CN117946088A - 细胞周期蛋白k降解剂 - Google Patents
细胞周期蛋白k降解剂 Download PDFInfo
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- CN117946088A CN117946088A CN202410172072.8A CN202410172072A CN117946088A CN 117946088 A CN117946088 A CN 117946088A CN 202410172072 A CN202410172072 A CN 202410172072A CN 117946088 A CN117946088 A CN 117946088A
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
本发明公开了化合物18及其制备方法。本发明的化合物18可用作细胞周期蛋白K(CyclinK蛋白)的降解剂,可以用于预防或治疗与CyclinK蛋白相关的疾病。
Description
技术领域
本发明涉及一种降解细胞周期蛋白K的化合物及其制备方式,以及使用其治疗/预防细胞周期蛋白K相关病症的方法。
背景技术
肿瘤是威胁人类健康的第二大杀手,全世界每年有约1000万人死于肿瘤。细胞蛋白质的异常表达被认为是导致肿瘤发生发展的重要因素,因此大多数药物所针对的靶点都是这些表达异常的蛋白质。相较于传统的基于抑制剂的药物开发,药物诱导的蛋白质降解是针对这些肿瘤相关蛋白的新策略。根据作用机制,可以将蛋白降解子分为3类,即蛋白质水解靶向嵌合体(PROTAC),单价降解子以及分子胶水降解子(Burslem,G.M.&Crews,C.M.Chem.Rev.117,11269–11301(2017).)。近年来,基于蛋白质降解的技术被成功运用到抗肿瘤药物研发上,预计在2021年底将会有至少15个蛋白降解药物进入临床。
PROTAC是目前使用最为广泛的蛋白降解技术,通常由蛋白靶向结合区,E3泛素连接酶募集区以及连接子组成。PROTAC分子通过结合靶蛋白并募集E3连接酶,使得靶蛋白泛素化并最终导致靶蛋白的降解。由于PROTAC分子量较大(通常700-1200之间),使得它们的透膜能力与口服生物利用度较差。单价降解子和分子胶水的分子量要远小于PROTAC,更契合Lipinski五原则(den Besten,W.etal.Nat Chem Biol 16,1157–1158(2020))。单价降解子通过与蛋白结合改变其构象或者其他变化来诱导其降解。分子胶水则是通过诱导Culin-RING E3连接酶与靶蛋白的相互作用最终导致靶蛋白的降解。分子胶水介导的靶蛋白的降解可以不依赖于靶蛋白的配体口袋,如目前已经报道的沙利度胺类似物(Simonetta,K.R.etal.Nat Commun 10,1402(2019))以及芳基磺胺类似物(Baek,K.etal.Nat ChemBiol 16,2–3(2020))等都是按照此类机制开发。因此,分子胶水能够为之前因为缺少合适的配体口袋而难以成药的靶点带来的新的希望。
CCNK即细胞周期蛋白K,也称Cyclin K,是细胞周期蛋白依赖性激酶12/13(CDK12/13)最为主要的细胞周期蛋白(eral.Int J Mol Sci.2021Mar;22(6):2935)。它能通过与CDK12/13形成复合物参与调控转录,转录后修饰,细胞周期,细胞增殖等多个生物学过程。早期的研究表明,CDK12/13通过与Cyclin K形成复合物,磷酸化RNA聚合酶II的C端结构域来调控其活性,进而调控DNA损伤修复基因的表达,如BRCA1,ATR,FANC1等(Malgorzata Krajewska etal.Nat Commun.2019Apr 15;10(1):1757.)。CDK12/13被认为是一个潜在的肿瘤治疗靶点(Cells 2020,9(6),1483;),通过设计针对Cyclin K的降解子来影响CDK12/13与Cyclin K蛋白复合物的形成,为抑制CDK12/13的功能提供了新的思路。2020年Benjamin L.Ebert等人报道(Nature 2020,585,293–297.),CDK抑制剂CR8是以分子胶水降解剂的机制诱导Cyclin K蛋白的降解。目前针对Cyclin K的分子胶水类降解剂还很少,急需发现更多对Cyclin K具有高降解活性的化合物用于药物研发。
发明内容
本发明提供了一类具有良好Cyclin K降解活性的化合物,及所述化合物与其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物、包含该化合物的药物组合物在治疗或者预防细胞周期蛋白K相关病症中的应用。
本发明的一个方面中,提供了具有式18结构的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体:
在一个方面,化合物18的制备包括如下步骤:
将化合物12-a和2-溴-6-羟甲基吡啶溶于1,4-二氧六环和水的混合物,加入碳酸钾和1,1'-二(二苯膦基)二茂铁二氯化钯(II)。混合物在氮气气氛95℃下搅拌3小时;过滤水洗色谱纯化得到化合物18-b;将化合物18-b溶于二氯甲烷,加入氯化氢二氧六环溶液。混合物在室温下搅拌2小时;将反应液直接浓缩得到化合物18-c;将化合物18-c和化合物1-a溶于N,N-二甲基甲酰胺,加入二异丙基乙基胺;混合物在80℃下搅拌2小时;色谱纯化得到化合物18。
在一个方面,化合物12-a的制备包括如下步骤:
将N-BOC-4-溴苄胺和双联硼酸频那醇酯溶于1,4-二氧六环,加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)和醋酸钾;混合物在氮气气氛95℃下搅拌16小时。将反应液冷却至室温,过滤并色谱纯化得到化合物12-a。
