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WO2025167237A1 - Composé de diphényltriazine, son procédé de préparation et son utilisation - Google Patents

Composé de diphényltriazine, son procédé de préparation et son utilisation

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Publication number
WO2025167237A1
WO2025167237A1 PCT/CN2024/130940 CN2024130940W WO2025167237A1 WO 2025167237 A1 WO2025167237 A1 WO 2025167237A1 CN 2024130940 W CN2024130940 W CN 2024130940W WO 2025167237 A1 WO2025167237 A1 WO 2025167237A1
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WO
WIPO (PCT)
Prior art keywords
compound
hours
reaction
preparation
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/130940
Other languages
English (en)
Chinese (zh)
Inventor
孙立杰
孙晓飞
杨娴
曹柳
李磊
朱树杰
郭志强
赵方红
路晓兵
侯海婷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shijiazhuang No 4 Pharmaceutical Co Ltd
Hebei Guolong Pharmaceutical Co Ltd
Original Assignee
Shijiazhuang No 4 Pharmaceutical Co Ltd
Hebei Guolong Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shijiazhuang No 4 Pharmaceutical Co Ltd, Hebei Guolong Pharmaceutical Co Ltd filed Critical Shijiazhuang No 4 Pharmaceutical Co Ltd
Publication of WO2025167237A1 publication Critical patent/WO2025167237A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present application belongs to the technical field of chemical medicines, and specifically relates to a diphenyltriazine compound, a preparation method thereof, and an application thereof.
  • Pulmonary arterial hypertension is a disease characterized by vasospasm, intimal hyperplasia, and remodeling of the pulmonary arterioles. This proliferation and remodeling leads to a progressive increase in pulmonary vascular resistance, ultimately causing right heart failure and ultimately death. PAH is ranked the third most common cardiovascular disease, second only to hypertension and coronary heart disease in prevalence. It has become a serious public health concern threatening human health and well-being, and is included in the World Health Organization's global monitoring of major chronic diseases.
  • PGI2 is a substance produced in vivo from arachidonic acid via prostaglandin H2 (PGH2).
  • PGI2 deficiency can cause pulmonary hypertension.
  • PGI2 receptor agonists include epoprostenol, beraprost, and iloprost, all of which are PGI2 analogs.
  • Selexipag is currently the only PGI2 receptor agonist that does not have a PGI2 skeleton but exhibits excellent selectivity for the PGI2 receptor and demonstrated efficacy. It has been approved for marketing in multiple countries for the treatment of adult pulmonary hypertension.
  • the present application provides a diphenyltriazine compound, a preparation method and application thereof.
  • the compound has good affinity for PGI2 receptors and very low adverse reactions, avoiding the shortcomings of current PGI2 analogs and selexipag.
  • the present application provides a diphenyltriazine compound or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, the structural formula of which is shown in Formula I:
  • the present application also provides a method for preparing the above-mentioned diphenyltriazine compounds, which specifically comprises the following operations:
  • the compound of formula II, methylsulfonamide, 4-dimethylaminopyridine (DMAP) and carbodiimide (EDCI) are mixed in dichloromethane, heated to 35-45°C for reaction for 2-3 hours, then cooled to 20-40°C.
  • the resulting reaction solution is washed with purified water and then with hydrochloric acid solution, and then dehydrated to remove the solvent to obtain the product.
  • the equivalent ratio of the methanesulfonamide to the compound of formula II is ⁇ 1.
  • the equivalent ratio of the methanesulfonamide to the compound of formula II is ⁇ 1.3.
  • the equivalent ratio of the 4-dimethylaminopyridine to the compound of formula II is ⁇ 1.
  • the equivalent ratio of the 4-dimethylaminopyridine to the compound of formula II is ⁇ 1.1.
  • the ratio of the equivalents of the carbodiimide to the equivalents of the compound of formula II is ⁇ 1.
  • the ratio of the equivalents of the carbodiimide to the equivalents of the compound of formula II is greater than ⁇ 1.1.
  • the amount of dichloromethane used can be sufficient to ensure that all reactants are dissolved therein, and this application does not impose any limitation on this.
