Thienothiophene organic small molecules with double free radicals, preparation method and application thereof

Abstract

The application discloses a thienothiophene and thiazole organic small molecule with double radicals and a preparation method and application thereof. The material has a structure shown in formula (I): wherein n is the same or different, and each is 0, 1, 2 or 3; X is the same or different, and each is one of nitrogen, oxygen, sulfur, selenium or tellurium elements; and R1 is the same or different, and each is hydrogen or an alkyl group or an alkoxy group. After the material is prepared into a nano drug, oxygen can be spatially and temporally separated under 808 nm near-infrared laser irradiation, a Type I active oxygen species is generated, and photo-thermal conversion is achieved, so that the problem of poor treatment effect caused by a complex microenvironment of a tumor is overcome.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic functional molecules, in particular to a preparation method and application of a thieno[3,4-c][1,2,5]thiadiazole organic small molecule material with double free radical characteristics. BACKGROUND

[0002] Cancer has become one of the major diseases endangering human health. Current means for cancer treatment such as surgical treatment, radiotherapy, chemotherapy, etc. have problems such as large postoperative trauma, strong side effects, and uncertain inflammatory reactions. In recent years, the emerging photothermal therapy and photodynamic therapy have the advantages of non-invasiveness, low toxicity, high selectivity, etc., and therefore have attracted more and more attention. Complete eradication of tumors is particularly important for alleviating pain and prolonging the life of patients. Due to the objective factors such as the hypoxic environment and heat tolerance of tumors, the cancer treatment effect of single photothermal therapy or photodynamic therapy is greatly affected, which brings great challenges to single photothermal therapy or photodynamic therapy for cancer.

[0003] In recent years, photothermal / photodynamic synergistic therapy can make up for the shortcomings of single treatment mode and exhibit unique advantages. The photothermal effect caused by photothermal therapy can accelerate blood circulation in the tumor, thereby causing more oxygen to be transported to the tumor and improving the treatment effect of photodynamic therapy. Photodynamic therapy can make up for the high-power dependence of photothermal therapy and avoid thermal damage to other normal tissues outside the tumor site. At the same time, photodynamic therapy can hinder the expression of heat shock proteins, avoiding the protective effect of heat shock proteins during photothermal therapy. In order to meet the above conditions at the same time, people often mix photothermal materials, photodynamic materials, and oxygen-producing materials together through physical coating to realize a nano-drug with the above various functions. However, the composite material prepared by this method usually has poor repeatability, which seriously hinders its clinical transformation. In addition, due to the different optical properties of the doped components, multiple different wavelengths of light are often needed to excite, which not only increases the complexity of the operation, but also causes treatment delay. Moreover, the excitation light wavelength of traditional photosensitizer drugs is usually less than 700 nm, which greatly limits the tissue penetration depth.

[0004] Therefore, it is particularly important to design a near-infrared absorbing drug that can meet the requirements of simultaneous space-time synchronization self-oxygen supply for photothermal / photodynamic synergistic application. SUMMARY

[0005] Current phototherapy drugs have many limitations, and it is difficult to achieve efficient treatment of cancer in the hypoxic microenvironment of tumors. In view of the technical problem, the present application provides a thieno[3,4-c][1,2,5]thiadiazole organic small molecule material with double free radical characteristics and a preparation method and application thereof. The material prepared into a drug can realize simultaneous oxygen evolution, generation of Type-I active oxygen species and photo-thermal conversion under 808 nm near-infrared laser irradiation.

[0006] One of the purposes of the present application is to provide a thieno[3,4-c][1,2,5]thiadiazole organic small molecule with double free radical characteristics, having the structure shown in formula (I):

[0007]

[0008] In formula (I), n is the same or different, and each is 0, 1, 2 or 3;

[0009] In formula (I), X is the same or different, and each is one of nitrogen, oxygen, sulfur, selenium or tellurium; in formula (I), R1 is the same or different, and each is hydrogen or alkyl or alkoxy.

