Antranexic acid-fluoroalkanol conjugate or composition thereof, and preparation method and application thereof

Abstract

A tranexamic acid-fluoroalkanol conjugate or a composition thereof, its preparation method, and its application belong to the field of pharmaceutical technology. The tranexamic acid-fluoroalkanol conjugate or its composition comprises a tranexamic acid-fluoroalkanol conjugate, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutical composition; wherein the tranexamic acid-fluoroalkanol conjugate is formed by an ester bond (-C(=O)-O-) between the carboxyl group of tranexamic acid and the hydroxyl group of the fluoroalkanol. The preparation method of the tranexamic acid-fluoroalkanol conjugate is as follows: tranexamic acid or its reactive derivative is reacted with a fluoroalkanol in an inert organic solvent. After the reaction, post-treatment and purification are performed to obtain the corresponding conjugate. The conjugate can be prepared into a stable foam sclerotherapy agent with blood replacement function using the Tessari method, for the sclerotherapy of hemangiomas, varicose veins, and venous malformations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of tranexamic acid-fluoroalkanol conjugates or their pharmaceutically acceptable salts, solvates, or stereoisomers, their preparation methods, pharmaceutical compositions containing the conjugates, and the use of the conjugates, their pharmaceutically acceptable salts, solvates, or stereoisomers, or the pharmaceutical compositions in the preparation of sclerosing agents for treating vascular diseases. The vascular diseases include, but are not limited to, hemangiomas, varicose veins, and vascular malformations. Background Technology

[0002] Vascular diseases are a heterogeneous group of diseases characterized by structural abnormalities in blood vessels or lymphatic vessels, mainly including infantile hemangiomas and congenital vascular malformations. In addition, although primary varicose veins of the lower extremities are a functional venous disorder, their pathological mechanisms involve abnormalities in the blood vessel wall, and therefore they are often considered a key focus and challenge in clinical treatment alongside these diseases. These diseases have a high incidence and long course, and can lead to bleeding, infection, ulceration, functional impairment, and even death.

[0003] From a pathophysiological perspective, abnormalities in the structure and function of the vascular wall are the core mechanisms of the aforementioned diseases. Infantile hemangiomas are characterized by abnormal endothelial cell proliferation-regression cycles, with endothelial cell proliferation activity significantly higher than in normal tissue during the proliferative phase. Primary varicose veins of the lower extremities are characterized by thinning of the venous wall due to collagen fiber degradation and smooth muscle cell apoptosis, as well as blood reflux caused by venous valve insufficiency. The essence of vascular malformations lies in the disordered regulation of angiogenesis during the embryonic period, resulting in permanent vascular lumens with missing wall layers and abnormal structures. These pathological changes lead to local hemodynamic disturbances, thereby causing serious secondary complications.

[0004] Currently, clinical interventions mainly include conservative treatment, traditional surgery, and sclerotherapy. Conservative treatment (such as pressure therapy) can only relieve symptoms and cannot reverse pathological changes; traditional surgery (such as hemangioma resection and high ligation and stripping of the great saphenous vein) is highly invasive, leaves obvious scars, and is difficult to completely remove lesions. In contrast, sclerotherapy has become an important treatment method due to its advantages such as being minimally invasive, repeatable, and having definite efficacy.

[0005] The core mechanism of sclerotherapy is to precisely inject a sclerosing agent into the lumen of the diseased blood vessel through interventional procedures. The chemical damage to the vascular endothelium induces local thrombosis, ultimately leading to fibrosis and occlusion of the diseased vessel. Sclerosing agents have undergone several generations of development: early osmotic sclerosing agents such as hypertonic saline and urea solutions lacked tissue selectivity, easily causing severe pain and tissue necrosis; chemical sclerosing agents such as sodium morrhuate posed systemic toxicity risks. Currently, widely used surfactant-based sclerosing agents (such as podocarboxylic acid and sodium tetradecyl sulfate) can be formulated into foam preparations, thereby reducing drug dosage, prolonging intravascular retention time, and offering greater safety.

[0006] However, existing surfactant-based hardeners still have the following technical drawbacks: (1) Insufficient foam stability: Existing foams have short half-lives, and improving stability often depends on the addition of exogenous stabilizers such as Tween 80, which not only increases the complexity of the formulation, but may also cause safety hazards such as allergic reactions.

[0007] (2) Local inflammatory reaction: The chemical damage of drugs to vascular endothelium can easily induce postoperative redness, swelling, pain and post-inflammatory pigmentation, affecting patient compliance and appearance.

[0008] (3) Incomplete fibrosis and high recurrence rate: Existing drugs are difficult to effectively induce complete and lasting fibrotic occlusion of diseased blood vessels, leading to disease recurrence. Clinical data show that the postoperative recurrence rate of patients with complex vascular malformations can reach 20% to 30%.

[0009] Therefore, there is an urgent need to develop a new type of sclerosing agent that combines high foam stability, low inflammatory irritation, and long-lasting fibrosis induction ability.

[0010] Fluoroalkyl alcohols are a class of alcohols containing fluorinated carbon chains, possessing unique amphiphilicity, low surface tension, high chemical stability, and good biocompatibility. The fluorinated carbon chains in their molecular structure can significantly reduce the surface tension of aqueous solutions, improving the dispersibility, wettability, and permeability of substances. Tranexamic acid is an antifibrinolytic drug that competitively inhibits the binding of plasminogen to fibrin, protecting existing thrombi from degradation.

