CN114805305B - 一种化合物及其应用 - Google Patents
一种化合物及其应用 Download PDFInfo
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- CN114805305B CN114805305B CN202210415080.1A CN202210415080A CN114805305B CN 114805305 B CN114805305 B CN 114805305B CN 202210415080 A CN202210415080 A CN 202210415080A CN 114805305 B CN114805305 B CN 114805305B
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- alkyl
- hydrogen
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- aryl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明提供了一种化合物及其应用，化合物或其立体异构体、药学上可接受的盐，具有式1结构。本发明提供的化合物对GHSR有较好的激动活性，同时对细胞色素P450同工酶的抑制活性较低。
Description
技术领域
本发明属于医药技术领域，具体涉及一种化合物及其应用。
背景技术
生长激素(GH)是脑垂体前叶分泌的一种由191个氨基酸组成的多肽，在调节个体生长和发育等代谢过程中发挥着重要作用。GH的分泌受到体内人生长素释放激素(GHRH)和生长激素释放抑制激素(SRIF)两种下丘脑激素的调节。一些人工合成的小分子肽和非肽类物质在体内和体外均可以促进GH分泌，将此类物质统称为生长激素促分泌素(GHS)。研究发现生长激素促分泌素受体(GHSR)在体内促进GH分泌的信号传导机制与已知的GHRH不同，因此，推测体内存在GHS的相应受体GHSR。当缺乏内源性的GHS时，补充外源性的GHS，可以促进GH分泌并调节相关腺体。
胃饥饿素是一种由28个氨基酸残基组成的脑肠肽，通过与其受体GHSR相结合而发挥多种生物学效应，具有促进生长激素分泌、增加食欲、抑制炎症因子释放等作用。
生长激素的释放也可由生长激素释放肽(GHRP)控制。例如，GHRP-6可以与GHSR相结合而产生激动活性，发挥生物学效应，在包含人在内的几种物种中以剂量依赖的方式从促生长激素细胞中释放生长激素。
专利WO1999058501(A1)报道了一种可口服的GHSR受体激动剂Anamorelin，可有效促进生长激素的释放Anamorelin的非临床研究结果表明，其具有较强的细胞色素P450(CYP)抑制和CYP诱导作用，对钠通道和刺激传导系统也有抑制作用，且有QT间隔延长的风险；同时患有心肌梗塞或心绞痛、严重的刺激传导系统障碍(完全性房室传导阻滞等)、郁血性心脏衰竭、肝功能障碍和消化道器质性异常的患者禁止使用，临床使用还需特别注意药物相互作用问题。
发明内容
有鉴于此，本发明的目的在于提供一种化合物及其应用，有利于提高对GHSR的激动活性，同时化合物对细胞色素P450同工酶的抑制活性较低。
为实现上述目的，本发明的技术方案为化合物或其立体异构体、药学上可接受的盐，具有式1结构：
其中，a为0、1、2或3；
b和c相互独立的为0、1、2、3、4或5，且b+c为3、4或5；
Ra为氢、C1-6烷基、卤素、氨基、羟基、芳基或杂芳基；
J为R1R2N-(CH2)d-(CR3R4)e-；
其中d和e相互独立的为0、1或2，R1、R2、R3和R4相互独立的为氢、C1-6烷基、卤素、氨基、羟基、芳基或杂芳基；R1、R2和与其相连的N、或者R2、R3和与其相连的N-(CH2)d-C、或者R2、R4和与其相连的N-(CH2)d-C、或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；
G为式(g-1)～(g-6)所示基团中的一种：
E为-CONR5R6、-CONR7NR8R9、-COONR8R9、-COOR5、-COOR8或-R8；
其中R5为氢、C1-6烷基、卤素、羟基、C1-6烷氧基、C1-6烷氧羰基、芳基或杂芳基，或者，R5为式(5-1)或(5-2)所示基团：
其中Q为CH或N；Z和L相互独立的为-CH2-、-CO-、-O-、-S-、-NR10-或一个共价键，其中R10为氢或C1-6烷基；M为-NR11-，其中R11为氢或者C1-6烷基；m和n相互独立的为0、1、2或3；
R5、R6相互独立的为氢、C1-6烷基、卤素、羟基、C1-6烷氧基、C1-6烷氧羰基、芳基或杂芳基；
R7、R9相互独立的为氢、可被任意一个或多个芳基或杂芳基取代的C1-6烷基、或可任意被一个或多个C1-6烷基取代的芳基或杂芳基；
R8为可被任意一个或多个C1-6烷基取代的芳基或杂芳基、C1-7酰基或者式(8-1)所示基团：
其中R12和R13为氢、C1-6烷基、卤素、羟基、C1-6烷氧基、C1-6烷氧羰基、芳基、杂芳基、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；
m为0、1、2或3；
T为R16CH或R17N、O或S，其中R16为氢、C1-6烷基、卤素、羟基、C1-6烷氧基、C1-6烷氧羰基、芳基、杂芳基或-CONR14R15，其中R14、R15、R17相互独立的为氢、C1-6烷基、芳基或杂芳基。
本发明所述立体异构体可以为旋光异构体，包括可分离的、纯化的或部分纯化的旋光异构体，或者，外消旋混合物。本发明所述化合物可具有一个或多个不对称中心(手性碳原子)，化合物可以为R或S构型，或者为R和S的混合体。
本发明所述药学上可接受的盐为由具有式I结构的化合物和药物可接受的酸加成形成的盐，药物可接受的酸包括无机和有机酸，所述药学上可接受的盐包括无机酸的盐和有机酸的盐，通过本领域已知的方法制备得到。本发明所述无机酸的盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、氨基磺酸盐、硼酸盐、碳酸盐、碳酸氢盐、磷酸盐、六氟磷酸盐和硝酸盐。本发明所述有机酸的盐包括但不限于甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、琥珀酸盐、己二酸盐、扁桃酸盐、乙醇酸盐、硬脂酸盐、乳酸盐、苹果酸盐、酒石酸盐、硬脂酸盐、柠檬酸盐、抗坏血酸盐、扑酸盐、草酸盐、马来酸盐、羟基马来酸盐、酒石酸盐、苯乙酸盐、谷氨酸盐、樟脑磺酸盐、苯甲酸盐、水杨酸盐、磺胺酸盐、2-乙酸基苯甲酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、乙烷二磺酸盐、草酸盐、羟乙磺酸盐、天冬氨酸盐、环己酸磺酸盐和延胡索酸盐。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有式I结构，其中E为-CONR5R6或R8，所述R8为(8-1)～(8-9)所示基团，所述R5为式(5-1)或(5-2)所示基团：
