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Piperidine carbamic acid ester derivative and application thereof

A methyl and group technology, applied in the field of pharmacy, can solve the problems of low bioavailability and limited clinical application prospects, achieve good oral bioavailability, and optimize the effect of blood sugar in vivo

Inactive Publication Date: 2010-06-16
廖国超
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the oral administration bioavailability of Alogliptin and Linagliptin is all low, and Alogliptin can increase its bioavailability by forming an acid salt, but the animal rat bioavailability of its ideal benzoate is only 45%. Although the animal and mouse bioavailability of linagliptin is higher than Alogliptin, about 51%, its human bioavailability is only 30% (European Journal of Pharmacology, 2008, 589: 306-314; The Journal of Clinical Pharmacology, 2008, 48 : 1171-1178; Journal of Medicinal Chemistry, 2007, 50, 6450-6453), severely limited the prospects of its clinical application

Method used

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  • Piperidine carbamic acid ester derivative and application thereof
  • Piperidine carbamic acid ester derivative and application thereof
  • Piperidine carbamic acid ester derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Isobutyric acid-1-((R)-1-(7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolinyl-2-yl) Methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-ylcarbamoyloxy)ethyl ester (compound 1) preparation

[0052] (R)-8-(3-aminopiperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl )methyl)-1H-purine-2,6(3H,7H)-diketone (Linagliptin, 1.46g, 3.1mmol) was dissolved in 40ml of anhydrous N,N-dimethylformamide solution, and triethylamine was added (1.3ml, 9.3mmol), under the protection of nitrogen, cooled to 0°C in an ice bath, slowly added 1-(isobutyryloxy)ethyl chloroformate (0.60g, 3.1mmol), and warmed to room temperature after the addition, The reaction was stirred for 6 hours. After the reaction was completed, 80 ml of ice water was added, extracted with dichloromethane (100 ml×3), washed with saturated brine, and dried overnight over anhydrous sodium sulfate. The desiccant was filtered off, concentrated under reduced pressure, and the residue was puri...

Embodiment 2

[0053] Example 2 pivalic acid-(R)-(1-(7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl) Preparation of -2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-ylcarbamoyloxy)methyl ester (compound 2)

[0054] Referring to the method for preparing compound 1 in Example 1, (R)-8-(3-aminopiperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-((4 -Methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (1.46g, 3.1mmol) and (pivaloyloxy)methyl chloroformate ( 0.60 g, 3.1 mmol) to obtain 1.08 g of powdery solid, yield 55.4%. 1 HNMR (CDCl 3 ), δ(ppm): 1.15-1.32(m, 10H), 1.53-1.94(m, 6H), 2.70-2.91(m, 5H), 2.94-3.10(m, 1H), 3.41(s, 3H), 3.54-3.73(m, 2H), 4.92(m, 2H), 5.34(s, 2H), 5.76(s, 2H), 7.70(m, 1H), 7.82(d, J=7.8Hz, 1H), 7.94 (m, 1H), 8.26 (d, J=7.8Hz, 1H). ESI-MS: 631.3 (M+1).

Embodiment 3

[0055] Example 3 Isobutyric acid-1-((R)-(1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6- Preparation of tetrahydro-pyrimidin-4-yl)piperidin-3-ylcarbamoyloxy)ethyl ester (compound 3)

[0056] Referring to the method for preparing compound 1 in Example 1, (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-oxo-3,4-di Hydropyrimidin-1(2H)-yl)methyl)benzocyanide (Alogliptin, 1.05 g, 3.1 mmol) was reacted with 1-(isobutyryloxy)ethyl chloroformate (0.60 g, 3.1 mmol) to give 0.89g powdery solid, yield 57.4%. 1 HNMR (CDCl 3 ), δ (ppm): 1.16 (d, J=8.2Hz, 6H), 1.40-1.69 (m, 5H), 1.85-2.21 (m, 2H), 2.41-2.73 (m, 3H), 2.90-3.46 ( m, 7H), 5.14-5.35(m, 3H), 6.80(m, 1H), 7.28(d, J=7.8Hz, 1H), 7.40(m, 1H), 7.61(m, 1H), 7.68(d , J=7.1Hz, 1H). ES-MS: 498.2 (M+1).

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Abstract

The invention provides a piperidine carbamic acid ester compound shown as the general formula I and possible isomers, medicinal salts, crystal forms, hydrates, solvates and medical compositions thereof. The invention also relates to applications of the possible isomers, the medicinal salts, the crystal forms, the hydrates, the solvates and the medical compositions in preparing medicaments for treating and / or preventing diseases related to DPP-IV, such as diabetes mellitus, particularly for non-insulin-dependent diabetes mellitus and impaired glucose tolerance, and the applications have good property of in vivo pharmacokinetics.

Description

technical field [0001] The invention belongs to the field of pharmacy, and more specifically relates to a class of dipeptidyl-peptidase-IV (DPP-IV) inhibitors and their therapeutic application, especially the application in the treatment of type I or type II diabetes. Background technique [0002] Diabetes is a multi-cause metabolic disease that seriously endangers health. About 5% of people in the world suffer from this chronic life-long disease. In my country, its incidence has risen from 0.67% in 1979 to 5.6% in recent years. The total number of patients exceeds 70 million, so diabetes has been considered as a worldwide epidemic disease. [0003] More than 90% of diabetic patients belong to type II diabetes, that is, non-insulin-resistant diabetes. The main reasons for its formation are excessive glucose intake, excessive liver gluconeogenesis, insufficient peripheral tissue intake, and insufficient insulin secretion. , compared with patients with type I diabetes (insulin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04C07D401/04A61K31/522A61K31/513A61P3/10A61P19/02A61P29/00A61P3/04A61P19/10
Inventor 廖国超孙玉琦曲昌海谢寅省
Owner 廖国超
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