CN101302246A - 黑色素皮质激素受体七肽类激动剂及其制备方法和用途 - Google Patents
黑色素皮质激素受体七肽类激动剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及具有MC3R/MC4R受体激动活性的七肽衍生物,其制备方法,含有它们的药物组合物,以及它们用于制备治疗肥胖及相关疾病以及性功能障碍等的药物的用途。
Description
技术领域
本发明涉及具有MC-Rs激动活性的七肽衍生物,非天然氨基酸的制备方法,含它们的药物组合物及它们用于制备治疗肥胖及相关疾病以及性功能障碍等疾病的药物的用途。
背景技术
随着生活节奏的加快、工作压力的加大,肥胖和性功能障碍都日益凸显出来,严重影响人们的生活质量。其中,肥胖是众所周知的导致动脉硬化、高血压、心脏病以及II型糖尿病等常见疾病的因素之一,而性功能障碍也严重影响到患者的身心健康和家庭幸福。
仅仅是轻微肥胖就会增加患糖尿病、高血压等疾病的几率,然而目前市场上用于治疗肥胖的有效药物只有少数几个,例如西布曲明(Sibutramine)和奥利司他(Orlistat);治疗性功能障碍的一线药物为西地那非等磷酸二酯酶抑制剂,但此类药物对女性患者无效,而且部分患者报道响应逐渐消失。因此新的治疗肥胖和性功能障碍的药物的研发是必须和当务之急的,具有十分广阔的前景。
α-MSH是一种源于前阿黑皮素(POMC)的线形十三肽。早在20世纪50年代,人们就发现,对狗、猴、猫以及兔子等中枢给予α-MSH后能引起其性兴奋,其作用机理是通过作用于黑皮素受体亚型MC-RS而产生调节性行为效应。研究表明,MC-Rs激动剂在治疗肥胖以及性功能障碍等方面有潜在的应用价值。
α-MSH是一个线状十三肽,C-端含有酰胺结构,N端乙酰化。α-MSH的一级结构如下:
Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-V
al13-NH2
后来人们研究发现,α-MSH的最小活性序列为His6-Phe7-Arg8-Trp9。围绕着此核心序列,人们设计合成了一系列此类化合物,包括线性肽和环肽,在治疗肥胖以及性功能障碍方面有一定的效果。其中,PT-141等化合物对男女性功能患者都有较好疗效,甚至对部分西地那非无响应患者也有效,现即将进入三期临床研究阶段;而针对MC-Rs,也有许多用于治疗肥胖的候选药物在研发当中。
本发明的目的是寻找新的MC-Rs激动剂。
发明内容
本发明人经研究现已发现,式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物:
R-Nle-S2-S3-S4-Arg-S6-Lys-B (Ia)
R-Nle-环(S2-S3-S4-Arg-S6-Lys)-B (Ib)
或其立体异构体或无生理毒性的盐具有良好的MC-Rs激动活性,因此式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物或其立体异构体或其无生理毒性的盐可作为药物用于肥胖及相关疾病以及性功能障碍的治疗。
因此,本发明的第一方面涉及化合物,其包括式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物,或其立体异构体或无生理毒性的盐:
R-Nle-S2-S3-S4-Arg-S6-Lys-B (Ia)
R-Nle-环(S2-S3-S4-Arg-S6-Lys)-B (Ib)
其中:
R为H-、R1C(O)-、R1R2NC(O)-、Boc、Fmoc,
R1和R2各自独立地为H,取代或未取代的C1-C6直链或者支链烷基,取代或未取代的C2-C6直链或者支链烯基或者炔基,取代或未取代的C1-C6直链或者支链烷氧基,取代或未取代的C1-C6直链或者支链烷硫基,取代或未取代的C2-C6直链或者支链烯基或者炔基氧基,取代或未取代的C2-C6直链或者支链烯硫基或者炔硫基,C3-C8环烷基,C3-C8环烯基,C6-C14芳基、C4-C10杂芳基、C3-C8杂环基;
B为-OH或-NR3R4,
R3和R4各自独立地为H-、R1-、R1C(O)-、R1R2NC(O)-,其中R1和R2的定义同前;
S2为Asp或Glu;
S3为L或D型的His、Pro或Z,
Z为下列结构I、II(Mob)、III(Tca)、IV、V或VI(Mpca):
各个R5独立地为R1、-NR1R2、-NHC(O)NR1R2、-C(O)NR1R2、-NH-C(O)R1,其中R1和R2的定义同前;
S4为D型的Z,Z的定义同前;
S6为L或D型的Trp或Z,Z的定义同前,
所述“芳基”为6-14元单环或双环芳香基团,如苯基或萘基,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代或三取代;
“杂芳基”为含有1-5个独立地选自N、O和S的杂原子的4-10元单环或双环芳香基团,如吡咯基、呋喃基、吡啶基等,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代;
“杂环基”为其环结构中含1-5个、优选1-3个独立地选自N、O和S的杂原子的3-8元非芳香环状基团,如吡喃基、哌啶基等,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代或三取代。
本发明的第二个方面涉及制备本发明化合物的方法,包括将化合物B连接到上述式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物或其立体异构体上的步骤。
本发明的第三个方面涉及含有至少一种上述式(Ia)线型七肽衍生物和/或式(Ib)环状七肽衍生物,或其立体异构体或无生理毒性的盐以及可药用载体或赋形剂的药物组合物。
本发明的第四个方面涉及本发明化合物用于制备治疗肥胖及相关疾病(如高血压)或性功能障碍的药物的用途。
本发明还涉及本发明化合物用于制备MC-Rs激动剂的用途。
本发明所使用的术语“式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物立体异构体”是指其相应的D-或L-立体构型。
根据本发明的一个实施方式,R为AC-、-CONH2、-CON(CH3)2、No-。
根据本发明的一个实施方式,B为-NH2或-OH。
根据本发明的一个实施方式,S2为Asp。
根据本发明的一个实施方式,S3为L或D型的His或Tic。
根据本发明的一个实施方式,S4为D-Tic、D-Mob、D-Fpa或D-Upa。
根据本发明的一个实施方式,S6为L型的Trp、Tic或Tca。
本发明优选下面的七肽衍生物,或其立体异构体或无生理毒性的盐:
(1)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2(MW:1054,ESI-MS:1054.2)
(2)Ac-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2(MW:1026,ESI-MS:1026.1)
(3)Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2(MW:1066,ESI-MS:1066.2)
(4)Ac-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2(MW:1085,ESI-MS:1085.3)
(5)Ac-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH2(MW:1058,ESI-MS:1058.6)
(6)Ac-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2(MW:1097,ESI-MS:1097.5)
(7)Ac-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2(MW:1059,ESI-MS:1059.2)
(8)Ac-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH2(MW:1034,ESI-MS:1034.4)
(9)Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2(MW:1072,ESI-MS:1072.8)
(10)Ac-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2(MW:1099,ESI-MS:1099.5)
(11)Ac-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2(MW:1072,ESI-MS:1072.6)
(12)Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2(MW:1111,ESI-MS:1111.4)
(13)Ac-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2(MW:1075,ESI-MS:1075.3)
(14)Ac-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2(MW:1048,ESI-MS:1048.7)
(15)Ac-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2(MW:1087,ESI-MS:1087.8)
(16)Ac-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2(MW:1107,ESI-MS:1107.5)
(17)Ac-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2(MW:1080,ESI-MS:1080.7)
(18)Ac-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2(MW:1119,ESI-MS:1119.6)
(19)Ac-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2(MW:1081,ESI-MS:1081.2)
(20)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2(MW:1054,ESI-MS:1054.1)
(21)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2(MW:1093,ESI-MS:1093.7)
(22)Ac-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2(MW:1122,ESI-MS:1122.5)
(23)Ac-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2(MW:1094,ESI-MS:1094.5)
(24)Ac-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2(MW:1133,ESI-MS:1133.8)
(25)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(26)Ac-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(27)Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(28)Ac-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(29)Ac-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(30)Ac-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH
(31)Ac-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(32)Ac-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(33)Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(34)Ac-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(35)Ac-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(36)Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(37)Ac-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(38)Ac-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(39)Ac-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(40)Ac-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(41)Ac-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(42)Ac-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(43)Ac-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(44)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(45)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(46)Ac-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(47)Ac-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(48)Ac-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(49)NH2CO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2(MW:1054,ESI-MS:1054.8)