J为R1R2N-(CH2)d-(CR3R4)e-，其中d为0、1或2，e为0、1或2，R1、R2、R3和R4相互独立的为氢、C1-6烷基、羟基、芳基或杂芳基；R1、R2和与其相连的N、或者R2、R3和与其相连的N-(CH2)d-C、或者R2、R4和与其相连的N-(CH2)d-C、或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；G、a、b、c和R6与式1所示相同，在此不在赘述。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有式1-1的结构：
其中，G、E、R1、R2、R3、R4、a和d与式1的结构所示相同，在此不在赘述。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有式(1-1-1)～(1-1-8)任一结构：
其中，G、T、R1、R2、R3、R4、R12、R13、R14、R15、a和d与式1的结构所示相同，在此不在赘述；式1-1-3中，R18为-NR7NR8R9、-NR5R6或-OR8。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有式(1-a)～(1-t)任一结构：
其中，G、T、R1、R2、R3、R4、R12、R13、R14、a和d与式1的结构所示相同，在此不在赘述式1-c、1-d和1-g中，R18为-NR7NR8R9、-NR5R6或-OR8。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有上述实施例所述式(1-a)～(1-t)任一结构：
其中，式1-a-1中，T为-O-、-S-或-N(CH3)-，R12为氢、卤素、C1-6烷基、芳基、-COOR14和-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基；
式1-b中，d为1或2，T为-O-、-S-或-N(CH3)-，R12为氢、卤素、C1-6烷基、芳基、-COOR14和-CONR14R15，其中R14和R15相互独立的为氢.、芳基或C1-6烷基，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；
式1-c中，R1为氢或C1-6烷基，R18为-NR5R6、-OR8、-OR5、-NHNR8R9或-ONR8R9；
式1-d中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；R18为-NR5R6、-OR8、-OR5、-NHNR8R9或-ONR8R9；
式1-e中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；
式1-f中，a为0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-g中，R18为-NR5R6、-OR8、-OR5、-NHNR8R9或-ONR8R9，a为0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-h中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、卤素、芳基、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；
式1-i中，T为-O-、-S-或-N(CH3)-；
式1-j中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；
式1-k中，T为-O-、-S-或-N(CH3)-；
式1-l中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；
式1-m中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；
式1-n中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-o中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-p中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-q中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；T为-O-、-S-或-N(CH3)-；
式1-r中，T为-O-、-S-或-N(CH3)-，a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-s中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-t中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有上述实施例所述式(1-a)～(1-i)、(1-k)、(1-m)～(1-n)、(1-q)、(1-s)或(1-t)的结构：
其中，式1-a中，T为-O-、-S-或-N(CH3)-，R12为氢、卤素、C1-6烷基、芳基、-COOR14和-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基；其中，T为-N(CH3)-，R12不为氢；
式1-b中，d为1或2，T为-O-、-S-或-N(CH3)-，R12为氢、卤素、C1-6烷基、芳基、-COOR14和-CONR14R15，其中R14和R15相互独立的为氢、芳基或C1-6烷基；R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；
式1-c中，R1为氢或C1-6烷基，R18为-NR5R6；
式1-d中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C可任意通过-O-、-S-或一个共价键成环；R18为-NR5R6；
式1-e中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C；或者R3、R4和与其相连的C可任意通过-O-、-S-或一个共价键成环；
式1-f中，a为的0、1或2，G为(g-3)～(g-6)所示基团中的一种：
