Deuterated 1,2,4-triazole apelin receptor agonist drug and use

Abstract

Disclosed in the present invention is a deuterated 1,2,4-triazole Apelin receptor agonist, as shown in the following formula I. The present invention relates to a deuterated 1,2,4-triazole Apelin receptor agonist and a pharmaceutical composition thereof, and a use.

Description

Deuterated 1,2,4-triazole apelin receptor agonists and their uses Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to deuterated 1,2,4-triazole apelin receptor agonist drugs and their uses. Background Technology

[0002] Apelin is an endogenous ligand of the G protein-coupled receptor APJ and is widely expressed in various organs. Recent studies have shown that Apelin / APJ plays an important role in aging. The expression of both Apelin and APJ receptors is downregulated with age. In mouse models, Apelin and APJ knockout accelerates aging, while Apelin repair enhances vitality and restores behavioral and circadian rhythm phenotypes. Furthermore, aging Apelin knockout mice exhibit progressive cardiac contractile dysfunction associated with systolic dysfunction. Apelin is crucial for maintaining cardiac contractility during aging. In addition, the Apelin / APJ system appears to be involved in regulating the renin-angiotensin-aldosterone system (RAAS), apoptosis, inflammation, and oxidative stress, thereby promoting aging. Similarly, the Apelin / APJ system regulates autophagy, stem cells, and the sirtuin family, thus contributing to anti-aging.

[0003] BGE-105 is an apelin receptor agonist developed by the anti-aging company BioAge Labs. It is currently in clinical Phase Ib trials, which collect muscle biomarker data. In an aged mouse model, BGE-105 significantly improved muscle atrophy caused by limb immobilization, prevented the loss of muscle function with age, and induced biomarkers of muscle regeneration, demonstrating its potential to prevent muscle atrophy and improve muscle function in the elderly.

[0004] Deuterated drugs are new drug molecules in which one or more carbon-hydrogen bonds of a drug molecule are replaced by carbon-deuterium bonds. They can improve the pharmacokinetic properties of the original drug and thus overcome its original defects such as easy metabolism and large side effects.

[0005] This invention relates to a multi-site deuterated 1,2,4-triazole apelin receptor agonist drug, which, compared to single-site deuterated compounds, can further improve the pharmacokinetic properties of the apelin receptor agonist BGE-105, reduce the dosage, and decrease potential toxic side effects. Summary of the Invention

[0006] The multi-site deuterated 1,2,4-triazole apelin receptor agonist drug BGE-105 and its pharmaceutically acceptable salt provided by this invention can further improve the pharmacokinetic properties of the deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt, and reduce the dosage and possible toxic side effects.

[0007] To achieve the above objectives, a deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt of the Apelin receptor agonist drug BGE-105, as described in this invention, are as follows:

[0008] Among them, R1, R2, R3, R4, and R5 are independently selected from H or deuterium, and R1, R2, R3, R4, and R5 are not all H at the same time.

[0009] Furthermore, the deuterated 1,2,4-triazole compound of the apelin receptor agonist drug BGE-105 described in this invention has the following structure:

[0010] The present invention relates to deuterated 1,2,4-triazole compounds of the Apelin receptor agonist drug and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are selected from methanesulfonate, maleate, hydrochloride or phosphate.

[0011] The deuterated 1,2,4-triazole compounds and their pharmaceutically acceptable salts described in this invention include their use in the preparation of Apelin receptor agonist drug inhibitors.

[0012] The deuterated 1,2,4-triazole compounds and their pharmaceutically acceptable salts described in this invention comprise deuterated 1,2,4-triazole compounds and their pharmaceutically acceptable salts as active ingredients and pharmaceutically acceptable carriers.

