Selenium-containing compound, polymer, injectable selenium-containing hydrogel, and preparation method and application thereof

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is disclosed. The invention also discloses a selenium-containing polymer, injectable selenium-containing hydrogel prepared from the selenium-containing polymer, and a preparation method and application of the injectable selenium-containing hydrogel. # imgabs0 #

Description

Technical Field

[0001] The present invention relates 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 of the selenium-containing polymer, and a preparation method and use thereof. Background Art

[0002] Osteoarthritis is one of the most common degenerative diseases, which is 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 suffer from symptomatic osteoarthritis of the knee worldwide (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 occur 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%, making it one of the five main diseases that cause disability in the elderly.

[0003] 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, and 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, and the occurrence of local adverse reactions is also related to the doctor's injection technique, the patient's post-injection activities, 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.

[0004] Hydrogel refers to a three-dimensional network polymer material with a water content of more than 70% and 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, there are many hydrogels used for the treatment of 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, and it is 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, and it is also difficult to complete long-term treatment.

[0005] Therefore, there is an urgent need in the art for an injectable hydrogel material with improved properties. Summary of the invention

[0006] 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:

[0007]

[0008] in,

[0009] L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0010] 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)-;

[0011] 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;

[0012] L 3Each occurrence is independently -O- or -S-;

[0013] x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20; and

[0014] m and n are each independently selected from integers of 0-20, with the proviso that 1≤m+n≤20.

[0015] 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.

[0016] 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)-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.

[0017] In some examples, L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z -, where 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.

[0018] In some examples, L is 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.

[0019] In some examples, L is -(CH2) 1-6 -.

[0020] In some examples, L is -CH2-CH2-.

[0021] In some examples, the compound is selected from the group consisting of:

[0022]

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

[0024]

[0025] With a compound of formula (III):

[0026]

[0027] Aggregation, where

[0028] L is selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0029] 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)-;

[0030] 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;

[0031] L 3 Each occurrence is independently -O- or -S-;

[0032] x, y and z are each independently an integer from 0 to 20, provided that 1≤x+y+z≤20;

[0033] m and n are each independently selected from integers of 0-20, provided that 1≤m+n≤20,

[0034] R 1 Selected from:

[0035] 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;

[0036] 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, C1-20 Alkoxyphenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl and halogenated phenyl, o and p are independently an integer of 0-4;

[0037] R 2 Selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0038] 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.

[0039] In some examples, the compound of formula (III) is selected from the following group:

[0040]

[0041] In some examples, the polymer has the following structure:

[0042]

[0043] Among them, x=0.001~0.5, t=10~10,000.

[0044] At least one embodiment of the present disclosure further provides an injectable selenium-containing hydrogel, which is formed by any of the above-mentioned selenium-containing polymers and an active thiol compound.

[0045] In some examples, the injectable selenium-containing hydrogel further comprises an isotonic and / or buffering agent.

[0046] In some examples, the isotonic and / or buffering agent is selected from phosphate, sodium chloride or a mixture thereof.

[0047] In some examples, 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.

[0048] At least one embodiment of the present disclosure also provides a method for preparing an injectable selenium-containing hydrogel, which comprises: swelling any of the above-mentioned selenium-containing polymers with an active thiol compound solution to obtain the injectable selenium-containing hydrogel.

[0049] 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.

[0050] In some examples, the polymer is deprotected or post-modified before swelling the selenium-containing polymer with the active thiol compound solution.

[0051] At least one embodiment of the present disclosure also provides a use of any of the above-mentioned injectable selenium-containing hydrogels for preparing drugs for intra-articular injection.

[0052] At least one embodiment of the present disclosure also provides a use of any of the above-mentioned injectable selenium-containing hydrogels for preparing drugs for scavenging reactive oxygen species.

[0053] At least one embodiment of the present disclosure also provides the use of any of the above-mentioned injectable selenium-containing hydrogels for preparing a drug for treating bone and joint-related inflammation.

