專利名稱：：黑色素皮質(zhì)激素受體七肽類激動劑及其制備方法和用途的制作方法
技術(shù)領(lǐng)域：
：本發(fā)明涉及具有MC-Rs激動活性的七肽衍生物，非天然氨基酸的制備方法，含它們的藥物組合物及它們用于制備治療肥胖及相關(guān)疾病以及性功能障礙等疾病的藥物的用途。
背景技術(shù)：
：隨著生活節(jié)奏的加快、工作壓力的加大，肥胖和性功能障礙都日益凸顯出來，嚴重影響人們的生活質(zhì)量。其中，肥胖是眾所周知的導(dǎo)致動脈硬化、高血壓、心臟病以及II型糖尿病等常見疾病的因素之一，而性功能障礙也嚴重影響到患者的身心健康和家庭幸福。僅僅是輕微肥胖就會增加患糖尿病、高血壓等疾病的幾率，然而目前市場上用于治療肥胖的有效藥物只有少數(shù)幾個，例如西布曲明(Sibutramine)和奧利司他(0rlistat);治療性功能障礙的一線藥物為西地那非等磷酸二酯酶抑制劑，但此類藥物對女性患者無效，而且部分患者報道響應(yīng)逐漸消失。因此新的治療肥胖和性功能障礙的藥物的研發(fā)是必須和當(dāng)務(wù)之急的，具有十分廣闊的前景。ot-MSH是一種源于前阿黑皮素(P0MC)的線形十三肽。早在20世紀50年代，人們就發(fā)現(xiàn)，對狗、猴、貓以及兔子等中樞給予ot-MSH后能引起其性興奮，其作用機理是通過作用于黑皮素受體亞型MC-RS而產(chǎn)生調(diào)節(jié)性行為效應(yīng)。研究表明，MC-Rs激動劑在治療肥胖以及性功能障礙等方面有潛在的應(yīng)用價值。ot-MSH是一個線狀十三肽，C-端含有酰胺結(jié)構(gòu)，N端乙?；t-MSH的一級結(jié)構(gòu)如下Ac-Ser^Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly"-Lys"-Pro"-Val13-NH2后來人們研究發(fā)現(xiàn)，ot-MSH的最小活性序列為His6-Phe7-Arg8-Trp9。圍繞著此核心序列，人們設(shè)計合成了一系列此類化合物，包括線性肽和環(huán)肽，在治療肥胖以及性功能障礙方面有一定的效果。其中，PT-141等化合物對男女性功能患者都有較好療效，甚至對部分西地那非無響應(yīng)患者也有效，現(xiàn)即將進入三期臨床研究階段；而針對MC-Rs，也有許多用于治療肥胖的候選藥物在研發(fā)當(dāng)中。本發(fā)明的目的是尋找新的MC-Rs激動劑。
發(fā)明內(nèi)容本發(fā)明人經(jīng)研究現(xiàn)已發(fā)現(xiàn)，式(Ia)線型七肽衍生物和式(lb)環(huán)狀七肽衍生物R-Nle-S2-S廠S廣Arg-Ss-Lys-B(la)R-Nle-環(huán)(S2-S3-S4-Arg-S6-Lys)-B(lb)或其立體異構(gòu)體或無生理毒性的鹽具有良好的MC-Rs激動活性，因此式(la)線型七肽衍生物和式(lb)環(huán)狀七肽衍生物或其立體異構(gòu)體或其無生理毒性的鹽可作為藥物用于肥胖及相關(guān)疾病以及性功能障礙的治療。因此，本發(fā)明的第一方面涉及化合物，其包括式(Ia)線型七肽衍生物和式Ub)環(huán)狀七肽衍生物，或其立體異構(gòu)體或無生理毒性的鹽<formula>formulaseeoriginaldocumentpage16</formula>(lb)其中R為H-、R:(0)-、RJUC(0)-、Boc、Fmoc，Ri和R2各自獨立地為H，取代或未取代的d-C6直鏈或者支鏈烷基，取代或未取代的C2-C6直鏈或者支鏈烯基或者炔基，取代或未取代的d-C6直鏈或者支鏈烷氧基，取代或未取代的d-C6直鏈或者支鏈烷硫基，取代或未取代的C廣C6直鏈或者支鏈烯基或者炔基氧基，取代或未取代的Cr"C6直鏈或者支鏈烯硫基或者炔硫基，C廣Cs環(huán)烷基，C廣Cs環(huán)烯基，C廣C"芳基、Crd。雜芳基、C廣C8雜環(huán)基；B為-0H或-歸4,l和R,各自獨立地為H-、R-、、C(0)-、lU2NC(0)-，其中Id和R2的定義同前；Ss為Asp或GlujS3為L或D型的His、Pro或Z，Z為下列結(jié)構(gòu)I、n(Mob)、m(Tea)、IV、V或VI(Mpca):In(Mob)in(Tea)各個Rs獨立地為IU-NIU2、-NHC(0)NRJU-C(0)NIU2、-NH-C(O)Rh其中^和R2的定義同前；S4為D型的Z，Z的定義同前；Ss為L或D型的Trp或Z，Z的定義同前，所述"芳基"為6-14元單環(huán)或雙環(huán)芳香基團，如苯基或萘基，其未被取代或被獨立地選自面素、硝基、羧基或d-C4烷基的取代基單取代或二取代或三取代；"雜芳基"為含有l(wèi)-5個獨立地選自N、O和S的雜原子的4-10元單環(huán)或雙環(huán)芳香基團，如吡咯基、呋喃基、吡咬基等，其未被取代或被獨立地選自卣素、硝基、羧基或d-C4烷基的取代基單取代或二取代；"雜環(huán)基"為其環(huán)結(jié)構(gòu)中含1-5個、優(yōu)選l-3個獨立地選自N、0和S的雜原子的3-8元非芳香環(huán)狀基團，如吡喃基、哌啶基等，其未被取代或被獨立地選自卣素、硝基、羧基或d-C4烷基的取代基單取代或二取代或三取代。本發(fā)明的第二個方面涉及制備本發(fā)明化合物的方法，包括將化合物B連接到上述式(Ia)線型七肽衍生物和式(Ib)環(huán)狀七肽衍生物或其立體異構(gòu)體上的步驟。本發(fā)明的第三個方面涉及含有至少一種上述式(Ia)線型七肽衍生物和/或式(Ib)環(huán)狀七肽衍生物，或其立體異構(gòu)體或無生理毒性的鹽以及可藥用載體或賦形劑的藥物組合物。本發(fā)明的第四個方面涉及本發(fā)明化合物用于制備治療肥胖及相關(guān)疾病(如高血壓)或性功能障礙的藥物的用途。本發(fā)明還涉及本發(fā)明化合物用于制備MC-Rs激動劑的用途。本發(fā)明所使用的術(shù)語"式(Ia)線型七肽衍生物和式(Ib)環(huán)狀七肽衍生物立體異構(gòu)體"是指其相應(yīng)的D-或L-立體構(gòu)型。根據(jù)本發(fā)明的一個實施方式，R為AC-、-C0NH2、-CON(CH3)2、No-。根據(jù)本發(fā)明的一個實施方式，B為-冊2或-0H。根據(jù)本發(fā)明的一個實施方式，S2為Asp。根據(jù)本發(fā)明的一個實施方式，S3為L或D型的His或Tic。根據(jù)本發(fā)明的一個實施方式，S4為D-Tic、D-Mob、D-Fpa或D-Upa。根據(jù)本發(fā)明的一個實施方式，Se為L型的Trp、Tic或Tca。本發(fā)明優(yōu)選下面的七肽衍生物，或其立體異構(gòu)體或無生理毒性的鹽(l)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2(MW:1054，ESI-MS:1054.2)(2)Ac-N1e-Asp-His-D-Tic-Arg-Tic-Lys-NH2(MW:1026，ESI-MS:1026.1)(3)Ac-N1e-Asp-His-D-Tic-Arg-Tca-s-NH2(MW:1066，ESI-MS:1066.2)(4)Ac-N1e-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-N1e-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-N1e-Asp-His-D-Upa-Arg-Trp-Lys-亂(MW:1099,ESI-MS:1099.5)(ll)Ac-Nle-Asp-His-D-Upa-Arg-Tic-Lys-NH2(MW:1072，ESI-MS:1072.6)(12)Ac-N1e-Asp-Hi^-D-Upa-Arg-Tca-Lys-肌(MW:llll，ESI-MS:1111.4)(13)Ac-N1e-Asp-Tic-D-Tic-Arg-Trp-Lys-NH2(MW:1075,ESI-MS:1075.3)(14)Ac-N1e-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2(MW:1048，ESI-MS:1048.7)(15)Ac-N1e-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2(MW:1087，ESI-MS:1087.8)(16)Ac-N].e--Asp-Tic一D-Mob-Arg-Trp-Lys--NH2(MW:1107，ESI--MS:1107.〗5)(17)Ac-N].e--Asp-Tic一D-Mob-Arg-Tic一Lys--NH2(MW:1080，ESI--MS:1080.'7)(18)Ac-N.e-匿Asp-Tic一D-Mob-Arg-Tca-Lys--NH2(MW:1119，ESI--MS:1119.6)(19)Ac-N].e--Asp-Tic-D-Fpa-Arg-Trp-Lys--NH2(MW:1081，ESI--MS:1081.2)(20)Ac-N].e--Asp-Tic-D-Fpa-Arg-Tic-Lys--NH2(MW:1054，ESI.-MS:1054.]L)(21)Ac-N].e誦-Asp-Tic+Fpa-Arg-Tca-Lys-NH2(MW:1093，ESI--MS:1093.'