[0013] The present invention relates to pharmaceutical compositions of deuterated 1,2,4-triazole compounds and their pharmaceutically acceptable salts, wherein the pharmaceutical compositions are selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches. Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0014] This invention provides a class of deuterated 1,2,4-triazole apelin receptor agonist drugs, which further improve the pharmacokinetic properties of apelin receptor agonist drugs and reduce the dosage and possible toxic side effects. Detailed Implementation

[0015] The present invention will be further described below with reference to embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0016] Example 1

[0017] Synthesis method

[0018] The starting materials 1-A (5 mmol), (Z)-but-2-en-2-yltrifluoroborate potassium (7.5 mmol), potassium phosphate (10 mmol), tricyclohexylphosphine (20% mol), and Pd2(dba)3 (10% mol) were dissolved in 1,4-dioxane / H2O (1:2). After nitrogen protection, the mixture was stirred overnight at 100°C. The reaction was confirmed to be complete by TLC. The insoluble matter was filtered off, concentrated, and purified by column chromatography to obtain intermediate 1-B.

[0019] Pyrimidine-2-thiol (5 mmol) was dissolved in DCM, and then thioyl chloride (5 mmol) was added. The mixture was stirred at 0°C for 1 hour, and after being cooled to room temperature, a DCM solution of intermediate 1-B (5 mmol) was added dropwise. The reaction was continued for 2 hours. The reaction was confirmed to be complete by TLC. The mixture was extracted with saturated sodium bicarbonate solution, and the organic phase was concentrated and purified by column chromatography to obtain intermediate 1-C.

[0020] Intermediate 1-C (5 mmol) was dissolved in dichloromethane, and m-chloroperoxybenzoic acid (10 mmol) was added. The mixture was stirred overnight at room temperature, quenched with a saturated sodium thiosulfate solution, and extracted with ethyl acetate. The concentrate was then column-secred to give intermediate 1-D.

[0021] Dissolve 1-D (5 mmol) in methanol, add potassium carbonate (10 mmol), react overnight at room temperature, and concentrate to obtain intermediate 1-E.

[0022] Potassium acetate (5 mmol) and amide peroxymonosulfuric acid (10 mmol) were added to an aqueous solution of 1-E (5 mmol). The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The aqueous phase was extracted with ethyl acetate (10 mL * 2), washed with water (20 mL * 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain intermediate 1-F.

[0023] Add zinc trifluoromethanesulfonate (0.25 mmol) and (R)-(-)-4,12-bis(diphenylphosphino)[2.2]p-cycloarane(1,5-cyclooctadiene)rhodium tetrafluoroborate to an ethanol solution (8 mL) of intermediate 1-F (5 mmol). The reaction was carried out at room temperature for 3 hours under hydrogen atmosphere. The reaction was detected as complete by TLC. The mixture was filtered, concentrated under reduced pressure, and column chromatography was used to obtain intermediate 1-G.

[0024] The starting material 1-H (5 mmol) was dissolved in dichloromethane, and triethylenediamine (15 mmol) was dissolved in 10 mL of acetone. The mixture was stirred at room temperature for 15 minutes until the solid dissolved. Then, 10 mL of carbon disulfide was added dropwise in portions. During the addition, a large amount of solid was produced in the solution. After the addition was complete, the mixture was stirred thoroughly for another two hours, and the reaction was monitored by TLC until complete. Stirring was stopped, the mixture was filtered, and the filter cake was washed twice with petroleum ether. The filter cake was collected and dried. The solid obtained above was then dissolved in 10 mL of chloroform and stirred at 0 °C. Triphosgene (1.8 mmol) was dissolved in 5 mL of chloroform and slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was transferred to room temperature and stirred overnight. The reaction was monitored by TLC until complete. The insoluble matter in the solution was filtered off, the solvent was evaporated, and the solution was purified by column chromatography. The purified liquid was obtained by filtration with ethyl acetate / petroleum ether (1:3) to give 1-I as a colorless liquid.