式1-g中，R18为-NR5R6、-OR8、-OR5、-NHNR8R9或-ONR8R9，a为0、1或2，G为g-2、g-4和g-5所示基团中的一种：
式1-h中，T为-O-、-S-或-N(CH3)-，R12和R13为氢；
式1-i中，T为-O-或-S-；
式1-k中，T为-O-；
式1-m中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基；
式1-n中，T为-O-、-S-或-N(CH3)-，R12为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-q中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R1、R2和与其相连的N；或者R2、R3和与其相连的N-(CH2)d-C；或者R2、R4和与其相连的N-(CH2)d-C可任意通过-O-、-S-或一个共价键成环；T为-O-、-S-或-N(CH3)-；
式1-s中，T为-O-、-S-或-N(CH3)-，R12和R13为氢、C1-6烷基、芳基、卤素、-COOR14或-CONR14R15，其中R14和R15相互独立的为氢、C1-6烷基、芳基或杂芳基；a为的0、1或2，G为(g-2)～(g-6)所示基团中的一种：
式1-t中，d为1或2，R1、R2、R3和R4相互独立的为氢或C1-6烷基，或者，R3、R4和与其相连的C可任意通过一个共价键成环。
在一个实施例中，化合物或其立体异构体、药学上可接受的盐，具有式002～125的结构：
本发明所述化合物可以采用本领域技术人员所熟知的肽偶合反应进行制备，本发明在此不做限定。
在一个实施例中，本发明所述化合物的一个典型合成路线为：
采用酰氯化试剂和化合物1制备酰氯化合物，所述酰氯化试剂可以为草酰氯，再与相应的胺偶合生成酰胺(化合物2)；采用本领域技术人员所熟知的方法除去化合物2的保护基，得到化合物3，所述保护基可以为叔丁基氧基碳基(Boc)；采用偶合剂，所述偶合剂可以溶于二甲基甲酰胺或二氯甲烷中，将化合物3与一种相应的羧酸化合物5偶合，得到化合物6，所述耦合剂可以为1-乙基-3-(3-二甲氨基丙基)碳二亚胺氢氯化物、1-羟基苯并三唑；将化合物6进行脱保护得到化合物7，采用适宜的偶合剂，将化合物7与羧酸化合物8进行偶合，得到化合物9。
在一个实施例中，本发明所述化合物中E为R8，R8为式(8-1)～(8-9)所示基团，本发明所述的另一个通用合成路线为：
采用化合物1与氨基化合物缩合后，得到酰胺或硫酰胺中间体，进行关环反应，形成杂环，采用本领域技术人员所熟知的方法除去保护基，连续两次缩合、脱保护反应，得到化合物。
本发明还提供了一种组合物，包括：上述技术方案所述的化合物或其立体异构体、药学上可接受的盐中的一种或多种；可接受的辅料。本发明所述辅料可以为药物上可接受的盐，也可以为药学上可接受的载体或赋形剂，本发明在此不做限定。
本发明还提供了一种化合物或其立体异构体、药学上可接受的盐在制备促进生长激素分泌的药物中的应用。本发明所述促进生长激素分泌的药物包括但不限于片剂、颗粒剂、胶囊剂和注射剂，本发明在此不做限定。
本发明公开的全部内容中，术语的含义说明如下：
术语“C1-6烷基”包括直链、支链或环状结构中的指定长度的烷基或亚烷基。直链烷基可以为甲基、乙基、丙基、丁基、戊基、已基，或者它们相应的不饱和直链烷基，不饱和烷基包括但不限于乙烯。支链烷基可以为异丙基、仲丁基、叔丁基、异戊基、异已基，或者它们相应的不饱和支链烷基，不饱和支链烷基包括但不限于异丙烯。环烷基可以为C3-6环烷基，如环丙基、环丁基、环戊基、环已基，或者它们相应的不饱和环烷基，不饱和环烷基包括但不限于环丙烯。
术语“C1-6烷氧基”包括直链、支链或环状结构中的指定长度的烷氧基。直链烷氧基可以为甲氧基、乙氧基、丙氧基、丁氧基、戊氧基和已氧基。支链烷氧基可以为异丙氧基、仲丁氧基、叔丁氧基、异戊氧基和异己氧基。环烷氧基可以为环丙氧基、环丁氧基、环戊氧基和环己氧基。
术语“C1-6烷氧羰基”包括直链、支链或环状结构中的指定长度的烷氧羰基。直链烷氧羰基可以为甲氧羰基、乙氧羰基、丙氧羰基、丁氧羰基、戊氧羰基和己氧羰基。支链烷氧基可以为异丙氧羰基、仲丁氧羰基、叔丁氧羰基、异戊氧羰基和异己氧羰基。环烷氧羰基可以为环丙氧羰基、环丁氧羰基、环戊氧羰基和环己氧羰基。
术语“C1-7酰基”包括直链或者支链或者环结构中的指定长度的那些酰基。直链酰基可以为甲酰基、乙酰基、丙酰基、丁酰基和戊酰基。支链酰基可以为异丁酰基、异戊酰基和新戊酰基。环酰基可以为环戊基羰基和环已基羰基。
术语“芳基”包括单价碳环的芳环部分，或为单环，或为二环，或为多环，例如选自由苯基和荼基组成的组，它可任意被一个或多个C1-6烷基、C1-6烷氧基、卤素、氨基或芳基取代。
术语“杂芳基”包括单价杂环的芳环部分，所述芳环部分可以为单环、二环和多环，芳环部分可以为吡啶基、1-H-四唑-5-基、咪唑基、吲哚基、咪唑基、噻唑基、噻二唑基、吡唑基、噁唑基、异噁唑基、噁二唑基、噻吩基、喹啉基、吡嗪基或异噻唑基，所述芳环部分可被任意一个或多个C1-6烷基、C1-6烷氧基、卤素、氨基或芳基取代。
术语“卤素”包括氯(Cl)、氧(F)、溴(Br)和碘(I)。
本发明中使用的缩写具有如下的含义：
TLC：薄层分析；
min：分钟；
h：小时；
三乙胺：Et3N；
五硫化二磷：P2S5；
Boc：叔丁基氧羰基；
DCM：二氯甲烷；
DMF：二甲基甲酰胺；
THF：四氢呋喃；
PE：石油醚；
EtOAc：乙酸乙酯；
EDCI：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；
HOBt：1-羟基苯并三唑；
HOOBt：3-羟基-1,2,3-苯并三嗪-4(3H)-酮；
HBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐；
DIEA：二异丙基乙胺；
TFA：三氟乙酸；
TsOH：对甲基苯磺酸；
TBD：1,5,7-三氮杂二环[4.4.0]癸-5-烯；
NHS：N-羟基琥珀酰亚胺；
DIC：N,N'-二异丙基碳二亚胺。
本发明提供了一种化合物及其应用，所述化合物或其立体异构体、药学上可接受的盐，具有式1结构。本发明提供的化合物为多肽类化合物，对GHSR具有较好的激动活性，同时对细胞色素P450同工酶的抑制活性较低，其IC50值均大于10μM。本发明提供的化合物作为GHSR-1a受体激动剂具有高活性、低毒副作用等优点，提供了治疗、预防和/或诊断由生长激素促分泌素受体介导产生的紊乱所致相关疾病的解决方案，有利于治疗或预防由生长激素缺乏引起的各种疾病。本发明提供的化合物具有非天然的砌块模拟天然的酰胺键，对于酶参与的蛋白质降解作用，具有较强的抵抗性，从而可以提高生物利用度。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述。但本发明不限于以下实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
