Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1988-05-26
1989-06-20
Hollrah, Glennon H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07F 710
Patent
active
048410543
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the art of organic synthesis, more specifically, to 1,4-dihydropyridine derivatives and, more particularly, to 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-d ihydropyridine.
The above-mentioned 1,4-dihydropyridine derivatives have hypotensive and coronarodilating effects and some of them are useful in medicine.
PRIOR ART
The most widespread 1,4-dihydropyridine derivatives is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(O-nitrophenyl)-1,4-dihydropyridine (Nifedipine) possessing hypotensive and coronarodilating effects (Arzneium.-Forsch, V.32, 1982, E. Kusano, J. Asano, K. Takeda, J. Matsumoto, A. Ebihar. "Hypotensive Effect of Nifedipine in Hypertensive Patients with Chronic Renal Failure", pp. 1575-1580).
Though Nifedipine is widely used in the medical practice, it is unstable in light and highly toxic.
The known 1,4-dihydropyridine derivatives containing silicon in the 3,5-ester group are substantially inferior to Nifedipine as regards their hypotensive activity (Eur. J. Med. Chem., V.18, No.2, 1983, R. Tacke, A. Bentlage, R. Towart, E. Moller, "Sila-Analogues of Nifediphine-Like dialkyl 2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylates", pp. 155-161).
Among 1,4-dihydropyridine derivatives known in the art is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2'-furyl)-1,4-dihydropyridine which also displays a hypotensive activity, though considerably lower than that of Nifedipine (Khimiko-pharmaceuticheskij Zhournal, No.6, 1979, V. V. Kastron, G. Ya. Dubur, R. O. Vitolin', A. A. Kimenis "Synthesis and pharmacological activity of 4-furyl-1,4-dihydropyridines", pp.57-62).
The above-mentioned derivatives of 1,4-dihydropyridine, though possess a hypotensive effect, this effect is not lasting which necessitates their repeated administration during the day's period. Furthermore, Nifedipine has a high toxicity.
DISCLOSURE OF THE INVENTION
The present invention is directed to the provision of such a derivative of 1,4-dihydropyridine which would exhibit a protracted hypotensive effect and, at the same time, would have a low toxicity.
This object is accomplished by a derivative of 1,4-dihydropyridine which, according to the present invention, is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(5'-trimethylsilyl-2'-furyl)-1,4-dihy dropyridine of the formula ##STR2##
This compound is novel. We have found that this compound displays a protracted hypotensive effect and has a relatively low toxicity.
This compound comprises a crystalline substance of a yellowish shade and m.p. of 158.degree.-159.degree. C. It is well soluble in methanol, ethanol, chloroform, acetone and substantially insoluble in water. This compound is stable both in the crystalline state and as solutions. When solid, upon storage in the light this compound does not change its UV spectrum within a year's period. In a alcoholic solution of the concentration of 5.times.10.sup.-5 mol the UV spectrum remained unchanged for 6 months. At the same time, in the UV spectrum of Nifedipine under similar conditions a maximum of the oxidized form of Nifedipine is observed already within 6 hours.
This compound is prepared by the method comprising condensation of methyl ester of acetoacetic acid, ammonia and 5-trimethylsilylfurfurol in solution of methanol. Furthermore, this compound can be obtained by condensation of methyl ester of acetoacetic acid, methyl ester of .beta.-aminocrotonic acid and 5-trimethylsilylfurfurol in a medium of an organic solvent. The reaction is carried out under normal pressure under heating. The product is obtained in a good yield.
The starting components employed for the preparation of the above-mentioned compound are known and available substances.
The pharmacological study of the compound according to the present invention was conducted in comparison with a preparation of the same series employed in clinical practice, viz. Nifedipine.
In experiments on spontaneously hypertensive rats the compound according to the present invention upon a single administration (10 mg/kg i
REFERENCES:
patent: 4237137 (1980-12-01), Tacke et al.
patent: 4277483 (1981-07-01), Materne et al.
E. Kusano, et al., Arzheim.-Forsch, 32, "Hypotensive Effect of Nifedipine in Hypertensive Patients with Chronic Renal Failure", 1575-1580, (1982).
R. Tacke, et al., Eur. J. of Med. Chem., 18, "Sila-Analgaes of Nifedipine-like . . . ", 155-161 (1983).
V. Kastron, et al., Khimiko-Pharmaceticheskij Zhournal, No. 6, "Synthesis and Pharmacological Activity of . . . ", 57-62 (1979).
Dubur Gunar Y.
Erchak Nikolai P.
Kastron Valeria V.
Kimenis Agris A.
Lukevits Edmund Y.
Hollrah Glennon H.
Russell Mark W.
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