CN1809354A - Akt活性抑制剂 - Google Patents
Akt活性抑制剂 Download PDFInfo
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- CN1809354A CN1809354A CNA200480017118XA CN200480017118A CN1809354A CN 1809354 A CN1809354 A CN 1809354A CN A200480017118X A CNA200480017118X A CN A200480017118XA CN 200480017118 A CN200480017118 A CN 200480017118A CN 1809354 A CN1809354 A CN 1809354A
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- Prior art keywords
- phenyl
- methyl
- piperidines
- tfa
- benzyl
- Prior art date
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Abstract
本发明涉及含取代吡啶部分的化合物,所述化合物抑制Akt(一种丝氨酸/苏氨酸蛋白激酶)的活性。本发明还涉及含本发明化合物的化疗组合物以及包括给予本发明化合物的癌症治疗方法。
Description
发明背景
本发明涉及含取代吡啶的化合物,所述化合物是丝氨酸/苏氨酸激酶Akt(也称为PKB;下文简称“Akt”)的一种或多种同工型的活性抑制剂。本发明还涉及包含这种化合物的药物组合物以及使用本发明化合物治疗癌症的方法。
细胞凋亡(程序性细胞死亡)在胚胎的发育和各种疾病(如退行性神经元疾病、心血管疾病和癌症)的发病机制中起到主要的作用。最近研究已鉴定出涉及程序性细胞死亡的调节或执行的各种促细胞凋亡和抗细胞凋亡基因产物。抗细胞凋亡基因如Bcl2或Bcl-xL的表达能抑制各种刺激因素诱导的细胞凋亡。另一方面,促细胞凋亡基因如Bax或Bad的表达会导致程序性细胞死亡(Aams等,Science,281:1322-1326(1998))。程序性细胞死亡的执行是由胱天蛋白酶-1相关蛋白酶介导的,包括胱天蛋白酶-3、胱天蛋白酶-7、胱天蛋白酶-8和胱天蛋白酶-9等(Thornberry等,Science,281:1312-1316(1998))。
磷脂酰肌醇3′-OH激酶(PI3K)/Akt途径对调节细胞生存/细胞死亡似乎很重要(Kulik等,Mol.Cell.Biol.17:1595-1606(1997);Franke等,Cell,88:435-437(1997);Kauffmann-Zeh等,Nature 385:544-548(1997)Hemmings Science,275:628-630(1997);Dudek等,Science,275:661-665(1997))。生存因子,如血小板衍生生长因子(PDGF)、神经生长因子(NGF)和胰岛素样生长因子-1(IGF-1),能通过诱导PI3K的活性促进细胞在各种条件下的生存(Kulik等,1997,Hemmings 1997)。活化PI3K导致产生磷脂酰肌醇(3,4,5)-三磷酸(PtdIns(3,4,5)-P3),后者又结合到含普列克底物蛋白同源性(PH)-结构域的丝氨酸/苏氨酸激酶Akt并促进其激活(Franke等,Cell,81:727-736(1995);Hemmings Science,277:534(1997);Downward,Curr.Opin.Cell Biol.10:262-267(1998),Alessi等,EMBO J.15:6541-6551(1996))。PI3K的特异性抑制剂或显性失活Akt突变体会完全破坏这些生长因子或细胞因子的促生存活性。之前揭示PI3K抑制剂(LY294002或渥曼青霉素)会阻断上游激酶对Akt的活化。此外,组成性活化PI3K或Akt突变体的引入能促进细胞在通常会发生细胞凋亡的条件下生存(Kulik等,1997,Dudek等,1997)。
已鉴定出第二信使调节的丝氨酸/苏氨酸蛋白激酶Akt亚家族的三个成员,并分别命名为Akt1/PKBα、Akt2/PKBβ和Akt3/PKBγ(以下简称“Akt1”、“Akt2”和“Akt3”)。这些同工型是同源的,特别是在编码催化域的区域。通过应答PI3K信号时出现的磷酸化,Akt被活化。PI3K磷酸化膜上肌醇磷脂,产生第二信使磷脂酰肌醇3,4,5-三磷酸和磷脂酰肌醇3,4-二磷酸,后两者已证实能结合Akt的PH结构域。现有的Akt活化模型提出通过3′-磷酸化的磷酸肌醇将酶募集到膜上,而上游激酶对Akt调节位点的磷酸化作用在膜上进行(B.A.Hemmings,Science 275:628-630(1997);B.A.Hemmings,Science276:534(1997);J.Downward,Science 279:673-674(1998))。
Akt1的磷酸化出现在两个调节位点:催化域活化环中的Thr308和靠近羧基末端的Ser473(D.R.Alessi等,EMBO J.15:6541-6551(1996)和R.Meier等,J.Biol.Chem.272:30491-30497(1997))。在Akt2和Akt3中也出现等效的磷酸化调节位点。在活化环位点磷酸化Akt的上游激酶已被克隆,并被命名为3′-磷酸肌醇依赖性蛋白激酶(PDK1)。PDK1不仅磷酸化Akt,也磷酸化p70核醣体S6激酶、p90RSK、血清和糖皮质激素调节的激酶(SGK)及蛋白激酶C。还没有鉴定出磷酸化靠近羧基末端的Akt调节位点的上游激酶,但最近报告暗示了整联蛋白偶联激酶(ILK-1,一种丝氨酸/苏氨酸蛋白激酶)或自身磷酸化的作用。
对人肿瘤中Akt水平的分析显示,Akt2在为数众多的卵巢癌(J.Q.Cheng等,Proc.Natl.Acad.Sci.U.S.A.89:9267-9271(1992))和胰腺癌中(J.Q.Cheng等,Proc.Natl.Acad.Sci.U.S.A.93:3636-3641(1996))过量表达。与此相似,发现Akt3在乳腺癌和前列腺癌细胞系中过量表达(Nakatani等,J.Biol.Chem.274:21528-21532(1999)。
肿瘤抑制蛋白PTEN,一种特异性去除PtdIns(3,4,5)-P3的3′-磷酸的蛋白质和脂质磷酸酶,是PI3K/Akt途径的负调节蛋白(Li等,Science 275:1943-1947(1997),Stambolic等,Cell 95:29-39(1998),Sun等,Proc.Natl.Acad.Sci.U.S.A.96:6199-6204(1999))。PTEN的种系突变引起人类癌症综合征如Cowden病(Liaw等,Nature Genetics 16:64-67(1997))。PTEN在大多数人肿瘤中缺失,无功能性PTEN的肿瘤细胞系显示活化Akt水平升高(Li等,出处同上,Guldberg等,CancerResearch 57:3660-3663(1997),Risinger等,Cancer Research 57:4736-4738(1997))。
以上这些观察结果表明,PI3K/Akt途径对于调节肿瘤发生中的细胞生存或者细胞凋亡起到重要的作用。
Akt活化和活性的抑制可通过用抑制剂如LY294002或渥曼青霉素抑制PI3K来实现。但是,PI3K的抑制可能会不加区别地影响所有三种Akt同工酶以及其他依赖PtdIns(3,4,5)-P3的含PH结构域信号分子,如酪氨酸激酶的Tec家族。此外,已揭示Akt可通过不依赖于PI3K的生长信号激活。
另外,Atk活性可通过阻断上游激酶PDK1的活性来抑制。还没有特异性PDK1抑制剂被公开。而且,PDK1的抑制会导致其活性依赖于PDK1的多种蛋白激酶,如非典型PKC同工型、SGK和S6激酶被抑制(Williams等,Curr.Biol.10:439-448(2000)。
本发明的一个目标是提供作为Akt抑制剂的新型化合物。
本发明的又一个目标是提供包含作为Akt抑制剂的新型化合物的药物组合物。
本发明的还一个目标是提供治疗癌症的方法,所述方法包括给予这种Akt活性抑制剂。
发明概述
本发明提供包含取代吡啶的化合物,所述化合物能抑制Akt活性。具体地说,所公开的化合物能选择性抑制一种或两种Akt同工型。本发明还提供包含这种抑制性化合物的组合物,以及通过将化合物给予需要治疗癌症的患者来抑制Akt活性的方法。
发明详述
本发明化合物可用于抑制丝氨酸/苏氨酸激酶Akt的活性。在本发明的第一个实施方案中,Akt活性抑制剂是式A所示的化合物或其药物可接受盐或立体异构体:
其中:
a是0或1;b是0或1;m是0、1或2;n是0、1、2或3;p是0、1或2;q是0、1、2或3;r是0或1;s是0或1;t是2、3、4、5或6;
为杂环基;
Q选自:C1-C6烷基、卤素、-NR6R7、芳基和杂环基,所述烷基、芳基和杂环基任选被1-3个RZ取代;
R1独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)bNR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)氧代、18)CHO、19)NO2、20)NRc(C=O)ObRa、21)O(C=O)ObC1-C10烷基、22)O(C=O)ObC3-C8环烷基、23)O(C=O)Ob芳基、24)C0-C6烷基(C=NRb)N(Rb)2、25)O(C=O)Ob-杂环、26)Oa-P=O(OH)2和27)-N=CHN(Rb)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个或多个选自RZ的取代基取代;
R2独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)NR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)CHO、18)NO2、19)NRc(C=O)ObRa、20)O(C=O)ObC1-C10烷基、21)O(C=O)ObC3-C8环烷基、22)O(C=O)Ob芳基、23)O(C=O)Ob-杂环和24)Oa-P=O(OH)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个、两个或三个选自RZ的取代基取代;
R3和R4独立选自:H、C1-C6-烷基和C1-C6-全氟烷基,或者R3和R4结合在一起形成-(CH2)t-,其中一个碳原子任选被选自O、S(O)m、-N(Rb)C(O)-和-N(CORa)-的部分置换;
R5独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)NR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)氧代、18)CHO、19)NO2、20)O(C=O)ObC1-C10烷基、21)O(C=O)ObC3-C8环烷基和22)Oa-P=O(OH)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个或多个选自RZ的取代基取代;
R6和R7独立选自:1)H、2)(C=O)ObRa、3)C1-C10烷基、4)芳基、5)C2-C10烯基、6)C2-C10炔基、7)杂环基、8)C3-C8环烷基、9)SO2Ra、10)(C=O)NRb 2、11)OH和12)Oa-P=O(OH)2,所述烷基、环烷基、芳基、杂环基、烯基和炔基任选被一个或多个选自Rz的取代基取代;或R6和R7可与它们连接的氮一起形成单环或双环杂环,每个环4-7元,除氮外任选包含一个或多个选自N、O和S的其它杂原子,所述单环或双环杂环任选被一个或多个选自RZ的取代基取代;
RZ独立选自:1)(C=O)rOs(C1-C10)烷基、2)Or(C1-C3)全氟烷基、3)(C0-C6)亚烷基-S(O)mRa、4)氧代、5)OH、6)卤素、7)CN、8)(C=O)rOs(C2-C10)烯基、9)(C=O)rOs(C2-C10)炔基、10)(C=O)rOs(C3-C6)环烷基、11)(C=O)rOs(C0-C6)亚烷基-芳基、12)(C=O)rOs(C0-C6)亚烷基-杂环基、13)(C=O)rOs(C0-C6)亚烷基-N(Rb)2、14)C(O)Ra、15)(C0-C6)亚烷基-CO2Ra、16)C(O)H、17)(C0-C6)亚烷基-CO2H、18)C(O)N(Rb)2、19)S(O)mRa、20)S(O)2N(Rb)2、21)NRc(C=O)ObRa、22)O(C=O)ObC1-C10烷基、23)O(C=O)ObC3-C8环烷基、24)O(C=O)Ob芳基、25)O(C=O)Ob-杂环和26)Oa-P=O(OH)2,所述烷基、烯基、炔基、环烷基、芳基和杂环基任选被最多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代、N(Rb)2和Oa-P=O(OH)2的取代基取代;
Ra为:取代或未取代的(C1-C6)烷基、取代或未取代的(C2-C6)烯基、取代或未取代的(C2-C6)炔基、取代或未取代的(C3-C6)环烷基、取代或未取代的芳基、(C1-C6)全氟烷基、2,2,2-三氟乙基或者取代或未取代的杂环基;
Rb为:H、(C1-C6)烷基、取代或未取代的芳基、取代或未取代的苄基、取代或未取代的杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra;
Rc选自:1)H、2)C1-C10烷基、3)芳基、4)C2-C10烯基、5)C2-C10炔基、6)杂环基、7)C3-C8环烷基和8)C1-C6全氟烷基,所述烷基、环烷基、芳基、杂环基、烯基和炔基任选被一个或多个选自Rz的取代基取代。
本发明的第二个实施方案是式B所示的化合物或其药物可接受盐或立体异构体:
其中:
所有取代基和变量如第一个实施方案中所定义。
本发明的第三个实施方案是式B所示的化合物或其药物可接受盐或立体异构体,其中:
Q选自:任选被1-3个RZ取代的-NR6R7、苯基和杂环基;
Ra为:(C1-C6)烷基、(C3-C6)环烷基、芳基或杂环基;
Rb为:H、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra;所有其它取代基和变量如第二个实施方案中所定义。
本发明的第四个实施方案是式B所示的化合物或其药物可接受盐或立体异构体,其中:
q为0;
R2独立选自:1)C1-C6烷基、2)芳基、3)杂环基、4)CO2H、5)卤素、6)CN、7)OH、8)S(O)2NR6R7和9)Oa-P=O(O(OH)2,所述烷基、芳基和杂环基任选被一个、两个或三个选自RZ的取代基取代;所有其它取代基和变量如第三个实施方案中所定义。
本发明的第五个实施方案是式C所示的化合物或其药物可接受盐或立体异构体:
其中:
n为0、1或2;
Q选自:任选被1-3个RZ取代的杂环基;所有其它取代基和变量如第四个实施方案中所定义。
本发明的具体化合物包括:
1)6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
2)6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
3)6-(4-{[4-(1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
4)6-(4-{[4-(6-甲基-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
5)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
6)6-(4-{[4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
7)6-(4-{[4-(苄基氨基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
8)6-{4-[(4-异喹啉-1-基哌嗪-1-基)甲基]苯基}-5-苯基烟腈;
9)6-(4-{[4-(4-甲基-4H-1,2,4-三唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈;
10)6-(4-{[4-(1,2-苯并异噻唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈;
11)6-(4-{[5-(4-氟苯基)-2,5-二氮杂二环[2.2.1]庚-2-基]甲基}苯基)-5-苯基烟腈;
12)6-(4-{[4-(2-氧代-3,4-二氢喹啉-1(2H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
13)5-苯基-6-{4-[(4-苯基哌啶-1-基)甲基]苯基}烟腈;
14)6-{4-[(4-氟哌啶-1-基)甲基]苯基}-5-苯基烟腈;
15)6-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-5-苯基烟腈;
16)6-[4-(吗啉-4-基甲基)苯基]-5-苯基烟腈;
17)6-(4-{[4-(2-氧代-2H-3,1-苯并噁嗪-1(4H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
18)4-氯-N-{1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]哌啶-4-基}-N-环丙基苯磺酰胺;
19)5-苯基-6-(4-{[4-(3-吡啶-3-基-1,2,4-噁二唑-5-基)哌啶-1-基]甲基}苯基)烟腈;
20)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮(1-6);
21)6-(4-{[4-(1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
22)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
23)2-甲基-1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
24)2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
25)5-甲基-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
26)5-氟-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
27)N-苄基-1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-胺;
28)N-{(3R)-1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]吡咯烷-3-基}-N′-乙基脲;
29)N-乙基-N′-((3R)-1-{4-[3-苯基-5-(2H-四唑-5-基)吡啶-2-基]苄基}吡咯烷-3-基)脲;
30)6-(4-{[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
31)9-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-9H-嘌呤-6-胺;
32)5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈;
33)N-{(3R)-1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]吡咯烷-3-基}-N′-吡啶-4-基脲;
34)6-(4-{[4-(4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
35)6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
36)5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)烟腈;
37)5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)烟腈;
38)2-氯-6-(4-{[4-(2-氧代-2,3--二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基]-5-苯基烟腈(2-6);
39)2-氯-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(2-7);
40)6-(4-{[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟腈(2-8);
41)2-氯-6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(2-9);
42)2-氯-6-(4-{[4-(4-氧化(oxido)-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(2-10);
43)2-氯-5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈(2-11);
44)6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟腈(2-12);
45)2-氟-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(2-13);
46)6-(4-[[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟酰胺(2-14);
47)2-氯-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟酰胺(2-15);
48)2-氯-6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟酰胺(2-16);
49)6-氟-2-(1-{4-[5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(3-3);
