CN117700401A - 一种氘代物及其在医药上的应用 - Google Patents
一种氘代物及其在医药上的应用 Download PDFInfo
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- CN117700401A CN117700401A CN202311096452.XA CN202311096452A CN117700401A CN 117700401 A CN117700401 A CN 117700401A CN 202311096452 A CN202311096452 A CN 202311096452A CN 117700401 A CN117700401 A CN 117700401A
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- acid
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- pharmaceutically acceptable
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Abstract
本发明涉及一种通式(I)所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与μ阿片受体(mu opioid receptor,MOR)相关疾病的药物中的应用。
Description
技术领域
本发明涉及一种通式(I)所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与μ阿片受体(mu opioid receptor,MOR)相关疾病的药物中的应用。
背景技术
阿片受体是一种G蛋白偶联受体(G protein coupled receptor,GPCR),是内源性阿片肽及阿片类药物结合的靶点。人体内存在多种阿片受体,并且广泛的分布在中枢神经系统,心脏,消化道,血管,肾脏等外周组织。阿片受体主要包括μ阿片受体(Mu opioidreceptor,MOR)、δ阿片受体(Delta opioid receptor,DOR)和k阿片受体(Kappa opioidreceptor,KOR)三类。内源性痛敏肽是阿片受体家族的第4个成员,发现相对较晚,被称为阿片受体样受体(opioid receptor like l-Nociceptin,ORL1)。μ受体有μ1和μ2两种亚型,δ受体有δ1和δ2两种亚型,κ受体有κ1、κ2、κ3三种亚型。经研究发现,μ阿片受体(mu opioidreceptor,MOR)与吗啡肽的结合能力最强,μ受体也是吗啡、芬太尼等镇痛药主要作用的受体蛋白位点。近年来有研究表明大鼠吗啡成瘾后下丘脑、额叶皮质、海马、纹状体的μ受体呈现出不同程度的下调,同时与之下降的还有μ受体的基因表达。
发明内容
本发明的目的是提供一种氘代化合物及其制备和应用。
本发明提供一种化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I)所示的化合物,其中
R选自或/>
R1、R2、R3、R4、R5a、R5b、R6a、R6b、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11a、R11b、R12a、R12b、R13a、R13b、R14a、R14b、R15、R16、R17a、R17b、R18a、R18b、R18c、R19、R20、R21、R22a、R22b、R23a、R23b各自独立的选自H或D,条件是至少有1个选自D。
本发明提供一种如下所示化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
本发明实施方案中,其中,药学上可接受的盐选自马来酸、富马酸、氢卤酸(优选为氢溴酸和盐酸)、硫酸、磷酸、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、D-葡萄糖醛酸、乙醇酸、粘酸、琥珀酸、乳酸、乳清酸、帕莫酸、丙二酸、龙胆酸、水杨酸、草酸或戊二酸。
本发明涉及一种药物组合物,包括上述化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体。
本发明涉及上述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用于制备预防或治疗疼痛药物中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物,例如人、陪伴动物、动物园动物和家畜,优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体,如酮式-烯醇式异构和酰胺-亚胺醇式异构等。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的,起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的,供应商包括:泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
