CN114957260A - 一种巴瑞替尼衍生物及其制备方法与用途 - Google Patents
一种巴瑞替尼衍生物及其制备方法与用途 Download PDFInfo
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- CN114957260A CN114957260A CN202210187492.4A CN202210187492A CN114957260A CN 114957260 A CN114957260 A CN 114957260A CN 202210187492 A CN202210187492 A CN 202210187492A CN 114957260 A CN114957260 A CN 114957260A
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- C07F9/02—Phosphorus compounds
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- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
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Abstract
本发明公开了一种巴瑞替尼衍生物及其制备方法与用途,该类衍生物在提高水溶性、增强用药安全性、提高疗效、增加药物耐受性方面具有显著的优越性,具有广阔的开发前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一系列JAK抑制剂的合成,通过调节JAK活性用于治疗和/或预防与JAK活性相关的疾病,以及在抗病毒及预防和治疗脱发相关领域的用途。
背景技术
RA(Rheumatic Arthritis)是一种慢性、进行性多关节滑膜炎的自身免疫性疾病,严重的可导致关节畸形和功能丧失,在我国发病率大约在0.32%~0.36%,随着年龄增长,发病率逐渐增高。早期治疗策略主要是采用经典药物,如非甾体抗炎药(NonsteroidalAnti-inflammatory Drugs,NSAIDs)、糖皮质激素和植物类药。最近几十年肿瘤坏死因子 -α(Tumor necrosis factor alpha,TNF-a)和白介素-6(Interleukin-6,IL-6) 拮抗剂的出现大大提高了RA的缓解率,但是一旦终止治疗,50%-80%的患者病情继续恶化。非受体酪氨酸激酶(Jauns kinase,JAK)/信号传导与转录激活因子(Signal Transducer andActivalor of Transcription, STAT)信号通路是I/II型细胞因子向细胞内传递信号的主要途径,与多种自身免疫病的发生有关,JAK/STAT信号通路逐渐成为RA治疗的重要目标。巴瑞替尼(Baricitinib)由美国Incyte制药公司研制的JAK 激酶抑制剂,用于治疗自身免疫性疾病的新药,收到了较好的治疗效果,为RA的治疗提供了重要手段。但是,巴瑞替尼的副作用也多见报导,如发热,皮肤过敏,溃疡,血痰等。由于其刚刚上市,对于其安全性也有待于进一步研究确证。另外有研究表明,巴瑞替尼还可用于治疗预防和治疗脱发相关疾病。
2020年11月19日,礼来制药与因赛特医疗(INCYTE)共同宣布,美国食品药品监督管理局(FDA)批准礼来制药巴瑞替尼的EUA(紧急使用授权),与瑞德西韦联用后用于成年住院患者、2岁及以上的儿童住院患者,这些患者为疑似或实验室确诊的2019新型冠状病毒肺炎 (COVID-19)病例。说明巴瑞替尼在抗病毒方面亦有卓越的效果。
发明内容
本发明的目的在于提供一种新的JAK抑制剂及其用途,该类抑制剂可以用于预防和/或治疗JAK介导的相关疾病以及在抗RNA病毒领域药物中的用途。
本发明达到一种有益技术效果是本发明的化合物体内具有良好的耐受性,预示本发明的化合物作为JAK抑制剂可以克服目前报道的作为JAK抑制剂的不良副作用,增强了药物的安全性。
本发明达到的另一种有益技术效果是本发明的化合物具有更好的水溶性,在体内具有更显著的抗炎效果,更适合于开发为临床药物。
本发明一方面提供一种如下通式(I)所示的巴瑞替尼衍生物或其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐:
式(I)中,R1选自被一个或多个基团A取代或未取代的下列基团: C1-C8的烷基、C3-C8的碳环基、C2-C8的杂环基;
R2代表氰基、氟、C1-C8的烷基或氰基取代的C1-C8的烷基;
X为P、或S;
Y1和Y2各自独立地为O、或N(H);
R3和R4各自独立地为H、金属离子、或选自被一个或多个基团 M取代或未取代的下列基团:C1-C8烷基、C3-C8的碳环基、C2-C8 的杂环基、或R3和R4相连成环;
“----”表示成键或不成键,且当X为S时,Y2为O,此时Y2与S 成双键,并且此时R4不存在;
其中所述的基团A为:氢、卤素、羟基、C1-C8烷基、C1-C8 烷氧基、C3-C8的环烷基、乙酰基、氰基、三氟甲基、二氟甲基;
