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Condensed imidazole derivatives

a technology of condensed imidazole and derivatives, which is applied in the field of new drugs, can solve the problems of no known dppiv inhibitor having a hypoxanthine or imidazopyridazinone structure backbone, and achieve excellent dppiv-inhibiting activity

Inactive Publication Date: 2006-03-23
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] The present inventors conducted extensive studies in view of the above background. As a result, they succeeded in synthesizing novel condensed imidazole derivatives, including hypoxanthine and imidazopyridazinone derivatives. To complete the present invention they also found that these compounds had excellent DPPIV-inhibiting activity. Specifically, the present invention comprises:

Problems solved by technology

However, there is no known DPPIV inhibitor having a hypoxanthine or imidazopyridazinone structure backbone.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

production example

Production Example 1

t-Butyl 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazin-1-carboxylate

(a) t-Butyl 5-methyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-carboxylate

[0597] A mixture consisting of 1.0 g of 5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 16 mg of 4-dimethylaminopyridine, 1.6 g of di-t-butyl dicarbonate, and 5 ml of tetrahydrofuran was stirred at room temperature overnight. Then, a 0.5-ml tetrahydrofuran solution containing 300 mg of di-t-butyl dicarbonate was added to the solution, and the resulting mixture was stirred at room temperature for three hours. 5 ml of t-butyl methyl ether was added to the reaction mixture, and the mixture was cooled with ice. The resulting crystals were collected by filtration to give 1.63 g of the title compound.

[0598]1H-NMR (CDCl3) δ 1.72 (s, 9H), 3.93 (s, 3H), 8.38 (s, 1H), 8.54 (s, 1H).

(b) 2-Chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one

[0599] 8.4 ml of lithium hexamethyldisila...

production example 2

t-Butyl 4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine-1-carboxylate

(a) 7-(2-Butynyl)-3-methyl-3,7-dihydropurine-2,6-dione

[0605] 55.3 ml of 1-bromo-2-butyne and 84.9 g of anhydrous potassium carbonate were added to a mixture of 100 g of 3-methyl xanthine [CAS No. 1076-22-8] and 1000 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 18 hours. 1000 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The resulting white precipitate was collected by filtration. The white solid was washed with water and then t-butyl methyl ether. Thus, 112 g of the title compound was obtained.

[0606]1H-NMR (DMSO-d6) δ 1.82 (t, J=2.2 Hz, 3H), 3.34 (s, 3H), 5.06 (q, J=2.2 Hz, 2H), 8.12 (s, 1H), 11.16 (br.s, 1H).

(b) 7-(2-Butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione

[0607] 112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g o...

example

Example 1

Ethyl [7-(2-chlorophenyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate

(a) [7-Benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate

[0613] 8.66 g of 7-benzylxanthine was dissolved in 300 ml of N,N-dimethylformamide, and 1.57 g of sodium hydride and 7.7 ml of chloromethyl pivalate were added thereto. The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.66 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:1).

[0614]1H-NMR (CDCl3) δ 1.18 (s, 9H), 5.45 (s, 2H), 6.06 (s, 2H), 7.34-7.39 (m, 5H), 7.58 (s, 1H), 8.18 (s, 1H).

(b) [7-Benzyl-1-methyl-2,6-dioxo-1,2,6,7-tet...

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Abstract

The present invention is related to compounds represented by the following formula, or salts or hydrates thereof wherein, T1 represents a 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, which is a monocyclic or bicyclic structure that may have one or more substituents; X represents a C1-6 alkyl group which may have one or more substituents, or such; Z1 and Z2 each independently represent a nitrogen atom or a group represented by the formula —CR2—; R1 and R2 independently represent a hydrogen atom, a C1-6 alkyl group which may have one or more substituents, or a C1-6 alkoxy group which may have one or more substituents, or such. These are novel compounds that exhibit an excellent DPPIV-inhibiting activity.

Description

TECHNICAL FIELD [0001] The present invention relates to novel condensed imidazole derivatives useful as dipeptidyl peptidase-IV (DPPIV) inhibitors and uses thereof. BACKGROUND ART [0002] Dipeptidyl peptidase IV (DPPIV) is a serine protease which specifically hydrolyzes dipeptide -X-Pro (X=arbitrary amino acid) from the free N terminus of a polypeptide chain. [0003] Glucose-dependent, insulin secretion-stimulating hormones, known as incretins (GLP-1: Glucagon-Like Peptide-1 and GIP: Glucose-dependent Insulinotropic Polypeptide) secreted in the digestive tract following meals are rapidly hydrolyzed and inactivated by DPPIV. When the hydrolysis by DPPIV is suppressed, the action of incretin (GLP-1 and GIP) is enhanced, which in turn increases the glucose-stimulated secretion of insulin from the cells of the pancreas. This has been shown to improve hyperglycemia in the oral glucose tolerance test (see Diabetologia 1999 November, 42(11), 1324-31). In addition, GLP-1 is known to be involv...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/522C07D473/02A61K31/4745C07D471/02C07D471/04A61K31/496A61K31/5025A61K31/5377A61K31/541A61P1/00A61P3/04A61P3/06A61P3/10A61P9/00A61P15/00A61P15/08A61P19/02A61P19/10A61P29/00A61P31/18A61P35/00A61P37/00A61P37/02A61P37/08A61P43/00C07D473/04C07D473/06C07D473/18C07D473/22C07D473/24C07D473/30C07D473/36C07D473/40C07D487/04C07D491/14
CPCC07D471/04C07D473/04C07D473/06C07D473/18C07D473/30C07D473/36C07D473/40C07D487/04C07D491/14A61P1/00A61P15/00A61P15/08A61P19/02A61P19/10A61P29/00A61P3/00A61P3/04A61P31/18A61P35/00A61P3/06A61P37/00A61P37/02A61P37/08A61P43/00A61P9/00A61P3/10
Inventor YOSHIKAWA, SEIJIEMORI, EITAMATSUURA, FUMIYOSHICLARK, RICHARDIKUTA, HIRONORIKIRA, KAZUNOBUYASUDA, NOBUYUKINAGAKURA, TADASHIYAMAZAKI, KAZUTO
Owner EISIA R&D MANAGEMENT CO LTD
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