核,并转录含有称为低氧反应元件(HRE)的DNA序列的基因。HIF-1α水平升高已经与癌症患者预后差相关联。
过表达HIF的肿瘤细胞是抗肿瘤治疗的重要靶点。Zhang等人报道地高辛等强心苷抑制HIF-1α的合成,阻断肿瘤生长。PNAS,2008,105(50):19579–19586。许多现有化学治疗剂可以改变HIF活性,包括2ME2、17-DMAG、17-AAG、喜树碱、PX-478和YC-1。Ellinghaus etal.报道BAY 87-2243抑制HIF-1α。Cancer Medicine,2013,2(5):611–624。在H460异种移植模型中证明了BAY 87-2243在体内的抗肿瘤活性。BAY 87-2243也抑制线粒体复合物I的活性。干扰线粒体功能以降低低氧诱导的HIF-1活性在肿瘤中被指示为克服低氧性肿瘤的化疗和放射治疗抗性的治疗方法。
许多专利申请报道了用于治疗低氧相关病症的小分子(参见例如,美国公开申请2013-0164218、WO 2004/087066、WO 2007/025169、WO 2010/006184和WO 2010/006189)。另见Sato et al.,2000,Proc Natl Acad Sci USA,97:10832-10837;Whitesell et al.,1994,Proc Natl Acad Sci USA.,91:8324-8328;Zhou et al.2004,J.Biol.Chem.279:13506-13513;Katschinski et al.,2002,J.Biol.Chem.277:9262-9267和Isaacs et al.,2002,J Biol Chem.,277:29936-44。
本文引用的参考文献不是对现有技术的承认。
概述
本公开涉及用于管理与低氧诱导因子(HIF)途径相关的病症的二苯基甲醇衍生物,例如在治疗癌症中的用途。在某些实施方案中,本公开涉及本文公开的化合物,作为前药,任选被一个或多个取代基取代,其衍生物或盐。在某些实施方案中,二苯基甲醇衍生物具有式I,
其中取代基在本文中描述。
在某些实施方案中,本公开涉及化合物和药物组合物。在某些实施方案中,本公开涉及包含本文公开的化合物或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物。
在某些实施方案中,药物组合物是丸剂、片剂、胶囊或凝胶的形式,以及任选地包封该形式的聚合物材料层。在某些实施方案中,化合物是大小为5纳米至1毫米或1厘米的颗粒形式,任选地具有包封颗粒的聚合材料层。在某些实施方案中,化合物为水溶液形式,还包含缓冲剂,油,磷酸盐缓冲液,钠或钾盐,糖,多糖或增溶剂。
在某些实施方案中,本公开涉及治疗癌症的方法,包括向有需要的受试者施用有效量的包含本文公开的化合物的药物组合物。在某些实施方案中,癌症选自胶质母细胞瘤(GBM)、乳腺癌、胰腺癌、结肠癌、转移性肺癌、膀胱癌、肺癌、眼癌、黑素瘤、结肠和直肠癌、非霍奇金淋巴瘤、子宫内膜癌、胰腺癌、肾癌、前列腺癌、白血病、甲状腺癌和脑癌。
在某些实施方案中,组合物与第二抗癌剂组合施用,第二抗癌剂如替莫唑胺、卡莫司汀、贝伐珠单抗、甲基苄肼、洛莫司汀、长春新碱、吉非替尼、厄洛替尼、多西他赛、顺铂、5-氟尿嘧啶、吉西他滨、替加氟、雷替曲塞、甲氨蝶呤、阿糖胞苷、羟基脲、阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素、光神霉素、长春花碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇、依托泊苷、替尼泊苷、安吖啶、托泊替康、喜树碱、硼替佐米、阿那格雷、他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、iodoxyfene、氟维司群、比卡鲁胺、氟他胺、尼鲁米特、环丙孕酮、戈舍瑞林、亮丙瑞林、布舍瑞林、甲地孕酮、阿那曲唑、来曲唑、伏氯唑、依西美坦、非那雄胺、马立马司他、曲妥珠单抗、西妥昔单抗、达沙替尼、伊马替尼、考布他汀、沙利度胺、和/或来那度胺或其组合。
在某些实施方案中,组合物与基质例如加载有化学治疗剂的生物可降解聚合物例如含有卡莫司汀的植入膜剂(gliadel wafer)组合施用。在某些实施方案中,聚合物被设计为在两周、三周或更多周的时间段内释放该试剂。将聚合物植入到切除的肿瘤床中,并且在初次切除后。
在某些实施方案中,本公开涉及防止害虫进食植物的方法,包括使植物与具有线粒体复合物I抑制性质的本文公开的化合物接触,从而防止害虫进食植物。
在某些实施方案中,本公开涉及防止害虫在受试者的皮肤或毛发中生活的方法,包括使受试者的皮肤或毛发与具有线粒体复合物I抑制性质的本文公开的化合物以对受试者有效的方式接触,该受试者具有风险、被怀疑、表现出症状或被诊断为有生活在受试者上的害虫。
附图简要说明
图1示出了本公开的某些实施方案的制备。从市售的1-溴-4-(溴甲基)苯1(图1)以两个步骤合成了对位取代的化合物。首先,1用相应的醇进行SN2置换,得到醚2a-w。接着,在锂化后,将2a-w与合适的醛反应,得到醇化合物3a-w。试剂和条件:(a)NaH,醇,0℃至室温,过夜,48-85%;b)n-BuLi,醛,-78℃,58-94%。使用相应的市售起始原料,例如1-溴-3-(溴甲基)苯和1-溴-2-(溴甲基)苯制备间位和邻位取代的取代物。
图2示出了本公开的某些实施方案的制备。通过与4-溴苯酚10或2-溴-5-羟基吡啶11的SN2反应两步合成13a,b,d-j,然后进行锂卤交换,分别得到醚12a,b,d;13a-d和醇14a,b,d;15a-d。对于化合物14c,在O-甲苯磺酰化17之前需要4-(2-羟基乙基)哌啶-1-甲酸叔丁酯16的N-Boc保护,得到中间体18。在该点,甲苯磺酰基被4-溴苯酚以SN2反应置换,得到醚12c,然后与3,4-二甲氧基苯甲醛偶联,得到醇化合物14c。
图3示出了本公开的某些实施方案的制备。1-溴-4-(溴甲基)苯1用吗啉或N-甲基哌嗪进行SN2置换,得到化合物20a-b。接着,将20a-c与正丁基锂然后与3,4-二甲氧基苯甲醛反应,得到醇21a-c。试剂和条件:(a)胺,K2CO3,乙腈,室温。(b)3,4-二甲氧基苯甲醛,n-BuLi,-78℃,85%。(c)3,4-二甲氧基溴苯,n-BuLi,-78℃,89%。
图4示出了本公开的某些实施方案的制备。从由芳基溴和芳基醛组成的市售起始原料22a-f和23一步合成化合物,它们偶联在一起产生醇24a-f,其中R=H,Y=Br,Z=CHO,24a;R=3,4-二甲氧基,Y=Br,Z=CHO,24b;R=24-二甲氧基,Y=Br,Z=CHO,24c;R=4-甲基溴,Y=Br,Z=CHO,24d;R=苯并呋喃,Y=CHO,Z=Br,24e。试剂和条件:(a)n-BuLi,-78℃,46-65%。
图5示出了本公开的某些实施方案的制备。从容易合成的醛25a,c和d一步或两步合成化合物。首先,通过锂化然后加成反应将醛25a,c和d与4-溴-1,2-二甲氧基苯偶联,得到醇26a-d。接着,将双键氢化成单键,得到化合物27c和27d。R1=H,X=C,25-26a和b;R1=OMe,X=C,25-27c;R1=H,X=N,25-27d;试剂和条件:(a)4-溴-1,2-二甲氧基苯,n-BuLi,-78℃,49-63%;(b)H2,Pd/C,MeOH,过夜。
图6示出了本公开的某些实施方案的制备。从容易合成的醛28a-d一步合成化合物29a-d。首先,将醛28a-d通过锂化然后加成反应与4-溴-1,2-二甲氧基苯偶联,得到醇29a-d。2,3-二氢苯并呋喃-5-基,28-29a;(4-甲基-3,4-二氢-2H-苯并[b][1,4]嗪-7-基),28-29b;萘-2-基,28-29c;(2,3-二氢苯并[b][1,4]二英-6-基),28-29d;(2-甲基苯并[b]噻吩-5-基),28-29e和f。试剂和条件:(a)4-溴-1,2-二甲氧基苯,n-BuLi,-78℃,49-63%。
图7示出了本公开的某些实施方案的制备。通过用相应的醇和6-溴萘-2-醇30的SN2反应两步合成化合物32a-d,然后进行锂卤交换,分别得到醚31a-d和醇32a-d。
