CN1514843A - 生长激素释放抑制因子-多巴胺嵌合类似物 - Google Patents
生长激素释放抑制因子-多巴胺嵌合类似物 Download PDFInfo
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Abstract
本发明公开了一系列的生长激素释放抑制因子－多巴胺嵌合体类似物，其在活体内既保留了生长激素释放抑制因子的活性也保留了多巴胺的活性。一个例子是6－正丙基－8β－麦角灵基甲基硫代乙酰基－D－Phe－环[Cys－Tyr－D－Trp－Lys－Abu－Cys]－Thr－NH2。
Description
发明背景
本发明描述了生长激素释放抑制因子-多巴胺嵌合类似物。
多巴胺是一种牵涉在帕金森病和精神分裂症的发病机制中的儿茶酚胺神经递质。Grarybiel等人.，Adv.Neurol.53，17-29(1990)；Goldstein等人.，FASEBJ.6，2413-2421(1992)；Olanow等人.，Annu.Rev.Neurosci.22，123-144(1999).Egan等人.，Curr.Opin.Neurobiol.7，701-707(1997)。多巴胺及相关分子在大鼠中显示出可以抑制一些类型的恶性肿瘤的生长，这种活性被不同地归因于对肿瘤细胞增生的抑制，对肿瘤免疫的刺激或在恶性黑色瘤中的黑色素代谢的结果。Wick，M.M.，J.Invest.Dermatol.71，163-164(1978)；Wick，M.M.，J.Natl.Cancer Inst.63，1465-1467(1979)；Wick，M.M.，Cancer Treat.Rep.63，991-997(1979)；Wick，M.M.，Cancer Res.40，1414-1418(1980)；Wick，M.M.，CancerTreat.Rep.65；861-867(1981)；Wick，M.M.& Mui，J.Natl.Cancer Inst.66，351-354(1981)；Dasgupta等人.，J.Cancer Res.Clin.Oncol.113，363-368(1987)；Basu等人.，Endocrine 12，237-241(2000)；Basu等人.，J.Neuroimmunol.102，113-124(2000)。最近的研究表明在内皮细胞的D2多巴胺受体的存在。Ricci等人.，J.Auton.Pharmacol.，14，61-68(1994)；Bacic等人.，J.Neurochem.57，1774-1780(1991)。最近报道多巴胺在非毒性水平强烈并选择性地抑制VPF/VEGF的血管渗透性和血管原性活性。Basu等人.，Nat.Med.7(5)，569-574(2001)。
生长激素释放抑制因子(SS)，即一种由Brazeau等人发现的十四肽，显示在组织中如脑下垂体、胰和胃肠道中对不同的分泌过程具有有效的抑制作用。SS在中枢神经系统中也可作为神经调节物。SS的这些在本质上都具有抑制作用的生物学效果是通过一系列G蛋白偶联受体引起，其中的五种不同亚型已经被表征(SSTR1-SSTR5)(Reubi JC等人，Cancer Res 47：551-558，Reisine T等人，Endocrine Review 16：427-442，Lamberts SW等人，Edocr Rev 12：450-482，4 Patel YC，1999 Front Neuroendocrinology 20：157-198)。这五种亚型对内生的SS配体具有相似的免疫亲和力但在不同的组织中具有不同的分布。生长激素释放抑制因子与五个受体亚型以对每个亚型相对较高和相等的免疫亲和力进行结合。
有证据表明，通过由SSTR1，2，4和5亚型阻止细胞生长，SS调节细胞增生(Buscail L.等人.，1995 Proc Natl Acad Sci USA 92：1580-1584；Buscail L.等人，1994 Proc Natl Acad Sci USA 91：2315-2319；Florio T，等人，1999 MolEndocrinol 13：24-37；Sharma K，等人，1999 Mol Endocrinol 13：82-90)，或通过由SSTR3亚型诱导凋亡作用，SS可调节细胞增生(Sharma K等人，1996 MolEndocrinol 10：1688-1696)。SS和不同的类似物已经显示出在活体内和体外通过特定的SS受体(SSTR’s)(Patel YC，1999 Front Neuroendocrinology 20：157-198)以及可能不同的受体后反应(Weckbecker G.等人，Pharmacol Ther 60：245-264；Bell G1，Reisine T 1993 Trends Neurosci 16：34-38；Patel YC等人，BiochemBiophys Res Commun 198：605-612；Law SF等人，Cell SigNal 7：1-8)抑制正常细胞和瘤细胞的增生。另外，有证据表明，不同的SSTR亚型在正常人体组织和瘤组织(9)中进行表达，由于不同SS类似物和对起治疗效果的不稳定的临床反应，从而产生了不同的组织免疫亲和力。
不同类型的生长激素释放抑制因子受体亚型的结合与多种病症和/或疾病的治疗相关。(SSTR2)(Raynor等人，Molecular Pharmacol.43：838(1993)；Lloyd等人，Am.J.Physiol.268：G 102(1995))。胰岛素的抑制则归因于生长激素释放抑制因子5-型受体(SSTR5)(Coy等人，197：366-371(1993))。2型和5型的活化与生长激素的抑制有关，尤其与GH分泌腺瘤(肢端肥大症)和TSH分泌腺瘤有关。2型而并非是5型的活化与治疗催乳素分泌腺瘤相关。其他与生长激素释放因子受体亚型相关的适应症包括对用于治疗糖尿病、血管病、增生性视网膜炎、，黎明现象(dawn Phenomenon)和肾病的抑制胰岛素和/或胰增血糖素进行抑制；抑制胃酸分泌并尤其是抑制消化器官溃疡，肠皮肤(enterocutaneous)和胰腺皮肤(pancreaticocutaneous)瘘管、过敏性肠综合症、倾倒综合症、含水腹泻综合症、与AIDS相关的腹泻、化疗引发的腹泻、急性和慢性胰腺炎和胃肠激素分泌肿瘤；治疗癌症如肝细胞瘤；抑制血管生成；治疗炎性疾病如关节炎、视网膜炎、慢性同种异体抑制排斥、血管成形术；防止脉管移植和胃肠出血。优选的类似物对特定的生长激素释放因子受体亚型具有选择性，或对能得到所希望的生物学反应的亚型具有选择性，因此减少了与其他会导致不希望的副作用的受体亚型进行反应。
生长激素释放因子(SS)和其受体(SSTR1-SSTR5)在正常的人体滤泡旁(parafollicular)C细胞和髓状甲状腺癌(MTC)中进行表达。MTC是一种由产生降钙素(CT)、生长激素抑制因子以及一些其他的肽的甲状腺滤泡旁C细胞引起的肿瘤(Moreau JP等人，Metabolism 45(8 Suppl 1)：24-26)。最近，Mato等人证明SS和SSTR’S在人类MTC中进行表达。(Mato E等人，J ClinEndocrinol Metab 83：2417-2420)。文献中还记载了SS和其类似物在血浆CT水平引起下降和在MTC病人中得到了症状改善。然而，直至现在，SS类似物对肿瘤细胞的抗增生活性还没有得到明确的证明(Mahler C等人，ClinEndocrinol 33：261-9；Lupoli G等人，Cancer 78：1114-8；Smid WM等人，Neth J.Med.40：240-243)。因此，SSTR亚型类似物选择性地对MTC细胞生长的发展和评估为临床研究提供了有用的工具。直至现在，没有报道过关于SSTR亚型与MTC细胞生长调节有关的数据。
发明概述
本发明涉及一系列生长激素释放抑制因子-多巴胺嵌合类似物，其在活体内既保留了生长激素释放因子的活性和又保留了多巴胺的活性，包括，其中的一些对单独的天然生长激素释放因子和多巴胺类似物显示出提高的生物学活性及其治疗用途。
一方面，本发明的特征在于式(I)的多巴胺-生长激素释放因子嵌合体，
其中，
X是H，Cl，Br，I，F，-CN，或C1-5烷基；
R1是H，C1-4烷基，烯丙基，链烯基或-CN；
R2和R3分别独立地为H或不存在，条件是当R2和R3不存在时，它们所连接的碳原子之间有双键；
R4是H或-CH3；
Y是-O-，-C(O)-，-S-，-S-(CH2)S-C(O)-，-S(O)-，-S(O)2-，-SC(O)-，-OC(O)-，-N(R5)-C(O)-，或-N(R6)-；
R5，R6，R7和R8分别独立地是H或C1-5烷基；