[0010] According to the present application, R1 can be selected in a wide range. In a preferred embodiment of the present application, R1 is hydrogen or alkyl containing 1-24 carbon atoms or alkoxy containing 1-24 carbon atoms; preferably, R1 is hydrogen or alkyl containing 1-12 carbon atoms, such as C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 carbon atoms; or R1 is alkoxy containing 1-12 carbon atoms, such as C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 carbon atoms.

[0011] The second purpose of the present application is to provide a preparation method of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule with double free radical characteristics described in the first purpose, comprising reacting a compound represented by formula (II) and malononitrile under anhydrous and anaerobic conditions, and in the presence of a catalyst and a solvent.

[0012]

[0013] According to the present application, the molar ratio of the compound represented by formula (II) and malononitrile can be selected in a wide range. In a preferred embodiment of the present application, the molar ratio of the compound represented by formula (II) and malononitrile is 1:(2-11), preferably 1:(5-8).

[0014] According to the present application, the amount of the catalyst can be selected in a wide range. In a preferred embodiment of the present application, the total amount of the catalyst is 0.3-1.2 mmol, preferably 0.5-0.9 mmol, relative to 1 mmol of the compound of formula (II).

[0015] According to the present application, the kind of the catalyst can be selected in a wide range. In a preferred embodiment of the present application, the catalyst is selected from ammonium acetate and / or β-alanine; preferably, the catalyst is selected from ammonium acetate and β-alanine, and further preferably, the molar ratio of ammonium acetate to β-alanine is 1:(0.01-0.12); preferably 1:(0.03-0.08).

[0016] According to the present application, the solvent can be selected in a wide range. In a preferred embodiment of the present application, the solvent is selected from glacial acetic acid and / or ethanol.

[0017] According to the present application, the amount of the solvent can be selected in a wide range. In a preferred embodiment of the present application, the amount of the solvent is 30-50 mL, more preferably 35-40 mL, relative to 1 mmol of the compound of formula (II).

[0018] According to the present application, the temperature condition of the reaction can be selected in a wide range. In a preferred embodiment of the present application, the reaction condition includes a temperature of 50-120°C.

[0019] According to the present application, the time condition of the reaction can be selected in a wide range. In a preferred embodiment of the present application, the reaction condition includes a time of 2-24 hours.

[0020] In a specific preferred embodiment of the present application, the preparation method includes: mixing the compound of formula (II) and malononitrile with the catalyst under anhydrous and anaerobic conditions, adding the solvent, and heating the mixture to 50-120°C, and reacting under mixing conditions for 2-24 hours.

[0021] In a preferred embodiment of the present application, the reaction path is:

[0022]

[0023] The preferred reaction conditions are as follows: under anhydrous and anaerobic conditions, a certain molar ratio of formula (II) and malononitrile is added to a two-necked round-bottom flask, a certain amount of catalyst ammonium acetate and beta-alanine is added, nitrogen is replaced three times, then a certain amount of glacial acetic acid is added to the reaction system, and the mixture is heated to 50-120 DEG C, and stirred for 2-24 hours to obtain the thieno[3,4-c][1,2,5]thiadiazole organic small molecule material with double free radical characteristics.

[0024] In a preferred embodiment of the present application, the preparation method further comprises a step of separating the obtained product after the reaction is completed.

[0025] For the separation method, a common separation method such as column chromatography can be used, and the present application is not particularly limited in this regard.

[0026] The third object of the present application is to provide the thieno[3,4-c][1,2,5]thiadiazole organic small molecule with double free radical characteristics for one of the purposes in the drug or medical device.

[0027] In a preferred embodiment of the present application, the drug can treat hypoxic tumors through photothermal / photodynamic synergistic therapy.

