CN116887821A - 将联苯基引入新型氨基烷酸的衍生物化合物及包含其的抗炎用组合物 - Google Patents
将联苯基引入新型氨基烷酸的衍生物化合物及包含其的抗炎用组合物 Download PDFInfo
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Abstract
本发明涉及一种将联苯基引入新型氨基烷酸的衍生物化合物及包含其的抗炎用组合物。本发明的目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物化合物、其盐和/或溶剂化物作为有效成分的用于预防或治疗纤维化疾病、炎症性疾病、自身免疫性疾病和/或过敏性疾病的药物组合物。
Description
技术领域
本发明涉及一种将联苯基引入氨基烷酸的衍生物化合物、其立体异构体或它们的药学上可接受的盐、以及包含其作为有效成分的抗炎用组合物。
背景技术
细胞因子在免疫系统中发挥重要作用,例如细胞介导的免疫和过敏反应。细胞因子分为促炎(proinflammatory)细胞因子和抗炎(anti-inflammatory)细胞因子。细胞因子主要由T淋巴细胞(T lymphosyte)产生,T淋巴细胞细胞表面存在的抗原特异性受体识别外来病原体。根据细胞表面分子的类型,T淋巴细胞分为CD4和CD8。表达CD4的T淋巴细胞产生最多的细胞因子,被称为辅助性T细胞(helper T cell)。并且,辅助性T细胞分为产生Th1型细胞因子的Th1和产生Th2型细胞因子的Th2。Th1型细胞因子主要引起炎症反应,维持免疫反应以消除细胞内的外来病原体,干扰素γ(interferon gamma)是主要的Th1型细胞因子。Th2型细胞因子包括白细胞介素-4、白细胞介素-5、白细胞介素-6、白细胞介素-13及白细胞介素-10等,与特应性中IgE和嗜酸性粒细胞反应(eosinophilic responses)的促进有关。
白细胞介素-6(IL-6)是一种在炎症反应早期产生的细胞因子,具有多种生物学功能,包括诱导急性期反应、炎症、造血、骨代谢和癌症进展。人IL-6的长度为183个氨基酸(aa),与小鼠和大鼠IL-6具有41%的氨基酸序列同源性。它由T细胞和巨噬细胞分泌,诱导炎症反应。由于IL-6具有诱导炎症和自身免疫反应的能力,抗IL-6药物正在被开发为多种疾病的潜在治疗方法,包括类风湿性关节炎和癌症。IL-6与多种生物现象有关,包括滑膜炎症(synovial inflammation)、免疫反应和造血(haematopoiesis)等。IL-6与IL-6受体(IL-6R)和糖蛋白130(gp130)结合形成六聚体复合物(hexameric complex)。细胞内信号传导途径包括Janus激酶(Janus kinase,JAK)以及信号转导子和转录激活子(signal transducerand activator of transcription,STAT))途径。IL-6信号传导的药理学抑制剂通过靶向细胞因子本身或其受体来抑制IL-6与IL-6R的结合。IL-6与多种疾病相关,包括类风湿性关节炎、全身型幼年特发性关节炎(systemic juvenile idiopathic arthritiss,JIA)、Castleman病(Castleman disease)、巨细胞动脉炎(giant cell arteritis)、Takayasu动脉炎(Takayasu arteritis)及细胞因子释放综合征(cytokine release syndrome)。如此,IL-6在免疫和炎症系统功能障碍中发挥多种作用,因此抗IL-6R药物可用于改善症状,例如:发烧、疲劳、疼痛、关节破坏(joint destruction)、贫血等。此外,已知IL-6是细胞因子风暴(cytokine storm)的主要原因。
胸腺基质淋巴细胞生成素(TSLP,Thymic stromal lymphopoietin)是一种受到病毒(virus)、细菌(bacteria)或真菌(fungus)等微生物、蛋白酶过敏原(proteaseallergen)、炎性细胞因子、化学物质、过敏原等刺激而由皮肤角质形成细胞(skinkeratinocyte)或肺和肠的上皮细胞(epithelial cell)形成。TSLP在发挥其生物学功能时首先与TSLP受体(TSLPR)结合,然后与IL-7受体(IL7Rα,interleukin-7-receptor subunitalpha)形成异二聚体(heterodimer)键,然后启动信号传导级联反应(signaling cascade)被激活。上述异二聚体使树突状细胞(dendritic cells)极化(polarized),诱导2型炎症反应,并作为皮肤、肠道(gut)和气道表面Th2免疫反应的主调控子(master regulator)发挥作用。当形成TSLPR和IL-7Ra复合物(complex)时,会诱导JAK1和JAK2的交叉磷酸化(cross-phosphorylation)以及随后的信号转导子和转录激活子(signal transducer andactivator of transcription,STAT5)。
已知TSLP不仅由上皮细胞和表皮细胞分泌,还由肥大细胞(mast cells)、气道平滑肌(airway smooth muscle)、成纤维细胞(fibroblasts)或树突状细胞(dendriticcells)分泌,以调节免疫反应。据报道,皮肤中TSLP的表达与各种过敏性疾病有关(StevenF.Ziegler et al.,J Allergy Clin Immunol,2012;130:845-52)。此外,在哮喘患者的支气管灌洗液中检测到TSLP,据报道,疾病敏感性与气道上皮细胞中TSLP表达增加之间存在相关性。研究发现,由皮肤细胞分泌的TSLP在接触抗原后会加剧过敏性炎症反应并促进哮喘发作(Juan et al.,Journal of Investigative Dermatology,2012)。TSLP受体(TSLPR)主要在造血细胞中表达,其中在树突状细胞(dendritic cells,DC)中表达最多。TSLP参与组织细胞和免疫细胞的通讯以及先天性和后天性免疫系统的相互作用。因此,已知TSLP及其信号传导与特应性皮炎(AD,atopic dermititis)、银屑病(psoriasis)、哮喘(asthma)、过敏性鼻炎(AR,allergic rhinitis)和嗜酸粒细胞性食管炎(EoE,eosinophilicesophagitis)等疾病有关。据报道,TSLP信号传导与其他免疫介导的疾病有关,例如实体癌(例如,乳腺癌、结肠癌和胰腺癌)和血液癌(例如,急性B淋巴细胞白血病(B-ALL))。此外,TSLP还是一种重要的瘙痒原(pruritogen)。作为一种靶向TSLP的药物,特泽鲁单抗(Tezepelumab)是一种人单克隆抗体,已知正在开发为哮喘和特应性皮炎的治疗剂(TSLP:from allergy to cancer,Jonathan Corren&Steven F.Ziegler,Nature Immunologyvolume 20,1603-1609(2019))。
TSLP还已知与纤维化(fibrosis)有关(Evidence for a functional TSLPsignalling axis in fibrotic lung disease,Arnab Datta,et al.,JImmunol.2013Nov1;191(9))。组织的纤维化(fibrosis)会严重损害组织功能。例如,肝的纤维化进展为肝硬化和肝癌,纤维化组织常见于慢性胰腺炎和胰腺癌。纤维化疾病(fbroticdisease)包括肝纤维化(liver fibrosis)、慢性肝炎(chronic hepatitis)、肝硬化(cirrhosis)、肝癌(hepatic cancer)、化疗相关性脂肪性肝炎(chemotherapy-associatedsteatohepatitis,CASH)、肺纤维化(lung fibrosis)、肾纤维化(renal fibrosis)、肾功能衰竭(renal failure)、胰腺纤维化(pancreatic fibrosis)、慢性胰腺炎(chronicpancreatitis)和胰腺癌(pancreatic cancer)等。
发明内容
技术问题
本发明的目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物化合物作为药理有效成分的抗炎用药物组合物。
并且,本发明的目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物化合物作为药理有效成分的药物组合物,其抑制IL-6信号传导(IL6/IL-6R/JAK)。
并且,本发明的目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物化合物作为药理有效成分的抗炎用组合物,其抑制TSLP信号传导(TSLP/TSLPR/IL-7Rα)。
本发明的再一目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物作为药理有效成分的药物组合物,其用于预防或治疗、预防及治疗炎症、免疫疾病、纤维化疾病和/或癌症,
本发明的另一目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物作为药理有效成分的药物组合物,其用于预防或治疗、预防及治疗瘙痒症。
本发明的还有一目的在于,提供一种包含将联苯基引入新型氨基烷酸的衍生物作为药理有效成分的药物组合物,其用于预防或治疗、预防及治疗过敏性疾病。
本发明的又一目的在于,提供一种通过给药包含将联苯基引入新型氨基烷酸的衍生物作为药理有效成分的药物组合物来治疗癌症、炎症性疾病、纤维化疾病、瘙痒症、过敏和/或免疫疾病的方法。
解决问题的方案
为了实现上述目的,本发明提供一种引入下述化学式1所示的联苯基的新型氨基烷烃衍生物或其药学上可接受的盐和/或溶剂化物:
化学式1:
在上述化学式1中,
n为0、1或2,
R1及R2各自独立地为H或C1-6烷基,
R3为C1-6烷基,
X为选自由卤素基、卤代C1-6烷基及卤代C1-6烷氧基组成的组中的相同或不同的m个(m为1至5的整数)取代基。
并且,上述化学式1所示的化合物为对与手性碳键合的取代基的三维排列结构没有限制地化合物,并且可以包含结构上可能的所有光学异构体或对映异构体化合物。具体地,上述化学式1所示的化合物能够以其(R)或(S)异构体单独或它们的混合物(例如,外消旋体)的形式提供。并且,能够以立体异构体、非对映异构体或互变异构体(tautomer),但并不限定于此。
本发明不仅包含上述化合物1或其药学上可接受的盐,而且还可以包含能够由其制备的具有相同功效的溶剂化物或水合物,均属于本发明的范围内。
本发明的化合物基于氨基烷酸,并且可以为其中引入联苯基的衍生物化合物。
例如,上述氨基烷酸可以为在侧链中包含C2-4的直链烃的α-氨基酸衍生物,例如,α-氨基丁酸、正缬氨酸或正亮氨酸。
本发明的术语“α-氨基丁酸(α-Aminobutyric acid,AABA)”为具有2-氨基丁酸(2-Aminobutanoic acid)的IUPAC名称的下述化学式10所示的化合物,是一种在生物化学中公知为高丙氨酸的化学式为C4H9NO2的非蛋白质α氨基酸。它比丙氨酸长C1,且在侧链中包含C2直链烃。
化学式10:
本发明的术语“正缬氨酸(Norvaline;Nva)”为具有2-氨基戊酸(2-Aminopentanoic acid)的IUPAC名称的下述化学式7所示的化合物,是一种支链氨基酸(branched chain amino acid;BCAA),为化学式为CH3(CH2)2CH(NH2)CO2H的作为缬氨酸异构体的水溶性氨基酸。
化学式7:
本发明的术语“正亮氨酸(Norleucine;Nle)”为具有2-氨基己酸(2-Aminohexanoic acid)的IUPAC名称的下述化学式8所示的化合物,是一种化学式为CH3(CH2)3CH(NH2)CO2H的氨基酸。
化学式8:
例如,本发明的化合物可以为R1及R2各自独立地为H或甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、环丁基、正戊基、环戊基、正己基或环己基且上述R3为甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、仲丁基或叔丁基的化合物。
并且,本发明的化合物可以为R1及R2各自独立地为H或甲基且R3为甲基、乙基或正丙基的化合物,但并不限定于此。
例如,在本发明的化合物中,X可以为由氟、氯、三氟甲基及三氟甲氧基组成的组中的一种或相同或不同的两个取代基。例如,上述取代基可以为一个或者相同或不同的两个以上。
例如,在本发明的化合物中,X可以为氟、氯、三氟甲基或三氟甲氧基,具体地,X可以为对氟、间氟、对、间-二氟、对氯、间氯、对、间-二氯、对三氟甲基或对三氟甲氧基,但并不限定于此。
具体地,上述化合物可以如下所示:
1)2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)丁酰胺;
2)2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)戊酰胺;
3)2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)己酰胺;
4)2-氨基-N-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)戊酰胺;
5)N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)丁酰胺;
6)N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)戊酰胺;
7)N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)己酰胺;
8)N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(二甲氨基)戊酰胺;
9)2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)戊酰胺;
10)2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)己酰胺;
11)2-氨基-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)戊酰胺;
12)2-氨基-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)己酰胺;
13)2-氨基-N-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)戊酰胺;
14)2-氨基-N-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)己酰胺;
15)N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)-2-(甲氨基)戊酰胺;
16)2-(甲氨基)-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)戊酰胺;
17)N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)-2-(二甲氨基)戊酰胺;
18)2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)丁酰胺;
19)2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)戊酰胺;
20)2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)己酰胺;
21)2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺;
22)2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺;
23)2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺;
24)2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺;
25)2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺;
26)2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺;
27)2-氨基-N-(2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙基)戊酰胺;
28)N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)丁酰胺;
29)N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)戊酰胺;
30)N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)己酰胺;
31)2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺;
32)2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺;
33)2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺;
34)2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺;
35)2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺;
36)2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺;或者
37)N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(二甲氨基)戊酰胺。
在本发明中,术语“手性”是指具有不与其镜像配对物重叠的特性的分子,“非手性”是指可以与其镜像配对物重叠的分子。“对映异构体”是指彼此不可重叠的镜像的两种立体异构体。在本发明中,术语“立体异构体”是指具有相同化学结构但原子或基团在空间中的排列不同的化合物。在本发明中,术语“非对映异构体”是指具有两个以上手性中心的且分子彼此不是镜像的立体异构体。本文中使用的立体化学定义和惯例通常如文献[S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-HillBook Company,New York]以及[Eliel,E.and Wilen,S.,"Stereochemistry of OrganicCompounds",John Wiley&Sons,Inc.,New York,1994]所述。
