CN117164565A - Novel oxo-pyrimidine compound and preparation method and application thereof - Google Patents

Novel oxo-pyrimidine compound and preparation method and application thereof Download PDF

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CN117164565A
CN117164565A CN202311150759.3A CN202311150759A CN117164565A CN 117164565 A CN117164565 A CN 117164565A CN 202311150759 A CN202311150759 A CN 202311150759A CN 117164565 A CN117164565 A CN 117164565A
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strokes
compound
pharmaceutically acceptable
stereoisomer
diseases
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黄龙
付海霞
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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 a medicament for treating and/or preventing diseases related to an XI a receptor, in particular application in preparing a medicament for treating and/or preventing cerebrovascular arterial diseases and/or peripheral arterial diseases, and has remarkable medicinal effect.

Description

Novel oxo-pyrimidine 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 of the present invention is a novel oxopyridine compound, and exhibits excellent anticoagulation and affinity to F XI a in vivo and in vitro.
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 another aspect, the present invention provides a process for the preparation of the above-described compounds, stereoisomers or pharmaceutically acceptable salts thereof, comprising the following routes:
。
in another aspect, the present invention also provides the use of any one of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof, or a composition thereof, for the preparation of a medicament for treating and/or preventing diseases associated with the FexI 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 in a FeCl 2-induced rabbit carotid artery thrombosis model, the weight of the rabbit carotid artery thrombus of the example compound 1 group is obviously reduced compared with that of the rabbit carotid artery thrombus of the comparative example 1 group, and the invention has statistical significance and obvious drug 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) -5-methoxy-2-oxopyrimidin-1 (2H) -yl) butyramide) -2-fluoro-N- (methyl-d 3) benzamide (compound 1):
step 1: preparation of intermediate b
Diisopropylamine (24 mmol) was dissolved in 25ml THF, cooled to below-60℃and 9.14ml of a 2.5M solution of n-butyllithium in hexane was added dropwise, after the addition was completed for about 1 hour, the mixture was stirred at-60℃for 15 minutes, 10ml of a solution of Compound a (20 mmol) was added dropwise, the mixture was stirred at-60℃for 2 hours, triisopropyl borate (22 mmol) was added dropwise, and the mixture was warmed up slowly to room temperature (20 ℃) and stirred for 30 minutes. A mixture of 4g of acetic acid and 21g 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 a solid. Yield 78.92%, HPLC purity: 98.26%.
ESI-MS:m/z=185.1 (M+H) + 。
Step 2: preparation of intermediate e
A mixed solution of compound d (10.0 mmol), pd (amphos) Cl2 (0.15 mmol) in 25ml of t-amyl alcohol was taken, heated to 85℃and a reaction was carried out for 1 hour at 85℃with dropwise addition of a mixture of compound c (1.2 mmol), sodium carbonate (30 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. Purifying by column chromatography to obtain intermediate e. Yield 78.11%, HPLC purity: 98.81%.
ESI-MS:m/z=319.1 (M+H) + 。
Step 3: preparation of intermediate f
Compound e (6 mmol), anhydrous lithium chloride (30 mmol), p-toluenesulfonic acid monohydrate (12 mmol) and 20ml of isopropanol were taken and mixed, and the mixture was heated under reflux for 16 hours. Cooling to room temperature, distilling off half of the solvent, adding 30ml of water, stirring at room temperature for 15 minutes, filtering, washing the filter cake with water, and drying in vacuum at 70 ℃ to obtain solid-like intermediate f. Yield: 89.20%, HPLC purity: 96.58%.
ESI-MS:m/z=305.1 (M+H) + 。
Step 4: preparation of intermediate h
