Sulfenyl compounds, methods of making and use thereof in promoting skin wound healing

Abstract

The present application relates to the technical field of wound healing drugs, and particularly relates to a sulfur-based compound, a preparation method thereof and application thereof in promoting skin wound healing. The sulfur-based compound has a structure shown in formula (I). The sulfur-based compound can not only promote the generation of blood vessels at a wound through the repair of damaged vascular endothelial cells at the wound, but also promote the growth of wound tissue and the generation of collagen at the damaged skin, promote the wound healing at the damaged skin, and thus achieve the purpose of treating skin damage related diseases. The sulfur-based compound can be used to promote skin wound healing in a flexible administration mode, and can be applied to the wound or administered by gavage, and both can accelerate the wound healing at the damaged skin.

Description

Technical Field

[0001] This invention relates to the field of wound healing pharmaceutical technology, and in particular to sulfur-based compounds, their preparation methods, and their applications in promoting skin wound healing. Background Technology

[0002] Normal skin tissue is in a stable state. When the skin is injured by external forces, this surface homeostasis is disrupted, resulting in a wound. Skin wounds not only cause severe pain and affect patients' quality of life, but in severe cases, infection can lead to amputation or even more serious sequelae. Therefore, promoting the healing process of skin wounds is crucial. Skin wound healing is a complex process, currently classified into five stages: inflammatory response, angiogenesis, epithelial cell migration and proliferation, repair tissue formation, and extracellular matrix remodeling. These stages are all vital to the wound healing process; any disruption in any stage can affect the skin's repair process and thus delay wound healing. Therefore, finding new drugs that can promote skin wound healing is essential.

[0003] Currently, promoting angiogenesis at damaged skin sites and fostering skin tissue growth and collagen production at wound sites has become an important drug screening target for drugs regulating diseases related to skin wound healing. Promoting the repair of vascular endothelial cells at skin wound sites further accelerates wound healing. However, sometimes single-drug administration to the wound site is insufficient to achieve rapid wound healing. Therefore, there is an urgent need to develop drugs that can be administered in multiple ways to treat skin wound healing, such as through topical application or gavage, to accelerate wound healing at damaged skin sites. Summary of the Invention

[0004] To address or partially address the problems existing in related technologies, this invention provides a sulfur-based compound, its preparation method, and its application in promoting skin wound healing.

[0005] This invention provides a sulfur-based compound having the structure shown in formula (I):

[0006]

[0007] Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl;

[0008] R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridinyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy groups.

[0009] Further, in the structure shown in formula (I), R2 is selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl or C1-C2 alkylpyridinyl; wherein, the phenyl in the C1-C2 alkylphenyl is an unsubstituted phenyl, a phenyl substituted with one or more groups selected from ethyl ester, C1-C2 alkoxy, and benzyloxy, or a phenyl substituted with two or more hydroxyl groups; the pyridinyl in the C1-C2 alkylpyridinyl is an unsubstituted pyridinyl or a pyridinyl group substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy.

[0010] Furthermore, in the structure shown in formula (I), R1 is hydrogen and R3 is hydrogen.

[0011] Further, in the structure shown in formula (I), R2 is a C2 alkylphenyl, wherein the phenyl in the C2 alkylphenyl is an unsubstituted phenyl, a phenyl substituted with C1-C2 alkoxy or benzyloxy, or a phenyl substituted with one or two hydroxyl groups.

[0012] Furthermore, it has any of the following molecular structures:

[0013]

[0014]

[0015] Furthermore, the compound shown in Formula A and the compound shown in Formula B undergo an acid-amine condensation reaction to obtain the sulfur-based compound shown in Formula (I);

[0016]

[0017] Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl;

[0018] R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridinyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy groups.

[0019] Furthermore, when R1 is hydrogen and R3 is hydrogen, the structure of the sulfur-based compound is shown in Formula II, and it is prepared according to the following method:

[0020] The compound shown in Formula C and the compound shown in Formula D undergo an acid-amine condensation reaction to obtain the sulfur-based intermediate shown in Formula E.

