CN114051496B - 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真菌药学组合物 - 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真菌药学组合物 Download PDFInfo
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- CN114051496B CN114051496B CN202080046307.9A CN202080046307A CN114051496B CN 114051496 B CN114051496 B CN 114051496B CN 202080046307 A CN202080046307 A CN 202080046307A CN 114051496 B CN114051496 B CN 114051496B
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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Abstract
本发明涉及丙氨酸和脯氨酸氨基酸的功能性衍生物,其目的在于,提供将联苯基引入新型氨基烷酸的衍生物、其盐和/或溶剂化物。经确认,本发明的化合物具有非常优异的抗真菌及杀真菌效果。并且,经确认,在与现有的抗真菌制剂联合给药时表现出协同作用。此外,本发明的化合物对广泛的真菌具有活性。因此,本发明的化合物可广泛用于需要用抗真菌或杀真菌制剂处理的人病原真菌、动物病原真菌及植物病原真菌的领域。
Description
技术领域
本发明涉及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用于预防或/治疗真菌感染疾病的药学组合物。
背景技术
随着现代人寿命的延长,由于免疫功能下降,由真菌引起的机会性感染在老年人中增加。并且,在因免疫抑制剂降低移植排斥反应而导致免疫功能下降的患者以及免疫功能损伤的器官移植患者或因化疗和获得性免疫缺陷综合征(AIDS)导致的免疫力下降的患者中,由机会性感染菌类引起的感染在世界范围内正在增加。过去,真菌感染主要是由脚癣、股癣、鹅口疮等局部感染引起,但近年来,全身性真菌感染变得非常普遍,以至于它们的发生频率在所有医院内感染中占第四位。据报道,代表性的机会性感染菌包括白假丝酵母(Candida albicans)、光滑念珠菌(Candida glabrata)、克鲁斯假丝酵母(Candidakrusei)及新型隐球菌(Cryptococcus neoformans)等。作为引起全身感染的病原性真菌的新型隐球菌常见于世界各地的土壤中,担孢子从周围环境通过人体呼吸道吸入至肺部。如器官移植患者或AIDS患者等免疫力降低的患者中,潜伏在肺部的真菌引起肺部感染,并通过血脑屏障(Blood-Brain Barrier,BBB)进入中枢神经***,由此会引起危及生命的脑髓膜炎。尤其,隐球菌引起的脑髓膜炎是脑髓膜炎中死亡率最高,众所周知,全世界每年有超过60万人死亡。但是,由于真菌类和哺乳类一样都是由真核细胞组成的,两者的生化和代谢途径非常相似,很难找到真菌特异性靶点,因此,迄今为止,用于治疗隐球菌病(cryptococcosis)的药物有几个局限性,因此只能进行有限的治疗。到目前为止,已开发的用于抑制隐球菌真菌的抗真菌剂可主要分为包括两性霉素B(amphotericin B)的多烯类(polyenes);包括酮康唑(ketoconazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、伏立康唑(voriconazole)的唑类(azole);包括非唑类的特比萘芬(terbinafine)、氟胞嘧啶(flucytosine)、卡泊芬净(caspofungin)的棘白菌素(echinocandins)。属于多烯类的两性霉素B与隐球菌的细胞膜中的麦角固醇结合,通过氧化损伤引起细胞凋亡,从而抑制细菌。但是,它对身体表现出高毒性而引起副作用。唑类药物抑制羊毛甾醇(lanosterol)转化为作为霉菌细胞膜必要因素的麦角固醇的14α-去甲基化酶(14α-demethylase),抑制生成麦角固醇,削弱细胞膜并引起细胞凋亡,从而起到抗真菌作用。据报告,唑类药物存在容易对药物的产生耐药性的问题。特比萘芬阻止角鲨烯(squalene)转化为角鲨烯环氧(squalene epoxy)来抑制麦角固醇的合成。氟胞嘧啶为抑制核酸合成的代谢拮抗剂,通过诱导真菌RNA的错码转导和拮抗DNA合成而起到抗真菌作用。棘白菌素类药物起到抑制真菌细胞壁的形成,与之前提到的作用于细胞膜的抗真菌剂相比,不同之处在于该类药物靶向细胞壁。由于以往开发的抗真菌剂根据药物种类表现出如毒性和耐性等各种副作用,因此,有必要开发可以在将这些副作用最小化的同时提高抗真菌效果的新型抗真菌剂。
发明内容
技术问题
本发明的目的在于,提供将联苯基引入新型氨基烷酸的衍生物、其盐和/或溶剂化物。
本发明的再一目的在于,提供包含本发明的将联苯基引入氨基烷酸的衍生物、其盐和/或溶剂化物作为有效成分的抗真菌用药学组合物。
本发明的另一目的在于,提供包含本发明的将联苯基引入氨基烷酸的衍生物、其盐和/或溶剂化物作为有效成分的抗真菌用农药制剂。
本发明的还有一目的在于,提供包含本发明的将联苯基引入氨基烷酸的衍生物、其盐和/或溶剂化物作为有效成分的动物用抗真菌制剂。
本发明的又一目的在于,提供包含本发明的将联苯基引入氨基烷酸的衍生物、其盐和/或溶剂化物的抗真菌组合物。
本发明的又一目的在于,提供包含本发明的将联苯基引入氨基烷酸的衍生物、其盐和/或溶剂化物的人体清洁用组合物、化妆品组合物或洗发水组合物。
并且,本发明的目的在于,提供本发明的苄氧基苄胺基氨基酸衍生物的制备方法。
解决问题的方案