其中所述的基团M为:氢、卤素、C1-C8烷基、C1-C8烷氧基、 C1-C8烷胺基、氨基、羟基、巯基、巯甲基、巯乙基、羧基、硝基、卤素、三氟甲基、二氟甲基。
在本发明的实施方案中,本发明提供的巴瑞替尼衍生物,如式(II) 所示:
式(II)中其它取代基的定义如式(I)所定义的。
在本发明的实施方案中,本发明提供的巴瑞替尼衍生物,如式(III) 所示:
式(III)中其它取代基的定义如式(I)所定义的。
在本申请的实施方案中,所述的烃基包含烷基。
在本申请的实施方案中,所述的烷基是指由碳原子组成的饱和的脂肪烃基,包括直链、支链或环状烷烃,也包括环烷基取代的烷烃和烷基取代的环烷烃;所述的C1-C8烷基表示1-8个碳原子的饱和的脂烃基,例如包括但不限于:甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基、环丙基、环丁基、环戊基、环己基、环庚基。
在本申请的实施方案中,所述的烷氧基是指烷基在任意合理的位置被氧原子、或羟基取代的脂肪烃基基团,包括直链、支链或环状烷氧烃基;所述的C1-C8烷氧基包括但不限于:甲氧基、乙氧基、异丙氧基、仲丁氧基、叔丁氧基、环戊氧基、环丙氧基、环己氧基。
在本申请的实施方案中,所述的烷胺基是指烷基在任意合理的位置被N、NH、或NH2取代的脂肪烃基基团,包括直链、支链或环状烷烃基;所述的C1-C8烷胺基包括但不限于:甲胺基、乙胺基、异丙胺基、仲丁胺基、叔丁胺基、环戊胺基、环丙胺基、环己胺基。
在本申请的实施方案中,所述的碳环基是指由碳原子组成的饱和或不饱和的脂肪烃基,包括直链、支链或环状烃,所述的C3-C8碳环基表示3-8个碳原子的饱和或不饱和的脂烃基,例如包括但不限于:环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环庚烯基。
在本申请的实施方案中,所述的杂环基是指由至少有一个杂原子的环烃基,所述的C2-C8杂环基表示2-8个碳原子与至少一个杂原子组成的环烃基,例如包括但不限于:环氧乙烷、四氢呋喃、吖丙啶、β-丙内酯、β-丙内酰胺、四氢噻吩、哌啶、四氢吡喃、吗啉、哌嗪。
在本申请的实施方案中,所述的卤素为氟、氯、溴或碘。
在本申请的实施方案中,所述的杂原子为氧、氮、硫、磷、或硼。
在本申请的实施方案中,所述的药学上可接受的盐,包括但不限于,无机酸盐,例如盐酸盐、硫酸盐、或磷酸盐等;有机酸盐,例如甲磺酸盐、乙磺酸盐、苯磺酸盐、苯甲磺酸盐、枸橼酸盐、或乙酸盐等。
在本申请的实施方案中,所述的药学上可接受的盐,包括但不限于与金属离子成盐,所述的金属离子包括但不限于钾盐、钠盐、锂盐、钙盐、铁盐、锌盐。
在本申请的实施方案中,所述的基团A为:氢、卤素、羟基、 C1-C8烷基、C1-C8烷氧基、C3-C8的环烷基、甲氧基、乙氧基、乙酰基、氰基、三氟甲基、二氟甲基;
在本申请的实施方案中,所述的基团M为:氢、卤素、C1-C8 烷基、C1-C8烷氧基、C1-C8烷胺基、氨基、羟基、巯基、巯甲基、巯乙基、羧基、硝基、卤素、三氟甲基、二氟甲基。
在一些实施方案中,R1选自被一个或多个基团A取代或未取代的下列基团:C3-C8的碳环基、C2-C8的杂环基;优选的,R1选自环丁基、环丙基;更优的,R1选自环丙基。
在一些实施方案中,R2为氰基;在一些实施方案中,R2为氟;在一些实施方案中,R2为C1-C8的烷基。
在一些实施方案中,R2为氰基取代的C1-C8的烷基;优选的, R2为氰基取代的甲基和乙基。
在一些实施方案中,Y1和Y2均为O。
在一些实施方案中,Y1和Y2均为N(H)。
在一些实施方案中,Y1为O,Y2为N(H)。
在一些实施方案中,Y2为O,Y1为N(H)。
在一些实施方案中,X为P。
在一些实施方案中,X为S,此时Y2为O,O与S成双键,R4不存在。
在一些实施方案中,R3和R4为氢;在一些实施方案中,R3和R4各自独立地选自被一个或多个基团M取代或未取代的下列基团: C1-C8烷基、C3-C8的碳环基、C2-C8的杂环基。
在一些实施方案中,R3和R4为金属离子;优选地,R3和R4为碱金属离子;更优的,R3和R4为钠离子或钾离子。
在一些实施方案中,R3和R4均为相同基团;在一些实施方案中, R3和R4为不同基团。
在一些实施方案中,R3和R4相连成环,R3和R4与X、Y1、Y2共同成5元至7元环。
在一些实施方案中,本发明提供的巴瑞替尼衍生物,选自下列化合物:
或者上述化合物的药学上可接受盐。
另一方面,本发明提供了包含上述化合物,及其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐的药物组合物。
本发明公开了一种药物组合物,其以本发明所述的化合物、互变异构体、立体异构体、溶剂化物或其药学上可接受盐为活性成分或主要活性成分,辅以药学上可接受的载体组成。
进一步地,所述的药学上可接受的盐,包括其无机酸盐、有机酸盐、金属盐。
第三方面,本发明还提供式(I)所示的巴瑞替尼衍生物的制备路线,该路线包括如下步骤:
在上述路线中涉及的取代基定义如式(I)中相应基团的定义,其中 L是活化离去基团,式(I-1)和式(I-2)在碱性条件下可以生成式(I)。
在本申请的制备路线中,所述式(I-1)和(I-2)化合物可以根据现有技术进行合成。
