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Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor

A DPP-IV, compound technology, applied in the field of medicine, can solve the problems of shearing, inactivation, short half-life, etc.

Active Publication Date: 2013-11-27
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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  • Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor
  • Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor
  • Heterocyclo pyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1. Synthesis of compound 1

[0078]

[0079] synthetic route:

[0080]

[0081] Synthesis of Compound 1-2

[0082]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%.

[0083] 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 + ].

[0084] Synthesis of Compounds 1-3

[0085] Mix the compound 1-2 (74.3mmol, 12.5g) obtain...

Embodiment 2

[0096] Embodiment 2. Synthesis of compound 2

[0097]

[0098] 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%.

[0099] 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

[0100] Embodiment 3. Synthesis of compound 3

[0101]

[0102] synthetic route

[0103]

[0104] Synthesis of compound 3-2

[0105] 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%.

[0106] 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 + ].

[0107] Synthesis of Compound 3-3

[0108] 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 isocyanate dropw...

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PUM

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Abstract

The invention relates to a compound shown in a formula I or a salt, a preparation and a composition thereof and application of the compound serving as a dipeptidyl peptidase-IV (DPP-IV) inhibitor to the prevention or treatment of diseases which benefit from DPP-IV inhibition. The compound has a simple preparation process, is readily available in raw materials and is suitable for large-scale industrial production; and in-vitro experiments verify that the compound has a good selective inhibition effect on the DPP-IV, and influences the activity of DPP-VIII and DPP-IX scarcely while the activity of the DPP-IV is inhibited effectively, so after the compound is developed to form medicaments, the toxicity is far lower than that of a control medicament, and the compound has prominent advantages.

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): C07D495/04C07D487/04C07D491/048A61K31/519A61K31/5377A61P3/10A61P3/06A61P3/08A61P3/00A61P3/04A61P35/00A61P25/00A61P37/02
Inventor 胡文辉张桂成兰小兵杨玲徐宏江
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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