在一个方面,化合物1-a的制备包括如下步骤:
将3-氧杂环丁醇和2,4-二氯-5-三氟甲基嘧啶溶于四氢呋喃,0℃下缓慢滴加双(三甲基硅基)氨基锂;向反应体系中加入氯化铵溶液,用乙酸乙酯萃取;合并后的有机相用水洗过滤色谱纯化得到化合物1-a。
本发明的另一个实施方案提供了一种药物组合物,该组合物包含如本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体,及任选地药学上可接受的载体。
本发明的另一个实施方案提供了一种前述本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者本发明所述的药物组合物在制备用于预防或治疗与CyclinK蛋白相关的疾病或病症的药物中的应用。特别地,所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明的另一个实施方案提供了一种治疗与CyclinK蛋白相关的疾病或病症的方法,其包括向有此需要的哺乳动物施用本发明所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物或其代谢产物,或者本发明所述的药物组合物。
具体实施方式
本发明的化合物或其前药在生物体中可具有优异的Cyclin K降解活性,且可用作癌症的预防或治疗药物、癌症增殖抑制剂或癌症转移抑制剂。本发明的化合物表现出Cyclin K降解活性,且本发明的化合物在功效表达、药代动力学(例如,吸收性、分布、代谢、排泄)、溶解度(例如,水溶性)以及与其它药用产品的相互作用(例如,药物代谢酶的抑制作用)、稳定性(例如,化学稳定性、对酶的稳定性)的方面也有望表现优异,因此该化合物可用作药物。
本发明的化合物可预期具有低毒性(例如,急性毒性、慢性毒性、遗传毒性、生殖毒性、心脏毒性、致癌性、中枢神经系统毒性),且可用于向哺乳动物(例如、小鼠、大鼠、仓鼠、兔、猫、狗、牛、绵羊、猴子、人)给药。
本发明的化合物可用作Cyclin K引起的病理或疾病的预防或治疗药剂。此外,本发明的化合物在降解Cyclin蛋白亚家族中的Cyclin K的选择性方面可为优越的,并且预期具有低毒性。
本发明的化合物有望用于预防或治疗例如癌症[例如,直结肠癌(例如,结肠癌、直肠癌、肛门癌、家族性直结肠癌、遗传性非息肉病性直结肠癌、胃肠道间质瘤)、肺癌(例如,非小细胞肺癌、小细胞肺癌、恶性间皮细胞瘤)、间皮细胞瘤、胰腺癌(例如,胰管癌、胰腺内分泌肿瘤)、咽癌、喉癌、食道癌、胃癌(例如,乳头状腺癌、粘液性腺癌、腺鳞癌)、十二指肠癌、小肠癌、乳腺癌(例如,浸润性导管癌、原位导管癌、炎症性乳腺癌)、卵巢癌(例如,卵巢上皮癌、性腺外生殖细胞肿瘤、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤)、睾丸癌、前列腺癌(例如,激素依赖性前列腺癌、非激素依赖性前列腺癌、去势抵抗性前列腺癌)、肝癌(例如,肝细胞瘤、原发性肝癌、肝外胆管癌)、甲状腺癌(例如,甲状腺髓样癌)、肾癌(例如,肾细胞癌(例如,透明细胞型肾细胞癌)、肾盂和输尿管中的移行细胞癌)、子宫癌(例如,子宫颈癌、子宫体癌、子宫肉瘤)、妊娠绒毛膜癌、脑肿瘤(例如,成神经管细胞瘤、神经胶质瘤、松果体星形细胞瘤、纤维性星形细胞瘤、弥漫性星形细胞瘤、间变性星形细胞瘤、垂体腺瘤)、成神经细胞瘤、视网膜胚细胞瘤、皮肤癌(例如,基底肉瘤、恶性黑色素瘤(黑素瘤))、肉瘤(例如,横纹肌肉瘤、平滑肌肉瘤、软组织肉瘤、梭形细胞肉瘤、骨肉瘤)、恶性骨肿瘤、膀胱癌、血液癌(例如,多发性骨髓瘤、白血病(例如,急性髓细胞性白血病、急性淋巴细胞性白血病)、恶性淋巴瘤、霍奇金病、慢性骨髓增殖性疾病)、原发性未知的癌症]、抑制癌症的扩散、抑制转移、促进细胞凋亡或预防或治疗癌前病变(例如,骨髓增生异常综合征)。此外,预期本发明的化合物可用于预防或治疗硬皮病、肝硬化、特发性肺纤维化、炎性肠病或肌营养不良。
本发明的化合物可以原样或作为与药物理学上可接受的载体混合的药物经向哺乳动物(优选人)给药。适合的给药途径包括但不限于,口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外,仅作举例说明,肠道外给药,包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。下面详细描述包含本发明的化合物的药物(有时简称为“本发明的药物”)。本发明的药物的剂型的实例包括口服制剂,例如片剂(例如,糖衣片、薄膜衣片、舌下片、口含片、口服速溶片)、丸剂、颗粒剂、粉剂、胶囊剂(例如,软胶囊、微胶囊)、糖浆、乳剂、悬浮液、薄膜(例如,口腔崩解膜、口腔粘膜贴膜)等。另外,本发明药物的剂型的实例包括注射剂、滴注剂、透皮剂(例如,离子电渗疗法透皮制剂)、栓剂、软膏剂、鼻腔制剂、肺制剂、滴眼剂等肠道外药剂。
本发明的化合物可与其它药物同时使用。具体而言,本发明的化合物可以与诸如激素治疗剂、化学治疗剂、免疫治疗剂、抑制细胞生长因子或细胞生长因子受体的作用的药物等药物一起使用。在下文中,可与本发明的化合物组合使用的药物简称为伴用药物。
作为“激素治疗剂”,可使用例如磷雌酚、己烯雌酚、氯烯雌醚、乙酸甲羟孕酮、甲地孕酮、氯地孕酮、乙酸赛普龙、达那唑、烯丙雌醇、孕三烯酮(gestrinone)、美帕曲星、雷诺昔酚、奥美昔芬(ormeloxifene)、左美洛昔芬、抗雌激素(例如,柠檬酸它莫西芬、柠檬酸托瑞米芬)、丸剂、美雄烷、睾内酯(testrolactone)、氨鲁米特、LH-RH激动剂(例如,乙酸性瑞林、布舍瑞林、乙酸亮丙瑞林)、屈洛昔芬、环硫雄醇、乙炔雌二醇磺酸酯、芳族酶抑制剂(例如,盐酸法屈唑、阿那曲唑、Retrozole、依西美坦、伏氯唑、福美坦)、抗雄激素(例如,氟他胺、Bicartamide、尼鲁米特、恩杂鲁胺(enzalutamido))、5α-还原酶抑制剂(例如,非那雄胺、依立雄胺、度他雄胺(dutas teride))、肾上腺皮质激素药物(例如,地塞米松、泼尼松龙(predonisolone)、倍他米松、氟羟脱氢皮醇)、雄激素合成抑制剂(例如,阿比特龙)、类视黄醇和延迟类视黄醇代谢的药物(例如,利阿唑)、甲状腺激素及其DDS(药物递送体系)制剂。