第四方面,本发明提供了上述巴瑞替尼衍生物、水合物、溶剂化物、多晶型物、同位素衍生物、互变异构体、立体异构体、及其药学上可接受的盐用于预防和/或治疗JAK(JanusKinase)介导的相关疾病以及在抗RNA(Deoxyribo Nucleic Acid)病毒领域药物中的用途。
进一步地,所述的JAK介导的相关疾病包括关节炎、炎症性肠病、皮肤病、癌症、风湿关节炎、类风湿关节炎、青少年关节炎、溃病性结肠炎、克罗恩病、狼疮、银屑病、牛皮癣、皮疹、特应性皮炎、腺癌、肾癌、肝癌、胰腺癌、胃癌、乳腺癌、肺癌、头颈部癌、甲状腺癌、胶质母细胞瘤、黑色素瘤淋巴瘤皮肤癌。
所述的抗RNA病毒领域药物中的用途包括在抗新冠肺炎(Corona Virus Disease2019,COVID-19)、丙型肝炎。
进一步地,所述的抗RNA病毒的用途包括与其他药物如瑞德西韦、利巴韦林、氯喹联用治疗新冠肺炎。
本发明化合物还可用于预防和治疗脱发相关疾病。
本发明所述巴瑞替尼衍生物可以被配制为药用组合物,按照多种合适选择的给予方式给患者用药,这些途径包括全身例如口服或胃肠外,通过静脉内、肌肉、透皮或皮下等。
在本发明的一些实例中,将本发明巴瑞替尼衍生物、乳糖及硬脂酸钙进行混合,进行粉碎制粒并进行干燥,制成适当尺寸的颗粒剂。接着添加硬脂酸钙,进行压缩成形而制成片剂。
在本发明的一些实例中,将本发明巴瑞替尼衍生物、乳糖及微晶纤维素进行混合,造粒后进行压片而制成口腔崩解片。
在本发明的一些实例中,将本发明巴瑞替尼衍生物制成注射剂。
在本发明的一些实例中,将本发明巴瑞替尼衍生物及乳糖进行混合并进行粉碎,由此制成吸入剂。
在本发明的一些实例中,将本发明巴瑞替尼衍生物及适量表面活性剂和渗透压调节剂共同溶解后,制成吸入用溶液剂。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚明白,下文中将对本发明的实施例进行详细说明。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互任意组合。
以下实施例可以使本领域技术人员更全面地理解本发明,但不以任何方式限制本发明,所有化合物的结构均经MS或1H NMR确定。
实施例一:化合物DSC3501、DSC3502、DSC3503的合成
化合物3的合成:
将氰甲基磷酸二乙酯(389.70g,2.1mol)加入至6.0L四氢呋喃中,氮气保护下降温至-5.0℃,向其中缓慢加入叔丁醇钾(258.08g, 2.3mol),保持内温≤0℃,移入室温搅拌反应1.0h,降温至0℃,向其中缓慢滴加1-Boc-3-氮杂环丁酮(342.38g,2.0mol)的四氢呋喃溶液 1.2L,滴加过程中保持内温≤10.0℃,滴加完毕后移入室温反应12.0h,向其中加入1.0L水,减压浓缩得棕色混合物,加入5.0L水,搅拌均匀后乙酸乙酯萃取(5.0L×2),合并的有机相用饱和食盐水洗涤 (5.0L×1),无水硫酸干燥,浓缩,所得固体用2.4L四氢呋喃/水(4:1,V/V) 重结晶,固体于45℃下鼓风干燥12.0h得中间体3精制品310.77g。收率:80%。[M+H]+=196.23。
化合物5的合成:
氮气保护下将化合物4(307.14g,2.0mol)加入至DMF中(1.0L),冷却至0℃,向其中缓慢加入氯甲酸苄酯(358.24g,2.1mol)与三乙胺 (242.86g,2.4mol),控制内温≤5.0℃,加入完毕后室温反应3.0h,冷却至0℃,向其中缓慢加入冰水3.0L,大量固体析出,搅拌析晶1.0h,过滤,滤饼水洗(50mL×2),滤饼用DMF/水重结晶得产物5,45℃鼓风干燥12.0h得443.06g中间体5。收率:77%。纯度:97.3%。 [M+H]+=288.37。
化合物6的合成:
向中间体5(401.80g,1.4mol)加入10L四氢呋喃,上述反应体系中加入丙烯醛(95.31g,1.7mol)和80%水合肼(118.89g,1.9mol),加热至回流,期间持续鼓入氧气,回流反应12.0h后停止反应,降温至室温,减压浓缩出去有机溶剂,向其中加入3.0L冰水,DCM萃取(5.0L×2),有机相饱和食盐水洗涤(3.0L×2),无水硫酸钠干燥,减压浓缩得固体, DMF/水重结晶纯化,所得固体45℃下鼓风干燥12.0h得362.11g中间体6。收率:81%。[M+H]+=320.40。
化合物7的合成:
将中间体6(319.32g,1.0mol)加入至3.2L乙腈中,加入中间体 3(213.65g,1.1mol)与1,8-二氮杂二环十一碳-7-烯(182.69g,1.2mol),加热至60℃反应2.0h,减压浓缩,加入1.5L(0.1M)盐酸酸化,乙酸乙酯萃取(1.6L×3),饱和食盐水洗涤(2.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体7精制品400.57g。收率:78%。纯度:98.7%。[M+H]+=514.25。
化合物8的合成:
将中间体7(308.13g,0.6mol)加入至3.0L乙腈中,加入300mL三氟乙酸(TFA),加热至60℃反应2.0h,降温至室温,减压浓缩后向其中加入3.0L碳酸氢钠溶液(0.5M),乙酸乙酯萃取(3.0L×2),饱和食盐水洗涤(3.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化, 45℃下鼓风干燥12.0h得中间体8精制品198.54g。收率:80%。纯度: 98.0%。[M+H]+=414.34。
