CN114057701A - 一种氘代哒嗪酮类化合物及其用途 - Google Patents
一种氘代哒嗪酮类化合物及其用途 Download PDFInfo
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- CN114057701A CN114057701A CN202110883520.1A CN202110883520A CN114057701A CN 114057701 A CN114057701 A CN 114057701A CN 202110883520 A CN202110883520 A CN 202110883520A CN 114057701 A CN114057701 A CN 114057701A
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- 150000001875 compounds Chemical class 0.000 claims abstract description 57
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Abstract
本发明公开了一种式(I)的氘代哒嗪酮类化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐及其组合物,以及相应的制备方法,并提供了所述化合物在制备治疗甲状腺激素受体介导的疾病的药物中的用途。式(I)中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10分别独立地选自H、D,且不同时为H。
Description
技术领域
本发明涉及一种氘代哒嗪酮类化合物及其立体异构体、溶剂化物、共晶、药学上可接受的盐,及其在制备治疗代谢相关疾病的药物中的用途。
背景技术
甲状腺激素对于正常生长和发育以及维持代谢平衡是关键的。甲状腺激素由甲状腺产生并且以下面的两种不同的形式分泌到循环***中:3,5,3’,5’-四-碘-L-甲状腺原氨酸(T4)和3,5,3’-三-碘-L-甲状腺原氨酸(T3)。尽管T4是由甲状腺分泌的主要形式,但是T3是生理上更活跃的形式。T4通过组织特异性脱碘酶被转化成T3,组织特异性脱碘酶存在于所有组织中,但是主要在肝和肾中。甲状腺激素的生物活性由甲状腺激素受体(TRs)介导。TRs属于已知为核受体的超家族。甲状腺激素受体源自两个分开的基因,α和β。这些不同的基因产物通过差别的RNA加工而产生多种形式的它们各自的受体。主要的甲状腺受体同工型是α1、α2、β1和β2。甲状腺激素受体α1、β1和p2结合甲状腺激素。已经显示,甲状腺激素受体亚型在它们对于特殊生理响应的贡献方面可以不同。最近的研究表明,TRβ1在肝中在调节TRH(促甲状腺激素释放激素)和调节甲状腺激素的作用中起重要作用。TRβ2在调节TSH(甲状腺刺激激素)方面起主要作用。TRβ1在调节心率方面起重要作用。
甲状腺激素的另一在治疗上的有益效果是降低血清低密度脂蛋白(LDL)。已经发现,甲状腺机能亢进与低的总血清胆固醇有关,这归因于甲状腺激素增加肝LDL受体表达并且刺激胆固醇向胆汁酸的代谢。甲状腺功能减退又与高胆固醇血症有关,并且已知甲状腺激素替代疗法降低了总胆固醇。
避免甲状腺机能亢进和甲状腺功能减退的不良效果、同时保持甲状腺激素的有益效果的甲状腺激素类似物的开发将打开治疗以下疾病患者的新的途径:代谢疾病如肥胖,高脂血症,高胆固醇血症,糖尿病和其它病症和疾病如肝脂肪变性和NASH,动脉粥样硬化,心血管疾病,甲状腺功能减退,甲状腺癌,甲状腺疾病,以及相关病症和疾病。迄今,天然存在的甲状腺激素的治疗用途受到与甲状腺机能亢进、特别是心血管毒性有关的不利副作用的限制。
因此,仍然需要具有甲状腺激素的有益效果同时又避免不良效果的新型甲状腺激素模拟物。
专利WO2019240938公开了一类新的哒嗪酮甲状腺激素模拟物,本发明提供了其如下式化合物的氘代物:
发明内容
本发明的目的是提供一种活性高、副作用小、生物利用度高、选择性高的新的甲状腺激素受体(THR)激动剂。
本发明提供的化合物及其立体异构体、溶剂化物、共晶或药学上可接受的盐,对THR具有激动作用,具有良好的药代动力学特征,高的生物利用度,安全性好,毒副作用小,具有口服给药、吸收快、清除率高等优点。
本发明首先提供了式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10分别独立地选自H、D,且不同时为H。
在一些具体实施方案中,前述式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10分别独立地选自H、D,且不同时为H,条件是,所述化合物不是
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(II)、(III)、或(IV)的结构:
R1-R10如式(I)中之定义。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(V)的结构:
其中,R3、R4、R5、R6、R7中至少一个为D,R8、R9、R10独立地为H或D。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(VI)的结构:
其中,R3、R4、R5、R6、R7中至少一个为D,R1、R2独立地为H或D。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(VII)的结构:
其中,R3、R4、R5、R6、R8、R9、R10独立地为H或D。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(VIII)的结构:
其中,R1、R2、R3、R4、R5、R6独立地为H或D。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物进一步具有式(IX)的结构:
其中,R1、R2、R5、R6、R7独立地为H或D。
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物具有以下结构之一:
在一些具体实施方案中,式(I)的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,所述化合物具有以下结构之一:
本发明还提供了一种药物组合物,所述组合物含有上述式(I)至式(Ⅸ)任一所述的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
本发明进一步提供了式(I)至式(IX)任一所述的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,或者其药物组合物在制备治疗甲状腺激素受体介导的疾病的药物中的用途。
更具体地,前述用途中所述的疾病包括但不限于肥胖、高脂血症、高胆固醇血症、糖尿病、非酒精性脂肪肝炎、非酒精性脂肪肝病、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌等。
合成路线
本领域技术人员可以结合专利WO2019240938以及已知的有机合成技术制备本发明的化合物,其起始原料为市售化学品和(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。