作为“化学治疗剂”,可以使用烷基化剂、抗代谢物、抗癌抗生素和植物-衍生的抗癌剂。
作为“烷基化剂”,可使用例如氮芥、氮芥-N-氧化物盐酸盐、Chlorambutyl、环磷酰胺、异环磷酰胺、硫替派、卡波醌、对甲苯磺酸英丙舒凡(Improsulfan)、白消安、盐酸嘧啶亚硝脲、二溴甘露醇、苯丙氨酸氮芥、达卡巴嗪、雷莫司汀(Ranimustine)、雌莫司汀磷酸钠、曲他胺、卡莫司汀、环己亚硝脲、链脲霉素、双溴丙基哌嗪、依托格鲁、卡铂、顺铂、米铂、奈达铂、奥沙利铂、六甲蜜胺、氨莫司汀、二溴螺氯铵(dibrospidium hydrochloride)、福莫司汀、松龙苯芥、嘌嘧替派(Pumitepa)、苯达莫司汀(Ribomustin)、替莫唑胺、曲奥舒凡(treosulfan)、氯乙环磷酰胺、净司他丁斯酯、阿多来新、半胱胺亚硝脲(cystemustine)、比折来新(bizelesin)及其DDS制剂。
作为“抗代谢物”,可使用例如巯基嘌呤、6-巯基嘌呤核糖核苷、硫肌苷、氨甲喋呤、培美曲唑(Pemetrexed)、依诺他滨、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、安西他滨盐酸盐、5-FU药物(例如,氟尿嘧啶、替加氟、UFT、去氧氟尿苷、卡莫氟、Gallocitabine、乙嘧替氟、卡培他滨)、氨基蝶呤、奈拉滨(nelzarabine)、亚叶酸钙、Tabloid、甘氨硫嘌呤(butocine)、亚叶酸钙、左亚叶酸钙、克拉屈滨、乙嘧替氟、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛、碘苷、丙脒腙、噻唑呋啉、氨莫司汀、苯达莫司汀及其DDS制剂。
作为“抗肿瘤抗生素”,可使用例如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、盐酸博来霉素、硫酸博来霉素、硫酸培洛霉素、盐酸柔红霉素、盐酸多柔比星、盐酸阿柔比星、盐酸吡柔比星、盐酸表柔比星、新制癌菌素、光神霉素、肉瘤霉素、嗜癌霉素、米托坦、盐酸佐柔比星、盐酸米托蒽醌、盐酸伊达比星及其DDS制剂(例如,包封多柔比星的PEG核糖体)。
作为“植物-衍生的抗肿瘤药剂”,可使用例如依托泊苷、磷酸依托泊苷、硫酸长春碱、硫酸醛基长春碱、硫酸去乙酰长春酰胺、表鬼臼毒噻吩糖苷、太平洋紫杉醇、多西他赛、卡巴他赛(cabazitaxel)、长春瑞宾以及其DDS制剂。
作为“免疫治疗剂”,可使用例如溶链菌制剂(picibanil)、云芝多糖K(krestin)、裂裥菌素、蘑菇多糖、乌苯美司、干扰素、白介素、巨噬细胞菌落-刺激因子、粒细胞菌落-刺激因子、红细胞生成素、淋巴细胞毒素、BCG疫苗、小棒状杆菌、左旋四咪唑、多醣K、苯咪唑丙酸(procodazol)、抗CTLA4抗体(例如,易普利姆玛(ipilimumab)、(tremelimumab)、抗PD-1抗体(例如,纳武单抗、派姆单抗)和抗PD-L1抗体。
“抑制细胞生长因子及其受体的作用的药物”中的“细胞生长因子”可以是任何能促进细胞增殖的物质,其通常是分子量不超过20000的肽,并能够通过与受体结合而在低浓度表达活性,且具体地可使用
(1)EGF(表皮生长因子)或具有与EGF基本相同活性的物质(例如,TGFα);
(2)胰岛素或具有与胰岛素基本相同活性的物质(例如,胰岛素、IGF(胰岛素样生长因子)-1、IGF-2);
(3)FGF(成纤维细胞生长因子)或具有与FGF基本相同活性的物质(例如,酸性FGF、碱性FGF、KGF(角质形成细胞生长因子)、FGF-10);
(4)其它细胞生长因子(例如,CSF(克隆刺激因子)、EPO(红细胞生成素)、IL-2(白细胞介素-2)、NGF(神经生长因子)、PDGF(血小板生长因子)、TGFβ(转化生长因子β)、HGF(肝细胞生长因子)、VEGF(血管内皮生长因子)、调节蛋白、血管生成素)。
“细胞生长因子受体”可为能够与上述任何细胞生长因子结合的任何受体,并且具体可使用:EGF受体、heregulin受体(例如,HER3)、胰岛素受体、IGF受体-1、IGF受体-2、FGF受体-1或FGF受体-2、VEGF受体、血管生成素(angiopoietin)受体(例如,Tie2)、PDGF受体等。
作为“抑制细胞生长因子及其受体的作用的药物”,例如,可使用EGF抑制剂、TGFα抑制剂、调节蛋白抑制剂、胰岛素抑制剂、IGF抑制剂、FGF抑制剂、KGF抑制剂、CSF抑制剂、EPO抑制剂、IL-2抑制剂、NGF抑制剂、PDGF抑制剂、TGFβ抑制剂、HGF抑制剂、VEGF抑制剂、血管生成素抑制剂、EGF受体抑制剂、HER2抑制剂、HER4抑制剂、胰岛素受体抑制剂、IGF-1受体抑制剂、IGF-2受体抑制剂、FGF受体-1抑制剂、FGF受体-2抑制剂、FGF受体-3抑制剂、FGF受体-4抑制剂、VEGF受体抑制剂、Tie-2抑制剂、PDGF受体抑制剂、Abl抑制剂、Raf抑制剂、FLT3抑制剂、c-Kit抑制剂、Src抑制剂、PKC抑制剂、Smo抑制剂、ALK抑制剂、ROR1抑制剂、Trk抑制剂、Ret抑制剂、mTOR抑制剂、Aurora抑制剂、PLK抑制剂、MEK(MEK1/2)抑制剂、MET抑制剂、CDK抑制剂、Akt抑制剂、ERK抑制剂、PI3K抑制剂等。