图8示出了本公开的某些实施方案的制备。从取代的溴酚33a-c和相应的烷基溴化物两步合成化合物。R1=甲氧基,R2=3-羟基四氢呋喃基,33-35a;R1=氟,R2=正戊基,33-35b;R1=甲基,R2=正戊基,33-35c;R1=甲基,R2=4-(氧甲基)哌啶-1-甲酸叔丁酯,33-35d;R1=甲基,R2=4-(氧甲基)哌啶-1-甲酸叔丁酯,33-35e;R1=甲基,R2=4-(氧甲基)哌啶-1-甲酸叔丁酯,33-35f。试剂和条件:(a)K2CO3,乙腈,回流;(b)4-溴-1,2-二甲氧基苯,n-BuLi,-78℃。
图9示出了某些HIF抑制剂的结构。
图10显示了复合物I活性测定中某些二苯基甲醇的IC50(MitoCheck Complex I活性测定Cayman Chemicals#700930)。
图11显示了含有半乳糖的培养基中KCN1和142对ATP产生影响的时间过程的数据。
详细讨论
在更详细地描述本公开之前,应当理解,本公开不限于所描述的特定实施方案,并且因此当然可以变化。还应当理解,本文使用的术语仅用于描述特定实施方案的目的,并不旨在限制,因为本公开的保护范围将仅由所附权利要求书限制。
除非另有定义,否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常理解的相同的含义。虽然与本文类似或等同的任何方法和材料也可用于本公开的实践或测试中,但是现在描述优选的方法和材料。
本说明书中引用的所有出版物和专利通过引用并入本文,就像每篇单独的出版物或专利被具体和单独地指明通过引用并入并且通过引用并入本文以公开和描述与所引用的出版物相关的方法和/或材料。任何出版物的引用是引用申请日前的公开,其不应被解释为承认本公开无权通过事先公开的方式提前发布此类出版物。此外,提供的出版物的日期可能与可能需要独立确认的实际发布日期不同。
对于本领域技术人员在阅读本公开后将显而易见的是,本文描述和示出的各个实施方案中的每一个具有分立的部件和特征,其可以容易地与其他几个实施方案的特征分开或组合而不脱离从本公开的范围或精神。任何所叙述的方法可以按照所叙述的事件的顺序或在逻辑上可能的任何其他顺序来执行。
除非另有说明,否则本公开的实施方案将采用本领域技术范围内的医学、有机化学、生物化学、分子生物学、药理学等技术。这些技术在文献中得到充分解释。
必须注意的是,除非上下文另有明确规定,否则如在说明书和所附权利要求书中所使用的,单数形式“一个”、“一种”和“该”包括复数指示物。在本说明书和下面的权利要求中,将提及应被定义为具有以下含义的若干术语,除非相反的意图是明显的。
在描述各种实施方案之前,提供以下定义,除非另有说明,否则应使用以下定义。
如本文所用,“烷基”是指非环状直链或支链的、不饱和的或饱和的烃,例如含有1至22个碳原子的烃,而术语“低级烷基”或“C1-4烷基”与烷基具有相同的含义,但含有1至4个碳原子。术语“高级烷基”具有与烷基相同的含义,但含有8至22个碳原子。代表性的饱和直链烷基包括甲基,乙基,正丙基,正丁基,正戊基,正己基,正九烷基,正辛基,正壬基等;而饱和支链烷基包括异丙基,仲丁基,异丁基,叔丁基,异戊基等。不饱和烷基在相邻碳原子之间含有至少一个双键或三键(分别称为“烯基”或“炔基”)。代表性的直链和支链烯基包括乙烯基(ethylenyl),丙烯基,1-丁烯基,2-丁烯基,异丁烯基,1-戊烯基,2-戊烯基,3-甲基-1-丁烯基,2-甲基-2-丁烯基,2,3-二甲基-2-丁烯基等;而代表性的直链和支链炔基包括乙炔基,丙炔基,1-丁炔基,2-丁炔基,1-戊炔基,2-戊炔基,3-甲基-1-丁炔基等。
非芳族单环或多环烷基在本文中称为“碳环”或“碳环基”基团。代表性的饱和碳环包括环丙基,环丁基,环戊基,环己基等;而不饱和碳环包括环戊烯基和环己烯基等。
“杂碳环”或“杂碳环基”基团是含有1至4个独立地选自氮、氧和硫的杂原子的碳环,其可以是饱和或不饱和的(但不是芳族的),单环或多环,并且其中氮和硫杂原子可以是任选被氧化的,氮杂原子可以是任选季铵化的。杂碳环可包括吗啉基,吡咯烷酮基,吡咯烷基,哌啶基,乙内酰脲基(hydantoinyl),戊内酰氨基,环氧乙烷基,氧杂环丁基,四氢呋喃基,四氢吡喃基,四氢吡啶基,四氢嘧啶基(tetrahydroprimidinyl),四氢噻吩基,四氢噻喃基,四氢嘧啶基(tetrahydropyrimidinyl),四氢噻吩基,四氢噻喃基等。
“芳基”是指芳族碳环单环或多环的环如苯基或萘基。只要其中一个环是芳族的,多环系统可以但并不必须含有一个或多个非芳族环。
如本文所用,“杂芳基”是指具有1至4个选自氮、氧和硫的杂原子并且含有至少1个碳原子的芳族杂碳环,包括单环和多环系统。只要其中一个环是芳族的,多环系统可以但不必须含有一个或多个非芳族环。代表性杂芳基是呋喃基,苯并呋喃基,噻吩基,苯并噻吩基,吡咯基,吲哚基,异吲哚基,氮杂吲哚基,吡啶基,喹啉基,异喹啉基,唑基,异唑基,苯并唑基,吡唑基,咪唑基,苯并咪唑基,噻唑基,苯并噻唑基,异噻唑基,哒嗪基,嘧啶基,吡嗪基,三嗪基,噌啉基,酞嗪基和喹唑啉基。预期使用术语“杂芳基”包括N-烷基化衍生物如1-甲基咪唑-5-基取代基。
如本文所用,“杂环”或“杂环基”是指具有1至4个选自氮、氧和硫的杂原子并且含有至少1个碳原子的单环和多环系。单环和多环系可以是芳族,非芳族或芳族和非芳族环的混合物。杂环包括杂碳杂环,杂芳基等。
“烷硫基”是指通过硫桥连接的如上定义的烷基。烷硫基的实例是甲硫基(即-S-CH3)。
“烷氧基”是指通过氧桥连接的如上定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和仲戊氧基。优选的烷氧基是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基和叔丁氧基。
“烷基氨基”是指通过氨基桥连接的如上所定义的烷基。烷基氨基的实例是甲基氨基(即-NH-CH3)。
“烷酰基”是指通过羰基桥连接的如上定义的烷基(即-(C=O)烷基)。
“烷基磺酰基”是指通过磺酰基桥如甲磺酰等连接的如上定义的烷基(即-S(=O)2烷基),“芳基磺酰基”是指通过磺酰基桥连接的芳基(即-S(=O)2芳基)。
“烷基亚磺酰基”是指通过亚磺酰基桥连接的如上所定义的烷基(即-S(=O)烷基)。
“氨基烷基”是指通过烷基桥连接的氨基。氨基烷基的实例是氨基甲基(即NH2-CH2-)。
“羟烷基”是指通过烷基桥连接的羟基。羟烷基的实例是羟乙基(即HO-CH2CH2-)。
术语“取代的”是指至少一个氢原子被取代基取代的分子。当被取代时,这些基团中的一个或多个是“取代基”。该分子可以是多取代的。在氧代取代基(“=O”)的情况下,两个氢原子被取代。该情况下的示例取代基包括卤素、羟基、烷基、烷氧基、硝基、氰基、氧代、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaNRb、-NRaC(=O)ORb、-NRaSO2Rb、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-ORa、-SRa、-SORa、-S(=O)2Ra、-OS(=O)2Ra和-S(=O)2ORa。在该情况下,Ra和Rb可以相同或不同、并且独立地是氢、卤素、羟基、烷基、烷氧基、烷基、氨基、烷基氨基、二烷基氨基、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基。
本文所用的术语“任选取代的”是指取代是任选的,因此指定的原子可能是未取代的。
如本文所用,“盐”是指所公开的化合物的衍生物,其中母体化合物被改性制备其酸或碱盐。盐的实例包括但不限于碱性残基如胺、烷基胺或二烷基胺的矿物或有机酸盐;酸性残基如羧酸的碱金属盐或有机盐;等等。在典型的实施方案中,盐是常规无毒的药学上可接受的盐,包括形成的母体化合物和无毒的无机或有机酸的季铵盐。优选的盐包括衍生自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐;由有机酸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸等制备的盐。
“受试者”是指任何动物,优选人患者,牲畜,啮齿动物,猴子或家养宠物。
术语“前药”是指在体内转化为生物活性形式的药剂。前药通常是有用的,因为在某些情况下,它们可能比母体化合物更容易施用。例如,它们可以通过口服施用是生物可利用的,而母体化合物不是。在药物组合物中,前药还可以相对于母体药物改善的溶解度。前药可以通过包括酶促过程和代谢水解的各种机制转化成母体药物。