化合物9的合成:
氮气保护下将中间体8(165.37g,0.4mol)加入至1.5L二氯甲烷中,冷却至0℃,向其中缓慢加入乙基磺酰氯(61.72g,0.48mol)与三乙胺 (60.83g,0.6mol),控制内温≤5.0℃,加入完毕后室温反应5.0h,水洗 (1.0L×1),饱和食盐水洗涤(1.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体9精制品145.60g。收率:72%。纯度:98.2%。[M+H]+=506.35。
化合物10的合成:
将中间体9(50.56g,0.1mol),加入1.25L甲醇中,加入钯碳(5.06g, 0.1w/w%),氢气氛围下加热回流2.0h,冷却至室温,过滤,滤饼用甲醇淋洗(0.1L×1),滤液浓缩,乙腈重结晶得固体,45℃下鼓风干燥12.0h 得中间体10精制品27.86g。收率:75%。纯度:98.4%。[M+H]+=372.29。
化合物DSC3501的合成:
氮气保护下将中间体10(3.71g,0.01mol)加入至15mL溶剂DMF 中,冷却至0℃,向其中缓慢加入NaH(0.60g,0.015mol),室温搅拌 30min后冷却至0℃,向其中缓慢加入氯甲氧基磷酸二乙酯(2.43g, 0.012mol),加入完毕后室温搅拌反应12.0h,向其中加入60mL冰水,乙酸乙酯萃取(100mL×2),饱和食盐水洗涤(100mL×1),无水硫酸钠干燥后浓缩,柱层析分离得3.70g产品DSC3501。收率:69%。纯度: 96.5%。[M+H]+=538.31。1H NMR(300MHz,CDCl3)δ:8.85(s,1H),8.43 (s,1H),8.38(s,1H),7.46(d,J=6.2Hz,1H),6.69(d,J=6.1Hz,1H), 5.92-5.90(m,2H),4.60(d,J=8.2Hz,2H),4.28(d,J=8.2Hz,2H), 4.04-4.03(m,4H),3.68(s,2H),3.51-3.49(m,2H),1.33(t,J=10.1Hz,3H), 1.29-1.27(m,6H)。
化合物DSC3502的合成:
在氮气保护下,将化合物DSC3501(2.69g,5.0mmol)溶解入60mL 乙腈中,降温至0℃,体系中加入1.84g(12.0mmol)三甲基溴硅烷 (TMSBr),室温下反应3.0h,浓缩除去过量的三甲基溴硅烷,加15mL 水淬灭,所得固体过滤,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h 得1.20g产物DSC3502。收率50%。纯度:98.4%。[M+H]+=482.23。1H NMR(300MHz,CDCl3)δ:8.82(s,1H),8.41(s,1H),8.37(s,1H), 7.44(d,J=6.1Hz,1H),6.66(d,J=6.1Hz,1H),5.89-5.87(m,2H),4.57 (d,J=8.0Hz,2H),4.25(d,J=8.0Hz,2H),3.68(s,2H),3.50-3.48(m, 2H),1.31(t,J=10.4Hz,3H)。
化合物DSC3503的合成:
将化合物DSC3502(0.96g,2.0mmol)溶解入10mL丙酮/水的混合溶剂中(1:1,V/V),加入氢氧化钠(0.32g,8.0mmol),加热至60℃反应 2.0h,冷却至4℃,有固体析出,抽滤,滤饼丙酮/水的混合溶剂淋洗 (1.0mL×2),所得固体45℃下鼓风干燥12.0h得0.47g产物DSC3503。收率45%。纯度:98.0%。[M+Na]+=548.40。1H NMR(300MHz,CDCl3) δ:8.84(s,1H),8.42(s,1H),8.38(s,1H),7.45(d,J=6.2Hz,1H),6.68(d, J=6.1Hz,1H),5.88-5.86(m,2H),4.57(d,J=8.3Hz,2H),4.27(d,J= 8.3Hz,2H),3.69(s,2H),3.51-3.48(m,2H),1.33(t,J=10.7Hz,3H)。
实施例二:化合物DSC3504、DSC3505的合成
化合物12的合成:
将氟甲基磷酸二乙酯(357.25g,2.1mol)加入至6.0L四氢呋喃中,氮气保护下降温至-5.0℃,向其中缓慢加入叔丁醇钾(258.08g, 2.3mol),保持内温≤0℃,移入室温搅拌反应1.0h,降温至0℃,向其中缓慢滴加1-Boc-3-氮杂环丁酮(342.38g,2.0mol)的四氢呋喃溶液 1.2L,滴加过程中保持内温≤10.0℃,滴加完毕后移入室温反应12.0h,向其中加入1.0L水,减压浓缩得棕色混合物,加入5.0L水,搅拌均匀后乙酸乙酯萃取(5.0L×2),合并的有机相用饱和食盐水洗涤 (5.0L×1),无水硫酸干燥,浓缩,所得固体用2.4L四氢呋喃/水(4:1,V/V) 重结晶,固体于45℃下鼓风干燥12.0h得中间体12精制品303.28g。收率:81%。[M+H]+=188.21。
化合物13的合成:
将中间体6(319.32g,1.0mol)加入至3.2L乙腈中,加入中间体12(205.93g,1.1mol)与1,8-二氮杂二环十一碳-7-烯(182.69g,1.2mol),加热至60℃反应2.0h,减压浓缩,加入1.5L(0.1M)盐酸酸化,乙酸乙酯萃取(1.6L×3),饱和食盐水洗涤(2.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化,45℃下鼓风干燥12.0h得中间体13的精制品390.02g。收率:77%。纯度:98.6%。[M+H]+=507.19。
化合物14的合成:
将中间体13(303.92g,0.6mol)加入至3.0L乙腈中,加入300mL 三氟乙酸(TFA),加热至60℃反应2.0h,降温至室温,减压浓缩后向其中加入3.0L碳酸氢钠溶液(0.5M),乙酸乙酯萃取(3.0L×2),饱和食盐水洗涤(3.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈重结晶纯化, 45℃下鼓风干燥12.0h得中间体14精制品190.20g。收率:78%。纯度:97.0%。[M+H]+=407.34。
化合物15的合成:
氮气保护下将中间体14(162.56g,0.4mol)加入至2.0L二氯甲烷中,冷却至0℃,向其中缓慢加入乙基磺酰氯(61.72g,0.48mol)与三乙胺(60.83g,0.6mol),控制内温≤5.0℃,加入完毕后室温反应5.0h,水洗(1.0L×1),饱和食盐水洗涤(1.0L×1),无水硫酸钠干燥后浓缩得固体,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得中间体15精制品 139.59g。收率:70%。纯度:98.0%。[M+H]+=499.25。
化合物16的合成:
将中间体15(48.85g,0.1mol),加入1.25L甲醇中,加入钯碳(5.06g, 0.1w/w%),氢气氛围下加热回流2.0h,冷却至室温,过滤,滤饼用甲醇淋洗(0.1L×1),滤液浓缩,乙腈重结晶得固体,45℃下鼓风干燥12.0h 得中间体16精制品27.69g。收率:76%。纯度:97.8%。[M+H]+=365.30。
化合物DSC3504的合成:
氮气保护下将中间体16(3.64g,0.01mol)加入至15mL溶剂DMF 中,冷却至0℃,向其中缓慢加入NaH(0.60g,0.015mol),室温搅拌 30min后冷却至0℃,向其中缓慢加入氯甲氧基磷酸二乙酯(2.43g, 0.012mol),加入完毕后室温搅拌反应12.0h,向其中加入60mL冰水,乙酸乙酯萃取(100mL×2),饱和食盐水洗涤(100mL×1),无水硫酸钠干燥后浓缩,柱层析分离得3.44g产品DSC3504。收率:65%。纯度: 96.7%。[M+H]+=531.30。1H NMR(300MHz,CDCl3)δ:8.85(s,1H),8.42 (s,1H),8.39(s,1H),7.48(d,J=6.3Hz,1H),6.68(d,J=6.4Hz,1H), 5.91-5.89(m,2H),4.59(d,J=8.1Hz,2H),4.46-4.44(m,2H),4.28(d,J =8.1Hz,2H),4.05-4.03(m,4H),3.52-3.50(m,2H),1.33(t,J=10.1Hz, 3H),1.28-1.26(m,6H)。
化合物DSC3505的合成:
在氮气保护下,将化合物DSC3504(2.65g,5.0mmol)溶解入60mL 乙腈中,降温至0℃,体系中加入0.92g(6.0mmol)三甲基溴硅烷 (TMSBr),室温下反应3.0h,浓缩除去过量的三甲基溴硅烷,加15mL 水淬灭,所得固体过滤,乙腈/水重结晶纯化,45℃下鼓风干燥12.0h得0.99g产物DSC3505。收率42%。纯度:98.7%。[M+H]+=475.23。1H NMR(300MHz,CDCl3)δ:8.83(s,1H),8.41(s,1H),8.38(s,1H), 7.46(d,J=6.0Hz,1H),6.68(d,J=6.4Hz,1H),5.90-5.87(m,2H),4.59 (d,J=8.1Hz,2H),4.45-4.42(m,2H),4.27(d,J=8.1Hz,2H),3.52-3.49(m,2H),1.33(t,J=10.2Hz,3H)。
实施例三:化合物DSC3506的合成
化合物DSC3506的合成:
在氮气保护下,将化合物DSC3502(2.41g,5.0mmol)溶解入30mL 乙腈中,降温至0℃,体系中加入氯化亚砜(1.43g,12.0mmol),室温下反应1.0h,降温至0℃,向其中缓慢加入3-辛氧基-1-丙醇(9.41g, 50.0mmol),三乙胺(1.52g,15.0mmol),加热至60℃反应2.0h,冷却,浓缩,加入20mL碳酸氢钠溶液(0.5M),乙酸乙酯萃取(30mL×2),合并的有机相用饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,浓缩,柱层析分离得2.22g产物DSC3506。收率54%。纯度:98.5%。 [M+H]+=823.04。1H NMR(300MHz,CDCl3)δ:8.83(s,1H),8.41(s,1H), 8.38(s,1H),7.46(d,J=6.0Hz,1H),6.66(d,J=6.3Hz,1H),5.93-5.91 (m,2H),4.57(d,J=8.0Hz,2H),4.24(d,J=8.0Hz,2H),4.02-3.99(m, 6H),3.67(s,2H),3.50-3.48(m,8H),2.00-1.96(m,4H),1.51-1.44(m,8H), 1.32-1.28(m,19H),0.99-0.96(m,6H)。