[0025] Intermediate 1-I (3 mmol) and 1-G (3 mmol) were dissolved in acetonitrile (10 mL), and cesium carbonate (4 mmol) was added. The mixture was stirred overnight under nitrogen protection and concentrated to obtain intermediate 1-J.

[0026] Intermediate 1-K (3 mmol) and hydrazine hydrate (6 mmol) were dissolved in ethanol (10 mL), and the mixture was heated to 80 °C and stirred for 16 hours. After concentration, petroleum ether was added and stirred to obtain intermediate 1-L.

[0027] Intermediate 1-J (5 mmol), 1-J (5 mmol) and silver nitrate (6 mmol) were reacted under nitrogen protection for 2 hours. Then, 3 mL of trifluoroacetic acid was added and the mixture was stirred at 100 degrees Celsius overnight. The reaction was confirmed to be complete by TLC. The mixture was filtered and subjected to column chromatography to obtain Example 1. 1 H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3Hz,1H),7.53(s,2H),7.16(t,J=7.5H z,1H),6.87(d,J=7.5Hz,2H),4.01(s,1H),3.85(s,6H),3.49(s,1H),2.32(s,3H),1.49(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0028] Example 2

[0029] Following the synthesis method of Example 1, replacing 1-A with 2-chloro-5-methylpyrimidine-4,6-d2 yields Example 2. 1H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3Hz,1H),7.16(t,J=7.5Hz,1H), 6.87(d,J=7.5Hz,2H),4.25(s,1H),3.85(s,6H),3.46(s,1H),2.32(s,3H),2.09(d,J=2.8Hz,3H),1.27(d,J=2.8Hz,3H).

[0030] Example 3

[0031] Example 3 can be prepared by replacing 1-K with methyl 5-(methyl-d3)nicotinic acid, following the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=1.2Hz,1H),8.32(s,2H),7.79–7.56(m,2H),7.16(t,J=7.5Hz,1H),6.87( d,J=7.5Hz,2H),4.01(s,1H),3.85(s,6H),3.48(s,1H),2.23(s,3H),1.49(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0032] Example 4

[0033] Following the synthesis method of Example 1, by replacing intermediate 1-H with 2,6-bis(methoxy-d3)aniline, Example 4 can be prepared. 1 H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.32(s,2H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3Hz,1H),7.24(t,J =7.4Hz,1H),6.87(d,J=7.5Hz,2H),4.01(s,1H),3.47(s,1H),2.32(s,3H),2.23(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0034] Example 5

[0035] Example 5 can be prepared by referring to the synthesis method of Example 1. 1H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.32(s,2H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3H z,1H),4.01(s,1H),3.80(s,6H),3.47(s,1H),2.32(s,3H),2.23(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0036] Example 6

[0037] Example 6 can be prepared by referring to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3Hz,1H),7.16(t,J=7.5H z,1H),6.87(d,J=7.5Hz,2H),4.25(s,1H),3.85(s,6H),3.46(s,1H),2.32(d,J=2.8Hz,3H),1.27(d,J=2.8Hz,3H).

[0038] Example 7

[0039] Referring to the synthesis method of Example 1, by replacing intermediate 11 with tert-butyl 4-bromo-5-(methyl-d3)-methyl-3-(methyl-d3)-1H-pyrazole-1-carboxylate, Example 7 can be prepared. 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=1.2Hz,1H),7.72–7.54(m,2H),7.16(t,J=7.5Hz,1H),6.87( d,J=7.5Hz,2H),4.25(s,1H),3.85(s,6H),3.46(s,1H),2.44(d,J=2.8Hz,2H),1.27(d,J=2.8Hz,3H).

[0040] Example 8

[0041] Example 8 can be prepared by referring to the synthesis method of Example 1. 1H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.22(d,J=1.3Hz,1H),7.91(t,J=1.3Hz,1H),7.24(t,J =7.4Hz,1H),6.87(d,J=7.5Hz,2H),4.25(s,1H),3.46(s,1H),2.32(d,J=2.8Hz,3H),1.27(d,J=2.8Hz,3H).

