Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-11-08
1997-12-30
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514456, 514457, 548525, 549288, 549289, A61K 3140, A61K 3135, C07D40704, C07D30910
Patent
active
057031134
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/HU93/00079 filed Dec. 20, 1993.
FIELD OF THE INVENTION
The present invention relates to novel benzopyran derivatives of the formula ##STR2## possessing pharmacological activity, as well as to pharmaceutical compositions containing the compounds of the formula (I). Further, the present invention relates to methods for preparing .these compounds and the pharmaceutical compositions containing these compounds as well as novel intermediates.
BACKGROUND OF THE INVENTION
The preparation of certain compounds of the formula (I) having hypotensive effect by activating the potassium canal and pharmaceutically acceptable acid addition salts thereof is disclosed in European patent specifications Nos. 0,076,075, 0,093,535, 0,120,426, 0,120,427, 0,120,428, 0126,311 and 0,126,350. In the formula (I) nitro, formyl or cyano group or a halo atom,
The preparation of the compounds as disclosed in the literature is illustrated by reaction scheme No. 1: ##STR3## comprising reacting a suitably substituted phenol of the formula (II) with 3-chloro-1-propyne of the formula (III) resulting in an arylpropargyl ether of the formula (IV), a chromene of the formula (V) is then formed from the ether by thermic cyclization. Thereafter 3-bromo-4-chromanol of the formula (VII) may be formed from the chromene of the formula (V) either in one step by adding hypobromic acid, or in two steps, by hydrolyzing in aqueous acetone 3,4-dibromochromane of the formula (VI) obtained by adding elemental bromine to chromene of the formula (V). 3-Bromo-4-chromanol is converted into a 3,4-epoxy derivative of the formula (VIII) in an alkaline medium, compounds of the formula (I) are then prepared in a specific reaction.
The symbols in reaction scheme i stand for the following reaction conditions: ammonium hydroxide and methanol;
If R.sub.2 does not stand for hydrogen in the process described above, two substances are formed in reaction b as the ring formation may occur at two places. The formed disadvantageous regioisomer of the formula (Va) has to be separated from the reaction mixture which process is complicated and decreases the total yield.
In European patent specification No. 0,277,611 the preparation of such benzopyran derivatives of the formula (I) is disclosed in which
In the electrophilic substitution of 4-chromanone of the formula ##STR4## wherein R.sub.2 stands for C.sub.1-4 alkoxy, R.sub.3 and R.sub.4 stand for C.sub.1-4 alkyl, a 4-chromanone of the formula ##STR5## is obtained, the latter being reduced to 4- chromanol of the formula ##STR6## in a further reaction to obtain a chromene of the formula (V) in a water eliminating reaction. The derivative of the formula (I) is obtained from this compound through compounds of the formula (VII), then (VIII).
In the formulae
No process is known at the same time for the preparation of the compounds of the formula (I), wherein cycloalkoxy, aryloxy, aralkoxy, hydroxy, nitro, cyano, formyl, C.sub.1-6 acyl or cyano-C.sub.1-6 -alkyl group or halo, aryloxy, aralkoxy or hydroxy group, or
The above compounds of the formula are novel.
According to literature data (J. Med. Chem. 1990, 33, 492) in compounds of the formula (I) for reaching hypotensive effect R.sub.1 should represent a strong electron withdrawing substituent and R.sub.2 generally a hydrogen atom.
We have, however, found that compounds of the formula (I) according the invention also possess a hypotensive effect. These compounds are characterized by being substituted together in positions 6 and 7, further, R.sub.1 is not necessarily a strong electron withdrawing substituent and R.sub.2 is not a hydrogen atom.
Further, we have found that benzopyrans of the formula (I) according to our invention also exert their effect by activating the potassium canal. Thus, these compounds may be useful according to David W. Robertson et al in the following fields of the therapy: a) hypertension; b) asthma; c) diseases of the urinary organs; d) heart failure, g) diseases of the central nervous system; and f) paralysis.
The inventio
REFERENCES:
patent: 5043344 (1991-08-01), Englert et al.
Bartik Tamas
Eszenyi Tibor
Frank Laszlo
Papp Gyula
Sebok Peter
Alkaloida Vegyeszeti Gyar
Dubno Herbert
McKane Joseph
Myers Jonathan
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