Cystamine derivative or salt thereof and application of cystamine derivative or salt in preparation of medicine with anti-oxidation effect

Abstract

The invention relates to a cystamine derivative or a salt thereof and an application of the cystamine derivative or the salt in preparation of a medicine with an anti-oxidation effect. According to the application of the cystamine derivative or the salt of the cystamine derivative in preparation of the medicine with the anti-oxidation effect, the cystamine derivative has the structural characteristics shown in a formula (1), a formula (2) or a formula (3). The research finds that the cystamine derivative or the salt thereof with the structural general formula can exert a better antioxidant effect, can be used for preventing and treating or improving diseases related to oxidative stress, has a protection effect on neuroglial cells and nerve cells, and has the characteristics of high efficiency and safety. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical compounds, and in particular to a cystamine derivative or a salt thereof and an application thereof in preparing a drug with antioxidant effect. Background Art

[0002] In the process of modern science and technology and industrial development, antioxidant problems are widely present in many fields and have a vital impact. In the biomedical field, oxidative stress is closely related to the occurrence and development of many diseases, such as cardiovascular disease, neurodegenerative diseases, etc. Oxidative damage in cells can destroy cell structure and function and affect normal physiological metabolism. Current antioxidant treatment methods commonly use antioxidant drugs, but they have disadvantages such as poor drug targeting and large side effects, making it difficult to accurately and effectively repair oxidative damage to cells.

[0003] Although traditional methods have made some progress in solving the antioxidant problem, they still face many limitations, such as unclear antioxidant effects and large side effects. Therefore, safer and more efficient antioxidant methods need to be further developed. Summary of the invention

[0004] Based on this, the present application provides the use of cystamine derivatives or salts thereof in the preparation of drugs with antioxidant effects, and a class of cystamine derivatives or salts thereof that can exert good antioxidant effects.

[0005] In a first aspect of the present application, a cystamine derivative or a salt thereof is provided for use in the preparation of a drug or health product having an antioxidant effect, wherein the cystamine derivative has a structural feature shown in the following formula (1), formula (2) or formula (3):

[0006] (1),

[0007] Among them, L 11 , L 12 are each independently an ester group or an amide group;

[0008] R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 11 , R 12 Each is independently substituted or unsubstituted by at least one S1, wherein S1 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0009] R13 , R 14 Each independently represents H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl;

[0010] (2),

[0011] Among them, L 21 is an ester group or an amide group;

[0012] R 21 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 is substituted or unsubstituted with at least one S2, wherein S2 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0013] R 22 It is amino group;

[0014] R 23 is H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl;

[0015] (3),

[0016] Among them, L 31 is an ester group or an amide group;

[0017] R 31 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 It is substituted or unsubstituted with at least one S3, wherein S3 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino.

[0018] In some embodiments, in formula (1), R 11 , R 12 Meet one or more of the following conditions:

[0019] (a) S1 includes alkoxy, L 11 For amide, R 13 When H, R 11 , R 12It is not -C2~C10 alkyl-C3~C15 heteroaryl;

[0020] (b) R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl;

[0021] (c) R 11 , R 12 The heteroaryl group in is a C6~C15 heteroaryl group;

[0022] (d) When S1 includes halogen, L 21 It is an amide group.

[0023] In some embodiments, in formula (2), R 21 It is a C1~C10 alkyl group.

[0024] In some embodiments, in formula (3), R 31 It is -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl.

[0025] In some embodiments, the cystamine derivative includes one or more of the structures shown in the following CS1 to CS35:

[0026] CS1: ;CS2: ;

[0027] CS3: CS4: ;

[0028] CS5: CS6: ;

[0029] CS7: ; CS8: ;

[0030] CS9: ;

[0031] CS10: ;CS11: ;

[0032] CS12: ;CS13: ;

[0033] CS14: ;CS15: ;

[0034] CS16: ;CS17: ;

[0035] CS18: ;CS19: ;

[0036] CS20: ;CS21: ;

[0037] CS22: ;CS23: ;

[0038] CS24: ;CS25: ;

[0039] CS26: ;CS27: ;

[0040] CS28: ;CS29: ;

[0041] CS30: ;CS31: ;

[0042] CS32: ;CS33: ;

[0043] CS34: ;CS35: .

[0044] In some embodiments, the antioxidant effect includes one of the protection against oxidative stress and the prevention, treatment or improvement of neurodegenerative diseases.

[0045] In some embodiments, the oxidative stress comprises toxin-induced oxidative stress; and / or the neurodegenerative disease comprises Parkinson's disease.

[0046] In some embodiments, the antioxidant effect includes one or more of the following characteristics:

[0047] (a) Enhance the protective effect of glial cells;

[0048] (b) Enhance the protective effect of nerve cells.