以下实施例中，采用高效液相色谱(HPLC)、核磁共振(NMR，400MHz)或液相色谱-质谱联用(LC-MS)确定化合物的结构。
所述HPLC分析方法具体为：
采用C-18二氧化硅色谱柱(InertSustain)进行HPLC逆向分析，柱温为30℃，流动相流速为1mL/min，紫外检测波长为220nm和254nm。采用含有5％乙腈的0.1％TFA的水溶液平衡所述色谱柱，采用自动进样器进样后，在30min内，将样品在浓度梯度为10～90％(乙腈+0.1％TFA)的相同缓冲水溶液中进行洗脱。
本发明所述LC-MS分析方法具体为：
采用CORTECS C-18色谱柱(内径为4.6mm，长度为50mm，粒径为2.7μm)和喷淋阳离子在/>ACQUITY QDa LC/MS系统上进行LC-MS分析。在4min内，所述色谱柱采用线性梯度为5～95％(乙腈+0.1％甲酸)和95～5％甲酸水溶液(0.1％甲酸)以0.8mL/min的流速进行洗脱。
实施例1：合成化合物002，路线如下：
步骤A：合成化合物002-3
在氮气保护下，将化合物002-1(200mg，0.626mmol)溶解在4mL DCM中，降温至-15～-10℃，依次加入草酰氯(111.3mg，0.876mmol)、DMF(2.29mg，0.05eq)。然后在30min内将三乙胺(107.7mg，1.064mmol)加入上述反应液中，反应1.5h，TLC显示结果显示无原料残留，得到反应液002-A。将化合物002-2(142.3mg，0.939mmol)、三乙胺(316.72mg，3.13mmol)溶于8mL无水二氧六环中，-15～-10℃下、于20min内分三次加入反应液002-A中，继续反应2h，升至室温，加水淬灭反应，用DCM萃取，有机相依次用1N HCl、饱和NaHCO3、饱和NaCl溶液洗涤、无水Na2SO4干燥，减压浓缩后再用PE打浆、过滤，得123mg化合物002-3。
LC-MS:Rt＝5.891min，m/z＝439.15(M+Na)+
步骤B：合成化合物002-6
脱保护条件：在0℃条件下，向化合物002-3(123mg，0.295mmol)中加入2mL 25％TFA/DCM溶液，缓慢升至室温，反应1h。减压浓缩得到化合物002-4粗品。
缩合条件：将002-4粗品溶于3mL DMF中，加入DIEA调节PH值至9，得到化合物002-4溶液，保存备用。将002-5N-Boc-D-色氨酸(90.0mg，0.295mmol)、HOBt(44mg，0.325mmol)、EDCI(62.3mg，0.325mmol)用3mL DMF溶解，在0℃条件下加入DIEA(57.3mg，0.442mmol)进行活化后，迅速加入到化合物002-4溶液中，恢复至室温反应3h。加入水淬灭，用EtOAc萃取，有机相依次用1N HCl、饱和NaHCO3溶液、饱和NaCl溶液洗涤、用无水Na2SO4干燥，过滤并减压浓缩得160mg化合物002-6粗品。
步骤C：合成化合物002-9
脱保护条件：在0℃条件下，将化合物002-6(160mg，0.265mmol)溶于4mL 25％TFA/DCM溶液，缓慢升温至室温，反应1h后减压浓缩得到化合物002-7粗品。
缩合条件：在0℃下将化合物002-8(54.0mg，0.266mmol)、HOBt(39.5mg，0.292mmol)、EDCI(56.0mg，0.292mmol)加入反应瓶中，加入5mL DMF溶解，并加入DIEA(51.5mg，0.398mmol)进行活化。将化合物002-7粗品溶于3mL DMF中并用DIEA调节PH值至8～9后加入活化液中，反应过夜。加水淬灭，用EtOAc萃取，有机相依次用1N HCl、饱和NaHCO3、饱和NaCl洗涤，用无水Na2SO4干燥，减压浓缩得到170mg化合物002-9粗品。
步骤D：合成化合物002
在0℃下，将化合物002-9(170mg，0.247mmol)溶于4mL 25％TFA/DCM溶液中，缓慢升温至室温，反应1h后，减压浓缩得到的粗品，采用Prep-HPLC制备纯化得到52.0mg化合物002。
1H NMR(400MHz,CD3OD)δ：7.60-7.58(m,1H),7.39-6.99(m,8H),7.13-7.34(m,4H),6.84(d,J＝4Hz,1H),.31-5.12(m,1H),4.30-4.24(m,1H,),4.00-3.49(m,3H),3.27-3.20(m,2H),3.13-3.05(m,1H),2.88(dd,J＝8Hz,24Hz,1H),2.48(dd,J＝8Hz,28Hz,1H),2.30-2.05(m,1H),1.93-1.90(m,1H),1.73-1.54(m,3H),1.54-1.36(m,6H).
HPLC：Rt＝16.867min，purity:97.0％.
LC-MS：m/z＝588.32[M+H]+.
实施例2：合成化合物003，路线如下：
步骤A：合成化合物003-2
在氮气保护下，将化合物003-1(1.00g，3.13mmol)溶于12mL DCM中，搅拌，控制温度在5～10℃。加入羰基二咪唑(534.0mg，3.29mmol)，缓慢升至室温反应2.5h，加入80％水合肼(258.0mg，4.07mmol)继续反应2h。加DCM稀释，分别用饱和NaHCO3、饱和NaCl洗涤、无水Na2SO4干燥，减压浓缩得到1.00g化合物003-2粗品。
步骤B：合成化合物003-3
将化合物003-2(1.00g，3.0mmol)中加入10mL冰醋酸，再加入丁二酸酐(420mg，4.20mmol)，加热回流反应6h后，减压浓缩除去冰醋酸，再用NaHCO3调节PH值至8，用DCM萃取，有机相用饱和NaCl洗涤、无水Na2SO4干燥，减压浓缩得到470mg化合物003-3。
步骤C：合成化合物003
按照实施例1的方法脱保护、缩合连接氨基酸，粗品经perp-HPLC制备纯化得到106.5mg化合物003。
1H NMR(400MHz,d6-DMSO)δ：10.84(br,1H),10.42(br,1H),8.051-7.94(m,4H),7.57-6.94(m,10H),5.07-4.89(m,1H),3.98-3.89(m,1H),3.67-3.49(m,1H),3.32-3.30(m,1H),3.08-2.88(m,4H),2.79(s,4H),2.73-2.61(m,1H),2.21-2.06(m,1H),1.68-1.52(m,3H),1.45-1.34(m,6H).
