CN1674927A - 生长激素释放肽 - Google Patents
生长激素释放肽 Download PDFInfo
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- CN1674927A CN1674927A CNA038186810A CN03818681A CN1674927A CN 1674927 A CN1674927 A CN 1674927A CN A038186810 A CNA038186810 A CN A038186810A CN 03818681 A CN03818681 A CN 03818681A CN 1674927 A CN1674927 A CN 1674927A
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
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Abstract
本发明公开了具有下式(I)结构的肽或肽模拟物类化合物及其药学可接受盐,所述物质可用作GHRP类似物:R1-A1-A2-A3-A4-A5-R2 (I),其中:A1是Aib,Apc或者Inp;A2是D-Bal,D-Bip,D-Bpa,D-Dip,D-1 Nal,D-2Nal,D-Ser(Bzl),或D-Trp;A3是D-Bal,D-Bip,D-Bpa,D-Dip,D-1 Nal,D-2Nal,D-Ser(Bzl),或D-Trp;A4是2Fua,Orn,2Pal,3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,3Thi,Thr(Bzl);A5是Apc,Dab,Dap,Lys,Orn,或缺失;R1是氢,(C1-6)烷基,(C5-14)芳基,(C1-6)烷基(C5-14)芳基,(C3-8)环烷基,或(C2-10)酰基;R2是OH或NH2。本发明还公开了其药物组合物及其使用方法。
Description
背景技术
生长激素从垂体促生长激素细胞的脉动性释放通过两种下丘脑神经肽进行调控:生长激素释放激素和生长激素释放抑制激素。生长激素释放激素刺激生长激素的释放,而生长激素释放抑制激素抑制生长激素的分泌(Frohmanetal.,Endocr.Rev.1986,7,223-253,and Strobiet al.,Pharmacol.Rev.1994,46,1-34.)。
生长激素从垂体促生长激素细胞的释放也可受到生长激素释放肽(GHRP’s)的控制。已经发现有一种六肽,His-D-Trp-Ala-Trp-D-Phe-Lys-amide(GHRP-6)在包括人的几种物种中以剂量依赖性方式从促生长激素细胞中释放生长激素(Bowers etal.,Endocrinology 1984,114,1537-1545)。其后对GHRP-6进行化学研究从而识别了其它一些有效的生长激素促释放素,例如GHRP-I、GHRP-2以及海沙瑞林(hexarelin)等(Cheng etal.,Endocrinology 1989,124,2791-2798,Bowers,C.Y.Novel GH-Releasing Peptides.In:Molecular and Clinical Advances in Pituitary Disorders.Ed:Melmed,S.;Endocrine Research and Education,Inc.,Los Angeles,CA,USA1993,153-157,and Deghenghi et al.,Iife Sci.1994,54,1321-1328):
GHRP-I Ala-His-D-(2’)-Nal-Ala-Trp-D-Phe-Lys-NH2;
GHRP-2 D-Ala-D-(2’)-Nal-Ala-Trp-D-Nal-Lys-NH2;
海沙瑞林 His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2。
GHRP-I、GHRP-2、GHRP-6以及海沙瑞林为合成的生长激素促释放素(GHS’s)。GHS’s通过与生长激素释放激素不同的机制而刺激生长激素的分泌(Bowerset al..Endocrinology 1984,114,1537-1545,Cheng etal.Endocrinology 1989,124,2791-2798,Bowers,C.Y.Novel GH-ReleasingPeptides. In:Molecular and Clinical Advances in Pituitary Disorders.Ed:Melmed,S.;Endocrine Research and Education,Inc.,Los Angeles,CA,USA 1993,153-157,and Deghenghi et al.,Life Sci.1994,54,1321-1328.)。
肽类生长激素促释放素具有很低的口服生物利用度(<1%),这使得人们寻找能够在垂体中模拟GHRP-6作用的非肽类化合物。有报道说,几种benzolactam和spiroindane在人类以及多种动物物种中都能刺激生长激素分泌(Smith et al.,Science 1993,260,1640-1643,Patchettet al.,Proc.Natl.Acad.Sci.USA.1995,92,7001-7005,and Chen et al.,Bioorg.Mod.Chem.Lett.1996,6,2163-2169.)。一种小型的spiroindane的特定例子是MK-0677(Patchett et al.Proc Natl.Acad.Sci.USA.1995,92,7001-7005):
上述GHS’s(肽类以及非肽类)的作用看起来是由特定的生长激素促释放素受体(GHS受体)所介导的(Howard etal.,Science 1996,273,974-977,andPong etal,Molecular Endocrinology 1996,10,57-61.)。该受体存在于多种哺乳动物的垂体和下丘脑中(GHSR1a),与生长激素释放激素(GHRH)受体具有显著区别。在中枢神经系统以及外周组织的其它区域也检测到GHS受体,例如在肾上腺和甲状腺、心、肺、肾以及骨骼肌等(Chen etal,Bioorg.Med.Chem.Lett.1996,6,2163-2169,Howard etal,Science 1996,273,974-977,Pongetal,Atlecular Endocrinology 1996,10,57-61,Guan et al,Mol.BrainRes.1997,48,23-29,and McKeeet al.,Genomics 1997,46,426 434.)。还有关于截短型GHSR1的报道(Howard etal.,Science 1996,273,974-977.)。
GHS受体是一种G蛋白偶联型受体。GHS受体活化的作用包括钾通道的去极化和抑制、细胞间肌醇三磷酸(IP3)浓度的增加、以及胞内钙浓度的瞬时增加等(Pong etal.,Molecular Endocrinology 1996,10,57-61,Guan etal.,Mol.Brain Res.1997,48,23-29,and McKee etal.,Genomics 1997,46,426-434.)。
胃饥饿素(Ghrelin)是一种天然生成的肽,认为其是GFS受体的内源性配基(Kojima etal.,Nature 1999,402,656-660.)。已知几种哺乳动物和非哺乳动物中胃饥饿素的天然结构(Kaiyaet al.,J.Biol.Chem.2001,276,40441-40448;International Patent ApplicationPCT/JP00/04907(WO01/07475).)。发现胃饥饿素的一个核心区域为GSH受体提供活性。这一核心区域包括四个N-末端氨基酸,其中第3位的丝氨酸通常被正辛酸所修饰。但是,除了正辛酸的酰化作用外,胃饥饿素还可被正癸酸所酰化(Kaiya eta/.,J.Biol.Chem.2001,276,40441-40448.)。除了用做研究工具,胃饥饿素类似物还具有多种不同的治疗用途。
发明概述
本发明提供了对GHS受体具有活性的肽类似物。本发明的类似物能够结合GHS受体,优选能引起信号转导。
因此,本发明的第一方案提供了具有下式(I)的化合物或其药学可接受盐:
R1-A1-A2-A3-A4-A5-R2
(I)
其中:
A1是Aib,Apc或者Inp;
A2是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A3是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A4是2Fua,Orn,2Pal,3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,3Thi,Thr(Bzl);
A5是Apc,Dab,Dap,Lys,Orn,或缺失;
R1是氢,(C1-6)烷基,(C5-14)芳基,(C1-6)烷基(C5-14)芳基,(C3-8)环烷基,或(C2-10)酰基;以及
R2是OH或NH2;
条件是
当A5是Dab,Dap,Lys,或Orn时:
A2是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A3是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A4是2Thi,3Thi,Taz,2Fua,2Pal,3Pal,4Pal,Orn,Thr(Bzl),或Pff;
当A°缺失时:
A3是D-Bip,D-Bpa,或D-Dip;或者
A4是2Fua,Pff,Taz,或Thr(Bzl);或者
A1是Apc并且
A2是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A3是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A4是2Thi,3Thi,Orn,2Pal,3Pal,或4Pal。
式(I)的一组优选化合物被称作第1组化合物,其是具有式(I)的化合物或其药学可接受盐,其中:
A1是Aib,Apc或H-Inp;
A2是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A3是D-Bal,D-Bpa,D-Dip,D-1Nal,D-2Nal,或D-Trp;
A4是Orn,3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,或Thr(Bzl);且
A5是Apc,Lys,或缺失。
第1组化合物的优选化合物被称作1A组化合物,其是具有所述式的化合物或其药学可接受盐,其中:
A1是Apc或H-Inp;
A2是D-Bal,D-Bip,D-1Nal或D-2Nal;
A3是D-Bal,D-1Nal,D-2Nal,或D-Trp;
A4是3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,或Thr(Bzl);
式(I)的另一组优选化合物被称作第2组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-NH2;
H-Inp-D-1Nal-D-Trp-3Pal-NH2;
H-Inp-D-Bip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-Dip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Bal-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-1Nal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-ApC-D-1Nal-D-Trp-2Fua-NH2;
H-Apc-D-1Nal-D-Trp-2Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-NH2;
H-Apc-D-1Nal-D-Trp-4Pal-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-NH2;
H-Apc-D-2Nal-D-Trp-2Pal-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-NH2;
H-Apc-D-2Nal-D-Trp-4Pal-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-NH2;