[0011] In theory, tranexamic acid and fluoroalkanol can be linked by ester bonds to form a conjugate, which can simultaneously exert the surface activity and foam stabilizing function of fluoroalkanol and the thromboprotective effect of tranexamic acid, thereby synergistically enhancing the efficacy of sclerotherapy and reducing the risk of recurrence.

[0012] Currently, there are no reports, either domestically or internationally, on the use of tranexamic acid-fluoroalkanol coupling compounds as sclerosing agents for the treatment of vascular diseases. Based on the aforementioned technical background, this invention, through extensive experimentation, has for the first time discovered that this type of coupling compound possesses excellent sclerosing activity, providing a new technical solution for the treatment of vascular diseases. Summary of the Invention

[0013] This invention aims to address the technical problems in the current field of arteriosclerosis treatment, such as the limited variety of sclerosing agents, unstable therapeutic effects, and significant side effects. To this end, this invention provides a class of tranexamic acid-fluoroalkanol coupling compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers, as well as methods for preparing and applying the pharmaceutical compositions.

[0014] The tranexamic acid-fluoroalkanol coupling compound of this invention has a structure in which tranexamic acid and fluoroalkanol are linked by an ester bond. This coupling compound can be prepared into a stable foam sclerosing agent with blood replacement function using the Tessari method, for sclerotherapy of hemangiomas, varicose veins, and venous malformations.

[0015] The conjugate contains both tranexamic acid pharmacologically active groups and hydrophobic and oleophobic fluoroalkyl chains in its molecular structure. It can construct a stable drug self-delivery foam system without the need to add any surfactants, foam stabilizers or other pharmaceutical excipients, thus avoiding allergic reactions and other non-pharmacologically active side effects caused by exogenous excipients from the source.

[0016] To achieve the above objectives, the present invention provides the following solution: This invention discloses a tranexamic acid-fluoroalkanol coupling compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the coupling compound is linked by an ester bond (-C(=O)-O-) formed between the carboxyl group of tranexamic acid (trans-4-(aminomethyl)cyclohexanecarboxylic acid) and the hydroxyl group of the fluoroalkanol.

[0017] The tranexamic acid-fluoroalkanol coupling compound has the structure shown in the following general formula:

[0018] Where n is an integer from 1 to 13.

[0019] Furthermore, the tranexamic acid-fluoroalkanol coupling compound includes the following compounds:

[0020] The technical solution of the present invention includes the following preparation steps: reacting tranexamic acid or its reactive derivative with fluoroalkanol in an inert organic solvent, and after the reaction is completed, performing post-treatment and purification to obtain the corresponding conjugate.

[0021] The reactive derivatives of tranexamic acid are those in which the carboxyl group is activated, including its acyl chloride, acid anhydride, or reactive ester forms.

[0022] The acyl chloride is prepared by reacting tranexamic acid with a chlorinating agent, wherein the chlorinating agent is selected from at least one of thionyl chloride and oxalyl chloride; the acid anhydride is prepared by the dehydration reaction of two molecules of tranexamic acid; and the activated ester includes NHS ester (N-hydroxysuccinimide ester) and phenolic active ester.

[0023] The inert organic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, ethyl acetate, acetone, toluene, benzene, pyridine, 2,6-dimethylpyridine, or a mixture thereof.

[0024] The reaction temperature is from -20°C to the reflux temperature of the solvent, preferably 0°C to 50°C. The post-processing steps include washing with water, washing with perfluorinated carbon solvent, extraction, drying, and concentration; the purification steps can be selected according to the properties and purity requirements of the target analyte, including recrystallization, column chromatography (such as silica gel column chromatography, ion exchange column chromatography, affinity chromatography, etc.), preparative high-performance liquid chromatography, as well as extraction, distillation (including vacuum distillation and steam distillation), dialysis, ultrafiltration, etc., or a combination of multiple technologies to achieve efficient purification.

[0025] The present invention reacts the obtained free base form of the conjugate with a pharmaceutically acceptable acid to form the corresponding salt form.

[0026] The pharmaceutically acceptable acid is selected from any one of lactic acid, malic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, benzenesulfonic acid, and acetic acid.

[0027] The present invention also provides a pharmaceutical composition comprising the tranexamic acid-fluoroalkanol conjugate or a pharmaceutically acceptable salt thereof, a solvent and a pharmaceutically acceptable excipient.

[0028] Optionally, the solvent includes one or more of the following: phosphate buffer solution, sterile water, physiological saline, dimethyl sulfoxide, propylene glycol, polyethylene glycol, glycerol, and vegetable oil.

[0029] The excipients include one or more of isotonic adjusters, pH buffers, antioxidants, local anesthetics, and foam stabilizers.

[0030] The pharmaceutical composition can be directly prepared as a foam curing agent. The tranexamic acid-fluoroalkanol coupling agent foam curing agent is prepared by the Tessari method. The specific method is as follows: the coupling agent is dissolved in a solvent, two disposable syringes containing the dissolved coupling agent solution and air are connected through a medical three-way valve, and the syringe pistons are repeatedly pushed and pulled to fully mix the solution and gas to obtain a uniform and stable foam.

[0031] The pharmaceutical composition can also be prepared as a lyophilized injection. Specifically: when used, the lyophilized foam hardener is dissolved in sterile water for injection or a specific solvent, and then prepared into a foam dosage form for administration using the Tessari method.

