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CN1781933B - Thymosin α1 Active Fragment Cyclic Peptide Analogs and Pegylated Derivatives - Google Patents

Thymosin α1 Active Fragment Cyclic Peptide Analogs and Pegylated Derivatives Download PDF

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CN1781933B
CN1781933B CN2004100964592A CN200410096459A CN1781933B CN 1781933 B CN1781933 B CN 1781933B CN 2004100964592 A CN2004100964592 A CN 2004100964592A CN 200410096459 A CN200410096459 A CN 200410096459A CN 1781933 B CN1781933 B CN 1781933B
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CN1781933A (en
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刘克良
蒋志龙
王良友
梁远军
许笑宇
吴萍
韩寒
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to a cyclic peptide derivative containing natural or non-natural amino acid substituted thymosin alpha 1 active fragment, its preparation method, medicinal composition containing them and their medicines for curing or preventing diseases related to immunodeficiency and hypoimmunity.

Description

胸腺素α1活性片段环肽类似物及其聚乙二醇化衍生物Thymosin α1 Active Fragment Cyclic Peptide Analogs and Pegylated Derivatives

发明领域field of invention

本发明涉及天然或非天然氨基酸取代的胸腺素α1活性片段和环肽类似物，及其聚乙二醇化衍生物，及其制备方法，含他们的药物组合物及其在治疗或者预防与免疫缺陷、免疫功能低下等有关疾病当中的用途。The present invention relates to natural or non-natural amino acid substituted thymosin α1 active fragments and cyclic peptide analogs, and their PEGylated derivatives, and their preparation methods, pharmaceutical compositions containing them and their therapeutic or prophylaxis and immunodeficiency , low immune function and other related diseases.

背景技术Background technique

胸腺素α1(Tα1)是一种重要的多肽类免疫调节因子，具有显著的增强免疫功能的作用是一种针对T淋巴细胞的免疫增强剂，能促进T细胞的成熟和分化，并且促使成熟的淋巴细胞分泌多种淋巴因子(如白介素-2和γ-干扰素等)还能促进白介素-2受体的生成。Tα1由28个氨基酸残基组成，分子量3108，等电点4.2，N-端为乙酰化结构，其氨基酸序列如下：Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asp-OHThymosin α1 (Tα1) is an important polypeptide immune regulatory factor, which has a significant effect of enhancing immune function. It is an immune enhancer for T lymphocytes, which can promote the maturation and differentiation of T cells, and promote the mature Lymphocytes secrete a variety of lymphokines (such as interleukin-2 and γ-interferon, etc.) and can also promote the production of interleukin-2 receptors. Tα1 consists of 28 amino acid residues, with a molecular weight of 3108, an isoelectric point of 4.2, and an acetylated structure at the N-terminal. Its amino acid sequence is as follows: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser- Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asp-OH

近年来，Tα1的研究主要集中于临床应用，关于其构效关系的研究报道不多。1980年，Wong等合成Tα1和desAc-Tα1，通过体外的硫唑嘌呤抑制E-玫瑰花结形成试验显示它们的活性与天然Tα1相当，说明Tα1的N-端乙酰化与否对其活性无影响。除Frasca等报道Tα1的N-端片段1-14能在成年大鼠(6-18月)体内促进IL-2受体表达，增强辅助性T细胞的活性外，其它研究表明Tα1的N-端片段基本上无活性，C-端部分片段具有较好的活性。Abiko等用体外的E-玫瑰花结形成试验证实Tα1的某些C-端片段具有部分活性：Tα1(100％)，14-28(9.83％)，19-28(1.04％)。Felix等用体内的免疫抑制小鼠试验证实N-端片段1-4、4-10、1-10和1-14基本无活性；C-端片段15-28和18-28与Tα1活性相当；21-28(75％)、23-28(50％)和25-28(50％)具有部分活性。Ciaredelli等用体外的混合淋巴细胞增殖试验(MLC)证实Tα1的C-端20-26、25-27及25-28具有约90％活性。Ho等报道C-端片段13-19与Tα1在体外具有相同的促脐带血T淋巴细胞分化成熟的活性，20-25和20-28具有部分活性。Ciaredelli等用体外的硫唑呤抑制E-玫瑰花结形成试验发现C-端17-28区域部分片段有较好的活性。In recent years, the research on Tα1 mainly focuses on clinical application, and there are few reports on its structure-activity relationship. In 1980, Wong et al. synthesized Tα 1 and desAc-Tα 1 , and the in vitro azathioprine inhibition of E-rosette formation test showed that their activity was equivalent to that of natural Tα 1 , indicating that the N-terminal acetylation of Tα 1 is important for Its activity has no effect. In addition to reports by Frasca et al. that the N-terminal fragment 1-14 of Tα 1 can promote the expression of IL-2 receptor and enhance the activity of helper T cells in adult rats (6-18 months), other studies have shown that the N-terminal fragment of Tα 1 The -terminal fragment is basically inactive, and the C-terminal partial fragment has better activity. Abiko et al. confirmed that some C-terminal fragments of Tα1 have partial activity by in vitro E-rosette formation assay: Tα1 (100%), 14-28 (9.83%), 19-28 (1.04%). Felix et al. confirmed that the N-terminal fragments 1-4, 4-10, 1-10, and 1-14 were basically inactive by in vivo immunosuppressive mouse experiments; the C-terminal fragments 15-28 and 18-28 were equivalent to Tα 1 activity ; 21-28 (75%), 23-28 (50%) and 25-28 (50%) were partially active. Ciaredelli et al. confirmed that the C-terminal 20-26, 25-27 and 25-28 of Tα 1 had about 90% activity by in vitro mixed lymphocyte proliferation assay (MLC). Ho et al. reported that the C-terminal fragments 13-19 and Tα 1 have the same activity in promoting the differentiation and maturation of umbilical cord blood T lymphocytes in vitro, and 20-25 and 20-28 have partial activities. Ciaredelli et al. found that some fragments of the C-terminal 17-28 region had better activity by using azithaline to inhibit the formation of E-rosettes in vitro.

Grottesi等通过圆二色谱(CD)和2D-NMR对Tα1在溶液中的构象进行了研究，结果表明：Tα1在水溶液中并不形成优势的二级构象，但在疏水环境中能形成一定的二级结构。在40％的三氟乙醇(TFE)水溶液中，Val5和Glu8之间形成β-转角，Lys17和Glu24之间形成α-螺旋。由于Tα1受体结构还尚未被发现，Grottesi等推测Tα1与淋巴细胞的作用机制可能是：Tα1首先通过极性氨基酸残基与细胞膜形成静电作用，然后诱导Lys17至Glu24之间序列形成α-螺旋结构并嵌入细胞膜，进而与IL-2受体跨膜区发生静电作用。这一作用模型有助于解释Tα1与IL-2在生物活性中的协同作用。Grottesi et al. studied the conformation of Tα 1 in solution by circular dichroism (CD) and 2D-NMR. The results showed that: Tα 1 does not form a dominant secondary conformation in aqueous solution, but can form a certain degree in a hydrophobic environment. secondary structure. In 40% trifluoroethanol (TFE) aqueous solution, a β-turn is formed between Val 5 and Glu 8 , and an α-helix is formed between Lys 17 and Glu 24 . Since the structure of the Tα 1 receptor has not yet been discovered, Grottesi et al. speculated that the mechanism of action between Tα 1 and lymphocytes may be: Tα 1 first forms an electrostatic interaction with the cell membrane through polar amino acid residues, and then induces the sequence between Lys 17 and Glu 24 It forms an α-helical structure and embeds in the cell membrane, and then electrostatically interacts with the transmembrane region of the IL-2 receptor. This model of action helps to explain the synergistic effect of Tα1 and IL-2 in biological activity.

病毒性乙型肝炎和丙型肝炎可以导致肝硬化引起肝癌，全球目前有3.5亿乙型肝炎病毒携带者和1.5亿丙型肝炎携带者。我国是乙肝大国，有1.2亿以上的乙型肝炎携带者，有三千万以上的乙型肝炎患者，化学合成的Tα1(日达仙)已于1996年首先在中国上市，单独使用或与α-干扰素联合使用治疗慢性乙型肝炎。日达仙在治疗乙型肝炎方面的疗效等同于或好于现有处方药品。日达仙对于许多其它疾病(如丙型肝炎、非小细胞肺癌、黑色素瘤和艾滋病等)都有一定的疗效。另外，日达仙还可作为疫苗辅助药，来加强流感疫苗和乙型肝炎疫苗的免疫效果。目前，日达仙正在美国进行治疗HCV的3期临床试验和治疗肝癌的2期临床试验，治疗HBV的3期临床试验正在日本进行，治疗恶性黑色素瘤的2期临床试验正在欧洲进行。由此可见，研究Tα1及其类似物，寻找更高效的免疫增强剂和抗病毒药具有良好的前景。Viral hepatitis B and C can lead to liver cirrhosis and liver cancer. There are currently 350 million hepatitis B virus carriers and 150 million hepatitis C carriers worldwide. China is a large hepatitis B country, with more than 120 million hepatitis B carriers and more than 30 million hepatitis B patients. The chemically synthesized Tα 1 (Ridaxian) was first listed in China in 1996. It is used alone or in combination with Combined use of α-interferon in the treatment of chronic hepatitis B. Zidaxian is as effective as or better than existing prescription drugs in the treatment of hepatitis B. Zidaxian has a certain effect on many other diseases (such as hepatitis C, non-small cell lung cancer, melanoma and AIDS, etc.). In addition, Zidaxian can also be used as a vaccine adjuvant drug to enhance the immune effect of influenza vaccine and hepatitis B vaccine. Currently, Zidaxian is conducting phase 3 clinical trials for the treatment of HCV and phase 2 clinical trials for the treatment of liver cancer in the United States, phase 3 clinical trials for the treatment of HBV in Japan, and phase 2 clinical trials for the treatment of malignant melanoma in Europe. It can be seen that the study of Tα1 and its analogues has a good prospect for finding more efficient immune enhancers and antiviral drugs.

目前临床使用的Tα1(日达仙)为化学合成品，价格昂贵、用药剂量大、周期长，因此进行构效关系研究发现更好的类似物有较好的应用前景。与其它肽类药物一样，Tα1具有诸如半衰期短、在体内易被降解等缺点，因此设计活性高、抗体内降解的Tα1类似物具有十分重要的意义。Currently, Tα1 (Ridaxian) in clinical use is a chemical synthetic product, which is expensive, has a large dosage, and a long cycle. Therefore, the research on the structure-activity relationship has found that better analogues have better application prospects. Like other peptide drugs, Tα1 has disadvantages such as short half-life and easy degradation in vivo. Therefore, it is of great significance to design Tα1 analogs with high activity and in vivo degradation.

发明内容：Invention content:

本发明人及其所在实验室研究现已发现Tα1及其衍生物具有良好的预防或治疗免疫缺陷、免疫功能低下有关疾病的生物活性，它们与聚乙二醇形成的衍生物在能够保持活性的同时，延长了如下(I)、(IV)、(VII)、(VIII)组的化合物在体内代谢的半衰期，从而降低了如下(I)、(IV)、(VII)、(VIII)组的化合物的用量并且延长了其在体内作用时间。The present inventors and their laboratories have found that Tα1 and its derivatives have good biological activity in preventing or treating diseases related to immunodeficiency and immunodeficiency, and their derivatives formed with polyethylene glycol can maintain activity. Simultaneously, prolong following (I), (IV), (VII), (VIII) the compound half-life of metabolism in vivo, thereby reduced following (I), (IV), (VII), (VIII) group The dosage of the compound and prolong its action time in vivo.

具体的，本发明涉及如下所示的Tα1活性片段衍生物及其立体异构体。Specifically, the present invention relates to Tα1 active fragment derivatives and stereoisomers thereof shown below.