〖)(22)Ac-N]e--Asp-Tic一D-Upa-Arg-Trp-Lys--NH2(MW:1122，ESI--MS:1122J(23)Ac-N]e--Asp-Tic一D-Upa-Arg-Tic~Lys國-NH2(MW:1094，ESI--MS:1094.:(24)Ac-N]■e--Asp-Tic一D-Upa-Arg-Tca-Lys誦-NH2(MW:1133，ESI-MS:1133,8)(25)Ac-N].e誦-Asp-His-D-Tic一Arg-Trp-Lys-國OH(26)Ac-N].e畫-Asp-His-D-Tic一Arg-Tic一Lys--OH(27)Ac-N].e--Asp-His-D-Tic-Arg-Tca-Lys--OH(28)Ac-N].e--Asp-His-D-Mob-Arg-Trp-Lys-OH(29)Ac-N].e誦-Asp-His-D-Mob-Arg-Tic一Lys--OH(30)Ac-N].e國-Asp-His-D-Mob-Arg-Tca-Lys--OH(31)Ac-N]e--Asp-His-D-Fpa-Arg-Trp-Lys-OH(32)Ac-N]e--Asp-His-D-Fpa-Arg-Tic-Lys--OH(33)Ac-N]e--Asp-His-D-Fpa-Arg-Tca-Lys--OH(34)Ac-N]e-隱Asp-His-D-Upa-Arg-Trp-Lys-陽OH(35)Ac-Ne--Asp-His-D-Upa-Arg-Tic一Lys--OH(36)Ac-Nle-Asp-His-D-(37)Ac-Nle-Asp-Tic-D-(38)Ac-Nle-Asp-Tic-D-(39)Ac-Nle-Asp-Tic-D-(40)Ac-Nle-Asp-Tic-D-(41)Ac-Nle-Asp-Tic-D-(42)Ac-Nle-Asp-Tic-D-(43)Ac-Nle-Asp-Tic-D.(44)Ac-Nle-Asp-Tic-D-(45)Ac-Nle-Asp-Tic-D.(46)Ac-Nle-Asp-Tic-D-(47)Ac-Nle-Asp-Tic-D國(48)Ac-Nle-Asp-Tic-D-(49)NH2CO-Nle-Asp-HisESI-MS:1054.8)(50)NH2CO-Nle-Asp-HisESI-MS:1027.4)(51)NH2CO-Nle-Asp-His(52)NH2CO-Nle-Asp-His(53)NH2CO-Nle-Asp-His(54)NH2CO-Nle-Asp-His(55)NH2CO-Nle-Asp-His(56)NH2C0-Nle-Asp-His(57)NH2C0-Nle-Asp-His(58)NH2CO-Nle-Asp-His(59)NH2CO-Nle-Asp-His(60)NH2CO-Nle-Asp-His(61)NH2CO-Nle-Asp-Tic(62)NH2CO-Nle-Asp-Tic-Upa-Arg-Tca-Lys-OH隱Tic一Arg-Trp-Lys-OH-Tic-Arg-Tic-Lys-OH-Tic-Arg-Tca-Lys-OH陽Mob-Arg-Trp-Lys-OH陽Mob-Arg-Tic-Lys-OH隱Mob-Arg-Tca-Lys-OH-Fpa-Arg-Trp-Lys-OH隱Fpa-Arg-Tic一Lys-OH隱Fpa-Arg-Tca-Lys-OH-Upa-Arg-Trp-Lys-OH-Upa-Arg-Tic-Lys-OH畫Upa-Arg-Tca-Lys-OH+Tic-Arg-Trp-Lys-NH2(MW:1054+Tic-Arg-Tic-Lys—NH2(MW:1027-D-Tic-Arg--D-Mob-Arg--D-Mob-Arg--D-Mob-Arg--D-Fpa-Arg--D-Fpa-Arg--D-Fpa-Arg--D-Upa-Arg--D-Upa-Arg--D-Upa-Arg--D-Tic-Arg--D-Tic一Arg-Tca-Lys—NH2Trp-Lys-冊2Tic-Lys-NH2Tca-Lys-NH2,Trp-Lys-NH2■Tic-Lys-NH2Tca_Lys-NH2Trp-Lys-NH2Tic-Lys-NH2Tca-Lys-NH2Trp-Lys-NH2Tic—Lys—NH2(63)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2(64)NH2C0-N1e-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2(65)NH2C0-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)NH2C0-N1e-Asp-Tic-D-Fpa-Arg-Tca-Lys-NH2(70)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-NH2(71)NH2C0-N1e-Asp-Tic-D-Upa-Arg-Tic-Lys-匪2(72)NH2C0-N1e-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)NH2C0-Nle-Asp-His-D-Mob-Arg-Tic-Lys-OH(78)NH2CO-Nle-Asp-His-D-Mob-Arg-Tca-Lys-OH(MW:1099ESI-MS:1099.7)(79)NH2C0-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-0H(80)NH2C0-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)NH2C0-N1e-Asp-His-D-Upa-Arg-Tic-Lys-OH(84)NH2CO-Nle-Asp-His-D-Upa-Arg-Tca-Lys-QH(85)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Trp-Lys-OH(86)NH2C0-Nle-Asp-Tic-D-Tic-Arg-Tic-Lys-OH(87)NH2C0-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH(88)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH(89)NH2C0-N1e-Asp-Tic-D-Mob-Arg-Tic-Lys-OH(90)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH91)NH2CO-Nle-Asp-Tic+Fpa-Arg-Trp-Lys-OH92)NH2C0-N1e-Asp-Tic+Fpa-Arg-Tic-Lys-OH93)NH2CO-Nle-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH94)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH95)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tic-Lys-OH96)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH97)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH298)(CH3)2NC0-N1e-Asp-His-D-Tic-Arg-Tic-Lys-NH299)(CH3)2NC0-N1e-Asp-His-D-Tic-Arg-Tca-Lys-NH2、100)(CH3)2NCO-Nle-Asp-Hi.s-陽D-Mob-Arg-Trp-Lys-NH2101)(CH3)2NCO-Nle-Asp-His--D-Mob-Arg-Tic一Lys--NH2:102)線)2腦-Nle-Asp-Hi.s--D-Mob-Arg-Tca-Lys--NH2103)(CH3)2NCO-Nle-Asp-His誦-D-Fpa-Arg-Trp-Lys--NH2104)(CH3)2腦-Nle-Asp-His--D-Fpa-Arg-Tic一Lys國-NH2105)(CH3)2NCO-Nle-Asp-His--D-Fpa-Arg-Tca-Lys--NH2106)(CH3)2NCO-Nle-Asp-His--D-Upa-Arg-Trp-Lys--NH2107)(CH3)2NCO-Nle-Asp-His-國D-Upa-Arg-Tic一Lys--NH2108)(CH3)2NCO-Nle-Asp-Hi.s-陽D-Upa-Arg-Tca-Lys--NH2109)(CH3)2NCO-Nle-Asp-Ti.c-畫D-Tic-Arg-Trp-Lys--NH2:110)(CH3)2NCO-Nle-Asp-T〗LC誦-D-Tic-Arg-Tic-Lys-NH2:111)(CH3)2NC0-Nle-Asp-Ti-C誦-D-Tic-Arg-Tca-Lys國-NH2:112)(CH3)2NCO-Nle-Asp-T〗LC--D-Mob-Arg-Trp-Lys-NH2:113)(CH3)2NCO-Nle-Asp-T〗LC-畫D-Mob-Arg-Tic-Lys--NH2:114)(CH3)2NCO-Nle-Asp-TiLC--D-Mob-Arg-Tca-Izys--NH2:115)(CH3)2NCO-Nle-Asp-TiLC--D-Fpa-Arg-Trp-Lys--NH2:ii6)(CH3)2NCO-Nle-Asp-T〗LC-陽D-Fpa-Arg-Tic-Lys--NH2:117)(CH3)2腦-Nle-Asp-TiLC--D-Fpa-Arg-Tca-Lys.