[0032] Furthermore, the tranexamic acid-fluoroalkanol coupling compound has a mass concentration of 0.1 wt% to 10 wt% in the pharmaceutical composition, preferably 0.2 wt% to 5 wt%.

[0033] The solvent is one or a mixture of two or more of the following: sterile water for injection, phosphate buffered saline, physiological saline, glycerol solution, polyethylene glycol solution, or 1,2-propanediol solution. The mass-volume concentration (w / v) of glycerol or 1,2-propanediol is 0.1% to 55%.

[0034] The use of the tranexamic acid-fluoroalkanol coupling compound or its composition or its pharmaceutically acceptable salt, solvate or stereoisomer as an active ingredient in the preparation of a hardener.

[0035] Furthermore, the sclerosing agent is used to treat vascular diseases, hemangiomas, varicose veins, or vascular malformations.

[0036] Compared with the prior art, the beneficial effects of the present invention include: ① Excellent foam stability: The coupling compound of the present invention contains both tranexamic acid pharmacologically active groups and hydrophobic and oleophobic fluoroalkyl chains in its molecular structure. Without the need for additional surfactants or foam stabilizers, a stable and uniform drug self-delivery foam system can be formed by the Tessari method, avoiding allergic reactions and other side effects caused by exogenous excipients.

[0037] ②Innovative breakthrough: This type of tranexamic acid-fluoroalkanol coupling compound has not been reported in existing literature, filling the technological gap of this type of compound as a foam curing agent and providing a brand-new option for the treatment of vascular diseases.

[0038] ③ Significant therapeutic effect: The foam sclerosing agent of this invention can effectively damage vascular endothelial cells, promote thrombus formation, and protect thrombi by utilizing the antifibrinolytic effect of tranexamic acid, inducing complete and lasting fibrotic closure of diseased blood vessels, resulting in a high success rate of treatment and reducing the risk of recurrence.

[0039] ④ Good safety: Compared with traditional surfactant-based sclerosing agents, the compounds of this invention cause milder local inflammatory reactions and lower tissue toxicity, and have good clinical safety. Attached Figure Description

[0040] Figure 1 These are the 1H NMR and mass spectra of TA-FA3 hydrochloride.

[0041] Figure 2 These are the 1H NMR and mass spectra of TA-FA4 hydrochloride.

[0042] Figure 3 These are the 1H NMR and mass spectra of TA-FA5 hydrochloride.

[0043] Figure 4 These are the 1H NMR and mass spectra of TA-FA6 hydrochloride.

[0044] Figure 5 These are the 1H NMR and mass spectra of TA-FA7 hydrochloride.

[0045] Figure 6 These are the results of the determination of the critical micelle concentration of tranexamic acid-fluoroalkanol coupling hydrochloride, (a) TA-FA3 hydrochloride, (b) TA-FA4 hydrochloride, (c) TA-FA5 hydrochloride, (d) TA-FA6 hydrochloride, (e) TA-FA7 hydrochloride.

[0046] Figure 7 It is the π-A isotherm of tranexamic acid-fluoroalkanol coupling hydrochloride.

[0047] Figure 8 It is the curve of the static elasticity of the monolayer of tranexamic acid-fluoroalkanol coupling hydrochloride as a function of surface pressure.

[0048] Figure 9 These are optical micrographs of tranexamic acid-fluoroalkanol coupling hydrochloride foams at different concentrations.

[0049] Figure 10 This is a curve showing the change in particle size of tranexamic acid-fluoroalkanol coupling hydrochloride foam formulation as a function of concentration.

[0050] Figure 11 These are the half-life curves of tranexamic acid-fluoroalkanol coupling hydrochloride foam formulations as a function of concentration: (a) TA-FA5 hydrochloride, (b) TA-FA6 hydrochloride, and (c) TA-FA7 hydrochloride.

[0051] Figure 12 These are the experimental results of Annexin V-FITC / PI staining to evaluate the cell membrane damage effect of tranexamic acid-fluoroalkanol conjugate hydrochloride.

[0052] Figure 13 These are observation images of rat tails at different time points in the NS control group and the rat tail treated with TA-FA6 hydrochloride foam sclerosing agent. (a) General translucent morphology of the rat tail, and (b) pseudo-color image of laser speckle blood flow imaging corresponding to the rat tail.

[0053] Figure 14 This is the result of HE staining after injection of foam sclerosing agent into the rat tail vein.

[0054] Figure 15 The results are HE staining of mouse organs at the treatment endpoint. Detailed Implementation

[0055] Unless otherwise stated, all technical and scientific terms have the meanings conventionally understood by one of ordinary skill in the art to which this invention pertains. In the embodiments, experimental methods not specified are conventional methods, and materials and reagents not specified in origin are commercially available; the purchase method does not affect the achievement of the technical effect. All components in the embodiments of this invention are expressed as a percentage by mass.

[0056] It should be understood that the terms "comprising," "including," "having," and "containing" used in this article are all open-ended terms, meaning that they include but are not limited to the listed elements. The term "or" is an inclusive statement, which is valid if any of the following conditions are met: A exists but B does not exist; A does not exist but B exists; or A and B exist simultaneously.

[0057] Certain parts of this document use terms such as "a," "an," "an," and "the," or similar terms to describe the components and technical features of the present invention. Such descriptions are for convenience only and to provide a general meaning for the technical features of the present invention. Therefore, unless otherwise specified, such descriptions should be understood to include one or at least one, and the singular also includes the plural.