本领域的参考书和专著,详细介绍了可用于制备本文所述化合物的反应物的合成,或提供了描述该制备方法的文章以供参考。这些参考书和专著包括:“SyntheticOrganic Chemistry”,John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,“OrganicFunctional Group Preparations,”2nd Ed.,Academic Press,New York,1983;H.O.House,“Modem Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,NewYork,1992;J.March,“Advanced Organic Chemistry:Reactions,Mechanisms andStructure”,4th Ed.,Wiley-Interscience,New York,1992;Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised andEnlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5;Hoffman,R.V.“OrganicChemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.“Comprehensive Organic Transformations:A Guide toFunctional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4thEdition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModemCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s 1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)JohnWiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)JohnWiley&Sons,in over 55 volumes;and“Chemistry of Functional Groups”John Wiley&Sons,in 73volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引,可以选择性地识别特定和类似的反应物,这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备,其中许多标准化学供应工厂(例如,上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,VerlagHelvetica Chimica Acta,Zurich,2002.
术语
“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。
“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。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时,则为水合物。
“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。
“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”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐或共晶,与其他组成成分的混合物,其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是: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,并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是:其本身并非治疗剂,用作稀释剂、辅料、粘合剂和/或媒介物,用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的,药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠);(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液(Ringer’s solution);(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;及(22)其他用于药物制剂中的无毒相容物质。
具体实施方式
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的,按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明,但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
检测方法
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-C18100×4.6mm,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。
实施例1
(R)-2-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物1)
(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitril(compound 1)
第一步:1-(甲基-d3)-2-氧代环戊烷-1-甲酸乙酯(1b)
ethyl 1-(methyl-d3)-2-oxocyclopentane-1-carboxylate(1b)
在10L的三口瓶中加入1a(0.65Kg,4.16mol),丙酮(6000mL)溶解,搅拌中加入碳酸钾(2.00Kg,3.32mol),室温下滴加氘代碘甲烷(1.80Kg,12.41mmol),滴完后室温搅拌100h,抽滤,浓缩,柱层析分离(石油醚:乙酸乙酯(v/v)=10:1)得标题化合物1b(580.10g,90%)。
LC-MS(ESI):m/z=174.2[M+H]+.
第二步:2-(甲基-d3)环戊酮(1c)
2-(methyl-d3)cyclopentan-1-one(1c)
在3L的单口瓶中加入1b(735.0g,4.2mol)和HCl(6M,1500mL),100摄氏度回流过夜,加入水(1500mL),DCM(800mL×3)萃取,合并有机相,用饱和食盐水(1000mL)洗涤,无水硫酸钠干燥,30摄氏度度低温浓缩得标题化合物1c(317.10g,74%)。
1H NMR(400MHz,CDCl3)δ2.37-2.17(m,2H),2.16-2.06(m,2H),2.04-1.96(m,1H),1.86-1.74(m,1H),1.54-1.43(m,1H).
