Muscarinic combinations and their use for combating hypocholinergic disorders of the central nervous system

Abstract

A combination of a muscarinic cholinergic receptor agonist, a non-anticholinergic antiemetic agent and a non-selective, peripheral anticholinergic agent for the treatment of hypocholinergic disorders of the central nervous system.

What is claimed is: 
     
         1 . A pharmaceutical combination comprising as Components:
 (a) a muscarinic cholinergic receptor agonist (MCRA)   (b) a non-anticholinergic antiemetic agent (naAEA); and   (c) a muscarinic receptor antagonist selected from the group consisting of the non-selective, peripheral anticholinergic agents (nsPAChAs).   
     
     
         2 . The combination of  claim 1 , wherein said MCRA Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier; said naAEA Component (b) is in a pharmaceutical composition in admixture with a pharmaceutical carrier, and said nsPAChA Component (c) is in a pharmaceutical composition in admixture with a pharmaceutical carrier. 
     
     
         3 . The combination of  claim 1 , wherein said MCRA Component (a) is in a pharmaceutical composition in admixture with a pharmaceutical carrier; said naAEA Component (b) is in a pharmaceutical composition in admixture with a pharmaceutical carrier, and said nsPAChA Component (c) is oxybutynin or a pharmaceutically acceptable salt thereof in a transdermal therapeutic system (TTS). 
     
     
         4 . The combination of  claim 3 , wherein said MCRA Component (a) is selected from the group consisting of cevimeline and pharmaceutically acceptable salts thereof, milameline and pharmaceutically acceptable salts thereof; xanomeline and pharmaceutically acceptable salts thereof, and MK-7622 and pharmaceutically acceptable salts thereof; said naAEA Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, domperidone and pharmaceutically acceptable salts and solvates thereof and metoclopramide and pharmaceutically acceptable salt and solvates thereof; and said nsPAChA Component (c) is oxybutynin in a transdermal patch. 
     
     
         5 . The combination of  claim 4 , wherein said MCRA Component (a) is selected from the group consisting of cevimeline and pharmaceutically acceptable salts thereof, in an amount (in cevimeline) of from 34.5 mg to 180 mg; milameline and pharmaceutically acceptable salts thereof, in an amount (in milameline) of from 2.4 mg to 12 mg; xanomeline and pharmaceutically acceptable salts thereof, in an amount (in xanomeline) of from 90 mg to 450 mg; and MK-7622 and pharmaceutically acceptable salts thereof, in an amount (in MK-7622) of from 5 mg to 270 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier; said naAEA Component (b) is selected from the group consisting of ondansetron and pharmaceutically acceptable salts and solvates thereof, in an amount (in ondansetron) of from 4 mg to 64 mg, domperidone and pharmaceutically acceptable salts and solvates thereof, in an amount, in domperidone of from 5 mg to 30 mg; and metoclopramide and pharmaceutically acceptable salts and solvates thereof, in an amount (in metoclopramide) of from 5 mg to 30 mg; in a pharmaceutical composition in admixture with a pharmaceutical carrier; and said nsPAChA Component (c) is oxybutynin in admixture with a pharmaceutical carrier or vehicle in a transdermal patch releasing from 3.9 mg/24 h to 7.8 mg/24 h oxybutynin. 
     
     
         6 . The combination of  claim 5 , wherein said MCRA Component (a) is cevimeline or a pharmaceutically acceptable salt thereof; said naAEA Component (b) is ondansetron or a pharmaceutically acceptable salt thereof; and (c) said nsPAChA is oxybutynin in a transdermal patch releasing 3.9 mg/24 h oxybutynin. 
     
     
         7 . A method for treating hypocholinergic disorders of the central nervous system, which comprises administering, to a patient in need of such a treatment, the combination according to  claim 1 . 
     
     
         8 . The method of  claim 7 , wherein Component (a), Component (b) and Component (c) of the combination are administered concurrently or sequentially to a patient suffering from a hypocholinergic disorder of the central nervous system, each Component being administered to said patient by the same or by a different administration route. 
     
