CN100360522C - 对gsk3具有选择性抑制作用的新型化合物 - Google Patents
对gsk3具有选择性抑制作用的新型化合物 Download PDFInfo
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- CN100360522C CN100360522C CNB2003801064833A CN200380106483A CN100360522C CN 100360522 C CN100360522 C CN 100360522C CN B2003801064833 A CNB2003801064833 A CN B2003801064833A CN 200380106483 A CN200380106483 A CN 200380106483A CN 100360522 C CN100360522 C CN 100360522C
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- phenyl
- amino
- alkyl
- pyrazine
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 167
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- 125000005842 heteroatom Chemical group 0.000 claims abstract description 42
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- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
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- 238000000034 method Methods 0.000 claims abstract description 17
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 28
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- 239000000376 reactant Substances 0.000 description 1
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- 230000000698 schizophrenic effect Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000019100 sperm motility Effects 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- 125000005270 trialkylamine group Chemical group 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及式(I)的新化合物,其中Z为N;Y是CONR5、NR5CO、SO2NR5、NR5SO2、CH2NR5、NR5CONR5、CH2CO、CO或CH2O;X为CH或N;P为苯基或包含一个或多个选自N、O或S杂原子的5或6元杂芳环,并且所述苯环或5到6元杂芳环可任选地与含有独立地选自C、N、O或S的原子的5或6元饱和、部分饱和或不饱和环稠合;Q为C1-6烷基、C2-6链烯基或C2-6炔基;所述化合物的制备方法及其中所用到的新的中间体,含有所述治疗活性的化合物的药物组合物以及所述活性化合物在治疗中的用途,如提供对GSK3具有选择性抑制作用的化合物。
Description
技术领域
本发明涉及式I的新化合物,该化合物为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物;涉及包含所述化合物的药物制剂并涉及所述化合物在治疗中的应用。本发明进一步涉及制备式I化合物的方法和涉及制备方法中使用的新型中间体。
发明背景
糖原合酶激酶3(GSK3)是由两种同工型(α和β)组成的丝氨酸/苏氨酸蛋白激酶,两种同工型通过不同的基因编码,但在催化区内高度类似。GSK3在中枢和外周神经体系中高度表达。GSK3磷酸化多种底物,包括τ、β-连环蛋白、糖原合酶、丙酮酸脱氢酶和延伸起始因子2b(eIF2b)。胰岛素和生长因子活化蛋白激酶B,其在丝氨酸9残基上磷酸化GSK3并使其钝化。
阿尔茨海默氏病(AD)痴呆和Tau蛋白病变(taupathies)
AD的特征在于认知下降、胆碱能机能障碍和神经元死亡、神经纤维缠结、和由淀粉状蛋白-β沉积构成的老年斑。这些事件在AD中的顺序仍不清楚,但是认为它们是相关的。糖原合酶激酶3β(GSK3β)或Tau(τ)磷酸化激酶在AD脑中任选地将神经元中微管相关蛋白质τ在其高度磷酸化的位点磷酸化。高度磷酸化的蛋白τ对微管的亲合力降低并作为成对螺旋状细丝积聚,细丝为构成AD脑中神经纤维缠结和神经纤维网丝状物的主要成分。这使得微管解聚,导致轴突顶梢枯死和神经突营养障碍。神经纤维缠结在例如AD、肌萎缩性侧索硬化、关岛帕金森氏综合症-痴呆综合症、皮质基底核变性、拳击员痴呆和头部外伤、唐氏综合症、脑炎后帕金森氏综合症、进行性核上麻痹、尼曼-皮克病、和皮克病中经常被发现。向原代海马培养物中加入淀粉状蛋白-β,通过诱导GSK活性,导致τ的高度磷酸化和类似成对螺旋状细丝状态,然后是轴突运输破坏和神经元死亡(Imahori和Uchida.,J.Biochem,121:179-188,1997)。GSK3β优先标记神经纤维缠结,并已经证明在AD脑中的神经元预缠结中有活性。在AD患者脑组织中的GSK3蛋白水平也增加50%。此外,GSK3β使丙酮酸脱氢酶(糖酵解途径中的关键酶)磷酸化,并防止丙酮酸向乙酰辅酶-A的转化(Hoshi等人,PNAS,93:2719-2723,1996)。乙酰辅酶-A对于乙酰胆碱的合成至关重要,所述乙酰胆碱为具有认知功能的神经递质。因此,GSK3β抑制可能对与阿尔茨海默氏病和其它上述疾病有关的发展和认知缺乏具有有益的效果。
慢性和急性神经变性疾病
已经表明,生长因子介导PI3K/Akt路径的活化对于神经元存活起着关键作用。这一路径的活化导致GSK3β抑制。最近的研究(Bhat等人,PNAS,97:11074-11079(2000))表明在神经变性例如脑缺血或在除去生长因子之后细胞和动物模型中GSK3β活性增加。例如,在易受细胞程序死亡伤害的神经元中,活性部位磷酸化增加,所述细胞程序死亡为通常在慢性和急性退行性疾病例如阿尔茨海默氏病、帕金森氏症、肌萎缩性侧索硬化、亨廷顿病和HIV痴呆、缺血性中风和头部外伤中发生的一种类型的细胞死亡。在抑制GSK3β的剂量下,锂对于抑制细胞和脑中的细胞程序死亡具有神经保护作用。因此,GSK3β抑制剂可用于减缓神经变性疾病的进程。
躁郁症(BD)
躁郁症的特征在于躁狂发作和抑郁发作。基于锂的情绪稳定效果,其已经用于治疗BD。锂的缺点在于其治疗窗窄,和可导致锂中毒的过量给药的危险。在治疗浓度下,锂抑制GSK3的新近发现提出了这种酶为锂在脑中的作用提供了关键靶的可能性(Stambolic等人,Curr.Biol.,6:1664-1668,1996;Klein和Melton,PNAS,93:8455-8459,1996)。因此,抑制GSK3β在BD的治疗以及在有情感障碍的AD患者中可能存在治疗相关性。
精神分裂症
GSK3涉及多个细胞过程中、特别是在神经发育过程中的信号转导级联。Kozlovsky等人(Am J Psychiatry,2000,五月,157(5):831-833)发现在精神分裂症患者中GSK3β水平比对照受试者的水平低41%。这一研究表明精神分裂症涉及神经发育病理学并且异常GSK3调节在精神分裂症中起作用。此外,已经报到在表现出精神分裂症的患者中β-连环蛋白水平降低(Cotter等人,Neuroreport:1379-1383(1998))。
糖尿病
胰岛素通过脱磷酸化并从而活化糖原合酶刺激骨骼肌中的糖原合成。在休止状态,GSK3通过脱磷酸化使糖原合酶磷酸化并钝化。GSK3在II型糖尿病患者的肌肉中也有过度表达(Nikoulina等人,Diabetes2000年2月,49(2):263-271)。抑制GSK3增加糖原合酶的活性,从而通过将葡萄糖转化为糖原而降低葡萄糖水平。因此,抑制GSK 3对于I型和I I型糖尿病、糖尿病性神经病变核糖尿病相关病症的治疗可能存在治疗相关性。
脱发
GSK3使β-连环蛋白磷酸化并降解。β-连环蛋白为keratonin合成路径的效应子。β-连环蛋白稳定可能导致毛发发育增加。通过使GSK3磷酸化位点突变而表现出β-连环蛋白稳定的小鼠经历了类似于重新生长毛发的过程(Gat等人,Cell,1998年11月25日,95(5):605-614))。新的毛囊形成皮脂腺和真皮乳头,它们通常只在胚胎发育中产生。因此,GSK3抑制可能提供对秃顶的治疗。
口服避孕药
Vijajaraghavan等人(Biol Reprod,2000年6月,62(6):1647-1654)报道,GSK3相对于不游动的精子的游动性高。免疫细胞化学显示,在鞭毛和精子头部前部存在GSK3。这些数据表明,GSK3可能是在附睾中精子游动性引发和调节成熟精子功能的关键因素。GSK3抑制剂可用作男用避孕剂。
发明公开
本发明的目的是提供对GSK3具有选择性抑制作用以及具有良好的生物利用度的化合物。因此,本发明提供式I化合物:
其中:Z为N;
Y为CONR5、NR5CO、SO2NR5、NR5SO2、CH2NR5、NR5CONR5、CH2CO、CO或CH2O;
X为CH或N;
P为苯基或包含一个或多个选自N、O或S杂原子的5或6元杂芳环,并且所述苯环或5到6元杂芳环可任选地与含有独立地选自C、N、O或S的原子的5或6元饱和、部分饱和或不饱和环稠合;
Q为C1-6烷基、C2-6链烯基或C2-6炔基;
R为CHO、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基(SO2)NR1R2、OC0-6烷基(SO2)NR1R2、OC1-6烷基(SO)NR1R2、C1-6烷基(SO)NR1R2、C0-6烷基NR1(SO)R2、OC1-6烷基NR1(SO)R2、C0-6烷基NR1(SO2)NR1R2、OC1-6烷基NR1(SO2)R2、C0-6烷基(SO2)C1-6烷基NR1R2、OC0-6烷基(SO2)C1-6烷基NR1R2、C0-6烷基(SO)C1-6烷基NR1R2、OC1-6烷基(SO)C1-6烷基NR1R2、C0-6烷基SC1-6烷基NR1R2、OC1-6烷基SC1-6烷基NR1R2、OC1-6烷基OC1-6烷基、C1-6烷基OC1-6烷基NR1R2、OC1-6烷基OC1-6烷基NR1R2、C0-6烷基CONR10R11、OC0-6烷基CONR1R2、OC1-6烷基NR1R2、C1-6烷基NR10(CO)R11、OC1-6烷基NR1(CO)OR2、C0-6烷基NR11(CO)R10、C0-6烷基COR11、OC1-6烷基COR1、C0-6烷基NR10R11、C0-6烷基O(CO)R11、OC1-6烷基O(CO)R1、C0-6烷基C(NR10)NR10R11、C0-6烷基C(NR11)N(R10)2、OC0-6烷基C(NR1)NR1R2C0-6烷基NR10(CO)OR11、OC1-6烷基NR1(CO)OR2、C0-6烷基NR11(CO)OR10、OC1-6烷基CN、NR1OR2、C0-6烷基(CO)OR8、OC1-6烷基(CO)OR1、NR1(CO)NR1R2、NR1(CO)(CO)R2、NR1(CO)(CO)NR1R2、OR12或SO3R1;
R1和R2独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C1-6烷基NR6R7、C0-6烷基芳基和C0-6烷基杂芳基,其中任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C0-6烷基芳基、C0-6烷基杂芳基可被一个和多个A取代;
R1和R2可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代;