本发明的一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其为(I)组的化合物：One aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, which are compounds of group (I):

X1-Y1-Y2-X2 X 1 -Y 1 -Y 2 -X 2

X1-X2-Y1-Y2-X3 X 1 -X 2 -Y 1 -Y 2 -X 3

X1-X2-X3-Y1-Y2-X4 X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

X1-X2-Y1-Y2-X3-X4 X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

X1-X2-X3-Y1-Y2-X4-X5 X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

X1-X2-Y1-Y2-X3-X4-Y3 X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

X1-X2-X3-Y1-Y2-X4-X5-Y3 X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

X1-X2-Y1-Y2-X3-X4-Y3-X5 X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

X1-X2-X3-X4-Y1-Y2-X5 X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

X1-X2-X3-X4-X5-Y1-Y2-X6 X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

X1-X2-X3-X4-X5-X6-Y1-Y2-X7 X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7     (I)X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 (I)

其中，X1、X2、X3、X4、X5、X6、X7独立地为L-或D-型的天然或非天然的碱性、酸性或芳香性氨基酸及其衍生物，所述碱性氨基酸选自Arg、Lys、Glu、Cys、His、Trp、Mob、Nal、Pya、Phe(X)、和Phg(X)，其中X为氢、卤素、硝基、羧基、或C1-C4烷基任选的单取代或者二取代，取代基选自H、4-F、3-F、2-F、4-Cl、2-Cl、4-Br、2-Br、3-Br、2、5-2Cl、4-F、3-Cl、3-NO2；酸性氨基酸选自：Asp、Glu、His、Tyr、Trp、Mob、Nal、Pya、和Phg(X)，其中X为氢、卤素、硝基、羧基、或C1-C4烷基任选的单取代或者二取代，取代基选自H、4-F、3-F、2-F、4-Cl、2-Cl、4-Br、2-Br、3-Br、2、5-2Cl、4-F、3-Cl、3-NO2；Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are independently L- or D-type natural or unnatural basic, acidic or aromatic amino acids and their derivatives, The basic amino acid is selected from Arg, Lys, Glu, Cys, His, Trp, Mob, Nal, Pya, Phe(X), and Phg(X), wherein X is hydrogen, halogen, nitro, carboxyl, or C1 -C4 alkyl is optionally monosubstituted or disubstituted, and the substituents are selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br , 2, 5-2Cl, 4-F, 3-Cl, 3-NO 2 ; the acidic amino acid is selected from: Asp, Glu, His, Tyr, Trp, Mob, Nal, Pya, and Phg(X), wherein X is Hydrogen, halogen, nitro, carboxyl, or C1-C4 alkyl are optionally monosubstituted or disubstituted, and the substituents are selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2, 5-2Cl, 4-F, 3-Cl, 3- NO2 ;

Y1、Y2、Y3、Y4独立的为L-或D-型的天然或非天然中性、亲脂性或者芳香性氨基酸及其衍生物，选自Gly、Ala、β-Ala、GABA、Val、Leu、Ile、Pro、His、Tyr、Trp、Mob、Nal、Pya、Phe(X)、Phg(X)，其中X为氢、卤素、硝基、羧基、或C1-C4烷基任选的单取代或者二取代，取代基选自H、4-F、3-F、2-F、4-Cl、2-Cl、4-Br、2-Br、3-Br、2、5-2Cl、4-F、3-Cl、3-NO2。Y 1 , Y 2 , Y 3 , and Y 4 are independently L- or D-type natural or unnatural neutral, lipophilic or aromatic amino acids and their derivatives, selected from Gly, Ala, β-Ala, GABA , Val, Leu, Ile, Pro, His, Tyr, Trp, Mob, Nal, Pya, Phe(X), Phg(X), wherein X is hydrogen, halogen, nitro, carboxyl, or C1-C4 alkyl any Optional mono-substitution or di-substitution, the substituents are selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2, 5- 2Cl, 4-F, 3-Cl, 3- NO2 .

本发明的另一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中上述(I)组中的化合物中任意位点的氨基经过PEG修饰，成为如下的(II)组所示的化合物，其中所述氨基包括N-端氨基和氨基酸侧链氨基：Another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein the amino group at any position in the compound in the above-mentioned (I) group is modified by PEG to become the following (II ) compound shown in the group, wherein the amino group includes N-terminal amino group and amino acid side chain amino group:

[PEG-X-(CH2)MCO-NH]Z-X1-Y1-Y2-X2 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -Y 1 -Y 2 -X 2

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X3 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 3

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X3-X4 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4-X5 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X3-X4-Y3 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4-X5-Y3 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X3-X4-Y3-X5 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-X4-Y1-Y2-X5 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-X4-X5-Y1-Y2-X6 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-X4-X5-X6-Y1-Y2-X7 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

[PEG-X-(CH2)MCO-NH]Z-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 [PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

[PEG-X-(CH2)MCO-NH]Z-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7(II)[PEG-X-(CH 2 ) M CO-NH] Z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 (II)

其中PEG表示：RO(CH2CH2O)n-CH2CH2，R＝H或C和CH3，其中n＝5-1000；X＝O、NH或NHCO；m＝0-6；Z＝1-3、X1、X2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如上述所示。Wherein PEG represents: RO(CH 2 CH 2 O) n -CH 2 CH 2 , R=H or C and CH 3 , wherein n=5-1000; X=O, NH or NHCO; m=0-6; Z =1-3, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are defined as above.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中(I)组化合物的任意位点的羧基经PEG共价修饰为如下所示的(III)组的化合物，其中所述羧基包括C-端羧基，天冬氨酸和谷氨酸侧链羧基：Another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein the carboxyl group at any position of the compound of group (I) is covalently modified by PEG into (III ) group of compounds, wherein the carboxyl includes C-terminal carboxyl, aspartic acid and glutamic acid side chain carboxyl:

[PEG-X-CO]z-X1-Y1-Y2-X2 [PEG-X-CO] z -X 1 -Y 1 -Y 2 -X 2

[PEG-X-CO]z-X1-X2-Y1-Y2-X3 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 3

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4 [PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

[PEG-X-CO]z-X1-X2-Y1-Y2-X3-X4 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4-X5 [PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

[PEG-X-CO]z-X1-X2-Y1-Y2-X3-X4-Y3 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4-X5-Y3 [PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

[PEG-X-CO]z-X1-X2-Y1-Y2-X3-X4-Y3-X5 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 [PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

[PEG-X-CO]z-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 [PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

[PEG-X-CO]z-X1-X2-X3-X4-Y1-Y2-X5 [PEG-X-CO] z -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

[PEG-X-CO]z-X1-X2-X3-X4-X5-Y1-Y2-X6 [PEG-X-CO] z -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

[PEG-X-CO]z-X1-X2-X3-X4-X5-X6-Y1-Y2-X7 [PEG-X-CO] z -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

[PEG-X-CO]z-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 [PEG-X-CO] z -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

[PEG-X-CO]z-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7(III)[PEG-X-CO] z -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 (III)

其中X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如前述所示，X＝O或NH，Z＝1-3。Wherein X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are as defined above, and X=O or NH, Z=1-3.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中在(I)组化合物所示肽序列中任意位置，包括N端和C端以及肽片段中引入半胱氨酸，形成如下所示的(IV)组的化合物：Another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein at any position in the peptide sequence shown in the compound of group (I), including N-terminal and C-terminal and peptide fragments Introduce cysteine in, form the compound of (IV) group as shown below:

Cys-X1-Y1-Y2-X2 Cys-X 1 -Y 1 -Y 2 -X 2

Cys-X1-X2-Y1-Y2-X3 Cys-X 1 -X 2 -Y 1 -Y 2 -X 3

Cys-X1-X2-X3-Y1-Y2-X4 Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

Cys-X1-X2-Y1-Y2-X3-X4 Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

Cys-X1-X2-X3-Y1-Y2-X4-X5 Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

Cys-X1-X2-Y1-Y2-X3-X4-Y3 Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3 Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5 Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

Cys-X1-X2-X3-X4-Y1-Y2-X5 Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

Cys-X1-X2-X3-X4-X5-Y1-Y2-X6 Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7 Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

Cys-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7  (IV)Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 (IV)

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其进一步将所述(IV)组的化合物经选自PEG-MAL、PEG-VS和PEG-IODS的方法修饰后形成如下所示的(V)组的化合物，其中PEG可以为链状、星状、环状、多臂型结构：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, which further comprises the compound of group (IV) selected from PEG-MAL, PEG-VS and PEG- The method of IODS is modified to form the compound of (V) group as shown below, wherein PEG can be chain, star, ring, multi-arm structure:

PEG-M-Cys-X1-Y1-Y2-X2 PEG-M-Cys-X 1 -Y 1 -Y 2 -X 2

PEG-M-Cys-X1-X2-Y1-Y2-X3 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 3

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4 PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

PEG-M-Cys-X1-X2-Y1-Y2-X3-X4 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4-X5 PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

PEG-M-Cys-X1-X2-Y1-Y2-X3-X4-Y3 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3 PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

PEG-M-Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

PEG-M-Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

PEG-M-Cys-X1-X2-X3-X4-Y1-Y2-X5 PEG-M-Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

PEG-M-Cys-X1-X2-X3-X4-X5-Y1-Y2-X6 PEG-M-Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

PEG-M-Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7 PEG-M-Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

PEG-M-Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 PEG-M-Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

PEG-M-Cys-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7(V)，PEG-M-Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 (V),

其中in

Figure G04196459220041207D000071
Figure G04196459220041207D000071

Cys为半胱氨酸，通过侧链硫原子和M基团共价相连；X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如前述。Cys is cysteine, which is covalently connected to the M group through the side chain sulfur atom; X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are as defined above.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中在所述(I)组的化合物之C端引入亲电性基团或者亲核性基团，而对应在N端引入相反的亲核性基团或者亲电性基团，得到如下所示的(VI)组的化合物，其中所述亲核试剂选自碘负离子、水、羟基负离子、甲氧基负离子、乙酰基负离子、氨基、硝酸根负离子、亚硝酸根负离子、叠氮基负离子、氰基负离子、1-丙炔基负离子、丙二酸二甲酯负离子、巯基负离子、甲硫基负离子、硫氰基负离子、二甲硫醚、三甲磷；所述亲电试剂选自硫代羧基乙酰氨、卤素、无机酸、有机酸、醛、活泼酮、羧酸、酯、硝基化合物：Still another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein an electrophilic group or a nucleophilic group is introduced into the C-terminus of the compound of the (I) group group, and corresponding to the introduction of the opposite nucleophilic group or electrophilic group at the N-terminus, the compound of (VI) group shown below is obtained, wherein the nucleophilic agent is selected from iodide anion, water, hydroxyl anion, Methoxy anion, acetyl anion, amino, nitrate anion, nitrite anion, azide anion, cyanide anion, 1-propynyl anion, dimethyl malonate anion, mercapto anion, methylthio Anion, thiocyanate anion, dimethyl sulfide, trimethylphosphine; the electrophile is selected from thiocarboxyacetamide, halogen, inorganic acid, organic acid, aldehyde, active ketone, carboxylic acid, ester, nitro compound:

Z1-X1-Y1-Y2-X2-Z2 Z 1 -X 1 -Y 1 -Y 2 -X 2 -Z 2

Z1-X1-X2-Y1-Y2-X3-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 3 -Z 2

Z1-X1-X2-X3-Y1-Y2-X4-Z2 Z 1 -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -Z 2

Z1-X1-X2-Y1-Y2-X3-X4-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Z 2

Z1-X1-X2-X3-Y1-Y2-X4-X5-Z2 Z 1 -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Z 2

Z1-X1-X2-Y1-Y2-X3-X4-Y3-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -Z 2

Z1-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 -Z 2

Z1-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4-Z2 Z 1 -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 -Z 2

Z1-X1-X2-X3-X4-Y1-Y2-X5-Z2 Z 1 -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 -Z 2

Z1-X1-X2-X3-X4-X5-Y1-Y2-X6-Z2 Z 1 -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 -Z 2

Z1-X1-X2-X3-X4-X5-X6-Y1-Y2-X7-Z2 Z 1 -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 -Z 2

Z1-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 -Z 2

Z1-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7-Z2  (VI)，Z 1 -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 -Z 2 (VI),

其中Z1和Z2为一组具有亲核性基团和亲电性基团的氨基酸残基或者其它片段，当Z1带有亲核性基团时Z2带有亲电性基团，当Z1带有亲电性基团时Z2带有亲核性基团。Wherein Z 1 and Z 2 are a group of amino acid residues or other fragments with nucleophilic groups and electrophilic groups, when Z 1 has a nucleophilic group, Z 2 has an electrophilic group, when Z 1 has an electrophilic group while Z 2 has a nucleophilic group.