     
         9 . The method of  claim 8 , wherein said hypocholinergic disorder of the central nervous system is selected from the group consisting of Alzheimer's disease (AD), Alzheimer-type dementia, mild cognitive impairment, Lewy body disease, Parkinson's disease dementia, Frontotemporal lobe dementia (FTD), Frontotemporal lobar degeneration, post-stroke dementia, vascular dementia, traumatic brain injury, Senile dementia, Autism, Down syndrome, anorexia nervosa, Tourette syndrome, tardive dyskinesia, Pick's disease, Huntington's disease, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, Cognitive Impairment associated with Multiple Sclerosis, and other disorders of the nervous system involving a deficit in acetyl-choline neurotransmission. 
     
     
         10 . The combination according to  claim 1 , for use in the treatment of hypocholinergic disorders of the CNS. 
     
     
         11 . The combination of  claim 10 , wherein said hypocholinergic disorder of the central nervous system is selected from the group consisting of Alzheimer's disease (AD), Alzheimer-type dementia, mild cognitive impairment, Lewy body disease, Parkinson's disease dementia, Frontotemporal lobe dementia (FTD), Frontotemporal lobar degeneration, post-stroke dementia, vascular dementia, traumatic brain injury, Senile dementia, Autism, Down syndrome, anorexia nervosa, Tourette syndrome, tardive dyskinesia, Pick's disease, Huntington's disease, Friedrich's ataxia, chronic neuropathic pain, falls, post-operative delirium, schizophrenia, Cognitive Impairment associated with Multiple Sclerosis, and other disorders of the nervous system involving a deficit in acetyl-choline neurotransmission. 
     
     
         12 . The combination of  claim 1 , further comprising an AChEI. 
     
     
         13 . A pharmaceutical combination comprising as Components:
 (a) a muscarinic receptor antagonist selected from the group consisting of the non-selective, peripheral anticholinergic agents (nsPAChAs); and   (b) a muscarinic receptor agonist selected from the group consisting of cholinergic receptor agonists (CRA).   
     
     
         14 . The combination of  claim 13 , wherein said muscarinic receptor antagonist is an nsPAChA 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, [2-[(1R)-3-(Di(propan-2-yl)amino)-1-phenylpropyl1-4-(hydroxymethyl)phenyl] 2-methylpropanoate (fesoterodine) and its pharmaceutically acceptable salts. 
     
     
         15 . The combination of  claim 14  wherein said quaternary ammonium nsPAChAs or sulfonium nsPAChAs has the formula (I)
 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. 
       
     
     
         16 . The combination of  claim 13 , wherein said muscarinic receptor antagonist is a nsPAChA selected from the group consisting of azoniaspiro[3β-benziloyloxy-(1α,5α)-nortropane-8,1′-pyrrolidine] (trospium) chloride, 3-[2-cyclopentyl(hydroxy)phenylacetoxy]-1,1-dimethylpyrrolidinium (glycopyrronium) bromide, solifenacin and the compound thereof with succinic acid (solifenacin succinate), propiverine and the hydrochloride thereof, oxyphencyclimine and the hydrochloride thereof, tolterodine and the hydrogen tartrate thereof, fesoterodine and the fumarate thereof 
     
     
         17 . The combination of  claim 13 , wherein said muscarinic receptor agonist is a CRA selected from the group consisting of 1-methylpiperidine-4-spiro-5′(2′-ethyl-1′,4′-thiazoline-3′-one) (AF267) and pharmaceutically acceptable salts and solvates thereof; cis-2′-methylspiro {1-azabicyclo [2.2.2] octane-3,5′-[1,3] oxathiolane} (cevimeline) and pharmaceutically acceptable salts and solvates thereof; 3-[3-(3-(3-fluorophenyl)-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine and pharmaceutically acceptable salts and solvates thereof; (E)-N-methoxy-1-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)methylamine (milameline) and pharmaceutically acceptable salts and solvates thereof 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS-86) and pharmaceutically acceptable salts and solvates thereof; (3R)-N-methoxyquinuclidine-3-carboximidoyl cyanide (sabcomeline) and pharmaceutically acceptable salts and solvates thereof; (3R)-3-(prop-2-yn-1-yloxy)-1-azabicyclo[2.2.2]octane (talsaclidine) and pharmaceutically acceptable salts and solvates thereof 5-[4-(hexylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine and pharmaceutically acceptable salts and solvates thereof; 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1-methyl-5,6-dihydro-2H-pyridine (xanomeline), 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h] quinazolin-4(3H)-one (MK-7622) and pharmaceutically acceptable salts and solvates thereof 
     
     
         18 - 33 . (canceled)