50)6-氟-2-(1-{4-[5-(5-甲基-1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(3-4);
51){2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1H-咪唑-5-基}甲醇(3-5);
52)2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-4,5-二氢-1H-咪唑-5-甲酰胺(3-6);
53)2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-甲脒(3-7);
54)1-(1-{4-[6-氯-5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮(3-8);
55)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-3-(1H-咪唑-2-基)-5-苯基吡啶-2-甲腈(3-9);
56)6-氟-2-(1-{4-[6-氟-5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(3-10);
57)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(4A-5);
58)5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4B-6);
59)5-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1,3,4-噻二唑-2-胺(4-1);
60)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-2);
61)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-3);
62)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-4);
63)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-5);
64)5-[5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-6);
65)5-[5-苯基-6-(4-{[4-(4-嘧啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-7);
66)5-[5-苯基-6-(4-{[4-(4-吡嗪-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4-8);
67)5-{5-苯基-6-[4-({4-[4-(1,3-噻唑-4-基)-1H-吡唑-1-基]哌啶-1-基}甲基)苯基]吡啶-3-基}-1,3,4-噻二唑-2-胺(4-9);
68)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(4-10);
69)5-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3,4-噻二唑-2-胺(4-11);
70)N-((3R)-1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}吡咯烷-3-基)-N′-吡啶-4-基脲(4-12);
71)N-乙基-N′-{5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-基}脲(4-13);
72)2-[2-(二甲氨基)乙氧基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(5-1);
73)2-甲氧基-6-(4-{[4-(2-氧代-2,3--二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(5-2);
74)2-乙氧基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(5-3);
75)2-(2-吗啉-4-基乙氧基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(5-4);
76)2-(甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-1);
77)2-(二甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-2);
78)2-氨基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-3);
79)2-[(2-吗啉-4-基乙基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-4);
80)2-{[2-(二甲氨基)乙基]氨基}-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-5);
81)2-[4-(2-羟基乙基)哌嗪-1-基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-6);
82)2-[(4-甲氧基苄基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-7);
83)N-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]-N′-乙基脲(7-1);
84)N-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]乙酰胺(7-2);
85)N′-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]-N,N-二甲基亚氨基甲酰胺(7-3);
86)6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶4-基)-1H-苯并咪唑(8-1);
87)9-(1-{4-[6-氯-3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶4-基)-9H-嘌呤-6-胺(8-2);
88)1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9-3);
89)1-(1-{4-[3-苯基-5-(1H-1,2,4-三唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9-4);
90)1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(10-5);
91)1-{1-[4-(5′-苯基-2,3′-联吡啶-6′-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶4-胺(10-6);
92)5-[2-({4-[2-(甲硫基)-6-苯基吡啶并[2,3-d]嘧啶-7-基]苄基}氨基)乙基]-1,3,4-噻二唑-2-胺(10-7);
或其药物可接受盐或立体异构体。
本发明化合物的具体盐包括:
1)6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
2)6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
3)6-(4-{[4-(1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
4)6-(4-{[4-(6-甲基-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
5)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
6)6-(4-{[4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
7)6-(4-{[4-(苄基氨基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
8)6-{4-[(4-异喹啉-1-基哌嗪-1-基)甲基]苯基}-5-苯基烟腈(TFA);
9)6-(4-{[4-(4-甲基-4H-1,2,4-三唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈(TFA);
10)6-(4-{[4-(1,2-苯并异噻唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈(TFA);
11)6-(4-{[5-(4-氟苯基)-2,5-二氮杂二环[2.2.1]庚-2-基]甲基}苯基)-5-苯基烟腈(TFA);
12)6-(4-{[4-(2-氧代-3,4-二氢喹啉-1(2H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
13)5-苯基-6-{4-[(4-苯基哌啶-1-基)甲基]苯基}烟腈(TFA);
14)6-{4-[(4-氟哌啶-1-基)甲基]苯基}-5-苯基烟腈(TFA);
15)6-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-5-苯基烟腈(TFA);
16)6-[4-(吗啉-4-基甲基)苯基]-5-苯基烟腈(TFA);
17)6-(4-{[4-(2-氧代-2H-3,1-苯并噁嗪-1(4H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
18)4-氯-N-{1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]哌啶-4-基}-N-环丙基苯磺酰胺(TFA);
19)5-苯基-6-(4-{[4-(3-吡啶-3-基-1,2,4-噁二唑-5-基)哌啶-1-基]甲基}苯基)烟腈(TFA);
20)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮(TFA,1-6);
21)6-(4-{[4-(1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
22)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
23)2-甲基-1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
24)2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
25)5-甲基-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
26)5-氟-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
27)N-苄基-1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-胺(TFA);
28)N-乙基-N′-((3R)-1-{4-[3-苯基-5-(2H-四唑-5-基)吡啶-2-基]苄基}吡咯烷-3-基)脲(TFA);
29)9-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基)哌啶-4-基)-9H-嘌呤-6-胺(TFA);
30)6-(4-{[4-(4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(HCl);
31)6-氟-2-(1-{4-[5-(5-甲基-1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA,3-4);
32){2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1H-咪唑-5-基}甲醇(TFA,3-5);
33)2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-4,5-二氢-1H-咪唑-5-甲酰胺(TFA,3-6);
34)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,4A-5);
35)5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4B-6);
36)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-2);
37)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-3);
38)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-4);
39)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-5);
40)5-[5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-6);
41)5-[5-苯基-6-(4-{[4-(4-嘧啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-7);
42)5-[5-苯基-6-(4-{[4-(4-吡嗪-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA,4-8);
43)5-{5-苯基-6-[4-({4-[4-(1,3-噻唑-4-基)-1H-吡唑-1-基]哌啶-1-基}甲基)苯基]吡啶-3-基}-1,3,4-噻二唑-2-胺(TFA,4-9);
44)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(TFA,4-10);
45)5-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3,4-噻二唑-2-胺(TFA,4-11);
46)N-((3R)-1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}吡咯烷-3-基)-N′-吡啶-4-基脲(TFA,4-12);
47)N-乙基-N′-{5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-基}脲(TFA,4-13);
48)2-[2-(二甲氨基)乙氧基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,5-1);
49)2-乙氧基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,5-3);
50)2-(2-吗啉-4-基乙氧基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,5-4);
51)2-(甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,6-1);
52)2-(二甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,6-2);
53)2-[(2-吗啉-4-基乙基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,6-4);
54)2-{[2-(二甲氨基)乙基]氨基}-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,6-5);
55)2-[4-(2-羟基乙基)哌嗪-1-基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA,6-6);
56)6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA,8-1);
57)9-(1-{4-[6-氯-3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-9H-嘌呤-6-胺(TFA,8-2);
58)1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,9-3);
59)1-(1-{4-[3-苯基-5-(1H-1,2,4-三唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,9-4);
60)1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,10-5);
61)1-{1-[4-(5′-苯基-2,3′-联吡啶-6′-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,10-6);
62)5-[2-({4-[2-(甲硫基)-6-苯基吡啶并[2,3-d]嘧啶-7-基]苄基}氨基)乙基]-1,3,4-噻二唑-2-胺(TFA,10-7);
或其立体异构体。
在另一个实施方案中,本发明的具体化合物为:1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮(1-6):
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:6-氟-2-(1-{4-[5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(3-3):
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(4B-6):
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(4A-5):
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(8-1);
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(9-3);
或其药物可接受盐或立体异构体。
在另一个实施方案中,本发明的具体化合物为:1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(10-4);
或其药物可接受盐或立体异构体。
本发明化合物可具有不对称中心、手性轴和手性平面(如在:E.L.Eliel和S.H.Wilen,Stereochemistry of Carbon Conapounds,John Wiley& Sons,New York,1994,第1119-1190页中描述),可以外消旋物、外消旋混合物以及单独非对映异构体的所有可能异构体及其混合物(包括旋光异构体)存在,所有这种立体异构体都包括在本发明的范围内。
此外,本文公开的化合物可以互变异构体的形式存在,虽然只描述一种互变异构结构,但两种互变异构形式均包括在本发明的范围内。例如,对以下化合物A的任何权利要求应理解为包括互变异构结构B(反之亦然)及它们的混合物。苯并咪唑酮基部分的两种互变异构形式也包括在本发明的范围内。
四唑以1H/2H互变异构体的混合物形式存在。四唑部分的互变异构形式也包括在本发明的范围内。
当任何变量(例如R1、R2、Rz等)在任何组分中出现超过一次时,其每次出现时的定义独立于其他各次出现时的定义。而且,取代基和变量的组合只有在这种组合能导致稳定的化合物时才是允许的。从取代基向环系统内绘制的线条表示所指示的键可与任何可取代的环原子相连接。如果环系统是多环,则指该键只与最接近的环上任何合适的碳原子相连接。
应理解的是,本发明化合物上的取代基和取代模式可由本领域普通技术人员进行选择,以提供可通过本领域公知技术以及下文介绍的方法从易得原料容易地合成的、化学上稳定的化合物。如果取代基本身被超过一个基团取代,可以理解,这几个基团可在同一个碳原子上,也可在不同的碳原子上,只要能得到稳定的结构即可。短语“任选被一个或多个取代基取代”应理解为与短语“任选被至少一个取代基取代”含义相当,在这种情况下,实施方案可能具有零至四个取代基,而另一个实施方案可能具有零至三个取代基。
本文所用“烷基”包括含指定数目碳原子的支链和直链饱和脂族烃基。例如,“C1-C10烷基”中的C1-C10定义为包括含呈线状或分支状排列的1、2、3、4、5、6、7、8、9或10个碳原子的基团。例如“C1-C10烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基等。术语“环烷基”指含指定数目碳原子的单环饱和脂族烃基。例如“环烷基”包括环丙基、甲基环丙基、2,2-二甲基环丁基、2-乙基-环戊基、环己基等。
“烷氧基”表示通过氧桥连接的含指定数目碳原子的环状或非环状烷基。因此,“烷氧基”包括上述烷基和环烷基的定义。
如果没有指定碳原子的数目,术语“烯基”指含2-10个碳原子和至少一个碳-碳双键的直链、支链或环状非芳族烃基。优选存在一个碳-碳双键,且可存在最多四个非芳族碳-碳双键。因此,“C2-C6烯基”指含2-6个碳原子的烯基。烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。烯基的直链、支链或环状部分可含有双键,且如果指出是取代烯基的话,所述部分可被取代。
术语“炔基”指含2-10个碳原子和至少一个碳-碳三键的直链、支链或环状烃基。可存在最多三个碳-碳三键。因此,“C2-C6炔基”指含2-6个碳原子的炔基。炔基包括乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基的直链、支链或环状部分可含有三键,且如果指出是取代炔基的话,所述部分可被取代。
在某些情况下,取代基可用包括零在内的碳原子范围来定义,如(C0-C6)烯基-芳基。如果芳基是苯基,则此定义将包括苯基本身以及-CH2Ph、-CH2CH2Ph、-CH(CH3)CH2CH(CH3)Ph等。
本文所用“芳基”意指每个环含最多7个原子的任何稳定的单环或双环碳环,其中至少一个环是芳环。这种芳基成分的实例包括苯基、萘基、四氢萘基、茚满基和联苯基。在芳基取代基为双环且一个环为非芳环的情况下,应理解的是通过芳环进行连接。