R6是H或C1-5烷基；
m是0或1；
n是0-10；
当Y是-S-，-S(O)-，-S(O)2-，-O-或-N(R6)-时；L是-(CH2)p-C(O)-，
当Y是-N(R6)-，-O-，或-S-时；L是-C(O)-(CR7R8)q-C(O)-，
p是1-10；
q是2-4；
s是1-10；
t是1-10；和
z是生长激素释放因子类似物，
或其药学上可接受的盐。
另一方面，本发明的特征在于式(II)的多巴胺-生长激素释放因子嵌合体，
其中：
X是H，Cl，Br，I，F，CN，或C1-5烷基；
R1是C1-4烷基，H，烯丙基，链烯基或-CN；
R2和R3分别独立地为H或不存在，条件是当R2和R3不存在时，它们所连接的碳原子之间有双键；
R4是H或-CH3；
R5是C1-5烷基基团，或式-CH2rN(CH3)q的基团；
Y是-O-，-C(O)-，-S-，-SC(O)-，-OC(O)-，-N(R6)-C(O)，-N(R7)-，或-N(R8)-(CH2)s-C(O)-；
R6，R7，R8，R9和R10分别独立为H或C1-5烷基；
当Y是-S-，-O-或-N(R7)-时，L是-(CH2)p-C(O)-；
当Y是-N(R7)-，-O-或-S-时，L是-(CO)-(CR9R10)q-C(O)-；
当Y是-C(O)-，-SC(O)-，-OC(O)-，-N(R8)-(CH2)s-C(O)-，或-N(R6)-C(O)-时，
L是-(Doc)t-；
m是0或1；
n是2-10；
q是2-4；
p是1-10；
s是1-10；
t是1-10；和
z是生长激素释放因子类似物，
或其药学上可接受的盐。
本发明的一个实施方式在于下式化合物或其药学上可接受的盐：
D-Phe-环[Cys-Tyr-D-Trp-Lys-Cys]-Nal-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Caeg＝N-(2-氨基乙基)-N-(2-胞嘧啶基-1-氧代-乙基)-甘氨酸
Doc-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)3-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)4-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
Doc-环[Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)2-环[Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
Doc-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)2-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Val-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
Doc-环[Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
环[Cys-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)2-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)3-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
AEPA-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
AEPA-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
AEPA＝4-(2-氨基乙基)-1-羧甲基-哌嗪
D-Phe-环[Cys-Phe-DTrp-Lys-Val-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
AEPA-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
AEPA-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
AEPA-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
AEPA-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
以及
在另一种实施方式中，本发明的特征在于下式的化合物或其药学上可接受的盐：
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
Aepa-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Aepa)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-(Aepa)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)10-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Aepa)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
或
一方面本发明的特征在于一种在需要的患者体内引起多巴胺受体激动剂作用的方法，其中所述方法包括以有效量的式(I)或式(II)化合物或其药学上可接受的盐对所述患者给药。在这一方面的一个优选的实施方式是所述化合物选自本发明在这里所公开的化合物。
本发明的另一方面的特征在于一种在需要的患者体内引起生长激素释放抑制因子受体激动剂作用的方法，其中所述方法包括以有效量的式(I)或式(II)化合物或其药学上可接受的盐对所述患者给药。在这一方面的一个优选的实施方式是所述化合物选自本发明在这里所公开的化合物。
本发明的另一方面的特征在于一种在需要的患者体内同时引起多巴胺受体激动剂作用和生长激素释放抑制因子受体激动剂作用的方法，其中所述方法包括以有效量的式(I)或式(II)化合物或其药学上可接受的盐对所述患者给药。在这一方面的一个优选的实施方式是所述化合物选自本发明在这里所公开的化合物。
本发明的另一方面的特征在于一种药物组合物，其包括有效量的式(I)或式(II)化合物，或其药学上可接受的盐。在这一方面的一个优选的实施方式是所述化合物选自本发明在这里所公开的化合物。
本发明的另一方面的特征在于一种为患者治疗疾病或症状的方法，所述方法包括以治疗有效量的式(I)或式(II)化合物或其药学上可接受的盐对患者给药，其中所述疾病选自肺癌、神经胶质瘤、厌食症、甲状腺机能减退、醛固酮过多症、幽门螺旋杆菌(H.pylori)增生、肢端肥大症、再狭窄、克朗氏病、系统性硬化症、外部和内部胰腺假囊肿和腹水、舒血管肠肽瘤(VIPoma)、胰岛细胞弥漫性增生、胰岛素分泌过多、胃泌素瘤、卓-艾二氏综合症、腹泻、与AIDS相关的腹泻、与化疗相关的腹泻、硬皮病、过敏性肠综合症、胰腺炎、小肠梗阻、胃食管回流、十二指肠胃回流、库兴氏综合症、促性腺素瘤、甲状旁腺机能亢进、格雷夫斯氏病、糖尿病性神经病、Paget氏病、多囊卵巢病、甲状腺癌、肝细胞瘤(hepatome)、白血病、脑膜炎、癌性恶病质、直立抵血压、餐后低血压、焦虑发作、GH分泌腺瘤、肢端肥大症、TSH分泌腺瘤、催乳素分泌腺瘤、胰岛腺瘤、高血糖素瘤、糖尿病、高脂血症、胰岛素麻木、X综合症、血管病、增生性视网膜炎、黎明现象(dawn phnomenon)、肾病、胃酸分泌、消化器官溃疡、肠皮肤瘘管、胰腺皮肤瘘管、倾倒综合症、含水腹泻综合症、胰腺炎、胃肠激素分泌肿瘤；血管生成、关节炎；同种异体抑制排斥、移植脉管出血、入口高血压(portal hypertension)、胃肠出血、肥胖、以及鸦片样物质过量。在优选的实施方式中化合物选自本文公开的化合物。在本发明这一方面的一个更优选的实施方式中所述疾病或症状是肢端肥大症。
在前述方法的具体优选实施方式中，化合物选自所列的化合物A到K，或选自所列的实施例L到V，其题目为“生长激素释放抑制因子-多巴胺嵌合体的合成”，如下文所公开。
本发明另一方面的特征在于如上式(I)和式(II)化合物的多巴胺激动剂，其中生长激素释放抑制因子类似物“z”被包括下列的部分取代：-H，-OH，(C1-C6)烷氧基、芳基烷氧基(如苄基、取代苄基等)、-NH2、-NR9R10，其中R9和R10如式(II)中定义。在这一方面的优选实施方式中，所述多巴胺激动剂选自如本文所公开的生长激素释放抑制因子-多巴胺嵌合体的多巴胺部分，或其药学上可接受的盐。在最优选的实施方式中，多巴胺激动剂是：