如本文所用,术语“衍生物”是指保留所鉴定的类似物的足够功能属性的结构相似的化合物。衍生物可以在结构上类似,因为它缺少一个或多个原子,被一个或多个取代基取代,盐,不同水合/氧化态,例如用单键或双键取代,用羟基取代酮,或因为分子内的一个或多个原子被切换,例如但不限于用硫或氮原子置换氧原子或用羟基置换氨基,反之亦然。在芳环中用氮置换碳是预期的衍生物。衍生物可以是前药。衍生物可以通过化学文献中提出的任何各种合成方法或适当的改编进行制备,如在合成或有机化学教科书中所提供的,例如提供于March's Advanced Organic Chemistry:Reactions,Mechanisms,andStructure,Wiley,6th Edition(2007)Michael B.Smith or Domino Reactions inOrganic Synthesis,Wiley(2006)Lutz F.Tietze,通过引用并入本文。
如本文所用,术语“预防(prevent)”和“预防(preventing)”包括预防复发、扩散或发作。本公开并不旨在完全预防。在一些实施方案中,发作被延迟,或疾病的严重程度被降低。
如本文所用,术语“治疗(treat)”和“治疗(treating)”不限于受治疗者(例如患者)治愈并消除疾病的情况。相反,本公开的实施方案也考虑了仅减少症状和/或延迟疾病进展的治疗。
如本文所用,术语“与...组合”用于描述用额外手段的施用意味着该药剂可以在额外治疗之前、一起或之后施用或其组合。
二苯基甲醇衍生物
在某些实施方案中,本公开涉及用于本文报道的任何用途的式I的二苯基甲醇衍生物。式I的化合物可以是
其前药或其盐,其中,
A是具有n为0、1、2或3的R9取代基的碳环基、芳基、苯基、苄基或杂环基环;
R4、R5、R6、R7和R9各自单独地并且独立地为氢、烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R4、R5、R6、R7和R9任选被一个或多个相同或不同的R20取代;
R20是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、硫代烷基、烷硫基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R20任选被一个或多个相同或不同的R21取代;和
R21是卤素、硝基、氰基、羟基、三氟甲氧基、三氟甲基、氨基、甲酰基、羧基、氨基甲酰基、巯基、氨磺酰基、甲基、乙基、甲氧基、乙氧基、异丙氧基、叔丁氧基、羟甲基、羟乙基、硫代甲基、硫代乙基、氨基甲基、氨基乙基、乙酰基、乙酰氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、N-甲基-N-乙基氨基、乙酰氨基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N,N-二甲基氨基甲酰基、N,N-二乙基氨基甲酰基、N-甲基-N-乙基氨基甲酰基、甲硫基、乙硫基、甲基亚磺酰基、乙基亚磺酰基、甲磺酰基、乙基磺酰基、甲氧基羰基、乙氧基羰基、异丙氧基羰基、叔丁氧基羰基、N-甲基氨磺酰基、N-乙基氨磺酰基、N,N-二甲基氨磺酰基、N,N-二乙基氨磺酰基、N-甲基-N-乙基氨磺酰基、碳环基、芳基或杂环基。
在某些实施方案中,R6是烷氧基或R5和R6是烷氧基。
在某些实施方案中,A是苯基。
在某些实施方案中,A是苄-4-基或苄-3-基环。
在某些实施方案中,R9为任选取代的烷氧基。
在某些实施方案中,R9为任选取代的羟烷基。
在某些实施方案中,R9为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R9为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式IA,
其前药或其盐,其中,
A是具有n为0、1、2或3个R9取代基的碳环基、芳基、苯基、苄基或杂环基环;
R4、R5、R7和R9与上文定义相同;
R10是烷基、甲酰基、烷酰基、氨基甲酰基、羟烷基、氨基烷基或硫代烷基,其中R10任选被一个或多个相同或不同的R20取代;
R20和R21与上文所定义的相同。
在某些实施方案中,R5是烷氧基。
在某些实施方案中,A是苯基。
在某些实施方案中,A是苄-4-基或苄-3-基环。
在某些实施方案中,R9为任选取代的烷氧基。
在某些实施方案中,R9为任选取代的羟烷基。
在某些实施方案中,R9为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R9为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式IB,
其前药或其盐,其中,
A是具有n为0、1、2或3个R9取代基的碳环基、芳基、苯基、苄基或杂环基环;
R4、R7和R9与上文定义相同;
R10是烷基、甲酰基、烷酰基、氨基甲酰基、羟烷基、氨基烷基或硫代烷基,其中R10任选被一个或多个相同或不同的R20取代;
R15是烷基、甲酰基、烷酰基、氨基甲酰基、羟烷基、氨基烷基或硫代烷基,其中R15任选被一个或多个相同或不同的R20取代;
R20和R21与上文所定义的相同。
在某些实施方案中,A是苯基。
在某些实施方案中,A是苄-4-基或苄-3-基环。
在某些实施方案中,R9为任选取代的烷氧基。
在某些实施方案中,R9为任选取代的羟烷基。
在某些实施方案中,R9为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R9为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式IC,
其前药或其盐,其中,
R1是氢、羟烷基或烷氧基,其中R1任选被一个或多个相同或不同的R20取代,R2是氢、烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R2任选被一个或多个相同或不同的R20取代;或者
R1是氢、烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R1任选被一个或多个相同或不同的R20取代,并且R2是氢、羟烷基或烷氧基,其中R2任选地被一个或多个相同或不同的R20取代;
R3、R4、R5、R7和R8各自单独地并且独立地为氢、烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R3,R4,R5,R7和R8任选被一个或多个相同或不同的R20取代;
R6是任选被一个或多个相同或不同的R20取代的烷氧基;
R20和R21与上文所定义的相同。
在某些实施方案中,R3是烷基。
在某些实施方案中,R6是烷氧基或R5和R6是烷氧基。
在某些实施方案中,R1或R2为任选取代的烷氧基。
在某些实施方案中,R1或R2是任选取代的羟烷基。
在某些实施方案中,R1或R2为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R1或R2为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式ID,
其前药或其盐,其中,
R1、R2、R3、R4、R5、R7、R8、R10、R20和R21如上文所定义。
在某些实施方案中,R3是烷基。
在某些实施方案中,R5是烷氧基。
在某些实施方案中,R1或R2为任选取代的烷氧基。
在某些实施方案中,R1或R2为任选取代的羟烷基。
在某些实施方案中,R1或R2为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R1或R2为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式IE,
其前药或其盐,其中,
R1、R2、R3、R4、R5、R7、R8、R10、R15、R20和R21如上文所定义。
在某些实施方案中,R3是烷基。
在某些实施方案中,R1或R2为任选取代的烷氧基。
在某些实施方案中,R1或R2为任选取代的羟烷基。
在某些实施方案中,R1或R2为((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
在某些实施方案中,R1或R2为(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
在某些实施方案中,式I的衍生物具有式IF,
其前药或其盐,其中,