H-Apc-D-Bal-D-Bal-2Pal-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Thi-NH2;
H-Apc-D-Bal-D-Bal-3Pal-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-3Thi-NH2;
H-Apc-D-Bal-D-Bal-4Pal-NH2;
H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;
H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;
H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;
H-Apc-D-Bal-D-Bal-Phe-NH2;
H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;
H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Fua-NH2;
H-Apc-D-Bal-D-Trp-2Pal-NH2;
H-Apc-D-Bal-D-Trp-3Pal-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-3Thi-NH2;
H-Apc-D-Bal-D-Trp-4Pal-NH2;
H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Trp-Pff-Lys-NH2;
H-Apc-D-Bal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-NH2;
H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-NH2;
H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Fua-NH2;
H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-NH2;
H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Fua-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;
H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-NH2;
H-Inp-D-Bal-D-Trp-Taz-NH2;
H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Fua-NH2;
H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-NH2;or
H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bip-D-Bal-Taz-NH2;
H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Fua-NH2;
H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bip-D-TrP-Pff-Lys-NH2;
H-Inp-D-Bip-D-Trp-Pff-NH2;
H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;或
H-Inp-D-Bip-D-Trp-Taz-NH2;
第2组化合物中的优选化合物被称作第2A组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-LyS-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-NH2;
H-Inp-D-Bal-D-Trp-2Fua-NH2;
H-Inp-D-Bal-D-Trp-Pff-NH2;
H-Apc-D-Bal-D-Trp-3Thi-NH2;
H-Apc-D-Bal-D-Trp-2Fua-NH2;
H-Apc-D-Bal-D-Trp-Pff-NH2;
H-Apc-D-Bal-D-Trp-4Pal-NH2;
H-Apc-D-Bal-D-Trp-3Pal-NH2;
H-Apc-D-Bal-D-Trp-2Pal-NH2;
H-Inp-D-Bal-D-Bal-Taz-NH2;
H-Inp-D-Bal-D-Bal-2Fua-NH2;
H-Inp-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-Phe-NH2;
H-Apc-D-Bal-D-Bal-2Thi-NH2;
H-Apc-D-Bal-D-Bal-3Thi-NH2;
H-Apc-D-Bal-D-Bal-Taz-NH2;
H-Apc-D-Bal-D-Bal-2Fua-NH2;
H-Apc-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-4Pal-NH2;
H-Apc-D-Bal-D-Bal-3Pal-NH2;
H-Apc-D-Bal-D-Bal-2Pal-NH2;
H-Inp-D-1Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-NH2;
H-Inp-D-1Nal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Bal-Taz-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-NH2;
H-Inp-D-1Nal-D-Bal-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-NH2;
H-Apc-D-1Nal-D-Trp-Pff-NH2;
H-Apc-D-1Nal-D-Trp-4Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Pal-NH2;
H-Apc-D-1Nal-D-Trp-2Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-NH2;
H-Apc-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-4Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Pal-NH2;
H-Apc-D-2Nal-D-Trp-2Pal-NH2;
H-Inp-D-Bip-D-Trp-Taz-NH2;
H-Inp-D-Bip-D-Trp-2Fua-NH2;
H-Inp-D-Bip-D-Trp-Pff-NH2;
H-Inp-D-Bip-D-Bal-Bal-Taz-NH2;
H-Inp-D-Bip-D-Bal-2Fua-NH2;或
H-Inp-D-Bip-D-Bal-Pff-NH2;
第2A组化合物中的优选化合物被称作第2B组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;或
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
第2B组化合物中的优选化合物被称作第2B-1组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;或
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
第2B-1组化合物中的优选化合物被称作第2B-1a组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;或
第2B-1组化合物中进一步优选的化合物被称作第2B-1b组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;或
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
第2B-1组化合物中再进一步优选的化合物被称作第2B-1c组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
第2B-1c组化合物中一个特别优选的化合物是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2。
第2B-1组化合物中另一组更优选的化合物被称作第2B-1d组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2。
第2B组化合物中另一组优选的化合物被称作第2B-2组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-1Na-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;或
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
第2B-2组化合物中优选的化合物被称作第2B-2a组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-1Na-D-Trp(Ψ)-Pim;或
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
第2组化合物中另一组优选的化合物被称作第2C组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-3Pal-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-NH2;
H-Inp-D-1Nal-D-Trp-3Pal-NH2;
H-Inp-D-Bip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-NH2;
H-Inp-D-Dip-D-Trp-Phe-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Bal-Phe-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;或
H-Apc-D-1Nal-D-Trp-Phe-NH2;
第2C组化合物中优选的化合物被称作第2C-1组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;或
H-Apc-D-1Nal-D-Trp-Phe-NH2;
本发明特别优选的化合物被称作第3组化合物,其是具有下式结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;或
H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;
本发明的另一方案提供了一种确定化合物与GHS受体结合能力的方法,所述方法包括下述步骤:测定该化合物对式(I)所述化合物或者对组1,1A,2,2A,2B,2B-1,2B-1a,2B-1b,2B-1c,2B-1d,2B-2,2B-2a,2C,或2C-1中任意一组所述化合物与所述受体、所述受体的片段、包含所述受体片段的多肽、或者所述多肽的衍生物的结合能力的影响。
本发明还提供了一种在个体中获得有益作用的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的化合物或其药学可接受盐的步骤,其中所述有效剂量是在帮助治疗(例如,治愈或减轻严重程度)或者预防(例如,降低发病的可能性或者见效严重程度)一种疾病或者病症中能够有效产生有益效果。
本发明的再一方案提供了一种刺激个体生长激素分泌的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素激动剂或其药学可接受盐,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测增加的剂量,优选为足以在患者中产生有益效果的剂量。
在前述方法的一个实施方案中,对所述生长激素的分泌进行刺激从而用于治疗生长激素不足的状态、增加肌肉块、增加骨质密度、治疗男性和女性的性功能障碍、促进体重增加、维持体重、维持身体机能、促进身体功能的恢复、和/或促进食欲增加等。优选地,所述促进体重增加、维持体重、和/或促进食欲增加用于处于伴随有体重减轻的疾病或病症状态、或进行治疗而伴随有体重减轻的患者。进一步优选地,所述伴随有体重减轻的疾病或病症包括厌食症、贪食症、癌症恶病质、AIDS、(例如,消耗)、(癌性)消瘦、以及孱弱老年性消耗。所述伴随有体重减轻的治疗还优选包括化疗、放疗、暂时性和永久性的固定、以及透析等。