[0054] In some examples, the bone and joint-related inflammation is osteoarthritis or rheumatoid arthritis.

[0055] In some cases, the drug is long-acting.

[0056] In some cases, the drug is administered by injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] 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, but are not intended to limit the present disclosure.

[0058] Figure 1 The invention shows a method for preparing L-selenohomocystine carboxylic anhydride (SeHC diNCA) according to an embodiment of the present disclosure;

[0059] Figure 2 The invention shows a method for preparing a selenium-containing hydrogel (Se-Gel) according to an embodiment of the present disclosure;

[0060] Figure 3 shows a scanning electron microscope image of Se-Gel (Se-Gel-5%) in which the molar ratio of the SeHC component in the hydrogel skeleton is 5 mol% according to an embodiment of the present disclosure;

[0061] Figure 4 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;

[0062] Figure 5 shows a rheological oscillation frequency scanning curve of Se-Gel-5% according to an embodiment of the present disclosure;

[0063] Figure 6 The H2O2 scavenging ability of Se-Gel according to an embodiment of the present disclosure is shown;

[0064] Figure 7 The glutathione peroxidase (GSH-Px) activity catalytic ability of the oxidative degradation product of Se-Gel according to an embodiment of the present disclosure is shown;

[0065] Figure 8 A method for preparing an injectable selenium-containing hydrogel (GSH@Se-Gel) containing glutathione as an active thiol compound according to an embodiment of the present disclosure is shown;

[0066] Fig. 9 The rheological gradient amplitude scanning curve and the oscillation frequency scanning curve of GSH@Se-Gel according to the embodiment of the present disclosure are shown;

[0067] Fig.10 The live-death staining results of the ATDC5 mouse chondrocyte cell line incubated in Se-Gel for 24 hours according to an embodiment of the present disclosure are shown;

[0068] Fig.11 The cytotoxicity results of GSH@Se-Gel according to an embodiment of the present disclosure are shown, wherein the cell line is ATDC5 cells;

[0069] Fig.12 Flow cytometry results after DHE staining according to an embodiment of the present disclosure are shown, wherein GSH@Se-Gel reduces the ROS concentration of ATDC5 after co-incubation with H2O2;

[0070] Fig.13 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 is shown;

[0071] Fig.14 The results of 6 and 12 weeks of GSH@Se-Gel treatment according to an embodiment of the present disclosure are shown; and

[0072] Fig.15 The organ toxicity after 12 weeks of GSH@Se-Gel treatment according to an embodiment of the present disclosure is shown. DETAILED DESCRIPTION

[0073] 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 specified to the contrary. 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 attached claims are approximate values ​​that vary according to the desired performance to be obtained by the present disclosure. At least it is not intended to limit the application of the doctrine of equivalents to the scope of the claims, and each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques.

[0074] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present 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.

[0075] In addition, it should be understood that any numerical range described 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 stated minimum value of 1 and the stated 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.

[0076] 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" may be expressly 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.

[0077] Osteoarthritis is one of the most common degenerative diseases, which often occurs in obese and middle-aged and elderly people. Most of them are symptomatic osteoarthritis of the knee joint. Not all patients with osteoarthritis will show symptoms. However, for patients who have already suffered from symptomatic osteoarthritis, active treatment is needed to prevent the destruction within the joint from gradually worsening, eventually developing to the point of joint deformity and loss of joint function.

[0078] At present, the clinical treatment of osteoarthritis includes topical and oral analgesics and anti-inflammatory drugs. This treatment method can relieve osteoarthritis symptoms in the short term, but it cannot reverse the progression of osteoarthritis, has a low utilization rate, and has the potential risk of systemic side effects. Alternatively, intra-articular drug injection can also be used clinically to treat osteoarthritis. Intra-articular injection of therapeutic drugs is an effective treatment strategy for osteoarthritis, but it is hindered by problems such as rapid drug diffusion and degradation, so high-frequency injection is required. For example, hyaluronic acid (HA) is the most commonly used joint lubricant in clinical practice, and it is one of the main components of synovial fluid. However, the highly expressed hyaluronidase in osteoarthritis will accelerate its degradation, and patients usually need to be injected once a week for several weeks. The commonly used anti-inflammatory drugs such as glucocorticoids in clinical practice have a short residence time in the body after single injection, and repeated injections are also required. 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 post-injection activities, and the purity of the drug.