X是苄基和R11之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R11是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R11任选被一个或多个相同或不同的R20取代;
R2、R3、R4、R5、R7、R8、R10、R20和R21与上文定义相同。
在某些实施方案中,R3是烷基。
在某些实施方案中,X是-CH2CH2O-
在某些实施方案中,R11是杂环基。
在某些实施方案中,式I的衍生物具有式IG,
其前药或其盐,其中,
X是苄基和R11之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R11是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R11任选被一个或多个相同或不同的R20取代;
R2、R3、R4、R7、R8、R10、R15、R20和R21与上文定义相同。
在某些实施方案中,R3是烷基。
在某些实施方案中,X是-CH2CH2O-
在某些实施方案中,R11是杂环基。
在某些实施方案中,式I的衍生物具有式IH,
其前药或其盐,其中,
X是苯基和R12之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R12是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R12任选被一个或多个相同或不同的R20取代;
R2、R3、R4、R5、R7、R8、R10、R20和R21与上文定义相同。
在某些实施方案中,R3是烷基。
在某些实施方案中,X是-CH2CH2O-
在某些实施方案中,R12是杂环基。
在某些实施方案中,式I的衍生物具有式II,
其前药或其盐,其中,
X是苯基和R12之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R2、R3、R4、R7、R8、R10、R12、R15、R20和R21与上文定义相同。
在某些实施方案中,R3是烷基。
在某些实施方案中,X是-CH2CH2O-
在某些实施方案中,R12是杂环基。
在某些实施方案中,式I的衍生物具有式IJ,
其前药或其盐,其中,
Z是苄基和R13之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R13是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R13任选被一个或多个相同或不同的R20取代;
R2、R3、R4、R7、R8、R10、R15、R20和R21与上文定义相同。
在某些实施方案中,Z是-O-。
在某些实施方案中,R14是杂环基。
在某些实施方案中,式I的衍生物具有式IK,
其前药或其盐,其中,
Z是苄基和R13之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R13是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R13任选被一个或多个相同或不同的R20取代;
R1、R3、R4、R7、R8、R10、R13、R15、R20和R21如上文所定义。
在某些实施方案中,Z是-O-。
在某些实施方案中,R14是杂环基。
在某些实施方案中,式I的衍生物具有式IL,
其前药或其盐,其中,
Z是苯基和R14之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R14是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R14任选被一个或多个相同或不同的R20取代;
R1、R3、R4、R5、R7、R8、R10、R20和R21如上文所定义。
在某些实施方案中,Z是-O-。
在某些实施方案中,R14是杂环基。
在某些实施方案中,式I的衍生物具有式IM,
其前药或其盐,其中,
Z是苯基和R14之间的桥连基团-O-、-S-、-NH-、-N-烷基-、C=O、-CH2-、-CH2O-、-CH2S-、-CH2NH-、-CH2(C=O)-、-CH2CH2-、-CH2CH2O-、-CH2CH2S-、-CH2CH2NH-、-CH2CH2N烷基-、-CH2CH2(C=O)-、-CH2CH2CH2-、或单键;
R14是烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R14任选被一个或多个相同或不同的R20取代;
R1、R3、R4、R7、R8、R10、R14、R15、R20和R21如上文所定义。
在某些实施方案中,Z是-O-。
在某些实施方案中,R14是杂环基。
在某些实施方案中,式I的衍生物具有式IN,
其前药或其盐,其中,
B是具有n为0、1、2或3个R9取代基的碳环基、芳基或杂环基环;
R3、R4、R5、R7、R8、R20和R21与上文定义相同。
R9独立地为氢、烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、烷氧基、羟烷基、烷硫基、硫代烷基、烷基氨基、氨基烷基、(烷基)2氨基、烷酰基、烷氧基羰基、烷基亚磺酰基、烷基磺酰基、芳基磺酰基、碳环基、芳基或杂环基,其中R9任选被一个或多个相同或不同的R20取代;
R6是任选被一个或多个相同或不同的R20取代的烷氧基;
与上文所定义的相同。
在某些实施方案中,式I的衍生物具有式IO,
其前药或其盐,其中,
B是具有n为0、1、2或3个R9取代基的碳环基、芳基或杂环基环;
R3、R4、R5、R7、R8、R9、R10、R20和R21与上文所定义的相同。
在某些实施方案中,式I的衍生物具有式IP,
其前药或其盐,其中,
B是具有n为0、1、2或3个R9取代基的碳环基、芳基或杂环基环;
R3、R4、R7、R8、R9、R10、R15、R20和R21与上文所定义的相同。
在某些实施方案中,式I的衍生物具有式IQ,
其前药或其盐,其中,
虚线是单键或双键;
R3、R4、R5、R7、R8、R9、R10、R20和R21与上文所定义的相同。
在某些实施方案中,式I的衍生物具有式IR,
其前药或其盐,其中,
虚线是单键或双键;
R3、R4、R7、R8、R9、R10、R15、R20和R21与上文所定义的相同。
管理癌症
低氧是实体肿瘤发展中普遍存在的病况。其也在骨髓中发现,产生“血癌”细胞。为了对抗有害影响,肿瘤细胞激活一系列适应性分子机制。低氧诱导因子(HIF)调节对低氧的初步转录反应。HIF由HIF-1α、2α或3α(O2调节亚单位)和组成型表达的HIF-1β组成。在正常氧条件下,α亚单位由脯氨酰羟脯酰酶家族羟化,以Von Hippel-Lindau蛋白依赖的方式泛素化,并在蛋白酶体中降解。在低氧条件下,α亚单位稳定、转运到细胞核中,在其中它们与HIF-1β亚单位相互作用,募集共激活物p300/CBP,并通过结合特异性DNA序列(称为低氧反应元件(HRE))调节靶基因。
CBP和p300是同源转录共激活因子。HIF-1α和p300/CBP之间的相互作用通过天冬酰胺酰羟化酶(FIH-1)的HIF-1α的C-末端反式激活结构域的O2-依赖性羟化作用进行生理调节。天冬酰胺803的羟化可阻止p300或CBP的结合,并抑制转录中的HIF-1功能。通过显示HIF-1α-p300/CBP相互作用的阻断显著减弱HIF活性,p300/CBP在HIF功能中的重要作用已被证实。
HIF激活的基因产物与肿瘤进展/转移的密切关系将HIF鉴定为有吸引力的治疗靶点。以前的研究已经确定,HIF途径的抑制可以抑制许多癌症中的恶性特征。参见Ryan etal.,HIF-1alpha is required for solid tumor formation and embryonicvascularization.EMBO J,1998,17:3005–15。另见Li et al.Cancer Res,2005,65:7249–58。
在典型的实施方案中,本公开涉及治疗或预防癌症的方法,包括向患者施用具有HIF抑制活性的本文公开的化合物。在一些实施方案中,本公开涉及用于治疗癌症的本文公开的化合物或其药学上可接受的盐。
在一些实施方案中,本公开涉及如本文所定义的本文所公开的化合物或其药学上可接受的盐,其用于治疗乳腺癌、结肠直肠癌、眼癌,肺癌(包括小细胞肺癌、非小细胞肺癌和支气管肺泡癌)和前列腺。
在一些实施方案中,本公开涉及如本文所定义的本文公开的化合物或其药学上可接受的盐,其用于治疗胆管、骨、膀胱、眼、头颈部、肾、肝、胃肠道组织、食管、卵巢、子宫内膜、胰腺、皮肤、睾丸、甲状腺、子宫、子宫颈和外阴的癌症,以及白血病(包括ALL和CML),多发性骨髓瘤和淋巴瘤。
