CN107531697A - 3‑(1h‑苯并咪唑‑2‑基)‑1h‑吡啶‑2‑酮衍生物 - Google Patents
3‑(1h‑苯并咪唑‑2‑基)‑1h‑吡啶‑2‑酮衍生物 Download PDFInfo
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- CN107531697A CN107531697A CN201680022247.0A CN201680022247A CN107531697A CN 107531697 A CN107531697 A CN 107531697A CN 201680022247 A CN201680022247 A CN 201680022247A CN 107531697 A CN107531697 A CN 107531697A
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- radicals
- bases
- pyridin
- benzimidazolyl
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Abstract
式I的化合物为ALK1、AL2和ALK5的抑制剂,且可用于治疗疾病例如癌症,其中W、R1、R2和R3具有权利要求1中说明的含义。
Description
发明背景
本发明的目标是发现具有有价值性质的新化合物,特别是可用于制备药物的那些化合物。
本发明涉及抑制激活素受体样激酶(ALK-1、ALK-2、ALK-5)的活性的3-(1H-苯并咪唑-2-基)-1H-吡啶-2-酮衍生物。本发明的化合物因此可用于治疗疾病例如癌症。
本发明还提供制备这些化合物的方法、包含这些化合物的药学组合物、和利用包含这些化合物的药学组合物治疗疾病的方法。
ALK5是TGFβR1的同义词。
ALK1抑制剂抑制新血管形成。ALK1抑制剂可用于其中涉及新血管形成的所有疾病,例如癌症、类风湿性关节炎和眼科疾病。它们可用于治疗年龄相关性黄斑变性和类似的眼科病症(WO 2013/04551)。
ALK2抑制剂可用于治疗进行性衰弱性肌肉骨骼疾病(progressivelydebilitating muscoskeletal disease)进行性骨化性纤维发育不良(FOP)。参见C. E.Sanvitale et al PLOS ONE, 2013年4月, 第8卷, 第4期, e62721。
评价患癌受试者对用ALK1拮抗剂治疗的响应性的方法描述于WO 2014/055869A1。
WO 2014/141118 A1涉及咪唑并[4,5-c]喹啉衍生物和它们用于治疗通过激酶例如PI3激酶或ALK1介导的疾病。WO 2014/141118 A1中描述的化合物可用于治疗癌症、炎症、血管形成相关病症和细菌感染。
R.S. Bhatt et al.在Clin. Cancer Res. 2014; 20:2838-2845中描述:两种ALK1抑制剂已进入临床试验, ACE-041 (dalantercept; Acceleron Pharma)和PF-03446962 (Pfizer)。
M. Petersen et al.在Kidney International (2008) 73, 705-715中描述使用GW788388,一种TGF-β I型和II型受体激酶的抑制剂,用于治疗肾纤维化。
WO 2014/151871 A2公开嘧啶衍生物作为ALK2抑制剂用于治疗癌症,例如骨髓增生性病症、淋巴瘤或实体瘤,此外还用于治疗慢性病贫血、慢性炎症贫血、癌症贫血或进行性骨化性纤维发育不良。
转化生长因子-β (TGF-β)超家族的成员,包括TGF-β、激活素(activin)、nodal和骨形态发生蛋白(BMP),为调节各种细胞响应(包括细胞增殖、分化、粘附、迁移和细胞凋亡)的多功能细胞因子。(1,2) TGF-β和相关蛋白质经过两种不同的丝氨酸/苏氨酸激酶受体,称为I型和II型,转导信号。(3,4) II型受体为细胞表面的主要配体结合受体,且包含构成上有活性的激酶,其使相应的I型受体磷酸化。已确定在哺乳动物中有7种I型受体,称为激活素受体样激酶(ALK)1至7。ALK-4、ALK-5和ALK-7在结构上彼此高度相关,并转导类似的(但不相同)细胞内信号。(5) TGF-β和激活素分别结合到ALK-5 (I型TGF-β受体;TβR-I)和ALK-4(IB型激活素受体;ActR-IB)。nodal蛋白的信号通过ALK-4以及ALK-7转导。(6)相比之下,ALK-1、ALK-2、ALK-3和ALK-6传导的信号彼此相似。BMP结合到ALK-2、ALK-3(IA型BMP受体;BMPR-IA)和ALK-6(IB型BMP受体;BMPR-IB),而ALK-1在内皮细胞中高度表达,并结合到这些细胞中的TGF-β。(7)
通过II型受体激活时,I型受体ALK经过各种蛋白质转导细胞内信号,其中Smad蛋白为TGF-β超家族蛋白的主要信号传导分子。(3,5)已经确定在哺乳动物中有8种不同的Smad蛋白,并分为三组:受体-调节型Smad (R-Smad)、共配偶体Smad (Co-Smad)和抑制型Smad (I-Smad)。Smad2和Smad3为通过TGF-β/激活素/nodal受体ALK-4、ALK-5和ALK-7激活的R-Smad,而Smad1、Smad5和Smad8为BMP-特异性R-Smad。(5)Smad4是TGF-β和激活素的信号通路和BMP的信号通路共有的Co-Smad。Smad6和Smad7是哺乳动物中的I-Smad;Smad6优先抑制BMP信号传导,而Smad7抑制BMP和TGF-β两者的信号传导。
TGF-β在癌症生物学中的作用是复杂的;取决于癌症类型,TGF-β可抑制或促进肿瘤生长。TGF-β有效抑制上皮细胞、内皮细胞和造血细胞谱系增殖的能力对于其肿瘤抑制作用至关重要。然而,随着肿瘤发展,它们通常变得对TGF-β介导的生长抑制不起反应,并使TGF-β过表达,这诱导肿瘤细胞的上皮至间质转化(EMT),并促进免疫抑制、细胞外基质沉积和血管形成。近来报导,抑制癌细胞中的自分泌TGF-β信号传导减少细胞侵入性和肿瘤转移,且TGF-β的这些作用与TGF-β诱导EMT和刺激细胞迁移的能力密切相关。(8,9) TGF-β信号通路相应变成肿瘤学领域中药物开发的有吸引力的靶标。(10,11)
G.J. Inman et al., Molecular Pharmacology 2002年7月1日 vol.62 no. 1, 65-74, 表征了一种被确定为激活素受体样激酶(ALK)5 (TGF-β I型受体)的抑制剂的小分子抑制剂(SB-431542)。他们表明其抑制ALK5,以及与其激酶结构域中的ALK5高度相关的激活素I型受体ALK4和nodal I型受体ALK7。
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Derynck R, Akhurst RJ, Balmain A. TGF-β signaling in tumor suppressionand cancer progression (肿瘤抑制和癌症发展中的TGF-β信号传导). Nat Genet 2001;29: 117–29.
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近来开发出ALK1的药理学抑制剂。ALK1已被描述为癌症抗血管形成治疗的新出现的靶标,S. I. Cunha et al.:http://www.bloodjournal.org/content/117/26/6999。
已在WO 2013/004551 A1中描述了使用ALK1抑制剂治疗血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)。
ALK2抑制剂可用于治疗进行性衰弱性肌肉骨骼疾病进行性骨化性纤维发育不良(FOP)。参见C. E. Sanvitale et al PLOS ONE, 2013年4月, 第8卷, 第4期, e62721。
所有已知的ALK1抑制剂也是ALK2抑制剂,反之亦然。
WO 2012/104007公开了显示TGF β受体I激酶抑制性质的化合物。
多种疾病已经与TGF-β1过量产生相关。细胞内TGF-β信号通路的抑制剂为纤维增生性疾病的适合治疗方式。特别地,纤维增生性疾病包括与未调节TGF-β活性和过度纤维化有关的肾病,包括肾小球性肾炎(GN),例如肾小球膜增殖性GN,免疫性GN和新月体性GN。其它的肾病况包括糖尿病性肾病、肾间质性纤维化、接受环孢菌素的移植患者的肾纤维化、和HIV相关肾病。胶原血管病症包括进行性全身性硬化、多发性肌炎、硬化性皮炎、皮肌炎、嗜酸性筋膜炎、硬斑病或与雷诺综合征发生有关的那些病症。由过度TGF-β活性导致的肺纤维化包括成人呼吸窘迫综合征、特发性肺纤维化和间质性肺纤维化,其通常与自身免疫性病症(例如系统性红斑狼疮和硬化性皮炎)、化学品接触或过敏有关。另一种与纤维增生性特征有关的自身免疫性病症是患风湿症性关节炎。
与纤维增生性病况有关的眼科疾病包括在视网膜复位手术期间发生的增生性玻璃体视网膜病变、伴随眼内晶状体植入的白内障摘除、和青光眼引流后手术(post-glaucoma drainage surgery),且与TGF-β1过量产生有关。
已经发现,根据本发明的化合物及其盐具有很有价值的药理学性质,同时良好耐受。
本发明特别涉及抑制ALK1 (ACVRL1)、ALK2(ACVR1)和/或ALK5 (TGFβR1)的式I化合物,涉及包含这些化合物的组合物,和涉及它们用于治疗ALK1-、ALK2-和/或ALK5-诱发疾病和不适的方法。此外,式I的化合物抑制BMP-诱导的SMAD1/5/8磷酸化。
所有已知的ALK1抑制剂也是ALK2抑制剂,反之亦然。已知未有真正的选择性ALK1或ALK2抑制剂。
根据本发明的化合物还抑制ALK1和ALK2两者。
式I的化合物还可另外用于分离和研究ALK的活性或表达。此外,它们特别适用于与未调节或干扰的ALK1、ALK2和/或ALK5活性相关的疾病的诊断方法。
宿主或患者可属于任何哺乳动物物种,例如灵长类物种,特别是人;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、母牛、狗、猫等。动物模型对于试验研究是重要的,前提是用于人类疾病治疗的模型。
特定细胞对用根据本发明的化合物治疗的敏感性可通过体外试验确定。通常,将细胞培养物与根据本发明的化合物以不同浓度合并,经过足以使活化剂例如抗IgM诱导细胞响应(例如表面标记物表达)的时间,通常为约1小时-1周。可使用来自血液或来自活检样品的培养细胞进行体外试验。表达的表面标记物的量通过流式细胞计使用识别该标记物的特异性抗体评价。
剂量取决于使用的特定化合物、特定疾病、患者状态等而变化。治疗剂量通常足够显著减少靶组织中不期望的细胞群体,同时保持患者的生存能力。治疗通常持续直到发生显著减少,例如细胞载量减少至少约50%,且可持续直到在体内基本不再检测到不期望的细胞。
现有技术
在WO 2007/056155 A1中已描述其它的苯并咪唑基衍生物化合物作为酪氨酸激酶调节剂。在WO 2013/033901 A1中已描述杂环取代的苯并呋喃衍生物用于治疗病毒性疾病。其它杂环化合物如用于治疗血管形成相关病症的ALK1抑制剂已描述于WO 2013/004551A1。
WO 2009/114180和WO 2014/138088中描述其它双环杂环化合物作为ALK2的抑制剂和BMP-诱导的SMAD1/5/8磷酸化的抑制剂。
发明内容
本发明涉及式I的化合物及其药学可接受的盐、互变异构体和立体立构体,包括它们按所有比例的混合物,
其中
R1表示Ar或Het,
R2表示H,A,Hal,CN,NO2,OR4,COOR4,CO(R4)2,CONR4[C(R4)2]mN(R4)2,-[C(R4)2]nNR4COA,-[C(R4)2]nNR4CO[C(R4)2]nHet1, -[C(R4)2]nN(R4)2, -[C(R4)2]nHet1, O[C(R4)2]mN(R4)2, O[C(R4)2]mHet1, -NR4[C(R4)2]mN(R4)2或-NR4[C(R4)2]nHet1,
R3表示H,A,Hal或OR4,
R4表示H或A’,
W表示CH或N,
A表示具有1-6个C原子的非支化或支化烷基,其中1-7个H原子可被OH,F,Cl和/或Br替代,和/或其中一个或两个CH2基团可被O, NH, S, SO, SO2和/或CH=CH基团替代, 或表示具有3-7个C原子的环烷基,
A’表示具有1-4个C原子的非支化或支化烷基,
Ar表示苯基或萘基,其未被取代或被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代,
Het表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被Hal, A, [C(R4)2]nOR4 和/或[C(R4)2]nN(R4)2单取代或二取代,
Het1 表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4, N(R4)2, Hal 和/或=O (羰基氧)单取代或二取代,
Hal表示F,Cl,Br或I,
n表示0,1,2或3,
m表示1,2,3或4。
本发明还涉及这些化合物的光学活性形式(立体异构体)、对映体、外消旋物、非对映体和水合物及溶剂合物。
此外,本发明涉及式I化合物的药学可接受的衍生物。
术语化合物的溶剂合物含义是惰性溶剂分子加合到化合物,由于它们的相互吸引力而形成。溶剂合物例如为一水合物或二水合物或醇盐。
应理解,本发明还涉及盐的溶剂合物。
术语药学可接受的衍生物含义是例如根据本发明的化合物的盐以及所谓的前药化合物。
如本文所用,除非另有说明,否则术语“前药”表示式I化合物的衍生物,其可在生物学条件下水解、氧化或另外反应(体外或体内),以提供活性化合物,特别是式I的化合物。前药的实例包括但不限于式I化合物的衍生物和代谢物,其包括生物可水解部分,例如生物可水解酰胺、生物可水解酯、生物可水解氨基甲酸酯、生物可水解碳酸酯、生物可水解酰脲和生物可水解磷酸酯类似物。在某些实施方案中,具有羧基官能团的化合物的前药为羧酸的较低级烷基酯。羧酸酯通过使分子上存在的任何羧酸部分酯化方便地形成。前药可通常使用公知方法制备,例如Burger 's Medicinal Chemistry and Drug Discovery 6th ed.(Donald J. Abraham ed., 2001, Wiley)和Design and Application of Prodrugs(H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh)描述的那些。
表述“有效量”表示引起例如研究人员或医师所寻求或期望的在组织、系统、动物或人中的生物学或医学响应的药物或药学活性成分的量。
此外,表述“治疗有效量”表示与未接受该量的对应受试者相比,具有以下结果的量:
改进的治疗、治愈、预防或消除疾病、综合征、病况、不适、病症或副作用,或者还降低疾病、不适或病症的发展。
表述“治疗有效量”还包括有效增加正常生理机能的量。
本发明还涉及式I化合物的混合物的用途,例如两种非对映体的混合物,例如按比例1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000。
这些特别优选为立体异构化合物的混合物。
“互变异构体”是指彼此处于平衡的化合物的异构形式。异构形式的浓度将取决于化合物所在的环境,且可以不同,取决于例如化合物是否为固体或在有机或水溶液中。
本发明涉及式I的化合物及其盐,并涉及用于制备式I的化合物及其药学可接受的盐、溶剂合物、互变异构体和立体异构体的方法,该方法特征在于
a)使式II的化合物在Suzuki型偶联中与式III的化合物反应
其中W、R2和R3具有权利要求1中说明的含义,
L-R1 III
其中R1具有权利要求1中说明的含义,
且L表示硼酸或硼酸酯基团,
得到式IV的化合物
其中W、R1、R2和R3具有权利要求1中说明的含义,
随后使式IV的化合物与无机酸反应,
或
b)通过用溶剂分解剂或水解剂处理,从其官能衍生物中的一种释出式I的化合物;
或
c)通过使氨基酰基化或烷基化,将基团R2转化为另一个基团R2;
和/或
将式I的碱或酸转化为其一种盐。
在上下文中,基团W、R1、R2和R3具有式I中说明的含义,除非另有明确说明。
A表示非支化(线性)或支化的烷基,并具有1, 2, 3, 4, 5, 6, 7或8个C原子。A优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还表示1-, 2-或3-甲基丁基、1,1-, 1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-, 2-, 3-或4-甲基戊基、1,1-, 1,2- , 1,3- , 2,2- , 2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,还优选例如三氟甲基。
A非常特别优选表示具有1, 2, 3, 4, 5或6个C原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