更具体地,可使用抗VEGF抗体(例如,贝伐单抗(Bevacizumab)、雷莫芦单抗(Ramucirumab))、抗HER2抗体(例如,曲妥珠单抗(Trastuzumab)、帕妥珠单抗(Pertuzumab))、抗EGFR抗体(例如,西妥昔单抗(Cetuximab)、帕尼单抗(Panitumumab)、马妥珠单抗(Matuzumab)、尼妥珠单抗(Nimotuzumab))、抗HGF抗体、伊马替尼(Imatinib)、埃洛替尼(Erlotini b)、吉非替尼(Gefitinib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)、达沙替尼(Dasatinib)、拉帕替尼(Lapatinib)、瓦他拉尼(Vatalanib)、依鲁替尼(Ibrutinib)、博舒替尼(Bosutinib)、卡博替尼(Cabozantinib)、克唑替尼(Crizotinib)、阿雷替尼(Alectinib)、维莫德吉(Vismodegib)、阿西替尼(Axitinib)、莫特塞尼(Motesanib)、尼洛替尼(Nilotinib)、6-[4-(4-乙基哌嗪-1-基甲基)苯基]-N-[1(R)-苯基乙基]-7H-吡咯并[2,3-D]嘧啶-4-胺(AEE-788)、凡德他尼(Vandetanib)、西罗莫司(Temsirolimus)、依维莫司(Everolimus)、Enzastaurin、陶扎色替(Tozasertib)、磷酸2-[N-[3-[4-[5-[N-(3-氟苯基)氨基甲酰基甲基]-1H-吡唑-3-基氨基]喹唑啉-7-基氧基]丙基]-N-乙基氨基]乙基酯(AZD-1152)、4-[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-D][2]苯并氮杂-2-基氨基]苯甲酸、N-[2-甲氧基-5-[(E)-2-(2,4,6-三甲氧基苯基)乙烯基磺酰基甲基]苯基]甘氨酸钠盐(ON-1910Na)、Volasertib、司美替尼(Selumetinib)、曲美替尼(Trametinib)、N-[2(R),3-二羟基丙氧基]-3,4-二氟-2-(2-氟-4-碘苯基氨基)苯甲酰胺(PD-0325901)、博舒替尼(Bosutinib)、瑞戈非尼(Regorafenib)、阿法替尼(Afatinib)、Idelalisib、Ceritinib、达拉非尼(Dabrafenib)等。
除上述药物之外,还可使用天冬酰胺酶、醋葡醛内酯、盐酸甲基苄肼、原卟啉-钴络合盐、汞血卟啉-钠、拓扑异构酶I抑制剂(例如,依立替康、托泊替康、Indotecan、Indimitecan)、拓扑异构酶II抑制剂(例如,索布佐生)、分化诱导性银子(例如,类视黄醇、维生素D)、其它血管生成抑制剂(例如,烟曲霉素、鲨鱼提取物、COX-2抑制剂)、α-阻断剂(例如,盐酸坦洛新)、二膦酸(例如,帕米膦酸盐、唑来膦酸盐)、沙利度胺、来那度胺(lenalidomide)、泊马度胺(Pomalidomide)、5-氮胞苷、地西他滨、蛋白酶体抑制剂(例如,硼替佐米(Bortezomib)、卡非佐米(carfilzomib)、(ixazomib)、NEDD8抑制剂(例如,pevonedistat)、UAE抑制剂、PARP抑制剂(例如,奥拉帕尼(Olaparib)、尼拉帕尼(Niraparib)、维利帕尼(Veliparib)、卢卡帕尼(Rucaparib))、抗肿瘤抗体,例如,抗CD20抗体(例如,利妥昔单抗、Obinutuzumab)、抗CCR4抗体(例如,Mogamulizumab)等、抗体-药物配合物(例如,曲妥珠单抗-美坦新(trastuzumabemtansine)、(brentuximabvedotin)等作为伴用药物。
在下文中,组合使用的本发明化合物和伴用药物称为“本发明的组合药剂”。作为本发明的化合物及伴用药物的给药方式,可提及以下方法:(1)同时配制本发明的化合物和伴用药物,制成给药的单一制剂。(2)分别配制本发明的化合物和伴用药物,制成两种制剂,以相同的给药途径将其同时给药。(3)分别配制本发明的化合物和伴用药物,得到两种制剂,以相同的给药途径、以交错的时间给药。(4)分别配制本发明的化合物和伴用药物,得到两种制剂,通过不同的给药途径同时给药。(5)分别配制本发明的化合物和伴用药物,得到两种制剂,分别以不同的给药途径、以交错的时间给药(例如,本发明的化合物和并用药物按此顺序或相反的顺序给药)等。
本发明的化合物或本发明的组合药剂可进一步与非药物疗法组合使用。具体而言,本发明的化合物或本发明的组合药剂可与非药物疗法组合使用,例如,(1)手术,(2)加压化学治疗,(3)基因治疗,(4)热疗,(5)冷疗,(6)激光烧灼,(7)放疗。
例如,在进行上述手术等之前或之后,或在将两种或三种以上的药物组合治疗之前或之后,使用本发明的化合物或本发明的组合药剂,可达到如预防耐药性表达、延长疾病等、延长无疾病期(无疾病生存期)、抑制癌症转移或复发、延长寿命等效果。
此外,本发明的化合物或本发明的组合药剂可与以下支持性的疗法组合:(i)给药多种抗生素(例如,β-内酰胺类如头孢替安(Pansporin)等,大环内酯类如克拉霉素等)以治疗传染病的组合,(ii)静脉内给药静脉输入营养液、氨基酸制剂、一般维生素制剂用于改善营养不良,(iii)给药吗啡以减轻疼痛,(iv)给药可改善副作用的药物,所述副作用例如恶心、呕吐、厌食、腹泻、白细胞减少症,血小板减少症、血红蛋白浓度降低、脱发、肝病、肾病、DIC、发热等(v)给药抑制癌症对多种药物耐药性的药物。
术语定义
下列定义用于更好地理解本发明。
在本文中,当提及具有特定结构式的“化合物”时,一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物,以及作为其替代性存在形式的可药用盐、溶剂合物、水合物等形式。本领域技术人员公知,一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式,它们都可以在一定条件下转化为所述化合物,因此,特别注意的是在本文中当提到一种化合物时,一般地还包括它的可药用盐,进而还包括其溶剂合物和水合物。