[0079] In recent years, a large number of osteoarthritis treatment studies have used new bioactive materials such as hydrogels as drug delivery carriers. Hydrogel refers to a three-dimensional network polymer material with a water content of more than 70% and formed by cross-linking. It has 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, and clinical applications are more difficult. Physically cross-linked hydrogels can be injected with a syringe, which is convenient to operate and suitable for implantation in the body, but the mechanical properties are low and the in vivo degradation time is short. At present, it is difficult for medical hydrogels to have good mechanical properties, long degradation time, and injectability at the same time.

[0080] To solve the above and other problems, the embodiments of the present disclosure provide an injectable selenium-containing hydrogel material and its application for the treatment of osteoarthritis. The injectable selenium-containing hydrogel disclosed herein uses selenium-containing polymers to replace the hyaluronic acid-based joint cavity injections commonly used in current literature and clinical practice, and 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. In 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, 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 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.

[0081] 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:

[0082]

[0083] in,

[0084] L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0085] L 1 and L 2 The alkyl groups may be independently selected from the group consisting of 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)-;

[0086] 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 Haloalkyl;

[0087] L 3 Each occurrence can be independently -O- or -S-;

[0088] x, y and z may each independently be an integer from 0 to 20, provided that 1≤x+y+z≤20;

[0089] m and n may each be independently selected from integers of 0-20, provided that 1≤m+n≤20.

[0090] 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 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 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.

[0091] In some 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.

[0092] In some 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 be independently integers of 0-12, provided that 1≤x+y+z≤12. For example, L can be -(CH2)1-6 -.

[0093] Alternatively, in some examples, L can be selected from -(CH2CH2-L 3 ) m -(CH2) n -, where L 3 is -O-; m is an integer of 0-20, and n is 0. For example, L can be -CH2-CH2-.

[0094] In some exemplary embodiments, the compounds described in the present disclosure may be selected from the following group:

[0095]

[0096] At least one embodiment of the present disclosure further provides a selenium-containing polymer, wherein the polymer is a compound of formula (I):

[0097]

[0098] With a compound of formula (III):

[0099]

[0100] Aggregation, where

[0101] L can be selected from -(CH2) x -L 1 -(CH2) y -L 2 -(CH2) z - and -(CH2CH2-L 3 ) m -(CH2) n -,in,

[0102] L 1 and L 2 The alkyl groups may be independently selected from the group consisting of 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)-;

[0103] 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 Haloalkyl;

[0104] L 3 Each occurrence can be independently -O- or -S-;

[0105] x, y and z may each independently be an integer from 0 to 20, provided that 1≤x+y+z≤20;

[0106] m and n can be independently selected from integers of 0-20, provided that 1≤m+n≤20,

[0107] R 1 Can be selected from:

[0108] 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;

[0109] 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 Haloalkyl, C 1-20 Alkylphenyl, C 1-20Alkoxyphenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl and halogenated phenyl, o and p are independently an integer of 0-4;

[0110] R 2 Can be selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl;

[0111] 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 by a group selected from hydroxy, carboxyl, ester, alkoxy and haloalkyl.

[0112] In some examples, the compound of formula (III) can be selected from the following group:

[0113]

[0114]

[0115] In other examples, a polymer may have the following structure:

[0116]

[0117] Among them, x=0.001~0.5, t=10~10,000.

[0118] 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" refers to the inclusion of covalently bound selenium (Se) elements in the structure of the hydrogel material; the term "injectable" means that the hydrogel material can be applied to the target site through a syringe / syringe. The hydrogel material can swell in water but not dissolve, has 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 action, hydrogen bonding, 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 applications 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.

