Optimization and therapeutic valorization of the symptomatic treatment of alzheimer's disease with rivastigmine, galantamine or donepezil, by selected aminotetrahydrofurans acting as mixed sigma-1 / muscarinic ligands

Abstract

The present invention involves the selected aminotetrahydrofurans AE37, AE37Met, AE14 and their enantiomers as original mixed sigma-1/muscarinic ligands for the optimization of the anticholinesterasic drugs and more specifically of Donepezil, Galantamine or Rivastigmine. Indeed, these aminotetrahydrofurans exhibited M2 and M3 muscarinic antagonisms against the cholinergic adverse effects of these drugs, which constitute the most limitating factor in the use of these drugs against the symptoms of the Alzheimer's disease (AD). Moreover, by their antagonism of the presynaptic muscarinic M2 cholinergic autoreceptors and their very selective sigma-1 agonism they constitute putative agents for the valorization of the anticholinesterasic drugs and more specifically of Donepezil, Galatamine or Rivastigmine from their present status of drugs acting against the symptoms of AD to the perspective of therapeutic agents against the evolution of AD.

1 . Pharmaceutical use of the original mixed sigma-1muscarinic ligand tetrahydro-N,N-dimethyl-2,2 diphenyl-3-furanomethanamine (AE37), its isomer tetrahydro-N,N-dimethyl-5,5-furanomethanamine (AE14), the unique metabolite of AE37, tetrahydro-N-methyl-2,2-diphenyl-3 -furanomethanamine (AE37Met), their enantiomers and their pharmacologically acceptable salts as optimization agents of the symptomatic treatments of the Alzheimer's disease (AD) by the inhibitors of cholinesterases (IChEases) and also in the valorization of the IChEases as therapeutic drugs against AD. 
     
     
         2 . All pharmacological compositions characterized by the fact that they do contain compounds of the  claim 1  and, at least, one pharmaceutically acceptable excipient. 
     
     
         3 . Pharmaceutical use of the compounds of the  claim 1  against the cholinergic adverse effects of the IChEases, in the symptomatic treatment of AD, by the antagonism of the M2 and M3 muscarinic receptors exerced by the compounds of the  claim 1 . 
     
     
         4 . Pharmaceutical use of the compounds of the  claim 1  for the valorization of IchEases as therapeutic agents against the evolution of AD, by the antagonism of the pre-synaptic muscarinic M2 autoreceptors in synergy with their sigma-1 selective agonism exersed by the compounds of the  claim 1 . 
     
     
         5 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) against the adverse cholinergic effects of Donepezil (orally 5, 10 or even 23 mgs/day) in the symptomatic treatment of AD, by their antagonism of the M2 and M3 muscarinic receptors. 
     
     
         6 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) for the valorization of Donepezil (orally, 5, 10 or even 23 mgs/day) as therapeutic drug against the evolution of AD, by their antagonism of the presynaptic muscarinic M2 autoreceptors in synergy with their sigma-1 selective agonism. 
     
     
         7 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) against, the adverse cholinergic effects of Rivastigmine (orally, 6 to 12 mgs/day or transdermal patch 4.6, 9.5 or 13.3 mgs/day), in the symptomatic treatment of AD, by their antagonism of the M2 and M3 muscarinic receptors. 
     
     
         8 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) for the valorization of Rivastigmine (orally, 6 to 12 mgs/day or transdermal patch 4.6, 9.5 or 13.3 mgs/day) as therapeutic drug against the evolution of AD, by their antagonism of the presynaptic muscarinic M2 autoreceptors in synergy with their selective sigma-1 agonism. 
     
     
         9 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) against the adverse cholinergic effects of Galantamine (orally, tablets of 4, 8 or 12 mgs/day or capsules of 8, 16 or 24 mgs/day) in the symptomatic treatment of AD, by their antagonism of the M2 and M3 muscarinic receptors. 
     
     
         10 . Pharmaceutical use of the compounds of the  claim 1  (orally, 1 to 10 mgs/day) for the valorization of Galantamine, (orally, tablets of 4, 8 or 12 mgs/day or capsules of 8, 16 or 24 mgs/day) as therapeutic drug against the evolution of AD, by their antagonism of the presynaptic muscarinic M2 autoreceptors in synergy with their selective sigma-1 agonism.