  • the concentration of the hydrochloric acid solution is 1.8 to 2.2 M (ie, mol/L).
  • 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 without affecting the reactants.
  • the compound represented by the structural formula II can be prepared by the following method, which specifically comprises the following steps:
  • the ratio of the equivalents of the semicarbazide hydrochloride to the equivalents of the benzil is greater than 1.
  • the ratio of the equivalents of the semicarbazide hydrochloride to the equivalents of the benzil is ⁇ 1.4.
  • the volume ratio of the glacial acetic acid to the purified water is 2 to 3:1.
  • 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 this application does not impose any limitation on this.
  • the mass ratio of the phosphorus oxychloride to the intermediate II-1 is ⁇ 6.5.
  • the volume ratio of toluene to isopropanol in the mixed solvent of toluene and isopropanol is 1:2.5-3.5.
  • step S3 of the preparation method purification is performed by 200-mesh silica gel column chromatography, and the eluent is a dichloromethane-methanol mixture with a volume ratio of 30:1.
  • the equivalent ratio of the Dess-Martin reagent to the intermediate II-3 is 1.5 to 3:1.
  • step S4 of the preparation method purification is performed by 200-mesh silica gel column chromatography, and the eluent is a mixture of n-hexane and ethyl acetate in a volume ratio of 2:1.
  • the equivalent ratio of the triethyl phosphoacetate to the intermediate II-4 is 1 to 2:1.
  • the equivalent ratio of the sodium hydride to the intermediate II-4 is 1 to 2:1.
  • FIG1 is a 1 H-NMR spectrum of Example 1 of the present application.
  • Figure 6 shows the effects of Compound A and Selexipag on the proliferation of human pulmonary artery smooth muscle cells in Example 2 of the present application
  • FIG7 shows the effects of Compound A and Selexipag on rat pulmonary artery ring tension in Example 2 of the present application
  • Figure 9 shows the effect of oral administration of Compound A and Selexipag on right ventricular systolic pressure (mmHg) in rats with pulmonary hypertension in Example 2 of the present application (*** indicates P ⁇ 0.001 compared with the model control group);
  • Figure 10 shows the effect of oral administration of Compound A and Selexipag on the right heart hypertrophy index (%) in rats with pulmonary hypertension in Example 2 of the present application (* indicates P ⁇ 0.05 compared with the model control group, *** indicates P ⁇ 0.001 compared with the model control group);
  • Figure 11 is a comparison of the percentage (%) of pulmonary arteriolar media thickness in each group of animals in Example 2 of the present application (*** indicates P ⁇ 0.001 compared with the model control group);
  • Figure 12 is a lung pathology image of each group of rats in Example 2 of the present application, 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 ⁇ .
  • PGI2 receptor agonists are currently commonly used drugs for the treatment of PAH, but they have a 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 it still has certain adverse reactions.
  • the present application 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.
  • isomers refer to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
  • optical isomers may exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are "R" or "S” configurations. 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 resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl groups or heterocyclic rings are designated as cis or trans configurations.
  • isotope includes all isotopes of atoms that appear in the compounds of the present application. 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 application 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 .
  • the isotopically labeled compounds of the present application can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents.
  • Such compounds have various potential uses, for example, 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 prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of the present application contain one or more acidic or basic groups
  • the present application also comprise their corresponding pharmaceutically acceptable salts.
  • the compound of the present application that contains acidic group can exist with salt form and can use according to the application, for example as alkali metal salt, alkaline earth metal salt or as ammonium salt, exemplary comprise sodium salt, potassium salt, calcium salt, magnesium salt or with ammonia or organic amine, for example the salt that ethylamine, ethanolamine, triethanolamine or amino acid become.
  • the compound of the present application that contains basic group can exist with salt form and can use according to the application with the form of addition salt of them and inorganic or organic acid.
  • suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic
  • the present application also includes inner salts or betaines in addition to the salt forms mentioned.
  • the respective salts can be obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts.
  • a “pharmaceutical composition” refers to a composition comprising one or more compounds described herein, or pharmaceutically acceptable salts, prodrugs, stable isotopic 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.
