Dibenzyl amine derivatives as cetp inhibitors

A compound, technology of alkyl, applied in the field of dibenzylamine derivatives as cholesteryl ester conversion protein inhibitors

Inactive Publication Date: 2009-05-20
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there remains an unmet medical need for approved therapeutic agents that increase plasma HDL levels to reverse or slow the progression of atherosclerosis

Method used

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  • Dibenzyl amine derivatives as cetp inhibitors
  • Dibenzyl amine derivatives as cetp inhibitors
  • Dibenzyl amine derivatives as cetp inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0364] Example 1: N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-[(dimethylamino)methyl]-5-(trifluoromethyl) Benzyl]-2-methyl-2H-tetrazol-5-amine

[0365]

[0366] Under nitrogen, 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4- To a solution of trifluoromethyl-benzaldehyde (0.025 g, 0.048 mmol) in dichloroethane (5 mL) was added dimethylamine (0.008 g, 0.195 mmol) and tetramethylammonium triacetoxyborohydride (0.038 g, 0.146 mmol). The reaction mixture was stirred at room temperature for 14 hours. LC-MS indicated the formation of the desired product (M+1 = 541.0). The reaction was partitioned between water and dichloromethane. The organic layer was separated and concentrated, then diluted with dimethyl sulfoxide (DMSO), and analyzed in preparative HPLC (Shimadzu, 30x50 C18, basic, 30-95%, 0.1% sodium hydroxide (NaOH), 8 min gradient, 220 UV) Purification above yielded 14.4 mg (54%) of the title compound. 1 H NMR (400MHz, CDCl 3 )δ2.1(s,...

Embodiment 2

[0367] Example 2: N-[3,5-bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(morpholin-4-ylmethyl)-5-(trifluoro Methyl)benzyl]-2H-tetrazol-5-amine

[0368]

[0369] Morpholine (8.5 mg, 0.0977 mmol) in dichloroethane was used according to the procedure described in Example 1. The reaction and purification as described in Example 1 yielded 16.6 mg (58%) of the title compound. 1 H NMR (400MHz, CDCl 3 )δ 2.4 (s, 2H) 3.4 (s, 2H) 3.6 (s, 2H) 4.2 (s, 2H) 4.7 (s, 2H) 5.0 (s, 2H) 7.4 (s, 1H) 7.4 (dd, 1H) 7.5(dd,1H)7.6(s,2H)7.7(s,1H).MS(ES + ) calculated value: 582.4, found value: 583.0 (M+1).

Embodiment 3

[0370] Example 3: N-[3,5-bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(tri Fluoromethyl)benzyl]-2H-tetrazol-5-amine

[0371]

[0372] To a solution of benzotriazole (25.6 mg, 0.215 mmol) in ethanol (2 mL) was added morpholine (18.7 mg, 0.215 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. Add 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl - A solution of benzaldehyde (100 mg, 0.195 mmol) in ethanol (2 mL), the reaction mixture was further stirred for 16 hours. MS indicates the formation of MH from the imine intermediate + = 581.4. Ethanol was removed by evaporation, and the residue was dissolved in toluene (3 mL). Ethylmagnesium bromide (0.19 mL, 0.586 mmol, 3M in ether) was added and the reaction mixture was heated at 50°C for 2 hours. LC-MS indicated the formation of the desired product. The reaction mixture was diluted with ethyl acetate, then washed with ...

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Abstract

Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and / or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

technical field [0001] The present invention relates to dibenzylamine compounds and derivatives, pharmaceutical compositions containing the compounds and their use in the following aspects: it is used for increasing certain plasma lipid levels (including high-density lipoprotein (HDL)-cholesterol) and lowering Certain other plasma lipid levels (such as low-density lipoprotein (LDL)-cholesterol and triglycerides), thereby treating certain mammals (including humans) affected by low levels of HDL cholesterol and / or high levels of LDL cholesterol and Diseases affected by triglycerides, such as atherosclerosis and cardiovascular disease. Background technique [0002] Atherosclerosis and its associated coronary artery disease (CAD) are the leading causes of death in the industrialized world. Despite efforts to improve general risk factors (smoking, obesity, physical inactivity) and to treat dyslipidemia through improved diet and drug therapy, coronary heart disease (CHD) remains ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/06C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D417/12C07D453/06C07D471/04C07D491/04C07D513/04C07D413/12A61K31/40A61P9/00
Inventor 乔治·钱格拉维·S·加里吉帕蒂布鲁斯·A·利夫克戴维·A·佩里
Owner PFIZER PRODS ETAT DE CONNECTICUT
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