-NH2:ii8)(CH3)2NCO-Nle-Asp-TiLC-隱D-Upa-Arg-Trp-Lys'-NH2:119)(CH3)2NCO-Nle-Asp-TiLC--D-Upa-Arg-Tic-Lys-NH2<formula>formulaseeoriginaldocumentpage24</formula>說明書第ll/23頁(147)Ac-N].e--環(huán)(Asp-His-D-Tic-Arg-Tca-Lys)(MW:1048，ESI--MS:1048.7(148)Ac-N].e--環(huán)(Asp-His-D-Mob-Arg-Trp-Lys)-NH2(MW:1067，ESI--MS:1067.8(149)Ac-N]■e--環(huán)(Asp-His-D-Mob-Arg-Tic-Lys)-NH2(MW:1040，ESI--MS:1040.6(150)Ac-N].e--環(huán)(Asp-His-D-Mob-Arg-Tca-Lys)-NH2(MW:1079，ESI.-MS:1079.5(151)Ac-N]■e--環(huán)(Asp-His-D-Fpa-Arg-Trp-Lys)-NH2(MW:1041，ESI--MS:1041.2(152)Ac-N■e--環(huán)(Asp-His-D-Fpa-Arg-Tic-Lys)-NH2(MW:1016，ESI.-MS:1016.4(153)Ac-Ne誦-環(huán)(Asp-His-D-Fpa-Arg-Tca-Lys)-NH2(MW:1054,ESI--MS:1054.8(154)Ac-N〗-環(huán)(Asp-His-D-Upa-Arg-Trp-Lys)-NH2(MW:1081，ESI--MS:1081.5(155)Ac-N].e--環(huán)(Asp-His-D-Upa-Arg-Tic-Lys)-NH2(156)Ac-N〗e--環(huán)(Asp-His-D-Upa-Arg-Tca-Lys)-NH2(157)Ac-N]■e-陽環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2(158)Ac-N.e--環(huán)(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2(159)Ac-N]■e--環(huán)(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2(160)Ac-N.e-陽環(huán)(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2(161)Ac-N]L6-畫環(huán)(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2(162)Ac-N.e-國環(huán)(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2(163)Ac-N].e-陽環(huán)(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2(164)Ac-N]-環(huán)(Asp-Tic-D-Fpa-Arg-Tic-Lys)-NH2(165)Ac-N].e--環(huán)(Asp-Tic-D-Fpa-Arg-Tca-Lys)-NH2(166)Ac-N.e--環(huán)(Asp-Tic-D-Upa-Arg-Trp-Lys)-NH2(167)Ac-N][6--環(huán)(Asp-Tic一D-Upa-Arg-Tic一Lys)-NH2〔168)Ac-畫N].e--環(huán)(Asp-TiLC--D-Upa-Arg-Tca-Lys)-NH2〔169〕Ac-畫N]■e--環(huán)(Asp-H3LS--D-Tic-Arg-Trp-Lys)_0H(170)Ac--N〕.e--環(huán)(Asp-HiLS--D-Tic-Arg-Tic-Lys)_0H〔171)Ac--N].e國-環(huán)(Asp-HiLS--D-Tic-Arg-Tca-Lys)-OH〔172〕Ac-陽N].e--環(huán)(Asp-HiLS--D-Mob-Arg-Trp-Lys:-OH〔173)Ac-畫N].e--環(huán)(Asp-HiLS--D-Mob-Arg-Tic"Lys)-OH〔174)Ac-隱N].e--環(huán)(Asp-HiLS--D-Mob-Arg-Tca"Lys)-OH〔175)Ac--N]■e--環(huán)(Asp-HiLS--D-Fpa-Arg-Trp-Lys)-OH〔176)Ac--N].e曙-環(huán)(Asp-HiLS--D-Fpa-Arg-Tic-Lys)-OH〔177)Ac--N.e--環(huán)(Asp-H〗LS--D-Fpa-Arg-Tca-Lys)-OH〔178)Ac-國N]■e--環(huán)(Asp-HiLS-陽D-Upa-Arg-Trp-Lys)-OH〔179)Ac--Ne--環(huán)(Asp-HilS誦-D-Upa-Arg-Tic-Lys)-OH〔180)Ac--N]e--環(huán)(Asp-HiLS--D-Upa-Arg-Tca-Lys)-OH〔181)Ac--N.6--環(huán)(Asp-Tic--D-Tic-Arg-Trp-Lys)-OH〔182)Ac--NL6--環(huán)(Asp-Ti.c--D-Tic-Arg-Tic-Lys)-OH:183)Ac--N.6--環(huán)(Asp-Tic--D-Tic-Arg-Tca"Lys)-OH:184)Ac--N陽環(huán)(Asp-Tic--D-Mob-Arg-Trp-Lys)-OH:185)Ac誦-N.6--環(huán)(Asp-Tic--D-Mob-Arg-Tic一Lys)-OH〔186)Ac--Ne-隱環(huán)(Asp-TiLC--D-Mob-Arg-Tca-Lys)-OH〔187)Ac--Ne--環(huán)(Asp-TilC_-D-Fpa-Arg-Trp-Lys)-OH〔188)Ac誦-N]e--環(huán)(Asp-TiLC--D-Fpa-Arg-Tic-Lys)-OH〔189)Ac-國Ne--環(huán)(Asp-TiLC--D-Fpa-Arg-Tca-Lys)-OH〔190)Ac-國NJe國陽環(huán)(Asp-TiLC--D-Upa-Arg-Trp-Lys)-OH〔191)Ac--N.e--環(huán)(Asp-TiLC--D-Upa-Arg-Tic-Lys)-OH〔192)Ac--N]L6國畫環(huán)(Asp-T3LC--D-Upa-Arg-Tca-!Lys)一OH193)NH2CO-N1e-環(huán)(Asp-His-D-Tic-Arg-Trp-Lys)-NH:194)NH2CO-Nle-環(huán)(Asp-His-D-Tic-Arg-Tic-Lys)-NH:195)NH2CO-Nle-環(huán)(Asp-His-D-Tic-Arg-Tca-Lys)-NH:196)NH2CO-N1e-環(huán)(Asp-His-D-Mob-Arg-Trp-Lys)-NH(197)冊2C0-Nle-環(huán)(Asp-His--D-Mob-Arg-Tic-陽Lys)-NH2(198)NH2C0-Nle-環(huán)(Asp-His--D-Mob-Arg-Tca-丄ys)-NH2(199)NH2CO-Nle-環(huán)(Asp-His--D-Fpa-Arg-Trp--Lys)-NH2(200)NH2CO-Nle-環(huán)(Asp-Hi.s--D-Fpa-Arg-Tic-丄ys)-NH2(201)NH2CO-Nle-環(huán)(Asp-His.-D-Fpa-Arg-Tca-丄ys)-NH2(202)冊2C0-Nle-環(huán)(Asp-Hi.s--D-Upa-Arg-Trp誦丄ys)-NH2(203)NH2CO-Nle-環(huán)(Asp-His--D-Upa-Arg-Tic誦畫Lys)-NH2(204)NH2CO-Nle-環(huán)(Asp-His--D-Upa-Arg-Tca誦丄ys)-NH2(20)冊2C0-Nle-環(huán)(Asp-Tic;-D-Tic-Arg-Trp-Lys)--NH2(206)NH2CO-Nle-環(huán)(Asp-Ti.c.-D-Tic-Arg-Tic誦陽Lys)-NH2(207)冊2C0-Nle-環(huán)(Asp-Tic-國D-Tic-Arg-Tca-國Lys〕-NH2(208)NH2CO-Nle-環(huán)(Asp-Ti.c.-D-Mob-Arg-Trp-陽Lys)-冊2(209)冊2C0-Nle-環(huán)(Asp-Tic-陽D-Mob-Arg-Tic國隱Lys)-NH2(210)NH2CO-Nle-環(huán)(Asp-Tic--D-Mob-Arg-Tca誦丄ys)-NH2(211)冊2C0-Nle-環(huán)(Asp-Tic.-D-Fpa-Arg-Trp國-Lys)-NH2(212)NH2C0-Nle-環(huán)(Asp-Tic-陽D-Fpa-Arg-Tic-丄ys)-NH2(213)冊-環(huán)(Asp-Tic--D-Fpa-Arg-Tca--匕ys)-NH2(214)冊2C0-Nle-環(huán)(Asp-Ti-C.