[0021] The sulfide-based intermediate shown in Formula E is converted into the sulfide-based compound shown in Formula II via base catalysis;

[0022]

[0023] Wherein, R2 is a C2 alkylphenyl, and the phenyl shown is an unsubstituted phenyl, or a phenyl substituted with C1-C2 alkoxy, benzyloxy, one or two hydroxyl groups.

[0024] The present invention also provides an application of the sulfur-based compounds described above in promoting skin wound healing.

[0025] The present invention also provides a medicament for treating diseases related to skin wound healing, characterized in that it comprises any one of the sulfur-based compounds described above.

[0026] Furthermore, it also includes pharmaceutically acceptable salts, esters, hydrates or combinations thereof, as well as excipients.

[0027] The technical solution provided by this invention may include the following beneficial effects:

[0028] The sulfur-based compounds provided by this invention not only promote angiogenesis at the wound site by repairing damaged vascular endothelial cells, but also promote the growth of wound tissue and collagen production at the site of skin injury, thereby accelerating wound healing and achieving the purpose of treating skin injury-related diseases. These sulfur-based compounds offer flexible administration methods for promoting skin wound healing; they can be applied topically or administered orally, both methods effectively accelerating wound healing at the site of skin injury.

[0029] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit the invention. Attached Figure Description

[0030] The above and other objects, features and advantages of the present invention will become more apparent from the more detailed description of exemplary embodiments of the invention in conjunction with the accompanying drawings, wherein the same reference numerals generally represent the same parts.

[0031] Figure 1 Different sulfur-based compounds were applied to the wounds of mice, and the wound healing status of the mice was recorded on days 0, 3, 6, and 9.

[0032] Figure 2 The study involved administering different sulfur-based compounds to mice via gavage and then tracking the wound healing progress on days 0, 3, 6, and 9.

[0033] Figure 3 The study involved administering a sulfur-based compound (No. 000) to mice via gavage and applying it to the wounds. The wound healing process was observed on days 0, 3, 6, and 9. Detailed Implementation

[0034] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular forms “a,” “the,” and “the” used in this invention and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any and all possible combinations of one or more of the associated listed items.

[0036] It should be understood that although the terms "first," "second," "third," etc., may be used in this invention to describe various information, this information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of this invention, first information may also be referred to as second information, and similarly, second information may also be referred to as first information. Thus, features defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0037] The present invention provides a sulfur-based compound having the structure shown in formula (I).

[0038]

[0039] Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl;

[0040] R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridinyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy groups.

[0041] The sulfur-based compounds provided in this embodiment can promote wound healing at the site of skin damage by regulating angiogenesis at the site of skin injury, regulating the migration of fibroblasts and epidermal cells on the skin surface, and promoting the growth of skin tissue and the production of collagen.

[0042] Preferably, R2 is selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein, the phenyl group in the C1-C2 alkylphenyl group is an unsubstituted phenyl, a phenyl substituted with one or more groups selected from ethyl ester, C1-C2 alkoxy, and benzyloxy, or a phenyl substituted with two or more hydroxyl groups; the pyridinyl group in the C1-C2 alkylpyridinyl group is an unsubstituted pyridinyl group or a pyridinyl group substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy.

[0043] In a preferred embodiment, R1 and R3 are hydrogen, and the sulfur-based compounds are more specifically thiol-based compounds, which have a superior effect on promoting skin healing. More preferably, R2 is a C2 alkylphenyl, wherein the phenyl group in the C2 alkylphenyl is an unsubstituted phenyl group, a phenyl group substituted with a C1-C2 alkoxy group or a benzyloxy group, or a phenyl group substituted with one or two hydroxyl groups.

[0044] As a preferred embodiment of the compound, the above-mentioned sulfide compounds have any of the following molecular structures:

[0045]

[0046]

[0047] More preferably, the sulfur-based compounds mentioned above are compounds represented by formulas 000, 003, 004, 011, 012 or 019.

