Alpha 7 nicotinic acetylcholine receptor agonists

Abstract

The invention concerns the use of certain alpha 7 nicotinic acetylcholine receptor agonists for the treatment, amelioration, prevention or delay of progression of fatigue, narcolepsy, excessive daytime sleepiness, nocturnal sleep disturbance, and/or cataplexy.

What is claimed is: 
     
         1 . A method of treatment, amelioration, prevention, or delay of progression of fatigue in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an alpha  7  nicotinic acetylchoine receptor agonist,
 wherein said alpha 7 nicotinic acetylcholine receptor agonist is (i) a compound of formula (I) 
 
       
         
           
           
               
               
           
         
       
       wherein 
       L 1  is —CH 2 —; L 2  is —CH 2 —CH 2 —; and L 3  is —CH 2 — or —CH(CH 3 )—; or 
       L 1  is —CH 2 —CH 2 —, L 2  is —CH 2 —; and L 3  is —CH 2 —CH 2 —; 
       L 4  is a group selector; frpm 
       
         
           
           
               
               
           
         
       
       wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety; 
       R 1  is methyl; 
       X 1  is —O— or —NH—; 
       A 2  is selected from 
       
         
           
           
               
               
           
         
       
       wherein the bond marked with the asterisk is attached to X 1 ; 
       A 1  is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R 2 , each R 2  independently is C 1-6 alkyl, C 1-6 halogenalkyl or halogen; or 
       (ii) a compound selected from the group consisting of 
       4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane; 
       (4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3,3,1.1 3,7 ]decane; 
       4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane; 
       4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1azatricyclo[3,3,1.1 3,7 ]decane; 
       4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane, 
       N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide; 
       N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide 
       N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide 
       N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2,2]oct-3-yl)benzofuran-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide, 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl) -5-methylthiophene-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide; 
       7,8,9,10-tetranydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine; 
       3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl; 
       N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2,2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]2-thienyl}methanamine; 
       N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine; 
       N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine; 
       (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, 
       5-{5-[(endo)-8-azabicyclo[3.2,1]octan-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(exo)-8-azabicyclo[3.2.1]octan-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-3-yl}-1H-indole; 
       (2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]; 
       1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester, and 
       5-{6-[1-azebicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole; 
       in free base form or in acid addition salt form. 
     
     
         2 . The method of  claim 1 , wherein the fatigue is fatigue associated with multiple sclerosis. 
     
     
         3 . The method of  claim 2 , wherein the fatigue is is fatigue associated with multiple sclerosis and is (i) caused be sleep deprivation, depression or general disabilities or (ii) lassitude. 
     
     
         4 . The method of  claim 1 , wherein the fatigue is chronic fatigue syndrome. 
     
     
         5 . The method of  claim 1 , wherein the fatigue is fatigue associated with an infectious disease. 
     
     
         6 . The method of  claim 5 , wherein the fatigue is fatigue associated with HIV infection. 
     
     
         7 . The method of  claim 1 , wherein the daily dosage of said agonist is from 1 to 100 mg. 
     
     
         8 . The method of  claim 1 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form. 
     
     
         9 . The method of  claim 1 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form and wherein the daily dosage of said agonist is from 1 to 100 mg. 
     
     
         10 . The method of  claim 2 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form and wherein the daily dosage of said agonist is from 1 to 100 mg. 
     
     
         11 . A method of treatment, amelioration, prevention, or delay of progression of narcolepsy, excessive daytime sleepiness, nocturnal sleep disruption or cataplexy in a subject in need of such treatment, which comprises:
 administering to said subject a therapeutically affective amount of an alpha 7 nicotinic acetylcholine receptor agonist, wherein said alpha 7 nicotinic acetylcholine receptor agonist is   
       (i) a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein 
       L 1  is —CH 2 —; L 2  is —CH 2 —CH 2 —: and L 3  is —CH 2 — or —CH(CH 3 )—; or 
       L 1  is —CH 2 —CH 2 —, L 2  is —CH 2 —; and L 3  is —CH 2 —CH 2 —, 
       L 4  is a group selected from 
       
         
           
           
               
               
           
         
       
       wherein the bond marked with the asterisk is attached to the azabicycloalkyl moiety; 
       R 1  is methyl; 
       X 1  is —O— or —NH—; 
       A 2  is selected from 
       
         
           
           
               
               
           
         
       
       wherein the bond marked with the asterisk is attached to X 1 ; 
       A 1  is phenyl, indole or 1,3-dihydro-indol-2-one, which may be substituted once or more than once by R 2 , each R 2  independently is C 1-6 alkyl, C 1-6 halogenalkyl or halogen; or 
       (ii) a compound selected from the group consisting of 
       4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3,3.1.1 3,7 ]decane; 
       (4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3,3,1.1 3,7 ]decane; 
       4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1azatricyclo[3.3.1.1 3,7 ]decane; 
       4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1azatricyclo[3,3,1.1 3,7 ]decane; 
       4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1azatricyclo[3,3,1.1 3,7 ]decane, 
       N-(1 -azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide; 
       N-((3R)-1-azabicyclo[2.2,2]oct-3-yl)-1H-indazole-3-carboxamide 
       N-((3S)-1-azabicyclo[2.2,2]oct-3-yl)-1H-indazole-3-carboxamide 
       N-(1 -azabicyclo[2,2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-((3R)-1-azabicyclo[2.2,2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-((3S)-1-azabicyclo[2.2,2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2,2,2]oct-3-yl)benzofuran-2-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2,2]oct-3-yl)-3,5-difluorobenzamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide; 
       N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide; 
       (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide; 
       7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine; 
       3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl; 
       N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2,2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine; 
       N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine; 
       N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine; 
       (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide; 
       5-{5-[(endo)-8-azabicyclo[3.2,1]octan-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(exo)-8-azabicyclo[3,2,1]octan-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(endo)-8-methyl-8-aza-bicyclo[3,2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       4-{5-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-2-yl}-1H-indole; 
       5-{6-[(exo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy]pyridin-3-yl}-1H-indole; 
       (2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]; 
       1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo-phenyl ester; and 
       5-{6-[1-azebicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole; 
       in free base form or in add addition salt form. 
     
     
         12 . The method of  claim 11 , for use in the treatment, amelioration, prevention or delay of progression of narcolepsy. 
     
     
         13 . The method of  claim 12 , wherein the narcolepsy is narcolepsy with cataplexy. 
     
     
         14 . The method of  claim 12 , wherein the narcolepsy is narcolepsy without cataplexy. 
     
     
         15 . The method of  claim 12 , wherein the narcolepsy is narcolepsy due to medical condition. 
     
     
         16 . The method of  claim 11 , for use in the treatment, amelioration, prevention or delay of progression of excessive daytime sleepiness. 
     
     
         17 . The method of  claim 11 , for use in the treatment, amelioration, prevention or delay of progression of nocturnal sleep disruption. 
     
     
         18 . The method of  claim 11 , for use in the treatment, amelioration, prevention or delay of progression of cataplexy. 
     
     
         19 . The method of  claim 11 , wherein the daily dosage of said agonist is from 1 to 100 mg. 
     
     
         20 . The method of  claim 11 , wherein the agonist is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form.