JPH0629245B2 - 1,4-dihydropyridine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel 1,4-dihydropyridine derivative having an excellent action on cardiovascular diseases. More specifically, the following general formula [I] (In the formula, R ¹ represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, and the group may optionally contain one oxygen atom in the chain, Or, optionally substituted with an aryl group, R ² represents a linear, branched or cyclic hydrocarbon group including two double bonds conjugated to each other, and X represents a trihalomethyl group or a nitro group. Means a 1,4-dihydropyridine derivative.

(Prior Art) Conventionally, as a 1,4-dihydropyridine derivative, 4-
(2-Nitrophenyl) -2,6-dimethyl-1,4-
Dihydropyridine-3,5-dicarboxylic acid dimethyl ester (U.S. Pat. No. 3,644,627; hereinafter abbreviated as nifedipine) or 4- (3-nitrophenyl) -2,6
-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- [2- (benzylmethylamino) ethyl] ester hydrochloride (Japanese Patent Publication No. 55-4
5075: hereinafter abbreviated as nicardipine) and the like are used for medical treatment as an antianginal drug, a cerebral circulation improving drug, or a drug for treating hypertension.

(Problems to be Solved by the Invention) Generally, it is considered that a drug having a sustained and slow blood pressure lowering effect is effective for treating hypertensive diseases.

However, the hypotensive effect of the compound disappears in a short time,
Moreover, the onset of its action is rapid. Therefore, these compounds cannot be said to be excellent drugs for treating hypertension.

(Means for Solving Problems) The inventors of the present invention have conducted research to overcome these problems, and as a result, two conjugating groups 2 in the 5-position carboxylic acid ester residue have been conjugated.
By introducing a heavy bond, the duration of the blood pressure lowering effect is long, and further, the maximum hypotension is delayed, and a slow blood pressure lowering effect is exhibited, and a general formula having excellent characteristics as a therapeutic agent for hypertension [ The present invention succeeded in providing a 1,4-dihydropyridine derivative represented by the formula [I].

The compound [I] of the present invention can be produced, for example, by the method shown below.

Production method 1 General formula [II] (Wherein R ¹ is as defined above) and a compound of the general formula [III] (Wherein X is as defined above) and a compound of the general formula [IV] (Wherein R ² has the same meaning as defined above) and a solvent inert to the reaction, such as methanol, ethanol, propanol,
Isopropanol, benzene, toluene, dioxane,
[I] can be obtained by heating in tetrahydrofuran, dimethylsulfoxide or dimethylformamide. At this time, the reaction temperature is 50 ° C to 150 ° C.
Is preferred, and a reaction time of 0.5 to 15 hours is usually sufficient.

Production method 2 General formula [V] And a compound represented by the general formula [III] and a general formula [VI] The compound of formula (I) is obtained by reacting the compound of formula (1) with the same reaction conditions as in production method 1.

Production method 3 General formula [VII] A method of reacting the compound of formula (I) with the compound of formula (IV) under the same reaction conditions as in production method 1.

Production Method 4 Compound represented by general formula [V] and general formula [VIII] A method of reacting the compound represented by: under the same reaction conditions as in production method 1.

Production method 5 A method of reacting the compound represented by the general formula [II] with the compound represented by the general formula [VIII] and ammonia under the same reaction conditions as in Production method 1.

Production method 6 A method of reacting the compound represented by the general formula [VII] with the compound represented by the general formula [VI] and ammonia under the same reaction conditions as in the production method 1.

Production method 7 General formula [IX] (In the formula, Z is a hydroxy group or an acid residue of an active ester, for example, a halogen atom, a methylsulfonyloxy group, a paratoluenesulfonyloxy group, a benzotriazole-1-
Represents an oxy group, etc., and other symbols have the same meanings as above)
A method of reacting the compound represented by the formula (I) with an alcohol represented by the general formula [X] HO-R ² [X]. When Z is a hydroxy group, this reaction is carried out in the presence of an acid such as hydrogen chloride, sulfuric acid or borotrifluorotrifluoride, or in the presence of a dehydrating condensing agent such as dicyclohexylcarbodiimide or the like, and optionally 4-dimethylaminopyridine or the like. It can be carried out in an inert solvent in the presence of the base.
When Z is an active ester residue, in an inert solvent,
If desired, it can be carried out in the presence of a base such as triethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate and the like.

Production Method 8 General Formula [XI] (Wherein each symbol in the formula has the same meaning as defined above) and a compound represented by the general formula [XII] R ¹ -OH [XII] are reacted under the same reaction conditions as in the production process 7.

The compound of [XI] can be produced by a known method similarly to the compound of [IX].

The compound of the general formula [I] thus obtained can be isolated and purified by a usual chemical operation.