[0048] The sulfur-based compounds provided in this invention not only promote angiogenesis at the wound site by repairing damaged vascular endothelial cells, but also promote the growth of wound tissue and collagen production at the site of skin injury, thereby promoting wound healing and achieving the purpose of treating skin injury-related diseases. These sulfur-based compounds offer flexible administration methods for promoting skin wound healing; they can be applied topically or administered orally, both methods effectively accelerating wound healing at the site of skin injury.

[0049] Another embodiment of the present invention also provides a method for preparing the above-mentioned sulfur-based compound, wherein the compound shown in formula A and the compound shown in formula B undergo an acid-amine condensation reaction to obtain the sulfur-based compound shown in formula (I);

[0050]

[0051] The reaction formula is as follows:

[0052]

[0053] Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl;

[0054] R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy. The preferred embodiments for R1, R2, and R3 are the same as those described in the above embodiments, and will not be repeated here.

[0055] As a preferred embodiment, when R1 is hydrogen and R3 is hydrogen, the structure of the sulfur-based compound is as shown in Formula II. In this case, the sulfur-based compound is more specifically a mercapto compound, which is prepared by the following method: the compound shown in Formula C and the compound shown in Formula D undergo an acid-amine condensation reaction to obtain the sulfur-based compound intermediate shown in Formula E.

[0056] The sulfide-based intermediate shown in Formula E is converted into the sulfide-based compound shown in Formula II via base catalysis;

[0057]

[0058] The reaction formula is as follows:

[0059]

[0060] The alkali is preferably sodium hydroxide, potassium hydroxide, or cesium hydroxide.

[0061] The following provides several specific methods for preparing the above-mentioned sulfur-based compounds.

[0062] The synthetic route for sulfur-based compound 000 is as follows:

[0063]

[0064] Synthetic route of sulfur-based compound 034:

[0065]

[0066] The base used in the reaction is selected from sodium hydroxide, potassium hydroxide, and cesium hydroxide. The molar ratio of compound b1 to base is 1:(2-5); preferably 1:(2-3). The molar ratio of compound b1 to compound b2 is 1:(1-2); preferably 1:(1-1.5). The solvent used in the reaction is selected from one or more of toluene, methanol, tetradifurran, DMSO, and water. The reaction temperature range is generally 0-30°C, preferably 10-30°C, more preferably 10-20°C. The reaction time is generally 2-10 h, preferably 4-8 h, more preferably 4-6 h.

[0067] Synthetic route of sulfur-based compound 023:

[0068]

[0069] Reaction Principle: Compound c1 and compound c2 undergo an acid-amine condensation reaction. The molar ratio of compound c1 to compound c2 is 1:(1-2); 1:(1-1.5); more preferably 1:1.2. The reaction conditions include a base and a condensing agent; further, the base is selected from one or more of DIPEA, DMAP, TEA, NMP, N-methylmorpholine, and pyridine; the condensing agent is selected from one or more of CDI, HBTU, BOP, PyBOP, DCC, HOBT, EDCI, POCl3, SOCl2, (COCl)2, and HATU. The molar ratio of compound c1 to base is 1:(2-5); preferably 1:(2-4.5). The molar ratio of compound c1 to condensing agent is 1:(1-3); preferably 1:(1-2.5). The solvent for the reaction is selected from one or more of dichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, water, and acetonitrile.

[0070] The specific reaction conditions can be selected from one of the following:

[0071] ① Mix compound c2, CDI, and solvent. After compound c2 has reacted completely, mix the reaction system with water, and then mix it with DIPEA and c1 to react. The solvent is DCM.

[0072] ② After mixing compound c1, compound c2, DIPEA, and solvent, HBTU is added in batches to react; the solvent is DMF;

[0073] ③ After mixing compound c1, compound c2, DIPEA, and solvent, BYBOP is added in batches to react; the solvent is DMF.

