JPS58201764A - Dihydropyridine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an ester residue having a 2-hydroxyethyl group represented by the general formula (wherein R means a lower alkyl group such as methyl, ethyl, or propyl). This invention relates to novel dihydropyridine derivatives.

The reaction of synthesizing 2,6-dicarboxylate derivatives by reacting benzylidene acetoacetate bleached conductor and β-aminocrotonate derivative, or benzylidene acetoacetate, acetoacetate i@4 form and ammonia is called Hantzsch reaction. is widely known, along with its variations [e.g.
, , 215.1 (1882); Ber, , 15.29
14 (1882) Ldan, 1521 (1884), Shi, 2
903 (1884), dish, 1338 (1887), 31
, 743 (1898); J. Ohem, 8oc.
413 (1943); J., Amar, Ohem, 8
oc, , 71, 4003 (1949) HJ
,Org,Ohem,.

50, 1914 (1965), etc. ].

Also, [2,6-dimethyl-4-phenyl 1.4-i)
The hydropyridine-45-dicarboxylate conductor is
It is also well known that it exhibits interesting pharmacological effects such as vasodilation and antihypertensive effects [for example, Naturwis
senshaftan, jjl, 578 (1971);
Arzneim, -Forsch, M1 (197
2); J, Pharm, Pharmcol, p. 917 (1972); J, Pharm, 8ci,
6L586 (1973); J, Med.

Ohem, 11956 (1974); Balg,
Pat, 6B9,577; U, 8° Pat, 44
See 85°847, etc. ].

Further, as a compound having a 2-hydroxyethyl group in the ester residue, a dihydropyridine derivative represented by the general formula (wherein Ar represents 2-trifluoromethylphenyl, 2-nitrophenyl, or 2-pyridyl) is used. Although these substances are known (for example, see ``Kiken 46-37549'' and JP-A-50-35173, etc.), substances having one 2-hydroxyethyl group like the substance of the present invention are not known.

In view of the current situation, the present inventors have conducted extensive research, and as a result, have discovered the compound (I) of the present invention, which has excellent vasodilatory and antihypertensive effects, as well as low toxicity, and has completed the present invention. . Furthermore, the formulation rI) of the present invention is also industrially useful as an intermediate for producing other pharmacologically active substances.

The compound of the present invention can be produced as follows. That is, ethylene glycol is combined with a base (e.g., sodium hydride, sodium ethoxide, triethylamine,
pyridine, etc.), and without isolating the product, further reacted with 3-nitrobenzaldehyde and β-aminocrotonate represented by the general formula (wherein R has the same meaning as above). By letting
It can be easily manufactured. (2) has good crystallinity, precipitates out when the reaction mixture is allowed to stand, and can be easily isolated;

The compound of the present invention (■) can be used alone or in combination with other compositions, for example, in the form of tablets, troches, gunpowders, granules, powders, capsules, ampoules, suppositories, etc. . Other compositions include, for example, starch, dextrin, sucrose, lactose, silicic acid, carboxymethylcellulose, cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium bicarbonate, paraffin, cetyl alcohol, stearate, Kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol 1. Examples include water, ethanol, isopropyl alcohol, and propylene glycol.

The appropriate daily dosage for oral administration of the compound (I) of the present invention is 0.005 to 20 per kg of body weight. Naturally, the dosage should be increased or decreased as appropriate depending on the condition at the time of administration.

The method for producing the compound (I) of the present invention will be explained in detail by giving further examples.

Example 50 q of 50% sodium hydride was added to 120 g of ethylene glycol, and 20 g of diketene was gradually added dropwise. Then, the mixture was heated on a water bath for 3 hours. To this mixture was added 32 g of 3-nitrobenzaldehyde and 24 p of methyl β-aminocrotonate. was added, mixed well, and then heated on a water bath for another 5 hours. Then allowed to cool to precipitate crystals. P was washed with isopropyl alcohol and dried to give 2-hydroxyethyl methyl 2,6-dimethyl-4-(3 -nitrophenyl) -1,4-dihydropyridine-6,5-dicarboxylate pale yellow prismatic crystals (45f, 57%)
get. Recrystallization from methanol-isopropyl alcohol gave pale yellow needles, mp 176-178°.

NM几(CD(E15)δ: 2.00(IHXbr)
, 2.39 (6H,s), 3.65 (3HXs),
3.65-4. o o (2g1m), 4.10 (2
H,m), 5°14 (IHLS), 6.06 (IHX
br), 7.23-8.20 (4H, m).

NMR (CD50D) δ52.40 (6HXs),
3.613 (3H,s), 5.67-3.95 (2
g1m), 4.07-4.35 (2H, m), 5.1
6 (IH.

S), 7.30-8.23 (4g1m).

Next, the results of pharmacological tests and toxicity tests for some of the compounds (I) of the present invention will be explained.

Compound A: 2-xyethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-t4-dihydropyridine-45-dicarboxylate Compound I3: Papaverine Effect on osseous and femoral artery blood flow The animals were anesthetized with bentoparbital sodium (3011 fl/9, iv), and vertebral and femoral artery blood flow was measured using an electromagnetic flowmeter under artificial respiration. Blood pressure was also measured at the same time.

The test drug was dissolved in polyethylene glycol, further diluted with physiological saline, and then administered into the femoral vein.

The results are shown in Table 1.

Table 1 As shown in Table 1, the compound of the present invention has a clearly superior effect compared to papaverine, and the effect is approximately 100%
It's about double that.

ddY male mice weighing 22 to 269 were used. The test drug was mixed with gum arabic powder and administered orally. L.D.
The so value was determined by Behreni-K from the number of deaths one week after administration.
It was determined by the hrber method.

The results are shown in Table 2.

As shown in Table 2, one compound of the present invention had extremely low toxicity compared to nof noverine.

Claims (1)

[Scope of Claims] A 1,4-dihydropyridine derivative represented by the general formula (wherein R means a lower alkyl group such as methyl, ethyl, propyl, etc.).