作为用于实现上述目的一方面,本发明提供下述化学式1所示的化合物、其立体异构体、或它们的药学上可接受的盐:
化学式1:
在上述化学式1中,
n为0、1、2、3、4或5,
R1、R2及R3各自独立地相同或不同,各自独立地选自氢、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,
X为选自由卤素基、卤代C1-7烷基及卤代C1-7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,
在本发明中,上述卤素可选自氟、氯、溴及碘中。
上述C1-7烷基可以为直链、支链或环状烷基,可选自甲基,乙基、丙基、异丙基、环丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基及辛基中。
上述C1-7烷氧基可选自甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、庚氧基及辛氧基中。
上述卤代C1-7烷基可选自二氟甲基、三氟甲基、二氟乙基、三氟乙基、三氟丙基、三氟戊基、三氟己基和三氟庚基中。
上述卤代C1-7烷氧基可选自二氟甲氧基,三氟甲氧基、二氟乙氧基、三氟乙氧基、三氟丙氧基、三氟戊氧基、三氟己氧基及三氟庚氧基中。
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6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6:
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,但并不限定于此。
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;
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(maleicacid)、琥珀酸、草酸、苯甲酸、酒石酸、富马酸(fumaric acid)、扁桃酸、丙酸(propionicacid)、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(glucuronicacid)、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式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,表现出与化学式1的化合物等效的药理活性,例如,只要表现出抗真菌活性的化学式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1中,
n为0、1、2、3、4或5,
R1、R2及R3各自独立地相同或不同,各自独立地选自氢、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,
X为选自由卤素基、卤代C1-7烷基及卤代C1-7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。
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',R2及R3各自独立地相同或不同,各自独立地选自氢、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中。
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C1-7烷基及卤代C1-7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。
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,本发明提供包含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作为有效成分的抗真菌组合物。
作为还有一个方面,本发明涉及包含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作为有效成分的用于治疗或预防真菌感染疾病的药学组合物。
例如,本发明的将联苯基引入新型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可对机会性感染真菌类发挥抗真菌活性,因此可用作抗真菌组合物,进而可用于真菌感染疾病的预防或治疗。
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。
例如,可用本发明的药学组合物预防或治疗的真菌感染疾病的非限制性例可包括由新型隐球菌(Cryptococcus neoformans)、白假丝酵母(Candida albicans)、耳念珠菌(Candida auris)、光滑念珠菌(Candida glabrata)、烟曲霉(Aspergillus fumigatus)引起的感染疾病。具体地,上述真菌感染疾病可以为由隐球菌引起的脑髓膜炎,但并不限定于此。
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、***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***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。
进一步地,本发明通过包括向需要上述药学组合物的个体给药上述药学组合物的步骤的真菌感染疾病的治疗方法。
本发明的术语“个体”是指已经患有或者可能会发生真菌感染疾病的包括人类在内的猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠等所有动物,可通过向个体给药本发明的药学组合物来有效预防或治疗上述疾病。并且,本发明的药学组合物通过抗真菌活性对由真菌感染诱导的疾病产生治疗效果,因此,若与现有的治疗剂联合给药,则会产生协同效果。
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
根据本发明的多个实例,提供针对多种真菌感染疾病的治疗及预防剂,其可通过以如α-氨基丁酸、正缬氨酸或正亮氨酸等包含联苯基的氨基烷酸作为基本骨架的化合物克服用作抗真菌剂的现有药物的缺点,具体地,可通过提高药物的稳定性及功效来缓解或消除现有药物的副作用,并提高治疗效果。并且,本发明的化合物可用于关于对革兰氏阳性、革兰氏阴性及MRSA具有耐性的细菌的抗菌组合物的制备。并且,本发明的化合物可用于抗炎症治疗剂的开发。
附图说明
图1为本发明的化合物74与市售中的对比药物的抗真菌活性的比较。
图2为本发明的化合物74与市售中的对比药物的杀真菌活性的比较。
图3为本发明的化合物74与市售中的对比药物的生物膜(biofilm)去除效果的比较。
具体实施方式
以下,通过下述制备例及实施例更详细地说明本发明。但是,下述制备例及实施例仅用于例示本发明,而本发明的范围并不限定于此。
首先,将用于本发明的化合物合成的反应概括和总结如下。
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***再结晶,得到标题化合物。
用于合成本发明的化合物的制备例如下所示。
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(indioxane))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(indioxane))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);
[462]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)。
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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)。
发明的实施方式
实施例
实施例1:对人体病原性真菌类的抗真菌活性分析
为了测定对在上述制备例中合成的化合物的机会性感染真菌类的抗真菌活性程度,根据美国临床和实验室标准协会(Clinical and Laboratory Standards Institute,CLSI)的指南进行了体外(in vitro)抗真菌敏感性检测。在本实施例中,以作为感染性真菌类的新型隐球菌(Cryptococcus neoformans)、白假丝酵母(Candida albicans)、光滑念珠菌(Candida glabrata)、烟曲霉(Aspergillus fumigatus)为对象,测量了化合物能够抑制真菌发育的最小抑菌浓度(Minimum Inhibitory Concentration,MIC),并在表1中示出。MIC值(μg/ml)表示为范围值。具体地,将念珠菌属(Candida species)和新型隐球菌(Cryptococcus neoformans)在沙氏葡萄糖琼脂(Sabouraud dextrose agar,SDA)(西格玛奥德里奇(Sigma-Aldrich))固体培养基中分别培养24小时及48小时。将培养后生长的单菌落溶解于0.85%的生理盐水中,以使悬浮液中的细胞浓度为1cells/ml至5×106cells/ml。将上述细胞悬浮液在RPMI 1640液体培养基西格玛奥德里奇(Sigma-Aldrich))中稀释2000倍,准备最终浓度为5×102cells/ml至2.5×103cells/ml的菌株悬浮液后,以195μl/孔分株于96孔板中。然后,将根据上述制备例合成的化合物分别稀释2倍,准备成最终浓度分别为128μg/ml、64μg/ml、32μg/ml、16μg/ml、8μg/ml、4μg/ml、2μg/ml、1μg/ml、0.5μg/ml,并分别以5μl/孔处理,准备最终200μl/孔的测试细胞。将处理了化合物的念珠菌属(Candidaspecies)培养48小时,在35℃的温度下培养新型隐球菌(新型隐球菌(C.neoformans))72小时后,肉眼观察96孔板的底部来确认是否生长,从而确定MIC。作为阳性对照组,使用了对人体具有高毒性但公知为代表性抗真菌剂的两性霉素B(Amphotericin B;AMB)。结果如表1至表3所示。
表1
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表2
表3
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实施例2:对化合物74的抗真菌活性分析
为了确认上述化合物74的抗真菌活性对根据美国临床和实验室标准协会(Clinical and Laboratory Standards Institute,CLSI)的指南确认能够抑制真菌生长的最小浓度的最小抑菌浓度(Minimum Inhibitory Concentration,MIC)进行了测定。将各菌株涂抹在YPD固体培养基(西格玛奥德里奇(Sigma-Aldrich)),以使红色发癣菌(T.rubrum)和须发癣菌(T.mentagrophytes)的最终浓度的小型分生孢子(microconidia)为2.5×103个,白假丝酵母(Candida albicans)、光滑念珠菌(Candida glabrata)、新型隐球菌(Cryptococcus neoformans)的最终浓度为2.5×103cfu/ml,如此准备后,以195μl/孔分株于96孔板中。将化合物74分别稀释2倍,准备成最终浓度分别为128μg/ml、64μg/ml、32μg/ml、16μg/ml、8μg/ml、4μg/ml、2μg/ml、1μg/ml、0.5μg/ml,并分别以5μl/孔处理,准备成最终为200μl/孔。将处理了化合物的念珠菌属(Candida species)培养48小时,在35℃的温度下培养新型隐球菌(新型隐球菌(C.neoformans))、毛癣菌属(Trichophyton species)72小时后,肉眼观察96孔板的底部来确认是否生长,从而确定MIC(μg/ml)。结果如表4所示。
表4
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实施例3:化合物74与市售中的竞争药物的速效性效果比较的确认
化合物74与市售中的竞争药物的速效性效果比较的确认
为了确认化合物74的速效性效果,通过对白假丝酵母处理相同浓度的化合物74和作为市售中的药物的艾氟康唑(Efinaconazole),他伐硼罗(Tavaborole),特比萘芬(Terbinafine)或环匹罗司(Ciclopirox)相同时间来确认白假丝酵母的生长。以2.5×103cfu/ml的浓度准备白假丝酵母,并以195μl/孔分株于96孔板中。然后,将化合物74及上述市售中的对比药物分别以50μg/ml、100μg/ml处理30分钟后,涂抹在YPD固体培养基(西格玛奥德里奇(Sigma-Aldrich))来确认生长的单菌落数。结果如图1所示。由此可确认,与市售中的竞争药物相比,化合物74的速效性效果优异。
实施例4:化合物74与市售中的药物的杀真菌效果比较的确认
为了确认化合物74的杀真菌效果,通过对红色发癣菌按预定时间处理MIC浓度的0.5倍、1倍、2倍、4倍、8倍、16倍的化合物74和作为市售中的药物的艾氟康唑(Efinaconazole)、阿莫罗芬(Amorolfine)、特比萘芬(Terbinafine)、环匹罗司(Ciclopirox)、两性霉素B(Amphotericin B)来确认红色发癣菌的生长。以6×103cfu/ml的浓度准备红色发癣菌,并以195μl/孔分株于96孔板中。然后,将化合物74及竞争药物分别以各药物的MIC浓度的0.5倍、1倍、2倍、4倍、8倍、16倍处理5μl,调至最终200μl/孔后,处理2小时、4小时、6小时、12小时、24小时、48小时、72小时、120小时,取各个时间段的样品涂抹在YPD固体培养基来确认所形成的单菌落数。结果如图2所示。通过图2确认,与市售中的药物相比,化合物74的MIC浓度与杀真菌浓度相同,这说明其与其他药物相比在低浓度下具有杀真菌效果。
实施例5:化合物74与市售中的药物的生物膜(biofilm)去除效果比较的确认
为了确认化合物74的速效性效果,使白假丝酵母形成物膜(biofilm)后,通过以4μg/ml、8μg/ml、16μg/ml、32μg/ml的浓度处理化合物74和作为市售中的药物的卡泊芬净(Caspofungin)、两性霉素B(Amphotericin B)、艾氟康唑(Efinaconazole)来确认白假丝酵母的生长。以2.5×103cfu/ml的浓度准备白假丝酵母,通过在96孔板中培养90分钟来形成生物膜后,处理化合物74及上述对比药物,经过24小时后,确认了白假丝酵母的生长。结果如图3所示。通过图3确认,与市售中的对比药物相比,通过破坏生物膜抑制白假丝酵母的生长的效果显著优异。
实施例6:抗菌活性分析
对在本发明中合成的化合物对革兰氏阴性菌或革兰氏阳性菌及多重耐药菌的抗菌活性进行了测定。根据美国临床和实验室标准协会(Clinical and LaboratoryStandards Institute,CLSI)的指南进行了MIC测试。使用大肠杆菌(E.coli)(-),绿脓杆菌(P.aeruginosa)(-)及肠道沙门菌(S.enterica)(-)作为革兰氏阴性菌,使用蜡样芽孢杆菌(B.cereus)(+),枯草芽孢杆菌(B.subtilis)(+),凝结芽孢杆菌(B.coagulans)(+),李斯特氏菌(L.monocytogenes)(+),藤黄微球菌(M.luteus)(+),痤疮丙酸杆菌(P.acnes)(+),表皮葡萄球菌(S.epidermidis)(+),金黄色葡萄球菌(S.aureus)(+)作为革兰氏阳性菌,使用耐甲氧西林金黄色葡萄球菌(lin-resistant Staphylococcus aureus,MRSA)作为多重耐药菌。在培养上述实验对象的细菌的固体培养基中所形成的单菌落的OD600调至0.1,在MHB液体培养基(西格玛奥德里奇(Sigma-Aldrich))稀释100倍,最终OD600调至0.001,以100μl/孔分株于96孔板中。然后,将本发明的化合物稀释2倍,准备成最终浓度分别为64μg/ml、32μg/ml、16μg/ml、8μg/ml、4μg/ml、2μg/ml、1μg/ml、0.5μg/ml,并以100μl/孔处理以使最终浓度成为200μl/孔。接着,在37℃的温度下培养各菌株24小时后,通过肉眼及OD600确定MIC(μg/ml)。使用诺氟沙星(Nofloxacin)和万古霉素(Vancomycin)作为阳性对照组。结果在表5至表8中示出。
表5
表6
表7
表8
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实施例7:抗炎活性分析。
通过在RAW264.7细胞中诱导白细胞介素6(IL-6)来确认在本发明中合成的化合物的抗炎效果。将作为小鼠巨噬细胞的RAW264.7细胞(韩国细胞系库)以5×105细胞/孔的初始数量接种于12孔板中,并在37℃的温度下培养16~24小时后,对培养上述RAW264.7细胞的培养液处理在本发明中合成的化合物,以使最终浓度分别成为0μg/ml或8μg/ml,并在37℃的温度下培养1小时。然后,处理脂多糖(Lipopolysaccharide(LPS),西格玛奥德里奇(Sigma-Aldrich),美国(USA)),以使最终浓度成为1μg/ml,并在37℃的温度下培养24小时来诱导IL-6。接着,根据制造商的说明书使用购自komabiotech的ELISA试剂盒来确认在RAW264.7细胞中生成的IL-6量。结果在表9中示出。在表9中,IL-6量表示为由LPS诱导的量与因用本发明的化合物处理而减少的量的比率(%)。
表9
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产业上的可利用性
本发明涉及新型化合物及其用途,可用于抗真菌及抗菌用组合物的制备,并可应用于用于抗真菌及抗真菌预防及治疗的药学组合物的开发。
Claims (21)
1.一种化合物、其立体异构体、或它们的药学上可接受的盐,其特征在于,
由下述化学式1所示:
化学式1:
在上述化学式1中,
n为0、1、2、3、4或5,
R1、R2及R3各自独立地相同或不同,R1及R2各自独立地选自氢、环丙基、环丁基、环戊基、环己基、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,R3独立地选自氢、环丙基、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,
X为选自由卤素基、卤代C1-7烷基及卤代C1-7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,
条件是:当n为0或1并且R1和R2为氢时,R3不是C1-3烷基;当n为0时,R3不是氢。
2.根据权利要求1所述的化合物、其立体异构体、或它们的药学上可接受的盐,其特征在于,
上述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、
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。
3.根据权利要求1所述的化合物、其立体异构体、或它们的药学上可接受的盐,其特征在于,上述X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。
4.根据权利要求3所述的化合物、其立体异构体、或它们的药学上可接受的盐,其特征在于,上述X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。
5.根据权利要求1所述的化合物、其立体异构体、或它们的药学上可接受的盐,其特征在于,
上述化合物为如下所示:
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。
6.一种权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,
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、2、3、4或5,
R1、R2及R3各自独立地相同或不同,R1及R2各自独立地选自氢、环丙基、环丁基、环戊基、环己基、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,R3独立地选自氢、环丙基、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中,
X为选自由卤素基、卤代C1-7烷基及卤代C1-7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。
7.根据权利要求6所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,
将下述化学式4所示的氨基酸衍生物与二碳酸二叔丁酯反应制备化学式2所示的由叔丁氧羰基保护基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'为氢,
R2及R3各自独立地相同或不同,各自独立地选自氢、C1-7烷基、羟基、卤素、卤代C1-7烷基、C1-7烷氧基及卤代C1-7烷氧基中。
8.根据权利要求7所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,化学式4的化合物中R2为氢,使化学式4的化合物进行在碱的存在下与卤代烃反应的烷基化步骤。
9.根据权利要求6所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,
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,由此制备化学式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C1-7烷基及卤代C1-7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。
10.根据权利要求9所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,与上述苯基硼酸衍生物的反应通过在碱的存在下基于金属催化剂进行交联反应来实现。
11.根据权利要求6所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,第一步骤通过在N-甲基吗啉及氯甲酸异丁酯的存在下在有机溶剂中进行的无水偶联反应实现。
12.根据权利要求6所述的化合物、其立体异构体、或它们的药学上可接受的盐的制备方法,其特征在于,在第二步骤之后,还包括对胺进行烷基化来形成叔胺的第三步骤,以获得R1及R2均为烷基的化合物。
13.一种抗真菌组合物,其特征在于,包含权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐作为有效成分。
14.根据权利要求13所述的抗真菌组合物,其特征在于,对新型隐球菌、白假丝酵母、光滑念珠菌或烟曲霉具有抗真菌活性。
15.一种用于治疗或预防真菌感染疾病的药学组合物,其特征在于,包含权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐作为有效成分。
16.根据权利要求15所述的用于治疗或预防真菌感染疾病的药学组合物,其特征在于,真菌感染疾病为由新型隐球菌、白假丝酵母、光滑念珠菌或烟曲霉的感染引起的疾病。
17.根据权利要求15所述的用于治疗或预防真菌感染疾病的药学组合物,其特征在于,还包含药学上可接受的载体、稀释剂或赋形剂。
18.一种抗菌组合物,其特征在于,包含权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐作为有效成分。
19.根据权利要求18所述的抗菌组合物,其特征在于,对革兰氏阴性菌、革兰氏阳性菌或多重耐药菌具有抗菌活性。
20.一种用于治疗或预防细菌感染疾病的药学组合物,其特征在于,包含权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐作为有效成分。
21.一种用于治疗或预防抗炎疾病的药学组合物,其特征在于,权利要求1至5中任一项所述的化合物、其立体异构体、或它们的药学上可接受的盐及药学上可接受的载体、稀释剂或赋形剂。
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WO2023128033A1 (ko) * | 2021-12-31 | 2023-07-06 | (주)앰틱스바이오 | 감염성 진균의 바이오필름 생성을 억제하는 신규한 항진균용 조성물 |
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US20060173023A1 (en) * | 2005-02-01 | 2006-08-03 | Wood Michael R | 2-(Bicyclo)alkylamino-derivatives as mediators of chronic pain and inflammation |
WO2007087442A2 (en) * | 2006-01-25 | 2007-08-02 | Synta Pharmaceuticals Corp. | Substituted biaryl compounds for inflammation and immune-related uses |
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US8969342B2 (en) | 2009-03-20 | 2015-03-03 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
WO2012125832A2 (en) * | 2011-03-15 | 2012-09-20 | Rib-X Pharmaceuticals, Inc. | Antimicrobial agents |
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TW201804994A (zh) | 2016-08-01 | 2018-02-16 | 中央研究院 | 抗真菌劑 |
WO2018026866A1 (en) | 2016-08-03 | 2018-02-08 | Neuropore Therapies, Inc. | Lipid-substituted amino 1,2-and 1,3-diol compounds as modulators of tlr2 dimerization |
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US20230067422A1 (en) | 2023-03-02 |
JP2022535613A (ja) | 2022-08-09 |
EP3992177A4 (en) | 2023-08-16 |
US20220144755A1 (en) | 2022-05-12 |
CN114051496A (zh) | 2022-02-15 |
EP3992177A1 (en) | 2022-05-04 |
CA3145394A1 (en) | 2020-12-30 |
CO2022000187A2 (es) | 2022-01-17 |
MX2021015652A (es) | 2022-02-03 |
US20230053855A1 (en) | 2023-02-23 |
US11479526B2 (en) | 2022-10-25 |
EP3992177B1 (en) | 2024-05-08 |
US20230056812A1 (en) | 2023-02-23 |
AU2020303814A1 (en) | 2022-02-03 |
CA3145394C (en) | 2024-01-09 |
WO2020262996A1 (ko) | 2020-12-30 |
KR102286897B1 (ko) | 2021-08-09 |
AU2020303814B2 (en) | 2023-02-23 |
KR20210030343A (ko) | 2021-03-17 |
JP7290361B2 (ja) | 2023-06-13 |
IL289445A (en) | 2022-02-01 |
BR112021026076A2 (pt) | 2022-03-29 |
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