CN117500501A - 化合物在设备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用、该化合物的用途 - Google Patents
化合物在设备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用、该化合物的用途 Download PDFInfo
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- CN117500501A CN117500501A CN202280042139.5A CN202280042139A CN117500501A CN 117500501 A CN117500501 A CN 117500501A CN 202280042139 A CN202280042139 A CN 202280042139A CN 117500501 A CN117500501 A CN 117500501A
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- Prior art keywords
- methyl
- alkyl
- pyrrolo
- imidazo
- pyridin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
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Abstract
本发明提供了一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用、该化合物的用途。该化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种。
Description
本发明涉及药物领域,具体而言,涉及一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用、该化合物的用途。
骨髓纤维化(Myelofibrosis,MF)是造血干细胞克隆性增殖所致的骨髓增殖性肿瘤(MPNs),包括原发性骨髓纤维化、继发于真性红细胞增多症或原发性血小板增多症的骨髓纤维化。骨髓纤维化(Myelofibrosis,MF)是以骨髓中出现网状纤维和胶原纤维为特征的疾病,临床表现包括贫血,疲劳,早饱感,腹部不适,活动力不佳,注意力不集中,夜间盗汗,皮肤瘙痒,弥漫性骨痛,发热,体重下降,脾肿大,肝肿大,严重影响患者生活质量。整体中位生存时间3.5~5.5年,风险等级越高,生存期越短,高危患者的中位生存时间2年左右。骨髓纤维化(MF)的病因尚不十分明确,患者常伴随有Janus激酶2(JAK2)、CALR和MPL等基因活化突变,从而使JAK-STAT通路的过度活化。约85%的MF患者存在JAK、MPL和CARL中的至少1种驱动基因突变(Klampfl T,et al.NEJM 2013;369(25):2379-90;Nangalia J,et al.NEJM 2013;369(25)2391-405)。在原发性骨髓纤维化患者中,三种主要驱动突变的发生比例分别为JAK2(~65%)、CALR(~25%)和MPL(~10%)(Tefferi A.Am J Hematol.2021 Jan;96(1):145-162.)。
骨髓纤维化的治疗,短期内以缓解症状,改善生活质量为目标,长期是以延长生存,改善/逆转骨髓纤维化,甚至治愈为目标。当前MF的治疗方法中,传统治疗药物针对临床表现对症治疗,且疗效有限。目前针对骨髓纤维化的靶向治疗药物较少,只有两款治疗骨髓纤维化的靶向药物诞生,分别是来自诺华(Novartis)的小分子JAK1/JAK2激酶抑制剂磷酸芦可替尼(ruxolitinib phosphate),以及百时美施贵宝(BMS)的高度特异性JAK2抑制剂fedratinib。其中,芦可替尼(ruxolitinib)是目前中国唯一获批治疗骨髓纤维化的靶向药物。但是,JAK抑制剂已显示在一些患者中引起或恶化血小板减少症、贫血、胃肠道紊乱、代谢异常、周围神经病变和停药期间症状的超急性复发。(Tefferi,A.JAK inhibitors for myeloproliferative neoplasms:clarifying facts from myths[J].Blood,2012,119(12):2721-2730.)。
基于以上原因,急需开发一种能够有效治疗骨髓纤维化及其相关症状/体征的药物。
发明内容
本发明的主要目的在于提供一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用、该化合物的用途,以作为治疗骨髓纤维化及其相关症状/体征的新药物。
为了实现上述目的,根据本发明的一个方面,提供了一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用,其特征在于,化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
式I中,
R
1和R
2分别独立地选自H、C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基任选地被C
1-6烷基取代基、-NH
2取代基、-OH取代基、C
6-10芳基取代基或C
5-10杂芳基取代基取代;C
5-10杂芳基取代基及C
5-10杂芳基分别独立地具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;
Q不存在或选自C
1-6亚烷基、-SO
2-或-NH-,C
1-6亚烷基或-NH-任选地被卤素、C
1-6烷基或C
1-6烷氧基取代;
X选自H、C
1-6烷基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
6-10芳基或C
5-10杂芳基任选地被卤素、卤代C
1-6烷基、C
1-6烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6烷氧羰基或C
1-6烷基-SO
2-取代;
Y为
其中
