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Acid addition salt of dihydropyridine derivative

A kind of technology of dihydrobromide and hydrobromide, applied in the field of pharmaceutical compositions, can solve problems such as not knowing

Inactive Publication Date: 2008-12-03
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 Azetidin-3-yl) ester 5-isopropyl dihydrobromide

[0118] In 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidine To a solution of 2.91 g (5.00 mmol) of 5-isopropyl (alk-3-yl) 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 was completed, 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, 12H), 7.94-...

Embodiment 2

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

[0123] In 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidine To a solution of 3.24 g (5.56 mmol) of 5-isopropyl ester in 11.1 ml of acetone, 11.1 g (5.83 mmol) of a solution in 11.1 ml of acetone was added dropwise at 25° C. over 30 minutes. After the dropwise addition was completed, 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(m, 1H),...

Embodiment 3

[0126] (Example 3) 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethyl Azetidin-3-yl) ester 5-isopropyl dimesylate

[0127] In 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidine To a solution of 4.66 g (8.00 mmol) of 5-isopropyl (alk-3-yl) ester in 32 ml of ethyl acetate, 1.04 ml (16.0 mmol) of methanesulfonic acid was added dropwise at 25°C over 30 minutes. After the dropwise addition was completed, 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 at 40° C. under reduced pressure for 2 hours to obtain 6.01 g (97%) of the target 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), 7.37-7.67(...

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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 antagonism effect, blood pressure lowering effect, vasodilator effect, cardioprotective effect, anti-arteriosclerosis effect, diuretic effect, renal damage inhibitory effect and effect of inhibiting lipid peroxide production, 3-(1-Diphenylmethylazetidin-3-yl) 4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 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-di Specific acid addition salts of phenylmethylazetidin-3-yl) ester 5-isopropyl ester as active ingredient, preferably 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 treatment or prevention of hyper...

Claims

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Application Information

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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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