HPLC：Rt＝16.292min,purity:100.0％.
LC-MS：m/z＝587.32[M+H]+.
实施例3：按照实施例1的方法制备化合物006。
1H NMR(400MHz,d6-DMSO/D2O)δ：7.52(d,J＝4Hz,1H),7.38-7.16(m,4H),7.15-7.06(m,1H),7.04-6.93(m,3H),6.70-6.63(m,1H),5.25-4.87(m,1H),3.52-3.33(m,2H),3.31-3.19(m,3H),3.14-3.09(m,3H),3.08-3.02(m,1H),2.96-2.91(m,1H),2.89-2.82(m,3H),2.80(s,1H),2.74(s,1H),2.67-2.55(m,1H),2.51-2.36(m,6H),1.87-1.75(m,2H),1.75-1.52(m,4H),1.45-1.32(m,1H),1.26-1.15(m,1H).HPLC：Rt＝18.073min,purity:94.3％.
LC-MS：m/z＝573.39[M+H]+.
实施例4：按照实施例3的方法制备化合物007。
1H NMR(400MHz,d6-DMSO/D2O)δ：7.56-7.51(m,1H),7.38-7.13(m,4H),7.13-7.06(m,1H),7.04-6.92(m,3H),5.25-4.95(m,1H),3.56-3.26(2H),3.25-3.10(m,5H),3.10-2.92(m,4H),2.91-2.83(m,1H),2.82-2.7(m,3H),2.68-2.56(m,1H),2.51-2.36(m,6H),2.30-1.75(m,3H),1.60-1.15(m,3H).
HPLC：Rt＝18.175min,purity:98.1％.
LC-MS：m/z＝559.33[M+H]+.
实施例5：按照实施例3的方法制备化合物008，其中步骤A替换为：
在氮气保护下，将化合物002-1(200mg，0.626mmol)和N-羟基琥珀酰亚胺(86.4mg，0.75mmol)溶于5mL DCM，在0℃下加入N,N'-二异丙基碳二亚胺(94.8mg，0.75mmol)，活化过夜，缓慢升温至室温。加水淬灭反应，用DCM萃取两次，有机相依次用1N HCl、饱和NaHCO3、饱和NaCl洗涤、无水Na2SO4干燥，减压浓缩得到270mg化合物008-2。
1H NMR(400MHz,CD3OD)δ：7.60-7.50(m,1H),7.41-7.3(m,2H),7.30-7.18(m,3H),7.14-6.98(m,4H,),5.33-5.05(m,1H),4.49-4.26(m,1H),3.92(d,J＝12Hz,1H),3.55-3.33(m,2H),3.25-3.11(m,2H),3.10-2.87(m,4H),2.86-2.65(m,5H),2.57-2.45(m,1H),2.28-2.05(m,2H),1.96-1.89(m,1H),1.86-1.55(m,5H),1.55-1.41(m,1H),1.40-1.27(m,1H).
HPLC：Rt＝18.088min,purity:90.7％.
LC-MS：m/z＝614.35[M+H]+.
实施例6：按照实施例3的方法制备化合物009。
1H NMR(400MHz,CD3OD)δ：8.08-7.97(m,1H),7.65-7.55(m,2H),7.53-7.46(m,1H),7.45-7.39(m,2H,),7.38-7.26(m,3H),7.22-7.06(m,3H),7.05-6.87(m,2H),5.43-5.18(m,1H),4.67-4.48(m,1H),4.04(d,J＝8Hz,1H),3.48-3.31(m,2H),3.29-2.90(m,5H),2.90-2.72(m,2H),2.72-2.53(m,1H),2.40-2.14(m,2H),2.06-1.92(m,1H),1.88-1.66(m,3H),1.57-1.43(m,2H),1.10-0.88(m,1H).
HPLC：Rt＝20.008min,purity:90.4％.
LC-MS：m/z＝559.34[M+H]+.
实施例7：按照实施例1的方法制备化合物011。
1H NMR(400MHz,d6-DMSO)δ：11.50(br,1H),8.50(br,1H),8.20(br,1H),8.13-7.85(m,4H),7.37-7.23(m,2H),7.23-7.15(m,2H),7.13-6.88(m,3H),5.17-5.02(m,1H),3.63-3.47(m,1H),3.40-3.15(m,3H),3.07-2.95(m,2H),2.92-2.94(m,3H),2.83-2.75(m,2H),2.52(s,4H),2.49-2.38(m,2H),1.82-1.53(m,2H),1.49-1.14(m,8H).
HPLC：Rt＝14.02min,purity:97.9％.
LC-MS：m/z＝548.37[M+H]+.
实施例8：按照实施例2的方法制备化合物013。
1H NMR(400MHz,d6-DMSO)δ：10.83(br,1H),10.40(br,1H),8.65-8.15(m,3H),7.71-7.48(m,1H),7.41-7.26(m,3H),7.26-7.02(m,5H),7.01-6.89(m,1H),5.03-4.81(m,1H),4.09-3.57(m,5H),3.36-3.16(m,4H),3.02-2.82(m,4H),2.78-2.61(m,2H),2.48-2.19(m,2H),2.01-1.82(m,1H),1.82-1.30(m,7H).
HPLC：Rt＝16.029min,purity:97.8％.
LC-MS：m/z＝613.38[M+H]+.