本文使用的术语杂芳基表示每个环中最多7个原子的稳定单环或双环,其中至少一个环为芳环并包含1-4个选自O、N和S的杂原子。该定义范围内的杂芳基包括但不限于:吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。如以下杂环的定义,“杂芳基”也应理解为包括任何含氮杂芳基的N-氧化物。在杂芳基取代基为双环且一个环为非芳环或不含杂原子的情况下,应理解的是分别通过芳环或含杂原子环进行连接。取代基Q的这种杂芳基部分包括但不限于:2-苯并咪唑基、2-喹啉基、3-喹啉基、4-喹啉基、1-异喹啉基、3-异喹啉基和4-异喹啉基。
本文所用术语“杂环”或“杂环基”意指含1-4个选自O、N和S的杂原子的3元至10元芳族或非芳族杂环,包括双环基团。因此,“杂环基”包括上述的杂芳基及其二氢和四氢类似物。“杂环基”的其它实例包括但不限于以下基团:苯并咪唑基、苯并咪唑酮基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、肉啉基、呋喃基、咪唑基、二氢吲哚基、吲哚基、吲嗪基(indolazinyl)、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、萘啶基(naphthpyridinyl)、噁二唑基、噁唑基、噁唑啉、异噁唑啉、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并吡啶基、哒嗪基、吡唑并嘧啶基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氢吡喃基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮杂环丁烷基、1,4-二噁烷基、六氢氮杂庚因基、哌嗪基、哌啶基、吡啶-2-酮基、吡咯烷基、吗啉基、硫代吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并噁唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲二氧基苯甲酰基、四氢呋喃基和四氢噻吩基以及它们的N-氧化物。杂环基取代基的连接可通过碳原子或通过杂原子而发生。
本领域普通技术人员会认识到,本文所用“卤素”包括氯、氟、溴和碘。
本文所用的取代烷基、取代环烷基、取代芳酰基、取代芳基、取代杂芳酰基、取代杂芳基、取代芳基磺酰基、取代杂芳基磺酰基和取代杂环包括除与化合物其余部分的连接点之外还含1-4个取代基(在另一个实施方案中含1-3个取代基)的部分,除非另有具体定义。这种取代基选自包括但不限于以下的基团:F、Cl、Br、CF3、NH2、N(C1-C6烷基)2、NO2、CN、(C1-C6烷基)O-、(芳基)O-、-OH、Oa-P=O(OH)2、(C1-C6烷基)S(O)m-、(C1-C6烷基)C(O)NH-、H2N-C(NH)-、(C1-C6烷基)C(O)-、(C1-C6烷基)OC(O)-、(C1-C6烷基)OC(O)NH-、苯基、吡啶基、咪唑基、噁唑基、异噁唑基、四唑基、噻唑基、噻吩基、呋喃基、异噻唑基和C1-C20烷基。例如,(C1-C6)烷基可被一个、两个、三个或四个(在另一个实施方案中被一个、两个或三个)选自OH、氧代、卤素、烷氧基、二烷基氨基或杂环基(如吗啉基、哌啶基等)的取代基取代。在这种情况下,如果一个取代基是氧代,另一个是OH,则以下基团落入上述定义:-(C=O)CH2CH(OH)CH3、-(C=O)OH、-CH2(OH)CH2CH(O)等。
当定义中同一碳原子上的R3和R4结合在一起形成-(CH2)t-时,形成的部分如下所示:
此外,这种环状部分可任选包括杂原子。这种含杂原子的环状部分的实例包括但不限于:
在某些情况下,R6和R7定义为它们可与它们连接的氮一起形成单环或双环杂环,每个环4-7元,除氮外任选包含一个或多个选自N、O和S的其它杂原子,所述杂环任选被一个或多个选自RZ的取代基取代。可这样形成的杂环的实例包括但不限于以下,需记住的是该杂环任选被一个或多个(在另一个实施方案中为一个、两个或三个)选自RZ的取代基取代:
在另一个实施方案中,p为0。
在另一个实施方案中,q为0。
在另一个实施方案中,Ra为(C1-C6)烷基或苯基。
(C=O)O(C1-C6)烷基、(C=O)(C1-C6)烷基或S(O)2Ra。
在另一个实施方案中,RZ独立选自NH(C=O)N(Rb)2、C1-C6烷基、苯基、杂环基、N(Rb)2、(C=O)aObC1-C6烷基、(C=O)NR6R7、卤素、(C1-C6)烷基羟基、OH、Oa-P=O(OH)2和氧代,所述苯基任选被O(C1-C6)烷基取代。
在另一个实施方案中,RZ独立选自NH(C=O)N(Rb)2、C1-C6烷基、苯基、杂环基、N(Rb)2、(C=O)aObC1-C6烷基、(C=O)NR6R7、卤素、(C1-C6)烷基羟基、OH、Oa-P=O(OH)2和氧代,其中所述杂环基选自:
其中所述苯基任选被O(C1-C6)烷基取代。
在另一个实施方案中,R1独立选自(C=O)bN(Rb)2、(C=NRb)N(Rb)2、-N=CHN(Rb)2、CN、杂环基、卤素、C0-C6烷基(C=NRb)N(Rb)2、ObC1-C6烷基、NR6R7、NRc(C=O)bNR6R7和NRc(C=O)ObRa,所述烷基和杂环基任选被1-3个选自RZ的取代基取代。
在另一个实施方案中,R1独立选自(C=O)bN(Rb)2、(C=NRb)N(Rb)2、-N=CHN(Rb)2、CN、杂环基、卤素、C0-C6烷基(C=NRb)N(Rb)2、ObC1-C6烷基、NR6R7、NRc(C=O)bNR6R7和NRc(C=O)ObRa,其中所述杂环基选自:
所述烷基和杂环基任选被1-3个选自RZ的取代基取代。
在另一个实施方案中,R3和R4选自H和C1-C6烷基。
在另一个实施方案中,R6和R7选自H、C1-C6烷基和芳基,任选被1-2个选自RZ的取代基取代,或R6和R7与它们连接的氮一起形成单环或双环杂环,任选被1-2个选自RZ的取代基取代。
在另一个实施方案中,R6和R7选自H或C1-C6烷基,任选被1-2个选自RZ的取代基取代,或R6和R7与它们连接的氮一起形成单环或双环杂环,任选被1-2个选自RZ的取代基取代。
在另一个实施方案中,
选自:
在一个实施方案中,当Q为杂环基时,所述杂环基选自2-氮杂环庚烯酮、苯并咪唑基、苯并咪唑酮基、2-二氮杂环庚烯酮(2-diazapinone)、咪唑基、2-咪唑烷酮、吲哚基、异喹啉基、吗啉基、哌啶基、哌嗪基、吡啶基、吡咯烷基、2-哌啶酮、2-嘧啶酮、2-吡咯烷酮、喹啉基、四唑基、四氢呋喃基、四氢异喹啉基、噻吩基、吡唑并嘧啶基、吡唑基、噻唑基、噁二唑基和三唑基,任选被1-3个RZ取代。
在另一个实施方案中,当Q为杂环基时,Q选自:
它们任选被1-3个选自RZ的取代基取代。
本发明包括式A化合物的游离形式以及其药物可接受盐和立体异构体。本文例示的某些分离的具体化合物是胺化合物的质子化盐。术语“游离形式”指非盐形式的胺化合物。本文包括的药物可接受盐不仅包括本文所述具体化合物例示的离析盐,而且包括式A化合物游离形式的所有典型药物可接受盐。本文描述的具体盐化合物的游离形式可用本领域公知的技术分离。例如,可通过用合适的稀碱水溶液如稀NaOH、碳酸钾、氨和碳酸氢钠水溶液处理盐,来再生游离形式。游离形式相对于其各自的盐形式在某些物理性质(例如在极性溶剂中的溶解度)上会有一定程度的差别,但是酸盐和碱盐对于本发明的目的来说在药学上与其各自的游离形式是相当的。
本发明化合物的药物可接受盐可通过常规化学方法从含碱性或酸性部分的本发明化合物合成。一般来说,碱性化合物的盐可通过离子交换色谱法制备,或通过使游离碱与化学计算量或过量的所需的成盐无机或有机酸在合适溶剂或溶剂各种组合中反应来制备。与此类似,酸性化合物的盐可通过与适当的无机或有机碱反应来形成。
因此,本发明化合物的药物可接受盐包括通过使本发明碱性化合物与无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒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,以及从有机酸如乙酸、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、苯基乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、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、三氟乙酸(TFA)等制成的盐。
当本发明化合物是酸性化合物时,合适的“药物可接受盐”指从药物可接受的无毒碱(包括无机碱和有机碱)制成的盐。衍生自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、三价锰盐、锰盐、钾盐、钠盐、锌盐等。特别优选的是铵盐、钙盐、镁盐、钾盐和钠盐。衍生自药物可接受的有机无毒碱的盐包括伯胺、仲胺和叔胺、取代胺(包括天然取代胺)、环胺和碱性离子交换树脂的盐,如精氨酸、甜菜碱、咖啡因、胆碱、N,N′-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、海巴胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.,1977:66:1-19对上述药物可接受盐和其他典型的药物可接受盐的制备进行了更充分的描述。
还应注意,本发明化合物是潜在的内盐或两性离子,因为在生理条件下,化合物中的脱质子化酸性部分(如羧基)可为阴离子,而此电荷可被质子化或烷基化的碱性部分(如季胺氮原子)的阳离子电荷在内部平衡掉。
用途
本发明化合物是Akt活性的抑制剂,因此可用于治疗癌症,特别是与Akt活性紊乱及Akt的下游细胞靶标相关的癌症。这些癌症包括但不限于卵巢癌、胰腺癌、乳腺癌和前列腺癌,以及其中肿瘤抑制蛋白PTEN发生突变的癌症(包括成胶质细胞瘤)(Cheng等,Proc.Natl.Acad.Sci.(1992)89:9267-9271;Cheng等,Proc.Natl.Acad.Sci.(1996)93:3636-3641;Bellacosa等,Int.J.Cancer(1995)64:280-285;Nakatani等,J.Biol.Chem.(1999)274;21528-21532;Graff,Expert.Opin.Ther.Targets(2002)6(1):103-113;及Yamada和Araki,J.Cell Science(2001)114:2375-2382;Mischel和Cloughesy,Brain Pathol.(2003)13(1):52-61)。
特别相信本文提供的化合物、组合物和方法能用于治疗包括实体瘤的癌症,如皮肤癌、乳腺癌、脑癌、宫颈癌、睾丸癌等。更具体的说,可用本发明化合物、组合物和方法治疗的癌症包括但不限于:
心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;
肺部:支气管癌(鳞状上皮细胞、未分化的小细胞、未分化的大细胞、腺癌)、肺泡癌(细支气管癌)、支气管腺癌、肉瘤、淋巴瘤、软骨错构瘤、间皮瘤;
胃肠:食道(鳞状上皮细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(胃癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛瘤、高血糖素瘤、促胃液素瘤、类癌肿瘤、VIP肿瘤)、小肠(腺癌、淋巴瘤、类癌肿瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、纤维神经瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);
泌尿生殖道:肾脏(腺癌、维姆氏瘤[肾母细胞瘤]、淋巴瘤、白血病)、膀胱和尿道(鳞状上皮细胞癌、过渡细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎性癌、恶性畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤);
肝脏:肝细胞瘤(肝细胞癌)、胆管癌、肝胚细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤;
骨:骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、成软骨细胞瘤、软骨粘液纤维瘤、骨样骨瘤和巨细胞瘤;
神经系统:颅骨(骨瘤、血管瘤、肉芽瘤、黄瘤、畸形性骨炎)、脑膜(脑膜瘤、脑膜癌、神经胶质瘤病)、大脑(星细胞瘤、成神经管细胞瘤、神经胶质瘤、室鼓膜瘤、生殖细胞瘤[松果体瘤]、多形性成胶质细胞瘤、少突神经胶质细胞瘤、神经鞘瘤、成视网膜细胞瘤、先天肿瘤)、脊髓(纤维神经瘤、脑膜瘤、神经胶质瘤、肉瘤);
妇科:子宫(子宫内膜癌)、子宫颈(子宫颈癌、肿瘤前子宫颈发育异常)、卵巢(卵巢癌[浆液性囊腺癌、粘液性囊腺癌、未分类的癌]、粒层细胞-卵泡膜细胞肿瘤、男性细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状上皮细胞癌、上皮内癌、腺癌、纤维肉瘤、黑素瘤)、阴道(透明细胞癌、鳞状上皮细胞癌、葡萄状肉瘤(胚胎横纹肌肉瘤)、输卵管癌);
血液科:血液(骨髓性白血病[急性和慢性]、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、骨髓增殖症、多发性骨髓瘤、骨髓发育不良综合征)、何杰金氏病、非何杰金氏淋巴瘤[恶性淋巴瘤];
皮肤:恶性黑素瘤、基底细胞癌、鳞状上皮细胞癌、卡波西肉瘤、发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣;及肾上腺:成神经细胞瘤。因此,本文提供的术语“癌细胞”包括被任何一种上述疾病累及的细胞。
Akt信号传导调节血管生成过程中的多个关键步骤。Shiojima和Walsh,Circ.Res.(2002)90:1243-1250。从文献中可知血管生成抑制剂在癌症治疗中的效用,所述文献参见例如J.Rak等,Cancer Research,55:4575-4580,1995和Dredge等,Expert Opin.Biol.Ther.(2002)2(8):953-966。在许多种类的癌症和组织中已显示出血管生成在癌症中的作用:乳腺癌(G.Gasparini和A.L.Harris,J.Clin.Oncol.,1995,13:765-782;M.Toi等,Japan.J.Cancer Res.,1994,85:1045-1049);膀胱癌(A.J.Dickinson等,Br.J.Urol.,1994,74:762-766);结肠癌(L.M.Ellis等,Surgery,1996,120(5):871-878);及口腔肿瘤(J.K.Williams等,Am.J.Surg.,1994,168:373-380)。其他癌症包括晚期肿瘤(advancedtumor)、毛细胞性白血病、黑素瘤、晚期头颈癌、转移性肾细胞、非何杰金氏淋巴瘤、转移性乳腺癌、乳腺腺癌、晚期黑素瘤、胰腺癌、胃癌、成胶质细胞瘤、肺癌、卵巢癌、非小细胞肺癌、前列腺癌、小细胞肺癌、肾细胞癌、各种实体瘤、多发性骨髓瘤、转移性前列腺癌、恶性神经胶质瘤、肾癌、淋巴瘤、顽固性迁延性疾病、顽固性多发性骨髓瘤、子宫颈癌、卡波西肉瘤、复发性间变神经胶质瘤和转移性结肠癌(Dredge等,Expert Opin.Biol.Ther.(2002)2(8):953-966)。因此,本申请公开的Akt抑制剂也可用于治疗这些血管生成相关性癌症。
已发生新血管形成的肿瘤表现出转移潜力升高。实际上,血管生成对肿瘤生长和转移是必要的。(S.P.Cunningham等,Can.Research,61:3206-3211(2001))。因此,本申请公开的Akt抑制剂也可用于预防或减少肿瘤细胞的转移。
包括在本发明范围内的还有治疗或预防涉及血管生成的疾病的方法,所述方法包括给予需要这种治疗的哺乳动物治疗有效量的本发明化合物。眼睛新血管疾病就是这类病症的一个实例,该病造成的大部分组织损伤都可归因于眼部血管的异常浸润(参见WO00/30651,2000年6月2日公开)。不良浸润可通过缺血性视网膜病引发,如由糖尿病性视网膜病、早产儿视网膜病、视网膜静脉闭塞等引发,或者通过退行性疾病如见于年龄相关性黄斑变性的脉络膜新血管形成引发。因此,通过给予本发明化合物抑制血管的生长将能防止血管的浸润,预防或治疗涉及血管生成的疾病,如视网膜血管形成、糖尿病性视网膜病、年龄相关性黄斑变性等眼部疾病。
包括在本发明范围内的还有治疗或预防涉及血管生成的非恶性疾病的方法,所述疾病包括但不限于:眼部疾病(如视网膜血管形成、糖尿病性视网膜病、年龄相关性黄斑变性)、动脉粥样硬化、关节炎、牛皮癣、肥胖症和阿尔茨海默病(Dredge等,Expert Opin.Biol.Ther.(2002)2(8):953-966)。在另一个实施方案中,治疗或预防涉及血管生成的疾病的方法包括:眼部疾病(如视网膜血管形成、糖尿病性视网膜病、年龄相关性黄斑变性)、动脉粥样硬化、关节炎、牛皮癣。
包括在本发明范围内的还有治疗增生型病症如再狭窄、炎症、自身免疫病和过敏/哮喘的方法。
包括在本发明范围内的还有治疗胰岛素分泌过多的方法。
在本发明的一个实施方案中,本发明化合物是选择性抑制剂,其抑制效力决定于PH结构域。在这个实施方案中,所述化合物对缺少PH结构域的截短Akt蛋白的体外抑制活性降低,或者没有体外抑制活性。
在又一个实施方案中,本发明化合物选自Akt1的选择性抑制剂、Akt2的选择性抑制剂及Akt1和Akt2两者的选择性抑制剂。
在另一个实施方案中,本发明化合物选自Akt1的选择性抑制剂、Akt2的选择性抑制剂、Akt3的选择性抑制剂及三种Akt同工型中两种的选择性抑制剂。
在另一个实施方案中,本发明化合物是所有三种Akt同工型的选择性抑制剂,但不是一种、两种或所有已被修饰而缺失PH结构域、铰链区或者同时缺失PH结构域和铰链区的Akt同工型的选择性抑制剂。
本发明还涉及抑制Akt活性的方法,所述方法包括给予有需要的哺乳动物药学上有效量的本发明化合物。
可按标准的药学规范,将本发明化合物单独或者与药物可接受的载体、赋形剂或稀释剂组合在药物组合物中,给予哺乳动物(包括人类)。化合物可经口给予,或者通过胃肠外给予,包括静脉内、肌肉内、腹膜内、皮下、直肠和局部给药途径。
含活性成分的药物组合物可采用适合口服的形式,例如为片剂、药片、锭剂、水混悬剂或油混悬剂、可分散粉末剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、糖浆剂或酏剂。供口服的组合物可按本领域公知的任何药物组合物制备方法进行制备,这种组合物可含有一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的添加剂,以提供药物上精致可口的制剂。片剂含有活性成分,与适合用于制备片剂的无毒药物可接受赋形剂混合。这些赋形剂可以是例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如微晶纤维素、交联羧甲纤维素钠、玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶;及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可不带包衣,或者可通过公知的技术包衣,以掩蔽药物的不良味道,或延迟在胃肠道中的分解和吸收,从而提供长时间的缓释作用。例如,可使用水溶性味觉掩蔽材料如羟丙基甲基纤维素或羟丙基纤维素,或延时材料如乙基纤维素、乙酸-丁酸纤维素。
用于口服的制剂还可作为硬明胶胶囊存在,其中活性成分与惰性固体稀释剂如碳酸钙、磷酸钙或高岭土混合,或者可作为软明胶胶囊存在,其中活性成分与水溶性载体(如聚乙二醇)或油性介质(如花生油、液体石蜡或橄榄油)混合。
水混悬剂含有活性物质,与适合用于制备水混悬剂的赋形剂混合。这种赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄芪树胶和阿拉伯树胶;分散剂或湿润剂可以是天然磷脂,例如卵磷脂,或者是烯化氧与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或者是环氧乙烷与长链脂肪醇的缩合产物,例如十七乙烯氧基鲸蜡醇(heptadecaethylene-oxycetanoL)、或者是环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物如聚氧乙烯山梨醇单油酸酯,或者是环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物如聚氧乙烯山梨醇酐单油酸酯。水混悬剂也可含有一种或多种防腐剂,例如如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种矫味剂,一种或多种甜味剂,如蔗糖、糖精或阿司巴甜。
油混悬剂可通过将活性成分悬浮于植物油或矿物油中来配制,所述植物油例如花生油、橄榄油、芝麻油或棕榈油,所述矿物油如液状石蜡。油混悬剂可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可添加甜味剂如上述甜味剂及矫味剂,以提供可口的口服制剂。这些组合物可通过添加抗氧化剂如丁基化羟基苯甲醚或α-生育酚来保藏。
适合用于通过加水制备水混悬剂的可分散粉末剂和颗粒剂包括活性成分,与分散剂或湿润剂、悬浮剂和一种或多种防腐剂混合。合适的分散剂或湿润剂和悬浮剂如上所述例示。也可存在另外的赋形剂,例如甜味剂、矫味剂和着色剂。这些组合物可通过添加抗氧化剂如抗坏血酸来保藏。
本发明药物组合物也可以为水包油乳液剂的形式。油相可以是植物油,例如橄榄油或花生油,或者是矿物油,例如液状石蜡,或者是这些油的混合物。合适的乳化剂可以是天然磷脂,例如大豆卵磷脂,及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如山梨醇酐单油酸酯,以及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨醇酐单油酸酯。乳液剂也可含有甜味剂、矫味剂、防腐剂和抗氧化剂。
糖浆剂和酏剂可用甜味剂,例如甘油、丙二醇、山梨醇或蔗糖来配制。这种制剂也可含有缓和剂、防腐剂、矫味剂和着色剂以及抗氧化剂。
本发明药物组合物可以为无菌可注射水溶液剂的形式。可以采用的可接受介质和溶剂为水、林格氏溶液和等渗氯化钠溶液。
