CN108884056B - 氨基嘧啶ssao抑制剂 - Google Patents
氨基嘧啶ssao抑制剂 Download PDFInfo
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- CN108884056B CN108884056B CN201780006868.4A CN201780006868A CN108884056B CN 108884056 B CN108884056 B CN 108884056B CN 201780006868 A CN201780006868 A CN 201780006868A CN 108884056 B CN108884056 B CN 108884056B
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- compound
- pharmaceutically acceptable
- acceptable salt
- fluoro
- pyrimidin
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Abstract
本发明提供式(I)化合物,或其医药学上可接受的盐,其中n和R1如本文所定义,治疗患者的肝病的方法,和制备所述化合物的方法。
Description
本发明涉及氨基嘧啶化合物、所述化合物的医药学上可接受的盐以及所述化合物和盐的治疗用途。
氨基脲-敏感性氨基氧化酶/血管粘附蛋白-1(SSAO)/VAP-1)是氨基脲敏感性氨基氧化酶家族的成员。SSAO/VAP-1或者称为VAP-1或SSAO。SSAO/VAP-1是以膜结合同种型和可溶性同种型两种形式存在的酶;其主要从内皮细胞表面、血管平滑肌和脂肪细胞表达。SSAO/VAP-1参与许多细胞过程,包括葡萄糖处置、炎症反应和白细胞募集。此酶的高活性水平与糖尿病、动脉粥样硬化、中风、慢性肾病和阿尔茨海默氏病(Alzheimer's disease)以及其它病症相关。最近,SSAO/VAP-1已涉及肝病,如脂肪肝的发病机理。(韦斯顿C.J.(Weston C.J.)等人,《神经传递杂志(J.Neural.Transm.)》,2011,118,1055-1064。)脂肪肝(fatty liver disease;FLD)涵盖一系列疾病病况,其中脂肪在肝脏中过量积累且伴随着炎症。FLD可引起特征在于胰岛素抗性的非酒精性脂肪肝病(non-alcoholic fatty liverdisease;NAFLD)。未受抑制的NAFLD发展为持续性发炎性反应或非酒精性脂肪性肝炎(non-alcoholic steatohepatitis;NASH)、进行性肝纤维化并最终发展为肝硬化。目前需要提供肝病(如NAFLD和/或NASH)的替代治疗疗法。
据认为,SSAO/VAP-1抑制剂将减少肝脏炎症和纤维化并进而提供针对肝病的治疗,尤其针对NAFLD和/或NASH的治疗。本发明提供抑制SSAO/VAP-1酶并可解决这些需求中的一或多种的化合物。
本发明提供式1化合物:
其中n是1或2;且R1是H或-CH3;或其药学上可接受的盐。说明为的到氟的键指示氟原子和甲氧基嘧啶基团相对于彼此可以是Z(同侧,在一起)或E(异侧,相对)(布雷彻J.(Brecher J.)等人,“立体化学构型的图形表示(Graphical Representation ofStereochemical Configuration)”,《理论和应用化学(Pure and Appl.Chem)》,2006,78(10)1897,第1959页)。由式1说明的结构包括具有Z立体化学构型、E立体化学构型的化合物,或呈Z或E立体化学构型的化合物的混合物。本发明的优选化合物具有E立体化学构型。
在一种形式中,本发明提供呈游离碱形式的式1化合物。在其它形式中,本发明提供呈酸加成盐(如单或二盐酸加成盐或磺酸盐、优选4-甲基苯磺酸盐(甲苯磺酸盐))形式的式1化合物。
在一种形式中,本发明提供式2化合物:
其中n是1或2;且R1是H或-CH3;或其药学上可接受的盐。
在另一形式中,本发明提供式3化合物:
其中n是1或2;且R1是H或-CH3;或其药学上可接受的盐。
在一个实施例中,本发明提供根据式1、2和3中的一个的化合物,其中n是1或其医药学上可接受的盐。在另一实施例中,本发明提供根据式1、2和3中的一个的化合物,其中n是2或其医药学上可接受的盐。
在另一实施例中,本发明提供根据式1、2和3中的一个的化合物,其中R1是H或其医药学上可接受的盐。在又一实施例中,本发明提供根据式1、2和3中的一个的化合物,其中R1是-CH3或其医药学上可接受的盐。
在另一形式中,本发明提供式4化合物
其中R1是H或-CH3,或其医药学上可接受的盐。
在另一形式中,本发明提供根据式5的化合物:
或其医药学上可接受的盐。在一个实施例中,式5化合物以酸加成盐形式提供。优选地,酸加成盐是单或二盐酸加成盐或磺酸盐,如甲基磺酸或4-甲基苯磺酸加成盐以提供甲磺酸盐或4-甲基苯磺酸盐(甲苯磺酸盐)。
在另一形式中,本发明提供医药组合物,其包含根据式1到5中的任一个的化合物,或其医药学上可接受的盐和医药学上可接受的载剂、稀释剂或赋形剂。在一个实施例中,医药组合物包含根据式5的化合物,或其医药学上可接受的盐。优选地,盐的医药学上可接受的阴离子是单或二氯离子,甲磺酸根或4-甲基苯磺酸根(甲苯磺酸根)。
在另一形式中,本发明提供治疗需要治疗的患者的肝脏病症的方法。方法包含向患者施用有效量的医药组合物,所述医药组合物包含根据式1到5中的任一个的化合物或其医药学上可接受的盐。
在另一形式中,本发明提供治疗需要治疗的患者的肝脏病症的方法。方法包含向患者施用有效量的根据式1到5中的任一个的化合物或其医药学上可接受的盐。肝脏病症的实例包括肝脏炎症、纤维化和脂肪性肝炎。在某些实施例中,方法包含治疗需要治疗的患者的肝脏病症,其中肝脏病症选自:肝纤维化、醇诱导的纤维化、醇脂肪变性、非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。在一特别优选的实施例中,所述方法包含治疗需要治疗的患者的非酒精性脂肪性肝炎(NASH)。