R3独立地选自卤素、硝基、CHO、C0-6烷基CN、OC1-6烷基CN、C0-6烷基OR6、OC1-6烷基OR6、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、OC1-6烷基OC1-6烷基NR6R7、NR6OR7、C0-6烷基CO2R6、OC1-6烷基CO2R6、C0-6烷基CONR6R7、OC1-6烷基CONR6R7、OC1-6烷基NR6(CO)R7、C0-6烷基NR6(CO)R7、O(CO)NR6R7、NR6(CO)OR7、NR6(CO)NR6R7、O(CO)OR6、O(CO)R6、C0-6烷基COR6、OC1-6烷基COR6、NR6(CO)(CO)R6、NR6(CO)(CO)NR6R7、SR6、C0-6烷基(SO2)NR6R7、OC1-6烷基NR6(SO2)R7、OC0-6烷基(SO2)NR6R7、C0-6烷基(SO)NR6R7、OC1-6烷基(SO)NR6R7、SO3R6、C0-6烷基NR6(SO2)NR6R7、C0-6烷基NR6(SO)R7、OC1-6烷基NR6(SO)R7、OC0-6烷基SO2R6、C0-6烷基SO2R6、C0-6烷基SOR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基,其中任何C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基可被一个或多个A取代;
R4独立地选自卤素、硝基、CHO、CN、OC1-6烷基CN、OR6、OC1-6烷基OR6、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、NR6R7、OC1-6烷基NR6R7、NR6OR7、CO2R6、OC1-6烷基CO2R6、CONR6R7、OC1-6烷基CONR6R7、OC1-6烷基NR6(CO)R7、NR6(CO)R7、O(CO)NR6R7、NR6(CO)OR7、NR6(CO)NR6R7、O(CO)OR6、O(CO)R6、COR6、OC1-6烷基COR6、NR6(CO)(CO)R6、NR6(CO)(CO)NR6R7、SR6、(SO2)NR6R7、OC1-6烷基NR6(SO2)R7、OC0-6烷基(SO2)NR6R7、(SO)NR6R7、OC1-6烷基(SO)NR6R7、SO3R6、NR6(SO2)NR6R7、NR6(SO)R7、OC1-6烷基NR6(SO)R7、OC1-6烷基SO2R6、SO2R6、SOR6、C3-6环烷基、苯基、包含一个或多个独立地选自N、O或S杂原子的5或6元杂芳环、包含一个或多个独立地选自N、O或S杂原子的5或6元杂环(该杂环可为饱和或不饱和的),并且所述苯环或5到6元杂芳环或5到6元杂环可任选地与包含独立地选自C、N、O或S的原子的5或6元饱和、部分饱和或不饱和环稠合,其中任何C3-6环烷基、苯基、包含一个或多个独立地选自N、O或S杂原子的5或6元杂芳环、或包含一个或两个独立地选自N、O或S杂原子的5或6元杂环可任选被一个或多个A取代;
m为0、1、2、3或4;
n为0、1、2、3或4;
R5为氢或C1-6烷基;
R6和R7独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基和C1-6烷基NR8R9;
R6和R7可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代并且其中的CH2基团可任选地被CO基团代替;
R8和R9独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基;
R8和R9可一起形成包含一个或多个独立地选自N、O或S杂原子的5或6元杂环,其中杂环可任选地被A取代;
R10为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基或C1-6烷基NR8R9;
R11为C1-6烷基NR8R9;
R11和R11可一起形成包含一个或多个选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;
R12为包含一个或多个独立地选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;其中在R5到R12下定义的任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C0-6烷基芳基、C0-6烷基杂芳基可被一个或多个A取代;
A为卤素、硝基、氧代(=O)、CHO、CN、OR6、C1-6烷基、C2-6链烯基、C2-6炔基;C0-6烷基C3-6环烷基、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、CO2R8、CONR6R7、NR6(CO)R6、O(CO)R6、COR6、SR6、(SO2)NR6R7、(SO)NR6R7、SO3R6、SO2R6或SOR6;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
本发明的一个方面涉及式I化合物,其中Z和X为N;P为苯基;R为C0-6烷基(SO2)NR1R2;和m为0。
在这一方面的一个实施方案中,C0-6烷基(SO2)NR1R2中的R1和R2一起形成包含一个或多个选自N、O或S杂原子的取代的5元或6元杂环。
在这一方面的另一个实施方案中,提供了其中所述杂环包括一个或多个N杂原子并且所述杂环任选地被A取代、优选被C1-6烷基取代的这种化合物。
本发明的另一方面涉及式I化合物,其中Y为CONR5;R5为氢;Q为C1-6烷基;R4选自苯基、包含一个或多个独立地选自N、O、或S杂原子的5元或6元杂芳环或包含一个或两个独立地选自N、O、或S杂原子的5元或6元杂环,所述杂环可为饱和的或不饱和的,CN、OR6、SO2R6、NR6(CO)R7、(SO2)NR6R7和CONR6R7;n为1;所述苯基、5元或6元杂芳环或5元或6元杂环可任选地被A取代。
这一方面的一个实施方案涉及其中A选自OR6、C1-6烷基、氧代(=O)和硝基;R6和/或R7选自C1-6烷基和氢的化合物。
在本发明的另一方面提供以下化合物:
3-氨基-N-(2-氰基乙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(3-氨基-3-氧代丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(2-硝基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(2-甲氧基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(3-吗啉-4-基丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-[3-(4-甲基哌嗪-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物,
3-氨基-N-(2-吗啉-4-基乙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-[2-(1H-咪唑-4-基)乙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-[3-(1H-咪唑-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(2-甲氧基乙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(3-甲氧基丙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(氰基甲基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺二盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(1H-吡咯-1-基)乙基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(甲基磺酰基)乙基]-2-吡嗪甲酰胺盐酸盐;
N-[2-(乙酰基氨基)乙基]-3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(2-氧代-1-咪唑烷基)乙基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-N-[2-(氨基磺酰基)乙基]-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
本发明的另一个方面为式XIXa、IV、XXII的化合物,其可用作制备式I化合物的中间体。
式XIXa的化合物
其中
P为苯基
R1的R2独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C1-6烷基NR6R7、C0-6烷基芳基和C0-6烷基杂芳基,其中任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C0-6烷基芳基、C0-6烷基杂芳基可被一个或多个A取代;
R1和R2可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代;
R3独立地选自卤素、硝基、CHO、C0-6烷基CN、OC1-6烷基CN、C0-6烷基OR6、OC1-6烷基OR6、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、OC1-6烷基OC1-6烷基NR6R7、NR6OR7、C0-6烷基CO2R6、OC1-6烷基CO2R6、C0-6烷基CONR6R7、OC1-6烷基CONR6R7、OC1-6烷基NR6(CO)R7、C0-6烷基NR6(CO)R7、O(CO)NR6R7、NR6(CO)OR7、NR6(CO)NR6R7、O(CO)OR6、O(CO)R6、C0-6烷基COR6、OC1-6烷基COR6、NR6(CO)(CO)R6、NR6(CO)(CO)NR6R7、SR6、C0-6烷基(SO2)NR6R7、OC1-6烷基NR6(SO2)R7、OC0-6烷基(SO2)NR6R7、C0-6烷基(SO)NR6R7、OC1-6烷基(SO)NR6R7、SO3R6、C0-6烷基NR6(SO2)NR6R7、C0-6烷基NR6(SO)R7、OC1-6烷基NR6(SO)R7、OC1-6烷基SO2 R6、C0-6烷基SO2R6、C0-6烷基SOR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基,其中任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基可任选地被一个或多个A取代;
R6和R7独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基和C1-6烷基NR8R9;
R6和R7可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代并且其中的CH2基团可任选地被CO基团代替;
R8和R9独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基;
R8和R9可一起形成包含一个或多个选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;
m为0、1,2、3或4;
R15为图解I中所示的基团,其中R16和R17为羟基,B为硼;
A为卤素、氧代(=O)、硝基、CHO、CN、OR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、CO2R8、CONR6R7、NR6(CO)R6、O(CO)R6、COR6、SR6、(SO2)NR6R7、(SO)NR6R7、SO3R6、SO2R6或SOR6;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
式XIXa的化合物:
其中R1和R2一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5元或6元杂环,该杂环可任选地被A取代;
m为0;
A为C1-6烷基;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
式IV化合物
其中Y为CONR5、NR5CO、SO2NR5、NR5SO2、CH2NR5NR5CONR5、CH2CO、CO或CH2O;
X为CH或N;
Z为N;
Q为C1-6烷基、C2-6链烯基或C2-6炔基;
R4独立地选自卤素、硝基、CHO、CN、OC1-6烷基CN、OR6、OC1-6烷基OR6、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、NR6R7、OC1-6烷基NR6R7、NR6OR7、CO2R6、OC1-6烷基CO2R6、CONR6R7、OC1-6烷基CONR6R7、OC1-6烷基NR6(CO)R7、NR6(CO)R7、O(CO)NR6R7、NR6(CO)OR7、NR6(CO)NR6R7、O(CO)OR6、O(CO)R6、COR6、C1-6烷基COR6、NR6(CO)(CO)R6、NR6(CO)(CO)NR6R7、SR6、(SO2)NR6R7、OC1-6烷基NR6(SO2)R7、OC0-6烷基(SO2)NR6R7、(SO)NR6R7、OC1-6烷基(SO)NR6R7、SO3R6、NR6(SO2)NR6R7、NR6(SO)R7、OC1-6烷基NR6(SO)R7、OC0-6烷基SO2R6、SO2R6、SOR6、C3-6环烷基、苯基、包含一个或多个独立地选自N、O或S杂原子的5元或6元杂芳环、或包含一个或多个独立地选自N、O或S杂原子的5元或6元杂环(该杂环可为饱和的或不饱和的),并且所述苯环或5元或6元杂芳环或5元或6元芳环可任选地与包含独立地选自C、N、O或S的原子的5元或6元饱和、部分饱和或不饱和环稠合,其中任何的C3-6环烷基、苯基、包含一个或两个独立地选自N、O或S杂原子的5元或6元杂芳环、或包含一个或两个独立地选自N、O或S杂原子的5元或6元杂环可任选地被一个或多个A取代;