本发明的又一方案提供了抑制个体生长激素分泌的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素拮抗剂或其药学可接受盐,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测降低的剂量,优选为足以在患者中产生有益效果的剂量。
在前述方法的一个实施方案中,对所述生长激素的分泌进行抑制从而用于治疗以生长激素过分分泌为特征的疾病或状态、促进体重降低、促进食欲降低、维持体重、治疗肥胖、治疗糖尿病、治疗包括视网膜病变等糖尿病并发症、和/或治疗心血管病症。
在前述方法的一个实施方案中,超重是下述疾病或状态的诱发因素:高血压、糖尿病、血脂异常、心血管疾病、胆结石、骨关节炎、以及癌症等。更优选地,所述促进体重降低减少了罹患这些疾病或者状态的可能性。进一步优选地,所述促进体重降低包括对所述疾病或状态的至少部分治疗。
在个体内产生胃饥饿素激动剂效果的方法包括给予所述个体有效剂量的一种或多种选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素激动剂或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测增加的剂量,优选为足以在患者中产生有益效果的剂量。
本发明的另一方案提供了在个体内产生胃饥饿素拮抗剂效果的方法,所述方法包括给予所述个体有效剂量的一种或多种选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素拮抗剂或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测降低的剂量,优选为足以在患者中产生有益效果的剂量。
本发明的化合物是对GHS受体有活性的化合物。所述化合物能够与受体结合,优选能够刺激受体活性。因此本发明化合物能够用作功能性的胃饥饿素的类似物,籍此用作研究工具和/或治疗剂。
研究工具的应用通常包括使用本发明化合物以及存在有GHS受体或其片段。GHS受体能够存在于不同环境中,例如存在于哺乳动物个体内、全细胞内、或者细胞膜片段内。研究工具应用的实例包括筛选对GHS具有活性的化合物、确定样品或制备物中GHS受体的存在、以及检测胃饥饿素的作用或效果等。
本发明的一个方案提供了筛选胃饥饿素激动剂和/或胃饥饿素拮抗剂的方法。胃饥饿素激动剂的筛选可通过使用诸如选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的一种所述化合物或其药学可接受盐而与受试化合物进行竞争性结合试验。胃饥饿素拮抗剂的筛选可通过使用诸如选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的一种所述化合物或其药学可接受盐来产生GHS受体活性然后检测受试化合物改变GHS受体活性的能力。
本发明另一方案提供了一种筛选化合物能够与GHS受体结合的方法。所述方法包括测定受试化合物对选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1所述的一种化合物或其药学可接受盐与包含胃饥饿素结合位点的任意受体、受体片段、包含所述片段的多肽、或者所述多肽的衍生物等的结合能力的影响。
胃饥饿素激动剂可用于在个体中产生有益效果。例如,胃饥饿素以剂量依赖性方式诱导生长激素从原代培养的垂体细胞的释放,而并不刺激其它垂体激素的释放。将胃饥饿素静脉注射至麻醉的大鼠体内,能够刺激生长激素的脉动性释放(Kojima et al..Nature 1999,402,656-660.)。这类有益效果的非排除性例子包括:治疗生长激素不足的状态、增加肌肉块、增加骨质密度、治疗男性或女性的性功能障碍、促进体重增加、维持体重、维持身体机能、促进身体功能的恢复、和/或促进食欲增加等。所述促进体重增加、维持体重、或食欲增加特别用于处于伴随有体重减轻的疾病或病症状态、或正进行治疗并伴随有体重减轻的患者。所述伴随有体重减轻的疾病或病症包括例如厌食症、贪食症、癌症恶病质、AIDS、(例如,消耗)、(癌性)消瘦、以及孱弱老年性消耗等。所述伴随有体重减轻的治疗还包括例如化疗、放疗、暂时性和永久性的固定、以及透析等。
本发明的另一方案还提供了在个体中产生有益效果的方法,所述方法包括给予所述个体有效剂量的一种或多种式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的所述化合物或其药学可接受盐的步骤,其中所述有效剂量在帮助治疗(例如,治愈或减轻严重程度)或者预防(例如,降低发病的可能性或者见效严重程度)一种疾病或者病症中能够有效产生有益的效果。
在本发明上述方法的一个优选实施方案中,所述有益效果包括在个体中刺激生长激素分泌,其包括给予个体有效剂量的一种或多种式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的所述化合物或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测增加的剂量,优选为足以在患者中产生有益效果的剂量。
在本发明上述方法的进一步优选实施方案中,对所述生长激素分泌的刺激用于治疗生长激素不足的状态、增加肌肉块、增加骨质密度、治疗男性或女性的性功能障碍、促进体重增加、维持体重、维持身体机能、促进身体功能的恢复、和/或促进食欲增加等。
在本发明上述方法的又一优选实施方案中,所述促进体重增加、维持体重、和/或食欲增加是指处于伴随有体重减轻的疾病或病症状态、或正进行伴随有体重减轻的治疗的患者。更优选地,所述伴随有体重减轻的疾病或病症包括例如厌食症、贪食症、癌症恶病质、AIDS、(例如,消耗)、(癌性)消瘦、以及孱弱老年性消耗等。
在本发明上述方法的进一步优选实施方案中,所述伴随有体重减轻的治疗包括例如化疗、放疗、暂时性和永久性的固定、以及透析等。
胃饥饿素拮抗剂也可用于在患者中产生有益效果。例如,胃饥饿素拮抗剂可用于促进体重降低、促进食欲降低、维持体重、治疗肥胖、治疗糖尿病、治疗包括视网膜病变等糖尿病并发症、和/或治疗心血管病症。超重是高血压、糖尿病、血脂异常、心血管疾病、胆结石、骨关节炎、以及某些癌症等疾病或状态的诱发因素。促进体重降低能减少诸如罹患这些疾病或者状态的可能性,并且可作为对所述疾病的部分治疗。
本发明的化合物也可以在体外及体内拮抗胃饥饿素的作用。而且本发明还提供了一种抑制个体生长激素分泌的方法,所述方法包括给予个体有效剂量的一种或多种式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1所述化合物或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测降低的剂量,优选为足以在患者中产生有益效果的剂量。
在上述方法的优选实施方案中,所述对生长激素分泌的抑制用于治疗生长激素过渡分泌的疾病或状态、促进体重降低、促进食欲降低、维持体重、治疗肥胖、治疗糖尿病、治疗包括视网膜病变等糖尿病并发症、和/或治疗心血管病症。
在上述方法的进一步优选实施方案中,超重是高血压、糖尿病、血脂异常、心血管疾病、胆结石、骨关节炎、以及癌症等疾病或状态的诱发因素。
在上述方法的另一个进一步优选的实施方案中,所述促进体重降低能减少诸如罹患这些疾病或者状态的可能性,及/或所述促进体重降低能减少包括对所述疾病的至少部分治疗。
如本领域技术人员所知,胃饥饿素及其激动剂也可用于对心血管产生有益效果(Nagaya,etal.,Regul Pept.2003 Jul 15:114(2-3):71-77.)。例如,已知胃饥饿素在体外抑制心肌细胞和内皮细胞的凋亡;对心力衰竭大鼠重复给予胃饥饿素能够增强心脏结构和功能并能减弱心肌衰弱的发展;对于人类心力衰竭患者,胃饥饿素能够降低系统血管阻力并增加心脏输出。(Id.)因此已经发现胃饥饿素以及胃饥饿素激动剂可用作治疗严重慢性心力衰竭。
在利用本文所述的胃饥饿素激动剂的每种方法的特别优选的实施方案中,胃饥饿素是具有下式的化合物或其药学可接受盐:
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2。
本发明的一种或多种化合物能够被施予至个体。“个体”指的是哺乳动物或者非哺乳动物,例如,其包括,但不限于:人类、大鼠、小鼠、或者豢养动物。所提到的个体并不必须患有一种疾病或障碍。因此,术语个体进一步包括例如,作为试验的一部分给予了胃饥饿素类似物的哺乳动物或者非哺乳动物;为有助于减轻疾病或障碍而进行治疗的哺乳动物或者非哺乳动物;以及为延迟或预防疾病或障碍的发作而进行预防性治疗的哺乳动物或者非哺乳动物等。
本发明的其它特定以及优点将由下述描述以及所附不同的实施例得到体现。所提供的实施例阐述了可应用于本发明的不同成分以及方法。这些实施例并非用于限定本发明。根据本发明公开的内容本领域技术人员能够鉴别使用其它可用于本发明的成分以及方法。
除非特别说明,具有手性中心的氨基酸为L-对映体。所述“其衍生物”指的是修饰的氨基酸,例如,对应的D-氨基酸、N-烷基化氨基酸、β-氨基酸、或者标记的氨基酸等。
发明详细描述
本发明涉及对GHS受体具有活性的肽类似物。人胃饥饿素是一个具有28个氨基酸的修饰的肽,其中丝氨酸的羟基被正辛酸所酯化(Kojima etal..Nature 1999,402,656-660,and Kojima,(Abstract),Third InternationalSymposium on Growth Hormone Secretagogues,Keystone,Colorado,USA2000,February 17-19.)。本发明化合物中出现的一些氨基酸如下所示:
A3c 1-氨基-1环丙烷羧酸
A4c 1-氨基-1环丁烷羧酸
A5c 1-氨基-1环戊烷羧酸
A6c 1-氨基-1环己烷羧酸
Abu α-氨基丁酸
Acc 1-氨基-1环(C3-C9)烷基羧酸
Act 4-氨基-4-羧基四氢吡喃,即:
Aib α-氨基异丁酸
Ala或A 丙氨酸
β-Ala β-丙氨酸
Arg或R 精氨酸
hArg 高精氨酸
Asn或N 天冬酰胺
Asp或D 天冬氨酸
Bpa 4-苯甲酰基苯丙氨酸,即:
Cha β-环己基丙氨酸;
Cys或C 半胱氨酸;
Dab 2,4-二氨基丁酸,(a,γ-二氨基丁酸);
Dap 2,3-二氨基丙酸,(α,β-二氨基丙酸);
Dhp 3,4-去氢脯氨酸
Dmt 5,5-二甲基噻唑烷-4-羧酸
2Fua β-(2-呋喃基)-丙氨酸,即:
Gln或Q 谷氨酰胺
Glu或E 谷氨酸
Gly或G 甘氨酸
His或H 组氨酸
3Hyp 反式-3-羟基-L-脯氨酸,即,(2S,3S)3-羟基吡咯烷基-2-羧酸;
4Hyp 4-羟基脯氨酸,即,(2S,4R)-4-羟基吡咯烷基-2-羧酸;
lle或I 异亮氨酸
Inc 吲哚啉-2-羧酸;
Inp 异哌啶酸,即:
Ktp 4-酮基脯氨酸
Leu或L 亮氨酸
hLeu 高亮氨酸
Lys或K 赖氨酸
Met或M 蛋氨酸
1Nal β-(1-萘基)丙氨酸
2Nal β-(2-萘基)丙氨酸;
Nle 正亮氨酸
Nva 正缬氨酸
Oic 八氢吲哚-2-羧酸
Orn 鸟氨酸
2Pal β-(2-吡啶基)-丙氨酸,即:
3Pal β-(3-吡啶基)-丙氨酸,即:
4Pal β-(4-吡啶基)-丙氨酸,即:
Phe或F 苯丙氨酸
hPhe 高苯丙氨酸
Pim 2’-(4-苯基)咪唑基,即:
Pip 哌啶酸
Pro或P 脯氨酸
Ser或S 丝氨酸
Taz β-(4-噻唑基)丙氨酸,即:
3Thi β-(3-噻吩基)丙氨酸,即:
Thr或T 苏氨酸
Thz 噻唑烷-4-羧酸
Tic 1,2,3,4-四氢异喹啉-3-羧酸
Tle 叔亮氨酸
Trp或W 色氨酸
Tyr或Y 酪氨酸
Val或V 缬氨酸
本文所用其它缩略词如下所述:
Boc: 叔丁氧羰基
BzI: 苄基
DCM: 二氯甲烷
DIC: N,N-二异丙碳二酰亚胺
DIEA: 二异丙基乙胺
Dmab: 4-{N-(1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基)-氨基}苄基
DMAP: 4-(二甲基氨基)吡啶
DMF: 二甲基甲酰胺
DNP: 2,4二硝基苯
Fmoc: 芴基甲氧羰基
HBTU: 2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基uronium六氟磷酸盐
cHex 环己基
HOAT: O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基uronium六氟磷酸盐
HOBt: 1-羟基-苯并三唑
HOSu: N-羟基琥珀酰亚胺
Mmt: 4-甲氧三苯甲基
NMP: N-甲基吡咯烷酮
Pbf: 2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基
tBu: 叔丁基
TIS: 三异丙基硅烷
