CH393313A - Process for the preparation of new adamantane derivatives - Google Patents

Description

  

  
 



  Process for the preparation of novel adamantane derivatives
 The present invention relates to a process for the preparation of novel adamantane derivatives of general formula:
EMI1.1
 as well as their salts.



   In formula (I), A represents a divalent, saturated or unsaturated aliphatic hydrocarbon radical, straight chain or branched, containing at most 4 carbon atoms, or a divalent mononuclear aromatic radical
 According to the process of the invention, the new adamantane derivatives of formula (I). are prepared by the action of an acid anhydride of general formula:
EMI1.2
 in which A has the same meaning as above, on "1-nydroxy adamantane.



   The reaction can be carried out by heating the reagents to a temperature between 50 and 1500, preferably in a solvent of the type of aromatic tertiary amines such as pyridine.



   The salts contemplated are most especially the salts formed with the alkali metals, the alkaline earth metals, and certain salts of amines such as the salts of ethanolamines. Their preparation can be carried out by direct action of the acid ester of adamantol on an alkali or alkaline earth metal derivative, such as for example hydroxide, carbonate or bicarbonate, or for an amine. It is possible to operate in an aqueous medium or in an organic liquid medium. The salt obtained under these conditions can be isolated by applying the usual techniques.



   The products obtained by the process of the present invention have interesting pharmacological properties: they are in particular potent choleretics which have proved to be very active both on the volume and on the quality of the bile excreted.



   Examples 1 to 6 which follow illustrate the process of the invention:
 Example 1
 A solution of 15 g of 1-hydroxy-adamantane and 10 g of succinic anhydride in 100 cm 3 of anhydrous pyridine is boiled at reflux for 77 hours. Allowed to cool and then the pyridine is evaporated off in a water bath under reduced pressure.



   The blackish residue thus obtained is taken up in 150 cm3 of ether and extracted with 3 times 50 cm3 of a 4% solution of sodium carbonate and then 2 times 25 cm3 of distilled water. The combined aqueous phases are decolorized by bringing to the boil rapidly with animal charcoal and then by filtering while hot.



  The solution obtained is then cooled to 0 and then acidified with 20 cm3 of 35% hydrochloric acid. The acid released is extracted with 5 times 50 cm3 of ether, the organic solution is dried over sodium sulphate and evaporated in a water bath. 11 g of succinyloxy-1 adamantane are thus obtained which, after recrystallization from methanol, is in the form of a white crystalline powder, melting at 800.



     The hydroxy-1 adamantane used as the starting material was prepared by hydrolysis of bromo-1 adamantane according to H. STETTER, M. SCHWARZ, A.



  HIRSCHHORN, Berichte, 92, 1629 (1959).



   Example 2
 A mixture of 5 g of adamantol and 5 g of phthalic anhydride in 50 cm3 of anhydrous pyridine is boiled for about 5 days.



   The treatment is carried out as in Example 1 and, after recrystatllization from aqueous ethanol (3/2), 5 g of adamantol phthalic monoester, melting at 1490, is obtained.



   Example 3
 A mixture of 20 g of adamantol and 17 g of glutaric anhydride in 250 cm3 of anhydrous pyridine is boiled for about 9 days.



   We process as in Example 1.



   The acid obtained in ethereal solution is washed with water until the complete elimination of the excess glutaric acid which it contains. After drying and evaporating off the solvent, 12.6 g of glutaryloxy-1 adamantane are obtained, melting at 55.



   Example 4
 A mixture of 30 g of adamantol and 27 g of 2-, 3-dimethyl succinic anhydride, melting at 870, in 200 cm3 of anhydrous pyridine, is boiled for about 9 days.



   The treatment is carried out as in the previous example, and 16 g of oc, p-dimethylsuccinyloxy-1 adamantane are obtained, melting at 750.



   1.752 g of succinyloxy-1 adamantane are suspended in 25 cm3 of distilled water and a solution of 0.583 g of sodium bicarbonate in 40 cm3 of distilled water (at 350) is added dropwise carefully.
 Stirring is continued for 15 minutes after the end of the casting. A clear solution is obtained, slightly yellow colored, which is filtered and freeze-dried.



   In this way, 2.887 g of the sodium salt of succinyloxy-1 adamantane are collected in the form of a white powder, very soluble in water.



   To a hot solution of 36.5 g of crude dimethyl-oc, p-succinyioxy-1 adamantane in 250 cm3 of ethyl acetate is added with stirring a solution of 7 g of monoethanolamine in 100 cm3 of ethyl acetate.



   The solution, which is clear when hot, allows the ethanolamine salt of dimethyl-oc, p 3 succinyloxy-l adamantane to precipitate on cooling, melting at 1200 after recrystallization from butanone; this gives 24.5 g of water soluble salt.



   For their use in therapy, the products obtained according to the process of the invention can be used in the form of solid or liquid compositions, which can be administered orally, rectally or parenterally.



   The most frequent solid compositions for oral administration are tablets, pills, powders, granules. In these compositions, one or more of the active products obtained by the process of the invention is (or are) mixed with one or more inert diluents such as calcium carbonate, starch, alginic acid, lactose . These compositions can also include substances other than diluents, for example a lubricant, such as magnesium stearate.



   For rectal administration, the products according to the invention can be placed in suppositories with cocoa butter or suppo-waxes.



   The most frequent liquid compositions for oral administration are pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions can also comprise substances other than diluents, for example wetting products, sweetening products or perfumes.



   Compositions for parenteral administration may comprise sterile aqueous or non-aqueous solutions, suspensions or emulsions.



  As solvent or vehicle, propylene glycols, polyethylene glycols, vegetable oils, in particular olive oil and injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting, emulsifying and dispersing agents. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved or suspended at the time of use in sterile water or any other sterile injectable medium.



   The daily doses depend on the desired therapeutic effect, on the route of administration and on the duration of treatment. They are generally around 100 to 500 mg of active product per day.
  

 

Claims (1)

CLAIM Process for preparing adamantane derivatives of general formula: EMI2.1 as well as their salts, formula in which A represents a divalent aliphatic hydrocarbon radical, saturated or not, with a straight or branched chain, containing at most 4 carbon atoms or a divalent mononuclear aromatic radical, characterized in that one causes to act an acid anhydride of the general formula: EMI3.1 on hydroxy-1 adamantane.