[0119] The injectable selenium-containing hydrogel according to the 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.

[0120] In other aspects, the solid content of the injectable selenium-containing hydrogel can be in the range of 0.1wt% to 20wt%, and the selenium content can be in the range of 10-10,000ppm based on the total weight of the hydrogel. In other aspects, the active thiol compound can be selected from glutathione, dithiothreitol, cysteine, N-acetylcysteine, penicillamine, thioglycolic acid, mercaptopropionic acid, mercaptobutyric acid and any mixture of two or more thereof.

[0121] In other aspects, before swelling the selenium-containing polymer with the active thiol compound solution, the polymer can be deprotected or post-modified. For example, the polymer can be deprotected or post-modified as follows: removing ester protecting groups (such as removing trifluoroacetyl groups, etc.) with potassium carbonate methanol / water solution, removing tert-butyloxycarbonyl protection with trifluoroacetic acid, etc.

[0122] 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 removing 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-acting and can be administered by injection.

[0123] The injectable selenium-containing hydrogel structure disclosed in the present invention utilizes the diselenide bond of the compound of formula (I) as a crosslinking point, and realizes 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,

[0124]

[0125] Moreover, the injectable selenium-containing hydrogel formed in this way utilizes selenium-containing polyamino acids to replace the hyaluronic acid-based joint cavity injections commonly used in current literature and clinics, and its degradation time in the joint cavity that develops into osteoarthritis is longer, reaching 10 weeks, which is much higher than the degradation time of hyaluronic acid-based hydrogels; in the treatment process based on this injectable selenium-containing hydrogel, patients can significantly reduce the frequency of joint cavity injections, and only need to be injected once every 1-3 months, which is much lower than the frequency of hyaluronic acid injections (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 that of hyaluronic acid-based injections.

[0126] Example

[0127] 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 only used to illustrate the present application and should not be considered as limiting the scope of the present application. If the specific conditions are not specified in the examples, the conditions recommended by the normal conditions or manufacturers are carried out. If the manufacturers are not specified in the reagents or instruments used, they are all conventional products that can be obtained commercially. Unless otherwise specified, all amounts listed are described in parts by weight based on the gross weight. The application should not be construed as being limited to the specific embodiments described.

[0128] Preparation Example 1: Preparation of Selenium-Containing Amino Acids and Their Carboxyl Ring Anhydrides

[0129]

[0130] Methionine (30.0 g, 200 mmol, 1.0 equivalent), methyl chloroacetate (23.0 mL, 260 mmol, 1.3 equivalent), tetrabutylammonium bromide (TBAB, 3.2 g, 10 mmol, 0.050 equivalent) were dissolved in 150 mL of deionized water and heated to 90 ° C and refluxed for 6 h. Cool to room temperature, add 40 mL of 40% hydrobromic acid, and stir at room temperature overnight. The next day, the reaction system was extracted with dichloromethane (250 mL × 2), and the aqueous phase after extraction 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 white powder compound 1 with a yield of 70%.

[0131] 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). The mixture was cooled to room temperature, filtered under reduced pressure, and the precipitate was washed with anhydrous ether to obtain white powder compound 2 with a yield of 93%.

[0132] Selenium powder (2.9 g, 37 mmol, 2.0 equivalent) was added to 200 mL of anhydrous ethanol. Under nitrogen protection, the temperature was raised to 50 ° C, NaBH4 (1.3 g, 35 mmol, 2.0 equivalent) was added to the system and stirred for 2 h. The reaction system was cooled to room temperature, and compound 2 (4.7 g, 18 mmol, 1.0 equivalent) was added to the reaction system in batches under nitrogen protection, and the reaction was carried out at room temperature and pressure for 3 h. After the reaction was completed, a large amount of solvent was removed by rotary evaporation, and 5% hydrochloric acid was added to quench the reaction. The supernatant was centrifuged, the pH was adjusted to 5-6 with 5M NaOH, and the precipitate was centrifuged again. The crude product was washed with an appropriate amount of deionized water, and weighed after freeze-drying to obtain yellow solid L-selenohomocystine with a yield of 82%.

