Sub-type selective amides of diazabicycloalkanes

Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are amide compounds which can be prepared from certain heteroaryl carboxylic acids and certain diazabicycloalkanes. The compounds exhibit selectivity for, and bind with high affinity to, neuronal nicotinic receptors of the α4β2 subtype in the central nervous system (CNS). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly CNS disorders. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects, and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g. side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastrointestinal tract, and significant effects upon skeletal muscle).

1 . A method of synthesizing compounds represented as Formula I: 
       
         
           
           
               
               
           
         
         wherein n has the value of 0 or 1, and Cy is a heteroaryl group chosen from the group of 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl and 4-pyridinyl, which heteroaryl groups are optionally substituted with up to three non-hydrogen substituents independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, C 2-6  alkenyl, substituted C 2-6  alkenyl, C 2-6  alkynyl, substituted C 2-6  alkynyl, C 3-8  heterocyclyl, substituted C 3-8  heterocyclyl, C 3-8  cycloalkyl, substituted C 3-8  cycloalkyl, C 5-10  aryl, C 5-10  heteroaryl, substituted C 5-10  aryl, substituted C 5-10  heteroaryl, C 1-6  alkyl-C 5-10  aryl, C 1-6  alkyl-C 5-10  heteroaryl, substituted C 1-6  alkyl-C 5-10  aryl, substituted C 1-6  alkyl-C 5-10  heteroaryl, C 5-10  aryl-C 1-6  alkyl, C 5-10  heteroaryl-C 1-6  alkyl, substituted C 5-10  aryl-C 1-6  alkyl, substituted C 5-10  heteroaryl-C 1-6  alkyl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are independently selected from hydrogen, C 1-6  alkyl, C 3-8  cycloalkyl, C 3-8  heterocyclyl, C 5-10  aryl, C 5-10  heteroaryl or C 5-10  aryl-C 1-6  alkyl, or R′ and R″ and the atoms to which they are attached together can form a C 3-8  heterocyclic ring, wherein the term “substituted”, as applied to alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, arylalkyl and heteroarylalkyl, refers to substitution by one or more alkyl, aryl, heteroaryl, halo, —OR′ and —NR′R″ groups, or pharmaceutically acceptable salts thereof, comprising coupling a mono-protected diazabicycle in which one of the two amine functional groups is rendered un-reactive by suitable derivatization with a suitably functionalized heteroaryl acid chloride or other reactive carboxylic acid derivative. 
       
     
     
         2 . The method according to  claim 1 , wherein:
 n has the value of 0 or 1, and Cy is a C 5-10  heteroaryl group chosen from the group of 2-furanyl or 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl and 4-pyridinyl, which heteroaryl groups are optionally substituted with up to three non-hydrogen substituents independently selected from C 1-6  alkyl, substituted C 1-6  alkyl, halo, and C 2-6  alkynyl substituted with phenyl.   
     
     
         3 . The method according to  claim 1 , wherein n is 0. 
     
     
         4 . The method according to  claim 1 , wherein n is O and Cy is 2-furanyl. 
     
     
         5 . The method according to  claim 1 , wherein Cy is 2-furanyl substituted with halo. 
     
     
         6 . The method according to  claim 1 , wherein the compound prepared is selected from the group consisting of:
 N-(furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(3-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(5-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(3-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(3-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(5-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(4-phenylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(5-(2-pyridinyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(5-(phenylethynyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(furan-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(oxazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(oxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(oxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isoxazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isoxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(3-bromoisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(3-methoxyisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,2,4-oxadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,2,4-oxadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,3,4-oxadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(thiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(thiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(thiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isothiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isothiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(isothiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,2,4-thiadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,2,4-thiadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(1,3,4-thiadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane,   N-(pyridin-4-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, and pharmaceutically acceptable salts thereof.   
     
     
         7 . The method according to  claim 1 , wherein the compound prepared is selected from the group consisting of:
 N-(furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(3-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(5-methylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(3-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(3-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(5-bromofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(4-phenylfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(5-(2-pyridinyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(5-(phenylethynyl)furan-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(furan-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(oxazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(oxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(oxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isoxazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isoxazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(3-bromoisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(3-methoxyisoxazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,2,4-oxadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,2,4-oxadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,3,4-oxadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(thiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(thiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(thiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isothiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isothiazol-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(isothiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,2,4-thiadiazol-3-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,2,4-thiadiazol-5-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(1,3,4-thiadiazol-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane,   N-(pyridin-4-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane, and pharmaceutically acceptable salts thereof.   
     
     
         8 . The method according to  claim 1 , wherein the compound prepared is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, or pharmaceutically acceptable salts thereof. 
     
     
         9 . The method according to  claim 1 , wherein the compound prepared is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.1]nonane, or pharmaceutically acceptable salts thereof.