CN109280076B - 肽酰胺类化合物及其制备方法和在医药上的用途 - Google Patents
肽酰胺类化合物及其制备方法和在医药上的用途 Download PDFInfo
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- CN109280076B CN109280076B CN201810774080.4A CN201810774080A CN109280076B CN 109280076 B CN109280076 B CN 109280076B CN 201810774080 A CN201810774080 A CN 201810774080A CN 109280076 B CN109280076 B CN 109280076B
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Abstract
本发明涉及一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶及其组合物、制备方法和在医药上的用途,通式(I)如下所示:
Description
技术领域
本发明涉及一种具有镇痛作用的肽酰胺类化合物及其制备方法和在医药上的用途。
背景技术
阿片类药物用于疼痛的治疗已有数千年的历史,其主要通过与已知的三种经典阿片受体μ,δ和κ相互结合而发挥生理作用。这三种受体都是G蛋白偶联受体家族的一员,主要分布在中枢神经系统,同时也存在于很多外周组织中。其中最为经典的药物属吗啡,其主要通过μ阿片受体的作用发挥镇痛效果。
此外常用的临床镇痛药物还包含其他μ阿片受体药物,如以二氢吗啡酮、芬太尼为代表的传统类阿片药物。
然而μ阿片受体类药物在长期使用后会产生多种副作用,例如耐受、依赖和呼吸抑制以及对胃肠运动的影响等,这不仅增加了治疗费用,更影响了患者康复周期。而一些非阿片类注射剂,如对乙酰氨基酚、NSAIDs(非甾体抗炎药),由于其镇痛效果差,限制了其使用范围和剂量;此外也有一定的副作用,如对乙酰氨基酚增加肝脏毒性,NSAIDs(非甾体抗炎药)导致各种胃肠道疾病。
随着现代社会生活工作压力的不断增大和老年社会的到来,以及阿片受体对于治疗不同类型的疼痛有着至关重要的作用,寻找具有高镇痛活性且低毒副作用的新型阿片药物具有重要的科学及社会意义。
研究发现通过使用κ阿片受体激动剂,可以将κ阿片受体作为干预的靶标以治疗疼痛和预防种类繁多的疾病和病况。如1993年Woold等在Anesthesia and Analgesia(1993,77,362-379)描述了将κ阿片受体激动剂用于治疗痛觉增敏在内的疼痛;1999年Wu等在Circulation Res(1999,84,1388-1395)提出将κ阿片受体激动剂作为预防和治疗心血管疾病的靶标;2003年Kaushik等在J.Postgraduate Medicine(2003,49(1),90-95)阐述了κ阿片受体激动剂的神经保护作用;2004年Potter等在.Pharmacol.Exp.Ther(2004,209,548-553)描述了κ阿片受体激动剂在眼部紊乱和眼部疼痛中的应用;2005年Wikstrom等在J.Am.Soc.Nephrol(2005,16,3742-3747.)描述了κ激动剂在治疗尿毒症和阿片引起的瘙痒的应用;2006年Bileviciute-Ljungar等在Rheumatology(2006,45,295-302)评估了κ阿片受体激动剂用于骨关节炎,类风湿性关节炎等炎性疾病的性质;2006年Lembo在Diges.Dis.(2006,24,91-98)中评估了κ阿片受体激动剂胃肠道疾病中的应用;2006年Jolivalt等在Diabetologia(2006,49(11),2775-2785)描述了κ阿片受体激动剂阿西马朵林在啮齿动物糖尿病神经病变中的作用;2008年卡拉治疗学股份有限公司的Schteingart,Claudio,D等在WO2008057608A2中评估了κ阿片受体激动剂在内脏疼痛、pH敏感型伤害感受器活化的相关疼痛以及辣椒素引起的眼部疼痛中的作用。
发明内容
本发明的目的是提供一种结构新颖,生物活性更好、镇痛效果更佳的κ阿片受体激动剂,及其制备方法和在医药上的用途。
本发明提供一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶:
其中,
A选自3至8元含氮杂环,所述的杂环含有1至3个任选自N、O或S的杂原子;
R1各自独立选自H、F、Cl、Br、I、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基或-NR1aR1b,所述的烷基、烷氧基、烯基、炔基、碳环基或杂环基任选进一步被0-5个选自F、Cl、Br、I、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R2、R3各自独立地选自OH、C1-6烷基、C1-6烷氧基、-O-C3-8碳环基、C3-8碳环基或3至8元杂环基,所述烷基、烷氧基、碳环基或杂环基任选进一步被0-5个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R4、R5、R9、R10各自独立地选自H、C1-6烷基、-C(=O)O-C1-4烷基、-C(=O)O-(CH2)q-C3-8碳环基、-C(=O)O-(CH2)q-(3至8元杂环基)或所述的烷基、碳环基和杂环基任选进一步被0-5个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R6独立选自H、C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)q-C3-8碳环基或-(CH2)q-C(=O)NR6aR6b,所述的烷基、烯基、炔基或碳环基任选进一步被0-5个选自F、Cl、Br、I、OH、CN、CF3、NO2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个选自N、O或S的杂原子;
R1a、R1b、R6a、R6b各自独立地选自H、C1-6烷基、-C(=O)O-C1-4烷基、-C(=O)O-(CH2)q-C3-8碳环基或-C(=O)O-(CH2)q-3至8元杂环基,所述的烷基、碳环基或者杂环基任选进一步被0-5个选自F、Cl、Br、I、OH、CF3、氰基、硝基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基所取代,所述的杂环基含有1至3个选自N、O或S的杂原子;
a选自0、1、2、3、4、5、6或7;
b选自0、1、2或3;
c选自0、1、2、3、4或5;
d选自0、1、2、3、4或5;
q选自0、1、2、3或4;
R7、R8每个各自独立选自F、Cl、Br、I、CF3、氰基、硝基、C1-4烷基、-OR7a、-C(O)OR7b、-SR7c、-S(O)R7d、-S(O)2R7e或-NR7fR7g;
R7a、R7b、R7c、R7d、R7e、R7f和R7g各自独立选自H或C1-4烷基;
作为选择,R7f、R7g与其连接的氮原子形成5至6元杂环,所述的杂环基含有1至3个任选自N、O或S的杂原子。
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,其中:A选自3至6元含氮杂环,所述的杂环含有1至3个任选自N、O或S的杂原子;