R5为氢或C1-6烷基;
R6和R7独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基和C1-6烷基NR8R9;
R6和R7可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代并且其中的CH2基团可任选地被CO基团代替;
R8和R9独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基;
R8和R9可一起形成包含一个或多个选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;
Hal为卤素;
n为0、1、2、3或4;
A为卤素、氧代(=O)、硝基、CHO、CN、OR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、CO2R8、CONR6R7、NR6(CO)R6、O(CO)R6、COR6、SR6、(SO2)NR6R7、(SO)NR6R7、SO3R6、SO2R6或SOR6;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
式IV化合物
其中
Y为CONR5;
X为N;
Z为N;
Q为C1-6烷基;
R4独立地选自CN、OR6、包含一个或多个独立地选自N、O或S杂原子的5元或6元杂芳环、或包含一个或多个独立地选自N、O或S杂原子的5元或6元杂环(该杂环可为饱和的或不饱和的),其中任何的包含一个或两个独立地选自N、O或S杂原子的5元或6元杂环可任选地被A取代;
R5为氢;
R6为C1-6烷基;
n为1;
A为氧代(=O);
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
式XXII化合物
其中:
Z为N;
X为CH或N;
P为苯基或包含一个或多个选自N、O或S杂原子的5元或6元杂芳环,并且所述苯环或5元或6元杂芳环可任选地与包含独立地选自C、N、O或S的原子的5元或6元的饱和、部分饱和或不饱和的环稠合;
R为CHO、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基(SO2)NR1R2、OC0-6烷基(SO2)NR1R2、OC1-6烷基(SO)NR1R2、C1-6烷基(SO)NR1R2、C0-6烷基NR1(SO)R2、OC1-6烷基NR1(SO)R2、C0-6烷基NR1(SO2)NR1R2、OC1-6烷基NR1(SO2)R2、C0-6烷基(SO2)C1-6烷基NR1R2、OC0-6烷基(SO2)C1-6烷基NR1R2、C0-6烷基(SO)C1-6烷基NR1R2、OC1-6烷基(SO)C1-6烷基NR1R2、C0-6烷基SC1-6烷基NR1R2、OC1-6烷基SC1-6烷基NR1R2、OC1-6烷基OC1-6烷基、C1-6烷基OC1-6烷基NR1R2、OC1-6烷基OC1-6烷基NR1R2、C0-6烷基CONR10R11、OC0-6烷基CONR1R2、OC1-6烷基NR1R2、C0-6烷基NR10(CO)R11、OC1-6烷基NR1(CO)R2、C0-6烷基NR11(CO)R10、C0-6烷基COR11、OC1-6烷基COR1、C0-6烷基NR10R11、C0-6烷基O(CO)R11、OC1-6烷基O(CO)R1、C0-6烷基C(NR10)NR10R11、C0-6烷基C(NR11)N(R10)2、OC1-6烷基C(NR1)NR1R2、C0-6烷基NR10(CO)OR11、OC1-6烷基NR1(CO)OR2、C0-6烷基NR11(CO)OR10、OC1-6烷基CN、NR1OR2、C0-6烷基(CO)OR8、OC1-6烷基(CO)OR1、NR1(CO)NR1R2、NR1(CO)(CO)R2、NR1(CO)(CO)NR1R2、OR12或SO3R1;
R1和R2独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C1-6烷基NR6R7、C0-6烷基芳基和C0-6烷基杂芳基,其中任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基杂环烷基、C0-6烷基芳基、C0-6烷基杂芳基可被一个或多个A取代;
R1和R2可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5元或6元杂环,其中杂环可任选地被A取代;
R3独立地选自卤素、硝基、CHO、C0-6烷基CN、OC1-6烷基CN、C0-6烷基OR6、OC1-6烷基OR6、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、OC1-6烷基OC1-6烷基NR6R7、NR6OR7、C0-6烷基CO2R6、OC1-6烷基CO2R6、C0-6烷基CONR6R7、OC1-6烷基CONR6R7、OC1-6烷基NR6(CO)R7、C0-6烷基NR6(CO)R7、O(CO)NR6R7、NR6(CO)OR7、NR6(CO)NR6R7、O(CO)OR6、O(CO)R6、C0-6烷基COR6、OC1-6烷基COR6、NR6(CO)(CO)R6、NR6(CO)(CO)NR6R7、SR6、C0-6烷基(SO2)NR6R7、OC1-6烷基NR6(SO2)R7、OC0-6烷基(SO2)NR6R7、C0-6烷基(SO)NR6R7、OC1-6烷基(SO)NR6R7、SO3R6、C0-6烷基NR6(SO2)NR6R7、C0-6烷基NR6(SO)R7、OC1-6烷基NR6(SO)R7、OC0-6烷基SO2R6、C0-6烷基SO2R6、C0-6烷基SOR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基,其中任何的C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基可任选地被一个或多个A取代;
R6和R7独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基和C1-6烷基NR8R9;
R6和R7可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环,该杂环可任选地被A取代并且其中的CH2基团可任选地被CO基团代替;
R8和R9独立地选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基和C0-6烷基杂芳基;
R8和R9可一起形成包含一个或多个独立地选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;
R10为氢、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、C0-6烷基芳基、C0-6烷基杂芳基或C1-6烷基NR8R9;
R11为C1-6烷基NR8R9;
R10和R11可一起形成包含一个或多个独立地选自N、O或S杂原子的5或6元杂环,该杂环可任选地被A取代;
A为卤素、氧代(=O)、硝基、CHO、CN、OR6、C1-6烷基、C2-6链烯基、C2-6炔基、C0-6烷基C3-6环烷基、氟代甲基、二氟甲基、三氟甲基、氟代甲氧基、二氟甲氧基、三氟甲氧基、C0-6烷基NR6R7、OC1-6烷基NR6R7、CO2R8、CONR6R7、NR6(CO)R6、O(CO)R6、COR6、SR6、(SO2)NR6R7、(SO)NR6R7、SO3R6、SO2R6或SOR6;
m为0、1、2、3或4;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
式XXII化合物
其中:
Z为N;
X为N;
P为苯基;
R为C0-6烷基(SO2)NR1R2;
R1和R2可一起形成包含一个或多个独立地选自N、O或S杂原子的取代的5或6元杂环;
m为0;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
本发明的另一个方面提供以下化合物,其可用作式I化合物制备中的中间体:
1-[(4-溴苯基)磺酰基]吡咯烷;
4-(吡咯烷-1-基磺酰基)苯基硼酸;
4-[(4-甲基哌嗪-1-基)磺酰基]苯基硼酸;
3-氨基-6-溴-N-(2-吗啉-4-基乙基)吡嗪-2-甲酰胺;
3-氨基-6-溴-N-[2-(1H-咪唑-4-基)乙基]吡嗪-2-甲酰胺;
3-氨基-6-溴-N-[3-(1H-咪唑-1-基)丙基]吡嗪-2-甲酰胺;
3-氨基-6-溴-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺;
3-氨基-6-溴-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺;
3-氨基-6-溴-N-(2-甲氧基乙基)吡嗪-2-甲酰胺;
3-氨基-6-溴-N-(3-甲氧基丙基)吡嗪-2-甲酰胺;
3-氨基-6-溴-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺;
3-氨基-6-溴-N-(氰基甲基)吡嗪-2-甲酰胺;
3-氨基-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酸甲酯;
3-{[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基}-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酸甲酯聚苯乙烯;
3-{[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基}-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酸聚苯乙烯;
其作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
下列为用于描述本发明的说明书和权利要求中使用的各种术语的定义。
为了避免引起疑问,应当理解,在本说明书中,当基团定义为“如上定义的”、“以上定义的”、“如以上的定义”或“同以上的定义”时,所述基团包括第一次出现的定义和最广泛的定义以及该基团的每个定义和所有优选的定义。
为了避免引起疑问,应当理解,在本说明书中,C0-6是指具有0、1、2、3、4、5或6个碳原子的碳基团。
本文中使用的术语“烷基”包括直链和支链烷基。C1-6烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、叔戊基、新戊基、己基。
本文中使用的术语“C3-6环烷基”是指具有3到6个碳原子的单环烃环。C3-6环烷基可为环丙基、环丁基、环戊基、环己基。
除非另外指出,术语“烷氧基”包括“烷基”O基团,其中“烷基”如以上定义,C1-6烷氧基可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基、叔戊氧基、新戊氧基、己氧基。
本文中使用的术语“链烯基”包括直链和支链链烯基,但对于个别的链烯基例如2-丁烯基,其只有直链的形式。C2-6链烯基可为但不限于乙烯基、烯丙基、丙烯基、异丙烯基、丁烯基、异丁烯基、2-丁烯基、戊烯基、异戊烯基或己烯基。
本文中使用的术语“炔基”包括直链和支链炔基,但对于个别的炔基例如2-丁炔基,其只有直链的形式。C2-6炔基可为但不限于乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基、异戊炔基或己炔基。
在本说明书中,除非另外指出,术语“芳基”是指任选取代的、包含至少一个芳环的单环或双环烃环体系。“芳基”可与C5-7环烷基环稠合形成双环烃环体系。术语“芳基”的例子和适当的值为苯基、萘基、2,3-二氢化茚基或1,2,3,4-四氢化萘基。
在本说明书中,除非另外指出,术语包含一个或多个选自N、O和S杂原子的“杂芳基”和“5或6元杂芳环”可为,但不限于,呋喃基、咪唑基、异唑基、异噻唑基、唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻唑基或噻吩基。