(Effect of the invention) The compound of the present invention has a strong vasodilatory action and hypotensive action, and compared with known compounds such as nifedipine,
These effects are extremely excellent, and at the same time, their efficacy is remarkably long, and further, the maximum hypotension of their antihypertensive effect is delayed, and has a characteristic of showing a gradual antihypertensive effect.
It is a very useful compound for treating hypertension.

<Hypertensive action> The hypotensive action of the compound of the present invention and the duration of the action were tested using spontaneously hypertensive rats without anesthesia.

1 mg / kg was administered into the duodenum via a cannula in which the test compound was pre-inserted as a 5% gum arabic suspension, and the tail pressure of rats and the duration of the blood pressure-lowering effect were measured with a strain pressure gauge (AP-620G, It was measured invasively using Nihon Kohden Co., Ltd. and recorded on a retigraph (8K, manufactured by JEOL Sanei Co., Ltd.).

The results are shown in Table-1.

The antihypertensive effect is the difference in mean blood pressure before and after administration of the test compound, and the duration is represented by the half-life of the effect, which is expressed in minutes. Furthermore, in order to show the gradual release of the action, the time required for reaching the maximum hypotension is also shown. For comparison, the same table also shows the results of nifedipine and nicardipine tested in the same manner as above.

As is clear from the table, it was confirmed that the compound of the present invention has a stronger antihypertensive action and a longer connection time than that of nifedipine or nicardipine, and further, the maximum hypotensive arrival time is delayed and expressed.

(Example) Next, a specific method for producing the compound [I] of the present invention will be described in detail with reference to examples.

Example-1 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 0.664 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 Mm)
And 4-dimethylaminopyridine 0.257 g (2.1 m
M) and were dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.734 g (yield 89%) of the title compound.

Mp 135 to 136.5 ° C. Elemental analysis C ₂₂ H ₂₄ N ₂ O ₆ Calculated (%) C: 64.07, H : 5.87, N: 6.79 Found (%) C: 64.14, H : 5.82, N: 6.76 NMRσ CDCl3 1.72 (d, 3H), 2.34 (s, 6H) 3.62 (s, 3H), 4.52 (d, 2H) 5.3 to 6.4 (m, 5H), 7.2 to 8.1 (m, 4H) Example-2 4- ( 3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 0.692 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 mM)
And 4 dimethylaminopyridine 0.257g (2.1m
M) and were dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 0.734 g (yield 86.1%).
Got

Mp 114.7 to 115.6 ° C. Elemental analysis C ₂₃ H ₂₆ N ₂ O ₆ Calculated (%) C: 64.78, H : 6.15, N: 6.57 Found (%) C: 64.89, H : 6.03, N: 6.76 NMRσ CDCl3 1.20 (t, 3H), 1.72 (d, 3H) 2.32 (s, 3H), 4.06 (q, 2H) 4.51 (d, 2H), 5.07 (s, 1H) 5.2〜6.4 (m, 5H), 7.1〜 8.1 (m, 4H) Example-3 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 0.721 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1
mM) and 4-dimethylaminopyridine 0.257 g
(2.1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.801 g of the title compound (yield 91
%) Melting point 102.8-104.3 ° C elemental analysis value C ₂₄ H ₂₈ N ₂ O ₆ calculated value (%) C: 65.44, H: 6.41, N: 6.36 measured value (%) C: 65.61, H: 6.28, _{N: 6.26 NMRσ CDCl3 1.08 (d} , 3H), 1.25 (d, 3H) 1.75 (d, 3H), 2.33 (s, 6H) 4.54 (d, 2H), 5.00 (q, 1H) 5.08 (s, 1H) , 5.2-6.4 (m, 5H) 7.2-8.2 (m, 4H) Example-4 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3- (2
-Methoxyethyl) ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3- (2
-Methoxyethyl) ester 0.753 g (2 mM) and 2,4-hexadiene-1-ol 0.206 g (2.
1 mM) and dicyclohexylcarbodiimide 0.433
g (2.1 mM) and 4-dimethylaminopyridine 0.2
57 g (2.1 mM) was dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.754 g)
(Yield 82.6%) was obtained.

Melting point 97.3-98.5 ° C Calculated value (%) C: 63.15, H: 6.18, N: 6.14 Measured value (%) C: 63.20, H: 5.98, N: 6.23 NMR σCDCl3 1.71 (d, 3H), 2.32 (s, 6H ) 3.51 (t, 2H), 4.16 (t, 2H) 4.50 (d, 2H), 5.10 (s, 1H) 5.2 ~ 6.4 (m, 5H), 7.1 ~ 8.2 (m, 4H) Example-5 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cyclohexyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cyclohexyl ester 0.799 g (2 mM) and 2,4-
Hexadiene-1-ol 0.206 g (2.1 mM)
And dicyclohexylcarbodiimide 0.433 g (2.
1 mM) and 4-dimethylaminopyridine 0.257 g
(2.1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.868 g (yield 90.3%) of the title compound as an oil.

