CN118598820A - A diphenyltriazine compound and its preparation method and application - Google Patents

Abstract

The present invention belongs to the technical field of chemical medicines, and specifically relates to a diphenyltriazine compound, a preparation method thereof and an application thereof. The diphenyltriazine compound does not have a PGI2 skeleton, has strong selectivity and affinity for PGI2 receptors, and has good target selectivity compared with PGI2 analogs. Experimental verification shows that the compound has better in vivo efficacy than selexipag, and its toxicity is far less than selexipag. Therefore, the compound can be used as a pulmonary arterial hypertension treatment drug with greater clinical value and development prospects.

Description

A diphenyltriazine compound and its preparation method and application

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of Chinese patent application CN202410169645.1, filed on February 6, 2024, and cites the full text of the above-mentioned Chinese patent application.

Technical Field

The invention belongs to the technical field of chemical medicines, and specifically relates to a diphenyltriazine compound and a preparation method and application thereof.

Background Art

Pulmonary arterial hypertension (PAH) is a disease characterized by vasospasm, intimal hyperplasia and remodeling of pulmonary arterioles. Vascular hyperplasia and remodeling of pulmonary arterioles lead to a progressive increase in pulmonary vascular resistance, eventually causing right heart failure and death. PAH has been ranked the third most common cardiovascular disease, second only to hypertension and coronary heart disease in prevalence. It has become a public health care issue that seriously threatens human physical and mental health, and has been included in the world's major chronic disease detection range by the World Health Organization.

PGI2 is a substance produced in vivo from arachidonic acid via prostaglandin H2 (PGH2). PGI2 deficiency can cause pulmonary hypertension. At present, the PGI2 receptor agonists that have been marketed include epoprostenol, beraprost, iloprost, etc., all of which are PGI2 analogs. However, due to the very short biological half-life of PGI2 and its poor selectivity for the target, it is difficult to separate the intended effect from other effects, so adverse reactions are prone to occur. Selexipag is currently the only PGI2 agonist that does not have a PGI2 skeleton but has good selectivity for PGI2 receptors and definite efficacy. It has been approved for marketing in many countries for the treatment of adult pulmonary hypertension. Its specific therapeutic effect is stronger and longer-acting than other drugs with similar mechanisms, but its high price undoubtedly adds a huge economic burden to patients with pulmonary hypertension who need long-term treatment. In addition, although selexipag has relatively good specificity, it still has obvious adverse reactions, such as headache, facial flushing, nausea, vomiting, etc. For patients who need long-term medication, the cumulative damage caused by the drug to the body will reduce their health level and quality of life to varying degrees.

Summary of the invention

In view of the above problems, the present invention provides a diphenyltriazine compound and a preparation method and application thereof. The compound has good affinity for PGI2 receptors and very low adverse reactions, thus avoiding the shortcomings of current PGI2 analogs and selexipag.

In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

In a first aspect, the present invention provides a diphenyltriazine compound or a pharmaceutically acceptable salt, a stable isotope derivative, an isomer and a mixture thereof, wherein the structural formula is shown in Formula I:

The compound does not have a PGI2 skeleton, has strong selectivity and affinity for PGI2 receptors, and has good target selectivity compared to PGI2 analogs. Experimental verification shows that the compound has better in vivo efficacy than selexipag, and its toxicity is far less than selexipag. Therefore, the compound can be used as a drug for the treatment of pulmonary arterial hypertension with greater clinical value and development prospects.

In a second aspect, the present invention also provides a method for preparing the above-mentioned diphenyltriazine compounds, which specifically comprises the following operations:

The compound shown in formula II, methylsulfonamide, 4-dimethylaminopyridine (DMAP) and carbodiimide (EDCI) are mixed in dichloromethane, heated to 35-45°C for reaction for 2-3h, then cooled to 20-40°C, the obtained reaction solution is washed with purified water, then washed with hydrochloric acid solution, and then dehydrated to remove the solvent to obtain the product.

In conjunction with the second aspect, the equivalent ratio of the methylsulfonamide to the compound of formula II is ≥ 1. Preferably, the equivalent ratio of the methylsulfonamide to the compound of formula II is ≥ 1.3.

In conjunction with the second aspect, the equivalent ratio of the 4-dimethylaminopyridine to the compound of formula II is ≥ 1. Preferably, the equivalent ratio of the 4-dimethylaminopyridine to the compound of formula II is ≥ 1.1.

In conjunction with the second aspect, the ratio of the equivalent of the carbodiimide to the equivalent of the compound of formula II is ≥ 1. Preferably, the ratio of the equivalent of the carbodiimide to the equivalent of the compound of formula II is greater than ≥ 1.1.

In conjunction with the second aspect, the amount of dichloromethane used can ensure that all reactants are dissolved therein, and the present invention is not limited to this.

In combination with the second aspect, the concentration of the hydrochloric acid solution is 1.8-2.2M.

In combination with the second aspect, the dehydration can be carried out by drying with anhydrous sodium sulfate. Anhydrous sodium sulfate can also be replaced by other desiccants that can dehydrate the organic phase and have no effect on the reactants.

In conjunction with the second aspect, the compound with the structural formula shown in Formula II can be prepared by the following method, and the specific steps include:

S1, glacial acetic acid, benzil, hydrochloric acid semicarbazide and purified water were mixed, the temperature was raised to 100-110°C and the reaction was kept warm for 2-2.5 hours, then the temperature was lowered to 30-40°C, purified water was added, the reaction was stirred at 20-30°C for 0.5-1 hour, the solid-liquid separation was performed, the obtained solid phase was placed in ethyl acetate, the reaction was refluxed for 2-3 hours, the solid-liquid separation was performed after the temperature was lowered, and the intermediate II-1 was obtained;

S2, mixing phosphorus oxychloride and the intermediate II-1, heating to 80-85° C., stirring to dissolve, keeping warm for 1-1.5 hours, removing the solvent, adding a mixed solvent of toluene and isopropanol to the obtained product, stirring to disperse, and performing solid-liquid separation to obtain the intermediate II-2;

S3, add intermediate II-2 and 4-(isopropylamino)butanol to the reaction flask in sequence, raise the temperature to 140-150°C, keep the temperature for reaction for 12-15h, cool to room temperature, pour the reaction solution into water, add ethyl acetate for extraction, wash the organic phase with saturated sodium chloride aqueous solution and dry, remove the solvent, and purify the obtained product with a silica gel column to obtain intermediate II-3;