相似地,在本文中当提到一种化合物时,一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐或药学上可接受的盐可使用无机酸或有机酸而形成,所述的“可药用盐”或“药学上可接受的盐”是指这样的盐:在合理的医学判断范围内,其适用于接触人和较低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐,或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐,如下概述。例如,游离碱可以与合适的酸反应。此外,当本发明的化合物带有酸性部分时,其合适的可药用盐可包括金属盐,例如碱金属盐(如钠盐或钾盐)和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如,盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如,醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐,或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子,例如,卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备,例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中,向其中添加过量的有机酸或无机酸水溶液,以使得盐从所得混合物中沉淀,从中除去溶剂和剩余的游离酸,然后分离所沉淀的盐。
本发明所述的前体或代谢物可以为本领域公知的前体或代谢物,只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药,在合理的医学判断范围内,其适用于接触人和更低等动物的组织,而没有不适当的毒性、刺激性、过敏反应等,称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物,例如通过在体内代谢,或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或更多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中,例如当一个或更多个溶剂分子纳入结晶固体的晶格中时,溶剂合物将能够被分离。溶剂合物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构,构型异构还可分为顺反异构和旋光异构(即光学异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象,常见的有烷烃和环烷烃类化合物的结构,如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或更多个不对称中心,因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心,每个不对称中心会产生两个光学异构体,本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在,其通过一个或更多个双键位移而具有不同的氢的连接点。例如,酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等,均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是:氢同位素:2H和3H;碳同位素:11C,13C和14C;氯同位素:35Cl和37Cl;氟同位素:18F;碘同位素:123I和125I;氮同位素:13N和15N;氧同位素:15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘2H和碳13C,由于它们容易标记且方便检测,运用更为广泛。某些重同位素,比如重氢(2H),的取代能增强代谢的稳定性,延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始,用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制,以下实施例使用本发明所公开的方法制备、分离和表征。
如果无另外说明,用于本发明申请(包括说明书和权利要求书)中的术语定义如下。必须注意,在说明书和所附的权利要求书中,如果文中无另外清楚指示,单数形式“一个”包括复数意义。如果无另外说明,使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中,如果无另外说明,使用“或”或“和”指“和/或”。
在说明书和权利要求书中,给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明,否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C=C双键、C=N双键、环系统等的许多几何异构体,且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体,且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时,其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件,以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话,则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐;可将盐转化成游离化合物或另一种盐;可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在,其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是,可存在的所有互变异构体形式均包括在本发明内。