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DPP-IV inhibitor

A technology selected from, compounds, applied in the field of medicine, can solve the problems of short half-life, inactivation, etc.

Active Publication Date: 2013-03-06
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Treatment based on GLP-1 can effectively control blood sugar, but as a substrate of DPP-IV, GLP-1 has a short half-life and will be rapidly cut and inactivated by DPP-IV within 1-2 minutes after secretion

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1. Synthesis of compound 1

[0077] Compound 1

[0078] synthetic route:

[0079]

[0080] Synthesis of Compound 1-2

[0081] Urea (1mol, 60g) was added to a 250ml dry single-necked round bottom flask, heated to 160°C in an oil bath to melt, and (0.13mol, 20g) methyl 3-aminothiophene-2-carboxylate was added, and the mixture was 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 6.5 with 2N HCl solution in an ice bath. A white solid was precipitated, filtered with suction, washed with ice and water, and dried to obtain 12.5 g of a white solid with a yield of 59%.

[0082] 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 + ].

[0083] Synthesis of Compounds 1-3

[0084] Mix the compound 1-2 (74.3mmol, 1...

Embodiment 2

[0095] Embodiment 2. Synthesis of compound 2

[0096]

[0097] Compound 2-1 was used to replace compound 1-1 in Example 1, and the synthesis method was referred to Example 1 to prepare compound 2 as a light yellow solid with a yield of 45%.

[0098] 1 H-NMR (400MHz, CD 3 OD): δ1.25(1H, m), 1.75(1H, m), 1.77(1H, m), 1.96(1H, m), 2.03(1H, m), 2.33(3H, s), 2.71(1H , m), 2.81(1H, s), 2.89(1H, m), 3.21(1H, m), 3.42(2H, m), 5.55(2H, ABq), 7.08(1H, d, J=8Hz), 7.39(1H, t, J=7.6Hz), 7.56(1H, t, J=7.8Hz), 7.59(1H, s), 7.69(1H, d, J=7.6Hz); MS: 380.1[M+H + ], 402.1 [M+Na + ].

Embodiment 3

[0099] Embodiment 3. Synthesis of compound 3

[0100] Compound 3

[0101] synthetic route

[0102]

[0103] Synthesis of compound 3-2

[0104] Add compound 3-1 (77.5g, 0.5mol), methyl cyanoacetate (99.1g, 1mol) and 50ml of methanol into a 250ml round bottom flask, add 1ml of DMF and 5ml of triethylamine dropwise under ice-cooling, and heat to 70°C After reacting for 3 hours, the solvent was evaporated under reduced pressure, and the residue was treated with 1 L of cold water and stirred to obtain a beige precipitate, which was filtered with suction, washed with cold water, and dried to obtain 113 g of gray solid compound 3-2 with a yield of 79.6%.

[0105] 1 H-NMR (400MHz, CDCl 3 ): δ6.98 (1H, d, J = 5.2Hz), 6.30 (1H, d, J = 5.2Hz), 4.0 (2H, s), 3.80 (3H, s); MS: 158.0 [M+H + ].

[0106] Synthesis of Compound 3-3

[0107] Dissolve the compound 3-2 (9.5g, 6mmol) obtained in the above step in 300ml of dry dichloromethane, cool to -60°C, add 9g of chlorosulfonyl isocy...

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PUM

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Abstract

The invention relates to a hybrid pyrimido ketone DPP-IV inhibitor shown as a formula I as well as salts, a preparation method, compounds and application thereof in the prevention or treatment of diseases that benefit from the DPP-IV inhibitor. A preparation process of the DPP-IV inhibitor is simple, easily-obtained in raw materials and suitable for industrial large-scale production; and in-vitro and in-vivo experiments verify that the DPP-IV inhibitor has very good selective inhibition effect to DPP-IV, nearly has no influence on activities of DPP-VIII and DPP-IX at the same time of effectively inhibiting the DPP-IV activity, lower toxicity after prepared medicine development, stronger effect and longer acting time compared with the effect of a medicine Alogliptin with the same mechanism and shows excellent effects of reducing the blood sugar and increasing the insulin sensitivity. The formula I is shown as follows.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound or a salt thereof with a heterocyclic pyrimidinone as a core nucleus, a preparation method, a composition thereof, and this type of compound as a dipeptidyl peptidase (DPP-IV) inhibitor Use in the prophylaxis or treatment of a disease which would benefit from inhibition of DPP-IV. Background technique [0002] Diabetes Mellitus (DM) is a metabolic disease with multiple etiologies, which is caused by an absolute or relative deficiency of insulin, resulting in an increase in blood sugar and causing metabolic disorders in the body. It can be divided into insulin-dependent diabetes mellitus (insulin-dependent diabetes mellitus, IDDM, type I diabetes) and noninsulin-dependent diabetes mellitus (NIDDM, type II diabetes), of which type II diabetes is the most common, accounting for diabetes patients more than 90 percent. At present, most of the research on diab...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04C07D487/04C07D491/048C07D473/18A61K31/519A61K31/522A61P43/00A61P3/10A61P3/06A61P3/08A61P3/04A61P35/00A61P25/00A61P37/00
Inventor 胡文辉张桂成杨玲徐宏江
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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