优选的，上述四肽至十一肽衍生物及其立体异构体，其为：Preferably, the above tetrapeptide to undecapeptide derivatives and their stereoisomers are:

CEVVE-SCH2CH2CONH2 CEVVE-SCH 2 CH 2 CONH 2

CKEVVE-SCH2CH2CONH2 CKEVVE-SCH 2 CH 2 CONH 2

CKKEVVE-SCH2CH2CONH2 CKKEVVE-SCH 2 CH 2 CONH 2

CKEVVEE-SCH2CH2CONH2 CKEVVEE-SCH 2 CH 2 CONH 2

CEKKEVVE-SCH2CH2CONH2 CEKKEVVE-SCH 2 CH 2 CONH 2

CKEKKEVVE-SCH2CH2CONH2 CKEKKEVVE-SCH 2 CH 2 CONH 2

CKEVVEKEVVE-SCH2CH2CONH2 CKEVVE KEVVE-SCH 2 CH 2 CONH 2

CKEVVEEAE-SCH2CH2CONH2 CKEVVEEAE-SCH 2 CH 2 CONH 2

CKEVVEEA-SCH2CH2CONH2，或CKEVVEEA-SCH 2 CH 2 CONH 2 , or

CKEVVEEAEN-SCH2CH2CONH2。 CKEVVEEAEN - SCH2CH2CONH2 .

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中在(IV)和(VI)组的化合物的任意位点引入脂肪族链、脂肪醚链、硫醚链、氨基酸以及其它柔性的链状结构单元，得到如下所示的(VII)组的化合物：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein aliphatic chains, aliphatic ether chains are introduced at any position in the compounds of groups (IV) and (VI) , thioether chain, amino acid and other flexible chain structural units, obtain the compound of (VII) group as shown below:

Cys-Ln-X1-Y1-Y2-X2 Cys-L n -X 1 -Y 1 -Y 2 -X 2

Cys-Ln-X1-X2-Y1-Y2-X3 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3

Cys-Ln-X1-X2-X3-Y1-Y2-X4 Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4

Cys-Ln-X1-X2-Y1-Y2-X3-X4 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4

Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5 Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5

Cys-Ln-X1-X2-Y1-Y2-X3-X4-Y3 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3

Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3 Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3

Cys-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5

Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6 Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6

Cys-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4

Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4 Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4

Cys-Ln-X1-X2-X3-X4-Y1-Y2-X5 Cys-L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5

Cys-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6 Cys-L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6

Cys-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7 Cys-L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7

Cys-Ln-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7 Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7

Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7，Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 ,

或者是以下结构：or the following structure:

Z1-Ln-X1-Y1-Y2-X2-Z2 Z 1 -L n -X 1 -Y 1 -Y 2 -X 2 -Z 2

Z1-Ln-X1-X2-Y1-Y2-X3-Z2 Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -Z 2

Z1-Ln-X1-X2-X3-Y1-Y2-X4-Z2 Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -Z 2

Z1-Ln-X1-X2-Y1-Y2-X3-X4-Z2 Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Z 2

Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-Z2 Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Z 2

Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3-Z2 Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -Z 2

Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4-Z2 Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 -Z 2

Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4-Z2 Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 -Z 2

Z1-Ln-X1-X2-X3-X4-Y1-Y2-X5-Z2 Z 1 -L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 -Z 2

Z1-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6-Z2 Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 -Z 2

Z1-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7-Z2 Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 -Z 2

Z1-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7-Z2 Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 -Z 2

Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7-Z2 (VII)Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 -Z 2 (VII)

其中，L表示任何柔性的链状结构单元，n＝1-4，以上通式中所示的L所在位点并不是可以引入的唯一位点，L可以在肽序列中除两端以外的任意位置。Among them, L represents any flexible chain structure unit, n=1-4, the position of L shown in the above general formula is not the only position that can be introduced, and L can be at any position in the peptide sequence except both ends. Location.

优选的，本发明所述的四肽至十一肽衍生物及其立体异构体，其包括：Preferably, the tetrapeptide to undecapeptide derivatives and their stereoisomers described in the present invention include:

CLEVVECLEVVE

CLKEVVECLKEVVE

CLKKEVVECLKKEVVE

CLKEVVEECLKEVVEE

CLEKKEVVECLEKKEVVE

CLKEKKEVVECLKEKKEVVE

CLKEVVEKEVVECLKEVVEKEVVE

CLKEVVEEAECLKEVVEEAE

CLKEVVEEACLKEVVEEA

CLKEVVEEAENCLKEVVEEAEN

CLLEVVECLLEVVE

CLLKEVVECLLKEVVE

CLLKKEVVECLLKKEVVE

CLLKEVVEECLLKEVVEE

CLLEKKEVVECLLEKKEVVE

CLLKEKKEVVECLLKEKKEVVE

CLLKEVVEKEVVECLLKEVVEKEVVE

CLLKEVVEEAECLLKEVVEEAE

CLLKEVVEEACLLKEVVEEA

CLLKEVVEEAEN，CLLKEVVEEAEN,

或者是以下结构的化合物：Or a compound of the following structure:

CLEVVE-SCH2CH2CONH2 CLEVVE-SCH 2 CH 2 CONH 2

CLKEVVE-SCH2CH2CONH2 CLKEVVE-SCH 2 CH 2 CONH 2

CLKKEVVE-SCH2CH2CONH2 CLKKEVVE-SCH 2 CH 2 CONH 2

CLKEVVEE-SCH2CH2CONH2 CLKEVVEE-SCH 2 CH 2 CONH 2

CLEKKEVVE-SCH2CH2CONH2 CLEKKEVVE-SCH 2 CH 2 CONH 2

CLKEKKEVVE-SCH2CH2CONH2 CLKEKKEVVE-SCH 2 CH 2 CONH 2

CLKEVVEKEVVE-SCH2CH2CONH2 CLKEVVEKEVVE-SCH 2 CH 2 CONH 2

CLKEVVEEAE-SCH2CH2CONH2 CLKEVVEEAE-SCH 2 CH 2 CONH 2

CLKEVVEEA-SCH2CH2CONH2 CLKEVVEEA-SCH 2 CH 2 CONH 2

CLKEVVEEAEN-SCH2CH2CONH2 CLKEVVEEAEN-SCH 2 CH 2 CONH 2

CLLEVVE-SCH2CH2CONH2 CLLEVVE-SCH 2 CH 2 CONH 2

CLLKEVVE-SCH2CH2CONH2 CLLKEVVE-SCH 2 CH 2 CONH 2

CLLKKEVVE-SCH2CH2CONH2 CLLKKEVVE-SCH 2 CH 2 CONH 2

CLLKEVVEE-SCH2CH2CONH2 CLLKEVVEE-SCH 2 CH 2 CONH 2

CLLEKKEVVE-SCH2CH2CONH2 CLLEKKEVVE-SCH 2 CH 2 CONH 2

CLLKEKKEVVE-SCH2CH2CONH2 CLLKEKKEVVE-SCH 2 CH 2 CONH 2

CLLKEVVEKEVVE-SCH2CH2CONH2 CLLKEVVEKEVVE-SCH 2 CH 2 CONH 2

CLLKEVVEEAE-SCH2CH2CONH2 CLLKEVVEEAE-SCH 2 CH 2 CONH 2

CLLKEVVEEA-SCH2CH2CONH2 CLLKEVVEEA-SCH 2 CH 2 CONH 2

CLLKEVVEEAEN-SCH2CH2CONH2，其中，L＝CLLKEVVEEAEN-SCH 2 CH 2 CONH 2 , where L=

-NHCH2CH2OCH2COO-。 -NHCH2CH2OCH2COO- . _

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中将任一前述(I)、(IV)、(VII)组的化合物以任何已知的环合方法进行环合，得到(VIII)组所示的环状化合物：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein any of the aforementioned compounds of (I), (IV), (VII) groups are combined with any known The cyclization method carries out cyclization, obtains the cyclic compound shown in (VIII) group:

环(X1-Y1-Y2-X2)Ring (X 1 -Y 1 -Y 2 -X 2 )

环(X1-X2-Y1-Y2-X3)Ring (X 1 -X 2 -Y 1 -Y 2 -X 3 )

环(X1-X2-X3-Y1-Y2-X4)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

环(X1-X2-Y1-Y2-X3-X4)Ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

环(X1-X2-X3-Y1-Y2-X4-X5)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

环(X1-X2-Y1-Y2-X3-X4-Y3)Ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

环(X1-X2-X3-Y1-Y2-X4-X5-Y3)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

环(X1-X2-Y1-Y2-X3-X4-Y3-X5)Ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

环(X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)Ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

环(X1-X2-X3-X4-Y1-Y2-X5)Ring (X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

环(X1-X2-X3-X4-X5-Y1-Y2-X6)Ring (X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

环(X1-X2-X3-X4-X5-X6-Y1-Y2-X7)Ring (X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

环(X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)Ring (X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

环(X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)Ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

或是以下结构：or the following structure:

环(Cys-X1-Y1-Y2-X2)Ring (Cys-X 1 -Y 1 -Y 2 -X 2 )

环(Cys-X1-X2-Y1-Y2-X3)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 )

环(Cys-X1-X2-X3-Y1-Y2-X4)Ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

环(Cys-X1-X2-Y1-Y2-X3-X4)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

环(Cys-X1-X2-X3-Y1-Y2-X4-X5)Ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

环(Cys-X1-X2-Y1-Y2-X3-X4-Y3)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3)Ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)Ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)Ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

环(Cys-X1-X2-X3-X4-Y1-Y2-X5)Ring (Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

环(Cys-X1-X2-X3-X4-X5-Y1-Y2-X6)Ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

环(Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)Ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

环(Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)Ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

或者是以下化合物：or the following compounds:

环(Z1-Ln-X1-Y1-Y2-X2)Ring (Z 1 -L n -X 1 -Y 1 -Y 2 -X 2 )

环(Z1-Ln-X1-X2-Y1-Y2-X3)Ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 )

环(Z1-Ln-X1-X2-X3-Y1-Y2-X4)Ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

环(Z1-Ln-X1-X2-Y1-Y2-X3-X4)Ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5)Ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3)Ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)Ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)Ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

环(Z1-Ln-X1-X2-X3-X4-Y1-Y2-X5)Ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

环(Z1-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6)Ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

环(Z1-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)Ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

环(Z1-Ln-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)Ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)    (VIII)Ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 ) (VIII)

其中，X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如前述所示，Z1的定义如前述所示、Ln的定义如前述所示。Among them, the definitions of X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are as mentioned above, and the definition of Z 1 The definition is as described above, and the definition of L n is as described above.

优选的，本发明所述的四肽至十一肽衍生物及其立体异构体，其为以下结构：Preferably, the tetrapeptide to undecapeptide derivatives and their stereoisomers described in the present invention have the following structures:

环(EVVE)Ring (EVVE)

环(KEVVE)Ring (KEVVE)

环(KKEVVE)Ring (KKEVVE)

环(KEVVEE)Ring (KEVVEE)

环(EKKEVVE)Ring (EKKEVVE)

环(KEKKEVVE)Ring (KEKKEVVE)

环(KEVVEKEVVE)Ring (KEVVEKEVVE)

环(KEVVEEAE)Ring (KEVVEEAE)

环(KEVVEEA)Ring (KEVVEEA)

环(KEVVEEAEN)Ring (KEVVEEAEN)

或者是or

环(CEVVE)Ring (CEVVE)

环(CKEVVE)Ring (CKEVVE)

环(CKKEVVE)Ring (CKKEVVE)

环(CKEVVEE)Ring (CKEVVEE)

环(CEKKEVVE)Ring (CEKKEVVE)

环(CKEKKEVVE)Ring (CKEKKEVVE)

环(CKEVVEKEVVE)Ring (CKEVVEKEVVE)

环(CKEVVEEAE)Ring (CKEVVEEAE)

环(CKEVVEEA)Ring (CKEVVEEA)

环(CKEVVEEAEN)Ring (CKEVVEEAEN)

或者是：or it could be:

环(CLEVVE)Ring (CLEVVE)

环(CLKEVVE)Ring (CLKEVVE)

环(CLKKEVVE)Ring (CLKKEVVE)

环(CLKEVVEE)Loop (CLKEVVEE)

环(CLEKKEVVE)Ring (CLEKKEVVE)

环(CLKEKKEVVE)Ring (CLKEKKEVVE)

环(CLKEVVEKEVVE)Ring (CLKEVVEKEVVE)

环(CLKEVVEEAE)Loop (CLKEVVEEAE)

环(CLKEVVEEA)Loop (CLKEVVEEA)

环(CLKEVVEEAEN)Ring (CLKEVVEEAEN)

或者是：or it could be:

环(CLLEVVE)Loop (CLLEVVE)

环(CLLKEVVE)Ring (CLLKEVVE)

环(CLLKKEVVE)Ring (CLLKKEVVE)

环(CLLKEVVEE)Ring (CLLKEVVEE)

环(CLLEKKEVVE)Ring (CLLEKKEVVE)

环(CLLKEKKEVVE)Ring (CLLKEKKEVVE)

环(CLLKEVVEKEVVE)Ring (CLLKEVVEKEVVE)

环(CLLKEVVEEAE)Ring (CLLKEVVEEAE)

环(CLLKEVVEEA)Ring (CLLKEVVEEA)

环(CLLKEVVEEAEN)。Ring (CLLKEVVEEAEN).