TOS: 甲苯磺酰基
trt 三苯甲基
TFA: 三氟乙酸
TFFH: 四甲基氟formamidinium六氟磷酸盐(tetramethylfluoroformamidinium)hexafluorohosphate)
Z: 苯甲氧羰基
除非有其它明显含义,本文中的氨基酸缩写(例如,Ala)代表-NH-C(R)(R’)-CO-结构,其中R和R’分别各自独立地为氢或者氨基酸侧链(例如,R=CH3,R’=H,代表丙氨酸),或者R和R’可以一起形成环体系。
“烷基”指的是含有一个或多个碳原子的烃基,其中如果有多个碳原子,则多个碳原子之间通过单键相连。烷烃基可以为直链或者包含一个或多个支链或环基。
“取代的烷基”指的是烷基的一个或多个氢原子被一个或多个取代基所取代,其中所述取代基选自卤素(例如,氟、氯、溴、碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、被1至6个卤素取代的-C1-2烷基、-CF3、-OCH3、-OCF3、以及-(CH2)0-4-COOH。在不同的实施方案中,存在1、2、3、或4个取代基。-(CH2)0-4-COOH的存在导致烷基酸的生成。烷基酸的例子包括-(CH2)0-4-COOH或者由其组成,包括2-降莰烷乙酸、叔丁酸、以及3-环戊丙酸。
“杂烷基”指的是烃基的一个或多个碳原子被一个或多个下述基团所取代的烷基:氨基、酰胺基、-O-或者羰基。在不同的实施方案中,存在1个或2个杂原子。
“取代的杂烷基”指的是烃基的一个或多个氢原子被一个或多个取代基所取代的杂烷基,其中所述取代基选自卤素(例如,氟、氯、溴、碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、被1至6个卤素取代的-C1-2烷基、-CF3、-OCH3、-OCF3、以及-(CH2)0-4-COOH。在不同的实施方案中,存在1、2、3、或4个取代基。
“烯基”指的是具有两个或多个碳并且存在一个或多个碳-碳双键的烃基。烯烃基可以为直链或者包含一个或多个支链或环基。
“取代的烯基”指的是烯基的一个或多个氢原子被一个或多个取代基所取代,其中所述取代基选自卤素(例如,氟、氯、溴、碘)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、被1至6个卤素取代的-C1-2烷基、-CF3、-OCH3、-OCF3、以及-(CH2)0-4-COOH。在不同的实施方案中,存在1、2、3、或4个取代基。
“芳基”指的是具有至少一个共轭II电子体系、含有至多2个共轭或者稠合环体系的任意取代的芳基。芳基包括碳芳基、杂芳基以及联芳基。优选地,所述芳基为5或6元环。杂芳基的优选原子为一个或多个硫、氧、和/或氮。芳基的例子包括苯基、1-萘基、2-萘基、吲哚、喹啉、2-咪唑、以及9-蒽等。芳基的取代基选自-C1-4烷基、-C1-4烷氧基、卤素(例如,氟、氯、溴、碘)、-OH、-CN、-SH、-NH2、-NO2、被1至5个卤素取代的-C1-2烷基、-CF3、-OCF3、以及-(CH2)0-4-COOH。在不同的实施方案中,芳基包括0、1、2、3、或4个取代基。
“烷基芳基”指的是“烷基”与“芳基”相连。
当本发明化合物的C-末端存在有非氨基酸的咪唑部分(例如,上面定义的Pim)时,可以理解,所述咪唑部分通过假肽键与相邻的氨基酸相连,在咪唑环的2位碳和氨基酸的α位碳之间形成一个键。例如,当相连的氨基酸是D-色氨酸(D-Trp)而咪唑部分为Pim时,肽的C-末端如下所示:
为了清楚表明,该化合物所标示的结构式中,该键的存在通过单独标于括号中的希腊字母“Ψ”来表示。例如,结构式H-Inp-D-Trp-D-2Nal(Ψ)-Pim表示下述结构:
本发明包括非对映异构体,也包括外消旋体和光学纯单体。胃饥饿素可包含D-氨基酸、L-氨基酸、或其混合物。优选地,存在于胃饥饿素中的氨基酸为L-异构体。
本发明类似物的优选的衍生物包括D-氨基酸、N-烷基-氨基酸、β-氨基酸、和/或一种或多种标记氨基酸(包括D-氨基酸、N-烷基-氨基酸、或β-氨基酸的标记形式)。标记的衍生物表示氨基酸或者氨基酸衍生物用可检测的标记物所改造。可检测的标记物的例子包括发光、酶学、以及放射标记物。标记物的类型以及标记的位置都能影响类似物的活性。标记物以及标记位置的选择实际上应该不改变胃饥饿素类似物在GHS受体中的活性。特定的标记物以及标记位置对胃饥饿素的作用能够通过测定胃饥饿素的活性和/或结合而确定。
在体内环境中,与C-末端羧基共价相连的保护基团降低羧基末端的反应性。羧基末端保护基优选与末端氨基酸的a-羰基相连。优选的羰基末端保护基包括氨基、甲氨基、以及乙氨基。
实施例
下面提供的实施例进一步对本发明的不同特征进行说明。所述实施例也阐述了实施本发明的有用的方法。这些实施例并非用于限制本发明。
合成
本发明的化合物能够利用本文实施例所公开的技术以及本领域公知的技术进行制备。例如,GHRP类似物的多肽区域能够通过化学以及生物化学的方法进行合成及修饰。生物化学合成技术的例子包括将核酸导入细胞并表达该核酸,如下述文献中所述:Ausubel,Current Protocols in Molecular Biology,JohnWiley,1987-1998,and Sambrook et al.,in Molecular Cloning,ALaboratory Manual,2″d Edition,Cold Spring Harbor Laboratory Press,1989。多肽的化学合成技术也是本领域技术人员所公知的(例如,参考Vincent in Peptide and Protein Drug Delivery,New York,N.Y.,Dekker,1990.)。例如,本发明的肽能够通过常规的固相肽合成方法进行制备(See,e.g,Stewart,J.M.,et al.,Solid Phase Synthesis(Pierce Chemical Co.,2d ed.1984)。
上述式(I)的取代基R’可采用本领域公知的常规方法连接于N-末端氨基酸的自由氨基上。例如,诸如(C1-C30)烷基等烷基基团能够采用还原烷基化的方法进行连接。诸如(C1-C30)羟烷基等羟烷基基团也能够采用还原烷基化的方法进行连接,其中自由羟基通过叔丁基酯进行保护。诸如COE1等酰基也可通过将完整树脂与3摩尔当量的游离酸以及二异丙基碳二酰亚胺在二氯甲烷中混合约1小时而将诸如E1COOH等游离酸偶联到N-末端氨基酸而与N-末端游离氨基进行连接。若游离酸含有游离羟基,例如,p-羟基苯丙酸,则应该额外加入3摩尔当量的HOBT进行偶联。
本发明的肽也可以、并且已经利用ACT 396 Multiple BiomolecularSynthesizer(Advanced ChemTech,Louisville,KY),(下文称作“合成器”,″synthesizer″)以平行方式进行合成。该合成器进行下述反应循环:(1)用二甲基甲酰胺(DMF)进行洗涤,(2)用溶于DMF的20%哌啶通过1×5min和1×25min脱去Fmoc保护基团,(3)用DMF洗涤,(4)在室温下,在二异丙基碳二酰亚胺(DIC)和1-羟基苯并三唑(HOBt)的存在下与Fmoc氨基酸偶联1小时,以及(5)重复步骤4。
实施例1-65
每一反应孔含有0.0675mmol的Rink Amide MBHA树脂(取代值=0.72mmol/g,Novabiochem,San Diego,CA)。采用下述的Fmoc氨基酸(Novabiochem,San Diego,CA;Chem-impex International,Wood Dale,IL;SyntheTech,Albany,OR;Pharma Core,High Poiht,NC):Fmoc-Lys(Boc)-OH,Fmoc-Phe-OH,Fmoc-H-Inp-OH,Fmoc-D-1Nal-OH,Fmoc-D-2Nal-OH,Fmoc-D-Trp(Boc)-OH,Fmoc-3Pal-OH,Fmoc-4Pal-OH,Fmoc-Orn(Boc)-OH,Fmoc-D-Bip-OH,Fmoc-Thr(Bzl)-OH,Fmoc-Pff-OH,Fmoc-2Thi-OH,Fmoc-Taz-OH,Frnoc-D-Dip-OH,Fmoc-D-Bpa-OH,Fmoc-D-Bal-OH,以及Fmoc-Apc(Boc)-OH。
将每一种Fmoc氨基酸溶解于0.3N HOBt的DMF溶液中,其中所得Fmoc氨基酸的浓度为0.3N。对每次偶联,使用4倍过量(0.27mmol,0.3N溶液中的0.9mL)的Fmoc氨基酸。每次偶联所用的偶联试剂为DIC(0.27mmol,0.45N溶于DMF的DIC溶液0.6mL)。利用溶于DMF的20%哌啶(每一残基用2×1.5mL)来脱保护。
在室温下用溶于三氟乙酸(TFA)的8%三异丙基硅烷(TIP)(每一反应孔1.5mL)对肽-树脂处理2小时,将肽从树脂上裂解。通过过滤移去树脂。将每一过滤液置于离心管中用25mL的醚溶解。将每管中的沉淀物离心,弃去溶剂。然后将每管中的沉淀物溶解于甲醇(3mL),并用水(1mL)稀释。利用LUNA 5u C8(2)(Phenomenex,Torrance,CA)柱(100×21.20mm,5,u)通过反相HPLC来对粗产物进行纯化。对每一种肽,用85%A和15%B至25%A和75%B的线性梯度对柱洗脱15分钟,流速为25mL/min。A为溶于水的0.1%TFA,B为溶于乙腈/水(80/20,v/v)的0.1%TFA。通过解析HPLC而对片段进行检测,将含有纯产物的部分收集起来进行冻干。
收率在13%至71%的范围内,由解析性HPLC分析得出,实施例1-65中的每一个纯度都超过了94%。进行了电喷雾离子质谱(ES-MS)分析,所观察到的分子量与计算得到的分子量一致。结果如下述表1所示。
实施例66-69
按照下述步骤合成实施例66-69。
1.a.将溶于甲醇(36ml)的BOC-(D)-Trp-OH(4.0g,13.1mmole)(Novabiochem San Diego,Calif.)和溶于水(10ml)的Cs2CO3(2.14g,6.57mmole)混合起来,搅拌混合物直至形成均匀的混合物。真空除去溶剂,将残留物溶解于DMF(45ml)。向溶液中加入溶解于DMF(9ml)的2-溴苯乙酮(2.61g,13.1mmole),所得溶液于室温搅拌30分钟。过滤除去溴化铯,滤出液真空浓缩。所得浓缩液溶解于二甲苯(45ml),加入NH4OAc(17.1g),加热溶液并回流1小时。冷却的溶液用饱和的NaHCO3溶液(45ml)洗涤,然后用饱和的NaCl洗涤。所得有机层通过闪柱色谱进行纯化,得到4.1g(77%)的1A中间产物,如反应路线1A所述(″化合物1A″)。
反应路线1A
1.b.利用三氟乙酸(TFA)(8ml)、二氯甲烷(DCM)(8ml)以及三异丙基硅烷(TIPS)(1.4ml)的混合物将化合物1A(403mg)脱保护。混合1小时后,所得溶液在氮气流下浓缩。残留物溶解于DCM(40ml),用NaHCO3(40ml)饱和溶液洗涤两次,然后用Na2SO4干燥,得到中间体产物1B的溶液,如下述反应路线1B所述。
反应路线1B
1c.-f.将前述的中间体产物1B的溶液分成4等份,与预先活化的FMOC保护的氨基酸的HOBT酯进行偶联,如下述反应路线1C,1D,1E,和1F所述。用于实施例66,67,68和69的各氨基酸如下所述:
实施例66:FMOC-D-2Nal-OH(130mg,0.30mmole)(Synthetech Albany,Oregon)
实施例67:FMOC-D-1Nal-OH(130mg,0.30mmole)(Advanced ChemtechLouisville,KY)
实施例68:FMOC-D-Bal-OH(132mg,0.30mmole)(Chem Impex Wood Dale,IL)
实施例69:FMOC-DSer(Bzl)-OH(124mg.0.30mmole)(ChemImpex Wood Dale,IL)
前述每一氨基酸预先用溶解于DCM(5ml)的HOBT(46mg,0.30mmole)和DIC(38mg,0.30mmole)活化10分钟,然后加入前述中间产物1B溶液的每一份中。然后于室温下进行偶联反应30分钟。
反应路线1C
反应路线1D
反应路线1E
反应路线1F
1.g-j.通过向前述步骤所得的每一反应混合物中加入三(2-氨基乙基)胺(0.9ml)并室温混合30分钟而从所得的每一化合物1C,1D,1E和1F中除去FMOC基团。含有脱保护化合物的反应混合物用10%pH5.5的磷酸盐缓冲液(10ml)洗涤三次。
所得的游离胺溶液与预先活化的FMOC或BOC保护的氨基酸的HOBT酯进行偶联,如下所述:
实施例66:FMOC-Inp-OH(105mg,0.30mmole)(Chem Impex Wood Dale,IL)
实施例67:FMOC-Inp-OH(105mg,0.30mmole)
实施例68:BOC-Inp-OH(68.3mg,0.30mmole)(Bachem Torrance,Calif.
