KR900007623B1 - 1,4-dihydropyridine derivatives - Google Patents

Abstract

1,4-Dihydropyridine derivs. of formula (I) are prepared. In (I), R1 and R2 are each C1-6 alkyl, lower alkenyl, lower alkoxyalkyl or aminoaryl (lower)alkyl opt. substd. by C1-4 alkyl; at least one of R1 and R2 is C3-6 alkenyl opt. substd. by C1-4 alkyl at 1- or 2- position; R3 is ortho-, meta- or para-nitro gp. (I) are useful as hypotensives.

Description

1,4-dihydropyridine derivative

1 is a graph showing the results of blood pressure and heart rate before and after drug administration using SHR to measure the blood pressure lowering effect and other drug duration of the drug according to the present invention.

2 is a graph showing the blood pressure and heart rate after the drug administration according to the administration concentration of the drug in the percentage (%) compared with the pre-drug administration, respectively, in the blood pressure lowering effect test of the drug according to the present invention.

3 is a graph showing the results of testing the pulmonary vasodilator effect of the drug according to the present invention.

Figure 4 is a graph showing the results of testing the negative muscle metabolism using the drug according to the present invention.

The present invention relates to a 1,4-dihydropyridine derivative, and more particularly to a novel 1,4-dihydropyridine derivative having an excellent effect on cerebrovascular expansion represented by the following structural formula (I).

In the above formula (I), R ¹ and R ² are substituted or unsubstituted lower alkyl groups having 1 to 4 carbon atoms or lower alkyl groups having 1 to 6 carbon atoms, lower alkenyl groups, lower alkoxy alkyl groups or aminoaryl (lower) As alkyl groups they are different from each other, at least one of which represents a lower alkenyl group having 3 to 6 carbon atoms substituted at position 1 or 2 with a lower alkyl group having 1 to 4 carbon atoms, and R ³ represents ortho-, Nitro groups which may be substituted in the meta- or para-positions.

Since the first development of Nifedipine as a Calcium Channel Antagonists in 1968 by Bayer, Germany, numerous calcium channel antagonists have been developed to this day.

In particular, derivatives of various 1,4-dihydropyridine-3,5-dicarboxylic acids are known as calcium channel blockers, among which asymmetric ester compounds having different ester groups at positions 3 and 5 It has been shown to have superior efficacy, and various synthetic methods for preparing such asymmetric ester compounds have been steadily researched and developed. The known methods include, for example, a production method by a so-called Hanzsch reaction in which an amino crotonate having an appropriate ester group is reacted with benzaldehyde, and acetoacetic acid ester and benzaldehyde first to react benzylidene. And a method of preparing the compound by reacting it with aminocrotonate, and replacing only one ester with a metal alkoxide.

Meanwhile, among the asymmetric ester compounds of the 1,4-dihydropyridine derivatives as described above, many compounds consisting of ester groups of a saturated or unsaturated hydrocarbon having a side chain are also known. In particular, recently, ester groups of the saturated or unsaturated hydrocarbons have been known. There is an active research to develop new 1,4-dihydropyridine-3,5- (asymmetric) dicarboxylic acid ester derivatives by variously changing the substituted side chains.

As a result of the research, for example, Japanese Patent Laid-Open No. 74-109,384 discloses 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3 represented by the following structural formula (I '). It is described that, 5-dicarboxylic acid-3-beta- (N-benzyl-N-methylamino) ethylester-5-methylester is a compound having a hypertension therapeutic effect.

However, the present inventors screened only the pharmaceutically active substances among the diester compounds of the various 1,4-dihydropyridine derivatives published so far, including the compound of formula (I ′). It has been found that compounds with simple alkyl ester groups exhibit particularly good efficacy without major changes in the basic structure, but such compounds have toxicological problems despite their excellent symbol.