本发明的化合物能够以药学上可接受的盐的形式存在。作为盐,由药学上可接受的游离酸(free acid)形成的酸价盐有用。本发明的术语“药学上可接受的盐”是指在对患者相对无毒和无害的具有有效作用的浓度下由这些盐引起的副作用不降低化学式1所示的化合物的有益功效的上述化合物的任何有机或无机加成盐。酸加成盐通过常规的方法制备,例如,通过将化合物溶解于过量的酸水溶液中,并用如甲醇、乙醇、丙酮或乙腈等水混溶性有机溶剂使其盐沉淀。可以加热等摩尔量的化合物及水中的酸或醇(例如,乙二醇单甲醚),接着,将上述混合物蒸发并干燥或者抽滤所析出的盐。此时,可使用有机酸和无机酸作为游离酸,作为有机酸,可使用盐酸、磷酸、硫酸、硝酸、酒石酸等,作为有机酸,可使用甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、马来酸(maleic acid)、琥珀酸、草酸、苯甲酸、酒石酸、富马酸(fumaric acid)、扁桃酸、丙酸(propionic acid)、柠檬酸(citric acid)、乳酸(lactic acid)、乙醇酸(glycollic acid)、葡萄糖酸(gluconic acid)、半乳糖醛酸、谷氨酸、戊二酸(glutaric acid)、葡萄糖醛酸(glucuronic acid)、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸(hydroiodic acid)等,但并不限定于此。
并且,可以使用碱制备药学上可接受的金属盐。例如,碱金属盐或碱土金属盐通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐后,将滤液蒸发干燥而得到。此时,制备钠盐、钾盐或钙盐作为金属盐在制药上是尤其合适的,但不限于此。相应的银盐也可以通过使碱金属或碱土金属盐与合适的银盐(例如,硝酸银)反应来得到。
除非另有说明,本发明的化合物的药学上可接受的盐包括可存在于上述化学式1的化合物中的酸性或碱性基团的盐。例如,药学上可接受的盐可包括羟基的钠盐、钙盐及钾盐等,氨基的其他药学上可接受的盐包括可通过本领域公知的制备盐的方法制备的氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、醋酸盐、磷酸二氢盐、醋酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐(methanesulfonate)(甲磺酸盐(mesylate))及对甲苯磺酸盐(甲苯磺酸盐(tosylate))等。
本发明的化学式1的化合物的盐为药学上可接受的盐,只要是表现出与化学式1的化合物等效的药理活性的化学式1的化合物的盐就可以不受限制地使用。
作为再一方面,本发明提供上述将联苯基引入氨基烷酸的衍生物化合物、其立体异构体或它们的药学上可接受的盐的制备方法,包括第一步骤,将下述化学式2所示的由叔丁氧羰基保护基(Boc protecting group)保护的氨基烷酸衍生物化合物与下述化学式3所示的包含伯胺基的联苯衍生物化合物反应形成肽键;以及第二步骤,将在第一步骤中获得的化合物与酸反应,去除叔丁氧羰基保护基:
化学式1:
化学式2:
化学式3:
在上述化学式中,
n为0、1或2,
R1及R2各自独立地为H或C1-6烷基,
R3为C1-6烷基,
X为选自由卤素基、卤代C1-6烷基及卤代C1-6烷氧基组成的组中的相同或不同的m个(m为1至5的整数)的取代基。
在本发明的制备方法中,可将下述化学式4所示的氨基酸衍生物与二碳酸二叔丁酯(di-tert-butyl dicarbonate,别名为叔丁氧羰基酸酐(Boc anhydride))反应准备化学式2所示的由叔丁氧羰基保护基(Boc protecting group)保护的氨基烷酸衍生物化合物:
化学式4:
在上述化学式中,
R1'及R2各自独立地为H或C1-6烷基,
R3为C1-6烷基。
此时,在最终制备的化合物的R2为烷基的情况下,在上述反应之后,还可以进行在碱的存在下与卤代烃反应的烷基化步骤。例如,上述烷基化可以如此进行,但并不限定于此:在如四氢呋喃等有机溶剂中溶解上述化学式4所示的化合物和相当于其5当量至20当量的如碘化烷烃等卤代烃化合物,在如0℃等低温下滴加作为碱的氢化钠后,在15℃至30℃的温度下使反应物反应12小时至48小时,并可以无限制地通过利用或改进本领域中公知的胺的烷基化反应来进行。
另一方面,在本发明的制备方法中,可将下述化学式5所示的一末端被卤代苯基取代的C0-2烷基胺衍生物与二碳酸二叔丁酯反应来将叔丁氧羰基保护基引入胺基后,与下述化学式6所示的苯基硼酸衍生物反应后,与酸反应去除叔丁氧羰基保护基,由此准备化学式3所示的包含伯胺基的联苯衍生物化合物:
化学式5:
化学式6:
在上述化学式中,
X'为卤素,
X为选自由卤素基、卤代C1-6烷基及卤代C1-6烷氧基组成的组中的相同或不同的m个(m为1至5的整数)的取代基。
此时,与上述苯基硼酸衍生物的反应可通过在碱的存在下基于金属催化剂进行交联反应来实现。例如,上述反应可在碱的存在下通过钯或镍等金属催化剂进行。上述金属催化剂可以为由膦配体结合在金属而形成的催化剂。例如,上述反应可以为在Na2CO3的存在下通过Pd(PPh3)4进行的Suzuki-Miyaura交叉偶联反应(Suzuki-Miyaura Cross-Couplingreaction),但并不限定于此。
例如,在本发明的制备方法中,第一步骤可通过在N-甲基吗啉(N-methylmorpholine;NMM)及氯甲酸异丁酯(isobutyl chloroformate;IBCF)的存在下在有机溶剂中进行的无水偶联反应实现。可使用四氢呋喃作为上述有机溶剂,但并不限定于此。例如,在本发明的制备方法中,为了去除叔丁氧羰基保护基而进行的第二步骤可以通过与盐酸反应来进行,但并不限定于此。进一步地,在本发明的制备方法中,在最终制备的化合物的R1及R2均为烷基的情况下,在第二步骤之后,还可包括对胺进行烷基化来形成仲胺的第三步骤。上述胺化可以通过在作为还原剂的Pd/C的存在下在供应氢气的同时与甲醛反应来进行。例如,上述反应可以通过在15℃至30℃的温度下反应6小时至24小时来进行,但并不限定于此,并可以无限制地通过利用或改进本领域中公知的胺的烷基化反应来进行。
作为另一方面,本发明提供一种包含将联苯基引入氨基烷酸的化学式1的衍生物化合物、其对映异构体、光学异构体、立体异构体、非对映异构体、互变异构体或其药学上可接受的盐作为有效成分的用于预防或治疗炎症性疾病的药物组合物。例如,可用本发明的药物组合物预防和/或治疗的炎症性疾病可以为选自由特应性皮炎(atopic dermatitis)、哮喘(asthma)、过敏性鼻炎(allergic rhinitis)、过敏性结膜炎(allergicconjunctivitis)、过敏性皮炎(allergic dermatitis)、银屑病(psoriosis),炎症性肠病(inflammatory bowel disease)及食物过敏(food allergy)组成的组中的有一种以上。
作为另一方面,本发明提供一种包含将联苯基引入氨基烷酸的化学式1的衍生物化合物、其对映异构体、光学异构体、立体异构体、非对映异构体、互变异构体或其药学上可接受的盐作为有效成分的用于预防或治疗纤维化疾病(fibrosis disease)的药物组合物。例如,可用本发明的药物组合物预防和/或治疗的纤维化疾病可以为选自由肝纤维化(liver fibrosis)、慢性肝炎(chronic hepatitis)、肝硬化(cirrhosis),肝癌(hepaticcancer)、化疗相关性脂肪性肝炎(chemotherapy-associated steatohepatitis,CASH)、非酒精性脂肪性肝炎(Nonalcoholic steatohepatitis,NASH)、肺纤维化(lung fibrosis)、肾纤维化(renal fibrosis)、肾功能衰竭(renal failure)、胰腺纤维化(pancreaticfibrosis)、慢性胰腺炎(chronic pancreatitis)及胰腺癌(pancreatic cancer)组成的组中的有一种以上。
本发明的术语“预防”是指通过给药上述药学组合物抑制或延迟对象疾病的发生、扩散及复发的所有行为,“治疗”是指通过给药上述药学组合物使对象疾病的症状好转或有益改变的所用行为。
本发明的药物组合物可以包含化学式1所示的化合物、其立体异构体、非对映异构体、对映异构体、光学异构体、互变异构体或它们的药学上可接受的盐作为有效成分,并且,还可以包含药学上可接受的载体、稀释剂或赋形剂。例如,根据不同的使用目的,可按照常规方法配制为散剂、颗粒剂、片剂、胶囊剂、悬浮剂、乳剂、糖浆剂、气雾剂等口服剂型、无菌注射液注射剂等各种剂型并使用,可以口服或通过多种途径给药,包括静脉内、腹腔内、皮下、直肠、局部等。作为可包含在这种组合物的合适的载体、赋形剂或稀释剂的例,可包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等。并且,本发明的组合物还可以包含填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂、防腐剂等。
用于口服给药的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,这些固体制剂在上述组合物中混合至少一种赋形剂来进行剂型化,例如,淀粉、碳酸钙、蔗糖、乳糖、明胶等。混合和配制。并且,除了简单的赋形剂之外,还可使用如硬脂酸镁、滑石等润滑剂。
作为用于口服给药的液体制剂,可例示悬浮剂、内用液剂、乳剂、糖浆剂等,除了作为常用的简单稀释剂的水、液体石蜡之外,还可以包括多种赋形剂,例如,润湿剂、甜味剂、芳香剂、保存剂等。
用于肠胃外给药的制剂包括无菌水溶液、非水性溶剂、悬浮剂、乳剂、冻干制剂、栓剂。作为非水性溶剂、悬浮剂,可使用丙二醇、聚乙二醇、如橄榄油等植物油、如油酸乙酯等可注射酯类等。作为栓剂的基质,可使用Witepsol、聚乙二醇、吐温61、可可脂、三月桂酸甘油酯(laurinum)、甘油明胶等。另一方面,注射剂可包括溶解剂、等渗剂、悬浮剂、乳化剂、稳定剂、防腐剂等现有的添加剂。
本发明的组合物以药学有效量给药。本发明的术语“药学有效量”是指足以以适用于医学治疗的合理收益/风险比治疗疾病且不引起副作用的量,有效剂量水平取决于患者的健康状况,疾病类型、严重程度、药物活性、对药物的敏感性、给药方法、给药时间、给药途径和排泄率、治疗周期、配合或同时使用的药物等因素,以及医学领域中众所周知的其他因素。本发明的组合物可以作为单独的治疗剂给药或与其他治疗剂联合给药,可以与现有的治疗剂依次或同时给药,并且可以单次或多次给药。考虑以上所有因素,以无副作用且以最小的量获得最大效果的量给药是很重要的,这对于本领域技术人员来说是很容易确定的。例如,上述给药量可随着给药途径、疾病严重程度、性别、体重、年龄等增加或减少,因此,上述给药量不以任何方法限制本发明的范围。在一实例中,本发明的上述化合物优选局部或口服给药。当局部给药时,本发明的化合物的治疗有效量可以为0.00001%(w/w)至约20%(w/w),优选为0.001%至3%,但并不限定于此。当口服给药时,本发明的上述化合物的治疗有效量可以为0.01mg/kg至约1000mg/kg,优选为1mg/kg至约300mg/kg,但并不限定于此。在本发明中,给药本发明的药物组合物的对象是人,并且可以包括动物。
本发明的术语“给药”是指通过任何合适的方法向患者提供预定物质,本发明的组合物的给药途径可以通过能够到达靶组织的任何一般途径给药。可以进行腹腔内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、局部给药、鼻内给药、肺内给药、直肠内给药,但并不限定于此。并且,本发明的药学组合物可通过能够使活性物质向靶细胞移动的任意装置给药。优选的给药方式及制剂为静脉注射剂、皮下注射剂、皮内注射剂、肌肉注射剂、滴注剂等。注射剂可利用如生理盐水和林格氏液等水性溶剂、如植物油、高级脂肪酸酯(例如,油酸乙酯等),醇类(例如,乙醇、苯甲醇、丙二醇、丙三醇等)等非水性溶剂等来制备,并且可包括用于防止变质的稳定剂(例如,抗坏血酸、亚硫酸氢钠、焦亚硫酸钠、BHA、生育酚、EDTA等),乳化剂,用于调节pH的缓冲剂、用于阻止微生物发育的保存剂(例如,硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等)等药学载体。
在本发明中与有效成分结合使用的术语“治疗学有效量”是指对对象疾病的治疗或预防有效的将联苯基引入氨基烷酸的衍生物化合物、其立体异构体或它们的药学上可接受的盐的量。
发明的效果
本发明的药物组合物抑制IL-6信号传导和/或TSLP/TSLPR/IL-7Rα信号传导,从而可用于开发有效预防及治疗炎症性疾病、免疫疾病、纤维化疾病、过敏、瘙痒症和/或癌症的药物。
附图说明
图1示出比较对RAW264.7细胞处理8μg/ml的本发明的化合物时的IL-6生成量与处理LPS时的IL-6生成量的结果。
图2示出比较对RAW264.7细胞处理8μg/ml的本发明的化合物时的TNF-α生成量与处理LPS时的TNF-α生成量的结果。
图3示出在HaCaT细胞中确认根据本发明的化合物的TSLP和白细胞介素-6的量的结果。
图4及图5示出使用HEK293T细胞确认本发明的化合物是否抑制TSLP和TSLPR之间相互作用的结果。
图6示出用艾达乐乳膏(Aldara cream)诱发的银屑病症状的皮肤照片。
图7为示出用艾达乐乳膏诱发的银屑病症状的皮肤指数值的柱状图。
图8为示出用艾达乐乳膏诱发的银屑病症状的致敏部位的搔抓次数的柱状图。
图9为示出用艾达乐乳膏诱发的银屑病症状的RNA水平(RNA level)的功效评价结果的柱状图。
具体实施方式
用于制备本发明化合物的反应式如下所示。在下述反应式中,未与英文字母一起使用的数字表示本发明中制备的化合物编号。即,1表示化合物1:
反应式a:叔丁氧羰基保护基(Boc protecting group)的引入
将正亮氨酸(1.0当量)、Boc酸酐(1.5当量)、碳酸氢钠(1.5当量)溶解于以1:1的比例混合蒸馏水和甲醇的混合溶剂中,在室温下反应36-48小时。在真空状态下浓缩混合物后,用1.0M的盐酸将水层的pH调节至2。然后,使用硫酸钠去除用乙酸乙酯萃取而获得的有机层的水分,在真空下蒸发溶剂,得到标题化合物。
反应式b:胺基的甲基化
将从上述反应式a获得的化合物(1.0当量)和碘甲烷(10当量)溶解于四氢呋喃溶剂中,在0℃的温度下缓慢滴加氢化钠(10当量)。在室温下使上述反应物反应24小时。反应结束后,用醚溶剂稀释并添加蒸馏水。用20%的柠檬酸溶液将水层的pH调节至2。然后,使用硫酸钠去除用乙酸乙酯萃取而获得的有机层的水分,在真空下蒸发溶剂。所得的残留物通过硅胶层析分离、纯化,得到标题化合物。
反应式c:在伯胺基引入叔丁氧羰基保护基
将4-溴苯乙胺(1.0当量)溶解于二甲基氯化物溶剂中后,加入碳酸钾(1.5当量)、Boc酸酐(1.05当量),在室温下反应约12-18小时。用二甲基氯化物稀释反应混合物,并清洗两次。用硫酸钠干燥有机层后,在真空下浓缩。用己烷清洗所得的残留物后,在真空状态下蒸发,得到标题化合物。
反应式d:联苯胺盐酸盐衍生物的合成
将从上述反应式c获得的化合物、(4-溴苄基)氨基甲酸叔丁酯或(4-溴苯基)氨基甲酸叔丁酯(1.0当量)、苯硼酸(1.5当量)、碳酸钠(5.0当量)、四(三苯基膦)钯(0.04当量)溶解于以2:1至2.5:1的比例混合的脱气(degassing)的甲苯和蒸馏水的混合溶剂中,在140℃的温度下进行回流反应约12-18小时。反应后,用硅藻土过滤去除催化剂,在真空状态下蒸发经过滤的有机层中的溶剂。所得的残留物通过硅胶层析分离、纯化。将纯化的产物溶解于乙酸乙酯溶剂中后,在添加4.0M的盐酸(6.0-10.0当量)的同时在室温下搅拌。用乙酸乙酯清洗所得的盐形式的白色固体后,在真空状态下完全干燥,得到标题化合物。
反应式e:混合酸酐偶联(MAC)反应
向蒸馏的四氢呋喃溶剂中加入根据上述反应式a合成的化合物或根据反应式b合成的化合物(1.0当量)、N-甲基吗啉(N-methylmorpholine;NMM,2.5-2.8当量),搅拌15分钟后,添加氯甲酸异丁酯(isobutyl chloroformate;IBCF,1.3当量)后,再搅拌15分钟后,添加从上述反应式d获得的化合物(1.05当量)。在室温下使反应混合物反应约3-5小时。过滤混合物并在真空状态下蒸发溶剂。所得的残留物通过硅胶层析分离、纯化,得到标题化合物。
反应式f:叔丁氧羰基保护基的去除
将从上述反应式e获得的化合物衍生物(1.0当量)溶解于乙酸乙酯溶剂中后,在添加4.0M的盐酸(6.0-10.0当量)的同时在室温下搅拌。用乙酸乙酯清洗所得的盐形式的白色固体后,在真空状态下完全干燥,得到标题化合物。
反应式g:胺基的二甲基化
将从上述反应式f获得的化合物(1.0当量)溶解于甲醇中,添加三乙胺(6.0当量)后,依次添加甲醛(37%by weight solution,1.0-2.5当量)和10%的钯催化剂(0.1-0.5当量)。在室温下使反应物反应18小时。反应后,用硅藻土过滤去除催化剂,在真空状态下蒸发经过滤的有机层来获得白色固体。将所得的产物用甲醇和二乙醚再结晶,得到标题化合物。
发明的实施方式
以下,通过优选实施例更详细地说明本发明。但是,对于本领域普通技术人员而言,这些实施例用于更加具体地说明本发明,而本发明的范围并不限定于此。
制备例
制备例1:(R)/(S)-2-((叔丁氧基羰基)氨基)丁酸(4)的制备
利用反应式a,将化合物1(2-氨基丁酸,5.00g,48.5mmol)、Boc酸酐(19.9ml,72.7mmol)及NaHCO3(6.11g,72.7mmol)反应合成白色粉末状的化合物4,(R)/(S)-2-((叔丁氧基羰基)氨基)丁酸(8.25g,83%)
Rf=0.00(DCM 9.5:甲醇(Methanol)0.5和几滴乙酸(few drops of aceticacid));
1H NMR(DMSO-d6,300MHz)12.40(C(O)OH),7.02(d,J=7.9Hz,Boc-NH),3.69-3.82(m,Chiral-H),1.48-1.72(m,CH2CH3),1.38(s,Boc),0.87(t,J=7.3Hz,CH2CH3)。
制备例2:(R)/(S)-2-((叔丁氧基羰基)氨基)戊酸(5)的制备
利用反应式a,将化合物2(2-氨基戊酸,10.00g,25.6mmol)、Boc酸酐(35.1ml,128.0mmol)及NaHCO3(10.8g,128.0mmol)反应合成白色粉末状的化合物5,(R)/(S)-2-((叔丁氧基羰基)氨基)戊酸(13.40g,83%)。
Rf=0.85(DCM 3:甲醇(Methanol)17);
1H NMR(DMSO-d6,400MHz)12.40(C(O)OH),7.03(d,J=8.0Hz,Boc-NH),3.75-3.89(m,Chiral-H),1.50-1.65(m,CH2CH2CH3),1.20-1.38(m,CH2CH2CH3,Boc),0.85(t,J=7.4Hz,CH2CH2CH3)。
制备例3:(R)/(S)-2-((叔丁氧基羰基)氨基)己酸(6)的制备
利用反应式a,将化合物3(2-氨基己酸,5.00g,38.1mmol),Boc酸酐(15.7ml,57.2mmol)及NaHCO3(4.80g,57.2mmol)反应合成白色粉末状的化合物6,(R)/(S)-2-((叔丁氧基羰基)氨基)己酸(7.14g,81%)。
Rf=0.40(DCM 9:甲醇(Methanol)1);
1H NMR(CDCl3,400MHz)10.26(C(O)OH),5.00(d,J=7.6Hz,Boc-NH),4.32-4.33(m,Chiral-H),1.63-1.87(m,CH2CH2CH2CH3),1.47(s,Boc),1.31-1.38(m,CH2CH2CH2CH3),0.93(t,J=7.0Hz,CH2CH2CH2CH3)。
制备例4:(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)丁酸(7)的制备
利用反应式b,将化合物4(3.00g,14.8mmol)、CH3I(9.2ml,147.6mmol)及NaH(3.54g,147.6mmol)反应合成黄色油状的化合物7,(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)丁酸(2.84g,88%)。
Rf=0.45(DCM 9:甲醇(Methanol)1和几滴乙酸(few drops of acetic acid));
1H NMR(DMSO-d6,300MHz)12.7(C(O)OH),4.14-4.43(m,Chiral-H),2.71(s,NCH3),1.50-1.73(m,CH2CH3,Boc),0.79-0.87(m,CH2CH3)。
制备例5:(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)戊酸(8)的制备
利用反应式b,将化合物5(1.50g,6.90mmol)、CH3I(4.3ml,69.0mmol)及NaH(1.66g,69.0mmol)反应合成黄色油状的化合物8,(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)戊酸(1.34g,83%)。
Rf=0.45(DCM 9:甲醇(Methanol)1和几滴乙酸(few drops of acetic acid));
1H NMR(DMSO-d6,300MHz)12.7(C(O)OH),4.54-4.28(m,Chiral-H),2.70(s,NCH3),1.79-1.64(m,CH2CH2CH3),1.41-1.37(m,CH2CH2CH3,Boc),1.37-1.29(m,CH2CH2CH3)。
制备例6:(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)己酸(9)的制备
利用反应式b,将化合物6(3.00g,13.0mmol)、CH3I(8.1ml,129.7mmol)及NaH(5.19g,129.7mmol)反应合成黄色油状的化合物9,(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)己酸(3.18g,100%)。
Rf=0.38(DCM 9:甲醇(Methanol)1);
1H NMR(CDCl3,400MHz)12.6(C(O)OH),4.25-4.52(m,Chiral-H),2.70(s,NCH3),1.66-1.79(m,CH2CH2CH2CH3),1.18-1.40(m,CH2CH2CH2CH3,Boc),0.86-0.89(m,CH2CH2CH2CH3)。
制备例7:(4-溴苯乙基)氨基甲酸叔丁酯(12)的制备
利用反应式c,将4-溴苯乙胺(3.9ml,25.1mmol)、K2CO3(5.21g,37.7mmol)及Boc酸酐(7.2ml,26.4mmol)反应合成白色粉末状的化合物12,(4-溴苯乙基)氨基甲酸叔丁酯(6.23g,83%)。
Rf=0.36(EtOAc 1:正己烷(n-hexane)5);
1H NMR(DMSO-d6,400MHz)7.46(d,J=8.6Hz,ArH),7.15(d,J=8.2Hz,ArH),6.87(s,NH),3.09-3.14(m,NHCH2CH2),2.64-2.67(m,NHCH2CH2),1.35(s,Boc)。
制备例8:3',4'-二氯-[1,1'-联苯]-4-胺盐酸盐(13)的制备
利用反应式d,将化合物10(4-溴苯基氨基甲酸叔丁酯,4.00g,14.7mmol)、3,4-二氯苯基硼酸(3.37g,17.6mmol)、四(三苯基膦)钯(0.68g,0.59mmol)及Na2CO3(7.80g,73.5mmol)反应获得化合物后,利用4.0M的HCl(7.9ml,31.5mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物13,3',4'-二氯-[1,1'-联苯]-4-胺盐酸盐(1.27g,34%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.94(s,NH3),7.95(d,J=2.0Hz,ArH),7.40-7.80(m,ArH),7.39(d,J=8.5Hz,ArH)。
制备例9:4'-(三氟甲氧基)-[1,1'-联苯]-4-胺盐酸盐(14)的制备
利用反应式d,将化合物10(3.99g,14.7mmol)、4-(三氟甲氧基)苯基硼酸(7.77g,22.0mmol)、四(三苯基膦)钯(0.68g,0.59mmol)及Na2CO3(7.77g,73.3mmol)反应获得化合物后,利用4.0M的HCl(12.8ml,51.1mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物14,4'-(三氟甲氧基)-[1,1'-联苯]-4-胺盐酸盐(1.99g,48%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.45(br s,NH3),7.77(d,J=8.7Hz,ArH),7.71(d,J=8.4Hz,ArH),7.45(d,J=8.4Hz,ArH),7.28(d,J=8.2Hz,ArH)。
制备例10:2-(3',4'-二氯-[1,1'-联苯]-4-基)甲-1-胺盐酸盐(15)的制备利用反应式d,将化合物11(4-溴苄基氨基甲酸叔丁基酯,6.00g,21.0mmol)、3,4-二氯苯基硼酸(4.80g,25.2mmol)、四(三苯基膦)钯(0.97g,0.84mmol)及Na2CO3(111.1g,104.8mmol)反应获得化合物后,利用4.0M的HCl(3.1ml,12.3mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物15,2-(3’,4’-二氯-[1,1’-联苯]-4-基)甲-1-胺盐酸盐(1.08g,17%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.71(s,NH3),7.97(s,ArH),7.63-7.83(m,ArH),4.07(s,NH3CH2)。
制备例11:(4’-(三氟甲基)-[1,1'-联苯]-4-基)甲胺盐酸盐(16)的制备
利用反应式d,将化合物11(6.00g,21.0mmol)、4-(三氟甲基)苯基硼酸(5.97g,31.5mmol)、四(三苯基膦)钯(0.97g,0.84mmol)及Na2CO3(11.1g,104.8mmol)反应获得化合物后,利用4.0M的HCl(17.9ml,71.7mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物16,(4’-(三氟甲基)-[1,1’-联苯]-4-基)甲胺盐酸盐(1.08g,66%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.49(s,NH3),7.93(d,J=8.2Hz,ArH),7.83(t,J=9.0Hz,ArH),7.64(d,J=8.2Hz,ArH),4.09(s,NH3CH2)。
制备例12:(4’-(三氟甲氧基)-[1,1'-联苯]-4-基)甲胺盐酸盐(17)的制备利用反应式d,将化合物11(4.00g,14.0mmol)、4-(三氟甲氧基)苯基硼酸(4.32g,21.0mmol)、四(三苯基膦)钯(0.65g,0.56mmol)及Na2CO3(7.41g,69.9mmol)反应获得化合物后,利用4.0M的HCl(13.9ml,55.6mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物17,(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲胺盐酸盐(2.73g,65%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.33(s,NH3),7.81-7.83(m,ArH),7.75(d,J=8.2Hz,ArH),7.59(d,J=8.2Hz,ArH),7.48(d,J=8.3Hz,ArH),4.08(s,NH3CH2)。
制备例13:2-(3',4'-二氯-[1,1'-联苯]-4-基)乙-1-胺盐酸盐(18)的制备利用反应式d,将化合物12((4-溴苯乙基)氨基甲酸叔丁酯,1.00g,3.33mmol)、3,4-二氯苯基硼酸(0.76g,4.00mmol)、四(三苯基膦)钯(0.15g,0.15mmol)及Na2CO3(1.77g,16.7mmol)反应获得化合物后,利用4.0M的HCl(2.50ml,10.0mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物18,2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙-1-胺盐酸盐(2.73g,65%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.33(s,NH3),7.93(d,J=1.9Hz,ArH),7.66-7.72(m,ArH),7.39(d,J=8.2Hz,ArH),2.98-3.07(m,NH3CH2CH2)。
制备例14:2-(4’-(三氟甲基)-[1,1'-联苯]-4-基)乙-1-胺盐酸盐(19)的制备
利用反应式d,将化合物12(0.50g,1.67mmol)、4-(三氟甲基)苯基硼酸(0.38g,2.00mmol)、四(三苯基膦)钯(0.08g,0.07mmol)及Na2CO3(0.88g,8.33mmol)反应获得化合物后,利用4.0M的HCl(1.25ml,5.00mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物19,2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙-1-胺盐酸盐(0.28g,56%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.37(s,NH3),7.71-7.91(m,ArH),7.44(d,J=8.1Hz,ArH),3.01-3.11(m,NH3CH2CH2)。
制备例15:2-(4’-(三氟甲氧基)-[1,1'-联苯]-4-基)乙-1-胺盐酸盐(20)的制备
利用反应式d,将化合物12(1.50g,5.00mmol)、4-(三氟甲氧基)苯基硼酸(1.23g,6.00mmol)、四(三苯基膦)钯(0.23g,0.20mmol)及Na2CO3(2.65g,25.0mmol)反应获得化合物后,利用4.0M的HCl(3.75ml,15.0mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物20,2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙-1-胺盐酸盐(0.88g,55%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.31(s,NH3),7.79(d,J=8.7Hz,ArH),7.66(d,J=8.1Hz,ArH),7.45(d,J=8.2Hz,ArH),7.40(d,J=8.1Hz,ArH),2.97-3.10(m,NH3CH2CH2)。
制备例16:2-(3',4'-二氟-[1,1'-联苯]-4-基)乙-1-胺盐酸盐(21)的制备利用反应式d,将化合物12(1.00g,3.33mmol)、3,4-二氯苯基硼酸(0.76g,4.00mmol)、四(三苯基膦)钯(0.15g,0.15mmol)及Na2CO3(1.77g,16.7mmol)反应获得化合物后,利用4.0M的HCl(2.50ml,10.0mmol在二恶烷中(in dioxane))去除Boc基团合成白色粉末状的化合物21,2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙-1-胺盐酸盐(2.73g,65%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)7.95(s,NH3),7.74-7.79(m,ArH),7.67(d,J=8.1Hz,ArH),7.48-7.54(m,ArH),7.37(d,J=8.1Hz,ArH),2.90-3.09(m,NH3CH2CH2)。
制备例17:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代丁-2-基)氨基甲酸叔丁酯(22)的制备
利用反应式e,将化合物4(0.63g,3.12mmol)、NMM(0.96ml,8.74mmol)、IBCF(0.53ml,4.06mmol)及化合物13(0.90g,3.28mmol)反应合成淡黄色粉末状的化合物22,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代丁-2-基)氨基甲酸叔丁酯(1.09g,82%)。
Rf=0.33(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.55(s,C(O)NH),7.58(d,J=7.3Hz,ArH),7.44-7.47(m,ArH),7.34(dd,J=1.8Hz,8.3Hz,ArH),5.12(s,Boc-NH),4.18(s,Chiral-H),1.67-2.05(m,CH2CH3),1.47(s,Boc),1.03(t,J=7.4Hz,CH2CH3)。
制备例18:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(23)的制备
利用反应式e,将化合物5(0.30g,1.52mmol)、NMM(0.42ml,3.80mmol)、IBCF(0.26ml,1.98mmol)及化合物13(0.44g,1.60mmol)反应合成白色粉末状的化合物23,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(0.61g,92%)。
Rf=0.37(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.53(s,C(O)NH),7.62(d,J=8.6Hz,ArH),7.48-7.50(m,ArH),7.38(dd,J=2.0Hz,8.3Hz,ArH),5.08(s,Boc-NH),4.24(s,Chiral-H),1.63-1.99(m,CH2CH2CH3),1.47-1.50(m,Boc,CH2CH2CH3),0.99(t,J=7.3Hz,CH2CH2CH3)。
制备例19:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(24)的制备
利用反应式e,将化合物6(0.80g,3.46mmol)、NMM(0.95ml,8.69mmol)、IBCF(0.58ml,4.50mmol)及化合物13(1.00g,3.64mmol)反应合成白色粉末状的化合物24,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(1.11g,71%)。
Rf=0.50(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)10.10(s,NH),7.91(d,J=1.9Hz,ArH),7.64-7.74(m,ArH),7.04(d,J=7.8Hz,NH),4.02-4.07(m,NHCHCH2),1.57-1.64(m,CH2CH2CH2CH3),1.39(s,Boc),1.26-1.32(m,CH2CH2CH2CH3),0.86(t,J=6.8Hz,CH2CH2CH2CH3)。
制备例20:(R)/(S)-(1-氧代-1-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)戊-2-基)氨基甲酸叔丁酯(25)的制备
利用反应式e,将化合物5(0.43g,1.97mmol)、NMM(0.61ml,5.52mmol)、IBCF(0.33ml,2.56mmol)及化合物14(0.60g,2.07mmol)反应合成白色粉末状的化合物25,(R)/(S)-(1-氧代-1-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基)戊-2-基)氨基甲酸叔丁酯(0.66g,73%)。
Rf=0.30(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.62(s,C(O)NH),7.61(d,J=7.3Hz,ArH),7.54(d,J=7.6Hz,ArH),7.49(d,J=7.9Hz,ArH),7.26-7.29(m,ArH),5.19(d,J=7.4Hz,Boc-NH),4.29(s,Chiral-H),1.65-1.98(m,CH2CH2CH3),1.43-1.56(m,Boc,CH2CH2CH3),0.99(t,J=7.1Hz,CH2CH2CH3)。
制备例21:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代丁-2-基)(甲基)氨基甲酸叔丁酯(26)的制备
利用反应式e,将化合物7(0.68g,3.12mmol)、NMM(0.96ml,8.74mmol)、IBCF(0.53ml,4.06mmol)及化合物13(0.90g,3.28mmol)反应合成油状的化合物26,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代丁-2-基)(甲基)氨基甲酸叔丁酯(0.74g,54%)。
Rf=0.50(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.50(s,C(O)NH),7.58-7.63(m,ArH),7.46-7.50(m,ArH),7.38(dd,J=1.8Hz,8.2Hz,ArH),4.57(s,Chiral-H),2.83(s,NCH3),1.71-2.04(m,CH2CH3),1.51(d,J=6.8Hz,Boc),0.97(t,J=7.3Hz,CH2CH3)。
制备例22:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(27)的制备
利用反应式e,将化合物8(0.86g,3.72mmol)、NMM(1.14ml,10.4mmol)、IBCF(0.63ml,4.83mmol)及化合物13(1.07g,3.90mmol)反应合成黄色粉末状的化合物27,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(0.79g,47%)。
Rf=0.48(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.49(s,C(O)NH),7.58-7.64(m,ArH),7.47-7.51(m,ArH),7.38(d,J=8.3Hz,ArH),4.66(s,Chiral-H),2.82(s,NCH3),1.67-2.04(m,CH2CH2CH3),1.51(s,Boc),1.33-1.39(m,CH2CH2CH3),0.99(t,J=7.3Hz,CH2CH2CH3)。
制备例23:(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代己-2-基)(甲基)氨基甲酸叔丁酯(28)的制备
利用反应式e,将化合物9(R)/(S)-2-((叔丁氧基羰基)(甲基)氨基)己酸(0.84g,3.47mmol)、NMM(1.10ml,9.71mmol)、IBCF(0.58ml,4.51mmol)及化合物13(1.00g,3.64mmol)反应合成油状的化合物28,(R)/(S)-(1-((3’,4’-二氯-[1,1’-联苯]-4-基)氨基)-1-氧代己-2-基)(甲基)氨基甲酸叔丁酯(0.86g,53%)。
Rf=0.55(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)8.49(s,C(O)NH),7.58-7.64(m,ArH),7.47-7.51(m,ArH),7.38(dd,J=2.1Hz,8.4Hz,ArH),4.64(s,Chiral-H),2.82(s,NCH3),1.67-2.01(m,CH2CH2CH2CH3),1.52(s,Boc),1.24-1.44(m,CH2CH2CH2CH3),0.93(t,J=7.1Hz,CH2CH2CH3)。
制备例24:(R)/(S)-2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)丁酰胺盐酸盐(29)的制备
利用反应式f,将化合物22(1.06g,2.50mmol)及4.0M的HCl(3.80ml,15.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物29,(R)/(S)-2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)丁酰胺盐酸盐(0.87g,97%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(CDCl3,400MHz)11.05(s,C(O)NH),8.38(s,NH3),7.93(d,J=1.9Hz,ArH),7.66-7.79(m,ArH),4.01-4.04(m,Chiral-H),1.86-1.91(m,CH2CH3),0.96(t,J=7.5Hz,CH2CH3)。
制备例25:(R)/(S)-2-氨基-N-(3',4'-二氯-[1,1'-联苯]-4-基)戊酰胺盐酸盐(30)的制备
利用反应式f,将化合物23(0.58g,1.33mmol)及4.0M的HCl(2.00ml,7.95mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物30,(R)/(S)-2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)戊酰胺盐酸盐(0.40g,81%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)11.05(s,C(O)NH),8.40(s,NH3),7.93(d,J=1.5Hz,ArH),7.66-7.79(m,ArH),4.06(s,Chiral-H),1.79-1.85(m,CH2CH2CH3),1.36-1.43(m,CH2CH2CH3),0.91(t,J=7.3Hz,CH2CH2CH3)。
制备例26:(R)/(S)-2-氨基-N-(3',4'-二氯-[1,1'-联苯]-4-基)己酰胺盐酸盐(31)的制备
利用反应式f,将化合物24(1.10g,2.44mmol)及4.0M的HCl(3.66ml,14.6mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物31,(R)/(S)-2-氨基-N-(3’,4’-二氯-[1,1’-联苯]-4-基)己酰胺盐酸盐(0.81g,86%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)10.97(s,C(O)NH),8.38(s,NH3),7.93(d,J=2.0Hz,ArH),7.66-7.78(m,ArH),4.03(s,Chiral-H),1.81-1.87(m,CH2CH2CH2CH3),1.33-1.39(m,CH2CH2CH2CH3),0.87(t,J=6.9Hz,CH2CH2CH2CH3)。
制备例27:(R)/(S)-2-氨基-N-(4’-(三氟甲氧基)-[1,1'-联苯]-4-基)戊酰胺盐酸盐(32)的制备
利用反应式f,将化合物25(0.64g,1.41mmol)及4.0M的HCl(2.12ml,8.46mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物32,(R)/(S)-2-氨基-N-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)戊酰胺盐酸盐(0.51g,93%)
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)10.90(s,C(O)NH),8.35(s,NH3),7.76-7.79(m,ArH),7.70(d,J=8.8Hz,ArH),7.45(d,J=8.2Hz,ArH),4.03(s,Chiral-H),1.82(q,J=6.9Hz,7.9Hz,CH2CH2CH3),1.34-1.47(m,CH2CH2CH3),0.92(t,J=7.3Hz,CH2CH2CH3)。
制备例28:(R)/(S)-N-(3',4'-二氯-[1,1'-联苯]-4-基)-2-(甲氨基)丁酰胺盐酸盐(33)的制备
利用反应式f,将化合物26(0.69g,1.58mmol)及4.0M的HCl(2.40ml,9.50mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物33,(R)/(S)-N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)丁酰胺盐酸盐(0.55g,93%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)11.00(s,C(O)NH),9.13(s,NH2),7.94(d,J=1.7Hz,ArH),7.66-7.78(m,ArH),3.96(t,J=5.5Hz,Chiral-H),2.57(s,NCH3),1.87-2.05(m,CH2CH3),0.94(t,J=7.5Hz,CH2CH3)。
制备例29:(R)/(S)-N-(3',4'-二氯-[1,1'-联苯]-4-基)-2-(甲氨基)戊酰胺盐酸盐(34)的制备
利用反应式f,将化合物27(0.38g,0.83mmol)及4.0M的HCl(1.25ml,4.98mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物34,(R)/(S)-N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)戊酰胺盐酸盐(0.23g,71%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)10.98(s,C(O)NH),9.09(s,NH2),7.94(s,ArH),7.66-7.76(m,ArH),3.96(t,J=6.1Hz,Chiral-H),2.57(s,NCH3),1.80-1.93(m,CH2CH2CH3),1.31-1.39(m,CH2CH2CH3),0.91(t,J=7.3Hz,CH2CH2CH3)。
制备例30:(R)/(S)-N-(3',4'-二氯-[1,1'-联苯]-4-基)-2-(甲氨基)己酰胺盐酸盐(35)的制备
利用反应式f,将化合物28(0.82g,1.77mmol)及4.0M的HCl(2.65ml,10.6mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物35,(R)/(S)-N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(甲氨基)己酰胺盐酸盐(0.60g,84%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)10.81(s,C(O)NH),9.05(s,NH2),7.94(d,J=2.0Hz,ArH),7.66-7.77(m,ArH),3.92(s,Chiral-H),2.57(s,NCH3),1.87-1.99(m,CH2CH2CH2CH3),1.29-1.33(m,CH2CH2CH2CH3),0.86(t,J=6.8Hz,CH2CH2CH2CH3)。
制备例31:(R)/(S)-N-(3',4'-二氯-[1,1'-联苯]-4-基)-2-(二甲氨基)戊酰胺(36)的制备
利用反应式g,将化合物30(1.0当量)、三乙胺(6.0当量)、甲醛(2.0当量)、钯催化剂(0.4当量)反应合成化合物36,(R)/(S)-N-(3’,4’-二氯-[1,1’-联苯]-4-基)-2-(二甲氨基)戊酰胺。
1H NMR(DMSO-d6,400MHz)10.98(s,C(O)NH),7.94(s,ArH),7.66-7.76(m,ArH),3.96(t,J=6.1Hz,Chiral-H),2.57(s,N(CH3)2),1.80-1.93(m,CH2CH2CH3),1.31-1.39(m,CH2CH2CH3),0.91(t,J=7.3Hz,CH2CH2CH3)。
制备例32:(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(37)的制备
利用反应式e,将化合物5(0.57g,2.64mmol)、NMM(0.73ml,6.60mmol)、IBCF(0.45ml,3.43mmol)及化合物15(0.80g,2.77mmol)反应合成白色粉末状的化合物37,(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(1.20g,100%)。
Rf=0.04(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.64(d,J=2.0Hz,ArH),7.49(dd,J=2.6Hz,8.5Hz,ArH),7.33-7.40(m,ArH),6.48(s,C(O)NH),4.93(s,Boc-NH),4.49(d,J=4.2Hz,NHCH2),4.07-4.09(m,Chiral-H),1.36-1.43(m,CH2CH2CH3,Boc),0.95(t,J=7.3Hz,CH2CH2CH3)。
制备例33:(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(38)的制备
利用反应式e,将化合物6(0.38g,1.65mmol)、NMM(0.45ml,4.13mmol)、IBCF(0.28ml,2.15mmol)及化合物15(0.50g,1.74mmol)反应合成白色粉末状的化合物38,(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(0.46g,60%)。
Rf=0.19(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.63(d,J=2.0Hz,ArH),7.49(dd,J=4.3Hz,8.2Hz,ArH),7.33-7.39(m,ArH),6.55(s,C(O)NH),4.98(d,J=3.8Hz,Boc-NH),4.49(d,J=5.5Hz,NHCH2),4.07-4.11(m,Chiral-H),1.58-1.90(m,CH2CH2CH2CH3),1.42(s,Boc),1.34(d,J=2.2Hz,CH2CH2CH2CH3),0.88-0.94(m,CH2CH2CH2CH3)。
制备例34:(R)/(S)-(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(39)的制备
利用反应式e,将化合物5(0.36g,1.66mmol)、NMM(0.46ml,4.14mmol)、IBCF((0.28ml,2.15mmol)及化合物16(0.50g,1.74mmol)反应合成白色粉末状的化合物39,(R)/(S)-(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(0.72g,96%)。
Rf=0.17(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,300MHz)7.62-7.70(m,ArH),7.44(dd,J=8.1Hz,44.7Hz,ArH),6.85(s,C(O)NH),5.16-5.18(m,Boc-NH),4.47-4.49(m,ArCH2),4.11-4.15(m,Chiral-H),1.54-1.89(m,CH2CH2CH3),1.41(s,Boc,CH2CH2CH3),0.93(t,J=7.2Hz,CH2CH2CH3)。
制备例35:(R)/(S)-(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)己-2-基)氨基甲酸叔丁酯(40)的制备
利用反应式e,将化合物6(0.54g,2.32mmol)、NMM(0.71g,6.49mmol)、IBCF(0.39ml,3.01mmol)及化合物16(0.70g,2.43mmol)反应合成白色粉末状的化合物40,(R)/(S)-(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)己-2-基)氨基甲酸叔丁酯(0.87g,81%)。
Rf=0.16(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.70(q,J=4.6Hz,8.6Hz,ArH),7.57(d,J=8.2Hz,ArH),7.39(d,J=8.2Hz,ArH),6.50(s,C(O)NH),4.96(s,Boc-NH),4.53(d,J=4.7Hz,NHCH2),4.09-4.10(m,Chiral-H),1.59-1.94(m,CH2CH2CH2CH3),1.45(s,Boc),1.37-1.38(m,CH2CH2CH2CH3),0.93(t,J=7.0Hz,CH2CH2CH2CH3)。
制备例36:(R)/(S)-(1-氧代-1(((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(41)的制备
利用反应式e,将化合物5(0.55g,2.51mmol)、NMM(0.77ml,7.02mmol)、IBCF(0.42ml,3.26mmol)及化合物17(0.80g,2.63mmol)反应合成白色粉末状的化合物41,(R)/(S)-(1-氧代-1(((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(1.05g,90%)。
Rf=0.09(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.57-7.61(m,ArH),7.53(d,J=8.2Hz,ArH),7.37(d,J=8.2Hz,ArH),7.30(d,J=8.2Hz,ArH),6.47(s,C(O)NH),4.96(s,Boc-NH),4.52(s,NHCH2),4.10-4.11(m,Chiral-H),1.59-1.94(m,CH2CH2CH3),1.37-1.45(m,CH2CH2CH3,Boc),0.97(t,J=7.3Hz,CH2CH2CH3)。
制备例37:(R)/(S)-(1-氧代-1(((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)氨基)己-2-基)氨基甲酸叔丁酯(42)的制备
利用反应式e,将化合物6(0.58g,2.51mmol)、NMM(0.77ml,7.02mmol)、IBCF(0.42ml,3.26mmol)及化合物17(0.80g,2.63mmol)反应合成白色粉末状的化合物42,(R)/(S)-(1-氧代-1(((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)氨基)己-2-基)氨基甲酸叔丁酯(1.06g,88%)。
Rf=0.18(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.58-7.61(m,ArH),7.53(d,J=8.1Hz,ArH),7.37(d,J=8.1Hz,ArH),7.30(d,J=8.5Hz,ArH),6.52(s,C(O)NH),4.99(s,Boc-NH),4.53(d,J=5.1Hz,NHCH2),4.09-4.11(m,Chiral-H),1.62-1.94(m,CH2CH2CH2CH3),1.45(s,Boc),1.36-1.37(m,CH2CH2CH2CH3),0.92(t,J=6.9Hz,CH2CH2CH2CH3)。
制备例38:(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(43)的制备
利用反应式e,将化合物8(0.38g,1.65mmol)、NMM(0.46ml,4.13mmol)、IBCF(0.28ml,2.15mmol)及化合物15(0.50g,1.73mmol)反应合成油状的化合物43,(R)/(S)-(1-(((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(0.57g,73%)。
Rf=0.18(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,300MHz)7.30-7.68(m,ArH),6.27-6.64(m,C(O)NH),4.41-4.59(m,NHCH2,Chrial-H),2.78(s,NCH3),2.04-1.63(m,CH2CH2CH3),1.44(s,Boc),1.32-1.26(m,CH2CH2CH3),0.96(t,J=7.3Hz,CH2CH2CH3)。
制备例39:(R)/(S)-甲基(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(44)的制备
利用反应式e,将化合物8(0.38g,1.66mmol)、NMM(0.46ml,4.14mmol)、IBCF(0.28ml,2.15mmol)及化合物16(0.50g,1.74mmol)反应合成油状的化合物44,(R)/(S)-甲基(1-氧代-1(((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)氨基)戊-2-基)氨基甲酸叔丁酯(0.49g,64%)。
Rf=0.22(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,300MHz)7.64-7.71(m,ArH),7.44(dd,J=7.9Hz,53.4Hz,ArH),6.28-6.64(m,C(O)NH),4.43-4.61(m,NHCH2,Chiral-H),2.78(s,NCH3),1.63-2.04(m,CH2CH2CH3),1.44(s,Boc),1.26-1.35(m,CH2CH2CH3),0.96(t,J=7.3Hz,CH2CH2CH3)。
制备例40:(R)/(S)-2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)戊酰胺盐酸盐(45)的制备
利用反应式f,将化合物37(1.19g,2.64mmol)及4.0M的HCl(3.95ml,15.8mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物45,(R)/(S)-2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)戊酰胺盐酸盐(0.73g,71%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,300MHz)9.04(s,C(O)NH),8.21(s,NH3),7.94(s,ArH),7.66-7.73(m,ArH),7.40(d,J=8.1Hz,ArH),4.39-4.41(m,NHCH2),3.78-3.82(t,J=6.3Hz,Chiral-H),1.68-1.76(m,CH2CH2CH3),1.29-1.39(m,CH2CH2CH3),0.89(t,J=7.2Hz,CH2CH2CH3)。
制备例41:(R)/(S)-2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)己酰胺盐酸盐(46)的制备
利用反应式f,将化合物38(0.46g,0.99mmol)及4.0M的HCl(1.48ml,1.48mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物46,(R)/(S)-2-氨基-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)己酰胺盐酸盐(0.27g,85%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.17(m,C(O)NH),8.32(s,NH3),7.94(d,J=2.0Hz,ArH),7.66-7.73(m,ArH),7.41(d,J=8.2Hz,ArH),4.34-4.45(m,NHCH2),3.81(t,J=6.1Hz,Chiral-H),1.75-1.76(m,CH2CH2CH2CH3),1.27-1.28(m,CH2CH2CH2CH3),0.85(t,J=6.6Hz,CH2CH2CH2CH3)。
制备例42:(R)/(S)-2-氨基-N-((4’-(三氟甲基)-[1,1'-联苯]-4-基)甲基)戊酰胺盐酸盐(47)的制备
利用反应式f,将化合物39(0.70g,1.55mmol)及4.0M的HCl(2.33ml,9.32mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物47,(R)/(S)-2-氨基-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)戊酰胺盐酸盐(0.60g,99%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,300MHz)9.37(t,J=5.7Hz,C(O)NH),8.46(s,NH3),7.71-7.92(m,ArH),7.45-7.51(m,ArH),4.40-4.43(m,NHCH2),3.89(s,Chiral-H),1.74-1.82(m,CH2CH2CH3),1.16-1.42(m,CH2CH2CH3),0.89(t,J=7.2Hz,CH2CH2CH3)。
制备例43:(R)/(S)-2-氨基-N-((4’-(三氟甲基)-[1,1'-联苯]-4-基)甲基)己酰胺盐酸盐(48)的制备
利用反应式f,将化合物40(0.85g,1.83mmol)及4.0M的HCl(2.75ml,11.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物48,(R)/(S)-2-氨基-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)己酰胺盐酸盐(0.72g,98%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.09(s,C(O)NH),8.23(s,NH3),7.89(d,J=8.2Hz,ArH),7.82(d,J=8.4Hz,ArH),7.73(d,J=8.1Hz,ArH),7.44(d,J=8.1Hz,ArH),4.36-4.46(m,NHCH2),3.80(t,J=6.4Hz,Chiral-H),1.74-1.76(m,CH2CH2CH2CH3),1.27-1.29(m,CH2CH2CH2CH3),0.85(t,J=6.5Hz,CH2CH2CH2CH3)。
制备例44:(R)/(S)-2-氨基-N-((4’-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)戊酰胺盐酸盐(49)的制备
利用反应式f,将化合物41(1.04g,2.22mmol)及4.0M的HCl(3.34ml,13.3mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物49,(R)/(S)-2-氨基-N-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)戊酰胺盐酸盐(0.82g,92%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.14(t,J=5.7Hz,C(O)NH),8.30(s,NH3),7.77-7.81(m,ArH),7.67(d,J=8.2Hz,ArH),7.46(d,J=8.1Hz,ArH),7.41(d,J=8.2Hz,ArH),4.40(d,J=5.8Hz,NHCH2),3.82(t,J=6.5Hz,Chiral-H),1.71-1.76(m,CH2CH2CH3),1.28-1.38(m,CH2CH2CH3),0.89(t,J=7.3Hz,CH2CH2CH3)。
制备例45:(R)/(S)-2-氨基-N-((4’-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)己酰胺盐酸盐(50)的制备
利用反应式f,将化合物42(1.04g,2.17mmol)及4.0M的HCl(3.26ml,13.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物50,(R)/(S)-2-氨基-N-((4'-(三氟甲氧基)-[1,1'-联苯]-4-基)甲基)己酰胺盐酸盐(0.88g,97%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.09(t,J=5.8Hz,C(O)NH),8.25(s,NH3),7.78(d,J=8.7Hz,ArH),7.66(d,J=8.2Hz,ArH),7.45(d,J=8.3Hz,ArH),7.41(d,J=8.2Hz,ArH),4.35-4.44(m,NHCH2),3.80(t,J=6.4Hz,Chiral-H),1.72-1.75(m,CH2CH2CH2CH3),1.27-1.28(m,CH2CH2CH2CH3),0.85(t,J=6.5Hz,CH2CH2CH2CH3)。
制备例46:(R)/(S)-N-((3',4'-二氯-[1,1'-联苯]-4-基)甲基)-2-(甲氨基)戊酰胺盐酸盐(51)的制备
利用反应式f,将化合物43(0.84g,1.81mmol)及4.0M的HCl(2.80ml,10.9mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物51,(R)/(S)-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)-2-(甲氨基)戊酰胺盐酸盐(0.64g,88%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,300MHz)9.10-9.78(m,NH2),9.57(t,J=5.5Hz,C(O)NH),7.96(s,ArH),7.69-7.72(m,ArH),7.43(d,J=10.7Hz,ArH),4.42-4.44(m,NHCH2),3.85-3.90(m,Chiral-H),2.48(s,NCH3),1.76-1.90(m,CH2CH2CH3),1.26-1.38(m,CH2CH2CH3),0.90(t,J=7.1Hz,CH2CH2CH3)。
制备例47:(R)/(S)-2-(甲氨基)-N-((4’-(三氟甲基)-[1,1'-联苯]-4-基)甲基)戊酰胺盐酸盐(52)的制备
利用反应式f,将化合物44(0.45g,0.97mmol)及4.0M的HCl(1.45ml,5.81mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物52,(R)/(S)-2-(甲氨基)-N-((4’-(三氟甲基)-[1,1’-联苯]-4-基)甲基)戊酰胺盐酸盐(0.32g,82%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,300MHz)9.03-9.81(m,NH2),9.52(t,J=5.5Hz,C(O)NH),7.72-7.92(m,ArH),7.46(d,J=8.2Hz,ArH),4.43-4.45(m,NHCH2),3.86(s,Chiral-H),2.48(s,NCH3),1.77-1.89(m,CH2CH2CH3),1.25-1.38(m,CH2CH2CH3),0.90(t,J=7.2Hz,CH2CH2CH3)。
制备例48:(R)/(S)-N-((3',4'-二氯-[1,1'-联苯]-4-基)甲基)-2-(二甲氨基)戊酰胺(53)的制备
利用反应式g,将化合物45(1.0当量)、三乙胺(6.0当量)、甲醛(1.05当量)及钯催化剂(0.2当量)反应合成化合物53,(R)/(S)-N-((3’,4’-二氯-[1,1’-联苯]-4-基)甲基)-2-(二甲氨基)戊酰胺。
1H NMR(DMSO-d6,300MHz)9.57(t,J=5.5Hz,C(O)NH),7.96(s,ArH),7.69-7.72(m,ArH),7.43(d,J=10.7Hz,ArH),4.42-4.44(m,NHCH2),3.85-3.90(m,Chiral-H),2.48(s,N(CH3)2),1.76-1.90(m,CH2CH2CH3),1.26-1.38(m,CH2CH2CH3),0.90(t,J=7.1Hz,CH2CH2CH3)。
制备例49:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代丁-2-基)氨基甲酸叔丁酯(54)的制备
利用反应式e,将化合物4(0.32g,1.57mmol)、NMM(0.43ml,3.93mmol)、IBCF(0.27ml,2.05mmol)及化合物18(0.50g,1.65mmol)反应合成白色粉末状的化合物54,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代丁-2-基)氨基甲酸叔丁酯(0.66g,93%)。
Rf=0.05(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.65(s,ArH),7.47-7.50(m,ArH),7.39(d,J=8.2Hz,ArH),7.26-7.28(m,ArH),6.07(s,C(O)NH),4.94(s,Boc-NH),3.93(d,J=6.6Hz,Chiral-H),3.50-3.94(m,NHCH2CH2),2.86(t,J=6.9Hz,NHCH2CH2),1.55-2.88(m,CH2CH3),1.43(s,Boc),0.91(t,J=7.4Hz,CH2CH3)。
制备例50:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(55)的制备
利用反应式e,将化合物5(0.50g,2.30mmol)、NMM(0.51ml,4.60mmol)、IBCF(0.39ml,2.99mmol)及化合物18(0.73g,2.42mmol)反应合成白色粉末状的化合物55,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(0.96g,89%)。
Rf=0.26(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.46-7.64(m,ArH),7.26-7.40(m,ArH),6.36(s,C(O)NH),5.07(s,Boc-NH),4.01-4.03(m,Chiral-H),3.47-3.61(m,NHCH2CH2),2.85(t,J=7.0Hz,NHCH2CH2),2.67(s,NCH3),1.48-1.80(m,CH2CH2CH3),1.42(s,Boc),1.26-1.36(m,CH2CH2CH3),0.90(t,J=7.2Hz,CH2CH2CH3)。
制备例51:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(56)的制备
利用反应式e,将化合物6(0.36g,1.57mmol)、NMM(0.43ml,3.93mmol)、IBCF(0.27g,2.05mmol)及化合物18(0.50g,16.5mmol)反应合成白色粉末状的化合物56,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代己-2-基)氨基甲酸叔丁酯(0.76g,100%)。
Rf=0.07(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.65(s,ArH),7.48(d,J=6.3Hz,ArH),7.39(d,J=8.0Hz,ArH),7.26-7.28(m,ArH),6.07(s,C(O)NH),4.91(s,Boc-NH),3.97(d,J=5.6Hz,Chiral-H),3.51-3.62(m,NHCH2CH2),2.86(t,J=6.1Hz,NHCH2CH2),1.51-1.81(m,CH2CH2CH2CH3),1.42(s,Boc),1.27(d,J=6.7Hz,CH2CH2CH2CH3),0.87(d,J=5.5Hz,CH2CH2CH2CH3)。
制备例52:(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁酯(57)的制备
利用反应式e,将化合物4(0.42g,2.08mmol)、NMM(0.57ml,5.21mmol)、IBCF(0.35ml,2.71mmol)及化合物19(0.66g,2.19mmol)反应合成白色粉末状的化合物57,(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁酯(0.92g,98%)。
Rf=0.16(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.70(s,ArH),7.57(d,J=8.0Hz,ArH),7.29-7.33(m,ArH),6.15(s,C(O)NH),5.00(s,Boc-NH),3.94-3.99(m,Chiral-H),3.53-3.66(m,NHCH2CH2),2.90(t,J=7.0Hz,NHCH2CH2),1.58-1.90(m,CH2CH3),1.45(s,Boc),0.93(t,J=7.5Hz,CH2CH3)。
制备例53:(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁酯(58)的制备
利用反应式e,将化合物5(0.55g,2.53mmol)、NMM(0.69ml,6.31mmol)、IBCF(0.43ml,3.28mmol)及化合物19(0.80g,2.65mmol)反应合成白色粉末状的化合物58,(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁酯(1.05g,89%)。
Rf=0.20(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,300MHz)7.67(s,ArH),7.41(dd,J=8.1Hz,63.6Hz,ArH),6.36(s,C(O)NH),5.05-5.07(m,Boc-NH),4.00-4.05(m,Chiral-H),3.45-3.66(m,NHCH2CH2),2.87(t,J=7.1Hz,NHCH2CH2),1.50-1.83(m,CH2CH2CH3),1.42(s,Boc),1.28-1.39(m,CH2CH2CH3),0.90(t,J=7.2Hz,CH2CH2CH3)。
制备例54:(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)氨基甲酸叔丁酯(59)的制备
利用反应式e,将化合物6(0.76g,3.16mmol)、NMM(0.87ml,7.89mmol)、IBCF(0.53ml,4.10mmol)及化合物19(1.00g,3.31mmol)反应合成白色粉末状的化合物59,(R)/(S)-(1-氧代-1-((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)氨基甲酸叔丁酯(1.34g,89%)。
Rf=0.13(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.87(d,J=8.2Hz,ArH,C(O)NH),7.80(d,J=8.5Hz,ArH),7.66(d,J=8.1Hz,ArH),7.35(d,J=8.1Hz,ArH),6.73(d,J=8.2Hz,Boc-NH),3.83(q,J=5.6Hz,8.4Hz,Chiral-H),3.24-3.43(m,NHCH2CH2),2.77(t,J=7.0Hz,NHCH2CH2),1.37-1.52(m,CH2CH2CH2CH3,Boc),1.15-1.20(m,CH2CH2CH2CH3),0.80(t,J=6.8Hz,CH2CH2CH2CH3)。
制备例55:(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁酯(60)的制备
利用反应式e,将化合物4(0.49g,2.40mmol)、NMM(0.66ml,6.00mmol)、IBCF(0.41ml,3.12mmol)及化合物20(0.80g,2.52mmol)反应合成白色粉末状的化合物60,(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁酯(0.94g,84%)。
Rf=0.14(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.68-7.73(m,ArH),7.51-7.62(m,ArH),7.29-7.33(m,ArH),6.17(d,J=5.6Hz,C(O)NH),5.01(s,NH),3.95-3.98(m,Chiral-H),3.51-3.67(m,NHCH2CH2),2.87-2.92(m,NHCH2CH2),1.56-1.92(m,CH2CH3),1.45(s,Boc),0.93(t,J=7.4Hz,CH2CH3)。
制备例56:(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁酯(61)的制备
利用反应式e,将化合物5(0.33g,1.50mmol)、NMM(0.41ml,3.75mmol)、IBCF(0.25ml,1.95mmol)及化合物20(0.50g,1.57mmol)反应合成白色粉末状的化合物61,(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁酯(0.70g,98%)。
Rf=0.12(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.88(t,J=5.6Hz,C(O)NH),7.74-7.77(m,ArH),7.59(d,J=8.2Hz,ArH),7.44(d,J=8.1Hz,ArH),7.32(d,J=8.2Hz,ArH),6.74(d,J=8.2Hz,Boc-NH),4.86(q,J=5.6Hz,8.2Hz,Chiral-H),3.26-3.40(m,NHCH2CH2),2.76(t,J=7.0Hz,NHCH2CH2),1.37-1.52(m,CH2CH2CH3,Boc),1.17-1.25(m,CH2CH2CH3),0.81(t,J=7.3Hz,CH2CH2CH3)。
制备例57:(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁酯(62)的制备
利用反应式e,将化合物6(0.50g,2.18mmol)、NMM(0.60ml,5.45mmol)、IBCF(0.37ml,2.83mmol)及化合物20(0.72g,2.29mmol)反应合成白色粉末状的化合物62,(R)/(S)-(1-氧代-1-((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁酯(0.95g,88%)。
Rf=0.13(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.70-7.73(m,ArH),7.57(d,J=8.1Hz,ArH),7.32(d,J=8.1Hz,ArH),6.15(s,C(O)NH),4.95(s,Boc-NH),4.00(q,J=6.4Hz,7.2Hz,Chiral-H),3.53-3.65(m,NHCH2CH2),2.90(t,J=7.0Hz,NHCH2CH2),1.52-1.85(m,CH2CH2CH2CH3),1.45(s,Boc),1.31-1.34(m,CH2CH2CH2CH3),0.90(t,J=6.9Hz,CH2CH2CH2CH3)。
制备例58:(R)/(S)-(1-((2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(63)的制备
利用反应式e,将化合物5(0.50g,2.29mmol)、NMM(0.70ml,6.40mmol)、IBCF(0.39ml,2.97mmol)及化合物21(0.80g,2.40mmol)反应合成白色粉末状的化合物63,(R)/(S)-(1-((2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)氨基甲酸叔丁酯(0.97g,98%)。
Rf=0.10(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.46(d,J=7.9Hz,ArH),7.33-7.38(m,ArH),7.17-7.27(m,ArH),6.11(s,C(O)NH),4.92(s,Boc-NH),3.96-4.01(m,Chiral-H),3.47-3.63(m,NHCH2CH2),2.85(t,J=7.0Hz,NHCH2CH2),1.48-1.82(m,CH2CH2CH3),1.42(s,Boc),1.26-1.36(m,CH2CH2CH3),0.90(t,J=7.3Hz,CH2CH2CH3)。
制备例59:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代丁-2-基)(甲基)氨基甲酸叔丁酯(64)的制备
利用反应式e,将化合物7(0.82g,3.78mmol)、NMM(1.04ml,9.44mmol)、IBCF(0.64ml,4.91mmol)及化合物18(1.20g,3.97mmol)反应合成油状的化合物64,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代丁-2-基)(甲基)氨基甲酸叔丁酯(1.38g,79%)。
Rf=0.22(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.66(d,J=2.0Hz,ArH),7.49-7.53(m,ArH),7.41(dd,J=2.1Hz,6.3Hz,ArH),7.27-7.29(m ArH),6.26(s,C(O)NH),4.44(s,Chiral-H),3.55-3.64(m,NHCH2CH2),2.87(t,J=6.7Hz,NHCH2CH2),2.70(s,NCH3),1.61-1.98(m,CH2CH3),1.45(s,Boc),0.88(t,J=7.4Hz,CH2CH3)。
制备例60:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(65)的制备
利用反应式e,将化合物8(0.35g,1.51mmol)、NMM((0.33ml,3.03mmol)、IBCF(0.26ml,1.97mmol)及化合物18(0.48g,1.59mmol)反应合成油状的化合物65,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代戊-2-基)(甲基)氨基甲酸叔丁酯(0.69g,95%)。
Rf=0.33(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.46-7.64(m,ArH),7.35-7.40(m,ArH),7.25-7.27(m,ArH),5.95-6.25(m,C(O)NH),4.51(s,Chiral-H),3.53-3.60(m,NHCH2CH2),2.84(t,J=6.6Hz,NHCH2CH2),2.67(s,NCH3),1.57-1.90(m,CH2CH2CH3),1.42(s,Boc),1.22-1.32(m,CH2CH2CH3),0.95(t,J=7.3Hz,CH2CH2CH3)。
制备例61:(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代己-2-基)(甲基)氨基甲酸叔丁酯(66)的制备
利用反应式e,将化合物9(0.29g,1.20mmol)、NMM(0.33ml,2.99mmol)、IBCF(0.20ml,0.16mmol)及化合物18(0.38g,1.26mmol)反应合成油状的化合物66,(R)/(S)-(1-((2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)氨基)-1-氧代己-2-基)(甲基)氨基甲酸叔丁酯(0.60g,97%)。
Rf=0.30(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.89(d,J=1.9Hz,ArH,C(O)NH),7.62-7.71(m,ArH),7.30(d,J=8.1Hz,ArH),4.27-4.47(m,Chiral-H),3.32-3.35(m,NHCH2CH2),2.77(t,J=6.5Hz,NHCH2CH2),2.67(s,NCH3),1.53-1.71(m,CH2CH2CH2CH3),1.39(s,Boc),1.12-1.28(m,CH2CH2CH2CH3),0.84(s,CH2CH2CH2CH3)。
制备例62:(R)/(S)-(1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁基甲酯(67)的制备
利用反应式e,将化合物7(0.62g,2.84mmol)、NMM(0.87ml,7.95mmol)、IBCF(0.48ml,3.69mmol)及化合物19(0.90g,2.98mmol)反应合成白色粉末状的化合物67,(R)/(S)-(1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁基甲酯(0.89g,67%)。
Rf=0.15(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.70(t,J=9.7Hz,ArH),7.56(d,J=7.9Hz,ArH),7.28-7.32(m,ArH),5.94-6.22(m,C(O)NH),4.45(s,Chiral-H),3.57-3.64(m,NHCH2CH2),2.89(d,J=6.1Hz,NHCH2CH2),2.70(s,NCH3),1.61-1.99(m,CH2CH3),1.45(s,Boc),0.89(t,J=7.3Hz,CH2CH3)。
制备例63:(R)/(S)-(1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁基甲酯(68)的制备
利用反应式e,将化合物8(0.58g,2.53mmol)、NMM(0.69ml,6.31mmol)、IBCF(0.43ml,3.28mmol)及化合物19(0.80g,2.65mmol)反应合成油状的化合物68,(R)/(S)-(1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁基甲酯(1.19g,98%)。
Rf=0.26(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,300MHz)7.64-7.70(m,ArH),7.41(dd,J=8.1Hz,67.4Hz,ArH),5.95-6.21(s,C(O)NH),4.52(s,Chiral-H),3.54-3.63(m,NHCH2CH2),2.86(t,J=6.8Hz,NHCH2CH2),2.67(s,NCH3),1.55-1.91(m,CH2CH2CH3),1.42(s,Boc),1.23-1.27(m,CH2CH2CH3),0.88-0.95(m,CH2CH2CH3)。
制备例64:(R)/(S)-((1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁基甲酯(69)的制备
利用反应式e,将化合物9(0.70g,2.84mmol)、NMM(0.87ml,7.95mmol)、IBCF(0.48ml,3.69mmol)及化合物19(0.90g,2.98mmol)反应合成黄色粉末状的化合物69,(R)/(S)-((1-氧代-1((2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁基甲酯(0.88g,63%)。
Rf=0.32(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.87(d,J=8.3Hz,ArH,C(O)NH),7.80(d,J=8.4Hz,ArH),7.66(d,J=8.2Hz,ArH),7.33(d,J=8.1Hz,ArH),4.27-4.47(m,Chiral-H),3.32-3.33(m,NHCH2CH2),2.78(t,J=6.8Hz,NHCH2CH2),2.66(s,NCH3),1.53-1.71(m,CH2CH2CH2CH3),1.39(s,Boc),1.12-1.28(m,CH2CH2CH2CH3),0.84-0.89(m,CH2CH2CH2CH3)。
制备例65:(R)/(S)-(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁基甲酯(70)的制备
利用反应式e,将化合物7(0.65g,3.00mmol)、NMM(0.92ml,8.99mmol)、IBCF(0.51ml,3.90mmol)及化合物20(1.00g,3.15mmol)反应合成油状的化合物70,(R)/(S)-(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)丁-2-基)氨基甲酸叔丁基甲酯(1.00g,69%)。
Rf=0.19(EtOAc 1:正己烷(n-hexane)3);
1H NMR(CDCl3,400MHz)7.51-7.70(m,ArH),7.29(t,J=3.7Hz,ArH),5.98-6.26(m,C(O)NH),4.45(s,Chiral-H),3.59-3.60(m,NHCH2CH2),2.87(s,NHCH2CH2),2.70(d,J=3.2Hz,NCH3),1.62-2.07(m,CH2CH3),1.45(s,Boc),0.90(m,CH2CH3)。
制备例66:(R)/(S)-(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁基甲酯(71)的制备
利用反应式e,将化合物8(0.25g,1.08mmol)、NMM(0.30ml,2.69mmol)、IBCF(0.18ml,1.40mmol)及化合物20(0.36g,1.13mmol)反应合成白色粉末状的化合物71,(R)/(S)-(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)戊-2-基)氨基甲酸叔丁基甲酯(0.32g,60%)。
Rf=0.18(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.89(s,C(O)NH),7.76(d,J=8.4Hz,ArH),7.59(d,J=7.8Hz,ArH),7.44(d,J=8.2Hz,ArH),7.30(d,J=7.8Hz,ArH),4.30-4.49(m,Chiral-H),3.28-3.40(m,NHCH2CH2),2.77(s,NHCH2CH2),2.66(s,NCH3),1.53-1.90(m,CH2CH2CH3),1.39(s,Boc),1.16-1.23(m,CH2CH2CH3),0.88-0.89(m,CH2CH2CH3)
制备例67:(R)/(S)-(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁基甲酯(72)的制备
利用反应式e,将化合物9(0.74g,3.00mmol)、NMM(0.92ml,8.99mmol)、IBCF(0.51ml,3.90mmol)及化合物20(1.00g,3.15mmol)反应合成油状的化合物72,(R)/(S)-甲(1-氧代-1((2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)氨基)己-2-基)氨基甲酸叔丁基甲酯(0.92g,60%)。
Rf=0.29(EtOAc 1:正己烷(n-hexane)3);
1H NMR(DMSO-d6,400MHz)7.88(s,C(O)NH),7.74-7.77(m,ArH),7.59(d,J=8.2Hz,ArH),7.44(d,J=8.0Hz,ArH),7.30(d,J=8.1Hz,ArH),4.28-4.47(m,Chiral-H),3.30-3.34(m,NHCH2CH2),2.77(t,J=6.7Hz,NHCH2CH2),2.66(s,NCH3),1.53-1.72(m,CH2CH2CH2CH3),1.39(s,Boc),1.12-1.29(m,CH2CH2CH2CH3),0.84-0.90(m,CH2CH2CH2CH3)。
制备例68:(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(73)的制备
利用反应式f,将化合物54(0.66g,1.47mmol)及4.0M的HCl(2.20ml,8.81mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物73,(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(0.52g,91%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.66(t,J=5.3Hz,C(O)NH),8.23(s,NH3),7.92(d,J=1.9Hz,ArH),7.65-7.72(m,ArH),7.35(d,J=8.1Hz,ArH),3.67(t,J=6.0Hz,Chiral-H),3.31-3.55(m,NHCH2CH2),2.79-2.83(m,NHCH2CH2),1.67-1.74(m,CH2CH3),0.79(t,J=7.4Hz,CH2CH3)。
制备例69:(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(74)的制备
利用反应式f,将化合物55(0.95g,2.04mmol)及4.0M的HCl(3.06ml,12.2mmol在二恶烷中(in dioxane))反应合成黄色粉末状的化合物74,(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(0.66g,80%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.82(t,J=5.3Hz,C(O)NH),8.34(s,NH3),7.64-7.90(m,ArH),7.35-7.38(d,J=8.1Hz,ArH),3.73(t,J=6.3Hz,Chiral-H),3.29-3.57(m,NHCH2CH2),2.82-2.85(m,NHCH2CH2),1.60-1.67(m,CH2CH2CH3),1.14-1.22(m,CH2CH2CH3),0.80(t,J=7.1Hz,CH2CH2CH3)。
制备例70:(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)己酰胺
盐酸盐(75)的制备
利用反应式f,将化合物56(0.75g,1.56mmol)及4.0M的HCl(2.35ml,9.39mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物75,(R)/(S)-2-氨基-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)己酰胺盐酸盐(0.60g,92%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.60(t,J=5.5Hz,C(O)NH),8.18(s,NH3),7.91(d,J=2.0Hz,ArH),7.65-7.72(m,ArH),7.35(d,J=8.2Hz,ArH),3.66(t,J=6.2Hz,Chiral-H),3.28-3.58(m,NHCH2CH2),2.81-2.85(m,NHCH2CH2),1.59-1.64(m,CH2CH2CH2CH3),1.14-1.23(m,CH2CH2CH2CH3),0.79(t,J=6.8Hz,CH2CH2CH2CH3)。
制备例71:(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(76)的制备
利用反应式f,将化合物57(0.90g,2.00mmol)及4.0M的HCl(3.00ml,12.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物76,(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(0.75g,96%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.62(s,C(O)NH),8.17(s,NH3),7.88(d,J=8.2Hz,ArH),7.81(d,J=8.4Hz,ArH),7.68(d,J=8.3Hz,ArH),7.38(d,J=8.1Hz,ArH),3.66(t,J=6.1Hz,Chiral-H),3.30-3.57(m,NHCH2CH2),2.82(t,J=7.0Hz,NHCH2CH2),1.67-1.74(m,CH2CH3),0.79(t,J=7.5Hz,CH2CH3)。