实施例69:BOC-Aib-OH(60.6mg,0.30mmole)(Bachem Torrance,Calif.)
前述每一氨基酸用溶于DCM(5ml)的HOBT(46mg,0.30mmole)和DIC(38mg,0.30mmole)预先活化10分钟,然后加入适当的脱保护胺。接下来在室温下进行偶联反应1小时。
脱保护—化合物66-67。通过加入三(2-氨基乙基)胺(0.9ml)并混合30分钟而从所得的FMOC保护化合物中脱去FMOC基团。将脱保护的化合物用10%的pH5.5的磷酸盐缓冲液(10ml)洗涤3次,收集沉淀,为粗产物。
脱保护—化合物68-69。BOC-保护的化合物通过闪柱色谱纯化,然后用溶于DCM(2.75ml)的TIPS(0.50ml)和TFA(0.50ml)脱保护1小时。所得粗产物浓缩,真空干燥。
通过HPLC纯化使得实施例66和67的化合物分别获得5%和29%的收率,实施例68和69的化合物分别获得15%和43%的收率。
前述的脱保护、偶联、以及脱保护步骤概括于下述反应路线1G,1H,1I以及1J中。
反应路线1G
反应路线1H
反应路线1I
反应路线1J
实施例70:H-lnp-D-Trp-D-2Nal(Ψ)-Pim
化合物70按照下述步骤进行合成。
2.a.1和2.a.2.:按照与化合物1A类似的方法制备化合物2A,利用BOC-D-2Nal-OH和2-溴苯乙酮作为起始原料。
步骤2.a.1.和2.a.2.概括于下述反应路线2A。
反应路线2A
2.b.1.用TFA(2ml)和DCM(2ml)对化合物2A(100mg,0.242mmole)脱保护1小时。在氮气流下除去挥发物,然后残留物溶解于DCM(10ml)。所得溶液用NaHCO3(10ml)饱和溶液洗涤三次,得到游离胺形式的化合物2A的溶液。
2.b.2.FMOC-D-Trp-(BOC)-OH(153mg,0.290mmole)的活性酯制备是用溶于DCM(1.5ml)的N-羟基琥珀酰亚胺(HOSu;33mg,0.290mmole)和DIC(37mg,0.290mmole)进行反应。1小时后通过过滤除去二异丙基脲,滤液中加入化合物2A(游离胺)溶液。所得溶液用DCM稀释至4ml,偶联反应进行30分钟。
步骤2.b.1.和2.b.2.概括于下述反应路线2B中。
反应路线2B
2.c.1.向前述偶联反应溶液中加入三(2-氨基乙基)胺(TAEA)(0.9mol)并于室温下混合30分钟,使化合物2B脱保护。然后用饱和的NaCl溶液(10ml)洗涤反应溶液3次,接下来用10%pH5.5的磷酸盐缓冲液洗涤3次(10ml),得到游离胺形式的化合物2B的溶液。
2.c.2.BOC-Inp-OH(66.5mg,0.290mmole)的活性酯制备是用溶于DCM(1.5ml)的HOSu(33mg,0.290mmole)和DIC(37mg,0.290mmole)进行反应。1小时后通过过滤除去二异丙基脲,滤液加入至化合物2B(游离胺)溶液中。所得溶液用DCM稀释至4ml,偶联反应进行12小时。
然后将反应混合物用10%pH5.5磷酸盐缓冲液洗涤三次,并用Na2SO4干燥。真空下除去溶剂,浓缩物通过闪柱色谱进行纯化。
2.c.3.将中间体用溶于DCM(2.75mol)的TFA(2.75ml)和TIPS(0.5ml)脱保护30分钟。在氮气流下除去挥发物,然后残留物中加醚(15ml)研磨成粉末。离心后,倾去醚,所得固体进行HPLC,得到收率为39%的实施例70化合物。
步骤2.c.1.和2.c.2.概括于下述反应路线2C中。
反应路线2C
本领域技术人员采用与本文所公开的实施方案类似的合成方法及/或前述实施例中所公开的方法也可以制备本发明的其它肽,如表1中所述的化合物。
表1
纯度 分子量 分子量
Ex.No. 序列 (计算) (MS-ES) (%)
1 H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2 787.96 787.4 96
2 H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2 787.96 787.4 99
3 H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2 753.94 753.4 98
4 H-Inp-D-Bip-D-Trp-Phe-Lys-NH2 813.01 812.4 99
5 H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2 831.03 830.4 98
6 H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2 876.92 876.3 98
7 H-Inp-D-2Nal-D-Trp-Thi-Lys-NH2 793.00 792.4 98
8 H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2 793.99 793.4 97
9 H-Inp-D-Dip-D-Trp-Phe-Lys-NH2 813.01 812.4 98
10 H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2 841.02 840.4 95
11 H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2 852.04 851.3 99
12 H-Inp-D-2Nal-D-Trp-3Pal-NH2 659.79 659.3 99
13 H-Inp-D-2Nal-D-Trp-4Pal-NH2 659.79 659.3 98
14 H-Inp-D-1Nal-D-Trp-3Pal-NH2 659.79 659.3 98
15 H-Inp-D-Bip-D-Trp-Phe-NH2 684.84 684.3 99
16 H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2 702.85 702.3 99
17 H-Inp-D-2Nal-D-Trp-Pff-NH2 748.75 748.2 99
18 H-Inp-D-2Nal-D-Trp-2Thi-NH2 664.83 664.2 99
19 H-Inp-D-2Nal-D-Trp-Taz-NH2 665.82 665.3 98
20 H-Inp-D-Dip-D-Trp-Phe-NH2 684.84 684.3 98
21 H-Inp-D-2Nal-D-Dip-Phe-NH2 695.86 695.3 99
22 H-Inp-D-Bal-D-Trp-Phe-NH2 664.83 664.3 97
23 H-Inp-D-2Nal-D-Bal-Phe-NH2 675.85 675.2 99
24 H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2 787.96 787.5 97
25 H-Inp-D-Bal-D-Trp-2Thl-Lys-NH2 799.03 798.4 99
26 H-Inp-D-Bal-D-Trp-Phe-Lys-NH2 793.00 792.4 99
27 H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2 793.00 792.4 99
28 H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2 784.96 784.4 98
29 H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2 784.96 784.4 98
30 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2 790.99 790.4 97
31 H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2 801.99 801.4 98
32 H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2 808.02 807.4 99
33 H-Inp-D-1Nal-D-Trp-2Thi-NH2 664.83 664.2 98
34 H-Apc-D-1Nal-D-Trp-Phe-NH2 673.81 673.3 99
35 H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2 793.99 793.5 99
36 H-Inp-D-Bal-D-Trp-Taz-Lys-NH2 800.02 799.4 99
37 H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2 809.00 808.5 99
38 H-Apc-D-Bal-D-Trp-Taz-Lys-NH2 815.03 814.4 99
39 H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2 814.04 813.4 98
40 H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2 790.99 790.5 97
41 H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2 797.01 796.4 97
42 H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2 806.00 805.5 97
43 H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2 812.03 811.4 98
44 H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2 801.99 801.5 98
45 H-Apc-D-Bal-D-Trp-Phe-Lys-NH2 808.02 807.5 99
46 H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2 799.97 799.5 98
47 H-Apc-D-Bal-D-Trp-Phe-Apc-NH2 806.00 805.5 98
48 H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2 811.00 810.5 95
49 H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2 811.00 810.5 96
50 H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2 813.01 812.5 99
51 H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2 817.02 816.5 96
52 H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2 817.02 816.5 94
53 H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2 819.04 818.5 99
54 H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2 819.04 818.5 98
55 H-Apc-D-1Nal-D-Trp-2Thi-NH2 679.84 679.2 98
56 H-Apc-D-Bal-D-Trp-Phe-NH2 679.84 679.3 99
57 H-Apc-D-1Nal-D-Trp-Taz-NH2 680.83 680.3 99
58 H-Apc-D-Bal-D-Trp-2Thi-NH2 685.87 685.2 97
59 H-Apc-D-Bal-D-Trp-Taz-NH2 686.86 686.2 99
60 H-Apc-D-2Nal-D-Trp-2Thi-NH2 679.84 679.2 95
61 H-Apc-D-2Nal-D-Trp-Taz-NH2 680.83 680.2 97
62 H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2 791.97 791.5 98
63 H-Inp-D-Bal-D-Trp-Taz-Apc-NH2 798.00 797.4 99
64 H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2 806.99 806.5 99
65 H-Apc-D-Bal-D-Trp-Taz-Apc-NH2 813.02 812.4 98
66 H-Inp-D-2Nal-D-Trp(Ψ)-Pim 610.77 611.4 99
67 H-Inp-D-1Nal-D-Trp(Ψ)-Pim 610.77 611.3 99
68 H-Inp-D-Bal-D-Trp(Ψ)-Pim 616.79 617.3 99
69 H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim 564.69 565.3 99
生物学检测