Therefore, the present inventors have been intensively researching to develop a new compound having excellent medicinal efficacy and low toxicity. Among the 1,4-dihydropyridine derivatives, an alkenyl ester group having a simple alkyl group side chain, which is not yet published, As a result of the synthesis and testing of various lower alkenyl ester derivatives in which a lower alkyl group such as methyl group is substituted at the 1st or 2nd position, especially asymmetric ester compounds, new compounds having low toxicity and long duration are obtained. It was obtained and reached the present invention.

Accordingly, an object of the present invention is to provide a novel low-toxic 1,4-dihydropyridine derivative represented by the structural formula (I), particularly excellent in the treatment of hypertension, the structural formula (I) according to the present invention There is no description or suggestion of the compound to be displayed and its excellent hypotensive action and low toxicity.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel 1,4-dihydropyridine derivative represented by the following structural formula (I), wherein the compound is a benzaldehyde derivative represented by the following structural formula (II) and an amino chromate represented by the following structural formula (III) Tonate lower alkyl, lower alkenyl, lower alkoxyalkyl, or aminoaryl (lower) alkyl esters and acetylacetic acid lower alkyl, lower alkenyl, lower alkoxyalkyl or aminoaryl (lower) alkyl esters represented by the following structural formula (lV): Can be prepared by reacting at the same time or by reacting in any order.

In the above formulas (I), (II), (III) and (IV), R ¹ and R ² and R ³ are as described above.

Hereinafter, the present invention will be described in more detail.

Of the three reactants used to prepare the target compound represented by the formula (I) according to the present invention, the compound (III), which is an enamine derivative, is prepared by reacting an excess of a primary amine with acetoacetic acid ester. The compound (lV) can be prepared, for example, by an ester substitution reaction of acetic acetate methyl ester with an alcohol, or a reaction of diketene with alcohol.

Therefore, according to the present invention, the compound (Il) and the compound (III) and (IV) prepared by the above-described method are reacted simultaneously, or any two compounds of the three compounds are reacted first and then 1,4-dihydropyridine derivative of formula (I) can be prepared by reacting the other compound to the compound, wherein the compounds are ethanol or isopropanol, dioxane, dimethylformamide, dimethyl sulfoxide or acetnitrile. It is preferable to react in a solvent such as the like.

The compounds of formula (I) according to the present invention thus prepared are separated and purified by conventional spraying methods such as extraction, tube chromatography, recrystallization, and the like, preferably in the form of pharmaceutically harmless salts such as hydrochloric acid or sulfuric acid. And inorganic salts such as phosphoric acid, and organic acid salts such as acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and the like.

In the above structural formulas (I) to (IV), the lower alkyl groups represented by R ¹ and R ² are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and t-butyl groups. Or a pentyl group, and the like. The lower alkenyl group is an alkenyl group having 3 to 6 carbon atoms in which a lower alkyl group of 1 to 4 carbon atoms is substituted or unsubstituted, and an aminobenzylmethyl group or the like as an aminoaryl (lower) alkyl group. And R ³ represents an ortho-, meta- or para-nitro group.

Particularly, in the present invention, R ¹ and R ² in the structural formula (I) are different from each other so that the drug is better. More preferably, at least one of R ¹ and R ² is a carbon source at position 1 or position 2 It was found that the 2-propenyl group substituted with the lower alkyl group of the embroidery 1 to 4, and the hydrogen at the terminal position 3, which was not substituted, showed the most preferable effect.

Examples of the compounds represented by the above formula (I) according to the present invention include the following compounds.

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-beta- (N-benzyl-N-methylamino) ethylester-5 -(1-methyl-2-propenyl) ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-isopropyl ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-methylester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-epiester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5- (2 -Methoxyethyl) ester

2,6-dimethyl-4- (3'-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-allyl ester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-methylester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl2-propenyl) ester-5-ethylester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-beta- (N-benzyl-N-methylamino) ethylester-5 -(2-methyl-2-propenyl) ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-isopropyl ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-methylester

2,6-dimethyl-4- (3'-nitrophenyl) -l, 4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-ethylester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5- (2 -Methoxyethyl) ester

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-allyl ester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-methylester