或
或其药学可接受的盐。
发明详述
我们相信本领域的普通技术人员根据本说明书可以完全理解本发明。因此下面的实施方式只是示例性的说明，而无论如何不是对本发明公开的剩余部分的限制。
除非特别定义，本文所用的所有的科技术语与本发明所属领域的技术人员通常理解的意思相同。所有的出版物、专利申请、专利和其他参考文献均全文选入作为参考。
已经分离出不同的生长激素释放抑制因子受体(SSTR’s)，如SSTR-1，SSTR-2，SSTR-3，SSTR-4和SSTR-5。因此生长激素释放抑制因子激动剂可以是一个或多个SSTR-1激动剂，SSTR-2激动剂，SSTR-3激动剂，SSTR-4激动剂和SSTR-5激动剂。例如生长激素释放抑制因子2-型受体激动剂(即SSTR-2激动剂)的意思是一种具有对SSTR-2具有高结合免疫亲和力(如Ki小于100nM，或优选小于10nm，或更优选小于1nM)的化合物(如由下面描述的受体结合测定来定义)。生长激素释放抑制因子2-型受体选择性激动剂的意思是一种对SSTR-2比对其他生长激素释放抑制因子受体具有更高的结合免疫亲和力的生长激素释放抑制因子2-型受体激动剂。
在一个实施方式中，SSTR-2激动剂也是一种SSTR-2选择性激动剂。可以用来实践本发明的SSTR-2激动剂的实例包括但不局限于：
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2；
环-[Tic-Tyr-D-Trp-Lys-Abu-Phe]；
4-(2-羟乙基)-1-哌嗪乙酰基-D-Phe 环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2；和
4-(2-羟乙基)-1-哌嗪-2-乙磺酰基-D-Phe-环-(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2。
生长激素释放抑制因子激动剂的更多实例是由下列出版物特别提到的化学式所覆盖的化合物，每篇文献均全文引入作为参考。
欧洲专利申请号P5 164 EU(发明人：G.Keri)；
Van Binst，G等人.肽研究5：8(1992)；
Horvath，A等人，摘要“具有抗肿瘤活性的生长激素释放抑制因子类似物的确认”，22nd European peptide Symposium，1992年9月13-19，Interlaken，瑞士。
PCT申请号WO 91/09056(1991)
欧洲专利申请号0 363 589 A2(1990)
美国专利号4,904,642(1990)；
美国专利号4,871,717(1989)；
美国专利号4,853,371(1989)；
美国专利号4,725,577(1988)；
美国专利号4,684,620(1987)；
美国专利号4,650,787(1987)；
美国专利号4,603,120(1986)；
美国专利号4,585,755(1986)；
欧洲专利申请号0 203 031 A2(1986)；
美国专利号4,522,813(1985)；
美国专利号4,486,415(1984)；
美国专利号4,485,101(1984)；
美国专利号4,435,385(1984)；
美国专利号4,395,403(1983)；
美国专利号4,369,179(1983)；
美国专利号4,360,516(1982)；
美国专利号4,358,439(1982)；
美国专利号4,328,214(1982)；
美国专利号4,316,890(1982)；
美国专利号4,310,518(1982)；
美国专利号4,291,022(1981)；
美国专利号4,238,481(1980)；
美国专利号4,235,866(1980)；
美国专利号4,224,199(1980)；
美国专利号4,211,693(1980)；
美国专利号4,190,648(1980)；
美国专利号4,146,612(1979)；
美国专利号4,133,782(1979)；
美国专利号5,506,339(1996)；
美国专利号4,261,885(1981)；
美国专利号4,728,638(1988)；
美国专利号4,282,143(1981)；
美国专利号4,215,039(1980)；
美国专利号4,209,426(1980)；
美国专利号4,190,575(1980)；
欧洲专利号0 389 180(1990)；
欧洲专利申请号0 505 680(1982)；
欧洲专利申请号0 030 920(1980)；
PCT申请号WO 88/05052(1988)；
PCT申请号WO 90/12811(1990)；
PCT申请号WO 97/01579(1997)；
PCT申请号WO 91/18016(1991)；
英国申请号GB 2,095,261(1981)和
法国申请号FR 2,522,655(1983)。
注意，对于本文描述的所有生长激素释放抑制因子激动剂，每个氨基酸基团代表-NH-C(R)H-CO-的结构，其中R是侧链(例如丙氨酸上的CH3)。氨基酸基团之间的线代表连接氨基酸的肽键。当氨基酸基团具有光学活性时，除非明确指定D-构型，其意思是L-型构型。为清楚起见，在Cys基团的两个游离硫醇间的二硫键没有表示出来。常规氨基酸的缩写与IUPAC-IUB的建议相符。
生长激素释放抑制因子激动剂的合成
文献中已报道过合成肽生长激素释放抑制因子激动剂的方法，因此该类方法属于本领域的普通技术人员的能力范围之内。例如，肽是在Rink酰胺MBHA树脂(4-(2′4′-二甲氧基苯基-Fmoc-氨基甲基)-苯氧基乙酰胺基-正亮氨酰基-MBHA树脂)上使用Fmoc化学的标准固相法合成的。在N-端带有自由氨基官能团的肽-树脂用含有多巴胺部分的相应化合物处理。最终产品可以从树脂和三氟乙酸(TFA)/水/三异丙基硅烷(TIS)混合物中分离出来。
例如，H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2可以通过欧洲专利申请0 395 417A1的实施例1所述的方法合成。带有取代的N-端的生长激素释放抑制因子激动剂的合成可以通过下列申请所描述的方法实现：PCT公开号WO 88/02756，PCT公开号WO 94/04752和/或欧洲专利申请号0 329 295。
用碘的甲醇/水溶液可以使肽环化，使用乙腈-0.1％三氟乙酸/水-0.1％三氟乙酸缓冲剂使肽在C18反向制备高效夜相色谱(HPLC)上纯化。用分析高效液相色谱和质谱来测定均一性，结果表明每种肽的均一性都大于95％。
从下述的零售商可购买一些非常规的氨基酸：从Chem-lmpex InternatioNalInc.(Wood Dale，IL，USA)购买Fmoc-Doc-OH和Fmoc-AEPA.从PerpSeptiveBiosystems(Framingham MA，USA)购买Fmoc-Caeg(Bhoc)-OH。Bhoc表示二苯甲氧羰基。
多巴胺激动剂的合成
已有文献报道过合成多种多巴胺激动剂的方法，因此合成方法属于本领域的技术人员可以实现的能力之内。如下的反应路线和实施例中公开了进一步的合成方法。
反应路线1
反应路线2
反应路线3
反应路线4
反应路线5
反应路线6
反应路线7
反应路线8
反应路线9
反应路线10：
18参见反应路线II
19参见反应路线II
反应路线11：
反应路线12：
反应路线13：
反应路线14：
反应路线15：
与化合物6，7，8相似
反应路线I
其中R″和R独立地是H或C1-C4烷基 。 19
反应路线II
反应路线III
反应路线V
反应式VI
生长激素释放抑制因子-多巴胺嵌合体的合成
生长激素释放抑制因子-多巴胺嵌合体可以根据下列反应路线和实施例来合成。在反应式I，II和III中表示的为制造化合物(I)，(II)和(III)的起始原料和中间体分别可商购或由下列文献中的记载来制备：Pharmazie 39，537(1984)；Collect Czech.Chem.Commun.33，577(1966)；Helv.Chim.Acta 32，1947，(1949)；USP.5,097,031；USP 3,901,894；EP 0003667；USP 4,526,892。肽的合成是本领域的技术人员公知的，但也可以从下列文献得到，见例如Stewart等人，固相合成，Pierce Chemical，2nd Ed.1984；G.A.Grant；合成肽。WH.，FreenandCo.，New York，1992；M.Bodenszky A.Bodanszky，肽合成的实践。SpringVenlag.N.Y.1984.
