CN1665808A - 噻二唑或噁二唑及其作为jak蛋白激酶抑制剂的用途 - Google Patents
噻二唑或噁二唑及其作为jak蛋白激酶抑制剂的用途 Download PDFInfo
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- CN1665808A CN1665808A CN038159546A CN03815954A CN1665808A CN 1665808 A CN1665808 A CN 1665808A CN 038159546 A CN038159546 A CN 038159546A CN 03815954 A CN03815954 A CN 03815954A CN 1665808 A CN1665808 A CN 1665808A
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Abstract
本发明涉及通式(I)的化合物或其药学上可接受的盐;其中W和X各自独立地是氧或硫;A是氮、CH、C-CN、或C-(C1-3脂族的);且R1和R2共同形成环。这些化合物可用作JAK激酶的抑制剂,特别用于治疗自身免疫病、神经变性疾病、或血癌。
Description
JAK蛋白激酶的抑制剂
相关申请的交叉参考
本申请要求35 U.S.C.§119(e)下的、2002年5月6日提交的,名称为“JAK蛋白激酶抑制剂”的美国临时申请号60/378,185的优先权,其全部内容均引入此处作为参考。
发明技术领域
本发明涉及用作蛋白激酶抑制剂的化合物。本发明还提供包含本发明化合物的药学上可接受的组合物以及使用该组合物治疗多种疾病的方法。
发明背景
近年来,通过更好地了解与疾病有关的酶和其它生物分子的结构,已经大大帮助了新治疗剂的研究。已成为广泛研究目标的其中一类重要的酶是蛋白激酶。
蛋白激酶由一大家族结构上相关的酶组成,它们负责细胞内各种信号转导过程的控制。(见,Hardie,G.和Hanks,S.The ProteinKinase Facts Book,I和II,Academic Press,San Diego,CA:1995)。由于蛋白激酶结构和催化功能的保守性,它们被认为是从共同的先祖基因进化的。几乎所有激酶都包含一个相似的250-300氨基酸催化结构域。通过激酶使其磷酸化的底物不同可将它们分成几个家族(例如,蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸,脂类等)。已经鉴定出了通常与这些激酶家族中的每一个相对应的序列基元(见,例如,Hanks,S.K.,Hunter,T.,FASEB J.1995,9,576-596;Knighton等人,Science1991,253,407-414;Hiles等人,Cell 1992,70,419-429;Kunz等人,Cell 1993,73,585-596;Garcia-Bustos等人,EMBO J.1994,13,2352-2361)。
通常,蛋白激酶通过影响从核苷三磷酸向参与信号传导途径的蛋白受体的磷酰基转移而介导胞内信号。这些磷酸化事件可起调制或调节目标蛋白生物功能的分子开关的作用。这种刺激物的例子包括环境和化学应激信号(例如,渗压震扰、热激、紫外线辐射、细菌内毒素、和H2O2)、细胞因子(例如,白介素-1(IL-1)和肿瘤坏死因子α(TNF-α))、和生长因子(例如,粒细胞巨嗜细胞-集落刺激因子(GM-CSF)和成纤维细胞生长因子(FGF))。胞外刺激物可影响与细胞生长、迁移、分化、激素分泌、转录因子激活、肌肉收缩,葡萄糖代谢,蛋白合成控制,以及细胞周期调节有关的一种或多种细胞反应。
很多疾病都与通过上述蛋白激酶-介导的事件所引发的异常细胞反应有关。这些疾病包括,但不限于,自身免疫病、炎性病、骨病、代谢病、神经和神经变性病、癌症、心血管病、变态反应和哮喘、阿尔茨海默氏病、和与激素有关的病。因此,药用化学方面的巨大努力已经找到了可有效作为治疗剂的蛋白激酶。
Janus激酶(JAK)属于酪氨酸激酶家族,由JAK1、JAK2、JAK3和TYK2组成。JAK在细胞因子信号传导中起着重要的作用。激酶JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK/STAT信号传导涉及很多异常免疫反应,如变态反应、哮喘、自身免疫病如移植排斥、类风湿性关节炎、肌萎缩性侧索硬化和多发性硬化以及实体和血液恶性肿瘤如白血病和淋巴瘤的介导。JAK/STAT途径的药物干预已被评论过[Frank Mol.Med. 1999,5,432-456和Seidel等人,Oncogène 2000,19,2645-2656]。
JAK1、JAK2、和TYK2为遍在表达,而JAK3则主要在造血细胞中表达。JAK3只与共同的细胞因子受体γ链(γc)结合并被IL-2、IL-4、IL-7、IL-9和IL-15激活。事实上,由IL-4和IL-9诱导的鼠肥大细胞的增殖和存活已经显示出依赖于JAK3-和γc-信号传导[Suzuki等人,Blood 2000,96,2172-2180]。
敏化肥大细胞的高亲和性免疫球蛋白(Ig)E受体的交联导致促炎介质,包括许多血管活性细胞因子,的释放从而导致急性变态反应,或介导(I型)过敏反应[Gordon等人,Nature 1990,346,274-276和Galli,N.Engl.J.Med. 1993,328,257-265]。JAK3在IgE受体-介导的肥大细胞反应中的重要作用已经在体外和体内建立[Malaviya等人,Biochem.Biophys.Res.Commun.1999,257,807-813]。此外,还报道了通过抑制JAK3而预防由肥大细胞-激活介导的I型过敏反应,包括过敏症[Malaviya等人,J.Biol.Chem.1999274,27028-27038]。用JAK3抑制剂针对肥大细胞可调节肥大细胞体外脱粒并预防体内IgE受体/抗原-介导的过敏反应。
近来的研究描述了用于免疫抑制和同种异体移植接受的JAK3的成功寻靶。研究证实了给予JAK3抑制剂后,水牛心脏同种异体移植在Wistar Furth受体中的剂量-依赖性存活,表明在移植物抗宿主疾病中调节有害免疫反应的可能性[Kirken,Transpl.Proc.2001,33,3268-3270]。
IL-4-介导的STAT-磷酸化被暗示涉及类风湿性关节炎(RA)的早期和晚期阶段。RA滑膜和滑膜液中的促炎细胞因子的上调是疾病的特征。已经证实了IL-4介导的IL-4/STAT途径的激活是通过Janus激酶(JAK 1&3)介导的,而IL-4相关的JAK激酶在RA滑膜中表达[Muller-Ladner等人,J.Immunol.2000,164,3894-3901]。
家族性肌萎缩性侧索硬化(FALS)是一种可影响约10%ALS患者的致命性神经变性疾病。FALS小鼠的存活率在用JAK3特异性抑制剂处理后增加。这表明JAK3在FALS中起作用[Trieu等人,Biochem.Biophys.Res.Commun.2000,267,22-25]。
转录蛋白的信号转导剂和激活剂(STAT)是尤其是由JAK家族激酶激活的。近来的研究结果暗示了通过用特异性抑制剂针对JAK家族激酶而干预JAK/STAT信号传导途径来治疗白血病的可能性[Sudbeck等人,Clin.Cancer Res.1999,5,1569-1582]。JAK3特异性化合物已显示出可抑制JAK3-表达细胞系DAUDI、RAMOS、LC1-19、NALM-6、MOLT-3和HL-60的克隆发生性生长。
在动物模型中,TEL/JAK2融合蛋白已经诱导了髓增殖疾病,且在造血细胞系中,TEL/JAK2的引入导致了STAT1、STAT3、STAT5的激活,以及细胞因子-依赖性生长[Schwaller等人,EMBO J.1998,17,5321-5333]。
JAK3和TYK2的抑制消除了STAT3的酪氨酸磷酸化,并抑制了蕈样肉芽肿,一种皮肤T-细胞淋巴瘤形式的细胞生长。这些结果暗示了组成型激活的JAK/STAT途径中的JAK家族激酶存在于蕈样肉芽肿中[Nielsen等人,Proc.Nat.Acad.Sci.U.S.A.1997,94,6764-6769]。同样,STAT3、STAT5、JAK1和JAK2被证实了在最初特征为LCK过量表达的小鼠T-细胞淋巴瘤中被组成型激活,从而进一步暗示了异常细胞生长中的JAK/STAT途径[Yu等人,J.Immunol.1997,159,5206-5210]。此外,IL-6介导的STAT3激活可被JAK抑制剂阻断,导致骨髓瘤细胞对编程性细胞死亡敏感[Catlett-Falcone等人,Immunity 1999,10,105-115]。
因此,非常需要研制出可用作蛋白激酶抑制剂的化合物。具体而言,希望研制出可用作JAK-3抑制剂的化合物,特别是对于涉及它们激活的绝大多数疾病而言,目前采用了不太适宜的治疗。
发明概述
现在已经发现了本发明的化合物,及其药学上可接受的组合物可有效作为蛋白激酶的抑制剂。在某些实施方案中,这些化合物可有效作为JAK-3蛋白激酶的抑制剂。这些化合物或其药学上可接受的衍生物具有通式I:
其中A、Q、W、X、R1、R2和R3如下面所定义的。
这些化合物及其药学上可接受的组合物用于治疗或减轻各种疾病,包括变应性疾病(如哮喘和特应性皮炎)、自身免疫病(如SLE狼疮和牛皮癣)以及与器官移植有关的病症的严重程度。
本发明提供的化合物还用于激酶在生物学和病理学现象中的研究;由这种激酶介导的胞内信号转导途径的研究;以及新的激酶抑制剂的比较性评价。
发明详述
1.苯发明化合物的一般性描述:
本发明涉及通式I的化合物,或其药学上可接受的盐:
其中:
W和X各自独立地是氧或硫;
A是氮、CH、C-CN、或C-(C1-3脂族的);
R1和R2共同形成具有0-3个独立选自氮、氧或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
Q是价键、-C(O)-、-C(O)NR-、-C(O)C(O)-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-6亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、-C(O)NR-、-OC(O)NR-、-NRC(O)-、NRCO2-、-NRC(O)NR-、-S(O)-、-SO2-、-NRSO2-、-SO2NR-、或-NRSO2NR-取代;
每个R独立地是氢或任选取代的C1-6脂族基团,其中:与同一氮原子结合的两个R任选与氮共同形成具有0-2个除了与其结合的氮之外的独立选自氮、氧、或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
R3是R或Ar;且
Ar是任选取代的环,选自:
(a)饱和、部分不饱和的3-8元单环或8-10元双环、或芳环;
(b)具有1-3个独立选自氮、氧、或硫的杂原子的3-7元杂环;或
(c)具有1-4个独立选自氮、氧、或硫的杂原子的5-6元单环或8-10元双环的杂芳环。
2.化合物和定义:
本发明的化合物包括上面一般性描述的那些,且它们由此处公开的类、子类、和种进一步举例说明。除非另有说明,否则应用此处所用的下列定义。就本发明的目的而言,化学元素是根据元素周期表,CAS版,Handbook of Chemistry and Physics,第75版鉴定的。此外,有机化学的一般原则在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March′s AdvancedOrganic Chemistry”,第五版,Smith,M.B.和March,J.编,JohnWiley & Sons,New York:2001中描述,它们的全部内容均引入此处作为参考。