表示双键或单键;U、W或Z分别独立地选自C或N;R
3不存在或选自H、卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基、氰基、氧代基或-N(R
4)-SO
2-R
5;R
4和R
5分别独立地选自H、C
1-6烷基或卤素取代的C
1-6烷基。
进一步地,Y为
进一步地,R
1选自H或为C
1-4烷基;优选地,R
1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,R
2选自H或C
1-3烷基;优选地,R
2选自H、甲基、乙基、正丙基或异丙基;和/或,Q不存在或为C
1-3亚烷基;优选地,Q选自亚甲基或亚乙基;和/或,X选自H、C
1-3烷基或苯基,可选地,苯基可被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
进一步地,化合物选自具有式II所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
式II中,Q为C
1-6亚烷基;X为苯基,苯基任选地被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
进一步地,化合物选自:
6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮中的一种或多种;
优选地,所述化合物为6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
进一步地,上述药物还包括辅料。
进一步地,上述药物为静脉给药、肌内给药、胃肠外给药、鼻给药、口服给药或直肠给药。
根据本发明的另一方面,还提供了一种治疗骨髓纤维化及其相关症状/体征的方法,其包括:提供包含化合物的药物,其中化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种;给予骨髓纤维化患者有效量的药物;
式I中,
R
1和R
2分别独立地选自H、C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基任选地被C
1-6烷基取代基、-NH
2取代基、-OH取代基、C
6-10芳基取代基或C
5-10杂芳基取代基取代;C
5-10杂芳基取代基和C
5-10杂芳基分别独立地具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;
Q不存在或选自C
1-6亚烷基、-SO
2-或-NH-,C
1-6亚烷基或-NH-任选地被卤素、C
1-6烷基或C
1-6烷氧基取代;
X选自H、C
1-6烷基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
6-10芳基或C
5-10杂芳基任选地被卤素、卤代C
1-6烷基、C
1-6烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6烷氧羰基或C
1-6烷基-SO
2-取代;
Y为
其中
表示双键或单键;U、W或Z分别独立地选自C或N;R
3不存在或选自H、卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基、氰基、氧代基或-N(R
4)-SO
2-R
5;R
4和R
5分别独立地选自H、C
1-6烷基或卤素取代的C
1-6烷基。
进一步地,Y为
进一步地,R
1选自H或为C
1-4烷基;优选地,R
1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,R
2选自H或C
1-3烷基;优选地,R
2选自H、甲基、乙基、正丙基或异丙基;和/或,Q不存在或为C
1-3亚烷基;优选地,Q选自亚甲基或亚乙基;和/或,X选自H、C
1-3烷基或苯基,可选地,苯基可被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
进一步地,化合物选自具有式II所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
式II中,Q为C
1-6亚烷基;X为苯基,苯基任选地被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
进一步地,化合物选自:
6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮中的一种或多种;
优选地,所述化合物为6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
进一步地,所述骨髓纤维化选自原发性骨髓纤维化、继发于真性红细胞增多症或原发性血小板增多症的骨髓纤维化。
进一步地,上述药物还包括辅料。
进一步地,上述药物为静脉内给药、肌内给药、胃肠外给药、鼻给药、口服给药或直肠给药。
进一步地,上述化合物的给药剂量为1~500mg/天。
进一步地,上述化合物以约3mg/天、或5mg/天、或10mg/天、或20mg/天、或25mg/天、或30mg/天、或35mg/天、或40mg/天、或45mg/天、或50mg/天、或55mg/天、或60mg/天、或70mg/天、或80mg/天、或90mg/天、或100mg/天、或150mg/天、或200mg/天的剂量口服施用。
本发明提供了一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用,该化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
该化合物对于JAK2V617F突变驱动的人骨髓增殖性肿瘤细胞HEL、SET-2的增殖具有明显的抑制作用,且对NF-κB的转录活性以及炎症因子IL-6的分泌展现出良好的抑制作用,可用于治疗骨髓纤维化疾病及其相关症状/体征。
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1示出了本发明实施例2中不同浓度下的化合物1对HEL细胞的增殖抑制曲线;
图2示出了本发明实施例2中不同浓度下的化合物1对SET-2细胞的增殖抑制曲线;