R1各自独立选自H、F、Cl、Br、I、CF3、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基、3至6元杂环基或-NR1aR1b,优选H、F、C1-4烷基、3至6元杂环基或-NR1aR1b,所述的烷基、烷氧基、烯基、炔基、碳环基或杂环基任选进一步被0-3个选自F、Cl、Br、I、CF3、硝基、氰基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基或3至6元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R2、R3各自独立地选自OH、C1-6烷基、C1-6烷氧基或-O-C3-8碳环基,优选OH、C1-4烷基、C1-4烷氧基,所述烷基、烷氧基或碳环基任选进一步被0-3个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-4碳环基或3至6元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R4、R5、R9、R10各自独立地选自H、C1-6烷基、-C(=O)O-C1-4烷基、-C(=O)O-(CH2)q-C3-8碳环基、-C(=O)O-(CH2)q-(3至8元杂环基)或优选H、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)O-(CH2)q-C3-6碳环基,所述的烷基、碳环基和杂环基任选进一步被0-3个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基或3至6元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R6独立选自H、C1-4烷基、C2-4烯基或C2-4炔基,优选C1-4烷基,所述的烷基、烯基、炔基或碳环基任选进一步被0-3个选自F、Cl、Br、I、OH、CN、CF3、NO2、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基或3至6元杂环基的取代基所取代,所述的杂环基含有1至3个选自N、O或S的杂原子;
R1a、R1b、R6a、R6b各自独立地选自H、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)O-(CH2)q-C3-6碳环基,所述的烷基或碳环基任选进一步被0-3个选自F、Cl、Br、I、OH、CF3、氰基、硝基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基或3至6元杂环基所取代,所述的杂环基含有1至3个选自N、O或S的杂原子;
a选自0、1、2、3、4、5、6或7;优选0、1或2;
b选自0、1、2或3;优选3;
c选自0、1、2、3、4或5,优选0或1;
d选自0、1、2、3、4或5,优选0或1;
q选自0、1、2、3或4,优选0或1;
R7、R8每个各自独立选自F、Cl、Br、I、CF3、氰基、硝基、C1-4烷基或-NR7fR7g,优选F、CF3或C1-4烷基;
R7f和R7g各自独立选自H或C1-4烷基。
本发明优选方案,本发明提供一种通式(I)所示化合物,其中该化合物选自通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,其中:
m、n独立选自0、1或2,条件是m、n不同时为0;
R1各自独立选自H、F、Cl、Br、I、CF3、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基或-NR1aR1b,优选H、F、C1-6烷基、C1-6烷氧基、3至8元杂环基或-NR1aR1b,进一步优选H、F、C1-4烷基、3至6元杂环基或-NR1aR1b,所述的烷基、烷氧基、烯基、炔基、碳环基或杂环基任选进一步被0-5个选自F、Cl、Br、I、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R1a、R1b各自独立地选自H、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)O-(CH2)q-C3-6碳环基,所述的烷基或碳环基任选进一步被0-3个选自F、Cl、Br、I、OH、CF3、氰基、硝基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6碳环基或3至6元杂环基所取代,所述的杂环基含有1至3个选自N、O或S的杂原子;
q选自0或1;
R2、R3各自独立地选自OH、C1-6烷基、C1-6烷氧基、-O-C3-8碳环基、C3-8碳环基或3至8元杂环基,优选OH、C1-4烷基或C1-4烷氧基,所述烷基、烷氧基、碳环基或杂环基任选进一步被0-5个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R4、R5、R9、R10各自独立地选自H、C1-6烷基、-C(=O)O-C1-4烷基、-C(=O)O-(CH2)q-C3-8碳环基或-C(=O)O-(CH2)q-(3至8元杂环基),优选H、C1-4烷基、-C(=O)-C1-4烷氧基或-C(=O)O-(CH2)q-C3-6碳环基,所述的烷基、碳环基和杂环基任选进一步被0-5个选自F、Cl、Br、I、OH、CF3、硝基、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基或3至8元杂环基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子。
本发明的优选方案,一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,其中:
m、n独立选自0、1或2,条件是m、n不同时为0;
R1独立选自H、F、C1-4烷基、3至6元杂环基或-NR1aR1b,所述的烷基或杂环基任选进一步被0-3个选自F、Cl、Br、I、CF3、氰基、硝基、甲基、乙基、甲氧基或乙氧基的取代基所取代,所述的杂环基含有1至3个任选自N、O或S的杂原子;
R1a、R1b各自独立地选自H、C1-4烷基或-C(=O)O-(CH2)q-C3-6碳环基;
q选自1;
R2、R3各自独立地选自OH、C1-4烷基、-O-C3-6碳环基或C1-4烷氧基,所述烷基、烷氧基或碳环基任选进一步被0-3个选自F、Cl、Br、I、OH、CF3、氰基、硝基、甲基、乙基、甲氧基或乙氧基的取代基所取代;
R4、R5、R9、R10各自独立地选自H、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)O-苄基。
本发明优选方案,本发明提供一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,其中:m、n独立选自0、1或2,条件是m、n不同时为0;
R2、R3各自独立地选自OH、甲基、乙基、甲氧基、乙氧基或苯氧基;
R4、R5、R9、R10各自独立地选自H、甲基、-C(=O)O-叔丁基。
本发明优选方案,本发明提供一种通式(I)或(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,其中该化合物包括但不限于如下结构式所示化合物之一:
本发明提供一种药物组合物,所述的药物组合物包含通式(I)或(II)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶,和一种或多种以上的药学上可接受的载体和/或赋形剂。
本发明通式(I)或(II)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶或包含通式(I)或(II)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐或共晶的药物组合物用于制造治疗或预防哺乳动物的κ阿片样物质受体相关的疾病或病况的药物的应用。
本发明的优选方案,其中所述κ阿片样物质受体相关的病况选自下组,其构成为:疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
本发明的优选方案,其中所述疼痛选自下组,其构成为:神经性疼痛、躯体痛、内脏痛和皮肤痛。
本发明的优选方案,其中所述疼痛选自下组,其构成为:关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、爆发性癌症疼痛和GI紊乱相关的疼痛。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的一价饱和烃基,主链包括1至10个碳原子,优选为1至8个碳原子,进一步优选为1至6个碳原子,更优选为1至4个碳原子的直链与支链基团,最优选1至2个碳原子,烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基等;所述的烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代,其中R19和R19a各自独立选自H、羟基、氨基、羧基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环基氧基或者4至10元杂环基氧基,k选自0、1、2、3、4或者5,j选自0、1或者2。本文中出现的烷基、k、j、R19和R19a,其定义如上所述。