[0028] The prepared organic small molecule material with double free radical characteristics has the functions of simultaneous oxygen evolution, generation of Type I reactive oxygen species and photothermal conversion under 808 nm laser irradiation. It is expected to realize simultaneous oxygen supply under the trigger of 808 nm near-infrared laser, and overcome the problem of poor treatment effect caused by the complex microenvironment of tumors. Through in vitro cell experiments and in vivo mouse tumor inhibition experiments, the outstanding performance of the prepared organic small molecule with double free radical characteristics in the treatment of hypoxic tumors is proved.

[0029] According to the above technical solution, the thieno[3,4-c][1,2,5]thiadiazole organic small molecule material has the characteristics of stable double free radicals in the aggregate state, excellent near-infrared absorption performance, and can decompose water to generate oxygen, reduce oxygen to generate superoxide radicals and perform efficient photothermal conversion under near-infrared light. The present application also provides a preparation method of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule material with double free radical characteristics and its application in photothermal / photodynamic synergistic therapy of cancer. After the material is prepared into a nano-drug, it can realize simultaneous oxygen evolution, generation of Type I reactive oxygen species and photothermal conversion under 808 nm near-infrared laser irradiation, and overcome the problem of poor treatment effect caused by the complex microenvironment of tumors. The preparation method is simple and controllable, and has high application value.

[0030] The small molecule has the above technical effects. The inventors of the present application believe, through research and verification, that the reason is that

[0031] With thieno[3,4-c][1,2,5]thiadiazole as an electron acceptor center, thienyl groups are connected on both sides as donor units (D) to form a 4,6-dithiophen-2-yl thieno[3,4-c][1,2,5]-thiadiazole core skeleton, and a highly electron-deficient unit (A) dicyano is used as a capping group to construct a molecule with a highly planar π-conjugated D-A structure. Strong D-A structure and diradical characteristics can promote red shift of molecular absorption. In addition, the D-A structure is beneficial to charge separation. Highly planar π-conjugation not only enhances π-π interaction in the aggregate state, but also reduces the exciton binding energy to promote charge separation. The strong stretching vibration of the C≡N bond in the capping dicyano group is beneficial to maintaining intramolecular motion in the aggregate state, thereby improving photothermal conversion. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 HNMR spectrum of the product of Example 1. 1 HNMR spectrum.

[0033] Figure 2 Electron paramagnetic resonance spectrum of the solid powder of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drug with diradical characteristics.

[0034] Figure 3 Absorption spectrum of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drug with diradical characteristics of Example 1.

[0035] Figure 4 Photothermal performance test of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drug with diradical characteristics under 808 nm near-infrared laser irradiation.

[0036] Figure 5 Test of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drug with diradical characteristics for generating reactive oxygen under 808 nm near-infrared laser irradiation.

[0037] Figure 6 Test of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drug with diradical characteristics for generating oxygen by decomposing water under 808 nm near-infrared laser irradiation.

[0038] Figure 7To image the intracellular reactive oxygen species (ROS) in the cells under the irradiation of 808 nm near-infrared light with or without the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drugs with biradical characteristics under the normal oxygen (21% O2) or hypoxic (1% O2) atmosphere.

[0039] Figure 8 To perform the photothermal / photodynamic synergistic treatment experiment of the space-time synchronous self-oxygenation under the irradiation of 808 nm laser (0.8 W·cm -2 ) after the injection of the phosphate buffered saline (PBS) and the thieno[3,4-c][1,2,5]thiadiazole organic small molecule drugs with biradical characteristics. DETAILED DESCRIPTION

[0040] The preparation of the thieno[3,4-c][1,2,5]thiadiazole organic small molecule material with biradical characteristics and the application thereof in the photothermal / photodynamic synergistic treatment of hypoxic tumors will be described in detail below with specific examples, and it is necessary to point out here that the following examples are only used to further illustrate the present application and cannot be understood as limiting the protection scope of the present application. Some non-essential improvements and adjustments of the present application made by the person skilled in the art according to the content of the present application still fall within the protection scope of the present application.