图3示出了本发明实施例3中不同浓度下的化合物1对NF-κB转录活性的抑制曲线;
图4示出了本发明实施例4中不同浓度下的化合物1对THP-1细胞IL-6的抑制曲线。
需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
术语解释:
本发明中,除另有说明,术语“卤素”(halogen)是指氟、氯、溴或碘。优选的卤素基团是指氟、氯和溴。
本发明中,除另有说明,术语“烷基”包括直链、支链或环状的饱和单价烃基。例如,烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似的,C
1-6烷基中的“C
1-6”是指含有1、2、3、4、5或6个碳原子以直链或支链形式排列的基团。
本发明中,除另有说明,术语“杂芳基”是指取代或未取代的稳定的5到10个环原子的至少含有一个芳香环的单环或双环基团,所述的芳香环含有一个、两个或三个选自N、O和S 的环杂原子,其余的环原子是C原子。此类杂芳基的实例包括但不限于,吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯并咪唑。
本发明中的术语“前药”是指很容易在体内转化成所需要的化合物的功能性衍生物。因此,本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物,或对受试者给药后能够在体内转化为本发明公开的化合物,用于治疗骨髓纤维化及其相关症状/体征。
当式I所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时,本发明“化合物”包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明采用的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明采用的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地,柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地,甲酸和盐酸。由于式I所示化合物将作为药物应用,所以优选使用基本上纯的形式,例如,至少60%纯度,更适当地至少75%的纯度,特别地至少98%的纯度(%是重量比)。
为了对骨髓纤维化及其相关症状/体征进行药物的治疗,本发明提供了一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用,并提供了一种治疗骨髓纤维化及其相关症状/体征的方法。上述方法包括:提供包含化合物的药物;给予骨髓纤维化患者有效量的药物。本发明还提供了一种用于治疗骨髓纤维化及其相关症状/体征的药物,该药物包含化合物。以上化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
式I中,
R
1和R
2分别独立地选自H、C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
1-6烷氧基、C
6-10芳基或C
5-10杂芳基任选地被C
1-6烷基取代基、-NH
2取代基、-OH取代基、C
6-10芳基取代基或C
5-10杂芳基取代基取代;C
5-10杂芳基取代基和上述C
5-10杂芳基分别独立地具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;
Q不存在或选自C
1-6亚烷基、-SO
2-或-NH-,C
1-6亚烷基或-NH-任选地被卤素、C
1-6烷基或C
1-6烷氧基取代;
X选自H、C
1-6烷基、C
6-10芳基或C
5-10杂芳基,C
1-6烷基、C
6-10芳基或C
5-10杂芳基任选地被卤素、卤代C
1-6烷基、C
1-6烷基、C
1-6烷氧基、C
1-6烷硫基、C
1-6烷氧羰基或C
1-6烷基-SO
2-取代;
Y为
其中
表示双键或单键;U、W或Z分别独立地选自C或N;R
3不存在或选自H、卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基、氰基、氧代基或-N(R
4)-SO
2-R
5;R
4和R
5分别独立地选自H、C
1-6烷基或卤素取代的C
1-6烷基。
本发明发明人出乎意料的发现该式I所示化合物对于JAK2V617F突变表型的人骨髓增殖性肿瘤细胞HEL、SET-2细胞的增殖有明显的抑制作用,且对NF-κB的转录活性以及炎症因子IL-6的分泌展现出良好的抑制作用相关症状/体征,可用于治疗骨髓纤维化疾病及其相关症状/体征。
此外,需说明的是,上述式I所示化合物中要求Y基团为
相比于其他5元和/或6元并环结构,如
本发明式I所示化合物对于骨髓纤维化方面的治疗是有显著差异的,具有明显的有效性。更优选地,Y为
出于进一步提高骨髓纤维化及相关症状/体征治疗效果的目的,在本发明一种优选的实施例中,R
1选自H或为C
1-4烷基;优选地,R
1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;更优选地,R
1为甲基。
在本发明一种优选的实施例中,R
2选自H或C
1-3烷基;优选地,R
2选自H、甲基、乙基、正丙基或异丙基;更优选地,R
2为H。
在本发明一种优选的实施例中,Q不存在或为C
1-3亚烷基;更优选地,Q选自亚甲基或亚乙基;更优选地,Q为亚甲基。
在本发明一种优选的实施例中,X选自H、C
1-3烷基或苯基,可选地,苯基可被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
在本发明一种优选的实施例中,上述化合物选自具有式II所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:
式II中,Q为C
1-6亚烷基;X为苯基,苯基任选地被卤素、C
1-3卤代烷基、C
1-3烷基、C
1-3烷氧基或C
1-3烷基-SO
2-取代。
示例性地,上述化合物选自:
6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮中的一种或多种;
