GB1569380A

GB1569380A - Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions

Info

Publication number: GB1569380A
Application number: GB23697/77A
Authority: GB
Original assignee: Continental Pharma Inc
Current assignee: Continental Pharma Inc
Priority date: 1976-06-04
Filing date: 1977-06-03
Publication date: 1980-06-11
Also published as: DE2724608C2; SE7706481L; FR2353288B1; NL7706177A; DE2724608A1; SE441183B; BE855320A; JPS6126526B2; CA1095416A; JPS5318721A; CH622023A5; FR2353288A1

Abstract

Glucuronic acid or a salt of this acid is reacted, in a solvent, with a substituted phenylaminoalcohol of formula I, in which R1 represents an alkyl with 1 to 4 C atoms, R2 an alkyl with 1 or 2 C atoms and R3 an alkyl with 4 to 16 C atoms, or with a salt of this alcohol. The compounds obtained by this process are of great therapeutic importance and can be administered orally, parenterally and preferably by intravenous injection or perfusion. <IMAGE>

Description

(54) PHARMACEUTICAL COMPOSITIONS COMPRISING SUBSTITUTED PHENYL-AMINO-ALCOHOL AND PROCESS FOR PREPARING THESE COMPOSITIONS (71) We, CONTINENTAL PHARMA, a Belgian Body Corporate, of 135 avenue Louise, Brussels, Belgium, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a hydrosoluble pharmaceutical composition based on phenyl-amino-alcohol.

There are several advantages in having hydrosoluble forms of medicaments. As a matter of fact, in addition to the possibility of administering such medicaments parenterally, a hydrosoluble form has several other advantages, namely to allow an optimum distribution of the medicament to be obtained automatically when screening tests are made and also to allow in vitro tests to be carried out. In therapeutics, an injectable form also allows to obtain a quick medicament action.

To administer medicaments orally, it is also sometimes useful to have rather hydrosoluble compounds with the object of accelerating or modifying the active product absorption.

According to the invention, there is provided a hydrosoluble pharmaceutical composition comprising a l-phenyl-2-amino alcohol or a salt thereof and glucuronic acid or a salt thereof, or the acid-base reaction product of a l-phenyl-2-amino alcohol and glucuronic acid.

The phenyl-amino-alcohols used in the invention have the general formula:

wherein R, is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of 1 or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms.

The invention also relates to processes for preparing such a hydrosoluble pharmaceutical composition.

In one such process glucuronic acid is reacted with the substituted phenyl-aminoalcohol in a solvent.

This invention also provides a method of use of said pharmaceutical composition in which this composition is administered intravenously or orally in doses between 1 and 50 mg/day.

It has been found that glucuronic acid, preferably D-glucuronic acid, is able to give 1 - phenyl - 2 - amino - alcohols a quite remarkable hydrosolubility which has not been reached with other kinds of acids.

It has become apparent that, amongst phenyl-amino-alcohols, a quite remarkable solubilization has been obtained with amino-alcohols, such as provided for example in Belgian Patent 799,379 and having the formula (I):

wherein R, is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of 1 or 2 carbon atoms, and R3 is an alkyl radical of 4 to 16 carbon atoms.

Amino-alcohols which are of a particular interest for the hydrosoluble pharmaceutical composition according to the invention are more particularly those of formula (I) wherein R, is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon atoms.

More particularly for compound 1 - (4 isopropylthio - phenyl) - 2 - n octylamino - 1 - propanol, the water solubility of the glucuronate appears to be unlimited while it is only 1510 mg/l for hydrochloride, of 550 mg/l for succinate, of 1505 mg/l for citrate and of 472 mg/l for lactate.

In general, it is known that these aminoalcohols have a very high therapeutical interest and have activities on the cardiovascular system, acting as antihypertensive agents, antispasmodic agents, peripheral vasodilators, protecting agents against myocardium anoxia, bronchodilatators, p-lytic agents, norm ol ipidemient agents, normolipoproteinemient agents, inhibitors of platelet aggregation and stimulator of cerebral energetic metabolism. Moreover, these compounds may also act on the central nervous system, for example as tranq uillizer.

The acute toxicity with an i.v.

administration was studied on mice for I (4 - isopropylthiophenyl) - 2- n octylamino - 1 - -propanol glucuronate.