化合物A的制备：
将化合物8(3eq.)与H-(脱氧皮质酮)3-D-Phe-Cys(丙烯酰胺)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(丙烯酰胺)-Thr(叔丁基)-Rink酰胺MBHA树脂(1eq.)，HBTU(2.9eq.)，HOBt(3.0eq)和DIEA(6eq.)在二甲基甲酰胺(DMF)中混合。将混合物在室温下震荡4小时。用二甲基甲酰胺(DMF)和二氯甲烷(DCM)冲洗树脂，并在减压下干燥。将干燥的树脂用TFA/TIS/水(92/5/3，v/v)在室温下处理1小时。将溶液过滤并浓缩。在浓缩液中加入冷的乙醚，收集沉淀物将其溶解在水-甲醇溶剂体系中。向溶液中加入溶于甲醇的碘溶液直至出现棕色。然后将溶液在室温下静置1小时。再向溶液中加入含水Na2S2O3溶液直至棕色消失。用C18反相制备性高效液相色谱纯化所得到的溶液，以线性梯度的缓冲液A(1％TFA水溶液)/缓冲液B(1％TFA的CH3CN溶液)进行洗脱。用分析高效液相色谱检测馏分。合并含有所需要的纯化合物，并冷冻至干燥。化合物的分子量用配有电雾化源的MS测定。
化合物B的制备：
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
将化合物12(其中R1是正丙基(1.5eq))与H-D-Phe-Cys(丙烯酰胺)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(丙烯酰胺)-Thr(叔丁基)-Rink酰胺MBHA树脂(1eq)和DIEA(2eq)在二甲基甲酰胺(DMF)中混合。将混合物在室温下震荡5小时。用二甲基甲酰胺(DMF)和二氯甲烷(DCM)冲洗树脂并在减压下干燥。用TFA/TIS/水(92/5/3，v/v)在室温下处理干燥的树脂达1小时。将溶液过滤和浓缩。在浓缩液中加入冷的乙醚，收集沉淀物将其溶解在水-甲醇溶剂体系中。向溶液中加入溶于甲醇中的碘溶液直至出现棕色。然后将溶液在室温下静置1小时。再向溶液中加入Na2S2O3溶液直至棕色消失。用C18反相制备性高效液相色谱纯化所得到的溶液，以线性梯度的缓冲液A(1％TFA水溶液)/缓冲液B(1％TFA的CH3CN溶液)进行洗脱。用分析高效液相色谱检测馏分。合并含有所需要的纯化合物并冷冻至干燥。化合物的分子量用配有电雾化源的MS测定。
化合物C的制备：
将其中R1是正丙基(1.5eq)的化合物11与H-AEPA-D-Phe-Cys(丙烯酰胺)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(丙烯酰胺)-Thr(叔丁基)Rink酰胺MBHA树脂(1eq)和DIEA(2eq)在二甲基甲酰胺(DMF)中混合。将混合物在室温下震荡5小时。用二甲基甲酰胺(DMF)和二氯甲烷(DCM)冲洗树脂并在减压下干燥。用TFA/TIS/水(92/5/3，v/v)在室温下处理干燥的树脂达1小时。将溶液过滤并浓缩。在浓缩液中加入冷的乙醚，收集沉淀物将其溶解在水-甲醇溶剂体系中。向溶液中加入溶于甲醇的碘溶液直至出现棕色。然后将溶液在室温下静置1小时。再向溶液中加入Na2S2O3溶液直至棕色消失。用C18反相制备性高效液相色谱纯化所得到的溶液，以线性梯度的缓冲液A(1％TFA水溶液)/缓冲液B(1％TFA的CH3CN溶液)进行洗脱。用分析高效液相色谱检测馏分。合并含有所需要的纯化合物并冷冻至干燥。化合物的分子量用配有电雾化源的MS测定。
化合物D的制备：
将化合物25(3eq)与H-Doc-D-Phe-Cys(丙烯酰胺)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(丙烯酰胺)-Thr(叔丁基)Rink酰胺MBHA树脂(1eq)、HBTU(2.9eq)，HOBt(3.0eq)和DIEA(6eq)在二甲基甲酰胺中混合。将混合物在室温下震荡4小时。用二甲基甲酰胺(DMF)和二氯甲烷(DCM)冲洗树脂并在减压下干燥。用TFA/TIS/水(92/5/3，v/v)在室温下处理干燥的树脂达1小时。将溶液过滤并浓缩。在浓缩液中加入冷的乙醚，收集沉淀物将其溶解在水-甲醇溶剂体系中。向溶液中加入溶于甲醇的碘溶液直至出现棕色。然后将溶液在室温下静置1小时。再向溶液中加入Na2S2O3溶液直至棕色消失。用C18反相制备性高效液相色谱纯化所得到的溶液，以线性梯度的缓冲液A(1％TFA水溶液)/缓冲液B(1％TFA的CH3CN溶液)进行洗脱。用分析高效液相色谱检查馏分。合并含有所需要的纯化合物并冷冻至干燥。化合物的分子量用配有电雾化源的MS测定。
化合物E的制备：
将化合物26(3eq)与H-(D-Ser(叔丁基))5-Lys(Boc)-D-Tyr(叔丁基)-D-Tyr(叔丁基)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Val-Cys(丙烯酰胺)-Trp(Boc)-Rink酰胺MBHA树脂(1eq)和HBTU(2.9eq)，HOBt(3.0eq)和DIEA(6eq)在二甲基甲酰胺(DMF)中混合。将混合物在室温下震荡4小时。用二甲基甲酰胺(DMF)和二氯甲烷(DMC)冲洗树脂并在减压下干燥。用TFA/TIS/水(92/5/3，v/v)在室温下处理干燥的树脂达1小时。将溶液过滤并浓缩。在浓缩液中加入冷的乙醚，收集沉淀物将其溶解在水-甲醇溶剂体系中。向溶液中加入溶于甲醇的碘溶液直至出现棕色。然后将溶液在室温下静置1小时。再向溶液中加入Na2S2O3溶液直至棕色消失。用C18反相制备性高效液相色谱纯化所得到的溶液，以线性梯度的缓冲液A(1％TFA水溶液)/缓冲液B(1％TFA的CH3CN溶液)进行洗脱。用分析高效液相色谱检测馏分。合并含有所需要的纯化合物并冷冻至干燥。化合物的分子量用配有电雾化源的MS测定。
化合物F的制备：
乙基-[6-甲基-8β-麦角灵基甲基(ergolinylmethyl)]硫代乙酸酯
在溶有240mg二氢麦角醇(dihydroLySergol)的10ml吡啶溶液中加入250μl甲磺酰氯。在室温下搅拌2小时后，将反应混合物倒入100ml水中，用氯仿(2×20ml)抽提，用水洗涤有机层，然后用MgSO4干燥，在真空下除去溶剂至干燥，得到140mg浅棕色固体。用NaHCO3碱性化后再一次从溶液中抽提，得到另外的100mg产品。共240mg。质谱(电雾化)335.2。