  • This embodiment provides a diphenyltriazine compound, a preparation method thereof, and structural characterization.
  • HPLC spectrum the retention time of the main peak is 5.520 minutes.
  • This experiment used cell lines stably expressing IP, EP1, EP2, EP3, EP4, DP, FP and TP receptors.
  • the HTRF cAMP and HTRF IP1 methods were used to study the functional activities of Compound A and Selexipag against eight targets, IP, EP1, EP2, EP3, EP4, DP, FP and TP, based on changes in cellular signal intensity.
  • the EC50 values in the corresponding concentration-effect curves were calculated ( EC50 generally refers to the dose required for an exogenous substance to cause a 50% change in a certain biological effect in the body, which means the drug concentration that causes 50% of individuals to be effective), see Figure 4.
  • Compound A has weaker agonist activity on IP receptors than Selexipag, but stronger target selectivity than Selexipag. Therefore, it is reasonable to infer that Compound A has less adverse reactions similar to those caused by Selexipag overactivating IP receptors, such as headache, facial flushing, nausea, and vomiting, and less adverse reactions due to stimulating other prostacyclin receptors, such as muscle pain.
  • Human pulmonary artery smooth muscle cells were cultured in a smooth muscle-specific culture medium in a cell culture incubator maintained at 37°C, 5% CO2 , and saturated humidity. Human pulmonary artery smooth muscle cells were plated at 6 ⁇ 10 ⁇ 3 /well on a 96-well cell culture plate (final volume: 100 ⁇ l). After 24 hours, the cells were starved with serum-free culture medium for 24 hours. Compound A and Selexipag were then serially diluted in culture medium containing a final concentration of 20ng/ml hPDGF-BB (serial dilution concentrations: 10,000, 3,000, 1,000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1nM, respectively).
  • Compound A and Selexipag demonstrated potent inhibitory effects on PDGF-induced pulmonary artery smooth muscle cell proliferation.
  • the IC50 value of Compound A was less than that of Selexipag, indicating that Compound A had a stronger inhibitory effect than Selexipag.
  • the heart and lungs were located and freed, then immersed in oxygenated perfusion fluid. After washing away the blood, the freed heart and lungs were placed in clean, oxygenated incubation fluid.
  • the pulmonary artery was located and freed under a microscope (be careful not to pull the pulmonary artery during this process). Blood remaining in the pulmonary artery endothelium was removed, and a vascular ring with an inner diameter of approximately 2mm to 3mm was prepared. The ring was hung on the hook of the tension transducer (be careful not to damage the endothelial cells), and the pulmonary artery branch was immersed in the liquid in the incubation tank.
  • mice Sixty-five rats were randomly divided into six groups: a normal control group, a model control group, a low-dose test article group, a medium-dose test article group, a high-dose test article group, and a positive control group.
  • the normal control group consisted of 10 rats, and the remaining five groups consisted of 11 rats each. Except for the normal control group, all other groups were treated with monocrotaline (60 mg/kg, 5 ml/kg) to establish a model.
  • the normal control group received an intraperitoneal injection of sodium chloride injection (5 ml/kg). Approximately 2 hours after the animals were administered the modeling agent, all other groups began receiving drug administration.
  • the right ventricular systolic pressure of the animals in the low-dose test article group (0.15 mg/kg), the medium-dose test article group (0.5 mg/kg), the high-dose test article group (1.5 mg/kg), and the positive control group (1 mg/kg) were significantly reduced, with the maximum reductions being approximately 15%, 33%, 43%, and 33%, respectively, and all showing statistically significant differences (P ⁇ 0.001), as shown in Figure 9 and Table 3.
  • the percentage of membrane thickness (MT) was significantly reduced in the 0.5 mg/kg and 1.5 mg/kg doses of Compound A and in the positive control group (P ⁇ 0.001).
  • the MT percentage in the 0.15 mg/kg Compound A group did not show a significant difference compared with the model control group.
  • the MT percentage in the positive control group was slightly reduced, as shown in Figure 11 and Table 5.