(50)NH2CO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2(MW:1027,ESI-MS:1027.4)
(51)NH2CO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2
(52)NH2CO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2
(53)NH2CO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH2
(54)NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2
(55)NH2CO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2
(56)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH2
(57)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2
(58)NH2CO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2
(59)NH2CO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2
(60)NH2CO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2
(61)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2
(62)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2
(63)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2
(64)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2
(65)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2
(66)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2
(67)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2
(68)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2
(69)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2
(70)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2
(71)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2
(72)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2
(73)NH2CO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(74)NH2CO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(75)NH2CO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(76)NH2CO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(77)NH2CO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(78)NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH (MW:1099,ESI-MS:1099.7)
(79)NH2CO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(80)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(81)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(82)NH2CO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(83)NH2CO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(84)NH2CO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(85)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(86)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(87)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(88)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(89)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(90)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(91)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(92)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(93)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(94)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(95)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(96)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(97)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2
(98)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2
(99)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2
(100)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2
(101)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH2
(102)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2
(103)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2
(104)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH2
(105)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2
(106)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2
(107)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2
(108)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2
(109)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2
(110)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2
(111)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2
(112)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2
(113)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2
(114)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2
(115)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2
(116)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2
(117)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2
(118)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2
(119)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2
(120)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2
(121)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(122)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(123)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(124)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(125)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(126)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH
(127)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(128)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(129)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(130)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(131)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(132)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(133)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(134)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(135)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(136)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(137)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(138)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(139)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(140)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(141)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(142)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(143)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(144)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(145)Ac-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2(MW:1036,ESI-MS:1036.5)
