Cyclic peptide derivatives, uses thereof, and inhibitors of complement component 5 thereof

Abstract

The invention relates to the technical field of therapeutic cyclic peptides, in particular to a cyclic peptide derivative, application of the cyclic peptide derivative and an inhibitor of a complement component 5 of the cyclic peptide derivative. The cyclic peptide derivative is a compound shown in the following structural formula. Wherein R1 is selected from any one of R1 and R2, m is any integer between 6 and 40, p is any integer between 6 and 18, and z is any integer between 6 and 18; r2 is selected from any one of a carboxyl group, a carboxylic ester group, a tetrazolyl group, a phosphate group and a phosphate group; n is any integer between 10 and 20. The compound can be used as an inhibitor of a complement component 5, and further has a better curative effect on diseases caused by the change of the content or activity of the complement component 5.

Description

[0001] This invention claims priority to Chinese Patent Application No. 202411262915X, entitled "Cyclic Peptide Derivatives, Their Applications and Inhibitors of Complement Component 5 Thereof," the contents of which are incorporated herein by reference in their entirety and are part of the original description of this invention. Technical Field

[0002] This invention relates to the field of therapeutic cyclic peptide technology, and more specifically, to cyclic peptide derivatives, their applications, and inhibitors of complement component 5. Background Technology

[0003] Complement is not a single molecule, but rather a collection of approximately 20 circulating proteins primarily synthesized by the liver. These are proteins that, upon activation, possess enzymatic activity and are found in tissue fluid, serum, and on the cell membrane surface. They include membrane-bound proteins and soluble proteins, and are therefore also known as the complement system. Complement plays a wide range of roles in immune regulation and microbial defense responses, and can also mediate damaging responses in immunopathology. The complement system has immune, opsonizing, antiviral, bactericidal, bioactive, and inflammatory mediator functions, making it a vital effector system and effect amplification system in the body.

[0004] A crucial component of immune activity is the immune system's ability to distinguish between non-self and self cells. Pathology arises when the immune system fails to differentiate between these cells. The complement system, in vertebrate cells, expresses proteins that protect them from the effects of the complement cascade, ensuring that its targets are limited to pathogenic cells. Many complement-related diseases are closely linked to abnormal self-cell destruction caused by the complement cascade, including but not limited to neurological disorders, autoimmune diseases, infectious diseases, and hematological disorders. Studies have shown that many complement-related conditions can be alleviated by inhibiting complement activity. Therefore, there is a significant need to develop compounds that can selectively block complement-mediated cell destruction.

[0005] In view of this, the present invention is proposed. Summary of the Invention

[0006] The purpose of this invention is to provide cyclic peptide derivatives, their applications, and inhibitors of complement component 5. An embodiment of this invention provides a cyclic peptide derivative that can act as an inhibitor of complement component 5, thereby exhibiting good therapeutic effects on diseases caused by alterations in complement 5 levels or activity.

[0007] This invention is implemented as follows:

[0008] In a first aspect, the present invention provides a cyclic peptide derivative, which is a compound of Formula 1 below or a chiral isomer, tautomer, or pharmaceutically acceptable salt, ester or amide thereof.

[0009]

[0010] Wherein, R1 is selected from Any one of the following, where m is any integer between 6 and 40, p is any integer between 6 and 18, and z is any integer between 6 and 18;

[0011] R2 is selected from any one of carboxyl, carboxylic acid ester, tetrazolium, phosphate, and phosphate ester groups;

[0012] n is any integer between 10 and 20.

[0013] Secondly, the present invention provides an inhibitor of complement component 5, which includes the cyclic peptide derivative described in the foregoing embodiments.

[0014] Thirdly, the present invention provides the use of the cyclic peptide derivative described in the foregoing embodiments in the preparation of a medicament for treating diseases caused by changes in complement content or activity.

[0015] In an optional implementation, the disease includes any one of the following: inflammatory indications, ocular diseases, autoimmune diseases, atypical hemolytic uremic syndrome, renal-related indications, vascular indications, paroxysmal nocturnal hemoglobinuria, and neurological indications.

[0016] The present invention has the following beneficial effects: The present invention provides a new cyclic peptide derivative, which can be used as a macrocyclic peptide inhibitor of complement component 5 (C5) and has good biological activity. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0018] In a first aspect, the present invention provides a cyclic peptide derivative, which is a compound of Formula 1 below or a chiral isomer, tautomer, or pharmaceutically acceptable salt, ester or amide thereof.