“亚烷基”是指直链和支链的二价饱和烃基,包括-(CH2)v-(v为1至10的整数),亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等;所述的亚烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代,当亚烷基中的取代基数量大于等于2个时,取代基可以稠合在一起形成环状结构。本文中出现的亚烷基,其定义如上所述。
“烷氧基”是指O-烷基的一价基团,其中,烷基如本文所定义,烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。
“烯基”是指直链和支链的一价不饱和烃基,其具有至少1个,通常有1、2或3个碳碳双键,主链包括2至10个碳原子,进一步优选2至6个碳原子,更优选在主链上有2至4个碳原子,烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等;所述的烯基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代。本文中出现的烯基,其定义如上所述。
“炔基”是指直链和支链的一价不饱和烃基,其具有至少1个,通常有1、2或3个碳碳三键,主链包括2至10个碳原子,进一步优选2至6个碳原子,更优选在主链上有2至4个碳原子,炔基实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等;所述的炔基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代。本文中出现的炔基,其定义如上所述。
“环烷基”是指一价饱和的碳环烃基,通常有3至10个碳原子,非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代。本文中出现的环烷基,其定义如上所述。
“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系,碳环基可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、苯基或萘基。所述的碳环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代。本文中出现的碳环,其定义如上所述。
“杂环”是指饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系,且包含1至4个选自N、O或S的杂原子,优选3至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻基、二氢呋喃基、二氢吡喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、=O、羟基、-SR19、硝基、氰基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8碳环基、3至8元杂环基、-(CH2)a-C(=O)-R19、-(CH2)k-C(=O)-O-R19、-(CH2)k-C(=O)-NR19R19a、-(CH2)k-S(=O)j-R19、-O-C(=O)-O-R19或者-NR19R19a的取代基所取代。本文中出现的杂环,其定义如上所述。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐,包括碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铁盐、铜盐、钴盐等;有机碱盐,如铵盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、乙二胺盐、胍盐、异丙基胺盐、三甲基胺盐、三丙基胺盐、三乙醇胺盐、二乙醇胺盐、乙醇胺盐、二甲基乙醇胺盐、二环己基胺盐、咖啡碱盐、普鲁卡因盐、胆碱盐、甜菜碱盐、苯明青霉素盐、葡萄糖胺盐、N-甲基葡糖胺盐、可可碱盐、氨丁三醇盐、嘌呤盐、哌嗪盐、吗啉盐、哌啶盐、N-乙基哌啶盐、四甲基胺盐、二苄基胺盐和苯基甘氨酸烷基酯盐等;氢卤酸盐,如氢氟酸盐、盐酸盐、氢碘酸盐、氢溴酸盐等;无机酸盐,如盐酸盐、硝酸盐、硫酸盐、高氯酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对甲苯磺酸盐等;有机酸盐,如乙酸盐、苯甲酸盐、富马酸盐、甲酸盐、三氟乙酸盐、糠酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酸盐、羟乙磺酸盐、乳酸盐、马来酸盐、苹果酸盐、扁桃酸盐、粘液酸盐、双羟萘酸盐、泛酸盐、硬脂酸盐、琥珀酸盐、磺胺酸盐、酒石酸盐、丙二酸盐、2-羟基丙酸盐、柠檬酸盐、水杨酸盐、草酸盐、羟乙酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、赖氨酸盐、精氨酸盐、门冬氨酸盐、肉桂酸盐等。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。
“共晶体”或“共晶”是指活性药物成分(active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。所述“共晶形成物”包括但不限于各种药学上可接受的酸、碱、非离子化合物、水、氨基酸、醇或其他溶剂,其非限制性实例包括丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、苯丙氨酸(Phe)、色氨酸(Trp)、蛋氨酸(Met)、甘氨酸(Gly)、丝氨酸(Ser)、苏氨酸(Thr)、半胱氨酸(Cys)、酪氨酸(Tyr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)、天冬氨酸(Asp)、谷氨酸(Glu)、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、甲醇、乙醇、丁炔二醇、1,2-丙二醇、(R)1,2-丙二醇、(S)1,2-丙二醇或1-甲基-1,2-乙二醇。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“溶剂化物”指本发明化合物或其盐,它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时,则为水合物。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,反应在氮气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
M为mol/L简写。
中间体1:
(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸(中间体1)
(2R)-6-(tert-butoxycarbonylamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoic acid
第一步:甲基(2R)-2-[[(2R)-2-(苄氧羰基氨基)-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1b)
methyl(2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoate
室温下,将甲基(2R)-2-氨基-6-(叔丁氧羰基氨基)己酸酯(1a)(2.6g,10mmol)溶于乙酸乙酯(50mL)中,降温至0℃。磁力搅拌下,将(2R)-2-(苄氧羰基氨基)-4-甲基-戊酸(2.8g,11mmol),1-羟基苯并三唑(1.62g,12mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.3g,12mmol)依次加至反应液中,升温至25℃,并于该温度反应15h。然后加入1M盐酸水溶液(25mL)萃取、分液。有机相中加入饱和碳酸氢钠水溶液(25mL)搅拌30分钟、分液。有机相用依次用1N盐酸溶液(25mL)、饱和碳酸氢钠水溶液(25mL)、饱和氯化钠水溶液(25mL)洗涤,无水硫酸钠(2g)干燥、过滤,滤液减压浓缩得到甲基(2R)-2-[[(2R)-2-(苄氧羰基氨基)-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1b),白色泡状固体(5.0g,产率99%)。
第二步:甲基(2R)-2-[[(2R)-2-氨基-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1c)