无菌可注射制剂也可以是无菌可注射水包油微乳液剂,其中活性成分溶于油相中。例如,活性成分可首先溶于大豆油和卵磷脂的混合物中。然后将油溶液引入到水和甘油的混合物中,加工形成微乳液剂。
可通过局部大剂量注射将可注射溶液剂或微乳液剂引入到患者的血流中。另外,按保持本发明化合物的恒定循环浓度的方式给予溶液剂或微乳液剂将比较有利。为维持这种恒定浓度,可采用连续静脉递药装置。这种装置的一个实例是Deltec CADD-PLUSTM 5400型静脉泵。
本发明药物组合物可以是无菌可注射水混悬剂或油混悬剂的形式,以供肌肉内或皮下给药。所述混悬剂可用上述合适的分散剂或湿润剂和悬浮剂按公知的技术进行配制。无菌可注射制剂也可以是无毒胃肠外可接受稀释剂或溶剂中的无菌可注射溶液剂或混悬剂,例如1,3-丁二醇的溶液。此外,无菌的不挥发性油通常用作溶剂或悬浮介质。为此,可使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于配制注射剂。
式A化合物也可以为栓剂的形式,以供直肠给药。这些组合物可通过将药物与合适的无刺激性赋形剂混合来配制,所述赋形剂在常温下为固体,但在直肠温度下为液体,因此会在直肠中熔化,释放药物。这种赋形剂材料包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇混合物与聚乙二醇的脂肪酸酯。
局部给药时,采用含式A化合物的乳膏剂、软膏剂、凝胶剂、溶液剂或混悬剂等。(对于这种应用目的,局部应用应包括漱口水和漱口剂。)
本发明化合物可以通过局部使用合适的鼻内介质和递药装置,来鼻内给药,或者通过透皮途径,使用本领域普通技术人员公知的透皮贴剂的形式来给予。为以透皮递药系统的形式给药,给药剂量在整个用药方案中当然是连续的而不是断续的。也可采用可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇混合物与聚乙二醇的脂肪酸酯等基质,将本发明化合物以栓剂的形式给药。
当将本发明组合物给予人对象时,日剂量通常由主治医师来确定,一般来说,会根据患者个人的年龄、体重和反应性以及患者症状的严重程度对所用剂量进行改动。
在一个实施方案中,给予进行癌症治疗的哺乳动物合适量的Akt抑制剂。给予的抑制剂的量为每天约0.1mg/kg体重至约60mg/kg体重,或为每天0.5mg/kg体重至约40mg/kg体重。另一个包括本发明组合物的治疗方案包括约0.01mg至约1000mg Akt抑制剂。在另一个实施方案中,所用剂量为约1mg至约1000mg Akt抑制剂。
本发明化合物也可与已知的治疗性药物和抗癌药物联合使用。例如,本发明化合物可以与已知的抗癌药物联合使用。本文公开的化合物与其他抗癌药物或化疗药物的组合包括在本发明的范围内。这些药物的实例见于V.T.Devita和S.Hellman(编辑),CancerPrinciples and Practice of Oncology,第6版(2001年2月15日),Lippincott Williams & Wilkins Publishers。本领域普通技术人员根据药物的特性和有关的癌症,将能够辨别哪种药物组合会有用。这种抗癌药物包括以下:雌激素受体调节剂、雄激素受体调节剂、类视黄醇受体调节剂、细胞毒剂/细胞抑制剂、抗增殖剂、异戊二烯基-蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂和其他血管生成抑制剂、细胞增殖和生存信号抑制剂、及干扰细胞周期关卡的药物。本发明化合物当与放射治疗共同给予时特别有用。
在一个实施方案中,本发明化合物也可与已知抗癌药物联合使用,抗癌药物包括以下:雌激素受体调节剂、雄激素受体调节剂、类视黄醇受体调节剂、细胞毒剂、抗增殖剂、异戊二烯基-蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂和其他血管生成抑制剂。
“雌激素受体调节剂”指不论通过何种机理干扰或抑制雌激素与受体结合的化合物。雌激素受体调节剂的实例包括但不限于他莫昔芬、雷洛昔芬、艾多昔芬、LY353381、LY117081、托瑞米芬、氟维司群、2,2-二甲基丙酸4-[7-(2,2-二甲基-1-氧代丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3-基)-苯酯、4,4′-二羟基二苯酮-2,4-二硝基苯腙和SH646。
“雄激素受体调节剂”指不论通过何种机理干扰或抑制雄激素与受体结合的化合物。雄激素受体调节剂的实例包括非那雄胺和其他5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和乙酸阿比特龙。
“类视黄醇受体调节剂”指不论通过何种机理干扰或抑制类视黄醇与受体结合的化合物。这种类视黄醇受体调节剂的实例包括贝沙罗汀、维A酸、13-顺维生素A酸、9-顺维生素A酸、α-二氟甲基鸟氨酸、ILX23-7553、反-N-(4′-羟苯基)视黄酰胺(retinamide)和N-4-羧基苯基视黄酰胺。
“细胞毒剂/细胞抑制剂”指主要通过直接干预细胞的功能或者抑制或干扰细胞减数分裂而导致细胞死亡或抑制细胞增殖的化合物,包括烷基化剂、肿瘤坏死因子、插入剂、低氧可激活化合物、微管抑制剂/微管稳定剂、有丝分裂驱动蛋白抑制剂、参与有丝分裂进程的激酶的抑制剂、参与生长因子和细胞因子信号转导途径的激酶的抑制剂、抗代谢物、生物反应调节物、激素/抗激素治疗性药物、造血生长因子、单克隆抗体靶向治疗性药物、拓扑异构酶抑制剂、蛋白体抑制剂和泛素连接酶抑制剂。
细胞毒剂/细胞抑制剂的实例包括但不限于sertenef、恶液质素(cachectin)、异环磷酰胺、他索纳明、氯尼达明、卡铂、六甲蜜胺、泼尼莫司汀、二溴卫矛醇、雷莫司汀、福莫司汀、奈达铂、奥沙利铂、替莫唑胺、heptaplatin、雌莫司汀、甲苯磺酸英丙舒凡、曲磷胺、尼莫司汀、二溴螺氯胺、嘌嘧替派、洛铂、沙铂、泊非霉素(profiromycin)、顺铂、伊罗夫文、右异环磷酰胺、顺-胺二氯(2-甲基-吡啶)合铂、苄基鸟嘌呤、葡磷酰胺、GPX100、四氯化(反,反,反)-双-μ-(己烷-1,6-二胺)-μ-[二胺-合铂(II)]双[二胺(氯)合铂(II)]、diarizidinylspermine、三氧化二砷、1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤、佐柔比星、伊达比星、柔红霉素、比生群、米托蒽醌、吡柔比星、吡萘非特、戊柔比星、氨柔比星、抗瘤酮、3′-去氨-3′-吗啉代-13-去氧代-10-羟基洋红霉素、脂质体蒽环霉素(annamycin)、加柔比星、依利奈法德、MEN10755、4-去甲氧基-3-去氨-3-氮杂环丙烷基-4-甲基磺酰基柔红比星(参见WO 00/50032)、Raf激酶抑制剂(如Bay43-9006)和mTOR抑制剂(如Wyeth的CCI-779)。
低氧可激活化合物的一个实例是替拉扎明。
蛋白体抑制剂的实例包括但不限于乳胞素和MLN-341(Velcade)。
微管抑制剂/微管稳定剂的实例包括紫杉醇、硫酸长春地辛、3′,4′-二脱氢-4′-脱氧-8′-去甲长春碱、多西他赛、根霉素、多拉司他汀、羟乙磺酸米伏布林、auristatin、西马多丁、RPR109881、BMS184476、长春氟宁、cryptophycin、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺、脱水长春碱、N,N-二甲基-L-缬氨酰-L-缬氨酰-N-甲基-L-缬氨酰-L-脯氨酰-L-脯氨酸-叔丁酰胺、TDX258、埃坡霉素(epothilone)(参见例如美国专利6,284,781和6,288,237)和BMS188797。在一个实施方案中,埃坡霉素不包括在微管抑制剂/微管稳定剂中。
拓扑异构酶的实例是托泊替康、hycaptamine、伊立替康、卢比替康、6-乙氧基丙酰-3′,4′-O-外-亚苄基-教酒菌素(chartreusin)、9-甲氧基-N,N-二甲基-5-硝基吡唑并[3,4,5-k1]吖啶-2-(6H)丙胺、1-氨基-9-乙基-5-氟-2,3-二氢-9-羟基-4-甲基-1H,12H-苯并[de]吡喃并[3′,4′:b,7]-中氮茚并[1,2b]喹啉-10,13(9H,15H)二酮、勒托替康、7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱、BNP1350、BNPI1100、BN80915、BN80942、磷酸依托泊苷、替尼泊苷、索布佐生、2′-二甲氨基-2′-脱氧-依托泊苷、GL331、N-[2-(二甲氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺、asulacrine、(5a,5aB,8aa,9b)-9-[2-[N-[2-(二甲氨基)乙基]-N-甲基氨基]乙基]-5-[4-羟基-3,5-二甲氧基苯基]-5,5a,6,8,8a,9-六氢呋喃并(3′,4′:6,7)萘并(2,3-d)-1,3-二氧杂环戊烯-6-酮、2,3-(亚甲二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-菲啶鎓、6,9-双[(2-氨基乙基)氨基]苯并[g]异喹啉(isoguinoline)-5,10-二酮、5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟乙基氨基甲基)-6H-吡唑并[4,5,1-de]吖啶-6-酮、N-[1-[2(二乙氨基)乙基氨基]-7-甲氧基-9-氧代-9H-噻吨-4-基甲基]甲酰胺、N-(2-(二甲氨基)乙基)吖啶-4-甲酰胺、6-[[2-(二甲氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮和地美司钠。
有丝分裂驱动蛋白、尤其是人有丝分裂驱动蛋白的抑制剂的实例在PCT出版物WO 01/30768和WO 01/98278以及待审的美国专利中请60/338,779(2001年12月6日提交)、60/338,344(2001年12月6日提交)、60/338,383(2001年12月6日提交)、60/338,380(2001年12月6日提交)、60/338,379(2001年12月6日提交)和60/344,453(2001年11月7日提交)中有描述。在一个实施方案中,有丝分裂驱动蛋白的抑制剂包括但不限于KSP抑制剂、MKLP1抑制剂、CENP-E抑制剂、MCAK抑制剂和Rab6-KIFL抑制剂。
“参与有丝分裂进程的激酶的抑制剂”包括但不限于aurora激酶的抑制剂、Polo-样激酶(PLK)的抑制剂(特别是PLK-1抑制剂)、bub-1抑制剂和bub-R1抑制剂。
“抗增殖剂”包括反义RNA和DNA寡核苷酸如G3139、ODN698、RVASKRAS、GEM231和INX3001,及抗代谢物如依诺他滨、卡莫氟、替加氟、喷司他丁、去氧氟尿苷、三甲曲沙、氟达拉滨、卡培他滨、加洛他滨、阿糖胞苷ocfosfate、水合fosteabine钠、雷替曲塞、paltitrexid、乙嘧替氟、噻唑呋啉、地西他滨、诺拉曲塞、培美曲塞、nelzarabine、2′-脱氧-2′-亚甲基(methylidene)胞苷、2′-氟亚甲基-2′-脱氧胞苷、N-[5-(2,3-二氢-苯并呋喃基)磺酰基]-N′-(3,4-二氯苯基)脲、N6-[4-脱氧-4-[N2-[2(E),4(E)-十四二烯酰]甘氨酰氨基]-L-甘油基-B-L-甘露糖基-吡喃庚糖基]腺嘌呤、aplidine、海鞘素(ecteinascidin)、曲沙他滨、4-[2-氨基-4-氧代-4,6,7,8-四氢-3H-嘧啶并[5,4-b][1,4]噻嗪-6-基-(S)-乙基]-2,5-噻吩酰-1-谷氨酸、氨蝶呤、5-氟尿嘧啶、阿拉诺新、乙酸11-乙酰-8-(氨基甲酰氧基甲基)-4-甲酰-6-甲氧基-14-氧杂-1,11-二氮杂四环(7.4.1.0.0)-十四-2,4,6-三烯-9-基酯、八氢吲嗪三醇、洛美曲索、右雷佐生、蛋氨酸酶、2′-氰基-2′-脱氧-N4-棕榈酰-1-B-D-阿糖呋喃胞嘧啶、3-氨基吡啶-2-甲醛缩氨基硫脲和曲妥单抗。
单克隆抗体定向治疗性药物的实例包括将细胞毒剂或放射性同位素连接到癌细胞特异性或靶细胞特异性单克隆抗体的治疗性药物。所述实例包括Bexxar。
“HMG-CoA还原酶抑制剂”指3-羟基-3-甲基戊二酰CoA还原酶的抑制剂。可以使用的HMG-CoA还原酶抑制剂的实例包括但不限于洛伐他汀(MEVACOR;参见美国专利4,231,938、4,294,926和4,319,039)、辛伐他汀(ZOCOR;参见美国专利4,444,784、4,820,850和4,916,239)、普伐他汀(PRAVACHOL;参见美国专利4,346,227、4,537,859、4,410,629、5,030,447和5,180,589)、氟伐他汀(LESCOL;参见美国专利5,354,772、4,911,165、4,929,437、5,189,164、5,118,853、5,290,946和5,356,896)、阿托伐他汀(LIPITOR;参见美国专利5,273,995、4,681,893、5,489,691和5,342,952)及西立伐他汀(也称为rivastatin和BAYCHOL;参见美国专利5,177,080)。可以用于本发明方法的这些HMG-CoA还原酶抑制剂和另外的HMG-CoA还原酶抑制剂的结构式在M.Yalpani“Cholesterol Lowering Drugs”,Chemistry &Industry,第85-89页(1996年2月5日)的第87页和美国专利4,782,084和4,885,314中有描述。本文所用术语HMG-CoA还原酶抑制剂包括所有药物可接受的内酯和开环的酸式(即内酯环打开形成游离酸)以及具有HMG-CoA还原酶抑制活性的化合物的盐和酯形式,因此,这些盐、酯、开环酸和内酯形式的应用包括在本发明的范围内。
“异戊二烯基蛋白转移酶抑制剂”指抑制任何一种或任何组合的异戊二烯基蛋白转移酶类的化合物,所述酶类包括法尼基蛋白转移酶(FPT酶)、I型牻牛儿基牻牛儿基蛋白转移酶(GGPT酶-I)和II型牻牛儿基牻牛儿基蛋白转移酶(GGPT酶-II,也称Rab GGPT酶)。
异戊二烯基蛋白转移酶抑制剂的实例见于以下出版物和专利:WO 96/30343、WO 97/18813、WO 97/21701、WO 97/23478、WO97/38665、WO 98/28980、WO 98/29119、WO 95/32987、美国专利5,420,245、美国专利5,523,430、美国专利5,532,359、美国专利5,510,510、美国专利5,589,485、美国专利5,602,098、欧洲专利出版物0 618 221、欧洲专利出版物0 675 112、欧洲专利出版物0 604 181、欧洲专利出版物0 696 593、WO 94/19357、WO 95/08542、WO95/11917、WO 95/12612、WO 95/12572、WO 95/10514、美国专利5,661,152、WO 95/10515、WO 95/10516、WO 95/24612、WO 95/34535、WO 95/25086、WO 96/05529、WO 96/06138、WO 96/06193、WO96/16443、WO 96/21701、WO 96/21456、WO 96/22278、WO 96/24611、WO 96/24612、WO 96/05168、WO 96/05169、WO 96/00736、美国专利5,571,792、WO 96/17861、WO 96/33159、WO 96/34850、WO96/34851、WO 96/30017、WO 96/30018、WO 96/30362、WO 96/30363、WO 96/31111、WO 96/31477、WO 96/31478、WO 96/31501、WO97/00252、WO 97/03047、WO 97/03050、WO 97/04785、WO 97/02920、WO 97/17070、WO 97/23478、WO 97/26246、WO 97/30053、WO97/44350、WO 98/02436和美国专利5,532,359。有关异戊二烯基蛋白转移酶抑制剂对血管生成的作用的实例,参见European J.of Cancer,第35卷,第9期,第1394-1401页(1999)。
“血管生成抑制剂”指不论通过何种机理抑制新血管形成的化合物。血管生成抑制剂的实例包括但不限于酪氨酸激酶抑制剂如酪氨酸激酶受体Flt-1(VEGFR1)和Flk-1/KDR(VEGFR2)抑制剂、表皮衍生的、纤维原细胞衍生的或血小板衍生的生长因子的抑制剂、MMP(基质金属蛋白酶)抑制剂、整联蛋白阻断剂、干扰素-α、白细胞介素-12、戊聚糖聚硫酸酯、环加氧酶抑制剂,包括非类固醇抗炎药(NSAID)如阿司匹林和布洛芬以及选择性环加氧酶-2抑制剂如塞来考昔和罗非考昔(PNAS,第89卷,第7384页(1992);JNCI,第69卷,第475页(1982);Arch.Opthalmol.,第108卷,第573页(1990);Anat.Rec.,第238卷,第68页(1994);FEBS Letters,第372卷,第83页(1995);Clin,Orthop.第313卷,第76页(1995);J.Mol.Endocrinol.,第16卷,第107页(1996);Jpn.J.Pharmacol.,第75卷,第105页(1997);Cancer Res.,第57卷,第1625页(1997);Cell,第93卷,第705页(1998);Intl.J.Mol.Met.,第2卷,第715页(1998);J.Biol.Chem.,第274卷,第9116页(1999))、类固醇抗炎药(如皮质类固醇、盐皮质激素、地塞米松、泼尼松、泼尼松龙、甲泼尼龙、倍他米松)、羧基酰胺三唑、考布他汀A-4、角鲨胺、6-O-氯乙酰-羰基)-烟曲霉醇(fumagillol)、沙利度胺、血管生长抑素、肌钙蛋白-1、血管紧张素II拮抗剂(参见Femandez等,J.Lab.Clin.Med.105:141-145(1985))和抗VEGF抗体(参见NatureBiotechnology,第17卷,第963-968页(1999年10月);Kim等,Nature,362,841-844(1993);WO 00/44777;和WO 00/61186)。
能调节或抑制血管生成且还可与本发明化合物联合使用的其他治疗性药物包括能调节或抑制血凝固和纤维蛋白溶解系统的药物(参见Clin.Chem.La.Med.38:679-692(2000)中的综述)。能调节或抑制血凝固和纤维蛋白溶解途径的这种药物的实例包括但不限于肝素(参见Thromb.Haemost 80:10-23(1998))、低分子量肝素和羧肽酶U抑制剂(也叫活性凝血酶可激活纤维蛋白溶解抑制剂[TAFIa]的抑制剂)(参见Thrombosis Res.101:329-354(2001))。TAFIa的抑制剂在美国专利60/310,927(2001年8月8日提交)和60/349,925(2002年1月18提交)中已有描述。
“干扰细胞周期关卡的药物”指抑制转导细胞周期关卡信号的蛋白激酶、从而使癌细胞对DNA损伤剂敏感的化合物。这种药物包括ATR抑制剂、ATM抑制剂、Chk1和Chk2激酶抑制剂及cdk和cdc激酶抑制剂,具体实例有7-羟基星孢素、flavopiridol(黄酮类抗肿瘤药)、CYC202(Cyclacel)和BMS-387032。
“细胞增殖和生存信号途径的抑制剂”指抑制细胞表面受体下游的信号转导级联的化合物。这种药物包括丝氨酸/苏氨酸激酶抑制剂(包括但不限于如在WO 02/083064、WO 02/083139、WO 02/083140和WO 02/083138中描述的Akt抑制剂)、Raf激酶抑制剂(例如BAY-43-9006)、MEK抑制剂(例如CI-1040和PD-098059)、mTOR抑制剂(例如Wyeth CCI-779)和PI3K抑制剂(例如LY294002)。
如上所述,与NSAID的组合涉及作为有效COX-2抑制剂的NSAID的应用。对于本说明书的目的,经细胞或微粒体分析测定,NSAID对COX-2抑制的IC50为1μM或更低时是有效的。
本发明也包括与作为选择性COX-2抑制剂的NSAID的组合。对于本说明书的目的,作为COX-2选择性抑制剂的NSAID定义为经细胞或微粒体分析评价,通过测定其对COX-2的IC50与对COX-1的IC50之比,其对COX-2的抑制特异性比对COX-1的抑制特异性至少高100倍的NSAID。这种化合物包括但不限于在美国专利5,474,995、美国专利5,861,419、美国专利6,001,843、美国专利6,020,343、美国专利5,409,944、美国专利5,436,265、美国专利5,536,752、美国专利5,550,142、美国专利5,604,260、美国专利5,698,584、美国专利5,710,140、WO 94/15932、美国专利5,344,991、美国专利5,134,142、美国专利5,380,738、美国专利5,393,790、美国专利5,466,823、美国专利5,633,272和美国专利5,932,598中公开的化合物,以上专利通过引用结合到本文中。
在本发明治疗方法中特别有用的COX-2抑制剂是:3-苯基-4-(4-(甲基磺酰基)苯基)-2-(5H)-呋喃酮;和5-氯-3-(4-甲基磺酰基)苯基-2-(2-甲基-5-吡啶基)吡啶;或它们的药物可接受盐。
已被描述为特异性COX-2抑制剂并因此可用于本发明的化合物包括但不限于以下:帕瑞考昔、BEXTRA和CELEBREX或它们的药物可接受盐。
血管生成抑制剂的其他实例包括但不限于内皮抑制素、ukrain、豹蛙酶、IM862、(氯乙酰)氨基甲酸5-甲氧基-4-[2-甲基-3-(3-甲基-2-丁烯基)环氧乙烷基]-1-氧杂螺[2,5]辛-6-基酯、acetyldinanaline、5-氨基-1-[[3,5-二氯-4-(4-氯苯甲酰)苯基]甲基]-1H-1,2,3-三唑-4-甲酰胺、CM101、角鲨胺、考布他汀、RPI4610、NX31838、硫酸化甘露戊糖磷酸酯、7,7-(羰基-双[亚氨基-N-甲基-4,2-吡咯并羰基亚氨基[N-甲基-4,2-吡咯]-羰基亚氨基]双-(1,3-萘二磺酸酯)和3-[(2,4-二甲基吡咯-5-基)亚甲基]-2-二氢吲哚酮(SU5416)。