向上述D-6-甲基-8β-甲磺酰基羟甲基-麦角灵(140mg)在3ml二甲基甲酰胺所形成的溶液中加入粉末K2CO3(150mg)，然后加入150μl乙基-2-巯基乙酸酯，将混合物在氮气下在40℃下加热2小时。在真空下除去溶剂至干燥，剩余物在氯仿和水之间进行分配，用MgSO4干燥有机层，蒸发掉溶剂后，剩余物用氯仿/甲醇(9∶1)作为展开剂流过制备性硅胶薄层色谱，分离出相应的部分，用氯仿-甲醇抽提后，在真空下除去溶剂至干燥。得到浅棕色固体100mg。质谱(电雾化)359.2。
化合物G的制备：
6-甲基-8β-麦角灵基甲基硫代乙酰基-D-Phe-环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2
向6-甲基-8β-麦角灵基甲基硫代乙酸(反应路线I，化合物7)和用Fmoc-化学法由固相合成制备的D-Phe-环(Cys-Tyr(OBT)-D-Trp-Lys(BOC)-Abu-Cys)-Thr-NH2(100mg)在100ml二甲基甲酰胺的溶液中加入200mg EDC(1-[3-(二甲氨基)-丙基]-3-乙基碳二亚胺-HCL)，100mg HOAT(1-羟基-7-氮杂苯并三唑(azabezotriazole))，然后加入200μl二异丙基乙胺，将混合物在室温下搅拌过夜。在真空下除去挥发性物质至干燥，剩余物在氯代甲醇和溴之间进行分配。用NaHCO3水溶液洗涤有机物层，用MgSO4干燥。溶剂蒸发后，剩余物用氯仿-甲醇(85∶15)做为展开剂流过制备性薄层色谱。分离出相应的部分，用氯仿-甲醇抽提，在真空下除去溶剂，得到40mg被保护的产品。质谱(电雾化)1500.7。
将被保护的产品用30％的三氟乙酸在含有几滴三异丙基硅烷的二氯甲烷(10ml)中处理30分钟，在真空下除去挥发性组分至干燥，剩余物用vydac C18高效液相色谱和CH3CN/0.1％TFA水溶液纯化，得到17mg白色固体。质谱(电雾化).1344.8，673.2。
化合物H的制备：
乙基-(6-正丙基-8β-麦角灵基)甲基硫代乙酸酯
从D-正丙基-8β-羟甲基麦角灵开始(其制备方法见EP 000,667)，用类似于化合物F的制备方法制备得到浅黄色固体。质谱(电雾化)387.2。
化合物I的制备
6-正丙基-8β-麦角灵基甲基硫代乙酰基-D-Phe-环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2
从6-正丙基-8β-麦角灵基甲基硫代乙酸(反应路线I，化合物6，其中R1是丙基且s＝1)和D-Phe-环[Cys-Tyr(OBT)-D-Trp-Lys(BOC)-Abu-Cys]-Thr-NH2开始，用与化合物G的制备方法类似的方法制备得到白色固体。质谱(电雾化)1372.5，687.3。
化合物J的制备：
6-D-甲基-8β-麦角灵基甲基硫基氨基琥珀酰基(ergolinylmethylthlaminosuccinoyl)-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2。
从6-D-甲基-8β-琥珀酰氨基麦角灵和D-Phe-环[Cys-Tyr(OBT)-D-Trp-Lys(BOC)-Abu-Cys]-Thr-NH2开始，以化合物G的制备方法相类似的方法制备得到白色固体。质谱(电雾化)1344.8，673.2。
化合物K的制备：
6-烯丙基-8β-(1-乙基-(3-N-甲基-3-羰甲基)氨基丙基-脲基羰基-麦角灵-D-Phe-环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2，即下列结构式的化合物
A.1-[[6-烯丙基麦角灵-8β-基]羰基]-1-[3-(N-(乙氧基羰基)甲基，N-甲基)氨基-丙基]-3-乙脲，即下式化合物
(1)3，3-BOC，N-甲基丙二胺
向3N-甲基丙二胺(1.8g)的二氯甲烷(30ml)溶液加入无水MgSO4(5.5gm)，然后加入苯甲醛(2.3g)，将混合物在室温下搅拌过夜。过滤后，滤出物用(BOC)2(4.3g)和DMAP(0.35g)处理并搅拌约1小时。然后用5％柠檬酸水溶液洗涤混合物，然后用MgSO4干燥。
溶剂蒸发后，将剩余物溶解在乙醇中(50ml)，然后加入Pd(OH)2(6O0mg)，乙酸(1ml)和环己烯(3ml)，整夜进行加氢反应。将混合物用硅藻土衬片过滤，滤出物在真空下蒸发至干燥，得到2.3g 3，3-BOC，N-甲基丙二胺无色液体。质谱(电雾化)＝189.1
(2)6-烯丙基-8β-(3，3-BOC，N-甲基-氨基丙基-氨基甲酰基-麦角灵
向6-烯丙基-二氢麦角酸(dihydroLySersic acid)(150mg)(由EP 0 003667公开的方法制备)和3，3-BOC，N-甲基-丙二胺(150MG)在二甲基甲酰胺(DMF)(5ml)中形成的溶液中加入二异丙基乙胺(175μl)，然后加入二乙基氰基膦酸酯(150μl)，将混合物在室温下搅拌过夜。在真空下除去挥发性物质至干燥，剩余物在CH3Cl和水之间进行分配。然后用NaHCO3水溶液洗涤有机层，用MgSO4干燥，在真空下除去溶剂，得到6-烯丙基-8β-(3，3-BOC，N-甲基-氨基丙基-氨基甲酰基)-麦角灵。
(3)6-烯丙基-8β-(3-N-甲基-氨基丙基-氨基甲酰基-麦角灵，TFA盐
将上一步骤得到的6-烯丙基-8β-(3，3-BOC，N-甲基-氨基丙基-氨基甲酰基)-麦角灵用30％TFA的二氯甲烷溶液洗涤30分钟，在真空下除去挥发性物质至干燥，得到250mg 6-烯丙基-8β-(3-N-甲基-氨基丙基-氨基甲酰基)-麦角灵，TFA盐。质谱(电雾化)＝367.2.
(4)6-烯丙基-8β-(3-N-甲基，3-乙酯基甲基)-氨基丙基-氨基甲酰基-麦角灵
向6-烯丙基-8β-(3-N-甲基-氨基丙基-氨基甲酰基)-麦角灵TFA盐(250mg)和K2CO3(140mg)在二甲基甲酰胺(DMF)(5ml)的溶液中加入溴代乙酸乙酯(70μl)，将得到的混合物在室温下搅拌过夜。蒸发掉溶剂后，剩余物在氯仿和水之间进行分配。用MgSO4干燥有机层，然后在真空下除去溶剂，得到粗6-烯丙基-8β-(3-N-甲基，3-乙酯基甲基)-氨基丙基-氨基甲酰基-麦角灵(240mg)。质谱(电雾化)＝453.2
(5)6-烯丙基-8β-(1-乙基-(3-N-甲基-3-乙酯基甲基)-氨基丙基-脲基羰基-麦角灵
将上一步骤得到的6-烯丙基-8β-(3-N-甲基，3-乙酯基甲基)-氨基丙基-氨基甲酰基-麦角灵溶解在甲苯(10ml)中，然后加入异氰酸乙酯(3ml)。将混合物在氮气下回流3天，蒸发掉挥发性物质后，剩余物以氯仿/甲醇为展开剂通过制备性硅胶色谱。用氯仿/甲醇抽提适当的组分，然后在真空下除去溶剂，得到6-烯丙基-8β-(1-乙基-(3-N-甲基3-乙酯基甲基)-氨基丙基-脲基羰基-麦角灵，其是浅黄色粘性物质(30mg)。质谱(电雾化)＝524.3.
