Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-05-15
1992-03-31
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514212, 514320, 514444, 540596, 546196, 548574, 549 64, A61K 3140, C07D29504, C07D33332, C07D40914
Patent
active
051009110
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new therapeutically-valuable thienyloxyalkylamine derivatives of the general formula ##STR2## wherein --O--CH.sub.2 --CH.sub.2 --NR.sub.2 R.sub.3 is in position 4 or 5 of the thiophene ring; cycloalkyl, alkenyl or alkynyl each having up to 8 C atoms, or NR.sub.2 R.sub.3 is a 5 to 7-membered saturated heterocyclic ring optionally containing a further hetero atom which is oxygen or nitrogen optionally substituted by an alkyl group having 1 to 3 C atoms; and
The new thienyloxyalkylamine derivatives exhibit advantageous anti-arrhythmic activity and have particular application in circulatory problems.
A preferred class of compounds of general formula I is that in which R.sub.1 =H and n=3.
The invention also relates to a process for the preparation of the new compounds of general formula I, in which a compound of the general formula ##STR3## wherein OH is in the 4 or 5-position of the thiophene ring and R.sub.1 and n are as defined above, is reacted with a compound of the general formula the presence of at least one equivalent of a strong base, in an inert organic solvent, and, optionally, converting the resultant base of formula I into the acid addition salt.
The reaction according to the invention is best conducted in a manner such that a compound of formula II is dissolved in an inert organic solvent such as, e.g. dimethylformamide (DMF), dimethyl sulphoxide (DMSO) or diethyl carbonate, and reacted with at least one equivalent of a strong base, preferably an alkali metal alkoxide or hydride, and, when an alkali metal alkoxide is used, the alcohol which is obtained or used as solvent for the alkoxide is distilled off. The reaction temperature for this is between 60.degree. and 120.degree. C. Reaction with the compound of the general formula III follows at a temperature between 50.degree. and 100.degree. C. The reaction time is then between 30 minutes and 2 hours.
Because the free bases of the general formula I are generally only poorly crystallisable and are generally undecomposed distillable oils, it is desirable to carry out purification via easily-crystallisable acid addition compounds, such as e.g. the hydrochloride, which can be easily recrystallised.
For this purpose, the crude base is dissolved in a suitable solvent, e.g. in a lower alcohol or ether, at least an equivalent amount of protic acid is added, the solvent is removed under vacuum and the residue is crystallised from methanol, ethanol or, preferably, acetone, optionally with the addition of ether.
These acid addition salts can be obtained in conventional manner, e.g. using alkalis or ion-exchangers, converted into the free compounds, from which they can be obtained by reaction with inorganic or organic acids, in particular those which are suitable for the formation of therapeutically-usable salts.
On account of the close relations between the new compounds and their salts, the corresponding salts are to be understood within the free bases, above and below, as the sense and object make necessary.
The compounds of general formula II can be prepared from compounds of formula IV already known in the literature, in which the --OCH.sub.3 group is in position 4 (S. Gronowitz, Ark. Kemi, 12, 239 (1958)) or 5 (J. Sice, J. Am. Chem. Soc. 75, 3697 (1953)) of the thiophene ring, and the compounds of formula VI known from the literature (e.g. N. P. Buu-Hoi, N. D. Xuong and N. V. Bac, J. Chem. Soc. (1964) 173), in which R.sub.1 and n are as defined above, according to the following reaction scheme, according to conventional chemical working methods familiar to the skilled man: ##STR4##
The compounds of formula III can be prepared starting from the compounds VIII known from the literature, insofar as they are not already known in the literature or commercially-available, in a manner known to the skilled man, e.g. ##STR5##
The acid addition salts of the end compounds can be converted into the free bases in a manner known per se, for example by the addition of an alkali or by using ion-exchangers. Other salts can be obtained therefrom b
REFERENCES:
patent: 4778803 (1988-10-01), Binder
patent: 4814330 (1987-03-01), Binder
Binder et al., "Thiophene as a Structural . . . ", CA 102:220824m, 1985.
Binder Dieter
Greier Gerhard
Hillebrand Friedrich
Rovenszky Franz
Chang Celia
Ebewe Arzneimittel Gesellschaft m.b.H.
Ivy C. Warren
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