Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-03-01
1995-09-12
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564304, 564364, 564365, A61K 31135, C07C21560
Patent
active
054496942
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP93/00896, filed Jun. 30, 1993.
BACKGROUND OF THE INVENTION
1. Field of the Art
The present invention relates to a novel optically active ritodrine compound which is effective for the treatment of threatened premature birth and threatened abortion as well as the treatment of dysmenorrhea.
2. Related Art
Ritodrine, (.+-.)-erythro-1-(p-hydroxyphenyl)-2-[2-(p-hydroxyphenyl)ethylamino]-1-pro panol, represented by the formula (I): ##STR1## is known to be effective in preventing premature birth owing to its excellent activity for suppressing uterine contraction (Japanese Patent Publication Nos. 10139/1968, 21810/1970 and 22732/1970).
Each of the erythro and threo types of ritodrine structure was anticipated to have two kinds of isomers because of asymmetric carbon atoms at 1- and 2-positions. However, since ritodrine is the racemate of the erythro type ((.+-.)-isomer, specific rotation [.alpha]sub.D.sup.25 =0.degree.) and the method for obtaining individually the (-)- and (+)-isomers has not been generalized, optically active ritodrines could not be obtained easily.
Therefore, the efficacies or the relationship with side effect of the isomers remained ambiguous and could not be examined. Ritodrines had problems to be solved including the examination of the properties of ritodrine isomers and of their possibilities as medicines, because ritodrines had side effects including an increase in heart rate.
SUMMARY OF THE INVENTION
Therefore, the object of the present invention consists in providing a useful, optically active ritodrine compound which is effective for the treatment of threatened premature birth and threatened abortion as well as the treatment of dysmenorrhea.
The present inventors conducted researches in order to obtain the respective isomers with high purities. It has been described in 10139/1968 that the ritodrine racemate can be resolved into isomers by fractional crystallization, but there is no actual examples in the publication. Furthermore, no reports of successful resolution were described.
The present inventors have also researches on resolving ritodrine by the selective crystallization method or the resolution method by forming various salts, but none of these methods were successful in resolving ritodrine.
However, the present inventors have surprisingly found as a result of examining the optically active column chromatography method that two isomers with such a high purity as no other isomer being detected therein can be obtained by selecting one of many optically active column chromatographies and using a certain solvent system.
The present inventors have also established the method for synthesizing stereoselectively these isomers.
Thus, according to the present invention, pure (-)-ritodrine containing substantially no (+)-ritodrine, that is (-)-erythro-1-(p-hydroxyphenyl)-2-[2-(p-hydroxyphenyl)ethylamino]-1-propan ol which is useful for the treatment of threatened premature birth and threatened abortion as well as the treatment of dysmenorrhea or a salt thereof are provided.
Also, according to the present invention, a pharmaceutical composition comprising (-)-ritodrine as an effective component is provided.
Furthermore, according to the present invention, the treatment of threatened premature birth and threatened abortion as well as the treatment of dysmenorrhea comprising administering an effective dose of (-)-ritodrin are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the relationship between the concentration of (.+-.)-ritodrine, (+)-ritodrine and (-)-ritodrine and the suppression rate (%) on the oxytocin-induced contraction of an isolated rat myometrium;
FIG. 2 is a graph showing the relationship between the dose of (.+-.)-ritodrine, (+)-ritodrine and (-)-ritodrine and the suppression rate (%) of the tension on the oxytocin-induced contraction of uterus in situ;
FIG. 3 is a graph showing the relationship between the dose of (.+-.)-ritodrine, (+)-ritodrine and (-)-ritodrine and the suppression rate (%) of the frequency of
REFERENCES:
patent: 5189219 (1993-02-01), Brussee et al.
Chemical Abstracts, 88(11) col. 69391n (1978).
Chemical Abstracts, 105(3) col. 19181t (1986).
Tetrahedron, 43(6) pp. 1177-1182 (1987).
Fukuda Yoshimasa
Kosugi Isao
Niizato Tetsutarou
Shibazaki Yoshiaki
Yamazaki Naoki
Meiji Seika Kabushiki Kaisha
Raymond Richard L.
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