[0041] In the following examples, the compound TTD-CHO is synthesized according to the method described in the literature: J. Mater. Chem., 2011, 21, 4679-4688.

[0042] The raw materials used in the examples and comparative examples are all publicly known in the art if not specifically limited, for example, can be directly purchased or prepared according to the publicly known preparation method.

[0043] In the following examples, the electron paramagnetic resonance spectrum is detected by an electron paramagnetic resonance spectrometer; the ultraviolet-visible absorption spectrum is detected by an ultraviolet-visible spectrophotometer; the temperature rise (Example 4) is detected by an infrared thermal imager; the active oxygen generation in Example 5 is detected by a fluorescence spectrometer with 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) active oxygen indicator as an index; the oxygen generation index in Example 6 is detected by a dissolved oxygen tester; the intracellular active oxygen imaging in Example 7 is detected by a confocal microscope with DCFH-DA active oxygen indicator as an index; and the temperature rise at the tumor site of the mouse in Example 8 is detected by an infrared thermal imager.

[0044] Example 1

[0045]

[0046] Compound TTD-CHO (0.395 mmol), malononitrile (2.443 mmol), ammonium acetate (0.274 mmol) and β-alanine (0.010 mmol) were added into a two-necked round bottom flask under anhydrous and anaerobic conditions, and the reaction system was replaced with nitrogen three times, then 15 mL of glacial acetic acid was added, and the mixture was heated to 120°C and stirred for 24 hours. After the reaction was completed, the solid was filtered off, and the solid was dissolved in dichloromethane and extracted. The extracted crude product was purified and separated by silica gel column, and the eluent was dichloromethane / petroleum ether (1:3). Finally, TTD-CN black product was obtained.

[0047] Example 2

[0048] The TTD-CN drug was prepared by nanoscale co-precipitation. The specific preparation process is as follows: first, TTD-CN solid powder (0.2 mg) was fully dissolved in 0.5 mL of tetrahydrofuran, and 1 mg of DSPE-PEG2000 (purchased from BBI) was fully dissolved in 0.5 mL of tetrahydrofuran. The two tetrahydrofuran solutions were mixed well and then added dropwise into 9 mL of deionized water through a cell disruptor. The aqueous solution after the addition was completed was dialyzed for 48 h (dialysis bag type MwCO: 1000D), and the water was changed every 8 h during the dialysis process. Finally, the TTD-CN drug was obtained. A 1 cm wide quartz cuvette was selected, 2 ml of TTD-CN drug aqueous solution with a concentration of 10 -5 The absorption spectrum of the drug was tested by ultraviolet-visible spectrophotometer. As shown in Figure 2 , the ultraviolet absorption range of TTD-CN drug extends from 300 nm to 950 nm, proving that the drug can be excited by near-infrared light for treatment.

[0049] Example 3

[0050] A certain amount of TTD-CN solid powder was weighed and its electron paramagnetic resonance spectrum was tested. As shown in Figure 3 , the small molecule shows obvious carbon free radical signal and has double free radical characteristics.

[0051] Example 4

[0052] A 1 cm wide quartz cuvette was selected, 1 ml of TTD-CN drug aqueous solution with a concentration of 100 μg / mL was added, and the photothermal performance of TTD-CN drug was tested by infrared thermal imager with 0.8 W·cm -2 of 808 nm laser as excitation light source. As shown in Figure 4 , the control group of pure water did not change in temperature under the same light source. The TTD-CN drug with a concentration of 100 μg / mL showed a temperature rise of 6.5°C under 808 nm laser (0.8 W·cm -2) can be stably raised by 27.3℃ under irradiation.