第三步:1-(5-(甲基-d3)环戊-1-烯-1-基)吡咯烷(1d)
1-(5-(methyl-d3)cyclopent-1-eh-1-yl)pyrrolidine(1d)
在3L的单口瓶中加入1c(326.80g,3.20mol),甲苯(1500mL)溶解,加入一水合对甲苯磺酸(306.86g,1.62mol)和四氢吡咯(344.60g,4.90mol),130摄氏度回流分水16h,浓缩得标题化合物1d(330.20g,粗品),直接用于下一步反应。
第四步:1,4-二氯-5-(甲基-d3)-6,7-二氢-5H-环戊[d]哒嗪(1f)
1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine(1f)
在5L的三口瓶中加入1d(330.20g,2.14mol),二氯甲烷(1650mL)溶解,干冰乙醇浴冷却至-60摄氏度以下,氮气保护中缓慢滴加1e(329.90g,2.14mol)的二氯甲烷溶液(1650mL),滴完后缓慢恢复到室温,搅拌过夜。反应液用HCl(3M,1500mL)洗涤,有机相用无水硫酸钠干燥,浓缩,柱层析(石油醚∶乙酸乙酯(v/v)=30∶1-10∶1)得标题化合物1f(120.02g,27%)。
LC-MS(ESI):m/z=206.0[M+H]+.
第五步:3,5-二氯-4-((4-氯-5-(甲基-d3)-6,7-二氢-5H-环戊[d]哒嗪-1-基)氧基)苯胺(1h)3,5-dichloro-4-((4-chloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)aniline(1h)
在2L的三口瓶中加入1f(120.00g,0.59mol),DMSO(1200mL)溶解,加入底物1g(114.90g,0.64mol),碳酸钾(161.70g,1.2mol),碘化亚铜(55.7g,0.29mol),氮气置换三次,100摄氏度反应7h。反应液加乙酸乙酯(1200mL)稀释,通过硅胶过滤,滤液用食盐水(1200mL)洗涤,有机相用无水硫酸钠干燥,浓缩,柱层析(石油醚∶乙酸乙酯(v/v)=10∶1-5∶1)得标题化合物1h(203.42g,59%)。
LC-MS(ESI):m/z=347.1[M+H]+.
第六步:N-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基]氧基]苯基乙酰胺(1i)
N-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)acetamide(1i)
在3L的单口瓶中加入底物1h(120.10g,0.35mol),乙酸(1200mL)溶解,加入乙酸钠(141.58g,1.73mol),120-125摄氏度反应24h,浓缩除去大部分乙酸,饱和碳酸氢钠溶液调节pH到8-9,乙酸乙酯(800mL×3)萃取,有机相浓缩得标题化合物1i(120.20g,94%),直接用于下一步反应。
LC-MS(ESI):m/z=371.0[M+H]+.
第七步:4-(4-氨基-2,6-二氯苯氧基)-7-(甲基-d3)-2,5,6,7-四氢-1H-环戊[d]哒嗪-1-酮(1j)4-(4-amino-2,6-dichlorophenoxy)-7-(methy1-d3)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(1j)
在3L的单口瓶中加入1i(120.20g,0.32mol),甲醇(600mL)和NaOH溶液(2M,600mL),80摄氏度搅拌过夜,浓缩除去甲醇,乙酸乙酯(200mL×3)萃取,有机相用无水硫酸钠干燥,浓缩,柱层析(石油醚∶乙酸乙酯(v/v)=10∶1-3∶2)分离得标题化合物1j(23.20g,22%)。
LC-MS(ESI):m/z=329.1[M+H]+.
第八步:(R)-4-(4-氨基-2,6-二氯苯氧基)-7-(甲基-d3)-2,5,6,7-四氢-1H-环戊[d]哒嗪-1-酮(1k)和(S)-4-(4-氨基-2,6-二氯苯氧基)-7-(甲基-d3)-2,5,6,7-四氢-1H-环戊[d]哒嗪-1-酮(1l)
(R)-4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(1k)and(S)-4-(4-amino-2,6-dichlor ophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(11)
化合物1j(22.8g,69.26mmol),手型制备分离得到化合物1k(7.05g,31%)和化合物1l(9.53g,42%),制备色谱条件:色谱柱ChiralCel OJ,300×50mm I.D.,10μm,流动相体系:二氧化碳/甲醇=65/35(v),流量200mL/min,得到化合物1k(出峰时间约为1.59min),化合物1l(出峰时间约为1.96min).