制备例72:(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(77)的制备
利用反应式f,将化合物58(1.03g,2.22mmol)及4.0M的HCl(5.56ml,22.2mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物77,(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(0.75g,85%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,300MHz)8.81(t,J=5.3Hz,C(O)NH),8.35(s,NH3),7.84(dd,J=8.2Hz,15.7Hz,ArH),7.54(dd,J=8.1Hz,73.4Hz,ArH),3.71-3.75(t,J=6.3Hz,Chiral-H),3.30-3.60(m,NH2CH2CH2),2.85(t,J=6.3Hz,NHCH2CH2),1.61-1.68(m,CH2CH2CH3),1.15-1.22(m,CH2CH2CH3),0.80(t,J=7.2Hz,CH2CH2CH3)。
制备例73:(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺盐酸盐(78)的制备
利用反应式f,将化合物59(1.32g,2.76mmol)及4.0M的HCl(4.14ml,16.6mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物78,(R)/(S)-2-氨基-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺盐酸盐(0.82g,72%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.69(t,J=4.9Hz,C(O)NH),8.26(s,NH3),7.88(d,J=8.2Hz,ArH),7.81(d,J=8.3Hz,ArH),7.68(d,J=8.1Hz,ArH),7.39(d,J=8.0Hz,ArH),3.69(t,J=6.2Hz,Chiral-H),3.29-3.59(m,NHCH2CH2),2.80-2.89(m,NHCH2CH2),1.61-1.67(m,CH2CH2CH2CH3),1.14-1.23(m,CH2CH2CH2CH3),0.79(t,J=6.8Hz,CH2CH2CH2CH3)。
制备例74:(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺盐酸盐(79)的制备
利用反应式f,将化合物60(0.91g,1.95mmol)及4.0M的HCl(2.92ml,11.7mmol在二恶烷中(in dioxane))反应合成黄色粉末状的化合物79,(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺盐酸盐(0.43g,54%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.67(s,C(O)NH),8.24(s,NH3),7.35-7.89(m,ArH),3.67(d,J=4.3Hz,Chiral-H),3.30-3.55(m,NHCH2CH2),2.80-2.85(m,NHCH2CH2),1.68-1.75(m,CH2CH3),0.80(t,J=7.5Hz,CH2CH3)。
制备例75:(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺盐酸盐(80)的制备
利用反应式f,将化合物61(0.70g,1.45mmol)及4.0M的HCl(2.18ml,8.70mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物80,(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺盐酸盐(0.55g,91%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.71(t,J=5.4Hz,C(O)NH),8.28(s,NH3),7.77(d,J=8.8Hz,ArH),7.62(d,J=8.2Hz,ArH),7.35-7.45(m,ArH),3.70(t,J=6.4Hz,Chiral-H),3.28-3.57(m,NHCH2CH2),2.80-2.86(m,NHCH2CH2),1.61-1.65(m,CH2CH2CH3),1.13-1.24(m,CH2CH2CH3),0.80(t,J=7.4Hz,CH2CH2CH3)。
制备例76:(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺盐酸盐(81)的制备
利用反应式f,将化合物62(0.79g,1.59mmol)及4.0M的HCl(2.38ml,9.54mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物81,(R)/(S)-2-氨基-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺盐酸盐(0.62g,91%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.66(t,J=5.4Hz,C(O)NH),8.23(s,NH3),7.88(d,J=8.2Hz,ArH),7.81(d,J=8.4Hz,ArH),7.68(d,J=8.2Hz,ArH),7.39(d,J=8.2Hz,ArH),3.68(t,J=6.4Hz,Chiral-H),3.29-3.59(m,NHCH2CH2),2.81-2.87(m,NHCH2CH2),1.60-1.66(m,CH2CH2CH2CH3),1.13-1.23(m,CH2CH2CH2CH3),0.79(t,J=7.0Hz,CH2CH2CH2CH3)。
制备例77:(R)/(S)-2-氨基-N-(2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(82)的制备
利用反应式f,将化合物62(0.94g,2.17mmol)及4.0M的HCl(3.26ml,13.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物82,(R)/(S)-2-氨基-N-(2-(3’,4’-二氟-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(0.68g,85%)。
Rf=0.00(EtOAc 9:aetone 1);
1H NMR(DMSO-d6,400MHz)8.55(s,C(O)NH),8.10(s,NH3),7.72-7.77(m,ArH),7.62(d,J=8.1Hz,ArH),7.50-7.53(m,ArH),7.33(d,J=8.1Hz,ArH),3.65(t,J=5.9Hz,Chiral-H),3.29-3.57(m,NHCH2CH2),2.78-2.84(m,NHCH2CH2),1.58(q,J=6.9Hz,8.8Hz,CH2CH2CH3),1.14-1.20(m,CH2CH2CH3),0.80(t,J=7.3Hz,CH2CH2CH3)。
制备例78:(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)丁酰胺盐酸盐(83)的制备
利用反应式f,将化合物64(1.31g,2.81mmol)及4.0M的HCl(4.20ml,16.9mmol在二恶烷中(in dioxane))反应合成黄色粉末状的化合物83,(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)丁酰胺盐酸盐(1.07g,94%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.79(s,C(O)NH,NH2),7.92(d,J=2.0Hz,ArH),7.65-7.72(m,ArH),7.36(d,J=8.1Hz,ArH),3.59(t,J=6.4Hz,Chiral-H),3.39-3.53(m,NHCH2CH2),2.83(t,J=6.8Hz,NHCH2CH2),2.38(t,J=6.1Hz,NCH3),1.68-1.80(m,CH2CH3),0.77(t,J=7.5Hz,CH2CH3)。
制备例79:(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)戊酰胺盐酸盐(84)的制备
利用反应式f,将化合物65(0.65g,1.36mmol)及4.0M的HCl(2.03ml,8.13mmol在二恶烷中(in dioxane))反应合成黄色粉末状的化合物84,(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)戊酰胺盐酸盐(0.33g,57%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.26(s,NH2),8.96(t,J=5.3Hz,C(O)NH),7.90-7.91(m,ArH),7.64-7.71(m,ArH),7.36(d,J=8.1Hz,ArH),3.64-3.68(m,Chiral-H),3.42-3.56(m,NHCH2CH2),2.84(t,J=6.8Hz,NHCH2CH2),2.35(s,NCH3),1.60-1.77(m,CH2CH2CH3),1.09-1.16(m,CH2CH2CH3),0.80(t,J=7.2Hz,CH2CH2CH3)。
制备例80:(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)己酰胺盐酸盐(85)的制备
利用反应式f,将化合物66(0.57g,1.16mmol)及4.0M的HCl(1.74ml,6.95mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物85,(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(甲氨基)己酰胺盐酸盐(0.38g,75%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.70-9.36(s,NH2),8.80(t,J=5.4Hz,C(O)NH),7.91(d,J=2.0Hz,ArH),7.65-7.72(m,ArH),7.35(d,J=8.2Hz,ArH),3.55(t,J=6.6Hz,Chiral-H),3.38-3.52(m,NHCH2CH2),2.83(t,J=6.8Hz,NHCH2CH2),2.35(s,NCH3),1.60-1.76(m,CH2CH2CH2CH3),1.05-1.23(m,CH2CH2CH2CH3),0.78(t,J=7.2Hz,CH2CH2CH2CH3)。
制备例81:(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(86)的制备
利用反应式f,将化合物67(0.86g,1.84mmol)及4.0M的HCl(2.77ml,11.1mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物86,(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)丁酰胺盐酸盐(0.65g,88%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.04(s,NH2),8.79(s,C(O)NH),7.87(d,J=8.3Hz,ArH),7.80(d,J=8.4Hz,ArH),7.68(d,J=8.2Hz,ArH),7.39(d,J=8.2Hz,ArH),3.59(t,J=2.5Hz,4.9Hz,Chiral-H),3.40-3.56(m,NHCH2CH2),2.84(t,J=6.9Hz,NHCH2CH2),2.37(s,NCH3),1.67-1.85(m,CH2CH3),0.77(t,J=7.5Hz,CH2CH3)。
制备例82:(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(87)的制备
利用反应式f,将化合物68(1.17g,2.45mmol)及4.0M的HCl(3.67ml,14.7mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物87,(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)戊酰胺盐酸盐(81%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.93-9.79(m,NH2),9.04(t,J=5.2Hz,C(O)NH),7.84(dd,J=8.3Hz,15.1Hz,ArH),7.54(dd,J=8.0Hz,73.4Hz,ArH),3.68-3.72(m,Chiral-H),3.42-3.58(m,NHCH2CH2),2.87(t,J=6.7Hz,NHCH2CH2),2.36(s,NCH3),1.64-1.82(m,CH2CH2CH3),1.09-1.22(m,CH2CH2CH3),0.81(t,J=7.1Hz,CH2CH2CH3)。
制备例83:(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺盐酸盐(88)的制备
利用反应式f,将化合物69(0.85g,1.72mmol)及4.0M的HCl(2.60ml,10.3mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物88,(R)/(S)-2-(甲氨基)-N-(2-(4’-(三氟甲基)-[1,1’-联苯]-4-基)乙基)己酰胺盐酸盐(0.53g,71%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.00(s,NH2),8.75(t,J=5.4Hz,C(O)NH),7.87(d,J=8.3Hz,ArH),7.81(d,J=8.4Hz,ArH),7.68(d,J=8.2Hz,ArH),7.38(d,J=8.2Hz,ArH),3.57-3.61(m,Chiral-H),3.40-3.55(m,NHCH2CH2),2.84(t,J=6.8Hz,NHCH2CH2),2.36(s,NCH3),1.60-1.75(m,CH2CH2CH2CH3),1.06-1.24(m,CH2CH2CH2CH3),0.78(t,J=7.2Hz,CH2CH2CH2CH3)。
制备例84:(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺盐酸盐(89)的制备
利用反应式f,将化合物70(0.97g,2.01mmol)及4.0M的HCl(3.00ml,12.1mmol在二恶烷中(in dioxane))反应合成黄色粉末状的化合物89,(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)丁酰胺盐酸盐(0.73g,88%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)9.00(s,NH2),8.77(s,C(O)NH),7.77(d,J=8.7Hz,ArH),7.61(d,J=8.2Hz,ArH),7.44(d,J=8.2Hz,ArH),7.35(d,J=8.1Hz,ArH),3.57-3.60(m,Chiral-H),3.39-3.55(m,NHCH2CH2),2.82(t,J=6.9Hz,NHCH2CH2),2.37(s,NCH3),1.67-1.83(m,CH2CH3),0.77(t,J=7.5Hz,CH2CH3)。
制备例85:(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺盐酸盐(90)的制备
利用反应式f,将化合物71(0.83g,1.67mmol)及4.0M的HCl(2.51ml,10.0mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物90,(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)戊酰胺盐酸盐(0.40g,61%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.85-9.19(m,NH2),8.75(s,C(O)NH),7.76(d,J=7.7Hz,ArH),7.61(d,J=7.5Hz,ArH),7.44(d,J=8.0Hz,ArH),7.35(d,J=7.4Hz,ArH),3.60(s,Chiral-H),3.40-3.56(m,NHCH2CH2),2.83(t,J=6.5Hz,NHCH2CH2),2.36(s,NCH3),1.60-1.66(m,CH2CH2CH3),1.09-1.17(m,CH2CH2CH3),0.80(t,J=7.0Hz,CH2CH2CH3)。
制备例86:(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺盐酸盐(91)的制备
利用反应式f,将化合物72(0.89g,1.74mmol)及4.0M的HCl(2.61ml,10.4mmol在二恶烷中(in dioxane))反应合成白色粉末状的化合物91,(R)/(S)-2-(甲氨基)-N-(2-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)乙基)己酰胺盐酸盐(0.66g,86%)。
Rf=0.00(EtOAc 9:丙酮(acetone)1);
1H NMR(DMSO-d6,400MHz)8.95(s,NH2),8.72(s,C(O)NH),7.76(d,J=8.7Hz,ArH),7.61(d,J=8.1Hz,ArH),7.44(d,J=8.4Hz,ArH),7.35(d,J=8.1Hz,ArH),3.57-3.60(m,Chiral-H),3.29-3.56(m,NHCH2CH2),2.83(t,J=6.8Hz,NHCH2CH2),2.37(s,NCH3),1.59-1.74(m,CH2CH2CH2CH3),1.08-1.24(m,CH2CH2CH2CH3),0.78(t,J=7.2Hz,CH2CH2CH2CH3)。
制备例87:(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(二甲氨基)戊酰胺(92)的制备
利用反应式g,将74(1.0当量)、三乙胺(6.0当量)、甲醛(1.05当量)及钯催化剂0.2当量)反应合成化合物92,(R)/(S)-N-(2-(3’,4’-二氯-[1,1’-联苯]-4-基)乙基)-2-(二甲氨基)戊酰胺。
