CH622023A5 - Process for the preparation of a water-soluble compound based on a substituted phenylaminoalcohol - Google Patents

Description

The object of the invention is to present a process for the preparation of a compound based on a substituted phenyl amino alcohol having a practically unlimited solubility in water and being usable in pharmaceutical compositions.

This object is achieved by the method according to the invention defined in claim 1.

The water-soluble compound obtained by the process according to the invention can be incorporated into pharmaceutical compositions which can be administered by intravenous or buccal route at doses of said compound of between 1 to 50 mg per day.

The present invention is based on the fact that it has been discovered that glucuronic acid, and more particularly D-glucuronic acid, could confer on phenyl-amino-substituted alcohols a water solubility quite remarkable that it does not exist. It is not possible to obtain by means of other types of acids.

It has appeared that, among the substituted phenyl amino alcohols, a quite remarkable solubilization has been obtained by the amino alcohols of formula I which are the subject of Belgian patent 799 379.

The amino alcohols which are of particular interest for the preparation of a water-soluble compound by the process according to the invention are especially those of formula (I) in which R 1 is an isopropyl radical, R 2 represents a methyl radical and R 3 represents a alkyl radical having from 6 to 14 carbon atoms.

Especially for the compound l- (4-isopropylthiophenyl) -2-n.octylamino-l-propanol, the solubility in water of glucuronate is infinite whereas it is only 1510 mg / 1 for the hydrochloride, 550 mg / 1 for succinate, 1505 mg / 1 for citrate and 4720 mg / I for lactate.

In general, it is known that these amino-alcohol compounds are of great therapeutic interest and are endowed with activities on the cardiovascular system, such as antihypertensive, antispasmodic, peripheral vasodilator, protective against myocardial anoxia, bronchodilator, ß-lytic, normolipidemic, normoliproteinemic, inhibitor of platelet aggregation and stimulator of cerebral energy metabolism. In addition, these compounds make it possible to act on the central nervous system, for example as a tranquilizer.

Acute intravenous toxicity has been studied in mice for 1- (4-isopropylthiophenyl) -2-n.oc-tylaminopropanol glucuronate.

The LD50 is 20 mg / kg (confidence limits for p = 0.95 = 18-22 mg / kg).

The oral toxicity in mice is similar to that of 1- (4-isopropy! Thiophenyl) -2-n.octylaminopropanol (> 4000 mg / kg).

Tolerance after repeated i.v. administration (5 consecutive days) has been studied in rabbits. No abnormality is observed up to the 0.03 mg / kg / ml dose.

The effects of 1- (4-isopropylthiophenyl) -2-n.octylaminopropanol glucuronate are at least the same as those of 1- (4-isopropylthiophenyl) -2-n.octy! Aminopropanol itself.

The antispasmodic activity was compared on guinea pig ileum (inhibition of contractions caused by histamine) and on the rat aorta (inhibition of contractions caused by calcium on depolarized strips).

The results are at least similar for the two compounds. The activity is of the musculotropic type, comprising a specific inhibition of the movements of calcium ions. On the guinea pig ileum, the pD'2 (-logarithm of the molar concentration reducing the maximum concentration by 50%) are 6.42 (± 0.19) and 6.66 (± 0.09), respectively for the glucuronate and 1- (4-isopropylthiophenyl) -2-n.octylaminopropanol. These two values are not significantly different.

On the rat aorta, the pA2 with respect to calcium (-logarithm of the molar concentration for which the effect of a double dose of antagonist is reduced to that of a single dose)

3

622,023

7.52 (± 0.08) and 7.46 (± 0.19), respectively for drata, by double decomposition with a salt of glucuro- acid

1 - (4-isopropylthiophenyl) -2-n.octylamino-1 -pronic glucuronate, for example a barium glucuronate, and that most panol and for l- (4-isopropylthiophenyl) -2-n.octylamino -l- Advantageously in aqueous solution. The resulting residual salt propanol. of this double decomposition, for example