[0019]

[0020] R1 is selected from In any one of the following, m is any integer between 6 and 40, such as any value between 6 and 40 or any range between any two values, such as 6, 8, 10, 12, 14, 16, 18, 20, 24, 25, 30, 35 and 40. For example, it is preferably any integer between 8 and 30, more preferably, m is any integer between 10 and 28, more preferably, any integer between 12 and 24; and even more preferably, 12 or 24.

[0021] p is any integer between 6 and 18, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18, or any integer between 6 and 18, or any range between any two values. For example, it is preferably any integer between 8 and 16, more preferably, p is any integer between 10 and 14; more preferably, it is any integer between 11 and 13; and even more preferably, it is 12.

[0022] z is any integer between 6 and 18; for example, any integer between 6 and 18, or any range between any two values, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. For example, it is preferably any integer between 8 and 16, more preferably, z is any integer between 10 and 14; more preferably, it is any integer between 11 and 13; and even more preferably, it is 12.

[0023] R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein R3 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; preferably a hydrogen atom or an unsubstituted C1-C3 alkyl group; more preferably any one of a hydrogen atom, methyl, ethyl and propyl, and most preferably a hydrogen atom.

[0024] R4 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; preferably a hydrogen atom or an unsubstituted C1-C3 alkyl group; more preferably any one of hydrogen, methyl, ethyl and propyl, and most preferably a hydrogen atom.

[0025] R5 is any one of hydrogen atom, substituted or unsubstituted C1-C3 alkyl group, metal ion and ammonium cation; preferably any one of hydrogen atom, unsubstituted C1-C3 alkyl group, metal ion and triethylamine, ethanolamine, arginine or lysine to form a cation; more preferably any one of hydrogen atom, methyl, ethyl, propyl and monovalent metal ion; further preferably any one of hydrogen atom, methyl, ethyl, sodium ion and potassium ion; most preferably any one of hydrogen atom, methyl, ethyl and propyl.

[0026] n is any integer between 10 and 20, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, etc., any integer between 10 and 20 or any range between two values, for example, preferably any integer between 12 and 20, more preferably, n is any integer between 13 and 18, more preferably, n is any integer between 13 and 17.

[0027] Furthermore, R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein R3 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; R4 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; and R5 is any one of a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a metal ion, and an ammonium cation.

[0028] Furthermore, m is any integer between 8 and 30, p is any integer between 8 and 16, and z is any integer between 8 and 16; R2 is selected from -COOR3, -PO(OR4)2, and Any one of the functional groups formed; wherein R3 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; R4 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; R5 is any one of a hydrogen atom, an unsubstituted C1-C3 alkyl group, a metal ion, and a cation formed by triethylamine, ethanolamine, arginine, or lysine; n is any integer between 12 and 20.

[0029] Furthermore, m is any integer between 10 and 28, p is any integer between 10 and 14; z is any integer between 10 and 14; R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein R3 is any one of hydrogen atom, methyl and ethyl, R4 is any one of hydrogen atom, methyl and ethyl, R5 is any one of hydrogen atom, methyl, ethyl and monovalent metal ion; n is any integer between 13 and 18.

[0030] Furthermore, m is any integer between 12 and 24; p is any integer between 11 and 13; z is any integer between 11 and 13; R2 is selected from -COOH, -PO(OH)2, and Any one of the functional groups formed; wherein R5 is any one of hydrogen atom, methyl, ethyl, sodium ion and potassium ion; n is any integer between 13 and 17.

[0031] Furthermore, m is 12 or 24; p is 12; z is 12; R2 is selected from -COOH, -PO(OH)2 and Any one of the functional groups formed; wherein R5 is any one of hydrogen atom, methyl and ethyl; and n is 13, 14, 15 or 17.

