Pyridine compounds as inhibitors of dipeptidyl peptidase iv

A compound, amylpyridine technology, applied in the field of pyridine compounds, can solve problems such as no compound report, and achieve the effect of excellent peptidase inhibitory effect

Inactive Publication Date: 2006-12-27
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0028] However, there are no reports on

Method used

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  • Pyridine compounds as inhibitors of dipeptidyl peptidase iv
  • Pyridine compounds as inhibitors of dipeptidyl peptidase iv
  • Pyridine compounds as inhibitors of dipeptidyl peptidase iv

Examples

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specific example

[0226] As examples of the "divalent chain hydrocarbon group" of L or Q, a divalent chain hydrocarbon group having 1 to 10 carbon atoms can be mentioned. Specific examples of this include:

[0227] (1)C 1-10 Alkylene (for example, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -CHCH 3 -, -C(CH 3 ) 2 -, -(CH(CH 3 )) 2 -, -(CH 2 ) 2 C(CH 3 ) 2 -, -(CH 2 ) 3 C(CH 3 ) 2 -);

[0228] (2)C 2-10 Alkenylene (for example, -CH=CH-, -CH 2 -CH=CH-, -CH=CH-CH 2 -, -CH=CH-CH 2 -CH 2 -, -C(CH 3 ) 2 -CH=CH-, -CH 2 -CH=CH-CH 2 -, -CH 2 -CH 2 -CH=CH-, -CH=CH-CH=CH-, -CH=CH-CH 2 -CH 2 -CH 2 -);

[0229] (3)C 2-10 Alkynylene (for example, -C=C-, -CH 2 -C=C-, -CH 2 -C=C-CH 2 -CH 2 -);Wait.

[0230] Preferably the "divalent chain hydrocarbon group" is C 1-10 Alkylene or C 2-10 Alkenylene, more preferably it is -CH 2 -, -(CH 2 ) 2 -, -CH=CH- etc.

[0231] L is preferably C 1-10 Alkylene, more preferably -CH 2 -Wait. ...

Embodiment 1

[0691] 5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid methyl ester

[0692] 1) A suspension of sodium hydride (60% in oil, 8.0 g, 0.2 mol) in tetrahydrofuran (80 mL) was heated under reflux with vigorous stirring. To the resulting suspension was added dropwise a mixture of methyl isovalerate (11.6 g, 0.1 mol), acetonitrile (10.5 mL, 0.2 mol) and tetrahydrofuran (25 mL), and the mixture was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, and 2-propanol (5 mL) was added thereto. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (100 mL), and washed successively with hexane and a hexane-ether mixed solution. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under r...

Embodiment 2

[0702] 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid dihydrochloride

[0703] 1) Dissolve 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphenyl)nicotinic acid methyl ester (0.90g, 2.76mmol) in tetrahydrofuran (25mL) To the solution, di-tert-butyl dicarbonate (0.76 mL, 3.31 mmol) was added, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4 -Methylphenyl)nicotinate (1.16 g, yield 98%), which is a white powder.

[0704] 1 H-NMR (CDCl 3 )δ: 0.97 (6H, d, J=6.8Hz), 1.39 (9H, s), 2.10-2.30 (1H, m), 2.39 (3H, s), 2.54 (3H, s), 2.78 (2H, d , J=7.2Hz), 3.50(3H, s), 4.15(2H, d, J=4.9Hz), 4.24(1H, t, J=4.9Hz), 7.06(2H, d, J=7.9Hz), 7.20 (2H, d, J = 7.9 Hz).

[0705]2) To 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-methylphenyl)nicoti...

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Abstract

A compound represented by the formula wherein R<1> and R<2> are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted hydroxy group; R<3> is an optionally substituted aromatic group; R<4> is an optionally substituted amino group; L is a divalent chain hydrocarbon group; Q is a bond or a divalent chain hydrocarbon group; and X is a hydrogen atom, a cyano group, a nitro group, an acyl group, a substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino group or an optionally substituted cyclic group; provided that when X is an ethoxycarbonyl group, then Q is a divalent chain hydrocarbon group. The compound has a peptidase inhibitory action, is useful as an agent for the prophylaxis or treatment of diabetes and the like, and is superior in efficacy, duration of action, specificity, lower toxicity and the like.

Description

technical field [0001] The present invention relates to pyridine compounds having peptidase inhibitory activity, which are useful as agents for the prevention or treatment of diabetes and the like. Background technique [0002] Peptidases are known to be associated with various diseases. As one of the peptidases, dipeptidyl dipeptidase-IV (hereinafter sometimes abbreviated as DPP-IV) is a serine protease that combines with a peptide containing proline (or alanine) at the 2nd position of the N-terminal Specifically binds and cleaves the C-terminus of proline (or alanine), yielding a dipeptide. DPP-IV has been shown to be the same molecule as CD26 and has also been reported to be closely related to the immune system. Although the role of DPP-IV in mammals is not completely clear, it is considered to play an important role in metabolism of neuropeptides, activation of T cells, attachment of cancer cells to endothelial cells, invasion of HIV into cells, and the like. Specific...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/82C07D213/56C07D213/55C07D401/12C07D213/59C07D401/06C07D413/06C07F9/40C07D213/71C07D213/75C07D409/12C07D405/12C07D213/12C07D413/12
Inventor 大井悟前崎博信铃木伸宏
Owner TAKEDA PHARMA CO LTD
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