-D-Upa-Arg-Trp-丄ys)-NH2(215)NH2CO-Nle-環(huán)(Asp-Tic.-D-Upa-Arg-Tic-陽乙ys)-NH2(216)亂CO-Nle-環(huán)(Asp-Ti-D-Upa-Arg-Tca-隱Lys〕-NH2(217)NH2C0-Nle-環(huán)(Asp-HilS-陽D-Tic一Arg-Trp--Lys)-OH(218)NH2CO-Nle-環(huán)(Asp-HiLS,-D-Tic-A^g-Ti(--Lys)-OH(219)NH2C0-Nle-環(huán)(Asp-HiLS.-D-Tic一A^g-Tca--I^ys)-OH(220)NH2C0-Nle-環(huán)(Asp-HiLS.-D-Mob-A^g-T^p--Lys)-OH(221)NH2CO-Nle-環(huán)(Asp-HiLS--D-Mob-Arg-Tic誦-Lys)-OH(222)NH2C0-Nle-環(huán)(Asp-HiLS'-D-Mob-Arg-Tca誦-Lys)-OH(MW:1081，MS:1081.8)(223)NH2CO-N1e-環(huán)(Asp-H〗LS'-D-Fpa-Arg-Trp誦畫Lys)-OH(224)NH2CO-Nle-環(huán)(Asp-H〗LS-D-Fpa-Arg-Tic--Lys)-OH<table>tableseeoriginaldocumentpage28</column></row><table><table>tableseeoriginaldocumentpage29</column></row><table>(283)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH(284)(CH3)2NC0-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH(285)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH(286)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH(287)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH(288)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH(289)No-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2(MW:1155，ESI-MS:1155.8)更優(yōu)選地，本發(fā)明化合物選自上述化合物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。本發(fā)明化合物的制備可以采用固相合成方法，以MBHA樹脂或PAM樹脂或Wang樹脂為載體，Boc-或F血oc-保護策略，DCC/HOBT或BOP/DIEA為縮合試劑，HCl/二氧六環(huán)或哌啶/DMF為脫保護試劑，反應(yīng)完后將七肽衍生物從樹脂上切割下來。根據(jù)本發(fā)明，式(la)線型七肽衍生物和式(lb)環(huán)狀七肽衍生物或其立體異構(gòu)體和其無生理毒性的鹽在初步的受體結(jié)合活性實驗以及小鼠減肥實驗中具有較好的活性.本發(fā)明所用術(shù)語"無生理毒性的鹽"是指可保留母體化合物預(yù)期生理活性而不會產(chǎn)生任何意料之外毒副作用的鹽，例如鹽酸鹽，氫溴酸鹽，硫酸鹽，磷酸鹽，硝酸鹽，醋酸鹽，草酸鹽，酒石酸鹽，琥珀酸鹽，蘋果酸鹽，苯甲酸鹽，雙羥萘酸鹽，海藻酸鹽，甲磺酸鹽，萘磺酸鹽等，以及陽離子鹽如鉀鹽，鈉鹽、鋰鹽，鋅鹽，銅鹽，鋇鹽，鉍鹽，鉤鹽，三烷基銨鹽等。本發(fā)明式(Ia)線型七肽衍生物和式(Ib)環(huán)狀七肽衍生物或其立體異構(gòu)體或無生理毒性的鹽可以單獨或以藥物組合物的形式給藥。本發(fā)明藥物組合物可根據(jù)給藥途徑配成各種適宜的劑型。適當(dāng)?shù)闹苿┬问饺Q于所選擇的給藥途徑，可以按照本領(lǐng)域熟知的常識進行制備。給藥途徑可以是口服、非腸道或局部給藥，優(yōu)選口服和注射形式給藥。可以口服的藥物制劑包括膠嚢劑和片劑等。本發(fā)明組合物也可以配制成用于腸胃外或者給藥、透皮給藥或者經(jīng)粘膜給藥的形式?；蛘卟捎盟▌┗蛘呗裰矂┑姆绞浇o藥。本領(lǐng)域技術(shù)人員可以理解，本發(fā)明化合物可以采用合適的藥物釋放系統(tǒng)(DDS)以得到更有利的效果。本發(fā)明式(la)線型七肽衍生物和式(lb)環(huán)狀七肽衍生物或其立體異構(gòu)體的給藥劑量取決于許多因素，例如所要預(yù)防或治療疾病的性質(zhì)和嚴重程度，患者或動物的性別、年齡、體重，敏感性及個體反應(yīng)，所用的具體化合物，給藥途徑，給藥次數(shù)以及所希望達到的治療效果等。上述劑量可以單一劑量形式或分成幾個，例如二、三、四個劑量形式給藥。單個最大劑量一般不超過10mg/Kg體重，例如0.001-10mg/Kg，優(yōu)選0.01-5mg/Kg，較佳劑量范圍為0.5-2mg/Kg體重。但是，在某些情況下，也可能使用10mg/Kg體重以上或者0.OOlmg/Kg以下的單個劑量。圖1為實驗小鼠體重變化曲線具體實施例方式下面的實施例及生物活性實驗用于進一步說明本發(fā)明，但其并不意味著對本發(fā)明的任何限制.在本發(fā)明中使用的縮寫具有下面的含義Ac乙?；鵄sp天冬氨酸殘基Arg精氨酸殘基Boc叔丁氧羰基BOP苯并三唑-l-氧-三(二甲氨基)磷六氟磷酸Bu正丁基DCC二環(huán)己基碳二亞胺DIEA二異丙基乙胺Fmoc藥甲氧羰基Fpa對氟苯丙氨酸殘基H0Bt1羥基苯并三唑His組氨酸殘基Lys賴氨酸殘基MBHA樹脂苯基氨甲基樹脂Mob一胡椒基丙氨酸殘基Mpca—(2s)-4-(4-甲基笨甲酰胺)-四氫吡咯-2-羧酸殘基Nle正亮氨酸殘基No壬?；鵓AM樹脂—羥曱基苯乙酰胺甲基樹脂Phe苯丙氨酸殘基Pro脯氨酸殘基RP-HPLC反相高效液相色謙Tea2，3，4,9-四氬-1^"吡咬-[3，4-6]W咮-3-羧酸殘基Tic1,2，3，4-四氫異喹啉-3-羧酸殘基Trp色氛酸殘基Ureido脲基Upa對脲基苯丙氨酸殘基在本發(fā)明中，所有氨基酸構(gòu)型除注明為D-型外，均為L-型。實施例所用固相合成載體MBHA樹脂、PAM樹脂以及Wang樹脂為天津南開合成責(zé)任有限公司產(chǎn)品；DCC、H0BT、B0P、DIEA以及保護的，保護的非天然氨基酸除說明外均由本實驗室合成提供?？诳诳趯嵤├?:化合物(3)的合成以100mgMBHA樹脂(0.096mmo1)為固相載體，BOP/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Boc固相多肽合成方法(參考文獻黃惟德，陳常慶著，多肽合成，科學(xué)出版社，1985)操作合成Ac-Nle-Asp-His-D-Tic-Arg-Tca-Lys-MBHA樹月旨。將上述肽樹脂放入HF切割儀的反應(yīng)器中，加入l.OmL苯甲醚，裝好后將HF切割儀的體系抽成真空，用液氮冷卻反應(yīng)器，轉(zhuǎn)入約10mL液態(tài)HF，于0C反應(yīng)40分鐘。用油泵抽走HF，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙醚洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得92.8mg白色干粉，經(jīng)RP-HPLC純化得純品(純度大于95%)23.7mg,純肽收率22.0%。ESI-MS:1066.2(理論值1066)。實施例2:化合物(8)的合成以100mgMBHA樹脂(0.096mmo1)為固相載體，B0P/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Boc固相多肽合成方法(參考文獻同實施例l)操作合成Ac-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-MBHA樹月旨。將上述肽樹脂放入HF切割儀的反應(yīng)器中，加入1.0mL苯甲醚，裝好后將HF切割儀的體系抽成真空，用液氮冷卻反應(yīng)器，轉(zhuǎn)入約10mL液態(tài)HF，于0TC反應(yīng)40分鐘。用油泵抽走HF，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙醚洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得95.6mg白色千粉，經(jīng)RP-HPLC純化得純品(純度大于95%)22.lmg，純肽收率21.2%。ESI-MS:1034.4(理論值1034)。實施例3:化合物(9)的合成以100mgMBHA樹脂(0.096mmo1)為固相載體，BOP/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Boc固相多肽合成方法(參考文獻同實施例1)操作合成Ac-Nle-Asp-His-D-Fpa-Arg-Tca-Lys-MBHA樹月旨。將上述肽樹脂放入HF切割儀的反應(yīng)器中，加入1.OmL苯甲醚，裝好后將HF切割儀的體系抽成真空，用液氮冷卻反應(yīng)器，轉(zhuǎn)入約10mL液態(tài)HF，于Gt:反應(yīng)40分鐘。