PE:石油醚;
EA:乙酸乙酯;
DMF:二甲基甲酰胺;
DCM:二氯甲烷。
实施例1:化合物1的富马酸盐的制备
(R)-N-((3-((甲氧基-d3)甲基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-恶螺[4.5]癸烷-9-基)乙烷-1,1-d2-1-胺(化合物1)的富马酸盐
(R)-N-((3-((methoxy-d3)methyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethan-1,1-d2-1-amine;Fumaric acid
第一步:化合物1B的制备
250mL三口瓶中,加入超干四氢呋喃(75mL),干冰浴冷却十分钟后加入氘代氢化锂铝(2.95g,70.16mmol),加完后冷却至内温为-5℃后,滴加(R)-2-(9-(吡啶-2-基)-6-二氧杂螺[4.5]癸烷-9-基)乙腈(CAS:1401031-38-6,7.2g,28.09mmol)的超干四氢呋喃(75mL)溶液,滴加过程中保持内温-5℃,加完后恢复室温反应过夜。反应液冷却至0-10℃,滴入重水(15mL)淬灭反应,然后加入10%氢氧化钠溶液(38mL),水(25mL),滴加完毕,室温搅拌30分钟,加入无水硫酸钠干燥,铺适量硅藻土,过滤,滤饼用二氯甲烷(150mL×5)洗,滤液减压浓缩干得到化合物1B(6.91g,收率:94%)。
LCMS m/z=263.3[M+H]+
第二步:化合物1D的制备
500mL三口瓶中,加入氢化钠(10.51g,262.78mmol)和超干四氢呋喃(120mL),冰浴冷却十分钟后加入化合物1C(20g,175.19mmol)的超干四氢呋喃(15mL)溶液,加完后滴加氘代碘甲烷(18.63g,131.24mmol),加完后升温至60℃搅拌反应2小时。反应液冷却至室温,缓慢滴加至100mL水中淬灭,乙酸乙酯(100mL×3)萃取,合并有机相并依次用水(100mL×1)、饱和食盐水(100mL×1)洗,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩后通过中压制备分离纯化(PE/EA:0%-10%)得化合物1D(23.2g,收率:99%)。
1H NMR(400MHz,CDCl3)δ7.33-7.28(m,1H),7.24–7.19(m,1H),7.10-7.04(m,1H),4.46(s,2H).
第三步:化合物1E的制备
500mL三口瓶中,加入化合物1D(23g,175.29mmol)和超干四氢呋喃(130mL),干冰-乙醇浴冷却十分钟后滴加正丁基锂(121mL,1.6M,192mmol),滴加完后保温反应30分钟,恢复冰水浴十分钟后滴加超干溶剂DMF(9.26g,126.63mmol),加完后保温反应1小时。向反应液中缓慢滴加饱和氯化铵溶液(100mL)淬灭,乙酸乙酯(100mL×3)萃取,合并有机相并依次用水(100mL×1)、饱和食盐水(100mL×1)洗,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩得化合物1E粗品(23g),直接投下一步。
LCMS m/z=160.1[M+H]+
第四步:化合物1的制备
在1.0L三口瓶中,加入化合物1B(15g,57.17mmol)、化合物1E(9.56g,60.03mmol)、无水硫酸钠(60g)和二氯甲烷(500mL),加完后室温搅拌反应过夜,反应液冰浴冷却下分批多次加入三乙酰氧基硼氢化钠(24.23g,114.34mmol),加完后室温反应2小时。反应液用饱和碳酸氢钠溶液调节pH约为13,二氯甲烷(500mL×2)萃取,合并有机相并用无水硫酸钠干燥,抽滤,滤液减压浓缩后柱层析分离纯化(PE/EA:0%-25%-50%,DCM/MeOH:0%-3%-5%)得到化合物1(6.5g,收率:28%)。
LCMS m/z=406.3[M+H]+
第五步:化合物1的富马酸盐的制备
在250mL反应瓶中,加入化合物1(6g,14.79mmol)、富马酸(1.72g,14.79mmol)、异丙醇(12mL)和乙酸乙酯(60mL),加完后油浴70℃下搅拌溶清,然后在室温下搅拌反应过夜,析出大量固体,反应液减压浓缩干,加入乙酸乙酯(60mL)打浆2小时,抽滤,滤饼用乙酸乙酯(15mL×2)洗,然后减压抽干得到化合物1的富马酸盐(2.9g,收率:38%)。
1H NMR(400MHz,CD3OD)δ8.60–8.52(m,1H),7.83–7.75(m,1H),7.51(d,1H),7.45(d,1H),7.32–7.22(m,1H),7.01(d,1H),6.68(s,2H),4.48(s,2H),4.28(s,2H),3.79–3.69(m,2H),2.54–2.42(m,2H),2.11(d,1H),1.95–1.78(m,2H),1.78–1.33(m,7H),1.14–1.01(m,1H),0.77–0.63(m,1H).
