CH447160A - Process for the preparation of therapeutically active organic aluminum compounds - Google Patents

Description

  

  



  Process for the preparation of therapeutically active organic aluminum compounds
 The invention relates to a process for the preparation of therapeutically active organic aluminum compounds having limited hydrolysis rates in acidic solution, d? ns water or in alkaline solution, so as not to exceed desired values.



   It is known that many aluminum compounds treated with an acid, an alkali or water, rapidly release the group bound to the aluminum. Rapid release is desirable in many cases, but in others it is not. If, for example, a pharmaceutical product is administered, the effect of which must be immediate, it is desirable that the release of the group bound to the aluminum be rapid, if, on the contrary, the product is to have a prolonged action, it is necessary that the compound releases as much of its active ingredient as possible at the rate at which the body deactivates it so that the effect is constant over a period of time.



   The process according to the invention is characterized in that an aluminum alkoxide is reacted with at least one pharmacologically active substance (A) having at least one carboxylic acid group and with at least one substance (B) providing a group capable of giving the product resistance to hydrolysis and also possessing at least one carboxylic acid group, so as to replace at least part of the alkoxide groups of the aluminum alkoxide by acyl residues of substances (A) and B).



   The substance which provides groups controlling the rate of hydrolysis can be a fatty acid such as, for example, oleic acid and stearic acid. Controlled hydrolysis can also be obtained by the attachment of groups, such as the benzoate group by means of benzoic acid, which impart to the resulting aluminum compound a limited solubility in aqueous solution.



   Aluminum compounds having any desired rate of hydrolysis, within certain limits, can be prepared by proper selection of the group limiting hydrolysis and the relative proportion of groups in the molecule.



   The aluminum alkoxides used are preferably derivatives of alcohols having 2 to 5 carbon atoms. The alcohol can be straight or branched, saturated or unsaturated, substituted or unsubstituted. The alkoxides of isopropyl alcohol and secondary butyl alcohol are preferably used in most cases. Acyl-oxyaluminum alkoxides can also be employed.



   The pharmaceutically active substance is for example: salicylic acid and its esters, acetylsalicylic acid, p-amino-salicylic acid, gluconic acid, penicillin, mandelic acid, ben zoic acid , lactic acid, chaulmoogric acid, nicotinic acid, and other substances of the type indicated described in the British pharmaceutical codex.



   The process according to the invention can be carried out by causing an aluminum alkoxide to react simultaneously with the substance containing a group limiting hydrolysis and the pharmacologically active substance. We
 can also react the aluminum alkoxide first with the substance containing a hydrolysis limiting group and then with the pharmacologically active substance.



   The figures below from Table I indicate, by way of example, the results which can be obtained by virtue of the invention by the hydrolysis of aluminum ascorbate (Vitamin C) at 370 ° C. in hydrochloric acid 0 , 01 lai.



   Table 1
 AI (Vit Ct2 s-Vit C
 Compound AI (Vit C} 3 Benzoate (Benz) 2
 Time in
 minutes 6 / o Hydrol. n / a Hydrol. t / o Hydlol.
 d ---
 5 100oxo 30 19
 15 100 / o 45 20
 30 100ouzo 46 31
 60 100 / o 53 34
 120 100ouzo 55 37
 The following figures, from Table II, were obtained by the hydrolysis of aluminum p-amino-salicylates at 37O C in 0.02 N hydrochloric acid.



   Table It
   AI (PAS), AI (PAS)
 Compound Al (PAS) 3 Stearate (Steamte)
 Time in
 minutes O / oHydrol. 10 / olHydrol. O / oFHydrol.



   0
 5 100oxo 30 14
 15 100 / o 49 14
 30 100oxo 69 19
 60 100 / o 72 28
 120 100 ouzo 75 47
 With a buffer solution of pH 8 at 370C, an aluminum p-amino-salicylate-oleate in which p-amino-salicylic acid and oleic acid are present in a proportion of 1 p-amino-salicylate radical for 2 oleate radicals, is hydrolyzed only to 3 / o after two hours. When the oleate is not present the aluminum tri-p-amino-salicylate is hydrolyzed almost immediately at 90-100ouzo in 5-10 minutes.



  Examples of implementation of the process according to the invention
Example 1:
 25.5 g of aluminum isopropoxide are dissolved in 100 mls of toluene, 35.5 g of stearic acid (equivalent weight 284) also dissolved in toluene are added to them slowly while the temperature is maintained at 100-110 C and the liberated isopropyl alcohol is removed by distillation. 38.3 g of p-amino-salicylic acid dissolved in 800 ml of hot isopropyl alcohol are added while the temperature of the oil bath is maintained at 100-110 ° C.

   The isopropyl alcohol is then removed by distillation and then the product is finally dried by distillation of the solvents under reduced pressure to obtain 76.5 g of a buff-colored powder of aluminum di-p-amino-salicy- late mono-stearate. .



     Example 2:
 10.3 g of p-amino-salicylic acid dissolved in 300 ml of isopropyl alcohol are added slowly to a solution of mono-isopropoxydia aluminum distearate in toluene heated by an oil bath at 105-110 C, distilled isaprapyl alcohol. e. The solvents are finally removed by vacuum distillation and 50.3 g of a golden waxy product which is aluminum mono-p-amino-salicylate distearate is obtained.



  Example 3:
 10.2 g of aluminum isopropoxide are stirred under reflux with 30 ml of isopropanol. A mixture of 8.8 g of ascorbic acid with 120 ml of hot isopropanol and a solution of 12.2 g of benzoic acid in 30 ml of hot isopropanol are added rapidly separately but simultaneously to the solution of isopropoxide d 'aluminum. The mixture is stirred and heated for a further 10 min after the addition, then cooled. and filter.



  The residue, which weighs 16 g after drying under vacuum at room temperature, is an aluminum benzoate ascorbate in which the ascorbic acid and benzoic acid radicals are respectively present in a proportion of 1 to 2 molecules per aluminum atom.


 

Claims (1)

CLAIM Process for the preparation of pharmaceutical products, characterized in that an aluminum alkoxide is reacted with at least one pharmacologically active substance (A) having at least one carboxylic acid group and with at least one substance (B) providing a group capable of giving the product resistance to hydrolysis and also having at least one carboxylic acid group, so as to replace at least part of the alkoxide groups of the aluminum alkoxide by acyl residues of the substances ( A) and (B). SUB-CLAIMS 1. Method according to claim, characterized in that the dtalumimum alkoxide is derived from an alcohol having 2-5 carbon atoms. 2. Method according to claim or sub-claim 1, characterized in that the macologically active phar substance is one of the following compounds: salicylic acid and its esters, acetyl-salicylic acid, p-amino-salicylic acid, acid. ascorbic, gluconic acid, penicillin, mandelic acid, benzoic acid, lactic acid, chaulmoogric acid and nicotinic acid. 3. Method according to claim, characterized in that the substance providing the group which limits hydrolysis is oleic acid, stearic acid or benzoic acid. 4. Method according to claim, characterized in that the aluminum alkoxide is reacted first with the substance containing a group limiting hydrolysis and then with said pharmacologically active substance. 5. Method according to claim, characterized in that the aluminum alkoxide is reacted simultaneously with the substance containing a group limiting hydrolysis and with said pharmacologically active substance.