在另一形式中,本发明提供式6化合物,其为(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐(1:1)。
在一个实施例中,(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐(1:1)呈结晶形式提供,其特征为获自CuKα源的X射线粉末衍射图,所述衍射图包含处于以下各处的峰:a)2θ为18.6、19.1、21.0、21.9以及22.4+/-0.2°,或b)2θ为17.6、11.0、16.8、18.6、19.1、21.0、21.9、22.4以及26.1+/-0.2°。
在另一形式中,本发明提供根据式1到6中的任一个的化合物,或其医药学上可接受的盐,以用于疗法。在优选实施例中,疗法是用于肝脏病症。优选地,疗法用于选自以下的肝脏病症:肝纤维化、醇诱导纤维化、醇脂肪变性、非酒精性脂肪肝病和非酒精性脂肪性肝炎。在一个实施例中,疗法是用于治疗肝纤维化。在另一实施例中,疗法是用于非酒精性脂肪肝病。在再又另一个实施例中,疗法是用于非酒精性脂肪性肝炎。
在另一形式中,本发明提供根据式1到6中的任一个的化合物,或其医药学上可接受的盐,以用于治疗肝脏病症。在一个实施例中,肝脏病症选自:肝纤维化、醇诱导纤维化、醇脂肪变性、非酒精性脂肪肝病和非酒精性脂肪性肝炎。在另一实施例中,肝脏病症是非酒精性脂肪肝病或非酒精性脂肪性肝炎。在一特别优选的实施例中,肝脏病症是非酒精性脂肪性肝炎(NASH)。
在又一实施例中,本发明提供根据式1到6中的任一个的化合物在制造用以治疗肝脏病症的药剂中的用途。在优选实施例中,肝脏病症选自:肝纤维化、醇诱导纤维化、醇脂肪变性、非酒精性脂肪肝病和非酒精性脂肪性肝炎。
如本文所用的术语“医药学上可接受的盐”是指被认为是临床和/或兽用可接受的本发明的化合物的盐。医药学上可接受的盐和其常见制备方法的实例可发现于“医药盐手册:特性、选择和用途(Handbook of Pharmaceutical Salts:Properties,Selection andUse)”P.斯塔尔(P.Stahl)等人,第2次修订版,约翰威立国际出版公司(Wiley-VCH),2011和S.M.贝尔奇(S.M.Berge)等人,“医药盐(Pharmaceutical Salts)”,《医药科学杂志(Journal of Pharmaceutical Sciences)》,1977,66(1),1-19中。
用于本发明的医药组合物可使用医药学上可接受的添加剂制备。如本文所用的用于医药组合物的术语“医药学上可接受的添加剂”指代一或多种与组合物或调配物的其它添加剂相容并对患者无害的载剂、稀释剂和赋形剂。医药组合物和其制备方法的实例可发现于“雷明顿:药学的科学和实践(Remington:The Science and Practice ofPharmacy)”,劳埃德V.(Loyd,V.)等人编,第22版,马克出版公司(Mack Publishing Co.),2012。医药学上可接受的载剂、稀释剂和赋形剂的非限制性实例包括以下:盐水、水、淀粉、糖、甘露糖醇和二氧化硅衍生物;粘合剂(如羧甲基纤维素和其它纤维素衍生物)、海藻酸盐、明胶和聚乙烯-吡咯烷酮;高岭土和膨润土;聚乙二醇。
如本文所用,术语“有效量”指代有效治疗病症的作为剂量的量,所述病症如包括肝脏炎症、纤维化和脂肪性肝炎的肝病。护理医师作为本领域技术人员可容易通过使用常规技术和通过观察在类似情况下获得的结果来确定有效量。在确定化合物的有效量或剂量时,考虑许多因素,包括但不限于:将施用所述化合物还是其盐;其它试剂(如果使用的话)的共同施用;哺乳动物的物种;其尺寸、年龄和一般健康状况;病症的涉及程度或严重程度;个体患者的反应;施用模式;所施用制剂的生物可用性特征;所选择的剂量方案;其它附随药剂的使用;以及其它相关情况。
如本文所用,术语“治疗(treating/to treat/treatment)”包括减缓、减少或逆转现有症状、病症、病状或疾病的进展或严重程度,其可包括治疗肝病,如肝脏炎症、纤维化和脂肪性肝炎。
如本文所用,术语“患者”指代哺乳动物、家禽或鱼。优选地,患者是人类或伴侣哺乳动物,如狗或猫或其它驯养哺乳动物,如牛、猪、马、绵羊、兔和山羊。
治疗医师、兽医或其它医疗人员将能够确定用于治疗有需要患者的化合物的有效量。优选的医药组合物可以调配为用于口服施用的片剂或胶囊、用于口服施用的溶液或可注射溶液。片剂、胶囊或溶液可以包括呈有效治疗需要治疗的患者的量的本发明的化合物。
本文中所用的缩写根据道布G.H.(Daub G.H.)等人,“首字母缩略词在有机化学中的使用(The Use of Acronyms in Organic Chemistry)”《奥德里奇化学公司杂志(Aldrichimica Acta)》,1984,17(1),6-23定义。其它缩写定义如下:“ACN”指代乙腈;“AUC”指代曲线下面积;“Boc”表示叔丁氧基羰基;“DCM”指代二氯甲烷;“DIPEA”指代N,N-二异丙基乙胺;“DMF”指代二甲基甲酰胺;“DMSO”指代二甲亚砜;“EDTA”指代乙二胺四乙酸;“EGTA”指代乙二醇四乙酸;“ES/MS”指代电喷雾质谱分析;“EtOAc”指代乙酸乙酯;“HEPES”指代4-(2-羟乙基)-1-哌嗪乙磺酸;“HPLC”指代高效液相色谱;“hr或hrs”指代小时(hour/hours);“HRP”指代辣根过氧化物酶;“IC50”指代产生所述试剂的可能的最大抑制反应的50%的试剂浓度(相对IC50),或相比于安慰剂对照产生目标活性的50%抑制的试剂浓度(绝对IC50);“MAOa和MAOb”分别指代单胺氧化酶a和b同种型;“MeOH”指代甲基醇或甲醇;“min”指代分钟;“MS”指代质谱;“PE”指代石油醚;“Rt”指代滞留时间;“SSAO”指代氨基脲敏感性胺氧化酶;且“hSSAO”指代人类SSAO。