第九步:乙基(R,E)-(2-氰基-2-(2-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊基[d]哒嗪-4-基)氧基)苯基)亚肼基)乙酰基氨基甲酸酯(1n)
ethyl(R,E)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(1n)
在1L的单口瓶中加入1k(15.00g,45.57mmol),水(450mL),浓盐酸(228mL),搅拌中冰浴冷却至0摄氏度,滴加亚硝酸钠溶液(3.96g,57.42mmol,20mL),加完后保温搅拌0.5h,固体消失,反应液变橙色,作为反应液1备用。在3L的反应瓶2中加入底物1m(7.83g,50.13mmol),水(730mL),吡啶(228mL),冰浴冷却至0摄氏度,加入反应液1,加完后冰浴中搅拌1.0h,有大量固体析出,加入乙酸乙酯(4×200mL)萃取,合并有机相,无水硫酸钠干燥,浓缩得成标题化合物1n(21.10g,93%)。
LC-MS(EAI):m/z=496.1[M+H]+.
第十步:(R)-2-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物1)
(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(compound 1)
在500mL的单口瓶中加入1N(11.00g,22.16mmol),DMF(55mL)溶解,加入乙酸钠(2.54g,31.02mmol),120摄氏度反应1.5h,LCMS检测反应完全,反应液冷却,倒入水(300mL)中,抽滤析出的固体,干燥,制备HPLC分离,冷冻干燥得化合物1(6.70g,67%)。
制备方法:仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm;样品用DMF溶解,用0.45μm滤头过滤,制成样品液;制备色谱条件:a.流动相A,B组成:流动相A:乙腈,流动相B:水(含5mM乙酸铵);b.梯度洗脱,流动相A含量从40%-70%;c.流量15mL/min。d.洗脱时间20min;保留时间:12.33min。
LC-MS(ESI):m/z=450.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ 12.08(s,1H),7.78(s,2H),7.09(s,1H),3.27(t,1H),3.09-3.00(m,1H),2.98-2.83(m,1H),2.46-2.33(m,1H),1.77-1.69(m,1H).
实施例2
(R)-2-(3,5-二氯-4-((7-甲基-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基]苯基-2,6-d2)-3,5-二氧杂-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物2)
(R)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2,6-d2)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(compound 2)
第一步:1-(5-甲基环戊-1-烯-1-基)吡咯烷(2c)
1-(5-methylcyclopent-1-en-1-y1)pyrrolidine(2c)
将2a(6.05g,61.22mmol)溶于甲苯(70mL),加入2b(6.53g,91.84mmol),一水合对甲苯磺酸(1.16g,6.12mmol),加毕130℃回流分水反应16h。冷却至室温,减压蒸馏即得到标题化合物2c(5.01g,65%)。无需纯化。
第二步:1,4-二氯-5-甲基-6,7-二氢-5H-环戊[d]哒嗪(2e)
1,4-dichloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyridazine(2e)
将2c(2.80g,18.54mmol)溶于二氯甲烷(100mL),降温至0℃,加入2d(5.60g,37.08mmol),加毕0℃反应15min。加入硅胶拌样柱层析分离(石油醚:乙酸乙酯=1/0~5/1)即得到标题化合物2e(3.08g,82%).
LC-MS(ESI):m/z=203.0[M+H]+
第三步:3,5-二氯-4-((4-氯-5-甲基-6,7-二氢-5H-环戊[d]哒嗪-1-基)氧基)苯胺(2g)
3,5-dichloro-4-((4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)aniline(2g)将2e(3.08g,15.25mmol)溶于二甲亚砜(60mL),氮气保护下依次加入2f(5.60g,37.08mmol),碳酸钾(2.62g,19.01mmol),碘化亚铜(969mg,5.08mmol),加毕90℃反应16h。冷却至室温,并倒入冰水(100mL)中,向其中加入乙酸乙酯(50mL)稀释,过滤滤饼使用乙酸乙酯/水(1/1,50mL*3)冲洗。乙酸乙酯(50mL*2)萃取得到有机相,硫酸钠干燥。减压蒸馏除去溶剂并且柱层析分离(石油醚:乙酸乙酯=3/1)即得到标题化合物2g(1.90g,54%).