[0133] L-selenohomocystine (1.5 g, 4.2 mmol, 1.0 equivalent) and triphosgene (1.0 g, 3.3 mmol, 0.8 equivalent) were mixed in a dry two-necked flask. Under nitrogen protection, 50 mL of anhydrous tetrahydrofuran was added to the system. The mixture was heated to 50 ° C and stirred continuously for 48 h. The crude product was separated by column chromatography with an ethyl acetate / petroleum ether mixed solution as the eluent to obtain yellow solid L-selenohomocystine carboxylic anhydride (i.e., SeHC-diNCA) with a yield of 57%.

[0134] Preparation Example 2: Preparation of Selenium-Containing Polymer

[0135]

[0136] In the glove box, SeHC diNCA (9.4 mg, 0.022 mmol, 1.0 equivalent) and Sar NCA (50.0 mg, 0.435 mmol, 19.0 equivalent) were dissolved in 100 μL DMF under nitrogen protection, and then 40 μL 0.5 M DIPEA was added. After 48 hours of reaction, the reaction system was transformed into a light yellow organogel. After dialysis for 48 hours, the organogel was transformed into the corresponding precursor hydrogel, wherein the molar ratio of SeHC crosslinker in the precursor hydrogel skeleton was 5%. The precursor hydrogel was freeze-dried to obtain a freeze-dried product, which was the title selenium-containing polymer. The product was a light yellow block solid with a yield of 93%. The remaining precursor hydrogels with different Se contents were prepared according to similar steps, and were named Se-Gel- (content %) according to the molar ratio of SeHC crosslinker in the precursor hydrogel skeleton. Preparation Example 3: Preparation of injectable selenium-containing hydrogel

[0137] GSH (2.46 g, 8.0 mmol) was dissolved in 9.5 mL PBS (pH 7.4) solution, and then adjusted to pH 7.4 with 5 M NaOH solution, and the volume was adjusted to 10.0 mL to prepare 80 mM GSH solution. 20 mg Se-Gel-2.5% lyophilized product was sterilized under ultraviolet light for 1 h, and then 380 μL 80 mM GSH solution (after sterilization operation) was added. After standing for 12 h, the system turned into a light yellow selenium-containing hydrogel, named GSH@Se-Gel. The preparation process is as follows Figure 8 shown.

[0138] Test Case

[0139] Various properties of precursor hydrogels

[0140] The 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 were as follows: Figure 3-7 shown.

[0141] 1. Scanning electron microscopy

[0142] The Se-Gel-5% freeze-dried sample was sliced ​​and observed and photographed under a scanning electron microscope S-4800 (Hitachi). Figure 3 As shown in the results, it can be seen that the network structure of Se-Gel-5% is basically complete, the internal pores are about 5 microns, and the hydrogel skeleton has good integrity.

[0143] (II) H NMR spectrum of oxidative degradation products of Se-Gel hydrogel

[0144] 100 mg of Se-Gel-5% lyophilized sample was oxidized with 5 mL of 1% H2O2 for 7 days to convert into an oxide solution (named Se-Gel-ox). The oxide solution was dialyzed in 5M NaCl solution for 24 h, then dialyzed in deionized water for 48 h, and then lyophilized. 20 mg of lyophilized Se-Gel-ox powder was weighed and dissolved in 500 μL D2O, and its nuclear magnetic resonance hydrogen spectrum was detected using a nuclear magnetic resonance instrument ARX400 (Bruker). The results are shown in Figure 2. Figure 4 As shown in the results, the composition of the oxidative degradation product of Se-Gel-5% is close to its initial feed ratio, which shows that the preparation method has good stability and can prepare Se-Gel according to the feed ratio.