实施例四:化合物DSC3507与DSC3508的合成
化合物17的合成:
取11.14g(30.0mmol)中间体11加入到200mL溶剂DCM中,氮气保护下加入乙酸氯甲酯(3.91g,36.0mmol),缓慢加入Et3N(4.55g, 45.0mmol),室温搅拌反应2.0h,反应完全后水洗(100mL×1),饱和食盐水洗涤(100mL×1),有机相浓缩得棕色固体,直接用于下一步反应。
化合物18的合成:
上步所得的中间体17加入120mL甲醇,10mL水,加入强氧化钠(0.52g,13.0mmol),加热至60℃反应2.0h,TLC检测反应完毕后浓缩,加入水(120mL),DCM萃取(150mL×2),饱和食盐水洗涤 (120mL×1),无水硫酸钠干燥,浓缩,柱层析分离得7.35g产物18。两步收率61%。纯度:97.2%。[M+H]+=402.11。1H NMR(300MHz, CDCl3)δ:8.87(s,1H),8.44(s,1H),8.39(s,1H),7.46(d,J=6.1Hz,1H), 6.70(d,J=6.2Hz,1H),5.25(s,2H),4.60(d,J=8.0Hz,2H),4.27(d,J =8.0Hz,2H),3.70(s,2H),3.52-3.50(m,2H),1.33(t,J=10.5Hz,3H)。
化合物DSC3507的合成:
在氮气保护下,将化合物18(4.01g,10.0mmol)溶解入50mL二氯甲烷中,降温至0℃,加入磺酰氯(1.62g,12.0mmol),缓慢滴加三乙胺(1.52g,15.0mmol),滴加完毕后室温下反应1.0h,加入30mL水洗涤,有机相分出后用饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,浓缩,柱层析分离得2.02g产物DSC3507。收率42%。纯度:98.2%。 [M+H]+=482.15。1H NMR(300MHz,CDCl3)δ:8.84(s,1H),8.41(s,1H), 8.38(s,1H),7.42(d,J=6.2Hz,1H),6.67(d,J=6.2Hz,1H),5.20(s,2H), 4.58(d,J=8.1Hz,2H),4.26(d,J=8.1Hz,2H),3.67(s,2H),3.50-3.47(m,2H),1.30(t,J=10.3Hz,3H)。
化合物DSC3508的合成:
在氮气保护下,将化合物DSC3508(1.92g,4.0mmol)溶解入15mL 丙酮中,加入1.0mL水,加入氢氧化钠(0.64g,16.0mmol),加入完毕后置于45℃搅拌反应3.0h,降温至室温,过滤除去不溶物,浓缩,所得固体用丙酮/水重结晶,干燥得0.70g产物DSC3508。收率35%。纯度:98.5%。[M+Na]+=526.29。1H NMR(300MHz,CDCl3)δ:8.83(s, 1H),8.41(s,1H),8.37(s,1H),7.41(d,J=6.1Hz,1H),6.66(d,J=6.1 Hz,1H),5.20(s,2H),4.58(d,J=8.0Hz,2H),4.25(d,J=8.0Hz,2H), 3.67(s,2H),3.49-3.47(m,2H),1.30(t,J=10.1Hz,3H)。
实施例五:化合物DSC3520的合成
化合物18的合成:
化合物18的合成,也可以按如下方法进行:反应瓶中加入1g化合物10,1.62g多聚甲醛和5ml三乙胺,加入15ml乙腈后加热至80℃搅拌24小时。体系过滤,滤液减压浓缩,剩余物过硅胶柱纯化得到 0.53g化合物18,收率48%。
化合物19的合成:
完全按照文献Tetrahedron:Asymmetry 11(2000)125–138所描述的方法合成化合物19。
化合物DSC3520的合成:
氮气保护下,化合物18溶解于无水二氯甲烷中,体系在降温至0℃,搅拌状态下加入1-甲基咪唑和化合物19。体系缓慢升温至室温,并反应18小时。体系降温至0℃,滴加饱和碳酸氢钠溶液,分出有机相。有机相浓缩至干,过硅胶柱分离得到化合物DSC3520,收率72%。 [M+H]+=522.18。1H NMR(300MHz,CDCl3)δ:8.88(s,1H),8.42(s,1H), 8.37(s,1H),7.41(d,J=6.1Hz,1H),6.73(d,J=6.2Hz,1H),5.20(s,2H), 4.60(d,J=8.0Hz,2H),4.10–4.43(m,6H),3.75(s,2H),3.52-3.55(m, 2H),1.89–2.13(1H,m),1.37–1.47(1H,m),1.33(t,J=10.5Hz,3H)。
按照与上述实施例同样的方法,使用市售化合物或由市售化合物适当合成的中间体化合物,合成了下列实施例化合物。
实施例六:MTT法测试细胞毒性实验
