CN117164562A - Oxopyridazine compound and preparation method and application thereof - Google Patents

Oxopyridazine compound and preparation method and application thereof Download PDF

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Publication number
CN117164562A
CN117164562A CN202311149889.5A CN202311149889A CN117164562A CN 117164562 A CN117164562 A CN 117164562A CN 202311149889 A CN202311149889 A CN 202311149889A CN 117164562 A CN117164562 A CN 117164562A
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strokes
compound
pharmaceutically acceptable
stereoisomer
diseases
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周广林
管玲
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Chengdu Shibeikang Biological Medicine Technology Co ltd
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Chengdu Shibeikang Biological Medicine Technology Co ltd
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Abstract

The invention discloses a compound shown in a formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof. The invention also provides application of the compound, stereoisomer or pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing diseases related to the F XI a receptor, in particular application in preparing medicaments for treating and/or preventing cerebrovascular arterial diseases and/or peripheral arterial diseases, and has better and safer medicinal effects.

Description

Oxopyridazine compound and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an oxo-pyridine compound or salts and isomers thereof, a preparation method thereof and application thereof in preparing medicaments for treating and/or preventing diseases related to an XI a receptor, in particular to application in preparing medicaments for treating cerebrovascular arterial diseases and/or peripheral arterial diseases and the like.
Background
Thromboembolic diseases are diseases caused by abnormal blood clots formed in blood vessels of humans and animals during survival, and clinically may be manifested as myocardial infarction, stroke, deep Vein Thrombosis (DVT), pulmonary embolism, atrial fibrillation, cerebral infarction, etc., taking millions of people worldwide each year. Factor XI (FXI) is a plasma serine protease zymogen necessary for maintaining the endogenous pathway, and activated to form activated factor XIa (FXIa) plays a key role in the amplification of the coagulation cascade. Therefore, drugs against FXIa targets block endogenous pathways and inhibit amplification of the coagulation cascade, thus having antithrombotic effects.
The reported FXIa inhibitors mainly comprise monoclonal antibodies, antisense oligonucleotides, chemical small molecules, polypeptides or protein or polypeptide mimics and the like. Currently, milvexin, developed in conjunction with robustly, has completed clinical phase II trials, which have shown less risk of bleeding. Phase I clinical trials of the intravenous injection of the small molecule FXIa inhibitor BMS-962122 have been completed and development has been suspended. The small molecule oral FXIa inhibitor ONO-7684 developed by Japan Kochia company enters clinical phase I study. BAY-2433334 developed by Bayer has completed a clinical phase II trial and is currently the most promising small molecule FXIa inhibitor. The monoclonal antibody and the antisense oligonucleotide need to be injected and administrated, and have the defects of high price, slow effect, possibly difficult control and the like, and the chemical small molecules have the advantages of relatively good oral bioavailability, better patient compliance and the like.
Therefore, the research and development of new FXIa small molecule inhibitor drugs with safety, effectiveness, good specificity and strong activity can be used for overcoming the defect that the current clinical anticoagulation anti-thrombus drugs are easy to cause bleeding complications and meeting the clinical unmet demands.
Disclosure of Invention
The compound is a novel oxo-pyridine compound, and the compound of the embodiment of the invention shows good anticoagulation effect, in-vitro affinity to the FexI a and in-vivo drug generation.
In one aspect, the present invention provides a compound of formula (i), a stereoisomer or a pharmaceutically acceptable salt thereof:
further, the pharmaceutically acceptable salt is a metal salt.
Further, the metal salt is selected from sodium salt, potassium salt, calcium salt, lithium salt, and magnesium salt.
In another aspect, the present invention provides a pharmaceutical composition of the above compound, a stereoisomer or a pharmaceutically acceptable salt thereof, which composition further comprises a pharmaceutically acceptable carrier and/or adjuvant.
In a third aspect, the present invention provides a process for the preparation of the above compound, a stereoisomer or a pharmaceutically acceptable salt thereof, comprising the following route:
in a fourth aspect, the present invention also provides the use of any one of the above compounds, stereoisomers or pharmaceutically acceptable salts or compositions thereof, for the preparation of a medicament for treating and/or preventing diseases associated with the F xi a receptor.