methyl(2R)-2-[[(2R)-2-amino-4-methyl-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoate
室温下,将甲基(2R)-2-[[(2R)-2-(苄氧羰基氨基)-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1b)(5.0g,10mmol)溶于乙酸乙酯(50mL)中,钯碳(1g,20wt%)加至反应液中,置换氢气3次,氢气(气球)氛围下,于该温度搅拌反应5h。将反应液用硅藻土过滤(3g),滤液减压浓缩至干,得到甲基(2R)-2-[[(2R)-2-氨基-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1c)粗品,白色泡状固体(3.7g,产率99%),并直接用于下一步反应。
第三步:甲基(2R)-2-[[(2R)-2-[[(2R)-2-(苄氧羰基氨基)-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1d)
methyl(2R)-2-[[(2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoate
室温下,将甲基(2R)-2-[[(2R)-2-氨基-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1c)粗品(3.7g,9.9mmol)溶于乙酸乙酯(50mL)中,降温至0℃。将(2R)-2-(苄氧羰基氨基)-3-苯基-丙酸(3.3g,11mmol),1-羟基苯并三唑(1.62g,12mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.3g,12mmol)依次加至反应液中,升温至25℃,于该温度搅拌反应5h。加入1M盐酸水溶液(25mL)、分液。有机相中加入饱和碳酸氢钠水溶液(25mL)搅拌30分钟、分液。有机相依次用1N盐酸溶液(25mL)、饱和碳酸氢钠水溶液(25mL)、饱和氯化钠水溶液(25mL)洗涤,无水硫酸钠(2g)干燥、过滤,滤液减压浓缩得到甲基(2R)-2-[[(2R)-2-[[(2R)-2-(苄氧羰基氨基)-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1d)粗品,白色泡状固体(3.0g,产率46%),并直接用于下一步反应。
第四步:甲基(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1e)
methyl(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoate
室温下,将甲基(2R)-2-[[(2R)-2-[[(2R)-2-(苄氧羰基氨基)-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1d)粗品(3.0g,4.58mmol)溶于乙酸乙酯(50mL)中,将钯碳(1g,33wt%)加至反应液中,置换氢气3次,氢气(气球)氛围下,于该温度反应5h。将反应液用硅藻土过滤(3g),滤液减压浓缩至干。加入乙酸乙酯(6ml)加热溶解残留物,加入石油醚(6ml)后缓慢降至室温析出固体,过滤,50℃减压烘干滤饼,得到甲基(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯,白色泡状固体(1e)(2.1g,产率88%)。
第五步:甲基(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸酯(1f)
methyl(2R)-6-(tert-butoxycarbonylamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(tert-butoxycarbonylam ino)-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoate
室温下,将甲基(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]-6-(叔丁氧羰基氨基)己酸酯(1e)(2.1g,4.0mmol)溶于乙酸乙酯(30mL)中,降温至0℃。将(2R)-2-(叔丁氧羰基)-3-苯基-丙酸(1.3g,4.9mmol)、1-羟基苯并三唑(0.65g,4.8mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.1g,5.7mmol)依次加至反应液中,升温至25℃,于该温度搅拌反应5h。加入1M盐酸水溶液(15mL)萃取分液。有机相中加入饱和碳酸氢钠水溶液(15mL)搅拌30分钟、分液。有机相用依次用1M盐酸水溶液(15mL)、饱和碳酸氢钠水溶液(15mL)、饱和氯化钠水溶液(15mL)洗涤,无水硫酸钠干燥、过滤,滤液减压浓缩,残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=100:1~5:1),得到甲基(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸酯(1f),白色泡状固体(2.3g,产率74%)。
第六步:(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸(中间体1)
(2R)-6-(tert-butoxycarbonylamino)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoic acid
室温下,将甲基(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸酯(1f)(2.3g,3.0mmol)溶于甲醇(20mL)中,将氢氧化钠(200mg,5.0mmol)的水溶液(20ml)加至反应液中,于该温度下搅拌反应5h。用1M盐酸水溶液调节pH小于4,用乙酸乙酯(40ml)萃取、分液,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,得到(2R)-6-(叔丁氧羰基氨基)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-(叔丁氧羰基氨基)-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酸(中间体1),白色泡状固体(2.1g,产率93%)。
Ms m/z(ESI):752.5[M-H]-;
1H NMR(400MHz,CDCl3)δ7.38-7.27(m,3H),7.25-7.07(m,7H),4.82-4.62(m,1H),4.61-4.41(m,2H),4.37-4.18(m,1H),3.37-2.67(m,6H),2.00-1.65(m,3H),1.59-1.37(m,15H),1.35-1.26(m,9H),0.90-0.80(m,6H).
实施例1:
[4-氨基-1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸三三氟乙酸盐(化合物1)
[4-amino-1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-4-piperidyl]phosphonic acid;2,2,2-trifluoroacetic acid
第一步:4-氨基-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1B)
tert-butyl 4-amino-4-dimethoxyphosphoryl-piperidine-1-carboxylate
将N-叔丁氧羰基-4-哌啶酮(1A)(4.0g,20.00mmol)加入到三口瓶中。加入氨甲醇溶液(7M,57mL),室温下搅拌2h。然后加入亚磷酸二乙酯(2.9g,21.00mmol),升温至65℃反应3h。反应结束后减压浓缩反应液得到4-氨基-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1B)粗品,黄色油状液体,直接用于下一步反应。
第二步:4-(苄氧基羰基氨基)-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1C)