[0032] Specifically, the compound is selected from:

[0033] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp-Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(19-carboxy-nonadecanoyl-γGlu-PEG24);

[0034] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp

[0035] -Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(19-carboxy-nonadecanoyl-γGlu-PEG12);

[0036] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp-Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(19-phospho-pentadecanoyl-γGlu-PEG24);

[0037] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp-Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(16-(1H-Tetrazol-5-yl)-hexadecanoyl-γGlu-PEG24);

[0038] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp-Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(19-carboxy-nonadecanoyl-γGlu-PEG12-PEG12);

[0039] Ac-Cyclo(Lys-Val-Glu-Arg-Phe-Asp)-NMeAsp-Tle-Tyr-AzaTrp-Glu-Tyr-Pro-Chg-Lys(19-carboxy-nonadecanoyl-γGlu-AEEA-AEEA).

[0040] Specifically, the structure is as follows:

[0041]

[0042]

[0043]

[0044] Furthermore, embodiments of the present invention provide a method for preparing a cyclic peptide derivative, comprising:

[0045] This invention utilizes a cyclic peptide synthesis column to synthesize peptides via SPPS using a Fmoc-based chemical method. The Fmoc-protected amino acids used in this method were all purchased from Shanghai Jier Biochemical Co., Ltd., including Fmoc-Lys(Dde)-Wang resin, Fmoc-Chg-OH, Fmoc-Pro-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-7-AzaTrp-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tle-OH, Fmoc-N-Me-Asp(OtBu)-OH, Fmoc-Asp(OAll)-OH, Fmoc-Phe-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, and Fmoc-Lys(OAll)-OH.

[0046] The resin used was Fmoc-Lys(Dde)-Wang resin from Tianjin Nankai Hecheng Co., Ltd., with a mesh size of 100-200 and a degree of substitution of 0.4-0.6 mmol / g. First, Fmoc was removed from the Fmoc-Lys(Dde)-Wang resin, followed by condensation with Fmoc-Chg-OH, where the molar ratio of Fmoc-Lys(Dde)-Wang to Fmoc-Chg-OH and DIC was 1:3:3. Before each subsequent coupling step, 20% piperidine / DMF was used to remove Fmoc. All amino acid couplings used a 3-molar ratio of Fmoc to protect the amino acid and a 3-molar ratio of DIC, coupled under nitrogen protection for 2-3 hours. After coupling, the mixture was washed with DMF and DCM. Then, cyclization was performed using a 0.1-molar ratio of tetrakis(triphenylphosphine)palladium and a 10-molar ratio of benzylsilane. Finally, the protecting group of lysine was removed using 2% hydrazine hydrate / DMF. The peptide resin is then obtained by condensing it with the side chain in sequence.

[0047] Cutting:

[0048] The synthesized dried peptide resin was cleaved at room temperature for 2.5 hours using a 10-fold volume lysis mixture (trifluoroacetic acid / ethylenedithiol / aniline sulfide / phenol / water = 87.5 / 2.5 / 5 / 2.5 / 2.5, v / v). The mixture was filtered, and ether was added to the filtrate. The precipitate was centrifuged, and the resulting solid was washed with ether and dried to obtain the crude peptide product.

[0049] purification:

[0050] The crude peptide was dissolved in MQ water containing 40% acetic acid and purified by reversed-phase preparative HPLC (Waters Delta Prep 4000) on a C18 silica column. Elution was performed with MeCN in MQ water containing 0.1% TFA using a gradually increasing gradient. Fractions were analyzed by UPLC. Fractions containing the purified target peptide were combined. The resulting solutions were analyzed (UPLC, LCMS), and the product was aliquoted into glass vials. The vials were capped with a Millipore glass fiber pre-filter. Lyophilization yielded the target compound as a white solid.

[0051] General LCMS method:

[0052] Mass spectrometry (MS) parameters:

[0053] Testing instrument: Agilent 6410 triple quadrupole liquid chromatography-mass spectrometry system; Ionization source: +ESI.

[0054] Liquid phase parameters:

[0055] Chromatographic column: Agilent ZORBAX SB-C18, specifications: 250×4.6mm, 5μm; detection wavelength: 195nm; column temperature: 30℃; injection volume: 10mL; flow rate: 1mL / min; mobile phase A: 0.05% glacial acetic acid; mobile phase B: acetonitrile.