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中所述(VIII)组的化合物中任意位点的氨基经过PEG修饰的，得到如下所示(XI)组的化合物，其中所述氨基包括N-端氨基和天然氨基酸或者非天然氨基酸的侧链氨基，Another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein the amino group at any position in the compound of (VIII) group is modified by PEG to obtain the following (XI) the compound of group, wherein said amino group comprises N-terminal amino group and side chain amino group of natural amino acid or non-natural amino acid,

[PEG-X-(CH2)MCO-NH]Z-环(X1-Y1-Y2-X2)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X3-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X3-X4-Y3-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-Y1-Y2-X2)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-Y1-Y2-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X3-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

或者是：or it could be:

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-Y1-Y2-X2)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-Y1-Y2-X3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

[PEG-X-(CH2)MCO-NH]Z-环(Z1-Ln -X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7) (XI)，[PEG-X-(CH 2 ) M CO-NH] Z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 ) (XI),

其中所述PEG表示：RO(CH2CH2O)n-CH2CH2，R＝H或C和CH3，n＝5-1000；X＝O、NH或NHCO；m＝0-6；Z＝1-3、X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如前述所示，Z1、Ln的定义如前述所示。Wherein said PEG represents: RO(CH 2 CH 2 O) n -CH 2 CH 2 , R=H or C and CH 3 , n=5-1000; X=O, NH or NHCO; m=0-6; Z=1-3, X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , X 7 , the definitions of Y 1 , Y 2 , Y 3 , and Y 4 are as mentioned above , Z 1 , and L n are as defined above.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，包括以下化合物：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, including the following compounds:

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVEE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVEE)

PEG-CH2CH2-X-(CH2)mCO-环(CEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CKEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVEKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVEKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVEEAE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVEEAE)

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVEEA)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVEEA)

PEG-CH2CH2-X-(CH2)mCO-环(CKEVVEEAEN)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CKEVVEEAEN)

或者是以下结构：or the following structure:

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVEE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVEE)

PEG-CH2CH2-X-(CH2)mCO-环(CLEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVEKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVEKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVEEAE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVEEAE)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVEEA)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVEEA)

PEG-CH2CH2-X-(CH2)mCO-环(CLKEVVEEAEN)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLKEVVEEAEN)

或者是以下结构的化合物：Or a compound of the following structure:

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVEE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVEE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEKKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEKKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVEKEVVE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVEKEVVE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVEEAE)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVEEAE)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVEEA)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVEEA)

PEG-CH2CH2-X-(CH2)mCO-环(CLLKEVVEEAEN)PEG-CH 2 CH 2 -X-(CH 2 ) m CO-ring (CLLKEVVEEAEN)

其中，X＝O、NH、或NHCO；M＝0-6。Wherein, X=O, NH, or NHCO; M=0-6.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中(VIII)组的化合物中任意位点的羧基经过PEG修饰，得到如下(IX)所示的化合物，其中所述氨基包括C-端氨基和天然氨基酸或者非天然氨基酸的侧链羧基：Another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein the carboxyl group at any position in the compound of group (VIII) is modified by PEG to obtain the following (IX) The compound, wherein the amino group includes a C-terminal amino group and a side chain carboxyl group of a natural amino acid or an unnatural amino acid:

[PEG-X-CO]z-环(X1-Y1-Y2-X2)[PEG-X-CO] z -ring (X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X3)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X3-X4)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X3-X4-Y3-X5)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-CO]z-环(X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-CO]z-环(X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-CO]z-环(X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-CO]z-环(X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-CO] z -ring (X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

[PEG-X-CO]z-环(X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-CO] z -ring (X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 )

[PEG-X-CO]z-环(Cys-X1-Y1-Y2-X2)[PEG-X-CO] z -ring (Cys-X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X3)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-Y1-Y2-X4)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X3-X4)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-CO]z-环(Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-CO]z-环(Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-CO] z -ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

或者是以下结构：or the following structure:

[PEG-X-CO]z-环(Z1-Ln-X1-Y1-Y2-X2)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -Y 1 -Y 2 -X 2 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-Y1-Y2-X3)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-X4-Y1-Y2-X5)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)[PEG-X-CO] z -ring (Z 1 -L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

[PEG-X-CO]z-环(Z1-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)[PEG-X-CO] z -ring (Z 1 -X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

[PEG-X-CO]z-环(Z1-Ln-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)(IX)[PEG-X-CO] z -ring(Z 1 -L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y3-Y4-X 7 )(IX )

其中，X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如权利要求1所示，Z1、Ln的定义如前述所示；X＝O或NH，Z＝1-3。Among them, X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are as defined in claim 1, Z 1. The definition of L n is as mentioned above; X=O or NH, Z=1-3.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，选自：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, selected from:

[PEG-X-CO]z-环(EVVE)[PEG-X-CO] z -ring (EVVE)

[PEG-X-CO]z环(KEVVE)[PEG-X-CO] z ring (KEVVE)

[PEG-X-CO]z环(KKEVVE)[PEG-X-CO] z ring (KKEVVE)

[PEG-X-CO]z环(KEVVEE)[PEG-X-CO] z ring (KEVVEE)

[PEG-X-CO]z环(EKKEVVE)[PEG-X-CO] z ring (EKKEVVE)

[PEG-X-CO]z环(KEKKEVVE)[PEG-X-CO] z ring (KEKKEVVE)

[PEG-X-CO]z环(KEVVEKEVVE)[PEG-X-CO] z ring (KEVVEKEVVE)

[PEG-X-CO]z环(KEVVEEAE)[PEG-X-CO] z ring (KEVVEEAE)

[PEG-X-CO]z环(KEVVEEA)[PEG-X-CO] z ring (KEVVEEA)

[PEG-X-CO]z环(KEVVEEAEN)[PEG-X-CO] z ring (KEVVEEAEN)

[PEG-X-CO]z-环(CEVVE)[PEG-X-CO] z -ring (CEVVE)

[PEG-X-CO]z环(CKEVVE)[PEG-X-CO] z ring (CKEVVE)

[PEG-X-CO]z环(CKKEVVE)[PEG-X-CO] z ring (CKKEVVE)

[PEG-X-CO]z环(CKEVVEE)[PEG-X-CO] z ring (CKEVVEE)

[PEG-X-CO]z环(CEKKEVVE)[PEG-X-CO] z ring (CEKKEVVE)

[PEG-X-CO]z环(CKEKKEVVE)[PEG-X-CO] z ring (CKEKKEVVE)

[PEG-X-CO]z环(CKEVVEKEVVE)[PEG-X-CO] z ring (CKEVVEKEVVE)

[PEG-X-CO]z环(CKEVVEEAE)[PEG-X-CO] z ring (CKEVVEEAE)

[PEG-X-CO]z环(CKEVVEEA)[PEG-X-CO] z ring (CKEVVEEA)

[PEG-X-CO]z环(CKEVVEEAEN)[PEG-X-CO] z ring (CKEVVEEAEN)

或者是以下结构：or the following structure:

[PEG-X-CO]z环(CLEVVE)[PEG-X-CO] z ring (CLEVVE)

[PEG-X-CO]z环(CLKEVVE)[PEG-X-CO] z ring (CLKEVVE)

[PEG-X-CO]z环(CLKKEVVE)[PEG-X-CO] z ring (CLKKEVVE)

[PEG-X-CO]z环(CLKEVVEE)[PEG-X-CO] z ring (CLKEVVEE)

[PEG-X-CO]z环(CLEKKEVVE)[PEG-X-CO] z ring (CLEKKEVVE)

[PEG-X-CO]z环(CLKEKKEVVE)[PEG-X-CO] z ring (CLKEKKEVVE)

[PEG-X-CO]z环(CLKEVVEKEVVE)[PEG-X-CO] z ring (CLKEVVEKEVVE)

[PEG-X-CO]z环(CLKEVVEEAE)[PEG-X-CO] z ring (CLKEVVEEAE)

[PEG-X-CO]z环(CLKEVVEEA)[PEG-X-CO] z ring (CLKEVVEEA)

[PEG-X-CO]z环(CLKEVVEEAEN)[PEG-X-CO] z ring (CLKEVVEEAEN)

或者是以下结构的化合物：Or a compound of the following structure:

[PEG-X-CO]z环(CLLEVVE)[PEG-X-CO] z ring (CLLEVVE)

[PEG-X-CO]z环(CLLKEVVE)[PEG-X-CO] z ring (CLLKEVVE)

[PEG-X-CO]z环(CLLKKEVVE)[PEG-X-CO] z ring (CLLKKEVVE)

[PEG-X-CO]z环(CLLKEVVEE)[PEG-X-CO] z ring (CLLKEVVEE)

[PEG-X-CO]z环(CLLEKKEVVE)[PEG-X-CO] z ring (CLLEKKEVVE)

[PEG-X-CO]z环(CLLKEKKEVVE)[PEG-X-CO] z ring (CLLKEKKEVVE)

[PEG-X-CO]z环(CLLKEVVEKEVVE)[PEG-X-CO] z ring (CLLKEVVEKEVVE)

[PEG-X-CO]z环(CLLKEVVEEAE)[PEG-X-CO] z ring (CLLKEVVEEAE)

[PEG-X-CO]z环(CLLKEVVEEA)[PEG-X-CO] z ring (CLLKEVVEEA)

[PEG-X-CO]z环(CLLKEVVEEAEN)。[PEG-X-CO] z- ring (CLLKEVVEEAEN).

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其中(VIII)组的化合物在肽序列或已有半胱氨酸位置或序列中任意位置引入半胱氨酸后，经选自PEG-MAL，PEG-VS和PEG-IODS的方法修饰，得到如下所示的(X)组的化合物，其中PEG可以为链状、星状、环状、多臂型结构：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, wherein the compound of group (VIII) is introduced in the peptide sequence or at the existing cysteine position or at any position in the sequence After cysteine, modified by a method selected from PEG-MAL, PEG-VS and PEG-IODS, the compound of (X) group as shown below is obtained, wherein PEG can be chain, star, ring, poly Arm structure:

PEG-M-环(Cys-X1-Y1-Y2-X2)PEG-M-ring (Cys-X 1 -Y 1 -Y 2 -X 2 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X3)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X3-X4)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4-X5)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

PEG-M-环(Cys-X1-X2-X3-X4-Y1-Y2-X5)PEG-M-ring (Cys-X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

PEG-M-环(Cys-X1-X2-X3-X4-X5-Y1-Y2-X6)PEG-M-ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )

PEG-M-环(Cys-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)PEG-M-ring (Cys-X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

PEG-M-环(Cys-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)PEG-M-ring (Cys-X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

也可以是以下结构：The following structures are also possible:

PEG-M-环(Cys-Ln-X1-Y1-Y2-X2)PEG-M-ring (Cys-L n -X 1 -Y 1 -Y 2 -X 2 )

PEG-M-环(Cys-Ln-X1-X2-Y1-Y2-X3)PEG-M-ring (Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 )

PEG-M-环(Cys-Ln-X1-X2-X3-Y1-Y2-X4)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 )

PEG-M-环(Cys-Ln-X1-X2-Y1-Y2-X3-X4)PEG-M-ring (Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 )

PEG-M-环(Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 )

PEG-M-环(Cys-Ln-X1-X2-Y1-Y2-X3-X4-Y3)PEG-M-ring (Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 )

PEG-M-环(Cys-Ln-X1-X2-Y1-Y2-X3-X4-Y3-X5-Y4)PEG-M-ring (Cys-L n -X 1 -X 2 -Y 1 -Y 2 -X 3 -X 4 -Y 3 -X 5 -Y 4 )

PEG-M-环(Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-Y3-X6-Y4)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -Y 3 -X 6 -Y 4 )

PEG-M-环(Cys-Ln-X1-X2-X3-X4-X5-X6-Y1-Y2-X7)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -Y 1 -Y 2 -X 7 )

PEG-M-环(Cys-X1-X2-Y1-Y2-X4-X5-X6-Y3-Y4-X7)PEG-M-ring (Cys-X 1 -X 2 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

PEG-M-环(Cys-Ln-X1-X2-X3-Y1-Y2-X4-X5-X6-Y3-Y4-X7)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -Y 1 -Y 2 -X 4 -X 5 -X 6 -Y 3 -Y 4 -X 7 )

PEG-M-环(Cys-Ln-X1-X2-X3-X4-Y1-Y2-X5)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -X 4 -Y 1 -Y 2 -X 5 )

PEG-M-环(Cys-Ln-X1-X2-X3-X4-X5-Y1-Y2-X6)(X)PEG-M-ring (Cys-L n -X 1 -X 2 -X 3 -X 4 -X 5 -Y 1 -Y 2 -X 6 )(X)

其中，in,

其中X1、Z1可以为半胱氨酸，通过侧链硫原子和M基团共价相连；X1、X2、Y1、Y2、X3、X4、X5、X6、X7，Y1、Y2、Y3、Y4的定义如前述所示，Z1、Ln的定义如前述所示。Among them, X 1 and Z 1 can be cysteine, which is covalently connected to the M group through the side chain sulfur atom; X 1 , X 2 , Y 1 , Y 2 , X 3 , X 4 , X 5 , X 6 , The definitions of X 7 , Y 1 , Y 2 , Y 3 , and Y 4 are as described above, and the definitions of Z 1 and L n are as described above.