用油泵抽走HF，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙醚洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得105.6mg白色干粉，經(jīng)RP-HPLC純化得純品(純度大于95%)22.5mg，純肽收率20.8%。ESI-MS:1072.8(理論值1072)。實施例4:化合物(12)的合成以100mgMBHA樹脂(0.096mmo1)為固相載體，BOP/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Boc固相多肽合成方法(參考文獻黃惟德，陳常慶著，多肽合成，科學(xué)出版社，1985)操作合成Ac-Nle-Asp-His-D-Upa-Arg-Tca-Lys-MBHA樹月旨。將上述肽樹脂放入HF切割儀的反應(yīng)器中，加入1.0mL苯甲瞇，裝好后將HF切割儀的體系抽成真空，用液氮冷卻反應(yīng)器，轉(zhuǎn)入約10mL液態(tài)HF,于OX:反應(yīng)40分鐘。用油泵抽走HF，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙醚洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得102.8mg白色干粉，經(jīng)RP-HPLC純化得純品(純度大于95%)28.3mg，純肽收率25.3%。ESI-MS:1111.4(理論值1111)。實施例5:化合物(78)的合成以100mgWang樹脂(0.065mmol)為固相載體，B0P/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Fmoc固相多肽合成方法(參考文獻同實施例1)操作合成冊2C0-Nle-Asp-His-D-Mob-Arg-Tca-Lys-Wang樹月旨。將上述肽樹脂放入裂解反應(yīng)器中，加入1.OmL苯甲醚、lmL間甲酚和8mL三氟乙酸，于0t:反應(yīng)40分鐘。減壓旋走三氟乙酸，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙醚洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得65.3mg白色干粉，經(jīng)RP-HPLC純化得純品(純度大于95%)20.5mg,純肽收率27.3%。ESI-MS:1153.6(理論值1153.3)。實施例6:化合物(145)的合成以100mgMBHA樹脂(0.096mmo1)為固相栽體，BOP/DIEA為縮合劑，根據(jù)化合物的氨基酸序列，按標準的Fmoc固相多肽合成方法(參考文獻同實施例1)操作合成Ac-Nle-環(huán)(Asp-His-D-Tic-Arg-Trp-Lys)-MBHA樹脂。將上述肽樹脂放入HF切割儀的反應(yīng)器中，加入1.OmL苯曱醚，裝好后將HF切割儀的體系抽成真空，用液氮冷卻反應(yīng)器，轉(zhuǎn)入約10mL液態(tài)HF,于0C反應(yīng)40分鐘，用油泵抽走HF，取下反應(yīng)器，加入冷凍無水乙醚沉淀出固體，再將混懸液轉(zhuǎn)移至砂芯漏斗中。用少量冷卻的無水乙鍵洗滌三次，再用10%的乙酸水溶液沖洗至樹脂不再相互粘附，收集洗滌液，冷凍干燥后得95.3mg白色千粉，經(jīng)RP-HPLC純化得純品(純度大于95%)13.lmg,純肽收率13.2%。ESI-MS:1036.5(理論值1036.3)。實施例7:受體結(jié)合活性評價實驗方法cAMP釋放實驗(I125-cAMP放射免疫分析試劑盒)，復(fù)管實驗。細胞林瞬時表達MC3R/MC4R的HEK293細胞實驗原理I"-cAMP與cAMP抗血清結(jié)合可產(chǎn)生抗原抗體復(fù)合物，經(jīng)離心去除游離未結(jié)合的I'"-cAMP后，用y-射線計數(shù)儀可測定沉淀中的同位素計數(shù)(B0)。藥物作用下細胞釋放的cAMP可與r5-cAMP共同竟爭與cAMP抗血清的結(jié)合，由此使Im-cAMP與cAMP抗血清的結(jié)合物減少，因此使同位素計數(shù)降低(B)。計算指標結(jié)合抑制百分率=1-B/B0xl00%結(jié)合抑制百分率越高表示藥物作用下cAMP釋放越多，對所給定的受體而言也即激動活性越強。藥物篩選選擇20nM和lOOnM兩個濃度，每個受試樣品重復(fù)3次。結(jié)果見表1和表2。_表1部分化合物MC3-R結(jié)合活性評價結(jié)果_化合物編號^幽制百分率m20nM100nM45753254959169424614551782894777表2部分化合物MC4-R結(jié)合活性評價結(jié)果化合物編號^結(jié)合抑制百^1H20nM100nM252729169584514545512895555實施例8:小鼠減肥模型評價根據(jù)放射配體結(jié)合實驗及cAMP釋放實驗結(jié)果，對篩選出來的化合物(化合物169)進行動物藥效學(xué)實驗。選用同性別昆明種小鼠，體重30克左右，分成若干組，每組6只小鼠。于第2天開始經(jīng)腦室分別注射5uL濃度為lug/uL的不同化合物，對照組注射5uL生理鹽水，連續(xù)給藥10天，每天觀察記錄體重變化，對比給藥前后體重的變化，并與對照組進行對比。結(jié)果見下表3(注表中數(shù)據(jù)為6只動物體重均值)以及圖1。_表3小鼠給藥后體重變化_<table>tableseeoriginaldocumentpage37</column></row><table>權(quán)利要求1.式(Ia)線型七肽衍生物和式(Ib)環(huán)狀七肽衍生物，或其立體異構(gòu)體或無生理毒性的鹽R-Nle-S2-S3-S4-Arg-S6-Lys-B(Ia)R-Nle-環(huán)(S2-S3-S4-Arg-S6-Lys)-B(Ib)其中R為H-、R1C(O)-、R1R2NC(O)-、Boc、Fmoc，R1和R2各自獨立地為H，取代或未取代的C1-C6直鏈或者支鏈烷基，取代或未取代的C2-C6直鏈或者支鏈烯基或者炔基，取代或未取代的C1-C6直鏈或者支鏈烷氧基，取代或未取代的C1-C6直鏈或者支鏈烷硫基，取代或未取代的C2-C6直鏈或者支鏈烯基或者炔基氧基，取代或未取代的C2-C6直鏈或者支鏈烯硫基或者炔硫基，C3-C8環(huán)烷基，C3-C8環(huán)烯基，C6-C14芳基、C4-C10雜芳基、C3-C8雜環(huán)基；B為-OH或-NR3R4，R3和R4各自獨立地為H-、R1-、R1C(O)-、R1R2NC(O)-，其中R1和R2的定義同前；S2為Asp或Glu；S3為L或D型的His、Pro或Z，Z為下列結(jié)構(gòu)I、II(Mob)、III(Tca)、IV、V或VI(Mpca)id="icf0001"file="S2008100967245C00011.gif"wi="160"he="25"top="205"left="29"img-content="drawing"img-format="tif"orientation="portrait"inline="no"/>III(Mob)III(Tca)id="icf0002"file="S2008100967245C00012.gif"wi="157"he="25"top="248"left="33"img-content="drawing"img-format="tif"orientation="portrait"inline="no"/>IVVVI(Mpca)各個R5獨立地為R1、-NR1R2、-NHC(O)NR1R2、-C(O)NR1R2、-NH-C(O)R1，其中R1和R2的定義同前；S4為D型的Z，Z的定義同前；S6為L或D型的Trp或Z，Z的定義同前，所述“芳基”為6-14元單環(huán)或雙環(huán)芳香基團，如苯基或萘基，其未被取代或被獨立地選自鹵素、硝基、羧基或C1-C4烷基的取代基單取代或二取代或三取代；“雜芳基”為含有1-5個獨立地選自N、O和S的雜原子的4-10元單環(huán)或雙環(huán)芳香基團，如吡咯基、呋喃基、吡啶基等，其未被取代或被獨立地選自鹵素、硝基、羧基或C1-C4烷基的取代基單取代或二取代；“雜環(huán)基”為其環(huán)結(jié)構(gòu)中含1-5個、優(yōu)選1-3個獨立地選自N、O和S的雜原子的3-8元非芳香環(huán)狀基團，如吡喃基、哌啶基等，其未被取代或被獨立地選自鹵素、硝基、羧基或C1-C4烷基的取代基單取代或二取代或三取代。2、根據(jù)權(quán)利要求1的化合物，其中R為AC-、-C0NH2、-CON(CH3)2、No-。3、根據(jù)權(quán)利要求l的化合物，4、根據(jù)權(quán)利要求l的化合物，5、根據(jù)權(quán)利要求l的化合物，6、根據(jù)權(quán)利要求1的化合物，或D-Upa。其中B為-NH2或-0H。其中Sz為Asp。其中S3為L或D型的His或Tic。