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外,术语“治疗有效量”意指这样的量:与未接受上述量的相应受试者相比,所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用,或降低在疾病或病症的进展速度。有效量可以一个或更多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括其广义上的含义,涵盖对对象的治疗性处理和/或预防性处理。具体而言,所述“治疗”包括导致病症、疾病、障碍等的缓和、抑制、消除和改善和/或预防的任何处理,例如减轻、减少、调节、改善、消除、预防、防止或改善其症状。所述治疗性处理包括缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;改善潜在代谢综合征;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或治疗由疾病或症状引起的征兆。所述预防性处理包括事先处理以防止、阻断或延迟、减缓疾病或病症的发生或发展或者减弱疾病或病症的严重程度。
同样,“治疗剂”也包括对对象具有治疗性处理和/或预防性处理的药剂或试剂。
术语“药用”或“药学上可接受的”在本文中用于指如下那些化合物、物质、组合物和/或剂型:在合理医学判断的范围内,其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症,并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质,其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”,如本文所用,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“癌症”,如本文所用,指一种不能控制的细胞的异常生长,并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于,实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语,如本文所用,指将几种所选的治疗药物给一个病人用药,以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”,如本文所用,指预期的结果能够在效价或是持续时间方面都有增加或延长。因此,在增强药物的治疗效果方面,术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”,指在理想的系统中,能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“对象”、“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于,哺乳类:人、非人灵长类如猩猩、猿及猴类;农业动物如牛、马、山羊、绵羊、猪;家畜如兔、狗;实验动物包括啮齿类,如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于,鸟、鱼等。在一优选例中,所选哺乳动物是人。
如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
具体实施例
本发明可以参考下列具体实施例得到更好的理解,所述实施例只是用于说明而非限定本发明。
原料
当未提及制备途径时,相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示,即δ值。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量:
仪器:Thermo U3000,ALLtech ELSD,MSQ,UV检测器结合ELSD和MSD(流出比为4:1)。柱:Waters X-Bridge C-18,3.5μm,4.6x50 mm;柱温:30℃。梯度【时间(min)/溶剂B在A中(%)】:0.00/5.0,1.40/95,2.80/95,2.82/5,3.00/5。(溶剂A=0.01%三氟乙酸在水中;溶剂B=0.01%三氟乙酸在乙腈中)。UV检测:214/254/280/300nm;DAD检测:210-350nm;流速:2mL/min;MS:ESI,100-1500m/z
制备型HPLC通常使用碱性方法(乙腈和水的梯度,水中含有10mM碳酸氢铵);用Thermo U3000 AFC-3000;柱:Globalsil C-18 12nm,250x 20mm,10μm,或相当;流速:20mL/min,进行分离。
实施例12:
将3-氧杂环丁醇和2,4-二氯-5-三氟甲基嘧啶溶于四氢呋喃,0℃下缓慢滴加双(三甲基硅基)氨基锂。混合物在0℃下搅拌3小时后,向反应体系中加入氯化铵溶液,用乙酸乙酯萃取两次。合并后的有机相用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物1-a。
将N-BOC-4-溴苄胺(3.00g,10.5mmol)和双联硼酸频那醇酯(2.93g,11.5mmol)溶于1,4-二氧六环(45mL),加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)(383mg,524μmol)和醋酸钾(3.09g,31.5mmol)。混合物在氮气气氛95℃下搅拌16小时。将反应液冷却至室温,加入50mL乙酸乙酯,用硅藻土过滤,滤液浓缩。残留物通过柱层析色谱纯化得到化合物12-a(3.30g,9.90mmol),无色油状液体,收率94.5%.