tert-butyl4-(benzyloxycarbonylamino)-4-dimethoxyphosphoryl-piperidine-1-carboxylate
将4-氨基-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1B)粗品(4g,13.00mmol)溶于二氯甲烷(30mL)中,将氢氧化钠(1.56g,38.90mmol)溶于15mL水中配置成溶液,然后加入到反应中,冰水浴0℃下,加入氯甲酸苄酯(4.43g,25.90mmol),加完后室温反应3天。反应结束后,向反应液中加入水(20mL)、分液,水相用二氯甲烷(30mL)萃取,合并有机相,无水硫酸钠干燥,浓缩得到的残留物用硅胶柱层析分离纯化(石油醚:乙酸乙酯(v:v)=2:1~1:1~1:2)得到4-(苄氧基羰基氨基)-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1C),白色泡状固体(4.0g,两步产率67.9%)。
第三步:N-(4-二甲氧基磷酰基-4-哌啶基)氨基甲酸苄酯(1D)
benzyl N-(4-dimethoxyphosphoryl-4-piperidyl)carbamate
将4-(苄氧基羰基氨基)-4-二甲氧基磷酰基-哌啶-1-甲酸叔丁酯(1C)(2.0g,4.52mmol)溶于二氯甲烷(20mL)中,冰水浴冷却至0℃,加入三氟乙酸(10mL),加完后升至室温反应30分钟。减压浓缩反应液,残留物加入二氯甲烷(15mL),然后用2M NaOH水溶液调节溶液pH>9后分液,分液后水相用二氯甲烷(10mL×2)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到的残留物通过硅胶柱层析分离纯化(二氯甲烷:甲醇(v:v)=20:1~10:1),得到N-(4-二甲氧基磷酰基-4-哌啶基)氨基甲酸苄酯(1D),淡黄色油状液体(0.7g,产率45.2%)。
第四步:N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-1-[4-(苄氧羰基氨基)哌啶-1-羰基]-5-(叔丁氧基羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-乙基]氨基甲酸叔丁酯(1E)
tert-butylN-[(1R)-1-benzyl-2-[[(1R)-1-benzyl-2-[[(1R)-1-[[(1R)-1-[4-(benzyloxycarbonylamino)-4-dimethoxyphosphoryl-piperidine-1-carbonyl]-5-(tert-butoxycarbonylamino)pentyl]carbamoyl]-3-methyl-butyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate
将N-(4-二甲氧基磷酰基-4-哌啶基)氨基甲酸苄酯(1D)(400mg,1.17mmol)加入到乙酸乙酯(15mL)中,氮气保护。冰水浴冷却至0℃,加入(中间体1)(969mg,1.29mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(269mg,1.40mmol)、1-羟基苯并三唑(190mg,1.40mmol),加完后在室温下反应1.5h。反应结束后,向反应液中加入1M盐酸水溶液(15mL),搅拌后分液。向有机相中加入饱和碳酸钠水溶液(15mL),搅拌30分钟后再次分液。有机相用饱和氯化钠水溶液洗涤(15mL)一次,无水硫酸钠干燥,过滤,滤液减压浓缩后得到N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-1-[4-(苄氧羰基氨基)哌啶-1-羰基]-5-(叔丁氧基羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-乙基]氨基甲酸叔丁酯(1E)粗品,白色泡状固体,并直接用于下一步。
第五步:[(1R)-2-[[(1R)-1-[[(1R)-1-(4-氨基-4-二甲氧基磷酰基-哌啶-1-羰基))-5-(叔丁氧羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-1-苄基-2-氧代-乙基]-1-苄基-2-氧代-乙基]氨基甲酸叔丁酯(1F)
tert-butylN-[(1R)-2-[[(1R)-2-[[(1R)-1-[[(1R)-1-(4-amino-4-dimethoxyphosphoryl-piperidine-1-carbonyl)-5-(tert-butoxycarbonylamino)pentyl]carbamoyl]-3-methyl-butyl]amino]-1-benzyl-2-oxo-ethyl]amino]-1-benzyl-2-oxo-ethyl]carbamate
将N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-1-[4-(苄氧羰基氨基)哌啶-1-羰基]-5-(叔丁氧基羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-乙基]氨基甲酸叔丁酯(1E)粗品(1.65g,1.53mmol)溶于乙酸乙酯(20mL)中,加入钯碳(320mg,20wt%),氢气置换三次,氢气氛围下(气球)室温搅拌4h。反应结束后用硅藻土过滤反应液,滤液减压浓缩,残留物通过硅胶柱层析分离纯化(二氯甲烷:甲醇(v:v)=40:1~20:1),得到[(1R)-2-[[(1R)-1-[[(1R)-1-(4-氨基-4-二甲氧基磷酰基-哌啶-1-羰基))-5-(叔丁氧羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-1-苄基-2-氧代-乙基]-1-苄基-2-氧代-乙基]氨基甲酸叔丁酯(1F),淡黄色油状液体(1.12g,产率77.2%)
第六步:[4-氨基-1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸三三氟乙酸盐(化合物1)
[4-amino-1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-4-piperidyl]phosphonic acid;2,2,2-trifluoroacetic acid
氮气保护下,将[(1R)-2-[[(1R)-1-[[(1R)-1-(4-氨基-4-二甲氧基磷酰基-哌啶-1-羰基))-5-(叔丁氧羰基氨基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-1-苄基-2-氧代-乙基]-1-苄基-2-氧代-乙基]氨基甲酸叔丁酯(1F)(1.0g,1.06mmol)加入到乙腈(5mL)中,加入三甲基溴硅烷(973mg,6.36mmol),加完升温至50℃下搅拌反应5h。然后冷却至室温,浓缩反应液,加入水(5mL),用1M氢氧化钠水溶液调pH至7-8,用二氯甲烷洗涤水层(10mL×2),分液,水相浓缩后,残留物用制备液相分离纯化(制备条件:仪器:Gilson GX-281;柱:Xbridge C18,150×30mm I.D.,5μm.;流动相:A for ACN and B for H2O;等度:A 65%;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;周期:18min;样品制备:化合物溶解于12mL甲醇中;注射:0.9mL/针),冻干后得到[4-氨基-1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸三三氟乙酸盐(化合物1),白色固体(750mg,两步产率66.0%)。
Ms m/z(ESI):358.8[M-3CF3COOH+2H]+/2;
1H NMR(400MHz,D2O)δ7.43-7.28(m,6H),7.28-7.17(m,4H),4.69-4.62(m,2H),4.34-4.18(m,2H),4.04-3.80(m,2H),3.78-3.39(m,2H),3.23-3.11(m,2H),3.11-2.90(m,4H),2.37-2.10(m,2H),2.07-1.81(m,2H),1.81-1.62(m,4H),1.61-1.31(m,5H),0.92(dd,6H).
