CA1037477A - Caroverin fumarate - Google Patents

Abstract

Caroverin fumarate Abstract of the Disclosure The invention provides 1-diethylamino-ethyl-3-(p-methoxybenzyl)-1,2-dihydro-quinoxalin-2-one fumarate (caroverin fumarate), a novel therapeutically active salt which is of superior stability to caroverin in the free base form.

Description

The prepaxation of l-diethylamino-ethyl-3-~p-methoxybenzyl)-1,2-dihydro-quinoxalin-2-one, in the form of the free base having a melting point of 69~C is described in Swiss - Patent specification No. 513'884. This base, known by the common name caroverin; and available under the trade mark "SPASMIUM";
has valuable therapeutic properties but has the disadvantage that it is rather unstable, in part~cular it is sensitive to light and heat. Also, the base is virtually insoluble in water. In an attempt to form a water-soluble salt, the hydrochloride has been made but this is even less stable than the base.
We have now prepared carov~rin fumarate and found that, sur-pri~ingly, thi~ f~alt is, in contrast to the hydrochloride, of appreciably greater ~tability than the fr~e basc:. Al~o, we hav~ fo~md that, in pharrna-cological ~paflmolysis te~t~, th~ f~lmarate i~ at loa~t a~ l3ff~ctiv~3 as the ba~c~.
:In fact, for equimolar doses thc fumarate tends to be rather more effective than the ba~e. Furthermore, caroverin umarate exhibits a marked effect on the blood vessels of the brain and on the flow of blood through the brain in the sense of arterial vessel expansion and increased flow of blood. These effects were not previously detected experi~nentally in the case of caroverin 20 base or other caroverin salts.
In on~ aspect of thi~ invention there is plovided a process for the preparation of caroverin fumarate cvmprisiny reacting, in an inert solvent, caroverin base with fumaric acid., ~ another aspect t-f this invention there is provided caroverin fumarate whenever prepared by the process set forth in the immediately preceding paragraph or by an ob~riou~ chernical equivalent thereof.
Carover~n fumarate may be administered for therapeutic purposes in generally similar ways to those suitable for caroverin base. Generally similar doses may be used as for caro-verin base and therapeutically effective amounts for any particularcase can readily be determined by a medical practitioner. Thera-peutic compositions may have similar forms to those ~

~37~J7P7 suitable for administration of caroverin base although the in-creased water solubility of the fumara~e permits a wider range of liquid formulations. Conventional phanmaceutically acceptable carriers or diluents may be employer e.g. solids and sterile liquidsO
The fumarate may conveniently be prepared by reaction, in an inert solvent, of the base with fumaric acid. The reaction temperature is not particularly irnportant but temperatures in the range of 35 to 60C are generally convenient: if rather low temperatures are used the solubility of the reactants in the chosen solvent may be inconveniently low and there is no advantage to be gained by the use of relatively hip~h tempera-tures. A wide range of solvents are suitablc for the proces~, especially relatively polnr 301~cnts such as thc a]Lcanol~ con-taining up to 4 carbon atoms e~. methanol~ propnnoL and, preferably, ethanol. Preferably the caroverin base and fumaric acid ~re employed in substantially equimolar proportions.
The invention is illustrated by the following e~ample.

36.5 g~(0~1 mol) of caroverin base were dissolved at 45 to 50C in 100 cc of ethanol. 11.6 g (0.1 mol) of fumaric acid was added to this solution. The resulting clear solution was cooled with stirring, the caroverin fumarate thereby being precipitated in the form of fine crystals. The precipitate was filtered and washed with cold e~hanol. The yield obtained was about 90% of the theoretical yield. The caroverin fumarate ob-tained had a melting point oE 155 ~o 157C and was pale yellow ~7~7 and sparingly soluble in cold water (much more in hot water~
but rather more soluble in me~hanol and ethanol, the latter solvents both being suitable for recrystallisation of the fumarate.
The following procedure was used to compare the stability of the fumarate with that of caroverin base and caroverin hydrochloride. 2% solutions of caroverin base, the hydrochloride and the fumarate in methanol were irradiated at 30C + 0.1C with UV-light (UV-flood light, Trade Name Original Hanau, Type PL 368). The content of the solutions was per:io-dically determined with the aid of quantitative DC.
The results of the above procedure are shown in the Table below.
_ rradiation time at % of unchange(l caroverln compo~ln~l 30 C (hours) Base ~Icl Fumarate , . _ _ , 1 99.00 98.38 99.32

2 98.85 97.46 99.32

3 98~52 96.42 99.32 97.28 93.63 97.62 7 95.64 92.~8 96.22 9 93.93 88.39 95.53 12 92.70 86.00 94.74 16 91.08 80~93 93.90 33 81.19 63.89 88.14 36 79~90 58.10 85,30 _ . ~ . . ....... 76.73 56.30 83.~5

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of caroverin fumarate comprising reacting, in an inert solvent, caroverin base with fumaric acid.

2. A process according to Claim 1 in which the solvent is an organic one, and the caroverin base and fumaric acid are used in substantially equimolar proportions.

3. A process according to Claim 1 or 2 in which the solvent is methanol, ethanol or propanol.

4. A process according to Claim 1 or 2 in which the solvent is ethanol.

5. A process according to Claim 1 or 2 in which the reaction is carried out at temperatures in the range of 35 to 60°C.

6. Caroverin fumarate whenever prepared by the process of Claim 1 or 2 or by an obvious chemical equivalent thereof.