[0058] The following definitions apply throughout the text: Hydroxyl group: refers to the -OH group.

[0059] Pharmaceutically acceptable salts: These are salts that are not highly toxic to the skin and can be prepared from organic bases, inorganic bases, organic acids, or inorganic acids. They include single salts or mixed salts.

[0060] Example 1 A method for preparing a tranexamic acid-fluoroalkyl alcohol coupling compound, the specific steps of which are as follows: First, tranexamic acid (100 g, 0.64 mol) was added to a 1000 mL three-necked flask, along with 500 mL of dichloromethane as a solvent. The reaction system was cooled in an ice bath for 30 min. Then, thionyl chloride (55.4 mL, 0.76 mol) was slowly added with stirring. After the addition was complete, the temperature was lowered to room temperature, and the reaction was continued for 12 h. The solvent was removed by rotary evaporation under reduced pressure to obtain tranexamic acid acyl chloride solid.

[0061] 8.757 g (0.05 mol) of tranexamic acid chloride and 125 mL of dichloromethane (DCM) were added to a 250 mL flask. Under low temperature and low-speed magnetic stirring, 1H,1H-pentafluoro-1-propanol (CAS: 422-05-9), 1H,1H-heptafluoro-1-butanol (CAS: 375-01-9), 1H,1H-nonafluoro-1-pentanol (CAS: 355-28-2), 1H,1H-undecanofluoro-1-hexanol (CAS: 423-46-1), and 1H,1H-tridecanofluoro-1-heptanol (CAS: 375-82-6) were slowly added dropwise. After the addition was complete, the mixture was placed at 25 °C and reacted for 18 h. After the reaction was complete, the dichloromethane was removed by vacuum distillation. Perfluorohexane was added to the remaining mixture, and the mixture was washed repeatedly in small amounts. Excess fluoroalkanols were removed by vacuum filtration to obtain the crude product. Add an appropriate amount of pure water to the crude product and dissolve it by sonication. Let it stand at 4°C until the product precipitates, then filter it. Dry it under vacuum to obtain tranexamic acid-fluoroalkanol coupling compounds TA-FA3 hydrochloride, TA-FA4 hydrochloride, TA-FA5 hydrochloride, TA-FA6 hydrochloride, and TA-FA7 hydrochloride, respectively.

[0062] The TA-FA3 hydrochloride, TA-FA4 hydrochloride, TA-FA5 hydrochloride, TA-FA6 hydrochloride, and TA-FA7 hydrochloride were detected by 1H NMR and mass spectrometry, respectively, and the results are shown below.

[0063] TA-FA3 hydrochloride: 1 H NMR (400 MHz, DMSO- d 6) δ 8.09 (s, 3H), 4.82 (td, J =13.7, 1.2 Hz, 2H), 2.62 (d, J = 6.9 Hz, 2H), 2.40 (tt, J = 12.1, 3.5 Hz, 1H), 1.94 (dd, J = 13.3, 2.9 Hz, 2H), 1.83 (dd, J = 13.1, 2.8 Hz, 2H), 1.56 (tdd, J =15.3, 6.9, 3.4 Hz, 1H), 1.31 (qd, J = 13.1, 3.4 Hz, 2H), 1.01 (qd, J = 13.1,3.5 Hz, 2H). MS(ESI)m / z: [M+H] + calcd for C 11 H 16F5NO2289.24, found 290.1. The spectrum is as follows. Figure 1 As shown. White powder, yield: 65.6%.

[0064] TA-FA4 hydrochloride: 1 H NMR (400 MHz, DMSO- d 6) δ 8.11 (s, 3H), 4.85 (t, J =14.2 Hz, 2H), 2.62 (d, J = 7.0 Hz, 2H), 2.40 (tt, J = 12.1, 3.6 Hz, 1H), 1.94(dd, J = 13.9, 3.6 Hz, 2H), 1.83 (dd, J = 13.9, 3.4 Hz, 2H), 1.57 (tdd, J =15.4, 7.0, 3.5 Hz, 1H), 1.31 (qd, J = 13.1, 3.3 Hz, 2H), 1.01 (qd, J = 13.1,3.4 Hz, 2H). MS (ESI) m / z: [M+H] + calcd for C 12 H 16 F7NO2339.25, found 340.1. Spectrum as follows. Figure 2 As shown. White powder, yield: 68.6%.

[0065] TA-FA5 hydrochloride: 1 H NMR (600 MHz, DMSO- d 6) δ 8.07 (s, 3H), 4.87 (t, J =14.3 Hz, 2H), 2.62 (d, J = 7.0 Hz, 2H), 2.40 (tt, J = 12.2, 3.5 Hz, 1H), 1.94(dd, J = 14.0, 3.5 Hz, 2H), 1.83 (dd, J = 13.9, 3.5 Hz, 2H), 1.56 (tdd, J =15.3, 7.0, 3.5 Hz, 1H), 1.31 (qd, J = 13.2, 3.5 Hz, 2H), 1.00 (qd, J = 13.2,3.5 Hz, 2H). MS (ESI) m / z: [M+H]+ calcd for C 13 H 16 F9NO2389.26, found 390.1. The spectrum is as follows. Figure 3 As shown. White powder, yield: 78.3%.

