Brain, spinal and nerve injury treatment

Abstract

A treatment for brain, spinal and nerve injury comprising use of a substance P receptor antagonist optionally in combination with a magnesium compound. There is also provided a formulation for use in this treatment comprising a substance P receptor antagonist and a magnesium compound.

1 . A method of treating a mechanical traumatic brain, spinal cord or nerve tissue injury by substantially reducing a secondary injury caused by a vasogenic oedema in the brain comprising administering to a patient in need of such treatment, a therapeutically effective amount of pharmaceutical preparation comprising a therapeutically effective amount of a substance P receptor antagonist selected from 
 N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide,    (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,    N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]4-o-tolyl-pyridin-3-yl}-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide,    [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine,    N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,    4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-5-phenyl-isonicotinamide,    N-(3,5-Dichloro-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,    2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2′-chloro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide,    4-(2-bromo-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-4-(2-bromo-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-bromo-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-4-(2-chloro-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-piperazin-1-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-methoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-methoxy-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluor-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluor-2-methyl-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-bromo-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-morpholin-4-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-methoxy-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-2-methyl-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-morpholin-4-yl-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide, and    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide; a non-toxic magnesium compound; and a pharmaceutically acceptable vehicle.    
     
     
         2 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    2′-Methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-4-naphthalen-1-yl-nicotinamide,    (4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]4-o-tolyl-pyridin-2-yl}-piperazin-1-yl)-acetic acid ethyl ester,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-propyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide, and    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide.    
     
     
         3 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-cyanomethyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-N-methyl-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(4-[1,2,4]oxadiazol-3-ylmethyl-piperazin-1-yl)-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[4-(5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-piperazin-1-yl]-4-o-tolyl-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-6-(4-formyl-piperazin-1-yl)-N-methyl-4-o-tolyl-nicotinamide,    N-Methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide, and    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide.    
     
     
         4 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-morpholin-4-yl-pyridin-3-yl]-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-pyridin-3-yl}-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, and    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide.    
     
     
         5 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-acetamide,    [2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methyl-amine,    N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,    4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide, and    N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide.    
     
     
         6 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,    N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-5-phenyl-isonicotinamide,    N-(3,5-Dichloro-benzyl)-5-(2-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-isonicotinamide,    2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2′-chloro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-carboxylic acid-(3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and    5-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.    
     
     
         7 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    5-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidin-4-yl]-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-piperazin-1-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-5-o-tolyl-pyrimidin-4-yl)-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-[5-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-N-methyl-isobutyramide,    4-(2-bromo-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and    (3R,5S)-4-(2-bromo-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.    
     
     
         8 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 4-(2-bromo-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-4-(2-chloro-phenyl)-2-(3,5-dimethyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-piperazin-1-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and    4-(2-methoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.    
     
     
         9 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-methoxy-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-fluoro-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluor-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-2-methyl-phenyl)-2-(4-methyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.    
     
     
         10 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 4-(4-fluor-2-methyl-phenyl)-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(4-methyl-piperazin-1-yl) 4 -naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    (3R,5S)-2-(3,5-dimethyl-piperazin-1-yl)-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-naphthalen-1-yl-2-piperazin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-bromo-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(2-chloro-phenyl)-2-(2-morpholin-4-yl-ethoxy)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, and    2-morpholin-4-yl-4-o-tolyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide.    
     
     
         11 . The method of  claim 1  wherein the substance P receptor antagonist is selected from 
 4-(2-methoxy-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    4-(4-fluoro-2-methyl-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-morpholin-4-yl-4-naphthalen-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyrimidin-5-yl]-isobutyramide,    2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-morpholin-4-yl-4-o-tolyl-pyrimidin-5-yl)-isobutyramide.