[0074] ④ After mixing compound c2, DIPEA, DMAP, DCC, and solvent, it is then mixed with compound c1 to react; the solvent is toluene.

[0075] ⑤ After mixing compound c1, compound c2, DIPEA, HOBT, and solvent, EDCI is added in batches to react under an inert gas and / or nitrogen atmosphere.

[0076] Synthetic route of sulfur-based compound 025:

[0077]

[0078] Reaction Principle: Compound d1 and compound d2 undergo an acid-amine condensation reaction. The molar ratio of compound d1 to compound d2 is 1:(1-2); preferably 1:(1-1.5); more preferably 1:1.2. Reaction conditions include a base and a condensing agent; further, the base is selected from one or more of DIPEA, DMAP, TEA, NMP, N-methylmorpholine, and pyridine; further, the condensing agent is selected from one or more of CDI, HBTU, BOP, PyBOP, DCC, HOBT, EDCI, POCl3, SOCl2, (COCl)2, and HATU. The molar ratio of compound d1 to base is 1:(2-5); preferably 1:(2-4.5). The molar ratio of compound d1 to condensing agent is 1:(1-3); preferably 1:(1-2.5). The solvent for the reaction is selected from one or more of dichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, water, and acetonitrile.

[0079] The specific reaction conditions can be selected from one of the following:

[0080] ① Mix compound d2, CDI, and solvent. After compound d2 has reacted completely, mix the reaction system with water, and then mix it with DIPEA and compound d1 to react. The solvent is DCM.

[0081] ② After mixing compound d1, compound d2, DIPEA, and solvent, HBTU is added in batches to react; the solvent is DMF;

[0082] ③ After mixing compound d1, compound d2, DIPEA, and solvent, BYBOP is added in batches to react; the solvent is DMF.

[0083] ④ After mixing compound d2, DIPEA, DMAP, DCC, and solvent, it is then mixed with compound d1 for reaction; the solvent is toluene;

[0084] ⑤ After mixing compound d1, compound d2, DIPEA, HOBT, and solvent, EDCI is added in batches to react under an inert gas and / or nitrogen atmosphere.

[0085] Synthetic route of sulfur-based compound 001:

[0086]

[0087] Reaction Principle: Sulfur-based compound 025 forms a thiol group via base catalysis. The base used in the reaction is selected from sodium bicarbonate, sodium carbonate, and potassium carbonate. The molar ratio of sulfur-based compound 025 to base is 1:(2-5); preferably 1:(2-4.5). The solvent used in the reaction is selected from one or more of methanol, ethanol, isoamyl alcohol, ethylene glycol, and glycerol. The reaction temperature range is generally 20-100℃, preferably 20-80℃, and more preferably 20-50℃. The reaction time is generally 10-24 h, preferably 10-16 h, and more preferably 13-16 h.

[0088] Synthetic route of sulfur-based compound 004:

[0089]

[0090] Reaction Principle: Sulfur-based compound O23 forms a thiol group through base catalysis. The base used in the reaction is selected from sodium bicarbonate, sodium carbonate, and potassium carbonate. The molar ratio of sulfur-based compound O23 to base is 1:(2-5); preferably 1:(2-4.5). The solvent used in the reaction is selected from one or more of methanol, ethanol, isoamyl alcohol, ethylene glycol, and glycerol. The reaction temperature range is generally 20-100℃, preferably 20-80℃, and more preferably 20-50℃. The reaction time is generally 10-24 h, preferably 10-16 h, and more preferably 13-16 h.

[0091] Another embodiment of the present invention provides an application of the above-mentioned sulfur-based compound in promoting skin wound healing. This sulfur-based compound offers flexible administration methods for promoting skin wound healing; it can be applied topically or administered orally, both methods effectively accelerating wound healing at the site of skin damage.

[0092] Another embodiment of the present invention provides a medicament for treating diseases related to skin wound healing, comprising the aforementioned sulfur-based compounds. This medicament can be used both topically and orally. Further, it also includes pharmaceutically acceptable salts, esters, hydrates, or combinations thereof, as well as excipients.