优选地,所述化合物为6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
在本发明一种实施方式中,骨髓纤维化相关症状/体征为以下一种或多种:贫血,脾肿大,肝肿大,疲劳,早饱感,腹部不适,活动力不佳,注意力不集中,夜间盗汗,皮肤瘙痒,弥漫性骨痛,发热,体重下降。
在实际应用过程中,上述药物还包括辅料。具体的辅料包括但不限于药学上可接受的载体、赋形剂或佐剂等辅料。而且,该药物可以制成不同的剂型以适应多样化的给药途径,具体可适用的给药途径包括静脉内给药、肌内给药、胃肠外给药、鼻给药、口服给药或直肠给药。药物的剂型包括片剂、胶囊剂、丸剂、粉末剂、栓剂、溶液剂、悬浮剂、气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。
上述药学上可接受的载体可以是,例如,固体载体、液体载体或气体载体。固体载体,包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体,包括糖浆、花生油、橄榄油和水。气体载体,包括二氧化碳和氮气。制备药物口服制剂时,可以使用任何方便的制药学上的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊,在此应用固体药学载体。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
上述药物的片剂可通过,任选一种或多种辅助组分或辅药一起压制或成型制备。活性组分以自由流动的形式如粉末或颗粒,与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合,在适当的机器中,通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过成型可以制得模制片。较优地,每个片剂含有大约0.05mg到5g的活性组分,每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如,拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至95%。单位剂型一般包含约1mg到约2g的活性组分,典型的是1mg、1.5mg、2mg、2.5mg、3mg、5mg、15mg、20mg、25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
上述适用于胃肠外给药的药物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇,及其在油中的混合物,也可以制得分散体系。进一步地,防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。
上述适用于注射的药物,可进一步包括无菌水溶液或分散体系。进一步地,上述药物可以制备成可用于即时配制无菌注射液或分散液的无菌粉末的形式。无论如何,最终的注射形式必须是无菌的,且为了易于注射,必须是易于流动的。此外,该药物在制备和储存过程中必须稳定。因此,优选抗微生物如细菌和真菌污染的保存。载体可以是溶剂或分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。
上述可以制成以固体为载体,适用于直肠给药的形式。优选的剂型为混合物形成单位剂量的栓剂。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备,首先药物组合物与软化或熔化的辅料混合,然后冷却和模具成型而制得。
除了上述提到的载体组分外,上述药学制剂还可以包括,适当的,一种或多种附加的辅料组分,如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。此外,其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含式I所示化合物,或其药学上可接受的盐的药物,也可以制备成粉剂或浓缩液的形式。
本发明中的“有效量”为治疗有效量。“治疗有效量”是指在必要的剂量和特定的持续时间下实现期望的治疗结果的有效量。药物的治疗有效量可以根据多种因素而改变,例如个体 的病状、年龄、性别、和体重,以及药物在个体体内引起期望的反应的能力。治疗有效量也是治疗有益效果超过药剂的任何毒性或有害效果的量。在一种实施方式中,本发明提供的治疗骨髓纤维化及其相关症状/体征的方法中,上述化合物的给药剂量为1~500mg/天,优选地该化合物给药剂量3~200mg/天,优选地该化合物给药剂量为5~150mg/天。示例性地,上述化合物以约3mg/天、或5mg/天、或10mg/天、或20mg/天、或25mg/天、或30mg/天、或35mg/天、或40mg/天、或45mg/天、或50mg/天、或55mg/天、或60mg/天、或70mg/天、或80mg/天、或90mg/天、或100mg/天、或150mg/天、或200mg/天的剂量口服施用。
以下结合具体实施例对本申请作进一步详细描述,这些实施例不能理解为限制本申请所要求保护的范围。
缩写列表:
ALT:丙氨酸氨基转移酶;
ANC:中性粒细胞绝对计数;
APTT:活化部分凝血活酶时间;
AST:天门冬氨酸氨基转移酶;
BID:每日给药2次;
CI:临床改善;
CT:计算机X线断层摄影;
CR:完全缓解;
Ccr:肌酐清除率;
cm:厘米;
DIEA:N,N-二异丙基乙胺;
DIPSS:动态国际预后积分系统;
DLTs/DLT:剂量限制性毒性;
DMSO:二甲基亚砜;
DCM:二氯甲烷;
EA:乙酸乙酯;
ECOG:美国东部肿瘤协作组;
ELN:欧洲白血病网;
HGB:血红蛋白;
INR:国际标准化比值;
IWG-MRT:骨髓增殖性肿瘤研究与治疗国际协作组;
LCMS/LC-MS:液相色谱质谱连用;
MF:骨髓纤维化;
MPN:骨髓增殖性肿瘤;
MPN-SAF:MPN症状评估表;
MPN-SAF TSS:MPN症状评估表-症状总积分;
MTD:最大耐受剂量;
MRI:核磁共振;
mg:毫克;
mL:毫升;
mM:毫摩尔每升;
nM:纳摩尔每升;
μM:微摩尔每升;
NCI CTCAE:美国国立癌症研究所不良事件通用术语标准;
Pd(dppf)Cl