大鼠肝细胞BRL-3A细胞(CRL-1442)在其生长培养基中以105细胞/孔的初始密度在96孔板上培养。温育24小时以允许细胞附着后,加药(含有0.01%DMSO助溶),最终浓度设置为:1.0nM、5.0nM、 25.0nM、50.0nM、125.0nM、625.0nM。孵育48小时后,将MTS试剂添加到每个孔中。将细胞在37℃下进一步温育30-60分钟,直到在线性范围内发生比色反应,并使用96孔板分光光度计(Victor 3板读数器)在450nm处测量样品的吸光度(装备有Wallac1420 Workstation vs 3.0软件)。IC50值使用程序Prism软件(GraphPad Software Inc.,San Diego,CA)通过非线性回归分析确定。测试结果如下表一:
表一:化合物额细胞毒性
化合物 | IC<sub>50</sub>(nM) | 化合物 | IC<sub>50</sub>(nM) | 化合物 | IC<sub>50</sub>(nM) |
DSC3501 | 45.33±1.45 | DSC3510 | 38.91±2.29 | DSC3519 | 46.19±1.46 |
DSC3502 | 42.09±3.78 | DSC3511 | 29.10±1.09 | DSC3520 | 33.17±2.10 |
DSC3503 | 49.22±1.89 | DSC3512 | 30.23±1.25 | DSC3521 | 29.88±2.01 |
DSC3504 | 30.15±2.98 | DSC3513 | 34.68±1.17 | DSC3522 | 36.31±1.98 |
DSC3505 | 35.47±1.99 | DSC3514 | 49.95±2.15 | DSC3523 | 34.56±0.99 |
DSC3506 | 36.79±0.90 | DSC3515 | 33.17±1.95 | 巴瑞替尼 | 8.05±0.49 |
DSC3507 | 47.35±2.06 | DSC3516 | 31.66±2.00 | ||
DSC3508 | 38.14±2.00 | DSC3517 | 34.34±1.64 | ||
DSC3509 | 30.81±0.81 | DSC3518 | 33.99±2.05 |
结果表明,本发明的化合物具有比巴瑞替尼更低的细胞毒性,尤其是DSC3501、DSC3503、DSC3507、DSC3514、DSC3519的细胞毒性是巴瑞替尼的约20%,预示化合物具有更高的安全性。
实施例七:化合物在水中的溶解度测试
根据药典2020版溶解度测试方法凡例测试化合物在水中的溶解度:
试验法:称取研成细粉的供试品1.0000g,于15℃±2℃下加入一定容量的水中,每隔5分钟强力振摇30秒钟,观察30分钟内的溶解情况,如无目视可见的溶质颗粒时,即视为完全溶解,每组实验室重复三次。测试结果如下表二中:
表二:化合物在水中的溶解度
从数据结果可以看出,合成的新化合物具有更好的水溶性,可以有效降低制剂过程中辅助有机溶剂的使用量,预期体内有更好的药物吸收。
实施例八:化合物DSC3501、DSC3503、DSC3514、与DSC3519 对小鼠足肿胀效果测试
取10周龄、体重24-26g的小鼠为实验动物,分为12组,每组10只,每个组中每种剂量一组,分别为:空白对照组(0.5%羟丙基甲基纤维素)、巴瑞替尼组、DSC3501组、DSC3503组、DSC3514组、 DSC3519组。适应性饲养一周后,给药30分钟后足底皮下注射 40mg/kg的角叉菜胶(Sigma,C1013)造模。灌胃给药,小鼠灌胃体积为10mL/kg,剂量为4.0mg/kg与2.0mg/kg,空白对照组仅仅给予相应体积的0.5%羟丙基甲基纤维素溶液。在造模前后的不同时间点(1.0 小时、2.0小时、3.0小时、4.0小时)通过足趾肿胀仪测定足体积。数据处理:足肿胀率=(给药后的测量足体积-起始测量足体积)/基础足体积×100%。实验结果如下表三:
表三:化合物体内抗炎活性
数据结果表明,合成的化合物DSC3501、DSC3503、DSC3514、DSC3519在大鼠体内有较好的抗急性炎症的效果,1.0h有明显效果,说明化合物可以比巴瑞替尼有较快的吸收,更快到达病变部位。并且 2.0mg/kg剂量的效果与巴瑞替尼4.0mg/kg剂量的效果相当,可大大减少用药量。
实施例九:化合物耐受性实验
实验动物:本地杂交大耳白兔,雌雄各半,体重1.80±0.20kg。
随即分为6组,每组10只,分别为:空白对照组、巴瑞替尼组、 DSC3501组、DSC3503组、DSC3514组、DSC3519组。适应性饲养一周后,灌胃给药,每日给药一次,每4天为一个给药周期,连续给药20天,剂量设计如下表四:
表四:化合物给药时间段与相应给药量
空白对照组仅给与相应质量的饮用水,连续给药20天后,再次对各组灌胃给药一次,剂量为320mg/kg,给药结束后继续观察20天,记录动物死亡的只数与死亡时间,统计数据如下表五:
表五:化合物体内药物耐受性测试
数据表明,空白对照组无动物死亡,说明所选的动物较为健康,数据可靠。给药组中巴瑞替尼在1-5天内已有4只实验动物死亡,本发明的化合物仅有1-2只动物死亡,并且本发明化合物的给药组总的死亡率明显低于巴瑞替尼组,表明本发明的化合物在动物体内具有更好的耐受性,更适合于开发为临床药物。