(146)Ac-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2(MW:1008,ESI-MS:1008.5)
(147)Ac-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2(MW:1048,ESI-MS:1048.7)
(148)Ac-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2(MW:1067,ESI-MS:1067.8)
(149)Ac-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2(MW:1040,ESI-MS:1040.6)
(150)Ac-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2(MW:1079,ESI-MS:1079.5)
(151)Ac-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2(MW:1041,ESI-MS:1041.2)
(152)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2(MW:1016,ESI-MS:1016.4)
(153)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2(MW:1054,ESI-MS:1054.8)
(154)Ac-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2(MW:1081,ESI-MS:1081.5)
(155)Ac-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(156)Ac-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(157)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(158)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(159)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(160)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(161)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(162)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(163)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2
(164)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(165)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(166)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(167)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(168)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(169)Ac-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(170)Ac-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(171)Ac-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(172)Ac-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(173)Ac-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(174)Ac-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH
(175)Ac-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(176)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(177)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(178)Ac-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(179)Ac-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(180)Ac-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(181)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(182)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(183)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(184)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH
(185)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(186)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(187)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(188)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(189)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(190)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(191)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(192)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(193)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2
(194)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2
(195)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2
(196)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2
(197)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2
(198)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2
(199)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2
(200)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2
(201)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2
(202)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2
(203)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(204)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(20)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(206)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(207)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(208)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(209)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(210)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(211)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2
(212)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(213)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(214)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(215)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(216)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(217)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(218)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(219)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(220)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(221)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(222)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH(MW:1081,ESI-MS:1081.8)
(223)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(224)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(225)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(226)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(227)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(228)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(229)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(230)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(231)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(232)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH
(233)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(234)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(235)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(236)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(237)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(238)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(239)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(240)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(241)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2
(242)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2
(243)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2
(244)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2
(245)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2
(246)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2
(247)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2
(248)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2
(249)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2
(250)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2
(251)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(252)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(253)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(254)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(255)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(256)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(257)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(258)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(259)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2
(260)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(261)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(262)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(263)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(264)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(265)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(266)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(267)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(268)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(269)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(270)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH
(271)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(272)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(273)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(274)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(275)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(276)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(277)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(278)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(279)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(280)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH
(281)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(282)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(283)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(284)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(285)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(286)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(287)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(288)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(289)No-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2(MW:1155,ESI-MS:1155.8)
更优选地,本发明化合物选自上述化合物3,8,9,12,18,19,22,27,30,33,36,43,45,46,51,54,55,58,76,78,79,82,100,103,106,124,127,130,145,147,152,153,156,162,163,166,169,171,174,177,179,186,188,189,194,197,198,201,219,221,222,225,243,246,264,267,269和289。
本发明化合物的制备可以采用固相合成方法,以MBHA树脂或PAM树脂或Wang树脂为载体,Boc-或Fmoc-保护策略,DCC/HOBT或BOP/DIEA为缩合试剂,HCl/二氧六环或哌啶/DMF为脱保护试剂,反应完后将七肽衍生物从树脂上切割下来。
根据本发明,式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物或其立体异构体和其无生理毒性的盐在初步的受体结合活性实验以及小鼠减肥实验中具有较好的活性。
本发明所用术语“无生理毒性的盐”是指可保留母体化合物预期生理活性而不会产生任何意料之外毒副作用的盐,例如:盐酸盐,氢溴酸盐,硫酸盐,磷酸盐,硝酸盐,醋酸盐,草酸盐,酒石酸盐,琥珀酸盐,苹果酸盐,苯甲酸盐,双羟萘酸盐,海藻酸盐,甲磺酸盐,萘磺酸盐等,以及阳离子盐如钾盐,钠盐、锂盐,锌盐,铜盐,钡盐,铋盐,钙盐,三烷基铵盐等。
本发明式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物或其立体异构体或无生理毒性的盐可以单独或以药物组合物的形式给药。本发明药物组合物可根据给药途径配成各种适宜的剂型。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制备。
给药途径可以是口服、非肠道或局部给药,优选口服和注射形式给药。可以口服的药物制剂包括胶囊剂和片剂等。本发明组合物也可以配制成用于肠胃外或者给药、透皮给药或者经粘膜给药的形式。或者采用栓剂或者埋植剂的方式给药。本领域技术人员可以理解,本发明化合物可以采用合适的药物释放系统(DDS)以得到更有利的效果。
本发明式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物或其立体异构体的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重,敏感性及个体反应,所用的具体化合物,给药途径,给药次数以及所希望达到的治疗效果等。上述剂量可以单一剂量形式或分成几个,例如二、三、四个剂量形式给药。单个最大剂量一般不超过10mg/Kg体重,例如0.001-10mg/Kg,优选0.01-5mg/Kg,较佳剂量范围为0.5-2mg/Kg体重。但是,在某些情况下,也可能使用10mg/Kg体重以上或者0.001mg/Kg以下的单个剂量。
附图说明
图1为实验小鼠体重变化曲线
具体实施方式
下面的实施例及生物活性实验用于进一步说明本发明,但其并不意味着对本发明的任何限制。
在本发明中使用的缩写具有下面的含义:
Ac 乙酰基
Asp 天冬氨酸残基
Arg 精氨酸残基
Boc 叔丁氧羰基
BOP 苯并三唑-1-氧-三(二甲氨基)磷六氟磷酸
Bu 正丁基
DCC 二环己基碳二亚胺
DIEA 二异丙基乙胺
Fmoc 芴甲氧羰基
Fpa 对氟苯丙氨酸残基
HOBt 1羟基苯并三唑
His 组氨酸残基
Lys 赖氨酸残基
MBHA树脂 苯基氨甲基树脂
Mob- 胡椒基丙氨酸残基
Mpca-(2s)-4-(4-甲基苯甲酰胺)-四氢吡咯-2-羧酸残基
Nle 正亮氨酸残基
No 壬酰基
PAM树脂-羟甲基苯乙酰胺甲基树脂
Phe 苯丙氨酸残基
Pro 脯氨酸残基
RP-HPLC 反相高效液相色谱
Tca 2,3,4,9-四氢-1H-吡啶-[3,4-b]吲哚-3-羧酸残基
Tic 1,2,3,4-四氢异喹啉-3-羧酸残基
Trp 色氨酸残基
Ureido 脲基
Upa 对脲基苯丙氨酸残基
在本发明中,所有氨基酸构型除注明为D-型外,均为L-型。实施例所用固相合成载体MBHA树脂、PAM树脂以及Wang树脂为天津南开合成责任有限公司产品;DCC、HOBT、BOP、DIEA以及保护的天然氨基酸由上海吉尔生化公司以及成都凯泰新技术有限责任公司产品,保护的非天然氨基酸除说明外均由本实验室合成提供。
实施例1:化合物(3)的合成
以100mg MBHA树脂(0.096mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Boc固相多肽合成方法(参考文献:黄惟德,陈常庆著,多肽合成,科学出版社,1985)操作合成Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-MBHA树脂。
将上述肽树脂放入HF切割仪的反应器中,加入1.0mL苯甲醚,装好后将HF切割仪的体系抽成真空,用液氮冷却反应器,转入约10mL液态HF,于0℃反应40分钟。用油泵抽走HF,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得92.8mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)23.7mg,纯肽收率22.0%。ESI-MS:1066.2(理论值1066)。
实施例2:化合物(8)的合成
以100mg MBHA树脂(0.096mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Boc固相多肽合成方法(参考文献同实施例1)操作合成Ac-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-MBHA树脂。