2.DCM:[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物;
RP2D:II期推荐剂量;
PE:石油醚;
PMF:原发性骨髓纤维化;
post-PV MF:真性红细胞增多症后骨髓纤维化;
post-ET MF:原发性血小板增多症后骨髓纤维化;
PLT:血小板;
PR:部分缓解;
PD:疾病进展;
Scr:血清肌酐;
SD:疾病稳定;
TBIL:血清总胆红素;
ULN:正常值上限;
WHO:世界卫生组织。
实施例1
6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶
-7(6H)-酮(化合物1)的制备
步骤1、化合物1-1的合成
将2-氨基-3,5-二溴吡嗪(10.00g)、4-三氟甲基苄胺(20.98g)和DIEA(25.54g)溶于DMSO(60mL),120℃加热搅拌4h,LCMS确认反应结束,冷却,加入冷水(250mL),EA萃取3次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化(流动相为PE:EA=100:15-100:30)即得化合物1-1(15.01g)。
LCMS:[M+1]
+=347.0
步骤2、化合物1-2的合成
将化合物1-1(15.43g)、原乙酸三乙酯(35.96g)和冰醋酸(200mL)混合,100℃反应过夜。冷却,浓缩,粗品加入EA稀释,饱和Na
2CO
3溶液洗涤3次,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化(流动相为PE:EA=100:20-100:50)即得化合物1-2(13.27g)。
LCMS:[M+1]
+=371.0
步骤3、化合物1-4的合成
将化合物1-2(1.10g)、2M-1(1.27g)、Pd(dppf)Cl
2.DCM(0.25g)溶于二氧六环(20mL)中,加入K
2CO
3(0.61g)及水(4mL),氮气保护,100℃加热搅拌过夜。冷却,倒入EA(50mL)及饱和Na
2CO
3(50mL)的混合溶剂中,分液,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩。粗品用柱层析纯化(流动相为DCM:MeOH=100:2)即得化合物1-4(1g)。
LCMS:[M+1]
+=593.1
步骤4、化合物1的合成
将化合物1-4(20.00g)溶于EtOH(80mL)及DCM(250mL)中,加入NaOH(2.70g),60℃搅拌过夜,浓缩。粗品柱层析纯化(流动相为DCM:MeOH=100:2)得到棕黄色粗粗品,将棕黄色粗品加入DCM(40mL)中打浆,过滤收集固体,减压干燥,得产品类白色固体即为化合物1(6.53g)。
LCMS:[M+1]
+=439.1。
1H NMR(400MHz,DMSO)δ12.13(s,1H),8.92(s,1H),7.99(d,J=35.1Hz,1H),7.76(t,J=17.0Hz,2H),7.49(d,J=8.0Hz,2H),7.28(s,1H),6.75(s,1H),5.68(s,2H),3.63(s,3H),2.63(s,3H)。
采用与实施例1基本类似的方法,应用相应的对三氟甲基苄胺衍生物替换实施例中的
(对三氟甲基苄胺)制备以下表1中的实施例。所述相应的对三氟甲基苄胺衍生物,例如
等均可以通过市售渠道购买得到。
表1
实施例2
本实施例中利用CTG方法检测化合物1对JAK2V617F活化突变表型的人骨髓增殖性肿瘤细胞HEL、SET-2细胞增殖的影响,以此评价化合物1对HEL、SET-2细胞增殖的半数抑制率(IC
50)。
实验方法:
1、细胞培养:
a)HEL细胞培养于RPMI 1640培养基中,加10%FBS和1%双抗,置于37℃、5%CO
2培养箱中培养。
b)SET-2细胞培养于RPMI 1640培养基中,加20%热灭活FBS和1%双抗,置于37℃、5%CO
2培养箱中培养。
2、细胞铺板
a)细胞常规培养至合适密度,收取细胞。
b)用相应的培养基重悬,计数,配制成合适密度的细胞悬液。
c)将细胞悬液加入384孔板,每孔30μL,细胞密度为HEL:1800/孔;SET-2:2000/孔。
d)细胞放在37℃,5%CO
2培养箱中过夜培养。
3、化合物制备
将化合物用DMSO从20mM稀释6.67倍到3mM,然后从3mM开始3倍稀释10个浓度。Staurosporine用DMSO从20mM稀释6.67倍到3mM,然后从3mM开始3倍稀释10个浓度。Vehicle control是100%DMSO,Positive control为3mM Staurosporine。
4.化合物处理
a)细胞铺板24小时以后,用Echo加100nL稀释好的化合物(步骤3中)到384细胞培养板。
b)2个待测化合物和Staurosporine终浓度为:10000,3333,1111,370.4,123.5,41.2,13.7,4.6,1.5,0.5nM。
c)Positive control终浓度是10μM Staurosporine,vehicle control终浓度是0.33%DMSO。
d)细胞放在37℃,5%CO
2培养箱中72小时。
5.CTG检测
a)每孔加30μL CTG试剂(CelltiterGlo试剂盒),放置快速振荡器振荡2分钟,室温避光放置30分钟。
b)用Envision仪器读取化学发光信号值。
6.数据分析
用GraphPad Prism 8software计算IC
50(半数抑制浓度),利用以下非线性拟合公式来得到化合物的IC
50。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
X:化合物浓度Log值,Y:抑制率(%inhibition)
%Inhibition=(LUM
High-LUM
cmpd)/(LUM
High-LUM
Low)*100
LUM
High是0.33%DMSO孔平均值,LUM
cmpd是化合物各孔读值,LUM
Low是10μM Staurosporine孔平均值。
实验结果:
不同浓度下的化合物1对HEL细胞的增殖抑制曲线见图1,对SET-2细胞的增殖抑制曲线见图2。
化合物1对HEL细胞和SET-2细胞增殖抑制的IC