B.6-烯丙基-8β-(1-乙基-(3-N-甲基-3-羧甲基)-氨基丙基-脲基羰基-麦角灵，即下式化合物：
向6-烯丙基-8β-(1-乙基-(3-N-甲基3-乙酯基甲基)-氨基丙基-脲基羰基-麦角灵(520mg)在10ml丙酮中的混合物中加入15ml 0.2M磷酸盐缓冲液(pH＝约7)和0.6ml ChiroCLEC-BL(Altus Bilogics，Cambridge，MA)。将混合物在约40℃下在旋转式混合器中温育过夜。用5％柠檬酸水溶液酸化混合物，然后用CHCl3-甲醇抽提。干燥有机抽提物，在真空下除去溶剂，得到6-烯丙基-8β-(1-乙基-(3-N-甲基3-羧甲基)-氨基丙基-脲基羰基-麦角灵。
C.6-烯丙基-8β-(1-乙基-(3-N-甲基-3-羧甲基)-氨基丙基-脲基羰基-麦角灵-D-Phe-环(Cys-Tyr-Trp-Lys-Abu-Cys)-Thr-NH2，即化合物K
向6-烯丙基-8β-(1-乙基-(3-N-甲基3-羧甲基)-氨基丙基-脲基羰基-麦角灵(50mg)和D-Phe-环(Cys-Tyr-D-Trp-Lys(FMOC)-Abu-Cys)-Thr-NH2(100mg，固相合成制备)在二甲基甲酰胺(10ml)的溶液中加入200mg EDC(1-[3-(二甲氨基)-丙基]-3-乙基碳二亚胺-HCl)，100mg HOAT(1-羟基-7-氮杂苯并三唑)，然后加入200μl二异丙基乙胺，将混合物在室温下搅拌过夜，在真空下除去挥发性物质至干燥。剩余物在氯仿甲醇和溴之间进行分配。用NaHCO3水溶液洗涤有机层，然后用MgSO4干燥。溶剂蒸发后，将被保护的产品用溶于二甲基甲酰胺(10ml)中的5％哌啶溶液处理30分钟。在真空下除去挥发性物质直至很小的体积(约2ml)。用VYDAC C18HPLC和CH3CN/0.1％TFA水溶液纯化，得到纯的，脱保护的产品。
实施例L
Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
A.H-Aepa-Lys(Boc)-D-Tyr(叔丁基)-Cys(trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(trt)-Thr(叔丁基)-Rink酰胺MBHA树脂
采芴基甲氧基羰基(Fmoc)化学，在应用生物系统(Applied Biosystems)(Foster City，CA)模型433A肽合成器上可以自动合成被保护的肽-树脂。使用取代度为0.72mmol/g的Rink酰胺MBHA树脂(Novabiochem.，San Diego，CA)。Fmoc氨基酸(AnaSpec，San Jose，CA)用于下列的侧链保护：Fmoc-Thr(叔]基)-OH，Fmoc-Cys(Trt)-OH，Fmoc-Lys(Boc)-OH，Fmoc-D-Trp(Boc)-OH，Fmoc-Tyr(叔丁基)-OH，Fmoc-D-Tyr(叔丁基)-OH，Fmoc-Phe-OH，Fmoc-Cys(Trt)-OH，Fmoc-Thr(叔丁基)-OH和Fmoc-Abu-OH。Fmoc-Aepa-OH从Chem-Impex InternatioNal，Inc.(Wood Dale，IL)购买。合成在0.25mmol规模上进行。通过用浓度为20％的哌啶的N-甲基吡咯烷酮(NMP)溶液处理30分钟除去Fmoc基团。在每个连接步骤中，Fmoc氨基酸(4eq，1mmol)在2ml 0.45M的六氟磷酸化2-(1-H-苯并三唑-1-基)-1，1，2，3-四甲基脲盐(tetramethyluronium)/1-羟基-苯并三唑(HBTU/UOBT)在N，N-二甲基甲酰胺(DMF)溶液中预活化。将该活化的氨基酸酯，1ml二异丙基乙胺(DIEA)和1mlNMP加入到树脂中。AB1 433A肽合成器被编程以实现下列反应循环：(1)用NMP洗涤，(2)用溶于NMP中的20％哌啶除去Fmoc保护基团达30分钟，(3)用NMP洗涤，(4)与预活化的Fmoc氨基酸偶联达1小时。树脂被依次偶联。肽链组装后，除去Fmoc，用DMF和二氯甲烷(DCM)彻底洗涤。
MBHA＝4-甲基二苯甲胺(Methylbenzylhydrylamine)
B.将得到的H-Aepa-Lys(Boc)-D-Tyr(叔丁基)-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂(0.188mmol)与化合物7(92mg，0.28mmol，1.5eq)，[7-氮杂苯并三唑-1-基-三(吡咯烷酮)鏻(PyAOP)(146mg，0.28mmol，1.5eq)和1-羟基-7-氮杂苯并三唑(HOAT)(38mg，0.28mmol，1.5eq)在5mL DCM中混合。将混合物震荡过夜。树脂干燥后，依次用DMF，甲醇和DCM洗涤。在空气中干燥后，用TFA，水和三异丙基硅烷(TIS)的混合物(9.5ml/0.85ml/0.8ml)处理该树脂达2小时。过滤该树脂，然后将滤出物倒入50ml冷乙醚中。离心分离后，收集沉淀物。将粗产品溶解在100ml 5％AcOH水溶液中，滴加碘的甲醇溶液直至保留有黄色。将反应溶液再搅拌1小时。加入10％Na2S2O3水溶液猝灭多余的碘。用有C18DYNAMAX-100柱的制备性HPLC系统(Varian，Walnut Creek，CA)纯化溶液中的粗产品。以从80％A和20％B至55％A和45％B的线性梯度在50分钟内洗脱该柱，其中A是0.1％TFA水溶液，B是0.1％TFA的乙腈溶液。用分析HPLC检测馏分。合并含有纯产品的那些物质并冷冻至干燥。收率40％。根据分析性HPLC的分析，纯度为96.8％。MS(电雾化)：1820.8(与计算的分子量1821.3一致)。
实施例M
实施例M基本上用H-Lys(Boc)-D-Tyr(叔丁基)-Tyr(叔丁基)-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L的方法合成。根据HPLC的分析，最终产物的纯度为97.9％。MS(电雾化)：1652.1(与计算的分子量1652.03一致)。
实施例N
实施例N基本上是使用H-Doc-Lys(Boc)-D-Tyr(叔丁基)-D-Tyr(叔丁基)-Lys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为99.2％。MS(电雾化)：1797.1(与计算的分子量1797.19一致)。
Fmoc-Doc-OH可从Chem-Impex InternatioNal，Inc.(Wood Dale，IL)商购。
实施例O
Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
实施例O基本上是使用(6-N-丙基-8β-麦角灵基)甲基硫代乙酸和H-Lys(Boc)-D-Tyr(叔丁基)-D-Tyr(叔丁基)-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为97.4％。MS(电雾化)：1680.6(与计算的分子量1680.1一致)。
实施例P
Aepa-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
实施例P基本上是使用(6-N-丙基-8β-麦角灵基)甲基硫代乙酸和H-Aepa-Aepa-D-Phe-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为99.9％。MS(电雾化)：1710.7(与计算的分子量1711.2一致)。
实施例Q
实施例Q基本上是使用(6-N-丙基-8β-麦角灵基)甲基硫代乙酸和H-Aepa-Aepa-DPhe-Cys(Trt)-(3-碘代)-Tyr-D-Trp(Boc)-Lys(Boc)-Val-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为99％。MS(电雾化)：1851.1(与计算的分子量1851.1一致)。
Fmoc-(3-碘代)-Tyr-OH可从Advanced ChemTech(Louisville，KY)商购。
(3-碘代)Tyr＝
实施例R
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
实施例R基本上是使用H-Aepa-Aepa-D-Phe-Cys(Trt)-Tyr(叔丁基)-D-Trp(BoC)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为98.3％。MS(电雾化)：1513.8(与计算的分子量1513.9一致)。
实施例S
Aepa-Aepa-D-Phe-环[Cys-(3-碘代)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
实施例 S基本上是使用H-Aepa-Aepa-D-Phe-Cys(Trt)-(3-碘代)-Tyr-D-Trp(Boc)-Lys(Boc)-Val-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为85.7％。MS(电雾化)：1822.9(与计算的分子量1823.06一致)。
实施例T
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
实施例T基本上是使用H-Doc-D-Phe-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂根据实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为98.9％。MS(电雾化)：1489.6(与计算的分子量1489.84一致)。
实施例U
实施例U基本上是使用H-Doc-D-Phe-Cys(Trt)-(3-碘代)Tyr-D-Trp(Boc)-Lys(Boc)-Val-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。MS(电雾化)：1629.8(与计算的分子量1629.7一致)
实施例V
该标题化合物基本上是使用H-Doc-Doc-D-Phe-Cys(Trt)-Tyr(叔丁基)-D-Trp(Boc)-Lys(Boc)-Abu-Cys(Trt)-Thr(叔丁基)-Rink酰胺MBHA树脂按照实施例L所描述的方法合成。根据HPLC的分析，最终产物的纯度为99％。MS(电雾化)：1635.0(与计算的分子量1633一致)。
本发明的某些化合物可具有至少一个不对称中心。分子中也可以有另外的不对称中心，这取决于分子上不同取代基的性质。每个这样的不对称中心产生两个旋光异构体，所有这些旋光异构体如分离的，纯的或部分纯的旋光异构体、外消旋混合物或其非对映混合物均包括在本发明的范围内。
