TWI331922B - Growth hormone releasing peptides - Google Patents
Growth hormone releasing peptides Download PDFInfo
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- TWI331922B TWI331922B TW092121571A TW92121571A TWI331922B TW I331922 B TWI331922 B TW I331922B TW 092121571 A TW092121571 A TW 092121571A TW 92121571 A TW92121571 A TW 92121571A TW I331922 B TWI331922 B TW I331922B
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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
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 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
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 206010048828 underweight Diseases 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000008096 xylene Substances 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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Description
1331922 玖、發明說明:' 【發明所屬之技術領域】 本發明的特色為GHS受體内具活性的肽類似物。本發 明的類似物可與GHS受體結合,並在理想情況下引發訊息 傳遞。 【先前技術】 由腦下垂體somatotrops脈動性分泌的生長激素受到 兩個下視丘神經肽所調節:生長激素分泌素和體制素。生 長激素分泌素促進生長激素的分泌,餿制素則會抑制生長 激素的分泌。(Frohman ei a/., 1986, 7,223-253, and Strobi ei a/., PAarmaco/. 1994,岑6,1-34) o 腦下垂體somatotrops分泌的生長激素也會受到生長 激素分泌肽(GHRP’s )的控制。在包括人類在内的某些物 種中 , 曾發 現一種 六胜肽 (His-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6))會從 somatotrops以劑量相關的方式分泌生長激素。(Bowers ei al.,Endocrinology 1984, 114, 1537-1545)。隨後對於 GHRP-6的化學研究找出其他有效的生長激素促泌素,例如 GHRP-I、GHRP-2 和 hexarelin (海沙瑞林)(Cheng ei α/., 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, USA 1993, 1331922 153-157, and Deghenghi et al.. Life 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; Hexarelin His-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2;· GHRP-I、GHRP_2、GHRP-6 和 hexarelin 都是合成的生 長激素促泌素。GHS促進生長激素分泌的機制和生長激素 分泌素不同。(Bowers ei α/·.五1984, 1537-1545, Cheng et al. 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, USA 1993, 153-157, and Deghenghi et al., Life Sci. 1994, 54, 1321-1328) »
肽基生長激素促泌素的口服生體可用性偏低(<1% ), 促使研究者尋找能夠模擬GHRP-6在腦下垂體活性的非肽 基化合物。報告指出某些benzolactams和spiroindanes可 在多種動物和人類身上促進生長激素的分泌。(Smith ei α/.. Science 1993, 260, 1640-1643, Patchett et al., Proc. Natl. Acad. Sci. USA. 1995, 92, 7001-7005, and Chen et al., Bioorg. Mod. Chem. Lett. 1996, 6, 2163-2169)。一種 λ!、型 spiroindane 4^· PJ A MK-0677 (Patchett et al. Proc. Natl.
Acad. Sci. USA. 1995, 92, 7001-7005 ): 6 1331922
上述GHS (肽及非肽皆然)的活性似乎受到某種特定 的生長激素促泌素受體所調節(GHS受體)(toward α/., Science 1996,275, 974-977, and Pong al> Molecular 幻;1996, 70,57-61) »這種受體存在於多種哺乳 類的腦下垂體和下視丘(GHSRla),與生長激素分泌素 (GHRH)有顯著不同。GHS受體也曾見於中樞神經系統 的其他部位和末梢組織’例如腎上腺和甲狀腺、心臟、肺 臟、腎贜和骨骼肌。(Chen ei a/, B/oorg. Mec/· Ckm. Leii. 1996, 6, 2163-2169, Howard et al, Science 1996,273, 974-977, Pong et al, Molecular Endocrinology 1996, 10, 57-61, Guan et al, Mol. Brain Res. 1997, 48, 23-29, and
McKee ei a/., 1997,426-434)。報告亦指出 GHSRla 有截斷形式。(Howard w a/., 1996,273, 974-977)。 GHS受體是一種G蛋白聯結受醴^ GHS受體活性的效 果包括鉀離子通道的退極與抑制,增加三磷酸肌醇(IP3) 的細胞間濃度,並會暫時增加細胞間鈣質的濃度。(pong W al., Molecular Endocrinology 1996, 10, 57-61, Guan et al., Mol. Brain Res. 1997, 48, 23-29, and McKee et al., 1997,从426-434)。 1331922 格瑞林(Ghelin)是一種天然肽,據信是GHS受體的内 生西體0 (Kojima ei a/.,1999,402,656-660) ° 目前 已知幾種哺乳動物及非哺乳動物中格瑞林的天然結構。 (Kaiya et aL, J. Biol. Chem. 2001, 276, 40441-40448; International Patent Application PCT/JP00/04907 (WO 01/07475))。格瑞林的核心區會提供在GHS受體的活性。 核心區由四個N端胺基酸組成,第三位置的絲胺酸通常會 由η辛酸變更。然而,除了由η辛酸醯基化,天然格瑞林 也可由 η 葵酸酿基化。(Kaiya ei <a/·,·/. jBio/. C/iew. 2001, 276, 40441-40448)。格瑞林類似物具有多種不同療效和作為研 究工具的效用。 【發明内容】 本發明的特色為GHS受體内具活性的肽類似物。本發 明的類似物可與GHS受體結合,並在理想情況下引發訊息 傳遞。 因此’本發明的第一.層面是一個基於以下分子式(I) 的化合物: R^A^A^A^A^A^R2 (I) 或是藥學上可接受之鹽,其中: A1 是 Aib、Ape 或 Inp ; A2 是 D-Ba卜 D-Bip、D-Bpa、D-Dip、D-lNa卜 D-2Nal、 D-Ser(Bzl)或 D-Trp ; 1331922 A3 是 D-Bai、D-Bip、D-Bpa、D-Dip、D - INal、D-2Nal、 D-Ser(Bzl)或 D-Trp ; A4 是 2Fua、Orn、2Pal、3Pal、4Pal、pff、phe ' Pim、
Taz、2TM、3TM、Thr(Bzl); A5 是 Ape、Dab、Dap、Lys、Orn 或刪除; R1 是氫、(Ci-6)烧基、(C5-i4)芳香基、(Cm)烧基、(C5_14) 芳香基、(C3-8)環烷基或(Cm)醯基;及 R2 是 OH 或 NH2 ; 前提為: A5 是 Dab、Dap、Lys 或 Orn,貝1J : A2 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A3 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A4 是 2Thi、3Thi、Taz、2Fua、2Pal、3Pa卜 4Pal、 Orn、Thr(Bzl)或 Pff ; A5刪除後,則: A3 是 D-Bip、D-Bpa 或 D-Dip ;或 A4 是 2Fua、Pff、Taz 或 Thr(Bzl);或 A1是Ape及- A2 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A3 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A4 是 2Thi、3Thi、Orn、2Pa卜 3Pal 或 4Pa卜 稱為第1組化合物的較佳分子式(I)化合物,是基於以 下分子式(I): 1331922 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-lNal-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; Η-Ιηρ-0-ΤΓρ-Ό-2Να1(Ψ)-Ρίιη; H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D -1 Nal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D - INal-D-Trp-Phe-Ape-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; 11 1331922
H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2; H-Apc-D- lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-NH2; H-Apc-D-lNal-D-Trp-Phe-NH2; H-Inp-D-2Nal-D-Trp(Y)-;Pim; H-Inp-D_lNal-D-Trp(V)-Pim; Η-Ιηρ-ϋ-Βα1-ϋ-ΤΓρ(Ψ)-Ρΐηι; H-Aib-D-Ser(Bzl)-D-Trp(T)-Pim; H-Inp-D - lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D - lNal-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 - lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D - lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Apc-D-lNal-D-Trp-2Thi-NH2; 12 H-Apc-D-Bal-D-Trp-Phe-NH2; H-Apc-D -1 Nal-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 - lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D,Trp-Taz-Apc-NH2; H-Apc-D - lNal-D-Trp-Taz-Apc-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;