本发明的又一个方面涉及如下所述的四肽至十一肽衍生物及其立体异构体，其选自：Yet another aspect of the present invention relates to tetrapeptide to undecapeptide derivatives and stereoisomers thereof as described below, which are selected from:

[PEG-M]-环(CEVVE)[PEG-M]-ring (CEVVE)

[PEG-M]-环(CKEVVE)[PEG-M]-ring (CKEVVE)

[PEG-M]-环(CKKEVVE)[PEG-M]-ring (CKKEVVE)

[PEG-M]-环(CKEVVEE)[PEG-M]-ring (CKEVVEE)

[PEG-M]-环(CEKKEVVE)[PEG-M]-ring (CEKKEVVE)

[PEG-M]-环(CKEKKEVVE)[PEG-M]-ring (CKEKKEVVE)

[PEG-M]环(CKEVVEKEVVE)[PEG-M] ring (CKEVVEKEVVE)

[PEG-M]环(CKEVVEEAE)[PEG-M] ring (CKEVVEEAE)

[PEG-M]-环(CKEVVEEA)[PEG-M]-ring (CKEVVEEA)

[PEG-M]-环(CKEVVEEAEN)[PEG-M]-ring (CKEVVEEAEN)

或者是以下结构：or the following structure:

[PEG-M]-环(CLEVVE)[PEG-M]-ring (CLEVVE)

[PEG-M]-环(CLKEVVE)[PEG-M]-ring (CLKEVVE)

[PEG-M]-环(CLKKEVVE)[PEG-M]-ring (CLKKEVVE)

[PEG-M]-环(CLKEVVEE)[PEG-M]-ring (CLKEVVEE)

[PEG-M]-环(CLEKKEVVE)[PEG-M]-ring (CLEKKEVVE)

[PEG-M]-环(CLKEKKEVVE)[PEG-M]-ring (CLKEKKEVVE)

[PEG-M]-环(CLKEVVEKEVVE)[PEG-M]-ring (CLKEVVEKEVVE)

[PEG-M]-环(CLKEVVEEAE)[PEG-M]-ring (CLKEVVEEAE)

[PEG-M]-环(CLKEVVEEA)[PEG-M]-ring (CLKEVVEEA)

[PEG-M]-环(CLKEVVEEAEN)[PEG-M]-ring (CLKEVVEEAEN)

或者是以下结构的化合物：Or a compound of the following structure:

[PEG-M]-环(CLLEVVE)[PEG-M]-ring (CLLEVVE)

[PEG-M]-环(CLLKEVVE)[PEG-M]-ring (CLLKEVVE)

[PEG-M]-环(CLLKKEVVE)[PEG-M]-ring (CLLKKEVVE)

[PEG-M]-环(CLLKEVVEE)[PEG-M]-ring (CLLKEVVEE)

[PEG-M]环(CLLEKKEVVE)[PEG-M] ring (CLLEKKEVVE)

[PEG-M]-环(CLLKEKKEVVE)[PEG-M]-ring (CLLKEKKEVVE)

[PEG-M]-环(CLLKEVVEKEVVE)[PEG-M]-ring (CLLKEVVEKEVVE)

[PEG-M]-环(CLLKEVVEEAE)[PEG-M]-ring (CLLKEVVEEAE)

[PEG-M]-环(CLLKEVVEEA)[PEG-M]-ring (CLLKEVVEEA)

[PEG-M]-环(CLLKEVVEEAEN)。[PEG-M]-ring (CLLKEVVEEAEN).

本发明还涉及至少一种选自上述(I)、(II)、(III)、、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)组的化合物或其任一组合在制备用于治疗和/或预防免疫缺陷或免疫力低下有关疾病的药物中用途。The present invention also relates to at least one selected from the above (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) The compounds of the group or any combination thereof are used in the preparation of medicines for treating and/or preventing immunodeficiency or immunocompromised diseases.

本发明还涉及药物组合物，其中包括至少一种选自上述(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)组的化合物，及药用载体或赋形剂。The present invention also relates to a pharmaceutical composition comprising at least one selected from the above-mentioned (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) ), a compound of group (X), and a pharmaceutically acceptable carrier or excipient.

本发明还涉及制备上述(I)、(II)、(III)、、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)组的化合物的方法，其包括用已知的溶液法和固相法合成。The present invention also relates to preparation of above-mentioned (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) group compound Methods, which include synthesis using known solution methods and solid phase methods.

本发明所用的PEG-OH结构为：RO(CH2CH2O)NCH2CH2OH，其中R＝H或者CH3，平均分子量由几百到几万的PEG-OH可以作为商品化试剂购买到，PEG-NH2、PEG-NHCOCH2CH2COOH可以通过如下途径反应获得：The structure of PEG-OH used in the present invention is: RO(CH 2 CH 2 O)NCH 2 CH 2 OH, wherein R=H or CH 3 , and PEG-OH with an average molecular weight ranging from several hundred to tens of thousands can be purchased as a commercial reagent It is known that PEG-NH 2 and PEG-NHCOCH 2 CH 2 COOH can be obtained through the following reaction:

Figure G04196459220041207D000251
Figure G04196459220041207D000251

具体的，在PEG的一端先引入氨基、羧基或制备PEG化的氨基酸，再用溶液法或者固相合成法偶联到肽序列中去，可实现对多肽的N-端氨基，C-端羧基，Lys侧链氨基，Asp或Glu侧链羧基的修饰，将PEG-NH2与马来酸酐，乙烯基亚砜、碘代乙酸酐反应可得到PEG-MAL、PEG-VS、PEG-IODO。Specifically, amino groups, carboxyl groups or PEGylated amino acids are first introduced at one end of PEG, and then coupled to the peptide sequence by solution method or solid-phase synthesis method, which can realize the N-terminal amino and C-terminal carboxyl groups of the polypeptide. , Lys side chain amino group, modification of Asp or Glu side chain carboxyl group, reacting PEG-NH 2 with maleic anhydride, vinyl sulfoxide, and iodoacetic anhydride to obtain PEG-MAL, PEG-VS, and PEG-IODO.

本发明所涉及的Wang Resin、MBHA Resin、DCC、HOBt、HBTU、BOP、Fmoc氨基酸、BOC保护氨基酸，TFA、DIEA、m PEG-OH、NMM等试剂均通过购买获得。所有非天然氨基酸均由本实验室合成并拆分。Wang Resin, MBHA Resin, DCC, HOBt, HBTU, BOP, Fmoc amino acid, BOC protected amino acid, TFA, DIEA, m PEG-OH, NMM and other reagents involved in the present invention are all purchased. All unnatural amino acids were synthesized and resolved in our laboratory.

根据本发明，与免疫缺陷或免疫功能低下有关的疾病有：乙型肝炎、丙型肝炎、非小细胞肺癌、黑色素瘤、艾滋病等。According to the present invention, diseases related to immunodeficiency or low immune function include: hepatitis B, hepatitis C, non-small cell lung cancer, melanoma, AIDS and the like.

根据本发明，所用的术语如Tα1(17-27)，指的是在Tα1中从N-端到C-端相应位置的序列。According to the present invention, the term used, such as Tα1(17-27), refers to the sequence in Tα1 corresponding to the position from the N-terminus to the C-terminus.

本发明所示(I)-(X)组的Tα1活性片段衍生物及其立体异构体或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。The Tα1 active fragment derivatives and stereoisomers of groups (I)-(X) shown in the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dose, and the route of administration can be enteral or parenteral, Such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneal or rectal, etc.

给药剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。Dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder injections wait. It can be common preparations, sustained-release preparations, controlled-release preparations and various microparticle drug delivery systems.

为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子，包括例如稀释剂与吸收剂，如淀粉、糊精、乳糖、甘露醇、蔗糖、葡萄糖、硫酸钙、氯化钠、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，如季铵盐、十二烷基硫酸钠等；润滑剂，如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将给药单元制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将给药单元制成胶囊，将有效成分式(I)-(X)Tα1活性片段衍生物或其立体异构体与上述的各种载体混合，并将由此得到的混合物置于硬胶囊或软胶囊中。也可将有效成分(I)-(X)组的三肽衍生物或其立体异构体制成微囊剂，混悬于水性介质中制成混悬剂，亦可装入硬胶囊中或制成注射剂应用。为了将给药单元制成注射用制剂，如溶液剂、乳剂、冻干粉针剂和混悬剂，可以使用本领域常用的所有稀释剂，如水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧基化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。Various carriers known in the art can be widely used for tableting unit dosage forms. Examples of carriers include, for example, diluents and absorbents such as starch, dextrin, lactose, mannitol, sucrose, glucose, calcium sulfate, sodium chloride, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin paste, sodium carboxymethylcellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbate Sugar alcohol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers , such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talcum powder, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. In order to formulate a dosage unit into a pellet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethylcellulose, etc. In order to formulate the administration unit into a suppository, various carriers known in the art can be widely used. Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like. In order to make the administration unit into a capsule, the active ingredient formula (I)-(X)Tα1 active fragment derivative or its stereoisomer is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard capsule or in soft capsules. The tripeptide derivatives of the active ingredients (I)-(X) group or their stereoisomers can also be made into microcapsules, suspended in an aqueous medium to make a suspension, and can also be packed into hard capsules or prepared into injection applications. For the preparation of the administration unit into injection preparations, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, such as water, ethanol, polyethylene glycol, 1,3-propylene glycol , Ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added.

此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

本发明(I)-(X)组的化合物，衍生物或其立体异构体的给药剂量取决于许多因素，例如所要预防或治疗(I)-(X)组的Tα1活性片段衍生物疾病的性质和严重程度，患者或动物的性别、年龄、体重及个体反应，所用的具体化合物，给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个，例如二、在、四个剂量形式给药。The compound of (I)-(X) group of the present invention, the administration dosage of derivative or its stereoisomer depends on many factors, for example will prevent or treat the Tα1 active fragment derivative disease of (I)-(X) group The nature and severity of the disease, the sex, age, body weight and individual response of the patient or animal, the specific compound used, the route of administration and the frequency of administration, etc. The above-mentioned dosage may be administered in a single dosage form or divided into several, for example, two, three or four dosage forms.