S4, mixing the intermediate II-3 with dichloromethane, cooling to 0-10°C, adding Dess-Martin reagent, reacting at 0-10°C for 12-15h, washing the resulting reaction solution with a saturated sodium bicarbonate solution, and then with a saturated sodium chloride aqueous solution, drying the organic phase, removing the solvent, and purifying the resulting product with a silica gel column to obtain an intermediate II-4;

S5, triethyl phosphoacetate and tetrahydrofuran are mixed, the temperature is reduced to 0-10°C, sodium hydride is added to react for 1-1.5h, the intermediate II-4 is added at 0-5°C, the temperature is raised to room temperature and the reaction is carried out for 2-3h, water is added dropwise to the reaction solution to quench the reaction, and then at least 80% of tetrahydrofuran is removed by concentration, ethyl acetate is added to the residue for extraction, the organic phase is washed with a saturated sodium chloride aqueous solution and dried, the solvent is removed, and the obtained product is purified by a silica gel column to obtain intermediate II-5;

S6, mixing the intermediate II-5, anhydrous ethanol and palladium carbon, replacing with hydrogen, reacting at room temperature for 5 to 8 hours, removing the palladium carbon, and removing the solvent from the resulting reaction solution to obtain intermediate II-6;

S7, mixing the intermediate II-6, tetrahydrofuran, sodium hydroxide and water, reflux reaction for 2-4h, concentrating to remove tetrahydrofuran, adding purified water and ethyl acetate, stirring evenly, standing to separate the liquids, retaining the aqueous phase, adding hydrochloric acid to the aqueous phase to adjust the pH to 3-5, adding methyl tert-butyl ether for extraction, drying the organic phase and removing the solvent to obtain a compound with the structural formula shown in Formula II;

Preferably, in step S1 of the preparation method, the ratio of the equivalent of the semicarbazide hydrochloride to the equivalent of the benzil is greater than 1. Preferably, the ratio of the equivalent of the semicarbazide hydrochloride to the equivalent of the benzil is ≥1.4.

Preferably, in step S1 of the preparation method, the volume ratio of the glacial acetic acid to the purified water is 2 to 3:1.

Preferably, in step S1 of the preparation method, the amount of glacial acetic acid and purified water used is sufficient to ensure that all reactants are dissolved therein, and the present invention is not limited thereto.

Preferably, in step S2 of the preparation method, the mass ratio of the phosphorus oxychloride to the intermediate II-1 is ≥6.5.

Preferably, in step S2 of the preparation method, the volume ratio of toluene to isopropanol in the mixed solvent of toluene and isopropanol is 1:2.5-3.5.

Preferably, in step S3 of the preparation method, the equivalent ratio of the 4-(isopropylamino)butanol to the intermediate II-2 is 3 to 5:1.

Preferably, in step S3 of the preparation method, purification is performed using a 200-mesh silica gel column, and the eluent is a dichloromethane-methanol mixture with a volume ratio of 30:1.

Preferably, in step S4 of the preparation method, the equivalent ratio of the Dess-Martin reagent to the intermediate II-3 is 1.5 to 3:1.

Preferably, in step S4 of the preparation method, purification is performed using a 200-mesh silica gel column, and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 2:1.

Preferably, in step S5 of the preparation method, the equivalent ratio of the triethyl phosphoacetate to the intermediate II-4 is 1 to 2:1.

Preferably, in step S5 of the preparation method, the equivalent ratio of the sodium hydride to the intermediate II-4 is 1 to 2:1.

Preferably, in step S5 of the preparation method, purification is performed using a 200-mesh silica gel column, and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 5:1.

Preferably, in step S5 of the preparation method, the mass of the palladium carbon is 5% to 20% of the mass of the intermediate II-5.

In a third aspect, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent, and the above-mentioned diphenyltriazine compound or its pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof as an active ingredient.

In conjunction with the third aspect, the dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form.

Illustratively, the above dosage forms include conventional dosage forms such as tablets, granules, capsules, powders or injections.

In a fourth aspect, the present invention also provides the use of the above-mentioned diphenyltriazine compounds or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing pulmonary hypertension, pulmonary arterial hypertension, chronic thrombotic pulmonary arterial hypertension, Fontan's disease and pulmonary hypertension associated with Fontan's disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis.

The above application is preferably used in the preparation of a drug for treating or preventing pulmonary hypertension, pulmonary arterial hypertension or chronic thrombotic pulmonary arterial hypertension.

In a fifth aspect, the present invention also provides the use of the above-mentioned diphenyltriazine compounds or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating or preventing peripheral circulatory disorders, connective tissue diseases, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases involving organ or tissue fibrosis, respiratory diseases, anti-ulcers, finger ulcers, diabetic gangrene, or diabetic foot ulcers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a ¹ H-NMR spectrum of Example 1 of the present invention;

FIG2 is a ¹³ C-NMR spectrum of Example 1 of the present invention;

Fig. 3 is a HPLC spectrogram in Example 1 of the present invention;

FIG4 is an EC ₅₀ graph of compound A in Example 2 of the present invention for IP, EP1, EP2, EP3, EP4, DP, FP, and TP targets;

FIG5 is a graph showing the EC ₅₀ of Selexipag for IP, EP1, EP2, EP3, EP4, DP, FP, and TP targets in Example 2 of the present invention;

FIG6 shows the effects of Compound A and Selexipag on the proliferation of human pulmonary artery smooth muscle cells in Example 2 of the present invention;

FIG7 shows the effects of Compound A and Selexipag on rat pulmonary artery ring tension in Example 2 of the present invention;

FIG8 shows the effect of intragastric administration of Compound A and Selexipag in Example 2 of the present invention on the survival rate (%) of rats with pulmonary hypertension (Note: survival rate (%) = number of surviving animals in a group/total number of animals in a group × 100%);

FIG. 9 shows the effect of intragastric administration of Compound A and Selexipag on right ventricular pressure (mmHg) in rats with pulmonary hypertension in Example 2 of the present invention. (*** indicates P ≤ 0.001 compared with the model control group);

