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Acid addition salt of dihydropyridine derivative

A technology of dipicolinic acid and dihydrogen, which is applied in the treatment or prevention of hypertension or heart disease, and the treatment or prevention of hypertension. domain, can solve problems such as ignorance

Inactive Publication Date: 2012-10-17
UBE IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, it is not known that acid addition salts of compound (I) can be obtained in the form of crystalline solids

Method used

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  • Acid addition salt of dihydropyridine derivative
  • Acid addition salt of dihydropyridine derivative
  • Acid addition salt of dihydropyridine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] (Example 1) 2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethyl) Azetidine-3-yl) ester 5-isopropyl ester dihydrobromide

[0118] 3-(1-Diphenylmethylazetidine in 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid To a methanol solution of 2.91 g (5.00 mmol) of alkyl-3-yl)ester 5-isopropyl ester in 12 ml of methanol, 1.27 ml (11.0 mmol) of 47 wt% hydrobromic acid was added dropwise at 25°C over 30 minutes. After the dropwise addition, the reaction solution was further stirred for 30 minutes. The resulting crude crystals were collected by filtration, washed with 12 ml of methanol, and dried under reduced pressure at 50° C. for 2 hours to obtain 2.90 g (78%) of the title compound as a white powder.

[0119] 1 H-NMR spectrum (DMSO-d 6 , δppm): 1.00 (d; J=6Hz, 3H), 1.19 (d; J=6Hz, 3H), 2.29 (s, 3H), 4.01-4.38 (m, 4H), 4.74-4.92 (m, 2H) , 4.96-5.23(m, 1H), 5.78-6.11(m, 1H), 6.85(brs, 2H), 7.37-7.77(m, ...

Embodiment 2

[0122] (Example 2) 2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethyl) Azetidine-3-yl) ester 5-isopropyl ester monocitrate

[0123] 3-(1-Diphenylmethylazetidine in 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid To a solution of 3.24 g (5.56 mmol) of alkane-3-yl) ester 5-isopropyl ester in 11.1 ml of acetone, a solution of 11.1 g (5.83 mmol) of 11.1 ml of acetone was added dropwise at 25°C over 30 minutes. After the dropwise addition, the reaction solution was further stirred for 40 minutes. The resulting crude crystals were collected by filtration, washed with 5 ml of acetone, and dried under reduced pressure at 50°C for 2 hours to obtain 3.42 g (79%) of the title compound as a yellow powder.

[0124] 1 H-NMR spectrum (DMSO-d 6 , δppm): 0.99 (d; J=6Hz, 3H), 1.18 (d; J=6Hz, 3H), 2.27 (s, 3H), 2.30-2.42 (m, 1H), 2.64 (d; J=15Hz, 2H), 2.75(d; J=15Hz, 2H), 2.86-2.97(m, 1H), 3.28-3.40(m, 1H), 3.49-3.58...

Embodiment 3

[0126] (Example 3) 2-Amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethyl) Azetidine-3-yl) ester 5-isopropyl ester dimethanesulfonate

[0127] 3-(1-Diphenylmethylazetidine in 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid To a solution of 4.66 g (8.00 mmol) of alkane-3-yl)ester 5-isopropyl ester in 32 ml of ethyl acetate was added dropwise 1.04 ml (16.0 mmol) of methanesulfonic acid at 25°C over 30 minutes. After the dropwise addition, the reaction solution was further stirred for 30 minutes. The resulting crude crystals were collected by filtration, washed with 20 ml of ethyl acetate, and dried under reduced pressure at 40°C for 2 hours to obtain 6.01 g (97%) of the title compound as a white powder.

[0128] 1 H-NMR spectrum (DMSO-d 6 , δppm): 1.00 (d; J=6Hz, 3H), 1.18 (d; J=6Hz, 3H), 2.28 (s, 3H), 2.38 (s, 6H), 4.03-4.42 (m, 4H), 4.73 -4.89(m, 2H), 4.96-5.18(m, 1H), 5.73-6.01(m, 1H), 6.85(brs, 2H), ...

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Abstract

Disclosed is an excellent pharmaceutical product for treatment or prevention of hypertension and the like. Specifically disclosed is a specific acid addition salt of 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidine-3-yl) ester 5-isopropyl ester, which is useful as a pharmaceutical product for treatment or prevention of hypertension and the like.

Description

technical field [0001] The present invention relates to 2-amino-1 exhibiting excellent calcium antagonistic action, blood pressure lowering action, vasodilatory action, cardioprotective action, anti-arteriosclerosis action, diuretic action, renal damage inhibitory action and action against lipid peroxide production, 4-Dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl)ester Specific acid addition salt of 5-isopropyl ester. [0002] The present invention relates to a pharmaceutical composition containing 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-dicarboxylic acid A specific acid addition salt of phenylmethylazetidin-3-yl) ester 5-isopropyl ester as an active ingredient is preferably used for the treatment or prevention of hypertension, heart disease, arteriosclerosis or kidney damage , more preferably for the treatment or prevention of hypertension or heart disease; most preferably for the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/4427A61P9/00A61P9/04A61P9/10A61P9/12A61P13/12
CPCC07D401/12A61P13/12A61P7/10A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61K31/4427
Inventor 萩原昌彦清水基久濑田康生小林克弘吉江泰志
Owner UBE IND LTD
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