Selenium-containing compound, polymer, injectable selenium-containing hydrogel, preparation method therefor, and use

Abstract

Disclosed is a compound as shown in formula (I), or a pharmaceutically acceptable salt or solvate thereof. Also disclosed are a selenium-containing polymer, an injectable selenium-containing hydrogel prepared from the selenium-containing polymer, a preparation method therefor, and a use.

Description

Selenium-containing compounds, polymers, injectable selenium-containing hydrogels, and their preparation and uses

[0001] This application claims priority to Chinese patent application No. 202311262481.9 filed on September 27, 2023. The contents of the above-mentioned Chinese patent application disclosure are hereby incorporated by reference in their entirety as a part of this application. Technical Field

[0002] The embodiments of the present disclosure relate to the technical field of medical polymer hydrogels, and in particular to a selenium-containing compound, a selenium-containing polymer, an injectable selenium-containing hydrogel made from the selenium-containing polymer, and a preparation method and use thereof. Background Art

[0003] Osteoarthritis is one of the most common degenerative diseases, and it is more common in obese and middle-aged and elderly people. Among them, the vast majority are symptomatic osteoarthritis of the knee. Studies have shown that as of 2020, approximately 654 million people aged 40 and above worldwide suffer from symptomatic osteoarthritis of the knee (Lu, H. et al., EClinical Medicine. 2020, 100587, 29). The 2018 osteoarthritis diagnosis and treatment guidelines show that the prevalence of symptomatic osteoarthritis of the knee in my country is as high as 8.1%. As the disease progresses, more and more obvious cartilage defects and osteophytes will appear in the joints, accompanied by characteristics such as joint pain, joint swelling, and reduced joint space. In addition, the disease has a long course and a disability rate of up to 53%. It is one of the five major diseases that cause disability in the elderly.

[0004] At present, clinical treatment is mainly achieved by injecting drugs into the joint cavity to reduce joint wear and reduce oxidative stress in the lesion. Hyaluronic acid (HA) is the most commonly used joint lubricant in clinical practice. It is one of the main components of synovial fluid. However, the high expression of hyaluronidase in osteoarthritis will accelerate its degradation, and patients usually need to be injected once a week for several weeks. Commonly used anti-inflammatory drugs in clinical practice are glucocorticoids, etc., which have a short residence time in the body after single injection and require repeated injections. As mentioned above, frequent injection of drugs into the joint cavity will increase the risk of joint swelling and infection. The occurrence of local adverse reactions is also related to the doctor's injection technique, the patient's activities after injection, and the purity of the drug. Therefore, there is an urgent need for new treatments for bone and joint diseases with long-term and sustained effects.

[0005] Hydrogel refers to a three-dimensional network-like polymer material with a water content of more than 70% formed by cross-linking. It has advantages such as excellent biocompatibility and can be used to replace hyaluronic acid (HA) to achieve lubrication, sustained drug release, etc. At present, a variety of hydrogels have been used to treat osteoarthritis. For example, Chinese patent application publication numbers CN113797319A, CN113999404A, CN104940944A, etc. teach the use of hyaluronic acid-based hydrogels to treat osteoarthritis. However, these hyaluronic acid-based hydrogels have a short residence time in the OA joint cavity, making it difficult to complete long-term (several weeks to several months) lubrication, sustained drug release and other functions. In addition, the anti-inflammatory drugs encapsulated inside are small molecule drugs, which are easy to diffuse and have a short half-life in the body, making it equally difficult to complete long-term treatment.

[0006] Therefore, there is an urgent need in the art for an injectable hydrogel material with improved performance.

[0007] Summary of the Invention

[0008] To solve the above and other problems, at least one embodiment of the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0009] in,

[0010] L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0011] L 1 and L 2 Each independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NRa -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a -, and -C(=O)-O-NR a -OC(=O)-;

[0012] R a Selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0013] L 3 Each occurrence is independently -O- or -S-;

[0014] x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20; and

[0015] m and n are each independently selected from integers of 0-20, with the proviso that 1≤m+n≤20.

[0016] In some examples, L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 Each independently selected from a chemical bond, -O-, -C(=O)-, -C(=O)O-, -OC(=)-, -OC(=O)-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -NR a -C(=O)-O- and -C(=O)-O-NR a -;R a Selected from -H and C 1-6 Alkyl; x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20.

[0017] In some examples, L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 One of them is a chemical bond and the other is -C(=O)-O- or -C(=O)-NRa -;R a Selected from -H and C 1-6 Alkyl; x, y and z are each independently an integer from 0 to 12, provided that 1≤x+y+z≤12.

[0018] In some examples, L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 are all chemical bonds; x, y and z are each independently an integer from 0 to 12, provided that 1≤x+y+z≤12.

[0019] In some examples, L is selected from -(CH2CH2-L 3 ) m -(CH2) n -, where L 3 -O-; m is an integer from 0 to 20, and n is 0.

[0020] In some examples, L is -(CH2) 1-6 -.

[0021] In some examples, L is -CH2-CH2-.

[0022] In some examples, the compound is selected from the group consisting of:

[0023] At least one embodiment of the present disclosure further provides a selenium-containing polymer, which is a compound of formula (I)

[0024] With a compound of formula (III):

[0025] Aggregated, where

[0026] L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0027] L 1 and L 2Each independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NR a -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a - and -C(=O)-O-NR a -OC(=O)-;

[0028] R a Selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0029] L 3 Each occurrence is independently -O- or -S-;

[0030] x, y and z are each independently an integer from 0 to 20, provided that 1 ≤ x + y + z ≤ 20;

[0031] m and n are each independently selected from integers of 0-20, provided that, 1≤m+n≤20,

[0032] R 1 Selected from:

[0033] a) -H, -OH, -NH2, halogen, C 1-20 Alkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, C 1-20 Alkoxy, C 1-20 Halogenated alkyl, phenyl, phenoxy, phenyl C 1-20 alkyl, carboxyl, hydroxy, carboxyalkyl, hydroxyalkyl, and cyano;

[0034] b)R 3 -(CH2) o -L4 -(CH2) p -, where L 4 Selected from -C 1-6 Alkylene, -C(=O)-, -OC(=O)-, -C(=O)-O-, -C(=O)-NH-, -NH-C(=O)-, -NH-C(=O)-O-, and -OC(=O)-NH-, R 3 Selected from -H, C 1-20 Alkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkyl, C 1-20 Alkylphenyl, C 1-20 Alkoxyphenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl and halophenyl, o and p are independently an integer from 0 to 4;

[0035] R 2 Selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0036] Or, R 1 and R 2 Together with the ring atoms to which they are attached, they form a five- or six-membered ring, which is optionally substituted with a group selected from hydroxy, carboxyl, ester, alkoxy and haloalkyl.