在一些实施方案中,本公开涉及如本文所定义的本文所公开的化合物或其药学上可接受的盐,其用于治疗黑素瘤和中枢神经系统及其转移瘤的肿瘤,以及用于治疗胶质母细胞瘤。
Helbig等人报道低氧诱导的基因激活抑制剂,在头颈部人异种移植物中按照时间表依赖性方式分级照射后改善局部肿瘤控制。Radiation Oncol,2014,9:207。在某些实施方案中,本公开涉及使用本文公开的化合物治疗鳞状细胞癌,例如头颈癌。
Platz等人报道地高辛(HIF抑制剂)作为前列腺癌治疗的可能药物。Cancerdiscovery,2011,2011(1):68–77。在某些实施方案中,本公开涉及使用本文公开的化合物治疗前列腺癌。
Wang等人报道低氧诱导因子-1的下调抑制三阴性乳腺癌细胞的恶性生物学行为。Int J Clin Exp Med,2014,7(11):3933-40。在某些实施方案中,本公开涉及使用本文公开的化合物治疗乳腺癌。
Niu等人报道LB-1通过抑制HIF-1α和Stat3信号传导在胰腺癌中发挥抗肿瘤活性。J Cell Physiol,2015,doi:10.1002/jcp.24949。在某些实施方案中,本公开涉及使用本文公开的化合物治疗胰腺癌。
Chen等人报道通过HIF-1α/VEGF-A途径在结肠直肠癌中抑制低氧诱导的血管生成。Alternat Med,2015,2015:454279。在某些实施方案中,本公开涉及使用本文公开的化合物治疗结肠直肠癌。
Tang等人报道HIF-1α诱导VE-钙粘蛋白表达并调节食管癌细胞中的血管生成拟态。World J Gastroenterol,2014,20(47):17894-904。在某些实施方案中,本公开涉及使用本文公开的化合物治疗食管癌。
Fisher等人报道帕比司他通过HIF-1α去稳定来降低非小细胞肺癌细胞的低氧诱导顺铂抗药性。Mol Cancer,2015,14(1):4。在某些实施方案中,本公开涉及使用本文公开的化合物治疗肺癌。
Chen等人报道HIF-α通过上调p21表达促进慢性骨髓性白血病细胞增殖。CellBiochem Biophys.2015。在某些实施方案中,本公开涉及使用本文公开的化合物治疗白血病。
Womeldorff等人报道在胶质母细胞瘤的病理生理和管理中的低氧诱导因子-1和相关的上游和下游蛋白。Neurosurg Focus,2014,37(6):E8。在某些实施方案中,本公开涉及使用本文公开的化合物治疗胶质母细胞瘤。
Borsi等人报道了多发性骨髓瘤中低氧和低氧诱导因子1α的治疗靶向。TranslRes,2014,pii:S1931-5244(14)00436-8。在某些实施方案中,本公开涉及使用本文公开的化合物治疗骨髓瘤。
Gao等人报道高车前素(Hispidulin)通过靶向HIF-1α抑制增殖并增强胆囊癌细胞的化学敏感性。Exp Cell Res,2014,pii:S0014-4827(14)00524-2。在某些实施方案中,本公开涉及使用本文公开的化合物治疗胆囊癌。
在一些实施方案中,本文公开的化合物可以作为单一试剂本身或与其它临床相关试剂组合用于临床。
本文定义的抗癌治疗可以作为唯一治疗应用,或者除了本公开的化合物之外,可以涉及常规手术或放射治疗或化疗。这样的化疗可以包括以下类别的抗肿瘤剂中的一种或多种:
(i)用于医学肿瘤学的抗增殖/抗肿瘤药物及其组合,例如烷化剂(例如顺铂,卡铂,环磷酰胺,氮芥,美法仑,苯丁酸氮芥,白消安和亚硝基脲);抗代谢物,核苷酸类似物和核碱基类似物(例如抗叶酸剂,如氟嘧啶,像5-氟尿嘧啶和吉西他滨,替加氟,雷替曲塞,甲氨蝶呤,阿糖胞苷和羟基脲);抗肿瘤抗生素(例如蒽环类药物,像阿霉素,博来霉素,多柔比星,道诺霉素,表柔比星,伊达比星,丝裂霉素-C,更生霉素和光神霉素);抗有丝分裂剂(例如长春花生物碱,像长春新碱,长春花碱,长春地辛和长春瑞滨,和紫杉烷类,像紫杉酚和他克唑泰尔);和拓扑异构酶抑制剂(例如表鬼臼毒素,像依托泊苷和替尼泊苷,安吖啶,托泊替康和喜树碱);和蛋白酶体抑制剂(例如硼替佐米));和试剂阿那格雷和试剂α-干扰素;
(ii)细胞抑制剂如抗雌激素(例如他莫昔芬,托瑞米芬,雷洛昔芬,屈洛昔芬和iodoxyfene),雌激素受体下调剂(例如氟维司群),抗雄激素(例如比卡鲁胺,氟他胺,尼鲁米特和醋酸环丙孕酮),LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林,亮丙瑞林和布舍瑞林),孕激素(例如醋酸甲地孕酮),芳香酶抑制剂(例如阿那曲唑,来曲唑,伏氯唑和依西美坦)和5α-还原酶抑制剂如非那雄胺;
(iii)抑制癌细胞侵袭的试剂(例如金属蛋白酶抑制剂如马立马司他和尿激酶纤溶酶原激活物受体功能的抑制剂);
(iv)生长因子功能抑制剂,例如此类抑制剂包括生长因子抗体,生长因子受体抗体(例如抗erbb2抗体曲妥珠单抗[HerceptinTM]和抗erbbl抗体西妥昔单抗),法呢基转移酶抑制剂,酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如:N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼),N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI1033),例如血小板衍生生长因子家族的抑制剂,例如肝细胞生长因子家族的抑制剂,例如抑制剂或磷脂酰肌醇3-激酶(PI3K),例如丝裂原活化蛋白激酶激酶(MEK1/2)的抑制剂,例如蛋白激酶B(PKB/Akt)的抑制剂,例如Src酪氨酸激酶家族和/或Abelson(AbI)酪氨酸激酶家族的抑制剂,如达沙替尼(BMS-354825)和甲磺酸伊马替尼(GleevecTM);和任何修饰STAT信号传导的试剂;
(v)抗血管生成剂,例如抑制血管内皮生长因子的作用的抗血管生成剂(例如抗血管内皮细胞生长因子抗体贝伐单抗[AvastinTM])和其它机制起作用的化合物(例如利诺胺,整合素αvβ3功能的抑制剂和血管抑素);
(vi)血管损伤剂如考布他汀A4;
(vii)反义治疗,例如针对上述靶标的那些反义治疗药物,例如抗ras反义物;
(viii)基因治疗方法,包括例如置换异常基因如异常p53或异常BRCA1或BRCA2的方法,GDEPT(基因定向酶前药治疗)方法,例如使用胞嘧啶脱氨酶,胸苷激酶或细菌硝基还原酶的酶和方法增加患者对化疗或放疗的耐受性,如多药耐药基因治疗;和
(ix)免疫治疗方法,包括例如提高患者肿瘤细胞的免疫原性的离体和体内方法,例如用细胞因子如白细胞介素2,白细胞介素4或粒细胞-巨噬细胞集落刺激因子转染,减少T-细胞无反应的方法,使用转染的免疫细胞如细胞因子转染的树突状细胞的方法,使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法,以及使用免疫调节药物沙利度胺和来那度胺的方法。
这种联合治疗可以通过治疗的各个组分的同时、连续或分开的给药来实现。这种组合产品在本文的剂量范围内使用本公开的化合物或其药学上可接受的盐,并且在其批准的剂量范围内使用其它药物活性剂。
管理其他病况
Park等人报道HMGB1通过HIF-1α激活诱导类风湿关节炎中的血管生成。Eur JImmunol,2014,doi:10.1002/eji.201444908。在某些实施方案中,本公开涉及使用本文公开的化合物治疗类风湿性关节炎。
Du等人报道肾酶(Renalase)是低氧诱导因子-1在心脏缺血再灌注损伤保护中的靶基因。Cardiovasc Res,2015,105(2):182-91。在某些实施方案中,本公开涉及使用本文公开的化合物治疗或预防心肌缺血再灌注损伤或缺血性心脏病如高血压性心脏病,冠状动脉疾病,心肌病,心力衰竭,心肌梗塞,心脏心律失常,心内膜炎,炎性心脏肥大,或心肌炎。
线粒体复合物I抑制剂作为农药
鱼藤酮是广谱杀虫剂和农药。它在某些植物的种子和茎中自然产生。鱼藤酮抑制复合物I的活性。因此,在某些实施方案中,本公开涉及使用本文公开的复合物I抑制剂作为杀虫剂和农药的用途。在某些实施方案中,本公开涉及使植物与本文公开的复合物I抑制剂接触以防止害虫进食植物的方法。在某些实施方案中,本公开涉及通过用溶液喷洒作物,种子或土壤或通过包含本文公开的复合物I抑制剂的撒粉来使植物接触。复合物I抑制剂由于扰乱细胞呼吸并杀死或致残害虫或昆虫而防止害虫如昆虫进食植物。