将上述肽树脂放入HF切割仪的反应器中,加入1.0mL苯甲醚,装好后将HF切割仪的体系抽成真空,用液氮冷却反应器,转入约10mL液态HF,于0℃反应40分钟。用油泵抽走HF,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得95.6mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)22.1mg,纯肽收率21.2%。ESI-MS:1034.4(理论值1034)。
实施例3:化合物(9)的合成
以100mg MBHA树脂(0.096mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Boc固相多肽合成方法(参考文献同实施例1)操作合成Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-MBHA树脂。
将上述肽树脂放入HF切割仪的反应器中,加入1.0mL苯甲醚,装好后将HF切割仪的体系抽成真空,用液氮冷却反应器,转入约10mL液态HF,于0℃反应40分钟。用油泵抽走HF,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得105.6mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)22.5mg,纯肽收率20.8%。ESI-MS:1072.8(理论值1072)。
实施例4:化合物(12)的合成
以100mg MBHA树脂(0.096mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Boc固相多肽合成方法(参考文献:黄惟德,陈常庆著,多肽合成,科学出版社,1985)操作合成Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-MBHA树脂。
将上述肽树脂放入HF切割仪的反应器中,加入1.0mL苯甲醚,装好后将HF切割仪的体系抽成真空,用液氮冷却反应器,转入约10mL液态HF,于0℃反应40分钟。用油泵抽走HF,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得102.8mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)28.3mg,纯肽收率25.3%。ESI-MS:1111.4(理论值1111)。
实施例5:化合物(78)的合成
以100mg Wang树脂(0.065mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Fmoc固相多肽合成方法(参考文献同实施例1)操作合成NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-Wang树脂。
将上述肽树脂放入裂解反应器中,加入1.0mL苯甲醚、1mL间甲酚和8mL三氟乙酸,于0℃反应40分钟。减压旋走三氟乙酸,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得65.3mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)20.5mg,纯肽收率27.3%。ESI-MS:1153.6(理论值1153.3)。
实施例6:化合物(145)的合成
以100mg MBHA树脂(0.096mmol)为固相载体,BOP/DIEA为缩合剂,根据化合物的氨基酸序列,按标准的Fmoc固相多肽合成方法(参考文献同实施例1)操作合成Ac-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-MBHA树脂。
将上述肽树脂放入HF切割仪的反应器中,加入1.0mL苯甲醚,装好后将HF切割仪的体系抽成真空,用液氮冷却反应器,转入约10mL液态HF,于0℃反应40分钟。用油泵抽走HF,取下反应器,加入冷冻无水乙醚沉淀出固体,再将混悬液转移至砂芯漏斗中。用少量冷却的无水乙醚洗涤三次,再用10%的乙酸水溶液冲洗至树脂不再相互粘附,收集洗涤液,冷冻干燥后得95.3mg白色干粉,经RP-HPLC纯化得纯品(纯度大于95%)13.1mg,纯肽收率13.2%。ESI-MS:1036.5(理论值1036.3)。
实施例7:受体结合活性评价
实验方法:cAMP释放实验(I125-cAMP放射免疫分析试剂盒),复管实验。
细胞株:瞬时表达MC3R/MC4R的HEK293细胞
实验原理:I125-cAMP与cAMP抗血清结合可产生抗原抗体复合物,经离心去除游离未结合的I125-cAMP后,用γ-射线计数仪可测定沉淀中的同位素计数(B0)。药物作用下细胞释放的cAMP可与I125-cAMP共同竞争与cAMP抗血清的结合,由此使I125-cAMP与cAMP抗血清的结合物减少,因此使同位素计数降低(B)。
计算指标:结合抑制百分率=1-B/B0×100%
结合抑制百分率越高表示药物作用下cAMP释放越多,对所给定的受体而言也即激动活性越强。
药物筛选:选择20nM和100nM两个浓度,每个受试样品重复3次。结果见表1和表2。
表1部分化合物MC3-R结合活性评价结果
表2部分化合物MC4-R结合活性评价结果
实施例8:小鼠减肥模型评价
根据放射配体结合实验及cAMP释放实验结果,对筛选出来的化合物(化合物169)进行动物药效学实验。选用同性别昆明种小鼠,体重30克左右,分成若干组,每组6只小鼠。于第2天开始经脑室分别注射5uL浓度为1ug/uL的不同化合物,对照组注射5uL生理盐水,连续给药10天,每天观察记录体重变化,对比给药前后体重的变化,并与对照组进行对比。结果见下表3(注:表中数据为6只动物体重均值)以及图1。
表3小鼠给药后体重变化
Claims (10)
1、式(Ia)线型七肽衍生物和式(Ib)环状七肽衍生物,或其立体异构体或无生理毒性的盐:
R-Nle-S2-S3-S4-Arg-S6-Lys-B (Ia)
R-Nle-环(S2-S3-S4-Arg-S6-Lys)-B (Ib)
其中:
R为H-、R1C(O)-、R1R2NC(O)-、Boc、Fmoc,
R1和R2各自独立地为H,取代或未取代的C1-C6直链或者支链烷基,取代或未取代的C2-C6直链或者支链烯基或者炔基,取代或未取代的C1-C6直链或者支链烷氧基,取代或未取代的C1-C6直链或者支链烷硫基,取代或未取代的C2-C6直链或者支链烯基或者炔基氧基,取代或未取代的C2-C6直链或者支链烯硫基或者炔硫基,C3-C8环烷基,C3-C8环烯基,C6-C14芳基、C4-C10杂芳基、C3-C8杂环基;
B为-OH或-NR3R4,
R3和R4各自独立地为H-、R1-、R1C(O)-、R1R2NC(O)-,其中R1和R2的定义同前;
S2为Asp或Glu;
S3为L或D型的His、Pro或Z,
Z为下列结构I、II(Mob)、III(Tca)、IV、V或VI(Mpca):
各个R5独立地为R1、-NR1R2、-NHC(O)NR1R2、-C(O)NR1R2、-NH-C(O)R1,其中R1和R2的定义同前;
S4为D型的Z,Z的定义同前;
S6为L或D型的Tr p或Z,Z的定义同前,
所述“芳基”为6-14元单环或双环芳香基团,如苯基或萘基,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代或三取代;
“杂芳基”为含有1-5个独立地选自N、O和S的杂原子的4-10元单环或双环芳香基团,如吡咯基、呋喃基、吡啶基等,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代;
“杂环基”为其环结构中含1-5个、优选1-3个独立地选自N、O和S的杂原子的3-8元非芳香环状基团,如吡喃基、哌啶基等,其未被取代或被独立地选自卤素、硝基、羧基或C1-C4烷基的取代基单取代或二取代或三取代。
2、根据权利要求1的化合物,其中R为AC-、-CONH2、-CON(CH3)2、No-。
3、根据权利要求1的化合物,其中B为-NH2或-OH。
4、根据权利要求1的化合物,其中S2为Asp。
5、根据权利要求1的化合物,其中S3为L或D型的His或Tic。
6、根据权利要求1的化合物,其中S4为D-Tic、D-Mob、D-Fpa或D-Upa。
7、根据权利要求1的化合物,其选自以下七肽衍生物,或其立体异构体或无生理毒性的盐:
(1)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2
(2)Ac-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2
(3)Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2
(4)Ac-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2
(5)Ac-N1e-Asp-His-D-Mob-Arg-Tic-Lys-NH2
(6)Ac-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2
(7)Ac-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2
(8)Ac-N1e-Asp-His-D-Fpa-Arg-Tic-Lys-NH2
(9)Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2
(10)Ac-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2
(11)Ac-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2
(12)Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2
(13)Ac-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2
(14)Ac-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2
(15)Ac-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2
(16)Ac-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2
(17)Ac-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2
(18)Ac-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2
(19)Ac-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2
(20)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2
(21)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2
(22)Ac-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2
(23)Ac-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2
(24)Ac-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2
(25)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(26)Ac-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(27)Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(28)Ac-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(29)Ac-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(30)Ac-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH
(31)Ac-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(32)Ac-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(33)Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(34)Ac-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(35)Ac-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(36)Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(37)Ac-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(38)Ac-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(39)Ac-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(40)Ac-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(41)Ac-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(42)Ac-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(43)Ac-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(44)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(45)Ac-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(46)Ac-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(47)Ac-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(48)Ac-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(49)NH2CO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2
(50)NH2CO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2
(51)NH2CO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2
(52)NH2CO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2
(53)NH2CO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH2
(54)NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2
(55)NH2CO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2
(56)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH2
(57)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2
(58)NH2CO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2
(59)NH2CO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2
(60)NH2CO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2
(61)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2
(62)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2
(63)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2
(64)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2
(65)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2
(66)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2
(67)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2
(68)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2
(69)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2
(70)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2
(71)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2
(72)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2
(73)NH2CO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(74)NH2CO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(75)NH2CO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(76)NH2CO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(77)NH2CO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(78)NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH
(79)NH2CO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(80)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(81)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(82)NH2CO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(83)NH2CO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(84)NH2CO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(85)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(86)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(87)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(88)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(89)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(90)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(91)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(92)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(93)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(94)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(95)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(96)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(97)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2
(98)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH2
(99)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH2
(100)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH2
(101)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH2
(102)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH2
(103)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH2
(104)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH2
(105)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-NH2
(106)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2
(107)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2
(108)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-NH2
(109)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2
(110)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2
(111)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2
(112)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2
(113)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2
(114)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-NH2
(115)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-NH2
(116)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-NH2
(117)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2
(118)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2
(119)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2
(120)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2
(121)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH
(122)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-OH
(123)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-OH
(124)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-OH
(125)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH
(126)(CH3)2NCO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH
(127)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH
(128)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-OH
(129)(CH3)2NCO-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-OH
(130)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-OH
(131)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tic-Lys-OH
(132)(CH3)2NCO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-OH
(133)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH
(134)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH
(135)(CH3)2NCO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH
(136)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH
(137)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tic-Lys-OH
(138)(CH3)2NCO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH
(139)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Trp-Lys-OH
(140)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tic-Lys-OH
(141)(CH3)2NCO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH
(142)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH
(143)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH
(144)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH
(145)Ac-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2
(146)Ac-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2
(147)Ac-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2
(148)Ac-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2
(149)Ac-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2
(150)Ac-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2
(151)Ac-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2
(152)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2
(153)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2
(154)Ac-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2
(155)Ac-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(156)Ac-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(157)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(158)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(159)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(160)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(161)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(162)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(163)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2
(164)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(165)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(166)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(167)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(168)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(169)Ac-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(170)Ac-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(171)Ac-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(172)Ac-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(173)Ac-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(174)Ac-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH
(175)Ac-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(176)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(177)Ac-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(178)Ac-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(179)Ac-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(180)Ac-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(181)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(182)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(183)Ac-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(184)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH
(185)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(186)Ac-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(187)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(188)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(189)Ac-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(190)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(191)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(192)Ac-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(193)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2
(194)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2
(195)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2
(196)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2
(197)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2
(198)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2
(199)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2
(200)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2
(201)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2
(202)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2
(203)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(204)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(20)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(206)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(207)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(208)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(209)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(210)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(211)NH2CO-Nle-环(Asp-Tic-D-Fpa-Ar g-Trp-Lys)-NH2
(212)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(213)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(214)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(215)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(216)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(217)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(218)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(219)NH2CO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(220)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(221)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(222)NH2CO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH
(223)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(224)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(225)NH2CO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(226)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(227)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(228)NH2CO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(229)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(230)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(231)NH2CO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(232)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tr p-Lys)-OH