实施例9：按照实施例2的方法制备化合物014。
1H NMR(400MHz,d6-DMSO/D2O)δ：7.57-7.42(m,1H),7.40-7.25(m,2H),7.28-7.18(m,3H),7.17-6.92(m,4H),5.05-4.83(m,1H),3.70-3.53(m,1H),3.41-3.32(m,1H),3.20-3.08(m,4H),3.07-2.96(m,2H),2.95-2.85(m,3H),2.83-2.63(m,5H),2.41-2.28(m,1H),2.25-1.97(m,2H),1.95-1.83(m,1H),1.71-1.31(m,3H).
HPLC：Rt＝16.724min,purity:96.4％.
LC-MS：m/z＝599.34[M+H]+.
实施例10：按照实施例1的方法制备化合物015。
1H NMR(400MHz,d6-DMSO)δ：11.20(br,1H),10.84(br,1H),10.13(br,1H),8.58-8.26(m,3H),7.57-7.47(m,1H),7.36-7.30(m,1H),7.29-7.25(m,1H),7.24-7.18(m,3H),7.13(br,1H),7.09-6.88(m,3H),5.09-4.88(m,1H),3.92-3.72(m,3H),3.31-3.15(m,3H),3.04-2.75(m,6H),2.61-2.53(m,1H),2.47-2.35(m,2H),2.03-1.92(m,1H),1.81-7.71(m,1H),1.64-1.51(m,5H),1.59-1.25(m,1H).
HPLC：Rt＝15.341min,purity:96.3％.
LC-MS：m/z＝614.35[M+H]+.
实施例11：按照实施例1的方法制备化合物016。
1H NMR(400MHz,d6-DMSO)δ：11.21(br,1H),10.86(br,1H),10.13(br,1H),8.83(br,2H),7.59-7.53(m,1H),7.38-7.32(m,1H),7.28-7.15(m,5H),7.11-6.96(m,2H),6.80(d,J＝4Hz,1H),5.18-4.90(m,1H),3.90-3.80(m,2H),3.76-3.68(m,1H),3.44-3.24(m,3H),3.23-2.87(m,8H),2.48-2.46(m,1H),3.17-2.04(m,2H),1.93-1.85(m,2H),1.65-1.60(m,1H),1.53-1.46(m,1H),1.32-1.22(m,1H).
HPLC：Rt＝18.404min,purity:93.1％.
LC-MS：m/z＝600.33[M+H]+.
实施例12：合成化合物017，路线如下：
步骤A：合成化合物017-3
按照实施例2步骤A的方法制备化合物003-2，将化合物003-2(700mg，2.1mmol)和硫代草氨酸乙酯(307.5mg，2.31mmol)溶于8mL乙醇中，加入TsOH(400mg，2.31mmol)，加热回流反应15h。减压浓缩，加入水，用DCM萃取两次，有机相用饱和NaCl洗涤、无水Na2SO4干燥。减压浓缩，粗品经柱层析纯化得300mg化合物017-3。
步骤B：合成化合物017-4
将化合物017-3(300mg，0.724mmol)溶于3mL THF中，加入2mol/L二甲胺的四氢呋喃溶液(0.869mmol)，再加入TBD(30.0mg，0.217mmol)，反应3h。减压浓缩，加入水，用EtOAc萃取，有机相用饱和NaCl洗涤、无水Na2SO4干燥。减压浓缩得340mg化合物017-4。
步骤：合成化合物017
按照实施例1的方法脱保护、缩合连接氨基酸，粗品经perp-HPLC制备得55mg化合物017。
1H NMR(400MHz,d6-DMSO)δ：10.9(br,1H),8.06(br,3H),7.65-7.42(m,1H),7.39-7.29(m,1H),7.28-7.10(m,4H),7.10-7.01(m,2H),7.01-6.94(m,1H),6.89-6.85(m,1H),5.09-4.89(m,1H),4.24(d,J＝8Hz,1H),3.59-3.49(m,2H),3.44-3.34(m,1H),3.18(s,3H),3.13-2.99(m,4H),2.98-2.72(m,3H),2.14-2.12(m,1H),1.94-1.91(m,1H),1.77-1.67(m,1H),1.66-1.54(m,1H),1.45-1.35(m,6H).
HPLC：Rt＝23.650min,purity:97.1％.
LC-MS：m/z＝586.34[M+H]+.
实施例13：按照实施例1的方法制备化合物019。
1H NMR(400MHz,d6-DMSO)δ：11.21(br,1H),10.14(br,1H),8.11-7.86(m,5H),7.45-6.86(m,8H),5.26-5.06(m,1H),4.07-3.91(m,3H),3.70-3.52(m,2H),3.30(d,J＝12Hz,1H),3.21-3.14(m,2H),2.83(dd,J＝8Hz,28Hz,2H),2.64-2.57(m,1H),2.07-2.05(m,1H),1.68-1.23(m,9H).
HPLC：Rt＝24.239min,purity:99.1％.
LC-MS：m/z＝605.28[M+H]+.
实施例14：按照实施例1的方法制备化合物021。
1H NMR(400MHz,d6-DMSO/D2O)δ：7.29-7.19(m,6H),7.18-7.09(m,4H),4.22(br,1H),4.08(br,1H),3.88-3.78(m,2H),3.68-3.44(m,3H),3.42-3.26(m,1H),3.22-3.10(m,1H),3.04-2.88(m,1H),2.88-2.66(m,4H),2.11(br,H),1.99(br,1H),1.70-1.88(m,1H),1.69-1.54(m,5H),1.54-1.38(m,5H).
HPLC：Rt＝23.183min,purity:95.7％.
LC-MS：m/z＝603.41[M+H]+.