LC-MS(ESI):m/z=344.0[M+H]+
第四步:N-(3,5-二氯-4-((4-羟基-5-甲基-6,7-二氢-5H-环戊[d]哒嗪-1-基)氧基)苯基)乙酰胺(2h)
N-(3,5-dichloro-4-((4-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)phenyl)acetamide(2h)
将2g(0.50g,1.45mmol)溶于乙酸(5mL),加入醋酸钠(416mg,5.08mmol),加毕100℃反应16h。冷却至室温并减压浓缩,残余物溶于水(10mL)中,向其中加入饱和碳酸氢钠溶液调节pH=8。乙酸乙酯(20mL*2)萃取,水相用6N盐酸酸化,乙酸乙酯(20mL)萃取得到有机相,硫酸钠干燥。减压蒸馏即得到标题化合物2h(533mg)。无需纯化。
LC-MS(ESI):m/z=368.2[M+H]+
第五步:(R)-4-(4-氨基-2,6-二氯苯氧基)-7-甲基-2,5,6,7-四氢-1H-环戊[d]哒嗪-1-酮(2i)
(R)-4-(4-amino-2,6-dichlorophenoxy)-7-methyl-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(2i)
将2h(533mg,1.45mmol)溶于甲醇(15mL),加入1N氢氧化钠(50mL),加毕120℃反应16h。冷却至室温并减压浓缩,残余物溶于水(30mL)中,乙酸乙酯(20mL*2)萃取,水相用6N盐酸酸化,乙酸乙酯(20mL)萃取得到有机相,硫酸钠干燥。减压蒸馏除去溶剂并经手性制备分离即得到标题化合物2i(227mg,48%)。
制备色谱条件:色谱柱ChiralCel OJ,300×50mm I.D.,10μm,流动相体系:二氧化碳/甲醇=65/35(v),流量200mL/min,化合物2i(出峰时间约为1.96min)。
LC-MS(ESI):m/z=326.1[M+H]+
第六步:(R)-4-(4-氨基-2,6-二氯苯氧基-3,5-d2)-7-甲基-2,5,6,7-四氢-1H-环戊[d]哒嗪-1-酮(2j)
(R)-4-(4-amino-2,6-dichlorophenoxy-3,5-d2)-7-methyl-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(2j)
将2i(1.10g,3.35mmol)加入到微波管中,加入DCl(20%in D2O,4mL)和重水(4mL),加毕放置于微波反应中180℃反应30min。冷却至室温,向其中加入饱和碳酸氢钠溶液调节pH=8,乙酸乙酯(20mL*2)萃取得到有机相,硫酸钠干燥。减压蒸馏除去溶剂并且柱层析分离(石油醚:乙酸乙酯=1/1~1/2),重复以上过程两次,即得到标题化合物2j(690mg,64.4%)。
LC-MS(ESI):m/z=328.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),5.58(s,2H),3.26(dd,1H),2.97(dd,1H),2.89-2.78(m,1H),2.46-2.24(m,1H),1.69(t,1H),1.24(d,3H).
第七步:(R,E)-(2-氰基-2-(2-(3,5-二氯-4-((7-甲基-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基-2,6-d2)肼基)乙酰基氨基甲酸酯(2l)
ethyl(R,E)-(2-cyano-2-(2-(3,5-dich1oro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2,6-d2)hydrazono)acetyl)carbamate(2l)
将2j(5.02g,15.24mmol)溶于DCl(20%in D2O,75mL),0℃下向其中缓慢滴加亚硝酸钠(1.32g,19.20mmol)的重水(150mL)溶液,保持在该温度反应半个小时。在另一个反应瓶中加入N-氰基乙酰尿烷(8.02g,51.21mmol),依次向其中加入重水(150mL)、吡啶(75mL),冷却到0℃。将第一个反应瓶中的溶液快速加入第二个反应瓶中,0℃反应30min。乙酸乙酯萃取有机相,减压蒸馏得到标题化合物2l(9.01g),粗品无需纯化。
LC-MS(ESI):m/z=495.1[M+H]+
第八步:((R)-2-(3,5-二氯-4-((7-甲基-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基]苯基-2,6-d2)-3,5-二氧杂-2,3,4,5-四氢-1,2,4-三嗪-6-腈(化合物1)
(R)-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2,6-d2)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(compound 1)将2l(9.01g)溶于氘代乙酸(75mL),向其中加入醋酸钠,升温至120℃反应2h。LCMS显示完全反应,减压蒸馏除去溶剂,使用硅胶柱过滤残余物,甲醇/二氯甲烷(1∶4)冲洗。滤液减压蒸馏得到6.50g粗品,并经制备HPLC得到化合物2(3.40g,49.7%,两步)。
制备方法:仪器:waters 2767制备液相;色谱柱:SunFire@Prep C18(19mm×250mm;样品用DMF溶解,用0.45μm滤头过滤,制成样品液;制备色谱条件:a.流动相A,B组成:流动相A:乙腈,流动相B:水(含5mM乙酸铵);b.梯度洗脱,流动相A含量从40%-70%;c.流量15mL/min。d.洗脱时间20min;保留时间:12.33min。
LC-MS(ESI):m/z=449.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.06(s,IH),7.08(s,1H),3.29(s,1H),3.09-2.98(m,1H),2.97-2.85(m,1H),2.38-2.36(m,1H),1.74-1.72(m,1H),1.26(d,3H).