  • the animals in the model control group and the drug-treated group were observed under a microscope, and some pulmonary and bronchial lesions caused by the pulmonary hypertension model were observed, such as alveolar foamy macrophage infiltration, alveolar hemorrhage, alveolar fibrinoid exudation, congestion, and pulmonary arteriolar media hypertrophy/luminal stenosis.
  • pulmonary and bronchial lesions caused by the pulmonary hypertension model were observed, such as alveolar foamy macrophage infiltration, alveolar hemorrhage, alveolar fibrinoid exudation, congestion, and pulmonary arteriolar media hypertrophy/luminal stenosis.
  • the incidence and severity of lung lesions in animals treated with Compound A and the positive control were reduced to a certain extent compared to the model control group.
  • the severity of lesions in the positive control group was reduced to a certain extent compared to the high, medium, and low doses of the test article groups, as shown in Figure 12.
  • the diphenyltriazine compounds of the present application have significant effects in the treatment or prevention of diseases such as pulmonary hypertension, pulmonary arterial hypertension, and chronic thrombotic pulmonary hypertension. Furthermore, they have significant effects in treating Fontan disease and Fontan disease-associated pulmonary hypertension, and sarcoidosis and sarcoidosis-associated pulmonary hypertension.
  • 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).
  • peripheral circulatory disorders e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease.
  • respiratory system diseases for example, interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease, digestive system diseases (for example, cirrhosis of the liver, 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.
  • Group 1 received the vehicle (0 mg/kg), while Groups 2-4 received low-, medium-, and high-dose Compound A at doses of 100, 300, and 1000 mg/kg, respectively. All animals received a single oral gavage dose of 10 ml/kg on Day 1 and were observed for 7 days.
  • the above-mentioned toxicity symptoms are generally consistent with those observed in rats after administration of selexipag.
  • Compound A did not cause severe toxicity symptoms such as tail blackening or loss in rats.
  • the non-lethal dose of selexipag in rats is 250 mg/kg, and the approximate lethal dose is 500 mg/kg.
  • the safe dose range of Compound A in rats is greater than that of selexipag, and the maximum tolerated dose of Compound A in rats is higher than that of selexipag.
  • Groups 1 to 4 were toxicity study groups (including solvent control group, low-dose group, medium-dose group, and high-dose group), with 15 animals per sex in each group;
  • Groups 5 to 8 were toxicity study groups (including solvent control group, low-dose group, medium-dose group, and high-dose group), with 5 animals per sex in each group.
  • Each group of animals was orally gavaged with different doses of compound A for 4 consecutive weeks, with the dosage being 0 mg/kg (solvent), 50 mg/kg, 150 mg/kg, and 500 mg/kg, respectively.
  • the dosage volume was 10 ml/kg, and the administration was once a day.
  • the no observed adverse effect level (NOAEL) for Compound A was 50 mg/kg. After repeated dosing for 28 days at the NOAEL, the AUC (0-24) for Compound A in males and females was 3784 h ⁇ ng/ml (males) and 7016 h ⁇ ng/ml (females), respectively. The NOAEL for selexipag is 6 mg/kg. After repeated dosing for 28 days at the NOAEL, the AUC (0-24) for selexipag in males and females was 10 h ⁇ ng/ml (males) and 40 h ⁇ ng/ml (females), respectively.
  • Administration of compound A ⁇ 500 mg/kg can cause salivation and increase in thyroid volume in animals.
  • Administration of compound A ⁇ 150 mg/kg can cause weight loss in animals, and increase in red blood cell (RBC), hemoglobin (HGB), and red blood cell volume (HCT)
  • RBC red blood cell
  • HGB hemoglobin
  • HCT red blood cell volume
  • RET/RET% an increase in alanine aminotransferase (ALT)
  • ALT alanine aminotransferase
  • an increase in urine volume an increase in liver weight
  • hypertrophy of thyroid follicular cells and hypertrophy of liver cells in histopathology. All changes recovered or showed a recovery trend at the end of the recovery period.
