Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof

A technology for pyrimidone and compound, which is applied in the field of thienopyrimidinone compounds and their preparation, can solve the problems such as the inability to maintain the inhibitory effect for a long time, the control effect is not good, the half-life is not long, and the like

Active Publication Date: 2019-01-04
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] General formula I, the half-life of the inhibitor described in this invention is not long in the body, and the inhibitory effect on DPP-IV cannot be maintained for a long time to continue to function, frequent medication is required, the use dependence may not be good, blood sugar fluctuations may also be large, and the control effect bad

Method used

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  • Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof
  • Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof
  • Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1 Synthesis of compound 1

[0128] synthetic route:

[0129]

[0130] Synthesis of compound 1-1:

[0131] Add urea (60g, 1mol) into a 250mL dry single-necked round-bottomed flask, heat to 160°C under an oil bath to melt, add 3-aminothiophene-2-carboxylic acid methyl ester (20g, 0.13mol), and the mixture is heated at 190- Heat and react at 200°C for 3 hours, cool, add 500mL of 10% aqueous sodium hydroxide solution, stir evenly, filter with suction, wash with 5-10% aqueous sodium hydroxide solution, and adjust the pH of the filtrate to 7.0 with 2N HCl solution in an ice bath. A white solid was precipitated, suction filtered, washed with ice water, and dried to obtain 12.5 g of a white solid, with a yield of 57%;

[0132] 1 H-NMR (400MHz, d 6 -DMSO): δ6.9 (1H, d, J = 5.2Hz), 8.10 (1H, d, J = 5.2Hz), 11.60-11.1 (2H, br, s); MS: 169.1 [M+H + ].

[0133] Synthesis of Compound 1-2:

[0134] Mix the compound 1-1 (12.5g, 74.3mmol) obtained in the above step wi...

Embodiment 2

[0145] Example 2 .Synthesis of Compound 2

[0146] synthetic route:

[0147]

[0148] Synthesis of Compound 2-1:

[0149] Dissolve methyl 3-amino-2-thiophenecarboxylate (20.4g, 0.13mol) in 300mL THF, add TEA (14.1g, 0.14mol), add trichloroacetyl chloride (25.5g, 0.14mol) dropwise at 2°C, gradually Raise to room temperature and stir for 30 minutes, add 300 mL of water to quench, extract with equal volume of EA three times, combine organic layers, wash with 5% aqueous sodium bicarbonate solution, water and saturated saline successively, dry over anhydrous sodium sulfate, filter, and filtrate The solvent was removed by pressure evaporation to obtain 33.4g compound 2-1, yield 85%; MS: 303.9[M+H + ].

[0150] Synthesis of compound 2-2:

[0151] Dissolve the compound 2-1 (33.4g, 0.11mol) obtained in the above step in 300mL of acetic acid, add liquid bromine (53.0g, 0.33mol) dropwise at 10°C, keep stirring at this temperature for 30 minutes, then heat and stir at 70°C Overn...

Embodiment 3

[0163] Example 3 Synthesis of compound 3

[0164] synthetic route:

[0165]

[0166] Replace the raw material 3-aminothiophene-2-methyl carboxylate in Example 1 with the raw material 3-amino-4-methylthiophene-2-methyl carboxylate, and refer to the synthetic method of Example 1 to synthesize compound 3-1 to compound 2.

[0167] Compound 3-1: 1H-NMR (400MHz, DMSO-d): δ2.20(1H, s), 7.68(1H, s), 11.20(1H, s), 11.38(1H, s); MS: 183.0[M+H + ].

[0168] Compound 3-2: MS: 218.9 [M+H + ].

[0169] Compound 3-3: 1 H-NMR (400MHz, CDCl 3 ):δ2.40(1H,s),7.52(1H,s); MS:200.9[M+H + ].

[0170] Compound 3-4: 1 H-NMR (400MHz, CDCl 3 ): δ2.41(1H,s),5.75(1H,s),6.86(1H,dd,J=2.0Hz,2.0Hz),7.12(1H,m),7.53(1H,s),7.75(1H ,m); MS:334.0[M+H + ].

[0171] Compound 3:MS:398.1[M+H + ].

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Abstract

The invention provides a thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and a preparation method and application thereof. The thienopyrimidinone compound or the pharmaceutically-acceptable salt thereof has a novel chemical structure, it is verified through in-vitro and in-vivo experiments that a very good selective inhibiting effect on DPP-IV is achieved, the activity of DPP-VIII and DPP-IX is barely affected while the activity of DPP-IV is effectively inhibited, meanwhile, the inhibition ratio of a potassium ion channel is low, and it can be predicted that the toxicity is low after the compound is developed into medicine. Compared with medicine trelagliptin orally taken once every week on the market, the thienopyrimidinone compound has fairly high or higher bioavailable efficiency, it can be predicted that after the compound is developed, the treatment effect that the compound is orally taken once for a long time, and the convenience and compliance of a patient are greatly improved. The preparation method is simple, the raw materials are easy to obtain, and the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a thienopyrimidinone compound and a preparation method and application thereof. Background technique [0002] Diabetes mellitus is caused by absolute or relative lack of insulin, resulting in elevated blood sugar, which can lead to serious complications and eventually lead to disability or death of the patient. Clinically, diabetes is divided into type 1 and type 2. Type 1 diabetes is due to the destruction of pancreatic β-cells and lack of insulin secretion, which leads to elevated blood sugar. Such patients can only rely on exogenous insulin; type 2 diabetes is caused by relatively insufficient insulin secretion or imperfect insulin action Hyperglycemia, its incidence rate accounts for more than 90% of all diabetic patients. Current drug research is mainly aimed at type 2 diabetes mellitus (T2DM). [0003] Promoting the secretion of insulin by pancreatic β-cells is the main m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/519A61P3/10A61P3/06A61P3/00A61P3/04A61P35/00A61P25/00A61P37/00
CPCC07D495/04
Inventor 曾少高胡文辉张桂成曾丽丽
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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