正如这里所述的,本发明的化合物可任选被一个或多个取代基取代,这些取代基是上面一般性举例说明的,或由本发明具体的类、子类、和种举例说明的。应当了解短语“任选取代的”可与短语“取代或未取代的”互换使用。通常,术语“取代的”,无论前面是否加了“任选”,都是指用指定的取代基取代已知结构中的氢基。除非另有说明,任选取代的基团可在基团的每个可取代位置具有取代基,且当可用不止一个选自指定基团的取代基取代任何已知结构中的不止一个位置时,每个位置上的取代基可以相同或不同。本发明预期的取代基组合优选可形成稳定或化学可用化合物的那些。此处所用术语“稳定的”是指当经历用于它们的产生、检测,且优选用于它们的回收、纯化的条件,和用于此处所公开的一种或多种目的时,基本上不会改变的化合物。在某些实施方案中,稳定的化合物或化学可用的化合物是在没有水分或其它化学反应性条件存在的条件下,当在40℃或更低的温度下保持至少一周时,基本上不会改变的化合物。
此处所用术语“脂族的”或“脂族基团”是指直链(即,无支链的)或支链、取代或未取代的烃链,它是完全饱和的或包含一个或多个不饱和单位,或是指单环烃或双环烃,它是完全饱和的或包含一个或多个不饱和单位,但其不是芳香的(此处也称作“碳环”“环脂族的”或“环烷基”),它具有与分子剩余部分相连的单一点。除非另有说明,脂族基团包含1-20个脂族碳原子。在某些实施方案中,脂族基团包含1-10个脂族碳原子。在其它实施方案中,脂族基团包含1-8个脂族碳原子。在其它实施方案中,脂族基团包含1-6个脂族碳原子,在其它实施方案中,脂族基团包含1-4个脂族碳原子。在某些实施方案中,“环脂族的”(或“碳环”或“环烷基”)是指单环的C3-C8烃或双环的C8-C12烃,它是完全饱和的或包含一个或多个不饱和单位,但它不是芳香的,具有与分子剩余部分相连的单一点,其中所述双环系统中的任一独立的环具有3-7元。适宜的脂族基团包括,但不限于,线型或支链的、取代或未取代的烷基、链烯基、炔基及其杂化物,如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。
此处所用的术语“杂脂族的”是指其中一个或两个碳原子独立地被一个或多个氧、硫、氮、磷或硅取代的脂族基团。杂脂族基团可以是取代或未取代的、支链或无支链的、环状或无环的,且包括“杂环”、“杂环基”、“杂环脂族的”或“杂环的”基团。
此处所用的术语“杂环”、“杂环基”、“杂环脂族的”或“杂环的”是指非芳香的单环、双环、或三环系统,其中一个或多个环节是独立选择的杂原子。在某些实施方案中,“杂环”、“杂环基”、“杂环脂族的”或“杂环的”基团具有3-14个环节,其中一个或多个环节是独立选自氧、硫、氮、或磷的杂原子,且系统中的每个环包含3-7个环节。
术语“杂原子”是指一个或多个氧、硫、氮、磷或硅(包括,氮、硫、磷或硅的任一氧化形式;任一碱性氮的季铵化形式或;杂环的可取代氮,例如N(3,4-二氢-2H-吡咯基)、NH(吡咯烷基)或NR+(如N-取代的吡咯烷基))。
此处所用的术语“不饱和的”是指该部分具有一个或多个不饱和单位。
此处所用的术语“烷氧基”、或“硫烷基”是指与通过氧(“烷氧基”)或硫(“硫烷基”)原子与主碳链相连的先前定义的烷基。
术语“卤烷基”、“卤烯基”和“卤烷氧基”是指根据具体情况用一个或多个卤原子取代的烷基、烯基或烷氧基。术语“卤素”是指F、Cl、Br或I。
此处单独使用或用作较大部分,如“芳烷基”、“芳烷氧基”、或“芳氧基烷基”中一部分的术语“芳基”是指具有总共5-14个环节的单环、双环和三环系统,其中系统中的至少一个环是芳香的且系统中的每个环都包含3-7个环节。术语“芳基”可与术语“芳环”互换使用。术语“芳基”还指此处下面定义的杂芳环系统。
单独使用或用作较大部分,如“杂芳烷基”或“杂芳基烷氧基”中一部分的术语“杂芳基”是指具有总共5-14个环节的单环、双环和三环系统,其中系统中的至少一个环是芳香的,系统中的至少一个环包含一个或多个杂原子,且其中系统中的每个环都包含3-7个环节。术语“杂芳基”可与术语“杂芳环”或术语“杂芳香的”互换使用。
芳基(包括芳烷基、芳烷氧基、芳氧基烷基等)或杂芳基(包括杂芳烷基和杂芳基烷氧基等)可包含一个或多个取代基。芳基或杂芳基的不饱和碳原子上的适宜取代基选自卤素、-R°、-OR°、-SR°、1,2-亚甲二氧基、1,2-亚乙二氧基、用R°任选取代的苯基(Ph)、用R°任选取代的-O(Ph)、用R°任选取代的-(CH2)1-2(Ph)、用R°任选取代的-CH=CH(Ph)、-NO2、-CN、-N(R°)2、-NR°C(O)R°、-NR°C(S)R°、-NR°C(O)N(R°)2、-NR°C(S)N(R°)2、-NR°CO2R°、-NR°NR°C(O)R°、-NR°NR°C(O)N(R°)2、-NR°NR°CO2R°、-C(O)C(O)R°、-C(O)CH2C(O)R°、-CO2R°、-C(O)R°、-C(S)R°、-C(O)N(R°)2、-C(S)N(R°)2、-OC(O)N(R°)2、-OC(O)R°、-C(O)N(OR°)R°、-C(NOR°)R°、-S(O2)R°、-S(O3)R°、-SO2N(R°)2、-S(O)R°、-NR°SO2N(R°)2、-NR°SO2R°、-N(OR°)R°、-C(=NH)-N(R°)2、或-(CH2)0-2NHC(O)R°,其中每个独立存在的R°选自氢、任选取代的C1-6脂族的、未取代的5-6元杂芳基或杂环、苯基、-(O)Ph、或-CH2(Ph)、或,虽然在上面定义,同一取代基或不同取代基上两个独立存在的R°与和每个R°基团结合的原子共同形成5-8元的杂环基、芳基、或杂芳环,或形成具有0-3个独立选自氮、氧或硫的杂原子的3-8元环烷基环。R°的脂族基团上的任选取代基选自NH2、NH(C1-4脂族的)、N(C1-4脂族的)2、卤素、C1-4脂族的、OH、O(C1-4脂族的)、NO2、CN、CO2H、CO2(C1-4脂族的)、O(卤代C1-4脂族的)、或卤代C1-4脂族的,其中R°每个前述的C1-4脂族基团都是未取代的。
脂族或杂脂族基团,或非芳香的杂环可包含一个或多个取代基。脂族或杂脂族基团、或非芳香杂环的饱和碳上的适宜取代基选自上面芳基或杂芳基的不饱和碳所列的那些,且此外还包括下列:=O、=S、=NNHR*、=NN(R*)2、=NNHC(O)R*、=NNHCO2(烷基)、=NNHSO2(烷基)、或=NR*,其中每个R*独立选自氢或任选取代的C1-6脂族的。R*的脂族基团上的任选取代基选自NH2、NH(C1-4脂族的)、N(C1-4脂族的)2、卤素、C1-4脂族的、OH、O(C1-4脂族的)、NO2、CN、CO2H、CO2(C1-4脂族的)、O(卤C1-4脂族的)、或卤C1-4脂族的,其中R*每个前述的C1-4脂族基团都是未取代的。
非芳香杂环的氮上的任选取代基选自-R+、-N(R+)2、-C(O)R+、-CO2R+、-C(O)C(O)R+、-C(O)CH2C(O)R+、-SO2R+、-SO2N(R+)2、-C(=S)N(R+)2、-C(=NH)-N(R+)2、或-NR+SO2R+;其中R+是氢、任选取代的C1-6脂族的、任选取代的苯基、任选取代的-O(Ph)、任选取代的-CH2(Ph)、任选取代的-(CH2)1-2(Ph)、任选取代的-CH=CH(Ph)、或具有1-4个独立选自氧、氮、或硫的杂原子的未取代的5-6元杂芳基或杂环,或,尽管如上面所定义的,同一取代基或不同取代基上两个独立存在的R+与和每个R+基团结合的原子共同形成5-8元的杂环基、芳基、或杂芳环,或形成具有0-3个独立选自氮、氧、或硫的杂原子的3-8元环烷基环。R+的脂族基团或苯环上的任选取代基选自NH2、NH(C1-4脂族的)、N(C1-4脂族的)2、卤素、C1-4脂族的、OH、O(C1-4脂族的)、NO2、CN、CO2H、CO2(C1-4脂族的)、O(卤代C1-4脂族的)或卤代(C1-4脂族的),其中R+个先前的C1-4脂族基团都是未取代的。
术语“亚烷基链”是指可以是完全饱和的或具有一个或多个不饱和单位且具有两个与分子剩余部分相连的点的直链或支链碳链。
如上所述,在某些实施方案中,两个独立存在的R°(或R+,或此处相似定义的任何其它变量)可与和每个变量相连的原子共同形成5-8元的杂环基、芳基、或杂芳环,或形成具有0-3个独立选自氮、氧、或硫的杂原子的3-8元环烷基环。两个独立存在的R°(或R+,或此处相似定义的任何其它变量)与和每个变量结合的原子共同形成的环的例子包括,但不限于下列:a)两个独立存在的R°(或R+,或此处相似定义的任何其它变量)与同一原子结合,并与该原子共同形成环,例如,N(R°)2,其中所存在的两个R°与氮原子共同形成哌啶-1-基、哌嗪-1-基、或吗啉-4-基;和b)两个独立存在的R°(或R+,或此处相似定义的任何其它变量)与不同的原子结合,并与那些原子共同形成环,例如,其中苯基被所存在的两个OR°
取代,所存在的这两个R°与和它们结合的氧原子共同形成一个稠合的6-元含氧环:
。应当认识到,当两个独立存在的R°(或R+,或此处相似定义的任何其它变量)与和每个变量结合的原子共同连接时,可形成各种其它环,且上面详细描述的例子不认为是限制。
除非另有说明,此处描述的结构还可包括该结构的所有同分异构体(例如,对映异构体、非对映异构体、和几何异构体(或构象异构体))形式;例如,每个不对称中心的R和S构型,(Z)和(E)的双键异构体,及(Z)和(E)的构象异构体。因此,本发明化合物的单一立体异构体以及对映异构体、非对映异构体、和几何异构体(或构象异构体)混合物也落在本发明的范围之内。除非另有说明,本发明化合物的所有互变异构形式都落在本发明的范围之内。此外,除非另有说明,此处所描述的结构还包括区别仅在于存在一个或多个同位素富集原子的化合物。例如,具有只是用氘或氚取代氢的本发明结构,或具有只是用13C-或14C-富集的碳取代碳的本发明结构的化合物也落在本发明的范围之内。例如,这种化合物可用作生物学测定法中的分析工具或探针。
3.举例性化合物的描述:
由通式I的R1和R2形成的优选环选自具有0-2个独立选自氮、氧、或硫的杂原子的任选取代的5-7元饱和、部分不饱和、或完全不饱和的环。更优选的,由R1和R2形成的任选取代的环选自苯并、噻吩并、环己、吡啶并、四氢吡啶并、或嘧啶并。由R1和R2形成的环上的优选取代基选自卤素、R°、OR°、N(R°)2、和SR°,其中R°是通常以及此处亚组中所定义的。由R1和R2形成的环上的更优选取代基选自氯、溴、氟、Me、Et、CF3、OH、和OCH3。
通式I的优选Q基团选自价键、-C(O)-、C(O)NR-、-CO2-、-C(O)CO2-、-SO2-、或C1-4亚烷基链,其中Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、或-SO2-取代。通式I的更优选Q基团选自价键、-C(O)-、-C(O)NH-、-CO2-、-C(O)CO2-、-SO2-、-C(O)CH2O-,-C(O)CH2S-、或C(O)NHCH2-。
通式I的优选R3基团选自任选取代的C1-6脂族基团,或选自如下的任选取代的环
(a)3-6元饱和的单环或芳环;
(b)具有1-2个独立选自氮、氧、或硫的杂原子的5-6元杂环;或
(c)具有1-3个独立选自氮、氧、或硫的杂原子的5-6元单环或9-10元双环的杂芳环。
通式I更优选的R3基团是选自甲基、乙基、丙基、异丙基、异丁基、叔丁基、环丙基、环戊基、环己基、苯基、吡啶基、噻吩基、呋喃基、异噁唑基、三唑基、苯并噻吩基、或苯并[1,3]间二氧杂环戊烯基的任选取代的基团。R3上的优选取代基,当存在时,选自R°、卤素、N(R°)2、OR°、或SR°,其中R°是通常以及此处亚组中所定义的。
按其中一个实施方案,本发明涉及通式II的化合物或其药学上可接受的盐:
其中:A、Q、X、R1、R2和R3如上面所定义的。
通式II的优选Q、R1、R2和R3基团在上面通式I的化合物中描述。
按照另一实施方案,本发明涉及通式III的化合物或其药学上可接受的盐:
其中:Q、X、R1、R2和R3如上面所定义的。
通式III优选的Q、R1、R2和R3基团在上面通式I的化合物中描述。
按照另一实施方案,本发明涉及通式IV的化合物或其药学上可接受的盐
其中:Q、X、R1、R2和R3如上面所定义的。
通式IV优选的Q、R1、R2和R3基团在上面通式I的化合物中描述。
按另一实施方案,本发明涉及通式II、III或IV的化合物,其中X是硫。
按照另一实施方案,本发明涉及通式II、III或IV的化合物,其中R1和R2形成苯并环。
通式I化合物的代表性例子在下面表1中给出。
表1.通式I化合物的例子:
4.通用性合成方法学
本发明的化合物大多可通过本领域那些技术人员已知的类似化合物的方法制备,如下面通用流程所举例说明的,以及下面的制备实施例。
流程I
试剂和条件:(a)NaH、DMF
上面的流程I表示用于制备其中Q是价键且R3是氢的通式I化合物(3)的一般方法。化合物1的离去基团L可被硫化物2取代形成化合物3。多种L离去基团都可用于这种合成,包括但不限于氯和溴。化合物3是一种有用的中间体,它可用于使用本领域技术人员已知的方法并按照下面合成流程所举例说明的形成各种通式I化合物。
流程II
试剂和条件:(a)R3C(O)Cl、Et3N、CH3CN、回流;或(b)R3CO2H、EtOC(O)Cl
上面的流程II表示用于制备其中的Q是羰基的通式I化合物的方法。这些化合物可通过用通式R3C(O)Cl的酰基氯处理化合物3而形成酰胺化合物4。可选择性地,如上面步骤(b)所示,可在有氯甲酸酯存在的条件下用羧酸处理化合物3而形成酰胺化合物4。多种脂族和芳基的酰基氯试剂都可经历该反应,从而形成各种通式I的化合物,其中R3是脂族的、芳基、杂环基、或杂芳基。
流程III
试剂和条件:(a)R3OC(O)Cl、吡啶
上面流程III表示用于制备其中的Q是-CO2-基团的通式I化合物的方法。这些化合物可通过用通式R3OC(O)Cl的氯甲酸酯化合物处理化合物3形成氨基甲酸酯化合物5而制备。多种脂族和芳基的氯甲酸酯试剂都可经历该反应,从而形成多种通式I的化合物,其中R3是脂族的、芳基、杂环基、或杂芳基。
流程IV
试剂和条件:a)R3NCO、CH3CN、回流;b)PhOCOCl、吡啶;c)R3NH2、DME、加热
上面的流程IV表示用于制备其中的Q是-C(O)NH-基团的通式I化合物的方法。这些化合物可通过用通式R3NCO的异氰酸酯化合物处理化合物3形成脲化合物6而制备。多种脂族和芳基的异氰酸酯试剂都可经历该反应从而形成各种通式I化合物,其中R3是脂族的、芳基、杂环基、或杂芳基。
流程V
试剂和条件:a)NaNO2、HCl-H2O;b)R3SO2NH2、K2CO3
上面的流程V表示用于制备其中的Q是-SO2-的通式I化合物的方法。可在有HCl-H2O存在的条件下,用硝酸钠处理化合物3而形成氯化合物9。然后用具有通式R3SO2NH2的试剂取代化合物9的氯取代基而形成氨磺酰化合物10。多种脂族和芳基的氨磺酰试剂都可经历该反应从而形成各种通式I化合物,其中R3是脂族的、芳基、杂环基、或杂芳基。
流程VI
试剂和条件:a)NaH、DMF
上述流程VI表示用于制备其中的Q是价键的本发明化合物(8)的方法。化合物1的离去基团L可被硫化物7取代形成化合物8。各种L离去基团都可用于该合成,包括但不限于氯和溴。多种脂族和芳基的氨磺酰试剂都可经历该反应,形成各种通式I化合物,其中R3是脂族的、芳基、杂环基、或杂芳基。
虽然上面和此处描述了某些举例性实施方案,但应当了解本发明的化合物可按照上面一般性描述的方法,使用适宜的起始材料,利用本领域普通技术人员通常可获得的方法制备。
5.用途,制剂和给药
药学上可接受的组合物
正如上面所讨论的,本发明提供蛋白激酶抑制剂化合物,且因此本发明的化合物可用于治疗病、疾病、和病症,包括但不限于,变应性疾病(如哮喘和特应性皮炎)、自身免疫病(如SLE狼疮和牛皮癣),以及与器官移植有关的病症。
因此,在本发明另一方面中,提供药学上可接受的组合物,其中这些组合物包含此处所述的任一化合物,且任选包含药学上可接受的载体、助剂或赋形剂。在某些实施方案中,这些化合物任选还包含一种或多种附加治疗剂。
本发明某些化合物可商业得到(Maybridge plc,Trevillett,Tintagel,Cornwall PL34 OHW,England)。然而,将这些化合物用作JAK激酶抑制剂还是未知的,且具有任何制药用途或作为药学上可接受组合物的组分也是未知的。本发明可商业得到的化合物选自:3-氯-苯并[b]噻吩-2-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-苯氧基-烟酰胺;
5-甲基-2-苯基-2H-[1,2,3]三唑-4-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
环丙烷羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]酰胺;
N-庚基[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-乙酰胺;噻吩-2-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
5-(6-乙基-噻吩并[2,3-d]嘧啶-4-基硫烷基)-[1,3,4]噻二唑-2-基胺;
5-(2-氯-噻吩并[2,3-b]吡啶-4-基硫烷基)-[1,3,4]噻二唑-2-基胺;
2-氯-N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-甲基-丙酰胺;
2-氯-N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-甲基-丙酰胺;
4-羟基-2-氧-2,3-二氢-喹啉-3-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]酰胺;
1,3,4-噻二唑-2-胺,5-[(7-甲基噻吩并[3,2-d]嘧啶-4-基)硫代]-;和乙酰胺,N-[5-(1H-嘌呤-6-基硫代)-1,3,4-噻二唑-2-基。
还应当认识到本发明的某些化合物可以游离形式存在用于处理,或适当的,以其药学上可接受的衍生物形式存在。按照本发明,药学上可接受的衍生物包括,但不限于,药学上可接受的盐、酯、所述酯的盐、或任何其它加合物或衍生物,它们在给予需要的患者后,能够直接或间接提供此处所述的化合物,或其代谢物或残渣。
此处所用术语“药学上可接受的盐”是指落在合理的医疗鉴定范围内、适用于和人类及低等动物的组织接触而没有毒性、刺激性、变应性反应等,且与合理的收益/风险比相称的那些盐。“药学上可接受的盐”是指本发明化合物的任何无毒的盐或酯的盐,给予受体后,它们能够直接或间接提供本发明的化合物或其抑制活性的代谢物或其残基。此处所用的术语“其抑制活性的代谢物或其残基”是指其代谢物或其残基也是JAK-3激酶的抑制剂。
药学上可接受的盐是本领域熟知的。例如,S.M.Berge等人在J.Pharmaceutical Sciences,1977,66,1-19中详细描述了药学上可接受的盐,其引入此处作为参考。本发明化合物的药学上可接受的盐包括从适宜的无机和有机的酸和碱衍生的那些。药学上可接受的、无毒的酸加成盐的例子是与无机酸,如盐酸、氢溴酸、磷酸、硫酸和高氯酸或与有机酸如醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸形成的氨基盐,或通过使用本领域所用的其它方法,如离子交换形成的氨基盐。其它药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、酸式硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡萄庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘化物、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐、十一烷酸盐、戊酸盐等。来源于适宜碱的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。本发明还预期了此处所公开化合物的任一碱性含氮基团的季铵化。水溶性或油溶性或可分散的产品可通过这种季铵化获得。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁等。其它药学上可接受的盐包括,适宜的,使用抗衡离子(如卤化物、氢氧化物、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸基和芳基磺酸基)形成的无毒的铵、季铵、和胺阳离子。
如上所述,本发明药学上可接受的组合物还可包含药学上可接受的载体、助剂、或赋形剂,如此处所用的,它们包括任何及所有溶剂、稀释剂、或其它液体赋形剂、分散或混悬助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘结剂、润滑剂等,适于所需的特定剂量形式。Remington′s Pharmaceutical Sciences,SixteenthEdition,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)公开了在配制药学上可接受的组合物时所用的各种载体以及用于制备它们的已知技术。除了与本发明化合物不相容的任何常规载体介质外,如产生任何不良的生物作用或以有害的方式与药学上可接受组合物的任何其它组分相互作用,预期它的使用落在本发明的范围之内。可作为药学上可接受载体的材料的一些例子包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(如磷酸盐、甘氨酸、山梨酸、或山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢二钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧化丙烯嵌段共聚物,羊毛脂、糖如乳糖、葡萄糖和蔗糖;淀粉如玉米淀粉和马铃薯淀粉;纤维素及其衍生物如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉状黄芪胶;麦芽;明胶;滑石粉;赋形剂如椰子油和栓剂蜡;油如花生油、棉籽油;红花子油;芝麻油;橄榄油;玉米油和豆油;二醇类;如丙二醇或聚乙二醇;酯类如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗生理盐水;林格氏溶液;乙醇、和磷酸盐缓冲溶液以及其它无毒相容的润滑剂如十二烷基硫酸钠和硬脂酸镁,以及着色剂、释放剂、涂层剂、甜味剂、调味剂和加香剂、防腐剂和抗氧化剂也可存在于组合物中,这要根据配制者的判断。
化合物和药学上可接受的组合物的使用
另一方面,提供一种用于治疗或减轻变应性疾病,如哮喘和特应性皮炎、自身免疫病如SLE狼疮和牛皮癣,以及与器官移植有关的病症的严重程度的方法,包括向需要的受治疗者给予其有效量的化合物,或包含化合物的药学上可接受的组合物。在本发明某些实施方案中,化合物或药学上可接受组合物的“有效量”是指有效治疗变应性疾病,如哮喘和特应性皮炎、自身免疫病如SLE狼疮和牛皮癣,以及与器官移植有关的病症的用量。
按照本发明的方法,所述化合物和组合物可使用有效治疗或减轻变应性疾病,如哮喘和特应性皮炎、自身免疫病如SLE狼疮和牛皮癣、以及与器官移植有关的病症的任何用量和任何给药途径给药。