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-ethylester

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-beta- (N-benzyl-N-methylamino) ethylester-5 -(1-methyl-2-propenyl) ester

1.06 g (7.022 mmol) 3-nitrobenzaldehyde, 1.10 g (7,022 mmol) N-benzyl-N-methylaminoethyl 3-aminocrotonate and 1.1 g 1-methyl-2-propenyl acetoacetate in 7 ml of isopropyl alcohol (7,022 mmole) was dissolved and refluxed for 6 hours. After distilling the reaction solution under reduced pressure, the residue was subjected to column chromatography and treated with 10% hydrochloric acid to obtain 2.36 g of hydrochloride of the target compound.

Yield: 60.4%

Melting Point: 66 ~ 69 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.15, 1.30 (d, 3H, -CH ₃ ), 2.20 (s, 3H, -N-CH ₃ ), 2.30 (s, 6H, -CH ₃ ), 2.60 (t _{, 2H, -CH 2 -N),} 3.45 (s, 2H, PhCH 2 -), 4.15 (t, 2H, -OCH 2 -), 4.70~5.35 (m, 1H, -OCH <), 5.05 (d, 2H, = CH ₂ ), 5.25 (s, 1H, -C ₄ -H), 5.40 to 4.90 (m, 1H, = CH-), 6.40 (b, 1H,> NH), 7.20 (s, 5H, Ph -), 7.30-8.15 (m, 4H, aromatic).

Example 2

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester 5-isopropylester

L-06g (7.022mmole) of 3-nitrobenzaldehyde, l.10g (7.022mmole) of 1-methyl-2-propenyl acetoacetate and 1.26g (7.022mmole) of isopropyl-3-aminocrotonate in 7m1 of isopropyl alcohol As a result of performing the same procedure as in Example 1 with the reaction solution obtained by dissolving, 2.2 g of the target compound was obtained.

Yield: 76%

Melting Point: 58 ~ 60 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.00-1.40 (m, 9H, = CH ₃ ), 2.35 (s, 6H, -CH ₃ ), 5.06 (d, 2H, = CH ₂ ), 5.30 (s, 1H , Cu-H) to 8.15 (m, 4H, aromatic).

Example 3

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5- (2 -Ethoxyethyl) ester

1.06 g (7.022 mmol) of 3-nitrobenzaldehyde, 1.10 g (7.022 mmol) of 1-methyl-2-propenyl acetoacetate and 1.12 g (7.022 mmol) of 2-methoxyethyl-3-aminocrotonate in 7 ml of isopropyl alcohol In the same manner as in Example 1 with the reaction solution obtained by dissolving), 1.6 g of the target compound was obtained.

Yield: 53%

Melting Point: 98 ~ 99 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.17-1.33 (d, 3H, -CH ₃ ), 2.35 (s, 6H, -CH ₃ ), 3.35 (s, 3H, -OCH ₃ ), 3.53 (t, 2H , -CH ₂ -OCH ₃ ), 4.17 (t, 2H, -OCH _2- ), 5.05 (d, 2H, = CH ₂ ), 4.70 to 5.35 (m, 1H, -OCH <), 5.27 (s, 1H , C ₄ -H), 5.40 to 6.10 (m, 1H, = CH—), 6.5 (b, 1H> NH), 7.20 to 8.15 (m, 4H, aromatic).

Example 4

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-ethylester

Dissolve 1.06 g (7.022 mmol) of 3-nitrobenzaldehyde, 1.10 g (7.022 mmol) of 1-methyl-2-propenyl acetoacetate, and 0.91 g (7.022 mmol) of ethyl-3-aminocrotonate in 7 ml of isopropyl alcohol. The resultant reaction solution was carried out in the same manner as in Example 1, whereby 2.0 g of the pure target compound was obtained.