在本说明书中,除非另外指出,术语“包含独立地选自C、N、O或S的原子的5或6元饱和、部分饱和或不饱和的环”可为,但不限于,呋喃基、异唑基、异噻唑基、唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻唑基、噻吩基、咪唑基、咪唑烷基、咪唑啉基、吗啉基、哌嗪基、哌啶基、哌啶酮基、吡唑烷基、吡唑啉基、吡咯烷基、吡咯啉基、四氢吡喃基、硫代吗啉基、环己基或环戊基。
在本说明书中,除非另外指出,术语“包含一个或多个独立地选自N、O或S杂原子的5或6元杂芳环”可为,但不限于,呋喃基、异唑基、异噻唑基、唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻唑基、噻吩基或咪唑基。
在本说明书中,除非另外指出,术语“包含一个或多个独立地选自N、O或S杂原子的5或6元杂环”可为,但不限于,咪唑烷基、咪唑啉基、吗啉基、哌嗪基、哌啶基、哌啶酮基、吡唑烷基、吡唑啉基、吡咯基、吡咯啉基、四氢吡喃基或硫代吗啉基。
在本说明书中,除非另外指出,术语“卤素”可为氟、氯、溴或碘。式中的术语Hal表示卤素。
本发明涉及以上定义的式I化合物及其盐、溶剂化物和盐的溶剂化物的应用。用于药物组合物中的盐可为可药用的盐,但其它盐也可用于制备式I化合物。
可使用有机酸和无机酸形成本发明化合物的无毒的可药用的酸加成盐,如盐酸盐。另外,具有足够酸性的本发明的化合物的适当药学可接受盐为碱金属盐、碱土金属盐或与有机碱的盐,其提供生理学可接受的阳离子。
应当理解本发明的某些化合物可作为溶剂化物如水合物以及非溶剂化物形式存在。应当理解本发明包括具有上述活性的所有这些溶剂化物形式。
式I的某些化合物可能具有手性中心和/或几何同分异构中心(E-和Z-异构体),应当理解本发明包括具有GSK3抑制活性的所有这些非对映异构体、光学异构体和几何异构体。
应当理解,本发明涉及I的化合物的任何形式和所有互变异构形式。
本发明的目的是提供用于治疗应用的式I化合物,特别是可用于预防和/或治疗与哺乳动物包括人的糖原合酶激酶-3(GSK3)有关的疾病的化合物。具体地,对GSK-3表现出选择性亲和作用的式I化合物。
制备方法
本发明的另一个方面提供制备式I化合物的方法,式I化合物作为游离碱或药学可接受盐、溶剂化物或盐的溶剂化物。
在这种方法的以下整个说明中,可以理解,如果适当的话,可以以有机合成领域技术人员容易理解的方法为多种反应物和中间体加上或从其上面去掉适当的保护基。使用这种保护基的常规过程以及适当的保护基的例子在例如“Protective Groups in OrganicSynthesis”,T.W.Green,P.G.M.Wuts,Wiley-Interscience,NewYork,1999中有所描述。
中间体的制备方法
中间体的制备方法包括以下步骤,其中,除非另外说明,Y、X、Z、P、Q、R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、A、m和n同式I中的定义:
(i)式II化合物卤化得到式III化合物,其中Z为N,X为N或CH,Hal为卤素;R13为氢、C1-6烷基,或当R13为氢时,其为盐如钠盐。可使用适当的卤化剂进行,卤化剂如碘、溴、氯、卤化物盐例如ICl、BrCl或HOCl或其它适当的卤化剂如N-溴代琥珀酰亚胺或三溴化磷,该反应可由金属或酸催化,如Fe盐、Cu盐、乙酸或硫酸;或在氧化剂如硝酸、过氧化氢或三氧化硫的帮助下进行。反应可在适当的溶剂如水、乙酸或氯仿中在-70℃到+100℃的温度下进行。
(ii)式III化合物酰胺化得到式IV化合物,式III中Z为N,X为N,Hal为卤素、R13为C1-6烷基,在式IV中,Y为CONR5,Q、R4和n同以上定义;可通过用适当的胺如式V的化合物处理式III化合物进行,在式V中,Q、R4、R5和n同以上定义。反应可在无溶剂下进行或使用适当的溶剂例如N,N-二甲基甲酰胺、二氯甲烷或乙酸乙酯在-25℃到+150℃的温度下进行。反应可在碱如碳酸钾、三乙胺或1,8-二氮杂双环[5.4.0]十一烷-7烯,或酸如三甲基铝或对甲苯磺酸的帮助下进行。
(R4)n-Q-NHR5
(V)
(iii)式III化合物酰胺化得到式IV化合物,在式III中R13为氢,在式IV中Y为CONR5,R4为对某些偶联剂不敏感的取代基,可通过用偶联剂处理式III化合物使其活化进行,偶联剂如1,3-二异丙基碳二酰亚胺、1-[3-(二甲氨基)丙基]-3-乙基碳二酰亚胺盐酸盐、1,3-二环己基碳二酰亚胺、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐、1,1′-羰基二咪唑或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐,其中反应可通过加入1-羟基苯并三唑水合物、或使用酰基卤试剂例如氰尿酰氯、草酰氯、氯化亚砜或溴代三吡咯烷基膦六氟磷酸盐的帮助下,然后在适当的溶剂如二氯甲烷、氯仿、乙腈或四氢呋喃中、在0℃到回流的温度下、用适当的胺如式V的化合物处理。该反应可通过使用碱如碳酸钾或三烷基胺如三乙胺或N-乙基-N,N-二异丙基胺帮助进行。
(iv)式VI的化合物卤化得到式VII化合物,式VI中R14为卤素如溴或氯、或CH3(CO)NH和P,R3和m同以上定义。可通过用卤化剂如氯化亚砜或草酰氯处理式VI的化合物进行。反应可在无溶剂下进行或使用适当的溶剂如四氢呋喃、二氧杂环己烷、N,N-二甲基甲酰胺或二氯甲烷在-20℃到+60℃的温度下进行。
(v)式VII化合物酰胺化得到式VIII化合物,在式VII中R14为卤素如溴或氯、或CH3(CO)NH,Hal为氟、氯或溴和P,R3和m同以上定义;在式VIII中R14为溴或CH3(CO)NH和P,R1、R2、R3和n同以上定义。可通过使式VII化合物与适当的胺HNR1R2反应进行。反应可在适当的溶剂如四氢呋喃、二氧杂环己烷、N,N-二甲基甲酰胺或二氯甲烷中、在0℃到+50℃的温度下进行。
(vi)式IX化合物转化为式XII化合物,在式IX中P、R3和m同以上定义;在式XII中P、R1、R2、R3和m同以上定义。可通过用磺化试剂如氯磺酸处理式IX化合物,然后加入适当的胺HNR1R2进行。反应可在无溶剂下进行或使用适当的溶剂如四氢呋喃或二氯甲烷在+25℃到回流的温度下进行。
(vii)式VIII化合物转化为式XII化合物,在式VIII中R14为CH3(CO)NH,R1、R2、R3、m和P同以上定义。可通过其与酸如盐酸或氢溴酸在+25℃到+110℃的温度下的反应进行。
(viii)式XII化合物转化为式VIII化合物,在式XII中R14为溴,R1、R2、R3、m和P同以上定义。可通过在适当的溶剂如水中在0℃到+5℃的温度下用亚硝酸钠和氢溴酸处理式XII化合物,然后加入溴化物源如CuBr进行。
(ix)式XV酰胺的形成,其中R10、R11、R3、m和P同以上定义。可通过用适当的胺HNR10R11处理式XIV的化合物进行,式XIV中R13为C1-6烷基。反应可在无溶剂下进行或使用适当的溶剂例如N,N-二甲基甲酰胺、二氯甲烷或乙酸乙酯在-25℃到+150℃的温度下进行。反应可在碱如碳酸钾、三乙胺或1,8-二氮杂双环[5.4.0]十一烷-7烯,或酸如三甲基铝或对甲苯磺酸的帮助下进行。
(x)式XIV化合物酰胺化得到式XV化合物,在式XIV中R13为氢,R3、m和P同以上定义。可通过用偶联剂处理式XIV化合物使其活化进行,偶联剂如1,3-二异丙基碳二酰亚胺、1-[3-(二甲氨基)丙基]-3-乙基碳二酰亚胺盐酸盐、1,3-二环己基碳二酰亚胺、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐、1,1′-羰基二咪唑或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐,其中反应可在加入1-羟基苯并三唑水合物、或使用酰基卤试剂例如氰尿酰氯、草酰氯、氯化亚砜或溴代三吡咯烷基膦六氟磷酸盐,然后用适当的胺HNR10R11处理的帮助下进行,反应可在适当的溶剂如N,N-二甲基甲酰胺、乙腈或二氯甲烷中、在-25℃到+150℃的温度下、在有或没有适当的碱的存在下进行。适当的碱如烷基胺如三乙胺或N-乙基-N,N-二异丙基胺或N-甲基吗啉、或碳酸钾或氢氧化钠。
(xi)式XVI化合物溴化得到式XV化合物,其中R10、R11、R3、m和P同以上定义。可通过用溴在有或没有适当的碱如乙酸钠的存在下在适当的溶剂如乙酸中处理式XVI化合物进行。
(xii)式XVII化合物转化为式XVIII化合物,在式XVII中R3、m和P同以上定义;在式XVIII中R1、R2、R3、m、C1-6烷基和P同以上定义。可通过使式XVII化合物在三苯膦和适当的叠氮二羧酸酯如叠氮二羧酸二乙酯的存在下与适当的醇R1R2NC1-6烷基OH反应进行。反应可以在适当的溶剂如四氢呋喃、甲苯或二氯甲烷中在0℃到+60℃的温度下进行。
(xiii)式VIII、XV和XVIII的化合物硼酰化得到式XIXa-c的化合物(由VIII得到XIXa,由XVIII得到XIXb,由XV得到XIXc),在式VIII化合物中,R14为卤素如溴,在式XIXa-c的化合物中,R15、R1、R2、R3、R10、R11、m、C1-6烷基和P同以上定义,R15可为图解I中定义的基团,其中B为硼,R16和R17为C1-6烷氧基或羟基、或稠合在一起形成5或6元环状硼-氧-C2-3烷基的C1-3烷氧基,并且烷氧基、芳基或5或6元环状硼-氧-C2-3烷基基团可被任选地取代。上述反应可通过
a)与丁基锂或镁和适当的硼化物如硼酸三甲酯或硼酸三异丙酯的反应进行。反应可在适当的溶剂如四氢呋喃、己烷或二氯甲烷中在-78℃到+20℃的温度下进行;
或者
b)与钯催化剂如四(三苯膦)钯、二苯膦二茂铁二氯化钯或乙酸钯在有或没有适当的配体如2-(二环己基膦)联苯的存在下,和适当的硼物源如双(邻苯二酚)二硼、双(频哪醇)二硼或频哪醇硼烷反应进行。可使用在反应条件下不促进式XIXa-c的化合物二聚的适当的碱,如叔胺如三乙胺或二异丙基乙基胺、或乙酸钾。反应可在溶剂如二氧杂环已烷、甲苯或乙腈中在+80℃到+100℃的温度下进行。
(xiv)式III化合物转化为式XX化合物,其中R13为C1-6烷基,X、Z、R、R3、P和m同以上定义。可通过与适当的式XIXa-c化合物的脱卤素偶联进行。
反应可通过式III化合物与适当的式XIXa-c的芳基硼酸或硼酸酯(可使用其中R14为卤素如溴和式VIII化合物、式XV化合物和式XVIII化合物和在(xiii)中所述的条件就地形成硼酸或硼酸酯)进行。反应可在有或没有适当的配体如三叔丁基膦的适当的钯催化剂如Pd(PPh3)4、Pd(dppf)Cl2或Pd(OAc)2进行,或使用与Zn和三苯膦三间磺酸钠一起的2-(二环己基膦)联苯或镍催化剂如炭载镍或Ni(dppe)Cl2进行。可在反应中使用适当的碱如烷基胺如三乙胺、或碳酸钾、碳酸钠、氢氧化钠或氟化铯,反应在使用油浴或微波炉的+20℃到+160℃的温度下、在适当的溶剂或溶剂混合物如甲苯、四氢呋喃、二甲氧基乙烷/水或N,N-二甲基甲酰胺中进行。
(xv)式XX化合物转化为式XXI化合物,在式XX中R13为C1-6烷基,R、R3、X、Z和m同以上定义。可通过在适当的溶剂如N,N-二甲基甲酰胺或二氯甲烷中、在适当的酸如乙酸和适当的还原剂如三乙酰氧基硼氢化钠或氰基硼氢化钠的存在下在0℃到+50℃的适当反应温度下、与适当的固相试剂如甲酰基聚苯乙烯如2-(3,5-二甲氧基-4-甲酰基苯氧基)乙基聚苯乙烯或2-(4-甲酰基-3-甲氧基苯氧基)乙基聚苯乙烯反应进行。反应可在三甲基氯化硅存在下辅助进行。
(xvi)式XXI化合物水解为式XXII化合物,在式XXI中R、R3、X、Z和m同以上定义。反应可在适当的溶剂如水、四氢呋喃或其混合物中、在适当的碱如氢氧化钠、氢氧化钾或氢氧化锂的存在下、在+25℃到回流的适当反应温度下进行。
最终产物的制备方法
本发明的另一个目的是制备通式I化合物的方法,其中,除非另外说明,Y、X、Z、P、Q、R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、A、m和n同式I中的定义,其包括:
A
式IV化合物与适当的芳基物质的脱卤素偶联,得到式I化合物,其中R3和R4为对反应中的某些试剂不敏感的取代基:
因此,方法A的脱卤素偶联可通过使式IV化合物与以下化合物的偶联进行:
a)在金属如铜、镍或锌和镍络合物、氧化亚铜或乙酸钯、和溴化四丁基铵、和碱如碳酸钾或三乙胺的存在下与适当的芳基卤如芳基碘、芳基溴或芳基氯偶联。反应可在20℃到180℃的温度下、在适当的溶剂如N,N-二甲基甲酰胺、甲苯或2-戊醇中进行;
或者
b)与适当的芳基硼酸或硼酸酯如式XIXa-c化合物(可使用其中R14为卤素如溴的式VIII化合物、式XV化合物和式XVIII化合物和在(xiii)中所述的条件就地形成硼酸或硼酸酯)偶联。反应可使用有或没有适当的配体如三叔丁基膦的适当的钯催化剂如Pd(PPh3)4、Pd(dppf)Cl2或Pd(OAc)2进行,或使用与Zn和三苯膦三间磺酸钠一起的2-(二环己基膦)联苯或镍催化剂如炭载镍或Ni(dppe)Cl2进行。可在反应中使用适当的碱如烷基胺如三乙胺、或碳酸钾、碳酸钠、氢氧化钠或氟化铯,反应在使用油浴或微波炉的+20℃到+160℃的温度下、在适当的溶剂或溶剂混合物如甲苯、四氢呋喃、二甲氧基乙烷/水或N,N-二甲基甲酰胺中进行;