FIG. 10 shows the effect of intragastric administration of compound A and Selexipag in Example 2 of the present invention on the right heart hypertrophy index (%) in rats with pulmonary hypertension (* indicates P≤0.05 compared with the model control group, *** indicates P≤0.001 compared with the model control group);

FIG. 11 is a comparison of the media thickness percentage (%) of the pulmonary arterioles of each group of animals in Example 2 of the present invention. (*** indicates P ≤ 0.001 compared with the model control group);

Figure 12 is the lung pathology pictures of rats in each group in Example 2 of the present invention, wherein Figure A is the normal control group, lung, HE staining, 200×; Figure B is the model control group, lung, HE staining, 200×; Figure C is the low-dose group of the test sample, lung, HE staining, 200×; Figure D is the medium-dose group of the test sample, lung, HE staining, 200×; Figure E is the high-dose group of the test sample, lung, HE staining, 200×; Figure F is the positive control group, lung, HE staining, 200×.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

the term

In the preparation method of the compound of the present application, "eq" means equivalent, which means equivalent in chemistry. This concept is very critical in stoichiometry and chemical reactions, especially when it comes to the molar ratio of substances. For example, if 0.3 mol (1 eq) of A is used in a reaction, and the amount of B used is 6 times that of A, that is, 6 eq., then the amount of B used is 1.8 mol. This representation method helps to make it more convenient and accurate when calculating the molar ratio of substances in chemical reactions.

In this application document, "eq" and "equivalent" are calculated in molar ratios, and each step can use its own independent equivalent standard to facilitate calculations and tests.

PGI2 receptor agonists are currently commonly used drugs for the treatment of PAH, but they have short biological half-life, poor target selectivity, and are prone to adverse reactions. Selexipag does not have a PGI2 skeleton and has relatively good target selectivity, but there are still certain adverse reactions. An embodiment of the present invention provides a diphenyltriazine compound, the structural formula of which is shown in Formula I:

This compound does not have a PGI2 skeleton and has strong target selectivity. The results of in vivo pharmacodynamic experiments have demonstrated that the compound is more effective than selexipag, and the results of toxicology experiments have demonstrated that the compound is far less toxic than selexipag. It has higher clinical value and broader development prospects in the treatment of pulmonary arterial hypertension.

As defined herein, "isomers" refer to compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

The compounds of the present invention may exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.

The compounds of the present invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof generated by the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl or heterocyclic rings are designated as cis or trans configurations.

"Isotope" includes all isotopes of atoms that occur in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as but not limited to ^2H , ^3H , ^13C , ^14C , ^15N , ^18O , ^17O , ^35S , ^18F and ^36Cl , respectively. Isotope-labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples using suitable isotope-labeled reagents instead of non-isotope-labeled reagents. Such compounds have various potential uses, such as as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to advantageously change biological, pharmacological or pharmacokinetic properties.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In the case where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compounds of the present invention containing acidic groups can exist in salt form and can be used according to the present invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts, exemplified by sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention containing basic groups can exist in salt form and can be used according to the present invention in the form of addition salts thereof with inorganic or organic acids. The example of suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acid well known to persons skilled in the art. If the compound of the present invention contains acidic and basic groups in the molecule simultaneously, the present invention also comprises inner salt or betaine except the salt form mentioned. Each salt can be obtained by conventional methods well known to persons skilled in the art, for example by making these contact with organic or inorganic acid or base in solvent or dispersant or by with other salt anion exchange or cation exchange.

"Pharmaceutical composition" refers to a composition containing one or more compounds described herein or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

The scheme of the present invention is described below through specific embodiments.

Example 1

This embodiment provides a diphenyltriazine compound and its preparation method and structural characterization.

Preparation method:

1. Preparation of the compound shown in Formula II

The intermediate shown in formula II (chemical name: 6-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)hexanoic acid) has a synthesis route as follows:

The specific synthesis method is as follows.

(1) Add glacial acetic acid (2.5 L), benzil (500 g, 1 eq), semicarbazide hydrochloride (889 g, 1.5 eq) and purified water (1 L) to the reaction flask in sequence, stir evenly, heat to 100-105 ° C and keep warm for 2.5 h, then cool to 30-40 ° C, add purified water, stir at 20-30 ° C for 1 h, filter, place the filter cake in ethyl acetate and reflux with stirring for 3 h, cool to room temperature and filter, and vacuum dry the filter cake to obtain 502 g of intermediate II-1 (chemical name: 5,6-diphenyl-1,2,4-triazine-3-ol-methane).

(2) Add phosphorus oxychloride (2L) and intermediate II-1 (500g, 1eq) to the reaction flask in sequence, raise the temperature to 80-85°C, stir to dissolve, and keep warm for 1.5h. After concentrating to remove phosphorus oxychloride, add a mixed solvent of toluene (500mL) and isopropanol (1500mL), stir and disperse at room temperature to obtain a solid, filter, and vacuum dry to obtain 350g of intermediate II-2 (chemical name: 3-chloro-5,6-diphenyl-1,2,4-triazine-methane).

(3) Add intermediate II-2 (100 g, 1 eq) and 4-(isopropylamino)butanol (171.5 g, 3.5 eq) to the reaction flask in sequence, raise the temperature to 140-150°C, keep the temperature for reaction for 14 h, cool to room temperature, pour the reaction solution into water, add ethyl acetate for extraction, wash the organic phase three times with saturated sodium chloride aqueous solution, dry the organic phase over anhydrous sodium sulfate, and concentrate to dryness. The residue is purified by silica gel column (200 mesh silica gel, eluent dichloromethane: methanol = 30:1) to obtain 71 g of intermediate II-3 (chemical name: 4-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)butan-1-ol).

(4) Add intermediate II-3 (70 g, 1 eq) and dichloromethane (700 ml) to the reaction flask, cool to 0-10°C, add Dess-Martin reagent (163.8 g, 2 eq) in batches, and keep at 0-10°C for 14 h. Stop the reaction, wash the reaction solution twice with saturated sodium bicarbonate solution, then wash with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, concentrate to dryness, and purify the residue with silica gel column (200 mesh silica gel, eluent n-hexane: ethyl acetate = 2:1) to obtain 41.3 g of intermediate II-4 (chemical name: 4-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)butyraldehyde).