A25 ml reaction flask was charged with compound f (2 mmol), tetramethylguanidine (7 mmol), isopropanol 6ml, acetone 1.5ml, stirred at room temperature for 15 minutes, compound g (2.2 mmol) was added and the reaction was stirred at room temperature overnight. The next day, adding water to terminate the reaction, adding EA to extract, separating out the water layer, washing the organic layer with saturated ammonium chloride, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating to dry the solvent, separating and purifying with chromatographic column, and collecting the product to obtain the pure product. The yield thereof was found to be 82.36% and the purity thereof was found to be 98.41%.
ESI-MS:m/z=584.2(M+H) + 。
Step 5: preparation of intermediate j
A25 ml reaction flask was charged with compound h (2 mmol), 16ml of methanol, dissolved with stirring and cooled to 0 ℃. Lithium hydroxide monohydrate (4 mmol) was weighed and dissolved in 8ml 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, performing column chromatography, and collecting target product to obtain intermediate j with yield 79.30% and purity of 98.20%.
ESI-MS:m/z=528.1 (M+H) + 。
Step 6: preparation of (S) -4- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyrimidin-1 (2H) -yl) butyramide) -2-fluoro-N- (methyl-d 3) benzamide (Compound 1)
50ml of reaction flask were charged with intermediate j (1 mmol), DMF 3ml, deuterated methylamine hydrochloride (1.1 mmol), EDCI (2 mmol), HOBT (2 mmol), cooled to 0℃and DIPEA (4 mmol) was added dropwise for reaction at room temperature for 12h, after completion of the reaction. Adding the reaction solution into cold water, extracting with ethyl acetate twice, washing with saturated saline, drying with anhydrous sodium sulfate, evaporating the solvent, and purifying with silica gel chromatographic column to obtain compound 1 with yield 75.47% and purity 98.51%.
ESI-MS:m/z=544.2 (M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.70 (s, 1H), 9.86 (s, 1H), 9.09 (s, 1H), 8.01 (d, J = 3.4 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.71 – 7.60 (m, 2H), 7.35 (dd, J = 8.6, 2.0 Hz, 1H), 7.10 (s, 1H), 5.54 (dd, 1H), 3.25 (s, 3H), 2.09 (m, 2H), 0.77 (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 compound 1 of the present invention on FXIa was comparable to that of compound 1 of comparative example 1 at the same molar concentration.
Test example 2: in vivo efficacy evaluation of rabbit arteriovenous shunt model
1. Test sample
Example compound 1 and comparative example 1.
2. Test method
Selecting New Zealand white rabbits, all male 30, 2.5-3.0. 3.0 kg. Divided into 3 groups, 10/group. The model group, the comparative example 1 group and the compound 1 group, respectively.
Comparative example 1 group and compound 1 group 6mg/kg of the compounds shown in comparative example 1 and compound 1, respectively, were administered via single injection into the femoral vein.
The animals were anesthetized by intramuscular injection of xylazine (5 mg/kg) and ketamine (40 mg/kg), and the anesthetic effect was maintained by intravenous infusion of xylazine and ketamine (80 mg+800mg, 12 ml) via the right auricular vein (5 ml/h) of rabbits. One common carotid artery was surgically exposed and after 30min of intravenous administration, one patch was used in Parafilm ® The filter paper (10 mm. Times.10 mm) on the strip was wrapped around carotid artery and the wrapping did not affect blood flow, and the filter paper contained 100. Mu.l FeCl at 13% concentration 2 An aqueous solution. After 5min, the filter paper was removed and the vessel was rinsed 2 times with 0.9% sodium chloride injection. After 30min using filter paper, the injured carotid artery was excised, and the intravascular thrombus was removed and weighed.
3. Test results
As shown in table 2, in the FeCl 2-induced rabbit carotid thrombus model, the weight of rabbit carotid artery thrombus in the example compound 1 group was significantly reduced compared to that in the comparative example 1 group, and it was statistically significant.
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.
CN202311150759.3A 2023-09-07 2023-09-07 Novel oxo-pyrimidine compound and preparation method and application thereof Pending CN117164565A (en)

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