[0056] The compounds provided in the embodiments of this invention are abbreviated as follows:

[0057] NMeAsp: N-methyl-L-aspartic acid; Tle: L-tert-leucine; AzaTrp: 7-aza-L-tryptophan; Chg: L-cyclohexylglycine; Boc: tert-butyloxycarbonyl; Fmoc: 9-fluorenylmethoxycarbonyl; tBu: tert-butyl; DIEA: N,N-diisopropylethylamine; EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOSu: N-hydroxysuccinimide; TFA: trifluoroacetic acid; AEEA-AEEA: 17- Amino-10-oxo-3,6,12,15-tetraoxa-9-azaheptadecanoic acid; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; PIP: piperidine; HOBt: 1-hydroxybenzotriazole; HBTU: benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; TIPS: triisopropylsilane; PHSME: methyl phenyl sulfide; Trt: triphenylmethyl.

[0058] Secondly, the present invention provides an inhibitor of complement component 5, which includes the cyclic peptide derivative described in the foregoing embodiments.

[0059] Thirdly, the present invention provides the use of the cyclic peptide derivative described in the foregoing embodiments in the preparation of a medicament for treating diseases caused by changes in complement content or activity.

[0060] In an optional implementation, the disease includes any one of the following: inflammatory indications, ocular diseases, autoimmune diseases, atypical hemolytic uremic syndrome, renal-related indications, vascular indications, paroxysmal nocturnal hemoglobinuria, and neurological indications.

[0061] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0062] Example 1

[0063] This embodiment provides a cyclic peptide derivative, the structural formula of which is shown below:

[0064]

[0065] This embodiment provides a method for preparing the above-mentioned cyclic peptide derivative, including:

[0066] Perform the synthesis according to the following synthesis path:

[0067]

[0068]

[0069] Specifically, at room temperature, 1.32 g (0.6 mmol) of Fmoc-Lys(Dde)-Wang resin was added to a 20 mL DMF solution, and the resin was swollen under nitrogen for 2 hours. The solvent was then removed by vacuum. 20 mL of 20% piperidine / DMF was added to remove Fmoc, yielding 1-C1. Fmoc-Chg-OH (1.8 mmol) and DIC (1.8 mmol) were then added, and the reaction was continued for 2 hours to obtain Fmoc-Chg-Lys(Dde)-Wang resin. Coupling reactions were carried out according to the sequences Fmoc-Pro-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-7-AzaTrp-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tle-OH, Fmoc-N-Me-Asp(OtBu)-OH, Fmoc-Asp(OAll)-OH, Fmoc-Phe-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Lys(OAll)-OH, and AcOH. After coupling, the mixture was washed three times with DMF and three times with DCM to obtain compound 1-C2.

[0070] DCM (50 mL), tetrakis(triphenylphosphine)palladium (0.06 mmol), and phenylsilane (6 mmol) were added, and the reaction was carried out for 30 minutes. The resin was washed 10 times with 2% DIPEA / 2% sodium diethyldithiocarbamate. DMF (20 mL), HBTU (1.71 mmol), and DIPEA (3.6 mmol) were added, and the reaction was carried out under suffocation for 18 hours to give compound 1-C3.

[0071] The solution was dried under vacuum, washed five times with DMF (50 mL), and then 2% hydrazine hydrate / DMF was added. The mixture was then purged with air for half an hour. The solution was dried under vacuum, and washed five times with DMF (50 mL) to obtain compound 1-C4.

[0072] Compound 1-C5 was obtained by following the sequence Fmoc-PEG24-CH2CH2COOH, Fmoc-Glu-OtBu, and tert-butyl eicosanoate. After coupling, the resin was washed three times with DMF, twice with DCM, and three times with methanol, and then dried to obtain compound 1-C5 (4.61 g).

[0073] Add 50 mL of lysis buffer (trifluoroacetic acid / ethylenedithiol / anisole / phenol / water = 87.5 / 2.5 / 5 / 2.5 / 2.5), shake on a shaker at room temperature for 2.5 hours, and filter. Add 8 times the volume of diethyl ether to the filtrate to precipitate, centrifuge the precipitate, wash the solid twice with 8 times the volume of diethyl ether, and then vacuum dry to obtain crude compound 1 (2.39 g, purity 54%). Take 1.113 g of the crude product, purify it by Pre-HPLC, and freeze-dry it to obtain the final product of compound 1 (148.9 mg).

[0074] LCMS: Calculated mass: (M-2) / 2 = 1822.5; Measured mass: (M-2) / 2 = 1822.9.