(5) Add triethyl phosphoacetate (29.8 g, 1.2 eq) and tetrahydrofuran (400 ml) to the reaction flask, cool to 0-10°C, add sodium hydride (4.4 g, 1 eq), stir for 1 h, add intermediate II-4 (40 g, 1 eq) at 0-5°C, warm to room temperature after addition and react for 2.5 h, dropwise add 50 ml of water to the reaction solution to quench the reaction, concentrate to remove most (more than 80%) of tetrahydrofuran, add 400 ml of ethyl acetate to the residue for extraction, wash the organic phase with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate to dryness. The residue is purified by silica gel column (200 mesh silica gel, eluent hexane: ethyl acetate = 5:1) to obtain 21.3 g of intermediate II-5 (chemical name: 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-2-hexenoic acid ethyl ester).

(6) Add 21 g of intermediate II-5, 2.1 g of 10% palladium on carbon, and anhydrous ethanol (210 ml) to the reaction bottle, replace with hydrogen, react at room temperature for 7 hours, filter to remove the palladium on carbon, and concentrate the filtrate to dryness to obtain 20.2 g of intermediate II-6 (chemical name: 6-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)hexanoic acid ethyl ester).

(7) Add intermediate II-6 (20 g, 1 eq), tetrahydrofuran (200 ml), purified water (20 ml), and sodium hydroxide (7.4 g, 4 eq) to the reaction flask in sequence, raise the temperature to reflux, react for 2 h, concentrate to remove tetrahydrofuran, add purified water (100 ml) and ethyl acetate (100 ml), stir evenly, stand for separation, retain the aqueous phase, add hydrochloric acid to the aqueous phase to adjust the pH to 3-5, add methyl tert-butyl ether for extraction, dry the organic phase with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 16.8 g of the compound represented by formula II; ¹ H-NMR (500 MHz, CDCl ₃ ): δ: 7.510~7.493(m, 2H), 7.475~7.448(m, 2H), 7.396~7.364(m, 1H), 7.317~7.269(m, 5H), 5.141~5.070(m, 1H), 3.592(m, 2H), 2.407~2.362(m, 2H) , 1.779～1.707(m, 4H), 1.506～1.445(m, 2H), 1.322～1.308(m, 6H), ppm.

2. Preparation of the compound shown in Formula I

Add the compound shown in formula II (1g, 1eq), dichloromethane (20ml), methylsulfonamide (353mg, 1.5eq), DMAP (362mg, 1.2eq) and EDCI (569mg, 1.2eq) to the reaction bottle in sequence, heat to 35-45°C for 3h, cool to room temperature, wash the resulting reaction solution once with purified water, once with 2M hydrochloric acid, and once with purified water. The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness to obtain 650mg of the compound shown in formula I (chemical name: 6-((5,6-diphenyl-1,2,4-triazine-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide)).

The structural characterization diagrams of the compound represented by Formula I are shown in Figures 1, 2 and 3, and the specific data are as follows:

¹ H-NMR (500MHz, CDCl ₃ ): δ: 10.144 (br, 1H), 7.480～7.497 (m, 2H), 7.447～7.466 (m, 2H), 7.398 (m, 1H), 7.262～7.321 (m , 5H), 5.075 (m, 1H), 3.622 (m, 2H), 3.236 (s, 3H), 2.370 ~ 2.399 (t, 2H), 1.854 ~ 1.716 (m, 4H), 1.460 ~ 1.487 (m, 2H ), 1.292~1.306(m, 6H), ppm.

¹³ C NMR: (500MHz, CDCl ₃ ): δ: 20.41, 23.89, 25.71, 36.13, 41.36, 41.67, 46.66, 77.25, 128.21, 128.30, 129.16, 129.69, 130.22, 136.14, 136.59, 147.75 ,158.84ppm.

High resolution mass spectrum: [M+1] ⁺ measured value (m/z): 482.2210.

HPLC spectrum: the retention time of the main peak is 5.520 minutes.

The elemental analysis results are shown in Table 1:

Table 1 Elemental analysis results

The above structural characterization results show that the compound has a structural formula as shown in Formula I:

Example 2

This example provides pharmacodynamic experiments and results of the compound represented by Formula I (hereinafter referred to as "Compound A").

1. Evaluation of the effect of compound A on IP, EP1, EP2, EP3, EP4, DP, FP, and TP targets

This experiment used a cell line that stably expressed IP, EP1, EP2, EP3, EP4, DP, FP and TP receptors. The HTRFcAMP and HTRF IP1 methods were used to study the functional activities of compound A and Selexipag on eight targets IP, EP1, EP2, EP3, EP4, DP, FP and TP based on changes in cell signal intensity, and the corresponding concentration-effect curve _EC50 values were calculated, see Figure 4.

The results showed that compound A had an agonistic effect on the IP target under the starting detection condition of 10000nM, and the absolute _EC50 value was 0.48nM; it had no obvious agonistic effect on the EP1, EP2, EP3, EP4, DP, FP and TP targets under the starting detection condition of 10000nM, and the absolute _EC50 values were all greater than 10000nM.

As a comparison, the effects of Selexipag on IP, EP1, EP2, EP3, EP4, DP, FP, and TP targets were detected. The results showed that under the initial detection condition of 10000nM, Selexipag had an agonistic effect on IP, EP2, and DP targets, with absolute EC ₅₀ values of 0.27nM, 9754.34nM, and 2736.01nM, respectively; there was no obvious agonistic effect on EP1, EP3, EP4, FP, and TP targets under the initial detection condition of 10000nM, and the absolute EC ₅₀ values were all greater than 10000nM, see Figure 5.

The above results indicate that the agonist activity of compound A on IP receptors is weaker than that of Selexipag, but its target selectivity is stronger than that of Selexipag. It is speculated that compound A has fewer side effects such as headache, facial flushing, nausea, vomiting, etc., similar to those caused by overactivation of IP receptors by Selexipag, and less adverse reactions such as muscle pain caused by stimulating other prostacyclin receptors.