[0037] In some examples, the compound of formula (III) is selected from the following group:

[0038] In some examples, the polymer has the following structure:

[0039] Wherein, x=0.001~0.5, t=10~10,000.

[0040] At least one embodiment of the present disclosure further provides an injectable selenium-containing hydrogel, which is formed from any of the above-mentioned selenium-containing polymers and an active thiol compound.

[0041] In some examples, the injectable selenium-containing hydrogel further comprises an isotonic and / or buffering agent.

[0042] In some examples, the isotonic and / or buffering agent is selected from phosphate, sodium chloride, or a mixture thereof.

[0043] In some examples, the injectable selenium-containing hydrogel has a solid content in a range of 0.1 wt% to 20 wt% and a selenium content in a range of 10-10,000 ppm based on the total weight of the hydrogel.

[0044] At least one embodiment of the present disclosure further provides a method for preparing an injectable selenium-containing hydrogel, comprising: swelling any of the above-mentioned selenium-containing polymers with an active thiol compound solution to obtain the injectable selenium-containing hydrogel.

[0045] In some examples, the active thiol compound is selected from glutathione, dithiothreitol, cysteine, N-acetylcysteine, penicillamine, thioglycolic acid, mercaptopropionic acid, mercaptobutyric acid, and a mixture of any two or more thereof.

[0046] In some examples, the polymer is deprotected or post-modified before swelling the selenium-containing polymer with the active thiol compound solution.

[0047] At least one embodiment of the present disclosure further provides a use of any of the above-mentioned injectable selenium-containing hydrogels for preparing drugs for intra-articular injection.

[0048] At least one embodiment of the present disclosure further provides a use of any of the above-mentioned injectable selenium-containing hydrogels for preparing a drug for scavenging reactive oxygen species.

[0049] At least one embodiment of the present disclosure further provides the use of any of the above-mentioned injectable selenium-containing hydrogels for preparing a drug for treating bone and joint-related inflammation.

[0050] In some examples, the bone and joint-related inflammation is osteoarthritis or rheumatoid arthritis.

[0051] In some cases, the drug is long-acting.

[0052] In some instances, the drug is administered by injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the drawings of the embodiments will be briefly introduced below. Obviously, the drawings in the following description only relate to some embodiments of the present disclosure, rather than limiting the present disclosure.

[0054] FIG1 shows a method for preparing L-selenohomocystine carboxylic anhydride (SeHC diNCA) according to an embodiment of the present disclosure;

[0055] FIG2 shows a method for preparing a selenium-containing hydrogel (Se-Gel) according to an embodiment of the present disclosure;

[0056] FIG3 shows a scanning electron micrograph of Se-Gel (Se-Gel-5%) in which the molar ratio of the SeHC component in the hydrogel matrix is ​​5 mol % according to an embodiment of the present disclosure;

[0057] FIG4 shows the hydrogen nuclear magnetic resonance spectrum of the oxidative degradation product of Se-Gel-5% according to the present disclosure, wherein the solvent is D2O;

[0058] FIG5 shows a rheological oscillation frequency sweep curve of Se-Gel-5% according to an embodiment of the present disclosure;

[0059] FIG6 shows the H 2 O 2 scavenging ability of Se-Gel according to an embodiment of the present disclosure;

[0060] FIG7 shows the glutathione peroxidase (GSH-Px) activity catalytic ability of the oxidative degradation products of Se-Gel according to an embodiment of the present disclosure;

[0061] FIG8 shows a method for preparing an injectable selenium-containing hydrogel (GSH@Se-Gel) comprising glutathione as an active thiol compound according to an embodiment of the present disclosure;

[0062] FIG9 shows a rheological gradient amplitude sweep curve and an oscillation frequency sweep curve of GSH@Se-Gel according to an embodiment of the present disclosure;

[0063] FIG10 shows the live-dead staining results of ATDC5 mouse chondrocyte cell line incubated in Se-Gel for 24 h according to an embodiment of the present disclosure;

[0064] FIG11 shows the cytotoxicity results of GSH@Se-Gel according to an embodiment of the present disclosure, wherein the cell line is ATDC5 cells;

[0065] FIG12 shows flow cytometry results after DHE staining according to an embodiment of the present disclosure, wherein GSH@Se-Gel reduces the ROS concentration of ATDC5 after co-incubation with H2O2;

[0066] FIG13 shows the degradation process of the product (GSH@Cy5.5-Se-Gel) in which the dye Cy5.5 is covalently linked to the backbone of GSH@Se-Gel according to an embodiment of the present disclosure in the joints of rats with surgically induced osteoarthritis;

[0067] FIG14 shows the results of 6 and 12 weeks of GSH@Se-Gel treatment according to an embodiment of the present disclosure; and

[0068] FIG. 15 shows organ toxicity after 12 weeks of GSH@Se-Gel treatment according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0069] For the purpose of the following detailed description, it should be understood that the present disclosure may adopt various alternative variations and step sequences, unless expressly provided otherwise. In addition, except for + in any operating example, or otherwise indicated, all numbers representing the amount of ingredients used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and the appended claims are approximate values ​​that vary according to the desired performance to be obtained by the present disclosure. At least not attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques.