所需的准确用量将根据被治疗者不同而变化,这取决于被治疗者的人种、年龄、和一般状况,感染的严重程度,特定的药剂,其给药方式等。优选将本发明的化合物配制成便于给药且剂量均匀的剂量单位形式。此处所用的表达方式“剂量单位形式”是指适于所治疗患者的药剂的实际分离单位。然而,应当理解,本发明化合物及组合物的总的每日使用情况将在合理的医疗鉴定范围内由主治医生决定。任何特定的患者或生物的具体有效剂量水平取决于各种因素,包括所治疗的疾病和疾病的严重程度;所用的具体化合物的活性;所用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;给药时间;给药途径;和所用具体化合物的排泄速率;治疗的持续时间;与所用具体化合物联合或同时使用的药物;以及医疗领域熟知的因素。此处所用的术语“患者”是指动物,优选哺乳动物,且最优选人。
可将本发明药学上可接受的组合物口服、直肠、非肠道、脑池内、阴道内、腹膜内、局部(如粉剂、软膏剂、或滴剂)、口腔、按口腔或鼻喷雾等给予患者,这取决于所治疗感染的严重程度。在某些实施方案中,本发明的化合物可以每天约0.01mg/kg被治疗者体重-约50mg/kg被治疗者体重,优选约1mg/kg被治疗者体重-约25mg/kg被治疗者体重的剂量水平口服或非肠道给药,每天一次或多次,从而获得所需的治疗效果。
用于口服给药的液体剂量形式包括,但不限于,药学上可接受的乳状液、微乳、溶液、混悬液、糖浆剂和酏剂。除活性化合物外,所述液体剂量形式还可包含本领域通常使用的惰性稀释剂如,例如,水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、醋酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽、花生、玉米、胚、橄榄、蓖麻和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇脂肪酸酯、及其混合物。除惰性稀释剂外,所述口服组合物还可包括助剂,如湿润剂、乳化剂和悬浮剂、甜味剂、调料、和加香剂。
可注射的制剂,例如,无菌的可注射含水或油状混悬液可按照本领域已知的,使用适宜的分散剂或润湿剂和悬浮剂配制。所述无菌可注射的制剂还可以是溶于无毒的非肠道可接受的稀释剂或溶剂,例如,1,3-丁二醇中无菌可注射溶液、混悬液或乳状液。所用的可接受的赋形剂和溶剂是水、林格氏溶液、U.S.P.和等渗的氯化钠溶液。此外,无菌的不挥发油通常可被用作溶剂或悬浮基质。就此目的而言,任何温和的不挥发油都可使用,包括合成的单甘油酯或二甘油酯。此外,脂肪酸如油酸可用于制备可注射的制剂。
可注射的制剂可通过,例如,滞留细菌的滤器,或通过掺入无菌固体组合物形式的灭菌剂而灭菌,所述无菌固定组合物形式的灭菌剂可在使用前,将其溶于或分散于无菌水或其它无菌的可注射基质中。
为了延长本发明化合物的作用,常需要减缓化合物从皮下或肌内注射吸收。这可通过使用具有较差水溶性的结晶或无晶形物质的液体混悬液而实现。然后化合物的吸收速率就取决于其溶解速率,依次,可取决于晶体的大小和结晶形式。可选择性地,非肠道给药的化合物形式的延迟吸收是通过将化合物溶解或混悬于油赋形剂中而实现的。可注射的储存形式是通过在生物降解聚合物,如聚丙交酯-聚乙醇酸交酯中形成化合物的微囊基质而制成的。根据化合物与聚合物的比例以及所用特定聚合物的性质,可控制化合物的释放速率。其它生物降解聚合物的例子包括聚(原酸酯)和聚(酸酐)。储存的可注射制剂还可通过将化合物埋入与肌体组织相容的脂质体或微乳中而制备。
用于直肠或阴道给药的组合物优选栓剂,它们可通过将本发明的化合物与适宜的无刺激性赋形剂或载体,如椰子油、聚乙二醇或栓剂蜡混合而制备,它们在室温下为固体,但在体温下为液体,因此可在直肠或阴道腔中溶化并释放活性化合物。
用于口服给药的固体剂量形式包括胶囊剂、片剂、丸剂、粉剂、和颗粒剂。在这种固体剂量形式中,将活性化合物与至少一种惰性、药学上可接受的赋形剂或载体如柠檬酸钠或磷酸二钙和/或a)填充剂或填料如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇、和硅酸,b)粘结剂如,例如,羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)湿润剂如甘油,d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐、和碳酸钠,e)溶解延迟剂如石蜡,f)吸收促进剂如季铵化合物,g)湿润剂如,例如,鲸蜡醇和一硬脂酸甘油酯,h)吸收剂如高岭土和膨润土,和i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠、及其混合物混合。对于胶囊剂、片剂和丸剂而言,所述剂量形式还可包含缓冲剂。
相似类型的固体组合物还可被用作软和硬-填充明胶胶囊中的填充剂,其中使用赋形剂如乳糖或乳糖以及高分子量的聚乙二醇等。片剂、糖衣丸、胶囊剂、丸剂、和颗粒剂的固体剂量形式可用涂层及壳体,如肠溶衣和药物配制领域熟知的其它涂层制备。它们可任选包含不透明剂且还可以是仅仅,或优选,在肠道某一特定部分,任选地,以延迟方式释放活性成分的组合物。可用的包埋组分的例子包括聚合物质和蜡。相似类型的固体组合物还可被用作软和硬-填充明胶胶囊中的填充剂,其中使用赋形剂如乳糖或乳糖以及高分子量的聚乙二醇等。
所述活性化合物还可以是具有上述一种或多种赋形剂的微囊形式。片剂、糖衣丸、胶囊剂、丸剂和颗粒剂的固体剂量形式可用涂层如肠溶衣、控释涂层和药物配制领域熟知的其它涂层制备。在这种固体剂量形式中,所述活性化合物可与至少一种惰性稀释剂如蔗糖、乳糖或淀粉混合。这种剂量形式还可包含,按照标准实践,除惰性稀释剂外的其它物质,例如片剂润滑剂和其它压片用助剂,如硬脂酸镁和微晶纤维素。就胶囊剂、片剂和丸剂而言,所述剂量形式还可包含缓冲剂。它们还可任选包含不透明剂且还可以是仅仅,或优选在肠道的特定部分,任选地,以延迟方式释放活性成分的组合物。可用的包埋组分的例子包括聚合物质和蜡。
用于局部或透皮给予本发明化合物的剂量形式包括软膏剂、糊剂、霜剂、洗剂、凝胶、粉剂、溶液、喷雾剂、吸入剂或贴剂。所述活性成分在无菌条件下与药学上可接受的载体混合,且可能需要任何所需的防腐剂或缓冲剂。眼用制剂,滴耳剂、和滴眼剂也被预期包括在本发明的范围之内。此外,本发明预期了透皮贴剂的使用,它具有将化合物控制释放到肌体的附加优点。这种剂量形式可通过将化合物溶解或分散于适宜的介质中而制备。吸收增强剂还可用于增加化合物穿过皮肤的通量。速率可通过提供速率控制薄膜或通过将化合物分散在聚合物基质或凝胶中而控制。
如上一般性所述,本发明的化合物可用作蛋白激酶抑制剂。在其中一个实施方案中,本发明的化合物和组合物是JAK-3的抑制剂,且因此,不希望受到任何特殊理论的限制,所述化合物和组合物特别用于治疗或减轻病、病症、或疾病的严重程度,其中JAK-3的一个或多个激活涉及所述病、病症、或疾病。当JAK-3的激活涉及特定的病、病症或疾病时,所述病、病症、或疾病还可被称作“JAK-3-介导的病”或疾病综合症。因此,另一方面,本发明提供一种用于治疗或减轻病、病症或疾病严重程度的方法,其中JAK-3的一个或多个激活涉及所述疾病状况。
在本发明中用作JAK-3抑制剂的化合物的活性可体外、体内、或在细胞系中测定。体外测定法包括测定激活JAK-3的磷酸化活性或ATP酶活性抑制的测定法。选择性的体外测定法可量化抑制剂与JAK-3结合的能力。抑制剂结合可通过在结合前放射性标记所述抑制剂,分离抑制剂/JAK-3复合体,并测定放射性标记结合的量而测量。可选择性地,抑制剂结合可通过进行竞争实验而测定,其中将新的抑制剂与和已知放射性配体结合的JAK-3培养。
此处所用术语“可测量地抑制”是指包含所述组合物和JAK-3激酶的样品与在没有所述组合物的条件下包含JAK-3激酶的等价样品之间JAK-3活性的可测量的改变。
此处所用术语“JAK-介导的病”是指已知JAK家族激酶,特别是JAK-3起作用的任何病或其它有害病症。这种病症包括,但不限于,免疫反应如变应性或I型过敏反应、哮喘、自身免疫性病如移植排斥、移植物抗宿主疾病、类风湿性关节炎、肌萎缩性侧索硬化、和多发性硬化、神经变性疾病,如家族性肌萎缩性侧索硬化(FALS)、以及实体和血液恶性肿瘤如白血病和淋巴瘤。
还应当了解本发明的化合物和药学上可接受的组合物可用于联合疗法中,即,所述化合物和药学上可接受的组合物可与一种或多种其它所需的治疗或医疗过程同时、在其之前、或之后给予。用于联合方案中的疗法(治疗或过程)的特定组合要考虑所需治疗和/或过程以及所希望获得的治疗效果的相容性。还应当认识到所用的疗法可相对于同一疾病获得所希望的效果(例如,本发明的化合物可与用于治疗同一疾病的其它药剂同时给药),或它们可获得不同的效果(例如,任何副作用的控制)。此处所用的、通常给药用于治疗或预防特定疾病、或病症的其它治疗剂被称作“适于所治疗的疾病、或病症”。
例如,化疗剂或其它抗增殖剂可与本发明的化合物联合治疗增殖性病和癌症。已知化疗剂的例子包括,但不限于,例如,可与本发明抗癌剂联合使用的其它疗法或抗癌剂包括手术、放疗(在一些实施例中,γ-射线、中子束放疗、电子束放疗、质子治疗、近程治疗、和系统性放射性同位素,仅仅是举几个例子)、内分泌疗法、生物反应改性剂(干扰素、白介素和肿瘤坏死因子(TNF),仅仅是举几个例子)、高温和冷疗法、减弱任何副作用的药剂(例如,止吐剂)、和其它批准的化疗药物,包括但不限于,烷基化药物(氮芥、苯丁酸氮芥、环磷酰胺、美法仑、异环磷酰胺)、抗代谢物(甲氨蝶呤)、嘌呤拮抗剂和嘧啶拮抗剂(6-巯基嘌呤、5-氟尿嘧啶、Cytarabile、吉西他滨)、纺锤体抑制剂(长春花碱、长春新碱、长春烯碱、紫杉醇)、鬼臼毒素(依托泊苷、伊立替康、拓扑替康)、抗生素(阿霉素、博莱霉素、丝裂霉素)、亚硝基脲(卡莫司汀、罗氮芥)、无机离子(顺铂、碳铂)、酶(天门冬酰胺酶)、和激素(他莫昔芬、利普安、氟他胺、和甲地孕酮)、GleevecTM、亚德里亚霉素、地塞米松、和环磷酰胺。更新的癌症疗法的更全面讨论见http://www.nci nih.gov/,FDA批准的肿瘤药物的列表见http://www.fda.gov/cder/cancer/druglistframe. Htm,和TheMerck Manual,Seventeenth Ed.1999,其全部内容引入此处作为参考。
本发明抑制剂的其它例子还可与下列治疗联合,它们包括但不限于:阿尔茨海默氏病的治疗如Aricept和Excelon;帕金森氏病的治疗如L-DOPA/卡比多巴、恩他卡朋、罗吡尼洛、派拉米苏、溴隐亭、硫丙麦角林、trihexephendyl、和金刚烷胺;治疗多发性硬化(MS)的药剂如β-干扰素(例如,Avonex和Rebif)、Copaxone、和米托蒽醌;哮喘的治疗如沙丁胺醇和Singulair;用于治疗精神分裂症的药剂如奥氮平、维斯通、喹迪平、和(卤)氟哌啶醇;抗炎剂如皮质类固醇、TNF阻断剂、IL-1 RA、硫唑嘌呤、环磷酰胺、和柳氮磺胺吡啶;免疫调节和免疫抑制剂如环孢菌素、他克莫司、瑞帕霉素、霉酚酸酯、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤、和柳氮磺胺吡啶;神经营养因子如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥剂、离子通道阻断剂、利鲁唑、和抗帕金森氏病的药剂;用于治疗心血管病的药剂如β-阻断剂、ACE抑制剂、利尿剂、硝酸盐、钙通道阻断剂、和他汀类;用于治疗肝病的药剂如皮质类固醇、考来烯胺、干扰素和抗病毒剂;用于治疗血液疾病的药剂如皮质类固醇、抗-白血病的药剂、和生长因子;以及用于治疗免疫缺损病的药剂如γ-球蛋白。
