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(Trifluoromethoxy) pyrrolidine benzamide compound and application of compound in treating thrombocytopenia

A technology of trifluoromethoxy and benzamide, applied in the field of thrombocytopenia and pyrrolidine benzamide compounds, which can solve the problems of not emphasizing the adjustment of platelet count, easy recurrence of patients, and many adverse reactions

Inactive Publication Date: 2018-06-08
窦玉玲
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The treatment of ITP aims to increase the level of peripheral platelets, reduce the time of platelets in crisis and the incidence of bleeding, thereby reducing the mortality rate, but does not emphasize the adjustment of platelet counts to normal levels, and there is no curative therapy
Clinical first-line drugs include glucocorticoids, intravenous immunoglobulin (intravenous immunoglobulin, IVIg), anti-RhD immunoglobulin (anti-dimmunoglobulin, anti-D). Some patients are prone to drug resistance

Method used

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  • (Trifluoromethoxy) pyrrolidine benzamide compound and application of compound in treating thrombocytopenia
  • (Trifluoromethoxy) pyrrolidine benzamide compound and application of compound in treating thrombocytopenia
  • (Trifluoromethoxy) pyrrolidine benzamide compound and application of compound in treating thrombocytopenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Synthesis of 2-bromo-1-(5-ethylbenzofuran-2-yl)ethan-1-one:

[0024]

[0025] 1-(5-Ethylbenzofuran-2-yl)ethan-1-one (compound 1) (4.18g, 22.21mmol) was dissolved in ether (30mL), and bromine water ( 1.5 mL) was added to the above solution, and after the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, add water and stir, separate the layers, and separate the organic phase. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Then the solvent was distilled under reduced pressure to obtain 2-bromo-1-(5-ethylbenzofuran-2-yl)ethan-1-one (compound 2), 5.05 g, yield 85.1%. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18(t, 3H), 2.72(q, 2H), 4.59(s, 2H), 7.13(d, 1H), 7.29(s, 1H), 7.50(d, 1H), 7.53(s, 1H ). 13 C-NMR (125 MHz, CDCl 3 ) δ: 13.19, 28.44, 32.01, 112.58, 112.86, 122.31, 126.10, 127.46, 136.67, 154.56, 158.66, 187.05. LC-MS(ESI, pos, ion) m / z: 267[M+1].

Embodiment 2

[0026] Example 2: Synthesis of 4-(5-ethylbenzofuran-2-yl)thiazol-2-amine:

[0027]

[0028] Compound 2 (5.05 g, 18.91 mmol) was dissolved in ethanol (30 mL), then thiourea (2.1 g, 27.59 mmol) was added at room temperature, and the reaction mixture was stirred at 80° C. overnight. After the reaction was completed, water was added, the precipitate was filtered, and the obtained solution was concentrated under reduced pressure, then chloroform was added, and the layers were separated. The organic layer was washed with potassium carbonate aqueous solution and brine in turn, and then dried over sodium sulfate. The obtained crude product was recrystallized from a solution of cyclohexane:EtOAc=1:1 to obtain 4.17 g of light yellow solid 4-(5-ethylbenzofuran-2-yl)thiazol-2-amine (compound 3), Yield 90.3%. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18(t,3H), 2.72(q, 2H), 7.03(s, 1H), 7.11(s, 1H), 7.34(d, 1H), 7.50(d, 1H), 7.63(s,2H ), 7.67(s, 1H). 13 C-NMR (125 MHz, CDCl 3 ) δ: 13.19, 28.4...

Embodiment 3

[0029] Example 3: Synthesis of 4-(5-ethylbenzofuran-2-yl)-5-(piperidin-1-yl)thiazol-2-amine:

[0030]

[0031] Compound 3 (4.17g, 17.07mmol) was dissolved in 50mL of DMF, then NBS (4.00g, 22.47mmol) was added under ice-water bath conditions, the mixture was stirred at 0°C for 1 hour, and then added to the reaction mixture Piperidine (2.91 g, 34.14 mmol) and triethylamine (6 mL) were added successively, and the mixture was stirred at 70° C. for 3 days. After the reaction was complete, the solvent was distilled off under reduced pressure, dissolved in chloroform, washed with potassium carbonate aqueous solution and brine successively, and dried over sodium sulfate. The obtained crude product was purified by silica gel column chromatography (eluent is cyclohexane:EtOAc=1:1) to give off-white 4-(5-ethylbenzofuran-2-yl)-5-(piperidine- 1-yl)thiazol-2-amine (compound 4) powder, 5.18 g, yield 92.6%. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18(t, 3H), 1.52-1.67(m, 6H), 2.72(q, 2H), 3.36(m...

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Abstract

The invention discloses a (trifluoromethoxy) pyrrolidine benzamide compound. A structural formula of the compound is as shown in the specification. A pharmacological experiment confirms that the compound has a better proliferation effect on 32D-MPL (myeloproliferative leukemia) cells containing a TPO (thrombopoietin) receptor; in-vivo activity and in-vitro activity are higher than those of a positive drug, eltrombopag; and the compound can be concluded to have an effect of a TPO receptor agonist. After the compound is administrated to a blood loss mouse, data analysis finds that data of the compound 6 in a test group on the seventh day and on the fourteenth day have significance as compared with a model group; a platelet concentration of tail blood on the fourteenth day is higher than thatof orbit blood; and the deeper research can be conducted in the aspect of thrombocytopenia related diseases.

Description

technical field [0001] The invention belongs to the field of drug design and synthesis, and relates to a (trifluoromethoxy)pyrrolidine benzamide compound and its application in treating thrombocytopenia. technical background [0002] Immune thrombocytopenia (ITP), also known as idiopathic thrombocytopenic purpura (ITP), or autoimmune thrombocytopenic purpura (AITP) , is an acquired autoimmune disease, the incidence rate accounts for about 1 / 3 of bleeding disorders, and is one of the most common bleeding disorders in clinical practice. [0003] The treatment of ITP aims to increase the level of peripheral platelets, reduce the time of platelets in crisis and the incidence of bleeding, and then reduce the mortality rate, but does not emphasize the adjustment of platelet counts to normal levels, and there is no curative therapy. Clinical first-line drugs include glucocorticoids, intravenous immunoglobulin (intravenous immunoglobulin, IVIg), anti-RhD immunoglobulin (anti-dimmun...

Claims

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Application Information

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IPC IPC(8): C07D417/12A61P35/02A61P7/06A61P37/06A61P37/02
CPCC07D417/12
Inventor 窦玉玲范铭强
Owner 窦玉玲
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