在本发明中使用的缩写具有下面的含义：Abbreviations used in the present invention have the following meanings:

Ac        乙酰基               HOBt          1-羟基苯并三唑Ac Acetyl HOBt 1-Hydroxybenzotriazole

Ala(A)    丙氨酸               HOSu          N-羟基琥珀酰亚胺Ala(A) Alanine HOSu HOSu N-Hydroxysuccinimide

Alloc     烯丙氧羰基           IL            白细胞介素Alloc Allyloxycarbonyl IL IL Interleukin

Allyl     烯丙基               IFN           干扰素Allyl Allyl IFN Interferon

Asn(N)    天冬酰氨             X(？)         -S-CH2CH2CONH2 Asn(N) Asparagine X(?) -S-CH 2 CH 2 CONH 2

Asp(D)    天冬氨酸             Lys(K)        赖氨酸Asp(D) Aspartic Acid Lys(K) Lysine

Boc       叔丁氧羰基           NK            自然杀伤Boc tert-butoxycarbonyl NK NK Natural Killer

Bzl       苄基                 OD            光密度Bzl Benzyl OD OD Optical Density

PMeOBzl   对甲氧基苄基         Y(？)         -NHCH2CH2OCH2COO-PMeOBzl p-methoxybenzyl Y(?) -NHCH 2 CH 2 OCH 2 COO-

tBU       叔丁氧羰基           MPEG          单甲氧基聚乙二醇tBU tert-butoxycarbonyl MPEG monomethoxypolyethylene glycol

ConA      刀豆蛋白             Val(V)        缬氨酸ConA Concanavalin Val(V) Valine

CY        环磷酰氨             P(Ph3)        三苯基磷CY Cyclophosphamide P(Ph 3 ) Triphenylphosphine

Cys(C)    半胱氨酸             HF            氟化氢Cys(C) Cysteine HF HF Hydrogen Fluoride

DCM       二氯甲烷             Ts-Cl         对甲苯磺酰氯DCM dichloromethane Ts-Cl p-toluenesulfonyl chloride

DMF       N，N-二甲基甲酰胺    RP-HPLC       反向高效液相色谱DMF N,N-Dimethylformamide RP-HPLC Reverse High Performance Liquid Chromatography

TFA       三氟醋酸             TEA           三乙胺TFA Trifluoroacetic Acid TEA Triethylamine

EDT       乙二硫醇             TLC           薄层色谱EDT Thin-Layer Chromatography

DIEA      二异丙基乙胺         mPEG-MAL      单甲氧基聚乙二醇化马DIEA Diisopropylethylamine mPEG-MAL Monomethoxy PEG-MAL

BOP       苯并三唑-1-氧-三(二  Glu(E)        谷氨酸BOP Benzotriazole-1-oxo-tris(di) Glu(E) Glutamic acid

Fmoc      芴甲氧羰基           DCC           二环己基碳二亚胺Fmoc fluorenylmethoxycarbonyl DCC dicyclohexylcarbodiimide

ESI-MS    电喷雾质谱           ELISA         酶联免疫实验ESI-MS Electrospray Mass Spectrometry ELISA ELISA

MALDI-TOF-MS  基质辅助激光解吸MALDI-TOF-MS matrix-assisted laser desorption

离子化飞行时间质谱ionization time-of-flight mass spectrometry

本发明中，所有氨基酸构型除注明为D-型外，均为L-型。In the present invention, all amino acid configurations are L-type except for D-type.

实施例Example

下列实施例代表本发明的说明性实施方案，但并不意味本发明受此实施例的限制。The following examples represent illustrative embodiments of the invention, but the invention is not meant to be limited by these examples.

实施例所用的固相合成载体Wang树脂从ACT公司购得，DCC、HOBt、HBTU、Fmoc保护氨基酸均由上海吉尔生化购得，TFA为ACROS公司产品，平均分子量为2000的PEG-OH为Sigma公司产品。The solid-phase synthesis carrier Wang resin used in the examples was purchased from ACT Company, DCC, HOBt, HBTU, and Fmoc protected amino acids were purchased from Shanghai Jill Biochemical, TFA was a product of ACROS Company, and PEG-OH with an average molecular weight of 2000 was purchased from Sigma Company product.

实施例1Example 1

BocNHCH2CH2OCH2COOH的合成： Synthesis of BocNHCH2CH2OCH2COOH :

Figure G04196459220041207D000281
Figure G04196459220041207D000281

●BocNHCH2CH2OH的合成●Synthesis of BocNHCH 2 CH 2 OH

将水30ml加入250ml反应器中，NH2CH2CH2OH6.1g(100mmol)加入反应器中，冷却到0℃。在冰浴条件下，(Boc)2O21.82g(100mmol)溶于30ml二氧六环中加入到反应器中，控制温度在0℃以下，滴加1mol/LnaOH溶液100ml，40min滴加完，自然升至室温，继续反应12小时，(Boc)2O消失，停止反应，点板检测，反应液用乙酸乙酯萃取三次，用饱和NaCl溶液洗涤，用无水Na2SO4干燥，减压蒸干，得到15.6g无色油状物，收率97.2％。Add 30ml of water into a 250ml reactor, add 6.1g (100mmol) of NH 2 CH 2 CH 2 OH into the reactor, and cool to 0°C. Under ice-bath conditions, (Boc) 2 O2 1.82g (100mmol) was dissolved in 30ml of dioxane and added to the reactor, the temperature was controlled below 0°C, 100ml of 1mol/L NaOH solution was added dropwise, and the dropwise addition was completed in 40min. Naturally rise to room temperature, continue to react for 12 hours, (Boc) 2 O disappears, stop the reaction, spot plate detection, the reaction solution is extracted three times with ethyl acetate, washed with saturated NaCl solution, dried with anhydrous Na 2 SO4, evaporated under reduced pressure After drying, 15.6 g of colorless oil was obtained, yield 97.2%.

●BocNHCH2CH2OCH2COOH的合成●Synthesis of BocNHCH 2 CH 2 OCH 2 COOH

于500ml三口瓶中加入重蒸DMF350ml，BocNH2CH2OH10.54g(0.1mol)，加入NaH(52％)8.15g(0.2mol)，至溶液中无气泡冒出，然后滴加BrCH2COOH13.65g(0.15mmol)的DMF溶液，室温搅拌20小时，进行处理，减压蒸去DMF，以适量水溶解，用适量乙醚萃取两次，水相用饱和硫酸钠调节pH值于2-3之间，用乙酸乙酯萃取水相三次，然后用饱和NaCl溶液洗涤，最后用无水硫酸钠干燥，减压蒸干，得到5.51g浅黄色油状物，收率38％。Add redistilled DMF 350ml, BocNH 2 CH 2 OH 10.54g (0.1mol) in a 500ml three-necked flask, add NaH (52%) 8.15g (0.2mol) until no bubbles come out of the solution, then add BrCH 2 COOH13. 65g (0.15mmol) of DMF solution, stirred at room temperature for 20 hours, processed, evaporated under reduced pressure to remove DMF, dissolved with appropriate amount of water, extracted twice with appropriate amount of ether, and adjusted the pH value of the aqueous phase between 2-3 with saturated sodium sulfate , the aqueous phase was extracted three times with ethyl acetate, then washed with saturated NaCl solution, finally dried with anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 5.51 g of light yellow oil with a yield of 38%.

实施例2：Example 2:

Cys-Glu-Val-Val-Glu-SCH2CH2CONH2的合成： Synthesis of Cys-Glu-Val-Val-Glu- SCH2CH2CONH2 :

350mgMBHA树脂(负载量为0.57mmol/g，0.2mmol)，悬浮于DMF中，依次加入0.12gHOBt，150μL 3-巯基丙酸(1.2mmol)，160mg DCC，加入少量的DCM溶解充分，在室温下磁力搅拌4个小时，用DMF、DCM、MeOH、DCM各洗涤两次，每次两分钟。茚三酮检验呈阴性。然后用50mg半胱氨酸甲酯盐酸盐(0.2mmol)，100mg(0.2mmol)三苯基磷和120μlDIEA(0.2mmol)混合溶于DMF，五分钟后加入树脂中，室温反应两小时，用DMF、DCM、MeOH、DCM洗涤各两次，4倍量的BOC保护的氨基酸、BOP、6倍量的DIEA混合，溶于DMF，五分钟后混合物加入到反应器中，室温反应2小时，以DMF、DCM、MeOH、DCM洗涤，用定性的Ellman实验检测，阴性溶液树脂为无色或淡黄色，如果呈橘红色则再以上述缩合配料量减半反应一个小时，应用BOC/Bzl固相缩合体系从C端逐步延长肽链，以4NHCl/DIOX(0.05％吲哚)脱保护，缩合反应以2倍量的BOC-AA与2倍量的DCC/HOBt反应1小时，每步缩合均用茚三酮实验检测，如果为阳性则再用4倍量的BOC-AA、BOP和6倍量的DIEA反应半个小时，肽链合成结束以后，线性肽硫酯用HF/P-thiocresol/m-cresol(93/2/5，v/v/v)，在0℃反应1.5小时后从树脂上切下，HF抽干后用钠丝干燥的冰冻的无水乙醚洗涤数次，用10％的冰醋酸提取粗肽，冻干保存。350mg MBHA resin (loading capacity: 0.57mmol/g, 0.2mmol), suspended in DMF, followed by adding 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, adding a small amount of DCM to fully dissolve, magnetically Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM, each for two minutes. Ninhydrin test was negative. Then mix and dissolve DMF with 50mg cysteine methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) triphenylphosphine and 120μl DIEA (0.2mmol), add in the resin after five minutes, react at room temperature for two hours, use DMF, DCM, MeOH, and DCM were washed twice each, mixed with 4 times the amount of BOC-protected amino acids, BOP, and 6 times the amount of DIEA, dissolved in DMF, and the mixture was added to the reactor after five minutes, and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test to detect. Negative solution resin is colorless or light yellow. If it is orange red, then react for one hour with the amount of the above condensation ingredients halved, and use BOC/Bzl solid-state condensation The system gradually extended the peptide chain from the C-terminus, deprotected with 4NHCl/DIOX (0.05% indole), and reacted with 2 times the amount of BOC-AA and 2 times the amount of DCC/HOBt for 1 hour in the condensation reaction. Triketone test, if it is positive, react with 4 times the amount of BOC-AA, BOP and 6 times the amount of DIEA for half an hour. cresol (93/2/5, v/v/v), cut off from the resin after reacting at 0°C for 1.5 hours, dried with HF and washed several times with frozen anhydrous ether dried with sodium silk, and washed with 10% Crude peptides were extracted with glacial acetic acid and stored in freeze-dried form.

实施例三：环(CEVVE)的合成：Embodiment three: the synthesis of ring (CEVVE):

350mgMBHA树脂(负载量为0.57mmol/g，0.2mmol)，悬浮于DMF中，依次加入0.12gHOBt，150μL 3-巯基丙酸(1.2mmol)，160mg DCC，加入少量的DCM溶解充分，在室温下磁力搅拌4个小时，用DMF、DCM、MeOH、DCM各洗涤两次，每次两分钟。茚三酮检验呈阴性。然后用50mg半胱氨酸甲酯盐酸盐(0.2mmol)，100mg(0.2mmol)三苯基磷和120μlDIEA(0.2mmol)混合溶于DMF，五分钟后加入树脂中，室温反应两小时，用DMF、DCM、MeOH、DCM洗涤各两次，4倍量的BOC保护的氨基酸、BOP、6倍量的DIEA混合，溶于DMF，五分钟后混合物加入到反应器中，室温反应2小时，以DMF、DCM、MeOH、DCM洗涤，用定性的Ellman实验检测，阴性溶液树脂为无色或淡黄色，如果呈橘红色则再以上述缩合配料量减半反应一个小时，应用BOC/BZL固相缩合体系从C端逐步延长肽链，以4NHCl/DIOX(0.05％吲哚)脱保护，缩合反应以2倍量的BOC-AA与2倍量的DCC/HOBt反应1小时，每步缩合均用茚三酮实验检测，如果为阳性则再用4倍量的BOC-AA、BOP和6倍量的DIEA反应半个小时，肽链合成结束以后，线性肽硫酯用HF/P-thiocresol/m-cresol(93/2/5，v/v/v)，在0℃反应1.5小时后从树脂上切下，HF抽干后用钠丝干燥的冰冻的无水乙醚洗涤数次，用10％的冰醋酸提取粗肽，冻干保存。也可将环合的缓冲溶液直接提取线性肽硫酯进行环合反应。如果肽硫酯溶解度不好，还可以考虑使用CH3CN/H2O提取粗肽，然后减压抽去CH3CN后冻干保存。350mg MBHA resin (loading capacity: 0.57mmol/g, 0.2mmol), suspended in DMF, sequentially add 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, add a small amount of DCM to dissolve fully, and magnetically Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM, each for two minutes. Ninhydrin test was negative. Then mix and dissolve DMF with 50mg cysteine methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) triphenylphosphine and 120μl DIEA (0.2mmol), add in the resin after five minutes, react at room temperature for two hours, use DMF, DCM, MeOH, and DCM were washed twice each, mixed with 4 times the amount of BOC-protected amino acids, BOP, and 6 times the amount of DIEA, dissolved in DMF, and the mixture was added to the reactor after five minutes, and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test to detect. Negative solution resin is colorless or light yellow. If it is orange-red, then react for one hour with the amount of the above condensation ingredients halved, and use BOC/BZL solid-state condensation The system gradually extended the peptide chain from the C-terminus, deprotected with 4NHCl/DIOX (0.05% indole), and reacted with 2 times the amount of BOC-AA and 2 times the amount of DCC/HOBt for 1 hour in the condensation reaction. Triketone test, if it is positive, react with 4 times the amount of BOC-AA, BOP and 6 times the amount of DIEA for half an hour. cresol (93/2/5, v/v/v), cut off from the resin after reacting at 0°C for 1.5 hours, dried with HF and washed several times with frozen anhydrous ether dried with sodium silk, and washed with 10% Crude peptides were extracted with glacial acetic acid and stored in freeze-dried form. It is also possible to directly extract linear peptide thioesters from the cyclization buffer solution for cyclization reaction. If the solubility of the peptide thioester is not good, you can also consider using CH 3 CN/H 2 O to extract the crude peptide, then extract the CH 3 CN under reduced pressure and freeze-dry it for storage.