H-Apc-D - lNal-D-Trp-2Fua-Apc-NH2; H-Apc-D - lNal-D-Trp-2Fua-Lys-NH2; H-Apc-D - lNal-D-Trp-2Fua-NH2; H-Apc-D -1 Nal-D-Trp-2Pal-NH2; Η-Apc-D - lNal-D-Trp-3Pal-NH2; H-Apc-D -1 Nal-D-Trp-3 Thi-Ape-NH2; H-Apc-D - lNal-D-Trp-3Thi-Lys-NH2; H-Apc-D-lNal-D-Trp-3Thi-NH2; H-Apc-D - lNal-D-Trp-4Pal-NH2; H-Apc-D-lNal-D-Trp-Pff-Apc-NH2; H-Apc-D - lNal-D-Trp-Pff-Lys-NH2; H-Apc-D - lNal-D-Trp-Pff-NH2; H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH2; H-Apc-D-2Nal-D-Trp-2Fua-Lys-NH2; 13 1331922 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; 14 1331922 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- lNal-D-Bal-2Fua-Lys-NH2; 15 1331922
H-Inp-D-lNal-D-Bal-2Fua-NH2; H-Inp-D-lNal-D-Bal-2Thi-Lys-NH2; H-Inp-D-lNal-D-Bal-3Thi-Lys-NH2; H-Inp-D- lNal-D-Bal-Pff-Lys-NH2; H-Inp-D-lNal-D-Bal-Pff-NH2; H-Inp-D - lNal-D-Bal-Phe-Lys-NH2; H-Inp-D - lNal-D-Bal-Taz-Lys-NH2; H-Inp-D-lNal-D-Bal-Taz-NH2; H-Inp-D - INal-D-Trp-2Fua-Ape-NH2; H-Inp-D - lNal-D-Trp-2Fua-Lys-NH2; H-Inp-D -IN al-D-Trp-2Fua-NH2; H-Inp-D-lNal-D-Trp-3Thi-Apc-NH2; H-Inp-D - lNal-D-Trp-3Thi-Lys-NH2; H-Inp-D - lNal-D-Trp-Pff-Apc-NH2; H-Inp-D-lNal-D-Trp-Pff-Lys-NH2; H-Inp-D-lNal-D-Trp-Pff-NH2; H-Inp-D -1 Nal-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; 16 1331922 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; 17 1331922 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; 或是藥學上可接受之鹽。
稱為第2A組化合物的較佳第2組化合物,是基於以下 分子式: H-Inp-D - lNal-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; 18 1331922 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-2NalW-Pim; H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D- lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D - lNal-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- lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp(V)-Pim; H-Inp-D -1Να1-0-ΤΓρ(Ψ)-Ρΐπι; Η-Ιηρ-0-Βα1-ϋ-ΤΓρ(Ψ)-Ρΐηι; Η-Αίΐ>-0-36Γ(Βζ1)-0-ΤΓρ(Ψ)-Ρίπι; H-Inp-D - lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H - Apc-D - lNal-D-Trp-Taz-Lys-NH2; 19 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- lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Apc-NH2; H-Apc-D-1 Nal-D-2Nal-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D - lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Apc-D-lNal-D-Trp-2Thi-NH2; H-Apc-D-Bal-D-Trp-Phe-NH2; H-Apc-D - lNal-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- lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D - INal-D-Trp-Taz-Ape-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2; H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH2; 1331922 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-lNal-D-Trp-3Thi-Lys-NH2; H-Inp-D- lNal-D-Trp-2Fua-Lys-NH2; H-Inp-D-lNal-D-Trp-Pff-Lys-NH2; 21 1331922
H-Inp-D-lNal-D-Bal-Phe-Lys-NH2; H-Inp-D- lNal-D-Bal-2Thi-Lys-NH2; H-Inp-D - lNal-D-Bal-3Thi-Lys-NH2; H-Inp-D - lNal-D-Bal-Taz-Lys-NH2; H-Inp-D -lNal-D-Bal-2Fua-Lys-NH2; H-Inp-D -lNal-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 -1 Nal-D-Trp-3Thi-Apc-NH2; H-Inp-D -1 Nal-D-Trp-2Fua-Apc-NH2; H-Inp-D -1 Nal-D-Trp-Pff-Apc-NH2; H-Apc-D -1 Nal-D-Trp-3Thi-Lys-NH2; H-Apc-D- lNal-D-Trp-2Fua-Lys-NH2; H-Apc-D -1 Nal-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; 22 1331922 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- lNal-D-Trp-3Thi-Apc-NH2; H-Apc-D- lNal-D-Trp-2Fua-Apc-NH2; H-Apc-D-lNal-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; 23 1331922 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- lNal-D-Trp-Taz-NH2; H-Inp-D- lNal-D-Trp-2Fua-NH2; 24
H-Inp-D -1 Nal-D-Trp-Pff-NH2; H-Inp-D - lNal-D-Bal-Taz-NH2; H-Inp-D-lNal-D-Bal-2Fua-NH2; H-Inp-D-lNal-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 - lNal-D-Trp-3Thi-NH2; H-Apc-D - lNal-D-Trp-2Fua-NH2; H-Apc-D-lNal-D-Trp-Pff-NH2; H-Apc-D-lNal-D-Trp-4Pal-NH2; H-Apc-D-lNal-D-Trp-3Pal-NH2; H-Apc-D-lNal-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 25 1331922 H-Inp-D-Bip-D-Bal-Pff-NH2; 或是藥學上可接受之鹽。 稱為第2B組化合物的較佳第2A組化合物,是基於以 下分子式: H-Inp-D- lNal-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-1Να1-ϋ-ΤΓρ(Ψ)-Ρΐπι; H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2; H-Inp-D-2Nal-D-Trp-Pff-NH2; H-Inp-D-2Nal-D-Trp(Y)_Pim; Η-Ιηρ-ϋ-ΤΓρ-ϋ-2Να1(Ψ)-Ρίιη; 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; 26 1331922 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 - lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Inp-D-1 Nal-D-Trp-2Thi-Lys-NH2; H-Inp-D-1 Nal-D-Trp-Taz-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D -1 Nal-D-Trp-Taz-Ape-NH2; H-Inp-D -1 Nal-D-Trp-Phe-Apc-NH2; H-Apc-D-1 Nal-D-Trp-2Thi-Lys-NH2; H-Apc-D-1 Nal-D-Trp-Taz-Lys-NH2; H-Apc-D-lNal-D-lNal-Phe-Lys-NH2; H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2; H-Apc-D-Bal-D-Trp-P he-Ape-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D-Bal-D-lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D -1 Nal-D-Trp-Taz-Apc-NH2; H-Apc-D - lNal-D-Trp-Phe-Apc-NH2; 27 1331922 H-Apc-D- INal-D- lNal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp(?)-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 - INal-D-Trp-2Thi-NH2; H-Apc-D - INal-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(T)-Pim; 或是藥學上可接受之鹽。 是基於 稱為第2B-1組化合物的較佳第2B組化合物, 以下分子式: H-Inp-D-lNal-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; 28 H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D - lNal-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-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D - lNal-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 - lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D- lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Apc-D-lNal-D-Trp-2Thi-NH2; 29 1331922 H-Apc-D-Bal-D-Trp-Phe-NH2; H-Apc-D- lNal-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 -1 Nal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -1 Nal-D-Trp-Taz-Apc-NH2;或 H-Apc-D-Bal-D-Trp-Taz-Apc-NH2; 或是藥學上可接受之鹽。 稱為第2B-la組化合物的較佳第2B-1組化合物,是基 於以下分子式:
H-Inp-D-lNal-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-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D -lNal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2; 30 1331922 H-Apc-D- lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D-1 Nal-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 -1 Nal-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-lNal-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 - lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -1 Nal-D-Trp-Taz-Apc-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;或 或是藥學上可接受之鹽。 稱為第2B-lb組化合物的更佳第2B-1組化合物,是基 於以下分子式: 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; 31 1331922 H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D -1 Nal-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-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2;
H-Apc-D - lNal-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-lNal-D-Trp-Phe-Apc-NH2;或 H-Apc-D-2Nal-D-Trp-2Thi-NH2; 或是藥學上可接受之鹽。 是基 稱為第2B-lc組化合物的更佳第2B-1組化合物 於以下分子式: H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Apc-D -1 Nal-D-Trp-Taz-Lys-NH2; 或是藥學上可接受之鹽。 特佳的第2B-lc組化合物是基於以下分子式: H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; 或是藥學上可接受之鹽。 32 1331922 稱為第2B-ld組化合物的另一個更佳第2B-1組化合 物*是基於以下分子式: H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; Η-Apc-D-1 Nal-D-Trp-Taz-Lys-NH2; H-Apc-D-Bal-D-Trp-Taz-Lys-NH2; Η-Apc-D - lNal-D-Trp-Phe-Apc-NH2;或 或是藥學上可接受之鹽。
稱為第2B-2組化合物的另一個較佳第2B組化合物, 是基於以下分子式: 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(W)-Pim; H-Inp-D-2Nal-D-Trp(T)-Pim; Η-Ιηρ-ϋ-1ΝΕ-ϋ-ΤΓρ(Ψ)-Ρίιη; Η-Ιηρ-ϋ-Βα1-ϋ-ΤΓρ(Ψ)-Ρΐιη;或 H-Aib-D-SeKBzU-D-TrpC^IO-Pim; 或是藥學上可接受之鹽。 稱為第2B-2a組化合物的較佳第2B-2組化合物,是基 於以下分子式: 33 1331922 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; Η-Ιηρ-0-1Να-ϋ-ΤΓρ(Ψ)-Ρΐιη;或 H-Inp-D-Bal-D-Trp(V)-Pim; 或是藥學上可接受之鹽。 稱為第2C組化合物的另一個較佳第2組化合物,是基 於以下分子式:
H-Inp-D-2Nal-D-Trp-3Pal-NH2; H-Inp-D-2Nal-D-Trp-4Pal-NH2; H-Inp-D-1 Nal-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-lNal-D-Trp-2Thi-NH2;或 H-Apc-D - lNal-D-Trp-Phe-NH2; 或是藥學上可接受之鹽。 稱為第2C-1組化合物的較佳第2C組化合物,是基於 以下分子式: H-Inp-D-2Nal-D-Trp-2Thi-NH2; H-Inp-D-Bal-D-Trp-Phe-NH2; 34 1331922 H-Inp-D-lNal-D-Trp-2Thi-NH2;或 H-Apc-D-lNal-D-Trp-Phe-NH2; 或是藥學上可接受之鹽。 稱為第3組化合物的特佳發明化合物,是基於以下分 子式: H-Inp-D-lNal-D-Trp-2Thi-Apc-NH2; H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Apc-NH2; H_Apc-D-Bal-D-Trp-2Thi-Apc-NH2;或 H-Apc-D-lNal-D-Trp-Phe-Lys-NH2; 或是藥學上可接受之鹽。 本發明的另一層面是確定化合物與GHS受體結合的方 法。該方法會測量化合物影響一種基於分子式⑴或1A、2、 2A、2B、2B-卜 2B-la、2B-lb、2B-lc、2B-ld、2B-2、2B-2a、 2C或2C-1組的化合物與該受體、該受體的片斷、包含該 受體片斷的多肽或該多肽衍生物結合的能力。 本發明的另一層面是使受試對象獲得有利效果的方 法。該方法會對受試對象投予一種基於分子式(1)、丨、1A、 2、2A、2B、2B_1、2B-la、2B-lb、2B-1C、2B-ld、2B-2、 2B-2a、2C或2C-1組的化合物或藥學上可接受之鹽的有效 劑量,該有效劑量可以有效產生有利效果以協助治療(例 如根治或減輕嚴重性)或預防(減少發生機率或嚴重性) 一種疾病或失調。 本發明的另一層面是對有需要的受試對象促進生長激 35 丄叫922 素的分泌。該方法會對受試對象投予一種基於分子式(1)、 lA 2、2A、2B、2B-1、2B-la、2B-lb、2B-lc、2B-ld、 _ 、2B-2a、2C或2C-1組的格瑞林類似物或藥學上可接 之鹽的有效劑量,該有效劑量至少足以使生長激素的分 、、達成可察覺的增加,而且其量最好足以對患者產生有利 的效果》 ▲在前述層面的一個實施例中,促進生長機素分泌適用 t治療生長激素的缺乏狀態、增加肌肉、增加骨骼密度、 療性機能障礙的男女、促進體重增加、促進維持體重、 促進維持身體機能、促進身體機能恢復’ & (或)增進食 愁°促進體重增加、保持體重,丨(或)促進食懲最適用 於患有某種伴有體重減輕的疾病或失調,或是接受-項伴 有體重減輕之治療的患者1有體重減輕的疾病或失調包 括厭食症、暴食症、癌症惡病質、愛滋病(如損耗)、惡病 質和虛弱老人的損耗。伴有體重減輕的治療包括化學治 療放射線治療、暫時或永久的固定不動,以及透析。 本發明的另-層面是對有需要的受試對象壓抑生長激 =的分泌。該方法會對受試對象投予一種基於分子式(1)、 2 2A、2B、2B-1 ' 2B-la、2B-lb、2B-lc、2B-ld、 成2 2B-2a、2C或2C-1組的格瑞林類似物或藥學上可接 又之鹽的有效劑量’該有效劑量至少足以使生長激素的分 泌達成可察覺的減少,而且其量最好足以對患者產生有利 的效果。 在前述層面的—個實施例中’壓抑生長激素的分泌適 36 1331922 用於…療生長激素分泌過多的疾病或失調、促進體 輕、促進食料低、促進維持體重、治療過胖治療糖展 病、冶療糖尿病的併發症如視網膜病變等,及(或 心jk管失調。 ' 在前述層面的一個較佳實施例中,體重過重是造成高 壓糖尿病、血脂異常、心血管疾病、膽結石、骨關節 炎和癌症等疾病或病症的原因之…理想上促進體重減^ 會減少這些疾病和病症發生的機率。而且促進體重減輕至 少應是治療這些疾病或病症的一部分。 促使受試對象引發格瑞林類似物效果的方法一 β 對受試對象投予一種或多種基於分子……八、;疋 2A、2B、2B-1、2B-la、2B_lb、2B_lc、2B_ld、2Β·2、23七、 2C或2C-1組的格瑞林類似物或藥學上可接受之鹽的有效 劑量,該有效劑量至少《以使生長激素的分泌達成可察覺 的增加,而且其量最好足以對患者產生有利的效果。 本發明的另—個層面是使受試對象引發格瑞林结抗劑 的效果。該方法會對受試對象投予—種或多種基於分子式 (I)、1、1A、2、2A、2B、2Β·1、2B-la、2B-lb、2B-lc、 2B-ld、2B-2、2B-2a、2C或2C-1組的格瑞林拮抗劑或藥 學上可接受之鹽的有效劑量,該有效劑量至少足以使生長 激素的分泌達成可察覺的減少,而且其量最好足以對患者 產生有利的效果。 本發明的化合物在GHS受體中具有活性。化合物可以 與受體結合,理想上能促進受體的活性。因此本發明的化 37 合物在作為研究工具及(或)治療劑方面都具有格瑞林類 似物的功效。 研究工具的應用-般是在GHS受體或片斷存在的情況 下使用發明的化合物。GHS受趙可存在於不同的環境例 如哺乳類受試對象、整個細胞或細胞膜片冑。研究工具的 應用範例包括薛檢GHS受體中有活性的化合物、判斷二個 樣本或製劑是M GHS受體,以及檢驗格瑞林的作用或效 果。 本發明的一個層面是篩檢格瑞林類似物及(或)格瑞 林拮抗劑的個方法。篩檢格瑞林類似物的方法之一是使 用一種基於分子式⑴、卜 2B-lb、2B-1C、2B.ld、2B-2、2B-2a、2C 或 2C-1 組的化 。物或藥學上可接受之鹽,與試驗化合物進行競爭實驗。 篩檢格瑞林拮抗劑的方法之一則是使用一種基於分子式 (I)、1、1A、2、2A、2B、2B-1、2B-la、2B-lb、2B-1C、 2B'ld、2Β·2、2B-2a、2C或2C-1組的化合物或藥學上可 接受之鹽,產生GHS受體的活性,然後測量試驗化合物 改變GHS受體活性的能力。 本發明另一個層面是篩檢一種能與GHS受體結合之 化合物的方法。該方法會測量試驗化合物影響一種基於分 子式(I)、卜 1A、2、2A、2B、2B-卜 2B-la、2B-lb、2B-1C、 2B'ld、2B-2、2B-2a、2C或2C-1組的化合物或藥學上可 接受之鹽與受體、包含格瑞林結合部位的受體另斷、包含 該受趙片斷的肽或該肽衍生物結合的能力。 38 1331922 格瑞林類似物可對受試對象造成有利效果。例如,格 瑞林會以劑量相關的方式使腦下垂體細胞初代培養分泌生 長激素’但不會引發其他腦下垂體荷爾蒙的分泌。若對麻 醉的老鼠靜脈注射格瑞林,會促進生長激素的脈動性分 泌。(Kojima ei “/.. Waiwre 1999, 402, 656-660)。因此有關 此種有利效果的部分清單如下:治療生長激素的缺乏狀 態、增加肌肉、增加骨骼密度、治療性機能障礙的男女、 促進體重增加、促進維持體重、促進維持身體機能、促進 身體機能恢復,及(或)增進食慾。促進體重增加、保持 體重,或促進食慾對於患有某種伴有體重減輕的疾病或失 調,或疋接受一項伴有體重減輕之治療的患者特別有用。 伴有體重減輕的疾病或失調包括厭食症、暴食症、癌症惡 病質、愛滋病(如損耗)、惡病質和虛弱老人的損耗等。伴 有體重減輕的治療包括化學治療、放射線治療、暫時或永 久的固定不動’以及透析等。 因此本發明的另一層面是在受試對象獲得有利效果的 方法。該方法是對受試對象投予一種或多種基於分子式 (I)、1、1A、2、2A、2B、2B-1、2B_la、2B-lb、2B-lc、 2B_ld' 2B_2、2B_2a、2C或2C-1組的化合物或藥學上可 接受之鹽的有效劑量,而該有效劑量可以有效產生有利效 果以協助療(例如根治或減輕嚴重性)或預肖(減少發 生機率或嚴重性)一種疾病或失調。 在前述方法的一個較佳實施例中,有利效果是指對有 需要的又試對象促進生長激素分泌的方法。該方法是對受 39 1331922 試對象投予一種或多種基於分子式⑴、i、ia、2、2a、 2B、2B-1、2B-la、2B-lb、2B-lc、2B-ld、2B-2、2B-2a、 2C或2C-1組的化合物或藥學上可接受之鹽的有效劑量, 該有效劑量至少足以使生長激素的分泌達成可察覺的增 加,而且其量最好足以對病人產生有利的效果。 在前述方法的一個更佳實施例令,促進生長機素分泌 適用於治療生長激素的不足狀態、增加肌肉、增加骨骼密 度、治療性機能障礙的男女、促進體重增加、促進保持體 重、促進維持身體機能、促進身體機能恢復,及(或)增 進食慾。 在前述方法的另一個較佳實施例中,促進體重增加、 保持體H (或)促進食㈣用於患有某種伴有體重減 輕的疾病或失調,或是接受一項伴有體重減輕之治療的患 者。伴有體重減輕的疾病或失調包括厭食症、暴食症、癌 症惡病質、愛滋病(如損耗)、惡病質和虛弱老人的損耗。 ▲在前述方法的另更佳實施射,伴有體重減輕的 A療包括化學治療、放射線治療 '暫時或永久的固 以及透析。 格瑞林拮抗劑也可以對受試對象造成有利效果。4 如,格瑞林拮抗劑可用來促進體重減輕、促 ^維持體重、治療過胖、治療糖尿病、治療料病咸= t如視網膜病變等,及(或)治療心血管失調。