JPS617255A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is 1-6C saturated or unsaturated hydrocarbon, provided that one O or S may be contained in the chain and substituted by halogen, cyano, aryl, aryloxy, etc.; R<2> is hydrocarbon containing mutually conjugated two double bonds; x is halogen, alkylthio, cyano, CF3 or NO2). EXAMPLE:3-Methyl 5-(2,4-hexadienyl) 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. USE:A medicine having powerful vasodilator and hypotensive action and long duration of efficacy thereof, and capable of expressing delayed maximum pressure drop of hypotensive action, and useful as a remedy for hypertension exhibiting slow hypotensive action. PREPARATION:For example, a compound expressed by formula II (Z is OH or acid residue of active ester) is reacted with an alcohol expressed by the formula HO-R<2> to give the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel 1,4-dihydropyridine derivative having excellent effects on circulatory system diseases. More specifically, the following general formula [I] (wherein R1 represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, and the group optionally contains one oxygen in the chain) or may contain a sulfur atom, or may be optionally substituted with a halogen atom, a cyan group, an aryl group, an aryloxy group, an arylthio group, or a di-substituted amino group, and R2 represents two disubstituted atoms conjugated to each other. Represents a straight chain, branched or cyclic hydrocarbon group containing a heavy bond, and X is a halogen atom, an alkylthio group, a cyano group,
Means a trihalomethyl group or a nitro group. ) This relates to a novel 1,4-dihydropyridine derivative represented by:

(Prior art) Conventionally, 1,4-dihydropyridine derivatives include 4-
(2-nitrophenyl)-2,6-cymethyl-1.4
-dihydropyridine-3,5-dicarnic acid dimethyl ester (US Pat. No. 3,649,627: hereinafter abbreviated as nifedipine) or 4-(3-nitrophenyl) -2
,6-dimethyl-1,4-dihydropyridine-3,5-
Gical? nicardipine acid 3-methyl ester-5-[2-(benzylmethylamino)ethyl] ester hydrochloride (PP!f Publication No. 33-45075: hereinafter abbreviated as nicardipine) is used as an antianginal drug, a cerebral circulation improving drug, or It is used medically as a drug to treat high blood pressure.

(Problems to be Solved by the Invention) It is generally believed that drugs having a sustained and slow blood pressure lowering effect are effective in treating hypertensive diseases.

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

(Means for Solving the Problems) As a result of research to overcome these problems, the present inventors found that two conjugated 2
By introducing a double bond, the general formula [I ) We have succeeded in providing a 1,4-dihydropyridine derivative represented by:

Compound CI) of the present invention can be produced, for example, by the method shown below.

Production method 1 A compound represented by the general formula [ID (wherein R1 has the same meaning as above) and a compound represented by the general formula [■] (wherein X has the same meaning as above) and a compound represented by the general formula [■] (wherein R (same meaning as above) is used without a solvent or in a solvent inert to the reaction, such as methanol, ethanol, glomerol, isopronol, benzene, toluene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide. A CD can be obtained by heating inside.

At this time, the reaction temperature is preferably 50°C to 150°C, and the reaction time is usually sufficient for 0.5 to 15 hours.

Production method 2 By reacting a compound represented by general formula [V) with a compound represented by general formula [111] and a compound represented by general formula (Vl) under the same reaction conditions as in production method 1, [ ■] Compound is obtained.

Production method 3 A method in which a compound represented by the general formula [■] and a compound represented by the general formula [IV] are reacted under the same reaction conditions as in the production method 1.

Production method 4 A method in which a compound represented by the general formula [■] and a compound represented by the general formula [■1] are reacted under the same reaction conditions as in the production method 1.

Manufacturing method 5 Method.

Production method 6 A method in which a compound represented by the general formula [■] is reacted with a compound represented by the general formula [VI] and ammonia under the same reaction conditions as in the production method 1.

Production method 7 A compound represented by the general formula [■] (wherein 2 is a hydroxy group or an acid residue of an active ester, such as a halodane atom, and the methylsulfonyl symbol has the same meaning as above) and the general formula [Xl HO- A method of reacting with an alcohol represented by R2[X].

When 2 is a hydroxy group, this reaction is carried out in the presence of an acid, such as hydrogen chloride, a dihydric acid, difluoride trifluoride, etc., or optionally in the presence of a dehydration condensing agent such as dicyclohexylcarbodiimide, 4-dimethylamino The reaction can be carried out in an inert solvent in the presence of a base such as pyridine. When 2 is an active ester residue, optionally a υ base such as triethylamine, 4
-dimethylaminopyridine, pyridine, potassium carbonate,
It can be carried out in the presence of

Production method 8 A compound represented by the general formula [X] (each symbol in the formula has the same meaning as above) and a compound represented by the general formula [Kari] R' -OH[X1l) were mixed under the same conditions as in Production method 7. How to react with

The compound [Xl) can be produced by a known method in the same manner as the compound [lX').