本发明的化合物通常可以其药学上可接受的酸加成盐的形式分离出来，如使用无机酸或有机酸得到的盐。所述酸的实例包括盐酸、硝酸、硫酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、马来酸、琥珀酸、D-酒石酸、L-酒石酸、丙二酸、甲磺酸等。另外，某些含有酸官能团如羧基的化合物可以其无机盐的形式分离出来，其中的抗衡离子选自Na，K，Li，Ca，Mg等，也可从有机碱中分离出来。
所述药学上可接受的盐可通过下述方法得到：取约1当量的本发明的化合物(如下述化合物C)，使其与约1当量或更多的所希望得到的相应盐的酸接触，合成方法和分离方法是本领域的技术人员所公知的。
本发明的化合物可以通过下列方式给药：口服、胃肠外(如肌内、腹膜内、静脉内或皮下注射，或移植)、鼻腔给药、阴道、直肠、舌下、或局部给药，本发明的化合物可与药学上可接受的载体一起制剂以提供与各种给药途径相适应的药剂形式。因此，本发明包括含有下列的药物组合物：作为活性组分的至少一种本发明的化合物，其与药学上可接受的载体相联合。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉末剂和粒剂。在这些固体剂型中，活性成分化合物与至少一种惰性的药学上可接受的载体混合，如蔗糖、乳糖、或淀粉。这些剂型也可包括除惰性稀释剂以外的物质，如润滑剂(如硬酯酸镁)。胶囊、片剂和丸剂还可含有缓冲剂。片剂和丸剂还可包有肠溶衣。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆、含有本领域常用的惰性稀释剂如水的酏剂。除上述惰性稀释剂以外，组合物也可包括辅剂，如润湿剂、乳化剂、悬浮剂和甜味剂、调味剂和芳香剂。
本发明用于胃肠外给药的制剂包括无毒水溶液或非水溶液、悬浮液或乳液。非水溶剂或载体的实例包括丙二醇、聚乙二醇、植物油如橄榄油和玉米油，明胶和可注射的有机酯类如油酸酯。该剂型还可包括辅剂如防腐剂、润湿剂、乳化剂和分散剂。它们可通过下列方式消毒：通过细菌保留过滤器(bacteria-retaining filter)进行过滤，在组合物中加入消毒剂，照射组合物或加热组合物。在使用前，可以制成溶解在无菌水或一些其他无菌可注射介质中的无菌固体组合物的形式。
用于直肠或阴道给药的组合物优选是栓剂，除活性物质外，其可含有赋型剂如可可乳脂或栓剂蜡。
用于鼻腔或舌下给药的组合物可与本领域公知的标准赋型剂一起制备。
通常，本发明的组合物中的活性组分的有效剂量可以不同，但活性组分的量必须是获得适宜剂型的量。选择的剂量取决于所希望达到的治疗效果、给药途径、和治疗持续的时间，这些都是本领域的公知常识。通常，对人和其他动物如哺乳动物的给药剂量每天在0.0001-100mg/kg体重。
优选的剂量范围在每天0.01-10.0mg/kg体重，其可以是一次给药的剂量或分为多次给药的剂量。
生长激素释放抑制因子特性和选择性分析
用来合成生长激素释放抑制因子-多巴胺嵌合体的生长激素释放抑制因子类似物的特性和选择性取决于对被每种SSTR亚型转染的CHO-K1细胞所进行的放射性配体结合试验，如下所述。
SSTR 1，2，3和4基因的完全编码序列和SSTR 5的cDNA无性系被亚克隆到哺乳纲表达载体pCMV上(Life Technologies，Lilano，Italy)。稳定表达SSTR’s 1-5的克隆细胞系由使用磷酸钙共沉淀法(Davis L等人，1994，分子生物学的基本方法，第二版，Appleton & Lange，Norwalk，CT，USA：611-646)转染至CHO-K1细胞中(ATCC，Manassas，Va，USA)而得到。pRSV-neo(ATCC)质粒作为可选择的标记包含于其中。在含有0.5mg/ml G418(Life Technologies，Milano，Italy)的RPMI 1640介质中选择克隆细胞系，进行环克隆，并在培养物中扩展。
在冰冷的50nM Tris-HCl中匀化表达SSTR’s亚型的CHO-K1细胞，在39000g(10分钟)离心分离两次，并立刻在新鲜的缓冲剂中进行再悬浮，得到用于体外受体结合分析的薄膜。最终的小颗粒在10nM Tris-HCl中进行再悬浮，以用于分析。为了分析SSTR 1，3，4和5，使薄膜制剂的等分试样在25℃下与0.05nM[125l-Tyr11]SS-14在50mM HEPES(pH7.4)中温育90分钟，该HEPES含有10mg/ml BSA，5mM MgCl2，200KIU/ml抑肽酶(Trasylol)，0.02mg/ml USP杆菌肽，和0.02mg/ml苯甲磺酰氟。最后的分析体积是0.3ml。为分析SSTR 2，采用0.05nM[125]MK-678为放射性配体，温育时间在25℃下为90分钟。使用Brandel过滤岐管通过GF/B过滤器将其快速过滤，从而终止温育。然后用5ml冰冷缓冲剂的等分试样分别冲洗每个管和过滤器3次。特异性结合定义为放射性配体的结合总数减去出现在1000nM SS-14中的结合(对于SSTR 1，3，4和5)或1000nM MK-678中的结合(对于SSTR2)。
多巴胺受体特性和选择性分析
用于合成生长激素释放抑制因子-多巴胺嵌合体的多巴胺类似物的多巴胺-2受体的特性和选择性，取决于放射性配体结合试验，如下所述。
采用Brinkman Polytron(设定为6，15秒)，在20ml冰冷的50nM Tris-HCl中匀化冷冻的鼠体纹状体(Zivic Laboratories，Pittsburgh，PA)，得到粗膜。加入缓冲剂使终体积为40ml，匀浆在SorVal SS-34转子以39000g在0-4℃下离心分离10分钟。倒掉所得上层清液，再将小颗粒在冰冷的缓冲剂中匀化，在37℃下预先温育10分钟，如前述进行稀释和离心分离。在缓冲剂中再悬浮最终小颗粒，并保存在冰上，用于受体结合分析试验。
为了进行分析，将洗涤过的薄膜制剂的等分试样和测试化合物与0.25nM[3H1]螺环哌啶酮(16.5Ci.mmol，New England Nuclear，Boston，MA)一起在50mM Tris HCl，120mM NaCl，5mM KCl，2mM CaCl2，1mM MgCl2中温育15分钟。最终分析体积为1.0ml。使用Brandel过滤岐管通过GF/B过滤器进行快速过滤，从而终止温育。然后用5ml冰冷缓冲剂的等分试样分别冲洗每个管和过滤器3次。特异性结合定义为放射性配体的结合总数减去出现在1000nM(+)丁克吗(butaclamol)中的结合。
其他实施方式
应该理解，当本发明结合详细说明来描述时，前述说明只是用于举例说明而并非是用于限制由后面的权利要求数所定义的本发明的范围。其他的方面、优点和改进也属于本发明的权利要求的范围。而且，本文所提到的所有文献均全文引入作为参考。
Claims (17)
1.式(I)化合物或其药学上可接受的盐，
其中：
X是H，Cl，Br，I，F，-CN或C1-5烷基；
R1是H，C1-4烷基，烯丙基，链烯基或-CN；
R2和R3分别独立地为H或不存在，条件是当R2和R3不存在时，它们所连接的炭原子之间有双键；
R4是H或-CH3；
Y是-O-，-C(O)-，-S-，-S-(CH2)s-C(O)-，-S(O)-，-S(O)2-，-SC(O)-，-OC(O)-，-N(R5)-C(O)-或-N(R6)-；
R5，R6，R7和R8分别独立地为H或C1-5烷基；
R6是H或C1-5烷基；
m是0或1；
n是0-10；
当Y是-S-，-S(O)-，-S(O)2-，-O-或-N(R6)-时，L是-(CH2)p-C(O)-；
当Y是-N(R6)-，-O-或-S-时；L是-C(O)-(CR7R8)q-C(O)-；
当Y是-C(O)-，-SC(O)-，-OC(O)-，-S-(CH2)s-C(O)-或-N(R5)-C(O)-时，L是-(Doc)t-；
p是1-10；
q是2-4；
s是1-10；
t是1-10；且
Z是生长激素释放因子类似物或含有-H，-OH，(C1-C6)烷氧基，芳基烷氧基，-NH2或-NR9R10，其中R9和R10分别独立地为H或C1-5烷基。
2.式(II)化合物或其药学上可接受的盐，
其中：
X是H，Cl，Br，I，F，-CN或C1-5烷基；
R1是C1-4烷基，H，烯丙基，链烯基或-CN；
R2和R3分别独立地为H或不存在，条件是当R2和R3不存在时，它们所连接的碳原子之间有双键；
R4是H或-CH3；
R5是C1-5烷基基团，或式-(CH2)rN(CH3)q的基团；
Y是-O-，-C(O)-，-S-，-SC(O)-，-OC(O)-，-N(R6)-C(O)-，-N(R7)-，或-N(R8)-(CH2)s-C(O)-；
R6，R7，R8，R9和R10分别独立地为H或C1-5烷基；
当Y是-S-，-O-或-N(R7)-时，L是-(CH2)p-C(O)-；
当Y是-N(R7)-，-O-或-S-时，L是-(CO)-(CR9R10)q-C(O)-；
当Y是-C(O)-，-SC(O)-，-OC(O)-，-N(R8)-(CH2)s-C(O)-或-N(R6)-C(O)-时，L是-(Doc)t-；
m是0或1；
n是2-10；
q是2-4；
p是1-10；
s是1-10；
t是1-10；和
Z是生长激素释放因子类似物或含有-H，-OH，(C1-C6)烷氧基，-NH2或-NR9R10。
3.下式化合物或其药学上可接受的盐：
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Caeg＝N-(2-氨基乙基)-N-(2-胞嘧啶基-1-氧代-乙基)-甘氨酸
Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)2-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)3-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)4-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
环[Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)3-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Val-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-(3-溴-Tyr)-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)3-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-D-Phe-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