[0145] (iii) Rheological oscillation frequency scanning curve;

[0146] After the Se-Gel-5% hydrogel reached equilibrium in PBS, a hydrogel sample with a diameter of 5 mm was cut and sealed with silicone oil to prevent water evaporation. Using a rotational rheometer AGES-G2 (TA Company), the hydrogel was subjected to an oscillatory strain scan 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 shown in the results, it can be seen that under low amplitude (such as static) conditions, the storage modulus of Se-Gel-5% is higher than the dissipation modulus, showing hydrogel properties.

[0147] (iv) H2O2 scavenging ability of selenium-containing hydrogels;

[0148] 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%.

[0149] Take 10mg 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:

[0150] H2O2 removal rate (%) = (A xt -A 0t ) / (A 1t -A 0t )×100%

[0151] The results showed that Se-Gel-5% had an extremely rapid H2O2 scavenging ability.

[0152] (V) Catalytic activity of glutathione peroxidase (GPx) of Se-Gel oxidative degradation products

[0153] The GPx catalytic activity of the selenium-containing polymer was determined by the NADPH colorimetric method using a microplate reader (Perkin Elmer).

[0154] 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 the working solution. 21.5 μL 70% tert-butyl peroxide TBHP solution was diluted in 4.0 mL deionized water to prepare the oxidation solution. 40 μL sample solution, 80 μL working solution and 20 μL oxidation 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:

[0155] 100×((R x -R0)×C Se / M Se ) / ((R eb -R0)×C eb / M eb )

[0156] Among them, R x , C Se 、M x The slope, selenium content and selenium molecular weight of the experimental group (selenium-containing polymer) are R0, R eb , C eb 、M eb They are the slope of the blank group, the slope of the control group (Ibrancel), the concentration of Ibrancel and the molecular weight of Ibrancel.

[0157] The results are as follows Figure 7 As shown in the results, it can be seen that Se-Gel-ox has good GSH-Px activity catalytic ability. Under the same selenium content, the GSH-Px activity catalytic ability of Se-Gel-ox is about 89% of that of ebselen.

[0158] (VI) Rheological gradient amplitude scanning curve and oscillation frequency scanning curve of selenium-containing hydrogel GSH@Se-Gel

[0159] First, cut a hydrogel sample with a diameter of 5 mm and seal it with silicone oil to prevent water evaporation. Next, use a rotational rheometer AGES-G2 (TA Company) to perform an oscillatory strain scan on the hydrogel at 25°C and 1 rad / s to determine the linear viscoelastic region and critical strain of the material. Then, an oscillatory frequency scan of the material was performed in the linear viscoelastic region to determine its viscoelasticity. In the dynamic strain amplitude cyclic scan, 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 as follows Fig. 9 As shown. From the results, it can be seen that under low amplitude (such as static), 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.

[0160] (VII) Live and dead staining results of ATDC5 mouse chondrocyte cell line incubated in Se-Gel for 24 hours

[0161] 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 4 The cells were incubated with 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) 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) 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 2. Fig.10 As shown in the results, Se-Gel-5% hydrogel has almost no cytotoxicity. Se-Gel hydrogel is safe for organisms.

[0162] (VIII) Cytotoxicity results of GSH@Se-Gel

[0163] ATDC5 mouse chondrocytes were seeded in 96-well plates (2×10 3cells, 100 μL culture medium). After incubation for 24 h, replace with 150 μL fresh culture medium, and then add 50 μL GSH@Se-Gel (experimental group), 80 mM GSH (control group) and PBS solution (blank group) to the corresponding holes. Continue to culture for 48 and 72 h, then remove the original culture medium and wash the plate 3 times with PBS. Add 100 μL fresh culture medium and 10 μL CCK-8 (Cell counting kit-8) and incubate at 37 °C for 1 h. Use a microplate reader Multimode plate reader (Perkin Elmer) to measure the optical density (OD) values ​​at 450 nm (detection wavelength) and 630 nm (reference wavelength). The results are shown in Fig.11 As shown in the results, GSH@Se-Gel hydrogel has almost no cytotoxicity. GSH@Se-Gel hydrogel is safe for organisms.