上文使用的“整联蛋白阻断剂”指选择性拮抗、抑制或阻碍生理配体与αvβ3整联蛋白结合的化合物,选择性拮抗、抑制或阻碍生理配体与αvβ5整联蛋白结合的化合物,拮抗、抑制或阻碍生理配体与αvβ5整联蛋白和αvβ5整联蛋白两者结合的化合物,还指拮抗、抑制或阻碍毛细管内皮细胞上表达的特殊整联蛋白活性的化合物。该术语也指αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1和α6β4整联蛋白的拮抗剂。该术语还指αvβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1和α6β4整联蛋白的任何组合的拮抗剂。
酪氨酸激酶抑制剂的具体实例包括N-(三氟甲基苯基)-5-甲基异噁唑-4-甲酰胺、3-[(2,4-二甲基吡咯-5-基)甲基茚基]二氢吲哚-2-酮、17-(烯丙基氨基)-17-脱甲氧基格尔德霉素、4-(3-氯-4-氟苯基氨基)-7-甲氧基-6-[3-(4-吗啉基)丙氧基]喹唑啉、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)-4-喹唑啉胺、BIBX1382、2,3,9,10,11,12-六氢-10-(羟甲基)-10-羟基-9-甲基-9,12-环氧-1H-二吲哚并[1,2,3-fg:3′,2′,1′-k1]吡咯并[3,4-i][1,6]苯并二氮杂环辛烯-1-酮、SH268、金雀异黄素、STI571、CEP2563、甲磺酸4-(3-氯苯基氨基)-5,6-二甲基-7H-吡咯并[2,3-d]嘧啶、4-(3-溴-4-羟苯基)氨基-6,7-二甲氧基喹唑啉、4-(4′-羟苯基)氨基-6,7-二甲氧基喹唑啉、SU6668、STI571A、N4-氯苯基-4-(4-吡啶基甲基)-1-酞嗪胺和EMD 121974。
与抗癌化合物之外的化合物的组合也在本发明方法的范围内。例如,本发明要求保护的化合物与PPAR-γ(即PPAR-伽马)激动剂和PPAR-δ(即PPAR-德耳塔)激动剂的组合可用于治疗某些恶性肿瘤。PPAR-γ和PPAR-δ是核过氧物酶体增殖物激活的受体γ和δ。PPAR-γ在内皮细胞上的表达及其在血管生成中的参与在文献中已有报道(参见J.Cardiovasc.Pharmacol.1998;31:909-913;J.Biol.Chem.1999;274:9116-9121;Invest.Ophthalmol Vis.Sci.2000;41:2309-2317)。最近揭示PPAR-γ激动剂能在体外抑制响应VEGF的血管生成;曲格列酮和马来酸罗格列酮均能抑制小鼠视网膜新血管形成的发展。(Arch.Ophthamol.2001;119:709-717)。PPAR-γ激动剂和PPAR-γ/α激动剂激动剂的实例包括但不限于噻唑烷二酮(如DRF2725、CS-011、曲格列酮、罗格列酮和吡格列酮)、非诺贝特、吉非贝齐、氯贝特、GW2570、SB219994、AR-H039242、JTT-501、MCC-555、GW2331、GW409544、NN2344、KRP297、NP0110、DRF4158、NN622、GI262570、PNU182716、DRF552926、2-[(5,7-二丙基-3-三氟甲基-1,2-苯并异噁唑-6-基)氧基]-2-甲基丙酸(在USSN 09/782,856中公开)和2(R)-7-(3-(2-氯-4-(4-氟苯氧基)苯氧基)丙氧基)-2-乙基苯并二氢吡喃(chromane)-2-甲酸(在USSN 60/235,708和60/244,697中公开)。
本发明的另一个实施方案是本文公开的化合物与基因疗法的组合在癌症治疗中的应用。有关癌症治疗的遗传学策略的综述参见Hall等(Am.J.Hum.Genet.61:785-789,1997)和Kufe等(Cancer Medicine,第5版,第876-889页,BC Decker,Hamilton 2000)。基因疗法可以用来传递任何肿瘤抑制基因。这种基因的实例包括但不限于可通过重组病毒介导的基因转移来传递的p53(参见例如美国专利6,069,134)、uPA/uPAR拮抗剂(“Adenovirus-Mediated Delivery of a uPA/uPARAntagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,”Gene Therapy,1998年8月;5(8):1105-13)和γ干扰素(J.Immunol.2000;164:217-222)。
本发明化合物也可与固有多重抗药性(MDR)、特别是与高表达水平转运蛋白相关的MDR的抑制剂联合给药。这种MDR抑制剂包括p-糖蛋白(P-gp)的抑制剂,如LY335979、XR9576、OC144-093、R101922、VX853和PSC833(伐司朴达)。
本发明化合物可与止吐药联合使用,以治疗恶心和呕吐,包括急性呕吐、延迟性呕吐、后期呕吐和先期呕吐,这些呕吐现象可因为单独使用本发明化合物或与放射疗法联合使用而造成的。为预防或治疗呕吐,本发明化合物可与其他止吐药联合使用,特别是神经激肽-1受体拮抗剂、5HT3受体拮抗剂如昂丹司琼、格拉司琼、托烷司琼和zatisetron、GABAB受体激动剂如巴氯芬、皮质类固醇如Decadron(地塞米松)、Kenalog、Aristocort、Nasalide、Preferid、Benecorten或例如在美国专利2,789,118、2,990,401、3,048,581、3,126,375、3,929,768、3,996,359、3,928,326和3,749,712中公开的其他皮质类固醇、抗多巴胺能药物如吩噻嗪(例如丙氯拉嗪、氟奋乃静、硫利哒嗪和美索哒嗪)、甲氧氯普胺或屈大麻酚。在另一个实施方案中,公开了采用选自神经激肽-1受体拮抗剂、5HT3受体拮抗剂和皮质类固醇的止吐药的联合疗法,用以治疗或预防本发明化合物给药时可导致的呕吐。
可与本发明化合物联合使用的神经激肽-1受体拮抗剂在例如以下专利中有充分的描述:美国专利5,162,339、5,232,929、5,242,930、5,373,003、5,387,595、5,459,270、5,494,926、5,496,833、5,637,699、5,719,147;欧洲专利公开物EP 0 360 390、0 394 989、0 428 434、0 429366、0 430 771、0 436 334、0 443 132、0 482 539、0 498 069、0 499 313、0 512 901、0 512 902、0 514 273、0 514 274、0 514 275、0 514 276、0 515 681、0 517 589、0 520 555、0 522 808、0 528 495、0 532 456、0 533 280、0 536 817、0 545 478、0 558 156、0 577 394、0 585 913、0 590 152、0 599 538、0 610 793、0 634 402、0 686 629、0 693 489、0 694 535、0 699 655、0 699 674、0 707 006、0 708 101、0 709 375、0 709 376、0 714 891、0 723 959、0 733 632和0 776 893;PCT国际专利出版物WO 90/05525、90/05729、91/09844、91/18899、92/01688、92/06079、92/12151、92/15585、92/17449、92/20661、92/20676、92/21677、92/22569、93/00330、93/00331、93/01159、93/01165、93/01169、93/01170、93/06099、93/09116、93/10073、93/14084、93/14113、93/18023、93/19064、93/21155、93/21181、93/23380、93/24465、94/00440、94/01402、94/02461、94/02595、94/03429、94/03445、94/04494、94/04496、94/05625、94/07843、94/08997、94/10165、94/10167、94/10168、94/10170、94/11368、94/13639、94/13663、94/14767、94/15903、94/19320、94/19323、94/20500、94/26735、94/26740、94/29309、95/02595、95/04040、95/04042、95/06645、95/07886、95/07908、95/08549、95/11880、95/14017、95/15311、95/16679、95/17382、95/18124、95/18129、95/19344、95/20575、95/21819、95/22525、95/23798、95/26338、95/28418、95/30674、95/30687、95/33744、96/05181、96/05193、96/05203、96/06094、96/07649、96/10562、96/16939、96/18643、96/20197、96/21661、96/29304、96/29317、96/29326、96/29328、96/31214、96/32385、96/37489、97/01553、97/01554、97/03066、97/08144、97/14671、97/17362、97/18206、97/19084、97/19942和97/21702;以及英国专利出版物2 266 529、2 268 931、2 269 170、2 269 590、2 271774、2 292 144、2 293 168、2 293 169和2 302 689。这些化合物的制备方法在上述专利和出版物中有充分的描述,上述专利和出版物通过引用结合到本文中。
在另一个实施方案中,与本发明化合物联合使用的神经激肽-1受体拮抗剂选自:2-(R)-(1-(R)-(3,5-双(三氟甲基)苯基)乙氧基)-3-(S)-(4-氟苯基)-4-(3-(5-氧代-1H,4H-1,2,4-三唑并)甲基)吗啉或其药物可接受盐,这在美国专利5,719,147中有描述。
本发明化合物也可与可用于治疗贫血的药物一起给药。这种贫血治疗药物例如为连续红血球生成受体激活剂(如阿法依泊汀)。
本发明化合物也可与可用于治疗嗜中性白细胞减少症的药物一起给药。这种中性白细胞减少症治疗药物例如为调节嗜中性白细胞生成和功能的造血生长因子,如人粒细胞集落刺激因子(G-CSF)。G-CSF的实例包括非格司亭。
本发明化合物也可与免疫增强药物如左旋咪唑、异丙肌苷和日达仙一起给药。
因此,本发明的范围包括本发明要求保护的化合物与选自以下的第二种化合物的联合应用:1)雌激素受体调节剂,2)雄激素受体调节剂,3)类视黄醇受体调节剂,4)细胞毒剂/细胞抑制剂,5)抗增殖剂,6)异戊二烯基蛋白转移酶抑制剂,7)HMG-CoA还原酶抑制剂,8)HIV蛋白酶抑制剂,9)逆转录酶抑制剂,10)血管生成抑制剂,11)PPAR-γ激动剂,12)PPAR-δ激动剂,13)固有多重抗药性抑制剂,14)止吐药,15)用以治疗贫血的药物,16)用以治疗嗜中性白细胞减少症的药物,17)免疫增强药物,18)细胞增殖和生存信号传导的抑制剂,19)干扰细胞周期关卡的药物。
涉及本发明化合物的术语“给药”或“给予”及其语法变体(例如“给予”化合物)意思是将化合物或化合物的前药引入需要治疗的动物的系统中。当本发明化合物或其前药与一种或多种其他活性药物(例如细胞毒剂等)一起提供时,“给药”或“给予”及其语法变体各自均可理解为包括同时和依次引入化合物或其前药和其他药物。
本文所用术语“组合物”包括含指定量的指定成分的产品,以及直接或间接由指定量的指定成分组合而成的任何产品。
本文所用术语“治疗有效量”指研究者、兽医、医院医生或其他临床医生正在探究的、能在组织、系统、动物或人体中引起生物或医学反应的活性化合物或药剂的量。
术语“治疗癌症”或“癌症治疗”指给药于患有癌症的哺乳动物,也指通过杀死癌细胞减轻癌症病况的作用,还指导致癌症的生长和/或转移受到抑制的作用。
在一个实施方案中,用作第二种化合物的血管生成抑制剂选自酪氨酸激酶抑制剂、表皮衍生的生长因子的抑制剂、纤维原细胞衍生的生长因子的抑制剂、血小板衍生的生长因子的抑制剂、MMP(基质金属蛋白酶)抑制剂、整联蛋白阻断剂、α干扰素、白细胞介素-12、戊聚糖聚硫酸酯、环加氧酶抑制剂、羧基酰胺三唑、考布他汀A-4、角鲨胺、6-O-氯乙酰-羰基)-烟曲霉醇、沙利度胺、血管生长抑素、肌钙蛋白-1或抗VEGF抗体。在一个实施方案中,雌激素受体调节剂是他莫昔芬或雷洛昔芬。
还包括在本发明权利要求范围内的是治疗癌症的方法,所述方法包括给予治疗有效量的式A化合物并联合使用放射疗法和/或联合使用选自以下的第二种化合物:1)雌激素受体调节剂,2)雄激素受体调节剂,3)类视黄醇受体调节剂,4)细胞毒剂/细胞抑制剂,5)抗增殖剂,6)异戊二烯基蛋白转移酶抑制剂,7)HMG-CoA还原酶抑制剂,8)HIV蛋白酶抑制剂,9)逆转录酶抑制剂,10)血管生成抑制剂,11)PPAR-γ激动剂,12)PPAR-δ激动剂,13)固有多重抗药性抑制剂,14)止吐药,15)用以治疗贫血的药物,16)用以治疗嗜中性白细胞减少症的药物,17)免疫增强药物,18)细胞增殖和生存信号传导的抑制剂,19)干扰细胞周期关卡的药物。
本发明的又一个实施方案是治疗癌症的方法,所述方法包括联合给予治疗有效量的式A化合物和紫杉醇或曲妥单抗。
本发明还包括治疗或预防癌症的方法,所述方法包括联合给予治疗有效量的式A化合物和COX-2抑制剂。
本发明也包括用于治疗或预防癌症的药物组合物,所述组合物包括治疗有效量的式A化合物和选自以下的第二种化合物:1)雌激素受体调节剂,2)雄激素受体调节剂,3)类视黄醇受体调节剂,4)细胞毒剂/细胞抑制剂,5)抗增殖剂,6)异戊二烯基蛋白转移酶抑制剂,7)HMG-CoA还原酶抑制剂,8)HIV蛋白酶抑制剂,9)逆转录酶抑制剂,10)血管生成抑制剂,11)PPAR-γ激动剂,12)PPAR-δ激动剂,13)细胞增殖和生存信号传导的抑制剂,14)干扰细胞周期关卡的药物。
所有本文指出的专利、出版物和待审的专利申请通过引用结合到本文中。
用于化学表达和以下实施例的缩写词是:AEBSF(对氨基乙基苯磺酰氟);BSA(牛血清白蛋白);BuLi(正丁基锂);CDCl3(氘代氯仿);CuI(碘化亚铜);CuSO4(硫酸铜);DCE(二氯乙烷);DCM(二氯甲烷);DEAD(偶氮二甲酸二乙酯);DMF(二甲基甲酰胺);DMSO(二甲亚砜);DTT(二硫苏糖醇);EDTA(乙二胺四乙酸);EGTA(乙二醇四乙酸);EtOAc(乙酸乙酯);EtOH(乙醇);HOAc(乙酸);HPLC(高效液相色谱);HRMS(高分辨质谱);LCMS(液相色谱-质谱联用仪);LHMDS(双(三甲基甲硅烷基)氨基锂);LRMS(低分辨质谱);MeOH(甲醇);MP-B(CN)H3(大孔-氰基氢硼化物);NaHCO3(碳酸氢钠);Na2SO4(硫酸钠);NH4OAc(乙酸铵);NBS(N-溴琥珀酰亚胺);NMR(核磁共振);PBS(磷酸缓冲盐水);PCR(聚合酶链式反应);Pd(dpPf)([1,1′-双(二苯基膦基)二茂铁]合钯);PS-DIEA(聚苯乙烯二异丙基乙胺);TBAF(氟化四丁基铵);THF(四氢呋喃);TFA(三氟乙酸)和TMSCH2N2(三甲基甲硅烷基重氮甲烷)。
本发明化合物除可通过文献中公知的或试验方法中例示的其他标准操作方法制备外,还可通过使用以下反应流程所示的反应来制备。因此,以下说明性反应流程不受所列化合物或用于说明目的的任何具体取代基的限制。在反应流程中显示的取代基编号不一定与权利要求书中使用的编号相对应,在按上述式A定义任选允许多个取代基的情况下,通常为明白起见,标示了与化合物连接的单个取代基。
用以产生本发明化合物的反应除可按文献中公知的或试验方法中例示的其他标准操作方法如酯水解、保护基的切割等来进行外,还可通过使用反应流程I-IX所示的反应来进行。
反应流程简述
反应流程I图解了本发明化合物的制备,从合适的取代羟基吡啶I-1开始。该原料可通过在吡啶中用三氟甲磺酸酐处理,转化为相应的三氟甲磺酸吡啶酯I-2。中间体I-2可与官能化芳基硼酸进行标准Suzuki偶联,产生I-3。然后该材料可与各种胺,例如
和聚合物载体上的硼氢化物进行平行还原胺化,获得1-4。
反应流程II图解了本发明化合物的合成,从根据文献(Renault,O.;Dallemagne,P;和Rault,S.Org.Prep.Proced.Int.,1999,31,324)制备的酮II-1开始。II-1与N,N-二甲基甲酰胺二甲基缩醛缩合,产生酮-烯胺II-2,后者与2-氰基乙酰胺一起环化,得到吡啶酮II-3。II-3用磷酰氯处理,产生氯吡啶II-4。后者进行自由基溴化作用,然后用适当的取代胺进行置换,产生胺II-5。
反应流程III图解了本发明化合物的制备。用LHMDS处理腈III-1获得脒III-2。随后与各种酮或醛环化,获得所需咪唑III-3。
反应流程IV图解了本发明化合物的制备。用氨基硫脲处理腈IV-1,直接获得噻二唑IV-2。
反应流程V图解了本发明化合物的制备。用各种醇钠处理氯吡啶V-1,获得化合物V-2。
反应流程VI图解了本发明化合物的制备。用各种胺处理氯吡啶VI-1,获得氨基吡啶VI-2。
反应流程VII图解了本发明化合物的合成,从合适的取代氨基吡啶VII-1开始。该材料通过用各种酰基化试剂、异氰酸酯、磺酰氯或烷基化试剂处理,转化为相应的胺、氨基甲酸酯、脲、磺酰胺或烷基胺VII-2。
反应流程VIII图解了本发明化合物的合成,从合适的取代氰基吡啶VIII-1开始。该材料在直接的两步转化中转化为相应的三唑VIII-2。
反应流程IX图解了本发明化合物的合成,从合适的取代氰基吡啶IX-1开始。用羟胺处理IX-1获得甲脒。随后环化获得噁二唑IX-2。
反应流程X图解了本发明化合物的合成,从根据文献(Renault,O.;Dallemagne,P.;和Rault,S.Org.Prep.Proced.Int.,1999,31,324)制备的酮X-1开始。X-1与2-氯-N,N-二甲氨基亚烯丙基二甲胺六氟磷酸盐反应,产生氯吡啶X-2,后者通过钯催化的偶联反应转化为X-3。X-3进行自由基溴化,然后用适当的取代胺进行置换,产生胺X-4。
反应流程I
反应流程II
反应流程III
反应流程IV
反应流程V
反应流程VI
反应流程VII
反应流程VIII
反应流程IX
反应流程X
实施例
以下提供的实施例旨在帮助进一步理解本发明。采用的具体材料、形式和条件旨在进一步说明本发明,而不是限制本发明的合理范围。在合成下表所示化合物中用到的试剂可通过市售途径获得,或容易由本领域普通技术人员制得。
流程1
三氟甲磺酸5-氰基-3-苯基吡啶-2-基酯(1-2)
在0℃下,向6-羟基-5-苯基烟腈(1-1)(1.962g,10.0mmol,60mL无水吡啶溶液)中搅拌滴加三氟甲磺酸酐(3.384g,1.20mmol)。加入三氟甲磺酸酐后,将吡啶溶液搅拌过夜,温度从0℃升至室温。第二天早上,将吡啶溶液溶于DCM(300mL),用水、饱和NaHCO3和盐水洗涤,无水Na2SO4干燥。过滤,浓缩,得到粗产物,通过快速硅胶色谱法纯化,得到纯三氟甲磺酸5-氰基-3-苯基吡啶-2-基酯。分析型LCMS:单峰(214nm),3.553分钟。1H MR(500MHz,CDCl3):δ8.64(d,J=2.2Hz,1H),8.16(d,J=2.2Hz,1H),7.52-7.56(m,3H),7.45-7.49(m,2H)。
6-(4-甲酰基苯基)-5-苯基烟腈(1-3)
在160℃下,用微波(Smith-Synthesizer)处理三氟甲磺酸5-氰基-3-苯基吡啶-2-基酯(1-2)(328mg,1.0mmol)、4-甲酰苯基硼酸(225mg,1.5mmol)、Pd(dppf)(CH2Cl2)(16mg,0.02mmol)、2M Cs2CO3水溶液(2mL,4mmol)和THF(2mL)的混合物10分钟。反应混合物冷却至室温后,用DCM(40mL)处理,然后用水、盐水洗涤,无水Na2SO4干燥。过滤,浓缩,得到粗产物,通过快速硅胶色谱法纯化,得到纯6-(4-甲酰苯基)-5-苯基烟腈(1-3)。分析型LCMS:单峰(214nm),3.240分钟。1H NMR(500MHz,CDCl3):δ10.01(s,1H),8.92(d,J=2.0Hz,1H),8.04(d,J=2.0Hz,1H),7.79(d,J=8.2Hz,2H),7.55(d,J=8.2Hz,1H),7.31-7.39(m,3H),7.13-7.18(m,2H)。
6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-
苯基烟腈(1-5)
在室温下,将6-(4-甲酰苯基)-5-苯基烟腈(1-3)(57mg,0.2mmol)、1-哌啶-4-基-1,3-二氢-2H-苯并咪唑-2-酮(1-4)(87mg,0.4mmol)和MP-BH3(CN)树脂(1g,1.2mmol)在DCE-HC(OMe)3-HOAc-(7∶2∶1,6mL)中的混合物振摇过夜。结束时,将树脂过滤,用MeOH(2×4mL)洗涤。浓缩合并的溶液,用LCMS纯化,得到所需纯产物(1-5;TFA盐)的浅黄色固体。分析型LCMS:单峰(214nm),2.452分钟。1H NMR(500MHz,DMSO-d6):δ10.94(s,1H),9.83(s,1H),9.14(d,J=2.0Hz,1H),8.44(d,J=2.0Hz,1H),7.48(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,1H),7.31-7.38(m,3H),7.24-7.30(m,3H),6.99-7.01(m,3H),4.44-4.54(m,1H),4.31-4.38(s,2H),3.47(d,J=12.3Hz,2H),3.13-3.23(m,2H),2.57-2.67(m,2H),1.92(d,J=13.4Hz,2H);HRMS,C31H28N5O(M+1)计算值,486.2289;测定值486.2296。
1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-
2H-苯并咪唑-2-酮(1-6)
165℃下,6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(1-5;TFA盐)(71mg,0.1mmol)、2M NaN3水溶液(0.75mL,1.5mmol)、2M ZnBr2水溶液(0.5mL,1.0mmol)的混合物微波(Smith-Synthesizer)处理15分钟。之后,浓缩溶液。残留物重新溶于DMSO(1mL),通过LCMS纯化,获得纯的所需产物(1-6;TFA盐)的浅黄色固体。分析型LCMS:单峰(214nm),2.248分钟。1H NMR(500MHz,,DMSO-d6):δ10.94(s,1H),9.74-9.90(s,1H),9.33(d,J=2.1Hz,1H),8.44(d,J=2.1Hz,1H),7.47-7.50(s,4H),7.36-7.40(m,3H),7.26-7.30(m,3H),6.98-7.02(m,3H),4.45-4.54(m,1H),4.33-4.38(s,2H),3.49(d,J=12.7Hz,2H),3.13-3.23(m,2H),2.58-2.69(m,2H),1.95(d,J=12.8Hz,2H);HRMS,C31H29N8O(M+1)计算值,529.2459;测定值529.2449。