或者,
c)在钯催化剂如Pd(PPh3)4、Pd(PPh3)2Cl2或Pd(dba)3和如果需要的帮助试剂如4-叔丁基邻苯二酚、氯化锂或碳酸钾的存在下、与适当的芳基锡烷偶联。适当的溶剂可为甲苯、四氢呋喃或N,N-二甲基甲酰胺。反应可在+20℃到+120℃的温度下进行。
B
式XXII化合物与适当的胺的酰胺化,其中R3和R4为对反应中的某些试剂不敏感的取代基:
因此,可以通过用偶联试剂处理式XXII化合物使其活化进行式XXII化合物的酰胺化,偶联试剂如1,3-二异丙基碳二酰亚胺、1-[3-(二甲氨基)丙基]-3-乙基碳二酰亚胺盐酸盐、1,3-二环己基碳二酰亚胺、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐、1,1′-羰基二咪唑或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐,其中可以通过加入1-羟基苯并三唑水合物帮助反应,或通过使用酰基卤试剂如氰尿酰氯、草酰氯、氯化亚砜或溴代三吡咯烷膦六氟磷酸盐、随后用适当的胺如式V化合物处理帮助反应,然后,
通过在适当的溶剂如二氯甲烷或氯仿中、在0℃到回流的反应温度下、用适当的酸如三氟乙酸处理分离固相部分,得到式(I)的化合物。
可通过在适当的溶剂如二氯甲烷、四氢呋喃、乙醚或二氯甲烷/甲醇混合物中、在0℃到+25℃的温度范围内、用盐酸处理式I化合物得到式I化合物的盐酸盐。
实施例
实施例1
1-[(4-溴苯基)磺酰基]吡咯烷
在0℃将吡咯烷(2.5g,35.2mmol)加入到4-溴苯磺酰氯(4.5g,17.6mmol)的二氯甲烷(10mL)溶液中。搅拌混合物2h并加入氢氧化钠水溶液(1M,5mL),并继续再搅拌10分钟。分离有机相并用二氯甲烷(40mL)稀释,用HCl水溶液(1M,10mL)、和水(2×10mL)洗。干燥(硫酸钠)有机相并蒸发溶剂。分离出5.0g(98%收率)标题化合物,为白色固体:1HNMR(CDCl3,400MHz)δ7.65(m,4H),3.20(m,4H),1.74(m,4H);13C NMR(CDCl3,100MHz)δ135.93,132.17,128.84,127.39,47.84,25.13;MS(ES)m/z 290和292(M++1)。
实施例2
4-(吡咯烷-1-基磺酰基)苯基硼酸
在氮气气氛在30分钟内将正丁基锂(20mL,31mmol)滴加到冷却(-78℃)的1-[(4-溴苯磺酰基)吡咯烷(3.0g,10.3mmol)和硼酸三异丙酯(7.2mL,30.9mol)的无水四氢呋喃(10mL)溶液中。在-78℃搅拌反应混合物1h,随后在3h内使温度升高到室温。加入硅胶并蒸发溶剂。在硅胶柱上进行色层分离,使用二氯甲烷(100%)到二氯甲烷/乙醇(1∶1)梯度洗脱,得到1.85g(70%收率)的标题化合物,为白色固体:1HNMR(CD3OD,400MHz)δ7.90(d,J=7Hz,2H),7.75(d,J=8Hz,2H),3.21(m,4H),1.72(m,4H);13C NMR(CDCl3/CD3OD(1∶1),100MHz)δ136.79,133.50,125.48,47.19,24.30;MS(ES)m/z 256(M++1)。
实施例3
4-[(4-甲基哌嗪-1-基)磺酰基]苯基硼酸
在氮气气氛将硼酸三异丙酯(0.64mL,2.8mmol)加入到-78℃的1-[(4-溴苯基)磺酰基]-4-甲基哌嗪(0.602g,1.9mmol;在Keasling,H.H.等人的J.Med.Chem.1965,8,548-550中有所描述)的无水四氢呋喃(7mL)溶液中,然后滴加正丁基锂(1.4mL,2.2mmol)。在-78℃搅拌得到的混合物2h并在室温下再搅拌16h。加入水(2.0mL)并搅拌混合物30分钟并蒸干。将残余物预吸附到二氧化硅上并通过柱色谱法在二氧化硅上纯化,使用二氯甲烷/甲醇(9∶1到1∶9)作为洗脱液。产物在水中重结晶,得到311mg(58%收率)的标题化合物,为白色晶体:mp 215-218℃;1H NMR(DMSO-d6,400MHz)δ8.47(brs,2H),8.05(d,J=8Hz,2H),7.73(d,J=8Hz,2H),3.77(m,2H),3.40(m,2H),3.13(m,2H),2.71(s,3H),2.65(m,2H);13C NMR(DMSO-d6,100MHz)δ133.7,133.3,124.7,49.8,41.6,41.4;MS(TSP)m/z 285(M++1)。
实施例4
3-氨基-6-溴-N-(2-吗啉-4-基乙基)吡嗪-2-甲酰胺
在0℃下将1-(3-二甲氨基丙基)-3-乙基碳二酰亚胺盐酸盐(0.68g,3.5mmol)一次加入到搅拌的2-吗啉-4-基乙胺(0.422g,3.2mmol)、3-氨基-6-溴吡嗪-2-羧酸(0.64g,3.0mmol,在Ellingson,R.C.,Henry,R.L.,J.Am.Chem.Soc.,1949,2798-2800中有所描述)、和1-羟基苯并三唑水合物(0.48g,3.5mmol)的乙腈(25mL)悬浮液中。除去冷却浴并继续在室温下搅拌7h。滤出固体,用乙腈洗并用柱色谱法在二氧化硅上纯化,使用二氯甲烷/甲醇/三乙胺(95∶5∶0.1)洗脱,得到0.68g(6 9%收率)的标题化合物:1HNMR(DMSO-d6,400MHz)δ8.53(m,1H),8.34(s,1H),8.68(brs,2H),3.57(t,J=5Hz,4H),3.37(q,J=7Hz,2H),2.47(q,J=7Hz,2H),2.40(m,4H);MS(ES)m/z330和332(M++1)。
实施例5
3-氨基-6-溴-N-[2-(1H-咪唑-4-基)乙基]吡嗪-2-甲酰胺
使用组胺如实施例4中所述制备标题化合物。收率:18%;1H NMR(DMSO-d6,400MHz)δ11.87(brs,1H),8.80(m,1H),8.34(s,1H),7.72(brs,2H),7.55(s,1H),6.83(s,1H),3.49(q,J=7Hz,2H),2.75(t,J=7Hz,2H);MS(ES)m/z 311和313(M++1)。
实施例6
3-氨基-6-溴-N-[3-(1H-咪唑-1-基)丙基]吡嗪-2-甲酰胺
使用3-(1H-咪唑-1-基)丙烷-1-胺如实施例4中所述制备标题化合物。收率:67%;1H NMR(DMSO-d6,400MHz)δ8.72(m,1H),8.34(s,1H),7.71(brs,2H),7.65(s,1H),7.20(s,1H),6.88(s,1H),3.98(t,J=7Hz,2H),3.24(q,J=6Hz,2H),1.95(quin,J=7Hz,2H);MS(ES) m/z325和327(M++1)。
实施例7
3-氨基-6-溴-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺
将3-氨基-6-溴吡嗪-2-羧酸(0.50g,2.3mmol,在Ellingson,R.C.,Henry,R.L.,J.Am.Chem.Soc.1949,2798-2800中有所描述)、1-羟基苯并三唑水合物(0.41g,2.7mmol)的乙腈(5mL)溶液加入到搅拌的2-噻吩-2-基乙胺(0.32g,2.5mmol)的乙腈(5mL)溶液中,随后加入1-(3-二甲氨基丙基)-3-乙基碳二酰亚胺盐酸盐(0.52g,2.7mmol)和乙腈(1.5mL)。在室温下搅拌得到的混合物过夜并蒸发溶剂。残余物从乙腈重结晶并随后从甲醇中重结晶,得到0.5g(66%收率)的标题化合物:1H NMR(DMSO-d6,400MHz)δ8.73(t,J=6Hz,1H),8.34(s,1H),7.71(brs,2H),7.34(dd,J=5,1Hz,1H),6.95(d,J=3Hz,1H),6.91(m,1H),3.50(q,J=7Hz,2H),3.05(t,J=7Hz,2H);MS(ES)m/z 327和329(M++1)。
如实施例7中所述制备以下实施例8-12。
实施例8
3-氨基-6-溴-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺
起始原料:1-噻吩-2-基甲胺。通过从甲醇重结晶纯化,得到标题化合物。收率:73%;1HNMR(DMSO-d6,400MHz)δ9.20(t,J=6Hz,1H),8.35(s,1H),7.72(brs,2H),7.37(dd,J=5,1Hz,1H),7.01(dd,J=3,1Hz,1H),6.95(dd,J=5,3Hz,1H),4.59(d,J=6Hz,2H);MS(ES)m/z 313和315(M++1)。
实施例9
3-氨基-6-溴-N-(2-甲氧基乙基)吡嗪-2-甲酰胺
起始原料:2-甲氧基乙胺。通过从甲醇重结晶纯化得到标题化合物。收率:77%;1H NMR(DMSO-d6,400MHz)δ 8.51(s,1H),8.36(s,1H),7.73(brs,2H),3.45(s,4H),3.27(s,3H);MS(ES)m/z 275和277(M++1)。
实施例10
3-氨基-6-溴-N-(3-甲氧基丙基)吡嗪-2-甲酰胺
起始原料:2-甲氧基丙胺。通过从甲醇重结晶纯化得到标题化合物。收率:42%;1H NMR(DMSO-d6,400MHz)δ8.64(m,1H),8.33(s,1H),7.70(brs,2H),3.37(t,J=6Hz,2H),3.31(t,J=7Hz,2H),3.24(s,3H),1.75(quin,J=7Hz,2H);MS(ES)m/z 289和291(M++1)。
实施例11
3-氨基-6-溴-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺
起始原料:1-(3-氨基丙基)-2-吡咯烷酮。通过在二氧化硅上的柱色谱纯化,使用二氯甲烷/甲醇/三乙胺(98∶2∶0.1)洗脱,得到标题化合物。收率:89%;1H NMR(DMSO-d6,400MHz)δ8.65(s,1H),8.36(s,1H),7.73(brs,2H),3.36(m,2H),3.22(m,4H),2.23(m,2H),1.93(m,2H),1.70(m,2H);MS(ES)m/z 342和344(M++1)。
实施例12
3-氨基-6-溴-N-(氰基甲基)吡嗪-2-甲酰胺
起始原料:氨基乙腈。通过从甲醇重结晶纯化,得到标题化合物。收率:47%;1H NMR(DMSO-d6,400MHz)δ9.21(t,J=6Hz,1H),8.41(s,1H),7.70(brs,2H),4.25(d,J=6Hz,2H)。
实施例13
3-氨基-N-(2-吗啉-4-基乙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐
在氮气气氛在10分钟内将正丁基锂(1.6mL,2.6mmol)滴加到冷却(-78℃)的硼酸三异丙酯(0.6mL,2.6mmol)、和1-[(4-溴苯基)磺酰基]吡咯烷(0.251g,0.86mmol)的无水四氢呋喃(10mL)溶液中,在-78℃搅拌得到的混合物1h,使混合物升温到室温。加入HCl水溶液(3M,1.4mL,4.3mmol)并搅拌混合物10分钟,然后加入碳酸钠(0.9g,8.6mmol)并继续再搅拌20分钟。加入3-氨基-6-溴-N-(2-吗啉-4-基乙基)吡嗪-2-甲酰胺(0.20g,0.61mmol)和四氢呋喃(4mL),然后加入Pd(dppf)Cl2(28mg,0.03mmol),并在65℃加热得到的化合物17小时。使混合物回到室温并蒸发溶剂。将得到的残余物悬浮在甲醇中,加入二氧化硅,蒸发溶剂。通过柱色谱在二氧化硅上纯化,使用二氯甲烷/甲醇/三乙胺(95∶5∶0.1)作为洗脱液,得到游离碱,随后将其溶解于热的甲醇中并用HCl(1M的乙醚溶液)处理。滤出形成的沉淀物并在真空中干燥,得到72mg(26%收率)的标题化合物,为黄色固体:1H NMR(DMSO-d6,400MHz)δ11.24(brs,1H),9.28(m,1H),8.98(s,1H),8.49(d,J=8Hz,2H),7.83(d,J=8Hz,2H),3.97(m,2H),3.87(d,J=12Hz,2H),3.78(m,2H),3.55(d,J=12Hz,2H),3.15(m,6H),1.65(m,4H);MS(ES)m/z 461(M++1)。
实施例14
3-氨基-N-[2-(1H-咪唑-4-基)乙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐
使用3-氨基-6-溴-N-[2-(1H-咪唑-4-基)乙基]吡嗪-2-甲酰胺如实施例13中所述制备标题化合物。通过HPLC(柱:C18,19×100mm,洗脱液:水+0.1% TFA/乙腈,50/20到50/50)纯化,然后用HCl(1M的乙醚溶液)处理碱(在甲醇中)。滤出形成的沉淀物并在真空中干燥,得到标题化合物,为黄色固体:收率:4%;1H NMR(DMSO-d6,400MHz)δ8.96(m,1H),8.42(d,J=8Hz,2H),7.87(d,J=8Hz,2H),7.68(brs,2H),6.97(brs,1H),3.56(m,2H),3.18(m,4H),2.81(m,2H),1.66(m,4H);MS(ES) m/z 442(M++1)。
