Piperazine compound and preparation and usage thereof

Abstract

The invention belongs to the technical field of medicaments with the effect of lowering blood sugar and provides a piperazine compound with the structure shown in a formula I and a pharmaceutically acceptable salt thereof, wherein X is a carbonyl group or a sulfonyl group, R1 is hydrogen, a C1-C4 straight chain or a branched chain alkyl group, and R2 is a pentabasic or hexabasic heterocycle, a phenyl group and a phenyl group substituted by a nitryl group and a methyl group. The invention further relates to a preparation method of the compound and also discloses a medicament combination in which the piperazine compound and the pharmaceutically acceptable salt thereof are used as active ingredients, and an application of the piperazine compound and the pharmaceutically acceptable salt thereof in lowering blood sugar.

Description

technical field

[0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of hypoglycemic compounds and their preparation methods, pharmaceutical compositions containing them and their use as hypoglycemic drugs. Background technique

[0002] According to the data and estimates of diabetes and impaired glucose tolerance (IGT) released by the International Diabetes Federation (IDF), the number of diabetic patients in 2003 was 194 million, and it will reach 333 million in 2025; It will be as high as 472 million. In recent years, with the continuous improvement of people's living standards and changes in dietary structure, the number of diabetic patients in my country has also experienced a large-scale increase. The anti-diabetic drugs currently in clinical use mainly include insulin, sulfonylurea, metformin, and recently listed α-glucosidase inhibitors and insulin sensitizers such as thiazolidinedione drugs. These drugs have a good...

Examples

Embodiment 1

[0058] 1-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)ethanone

[0059]

[0060] Add 21.5g of intermediate II-1 to the reaction flask equipped with stirring, condenser and thermometer, dissolve it with 80ml of acetonitrile and 20.2g of triethylamine, then add piperazin-1-yl (tetrahydrofuran-2-yl) 18.4 g of methyl ketone was stirred at room temperature for 7 hours, the reaction solution was washed with saturated brine (50ml×3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was rotary evaporated, and the residue was separated by silica gel column chromatography to obtain Yellow liquid (HPLC: 99.5%). HRMS(m / z)[M+H] + : 364.1682. 1 H-NMR (400MHz, DMSO-d6) δ: 1.773-1.841 (m, 2H), 1.935-2.013 (m, 2H), 2.380-2.425 (t, 3H), 2.486-2.495 (t, 4H), 2.749 ( s, 1H), 2.886(s, 1H), 3.252-3.293(t, 2H), 3.432-3.488(m, 4H), 3.699-3.803(m, 4H), 4.505(s, 1H), 4.590-4.638( q, 2H), 6.876-6.888 (s, 1H)...

Embodiment 2

[0065] Compound I-1 into hydrochloride: Take 4.0 g of the yellow liquid product of I-1 and dissolve it in 11 mL of anhydrous ether. Cool in an ice-water bath to 5°C, add 11.1% diethyl ether solution of hydrochloric acid dropwise until the pH is 2, and continue stirring for about 1 h in an ice-water bath. Filter to obtain a light yellow solid.

Embodiment 3

[0067] Sulfate formation of compound I-2: Take 4.3 g of the yellow liquid product of I-2 and dissolve it in 25 mL of acetone. Cool in an ice-water bath to 5°C, add 9.8% sulfuric acid acetone solution dropwise until the pH is 3, and continue stirring for about 1 h in an ice-water bath. Filter to obtain a yellow solid.

technical field

[0001] The invention belongs to the technical field of medicine, more specifically, relates to a class of hypoglycemic compounds and their preparation methods, pharmaceutical compositions containing them and their use as hypoglycemic drugs. Background technique

[0002] According to the data and estimates of diabetes and impaired glucose tolerance (IGT) released by the International Diabetes Federation (IDF), the number of diabetic patients in 2003 was 194 million, and it will reach 333 million in 2025; It will be as high as 472 million. In recent years, with the continuous improvement of people's living standards and changes in dietary structure, the number of diabetic patients in my country has also experienced a large-scale increase. The anti-diabetic drugs currently in clinical use mainly include insulin, sulfonylurea, metformin, and recently listed α-glucosidase inhibitors and insulin sensitizers such as thiazolidinedione drugs. These drugs have a good...

Examples

Embodiment 1

[0058] 1-(6,7-Dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)ethanone

[0059]

[0060] Add 21.5g of intermediate II-1 to the reaction flask equipped with stirring, condenser and thermometer, dissolve it with 80ml of acetonitrile and 20.2g of triethylamine, then add piperazin-1-yl (tetrahydrofuran-2-yl) 18.4 g of methyl ketone was stirred at room temperature for 7 hours, the reaction solution was washed with saturated brine (50ml×3), the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic solvent was rotary evaporated, and the residue was separated by silica gel column chromatography to obtain Yellow liquid (HPLC: 99.5%). HRMS(m / z)[M+H] + : 364.1682. 1 H-NMR (400MHz, DMSO-d6) δ: 1.773-1.841 (m, 2H), 1.935-2.013 (m, 2H), 2.380-2.425 (t, 3H), 2.486-2.495 (t, 4H), 2.749 ( s, 1H), 2.886(s, 1H), 3.252-3.293(t, 2H), 3.432-3.488(m, 4H), 3.699-3.803(m, 4H), 4.505(s, 1H), 4.590-4.638( q, 2H), 6.876-6.888 (s, 1H)...

Embodiment 2

[0065] Compound I-1 into hydrochloride: Take 4.0 g of the yellow liquid product of I-1 and dissolve it in 11 mL of anhydrous ether. Cool in an ice-water bath to 5°C, add 11.1% diethyl ether solution of hydrochloric acid dropwise until the pH is 2, and continue stirring for about 1 h in an ice-water bath. Filter to obtain a light yellow solid.

Embodiment 3

[0067] Sulfate formation of compound I-2: Take 4.3 g of the yellow liquid product of I-2 and dissolve it in 25 mL of acetone. Cool in an ice-water bath to 5°C, add 9.8% sulfuric acid acetone solution dropwise until the pH is 3, and continue stirring for about 1 h in an ice-water bath. Filter to obtain a yellow solid.

Images