[0049] In a second aspect of the present application, a cystamine derivative or a salt thereof is provided, wherein the cystamine derivative has a structural feature shown in the following formula (4) or formula (5):

[0050] (4),

[0051] Among them, L 41 , L 42 are each independently an ester group or an amide group;

[0052] R 41 , R 42 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 41 , R 42 is unsubstituted, or R 41 , R 42 is substituted by halogen, and R 41 , R 42 Each is independently -C2~C10 alkyl-C3~C15 heteroaryl;

[0053] (5),

[0054] Among them, L 51 is an ester group or an amide group;

[0055] R 51 is C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 51 is substituted or unsubstituted with at least one S5, wherein S5 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0056] R 52 It is amino.

[0057] In some embodiments, the cystamine derivative has one of the following structures:

[0058] CS1: ;CS3: ;

[0059] CS4: ; CS7: ;

[0060] CS9: ;CS10: ;

[0061] CS13: ;CS21: .

[0062] The present application has found that cystamine derivatives or salts thereof having the general structural formula shown above can exert good antioxidant effects, can be used to prevent or improve diseases related to oxidative stress, and have a protective effect on glial cells and nerve cells, and are highly effective and safe. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is a graph showing the antioxidant activity test results of compounds CS1~CS35 on BV2 cells. Ctrl represents the normal cell control group without LPS stimulation.

[0064] Figure 2 Compound CS1 toxin H2O2 or MPP + The protective effect of induced oxidative stress in BV2 cells. Ctrl means no toxin H2O2 or MPP was used. + Induced normal cell control group.

[0065] Figure 3 This is a graph showing the results of a study on the protective effect of compound CS1 on glial cells. Ctrl represents a normal cell control group that was not stimulated with LPS.

[0066] Figure 4 This is a graph showing the protective effect of compound CS1 on mitochondria of BV2 cells. Ctrl indicates that MPP was not used. + Induced normal cell control group.

[0067] Figure 5 This is a graph showing the protective effect of compound CS1 on mitochondria of SY5Y cells. Ctrl indicates that MPP was not used. + Induced normal cell control group.

[0068] Figure 6 This is a graph showing the results of a study on the improvement of Parkinson's disease by compound CS1. Ctrl represents normal mice injected with only saline.

[0069] Figure 7 This is a comparison chart of the antioxidant effects of compound CS1 and traditional antioxidant compounds. Ctrl represents the normal cell control group without LPS stimulation. DETAILED DESCRIPTION

[0070] The following is a further detailed description of the cystamine derivatives or salts thereof of the present application and their use in the preparation of medicines with antioxidant efficacy in conjunction with specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0072] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0073] In this application, "the first aspect", "the second aspect", etc. are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "the first", "the second", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0074] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0075] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0076] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0077] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0078] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0079] The room temperature in this application generally refers to 4°C~30°C, preferably 20±5°C.

[0080] In this application, "ester group" refers to .

[0081] In this application, "amide group" refers to .

[0082] In the present application, "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. A phrase containing this term, for example, "C1~C10 alkyl" refers to an alkyl containing 1 to 10 carbon atoms, and each occurrence may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl or C10 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH( 2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0083] In the present application, "alkoxy" refers to a group having a structure of -O- alkyl, i.e., an alkyl group as defined above is connected to an adjacent group via an oxygen atom. A phrase comprising the term, for example, "C1~C10 alkoxy" refers to an alkyl moiety comprising 1~10 carbon atoms, and each occurrence may be independently of one another C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C7 alkoxy, C8 alkoxy, C9 alkoxy, C10 alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt) and tert-butoxy (-OC(CH3)3 or -OtBu).

[0084] In the present application, "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, which can be a monocyclic aryl, a condensed ring aryl, or a polycyclic aryl. For polycyclic rings, at least one is an aromatic ring system. For example, "C6~C15 aryl" refers to an aryl containing 6 to 15 carbon atoms, and each occurrence can be independently C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, C11 aryl, C12 aryl, C13 aryl, C14 aryl, C15 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene and their derivatives.

[0085] In the present application, "heteroaryl" means that at least one carbon atom is replaced by a non-carbon atom on the basis of an aryl group, and the non-carbon atom may be an N atom, an O atom, an S atom, etc. For example, "C3-C15 heteroaryl" means a heteroaryl group containing 3 to 15 carbon atoms, and each occurrence may be independently a C3 heteroaryl group, a C4 heteroaryl group, a C5 heteroaryl group, a C6 heteroaryl group, a C7 heteroaryl group, a C8 heteroaryl group, a C9 heteroaryl group, a C10 heteroaryl group, a C11 heteroaryl group, a C12 heteroaryl group, a C13 heteroaryl group, a C14 heteroaryl group, or a C15 heteroaryl group. Suitable examples include, but are not limited to, furanyl, benzofuranyl, thienyl, benzothienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiazolyl, tetrazolyl, indolyl, carbazolyl, pyrroloimidazolyl, pyrrolopyrrolyl, thienopyrrolyl, thienothiphenyl, furopyrrolyl, furofuranyl, thienofuranyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, o-naphthyl, quinoxalinyl, phenanthridinyl, primidinyl, quinazolinyl, and quinazolinonyl.