體重& 疋造成高血壓、糖尿病、血脂異常、心血管疾病、膽名 石、骨關節炎和癌症等疾病或病症的原因之—。體重減聋 40 ’也可作為治療此類疾 可以用來減少ϋ些疾病的發生機率 病的一部分。 發明的化合物也可以拮抗格瑞林在試管内和活體内的 因此本發明的另一層面是對有需要的受試對象抑制 生長激素分泌的方法。該方法會對受㈣象投予—種或多 種基於分子式⑴、卜1A、2、2A、2B、2B小2B-la'2B-lb、 2B-U、2B_ld、2B_2、2B_2a、% 或 2c i 組的化合物或藥 干上可接受之鹽的有效劑量,該有效劑量至少足以使生長 激素的分泌達成可察覺的減少,而且其量最好足以對病人 產生有利的效果》 在前述方法的一個較佳實施例令,壓抑生長激素分泌 適用於治療生長激素分泌過多的疾病或失調、促進體重減 輕、促進食慾減低、促進維持體重、治療過胖、治療糖尿 病、治療糖尿病的併發症如視網膜病變等,及(或)治療 心血管失調。 在前述方法的一個更佳實施例中,體重過重是造成高 如壓、糖尿病、血_脂異常、心血管疾病、膽結石、骨關節 炎和癌症等疾病或病症的原因之一。 前述方法的另一個較佳實施例中,促進體重減輕會降 低此類疾病或病症的發生機率,且(或)促進體重減輕至 少是治療此類疾病或病症的一部分。 專業人員亦知道,格瑞林和類似物也可以用來達成良 妤的心血管效果。(Nagaya,et al” Regul Pept. 2003 Jul 15:114(2-3).71-77)°舉例而言’已知格瑞林在試管内會 1331922 抑制心肌細胞和内皮細胞的凋零,重複投予格瑞林會改善 -心臟結構和功能’並使心贜衰竭的老鼠減缓心因性惡病質 · 的惡化,而且格瑞林會減少心臟衰竭人類患者的全身血管 阻力並增加心輸出量。(Id.)因此已知格瑞林和格瑞林類似 物對於嚴重慢性心臟衰竭者具有潛在的療效。 在每一種使用格瑞林類似物之方法的一個特佳實施例 中’格瑞林類似物是基於以下分子式的化合物: H-Inp-D-Bal-D-Trp-Phe-Apc-NH2 ; 或是藥學上可接受之鹽。 _ 化合物或本發明的化合物可以投予受試對象^「受試對 象」疋指哺乳或非哺乳動物,包括但不限於人類、老鼠、 小鼠或農場動物。提到受試對象時並不一定意指該對象患 :疾病或失調。因&「受試對象」一詞亦涵蓋在實驗中接 受格瑞林類似物劑量的哺乳動物或非哺乳動物、接受治療 以減輕-種疾病或失調的哺乳或非哺乳動物,以及接受預 :治療以減緩或預防疾病或失調發生的哺乳或非哺乳 a 發明的其他特性和優點可見於本文的其他說明。 =同的範例在^此處提供的範㈣述實施本發明的多 用成分和方法’並不限制主張專利的發明。專業人員 β以根據目前的說明,找出 成分和方法。 #出並使用實施本發明的其他有用 除非另有指明 鏡像異構物中提供 ,否則具有對掌中心的胺基酸會在L型 *「衍生物」是指改良胺基酸,例如相應 42 1331922 的D型胺基酸、N_烷基-胺基酸、力型胺基酸或是標記胺基 酸0 【實施方式】 本發明是具有GHS受體活性的肽類似物。人類的格瑞 林是一個具有28個胺基酸的修飾肽,其中絲胺酸的一個烴 被 η-辛酸 6旨 ^(匕 ° ( Kojima ei a/.· iVaiwre 1999,莩02, 656-660, 及 Kojima, (Abstract), Third International Symposium on Growth Hormone Secretagogues, Keystone, Colorado, USA 2000, February 17-19)。 本發明化合物中的某些胺基酸表示如下: A3c 1-胺基-1-環丙烷羧酸 A4c 1-胺基-1-環丁烷羧酸 A5c 1-胺基-1-環戊烷羧酸 A6c 1-胺基-1-環己烷羧酸
Abu α-胺基丁酸
Acc 1-胺基-1-環(C3-C9)烷基羧酸
Act 4 -胺基-4-叛基四氮β比喃,亦即: Ο
Aib α-胺基異丁酸
Ala或Α丙胺酸 Ala β·丙胺酸 43 01331922
Ape 胺基吡啶羧酸,亦即:
Arg或R是精胺酸, hArg是高精胺酸,
Asn或N是天冬醯胺酸, Asp或D是天冬胺酸, .ς
Bal 3-苯并噻吩基丙胺酸,亦即
Bip 4,4’-聯苯基丙胺酸,亦即:
Bpa 4-苯醯基苯基丙胺酸,亦即
Cha β-環己基丙胺酸;
Cys或C是半胱胺酸;
Dab 2,4-二胺基丁酸,(α,γ-二胺基丁酸); 44 1331922
Dap 2,3-二胺基丙酸,(α,β-二胺基丙酸);
Dip β,β-二苯基丙胺酸,亦即:
Dhp 3,4-脫氫脯胺酸
Dmt 5,5-二甲基四氫噻唑-4-羧基酸
2Fua β-(2-呋喃基)-丙胺酸,亦即: ;
Gin或Q是麵胺酿胺 Glu或E是麩胺酸 Gly或G是甘胺酸 His或Η是織胺酸 3Hyp 是反式-3-羥基-L-脯胺酸,亦即(2S,3S)-3-羥 基四氫》比洛-2-緩酸; 4Hyp 是4-經基脯胺酸,亦即(2S,4R)-4-經基四氫0比 咯-2-羧酸; lie或I是異白胺酸 Inc是吲噪-2-叛酸
Inp 是異呱啶酸,亦即:
Ktp 是4-酮脯胺酸 1331922
Leu或L是白胺酸 hLeu是高白胺酸
Lys或K是離胺酸
Met或Μ是曱硫胺酸 INal fl-(l-Naphthyl)丙胺酸: 2Nal fl-(2-Naphthyl)丙胺酸;
Nle 是正白胺酸
Nva 是正纈胺酸
Oic 是八羥基吲哚-2-羧酸
Orn 是鳥胺酸 2Pal β-(2-吡啶基)-丙胺酸,亦即
3Pal β-(3-吡啶基)-丙胺酸,亦即:
4Pal β-(4-吡啶基)-丙胺酸,亦即:
46 1331922
Pff 五氟苯基丙胺酸,亦即
Phe或F是苯基丙胺酸 hPhe 人苯基丙胺酸
Pim 2'-(4-苯基)咪唑基,亦即: Pip是c瓜唆酸,
Pro或P是脯胺酸,
Ser或S是絲胺酸,
Taz是β-(4-噻唑基)丙胺酸,
2Thi是β-(2-噻吩基)丙胺酸,亦即
3Thi是β-(3-噻吩基)丙胺酸,亦即:
Thr或Τ是蘇胺酸,
47 1331922
Thz是四氫售唑-4-羧酸,
Tic是1,2,3,4-四氫異喹啉-3-羧酸,
Tie是支鏈一白胺酸,
Trp或W是色胺酸,
Tyr或Y是酪胺酸,並且 Val或V是纈胺酸。 這裏所用的某些其他縮寫定義如下:
Boc是2;# — 丁基氧幾基,
Bzl是苯曱基, DCM是二氯甲烷, DIC是N,N-二異丙基碳化二亞胺, DIEA是二異丙基乙胺,
Dmab是4-{N-(卜(4,4-二甲基-2,6-二氧環亞己基)-3-甲基丁基)-胺基}苯甲基, DMAP是4-(二甲基胺基)嘧啶, DMF是二曱基曱醯胺, DNP是2,4-二硝基苯基,
Fmoc是芴基曱基氧叛基, HBTU是2-(1Η-笨并三唑-l-yl)-l,l,3,3-四曱基脲陽離 子六氟磷酸鹽, cHex是環己基, HOAt是0-(7-氮雜苯并三唑-l-yl)-l,l,3,3-四甲基脲 陽離子六氟磷酸鹽, HOBt是1-羥基-苯并三唑, 1331922
Mmt是4-甲氧三苯曱游基, NM是N-甲基吡咯烷酮,
Pbf是2,2,4,6,7-五甲基二經基笨并呋喃_5確酿, tBu是支鍵一丁基,
Tis是二異丙基梦炫!, TOS是甲苯磺醯基, trt是三苯甲游基, TFA是三氟乙酸, TFFH疋四曱基服陽離子六氣鱗酸鹽,並且 Z是苯甲氧羰基。 除非另有指明’此處的胺基酸縮寫(例如Ala )代表結 構為-NH-C(R)(R')-CO- ’其中R和R’分別為一個胺基酸 的氫或側鍵(例如,R=Ala的CH3,R’=Ala的Η),或r 和R’可以連成一個環狀系統。 「焼•基」是指包含一個或多個碳原子的烴基團,其中 若有多個碳原子,可以由單鍵連接。院基的烴基團可以是 直鏈或包含一個或幾個側鏈或環狀基團。 「取代烷基」是指一個烷基中的一個或多個氫原子被 一個或多個包括自素(亦即氟、氣、溴、蛾)、-OH、-CN、 -SH、-NH2、-NHCH3、·Ν02,以及被 1 至 6 個鹵素、-CF3、 -OCH3、-OCF3 和-(CH2)〇.4-COOH 取代的-Ci.2 烷基在内的 基團所替代。不同的實施例中會有I、2、3或4個取代物。 -(CH2)〇.4-COOH的出現會產生烷酸。包含-(CH2)〇-4-COOH 或由其組成的烷酸,包括2-雙羧醯胺醋酸、三丁酸和3-環 1331922 戊丙酸在内。 「雜烷基」是指烷基的烴基團中一個或多個碳原子被 一個或多個以下基團取代:胺基(amino )、醯胺基(amido )、 或羰基。不同的實施例中會有1或2個異原子。 取代雜烷基」是指一個異烷基之烴基團中的一個或 多個氫原子被一個或多個鹵素(亦即氟、氯、溴、碘)、〇H、 -CN、-SH、-NH2、-NHCH3、-N〇2 以及被 1 至 6 個齒素、 -CF3、-〇CH3、-OCF3 和-((:Η2ν4·(:ΟΟΗ 取代的-Cu 烷
基所替代。不同的實施例中會有1、2、3或4個取代物。 「烯基」是指由兩個或以上的碳原子構成的烴基團, 其中存在一個或多個破-碳雙鍵。烯基的烴基團可以是直鏈 或包含一個或多個支鏈或環狀基團。 「取代烯基」是指一個烯基的一個或多個氫原子被一 個或多個包括鹵素(亦即氟、氣、溴、碘)、_〇H、_cn, -SH、-NH2、-NHCH3、_N〇2,以及被 i 至 6 個自素、_cf3
-〇CH3、-〇CF3和-(CH2WC00H取代的c 2烷基在户 的基團所替代。*同的實施财存會有丨、2、3或4個耳 代物。 〇 〜1回畀有共軛τ電子體系的環 隨意取代的芳香族基圈’包含最多2個共輛或 艘系。芳香基包括碳環形芳香基、異環形芳香基和雙芳^ 基基團。最好,芳香基是一個5至 6疋環。對於異環笔棄 基而言,較佳的異原子是一個或 、衣方香 多個硫、氧和(或)翁 芳香基的範例包括笨、1_萘基、2_ 佘丞 '吲哚 '喹啉、2· 50 1331922 咪唑和9·蒽。芳香基的取代物是取自包括-Cw烷基、-Cw 烷氡基、鹵素(亦即氟、氣、溴、碘)、-OH、-CN、-SH、 -NH2、-N02 以及被 1 至 5個_ 素、_cf3、_〇cf3 和 -(CH2)〇_4-COOH取代的-C^.2烧基的基團。在不同的實施例 中’芳香基包含〇、1、2、3或4個取代物。 「烧芳香基」是指一個「烧基」與一個「芳香基」於 合。 如果一個非胺基酸咪唑部分(例如前述的pim)在本
發明一個化合物的C末端,即 鍵連結在鄰近的胺基酸上,其 位碳原子與胺基酸的α碳原子 胺基酸是D-色胺酸(D-Trp), 0末端將如下所示: 表不咪唑部分透過一個假肽 中一個鍵是由咪唑環的第2 所形成。例如,如果鄰近的 而嗦嗅環是pim,則該肽的
中’這個鍵本 ’書寫分子式 為了清楚說明,在此類化合物的書寫分子式 身會以括弧中的希臘字母Γψ」纟示。例二 代表以下結構 51 1331922
本發明包括對映立體異構體以及消旋和立體對映性溶 解的純形式。格瑞林類似物可以包含D型胺基酸,l型胺 基酸或它們的結合體。理想上,格瑞林類似物中的胺基酸 以L型對映物為佳。 本發明類似物的較佳衍生物包含D型胺基酸、N-院基 胺基酸、卢胺基酸’和(或)一個或多個標記胺基酸(包 括D型胺基酸、N-烷基胺基酸、冷胺基酸的標記形式 > 標 記衍生物表示一個具有可探測標記的胺基酸或胺基酸衍生 物之變化。可探測標記的範例包括發冷光、酶和放射性的 標記。標記物的類型和位置會影響類似物的活性。標記物 的選擇和定位應不至於實質上改變格瑞林類似物在GHS聋 體的活性。特定標記物的效應及其在格瑞林活性的位置可 以透過測量格瑞林的活性和(或)結合來確定。 在體内環境中,一個保護性基團與C末端的羧基共價 結合以減少羧基末端的反應性。羧基末端的保護性基團最 好能與最後一個胺基酸的α羧基連結。較佳的羧基末端保 護性基團包括氣化物、曱胺和乙胺。 52 1331922 實例 以下提供的範例將進一步闞明本發明的不同特色,也 會闡述運用本發明的方法。這些範例並不限制本申請專利 範圍。 合成 本發明的化合物可以透過使用在範例中所述的技術和 專業中廣為人知的技術來生產。例如,GHRP類似物的一 個多肽區可以透過化學或生化的方法合成與修飾。生化合 成技術的範例包括將核酸引入細胞以及核酸的表達,可見 於 Ausubel,Cwrrewi /Voioco/s k Mo/ecw/ar Βζ·ο/〇π, John Wiley, 1987-1998 與 Sambrook ei a/。in M〇/ecw/ar
Cloning, A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press, 1989。化學合成多肽的技術在專 業中也是廣為人知。(例見Vincent in尸epizWe /Voie/n
