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Deuterated imidazothiadiazole derivative and medical application thereof

A technology of thiadiazole derivatives and imidazolo, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, antineoplastic drugs, etc., can solve problems such as perishable, affecting metabolic stability, and reducing activity

Inactive Publication Date: 2019-09-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In actual research, the inventors found that BMS-986120 is not stable in aqueous solution, and it is easy to deteriorate and reduce activity after being placed at room temperature for about 6 hours. This may be caused by the structure of methoxy-substituted imidazothiadiazole of
This may also further affect its metabolic stability in vivo

Method used

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  • Deuterated imidazothiadiazole derivative and medical application thereof
  • Deuterated imidazothiadiazole derivative and medical application thereof
  • Deuterated imidazothiadiazole derivative and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] 6-(4-(Benzyloxy)-6-(trideuteromethoxy)benzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4] Thiadiazole (compound 1)

[0095]

[0096] Under Ar atmosphere, phloroglucinol (3 g, 0.024 mol) was dissolved in anhydrous DMF (30 mL), and phosphorus oxychloride (2.2 mL, 0.024 mol) was slowly added dropwise at 0° C. Stir at room temperature for 4 hours. After the reaction, the reaction solution was poured into ice to quench, extracted with a mixed solvent (dichloromethane:methanol=10:1), concentrated, dissolved in ethyl acetate, and then repeatedly washed with saturated saline and 20% LiCl solution The remaining DMF was washed away, the solvent was evaporated to dryness under reduced pressure, and compound 1-1 (white solid, 2.9 g) was obtained by flash column chromatography (petroleum ether: ethyl acetate = 2:1), with a yield of 80%. 1 H NMR (300MHz, DMSO) δ11.46(s, 2H), 10.65(s, 1H), 9.93(s, 1H), 5.79(s, 2H).

[0097] Under the protection of Ar, 2,4,6-trihydroxybenzaldehyde (com...

Embodiment 2

[0106] 4-(4-(((6-(trideuteromethoxy)-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Benzofuran-4-yl)oxy)methyl)-5-methylthiazol-2-yl)morpholine (compound 2)

[0107]

[0108] The synthesis method of compound 2-1 refers to patent WO 2013 / 163279 A1.

[0109] (5-Methyl-2-morpholinothiazol-4-yl)methanol (compound 2-1) (0.25g, 1.16mmol) was dissolved in 5ml of anhydrous dichloromethane, and tribromo Phosphate (60 μL, 0.58 mmol) was dissolved in 1 ml of dichloromethane, and was added dropwise to the above system. After the addition was complete, react at room temperature for 4 hours, and add 10 ml of saturated sodium bicarbonate solution to quench the reaction, and extract the aqueous phase with dichloromethane. (5mLx3), the organic phase was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness to obtain a crude product, and the compound 2- 2 (white crystal, 0.145g), yield 45%.

[0110]...

Embodiment 3

[0113] 4-(4-(((6-(trideuteromethoxy)-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl) Benzofuran-4-yl)oxy)methyl-deuterium)-5-methylthiazol-2-yl)morpholine (compound 3)

[0114]

[0115] Dissolve (5-methyl-2-morpholinothiazol-4-yl)methanol (compound 2-1) (0.05g, 0.23mmol) in 5ml of dichloromethane solution, add pyridine (45μL, 0.56mmol), Dess Martin reagent (0.12g, 0.28mmol), reacted at room temperature for 2h, TLC monitored the reaction to be basically complete, filtered, washed the filter cake with dichloromethane, collected the filtrate, concentrated, flash column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound 3-1 (light cyan solid, 0.032g), yield: 65%.

[0116] 5-Methyl-2-morpholinothiazole-4-carbaldehyde (compound 3-1) (0.187g, 0.88mmol) was dissolved in 8ml of deuterated methanol, and sodium borodeuteride (0.037g, 0.88mmol), keep the reaction at room temperature for 5h, TLC monitoring after the completion of the reaction, add 5ml of water...

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Abstract

The invention relates to a deuterated imidazothiadiazole derivative as shown in a formula (I) which is shown in the description, or pharmaceutically acceptable salts or esters or solvates thereof. The compound provided by the invention can be used in preparation of drugs used for preventing or treating thromboembolic diseases.

Description

technical field [0001] The present invention relates to deuterated imidazothiadiazole derivatives or pharmaceutically acceptable salts or esters or solvates thereof. The compounds of the present invention are useful in the preparation of medicaments for the prevention or treatment of thromboembolic disorders. Background technique [0002] Thrombin activation of platelet protease-activated receptor 4 (PAR4) plays an important role in thrombus propagation and pathological vascular embolism. PAR4 antagonists have potential utility in the treatment and prevention of thromboembolic disease. Preclinical models of arterial thrombosis have been shown to be more effective than existing antithrombotic drugs (such as aspirin, clopidogrel, vorapaxar, etc.), but with a lower risk of bleeding. BMS-986120 is a derivative of imidazothiadiazole disclosed in WO 2013 / 163279 A that has undergone phase one clinical evaluation. It is a PAR4 antagonist, which can inhibit platelet aggregation and...

Claims

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Application Information

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IPC IPC(8): C07D513/04C07B59/00A61K31/5377A61K31/433A61P7/02A61P9/04A61P9/10A61P25/00A61P13/12A61P11/00A61P35/00
CPCC07D513/04C07B59/002
Inventor 孙宏斌陈盼盼孔毅宋航宇温小安柳军
Owner CHINA PHARM UNIV
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