CH605949A5 - Vincanol derivs - Google Patents

Abstract

Vincanol derivs used against cerebral vascular pain and cerebral sclerosis

Description

  

  
 



   The invention relates to new heterocyclic compounds of the group vincanol-epivincanol (formula I),
EMI1.1
 where X is
EMI1.2
 stands, where R1 and R2 are each hydrogen, lower alkyl, aryl or aralkyl, and their salts and processes for the preparation.



   If the radicals R1 or R2 stand for lower alkyl, these radicals preferably contain 1 to 6 carbon atoms. If the radicals Rt and R2 are aryl or aralkyl, these radicals can in particular denote phenyl or phenyl which is optionally substituted by halogen, lower alkyl or lower alkoxy.



   Compounds of the formula I in which the hydrogen atom in position 14 is in the cis position to the hydrogen atom in position C3 correspond to compounds of the epivincanol type; Compounds of the formula I in which the hydrogen atom in position 14 is trans to the hydrogen atom in position C3, corresponding to compounds of the vincanol type.



   The process is characterized in that (-) Eburnamenin (Formula II)
EMI1.3
 treated with hydrogen halide at temperatures below 0, then the resulting hydrogen halide addition product, which is not stable at room temperature, with a compound of the formula III,
H-X (III) where X is
EMI1.4
 where Rt and R2 are each hydrogen, lower alkyl, aryl or aralkyl, and then the compounds of the formula I obtained are isolated in a manner known per se and optionally converted into their salts.



   The reaction can be carried out, for example, by allowing (-) eburnamenine to react with absolutely dry halogen-free hydrogen halide at temperatures below 0, preferably at temperatures between 200 and 1500. The preferred hydrogen halide is hydrogen bromide, but hydrogen chloride or hydrogen iodide can also be used. The solution is then evaporated to dryness at temperatures below 200, and the residue is then dried for several hours at reduced pressure and at temperatures below. After releasing the vacuum with nitrogen, the residue is pulverized at temperatures below 20 ".

  A compound of the formula III, in which X, Rt and R2 have the above meanings, is added to the pulverized residue at temperatures below 20 ", optionally in a suitable solvent that does not freeze at the specified temperatures, and left with stirring for two hours at temperatures from -20" to +20, any components boiling below 20 evaporate at -200 to +200 under reduced pressure, the reaction mixture is distributed between 2N ammonia and methylene chloride and then the compounds of the formula I obtained are isolated from the reaction mixture in a manner known per se.



   The compounds of the formula I are distinguished by interesting pharmacological properties and can be used as medicinal products.



   In the observation test on the mouse, an increase in excitability at doses of 10 to 100 mg / kg p. o. be observed. The sleep phases in the electroencephalogram of the rat showed a decrease in sleep and an increase in wakefulness at doses of 10 mg / kg i. p. Such changes are an expression of an increase in vigilance and psychostimulation. The compounds are therefore indicated for cerebral vascular damage, cerebral sclerosis, cerebral insufficiency or loss of consciousness due to head trauma.



   The doses to be used naturally vary depending on the substance used, the type of administration and the condition to be treated. In general, however, satisfactory results are achieved in animal experiments with a dose of 10 to 100 mg / kg body weight. For larger mammals, the daily dose is around 1 to 500 mg. If necessary, these doses can be administered in 2 to 3 portions of 0.5-30 mg of a compound of the formula I in addition to solid or liquid carriers or diluents or as a sustained-release form.



   The compounds of the formula I or



  their physiologically tolerable salts are administered alone or in suitable pharmaceutical forms with pharmacologically inert adjuvants.



   In the following example, which explains the invention in more detail but is not intended to limit its scope in any way, all temperatures are given in degrees Celsius and are uncorrected.



   For example
14-Deoxy-14-dimethylaminovincanol a) Preparation of the hydrogen halide addition product of (-) eburnamenin
To 27.84 g of dry, oily (-) ebumamenine, hydrogen bromide gas is passed with stirring at -78 absolute and condensed until a clear yellow solution forms at a volume of 100 ml.



   Still in the dry ice bath, the mixture is then concentrated to a solidified paste under a vacuum of 200 torr with stirring and the residue is then dried without stirring at 20 torr and -780 for 16 hours. After releasing the vacuum with nitrogen, the brittle residue is pulverized at -75.

 

   b) 14-deoxy-14-dimethylaminovincanol
200 ml of hexane are added to the pulverized residue at -75 while stirring and 100 ml of dimethylamine are then added to the suspension obtained, the mixture is allowed to warm to 00 for one hour, stirring is continued for one hour at this temperature, the solvent is evaporated and distributed Reaction mixture between 500 ml of 2N ammonia and 200 ml of methylene chloride. The methylene chloride solution is evaporated, the residue is chromatographed on silica gel with methylene chloride / methanol (95: 5) and the title compound is crystallized from n-hexane.



     M.p. 134 ", [a] D = + 104 (approx. 1% in chloroform) Example 2
14-deoxy-14-amino-epivincanol
The title compound is obtained analogously to Example 1 b) by reaction with NH3. M.p. 1230.

 

Claims (1)

PATENT CLAIM Process for the preparation of new compounds of the group Vincanol-Epivincanol (Formula I), EMI2.1 where X is EMI2.2 stands, where Rl and R2 are each hydrogen, lower alkyl, aryl or aralkyl, and their salts, characterized in that (-) eburnamenin (formula II) EMI2.3 treated with hydrogen halide at temperatures below 0 "and then the resulting reaction product with a compound of formula III, H-X (III) where X is EMI2.4 is, where Rl and R2 are each hydrogen, lower alkyl, aryl or aralkyl, and, if appropriate, converts the compounds of the formula I thus obtained into their salts.