Yield: 71%

Melting Point: 96 ~ 98 ℃

¹ HNMR (CDC1 ₃ ): ∂ = 1.17, 1,33 (d, 3H.-CH ₃ ), 1.20 (t, 3H, -CH ₃ ), 2.33 (s, 6H, -CH ₃ ), 4.07 (q, 2H, OCH _2- ), 5.05 (d, 2H, -CH _2- ), 5.27 (s, 1H, C ₄ -H), 4.75 to 5.35 (m, lH, -OCH <), 5.50 to 6.10 (m, lH, = CH-), 6.35 (b, lH,> NH), 7.20-8.20 (m, 4H, aromatic).

Example 5

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5- (1-methyl-2 -propenyl) ester

Dissolve 1.06 g (7.022 mmol) 3-nitrobenzaldehyde, 1.10 g (7.022 mmol) 1-methyl-2-propenyl acetoacetate and 0.81 g (7.022 mmol) methyl-3-aminocrotonate in 7 ml of isopropyl alcohol. After refluxing for 4 hours, the same procedure as in Example 1 was carried out to obtain 2.0 g of the pure target compound.

Yield = 73.8%

Melting Point: 98 ~ 99 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.17, 1.33 (d, 3H, -CH ₃ ), 1.20 (s, 3H, -N-CH ₃ ), 2.33 (s, 6H, -CH ₃ ), 4.07 (q , 2H, -OCH _2- ), 5.05 (d, 2H, -CH _2- ), 5.27 (s, 1H, C ₄ -H), 5.30-5.90 (m, 1H, = CH-), 6.30 (b, 1H,> NH), 7.15 to 8.15 (m, 4H, aromatic).

Example 6

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) ester-5-allyl ester

Dissolve 1.06 g (7.022 mmol) of 3-nitrobenzaldehyde, 1.10 g (7.022 mmol) of 1-methyl-2-propenyl acetate, and 0.99 g (7.022 mmol) of allyl-3-amino crotonate in 7 ml of isopropyl alcohol. The resultant reaction solution was carried out in the same manner as in Example 5 to obtain 2.2 g of the target compound as pure.

Yield: 76.5%

Melting Point: 73 ~ 75 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.17, 1.33 (d, 3H, -CH ₃ ), 2.35 (s, 6H, -CH ₃ ), 4.53 (d, 2H, -OCH _2- ), 4.95 to 5.25 ( m, 4H, CH ₂ =), 5.27 (s, 1H, CH ₄ -H), 4.70 to 5.50 (m, 1H, -OCH <), 5.50 to 6.10 (m, 2H, -CH =), 6.40 (b , 1H,> NH), 7.20 to 8.15 (m, 4H, aromatic).

Example 7

2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (1-methyl-2-propenyl) -5- (2- Methyl-2-propenyl) ester

1.06 g (7.022 mmol) of 3-nitrobenzaldehyde, 1.10 g (7.022 mmol) of 1-methyl-2-propenyl acetoacetate and 1.10 g (7.022 mmol) of 2-methyl-1-propenyl amino crotonate in 7 ml of isopropyl alcohol In the same manner as in Example 5 with the reaction solution obtained by dissolving), 2.1 g of the target compound pure was obtained in an oil state.

Yield: 70.2%

¹ H NMR (CDCL1 ₃ ): δ = 1.07, 1.30 (d, 3H, -CH ₃ ), 1.60 (s, 3H, -N-CH ₃ ), 2.27, 2.32 (s, each 3H, -CH ₃ ), 4.45 (s, 2H, -OCH _2- ), 4.70, 4.73 (s, 2H, CH ₂ =), 4.85-5.45 (m, 2H, -OCH <, CH =), 5.90 (s, 1H, CH _4- ) H), 6.13 (b, 1H, 1H,> NH) and 7.05 to 7.80 (m, 4H, aromatic).

Example 8

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-beta- (N-benzyl-N-methylamino) ethylester-5 -(2-methyl-2-propenyl) ester

2.45 g (16.18 nmole) of 3-nitrobenzaldehyde, 4.05 g (16.18 mmol) of N-benzyl-N-methylaminoethyl 3-aminocrotonate and 2.52 g of 1-methyl-2-propenyl acetoacetate in 15 ml of isopropyl alcohol (16.18 mmol) was dissolved and refluxed for 6 hours. Subsequently, the residue obtained by distillation under reduced pressure was subjected to tube chromatography and treated with 10% hydrochloric acid to obtain 5.56 g of hydrochloride of the target compound.