1H NMR(DMSO-d6,400MHz)8.96(t,J=5.3Hz,C(O)NH),7.90-7.91(m,ArH),7.64-7.71(m,ArH),7.36(d,J=8.1Hz,ArH),3.64-3.68(m,Chiral-H),3.42-3.56(m,NHCH2CH2),2.82-2.85(m,NHCH2CH2),2.35(s,N(CH3)2),1.60-1.77(m,CH2CH2CH3),1.09-1.16(m,CH2CH2CH3),0.80(t,J=7.2Hz,CH2CH2CH3)。
实施例
实施例1:细胞培养
使用添加10%胎牛血清(fetal Bovine serum,FBS,Gibco,Cat No.26140-079)和10000U/mL的青霉素-链霉素(penicillin-Streptomycin)(Gibco,Cat No.15140-122)的杜贝克改良鹰培养基(Dulbecco's modified Eagle's medium,DMEM,Gibco CatNo.11995073),在CO2培养箱(Thermo Scientific,Cat No.51023121)中在37℃的温度条件下培养小鼠巨噬细胞系Raw264.7细胞系(购自韩国细胞系库)和HaCaT角质形成细胞(keratinocyte)细胞系(购自Addexbio,T0020001)。
实施例2:通过在RAW264.7细胞中诱导白细胞介素6(IL-6)来确认化合物的抗炎效
果
(1)使用LPS诱导IL-6的生成
对抑制诱导IL-6细胞因子生成的能力进行分析。将RAW 264.7细胞(购自韩国细胞系库)以5×105细胞/孔接种于12孔板中,并在包含5%二氧化碳和饱和水蒸气的37℃培养箱中进行稳定化。培养24小时后,将本发明的化合物在DMEM中制备成浓度为0μg/ml或8μg/ml,然后预处理30分钟。之后,将LPS(Sigma-Aldrich,Cat No.L2887)处理至1μg/ml的浓度来诱导炎症反应24小时。然后,使用小鼠IL-6ELIS试剂盒(Labiskoma,Cat No.K0331230P)和小鼠TNF-αELISA试剂盒(Labiskoma,Cat No.K0331186P)并按照说明书进行后测量吸光度。使用FK506(FK-506一水合物(monohydrate),制造商:MilliporeSigma,产品编号:F4679,美国)作为对照物质。
(2)使用TNF-α或IFN-β诱导IL-6的生成
分别使用浓度为50ng/ml的TNF-α(Sigma-Aldrich,Cat No.T6674)或IFN-β(SinoBiolgical,Cat No.10704-HNAS)处理后,诱导炎症反应24小时,将对照物质和本发明的化合物分别预处理1小时。其他方法与上述(1)相同。
(3)IL-6分析
在上述(1)及(2)中诱导炎症后,回收上清液,按照制造商的说明进行IL-6ELISA(小鼠IL-6ELISA试剂盒,pink-ONE,制造商:Komabiotech,产品编号:K0331230P)。具体地,按照ELISA试剂盒的方案用上述上清液定量上清液中IL-6的含量,使用酶标仪(MultiskanSky,制造商:Thermo Fisher Scientific)在OD 450nm处测量吸光度。本发明的化合物对通过LPS处理诱导的IL-6生成的抑制活性如表1至表3以及图1至图2所示。下表1及表2为将本发明的化合物77及化合物51各自的LPS处理后IL-6的生成量与对照药物比较来确认的结果。表3为将本发明的各化合物的LPS处理后IL-6的生成量与对照药物比较来确认的结果。在本实施例中,确认到与通过处理LPS、TNF-α或IFN-β诱导的IL-6生成量相比,处理本发明的化合物的组的IL-6生成量显着减少。在上表1至表3、图1及图2中,以通过LPS、TNF-α或IFN-β诱导的IL-6生成量(100%)为基准,将通过预处理本发明的化合物生成的IL-6的相对值以%表示。
表1
1孔(well) | 2孔 | IL-6(pg/ml) | IL-6(%) | |
- | 0.10 | 0.10 | 102.62 | 7.08 |
LPS | 1.02 | 0.91 | 1449.82 | 100.00 |
化合物77(8μg/ml) | 0.18 | 0.15 | 191.20 | 13.19 |
FK506 | 0.49 | 0.47 | 656.86 | 45.31 |
表2
1孔 | 2孔 | std | avg | avg(%) | |
- | 0 | 0 | 0 | 0 | 0.00 |
LPS | 4628.00 | 4695.00 | 47.38 | 4661.50 | 100.00 |
化合物51(2μg/ml) | 2815.00 | 2416.00 | 282.14 | 2615.50 | 56.11 |
化合物51(4μg/ml) | 669.30 | 504.60 | 116.46 | 586.95 | 12.59 |
表3
实施例3:通过在角质形成细胞HaCaT细胞中诱导TSLP和白细胞介素-6来确认化合
物77的抗炎效果
皮肤角质形成细胞系HaCaT细胞(购自韩国细胞系库)以1×105细胞/孔计数并分株于12孔板中,并在包含5%二氧化碳和饱和水蒸气的37℃培养箱中培养12小时以上。使用本发明的化合物77(0μg/ml或8μg/ml)和作为对照组的免疫抑制剂FK506(FK-506一水合物(monohydrate),制造商:MilliporeSigma,产品编号:F4679,美国)预处理1小时后,将炎症反应诱导剂TNF-α(人肿瘤坏死因子-α(Tumor Necrosis Factor-αhuman),制造商:MilliporeSigma)以100ng/mL的浓度处理24小时。然后,获得上清液来进行TSLP和IL-6ELISA(人TSLP和IL-6ELISA试剂盒,pink-ONE,制造商:Komabiotech)。具体地,按照ELISA试剂盒的方案用上述上清液定量上清液中TSLP和IL-6的含量,使用酶标仪(MultiskanSky,制造商:Thermo Fisher Scientific,产品编号:51119600DP)在450nm波长处测量吸光度。图3为确认本发明实施例的TSLP和白细胞介素-6的量的结果。如图3所确认,与作为对照组的FK506相比,处理本发明的化合物77后的TSLP和白细胞介素-6量相对显着减少,由此确认具有抗炎效果。
实施例4:抑制TSLP和TSLPR之间的相互作用的活性确认
使用HEK293T细胞检测TSLP引起的Ca2+流入,并分析本发明的化合物是否抑制TSLP和TSLPR之间的相互作用。瞬时转染三种基因(小鼠TSLPR、IL-7Rα、TRPA1,以下为嘉泉大学深元植(Won-Sik Shim)教授)的HEK293T细胞购自韩国嘉泉大学深元植(Won-Sik Shim)教授并用于实验。为了测量Ca2+流入(influx),使用了钙特异性荧光染料Fluo3-AM(Sigma-Aldrich)。应用小鼠TSLP(2.5ng/mL),并记录荧光强度长达15分钟。为了比较,在处理TSLP之前预处理本发明的化合物77(0.1nM~10μM)10分钟。图4及图5示出其结果。反应表示第一个时间点(0分钟)的最大荧光强度。
实验例:确认本发明的化合物在小鼠银屑病模型中的功效
试验物质的配制及小鼠模型的制作
使用DMSO(二甲基亚砜(Dimethyl sulfoxide),Sigma,Cat No.472301)溶解试验物质(本发明的化合物51)后,使用PBS(HyClone,Cat No.SH30028.02)配制成适当浓度。使用100%乙醇(Medchem,Cat No.HY-13571)溶解试验物质来配制经皮用试验物质。将作为阳性对照物质的二丙酸倍他米松(Betamethasone dipropionate,Sigma,Cat No.D1756,LotNo.BCBW7684)溶解于DMSO中,然后根据给药剂量,使用PEG400(Sigma,Cat No.06855)和30%乙醇(Daejung,Cat No.4023-4100)配制。以与阳性对照物质溶剂对照组(vehicle)相同的方式应用阴性对照物质。
将BALB/c小鼠(通过JA BIO购买,雄性,27只,8周龄)驯化1周。在涂抹艾达乐乳膏(Aldara cream)前3天用异氟烷(isoflurane)麻醉后,使用剃毛器去除背部(3×3cm)的毛。放置脱毛膏1分钟完全去除剩余的毛,并放置72小时以治愈微伤口。为了诱发银屑病,在同一时间点(AM 10:00)涂抹艾达乐乳膏(5%咪喹莫特(Imiquimod),Dong-A ST)62.5mg,1次/天,共7次,第4天开始,在同一时间点(PM 14:00)将试验物质和阳性对照物质分别以150μl浓度涂抹。各实验组的组成如下:a)Con:正常(Normal)+赋形剂涂抹组:8只;b)Veh:艾达乐乳膏(Aldara cream)+赋形剂涂抹组:8只;c)Beta:艾达乐(Aldara)+倍他米松(Betamethasone)0.05%涂抹组:8只;以及d)化合物51 1%:艾达乐(Aldara)+化合物511%涂抹组:3只。尸检在非禁食状态下进行,所有个体均摘除背部皮肤,在液氮中快速冷冻,保存在-80℃备用。
功效评价及结果分析
(1)一般症状观察
在给药和观察期间,每天至少观察一次所有动物的死亡、一般症状类型、表现日期和症状严重程度。
(2)银屑病面积和严重程度指数(Psoriasis area and severity index,PASI)评分
第0天、第4天、第8天拍照以测量皮肤指数值后,为了测量背部皮肤病变程度,肉眼观察并记录。根据评价指标(红斑、皮肤厚度、皮肤角质)对各组银屑病皮肤病变状态进行评分:无(0)、轻度(1)、中度(2)、重度(3)、极重度(4),将三项评分相加,计算出最低0分、最高12分之间的评价分值。比较第8天的照片时,确认与Con相比,Veh组诱发了银屑病,并且肉眼观察到Beta和KDS6002处理组的皮肤病变得到改善。图6示出其结果。各组在第0天、第4天、第8天拍照后,根据评价指标(红斑、皮肤厚度、皮肤角质)将各组银屑病皮肤病变状态以柱状图示出。与Con相比,Veh组的PASI评分增加,而Beta和化合物51处理组的PASI评分显着降低。(p<0.001,参照图7)
(3)抓痕(Scratching)评价
尸检当天,本试验组每个个体在无刺激的空间内进行1小时的适应时间,然后拍摄视频30分钟,然后测量致敏部位的搔抓次数。将由给药本发明的化合物51引起的瘙痒的变化与作为银屑病诱发组的Veh组进行比较。第8天测定的瘙痒评价中,确认Veh组显着增加,Beta组显着减少。在本发明的化合物51处理组中确认了减少瘙痒的趋势。其结果如图8所示。
(4)定量(Quantitative)RT-PCR(qRT-PCR)检测
为了确认银屑病小鼠模型的功效,通过RT-qPCR使用每个特定基因的引物组来确认本发明的化合物51对基因表达的影响。考察银屑病相关细胞因子基因IL-17A、IL-17F、IL-23A(p19)、IL-12A(p35)、IL-12B(p40)、IL-1β的结果显示,确认Veh组的银屑病相关细胞因子基因显着增加,Beta组和本发明的化合物51处理组显着减少。(*p<0.05,**p<0.01,***p<0.001,图9)
向组织(Tissue)中放入TRIzolTM试剂(Invitrogen,Cat.No.15596018)后使用T10基本ULTRA-TURRAX均质器(T10 basic ULTRA-TURRAX Homogenizer,IKA,Cat.No.3737000)粉碎。然后使用异丙醇(isopropyl alcohol,Sigma,Cat No.190764)和乙醇(Daejung,CatNo.4023-4100)获得RNA后,溶解于DEPC水(Biosesang,Cat No.WR2004-050-00)中并保存。使用分光光度计(spectrophotometer)测量RNA后,使用逆转录酶(reversetranscriptase)和oligo dT将其合成为cDNA,然后进行定量(quantitative)RT-PCR。将测量结果用内标准基因(endogenous reference gene)18s rRNA进行标准化(nomalized)。qRT-PCR中使用的引物如下:FW-IL-17A:TCTCCACCGCAATGAAGACC(序列号1),RV-IL-17A:AAAGTGAAGGGGCAGCTCTC(序列号2)、FW-IL-17F:TGCTACTGTTGATGTTGGGAC(序列号3)、RV-IL-17F:AATGCCCTGGTTTTGGTTGAA(序列号4)、FW-IL-23A(p19):TGGAGCAACTTCACACCTCC(序列号5)、RV-IL-23A(p19):GGCAGCTATGGCCAAAAAGG(序列号6)、FW-IL-12A(p35):ACCTGCTGAAGACCACAGATG(序列号7)、RV-IL-12A(p35):GCTCCCTCTTGTTGTGGAAGA(序列号8)、FW-IL-12B(p40):CCTGTGACACGCCTGAAGAA(序列号9)、RV-IL-12B(p40):GTGAGTGGCTCAGAGTCTCG(序列号10)、FW-IL-1β:CCAAAAGATGAAGGGCTGCTT(序列号11)、RV-IL-1β:GAAAAGAAGGTGCTCATGTCCTC(序列号12)、FW-18s rRNA:GTAACCCGTTGAACCCCATT(序列号13)、RV-18s rRNA:CCATCCAATCGGTAGTAGCG(序列号14)。
实验中获得的所有实验结果均以平均值±标准差表示,并使用GraphPad Prism软件(版本5.01;GraphPad Software,Inc.)绘制图表。当通过单因素方差分析(One-wayanalysis of variance,ANOVA)观察显着性时,为了找出与对照组Veh有显着差异的试验组,采用Dunnett多重比较法(Dunnett’smultiple comparison method)进行事后检验。
产业上的可利用性
本发明的化合物可用于预防或治疗与Th2免疫应答调节相关的疾病,尤其炎症性疾病。包含本发明的化合物的组合物可用于预防或治疗哮喘、银屑病、特应性皮炎及炎症性肠病。
<110> 阿米蒂比奥有限公司
<120> 将联苯基引入新型氨基烷酸的衍生物化合物及包含其的抗炎用组合物
<130> AMTIX20P12WO
<150> KR 10-2020-0184007
<151> 2020-12-25
<160> 14
<170> KoPatentIn 3.0
<210> 1
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<212> DNA
<213> 人工序列
<220>
<223> 正向 IL-17A
<400> 1
tctccaccgc aatgaagacc 20
<210> 2
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 反向 IL-17A
<400> 2
aaagtgaagg ggcagctctc 20
<210> 3
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 正向 IL-17F
<400> 3
tgctactgtt gatgttggga c 21
<210> 4
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 反向 IL-17F
<400> 4
aatgccctgg ttttggttga a 21
<210> 5
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 正向 IL-23A p19
<400> 5
tggagcaact tcacacctcc 20
<210> 6
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 反向 IL-23A p19
<400> 6
ggcagctatg gccaaaaagg 20
<210> 7
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 正向 IL-12A p35
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<213> 人工序列
<220>
<223> 反向 IL-12A p35
<400> 8
gctccctctt gttgtggaag a 21
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<213> 人工序列
<220>
<223> 正向 IL-12B p40
<400> 9
cctgtgacac gcctgaagaa 20
<210> 10
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<213> 人工序列
<220>
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<213> 人工序列
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<213> 人工序列
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<213> 人工序列
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Claims (8)
1.一种用于预防或治疗炎症性疾病的药物组合物,其特征在于,包含下述化学式1所示的化合物、其对映异构体、光学异构体、立体异构体、非对映异构体、互变异构体或其药学上可接受的盐作为有效成分,
化学式1:
在上述化学式1中,
n为0、1或2,
R1及R2各自独立地为H或C1-6烷基,
R3为C1-6烷基,
X为选自由卤素基、卤代C1-6烷基及卤代C1-6烷氧基组成的组中的相同或不同的m个取代基,其中,m为1至5的整数。
2.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物,其特征在于,上述炎症性疾病为选自由特应性皮炎、哮喘、过敏性鼻炎、过敏性结膜炎、过敏性皮炎、银屑病、炎症性肠病及食物过敏组成的组中的一种以上。
3.一种用于预防或治疗纤维化疾病的药物组合物,其特征在于,包含下述化学式1所示的化合物、其对映异构体、光学异构体、立体异构体、非对映异构体、互变异构体或其药学上可接受的盐作为有效成分,
化学式1:
在上述化学式1中,
n为0、1或2,
R1及R2各自独立地为H或C1-6烷基,
R3为C1-6烷基,
X为选自由卤素基、卤代C1-6烷基及卤代C1-6烷氧基组成的组中的相同或不同的m个取代基,其中,m为1至5的整数。
4.根据权利要求3所述的用于预防或治疗纤维化疾病的药物组合物,其特征在于,上述纤维化疾病为肝纤维化、慢性肝炎、肝硬化、肝癌、化疗相关性脂肪性肝炎、非酒精性脂肪性肝炎、肺纤维化、肾纤维化、肾功能衰竭、胰腺纤维化、慢性胰腺炎及胰腺癌组成的组中的一种以上。
5.根据权利要求1或2所述的用于预防或治疗炎症性疾病的药物组合物,其特征在于,抑制胸腺基质淋巴细胞生成素信号传导。
6.根据权利要求3或4所述的用于预防或治疗纤维化疾病的药物组合物,其特征在于,抑制胸腺基质淋巴细胞生成素信号传导。
7.一种炎症性疾病的预防或治疗方法,其特征在于,包括向需要预防或治疗炎症性疾病的患者给予权利要求2所述的药物组合物。
8.一种纤维化疾病的预防或治疗方法,其特征在于,包括向需要预防或治疗纤维化疾病的患者给予权利要求4所述的药物组合物。
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