DrwgDWzveAxNewYorl^N.YMDekkeLBQO)。例如,本發 明的肽可以使用標準的固相肽合成法來製備。(例見 Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984))。 在上述分子式(i)中的取代物R1可以透過專業中已 知的標準方法連接到N末端胺基酸的游離胺基上。例如, 烷基團(如(Ci-Cw)烷)可以透過還原的烷基化作用而連 接。羥基烷基團(如(Ci-Cw)羥基炫)也可以透過還原的烷 基化作用而連接,其中的游離羥基困受到一個卜丁基酯所 保護。醯基團如COE1可以透過偶聯游離鲮(如e1C〇〇h) 53 1331922 結合於N末端胺基酸的游離胺基,方法是將完成樹脂與3 克分子濃度當量的游離酸和二氣甲燒中的二異丙基碳化二 亞胺混合大約一小時。如果該游離酸包含一個游離經基(如 經苯基丙酸),則亦應與HOBT另外3克分子當量進行偶聯。 本發明的肽也可以在ACT396多重生物分子合成器以 並行方式合成(Advanced ChemTech,肯塔基州路易斯維爾) (「合成器」),並已有先例可循,如下所述。該反應器設定 執行以下反應週期:(1)用二甲基甲酿胺(DMF )洗蘇,(2 ) 用20%狐咬DMF液分別進行1X5分鐘和 IX 25分鐘以 除去Fmoc保護基團,(3 )用DMF洗滌,(4)在室溫及二 異丙基破化二亞胺(DIC)和1-經基笨丙三嗤(HOBt)參 與下與Fmoc胺基酸偶聯1小時,(5)重複步驟4。 實例1-65 每一個反應井都包含0.0675mmol的 Rink Amide MBHA 樹脂(取代物=0.72mmol/g,Novabiochem,加州聖 地牙哥)。以下的Fmoc胺基酸(Novabiochem,加州聖地 牙哥;Chem-Impex International » 伊利諾州 Wood Dale ; SyntheTech,奥瑞岡州 Albany ; Pharma Core,北卡羅來 納州 High Point )被用於:Fmoc-Lys(Boc)-OH、 Fmoc-Phe-OH 、 Fmoc-H-Inp-OH 、 Fmoc-D-INal-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 、 54 1331922
Fmoc-Taz-OH 、 Fmoc-D-Dip-OH 、 Fmoc-D-Bpa-OH 、 Fmoc-D-Bal-OH 和 Fmoc-Apc(Boc)-OH。 每一種Fmoc胺基酸溶解於0.3N之HOBt的DMF溶液 中,其中Fmoc胺基酸的終濃度為0.3N。每次偶聯均使用 超過 4 倍(0.27 mmol,0.9 mL0.3 N 溶液)的 Fmoc 胺基 酸。DIC ( 0.27 mmol,0.6 mL 之 0.45 N DIC 的 DMF 溶 液)作為每次偶聯的偶聯試劑。使用20%呱啶DMF液去保 護(2 X 1.5 mL每殘基)。 在室溫下將肽樹脂與8%三異丙基矽烷(TIP)的三氟 乙酸(TFA)溶液(1.5 mL每反應井)反應2小時,使樹 脂從肽分離。從過溏清除樹脂。每次濾液在乙喊參與下於 離心管内稀釋至25mL’每個試管的沈殿物經離心管離心, 傾析溶劑’分離沈殿物。每個試管中的沈殿物以甲醇溶解 (3mL),並以水稀釋(lmL)。透過一個LUNA 5μ C8(2) 柱(100 X 21.20 mm,5μ)的反相預備Hplc方法純化粗產 品(Phenomenex,加州Torrance )。對每一種肽,層析柱以
25 mL/分鐘的流速從85% A與15% B至25% A與75% B 的線性梯度沖提15分鐘。A是〇· 1 % TFA的水溶液,B是 0.1 TFA的乙腈/水溶液(80/20,v/v )。分館部分透過分 析性HPLC檢驗,包含純淨產品的部分匯整後凍乾。 產率範圍為13%至71%,實例丨_65每種產物的純度以 分析性HPLC分析後均超過94%。使用電子喷霧離子化質 譜測量法(ES-MS)分析’觀察的分子重量符合適當的分子重 量。詳細結果詳列於以下表格i。 55 1331922 實例66-69 實例66-69根據以下步驟合成β l.a. 溶於甲醇(36ml)的 B〇c_(D)_Trp_〇H (4 〇g 13.1mm〇le) ( Novabiochem,加州聖地牙哥)和溶於水 (10ml)的 Cs2C03 (2.14g’ 6.57mmole)結合,攪拌混 合物,直至均勻混合。在真空中除去溶劑,殘渣溶解於DMF (45ml)。將溶解於DMF(9ml)的2-溴苯乙酮(2.61g, 13.1mm〇le)加入溶液,室溫下攪拌3〇分鐘。透過過濾除 去溴化絶’將過濾液在真空中濃縮。將獲得的濃縮物溶解 於二甲苯(45ml),加入NH4OAc ( 17.1g),將溶液在逆流 中加熱1小時。冷卻的溶液以飽和的NaHC03溶液(45ml) 洗滌2次,再以飽和的NaCl溶液洗滌。使用閃光色譜法純 化獲得的有機層’獲得4. lg ( 77%)的中間產物1A,如 下面流程1A所示 (「化合物 1A」)。
流裎 1A
lb.使用三氟乙酸(TFA) ( 8ml)、二氣甲烷化合物(DCM) (8ml)和三異丙基矽烷(TIPS )( 1.4ml)的混合物將化合 物1A ( 403mg ) 去阻滯。混合一小時後,將溶液在IL氣 氣流下濃縮。殘餘物溶解於DCM ( 40ml)’用飽和NaHCCh 56 1331922 (40ml)洗滌2次,然後在Na2S04上乾燥,以獲得中間 產物1B,如下面流程1B所示:
流程1B
lc.-f. 前述中間產物1B的溶液被分成4個同等部分,與 FMOC被保護的胺基酸和預活化狀態的HOBT形成酯偶 聯,如下面反應流程1C、ID、1E和1F總結所示。用於實 例66、67、68、69的胺基酸如下所示: -實例 66 : FMOC-D-2Nal-OH ( 130mg,0.30mmole ) (Synthetech,奥瑞岡州 Albany)
實例 67 : FMOC-D-lNal-OH ( 130mg,0.30mmole ) (Advanced Chemtech,肯塔基州路易斯維爾) -實例 68 : FMOC-D-Bal-OH ( 132mg,0.30mmole) ( Chem
Impex,伊利諾州 Wood Dale ) -實例 69 : FMOC-DSer(Bzl)-OH ( 124mg,0.30mmole) (Chem Impex,伊利諾州 Wood Dale ) 將每一種前述的胺基酸與溶解於DCM (5ml)的HOBT (46mg,0.30mmole )和 DIC ( 38mg,0.30mmole )混合 10分鐘,使之處與預活化狀態,然後加至前述中間產物IB 的四個部分之一中,在室溫下進行偶聯反應30分鐘。 57 1331922
流程1C
FM0C-D2Nal-0H/ HOBT/ DIC/ DCM
1B
1C
流裎 ID
流程IE
1B
1E 58 1331922
流裎IF
l.g-j. 在前一步驟得到的反應混合物中分別加入三(2-胺基乙烷)胺(0.9ml)並在室溫下混合30分鐘,從每種 得到的化合物1C、ID、1E和1F中除去FMOC基團。然後 將包含去阻滯化合物的反應混合物用1〇%ΡΗ5.5的磷酸緩 衝液(10ml)洗滌3次。 由此獲得的游離胺基溶液與FMOC預活化的HOBT酯 或BOC被保護胺基酸形成的酯偶聯,如下所示: -實例 66 : FMOC-Inp-OH ( 105mg,0.30mmole ) ( Chem Impex,伊利諾州 WoodDale) -實例 67 : FMOC-Inp-OH ( 105mg,0.30mmole) -實例 68 : BOC-Inp-OH( 68.3mg,0.30mmole )( Bachem, 加州 Torrance ) -實例 69 : BOC-Aib-OH( 60.6mg,0.30mmole )( Bachem, 加州 Torrance ) 將每一種前述的胺基酸與溶解於DCM (5ml)的 HOBT (46mg,0.30mmole)和 DIC (38mg,0.30mmole)混合 10 分 鐘,使之處與預活化狀態,然後加至適當的去保護胺基中, 59 1331922 在室溫下進行偶聯反應丨小時。 去保護-化合物66-67。在獲得的fm〇C-保護性化合物 中加入—(2•胺基乙烷)胺(0.9ml)並混合30分鐘以除去 FMOC基團。用1〇0/〇pH5 5的碟酸緩衝液(i〇mi)洗務去 阻滯化合物3 :欠’並收集粗產品作為沈澱物。 去保護-化合物68-69。透過閃光色譜法純化B〇c_保護 性化合物,然後用溶解於DCM(2.75ml)的TIps(〇 5〇mi)、
TFA(〇.5Gml)去阻滯1小時。然後將粗產品濃縮並在真空 中乾燥》 $ 通過純化,實例 29%,實例68和69的產率分別達到15%和43%。 以下的反應流程1G、1H、II和u總結了前 偶聯和去保護步驟。 °
流鋥 1G
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流裎1H
流裎II
實例 70 : Η-Ιηρ-0-ΤΓρ-ϋ-2Ν&1(Ψ)_Ρίπι 化合物70是基於以下過程所合成。 2.a.l和2.a.2.:化合物2Α是以和化合物1Α類似的方 61 1331922
流程2B
2_c.l· 在前述的偶聯反應溶液中加入三(2-胺基乙 烧)胺(TAEA) ( 0.9ml ) ’並在室溫下混合30分鐘以使化 合物2B去阻滞。然後用飽和NAC1溶液(i〇mi)洗滌反應 溶液3次’再用i〇%ph 5.5的碗酸緩衝液(i〇ml)洗蘇3 次’得到游離胺基形式的化合物2B溶液。 2.C.2. 由 BOC-Inp-OH ( 66..5mg,〇.290mmole )和溶 解於DCM ( 1.5ml)的N-經基琥珀酿亞胺(h〇Su; 33mg, 〇.290mm〇le)及 DIC ( 37mg,0.290mm〇le)預先形成活性 SI。經過1小時過濾’除去二異丙基脲,將濾液加入到化 合物2B (游離胺基)溶液中。得到的溶液以DCM稀釋到 4ml,然後進行偶聯反應12小時。 然後將反應混合物用10%ΡΗ 5.5的填酸緩衝液(l〇mi) 洗蘇3次’在NajO4上乾燥。在真空中除去溶劑,用閃光 色譜法純化濃縮物。 2.C.3. 將中間產物用溶解於DCM ( 2.75ml)的TFA (2.75ml)和TIPS (0.5ml)去阻滯30分鐘。在氮氣氣流 中從反應混合物除去揮發物將殘餘物用乙鍵(15 ml )搗 碎。離心後傾析乙醚,得到的固體經過HPLC,獲得產率為 39%的純淨化合物70。 63 1331922 以下流程2C中總結了步驟2.C.I.、2.C.2.和2.C.3.。
流程 2C
本發明的其他肽可由具有一般專業技能者使用與上述 一般性方法和(或)前述實例特別闡述之方法類似的合成 過程製備,如表格1中所列之化合物: 表1 實例 序號 庠列 分子量 (Calc.) 分子量 iMS-ES) 純度 (%) 1 H-Inp-D- lNal-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-Om-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 64 H-Inp-D-Bpa-D-Trp-Phe-Lys-NH2 841.02 840.4 H-Inp-D-2Nal-D-Bpa-Phe-Lys-NH2 852.04 851.3 H-Inp-D-2Nal-D-Trp-3Pal-NH2 659.79 659.3 H-Inp-D-2Nal-D-Trp-4Pal-NH2 659.79 659.3 H-Inp-D- lNal-D-Trp-3Pal-NH2 659.79 659.3 H-Inp-D-Bip-D-Trp-Phe-NH2 684.84 684.3 H-Inp-D-2Nal-D-Trp-Thr(Bzl)-NH2 702.85 702.3 H-Inp-D-2Nal-D-Trp-PfF-NH2 748.75 748.2 H-Inp-D-2Nal-D-Trp-2Thi-NH2 664.83 664.2 H-Inp-D-2Nal-D-Trp-Taz-NH2 665.82 665.3 H-Inp-D-Dip-D-Trp-Phe-NH2 684.84 684.3 H-Inp-D-2Nal-D-Dip-Phe-NH2 695.86 695.3 H-Inp-D-Bal-D-Trp-Phe-NH2 664.83 664.3 H-Inp-D-2Nal-D-Bal-Phe-NH2 675.85 675.2 H-Inp-D-2Nal-D-Trp-3Pal-Lys-NH2 787.96 787.5 H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2 799.03 798.4 H-Inp-D-Bal-D-Trp-Phe-Lys-NH2 793.00 792.4 H-Inp-D- lNal-D-Trp-2Thi-Lys-NH2 793.00 792.4 H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2 784.96 784.4 H-Inp-D- lNal-D-Trp-Phe-Apc-NH2 784.96 784.4 H-Inp-D-Bal-D-Trp-Phe-Apc-NH2 790.99 790.4 H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2 801.99 801.4 H-Apc-D- lNal-D-Trp-2Thi-Lys-NH2 808.02 807.4 H-Inp-D- lNal-D-Trp-2Thi-NH2 664.83 664.2 65 H-Apc-D- lNal-D-Trp-Phe-NH2 673.81 673.3 H-Inp-D-lNal-D-Trp-Taz-Lys-NH2 793.99 793.5 H-Inp-D-Bal-D-Trp-Taz-Lys-NH2 800.02 799.4 