Doc-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(D-Ser)5-Nle-D-Tyr-D-Ser-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)3-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Trp-NH2
(Doc)2-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)3-Caeg-D-Phe-环[D-Cys-Pal-D-Trp-Lys-D-Cys]-Thr-(Bzl)-Tyr-NH2
(Doc)2-Lys-D-Tyr-D-Tyr-环[Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)3-环[Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys]-NH2
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
AEPA-Lys-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
AEPA-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-D-Phe-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
(D-Ser)10-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-醇
D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
AEPA＝4-(2-氨基乙基)-1-羧甲基-哌嗪
D-Phe-环[Cys-Phe-DTrp-Lys-Val-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Phe-DTrp-Lys-Val-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
AEPA-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
AEPA-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
AEPA-Nle-D-Tyr-D-Ser-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2
以及
AEPA-Lys-D-Tyr-D-Tyr-环[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-NH2。
4、下式化合物或其药学上可接受的盐：
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)3-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-(Aepa)2-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Aepa)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Aepa-D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Thr-醇
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)2-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Doc-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)10-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-D-Nal-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH2
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Doc-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)4-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)5-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Aepa)2-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)2-Aepa-D-Phe环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)3-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
(Doc)4-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(Doc)6-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
Aepa-Aepa-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
Aepa-Aepa-D-Phe-环[Cys-(3-碘-Tyr)-D-Trp-Lys-Val-Cys]-Thr-NH2
或
5、下式化合物或其药学上可接受的盐：
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2
(D-Ser)5-Lys-D-Tyr-D-Tyr-环[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2
乙基-[6-甲基-8β-麦角灵基甲基]硫代乙酸酯；
6-甲基-8β-麦角灵基甲基硫代乙酰基-D-Phe-环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH2；
乙基-(6-正丙基)-8β-麦角灵基)甲基硫代乙酸酯；
6-正丙基-8β-麦角灵基甲基硫代乙酰基-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2；
6-D-甲基-8β-麦角灵基甲基硫代氨基琥珀酰基
(ergolinylmethylthlaminosuccinoyl)-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2；
D-Phe-环(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Th-NH2
Aepa-Aepa-D-Phe-环(Cys-(3-碘)Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2
Doc-D-Phe-环(Cys-(3-碘)Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2
6、下式化合物或其药学上可接受的盐：
Doc-D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2；
7、一种在需要的患者体内引起多巴胺受体激动剂作用的方法，其中，所述方法包括以有效量的权利要求1-6中任一项所述的化合物或其药学上可接受的盐对所述患者给药。
8、一种在需要的患者体内引起生长激素释放抑制因子受体激动剂作用的方法，其中，所述方法包括以有效量的权利要求1-6中任一项所述的化合物或其药学上可接受的盐对所述患者给药。
9、一种在需要的患者体内同时引起多巴胺受体激动剂作用和生长激素释放抑制因子受体激动剂作用的方法，其中，所述方法包括以有效量的权利要求1-6中任一项所述的化合物或其药学上可接受的盐对所述患者给药。
10、一种药物组合物，包括有效量的权利要求1-6中任一项所述的化合物或其药学上可接受的盐。
11、一种为患者治疗疾病的方法，所述方法包括以治疗有效量的权利要求1-6任一项所述的化合物对所述患者给药，其中所述疾病选自肺癌、神经胶质瘤、厌食症、甲状腺机能减退、醛固酮过多症、幽门螺旋杆菌增生、肢端肥大症、再狭窄、克朗氏病、系统性硬化症、外部和内部的胰腺假囊肿和腹水、舒血管肠肽瘤、胰岛细胞弥漫性增生、胰岛素分泌过多、胃泌素瘤、卓-艾二氏综合症、腹泻、与AIDS相关的腹泻、与化疗相关的腹泻、硬皮病、过敏性肠综合症、胰腺炎、小肠梗阻、胃食管回流、十二指肠胃回流、库兴氏综合症、促性腺素瘤、甲状旁腺机能亢进、格雷夫斯氏病、糖尿病性神经病、Paget氏病、多囊卵巢病、甲状腺癌、肝细胞瘤、白血病、脑膜炎、癌性恶病质、直立低血压、餐后低血压、焦虑发作、GH分泌腺瘤、肢端肥大症、TSH分泌腺瘤、催乳素分泌腺瘤、胰岛腺瘤、高血糖素瘤、糖尿病、高脂血症、胰岛素麻木、X综合症、血管病、增生性视网膜炎、黎明现象、肾病、胃酸分泌、消化器官溃疡、肠皮肤瘘管、胰腺皮肤瘘管、倾倒综合症、含水腹泻综合症、胰腺炎、胃肠激素分泌肿瘤；血管生成、关节炎；同种异体抑制排斥、移植脉管出血、入口高血压、胃肠出血、肥胖、以及鸦片样物质过量。
12、根据权利要求11所述的方法，其中，所述的疾病或症状是肢端肥大症。
13、根据权利要求7，8，9或12中任一项所述的方法，其中，所述的化合物为
D-Phe-环[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH2；
或其药学上可接受的盐。
14、根据权利要求10所述的药物组合物，其中，所述化合物是
或其药学上可接受的盐。
15、根据权利要求1或2所述的化合物或其药学接受的盐，其中，Z是含有-H，-OH，(C1-C6)烷氧基，芳氧基，-NH2或-NR9R10的基团。
16、根据权利要求15的化合物或其药学接受的盐，其中，Z是含有-H，-OH，(C1-C6)烷氧基或苄基的基团。
17、根据权利要求15的化合物或其药学上可接受的盐，其中，所述化合物具有下式
或
或其药学可接受的盐。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103547591A (zh) * | 2011-04-21 | 2014-01-29 | 瑟瑞技术公司 | 生长激素释放因子(grf)类似物及其用途 |
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