将化合物12-a(100mg,300μmol)和2-溴苯甲醚(56.1mg,300μmol)溶于1,4-二氧六环(3mL)和水(0.3mL)的混合物,加入碳酸钾(124mg,900μmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(11.0mg,15.0μmol)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入20mL乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物12-b(80.0mg,255μmol),无色油状液体,收率85.1%.
将化合物12-b(80mg,255μmol)溶于二氯甲烷(2mL),加入氯化氢二氧六环溶液(4N,1mL)。混合物在室温下搅拌2小时。将反应液直接浓缩得到化合物12-c(63.8mg,255μmol),盐酸盐,白色固体,收率100%.
将化合物12-c(29.4mg,118μmol)和化合物1-a(30mg,118μmol)溶于N,N-二甲基甲酰胺(2mL),加入二异丙基乙基胺(45.7mg,354μmol)。混合物在80℃下搅拌2小时。将反应液冷却至室温,通过制备液相色谱纯化得到化合物12(15.0mg,34.8μmol),白色固体,收率29.5%。1H NMR(400MHz,DMSO-d6)δ8.70–8.38(m,2H),7.44–7.30(m,5H),7.29–7.20(m,1H),7.15–6.94(m,2H),5.66–5.56(m,1H),4.91–4.73(m,2H),4.67–4.35(m,4H),3.88–3.61(m,3H);MS(ESI):m/z 432.4(M+H)+.
实施例18:
从2-溴-6-羟甲基吡啶起,参照化合物12的合成得到化合物18。具体如下:
将化合物12-a和2-溴-6-羟甲基吡啶溶于1,4-二氧六环和水的混合物,加入碳酸钾和1,1'-二(二苯膦基)二茂铁二氯化钯(II)。混合物在氮气气氛95℃下搅拌3小时。将反应液冷却至室温,加入乙酸乙酯,用硅藻土过滤,滤液用水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物通过柱层析色谱纯化得到化合物18-b。
将化合物18-b溶于二氯甲烷,加入氯化氢二氧六环溶液。混合物在室温下搅拌2小时。将反应液直接浓缩得到化合物18-c。
将化合物18-c和化合物1-a溶于N,N-二甲基甲酰胺,加入二异丙基乙基胺。混合物在80℃下搅拌2小时。将反应液冷却至室温,通过制备液相色谱纯化得到化合物18。
1H NMR(400MHz,DMSO-d6)δ8.74–8.39(m,2H),8.08–8.00(m,2H),7.90–7.84(m,1H),7.81–7.76(m,1H),7.44–7.38(m,3H),5.68–5.50(m,1H),5.49–5.43(m,1H),4.91–4.69(m,2H),4.65–4.61(m,2H),4.61–4.41(m,4H);MS(ESI):m/z 433.4
测试实施例
HGC27(人胃癌细胞)细胞生长抑制的生物活性检测
本检测方法用于本发明所述化合物的细胞水平生物学活性评价。
收获HGC27细胞(购买自中科院),用完全培养基重悬并调整细胞密度为每毫升0.2x 106个细胞。按照100μL每孔,将细胞悬液加入96孔板中,于37℃、5%CO2培养箱培养过夜。准备待测化合物,加入细胞孔板中,使得化合物的最高浓度为10μM。按照3倍稀释设置8个浓度点。同时设置100%抑制对照孔,即不加入细胞,只有等体积完全培养基的孔;以及0%抑制的对照孔,即加入0.1%DMSO的细胞孔。将上述细胞板于37℃、5% CO2培养24小时。取出细胞培养板,每孔加入25μlLuminescent Cell Viability试剂(promega cat#G7573),避光孵育10分钟后转移100μL到白板中使用Molecular DevicesSpectraMax i3检测化学发光。数据处理采用如下公式计算抑制率:化合物抑制率=(0%抑制对照孔信号-化合物处理孔信号)/(0%抑制对照孔信号-100%抑制对照孔信号)*100%。计算得到的数据利用graphpad prism软件进行四参数拟合并计算其对应的IC50。
根据上述检测方法,对本发明所述化合物进行细胞水平生物学活性评价,活性结果见下表。其中CR8为文献化合物,其采购自上海毕得医药,具体结构如下:
由上述结果可见,本发明的化合物具有良好的肿瘤细胞生长抑制活性。
Claims (7)
1.具有如下结构的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体:
2.权利要求1所述的化合物18的制备包括如下步骤:
将化合物12-a和2-溴-6-羟甲基吡啶溶于1,4-二氧六环和水的混合物,加入碳酸钾和1,1'-二(二苯膦基)二茂铁二氯化钯(II)。混合物在氮气气氛95℃下搅拌3小时;过滤水洗色谱纯化得到化合物18-b;
将化合物18-b溶于二氯甲烷,加入氯化氢二氧六环溶液。混合物在室温下搅拌2小时;将反应液直接浓缩得到化合物18-c;
将化合物18-c和化合物1-a溶于N,N-二甲基甲酰胺,加入二异丙基乙基胺;混合物在80℃下搅拌2小时;色谱纯化得到化合物18。
3.如权利要求2所述的化合物12-a的制备包括如下步骤:
将N-BOC-4-溴苄胺和双联硼酸频那醇酯溶于1,4-二氧六环,加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)和醋酸钾;混合物在氮气气氛95℃下搅拌16小时。将反应液冷却至室温,过滤并色谱纯化得到化合物12-a。
4.如权利要求2所述的化合物1-a的制备包括如下步骤:
将3-氧杂环丁醇和2,4-二氯-5-三氟甲基嘧啶溶于四氢呋喃,0℃下缓慢滴加双(三甲基硅基)氨基锂;向反应体系中加入氯化铵溶液,用乙酸乙酯萃取;合并后的有机相用水洗过滤色谱纯化得到化合物1-a。
5.药物组合物,其包含如权利要求1所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体,及任选地药学上可接受的载体。
6.如权利要求1所述的化合物或其药学上可接受的盐、前药、同位素衍生物、异构体,或者如权利要求5所述的药物组合物在制备用于预防或治疗与Cyclin K蛋白相关的疾病或病症的药物中的应用。
7.如权利要求6所述的应用,其中所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
