Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-11-18
1995-06-13
Chan, Nicky
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D31920
Patent
active
054244560
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/CS92/00015 filed May 27, 1992.
TECHNICAL FIELD
The present invention relates to novel N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine and its enantiomers, the pharmaceutically acceptable acid addition salts thereof, and the process of preparation thereof. These compounds exhibit pronounced calcium channel blocking, .alpha..sub.1 -adrenergic as well as antithrombotic activities and can be used for treatment of hypertension and other cardiovascular diseases.
BACKGROUND ART
It is already known that the number of compounds represented by the general formula (II) ##STR1##
wherein Ar represents phenyl or substituted phenyl, R represents H or methyl, n is 2 or 3 and Ar.sub.1 represents substituted phenyl, possess calcium channel blocking activity. From these substances Verapamil (generic name, Merck index, 11th Edition, 9851) represented by the general formula (II), wherein Ar and Ar.sub.1 represent 3,4-dimethoxyphenyl, R represents methyl, n is 2, has effective calcium channel blocking activity and has been clinically used for the treatment of ischemic heart disease, arrhythmias and hypertension. In an advanced phase of clinical testing is Mepamil (proposed generic name) represented by the general formula (II), wherein Ar represents 2-methylphenyl, R represents methyl, n is 2 and Ar.sub.1 represents 3,4-dimethoxyphenyl. The latter compound exhibits, compared to Verapamil, lower negative inotropic activity (Blaha L. et al. CS Patent 258534).
It is already known from the literature (Mitani K. et al.: Chem. Pharm. Bull., 36, 367 (1988), Mitani K. et al.: Chem. Pharm. Bull., 36, 373 (1988)), that compounds of general formula (II), wherein Ar represents phenyl, alkoxyphenyl, dialkoxyphenyl or trialkoxyphenyl group, R represents H or methyl, and Ar.sub.1 represents substituted phenyloxy group exhibit calcium channel blocking and .alpha.-adrenergic blocking activity.
Furthermore, it is known, that some derivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine, e.g. Piperoxan (generic name, Merck index, 11th Edition, 7448) block the .alpha.-adrenergic receptors in a competitive manner and that the activity of the S-enantiomer is more pronounced, than that of the R-enantiomer (Nelson, L. N., Wennerstrom, J. E.: J. Med. Chem., 20, 880 (1977)).
According to our knowledge, derivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine exhibiting except of the .alpha.-adrenergic blocking activity also calcium channel blocking activity have not been described yet.
DISCLOSURE OF INVENTION
As a result of extensive investigation, it has been found, that novel N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodioxine and (+)- (-)-enantiomers thereof, represented by the general formula (I) wherein R.sub.1 and R.sub.2 represent methoxy and R.sub.3 represents H (in further text assigned as VUFB 17951 for the hydrochloride of the racemic amine, VUFB 18019 for the hydrochloride of the (+)-enantiomer and VUFB 18020 for the hydrochloride of the (-)-enantiomer), or R.sub.1 and R.sub.2 represent H and R.sub.3 represents methyl (in further text assigned as VUFB 17959 for the hydrochloride of the ##STR2## racemic amine, VUFB 18007 for the hydrochloride of the (+)-enantiomer and VUFB 18018 for the hydrochloride of the (-)-enantiomer) or R.sub.1 and R.sub.2 and R.sub.3 represent H (in further text assigned as VUFB 18087 for the racemic amine) and the pharmaceutically acceptable acid addition salts thereof exhibit in pharmacological tests pronounced hypotensive activity as a result of a calcium channel blocking and .alpha.-adrenergic blocking activity and a pronounced antithrombotic activity. In test animals they also lower intraocular pressure and lower the opening pressure of the urinary bladder sphincter.
Further, according to the present invention, processes are provided for preparation of the novel N-arylalkylderivatives of 2-aminomethyl- 2,3-dihydro-1,4-benzodioxine represented by the general formula (I), as well as pharmaceutical compositions; thereof and method of tre
REFERENCES:
patent: 3444210 (1969-05-01), Moed et al.
patent: 4438131 (1984-03-01), Ehrmann et al.
K. Mitani, et al., Novel Phenoxyalkylamine Derivatives. II. Synthesis and Calcium Ion Antagonistic Activities of Alpha-Alkyl-Alpha-[(phenoxypropylamino)Propyl]Benzeneacetonitrile Derivatives, Chemical and Pharmaceutical Bulletin, vol. 36, No. 1, Jan. 1988, pp. 373-385.
Butora Gabriel
Helfert Ivan
Rajsner Miroslav
Trcka Vaclav
Chan Nicky
Vyzkumny Ustav Pro Farmacii A Biochemii s.p.
LandOfFree
N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodio does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodio, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-arylalkylderivatives of 2-aminomethyl-2,3-dihydro-1,4-benzodio will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1310506