Further, the above-mentioned diseases related to the F XI a receptor are selected from thrombosis or thromboembolic related disorders.
Further, the above-mentioned diseases related to the F XI a receptor are selected from cerebrovascular arterial diseases and/or peripheral arterial diseases.
Further, the above-mentioned cerebrovascular arterial diseases include, but are not limited to, transient Ischemic Attacks (TIAs), ischemic strokes or events that lead to thrombosis and/or thromboembolic origin of strokes or TIAs; such peripheral arterial disease includes, but is not limited to, peripheral arterial occlusion, acute limb ischemia, amputation, reocclusion and restenosis following interventions (e.g., angioplasty, stent implantation or surgery and bypass), and/or stent thrombosis.
Further, the ischemic stroke includes, but is not limited to, cardiac stroke, non-cardiac stroke, stroke due to aortic or arteriolar diseases, stroke due to adventitious causes, cryptogenic stroke, embolic stroke, or embolic stroke of adventitious origin.
Further, the above-mentioned cardiac strokes include, but are not limited to, strokes due to atrial fibrillation; such non-cardiac strokes include, but are not limited to, lacunar strokes.
The beneficial effects are that: compared with the prior art, the invention has good FXIa inhibition effect and anti-human plasma coagulation effect, and in vivo pharmacokinetics of rats shows that the invention has higher AUC and Cmax, and has quicker metabolism, thus avoiding the risk of increasing bleeding due to long-time effect.
Detailed Description
The present invention will be described in further detail with reference to the following examples and experimental examples, which are only for illustrating the technical scheme of the present invention, but not for limiting the present invention, and any equivalent substitution in the art according to the disclosure of the present invention shall fall within the scope of the present invention.
The structure of the compound is nuclear magnetic resonance 1 H NMR) or liquid mass spectrometry (LC-MS).
The liquid chromatography-mass spectrometer (LC-MS) is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance apparatus 1 H NMR) of Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance 1 H NMR) shift [ ]δ) Given in parts per million (ppm), the internal standard is Tetramethylsilane (TMS), the chemical shift is 10 -6 (ppm) is given as a unit.
The term "room temperature" according to the invention means a temperature between 10 and 30 ℃.
Example 1: preparation of (S) -4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3- (methoxy-d 3) -6-oxopyridazin-1 (6H) -yl) butyramide) -2-fluoro-N- (methyl-d 3) benzamide (compound 1):
step 1: preparation of intermediate b
6-methoxypyridazin-3-ol (2 g,15.8 mmol) was taken, dissolved by adding 40ml DMF, cesium carbonate (10.3 g,31.6 mmol) was added, cooled to 0℃and deuterated iodomethane (3.5 g,24.1 mmol) was added dropwise over about 30 minutes, and the reaction was stirred at room temperature for 4 hours after the addition. EA, water, extraction, water washing, saturated brine washing, anhydrous sodium sulfate drying, filtration, evaporation of the solvent, column chromatography purification, 2g of intermediate b were obtained. Yield: 88.42%, HPLC purity: 98.81%.
ESI-MS:m/z=144.1 (M+H) +
Step 2: preparation of intermediate c
Diisopropylamine (1.7 g,16.8 mmol) was dissolved in 20ml THF, cooled to below-60℃and added dropwise with 6.4ml of 2.5M n-butyllithium-n-hexane solution over about 1 hour, followed by stirring at-60℃for 15 minutes, followed by adding dropwise with 5ml THF solution of compound b (2 g,14.0 mmol) for about 1 hour, followed by stirring at-60℃for 2 hours, followed by adding dropwise triisopropylborate (2.9 g,15.4 mmol) for 30 minutes, followed by slowly heating to room temperature (20 ℃) and stirring for 30 minutes. A mixture of 3g of acetic acid and 15g of water was added dropwise to terminate the reaction. After the addition, stirring at room temperature for 30 minutes. The organic solvent was distilled off, a little water was added, stirred at room temperature for 15 minutes, filtered, and the cake was washed with water and dried under vacuum at 70℃to give 2.1g of solid. Yield 80.22%, HPLC purity: 98.12%.