(233)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(234)NH2CO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(235)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(236)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(237)NH2CO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(238)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(239)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(240)NH2CO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(241)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-NH2
(242)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-NH2
(243)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-NH2
(244)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-NH2
(245)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-NH2
(246)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-NH2
(247)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2
(248)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2
(249)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2
(250)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-NH2
(251)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-NH2
(252)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-NH2
(253)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2
(254)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2
(255)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2
(256)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2
(257)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2
(258)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2
(259)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2
(260)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2
(261)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2
(262)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2
(263)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-NH2
(264)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-NH2
(265)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Trp-Lys)-OH
(266)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tic-Lys)-OH
(267)(CH3)2NCO-Nle-环(Asp-His-D-Tic-Arg-Tca-Lys)-OH
(268)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Trp-Lys)-OH
(269)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tic-Lys)-OH
(270)(CH3)2NCO-Nle-环(Asp-His-D-Mob-Arg-Tca-Lys)-OH
(271)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Trp-Lys)-OH
(272)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tic-Lys)-OH
(273)(CH3)2NCO-Nle-环(Asp-His-D-Fpa-Arg-Tca-Lys)-OH
(274)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Trp-Lys)-OH
(275)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tic-Lys)-OH
(276)(CH3)2NCO-Nle-环(Asp-His-D-Upa-Arg-Tca-Lys)-OH
(277)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH
(278)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tic-Lys)-OH
(279)(CH3)2NCO-Nle-环(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH
(280)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH
(281)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tic-Lys)-OH
(282)(CH3)2NCO-Nle-环(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH
(283)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH
(284)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH
(285)(CH3)2NCO-Nle-环(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH
(286)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH
(287)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH
(288)(CH3)2NCO-Nle-环(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH
(289)No-Nle-环(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2。
8、药物组合物,其含有至少一种权利要求1-7任一项的化合物以及可药用载体或赋形剂。
9、权利要求1-7任一项的化合物用于制备治疗肥胖及相关疾病(如高血压)或性功能障碍的药物的用途。
10、权利要求1-7任一项的化合物用于制备MC-Rs激动剂的用途。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2465521A4 (en) * | 2009-06-04 | 2012-12-19 | Bio Peptid Company Ltd | STIMULATOR OF THE GENITAL, SEXUAL AND REPRODUCTIVE FUNCTION |
US8455617B2 (en) | 2009-06-08 | 2013-06-04 | Astrazeneca Ab | Melanocortin receptor-specific peptides |
CN105037502A (zh) * | 2009-06-08 | 2015-11-11 | 帕拉丁科技公司 | 黑皮质素受体特异性肽 |
US9409947B2 (en) | 2012-03-28 | 2016-08-09 | “Ivix” Ltd. | Method for producing a recombinant peptide and resultant peptide |
US10836794B2 (en) | 2016-10-24 | 2020-11-17 | “Ivix” Ltd. | Group of peptides for treating female sexual dysfunction |
EP4100040A4 (en) * | 2020-02-03 | 2024-06-05 | Palatin Technologies, Inc. | DIAMINE-LINKED RECEPTOR-SPECIFIC CYCLIC PEPTIDES |
Family Cites Families (1)
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US6211156B1 (en) * | 1999-11-10 | 2001-04-03 | Asta Medica A.G. | Peptides for treatment of erectile dysfunction |
-
2008
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2465521A4 (en) * | 2009-06-04 | 2012-12-19 | Bio Peptid Company Ltd | STIMULATOR OF THE GENITAL, SEXUAL AND REPRODUCTIVE FUNCTION |
US8883741B2 (en) | 2009-06-04 | 2014-11-11 | Bio Peptid Company Limited | Stimulator of genital, sexual and reproductive function |
US8455617B2 (en) | 2009-06-08 | 2013-06-04 | Astrazeneca Ab | Melanocortin receptor-specific peptides |
US8455618B2 (en) | 2009-06-08 | 2013-06-04 | Astrazeneca Ab | Melanocortin receptor-specific peptides |
US9040663B2 (en) | 2009-06-08 | 2015-05-26 | Astrazeneca Ab | Melanocortin receptor-specific peptides |
CN105037502A (zh) * | 2009-06-08 | 2015-11-11 | 帕拉丁科技公司 | 黑皮质素受体特异性肽 |
US9409947B2 (en) | 2012-03-28 | 2016-08-09 | “Ivix” Ltd. | Method for producing a recombinant peptide and resultant peptide |
US10836794B2 (en) | 2016-10-24 | 2020-11-17 | “Ivix” Ltd. | Group of peptides for treating female sexual dysfunction |
EP4100040A4 (en) * | 2020-02-03 | 2024-06-05 | Palatin Technologies, Inc. | DIAMINE-LINKED RECEPTOR-SPECIFIC CYCLIC PEPTIDES |
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