鱼藤酮也以粉末形式用于治疗疥疮和虱子,以及鸡和其他牲畜以及家养宠物的寄生螨虫。在某些实施方案中,本公开涉及通过使受试者的皮肤或毛发与本文公开的复合物I抑制剂对受试者有效的方式接触治疗或预防受试者的皮肤或毛发中携带的害虫,该受试者具有风险、被怀疑、表现出症状或被诊断为有疥疮、虱子、寄生虫或害虫。
在某些实施方案中,本公开涉及包含本文公开的复合物I抑制剂与其它农药或杀虫剂的组合的组合物,所述农药或杀虫剂如有机氯化物,滴滴涕,有机磷酸酯类,拟除虫菊酯,驱虫剂(pyrethrum),新烟碱,尼古丁,吡虫啉,鱼尼汀类(ryanoids),鱼尼汀,氯虫苯甲酰胺(chlorantraniliprole),昆虫生长调节剂,除虫脲,保幼激素类似物,烯虫酯,烯虫乙酯,烯虫炔酯或虫酰肼。
制剂
如下文一般性描述的,本文公开的药物组合物可以是药学上可接受的盐的形式。合适的药学上可接受的有机和/或无机酸的一些优选但非限制性实例是盐酸,氢溴酸,硫酸,硝酸,乙酸和柠檬酸,以及本身已知的其它药学上可接受的酸(参考以下参考文献)。
当本公开的化合物含有酸性基团以及碱性基团时,本公开的化合物还可以形成内部盐,并且这样的化合物在本公开的范围内。当本公开的化合物含有供氢的杂原子(例如NH)时,本公开还涵盖通过将氢原子转移到分子内的碱性基团或原子而形成的盐和/或异构体。
化合物的药学上可接受的盐包括其酸加成盐和其碱盐。合适的酸加成盐由形成无毒盐的酸形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己烷氨基磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸、蔗糖酸盐、硬脂酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和xinofoate盐。合适的碱盐由形成无毒盐的碱形成。实例包括铝、精氨酸、苄星、钙、胆碱、二乙胺、二醇胺、甘氨酸、赖氨酸、镁、葡甲胺、醇胺、钾、钠、氨丁三醇和锌盐。也可以形成酸和碱的半盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use by Stahl and Wermuth(Wiley-VCH,2002),其通过引用并入本文。
本文的化合物可以前药的形式施用。前药可以包括共价键合的载体,当向哺乳动物受试者施用时释放活性母体药物。前药可以通过修饰化合物中存在的官能团来制备,使得修饰物在常规操作中或在体内被切割成母体化合物。前药包括例如其中羟基与向哺乳动物受试者施用时切割形成游离羟基的任何基团键合的化合物。前药的实例包括但不限于化合物中醇官能团的乙酸盐、甲酸盐和苯甲酸盐衍生物。化合物作为前药的结构化方法可见于Testa和Mayer的书Hydrolysis in Drug and Prodrug Metabolism,Wiley(2006)中。典型的前药通过水解酶转化前药,酰胺、内酰胺、肽、羧酸酯、环氧化物的水解或无机酸酯的切割形成活性代谢物。制备酯前药例如游离羟基的乙酰酯完全处于本领域普通技术人员的能力范围内。众所周知的是,酯前药容易在体内降解而释放相应的醇。参见例如Imai,DrugMetab Pharmacokinet.(2006)21(3):173-85,题目为“Human carboxylesteraseisozymes:catalytic properties and rational drug design”。
用于本公开的药物组合物通常包含有效量的化合物和合适的药学上可接受的载体。制剂可以本身已知的方式制备,其通常包括将根据本公开的至少一种化合物与一种或多种药学上可接受的载体混合,并且如果需要,与其它药物活性化合物组合,根据需要在无菌条件下。参考美国专利号6,372,778、美国专利号6,369,086、美国专利号6,369,087和美国专利号6,372,733以及上述进一步的参考文献,以及标准手册,如最新版的Remington'sPharmaceutical Sciences。
通常,对于药物使用,化合物可以配制成包含至少一种化合物和至少一种药学上可接受的载体、稀释剂或赋形剂以及任选地一种或多种其它药学活性化合物的药物制剂。
本公开的药物制剂优选为单位剂量,并且可以适当地包装在例如盒、泡罩、小瓶、瓶、小药囊、安瓿或任何其它合适的单剂量或多剂量持器或容器中(可以适当标记);可选地具有一个或多个包含产品信息和/或使用说明的小册子。通常,这样的单位剂量将含有1至1000mg,通常为5至500mg的至少一种本公开的化合物,例如每单位剂量约10、25、50、100、200、300或400mg。
化合物可以通过各种途径施用,包括口服,眼,直肠,透皮,皮下,静脉内,肌肉内或鼻内途径,主要取决于所用的具体制剂。化合物通常以“有效量”施用,其意指任何量的化合物,其在合适的施用后足以在其所施用的受试者中达到所需的治疗或预防效果。通常,根据待预防或治疗的病况和施用途径,这样的有效量通常为每天每千克患者体重0.01至1000mg,更常见于每天每千克患者体重0.1至500mg,例如1至250mg,例如约5、10、20、50、100、150、200或250mg,其可以单次日剂量施用,分成一个或多个日剂量。待施用的量、施用途径和进一步治疗方案可以由治疗临床医生根据患者的年龄、性别和一般状况,以及要治疗的疾病/症状的性质和严重性等因素确定。参考美国专利号6,372,778、美国专利号6,369,086、美国专利号6,369,087和美国专利号6,372,733以及上述进一步的参考文献,以及标准手册,如最新版的Remington's Pharmaceutical Sciences。
对于口服施用形式,化合物可以与适当的添加剂如赋形剂、稳定剂或惰性稀释剂混合,并通过常规方法加入合适的施用形式,例如片剂,包衣片剂,硬胶囊剂,水性,酒精或油性溶液。合适的惰性载体的实例是阿拉伯树胶,氧化镁,碳酸镁,磷酸钾,乳糖,葡萄糖或淀粉,特别是玉米淀粉。在这种情况下,制剂可以作为干燥和湿润颗粒实现。合适的油性赋形剂或溶剂是植物油或动物油,例如向日葵油或鱼肝油。适用于水或醇溶液的溶剂是水,乙醇,糖溶液或其混合物。聚乙二醇和聚丙二醇也可用作其它施用形式的进一步的助剂。作为立即释放片剂,这些组合物可以含有微晶纤维素,磷酸二钙,淀粉,硬脂酸镁和乳糖和/或本领域已知的其它赋形剂,粘合剂,增量剂,崩解剂,稀释剂和润滑剂。
当通过鼻气雾剂或吸入剂施用时,可以根据药物制剂领域众所周知的技术制备组合物,并且可以使用苄醇或其它合适的防腐剂、吸收促进剂、碳氟化合物和/或本领域已知的其它增溶剂或分散剂制备为盐水中的溶液以提高生物利用度。用于以气溶胶或喷雾剂形式施用的合适的药物制剂是例如本公开的化合物或其生理上可耐受的盐在药学上可接受的溶剂如乙醇或水或此类溶剂的混合物中的溶液、悬浮液或乳液。如果需要,制剂可以另外含有其它药物助剂如表面活性剂、乳化剂和稳定剂以及推进剂。
对于皮下或静脉内施用,化合物(如果需要)与常规的物质如增溶剂、乳化剂或其它助剂一起进入溶液、悬浮液或乳液。化合物也可以被冻干,所得的冻干物例如用于生产注射或输注制剂。合适的溶剂是例如水,生理盐水溶液或醇,例如乙醇,丙醇,甘油,糖溶液如葡萄糖或甘露醇溶液,或所提及的各种溶剂的混合物。可以根据已知技术,使用合适的无毒、肠胃外可接受的稀释剂或溶剂,如甘露醇,1,3-丁二醇,水,林格氏溶液或等渗氯化钠溶液,或合适的分散剂或润湿和悬浮剂,例如无菌,温和,固定油,包括合成的甘油单酯或甘油二酯,和脂肪酸,包括油酸,配制注射液或悬浮液。
当以栓剂的形式直肠施用时,可以通过将式I化合物与适合的无刺激性赋形剂如可可脂、合成甘油酯或聚乙二醇混合来制备制剂,赋形剂在常温下是固体,但在直肠腔中液化和/或溶解以释放药物。
在某些实施方案中,预期这些组合物可以是延长释放制剂。典型的延长释放层使用肠溶衣。通常,将屏障应用于控制消化系统中被吸收的位置的口服药物。肠溶衣阻止药物在到达小肠前释放。肠溶衣可以含有多糖的聚合物,如麦芽糖糊精,黄原胶,硬葡聚糖,葡聚糖,淀粉,藻酸盐,短梗霉聚糖,透明质酸,壳多糖,壳聚糖等;其他天然聚合物,如蛋白质(白蛋白,明胶等),聚-L-赖氨酸;聚(丙烯酸)钠;聚(甲基丙烯酸羟烷基酯)(例如聚(甲基丙烯酸羟乙酯));羧基聚亚甲基(例如CarbopolTM);卡波姆;聚乙烯吡咯烷酮;树胶,如瓜尔胶,阿拉伯树胶,刺梧桐胶,印度树胶,刺槐豆胶,罗望子胶,结冷胶,黄蓍胶,琼脂,果胶,麸质等;聚乙烯醇;乙烯-乙烯醇;聚乙二醇(PEG);和纤维素醚,如羟甲基纤维素(HMC),羟乙基纤维素(HEC),羟丙基纤维素(HPC),甲基纤维素(MC),乙基纤维素(EC),羧乙基纤维素(CEC),乙基羟乙基纤维素(EHEC),羧甲基羟乙基纤维素(CMHEC),羟丙基甲基纤维素(HPMC),羟丙基乙基纤维素(HPEC)和羧甲基纤维素钠(Na CMC);以及任何上述聚合物的共聚物和/或(简单)混合物。