环烷基优选表示环丙基、环丁基、环戊基、环己基。
此外,A优选表示CH2OCH3、CH2CH2OH或CH2CH2OCH3。
A’表示非支化(线性)或支化的烷基,并具有1, 2, 3或4个C原子。A’优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基。
R2优选表示H, A, Hal, CN, OR4, COOR4, CONR4[C(R4)2]mN(R4)2, -[C(R4)2]nNR4COA, -[C(R4)2]nNR4CO[C(R4)2]nHet1, -[C(R4)2]nN(R4)2, -[C(R4)2]nHet1, O[C(R4)2]mHet1或-NR4[C(R4)2]nHet1。
R3优选表示H或OR4。
R4优选表示H或甲基。
W优选表示CH。
Ar优选表示被Hal, A, [C(R4)2]nOR4 和/或[C(R4)2]nN(R4)2单取代、二取代或三取代的苯基。
Het优选表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被A单取代。
Het1优选表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4 和/或N(R4)2单取代或二取代。
在整个本发明中,所有出现多于一次的基团可相同或不同,即彼此独立。
式I的化合物可具有一个或多个手性中心,因此可按不同的立体异构形式出现。式I包含所有这些形式。
因此,本发明特别涉及其中至少一个所述基团具有以上说明的优选含义之一的式I化合物。化合物的一些优选基团可通过以下子式Ia至Ij表示,这些子式符合式I,且其中未更详细指明的基团具有对式I说明的含义,但其中
在Ia中R2表示H,A,Hal,CN,OR4,COOR4,CONR4[C(R4)2]mN(R4)2,-[C(R4)2]nNR4COA, -[C(R4)2]nNR4CO[C(R4)2]nHet1,-[C(R4)2]nN(R4)2,-[C(R4)2]nHet1,O[C(R4)2]mHet1或-NR4[C(R4)2]nHet1;
在Ib中R3表示H或OR4;
在Ic中R4表示H或甲基;
在Id中W表示CH;
在Ie中A表示具有1-6个C原子的非支化或支化烷基;
在If中A’表示具有1-4个C原子的非支化或支化烷基;
在Ig中Ar表示被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代的苯基;
在Ih中Het表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被A单取代;
在Ii中Het1表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4 和/或N(R4)2单取代或二取代;
在Ij中R1表示Ar或Het,
R2表示H,A,Hal,CN,OR4,COOR4,ONR4[C(R4)2]mN(R4)2,-[C(R4)2]nNR4COA, -[C(R4)2]nNR4CO[C(R4)2]nHet1,-[C(R4)2]nN(R4)2,-[C(R4)2]nHet1,O[C(R4)2]mHet1或-NR4[C(R4)2]nHet1,
R3表示H或OR4,
R4表示H或A’,
W表示CH,
A表示具有1-6个C原子的非支化或支化烷基,
A’表示H或甲基,
Ar表示被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代的苯基,
Het表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被A单取代,
Het1表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4和/或N(R4)2单取代或二取代,
Hal表示F,Cl,Br或I,
n表示0,1,2或3,
m表示1,2,3或4,
及其药学可接受的盐、互变异构体和立体立构体,包括它们按所有比例的混合物。
此外,通过本身已知的方法制备式I的化合物以及用于其制备的原料,如文献所述(例如在标准著作中,如Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Georg-Thieme-Verlag, Stuttgart),准确地说,在已知的和适于所述反应的反应条件下。在此还可使用本身已知的在此未详细提及的变体。
式II和III的起始化合物是公知的。然而,如果它们是新的,它们可通过本身已知的方法制备。
式I的化合物优选可通过在第一步中使式II的化合物与式III的化合物反应得到式IV的化合物来获得。
在式III的化合物中,L优选表示
式I的化合物可通过式II的溴-杂环和式III的芳基硼酸酯或硼酸之间的偶联反应(“Suzuki偶联”)得到式IV的化合物来合成。
该偶联通常在升高的温度使用钯催化剂、碱和惰性溶剂进行。催化剂和反应条件的综述在文献中可见[参见,例如S. Kotha et al., Tetrahedron 2002, 58, 9633-9695;T. E. Barder et al., J. Am. Chem. Soc. 2005, 127, 4685-4696]。该反应中的优选催化剂为四(三苯基膦)钯(0)。优选的碱是作为水溶液使用的碳酸钠。在反应条件下,在惰性有机溶剂例如1,4-二氧杂环己烷、乙腈、N,N-二甲基甲酰胺(DMF)或二甲基亚砜(DMSO)中或在水中或在这些溶剂的混合物中进行反应。优选地,在1,4-二氧杂环己烷和水或乙腈和水的混合物中进行反应。通常在+100℃和+250℃之间的温度下进行反应,优选在+110℃至+150℃。加热优选通过单模式微波元件实现。通常在惰性气体气氛,优选在氩气下进行反应。
在第二步中,使式IV的化合物与无机酸如HCl反应。
还可将式I的化合物转化为式I的其它化合物,例如通过将硝基还原为氨基(例如通过在惰性溶剂例如甲醇或乙醇中在雷尼镍或Pd/碳上氢化)。
游离氨基还可使用酰基氯或酸酐按常规方式酰化,或使用未取代或被取代的烷基卤烷基化,有利地在惰性溶剂中,例如二氯甲烷或THF,和/或在碱(例如三乙胺或吡啶)存在下,在-60和+30℃之间的温度下。
烷基化也可在还原性烷基化条件下进行,例如使用HCHO和NaBH3CN。
式I的化合物还可通过溶剂分解,特别是水解,或通过氢解,使它们从其官能衍生物释出而获得。
用于溶剂分解或氢解的优选原料为包含相应的受保护氨基和/或羟基代替一个或多个游离的氨基和/或羟基的那些材料,优选携带氨基保护基团代替与N原子键合的H原子的那些材料,例如符合式I但包含NHR’基团(其中R’是氨基保护基团,例如BOC或CBZ)代替NH2基团的那些材料。
更优选携带羟基保护基团代替羟基的H原子的原料,例如符合式I但包含R”O-苯基(其中R”是羟基保护基团)代替羟基苯基的那些材料。
还可在原料分子中存在多个相同或不同的受保护氨基和/或羟基。如果存在的保护基团彼此不同,则它们在很多情况下可选择性断裂。
术语“氨基保护基团”在一般术语中已知,且涉及适于保护(封闭)氨基以防化学反应,但在期望的化学反应已经在分子的其它地方进行以后容易去除的基团。这样的基团的典型特别是未取代或被取代的酰基、芳基、芳烷氧基甲基或芳烷基。此外,因为在期望的反应(或反应系列)后去除氨基保护基团,它们的类型和大小不是重要的;然而,优选具有1-20,特别地1-8个碳原子的那些基团。应结合本发明方法以最宽泛的意义理解术语“酰基”。其包括得自脂族、芳香脂族、芳族或杂环羧酸或磺酸的酰基,特别是烷氧基羰基、芳基氧基羰基,尤其是芳烷氧基羰基。这样的酰基的实例为烷酰基,例如乙酰基、丙酰基和丁酰基;芳烷酰基,例如苯基乙酰基;芳酰基,例如苯甲酰基和甲苯基;芳氧基烷酰基,例如POA;烷氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC和2-碘乙氧基羰基;芳烷氧基羰基,例如CBZ (“苄氧羰基”)、4-甲氧基苄氧羰基和FMOC;和芳基磺酰基,例如Mtr、Pbf和Pmc。优选的氨基保护基团为BOC和Mtr,还有CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基团”同样在一般术语中已知,且涉及适于保护羟基以防化学反应,但在期望的化学反应已经在分子的其它地方进行以后容易去除的基团。这样的基团的典型为上述未取代或被取代的芳基、芳烷基或酰基,还有烷基。因为它们也在期望的化学反应或反应系列后去除,羟基保护基团的特性和大小并不重要;优选具有1-20,特别地1-10个碳原子的基团。羟基保护基团的实例尤其为叔丁氧羰基、苄基、对硝基苯甲酰基、对甲苯磺酰基、叔丁基和乙酰基,其中苄基和叔丁基特别优选。
从其官能衍生物释出式I的化合物,取决于使用的保护基团,例如用强酸,有利地用TFA或高氯酸,但还使用其它强无机酸,例如盐酸或硫酸,强有机羧酸,例如三氯乙酸,或磺酸,例如苯磺酸或对甲苯磺酸。另外的惰性溶剂可存在,但并不总是必需的。适合的惰性溶剂优选为有机物,例如羧酸,例如乙酸;醚,例如四氢呋喃或二氧杂环己烷;酰胺,例如DMF;卤代烃,例如二氯甲烷;还有醇,例如甲醇、乙醇或异丙醇;和水。上述溶剂的混合物也是适合的。优选过量使用TFA,不添加另外的溶剂,且高氯酸优选按乙酸和70%高氯酸以9:1比例的混合物的形式使用。断裂的反应温度有利地为约0℃-约50℃,优选15℃-30℃(室温)。
BOC、OBut、Pbf、Pmc和Mtr基团可例如优选使用二氯甲烷中的TFA或使用二氧杂环己烷中的约3至5N HCl在15-30℃下断裂,且FMOC基团可使用约5至50%的二甲胺、二乙胺或哌啶在DMF中的溶液在15-30℃断裂。
可氢解去除的保护基团(例如CBZ或苄基)可例如通过在催化剂(例如贵金属催化剂,例如钯,有利地在载体上,例如碳)存在下用氢处理断裂。本文的适合溶剂为以上说明的那些,特别地例如醇,例如甲醇或乙醇;或酰胺,例如DMF。氢解通常在约0-100℃的温度下进行,压力为约1-200bar,优选在20-30℃和1-10bar。CBZ基团的氢解例如在5-10%Pd/C上在甲醇中或使用甲酸铵(代替氢)在Pd/C上在甲醇/DMF中在20-30℃成功进行。
优选在反应步骤期间通过苯基磺酰基保护氮杂吲哚基团。该基团优选用CF3CH2OH/THF中的Cs2CO3断裂。
药学盐和其它形式
本发明的所述化合物可按其最终非盐形式使用。在一方面,本发明还包括以其药学可接受盐的形式使用这些化合物,所述药学可接受的盐可通过本领域中已知的程序由各种有机和无机酸和碱得到。式I的化合物的药学可接受的盐形式大部分通过常规方法制备。如果式I的化合物含有羧基,则可以通过使该化合物与合适的碱反应以产生相应的碱加成盐来形成其合适的盐之一。此类碱是例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,诸如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,诸如哌啶、二乙醇胺和N-甲基谷氨酰胺。同样包括式I的化合物的铝盐。在式I的某些化合物的情况下,可以通过用药学可接受的有机和无机酸,例如卤化氢,诸如氯化氢、溴化氢或碘化氢、其它无机酸及其相应的盐,诸如硫酸盐、硝酸盐或磷酸盐等,和烷基-和单芳基磺酸盐,诸如乙磺酸盐、甲苯磺酸盐和苯磺酸盐,和其它有机酸及其相应的盐,诸如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等处理这些化合物来形成酸加成盐。相应地,式I的化合物的药学可接受的酸加成盐包括下列:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、二氢磷酸盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、甲酸盐、粘酸盐(galacterate)(由粘酸形成)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴化物、氢碘化物、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不代表限制。
此外,根据本发明的化合物的碱性盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但这无意代表限制。在上述盐中,优选铵;碱金属盐钠和钾,和碱土金属盐钙和镁。衍生自药学可接受的有机无毒碱的式I的化合物的盐包括伯胺、仲胺和叔胺、取代胺,也包括天然存在的取代胺、环胺和碱性离子交换树脂,例如精氨酸、内铵盐、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星)、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、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、hydrabamine、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲基胺(氨丁三醇)的盐,但这无意代表限制。
含有碱性含氮基团的本发明的化合物可以用诸如(C1-C4)烷基卤,例如甲基、乙基、异丙基和叔丁基氯、溴和碘;硫酸二(C1-C4)烷基酯,例如硫酸二甲酯、二乙酯和二戊酯;(C10-C18)烷基卤,例如癸基、十二烷基、月桂基、十四烷基和十八烷基氯、溴和碘;和芳基(C1-C4)烷基卤,例如苄基氯和苯乙基溴的试剂季铵化。根据本发明的水溶性和油溶性化合物都可以使用此类盐制备。
优选的上述药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴化物、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这无意代表限制。
特别优选的是盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
通过使游离碱形式的化合物与足量的所需酸接触以致以常规方式形成盐来制备式I的碱性化合物的酸加成盐。可以通过使该盐形式与碱接触并以常规方式分离游离碱来再生游离碱。游离碱形式在某些方面,就某些物理特性,诸如在极性溶剂中的溶解度而言不同于其相应的盐形式;然而,出于本发明的目的,该盐在其它方面相当于其各自的游离碱形式。
如所提及,用金属或胺,诸如碱金属和碱土金属或有机胺形成式I的化合物的药学可接受的碱加成盐。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
通过使游离酸形式的化合物与足量的所需碱接触以致以常规方式形成盐来制备根据本发明的酸性化合物的碱加成盐。可以通过使该盐形式与酸接触并以常规方式分离游离酸来再生游离酸。游离酸形式与其对应盐形式在某些方面不同,关于某些物理性质,例如在极性溶剂中的溶解度;然而,出于本发明的目的,该盐在其它方面对应于其相应的游离酸形式。
如果根据本发明的化合物含有多于一个能形成这种类型的药学可接受的盐的基团,则本发明还包括多盐(multiple salt)。典型的多盐形式包括例如,酒石酸氢盐、双乙酸盐、富马酸氢盐、二葡甲胺、二磷酸盐、二钠和三盐酸盐,但这无意代表限制。
根据上文所陈述的内容可以看出,表述“药学可接受的盐”在本文中用来表示包含处于其盐之一的形式的式I的化合物的活性成分,特别是如果该盐形式与该活性成分的游离形式或之前使用的该活性成分的任何其它盐形式相比为该活性成分提供改进的药代动力学性质。该活性成分的药学可接受的盐形式也可首次为该活性成分提供其先前没有的期望的药代动力学性质,且可以甚至在其体内治疗效力方面对这种活性成分的药效学具有积极影响。
同位素
此外,式I化合物旨在包括其同位素-标记的形式。同位素-标记形式的式I化合物与该化合物是相同的,但除了这样的事实外,即化合物的一个或多个原子已被具有不同于通常天然存在的原子的原子质量或质量数的原子质量或质量数的一个或多个原子置换。可容易经市售获得的和可通过熟知的方法掺入到式I化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别为例如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。含有一个或多个上述同位素和/或其它原子的其它同位素的式I化合物、其前药,或药学可接受的盐旨在为本发明的部分。同位素-标记的式I化合物可以许多有益的方式使用。例如,放射性同位素,例如3H或14C已被掺入的同位素-标记的式I化合物适用于药物和/或底物组织分布测定(substrate tissue distribution assay)。这些放射性同位素,即氚(3H)和碳-14(14C),由于制备简单和优良的可检测性而为特别优选的。较重的同位素,例如氘(2H)掺入到式I化合物中,由于这种同位素-标记的化合物的较高代谢稳定性而具有治疗优势。较高的代谢稳定性直接转化为增加的体内半衰期或较低的剂量,其在大多数情况下将代表本发明的优选的实施方案。同位素-标记的式I化合物通常可通过进行合成方案和相关描述中公开的程序,在本文的实施例部分和在制备部分,用可容易获得的同位素-标记的反应物置换非同位素-标记的反应物来制备。
