CN102161627A - ω-(N取代-氨基烷基)辛酰胺 - Google Patents
ω-(N取代-氨基烷基)辛酰胺 Download PDFInfo
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Abstract
ω-(N取代-氨基烷基)辛酰胺,本发明涉及其中取代基R1、R2、和R各自如权利要求1中定义的通式(I)化合物,该化合物具有肾素抑制活性,可以用作药物,特别是作为肾素抑制剂。
Description
技术领域
本发明涉及新的烷基酰胺、其制备方法以及该化合物作为药物的应用,尤其是作为肾素抑制剂。
背景技术
肾素-血管紧张素系统(RAS)在调节血压与体液平衡中起重要作用,RAS抑制剂如血管紧张素抑制剂(ACEI)与血管紧张素II受体拮抗剂(ARB)已广泛应用于高血压、心血管及肾脏疾病治疗,但这些药物只能部分抑制RAS,且长期应用可引起血浆肾素活性(PRA)反馈性升高。肾素是肾素-血管紧张素系统上游的限速酶,抑制肾素活性被认为能更彻底的抑制RAS系统活性。阿利克仑(Aliskiren)是首个上市的肾素抑制剂类抗高血压药物,临床试验证实阿利克仑具有与氯沙坦等常规降压药物相当的降血压活性,且具有与血管紧张素抑制剂和血管紧张素II受体拮抗剂类药物相同的靶器官保护作用(Hypertension,2003,42:1137-1143);阿利克仑与氢氯噻嗪等其他类抗高血压药物联用,能起到显著的协同降压作用,其与氢氯噻嗪的复方制剂“Tekturna HCT”,与缬沙坦的复方制剂“Valturna”,与氨氯地平的复方制剂“Tekamlo”都已经批准上市,长期临床显示药物联用能更好实现的血压调控,同时表现出良好的耐受性(Curr Med Res Opin,2010,26(12):2841-9)。以阿利克仑为代表的肾素抑制剂为高血压和相关疾病的治疗提供了新的选择方案,同时也使已有治疗方案更为有效和成熟。寻找活性更高,药效学特性更好的抑制剂分子是当下肾素抑制剂类药物研究的主要方向。
发明内容
用作药物的烷基酰胺是已知的,例如从EP 0678503中是已知的,本文设计和合成了新的烷基酰胺肾素抑制剂,具有特殊的“N取代-氨基烷基”连接片段,活性测试表明较现有抑制剂有更高的肾素抑制活性。
本发明提供了通式(1)化合物:
其中,
X为任意取代的低级烷基或环烷基、低级烷基-环烷基、环烷基-低级烷基、低级烷基-环烷基-低级烷基;
R1为任意取代的烷基酰基、烷基硫代酰基、烷基硫酰基、烷基亚硫酰基、氨基硫酰基、氨基甲酰基、烷基氧甲酰基,或与R2取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;
R2是氢、取代或未取代的低级烷基或低级烷基酰基,或与R1取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;
R各自独立地是选自以下的1-4个基团:氢、卤素、C1-C8-烷基、3-到8-元环烷基、多卤代-C1-C4-烷基、多卤代-C1-C4-烷氧基、C1-C4-烷氧基-C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷氧基-C1-C4-烷基、3-到8-元环烷氧基-C1-C4-烷基、羟基、C1-C0-烷酰氧基-C1-C4-烷基、C1-C4-烷硫基-C1-C4-烷基、C1-C8-烷磺酰基-CI-C4-烷基、C1-C4-烷磺酰基氨基-C1-C4-烷基、三氟-C1-C8-烷磺酰基氨基-C1-C4-烷基、氰基-CI-C4-烷基、C1-C4-烷氧羰基-C1-C4-烷基、氨基甲酰基-C1-C8-烷基、N-单-或N,N-二-C1-C4-烷基氨基甲酰基-C1-C4-烷基、任选被C1-C4-烷基、C1-C4-烷氧基、C1-C4-烷氨基、二-C1-C4-烷氨基、卤素和/或三氟甲基单-、二-或三取代的苯基、任选被C1-C4-烷基、C1-C4-烷氧基、羟基、c1-c4-烷氨基、二-C1-C4-烷氨基、卤素和/或三氟甲基单一、二-或三取代的萘基,及其盐,尤其是药学可用的盐。
上述化合物中优选的化合物的特征在于:
X为取代或非取代的C2-C5-烷基、环烷基、C1-C3-烷基-环烷基、环烷基-C1-C3-烷基、C1-C3-烷基-环烷基-C1-C3-烷基;
R1为C1-C6-烷基酰基、C1-C6-烷基硫代酰基、C1-C6-烷基硫酰基、C1-C6-烷基亚硫酰基、氨基硫酰基、C1-C6-氨基甲酰基、C1-C6-烷基氧甲酰基,各自独立的被以下基团取代:氢,任意的卤素或多卤素取代,C1-C6-低级烷基、环烷基、C1-C6-低级烷基-环烷烃,卤代或多卤代的C1-C6-低级烷基、环烷基、C1-C6-低级烷基-环烷烃,游离的或脂肪族酯化的或醚化的羟基,游离的或脂肪族酯化的或醚化的硫代羟基,氰基,苯基或取代苯基,杂芳基或取代杂芳基,苯基或取代苯基-C1-C6-烷基,杂芳基或取代杂芳基-C 1-C6-烷基;或与R2取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;
R2是氢、或与R1取代基一同构成饱和氮杂环、不饱和氮杂环;
R各自独立地是选自以下的1-4个基团:氢、卤素、C1-C4-烷基、C1-C4--烷氧基-C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷氧基-C1-C4-烷基、C1-C4-烷氧基和C1-C4-烷氧基-C1-C4-烷氧基;
更特征的化合物可以是下列化合物及其药学上可接受的盐或溶剂化物:
(2S,4S,5S,7S)-5-氨基-N-(3-氨基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(M2);
(2S,4S,5S,7S)-N-(3-乙酰氨基-2,2-二甲基丙基)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Ma2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2,2,2-三氟乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Md2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-丙酰胺基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mf2);
(2S,4S,5S,7S)-5-氨基-N-(3-丁酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mg2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(3-甲基丁酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mi2);
(2S,4S,5S,7S)-5-氨基-N-(3-己酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(My2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mj2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-特戊酰基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mk2);
乙基(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯(Mn2);
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺(Mo2);
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)-4-甲氧基苯甲酰胺(Mp2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2-苯乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mq2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(甲磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mr2);
(2S,4S,5S,7S)-5-氨基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mw2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Za2);
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(氨磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MA2);
(2S,4S,5S,7S)-5-氨基-N-(3-(乙基磺酰基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MB2)。
由于不对称碳原子的存在,本发明化合物可以以异构体混合物的形式存在,如外消旋体;或以纯异构体的形式存在,如旋光对映体。本发明包括了所有这些形式。可用常规方法分离非对映体混合物、非对映的外消旋体或非对映的外消旋体混合物,例如通过柱色谱、薄层色谱、HPLC等。也可以旋光纯的形式制备式(I)化合物。对映体的分离可通过已知方法来完成,优选在合成的早期阶段通过与手性氨例如奎宁或奎尼丁成盐,并通过结晶分离非对映体盐,或者优选在较晚的阶段通过与手性助剂构建块来衍生,并通过色谱法和/或结晶作用分离非对映体产物,随后裂解键,游离手性助剂。为了确定本发明化合物的绝对构型,手性HPLC分析纯非对映体盐和衍生物。
本文中所述化合物多含碱性氨基,可与酸成药学可用的盐或无毒的盐。式(I)化合物与合适的无机酸,如盐酸、氢溴酸、硫酸、磷酸,或与有机酸,如乙酸、丙酸、乙醇酸、琥珀酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、葡萄糖酸、葡糖二酸、葡萄糖醛酸、枸糠酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、扑酸、烟酸、异烟酸、各种天然非天然氨基酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙烷-1,2-二磺酸、苯磺酸、4-甲苯磺酸、萘-2-磺酸,2-或3-磷酸甘油酸、葡萄糖-6-磷酸、N-环己基氨基磺酸、抗坏血酸等成盐。
另外,药学不适合的盐也可被用于分离和纯化。
式(I)化合物也包括其中一个或多个原子被其稳定的、非放射性同位素取代的化合物,例如氢原子被氘取代,可直接用于生物体稳定同位素示踪,也能提高药物的稳定性,增加药物定量的专一性和灵敏度。
式(I)化合物可与文献的制备方法类似地制备(参见WO2001009083和WO2002008172或其中引用的文献)。
具体的制备参数的细节可以从实施例中获得。
测定肾素抑制剂抑制活性的是通过体外试验进行的,测量血管紧张素I在合成的肾素底物(带荧光检测基团的多肽)存在的条件下,缓冲液体系中形成的多少中合成的或天然的肾素底物)中的形成的减少。使用了Anaspec公司提供的“SensoLyteTM 390 Renin Assay Kit”试剂盒(方法参考Biochem.J.382:1031).