The compound of general formula [I] thus obtained can be isolated and purified by conventional chemical operations.

(Effects of the Invention) The compound of the present invention has strong vasodilatory and antihypertensive effects, and is superior in these effects to known compounds such as nifedipine, and at the same time has a significantly longer efficacy. It is an extremely useful compound in the treatment of hypertension, as its maximum blood pressure lowering effect is delayed and it exhibits a slow blood pressure lowering effect.

Next, pharmacological test results for representative compounds of the compound [I] of the present invention will be shown.

<Hypertensive action> The hypotensive action and duration of this action of the compounds of the present invention were tested using unanesthetized spontaneously hypertensive rats.

The test compound was measured invasively using a 5% gum arabic suspension and a strain pressure gauge (AP-620G, manufactured by Nihon Kohden Co., Ltd.) for 1 to 1 hour. ) was recorded. The results are shown in Table-1.

The blood pressure lowering effect was the difference in mean blood pressure before and after administration of the test compound, and the duration was expressed in minutes using the half-life of the effect. Furthermore, to show the slowness of the action, the time to reach the maximum blood pressure reduction is also expressed. In addition, for comparison, the results of nifedipine and nicardipine, which were tested in the same manner as above, are also listed in the same table.

As is clear from the table, the compound of the present invention had a stronger and longer hypotensive effect than nifedipine or nicardipine, and it was observed that the time to reach the maximum hypotensive was delayed.

(Example) Next, a specific method for producing the compound m of the present invention will be described in detail by giving an example.

Example-1 4-(3-nitrophenyl)-2,6-cymethyl-1
．． 4-dihydropyridine-3,5-dicardenoic acid 3-)
f ester 5-(2,4-hexagenyl)ester 4-(3-nitrophenyl)-2,6-nomethyl-1
, 4-dihydropyridine-3,5-dicardenoic acid 3-methyl ester 0.664Ii (2mM) and 2,4-hexadien-1-ol 0.206# (2,1mM)
and dicyclohexylcar are diimide 0.4331 (2
, 1mM) and 0.4-dimethylaminopyridine.
257,19 (2.1mM) in dichloroethane 20+
++l and heated to reflux 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 obtain the title compound (0.7
34.9 (yield: 89 cm) was obtained.

Melting point 135-136.5°C Elemental analysis value C22H24N206 Calculated value (%) C: 64.07. H:5.87.
N: 6.79 Actual value (%) C: 64.14.
H:5.82. N: 6.76NMRδcock
31.72 (d, 3H) t2.34 (s, 6H)
3.62 (a, 3H), 4.52 (d, 2H) 5.3-
6.4 (m, 5H), 7.2-8.1 (m
, 4H) Example-2 4-(3-nitrophenyl)-2,6-cymethyl-1
,4-dihydrobiridine-3,5-dical? 3-ethyl ester 5-(2,4-hexagenyl)ester 4-(3-nitrophenyl)-2,6-thmethyl-
0.692 g (2 mM) of 1,4-dihydropyridine 3,5-dicarnic acid 3-ethyl ester, 0.2061 g (2,1 mM) of 2,4-hexadien-1-ol, and 0.4331 g of dicyclohexylcal diimide / (2,
1mM) and 4-tefocodimethylaminopyridine 0.2
51F (2.1 mM) was dissolved in 20 ml of dichloroethane by heating and refluxed for 2 hours. After filtering off the insoluble materials, the solvent was distilled off under reduced pressure, and the residue was purified by silica dull column chromatography to obtain the title compound 0.734F (yield: 86.1%).

Melting point 114.7-115.6°C Elemental analysis value C23H26N206 Calculated value (2)) C: 64.78. H:6.1
5. N: 6.57 Actual value (%) C: 64.8
9. H:6.03. N: 6.76 orchid δCDC
131,20 (t, 3H), 1.72 (d, 3H)2.
32 (s, 3H), 4.06 (q, 2H) 4.5
1 (d, 2H), 5.07 (s, IH) 5.2-6.4
(m, 5H), 7.1-8.1 (m,
4H) Example-3 4-(3-nitrophenyl)-2,6-cymethyl-1
．． 4-dihydropyridine-3,5-zocarganic acid 3-inglobyl ester 5-(2,4-hexagenyl)
Ester 4-(3-nitrophenyl)-2,6-cymethyl-1
, 4-dihydropyridine 3,5-dicarboxylic acid 3-isozolobyl ester 0.7211! (2mM) and 2,
4-Hegizadien-1-ol 0.206. ? (2,
1mM) and dicyclohexylcal diimide 0.43
3F (2.1mM) and 4-ridge 5i←=dimethylaminopyridine 0.257,! i' (2.1 mM) was dissolved in 20 ml of dichloroethane with heating and refluxed for 2 hours. After filtering out the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica dull column chromatography to obtain the title compound 0.8011I (yield 91%).