生物测试
1、THR共激活剂招募测定
化合物与THRβ或THR a受体的结合导致配体结合域中螺旋12周围的构象变化,从而对共激活肽产生更高的亲和力。用LanthaScreenTMTR-FRET-TR共激活试剂盒(ThermoFisher)进行共激活子招募试验(coactivator recruitment assay)。在TR-FRET共调节缓冲液C中,使用液体分配器(Tecan D300e)以最终试验浓度的2倍制备甲状腺激素T3(最高剂量500nm)的10∶1~5稀释系列和试验化合物(最高剂量6250nm)的9∶1~4稀释系列。将THRβ-FBD(配体结合域)或THRα-FBD以2.5nM的最终浓度添加到试验化合物中,然后添加荧光素-共激活肽和铽结合抗GST抗体的混合物。将稀释的试验化合物与相同体积的其他试剂(10μL∶10μL)混合。在室温下孵育2小时后,使用Envison读板仪(PerkinElmer)在520nm和495nm波长下读取。计算了520:495的TR-FRET比值,并利用该比值从受试化合物的剂量-反应曲线确定了EC50。
本发明化合物对THR受体显示有激动活性,实施例化合物对THR的EC50值在0.01-1000uM。其中,部分实施例的测试结果如表1所示:
表1化合物的体外结合活性测定结果
实施例 | TRα EC50(uM) | TR β EC50(uM) |
实施例1 | >10 | 2.261 |
实施例2 | >10 | 3.168 |
结论:化合物1、2对THR a受体和THRβ受体具有较好的激动活性,尤其是对THRβ受体表现出了优异的激动活性。
2.大鼠药代动力学测试
实验目的:通过单剂量静脉和灌胃给予受试物于SD大鼠,测定大鼠血浆中受试物的浓度,评价受试物在大鼠体内药代特征和生物利用度。
实验对象:MGL-3196及本发明实施例化合物1,2。
试验动物:雄性SD大鼠,220g左右,6~8周龄,6只/化合物。购于成都达硕实验动物有限公司。
试验方法:试验当天,6只SD大鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。按照表2给药。
表2给药信息
*剂量以游离碱计。
样品采集
于给药前及给药后异氟烷麻醉经眼眶取血0.1ml,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。
G1组采集血浆时间点:0,5,15,30min,1,2,4,6,8,24h。
G2组采集血浆时间点:0,15,30min,1,2,4,6,8,24h。
分析检测前,所有样品存于-80℃。
样品前处理
取30μL血浆样品、标曲和质控样品,加入200μL的含内标乙腈溶液,涡旋混匀之后,4℃,12000rpm离心10min。取170μL上清于96孔板中,LC-MS/MS分析,进样量为6μL。
主要药代动力学参数用WinNonlin 8.0软件非房室模型分析。实验结果如表3所示。
表3测试化合物的大鼠药代动力学
MGL-3196为结构如下:
结论:化合物1、2具有较好的生物利用度,具有良好的药代动力学特征。
Claims (12)
10.一种药物组合物,含有权利要求1-9任意一项所述的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,以及药学上可接受的载体和/或赋形剂。
11.权利要求1-9任意一项所述的化合物,其立体异构体、溶剂化物、共晶或药学上可接受的盐,或者权利要求10所述的药物组合物在制备治疗甲状腺激素受体介导的疾病的药物中的用途。
12.根据权利要求11所述的用途,其中,所述疾病选自肥胖、高脂血症、高胆固醇血症、糖尿病、非酒精性脂肪肝炎、非酒精性脂肪肝病、动脉粥样硬化、心血管疾病、甲状腺功能减退和甲状腺癌。
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WO2023147752A1 (zh) * | 2022-02-07 | 2023-08-10 | 四川海思科制药有限公司 | 作为甲状腺激素受体激动剂的多晶型物及其用途 |
WO2023147779A1 (zh) * | 2022-02-07 | 2023-08-10 | 四川海思科制药有限公司 | 一种哒嗪酮衍生物制备方法及其中间体 |
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