[0075] Examples 2-6

[0076] Examples 2-6 each provide a cyclic peptide derivative and its preparation method, the preparation method of which is similar to that provided in Example 1, and will not be described in detail in the following examples. Specifically, the structural formula of the cyclic peptide derivative provided in Example 2 is as follows:

[0077]

[0078] LCMS

[0079] Calculated mass: (M+2) / 2 = 1560.4, (M+3) / 3 = 1040.6, (M+4) / 4 = 780.7; Actual mass: (M+2) / 2 = 1560.3, (M+3) / 3 = 1040.6, (M+4) / 4 = 780.7.

[0080] The structural formula of the cyclic peptide derivative provided in Example 3 is as follows:

[0081]

[0082] LCMS

[0083] Calculated mass: (M-2) / 2 = 1841.0, (M-3) / 3 = 1226.7, (M-4) / 4 = 919.7; Actual mass: (M-2) / 2 = 1840.8, (M-3) / 3 = 1226.6, (M-4) / 4 = 919.7.

[0084] The structural formula of the cyclic peptide derivative provided in Example 4 is as follows:

[0085]

[0086] LCMS

[0087] Calculated mass: (M-2) / 2 = 1814.0;

[0088] Measured mass: (M-2) / 2=1813.9.

[0089] The structural formula of the cyclic peptide derivative provided in Example 5 is as follows:

[0090]

[0091] LCMS

[0092] Calculated mass: (M+2) / 2=1860.0, (M+3) / 3=1240.7, (M+4) / 4=930.8, (M+5) / 5=744.8;

[0093] Measured mass: (M+2) / 2=1860.0, (M+3) / 3=1240.4, (M+4) / 4=930.7, (M+5) / 5=744.7.

[0094] The structural formula of the cyclic peptide derivative provided in Example 6 is as follows:

[0095]

[0096] LCMS

[0097] Calculated mass: (M+2) / 2 = 1405.8, (M+3) / 3 = 937.5, (M+4) / 4 = 703.4;

[0098] Measured mass: (M+2) / 2=1405.7, (M+3) / 3=937.6, (M+4) / 4=703.6.

[0099] Test Example 1: Inhibitory effect of cyclic peptide derivatives on classical complement pathway activation

[0100] The functional activity of cyclic peptide derivatives in the erythrocyte hemolysis assay was tested using human C5-depleted serum and purified human C5 serum instead of whole human serum to evaluate the inhibitory effect of cyclic peptide derivatives on classical complement pathway activation.

[0101] Cell suspension preparation

[0102] Antibody-sensitized Mianyang erythrocytes (Complement Technology, Tyler, TX) were plated in 3 x 10⁻¹ plates with 1.5% human C5-depleted serum (Complement Technology, Tyler, TX) and 0.5 nM purified human C5 (Complement Technology, Tyler, TX). 7Cells / well. Antibody-sensitized Mianyang red blood cells were centrifuged at 1900Xg for three minutes at 4°C and resuspended in fresh GVB++ (Complement Technology, Tyler, TX).

[0103] Compound and cell incubation

[0104] Mix 50 μl of serially diluted cyclic peptide derivative with 25 μl of C5-depleted serum, 25 μl of purified human C5, 100 μl of cells, and GVB++ buffer in a single 96-well plate and incubate at 37°C for one hour.

[0105] Activity assay

[0106] After incubation, the samples were centrifuged at 1900X g for three minutes at 4°C to precipitate the remaining intact red blood cells, and the supernatant was collected. The absorbance of the supernatant was read at 412 nm using a microplate reader to detect the hemoglobin released from red blood cell lysis. The data were fitted using a logarithmic-sublogarithmic formula to generate the IC50. 50 The results are shown in Table 1.

[0107] Table 1 Hemolysis test data

[0108] Compound numbering <![CDATA[IC 50 (nM)]]> Zilucoplan 18.55 Example 1 1.44 Example 2 1.27 Example 3 1.68 Example 4 0.95 Example 5 1.54 Example 6 1.12

[0109] result

[0110] As shown in Table 1, the cyclic peptide derivatives provided in the embodiments of the present invention can all inhibit the activation of the classical complement pathway, and the overall effect is more than 10 times better than Zilucoplan.

[0111] Test Example 2 evaluates C5 inhibition using enzyme immunoassay.