本发明化合物对GHS受体的活性可以通过、并且已经通过下述实施例所描述的技术进行测定。在不同的实施方案中,利用下述的一种或多种功能活性检测发现,胃饥饿素类似物具有至少约50%、至少约60%、至少约70%、至少约80%、或至少约90%的胃饥饿素的功能活性;及/或采用下述的受体结合试验发现其IC50大于约1,000nM、大于约100nM、或大于约50nM。IC50越大意味着需要越小的量就能达到结合抑制作用。
测定化合物与GHS受体结合能力的实验需要GHS受体、含有胃饥饿素结合位点的受体片段、含有该片段的多肽、或者该多肽的衍生物。优选地,所述试验使用GHS受体或其片段。含有能够与胃饥饿素结合的GHS受体片段的多肽也可以含有一个或多个未在GHS受体中发现的多肽区域。这种多肽的衍生物包含能够与胃饥饿素结合的GHS受体片段以及一个或多个非肽成分。
与结合有关的GHS受体氨基酸序列能够利用标记的胃饥饿素或者胃饥饿素的结构或功能类似物以及不同的受体片段来进行鉴别。可使用不同的方法来选择待检测片段从而减少结合区域。这类方法的具体例子包括检测由N-末端起始的长度约15个氨基酸的连续片段,以及检测更长的片段。如果检测更长的片段,则可将结合胃饥饿素的片段细分使之进一步位于胃饥饿素的结合区域。用于结合研究的片段能够采用重组核苷酸技术来生成。
可利用单独的化合物或者含有不同数量化合物的制剂来进行结合试验。能够与GHS受体结合的含有不同数量化合物的制剂可以分为能够通过检测鉴定与GHS受体结合的化合物的更小的化合物组。在本发明的一个实施方案中,在结合试验中使用含有至少10种化合物的受试制剂。
可利用存在于不同环境的通过重组制备的GHS受体来进行结合试验。所述环境包括,例如,含有由重组核苷酸或者天然核苷酸表达的GHS受体多肽的细胞提取物以及纯化的细胞提取物;也可包括,例如,使用由重组方法制备的或者由导入不同环境的天然核苷酸所生成的纯化GHS受体多肽。
GHS受体活性化合物的筛选
GHS受体活性化合物的筛选是通过重组表达受体来完成的。利用重组表达GHS受体提供了几种优点,例如能够在确定的细胞系统中表达受体从而能够更容易区分化合物对GHS受体的反应与对其它受体的反应。例如,可利用通常不用表达载体表达GHS受体的诸如HEK 293、COS 7、以及CHO等细胞系中表达GHS受体,而利用没有表达载体的相同细胞系作为对照。
对降低GHS受体活性的化合物的筛选是通过在试验中使用胃饥饿素功能类似物来进行的。在筛选试验中使用胃饥饿素功能类似物提供了GHS受体活性。受试化合物对该活性的影响可通过鉴别诸如变构调节剂以及拮抗剂等而进行测量。
可利用不同的技术来测量GHS受体的活性,例如,可通过检测GHS受体细胞内构象的变化、G-蛋白偶联活性的变化、和/或细胞内信使的变化等来进行测量。优选采用诸如测定细胞内Ca2+的技术来测量GHS受体活性。本领域公知的可用于测量Ca2+的技术的例子包括使用诸如Fura-2等染料以及使用诸如钙敏感光蛋白(aequorin)等Ca2+-生物发光敏感受体蛋白等。用于钙敏感光蛋白来检测G-蛋白活性的细胞系的一个例子是HEK293/aeq17.(Button eta/.,1993.Cell Calcium 14,663-671,andFeig h ner et aL,1999,Science284,2184-2188.)。
与不同G-蛋白功能性偶联的包含胃饥饿素结合区域的嵌合受体也可用于测量GHS受体的活性。嵌合GHS受体包含N-末端细胞外结构域;由跨膜区域、细胞外环状区域、以及细胞内环状区域组成的跨膜结构域;以及细胞内羧基末端。制备嵌合受体以及测量G-蛋白偶联反应的技术在例如国际申请号WO97/05252以及U.S.专利号5,264,565中都有叙述,这两篇文献引入本文作为参考。
GHS受体活性的刺激
可利用胃饥饿素的结构和/或功能类似物来刺激GHS受体活性。这种刺激可用于,例如,研究GHS受体调节的作用、研究生长激素分泌的作用、寻找或研究胃饥饿素拮抗剂、或者获得对个体有益的作用。可获得的有益作用包括:治疗生长激素不足的状态、增加肌肉块、增加骨质密度、治疗男性或女性的性功能障碍、促进体重增加、维持体重、维持身体机能、促进身体功能的恢复、和/或促进食欲增加等。
促进体重或食欲增加能够用于体重不足的个体或者具有影响体重或食欲的疾病或正在进行治疗的患者,从而维持其体重或者使之增加体重或食欲。另外,例如,也可用于诸如猪、牛、以及鸡等豢养动物使之增加体重。
体重不足的个体包括体重低于“正常”体重范围或者体重指数(″BMI″)的最低值约10%或更低、20%或更低、30%或更低的个体。BMI为个体的身高/体重比率,其是通过计算体重的千克数除以身高(米)的平方而得到的。BMI测定了你的身高/体重比率。其是通过计算体重的千克数除以身高(米)的平方而得到的。人类BMI的“正常”范围通常为19-22。“正常”体重范围对本领域技术人员是公知的,该范围要考虑个体的年龄、身高、以及体型等。
生物学检测-实施例
1.受体结合试验
A.表达人重组GHS受体的CHO-K1细胞的制备
利用人脑RNA作为模板(Clontech,Palo Alto,CA),连有hGHS-R全长编码序列的基因特异性引物(S:5’-ATGTGGAACGCGACGCCCAGCGAAGAG-3’(SEQIDNO:1)和AS:5’-TCATGTATTAATACTAGATTCTGTCCA-3’)(SEQ ID NO:2),使用Advantage 2 PCR试剂盒(Clontech),通过聚合酶链反应(PCR)来克隆人生长激素促分泌素受体(hGHS-R,或者胃饥饿素受体)的cDNA。利用Original TA Cloning试剂盒(Invitrogen,Carlsbad,CA)将PCR产物克隆进pCR2.1载体。将人GHS-R的全长序列亚克隆进入哺乳动物表达载体pcDNA 3.1(Invitrogen)内。利用磷酸钙法(Wigler,M etal.,Cell 11,223,1977)将质粒转染入中国仓鼠卵细胞系CHO-K1(American Type Culture Collection,Rockville,MD)内。通过选择在添加了10%胎牛血清和含有0.8mg/ml G418(Gibco,Grand Island,NY)的1mM丙酮酸钠的RPMI 1640培养基中生长于克隆环的转染细胞而得到稳定表达hGHS-R的单细胞克隆。
B.GHS-R结合试验
用于放射配体结合试验的膜可通过、并且已经通过在20ml冰冷的50mMTris HCI中用Brinkman Poltron(Westbury,NY)(设置6,15秒)匀浆前述的表达人重组GHS受体的CHO-K1细胞的方法而得到。匀浆物通过离心(39,000g/10min)洗涤两次,最终沉淀物重悬于含有2.5mM MgCI2和0.1%BSA的50mM Tris-HCI中。检测时,将等分液(0.4ml)与0.05nM(125I)胃饥饿素(~2000Ci/mmol,Perkin Elmer Life Sciences,Boston,MA)、在0.05ml本发明未标记竞争性受试化合物存在或不存在下一起孵育。孵育(4℃)60分钟后,利用GF/C过滤器(Brandel,Gaithersburg,MD)通过快速过滤来分离结合型(125I)胃饥饿素与游离型,其中所述过滤器预先用0.5%聚乙烯亚胺/0.1%BSA浸透。然后用5ml冰冷的50mM Tris-HCI和0.1%牛血清白蛋白等分液洗涤三次,过滤器捕获的结合型放射活性通过γ光谱测定仪(Wallac LKB,Gaithersburg,MD)进行计数。特异性结合为总的(125I)胃饥饿素减去1000nM胃饥饿素(Bachem,Torrence,CA)存在下的结合数。
2.GHS-R功能活性检测
A.体外受体介导的细胞内iCa2+流动
通过在0.3%EDTA/磷酸盐缓冲液(25℃)中孵育收获前述表达人GSH受体的CHO-K1细胞,然后离心洗涤两次。洗涤后的细胞重悬于Hank’s-缓冲盐溶液(HBSS)中,用于与荧光Ca2+指示剂Fura-AM结合。约106细胞/ml的细胞悬液与2uM的Fura-2AM在约25℃孵育30分钟。以HBBS离心2次除去未结合的Fura-2AM,最终悬液移至装配有磁力搅拌装置和温度调节管架的分光荧光计(Hitachi F-2000)中。平衡至37℃后,加入本发明的化合物,测定细胞内Ca2+的流动。激发和发射波长分别为340和510nm。
B.体内GH释放/抑制
如本领域所公知,可以在体内检测化合物刺激或抑制生长激素(GH)释放的能力(例如,参见,Deghenghi,R.,et al.,Life Sciences 54,1321-1328(1994);国际申请No.WO02/08250.)。因此,例如,为了确定化合物在体内刺激GH释放的能力,可将化合物通过皮下注射到10日龄大鼠的体内,注射剂量例如为300mg/kg。然后可以在例如注射15分钟后测定循环中GH的含量,并与注射溶剂对照大鼠体内的GH水平相比较。
类似地,还可在体内检测化合物拮抗胃饥饿素诱导的GH分泌的能力。对此可将化合物通过皮下注射到10日龄大鼠的体内,注射剂量例如为300mg/kg,并同时注射胃饥饿素。然后可以在例如注射15分钟后测定循环中GH的含量,并与仅注射胃饥饿素大鼠体内的GH水平相比较。
化合物的施用
本发明的化合物可以采用本文提供的指导以及本领域公知的技术进行制剂以及施用。优选的给药途径能够保证有效剂量的化合物到达作用位点。关于药物施用的指南在例如Remington’sPharmaceutical Sciences 18fh Edition,Ed.Gennaro,Mack Publishing,1990,以及Modem Pharmaceutics2ndEdition,Eds.Banker and Rhodes,Marcel Dekker,Inc.,1990中都有说明,上述文献引入本文作为参考。
本发明的化合物可以制备为酸性或碱性盐。药学可接受的盐(为水溶或油溶形式,或者为可分散制品)包括与无机或有机酸或碱形成的常规的无毒盐或者季铵盐。这类盐的例子包括酸加成盐,诸如乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、安息香酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡糖正庚酸盐、甘油磷酸盐、半硫酸盐、正庚酸盐、正己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、以及十一酸盐等;以及铵盐、与诸如钠和钾等形成的碱金属盐、与诸如钙和镁等形成的碱土金属盐、与诸如二环己胺和N-甲基-D-葡萄糖胺等有机碱形成的盐、以及与诸如精氨酸和赖氨酸等氨基酸形成的盐等碱性盐。
本发明的化合物可以采用诸如口腔、鼻内、注射、透皮、以及透粘膜等不同的途径给药。做成悬浮液形式可口服给予的活性成分能够采用本领域公知的药物制剂技术进行制备,并且可包含用于赋形的微晶纤维素、用作悬浮剂的海藻酸或者海藻酸钠、用作增稠剂的甲基纤维素、以及甜味剂/改味剂等。若做成即时释放的片剂,则该组合物可包含微晶纤维素、磷酸氢钙、淀粉、硬脂酸镁、以及乳糖和/或其它赋形剂、结合剂、填充剂、分解剂、稀释剂、以及润滑剂等。
通过鼻腔气溶胶或者吸入给药的剂型可制备为,例如生理盐溶液的形式,其中可添加苯甲醇或其它适宜的防腐剂、增加生物利用度的吸收促进剂、还可添加碳氟化合物、和/或添加其它溶解或分散剂。
本发明的化合物还可通过静脉内(静脉注射(bolus)及输注)、腹膜内、皮下、封闭或不封闭的局部给药、或者肌肉内等方式进行给药。当采用注射给药时,可注射的溶液或悬浮液可利用诸如林格氏液或者等渗氯化钠溶液等适宜的无毒、肠胃外可接受的稀释剂或者溶剂进行制备,或者采用包括诸如合成的一-或二甘油酯的无菌温和的不挥发油、以及诸如油酸等脂肪酸等适宜的分散或润湿以及悬浮剂进行制备。
适宜的给药方法优选考虑本领域公知的因素进行确定,这些因素包括:服药个体的类型;个体的年龄、体重、性别、以及医疗条件;给药途径;个体的肾脏以及肝脏功能;所需疗效;以及所用的特定化合物等。
能够达到产生疗效而不产生毒性的药物浓度的最佳精度需要考虑到药物在靶点利用率的动力学特性而制定具体给药方式。这需要考虑到药物的分布、平衡、以及消除等。预计对个体的每日剂量为0.01至1,000mg/个体/天。
本发明的化合物可制备为试剂盒。这类试剂盒通常包括给药剂型的活性化合物。该剂型包括足够剂量的活性化合物,当药物在一日或多日的疗程内通过常规的时间间隔(例如,每日1至6次)施用至个体内时,可产生所需的疗效。优选地,试剂盒包括说明书,对剂型的使用进行指导,使之产生所需的疗效;并对特定时间范围所需服用的剂型的用量进行指导。
由上已经对本发明进行了示例性描述,可以理解,所用的术语为说明书中词汇的本意而非进行限制。很显然,根据本发明的上述教导可对本发明进行多种修饰以及变化。因此,可以理解,可在所附权利要求书的范围内对本发明进行实施,而并非将本发明囿于特定描述的范围内。
本文所提及的专利以及科学文献皆为本领域技术人员可得到的知识。本文所提及的所有专利、专利出版物、以及其它出版物皆全文引入本文用作参考。
其它实施方案
可以理解,尽管本发明采用了详细的说明书进行描述,但是签署说明书仅欲说明本发明,而非欲对本发明做出限制,本发明的保护范围由所述的权利要求书所界定。本发明的其它方面、优点、以及修饰都在权利要求书的范围内。
序列表
<110>研究及应用科学协会股份有限公司
董正欣
<120>生长激素释放肽
<130>BIO-120.1PCT
<150>60/402,263
<151>2002-08-09
<160>2
<170>Patent In version 3.2
<210>1
<211>27
<212>DNA
<213>人工序列
<220>
<223>用于克隆hGHS-R的基因特异性引物
<400>1
atgtggaacg cgacgcccag cgaagag 27
