CN102757448A - 大环类激酶抑制剂化合物、制备方法及其作为药物的应用 - Google Patents
大环类激酶抑制剂化合物、制备方法及其作为药物的应用 Download PDFInfo
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及具有结构式(I)所示的化合物,其中L,R1,Z,A,B,C如本申请说明书中所定义。本法明还涉及具有结构式(I)所示的一类化合物在作为激酶抑制剂方面的应用。
Description
技术领域
本发明涉及医药领域,具体涉及大环类激酶抑制剂化合物、制备方法及其在医药方面的应用。
背景技术
癌症的传统治疗方法存在对正常细胞也有不利影响的缺陷;激酶是靶向抗癌药物的靶点,蛋白激酶(“激酶”)构成了一大类酶,此类酶使用三磷酸腺苷(“ATP”)作为磷酸酯的来源将其它蛋白质磷酸化。它们包括丝氨酸激酶和酪氛酸激酶,这两类酶可以分别将其靶蛋白上的丝氨酸和酪氛酸残基上的羟基磷酸化。激酶也可以有双重功能,即它们能将丝氨酸和酪氨酸残基两者都磷酸化。靶蛋白可以是酶、膜通道或是其它蛋白质。
细胞活动通常受外部信号分子(例如,激素或促分裂原(mitogen))控制,这些外部信号分子与细胞表面同源受体的结合激发或抑制各种细胞内事件。起始的信号分子一受体相互作用引发细胞内其它蛋白质相互作用的信号级联放大(signaling cascade)或细胞信号传导途径(cell-signaling pathway),这通常涉及到激酶介导的蛋白质磷酸化作用(信号传导)。因此,在分子水平上,细胞活动受相关激酶和其它蛋白质如转录因子的磷酸化作用(和去磷酸化作用)调节。像这样受调节的细胞活动包括细胞生长、细胞分裂和细胞凋亡。
许多有害的细胞增殖疾病(例如癌症、牛皮癣(psoriasis)、再狭窄(restenosis))的特征在于信号级联放大中断,导致细胞增殖变得不受抑制。通常中断是由位于信号级联放大上游蛋白质的单突变引起的,这影响到下游多种激酶的调节。因此,抑制受影响的一种或多种激酶已经发展为治疗癌症的基础(Sausville et al.,Ann.Rev.Pharmacol.toxicol.2003,43,199-231,“5 ignal Transduction-Directed Cancer Treatments”)。二羟基苯甲酸内酯(“RALs”)是天然产物的一个家族,其具有含有二羟基苯甲酸残基的14元内醋环,一个实例为寄端霉素(hyPothemycin):
存在一些公开内容,其显示RALs以及其半合成或者合成的类似物或衍生物是激酶抑制剂,并因此用于治疗特征为异常激酶活性的疾病。参见例如,Giese et al.,USS,795,910(1998);Chiba et al.,US2004/0224493A1(2004);和Santi et al.,US2006/0079494A1(2006)。
目前已经有激酶抑制剂药物上市;已有激酶抑制剂存在如易产生耐药性、适应症不广的缺点,因此需要进一步研究各种激酶在细胞信号转导过程中的作用或者寻找新的激酶抑制剂药物。
发明内容
针对现有抗癌药物的不足,本发明提供了一种大环类激酶抑制剂化合物或其异构体、非对映体、对映体,或其医药用盐,其化学结构通式如式(I)所示:
L为下式所示的基团:
-X-Y-,
式中X与A基团相连,Y与N原子相连;
X为杂烷基或者没有此基团;
Y为烷基、-CH=CH-烷基或者没有此基团;
R1基团为:
其中m代表2~8,n代表2~8,s代表0~3,p代表2~8,r代表2~8,t代表2~8;
R2基团为:H、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
Z为烷基或者没有此基团;
A基团为:
R3基团为:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
B基团为:
R4基团为:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
C基团为:
本发明通式(I)中的化合物,优选为:
X优选为氧烷基或烷氧基;
Y优选为烷基或-CH=CH-烷基;
其中“烷基”优选为C1-C8直链或支链脂族烃基团;
Z优选为-CH2-;
A基团优选为:
B基团优选为:
C基团优选为:
本发明通式(I)中的化合物,包括以下六大类化合物:
第一大类为:通式(I)中
X为氧烷基;
Y为:C1-C5烷基;
R1基团为:
其中n代表2~8,s代表0~3;
C基团为:
第二大类为:通式(I)中
X为烷氧基;
Y为:-CH=CH-(C1-C5烷基);
R1基团为:
其中n代表2~8,s代表0~3;
C基团为:
所述n优选代表4~6。
第三大类为:通式(I)中
X为烷氧基;
Y为:-CH=CH-(C1-C5烷基);
R1基团为:
C基团为:
第四大类为:通式(I)中
X为烷氧基;
Y为:-CH=CH-(C1-C5烷基);
R1基团为:
C基团为:
第五大类为:通式(I)中
X为烷氧基;
Y为:-CH=CH-(C1-C5烷基);
R1基团为:
C基团为:
第六大类为:通式(I)中
X为烷氧基;
Y为:C1-C5烷基;
R1基团为:
C基团为:
本发明通式(I)中的化合物,包括以下具体化合物:
除通式(I)所表示的化合物以外,本发明还包括这些化合物的药学上可接受的盐、药学上可接受的前药和医药活性代谢物,和这些代谢物在药学上可接受的盐。
本发明提供使用有效量的通式(I)所示的化合物或含有通式(I)所示的化合物的药物组合物单独或与其它药物联合使用用于制备治疗由细胞增殖和/或血管新生的破坏所导致、与该破坏关联或伴随的病症的药物方法。
本发明另一方面还公开了通式(I)所表示的化合物或含有通式(I)所表示的化合物的药物组合物在制备治疗细胞增殖和/或血管新生的破坏所导致、关联或伴随的病症的药物中的应用。
上述病症包括:增生性病症(例如癌症);神经变性疾病,包括:聚谷氨酰胺病、亨廷顿病、帕金森病、阿尔茨海默病、癫痫发作、纹状体黑质变性、进行性核上性麻痹、痉挛性斜颈和运动障碍、扭转张力不全、家族性震颤、抽动秽语综合症、弥漫性Lewy体疾病、皮克病、脊髓性肌肉萎缩症、肌萎缩侧索硬化症、颅内出血、原发性侧索硬化症、肥大性间质性多神经病、视网膜色素变性、遗传性视神经萎缩、遗传性痉挛性截瘫、Shy-Drager症候群和进行性共济失调症;眼部退化疾病,包括:青光眼、老年黄斑变性、虹膜红变性青光眼;代谢性疾病,包括:2型糖尿病;炎性疾病和/或免疫系统病症,包括:类风湿性关节炎(RA)、骨性关节炎、移植物抗宿主病、青少年慢性关节炎、牛皮癣、克罗恩病、哮喘、脊椎关节病变、牛皮癣、炎性肠病、结肠溃疡、酒精性肝炎、糖尿病、Sjoegrens综合征、多发性硬化症、强直性脊椎炎、椎间盘性疼痛、膜性肾小球病、全身性红斑狼疮;血管新生性的疾病,包括:癌症、牛皮癣、类风湿性关节炎;纤维化疾病,包括:肝纤维化、囊性纤维病和血管纤维痛;心理病症,包括:双相性精神障碍、精神分裂症、抑郁和痴呆、躁狂症;心血管疾病包括:心力衰竭、再狭窄和动脉硬化;感染性疾病,包括:细菌感染、病毒性感染,例如:单纯疱疹;真菌感染,例如:白色念珠菌感染;原虫感染,例如:疟疾、布氏锥虫感染、利什曼原虫感染、球虫病和弓形体病;以及造血性病症,包括:贫血和镰状细胞性贫血及海洋性贫血。
本文中的术语“癌症”一般是指广泛的以细胞的失控性异常生长为特征的病症。
本发明的化合物预料可用以治疗各种癌症,包括:妇科癌类,例如:卵巢癌、子宫颈癌、阴道癌、阴部癌、子宫/子宫内膜癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤;内分泌癌类,例如:肾上腺皮质癌、脑垂体癌、胰癌、甲状腺癌、副甲状腺癌、胸腺癌、多发性内分泌肿瘤;骨癌类,例如:骨肉瘤、尤因肉瘤、软骨肉瘤等;肺癌类,例如:小细胞肺癌、非小细胞肺癌;脑和CNS肿瘤,例如:神经母细胞瘤、听神经瘤、神经胶瘤和其他脑肿瘤,脊髓肿瘤、乳癌、结肠直肠癌、晚期结肠直肠腺癌;胃肠癌类,例如:肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌、胃癌、食道癌、小肠癌;泌尿生殖器癌类,例如:阴茎癌、翠丸癌、前列腺癌;头和颈部肿瘤类,例如:鼻癌、鼻窦癌、鼻咽癌、口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、正咽癌;血癌类,例如:急性骨髓性白血病、急性淋巴性白血病、儿童白血病、慢性淋巴性白血病、慢性骨髓性白血病、发状细胞性白血病、急性早幼粒细胞白血病、血浆细胞性白血病;骨髓癌血液病症,例如:骨髓分化不良症候群、骨髓增生性病症、范禾尼贫血、再生障碍性贫血、特发性巨球蛋白血症;淋巴癌类,例如:霍奇金病、非霍奇金氏淋巴瘤、周围T-细胞林巴瘤、皮肤型T-细胞淋巴瘤、AIDS相关性淋巴瘤;眼癌类,包括:视网膜母细胞瘤、葡萄膜黑色素瘤;皮肤癌类,例如:黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌;软组织肉瘤类,例如:卡波希肉瘤、儿童软组织肉瘤、成人软组织肉瘤、泌尿系统癌症,例如:肾癌维尔姆斯肿瘤、膀肤癌、尿道癌和转移性细胞癌。
本文中的术语“卤素”是指氟、氯、溴和碘;
“烷基”为C1-C14直链或支链脂族烃基团;
“杂原子”指S、O和N原子;
“杂烷基”指C1-C14直链或支链烷基,其中一个或者多个碳被杂原子取代,杂原子的定义如上所述;
“环烷基”是指饱和或部分饱和的单环、稠环或螺环的碳环;
“环烯基”是指非芳香性单环或多环环系,其中至少含有一个碳-碳双键且每环有5-10个碳原子;
“杂环烷基”是指至少含有一个杂原子的环烷基;
“芳基”表示可被任选取代的单环或稠多环、芳香族的碳环;
“杂芳基”指含有芳环的基团,其在芳环的环原子中具有一或多个杂原子;
“环烷基烷基”表示环烷基-烷基,其中环烷基和烷基部分如上所述;
“芳基烷基”是指:(芳基-烷基)-的基团,其中,芳基和烷基如上文定义;
“杂芳基烷基”是指(杂芳基-烷基)-的基团,其中,芳基和烷基部分如上文定义;
“芳基杂烷基”是指(芳基-杂烷基)-的基团,其中,芳基和杂烷基如上文定义;
“环烷基杂烷基”是指(环烷基-杂烷基)-的基团,其中,环烷基和杂烷基如上文定义;
“杂环烷基杂烷基”是指(杂环烷基-杂烷基)-的基团,其中,杂环烷基和杂烷如上文定义;