[0053] Example 5

[0054] It is well known to those skilled in the art that active oxygen has high chemical reactivity due to containing unpaired electrons. Active oxygen causes damage to cancer cells by reacting with cellular substrates. In order to evaluate whether TTD-CN drugs can generate active oxygen under 808 nm laser excitation, a commercial active oxygen indicator DCFH-DA was used for active oxygen detection. The active oxygen generated by TTD-CN drugs can oxidize the active oxygen indicator to fluorescein with strong green fluorescence, and then the fluorescence change of the active oxygen indicator is detected by a fluorescence spectrometer to determine whether TTD-CN drugs can generate active oxygen. As shown in Figure 5 , under 808 nm laser (0.8 W·cm -2 ) irradiation, the fluorescence intensity of the active oxygen indicator increased significantly, indicating that TTD-CN drugs generated active oxygen and can be used as active oxygen generating agents for photodynamic therapy.

[0055] Example 6

[0056] The effect of TTD-CN drugs on the decomposition of water to generate oxygen under 808 nm near-infrared laser irradiation was tested by a dissolved oxygen tester. As shown in Figure 6 , under no light conditions, the dissolved oxygen tester reading remained basically unchanged with the extension of time, indicating that TTD-CN drugs would not generate oxygen without light excitation. When other conditions remained unchanged, the dissolved oxygen tester reading gradually increased with the extension of time after only providing light, and the oxygen evolution amount of TTD-CN drugs reached 1.1 mg / mL within 20 min. This indicates that TTD-CN drugs can generate oxygen by decomposing water under 808 nm light excitation.

[0057] Example 7

[0058] In order to further prove that TTD-CN drugs also have active oxygen generation ability in living cells. The active oxygen generated by TTD-CN drugs in living cells was detected by a DCFH-DA active oxygen kit. TTD-CN drugs were co-incubated with 4T1 cells for 6 h, and then 4T1 cells were irradiated by 808 nm laser after TTD-CN drugs were endocytosed by 4T1. The active oxygen generated by TTD-CN drugs after light irradiation will make the active oxygen indicator emit bright green fluorescence. Whether TTD-CN drugs can generate active oxygen in 4T1 cells was observed by taking pictures with a confocal microscope, as shown in Figure 7 The cells endocytosed TTD-CN drugs emitted bright green fluorescence, indicating that TTD-CN drugs can also generate active oxygen in living cells.

[0059] Example 8

[0060] In the experiment of inhibiting tumor tissue growth in tumor-bearing mice by photothermal / photodynamic synergistic therapy, 0.8 W·cm -2 Near-infrared light at 808 nm was used to irradiate tumor tissue in mice, and temperature changes at the tumor site were detected using a temperature-sensing camera. The warming effect of the tumor site during the irradiation process was as follows: Figure 8 As shown in Figure a.

[0061] from Figure 8 From a, it can be concluded that after TTD-CN is injected into mice via the tail vein, it can accumulate well at the tumor site, and at 0.8 W·cm⁻¹ -2 Under 808nm near-infrared light irradiation, it exhibits excellent photothermal heating effect, ultimately reaching a temperature plateau of 48.8℃. For drugs not containing TTD-CN, at 0.8W·cm -2 The temperature barely increased after 15 minutes of irradiation with 808nm near-infrared light. This demonstrates the photothermal conversion efficiency of the TTD-CN drug and its potential for photothermal therapy in vivo.

[0062] The tumor suppression assay was performed on TTD-CN drug under 808nm laser (0.8W·cm²) to test its efficacy. -2 The therapeutic effect of self-oxygenated photothermal / photodynamic therapy under irradiation. Mice with 4T1 tumors were randomly divided into four groups: (a) TTD-CN drug, (b) TTD-CN drug + light irradiation (808nm, 0.8W·cm). -2 (c) PBS and (d) PBS + light (808nm, 0.8W·cm) -2 Mouse body weight and tumor volume were recorded every two days for a total of 15 days. Figure 8 As shown in Figure b, the tumor was completely eliminated after 9 days of treatment. Furthermore, there was no recurrence throughout the entire experimental period, indicating that the TTD-CN drug effectively responded to 808nm laser (0.8W·cm²) treatment. -2 The synergistic treatment modality of self-oxygenated irradiation can completely inhibit tumor growth. In experiments recording mouse body weight every two days, such as... Figure 8 As shown in Figure c, the body weight of all four groups of tumor-bearing mice increased, indicating that TTD-CN has excellent biocompatibility and low toxicity in vivo. The tumor resection images of mice 15 days after different treatments provide a clear visual indication of this. Figure 8 In the treatment group (d), the tumors almost completely disappeared, further demonstrating the excellent synergistic effect of TTD-CN in vivo.