2. Effect of Compound A on the Proliferation of Human Pulmonary Artery Smooth Muscle Cells

Human pulmonary artery smooth muscle cells were cultured in a smooth muscle-specific medium and placed in a cell culture incubator at 37°C, 5% CO ₂ concentration, and saturated humidity. 6×10 ³ cells were plated on a 96-well plate and cultured in a 96-well plate (final volume: 100 μl). After 24 hours, they were starved with serum-free medium for 24 hours, and then compound A and Selexipag (10000, 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1 nM) were gradiently diluted with medium containing a final concentration of 20 ng/ml hPDGF-BB. The medium in the cell culture wells was removed, and the test substances after gradient dilution were added to the cell culture wells in a volume of 100 μl. The CTG method was used to study the inhibitory effects of the test substances, compound A and Selexipag, on the proliferation of human pulmonary artery smooth muscle cells and to fit their half-maximal inhibitory concentrations IC ₅₀ to evaluate the potential of the test substances in treating pulmonary hypertension.

The results showed (see Figure 6): Compound A and Selexipag had _IC50 of 9.65 and 18.69 μM, respectively, for inhibiting PDGF-induced pulmonary artery smooth muscle cell proliferation. The inhibitory effect of Compound A at a concentration of 0.3-10 μM was positively correlated with the compound concentration.

In summary, compound A and Selexipag showed effective inhibition of PDGF-induced pulmonary artery smooth muscle cell proliferation. The IC ₅₀ value of the inhibitory effect of compound A was less than that of Selexipag, indicating that the inhibitory effect of compound A was stronger than that of Selexipag.

3. Effect of Compound A on Pulmonary Artery Ring Tension in Rats

After SD rats are anesthetized, the heart and lungs are found and freed, and immersed in oxygenated perfusion fluid. After washing away the blood, the freed heart and lungs are placed in clean, oxygenated incubation fluid. The pulmonary artery is found and freed under a microscope. Be careful not to pull the pulmonary artery during this process, remove the blood remaining in the vascular endothelium, prepare a vascular ring with an inner diameter of about 2mm to 3mm, hang it on the hook on the tension transducer (be careful not to damage the endothelial cells), and immerse the pulmonary artery branch in the liquid in the incubation tank. The basic tension of the pulmonary artery branch is adjusted to about 0.8 to 1g through micromanipulation, and stabilized for 1 to 2 hours. After the basal tension of the pulmonary artery ring was stabilized, high K ⁺ incubation medium was used to induce an increase in the tension of the pulmonary artery ring and stabilize it. Then, incubation medium containing different concentrations of the test compound, compound A (1μM, 5μM, 10μM, 20μM, 60μM) and Selexipag (5μM, 10μM, 20μM, 40μM, 60μM), was added, N=5, and the changes in the tension of the pulmonary artery ring were recorded. After the maximum efficacy of the drug was observed, the basal incubation medium was used to replace the incubation medium to restore the tension of the pulmonary artery ring to the basal level.

The results show (see Figure 7): Compound A and Selexipag can inhibit high K ⁺ -induced rat pulmonary artery vasoconstriction to varying degrees at the five concentrations tested, and the inhibitory effect IC ₅₀ is 11.15 μM and 23.97 μM, respectively. The IC ₅₀ of each compound can reflect the inhibitory efficiency of the compound from high to low: Compound A>Selexipag. In summary, Compound A and Selexipag can effectively inhibit high K ⁺ -induced pulmonary artery vasoconstriction, and the inhibitory effect of Compound A is greater than that of Selexipag.

IV. Pharmacological efficacy of compound A on MCT-induced pulmonary hypertension model rats

65 rats were divided into 6 groups, 10 rats in the normal control group, 11 rats in each of the other 5 groups, and 5 model groups were respectively used as the model control group, the test article low-dose group, the test article medium-dose group, the test article high-dose group and the positive control group. Among them, monocrotaline, 60mg/kg, 5ml/kg was used to prepare the model. The animals in the normal control group were intraperitoneally injected with sodium chloride injection (5ml/kg). About 2 hours after the animals were given the modeling agent, the animals in each group began to be given the drug.

The normal control group and the model control group were gavaged with 0.5% CMC-Na, the low-dose group was gavaged with 0.15 mg/kg of compound A, the medium-dose group was gavaged with 0.5 mg/kg of compound A, the high-dose group was gavaged with 1.5 mg/kg of compound A, and the positive control group was gavaged with 1 mg/kg of Selexipag, twice a day, for 19 consecutive days.

The weight changes of rats were recorded and the survival rate was observed. The mean pulmonary artery pressure of rats was measured by right cardiac catheterization. HE staining was used to observe the pathological changes of right ventricular and lung tissues, and the percentage of media thickness and right heart hypertrophy index were calculated.

The results show:

(1) Effect of Compound A on Body Weight of Rats with Pulmonary Hypertension

After the animals were given the modeling reagent, their body weight was significantly lower than that of the animals in the normal control group. As the experimental period prolonged, the average body weight of the animals in each drug-treated group increased steadily, and the body weight of the animals in the model control group decreased significantly. As shown in Table 2.

Table 2 Effects of Compound A and Selexipag on body weight (g) of rats with pulmonary hypertension (x±SD)

Note: Compared with the model control group, "*" indicates P≤0.05, "**" indicates P≤0.01, and "***" indicates P≤0.001.

(2) Compound A reduces mortality in rats with pulmonary hypertension

During the experiment, the survival rate of the animals in the model control group was 82%, and no animals died in the other groups, with a survival rate of 100%.

(3) Compound A dose-dependently reduced right ventricular systolic pressure, right heart hypertrophy index and pulmonary arteriolar media thickness in rats

Compared with the right ventricular systolic pressure (RVSP, mmHg) of the model control group, the low-dose group (0.15 mg/kg), the medium-dose group (0.5 mg/kg), the high-dose group (1.5 mg/kg), and the positive drug control group (1 mg/kg) of the test article were significantly reduced, with the maximum reductions being approximately 15%, 33%, 43%, and 33%, respectively, and all of them were statistically significant (P≤0.001), as shown in Figure 9 and Table 3.

Table 3 Effects of Compound A and Selexipag administered orally on pulmonary artery blood pressure (mmHg) in rats with pulmonary hypertension

Note: Compared with the model control group, "***" indicates P ≤ 0.001.

Compared with the model control group, compound A at 0.15 mg/kg, 0.5 mg/kg, and 1.5 mg/kg significantly reduced the right heart hypertrophy index of rats, with the maximum reductions of 17%, 27%, and 29%, respectively. Selexipag at a dose of 1 mg/kg reduced the right heart hypertrophy index of rats by 26%, as shown in Figure 10 and Table 4.