“杂芳基杂烷基”是指(杂芳基-杂烷基)-的基团,其中,杂芳基和杂烷基如上文定义;
“氨基烷基”是指(氨基-烷基)-的基团,其中,烷基如上文定义;
“烷氧基”指-O-烷基,其中烷基如上文定义;
“烷基氨基”指单烷基氨基和二烷基氨基;
“单烷基氨基”指-NH-烷基,其中烷基如上定义;
“二烷基氨基”指-N(烷基)2,其中各烷基可以相同或不同;
“芳基氨基”包括单芳基氨基和二芳基氨基。“单芳基氨基”表示式芳基-NH-,其中芳基如上定义。二芳基氨基表示式(芳基)2N-,其中各芳基可以相同或不同;
“酰基”表示烷基-CO-,其中烷基如上所定义;
“酰基氨基”表示(酰基-氨基)-的基团,其中酰基、烷基如上文所定义;
“烷基磺酰基”指-S(O)2-烷基,其中烷基如上文所定义;
“羟基烷基”是指-烷基-羟基的基团,其中烷基如上文所定义。
术语“医药用盐”指保留所需生物活性的以上化合物的盐,包括药学上可接受的酸加成盐和碱加成盐。式(I)所示化合物的酸加成盐可从无机酸或有机酸制备。无机酸可以但不限于为盐酸、磷酸和硫酸。合适的有机酸可以为但不限于甲酸、乙酸、丙酸、琥珀酸、烷基磺酸、乙醇酸、葡糖酸、乳酸、苹果酸、柠檬酸、酒石酸、反丁烯二酸、顺丁烯二酸、芳基磺酸。式(I)所示化合物的碱加成盐包括但不限于从锂、钠、钾、钙、镁、铝和锌制备的金属盐,以及从胆碱、吗啉、二乙醇胺等有机碱制备的有机盐。
式(I)所示化合物的包括异构体形式,包括非对映异构体、对映异构体、互变异构体和处于“E”或“Z”构型异构体的几何异构体或E和Z异构体的混合物。实施例中的一些化合物可以作为单一立体异构体、外消旋体和/或对映异构体和/或非对映异构体的混合物而存在。
此外,式(I)应包含该化合物的溶剂化和未溶剂化的形式。
合成路线一:
具体的说,如合成路线一所示,化合物i在铃木(Suzuki)偶联条件下与具有合适取代基的化合物ii反应得到联芳基化合物化合物iii。在合适的碱存在的条件下,化合物iii与烯基溴化物iv发生缩合反应得到化合物v。所得到的化合物v与化合物vi在合适的催化剂存在的条件下偶联生成具有末端烯烃的环合前中间体vii。该中间体经格鲁布斯II代(Grubbs II)催化剂催化发生关环复分解反应(ring-closing metathesis)得到大环中间体viii。在酸性条件下脱除中间体viii的保护基团得到化合物ix后,在碱性条件下用合适的溴化物处理化合物ix即得到目标化合物x。
其中R1、R3和R4如前文所定义,q代表1~5。
合成路线二:
化合物i与具有合适取代基化合物ii在铃木(Suzuki)偶联条件下反应生成联芳基化合物iii。在碱催化下化合物iii与合适的溴化物xii反应获得化合物xi。同样在碱存在的条件下用合适的苄胺化合物xiii处理化合物xi获得化合物xiv。在碱的作用下,化合物xiv与适合的脂肪酮类化合物xv发生反应得到化合物xvi。然后以二水合氯化亚锡为催化剂,在酸性溶液中将化合物xvi分子中的硝基还原为氨基得到环合前关键中间体xvii。该中间体xvii在合适的催化剂的催化下发生分子内的偶联反应,得到目标化合物xviii。
其中i代表3~7,n、s、R2和R3如前文所定义。
具体实施方式
在下列实施例中,除非另有指明,所有温度单位为摄氏度。
各种起始原料和试剂均来自市售。供应商包括但不限于:Aldrich Chemical Company、Lancaster Synthesis Ltd等等。除非另有指明,市售原料和试剂均不经进一步纯化直接使用。
玻璃器皿用烘箱干燥和/或加热干燥。反应用玻璃硅胶-60F254平板(0.25mm)(TLC)上进行跟踪。分析性薄层层析并以适当的溶剂比例(v/v)加以展开。以TLC上反应起始原料耗尽时为反应终点。
1H-NMR图谱是用Bruker仪器(300MHz或者400MHz)测定而得,化学位移用ppm表示。使用氯仿作为参照标准(7.25ppm)或四甲基硅烷内标准(0.00ppm)。视需要,也可以使用其它NMR常用的溶剂。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=加宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用MS仪测定得到,离子化方式可为ESI或APCI。
下面的实例仅仅是用来说明所发明的具体化合物的合成方法。但在合成方法上并没有任何限制。在实施例中未列出的化合物,也可以用与下面同样的合成路线与合成方法,选择适当的起始原料,在有必要的地方稍加适当的常识性的反应条件调整即可制备。
实施例1
合成路线一
(1)3-(2-氯-嘧啶-4-基)-苯甲醇(iiiA)
向100mL圆底烧瓶中依次加入化合物iiA(10.0g,0.065mol),化合物iA(10.8g,0.072mol),四(三苯基膦钯)(5.2g,0.0045mol),二水合氟化钾(25.2g,0.264mol),二氧六环(170mL)和水(30mL),所得的悬浮液置于油浴110℃下搅拌反应4h。将反应液冷却至室温后过滤,滤液减压蒸干溶剂得红棕色固体。将该固体以乙酸乙酯重结晶得浅黄色固体5.2g(化合物iiiA)。1H NMR(400MHz,DMSO-d6):δ8.67(d,J=5.2Hz,1H),8.09(s,1H),7.97(dd,J=1.4and 6.8Hz,1H),7.65(d,J=5.2Hz,1H),7.55-7.47(m,2H),4.79(d,J=6.0Hz,2H),2.36(t,J=6.0Hz,1H)。MS(m/z):243(M Na)+。