Elemental analysis C ₂₇ H ₃₂ N ₂ O ₆ Calculated (%) C: 67.48, H : 6.71, N: 5.83 Found (%) C: 67.62, H : 6.49, N: 5.76 NMRσ CDCl3 0.9~2.1 (m , 10H), 1,73 (d, 3H) 2.31 (s, 6H), 4.4 ~ 4.9 (m, 1H) 4.51 (d, 2H), 5.08 (s, 1H) 5.2 ~ 6.4 (m, 4H), 6.77 (s, 1H) 7.1 to 8.2 (m, 4H) Example-6 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cinnamyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cinnamyl ester 0.868 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 m)
M) and 4-dimethylaminopyridine 0.257 g (2.
1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.926 g (yield 90%) of the title compound.

Mp 141-142 ° C. Elemental analysis C ₃₀ H ₃₀ N ₂ O ₆ Calculated (%) C: 70.02, H : 5.88, N: 5.44 Found (%) C: 70.21, H : 5.68, N: 5.26 NMRσ CDCl3 1.67 (d, 3H), 2.31 (s, 6H) 4.50 (d, 2H), 4.68 (d, 2H) 5.16 (s, 1H), 5.2 to 6.9 (m, 7H) 7.1 to 8.2 (m, 9H) Implemented Example-7 4- (3-trifluoromethylphenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2,4-hexadienyl)
Ester 2- (3-trifluoromethylbenzylidene) acetoacetic acid (2,4-hexadienyl) ester 0.338 g (1
mM) and 3-aminocrotonic acid methyl ester 0.13
A mixture with 8 g (1.2 mM) was reacted at 120 ° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound 0.279 g (yield 64
%) Was obtained.

Mp from 129.5 to 131.1 ° C. Elemental analysis C ₂₃ H ₂₄ F ₃ NO ₆ Calculated (%) C: 59.10, H : 5.18, N: 3.00 Found (%) C: 59.23, H : 5.11, N: 2.87 NMRσ CDCl3 1.73 (d, 3H), 2.30 (s, 6H) 4.51 (d, 2H), 5.03 (s, 1H) 5.2 to 6.3 (m, 5H), 7.1 to 7.6 (m, 4H) Example-8 4- ( 3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3,5-
Di (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-
(2,4-hexadienyl) ester 0.398 g (1
mM) and 2,4-hexadiene-1-ol 0.108
g (1.1 mM), dicyclohexylcarbodiimide 0.227 g (1.1 mM) and 4-dimethylaminopyridine 0.134 g (1.1 mM) were added to dichloroethane 2
In 0 m, it was heated to dissolve and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 0.4
28 g (yield 89.4%) was obtained.

Mp from 145.1 to 146.1 ° C. Elemental analysis C ₂₇ H ₃₀ N ₂ O ₆ Calculated (%) C: 67.77, H : 6.32, N: 5.85 Found (%) C: 67.91, H : 6.19, N: 5.71 NMRσ CDCl3 1.71 (d, 6H), 2.30 (s, 6H) 4.51 (d, 4H), 5.10 (s, 1H) 5.2 to 6.4 (m, 8H), 6.60 (s, 1H) 7.2 to 8.2 (m, 4H) Example-9 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- {2- [4- (2,6,6-trimethyl-1-cyclohexen-1-yl) -3-butenyl]}
Ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 0.332 g (1 mM) and 4- (2,6,6
-Trimethyl-1-cyclohexen-1-yl) -3-
0.213 g (1.1 mM) butene-2-ol and 0.103 g (1.1 m) dicyclohexylcarbodiimide
M) and 4-dimethylaminopyridine 0.124 g (1.
1 mM) was dissolved in 20 m of dichloroethane by heating and the mixture was refluxed for 2 hours. After filtering the insoluble matter,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.468) as an oil.
g (yield 92.1%) was obtained.

Elemental analysis C ₂₉ H ₃₆ N ₂ O ₆ Calculated (%) C: 68.48, H : 7.13, N: 5.51 Found (%) C: 68.59, H : 6.99, N: 5.36 NMRσ CDCl3 0.68~2.30 (m , 9H), 0.95 (s, 3H) 0.98 (s, 3H), 1.63 (s, 3H) 2.34 (s, 6H), 3.62 (s, 3H) 5.09 (s, 1H), 5.20 ~ 6.25 (m, 3H ) 6.30 (s, 1H), 7.10 ~ 8.16 (m, 4H)

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, and the group may optionally contain one oxygen atom in the chain, Or, optionally substituted with an aryl group, R ² represents a linear, branched or cyclic hydrocarbon group including two double bonds conjugated to each other, and X represents a trihalomethyl group or a nitro group. 1,4-dihydropyridine derivative represented by the formula (1).