其中S4為D-Tic、D-Mob、D-Fpa7、根據(jù)權(quán)利要求1的化合物，其選自以下七肽衍生物，或其立體異構(gòu)體或無生理毒性的鹽(1)Ac-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH2(2)Ac-N1e-Asp-His-D-Tic-Arg-Tic-Lys-NH2(3)Ac-N1e_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-N1e-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-N1e-Asp-Tic-D-Tic-Arg-Tic-Lys-NH2(15)Ac-N1e-Asp-Tic-D-Tic-Arg-Tca-Lys-NH2(16)Ac-N1e-Asp-Tic-D-Mob-Arg-Trp-Lys-NH2(17)Ac-N1e-Asp-Tic-D-Mob-Arg-Tic-Lys-NH2(18)Ac-N1e-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-跳(23)Ac-N1e-Asp-Tic-D-Upa-Arg-Tic-Lys-NH2(24)Ac-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2(25)Ac-N1e-Asp-His-D-Tic-Arg-Trp-Lys-OH(26)Ac-N1e-Asp-His-D-Tic-Arg-Tic~Lys-OH(27)Ac-N1e-Asp-His-D-Tic一Arg-Tca-Lys-OH(28)Ac-N].e--Asp-HLS.-D-Mob-Arg-Trp-Lys--OH(29)Ac-N].e--Asp-H]LS--D-Mob-Arg-Tic一Lys--OH(30)Ac-N.e--Asp-H[s--D-Mob-Arg-Tca-Lys--OH(31)Ac-N].e--Asp-H[s.-D-Fpa-Arg-Trp-Lys--OH(32)Ac-N].e--Asp-HLS--D-Fpa-Arg-Tic一Lys--OH(33)Ac-N].e--Asp-H1LS--D-Fpa-Arg-Tca-Lys--OH(34)Ac-N].e--Asp-HLS--D-Upa-Arg-Trp-Lys--OH(35)Ac-N]e--Asp-H〗LS--D-Upa-Arg-Tic一Lys--OH(36)Ac-NJ■e--Asp-H]LS--D-Upa-Arg-Tca-Lys--OH(37)Ac-N]■e--Asp-T]LC-陽D-Tic-Arg-Trp-Lys--OH(38)Ac-N].e--Asp-T〗LC--D-Tic-Arg-Tic-Lys--OH(39)Ac-N]e--Asp-TiLC--D-Tic-Arg-Tca-Lys--OH(40)Ac-Ne--Asp-TiLC--D-Mob-Arg-Trp-Iyys--OH(41)Ac-NL6--Asp-TilC--D-Mob-Arg-Tic一Lys國-OH(42)Ac-Nl6--Asp-Ti.c--D-Mob-Arg-Tca-Lys--OH(43)Ac-N6-陽Asp-Tic--D-Fpa-Arg-Trp-Lys-OH(44)Ac-N.6--Asp-Ti.c--D-Fpa-Arg-Tic一Lys隱-OH(45)Ac-N6--Asp-Tic-畫D-Fpa-Arg-Tca-Lys--OH(46)Ac-N6誦隱Asp-Tic--D-Upa-Arg-Trp-Lys--OH(47)Ac-N.6--Asp-H.c--D-Upa-Arg-Tic-Lys-OH(48)Ac-N.6--Asp-Tic--D-Upa-Arg-Tca-Lys-OH(49)NH2C0-Nle-Asp-His-D-Tic-Arg-Trp-Lys-NH(50)NH2CO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH(51)NH2CO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH(52)NH2CO-Nle-Asp-His-D-Mob-Arg-Trp-Lys-NH:(53)NH2CO-Nle-Asp-His-D-Mob-Arg-Tic-Lys-NH:(54)NH2C0-Nle-Asp-His-D-Mob-Arg-Tca-Lys-NH(55)NH2C0-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-NH(56)NH2CO-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-NH:(57)NH2CO-Nle-Asp-His+Fpa-Arg-Tca-Lys-NH2(58)NH2CO-Nle-Asp-His-D-Upa-Arg-Trp-Lys-NH2(59)NH2C0-N1e-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)NH2C0-N1e-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)NH2C0-N1e-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)NH2C0-N1e-Asp-Tic-D-Upa-Arg-Tca-Lys-NH2(73)NH2CO-Nle-Asp-His-D-Tic-Arg-Trp-Lys-OH(74)NH2C0-N1e-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)NH2C0-N1e-Asp-His-D-Mob-Arg-Tic-Lys-OH(78)NH2CO~Nle-Asp-His-D-Mob-Arg-Tca-Lys一OH(79)NH2CO-Nle-Asp-His-D-Fpa-Arg-Trp-Lys-OH(80)NH2C0-Nle-Asp-His-D-Fpa-Arg-Tic-Lys-0H(81)NH2CO-Nle-Asp-His+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)NH2C0-N1e-Asp-Tic-D-Tic-Arg-Trp-Lys-OH86)觀C0-N1e-Asp-Tic-D-Tic-Arg-Tic-Lys-0H87)NH2CO-Nle-Asp-Tic-D-Tic-Arg-Tca-Lys-OH88)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Trp-Lys-OH89)NH2C0-N1e-Asp-Tic-D-Mob-Arg-Tic-Lys-OH90)NH2CO-Nle-Asp-Tic-D-Mob-Arg-Tca-Lys-OH91)NH2CO-Nle-Asp_Tic+Fpa-Arg-Trp-Lys-OH92)NH2CO-Nle-Asp-Tic+Fpa-Arg-Tic-I>ys-OH93)NH2CO_N1e-Asp-Tic-D-Fpa-Arg-Tca-Lys-OH94)NH2CO-Nle-Asp-Tic-D-Upa-Arg-Trp-Lys-OH95)NH2CO-N1e-Asp-Tic-D-Upa-Arg-Tic-Lys-OH96)NH2CO-N1e-Asp-Tic-D-Upa-Arg-Tca-Lys-OH97)(CH3)2NCO-N1e-Asp-His-D-Tic-Arg-Trp-Lys-NH98)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tic-Lys-NH99)(CH3)2NCO-Nle-Asp-His-D-Tic-Arg-Tca-Lys-NH100)(CH3)2NCO-Nle-Asp-Hi.s--D-Mob-Arg-Trp-Lys-NH2101)(CH3)2腦-N1e-Asp-Hi.s--D-Mob-Arg-Tic-Lys-NH2102)(CH3)2NCO-Nle-Asp-His--D-Mob-Arg-Tca-Lys-NH2103)(CH3)2NCO-Nle-Asp-Hi-S-陽D-Fpa-Arg-Trp-Lys-NH2104)(CH3)2NCO-Nle-Asp-His-陽D-Fpa-Arg-Tic-Lys-NH2105)(CH3)2NCO-Nle-Asp-His-隱D-Fpa-Arg-Tca-Lys-NH2106)(CH3)2NCO-Nle-Asp-Hi.s-隱D-Upa-Arg-Trp-Lys-NH2107)(CH3)2NC0-N1e-Asp-HiLS-陽D-Upa-Arg-Tic-Lys-NH2108)(CH3)2NC0-N1e-Asp-HiLS國-D-Upa-Arg-Tca-tys-NH2109)(CH3)2NCO-Nle-Asp-TiLC--D-Tic-Arg-Trp-Lys-NH2110)(CH3)2NCO-Nle-Asp-TiLC--D-Tic_Arg-Tic-Lys-NH2111)(CH3)2NCO-Nle-Asp-TiLC--D-Tic-Arg-Tca-Lys-NH2112)(CH3)2NCO-Nle-Asp-T〗LC-陽D-Mob-Arg-Trp-Lys-NH2113)(CH3)2NCO-Nle-Asp-TiLC-畫D-Mob-Arg-Tic-Lys-NH2114)(CH3)2NCO-Nle-Asp-TiLC--D-Mob-Arg-Tca-Lys-NH2(115)線)2腦-N16--Asp-Tic畫-D-Fpa-Arg-Trp-Lys誦-NH2(116)(CH3)2NC0-N16--Asp-Tic--D-Fpa-Arg-Tic-Lys--NH2(117)(CH3)2NC0-N16_-Asp-Tic--D-Fpa-Arg-Tca-Lys--NH2(118)