LCMS m/z=406.3[M+H]+
实施例2:化合物2的富马酸盐的制备
(R)-N-((3-((甲氧基-d3)甲基-d2)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-恶螺[4.5]癸-9-基)乙烷-1-胺(化合物2)的富马酸盐
(R)-N-((3-((methoxy-d3)methyl-d2)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethan-1-amine;Fumaric acid
第一步:化合物2B的制备
1.0L三口瓶中,加入超干四氢呋喃(200mL),干冰浴冷却十分钟后加入氢化锂铝(7.4g,195mmol),加完后冷却至内温为-5℃后,滴加(R)-2-(9-(吡啶-2-基)-6-二氧杂螺[4.5]癸烷-9-基)乙腈(CAS:1401031-38-6,20g,78mmol)的超干四氢呋喃(100mL)溶液,滴加过程中保持内温-5℃,加完后恢复室温反应过夜。反应液冷却至0-10℃,滴入水(7.5mL)淬灭反应,然后加入10%氢氧化钠溶液(15mL),水(10mL),滴加完毕,室温搅拌30分钟,加入无水硫酸钠干燥,铺适量硅藻土,过滤,滤饼用二氯甲烷(50mL×4)洗,滤液减压浓缩干得到化合物2B(19g,收率:94%)。
LCMS m/z=261.3[M+H]+
第二步:化合物2D的制备
250mL三口瓶中,加入超干四氢呋喃(75mL),干冰/乙醇/水冷却至-20℃,加入氘代氢化锂铝(4.09g,97.5mmol),加完后冷却至内温为-10℃后,滴加3-噻吩甲酸(CAS:88-13-1,5g,39mmol)的超干四氢呋喃(25mL)溶液,滴加过程中保持内温-5℃,加完后恢复室温反应过夜。反应液冷却至0-10℃,滴入重水(3mL)淬灭反应,然后加入10%氢氧化钠溶液(6mL),水(3mL),滴加完毕,室温搅拌30分钟,加入硫酸钠干燥,铺适量硅藻土,过滤,滤饼二氯甲烷(150mL×5)洗,滤液减压浓缩干得到化合物2D(4.09g,收率:90%)。
1H NMR(400MHz,CDCl3)δ7.32(dd,1H),7.23(dd,1H),7.10(dd,1H).
第三步:化合物2E的制备
100mL三口瓶中,加入氢化钠(1.03g,25.82mmol)和超干四氢呋喃(50mL),冰浴冷却十分钟后加入化合物2D(2.0g,17.21mmol)的超干四氢呋喃(15mL)溶液,加完后滴加氘代碘甲烷(2.74g,18.93mmol),加完后升温至60℃搅拌反应2小时。反应液冷却至室温,缓慢滴加至100mL水中淬灭,乙酸乙酯(100mL×3)萃取,合并有机相并依次用水(100mL×1)、饱和食盐水(100mL×1)洗,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩后通过中压制备分离纯化(PE/EA:0%-3%)得化合物2E(0.82g,收率:36%)。
1H NMR(400MHz,CDCl3)δ7.30(dd,1H),7.21(dd,1H),7.07(dd,1H).
第四步:化合物2F的制备
500mL三口瓶中,加入化合物2E(0.8g,6.01mmol)和超干四氢呋喃(50mL),干冰-乙醇浴冷却十分钟后滴加正丁基锂(4.1mL,1.6M,6.6mmol),滴加完后保温反应30分钟,恢复冰水浴十分钟后滴加超干溶剂DMF(0.57g,7.8mmol),加完后保温反应1小时。向反应液中缓慢滴加重水(10mL)淬灭,然后加入水(30mL),乙酸乙酯(30mL×2)萃取,合并有机相并用无水硫酸钠干燥,抽滤,滤液减压浓缩得化合物2F粗品(0.95g),直接投下一步。
LCMS m/z=162.1[M+H]+
第五步:化合物2的制备
在1.0L三口瓶中,加入化合物2B(1.27g,4.88mmol)、化合物2F(0.94g,5.86mmol)、无水硫酸钠(3.46g)和二氯甲烷(20mL),加完后室温搅拌反应过夜,反应液冰浴冷却下分批多次加入三乙酰氧基硼氢化钠(2.07g,9.76mmol),加完后室温反应2小时。反应液用饱和碳酸氢钠溶液调节pH约为13,二氯甲烷(50mL×2)萃取,合并有机相并用无水硫酸钠干燥,抽滤,滤液减压浓缩后柱层析分离纯化(PE/EA:0%-25%-50%,DCM/MeOH:0%-3%-5%)得到化合物2(384mg,收率:19%)。
LCMS m/z=406.3[M+H]+
第六步:化合物2的富马酸盐的制备