线性肽硫酯在用凝胶柱层析初步纯化或者HPLC纯化后进行环合反应，反应在NaHCO3的水溶液中进行，如果溶解度不好可以适当加入CH3CN的浓度，控制pH值在7.3-7.6，加入TCEP防止巯基的氧化，反应由HPLC监控，反应在4小时内完成，产物用ESI-MS进行鉴定。The linear peptide thioester is subjected to cyclization reaction after preliminary purification by gel column chromatography or HPLC purification. The reaction is carried out in an aqueous solution of NaHCO 3 . If the solubility is not good, the concentration of CH 3 CN can be added appropriately to control the pH value at 7.3- 7.6. Add TCEP to prevent the oxidation of sulfhydryl groups. The reaction is monitored by HPLC. The reaction is completed within 4 hours, and the product is identified by ESI-MS.

实施例四：PEG-MAL-环(CKEVVEE的合成Embodiment four: the synthesis of PEG-MAL-ring (CKEVVEE

1mPEG5000-MAL的合成Synthesis of 1mPEG 5000 -MAL

称取mPEG5000-OH 20g(4mmol)置于250ml反应瓶中，加入100mlCH2Cl2，固体溶解后再加入3.0ml Et3N(20mmmol)和3.8gTs-Cl(20mmol)，室温搅拌反应。TLC(CH3OH∶CH2Cl2＝1∶6)监测反应完全后，旋转蒸发除去溶剂，加100ml无水乙醚沉淀出固体，再用无水乙醇重结晶两次，得15.2g mPEG5000-OTs，收率70％。Weigh 20g (4mmol) of mPEG 5000 -OH into a 250ml reaction flask, add 100ml CH 2 Cl 2 , add 3.0ml Et 3 N (20mmmol) and 3.8g Ts-Cl (20mmol) after the solid is dissolved, and stir the reaction at room temperature. TLC (CH 3 OH: CH 2 Cl 2 = 1: 6) monitored the completion of the reaction, removed the solvent by rotary evaporation, added 100 ml of anhydrous ether to precipitate a solid, and then recrystallized twice with absolute ethanol to obtain 15.2 g of mPEG 5000 - OTs, yield 70%.

将15g mPEG5000-OTs(3mmol)溶于30ml DMF，加入1.68g(18mmol)邻苯二甲酰亚胺钾盐，在N2保护下，120℃反应4小时。减压蒸去溶剂，将残余物溶于50ml无水乙醇，加入2.0ml水合肼，回流反应4小时。旋转蒸发除去溶剂，将残余物溶于CH2Cl2，过滤除去不溶物，再将滤液旋转蒸发除去溶剂，用无水乙醚沉淀出固体，再以无水乙醇-乙醚重结晶，得12.5g mPEG5000-NH2，收率83％。Dissolve 15g mPEG 5000 -OTs (3mmol) in 30ml DMF, add 1.68g (18mmol) phthalimide potassium salt, and react at 120°C for 4 hours under the protection of N 2 . The solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of absolute ethanol, 2.0 ml of hydrazine hydrate was added, and the mixture was refluxed for 4 hours. The solvent was removed by rotary evaporation, the residue was dissolved in CH 2 Cl 2 , the insoluble matter was removed by filtration, the solvent was removed by rotary evaporation of the filtrate, the solid was precipitated with anhydrous diethyl ether, and then recrystallized with anhydrous ethanol-diethyl ether to obtain 12.5 g of mPEG 5000 -NH 2 , yield 83%.

将1.25g mPEG5000-NH2溶于10ml二氧六环，加入马来酸酐0.1g，80℃搅拌反应30min。减压蒸去溶剂，加入50ml无水乙醚，冷却沉淀出固体，滤集固体，干燥后得1.10g。将所得固体溶于15ml乙酸酐，加入0.5g乙酸钠，100℃搅拌反应45min。减压蒸去溶剂，将残余物用二氯甲烷溶解，滤去不溶物，向滤液中加入适量活性炭，放置30min，滤除活性炭，将滤液浓缩至干，加入无水乙醚，沉淀出固体，滤集、干燥后得浅黄色固体0.61g mPEG5000-MAL，收率48％。RP-HPLC分析：tR＝36.79min。Dissolve 1.25g of mPEG 5000 -NH 2 in 10ml of dioxane, add 0.1g of maleic anhydride, and stir at 80°C for 30min. The solvent was evaporated under reduced pressure, 50ml of anhydrous diethyl ether was added, and a solid was precipitated by cooling. The solid was collected by filtration and dried to obtain 1.10g. The obtained solid was dissolved in 15ml of acetic anhydride, 0.5g of sodium acetate was added, and the reaction was stirred at 100°C for 45min. Evaporate the solvent under reduced pressure, dissolve the residue with dichloromethane, filter off the insoluble matter, add an appropriate amount of activated carbon to the filtrate, let it stand for 30 minutes, filter out the activated carbon, concentrate the filtrate to dryness, add anhydrous ether, precipitate a solid, filter After collection and drying, 0.61 g of mPEG 5000 -MAL was obtained as a light yellow solid with a yield of 48%. RP-HPLC analysis: t R =36.79 min.

色谱条件：Waters 600 HPLCChromatographic conditions: Waters 600 HPLC

色谱柱：Inersil ODS-3(10×250mm)  紫外检测波长：215nmChromatographic column: Inersil ODS-3 (10×250mm) UV detection wavelength: 215nm

流动相：A-0.05％TFA/H2O  B-0.05％TFA/70％CH3CN/H2OMobile phase: A-0.05% TFA/H 2 O B-0.05% TFA/70% CH 3 CN/H 2 O

流速：2.0mL/minFlow rate: 2.0mL/min

洗脱梯度(线性)：t(min)    A％     B％Elution gradient (linear): t(min) A% B%

0         100     00 100 0

5         100     05 100 0

35        0       10035 0 100

40        0       10040 0 100

45        100     045 100 0

350mgMBHA树脂(负载量为0.57mmol/g，0.2mmol)，悬浮于DMF中，依次加入0.12gHOBt，150μL 3-巯基丙酸(1.2mmol)，160mg DCC，加入少量的DCM溶解充分，在室温下磁力搅拌4个小时，用DMF、DCM、MeOH、DCM各洗涤两次，每次两分钟。茚三酮检验呈阴性。然后用50mg半胱氨酸甲酯盐酸盐(0.2mmol)，100mg(0.2mmol)三苯基磷和120μlDIEA(0.2mmol)混合溶于DMF，五分钟后加入树脂中，室温反应两小时，用DMF、DCM、MeOH、DCM洗涤各两次，4倍量的BOC保护的氨基酸、BOP、6倍量的DIEA混合，溶于DMF，五分钟后混合物加入到反应器中，室温反应2小时，以DMF、DCM、MeOH、DCM洗涤，用定性的Ellman实验检测，阴性溶液树脂为无色或淡黄色，如果呈橘红色则再以上述缩合配料量减半反应一个小时，应用BOC/Bzl固相缩合体系从C端逐步延长肽链，以4NHCl/DIOX(0.05％吲哚)脱保护，缩合反应以2倍量的BOC-AA与2倍量的DCC/HOBt反应1小时，每步缩合均用茚三酮实验检测，如果为阳性则再用4倍量的BOC-AA、BOP和6倍量的DIEA反应半个小时，肽链合成结束以后，线性肽硫酯用HF/P-thiocresol/m-cresol(93/2/5，v/v/v)，在0℃反应1.5小时后从树脂上切下，HF抽干后用钠丝干燥的冰冻的无水乙醚洗涤数次，用10％的冰醋酸提取粗肽，冻干保存。350mg MBHA resin (loading capacity: 0.57mmol/g, 0.2mmol), suspended in DMF, followed by adding 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, adding a small amount of DCM to fully dissolve, magnetically Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM, each for two minutes. Ninhydrin test was negative. Then mix and dissolve DMF with 50mg cysteine methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) triphenylphosphine and 120μl DIEA (0.2mmol), add in the resin after five minutes, react at room temperature for two hours, use DMF, DCM, MeOH, and DCM were washed twice each, mixed with 4 times the amount of BOC-protected amino acids, BOP, and 6 times the amount of DIEA, dissolved in DMF, and the mixture was added to the reactor after five minutes, and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test to detect. Negative solution resin is colorless or light yellow. If it is orange red, then react for one hour with the amount of the above condensation ingredients halved, and use BOC/Bzl solid-state condensation The system gradually extended the peptide chain from the C-terminus, deprotected with 4NHCl/DIOX (0.05% indole), and reacted with 2 times the amount of BOC-AA and 2 times the amount of DCC/HOBt for 1 hour in the condensation reaction. Triketone test, if it is positive, react with 4 times the amount of BOC-AA, BOP and 6 times the amount of DIEA for half an hour. cresol (93/2/5, v/v/v), cut off from the resin after reacting at 0°C for 1.5 hours, dried with HF and washed several times with frozen anhydrous ether dried with sodium silk, and washed with 10% Crude peptides were extracted with glacial acetic acid and stored in freeze-dried form.

2、环(CEVVE)的合成：2. Synthesis of ring (CEVVE):

350mgMBHA树脂(负载量为0.57mmol/g，0.2mmol)，悬浮于DMF中，依次加入0.12gHOBt，150μL 3-巯基丙酸(1.2mmol)，160mg DCC，加入少量的DCM溶解充分，在室温下磁力搅拌4个小时，用DMF、DCM、MeOH、DCM各洗涤两次，每次两分钟。茚三酮检验呈阴性。然后用50mg半胱氨酸甲酯盐酸盐(0.2mmol)，100mg(0.2mmol)三苯基磷和120μlDIEA(0.2mmol)混合溶于DMF，五分钟后加入树脂中，室温反应两小时，用DMF、DCM、MeOH、DCM洗涤各两次，4倍量的BOC保护的氨基酸、BOP、6倍量的DIEA混合，溶于DMF，五分钟后混合物加入到反应器中，室温反应2小时，以DMF、DCM、MeOH、DCM洗涤，用定性的Ellman实验检测，阴性溶液树脂为无色或淡黄色，如果呈橘红色则再以上述缩合配料量减半反应一个小时，应用BOC/BZL固相缩合体系从C端逐步延长肽链，以4NHCl/DIOX(0.05％吲哚)脱保护，缩合反应以2倍量的BOC-AA与2倍量的DCC/HOBt反应1小时，每步缩合均用茚三酮实验检测，如果为阳性则再用4倍量的BOC-AA、BOP和6倍量的DIEA反应半个小时，肽链合成结束以后，线性肽硫酯用HF/P-thiocresol/m-cresol(93/2/5，v/v/v)，在0℃反应1.5小时后从树脂上切下，HF抽干后用钠丝干燥的冰冻的无水乙醚洗涤数次，用10％的冰醋酸提取粗肽，冻干保存。也可将环合的缓冲溶液直接提取线性肽硫酯进行环合反应。如果肽硫酯溶解度不好，还可以考虑使用CH3CN/H2O提取粗肽，然后减压抽去CH3CN后冻干保存。350mg MBHA resin (loading capacity: 0.57mmol/g, 0.2mmol), suspended in DMF, sequentially add 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, add a small amount of DCM to dissolve fully, and magnetically Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM, each for two minutes. Ninhydrin test was negative. Then mix and dissolve DMF with 50mg cysteine methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) triphenylphosphine and 120μl DIEA (0.2mmol), add in the resin after five minutes, react at room temperature for two hours, use DMF, DCM, MeOH, and DCM were washed twice each, mixed with 4 times the amount of BOC-protected amino acids, BOP, and 6 times the amount of DIEA, dissolved in DMF, and the mixture was added to the reactor after five minutes, and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test to detect. Negative solution resin is colorless or light yellow. If it is orange-red, then react for one hour with the amount of the above condensation ingredients halved, and use BOC/BZL solid-state condensation The system gradually extended the peptide chain from the C-terminus, deprotected with 4NHCl/DIOX (0.05% indole), and reacted with 2 times the amount of BOC-AA and 2 times the amount of DCC/HOBt for 1 hour in the condensation reaction. Triketone test, if it is positive, react with 4 times the amount of BOC-AA, BOP and 6 times the amount of DIEA for half an hour. cresol (93/2/5, v/v/v), cut off from the resin after reacting at 0°C for 1.5 hours, dried with HF and washed several times with frozen anhydrous ether dried with sodium silk, and washed with 10% Crude peptides were extracted with glacial acetic acid and stored in freeze-dried form. It is also possible to directly extract linear peptide thioesters from the cyclization buffer solution for cyclization reaction. If the solubility of the peptide thioester is not good, you can also consider using CH 3 CN/H 2 O to extract the crude peptide, and then extract the CH 3 CN under reduced pressure and freeze-dry it for storage.