实施例15：按照实施例1的方法制备化合物022。
1H NMR(400MHz,d6-DMSO)δ：11.22(br,1H),10.88(br,1H),10.11(br,1H),8.42(br,3H),7.56-7.49(m,1H),7.34(d,J＝4Hz,1H),7.31-7.26(m,1H),7.26-7.19(m,3H),7.15(br,1H),7.10-6.98(m,3H),5.11-4.91(m,1H),4.05-3.99(m,1H),3.87-3.84(m,3H),3.56-3.48(m,1H),3.32-3.27(m,1H),3.04-2.95(m,2H),2.83(dd,J＝8Hz,32Hz,1H),2.67-2.56(m,1H),2.05-2.02(m,1H),1.70-1.14(m,7H).
HPLC：Rt＝21.196min,purity:99.6％.
LC-MS：m/z＝586.30[M+H]+.
实施例16：按照实施例1的方法制备化合物023。
1H NMR(400MHz,d6-DMSO)δ：11.20(br,1H),10.88(br,1H),10.14(br,1H),8.41-8.34(m,3H),7.62-7.48(m,1H),7.36-7.20(m,6H),7.09-6.93(m,3H),5.19-4.95(m,1H),4.08-3.82(m,3H),3.58-3.54(m,1H),3.32-3.27(m,1H),3.13-3.04(m,2H),2.83(dd,J＝8Hz,28Hz,1H),2.64-2.54(m,2H),2.45-2.39(m,1H),2.18-1.95(m,5H),1.89-1.34(m,4H).
HPLC：Rt＝15.676min,purity:97.6％.
LC-MS：m/z＝600.35[M+H]+.
实施例17：按照实施例1的方法制备化合物024。
1H NMR(400MHz,d6-DMSO)δ：11.21(br,1H),10.87(br,1H),10.13(br,1H),8.12-7.99(m,3H),7.54(d,J＝4Hz,,1H),7.36-7.16(m,6H),7.09-6.93(m,3H),5.16-4.92(m,1H),4.07-4.01(m,1H),3.94-3.79(m,2H),3.33-3.25(m,2H),3.10-2.97(m,2H),2.87-2.57(m,3H),2.20-2.01(m,3H),1.84-1.34(m,9H).
HPLC：Rt＝22.305min,purity:94.0％.
LC-MS：m/z＝614.34[M+H]+.
实施例18：按照实施例1的方法制备化合物025。
1H NMR(400MHz,d6-DMSO)δ：11.21(br,1H),10.86(br,1H),10.12(br,1H),8.14-8.00(m,3H),7.59-7.50(m,1H),7.36-7.20(m,6H),7.14-6.88(m,3H),5.18-4.92(m,1H),4.00(d.J＝8Hz,1H),3.94-3.83(m,2H),3.34-3.22(m,2H),3.08-2.98(m,2H),2.82(dd,J＝8Hz,28Hz,2H),2.61-2.54(m,1H),2.09-2.02(m,3H),1.69-1.31(m,11H).
HPLC：Rt＝16.566min,purity:99.6％.
LC-MS：m/z＝628.37[M+H]+.
实施例19：化合物004、005、010、012、018、020、026、027、028、029、031-040的制备参考实施例1。
实施例20：合成化合物030，路线如下：
中间体030-3的合成：
按照实施例2步骤A的方法制备化合物003-2，将003-2(200mg，0.6mmol)溶于4mLEtOH中，再依次加入NH4Cl(16.1mg，0.3mmol)、原甲酸三乙酯(70.1mg,0.66mmol)，氮气保护下加热回流反应4h。冷却至室温，减压浓缩，再加水稀释，用EtOAc萃取3次，有机相用饱和Na2CO3中和洗涤、无水Na2SO4干燥，减压浓缩得粗品，经柱层析纯化得到160mg化合物030-3。
后续反应步骤参考实施例1。最终得到84mg化合物030。
实施例21：合成化合物043
按照实施例2步骤A的方法制备化合物003-2，向003-2(200mg，0.9mmol)中加入2ml甲酸，氮气保护，反应过夜。减压浓缩后，加入5ml二甲苯，再加入P2S5(292mg，1.31mmol)，氮气保护，加热回流反应5h，减压浓缩，得340mg 043-3粗品。按实施例20中步骤制备043。
实施例22：合成化合物041和042
参考实施例21的方法，采用酰胺或硫酰胺中间体进行关环反应，得到的中间体041-2和042-2参考实施例1的方法脱保护、缩合和脱保护，最终得到目标化合物041和042.