本发明的化合物或其盐可以通过多种程序制备,所述程序中的一些说明于下文制备和实例中。下文程序中的每个步骤的产物可以通过常规方法回收,所述方法包括萃取、蒸发、沉淀、色谱、过滤、研磨和结晶。除非提及相反情况,否则试剂和起始物质可容易获得。
在本文中所描述的制备中,羟基和氨基官能团可以加以保护以促进本文所描述的化合物的合成。保护官能团的实例可以发现于“格林氏有机合成中的保护基团(Greene'sProtective Groups in Organic Synthesis),”伍兹P.G.M.(Wuts P.G.M.)等人编,第5版,《约翰·威利父子出版公司(John Wiley and Sons)》,2014。可以使用可以容易转化为羟基或氨基的其它官能团。这类官能团、制备和这些基团的转化可以发现于拉洛克R.C.(Larock.R.C.),约翰威立国际出版公司(Wiley VCH),1999的“综合有机转化:官能团制备指导(Comprehensive Organic Transformations:A Guide to Functional GroupPreparations)”和“玛奇氏高级有机化学:反应、机制和结构(March's Advanced OrganicChemistry:Reactions,Mechanisms and Structure),”史密斯M.B.(Smith M.B.)编,第7版,《威利跨学科(Wiley-Interscience)》,2013中。
化学合成部分
以下制备和实例进一步说明本发明并表示本发明的化合物的典型合成。
制备1
(3S)-3-甲氧基吡咯烷-1-羧酸叔丁酯
将碘甲烷(0.398g,2.80mmol)添加到(3S)-3-羟基吡咯烷-1-羧酸叔丁酯(0.500g,2.67mmol)和氢化钠(矿物油中为60质量%)(0.160g,4.01mmol)于DMF(5mL)中的的混合物。在室温下将所得混合物搅拌2小时。用饱和NH4Cl水溶液(30mL)淬灭反应物且用EtOAc(3×30mL)萃取。丢弃水层。合并有机萃取物且用盐水洗涤,经由Na2SO4干燥,过滤且蒸发滤液到干燥以得到标题化合物(475mg,0.475g,88.4%)。粗物质可以不经进一步纯化即用于下一步骤中。ES/MS(m/z):224.2(M+Na)。
制备2
(3S)-3-甲氧基吡咯烷
在室温下将(3S)-3-甲氧基吡咯烷-1-羧酸叔丁酯(475mg,2.36mmol)和三氟乙酸(1mL,13.23mmol)于DCM(3mL)中的溶液搅拌1小时。在真空下浓缩反应混合物以得到标题化合物(240mg,2.35mmol,99.5%),其可以不经进一步纯化即用于下一步骤。
制备3
1-(5-卞基氧基嘧啶-2-基)哌啶-4-醇
在N2氛围下在100℃下将5-苯甲氧基-2-氯-嘧啶(2.30g,9.90mmol)、哌啶-4-醇(1.23g,11.9mmol)和DIPEA(3.88mL,29.7mmol)于DMF(30mL,388mmol)中的混合物搅拌17小时。用水(200mL)稀释混合物且用EtOAc(3×50mL)萃取。合并有机萃取物;用盐水(3×50mL)洗涤,经由Na2SO4干燥、过滤且浓缩滤液。使残余物经受用60%EtOAc和40%PE的混合物洗脱的硅胶快速柱色谱以得到呈白色固体状的标题化合物(2.00g,6.31mmol,63.7%)。1H NMR(400MHz,CDCl3)δ1.40-1.60(m,2H),1.90-1.99(m,2H),3.17-3.29(m,2H),3.85-3.95(m,1H),4.25-4.39(m,2H),5.09(s,2H),7.38-7.52(m,5H),8.14(s,2H)。
制备4
2-(4-羟基-1-哌啶基)嘧啶-5-醇
将钯(碳上的10质量%,600mg,0.564mmol)添加到MeOH(40mL,989mmol)中的1-(5-卞基氧基嘧啶-2-基)哌啶-4-醇(2.00g,6.31mmol)。在氢氛围(103kPa)下在15℃下将所得混合物搅拌2小时。经由硅藻土过滤所得混合物。浓缩滤液以得到呈黄色固体状的标题化合物(0.70g,3.59mmol,56.8%)。1H NMR(400MHz,CDCl3)δ1.23-1.38(m,2H),1.60-1.77(m,2H),2.65-2.90(m,2H),3.00-3.25(m,2H),3.50-3.70(m,2H),4.05-4.16(m,1H),7.90(s,2H)。
制备5
N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯
将K2CO3(5.71g,41.3mmol)添加到2-氯嘧啶-5-醇(5.01g,38.3mmol)和N-[(E)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(3.67g,13.7mmol)于DMF(25mL)中的溶液。在室温下将所得溶液搅拌12小时。通过添加水(80mL)和EtOAc(100mL)淬灭反应物。分离有机相和水相。用EtOAc(3×100mL)萃取水相。合并全部有机萃取物。经由Na2SO4干燥经合并的有机萃取物,过滤且在真空下浓缩滤液,得到残余物。使残余物经受用30%EtOAc于己烷中的混合物洗脱的硅胶快速色谱以得到呈白色固体状的标题化合物(4.15g,13.1mmol,96%产率)。ES/MS(m/z):340(M+Na)。
制备6
N-[(Z)-3-氟-2-[[2-(4-羟基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