[0070] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0071] Furthermore, it should be understood that any numerical range recited herein is intended to include all subranges subsumed therein. For example, a range of "1 to 10" is intended to include all subranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, i.e., having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10.

[0072] In this disclosure, unless otherwise expressly stated, the use of the singular includes the plural and the plural includes the singular. Furthermore, in this disclosure, unless otherwise expressly stated, the use of "or" means "and / or," even though "and / or" could be explicitly used in certain circumstances. Furthermore, in this disclosure, unless otherwise expressly stated, the use of "a" or "an" means "at least one." For example, "a" polymer, "a" composition, etc., refers to one or more of any of these items.

[0073] Osteoarthritis is one of the most common degenerative diseases, particularly in obese and middle-aged individuals. The vast majority of cases are symptomatic knee osteoarthritis. Not all patients with osteoarthritis will experience symptoms. However, those who do develop symptomatic osteoarthritis require active treatment to prevent progressive joint damage, ultimately leading to joint deformity and loss of function.

[0074] Current clinical treatments for osteoarthritis include topical and oral analgesics and anti-inflammatory drugs. These treatments can provide short-term relief from osteoarthritis symptoms but cannot reverse the progression of the disease, have low utilization rates, and carry the potential risk of systemic side effects. Alternatively, intra-articular drug injections can be used clinically to treat osteoarthritis. While intra-articular drug injections are an effective treatment strategy for osteoarthritis, they are hampered by issues such as rapid drug diffusion and degradation, necessitating frequent injections. For example, hyaluronic acid (HA) is the most commonly used joint lubricant in clinical practice and a major component of synovial fluid. However, high expression of hyaluronidase in osteoarthritis accelerates its degradation, necessitating weekly injections for multiple weeks. Commonly used anti-inflammatory drugs, such as glucocorticoids, have a short residence time in the body after single injection, necessitating repeated injections. Frequent intra-articular drug injections increase the risk of joint swelling and infection. The occurrence of local adverse reactions is also related to the physician's injection technique, the patient's post-injection activity, and the purity of the drug.

[0075] In recent years, a large number of osteoarthritis treatment studies have used new bioactive materials such as hydrogels as drug delivery carriers. Hydrogels refer to three-dimensional network polymer materials with a water content of more than 70% formed by cross-linking. They have advantages such as excellent biocompatibility and can be used to achieve lubrication, sustained drug release, etc. According to the type of cross-linking points, hydrogels can be divided into chemically cross-linked hydrogels and physically cross-linked hydrogels. Chemically cross-linked hydrogels have better mechanical properties and longer in vivo degradation time, but they are difficult to inject with a syringe, making clinical application more difficult. Physically cross-linked hydrogels can be injected with a syringe, are easy to operate, and are suitable for implantation in the body, but have lower mechanical properties and a short in vivo degradation time. At present, it is difficult for medical hydrogels to simultaneously possess properties such as good mechanical properties, long degradation time, and injectability.

[0076] To solve the above and other problems, the present disclosure provides an injectable selenium-containing hydrogel material and its application for the treatment of osteoarthritis. The injectable selenium-containing hydrogel disclosed herein utilizes selenium-containing polymers to replace the hyaluronic acid-based joint cavity injection commonly used in current literature and clinical practice. The degradation time in the joint cavity that has developed into osteoarthritis is longer (up to 10 weeks), which is much higher than the degradation time of hyaluronic acid-based hydrogels. During the treatment process based on the selenium-containing polymer, the patient can significantly reduce the frequency of joint cavity injection, and only needs to be injected once every 1-3 months, which is much lower than the frequency of hyaluronic acid injection (usually about once a week for five consecutive weeks). In addition, the present invention utilizes selenium-containing polyamino acids to simulate glutathione reductase, which efficiently removes reactive oxygen species (ROS) and significantly reduces inflammation at osteoarthritis. Under the same injection frequency and dosage, its therapeutic effect is better than that of hyaluronic acid-based injections. Moreover, the present invention also utilizes the dynamic exchange reaction of thiol-diselenide bonds to achieve the injectability of chemically cross-linked hydrogels.

[0077] In some aspects, at least one embodiment of the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0078] in,

[0079] L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0080] L 1 and L 2 Each of the above may be independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NR a -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a - and -C(=O)-O-NR a -OC(=O)-;

[0081] R a Can be selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0082] L 3 Each occurrence can be independently -O- or -S-;

[0083] x, y and z may each independently be an integer from 0 to 20, provided that 1 ≤ x + y + z ≤ 20;

[0084] m and n may each be independently selected from integers ranging from 0 to 20, provided that 1≤m+n≤20.

[0085] In some examples, L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 can be independently selected from chemical bonds, -O-, -C(=O)-, -C(=O)O-, -OC(=)-, -OC(=O)-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -NR a -C(=O)-O- and -C(=O)-O-NR a -;R a Can be selected from -H and C 1-6 Alkyl; x, y and z may each independently be an integer from 0 to 20, provided that 1≤x+y+z≤20.

[0086] In other examples, L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 One of them may be a chemical bond and the other may be -C(=O)-O- or -C(=O)-NR a -;R a Can be selected from -H and C 1-6 Alkyl; x, y and z may each independently be an integer from 0 to 12, provided that 1≤x+y+z≤12.

[0087] In other examples, L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where L 1 and L 2 x, y and z can each independently be an integer from 0 to 12, provided that 1≤x+y+z≤12. For example, L can be -(CH2) 1-6 -.

[0088] Alternatively, in some examples, L can be selected from -(CH2CH2-L 3 ) m -(CH2) n -, where L 3 is -O-; m is an integer from 0 to 20, and n is 0. For example, L can be -CH2-CH2-.

[0089] In some exemplary embodiments, the compound described in the present disclosure may be selected from the following group:

[0090] At least one embodiment of the present disclosure further provides a selenium-containing polymer, wherein the polymer is a compound of formula (I)

[0091] With a compound of formula (III):

[0092] Aggregated, where

[0093] L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0094] L 1 and L 2 Each of the above may be independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -, -C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NR a -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a - and -C(=O)-O-NR a -OC(=O)-;

[0095] R a Can be selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0096] L 3 Each occurrence can be independently -O- or -S-;

[0097] x, y and z may each independently be an integer from 0 to 20, provided that 1 ≤ x + y + z ≤ 20;

[0098] m and n can each be independently selected from an integer of 0-20, provided that, 1≤m+n≤20,

[0099] R 1 Can be selected from:

[0100] a) -H, -OH, -NH2, halogen, C 1-20 Alkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, C 1-20 Alkoxy, C 1-20 Halogenated alkyl, phenyl, phenoxy, phenyl C 1-20 alkyl, carboxyl, hydroxy, carboxyalkyl, hydroxyalkyl, and cyano;

[0101] b)R 3 -(CH2) o -L 4 -(CH2) p -, where L 4 Can be selected from -C 1-6 Alkylene, -C(=O)-, -OC(=O)-, -C(=O)-O-, -C(=O)-NH-, -NH-C(=O)-, -NH-C(=O)-O-, and -OC(=O)-NH-, R 3 Can be selected from -H, C 1-20 Alkyl, C 1-20 Alkoxy, C 1-20 Halogenated alkyl, C 1-20 Alkylphenyl, C 1-20 Alkoxyphenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl and halophenyl, o and p are independently an integer from 0 to 4;

[0102] R 2 Can be selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0103] Or, R 1 and R 2 Together with the ring atoms to which they are attached, they may form a five- or six-membered ring, which may be optionally substituted with a group selected from hydroxy, carboxyl, ester, alkoxy and haloalkyl.

[0104] In some examples, the compound of formula (III) can be selected from the following group:

[0105] In other examples, polymers may have the following structures:

[0106] Wherein, x=0.001~0.5, t=10~10,000.

[0107] At least one embodiment of the present disclosure also provides an injectable selenium-containing hydrogel. As used herein, the term "hydrogel" is a three-dimensional network polymer material with a water content of more than 70% and formed by cross-linking; the term "selenium-containing" means that the structure of the hydrogel material contains covalently bound selenium (Se) elements; the term "injectable" means that the hydrogel material can be administered to the target site through a syringe / syringe. Hydrogel materials can swell in water but do not dissolve, have excellent biocompatibility, etc., and can be used for a variety of medical purposes such as lubrication, sustained drug release, etc. According to the type of cross-linking points, hydrogels can be divided into chemically cross-linked hydrogels and physically cross-linked hydrogels. As used herein, the term "chemically cross-linked hydrogel" is a three-dimensional network polymer formed by chemical bond cross-linking, which is permanent and is also called a true gel; the term "physically cross-linked hydrogel" is a non-permanent material formed by physical forces such as electrostatic effects, hydrogen bonds, chain entanglement, etc., which can be converted into a solution by heating. Chemically cross-linked hydrogels have better mechanical properties and longer in vivo degradation time, but are difficult to inject via syringe, making clinical application more difficult; while physically cross-linked hydrogels can be injected via syringe, are easy to operate, and are suitable for implantation in the body, but have lower mechanical properties and a short in vivo degradation time.

[0108] The injectable selenium-containing hydrogel according to an embodiment of the present disclosure can be prepared by swelling the selenium-containing polymer described in the present disclosure with an active thiol compound to obtain the injectable selenium-containing hydrogel.

[0109] In other aspects, the solid content of the injectable selenium-containing hydrogel can be in the range of 0.1 wt% to 20 wt%, and the selenium content can be in the range of 10-10,000 ppm, based on the total weight of the hydrogel. In other aspects, the reactive thiol compound can be selected from glutathione, dithiothreitol, cysteine, N-acetylcysteine, penicillamine, thioglycolic acid, mercaptopropionic acid, mercaptobutyric acid, and mixtures of any two or more thereof.

[0110] In other aspects, the selenium-containing polymer can be deprotected or post-modified before swelling it with the active thiol compound solution. For example, the polymer can be deprotected or post-modified by removing ester protecting groups (such as trifluoroacetyl groups) with a potassium carbonate methanol / water solution or removing tert-butyloxycarbonyl protection with trifluoroacetic acid.

[0111] The injectable selenium-containing hydrogel provided by the present disclosure can be used as or for preparing a drug for intra-articular injection, for example, it can be used as or for preparing a drug for scavenging reactive oxygen species. In some aspects, the injectable selenium-containing hydrogel provided by the present disclosure can be used to treat osteoarthritis-related inflammation, for example, it can be used as or for preparing a drug for treating osteoarthritis-related inflammation. For example, the osteoarthritis-related inflammation described in the present disclosure can be osteoarthritis or rheumatoid arthritis. In a further aspect, the injectable selenium-containing hydrogel provided by the present disclosure can be used as a drug or a drug prepared using the injectable selenium-containing hydrogel provided by the present disclosure can be long-lasting and can be administered by injection.

[0112] The injectable selenium-containing hydrogel structure disclosed herein utilizes the diselenide bond of the compound of formula (I) as a crosslinking point, and achieves the injectability of the chemically crosslinked hydrogel through the dynamic exchange reaction of the thiol-diselenide bond. Taking glutathione as an active thiol compound as an example,

[0113] Moreover, the injectable selenium-containing hydrogel formed in this way utilizes selenium-containing polyamino acids to replace the hyaluronic acid-based joint cavity injection commonly used in current literature and clinical practice. Its degradation time in the joint cavity that develops into osteoarthritis is longer, reaching 10 weeks, which is much higher than the hyaluronic acid-based hydrogel degradation time; Based on the treatment process of this injectable selenium-containing hydrogel, the patient can significantly reduce the frequency of joint cavity injection, only needing to inject once every 1-3 months, which is much lower than the hyaluronic acid injection frequency (about once a week, for five consecutive weeks). In addition, the selenium-containing polyamino acids in this hydrogel structure can also simulate glutathione reductase, efficiently remove reactive oxygen species, and significantly reduce inflammation at osteoarthritis. Under the same injection frequency and dosage, its therapeutic effect is better than hyaluronic acid-based injection.

[0114] Example

[0115] The embodiments of the present application will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are merely illustrative of the present application and should not be construed as limiting the scope of the present application. Specific conditions not specified in the examples are carried out according to conventional conditions or manufacturer recommendations. Reagents used or instruments not specified in the manufacturers are conventional products that can be obtained commercially. Unless otherwise indicated, all amounts listed are described in parts by weight based on gross weight. The application should not be construed as being limited to the specific examples described.

[0116] Preparation Example 1: Preparation of Selenium-Containing Amino Acids and Their Carboxyl Ring Anhydrides

[0117] Methionine (30.0 g, 200 mmol, 1.0 equiv), methyl chloroacetate (23.0 mL, 260 mmol, 1.3 equiv), and tetrabutylammonium bromide (TBAB, 3.2 g, 10 mmol, 0.050 equiv) were dissolved in 150 mL of deionized water and heated to 90°C and refluxed for 6 h. The mixture was cooled to room temperature, and 40 mL of 40% hydrobromic acid was added. The mixture was stirred at room temperature overnight. The next day, the reaction system was extracted with dichloromethane (250 mL x 2). The aqueous phase was evaporated to remove the solvent until a large amount of crystals precipitated. After cooling to room temperature, the product was filtered under reduced pressure and washed with anhydrous ethanol to obtain compound 1 as a white powder with a yield of 70%.

[0118] Compound 1 (30.0 g, 166 mmol) and 200 mL of 33% HBr / HOAc solution were mixed in a 250 mL thick-walled pressure bottle. After sealing, the reaction system was heated to 90°C and stirred for several hours (6-8 h). After cooling to room temperature, the mixture was filtered under reduced pressure and the precipitate was washed with anhydrous ether to obtain compound 2 as a white powder in a 93% yield.

[0119] Selenium powder (2.9 g, 37 mmol, 2.0 equiv) was added to 200 mL of anhydrous ethanol. Under nitrogen, the temperature was raised to 50°C, and NaBH₄ (1.3 g, 35 mmol, 2.0 equiv) was added, followed by stirring for 2 h. The reaction system was cooled to room temperature, and compound 2 (4.7 g, 18 mmol, 1.0 equiv) was added portionwise under nitrogen. The reaction was allowed to react at room temperature and pressure for 3 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the reaction was quenched by addition of 5% hydrochloric acid. The supernatant was centrifuged, the pH was adjusted to 5-6 with 5 M NaOH, and the precipitate was centrifuged again to obtain the precipitate. The crude product was washed with deionized water, lyophilized, and weighed to obtain L-selenohomocystine as a yellow solid in an 82% yield.

[0120] L-selenohomocystine (1.5 g, 4.2 mmol, 1.0 equiv) and triphosgene (1.0 g, 3.3 mmol, 0.8 equiv) were mixed in a dry, two-necked flask. Under nitrogen, 50 mL of anhydrous tetrahydrofuran was added. The mixture was heated to 50°C and stirred continuously for 48 hours. The crude product was separated by column chromatography using an ethyl acetate / petroleum ether mixture as the eluent to obtain L-selenohomocystine carboxylic anhydride (SeHC-diNCA) as a yellow solid in a 57% yield.

[0121] Preparation Example 2: Preparation of Selenium-Containing Polymer

[0122] In a glove box, SeHC diNCA (9.4 mg, 0.022 mmol, 1.0 equiv) and Sar NCA (50.0 mg, 0.435 mmol, 19.0 equiv) were dissolved in 100 μL of DMF under nitrogen, followed by the addition of 40 μL of 0.5 M DIPEA. After 48 hours of reaction, the reaction system transformed into a pale yellow organogel. After 48 hours of dialysis, the organogel transformed into the corresponding precursor hydrogel, in which the molar ratio of SeHC crosslinker in the precursor hydrogel backbone was 5%. This precursor hydrogel was lyophilized to obtain the lyophilized product, the titled selenium-containing polymer. This product was a pale yellow blocky solid with a yield of 93%. Similar procedures were followed to prepare other precursor hydrogels with varying Se contents and were designated Se-Gel-(content %) according to the molar ratio of SeHC crosslinker in the precursor hydrogel backbone.

[0123] Preparation Example 3: Preparation of injectable selenium-containing hydrogel

[0124] GSH (2.46 g, 8.0 mmol) was dissolved in 9.5 mL of PBS (pH 7.4), then adjusted to pH 7.4 with 5 M NaOH and dilute to 10.0 mL, resulting in an 80 mM GSH solution. 20 mg of 2.5% freeze-dried Se-Gel was sterilized under UV irradiation for 1 hour, followed by the addition of 380 μL of the 80 mM GSH solution (sterilized). After 12 hours of stabilization, the system transformed into a pale yellow selenium-containing hydrogel, designated GSH@Se-Gel. The preparation process is shown in Figure 8.

[0125] Test Case

[0126] Various properties of precursor hydrogels

[0127] Se-Gel-5% prepared in Preparation Example 2 was formed into a hydrogel (without active thiol compounds), and various performance tests were performed on it. The results are shown in Figures 3 to 7, respectively.

[0128] (1) Scanning electron microscopy

[0129] A freeze-dried Se-Gel-5% sample was sliced ​​and observed and photographed under a scanning electron microscope (S-4800, Hitachi). The results are shown in Figure 3. As can be seen, the Se-Gel-5% network structure is essentially intact, with internal pores approximately 5 microns, indicating good hydrogel backbone integrity.

[0130] (2) H NMR spectrum of oxidative degradation products of Se-Gel hydrogel

[0131] A 100mg freeze-dried sample of Se-Gel-5% was oxidized with 5mL of 1% H2O2 for 7 days to convert it into an oxide solution (designated Se-Gel-ox). This oxide solution was dialyzed against a 5M NaCl solution for 24h, then dialyzed against deionized water for 48h, and then freeze-dried. 20mg of freeze-dried Se-Gel-ox powder was weighed, dissolved in 500μL of D2O, and its H NMR spectrum was measured using an ARX400 nuclear magnetic resonance spectrometer (Bruker). The results are shown in Figure 4. As can be seen from the results, the composition of the oxidative degradation products of Se-Gel-5% is close to its initial feed ratio, indicating that the preparation method is stable and can produce Se-Gel according to the feed ratio.

[0132] (3) Rheological oscillation frequency sweep curve;

[0133] After the Se-Gel-5% hydrogel reached equilibrium in PBS, a 5 mm diameter hydrogel sample was cut and sealed with silicone oil to prevent water evaporation. Using a rotational rheometer AGES-G2 (TA Company), an oscillatory strain sweep was performed on the hydrogel at 25°C and 1 rad / s to determine the linear viscoelastic region and critical strain of the material. The results are shown in Figure 5. As can be seen from the results, under low amplitude (such as static) conditions, the storage modulus of Se-Gel-5% is higher than the dissipation modulus, showing hydrogel properties.

[0134] (IV) H2O2 scavenging ability of selenium-containing hydrogels;

[0135] The titanium sulfate colorimetric method was used, with the sulfur-containing polymer S-Gel-5% (similar in structure to Se-Gel-5%, with diselenide bonds at the cross-linking points replaced by disulfide bonds) as the control hydrogel, and a microplate reader Multimode plate reader (Perkin Elmer) was used to evaluate the H2O2 scavenging ability of Se-Gel-5%.

[0136] Take 10mg of Se-Gel-5% or S-Gel-5% and fully swell it in 200μL PBS solution (place it in a constant temperature and humidity chamber at 37℃ for 1h), then add 1000μL 10mM H2O2 solution. The reaction system is incubated at 37℃ with slow shaking. At appropriate intervals, take 50μL of supernatant and incubate it with 100μL 5mM Ti(SO4)2 solution (Ti(SO4)2 dissolved in 3M H2SO4) in a 96-well plate at 37℃ for 10min, and measure the absorbance at 405nm. Calculate the H2O2 clearance rate (%) according to the following formula: H2O2 clearance rate (%) = (A xt -A 0t ) / (A 1t -A 0t )×100%

[0137] The results showed that Se-Gel-5% had an extremely rapid H2O2 scavenging ability.

[0138] (V) Catalytic activity of glutathione peroxidase (GPx) of Se-Gel oxidative degradation products

[0139] The GPx catalytic activity of the selenium-containing polymer was determined by the NADPH colorimetric method using a microplate reader (Perkin Elmer).

[0140] The experimental group was Se-Gel-5%'s oxidative metabolite Se-Gel-ox (0.5 mg / mL), the control group was the selenium-containing small molecule drug Ebselen (0.05 mg / mL), and the blank group was pure water. 20 μL 100 mM NADPH solution, 20 μL 75 mM GSH solution, 10 μL glutathione reductase GR solution and 750 μL PBS solution were fully mixed to prepare a working solution. 21.5 μL 70% tert-butyl peroxide TBHP solution was diluted in 4.0 mL deionized water to prepare an oxidizing solution. 40 μL sample solution, 80 μL working solution and 20 μL oxidizing solution were added in sequence, and the decrease in absorbance at 340 nm was detected at room temperature. The GPx catalytic activity of Ebselen was set to 100, and the GPx catalytic activity of the selenium-containing polymer was detected by the following formula: 100×((R x -R0)×C Se / M Se ) / ((R eb -R0)×C eb / M eb )

[0141] Among them, R x 、C Se 、M xThe slope, selenium content and selenium molecular weight of the experimental group (selenium-containing polymer) are shown in order, R0, R eb 、C eb 、M eb They are the slope of the blank group, the slope of the control group (Ibrahim Selenium), the concentration of Ibrahim Selenium and the molecular weight of Ibrahim Selenium.

[0142] The results are shown in Figure 7. It can be seen that Se-Gel-ox has good catalytic activity for GSH-Px. Under the same selenium content, the catalytic activity of Se-Gel-ox for GSH-Px is approximately 89% of that of ebselen.

[0143] (VI) Rheological gradient amplitude scanning curve and oscillation frequency scanning curve of selenium-containing hydrogel GSH@Se-Gel

[0144] First, a hydrogel sample with a diameter of 5 mm was cut and sealed with silicone oil to prevent water evaporation. Next, the hydrogel was subjected to an oscillatory strain sweep at 25°C and 1 rad / s using a rotational rheometer AGES-G2 (TA Company) to determine the linear viscoelastic region and critical strain of the material. Then, the material was subjected to an oscillatory frequency sweep within the linear viscoelastic region to determine its viscoelasticity. In the dynamic strain amplitude cyclic sweep, 5 times the critical strain was first applied to the material for 60 seconds, and then 0.1 times the critical strain was applied for 60 seconds. The above process was repeated 4 times. The results are shown in Figure 9. It can be seen from the results that under low amplitude (such as static) conditions, the storage modulus of GSH@Se-Gel is higher than the dissipation modulus, showing hydrogel properties. GSH@Se-Gel has shear thinning properties. Therefore, it can be determined that GSH@Se-Gel is an injectable selenium-containing hydrogel.

[0145] (VII) Live / dead staining results of ATDC5 mouse chondrocyte cell line incubated in Se-Gel for 24 h

[0146] 20 mg of Se-Gel-5% freeze-dried sample was placed in a confocal dish, and then 1 mL of ATDC5 mouse chondrocytes (about 5×10 4The cells were plated in fresh culture medium (DMEM containing 10% bovine serum (vol / vol), 1% penicillin-streptomycin (vol / vol). All cell experiments used the same culture medium and will not be repeated here), and incubated for 48 hours. Then, the Se-Gel-5% hydrogel containing ATDC5 was immersed in 60 μL of working solution containing calcein AM (2 μM) and ethidium homodimer-1 (2 μM) and immersed at 37°C for 1 hour. The distribution and morphology of live (green) and dead (red) cells were observed under a confocal microscope (excitation wavelength of 488 or 568 nm). The results are shown in Figure 10. As can be seen from the results, Se-Gel-5% hydrogel has almost no cytotoxicity. Se-Gel hydrogel is safe for organisms.

[0147] (VIII) Cytotoxicity results of GSH@Se-Gel

[0148] ATDC5 mouse chondrocytes were seeded into 96-well plates (2 × 10 3 cells, 100 μL culture medium). After incubation for 24 hours, 150 μL of fresh culture medium was replaced, and 50 μL of GSH@Se-Gel (experimental group), 80 mM GSH (control group) and PBS solution (blank group) were added to the corresponding wells respectively. The culture was continued for 48 and 72 hours, and then the original culture medium was removed and the well plate was washed 3 times with PBS. 100 μL of fresh culture medium and 10 μL of CCK-8 (Cell counting kit-8) were added and incubated at 37°C for 1 hour. The optical density (OD) values ​​at 450 nm (detection wavelength) and 630 nm (reference wavelength) were measured using a microplate reader Multimode plate reader (Perkin Elmer). The results are shown in Figure 11. As can be seen from the results, GSH@Se-Gel hydrogel has almost no cytotoxicity. GSH@Se-Gel hydrogel is safe for organisms.

[0149] (IX) Flow cytometry results after DHE staining

[0150] ATDC5 mouse chondrocytes were seeded in 24-well plates (approximately 1×10 4cells, 500 μL culture medium), and incubated for 12 hours. H2O2 was added to 500 μM, and then 2.5 μL GSH@Se-Gel (experimental group), 80 mM GSH and PBS solution (blank group) were added to the corresponding dishes respectively. The control group was cultured with equal density of ATDC5 cells using only culture medium and incubated for another 2 hours. The culture medium was removed, washed 3 times with PBS, and Opti MEM culture medium containing 1 μM DHE (a commonly used superoxide anion fluorescent probe) was added. After incubation for 20 minutes, the cells were washed 3 times with PBS to prepare a cell suspension, and flow cytometry was performed using a flow cytometer. The results are shown in Figure 12. It can be seen from the results that GSH@Se-Gel has more significant antioxidant properties than GSH.

[0151] (10) Degradation process of GSH@Cy5.5-Se-Gel in the joints of rats with surgically induced osteoarthritis

[0152] 0.45 mg of Cy5.5-NHS activated ester and 20 mg of Se-Gel-2.5% lyophilized gel were reacted in 200 μL of DMF for 24 hours and then dialyzed for 72 hours to remove residual dye and DMF. After freeze-drying, the fluorescently labeled Se-Gel-2.5% lyophilized gel was swollen in 80 mM GSH solution according to the previous steps to produce Cy5.5-GSH@Se-Gel. 25 μL of Cy5.5-GSH@Se-Gel was injected into the knee joints of OA-induced rats. In situ degradation of the GSH@Se-Gel hydrogel in the OA joint was observed using an in vivo bioluminescence imaging system at 0, 1, 3, 5, 7, and 10 weeks. The results are shown in Figure 13. As shown, the degradation time of the GSH@Se-Gel hydrogel in the OA joint cavity was longer than 10 weeks, significantly longer than that of the hyaluronic acid-based hydrogel.

[0153] (11) Effect of GSH@Se-Gel in treating osteoarthritis

[0154] Six and 12 weeks after intra-articular injection of GSH@Ge-Sel, knee joint specimens were collected from SD rats and fixed in 10% neutral formaldehyde for 48 hours. The knee joints were scanned using a micro-computed tomography (micro-CT) scanner, and the trabecular parameters of the subchondral bone of the medial tibial plateau were measured. The contours of the subchondral bone trabeculae, excluding cortical bone, were manually annotated in each two-dimensional sagittal section. The results are shown in Figure 14. As can be seen, the CON, GSH, and GSH@HA-Gel groups (same concentration of GSH solution encapsulated in a hyaluronic acid-based injectable selenium-containing hydrogel) all developed significant osteophytes and bone defects at both six and twelve weeks, with the defects being more pronounced at 12 weeks. The cartilage in the GSH@Se-Gel group at both six and twelve weeks was nearly identical to that in the sham group (sham surgery), with intact cartilage structure and a smooth surface. The GSH@Se-Gel group demonstrated a significant therapeutic effect. GSH@Se-Gel was significantly more effective in treating osteoarthritis at 6 and 12 weeks than GSH solution and GSH@HA-Gel hydrogel. A single injection could provide 12 weeks of treatment.

[0155] (XII) Organ toxicity after 12 weeks of GSH@Se-Gel treatment.

[0156] Twelve weeks after intra-articular injection of GSH@Ge-Sel into rats, all rats in each group were sacrificed and autopsied. The heart, liver, spleen, lungs, and kidneys were fixed in neutral formalin for 2 minutes, sectioned, stained with H&E, and imaged under a microscope. The results are shown in Figure 15. As can be seen, the organ structures of all rats in each group were relatively intact, with no obvious defects. GSH@Se-Gel showed no significant toxicity.

[0157] The above description is only a specific embodiment of the present disclosure, but the protection scope of the present disclosure is not limited thereto. The protection scope of the present disclosure shall be based on the protection scope of the claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: in, L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in, L 1 and L 2 Each is independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -、-C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NR a -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a - and -C(=O)-O-NR a -OC(=O)-; R a Selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; L 3 Each occurrence is independently -O- or -S-; x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20; and m and n are each independently selected from integers of 0-20, with the proviso that 1≤m+n≤20.