[0086] In the present application, "halogen" refers to F, Cl, Br or I.

[0087] As used herein, "amino" refers to -NH2.

[0088] In some embodiments of the present application, a cystamine derivative or a salt thereof is provided for use in the preparation of a drug or health product having an antioxidant effect. The cystamine derivative has a structural feature shown in the following formula (1), formula (2) or formula (3):

[0089] (1),

[0090] Among them, L 11 , L 12 are each independently an ester group or an amide group;

[0091] R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 11 , R 12 Each is independently substituted or unsubstituted by at least one S1, wherein S1 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0092] R 13 , R 14 Each independently represents H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl;

[0093] (2),

[0094] Among them, L 21 is an ester group or an amide group;

[0095] R 21 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 is substituted or unsubstituted with at least one S2, wherein S2 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0096] R 22 It is amino group;

[0097] R 23 is H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl;

[0098] (3),

[0099] Among them, L 31 is an ester group or an amide group;

[0100] R 31 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 It is substituted or unsubstituted with at least one S3, wherein S3 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino.

[0101] Without limitation, R 11 , R 12 , R 21 , R 31 The heteroaryl groups in the above-mentioned may each independently be indolyl or pyridyl, and the aryl groups may each independently be phenyl or naphthyl.

[0102] In some embodiments, in formula (1), R 11 , R 12 Meet one or more of the following conditions:

[0103] (a) S1 includes alkoxy, L 11 For amide, R 13 When H, R 11 , R 12 is not -C2~C10 alkyl-C3~C15 heteroaryl; further, S1 includes alkoxy, L 11 For amide, R 13 When H, R 11 , R 12 Each is independently -C1 alkyl-C3~C15 heteroaryl or C3~C15 heteroaryl;

[0104] (b) R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl;

[0105] (c) R 11 , R 12 The heteroaryl in is a C6~C15 heteroaryl; further, R 11 , R 12 The heteroaryl in is indolyl;

[0106] (d) When S1 includes halogen, L 21 It is an amide group.

[0107] In some embodiments, in formula (2), R 21 It is a C1~C10 alkyl group.

[0108] In some embodiments, in formula (3), R 31 is -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl. 31 It is -C1~C5 alkyl-C3~C15 heteroaryl.

[0109] Without limitation, the cystamine derivatives include one or more of the structures shown in the following CS1 to CS35:

[0110] CS1: ;CS2: ;

[0111] CS3: CS4: ;

[0112] CS5: CS6: ;

[0113] CS7: ; CS8: ;

[0114] CS9: ;

[0115] CS10: ;CS11: ;

[0116] CS12: ;CS13: ;

[0117] CS14: ;CS15: ;

[0118] CS16: ;CS17: ;

[0119] CS18: ;CS19: ;

[0120] CS20: ;CS21: ;

[0121] CS22: ;CS23: ;

[0122] CS24: ;CS25: ;

[0123] CS26: ;CS27: ;

[0124] CS28: ;CS29: ;

[0125] CS30: ;CS31: ;

[0126] CS32: ;CS33: ;

[0127] CS34: ;CS35: .

[0128] In some embodiments, the antioxidant effect includes one of a protective effect against oxidative stress and a preventive, therapeutic or ameliorative effect on neurodegenerative diseases.

[0129] Optionally, the oxidative stress comprises toxin-induced oxidative stress.

[0130] Optionally, the neurodegenerative disease comprises Parkinson's disease.

[0131] In some embodiments, the antioxidant effect includes one or more of the following characteristics:

[0132] (a) Enhance the protective effect of glial cells;

[0133] (b) Enhance the protective effect of nerve cells.

[0134] In some other embodiments of the present application, a cystamine derivative or a salt thereof is provided, wherein the cystamine derivative has a structural feature shown in the following formula (4) or formula (5):

[0135] (4),

[0136] Among them, L 41 , L 42 are each independently an ester group or an amide group;

[0137] R 41 , R42 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 41 , R 42 is unsubstituted, or R 41 , R 42 is substituted by halogen, and R 41 , R 42 Each is independently -C2~C10 alkyl-C3~C15 heteroaryl;

[0138] (5),

[0139] Among them, L 51 is an ester group or an amide group;

[0140] R 51 is C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 51 is substituted or unsubstituted with at least one S5, wherein S5 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino;

[0141] R 52 It is amino.