某些上述聚合物还可以通过标准技术进行交联。聚合物的选择将由本公开的组合物中使用的活性成分/药物的性质以及期望的释放速率来确定。特别地,本领域技术人员将会理解,例如在HPMC的情况下,更高的分子量将通常提供较慢的药物从组合物释放的速率。此外,在HPMC的情况下,甲氧基和羟丙氧基的不同取代度将导致药物从组合物释放速率的变化。在这方面,并且如上所述,可能需要以包衣的形式提供本公开的组合物,其中通过两种或更多种例如不同分子量的聚合物的共混物提供聚合物载体,以产生特定所需或期望的释放曲线。
聚丙交酯,聚乙交酯及其共聚物(丙交酯-共-乙交酯)的微球可用于形成缓释蛋白递送系统。蛋白质可以通过多种方法包埋在聚(丙交酯-共-乙交酯)微球库中,包括用水性蛋白和有机溶剂型聚合物形成油包水乳液(乳液法),将固体蛋白质分散在溶剂型聚合物溶液中形成固体油悬浮液(悬浮法),或将该蛋白质溶解在溶剂型聚合物溶液中(溶解法)。人们可以将聚(乙二醇)连接到蛋白质(PEG化)上,以增加循环治疗蛋白的体内半衰期并降低免疫应答的机会。
实验
化合物的合成
溴化物或甲苯磺酰基通过醇的SN2置换的一般程序:将1.0当量醇试剂溶于无水THF中,并在冰浴中冷却。在搅拌下加入1.5当量NaH,30分钟后,加入1.0当量相应的亲电子试剂,反应继续搅拌过夜,同时温热至室温。用饱和NH4Cl淬灭反应物,吸收在乙酸乙酯中,用卤水洗涤,用MgSO4干燥,并通过快速柱色谱纯化。
将芳基溴和芳基醛偶联以形成醇的一般程序:在氩气下将1.0当量芳基溴溶于无水THF中,并在干冰/丙酮浴中冷却。20分钟后,加入1.4当量的n-BuLi。20分钟后,加入1.4当量的芳基醛。将反应在干冰/丙酮浴中搅拌40分钟,然后使反应温度达到室温,然后用饱和NH4Cl淬灭。将反应混合物吸收在乙酸乙酯中,用卤水洗涤,用MgSO4干燥,并通过快速柱色谱纯化。以下是选择化合物的示例性表征数据。
(3,4-二甲氧基苯基)(4-((((S)-四氢呋喃-3-基)氧基)甲基)苯基)甲醇(3a)。
收率:94%。1H NMR(400MHz,CDCl3):δ7.26-7.24(d,J=7.6Hz,2H),7.19-7.17(d,J=7.6Hz,2H),6.83(s,1H),6.76-6.74(d,J=8.5Hz,1H),6.69-6.67(d,J=8.4Hz,1H),5.58(s,1H),4.35(s,2H),4.06(s,1H),3.73-3.60(m,10H),1.91-1.81(m,2H)ppm。C20H23O5[(M-H)-]的HRMS(ESI)m/z计算为343.1545,发现为343.1532。
(4-(丁氧基甲基)苯基)(3,4-二甲氧基苯基)甲醇(3i)。
1H NMR(400MHz,CDCl3):δ7.34-7.32(d,J=8Hz,2H),7.30-7.28(d,J=8.0Hz,2H),6.90(s,1H),6.87-6.85(d,J=8.0Hz,1H),6.81-6.79(d,J=8.0Hz,1H),5.76(s,1H),4.46(s,2H),3.84(s,3H),3.83(s,3H),3.47-3.44(t,J=6.0Hz,2H),2.38(s,1H),1.62-1.54(m,2H),1.40-1.35(m,2H),0.92-0.88(t,J=8.0Hz,3H)ppm。
4-((3-((3,4-二甲氧基苯基)(羟基)甲基)苄基)氧基)哌啶-1-甲酸叔丁酯(6b)。
1H NMR(400MHz,CDCl3):δ7.37(s,1H),7.34-7.26(m,3H),6.94(s,1H),6.90-6.88(d,J=8.0Hz,1H),7.6.84-6.82(d,J=8.0Hz,1H),4.55(s,2H),3.88(s,3H),3.86(s,3H),3.76(m,2H),3.57-3.54(m,1H),3.12-3.06(m,2H),1.84(m,2H),1.62-1.57(m,2H),1.47(s,9H)ppm。
4-(2-(4-((3,4-二甲氧基苯基)(羟基)甲基)-3-甲基苯氧基)乙基)哌啶-1-甲酸叔丁酯(35e)。
1H NMR(400MHz,CDCl3)δ7.37(d,J=8.0Hz,1H),6.92(s,1H),6.83(s,2H),6.80–6.68(m,2H),5.94(s,1H),4.32-4.11(m,2H),4.02(t,J=5.6Hz,2H),3.88(s,3H),3.86(s,3H),2.75-2.71(m,2H),2.27(s,3H),2.03(s,1H),1.75-1.71(m,5H),1.48(s,9H),1.26–1.12(m,2H)ppm。
4-(2-(4-(羟基(3,4,5-三甲氧基苯基)甲基)-3-甲基苯氧基)乙基)哌啶-1-甲酸叔丁酯(35g)。
1H NMR(400MHz,CDCl3)δ7.29(d,J=8.0Hz,1H),6.75-6.72(m,2H),6.58(s,2H),5.90(s,1H),4.17–4.03(m,2H),3.99(t,J=5.6Hz,2H),3.83(s,3H),3.81(s,6H),2.76-2.66(m,2H),2.30(s,3H),2.11(s,1H),1.75-1.69(m,5H),1.45(s,9H),1.23–1.09(m,2H)ppm。
抑制神经胶质瘤细胞外源性HRE报道构建体驱动的低氧诱导基因表达
通过用双向报道构建体(pBIGL-V6R)稳定转染人LN229神经胶质瘤细胞产生LN229HRE-luc/lacZ细胞,其中萤火虫萤光素酶和LacZ报道基因处于VEGF HRE(低氧反应元件-内源性HIF-1靶基因)的6个头尾串联拷贝以如在Yin et al.Clinical CancerResearch,2012,1-11报道的向右取向的控制下(克隆LN229V6R#18;Hygro选择600mg/mL)。
细胞用不同剂量的测试化合物或1%DMSO(介质中的最终浓度)载体对照在正常氧气(21%O2)下预处理1小时;然后使用低氧培养箱(Thermo Forma型号3130),在常氧或低氧(1%O2)下继续培养。在20/20n Luminometer(Promega)中用双荧光素酶报道基因测定系统(Promega)测量LN229HRE-luc/LacZ细胞裂解物中的萤火虫荧光素酶活性。从剂量反应曲线确定每种化合物的IC50(μM)值。
线粒体抑制
复合物I(NADH:泛醌氧化还原酶或NADH脱氢酶(泛醌))是呼吸链酶复合物,其催化电子从NADH转移到位于线粒体内膜中的辅酶Q10(CoQ10)。Ellinghaus等人报道BAY 87-2243抑制HIF-1α。Cancer Medicine,2013,2(5):611–624。在H460异种移植模型中证明了BAY 87-2243在体内的抗肿瘤活性。BAY 87-2243也抑制线粒体复合物I活性。干扰线粒体功能从而减少低氧诱导的肿瘤中的HIF-1活性被示为克服低氧性肿瘤的化疗和放疗抗药性的治疗方法。Helbig等人报道BAY 87-2243在头颈部人异种移植物中按照时间表依赖性方式分级照射后改善局部肿瘤控制。Radiation Oncology 2014,9:207。Santidrian等人报道线粒体复合物I活性和NAD+/NADH平衡调节乳腺癌进展。J Clin Invest,2013,123(3):1068-81。另见Ellinghaus et al.,Cancer Med,2013,2(5):611-624.Chang et al.,ClinCancer Res,2015,21(2):335-46;Fulda et al.,Antioxid Redox Signal,2011,15:2937–2949;Wenner,J Cell Physiol,2012,227:450–456;Fulda et al.,Nat Rev Drug Discov,2010,9:447–464。