在60℃下将2-(4-羟基-1-哌啶基)嘧啶-5-醇(400mg,2.05mmol)、N-[(Z)-2-(溴甲基)-3-氟-烯丙基]氨基甲酸叔丁酯(1.10g,4.02mmol)和K2CO3(0.858g,6.15mmol)于DMF(10mL)中的混合物搅拌3小时。用EtOAc(50mL)稀释所得混合物。用水(100mL)随后盐水(2×50mL)依序洗涤混合物。经由Na2SO4干燥有机相,过滤且浓缩滤液,得到残余物。使残余物经受65-75%EtOAc于PE中的梯度洗脱的硅胶快速柱色谱以得到呈黄色胶状物的标题化合物(558mg,1.46mmol,71.2%)。1H NMR(400M Hz,CDCl3)δ1.25(s,9H),1.40-1.65(m,4H),1.89-1.98(m,2H),3.23-3.30(m,2H),3.91(s,1H),3.89-3.97(m,1H),4.36-4.40(m,2H),4.64(s,2H),4.76(br,1H),6.62(d,J=84.0Hz,1H)8.10(s,2H)。
制备7
N-[(E)-3-F-2-[[2-(4-羟基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(21.3g,67.0mmol)、哌啶-4-醇(25.0g,235mmol)和DIPEA(41mL,235mmol)合并于1,4-二噁烷(200mL)中。在N2氛围下将所得混合物加热到105℃持续7小时。浓缩混合物且使其在水(100mL)与EtOAc(150mL)之间分隔,随后分离相。用EtOAc(100mL)萃取水相。合并全部有机相。用盐水(100mL)洗涤,经由Na2SO4干燥,过滤且浓缩滤液,得到残余物。将残余物溶解于EtOAc(21mL)中,且随后逐滴添加庚烷(126mL)。在室温下将所得混合物搅拌20小时。过滤混合物以收集固体,用EtOAc/庚烷(5:1,21mL)冲洗固体。在真空下干燥固体以得到标题化合物(23.5g,61.5mmol,91.7%)。ES/MS(m/z):383(M+H)。
制备8
N-[(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(4.10g,12.9mmol)分为2等份(2.05g+2.05g)且各自放置在单独的微波小瓶(20mL)中。将4-甲氧基哌啶(4.31g,37.3mmol)、1,4-二噁烷(30mL,15mL)和DIPEA(6mL,34.4mmol,3mL)添加到每个小瓶中。用N2气体冲刷小瓶,密封且通过微波加热到120℃持续12小时。合并两种反应混合物且在真空下浓缩,得到残余物。使残余物经受用30%EtOAc于己烷中的混合物洗脱的硅胶快速色谱以得到呈黄色油状的标题化合物(4.24g,10.2mmol,79%)。ES/MS(m/z):397(M+H)。
制备9
N-[(E)-3-氟-2-[[2-[(3S)-3-甲氧基吡咯烷-1-yl]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(400mg,1.26mmol)添加到(3S)-3-甲氧基吡咯烷(240mg,2.37mmol)和K2CO3(0.696g,5.04mmol)于1,4-二噁烷(5mL)中的混合物。在微波条件下在120℃下将所得混合物搅拌12小时。在真空下浓缩混合物,得到呈粗物质形式的标题化合物,所述标题化合物可以不经进一步纯化即用于下一步骤(481mg,1.26mmol,99.9%)。ES/MS(m/z):383.2(M+H)。
制备10
N-[(E)-3-氟-2-[[2-[(3S)-3-羟基吡咯烷-1-基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯
将N-[(E)-2-[(2-氯嘧啶-5-基)氧基甲基]-3-氟-烯丙基]氨基甲酸叔丁酯(594.3mg,1.87mmol)和(3S)-吡咯烷-3-醇(488.9mg,5.61mmol)溶解于1,4-二噁烷(15mL)和DIPEA(3mL,17.2mmol)中。用N2气体冲刷溶液,密封容器,且通过微波将混合物加热到120℃持续12小时。在真空下浓缩所得混合物,得到残余物。使残余物经受用80-90%EtOAc于己烷中的梯度洗脱的硅胶快速色谱以得到呈黄色泡沫状的标题化合物(608.8mg,1.57mmol,84%)。ES/MS(m/z):369(M+H)。
实例1
1-[5-[(Z)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-醇盐酸盐
将N-[(Z)-3-氟-2-[[2-(4-羟基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(558mg,1.46mmol)添加到HCl(4mol/L)和MeOH(10mL)。在10℃下将所得混合物搅拌1.5小时。在减压下浓缩混合物,得到残余物。使残余物经受制备型HPLC管柱:(Phenomenex Synergi C18 150 30mm,4μm)用10到15%0.05%HCl水溶液于ACN中的梯度洗脱;流动速率:25mL/min,Rt:5.95min以得到呈黄色固体状的Z:E比值大于20:1的标题化合物(456mg,1.43mmol,98.0%)。ES/MS(m/z):283.1(M+H),1HNMR(400MHz,d4-MeOD)δ1.56-1.78(m,2H),1.92-2.13(m,2H),3.61-3.72(m,2H),3.75(s,2H),3.95-4.06(m,1H),4.11-4.25(m,2H),4.89-4.93(m,2H),7.19(d,J=80.4Hz,1H),8.47(s,2H)。
实例2
1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]哌啶-4-醇二盐酸盐