[0093] The technical solution of the present invention will be further described below with reference to specific embodiments:

[0094] Example 1: Preparation of sulfur-based compounds 000

[0095] 1. Add 4.3 g of methacrylic acid and 5.7 g of thioacetic acid to a single-necked flask, dissolve in 20 mL of THF, and react overnight. After the reaction is complete, remove the THF, and vacuum distill at a pressure of 0.1 mmHg and a temperature of 110-120 °C. A yellow oily liquid is distilled off, which solidifies into a yellow solid. The product is a yellow oily liquid, which is compound a1. The reaction formula is as follows:

[0096]

[0097] The product obtained in this step was subjected to NMR analysis, and the results are as follows: 1H NMR (400MHz, CDCl3): δppm 3.11 (m, 2H), 2.77 (dd, 1H), 2.37 (s, 3H), 1.31 (d, 3H)

[0098] 2. At room temperature, compound a1 (1 g, 6.17 mmol), EDCI (1.755 g, 9.26 mmol), HOBt (1.472 g, 9.26 mmol), and NMM (1.38 mL, 12.34 mmol) were added to 10 mL of dichloromethane and 10 mL of DMF. After 5 minutes, compound a2 (0.931 g, 6.79 mmol) was added, followed by stirring at room temperature for 4 hours. The reaction was quenched by adding 100 mL of saturated sodium bicarbonate solution. The reaction was then terminated with 100 mL of saturated sodium bicarbonate solution, and the aqueous phase was extracted with 150 mL of ethyl acetate. The organic phase was washed twice with 100 mL × 2 KHSO4 5% aqueous solution, and then once with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give product compound a3. The reaction formula is as follows:

[0099]

[0100] The products obtained in this step were subjected to NMR analysis, and the results are as follows: ¹H NMR (400MHz, CDCl₃): δppm 7.04 (d, J = 8.4Hz, 2H), 6.78 (dd, J = 2.0, 6.8Hz, 2H), 5.80 (s, 1H), 5.64 (s, 1H), 3.42–3.54 (m, 2H), 3.03–3.08 (m, 1H), 2.89–2.94 (m, 1H), 2.74 (t, J = 6.8Hz, 1H), 2.29–2.72 (m, 4H), 1.17 (d, J = 7.2Hz, 3H)

[0101] 3. Compound a3 (1.2 g, 4.26 mmol), 20 mL of methanol, and 10 mL of 1 M NaOH solution were added sequentially to a 100 mL three-necked round-bottom flask. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, 90 mL of 1 M NaOH solution was added to the mixture, and the mixture was washed twice with 100 mL of ethyl acetate. The pH was then adjusted to 3-4 with 5% KHSO4 aqueous solution. The product was extracted with 150 mL of ethyl acetate. The organic phase was washed sequentially with 100 mL of 5% KHSO4 solution and 100 mL of saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain an oily crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1, formic acid = 5%) to give 850 mg of a white solid, namely sulfur-based compound 000, with a yield of 83.3%. The reaction formula is as follows:

[0102]

[0103] The products obtained in this step were subjected to NMR analysis, and the results are as follows: ¹H NMR (400MHz, CDCl₃): δppm 9.14 (s, ¹H), 7.89 (t, J = 5.2Hz, ¹H), 6.98 (d, J = 8.8Hz, 2H), 6.66 (d, J = 8.4Hz, 2H), 3.19–3.24 (m, 2H), 2.57–2.63 (m, 3H), 2.34–2.42 (m, 2H), 2.06 (t, J = 8.4Hz, 1H), 1.02 (d, J = 6.8Hz, 3H)