Melting point 102.8-104.3°C Elemental analysis value C24H213N2o6 Calculated value ←) C: 65.44. H:6.41.
N: 6.36 Actual value (%) C: 65.61.
H:6.28. N: 6.26 immediately δCDCt3
1.08 (d, 3H), 1.25 (d, 3H).

1.75 (d, 3H), 2.33 (s, 6H).

4.54 (d, 2H), 5. oo(q, IH)
.

5.08 (s, IH), 5.2-6.4 (m, 5H).

7.2-8.2 (m, 4H) Example-4 4-(3-nitrophenyl)-2,6-simethyl-1
．． 4-dihydropyridine-3,5-dicarboxylic acid 3-(
2-methoxyethyl)ester 5-(2,4-hexagenyl)ester 4-(3-nitrophenyl)-2,6-simethyl-1
,4-dihydropyridine 3,5-dicarboxylic acid 3-(2
-methoxyethyl)ester 0.753.12mM) and 2,4-hexadien-1-ol 0.2061I (2
,1mM),! Rainbow cyclohexylcarbodiimide 0.433. ! i' (2.1mM) and 0.257.9 (2.1mM) of 4-Q-dimethylaminopyridine were dissolved in 20ml of dichloroethane by heating and refluxed for 2 hours.

After filtering the insoluble materials, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.7541!). (yield: 82.6 cm).

Melting point 97.3-985°C Elemental analysis value CHNO Calculated value (%) C: 63.15. H:6.18
．． N: 6.14 Actual value (%) C: 63.20
．． H:5.98. N: 6.23NMRδCDC
l3 1.71 (d, 3H), 2.32 (s, 6
H) 3.51 (t, 2H), 4.16 (t, 2H) 4.
50 (d, 2) (), 5.10 (s, IH) 5.2-6
．． 4(m, 5H), 7.1-8.2(m, 4H) Example-5 4-(3-nitrophenyl)-2,6-cymethyl-1
,4-dihydropyridine-3,5-dicarboxylic acid 3-
(2,4-hexagenyl)ester 5-(2-cyanethyl)ester 2-(3-nitrobenzylidene)acetoacetic acid(2-cyanethyl)ester 5.491 (20mM) and 3-
A mixture of 3.631 (20 mM) aminocrotonic acid (2,4-hexagenyl) ester was reacted at 120°C for 3 hours. The reaction mixture was purified by silica dull column chromatography to obtain the title compound 5.84 # (yield 65 #).

Melting point 126.8-127.8°C Elemental analysis value C24H25N306 Calculated value ←) C: 63.85. H:5.58.
N: 9.31 Actual value (related) C: 63.93.
H:5.39. N: 9.18 immediately δCDC13
1,73(d, 3H), 2.34(s, 6H)2
．． 69 (t, 2H), 4.25 (t, 3H) 4.5
4 (d, 2H), 5.60 (s, IH) 5.1-6
．． 4 (m, 4H), 6.97 (s, IH) 7.2-8.
2 (m, 4H) Example-6 4-(3-nitrophenyl)-2,6-cymethyl-1
,4-dihydropyridine-3,5-dicarnic acid 3-cyclohexyl ester 5-(2,4-hexagenyl)
Ester 4-(3-nitrophenyl)-2,6-cymethyl-1
, 4-dihydropyridine 3,5-nocarboxylic acid 3-cyclohexyl ester 0.799F (2mM) and 2.4-
Hexadien-1-ol 0.2061/ (2.1 m
M ) and dicyclohexylcarkaimide 0.431
(2.1mM) and 0.4-Q-dimethylaminopyridine.
257J7 (2,1mM)
The mixture was heated to melt in 100 liters of water and refluxed for 2 hours. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as an oil.
68 g (yield 90.3%) was obtained.

Elemental analysis value C27H32N206 Calculated value (%) C: 67.48. H:6.71.
N: 5.83 Actual value book) C: 67.62. H:6.
49. N: 5.76NMRδcr3,430.9-
2.1 (m, 10H), 1. ．． 73 (d, 3H) 2.3
1 (s, 6H), 4.4-4,9 (m,
IH) 4.51 (d, 2H), 5.08 (s, IH) 5
．． 2-fi, 4(m, 4H), 6.77(s, IH
)7.1-8.2 (m, 4H) Example-7 4-(3-nitrophenyl)-2,6-tumethyl-
1.4-cyhydrohyridine-3.5-dicaldic acid 3
-Cinnamyl ester 5- (2,4-hexagenyl) ester 4-(3-nitrophenyl) -2,6-cymethyl-1
, 4-dihydropyridine 3,5-dicarboxylic acid 3-cinnamyl ester 0.868. ! i' (2mM) and 2
, 4-hexadien-1-ol 0.206. P(2,
1mM) and dicyclohexylcarbodiimide 0.43
3,! i' (2.1mM) and 0.2579 (2.1mM) of 4-$dimethylaminopyridine were dissolved in 20ml of dichloroethane by heating and refluxed for 2 hours. After filtering out the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound 0.
．． 921' (yield: 90 cm) was obtained.