本申请描述了多个实施例,但是该描述是示例性的,而不是限制性的,并且对于本领域的普通技术人员来说显而易见的是,在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。
Claims (10)
1.一种如下通式(I)所示的巴瑞替尼衍生物或其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐:
式(I)中,R1选自被一个或多个基团A取代或未取代的下列基团:C1-C8的烷基、C3-C8的碳环基、C2-C8的杂环基;
R2代表氰基、氟、C1-C8的烷基或氰基取代的C1-C8的烷基;
X为P、或S;
Y1和Y2各自独立地为O、或N(H);
R3和R4各自独立地为H、金属离子、或选自被一个或多个基团M取代或未取代的下列基团:C1-C8烷基、C3-C8的碳环基、C2-C8的杂环基、或R3和R4相连成环;
“----”表示成键或不成键,且当X为S时,Y2为O,此时Y2与S成双键,并且此时R4不存在;
其中所述的基团A为:氢、卤素、羟基、C1-C8烷基、C1-C8烷氧基、C3-C8的环烷基、乙酰基、氰基、三氟甲基、二氟甲基;
其中所述的基团M为:氢、卤素、C1-C8烷基、C1-C8烷氧基、C1-C8烷胺基、氨基、羟基、巯基、巯甲基、巯乙基、羧基、硝基、卤素、三氟甲基、二氟甲基。
4.如权利要求1~3所述巴瑞替尼衍生物,R3和R4可选的金属离子包括:锂离子、钠离子、钾离子、钙离子、铁离子、锌离子。
6.权利要求1所述的药学上可接受的盐,包括其无机酸盐、有机酸盐、金属盐。
7.一种药物组合物,包含权利要求1~6中任一项所述的化合物,或者其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐。
8.权利要求1~6中任一项所述的化合物,包括其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐,及权利要求7所述的药物组合物可用于预防和/或治疗JAK(Janus Kinase)介导的相关疾病以及在抗RNA(Deoxyribo Nucleic Acid)病毒领域药物中的用途。
9.权利要求8所述的抗RNA病毒的用途还包括与其他抗病毒药物如瑞德西韦、利巴韦林、氯喹联用治疗新冠肺炎。
10.权利要求1~6中任一项所述的化合物,包括其水合物、溶剂化物、多晶型物、同位素衍生物、药学上可接受的盐,及权利要求7所述的药物组合物可用于预防和/或治疗脱发相关疾病。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009114512A1 (en) * | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
CN106496233A (zh) * | 2016-09-26 | 2017-03-15 | 东南大学 | 吡咯并嘧啶类化合物、其制备方法及其用途 |
WO2017133517A1 (zh) * | 2016-02-03 | 2017-08-10 | 四川海思科制药有限公司 | 一种磷酰胺衍生物及制备方法和用途 |
CN109867675A (zh) * | 2017-12-01 | 2019-06-11 | 北京普祺医药科技有限公司 | 一种吡咯并嘧啶衍生的化合物、药物组合物以及其用途 |
-
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- 2022-02-28 CN CN202210187492.4A patent/CN114957260B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009114512A1 (en) * | 2008-03-11 | 2009-09-17 | Incyte Corporation | Azetidine and cyclobutane derivatives as jak inhibitors |
WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
WO2017133517A1 (zh) * | 2016-02-03 | 2017-08-10 | 四川海思科制药有限公司 | 一种磷酰胺衍生物及制备方法和用途 |
CN106496233A (zh) * | 2016-09-26 | 2017-03-15 | 东南大学 | 吡咯并嘧啶类化合物、其制备方法及其用途 |
CN109867675A (zh) * | 2017-12-01 | 2019-06-11 | 北京普祺医药科技有限公司 | 一种吡咯并嘧啶衍生的化合物、药物组合物以及其用途 |
Non-Patent Citations (1)
Title |
---|
姬勋等: "磷酸酯前药在药物研究中的应用", 《药学学报》, vol. 48, no. 5, pages 621 * |
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