Yield: 61.8%

Melting Point: 96 ~ 110 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.63, 1.30 (d, 3H, -CH ₃ ), 2.17 (s, 3H, -N-CH ₃ ), 2.30, 2.33 (s, each 3H, -CH ₃ ), 2.60 (t, 2H, -CH ₂ -N), 3.43 (s, 2H, PhCH _2- ), 4.10 (t, 2H, -OCH _2- ), 4.40 (s, 2H, -OCH _2- ), 4.67- 4.83 (m, 2H, = CH ₂ ), 5.07 (s, lH, -C ₄ -H), 6.03 (b, lH,> NH), 7.13 (s, 5H, Ph-), 7.30 to 8.20 (m, 4H, aromatic).

Example 9

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-isopropyl ester

In 7 ml of isopropyl alcohol, 1.33 g (8.775 mmol) of 3-nitrobenzaldehyde, 1.37 g (8.775 mmol) of 2-methyl-2-propenyl acetoacetate and l.26 g (8.775 mmol) of isopropyl-3-aminocrotonate were added. After dissolution was carried out in the same manner as in Example 8 to obtain 2.29 g of the pure target compound.

Yield: 63%

Melting Point: 124 ~ 125 ℃

¹ HNMR (CDC1 ₃ ): ∂ = 1.08.1.21 (d, each 3H, -CH ₃ ), 1.60 (s, 3H, -CH ₃ ), 2.27,2.30 (s, each 3H, -CH ₃ ), 4.27 to _{4.40 (m, 2HI, -OCH 2} -), 4.63~5.10 (m, 4H, -OCH <, - CH 2 =, C 4 -H), 5.97 (b, lH,> NH), 7.03~8.10 (m , 4H, aromatic).

Example 10

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5- (2 -Ethoxyethyl) ester

1.33 g (8.775 mmol) of 3-nitrobenzaldehyde, 1.37 g (8.775 mmol) of 2-methyl-2-propenyl acetoacetate and l.40 g of 2-methoxy ethyl-3-aminocrotonate in 7 ml of isopropyl alcohol. As a result of dissolving mmole) in the same manner as in Example 8, pure 2.98 g of the target compound was obtained.

Yield: 78.8%

Melting Point: 89 ~ 90 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.8 (d, 3H, -CH ₃ ), 2.3 (s, 6H, -CH ₃ ), 3.35 (s, 3H, -OCH ₃ ), 3.53 (t, 2H,- CH ₂ -OCH ₃ ), 4.17 (t, 2H, -OCH _2- ), 5.05 (d, 2H, = CH ₂ ), 4.70 to 5.35 (m, 1H, -OCH <), 5.27 (m, 1H, = OCH <), 5.27 (s, 1H, -C ₄ -H), 5.40 to 6.10 (m, 1H, = CH-), 6.5 (b, lH,> NH), 7.20 to 8.15 (m, 4H, aromatic) .

Example 11

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-ethylester

1.33 g (8.775 mmol) of 3-nitrobenzaldehyde, 1.37 g (8.775 mmol) of 1-methyl-2-propenyl acetoacetate, and 1.13 g (8.775 mmol) of ethyl-3-aminocrotonate were dissolved in 7 ml of isopropyl alcohol. After the same procedure as in Example 8, to obtain 2.42 g of the pure target compound.

Feeding: 69%

Melting Point: 118 ~ 119 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.17 (t, 3H, -CH ₃ ), 1.60 (s, 3H, -CH ₃ ), 2.27, 2.30 (s, each 3H, -CH ₃ ), 3.97 (q, 2H, -OCH _2- ), 4.33 (s, 2H, -OCH _2- ), 4.70 (s, 2H, = CH ₂ ), 5.50 (s, 1H, -C ₄ -H), 6.07 (b, 1H, > NH), 6.97-8.00 (m, 4H, aromatic).