(2)4-(3-(烯丙氧基甲基)-苯基)-2-氯嘧啶(vA)
向盛有化合物iiiA(6.6g,30mmol)、碳酸铯(49.0g,150mmol)的圆底烧瓶中依次加入化合物ivA(13.0mL)及50.0mL N,N-二甲基甲酰胺,所得的混合物室温搅拌17h后,向该混合物中加入乙酸乙酯适量,过滤,滤液以乙酸乙酯萃取(50.0mL×3),浓缩乙酸乙酯层,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=6∶1]得黄色油状物5.0g(化合物vA)。1H NMR(400MHz,DMSO-d6):δ8.64-7.47(m,6H),6.07-5.94(m,2H),5.37-5.22(m,4H),4.61(s,2H),4.09(d,2H,J=10.8Hz)。MS(m/z):261(MH)+。
(3)叔丁基烯丙基(3-氨基苄)氨基甲酸酯(vii)
向1000mL圆底烧瓶中依次加入间硝基苯甲醛(30.2g,0.20mol),无水硫酸钠(80.2g,0.60mol)和二氯甲烷(400mL),向滴液漏斗中加入22mL(0.30mol)烯丙基胺,滴入反应烧瓶中,所得的混合物室温搅拌2h,减压除去溶剂,向反应混合物中加入甲醇400mL,搅拌下加入硼氢化钠(6.7g,0.15mol),10min后停止反应,减压除去甲醇后向反应混合物中加入4N氯化氢溶液400mL和二氯甲烷150mL,析出白色固体,过滤,滤液以二氯甲烷萃取(50mL×3)。萃取液水层加入碳酸钠调节pH至中性,二氯甲烷萃取(50mL×3)后弃之。白色固体以800mL水溶解后加入碳酸钠调节溶液pH至中性,二氯甲烷萃取(50mL×3)。合并萃取液,加入无水硫酸钠固体干燥过夜,减压除去溶剂,得37.30g红棕色液体。
向1000mL圆底烧瓶中依次加入上述红棕色液体(15.4g,80mmol),二水合氯化亚锡(67.7g,300mmol),甲酸(16mL,278mmol)和甲醇(160mL),所得的混合物置于室温搅拌20min,然后在冰浴下向该混合物中加入4N氢氧化钠溶液350mL,搅拌10min后再加入Boc酸酐(14.4mL,68mmol),所得的混合物室温搅拌16h后停止反应,减压除去甲醇,加水800mL,二氯甲烷萃取(100mL×3),萃取液浓缩,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=6∶1]得到红棕色油状物8.27g(化合物vi)。1H NMR(400MHz,DMSO-d6):δ6.95-6.35(m,4H),5.78-5.69(m,1H),5.13-5.05(m,4H),4.19(s,2H),3.72(br s,1H),3.67(brs,1H),1.41(s,9H)。MS(m/z):285(MH)+。
(4){3-[(烯丙基-叔丁氧羰基-氨基)-甲基]-苯基}-[4-(3-丙-3-烯氧甲基-苯基)-嘧啶-2-基]-胺(viiA)
向250mL三口瓶中依次加入化合物vA(2.6g,10mmol),化合物vi(2.9g,11mmol),四三苯基膦钯(1.73g,0.15mmol),双(二苯基膦基)二茂铁(11g,2mmol)和碳酸铯(6.5g,20mmol),N2保护后,注射加入干燥的二氧六环150mL,置于油浴100℃下搅拌反应4h。将反应液冷却至室温后过滤,滤液浓缩,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=5∶1]得红棕色油状物5.42g(化合物viiA)。1H NMR(400MHz,DMSO-d6):δ8.47-6.93(m,11H),6.04-5.91(m,1H),5.77(brs,1H),5.37-5.08(m,4H),4.61(s,2H),4.45(s,2H),4.07(d,J=1.6Hz,2H),3.88(br s,1H),3.78(br s,1H),1.47(s,9H)。MS(m/z):488(MH)+。
(5)大环中间体的合成(viiiA)
向装有恒压滴液漏斗的500mL三口瓶中加入化合物viiA(500mg,1.00mmol),接着向该三口瓶上的恒压滴液漏斗中加入Grubbs II代催化剂(85mg,0.01mmol)。氮气保护后向反应瓶中注射加入干燥的二氯甲烷250mL,然后向反应瓶上的恒压滴液漏斗中注射加入15mL的干燥二氯甲烷。打开该恒压漏斗的活塞,让催化剂的二氯甲烷溶液滴入反应液中。滴毕后室温搅拌14h后停止反应,浓缩反应液,硅胶柱层析[V(石油醚)∶V(丙酮)=9∶1]得黄绿色固体200mg。石油醚/丙酮重结晶得白色晶体117mg(化合物viiiA)。1H NMR(400MHz,DMSO-d6):δ8.75-6.81(m,11H),5.80-5.64(m,2H),4.62(s,2H),4.59(s,2H),4.07(d,J=6.8Hz,2H),3.91(s 2H),1.53(s,9H)。MS(m/z):482(MH)+。