将N-[(E)-3-氟-2-[[2-(4-羟基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(31g,81.07mmol)、MeOH(20mL,494mmol)和HCl合并于MeOH(120mL,4mol/L,486.4mmol)中。在室温下在N2氛围下将所得混合物搅拌30小时。逐滴添加EtOAc(250mL)且将混合物搅拌30分钟。过滤混合物以收集固体,用EtOAc(20mL)冲洗固体,且在真空下干燥固体以得到E:Z比值大于20:1的标题化合物(26.4g,72.8mmol,89.8%)。ES/MS(m/z):283(M+H),1H NMR(500MHz,d6-DMSO)δ1.28-1.36(m,2H),1.73-1.76(m,2H),3.18-3.25(m,2H),3.55-3.60(m,2H),3.68-3.75(m,1H),4.18(dt,J=13.5,4.5Hz,2H),4.65(d,J=3.0Hz,2H),6.55-7.10(br,2H),7.27(d,J=82.0Hz,1H),8.27(s,2H),8.32-8.45(br,3H),19F NMR(500MHz,d6-DMSO)δ122.2(s)。
实例3
(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]丙-2-烯-1-胺,二盐酸盐
将HCl中的N-[(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(4.2374g,10.69mmol)溶解于MeOH(100mL,50mmol,0.5mol/L)中。将所得澄清溶液加热到60℃持续4小时。在真空下浓缩混合物,得到残余物(3.95g)。将残余物悬浮于MeOH(7mL)中且回流混合物,得到澄清溶液。将溶液冷却到室温以得到针状晶体,且随后将混合物冷却到-20℃。过滤混合物以收集固体,用冷却MeOH洗涤固体以得到呈淡黄色晶体状的标题化合物(2.73g,7.01mmol,66%)。所得黄色晶体可以用上文所述的相同程序经由再结晶进一步纯化以得到E:Z比值大于20:1的呈无色结晶物质的标题化合物。ES/MS(m/z):297(M+H),1H NMR(500MHz,d6-DMSO)δ1.33-1.40(m,2H),1.84-1.89(m,2H),3.26(dt,J=13.5,9.5Hz,2H),3.27(s,3H),3.40-3.45(m,1H),3.56-3.62(m,2H),4.11(dt,J=13.5,5.0Hz,2H),4.62(d,J=3.0Hz,2H),5.26-5.94(br,1H),7.27(d,J=82.0Hz,1H),8.26(s,2H),8.21-8.31(br,3H),19F NMR(500MHz,d6-DMSO)δ122.1(s)。
实例4
(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]丙-2-烯-1-胺
将氨基甲酸N-[(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]烯丙基]酯(167.0mg,0.42mmol)溶解于18mL EtOAc/MeOH(10:1v/v)中的0.95M HCl溶液。搅拌混合物过夜。在真空下浓缩所得悬浮液且将残余物溶解于水中。使残余物经受制备型HPLC;LC柱:C18 30×150mm 5μm;用14到24%10mM NH4HCO3水溶液于ACN中的梯度洗脱0-11分钟;柱温:室温;流动速率:35mL/min,Rt=7.8分钟,在通过UV监测17分钟之后停止。收集且浓缩适当洗脱份,得到呈油状物的残余物。将残余物溶解于水中且冻干以得到E:Z比值大于20:1的呈白色固体状的标题化合物(97mg,0.31mmol,74%,95%纯度)。ES/MS(m/z):297(M+H),1H NMR(500MHz,d6-DMSO)δ1.33-1.41(m,2H),1.52-1.69(br,1H),1.83-1.89(m,2H),3.23-3.29(m,4H),3.27(s,3H),3.30-3.35(br,1H),3.38-3.44(m,1H),4.11(dt,J=13.5,4.5Hz,2H),4.55(d,J=4.5Hz,2H),6.93(d,J=85.0Hz,1H),8.22(s,2H),19F NMR(500MHz,d6-DMSO)δ131.8(s)。
实例4a
(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐(1:1)
将(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]丙-2-烯-1-胺(2.316g,7.81mmol)溶解于乙酸甲酯(3mL)中且在室温下搅拌1000rpm以得到淡黄色溶液。将4-甲苯磺酸单水合物(1.62g,8.43mmol)加入乙酸甲酯(4mL)的溶液中。混合物变得混浊且迅速形成粘稠黄色浆液。经由滤纸通过真空过滤过滤固体。用乙酸甲酯(4mL)冲洗滤饼以得到白色滤饼。在真空空气流下干燥固体持续10分钟且随后在室温下在真空烘箱中干燥过夜以得到标题化合物(3.00g,81.8%)。
实例4a的X射线粉末衍射
结晶形(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐的X射线粉末衍射(XRD)图案在Bruker D4Endeavor X射线粉末衍射仪上获得,所述衍射仪配备有CuKa源和Vantec检测器,在35kV和50mA下操作。样品在2θ为4与40°之间扫描,具有2θ为0.009°步长大小和0.5秒/步长的扫描速率,且具有0.6mm发散,5.28固定防散射,和9.5mm检测器狭缝。将干粉填充在石英试样架上且使用玻璃载片获得平滑表面。在环境温度和相对湿度下收集晶体形式衍射图案。晶体学领域中熟知,对于任何给定的晶体形式而言,衍射峰的相对强度可以由于由如晶体形态和惯态等因素产生的优选取向而改变。在优选取向的作用存在情况下,峰值强度变化,但多晶型物的特征峰位置不变。参见例如美国药典第23版,国家处方集第18版,第1843-1844页,1995。此外,晶体学领域中还熟知对于任何给定晶体形式而言,角峰位置可以略微改变。举例而言,峰位置可能由于分析样品所处的温度或湿度、样品位移或内标物存在与否而移位。在当前情况中,2θ为±0.2的峰位置变化将考虑这些可能的变化而不妨碍所指示晶体形式的明确鉴别。晶体形式的确认可以基于区别峰(以°2θ为单位)的任何独特组合,通常更加突出的峰进行。收集在环境温度和相对湿度下的晶体形式衍射图案且基于在8.853和26.774°2θ下的NIST 675标准峰调整。
