Use and composition for treating dementia

Abstract

There is described a method for increasing the maximal tolerated dose and thus the efficacy of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by administration of said AChEI in combination with a non-selective, peripheral anticholinergic agent, whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and alleviation of the symptoms of Alzheimer type dementia in said patient is thereby improved to a greater extent. The use of a non-selective, peripheral anticholinergic agent (nsPAChA) for the preparation of a pharmaceutical composition for increasing the maximal tolerated dose and thus the efficacy of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia and pharmaceutical compositions comprising a non-selective peripheral anticholinergic agent of formula II as illustrated in the description and an acetylcholine esterase inhibitor are also described.

1 . Use of a non-selective, peripheral anticholinergic agent (nsPAChA) for the preparation of pharmaceutical compositions for the treatment of Alzheimer type dementia in combination with an acetyl choline esterase inhibitor (AChEI), whereby the maximal tolerated dose of said AChEI is increased, a higher acetyl choline esterase inhibition in the CNS is achieved and relief of the symptoms of Alzheimer type dementia is improved, by concomitantly decreasing concurrent adverse effects. 
     
     
         2 . The use of  claim 1  wherein said nsPAChA is selected from the group consisting of quaternary ammonium nsPAChAs, sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) and its pharmaceutically acceptable salts, 1-methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceutically acceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethyl α-cyclohexyl-α-hydroxy-α-phenylacetate (oxyphencyclimine) and its pharmaceutically acceptable salts, (R)—N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine) and its pharmaceutically acceptable salts. 
     
     
         3 . The use of  claim 2  wherein said quaternary ammonium nsPAChAs or sulfonium nsPAChAs has the formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 R is a radical selected from the group consisting of those of formulas (a)-(e) 
 
       
         
           
           
               
               
           
         
         A being methyl and A′ being (C 1 -C 4 )alkyl or 2-fluoroethyl group or A and A′ forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk′ each being (C 1 -C 4 )alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion; 
         n and m, independently, are zero or 1; 
         X is a (C 2 -C 3 )alkylene group; 
         R 1  and R 2  are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C 1 -C 4 )alkyl; 
         R 3  is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C 1 -C 4 )alkyl group. 
       
     
     
         4 . The use of  claim 1  wherein said nsPAChA selected from the group consisting of pharmaceutically acceptable salts of azoniaspiro[3β-benziloyloxy-(1α,5α)-nortropane-8,1′-pyrrolidine] (trospium), solifenacin and the compound thereof with succinic acid, propiverine and the hydrochloride thereof, oxyphencyclimine and the hydrochloride thereof, tolterodine and the hydrogen tartrate thereof. 
     
     
         5 . The use of  claim 1  wherein said AChEI is selected from the group consisting of 1,2,3,4-tetrahydro-9-acridinamine (tacrine), (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and its pharmaceutically acceptable salts, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate (rivastigmine) and its pharmaceutically acceptable salts, 4aS,6R,8aS-3-methoxy-11-methyl-4-a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine); and (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0 2,7 ]trideca-2(7),3,10-trien-5-one (huperzine A). 
     
     
         6 . The use of  claim 5  wherein the dose of said AChEI is from 100% to 400% of the maximal tolerated dose of said AChEI when used alone. 
     
     
         7 . A pharmaceutical unit form which comprises
 (a) a nsPAChA selected from the group consisting of solifenacin, pharmaceutically acceptable salts of solifenacin, propiverine, pharmaceutically acceptable salts of propiverine, oxyphencyclimine, pharmaceutically acceptable salts of oxyphencyclimine, tolterodine, pharmaceutically acceptable salts of tolterodine and quarternary ammonium or sulfonium compound of formula II   
       
         
           
           
               
               
           
         
         
           wherein
 R is a radical selected from the group consisting of those of formulas (a)-(e) 
 
         
       
       
         
           
           
               
               
           
         
         
           
             A being methyl and A′ being (C 1 -C 4 )alkyl or 2-fluoroethyl group or A and A′ forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk′ each being (C 1 -C 4 )alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion; 
             n and m, independently, are zero or 1; 
             X is a (C 2 -C 3 )alkylene group; 
             R 1  and R 2  are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C 1 -C 4 )alkyl; 
             R 3  is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C 1 -C 4 )alkyl group; and 
           
         
         (b) an AChEI; 
         in admixture with at least a pharmaceutical carrier. 
       
     
     
         8 . The unit form of  claim 7 , wherein said nsPAChA is a selected from the group consisting of pharmaceutical acceptable salts of trospium, pharmaceutically acceptable salts of solifenacin, pharmaceutically acceptable salts of propiverine, pharmaceutically acceptable salts of oxyphencyclimine and pharmaceutically acceptable salts of tolterodine. 
     
     
         9 . The unit form of  claim 7 , wherein said nsPAChA is a pharmaceutical acceptable salt of trospium in an amount of from 4 mg to 120 mg. 
     
     
         10 . The unit form of  claim 7 , wherein said nsPAChA is a pharmaceutically acceptable salt of trospium and AChEI is selected from the group consisting of tacrine, in an amount of from 10 mg to 160 mg, donepezil and its pharmaceutically acceptable salts, in an amount of from 5 mg to 40 mg, rivastigmine and its pharmaceutically acceptable salts, in an amount of from 1.5 to 36 mg, galantamine, in an amount of from 4 to 48 mg and huperzine A, in an amount of from 100 μg to 1.2 mg. 
     
     
         11 . A method for increasing the maximal tolerated dose of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia without concurrent, appreciable adverse effects, which comprises administering to said patient said AChEI in combination with a non-selective, peripheral anticholinergic agent (nsPAChA), whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and the symptoms of an Alzheimer type dementia in said patient are improved. 
     
     
         12 . A pharmaceutical composition for inducing a higher acetyl choline esterase inhibition in the CNS of a patient suffering from Alzheimer type dementia, said patient taking a dose of acetyl choline esterase inhibitor (AChEI) higher than the maximal tolerated dose attainable when given alone, comprising, as an active ingredient, a non-selective, peripheral anticholinergic agent (nsPAChA) in admixture with a pharmaceutical carrier.