[0112] In the C5-mediated hemolysis assay (Test Example 1), the levels of C5a and membrane attack complex (MAC or sC5b9) in the supernatant were quantified using an enzyme immunoassay kit (Quidel Corporation, San Diego, CA, USA) to evaluate C5 inhibitory activity.

[0113] C5a enzyme immunoassay

[0114] The supernatant from the hemolysis assay of the cyclic peptide derivative in Test Example 1 was diluted 1:30 and measured by C5a enzyme immunoassay. The data were converted to the percentage of C5a generation inhibition and IC50 was generated using GraphPad Prism software. 50 .

[0115] sC5b9 enzyme immunoassay

[0116] The supernatant from the hemolysis assay of the cyclic peptide derivative in Test Example 1 was diluted 1:4 and analyzed by sC5b9 enzyme immunoassay. The data were converted to the percentage of sC5b9 production inhibition and IC50 was generated using GraphPad Prism software. 50 The results are shown in Table 2.

[0117] Table 2. Enzyme Immunoassay Data

[0118] Compound numbering <![CDATA[IC of C5a 50 (nM)]]> <![CDATA[sC5b9a IC 50 (nM)]]> Zilucoplan 6.74 8.85 Example 1 0.46 0.51 Example 2 0.41 0.47 Example 3 0.68 0.69 Example 4 0.32 0.29 Example 5 0.37 0.33 Example 6 0.43 0.35

[0119] result

[0120] As shown in Table 2, the cyclic peptide derivatives of the present invention all inhibit the formation of C5a and sC5b9a, and are generally superior to Zilucoplan.

[0121] Test Example 3: Evaluation of C5 affinity using surface plasmon resonance (SPR)

[0122] Surface plasmon resonance assays were performed using a Biacore 8K (GE Healthcare) to evaluate the affinity of the cyclic peptide derivative for C5.

[0123] The temperature of the Biacore 8K flow cell and sample cell was set to 25℃. 10 μl / mL of human C5 (ACRO, CO5-H52Ha) was immobilized on the CM5 sensor chip (Cytiva) of the Biacore 8K at a flow rate of 10 μl / min and a contact time of 600 s. The cyclic peptide derivative was then flowed through the chip in HEPES buffer (pH 7.4, 150 mM NaCl, 1 mM MgCl2, 0.05% surfactant P-20, 1% DMSO) at a flow rate of 50 μl / min, a contact time of 180 s, and a dissociation time of 400 s. The generated SPR sensor map was recorded and analyzed using Biacore 8K software to obtain the binding rate constant (ka), dissociation rate constant (kd), and binding affinity (KD). The results are shown in Table 3.

[0124] Table 3 SPR test data

[0125] Compound numbering ka(1 / Ms) kd(1 / s) KD(nM) Zilucoplan <![CDATA[1.47X 10 7 ]]> <![CDATA[4.19X 10 -3 ]]> 0.285 Example 1 <![CDATA[5.54X 10 5 ]]> <![CDATA[8.70X 10 -5 ]]> 0.157 Example 2 <![CDATA[5.35X 10 5 ]]> <![CDATA[1.21X 10 -7 ]]> <![CDATA[2.26X 10 -4 ]]> Example 3 <![CDATA[4.87X 10 5 ]]> <![CDATA[1.14X 10 -5 ]]> <![CDATA[2.34X 10 -2 ]]> Example 4 <![CDATA[3.68X 10 5 ]]> <![CDATA[2.68X 10 -7 ]]> <![CDATA[7.28X 10 -4 ]]> Example 5 <![CDATA[3.28X 10 5 ]]> <![CDATA[2.22X 10 -8 ]]> <![CDATA[6.78X 10 -5 ]]> Example 6 <![CDATA[6.84X 10 5 ]]> <![CDATA[1.92X 10 -5 ]]> <![CDATA[2.80X 10 -2 ]]>

[0126] As shown in Table 3, the cyclic peptide derivatives provided in the embodiments of the present invention have a strong affinity for C5 binding, which is generally superior to the affinity of Zilucoplan, and the affinity of some cyclic peptide derivatives is increased by more than 1000 times.

[0127] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A cyclic peptide derivative, characterized in that, It is a compound of Formula 1 below or its chiral isomer, tautomer, or pharmaceutically acceptable salt, ester or amide; Wherein, R1 is selected from Any one of the following, where m is any integer between 6 and 40, p is any integer between 6 and 18, and z is any integer between 6 and 18; R2 is selected from any one of carboxyl, carboxylic acid ester, tetrazolium, phosphate, and phosphate ester groups; n is any integer between 10 and 20.

2. The cyclic peptide derivative according to claim 1, characterized in that, m is any integer between 8 and 30, preferably, m is any integer between 10 and 28, more preferably, m is any integer between 12 and 24; and even more preferably, m is 12 or 24. p is any integer between 8 and 16, preferably, p is any integer between 10 and 14; more preferably, p is any integer between 11 and 13; and even more preferably, p is 12. z is any integer between 8 and 16, preferably z is any integer between 10 and 14; more preferably z is any integer between 11 and 13; and even more preferably z is 12. n is any integer between 12 and 20, preferably n is any integer between 13 and 18, more preferably n is any integer between 13 and 17; Preferably, R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein, R3 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; R4 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; R5 is any one of a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a metal ion, and an ammonium cation; Preferably, R3 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; more preferably, it is any one of hydrogen, methyl, and ethyl, and most preferably, it is a hydrogen atom. Preferably, R4 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; more preferably, it is any one of hydrogen atom, methyl, and ethyl; most preferably, it is a hydrogen atom. Preferably, R5 is any one of hydrogen atom, unsubstituted C1-C3 alkyl group, metal ion, and cation formed by triethylamine, ethanolamine, arginine or lysine; more preferably, it is any one of hydrogen atom, methyl, ethyl and monovalent metal ion; even more preferably, it is any one of hydrogen atom, methyl, ethyl, sodium ion and potassium ion; most preferably, it is any one of hydrogen atom, methyl and ethyl.

3. The cyclic peptide derivative according to claim 1 or 2, characterized in that, R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein, R3 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; R4 is a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group; R5 is any one of a hydrogen atom, a substituted or unsubstituted C1-C3 alkyl group, a metal ion, and an ammonium cation; Preferably, m is any integer between 8 and 30, p is any integer between 8 and 16, and z is any integer between 8 and 16. R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein R3 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; R4 is a hydrogen atom or an unsubstituted C1-C3 alkyl group; R5 is any one of a hydrogen atom, an unsubstituted C1-C3 alkyl group, a metal ion, and a cation formed by triethylamine, ethanolamine, arginine, or lysine; n is any integer between 12 and 20.

4. The cyclic peptide derivative according to claim 1 or 2, characterized in that, m is any integer between 10 and 28, p is any integer between 10 and 14; z is any integer between 10 and 14; R2 is selected from -COOR3, -PO(OR4)2 and Any one of the functional groups formed; wherein R3 is any one of hydrogen atom, methyl and ethyl, R4 is any one of hydrogen atom, methyl and ethyl, and R5 is any one of hydrogen atom, methyl, ethyl and monovalent metal ion; n is any integer between 13 and 18.

5. The cyclic peptide derivative according to claim 1 or 2, characterized in that, m is any integer between 12 and 24; p is any integer between 11 and 13; z is any integer between 11 and 13; R2 is selected from -COOH, -PO(OH)2 and Any one of the functional groups formed; wherein R5 is any one of hydrogen atom, methyl, ethyl, sodium ion and potassium ion; n is any integer between 13 and 17.

6. The cyclic peptide derivative according to claim 1 or 2, characterized in that, m is 12 or 24; p is 12; z is 12; R2 is selected from -COOH, -PO(OH)2 and Any one of the functional groups formed; wherein R5 is any one of hydrogen atom, methyl and ethyl; n is 13, 14, 15 or 17.

7. The cyclic peptide derivative according to claim 1, characterized in that, The cyclic peptide derivative is selected from any one of the compounds described in the following structural formulas:

8. An inhibitor of complement component 5, characterized in that, It includes the cyclic peptide derivatives as described in claim 1.

9. The use of the cyclic peptide derivative of claim 1 in the preparation of a medicament for treating diseases caused by alterations in complement content or activity.

10. The application according to claim 9, characterized in that, The diseases mentioned include any one of the following: inflammatory indications, ocular diseases, autoimmune diseases, atypical hemolytic uremic syndrome, renal-related indications, vascular indications, paroxysmal nocturnal hemoglobinuria, and neurological indications.

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