实施例2:
[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-3-吡咯烷-1-基-氮杂环丁烷-3-基]膦酸三三氟乙酸盐(化合物2)
[1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-3-pyrrolidin-1-yl-azetidin-3-yl]phosphonicacid;2,2,2-trifluoroacetic acid
第一步:3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羧酸叔丁酯(2B)
tert-butyl 3-diethoxyphosphoryl-3-pyrrolidin-1-yl-azetidine-1-carboxylate
将1-叔丁氧羰基-3-氧代氮杂环丁烷(2A)(10.00g,58.41mmol)、四氢吡咯(4.15g,58.41mmol)和苯硼酸(0.356g,2.91mmol)加入到反应瓶中,室温下搅拌30分钟。然后加入亚磷酸二乙酯(8.47g,61.34mmol),升温至50℃反应1h。然后冷却至室温,将反应残留物直接硅胶柱层析分离纯化(石油醚/乙酸乙酯(v:v)=4:1~2:1)得到3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羧酸叔丁酯(2B),淡黄色油状液体(7.0g,产率33.1%)。
第二步:1-(3-二乙氧基磷酰基氮杂环丁烷-3-基)吡咯烷(2C)
1-(3-diethoxyphosphorylazetidin-3-yl)pyrrolidine
将3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羧酸叔丁酯(2B)(7.0g,19.3mmol)溶于二氯甲烷(15mL)中,冰水浴冷却至0℃,加入三氟乙酸(15mL),加完后室温下反应30分钟。反应结束后,减压浓缩反应液,向残留物加入二氯甲烷(15mL),然后用2M NaOH水溶液调溶液pH>9后分液,用二氯甲烷萃取水相(10mL×2),合并有机相,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,残留物通过硅胶柱层析分离纯化(二氯甲烷/甲醇(v:v)=20:1~10:1)得到1-(3-二乙氧基磷酰基氮杂环丁烷-3-基)吡咯烷(2C),淡黄色油状液体(550mg,产率11.0%)。
第三步:[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧基羰基氨基)-1-(3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-氨基甲酸酯(2D)
tert-butylN-[(1R)-1-benzyl-2-[[(1R)-1-benzyl-2-[[(1R)-1-[[(1R)-5-(tert-butoxycarbonylamino)-1-(3-diethoxyphosphoryl-3-pyrrolidin-1-yl-azetidine-1-carbonyl)pentyl]carbamoyl]-3-methyl-butyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate
将1-(3-二乙氧基磷酰基氮杂环丁烷-3-基)吡咯烷(2C)(320mg,1.22mmol)加入到乙酸乙酯(15mL)中,氮气保护。冰水浴冷却至0℃,加入(中间体1)(1.01g,1.34mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(281mg,1.46mmol)、1-羟基苯并三唑(198mg,1.46mmol),加完后室温下搅拌反应1.5h。然后,向反应液中加入1M盐酸水溶液(15mL),搅拌后分液。有机相加入饱和碳酸钠水溶液(15mL),搅拌30分钟后分液。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,滤液浓缩后得到[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧基羰基氨基)-1-(3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-氨基甲酸酯(2D)的粗品,黄色泡状固体,直接用于下一步反应。
第四步:[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-3-吡咯烷-1-基-氮杂环丁烷-3-基]膦酸三三氟乙酸盐(化合物2)
[1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-3-pyrrolidin-1-yl-azetidin-3-yl]phosphonicacid;2,2,2-trifluoroacetic acid
氮气保护下,将[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧基羰基氨基)-1-(3-二乙氧基磷酰基-3-吡咯烷-1-基-氮杂环丁烷-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]氨基]-2-氧代-氨基甲酸酯(2D)的粗品(800mg,0.80mmol)加入到乙腈(5mL)中,加入三甲基溴硅烷(734mg,4.80mmol),加完升温至50℃搅拌反应5h。然后冷却至室温,浓缩反应液,加入水(5mL),用1M氢氧化钠水溶液调pH=7-8,用二氯甲烷洗水相(10mL×2),分液,水相浓缩后用制备液相分离纯化(制备条件:仪器:Gilson GX-281;柱:Xbridge C18,150×30mm I.D.,5μm.;流动相:A for ACN and B for H2O;等度:A 65%;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;周期:18min;样品制备:化合物溶解于12mL甲醇中;注射:0.9mL/针),冻干后得到[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-3-吡咯烷-1-基-氮杂环丁烷-3-基]膦酸三三氟乙酸盐(化合物2),白色固体(100mg,两步产率:16.8%)。
Ms m/z(ESI):742.7[M-3CF3COOH+1H]+,371.9[M-3CF3COOH+2H]+/2;
1H NMR(400MHz,D2O)δ7.44-7.28(m,6H),7.23(d,4H),4.74-4.49(m,3H),4.45-4.11(m,5H),3.78-3.51(m,4H),3.23-3.12(m,2H),3.10-2.92(m,4H),2.20-2.03(m,4H),1.87-1.62(m,4H),1.62-1.34(m,5H),0.99-0.82(m,6H).
实施例3:
[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸(化合物3)
[1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-4-piperidyl]phosphonic acid
第一步:1-苄基-4-二乙氧基磷酰基-哌啶-4-醇(3B)
1-benzyl-4-diethoxyphosphoryl-piperidin-4-ol
将N-苄基-4-哌啶酮(3A)(4.0g,21.14mmol)、亚磷酸二乙酯(2.24g,21.14mmol)和二乙基胺(1.7g,23.25mmol)加入到反应瓶中,室温下搅拌2h,然后升温至40℃反应3h。然后冷却至室温,减压浓缩得到1-苄基-4-二乙氧基磷酰基-哌啶-4-醇(3B)粗品,黄色油状液体,直接用于下一步反应。
第二步:1-苄基-4-二乙氧基磷酰基-3,6-二氢-2H-吡啶(3C)
1-benzyl-4-diethoxyphosphoryl-3,6-dihydro-2H-pyridine
将1-苄基-4-二乙氧基磷酰基-哌啶-4-醇(3B)粗品(6.92g,21.10mmol)溶于甲苯(50mL)中,加入氯化亚砜(3.77g,31.70mmol),升温至60℃反应1h。然后,降温至室温,浓缩溶剂至少量剩余,冰水浴冷却至0℃,缓慢滴加2M氢氧化钠水溶液调节pH至8-10。然后用乙酸乙酯萃取(50mL×3),合并有机相,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩后得到的残留物通过硅胶柱层析分离纯化(石油醚/乙酸乙酯(v:v)=1:5),得到红棕色油状液体1-苄基-4-二乙氧基磷酰基-3,6-二氢-2H-吡啶(3C)(1.8g,两步产率28.0%)。
第三步:4-二乙氧基磷酰基哌啶(3D)
4-diethoxyphosphorylpiperidine
将1-苄基-4-二乙氧基磷酰基-3,6-二氢-2H-吡啶(3C)(1.7g,5.50mmol)于甲醇(10mL)中,加入钯碳(450mg,25wt%),氢气置换三次,氢气氛围下(气球)室温搅拌48h。用硅藻土过滤反应液,滤液减压浓缩,残留物通过硅胶柱层析分离纯化(二氯甲烷/甲醇(v:v)=20:1~10:1),得到4-二乙氧基磷酰基哌啶(3D),淡黄色油状(0.75g,产率61.7%)。
第四步:N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二乙氧基磷酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(3E)