[0104] Example 2: Preparation of sulfur-based compound 034

[0105] N-(4-hydroxyphenylethyl)methacrylamide (23.91 g, 0.10 mol) was dissolved in 400 mL of toluene solution, and sodium hydroxide (8.8 g, 0.22 mol) was dissolved in 95 mL of deionized water. The two solutions were mixed in an ice bath, maintaining the temperature at approximately 10°C. Benzoyl chloride (14.0 g, 0.10 mol) was added dropwise to an isobaric tube in the reaction flask. The mixture was stirred at 10°C for 30 minutes, and then stirred for another 4 hours at 20°C. After the reaction was complete, the solution was transferred to a separating funnel. The lower layer (aqueous layer) was removed, and the organic layer was rinsed four times with deionized water. Next, the pH of the entire aqueous phase was adjusted to 1 using concentrated hydrochloric acid. The filter retained a white solid. The solid was rinsed with ice water and dried, yielding a white solid product (31.55 g, 92%), which was the sulfur-based compound 034.

[0106] Example 3: Preparation of sulfur-based compound 023

[0107] To a 1L three-necked flask, p-benzylamine (10.7 g, 0.10 mol), 3-acetylthio-2-methylpropionic acid (19.44 g, 0.12 mol), DIPEA (25.84 g, 2.0 mmol), HOBT (27.05 g, 2.0 mmol), EDCI (38.25 g, 2.0 mmol), and 550 mL of tetrahydrofuran were added sequentially. After thorough mixing, the system was bubbled through a bottom tube to remove oxygen for half an hour, followed by stirring for 15 h. After confirming complete reaction of the substrate by TLC, 600 mL of water was added to wash the organic phase, and the dichloromethane phase was separated. The mixture was dried over anhydrous sodium sulfate for 1 h, and 50 g of silica gel was added. The mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography to obtain 21.33 g (yield 85.3%) of a yellowish-brown solid, namely the sulfide compound 023.

[0108] Example 3: Preparation of sulfur-based compound 025

[0109] To a 1L three-necked flask, p-2-phenylethylamine (12.1 g, 0.10 mol), 3-acetylthio-2-methylpropionic acid (19.44 g, 0.12 mol), DIPEA (25.84 g, 2.0 mmol), HOBT (27.05 g, 2.0 mmol), EDCI (38.25 g, 2.0 mmol), and 600 mL of dichloromethane were added sequentially. After thorough mixing, the system was bubbled through a bottom tube to remove oxygen for half an hour, followed by stirring for 18 hours. After confirming complete reaction of the substrate by TLC, 600 mL of water was added to wash the organic phase, and the dichloromethane phase was separated. The mixture was dried over anhydrous sodium sulfate for 1 hour, and 50 g of silica gel was added. The mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography to obtain 18.19 g (69.5% yield) of a pale yellow solid, which was identified as sulfide compound 025.

[0110] Example 4: Preparation of sulfur-based compound 001

[0111] A sulfur-based compound 025 (18.19 g, 0.068 mol), sodium bicarbonate (13.73 g, 0.136 mol), and 500 mL of methanol were added sequentially to a 1 L three-necked flask. After thorough mixing, the system was bubbled through a bottom tube to remove oxygen for half an hour, and then stirred at 25 °C for 13 h. After confirming complete reaction of the substrate by TLC, the solvent was removed under vacuum, and the residue was dissolved in water. The aqueous layer was acidified with 5% KHSO4 (500 mL), then extracted with ethyl acetate (4 × 600 mL), and the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product. 10.71 g (70.2% yield) of a pale yellow solid was obtained, which was the sulfur-based compound 001.

[0112] Example 5: Preparation of sulfur-based compound 004

[0113] HMPA-23 (18.03 g, 0.07 mol), potassium carbonate (19.32 g, 0.14 mol), and 600 mL of methanol were added sequentially to a 1 L three-necked flask. After thorough mixing, the system was bubbled through a bottom tube to remove oxygen for half an hour, and then stirred at 30 °C for 14 h. After confirming complete reaction of the substrate by TLC, the solvent was removed under vacuum, and the residue was dissolved in water. The aqueous layer was acidified with 5% KHSO4 (500 mL), then extracted with ethyl acetate (5 × 600 mL), and the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product. 11.54 g (77.3% yield) of a brownish-yellow solid was obtained, which was the sulfur-based compound 004.