表1中的化合物按流程1合成,但用适当的取代胺代替流程1中的化合物(1-4):除非另有指明外,所示化合物的TFA盐通过质谱控制的HPLC纯化法分离。
表1
流程2
3-(二甲氨基)-1-(4-甲基苯基)-2-苯基丙-2-烯-1-酮(2-2)
在110℃下,将1-(4-甲基苯基)-2-苯基乙酮(2-1)(Renault,O;Dallemagne,P;和Rault,S.Org.Prep.Proced.Int.1999,31,324)(3.29g,15.65mmol)和N,N-二甲基甲酰胺二甲基缩醛(4.66g,39.12mmol)的DMF(15mL)溶液搅拌1小时。真空浓缩所得混合物,得到3-(二甲氨基)-1-(4-甲基苯基)-2-苯基丙-2-烯-1-酮(2-2)。LRMS m/z(M+H)计算值:266.4,实测值:266.2。
6-(4-甲基苯基)-2-氧代-5-苯基-1,2-二氢吡啶-3-甲腈(2-3)
在0℃下,40分钟内向NaH(1.38g,矿物油中,60%,34.41mmol)的DMF(20mL)淤浆中滴加3-(二甲氨基)-1-(4-甲基苯基)-2-苯基丙-2-烯-1-酮(2-2;4.15g,15.64mmol)和2-氰基乙酰胺(1.45g,17.2mmol)的MeOH(1.5mL)和DMF(40mL)溶液。所得混合物在90℃下搅拌4小时,然后冷却至室温。将混合物倒入稀HCl水溶液(240mL,0.25M)中,过滤,用水(40mL)洗涤,真空干燥,得到6-(4-甲基苯基)-2-氧代-5-苯基-1,2-二氢吡啶-3-甲腈(2-3)。1H NMR(500MHz,CDCl3):δ7.96(s,1H),7.15-7.28(m,7H),7.05-7.07(m,2H),2.36(s,3H)。LRMSm/z(M+H)计算值:287.3,实测值:287.1。
2-氯-6-(4-甲基苯基)-5-苯基烟腈(2-4)
将6-(4-甲基苯基)-2-氧代-5-苯基-1,2-二氢吡啶-3-甲腈(2-3;1.5g,5.24mmol)与POCl3(15mL)的混合物加热至100℃,持续3小时并浓缩。残余物用碳酸钠水溶液碱化,用CH2Cl2(3×30mL)萃取。合并有机层,干燥,过滤,浓缩。残余物通过硅胶色谱法(5-10%EtOAc的己烷溶液)纯化,得到2-氯-6-(4-甲基苯基)-5-苯基烟腈(2-4)。1H NMR(500MHz,CDCl3):δ7.95(s,1H),7.33-7.35(m,3H),7.28(d,J=8.3,2H),7.16-7.18(m,2H),7.06(d,J=7.9,2H),2.32(s,3H)。LRMS m/z(M+H)计算值:305.2,实测值:305.1。
6-[4-(溴甲基)苯基]-2-氯-5-苯基烟腈(2-5)
将2-氯-6-(4-甲基苯基)-5-苯基烟腈(2-4;0.066g,0.217mmol)、NBS(0.046g,0.26mmol)和过氧化苯甲酰(0.010g,0.043mmol)的CDCl3(2mL)溶液加热回流过夜。浓缩所得混合物,得到6-[4-(溴甲基)苯基]-2-氯-5-苯基烟腈(2-5),不经进一步纯化即可使用。LRMS m/z(M+H)计算值:383.7,实测值:383.1。
2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯
基]-5-苯基烟腈(2-6)
向6-[4-(溴甲基)苯基]-2-氯-5-苯基烟腈(2-5;0.078g,0.203mmol)的MeOH(1mL)和THF(1mL)溶液中加入4-(2-酮-1-苯并咪唑啉基)-哌啶(0.066g,0.305mmol;市售)和DIEPA(0.131g,1.02mmol)。混合物室温下搅拌过夜,浓缩。残留物用Na2CO3水溶液(5mL,2M)处理,用CH2Cl2(3×10mL)萃取。合并有机层,干燥,过滤并浓缩。残留物通过硅胶色谱法纯化(3-5%MeOH/CH2Cl2),得到2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基]-5-苯基烟腈(2-6)。1H-NMR(500MHz,CDCl3)δ7.98(s,1H),7.31-7.37(m,4H),7.25-7.29(m,4H),7.17-7.19(m,2H),7.05-7.09(m,3H),4.31-4.36(m,1H),3.54(s,2H),2.97-2.99(m,2H),2.41-2.47(m,2H),2.12-2.17(m,2H),1.78-1.80(m,2H)。LRMS m/z(M+H)计算值:520.0,测定值:520.0。
表2中的下列化合物以类似的方法制备:
表2
流程3
6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-
甲脒(3-2)
0℃下向6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(3-1,0.050g,0.103mmol,根据流程1制备,但用合适的胺代替(1-4))的无水THF溶液(3mL)中加入LiHMDS(1M的THF溶液,0.513mL,0.513mmol)。反应物升至室温,搅拌1.5小时。加入1M HCl(1.5mL),搅拌反应物30分钟。然后加入1M NaOH(3mL),所得混合物用CH2Cl2萃取(3×15mL)。合并有机物,干燥(无水Na2SO4),过滤并浓缩。用醚研磨所得材料,真空干燥。HRMSm/z(M+H)计算值:505.7571,测定值:505.2544。
6-氟-2-(1-{4-[5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-
苯并咪唑(3-3)
向6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-甲脒(3-2,0.030g,0.059mmol)的二噁烷溶液(1.5mL)中加入氯乙醛(50%水溶液,0.019mL,0.119mmol),然后加入碳酸钠(0.016mg,0.149mmol)。反应物加热至110℃,持续1小时。冷却混合物,在饱和碳酸氢钠水溶液和CH2Cl2之间分配,萃取3次。合并有机物,干燥(无水Na2SO4),过滤并浓缩。残留物通过硅胶色谱法纯化(6-8%MeOH/CH2Cl2)。1H-NMR(500MHz,d6 DMSO)δ12.83(s,1H),12.31(s,1H),9.21(d,J=1.95,1H),8.74(s,1H),8.30(d,J=2.2,1H),7.08-7.42(m,12H),6.97(bs,1H),3.61(bs,2H),3.50(bs,1H),3.13(bs,2H),2.87(bs,2H),1.98(bs,2H),1.84(bs 2H)。HRMS m/z(M+H)计算值:529.2511,测定值:529.2532。
表3中的下列化合物以类似的方式制备。
表3
流程4A
4-(4-氯-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(4A-1)
N2下向火焰干燥的圆底烧瓶中加入4-氯吡唑并(3,4-d)嘧啶(J.Am.Chem.Soc.1956,78,784.)(1.80g,11.65mmol)、4-羟基-1-哌啶甲酸叔丁酯(2.46g,12.23mol)和PS-PPh3(9.211g,1.77mmol/g)的无水THF溶液(200mL)。混合物冷却至0℃,滴加THF(20mL)中的DEAD(2.20mL,13.98mmol)。混合物升至室温,搅拌过夜。然后过滤反应物,吸收在CH2Cl2中。过滤除去不溶物。浓缩滤液,再吸收在CH2Cl2中,置于冰箱中5小时。过滤形成的晶体,滤液通过硅胶色谱法纯化(0-2%MeOH/CH2Cl2)。1H-NMR(500MHz,CDCl3)δ8.76(s,1H),8.16(s,1H),4.92-5.02(m,1H),4.32(bs,2H),2.97(bs,2H),2.20-2.31(m,2H),1.96-2.05(m,2H)。LRMS m/z(M+H)计算值:337.13,测定值:338.09。
4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(4A-2)
4-(4-氯-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(4A-1;0.050g,0.148mmol)在饱和NH3的EtOH溶液(1mL)中的混合物在微波中加热至80℃,持续30分钟。冷却混合物,浓缩并真空干燥。无需纯化即可使用。1H-NMR(500MHz,CDCl3)δ8.38(s,1H),7.93(s,1H),5.60(bs,2H),4.84-4.95(m,1H),4.29(bs,2H),2.95(bs,2H),2.13-2.28(m,2H),1.92-2.03(m,2H)。LRMS m/z(M+H)计算值:319.1,测定值:319.1。
1-哌啶-4-基-1H-吡唑并[3,4-d]嘧啶-4-胺(4A-3)
4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(4A-2;1.30g,4.08mmol)在4M HCl二噁烷(12mL)中的混合物搅拌1小时。浓缩反应物,用醚研磨,得到二氯化4-氨基-1-哌啶鎓-4-基-1H-吡唑并[3,4-d]嘧啶-2-鎓。对于游离碱:将上述盐溶于水,经过Dowex1X2-400离子交换树脂(-OH型)。用水洗涤树脂,然后用MeOH洗涤。浓缩滤液,真空干燥,获得纯的游离碱。1H-NMR(500MHz,d6 DMSO)δ8.14(s,1H),8.07(s,1H),7.64(bs,2H),4.57-4.67(m,1H),3.05(d,J=12.46 2H),2.55-2.67(m,2H),2.06(bs,1H),1.90-2.12(m,2H),1.73-1.80(m,2H)。LRMS m/z(M+H)计算值:219.1,测定值:219.1。
6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-
苯基烟腈(4A-4)
N2下向火焰干燥的圆底烧瓶中加入5%AcOH:DMF(2mL)中的二氯化4-氨基-1-哌啶鎓-4-基-1H-吡唑并[3,4-d]嘧啶-2-鎓(0.183g,0.901mmol)、6-(4-甲酰基苯基)-5-苯基烟腈(1-3;0.170g,0.598mmol)和Et3N(0.163mL,1.20mmol)。混合物搅拌1小时,加入NaBH(OAc)3(0.191g,0.658mmol)。混合物在饱和NaHCO3水溶液和CH2Cl2之间分配,搅拌1小时。水层再用CH2Cl2萃取2次,合并有机物,干燥(无水Na2SO4),过滤并浓缩。残留物吸附在硅胶上,通过硅胶色谱法纯化(2-4%MeOH/CH2Cl2)。1H-NMR(500MHz,CDCl3)δ8.92(d,J=1.96,1H),8.36(s,1H),7.97(d,J=1.96,1H),7.91(s,1H),7.12-7.40(m,9H),5.51(bs,2H),4.65-4.80(m,1H),3.56(s,2H),3.00(d,J=9.77,2H),2.15-2.45(m,4H),1.95(d,J=10.74,2H)。HRMS(ES)m/z(M+H)计算值:487.2353,测定值:487.2335。
1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-
基)-1H-吡唑并[3,4-d]嘧啶-4-胺(4A-5)
6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(4A-4;0.035g,0.072mmol)和氨基硫脲(0.010g,0.108mmol)的TFA溶液(2mL)加热至60℃,持续16小时。冷却反应物,倾在冰上,用饱和碳酸氢钠水溶液碱化。过滤所得沉淀,吸收在DMF中,通过反相HPLC纯化(5%CH3CN:95%H2O+0.1%TFA至95%CH3-CN:5%H2O+0.1%TFA)。1H-NMR(500MHz,d6 DMSO)δ9.72(bs,1H),9.07(d,J=2.19,1H),8.93(bs,1H),8.42(bs,1H),8.36(s,1H),8.29(s,1H),8.10(d,J=1.96,1H),7.65(bs,2H),7.22-7.49(m,9H),4.93-5.03(m,1H),4.34(s,2H),3.49(d,J=12.21,2H),3.19-3.35(m,2H),2.32-2.56(m,2H),2.15(d,J=11.96,2H)。HRMSm/z(M+H)计算值:561.2292,测定值:561.2256。
流程4B
氢溴酸4-(3-哌啶-4-基-1H-吡唑-5-基)吡啶(4B-4)
盐酸4-乙酰哌啶(4B-1,5.0g,30.55mmole)吸收在CH2Cl2(150mL)中。向其中加入Et3N(9.8mL,70.27mmole),悬浮液变成溶液。混合物冷却至0℃,向其中加入氯甲酸苄酯(5.2mL,36.66mmole)。加入完成后,混合物升至室温。18小时后,用H2O稀释混合物。分离各层,水层用CH2Cl2萃取(3x)。合并有机层,干燥(MgSO4),过滤并浓缩,获得4-乙酰哌啶-1-甲酸苄酯的黄白色固体(4B-2):1H-NMR(500MHz,CDCl3)δ7.35(m,5H),5.13(s,2H),4,18(bs,2H),2.88(bs,2H),2.49(m,1H),2.17(s,3H),1.86(bs,2H),1.55(m,2H)。
0℃下向4-乙酰哌啶-1-甲酸苄酯(4B-2;4.75g,18.18mmole)的无水DMF溶液(40mL)中一次性加入NaH(2.11g,60%,分散在矿物油中,52.72mmole)。30分钟后加入异烟酸甲酯(2.8mL,23.63mmole)。混合物升至室温。18小时后浓缩混合物。残留物吸收在饱和NH4Cl中,用EtOAc萃取(3x)。合并有机层,干燥(MgSO4),过滤并浓缩。将材料分为2部分,各自通过快速柱色谱法纯化(100%EtOAc),获得橙色油。1H-NMR显示为氨基甲酸甲酯和苄酯(2.99g)的4∶1昆合物,其纯度足以用于下一步骤。
向二酮(4B-3a和4B-3b,2.99g,10.3mmole)的EtOH(50mL)溶液中加入一水合肼(0.55mL,11.33mmole),然后混合物加热至回流。3小时后冷却混合物至室温,浓缩。残留物吸收在30%HBr的HOAc溶液(50mL)中。18小时后浓缩混合物。残留物吸收在HOAc(50mL)中,浓缩(2x)。残留物吸收在MeOH(50mL)中,浓缩。用MeOH研磨,获得氢溴酸4-(3-哌啶-4-基-1H-吡唑-5-基)吡啶的浅褐色固体(4B-4):1H-NMR(500MHz,DMSO-d6)δ13.62(bs,1H),8.87(d,J=6.10Hz,2H),8.69(bs,1H),8.44(bs,1H),8.34(d,J=5.62Hz,2H),7.11(s,1H),3.37(m,2H),3.11(m,3H),2.15(m,2H),1.82(m,2H)。
5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈
(4B-5)
以与化合物(4A-4)相同的方法制备标题化合物。HRMS(ES)m/z(M+H)计算值:497.2448,测定值:497.2429。
5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)
吡啶-3-基]-1,3,4-噻二唑-2-胺(4B-6)
5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈(4B-5;0.030g,0.060mmol)和氨基硫脲(0.006g,0.066mmol)的TFA溶液(1.5mL)加热至60℃,持续16小时。然后冷却反应物,倾在冰上,用饱和碳酸氢钠水溶液碱化。过滤所得沉淀(4B-6),吸收在DMF中,通过反相HPLC纯化(5%CH3CN:95%H2O+0.1%TFA至95%CH3-CN:5%H2O+0.01%TFA)。1H-NMR(500MHz,d6 DMSO)δ13.54(bs,1H),9.64(s,1H),9.07(d,J=1.96,1H),8.81(d,J=6.11,2H),8.21(s,2H),8.10(d,J=2.2,1H),7.65(s,2H),7.23-7.49(m,9H),7.00(s,1H),4.33(d,2H),3.45(d,J=10.5,2H),2.95-3.15(m,3H),2.21(d,J=12.69,2H),1.76-1.90(m 2H)。HRMS m/z(M+H)计算值:571.2387,测定值:571.2359。
表4中的下列化合物以类似的方式制备。
表4
流程5
2-[2-(二甲氨基)乙氧基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)
哌啶-1-基]甲基}苯基)-5-苯基烟腈(5-1)
向N,N-二甲氨基乙醇在DMSO(1mL)中的混合物中加入NaH(60%,分散在矿物油中,0.019g,0.481mmol)。混合物加热至50℃,持续15分钟。冷却后,加入2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基]-5-苯基烟腈(2-6,0.050g,0.096mmol),反应在室温下搅拌16小时。用水(10mL)稀释所得混合物,过滤所得沉淀。滤饼通过反相HPLC纯化(5%CH3CN:95%H2O+0.01%TFA至95%CH3CN:5%H2O+0.01%TFA)。1H-NMR(500MHz,d6 DMSO)δ10.93(s,1H),9.86(bs,2H),8.45(s,1H),7.40-7.55(m,4H),7.25-7.40(m,6H),7.00(d,J=2.93,3H),4.85(t,J=4.89,2H),4.45-4.55(m,1H),4.34(s,2H),3.64(bs,2H),3.46(d,J=11.72,2H),3.10-3.25(m,2H),2.94(d,J=4.15,6H),2.56-2.69(m 2H),1.93(d,J=12.00,2H)。HRMS m/z(M+H)计算值:573.2973,测定值:573.2957。
表5中的下列混合物以相似的方法制备。
表5
流程6
2-(甲基氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]
甲基}苯基)-5-苯基烟腈(6-1)
2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基]-5-苯基烟腈(2-6,0.040g,0.077mmol)和甲胺(2M的THF溶液,0.192mL,0.385mmol)在i-PrOH(1mL)中的混合物在微波中150℃下加热15分钟。浓缩混合物,吸收在DMF中,通过反相HPLC纯化(6-1;5%CH3CN:95%H2O+0.01%TFA至95%CH3CN:5%H2O+0.01%TFA)。1H-NMR(500MHz,d6 DMSO)δ10.93(s,1H),9.59(bs,1H),8.00(s,1H),7.37-7.47(m,4H),7.18-7.37(m,5H),7.12(dd,J=1.96,8.06,2H),6.95-7.05(m,3H),4.43-4.53(m,1H),4.32(d,J=5.00,2H),3.47(d,J=10.99,2H),3.10-3.25(m,2H),2.94(d,J=4.39,3H),2.55-2.69(m,2H),1.92(d,J=11.48,2H)。HRMS m/z(M+H)计算值:515.2554,测定值:515.2552。
表6中的下列混合物以类似的方式制备。
表6
流程7
N-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲
基}苯基)-5-苯基吡啶-2-基]-N′-乙基脲(7-1)
2-氨基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(6-3;0.025g,0.05mmol)和异氰酸乙酯(0.007mg,0.100mmol)在THF(1mL)中的混合物加热至100℃,持续0.5小时,浓缩。残留物通过硅胶色谱法纯化(3-6%MeOH/CH2Cl2),获得标题化合物(7-1)。LRMS m/z(M+H)计算值:572.7,测定值:572.2。
表7中的下列混合物以类似的方式制备。通过在高温下用N,N-二甲基甲酰胺二甲基缩醛处理(6-3),合成化合物(7-3)。
表7
流程8
6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-
基)-1H-苯并咪唑(8-1)
-5℃下向TMS重氮甲烷(2M的己烷溶液,0.205mL,0.410mmol)的无水THF溶液(1mL)中滴加正丁基锂(2.5M的己烷溶液,0.164mL,0.410mmol)。混合物在-5℃下搅拌20分钟,然后在-5℃下将该溶液滴加至6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(4-1,0.050g,0.103mmol)在THF(1mL)中的混合物中。反应物在-5℃下搅拌3小时,然后用饱和Na2HCO3水溶液猝灭,用CH2Cl2萃取(3×15mL)。合并有机物,干燥(无水Na2SO4),过滤并浓缩。残留物吸收在THF(2mL)中,加入TBAF(1M的THF溶液,0.205mL)。反应物加热至60℃,持续2小时,此时将其冷却并浓缩。所得残留物吸收在DMF中,通过反相HPLC纯化(8-1;5%CH3CN:95%H2O+0.01%TFA至95%CH3CN:5%H2O+0.01%TFA)。1H-NMR(500MHz,d6DMSO)δ9.74(bs,1H),9.20(d,J=2.20,1H),8.65(bs,1H),8.29(d,J=2.21,1H),7.60-7.70(m,1H),7.25-7.55(m,12H),7.18(t,J=7.08,1H),4.35(s,2H),3.50(d,J=12.06,2H),3.25-3.39(m,1H),3.09-3.20(m,2H),2.29-2.39(m,2H),1.97-2.10(m,2H)。HRMS m/z(M+H)计算值:530.2463,测定值:530.2454。
