Cystamine derivatives or salts thereof and use thereof in preparing drugs with antioxidant effects

Abstract

This application relates to cystamine derivatives or salts thereof and their use in the preparation of drugs with antioxidant effects. The use of the cystamine derivatives or salts thereof in the preparation of drugs with antioxidant effects, the cystamine derivatives having the structural characteristics shown in the following formula (1), formula (2) or formula (3). The present application has found that the 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. #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 efficacy. Background Art

[0002] In the process of modern scientific and industrial development, antioxidant issues 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 various diseases, such as cardiovascular disease and neurodegenerative diseases. 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, as well as 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 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;

[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 12is 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 comprises one or more of the structures shown below in 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 a protection against oxidative stress and a 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 the structural characteristics 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 a C1~C10 alkyl group, a C3~C15 heteroaryl group, a -C1~C10 alkyl group-C6~C15 aryl group, or a C6~C15 aryl group; 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 an amino group.

[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 study found that cystamine derivatives or their salts 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 The graph shows the antioxidant activity test results of compounds CS1 to 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 indicates that no toxin H2O2 or MPP was used. + Induced normal cell control group.

[0065] Figure 3 This figure shows the results of the study on the protective effect of compound CS1 on glial cells. Ctrl represents the normal cell control group without LPS stimulation.

[0066] Figure 4 This is a graph showing the protective effect of compound CS1 on mitochondria in 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 in SY5Y cells. Ctrl indicates that MPP was not used. + Induced normal cell control group.

[0068] Figure 6 This figure shows the research results of the improvement effect of compound CS1 on Parkinson's disease. Ctrl represents normal mice injected with only saline.

[0069] Figure 7 This is a comparison 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 medicaments having antioxidant efficacy, with reference to specific examples. The present application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided for the purpose of providing a more thorough and comprehensive understanding of the disclosure of the present application.

[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 pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only 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, terms such as "first aspect" and "second aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor as implicitly indicating the importance or quantity of the technical features indicated. Furthermore, terms such as "first" and "second" serve only as non-exhaustive enumeration and description and should not constitute a closed-ended limitation on quantity.

[0074] In this 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 referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0076] Unless otherwise specified, the percentage contents mentioned in this application refer to mass percentage for solid-liquid mixture and solid-solid mixture, and refer to volume percentage for liquid-liquid mixture.

[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 for temperature fluctuations within the precision range of instrument control.

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

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

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

[0082] As used herein, "alkyl" refers to a monovalent residue resulting from the loss of a hydrogen atom from a saturated hydrocarbon containing primary, secondary, tertiary, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, such as "C1-C10 alkyl," refer to an alkyl group containing 1 to 10 carbon atoms, each occurrence of which can independently be 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 this 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 to 10 carbon atoms, each occurrence of which can 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] As used herein, "aryl" refers to an aromatic hydrocarbon radical derived from an aromatic ring compound by removing a hydrogen atom. It may be a monocyclic aryl, a condensed-ring aryl, or a polycyclic aryl. For polycyclic rings, at least one ring system is aromatic. For example, "C6-C15 aryl" refers to an aryl group containing 6 to 15 carbon atoms, and each occurrence may independently be a C6 aryl, a C7 aryl, a C8 aryl, a C9 aryl, a C10 aryl, a C11 aryl, a C12 aryl, a C13 aryl, a C14 aryl, or a 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" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which may be a nitrogen atom, an oxygen atom, an sulfur atom, etc. For example, "C3-C15 heteroaryl" refers to a heteroaryl group containing 3 to 15 carbon atoms, and each occurrence thereof may independently be 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, furyl, 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, quinolinyl, isoquinolinyl, o-naphthyl, quinoxalinyl, phenanthridinyl, primidinyl, quinazolinyl, and quinazolinonyl.

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

[0087] In this application, "amino" refers to -NH2.

[0088] In some embodiments of the present application, a cystamine derivative or a salt thereof is provided for use in preparing a drug having an antioxidant effect. The cystamine derivative has the structural characteristics 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;

[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 restriction, R 11 、R 12 、R 21 、R 31 The heteroaryl groups in the group 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 group in is a C6~C15 heteroaryl group; further, R 11 、R 12 The heteroaryl group 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 CS1 to CS35 below:

[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 protection effect against oxidative stress and a prevention, treatment or improvement 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 the structural characteristics 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 a C1~C10 alkyl group, a C3~C15 heteroaryl group, a -C1~C10 alkyl group-C6~C15 aryl group, or a C6~C15 aryl group; 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 an amino group.

[0142] Without restriction, R 41 、R 42 、R 51 The heteroaryl groups in the group 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 group in is a C6~C15 heteroaryl group; 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 following structures:

[0148] CS1: CS3: ;

[0149] CS4: ;CS7: ;

[0150] CS9: ;CS10: ;

[0151] CS13: ;CS21: .

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

[0153] The raw materials and reagents involved in the following specific examples can be obtained commercially, 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 with reference to existing methods or the preparation methods of the following compounds CS1, CS3, CS4, CS7, CS9, CS10, CS13 and CS21.