(6)大环中间体的合成(ixA):
向50mL圆底烧瓶中依次加入化合物viiiA(140mg,0.29mmol)和乙酸乙酯的氯化氢溶液(15.0mL),室温搅拌3h后停止反应,过滤得淡黄色固体。将该固体用10.0mL水溶解,加入1N氢氧化钠溶液调节溶液pH为10,析出白色固体,过滤,干燥得97mg白色固体(化合物ixA)。1H NMR(400MHz,DMSO-d6):δ8.81-6.81(m,11H),5.79-5.76(m,2H),4.64(s,2H),4.08(d,J=4.0Hz,2H),3.86(s,2H),3.41(s,2H),1.82(br s,1H)。MS(m/z):360(MH)+。
(7)化合物xA的合成:
向50mL圆底烧瓶中依次加入化合物ixA(97mg,0.27mmol),碳酸钾(374mg,2.7lmmol),5-溴戊酸甲酯(158mg,0.81mmol),所得的混合物在90℃下搅拌反应27h。过滤,浓缩滤液,硅胶柱层析[V(石油醚)∶V(丙酮)=6∶1]得到白色固体90mg(化合物xA)。1H NMR(400MHz,DMSO-d6):δ8.53-6.84(m,11H),5.86-5.66(m,2H),4.61(s,2H),3.98(d,J=4.8Hz,2H),3.63(s 2H),3.61(s,3H),3.15(s,2H),2.39(t,2H),2.18(t,2H),1.55-1.40(m,4H).MS(m/z):474(MH)+。
(8)目标化合物的合成:
向25mL圆底烧瓶中加入化合物xA(100mg,0.2mmol),无水甲醇1mL,加热使固体溶解,快速加入盐酸羟胺(556mg,8mmol)和甲醇钠(2mL,10mmol),所得的混合物室温搅拌5min后向反应液中加入氯化氢的甲醇溶液调节pH至弱酸性,再加入Na2CO3调节pH至弱碱性,过滤,滤液浓缩至5mL,加人10mL水,析出白色固体,冷冻静置,离心得黄白色固体。加入1N HCl溶液1mL使固体溶解,反相硅胶柱层析[V(甲醇)∶V(水)=9∶1]得黄白色晶体35mg(化合物23)。1H NMR(400MHz,DMSO-d6):δ9.80(s,1H),8.68(s,1H),8.61(s,1H),8.50(d,J=5.2Hz,1H),8.44(s,1H),8.03(d,J=7.6Hz,1H),7.80(s,1H),7.60-7.52(m,1H),7.42(d,J=5.2Hz,1H),7.24(t,J=7.6Hz,1H),7.13(d,J=8.0Hz,1H),7.00(d,J=6.8Hz,1H),5.84-5.68(m,2H),4.61(s,2H),3.97(d,J=4.8Hz,2H),3.64(s,2H),3.16(d,J=6.0Hz,2H),2.40(t,J=4.8Hz,2H),1.49-1.43(m,4H)。MS(m/z):474(MH)+。
实施例2:
前面1-6步同实施例1
向50mL圆底烧瓶中依次加入化合物ixA(100mg,0.28mmol),碳酸钾(387mg,2.8mmol),xvA(151mg,0.84mmol)及乙腈(10mL),所得的混合物在90℃下搅拌反应36h。将反应液冷却至室温后过滤,浓缩滤液,硅胶柱层析[V(石油醚)∶V(丙酮)=5∶1]得到白色固体87mg(化合物22)。1H NMR(400MHz,CDCl3):δ9.59(s,1H),8.54(d,J=4.8Hz,1H),8.43(s,1H),8.27(s,1H),8.04(s,1H),7.54-7.51(m,2H),7.44(d,J=5.2Hz,1H),7.20(t,J=7.6Hz,1H),7.06(d,J=8.0Hz,1H),6.90(d,J=7.2Hz,1H),5.73-5.63(m,2H),4.52(s,2H),3.92(s,2H),3.54(s,2H),3.08(s,2H),2.27-2.22(m,4H),1.93(s,3H),1.30(m,4H)。MS(m/z):457(MH)+。
实施例3
前面1-6步同实施例1
向50mL圆底烧瓶中依次加入N,N-二环己基碳二亚胺(330mg,1.6mmol),辛二酸单甲酯(152mg,0.80mmol)及二氯甲烷(5mL),所得的混合物在室温下搅拌10min后,向其中加入化合物ixA(145mg,0.40mmol),所得的混合物在室温下搅拌反应0.5h。将反应液过滤,浓缩滤液,硅胶柱层析[V(石油醚)∶V(丙酮)=2∶1]得到白色固体137mg(化合物15)。1HNMR(400MHz,DMSO-d6):δ9.83(d,J=10.8Hz,1H),8.68-6.68(m,10H),5.75-5.57(m,2H),4.63(s,2H),4.49(d,J=8.0Hz,2H),3.98(d,J=5.2Hz,2H),3.57(d,J=6.4Hz,3H),2.33-2.26(m,2H),1.73-1.50(m,8H)。
实施例4
前面1-6步同实施例1