在100mL反应瓶中,加入化合物2(0.38g,0.94mmol)、富马酸(0.11g,0.94mmol)、异丙醇(1mL)和乙酸乙酯(5.0mL),加完后油浴70℃下搅拌溶清,然后在室温下搅拌反应过夜,析出大量固体,反应液减压浓缩干,加入乙酸乙酯(60mL)打浆2小时,抽滤,滤饼用乙酸乙酯(10mL)洗,然后减压抽干得到化合物2的富马酸盐(324mg,收率:66%)。
LCMS m/z=406.3[M+H]+
1H NMR(400MHz,CD3OD)δ8.63–8.50(m,1H),7.84–7.75(m,1H),7.50(d,1H),7.44(d,1H),7.30–7.22(m,1H),7.01(d,1H),6.68(s,2H),4.27(s,2H),3.78–3.67(m,2H),3.01–2.87(m,1H),2.55–2.35(m,3H),2.18–2.04(m,1H),1.94–1.79(m,2H),1.77–1.34(m,7H),1.14-1.04(m,1H),0.76–0.63(m,1H).
实施例3:化合物3的富马酸盐的制备
(R)-N-((3-(甲氧基甲基-d2)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-恶螺[4.5]癸-9-基)乙烷-1-胺(化合物3)的富马酸盐
(R)-N-((3-(methoxymethyl-d2)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethan-1-amine;Fumaric acid
第一步:化合物3A的制备
100mL三口瓶中,加入氢化钠(1.03g,25.82mmol)和超干四氢呋喃(50mL),冰浴冷却十分钟后加入化合物2D(2.0g,17.21mmol)的超干四氢呋喃(15mL)溶液,加完后滴加碘甲烷(2.69g,18.93mmol),加完后升温至60℃搅拌反应2小时。反应液冷却至室温,缓慢滴加至100mL水中淬灭,乙酸乙酯(100mL×3)萃取,合并有机相并依次用水(100mL×1)、饱和食盐水(100mL×1)洗,有机相用无水硫酸钠干燥,抽滤,滤液减压浓缩后通过中压制备分离纯化(PE/EA:0%-10%)得化合物3A(1.3g,收率:58%)。
1H NMR(400MHz,CDCl3)δ7.30(dd,1H),7.21(dd,1H),7.07(dd,1H),3.37(s,3H).
第二步:化合物3B的制备
500mL三口瓶中,加入化合物3A(1.30g,9.98mmol)和超干四氢呋喃(50mL),干冰-乙醇浴冷却十分钟后滴加正丁基锂(6.86mL,1.6M,11mmol),滴加完后保温反应30分钟,恢复冰水浴十分钟后滴加超干溶剂DMF(0.95g,13mmol),加完后保温反应1小时。向反应液中缓慢滴加重水(10mL)淬灭,然后加入水(30mL),乙酸乙酯(30mL×2)萃取,合并有机相并用无水硫酸钠干燥,抽滤,滤液减压浓缩得化合物3B粗品(1.6g,收率:100%),直接投下一步。
LCMS m/z=159.1[M+H]+
第三步:化合物3的制备
在1.0L三口瓶中,加入化合物2B(1.78g,6.84mmol)、化合物3B(1.30g,8.21mmol)、无水硫酸钠(4.86g)和二氯甲烷(20mL),加完后室温搅拌反应过夜,反应液冰浴冷却下分批多次加入三乙酰氧基硼氢化钠(2.90g,13.68mmol),加完后室温反应3小时。反应液用饱和碳酸氢钠溶液调节pH约为13,二氯甲烷(50mL×2)萃取,合并有机相并用无水硫酸钠干燥,抽滤,滤液减压浓缩后柱层析分离纯化(PE/EA:0%-25%-50%,DCM/MeOH:0%-3%-5%)得到化合物3(400mg,收率:15%)。
LCMS m/z=403.3[M+H]+
第四步:化合物3的富马酸盐的制备
在100mL反应瓶中,加入化合物3(0.4g,0.99mmol)、富马酸(0.11g,0.99mmol)、异丙醇(1mL)和乙酸乙酯(5.0mL),加完后油浴70℃下搅拌溶清,然后在室温下搅拌反应过夜,析出大量固体,反应液减压浓缩干,加入乙酸乙酯(20mL)打浆2小时,抽滤,滤饼用乙酸乙酯(10mL)洗,然后减压抽干得到化合物3的富马酸盐(369mg,收率:72%)。
LCMS m/z=403.1[M+H]+
1H NMR(400MHz,CD3OD)δ8.61–8.51(m,1H),7.84–7.74(m,1H),7.51(d,1H),7.44(d,1H),7.30–7.21(m,1H),7.01(d,1H),6.68(s,2H),4.26(s,2H),3.77–3.67(m,2H),3.35(s,3H),3.04–2.85(m,1H),2.54–2.35(m,3H),2.16–2.06(m,1H),1.94–1.80(m,2H),1.78–1.34(m,7H),1.14–1.04(m,1H),0.76–0.63(m,1H).
生物测试例
测试例1:化合物对阿片μ受体介导的胞内cAMP抑制作用测试
OPRM1细胞(来源于DiscoverX)培养于含10%胎牛血清与双抗(1×)的DMEM-F12培养基。用5mM EDTA(乙二胺四乙酸)消化细胞,离心收集,用1×Stimulation Buffer(Cisbio,Lance试剂盒)重悬细胞,调整细胞至合适密度。用1×Stimulation Buffer配制毛喉素(forskolin,终浓度为1.5μM)与不同浓度化合物的混合溶液,以每孔5μL加入384孔白板。每孔再加入5μL细胞悬液,室温孵育30分钟。孵育结束后,每孔加入5μL 4×Eu-cAMPtracer工作液(Lance试剂盒,用cAMP Detection Buffer稀释Eu-cAMP stock solution 50倍)。然后每孔加入5μL 4×Ulight-anti-cAMP工作液(Lance试剂盒,用cAMP DetectionBuffer稀释ULight-anti-cAMP stock solution 150倍),并在室温下避光孵育1小时。384孔板用BMG酶标仪(PHERAstar FSX)检测TR-FRET,使用GraphPad软件中四参数非线性方程拟合EC50值。
结论:本发明化合物具有良好的阿片μ受体激动活性。
生物测试例2:CYP450酶抑制测试
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的几种同工酶(CYP1A2、CYP2C9、CYP2C19和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育,加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应,在反应结束后,通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物,测定CYP酶活性的变化,计算IC50值,评价受试物对各CYP酶亚型CYP1A2、CYP2C9、CYP2C19、CYP3A4-M(以咪达唑仑为底物)的抑制潜能。
实验结果:在测试条件下,孵育浓度为0~50或0~100μM时,各测试化合物对CYP酶抑制作用的IC50值见表1:
表1测试化合物对CYP酶抑制作用的结果
化合物编号 | CYP1A2(μM) | CYP2C9(μM) | CYP2C19(μM) | CYP3A4-M(μM) |
化合物2的富马酸盐 | >30 | >30 | 4.61 | 18.1 |
化合物3的富马酸盐 | >30 | >30 | 6.35 | 15.1 |
Claims (5)
1.一种化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I)所示的化合物,其中,
R选自
R1、R2、R3、R4、R5a、R5b、R6a、R6b、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11a、R11b、R12a、R12b、R13a、R13b、R14a、R14b、R15、R16、R17a、R17b、R18a、R18b、R18c、R19、R20、R21、R22a、R22b、R23a、R23b各自独立的选自H或D,条件是至少有1个选自D。
2.根据权利要求1所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中化合物选自如下结构之一:
3.根据权利要求1-2任一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,药学上可接受的盐选自马来酸、富马酸、氢卤酸(优选为氢溴酸和盐酸)、硫酸、磷酸、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、D-葡萄糖醛酸、乙醇酸、粘酸、琥珀酸、乳酸、乳清酸、帕莫酸、丙二酸、龙胆酸、水杨酸、草酸或戊二酸。
4.一种药物组合物,包括权利要求1-3任意一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体。
5.根据权利要求1-3任意一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用于制备预防或治疗疼痛药物中的用途。
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