50分别为154.1nM和103.6nM。该结果表明化合物1对HEL、SET-2细胞增殖具有较好的抑制作用。
表2.细胞增殖抑制作用的IC
50(nM)
细胞系 | 化合物 | IC 50(nM) | Hillslope | Bottom | Top |
HEL | 化合物1 | 154.1 | 1.8 | 6.4 | 102.5 |
SET-2 | 化合物1 | 103.6 | 1.6 | 4.7 | 104.6 |
实施例3
本实施例中在HEK293细胞中,利用报告基因实验方法,测定化合物1对NF-κB转录活性的抑制作用,评估化合物对NF-κB转录活性的影响。
实验方法:
1、化合物制备
a)所有的化合物用DMSO进行3倍梯度稀释,10个浓度梯度,起始浓度为10mM。
b)阳性化合物CDDO-Me用DMSO进行3倍梯度稀释,10个浓度梯度,起始浓度为10mM。
c)准备1000×的阳性对照(100%DMSO)和1000×的阴性对照(100%DMSO)。
d)将化合物板子封闭,并震荡5min。
2、细胞悬液制备
a)所有细胞都按照ATCC标准操作培养,HEK293T-NFκB在指数生长期进行实验。
b)轻轻弃去培养基上清。用PBS清洗细胞2次。
c)用胰酶消化液消化细胞,用完全培养基终止消化,收集细胞并计数。
d)分别接种6*10
6HEK293T细胞到一个100mm细胞培养皿中。
e)将种好细胞的培养皿置于37℃,5%CO2培养箱中过夜培养18~20h。
3、化合物处理
a)将稀释好的化合物(见步骤1)用Echo655转移25nL到细胞培养板中。
b)将细胞(见步骤2)种到384细胞培养板中,每孔17,000细胞数,25μL含5%炭吸附FBS和8ng/ml TNFα的培养基。
c)细胞培养板在37℃,5%CO
2培养箱中过夜培养16~20h。
4、化合物检测
a)将Britelite plus检测试剂放置室温。
b)将384细胞板(见步骤3)放置室温。
c)每孔加入25μL Britelite plus检测试剂于细胞培养板。
d)用Envision检测发光值。
5.数据分析
5.1抑制百分率计算如下:
RLU:Resulting Luminescence
整板所有空白对照孔Luminescence的平均值。
整板所有阴性对照孔Luminescence的平均值。
5.2计算IC
50以及拟合化合物量效曲线:
用Graphpad8.0,利用以下非线性拟合公式来得到化合物的IC
50。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
X:化合物浓度log值;Y:化合物抑制百分率
实验结果:
不同浓度下的化合物1对NF-κB转录活性的抑制曲线见图3。
本实验条件下,在稳定转染了NF-κB报告基因的HEK293细胞中,化合物1可抑制NF-κB的转录活性。
表3.化合物对NF-κB转录活性抑制作用的IC
50(nM)
化合物 | IC 50(nM) | Hillslope | Bottom | Top |
化合物1 | 147.6 | 1.3 | -6.5 | 87.4 |
实施例4
本实施例中利用R&D公司提供的Human IL-6Valukine ELISA试剂盒,通过ELISA方法测定细胞上清中IL-6的含量。按照下面所示的实验步骤来测定化合物对LPS刺激后THP-1细胞上清中IL-6分泌的影响。
实验方法:
1、细胞培养
THP-1细胞培养于RPMI 1640培养基中,加10%FBS,1%双抗和2-Mercaptoethanol(1X),置于37℃、5%CO
2培养箱中培养。
2、细胞铺板
a)细胞常规培养至细胞融合度为80%-90%,收取细胞。
b)用培养基(RPMI Medium 1640加10%热灭活FBS和1%双抗)重悬,计数,配制成合适密度的细胞悬液。
c)将细胞悬液加入96孔板,每孔100μL,细胞密度为150000/孔。
d)细胞放在37℃,5%CO
2培养箱中。
3、化合物制备
a)待测化合物用DMSO从20mM稀释2倍到10mM,然后从10mM开始3倍稀释9个浓度。
b)Vehicle control是100%DMSO。
c)取5μL梯度稀释化合物到45μL培养基中混匀,作为工作储液。
4、化合物处理
a)每孔补96μL的培养基,然后加入2μL步骤3准备的化合物到孔中。
b)30min后,试验孔中加入2μL LPS(终浓度为4μg/mL)。
c)待测化合物终浓度为:10000,3333,1111,370.4,123.5,41.2,13.7,4.6,1.5,0nM。
d)Vehicle control终浓度为0.1%DMSO,空白对照为有细胞无LPS。
e)细胞放在37℃,5%CO2培养箱中24小时。
5、IL-6 ELISA检测
a)96孔板离心5min,1500rpm。从96孔板中吸取150μL上清。
b)使用前,将所用试剂室温平衡,充分混匀,避免产生泡沫。
c)根据实验孔(空白和标准品)数量,确定所需的板条数目。
d)加样:每孔加入100μL稀释后的标准品和检测样品,盖上封板膜,室温孵育2小时。
e)洗板:扣去孔内液体,300μL/well加入1×Wash Buffer;停留1分钟后弃去孔内液体。重复3次,每一次在滤纸上扣干。
f)加检测抗体:每孔加入200μL的Human IL-6 Conjugate。盖上封板膜,室温孵育2小时。
g)洗板:重复步骤e)。
h)显色:每孔加入200μL的Substrate Solution,室温避光孵育20分钟。
i)终止反应:迅速加入50μL的Stop solution终止反应。
j)读板:终止后30分钟内,用检测波长(measurement wavelength)450nm读值。
6、CTG检测
a)每孔加入50μL培养基。
b)每孔加100μL CTG试剂(CelltiterGlo试剂盒),放置快速振荡器振荡2分钟,室温避光放置30分钟,转移至CTG检测板中。
c)用Envision仪器读取化学发光信号值。
7、数据分析
用GraphPad Prism 8 software计算IC
50(半数抑制浓度),利用以下非线性拟合公式来得到化合物的IC
50。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*HillSlope))