  • Genotoxicity test procedure Test compound A and selexipag were diluted serially into eight concentrations at a final concentration of 1000 ⁇ g/well. A 6-well plate incorporation method was used, with two wells treated in parallel. Negative (DMSO) and positive controls were also included. Parallel experiments were performed with or without a metabolic activation system ( ⁇ S9). After 48-72 hours of incubation, the test samples were observed for precipitation and background plaque growth, and the number of revertant colonies in each well was counted. The test results are shown in Tables 6-9.
  • the number of revertant colonies shows a dose-dependent increase with or without metabolic activation, and the number of revertant colonies is 2 times or more that of the negative control group.
  • test sample 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.
  • test article can be determined to be a non-mutagenic agent.
  • Solubility of test/reference substance P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.
  • Solubility of test/reference substance P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.
  • Solubility of test/reference substance P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.
  • the positive drugs when S9 was not added and added were 2-nitrofluorene (0.4 ⁇ g/well) and 2-aminoanthracene (0.6 ⁇ g/well), respectively.
  • T0 is normal; T1 background plaque is slightly reduced; T3 background plaque is severely reduced; T4 background plaque disappears.
  • Solubility of test/reference substance P0 normal/no precipitation; P1 non-interfering precipitation under the microscope.
  • the positive drugs in the absence and addition of S9 were sodium azide (0.4 ⁇ g/well) and 2-aminoanthracene (0.6 ⁇ g/well), respectively.
  • the NOAEL for Compound A in rats is 100 times the effective dose, while the NOAEL for selexipag is 6 times the effective dose, indicating that Compound A has a greater safety margin than selexipag. Furthermore, compared to selexipag, repeated administration of Compound A for 4 weeks did not cause severe adverse reactions. These results demonstrate that Compound A is safer than selexipag.
  • This embodiment provides a tablet for treating pulmonary arterial hypertension, the preparation method of which is as follows: using the compound represented by Formula I as the active ingredient, and preparing the tablet according to conventional processes with tablet excipients.
  • the excipients generally include diluents, binders, disintegrants, etc. to meet the tablet preparation process and product quality.
  • This embodiment also provides other dosage forms of the pharmaceutical composition for treating pulmonary arterial hypertension, including granules, capsules, powders, and injections, all of which are prepared using conventional preparation processes in the art.

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Abstract

La présente demande se rapporte au domaine technique de la médecine chimique, et concerne en particulier un composé de diphényltriazine, son procédé de préparation et son utilisation. Le composé de diphényltriazine ne présente pas de squelette PGI2, présente une forte sélectivité et une forte affinité pour un récepteur PGI2, et présente une bonne sélectivité cible par comparaison avec un analogue de PGI2. Des expériences ont démontré que l'efficacité in vivo du composé est supérieure à celle de Sélexipag, et la toxicité du composé est significativement inférieure à celle de Sélexipag. Par conséquent, le composé peut être utilisé en tant que médicament thérapeutique contre l'hypertension artérielle pulmonaire ayant une valeur clinique et une perspective de développement plus élevées.
PCT/CN2024/130940 2024-02-06 2024-11-08 Composé de diphényltriazine, son procédé de préparation et son utilisation Pending WO2025167237A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202410169645.1 2024-02-06
CN202410169645 2024-02-06
CN202410701022.4A CN118598820B (zh) 2024-02-06 2024-05-31 一种二苯基三嗪类化合物及其制备方法和应用
CN202410701022.4 2024-05-31

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Publication Number Publication Date
WO2025167237A1 true WO2025167237A1 (fr) 2025-08-14

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Application Number Title Priority Date Filing Date
PCT/CN2024/130940 Pending WO2025167237A1 (fr) 2024-02-06 2024-11-08 Composé de diphényltriazine, son procédé de préparation et son utilisation
PCT/CN2024/141731 Pending WO2025167361A1 (fr) 2024-02-06 2024-12-24 Forme cristalline a de 6- ((5,6-diphényl -1,2,4-triazine-3-yl) (isopropyl) amino)-n- (méthylsulfonyl) hexanamide, et son utilisation et son procédé de préparation
PCT/CN2024/141737 Pending WO2025167362A1 (fr) 2024-02-06 2024-12-24 Forme cristalline b de 6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(méthylsulfonyl)hexanamide, son utilisation et son procédé de préparation

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