The antiplatelet and antithrombotic activity has been studied 5 barium, can then be removed by filtration.

under various conditions. ^ ■,. , ,,

y 1,,. ,,. ,, „,. Although a pharmaceutical composition prepared from a

The glucuronate of l- (4-1sopropylthiophenyl) -2-nx, ctylami- œ é obtained £ ed ed according to rinve ^ pujsse to be no-l-propanol has been tested for its antithrombotic activity on administered bu oral route to its very solubmity

thrombosis induced in rats by application of ADP to the in, it is particularly relevant for administrators

arteries that have undergone prior injection or intravenous infusion.

standardized electrical stimulation. Due to the low toxicity of glucuronic acid, it is

•, 1X ^ °? ? th ™ m ^ US redui'e deumamere s! gmflca "possible to obtain compounds with a tive therapeutic index (80%) at a dose of 1 mg / kg iv It is also very favorable that the latency period for The appearance of the thrombus is The invention is further illustrated by a series of examples which are increased and that the rate of formation is slowed down The effect of erosion of specific compounds by the process according to the product protector lasts one hour. 'invention

Using the “filter loop” technique, it is observed that the product, at a dose of 1 mg / kg i.v., inhibits aggregation by 70% Example 1

ADP-induced platelet and is 10 times more active than a Qn me] 20 (0 103 mole) of D. glucuronic acid and reference drug such as dipyndamole. 3Q 9 (Q1 mole) of i. ^. Isopropyithiophén ^^ - n.hexylamino-

The stability of 1- (4-isopropylthiophenyl) -2- d glucuronate with 2Q M d> water n sg forms a clear siro

n.octylamino-1-propanol in aqueous solution was revealed quickly, water by the use of the solution; a solution at 1 mg / ml without vanation obtains 52 of it dry (containing 21% in ids of water) detectable from the product content after 120 days at 20 C and

40 ° C 25 Example 2

Compatibility of 1- (4-isopropylthiophide glucuronate) 24 g (0.123 mol) of D-glucuronic acid and nyl) -2-n.octylamino-1-propanol are mixed with solutions for perfusion 41.9 g ( 0.1 mol) of 1- (4-isopropylthiophenyl) -2-n.tetradecyl-sion the most common in hospital use (Ringer lactate and aminopropanol with 50 ml of water. Shake until Trophysan carbohydrate 100 is dissolved for example ) was also found to be complete (a few minutes). A very favorable solution is thus obtained. 30 clear, dilutable at will with distilled water.

The reaction of the process according to the invention can for example be carried out by adding little by little to an aqueous solution of Example 3

glucuronic acid, an equimolecular amount of phenyl- 20.4 g (0.105 mole) of D-glucuronic acid is dissolved in substituted amino alcohol of formula I, this mixture being stirred 283.5 g of water and add, with stirring, 33.76 g (0.1 mole) of until a clear solution is obtained. 35 l- (4-isopropylthiophenyl) -2-n.octylaminopropanol to this solution

The aqueous solution thus obtained can be used directly. Stir until completely dissolved, which requires ment for therapeutic uses or be brought to about half an hour. A clear solution is thus obtained, desired concentration by concentration or dilution. containing 10% by weight of 1- (4-isopropylthiophenyl) -n.octyl-

In some cases, it may be advantageous to heat the aminopropanol.

An aqueous solution of glucuronic acid before the addition of the ph 40 Instead of working at room temperature, as substituted nyl-amino alcohol and this preferably at a temperature. In the present example, in a variant, the procedure is carried out at tures from 40 to 60 ° C. higher temperatures, especially in water brought to

Optionally, a slight excess of acid can be used (around 60 ° C).

glucuronic.