Table 4 Effects of Compound A and Selexipag administered orally on right heart hypertrophy index (%) in rats with pulmonary hypertension

Note: Compared with the model control group, “*” indicates P≤0.05, and “***” indicates P≤0.001.

Compared with the model control group, the percentage of membrane thickness in the 0.5 mg/kg and 1.5 mg/kg doses of compound A and the positive control group was significantly reduced (P≤0.001); the percentage of membrane thickness in the 0.15 mg/kg group of compound A was not significantly different from that in the model control group. Compared with the 1.5 mg/kg group of compound A, the percentage of membrane thickness in the positive control group was slightly reduced. As shown in Figure 11 and Table 5.

Table 5 Effects of Compound A and Selexipag on the percentage (%) of pulmonary artery media thickness in rats with pulmonary hypertension

Note: Compared with the model control group, "***" indicates P ≤ 0.001.

(4) Compound A alleviates lung tissue pathological damage in rats with pulmonary hypertension

Microscopic observation of the animals in the model control group and the drug-treated group showed some lesions in the lungs and bronchi caused by the pulmonary hypertension model, such as alveolar foamy macrophage infiltration, alveolar hemorrhage, alveolar fibrinoid exudation, congestion, thickening of the lining of the pulmonary arteries/luminal stenosis, etc. In terms of the overall lung lesions, compared with the model control group, the incidence and degree of lung lesions in animals treated with compound A and the positive control were reduced to a certain extent. In addition, compared with the high, medium and low doses of the test group, the degree of lesions in the positive control group was reduced to a certain extent, as shown in Figure 12.

From the above results, it can be seen that under the experimental conditions, compound A at 0.15 mg/kg, 0.5 mg/kg, 1.5 mg/kg and Selexipag at 1 mg/kg, both gavage, 2 times/day, 19 consecutive days, a total of 38 times, can significantly reduce the pulmonary artery pressure, right heart hypertrophy index and pulmonary artery media thickness percentage of rats with pulmonary hypertension induced by monocrotaline, improve the survival rate, have a certain improvement effect on lung tissue lesions, and have a dose-response relationship. The dose effect of compound A 0.5 mg/kg is close to that of the positive control Selexipag (1 mg/kg).

In summary, the diphenyltriazine compounds of the present invention or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof have significant effects in the treatment or prevention of diseases such as pulmonary hypertension, pulmonary arterial hypertension, chronic thrombotic pulmonary arterial hypertension, etc. In addition, they have significant effects in Fontan's disease and pulmonary hypertension associated with Fontan's disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis.

Based on the same mechanism, the diphenyltriazine compounds of the present application or their pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof have therapeutic or preventive effects on peripheral circulatory disorders (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease).

Based on the same mechanism, in terms of connective tissue diseases, for example, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis syndrome have a therapeutic or preventive effect. In terms of arteriosclerosis and thrombosis, there is a therapeutic or preventive effect, for example, acute cerebral thrombosis, pulmonary embolism, etc. In thrombocytopenia caused by dialysis, diseases involving organ or tissue fibrosis have a preventive or therapeutic effect, for example, nephropathy such as tubulointerstitial nephritis. In respiratory diseases, for example, interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease, digestive system diseases (for example, cirrhosis, viral hepatitis, chronic pancreatitis and sclerosing gastric cancer), and anti-ulcer, finger ulcer, diabetic gangrene, or diabetic foot ulcer, there is a preventive or therapeutic effect.

Example 3

This example provides toxicological experiments and results of the compound represented by Formula I (hereinafter referred to as "Compound A").

1. Acute toxicity test of compound A in rats by oral gavage

24 healthy SD rats, half male and half female, were randomly divided into 4 groups according to body weight. Group 1 was the vehicle group, and groups 2 to 4 were low-, medium-, and high-dose groups of compound A, with doses of 100, 300, and 1000 mg/kg, respectively. All animals were orally gavaged once on Day 1, with a dosing volume of 10 ml/kg, and observed for 7 days after dosing.

One female rat in Group 4 was moribund on Day 2 and was subsequently euthanized.

In the detailed clinical observation, it can be seen that the female animals in the high-dose (1000 mg/kg) group of Compound A had loss of righting reflex, cold skin when touched, disheveled hair, and dying on Day 2. The above symptoms are considered to be toxic reactions caused by Compound A; two female rats in the medium-dose (300 mg/kg) group of Compound A had symptoms of red nasal discharge on Day 2. Nasal discharge only appeared on Day 2 and then returned to normal, with no obvious dose correlation. It is considered to be related to Compound A, but not a toxic reaction. Compared with the body weight during the adaptation period, the body weight of female animals in the high-dose (1000 mg/kg) group of Compound A decreased on Day 2, which is considered to be a toxic reaction caused by Compound A. No obvious abnormalities were found in the food consumption and gross anatomical observations of animals in each dose group. After a single oral gavage of Compound A to SD rats, the MTD was less than 1000 mg/kg.

The above toxicity symptoms are basically consistent with those of rats after administration of Selexipag, but Compound A did not cause serious toxicity symptoms such as blackening or falling off of the rats' tails. The non-lethal dose of Selexipag in rats is 250 mg/kg, and the approximate lethal dose is 500 mg/kg. Combined with the efficacy data, the safe dose range of Compound A in rats is greater than that of Selexipag, and the tolerable dose of Compound A in rats is higher than that of Selexipag.

II. Toxicity test of compound A in rats after repeated administration for 4 weeks

160 healthy SD rats (SPF grade), half male and half female, were randomly divided into 8 groups according to sex and weight. Groups 1 to 4 were toxicity study groups, with 15 animals per sex in each group; groups 5 to 8 were toxicity metabolism study groups, with 5 animals per sex in each group. All animals were given different doses of compound A by oral gavage once a day for 4 consecutive weeks, with the doses being 0 mg/kg (solvent), 50 mg/kg, 150 mg/kg, and 500 mg/kg, respectively, and the administration volume was 10 ml/kg.

During the experiment, the behavior and physical signs of the animals were observed and recorded. The body weight and food intake of groups 1 to 4 were measured once a week during the dosing period and the recovery period, and fundus examination was performed at the end of dosing and the end of the recovery period. Clinical pathological examinations (including hematology, coagulation, serum biochemistry and urine analysis) were performed on the animals planned for dissection at the end of dosing and the end of the recovery period. All animals planned for collection were fasted overnight (≥10 h) before clinical pathological samples were collected, and urine for about 12 h was collected one day in advance for urine analysis. Gross anatomical examinations, organ weighing and histopathological examinations were performed on the animals planned for dissection at the end of dosing and the end of the recovery period.