实施例23：按照实施例1、实施例20、实施例21的方法制备化合物044～125。
实施例1～22公开的实施方案的合成方法得到的化合物的分子量和纯度如表1所示。结果表明，化合物002～125的纯度在84.7～100.0范围内。
表1合成化合物列表
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实施例24：测定化合物对GHSR的激动活性。
GHSR活性化合物的筛选通过重组表达受体来完成，利用重组表达GHSR具有能够在确定的细胞系统中表达受体从而能够更容易区分化合物对GHSR的反应与对其它受体的反应的优点。可利用通常不用表达载体表达GHSR，例如HEK293、COS7、以及CHO等细胞系，利用没有表达载体的相同细胞系作为对照。
测定GHSR的活性可利用不同的技术，例如，可通过检测GHSR细胞内构象的变化、G-蛋白偶联活性的变化、和/或细胞内信使的变化等来进行测量。优选采用通过测定细胞内Ca2+的技术来测定GHSR活性。本领域公知的用于测定细胞内Ca2+的技术包括使用钙离子检测试剂盒等。/>钙离子检测试剂盒采用了钙离子敏感的指示剂以及屏蔽染料以确保研究者进行高灵敏的用于G蛋白偶联受体、离子通道和其它钙离子敏感的靶标的荧光筛选。
本实验采用FLIPR钙6检测试剂盒和FLIPR钙6-QF检测试剂盒进行化合物对GHSR的激动活性的测定。
细胞培养及试剂配制：
a)细胞系：Flp In-CHO-GHSR Stable Pool；
b)完全培养基：F12K+10％胎牛血清+1x盘尼西林-链霉素(PS)+600μg/ml潮霉素B；
c)细胞播种培养基：F12K+10％胎牛血清。
d)检测缓冲液：1X HBSS+20mM HEPES。
e)10X A组分：取试验缓冲液和A组分放至室温，加10mL缓冲液于A组分中，涡旋1～2min，保存于-20℃；
化合物管理：
a)化合物库存溶液：按照标准协议，将Anamorelin作为化合物001，分别将化合物001和实施例1～21得到的化合物002～125溶于DMSO中得到浓度为10mM的溶液。
b)化合物存储：DMSO中的所有化合物均存放在室温干燥器中进行存储(存储时间≤4个月)。剩余的化合物在-20℃下长期保存。
测定化合物对GHSR的激动活性：
a)用完全培养基培养Flp In-CHO-GHSR Stable Pool细胞；
b)去除完全培养基，将浓度为7000个/孔的细胞和25磅/英寸细胞播种培养基置于384孔细胞培养板(型号为Corning 3764)中培养，置于37℃、5％CO2培养箱中培养过夜；
c)在室温条件下解冻20X A组分，采用试验缓冲液将A组分稀释至2X，置于室温条件下；
d)从培养箱中取出细胞培养板，室温平衡10min。去除细胞播种培养基，加入杏色缓冲液洗涤，洗涤结束后各孔分别加入20μL杏色缓冲液，然后各孔分别加入2X A组分20μL，置于37℃孵育3～5s；
e)孵育结束后，各孔分别添加5X化合物10μl，采用FLIPR Tetra实时采集数据，并根据以下公式进行数据分析：
1)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；
2)CVMax＝(SDMax/MeanMax)*100％；
3)CVMin＝(SDMin/MeanMin)*100％；
4)S/B＝Singal/Background；
5)IC50值的计算公式：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))；
X：化合物浓度的对数值；
Y：促进率(％)或抑制率(％)。
化合物对GHSR的激动活性测试结果如表2所示，表2为化合物对GHSR的激动活性，实验结果可知，由表2结果可知，本发明提供的大多数化合物对GHSR具有较好的激动活性。大多数化合物对GHSR激动活性优于阳性对照化合物Anamorelin，其中化合物002、003、012、017、030、041、042、043、044、045、046、050、051、067和070对GHSR的激动活性为阳性对照Anamorelin10倍以上，尤其化合物030对GHSR的激动活性为Anamorelin的76倍。
表2化合物对GHSR的激动活性
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实施例25：测定化合物对细胞色素P450氧化酶的抑制作用。
将含有细胞色素P450的人肝微粒体(0.253mg/mL蛋白)与实施例1～21的化合物002～125(浓度为0.05～50μM)、CYPs底物(包括10μM对乙酰氨基酚、5μM双氯芬酸、30μM美芬妥因、5μM氢溴酸右美沙芬和2μM米达唑仑)、1.0mM烟酰胺腺嘌呤二核苷酸磷酸(NADP)在37℃温育10分钟。将Anamorelin、萘黄酮、磺胺苯吡唑、N-3-苄基尼凡、奎尼定、酮康唑作作为参比抑制剂，测定化合物对细胞色素P450同工酶的抑制活性。
结果如表3所示，表3为化合物对细胞色素P450同工酶的抑制活性(IC50值)，实验结果表明，本发明提供的化合物对细胞色素P450同工酶的抑制IC50值均大于10μM。本发明的化合物对于CYP3A4-M亚型的抑制作用明显低于阳性对照化合物Anamorelin，因此，本发明提供的化合物比化合物Anamorelin更加具有潜在的安全性优势。
表3化合物对细胞色素P450同工酶的抑制活性(IC50值)
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以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (3)
1.化合物或其立体异构体、药学上可接受的盐，具有式002～008、010、012～013、015、017、020、022、026～027、029～032、036～038、040～051、054、056、058、062、065、067、069～070、072～079、081、083～084、086、088～090、092、094、099、105～106、109、111～113、117、121～124任一结构：
2.一种组合物，包括：权利要求1所述化合物或其立体异构体、药学上可接受的盐中的一种或多种；可接受的辅料。
3.权利要求1所述化合物或其立体异构体、药学上可接受的盐在制备促进生长激素分泌的药物中的应用。
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995013069A1 (en) * | 1993-11-09 | 1995-05-18 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| WO1997036873A1 (en) * | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| US5721250A (en) * | 1993-12-23 | 1998-02-24 | Merck & Co. Inc. | Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| CN1300281A (zh) * | 1998-05-11 | 2001-06-20 | 诺沃挪第克公司 | 具有释放生长激素特性的化合物 |
| CN1420878A (zh) * | 1999-11-10 | 2003-05-28 | 诺沃挪第克公司 | 具有释放生长激素特性的化合物 |
| CN108239141A (zh) * | 2016-12-23 | 2018-07-03 | 江苏先声药业有限公司 | 一种阿拉莫林的制备方法 |
-
2022
- 2022-04-20 CN CN202210415080.1A patent/CN114805305B/zh active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995013069A1 (en) * | 1993-11-09 | 1995-05-18 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| CN1174504A (zh) * | 1993-11-09 | 1998-02-25 | 麦克公司 | 促进生长激素释放的哌啶、吡咯烷和六氢－1h－吖庚因 |
| US5721250A (en) * | 1993-12-23 | 1998-02-24 | Merck & Co. Inc. | Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
| WO1997036873A1 (en) * | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
| CN1300281A (zh) * | 1998-05-11 | 2001-06-20 | 诺沃挪第克公司 | 具有释放生长激素特性的化合物 |
| CN1420878A (zh) * | 1999-11-10 | 2003-05-28 | 诺沃挪第克公司 | 具有释放生长激素特性的化合物 |
| CN108239141A (zh) * | 2016-12-23 | 2018-07-03 | 江苏先声药业有限公司 | 一种阿拉莫林的制备方法 |
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