<210>2
<211>27
<212>DNA
<213>人工序列
<220>
<223>用于克隆hGHS-R的基因特异性引物
<400>2
tcatgtatta atactagatt ctgtcca 27
Claims (40)
1.具有下述式(I)结构的化合物或其药学可接受盐:
R1-A1-A2-A3-A4-A5-R2
(I)
其中:
A1是Aib,Apc或者Inp;
A2是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A3是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A4是2Fua,Orn,2Pal,3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,3Thi,Thr(Bzl);
A5是Apc,Dab,Dap,Lys,Orn,或缺失;
R1是氢,(C1-6)烷基,(C5-14)芳基,(C1-6)烷基(C5-14)芳基,(C3-8)环烷基,或(C2-10)酰基;以及
R2是OH或NH2;
条件是
当A5是Dab,Dap,Lys,或Orn时:
A2是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A3是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A4是2Thi,3Thi,Taz,2Fua,2Pal,3Pal,4Pal,Orn,Thr(Bzl),或Pff;
当A5缺失时:
A3是D-Bip,D-Bpa,或D-Dip;或者
A4是2Fua,Pff,Taz,或Thr(Bzl);或者
A1是Apc并且
A2是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A3是D-Bip,D-Bpa,D-Dip或D-Bal;或者
A4是2Thi,3Thi,Orn,2Pal,3Pal,或4Pal。
2.权利要求1所述的化合物或其药学可接受盐,其中:
A1是Aib,Apc或H-Inp;
A2是D-Bal,D-Bip,D-Bpa,D-Dip,D-1Nal,D-2Nal,D-Ser(Bzl),或D-Trp;
A3是D-Bal,D-Bpa,D-Dip,D-1Nal,D-2Nal,或D-Trp;
A4是Orn,3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,或Thr(Bzl);
A5是Apc,Lys,或缺失。
3.权利要求2所述的化合物或其药学可接受盐,其中:
A1是Apc或H-Inp;
A2是D-Bal,D-Bip,D-1Nal或D-2Nal;
A3是D-Bal,D-1Nal,D-2Nal,或D-Trp;
A4是3Pal,4Pal,Pff,Phe,Pim,Taz,2Thi,或Thr(Bzl)。
4.权利要求1所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-NH2;
H-Inp-D-1Nal-D-Trp-3Pal-NH2;
H-Inp-D-Bip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-Dip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Bal-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-1Nal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1 Nal-Phe Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-NH2;
H-Apc-D-1Nal-D-Trp-2Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-NH2;
H-Apc-D-1Nal-D-Trp-4Pal-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-NH2;
H-Apc-D-2Nal-D-Trp-2Pal-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-NH2;
H-Apc-D-2Nal-D-Trp-4Pal-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-NH2;
H-Apc-D-Bal-D-Bal-2Pal-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Thi-NH2;
H-Apc-D-Bal-D-Bal-3Pal-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-3Thi-NH2;
H-Apc-D-Bal-D-Bal-4Pal-NH2;
H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;
H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;
H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;
H-Apc-D-Bal-D-Bal-Phe-NH2;
H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;
H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Fua-NH2;
H-Apc-D-Bal-D-Trp-2Pal-NH2;
H-Apc-D-Bal-D-Trp-3Pal-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-3Thi-NH2;
H-Apc-D-Bal-D-Trp-4Pal-NH2;
H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Trp-Pff-Lys-NH2;
H-Apc-D-Bal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-NH2;
H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-NH2;
H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Fua-NH2;
H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-NH2;
H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Fua-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;
H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-NH2;
H-Inp-D-Bal-D-Trp-Taz-NH2;
H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Fua-NH2;
H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-NH2;or
H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bip-D-Bal-Taz-NH2;
H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Fua-NH2;
H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bip-D-Trp-Pff-NH2;
H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;或
H-Inp-D-Bip-D-Trp-Taz-NH2;
5.权利要求4所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-Drp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bal-D-Bal-Phe-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bal-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Bal-Phe-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Lys-NH2;
H-Apc-D-Bal-D-Bal-Taz-Lys-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Lys-NH2;
H-Apc-D-Bal-D-Bal-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Phe-Lys-NH2;
H-Inp-D-1Nal-D Bal-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Taz-Lys-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH2;
H-Inp-D-1Nal-D-Bal-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bip-D-Trp-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Trp-Pff-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-3Thi-Lys-NH2;
H-Inp-D-Bip-D-Bal-Taz-Lys-NH2;
H-Inp-D-Bip-D-Bal-2Fua-Lys-NH2;
H-Inp-D-Bip-D-Bal-Pff-Lys-NH2;
H-Apc-D-Bal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Trp-Pff-Apc-NH2;
H-Apc-D-Bal-D-Bal-Phe-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-3Thi-Apc-NH2;
H-Apc-D-Bal-D-Bal-Taz-Apc-NH2;
H-Apc-D-Bal-D-Bal-2Fua-Apc-NH2;
H-Apc-D-Bal-D-Bal-Pff-Apc-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Pff-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Pff-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-NH2;
H-Inp-D-Bal-D-Trp-2Fua-NH2;
H-Inp-D-Bal-D-Trp-Pff-NH2;
H-Apc-D-Bal-D-Trp-3Thi-NH2;
H-Apc-D-Bal-D-Trp-2Fua-NH2;
H-Apc-D-Bal-D-Trp-Pff-NH2;
H-Apc-D-Bal-D-Trp-4Pal-NH2;
H-Apc-D-Bal-D-Trp-3Pal-NH2;
H-Apc-D-Bal-D-Trp-2Pal-NH2;
H-Inp-D-Bal-D-Bal-Taz-NH2;
H-Inp-D-Bal-D-Bal-2Fua-NH2;
H-Inp-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-Phe-NH2;
H-Apc-D-Bal-D-Bal-2Thi-NH2;
H-Apc-D-Bal-D-Bal-3Thi-NH2;
H-Apc-D-Bal-D-Bal-Taz-NH2;
H-Apc-D-Bal-D-Bal-2Fua-NH2;
H-Apc-D-Bal-D-Bal-Pff-NH2;
H-Apc-D-Bal-D-Bal-4Pal-NH2;
H-Apc-D-Bal-D-Bal-3Pal-NH2;
H-Apc-D-Bal-D-Bal-2Pal-NH2;
H-Inp-D-1Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-2Fua-NH2;
H-Inp-D-1Nal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Bal-Taz-NH2;
H-Inp-D-1Nal-D-Bal-2Fua-NH2;
H-Inp-D-1Nal-D-Bal-Pff-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-2Fua-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-1Nal-D-Trp-3Thi-NH2;
H-Apc-D-1Nal-D-Trp-2Fua-NH2;