[0175] Compounds CS1, CS3, CS4, CS7, CS9, CS10, CS13, and CS21 are homemade compounds. The 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), followed by the addition of EDCI (1.02 g, 5.32 mM, 4 eq) and NHS (612 mg, 5.32 mM, 4 eq). The reaction was allowed 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 of ACN and added dropwise to the reaction system. The reaction was allowed to react at room temperature overnight. After TLC monitoring, the reaction solution was spin-dried, re-dissolved in DCM, and extracted three times with water. The DCM layers were combined and washed with saturated brine. The DCM layer was then added to silica gel and spin-dried. The target spot was collected and spin-dried to obtain a white solid (321 mg, yield: 49%). This was recrystallized to obtain 130 mg of the 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] Butyric acid (366 μL, 4 mM, 3 eq) was dissolved in 6 mL of DCM, followed by the addition of EDCI (1.02 g, 5.32 mM, 4 eq) and NHS (612 mg, 5.32 mM, 4 eq). The mixture was allowed 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 of ACN and added dropwise to the reaction system. The reaction was allowed to react at room temperature overnight. After TLC monitoring, the reaction solution was spin-dried, re-dissolved in DCM, and extracted three times with water. The DCM layers were combined and washed with saturated brine. The DCM layer was then added to silica gel and spin-dried. The target spot was 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 of DCM, and HOBt (540 mg, 3.99 mM, 3 eq) and EDCl (765 mg, 3.99 mM, 3 eq) were added. The reaction was stirred at room temperature for 20 min under N2 protection. Cystamine hydrochloride (300 mg, 1.33 mM, 1 eq) and Et3N (924 μL, 6.65 mM, 5 eq) were then added. The reaction was allowed to proceed overnight. TLC monitored the reaction to be nearly complete. Saturated NaHCO3 was added and the mixture was extracted with DCM three times. The combined DCM layers were washed with saturated brine. The DCM layers were added with silica gel and dried by spin drying. The product was passed through a fast silica gel column (DCM:MeOH / 25:1) and the target spot was collected by spin drying to obtain 388 mg of the product (yield 80%). The product was then dissolved in DCM / MeOH (5 / 5 mL) and recrystallized with about 10 mL of n-hexane. 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, the pH was adjusted to 6.0 with 0.1 M NaOH, and the reaction was carried out 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 stirred 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 monitoring the completion of the basic reaction 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 to dryness and purified on a 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 stirred 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 reaction was stopped and the reaction solution was washed with saturated NaHCO3, ultrapure water, and saturated NaCl. The reaction solution was then added to silica gel for spin drying and purified on a 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 of DCM and stirred 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 of DCM and added to the reaction system. The reaction was allowed to proceed overnight. After monitoring the completion of the basic reaction 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 to dryness and purified on a 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 stirred at room temperature 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. After monitoring the completion of the basic reaction 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 to dryness and purified on a 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 effect 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 to 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, 1mM H2O2 was added for 1h to induce oxidative stress in U937 cells. Figure 2 As shown in Figure A, CS1 can effectively alleviate the oxidative stress induced by H2O2. BV2 cells were seeded in 12-well plates, 2.5×10 4 / mL, add 2mM MPP + Treatment for 24 hours caused oxidative stress in BV2 cells. Figure 2 As shown in B, CS1 can effectively alleviate MPP + Induced oxidative stress.

[0208] Example 4

[0209] This example provides research 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, 5×10 5 / mL, 2μg / mL LPS was added for 10h to induce apoptosis in BV2 cells. Figure 3As shown, CS1 has a good protective effect on glial cells.

[0211] Example 5

[0212] This example provides research on the protective effect of CS1 on mitochondria in nerve 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 and SY5Y cells were damaged and the mitochondrial membrane potential was lost. Figures 4 and 5 As shown, CS1 can effectively alleviate MPP + It 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 research on the improvement effect of CS1 on Parkinson's disease.

[0216] Parkinson's disease was 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 orally. 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 was performed to detect Parkinson's disease-related pathological phenotypes. The results are shown in Figure 2. 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] The antioxidant capacity of CS1 and several compounds with certain antioxidant activity (vitamin C (VC), astaxanthin (ASTA), ergothioneine (EGT), melatonin (MET), and water-soluble vitamin E (Trolox)) were compared at the cellular level using BV2 cells. BV2 cells were seeded in 6-well plates at 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 10 hours. Figure 7 As shown in the results, CS1 has a better antioxidant effect than other compounds.

[0220] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned 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 embodiments described above only express several implementation methods of the present application, which are convenient for understanding the technical solutions of the present application in a specific and detailed manner, but they 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 variations and improvements can be made, which all fall within 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 application 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 having an antioxidant effect, wherein the antioxidant effect is the prevention, treatment or improvement of a neurodegenerative disease, wherein the neurodegenerative disease is Parkinson's disease; .

2. The use according to claim 1, characterized in that The antioxidant effect includes enhancing glial cell protection.

3. The use according to claim 1 or 2, characterized in that The antioxidant effect includes enhancing the protection of nerve cells.

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