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2-oxo-1,2-dihydroquinoline derivative, preparation method and medical applications thereof
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A reaction, drug technology, applied in the field of medicine
Active Publication Date: 2020-05-12
TIANJIN INSTITUTE OF PHARMA RESEARCH
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However, the known physicochemical properties of FⅪa inhibitors, pharmacokinetic properties in vivo, there are still many deficiencies
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Embodiment 1
[0087] Example 1: 5-(((2S)-1-(((6-chloro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)(methyl)amino)-3 Synthesis of -(4-(2-methylcyclopropane-1-carboxamido)phenyl)-1-oxopropan-2-yl)carbamoyl)thiophene-2-carboxylic acid (compound 1)
[0088]
[0089] The first step: (2S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-methylcyclopropyl-1-carboxamido)phenyl)propanoic acid methyl ester (3b) Synthesis
[0090]
[0091] 2-Methylcyclopropanecarboxylic acid (3a) (2.98g, 29.8mmol) and (S)-methyl 3-(4-nitrophenyl)-2-(tert-butoxycarbonylamino)propionate (intermediate 1) (7.30g, 24.8mmol) was dissolved in DMF (80mL), PyBOP (15.5g, 27.7mmol), DIEA (6.41g, 49.6mmol) and DMAP (0.61g, 4.96mmol) were added, and the reaction was stirred at room temperature. After 16 h, water (800 mL) was added to the reaction solution, and a solid was precipitated. Suction filtration, washing with water (100 mL), drying at 50°C for 3 h, and purification by column chromatography gave the title compound 3b (7.40 g, yie...
Embodiment 2
[0119] Example 2: (R)-5-((1-(((6-chloro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)(methyl)amino)-3 Synthesis of -(4-(cyclopropylcarboxamido)phenyl)-1-oxopropan-2-yl)carbamoyl)thiophene-2-carboxylic acid (Compound 2)
[0120]
[0121] In the first step of this example, cyclopropanecarboxylic acid (4a) was used instead of 2-methylcyclopropanecarboxylic acid (3a) in the first step of Example 1, and the title compound was obtained by a method similar to that of Example 1.
[0124] Example 3: 5-(((2S)-1-(((6-chloro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)(methyl)amino)-3 Synthesis of -(4-(2,2-Dimethylcyclopropyl-1-carboxamido)phenyl)-1-oxopropan-2-yl)carbamoyl)thiophene-2-carboxylic acid (Compound 3)
[0125]
[0126] In the first step of this example, use 2,2-dimethylcyclopropanecarboxylic acid (5a) to replace 2-methylcyclopropanecarboxylic acid (3a) in the first step of Example 1, using a method similar to Example 1 The title compound was obtained.
[0127] 1 H NMR (400MHz, DMSO-d6): δ13.60–12.87(m,1H),11.82(s,1H),9.97(s,1H),9.17(d,1H),7.91(d,1H),7.78 (d,1H),7.68(d,1H),7.52(d,1H),7.46(d,2H),7.32(d,1H),7.24(d,2H),6.33(s,1H),5.05( d,1H),4.72(s,2H),3.06–2.98(m,4H),2.94(s,1H),1.67–1.53(m,1H),1.12(dd,6H),0.92(d,1H) ,0.73(s,1H).
[0128] MS m / z=634.85[M+H] + .
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Abstract
The invention relates to a 2-oxo-1,2-dihydroquinoline compound represented by a formula (I), and a preparation method thereof, and applications in medicines for preventing and / or treating thromboembolic diseases and / or thromboembolic complications, wherein R<1> is selected from the following groups defined in the specification, R<2> is selected from C1-6 alkyl, and n is selected from 0, 1 and 2. Compared with the compound in the prior art, the compound provided by the invention has obvious advantages due to high activity, high solubility and good pharmacokinetic properties.
Description
technical field [0001] The invention relates to the field of medicines, in particular to a 2-oxo-1,2-dihydroquinoline compound, its preparation method and application. Background technique [0002] Thromboembolic disease not only has a high incidence rate, but also has a high mortality and disability rate. For example, myocardial infarction, cerebral infarction, and pulmonary infarction caused by thromboembolism rank first among various causes of death. Drugs for the prevention and treatment of thrombotic diseases mainly include anticoagulant, antiplatelet and thrombolytic drugs. Bleeding is the main and most common complication in the prevention and treatment of clinical antithrombotic drugs. Traditional anticoagulant drugs, such as warfarin, heparin, low molecular weight heparin (LMWH), and new drugs that have been marketed in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) Gatran etexilate, hirudin, etc.) all have a good effect on reducing thrombus fo...
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