a)CTG检测:X:化合物浓度Log值,Y:Inhibition%
Inhibition%=(1-Compd/Vehicle control)*100
b)IL-6检测:X:化合物浓度Log值,Y:IL-6浓度(pg/mL)
IL-6浓度依据标准品稀释浓度及波长检测读值得到线性方程计算。
Plate 1:y=0.0117x+0.0421 R
2=0.9998 Plate 2:y=0.0111x+0.0445 R
2=0.9996
注:当抑制率大于30%时,此化合物浓度下IL-6不参与计算IC
50。
实验结果:
不同浓度下的化合物1对THP-1细胞IL-6抑制曲线见图4。
随着化合物浓度的升高,THP-1细胞上清中IL-6的浓度降低,表明化合物1能够抑制THP1单核细胞中IL-6炎症因子的表达。
表4.THP-1细胞IL-6分泌抑制作用的IC
50(nM)
化合物 | IC 50(nM) | Hillslope | Bottom | Top |
化合物1 | 22.4 | -2.7 | 4.2 | 53.9 |
由以上数据可知,本发明化合物对于骨髓纤维化直接相关的JAK2V617F突变表型的人骨髓增殖性肿瘤细胞HEL、SET-2细胞的增殖具有显著的抑制作用,且对NF-κB的转录活性以及炎症因子IL-6的分泌展现出良好的抑制作用。
实施例5
对化合物1在骨髓纤维化患者中的安全性,耐受性,药代动力学和有效性进行I期临床研究,确定MTD和RP2D
目标人群:原发性骨髓纤维化,真性红细胞增多症后骨髓纤维化,原发性血小板增多症后骨髓纤维化患者。
入组标准:
1、年龄≥18周岁,男女不限;
2、根据WHO标准诊断为原发性骨髓纤维化(PMF)的患者或根据IWG-MRT标准诊断为真性红细胞增多症后骨髓纤维化(post-PV MF)或原发性血小板增多症后骨髓纤维化(post-ET MF)患者;
3、剂量递增阶段:根据动态国际预后积分系统(DIPSS)判断处于中危-1及以上(具有一种或多种不良预后因素)且接受过至少一次治疗的骨髓纤维化(MF)患者,患者无法从现有治疗方式获益或研究者认为现有治疗方式不适合患者目前的治疗;
4、扩大入组阶段:根据动态国际预后积分系统(DIPSS)判断处于中危-1及以上(具有一种或多种不良预后因素)的MF患者;
5、扩大入组研究要求患者伴症状性脾脏肿大:触诊脾缘达到或超过肋下至少5cm(肋缘至脾脏突出最远点距离);
6、预期生存期≥24周;
7、美国东部肿瘤协作组(ECOG)体能状态评分0-2;
8、根据MPN症状评估表(MPN-SAF)评定,患者拥有可评定的总症状评分(≥1);
9、骨髓和外周血原始细胞≤20%;
10、筛选前6个月内没有进行过脾脏放疗的患者;
11、有足够器官功能,必须满足以下标准:
a)血常规:中性粒细胞绝对计数(ANC)≥1.0×10
9/L,血小板(PLT)≥100×10
9/L,血红蛋白(HGB)≥7.5g/dL(75g/L)(筛选检查前14天内未输注红细胞);
b)凝血功能:没有正在接受抗凝治疗者,国际标准化比值(INR)以及活化部分凝血活酶时间(APTT)≤1.5倍正常值上限(ULN);
c)肝脏:血清总胆红素(TBIL)≤2.0×ULN,若为Gilbert综合征,则要求TBIL≤3.0×ULN;天门冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)≤2.5×ULN;
d)肾脏:血清肌酐(Scr)≤1.5×ULN或肌酐清除率(Ccr)≥50mL/min(根据Cockcroft-Gault公式计算);
12、既往抗肿瘤治疗的毒性反应恢复至治疗前的严重程度或NCI CTCAE 4.03版≤1级(脱发或研究者认为对患者无安全风险的其他毒性除外);
13、对于有生育潜能的妇女,必须在开始治疗之前的7天内进行血清妊娠试验,且结果为阴性,且须为非哺乳期;所有入组患者均应在整个治疗期间及最后一次服用研究药物后3个月内采取医学认可的避孕措施;
14、能够依从研究和随访程序;
15、签署书面知情同意书。
剂量的递增方法:
本研究采用“3+3”设计,初步设计3个剂量水平,即在确定初始剂量60mg后,按33%以及25%递增试验剂量,分别为60mg/d、80mg/d以及100mg/d。“3+3”剂量递增规则:①若3例DLT可评价患者中无DLTs出现,可递增至下一剂量组;②若3例DLT可评价患者中出现1例DLT,需要再入组3例DLT可评价患者,一旦再出现≥1例DLT(即DLT患者总数达到≥2例),该剂量的前一个剂量即被确定为最大耐受剂量(MTD);③若3例DLT可评价患者中出现2例及以上DLTs,则停止在该剂量及更高剂量水平的入组,该剂量的前一个剂量水平被确定为MTD。
每日2次(BID,本研究中采用Q12H,即每天两次给药间隔12小时)给药研究,后续基于药代动力学、安全耐受性及疗效数据,经申办方和研究者讨论决定,可对剂量设置及给药方案(包括但不限于起始剂量、拟爬坡最高剂量、中间剂量设置、给药频率和间隔)进行适当调整。每周期21天。
疗效评价方法:
a)血常规、外周血涂片
b)骨髓活检或骨髓细胞学涂片
c)核磁共振(MRI)
d)脾脏触诊
e)脾脏超声
f)骨髓纤维化程度评价
g)骨髓增生等级评价
疗效评价标准:
采用2013年的ELN和IWG-MRT共识标准。
表5.疗效评价标准
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (15)
- 一种化合物在制备用于治疗骨髓纤维化及其相关症状/体征的药物中的应用,其特征在于,所述化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:所述式I中,R 1和R 2分别独立地选自H、C 1-6烷基、C 1-6烷氧基、C 6-10芳基或C 5-10杂芳基,所述C 1-6烷基、所述C 1-6烷氧基、所述C 6-10芳基或所述C 5-10杂芳基任选地被C 1-6烷基取代基、-NH 2取代基、-OH取代基、C 6-10芳基取代基或C 5-10杂芳基取代基取代;所述C 5-10杂芳基取代基及所述C 5-10杂芳基分别独立地具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;Q不存在或选自C 1-6亚烷基、-SO 2-或-NH-,所述C 1-6亚烷基或-NH-任选地被卤素、C 1-6烷基或C 1-6烷氧基取代;X选自H、C 1-6烷基、C 6-10芳基或C 5-10杂芳基,所述C 1-6烷基、所述C 6-10芳基或所述C 5-10杂芳基任选地被卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氧羰基或C 1-6烷基-SO 2-取代;Y为 其中 表示双键或单键;U、W或Z分别独立地选自C或N;R 3不存在或选自H、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、氰基、氧代基或-N(R 4)-SO 2-R 5;R 4和R 5分别独立地选自H、C 1-6烷基或卤素取代的C 1-6烷基。