向50mL圆底烧瓶中依次加入化合物ixA(73mg,0.18mmol),碳酸钾(382mg,2.8mmol),溴化苄(95mg,0.56mmol)及乙腈(7mL),所得的混合物在室温下搅拌反应3.5h。将反应液过滤,浓缩滤液,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=4∶1]得到白色固体12mg(化合物24)。1H NMR(400MHz,DMSO-d6):δ8.64(s,1H),8.47(d,J=5.4Hz,1H),8.42(s,1H),7.86(d,J=7.8Hz,1H),7.59(d,J=4.5Hz,1H),7.50(t,J=7.5Hz,1H),7.26-7.16(m,7H),7.06(d,J=6.9Hz,1H),6.86(d,J=7.5Hz,1H),5.84-5.65(m,2H),4.63(s,2H),3.96(d,J=5.7Hz,2H),3.75(s,2H),3.52(s,2H),3.08(d,J=6.0Hz,2H)。MS(m/z):449(MH)+。
实施例5
合成路线二
(1)4-(3-(5-溴戊氧基苯基)-2-氯嘧啶(xiA)的合成:
向100mL梨形瓶中依次加入化合物iiiB(3.03g,0.015mol),碳酸铯(19.12g,0.06mol),N,N-二甲基甲酰胺(35mL),1,4-二溴丁烷(12.67g,0.06mol)所得的混合物置于70℃下搅拌反应10min后停止反应。将反应混合物倒入盛有350mL水的烧杯中,二氯甲烷萃取(50mL×3,浓缩二氯甲烷层,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=5∶1]得到白色固体3.0g(化合物xiA)。1H NMR(400MHz,CDCl3):δ8.64(d,J=5.2Hz,1H),7.67-7.61(m,3H),7.42(t,J=7.6Hz,1H),7.09-7.06(m,1H),4.10(t,J=5.2Hz,2H),3.52(t,J=6.4Hz,2H),2.17-1.90(m,4H).。MS(m/z):343(MH)+。
(2)间硝基苄胺(xiiiA)的合成:
冰浴搅拌下向盛有间硝基苯腈(10.0g,0.0675mol),四氢呋喃(100mL)的500mL三口瓶中加入硼氢化钠(7.7g,0.27mol),然后向反应瓶中滴加三氟化硼的乙醚溶液(62g,0.27mol),滴完后冰浴搅拌反应0.5h后停止反应。向反应瓶中滴加甲醇至不再产生气泡,过滤,滤渣以四氢呋喃洗涤,滤液浓缩得黄色固体,将该固体以无水乙醇重结晶得黄白色固体4.4g。1H NMR(400MHz,DMSO-d6):δ8.42(t,J=2.0Hz,1H),8.28-8.25(m,1H),8.19(br s,2H),7.92-7.90(m,1H),7.75(t,J=8.0Hz,1H),4.21(s,2H)。MS(m/z):136(MH)+。
(3)4-(3-(2-氯嘧啶-4-基)苯氧基)-N-(3-硝基苄基)丁烷-1-胺(xivA)的合成:
向50mL梨形瓶中依次加入化合物xiA(1.8g,0.0053mol),化合物xiiA(2.4g,0.0158mol),碳酸钾(3.6g,0.026mol),碘化钠(118g,0.0079mol)和N,N-二甲基甲酰胺(15mL),所得的混合物置于40℃下搅拌反应3h后停止反应。将反应液倒入150mL水中,二氯甲烷萃取(15mL×3),所得的二氯甲烷层加无水硫酸钠干燥。浓缩干燥后的二氯甲烷层得到红棕色油状物。向该油状物中加入无水乙醇5mL,搅拌使其均相,冰浴下滴加浓盐酸调其pH为1~2,减压除去乙醇得黄白色固体。将该固体以丙酮洗涤(30mL×3),干燥得白色固体1.4g(化合物xivA)。1H NMR(400MHz,DMSO-d6):δ9.46(s,2H),8.83(d,J=5.2Hz,1H),8.52(t,J=2.0Hz,1H),8.28-8.26(m,1H),8.19(d,J=5.2Hz,1H),8.05(d,J=7.6Hz,1H),7.79-7.70(m,3H),7.49(t,J=8.0Hz,1H),7.19-7.16(m,1H),4.32(t,J=5.6Hz,2H),4.11(t,J=5.6Hz,2H),3.46(s,1H),3.20(m,2H),1.89-1.84(m,4H)。MS(m/z):413(MH)+。
(4)6-((4-(3-(2-氯嘧啶-4-基)苯氧基)丁基)(3-硝基苯基)氨基)-2-己酮(xviA)合成:
向50mL梨形瓶中依次加入化合物xivA(880mg,1.9mmol),碳酸钾(2.7g,19.5mmol),化合物xvA(1051mg,5.8mmol)和乙腈(25mL),所得的混合物置于90℃下回流搅拌反应36h后停止反应。将反应液冷却至室温后过滤,滤液浓缩,硅胶柱层析[V(石油醚)∶V(丙酮)=6∶1]得到黄色油状物627mg(化合物xviA)。1H NMR(400MHz,CDCl3):δ8.63(d,J=5.2Hz,1H),8.20(s,1H),8.07(d,J=8.0Hz,1H),7.68-7.60(m,4H),7.48-7.38(m,2H),7.04-7.01(m,1H),4.01(t,J=6.0Hz,2H),3.64(s,2H),2.50-2.39(m,6H),2.11(s,3H),1.83-1.47(m,8H)。MS(m/z):511(MH)+。