[0063] Example 9

[0064] Compound TTD-CHO (0.392 mmol), malononitrile (3.100 mmol), ammonium acetate (0.272 mmol) and β-alanine (0.009 mmol) were added into a two-necked round bottom flask under anhydrous and anaerobic conditions, and the reaction system was replaced with nitrogen three times. Then 15 mL of glacial acetic acid was added into the reaction system, and the mixture was heated to 120°C and stirred for 24 hours. After the reaction was completed, the solid was filtered out and dissolved in dichloromethane for extraction. The crude product after extraction was separated by silica gel column purification with dichloromethane / petroleum ether (1:3) as the eluent. It was detected that the final TTD-CN black product was obtained with a yield comparable to that of Example 1.

[0065] Example 10

[0066] Compound TTD-CHO (0.396 mmol), malononitrile (2.458 mmol), ammonium acetate (0.257 mmol) and β-alanine (0.020 mmol) were added into a two-necked round bottom flask under anhydrous and anaerobic conditions, and the reaction system was replaced with nitrogen three times. Then 15 mL of glacial acetic acid was added into the reaction system, and the mixture was heated to 120°C and stirred for 24 hours. After the reaction was completed, the solid was filtered out and dissolved in dichloromethane for extraction. The crude product after extraction was separated by silica gel column purification with dichloromethane / petroleum ether (1:3) as the eluent. It was detected that the final TTD-CN black product was obtained with a yield comparable to that of Example 1.

[0067] Example 11

[0068] Compound TTD-CHO (0.454 mmol), malononitrile (3.193 mmol), ammonium acetate (0.351 mmol) and β-alanine (0 mmol) were added into a two-necked round bottom flask under anhydrous and anaerobic conditions, and the reaction system was replaced with nitrogen three times. Then 15 mL of glacial acetic acid was added into the reaction system, and the mixture was heated to 120°C and stirred for 24 hours. After the reaction was completed, the solid was filtered out and dissolved in dichloromethane for extraction. The crude product after extraction was separated by silica gel column purification with dichloromethane / petroleum ether (1:3) as the eluent. It was detected that the final TTD-CN black product was obtained. Compared with Example 1, the yield of TTD-CN was slightly reduced.

[0069] Comparative Example 1

[0070] Comparative Example 2 The same method was used for testing (commercially available), although the compound was similar in structure to TTD-CN in the present application, it was found that this compound did not have a double free radical signal.

[0071] The products from the above Examples 9-11 were tested for electron paramagnetic resonance spectra according to the method of Example 3. The small molecules from the respective examples exhibited a clear carbon radical signal with a doublet radical signature. The results are shown in Table 1.

[0072] Table 1

[0073] With or without double radical signal Example 1 Yes Example 9 Yes Example 10 Yes Example 11 Yes Comparative Example 1 No

[0074] It should be noted that the foregoing examples have been presented by way of explanation of the present application, and not limitation. The present application has been described in terms of exemplary embodiments thereof, and it is understood that the words which have been used are words of description rather than limitation. Modifications can be made within the scope of the present application as set forth in the following claims, and it is intended to cover any and all such modifications within the scope of the present application. Although the present application has been described in terms of particular methods, materials, and embodiments, it is understood that the present application is not limited to the particular examples disclosed. Rather, the present application extends to all functionally equivalent structures and the like.