DL, was 20 mg/kg (confidence limits for p=0,95: 18-22 mg/kg).

The oral toxicity on mice is similar to that ol 1 - (4 - isopropylthiophenyl) - 2 - n octylamino - I - propanol ( > 4000 mg/kg).

The tolerance after repeated i.v.

administrations (5 successive days) was studied on rabbits. No anomaly was observed till the dose of 0,03 mg/kg/ml.

The efficacy of I - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate is at least the same as that of the 1 - (4 - isopropylthiophenyl) - 2 - n octylamino - 1 - propanol itself).

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

The results are at least similar for both compounds. The activity is of the musculatrope type, comprising a specific inhibition of movements of calcium ions. On guinea pig ileum, the pD'2 values (logarithm of the molar concentration reducing maximum concentration by 50%) are 6.42 (+0.19) and 6.66 (+0.09) respectively for glucuronate and 1 - (4 - isopropylthiophenyl)- 2 - n - octylamino - 1 - propanol. These two values are significantly different.

On rat aorta, the pA2 values in relation to calcium (logarithm of the molar concentration for which the effect of a double antagonist dose is reduced to that of a simple dose) are 7.52 (+0.08) and 7.46 (+0.19) respectively for 1 - (4 isopropylthiophenyl) -2- n - octylamino - 1 - propanol glucuronate and for 1 - (4 isopropylthiophenyl) -2- n - octylamino - 1 - propanol.

The anti-platelet and antithrombotic activity was studied under various conditions.

The I - (4 - isopropylthiophenyl) - 2 n - octylamino - 1 - propanol was tested relating to its antithrombotic activity on thromboses induced in rats by applying ADP on mesenteric arteries having previously received a standard electric stimulation.

Formation of thrombus is significantly reduced (by 80van) at a dose of Img/kg i.v. It is also found that the latency period before a thrombus appears is increased and that the formation rate is decreased. The duration of the protection effect of the product is 1 hour.

By using the filter loop technique, it was noticed that the product, at a dose of lmg/kg i.v. inhibits the platelet aggregation induced by ADP by 70% and is ten times as active as a reference drug such as dipyridamole.

The stability of I - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate in aqueous solution has revealed as being excellent; a solution at Img/ml does not show any detectable variation of the product content after 110 days at 200C and 40"C.

Compatibility of 1 - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate with the most current clinically used perfusion solutions (Ringer lactate and glucidic Trophysan 100 for example) has also been found very favourable.

The hydrosoluble pharmaceutical composition according to the invention can be prepared by reacting glucuronic acid and substituted phenyl-amino-alcohol in a preferably aqueous solvent.

This reaction can be for example carried out by slowly adding an equimolecular amount of phenyl-amino-alcohol to an aqueous solution of glucuronic acid, this mixture being stirred until a clear solution is obtained.

The obtained aqueous solution can be directly used for therapeutical uses or can be brought to the desired concentration by concentration or dilution.

In some cases, it may be advantageous to heat the aqueous solution of glucuronic acid before addition of phenyl-amino-alcohol, preferably to a temperature of 40--60"C.

A low excess of glucuronic acid may be optionally used.

Inversely, it is possible to add the aqueous solution of glucuronic acid to the phenylamino-alcohol, the latter being optionally suspended in water.

According to the invention, the compound can also be dissolved and suspended in water or in a mixture of water miscible organic solvent, such as alcohols, more particularly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran.

After addition of glucuronic acid, the solution may be still evaporated under reduced pressure or lyophilised in the case of aqueous solutions.

Thus, a water soluble powder is obtained, which can be used for preparing aqueous solutions having a desired dilution (extemporaneous preparation).

In some cases, it may be useful to prepare hydrosoluble pharmaceutical compositions according to the invention from a phenylamino-alcohol salt, such as for example hydro-chloride, by double decomposition with a glucuronic acid salt, for example barium glucuronate, most advantageously in aqueous solution. The residual salt resulting from this double decomposition, fdr example barium chloride, is then removed, e.g. filtered out.

Although the pharmaceutical composition according to the invention may be administered orally, due to its very high water solubility, it is more particularly suitable for administration by intravenous injection or perfusion.

Due to the low toxicity of glucuronic acid, it is possible to obtain compositions having a very favourable therapeutical index.