[0142] Without limitation, R 41 , R 42 , R 51 The heteroaryl groups in the above-mentioned may each independently be indolyl or pyridyl, and the aryl groups may each independently be phenyl or naphthyl.

[0143] In some embodiments, in formula (4), R 41 , R 42 Meet one or more of the following conditions:

[0144] (a) R 41 , R 42 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl;

[0145] (b) R 41 , R 42 The heteroaryl in is a C6~C15 heteroaryl; further, R 11 , R 12 The heteroaryl group is indolyl.

[0146] In some embodiments, in formula (5), R 51 It is a C1~C10 alkyl group.

[0147] Without limitation, the cystamine derivative has one of the structures shown below:

[0148] CS1: ;CS3: ;

[0149] CS4: ; CS7: ;

[0150] CS9: ;CS10: ;

[0151] CS13: ;CS21: .

[0152] For experimental parameters not specified in the following specific embodiments, reference is made to the instructions given in the present application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by manufacturers.

[0153] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources, or can be prepared by those skilled in the art according to known methods.

[0154] Example 1

[0155] This example provides compounds CS1 to CS35, the structures of which are shown below:

[0156] CS1: ;CS2: ;

[0157] CS3: CS4: ;

[0158] CS5: CS6: ;

[0159] CS7: ; CS8: ;

[0160] CS9: ;

[0161] CS10: ;CS11: ;

[0162] CS12: ;CS13: ;

[0163] CS14: ;CS15: ;

[0164] CS16: ;CS17: ;

[0165] CS18: ;CS19: ;

[0166] CS20: ;CS21: ;

[0167] CS22: ;CS23: ;

[0168] CS24: ;CS25: ;

[0169] CS26: ;CS27: ;

[0170] CS28: ;CS29: ;

[0171] CS30: ;CS31: ;

[0172] CS32: ;CS33: ;

[0173] CS34: ;CS35: .

[0174] Among them, compounds CS2, CS5, CS6, CS8, CS11, CS12, CS14, CS15, CS16, CS17, CS18, CS19, CS20, CS22, CS23, CS24, CS25, CS26, CS27, CS28, CS29, CS30, CS31, CS32, CS33, CS34 and CS35 are existing compounds and can be synthesized by referring to existing methods or the preparation methods of the following compounds CS1, CS3, CS4, CS7, CS9, CS10, CS13, CS21.

[0175] Compounds CS1, CS3, CS4, CS7, CS9, CS10, CS13 and CS21 are homemade compounds, and their preparation methods and structural identification data are as follows:

[0176] Synthesis of CS-1:

[0177]

[0178] 3-Indolepropionic acid (630 mg, 3.33 mM, 2.5 eq) was dissolved in DCM: ACN (6: 3), and then EDCI (1.02 g, 5.32 mM, 4 eq) and NHS (612 mg, 5.32 mM, 4 eq) were added to react at room temperature for 2 h. Cystamine dihydrochloride (300 mg, 1.33 mM, 1 eq) and triethylamine (1.6 mL, 11.9 mM, 9 eq) were dissolved in 10 mL ACN and added dropwise to the reaction system. The reaction was allowed to react overnight at room temperature. After TLC monitoring of the reaction was complete, the reaction solution was spin-dried, re-dissolved in DCM, extracted with water for 3 times, the DCM layers were combined, washed with saturated brine, the DCM layer was spin-dried with silica gel, and passed through a fast silica gel column (DCM: MeOH / 150: 1). The target point was collected and spin-dried to obtain a white solid (321 mg, yield: 49%), which was finally recrystallized to obtain 130 mg of pure product. 1 HNMR (400 MHz, DMSO) δ10.7 (s, 2H), 8.05 (t, J = 5.52 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.04 Hz, 2H), 7.08-7.03 (m, 4H), 6.95 (t, J = 7.08 Hz, 2H), 3.34 (m, 4H), 2.91 (t, J =7.44 Hz, 4H), 2.74 (t, J = 6.92 Hz, 4H), 2.44 (t, J = 8.12 Hz, 4H), ESI-MS:calcd for C 26 H 30 N4O2S2, [M+H] + m / z 517.1702, found, 517.1722, purity 99%.