[0042] Example 9

[0043] Example 9 can be prepared by referring to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ8.97(d,J=1.2Hz,1H),8.32(s,2H),8.22(d,J=1.3Hz,1H),7.91(t,J =1.3Hz,1H),4.01(s,1H),3.47(s,1H),2.32(s,3H),2.23(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0044] Example 10

[0045] Example 10 can be prepared by referring to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=1.2Hz,1H),8.32(s,2H),7.81–7.35( m,2H),4.01(s,1H),3.47(s,1H),2.23(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0046] Example 11

[0047] Example 11 can be prepared by referring to the synthesis method of Example 1. 1 H NMR (500MHz, Chloroform-d) δ9.02(d,J=1.2Hz,1H),7.78–7.49(m,2H),4.25(s,1H),3.44(s,1H),2.46(d,J=2.8Hz,3H),1.27(d,J=2.8Hz,3H).

[0048] Example 12

[0049] Example 12 can be prepared by referring to the synthesis method of Example 1. 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=1.1Hz,1H),8.32(s,2H),7.72–7.52(m,2H),7.24(t,J=7.4H z,1H),6.87(d,J=7.5Hz,2H),4.01(s,1H),3.47(s,1H),2.23(d,J=2.8Hz,3H),1.20(d,J=2.8Hz,3H).

[0050] Experimental Example 1: PathHunterβ-arrestin eXpress GPCR Assay

[0051] CHO cells stably expressing the human apelin receptor were added to 96-well plates and incubated overnight at 37°C. The test compound was dissolved in DMSO and diluted 3-fold to the corresponding test concentration. The test compound was added and co-incubated with the cells at 37°C for three hours. After adding PathHunter assay solution, fluorescence intensity was detected at 485 and 525 nm after 30 minutes of incubation.

[0052] Table 1. Compound EC 50 value

[0053] As can be seen from Table 1, the compounds in the examples all showed varying degrees of increased activity compared to the positive control drug BGE-105, with significant gains.

[0054] Experimental Example 2: Pharmacokinetic Experiment of Compounds

[0055] In the examples, BGE-105 was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution, which was then administered orally. Blood samples of 0.5 mL heparin were continuously collected from the fundus venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after oral administration. The samples were centrifuged at 8000 rpm and 4 °C for 10 min, and 0.15 mL of the supernatant plasma was collected and stored at -20 °C for LC-MS / MS analysis. Data were analyzed using a WinNolin non-compartmental model to obtain key pharmacokinetic parameters.

[0056] (I) Experimental Results

[0057] Table 2. Pharmacokinetic parameters

[0058] Compared to BGE-105, the compounds in the examples in Table 2 have a significantly longer oral half-life, which can effectively improve the dosage and thus reduce the toxic side effects of high-dose administration.

[0059] Finally, it is necessary to clarify that the specific embodiments of the present invention have been described in detail above, but these are merely examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A deuterated 1,2,4-triazole compound of formula I and its pharmaceutically acceptable salt, characterized in that... The structure is as follows: Among them, R1, R2, R3, R4, and R5 are independently selected from H or deuterium, and R1, R2, R3, R4, and R5 are not all H at the same time.

2. The deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt according to claim 1, characterized in that... The compound is selected from the following structures:

3. The deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that... The pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

4. The use of a deuterated 1,2,4-triazole compound according to claim 1 or 2 and a pharmaceutically acceptable salt thereof in the preparation of an Apelin receptor agonist medicament.

5. The pharmaceutical composition of the deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt according to claim 1 or 2, characterized in that, The pharmaceutical composition comprises the deuterated 1,2,4-triazole compound and its pharmaceutically acceptable salt as the active ingredient and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of the deuterated 1,2,4-triazole apelin receptor agonist according to claim 5, characterized in that, The pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

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