氘(2H)也可掺入式I化合物中,为了通过一级动力学同位素作用操纵化合物的氧化代谢的目的。一级动力学同位素作用是改变由同位素核的交换引起的化学反应的速率,其继而通过在这种同位素交换后为共价键形成所必需的基态能量变化而引起。较重同位素的交换通常导致化学键的基态能量的降低并因此引起限速键断裂(rate-limiting bondbreakage)速率的下降。如果键断裂发生在沿着多产物反应坐标(coordinate of a multi-product reaction)的鞍点区(saddle-point region)或鞍点区附近,产物分配比率可显著改变。为了解释:如果氘在非-可交换的位置键合于碳原子,kM/kD = 2-7的率差(ratedifference)是典型的。如果这种率差被成功应用于易受氧化作用影响的式I化合物,则这种化合物的体内分布概况(profile)可显著改善并导致改进的药代动力学特性。
当发现和开发治疗剂时,本领域技术人员试图使药代动力学参数最优化,同时保留所需的体外特性。合理的是假定许多具有不良药代动力学概况的化合物易受氧化代谢的影响。目前可获得的体外肝微粒体测定提供关于这种类型氧化代谢的过程的有价值信息,其继而允许合理设计具有通过抵抗这样的氧化代谢而改进稳定性的氘化式I化合物。由此式I化合物的药代动力学概况获得显著改进,并可根据体内半衰期(t1/2)的增加,最大疗效时的浓度(Cmax),剂量反应曲线下面积(AUC)和F;并根据减少的清除、剂量和材料成本进行定量表示。
以下意欲举例说明上文:具有对于氧化代谢的多个潜在攻击位点(例如键合于氮原子的苄型氢原子和氢原子)的式I化合物被制备为一系列类似物,其中氢原子的多种组合被氘原子置换,以使这些氢原子中的一些、大多数或全部都已被氘原子置换。半衰期测定使得能够有利和精确测定改进对氧化代谢的抵抗的改进程度。以这种方式确定的是,由于这种类型的氘-氢交换,母体化合物的半衰期可延长多达100%。
式I化合物中的氘-氢交换也可用于获得起始化合物的代谢谱的有利改善,以减少或消除不需要的毒性代谢物。例如,如果毒性代谢物通过氧化性碳-氢(C-H)键断裂开而产生,则可合理地假定氘化类似物将极大地减少或消除不需要的代谢物的产生,即使特定的氧化不是限速步骤。更多的关于涉及氘-氢交换的现有技术水平的信息可参见例如Hanzlik等人, J. Org. Chem. 55, 3992-3997, 1990, Reider等人, J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al,Biochemistry 33(10) 2927-2937, 1994,和Jarman等人Carcinogenesis 16(4), 683-688, 1993。
本发明另外涉及包含至少一种式I化合物和/或其药学上可接受的衍生物、溶剂合物和立体异构体,包括它们按所有比例的混合物,和任选的赋形剂和/或辅助剂的药物。
药物制剂可以每剂量单位包含预定量的活性成分的剂量单位形式给药。这样的单位可包含,例如0.5 mg-1 g,优选1 mg-700 mg,特别优选5 mg-100 mg的根据本发明的化合物,这取决于所治疗的病况、给药方法和患者的年龄、体重和状况,或者药物制剂可以包含预定量的活性成分/每剂量单位的剂量单位形式给药。优选的剂量单位制剂为包含如上指明的日剂量或部分剂量,或其活性成分的对应部分的那些制剂。此外,这种类型的药物制剂可使用药物领域一般已知的方法制备。
药物制剂可适合于经由任何所需的合适方法,例如通过口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或透皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)方法给药。这样的制剂可使用药物领域已知的所有方法,通过例如使活性成分与赋形剂或辅助剂混合来制备。
适合于口服给予的药物制剂可作为分开的单位,例如,胶囊或片剂;散剂或颗粒剂;在水性或非-水性液体中的溶液剂或混悬剂;可食用泡沫剂或发泡食物;或水包油液体乳剂或油包水液体乳剂给予。
因此,例如,在以片剂或胶囊的形式口服给予的情况下,活性成分组分可与口服的、非毒性的和药学上可接受的惰性赋形剂,例如,乙醇、甘油、水等混合。散剂通过将化合物粉碎为合适的精细粒度并使其与以类似的方式粉碎的药用赋形剂,例如可食用碳水化合物,例如淀粉或甘露醇混合来制备。同样可存在矫味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并填充到成形的明胶壳内而产生。助流剂和润滑剂,例如,高分散性硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇可加入到粉末混合物中,然后进行填充操作。同样可加入崩解剂或增溶剂,例如,琼脂、碳酸钙或碳酸钠,以改进胶囊被摄取后药物的可利用度。
此外,如果需要或必要,合适的粘合剂、润滑剂和崩解剂以及染料可同样被掺入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖,例如葡萄糖或β-乳糖、由玉米制得的甜味剂、天然和合成橡胶,例如阿拉伯胶、黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,但不限于此,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过例如制备粉末混合物,将该混合物制粒或干燥-压制,加入润滑剂和崩解剂并压制整个混合物来配制,得到片剂。粉末混合物通过将以合适的方式粉碎的化合物与如上所述的稀释剂或基质,和任选地与粘合剂,例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮、溶解迟滞剂例如石蜡,吸收促进剂例如季胺盐,和/或吸收剂例如膨润土、高岭土或磷酸二钙混合来制备。粉末混合物可通过将其用粘合剂例如糖浆、淀粉糊、阿拉伯胶或纤维素或聚合物材料的溶液湿润并压其过筛来制粒。作为对制粒的备选,可使粉末混合物通过压片机,得到不均匀形状的块状物,将其破碎而形成颗粒。所述颗粒可通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油进行润滑,以防止粘附到片剂铸模上。然后压制经润滑的混合物,得到片剂。根据本发明的化合物也可与自由流动的惰性赋形剂混合,然后无需进行制粒或干燥-压制步骤而直接压制,得到片剂。可存在由虫胶密封层、糖或聚合物材料层和蜡的光泽层组成的透明的或不透明的保护层。可将染料加入到这些包衣料中,以便能够在不同的剂量单位之间进行区分。
口服液体,例如,溶液、糖浆剂和酏剂,可以剂量单位的形式制备,以使给定的量包含预定量的化合物。糖浆剂可通过将化合物溶于含合适的矫味剂的水性溶液中制备,而酏剂使用无毒的醇性溶媒制备。混悬剂可通过将化合物分散于无毒的溶媒中来配制。同样可加入增溶剂和乳化剂,例如,乙氧基化异硬脂醇和聚氧乙烯山梨醇醚、防腐剂、香料添加剂,例如薄荷油或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要,可将供口服给予的剂量单位制剂封装到微囊中。也可以这样一种方式,例如,通过将颗粒材料包衣或包埋在聚合物、蜡等中,延长或延迟释放来制备所述制剂。
式I的化合物及其药学可接受的盐、互变异构体和立体异构体也可以脂质体递送系统,例如小单层囊泡、大单层囊泡和多层囊泡的形式给予。脂质体可由多种磷脂,例如胆固醇、硬脂酰胺或磷脂酰胆碱形成。
式I的化合物及其盐、互变异构体和立体异构体也可使用作为化合物分子偶联的单个载体的单克隆抗体递送。化合物也可偶联于作为靶向药物载体的可溶性聚合物。这样的聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天门冬氨酰基苯酚或聚氧化乙烯聚赖氨酸(被棕榈酰基取代)。化合物可以另外偶合于一类可生物降解的聚合物,其适合于实现药物的控制释放,所述聚合物例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲性嵌段共聚物。
适于经皮给药的药物制剂可作为与接受者的表皮长期、紧密接触的独立硬膏剂而给药。因此,例如,活性成分可以通过离子电渗疗法(如Pharmaceutical Research,3(6),318 (1986)的通用术语中所述),由硬膏剂递送。
适于局部给药的药物化合物可以被配制成软膏、乳膏、混悬液、洗剂、粉末剂、溶液剂、糊剂、凝胶、喷雾剂、气雾剂或油。
对于眼睛或其它外部组织,例如口腔和皮肤的治疗而言,制剂优选作为局部软膏或乳膏应用。在给予软膏的制剂的情况中,活性成分可以与石蜡或者水混溶性乳膏基质一起使用。或者,可以将活性成分用水包油乳膏基质或油包水基质配制而得到乳膏。
适于局部应用于眼睛的药物制剂包括滴眼剂,其中活性成分被溶解或混悬于适宜的载体,特别是水性溶剂中。
适于局部应用于口腔的药物制剂包括锭剂、软锭剂和漱口剂。
适于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中载体物质为固体的适于鼻给药的药物制剂包含粒度为例如20-500微米的粗粉末,其以用鼻吸入的方式被给药,即通过经由鼻道从保持靠近鼻子的含粉末容器中快速吸入来给药。用于作为鼻喷雾剂或滴鼻剂(其中液体作为载体物质)给药的适宜制剂包含在水或油中的活性成分溶液。
适于通过吸入进行给药的药物制剂包含细颗粒粉尘或雾,其可以通过各种类型的具有气雾剂的加压分散器、喷雾器或吸入器来产生。
适于阴道给药的药物制剂可以作为阴道栓、塞子、乳膏、凝胶、糊剂、泡沫剂或喷雾制剂给药。
适于胃肠外给药的药物制剂包括包含抗氧化剂、缓冲剂、抑菌剂和溶质(借助于此,使制剂与被治疗的接受者的血液等渗)的水性和非水性无菌注射溶液;以及可包含混悬介质和增稠剂的水性和非水性无菌混悬液。该制剂可以单剂量或多剂量容器,例如密封安瓿和小瓶给予,并且以冷冻干燥(冻干)状态储存,从而使得仅需要在临用前加入无菌的载体液体,例如注射用水。根据处方制备的注射溶液和混悬液可以由无菌粉末、颗粒和片剂制备。
不言而喻,除上面特别提及的组分外,对特定类型的制剂而言,制剂还可包含本领域常用的其它剂;因此,例如适于口服给药的制剂可包含矫味剂。
式I化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的精确病况及其严重性、制剂的性质和给药方法,并且最终由进行治疗的医生或兽医确定。然而,依据本发明的化合物的有效量通常在每天0.1至100mg/kg接受者(哺乳动物)体重范围内,并且特别典型地在每天1至10mg/kg体重范围内。因此,对体重为70kg的成年哺乳动物而言,每天的实际量通常为70至700mg,其中这个量每天可以作为单剂量给予或者通常可以每天以一系列部分剂量(例如两个、三个、四个、五个或六个)给予,从而使得总的日剂量相同。盐或溶剂化物或其生理学上的功能衍生物的有效量可以作为根据本发明的化合物本身有效量的分数来确定。可以推定相似的剂量也适用于治疗上述的其它病况。
这种类型的联合治疗可借助于同时、顺序或分开分配该治疗的各组分来实现。这种类型的组合产品使用根据本发明的化合物。
本发明另外涉及包含至少一种式I化合物和/或其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,和至少一种另外的药物活性成分的药物。
本发明也涉及套装(set)(药盒),其由以下分开的包装组成:
(a) 有效量的式I化合物和/或其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
和
(b) 有效量的另外的药物活性成分。
套装包含合适的容器,例如盒、各个瓶、袋或安瓿。套装可,例如,包含分开的安瓿,每个安瓿含有有效量的式I化合物和/或其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,
和溶解或冻干形式的有效量的另外的药物活性成分。
如在本文所用的"治疗"意指全部或部分缓解与病症或疾病有关的症状,或延缓或中断这些症状的进一步发展或恶化,或防止或预防处于发生疾病或病症的风险的受试者的疾病或病症。
与式(I)化合物有关的术语"有效量"可意指能够全部或部分缓解与病症或疾病有关的症状,或延缓或中断这些症状的进一步发展或恶化,或防止或预防患有本文公开的疾病或处于发生所述疾病风险的受试者的疾病或病症的量,所述疾病例如炎性疾病、免疫性疾病、癌症或代谢性疾病。
在一个实施方案中,式(I)化合物的有效量是在例如体外或体内抑制细胞中的端锚聚合酶的量。在一些实施方案中,与在未治疗细胞中的端锚聚合酶的活性比较,式(I)化合物的有效量抑制细胞中的端锚聚合酶的10%、20%、30%、40%、50%、60%、70%、80%、90%或99%。例如在药物组合物中的式(I)化合物的有效量可以是将发挥所需效果的水平;例如,对于口服和胃肠外给药二者,在单位剂量中为约0.005 mg/kg受试者体重至约10 mg/kg受试者体重。
用途
本发明化合物适合作为药学活性成分在癌症治疗中用于哺乳动物,尤其是用于人,用于治疗血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)。
本发明包括式I化合物和/或其药学可接受的盐、互变异构体和立体异构体用于制备药物的用途,所述药物用于治疗或预防癌症,用于治疗血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)。
此外,本发明包括式I化合物和/或其药学可接受的盐、互变异构体和立体异构体用于制备药物的用途,所述药物用于治疗或预防癌症、年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变、糖尿病性黄斑水肿(DME)、进行性骨化性纤维发育不良、炎症、血管形成相关病症和细菌感染。
此外,本发明包括式I的化合物和/或其药学可接受的盐、互变异构体和立体异构体用于制备药物的用途,所述药物用于治疗或预防进行性骨化性纤维发育不良、炎症、血管形成相关病症和细菌感染。
还包括式I的化合物和/或其药学可接受的盐、互变异构体和立体异构体用于制备药物的用途,所述药物用于治疗或预防哺乳动物中ALK1-、ALK2-和/或ALK5-诱导的疾病或ALK1-、ALK2-和/或ALK5-诱导的病况,其中对于该方法,将治疗有效量的本发明化合物给予需要这种治疗的患病哺乳动物。治疗量根据特定疾病变化,且可在没有过度工作的情况下由本领域技术人员确定。
表述“ALK1-、ALK2-和/或ALK5-诱导的疾病或病况”是指取决于ALK1、ALK2、ALK5活性的病理病况。与ALK1、ALK2、ALK5活性相关的疾病包括癌症,血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)。
本发明特别涉及式I的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗其中抑制、调节和/或调控抑制ALK1、ALK2和/或ALK5起作用的疾病。
本发明特别涉及式I的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于抑制ALK1、ALK2和/或ALK5。
本发明特别涉及式I的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗癌症,血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)。
此外,本发明特别涉及式I的化合物及其药学可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗和/或预防癌症、年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变、糖尿病性黄斑水肿(DME)、进行性骨化性纤维发育不良、炎症、血管形成相关病症和细菌感染。
本发明特别涉及用于治疗或预防癌症,血管形成相关的眼科疾病,例如年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变和糖尿病性黄斑水肿(DME)的方法,该方法包括给予有需要的受试者有效量的式I化合物或其药学可接受的盐、互变异构体、立体异构体或溶剂合物。
式I化合物可用于治疗或预防的代表性癌症包括但不限于:头癌、颈癌、眼癌、口腔癌、咽喉癌、食道癌、支气管癌、喉癌、咽癌、胸癌、骨癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、宫颈癌、乳腺癌、卵巢癌、睾丸癌或其它生殖器官癌、皮肤癌、甲状腺癌、血液癌、淋巴结癌、肾癌、肝癌、胰腺癌、脑癌、中枢神经系统癌、实体瘤和血液肿瘤。
优选地,本发明涉及其中疾病为癌症的方法。
特别优选,本发明涉及一种方法,其中疾病为癌症,其中给药与至少一种其它活性药剂给药同时、连续或交替。
公开的式I化合物可与其它已知的治疗剂,包括抗癌剂联合给予。本文所用术语“抗癌剂”涉及给予患有癌症的患者用于治疗癌症目的的任何药剂。
以上限定的抗癌治疗可作为单一疗法应用,或可除本文公开的式I化合物以外还包括常规手术或放射疗法或药物疗法。这样的药物疗法例如化疗或靶向疗法,可包括一种或多种,但优选一种以下的抗肿瘤剂:
烷基化剂
例如六甲蜜胺,苯达莫司汀,白消安,卡莫司汀,苯丁酸氮芥,氮芥(chlormethine),环磷酰胺,达卡巴嗪,异环磷酰胺,英丙舒凡, 甲苯磺酸盐, 洛莫司汀, 美法仑, 二溴甘露醇, 二溴卫矛醇, 尼莫司汀, 雷莫司汀, 替莫唑胺, 塞替派, 曲奥舒凡, 氮芥(mechloretamine), 卡波醌;
apaziquone,福莫司汀,葡磷酰胺,palifosfamide,哌泊溴烷,曲磷胺,乌拉莫司汀,TH-3024, VAL-0834;
铂化合物
例如卡铂,顺铂,依他铂,米铂(miriplatine)水合物,奥沙利铂,洛铂,奈达铂,吡铂(picoplatin),沙铂;
洛铂,奈达铂,吡铂,沙铂;
DNA改变剂
例如氨柔比星,比生群,地西他滨,米托蒽醌,丙卡巴肼,曲贝替定,氯法拉滨;
安吖啶,brostallicin,pixantrone,laromustine1,3;
拓扑异构酶抑制剂
例如依托泊苷,伊立替康,雷佐生,索布佐生,替尼泊苷,拓扑替康;
氨萘非特,贝洛替康,elliptinium乙酸盐, voreloxin;
微管调节剂
例如卡巴他赛,多西紫杉醇,艾日布林,伊沙匹隆(ixabepilone),紫杉醇,长春碱,长春新碱,长春瑞滨,长春地辛,长春氟宁;
fosbretabulin,替司他赛;
抗代谢物
例如天冬酰胺酶3,阿扎胞苷,左亚叶酸钙,卡培他滨,克拉屈滨, 阿糖胞苷, 依诺他滨, 氟尿苷, 氟达拉滨,氟尿嘧啶,吉西他滨,巯基嘌呤,甲氨蝶呤,奈拉滨,培美曲塞,普拉曲塞,硫唑嘌呤,硫鸟嘌呤,卡莫氟;
去氧氟尿苷, elacytarabine,雷替曲塞,沙帕他滨,替加氟2,3,三甲曲沙;
抗癌抗生素
例如博来霉素, 更生霉素, 多柔比星, 表柔比星, 伊达比星, 左旋咪唑, 米替福新,丝裂霉素C,罗米地辛,链脲菌素,戊柔比星,净司他丁,佐柔比星,柔红霉素,普卡霉素;
阿柔比星,培罗霉素,吡柔比星;
激素/拮抗剂
例如阿巴瑞克,阿比特龙,比卡鲁胺,布舍瑞林,卡普睾酮,氯烯雌醚,地加瑞克(degarelix),地塞米松,雌二醇,氟可龙,氟甲睾酮,氟他胺,氟维司群,戈舍瑞林,组氨瑞林,亮丙瑞林,甲地孕酮,米托坦,那法瑞林,诺龙,尼鲁米特,奥曲肽,泼尼松龙,雷洛昔芬,他莫昔芬,促甲状腺激素α,托瑞米芬,曲洛司坦,曲普瑞林,己烯雌酚;
阿佐比芬(acolbifene),达那唑,地洛瑞林,环硫雄醇,orteronel,enzalutamide1,3;
芳香酶抑制剂
例如氨鲁米特,阿那曲唑,依西美坦,法倔唑,来曲唑,睾内酯;
福美坦;
小分子激酶抑制剂
例如crizotinib,达沙替尼,厄洛替尼,伊马替尼,拉帕替尼,尼洛替尼,帕唑帕尼,regorafenib,ruxolitinib,索拉非尼,舒尼替尼,凡德他尼,vemurafenib,波舒替尼,吉非替尼,阿西替尼;
阿法替尼,alisertib,dabrafenib,dacomitinib,dinaciclib,dovitinib,enzastaurin,nintedanib,lenvatinib,linifanib,linsitinib,masitinib,米哚妥林,motesanib,来那替尼,orantinib,哌立福辛(perifosine),ponatinib,radotinib,rigosertib,tipifarnib,tivantinib,tivozanib,trametinib,pimasertib,brivanibalaninate, cediranib, apatinib4, cabozantinib S-malate1,3, ibrutinib1,3,icotinib4, buparlisib2, cipatinib4, cobimetinib1,3, idelalisib1,3, fedratinib1,XL-6474;
光敏剂
例如甲氧沙林3;
卟吩姆钠,他拉泊芬,替莫泊芬;
抗体
例如阿仑单抗,besileomab,brentuximab vedotin,西妥昔单抗,denosumab,ipilimumab,ofatumumab,帕尼单抗,利妥昔单抗,托西莫单抗,曲妥珠单抗,贝伐单抗,帕妥珠单抗2,3;
catumaxomab,elotuzumab,依帕珠单抗,farletuzumab,mogamulizumab,necitumumab,尼妥珠单抗,obinutuzumab,ocaratuzumab,oregovomab,ramucirumab,rilotumumab,siltuximab,tocilizumab,扎妥木单抗,zanolimumab,马妥珠单抗,dalotuzumab1,2,3,onartuzumab1,3, racotumomab1, tabalumab1,3, EMD-5257974, nivolumab1,3;
细胞因子
例如阿地白介素,干扰素α2,干扰素α2a3,干扰素α2b2,3;
西莫白介素,他索纳明,替西白介素,奥普瑞白介素1,3,重组干扰素β-1a4;
药物缀合物
例如地尼白介素(denileukin diftitox),替伊莫单抗,碘苄胍I123,泼尼莫司汀,曲妥珠单抗emtansine,雌莫司汀,吉姆单抗,奥佐米星,阿柏西普;
cintredekin besudotox, edotreotide, 伊替单抗奥佐米星,naptumomabestafenatox,oportuzumab monatox,锝(99mTc)阿西莫单抗1,3,vintafolide1,3;
疫苗
例如sipuleucel3; vitespen3, emepepimut-S3, oncoVAX4, rindopepimut3,troVax4, MGN-16014, MGN-17034;
其它
阿利维A酸,贝沙罗汀,硼替佐米,依维莫司,伊班膦酸,咪喹莫特,来那度胺,香菇多糖,甲酪氨酸,mifamurtide,帕米膦酸,培门冬酶,喷司他丁,sipuleucel3,西佐喃,他米巴罗汀,西罗莫司,沙利度胺,维甲酸,vismodegib,唑来膦酸,伏立诺他;
塞来昔布,西仑吉肽,entinostat,依他硝唑,ganetespib,idronoxil,iniparib,ixazomib,氯尼达明,尼莫唑,帕比司他,peretinoin,plitidepsin,pomalidomide,丙考达唑,ridaforolimus,tasquinimod,telotristat,胸腺法新,替拉扎明,tosedostat,trabedersen,乌苯美司,伐司朴达,gendicine4,溶链菌4, reolysin4, retaspimycin盐酸盐1,3, trebananib2,3, 维鲁利秦(virulizin)4, carfilzomib1,3, 内皮他丁(endostatin)4, immucothel4, belinostat3, MGN-17034;
1 Prop. INN (提议的国际非专有名称)
2 Rec. INN (推荐的国际非专有名称)
3 USAN (美国采用的名称)
4 非INN。
下文的缩写分别指以下定义:
aq(含水), h (小时), g(克), L (升), mg (毫克), MHz(兆赫兹), min. (分钟),mm (毫米), mmol (毫摩尔), mM(毫摩尔体积浓度), m.p. (熔点), eq (当量), mL (毫升), μL(微升), ACN (乙腈), AcOH (乙酸), CDCl3 (氘代氯仿), CD3OD (氘代甲醇),CH3CN (乙腈), c-hex (环己烷), DCC (二环己基碳二亚胺), DCM (二氯甲烷), DIC (二异丙基碳二亚胺), DIEA (二异丙基乙胺), DMF (二甲基甲酰胺), DMSO (二甲基亚砜),DMSO-d6 (氘代二甲基亚砜), EDC (1-(3-二甲基-氨基-丙基)-3-乙基碳二亚胺), ESI(电喷离子化), EtOAc (乙酸乙酯), Et2O (乙醚), EtOH (乙醇), HATU (二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-六氟磷酸铵), HPLC (高效液相色谱), i-PrOH (2-丙醇), K2CO3 (碳酸钾), LC(液相色谱), MeOH (甲醇), MgSO4 (硫酸镁), MS (质谱), MTBE (甲基叔丁基醚), NaHCO3 (碳酸氢钠), NaBH4 (硼氢化钠),NMM (N-甲基吗啉), NMR (核磁共振), PyBOP (苯并三唑-1-基-氧基-三-吡咯烷基-六氟磷酸鏻), RT (室温), Rt(保留时间), SPE (固相萃取), TBTU (2-(1-H-苯并三唑-1-基)-1,1,3,3-四甲基四氟硼酸脲鎓), TEA (三乙胺), TFA (三氟乙酸), THF (四氢呋喃), TLC (薄层色谱), UV (紫外光)。
上下文中所有温度以℃表示。在以下实例中,“常规后处理”表示:如有需要则添加水,如有需要则调节pH至2-10的值,取决于最终产品组成,用乙酸乙酯或二氯甲烷萃取混合物,分离各相,有机相经硫酸钠干燥并蒸发,通过在硅胶上层析和/或通过结晶纯化残余物。硅胶上的Rf值;洗脱剂:乙酸乙酯/甲醇 9:1。
在Bruker DPX-300, DRX-400, AVII-400或在500 MHz光谱仪上记录1H NMR,使用氘代溶剂的残余信号作为内参比。化学位移(δ)按相对于残余溶剂信号的ppm报道(δ =2.49 ppm,DMSO-d6中的1H NMR)。1H NMR数据如下报道:化学位移(多重谱线,耦合常数,氢数)。多重谱线简写如下:s (单峰), d (双重峰), t (三重峰), q (四重峰), m (多重峰), br (宽峰)。
HPLC/MS条件:
HPLC/MS: Agilent 1200 / 6100
洗脱剂A: 水+ 0.05%甲酸
洗脱剂B: 乙腈+ 0.04%甲酸
柱: Kinetex XB-C18; 2.6 μm; 50-4.6 mm
流速: 2.5 ml/min
梯度: 0% -> 100% B: 0.0 -> 1.4 min | 100% B: 1.4 -> 2.0 min
UV检测: 220 nm
MS检测: 65-800 amu正
测定法
靶向的激酶的蛋白质序列和附带信息在公开可得的数据库中有描述http://www.uniprot.org/uniprot/,对于ALK1 www.uniprot.org/uniprot/P37023,对于ALK2www.uniprot.org/uniprot/Q04771,和对于ALK5www.uniprot.org/uniprot/P36897。描述的新抑制剂的IC50测定在Reaction Biology Corp., Malvern, PA, USA进行,测定条件对公众公开,和www.reactionbiology.com/webapps/site/Kinase_Assay_Protocol.aspx。此外,它们在Anastassiadis et al. Nat. Biotechnol. ; 29(11): 1039–1045. doi:10.1038/nbt.2017中先前有说明。
A1) ALK1激酶抑制测定
用N末端GST-修饰的激酶结构域ACVRL1(139-503)和20 mg/ml酪蛋白作为底物,在20mM HEPES pH 7.5, 10 mM MgCl2, 1mM EGTA, 0.02% Brij, 0.02 mg/ml BSA, 0.1 mMNa3VO4, 2mM DTT, 1% DMSO反应缓冲液中进行。将化合物溶于DMSO,得到10 mM储备溶液,并以从10 μM稀释到0.1 nM的浓度送到反应中,约20 min后,加入ATP (Sigma , St.Louis, MO, USA)和33P-ATP (Perkin Elmer, Waltham, MA, USA)的混合物,达到100 µM(Km ATP)的最终浓度。在环境温度进行反应120 min,随后将反应物点涂到P81离子交换滤纸上(Whatman Inc., Picataway, NJ, USA)。通过在0.75%磷酸中充分洗涤滤纸去除未结合的磷酸盐。在扣除来自无酶活性的对照反应的背景后,激酶活性数据表示为试验样品中的剩余激酶活性与媒介物(DMSO)反应相比的百分数。用Prism (GraphPad Software)获得IC50值和曲线拟合。
A2) ALK2激酶抑制测定
类似于程序A1,用N末端GST-修饰的激酶结构域ACVR1(145-509)和1 mg/ml酪蛋白作为底物,在20 mM HEPES pH 7.5, 10 mM MgCl2, 1mM EGTA, 0.02% Brij, 0.02 mg/ml BSA,0.1 mM Na3VO4, 2mM DTT, 1% DMSO反应缓冲液中进行。将化合物溶于DMSO,得到10 mM储备溶液,并以从10 μM稀释到0.1 nM的浓度送到反应中,约20 min后,加入ATP (Sigma ,St. Louis, MO, USA)和33P-ATP (Perkin Elmer, Waltham, MA, USA)的混合物,达到20µM (Km ATP)的最终浓度。在环境温度进行反应120 min,随后将反应物点涂到P81离子交换滤纸上(Whatman Inc., Picataway, NJ, USA)。通过在0.75%磷酸中充分洗涤滤纸去除未结合的磷酸盐。在扣除来自无酶活性的对照反应的背景后,激酶活性数据表示为试验样品中的剩余激酶活性与媒介物(DMSO)反应相比的百分数。用Prism (GraphPad Software)获得IC50值和曲线拟合。
A3) ALK5激酶抑制测定类似于程序A1和A2,用GST-修饰的TGFBR1(200-503)和1mg/ml酪蛋白作为底物,以200 µM ATP进行。
Smad 1/5
基于体外细胞的免疫荧光测定用于确定HUVEC细胞内ALK1-介导的SMAD1/5磷酸化的抑制剂:
ALK1是对于配体的TGF-β超家族的I型细胞表面受体。在成人中,ALK1主要在激活的内皮细胞上表达,例如在创伤愈合或肿瘤血管形成期间。BMP9和BMP10为ALK1的高亲和性配体。
BMP9和BMP10结合导致羰基末端基序SSXS中Ser463和Ser465上的所谓Smad1的磷酸化,以及在其相应位点上的Smad5和Smad8的磷酸化。这些磷酸化的Smad与共激活的Smad4二聚,并转运到核,它们在此刺激靶基因的转录。
将原代内皮细胞(HUVEC:人脐带静脉内皮细胞;供应商Promocell)在得自Promocell的培养基中培养(具有对应于5% FCS的补充物)最多5代,接种到具有透明底部的黑色384-孔培养板中(3000细胞/孔/30 μl),并在37℃、5 % CO2和90 % rH孵育16-24小时。
第二天,使细胞血清饥饿2-3h以停止源自FBS中存在的配体的TGF-β-介导的信号传导。然后连同试验化合物平行加入1.5ng/ml BMP-9,在37℃、5% CO2经2h,以确定使ALK1的官能活性阻断(导致SMAD1/5/8磷酸化和核转运)的化合物。
在固定(15min,PBS中4%甲醛)和渗透(10min,PBS中0.2% Triton X-100)后,用特异性磷酸-Smad1/5 (Ser463/465)抗体(Cell Signaling #9516)和Alexa488-标记的第二抗-兔-IgG-抗体进行间接免疫细胞化学染色。用碘化丙啶进行DNA染色允许平行细胞计数。在MDS ImageXpress Ultra confocal High Content Reader上进行图像获取和分析,使用图像分析软件MetaXpress。
最终读数为%核,在定义的背景上方有pSMAD1/5信号。
测定中的最终DMSO浓度为0.5%。经DMSO处理的HUVEC细胞用作中性对照(= 0%),且用专利中描述的10µM参比抑制剂处理的细胞用作抑制剂对照(= -100%)。将原始数据相对于中性和抑制性参比归一化。按剂量响应进行测定(10个化合物稀释物, 1 nM-30 µM)。
药理学数据
表1 一些代表性的式I化合物的ALK1、ALK2、ALK5 (TGFβR1)和Smad 1/5抑制(IC50)
说明:1.4 E-6表示1.4 x 10-6
表1中显示的化合物是根据本发明特别优选的化合物。
合成中间体
邻苯二胺衍生物
合成4-(3,4-二氨基苯基)哌嗪-1-甲酸叔丁酯
向哌嗪-1-甲酸叔丁酯(5.74 g, 30.8 mmol)和4-氟-1,2-二硝基苯(5.74 g, 30.8mmol)在乙腈(60 ml)的溶液加入碳酸钠(3.27 g, 30.8 mmol),并使所得悬浮液在室温搅拌20小时。用水稀释反应混合物,并使乙腈真空蒸发。滤出固体并真空干燥。用叔丁基甲基醚研制残余物,得到4-(3,4-二硝基苯基)哌嗪-1-甲酸叔丁酯,为黄色晶体;HPLC/MS 1.59min, [M-异丁烯]+ 297, 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 9.5 Hz, 1H),7.47 (d, J = 2.8 Hz, 1H), 7.13 (dd, J = 9.6, 2.8 Hz, 1H), 3.62 – 3.53 (m,4H), 3.53 – 3.40 (m, 4H), 1.42 (s, 9H).