[0179] Synthesis of CS-3 (Cystamine Dibutyrate):

[0180]

[0181] Dissolve n-butyric acid (366 μL, 4 mM, 3 eq) in 6 mL DCM, add EDCI (1.02 g, 5.32 mM, 4 eq) and NHS (612 mg, 5.32 mM, 4 eq), react at room temperature for 2 h, dissolve cystamine dihydrochloride (300 mg, 1.33 mM, 1 eq) and triethylamine (1.6 mL, 11.9 mM, 9 eq) in 10 mL ACN, add dropwise to the reaction system, and react at room temperature overnight. After TLC monitoring of the reaction is complete, the reaction solution is spin-dried, re-dissolved in DCM, extracted with water 3 times, the DCM layers are combined, washed with saturated brine, the DCM layer is spin-dried with silica gel, and passed through a fast silica gel column (DCM: MeOH / 100:1), the target point is collected, and spin-dried to obtain a white solid (158 mg, yield: 41%). 1 HNMR (400MHz, CDCl3) δ 6.35 (s, 2H), 3.57 (dd, J = 12. 56, 6.32 Hz, 4H), 2.83 (t, J =6.4 Hz, 4H), 2.20 (t, J = 7.36 Hz, 4H), 1.72-1.63 (m, 4H), 0.95 (t, J = 7.36Hz, 6H), ESI-MS: calcd for C 12 H 24 N2O2S2, [M+Na] + m / z 315.1171, found, 315.1195, purity 97%.

[0182] Synthesis of CS4 (Cystamine dinicotinate):

[0183]

[0184] Nicotinic acid (410 mg, 3.33 mM, 2.5 eq) was dissolved in 20 mL DCM, and HOBt (540 mg, 3.99 mM, 3 eq) and EDCl (765 mg, 3.99 mM, 3 eq) were added. The mixture was protected by N2 and stirred at room temperature for 20 min. Cystamine hydrochloride (300 mg, 1.33 mM, 1 eq) and Et3N (924 μL, 6.65 mM, 5 eq) were added and the reaction was allowed to proceed overnight. The reaction was basically complete after TLC monitoring. Saturated NaHCO3 was added and the mixture was extracted with DCM three times. The combined DCM layers were washed with saturated brine. The DCM layer was dried with silica gel and passed through a fast silica gel column (DCM: MeOH / 25:1). The target spots were collected and dried to obtain 388 mg of the product (yield 80%). The product was then dissolved in DCM / MeOH (5 / 5 mL), and about 10 mL of n-hexane was added for recrystallization. 295 mg of the product was collected by filtration. 1HNMR (400 MHz, DMSO) δ 9.0 (s, 2H), 8.86 (s, 2H), 8.70 (s, 2H), 8.17 (d, J = 7.52 Hz, 2H), 7.51 (d, J = 4.4 Hz, 2H), 3.59 (d, J = 5.52Hz, 4H), 2.95 (t, J = 6.08 Hz, 4H), ESI-MS: calcd for C 16 H 18 N4O2S2, [M+Na]+cald 385.0763, found 385.0777, purity 99%.

[0185] Synthesis of CS7 (Cystamine Monobutyrate):

[0186]

[0187] Butyric acid (100 μL, 1.09 mM, 1 eq), EDCI (1.045 g, 5.45 mM, 5 eq), and cystamine dihydrochloride (1.23 g, 5.45 mM, 5 eq) were dissolved in 3 mL of H2O, and the pH was adjusted to 6.0 with 0.1 M NaOH. The reaction was allowed to react at room temperature for 4 h. The reaction was monitored by HPLC, and 5 peaks were collected for mass spectrometry identification. The 5th peak was the target peak, which was separated and purified by HPLC and freeze-dried to obtain an oily product. 1 HNMR (400 MHz, DMSO) δ 8.0 (t, J = 4.92 Hz, 1H), 7.92 (s, 2H), 3.34 (dd, J=12.92, 6.48 Hz, 2H), 3.10 (d, J =5.32 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H),2.79 (t, J = 6.92 Hz, 2H), 2.04 (t, J = 7.28 Hz, 2H), 1.55-1.46 (m, 2H), 0.85(t, J = 7.36 Hz, 3H), ESI-MS: calcd for C8H 18 N2OS2, [M+H] + 223.3, found 223.2, purity 97%.