[0066] TA-FA6 hydrochloride: 1 H NMR (600 MHz, DMSO- d 6) δ 8.04 (s, 3H), 4.87 (t, J =14.3 Hz, 2H), 2.62 (d, J = 7.0 Hz, 2H), 2.40 (tt, J = 12.2, 3.6 Hz, 1H), 1.94(dd, J = 14.0, 3.5 Hz, 2H), 1.82 (dd, J = 13.5, 3.0 Hz, 2H), 1.55 (tdd, J =15.2, 6.9, 3.5 Hz, 1H), 1.31 (qd, J = 13.2, 3.5 Hz, 2H), 1.00 (qd, J = 13.2,3.5 Hz, 2H). MS (ESI) m / z: [M+H] + calcd for C 14 H 16 F 11 NO2439.10, found 439.9. Spectrum as follows. Figure 4 As shown. White powder, yield: 71.9%.

[0067] TA-FA7 hydrochloride: 1 H NMR (600 MHz, DMSO- d6) δ 8.05 (s, 3H), 4.87 (t, J =14.3 Hz, 2H), 2.62 (d, J = 5.5 Hz, 2H), 2.40 (tt, J = 12.1, 3.6 Hz, 1H), 1.93(dd, J = 14.0, 3.5 Hz, 2H), 1.82 (dd, J = 13.6, 3.0 Hz, 2H), 1.55 (tdd, J =15.3, 7.0, 3.5 Hz, 1H), 1.31 (qd, J = 13.2, 3.5 Hz, 2H), 1.00 (qd, J = 13.2,3.5 Hz, 2H). MS (ESI) m / z: [M+H] + calcd for C 15 H 16 F 13 NO2489.10, found 490.1. Spectrum as follows. Figure 5 As shown. White powder, yield: 77.9%.

[0068] Example 2 Determination of critical micelle concentration of tranexamic acid-fluoroalkanol coupling compound hydrochloride: The surface tension (γ) of the aqueous solution of the test compound was measured using a rotating drop interfacial tension meter, and its critical micelle concentration (CMC) was determined based on the surface tension-concentration logarithmic curve. The specific steps are as follows: Using TA-FA3 hydrochloride, TA-FA4 hydrochloride, TA-FA5 hydrochloride, TA-FA6 hydrochloride, and TA-FA7 hydrochloride as representative examples, a series of aqueous solutions with concentration gradients of the compounds were prepared. At 25°C, 950 µL of the test solution was added to a dedicated quartz sample tube, which was immediately capped and sealed. The sample tube was placed at the rotation axis of the instrument, and the rotation speed was adjusted until the droplet was stretched into a stable cylindrical shape under centrifugal force. The droplet profile image was acquired in real time using a CCD optical imaging system. The droplet length (L) and diameter (D) were fitted, the equivalent radius (r) was calculated, and the surface tension value was calculated using the Vonnegut equation.

[0069] Each group was measured in triplicate, and the arithmetic mean was taken as the surface tension at that concentration. A γ-lg c curve was plotted with surface tension (γ, in mN / m) as the ordinate and the logarithm of surfactant concentration (lg c) as the abscissa. The critical micelle concentration was determined using piecewise linear regression: least squares linear fitting was performed on the sharply decreasing segment of the curve (monomer adsorption region) and the plateau region (micelle formation region), respectively. The concentration corresponding to the intersection of the two fitted lines was the critical micelle concentration of the compound. Relevant measurement data are shown in Table 1 and... Figure 6 As shown.

[0070] Table 1 Critical micelle concentration results

[0071] The measurement results are shown in Table 1 and Figure 6 As shown, the CMC of the TA-FAn hydrochloride series decreases with the elongation of the fluorocarbon chain. This indicates that as the fluorocarbon chain lengthens, the hydrophobic volume of the molecules increases, the intermolecular Fluorophobic effect enhances intermolecular cohesion, and can effectively reduce surface tension.

[0072] Example 3 Monolayer properties of tranexamic acid-fluoroalkanol coupling hydrochloride: The Langmuir-Blodgett membrane analyzer was used for monomolecular membrane assembly and interfacial performance characterization. This instrument, equipped with a Wilhelmy surface tension sensor and a constant-temperature bath, simultaneously records the surface tension values ​​(γ0) of the ultrapure water subphase and the surface tension values ​​(γ) of the monomolecular membrane, and calculates the surface pressure (π) in real time using the formula π = γ0 - γ. The average molecular area (A) of a single molecule is calculated as the ratio of the effective area of ​​the bath to the total number of spread molecules.

[0073] Representative examples include TA-FA4 hydrochloride, TA-FA5 hydrochloride, and TA-FA6 hydrochloride. These molecules form a typical amphiphilic structure through hydrophobic fluorinated alkyl chains and hydrophilic amino groups, which can form stable monolayers at the gas-liquid interface. They were used to investigate the effect of fluorinated alkyl chain length on interfacial adsorption characteristics and membrane phase behavior.