线性肽硫酯在用凝胶柱层析初步纯化或者HPLC纯化后进行环合反应，反应在NaHCO3的水溶液中进行，如果溶解度不好可以适当加入CH3CN的浓度，控制pH值在7.3-7.6，加入TCEP防止巯基的氧化，反应由HPLC监控，反应在4小时内完成，产物用ESI-MS进行鉴定。The linear peptide thioester is subjected to cyclization reaction after preliminary purification by gel column chromatography or HPLC purification. The reaction is carried out in an aqueous solution of NaHCO 3 . If the solubility is not good, the concentration of CH 3 CN can be added appropriately to control the pH value at 7.3- 7.6. Add TCEP to prevent the oxidation of sulfhydryl groups. The reaction is monitored by HPLC. The reaction is completed within 4 hours, and the product is identified by ESI-MS.

3、环肽的PEG-MAL修饰3. PEG-MAL modification of cyclic peptide

将经RP-HPLC纯化后的环(CEVVE)溶于水中，以碳酸氢钠调pH至8，加入3倍当量的mPEG5000-MAL，室温反应，用RP-HPLC监测反应进程和分离产物，反应一般在四小时内完成。Dissolve the cyclic (CEVVE) purified by RP-HPLC in water, adjust the pH to 8 with sodium bicarbonate, add 3 times the equivalent of mPEG 5000 -MAL, react at room temperature, monitor the reaction process and isolate the product by RP-HPLC, and react Usually completed within four hours.

Cys(mPEG5000-MAL)-Tα1(17-24)经MALDI-TOF-MS分析，在6173附近有一系列峰，相邻两峰分子量相差约44，具有聚乙二醇的典型结构特征。通过和没有接上环肽分子的mPEG-NH2比较，减去作为活化官能团的马来酰亚氨的式量，其值基本和环肽的分子量相对应，证明成功实现了环肽类化合物的mPEG化修饰。Cys(mPEG 5000 -MAL)-Tα 1 (17-24) was analyzed by MALDI-TOF-MS, and there were a series of peaks around 6173, and the molecular weight difference between the two adjacent peaks was about 44, which had the typical structural characteristics of polyethylene glycol. By comparing with mPEG-NH 2 without cyclic peptide molecules, subtracting the formula weight of maleimide as an activated functional group, the value basically corresponds to the molecular weight of cyclic peptides, which proves that the cyclic peptide compounds have been successfully synthesized. mPEGylation modification.

实施例5：3H-tdR掺入法检测对小鼠脾淋巴细胞的增值反应：Example 5: 3 H-tdR incorporation method to detect the proliferation response to mouse spleen lymphocytes:

脾细胞悬液的制备：无菌取出脾脏，用毛玻璃片将小鼠脾脏磨碎，制成脾细胞悬液。裂解红细胞后，洗涤三次，计数(活细胞在95％以上)。用含10％FBS的RPMI1640培养液将脾细胞浓度调为4×106细胞/ml。本实验加入ConA(刀豆蛋白A)5ug/ml诱导T淋巴细胞增殖。以3H-TdR掺入法定量测定细胞的增殖。在37℃，5％CO2培养箱中培养48小时。在结束培养前7-8小时，每孔加入25μl3H-胸腺嘧啶核苷酸(含2×104Bq)。在培养结束后，用细胞收集仪(HARVESTER，TOMTEC)收集细胞于玻璃纤维膜上，用液闪记数仪(MicroBeta Trilux，PerkinElmer)检测[3H]-胸腺嘧啶核苷在DNA中的掺入量，以cpm值代表细胞增殖情况。具体检测结果参见表1。Preparation of splenocyte suspension: Aseptically remove the spleen, grind the mouse spleen with ground glass to prepare splenocyte suspension. After the red blood cells were lysed, they were washed three times and counted (the live cells were above 95%). Adjust the splenocyte concentration to 4×10 6 cells/ml with RPMI1640 medium containing 10% FBS. In this experiment, ConA (ConA) 5ug/ml was added to induce the proliferation of T lymphocytes. Cell proliferation was quantified by 3 H-TdR incorporation method. Incubate for 48 hours at 37°C in a 5% CO2 incubator. 7-8 hours before the end of the culture, 25 μl 3 H-thymidine nucleotide (containing 2×10 4 Bq) was added to each well. After the culture was over, the cells were collected on the glass fiber membrane with a cell harvester (HARVESTER, TOMTEC), and the incorporation of [ 3 H]-thymidine into DNA was detected with a liquid scintillation counter (MicroBeta Trilux, PerkinElmer) The amount was expressed in cpm to represent cell proliferation. The specific test results are shown in Table 1.

结果评定：淋巴细胞的增殖反应采用被检测样品cpm值减去阳性对照样品cpm值，然后除阳性对照样品cpm值，标记为+增强/-抑制的％。鉴于测试样品没有非特异细胞毒性作用，结果标记为+(增强)/-(抑制)的15％以上(根据P值时通常10％以上也可)，就表示样品有活性。Result evaluation: The proliferative response of lymphocytes is measured by subtracting the cpm value of the positive control sample from the cpm value of the tested sample, and then subtracting the cpm value of the positive control sample, which is marked as +enhanced/-inhibited %. In view of the fact that the test sample has no non-specific cytotoxic effect, the result marked as + (enhancement)/- (inhibition) of 15% or more (usually 10% or more according to the P value) indicates that the sample has activity.

表1Tα1及其类似物的T淋巴细胞增殖反应结果Table 1 T lymphocyte proliferation response results of Tα 1 and its analogues

  测定浓度Determination of concentration T淋巴细胞T lymphocytes T细胞增殖T cell proliferation 活性结果active result   样品名Sample name  Con A刺激Con A stimulus   综合活性评定Comprehensive Activity Evaluation   ug/mlug/ml  CPM平均值Average CPM   SDSD   P值P value   对照control  2865928659   420420   CKEVVEKEVVECKEVVEKEVVE   1 1  2520525205   18641864   0.07840.0784   -12.05％-12.05%   1010  2851228512   524524   0.72450.7245   -0.05％-0.05%   100100  4134241342   29422942   0.01590.0159   44.26％44.26%   CKEVVEEACKEVVEEA   1 1  2940529405   29502950   0.70550.7055   2.60％2.60%   1010  3071530715   28412841   0.33620.3362   7.17％7.17%   100100  6128161281   25312531   0.00160.0016   113.83％113.83%   环(CKEVVEEAE)Ring (CKEVVEEAE)   1 1  2756127561   11131113   0.22330.2233   -3.83％-3.83%   1010  3279232792   424424   0.00030.0003   14.42％14.42%   100100  6147661476   122122   0.00000.0000   114.51％114.51%   环(CKEVVE)Ring (CKEVVE)   1 1  2814328143   16331633   0.64340.6434   -1.80％-1.80%   1010  3406534065   14271427   0.01620.0162   18.86％18.86%   100100  6176661766   51635163   0.00770.0077   115.52％115.52%

  环(CEVVE)Ring (CEVVE)   1 1  3006530065   20552055   0.35760.3576   4.90％4.90%   1010  3346233462   34313431   0.13420.1342   16.76％16.76%   100100  5866958669   10591059   0.00010.0001   104.71％104.71%   环(CKEVVEEA)Ring (CKEVVEEA)   1 1  2700027000   29802980   0.43710.4371   -5.79％-5.79%   1010  3220632206   21112111   0.09540.0954   12.38％12.38%   100100  5392753927   54125412   0.01450.0145   88.17％88.17%   环(CLKEVVE)Ring (CLKEVVE)   1 1  2120521205   897897   0.00130.0013   -26.01％-26.01%   1010  4706047060   529529   0.00000.0000   64.21％64.21%   100100  5710357103   17331733   0.00070.0007   99.25％99.25%   环(CKEVVEKEVVE)Ring (CKEVVEKEVVE)   1 1  2746127461   831831   0.11350.1135   -4.18％-4.18%   1010  3190731907   967967   0.01640.0164   11.33％11.33%   100100  4482644826   18711871   0.00310.0031   56.41％56.41%   环(CKEVVEE)Ring (CKEVVEE)   1 1  2955729557   15741574   0.42930.4293   3.13％3.13%   1010  3413734137   737737   0.00120.0012   19.11％19.11%   100100  3768437684   19901990   0.01290.0129   31.49％31.49%

cpm值代表细胞增殖情况，SD为数据的标准差，P值表示实验数据与ConA对照组数据这间进行统计分析的有无差异的概率，P＜0.05表示两组数据间有显著性差异。L＝-NHCH2CH2OCH2COOH-The cpm value represents the cell proliferation, SD is the standard deviation of the data, and the P value represents the probability of statistical analysis between the experimental data and the ConA control group data, and P<0.05 represents a significant difference between the two groups of data. L = -NHCH2CH2OCH2COOH-

Claims (5)

1.选自下列的肽衍生物及其立体异构体：1. Peptide derivatives and stereoisomers thereof selected from the group consisting of: CEVVE-SCH2CH2CONH2 CEVVE-SCH 2 CH 2 CONH 2 CKEVVEKEVVE-SCH2CH2CONH2或CKEVVEKEVVE-SCH 2 CH 2 CONH 2 or CKEVVEEA-SCH2CH2CONH2。CKEVVEEA - SCH2CH2CONH2 . 2.肽衍生物及其立体异构体，其包括：2. Peptide derivatives and stereoisomers thereof, comprising: CLEVVE-SCH2CH2CONH2 CLEVVE-SCH 2 CH 2 CONH 2 CLKEVVE-SCH2CH2CONH2 CLKEVVE-SCH 2 CH 2 CONH 2 CLKEVVEKEVVE-SCH2CH2CONH2 CLKEVVEKEVVE-SCH 2 CH 2 CONH 2 CLKEVVEEA-SCH2CH2CONH2 CLKEVVEEA-SCH 2 CH 2 CONH 2 CLLEVVE-SCH2CH2CONH2 CLLEVVE-SCH 2 CH 2 CONH 2 CLLKEVVE-SCH2CH2CONH2 CLLKEVVE-SCH 2 CH 2 CONH 2 CLLKEVVEKEVVE-SCH2CH2CONH2 CLLKEVVEKEVVE-SCH 2 CH 2 CONH 2 CLLKEVVEEA-SCH2CH2CONH2 CLLKEVVEEA-SCH 2 CH 2 CONH 2 其中，L＝-NHCH2CH2OCH2COO-。Wherein, L=-NHCH 2 CH 2 OCH 2 COO-. 3.肽衍生物及其立体异构体，其为以下结构的化合物：3. Peptide derivatives and stereoisomers thereof, which are compounds of the following structure: 环(CEVVE)。Ring (CEVVE). 4.选自权利要求1～3任一项所述的肽衍生物及其立体异构体的任一化合物及其任意组合用于制备治疗和/或预防免疫缺陷、免疫功能低下相关疾病的药物的用途。4. Any compound selected from any of the peptide derivatives and stereoisomers thereof according to any one of claims 1 to 3 and any combination thereof for the preparation of medicines for treating and/or preventing immunodeficiency and immunodeficiency related diseases the use of. 5.选自权利要求1～3任一项所述的肽衍生物及其立体异构体的任一化合物及其任意组合用于制备保健品及化妆品的用途。5. The use of any compound selected from the peptide derivatives and stereoisomers thereof according to any one of claims 1 to 3 and any combination thereof for the preparation of health care products and cosmetics.
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Publication number Priority date Publication date Assignee Title
CN102174084B (en) * 2004-12-01 2015-11-18 中国人民解放军军事医学科学院毒物药物研究所 Thymosin α1 active fragments cyclic peptide analogue and polyethylene glycol derivative thereof

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