H-Apc-D-1Nal-D-Trp-Pff-NH2;
H-Apc-D-1Nal-D-Trp-4Pal-NH2;
H-Apc-D-1Nal-D-Trp-3Pal-NH2;
H-Apc-D-1Nal-D-Trp-2Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Thi-NH2;
H-Apc-D-2Nal-D-Trp-2Fua-NH2;
H-Apc-D-2Nal-D-Trp-Pff-NH2;
H-Apc-D-2Nal-D-Trp-4Pal-NH2;
H-Apc-D-2Nal-D-Trp-3Pal-NH2;
H-Apc-D-2Nal-D-Trp-2Pal-NH2;
H-Inp-D-Bip-D-Trp-Taz-NH2;
H-Inp-D-Bip-D-Trp-2Fua-NH2;
H-Inp-D-Bip-D-Trp-Pff-NH2;
H-Inp-D-Bip-D-Bal-Taz-NH2;
H-Inp-D-Bip-D-Bal-2Fua-NH2;或
H-Inp-D-Bip-D-Bal-Pff-NH2;
6.权利要求5所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Dip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Dip-Phe-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-3Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-Bal-Drp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;或
H-Aib-D-Ser(Bzl)-D-Trp(Ψ)-Pim;
7.权利要求6所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2;
H-Inp-D-Bip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-TPhe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2;
H-Inp-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-1Nal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-1Nal-Phe-Lys-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Phe-NH2;
H-Apc-D-1Nal-D-Trp-Taz-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Trp-Taz-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;或
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
8.权利要求7所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-1Nal-D-Trp-3Pal-Lys-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-Bal-D-Tip-Phe-NH2;
H-Apc-D-Bal-D-Trp-2Thi-NH2;
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Inp-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Apc-NH2;
H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;或
9.权利要求8所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-1Nal-D-Trp-Phe-Apc-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-Bal-D-Trp-Phe-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;或
H-Apc-D-2Nal-D-Trp-2Thi-NH2;
10.权利要求9所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
11.权利要求9所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Taz-Lys-NH2;
H-Apc-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D-1Nal-D-Trp-Phe-Apc-NH2;
12.权利要求6所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-DDip-D-Trp-Phe-Lys-NH2;
H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-2Nal-DDip-Phe-NH2;
H-Inp-D-Trp-D-2Nal(Ψ)-Pim
H-Inp-D-2Nal-D-Trp(Ψ)-Pim
H-Inp-D-1Nal-D-Trp(Ψ)-Pim
H-Inp-D-Bal-D-Trp(Ψ)-Pim
H-Aib-DSer(Bzl)-D-Trp(Ψ)-Pim
H-Inp-D-Bal-D-色氨醇;
H-Inp-D-Bal-D-色氨酰苄基醚。
13.权利要求12所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-Pff-Lys-NH2;
H-Inp-DDip-D-Trp-Phe-Lys-NH2;
H-Inp-D-2Nal-D-Trp-Pff-NH2;
H-Inp-D-1Nal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-Trp(Ψ)-Pim;
H-Inp-D-Bal-D-色氨醇;
H-Inp-D-Bal-D-色氨酰苄基醚。
14.权利要求4所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-3Pal-NH2;
H-Inp-D-2Nal-D-Trp-4Pal-NH2;
H-Inp-D-1Nal-D-Trp-3Pal-NH2;
H-Inp-D-Bip-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-2Nal-D-Trp-3Thi-NH2;
H-Inp-D-Dip-D-Trp-Phe-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-2Nal-D-Bal-Phe-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;
H-Apc-D-1Nal-D-Trp-Phe-NH2;
15.权利要求14所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-2Nal-D-Trp-2Thi-NH2;
H-Inp-D-Bal-D-Trp-Phe-NH2;
H-Inp-D-1Nal-D-Trp-2Thi-NH2;或
H-Apc-D-1Nal-D-Trp-Phe-NH2;
16.具有下列结构的化合物或其药学可接受盐:
H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;
H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;
H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;或
H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;
17.确定化合物与GHS受体结合能力的方法,所述方法包括下述步骤:测定化合物影响式(I)所述化合物或者组1,1A,2,2A,2B,2B-1,2B-1a,2B-1b,2B-1c,2B-1d,2B-2,2B-2a,2C,或2C-1中任意一组所述化合物与所述受体、所述受体的片段、包含所述受体片段的多肽、或者所述多肽的衍生物相结合的能力。
18.在个体中产生有益作用的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的化合物或其药学可接受盐的步骤,其中所述有效剂量能在帮助治疗(例如,治愈或减轻严重程度)或者预防(例如,降低发病的可能性或者见效严重程度)一种疾病或者病症中有效产生有益的效果。
19.刺激个体生长激素分泌的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素激动剂或其药学可接受盐,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测增加的剂量,优选为足以在患者中产生有益效果的剂量。
20.权利要求19所述的方法,其中对所述生长激素的分泌进行刺激从而用于治疗生长激素不足的状态、增加肌肉块、增加骨质密度、治疗男性和女性的性功能障碍、促进体重增加、维持体重、维持身体机能、促进身体功能的恢复、和/或促进食欲增加。
21.权利要求20所述的方法,其中所述促进体重增加、维持体重、和/或促进食欲增加用于处于伴随有体重减轻的疾病或病症状态、或进行伴随有体重减轻的治疗的患者。
22.权利要求21所述的方法,其中所述伴随有体重减轻的疾病或病症包括厌食症、贪食症、癌症恶病质、AIDS、AIDS性消耗、癌性消瘦、以及孱弱老年性消耗。
23.权利要求21所述的方法,其中所述伴随有体重减轻的治疗包括化疗、放疗、暂时性和永久性的固定、以及透析。
24.抑制个体生长激素分泌的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素拮抗剂或其药学可接受盐,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测降低的剂量,优选为足以在患者中产生有益效果的剂量。
25.权利要求24所述的方法,其中对所述生长激素的分泌进行抑制从而用于治疗以生长激素过量分泌为特征的疾病或状态、促进体重降低、促进食欲降低、维持体重、治疗肥胖、治疗糖尿病、治疗包括视网膜病变等糖尿病并发症、和/或治疗心血管病症。
26.权利要求25所述的方法,其中超重是下述疾病或状态的诱发因素:高血压、糖尿病、血脂异常、心血管疾病、胆结石、骨关节炎、以及癌症。
27.权利要求26所述的方法,其中所述促进体重降低减少了罹患所述疾病或者状态的可能性。
28.权利要求26所述的方法,其中所述促进体重降低包括对所述疾病或状态的至少部分治疗。
29.在个体内产生胃饥饿素激动剂效果的方法,所述方法包括给予所述个体有效剂量的一种或多种选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素激动剂或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测增加的剂量,优选为足以在患者中产生有益效果的剂量。
30.在个体内产生胃饥饿素拮抗剂效果的方法,所述方法包括给予所述个体有效剂量的一种或多种选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素拮抗剂或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以使生长激素的分泌产生可检测降低的剂量,优选为足以在患者中产生有益效果的剂量。
31.在个体内产生有益的心血管作用的方法,所述方法包括给予所述个体有效剂量的选自式(I)、组1、组1A、组2、组2A、组2B、组2B-1、组2B-1a、组2B-1b、组2B-1c、组2B-1d、组2B-2、组2B-2a、组2C、或组2C-1的胃饥饿素激动剂或其药学可接受盐的步骤,其中所述的有效剂量为至少能足以在所述个体中产生有益效果的剂量。
32.权利要求31的方法,其中所述有益的心血管作用包括抑制心肌细胞、心内皮细胞或者血管内皮细胞的凋亡。
33.权利要求31的方法,其中所述有益的心血管作用包括改善心脏结构或功能。
34.权利要求31的方法,其中所述有益的心血管作用包括降低心脏恶疾的发展。
35.权利要求31的方法,其中所述有益的心血管作用包括降低系统血管阻力。
36.权利要求31的方法,其中所述有益的心血管作用包括增加心脏的输出。
37.权利要求31-36任意一项所述的方法,其中所述个体包括人。
38.权利要求37的方法,其中所述人患有慢性心力衰竭或严重的慢性心力衰竭。
39.权利要求11所述的化合物或其药学可接受盐,其具有下列结构:
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2。
40.权利要求17-23、29、或者31-38任意一项所述的方法,其中所述胃饥饿素激动剂为具有下述结构的化合物或其药学可接受盐:
H-Inp-D-Bal-D-Trp-Phe-Apc-NH2。
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