所制备的(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐的样品的特征在于XRD图案,所述图案使用CuKa辐射且具有如下表1中所描述的衍射峰(2θ值),且尤其具有在18.6下的峰与选自22.4、19.1和21.0的峰中的一或多个的组合;具有2θ为+/-0.2°的衍射角的公差,或者盐的特征可以是具有在2θ为18.6、19.1、21.0、21.9和22.4+/-0.2°、或2θ为17.6、11.0、16.8、18.6、19.1、21.0、21.9、22.4和26.1+/-0.2°下的一或多个峰的XRD图案。
表1
(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐的X射线粉末衍射峰
峰值 | 角度(°2θ)+/-0.2° | 相对强度(最强峰值的%) |
1 | 7.4 | 17.6% |
2 | 11.0 | 23.4% |
3 | 12.7 | 5.2% |
4 | 16.8 | 10.1% |
5 | 18.6 | 100.0% |
6 | 19.1 | 42.2% |
7 | 21.0 | 41.9% |
8 | 21.9 | 31.6% |
9 | 22.4 | 77.5% |
10 | 26.2 | 18.6% |
实例5
(E)-3-氟-2-[[2-[(3S)-3-甲氧基吡咯烷-1-基]嘧啶-5-基]氧基甲基]丙-2-烯-1-胺
在室温下将N-[(E)-3-氟-2-[[2-[(3S)-3-甲氧基吡咯烷-1-基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(481mg,1.26mmol)和三氟乙酸(1mL,13.23mmol)于DCM(3mL)中的溶液搅拌1小时。在真空下浓缩混合物。使残余物经受制备型HPLC:LC柱:C1830×150mm 5μm;用ACN中的5%10mM NH4HCO3水溶液洗脱0-2分钟,随后为6-11%10mMNH4HCO3水溶液于ACN中的梯度历经2-12分钟;在18分钟时停止;柱温度:室温;流动速率:35mL/分钟,Rt=10.6分钟;通过UV监测以得到E:Z比值大于20:1的呈白色固体状的标题化合物(226mg,61.7%)。ES/MS(m/z):283.1(M+H),1H NMR(500MHz,CDCl3)δ1.12-1.78(br,2H),2.07-2.16(m,2H),3.37(s,3H),3.53-3.68(m,6H),4.07(m,1H),4.44(s,2H),6.57(d,J=83.0Hz,1H),8.12(s,2H)。
实例6
(3S)-1-[5-[(E)-2-(氨甲基)-3-氟-烯丙氧基]嘧啶-2-基]吡咯烷-3-醇;二盐酸盐
将N-[(E)-3-氟-2-[[2-[(3S)-3-羟基吡咯烷-1-基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(605.9mg,1.65mmol)溶解于HCl于MeOH(30mL,15mmol,0.5mol/L)中和HCl于水(5mL,60mmol,12mol/L)中的混合物。将所得澄清溶液搅拌过夜。在真空下浓缩反应混合物,得到残余物。使残余物经受制备型HPLC:LC柱:C18 30×150mm 5μm;H2O10nM NH4HCO3;在室温下;用2%ACN洗脱0-2分钟,随后为2-10%ACN的梯度历经2-10分钟;流动速率在:35mL/分钟下,Rt=8.0分钟(经由UV检测监测);在16分钟时停止。收集适当洗脱份且浓缩,得到标题化合物的游离碱。将游离碱化合物溶解于MeOH(15mL)中的0.5M HCl中。浓缩溶液,添加水,且随后冻干以得到E:Z比值大于20:1(352.7mg,0.982mmol,59%)的呈淡黄色固体状的标题产物。ES/MS(m/z):269(M+H),1H NMR(500MHz,d6-DMSO)δ1.87-1.94(m,1H),1.98-2.05(m,1H),3.44(d,J=11.5Hz 1H),3.51-3.61(m,5H),4.39-4.42(m,1H),4.66(d,J=3.0Hz,2H),5.33-5.90(br,2H),7.28(d,J=82.0Hz,1H),8.35(s,2H),8.35-8.44(br,3H),19F NMR(500MHz,d6-DMSO)δ121.9(s)。
实例6的替代制备
将N-[(E)-3-氟-2-[[2-[(3S)-3-羟基吡咯烷-1-基]嘧啶-5-基]氧基甲基]烯丙基]氨基甲酸叔丁酯(1.1601g,3.15mmol)溶解于HCl于EtOAc(50mL,50mmol,1.0mol/L)中的溶液(与MeOH中的0.5mol/L HCl预先混合,5mL)中。将所得溶液搅拌过夜。在真空下浓缩白色悬浮液,得到白色粉末。将白色粉末溶解于水中且冻干溶液,得到呈淡黄色固体状的标题化合物(860.7mg,2.42mmol,77%)。