表8中的下列混合物以类似的方式制备。
表8
流程9
6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-N′-
羟基-5-苯基吡啶-3-甲脒(9-2)
向6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(9-1(用流程1制备),0.036g,0.074mmol)的EtOH溶液(1.5mL)中加入羟胺(50%水溶液,0.010mL,0.148mmol)。反应物加热至88℃,持续3小时,此时将其冷却并浓缩。LRMS m/z(M+H)计算值:520.1,测定值:520.09。
1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-
吡唑并[3,4-d]嘧啶-4-胺(9-3)
向6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-N′-羟基-5-苯基吡啶-3-甲脒(9-2,0.035g,0.067mmol)在原甲酸三甲酯(2mL)中的混合物中加入4滴甲酸,反应物加热至100℃,持续16小时。冷却反应物,浓缩,吸收在DMF中,通过反相HPLC纯化(9-3;5%CH3CN:95%H2O+0.01%TFA至95%CH3CN:5%H2O+0.01%TFA)。1H-NMR(500MHz,d6DMSO)δ9.97(s,1H),9.71(bs1H),9.30(d,J=2.20,1H),8.70(bs,1H),8.14-8.40(m,4H),7.40-7.55(m,4H),7.27-7.40(m,5H),4.90-5.04(m,1H),4.35(bs,2H),3.49(d,J=12.70,2H),3.19-3.34(m,2H),2.32-2.45(m,2H),2.14(d,J=11.23,2H)。HRMS m/z(M+H)计算值:530.2414,测定值:530.2368。
表9中的下列化合物以类似的方式,用取代肼代替羟胺而制备。
表9
流程10
5-氯-2-(4-甲基苯基)-3-苯基吡啶(10-2)
在0℃下,向1-(4-甲基苯基)-2-苯基乙酮(10-1)(Renault,O;Dallemagne,P.;和Rault,S.Org.Prep.Proced.Int.1999,31,324)(0.5g,2.38mmol)的THF(5mL)溶液加入叔丁醇盐的THF溶液(2.6mL,1M)。所得淤浆在室温下搅拌45分钟。加入2-氯-N,N-二甲氨基亚烯丙基二甲胺六氟磷酸盐(1.1g,3.6mmol),所得混合物加热至45℃,保持3小时。再加入乙酸铵(0.367g,4.76mmol),然后将所得混合物加热回流6小时。所得溶液用水稀释,EtOAc萃取。合并有机层,干燥,过滤,浓缩。残余物通过硅胶色谱法(2-4%EtOAc的己烷溶液)纯化,得到标题化合物。LRMS m/z(M+H)计算值:280.8,实测值280.2。
2-[6-(4-甲基苯基)-5-苯基吡啶-3-基]嘧啶(10-3)
5-氯-2-(4-甲基苯基)-3-苯基吡啶(10-2;0.050g,0.179mmol)、二硼酸二频哪醇酯(0.054g,0.214mmol)、乙酸钾(0.026g,0.268mmol)、Pd2(dba)3(5mg,0.005mmol)、三环己基膦(4mg,0.013mmol)在无水二噁烷(2mL)中的混合物脱气(3×泵/N2),在微波中160℃下加热1小时,形成硼酸。在同一罐中,加入2-溴嘧啶(0.042g,0.26mmol)、四(三苯基膦)合钯(0.010g,0.00895mmol)和2M Na2CO3水溶液(1mL),所得混合物脱气(3×泵/N2),在微波中150℃下加热3小时。反应物在CH2Cl2和水之间分配,用CH2Cl2萃取3次,合并有机物,干燥(干燥Na2SO4),过滤并浓缩。残留物通过硅胶色谱法纯化(10-20%EtOAc/己烷),获得标题化合物。1H-NMR(500MHz,CDCl3)δ9.69(d,1H,J=2.0Hz),8.86(d,2H,J=4.9Hz),8.73(d,1H,J=2.0Hz),7.37-7.23(m,8H),7.08(d,2H,J=7.82Hz),2.33(s,3H)。LRMS m/z(M+H)计算值:324.0,测定值:324.0。
2-{6-[4-(溴甲基)苯基]-5-苯基吡啶-3-基}嘧啶(10-4)
向2-[6-(4-甲基苯基)-5-苯基吡啶-3-基]嘧啶(10-3;0.040g,0.124mmol)在CDCl3(2mL)中的混合物中加入NBS(0.024g,0.134mmol)和过氧化苯甲酰(0.006g,0.025mmol)。反应物加热至回流,持续15小时,此时冷却反应物并浓缩,获得标题化合物粗品。LRMS m/z(M+H)计算值:403.9,测定值:403.9。
1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并
[3,4-d]嘧啶-4-胺(10-5)
粗2-{6-[4-(溴甲基)苯基]-5-苯基吡啶-3-基}嘧啶(0.050g,0.124mmol)、1-哌啶-4-基-1H-吡唑并[3,4-d]嘧啶-4-胺(0.030g,0.137mmol)和DIEA(0.065mL,0.373mmol)在1∶1 MeOH∶THF(1mL)中的混合物搅拌1小时。浓缩反应物,残留物通过反相HPLC纯化(5%CH3CN∶95%H2O∶0.01%TFA至95%CH3CN∶5%H2O∶0.01%TFA),得到标题化合物。1H-NMR(500MHz,d6 DMSO)δ9.77(bs,1H),9.60(d,1H,J=2.0Hz),9.00(d,2H,J=4.9Hz),8.70(bs,1H),8.68(d,2H J=2.0Hz),8.45(bs,1H),8.37(s,1H),8.30(s,1H),7.58(t,1H,J=4.9Hz),7.54-7.37(m,9H),5.05-4.93(m,1H),4.35(s,2H),3.49(d,2H,J=11.23Hz),3.37-3.21(m,2H),2.47-2.33(m,2H),2.15(d,2H,J=11.7Hz)。HRMS m/z(M+H)计算值:540.2619,测定值:540.2616。
以类似的方式制备下列化合物:
表10
实施例1
人Akt同工型和ΔPH-Akt1的克隆
如下制备pS2neo载体(2001年4月3日保藏于ATCC,保藏号ATCC PTA-3253):pRmHA3载体(按Nucl.Acid Res.16:1043-1061(1988)中的描述制备)用BglII切割,分离出2734bp的片段。PUChsneo载体(按EMBO J.4:167-171(1985)中的描述制备)也用BglII切割,分离出4029bp的条带。将所述两个分离片段连接在一起,产生载体pS2neo-1。这个质粒在金属硫蛋白启动子和醇脱氢酶加poly A位点之间含有多接头。它还具有由热激启动子驱动的neo抗性基因。pS2neo-1载体用Psp5II和BsiWI切割。合成两条互补的寡核苷酸,然后退火(CTGCGGCCGC(SEQ.ID.NO.:1)和GTACGCGGCCGCAG(SEQ.ID.NO.:2))。将切割的pS2neo-1和退火的寡核苷酸连接在一起,产生第二个载体pS2neo。在转染S2细胞之前,向此转化物中加入NotI位点,以协助线性化。
人Akt1基因用5′引物:5′CGCGAATTCAGATCTACCATG-AGCGACGTGGCTATTGTG 3′(SEQ ID NO.:3),和3′引物:5′CGCTCTAGAGGATCCTCAGGCCGTGCTGCTGGC3′(SEQ ID NO.:4),通过PCR(Clontech)从人脾cDNA(Clontech)扩增。5′引物包括EcoRI和BglII2位点。3′引物包括XbaI和BamHI位点,以作克隆用途。所得PCR产物作为EcoRI/Xba I片段亚克隆到pGEM3Z(Promega)中。出于表达/纯化的目的,用PCR引物5′GTACGATGC-TGAACGATATCTTCG 3′(SEQ.ID.NO.:5)将中T标记添加到全长Akt1基因的5′末端。所得PCR产物包含5′KpnI位点和3′BamHI位点,用以在同一框内将片段亚克隆至含生物素标记的昆虫细胞表达载体pS2neo。
为表达缺失普列克底物蛋白同源结构域(PH)(Δaa 4-129,包括缺失Akt1铰链区的一部分)的Akt1,用pS2neo载体中的全长Akt1基因为模板,进行PCR缺失诱变。PCR用以下重叠内部引物分两个步骤进行:(5′GAATACATGCCGATGGAAAGCGACGGGGCTGAA-GAGATGGAGGTG 3′(SEQ.ID.NO.:6)和5′CCCCTCCATCTCTTC-AGCCCCGTCGCTTTCCATCGGCATGTATTC 3′(SEQ.ID.NO.:7)),所述重叠内部引物包含缺失,并在5′末端包含含有KpnI位点和中T标记的5′和3′侧翼引物。最终PCR产物用Kpnl和SmaI消化,并连接到pS2neo全长Akt1 KpnI/Sma I切割载体,这样就有效地用缺失版本置换克隆物的5′末端。
人Akt3基因用氨基末端寡核苷酸引物:5′GAATTCAGATCTACCATGAGCGATGTTACCATTGTG 3′(SEQ.ID.NO.;8);和羧基末端寡核苷酸引物:5′TCTAGATCTTAT-TCTCGTCCACTTGCAGAG3′(SEQ.ID.NO.:9),通过PCR从成人大脑cDNA(Clontech)扩增。这些引物包含5′EcoRI/BgIII位点和3′XbaI/BgIII位点,以作克隆用途。所得PCR产物克隆到pGEM4Z(Promega)的EcoRI和XbaI位点。出于表达/纯化的目的,用PCR引物:5′GGTACCATGGAATACATGCCGATGGAAAGCGATGTT-ACCATTGTGAAG 3′(SEQ.ID.NO.;10)将中T标记添加到全长Akt3克隆的5′末端。所得PCR产物包含5′KpnI位点,这样允许与含生物素标记的昆虫细胞表达载体pS2neo在同一框内进行克隆。
人Akt2基因用氨基末端寡核苷酸引物:5′AAGCTTAGATCTACCATGAATGAGGTGTCTGTC 3′(SEQ.ID.NO.:11);和羧基末端寡核苷酸引物:5′GAATTCGGATCCTCACTC-GCGGATGCTGGC 3′(SEQ.ID.NO.:12),通过PCR从人胸腺cDNA(Clontech)扩增。这些引物包含5′HindIII/BgIII位点和3′EcoRI/BamHI位点,以作克隆用途。所得PCR产物亚克隆到pGEM3Z(Promega)的HindIII/EcoRI位点。出于表达/纯化的目的,用PCR引物:5′GGTACCATGGAATACATGCCGATGGAAAATGAGGTGTCTGTCATCAAAG 3′(SEQ.ID.NO.:13)将中T标记添加到全长Akt2的5′末端。所得PCR产物如上所述亚克隆到pS2neo载体中。
实施例2
人Akt同工型和ΔPH-Akt1的表达
纯化pS2neo表达载体中含克隆Akt1、Akt2、Akt3和ΔPH-Akt1基因的DNA,用以通过磷酸钙方法转染果蝇(Drosophila)S2细胞(ATCC)。选出抗生素(G418,500μg/ml)抗性细胞集合体。将细胞稀释至1.0L的体积(~7.0×106/ml),加入生物素和CuSO4,至终浓度分别为50μM和50mM。细胞在27℃下培养72小时后,离心收集。细胞团在-70℃下冷藏备用。
实施例3
人Akt同工型和ΔPH-Akt1的纯化
从实施例2所述的1升S2细胞获得的细胞团进行超声裂解,使用缓冲液A:(50mM Tris pH7.4,1mM EDTA,1mM EGTA,0.2mMAEBSF,10μg/ml苄脒,5μg/ml(分别)亮抑酶肽、抑蛋白酶肽和抑胃酶肽,10%甘油和1mM DTT)中的50ml 1%CHAPS。可溶性级份用蛋白GSepharose高流速(Pharmacia)柱纯化,所述柱子荷载9mg/ml抗中T单克隆抗体,用含25%甘油的缓冲液A中的75μM EYMPME(SEQ.ID.NO.:14)肽洗脱。合并含Akt的级份,通过SDS-PAGE鉴定蛋白质纯度。纯化蛋白用标准的Bradford法进行定量。纯化蛋白用液氮快速冷冻,在-70℃下保藏。
从S2细胞纯化的Akt和Akt普列克底物蛋白同源结构域缺失体需要进行活化。Akt和Akt普列克底物蛋白同源结构域缺失体在含10nM PDK1(Upstate Biotechnology,Inc.)、脂小泡(10μM磷脂酰肌醇-3,4,5-三磷酸-Metreya,Inc、100μM磷脂酰胆碱和100μM磷脂酰丝氨酸-Avanti Polar lipids,Inc.)和活化缓冲液(50mM Tris pH7.4,1.0mM DTT,0.1mM EGTA,1.0μM微囊藻素-LR,0.1mM ATP,10mMMgCl2,333μg/ml BSA和0.1mM EDTA)的反应体系中进行活化(Alessi等,Current Biology 7;261-269)。反应在22℃下孵育4小时。等份反应液用液氮快速冷冻。
实施例4
Akt激酶的测定
活化Akt同工型和普列克底物蛋白同源结构域缺失构建物采用GSK衍生的生物素化肽底物进行分析。通过联合使用磷酸肽特异性镧系螯合物(Lance)偶联单克隆抗体和链霉抗生物素蛋白(与肽的生物素部分结合)连接的别藻蓝蛋白(SA-APC)荧光团,用均相时间分辨荧光法(HTRF)测定肽磷酸化的程度。当Lance和APC靠近时(即与同一磷酸肽分子结合),从Lance到APC出现非放射性能量转移,然后从APC以665nm的波长发射光线。
分析所需材料
A.活化Akt同工酶或普列克底物蛋白同源结构域缺失构建物;
B.Akt肽底物:GSK3α(S21)肽no.3928生物素-GGRARTSSFAEPG(SEQ.ID.NO.:15),Macromolecular Resources;
C.Lance标记抗磷酸GSK3α单克隆抗体(Cell SignalingTechnology,clone#27);
D.SA-APC(Prozyme目录号PJ25S批号896067);
E.MicrofluorB U形底微量滴定板(Dynex Technologies,目录号7205)
F.DiscoveryHTRF微型板分析仪,Packard Instrument Company;
G.100X蛋白酶抑制剂混合物(PIC):1mg/ml苄脒,0.5mg/ml抑胃酶肽,0.5mg/ml亮抑酶肽,0.5mg/ml抑蛋白酶肽;
H.10X分析缓冲液:500mM HEPES,pH7.5,1%PEG,mM EDTA,1mM EGTA,1%BSA,20mMθ-甘油磷酸;
I.猝灭缓冲液:50mM HEPES pH7.3,16.6mM EDTA,0.1%BSA,0.1%Triton-100,0.17nM Lance标记单克隆抗体克隆#27,0.0067mg/ml SA-APC;
J.ATP/MgCl2工作液:1X分析缓冲液,1mM DTT,1X PIC,125mM KCl,5%甘油,25mM MgCl2,375TM ATP;
K.酶工作液:1X分析缓冲液,1mM DTT,1X PIC,5%甘油,活性Ak。选择酶的终浓度,使得分析在线性响应范围内进行;
L.肽工作液:1X分析缓冲液,1mM DTT,1X PIC,5%甘油,2TMGSK3生物素化肽#3928。
将16TL ATP/MgCl2工作液加入的96孔微量滴定板的适当孔中,组装反应系统。加入抑制剂或载体(1.0T1),然后加入10T1肽工作液。通过加入13T1酶工作液并混合,开始反应。让反应进行50分钟,然后通过加入60 T1 HTRF猝灭缓冲液终止反应。终止的反应在室温下孵育至少30分钟,然后在Discovery仪器上读数。
PKA分析:
各独立PKA分析由以下组分组成:
A.5X PKA分析缓冲液(200mM Tris pH7.5,100mM MgCl2,5mMθ-巯基乙醇,0.5mM EDTA);
B.50μM肯普肽(Sigma)贮存液,用水稀释;
C.33P-ATP,通过将1.0μl 33P-ATP[10mCi/ml]稀释到200Tl的50μM未标记ATP贮存液中配制;
D.10μl 70nM PKA催化亚单位(UBI目录号14-114)贮存液,用0.5mg/ml BSA稀释;
E.PKA/肯普肽工作液:等体积5X PKA分析缓冲液、肯普肽溶液和PKA催化亚单位。
在96深孔分析板中组装反应系统。将抑制剂或载体(1.0T1)加入到10 T1 33P-ATP溶液中,通过向各孔加入30 T1 PKA/肯普肽工作液启动反应。将反应液混合,并在室温下孵育20分钟。通过加入50T1100mM EDTA和100mM焦磷酸钠并混合,终止反应。
将酶反应产物(磷酸化肯普肽)收集到p81磷酸纤维素96孔滤板(Millipore)上。使p81滤板的各孔充满75mM磷酸,从而制备滤板。通过在滤板的底部施加真空,使各孔能从滤板排空。将磷酸(75mM,170μl)加入到各孔中。从已终止反应的各PKA反应取30μl等份样品,加入滤板上含磷酸的相应各孔。施加真空后,肽被捕集在滤板上,用75mM磷酸洗涤滤板5次。最后一次洗涤后,让滤板风干。向各孔加入闪烁液(30μl),用TopCount(Packard)对滤板进行计数。
PKC分析:
各个PKC分析由以下组分组成:
A.10X PKC共活化缓冲液:2.5mM EGTA,4mM CaCl2;
B.5X PKC活化缓冲液:1.6mg/ml磷脂酰丝氨酸,0.16mg/ml二酰甘油,100mM Tris pH7.5,50mM MgCl2,5mMθ-巯基乙醇;
C.33P-ATP,通过将1.0μl 33P-ATP[10mCi/ml]稀释到100μl的100μM未标记ATP贮存液中配制;
D.髓鞘碱性蛋白(350μg/ml,UBI),用水稀释;
E.PKC(50ng/ml,UBI目录号14-115),用0.5mg/ml BSA稀释;
F.PKC/髓鞘碱性蛋白工作液:通过将各5体积的PKC共活化缓冲液和髓鞘碱性蛋白与各10体积的PKC活化缓冲液和PKC混合制得。
在96深孔分析板中组装分析系统。将抑制剂或载体(1.0T1)加入到5.0ul 33P-ATP中。通过加入PKC/髓鞘碱性蛋白工作液并混合,启动反应。将反应液在30℃下孵育20分钟。通过加入50 T1 100mMEDTA和100mM焦磷酸钠并混合,终止反应。将磷酸化髓鞘碱性蛋白收集到96孔滤板中的PVDF膜上,通过闪烁计数法进行定量。
本发明的具体化合物在上述分析中进行检测,发现对Akt1、Akt2和Akt3中的一个或者多个其IC50≤50μM。
实施例5
测定Akt抑制的基于细胞的分析
将细胞(例如LnCap或携有活化Akt的PTEN(-/-)肿瘤细胞系)涂布于100mM平皿中。当细胞铺满平皿约70-80%时,用5ml新鲜培养基再培养细胞,并向溶液中加入待试化合物。对照品包括未处理的细胞,载体处理的细胞和分别用20μM或200nM LY294002(Sigma)或渥曼青霉素(Sigma)处理的细胞。将细胞孵育2、4或6小时,然后除去培养基。用PBS洗涤细胞,将细胞刮取并转移到离心管中。离心细胞,得粒状沉淀,用PBS再次洗涤。最后,将细胞沉淀重新悬浮于裂解缓冲液(20mM Tris pH8,140mM NaCl,2mM EDTA,1%Triton,1mM焦磷酸钠,10mMθ-甘油磷酸,10mM NaF,0.5mmNaVO4,1μM Microsystine和1x蛋白酶抑制剂混合物),置于冰上15分钟,轻轻旋动,以裂解细胞。裂解液在4℃下以100,000xg的转速在Beckman台式超速离心机中旋转离心20分钟。上清液蛋白通过标准的Bradford法(BioRad)量,并在-70℃下保藏备用。
蛋白质从澄清裂解液如下免疫沉淀(IP):对于Akt1,将裂解液与Santa Cruz sc-7126(D-17)的NETN(100mM NaCl,20mM Tris pH8.0,1mM EDTA,0.5%NP-40)溶液混合,并加入蛋白A/G琼脂糖(SantaCruz sc-2003)。对于Akt2,将裂解液在NETN中与抗Akt-2琼脂糖(Upstate Biotechnology #16-174)混合,对于Akt3,将裂解液在NETN中与抗Akt3琼脂糖(Upstate Biotechnology #16-175)混合。免疫沉淀物在4℃下温育过夜,洗涤,SDS-PAGE分离。
用蛋白质印迹,分析总Akt、pThr308 Akt1、pSer473 Akt1和Akt2及Akt3上的相应磷酸化位点,以及用特异性抗体(Cell SignalingTechnology):抗总Akt(目录号9272)、抗磷酸Akt丝氨酸473(目录号9271)和抗磷酸Akt苏氨酸308(目录号9275),分析Akt的下游靶标。印迹在4℃下与稀释于PBS+0.5%脱脂奶粉(NFDM)的合适第一抗体温育过夜后,洗涤,在室温下与稀释于PBS+0.5%NFDM的辣根过氧化物酶(HRP)标记第二抗体温育1小时。蛋白质用ECL试剂检测(Amersham/Pharmacia Biotech RPN2134)。
实施例6
调蛋白刺激的Akt活化
MCF7细胞(人乳腺癌细胞系,PTEN+/+)以每100mM板1×106个细胞的浓度涂布。当细胞铺满平皿约70-80%时,补充5ml无血清培养基,温育过夜。第二天早上,加入化合物,细胞温育1-2小时,然后在30分钟内加入调蛋白(以诱导Akt的活化),如上所述对细胞进行分析。
实施例7
肿瘤生长的抑制
癌细胞生长抑制剂的体内功效可通过本领域公知的几种方法进行确认。
第0天,将PI3K途径(如LnCaP、PC3、C33a、OVCAR-3、MDA-MB-468等)失调的人肿瘤细胞系皮下注射到6-10周龄雌性裸鼠(Harlan)的左侧腹。将裸鼠随机分配到载体、化合物或组合治疗小组。从第1天开始,每日进行皮下给药,持续整个实验过程。另外,待试的抑制剂化合物可通过连续灌注泵给予。化合物、化合物组合或载体给予的总体积是0.2ml。当所有的载体处理裸鼠出现直径为0.5-1.0cm的损伤时,通常在细胞注射后的4-5.5周,切除肿瘤,称重。计算各细胞系的各实验组中肿瘤的平均重量。
序列表
<110>麦克公司(Merck & Co.,Inc.)
Bilodeau,Mark T.
Duggan.Mark E.
Hartnett,John C.
Lindsley.Craig W.