tert-butylN-[(1R)-1-benzyl-2-[[(1R)-1-benzyl-2-[[(1R)-1-[[(1R)-5-(tert-butoxycarbonylamino)-1-(4-diethoxyphosphorylpiperidine-1-carbonyl)pentyl]carbamoyl]-3-methyl-butyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate
将4-二乙氧基磷酰基哌啶(3D)(0.32g,1.45mmol)加入到乙酸乙酯(15mL)中,氮气保护。冰水浴冷却至0℃,加入(中间体1)(1.20g,1.59mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(330mg,1.74mmol)、1-羟基苯并三唑(235mg,1.74mmol),加完后室温下反应1.5h。反应结束后,反应液加入1M盐酸水溶液(15mL)搅拌后分液。分出的有机相加入饱和碳酸钠水溶液(15mL)搅拌30分钟后再次分液。有机相继续用饱和氯化钠水溶液(15mL)洗涤一次,无水硫酸钠干燥,过滤,滤液减压浓缩后残留物通过硅胶柱层析分离纯化(乙酸乙酯),得到N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二乙氧基磷酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(3E),白色泡状固体(1.20g,产率86.7%)。
第五步:[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸(化合物3)
[1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanoyl]amino]hexanoyl]-4-piperidyl]phosphonic acid
氮气保护,将N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二乙氧基磷酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(3E)(1.10g,1.15mmol)加入到乙腈(10mL)中,加入三甲基溴硅烷(897mg,5.75mmol),加完升温至50℃搅拌反应5h。然后降温至室温,并将反应液减压浓缩,加入水(5mL),用1M氢氧化钠水溶液调pH=7-8,用二氯甲烷洗涤水相(10mL×2),水相浓缩后用制备液相分离纯化(制备条件:仪器:Gilson GX-281;柱:Xbridge C18,150×30mm I.D.,5μm.;流动相:A for ACN and B for H2O;等度:A 65%;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;周期:18min;样品制备:化合物溶解于12mL甲醇中;注射:0.9mL/针)。制备液相分离纯化后再过离子交换树脂(水~3.3%氨水洗脱),冻干后得到[1-[(2R)-6-氨基-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰基]氨基]己酰基]-4-哌啶]膦酸(化合物3),白色固体(650mg,产率80.7%)。
Ms m/z(ESI):351.3[M+2H]+/2;699.4[M-H]-。
1H NMR(400MHz,D2O)δ7.46-7.27(m,6H),7.28-7.12(m,4H),4.73-4.58(m,2H),4.50-4.25(m,2H),4.14-3.99(m,2H),3.27-2.60(m,8H),2.10-1.93(m,2H),1.88-1.63(m,5H),1.63-1.30(m,7H),0.97-0.89(m,6H).
实施例4:
(2R)-N-[(1R)-5-氨基-1-(4-二甲基膦酰基哌啶-1-羰基)戊基]-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰胺二三氟乙酸盐(化合物4)
(2R)-N-[(1R)-5-amino-1-(4-dimethylphosphorylpiperidine-1-carbonyl)pentyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanamide;
2,2,2-trifluoroacetic acid
第一步:1-苄基-4-二甲基磷酰基-3,6-二氢-2H-吡啶(4A)
1-benzyl-4-dimethylphosphoryl-3,6-dihydro-2H-pyridine
将1-苄基-4-二乙氧基磷酰基-3,6-二氢-2H-吡啶(3C)(0.6g,1.94mmol)和三氟甲磺酸钠(2.0g,11.6mmol)加入到干燥的四氢呋喃(5mL)中。待溶清后降温至0℃,滴加甲基溴化镁的四氢呋喃溶剂5.8mL(2M,11.6mmol),加完后回流反应5h。反应液用冰水浴冷却,加入饱和氯化铵(30mL)淬灭反应,用乙酸乙酯萃取(30mL×2),合并有机相,无水硫酸钠干燥,滤液减压浓缩,残留物通过硅胶柱层析(二氯甲烷/甲醇(v:v)=15:1~10:1)分离纯化得到1-苄基-4-二甲基磷酰基-3,6-二氢-2H-吡啶(4A),淡黄色油状液体(210mg,产率43.3%)。
第二步:4-二甲基磷酰基哌啶(4B)
4-dimethylphosphorylpiperidine
将1-苄基-4-二甲基磷酰基-3,6-二氢-2H-吡啶(4A)(200mg,0.802mmol)溶于甲醇(5mL)中,加入钯碳(100mg,50wt%),氢气置换三次,氢气氛围(气球)下室温反应2h。然后,将反应液通过硅藻土过滤,滤液减压浓缩,得到4-二甲基磷酰基哌啶(4B)粗产品,黄色油状液体,直接用于下一步反应。
Ms m/z(ESI):162.1[M+1H]+。
第三步:N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二甲基膦酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(4C)
tert-butylN-[(1R)-1-benzyl-2-[[(1R)-1-benzyl-2-[[(1R)-1-[[(1R)-5-(tert-butoxycarbonylamino)-1-(4-dimethylphosphorylpiperidine-1-carbonyl)pentyl]carbamoyl]-3-methyl-butyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate
将4-二甲基磷酰基哌啶(4B)(0.10g,0.62mmol)粗产品加入到乙酸乙酯(15mL)中,氮气保护。冰水浴冷却至0℃,加入(中间体1)(0.468g,0.62mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(143mg,0.75mmol)、1-羟基苯并三唑(101mg,0.75mmol),加完后室温下反应72h。然后,向反应液中加入1M盐酸水溶液(15mL)搅拌后分液。有机相加入饱和碳酸钠水溶液(15mL)搅拌30分钟后再次分液。有机相用饱和氯化钠水溶液(15mL)洗涤一次,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物通过硅胶柱层析分离纯化(二氯己烷/甲醇(v:v)=10:1),得到N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二甲基膦酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(4C),白色泡状固体(200mg,两步产率35.9%)。
第四步:(2R)-N-[(1R)-5-氨基-1-(4-二甲基膦酰基哌啶-1-羰基)戊基]-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰胺二三氟乙酸盐(化合物4)
(2R)-N-[(1R)-5-amino-1-(4-dimethylphosphorylpiperidine-1-carbonyl)pentyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propanoyl]amino]-3-phenyl-propanoyl]amino]-4-methyl-pentanamide;
2,2,2-trifluoroacetic acid
将N-[(1R)-1-苄基-2-[[(1R)-1-苄基-2-[[(1R)-1-[[(1R)-5-(叔丁氧羰基氨基)1-(4-二甲基膦酰基哌啶-1-羰基)戊基]氨基甲酰基]-3-甲基-丁基]氨基]-2-氧代-乙基]乙基]氨基甲酸叔丁酯(4C)(200mg,0.223mmol)溶于二氯甲烷(7.5mL)中,加入三氟乙酸(3.5mL),室温下搅拌1h。减压浓缩反应液,进行制备液相分离纯化(制备条件:仪器:GilsonGX-281;柱:Xbridge C18,150×30mm I.D.,5μm.;流动相:A for ACN and B for H2O;等度:A 65%;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;周期:18min;样品制备:化合物溶解于12mL甲醇中;注射:0.9mL/针)后冻干,得到(2R)-N-[(1R)-5-氨基-1-(4-二甲基膦酰基哌啶-1-羰基)戊基]-2-[[(2R)-2-[[(2R)-2-氨基-3-苯基-丙酰基]氨基]-3-苯基-丙酰基]氨基]-4-甲基-戊酰胺二三氟乙酸盐(化合物4),白色固体(80mg,产率40%)。
Ms m/z(ESI):349.3[M+2H]+/2。
1H NMR(400MHz,D2O)δ7.41-7.22(m,10H),4.88-4.80(m,1H),4.67-4.05(m,6H),3.38-2.68(m,9H),2.33-1.09(m,18H),0.97-0.89(m,6H).