No animal died during the test. The NOAEL is 50 mg/kg. After repeated administration for 28 days at the NOAEL dose, the AUC _{(0-24 ) of compound A in male and female animals was 3784 h×ng/ml (male) and 7016 h×ng/ml (female), respectively. The NOAEL of Selexipag is 6 mg/kg. After repeated administration for 28 days at the NOAEL dose, the AUC (0-24)} of Selexipag in male and female animals was 10 h×ng/ml (male) and 40 h×ng/ml (female), respectively.

Compound A ≥ 500 mg/kg can cause salivation and thyroid volume enlargement in animals. Compound A ≥ 150 mg/kg can cause weight loss, decreased RBC, HGB, and HCT, increased RET/RET%, increased ALT, increased urine volume, increased liver weight, and hypertrophy of the distal endocrine cells of the pituitary (male), hypertrophy of thyroid follicular cells, and hypertrophy of liver cells in the histopathological examination. All changes were recovered or showed a recovery trend at the end of the recovery period. Among the above changes, salivation only occurred on some test days of some animals and disappeared after drug withdrawal. The body weight in the medium dose (150 mg/kg) group changed little, and the RBC, HGB, and HCT decreased little. The increase in RET/RET% was considered a compensatory effect. The urine volume increased, but other indicators showed no obvious abnormalities, which were all considered to be non-harmful reactions related to compound A. No toxic reactions related to compound A were found in the food consumption, ophthalmic examination, and coagulation examination of animals in each group.

III. Genotoxicity test of compound A

Genetic toxicity test process: The test compound A and Selexipag were diluted to 8 concentrations with a final concentration of 1000 μg/well. The 6-well plate incorporation method was used, 2 wells were treated in parallel, and negative (DMSO) and positive controls were set up at the same time. Parallel tests were performed with or without metabolic activation system (±S9). After 48 to 72 hours of incubation, the test products were observed for precipitation and the growth of background plaques, and the number of reverse mutant colonies in each well was counted. The test results are shown in Tables 6 to 9.

Positive result determination

A result is considered positive if it meets 1 or 2 of the following criteria:

1) In at least one strain, the number of revertant colonies increased in a dose-dependent manner with or without metabolic activation, and the number of revertant colonies was 2 times or more than that of the negative control group.

2) With or without metabolic activation, the number of reverse mutant colonies in one or more dose groups increases significantly and reproducibly, and the number of reverse mutant colonies is 2 times or more than that in the negative control group.

After the test sample is tested with two test strains, as long as one of the test strains is positive, regardless of whether S9 mixed solution is added or not, the test sample can be determined to be a mutagen.

Negative result judgment

If the test results show that there is no dose-dependent increase in the number of reverted colonies of each test strain, and the peak value of the number of reverted mutant colonies in each dose group of all strains does not exceed twice that of the negative control group, the test article can be determined to be a non-mutagenic agent.

The results showed that: under ±S9 conditions, for TA98 and TA100 strains, non-interfering precipitation was observed when the final concentration of Selexipag was ≥250μg/well; non-interfering precipitation was observed only when the final concentration of compound A was 1000μg/well. Under ±S9 conditions, for TA98 and TA100 strains, a reduction in background plaques was observed when the final concentration of Selexipag was ≥250μg/well; no abnormal background plaques were observed at any concentration of compound A. For TA98 and TA100 strains, under ±S9 conditions, the number of reverse mutant colonies in each concentration group of compound A and Selexipag did not reach twice that of the negative control group, and there was no concentration-effect relationship, so the test results were considered negative.

Therefore, Compound A and Selexipag were not genotoxic.

Table 6. Results of the initial screening test of compound A in 6-well plate for bacterial reverse mutation (TA98 strain)

Remark:

Background plaque: T0 normal.

Solubility of test sample/reference sample: P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.

*: The number of reverse mutant colonies in the positive control group was 3 times higher than that in the negative control group.

Table 7 Results of the initial screening test of compound A in bacterial reverse mutation in 6-well plates (TA100 strain)

Remark:

Background plaque: T0 normal.

Solubility of test sample/reference sample: P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.

*: The number of reverse mutant colonies in the positive control group was 3 times higher than that in the negative control group.

Table 8. Results of the initial screening test of Selexipag bacterial reverse mutation in 6-well plates (TA98 strain)

Remark:

NA: Not counted.

Background plaque: T0 is normal; T1 background plaque is slightly reduced; T3 background plaque is severely reduced; T4 background plaque disappears.

Solubility of test sample/reference sample: P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.

^a : The positive drugs without and with S9 were sodium azide (0.4 μg/well) and 2-aminoanthracene (0.6 μg/well). *: The number of reverse mutant colonies in the positive control group was 3 times higher than that in the negative control group.

Table 9 Results of the initial screening test of Selexipag bacterial reverse mutation in 6-well plates (TA100 strain)

Remark:

NA: Not counted.

Background plaque: T0 is normal; T1 background plaque is slightly reduced; T3 background plaque is severely reduced; T4 background plaque disappears.

Solubility of test sample/reference sample: P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.

^a : The positive drugs without and with S9 were sodium azide (0.4 μg/well) and 2-aminoanthracene (0.6 μg/well). *: The number of reverse mutant colonies in the positive control group was 3 times higher than that in the negative control group.

In summary, the NOAEL of Compound A in rats is 100 times the effective dose, and the NOAEL of Selexipag is 6 times the effective dose, indicating that the safety range of Compound A is greater than that of Selexipag. In addition, compared with Selexipag, repeated administration of Compound A for 4 weeks did not cause serious adverse reactions. The above results show that Compound A is safer than Selexipag.