(CH3)2NC0-N16_-Asp-Tic--D-Upa-Arg-Trp-Lys--NH2(119)(CH3)2NC0-N16--Asp-Tic--D-Upa-Arg-Tic一Lys--NH2(120)(CH3)2NC0-N16-陽Asp-Tic--D-Upa-Arg-Tca-Lys--NH2(121)(CH3)2NC0-N16--Asp-His--D-Tic一Arg-Trp-:Lys--OH(122)(CH3)2NC0-N16_-Asp-His--D-Tic-Arg-Tic-Lys--OH(123)(CH3)2NC0-N16--Asp-His-匿D-Tic-Arg-Tca-Lys--OH(124)(CH3)2NC0-N16_-Asp-His--D-Mob-Arg-Trp-Lys--OH(125)(CH3)2NC0-N16--Asp-His--D-Mob-Arg-Tic-Lys誦國OH(126)(CH3)2NC0-N16_-Asp-His誦-D-Mob-Arg-Tca-Lys--OH(127)(CH3)2NC0-N16--Asp-His--D-Fpa-Arg-Trp-Lys誦國OH(128)(CH3)2NC0-N16_-Asp-His-曙D-Fpa-Arg-Tic-Lys-國OH(129)(CH3)2腦-N16_-Asp-His--D-Fpa-Arg-Tca-!Lys--OH(130)(CH3)2歸-N16_-Asp-His--D-Upa-Arg-Trp-Lys誦-OH(131)(CH3)2腦-N〗.6--Asp-Hi.s-陽D-Upa-Arg-Tic-Lys-OH(132)(CH3)2NCO-Ne--Asp-HiLS--D-Upa-Arg-Tca-!Lys--OH(133)(CH3)2歸-N.e-國Asp-TiLC-畫D-Tic-Arg-Trp-Lys--OH(134)(CH3)2NCO-N]L6--Asp-"HLC--D-Tic-Arg-Tic-Lys--OH(135)(CH3)2NCO-N.e--Asp-TiLC--D-Tic-Arg-Tca-Lys--OH(136)(CH3)2NCO-N.e--Asp-T〗LC.-D-Mob-Arg-Trp-!Lys--OH(137)(CH3)2NCO-N]e--Asp-TLC-隱D-Mob-Arg-Tic-Lys--OH(138)(CH3)2NC0-N].e--Asp-T.c--D-Mob-Arg-Tca-Lys--OH(139)(CH3)2NCO-N].e-陽Asp-T〗ic--D-Fpa-Arg-Trp-Lys--OH(140)(CH3)2NC0-NLe--Asp-Tic--D-Fpa-Arg-Tic-Lys-OH(141)(CH3)2NC0-NLe--Asp-Tle--D-Fpa-Arg-Tca-Lys.-OH(142)(CH3)2NC0-NLe--Asp-Tlc--D-Upa-Arg-Trp-Lys--OH(143)(CH3)2NC0-NLe--Asp-TLc--D-Upa-Arg-Tic一:Lys--OH144)(CH3)2NCO-Nle-Asp-Tic-D-Upa-Arg-Tca-Lys-OH145)Ac-隱N].e--環(huán)(Asp-H]ls--D-Tic-Arg-Trp-Lys〕-NH2146)Ac--N].e--環(huán)(Asp-H]ls--D-Tic-Arg-Tic-Lys〕-NH2147〕Ac--N].e--環(huán)(Asp-Hls--D-Tic-Arg-Tca-Lys〕-NH2148)Ac--N].e--環(huán)(Asp-H]ls.-D-Mob-Arg-Trp-Lys)-NH2149〕Ac--N〕.e--環(huán)(Asp-H]ls.-D-Mob-Arg-Tic-Lys〕-NH2150)Ac-隱N].e-陽環(huán)(Asp-H〗LS--D-Mob-Arg-Tca-Lys〕-NH2151)Ac誦-N].e--環(huán)(Asp-Hils.-D-Fpa-Arg-Trp"Lys〕-NH2152)Ac--N〗e曙-環(huán)(Asp-HiLS.-D-Fpa-Arg-Tic-:Lys)-NH2153〕Ac-隱N].e--環(huán)(Asp-H〗ls--D-Fpa-Arg-Tca-Lys〕-NH2154)Ac-國N.e--環(huán)(Asp-H〗ls--D-Upa-Arg-Trp-Lys)-NH2155)Ac國-N]e-國環(huán)(Asp-H〗ls--D-Upa-Arg-Tic-Lys)-NH2156)Ac-陽N].e--環(huán)(Asp-Hils--D-Upa-Arg-Tca-Lys)-NH2157)Ac--N]e--環(huán)(Asp-T〗LC--D-Tic-Arg-Trp-Lys)-NH2158)Ac誦-N,e--環(huán)(Asp-Ti.c--D-Tic-Arg-Tic-Lys)-NH2159)Ac--N]L6誦-環(huán)(Asp-Tic--D-Tic-Arg-Tca-Lys)-匪2160)Ac--Ne--環(huán)(Asp-TilC--D-Mob-Arg-Trp-Lys)-NH2161)Ac--Ne-陽環(huán)(Asp-TiLC--D-Mob-Arg-Tic-Lys)-NH2162)Ac--NJe誦國環(huán)(Asp-TiLC--D-Mob-Arg-Tca-Lys)-NH2163)Ac-國Ne--環(huán)(Asp-T〗LC.-D-Fpa-Arg-Trp-Lys)-NH2164)Ac--N.e-國環(huán)(Asp-TiLC--D-Fpa-Arg-Tic-Lys)-NH2165)Ac誦國N〗e誦國環(huán)(Asp-TiLC--D-Fpa-Arg-Tca-Lys)-NH2166)Ac-隱N.e-陽環(huán)(Asp-TiLC--D-Upa-Arg-Trp"Lys)-NH2167)Ac--N.e-畫環(huán)(Asp-Tilc--D-Upa~Arg-Tic一Ly5)-NH2168)Ac誦國N]e誦畫環(huán)(Asp-Tilc-D-Upa-Arg-Tca-Lys)-NH2169)Ac-陽N〗e-陽環(huán)(Asp-Hils--D-Tic-Arg-Trp-Lys)-OH170)Ac--N.e-畫環(huán)(Asp-H3ls--D-Tic-Arg-Tic-Lys)-OH171)Ac-畫N]e-畫環(huán)(Asp-Hils--D-Tic-Arg-Tca-Lys)-OH172)Ac--NJe誦畫環(huán)(Asp-Hils--D-Mob-Arg-Trp"Lys)-OH<formula>formulaseeoriginaldocumentpage10</formula>(202)NH2CO-Nle-環(huán)(Asp-His--D-Upa-Arg-Trp-Lys)-NH2(203)NH2C0-Nle-環(huán)(Asp-His--D-Upa-Arg-Tic-Lys)-NH2(204)NH2CO-Nle-環(huán)(Asp-His--D-Upa-Arg-Tca-Lys)-NH2(20)NH2CO-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)畫-NH2(206)冊2CO-Nle-環(huán)(Asp-Ti,c--D-Tic-Arg-Tic-Lys)-NH2(207)NH2CO-Nle-環(huán)(Asp-Ti-C--D-Tic-Arg-Tca-Lys)-NH2(208)NH2CO-Nle-環(huán)(Asp-TiLC--D-Mob-Arg-Trp-Lys)-NH2(209)NH2CO-Nle-環(huán)(Asp-T,c--D-Mob-Arg-Tic~Lys)-NH2(210)NH2C0-Nle-環(huán)(Asp-TiLC--D-Mob-Arg-Tca-Lys)-NH2(211)NH2CO-Nle-環(huán)(Asp-TiLC--D-Fpa-Arg-Trp-Lys)-NH2(212)NH2CO-Nle-環(huán)(Asp-TiLC--D-Fpa-Arg-Tic-Lys)-NH2(213)冊2C0-Nle-環(huán)(Asp-TiLC--D-Fpa-Arg-Tca-Lys)-NH2(214)NH2CO-Nle-環(huán)(Asp-TiLC-畫D-Upa-Arg-Trp-Lys)-NH2(215)NH2CO-Nle-環(huán)(Asp-Ti-D-Upa-Arg-Tic-Lys)-NH2(216)NH2CO-Nle-環(huán)(Asp-Tic--D-Upa-Arg-Tca-Lys)-匪2(217)NH2CO-Nle-環(huán)(Asp-HiLS國隱D-Tic-Arg-Trp-Lys)-OH(218)冊2CO-Nle-環(huán)(Asp-Hi.s-國D-Tic-Arg-Tic-Lys)-OH(219)冊2C0-Nle-環(huán)(Asp-HiLS-曙D-Tic-Arg-Tca-Lys)-OH(220)NH2CO-Nle-環(huán)(Asp-HiLS--D-Mob-Arg-Trp-Lys)-OH(221)NH2CO-Nle-環(huán)(Asp-HiLS-畫D-Mob-Arg-Tic-Lys)-OH(222)NH2CO-Nle-環(huán)(Asp-HLS-國D-Mob-Arg-Tca-Iiys)-OH(223)NH2C0-Nle-環(huán)(Asp-HLS-陽D-Fpa-Arg-Trp-Lys)-OH(224)NH2CO-Nle-環(huán)(Asp-HiLS.