Wu.Zhicai
Zhao,Zhijian
<120>Akt活性抑制剂
<130>21299Y
<150>60/465,260
<151>2003-04-24
<160>15
<170>FastSEQ for Windows Version 4.0
<210>1
<211>10
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>1
ctgcggccgc 10
<210>2
<211>14
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>2
gtacgcggcc gcag 14
<210>3
<211>39
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>3
cgcgaattca gatctaccat gagcgacgtg gctattgtg 39
<210>4
<211>33
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>4
cgctctagag gatcctcagg ccgtgctgct ggc 33
<210>5
<211>24
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>5
gtacgatgct gaacgatatc ttcg 24
<210>6
<211>45
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>6
gaatacatgc cgatggaaag cgacggggct gaagagatgg aggtg 45
<210>7
<211>45
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>7
cccctccatc tcttcagccc cgtcgctttc catcggcatg tattc 45
<210>8
<211>36
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>8
gaattcagat ctaccatgag cgatgttacc attgtg 36
<210>9
<211>30
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>9
tctagatctt attctcgtcc acttgcagag 30
<210>10
<211>48
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>10
ggtaccatgg aatacatgcc gatggaaagc gatgttacca ttgtgaag 48
<210>11
<211>33
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>11
aagcttagat ctaccatgaa tgaggtgtct gtc 33
<210>12
<211>30
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>12
gaattcggat cctcactcgc ggatgctggc 30
<210>13
<211>49
<212>DNA
<213>人工序列
<220>
<223>全合成DNA序列
<400>13
ggtaccatgg aatacatgcc gatggaaaat gaggtgtctg tcatcaaag 49
<210>14
<211>6
<212>PRT
<213>人工序列
<220>
<223>全合成氨基酸序列
<400>14
Glu Tyr Met Pro Met Glu
1 5
<210>15
<211>13
<212>PRT
<213>人工序列
<220>
<223>全合成氨基酸序列
<400>15
Gly Gly Arg Ala Arg Thr Ser Ser Phe Ala Glu Pro Gly
1 5 10
Claims (20)
1.一种式A的化合物或其药物可接受盐或立体异构体:
其中:
a是0或1;b是0或1;m是0、1或2;n是0、1、2或3;p是0、1或2;q是0、1、2或3;r是0或1;s是0或1;t是2、3、4、5或6;
Q选自:C1-C6烷基、卤素、-NR6R7、芳基和杂环基,所述烷基、芳基和杂环基任选被1-3个RZ取代;
R1独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)bNR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)氧代、18)CHO、19)NO2、20)NRc(C=O)ObRa、21)O(C=O)ObC1-C10烷基、22)O(C=O)ObC3-C8环烷基、23)O(C=O)Ob芳基、24)C1-C6烷基(C=NRb)N(Rb)2、25)O(C=O)Ob-杂环、26)Oa-P=O(OH)2和27)-N=CHN(Rb)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个或多个选自RZ的取代基取代;
R2独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)NR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)CHO、18)NO2、19)NRc(C=O)ObRa、20)O(C=O)ObC1-C10烷基、21)O(C=O)ObC3-C8环烷基、22)O(C=O)Ob芳基、23)O(C=O)Ob-杂环和24)Qa-P=O(OH)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个、两个或三个选自RZ的取代基取代;
R3和R4独立选自:H、C1-C6-烷基和C1-C6-全氟烷基,或者R3和R4结合在一起形成-(CH2)t-,其中一个碳原子任选被选自O、S(O)m、-N(Rb)C(O)-和-N(CORa)-的部分置换;
R5独立选自:1)(C=O)aObC1-C10烷基、2)(C=O)aOb芳基、3)C2-C10烯基、4)C2-C10炔基、5)(C=O)aOb杂环基、6)(C=O)aObC3-C8环烷基、7)CO2H、8)卤素、9)CN、10)OH、11)ObC1-C6全氟烷基、12)Oa(C=O)bNR6R7、13)NRc(C=O)NR6R7、14)S(O)mRa、15)S(O)2NR6R7、16)NRcS(O)mRa、17)氧代、18)CHO、19)NO2、20)O(C=O)ObC1-C10烷基、21)O(C=O)ObC3-C8环烷基和22)Oa-P=O(OH)2,所述烷基、芳基、烯基、炔基、杂环基和环烷基任选被一个或多个选自RZ的取代基取代;
R6和R7独立选自:1)H、2)(C=O)ObRa、3)C1-C10烷基、4)芳基、5)C2-C10烯基、6)C2-C10炔基、7)杂环基、8)C3-C8环烷基、9)SO2Ra、10)(C=O)NRb 2、11)OH和12)Oa-P=O(OH)2,所述烷基、环烷基、芳基、杂环基、烯基和炔基任选被一个或多个选自Rz的取代基取代;或R6和R7可与它们连接的氮一起形成单环或双环杂环,每个环4-7元,除氮外任选包含一个或多个选自N、O和S的其它杂原子,所述单环或双环杂环任选被一个或多个选自RZ的取代基取代;
RZ独立选自:1)(C=O)rOs(C1-C10)烷基、2)Or(C1-C3)全氟烷基、3)(C0-C6)亚烷基-S(O)mRa、4)氧代、5)OH、6)卤素、7)CN、8)(C=O)rOs(C2-C10)烯基、9)(C=O)rOs(C2-C10)炔基、10)(C=O)rOs(C3-C6)环烷基、11)(C=O)rOs(C0-C6)亚烷基-芳基、12)(C=O)rOs(C0-C6)亚烷基-杂环基、13)(C=O)rOs(C0-C6)亚烷基-N(Rb)2、14)C(O)Ra、15)(C0-C6)亚烷基-CO2Ra、16)C(O)H、17)(C0-C6)亚烷基-CO2H、18)C(O)N(Rb)2、19)S(O)mRa、20)S(O)2N(Rb)2、21)NRc(C=O)ObRa、22)O(C=O)ObC1-C10烷基、23)O(C=O)ObC3-C8环烷基、24)O(C=O)Ob芳基、25)O(C=O)Ob-杂环和26)Qa-P=O(OH)2,所述烷基、烯基、炔基、环烷基、芳基和杂环基任选被最多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代、N(Rb)2和Oa-P=O(OH)2的取代基取代;
Ra为:取代或未取代的(C1-C6)烷基、取代或未取代的(C2-C6)烯基、取代或未取代的(C2-C6)炔基、取代或未取代的(C3-C6)环烷基、取代或未取代的芳基、(C1-C6)全氟烷基、2,2,2-三氟乙基或者取代或未取代的杂环基;
Rb为:H、(C1-C6)烷基、取代或未取代的芳基、取代或未取代的苄基、取代或未取代的杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra;
Rc选自:1)H、2)C1-C10烷基、3)芳基、4)C2-C10烯基、5)C2-C10炔基、6)杂环基、7)C3-C8环烷基和8)C1-C6全氟烷基,所述烷基、环烷基、芳基、杂环基、烯基和炔基任选被一个或多个选自Rz的取代基取代。
3.权利要求2的化合物或其药物可接受盐或立体异构体,其中:
Q选自:任选被1-3个RZ取代的-NR6R7、苯基和杂环基;
Ra为:(C1-C6)烷基、(C3-C6)环烷基、芳基或杂环基;
Rb为:H、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或S(O)2Ra。
4.权利要求3的化合物或其药物可接受盐或立体异构体,其中:
q为0;
R2独立选自:1)C1-C6烷基、2)芳基、3)杂环基、4)CO2H、5)卤素、6)CN、7)OH、8)S(O)2NR6R7和9)Oa-P=O(OH)2,所述烷基、芳基和杂环基任选被一个、两个或三个选自RZ的取代基取代。
5.权利要求4的化合物或其药物可接受盐或立体异构体,所述化合物为式C:
其中:
n为0、1或2;
Q选自:任选被1-3个RZ取代的杂环基。
6.一种选自以下的化合物:
1)6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
2)6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
3)6-(4-{[4-(1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
4)6-(4-{[4-(6-甲基-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
5)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
6)6-(4-{[4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
7)6-(4-{[4-(苄基氨基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
8)6-{4-[(4-异喹啉-1-基哌嗪-1-基)甲基]苯基}-5-苯基烟腈;
9)6-(4-{[4-(4-甲基-4H-1,2,4-三唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈;
10)6-(4-{[4-(1,2-苯并异噻唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈;
11)6-(4-{[5-(4-氟苯基)-2,5-二氮杂二环[2.2.1]庚-2-基]甲基}苯基)-5-苯基烟腈;
12)6-(4-{[4-(2-氧代-3,4-二氢喹啉-1(2H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
13)5-苯基-6-{4-[(4-苯基哌啶-1-基)甲基]苯基}烟腈;
14)6-{4-[(4-氟哌啶-1-基)甲基]苯基}-5-苯基烟腈;
15)6-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-5-苯基烟腈;
16)6-[4-(吗啉-4-基甲基)苯基]-5-苯基烟腈;
17)6-(4-{[4-(2-氧代-2H-3,1-苯并噁嗪-1(4H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
18)4-氯-N-{1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]哌啶-4-基}-N-环丙基苯磺酰胺;
19)5-苯基-6-(4-{[4-(3-吡啶-3-基-1,2,4-噁二唑-5-基)哌啶-1-基]甲基}苯基)烟腈;
20)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮;
21)6-(4-{[4-(1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
22)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
23)2-甲基-1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
24)2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
25)5-甲基-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
26)5-氟-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
27)N-苄基-1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-胺;
28)N-{(3R)-1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]吡咯烷-3-基}-N′-乙基脲;
29)N-乙基-N′-((3R)-1-{4-[3-苯基-5-(2H-四唑-5-基)吡啶-2-基]苄基}吡咯烷-3-基)脲;
30)6-(4-{[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
31)9-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-9H-嘌呤-6-胺;
32)5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈;
33)N-{(3R)-1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]吡咯烷-3-基}-N′-吡啶-4-基脲;
34)6-(4-{[4-(4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
35)6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
36)5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)烟腈;
37)5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)烟腈;
38)2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基]-5-苯基烟腈;
39)2-氯-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
40)6-(4-{[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟腈;
41)2-氯-6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
42)2-氯-6-(4-{[4-(4-氧化-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
43)2-氯-5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)烟腈;
44)6-(4-{[4-(4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟腈;
45)2-氟-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
46)6-(4-{[4-(6-氨基-9H-嘌呤-9-基)哌啶-1-基]甲基}苯基)-2-氯-5-苯基烟酰胺;
47)2-氯-6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟酰胺;
48)2-氯-6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟酰胺;
49)6-氟-2-(1-{4-[5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
50)6-氟-2-(1-{4-[5-(5-甲基-1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
51){2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1H-咪唑-5-基}甲醇;
52)2-[6-(4-{{4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-4,5-二氢-1H-咪唑-5-甲酰胺;
53)2-氯-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-甲脒;
54)1-(1-{4-[6-氯-5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮;
55)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-3-(1H-咪唑-2-基)-5-苯基吡啶-2-甲腈;
56)6-氟-2-(1-{4-[6-氟-5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑;
57)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺;
58)5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
59)5-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1,3,4-噻二唑-2-胺;
60)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
61)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
62)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
63)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
64)5-[5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
65)5-[5-苯基-6-(4-{[4-(4-嘧啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
66)5-[5-苯基-6-(4-{[4-(4-吡嗪-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺;
67)5-{5-苯基-6-[4-({4-[4-(1,3-噻唑-4-基)-1H-吡唑-1-基]哌啶-1-基}甲基)苯基]吡啶-3-基}-1,3,4-噻二唑-2-胺;
68)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
69)5-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3,4-噻二唑-2-胺;
70)N-((3R)-1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}吡咯烷-3-基)-N′-吡啶-4-基脲;
71)N-乙基-N′-{5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-基}脲;
72)2-[2-(二甲氨基)乙氧基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
73)2-甲氧基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
74)2-乙氧基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
75)2-(2-吗啉-4-基乙氧基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
76)2-(甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
77)2-(二甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
78)2-氨基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
79)2-[(2-吗啉-4-基乙基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
80)2-{[2-(二甲氨基)乙基]氨基}-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
81)2-[4-(2-羟基乙基)哌嗪-1-基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
82)2-[(4-甲氧基苄基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈;
83)N-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]-N′-乙基脲;
84)N-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]乙酰胺;
85)N′-[3-氰基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-2-基]-N,N-二甲基亚氨基甲酰胺;
86)6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶4-基)-1H-苯并咪唑;
87)9-(1-{4-[6-氯-3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶4-基)-9H-嘌呤-6-胺;
88)1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺;
89)1-(1-{4-[3-苯基-5-(1H-1,2,4-三唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺;
90)1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺;
91)1-{1-[4-(5′-苯基-2,3′-联吡啶-6′-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶4-胺;
92)5-[2-({4-[2-(甲硫基)-6-苯基吡啶并[2,3-d]嘧啶-7-基]苄基}氨基)乙基]-1,3,4-噻二唑-2-胺;
或其药物可接受盐或立体异构体。
7.权利要求1的化合物的盐,所述化合物为:
1)6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
2)6-(4-{[4-(2-甲基-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
3)6-(4-{[4-(1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
4)6-(4-{[4-(6-甲基-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
5)6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
6)6-(4-{[4-(2-氧代-4-苯基-2,3-二氢-1H-咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
7)6-(4-{[4-(苄基氨基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
8)6-{4-[(4-异喹啉-1-基哌嗪-1-基)甲基]苯基}-5-苯基烟腈(TFA);
9)6-(4-{[4-(4-甲基-4H-1,2,4-三唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈(TFA);
10)6-(4-{[4-(1,2-苯并异噻唑-3-基)哌嗪-1-基]甲基}苯基)-5-苯基烟腈(TFA);
11)6-(4-{[5-(4-氟苯基)-2,5-二氮杂二环[2.2.1]庚-2-基]甲基}苯基)-5-苯基烟腈(TFA);
12)6-(4-{[4-(2-氧代-3,4-二氢喹啉-1(2H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
13)5-苯基-6-{4-[(4-苯基哌啶-1-基)甲基]苯基}烟腈(TFA);
14)6-{4-[(4-氟哌啶-1-基)甲基]苯基}-5-苯基烟腈(TFA);
15)6-{4-[(4-甲基哌嗪-1-基)甲基]苯基}-5-苯基烟腈(TFA);
16)6-[4-(吗啉-4-基甲基)苯基]-5-苯基烟腈(TFA);
17)6-(4-{[4-(2-氧代-2H-3,1-苯并噁嗪-1(4H)-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
18)4-氯-N-{1-[4-(5-氰基-3-苯基吡啶-2-基)苄基]哌啶-4-基}-N-环丙基苯磺酰胺(TFA);
19)5-苯基-6-(4-{[4-(3-吡啶-3-基-1,2,4-噁二唑-5-基)哌啶-1-基]甲基}苯基)烟腈(TFA);
20)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-苯并咪唑-2-酮(TFA,1-6);
21)6-(4-{[4-(1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
22)1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
23)2-甲基-1-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
24)2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
25)5-甲基-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
26)5-氟-2-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
27)N-苄基-1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基}哌啶-4-胺(TFA);
28)N-乙基-N′-((3R)-1-{4-[3-苯基-5-(2H-四唑-5-基d)吡啶-2-基]苄基}吡咯烷-3-基)脲(TFA);
29)9-(1-{4-[3-苯基-5-(1H-四唑-5-基)吡啶-2-基]苄基)哌啶-4-基)-9H-嘌呤-6-胺(TFA);
30)6-(4-{[4-(4-羟基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(HCl);
31)6-氟-2-(1-{4-[5-(5-甲基-1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
32){2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-1H-咪唑-5-基}甲醇(TFA);
33)2-[6-(4-{[4-(6-氟-1H-苯并咪唑-2-基)哌啶-1-基]甲基}苯基)-5-苯基吡啶-3-基]-4,5-二氢-1H-咪唑-5-甲酰胺(TFA);
34)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA);
35)5-[5-苯基-6-(4-{[4-(5-吡啶-4-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
36)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
37)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-b]吡啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
38)5-[5-苯基-6-(4-{[4-(1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
39)5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-4H-1,2,4-三唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
40)5-[5-苯基-6-(4-{[4-(4-吡啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
41)5-[5-苯基-6-(4-{[4-(4-嘧啶-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
42)5-[5-苯基-6-(4-{[4-(4-吡嗪-2-基-1H-吡唑-1-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-胺(TFA);
43)5-{5-苯基-6-[4-({4-[4-(1,3-噻唑-4-基)-1H-吡唑-1-基]哌啶-1-基}甲基)苯基]吡啶-3-基}-1,3,4-噻二唑-2-胺(TFA);
44)1-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(TFA);
45)5-(1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1,3,4-噻二唑-2-胺(TFA);
46)N-((3R)-1-{4-[5-(5-氨基-1,3,4-噻二唑-2-基)-3-苯基吡啶-2-基]苄基}吡咯烷-3-基)-N′-吡啶-4-基脲(TFA);
47)N-乙基-N′-{5-[5-苯基-6-(4-{[4-(5-吡啶-2-基-1H-吡唑-3-基)哌啶-1-基]甲基}苯基)吡啶-3-基]-1,3,4-噻二唑-2-基}脲(TFA);
48)2-[2-(二甲氨基)乙氧基]-6-(4-{[4-(2-氧代-2,3--二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
49)2-乙氧基-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
50)2-(2-吗啉-4-基乙氧基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
51)2-(甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
52)2-(二甲氨基)-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
53)2-[(2-吗啉-4-基乙基)氨基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
54)2-{[2-(二甲氨基)乙基]氨基}-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
55)2-[4-(2-羟基乙基)哌嗪-1-基]-6-(4-{[4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶-1-基]甲基}苯基)-5-苯基烟腈(TFA);
56)6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑(TFA);
57)9-(1-{4-[6-氯-3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-9H-嘌呤-6-胺(TFA);
58)1-(1-{4-[5-(1,2,4-噁二唑-3-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA);
59)1-(1-{4-[3-苯基-5-(1H-1,2,4-三唑-5-基)吡啶-2-基]苄基}哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA);
60)1-{1-[4-(3-苯基-5-嘧啶-2-基吡啶-2-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,10-5);
61)1-{1-[4-(5′-苯基-2,3′-联吡啶-6′-基)苄基]哌啶-4-基}-1H-吡唑并[3,4-d]嘧啶-4-胺(TFA,10-6);
62)5-[2-({4-[2-(甲硫基)-6-苯基吡啶并[2,3-d]嘧啶-7-基]苄基}氨基)乙基]-1,3,4-噻二唑-2-胺(TFA,10-7);
或其立体异构体。
9.权利要求6的化合物,所述化合物为6-氟-2-(1-{4-[5-(1H-咪唑-2-基)-3-苯基吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑:
或其药物可接受盐或立体异构体。
12.权利要求6的化合物,所述化合物为6-氟-2-(1-{4-[3-苯基-5-(1H-1,2,3-三唑-4-基)吡啶-2-基]苄基}哌啶-4-基)-1H-苯并咪唑:
或其药物可接受盐或立体异构体。
15.一种药物组合物,所述药物组合物包含药物载体和分散在载体中的治疗有效量的权利要求1化合物。
16.一种药物组合物,所述药物组合物包含药物载体和分散在载体中的治疗有效量的权利要求6化合物。
17.一种治疗癌症的方法,所述方法包括给予有需要的哺乳动物治疗有效量的权利要求1化合物。
18.一种治疗癌症的方法,所述方法包括给予有需要的哺乳动物治疗有效量的权利要求6化合物。
19.权利要求15的组合物,所述组合物还包含选自以下的第二种化合物:1)雌激素受体调节剂,2)雄激素受体调节剂,3)类视黄醇受体调节剂,4)细胞毒剂/细胞抑制剂,5)抗增殖剂,6)异戊二烯基蛋白转移酶抑制剂,7)HMG-CoA还原酶抑制剂,8)HIV蛋白酶抑制剂,9)逆转录酶抑制剂,10)血管生成抑制剂,11)PPAR-γ激动剂,12)PPAR-δ激动剂,13)细胞增殖和生存信号传导的抑制剂和14)干扰细胞周期关卡的药物。
20.一种治疗癌症的方法,所述方法包括联合给予治疗有效量的权利要求1化合物和放射疗法。
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CN102361872A (zh) * | 2009-02-13 | 2012-02-22 | 拜耳医药股份有限公司 | 作为akt抑制剂的稠合嘧啶 |
CN102361872B (zh) * | 2009-02-13 | 2014-12-03 | 拜耳知识产权有限责任公司 | 作为akt抑制剂的稠合嘧啶 |
WO2020135210A1 (zh) * | 2018-12-28 | 2020-07-02 | 四川科伦博泰生物医药股份有限公司 | 取代芳基化合物及其制备方法和用途 |
CN111377873A (zh) * | 2018-12-28 | 2020-07-07 | 四川科伦博泰生物医药股份有限公司 | 氨基嘧啶化合物及其制备方法和用途 |
CN111377873B (zh) * | 2018-12-28 | 2023-03-28 | 四川科伦博泰生物医药股份有限公司 | 氨基嘧啶化合物及其制备方法和用途 |
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US7579355B2 (en) | 2009-08-25 |
CA2522431A1 (en) | 2004-11-11 |
EP1622616A2 (en) | 2006-02-08 |
AU2004233828B2 (en) | 2009-05-28 |
US20070043001A1 (en) | 2007-02-22 |
JP4616831B2 (ja) | 2011-01-19 |
ATE512957T1 (de) | 2011-07-15 |
JP2006524696A (ja) | 2006-11-02 |
EP1622616A4 (en) | 2010-04-21 |
EP1622616B1 (en) | 2011-06-15 |
WO2004096131A3 (en) | 2005-11-03 |
WO2004096131A2 (en) | 2004-11-11 |
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