将如实例6制备的材料溶解于水(5mL)中且与水(5mL)中的替代实例6的物质合并。冻干混合物以得到E:Z比值大于20:1的标题化合物(1.151g 3.27mmol)。ES/MSm/z:269(M+H),1H NMR(500MHz,d6-DMSO)δ1.87-1.94(m,1H),1.98-2.05(m,1H),3.44(d,J=11.5Hz1H),3.51-3.61(m,5H),4.39-4.42(m,1H),4.66(d,J=3.0Hz,2H),5.33-5.90(br,2H),7.28(d,J=82.0Hz,1H),8.35(s,2H),8.35-8.44(br,3H),19F NMR(500MHz,d6-DMSO)δ121.9(s)。
生物分析
SSAO/VAP-1体外活性
使用来自普洛麦格(Promega)(V1402)的MAO-GloTM分析试剂盒测量重组SSAO、MAOa和MAOb同种型的胺氧化酶活性。在室温下将测试化合物(使用DMSO作为媒剂,SSAO为0.5%v/v)和酶培育10分钟,随后添加发光底物。人类重组SSAO的底物浓度为10μM。分析在孔板中在pH 7.4缓冲液(50mM HEPES、120mM NaCl、5mM KCl、2mM CaCl2、1.4mM MgCl2、0.001%Tween-20)中进行。底物氧化进行2小时,随后根据制造商的方案添加检测试剂。测试化合物的IC50值通过使用4-参数非线性回归程序拟合剂量反应曲线计算。实例3、5和6的化合物的IC50值列于表2中。
表2
实例 | hSSAO抑制相对IC<sub>50</sub>(nM) |
3 | 12±1,n=5 |
5 | 32±7,n=4 |
6 | 52±5,n=7 |
数据以分析数量(n)的平均值±SEM(SEM=平均值的标准误差)呈现。
实例的化合物显示小于60nM的hSSAO的IC50。实例的化合物分别显示超过50μM和200μM的IC50hMAOa和hMAOb,表明实例的化合物相比于hMAOa或hMAOb对hSSAO具有选择性。
SSAO靶接合
使用来自普洛麦格(V1402)的MAO-GloTM分析试剂盒测量大鼠血浆和肝脏组织中的SSAO活性。在化合物治疗之后大鼠中的残余SSAO活性通过测量对MAO抑制剂氯吉兰(Clogyline)和帕吉林(Pargyline)的存在不敏感的血浆或肝脏溶解产物中的总胺氧化酶活性来估算。以15、3、0.6、0.12、0.025、0.005mg/kg的剂量向大鼠施用实例2的化合物。向对照组施用相同体积(2ml/kg)的给药媒剂(羟基乙基纤维素1%w/v,0.25%Tween 80)。收集化合物治疗2或24小时后的血浆和肝脏且储存在-78℃下直到分析。组织溶解产物通过在溶解缓冲液(20mM HEPES,pH 7.4;150mM NaCl、1mM EDTA、1mM EGTA、1%Triton X-100和1×罗氏完全蛋白酶抑制剂片剂(Roche Complete protease inhibitor tablet))中均质化来制备。组织颗粒通过在4℃下以12,000rpm离心30分钟移出。在室温下将40μl血浆或肝脏溶解产物与氯吉兰(10μM)和帕吉林(10μM)一起培育20分钟,之后添加发光底物(50μM),持续60分钟。根据制造商的程序定量所产生的产物。对MAO抑制剂的存在不敏感的活性部分用作针对残余SSAO活性的替代物。在基本上如上文所述的方案中评估以各种剂量施用的实例2的化合物。结果列于表3中。
表3
实例2的SSAO靶接合
数据以平均值±SEM,n=6呈现
结果表明实例2的化合物在大鼠血浆和肝脏中剂量依赖性地抑制SSAO活性。
通过3H饮食诱导的NASH和纤维化的小鼠模型
用D09100301饮食(研究饮食,40%脂肪、2%胆固醇、24%果糖,(高脂肪、高胆固醇和高果糖,“3H饮食”))喂养雄性C57BL/6N小鼠150天。随后在5天适应时段之后单独圈养每只小鼠。测量血浆丙氨酸转氨酶(ALT)和细胞角蛋白18(CK18)。在恢复一周之后,基于其ALT值、CK18值和体重将小鼠随机分为5组。每组动物每日一次施用媒剂(0.5%甲基纤维素(MC)+蒸馏水中的0.25%Tween 80)或实例6的化合物(剂量为0.06、2、6和20mg/kg),体积为5ml/kg,历时11周。
在最后一次剂量2小时之后从用实例6的化合物治疗76天的小鼠收集血液。通过质谱分析血浆中的化合物含量。结果列于下文表4中。经治疗的小鼠展现血浆化合物含量的剂量依赖性增加。用实例6治疗的全部小鼠组展现ALT的显著减少,表明那些动物中减少的肝病变。用6和20mg/kg实例6的化合物治疗的动物也展现血液中降低的三酸甘油酯含量。
在研究完成时,处死动物且切除其肝脏。将左叶和右叶的两个切片固定于中性缓冲10%福尔马林中。肝脏组织载片用苏木精和曙红(H&E)、天狼星红和马松三色(Masson'sTrichrome)染色以制备用于病理分析的载片。全部试样都在显微镜下检测且按修改后的布伦特分数NASH活性分数(Brunt score NASH Activity Score)评分。分数基于如布伦特E.M(Brunt E.M)等人,“非酒精性脂肪性肝病的组织病理学(Histopathology ofnonalcoholic fatty liver disease),”《世界胃肠病学杂志(World J.ofGastroenterol)》,2010,16(42),5286-5296中所描述的分级方案和终点。随后针对每个个体终点计算组平均值。以下终点用于表征如从NASH终点修改的小鼠中的NASH的快速食物模型(参见布伦特E.M.“非酒精性脂肪性肝病的组织病理学,”《肝病临床(Clin LiverDis.)》,2009,13,533-544和布伦特E.M等人,“非酒精性脂肪性肝炎:用于分级和分期组织学病变的提议(Nonalcoholic steatohepatitis:A proposal for grading and stagingthe histological lesions)”,《美国肠胃病学杂志(Am J Gastroenterology)》,1999,94(9),2467-2474)。
来自用实例6的化合物治疗的小鼠的肝脏的组织病理学分析提供于表4中。结果表明用20mg/kg实例6的化合物治疗的小鼠中的肝炎、大泡性空泡形成和窦周纤维化存在显著减少。