[0074] Weigh appropriate amounts of TA-FA4 hydrochloride, TA-FA5 hydrochloride, and TA-FA6 hydrochloride respectively, dissolve them in a chloroform and methanol mixture (volume ratio 4:1), and prepare a stock solution with a concentration of 0.01 mol / L. Dilute to 0.001 mol / L before use. Before the experiment, thoroughly clean the Langmuir tank and moving barriers, rinsing with anhydrous ethanol and then ultrapure water (at least three times each). Pour Milli-Q ultrapure water into the tank as a subphase, with the liquid level approximately 5 mm from the tank rim. Monitor baseline stability using a tension sensor; when the surface pressure fluctuation is less than 0.2 mN / m and remains drift-free for 3 minutes, the experimental requirements are considered met. Use a microsyringe to uniformly drop the sample solution onto the gas-liquid interface. After the organic solvent has completely evaporated (approximately 10-15 minutes), initiate a symmetrical compression program, with both barriers moving synchronously inward at a speed of 1.0 mm / s, while continuously acquiring dynamic changes in surface pressure versus molecular area (π-A). The compression endpoint was set at 10% of the initial molecular area. Each sample was measured independently and repeatedly three times. The average of the three measurements was used to plot the π-A isotherm to analyze the adsorption characteristics, phase transition behavior, and film stability of TA-FAn hydrochloride with different chain lengths in the monolayer, thereby elucidating the structure-activity relationship between molecular structure and interfacial properties.

[0075] Relevant measurement data such as Figure 7 and Figure 8 As shown. Figure 7 Test results show that the limiting molecular area A0 (i.e. the molecular area occupied when the surface pressure begins to rise) of the TA-FAn hydrochloride series increases monotonically with the increase of fluoroalkyl chain length, indicating that the intermolecular hydrophobicity, intramolecular fluoride-repellent effect and the deformation resistance of the molecular film are enhanced with the extension of carbon chain. Figure 8 This indicates that no other phase transitions or monolayer collapse were observed within the instrument's measurement range, demonstrating good compressibility.

[0076] Example 4 Preparation and characterization of tranexamic acid-fluoroalkanol coupling compound hydrochloride foam hardener: Preparation method of foam curing agent: Taking TA-FA3 hydrochloride, TA-FA4 hydrochloride, TA-FA5 hydrochloride, TA-FA6 hydrochloride and TA-FA7 hydrochloride as representative examples, a series of concentration gradient solutions of 0.25%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5% and 3.0% (w / v) of the compounds were prepared using physiological saline as solvent. Two 1 mL disposable sterile syringes were used, one to draw the curing agent solution and the other to draw air, and then connected to a three-way valve. The three-way valve was opened to connect the two syringes, and the external passage was closed. One hand held syringe A, and the other hand quickly pushed the piston of syringe B, causing the gas-liquid mixture to flow at high speed through the three-way valve; then the piston was pushed in the opposite direction, causing the mixture to flow back to the other syringe. This push-pull method was repeated 40 times, using high-speed turbulence to shear and disperse the gas in the liquid curing agent, forming a uniform and stable foam curing agent.

[0077] Thirty seconds after foam formation, its microstructure was observed using an optical microscope, and photographs were taken. ImageJ software was used to count and analyze the size of the bubbles within the field of view. After foam formation, all foam was injected into a syringe and detached from the three-way valve. The syringe was placed vertically and a timer was started. The bottom foam was continuously observed. The half-life of the foam was defined as the volume of liquid formed at the bottom reaching half the initial solvent volume.

[0078] Relevant measurement data such as Figure 9 The test results show that TA-FA3 and TA-FA4 hydrochlorides cannot form stable foam formulations, while TA-FA5, TA-FA6, and TA-FA7 hydrochlorides can all produce uniform and stable foams. The overall foam particle size of TA-FA5 hydrochloride is larger than that of TA-FA6 and TA-FA7 hydrochlorides. The TA-FA6 hydrochloride system exhibits high foaming performance and wide-window stability at low concentrations, showing good preparation results. In contrast, the TA-FA7 hydrochloride system exhibits unstable fluctuations and poor stability.

[0079] ImageJ image analysis software was used to count and analyze the size of bubbles within the field of view. The test results are as follows: Figure 10As shown, the foam particle size of the three compounds differs significantly with concentration, reflecting the profound influence of carbon chain length on the foam stabilization mechanism. The overall foam particle size of TA-FA5 hydrochloride is larger than that of TA-FA6 and TA-FA7 hydrochlorides, and the particle size increases significantly at high concentrations. This indicates that the shorter carbon chain (C5) has weaker hydrophobicity and cannot provide sufficient steric hindrance at high concentrations, leading to increased bubble coalescence and decreased system stability. In contrast, the TA-FA6 system exhibits an ideal trend of continuous refinement. As the concentration increases from 0.25% to 1.5%, the particle size fluctuates slightly. The average bubble particle size decreases monotonically from 1.5% to 3.0%, dropping to approximately 13.5 μm at a concentration of 2.0%. At this point, the slope of the curve becomes significantly flatter, indicating that the adsorption of surfactant molecules at the gas-liquid interface has become saturated. Further increases in concentration have a weaker marginal effect on particle size refinement, confirming that the longer carbon chain provides stronger steric hindrance and interfacial adsorption capacity, effectively inhibiting Ostwald ripening and bubble coalescence. The TA-FA7 system exhibits unstable fluctuations, with a local peak of about 16.5 μm at a concentration of 0.5%, followed by a minimum value of about 13.0 μm at 1.5%, but rising back to about 15.5 μm when the concentration exceeds 2.0%. It is speculated that the excessively long carbon chains lead to excessively strong hydrophobicity or excessive viscosity, which easily forms network aggregates at high concentrations, hindering the uniform dispersion of bubbles.