H-Apc-D-1 Nal-D-Trp-Taz-Lys-NH2 809.00 808.5 H-Apc-D-Bal-D-Trp-Taz-Lys-NH2 815.03 814.4 H-Apc-D-Bal-D-Trp-2Thi-Lys-NH2 814.04 813.4 H-Inp-D- lNal-D-Trp-2Thi-Apc-NH2 790.99 790.5 H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2 797.01 796.4 H-Apc-D- lNal-D-Trp-2Thi-Apc-NH2 806.00 805.5 H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2 812.03 811.4 H-Apc-D-1 Nal-D-Trp-Phe-Lys-NH2 801.99 801.5 H-Apc-D-Bal-D-Trp-Phe-Lys-NH2 808.02 807.5 H-Apc-D- lNal-D-Trp-Phe-Apc-NH2 799.97 799.5 H-Apc-D-Bal-D-Trp-Phe-Apc-NH2 806.00 805.5 H-Apc-D- INal-D- lNal-Phe-Apc-NH2 811.00 810.5 H-Apc-D- lNal-D-2Nal-Phe-Apc-NH2 811.00 810.5 H-Apc-D- INal-D- lNal-Phe-Lys-NH2 813.01 812.5 H-Apc-D-Bal-D- lNal-Phe-Apc-NH2 817.02 816.5 H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2 817.02 816.5 H-Apc-D-Bal-D- lNal-Phe-Lys-NH2 819.04 818.5 H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2 819.04 818.5 H-Apc-D-lNal-D-Trp-2Thi-NH2 679.84 679.2 H-Apc-D-Bal-D-Trp-Phe-NH2 679.84 679.3 H-Apc-D-1 Nal-D-Trp-Taz-NH2 680.83 680.3 66 1331922 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- lNal-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- lNal-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(^-Pim 610.77 611.4 99 67 H-Inp-D-lNal-D-Trp〇i〇-Pim 610.77 611.3 99 68 H-Inp-D-Bal-D-TrpW-Pim 616.79 617.3 99 69 Η-ΑΛ-0-86Γ(Βζ1)-0-Τιρ(Ψ)-Ρϊιη 564.69 565.3 99 70 H-Inp-D-Trp-D-2Nal(^-Pim 610.77 611.4 99
生物學測定 本發明化合物在GHS受體的活性可以運用以下範例所 述的技術予以確定,而且已有前例可循。在不同的實施例 中,使用以下所述的一個或多個格瑞林e功能活性測定法, 格瑞林類似物對格瑞林有至少約50%、至少約60%、至少 約70%、至少約80%,或至少約90%的功能活性;使用下 述的受體結合測定法,其IC50大於約ΙΟΟΟηΜ、大於約 ΙΟΟηΜ,或大於約50nM。IC50的數值較大表示效力較大, 因此需要較少份量就足以抑制結合。 測量一種化合物與GHS受體結合能力的測定會用到一 67 1331922 種GHS受體、包含格瑞林結合位點的受體片斷、包含該片 斷的多肽’或是該多肽的衍生物。該測定法最好使用㈣ 受體或包含格瑞林結合位點的受體片斷。包含能結合格瑞 林之GHS受體片斷的多肽也可以含有一個或多個咖受 體不具備的多肽區。此種多肽衍生物包含能結合格瑞林的 GHS受體片斷以及一個或多個非肽部分。 使用標記的格瑞林或格瑞林結冑或功㈣似物以及不 同的受體片斷’可以輕易識別GHS受體上有關結合的胺基 酸順序。可運用不同的策略來選擇測試的片斷,以縮小結# 合區的範圍。此類策略的範例包括測定自N末端起連續約 15個胺基酸長度的片斷,以及測定更長的胺基酸片斷。如 要測定更長的片斷,可以進一步細分一個格瑞林結合片 斷以便進步確疋格瑞林結合區。用於結合區研究所需 的片斷可由重組核酸技術獲得。 結合測定可以使用單一化合物或包含不同數量化合物 的製劑。製劑若具有多種可與GHS受體結合的化合物,可 以分成更小的組別’以鑒別能與GHS受體結合的化合物。鲁 在本發明的一個實施例中,一項結合測定中使用了 一個至 少包含10種化合物的試驗製劑。 結合測定可以使用各種環境下中重組產生的GHS受趙 多肽。舉例來說’這種環境包括從重組核酸或天然存在的 核酸中榨出包含GHS受體多肽的細胞提取物或經純化的細 胞提取物;同樣也包括使用透過重組手段或從被引入一個 不同環境的天然存在核酸生產出的純化GHS受體多狀。 68 山 1922 GHS受體活性化合物的篩檢 使用重组表達的受體,可以促進GHS受體活性化合物 的篩檢。使用重組表達的GHS受體有一些優點,例如能在 一個特定的細胞系統中表達受體,因此對於GHS受體化合 物的反應更容易從對其他受體的反應中予以辨識。例如Y GHS受體可以在一般不會以表達載體來表達受體的細胞系 做表達,例如HEK293、COS 7和CH0,而同一個沒有表 達載體的細胞系可以作為對照組。 在測定中使用格瑞林功能類似物,可以促進篩檢減低 GHS受體活性的化合物。在篩檢測定中使用格瑞林功能類 似物可提供GHS受體活性❶測量受試化合物在活性上的效 應’可識別變構調節劑和拮抗劑等。 GHS受體活性可以透過不同的技術測量,例如探測在 GHS受體的細胞内構造、G蛋白偶聯的活動,和(或)細 胞内信使中的變化。最好以測量細胞内Ca2+的技術來測量 GHS受體活性。專業中測量Ca2+的普遍技術包括使用染 料,如FurA-2和Ca2'生物發光敏感性報告蛋白(如鈣敏 感光蛋白)。使用鈣敏感光蛋白測量G蛋白活性之細胞系的 個例子走 HEK293/Aeqi7。( Button ei a/.,1993. Ce// Ca/c’ww 14,663-671,和 Feighner w β/·,1999, 284, 2184-2188)〇 包含一個格瑞林結合區的嵌合受體,在功能上與一個 不同的G蛋白偶聯,也可以用來測量ghs受體活性。嵌合 69 1331922 的GHS受體包含一個N末端的胞外結構域;一個由跨膜區 組成的跨膜結構域;細胞外環狀區;以及細胞内環狀區和 一個細胞内的羧基末端。產生嵌合受體和測量G蛋白偶聯 反應的技術可見於國際申請號碼W0 97/05252和美國專利 號碼5,264,565,在此一併提及作為參考。 GHS受體活性的刺激
Grehlin的結構或功能性類似物可以用來刺激GHs受 體的活性。舉例來說,這種刺激可用來研究GHS受體調節鲁 效應、研究生長激素分泌的效應、尋找或研究格瑞林拮抗 劑、或對受試對象逹成有利的效果。可達成的一個或多個 有利效果如下:治療生長激素缺乏狀態、增加肌肉體積、 增加骨骼密度、治療性機能障礙的男女、促進體重增加、 促進體重維持、促進身體機能維持、促進身趙機能恢復, 及(或)增進食欲。 對於體重不足的受試冑象或患有會影響體重和食欲的 疾病或接受會影響體重和食欲之治療的患者,增加體重或_ 增進食欲有助於維持趙重、增加趙重或促進食欲。還有\ 比如對豬牛和雞等農場動物進行治療以增加體重。 體重不足的受試對象包括體重比正常體重範圍或身體 質量係數(「BMI」)的低限還輕1()%或以下、游。或以 下,或30%或以下。BMI測量受試對象的身高/體重比 值’以公斤表示的體重除以公尺表示的身高的平方值。BMI 測量您的身高/體重比值,以公斤表示的趙重除以公尺表 70 1331922 不的身南的平方僧。人缸「 類正常J的BMI範圍介於19-22。 「正的體重範圍在專 寻系T來所周知,會受到一個受試 對象的年齡、身高和體型等因素所影響。 定法—章上}_ 1 · 受體結合測定
A.製備表達人類重組GHS受體的ch〇 ki細胞 人類生長激素促泌素受體(HGHS R,或格瑞林受體) 的圖A卩人腦#RNA作冑本,透過聚合酶鍵反應(pcR) (Clontech,加州Pal〇 AU〇 ),基因特異引子位於hGHS R 全長的編碼序列之側(s: 5· _ A T G T G g A A c G C G A C GCCCAGCGAAGAG-3' ^ AS:5'-TCATGTAT TAATACTAGATTCTGTCCA 3,);以及透過 Advantage 2 PCR 試劑盒(Clontech )複製得出。使用 〇rigin ΤΑ克隆試劑盒將PCR產物複製入pcR2」載體 (Invitrogen,加州Carisbad )。全長的人類GHS R被亞複 製入哺乳動物的表達載體PCDNA3.! (Invitr〇gen)。將質粒 透過磷酸鈣法(Wigler,M et al.,Cell 11,223,1977)轉染 中國倉鼠的卵巢細胞系CH0-K1 ( American Type Cuiture
Collection, Rockville,MD)。在 RPMI 1640 培養基中補充 10%胎牛血清和ImM含有0.8mg/ml G418的丙酮酸鈉, 透過選擇在複製環内生長的轉染細胞,而得到持續表達 hGHS-R的單細胞複製(Gibco ’紐約州Grand Island )。 B. GHS-R結合測定: 用於放射配體結合研究的膜可以前述的CHO-K1細胞 71 1331922 均質化作用製備,並已有前例可循,該種細胞在20ml濃度 ‘ 為 50mM 帶有 Brinkman Polytron (紐約州 Westbury)的冰 . 冷Tris-HCl中(放置6’ 15秒)表達人類重組ghs受體。 組織勻漿透過離心(39000克/10分鐘)洗滌2次,將獲 得的片狀沈積物再次放入含有2.5mM MgCl2和0.1% BSA 的50mM Tris-HCl重新懸浮。為了進行測定,在等量(〇 4 ml)的 0·05ηΜ( I)格瑞林(〜2000 Ci/mmol,Perkin Elmer Life Sciences ’麻省波士頓)中加入或不加入本發明未標記 的0.05 ml競爭性測試成分進行孵育。在4。^下孵育60分鲁 鐘後’透過預先用0.5%聚乙烯亞胺/0.1 〇/0 BSA浸泡過的 GF/C過濾器(Brande卜馬里蘭Gaithersburg)快速過濾, 使結合的(1251)格瑞林與游離基分離。然後用等量的5ml冰 冷50mM Tris-HCl和0.1 %牛血清蛋白清洗過濾器三次’並 用伽馬光譜測定法(Wallac LKB,馬里蘭Gaithersburg )計 數濾器上捕獲的結合型放射活性。特異性結合的定義是總 結合的(1251)格瑞林量減去在l〇〇〇nM格瑞林(Bachem, 鲁 加州Torrence)存在時結合的量。 2 . GHS-R功能活性測定 A ·體外GSH受體介導的細胞内iCa2+流通 上述表達人類GSH受體的CHO-K1細胞是透過在0.3% EDTA/填酸緩衝鈉鹽中(25。c )孵育並離心洗脫兩次後而 得。將洗脫後的細胞在Hank,s緩衝鈉鹽(HBSS)重新懸 浮’以載入帶有螢光的Ca2+指示劑Fura-2AM。在大約25。C 下將大約106個細胞/毫升的細胞懸浮液在2 μΜ 72 1331922
Fura-2AM中孵育30分鐘。透過在HBBS中離心兩次除去 未載入Fura-2AM的細胞’再將最終懸浮液轉移到配有磁攪 拌機制和溫度調節比色杯的螢光分光光度計(Hitachi F-2000)中。在37°C下達成平衡後,加入本發明的化合物 進行細胞内Ca2+流通的測定。其激發和發射波長分別為340 和 510 nm。 B ·體内GH分泌/抑制 專業人員熟知,化合物在體内促進或抑制生長激素 (GH)分泌的能力可以被測定。(例見Deghenghi,R.,et al., Life Sciences 54, 1321-1328 (1994); International Application No. WO 02/08250 )。因此,若想測定一種化合 物在體内促進GH分泌的能力,可在1〇天大的老鼠中皮下 注射一定量(如300毫克/公斤)的該化合物。例如在注 射15分鐘後,可以測定循環中的gh含量,並與注射溶劑 之對照老鼠的GH含量相比較。 同理,也可以測定化合物在體内拮抗誘導格瑞林之Gjj 分泌的能力。例如,可以將該化合物例按300毫克/公斤 的劑量與格瑞林同時注入1〇天大的老鼠皮下。在注射15 分鐘後測定循環中的GH含量,並與只注射格瑞林之老鼠 的GH含量進行比較。 本發明的化合物可以按照此處提供的指引和衆所周知 的技術調’並對受試對象給藥。最佳的給藥途徑能保證足 量的化合物達到乾目標…般的給藥指引在及謂邮… 73 1331922
Pharmaceutical Sciences 18th Edition, Ed. Gennaro, Mack
Publishing, 1990 和 MWew P/jarwacewncTi 2nd 五价/⑽,Eds.