已经发现本文公开的某些HIF抑制剂也是线粒体抑制剂。KCN1在来自CaymanChemicals#700930的MitoCheck Complex I活性测定中的IC50为约15μM,64b为约15μM,化合物208为约0.5nM,化合物210为约40nM。参见图9和10。KCN1是一种HIF抑制剂,其由于葡萄糖消耗被认为是由于乳酸生成增加而强烈酸化细胞培养基。KCN1诱导培养基酸化可能是由于其线粒体抑制活性的结果。抑制线粒体复合物I干扰电子传递链的正常功能。这实际上可以损害线粒体的DNA和特定成分,其通过产生活性氧物质导致细胞死亡。
为了被代谢,半乳糖必须在能量消耗过程中转化为葡萄糖,这不能通过糖酵解代谢平衡。因此,在半乳糖中生长的细胞主要依靠氧化磷酸化产生ATP,并且比在高葡萄糖培养基中生长的细胞对线粒体抑制剂更敏感。在半乳糖存在下KCN1对LN229细胞有毒性。该数据表明与本文公开的线粒体复合物I抑制剂组合给予受试者无糖饮食(半乳糖或生酮饮食)可能是有益的。因此,在某些实施方案中,本公开涉及将本文公开的化合物与限制性或低葡萄糖饮食组合施用,任选与半乳糖组合。
Claims (12)
1.具有式I的化合物
或其盐,其中:
A是苯基;
n为1、2或3
R4和R7各自单独地并且独立地为氢、C1-4烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、C1-4烷氧基、C1-4羟烷基、C1-4烷硫基、C1-4硫代烷基、C1-4烷基氨基、C1-4氨基烷基、C1-4(烷基)2氨基、C1-4烷酰基、C1-4烷氧基羰基、C1-4烷基亚磺酰基或C1-4烷基磺酰基;
R5和R6各自是C1-4烷氧基;
各R9是被相同或不同R20取代的C1-4烷氧基;
R20是杂环基,其选自吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰氨基、环氧乙烷基、氧杂环丁基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢噻吩基、四氢噻喃基、四氢嘧啶基、呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、吡咯基、吲哚基、异吲哚基、氮杂吲哚基、吡啶基、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噌啉基、酞嗪基和喹唑啉基,其中R20被一个或多个相同或不同的R21取代;以及
R21是卤素、硝基、氰基、羟基、三氟甲氧基、三氟甲基、氨基、甲酰基、羧基、氨基甲酰基、巯基、氨磺酰基、甲基、乙基、甲氧基、乙氧基、异丙氧基、叔丁氧基、羟甲基、羟乙基、硫代甲基、硫代乙基、氨基甲基、氨基乙基、乙酰基、乙酰氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、N-甲基-N-乙基氨基、乙酰氨基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N,N-二甲基氨基甲酰基、N,N-二乙基氨基甲酰基、N-甲基-N-乙基氨基甲酰基、甲硫基、乙硫基、甲基亚磺酰基、乙基亚磺酰基、甲磺酰基、乙基磺酰基、甲氧基羰基、乙氧基羰基、异丙氧基羰基、叔丁氧基羰基、N-甲基氨磺酰基、N-乙基氨磺酰基、N,N-二甲基氨磺酰基、N,N-二乙基氨磺酰基或N-甲基-N-乙基氨磺酰基。
2.根据权利要求1所述的化合物,其中R9是((哌啶-4-基)氧基)甲基或(((N-烷氧基羰基)哌啶-4-基)氧基)甲基。
3.根据权利要求1或2所述的化合物,其中R9是(2-哌啶-4-基)乙氧基或(2-(N-烷氧基羰基)哌啶-4-基)乙氧基。
4.具有式II的化合物,
及其盐,其中
X是-CH2O-或-CH2CH2O-;
R12是杂环基,其选自吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰氨基、环氧乙烷基、氧杂环丁基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢噻吩基、四氢噻喃基、四氢嘧啶基、呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、吡咯基、吲哚基、异吲哚基、氮杂吲哚基、吡啶基、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噌啉基、酞嗪基和喹唑啉基,其中R12被一个或多个相同或不同的R20取代;
R20是C1-4烷基、卤素、硝基、氰基、羟基、氨基、巯基、甲酰基、羧基、氨基甲酰基、C1-4羟烷基、C1-4烷氧基、C1-4硫代烷基、C1-4烷硫基、C1-4氨基烷基、C1-4烷基氨基、C1-4(烷基)2氨基、C1-4烷酰基、C1-4烷氧基羰基、C1-4烷基亚磺酰基或C1-4烷基磺酰基,其中R20被一个或多个相同或不同的R21取代;以及
R21是卤素、硝基、氰基、羟基、三氟甲氧基、三氟甲基、氨基、甲酰基、羧基、氨基甲酰基、巯基、氨磺酰基、甲基、乙基、甲氧基、乙氧基、异丙氧基、叔丁氧基、羟甲基、羟乙基、硫代甲基、硫代乙基、氨基甲基、氨基乙基、乙酰基、乙酰氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、N-甲基-N-乙基氨基、乙酰氨基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N,N-二甲基氨基甲酰基、N,N-二乙基氨基甲酰基、N-甲基-N-乙基氨基甲酰基、甲硫基、乙硫基、甲基亚磺酰基、乙基亚磺酰基、甲磺酰基、乙基磺酰基、甲氧基羰基、乙氧基羰基、异丙氧基羰基、叔丁氧基羰基、N-甲基氨磺酰基、N-乙基氨磺酰基、N,N-二甲基氨磺酰基、N,N-二乙基氨磺酰基或N-甲基-N-乙基氨磺酰基;
R2是氢、C1-4烷基、卤素或C1-4烷氧基;
R3是氢、C1-4烷基、卤素或C1-4烷氧基;
R4、R7和R8各自是氢;
R10是C1-4烷基、甲酰基、烷酰基、氨基甲酰基、C1-4羟烷基、C1-4氨基烷基或C1-4硫代烷基,其中R10任选被一个或多个相同或不同的R20取代;以及
R15是C1-4烷基、甲酰基、烷酰基、氨基甲酰基、C1-4羟烷基、C1-4氨基烷基或C1-4硫代烷基,其中R15任选被一个或多个相同或不同的R20取代。
5.根据权利要求4所述的化合物,其中X是-CH2CH2O-。
6.根据权利要求1所述的化合物,其选自:
4-((3-((3,4-二甲氧基苯基)(羟基)甲基)苄基)氧基)哌啶-1-甲酸叔丁酯,
4-(2-(4-(羟基(3,4-二甲氧基苯基)甲基)-3-甲基苯氧基)乙基)哌啶-1-甲酸叔丁酯,以及
4-(2-(4-(羟基(3,4,5-三甲氧基苯基)甲基)-3-甲基苯氧基)乙基)哌啶-1-甲酸叔丁酯。
7.药物组合物,其包含根据权利要求1~6任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的赋形剂。
8.根据权利要求1~6任意一项所述的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
9.根据权利要求8所述的用途,其中所述的癌症选自胶质母细胞瘤、乳腺癌、眼癌、胰腺癌、结肠癌、膀胱癌、肺癌、黑素瘤、结肠和直肠癌、非霍奇金淋巴瘤、子宫内膜癌、肾癌、前列腺癌、白血病、甲状腺癌和脑癌。
10.根据权利要求8所述的用途,其中所述的癌症是转移性肺癌。
11.根据权利要求9或10所述的用途,其中所述的药物进一步包含第二抗癌剂。
12.根据权利要求11所述的用途,其中所述的第二抗癌剂是替莫唑胺、卡莫司汀、贝伐珠单抗、甲基苄肼、洛莫司汀、长春新碱、吉非替尼、厄洛替尼、多西他赛、顺铂、5-氟尿嘧啶、吉西他滨、替加氟、雷替曲塞、甲氨蝶呤、阿糖胞苷、羟基脲、阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、更生霉素和光神霉素、长春花碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇、依托泊苷、替尼泊苷、安吖啶、托泊替康、喜树碱、硼替佐米、阿那格雷、他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、iodoxyfene、氟维司群、比卡鲁胺、氟他胺、尼鲁米特、环丙孕酮、戈舍瑞林、亮丙瑞林、布舍瑞林、甲地孕酮、阿那曲唑、来曲唑、伏氯唑、依西美坦、非那雄胺、马立马司他、曲妥珠单抗、西妥昔单抗、达沙替尼、伊马替尼、考布他汀、沙利度胺、和/或来那度胺或其组合。
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