- 根据权利要求1所述的应用,其特征在于,Y为
- 根据权利要求1或2所述的应用,其特征在于,R 1选自H或为C 1-4烷基;优选地,R 1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或R 2选自H或C 1-3烷基;优选地,R 2选自H、甲基、乙基、正丙基或异丙基;和/或Q不存在或为C 1-3亚烷基;优选地,Q选自亚甲基或亚乙基;和/或X选自H、C 1-3烷基或苯基,可选地,苯基可被卤素、C 1-3卤代烷基、C 1-3烷基、C 1-3烷氧基或C 1-3烷基-SO 2-取代。
- 根据权利要求1所述的应用,其特征在于,所述化合物选自具有式II所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:所述式II中,Q为C 1-6亚烷基;X为苯基,所述苯基任选地被卤素、C 1-3卤代烷基、C 1-3烷基、C 1-3烷氧基或C 1-3烷基-SO 2-取代。
- 根据权利要求1所述的应用,其特征在于,所述化合物选自:6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮中的一种或多种;优选地,所述化合物为6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
- 根据权利要求1至5中任一项所述的应用,其特征在于,所述药物还包括辅料。
- 根据权利要求1至5中任一项所述的应用,其特征在于,所述药物为静脉给药、肌内给药、胃肠外给药、鼻给药、口服给药或直肠给药。
- 一种治疗骨髓纤维化及其相关症状/体征的方法,其特征在于,所述方法包括:提供包含化合物的药物,其中所述化合物选自具有式I所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种;给予骨髓纤维化患者有效量的所述药物;所述式I中,R 1和R 2分别独立地选自H、C 1-6烷基、C 1-6烷氧基、C 6-10芳基或C 5-10杂芳基,所述C 1-6烷基、所述C 1-6烷氧基、所述C 6-10芳基或所述C 5-10杂芳基任选地被C 1-6烷基取代基、-NH 2取代基、-OH取代基、C 6-10芳基取代基或C 5-10杂芳基取代基取代;所述C 5-10杂芳基取代基和所述C 5-10杂芳基分别独立地具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;Q不存在或选自C 1-6亚烷基、-SO 2-或-NH-,所述C 1-6亚烷基或-NH-任选地被卤素、C 1-6烷基或C 1-6烷氧基取代;X选自H、C 1-6烷基、C 6-10芳基或C 5-10杂芳基,所述C 1-6烷基、所述C 6-10芳基或所述C 5-10杂芳基任选地被卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氧羰基或C 1-6烷基-SO 2-取代;Y为 其中 表示双键或单键;U、W或Z分别独立地选自C或N;R 3不存在或选自H、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、氰基、氧代基或-N(R 4)-SO 2-R 5;R 4和R 5分别独立地选自H、C 1-6烷基或卤素取代的C 1-6烷基。
- 根据权利要求8所述的方法,其特征在于,Y为
- 根据权利要求8所述的方法,其特征在于,R 1选自H或为C 1-4烷基;优选地,R 1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;优选地,R 2选自H或C 1-3烷基;更优选地,R 2选自H、甲基、乙基、正丙基或异丙基;优选地,Q不存在或为C 1-3亚烷基;更优选地,Q选自亚甲基或亚乙基;优选地,X选自H、C 1-3烷基或苯基,可选地,苯基可被卤素、C 1-3卤代烷基、C 1-3烷基、C 1-3烷氧基或C 1-3烷基-SO 2-取代。
- 根据权利要求8所述的方法,其特征在于,所述化合物选自具有式II所示结构的化合物及其药学上可接受的盐、前药、溶剂化物、水合物中的一种或多种:所述式II中,Q为C 1-6亚烷基;X为苯基,所述苯基任选地被卤素、C 1-3卤代烷基、C 1-3烷基、C 1-3烷氧基或C 1-3烷基-SO 2-取代。
- 根据权利要求8所述的方法,其特征在于,所述化合物选自:6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮中的一种或多种;优选地,所述化合物为6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
- 根据权利要求8所述的方法,其特征在于,所述药物还包括辅料。
- 根据权利要求8所述的方法,其特征在于,所述药物为静脉内给药、肌内给药、胃肠外给药、鼻给药、口服给药或直肠给药。
- 根据权利要求8所述的方法,其特征在于,所述化合物的给药剂量为1~500mg/天,优选地,所述化合物以约3mg/天、或5mg/天、或10mg/天、或20mg/天、或25mg/天、或30mg/天、或35mg/天、或40mg/天、或45mg/天、或50mg/天、或55mg/天、或60mg/天、或70mg/天、或80mg/天、或90mg/天、或100mg/天、或150mg/天、或200mg/天的剂量口服施用。
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