Banker 和 Rhodes,Marcel Dekker,Inc.,1990 等書中有描 述,兩本書一併在此提及作為參考。 本發明的化合物可以按酸性或鹼性鹽來製備。藥學上 可接受之鹽(水溶或脂溶或分散的產品)包括從無機鹽到 有機的酸或鹼形成的傳統無毒性鹽或四銨鹽。此種鹽類包 括酸性鹽,例如乙酸鹽、已二酸鹽、海藻酸鹽、天冬胺酸 鹽、安息香酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸 _ 鹽、樟腦化合物、樟腦磺酸鹽、環戊基丙酸鹽、雙葡糖酸 鹽、十二基硫酸鹽、乙烯磺酸鹽、延胡索酸鹽、葡庚酸鹽、 甘油磷酸鹽、硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸 鹽、碘氫酸鹽、2-羥基乙烷磺酸鹽、乳酸鹽、馬來酸鹽、 甲磺酸、2-萘磺酸鹽、煙酸鹽、草酸鹽、雙羥萘酸鹽、果 膠酸鹽、過二硫酸鹽、3-苯丙酸鹽、苦味酸鹽、三曱其乙 酸鹽、丙酸鹽琥珀酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸 鹽和十一酸鹽;銨鹽等鹼性鹽,鈉鹽和鉀鹽等鹼金屬鹽,_ 鈣鹽和鎂鹽等鹼性土金屬鹽,二環己基胺鹽、N•甲基·〇葡 糖胺鹽等有機鹼性金屬鹽,精胺酸鹽和離胺酸鹽等胺基酸 鹽。 本發明的化合物可以透過口服 '鼻腔、注射、經皮和 經黏膜等不同途徑给藥。以懸浮劑的形式透過口服給藥的 活性成分能以化學製劑常用的技術來製備,可以包含辦加 體積的微晶纖維素、作為懸浮劑的海藻酸和海藻酸鹽、作 74 1331922 為黏性增強劑的曱基纖維素,以及甜味劑/芳香劑。快速 · 釋放型樂片的成分則包括微晶纖維素、鱗酸二釣鹽、殿粉、 硬脂酸鎮鹽和乳糖以及(或)其他賦形劑、粘合劑、擴充 劑、崩解劑、稀釋劑和潤滑劑。 例如,鼻腔氣霧劑和吸入劑製備可用笨甲醇或其他合 適的防腐劑製成鹽溶液,以碳I化合物和(或)其他溶解 劑或分散劑製成增加生物利用度的吸收促進劑。 本發明的化合物也可以透過靜脈内(包括推注和滴 注)、腹膜腔内、皮下、封閉或不封閉的局部給藥或肌肉注籲 射給藥。透過注射給藥時,注射溶液或懸浮液的製備應該 使用合適的無毒、適合胃腸外使用的稀釋劑或溶劑,例如 林格氏液或等滲的氣化鈉溶液,或合適的分散劑或濕化劑 和懸浮劑,例如無菌、溫和的不揮發油,包括合成的單或 二脂酸甘油醋和油酸等脂肪酸。 如專業所知,合適的給藥劑量應該透過以下因素來決 定,包括受試對象的類型;受試對象的年齡、體重、性別 和醫學狀況;給藥途徑;受試對象的腎功能和肝功能;期* 望的療效;以及使用的特定化合物。 藥品的最佳濃度是藥品能產生療效卻不至於產生毒性 的濃度範圍,這是基於該藥可用性對靶位點的藥品動力 學,其中涉及對於藥品分佈、平衡和排除的考慮。每個受 試對象每天的劑量預計為〇.〇1到1,〇〇〇毫克。 本發明的化合物可以透過試劑盒的形式供給。這種試 劑盒通常含有給藥劑型的活性成分。如果受試對象規律給 75 1331922 藥’例如一天到多天之内每天服用i到6次,則給藥劑型 含有的活性成分應足以獲得期望的療效。理想上,試劑盒 中應含有指示’說明如何使用劑型以獲得期望效果,以及 在特定時間内應服用多少劑量。 本發明以說明性的方式闡述,因此使用的術語都屬於 描述性,而非限制性。顯然上述宗旨可以有許多修改和變 化。因此必須明白,在附錄申請專利範圍内,本發明可用 特定描述之外的方法實行。 此處提及的專利和科學文獻是專業人員可以獲得的資春 訊。本文引述的所有專利、專利出版物和其他出版物完整 以參考方式被併入。 其他實施例 應了解儘管本發明與本文的具體細節一併說明,然而 上述說明八疋作為闞述,並非限制本發明的範圍,本發明 的範圍由附錄的申請專利範圍界定。其他層面優點和修 正也屬於申請專利範圍内。 76
Claims (1)
1331922 拾、1. 種基於分子式(I)之化合物 Rl-A1-A2-A3-A4.A5_R: (2007年5月修正) (I) 或是藥學上可接受之鹽,其中: A1 是 Aib、Ape 或 Inp ; A2 是 D-Bal、D-Bip、D-Bna、η τλ. ^ p 、D-Dip、D-lNa卜 D-2Na卜 D-Ser(Bzl)或 D-Trp ;
A 是 2Fua ' Orn、2Pal、3Pal、4Pal、Pff、Phe、Pim、 Taz、2Thi、3Thi、Thr(Bzl); A5是Ape ' Lys或刪除; R1是氫或(Cu)烷基;及 R2 是 OH 或 NH2 ; 前提為: A5 是 Lys,則: A2 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A3 是 D-Bpa、D-Dip 或 D-Bal ;或 A4 是 2Thi、3Thi、Taz、2Fua、2Pal、3Pal.、4Pal、Orn、 Thr(Bzl)或 Pff ; A5刪除後,則: A3 是 D-Bpa 或 D-Dip ;或 A4 是 2Fua、Pff、Taz 或 Thr(Bzl);或 A1是Ape及- 77 1331922 (2007年5月修正) A2 是 D-Bip、D-Bpa、D-Dip 或 D-Bal ;或 A3 是 D-Bpa、D-Dip 或 D-Bal ;或 A4 是 2Thi、3Thi、Orn、2Pal、3Pal 或 4Pal。 2.如申請專利範圍第1項之化合物,其中: A1 是 Aib、Ape 或 Inp ; A 是 D-Bal、D-Bip、D-Bpa、D-Dip、D-lNal、D-2Nal、 D-Ser(Bzl)或 D_Trp ;
A3 是 D-Bal、D-Bpa、D-Dip、D-lNa卜 D-2Nal 或 D-Trp; A 是 Orn、3Pal、4Pal、Pff、Phe、Pim、Taz、2Thi 或 Thr(Bzl);及 A5是Ape ' Lys或刪除; 或是藥學上可接受之鹽。 3.如申請專利範圍第2項之化合物,其中: A1 是 Ape 或 Inp ; A2 是 D-Bal、D-Bip、D-lNal 或 D-2Nal ; A3 是 D-Bal、D-lNal、D-2Nal 或 D-Trp ;而且 A4 是 3Pa卜 4Pa卜 Pff、Phe、Pim、Taz、2Thi 或 Thr(Bzl); 或是藥學上可接受之鹽。 4.如申請專利範圍第1項之化合物,該化合物是基於以下 分子式: H-Inp-D-1 Nal-D-Trp-3Pal-Lys-NH2; 78 1331922 (2007年5月修正) 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-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D-lNal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; 79 H-Apc-D - lNal-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 - lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-1 Nal-D-1 Nal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D-lNal-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-1 Nal-D-Trp-2Thi-NH2; 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-2Nal-D-Trp-2Thi-NH2; H-Inp-D-1 Nal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -lNal-D-Trp-Taz-Apc-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -lNal-D-Trp-2Fua-Apc-NH2; H-Apc-D - lNal-D-Trp-2Fua-Lys-NH2; H-Apc-D -lNal-D-Trp-2Pal-NH2; 1331922 (2007年5月修正) H-Apc-D-lNal-D-Trp-3Pal-NH2; H-Apc-D-lNal-D-Trp-3Thi-Apc-NH2; H-Apc-D-lNal-D-Trp-3Thi-Lys-NH2; H-Apc-D-lNal-D-Trp-3Thi-NH2; H-Apc-D-lNal-D-Trp-4Pal-NH2; H-Apc-D-lNal-D-Trp-Pff-Apc-NH2; H-Apc-D-lNal-D-Trp-Pff-Lys-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-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-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; 81 1331922 (2007年5月修正) 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; 82 1331922 (2007年5月修正) H-Apc-D-Bal-D-Trp-3Thi-Lys-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-lNal-D-Bal-2Fua-Lys-NH2; H-Inp-D-lNal-D-Bal-2Fua-NH2; H-Inp-D-lNal-D-Bal-2Thi-Lys-NH2;
H-Inp-D-lNal-D-Bal-3Thi-Lys-NH2; H-Inp-D-lNal-D-Bal-Pff-Lys-NH2; H-Inp-D-lNal-D-Bal-Pff-NH2; H-Inp-D-lNal-D-Bal-Phe-Lys-NH2; H-Inp-D-lNal-D-Bal-Taz-Lys-NH2; H-Inp-D - lNal-D-Bal-Taz-NH?; H-Inp-D-lNal-D-Trp-2Fua-Apc-NH2;
H-Inp-D-lNal-D-Trp-2Fua-Lys-NH2; H-Inp-D-lNal-D-Trp-2Fua-NH2; H-Inp-D -1 Nal-D-Trp-3Thi-Apc-NH2; H-Inp-D-lNal-D-Trp-3Thi-Lys-NH2; H-Inp-D -1 Nal-D-Trp-Pff-Apc-NH2; H-Inp-D-lNal-D-Trp-Pff-Lys-NH2; H-Inp-D -lNal-D-Trp-Pff-NH2; H-Inp-D -lNal-D-Trp-Taz-NH2; H-Inp-D-2Nal-D-Trp-2Fua-Apc-NH2; 83 1331922 (2007年5月修正) 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-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; 84 1331922 (2007年5月修正)
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; 或是藥學上可接受之鹽。 5.如申請專利範圍第4項之化合物,該化合物是基於以下 分子式: H-Inp-D-lNal-D-Trp-3Pal-Lys-NH2; H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2; 85 (2007年5月修正) 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-Bal-D-Trp-2Thi-Lys-NH2;
H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D-lNal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D-lNal-D-Trp-Taz-Lys-NH2; 86 1331922 (2007年5月修正) 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-lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D- INal-D-1 Nal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2;