存在于本发明组合物中的其它治疗剂的用量不会超过在仅包含该治疗剂作为活性剂的组合物中通常给药的用量。优选,目前公开的组合物中的其它治疗剂的用量为通常存在于仅包含该药剂作为治疗活性剂的组合物中用量的约50%-100%。
本发明的化合物或其药学上可接受的组合物还可掺入到用于涂覆可植入的医疗装置,如假体、人造瓣膜、血管移植物、移植片固定模和导管的组合物中。因此,本发明另一方面包括用于涂覆可注入装置的组合物,其包含上面一般性描述以及此处的类和子类中描述的本发明化合物,和适于涂覆所述可植入装置的载体。另一方面,本发明包括用组合物涂覆的可注入装置,该组合物包含上面一般性描述以及此处的类和子类中描述的本发明化合物,以及适于涂覆所述可植入装置的载体。
血管移植片固定模,例如,已经用于克服再狭窄(损伤后血管壁的再狭窄)。然而,使用移植片固定模或其它可植入装置的患者会有凝块形成或血小板活化的危险。这些有害的作用可通过用包含激酶抑制剂的药学上可接受的组合物预先涂覆所述装置而防止或缓和。适宜的涂层和涂覆的可植入装置的一般性制备在美国专利6,099,562、5,886,026、和5,304,121中描述。涂层通常是生物适合的聚合材料如水凝胶聚合物、聚甲基二硅氧烷、聚己内酯、聚乙二醇、聚乳酸、乙烯醋酸乙烯酯、及其混合物。所述涂层还可任选被氟硅氧烷、多糖、聚乙二醇、磷脂或其组合的适合包衣进一步覆盖,从而赋予组合物控释特性。
本发明另一方面涉及抑制生物样品或患者中的JAK-3活性,该方法包括给予患者,或使所述生物样品与通式I的化合物或包含所述化合物的组合物接触。此处所用的术语“生物样品”包括,但不限于,细胞培养物或其提取物;从哺乳动物或其提取物获得的活组织检查材料;以及血液、唾液、尿液、粪便、泪液、或其它体液或其提取物。
生物样品中JAK-3激酶活性的抑制可用于本领域技术人员已知的各种目的。这种目的的例子包括,但不限于,输血、器官移植、生物样品贮藏、和生物测定。
合成实施例
A)概述
使用Bruker DPX 400仪器记录400MHz下的1H NMR光谱。使用相同的仪器记录13C NMR光谱。LC/MS数据是用Micromass ZQ或具有大气压化学电离的平台仪器获得的。HPLC分析是在维持于40℃下的Phenomenex C18(2)Luna柱(30×4.6mm)上进行的。将1-5μL约1mg/mL浓度的样品乙腈溶液注射到系统中。使用下列梯度,以2mL/分钟的速度洗脱该化合物。
0分、 80%H2O-20%MeCN,
2.5分、0%H2O-100%MeCN,
3.5分、0%H2O-100%MeCN
然后将洗脱混合物放回到起始条件下,并将柱子再平衡1分钟。检测是经由二极管阵列检测器进行的,采集214和254的色谱。在所有情况下,两个波长的洗脱时间都是相同的。
所有试剂都是商业获得的并可直接使用。在4分子筛(FisherScientific)上干燥DMF。柱层析使用硅胶60(Fluka)。TLC是使用预-涂覆的塑料片Polygram SIL G/UV254(Macherey-Nagel)进行的。
B)举例性化合物的合成:
5-氨基-[1,3,5]噻二唑-2-硫醇和氯杂环化合物缩合的一般过程
室温下,将部分NaH(1.2mmol)加入到5-氨基-噻二唑-2-硫醇(1.1mmol)溶于DMF(8ml)的溶液中。加入完成后,室温搅拌该混合物20分钟。然后加入部分氯杂环化合物(1.1mmol)并在80-90℃(油浴温度)下加热该混合物18小时。将反应混合物冷却至室温,并加水(20-40ml)。过滤分离沉淀物,用冷水然后用Et2O洗涤若干次,并干燥以提供产物(25-96%产率)。
制备酰胺的一般过程
过程A:
将NEt3(0.45mmol)滴加到胺(0.3mmol)溶于MeCN(9ml)的混悬液中。然后将混合物冷却至0℃,并滴加酰基氯(0.36mmol)。0℃搅拌20分钟后,将混合物温热至室温,然后在80℃(油浴温度)下加热18小时。产物在反应过程中结晶,并通过过滤从温热的溶液中分离,用冷Et2O洗涤并干燥。在产物没有结晶的情况下,减压蒸发溶剂并将固体残渣悬浮在水(约5ml)中。过滤分离没有溶解的物质,用水然后用Et2O洗涤若干次,并干燥以提供产物(40-96%产率)。
过程B
向胺(0.34mmol)溶于THF(15ml)的混悬液中加入酸(0.37mmol),接着加入NEt3(0.41mmol)。然后将混合物冷却至0℃,并加入部分HBTU(0.37mmol)。0℃搅拌40分钟后,将混合物温热至室温,然后在50-60℃(油浴温度)下加热18小时。将反应混合物冷却至室温并加水(约40ml)。过滤分离沉淀物,用水、Et2O洗涤若干次,然后干燥以提供产物(43-56%产率)。
过程C
向酸(0.39mmol)溶于THF(15ml)的混悬液中加入胺(0.43mmol),接着加入EDCI(0.78mmol)。在氮气下,60℃加热混合物18小时。将反应混合物冷却至室温并加水(约40ml)。过滤分离沉淀物并用少量水、Et2O洗涤,干燥以提供产物(58-69%产率)。
酰胺的纯化
当产物是酰胺与起始胺的混合物时,使用下列过程进行进一步的纯化:
将混合物(0.15mmol)(包括约15%胺、基于1H NMR)溶于DMF(2ml)中。向该溶液中加入甲基异氰酸聚苯乙烯酯(3eq)并在50-60℃下振摇该混合物18小时。冷却至室温后,过滤混合物并用温热的DMF洗涤树脂(3x~2ml)。减压蒸发溶剂,并用Et2O洗涤固体残渣,干燥以提供产物。
制备氨基甲酸酯衍生物的一般过程
向胺(0.26mmol)溶于冷却至0℃的无水吡啶中的混合物中滴加氯氨基甲酸酯(0.33mmol)。将混合物温热至室温并再搅拌48小时。然后加水(5ml),过滤收集沉淀物,用水和Et2O洗涤,并干燥以提供产物(41-72%产率)。
当起始胺存在于产物中时,使用甲基异氰酸盐聚苯乙烯通过上述方法纯化产物。
制备脲衍生物的一般过程
过程A
将异氰酸盐(0.29mmol)加入到胺(0.22mmol)溶于MeCN(10ml)的溶液中,并在70-75℃(油浴温度)下加热该混合物18小时。产物在反应过程中沉淀,通过过滤从温热的反应混合物中分离,用Et2O洗涤并干燥(35-67%产率)。
过程B
将胺(0.19mmol)加入到氨基甲酸酯(0.15mmol)溶于DME(10ml)的混悬液中,然后在约80℃(油浴温度)下加热该混合物18小时。蒸发溶剂并用Et2O洗涤固体残渣若干次以提供产物(14-63%产率)。
4-(5-氯-[1,3,4]噻二唑-2-基硫烷基)喹啉的合成
向胺(4.93mmol)溶于冷却至-10℃的浓HCl(20ml)的溶液中滴加NaNO2(14.8mmol)溶于H2O(4ml)的溶液,保持温度低于0℃。在相同温度下再搅拌反应混合物3小时,然后温热至室温。加H2O(20ml),用固体K2CO3中和混合物,并萃取(EtOAc)。干燥萃取物(MgSO4),减压蒸发溶剂并通过柱层析纯化残渣(SiO2、石油醚/乙酸乙酯1∶1 v/v)以提供产物(53-95%产率)。
制备4-(5-氨基-[1,3,4]噻二唑-2-基硫烷基)喹啉衍生物的一般过程
向氯化物(0.72mmol)溶于NMP(5ml)中的溶液中加入NEt3(0.8mmol)接着加入胺(0.72mmol)。在氮气下,70℃(主块温度)加热混合物72小时。然后减压蒸发溶剂并在EtOAc/H2O(20ml、1∶1 v/v)之间分配残渣。分离有机层并萃取水层(EtOAc)。干燥结合有机层(MgSO4),减压蒸发溶剂并通过柱层析纯化残渣(SiO2、石油醚/EtOAc1∶1 v/v)以提供产物。
制备氨磺酰衍生物的一般过程
向氯化物(0.12mmol)溶于DMF(2ml)的溶液中加入氨磺酰(0.14mmol),接着加入K2CO3(0.24mmol),并在70℃(油浴温度)下加热该混合物72小时。减压蒸发溶剂并在EtOAc/H2O(20ml、1∶1 v/v)中分配残渣。分离水层,酸化(2M HCl)至pH2,然后萃取(EtOAc)。干燥萃取物(MgSO4)并减压蒸发溶剂以提供产物(8-56%产率)。
N-取代的5-氨基-噻二唑-2-硫醇与4,7-二氯-喹啉稠合的一般过程
在室温、氮气下,将部分NaH(1.2mmol)加入到N-取代的5-氨基-噻二唑-2-硫醇(1.1mmol)溶于DMF(8ml)的溶液中,然后搅拌该混合物20分钟。加入部分氯杂环化合物(1.1mmol)并在70℃(油浴温度)下加热该混合物3-18小时。将反应混合物冷却至室温并加水(20-40ml)。过滤分离沉淀的产物,用冷水然后用Et2O洗涤若干次并干燥,以提供产物(10-95%产率)。
5-(7-氯-喹啉-4-氧基)-[1,3,4]噻二唑-2-羧酸乙酯的合成
室温下将NaH(0.022mg、0.5mmol)部分加入到7-氯-4-羟基喹啉(0.093mg、0.5mmol)溶于DMF(6ml)的溶液中,室温搅拌该混合物20分钟。然后加入部分2-氯-[1,3,4]噻二唑衍生物(0.097mg、0.5mmol)并在70-80℃(油浴温度)下加热该混合物18小时。将反应混合物冷却至室温并加水(15-30ml)。过滤分离沉淀物,用冷水然后用Et2O洗涤若干次,并干燥以提供产物(0.081mg、47%产率)。
(7-氯-喹啉-4-氧基)-[1,3,4]噻二唑-2-羧酸(呋喃-2-基甲基)-酰胺的合成
将酯(0.042mg、12.0mmol)加入到胺(0.035mg、0.36mmol)溶于DME(4ml)的溶液中。80℃下加热该混合物18小时。蒸发溶剂并用Et2O研磨残渣以提供产物(0.035mg、75%)。
杂环硫醇与杂环溴化物缩合的一般过程
在0℃氮气下,将NaOMe(19.2mmol)部分加入到溴衍生物(16mmol)和硫醇(16mmol)溶于MeOH(15ml)的混悬液中。0℃搅拌该混合物10分钟,温热至室温,然后在45-50℃下加热4-18小时。将反应混合物冷却至室温,减压蒸发溶剂并通过柱层析(SiO2、Et2O)纯化残渣以提供产物。
自杂环硝基化合物合成杂环胺
将活性Fe(0.22g、3.9mmol)加入到2-硝基噻吩衍生物(0.1g、0.3mmol)溶于AcOH(3ml)的溶液中。80℃(油浴温度)下加热该混合物10分钟,冷却至室温,然后在硅藻土上过滤。用H2O洗涤硅藻土饼。萃取滤液(EtoAc),将含水层碱化(Na2CO3)并萃取(EtOAc)。用NaOH溶液(2M)洗涤结合有机层,干燥(MgSO4)并在减压下除去溶剂。残渣通过柱层析(SiO2、Et2O)纯化以提供产物。
噻吩-2-羧酸酰胺的合成
这些化合物已经按照用于制备酰胺的一般过程(过程A)合成。粗反应混合物是通过柱层析(SiO2、Et2O)纯化而提供产物(18-62%产率)的。
5-氯-[1,3,4]噻二唑-2-羧酸(7-氯-喹啉-4-基)-酰胺的合成
室温下将NaH(0.023g、0.58mmol)部分加入到4-氨基-7-氯-喹啉(0.1g、0.56mmol)溶于DMF(6ml)的溶液中,并搅拌该混合物20分钟。然后加入部分5-氯-[1,3,4]噻二唑衍生物(0.108 g、0.56mmol),并在80℃(油浴温度)下加热该混合物18小时。将反应混合物冷却至室温,并加水(15ml)。过滤分离沉淀物,用Et2O洗涤并干燥以提供产物(0.08g、60%产率)。
本发明举例性化合物的LCMS数据在下面的表2中给出。
表2
JAK抑制测定法
JAK的化合物抑制是通过G.R.Brown等人,Bioorg.Med.CHem.Lett.2000,vol.10,pp575-579所述的方法以下列方式测定的。向先前在4℃下用聚(Glu、Ala、Tyr)6∶3∶1涂覆、然后用磷酸盐缓冲的生理盐水0.05%和吐温(PBST)洗涤的Maxisorb平板中加入2μM ATP、5mM MgCl2、和化合物溶于DMSO的溶液。反应是用JAK酶开始的并在30℃下培养该平板60分钟。然后用PBST洗涤平板,加入100μl HRP-接合的4G10抗体,并在30℃下培养该平板90分钟。再次用PBST洗涤该平板,加入100μL TMB溶液,并在30℃下再次培养该平板30分钟。加入硫酸(1M、100μL)终止反应,在450nm阅读该平板从而获得光密度以进行分析确定IC50值。