2. The compound according to claim 1, wherein L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -,in, L 1 and L 2 Each independently selected from a chemical bond, -O-, -C(=O)-, -C(=O)O-, -OC(=)-, -OC(=O)-, -NR a -、-C(=O)-NR a -、-NR a -C(=O)-, -NR a -C(=O)-O- and -C(=O)-O-NR a -; R a Selected from -H and C 1-6 alkyl; x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20.

3. The compound according to claim 1 or 2, wherein L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -,in, L 1 and L 2 One of them is a chemical bond and the other is -C(=O)-O- or -C(=O)-NR a -; R a Selected from -H and C 1-6 alkyl; x, y and z are each independently an integer from 0 to 12, provided that 1≤x+y+z≤12.

4. The compound according to claim 2, wherein L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -,in, L 1 and L 2 All are chemical bonds; x, y and z are each independently an integer from 0 to 12, provided that 1≤x+y+z≤12.

5. The compound according to claim 1, wherein L is selected from -(CH2CH2-L 3 ) m -(CH2) n -,in, L 3 for -O-; m is an integer from 0 to 20, n is 0.

6. The compound according to claim 1, wherein L is -(CH2) 1-6 -.

7. The compound according to claim 6, wherein L is -CH2-CH2-.

8. The compound according to claim 1, wherein The compound is selected from the group consisting of:

9. A selenium-containing polymer, which is a compound of formula (I) With a compound of formula (III): Aggregation, where L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in, L 1 and L 2 Each is independently selected from a chemical bond, -O-, -C(=O)-, -C(=S)-, -OC(=O)-, -C(=O)-O-, -OC(=O)O-, -S-, -C(=S)-, -C(=S)-, -SC(=S)-, -C(=S)-S-, -SC(=S)-S-, -SC(=O)-, -OC(=S)-, -C(=O)-S-, -C(=S)-O-, -SC(=O)-S-, -SC(=O)-O-, -OC(=O)-S-, -OC(=S)-O-, -OC(=S)-S-, -SC(=S)-O-, -NR a -、-C(=O)-NR a -、-NR a -C(=O)-, -C(=O)-NR a -C(=O)-, -NR a -C(=O)-O-, -C(=O)-O-NR a - and -C(=O)-O-NR a -OC(=O)-; R a Selected from -H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; L 3 Each occurrence is independently -O- or -S-; x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20; m and n are each independently selected from integers of 0-20, provided that 1≤m+n≤20, R 1 Selected from: a) -H, -OH, -NH2, halogen, C 1-20 Alkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, C 1-20 Alkoxy, C 1-20 Halogenated alkyl, phenyl, phenoxy, phenyl C 1-20 alkyl, carboxyl, hydroxyl, carboxyalkyl, hydroxyalkyl and cyano; b) R 3 -(CH2) o -L 4 -(CH2) p -, where L 4 Selected from -C 1-6 Alkylene, -C(=O)-, -OC(=O)-, -C(=O)-O-, -C(=O)-NH-, -NH-C(=O)-, -NH-C(=O)-O-, and -OC(=O)-NH-, R 3 Selected from -H, C 1-20 Alkyl, C 1-20 Alkoxy, C 1-20 Haloalkyl, C 1-20 Alkylphenyl, C 1-20 Alkoxyphenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl and halogenated phenyl, o and p are independently an integer of 0-4; R 2 Selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; Or, R 1 and R 2 Together with the ring atoms to which they are attached, they form a five- or six-membered ring, which is optionally substituted by a group selected from hydroxy, carboxyl, ester, alkoxy and haloalkyl.

10. The selenium-containing polymer according to claim 9, wherein The compound of formula (III) is selected from the following group:

11. The selenium-containing polymer according to claim 9 or 10, wherein The polymer has the following structure: Among them, x=0.001~0.5, t=10~10,000.

12. An injectable selenium-containing hydrogel, which is made of the selenium-containing polymer according to any one of claims 9 to 11 and an active thiol compound.

13. The injectable selenium-containing hydrogel according to claim 12, further comprising an isotonic and / or buffering agent.

14. The injectable selenium-containing hydrogel according to claim 13, wherein: The isotonic and / or buffering agent is selected from phosphate, sodium chloride or a mixture thereof.

15. The injectable selenium-containing hydrogel according to any one of claims 12 to 14, wherein The injectable selenium-containing hydrogel has a solid content in the range of 0.1 wt% to 20 wt% and a selenium content in the range of 10-10,000 ppm based on the total weight of the hydrogel.

16. A method for preparing an injectable selenium-containing hydrogel, comprising: The selenium-containing polymer according to any one of claims 9 to 11 is swollen with an active thiol compound solution to obtain the injectable selenium-containing hydrogel.

17. The method of claim 16, wherein: The active thiol compound is selected from glutathione, dithiothreitol, cysteine, N-acetylcysteine, penicillamine, thioglycolic acid, mercaptopropionic acid, mercaptobutyric acid and a mixture of any two or more thereof.

18. The method according to claim 16 or 17, wherein: Before the selenium-containing polymer is swollen with the active thiol compound solution, the polymer is deprotected or post-modified.

19. Use of the injectable selenium-containing hydrogel according to any one of claims 12 to 15 for preparing drugs for intra-articular injection.

20. Use of the injectable selenium-containing hydrogel according to any one of claims 12 to 15 for preparing a drug for scavenging reactive oxygen species.

21. Use of the injectable selenium-containing hydrogel according to any one of claims 12 to 15 for preparing a medicament for treating inflammation related to bone and joints.

22. The use according to claim 21, wherein The bone and joint related inflammation is osteoarthritis or rheumatoid arthritis.

23. The use according to any one of claims 19 to 22, wherein the drug is long-acting.

23. The use according to any one of claims 19 to 22, wherein The drug is administered by injection.

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