向4-(3,4-二硝基苯基)哌嗪-1-甲酸叔丁酯(9.03 g, 25.6 mmol)在THF (90 ml)中的悬浮液加入湿的活性炭载钯(5% Pd, 约54%水, 2.2g),并将混合物在室温和大气压下氢化22小时。滤出催化剂并将滤液真空蒸发。用叔丁基甲基醚研制残余物,得到4-(3,4-二氨基苯基)哌嗪-1-甲酸叔丁酯,为浅灰色粉末;HPLC/MS 1.06 min, [M+H]+ 293; 1H NMR (400MHz, DMSO-d6) δ 6.40 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 2.7 Hz, 1H), 6.03 (dd,J = 8.3, 2.6 Hz, 1H), 4.36 (s, 2H), 4.02 (s, 2H), 3.40 (t, J = 5.1 Hz, 4H),2.85 – 2.72 (m, 4H), 1.41 (s, 9H).
类似地制备以下化合物:
5-吗啉-4-基-2-硝基-苯基胺
深棕色固体; HPLC/MS 0.72 min, [M+H]+ 194; 1H NMR (400 MHz, DMSO-d6) δ 6.40(d, J = 8.3 Hz, 1H), 6.20 (d, J = 2.6 Hz, 1H), 6.02-5.99 (m, 1H), 4.36 (br s,2H), 3.98 (br s, 2H), 3.67 (t, J = 4.6 Hz, 4H), 2.83 (t, J = 4.8 Hz, 4H).
5-吗啉-4-基-2-硝基-苯基胺
深棕色油; HPLC/MS 0.95 min, [M+H]+ 193.
3-(3,4-二氨基苯基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸叔丁酯
浅灰色固体; HPLC/MS 1.13 min, [M+H]+ 319;
1H NMR (400 MHz, DMSO-d6) δ 6.40 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 2.7Hz, 1H), 5.97 (dd, J = 8.4, 2.7 Hz, 1H), 4.35 (s, 2H), 4.16 (s, 2H), 3.94 (s,2H), 3.32 (s, 2H), 3.17 (d, J = 10.3 Hz, 2H), 2.72 – 2.58 (m, 2H), 1.92 –1.69 (m, 4H), 1.42 (s, 9H).
4-(3,4-二氨基苯基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯
深棕色泡沫; HPLC/MS 1.09 min, [M+H]+ 307.
1-(3,4-二氨基-苯基)-哌啶-4-醇
深棕色固体; HPLC/MS 0.27 min, [M+H]+ 208.
[1-(3,4-二氨基-苯基)-哌啶-4-基]-氨基甲酸叔丁酯
棕色固体; HPLC/MS 0.96 min, [M+H]+ 307;
1H NMR (400 MHz, DMSO-d6) δ 6.77 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 8.2Hz, 1H), 6.23 (d, J = 2.6 Hz, 1H), 6.03 (dd, J = 8.3, 2.6 Hz, 1H), 4.32 (s,2H), 3.94 (s, 2H), 3.3 (m, 5H), 1.76 (d, J = 12.2 Hz, 2H), 1.49 (m, 2H), 1.40(s, 9H).
2-(5-溴-2-甲氧基-3-吡啶基)-1H-苯并咪唑衍生物:
合成4-[2-(5-溴-2-甲氧基-3-吡啶基)-1H-苯并咪唑-5-基]哌嗪-1-甲酸叔丁酯
向5-溴-2-甲氧基-吡啶-3-甲醛(2.16 g, 10.0 mmol)和4-(3,4-二硝基苯基)哌嗪-1-甲酸叔丁酯(2.92 g, 10.0 mmol)在DMF (20 ml)中的溶液加入焦亚硫酸钠(5.70 g, 30mmol)。将所得悬浮液加热到120℃并在该温度下搅拌30分钟。使反应混合物冷却到室温并倒入水中(800 ml)。将所得沉淀物滤出,用水洗涤并真空干燥。用叔丁基甲基醚研制残余物,得到4-[2-(5-溴-2-甲氧基-3-吡啶基)-1H-苯并咪唑-5-基]哌嗪-1-甲酸叔丁酯,为浅灰色晶体; HPLC/MS 1.47 min, [M+H]+ 488,490;
1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 8.80 (d, J = 2.4 Hz, 1H), 8.64 (d, J =2.4 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.47 (dd, J = 9.2, 2.3 Hz, 1H), 7.33(d, J = 2.2 Hz, 1H), 4.19 (s, 3H), 3.62 (t, J = 5.2 Hz, 4H), 3.33 (t, J = 5.2Hz, 4H), 1.46 (s, 9H).
类似地制备以下化合物
2-(5-溴-2-甲氧基-吡啶-3-基)-5-甲氧基-1H-苯并咪唑
棕色树脂; HPLC/MS 2.365 min, [M+H]+ 334,335.
2-(5-溴-2-甲氧基-吡啶-3-基)-5-哌啶-1-基-1H-苯并咪唑
橙棕色固体; HPLC/MS 2.05 min, [M+H]+ 387,389.
3-[2-(5-溴-2-甲氧基-吡啶-3-基)-3H-苯并咪唑-5-基]-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸叔丁酯
淡棕色固体; HPLC/MS 1.52 min, [M+H]+ 514,516.
4-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-[1,4]二氮杂环庚烷-1-甲酸叔丁酯
米黄色固体; HPLC/MS 1.36 min, [M+H]+ 502,504.
2-(5-溴-2-甲氧基-吡啶-3-基)-5-吗啉-4-基-1H-苯并咪唑
深棕色固体; HPLC/MS 2.19 min, [M+H]+ 389,391.
1-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-哌啶-4-醇
棕色胶; HPLC/MS 1.10 min, [M+H]+ 403,405;
1H NMR (400 MHz, DMSO-d6, d-TFA) δ 8.78 (d, J = 2.4 Hz, 1H), 8.60 (d, J =2.4 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.83 (dd, J= 9.0, 2.2 Hz, 1H), 4.14 (s, 3H), 3.96 (tt, J = 7.5, 3.5 Hz, 1H), 3.78 (m,2H), 3.60 (m, 2H), 2.13 (m, 2H), 1.95 – 1.83 (m, 2H).
{1-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-哌啶-4-基}-氨基甲酸叔丁酯
黄色固体; HPLC/MS 1.29 min, [M+H]+ 502,504;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 8.77 (d, J = 2.4 Hz, 1H), 8.59 (d, J =2.4 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.84 (dd, J= 9.1, 2.2 Hz, 1H), 4.13 (s, 3H), 3.80 (s, 1H), 3.77 – 3.62 (m, 4H), 2.11 (m,2H), 1.90 (m, 2H), 1.39 (s, 9H)。
实施例
5-(3-羟甲基-苯基)-3-(5-吗啉-4-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A1”)
向微波瓶加入2-(5-溴-2-甲氧基-吡啶-3-基)-5-吗啉-4-基-1H-苯并咪唑 (195 mg,0.50 mmol)、[3-(羟甲基)苯基]硼酸(85 mg, 0.56 mmol)碳酸氢钾(80 mg, 0.80 mmol)、DMF (1.50 ml)和水(0.75 ml)。瓶用氮气吹洗。然后在氮气下加入双(三苯基膦)氯化钯(II)(8.0 mg, 11 µmol),并将反应混合物在120℃下在微波反应器中辐照1小时。在硅藻土上过滤反应混合物,并用二氯甲烷洗涤滤饼。蒸发滤液,并在硅胶柱上用二氯甲烷/甲醇作为洗脱剂将残余物层析,得到{3-[6-甲氧基-5-(5-吗啉-4-基-1H-苯并咪唑-2-基)-吡啶-3-基]-苯基}-甲醇,为棕色固体; HPLC/MS 1.16 min, [M+H]+ 417.
向微波瓶加入{3-[6-甲氧基-5-(5-吗啉-4-基-1H-苯并咪唑-2-基)-吡啶-3-基]-苯基}-甲醇 (83.3 mg, 0.20 mmol)、水(1 ml)和盐酸水溶液(37%重量, 1 ml)。瓶在微波反应器中在100℃下辐照15分钟。在硅藻土上吸收反应混合物并在硅胶柱上用二氯甲烷/甲醇作为洗脱剂层析,得到5-(3-羟甲基-苯基)-3-(5-吗啉-4-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮,为黄色晶体; HPLC/MS 1.06 min, [M+H]+ 403;
1H NMR (500 MHz, DMSO-d6, TFA-d1 ) δ 9.03 (d, J = 2.7 Hz, 1H), 8.24 (d, J= 2.7 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 8.2 Hz,1H), 7.45 (d, J = 7.6 Hz, 1H), 7.43 – 7.39 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H),4.60 (s, 2H), 3.86 – 3.76 (m, 4H), 3.30 (t, J = 4.9 Hz, 4H).
类似地制备以下化合物:
3-(1H-苯并咪唑-2-基)-5-喹啉-4-基-1H-吡啶-2-酮 (“A2”)
浅棕色晶体, MS-ESI: [M+H]+ 339; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H),12.63 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.75 (d, J = 2.7 Hz, 1H), 8.14 (d, J= 8.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.84 (ddd,J = 8.4, 6.8, 1.4 Hz, 1H), 7.80 – 7.48 (m, 4H), 7.18 (m, 2H).
5-(5-氯-1H-苯并咪唑-2-基)-1H-[3,4']二吡啶基-6-酮 (“A3”)
灰色晶体, MS-ESI: [M+H]+ 323; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.38 (d,J = 2.8 Hz, 1H), 9.06 (d, J = 6.1 Hz, 2H), 9.02 (d, J = 2.8 Hz, 1H), 8.49 (d,J = 6.2 Hz, 2H), 8.07 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.64(dd, J = 8.8, 2.1 Hz, 1H).
5-(5-甲基-1H-苯并咪唑-2-基)-1H-[3,4']二吡啶基-6-酮 (“A4”)
浅绿色晶体, MS-ESI: [M+H]+ 303; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.29(d, J = 2.7 Hz, 1H), 9.02 (d, J = 6.2 Hz, 2H), 8.94 (d, J = 2.7 Hz, 1H), 8.44(d, J = 6.2 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.41 (d, J = 8.5Hz, 1H), 2.51 (s, 3H).
5-(4-甲基-1H-苯并咪唑-2-基)-1H-[3,4']二吡啶基-6-酮 (“A5”)
浅棕色晶体, MS-ESI: [M+H]+ 303; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.35(d, J = 2.8 Hz, 1H), 9.00 (d, J = 6.7 Hz, 2H), 8.92 (d, J = 2.8 Hz, 1H), 8.44(d, J = 6.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36(d, J = 7.4 Hz, 1H), 2.68 (s, 3H).
5-(5,6-二甲氧基-1H-苯并咪唑-2-基)-1H-[3,4']二吡啶基-6-酮 (“A6”)
黄色固体, MS-ESI: [M+H]+ 349; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.29 (d,J = 2.4 Hz, 1H), 9.05 (d, J = 6.6 Hz, 2H), 8.92 (d, J = 2.8 Hz, 1H), 8.48 (d,J = 6.7 Hz, 2H), 7.43 (s, 2H), 3.93 (s, 6H).
2-(6-氧代-1,6-二氢-[3,4']二吡啶基-5-基)-1H-苯并咪唑-5-甲腈 (“A7”)
MS-ESI: [M+H]+ 314; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.36 (d, J = 2.8Hz, 1H), 9.01 (d, J = 7.0 Hz, 2H), 8.98 (d, J = 2.7 Hz, 1H), 8.45 (d, J = 7.1Hz, 2H), 8.43 – 8.42 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.90 (dd, J = 8.5,1.5 Hz, 1H).
2-[2-氧代-5-(4-吡啶基)-1H-吡啶-3-基]-1H-苯并咪唑-5-甲酸甲酯 (“A8”)
MS-ESI: [M+H]+ 347; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.43 (d, J = 2.7Hz, 1H), 9.06 (d, J = 6.4 Hz, 2H), 9.02 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 1.6Hz, 1H), 8.51 (d, J = 6.5 Hz, 2H), 8.19 (dd, J = 8.6, 1.5 Hz, 1H), 8.08 (d, J= 8.6 Hz, 1H), 3.96 (s, 3H).
3-(6-吗啉-4-基-1H-苯并咪唑-2-基)-5-喹啉-4-基-1H-吡啶-2-酮 (“A9”)
MS-ESI: [M+H]+ 424; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.51 (d, J = 5.7Hz, 1H), 9.05 (d, J = 2.6 Hz, 1H), 8.53 – 8.42 (m, 3H), 8.26 (m, 2H), 8.05(dd, J = 8.5, 7.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.53 – 7.43 (m, 2H),3.89 (dd, J = 6.1, 3.5 Hz, 4H), 3.44 – 3.31 (m, 4H).
3-[5-(吡啶-4-基氧基)-1H-苯并咪唑-2-基]-5-喹啉-4-基-1H-吡啶-2-酮 (“A10”)
MS-ESI: [M+H]+ 432; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.48 (d, J = 5.6Hz, 1H), 9.08 (d, J = 2.6 Hz, 1H), 8.88 (d, J = 7.4 Hz, 2H), 8.54 (d, J = 2.6Hz, 1H), 8.46 (d, J = 8.7 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.31 – 8.21 (m,2H), 8.13 (d, J = 8.9 Hz, 1H), 8.03 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.94 (d,J = 2.2 Hz, 1H), 7.62 – 7.50 (m, 3H).
5-(2-氯-5-羟甲基-苯基)-3-(5-吗啉-4-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A11”)
HPLC/MS 1.09 min, [M+H]+ 437; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 8.77 (d,J = 2.6 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 9.8 Hz, 1H), 7.52 (d,J = 8.2 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.44 – 7.33 (m, 3H), 4.56 (s, 2H),3.83 (t, J = 5.0 Hz, 4H), 3.30 (t, J = 4.9 Hz, 4H).