ESI-MS:m/z=188.1 (M+H) +
Step 3: preparation of intermediate e
A mixed solution of compound d (2.59 g,10.0 mmol), pd (amphos) Cl2 (107.5 mg,0.15 mmol) in 25ml of t-amyl alcohol was taken, heated to 85℃and a reaction was carried out at 85℃for 1 hour after about 1 hour with dropwise addition of a mixed solution of compound c (2.22 g,11.9 mmol), sodium carbonate (3.2 g,30.2 mmol) and 25ml of water. Cooling to room temperature, adding EA/water, extracting, separating out water layer, washing organic layer with water and saturated salt water, drying with anhydrous sodium sulfate, filtering, and evaporating solvent. Purification by column chromatography gave 2.4g of intermediate e. Yield 74.59%, HPLC purity: 98.63%.
ESI-MS:m/z=322.1 (M+H) +
Step 4: preparation of intermediate f
Compound e (1.87 g,5.80 mmol), anhydrous lithium chloride (1.3 g,30.7 mmol), p-toluenesulfonic acid monohydrate (2.2 g,11.6 mmol) and 20ml of isopropanol were taken and mixed, and reacted under reflux with heating for 16 hours. Cooled to room temperature, half of the solvent was distilled off, 30ml of water was added, stirred at room temperature for 15 minutes, filtered, and the cake was washed with water and dried under vacuum at 70℃to give 1.61g of solid. Yield: 90.21%, HPLC purity: 96.43%.
ESI-MS:m/z=308.1 (M+H) +
Step 5: preparation of intermediate h
A25 ml reaction flask was charged with compound f (803 mg,1.70 mmol), tetramethylguanidine (681 mg,5.91 mmol), isopropanol 6ml, acetone 1.5ml, and stirred at room temperature for 15 minutes, compound g (684 mg,1.9 mmol) was added, and the reaction was stirred at room temperature overnight. The next day, water is added to terminate the reaction, EA is added to extract, the water layer is separated, the organic layer is washed with saturated ammonium chloride, water, saturated saline water and anhydrous sodium sulfate in sequence, the mixture is dried, filtered, the solvent is evaporated, and the chromatographic column is used for separating and purifying, and the product is collected to obtain 832mg of pure product. The yield thereof was found to be 83.37% and the purity thereof was found to be 98.32%.
ESI-MS:m/z=587.1(M+H) +
Step 6: preparation of intermediate j
A25 ml reaction flask was charged with compound h (587 mg,1 mmol), methanol 8ml, dissolved with stirring and cooled to 0deg.C. Lithium hydroxide monohydrate (84 mg,2 mmol) was weighed and dissolved in 4ml of water, and the mixture was added dropwise to a reaction flask and reacted at room temperature for 2 hours. Adding water to terminate the reaction, adjusting pH to weak acidity with 5% citric acid, adding EA to extract, separating water layer, washing organic layer with water, saturated NaCl, drying with anhydrous sodium sulfate, filtering, evaporating solvent, and performing column chromatography to obtain 432mg of intermediate j with yield of 81.36% and purity of 98.30%.
ESI-MS:m/z=531.1 (M+H) +
Step 7: preparation of (S) -4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3- (methoxy-d 3) -6-oxopyridazin-1 (6H) -yl) butyramide) -2-fluoro-N- (methyl-d 3) benzamide (Compound 1)
50ml of reaction flask was charged with intermediate j (0.3 g,0.57 mmol), DMF 3ml, deuterated methylamine hydrochloride (48.2 mg,0.68 mmol), EDCI (218.7 mg,1.14 mmol), HOBT (154 mg,1.14 mmol), cooled to 0deg.C, DIPEA (295 mg,2.28 mmol) was added dropwise, reacted at room temperature for 12h, and the starting material was completed. The reaction solution was added to cold water, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give 210mg of Compound 1, which was purified on a silica gel column with a yield of 67.35% and a purity of 98.80%.
ESI-MS:m/z=547.2(M+H) +
1 H NMR (400 MHz, DMSO-d6) δ: 10.76 (s, 1H), 9.12 (s, 1H), 8.10 (s, 1H), 7.90 – 7.76 (m, 3H), 7.71 – 7.60 (m, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 5.52 (s, 1H), 2.10 (d, J = 7.1 Hz, 2H), 0.79 (t, J = 7.2 Hz, 3H)。
Comparative example 1: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluorobenzamide
Synthesized according to the method described in patent CN108026072B, purity: 98.5%.
