Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-10-19
1994-06-21
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544369, 544394, 548186, 548199, 548202, A61K 31495, C07D41712
Patent
active
053228464
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 4-methylthiazole derivatives, more precisely amino derivatives of 4-methyl-5-oxythiazole, to their methods of preparation and to pharmaceutical compositions in which they are present.
The compounds according to the invention are 4-methylthiazole derivatives of the general formula ##STR2## which n is equal to 0 or 1 and R.sub.1 and R.sub.2, which are identical or different, are selected from a hydrogen atom, a halogen atom, a hydroxyl group, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms and an alkoxy group having from 1 to 5 carbon atoms.
The framework of the invention also includes all the possible optical isomers of the compounds of formula (I) and mixtures thereof.
The framework of the invention also includes the salts of the above-mentioned compounds of formula (I).
In this formula, a halogen atom is preferably a chlorine or fluorine atom.
The alkyl and alkoxy groups can have a linear or branched chain.
An alkyl group having from 1 to 4 carbon atoms is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group, preferably a methyl or ethyl group.
An alkoxy group having from 1 to 5 carbon atoms is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy or neopentoxy group, preferably a methoxy, ethoxy, propoxy or isopropoxy group.
The general method of preparing the compounds according to the invention of formula (I), as defined above, in which n is equal to 0 involves a condensation reaction between 5-bromo-4-methylthiazole and the sodium salt of a 2-(4-arylpiperazin-1-yl)ethanol, of the formula ##STR3## in which R.sub.1 and R.sub.2 are as defined above.
According to one particular characteristic, the 5-bromo-4-methylthiazole is obtained by brominating 2-amino-4-methylthiazole under conditions which make it possible to obtain 2-amino-5-bromo-4-methylthiazole, and deaminating the resulting 2-amino-5-bromo-4-methylthiazole.
2-Amino-4-methylthiazole is a known product whose method of preparation is described in the literature (Merck Index, 10th edition, no. 454).
The method of preparing the compounds according to the invention of formula (I) in which n is equal to 0 is therefore preferably carried out in three steps in accordance with the reaction scheme described below: ##STR4##
The general method of preparing the compounds according to the invention of formula (I), as defined above, in which n is equal to 1 involves reacting 3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane with a 4-arylpiperazine of the formula ##STR5## in which R.sub.1 and R.sub.2 are as defined above.
According to one particular characteristic, the 3-(4-methylthiazolyl-5-oxy)-1,2-epoxypropane is obtained by:
a--reaction of the sodium salt of glycerol acetonide with 5-bromo-4-methylthiazole;
b--acid hydrolysis of the resulting compound under conditions which make it possible to obtain 3-(4-methylthiazolyl-5-oxy)propane-1,2-diol; and
c--reaction of the compound obtained in step b with ethyl azodicarboxylate and triphenylphosphine.
Glycerol acetonide (or 2,2-dimethyl-1,3-dioxolane-4-methanol), sold by ALDRICH, is a known product whose method of preparation is described for example in Beilstein 19, 65; Merck Index 10, 3236.
Thus the method of preparing the compounds according to the invention of formula (I) in which n is equal to 1 is therefore preferably carried out in four steps in accordance with the reaction scheme described below: ##STR6##
The compounds of formula (I) according to the invention and their pharmaceutically acceptable salts have valuable pharmacological properties which make it possible to predict a therapeutic application of these compounds, especially in the treatment of cardiovascular manifestations associated with hyperactivity of the sympathetic nervous system of the .alpha.-adrenergic type.
Thus, according to another feature, the invention also aims to cover novel pharmaceutical compositions which contain at least one compound of formula (I) or a non-toxic addition salt thereof as
REFERENCES:
patent: 3787411 (1974-01-01), Ruschig et al.
patent: 3850946 (1974-11-01), Edwards
patent: 5120736 (1992-06-01), Houziaux et al.
Bogdal et al, Chemical Abstracts, vol. 100, No. 156531 (1984).
Toshima et al, Bull. Chem. Soc. Jpn. 61, p. 2369 (1988).
Mikkilineni et al, J. Org. Chem. 53, p. 6005 (1988).
Danree Bernard
Houziaux Patrick
Jobard-Rouppert Fabienne
Lacolle Jean-Yves
Riffaud Jean-Pierre
Bernhardt Emily
Institut de Recherches Chimiques et Biologiques Appliquees (I.R.
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