The invention is still illustrated by a number of preparation examples of specific compositions according to the invention.

Example I 20 g (0.103 mole) of D-glucuronic acid and 30.9- g (0.1 mole) of 1 - (4 - isopropylthiophenyl) - 2 - n - hexylamino 1 - propanol are mixed with 20 ml of water.

A clear syrup is formed, which can be diluted with distilled water at will. By lyophilisation of the solution, 52 g of dry product is obtained (comprising 2.1% of water).

Example 2 24 g (0.127 mole) of D-glucuronic acid and 41.9 g (0.1 mole) of 1-(4- isopropylthiophenyl) - 2 - n tetradecylamino - 1 - propanol are mixed with 50 ml of water. Stirring is maintained until complete solution (a few minutes). So a clear solution, which can be diluted with distilled water at will is obtained.

Example 3 20.4 g (0.105 mole) of D-glucuronic acid are dissolved in 283.5 g of water and 33.76 p (0.1 mole) of 1 - (4 - isopropylthiophenol) - 2 - n - octylamino I - propanol are added to this solution with stirring. Stirring is continued until complete solution, which requires about 1/2 hour. A clear solution containing I 00/,, of I - (4 isopropylthiophenyl) - 2 - n octylamino - 1 - propanol is so obtained.

Instead of treating at room temperature, as in the present example, higher temperatures are used according to a variant, more particularly in water heated to about 60"C.

Example 4 To 33.76 g (0.1 mole) of I - (4 - isopropylthiophenyl) - 2 - n - octylamino 1- - propanol dissolved in 330 ml of tetrahydrofuran, 19,41 g (0.1 mole) of Dglucuronic acid and 50 ml of water are added and stirring is continued until complete solution of glucuronic acid, which requires about 2 hours. Solvents are evaporated under vacuum and 53.3 g of dry product are obtained.

The preparation of injectable solutions or of aqueous solutions for oral administration can be made directly from a solution prepared according te Example 2 or from a solid product prepared according to Example 1 after dissolution in water.

Hereinafter two typical pharmaceutical formulations are given for injectable compositions.

1. 1 - (4 - isopropyl thiophenyl) - 2 - n - octyl amino - I - propanol I mg D-glucuronic acid 0.6 mg Anhydrous dextrose 55.1 mg Bidist. water, q.s. h I ml 2. 1 - (4 - isopropyl thiophenyl) - 2 - n - octyl amino - 1 - propanol 20 mg D-glucuronic acid 12 mg Anhydrous dextrose Bidist, water, q.s. 1 ml The daily doses of substituted phenylamino-alcohols in association with glucuronic acid, proposed for humans, are about 1 to 50 mg, preferably 0.001 to 1 mjkg.

Application is preferably made by intravenous injection or perfusion.

WHAT WE CLAIM IS: 1. A hydrosoluble pharmaceutical composition comprising a l-phenyl-2-amino alcohol of the general formula:

wherein R, is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of I or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms, or a salt thereof, and glucuronic acid or a salt thereof, or a reaction product of the l-phenyl-2-amino alcohol and glucuronic acid.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. solution may be still evaporated under reduced pressure or lyophilised in the case of aqueous solutions. Thus, a water soluble powder is obtained, which can be used for preparing aqueous solutions having a desired dilution (extemporaneous preparation). In some cases, it may be useful to prepare hydrosoluble pharmaceutical compositions according to the invention from a phenylamino-alcohol salt, such as for example hydro-chloride, by double decomposition with a glucuronic acid salt, for example barium glucuronate, most advantageously in aqueous solution. The residual salt resulting from this double decomposition, fdr example barium chloride, is then removed, e.g. filtered out. Although the pharmaceutical composition according to the invention may be administered orally, due to its very high water solubility, it is more particularly suitable for administration by intravenous injection or perfusion. Due to the low toxicity of glucuronic acid, it is possible to obtain compositions having a very favourable therapeutical index. The invention is still illustrated by a number of preparation examples of specific compositions according to the invention. Example I 20 g (0.103 mole) of D-glucuronic acid and 30.9- g (0.1 mole) of 1 - (4 - isopropylthiophenyl) - 2 - n - hexylamino 1 - propanol are mixed with 20 ml of water. A clear syrup is formed, which can be diluted with distilled water at will. By lyophilisation of the solution, 52 g of dry product is obtained (comprising 2.1% of water). Example 2 24 g (0.127 mole) of D-glucuronic acid and 41.9 g (0.1 mole) of 1-(4- isopropylthiophenyl) - 2 - n tetradecylamino - 1 - propanol are mixed with 50 ml of water. Stirring is maintained until complete solution (a few minutes). So a clear solution, which can be diluted with distilled water at will is obtained. Example 3 20.4 g (0.105 mole) of D-glucuronic acid are dissolved in 283.5 g of water and 33.76 p (0.1 mole) of 1 - (4 - isopropylthiophenol) - 2 - n - octylamino I - propanol are added to this solution with stirring. Stirring is continued until complete solution, which requires about 1/2 hour. A clear solution containing I 00/,, of I - (4 isopropylthiophenyl) - 2 - n octylamino - 1 - propanol is so obtained. Instead of treating at room temperature, as in the present example, higher temperatures are used according to a variant, more particularly in water heated to about 60"C. Example 4 To 33.76 g (0.1 mole) of I - (4 - isopropylthiophenyl) - 2 - n - octylamino 1- - propanol dissolved in 330 ml of tetrahydrofuran, 19,41 g (0.1 mole) of Dglucuronic acid and 50 ml of water are added and stirring is continued until complete solution of glucuronic acid, which requires about 2 hours. Solvents are evaporated under vacuum and 53.3 g of dry product are obtained. The preparation of injectable solutions or of aqueous solutions for oral administration can be made directly from a solution prepared according te Example 2 or from a solid product prepared according to Example 1 after dissolution in water. Hereinafter two typical pharmaceutical formulations are given for injectable compositions.

Application is preferably made by intravenous injection or perfusion.

2. A composition as claimed in claim 1,

wherein the glucuronic acid is D-glucuronic acid.

3. A composition as claimed in claim 1 or claim 2 wherein R1 is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon atoms.

4. A composition as claimed in claim 3, wherein the compound of formula (I) is 1 (4 - isopropylthiophenyl) - 2 - n octylamino - 1 - propanol.

5. A composition as claimed in any one of claims 1 to 4, wherein the composition is an aqueous solution of the l-phenyl-2-amino- alcohol and glucuronic acid.

6. A composition as claimed in any one of claims 1 to 4, in the form of a water soluble powder.

7. A composition as claimed in any of claims I to 5, in a form suitable for intravenous injection or perfusion.

8. A process for preparing a hydrosoluble pharmaceutical composition as claimed in any one of claims 1 to 7, wherein glucuronic acid is reacted in a solvent with a l-phenyl- 2-amino-alcohol of formula (I).

9. A process as claimed in claim 8, wherein an at least equimolecular amount of the l-phenyl-2-amino-alcohol is gradually added to an aqueous solution of glucuronic acid and the mixture is stirred until a clear solution is obtained.

10. A process as claimed in claim 8, wherein an aqueous solution of glucuronic acid is added to the l-phenyl-2-amino- alcohol in suspension or solution in a solvent.

11. A process as claimed in claim 10, wherein water or a mixture of water and one or more water miscible organic solvents, is used as solvent.

12. A process as claimed in any one of claims 8 to 11, wherein glucuronic acid is heated to a temperature of 40 to 600C before contacting it with the l-phenyl-2amino-alcohol.

13. A process as claimed in any one of claims 8 to 12, wherein solvent is removed after reaction between the glucuronic acid and the l-phenyl-2-amino-alcohol until the reaction product is obtained as a powder.

14. A process for preparing a hydrosoluble pharmaceutical composition as claimed in any one of claims 1 to 7, wherein a salt of glucuronic acid is reacted with a salt of the l-phenyl-2-amino-alcohol to form the glucuronic acid salt of the amino-alcohol and another salt by double decomposition, and then the mixture is freed of the other salt.

15. A hydrosoluble pharmaceutical composition, substantially as hereinbefore described.

16. A process for preparing a hydrosoluble composition, substantially as hereinbefore described.

17. A hydrosoluble pharmaceutical composition as substantially as hereinbefore described in any one of the specific Examples.

18. A process for producing a hydrosoluble pharmaceutical composition substantially as hereinbefore described in any one of the specific Examples.