[0080] like Figure 11 As shown, when the mass concentration reaches 1%, the half-life of all three foam groups is higher than 200s, indicating stable foam characteristics. Among them, the TA-FA6 hydrochloride foam formulation can maintain its properties for a longer time at lower concentrations, demonstrating good application potential.

[0081] Example 5 Annexin V-FITC / PI staining was used to evaluate the cell membrane damage effect of tranexamic acid-fluoroalkanol conjugate hydrochloride. Based on the phosphatidylserine eversion detection principle, Annexin V-FITC combined with PI double labeling was used to distinguish normal, early apoptotic, and late apoptotic / necrotic cells. Using TA-FA6 hydrochloride as a representative example, the effects of tranexamic acid-fluoroalkanol conjugate on the physiological state of human umbilical vein endothelial cells (HUVECs) cell membranes were evaluated. HUVECs were analyzed at a concentration of 1×10⁻⁶. 5Cells were seeded per well in 12-well plates and cultured at 37°C with 5% CO2 for 12 h. The original culture medium was discarded, and 1 mL of basal medium containing TA-FA6 hydrochloride was added to each well, with final concentrations of 10, 20, 30, 40, and 50 μg / mL, respectively. The cells were incubated for 10 min. A negative control containing only an equal volume of basal medium was also included. Each group had three replicates. After treatment, the culture medium was aspirated, and the cells were gently washed twice with pre-cooled PBS (pH 7.4). 500 µL of binding buffer, 10 µL of Annexin V-FITC, and 20 µL of PI were added to each well sequentially, and the cells were incubated at room temperature in the dark for 20 min. After staining, the samples were fixed with 4% paraformaldehyde for 30 min, washed twice with PBS, mounted with an anti-fluorescence quencher, and imaged using a laser confocal microscope.

[0082] Fluorescence imaging results as follows Figure 12 As shown, a significant Annexin V-FITC fluorescence signal was observed in the TA-FA6 treatment group at 30 μg / mL, indicating that the phosphatidylserine residues in the cell membrane were significantly everted, and that TA-FA6 hydrochloride has a highly efficient cell membrane damage ability.

[0083] Example 6 Evaluation of the in vivo therapeutic effect of tranexamic acid-fluoroalkanol coupling compound hydrochloride foam sclerotherapy on vascular sclerosis: Using TA-FA6 hydrochloride foam as a representative example, the tail vein of mice was used as a slow-velocity vascular model to investigate the efficacy of sclerotherapy. Male Kunming mice aged 3-5 weeks and weighing 25-30 g were randomly divided into two groups. Each group was injected into the tail vein with 20 μL of normal saline (NS) solution and 2% TA-FA6 hydrochloride sclerotherapy foam, respectively. Before administration and at 6 h, 2 d, 5 d, 9 d, and 14 d after administration, the tail vein morphology and blood perfusion changes were dynamically monitored using laser speckle imaging. Simultaneously, three mice from each group were randomly sacrificed at each observation time point. The remaining six mice were sacrificed 14 d after administration to obtain the tail of the sclerotherapy area. The tails were fixed in 4% paraformaldehyde, decalcified, embedded in paraffin, sectioned, and stained with hematoxylin-eosin (HE) to observe the physiological changes of the vascular tissue in the sclerotherapy area.

[0084] Relevant measurement data such as Figure 13As shown, no significant changes were observed in the tail vein of the rats in the NS group after injection, and the appearance morphology remained unchanged during the treatment period. In the TA-FA6 hydrochloride foam sclerotherapy group, 6 hours after injection, mild congestion and swelling were observed around the injected vessel, with slight narrowing of the vessel (blue hypoperfusion, indicating dense thrombus formation); 2 days after administration, the injected segment gradually became red and swollen, the vessel outline became blurred, and some parts appeared dark (mostly blue hypoperfusion, with a small amount of yellow signal recovery, indicating minor thrombus formation, and swelling obscuring the vessel morphology); 5 days after administration, the injected vessel became even darker, and the swelling did not decrease (distributed yellow-red patchy high perfusion signal, indicating thrombus organization with inflammatory cell infiltration and angiogenesis); 9 days after administration, the redness and swelling gradually subsided, and the vessels became narrower in the transillumination image (blue-green hypoperfusion, indicating the thrombus entered the fibrotic remodeling stage); 14 days after administration, the morphology of the injected segment returned to normal and there was no vascular visualization (complete blue hypoperfusion, no blood flow signal), indicating permanent occlusion of the lumen.

[0085] HE staining results of blood vessels in the treatment area are as follows Figure 14 The results showed that in the NS blank control group, the vascular endothelium remained intact and the lumen was patent from 6 h to 14 days, with no thrombus formation or significant inflammatory cell infiltration. In the TA-FA6 hydrochloride foam sclerotherapy group, endothelial peeling occurred 6 h after administration, with the lumen filled with a large amount of dense thrombus, accompanied by significant erythrocyte extravasation and acute inflammatory cell infiltration. On day 2, a large amount of mixed erythrocyte / fibrin thrombus was present in the lumen, with full-thickness inflammatory cell infiltration in the vessel wall. On day 5, the lumen was completely filled with dense fibrous connective tissue, and the normal vascular structure disappeared. On day 14, the vessel cross-section showed a solid fibrotic cord-like structure, the lumen completely disappeared, and collagen fibers were densely arranged. In conclusion, TA-FA6 hydrochloride foam sclerotherapy can induce rapid and dense thrombus formation in blood vessels, which gradually organizes and fibroses, ultimately achieving permanent luminal occlusion.

