5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative

A trifluoromethyl, trifluoromethoxy technology, applied in drug combination, metabolic diseases, cardiovascular system diseases, etc.

Inactive Publication Date: 2016-08-17
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent Document 2 does not mention the LCAT activation effect, although the document discloses the effect of anti-LPA receptor

Method used

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  • 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative
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  • 5-hydroxy-4-(trifluoromethyl)pyrazolopyridine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0254] (Reference Example 1) 1-(Diphenylmethyl)-3-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1H-pyrazole-5 -amine

[0255] [Formula 8]

[0256]

[0257] n-BuLi (2.69M solution in hexane, 17.5 mL, 47.1 mmol) was added dropwise to a solution of anhydrous acetonitrile (2.47 mL, 47.1 mmol) in anhydrous THF (70 mL) at -78 °C, and The mixture was stirred at the same temperature as above for 10 minutes. At the same temperature as above, ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate (compound described in WO2005 / 40119 pamphlet, 5.69 g , 18.8 mmol) in THF (30 mL), and the mixture was stirred for 30 min. Then, acetic acid (6 mL) was added thereto, and the temperature of the mixture was raised to room temperature. Ethyl acetate and Celite (R) were added to the reaction solution, and the mixture was stirred for about 10 minutes and filtered through Celite. The solvent in the filtrate was distilled off under reduced pressure. The obtained residue was p...

Embodiment 22

[0364] (Reference Example 22) cis-1-(diphenylmethyl)-5-hydroxy-4-(trifluoromethyl)-3-{1-[4-(trifluoromethyl)-1,3- Thiazol-2-yl]piperidin-4-yl}-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0365] [Formula 29]

[0366]

[0367] Using 2-chloro-4-(trifluoromethyl)-1,3-thiazole (45mg, 0.13mmol) in place of 3-chloro-6-(trifluoromethyl)pyridazine by the method described in Reference Example 17 The title compound (12 mg, yield: 15%) was obtained by the same reaction.

[0368] 1 H-NMR (400MHz, CDCl 3 ) δ: 7.39-7.33 (7H, m), 7.08-7.02 (4H, m), 6.90(1H, d, J=1Hz), 6.81 (1H,brs), 6.67 (1H, s), 4.49 (1H, d, J=7Hz), 4.07-3.96(2H, m), 3.65 (1H, d, J=2Hz), 3.18-3.09 (2H, m), 2.83-2.74 (1H, m), 1.99-1.76(4H , m).

[0369] (Reference Example 23) cis-1-(diphenylmethyl)-5-hydroxy-4-(trifluoromethyl)-3-{1-[6-(trifluoromethyl)pyridin-2-yl ]piperidin-4-yl}-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0370] [Formula 30]

[0371]

[0372] Obtained by the same reaction a...

Embodiment 1

[0379] (Example 1) Trans-5-hydroxyl-4-(trifluoromethyl)-3-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1, 4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridin-6-one

[0380] [Formula 32]

[0381]

[0382] Triethylsilane (0.02mL, 0.13mmol) and trifluoroacetic acid (2mL) were added to the trans-1-(diphenylmethyl)-5-hydroxy-4-(trifluoromethane Base)-3-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1,4,5,7-tetrahydro-6H-pyrazolo[3, 4-b] A solution of pyridin-6-one (34 mg, 0.0552 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate 3 times. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution: hexane / ethyl acetate=60 / 40-0 / 100 (gradient)] to ...

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PUM

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Abstract

A compound which has excellent LCAT activation effects, is useful as an active ingredient of a therapeutic or preventive agent for arteriosclerosis, arteriosclerotic cardiovascular disease, coronary heart disease (including heart failure, myocardial infarction, angina, cardiac ischemia, cardiovascular disorder, and angioplastic restenosis), cerebrovascular disease (including cerebral stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complication), dyslipidemia, low HDL cholesterol, high HDL cholesterol, or kidney disease, in particular, of an anti-arteriosclerosis agent, and is represented by general formula (I) (I) [In the formula, R is an aryl group which may be substituted or a heteroaryl group which may be substituted, and R1 is a hydrogen atom or a hydroxyl group.] or a pharmacologically acceptable salt thereof (as shown in the description).

Description

technical field [0001] The present invention relates to a pyrazolopyridine derivative or a pharmacologically acceptable salt thereof, which has an excellent lecithin-cholesterol acetyltransferase (hereinafter referred to as LCAT)-activating effect (preferably a reversible LCAT activating effect). Background technique [0002] Cardiovascular diseases such as heart disease, cerebrovascular disease, and kidney disease caused by hypertension, dyslipidemia, diabetes, etc. are a major problem in developed countries. Antihypertensive, antidyslipidemic and antidiabetic agents are used in the treatment of hypertensive, dyslipidemic and hyperglycemic disorders, respectively. In clinical settings, alpha and beta blockers, diuretics, calcium antagonists, ACE inhibitors, and A-II antagonists, among others, are used as antihypertensives; HMG-CoA reductase inhibitors, anion exchange resins, niacin Derivatives, probucol, and fibrates are used as anti-dyslipidemic drugs; while insulin, sulf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545A61K31/497A61K31/501A61K31/506A61P3/06A61P9/04A61P9/10A61P13/12A61P43/00
CPCC07D471/04A61P13/12A61P3/06A61P9/04A61P9/10A61K31/437A61K31/4545A61K31/497A61K31/501
Inventor 小林英树荒井雅巳金子俊雄寺坂直生
Owner DAIICHI SANKYO CO LTD
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