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CN202410172069.6A Pending CN117946075A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202410172071.3A Pending CN117903116A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202280013621.6A Pending CN116848099A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202410172070.9A Pending CN117946076A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202410172072.8A Pending CN117946088A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
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CN202410172069.6A Pending CN117946075A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202410172071.3A Pending CN117903116A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202280013621.6A Pending CN116848099A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
CN202410172070.9A Pending CN117946076A (zh) | 2021-08-27 | 2022-08-25 | 细胞周期蛋白k降解剂 |
Country Status (5)
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EP (1) | EP4382519A1 (zh) |
JP (1) | JP2024532597A (zh) |
CN (5) | CN117946075A (zh) |
TW (1) | TW202328097A (zh) |
WO (1) | WO2023025225A1 (zh) |
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US6969720B2 (en) * | 1999-03-17 | 2005-11-29 | Amr Technology, Inc. | Biaryl substituted purine derivatives as potent antiproliferative agents |
US6627633B2 (en) * | 1999-03-17 | 2003-09-30 | Albany Molecular Research, Inc. | 6-substituted biaryl purine derivatives as potent cyclin/CDK inhibitors and antiproliferative agents |
US6667311B2 (en) * | 2001-09-11 | 2003-12-23 | Albany Molecular Research, Inc. | Nitrogen substituted biaryl purine derivatives as potent antiproliferative agents |
US6812232B2 (en) * | 2001-09-11 | 2004-11-02 | Amr Technology, Inc. | Heterocycle substituted purine derivatives as potent antiproliferative agents |
-
2022
- 2022-08-25 CN CN202410172069.6A patent/CN117946075A/zh active Pending
- 2022-08-25 CN CN202410172071.3A patent/CN117903116A/zh active Pending
- 2022-08-25 CN CN202280013621.6A patent/CN116848099A/zh active Pending
- 2022-08-25 JP JP2024536343A patent/JP2024532597A/ja active Pending
- 2022-08-25 CN CN202410172070.9A patent/CN117946076A/zh active Pending
- 2022-08-25 CN CN202410172072.8A patent/CN117946088A/zh active Pending
- 2022-08-25 WO PCT/CN2022/114693 patent/WO2023025225A1/zh active Application Filing
- 2022-08-25 EP EP22860571.3A patent/EP4382519A1/en active Pending
- 2022-08-26 TW TW111132353A patent/TW202328097A/zh unknown
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EP4382519A1 (en) | 2024-06-12 |
CN116848099A (zh) | 2023-10-03 |
WO2023025225A1 (zh) | 2023-03-02 |
CN117946076A (zh) | 2024-04-30 |
JP2024532597A (ja) | 2024-09-05 |
CN117946075A (zh) | 2024-04-30 |
TW202328097A (zh) | 2023-07-16 |
CN117903116A (zh) | 2024-04-19 |
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