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Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors

A technology of solvates and compounds, applied in the field of medicine, can solve problems such as inactivation and short half-life

Active Publication Date: 2012-01-25
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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  • Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors
  • Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors
  • Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1. Synthesis of compound 1

[0085]

[0086] synthetic route:

[0087]

[0088] Synthesis of Compound 1-2

[0089] 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%.

[0090] 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 + ].

[0091] Synthesis of Compounds 1-3

[0092] Mix the compound 1-2 (74.3mmol, 12.5g) obtai...

Embodiment 2

[0103] Embodiment 2. Synthesis of compound 2

[0104]

[0105] 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%.

[0106] 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

[0107] Embodiment 3. Synthesis of compound 3

[0108]

[0109] synthetic route

[0110]

[0111] Synthesis of compound 3-2

[0112] 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%.

[0113] 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 + ].

[0114] Synthesis of Compound 3-3

[0115] 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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Abstract

The invention belongs to the technical field of medicines, and particularly relates to compounds which are shown as a general formula I and in which pyrrolopyrimidone is taken as a parent nucleus or salts thereof, a method for preparing the compounds, a composition, and use of the compounds as dipeptidyl peptidase-IV (DPP-IV) inhibitors in the prevention or treatment of diseases which benefit from DPP-IV inhibition. The preparation process for the compounds is simple, raw materials are readily available, and the method is suitable for industrialized production; through in-vitro experiments, the compounds have a good effect of selectively inhibiting DPP-IV, and almost do not affect the activities of DPP-VIII and DPP-IX when the activity of the DPP-IV is effectively inhibited; and the compounds are expected to have low toxicity after being developed into medicines, and have outstanding advantages.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound or its salt with pyrrolopyrimidinone as the core nucleus, its preparation method, composition and such compound as dipeptidyl peptidase (DPP-IV) inhibitor in Use in the prevention or treatment of a disease that would benefit from DPP-IV inhibition. 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 diabetes treatment drugs is launched ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D487/04A61K31/519A61P3/10A61P3/06A61P3/08A61P39/02A61P3/00A61P3/04A61P35/00A61P25/00A61P37/00
Inventor 胡文辉张桂成曾丽丽曾少高杨玲徐宏江
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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