ESI-MS: m/z =593.1(M+H) +
1 H NMR (400 MHz, DMSO-d6) δ: 10.78 (s, 1H), 9.14 (s, 1H), 7.88 – 7.77 (m, 3H), 7.72 – 7.61 (m, 2H), 7.55 (d, 2H), 7.37 (dd, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (dd, 1H), 3.25 (s, 3H), 2.18 – 2.00 (m, 2H), 0.78 (t, 3H)。
Test example 1: inhibition of coagulation factor FXIa
1. Test sample
Example compound 1 and comparative example 1.
2. Test procedure
1) Experiment buffer (50 mM HEPES,5mM KCl,145mM NaCl,1mg/ml PEG8000, pH 7.4) was prepared and equilibrated to room temperature.
2) Preparing 10X compound working solution.
3) Preparing 0.8nM Human FXIa working solution (2X), and mixing.
4) Add 20. Mu.L of FXIa working fluid from step 3) to all experimental wells of 384 well plates (Coring, 3702), 200g, RT, centrifuge for 10s.
5) Add 4. Mu.L of the compound working solution from step 2) to the corresponding experimental well in 384 well plates, 200g, RT, centrifuge for 10s, and then incubate the plates at 25℃for 20min.
6) Preparing 750 mu M S-2366 working solution (2.5X), and uniformly mixing for later use.
7) mu.L of the S-2366 working solution from step 6) was added to all experimental wells in 384-well plates, 200g, RT, centrifuged for 10S, and the plates were incubated at 37℃for 45min.
8) After incubation was completed, absorbance at OD405nm was read using EnVision and data was collected.
Setting 5 concentrations, namely: 200nM, 40nM, 8nM, 1.6nM, 0.32nM, detection IC 50 Values.
3. Data analysis
1) Z’ factor = 1-3*(SD Max +SD Min )/(Mean Max -Mean Min );
2) CV Max = (SD Max /Mean Max )*100%;
3) CVMin = (SD Min /Mean Min )*100%;
4) S/B = Singal/Background;
5) Blank control: 0.1% DMSO; positive control, comparative example 1;
6)IC 50 the calculation formula of (2) is Y=bottom+ (Top-Bottom)/(1+10 ((LogIC) 50 -X)*HillSlope))。
X is the log value of the compound concentration; y is Inhibition%.
4. Test results
The test results are shown in the following table, and the results show that: the in vitro inhibition activity of the compounds of the invention against FXIa was comparable to that of the compound of comparative example 1 at equimolar concentrations.
Test example 2: determination of in vitro anticoagulation of human plasma
1. Test sample
Example compound 1 and comparative example 1.
2. Test method
And (3) using a sodium citrate (1:9) anticoagulation tube, immediately mixing the blood with an anticoagulant fully and uniformly after collecting the blood of a healthy person, centrifuging at 4000r/min for 15 minutes at normal temperature, sucking a plasma sample by using a pipette after centrifugation, and freezing (-80 ℃) for standby.
Weighing a proper amount of compound, and preparing 10-100 mM mother liquor by using 100% DMSO (the concentration of the specific mother liquor is determined according to the nature of the compound); preparing working solutions (specifically: 0, 0.3, 1, 3, 10, 30, 60, 100, 300 μm) with different concentrations by taking healthy human blood plasma as solution, and fully and uniformly mixing; APTT determination was performed on the machine (model CS-2000I) after incubation at 37℃for 3 min.
3. Data processing
Curve fitting was performed using GraphPad Prism software to calculate the EC150 value, i.e., the effective concentration of the compound corresponding to 50% extension of APTT relative to the blank.
4. Test results
The results are shown in the following table, and the APTT EC150 of compound 1 tested is superior to that of the compound of comparative example 1.
Test example 3: rat pharmacokinetic study
1. Test sample
Example compound 1 and comparative example 1.
2. Test object preparation method and environmental requirements
The preparation of the test substances is carried out on a conventional working table of the preparation room.