表4
实例6的化合物的功效结果
剂量(mg/kg) | 动物数量 | 医药化合物含量(ng/ml) | ALT(IU/L)<sup>1</sup> | 血浆TG(mg/dL)<sup>1</sup> |
媒剂 | 12 | - | 713±43 | 69±4 |
0.6 | 13 | 66.±5 | 530±45* | 55±6 |
2 | 13 | 163±21 | 483±44** | 70±11 |
6 | 11 | 560±29 | 495±25* | 46±4* |
20 | 11 | 2117±219 | 466±37*** | 45±5* |
1应用MIXED模型以比较通过化合物治疗组与媒剂组之间的基线调节的自基线的倍数变化,(参见“通用型、线性和混合模型(Generalized,Linear,and Mixed Models),”麦卡洛克C.E.(McCulloch,C.E.)和塞尔S.R.(Searle,S.R.)编约翰·威利父子出版公司(John Wiley and Sons),2000和“S和S-PLUS的混合作用模型(Mixed-Effects Models inS and S-PLUS)”,皮涅罗J.C.(Pinheiro J.C.)和贝茨D.M.(Bates,D.M.)编施普林格(Springer),2000。)数据以平均值±SEM形式呈现。*p<0.05;**p<0.01;***p<0.001
表5
实例6的化合物的肝脏组织病理学分析
1应用非参数测试以比较化合物治疗组与媒剂组之间的分数。分别比较左、右侧的分数。
数据以平均值±SEM形式呈现。
*p<0.05;**p<0.01;***p<0.001。
Claims (15)
3.根据权利要求1或2所述的化合物,其中n是1,或其医药学上可接受的盐。
4.根据权利要求1或2所述的化合物,其中n是2,或其医药学上可接受的盐。
5.根据权利要求1或2所述的化合物,其中R1是H,或其医药学上可接受的盐。
6.根据权利要求1或2所述的化合物,其中R1是-CH3,或其医药学上可接受的盐。
9.根据权利要求1、2或8中任一权利要求所述的化合物,其以单或二盐酸加成盐、甲基磺酸加成盐、或4-甲基苯磺酸加成盐形式提供。
10.一种根据权利要求8所述的化合物,其为(2E)-3-氟-2-({[2-(4-甲氧基哌啶-1-基)嘧啶-5-基]氧基}甲基)丙-2-烯-1-胺4-甲基苯磺酸盐。
12.一种化合物,其为(E)-3-氟-2-[[2-(4-甲氧基-1-哌啶基)嘧啶-5-基]氧基甲基]丙-2-烯-1-胺二盐酸盐。
13.一种医药组合物,其包含根据权利要求1-12中任一权利要求所述的化合物或其医药学上可接受的盐和医药学上可接受的载剂、稀释剂或赋形剂。
14.一种根据权利要求13所述的医药组合物在制造用于治疗需要治疗的患者的非酒精性脂肪性肝炎的药剂中的用途。
15.一种根据权利要求1-12中任一权利要求所述的化合物或其医药学上可接受的盐在制造用以治疗非酒精性脂肪性肝炎的药剂中的用途。
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WO2018027892A1 (en) | 2016-08-12 | 2018-02-15 | Eli Lilly And Company | Amino pyrimidine ssao inhibitors |
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CN109810041B (zh) | 2017-11-21 | 2023-08-15 | 药捷安康(南京)科技股份有限公司 | 卤代烯丙基胺类ssao/vap-1抑制剂及其应用 |
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CN110938059A (zh) * | 2018-09-25 | 2020-03-31 | 上海轶诺药业有限公司 | 胺基脲敏感性胺氧化酶抑制剂制备及其应用 |
WO2020063854A1 (zh) * | 2018-09-27 | 2020-04-02 | 南京明德新药研发有限公司 | 作为vap-1抑制剂的喹啉类衍生物 |
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CN112955215B (zh) | 2018-10-29 | 2024-05-17 | 勃林格殷格翰国际有限公司 | 吡啶基磺酰胺衍生物、药物组合物及其用途 |
TW202039486A (zh) | 2018-12-14 | 2020-11-01 | 南韓商柳韓洋行股份有限公司 | 三唑并吡啶-3-酮化物或其鹽及包含彼之醫藥組合物 |
TWI835945B (zh) * | 2018-12-14 | 2024-03-21 | 南韓商柳韓洋行股份有限公司 | 3,3-二氟烯丙胺化物或其鹽及包含彼的醫藥組合物 |
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EP4125968A4 (en) * | 2020-03-25 | 2024-04-10 | Terns, Inc. | TREATMENT OF RESPIRATORY DISORDERS |
EP4149453A4 (en) * | 2020-05-13 | 2024-05-22 | Terns Pharmaceuticals, Inc. | COMBINATION TREATMENT OF LIVER DISEASES |
KR20230058112A (ko) | 2020-08-25 | 2023-05-02 | 일라이 릴리 앤드 캄파니 | Ssao 억제제의 다형체 |
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