(5)6-((4-(3-(2-氯嘧啶-4-基)苯氧基)丁基)(3-氨基苯基)氨基)-2-己酮(xviiA)的合成:
向100mL梨形瓶中依次加入化合物xviA(620mg,1.23mmol),醋酸/甲醇溶液(V(醋酸)∶V(甲醇)=1∶9,10mL)及二水合氯化亚锡(1387mg,6.15mmol),所得的混合物置于50℃下搅拌反应0.5h后停止反应。向反应液中加入适量二氯甲烷,冰浴搅拌下向其中滴加氢氧化钾的甲醇溶液调其pH为8~9,所得的悬浮液过滤,滤液浓缩,硅胶柱层析[V(二氯甲烷)∶V(MeOH)=40∶1]得到黄色油状物422mg(化合物xviiA)。1H NMR(400MHz,DMSO-d6):δ8.62(d,J=5.2Hz,1H),7.64-7.42(m,3H),7.40(t,J=8.0Hz,2H),7.08-7.04(m,2H),6.70-6.53(m,3H),4.00(t,J=6.4Hz,2H),3.63(s,2H),3.48(s,2H),2.49-2.10(m,6H),1.86(s,3H),1.86-1.48(m,8H)。MS(m/z):481(MH)+。
(6)
向250mL三口瓶中依次加入化合物xvii(200mg,0.42mmol),四(三苯基磷)钯(72mg,0.063mmol),1,1-双二苯基膦二茂铁(126mg,0.126mmol)及碳酸铯(273mg,0.88mmol),氮气保护后,注射加入无水二氧六环60mL。将反应瓶置于110℃下搅拌反应9h后停止反应。将反应液冷却至室温后过滤,滤液浓缩,硅胶柱层析[V(石油醚)∶V(乙酸乙酯)=4∶1]得到白色固体48mg(化合物11)。1H NMR(400MHz,CDCl3):δ8.63-6.79(m,11H),4.37(t,J=4.0Hz,2H),3.58(s,2H),2.55(t,J=6.0Hz,2H),2.28(t,J=7.2Hz,2H),2.16(t,J=7.2Hz,2H),2.07-1.99(m,2H),1.90(s,3H),1.76-1.70(m,2H),1.45-1.25(m,2H)。MS(m/z):445(MH)+。
实施例6:
本发明化合物的体外活性试验验证:
通过下述试验证明本发明的生物学功效。
人类癌细胞系Colo205(结肠腺癌细胞系)购自ATCC。根据ATCC的工作说明书将其培养于培养基中。然后将Colo205以每孔5000个细胞的密度接种于96孔板中。将平板于37℃、5%CO2中培育24小时。用不同浓度的化合物22处理细胞96小时。接着采用威斯康星州麦迪逊市普罗麦加公司的细胞滴度96水性单分辨率细胞增殖试验(Celltiter 96Aqueous OneSolution Cell Proliferation Assay)监测细胞的生长。采用XL-拟合绘制剂量反应曲线以确定化合物的GI50值。GI50定义为抑制50%细胞生长所需要的化合物浓度。
如表1所示,本发明化合物抑制细胞增殖。数据显示,本发明化合物的生长有活性。
表1本发明实施例中的化合物的活性数据
+:Aurora A IC50>5μM
++:1μM<Aurora A IC50<5μM
+++:Aurora A IC50<1μM
实施例7--29:
表2中的23种化合物均按上述合成路线1或2合成,并且按照实施例6的方法测量活性数据如表2所示:
表2可用本发明的方法合成的具有化学结构式(1)的化合物及其活性数据
+:Aurora A IC50>5μM
++:1μM<Aurora A IC50<5μM
+++:Aurora A IC50<1μM
实施例30-44:
表3中的15种化合物均按上述合成路线1或2合成,并且按照实施例6的方法测量该化合物分别对Aurora A(没有中文名)、CDK2(细胞周期素依赖激酶)和FLT3(FMS样的酪氨酸激酶3)的抑制数据。
表3 15种新的化合物及其活性数据
Claims (10)
1.一种大环类激酶抑制剂化合物或其异构体、非对映体、对映体,或其医药用盐,其化学结构通式如式(I)所示:
L为下式所示的基团:
-X-Y-,
式中X与A基团相连,Y与N原子相连;
X为杂烷基或者没有此基团;
Y为烷基、-CH=CH-烷基或者没有此基团;
R1基团为:
其中m代表2~8,n代表2~8,s代表0~3,p代表2~8,r代表2~8,t代表2~8;
R2基团为:H、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
Z为烷基或者没有此基团;
A基团为:
R3基团为:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
B基团为:
R4基团为:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基;
C基团为:
其中,“卤素”是指氟、氯、溴和碘;
“烷基”为C1-C14直链或支链脂族烃基团;
“杂原子”指S、O和N原子;
“杂烷基”指C1-C14直链或支链烷基,其中一个或者多个碳被杂原子取代,杂原子的定义如上所述;
“环烷基”是指饱和或部分饱和的单环、稠环或螺环的碳环;
