Patent EA-003192-B1 (EA)
Title: A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity
Inventor: CHIESI PAOLO
IPC: C07D498/04
Filed: 1998-10-07
Abstract: 1. Compounds of formula (Ia) wherein R is phenyl or benzyl group, which can optionally be substituted by C1-C4 alkyl, halogen or C1-C4 alkoxy group or by their pharmaceutically acceptable salts. 2. Compounds according to claim 1, wherein R is selected from the group consisting of 2-ethylphenyl, 3-methylphenyl, 2-methylphenyl. 3. A process for the preparation of compounds of formula (Ia), wherein a) oxidation of a compound of formula (II) with peracids or peroxides wherein R1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions without reducing the geneserino-like N-oxide group, in an alcoholic solvent or in a water-alcohol mixture to give a compound of formula (III); b) hydrolysis of the compound of formula (III) to geneseroline with a mineral acid or an organic acid, which does not reduce the N-oxide group; c) acylation of geneseroline with an isocyanate of formula R-N=C=O, wherein R is as defined above, in the presence of a basic catalyst selected from the group consisting of alkali alcoholates, carbonates or hydroxides; d) optional transformation into a pharmaceutically acceptable salt. 4. A process according to claim 3, wherein hydrolysis of compound (II) or (III) is carried out with an acid selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, a strongly acidic ion-exchange resin. 5. A process according to claim 3, wherein hydrolysis is carried out with sulfuric acid at a concentration ranging from 10 to 85% w/w. 6. A process according to claim 3, wherein hydrolysis is carried out with hot 85% w/w phosphoric acid. 7. A process according to claim 3, wherein hydrolysis is carried out with methanesulfonic acid at 90 degree C. 8. A process according to claim 3, wherein hydrolysis is carried out with hot trifluoroacetic acid or 10% hydrochloric acid at 40 degree C. 9. A process according to claim 3, wherein hydrolysis is carried out with a strongly acidic ion-exchange resin. 10. A process according to claim 3, wherein, in the acylation step, the basic catalyst is added with a phase transfer catalyst or an ultrasound source is used. 11. Compounds of formula (II): wherein R1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions as intermediates in the process of claim 3. 12. The use (II) according to claim 11, wherein R1 is isopropyl, tert-butyl or methoxymethyl. 13. Compounds of formula (III): wherein R1 is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions as intermediates in the process of claim 3. 14. Compounds of formula (III) according to claim 13, wherein R1 is alkyl, alkoxylalkyl or tetrahydropyranyl. 15.. Pharmaceutical compositions containing an effective amount of a compound of claim 1 in admixture with pharmaceutically acceptable carriers and excipients. 16. The use of the compounds of claim 1 for the preparation of a medicament having acetylcholinesterase inhibiting activity. 17. The use according to claim 16, wherein said medicament is selective with respect to brain acetylcholinesterase. 18. The use according to claim 17, wherein said medicament is useful for the treatment of Alzheimer disease and other neurovegetative pathologies. 19. The use according to claim 18, wherein said medicament is devoid of peripheral side effects.