[0188] Synthesis of CS9 (Cystamine diindolebutyrate):

[0189]

[0190] Indolebutyric acid (338 mg, 1.665 mmoL, 2.5 eq), EDCI (383 mg, 2 mmoL, 3 eq), and HOBt (230 mg, 2 mmoL, 3 eq) were dissolved in 15 mL DCM and reacted with stirring at room temperature for 10 min. Cystamine dihydrochloride (150 mg, 0.66 mmoL, 1 eq) and Et3N (463 μL, 3.33 mmoL, 5 eq) were dissolved in 5 mL DCM and added to the reaction system. The reaction was allowed to proceed overnight. After TLC monitoring, the basic reaction was complete and the reaction was stopped. The reaction solution was washed with saturated NaHCO3, ultrapure water, and saturated NaCl, and then silica gel was added and spin-dried. The solution was purified by silica gel column (DCM:MeOH / 75:1) to obtain diindolebutyric acid cystamine (220 mg, yield: 64%). 1 HNMR (400 MHz, DMSO) δ10.74 (s, 2H), 7.98 (t, J = 5.52 Hz, 2H), 7.48 (d, J = 7.84 Hz, 2H), 7.31 (d,J = 8.04 Hz, 2H), 7.08-7.02 (m, 4H), 6.94 (t, J = 7.76 Hz, 2H), 3.35-3.30 (m,4H), 2.77 (t, J = 6.84 Hz, 4H), 2.65 (t, J = 7.44 Hz, 4H), 2.13 (t, J = 7.36Hz, 4H), 1.89-1.82 (m, 4H), ESI-MS: calcd for C 28 H 34 N4O2S2, [M+Na] + 545.7, found 545.25, purity 99%.

[0191] Synthesis of CS10 (Cystamine diindolecarboxylate):

[0192]

[0193] Indolecarboxylic acid (268 mg, 1.665 mmoL, 2.5 eq), EDCI (383 mg, 2 mmoL, 3 eq), and HOBt (230 mg, 2 mmoL, 3 eq) were dissolved in 15 mL DCM and reacted with stirring at room temperature for 10 min. Cystamine dihydrochloride (150 mg, 0.66 mmoL, 1 eq) and Et3N (463 μL, 3.33 mmoL, 5 eq) were dissolved in 5 mL DCM and added to the reaction system. The reaction was allowed to proceed overnight. The reaction was monitored to be complete by TLC. The reaction was stopped. The reaction solution was washed with saturated NaHCO3, ultrapure water, and saturated NaCl, and then silica gel was added and spin-dried. The mixture was purified by silica gel column (DCM:MeOH / 50:1) to obtain diindolecarboxylic acid cystamine (106 mg, yield: 37%). 1 HNMR (400 MHz, DMSO) δ11.53 (s, 2H), 8.14-8.10 (m, 4H), 8.01 (d, J = 2.92 Hz, 2H), 7.41 (d, J =7.92 Hz, 2H), 7.15-7.06 (m, 4H), 3.57 (dd, J = 13.48, 6.24 Hz, 4H), 2.95 (t,J = 2.92 Hz, 4H), ESI-MS: calcd for C 22 H 22 N4O2S2, [M+H] + 439.56, found 439.15, purity 99%.

[0194] Synthesis of CS13 (Cystamine diindoleacetic acid):

[0195]

[0196] Indoleacetic acid (194 mg, 1.11 mmoL, 2.5 eq), EDCI (255 mg, 1.332 mmoL, 3 eq), and HOBt (153 mg, 1.332 mmoL, 3 eq) were dissolved in 10 mL DCM and reacted with stirring at room temperature for 10 min. Cystamine dihydrochloride (100 mg, 0.44 mmoL, 1 eq) and Et3N (309 μL, 2.22 mmoL, 5 eq) were dissolved in 5 mL DCM and added to the reaction system. The reaction was allowed to proceed overnight. After TLC monitoring, the basic reaction was complete and the reaction was stopped. The reaction solution was washed with saturated NaHCO3, ultrapure water, and saturated NaCl, and then silica gel was added and spin-dried. The solution was purified by silica gel column (DCM:MeOH / 30:1) to obtain diindoleacetic acid cystamine (113 mg, yield: 55%). 1HNMR (400 MHz, DMSO) δ 10.85 (s, 2H), 8.05 (t, J = 5.56 Hz, 2H), 7.53 (d, J = 7.92Hz, 2H), 7.32 (d, J = 8.08 Hz, 2H), 7.17 (s, 2H), 7.07-7.03 (m, 2H), 6.97-6.93 (m, 2H), 3.50 (s, 4H), 3.34-3.29 (m, 4H), 2.74 (t, J = 6.96 Hz, 4H),ESI-MS: calcd for C 24 H 26 N4O2S2, [M+Na] + 489.62, found 489.15, purity 98%.