在上述JAK抑制测定法中试验了本发明的某些化合物(包括表1描述的那些),并发现它们具有小于2μM的IC50。
在上述JAK抑制测定法中还试验了本发明某些其它化合物(包括表1中描述的那些),并发现它们具有2-5μM的IC50。
Claims (24)
1.通式I的化合物或其药学上可接受的盐:
其中W和X各自独立地是氧或硫;
A是氮、CH、C-CN、或C-(C1-3脂族的);
R1和R2共同形成具有0-3个独立地选自氮、氧或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
Q是价键、-C(O)-、-C(O)NR-、-C(O)C(O)-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-6亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选地且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、-C(O)NR-、-OC(O)NR-、-NRC(O)-、NRCO2-、-NRC(O)NR-、-S(O)-、-SO2-、-NRSO2-、-SO2NR-、或-NRSO2NR-取代;
每个R独立地是氢或任选取代的C1-6脂族基团,其中:与同一氮原子结合的两个R任选地与氮共同形成具有0-2个除了与其结合的氮之外的独立选自氮、氧、或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
R3是R或Ar;且
Ar是任选取代的环,选自:
(a)饱和、部分不饱和的3-8元单环或8-10元双环、或芳环;
(b)具有1-3个独立选自氮、氧、或硫的杂原子的3-7元杂环;或
(c)具有1-4个独立选自氮、氧、或硫的杂原子的5-6元单环或8-10元双环的杂芳环,条件是所述化合物不是选自下列的化合物:
3-氯-苯并[b]噻吩-2-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-苯氧基-烟酰胺;
5-甲基-2-苯基-2H-[1,2,3]三唑-4-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
环丙烷羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]酰胺;
N-庚基[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-乙酰胺;
噻吩-2-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
5-(6-乙基-噻吩并[2,3-d]嘧啶-4-基硫烷基)-[1,3,4]噻二唑-2-基胺;
5-(2-氯-噻吩并[2,3-b]吡啶-4-基硫烷基)-[1,3,4]噻二唑-2-基胺;
2-氯-N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-甲基-丙酰胺;
2-氯-N-[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-2-甲基-丙酰胺;
4-羟基-2-氧代-2,3-二氢-喹啉-3-羧酸[5-(7-氯-喹啉-4-基硫烷基)-[1,3,4]噻二唑-2-基]-酰胺;
1,3,4-噻二唑-2-胺,5-[(7-甲基噻吩并[3,2-d]嘧啶-4-基)硫]-;和
乙酰胺,N[5-(1H-嘌呤-6-基硫代)-1,3,4-噻二唑-2-基。
2.根据权利要求1所述的化合物,其中:
R1和R2共同形成具有0-2个独立选自氮、氧、或硫的杂原子的任选取代的5-7元饱和、部分不饱和、或完全不饱和的环。
3.根据权利要求2所述的化合物,其中:
R1和R2共同形成任选取代的苯并、噻吩并、环己并、吡啶并、四氢吡啶并、或嘧啶并环。
4.根据权利要求1所述的化合物,其中:Q是价键、-C(O)-、-C(O)NR-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-4亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、或-SO2-取代。
5.根据权利要求1所述的化合物,其中:
R3是任选取代的C1-6脂族基团,或选自如下的任选取代的环:
(a)3-6元饱和的单环或芳环;
(b)具有1-2个独立选自氮、氧、或硫的杂原子的5-6元杂环;或
(c)具有1-3个独立选自氮、氧、或硫的杂原子的5-6元单环或9-10元双环的杂芳环。
6.根据权利要求5所述的化合物,其中
R3是选自甲基、乙基、丙基、异丙基、异丁基、叔丁基、环丙基、环戊基、环己基、苯基、吡啶基、噻吩基、呋喃基、异噁唑基、三唑基、苯并噻吩基、或苯并[1,3]间二氧杂环戊烯基的任选取代的基团。
7.根据权利要求1-6任何一项所述的化合物,其中W是硫。
8.根据权利要求7所述的化合物,其中X是硫。
9.根据权利要求8所述的化合物,其中A是氮。
10.根据权利要求8所述的化合物,其中A是CH。
12.一种包含有效量的通式I化合物或其药学上可接受的盐,以及药学上可接受的载体、助剂、或赋形剂的组合物:
其中W和X各自独立地是氧或硫;
A是氮、CH、C-CN、或C-(C1-3脂族的);
R1和R2共同形成具有0-3个独立选自氮、氧或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
Q是价键、-C(O)-、-C(O)NR-、-C(O)C(O)-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-6亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、-C(O)NR-、-OC(O)NR-、-NRC(O)-、NRCO2-、-NRC(O)NR-、-S(O)-、-SO2-、-NRSO2-、-SO2NR-、或-NRSO2NR-取代;
每个R独立地是氢或任选取代的C1-6脂族基团,其中:与同一氮原子结合的两个R任选与氮共同形成具有0-2个除了与其结合的氮之外的独立选自氮、氧、或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
R3选自R或Ar;且
Ar是选自如下的任选取代的环:
(a)饱和、部分不饱和的3-8元单环或8-10元双环、或芳环;
(b)具有1-3个独立选自氮、氧、或硫的杂原子的3-7元杂环;或
(c)具有1-4个独立选自氮、氧、或硫的杂原子的5-6元单环或8-10元双环的杂芳环。
13.根据权利要求12所述的组合物,其中
R1和R2共同形成具有0-2个独立选自氮、氧、或硫的杂原子的任选取代的5-7元饱和、部分不饱和、或完全不饱和的环。
14.根据权利要求12所述的组合物,其中
Q是价键、-C(O)-、-C(O)NR-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-4亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、或-SO2-取代。
15.根据权利要求12所述的组合物,其中
R3是任选取代的C1-6脂族基团,或选自如下的任选取代的环
(a)3-6元饱和的单环或芳环;
(b)具有1-2个独立选自氮、氧、或硫的杂原子的5-6元杂环;或
(c)具有1-3个独立选自氮、氧、或硫的杂原子的5-6元单环或9-10元双环的杂芳环。
16.根据权利要求12-15任何一项所述的组合物,其中W是硫。
17.根据权利要求16所述的组合物,其中X是硫。
18.根据权利要求16所述的组合物,其中A是氮。
19.根据权利要求16所述的组合物,其中A是CH。
20.根据权利要求12所述的组合物,此外它还包含选自抗增殖剂、抗炎剂、免疫调节剂、神经营养因子、或用于治疗心血管病的药剂的附加治疗剂。
21.一种抑制(a)患者或(b)生物样品中JAK-3激酶活性的方法,该方法包括给予所述患者,或使所述生物样品接触权利要求12所述的组合物,或通式I的化合物或其药学上可接受的盐:
其中:W和X各自独立地是氧或硫;
A是氮、CH、C-CN、或C-(C1-3脂族的);
R1和R2共同形成具有0-3个独立选自氮、氧或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
Q是价键、-C(O)-、-C(O)NR-、-C(O)C(O)-、-CO2-、-C(O)CO2-、-SO2-、或任选取代的C1-6亚烷基链,其中:Q的一个或两个不相邻的亚甲基单位任选且独立地被-O-、-S-、-NR-、-C(O)-、-CO2-、-C(O)NR-、-OC(O)NR-、-NRC(O)-、NRCO2-、-NRC(O)NR-、-S(O)-、-SO2-、-NRSO2-、-SO2NR-、或-NRSO2NR-取代;
每个R独立地是氢或任选取代的C1-6脂族基团,其中:与同一氮原子结合的两个R任选与氮共同形成具有0-2个除了与其结合的氮之外的独立选自氮、氧、或硫的杂原子的任选取代的3-7元饱和、部分不饱和、或完全不饱和的环;
R3是R或Ar;且
Ar是选自如下的任选取代的环:
(a)饱和、部分不饱和的3-8元单环或8-10元双环、或芳环;
(b)具有1-3个独立选自氮、氧、或硫的杂原子的3-7元杂环;或
(c)具有1-4个独立选自氮、氧、或硫的杂原子的5-6元单环或8-10元双环的杂芳环。
22.一种治疗或减轻自身免疫病、神经变性疾病、或血癌的严重程度的方法,包括给予所述患者权利要求12所述的组合物的步骤。
23.根据权利要求22所述的方法,其中所述病或病症是变应性或I型过敏反应、哮喘、移植排斥、移植物抗宿主疾病、类风湿性关节炎、肌萎缩性侧索硬化、多发性硬化、家族性肌萎缩性侧索硬化(FALS)、白血病或淋巴瘤。
24.根据权利要求22所述的方法,包括给予所述患者选自抗增殖剂、抗炎剂、免疫调节剂、神经营养因子、或用于治疗心血管病的药剂的附加治疗剂的附加步骤,其中:
所述附加治疗剂适于所治疗的病;且
所述附加治疗剂与所述组合物作为单一剂量形式共同给药或作为多个剂量形式的一部分与所述组合物分开给药。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN108148058A (zh) * | 2018-02-08 | 2018-06-12 | 中国人民解放军第四军医大学 | 一种4-(2-巯基噻二唑)取代的嘧啶衍生物其制备方法及应用 |
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Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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DE102004009933A1 (de) * | 2004-02-26 | 2005-09-15 | Merck Patent Gmbh | Verwendung von Thiadiazolharnstoffderivaten |
US7550499B2 (en) | 2004-05-12 | 2009-06-23 | Bristol-Myers Squibb Company | Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