5-(3-羟甲基-苯基)-3-[5-(4-羟基-哌啶-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮(“A12”)
黄色固体; HPLC/MS 0.97 min, [M+H]+ 417; 1H NMR (500 MHz, DMSO-d6) δ 9.12(d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.07(d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.0, 2.2 Hz, 1H), 7.69 (s, 1H), 7.59 (dt,J = 7.8, 1.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H),4.60 (s, 2H), 3.97 (tt, J = 7.4, 3.5 Hz, 1H), 3.77 (ddd, J = 11.4, 7.4, 3.7Hz, 2H), 3.62 (ddd, J = 11.6, 7.9, 3.6 Hz, 2H), 2.14 (m, 2H), 1.91 (m, 2H).
5-(3-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐(“A13”)
向微波瓶加入4-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-哌嗪-1-甲酸叔丁酯(488 mg, 1.00 mmol)、[3-(羟甲基)苯基]硼酸(182 mg, 1.20 mmol)、碳酸氢钾(101 mg, 1.20 mmol)、DMF (4.0 ml)和水(1.0 ml)。瓶用氮气吹洗。然后在氮气下加入双(三苯基膦)氯化钯(II)(14 mg, 20 µmol),并将反应混合物在120℃下在微波反应器中辐照1小时。用水猝灭反应混合物。滤出所得沉淀,用水洗涤并真空干燥,得到4-{2-[5-(3-羟甲基-苯基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌嗪-1-甲酸叔丁酯,为黄色固体; HPLC/MS 1.31 min, [M+H]+ 516; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 8.93 (d,J = 2.4 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.81 (s,1H), 7.70 (dt, J = 7.9, 1.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.50 (dd, J =9.2, 2.3 Hz, 1H), 7.45 (dt, J = 7.8, 1.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H),4.68 (s, 2H), 4.27 (s, 3H), 3.64 (t, J = 5.2 Hz, 4H), 3.36 (t, J = 5.2 Hz,4H), 1.47 (s, 9H).
向4-{2-[5-(3-羟甲基-苯基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌嗪-1-甲酸叔丁酯(510 mg, 0.99 mmol)加入水(3.5 ml)和盐酸水溶液(37%重量, 4.4 ml)。将所得悬浮液在80℃下搅拌14小时。减压浓缩反应混合物,并用乙醇研制残余物,得到5-(3-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐,为橙色晶体;HPLC/MS 0.92 min, [M+H]+ 402; 1H NMR (400 MHz, DMSO-d6) δ 14.99 (bs, 1H),14.85 (bs, 1H), 13.34 (s, 1H), 9.46 (s, 2H), 9.41 (d, J = 2.6 Hz, 1H), 8.28(s, 1H), 7.82 – 7.76 (m, 2H), 7.72 (dt, J = 7.9, 1.3 Hz, 1H), 7.45 (t, J =7.7 Hz, 1H), 7.40 – 7.32 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 4.60 (s, 2H),3.47 (m, 4H), 3.28 (m, 4H).
类似地制备以下化合物:
3-(6-哌嗪-1-基-1H-苯并咪唑-2-基)-5-喹啉-4-基-1H-吡啶-2-酮 (“A14”)
MS-ESI: [M+H]+ 423; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.51 (d, J = 5.7Hz, 1H), 9.04 (d, J = 2.6 Hz, 1H), 8.50 – 8.44 (m, 3H), 8.31 – 8.22 (m, 2H),8.04 (ddd, J = 8.4, 6.9, 1.1 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.39 (dd, J =9.1, 2.3 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 3.49 (dd, J = 6.9, 3.7 Hz, 4H),3.37 (dd, J = 6.7, 3.8 Hz, 4H).
5-(1H-吲哚-3-基)-3-(6-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (“A15”)
MS-ESI: [M+H]+ 411; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.22 (d, J = 2.6Hz, 1H), 8.45 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 7.8Hz, 1H), 7.45 – 7.37 (m, 3H), 7.15 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz,1H), 3.48 (dd, J = 6.7, 3.6 Hz, 4H), 3.36 (dd, J = 6.8, 3.6 Hz, 4H).
5-(4-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (“A16”)
HPLC/MS 0.91 min, [M+H]+ 402; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.05 (d,J = 2.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.60 (d,J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 2.2 Hz, 1H), 7.23(dd, J = 9.1, 2.3 Hz, 1H), 4.52 (s, 2H), 3.41 (dd, J = 7.0, 3.6 Hz, 4H), 3.34– 3.23 (m, 4H).
3-(5-[1,4]二氮杂环庚烷-1-基-1H-苯并咪唑-2-基)-5-(3-羟甲基-苯基)-1H-吡啶-2-酮 (“A17”)
橙色固体, HPLC/MS 0.94 min, [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.01 (d, J = 2.7 Hz, 1H), 8.30 – 8.17 (m, 1H), 7.73 (d, J = 9.1 Hz, 1H),7.69 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.14 (d, J = 9.3 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 4.60 (s,2H), 3.80 (t, J = 5.1 Hz, 2H), 3.60 (t, J = 6.1 Hz, 2H), 3.34 (t, J = 5.1 Hz,2H), 3.23 – 3.13 (m, 2H), 2.14 (p, J = 6.2 Hz, 2H).
5-呋喃并[3,2-b]吡啶-7-基-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A18”)
橙色固体, HPLC/MS 0.90 min, [M+H]+ 413; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.58 (d, J = 2.7 Hz, 1H), 9.06 (d, J = 6.3 Hz, 1H), 9.01 (d, J = 2.6 Hz,1H), 8.86 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 6.4 Hz, 1H), 7.88 (d, J = 9.7 Hz,1H), 7.55 (d, J = 2.3 Hz, 1H), 7.46 – 7.35 (m, 2H), 3.52 (m, 4H), 3.43 – 3.35(m, 4H).
5-(3-甲氧基甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A19”)
黄色固体, HPLC/MS 0.98 min, [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.06 (d, J = 2.7 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 8.9 Hz,1H), 7.64 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.34 –7.15 (m, 3H), 4.45 (s, 2H), 3.43 (m, 4H), 3.30 (m, 7H).
5-(4-氟-3-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A20”)
橙色固体, HPLC/MS 0.95 min, [M+H]+ 420; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.13 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.88 (dd, J = 6.9, 2.5Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.69 (ddd, J = 7.9, 4.8, 2.6 Hz, 1H), 7.43– 7.34 (m, 2H), 7.28 (dd, J = 9.8, 8.5 Hz, 1H), 4.69 (s, 2H), 3.50 (m, 5H),3.37 (m, 4H).
5-(3,5-二氟-4-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐 (“A21”)
黄色固体, HPLC/MS 0.91 min, [M+H]+ 438; 1H NMR (500 MHz, DMSO-d6, TFA-d1)δ 9.25 (d, J = 2.7 Hz, 1H), 8.49 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.0 Hz,1H), 7.61 (m, 2H), 7.39 (dd, J = 9.1, 2.3 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H),4.57 (s, 2H), 3.49 m, 4H), 3.40 – 3.29 (m, 4H).
5-(2-氯-5-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐 (“A22”)
黄色固体, HPLC/MS 0.92 min, [M+H]+ 436; 1H NMR (500 MHz, DMSO-d6, TFA-d1)δ 8.87 (d, J = 2.6 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 9.0 Hz,1H), 7.58 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.44 (dd, J = 8.3,2.1 Hz, 1H), 7.37 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 4.62(s, 2H), 3.49 (m, 4H), 3.41 – 3.25 (m, 4H).
5-(2-氟-3-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮(“A23”)
橙色粉末, HPLC/MS 0.89 min, [M+H]+ 420; 1H NMR (500 MHz, DMSO-d6, TFA-d1)δ 8.98 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 9.1 Hz,1H), 7.58 (m, 2H), 7.41 – 7.33 (m, 3H), 4.68 (s, 2H), 3.49 (m, 4H), 3.43 –3.30 (m, 4H).
3-(5-[1,4]二氮杂环庚烷-1-基-1H-苯并咪唑-2-基)-5-(4-氟-3-羟甲基-苯基)-1H-吡啶-2-酮 (“A24”)
橙色粉末, HPLC/MS 0.93 min, [M+H]+ 434; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.06 (d, J = 2.6 Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.91 – 7.84 (m, 1H),7.76 (d, J = 9.0 Hz, 1H), 7.61 (m, 1H), 7.23 (t, J = 9.2 Hz, 1H), 7.19 – 7.11(m, 2H), 4.74 (s, 2H), 3.92 – 3.82 (m, 2H), 3.76 – 3.57 (m, 3H), 3.42 (t, J =5.0 Hz, 2H), 3.28 – 3.18 (m, 2H), 2.23 (m, 2H).
5-(3-氟-4-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二(三氟乙酸盐) (“A25”)
橙色固体, HPLC/MS 0.90 min, [M+H]+ 430; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.10 (d, J = 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 9.8 Hz,1H), 7.67 – 7.56 (m, 3H), 7.43 – 7.32 (m, 2H), 4.66 (s, 2H), 3.50 (m, 4H),3.43 – 3.33 (m, 4H).
3-[5-(4-氨基-哌啶-1-基)-1H-苯并咪唑-2-基]-5-(3-羟甲基-苯基)-1H-吡啶-2-酮二盐酸盐 (“A26”)
橙色固体, HPLC/MS 0.90 min, [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6, TFA-d1)1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 2.6 Hz, 1H), 8.28 (d, J = 2.8 Hz,1H), 7.95 (m, 2H), 7.70 (m, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.6Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 4.59 (s, 2H), 3.79 (d, J = 12.5 Hz, 2H),3.45 (m, 3H), 2.19 (d, J = 13.2 Hz, 2H), 2.03 (m, 2H).
5-(3-羟甲基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮(“A27”)
向5-(3-羟甲基-苯基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐(94.9 mg, 0.20 mmol)和碳酸钠(64 mg, 0.60 mmol)在乙腈(1 ml)中的悬浮液加入甲醛(35%水溶液, 78 µl, 1.0 mmol)。将混合物在室温搅拌5分钟。然后,加入氰基硼氢化钠(15.1 mg, 0.40 mmol),并将反应混合物在室温搅拌22小时。过滤反应混合物,并真空蒸发滤液。通过制备型HPLC纯化残余物,得到5-(3-羟甲基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮,为黄色固体; HPLC/MS 0.93 min, [M+H]+ 416;
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.08 (d, J = 2.6 Hz, 1H), 8.29 (d, J =2.6 Hz, 1H), 8.12 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J= 8.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.38 (m,2H), 4.65 (s, 2H), 3.94 (d, J = 12.5 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.30(t, J = 11.5 Hz, 2H), 3.15 (t, J = 12.7 Hz, 2H), 2.95 (s, 3H).
类似地制备以下化合物
5-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-[3,4']二吡啶基-6-酮 (“A28”)
MS-ESI: [M+H]+ 387; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.38 (d, J = 2.7Hz, 1H), 9.07 – 9.00 (m, 2H), 8.97 (dd, J = 2.8, 1.4 Hz, 1H), 8.51 (d, J =7.1 Hz, 2H), 8.10 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.44 (d, J =2.2 Hz, 1H), 7.43 – 7.38 (m, 1H), 3.94 (d, J = 13.0 Hz, 2H), 3.67 (d, J =12.0 Hz, 2H), 3.43 – 3.27 (m, 2H), 3.28 – 3.13 (m, 2H), 2.97 (s, 3H).
3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-喹啉-4-基-1H-吡啶-2-酮(“A29”)
MS-ESI: [M+H]+ 437; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.47 (d, J = 5.6Hz, 1H), 8.97 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.44 (d, J = 8.7Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.23 (m, 2H), 8.00 (t, J = 7.8 Hz, 1H),7.80 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 9.2, 2.3 Hz, 1H), 7.30 (d, J = 2.2Hz, 1H), 3.91 (d, J = 13.1 Hz, 2H), 3.60 (d, J = 12.1 Hz, 2H), 3.25 (td, J =12.1, 2.9 Hz, 2H), 3.08 (t, J = 11.8 Hz, 2H), 2.91 (s, 3H).
3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-(1-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮 (“A30”)
MS-ESI: [M+H]+ 390; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 8.95 (d, J = 2.5Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.84 (d, J =8.9 Hz, 1H), 7.47 – 7.34 (m, 2H), 3.92 (m, 5H), 3.64 (d, J = 12.1 Hz, 2H),3.37 – 3.21 (m, 2H), 3.19 – 3.06 (m, 2H), 2.94 (s, 3H).
5-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-[3,3']二吡啶基-6-酮 (“A31”)
MS-ESI: [M+H]+ 387.
3-[6-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-(3-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮(“A32”)
MS-ESI: [M+H]+ 390; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 8.79 (d, J = 2.6Hz, 1H), 8.12 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H),7.40 (dd, J = 9.1, 2.3 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 3.93 (d, J = 13.2Hz, 2H), 3.69 – 3.59 (m, 2H), 3.29 (td, J = 11.9, 3.0 Hz, 2H), 3.19 – 3.05(m, 2H), 2.94 (s, 3H), 2.48 (s, 3H).
5-(3-羟甲基-苯基)-3-[5-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮 (“A33”)
橙棕色固体, HPLC/MS 0.94 min, [M+H]+ 430; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.00 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.09 (s, 1H,甲酸盐), 7.74 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45(t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 9.2, 2.4 Hz,1H), 7.03 (d, J = 2.3 Hz, 1H), 4.60 (s, 2H), 3.89 (m, 1H), 3.75 (m, 1H), 3.66– 3.45 (m, 4H), 3.31 (m, 1H), 3.26 – 3.17 (m, 1H), 2.88 (s, 3H), 2.23 (m,2H).
5-(4-氟-3-羟甲基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮 (“A34”)
黄色固体, HPLC/MS 0.95 min, [M+H]+ 434; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.06 (d, J = 2.7 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H), 8.12 (s, 1H,甲酸盐),7.87 (dd, J = 7.0, 2.5 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.66 (ddd, J = 7.9,4.8, 2.6 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.28 (dd, J = 9.8, 8.5 Hz, 1H), 4.70(s, 2H), 3.94 (d, J = 13.1 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.41 – 3.23(m, 2H), 3.25 – 3.09 (m, 2H) 2.96 (s, 3H).
5-(4-羟甲基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮(“A35”)
黄色固体, HPLC/MS 0.92 min, [M+H]+ 416; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.10 (d, J = 2.7 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 9.8 Hz,1H), 7.73 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.43 – 7.33 (m, 2H),4.61 (s, 2H), 3.94 (d, J = 13.1 Hz, 2H), 3.65 (d, J = 12.0 Hz, 2H), 3.31 (t,J = 11.4 Hz, 2H), 3.16 (t, J = 12.3 Hz, 2H), 2.96 (s, 3H).
3-[5-(4-二甲基氨基-哌啶-1-基)-1H-苯并咪唑-2-基]-5-(3-羟甲基-苯基)-1H-吡啶-2-酮甲酸盐 (“A36”)
黄色固体, HPLC/MS 0.92 min, [M+H]+ 445; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 9.03 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.11 (s, 1H,甲酸盐),7.80 (d, J = 8.9 Hz, 1H), 7.69 (t, J = 1.7 Hz, 1H), 7.60 (dt, J = 7.8, 1.5Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.43 – 7.30 (m, 3H), 4.61 (s, 2H), 3.91(d, J = 12.7 Hz, 2H), 3.40 (ddt, J = 11.8, 7.4, 3.7 Hz, 1H), 3.04 – 2.87 (m,2H), 2.82 (s, 6H), 2.17 (d, J = 11.2 Hz, 2H), 1.82 (qd, J = 12.1, 4.0 Hz,2H).
