Compositions for treating spinal muscular atrophy

Abstract

The present invention provides pharmaceutical compositions comprising a compound of formula (I) wherein A, R 1 , R 2 and R 3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the pharmaceutical compositions comprising a compound of formula (I) and their use as medicaments.

1 . A pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is hydrogen or C 1-7 -alkyl; 
         R 2  is hydrogen, cyano, C 1-7 -haloalkyl or C 3-8 -cycloalkyl; 
         R 3  is hydrogen, C 1-7 -alkyl, or C 3-8 -cycloalkyl; 
         A is N-heterocycloalkyl or NR 12 R 13 , wherein N-heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ; 
         R 12  is heterocycloalkyl comprising 1 nitrogen ring atom, wherein heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ; 
         R 13  is hydrogen, C 1-7 -alkyl or C 3-8 -cycloalkyl; 
         R 14  is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3-8 -cycloalkyl and heterocycloalkyl or two R 14  together form C 1-7 -alkylene; 
         with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R 14  substituent is amino or amino-C 1-7 -alkyl; 
         wherein the composition is an oral aqueous solution or a dry powder suitable for constitution of an oral aqueous solution. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  is hydrogen or C 1-7 -alkyl;   R 2  is hydrogen, cyano, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;   R 3  is hydrogen, C 1-7 -alkyl, or C 3-8 -cycloalkyl;   A is N-heterocycloalkyl comprising 1 or 2 nitrogen ring atoms, wherein N-heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R 14 ;   R 14  is independently selected from hydrogen, C 1-7 -alkyl, amino, amino-C 1-7 -alkyl, C 3-8 -cycloalkyl and heterocycloalkyl or two R 14  together form C 1-7 -alkylene;   with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R 14  substituent is amino or amino-C 1-7 -alkyl.   
     
     
         3 . The pharmaceutical composition according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 A is   
       
         
           
           
               
               
           
         
       
       wherein
 X is N or CH; 
 R 4  is hydrogen, C 1-7 -alkyl or —(CH 2 ) m —NR 9 R 10 ; 
 R 5  is hydrogen or C 1-7 -alkyl; 
 R 6  is hydrogen or C 1-7 -alkyl; 
 R 7  is hydrogen or C 1-7 -alkyl; 
 R 8  is hydrogen or C 1-7 -alkyl; 
 R 9  and R 10  are independently selected from hydrogen, C 1-7 -alkyl and C 3-8 -cycloalkyl; 
 R 13  is hydrogen, C 1-7 -alkyl or C 3-8 -cycloalkyl; 
 n is 0, 1 or 2; 
 m is 0, 1, 2 or 3; 
 or R 4  and R 5  together form C 1-7 -alkylene; 
 or R 4  and R 7  together form C 1-7 -alkylene; 
 or R 5  and R 6  together form C 2-7 -alkylene; 
 or R 5  and R 7  together form C 1-7 -alkylene; 
 or R 5  and R 9  together form C 1-7 -alkylene; 
 or R 7  and R 8  together form C 2-7 -alkylene; 
 or R 7  and R 9  together form C 1-7 -alkylene; 
 or R 9  and R 10  together form C 2-7 -alkylene; 
 with the proviso that if X is CH then R 4  is —(CH 2 ) m —NR 9 R 10 ; and 
 with the proviso that if X is N and R 4  is —(CH 2 ) m —NR 9 R 10  then m is 2 or 3. 
 
     
     
         4 . The pharmaceutical composition according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group of: 
       
         
           
           
               
               
           
         
       
       wherein R 11  is hydrogen or C 1-7 -alkyl. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
 2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-(4-methylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aR)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-(1,4-diazepan-1-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-(1,4-diazepan-1-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aR)-8a-methyl-1,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-pyrrolidin-1-ylpyrrolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-pyrrolidin-1-ylpyrrolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(3,3-dimethylpiperazin-1-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(3,3-dimethylpiperazin-1-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3 S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R,5 S)-3,5-dimethylpiperazin-1-yl]-9-methyl-pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-(3,3-dimethylpiperazin-1-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3 S,5 S)-3,5-dimethylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3 S)-3-pyrrolidin-1-ylpyrrolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3 S)-3-pyrrolidin-1-ylpyrrolidin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-[(3 S,5 S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3 S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)-7-[(3R)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-[(3R,5 S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(3,3-dimethylpiperazin-1-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(3 S,5 S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(3R)-3-ethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   and pharmaceutically acceptable salts thereof.   
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
 7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-[(8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-9-methyl-pyrido[1,2-a]pyrimidin-4-one;   7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   7-(4,7-diazaspiro[2.5]octan-7-yl)-9-methyl-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one;   and pharmaceutically acceptable salts thereof.   
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is 7-[(8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-yl]-2-(2-methylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein the compound of formula (I) is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the oral aqueous solution has a pH of less than pH4. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition further comprises a citrate, malate, maleate or tartrate buffer system; or alternatively tartaric acid. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a extragranular filler selected from lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, and combinations thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a diluent selected from lactose, starch, hydrolyzed starch, maltodextrin, microcrystalline cellulose, mannitol, isomalt, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, and combinations thereof. 
     