[0114] Based on the above reaction principle, sulfur-based compounds 002-003, 005-022, 024, 026-033, and 035-039 were prepared.

[0115] Experimental example: The efficacy of sulfur-based compounds was tested using a mouse skin wound model.

[0116] In the following experiments, the sulfur-based compounds used for topical application were suspensions of the sulfur-based compounds (an appropriate amount of HMPA was weighed and suspended in 2.5% sodium carboxymethyl cellulose to prepare a 15 mg / kg HMPA-CMC suspension, which was prepared fresh for each use). The concentration of the sulfur-based compounds in the injectable drugs was 15 mg / kg.

[0117] Experimental steps:

[0118] A. Establishment of a mouse skin trauma model: Six healthy mice aged 6-8 weeks were selected in each group. First, the mice were dehaired using hair removal cream. Then, a 6mm diameter wound was made on the back of each mouse using a punch. The mice in the following steps were all treated according to this procedure to establish a skin trauma model.

[0119] B. Statistical analysis of the therapeutic effects of different sulfur-based compounds on mouse wound healing: Healthy mice aged 6-8 weeks were selected, with 6 mice in each group. Starting from the second day, sulfur-based compounds No. 000 to No. 039 were applied to the wounds of mice in different groups, and the wound healing was observed and recorded. On the 6th day, the length and width of the mouse wounds after treatment with different sulfur-based compounds were measured with calipers, and the wound area was calculated. The healing rate of different sulfur-based compounds on mouse wounds on the 6th day is shown in Table 1. According to Table 1, sulfur-based compounds No. 000, No. 003, No. 004, No. 011, No. 012, and No. 019 had better therapeutic effects.

[0120] C. Statistical analysis of the therapeutic effects of sulfur-based compounds on mouse skin wound healing: Healthy mice aged 6-8 weeks were selected, with 6 mice in each group. Starting from the second day, sulfur-based compounds No. 000, 003, 004, 011, 012, and 019 were applied to the wounds of mice in different groups, respectively. The wound healing status of the mice was observed, recorded, and statistically analyzed. The line graph of wound healing rate for different sulfur-based compounds is shown below. Figure 1 As shown.

[0121] Healthy mice aged 6-8 weeks were selected, with 6 mice in each group. Starting from the second day, mice in different groups were injected intragastricly with sulfur-based compounds No. 000, 003, 004, 011, 012, and 019. The wound healing of the mice was observed and recorded, and the results were statistically analyzed. The line graph of wound healing rate for different sulfur-based compounds is shown below. Figure 2 As shown.

[0122] D. Statistical analysis of the effects of different administration methods on skin wound healing in mice:

[0123] Healthy mice aged 6-8 weeks were selected, with 6 mice in each group. On the second day, mice in different groups were either coated with sulfur-based compound No. 000 or injected into the stomach with sulfur-based compound No. 000. The wound healing of the mice was observed, recorded, and statistically analyzed. Figure 3 The figure shows the wound healing of mice under different administration methods of the sulfur-based compound No. 000.

[0124] Table 1. Healing rate of different sulfur compounds on mouse wounds on day 6.

[0125]

[0126]

[0127] Experimental results:

[0128] As shown in Table 1, different sulfur-based compounds, when applied to the wounds of mice, showed better therapeutic effects on the wounds compared to the control group on day 6. Among them, sulfur-based compounds No. 000, 003, 004, 011, 012, and 019 exhibited the best therapeutic effects.

[0129] like Figure 1 As shown, over time, different sulfur-based compounds applied to mouse wounds at days 0, 3, 6, and 9 significantly reduced the wound area and promoted wound healing compared to the control group. Among the sulfur-based compounds, compound number 000 showed the most significant effect in promoting wound healing. Figure 2 As shown, over time, intragastric administration of different sulfur-based compounds at 0, 3, 6, and 9 days significantly reduced the area of ​​wounds in mice and promoted wound healing compared to the control group.