5-(2-氟-3-羟甲基-苯基)-3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮三氟乙酸盐 (“A37”)
黄色固体, HPLC/MS 0.90 min, [M+H]+ 434; 1H NMR (400 MHz, DMSO-d6, TFA-d1)δ 8.94 (d, J = 2.6 Hz, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 9.0 Hz,1H), 7.57 (m, 2H), 7.45 – 7.26 (m, 3H), 4.69 (s, 2H), 3.93 (d, J = 13.4 Hz,2H), 3.65 (d, J = 11.6 Hz, 2H), 3.43 – 3.25 (m, 2H), 3.23 – 3.05 (m, 2H),2.95 (s, 3H).
3-[5-(4-羟基-哌啶-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A38”)
向微波瓶加入1-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-哌啶-4-醇(371 mg, 0.92 mmol)、1-苯基磺酰基-1H-吡咯并[2,3-b]吡啶-4-硼酸频哪醇酯(368 mg,0.96 mmol)、碳酸氢钾(122 mg, 1.22 mmol)、DMF (2.0 ml)和水(0.4 ml)。瓶用氮气吹洗。然后在氮气下加入双(三苯基膦)氯化钯(II)(13 mg, 18 µmol),并将反应混合物在微波反应器中在120℃下辐照1小时。将反应混合物倒入水中(20 ml),滤出所得沉淀并用水洗涤。在硅胶柱上用二氯甲烷/甲醇作为洗脱剂将残余物层析,得到1-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌啶-4-醇,为黄色固体; HPLC/MS 1.22 min, [M+H]+ 581; 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J =2.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.23 – 8.13(m, 2H), 8.05 (m, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 9.0, 2.2 Hz,1H), 7.75 – 7.67 (m, 1H), 7.67 – 7.58 (m, 2H), 7.55 (d, J = 5.1 Hz, 1H), 7.12(d, J = 4.1 Hz, 1H), 4.23 (s, 3H), 3.94 (tt, J = 7.5, 3.6 Hz, 1H), 3.77 (ddd,J = 11.2, 7.7, 4.4 Hz, 2H), 3.57 (ddd, J = 11.7, 8.2, 3.4 Hz, 2H), 2.21 –2.06 (m, 2H), 1.87 (m, 2H).
向微波瓶加入1-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌啶-4-醇(308 mg, 0.53 mmol)、水(1.8 ml)和盐酸水溶液(37%重量, 1.8 ml)。瓶在微波反应器中在100℃辐照15分钟。将反应混合物倒入30 ml 1 NNaOH溶液。滤出所得沉淀,用水洗涤并真空干燥,得到5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-[5-(4-羟基-哌啶-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮,为棕色固体;HPLC/MS 1.10 min, [M+H]+ 567; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.06 (d, J =2.6 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.37 (d, J = 2.6 Hz, 1H), 8.22 (d, J =2.1 Hz, 1H), 8.19 – 8.13 (m, 2H), 8.05 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 4.1Hz, 1H), 7.89 (dd, J = 9.0, 2.2 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.60 (t, J= 7.9 Hz, 2H), 7.49 (d, J = 5.0 Hz, 1H), 7.09 (d, J = 4.1 Hz, 1H), 3.96 (tt,J = 7.3, 3.5 Hz, 1H), 3.76 (ddd, J = 11.3, 7.4, 3.7 Hz, 2H), 3.61 (ddd, J =11.6, 7.8, 3.6 Hz, 2H), 2.15 (ddt, J = 14.2, 6.9, 3.5 Hz, 2H), 1.92 (dtd, J =14.1, 7.7, 3.6 Hz, 2H).
向5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-[5-(4-羟基-哌啶-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮 (153 mg, 0.27 mmol)和碳酸铯(259 mg, 0.80 mmol)在THF(500 µl)的悬浮液加入2,2,2-三氟乙醇(500 µl),并在80℃下将反应混合物搅拌2小时。减压浓缩反应混合物,并在硅胶柱上将残余物层析,得到3-[5-(4-羟基-哌啶-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮,为黄色固体; HPLC/MS0.92 min, [M+H]+ 427; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.22 (d, J = 2.7 Hz,1H), 8.61 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 2.1 Hz,1H), 8.07 (d, J = 9.0 Hz, 1H), 7.92 – 7.84 (m, 2H), 7.77 (d, J = 6.3 Hz, 1H),7.15 (d, J = 3.6 Hz, 1H), 3.97 (tt, J = 7.1, 3.4 Hz, 1H), 3.78 (ddd, J =11.4, 7.7, 3.6 Hz, 2H), 3.61 (ddd, J = 11.7, 7.6, 3.6 Hz, 2H), 2.15 (ddd, J =14.3, 7.3, 3.7 Hz, 2H), 1.91 (m, 2H).
类似地制备以下化合物
3-(1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A39”)
MS-ESI: [M+H]+ 328; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (bs, 1H), 11.96 (s,1H), 9.09 (d, J = 2.6 Hz, 1H), 8.41 – 8.29 (m, 2H), 7.90 (m, 2H), 7.66 – 7.62(m, 1H), 7.54 (m, 2H), 7.31 (d, J = 5.0 Hz, 1H), 6.81 – 6.75 (m, 1H).
3-[5-(吡啶-4-基氧基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A40”)
MS-ESI: [M+H]+ 421.
3-(5-吗啉-4-基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A41”)
HPLC/MS 0.97 min, [M+H]+ 413; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.13 (d,J = 2.6 Hz, 1H), 8.60 (d, J = 6.3 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 7.86 (d,J = 3.6 Hz, 1H), 7.82 (d, J = 9.8 Hz, 1H), 7.75 (d, J = 6.3 Hz, 1H), 7.50 –7.37 (m, 2H), 7.15 (d, J = 3.6 Hz, 1H), 3.87 – 3.79 (m, 4H), 3.45 – 3.23 (m,4H).
3-(5-甲氧基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮(“A42”)
MS-ESI: [M+H]+ 358; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.12 (d, J = 2.6Hz, 1H), 8.53 (d, J = 6.3 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 3.6Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 6.3 Hz, 1H), 7.30 (d, J = 2.4Hz, 1H), 7.15 – 7.07 (m, 2H), 3.81 (s, 3H).
3-(5-哌啶-1-基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A43”)
HPLC/MS 1.01 min, [M+H]+ 411; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.23 (d,J = 2.7 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.53 (d, J = 6.2 Hz, 1H), 8.26 (d,J = 2.1 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.89 (dd, J = 9.0, 2.2 Hz, 1H),7.78 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 6.3 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H),3.63 (t, J = 5.5 Hz, 4H), 1.96 (m, 4H), 1.78 – 1.63 (m, 2H).
3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮二盐酸盐 (“A44”)
向微波瓶加入4-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-哌嗪-1-甲酸叔丁酯(464 mg, 0.95 mmol)、1-苯基磺酰基-1H-吡咯并[2,3-b]吡啶-4-硼酸频哪醇酯(588 mg, 1.53 mmol)、碳酸氢钾(125 mg, 1.25 mmol)、DMF (2.4 ml)和水(1.2 ml)。瓶用氮气吹洗。然后在氮气下加入双(三苯基膦)氯化钯(II)(42 mg, 0.06 mmol),并在微波反应器中在120℃辐照反应混合物2小时。在硅藻土上过滤反应混合物,真空浓缩滤液。在硅胶柱上用二氯甲烷/甲醇作为洗脱剂将残余物层析,得到4-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌嗪-1-甲酸叔丁酯,为米黄色无定形固体; HPLC/MS 2.82 min, [M+H]+ 666; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 8.84 (d, J = 2.3 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.20 – 8.12 (m, 2H), 7.98 (d, J = 4.1 Hz, 1H), 7.76 (d, J = 9.0 Hz,1H), 7.67 – 7.62 (m, 1H), 7.55 (m, 2H), 7.48 (d, J = 5.0 Hz, 1H), 7.42 (dd, J= 9.1, 2.3 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.06 (d, J = 4.1 Hz, 1H), 4.21(s, 3H), 3.57 (t, J = 5.1 Hz, 4H), 3.28 (t, J = 5.2 Hz, 4H), 1.39 (s, 9H).
向微波瓶加入4-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-哌嗪-1-甲酸叔丁酯(266 mg, 0.40 mmol)、水(1.5 ml)和盐酸水溶液(37%重量, 1.5 ml)。瓶在微波反应器中在100℃辐照30分钟。将反应混合物倒入30ml 1 N NaOH溶液。将所得沉淀蒸发,得到5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐,为米黄色固体; HPLC/MS1.05 min, [M+H]+ 552.
向5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮二盐酸盐(50 mg, 0.08 mmol)和碳酸铯(200 mg, 0.61 mmol)在THF (1ml)中的悬浮液加入2,2,2-三氟乙醇(1 ml),并将反应混合物在80℃搅拌45小时。减压浓缩反应混合物,并通过制备型HPLC纯化残余物。合并和蒸发含产物的级分。将残余物溶于2 NHCl (1 ml),并在80℃搅拌2小时。蒸发溶液并真空干燥残余物,在硅胶柱上得到3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮二盐酸盐,为橙色细粉末; HPLC/MS 0.87 min, [M+H]+ 412. 1H NMR (400 MHz, DMSO-d6) δ 16(bs, 2H), 12.37 (s, 1H), 11.87 (s, 1H), 9.9 (bs, 2H), 9.01 (d, J = 2.7 Hz,1H), 8.30 (d, J = 4.9 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.61 (dd, J = 3.5,2.5 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 7.23 (s,1H), 7.00 (dd, J = 8.9, 2.4 Hz, 1H), 6.65 (dd, J = 3.6, 1.7 Hz, 1H), 3.34 –3.23 (m, 4H), 3.22 – 3.13 (m, 4H).
类似地制备以下化合物
5-(2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (“A45”)
HPLC/MS 0.89 min, [M+H]+ 426; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 8.95 (d,J = 2.5 Hz, 1H), 8.68 (dd, J = 7.9, 1.2 Hz, 1H), 8.49 (dd, J = 5.9, 1.2 Hz,1H), 8.06 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 7.9,5.9 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 9.1, 2.3 Hz, 1H), 3.52(dd, J = 7.0, 3.6 Hz, 4H), 3.45 – 3.31 (m, 4H), 2.67 (s, 3H).
3-[6-(3,8-二氮杂二环[3.2.1]辛-3-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A46”)
棕色固体, HPLC/MS 0.93 min, [M+H]+ 438; 1H NMR (400 MHz, DMSO-d6) δ 9.20(d, J = 2.6 Hz, 1H), 8.67 (d, J = 6.2 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.92(d, J = 3.6 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.35(dd, J = 9.2, 2.3 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 3.7 Hz,1H), 4.26 (s, 2H), 3.76 (d, J = 11.2 Hz, 2H), 3.27 (d, J = 11.8 Hz, 2H), 2.09(s, 4H).
3-(5-[1,4]二氮杂环庚烷-1-基-1H-苯并咪唑-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A47”)
浅棕色固体, HPLC/MS 0.93 min, [M+H]+ 426; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.10 (d, J = 2.6 Hz, 1H), 8.57 (d, J = 6.3 Hz, 1H), 8.49 (d, J = 2.6Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.73 (d, J = 6.3 Hz, 1H), 7.71 (d, J = 9.2Hz, 1H), 7.14 – 7.09 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 3.79 (t, J = 5.0 Hz,2H), 3.58 (t, J = 6.1 Hz, 2H), 3.38 – 3.27 (m, 2H), 3.16 (dd, J = 6.6, 4.3Hz, 2H), 2.14 (p, J = 5.9 Hz, 2H).
5-(1H-吲哚-4-基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (“A48”)
橄榄黄色固体, HPLC/MS 0.97 min, [M+H]+ 411; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.00 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 8.9Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.24 – 7.12 (m, 3H), 7.08(d, J = 7.2 Hz, 1H), 3.37 (m, 4H), 3.24 (m, 4H).
5-(2-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-(5-哌嗪-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (“A48a”)
1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.10 (d, J = 2.7 Hz, 1H), 8.47 (d, J =2.6 Hz, 1H), 8.44 (d, J = 6.3 Hz, 1H), 7.77 (d, J = 9.7 Hz, 1H), 7.67 (d, J =6.3 Hz, 1H), 7.34 – 7.25 (m, 2H), 6.82 (s, 1H), 3.40-3-45 (m, 4H), 3.27-3.32(m, 4H), 2.51 (s, 3H).
3-[5-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A49”)
向微波瓶加入4-[2-(5-溴-2-甲氧基-吡啶-3-基)-1H-苯并咪唑-5-基]-[1,4]二氮杂环庚烷-1-甲酸叔丁酯(502 mg, 1.00 mmol)、1-苯基磺酰基-1H-吡咯并[2,3-b]吡啶-4-硼酸频哪醇酯(500 mg, 1.30 mmol)、碳酸氢钠(119 mg, 1.42 mmol)、DMF (4.7 ml)和水(1.2 ml)。瓶用氮气吹洗。然后在氮气下加入双(三苯基膦)氯化钯(II)(17 mg, 0.02mmol),并将反应混合物在120℃下在微波反应器中辐照30分钟。将反应混合物倒入水(80ml)中,并滤出所得沉淀,用水洗涤并真空干燥。在硅藻土上过滤残余物,并真空浓缩滤液。在硅胶柱上用环己烷/乙酸乙酯作为洗脱剂将残余物层析,得到4-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-[1,4]二氮杂环庚烷-1-甲酸叔丁酯,为黄色蜡; HPLC/MS 1.45 min, [M+H]+ 680.
在反应瓶中,将4-{2-[5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-2-甲氧基-吡啶-3-基]-1H-苯并咪唑-5-基}-[1,4]二氮杂环庚烷-1-甲酸叔丁酯(680 mg, 1.00 mmol)悬浮在水(2.5 ml)和盐酸水溶液(37%重量, 2.5 ml)中。将反应混合物在80℃搅拌2小时。将反应混合物冷却至室温,并用2 N NaOH溶液使其显碱性。滤出所得沉淀,用水洗涤并真空干燥,得到5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-(5-[1,4]二氮杂环庚烷-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮,为黄色晶体, HPLC/MS 1.06 min, [M+H]+ 566.
向5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-(5-[1,4]二氮杂环庚烷-1-基-1H-苯并咪唑-2-基)-1H-吡啶-2-酮 (356 mg, 0.63 mmol)和碳酸钠(66.9 mg, 0.63mmol)在乙腈(5 ml)中的悬浮液加入甲醛(35%水溶液, 248 µl, 3.2 mmol)。将混合物在室温搅拌5分钟。然后,加入氰基硼氢化钠(97.3 mg, 1.26 mmol)并在室温搅拌反应混合物42小时。蒸发反应混合物,并用饱和碳酸氢钠溶液处理残余物。滤出所得沉淀,用水洗涤并真空干燥,得到5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-[5-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮,为棕色固体; HPLC/MS 1.07 min, [M+H]+ 580.
向5-(1-苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3-[5-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-苯并咪唑-2-基]-1H-吡啶-2-酮 (267 mg, 0.46 mmol)在THF (2.2 ml)中的溶液加入碳酸铯(454 mg, 1.39 mmol)和2,2,2-三氟乙醇(2.2),并将反应混合物在80℃搅拌2小时。在硅藻土上过滤反应混合物,并蒸发滤液。通过制备型HPLC纯化残余物,得到3-[5-(4-甲基-[1,4]二氮杂环庚烷-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮,为橙色晶体; HPLC/MS 0.92 min, [M+H]+ 440.