Example 12

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5- (2-methyl-2 -propenyl) ester

1.33 g (8.775 mmol) of 3-nitrobenzaldehyde was dissolved in 1.37 g (8.775 mmol) of 2-methyl-2-propenylacetoacetate and 1.0 lg (8.775 mmol) of methyl-3-aminocrotonate in 7 ml of isopropyl alcohol. After the same procedure as in Example 8, l.83 g of the target compound was obtained.

Yield: 54%

Melting Point: 122 ~ 123 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.60 (s, 3H, -CH ₃ ), 2.30, 2.33 (s, each 3H, -N-CH ₃ ), 3.57 (s, 3H, -OCH ₃ ), 4.37 ( s, 2H, -OCH _2- , 4.73 (s, 2H, = CH 2), 5.03 (s, lH, C4-H), 6.07 (b, lH,> NH), 7.03 to 8.07 (m, 4H, aromatic ).

Example 13

2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2-methyl-2-propenyl) ester-5-allyl ester 1.33 g (8.775 mmol) of 3-nitrobenzaldehyde, 1.37 g (8.775 mmol) of 2-methyl-2-propenylacetoacetate and 1.235 g (8.775 mmol) of allyl-3-amino crotonate were dissolved in 7 ml of isopropyl alcohol. After the same procedure as in Example 8, to obtain 2.92 g of the pure target compound.

Yield: 81%

Melting Point: 87 ~ 88 ℃

¹ H NMR (CDCL1 ₃ ): δ = 1.63 (s, 3H, -CH ₃ ), 2.33 (s, 6H, -CH ₃ ), 4.40 (s, 4H, -OCH _2- ), 4.53 (s, 2H, CH ₂ = C <), 4.73 (s, 2H, = CH ₂ ), 5.03-5,27 (m, 2H, C ₄ -H, -CH =), 6.63 (b, lH,> NH), 7.07 ~ 8.07 (m, 4H, aromatic).

As described above, the novel 1,4-dihydropyridine derivative represented by Structural Formula (I) prepared according to an embodiment of the present invention was tested for its efficacy and toxicity according to the following test method, in particular, its efficacy Showed excellent and sustained blood pressure lowering effect, it was confirmed that the toxicity in terms of toxicity compared to conventional drugs.

Hypotensive effect test

After intraperitoneal administration of Pentobarbital sodium 50 mg / kg to SHR (congenital hypertension rats) aged 13 to 20 weeks, anesthesia is intravenously injected at a rate of 5 mg / kg / hour using an infusion pump to anesthetize the SHR.

A catheter for drug administration is then inserted into the right carotid artery of the anesthetized SHR, and blood pressure and heart rate are continuously measured before and after drug administration using a pressure transducer and recorded on a polygraph.

The drug efficacy according to the change in the concentration of the drug is expressed as a percentage (%) comparing the blood pressure and the heart rate after the drug administration, and the duration of the drug is also compared with the drug administration before the administration of 30 μg / kg. Based on the 50% range of change time for the maximum change, the results are shown in Table 1 and accompanying drawings 1 and 2.

TABLE 1

(Note) (1) = D.B.P. Diastolic Blood Pressure

(2): S.B.P. Systolic Blood Pressure

(3): H.R. Heart Rate

Toxicity Test

In order to test the acute toxicity of the novel 1,4-dihydropyridine derivatives according to the present invention, the drugs prepared in the above examples were orally administered to selected SPF mice, and the limit and preliminary tests were carried out as follows. LD ₅₀ (ie, the dose of drug showing 50% mortality) was determined and shown in Table 2 below.

Limit test

Five SPF mice (ICR) males and females of 20-30 g (mean ± 20%) of body weight purified for 5 days were used, and a positive control group was used to investigate the toxicity of the vehicle itself. Used.