实施例15
3-氨基-N-[3-(1H-咪唑-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐
使用3-氨基-6-溴-N-[3-(1H-咪唑-1-基)丙基]吡嗪-2-甲酰胺如实施例13中所述制备标题化合物。通过柱色谱在二氧化硅上纯化,使用二氯甲烷/甲醇/三乙胺(95∶5∶0.1)洗脱,得到游离碱,随后将其溶解于甲醇中并用HCl(1M的乙醚溶液)处理。另外加入乙醚,滤出形成的沉淀物并在真空中干燥,得到标题化合物,为黄色固体:收率:18%;1H NMR(DMSO-d6,400MHz)δ9.21(s,1H),9.06(m,1H),8.96(s,1H),8.43(d,J=8Hz,2H),7.85(m,3H),7.70(s,1H),4.27(t,J=7Hz,2H),3.36(q,J=7Hz,2H),3.17(m,4H),2.14(quin,J=7Hz,2H),1.65(m,4H);MS(ES)m/z 456(my++1)。
实施例16
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基)-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺盐酸盐
在氮气气氛将硼酸三异丙酯(0.82mL,3.6mmol)加入到在-78℃下搅拌的1-[(4-溴苯基)磺酰基]-4-甲基哌嗪(0.38g,1.2mmol,在Keasling,H.H.等人,J.Med.Chem.,1965,8,548-550中有所描述)的无水四氢呋喃(15mL)溶液中,然后在10分钟内滴加正丁基锂(2.4mL,3.6mmol)。使得到的混合物升温到室温并在环境温度下再搅拌10分钟。加入HCl水溶液(3M,1.9mL,6.0mmol)并搅拌混合物10分钟,随后加入碳酸钠(1.26g,11.9mmol)。加入3-氨基-6-溴-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺(0.272g,0.83mmol)和Pd(dppf)Cl2(39mg,0.05mmol)并在65℃加热得到的混合物1h。蒸发溶剂,将得到的残余物溶解于二氯甲烷/水中,用乙酸乙酯萃取水相。蒸发合并的有机相,加入甲醇,并滤掉不溶性物质。蒸发溶剂并将残余物在硅胶柱上纯化,使用二氨甲烷/甲醇/三乙胺(98∶2∶0.1)作为洗脱液。通过从甲醇重结晶纯化粗产物,得到游离碱,将其用HCl水溶液(1.0M的乙醚溶液,0.6mmol)处理。滤出形成的沉淀物并在真空下干燥,得到25mg(6%收率)的标题化合物,为黄色固体:1H NMR(DMSO-d6,400MHz)δ10.55(brs,1H),9.05(m,1H),8.99(s,1H),8.46(d,J=8Hz,2H),7.82(d,J=8Hz,2H),7.37(d,J=5Hz,1H),6.98(m,2H),3.83(m,2H),3.58(m,2H),3.46(m,2H),3.13(m,4H),2.75(s,3H),2.67(m,2H);MS(ES)m/z 487(m++1)。
实施例17
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺盐酸盐
使用3-氨基-6-溴-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺如实施例16中所述制备标题化合物。收率:46%;1H NMR(DMSO-d6,400MHz)δ10.9(brs,1H),9.56(t,J=6Hz,1H),8.99(s,1H),8.48(d,J=8Hz,2H),7.81(d,J=8Hz,2H),7.38(d,J=4Hz,1H),7.05(s,1H),6.97(dd,J=5.4Hz,1H),4.68(d,J=6Hz,2H),3.81(d,J=12Hz,2H),3.44(d,J=12Hz,2H),3.15(m,4H),2.72(s,3H);MS(ES) m/z 473(M++1)。
实施例18
3-氨基-N-(2-甲氧基乙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基)吡嗪-2-甲酰胺盐酸盐
使用3-氨基-6-溴-N-(2-甲氧基乙基)吡嗪-2-甲酰胺如实施例16中所述制备标题化合物。收率:44%;1H NMR(DMSO-d6,400MHz)δ11.0(brs,1H),8.98(s,1),8.92(s,1H),8.46(d,J=8Hz,2H),7.82(d,J=8Hz,2H),3.82(d,J=13Hz,2H),3.50(s,3H),3.45(d,J=13Hz,2H),3.28(s,3H),3.15(m,2H),2.72(m,6H);MS(ES)m/z 435(M++1)。
实施例19
3-氨基-N-(3-甲氧基丙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺盐酸盐
在氮气气氛将硼酸三异丙酯(0.82mL,3.6mmol)加入到在-78℃下搅拌的1-[(4-溴苯基)磺酰基]-4-甲基哌嗪(0.38g,1.2mmol,在Keasling,H.H.等人,J.Med.Chem.,1965,8,548-550中有所描述)的无水四氢呋喃(15mL)溶液中,然后在10分钟内滴加正丁基锂(2.4mL,3.6mmol)。使得到的混合物升温到室温并在环境温度下再搅拌10分钟。加入HCl(3M,1.9mL,6.0mmol)并搅拌混合物10分钟,随后加入碳酸钠(1.26g,11.9mmol)。在30分钟后,加入3-氨基-6-溴-N-(3-甲氧基丙基)吡嗪-2-甲酰胺(0.24g,0.83mmol)和Pd(dppf)Cl2(39mg,0.05mmol)并在65℃加热得到的混合物22h。蒸发反应混合物,并将残余物溶解于NaHCO3(饱和水溶液)/乙酸乙酯中,用乙酸乙酯萃取水相,蒸发合并的有机相,将粗产物在硅胶柱上纯化,使用二氯甲烷/甲醇/三乙胺(9∶1∶0.1)作为溶剂,使用甲醇从二氧化硅上洗脱产物并蒸发溶剂,得到游离碱,将碱溶解于甲醇(10mL)中,用HCl水溶液(1.0M的乙醚溶液,0.6mmol)处理混合物,然后加入乙醚(5mL)。滤出形成的沉淀物并在40℃下在真空下干燥,得到70mg(19%收率)的标题化合物,为黄色固体:1HNMR(DMSO-d6,400MHz)δ11.02(brs,1H),8.97(s,2H),8.46(d,J=9Hz,2H),7.82(d,J=9Hz,2H),3.82(d,J=13Hz,2H),3.41(m,6H),3.27(s,3H),3.15(m,2H),2.72(m,5H),1.81(m,2H);MS(ES) m/z 449(M++1)。
实施例20
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺盐酸盐
使用3-氨基-6-溴-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺如实施例19中所述制备标题化合物。收率:22%;1H NMR(DMSO-d6,400MHz)δ11.12(brs,1H),9.07(t,J=6Hz,1H),9.00(s,1H),8.52(d,J=8Hz,2H),7.80(d,J=8Hz,2H),3.82(d,J=12Hz,2H),3.40(m,4H),3.27(m,4H),3.16(m,2H),2.73(m,5H),2.25(t,J=8Hz,2H),1.93(t,J=7Hz,2H),1.72(t,J=7Hz,2H);MS(ES)m/z 502(M++1)。
实施例21
3-氨基-N-(氰基甲基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺二盐酸盐
使用3-氨基-6-溴-N-(氰基甲基)吡嗪-2-甲酰胺如实施例19中所述制备标题化合物。收率:19%;1H NMR(DMSO-d6,400MHz)δ10.49(brs,1H),9.50(t,J=6Hz,1H),9.05(s,1H),8.49(d,J=8Hz,2H),7.84(m,1H),7.83(d,J=8Hz,2H),4.36(d,J=6 Hz,2H),3.83(d,J=12Hz,2H),3.36(m,2H),3.16(m,2H),2.74(s,3H),2.66(m,2H);MS(ES)m/z 416(M++1)。
实施例22
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(1H-吡咯-1-基)乙基]-2-吡嗪甲酰胺盐酸盐
将三乙胺(0.57mL,4.13mmol)加入到3-氨基-6-溴-2-吡嗪甲酸(0.30g,1.38mmol,在Ellingson,R.C.,Henry,R.L.,J.Am.Chem.Soc.,1949,2798-2800中有所描述)、O-(苯并三唑-1-基)-N,N,N′,N,-四甲基脲四氟硼酸盐(0.486g,1.51mmol)和1-羟基苯并三唑(0.204g,1.51mmol)的N,N-二甲基甲酰胺/乙腈(1∶1,5mL)溶液中。在室温下搅拌0.5h之后,加入2-(1H-吡咯-1-基)-1-乙胺(0.182g,1.65mmol)并在室温下搅拌得到的混合物过夜。加入大约10mL水,形成沉淀。过滤沉淀并用水洗,得到0.21g(50%收率)的浅棕色固体:MS(ESP)m/z 310,312(M++1)。
将上一步中制备的固体(0.16g,0.516mmol)与[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]硼酸(0.220g,0.77mmol)、碳酸钠(0.164g,1.55mmol)和Pd(dppf)Cl2(0.013g,1.5nmmol)溶解于四氢呋喃/水(5∶1,5mL)中。将得到的混合物在70℃搅拌过夜(在N2气氛)。在二氧化硅上蒸发混合物并在二氧化硅上纯化,使用甲苯/乙腈(1∶2到1∶4)作为洗脱液,得到黄色固体,将其在40℃下在真空中干燥。将产物溶解于二氯甲烷/甲醇混合物(9∶1)中并加入盐酸乙醚(0.28mL,1M)。用乙醚洗沉淀物并在真空中干燥,得到69mg(23%收率)的标题化合物:1H NMR(DMSO-d6)δ8.94(s,1H),8.90(t,J=6Hz,1H),8.43(d,J=8Hz,2H),7.82(d,J=8Hz,2H),6.79(t,J=2Hz,2H),6.01(t,J=2Hz,2H),4.12(t,J=7Hz,2H),3.83(d,J=12Hz,2H),3.63(quart,J=6Hz,2H),3.44(d,J=12Hz,2H),3.15(m,2H),2.73(m,5H); 13C NMR(DMSO-d6)δ165.8,154.5,144.8,140.8,135.9,133.3,127.9,126.1,124.6,120.7,107.8,51.5,47.6,43.0,41.8;MS(ESP)m/z 470(M++1)。
如实施例22中所述合成以下实施例23-26。
实施例23
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(甲基磺酰基)乙基]-2-吡嗪甲酰胺盐酸盐
起始原料:2-氨基乙基甲基砜盐酸盐。通过在硅胶上的色层分离纯化标题化合物,使用梯度的甲苯/乙腈(1∶0到1∶2)作为洗脱液,随后形成盐酸盐。收率:18%;1H NMR(D2O)δ8.43(s,1H),7.89(d,J=8Hz,2H)7.74(d,J=8Hz,2H),3.97(d,J=14Hz,2H),3.89(t,J=6Hz,2H),3.63(m,4H),3.29(m,2H),3.25(s,3H),2.94(s,3H),2.88(t,J=12Hz,2H);13C NMR(D2O)δ166.3,163.3,143.4,133.5,128.4,125.9,53.1,53.0,43.5,43.1,10.9,33.0;MS(ESP)m/z 483(M++1)。
实施例24
N-[2-(乙酰基氨基)乙基]-3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐
起始原料:N-乙酰基乙二胺。通过在硅胶上的色层分离纯化标题化合物,使用梯度的甲苯/乙腈(1∶0到0∶1)作为洗脱液,随后形成盐酸盐。收率:25%;1H NMR(D2O)δ8.42(s,1H),7.93(d,J=8Hz,2H),7.74(d,J=8Hz,2H),3.96(d,J=13Hz,2H),3.64(d,J=13Hz,2H),3.43(m,4H),3.28(m,2H),2.93(s,3H),2.87(s,2H),2.02(s,3H);13C NMR(D2O)δ174.6,166.1,152.2,141.1,139.9,136.6,133.3,128.2,125.8,52.7,43.3,42.9,39.1,38.7,22.1;MS(ESP)m/z 462(M++1)。