“环烯基”是指非芳香性单环或多环环系,其中至少含有一个碳-碳双键且每环有5-10个碳原子;
“杂环烷基”是指至少含有一个杂原子的环烷基;
“芳基”表示可被任选取代的单环或稠多环、芳香族的碳环;
“杂芳基”指含有芳环的基团,其在芳环的环原子中具有一或多个杂原子;
“环烷基烷基”表示环烷基-烷基,其中环烷基和烷基部分如上所述;
“芳基烷基”是指:(芳基-烷基)-的基团,其中,芳基和烷基如上文定义;
“杂芳基烷基”是指(杂芳基-烷基)-的基团,其中,芳基和烷基部分如上文定义;
“芳基杂烷基”是指(芳基-杂烷基)-的基团,其中,芳基和杂烷基如上文定义;
“环烷基杂烷基”是指(环烷基-杂烷基)-的基团,其中,环烷基和杂烷基如上文定义;
“杂环烷基杂烷基”是指(杂环烷基-杂烷基)-的基团,其中,杂环烷基和杂烷如上文定义;
“杂芳基杂烷基”是指(杂芳基-杂烷基)-的基团,其中,杂芳基和杂烷基如上文定义;“氨基烷基”是指(氨基-烷基)-的基团,其中,烷基如上文定义;
“烷氧基”指-O-烷基,其中烷基如上文定义;
“氧烷基”指烷基-O-,其中烷基如上文定义
“烷基氨基”指单烷基氨基和二烷基氨基;
“单烷基氨基”指-NH-烷基,其中烷基如上定义;
“二烷基氨基”指-N(烷基)2,其中各烷基可以相同或不同;
“芳基氨基”包括单芳基氨基和二芳基氨基。“单芳基氨基”表示式芳基-NH-,其中芳基如上定义。二芳基氨基表示式(芳基)2N-,其中各芳基可以相同或不同;
“酰基”表示烷基-CO-,其中烷基如上所定义;
“酰基氨基”表示(酰基-氨基)-的基团,其中酰基、烷基如上文所定义;
“烷基磺酰基”指-S(O)2-烷基,其中烷基如上文所定义;
“羟基烷基”是指-烷基-羟基的基团,其中烷基如上文所定义。
8.权利要求1-7中任一项所述的化合物与药学上可接受的稀释剂、赋形剂或载体所形成的任何一种药物剂型。
9.权利要求1-7之一所述的一种大环类激酶抑制剂化合物或其异构体、非对映体、对映体,或其医药用盐的用途,包括以下几种:
(1)作为激酶抑制剂的应用;
(2)在制备治疗由细胞增殖和/或血管新生的破坏所导致、与该破坏关联或伴随的病症的药物中的应用,其中,所述病症选自:增生性病症;神经变性疾病,包括:聚谷氨酰胺病、亨廷顿病、帕金森病、阿尔茨海默病、癫痫发作、纹状体黑质变性、进行性核上性麻痹、痉挛性斜颈和运动障碍、扭转张力不全、家族性震颤、抽动秽语综合症、弥漫性Lewy体疾病、皮克病、脊髓性肌肉萎缩症、肌萎缩侧索硬化症、颅内出血、原发性侧索硬化症、肥大性间质性多神经病、视网膜色素变性、遗传性视神经萎缩、遗传性痉挛性截瘫、Shy-Drager症候群和进行性共济失调症;眼部退化疾病,包括:青光眼、老年黄斑变性、虹膜红变性青光眼;代谢性疾病,包括:II型糖尿病;炎性疾病和/或免疫系统病症,包括:类风湿性关节炎、骨性关节炎、移植物抗宿主病、青少年慢性关节炎、牛皮癣、克罗恩病、哮喘、脊椎关节病变、牛皮癣、炎性肠病、结肠溃疡、酒精性肝炎、糖尿病、Sjoegrens综合征、多发性硬化症、强直性脊椎炎、椎间盘性疼痛、膜性肾小球病、全身性红斑狼疮;血管新生性的疾病,包括:癌症、牛皮癣、类风湿性关节炎;纤维化疾病,包括:肝纤维化、囊性纤维病和血管纤维痛;心理病症,包括:双相性精神障碍、精神分裂症、抑郁和痴呆、躁狂症;心血管疾病包括:心力衰竭、再狭窄和动脉硬化;感染性疾病,包括:细菌感染、病毒性感染,例如:单纯疱疹;真菌感染,例如:白色念珠菌感染;原虫感染,例如:疟疾、布氏锥虫感染、利什曼原虫感染、球虫病和弓形体病;以及造血性病症,包括:贫血和镰状细胞性贫血及海洋性贫血;
所述癌症优选结肠腺癌。
10.制备如权利要求1中通式(I)所述的大环类激酶抑制剂化合物或其异构体、非对映体、对映体,或其医药用盐的方法,其特征在于:制备方法选自以下两种方法之一:
合成路线一:化合物i在铃木偶联条件下与具有合适取代基的化合物ii反应得到联芳基化合物化合物iii。在合适的碱存在的条件下,化合物iii与烯基溴化物iv发生缩合反应得到化合物v。所得到的化合物v与化合物vi在合适的催化剂存在的条件下偶联生成具有末端烯烃的环合前中间体vii。该中间体经格鲁布斯II代催化剂催化发生关环复分解反应得到大环中间体viii;在酸性条件下脱除中间体viii的保护基团得到化合物ix后,在碱性条件下用合适的溴化物处理化合物ix即得到目标化合物x;
其中R1、R3和R4如前文所定义,q代表1~5;
化合物i与具有合适取代基化合物ii在铃木偶联条件下反应生成联芳基化合物iii。在碱催化下化合物iii与合适的溴化物xii反应获得化合物xi。同样在碱存在的条件下用合适的苄胺化合物xiii处理化合物xi获得化合物xiv。在碱的作用下,化合物xiv与适合的脂肪酮类化合物xv发生反应得到化合物xvi;然后以二水合氯化亚锡为催化剂,在酸性溶液中将化合物xvi分子中的硝基还原为氨基得到环合前关键中间体xvii。该中间体xvii在合适的催化剂的催化下发生分子内的偶联反应,得到目标化合物xviii;
其中i代表3~7,n、s、R2和R3如前文所定义;
所述化合物i-viii如下所示。
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