Preparing stock solution of the building method: prepared according to the dispensing protocol, 1.00mg/mL stock solutions of example compound 1 and comparative example 1 were prepared using methanol as the solvent.
Preparation of rat dosing solution: prepared by using 0.5% CMC-Na as solvent. The oral administration concentration is 30mg/mL.
3. Test procedure
(1) Administration and sample collection
Rats were fasted for 12h before dosing and were free to drink water. The experiment used 12 SD rats, each half of male and female, divided into 2 groups of 6.
Collecting blank blood before administration, and pressing after administrationTaking blood at a preset time point:2min、5min、10min、15min、30min、 45min、1h、2h、3h、5h、7h、24h,blood was collected at about 0.5mL, placed in EDTA-K2 tube, centrifuged to separate plasma, and stored at-80 ℃.
(2) Animal handling
At the end of the experiment, all animals were euthanized according to institutional SOP.
(3) Instrument for measuring and controlling the intensity of light
Liquid phase-mass spectrometry analysis system (LC-MS/MS) comprising Shimadzu LC-20AD series binary pump and SIL-20AC autosampler, AB company API-4000Q-Trap mass spectrum detector (containing ESI ion source), chromatographic column: ODS-C18 (4.6X150 mm, 3 μm).
(4) Sample processing
Standard curve sample treatment: a series of working fluids containing different concentrations of comparative example 1 and compound 1 were prepared. Taking 20 mu L of working solution, adding 100 mu L of blank plasma sample, vortex mixing, adding 300 mu L of acetonitrile solution containing 40 ng/mL of propranolol internal standard, vortex mixing, centrifuging at 4 ℃ for half an hour at 14000g, and taking supernatant for LC-MS/MS detection.
Rat plasma sample treatment: 20. Mu.L of acetonitrile was taken, 100. Mu.L of plasma sample was added, vortexed and mixed, 300. Mu.L of acetonitrile solution containing 40 ng/mL of propranolol as an internal standard was further added, vortexed and mixed, and centrifuged at 4℃and 14000g for half an hour, and the supernatant was taken for detection.
(5) Pharmacokinetic analysis
The pharmacokinetic parameters were calculated using DAS 2.0 software based on the plasma concentration data of the drug.
4. Results
The results of pharmacokinetic studies with oral administration in rats are shown in the following table, with superior absorption and AUC for example compound 1 compared to comparative example 1 (0-t) And Cmax, while having a shorter half-life, with rapid elimination of pharmacokinetic profile, and lower safety risk for potential bleeding.
The above embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.

Claims (9)

1. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:
2. the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the salt is a metal salt.
3. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, wherein the metal salt is selected from sodium, potassium, calcium, lithium, magnesium salts.
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the composition further comprises a pharmaceutically acceptable carrier and/or adjuvant.
5. A process for the preparation of a compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, which comprises the following route:
6. use of a compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, or a composition according to claim 4 for the preparation of a medicament for the treatment and/or prevention of diseases associated with the F xi a receptor.
7. The use according to claim 6, wherein the disease associated with the F xi a receptor is selected from thrombosis and thromboembolic related disorders.
8. Use according to claim 6, wherein the diseases related to the F xi a receptor are selected from cerebrovascular arterial diseases and/or peripheral arterial diseases.
9. Use according to claim 6, wherein the diseases related to the F-xi a receptor are selected from Transient Ischemic Attacks (TIA) or ischemic strokes, including cardiac strokes, strokes such as those caused by atrial fibrillation, non-cardiac strokes, strokes such as lacunar-tive strokes, strokes caused by aortic or arteriolar diseases, or strokes caused by adventitious causes, cryptogenic strokes, embolic strokes of adventitious origin, or events of thrombotic and/or thromboembolic origin leading to strokes or TIA, and/or conditions of the peripheral arteries leading to peripheral arterial diseases, including peripheral arterial occlusion, acute limb ischemia, amputation, reocclusion and restenosis following interventions such as angioplasty, stent implantation or surgery and bypass, and/or stent thrombosis.
CN202311149889.5A 2023-09-07 2023-09-07 Oxopyridazine compound and preparation method and application thereof Pending CN117164562A (en)

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