Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1998-08-21
2000-10-17
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544180, 544238, 544333, 544405, 546256, 546263, 5462697, 5462751, C07D25100, C07D40100, C07D21379, C07D41700, C07D40300
Patent
active
06133443&
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to optically active 1,4-dihydropyridine derivatives useful as circulatory system drugs such as hypotensors and vasodilators and to a production method therefor.
BACKGROUND ART
1,4-Dihydropyridine derivatives, such as nifedipine and nirvadipine, have calcium antagonism and, hence, are useful as a circulatory system drug such as a hypotensor and a vasodilator. However, their water solubility is insufficient so that it has been tried to convert them into inclusion compounds with cyclodextrin, i.e., forms with an increased water solubility, in order to impart them with pharmaceutical characteristics such as bioavailability and controlled release (Japanese Patent Application (Kokai) No. 6-100537).
It has also been tried to increase the water solubility of 1,4-dihydropyridine derivatives by introducing a basic tertiary amino group into themselves to form a medically acceptable salt.
For example, (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester (YM-09730) represented by the following formula ##STR2## [J. Med. Chem., 29, 2504 (1986)], (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-diydropyridine-3,5-dicarboxylic acid 3-{2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl} ester 5-methyl ester represented by the following formula ##STR3## [Chem. Pharm. Bull., 39, 108 (1991)] and salts thereof are known to have calcium antagonistic activity as well as vasodilating activity and hypotensive activity, with these activities lasting [Arzneim. -Forsch./Drug Res. 38(11), 1666(1988), J. Med. Chem., 29, 2504 (1986), and Japanese Patent Publication (Kokoku) No. 57-30111]
However, only few 1,4-dihydropyridine derivatives have been known that themselves have electric charges and are imparted with, in a sense, permanent water solubility [J. Med. Chem., 3, 3743 (1993)].
Therefore, an object of the present invention is to provide optically active 1,4-dihydropyridine derivatives having themselves electric charges and permanently having water solubility.
Another object of the present invention is to provide a production method for producing such optically active 1,4-dihydropyridine derivatives.
DISCLOSURE OF THE INVENTION
As a result of intensive investigation, the present inventors have found that novel optically active 1,4-dihydropyridine derivatives represented by general formula (I) ##STR4## (wherein R.sup.1 represents a C.sub.1-6 alkyl group, R.sup.2 represents a nitrogen-containing heterocyclic group forming a quaternary ammonium salt which may be substituted, and n is an integer of 1, 2 or 3) and anion salts thereof have excellent vasodilating and hypotensive activities and also excellent water solubility, and completed the present invention based on the discovery.
That is, the present invention relates to optically active 1,4-dihydropyridine derivatives represented by general formula (I) ##STR5## (wherein the symbols have the same meanings as defined above) and anion salts thereof and to a production method therefor.
Hereafter, the present invention will be described in greater detail.
In general formula (I), the C.sub.1-6 alkyl group represented by R.sup.1 may be a linear, branched or cyclic alkyl group. Its examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, and a cyclohexyl group.
In general formula (I), the nitrogen-containing heterocyclic group represented by R.sup.2 may include at least one nitrogen atom as a ring-forming atom and form a quaternary ammonium. The heterocyclic ring is preferably an aromatic ring, examples of which include a pyridinium group, a pyridazinium group, a pyrimidinium group, a pyrazinium group, a triazinium group, an imidazolium group, a pyrazolium group, an oxazolium group, and a thiazolium group.
These heterocyclic groups may be substituted. Examples of the substituent include a cyano group, a C.sub.1-4 alkyl group, a C.sub.2-5 alkoxycarbonyl group, a dialkylamino group having 1-4 carbon atoms in each alkyl
REFERENCES:
Watanabe et al., "L-Type Ca Channel Block by Highly Hydrophilic Dihydropyridines in Single Ventricular Cells of Guinea-pig Hearts," J. Mol. Cell. Cardiol., vol. 27, No. 6, pp. 1271-1279, 1995.
Boer et al., "Interaction of cytostatics and chemosensitizers with the dexniguldipine binding site on P-glycoprotein," Eur. J. Pharmacol., vol. 295, No. 2/3, pp. 253-260, Jan. 1996.
Boer et al., "Reversible Labeling of a Chemosensitizer Binding Domain of p-Glycoprotein with a Novel 1,4-Dihydropyridine Drug Tansport Inhibitor," Biochemistry, vol. 35, No. 5, pp. 1387-1396, 1996.
Agata Naoki
Isshiki Kunio
Nakashima Takashi
Sakata Noriaki
Yoshioka Takeo
Foutch Louise A.
LaPointe Dennis G.
Mercian Corporation
Schroeder Ben
Shah Mukund J.
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