实验材料:
384孔全黑微孔板;“SensoLyteTM 390 Renin Assay Kit”试剂盒,包括:组分A 肾素底物(2mM),组分B Mc-Ala(荧光标记的Ala)标准品(3mM,5μL),组分C重组人肾素(100μL),组分D缓冲液(25mL),组分E肾素抑制剂Ac-HPFV-(Sta)-LF-NH2对照标准品(1mM DMSO solution,5μL);微孔板酶标仪;封板机;水平式微孔板摇床(700-900rpm);
预处理准备:
肾素底物预处理:以组分D(100∶1)稀释组分A,使用前配制;肾素预处理:以组分D(100∶1)稀释组分C,此浓度可用于384微孔板;抑制剂预处理:将1mM组分E加至10μM组分D中制成溶液,取5μl加至微孔,构成抑制剂对照组。
实验方法:
1.设置酶反应
将测试化合物(5μL)和肾素溶液(28μL)加入到微孔板(384)测试孔中;
按需要设立以下对照:
阳性对照,包括稀释的肾素溶液不含测试化合物;
抑制剂对照,包括稀释的肾素溶液和稀释的肾素抑制剂标准品溶液;
载体对照,包括稀释的肾素溶液和载体溶液(DMSO);
底物对照,包括缓冲液;
以缓冲液将所有对照补充至33μL。
2.预保温
温育微孔板30分钟,同时将肾素底物37℃预热。
3.启动酶反应
加17μL肾素底物溶液至微孔,将各种试剂摇匀,混合(不超过30秒),测试荧光信号;
动态监控:立即开始测量Ex/Em=330nm/390nm范围内的荧光强度,连续记录,每分钟1次,15分钟(37℃推荐)。
终点监控:在37℃温育反应15分钟,避光,然后测量Ex/Em=330nm/390nm范围的荧光强度。
4.数据分析。
附图说明
图1是(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺化合物的核磁共振氢谱;
图2是乙基(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯化合物的核磁共振氢谱;
图3是N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺化合物的核磁共振氢谱;
图4是(2S,4S,5S,7S)-5-氨基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺化合物的核磁共振氢谱;
图5是(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺化合物的核磁共振氢谱;
图6是3-叠氮-2,2-二甲基丙基-1-胺盐酸盐化合物的核磁共振氢谱;
图7-10是特征化合物的IC50抑制曲线。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。
实施例1
(2S,4S,5S,7S)-5-氨基-N-(3-氨基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(M2)
(2S,4S,5S,7S)-5-叠氮基-N-(3-叠氮基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(37mg),乙醇胺μL溶于叔丁基甲基醚6ml,加入乙醇胺少量,Pd/C(10%)适量,通氢气,搅拌反应3小时,过滤除去固体,滤液以清水洗涤,干燥,减压蒸干,得无色油状物30mg。Rf=0.15(200∶40∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-8.8(c 0.18,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~1.00(m,18H),1.15~1.48(m,3H),1.60~2.00(m,11H),2.34(br,1H),2.46~2.51(d,J=6.8Hz,2H),2.52(s,2H),3.04~3.27(m,3H),3.36(s,3H),3.58(t,J=6.0Hz,2H),3.83(s,3H),4.10(t,J=6.3Hz,2H),6.68~6.82(m,3H),6.85(br,1H);13C NMR(300MHz,CDCl3)δ17.4,20.1,20.4,21.3,23.6,23.7,27.0,29.6,30.5,34.8,35.2,35.3,37.8,42.6,47.5,51.0,51.4,54.6,56.0,58.7,66.2,69.4,72.1,111.8,114.3,121.2,134.2,147.7,148.3,175.7;ESI-MS m/z:538.4[M+H]+;HRMS forC30H55N3O5+H calcd 538.4220,found 538.4226.
实施例2
(2S,4S,5S,7S)-5-叠氮基-N-(3-叠氮基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(M3)
(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,3-叠氮-2,2-二甲基丙基-1-胺盐酸盐41.5mg,2-羟基吡啶6.3mg,三乙胺157μl,80℃搅拌反应20h。反应液用有机溶剂萃取,水洗涤,硅胶柱层析(石油醚∶乙酸乙酯=5∶1),得无色油状物41mg。Rf=0.32(2∶1石油醚-乙酸乙酯);[α]23 D-14.2(c 0.11,CHCl3);1H NMR(300MHz,CDCl3)δ0.87~0.96(m,18H),1.35~1.45(m,1H),1.50~2.00(m,H),2.07~2.12(m,3H),2.48~2.54(m,3H),2.92(br,1H),3.15(s,2H),3.08~3.28(m,2H),3.36(s,3H),3.41(br,1H),3.58(t,J=6.3Hz,2H),3.84(s,3H),4.10(t,J=6.6Hz,2H),5.85(br,1H),6.69~6.81(m,3H);13C NMR(300MHz,CDCl3)δ17.5,19.8,20.3,21.2,23.4,29.6,29.8,30.2,32.1,34.2,37.5,42.5,47.2,51.1,56.1,58.6,60.9,66.1,66.8,69.4,71.9,111.9,114.2,121.2,133.7,147.8,148.5,175.5;ESI-MS m/z:612.3[M+Na]+;HRMS forC30H52N7O5+H calcd 590.4030,found 590.4035.
实施例3
(2S,4S,5S,7S)-N-(3-乙酰氨基-2,2-二甲基丙基)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Ma2)
类似于实施例1,由(2S,4S,5S,7S)-N-(3-乙酰氨基-2,2-二甲基丙基)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺25mg制得无色油状物20mg。Rf=0.11(400∶20∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-15.7(c 0.12,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.97(m,18H),1.25~1.43(m,3H),1.66~2.22(m,10H),2.02(s,3H),2.48(m,1H),2.31(br,1H),2.89~3.11(m,5H),3.36(s,3H),3.58(t,J=6.0Hz,2H),3.83(s,3H),4.10(t,J=6.3Hz,2H),6.48(br,1H),6.68~6.79(m,3H),6.94(br,1H);13CNMR(300MHz,CDCl3)δ17.5,20.0,20.3,21.2,23.5,23.6,23.7,29.6,29.7,30.5,34.8,35.4,36.3,37.8,42.6,45.6,46.3,51.3,54.6,56.1,58.7,66.2,69.4,72.0,111.9,114.4,121.2,134.1,147.8,148.4,170.7,176.9;ESI-MS m/z:580.4[M+H]+;HRMS for C32H58N3O6+H calcd 580.4326,found 580.4332.
实施例4
(2S,4S,5S,7S)-N-(3-乙酰氨基-2,2-二甲基丙基)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)乙酰胺36.5mg,制得淡黄色油状物24mg。Rf=0.18(1∶1石油醚-乙酸乙酯);[α]23 D-21.6(c 0.12,CHCl3);1H NMR(500MHz,CDCl3)δ0.86~0.96(m,18H),1.32(m,1H),1.61~1.80(m,5H),1.91(m,1H),2.03(s,3H),2.09(t,J=6.5Hz,2H),2.12(br,1H),2.50(m,2H),2.92(m,3H),3.12(m,2H),3.36(s,3H),3.42(br,1H),3.58(t,J=6.5Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,3H),6.46(br,1H),6.67~6.80(m,3H);13C NMR(500MHz,CDCl3)δ17.5,19.9,20.3,21.2,23.3,23.6,23.9,29.6,30.0,31.9,34.3,36.1,37.5,42.5,45.8,46.1,51.2,56.1,58.6,66.2,66.4,69.4,72.0,112.0,114.4,121.3,133.9,147.9,148.5,171.1,176.4;ESI-MS m/z:606.4[M+H]+;HRMS for C32H55N5O6+H calcd 606.4231,found 606.4235.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)乙酰胺
N-(3-叠氮基-2,2-二甲基丙基)乙酰胺60mg,溶于甲醇5ml,加Pd/C(10%)适量,通氢气,搅拌反应3小时,过滤除去固体,减压蒸干,得白色固体50mg。Rf=0.12(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.89(s,6H),1.52(br,1H),1.98(s,3H),2.54(s,2H),3.15(d,J=5.8Hz,2H),6.92(br,1H);13C NMR(300MHz,CDCl3)δ23.3,23.5,34.8,48.6,51.4,170.1;ESI-MS m/z:145.1[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)乙酰胺
3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,溶于二氯甲烷5ml,加三乙胺33.6μl,醋酸酐110μl,搅拌反应25小时,以有机溶剂萃取,清水洗涤,干燥,减压蒸干,得无色油状物110mg。Rf=0.25(1∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.95(s,6H),2.04(s,3H),3.15~3.19(m,4H),6.04(br,1H);13C NMR(500MHz,CDCl3)δ23.2,23.3,23.9,36.3,47.4,60.8,170.3;ESI-MS m/z:193.2[M+Na]+.
实施例5
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2,2,2-三氟乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Md2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(2,2,2-三氟乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺17.5mg制得无色油状物15mg。Rf=0.70(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-4.8(c 0.18,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,18H),1.26~1.39(m,3H),1.65~2.00(m,5H),2.07~2.24(m,6H),2.43~2.53(m,2H),2.98~3.21(m,5H),3.36(s,3H),3.58(t,J=6.3Hz,2H),3.83(s,3H),4.10(t,J=6.6Hz,2H),6.36(br,1H),6.67~6.79(m,3H),8.71(br,1H);13C NMR(300MHz,CDCl3)δ17.6,17.8,19.8,20.3,21.2,23.5,23.6,29.6,30.0,30.4,30.7,34.8,35.6,36.6,37.9,42.6,45.3,46.6,51.1,54.6,56.0,58.6,66.3,69.4,71.9,111.9,114.4,121.2,134.0,147.8,148.4,177.7;ESI-MS m/z:634.4[M+H]+;HRMS forC32H54N3O6F3+H calcd 634.4043,found 634.4048.
实施例6
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(2,2,2-三氟乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Md1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-2,2,2-三氟乙酰胺48mg,制得淡黄色油状物45mg。Rf=0.34(3∶2石油醚-乙酸乙酯);[α]23 D-5.4(c 0.14,CHCl3);1H NMR(300MHz,CDCl3)δ0.88~0.96(m,18H),1.35~1.40(m,1H),1.50~1.91(m,6H),2.07~2.14(m,3H),2.27(br,1H),2.40~2.47(dd,J=13.8,7.5Hz,1H),2.56~2.62(dd,J=13.6,6.6Hz,1H),2.83~3.00(m,3H),3.12~3.19(dd,J=14.4,6.9Hz,2H),3.30(br,1H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,3H),6.16(br,1H),6.69~6.81(m,3H),8.54(br,1H);13C NMR(300MHz,CDCl3)δ17.8,19.6,20.2,21.1,23.5,23.6,29.6,30.1,30.4,32.4,34.1,36.7,37.6,42.5,45.4,46.7,50.7,56.1,58.6,66.2,66.7,69.4,72.0,111.9,114.3,121.3,133.7,147.9,148.5,157.6,158.1,177.3;ESI-MS m/z:660.4[M+H]+;HRMS for C32H52N5O6F3+H calcd 660.3948,found 660.3959.
实施例7
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-丙酰胺基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mf2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-丙酰胺基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺14.8mg制得无色油状物13mg。Rf=0.55(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-7.2(c 0.13,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.96(m,18H),1.18~1.21(m,3H),1.15~1.45(m,3H),1.60~1.95(m,5H),1.95~2.29(m,8H),2.46~2.48(m,2H),2.90~3.17(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.49(br,1H),6.68~6.82(m,4H);13C NMR(300MHz,CDCl3)δ10.2,17.4,19.9,20.3,21.2,23.6,23.8,27.0,29.6,30.0,30.4,34.8,35.4,36.3,37.8,42.5,45.4,46.2,51.3,54.6,56.0,58.7,66.2,69.4,72.0,111.8,114.4,121.2,134.1,147.7,148.3,174.5,176.8;ESI-MS m/z:594.4[M+H]+;HRMS for C33H59N3O6+H calcd594.4482,found 594.4487.
实施例8
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-丙酰胺基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mf1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)丙酰胺40mg,制得淡黄色油状物60mg。Rf=0.40(2∶1石油醚-乙酸乙酯);[α]23 D-6.6(c 0.19,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.97(m,18H),1.82(t,J=7.6Hz,3H),1.30~1.40(m,1H),1.59~1.92(m,7H),2.05~2.22(m,3H),2.22~2.35(m,2H),2.50(d,J=7.1Hz,1H),2.83~2.99(m,3H),3.11~3.23(m,2H),3.36(s,3H),3.36~3.50(br,1H),3.58(t,J=6.2Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,3H),6.38(br,1H),6.69~6.80(m,4H);13C NMR(300MHz,CDCl3)δ10.0,17.4,20.0,20.3,21.3,23.5,23.9,29.5,29.6,29.9,31.8,34.4,36.1,37.5,42.5,45.6,46.0,51.2,56.1,58.6,66.1,66.4,69.4,72.0,111.9,114.3,121.2,133.9,147.8,148.5,175.1,176.4;ESI-MS m/z:642.4[M+Na]+;HRMS for C33H56N5O6+Na calcd 642.4207,found642.4214.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)丙酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)丙酰胺100mg制得无色油状物80mg。Rf=0.26(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,6H),1.16(t,J=7.6Hz,3H),1.87(br,2H),2.22(q,J=15.1,7.6Hz,2H),2.53(s,2H),3.15(d,J=5.8Hz,2H),6.92(br,1H);13C NMR(300MHz,CDCl3)δ10.1,23.5,29.9,35.0,48.3,51.4,174.0;ESI-MS m/z:159.1[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)丙酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,丙酸酐156μL制得无色油状物151mg。Rf=0.51(2∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.90(s,6H),1.17(t,J=7.7Hz,3H),2.23(q,J=15.2,7.6Hz,2H),3.16(s,1H),3.18(s,3H),5.71(br,1H);13C NMR(300MHz,CDCl3)δ10.0,23.2,29.9,36.4,47.3,60.9,174.0;ESI-MS m/z:185.1[M+H]+.
实施例9
(2S,4S,5S,7S)-5-氨基-N-(3-丁酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mg2)
类似于实施例1,由(2S,4S,5S,7S)-5-氨基-N-(3-丁酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺20mg制得无色油状物16mg。Rf=0.38(200∶20∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-7.8(c 0.28,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.98(m,21H),1.18~1.45(m,3H),1.62~1.95(m,6H),1.95~2.27(m,8H),2.23(br,1H),2.47(d,J=7.0Hz,2H),2.90~3.14(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.48(br,1H),6.68~6.82(m,3H),6.85(br,1H);13C NMR(300MHz,CDCl3)δ13.8,17.6,19.9,20.0,20.3,21.2,23.6,23.8,2,29.6,29.7,30.4,34.8,35.3,36.2,37.8,39.0,42.5,45.4,46.2,51.3,54.7,56.1,58.6,66.2,69.4,72.0,111.9,114.4,121.2,134.1,147.8,148.4,173.7,176.8;ESI-MS m/z:608.5[M+H]+;HRMS forC34H61N3O6+H calcd 608.4629,found 608.4643.
实施例10
(2S,4S,5S,7S)-5-氨基-N-(3-丁酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mg1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)丁酰胺41mg,制得淡黄色油状物39mg。Rf=0.35(1∶1石油醚-乙酸乙酯);[α]23 D-29.8(c 0.63,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.98(m,21H),1.26~1.34(m,1H),1.59~2.00(m,9H),2.00~2.23(m,5H),2.50(d,J=7.1Hz,2H),2.84~2.90(m,3H),3.10~3.23(m,2H),3.36(s,3H),3.36~3.55(br,1H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.4Hz,3H),6.30(br,1H),6.68~6.99(m,4H);13C NMR(300MHz,CDCl3)δ13.7,17.3,19.2,20.0,20.3,21.3,23.5,23.9,29.5,29.8,31.8,34.4,36.0,37.5,42.4,45.5,46.0,51.2,56.1,58.6,66.1,66.3,69.4,72.0,111.9,114.2,121.2,133.8,147.8,148.4,174.2,176.4;ESI-MS m/z:656.4[M+Na]+;HRMSfor C34H60N5O6+H calcd 634.4544,found 634.4550.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)丁酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)丁酰胺80mg制得无色油状物60mg。Rf=0.32(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,6H),0.95(t,J=7.3Hz,3H),1.65(m,2H),1.67(br,2H),2.16(t,J=7.3Hz,2H),2.53(s,2H),3.15(d,J=5.9Hz,2H),6.83(br,1H);13C NMR(300MHz,CDCl3)δ13.8,19.3,23.5,38.9,48.3,51.4,173.1;ESI-MS m/z:133.1[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)丁酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,丁酸酐150μL制得无色油状物120mg。Rf=0.50(3∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.89~0.99(m,9H),1.70(m,2H),2.19(t,J=7.3Hz,2H),3.13~3.24(m,4H),5.69(br,1H);13C NMR(300MHz,CDCl3)δ13.8,19.2,23.3,36.4,38.9,47.2,60.9,173.1;ESI-MS m/z:199.1[M+H]+.
实施例11
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(3-甲基丁酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mi2)
类似于实施例1,(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(3-甲基丁酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺27.9mg制得无色油状物25mg。Rf=0.65(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-5.3(c 0.18,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.97(m,24H),1.19~1.44(m,3H),1.66~2.00(m,6H),2.00~2.21(m,7H),2.31(br,1H),2.47(d,J=6.6Hz,2H),2.91~3.20(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.52(br,1H),6.68~6.79(m,4H);13C NMR(300MHz,CDCl3)δ17.4,20.1,20.3,21.2,22.5,23.6,23.8,29.6,29.7,30.4,34.8,35.4,36.2,37.8,42.5,45.4,46.1,46.4,51.3,54.6,56.0,58.6,66.2,69.4,72.1,111.8,114.4,121.2,134.2,147.8,148.3,173.1,176.7;ESI-MS m/z:622.5[M+H]+;HRMS for C35H63N3O6+H calcd622.4795,found 622.4806.
实施例12
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(3-甲基丁酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mi1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-3-甲基丁酰胺50mg,制得淡黄色油状物70mg。Rf=0.55(1∶1石油醚-乙酸乙酯);[α]23 D-37.4(c 0.12,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.97(m,24H),1.30~1.40(m,1H),1.58~2.00(m,7H),2.05~2.20(m,6H),2.50(d,J=7.1Hz,2H),2.84~2.91(m,3H),3.11~3.24(m,2H),3.36(s,3H),3.42(br,1H),3.58(t,J=6.2Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,3H),6.32(br,1H),6.69~6.84(m,4H);13C NMR(300MHz,CDCl3)δ17.3,20.0,20.2,20.5,21.3,22.4,23.6,23.8,24.0,26.1,29.6,29.8,31.8,34.4,36.0,37.5,42.4,45.5,46.1,51.2,56.1,58.6,66.1,66.3,69.4,72.0,111.9,114.3,121.2,133.8,147.8,148.4,173.7,176.3;ESI-MS m/z:670.5[M+Na]+;HRMS for C35H61N5O6+Na calcd 670.4520,found 670.4526.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-3-甲基丁酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-3-甲基丁酰胺80mg制得无色油状物65mg。Rf=0.40(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,6H),0.96(d,J=6.2Hz,6H),1.90(br,2H),2.03~2.14(m,3H),2.54(s,2H),3.16(d,J=5.8Hz,2H),6.80(br,1H);13C NMR(300MHz,CDCl3)δ22.5,23.6,26.1,35.0,46.4,48.2,51.3,172.6;ESI-MS m/z:187.1[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)-3-甲基丁酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,异戊酰氯120μL制得无色油状物105mg。Rf=0.48(3∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.95~0.98(m,12H),2.05~2.17(m,2H),3.16~3.18(m,4H),5.69(br,1H);13C NMR(300MHz,CDCl3)δ22.5,23.3,26.1,36.4,46.3,47.2,60.9,172.6;ESI-MS m/z:235.1[M+Na]+.
实施例13
(2S,4S,5S,7S)-5-氨基-N-(3-己酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(My2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(3-己酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺32mg制得无色油状物25mg。Rf=0.35(200∶40∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-6.9(c 0.28,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,21H),1.26~1.50(m,7H),1.66~2.00(m,6H),2.00~2.27(m,8H),2.31(br,1H),2.47(d,J=6.5Hz,2H),2.92~3.17(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.52(br,1H),6.68~6.79(m,4H);13C NMR(300MHz,CDCl3)δ13.9,17.4,20.1,20.3,21.2,22.4,23.6,23.8,25.6,29.6,29.7,30.4,34.8,35.4,36.3,37.0,37.8,42.5,45.4,46.2,51.3,54.6,56.0,58.7,66.2,69.4,72.1,111.8,114.4,121.2,134.2,147.8,148.3,173.8,176.7;ESI-MS m/z:636.4[M+H]+;HRMS for C36H65N3O6+Hcalcd 636..4952,found 636.4958.
实施例14
(2S,4S,5S,7S)-5-叠氮基-N-(3-己酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(My1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-己酰胺51mg,制得淡黄色油状物60mg。Rf=0.50(1∶1石油醚-乙酸乙酯);[α]23 D-37.4(c 0.12,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,21H),1.26~1.41(m,5H),1.58~1.81(m,8H),1.81~2.00(m,1H),2.00~2.25(m,5H),2.49(d,J=7.1Hz,2H),2.84~2.94(m,3H),3.12~3.22(m,2H),3.36(s,3H),3.43(br,1H),3.58(t,J=6.2Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,2H),6.39(br,1H),6.69~6.84(m,4H);13C NMR(300MHz,CDCl3)δ13.9,17.3,20.0,20.2,21.3,22.3,23.5,23.9,25.5,29.5,29.6,29.8,31.4,31.8,34.3,36.0,36.9,37.5,42.4,45.6,46.0,51.2,56.1,58.6,66.1,66.4,69.4,72.0,111.9,114.3,121.2,133.8,147.8,148.4,174.4,176.4;ESI-MS m/z:662.5[M+H]+;HRMS for C36H63N5O6+H calcd 662.4857,found 662.4838.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-己酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-己酰胺170mg制得无色油状物150mg。Rf=0.18(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,9H),1.30~1.34(m,4H),1.65(br,2H),2.18(t,J=7.4Hz,2H),2.53(s,2H),3.15(d,J=5.9Hz,2H),6.85(br,1H);13C NMR(300MHz,CDCl3)δ13.9,22.4,23.5,25.6,31.5,35.0,37.0,48.3,51.4,173.3;ESI-MS m/z:201.2[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)-己酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,己酸酐130μL制得无色油状物105mg。Rf=0.40(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.88~0.94(m,9H),1.32~1.34(m,4H),1.64(br,2H),2.19(t,J=7.4Hz,2H),3.15~3.18(m,4H),5.69(br,1H);13C NMR(300MHz,CDCl3)δ13.9,22.4,23.3,25.5,31.5,36.9,47.2,60.1,173.3;ESI-MS m/z:249.2[M+Na]+.
实施例15
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mj2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺28.8mg制得无色油状物25mg。Rf=0.72(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D 5.1(c 0.13,CHCl3);1H NMR(300MHz,CDCl3)δ0.73~0.94(m,18H),1.15~1.45(m,3H),1.61~1.90(m,5H),2.00~2.21(m,5H),2.26(br,1H),2.40(s,3H),2.40~2.57(m,3H),2.60~2.57(m,3H),2.61~2.67(m,1H),2.77~2.88(m,1H),2.99(br,1H),3.22~3.31(m,1H),3.36(s,3H),3.57(t,J=6.2Hz,2H),3.84(s,3H),4.09(t,J=6.5Hz,2H),6.23(br,1H),6.71~6.79(m,3H),7.24~7.75(m,5H);13C NMR(300MHz,CDCl3)δ17.6,20.0,20.2,21.1,21.4,23.6,23.8,29.6,29.9,30.3,34.8,35.3,35.6,37.8,42.6,46.6,50.0,51.0,51.3,54.7,56.0,58.6,66.2,69.4,71.8,111.9,114.4,121.2,127.0,129.5,134.1,142.7,147.8,176.9;ESI-MS m/z:692.4[M+H]+;HRMSfor C37H61N3O7S+H calcd 692.4308,found 692.4311.
实施例16
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mj1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-对甲基苯磺酰胺60mg,制得淡黄色油状物36mg。Rf=0.1(2∶1石油醚-乙酸乙酯);[α]23 D-3.0(c 0.11,CHCl3);1H NMR(300MHz,CDCl3)δ0.76~0.93(m,18H),1.30~1.40(m,1H),1.49~1.85(m,6H),2.02~2.13(m,3H),2.40(s,3H),2.42~2.66(m,4H),2.82~2.98(m,2H),3.23~3.35(m,2H),3.35(s,3H),3.57(t,J=6.2Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,2H),6.12(br,2H),6.69~6.81(m,3H),7.26~7.73(m,5H);13C NMR(300MHz,CDCl3)δ17.7,19.7,20.2,21.0,21.4,23.6,23.8,29.6,29.8,30.2,32.1,34.2,35.7,37.5,42.5,46.4,50.1,50.7,56.1,58.6,66.1,66.5,69.4,71.9,111.9,114.3,121.3,126.9,129.6,133.7,137.3,143.0,147.8,148.4,176.6;ESI-MS m/z:740.4[M+Na]+;HRMS for C37H59N5O7S+Na calcd 740.4033,found 740.4052.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-对甲基苯磺酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-对甲基苯磺酰胺100mg制得白无色固体66mg。Rf=0.50(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,6H),2.42(s,3H),2.58(s,2H),2.79(s,2H),4.98(br,1H);13C NMR(300MHz,CDCl3)δ22.3,27.6,36.4,38.8,47.4,61.2,178.5;ESI-MS m/z:235.1[M+Na]+.
N-(3-叠氮基-2,2-二甲基丙基)-对甲基苯磺酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐200mg,对甲苯磺酰氯232mg制得无色油状物180mg。Rf=0.80(2∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.91(s,6H),2.43(s,3H),2.56(s,2H),2.70(br,1H),3.13~3.18(m,2H),7.26~7.75(m,4H);13CNMR(300MHz,CDCl3)δ21.5,23.6,34.2,51.8,53.1,59.8,127.0,129.7,137.2,142.9;ESI-MSm/z:257.0[M+H]+.
实施例17
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-特戊酰基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mk2)
类似于实施例1,由(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-特戊酰基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺32mg制得无色油状物26mg。Rf=0.21(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-7.9(c 0.12,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.96(m,18H),1.24(s,9H),1.15~1.45(m,3H),1.61~2.00(m,6H),2.00~2.22(m,4H),2.31(br,1H),2.47(d,J=6.7Hz,2H),2.88~3.19(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,2H),6.55(br,1H),6.68~6.79(m,3H),6.97(br,1H);13C NMR(300MHz,CDCl3)δ17.4,20.1,20.3,21.2,23.6,23.8,27.7,29.6,30.3,34.7,35.4,36.3,37.8,38.9,42.5,45.2,45.9,51.3,54.6,56.0,58.7,66.2,69.4,72.1,111.8,114.3,121.2,134.1,147.7,148.3,159.8,176.6,179.3;ESI-MS m/z:622.5[M+H]+;HRMSfor C31H63N3O6+H calcd 622.4795,found 622.4790.
实施例18
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-特戊酰基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mk1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-特戊酰胺50mg,制得淡黄色油状物42mg。Rf=0.23(1∶1石油醚-乙酸乙酯);[α]23 D-33.4(c 0.10,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.97(m,18H),1.23(s,9H),1.26~1.35(m,1H),1.55~2.00(m,6H),2.00~2.25(m,3H),2.50(d,J=6.6Hz,2H),2.77~2.95(m,4H),3.13~3.22(m,2H),3.36(s,3H),3.41(br,1H),3.58(t,J=6.3Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.47(br,1H),6.68~6.80(m,4H),6.84(br,1H);13C NMR(300MHz,CDCl3)δ17.2,20.0,20.2,21.3,23.5,23.9,27.6,29.5,29.6,29.8,31.8,34.4,37.5,38.9,42.4,45.3,45.9,51.2,56.1,58.6,66.1,66.3,69.4,72.1,111.9,114.3,121.2,133.8,147.8,148.4,176.3,179.9;ESI-MS m/z:670.5[M+Na]+;HRMS for C35H61N5O6+Na calcd 670.4520,found 670.4528.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-特戊酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-特戊酰胺96mg制得无色油状物78mg。Rf=0.21(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.94(s,6H),1.21(s,9H),3.15~3.18(m,4H),5.95(br,1H);13C NMR(300MHz,CDCl3)δ22.3,27.6,36.4,38.8,47.4,61.2,178.5;ESI-MS m/z:235.1[M+Na]+.
N-(3-叠氮基-2,2-二甲基丙基)-特戊酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,特戊酰氯147mg制得无色油状物106mg。Rf=0.26(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.86(s,9H),1.20(s,9H),2.56(s,2H),2.70(br,1H),3.13~3.18(m,2H),5.99(br,1H);13C NMR(300MHz,CDCl3)δ23.9,27.6,35.0,38.7,48.4,51.1,61.2,178.8;ESI-MS m/z:187.2[M+H]+.
实施例19
乙基(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯(Mn2)
类似于实施例1,乙基(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯32mg制得无色油状物26mg。Rf=0.35(200∶20∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-9.3(c 0.30,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,18H),1.23(t,J=7.2Hz,3H),1.15~1.45(m,3H),1.61~1.95(m,5H),1.95~2.22(m,5H),2.30(br,1H),2.48(m,2H),2.86~3.19(m,5H),3.36(s,3H),3.58(t,J=6.2Hz,2H),3.83(s,3H),4.10(m,4H),5.84(br,1H),6.40(br,1H),6.68~6.79(m,3H);13C NMR(300MHz,CDCl3)δ14.6,17.4,20.0,20.3,21.2,23.4,23.5,29.6,29.7,30.4,34.8,35.4,36.3,37.8,42.6,46.1,47.5,51.3,54.6,56.0,58.7,60.7,66.2,69.4,72.1,111.8,114.4,121.2,134.2,147.8,148.3,157.6,176.4;ESI-MS m/z:610.4[M+H]+;HRMSfor C33H59N3O7+H calcd 610.4431.found 610.4441.
实施例20
乙基(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯(Mn1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,乙基(3-氨基-2,2-二甲基丙基)氨基甲酸酯58mg,制得淡黄色油状物40mg。Rf=0.50(3∶2石油醚-乙酸乙酯);[α]23 D-27.5(c 0.11,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,18H),1.24(t,J=7.1Hz,3H),1.30~1.39(m,1H),1.50~2.00(m,6H),2.07~2.12(m,3H),2.50(d,J=7.0Hz,2H),2.88~3.22(m,5H),3.36(s,3H),3.43(br,1H),3.58(t,J=6.1Hz,2H),3.84(s,3H),4.10(m,4H),5.47(br,1H),6.59(br,1H),6.71~6.80(m,3H);13C NMR(300MHz,CDCl3)δ14.6,17.4,19.9,20.3,21.2,23.3,23.7,29.6,30.0,31.9,34.3,36.1,37.5,42.5,45.6,47.7,51.2,56.1,58.6,66.1,66.5,69.4,72.1,111.9,114.2,121.2,133.8,147.8,148.4,157.8,176.1;ESI-MS m/z:658.4[M+Na]+;HRMS for C33H57N5O7+Na calcd 658.4156,found 658.4172.
原料的制备方法:
乙基(3-氨基-2,2-二甲基丙基)氨基甲酸酯
类似于实施例2,由乙基(3-叠氮基-2,2-二甲基丙基)氨基甲酸酯90mg制得无色油状物76mg。Rf=0.29(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.88(s,6H),1.24(t,J=7.0Hz,3H),1.95(br,2H),2.52(s,2H),3.06(d,J=6.1Hz,2H),4.07~4.12(m,2H),5.54(br,1H);13C NMR(300MHz,CDCl3)δ14.6,23.2,35.5,38.8,49.2,50.6,60.7,157.1;ESI-MS m/z:175.0[M+H]+.
乙基(3-叠氮基-2,2-二甲基丙基)氨基甲酸酯
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,氯甲酸乙酯116μL制得无色油状物115mg。Rf=0.50(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.93(s,6H),1.25(t,J=7.0Hz,3H),3.07(d,J=6.6Hz,2H),3.17(s,2H),4.08~4.15(m,2H),4.81(br,1H);13C NMR(300MHz,CDCl3)δ14.5,23.1,36.5,48.8,60.4,60.9,157.0;ESI-MSm/z:223.1[M+Na]+.
实施例21
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺(Mo2)
类似于实施例1,由N-(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺49mg制得无色油状物45mg。Rf=0.50(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-11.8(c0.14,CHCl3);1H NMR(300MHz,CDCl3)δ0.72~1.00(m,18H),1.15~1.45(m,3H),1.61~2.00(m,6H),2.00~2.35(m,5H),2.46(m,2H),2.96~3.36(m,5H),3.36(s,3H),3.57(t,J=6.1Hz,2H),3.82(s,3H),4.09(t,J=6.6Hz,2H),6.51(br,1H),6.66~6.77(m,3H),7.45~7.96(m,6H);13C NMR(300MHz,CDCl3)δ17.4,20.0,20.3,21.3,23.8,27.0,29.6,29.7,30.4,34.8,35.5,36.7,37.8,42.6,45.6,46.4,51.3,54.6,56.0,58.6,66.2,69.4,72.1,111.8,114.3,121.2,127.1,128.5,131.2,134.1,134.5,147.7,148.3,167.5,177.0;ESI-MS m/z:642.4[M+H]+;HRMS forC37H59N3O6+H calcd 642.4482,found 642.4485.
实施例22
N-(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺(Mo1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-苯甲酰胺60mg,制得淡黄色油状物41mg。Rf=0.45(1∶1石油醚-乙酸乙酯);[α]23 D-28.3(c 0.26,CHCl3);1H NMR(300MHz,CDCl3)δ0.82~0.96(m,18H),1.35~1.45(m,1H),1.57~2.01(m,6H),2.01~2.13(m,2H),2.20(m,1H),2.48(m,3H),2.85~3.25(m,4H),3.36(s,3H),3.30~3.47(m,2H),3.59(t,J=6.2Hz,2H),3.84(s,3H),4.09(t,J=6.5Hz,2H),6.67~6.78(m,4H),7.43~7.89(m,6H);13C NMR(300MHz,CDCl3)δ17.4,19.9,20.3,21.3,23.7,24.0,29.6,29.7,30.1,32.0,34.3,36.6,37.5,42.5,46.1,51.1,56.1,58.6,66.1,66.4,69.4,72.1,111.9,114.3,121.2,127.0,128.6,131.6,133.8,134.1,147.8,148.4,168.1,176.6;ESI-MS m/z:690.4[M+Na]+;HRMS for C37H57N5O6+Na calcd 690.4207,found 690.4211.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-苯甲酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-苯甲酰胺60mg制得无色油状物50mg。Rf=0.20(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.96(s,6H),1.81(br,2H),2.68(s,2H),3.37(d,J=5.3Hz,2H),7.38~7.82(m,5H),8.42(br,1H);13C NMR(300MHz,CDCl3)δ23.8,34.6,50.1,52.1,126.9,128.4,131.1,134.8,167.3;ESI-MS m/z:207.2[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)-苯甲酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,苯甲酰氯130μL制得无色油状物110mg。Rf=0.38(2∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ1.07(s,6H),3.27(s,2H),3.38(d,J=6.3Hz,2H),6.47(br,1H),7.42~7.78(m,5H);13C NMR(300MHz,CDCl3)δ23.4,36.5,48.0,61.2,126.8,128.6,131.5,134.6,167.6;ESI-MS m/z:255.1[M+Na]+.
实施例23
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)-4-甲氧基苯甲酰胺(Mp2)
类似于实施例1,由N-(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)-4-甲氧基苯甲酰胺28mg制得无色油状物24mg。Rf=0.30(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-13.3(c 0.49,CHCl3);1H NMR(300MHz,CDCl3)δ0.79~0.97(m,18H),1.15~1.45(m,3H),1.60~2.00(m,6H),2.00~2.18(m,3H),2.18~2.51(m,5H),3.03~3.35(m,5H),3.35(s,3H),3.57(t,J=6.1Hz,2H),3.82(s,3H),3.84(s,3H),4.09(t,J=6.6Hz,2H),6.50(br,1H),6.66~6.77(m,3H),6.93~7.96(m,4H),7.75(br,1H);13C NMR(300MHz,CDCl3)δ17.4,20.0,20.3,21.3,23.8,29.6,29.7,30.4,34.8,35.5,36.6,37.8,42.6,45.6,46.4,51.3,54.6,55.3,56.0,58.6,66.2,69.4,72.1,111.8,113.7,114.4,121.2,126.8,128.9,134.1,147.8,148.3,162.0,167.1,176.9;ESI-MS m/z:672.4[M+H]+;HRMS for C38H61N3O7+H calcd 672.4588,found 672.4593.
实施例24
N-(3-((2S,4S,5S,7S)-5-叠氮基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)-4-甲氧基苯甲酰胺(Mp1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-4-甲氧基苯甲酰胺60mg,制得淡黄色油状物45mg。Rf=0.40(1∶1石油醚-乙酸乙酯);[α]23 D-29.9(c 0.18,CHCl3);1H NMR(300MHz,CDCl3)δ0.82~0.98(m,18H),1.35~1.45(m,1H),1.57~2.00(m,6H),2.00~2.15(m,2H),2.19(m,1H),2.48(d,J=7.1Hz,2H),2.38~2.52(br,1H),2.85~3.25(m,4H),3.36(s,3H),3.40(m,2H),3.57(t,J=6.2Hz,2H),3.82(s,3H),3.84(s,3H),4.09(t,J=6.4Hz,2H),6.67~6.78(m,4H),7.27(br,1H),6.95~7.85(m,4H);13C NMR(300MHz,CDCl3)δ17.4,19.9,20.3,21.3,23.7,24.0,29.6,30.0,31.9,34.4,36.5,37.5,42.5,45.9,46.1,51.2,55.4,56.1,58.6,66.1,66.4,69.4,72.1,111.9,113.8,114.3,121.2,126.3,128.9,133.8,147.8,148.4,162.3,167.6,176.5;ESI-MS m/z:698.5[M+H]+;HRMS forC38H59N5O7+H calcd 698.4493,found 698.4506.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-4-甲氧基苯甲酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-4-甲氧基苯甲酰胺105mg制得无色油状物83mg。Rf=0.32(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.96(s,6H),1.80(br,2H),2.68(s,2H),3.36(d,J=5.3Hz,2H),3.83(s,3H),6.90(d,J=8.6Hz,2H),7.77(d,J=8.6Hz,2H),8.25(br,1H);13C NMR(300MHz,CDCl3)δ23.8,34.7,50.0,52.1,55.3,113.6,127.2,128.7,161.9,166.9;ESI-MS m/z:237.2[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)-4-甲氧基苯甲酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,对甲氧基苯甲酰氯110μL制得无色油状物110mg。Rf=0.42(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ1.00(s,6H),3.25(s,2H),3.35(d,J=6.4Hz,2H),3.84(s,3H),6.39(br,1H),6.92(d,J=8.8Hz,2H),7.74(d,J=8.6Hz,2H);13C NMR(300MHz,CDCl3)δ23.4,36.6,47.9,55.3,61.2,113.8,126.9,128.6,162.2,167.1;ESI-MS m/z:263.2[M+H]+.
实施例25
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2-苯乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mq2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(2-苯乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺35mg制得无色油状物31mg。Rf=0.26(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-9.3(c 0.46,CHCl3);1H NMR(300MHz,CDCl3)δ0.78~0.96(m,18H),1.15~1.45(m,3H),1.60~2.20(m,10H),2.34(br,1H),2.48(d,J=6.8Hz,2H),2.83~3.13(m,5H),3.36(s,3H),3.57(m,4H),3.83(s,3H),4.10(t,J=6.6Hz,2H),6.57(br,1H),6.65~6.79(m,4H),7.27~7.33(m,5H);13C NMR(300MHz,CDCl3)δ17.4,20.1,20.3,21.2,23.5,23.7,27.0,29.6,30.4,34.7,35.3,36.4,37.8,42.5,44.0,45.8,45.9,51.2,54.6,56.0,58.6,66.2,69.4,72.1,111.8,114.4,121.2,127.1,128.8,129.2,134.2,135.3,147.8,148.3,171.7,176.5;ESI-MS m/z:656.5[M+H]+;HRMSfor C38H61N3O6+H calcd 656.4639,found 656.4643.
实施例26
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(2-苯乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mq1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-2-苯乙酰胺60mg,制得淡黄色油状物42mg。Rf=0.48(1∶1石油醚-乙酸乙酯);[α]23 D-30.5(c 0.27,CHCl3);1H NMR(300MHz,CDCl3)δ0.77~0.96(m,18H),1.30~1.40(m,1H),1.55~2.00(m,7H),2.00~2.22(m,3H),2.50~2.51(d,J=7.1Hz,2H),2.77~3.17(m,5H),3.35(s,3H),3.45(br,1H),3.57(m,4H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.16(br,1H),6.69~6.83(m,4H),7.28~7.40(m,5H);13C NMR(300MHz,CDCl3)δ17.3,20.0,20.2,21.3,23.4,23.8,29.5,29.6,29.8,31.7,34.2,36.2,37.5,42.5,43.9,45.4,46.2,51.2,56.1,58.6,66.1,66.3,69.4,71.9,111.9,114.3,121.2,127.1,127.5,129.1,129.2,133.9,134.8,147.8,148.4,172.3,176.2;ESI-MS m/z:682.5[M+H]+;HRMS for C38H59N5O6+H calcd 682.4544,found 682.4532.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-2-苯乙酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-2-苯乙酰胺120mg制得无色油状物100mg。Rf=0.25(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.83(s,6H),1.21(br,2H),2.41(s,2H),3.10(d,J=5.7Hz,2H),3.56(s,2H),6.86(br,1H),7.25~7.36(m,5H);13C NMR(300MHz,CDCl3)δ23.3,35.0,44.0,48.5,51.4,127.1,128.8,129.5,135.2,171.1;ESI-MS m/z:221.1[M+H]+.
N-(3-叠氮基-2,2-二甲基丙基)-2-苯乙酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,苯乙酰氯100μL制得无色油状物103mg。Rf=0.33(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.83(s,6H),3.03(s,2H),3.10(d,J=6.2Hz,2H),3.60(s,2H),5.68(br,1H),7.26~7.40(m,5H);13C NMR(300MHz,CDCl3)δ23.1,36.1,44.0,47.6,61.0,127.5,129.0,129.4,134.9,171.1;ESI-MS m/z:269.1[M+Na]+.
实施例27
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(甲磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mr2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(甲磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺34mg制得无色油状物31mg。Rf=0.18(200∶30∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.86~0.96(m,18H),1.15~1.45(m,3H),1.60~2.00(m,6H),2.00~2.20(m,4H),2.28(br,1H),2.39~2.56(m,2H),2.86~3.21(m,5H),2.89(s,3H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.6Hz,2H),6.23(br,2H),6.68~6.80(m,3H);13C NMR(300MHz,CDCl3)δ17.6,20.0,20.3,21.1,23.6,23.7,27.0,29.6,30.0,30.5,34.8,35.4,35.8,37.9,39.8,42.6,46.6,50.0,51.0,54.7,56.1,58.6,66.3,69.4,71.9,111.9,114.4,121.2,134.1,147.8,148.4,177.1;ESI-MS m/z:616.4[M+H]+;HRMS for C31H57N3O7S+H calcd 616.3995,found616.4003.
实施例28
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(甲磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mr1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-甲基磺酰胺45mg,制得淡黄色油状物35mg。Rf=0.15(1∶1石油醚-乙酸乙酯);[α]23 D-20.1(c 0.28,CHCl3);1H NMR(300MHz,CDCl3)δ0.72~0.95(m,18H),1.30~1.40(m,1H),1.50~1.95(m,6H),2.05~2.18(m,3H),2.44~2.70(m,3H),2.74~3.20(m,5H),2.90(s,3H),3.35(s,3H),3.37(br,1H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.6Hz,2H),5.95(br,1H),6.18(br,1H),6.69~6.83(m,3H);13C NMR(300MHz,CDCl3)δ17.7,19.7,20.3,21.1,23.5,23.7,29.6,29.9,30.2,32.1,34.1,35.8,37.6,39.8,42.5,46.4,50.0,50.7,56.1,58.6,66.2,66.6,69.4,72.0,112.0,114.4,121.3,133.8,147.9,148.5,176.8.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-甲基磺酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-甲基磺酰胺100mg制得无色油状物70mg。Rf=0.20(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.95(s,6H),2.64(s,2H),2.93(s,3H),3.01(s,2H),3.01~3.40(br,2H);13C NMR(300MHz,CDCl3)δ23.7,34.4,39.7,51.6,52.9.
N-(3-叠氮基-2,2-二甲基丙基)-甲基磺酰胺
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐250mg,甲磺酰氯201mg制得无色油状物206mg。Rf=0.40(4∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.99(s,6H),2.97(s,3H),2.98(d,J=6.2Hz,2H),3.20(s,2H),4.74(br,1H);ESI-MS m/z:205.1[M-H]-.
实施例29
(2S,4S,5S,7S)-5-氨基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mw2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺28mg制得无色油状物24mg。Rf=0.11(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-14.7(c 0.32,CHCl3);1H NMR(300MHz,CDCl3)δ0.83~0.96(m,18H),1.15~1.45(m,3H),1.60~2.00(m,6H),2.00~2.20(m,4H),2.44(br,1H),2.47(d,J=6.8Hz,2H),2.93(s,6H),2.90~3.20(m,5H),3.36(s,3H),3.58(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),5.59(br,2H),6.68~6.82(m,4H);13C NMR(300MHz,CDCl3)δ17.4,20.1,20.3,21.3,23.6,23.8,27.0,29.6,30.3,34.7,35.4,35.8,36.0,36.3,37.8,42.5,45.8,46.9,51.4,54.5,56.1,58.6,66.2,69.4,72.2,111.9,114.4,121.2,134.2,147.7,148.3,159.0,176.5;ESI-MS m/z:609.5[M+H]+;HRMS for C33H60N4O6+H calcd 609.4591,found 609.4603.
实施例30
(2S,4S,5S,7S)-5-叠氮基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Mw1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,3-(3-氨基-2,2-二甲基丙基)-1,1-二甲基脲43mg,制得淡黄色油状物54mg。Rf=0.13(1∶1石油醚-乙酸乙酯);[α]23 D-49.1(c 0.41,CHCl3);1H NMR(300MHz,CDCl3)δ0.83~0.96(m,18H),1.26~1.35(m,1H),1.55~2.00(m,6H),2.05~2.22(m,3H),2.51(m,2H),2.79~3.30(m,5H),2.93(s,6H),3.36(s,3H),3.45(br,1H),3.57(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),5.07(br,1H),6.68~6.80(m,3H),7.15(br,1H);13C NMR(300MHz,CDCl3)δ17.2,20.1,20.2,21.3,23.4,24.0,29.4,29.6,31.7,34.6,35.8,36.3,37.5,42.5,45.2,47.5,51.2,56.1,58.6,66.1,66.5,69.4,72.1,111.9,114.3,121.2,133.9,147.8,159.0,176.1;ESI-MS m/z:635.5[M+H]+;HRMS forC33H58N6O6+H calcd 635.4496,found 635.4508.
原料的制备方法:
3-(3-氨基-2,2-二甲基丙基)-1,1-二甲基脲
类似于实施例2,由3-(3-叠氮基-2,2-二甲基丙基)-1,1-二甲基脲100mg制得无色油状物83mg。Rf=0.11(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.89(s,6H),2.17(br,2H),2.56(s,2H),2.89(s,6H),3.13(d,J=5.3Hz,2H),5.98(br,1H);13CNMR(300MHz,CDCl3)δ23.6,34.9,36.2,50.1,51.3,158.9.
3-(3-叠氮基-2,2-二甲基丙基)-1,1-二甲基脲
类似于实施例2,由3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg,N,N-二甲酰氯90μL制得无色油状物95mg。Rf=0.15(1∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ0.94(s,6H),2.92(s,6H),3.15(d,J=6.2Hz,2H),3.19(s,2H),4.67(br,1H);13C NMR(300MHz,CDCl3)δ23.2,36.2,49.0,61.1,158.5;ESI-MS m/z:222.1[M+Na]+.
实施例31
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Za2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺28mg制得无色油状物25mg。Rf=0.18(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-6.6(c 0.31,CHCl3);1H NMR(300MHz,CDCl3)δ0.82~0.98(m,18H),1.15~1.45(m,3H),1.55~2.15(m,7H),2.00~2.15(m,2H),2.24(br,1H),2.32(br,1H),2.48(m,2H),3.01~3.21(m,3H),3.36(s,3H),3.57(t,J=6.2Hz,2H),3.83(s,3H),4.09(t,J=6.5Hz,2H),4.21(s,2H),6.38(br,1H),6.66~6.79(m,3H),7.69(s,1H),7.76(s,1H);13C NMR(300MHz,CDCl3)δ17.4,20.0,20.3,21.3,23.7,23.9,29.6,29.7,30.5,34.8,35.5,37.0,37.8,42.6,46.2,51.2,54.6,56.1,57.3,58.7,66.3,69.4,72.1,111.9,114.5,121.2,125.1,133.5,134.2,147.8,148.4,176.2;ESI-MSm/z:590.4[M+H]+;HRMS for C32H55N5O5+H calcd 590.4281,found 590.4293.
实施例32
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(Za1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙烷-1-胺60mg,制得淡黄色油状物45mg。Rf=0.21(1∶1石油醚-乙酸乙酯;[α]23 D-19.2(c 0.27,CHCl3);1H NMR(300MHz,CDCl3)δ0.86~0.97(m,18H),1.30~1.40(m,1H),1.50~2.00(m,6H),2.04~2.22(m,3H),2.50(m,2H),2.93~3.18(m,4H),3.35(s,3H),3.44(br,1H),3.57(t,J=6.2Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),4.20(s,2H),6.40(br,1H),6.68~6.80(m,3H),7.67(s,1H),7.71(s,1H);13C NMR(300MHz,CDCl3)δ17.5,19.9,20.2,21.2,23.9,24.0,29.6,29.7,30.1,32.0,34.1,37.1,37.5,42.5,46.2,51.1,56.1,57.5,58.6,66.2,66.6,69.4,71.9,111.9,114.3,121.2,125.1,133.6,133.8,147.8,148.5,176.1;ESI-MS m/z:638.4[M+Na]+;HRMS for C33H53N7O5+Na calcd 638.4006,found 638.4014.
原料的制备方法:
2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙烷-1-胺
3-叠氮-2,2-二甲基丙基-1-胺盐酸盐164mg溶于二氯甲烷5ml中,加三乙胺33.6μl,硫酸铜溶液适量,缓慢通入乙炔气体,搅拌反应2小时。过滤除去不溶性杂质,有机溶剂萃取,洗涤,干燥,减压蒸干,得桔黄色油状物100mg。Rf=0.12(200∶20∶1二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.93(s,6H),1.49(br,2H),2.44(s,2H),4.29(s,2H),7.57(s,1H),7.68(s,1H);13C NMR(300MHz,CDCl3)δ23.5,36.7,49.4,56.9,124.8,133.2;ESI-MS m/z:155.1[M+H]+.
实施例33
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(氨磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MA2)
类似于实施例1,由(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(氨磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺34mg制得无色油状物29mg。Rf=0.08(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-5.8(c 0.21,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.95(m,18H),1.15~1.45(m,3H),1.55~2.00(m,5H),2.00~2.15(m,3H),2.30(br,1H),2.38~2.59(m,2H),2.80(br,2H),2.95~3.25(m,6H),3.36(s,3H),3.36(br,1H),3.57(t,J=6.1Hz,2H),3.83(s,3H),4.10(t,J=6.5Hz,2H),6.26(br,1H),6.68~6.80(m,3H),7.69(s,1H),7.76(s,1H);13C NMR(300MHz,CDCl3)δ17.8,19.8,20.3,21.1,23.7,23.9,29.6,30.0,30.6,34.3,35.2,35.4,37.8,42.8,46.6,50.4,51.1,54.5,56.1,58.6,66.3,69.4,72.2,111.9,114.6,121.3,134.2,147.8,148.3,176.8;ESI-MS m/z:617.4[M+H]+;HRMS for C30H56N4O7S+H calcd 617.3948,found 617.3956.
实施例34
(2S,4S,5S,7S)-5-叠氮基-N-(2,2-二甲基-3-(氨磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MA1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-氨基磺酰胺50mg,制得淡黄色油状物45mg。Rf=0.35(1∶1石油醚-乙酸乙酯);[α]23 D-12.5(c 0.20,CHCl3);1H NMR(300MHz,CDCl3)δ0.84~0.96(m,18H),1.30~1.40(m,1H),1.50~2.00(m,6H),2.03~2.18(m,4H),2.38~2.65(m,2H),2.70~3.23(m,5H),3.37(s,3H),3.44(br,1H),3.58(t,J=6.1Hz,2H),3.85(s,3H),4.11(t,J=6.5Hz,2H),4.83(br,2H),5.82(br,1H),6.17(br,1H),6.72~6.83(m,3H);13C NMR(300MHz,CDCl3)δ17.9,19.5,20.3,21.2,23.8,23.9,29.5,30.0,30.1,32.2,34.1,35.5,37.5,42.6,46.5,50.3,50.9,56.1,58.6,66.1,66.6,69.4,71.8,111.8,114.2,121.3,133.8,147.7,148.3,176.9;ESI-MS m/z:665.4[M+Na]+;HRMS forC30H54N6O7S+Na calcd 665.3668,found 665.3668.
原料的制备方法:
N-(3-氨基-2,2-二甲基丙基)-氨基磺酰胺
类似于实施例2,由N-(3-叠氮基-2,2-二甲基丙基)-氨基磺酰胺60mg制得无色油状物51mg。Rf=0.21(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.95(s,6H),2.65(s,2H),3.02(s,2H),7.57(s,1H),3.00~4.00(br,2H);13C NMR(300MHz,CDCl3)δ23.7,34.2,51.8,53.4;ESI-MS m/z:180.0[M-H]-.
N-(3-叠氮基-2,2-二甲基丙基)-氨基磺酰胺
3-叠氮-2,2-二甲基丙基-1-胺盐酸盐200mg溶于乙醚5ml中,以0.5氢氧化钠水溶液游离有机碱,所得游离碱以二氧六环10ml溶解,加入磺酰胺900mg,105℃回流反应15小时,停止反应,有机溶剂萃取,洗涤,干燥,蒸干,得米黄色固体210mg。Rf=0.15(200∶40∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,CDCl3)δ0.98(s,6H),2.97(d,J=7.1Hz,2H),3.23(s,2H),4.76(m,3H);13C NMR(300MHz,CDCl3)δ23.2,35.7,51.1,59.9;ESI-MS m/z:206.1[M-H]
实施例35
(2S,4S,5S,7S)-5-氨基-N-(3-(乙基磺酰基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MB2)
类似于实施例1,由(2S,4S,5S,7S)-5-氨基-N-(3-(乙基磺酰基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺35mg制得无色油状物29mg。Rf=0.22(200∶30∶5二氯甲烷-甲醇-25%浓氨水);[α]23 D-5.9(c0.30,CHCl3);1H NMR(300MHz,CDCl3)δ0.85~0.96(m,18H),1.15~1.45(m,3H),1.35(t,J=7.4Hz,3H),1.55~2.00(m,6H),2.00~2.17(m,4H),2.25(br,1H),2.50(m,2H),2.70(m,2H),2.90~3.23(m,5H),3.36(s,3H),3.58(t,J=6.0Hz,2H),3.84(s,3H),4.10(t,J=6.5Hz,2H),6.29(br,2H),6.68~6.79(m,3H);13C NMR(300MHz,CDCl3)δ8.2,17.5,20.0,20.3,21.2,23.6,23.7,27.0,29.6,29.9,30.5,34.8,35.5,35.8,37.9,42.7,46.6,49.9,51.0,54.7,56.1,58.6,66.3,69.4,72.0,111.9,114.4,121.2,134.1,147.8,148.4,177.0;ESI-MS m/z:630.4[M+H]+;HRMS forC32H59N3O7S+H calcd 630.4152,found 630.4157.
实施例36
(2S,4S,5S,7S)-5-氨基-N-(3-(乙基磺酰基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺(MB1)
类似于实施例1,由(3S,5S)-5-((1S,3S)-1-叠氮基-3-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-4-甲基戊基)-3-异丙基二氢呋喃-2(3H)-酮50mg,N-(3-氨基-2,2-二甲基丙基)-乙基磺酰胺50mg,制得淡黄色油状物35mg。Rf=0.50(1∶1石油醚-乙酸乙酯);[α]23 D-16.9(c 0.34,CHCl3);1H NMR(300MHz,CDCl3)δ0.89~0.96(m,18H),1.30~1.40(m,1H),1.35(t,J=7.4Hz,3H),1.50~1.95(m,6H),2.04~2.18(m,3H),2.44~2.60(m,2H),2.60~2.68(m,1H),2.72~2.83(m,2H),2.91(br,1H),2.97~3.09(m,1H),3.13~3.25(m,1H),3.37(s,3H),3.41(br,1H),3.59(t,J=6.2Hz,2H),3.85(s,3H),4.11(t,J=6.5Hz,2H),5.87(br,1H),6.18(br,1H),6.71~6.84(m,3H);13C NMR(300MHz,CDCl3)δ8.2,17.6,19.8,20.3,21.1,23.5,23.6,29.6,29.9,30.2,32.1,34.1,35.9,37.6,42.5,46.3,46.7,50.0,50.7,56.1,58.6,66.2,66.6,69.4,72.0,112.0,114.3,121.3,133.8,147.9,148.5,176.7;ESI-MS m/z:678.4[M+Na]+;HRMS forC32H57N5O7S+Na calcd 678.3876,found 678.3888.
实施例37
中间体的制备:
3-叠氮-2,2-二甲基丙基-1-胺盐酸盐
2-(3-叠氮-2,2-二甲基丙基)异二氢吲哚-1,3二酮2.6g,溶于乙醇40ml,加85%水合肼3.12ml,80℃回流反应4小时,冷却,将不溶性固体滤除,反应液以有机溶剂萃取,水洗涤,干燥,通干燥HCl至酸性,减压蒸干,得淡黄色固体1.83g。Rf=0.30(200∶10∶5二氯甲烷-甲醇-25%浓氨水);1H NMR(300MHz,DMSOd6)δ0.96(s,6H),2.66(s,2H),3.48(s,2H),8.25(br,3H);13C NMR(300MHz,DMSOd6)δ22.5,34.5,45.8,58.3;ESI-MS m/z:129.1[M+H]+.
2-(3-叠氮-2,2-二甲基丙基)异二氢吲哚-1,3二酮
2-(3-溴-2,2-二甲基丙基)异二氢吲哚-1,3二酮480mg溶于DMF 2ml中,加叠氮化钠127mg,90℃反应10小时,有机溶剂萃取,洗涤,干燥,蒸干,得淡黄色油状物390mg。Rf=0.60(6∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ1.01(s,6H),3.24(s,2H),3.59(s,2H),7.72~7.88(m,4H);13C NMR(300MHz,CDCl3)δ23.7,38.0,45.7,60.8,123.3,131.9,134.1.168.9.
2-(3-溴-2,2-二甲基丙基)异二氢吲哚-1,3二酮
1,3-二溴-2,2-二甲基丙烷1g,邻苯二甲酰亚胺0.21g,碳酸钾0.59g,溶于DMF 10ml中,90℃反应10小时,有机溶剂萃取,洗涤,干燥,蒸干,得白色固体0.31g。Rf=0.60(6∶1石油醚-乙酸乙酯);1H NMR(300MHz,CDCl3)δ1.11(s,6H),3.38(s,2H),3.70(s,2H),7.72~7.88(m,4H).
1,3-二溴-2,2-二甲基丙烷
三苯基膦26.2g分散在50ml乙腈中,冰盐浴下缓慢滴加液溴5.13ml的乙腈溶液30ml,加入新戊二醇固体5.2g,升温至80℃,回流反应10小时,蒸出溶剂,减压蒸馏得淡黄色油状物7.5g。1H NMR(300MHz,CDCl3)δ1.17(s,6H),3.41(s,2H),3.47(s,2H).
实施例38
使用“Sensolyte 390 Renin assay kit”测试盒,在500nM,100nM,20nM,4nM,0.8nM,0.16nM六个浓度梯度下测试了化合物的肾素抑制活性,得到化合物IC50测试结果如表1所示:
表1特征化合物与Aliskiren IC50值
化合物编号 | IC50值(纳摩尔/升) |
M2 | 2.88 |
Ma2 | 2.17 |
Md2 | 4.85 |
Mf2 | 1.08 |
Mg2 | 1.12 |
Mi2 | 1.48 |
Mj2 | 1.15 |
Mk2 | 4.13 |
Mn2 | 0.81 |
Mo2 | 1.02 |
Mp2 | 3.84 |
Mq2 | 1.64 |
Mr2 | 4.23 |
Mw2 | 0.36 |
My2 | 0.83 |
Za2 | 0.20 |
MA2 | 0.79 |
MB2 | 0.91 |
Aliskiren | 2.21 |
Claims (11)
1.通式I的化合物或其药学上可接受的盐:
其中,X为任意取代的低级烷基或环烷基、低级烷基-环烷基、环烷基-低级烷基、低级烷基-环烷基-低级烷基;
R1为任意取代的烷基酰基、烷基硫代酰基、烷基硫酰基、烷基亚硫酰基、氨基硫酰基、氨基甲酰基、烷基氧甲酰基,或与R2取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;
R2是氢、取代或未取代的低级烷基或低级烷基酰基,或与R1取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;
R各自独立地是选自以下的1-4个基团:氢、卤素、C1-C8-烷基、3-到8-元环烷基、多卤代-C1-C4-烷基、多卤代-C1-C4-烷氧基、C1-C4-烷氧基-C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷氧基-C1-C4-烷基、3-到8-元环烷氧基-C1-C4-烷基、羟基、C1-C0-烷酰氧基-C1-C4-烷基、C1-C4-烷硫基-C1-C4-烷基、C1-C8-烷磺酰基-CI-C4-烷基、C1-C4-烷磺酰基氨基-C1-C4-烷基、三氟-C1-C8-烷磺酰基氨基-C1-C4-烷基、氰基-CI-C4-烷基、C1-C4-烷氧羰基-C1-C4-烷基、氨基甲酰基-C1-C8-烷基、N-单-或N,N-二-C1-C4-烷基氨基甲酰基-C1-C4-烷基、任选被C1-C4-烷基、C1-C4-烷氧基、C1-C4-烷氨基、二-C1-C4-烷氨基、卤素和/或三氟甲基单-、二-或三取代的苯基、任选被C1-C4-烷基、C1-C4-烷氧基、羟基、c1-c4-烷氨基、二-C1-C4-烷氨基、卤素和/或三氟甲基单一、二-或三取代的萘基。
2.根据权利要求1的化合物或其盐,其中,X为低级烷基、环烷基、烷基-代环烷基、烷基-环烷基-烷基,以及各自独立的被以下基团取代:任意的卤素取代或多卤素取代,游离的或脂肪族酯化的或醚化的羟基取代,游离的或脂肪族酯化的或醚化的硫代羟基取代,或者氰基取代。
3.根据权利要求1的化合物或其盐,其中,R1为烷基酰基、硫代烷基酰基、烷基硫酰基、烷基亚硫酰基、氨基硫酰基、氨基甲酰基、烷基氧甲酰基,各自独立的被以下基团取代:氢,任意的卤素或多卤素取代,低级烷基、环烷基、低级烷基-环烷烃,卤代或多卤代的低级烷基、环烷基、低级烷基-环烷烃,游离的或脂肪族酯化的或醚化的羟基,游离的或脂肪族酯化的或醚化的硫代羟基,氰基,酰胺基,羧基,游离的或烷基化、酰胺化、磺酰化、亚硫酰化、氨基磺酰化、氨基甲酰化、烷基氧甲酰化的氨基,游离的或脂肪族酯化的或醚化的羟基-烷基,游离的或脂肪族酯化的或醚化的硫代羟基-烷基,氰基-烷基,酰胺基-烷基,羧基-烷基,游离的或烷基化、酰胺化、磺酰化、亚硫酰化、氨基磺酰化、氨基甲酰化、烷基氧甲酰化的氨基-烷基,苯基或取代苯基,杂芳基或取代杂芳基,苯基或取代苯基-烷基,杂芳基或取代杂芳基-烷基;或与R2取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环。
4.根据权利要求1的化合物及其盐,其中,R1为氨基硫酰基、N-烷基化的氨基硫酰基、任意取代的N-烷基化的氨基硫酰基。
5.根据权利要求1的化合物及其盐,其中,X为取代或非取代的C2-C5-烷基、环烷基、C1-C3-烷基-环烷基、C1-C3-烷基-环烷基-C1-C3-烷基;R1为C1-C6-烷基酰基、C1-C6-烷基硫代酰基、C1-C6-烷基硫酰基、C1-C6-烷基亚硫酰基、氨基硫酰基、C1-C6-氨基甲酰基、C1-C6-烷基氧甲酰基,各自独立的被以下基团取代:氢,任意的卤素或多卤素取代,C1-C6-低级烷基、环烷基、C1-C6-低级烷基-环烷烃,卤代或多卤代的C1-C6-低级烷基、环烷基、C1-C6-低级烷基-环烷烃,游离的或脂肪族酯化的或醚化的羟基,游离的或脂肪族酯化的或醚化的硫代羟基,氰基,苯基或取代苯基,杂芳基或取代杂芳基,苯基或取代苯基-C1-C6-烷基,杂芳基或取代杂芳基-C1-C6-烷基;或与R2取代基一同构成饱和或不饱和氮杂环、取代的饱和或不饱和氮杂环;R2是氢、或与R1取代基一同构成饱和氮杂环、不饱和氮杂环;R各自独立地是选自以下的1-4个基团:氢、卤素、C1-C4-烷基、C1-C4--烷氧基-C1-C4-烷基、C1-C4-烷氧基-C1-C4-烷氧基-C1-C4-烷基、C 1-C4-烷氧基和C1-C4-烷氧基-C1-C4-烷氧基。
6.权利要求1所述的化合物,其特征化合物可以是下列任一化合物或其药学上可接受的盐或溶剂化物:
(2S,4S,5S,7S)-5-氨基-N-(3-氨基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-N-(3-乙酰氨基-2,2-二甲基丙基)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2,2,2-三氟乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-丙酰胺基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(3-丁酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(3-甲基丁酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(3-己酰基-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(4-甲基苯磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-特戊酰基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
乙基(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)氨基甲酸酯;
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)苯甲酰胺;
N-(3-((2S,4S,5S,7S)-5-氨基-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺)-2,2-二甲基丙基)-4-甲氧基苯甲酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(2-苯乙酰氨基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(甲磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(3-(3,3-二甲基脲基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(1H-1,2,3-三唑-1-基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(2,2-二甲基-3-(氨磺酰基)丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺;
(2S,4S,5S,7S)-5-氨基-N-(3-(乙基磺酰基)-2,2-二甲基丙基)-4-羟基-2-异丙基-7-(4-甲氧基-3-(3-甲氧基丙氧基)苄基)-8-甲基壬酰胺。
7.权利要求1所述的化合物其制备使用到中间体(II)或其盐,
其中,X如权利要求1、2、5所定义,为取代的低级烷基或环烷基、低级烷基-环烷基、低级烷基-环烷基-低级烷基,其制备方法包括以下步骤:
步骤(1):式(a)化合物与试剂P-NH或其盐在有机溶剂中,在碱存在下反应得到式(b)化合物。其中,A为任意离去基团,如甲磺酰基,三氟甲磺酰基,苯磺酰基,对甲苯磺酰基,对甲氧基苯磺酰基及其活化的醇羟基、F、Cl、Br、I等;B为碱性缚酸剂,如三乙胺、二异丙基乙胺、吡啶、碳酸氢钾、碳酸氢钠、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾;P-NH为可提供保护的氮原子的试剂,如邻苯二甲酰基亚胺、任意硝基取代的邻苯二甲酰亚胺、任意卤素取代的邻苯二甲酰亚胺、四氢邻苯二甲酰亚胺、六氢邻苯二甲酰亚胺及对应碱金属盐;有机溶剂可以是苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂,优选四氢呋喃、乙腈或N,N-二甲基甲酰胺;反应温度为0℃至150℃,优选温度为40℃至140℃。
步骤(2):式(b)化合物与叠氮化试剂在有机溶剂中,在碱性条件下反应得到式(c)化合物。其中,A为任意离去基团,如甲磺酰基,三氟甲磺酰基,苯磺酰基,对甲苯磺酰基,对甲氧基苯磺酰基及其活化的醇羟基、F、Cl、Br、I等;碱性缚酸剂为三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸钠;叠氮化试剂为叠氮酸及其钾盐、钠盐、对甲苯磺酰叠氮、对乙酰氨基苯磺酰叠氮;有机溶剂可以是苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂,优选四氢呋喃、乙腈或N,N-二甲基甲酰胺;反应温度为0℃至150℃,优选温度为60℃至120℃。
步骤(3):式(c)化合物与碱性试剂在有机溶剂中,加热反应得到式(d)化合物。其中,P是可为氮原子提供保护的双取代基团,如邻苯二甲酰基、任意硝基取代的邻苯二甲酰基、任意卤素取代的邻苯二甲酰基、四氢邻苯二甲酰基、六氢邻苯二甲酰基;有机溶剂可以是苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N,N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂,优选四氢呋喃、甲醇或乙醇;反应温度为0℃至120℃,优选温度为50℃至100℃。
步骤(4):式(d)化合物溶于有机溶剂,加入或通入各种酸试剂,制得相应的盐式(e)化合物。其中,酸可以为盐酸、氢溴酸、硫酸、乙酸、磷酸或对甲苯磺酸;有机溶剂可以是苯、甲苯、氯仿、正己烷、环己烷、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氯化碳、乙酸乙酯、乙酸丙酯、乙酸丁酯、甲醇、乙醇、丙酮、四氢呋喃、乙醚、乙腈、N;N-二甲基甲酰胺、二甲亚砜或者用这些溶剂任选组成的混合溶剂,优选二氯甲烷、氯仿或乙醚;反应温度为室温。
8.根据权利要求1的式(I)化合物用于制备预防、控制、或治疗高血压、心力衰竭、青光眼、心肌梗塞、肾衰竭、再狭窄或中风的人用药物的应用,或作为相关疾病的诊断试剂。
9.预防、控制、或治疗高血压、心力衰竭、青光眼、心肌梗塞、肾衰竭、再狭窄或中风的方法,其中使用治疗有效量的权利要求1的通式(I)化合物。
10.包含权利要求1的通式(I)化合物和常用赋形剂的药物制剂。
11.制剂形式或由各个组分组成的药盒形式的药物组合,包含a)权利要求1的通式(I)化合物,和b)至少一种其活性成分具有心血管作用的药物形式。
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WO2003103653A1 (en) * | 2002-06-11 | 2003-12-18 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease using aryl alkanoic acid amides |
CN1882528A (zh) * | 2003-11-26 | 2006-12-20 | 诺瓦提斯公司 | 有机化合物 |
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CN1117960A (zh) * | 1994-04-18 | 1996-03-06 | 西巴-盖尔基股份公司 | 新的δ-氨基-γ羟基-ω-芳基-链烷酰胺类化合物 |
WO2003103653A1 (en) * | 2002-06-11 | 2003-12-18 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease using aryl alkanoic acid amides |
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