The rats were cut for 4 hours prior to drug administration, followed by forced intragastric administration, followed by four observations every hour on the first day and once daily for 13 days from the next day. The clinical symptoms, mortality and time of death of each rat shall be recorded, but the dead rats shall be weighed and autopsied immediately upon detection, followed by histopathologic examination of the lesions visible to the naked eye. An autopsy was performed.

2. Range finding test

When mortality rate of 50% or more was observed in the limit test, preliminary tests were performed with three groups administered before and after the estimated LD ₅₀ value. The preliminary test was conducted in the same manner as the limit test, but the test period was 14 days.

TABLE 2

The guinea-pig was stunned and then bleeded, and the pulmonary artery was quickly cut out to a length of 3 to 5 mm and spirally cut in Tyrode so1'n to 10 to 20 mm in length. Got a strip of. This strip organ hyeopja (organ clip) to the concentration of the organ bath (organ bath) putting, a process using the A, B, C a solution of the composition, such as Table 3 in the order following each test drug 10 by ^- Cumulative application with varying concentrations from ¹⁰ M to 10 ^-5 M yielded a curve of dose-relaxation rate as shown in Figure 3 of the accompanying drawings, and the EC ₅₀ value of each test drug (i.e., the drug showing a relaxation rate of 50%) Concentration) is shown in Table 4 below.

At this time, the relaxation rate was calculated according to the following formula.

TABLE 3

TABLE 4

Negative muscular dysfunction test

In order to test the negative inotropic effects of the 1,4-dihydropyridine derivatives according to the present invention, the change in contraction force of the left atrium in the tissue chamber was measured.

In other words, after the male guinea pig was stunned, the heart was separated, the left atrium was carefully removed, and both muscles were fixed in the tissue chamber using a holder, followed by electric stimulation. At this time, the voltage was about 10V, which is 10% higher than the threshold, and the voltage application time was about 5MS. After the contraction force is maintained (approximately 1 hour), each test drug is dissolved in DMSO and cumulative doses are changed from 10 ^-8 M to 10 ^-4 M, but the tissues are diluted 1/100. Was added.

The change in contractile force with respect to isometric tension before drug administration was measured, and the increase / decrease rate was calculated as a percentage to obtain a curve of dose-shrinkage reduction rate as shown in FIG.

Claims (2)

The novel 1,4-dihydropyridine derivative represented by the following structural formula (I).

In formula (I), R ¹ and R ² are substituted or unsubstituted lower alkenyl, lower alkoxyalkyl or aminoaryl (lower) alkyl groups having 1 to 6 carbon atoms, which are each substituted with a lower alkyl group having 1 to 4 carbon atoms. At least one of which represents a lower alkenyl group having 3 to 6 carbon atoms substituted at position 1 or 2 with a lower alkyl group having 1 to 4 carbon atoms, and R ³ represents ortho-, meta-, or Represents nitro groups which may be substituted in the para-position. Benzaldehyde derivatives represented by the following structural formula (II) and amino crotonate lower alkyl, lower alkenyl, lower alkoxyalkyl or aminoaryl (lower) alkyl esters represented by the following structural formula (III) and the following structural formula (IV) 1,4- represented by the following structural formula (I) characterized by reacting acetylacetic acid lower alkyl, lower alkenyl, lower alkoxyalkyl or aminoaryl (lower) alkyl esters simultaneously or in any order Method for preparing a dihydropyridine derivative.

In the above structural formulas (I), (II), (III) and (IV), R ¹ and R ² are lower alkyl groups having 1 to 6 carbon atoms, or unsubstituted or substituted with lower alkyl groups having 1 to 4 carbon atoms. Alkenyl groups, lower alkoxyalkyl groups or aminoaryl (lower) alkyl groups, which are different from each other, at least one of which has a lower carbon having 3 to 6 carbon atoms in which the 1 or 2 position is substituted with a lower alkyl group having 1 to 4 carbon atoms Represents a kenyl group, and R ³ represents a nitro group which may be substituted at the ortho-, meta-, or para-position relative to the phenyl group.

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