     
         14 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a diluent selected from lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, and combinations thereof. 
     
     
         15 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a preservative, stabilizer or antioxidants selected from vitamin A, vitamin C, vitamin E, vitamin E TPGS, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, disodium edetate, butyl hydroxyl toluol, riboflavin, ascorbic acid and combinations thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a preservative selected from sorbic acid and sodium benzoate. 
     
     
         17 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises an antioxidant selected from ascorbic acid. 
     
     
         18 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a stabilizer selected from disodium ethylenediaminetetraacetate. 
     
     
         19 . The pharmaceutical composition according to  claim 1 , wherein the composition further comprises a lubricant selected from poly(ethylene glycol). 
     
     
         20 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises:
 1 to 10% wt of a compound of formula (I) or a pharmaceutically acceptable salt thereof;   5 to 15% wt of a buffer system or alternatively the corresponding acid of a buffer system alone;   40 to 70% wt of a diluent;   1 to 4% wt of an antioxidant;   0.5 to 2% wt of a stabilizer;   0.5 to 2% w of a lubricant;   1 to 8% wt of a preservative,   0 to 3% wt of a sweetener; and   0 to 20% wt of a flavor; and   wherein the total amount of ingredients does not exceed 100% wt.   
     
     
         21 . The pharmaceutical composition according to  claim 1 , wherein the composition comprises:
 1 to 10% wt of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one or a pharmaceutically acceptable salt thereof;   5 to 15% wt of a buffer system selected from citrate, malate, maleate or tartrate or alternatively tartaric acid alone;   40 to 70% wt of a diluent selected from mannitol or a mixture of mannitol and isomalt;   1 to 4% wt of ascorbic acid;   0.5 to 2% wt of disodium edetate;   0.5 to 2% w of PEG6000;   1 to 8% wt of a preservative selected from sorbic acid or sodium benzoate,   0 to 3% wt of a sweetener selected from sucralose or sodium saccharin; and   0 to 20% wt of a flavor selected from strawberry flavor or vanilla flavor; and   wherein the total amount of ingredients does not exceed 100% wt.   
     
     
         22 . The pharmaceutical composition according to  claim 1 , wherein the composition is an oral aqueous solution. 
     
     
         23 . The pharmaceutical composition according to  claim 1 , wherein the composition is dry powder suitable for constitution of an oral aqueous solution. 
     
     
         24 . A kit for the preparation of pharmaceutical compositions comprising the dry powder of  claim 23  and water as solvent for constitution. 
     
     
         25 .- 29 . (canceled) 
     
     
         30 . A pharmaceutical composition according to  claim 1  further comprising olesoxime. 
     
     
         31 . The pharmaceutical composition according to  claim 30  further comprising an oil selected from sesame oil, olive oil, soya oil, cotton oil, castor oil, nut oil, rapeseed oil, corn oil, almond oil, sunflower oil, and combinations thereof. 
     
     
         32 . The pharmaceutical composition according to  claim 31  further comprising an emulsifying and/or lipophilic solubilizing agent selected from glyceryl mono-oleate, glyceryl mono-linoleate, sorbitan mono-oleate, oleic acid, and combinations thereof; and optionally a polar surfactant. 
     
     
         33 . The pharmaceutical composition according to  claim 33  wherein the polar surfactant is selected from polysorbate 80, caprylocaproyl polyoxyl glycerides, and combinations thereof. 
     
     
         34 . A kit for the preparation of pharmaceutical compositions comprising:
 a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof;   a powder blend as vehicle suitable for constitution of the compound of formula (I) or a pharmaceutically acceptable salt thereof;   optionally water as solvent for constitution;   olesoxime;   an oil;   an emulsifying and/or lipophilic solubilizing agents; and   optionally a polar surfactant.   
     
     
         35 .- 36 . (canceled) 
     
     
         37 . A method for the treatment, prevention, delaying progression and/or amelioration of diseases caused by an inactivating mutation or deletion in the SMN1 gene and/or associated with loss or defect of SMN1 gene function, which method comprises administering a pharmaceutical composition according to  claim 1  to a subject. 
     
     
         38 .- 51 . (canceled) 
     
     
         52 . A method for the treatment, prevention, delaying progression and/or amelioration of diseases caused by an inactivating mutation or deletion in the SMN1 gene and/or associated with loss or defect of SMN1 gene function, and/or for the protection of cells implicated in the pathophysiology of the disease, which method comprises administering a combination of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof and olesoxime to a subject. 
     
     
         53 .- 57 . (canceled)