Conversely, it is possible to add the aqueous solution 45 Example 4

glucuronic acid to substituted phenyl amino alcohol, the latter having 33.76 g (0.1 mole) of 1- (4-isopropylthiophenyl) -2-n.octy-possibly being suspended in water . laminopropanol dissolved in 330 ml of tetrahydrofuran, we

The compound obtained can also be dissolved and added 19.41 g (0.1 mole) of D-glucuronic acid and 50 ml of water suspension in water or in a mixture of water and solvent and stirred until complete dissolution of the glucuronic acid, organic miscible with water, such as alcohols, such as 50 which requires about 2 hours. The solvents are evaporated off methanol, ethanol, isopropanol, dioxane and tetrahydro- in vacuo and 53.3 g of dry product are obtained.

furan. Preparation of injectable solution or solutions

After the addition of glucuronic acid, the aqueous solution can for oral administration can take place then be evaporated under reduced pressure or freeze-dried in directly from a solution prepared according to Example 2 in the case of solutions watery. 55 or else from a solid product prepared according to Example 1

A water-soluble powder is thus obtained which can be after dissolution in water.

used for the preparation of auqueses solutions having the Daily doses of compounds obtained by the process

desired dilution (extemporaneous preparation). according to the invention, recommended in humans, are of the order of 1

In some cases, it may be useful to prepare the compound at 50 mg and preferably from 0.001 to 1 mg / kg.

water-soluble by the process according to the invention from a salt of 60 The application is preferably carried out by injection or perfusion of phenyl-amino-substituted alcohol, such as, for example, chloro-intravenous.

VS

Claims (10)

622,023 2 CLAIMS 1. Process for the preparation of a water-soluble compound based on a substituted phenyl amino alcohol, characterized in that glucuronic acid or a salt of this acid is reacted in a solvent with a phenyl -substituted amino alcohol of the formula RjS- CHOH-C H-NHR, (I) in which R, is an alkyl radical having from 1 to 4 carbon atoms, R2 represents an alkyl radical having 1 or 2 carbon atoms, R3 is an alkyl radical having from 4 to 16 carbon atoms, or with a salt thereof alcohol. , 5 2. Method according to claim 1, characterized in that D-glucuronic acid is used. 3. Method according to claim 1 or 2, characterized in that a substituted phenylaminoalcohol of formula I is used, in which Rj is an isopropyl radical, R2 represents a methyl radical and R3 represents an alkyl radical of 6 to 14 carbon atoms. 4. Method according to one of the preceding claims, characterized in that l- (4-isopropylthiophenyl) -2-n.octylaminopropanol is used as substituted phenyl-amino alcohol. 25 5. Method according to one of the preceding claims, characterized in that one gradually adds to an aqueous solution of glucuronic acid an at least equimo-lecular quantity of the substituted phenyl-amino-alcohol and agitates the mixture until obtaining a clear solution. 30 6. Method according to one of the preceding claims, characterized in that an aqueous solution of glucuronic acid is added to the substituted phenyl amino alcohol in suspension or in dissolution in a solvent. 7. Method according to claim 6, characterized in that water or a mixture of water and organic solvents miscible with water, such as alcohols, such as methanol, are used as solvent. ethanol, isopropanol, dioxane and tetrahy-drofuran. 8. Method according to one of the preceding claims, characterized in that the glucuronic acid is heated, before bringing it into contact with the substituted phenylamino alcohol, at a temperature of 40 to 60 ° C . 9. Method according to one of the preceding claims, characterized in that the solvent is removed after the reaction between glucuronic acid and phenyl amino alcohol until the reaction products are obtained in powder form. 10. Method according to one of the preceding claims, characterized in that a salt of glucuronic acid is reacted with a salt of the substituted phenylamino alcohol and then eliminates the residual salt resulting from the double decomposition thus obtained . 55 The advantage of being able to have water-soluble forms of drugs is multiple. Indeed, in addition to the possibility of administering such drugs parenterally, a water-soluble form has several other advantages, in particular making it possible to surely obtain the optimal distribution 60 of the drug during screening tests and also to allow the realization in vitro tests. In therapy, an injectable form also allows rapid action of the drug. For the administration of drugs by the oral route, it is also sometimes advantageous to have fairly water-soluble compounds and this in order to speed up or modify the absorption of the active product.