[0164] (IX) Flow cytometry results after DHE staining

[0165] ATDC5 mouse chondrocytes were seeded in 24-well plates (about 1×10 4 cells, 500μL culture medium), and incubate for 12h. H2O2 was added to 500μM, and then 2.5μL GSH@Se-Gel (experimental group), 80mM 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 continued to incubate for 2h. The culture medium was removed, washed 3 times with PBS, and Opti MEM culture medium containing 1μM DHE (a commonly used superoxide anion fluorescent probe) was added. After incubation for 20min, PBS was washed 3 times to make a cell suspension, and flow cytometry detection was performed using a flow cytometer. The results are shown in Fig.12 As shown in the results, it can be seen that GSH@Se-Gel has more significant antioxidant properties than GSH.

[0166] (X) Degradation process of GSH@Cy5.5-Se-Gel in the joints of rats with surgically induced osteoarthritis

[0167] 0.45 mg Cy5.5-NHS activated ester and 20 mg Se-Gel-2.5% lyophilized gel were reacted in 200 μL DMF for 24 h, and then dialyzed for 72 h to remove residual dye and DMF. After freeze-drying and storage, the fluorescently labeled Se-Gel-2.5% lyophilized gel was swollen in 80 mM GSH solution according to the previous steps to obtain Cy5.5-GSH@Se-Gel. 25 μL Cy5.5-GSH@Se-Gel was injected into the knee joint cavity of OA-induced rats, and its in situ degradation in OA joints was observed using an in vivo bioluminescence imaging system at 0, 1, 3, 5, 7, and 10 weeks. The results are shown in Figure 2. Fig.13 As shown in the results, it can be seen that the degradation time of GSH@Se-Gel hydrogel in the OA joint cavity is longer than 10 weeks, which is much longer than the degradation time of hyaluronic acid-based hydrogel.

[0168] (XI) Effect of GSH@Se-Gel in treating osteoarthritis

[0169] Six and 12 weeks after intra-articular injection of GSH@Ge-Sel, knee joint samples of SD rats were collected and fixed in 10% neutral formaldehyde for 48 hours. The knee joints were scanned with a micro-computed tomography (micro-CT) scanner, and the trabecular parameters of the subchondral bone of the medial tibial plateau were measured. In each two-dimensional sagittal slice, the contours of the subchondral bone trabeculae area excluding the cortical bone were manually annotated. The results are shown in Fig.14 As shown. The results show that the CON group, GSH group, and GSH@HA-Gel group (the same concentration of GSH solution encapsulated in a hyaluronic acid-based injectable selenium-containing hydrogel) all showed significant osteophytes and bone defects at 6 and 12 weeks, and the 12th week was more significant. The cartilage of the GSH@Se-Gel group was almost the same as that of the Sham group (sham operation group) at 6 and 12 weeks, with intact cartilage structure and smooth surface. The GSH@Se-Gel group had a significant therapeutic effect. The therapeutic effect of GSH@Se-Gel on osteoarthritis at 6 and 12 weeks was significantly better than that of GSH solution and GSH@HA-Gel hydrogel. A single injection can achieve 12 weeks of treatment.

[0170] (XII) Organ toxicity after 12 weeks of GSH@Se-Gel treatment.

[0171] Twelve weeks after intra-articular injection of GSH@Ge-Sel into rats, rats in each group were killed and dissected, and the heart, liver, spleen, lung, and kidney were fixed in neutral formalin for 2 minutes, sliced, stained with H&E, and imaged under a microscope. Fig.15 As shown in the results, the organ structures of rats in each group were relatively intact without obvious defects. GSH@Se-Gel had no obvious toxicity.

[0172] The above description is only a specific implementation 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-, -O- C(=)-、-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 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.

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

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