KR20070032648A (ko) * | 2004-05-12 | 2007-03-22 | 브리스톨-마이어스 스큅 컴퍼니 | 혈전 상태의 치료에 유용한 p2y1 수용체의 우레아길항제 |
WO2006014325A2 (en) * | 2004-07-02 | 2006-02-09 | Exelixis, Inc. | C-met modulators and method of use |
US7329652B2 (en) * | 2004-09-17 | 2008-02-12 | Vertex Pharamaceuticals Incorporated | Diaminotriazole compounds useful as protein kinase inhibitors |
EA012181B1 (ru) * | 2004-10-18 | 2009-08-28 | Амген, Инк. | Соединения тиадиазола и их применение |
CA2590294A1 (en) * | 2004-12-13 | 2006-06-22 | Sunesis Pharmaceuticals, Inc. | Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors |
KR20070100894A (ko) * | 2005-01-19 | 2007-10-12 | 브리스톨-마이어스 스큅 컴퍼니 | 혈전색전성 장애 치료용 p2y1 수용체 억제제로서의2-페녹시-n-(1,3,4-티아디졸-2-일)피리딘-3-아민 유도체및 관련 화합물 |
US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
NZ563454A (en) | 2005-06-08 | 2011-03-31 | Rigel Pharmaceuticals Inc | 2,4-diaminopyrimidine derivatives for inhibition of the JAK pathway |
DE602006020871D1 (de) | 2005-06-27 | 2011-05-05 | Bristol Myers Squibb Co | Lineare harnstoffmimetika-antagonisten des p2y1-rezeptors zur behandlung von thromboseleiden |
TW200726764A (en) * | 2005-06-27 | 2007-07-16 | Bristol Myers Squibb Co | N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
WO2007002634A1 (en) * | 2005-06-27 | 2007-01-04 | Bristol-Myers Squibb Company | Carbocycle and heterocycle antagonists of p2y1 receptor useful in the treatment of thrombotic conditions |
DE602006017694D1 (de) * | 2005-06-27 | 2010-12-02 | Bristol Myers Squibb Co | C-verknüpfte zyklische antagonisten des p2y1-rezeptors mit eignung bei der behandlung thrombotischer leiden |
AU2006299671A1 (en) * | 2005-10-05 | 2007-04-12 | Merck Frosst Canada Ltd | Substituted quinolines as inhibitors of leukotriene biosynthesis |
EP1991532B1 (en) | 2006-02-24 | 2017-01-11 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
WO2007106391A1 (en) * | 2006-03-10 | 2007-09-20 | Lymphosign Inc. | Compounds for modulating cell proliferation, compositions and methods related thereto |
AU2007303846B2 (en) | 2006-10-04 | 2011-03-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as calcium receptor antagonists |
US7960569B2 (en) * | 2006-10-17 | 2011-06-14 | Bristol-Myers Squibb Company | Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
WO2008139845A1 (ja) * | 2007-04-24 | 2008-11-20 | Daiichi Sankyo Company, Limited | 新規アミド誘導体 |
MX2010008926A (es) | 2008-02-15 | 2011-02-23 | Rigel Pharmaceuticals Inc | Compuestos de pirimidin-2-amina y su uso como inhibidores de jak cinasas. |
US8138339B2 (en) | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
ES2546502T3 (es) | 2008-04-16 | 2015-09-24 | Portola Pharmaceuticals, Inc. | 2,6-Diamino-pirimidin-5-il-carboxamidas como inhibidores de syk o JAK quinasas |
JP2011518219A (ja) | 2008-04-22 | 2011-06-23 | ポートラ ファーマシューティカルズ, インコーポレイテッド | タンパク質キナーゼの阻害剤 |
CN102099352B (zh) * | 2008-07-10 | 2014-02-26 | 一般社团法人创药分子Ip | 以喹啉甲酰胺衍生物为有效成分的stat3抑制剂 |
PL2520575T3 (pl) * | 2009-12-28 | 2017-05-31 | General Incorporated Association Pharma Valley Project Supporting Organization | Związek 1,3,4-oksadiazolo-2-karboksyamidowy |
KR101483215B1 (ko) * | 2010-01-29 | 2015-01-16 | 한미약품 주식회사 | 단백질 키나아제 저해활성을 갖는 비시클릭 헤테로아릴 유도체 |
SG186229A1 (en) | 2010-06-07 | 2013-01-30 | Novomedix Llc | Furanyl compounds and the use thereof |
CN101891697B (zh) * | 2010-07-02 | 2011-08-31 | 山东大学 | 含1,2,4-噁二唑杂环α,β-不饱和酮类化合物 |
EP2975027A1 (en) | 2010-11-01 | 2016-01-20 | Portola Pharmaceuticals, Inc. | Nicotinamides as jak kinase modulators |
US9359308B2 (en) | 2011-11-23 | 2016-06-07 | Portola Pharmaceuticals, Inc. | Pyrazine kinase inhibitors |
KR101328126B1 (ko) * | 2012-04-10 | 2013-11-08 | 연세대학교 원주산학협력단 | 신규한 옥사디아졸 유도체 및 이의 알레르기 질환의 예방, 개선 또는 치료적 용도 |
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WO2014013014A1 (en) | 2012-07-18 | 2014-01-23 | Fundació Privada Centre De Regulació Genòmica (Crg) | Jak inhibitors for activation of epidermal stem cell populations |
WO2014058921A2 (en) | 2012-10-08 | 2014-04-17 | Portola Pharmaceuticals, Inc. | Substituted pyrimidinyl kinase inhibitors |
JP6218848B2 (ja) * | 2012-11-20 | 2017-10-25 | プロキナーゼ ゲゼルシャフト ミット ベシュレンクテル ハフツング | プロテインキナーゼ阻害剤としてのチオエーテル誘導体 |
CL2012003253A1 (es) * | 2012-11-22 | 2013-01-11 | Univ Concepcion | Compuestos derivados de 1,3,4-tiadiazol alquilamidas y de chalconas, antagonistas del receptor trpv-1; uso de los compuestos para tratar el dolor cronico. |
KR102216284B1 (ko) | 2013-03-12 | 2021-02-18 | 버텍스 파마슈티칼스 인코포레이티드 | Dna-pk 억제제 |
HUE041877T2 (hu) | 2013-10-17 | 2019-06-28 | Vertex Pharma | (S)-N-Metil-8-(1-((2'-metil-[4,5'-bipirimidin]-6-il)amino)propán-2-il)kinolin-4-karboxamid kokristályai és deuterált származékai DNS-PK inhibitorokként |
US9771333B2 (en) | 2013-11-20 | 2017-09-26 | Signalchem Lifesciences Corp. | Quinazoline derivatives as TAM family kinase inhibitors |
JP6269942B2 (ja) * | 2014-02-20 | 2018-01-31 | 国立研究開発法人理化学研究所 | p38MAPキナーゼγおよび/またはδ阻害剤 |
WO2018041989A1 (en) | 2016-09-02 | 2018-03-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for diagnosing and treating refractory celiac disease type 2 |