[0075] All publications, patent applications, patents and other references mentioned in this specification are herein incorporated by reference. Unless otherwise defined, all technical and scientific terms used in this specification are intended to have the meanings commonly attributed to them by those of ordinary skill in the art. In case of conflict between the definitions in this specification and those of any incorporated reference, the definition in this specification will control.

[0076] Where the specification states a genus of elements with limitations of "substantially" or "essentially" or "only" or "consisting essentially of, the phrase is intended to refer to elements of the genus that do not materially affect the desired attributes of the subject matter.

[0077] The endpoints of the ranges and any values described herein are not limited to the precise values stated. The ranges and values should be construed to be roughly about the ranges and values. The endpoints of the ranges and any values are provided as approximations only, and are understood to be open-ended. Each range and value given herein should be interpreted as being approximate as though the terms "about" and "approximately" preceded the value. The endpoints of the ranges and any values are provided as approximations only, and are understood to be open-ended. Each range and value given herein should be interpreted to be approximately that range or value. In this context, "about" and "approximately" mean that the value is within 10% of the value, preferably within 5% of the value, more preferably within 1% of the value, and most preferably within 0.1% of the value.

[0078] In the context of this specification, unless otherwise indicated, any materials, substances, methods, steps, devices or components not mentioned that are known in the art are taken to be directly applicable without any modification.

[0079] Moreover, any implementation described herein can be freely combined with one or more other implementations described herein, and the resulting technical solutions or technical ideas are considered to be part of the original disclosure or original description of the present application, and should not be considered as new content that has not been disclosed or anticipated herein, unless the combination is considered to be obviously unreasonable by those skilled in the art.

Claims

1.A thieno[3,4-c][1,2,5]thiadiazole organic small molecule with biradical characteristics, having a structure shown in formula (I) : wherein n is 1; X is sulfur; and R 1 is hydrogen. wherein 2.A method for preparing the thieno[3,4-c][1,2,5]thiadiazole organic small molecule with biradical characteristics according to claim 1, comprising the step of reacting a compound shown in formula (II) with malononitrile in the presence of a catalyst and a solvent under anhydrous and anaerobic conditions. 3.The method according to claim 2, wherein the molar ratio of the compound shown in formula (II) to malononitrile is 1: (2-11). 4.The method according to claim 2, wherein the molar ratio of the compound shown in formula (II) to malononitrile is 1: (5-8). 5.The method according to claim 2, wherein the total amount of the catalyst is 0.3-1.2 mmol relative to 1 mmol of the compound shown in formula (II) ; and the catalyst is selected from ammonium acetate and / or β-alanine. 6.The method according to claim 5, wherein the total amount of the catalyst is 0.5-0.9 mmol relative to 1 mmol of the compound shown in formula (II). 7.The method according to claim 5, wherein the molar ratio of ammonium acetate to β-alanine is 1: (0.01-0.12). 8.The method according to claim 7, wherein the molar ratio of ammonium acetate to β-alanine is 1: (0.03-0.08). 9.The method according to claim 2, wherein the solvent is selected from glacial acetic acid and / or ethanol; and the amount of the solvent is 30-50 mL relative to 1 mmol of the compound shown in formula (II). 10.The method according to claim 9, wherein the amount of the solvent is 35-40 mL relative to 1 mmol of the compound shown in formula (II). 11.The method according to claim 2, wherein the reaction conditions include a temperature of 50-120 ℃ and / or a time of 2-24 hours. 12.The method according to claim 2, wherein the compound shown in formula (II) and malononitrile are first mixed with the catalyst under anhydrous and anaerobic conditions, then the solvent is added, and the mixture is heated to 50-120 ℃ and reacted under mixing conditions for 2-24 hours. 13.The method according to claim 2, further comprising the step of separating the obtained product after the reaction is completed. 14.The thieno[3,4-c][1,2,5]thiadiazole organic small molecule with biradical characteristics according to claim 1 for use in the preparation of a medicament or a medical device. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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