生物测试例
测试1:对人κ-阿片受体的激动活性
Forskolin(毛喉素)能够刺激人κ-阿片受体高表达细胞株——OPRK1细胞(DiscoveRx)cAMP的释放,而κ-阿片受体激动剂能够抑制forskolin刺激的cAMP释放。通过检测受试化合物对forskolin刺激的cAMP释放的抑制作用,能够测定化合物对人κ-阿片受体的激动活性。首先用一定浓度的forskolin和不同浓度的受试化合物与人κ-阿片受体高表达细胞株一起孵育。使用基于时间分辨荧光共振能量转移(TR-FRET)的cAMP免疫测试法(PerkinElmer)来确定所激发的OPRK1细胞中的cAMP水平。具体方法如下:
高表达人κ-阿片受体的OPRK1细胞(DiscoveRx)培养于含10%FBS(Gibco 10099-141)的McCoy's 5A(Gibco 16600-082)培养基中。实验当天,将在指数生长期的细胞,用PBS/5mM EDTA冲洗分离,离心收集,并用Stimulation Buffer重悬细胞并计数,调整细胞浓度至3*105cells/ml。用DMSO分别溶解Forskolin和受试化合物,使其母液浓度均为10mM,再用Stimulation Buffer稀释Forskolin至4μM,加入不同浓度受试化合物(浓度依次为80、16、3.2、0.64、0.128、0.0256、0.00512、0.001024、0μM),以每孔5μl加入384孔板。再向每孔中加入5μl细胞悬液,室温孵育30min。随后,每孔分别加入5μl 4 x Eu-cAMP tracer工作溶液(用cAMP Detection Buffer稀释Eu-cAMP stock solution 50倍)和5μl 4 x Ulight-anti-cAMP工作溶液(用cAMP Detection Buffer稀释ULight-anti-cAMP stock solution150倍),室温下孵育1小时。384孔板用酶标仪(Perkin Elmer,Envision)TR-FRET方法检测cAMP水平。所得数据用origin7.5软件处理和拟合EC50。本发明化合物人κ-阿片受体的激动活性通过以上的实验进行测定,测得的EC50值见表1。
Stimulation Buffer配制方法:将14mL 1*HBSS(invitrogen,cat.#14025-092)、75μL 1M HEPES(Invitrogen,cat.#15630-080)、30μL 250mM IBMX溶于DMSO(Sigma,cat.#17018)和200μL 7.5%BSA Stabilizer混合,用0.1N NaOH调节溶液pH到7.4,并用1*HBSS定容到15mL。
表1 受试化合物对人κ-阿片受体的激动活性
化合物编号 | EC<sub>50</sub>(nM) |
化合物3 | 3.75 |
化合物4 | 0.14 |
结论:本发明化合物对人κ-阿片受体具有明显激动作用。
测试2:小鼠扭体实验
小鼠腹腔注射乙酸后,能够引起小鼠扭体行为。扭体反应指小鼠表现出典型的腹部肌肉收缩或伸张特征性的行为反应。通过检测化合物对乙酸引起的小鼠扭体行为的抑制作用,可以反应化合物的镇痛活性。具体方法如下:
8周龄ICR小鼠(购自成都达硕生物科技公司,许可证号:SCXK(川)2008-24(NO:51203500002150))。随机分组,每组10只动物,雌雄各半;实验前12h禁食不禁水。实验当天,分别静脉给予1.0mg/kg受试化合物,对照组给予空白试剂。给药后15min,以0.4mL/只的剂量腹腔内注射0.6%(v/v)醋酸溶液。记录注射醋酸后15min内的小鼠扭体次数,并计算受试化合物对乙酸引起的小鼠扭体行为的抑制百分率,分析结果如表2所示。
抑制百分率%=(对照组扭体次数-给药组扭体次数)/对照组扭体次数。
表2 受试化合物对乙酸引起的小鼠扭体行为的抑制百分率
化合物编号 | 抑制百分率(%) |
化合物1 | 86.51 |
化合物3 | 87.23 |
结论:本发明化合物具有明显镇痛作用。
Claims (8)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
R1独立选自H、氨基、-NHC(=O)O-苄基;
R2、R3各自独立地选自OH、甲基、乙基、甲氧基、乙氧基;
R4、R5、R9、R10各自独立地选自H、-C(=O)O-叔丁基。
4.一种药物组合物,所述的药物组合物包含权利要求1~3任一项所述的化合物或其药学上可接受的盐,和一种或多种以上的药学上可接受的载体和/或赋形剂。
5.权利要求1~3任一项所述的化合物或其药学上可接受的盐,或者权利要求4所述的药物组合物用于制造治疗或预防哺乳动物的κ阿片样物质受体相关的疾病或病况的药物的应用。
6.如权利要求5所述的应用,其中所述κ阿片样物质受体相关的病况选自下组,其构成为:疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
7.如权利要求6所述的应用,其中所述疼痛选自下组,其构成为:神经性疼痛、躯体痛、内脏痛和皮肤痛。
8.如权利要求6所述的应用,其中所述疼痛选自下组,其构成为:关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、爆发性癌症疼痛和GI紊乱相关的疼痛。
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