[0197] Synthesis of CS21 (5-bromo-indolepropionic acid cystamine):

[0198]

[0199] 5-Bromo-indolepropionic acid (298 mg, 1.11 mmoL, 2.5 eq), EDCI (255 mg, 1.32 mmoL, 3 eq), and HOBt (153 mg, 1.32 mmoL, 3 eq) were dissolved in 10 mL DCM and reacted at room temperature with stirring for 10 min. Cystamine dihydrochloride (100 mg, 0.44 mmoL, 1 eq) and Et3N (309 μL, 2.2 mmoL, 5 eq) were dissolved in 5 mL DCM and added to the reaction system. The reaction was allowed to proceed overnight. The reaction was stopped after TLC monitoring that the basic reaction was complete. The reaction solution was washed with saturated NaHCO3, ultrapure water, and saturated NaCl, and then silica gel was added and spin-dried. The solution was purified by silica gel column (DCM:MeOH / 40:1) to obtain 5-bromo-indolepropionic acid cystamine (189 mg, yield: 66%). 1 HNMR (400 MHz, DMSO) δ10.96 (s, 2H), 8.03 (t, J = 5.52 Hz, 2H), 7.69 (d, J = 1.76Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 7.16-7.14 (m, 4H), 3.32 (t, J = 7.24 Hz, 4H), 2.89 (t, J = 7.44 Hz, 4H), 2.73 (t, J = 6.96 Hz, 4H), 2.41 (t, J = 7.6Hz, 4H), ESI-MS: calcd for C 26H 28 Br2N4O2S2, [M+Na] + 672.9913, found 672.9903, purity 99%.

[0200] Example 2

[0201] This example provides a study on the antioxidant activity of compounds CS1 to CS35.

[0202] BV2 cells were used to study the inhibitory effects of compounds on oxidative stress at the cellular level. BV2 cells were seeded in 12-well plates at 2.5×10 4 1 μg / mL LPS was added to induce oxidative stress in BV2 cells. Figure 1 As shown in Table 1, it can be seen that compounds CS1~CS35 have good antioxidant activity.

[0203] Table 1

[0204]

[0205] Example 3

[0206] This example provides a study on the protective effect of compound CS1 on oxidative stress induced by various toxins.

[0207] U937 cells and BV2 cells were used to study the inhibitory effect of CS1 on oxidative stress at the cellular level. U937 cells were seeded in 12-well plates at 4×10 5 / mL, adding 1mM H2O2 for 1h, causing U937 cells to produce oxidative stress. Figure 2 As shown in Figure A, CS1 can effectively alleviate the oxidative stress caused by H2O2. BV2 cells were seeded in 12-well plates, and 2.5×10 4 / mL, add 2mM MPP + After 24 hours of treatment, BV2 cells developed oxidative stress. Figure 2 As shown in B, CS1 can effectively alleviate MPP + Induced oxidative stress.

[0208] Example 4

[0209] This example provides a study on the protective effect of CS1 on glial cells.

[0210] BV2 cells were used to study the inhibitory effect of CS1 on apoptosis at the cellular level. BV2 cells were seeded in 6-well plates at 5×10 5 / mL, adding 2μg / mL LPS to induce for 10h, causing BV2 cells to produce apoptosis. Figure 3As shown, CS1 has a good protective effect on glial cells.

[0211] Example 5

[0212] This example provides a study on the protective effect of CS1 on mitochondria of neural cells.

[0213] BV2 cells and SY5Y cells were used to study the protective effect of CS1 on neuronal mitochondria at the cellular level. BV2 cells and SY5Y cells were seeded in 12-well plates, and 3×10 5 / mL, add 1mM MPP + After 24 hours of treatment, the mitochondria of BV2 cells and SY5Y cells were damaged and the mitochondrial membrane potential was lost. Figures 4 and 5 As shown, CS1 can effectively alleviate MPP + Induced mitochondrial damage, and it was observed in BV2 cells that the recovery effect of mitochondrial damage was dependent on the concentration of CS1, and 40μM CS1 had the best mitochondrial recovery effect.

[0214] Example 6

[0215] This example provides a study on the improvement effect of CS1 on Parkinson's disease.

[0216] Parkinson's disease mice were simulated by intraperitoneal injection of MPTP (20 mg / kg) into C57BL / 6J mice. The body temperature and weight of the mice were recorded before the experiment. After intraperitoneal injection of MPTP (20 mg / kg), 10 mg / kg of CS1 was administered by gavage at the same time, and the body temperature and weight of the mice were measured every 2 hours. 12 hours after administration, the striatum region of the mouse brain was removed, and protein immunoblotting experiments were performed to detect Parkinson's-related pathological phenotypes. The results are shown in Figure 6 As shown, CS1 can improve the survival rate of mice and effectively improve the phenotypes related to Parkinson's disease in mice.

[0217] Example 7

[0218] This example provides that CS1 has a stronger antioxidant effect than first-line antioxidant drugs.