RU2758669C2 (ru) | 2016-09-27 | 2021-11-01 | Вертекс Фармасьютикалз Инкорпорейтед | Способ лечения рака с применением сочетания днк-поражающих агентов и ингибиторов днк-пк |
US11273154B2 (en) * | 2017-03-03 | 2022-03-15 | Progenra, Inc. | Azole compounds as ubiquitin-specific protease USP7 inhibitors |
AU2020242287A1 (en) | 2019-03-21 | 2021-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A Dbait molecule in combination with kinase inhibitor for the treatment of cancer |
US20220177978A1 (en) | 2019-04-02 | 2022-06-09 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of predicting and preventing cancer in patients having premalignant lesions |
US20220202820A1 (en) | 2019-04-16 | 2022-06-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of jak inhibitors for the treatment of painful conditions involving nav1.7 channels |
CN114761006A (zh) | 2019-11-08 | 2022-07-15 | Inserm(法国国家健康医学研究院) | 对激酶抑制剂产生耐药性的癌症的治疗方法 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
CN118201924A (zh) * | 2021-11-08 | 2024-06-14 | 万特斯治疗美国公司 | 杂环化合物及其用途 |
WO2023222565A1 (en) | 2022-05-16 | 2023-11-23 | Institut National de la Santé et de la Recherche Médicale | Methods for assessing the exhaustion of hematopoietic stems cells induced by chronic inflammation |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5716981A (en) | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
WO1999031096A1 (en) * | 1997-12-18 | 1999-06-24 | Shaman Pharmaceuticals, Inc. | Piperazine derivatives useful as hypoglycemic agents |
CA2333770A1 (en) * | 1998-06-04 | 1999-12-09 | Abbott Laboratories | Cell adhesion-inhibiting antinflammatory compounds |
US6232320B1 (en) * | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
US6486158B1 (en) * | 1998-08-14 | 2002-11-26 | Cell Pathways, Inc. | [4,5]-fused-3,6-disubstituted-pyridazines with sulfur-containing substituents in position three for the treatment of neoplasia |
US6080747A (en) | 1999-03-05 | 2000-06-27 | Hughes Institute | JAK-3 inhibitors for treating allergic disorders |
WO2000075145A1 (en) * | 1999-06-03 | 2000-12-14 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
JP2001354658A (ja) * | 2000-06-15 | 2001-12-25 | Taisho Pharmaceut Co Ltd | ヒドロキシホルムアミジン化合物及びその塩並びにそれらを含む医薬 |
PL360439A1 (en) | 2000-06-28 | 2004-09-06 | Astrazeneca Ab | Substituted quinazoline derivatives and their use as inhibitors |
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- 2003-05-06 AU AU2003299472A patent/AU2003299472A1/en not_active Withdrawn
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- 2003-05-06 KR KR10-2004-7017933A patent/KR20050006237A/ko not_active Application Discontinuation
- 2003-05-06 US US10/430,805 patent/US7271179B2/en not_active Expired - Fee Related
- 2003-05-06 EP EP03799762A patent/EP1501829B1/en not_active Expired - Lifetime
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- 2003-05-06 CA CA002485429A patent/CA2485429A1/en not_active Abandoned
- 2003-05-06 CN CN038159546A patent/CN1665808A/zh active Pending
- 2003-05-06 JP JP2004563181A patent/JP4681302B2/ja not_active Expired - Fee Related
- 2003-05-06 EP EP10182153A patent/EP2316834A1/en not_active Withdrawn
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- 2004-12-02 NO NO20045282A patent/NO20045282L/no not_active Application Discontinuation
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102395576A (zh) * | 2009-02-27 | 2012-03-28 | 埃姆比特生物科学公司 | 调控jak激酶的喹唑啉衍生物和其使用方法 |
CN102471346A (zh) * | 2009-07-27 | 2012-05-23 | 弗·哈夫曼-拉罗切有限公司 | Jak的三环抑制剂 |
CN102471346B (zh) * | 2009-07-27 | 2014-05-14 | 弗·哈夫曼-拉罗切有限公司 | Jak的三环抑制剂 |
CN102933583A (zh) * | 2010-06-15 | 2013-02-13 | 阿尔米雷尔有限公司 | 作为jak抑制剂的杂芳基咪唑酮衍生物 |
CN103382206A (zh) * | 2012-05-04 | 2013-11-06 | 上海恒瑞医药有限公司 | 喹啉或喹唑啉类衍生物、其制备方法及其在医药上的应用 |
CN103382206B (zh) * | 2012-05-04 | 2016-09-28 | 上海恒瑞医药有限公司 | 喹啉或喹唑啉类衍生物、其制备方法及其在医药上的应用 |
CN108148058A (zh) * | 2018-02-08 | 2018-06-12 | 中国人民解放军第四军医大学 | 一种4-(2-巯基噻二唑)取代的嘧啶衍生物其制备方法及应用 |
CN108148058B (zh) * | 2018-02-08 | 2021-03-16 | 中国人民解放军第四军医大学 | 一种4-(2-巯基噻二唑)取代的嘧啶衍生物其制备方法及应用 |
CN114380817A (zh) * | 2020-10-21 | 2022-04-22 | 中国医学科学院药物研究所 | 苯并咪唑并2-氨基-1,3,4-噻二唑化合物及其制法和药物用途 |
CN114380817B (zh) * | 2020-10-21 | 2024-06-21 | 中国医学科学院药物研究所 | 苯并咪唑并2-氨基-1,3,4-噻二唑化合物及其制法和药物用途 |
Also Published As
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WO2004058753A8 (en) | 2005-06-16 |
AU2003299472A1 (en) | 2004-07-22 |
JP2006513192A (ja) | 2006-04-20 |
KR20050006237A (ko) | 2005-01-15 |
EP2316834A1 (en) | 2011-05-04 |
JP2010159306A (ja) | 2010-07-22 |
US7271179B2 (en) | 2007-09-18 |
EP1501829A1 (en) | 2005-02-02 |
JP4681302B2 (ja) | 2011-05-11 |
EP1501829B1 (en) | 2010-11-24 |
WO2004058753A1 (en) | 2004-07-15 |
ATE489384T1 (de) | 2010-12-15 |
MXPA04011048A (es) | 2005-02-17 |
US20040038992A1 (en) | 2004-02-26 |
CA2485429A1 (en) | 2004-07-15 |
NO20045282L (no) | 2005-02-07 |
DE60335099D1 (de) | 2011-01-05 |
IL165067A0 (en) | 2005-12-18 |
RU2004135386A (ru) | 2005-07-20 |
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