Melting point 141-142℃ Elemental analysis value 050H3ON2°6 Calculated value (a) C near 0.02. H:5.88. N:
5.44 Actual value (→ C near 0.21, H: 5.6
8, N:5.26NMRδcDct31.67(d,
3H), 2.31 (s, 6H) 4.50 (d, 2H)
, 4.68 (d, 2H) 5.16 (a, IH)
, 5.2-6.9 (m, 7H) 7.1-8.2 (m, 9
H) Example-8 4-(3-trifluoromethylphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarganic acid 3-methyl ester 5-(2,4-hexagenyl) Ester 2-(3-trifluoromethylbenzylidene)ace)acetic acid (2,4-hexagenyl) ester 0.338,9(
1mM) and 3-aminocrotonic acid methyl ester 0.1
38,! i' (1,2mM) at 120
'C for 3 hours. The reaction mixture was purified by silica dull column chromatography to obtain the title compound 0.27
9 g (yield 64%) was obtained.

Melting point 129.5-131.1°C Elemental analysis value C23H24F5NO6 Calculated value (%) C: 59.10. H:5.18
．． N: 3.00 Actual value (%) C: 59.23
．． H:5.11. N: 2.87 immediately δCDCt
3 1.73(d, 3H), 2.30(a, 6H
) 4.51 (d, 2H), 5.03 (s, IH) 5.2
~6.3 (m, 5H) + 7.1~7.6 (
m, 4H) Example-9 4-(3-nitrophenyl)-2,6-cymethyl-1
,4-dihydrobiridine-3,5-dicarboxylic acid 3.5
- cy(2,4-hexagenyl)ester 4-(3-
Nitrophenyl) -2,6-dimethyl-1,4-dihydropyridine 3,5-dicarboxylic acid 3- (2,4-hex'rshe=v) Varnish f 0.398. P (1m
M) and 2,4-hexadix:y-1-,t-ruo,1
08N (1.1mM) and dicyclohexylcarbodiimide 0.227J7 (1.1mM) and 4-dimethylaminopyridine 0.134. ! i'(1,1mM
) was dissolved in 20 mJ of dichloroethane with heating and refluxed for 2 hours.

After filtering the insoluble matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica dull column chromatography to obtain the title compound 0.42L9 (yield: 89.4H).

Melting point 145.1-146.1℃ Elemental analysis value C27H5oN206 Calculated value (chi) C: 67.77, H: 6.32
．． N: 5.85 Actual value (Double C: 67.91.
H:6.19. N: 5.71 pull δcnct31
．． 71 (d T 6 H) + 2.30 (s +
6 H) 4.51 (d, 4H), 5.10 (s
, IH) 5.2-6.4 (m, 8H), 6.60 (s
, IH) 7.2-8.2 (m, 4H) Example-10 4-(3-nitrophenyl)-2,6-simethyl-1
．． 4-dihydropyridine-3,5-dicardenoic acid 3-methyl ester 5-(2-[4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-butenyl]) ester 4-(3 -nitrophenyl) -2,6-cymethyl-1
．． 4-dihydropyridine-3,5--,'carboxylic acid 3
-Methyl ester 0.332. ! i' (1 mM) and 4-(2°6.6-)rifthyl-1-cyclohexen-1-yl)-3-buten-2-ol 0.213,
! i' (1-,1mM), dicyclohexylcarbodiimide 0.10311.1mM), and 4-dimethylaminopyridine 0.121i' (1,1mM) were dissolved in 20ml of dichloroethane by heating, and the mixture was stirred for 2 hours. It refluxed. After filtering out the insoluble matter, the solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography with SW+
,, oily title compound 0.46811 (yield 92.1%
) was obtained.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, The group may optionally contain one oxygen or sulfur atom in the chain;
Alternatively, it may be optionally substituted with a halogen atom, a cyano group, an aryl group, an aryloxy group, an arylthio group, or a di-substituted amino group, and R^2 is a straight chain containing two double bonds that are conjugated to each other, It represents a branched or cyclic hydrocarbon group, and X means a halogen atom, an alkylthio group, a cyano group, a trihalomethyl group, or a nitro group. ) A 1,4-dihydropyridine derivative represented by: