Pharmaceutical compositions based on anticholinergics and NK1-receptor antagonists

Abstract

The present invention relates to novel pharmaceutical compositions based on anticholinergics and NK 1 -receptor antagonists, processes for preparing them and their use in the treatment of respiratory tract diseases.

What is claimed is:  
     
         1 . A pharmaceutical composition of matter comprising one or more anticholinergics and one or more NK 1 -receptor antagonists as active components of the pharmaceutical composition, wherein one or more of the active components may be an enantiomer, a mixture of enantiomers, a racemate, a solvate or an hydrate.  
     
     
         2 . The pharmaceutical composition as recited in  claim 1  wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.  
     
     
         3 . The pharmaceutical composition as recited in  claim 1  wherein the active components are present together in a single formulation.  
     
     
         4 . The pharmaceutical composition as recited in  claim 1  wherein the active components are in at least two separate formulations.  
     
     
         5 . The pharmaceutical composition as recited in  claim 1  wherein the anticholinergic is selected from the group consisting of one or more tiotropium salts, one or more oxitropium salts and one or more ipratropium salts.  
     
     
         6 . The pharmaceutical composition as recited in  claim 5  wherein the anticholinergic is one or more tiotropium salts.  
     
     
         7 . The pharmaceutical composition as recited in  claim 1  wherein one or more anticholinergic is present in the form of a chloride, bromide, iodide, methanesulphonate, paratoluene sulphonate or a methyl sulphate.  
     
     
         8 . The pharmaceutical composition as recited in  claim 7  wherein one or more anticholinergics is present in the form of a bromide.  
     
     
         9 . The pharmaceutical composition as recited in  claim 1  wherein one or more NK 1 -receptor antagonists is selected from among BIIF 1149, CP-122721, FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968(Saredutant), SR 140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant), MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-I, CJ-11974, TAK-637, GR 205171, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, BIIM1310 N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and the arylglycinamide derivatives of general formula 3  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  together with the N to which they are bound form a ring of formula  
                     
 wherein r and s are 2 or 3;  
 R 6  denotes H, —C 1 -C 5 -alkyl, C 3 -C 5 -alkenyl, propynyl, hydroxy(C 2 -C 4 )alkyl, methoxy(C 2 -C 4 )alkyl, di(C 1 -C 3 )alkylamino(C 2 -C 4 )alkyl, amino(C 2 -C 4 )alkyl, amino, di(C 1 -C 3 )alkylamino, monofluoro to perfluoro(C 1 -C 2 )alkyl, N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,  
 R 7  has one of the meanings (a) to (d),  
 (a) hydroxy  
 (b) 4-piperidinopiperidyl,  
 (c)  
                     
 wherein R 16  and R 17  independently of each other denote H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 2 -C 4 )alkyl, dihydroxy(C 2 -C 4 )alkyl, (C 1 -C 3 )alkoxy(C 2 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl or di(C 1 -C 3 )alkylamino(C 2 -C 4 )alkyl,  
 R 8  denotes H,  
 optionally in the form of the enantiomers and mixtures of enantiomers thereof, optionally in the form of the racemates thereof.  
 
     
     
         10 . The pharmaceutical composition as recited in  claim 1  wherein one or more NK,-receptor antagonists is selected from among BIIF 1149, CP-122721, CGP 60829, MK-869, CJ-11974, GR 205171, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(3-hydroxy-propyl)-methyl-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide, BIIM1310 N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide, N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide and the arylglycinamide derivatives of general formula 3, wherein 
 R 1  and R 2  together with the N to which they are bound form a ring of formula  
                     
 wherein s is 2 or 3;  
 R 7  denotes a group  
                     
 wherein R 16  and R 17  independently of each other denote H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 2 -C 4 )alkyl, dihydroxy(C 2 -C 4 )alkyl, (C 1 -C 3 )alkoxy(C 2 -C 4 )alkyl, phenyl(C 1 -C 4 )alkyl or di(C 1 -C 3 )alkylamino(C 2 -C 4 )alkyl,  
 R 8  denotes H,  
 optionally in the form of the enantiomers and mixtures of enantiomers thereof and optionally in the form of the racemates thereof.  
 
     
     
         11 . The pharmaceutical composition as recited in  claim 1  wherein one or more NK 1 -receptor antagonists is (S)-N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(2-hydroxy-1-hydroxymethyl-ethylamino)-piperidin-1-yl]-N-methyl-2-phenylacetamide or an acid addition salt thereof.  
     
     
         12 . The pharmaceutical composition as recited in  claim 1  wherein the weight ratio of the anticholineigic to the NK 1 -receptor antagonist is in the range from about 1:300 to about 50:1.  
     
     
         13 . The pharmaceutical composition as recited in  claim 12  wherein the weight ratio of the anticholinergic to the NK 1 -resceptor antagonist is about 1:250 to about 40:1.  
     
     
         14 . The pharmaceutical composition as recited in  claim 1  which is a formulation suitable for inhalation.