[0219] Using BV2 cells, the antioxidant capacity of CS1 and a variety of compounds with a certain degree of antioxidant activity (vitamin C (VC), astaxanthin (ASTA), ergothioneine (EGT), melatonin (MET), water-soluble vitamin E (Trolox)) were compared at the cellular level. BV2 cells were seeded in 6-well plates, 5×10 5 / mL, 1μg / mL LPS was added to induce oxidative stress in BV2 cells. The concentration of each drug tested was 10μM, and it was added at the same time as LPS for a total of 10h. Figure 7 As shown in the results, CS1 has a better antioxidant effect than other compounds.

[0220] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0221] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. Use of a cystamine derivative or a salt thereof in the preparation of a drug or health product with antioxidant effect, wherein the cystamine derivative has a structural feature shown in the following formula (1), formula (2) or formula (3): （1）， in, L 11 , L 12 are each independently an ester group or an amide group; R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 11 , R 12 Each is independently substituted or unsubstituted by at least one S1, wherein S1 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino; R 13 , R 14 Each independently represents H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl; （2）， Among them, L 21 is an ester group or an amide group; R 21 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 is substituted or unsubstituted with at least one S2, wherein S2 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino; R 22 It is amino group; R 23 is H, -ester-C1~C10 alkyl or -amide-C1~C10 alkyl; （3）， Among them, L 31 is an ester group or an amide group; R 31 is -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 21 It is substituted or unsubstituted with at least one S3, wherein S3 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino.

2. The use according to claim 1, characterized in that: In formula (1), R 11 , R 12 Meet one or more of the following conditions: (a) S1 includes alkoxy, L 11 For amide, R 13 When H, R 11 , R 12 It is not -C2~C10 alkyl-C3~C15 heteroaryl; (b) R 11 , R 12 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; (c) R 11 , R 12 The heteroaryl group in is a C6~C15 heteroaryl group; (d) When S1 includes halogen, L 21 It is an amide group.

3. The use according to claim 1, characterized in that: In formula (2), R 21 It is a C1~C10 alkyl group.

4. The use according to claim 1, characterized in that: In formula (3), R 31 It is -C1~C10 alkyl-C3~C15 heteroaryl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl.

5. The use according to claim 1, characterized in that: The cystamine derivatives include one or more of the structures shown in the following CS1 to CS35: CS1: ; CS2: ; CS3: ; CS4: ; CS5: ; CS6: ; CS7: ; CS8: ; <h2 style=";text-align:left;direction:ltr">CS9:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ; CS10: ; CS11: ; CS12: ; CS13: ; CS14: ; CS15: ; CS16: ; CS17: ; CS18: ; CS19: ; CS20: ; CS21: ; CS22: ; <h2 style=";text-align:left;direction:ltr">CS23:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ; CS24: ; CS25: ; CS26: ; CS27: ; CS28: ; CS29: ; CS30: ; CS31: ; <h2 style=";text-align:left;direction:ltr">CS32:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ; <h2 style=";text-align:left;direction:ltr">CS33:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ; CS34: ; <h2 style=";text-align:left;direction:ltr">CS35:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 。 6. The use according to any one of claims 1 to 5, characterized in that: The antioxidant effect includes one of the protective effect on oxidative stress and the prevention, treatment or improvement of neurodegenerative diseases.

7. The use according to claim 6, characterized in that: The oxidative stress comprises toxin-induced oxidative stress; and / or, the neurodegenerative disease comprises Parkinson's disease.

8. The use according to any one of claims 1 to 5, characterized in that: The antioxidant effect includes one or more of the following characteristics: (a) Enhance the protective effect of glial cells; (b) Enhance the protective effect of nerve cells.

9. A cystamine derivative or a salt thereof, characterized in that: The cystamine derivative has a structural feature as shown in the following formula (4) or formula (5): （4）， Among them, L 41 , L 42 are each independently an ester group or an amide group; R 41 , R 42 Each is independently -C1~C10 alkyl-C3~C15 heteroaryl, C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 41 , R 42 is unsubstituted, or R 41 , R 42 is substituted by halogen, and R 41 , R 42 Each is independently -C2~C10 alkyl-C3~C15 heteroaryl; （5）， Among them, L 51 is an ester group or an amide group; R 51 is C1~C10 alkyl, C3~C15 heteroaryl, -C1~C10 alkyl-C6~C15 aryl or C6~C15 aryl; R 51 is substituted or unsubstituted with at least one S5, wherein S5 includes one or more of H, C1~C10 alkoxy, halogen, -ester-C1~C10 alkyl, -amide-C1~C10 alkyl, -ester-C1~C10 alkoxy, -amide-C1~C10 alkoxy and amino; R 52 It is amino.

10. The cystamine derivative or salt thereof according to claim 9, characterized in that The cystamine derivative has one of the following structures: CS1: ; CS3: ; CS4: ; CS7: ; <h2 style=";text-align:left;direction:ltr">CS9:<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ; CS10: ; CS13: ; CS21: 。

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