1H NMR (500 MHz, DMSO-d6) δ 12.2 (bs, 3H), 11.84 (s, 1H), 8.96 (d, J =2.7 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 8.20 (s, 2H, 甲酸盐-H), 8.02 (d, J =2.7 Hz, 1H), 7.60 (dd, J = 3.5, 2.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.25(d, J = 5.0 Hz, 1H), 6.94 (s, 1H), 6.76 (dd, J = 8.9, 2.4 Hz, 1H), 6.65 (dd,J = 3.5, 1.8 Hz, 1H), 3.58 (m, 2H), 3.49 (t, J = 6.3 Hz, 2H), 2.76 (t, J =4.8 Hz, 2H), 2.58 (t, J = 5.4 Hz, 2H), 2.35 (s, 3H), 1.98 (dt, J = 11.8, 6.1Hz, 2H).
类似地制备以下化合物
3-[6-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A50”)
HPLC/MS 0.91 min, [M+H]+ 426; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.25 (d,J = 2.7 Hz, 1H), 8.63 (d, J = 6.2 Hz, 1H), 8.55 (d, J = 2.6 Hz, 1H), 7.87 (d,J = 3.6 Hz, 1H), 7.82 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.36(dd, J = 9.2, 2.3 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 3.6 Hz,1H), 3.89 (d, J = 12.9 Hz, 2H), 3.59 (d, J = 11.8 Hz, 2H), 3.25 (m, 2H), 3.15(t, J = 12.1 Hz, 2H), 2.88 (s, 3H).
3-[6-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-5-基)-1H-吡啶-2-酮 (“A51”)
MS-ESI: [M+H]+ 426; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 9.15 (d, J = 2.7Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.48 (d, J = 2.6Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 3.4 Hz, 1H), 7.41 (dd, J =9.1, 2.3 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H), 3.94(d, J = 13.3 Hz, 2H), 3.64 (d, J = 12.1 Hz, 2H), 3.29 (m, 2H), 3.20 – 3.08(m, 2H), 2.94 (s, 3H).
3-[5-(4-甲基-哌嗪-1-基)-1H-苯并咪唑-2-基]-5-(2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-1H-吡啶-2-酮 (“A52”)
HPLC/MS 0.88 min, [M+H]+ 440; 1H NMR (500 MHz, DMSO-d6, TFA-d1) δ 8.80 (d,J = 2.5 Hz, 1H), 8.60 (dd, J = 7.9, 1.2 Hz, 1H), 8.50 (dd, J = 5.8, 1.2 Hz,1H), 8.08 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 7.9,5.8 Hz, 1H), 7.36 (dd, J = 9.1, 2.3 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 3.88(d, J = 13.3 Hz, 2H), 3.59 (d, J = 12.2 Hz, 2H), 3.25 (td, J = 12.2, 3.1 Hz,2H), 3.15 – 3.04 (m, 2H), 2.90 (s, 3H), 2.59 (s, 3H).
3-[6-(8-甲基-3,8-二氮杂二环[3.2.1]辛-3-基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A53”)
棕色固体, HPLC/MS 0.94 min, [M+H]+ 452; 1H NMR (400 MHz, DMSO-d6) δ 9.22(d, J = 2.6 Hz, 1H), 8.66 (d, J = 6.3 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.91(d, J = 3.6 Hz, 1H), 7.83 (m, 2H), 7.36 (d, J = 9.3 Hz, 1H), 7.34 – 7.26 (m,1H), 7.21 (d, J = 3.6 Hz, 1H), 4.17 (s, 2H), 3.84 (d, J = 12.5 Hz, 2H), 3.36(d, J = 12.3 Hz, 2H), 2.88 (s, 3H), 2.40 – 2.27 (m, 2H), 2.15 (d, J = 8.8 Hz,2H).
5-(5-氨基甲基-1H-苯并咪唑-2-基)-1H-[3,4']二吡啶基-6-酮 (“A54”)和N-[2-(6-氧代-1,6-二氢-[3,4']二吡啶基-5-基)-1H-苯并咪唑-5-基甲基]-乙酰胺 (“A55”)
“A54”: MS-ESI: [M+H]+ 318; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.36 (d, J= 2.7 Hz, 1H), 9.06 (d, J = 7.0 Hz, 2H), 9.01 (d, J = 2.7 Hz, 1H), 8.48 (d, J= 7.0 Hz, 2H), 8.10 – 8.00 (m, 2H), 7.71 (dd, J = 8.6, 1.6 Hz, 1H), 4.30 (s,2H).
“A55”: MS-ESI: [M+H]+ 360; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.33 (d, J= 2.8 Hz, 1H), 9.06 (d, J = 7.0 Hz, 2H), 8.98 (d, J = 2.7 Hz, 1H), 8.48 (d, J= 7.1 Hz, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 1.6, 0.8 Hz, 1H), 7.53(dd, J = 8.6, 1.6 Hz, 1H), 4.48 (s, 2H), 1.95 (s, 3H).
2-(6-氧代-1,6-二氢-[3,4']二吡啶基-5-基)-3H-苯并咪唑-5-甲酸(“A56”)和2-(6-氧代-1,6-二氢-[3,4']二吡啶基-5-基)-3H-苯并咪唑-5-甲酸(2-二乙基氨基-乙基)-酰胺(“A57”)
“A56”: MS-ESI: [M+H]+ 333; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.61 (d, J= 2.7 Hz, 1H), 9.01 (d, J = 7.0 Hz, 2H), 8.98 (d, J = 2.7 Hz, 1H), 8.54 (d, J= 7.1 Hz, 2H), 8.48 (dd, J = 1.5, 0.7 Hz, 1H), 8.13 (dd, J = 8.6, 1.5 Hz,1H), 7.98 (dd, J = 8.6, 0.7 Hz, 1H).
“A57”: MS-ESI: [M+H]+ 431; 1H NMR (400 MHz, DMSO-d6, TFA-d1) δ 9.41 (d, J= 2.7 Hz, 1H), 9.05 (d, J = 7.0 Hz, 2H), 9.01 (d, J = 2.7 Hz, 1H), 8.50 (d, J= 7.2 Hz, 2H), 8.45 (t, J = 1.1 Hz, 1H), 8.10 (dd, J = 8.7, 1.5 Hz, 1H), 8.07(dd, J = 8.7, 0.8 Hz, 1H), 3.72 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.6 Hz,2H), 3.29 (qd, J = 7.1, 1.4 Hz, 4H), 1.28 (t, J = 7.2 Hz, 6H).
类似地制备以下化合物:
2-(6-氧代-1,6-二氢-[3,4']二吡啶基-5-基)-3H-苯并咪唑-5-甲酸(1-甲基-哌啶-4-基)-酰胺 (“A58”)
MS-ESI: [M+H]+ 429.
3-[6-(1-甲基-哌啶-4-基氧基)-1H-苯并咪唑-2-基]-5-喹啉-4-基-1H-吡啶-2-酮(“A59”)
MS-ESI: [M+H]+ 452.
类似地制备以下化合物:
3-[6-(1-甲基-哌啶-4-基氧基)-1H-苯并咪唑-2-基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡啶-2-酮 (“A60”)
MS-ESI: [M+H]+ 441。
以下实施例涉及药物:
实施例A: 注射小瓶
用2 N盐酸将100 g的式I的活性成分和5 g磷酸氢二钠在3 l重蒸馏水中的溶液调节至pH 6.5,无菌过滤,转移至注射小瓶中,在无菌条件下冻干并在无菌条件下密封。每个注射小瓶含有5 mg活性成分。
实施例B: 栓剂
将20 g的式I的活性成分与100 g大豆卵磷脂和1400 g可可酯的混合物熔化,倾入模具中并使之冷却。每个栓剂含有20 mg活性成分。
实施例C:溶液
由1 g式I的活性成分、9.38 g NaH2PO4∙2 H2O、28.48 g Na2HPO4∙12 H2O和0.1 g苯扎氯铵在940 ml重蒸馏水中制备溶液。将pH调节至6.8,并使溶液补充至1 l并经辐照灭菌。这种溶液可用于滴眼剂形式。
实施例D:软膏剂
将500 mg式I的活性成分与99.5 g凡士林在无菌条件下混合。
实施例E:片剂
将1 kg式I的活性成分、4 kg乳糖、1.2 kg马铃薯淀粉、0.2 kg滑石粉和0.1 kg硬脂酸镁的混合物以常规方式压制,得到片剂,以这样的方式使得每一片剂含有10 mg活性成分。
实施例F:糖衣丸
类似于实施例E压制片剂,随后用蔗糖、马铃薯淀粉、滑石粉、黄蓍胶和染料的包衣料以常规方式包衣。
实施例G: 胶囊
将2 kg式I的活性成分以常规方式引入硬明胶胶囊,以这样的方式使得每粒胶囊含有20 mg活性成分。
实施例H:安瓿
将1 kg式I的活性成分在60 l重蒸馏水中的溶液无菌过滤,转移至安瓿中,在无菌条件下冻干并在无菌条件下密封。每个安瓿含有10 mg活性成分。
Claims (17)
1.式I的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物:
其中
R1表示Ar或Het,
R2表示H, A, Hal, CN, NO2, OR4, COOR4, CO(R4)2, CONR4[C(R4)2]mN(R4)2, -[C(R4)2]nNR4COA, -[C(R4)2]nNR4CO[C(R4)2]nHet1, -[C(R4)2]nN(R4)2, -[C(R4)2]nHet1, O[C(R4)2]mN(R4)2, O[C(R4)2]mHet1, -NR4[C(R4)2]mN(R4)2或-NR4[C(R4)2]nHet1,
R3表示H,A,Hal或OR4,
R4表示H或A’,
W表示CH或N,
A表示具有1-6个C原子的非支化或支化烷基,其中1-7个H原子可被OH,F,Cl和/或Br替代,和/或其中一个或两个CH2基团可被O, NH, S, SO, SO2和/或CH=CH基团替代, 或表示具有3-7个C原子的环烷基,
A’ 表示具有1-4个C原子的非支化或支化烷基,
Ar表示苯基或萘基,其未被取代或被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代,
Het 表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被Hal, A, [C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代或二取代,
Het1表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4, N(R4)2, Hal和/或=O (羰基氧)单取代或二取代,
Hal 表示F, Cl, Br或I,
n表示0,1,2或3,
m表示1,2,3或4。
2.权利要求1的化合物及其药学可接受的溶剂合物、盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
R2表示H,A,Hal,CN,OR4,COOR4,CONR4[C(R4)2]mN(R4)2,-[C(R4)2]nNR4COA,-[C(R4)2]nNR4CO[C(R4)2]nHet1, -[C(R4)2]nN(R4)2, -[C(R4)2]nHet1, O[C(R4)2]mHet1或-NR4[C(R4)2]nHet1。
3.权利要求1或2的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
R3表示H或OR4。
4.权利要求1-3中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
W表示CH。
5.权利要求1-4中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
A表示具有1-6个C原子的非支化或支化烷基。
6.权利要求1-5中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
A’ 表示H或甲基。
7.权利要求1-6中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
Ar表示苯基,其被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代。
8.权利要求1-7中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
Het 表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被A单取代。
9.权利要求1-8中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
Het1表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基,其未被取代或被A, OR4和/或N(R4)2单取代或二取代。
10.权利要求1-9中一项或多项的化合物及其药学可接受的盐、互变异构体和立体异构体,包括它们按所有比例的混合物,其中
R1表示Ar或Het,
R2表示H,A,Hal,CN,OR4,COOR4,CONR4[C(R4)2]mN(R4)2,-[C(R4)2]nNR4COA,-[C(R4)2]nNR4CO[C(R4)2]nHet1,-[C(R4)2]nN(R4)2,-[C(R4)2]nHet1,O[C(R4)2]mHet1或-NR4[C(R4)2]nHet1,
R3表示H或OR4,
R4表示H或A’,
W表示CH,
A表示具有1-6个C原子的非支化或支化烷基,
A’ 表示H或甲基,
Ar表示苯基,其被Hal,A,[C(R4)2]nOR4和/或[C(R4)2]nN(R4)2单取代、二取代或三取代,
Het 表示吡啶基、喹啉基、[1,8]-萘啶基、吡唑基、嘧啶基、吲哚基、二氢吲哚基、1H-吡咯并[2,3-b]吡啶基、呋喃基、吡唑并[1,5-a]吡啶基或呋喃并[3,2-b]吡啶基,其可未被取代或被A单取代,
Het1表示哌嗪基、吡啶基、哌啶基、吡唑基、吗啉基、咪唑基、3,8-二氮杂二环[3.2.1]辛基或[1,4]-二氮杂环庚烷基、其未被取代或被A, OR4和/或N(R4)2单取代或二取代,
Hal 表示F, Cl, Br或I,
n表示0,1,2或3,
m表示1,2,3或4。
11.权利要求1的化合物及其药学可接受的溶剂合物、盐、互变异构体和立体异构体,包括它们按所有比例的混合物,所述化合物选自:
。
12.制备权利要求1-11的式I化合物及其药学可接受的盐、溶剂合物、互变异构体和立体异构体的方法,其特征在于:
a)使式II的化合物在Suzuki型偶联中与式III的化合物反应,
其中W、R2和R3具有权利要求1中说明的含义,
L-R1III
其中R1具有权利要求1中说明的含义,
且L表示硼酸或硼酸酯基团,
得到式IV的化合物
其中W、R1、R2和R3具有权利要求1中说明的含义,
式IV的化合物随后与无机酸反应;
或
b)通过用溶剂分解剂或水解剂处理,使它从其官能衍生物中的一种释出;
或
c)通过使氨基酰基化或烷基化,将基团R2转化为另一个基团R2;
和/或
将式I的碱或酸转换为其一种盐。
13.包含以下的药物:至少一种式I的化合物和/或其药学可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们按所有比例的混合物,以及任选药学可接受的载体、赋形剂或媒介物。
14.权利要求1的式I的化合物及其药学可接受的盐、溶剂合物、互变异构体和立体异构体,包括它们按所有比例的混合物,用于治疗和/或预防癌症、年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、糖尿病性视网膜病变、糖尿病性黄斑水肿(DME)、进行性骨化性纤维发育不良、炎症、血管形成相关病症和细菌感染。
15.权利要求14的化合物,用于治疗和/或预防选自以下的疾病:头癌、颈癌、眼癌、口腔癌、咽喉癌、食道癌、支气管癌、喉癌、咽癌、胸癌、骨癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、宫颈癌、乳腺癌、卵巢癌、睾丸癌或其它生殖器官癌、皮肤癌、甲状腺癌、血液癌、淋巴结癌、肾癌、肝癌、胰腺癌、脑癌、中枢神经系统癌、实体瘤和血液肿瘤。
16.包含以下的药物:至少一种权利要求1的式I化合物和/或其药学可接受的盐、溶剂合物和立体异构体,包括它们按所有比例的混合物,以及至少一种另外的药物活性成分。
17.由以下分开的包装组成的套装(药盒):
(a) 有效量的权利要求1的式I化合物和/或其药学可接受的盐、溶剂合物、盐和立体异构体,包括它们按所有比例的混合物,
和
(b) 有效量的另外的药物活性成分。
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AU2017250302B2 (en) | 2016-04-15 | 2021-01-21 | Blueprint Medicines Corporation | Inhibitors of activin receptor-like kinase |
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AU2019216761A1 (en) * | 2018-02-09 | 2020-09-03 | Acceleron Pharma Inc. | Methods for treating heterotopic ossification |
MX2021000977A (es) | 2018-07-26 | 2021-04-12 | Sumitomo Pharma Oncology Inc | Metodos para tratar enfermedades asociadas con expresion anormal de receptor de activina a tipo 1 (acvr1) e inhibidores de acvr1 para uso en los mismos. |
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US20180099947A1 (en) | 2018-04-12 |
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US10179777B2 (en) | 2019-01-15 |
IL254747A0 (en) | 2017-11-30 |
AU2016249537A1 (en) | 2017-11-30 |
WO2016165808A1 (en) | 2016-10-20 |
JP2018511640A (ja) | 2018-04-26 |
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