实施例25
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(2-氧代-1-咪唑烷基)乙基]-2-吡嗪甲酰胺盐酸盐
起始原料:1-(2-氨基乙基)咪唑烷-2-酮三氟乙酸(McKay,A.F.,Paris,G.Y.,Kreling,M.-E.,J.Amer.Chem.Soc.,1957,79,5276)。通过在硅胶上的色层分离纯化标题化合物,使用梯度的氯仿/甲醇(98∶2到4∶1)作为洗脱液,随后形成盐酸盐。收率:4%:1H NMR(D2O)δ8.56(s,1H),8.06(d,J=8Hz,2H),7.83(d,J=8Hz,2H),3.98(d,J=14Hz,2H),3,65(m,4H),3.57(t,J=5Hz,2H),3.45(m,4H),3.28(m,2H),2.93(s,3H),2.86(m,2H);MS(ESP)m/z 489(M++1)。
实施例26
3-氨基-N-[2-(氨基磺酰基)乙基]-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐
起始原料:2-氨基乙磺酰胺盐酸盐。通过在硅胶上的色层分离纯化标题化合物,使用梯度的甲苯/乙腈(1∶0到0∶1)作为洗脱液,随后形成盐酸盐。收率:21%的标题化合物,为黄色固体;1H NMR(DMSO-d6)δ9.13(t,J=6Hz,1H),8.99(s,1H),8.42(d,J=8Hz,2H),7.77(d,J=8Hz,2H),7.03(s,2H),3.74(quart,J=6Hz,2H),3.28(m,2H),2.95(brs,4H),2.45(brs,4H),2.20(brs,3H);MS(ESP)m/z484(M++1)。
实施例27
3-氨基-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-羧酸甲酯
将4-(吡咯烷-1-基磺酰基)苯基硼酸(0.33g,1.29mmol)、3-氨基-6-溴吡嗪-2-羧酸甲酯(0.25g,1.08mmol,在H.Ellingson,J.Amer.Chem.Soc.,1949,2798中有所描述)、K3PO3(3M,1.1mL,3.2mmol)、和Pd(dppf)Cl2(0.044g,54μmol)悬浮在乙二醇二甲醚/水(1.5∶0.5mL)中,并在微波炉中在160℃加热10分钟。反应重复3次。将合并的产物混合物与硅胶蒸发并通过色层分离在硅胶上纯化粗产物,使用梯度庚烷/乙酸乙酯作为洗脱液,得到0.96g(82%收率)的标题化合物:MS(ES)m/z 363(M++1)。
实施例28
3-{[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基}-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-羧酸甲酯聚苯乙烯
三乙酰氧基硼氢化钠(2.6g,12.2mmol)的N,N-二甲基甲酰胺/乙酸(98∶2,20mL)溶液和三甲基氯化硅(1.17mL,9.18mmol)加入到3-氨基-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-羧酸甲酯(4.4g,12.2mmol)和2-(3,5-二甲氧基-4-甲酰基苯氧基)乙基聚苯乙烯(12g,0.51mmol/g)的N,N-二甲基甲酰胺(60mL)溶液中。振摇混合物3h然后过滤。用N,N-二甲基甲酰胺洗涤聚苯乙烯树脂三次,用二氯甲烷洗涤三次。使用三乙酰氧基硼氢化钠(2.6g,12.24mmol)的N,N-二甲基甲酰胺/乙酸(98∶2,20mL)溶液、三甲基氯化硅(1.17ml,9.18mmol)和3-氨基-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-羧酸甲酯(12g,0.51mmol/g)重复该过程并继续振摇18h。用N,N-二甲基甲酰胺洗涤聚苯乙烯树脂三次,用二氯甲烷洗涤三次,用甲醇洗涤三次。真空干燥树脂,得到12.5g的标题化合物。
分析:用在二氯甲烷中的三氟乙酸(浓度:95%)处理标题化合物(50mg)30分钟,过滤,通过MS分析溶剂:MS(ESI)363 m/z(M++1)(其相应于起始化合物)。
实施例29
3-[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基-6-[4-(吡咯烷-1-基磺酰基)苯基]哌嗪-2-羧酸聚苯乙烯
将氢氧化锂的水溶液(4M,10mL)加入到3-{[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基}-6-[4-(吡咯烷-1-基磺酰基)苯基]哌嗪-2-羧酸甲酯聚苯乙烯(12g,0.51mmol/g)的四氢呋喃(100mL)悬浮液中。振摇混合物17h。过滤并用N,N二甲基甲酰胺/水(4∶1)洗涤树脂三次,用N,N-二甲基甲酰胺/乙酸(98∶2)洗涤三次,甲醇洗涤三次,将树脂干燥,得到11.8g标题化合物。
分析:用在二氯甲烷中的三氟乙酸(浓度:95%)处理标题化合物(50mg)30分钟,过滤,通过MS分析溶剂:MS(ESI)349m/z(M++1)。
实施例30
3-氨基-N-(2-氰基乙基)-6-[4-(吡咯烷-1-基磺酰基)苄基]吡嗪-2-甲酰胺
将3-氨基丙腈(36mg,0.51mmol)、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐(0.164g,0.51mmol)和1-羟基苯并三唑水合物(69mg,0.51mmol)加入到3-{[2,6-二甲氧基-4-(2-苯基乙氧基)苄基]氨基}-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-羧酸聚苯乙烯(0.50g,0.51mmol/g,0.255mmol)的N,N-二甲基甲酰胺(2mL)溶液中。在振摇混合物5分钟之后加入二异丙基乙基胺(0.133mL,0.765mmol)。振摇混合物18h,过滤并用N,N-二甲基甲酰胺洗并用二氯甲烷洗涤三次。通过用三氟乙酸的二氯甲烷(浓度95%)溶液处理30分钟分离产物,然后过滤。使溶液蒸发并通过制备HPLC(柱:XTerra C8 19×300mm,洗脱液:梯度的乙腈/水(20∶80到80∶20))纯化得到1mg(1%收率)的标题化合物:1H NMR(CDCl3,400MHz)δ8.70(s,1H),8.01(d,J=8Hz,2H),7.93(d,J=8Hz,2H),3.79(m,2H),3.30(m,4H),2.79(t,J=6Hz,2H),1.80(m,4H);MS(ESI)401 m/z(M++1).
如实施例30所述合成以下实施例31-35。
实施例31
3-氨基-N-(3-氨基-3-氧代丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺
起始原料:β-丙氨酸酰胺。收率:2%:1H NMR(CDCl3,400MHz)δ8.60(s,1H),8.03(d,J=8Hz,2H),7.85(d,J=8Hz,2H),3.64(t,J=6Hz,2H),3.20(m,4H),2.50(t,J=6Hz,2H),1.72(m,4H);MS(ESI)419 m/z(M++1)。
实施例32
3-氨基-N-(2-硝基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺
起始原料:1-(2-硝基苯基)甲胺。收率:1.8%;1H NMR(CDCl3,400MHz)δ8.80(s,H),8.70(s,H),8.12(d,J=7Hz,1H),8.04(d,J=8Hz,2H),7.90(d,J=8 Hz,2H),7.73(dd,J=8Hz,1H),7.50(m,1H),7.66(m,IH),4.94(d,J=7Hz,2H),3.30(m,4H),1.8(m,4H);MS(ESI)483 m/z(M++1)。
实施例33
3-氨基-N-(2-甲氧基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺
起始原料:1-(2-甲氧基苯基)甲胺。收率:1.6%;1H NMR(CDCl3,400MHz)δ 8.64(s,1H),8.01(d,J=8Hz,2H),7.89(d,J=8Hz,2H),7.31(d,J=7Hz,2H),6.94(m,2H),4.68(d,J=6Hz,2H),3.94(m,3H),3.41(m,1H),3.27(m,4H),1.8(m,4H);MS(ESI)468m/z (M++1)。
实施例34
3-氨基-N-(3-吗啉-4-基丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺
起始原料:3-吗啉-4-基丙烷-1-胺。收率:1.4%;1H NMR(CDCl3,400MHz)δ8.67(s,1H),8.02(d,J=8Hz,2H),7.94(d,J=8Hz,2H),3.66(t,J=5Hz,4H),3.58(m,2H),3.30(m,4H),2.49(t,J=7Hz,2H),2.48(m,4H),1.85(t,J=7Hz,2H),1.79(m,4H);MS(ESI)475m/z(M++1)。
实施例35
3-氨基-N-[3-(4-甲基哌嗪-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺
起始原料:3-(4-甲基哌嗪-1-基)丙烷-1-胺。收率:3.8%;1H NMR(CD30D,400MHz)δ8.77(s,1H),8.24(d,J=8Hz,2H),7.05(d,J=8Hz,2H),3.54(t,J=7 Hz,2H),3.36(m,4H),3.32(m,4H),2.56(d,J=7Hz,4H),2.28(s,3H),2.09(s,1H),1.90(m,2H),1.84(m,4H);MS(ES I)488 m/z(M++1)。
药物组合物
根据本发明的一个方面,提供了包括式I化合物的药物组合物,该药物组合物用于预防和/或治疗与糖原合酶激酶-3有关的疾病,其中式I化合物为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
组合物可为适合于口服给药的形式如为片剂、或作为无菌溶液或悬浮液的肠胃外注射剂形式。通常,可以以常规的方式使用药学载体或稀释剂制备上述组合物。治疗哺乳动物包括人的式I化合物的适当的日剂量为:口服给药为约0.01到250mg/kg体重,肠胃外给药为约0.001到250mg/kg体重。活性成分的典型日剂量在宽的范围内变化,并取决于多种因素,如患者的相关指标、给药途径、年龄、体重、性别,并可由医生决定。
可将式I化合物或其药学可接受盐、溶剂化物或盐的溶剂化物单独使用,但通常以其中将式I化合物/盐/溶剂化物(活性成分)与可药用的稀释剂或载体结合的药物组合物形式给药。取次于给药方式,药物组合物可包括0.05到99重量%(重量百分比)例如0.10到50重量%的活性成分,所有的重量百分比都相对于组合物总重量计。
稀释剂或载体包括水、含水聚乙二醇、碳酸镁、硬脂酸镁、滑石、糖(如乳糖)、果胶、糊精、淀粉、黄芪胶、微晶纤维素、甲基纤维素、羧甲基纤维素钠或可可油。
本发明的组合物可为片剂或可注射形式。片剂可另外包括崩解剂和/或可包衣(例如具有肠溶衣或涂有包衣剂如羟丙基甲基纤维素)。
本发明另外提供制备本发明的药物组合物的方法,其包括将上述定义的式I化合物或其药学可接受盐、溶剂化物或盐的溶剂化物与可药用的稀释剂或载体混合。
本发明的药物组合物的例子为可注射溶液,其包含上述本发明的化合物或其药学可接受盐、溶剂化物或盐的溶剂化物、和无菌水,并且如有必要,也包含氢氧化钠或盐酸使最终组合物的pH为约pH5,和任选地包含表面活性剂以助溶。
包括溶解于水中的式I化合物(其为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物)的液体溶液
溶液 | mg/mL |
化合物X | 5.0%w/v |
纯水 | 到100% |
医疗应用
令人惊讶地是,已经发现本发明中定义的化合物,该化合物为游离碱或其可药用的盐、溶剂化物或盐的溶剂化物,非常适合于抑制糖原合酶激酶-3(GSK3)。因此,可以期望本发明的化合物用于预防和/或治疗与糖原合酶激酶-3活性有关的疾病,即该化合物可用于在需要这种预防和/或治疗的哺乳动物包括人中产生GSK3抑制效果。
GSK3在中枢和外周神经体系及其它组织中高度表达。因此,可以期望本发明的化合物非常适合于预防和/或治疗与中枢和外周神经体系中的糖原合酶激酶-3有关的疾病。具体地,期望本发明的化合物适合于预防和/或治疗特别是与痴呆、阿尔茨海默氏病、帕金森氏症、额颞叶痴呆帕金森型病、关岛帕金森-痴呆综合症、HIV痴呆、与神经纤维缠结病理学有关的疾病和拳击员痴呆。
其它疾病选自肌萎缩性侧索硬化、皮质基底核变性、唐氏综合症、亨廷顿病、脑炎后帕金森氏综合症、进行性核上麻痹、皮克病、尼曼-皮克病、中风、头部外伤、和其它慢性神经变性疾病、躁郁症、情感障碍、抑郁、精神分裂症、认知紊乱、脱发和避孕治疗,I型和I I型糖尿病、糖尿病性神经病和糖尿病相关病症。
此外,疾病选自预精神错乱状态、中度认知损伤、年纪相关性记忆损伤、年纪相关性认知下降、非痴呆性认知损伤、中度认知下降、中度神经认知下降、老年性健忘、记忆损伤和认知损伤、血管性痴呆、莱维体痴呆和额颞叶性痴呆。
本发明的一个实施方案涉及痴呆和阿尔茨海墨氏疾病的预防和/或治疗。
本发明的另一个实施方案涉及I型和II型糖尿病、糖尿病性神经病和糖尿病相关病症的预防和/或治疗。
对于特定疾病的治疗或预防性治疗所需的剂量必须取决于被治疗主体、给药途径和被治疗疾病的严重程度而改变。
本发明还涉及上述定义的式I化合物在生产用于预防和/或治疗与糖原合酶激酶-3有关的疾病的药物中的应用。
在本说明书的语境下,术语“治疗”也包括“预防”,除非特别指明不包括。术语“治疗”和“治疗地”也作应相应地理解。
本发明还提供治疗和/或预防与糖原合酶激酶-3有关的疾病的方法,其包括对需要这种治疗和/或预防的哺乳动物包括人给药治疗有效量的上述定义的式I化合物。
非医疗应用
除了在治疗药物中的应用之外,式I化合物作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物也可用作药理学工具,用在作为寻找新型治疗药物的一部分中的实验动物如猫、狗、兔、猴子、大鼠和小鼠中的GSK3抑制剂相关活性的体外和体内的试验体系的研发和标准化中。
药理学
闪烁亲近GSK3β测定法中测定ATP竞争
GSK3β闪烁亲近测定法
在透明底微量滴定板(Wallac,Finland)中在10个不同的抑制剂浓度下、一式两份进行竞争实验。在分析缓冲液中加入最终浓度为1μM的生物素化肽底物,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO3H2)-Pro-Gln-Leu(AstraZeneca,Lund),所述分析缓冲液包含1mU的重组人GSK3β(Dundee University,UK)、12mM的吗啉丙磺酸(MOPS)、pH7.0、0.3mM的EDTA、0.01%的β-巯基乙醇、0.004%的Brij 35(天然清洁剂)、0.5%的甘油和0.5μg的BSA/25μl。通过加入0.04μCi[γ-33P]ATP(Amersham,UK)和最终浓度为1μM的未标记ATP引发反应,分析体积为25μl。在室温下培养20分钟之后,通过加入25μl的终止溶液终止每个反应,终止溶液包含5mM的EDTA、50μM的ATP、0.1%的Triton X-100和0.25mg的涂有链霉亲和素的闪烁亲近测定法(SPA)小珠(Amersham,UK)。6小时后在液体闪烁计数器(1450 MicroBeta Trilux,Wallac)中测定放射性。使用GraphPad Prism,USA通过非线性回归分析抑制曲线。使用ATP的Km值计算各种化合物的GSK3β的抑制常数(Ki)为20μM。
其中使用了以下缩写:
MOPS 吗啉丙磺酸
EDTA 乙二胺四乙酸
BSA 牛血清白蛋白
ATP 腺苷三磷酸
SPA 闪烁亲近测定法
GSK3 糖原合酶激酶3
结果
本发明化合物的典型Ki值为约0.001到约10,000nM。其它Ki值为约0.001到约1000nM。另外的Ki值为约0.001nM到约300nM。
Claims (7)
1.式I化合物:
其中:
Z为N;
Y为CONR5;
X为N;
P为苯基;
Q为C1-6烷基;
R为C0-6烷基(SO2)NR1R2;
R1和R2一起形成包含一个或多个独立地选自N杂原子的取代的5或6元杂环,该杂环任选地被A取代;
R3不存在;
R4独立地选自CN、CONR6R7、SO2R6、苯基、包含一个或多个独立地选自N、O或S的杂原子的5或6元杂芳环或包含一个或多个独立地选自N、O或S的杂原子的5或6元杂环,该杂环为饱和或不饱和的,并且所述苯环或5或6元杂芳环或5或6元杂环任选地被一个或多个A取代;
m为0;
n为1;
R5为氢或C1-6烷基;
R6和R7独立地选自氢、C1-6烷基;
A为氧代、硝基、OR6或C1-6烷基;
该化合物作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
2.权利要求1的化合物,其中所述杂环包括一个或多个N杂原子并且所述杂环任选被C1-6烷基取代。
3.权利要求1-2中任一项的化合物,其中R5为氢。
4.化合物,其为:
3-氨基-N-(2-氰基乙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(3-氨基-3-氧代丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(2-硝基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(2-甲氧基苄基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-(3-吗啉-4-基丙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
3-氨基-N-[3-(4-甲基哌嗪-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺;
这些化合物为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物;
3-氨基-N-(2-吗啉-4-基乙基)-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-[2-(1H-咪唑-4-基)乙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-[3-(1H-咪唑-1-基)丙基]-6-[4-(吡咯烷-1-基磺酰基)苯基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-(2-噻吩-2-基乙基)吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-(噻吩-2-基甲基)吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(2-甲氧基乙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(3-甲氧基丙基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺盐酸盐;
3-氨基-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}-N-[3-(2-氧代吡咯烷-1-基)丙基]吡嗪-2-甲酰胺盐酸盐;
3-氨基-N-(氰基甲基)-6-{4-[(4-甲基哌嗪-1-基)磺酰基]苯基}吡嗪-2-甲酰胺二盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(1H-吡咯-1-基)乙基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(甲基磺酰基)乙基]-2-吡嗪甲酰胺盐酸盐;
N-[2-(乙酰基氨基)乙基]-3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-N-[2-(2-氧代-1-咪唑烷基)乙基]-2-吡嗪甲酰胺盐酸盐;
3-氨基-N-[2-(氨基磺酰基)乙基]-6-[4-[(4-甲基-1-哌嗪基)磺酰基]苯基]-2-吡嗪甲酰胺盐酸盐;
这些化合物或作为游离碱或其药学可接受盐、溶剂化物或盐的溶剂化物。
5.药物制剂,包括治疗有效量的权利要求1-4中任一项的化合物作为活性成分以及药学可接受载体或稀释剂。
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CA2720659C (en) * | 2008-04-24 | 2016-10-18 | Abbott Gmbh & Co. Kg | 1-(7-(hexahydropyrrolo[3,4-c]pyrrol-2(1h)-yl)quinolin-4-yl)-3-(pyrazin-2-yl)urea derivatives and related compounds as glycogen synthase kinase 3 (gsk-3) |
EP2438041A4 (en) * | 2009-06-01 | 2012-11-21 | Merck Sharp & Dohme | PYRAZINE-carboxamide-orexin receptor Antagonist |
MX2012008328A (es) | 2010-01-19 | 2012-08-08 | Astrazeneca Ab | Derivados de pirazina. |
TWI712598B (zh) | 2016-07-20 | 2020-12-11 | 瑞士商諾華公司 | 胺基吡啶衍生物及其作為選擇性alk-2抑制劑之用途 |
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US20010031772A1 (en) * | 2000-03-07 | 2001-10-18 | Karl Schoenafinger | Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals |
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US20010031772A1 (en) * | 2000-03-07 | 2001-10-18 | Karl Schoenafinger | Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals |
WO2001068612A2 (en) * | 2000-03-10 | 2001-09-20 | Euro-Celtique S.A. | Aryl substituted pyridines, pyrimidines, pyrazines and triazines and the use thereof |
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CN1726210A (zh) | 2006-01-25 |
PT1575942E (pt) | 2007-07-09 |
ZA200504874B (en) | 2006-04-26 |
SE0203753D0 (sv) | 2002-12-17 |
WO2004055009A8 (en) | 2005-06-30 |
ATE361291T1 (de) | 2007-05-15 |
BR0317299A (pt) | 2005-11-08 |
US20100087396A1 (en) | 2010-04-08 |
US7595321B2 (en) | 2009-09-29 |
EP1575942B1 (en) | 2007-05-02 |
AU2003287137B2 (en) | 2007-07-05 |
JP2006512337A (ja) | 2006-04-13 |
ES2285221T3 (es) | 2007-11-16 |
MXPA05006244A (es) | 2005-08-19 |
TW200505905A (en) | 2005-02-16 |
AU2003287137A1 (en) | 2004-07-09 |
KR20050084362A (ko) | 2005-08-26 |
DE60313658T2 (de) | 2008-01-10 |
NZ540450A (en) | 2007-10-26 |
AR042343A1 (es) | 2005-06-15 |
CY1106709T1 (el) | 2012-05-23 |
CA2508045A1 (en) | 2004-07-01 |
DE60313658D1 (de) | 2007-06-14 |
HK1080854A1 (en) | 2006-05-04 |
WO2004055009A1 (en) | 2004-07-01 |
EP1575942A1 (en) | 2005-09-21 |
NO20053459L (no) | 2005-08-12 |
US20060116385A1 (en) | 2006-06-01 |
DK1575942T3 (da) | 2007-09-03 |
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