[0130] like Figure 3 As shown, over time, the wound area of ​​the control group mice gradually decreased on days 0, 3, 6, and 9. The reduction in wound area was more significant in the HMPA gavage group compared to the control group, and the most significant reduction was observed in the HMPA wound application group, where the wounds were almost completely healed by day 9.

[0131] In summary, the sulfur-based compounds provided by this invention not only promote angiogenesis at the wound site by repairing damaged vascular endothelial cells, but also promote the growth of wound tissue and collagen production at the site of skin injury, thereby accelerating wound healing and achieving the purpose of treating skin injury-related diseases. These sulfur-based compounds offer flexible administration methods for promoting skin wound healing; they can be applied topically or administered orally, both methods effectively accelerating wound healing at the site of skin injury.

[0132] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or improvement of the technology in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. The use of a sulfur-based compound in the preparation of a drug that promotes skin wound healing, characterized in that, The thiolated compounds have the structure shown in formula (I): （I） Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl; R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridinyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy groups.

2. The application according to claim 1, characterized in that, In the structure shown in formula (I), R2 is selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl or C1-C2 alkylpyridinyl; wherein, the phenyl in the C1-C2 alkylphenyl is an unsubstituted phenyl, a phenyl substituted with one or more groups selected from ethyl ester, C1-C2 alkoxy, and benzyloxy, or a phenyl substituted with two or more hydroxyl groups; the pyridinyl in the C1-C2 alkylpyridinyl is an unsubstituted pyridinyl or a pyridinyl group substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy.

3. The application according to claim 1, characterized in that, In the structure shown in formula (I), R1 is hydrogen and R3 is hydrogen.

4. The application according to claim 3, characterized in that, In the structure shown in formula (I), R2 is a C2 alkylphenyl, wherein the phenyl in the C2 alkylphenyl is an unsubstituted phenyl, a phenyl substituted with C1-C2 alkoxy or benzyloxy, or a phenyl substituted with one or two hydroxyl groups.

5. The application according to claim 3, characterized in that, It has any of the following molecular structures: 。 6. The application according to claim 1, characterized in that, The method for preparing the sulfur-based compound is as follows: the compound shown in formula A and the compound shown in formula B undergo an acid-amine condensation reaction to obtain the sulfur-based compound shown in formula (I); (A) (B) Wherein, R1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C1-C2 alkyl, phenyl, and benzoalkyl; R2 and R3 are independently selected from hydrogen, C1-C3 alkyl, C1-C2 alkylpyrimidinyl, C1-C2 alkylcyclopentadienyl, C1-C2 alkylfuranyl, C1-C2 alkylthiophenyl, C1-C2 alkylphenyl, or C1-C2 alkylpyridinyl; wherein the phenyl group in the C1-C2 alkylphenyl group and the pyridinyl group in the C1-C2 alkylpyridinyl group are unsubstituted or substituted with one or more groups selected from hydroxyl, ethyl ester, C1-C2 alkoxy, and benzyloxy groups.

7. The application according to claim 6, characterized in that, When R1 is hydrogen and R3 is hydrogen, the structure of the sulfur-based compound shown is as shown in Formula II, and it is prepared according to the following method: The compound shown in Formula C and the compound shown in Formula D undergo an acid-amine condensation reaction to obtain the sulfur-based intermediate shown in Formula E. The sulfide-based intermediate shown in Formula E is converted into the sulfide-based compound shown in Formula II via base catalysis; (C) (D) (HAVE BEEN) (II) Wherein, R2 is a C2 alkylphenyl, and the phenyl shown is an unsubstituted phenyl, or a phenyl substituted with C1-C2 alkoxy, benzyloxy, one or two hydroxyl groups.

8. The application according to claim 1, characterized in that, The drug is a drug for treating diseases related to skin wound healing, and the drug includes the sulfur-based compound, as well as pharmaceutically acceptable salts, esters or combinations thereof, and excipients.

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