H-Apc-D-Bal-D-lNal-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-lNal-D-Trp-2Thi-NH2; 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-2Nal-D-Trp-2Thi-NH2; H-Inp-D-lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D - lNal-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; 87 1331922 (2007年5月修正) 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-lNal-D-Trp-3Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-2Fua-Lys-NH2; H-Inp-D-lNal-D-Trp-Pff-Lys-NH2; H-Inp-D-lNal-D-Bal-Phe-Lys-NH2; H-Inp-D-lNal-D-Bal-2Thi-Lys-NH2; H-Inp-D-lNal-D-Bal-3Thi-Lys-NH2; 88 1331922 (2007年5月修正) H-Inp-D-lNal-D-Bal-Taz-Lys-NH2; H-Inp-D-lNal-D-Bal-2Fua-Lys-NH2; H-Inp-D-lNal-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 - lNal-D-Trp-3Thi-Apc-NH2; H-Inp-D-lNal-D-Trp-2Fua-Apc-NH2; H-Inp-D -1 Nal-D-Trp-Pff-Apc-NH2; H-Apc-D-lNal-D-Trp-3Thi-Lys-NH2; H-Apc-D-lNal-D-Trp-2Fua-Lys-NH2; H-Apc-D-lNal-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; 89 1331922 (2007年5月修正) 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-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 -1 Nal-D-Trp-3Thi-Apc-NH2 ; H-Apc-D-lNal-D-Trp-2Fua-Apc-NH2;
H-Apc-D -1 Nal-D-Trp-Pff-Ape-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; 90 1331922 (2007年5月修正) 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-lNal-D-Trp-Taz-NH2; H-Inp-D-lNal-D-Trp-2Fua-NH2; H-Inp-D-lNal-D-Trp-Pff-NH2; H-Inp-D-lNal-D-Bal-Taz-NH2; H-Inp-D-lNal-D-Bal-2Fua-NH2; H-Inp-D-lNal-D-Bal-Pff-NH2; 91 1331922 (2007年5月修正) 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-lNal-D-Trp-3Thi-NH2; H-Apc-D-lNal-D-Trp-4Pal-NH2; H-Apc-D-lNal-D-Trp-3Pal-NH2; H-Apc-D-lNal-D-Trp-2Pal-NH2; H-Apc-D-2Nal-D-Trp-3Thi-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; 或是藥學上可接受之鹽。 6.如申請專利範圍第5項之化合物,該化合物是基於以下 分子式: H-Inp-D-lNal-D-Trp-3Pal-Lys-NH2; H-Inp-D-2Nal-D-Trp-4Pal-Lys-NH2; H-Inp-D-2Nal-D-Trp-Orn-Lys-NH2; 92 1331922 (2007年5月修正) 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-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- lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; 93 1331922 (2007年5月修正) H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D -1 Nal-D-Trp-Taz-Apc-NH2; H-Inp-D-lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Apc-D-lNal-D-Trp-Taz-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-lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D - lNal-D-Trp-Taz-Apc-NH2; H-Apc-D-lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Apc-NH2; H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; 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-lNal-D-Trp-2Thi-NH2;或 H-Apc-D-2Nal-D-Trp-2Thi-NH2; 或是藥學上可接受之鹽。 7.如申請專利範圍第6項之化合物,該化合物是基於以下 分子式: H-Inp-D -1 Nal-D-Trp-3Pal-Lys-NH2; 94 1331922 (2007年5月修正) 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-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-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D-1 Nal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2;
H-Inp-D -1 Nal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D-lNal-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-lNal-D-Trp-Phe-Apc-NH2; H-Apc-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-lNal-Phe-Apc-NH2; 95 1331922 (2007年5月修正) H-Apc-D-lNal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D- lNal-Phe-Apc-NH2; H-Apc-D-Bal-D-2Nal-Phe-Apc-NH2; H-Apc-D-Bal-D-lNal-Phe-Lys-NH2; H-Apc-D-Bal-D-2Nal-Phe-Lys-NH2; H-Apc-D -1 Nal-D-Trp-2Thi-NH2;
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-2Nal-D-Trp-2Thi-NH2; H-Inp-D-lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -1 Nal-D-Trp-Taz-Apc-NH2;或 H-Apc-D-Bal-D-Trp-Taz-Apc-NH2; 或是藥學上可接受之鹽。 8.如申請專利範圍第7項之化合物,該化合物是基於以下 分子式: H-Inp-D-lNal-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-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; 96 1331922 (2007年5月修正) H-Inp-D-2Nal-D-Trp-Phe-Apc-NH2; H-Inp-D-lNal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Taz-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D -1 Nal-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 -1 Nal-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 -1 Nal-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-lNal-D-Trp-Taz-Apc-NH2; H-Inp-D-Bal-D-Trp-Taz-Apc-NH2; H-Apc-D -lNal-D-Trp-Taz-Apc-NH2; H-Apc-D-Bal-D-Trp-Taz-Apc-NH2;或 或是藥學上可接受之鹽。 97 1331922 (2007年5月修正) 9.如申請專利範圍第8項之化合物,該化合物是基於以下 分子式: H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-lNal-D-Trp-Phe-Apc-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2;
H-Apc-D-lNal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D - lNal-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 -1 Nal-D-Trp-Phe-Apc-NH2;或 H-Apc-D-2Nal-D-Trp-2Thi-NH2; 或是藥學上可接受之鹽。 10.如申請專利範圍第9項之化合物,該化合物是基於以 下分子式: H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH2; H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; H-Apc-D -IN al-D-Trp-2Thi-Lys-NH2; H-Apc-D-1 Nal-D-Trp-Taz-Lys-NH2; 98 1331922 (2007年5月修正) 或是藥學上可接受之鹽。 11.如申請專利範圍第9項之化合物,該化合物是基於以 下分子式:
H-Inp-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D-lNal-D-Trp-Taz-Lys-NH2; H-Apc-D-Bal-D-Trp-Taz-Lys-NH2; H-Apc-D - lNal-D-Trp-Phe-Apc-NH2;或 或是藥學上可接受之鹽。 12,如申請專利範圍第6項之化合物,該化合物是基於以 下分子式: 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-Bal-D-色胺醇 H-Inp-D-Bal-D -色胺基苄基醚 或是藥學上可接受之鹽。 13.如申請專利範圍第12項之化合物,該化合物是基於以 99 1331922 (2007年5月修正) 下分子式: 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-Bal-D-色胺酵 H-Inp-D-Bal-D-色胺基苄基醚 或是藥學上可接受之鹽。
14. 一種基於以下分子式之化合物: H-Inp-D-1 Nal-D-Trp-2Thi-Apc-NH2; H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2; H-Apc-D-lNal-D-Trp-2Thi-Apc-NH2; H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2; H-Inp-D-2Nal-D-Trp-3Pal-NH2; H-Inp-D-2Nal-D-Trp-4Pal-NH2;
H-Inp-D-lNal-D-Trp-3Pal-NH2; H-Inp-D-Bip-D-Trp-Phe-NH2; H-Inp-D-2Nal-D-Trp-2Thi-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-Trp-DJNalW-Pim H-Apc-D-2Nal-D-Trp-Phe-Lys-NH2; H-Inp-D-lNal-D-Trp-2Thi-NH2; 100 1331922 (2007年5月修正) H-Apc-D-lNal-D-Trp-Phe-NH2; H-Inp-D-2Na 卜 D-TrpW)-Pim; Η-Ιηρ-ϋ-1Ν3ΐ-0-ΤΓρ(Ψ)-Ρίιη; Η-Ιηρ-0-Βα1-0-ΤΓρ(Ψ)-Ρΐπι; H-Aib-D-SeKBzU-D-TrpC'JO-Pim; H-Apc-D-lNal-D-lNal-Phe-Lys-NH2; H-Apc-D-lNal-D-Trp-Taz-NH2; H-Apc-D-2Nal-D-Trp-Taz-NH2;
H-Apc-D- lNal-D-Trp-2Fua-NH2; H-Apc-D-lNal-D-Trp-Pff-NH2; H-Apc-D-Bal-D-Trp-3Thi-NH2; H-Apc-D-2Nal-D-Trp-2Fua-NH2; H-Apc-D-2Nal-D-Trp-Pff-NH2;或 H-Inp-D-2Nal-D-Trp-3Thi-NH2; 或是藥學上可接受之鹽。 15.如申請專利範圍第10項之化合物,其中該化合物是基 於以下分子式: H-Inp-D-Bal-D-Trp-Phe-Apc-NH2; 或是藥學上可接受之鹽。 101
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