Example 4

This embodiment provides a tablet for treating pulmonary hypertension, and the preparation method thereof is as follows: the compound represented by formula I is used as an active ingredient, and the tablet is prepared with tablet excipients according to conventional processes.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (12)

1. A diphenyltriazine compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof, characterized in that its structural formula is as shown in Formula I: 2. The method for preparing the diphenyltriazine compound according to claim 1, characterized in that it specifically comprises the following steps: The compound of formula II, methylsulfonamide, 4-dimethylaminopyridine and carbodiimide are mixed in dichloromethane, heated to 35-45°C for reaction for 2-3h, then cooled to 20-40°C, the obtained reaction solution is washed with purified water, then washed with hydrochloric acid solution, then dehydrated and the solvent is removed to obtain; 3. The preparation method according to claim 2, characterized in that the equivalent ratio of the methylsulfonamide to the compound of formula II is ≥1; and/or The equivalent ratio of the 4-dimethylaminopyridine to the compound of formula II is ≥1; and/or The ratio of the equivalent of the carbodiimide to the equivalent of the compound having the structural formula shown in Formula II is ≥1. 4. The preparation method according to claim 2, characterized in that the preparation method of the compound with the structural formula as shown in Formula II specifically comprises the following steps: S1, glacial acetic acid, benzil, semicarbazide hydrochloride and purified water were mixed, the temperature was raised to 100-110°C and the reaction was kept warm for 2-2.5 hours, then the temperature was lowered to 30-40°C, purified water was added, stirred and reacted at 20-30°C for 0.5-1 hour, solid-liquid separation was performed, the obtained solid phase was placed in ethyl acetate, refluxed for 2-3 hours, and solid-liquid separation was performed after cooling to obtain intermediate II-1; S2, mixing phosphorus oxychloride and the intermediate II-1, heating to 80-85° C., stirring to dissolve, keeping warm for 1-1.5 hours, removing the solvent, adding a mixed solvent of toluene and isopropanol to the obtained product, stirring to disperse, and separating the solid and liquid to obtain the intermediate II-2; S3, add intermediate II-2 and 4-(isopropylamino)butanol to the reaction flask in sequence, raise the temperature to 140-150°C, keep the temperature for reaction for 12-15h, cool to room temperature, pour the reaction solution into water, add ethyl acetate for extraction, wash the organic phase with saturated sodium chloride aqueous solution and dry, remove the solvent, and purify the obtained product with a silica gel column to obtain intermediate II-3; S4, mixing the intermediate II-3 with dichloromethane, cooling to 0-10°C, adding Dess-Martin reagent, reacting at 0-10°C for 12-15h, washing the resulting reaction solution with a saturated sodium bicarbonate solution, and then with a saturated sodium chloride aqueous solution, drying the organic phase, removing the solvent, and purifying the resulting product with a silica gel column to obtain an intermediate II-4; S5, triethyl phosphoacetate and tetrahydrofuran are mixed, the temperature is reduced to 0-10°C, sodium hydride is added to react for 1-1.5h, the intermediate II-4 is added at 0-5°C, the temperature is raised to room temperature and the reaction is carried out for 2-3h, water is added dropwise to the reaction solution to quench the reaction, and then at least 80% of tetrahydrofuran is removed by concentration, ethyl acetate is added to the residue for extraction, the organic phase is washed with a saturated sodium chloride aqueous solution and dried, the solvent is removed, and the resulting product is purified by a silica gel column to obtain an intermediate II-5; S6, mixing the intermediate II-5, anhydrous ethanol and palladium carbon, replacing with hydrogen, reacting at room temperature for 5 to 8 hours, removing the palladium carbon, and removing the solvent from the resulting reaction solution to obtain intermediate II-6; S7. Mix the intermediate II-6, tetrahydrofuran, sodium hydroxide and water, reflux for 2 to 4 hours, concentrate to remove tetrahydrofuran, add purified water and ethyl acetate, stir evenly, stand to separate the liquids, retain the aqueous phase, add hydrochloric acid to the aqueous phase to adjust the pH to 3 to 5, add methyl tert-butyl ether for extraction, dry the organic phase and remove the solvent to obtain a compound with the structural formula shown in Formula II. 5. The preparation method according to claim 4, characterized in that, in step S1, the equivalent ratio of the semicarbazide hydrochloride to the benzil is greater than 1; and/or The volume ratio of the glacial acetic acid to the purified water is 2 to 3:1; and/or In step S2, the mass ratio of the phosphorus oxychloride to the intermediate II-1 is ≥ 6.5; and/or In step S2, the volume ratio of toluene to isopropanol in the mixed solvent of toluene and isopropanol is 1:2.5-3.5; and/or In step S3, the equivalent ratio of the 4-(isopropylamino)butanol to the intermediate II-2 is 3 to 5; and/or In step S3, purification is performed using a 200 mesh silica gel column, and the eluent is a dichloromethane-methanol mixture with a volume ratio of 30:1; and/or In step S4, the equivalent ratio of the Dess-Martin reagent to the intermediate II-3 is 1.5 to 3:1; and/or In step S4, purification is performed using a 200 mesh silica gel column, and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 2:1; and/or In step S5, the equivalent ratio of the triethyl phosphoacetate to the intermediate II-4 is 1 to 2:1; and/or In step S5, the equivalent ratio of the sodium hydride to the intermediate II-4 is 1 to 2:1; and/or In step S5, purification is performed using a 200 mesh silica gel column, and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 5:1; and/or The mass of the palladium carbon in step S6 is 5% to 20% of the mass of the intermediate II-5. 6. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier, excipient or diluent, and the compound according to claim 1 or its pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof as an active ingredient. 7. The pharmaceutical composition according to claim 6, characterized in that the dosage form of the pharmaceutical composition is a pharmaceutically acceptable dosage form. 8. The pharmaceutical composition according to claim 7, wherein the dosage form comprises tablets, granules, capsules, powders or injections. 9. Use of the diphenyltriazine compound or its pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof according to claim 1 or the pharmaceutical composition according to any one of claims 6 to 8 in the preparation of a drug for treating or preventing pulmonary arterial hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis. 10. The use according to claim 9, characterized in that it includes use in preparing a drug for treating or preventing pulmonary hypertension. 11. The use according to claim 10, characterized in that the pulmonary hypertension is chronic thrombotic pulmonary hypertension. 12. Use of the diphenyltriazine compound or its pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof as claimed in claim 1 or the pharmaceutical composition as claimed in any one of claims 6 to 8 in the preparation of a drug for treating or preventing peripheral circulatory disorders, connective tissue diseases, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases involving organ or tissue fibrosis, finger ulcers, diabetic gangrene or diabetic foot ulcers.