-D-Fpa-Arg-Tic-Lys)-OH(225)NH2CO-Nle-環(huán)(Asp-HiLS-國D-Fpa-Arg-Tca-Lys)-OH(226)NH2CO-Nle-環(huán)(Asp-H〗LS--D-Upa-Arg-Trp-Lys)-OH(227)NH2CO-Nle-環(huán)(Asp-H〗LS--D-Upa-Arg-Tic-Lys)-OH(228)NH2CO-Nle-環(huán)(Asp-H〗LS--D-Upa-Arg-Tca-Lys)-OH(229)NH2CO-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)-OH(230)NH2C0-N1e-環(huán)(Asp-Tic-D-Tic-Arg-Tic-Lys)一OH(231)NH2C0-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Tca-Lys)-OH(232)NH2CO-Nle-Sf(Asp-Tic-D-Mob-Arg-Trp-Lys)-OH(233)NH2C0-Nle;(Asp-Tic+Mob-Arg-Tic-Lys)-OH(234)NH2C0-Nle-環(huán)(Asp-Tic-D-Mob-Arg-Tca-Lys)-OH(235)NH2C0-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Trp-Lys)-OH(236)NH2C0-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Tic-Lys)-OH(237)NH2C0-Nle-環(huán)(Asp-Tic-D-Fpa-Arg-Tca-Lys)-OH(238)NH2C0-Nle-環(huán)(Asp-Tic-D-Upa-Arg-Trp-Lys)-OH(239)NH2C0-N1e-環(huán)(Asp-Tic-D-Upa-Arg-Tic-Lys)-OH(240)冊2-環(huán)(Asp-Tic-D-Upa-Arg-Tca-Lys)-OH(241)(CH3)2NCO-N1e-環(huán)(Asp-His-D-Tic-Arg-Trp-Lys)-冊2(242)(CH3)2NCO-N1e-環(huán)(Asp-His-D-Tic-Arg-Tic-Lys)-NH2(243)(CH3)2NCO-Nle-環(huán)(Asp-His-D-Tic—Arg-Tca-Lys)-NH2(244)(CH3)2NCO-Nle-環(huán)(Asp-His-D-Mob-Arg-Trp-Lys)-NH2(245)(CH3)2NCO-N1e-環(huán)(Asp-His-D-Mob-Arg-Tic-Lys)-匪2(246)(CH3)2NC0-Nle-環(huán)(Asp-His-D-Mob-Arg-Tca-Lys)-NH2(247)(CH3)2NC0-Nle-環(huán)(Asp-His-D-Fpa-Arg-Trp-Lys)-匪2(248)(CH3)2NCO-N1e-環(huán)(Asp-His-D-Fpa-Arg—Tic-Lys)-冊2(249)(CH3)2腦-Nle-環(huán)(Asp-His-D-Fpa-Arg-Tca-Lys)-冊2(250)(CH3)2NC0-Nle-環(huán)(Asp-His-D-Upa-Arg-Trp-Lys)-NH2(251)(CH3)2NCO-Nle-環(huán)(Asp-His-D-Upa-Arg-Tic-Lys)-亂(252)(CH3)2NCO-Nle-環(huán)(Asp-His-D-Upa-Arg-Tca-Lys)-NH2(253)(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2(254)(CH3)2NC0-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Tic-Lys)-NH2(255)(CH3)2NC0-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Tca-Lys)-NH2(256〕(CH3)2NCO-Nle-環(huán)(Asp-Tic-D-Mob-Arg-Trp-Lys)-NH2(257)(CH3)2NC0-Nle-環(huán)(Asp-Tic-D-Mob-Arg-Tic-Lys)-NH2(258〕(CH3)2NC0-Nle-環(huán)(Asp-Tic-D-Mob-Arg-Tca-Lys)-NH2(259〕(CH3)2NC0-N1e-環(huán)(Asp-Tic-D-Fpa-Arg-Trp-Lys)-NH2(260)(CH3〕2腳-Nle-環(huán)(Asp-T]LC--D-Fpa-Arg-Tic-Lys〕-NH2(261)(CH3〕2腳-Nle-環(huán)(Asp-TLC--D-Fpa-Arg-Tca-Lys〕-NH2(262)線〕2NC0-Nle-環(huán)(Asp-TLC.-D-Upa-Arg-Trp-Lys〕-NH2(263)線〕2NCO-Nle-環(huán)(Asp-TLC.-D-Upa-Arg-Tic-Lys〕-NH2(264)(CH3〕2NC0-Nle-環(huán)(Asp-T〗LC--D-Upa-Arg-Tca-Lys〕-NH2(265)(CH3〕2NC0-Nle-環(huán)(Asp-H〗LS--D-Tic-Arg-Trp-Lys〕-OH(266)(CH3〕2NC0-Nle-環(huán)(Asp-H〗LS--D-Tic-Arg-Tic-Lys〕-OH(267)(CH3〕2NC0-Nle-環(huán)(Asp-HLS.-D-Tic-Arg-Tca"Lys〕_0H(268)(CH3)2NC0-Nle-環(huán)(Asp-HiLS--D-Mob-Arg-Trp"Lys)-OH(269)(CH3〕2NC0-Nle-環(huán)(Asp-HLS--D-Mob-Arg-Tic"Lys)-OH(270)線)2NC0-Nle-環(huán)(Asp-HiLS--D-Mob-Arg-Tca-Lys)-OH(271)(CH3)2腳-Nle-環(huán)(Asp-HiLS--D-Fpa-Arg-Trp-Lys)-OH(272)(CH3)2腳-Nle-環(huán)(Asp-HiLS國-D-Fpa-Arg-Tic-Lys)-OH(273)(CH3)2NC0-Nle-環(huán)(Asp-His--D-Fpa-Arg-Tca"Lys)-OH(274)(CH3)2NC0-Nle-環(huán)(Asp-HiS誦-D-Upa-Arg-Trp-:Lys)-OH(275)(CH3)細-Nle-環(huán)(Asp-H〗s--D-Upa-Arg-Tic"Lys)-OH(276)(CH3)2腳-Nle-環(huán)(Asp-His--D-Upa-Arg-Tca-Lys)-OH(277)(CH3)2NC0-Nle-環(huán)(Asp-Tic--D-Tic-Arg-Trp-Lys)-OH(278)(CH3)2腳-Nle-環(huán)(Asp-Tic-陽D-Tic-Arg-Tic-Lys)-OH(279)(CH3)2NC0-Nle-環(huán)(Asp-Tic國陽D-Tic-Arg-Tca-Lys)-OH(280)(CH3)2NC0-Nle-環(huán)(Asp-Ti.c誦畫D-Mob-Arg-Trp-Lys)-OH(281)(CH3)2NC0-Nle-環(huán)(Asp-T〗c-畫D-Mob-Arg-Tic-Lys)-OH(282)(CH3)2NC0-Nle-環(huán)(Asp-Ti.c--D-Mob-Arg-Tca-Lys)-OH(283)(CH3)2NC0-Nle-環(huán)(Asp-Tic-畫D-Fpa-Arg-Trp-Lys)-OH(284)(CH3)2NC0-Nle-環(huán)(Asp-Tic-陽D-Fpa-Arg-Tic-Lys)-OH(285)(CH3)2NC0-Nle-環(huán)(Asp-Tic-隱D-Fpa-Arg-Tca-Lys)-OH(286)(CH3)2腳-Nle-環(huán)(Asp-Tic-陽D-Upa-Arg-Trp-Lys)-OH(287)(CH3)2NC0-Nle-環(huán)(Asp-Tic--D-Upa-Arg-Tic-Lys)-OH(288)(CH3)2NC0-Nle-環(huán)(Asp-Tic--D-Upa-Arg-Tca-Lys)-OH(289)No-Nle-環(huán)(Asp-Tic-D-Tic-Arg-Trp-Lys)-NH2。8、藥物組合物，其含有至少一種權(quán)利要求l-7任一項的化合物以及可藥用載體或賦形劑。9、權(quán)利要求1-7任一項的化合物用于制備治療肥胖及相關(guān)疾病(如高血壓)或性功能障礙的藥物的用途。10、權(quán)利要求1-7任一項的化合物用于制備MC-Rs激動劑的用途。全文摘要本發(fā)明涉及具有MC3R/MC4R受體激動活性的七肽衍生物，其制備方法，含有它們的藥物組合物，以及它們用于制備治療肥胖及相關(guān)疾病以及性功能障礙等的藥物的用途。文檔編號A61P9/12GK101302246SQ20081009672公開日2008年11月12日申請日期2008年5月9日優(yōu)先權(quán)日2007年5月9日發(fā)明者馮思良,劉克良,寧周,孫彭利,梁遠軍,許笑宇,郄建坤,寒韓申請人:中國人民解放軍軍事醫(yī)學(xué)科學(xué)院毒物藥物研究所