[0086] Example 7 Preliminary in vivo safety evaluation of tranexamic acid-fluoroalkanol coupling compound hydrochloride foam hardener: After the in vivo treatment cycle in Example 6 was completed, the mice in each group were euthanized, and the major organs (heart, liver, spleen, lung and kidney) were collected, embedded in paraffin, prepared into sections and subjected to HE staining analysis to evaluate the effect of tranexamic acid-fluoroalkanol coupling hydrochloride foam hardener on the physiological structure of the major organ tissues.

[0087] Histological observation results as follows Figure 15 As shown, all major organs in the TA-FA6 hydrochloride foam sclerotherapy group and the control group exhibited intact structures, with no obvious pathological changes, inflammatory cell infiltration, tissue necrosis, or thrombosis. The results indicate that this tranexamic acid-fluoroalkanol conjugate foam sclerotherapy did not cause significant systemic toxicity or induce ectopic thromboembolism under the treatment regimen provided in Example 6, demonstrating high treatment safety.

Claims

1. A tranexamic acid-fluoroalkanol coupling compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that, The general structure of the coupling is shown below: Where n is an integer from 1 to 13.

2. The tranexamic acid-fluoroalkanol coupling compound according to claim 1, or its pharmaceutically acceptable salt or stereoisomer thereof, is characterized in that, The tranexamic acid-fluoroalkanol coupling compounds include the following compounds: 。 3. The tranexamic acid-fluoroalkanol coupling compound according to claim 1, or its pharmaceutically acceptable salt or stereoisomer, is characterized in that, The tranexamic acid-fluoroalkanol coupling compound reacts with a pharmaceutically acceptable acid to form the corresponding salt form, wherein the pharmaceutically acceptable acid is selected from any one of lactic acid, malic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, benzenesulfonic acid, and acetic acid.

4. A method for preparing a tranexamic acid-fluoroalkanol coupling compound according to claim 1 or 2, characterized in that, Tranexamic acid or its reactive derivatives are reacted with fluoroalkanols in an organic solvent. After the reaction is completed, post-treatment and purification are performed to obtain tranexamic acid-fluoroalkanol conjugates.

5. The method for preparing the tranexamic acid-fluoroalkanol coupling compound according to claim 4, characterized in that, The reactive derivatives of tranexamic acid include acyl chlorides, acid anhydrides, or active esters of tranexamic acid; wherein, the acyl chloride is prepared by reacting tranexamic acid with a chlorinating agent, the chlorinating agent being selected from at least one of thionyl chloride and oxalyl chloride; the acid anhydride is prepared by the dehydration reaction of two molecules of tranexamic acid; and the active ester includes N-hydroxysuccinimide ester and phenolic active esters.

6. The method for preparing the tranexamic acid-fluoroalkanol coupling compound according to claim 4, characterized in that, The organic solvent is an inert organic solvent selected from at least one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, ethyl acetate, acetone, toluene, benzene, pyridine, 2,6-dimethylpyridine, or mixed solvents thereof; the reaction temperature is from -20°C to the reflux temperature of the inert organic solvent; the post-treatment steps include washing with water, washing with perfluorinated carbon solvent, extraction, drying, and concentration; the purification steps include recrystallization, column chromatography, preparative high-performance liquid chromatography, as well as extraction, distillation, dialysis, ultrafiltration, or a combination of multiple techniques.

7. A pharmaceutical composition, characterized in that, It comprises the tranexamic acid-fluoroalkanol coupling compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

8. A tranexamic acid-fluoroalkanol coupling foam curing agent, characterized in that, The pharmaceutical composition according to claim 7 is used to prepare the tranexamic acid-fluoroalkanol conjugate. The tranexamic acid-fluoroalkanol conjugate solution and air are dissolved in a solvent. Two disposable syringes containing the dissolved tranexamic acid-fluoroalkanol conjugate solution and air are connected via a medical three-way valve. The syringe plungers are repeatedly pushed and pulled to fully mix the solution and gas, obtaining a uniform and stable foam. The tranexamic acid-fluoroalkanol conjugate has a mass concentration of 0.1 wt% to 10 wt% in the pharmaceutical composition. The solvent is one or a mixture of two or more of the following: sterile water for injection, phosphate buffer solution, physiological saline, glycerol solution, polyethylene glycol solution, or 1,2-propanediol solution.

9. A lyophilized injection of the tranexamic acid-fluoroalkanol coupling foam curing agent according to claim 8, characterized in that, When used, the lyophilized foam hardener is dissolved in a solvent and then prepared into a foam dosage form for administration using the Tessari method; wherein, the solvent is one or a mixture of two or more of the following: sterile water for injection, phosphate buffer solution, physiological saline, glycerol solution, polyethylene glycol solution, or 1,2-propanediol solution.

10. The use of the lyophilized injection of the tranexamic acid-fluoroalkanol coupling compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition according to claim 7, or the tranexamic acid-fluoroalkanol coupling compound foam curing agent according to claim 8, or the tranexamic acid-fluoroalkanol coupling compound foam curing agent according to claim 9, in the preparation of a curing agent; wherein, The sclerosing agent is used to treat vascular diseases, hemangiomas, varicose veins, or vascular malformations.

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