Spirocyclic azaadamantane derivatives and methods of use

Abstract

The invention relates to compounds that are spirocyclic azaadamantane derivatives, particularly spirocyclic azaadamantanyl ether or amine derivatives, compositions comprising such compounds, methods of using such compounds and compositions, processes for preparing such compounds, and intermediates obtained during such processes.

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein 
         A is N or N + —O − ; 
         X 1  is CR x1  or N; 
         X 2  is CR x2  or N; 
         X 3  is CR x3  or N; 
         X 4  is CR x4  or N; 
         L 1  and L 2  are each independently —O—, —NR b ; —R c C═O, or C 1 -C 3  alkyl; 
         R x1 , R x2 , R x3 , and R x4  are each independently H, alkyl, aryl, cyclic alkyl, halogen, halo alkyl, heteroaryl, OR b , NR d R e , COR b , CN, CO 2 R b , or CONR d R e ; 
         R b , R d , and R e  are independently H, alkyl, aryl, alkylcarbonyl, alkoxylcarbonyl, or heteroaryl; and 
         R c  is absent or R c  is —O—, or —NR b . 
       
     
     
         2 . The compound according to  claim 1 , have the formula (II), (III), or (IV); 
       
         
           
           
               
               
           
         
         wherein R x1 , R x2 , R x3 , and R x4  are each independently H, alkyl, aryl, cyclic alkyl, halogen, halo alkyl, heteroaryl, OR b , NR d R e , COR b , CN, CO 2 R b , or CONR d R e . 
       
     
     
         3 . The compound according to  claim 2 , wherein L 1  is selected from O and NR b . 
     
     
         4 . The compound according to  claim 3 , wherein L 2  is CH 2 , O, or NR b . 
     
     
         5 . The compound according to  claim 4 , wherein R x1 , R x2 , R x3 , and R x4  are each independently H, alkyl, aryl, halogen, heteroaryl, OR b , or NR d R e . 
     
     
         6 . The compound according to  claim 5 , wherein at least one R x1 , R x2 , R x3 , and R x4  is 
       
         
           
           
               
               
           
         
         wherein 
         X 5  is CR x5  or N; 
         X 6  is CR x6  or N; 
         X 7  is CR x7  or N; 
         X 8  is CR x8  or N; 
         X 9  is CR x9  or N; 
         X 10  is CR x10  or N; 
         Y 1  is CR y1 , N; O, or S; 
         Y 2  is CR y2 , N; O, or S; 
         Y 3  is CR y3 , N; O, or S; 
         Y 4  is CR y4 , N; O, or S; 
         Y 5  is CR y5 , N; O, or S; 
         R x5 , R x6 , R x7 , R x8 , R x9 , and R x10  are each independently H, alkyl, aryl, cycloalkyl, halogen, halo alkyl, heteroaryl, OR b , NR d R e , COR b , CN, CO 2 R b , or CONR d R e ; 
         R y1 , R y2 , R y3  and R y4  are each independently H, alkyl, aryl, cycloalkyl, halogen, halo alkyl, heteroaryl, OR b , NR d R e , COR b , CN, CO 2 R b , or CONR d R e ; and 
         R y5  is H, alkyl, aryl, alkylcarbonyl, alkoxylcarbonyl, or heteroaryl. 
       
     
     
         7 . The compound according to  claim 6 , wherein,
 one of R x2  or R x3  is   
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 7 , wherein
 L 1  is —O—; and   L 2  is —CH 2 —.   
     
     
         9 . The compound according to  claim 7 , wherein
 L 1  is —NR b —; and   L 2  is —CH 2 —.   
     
     
         10 . The compound according to  claim 8 , wherein
 one of R x2  or R x3  is   
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 10 , wherein R b  is H. 
     
     
         12 . A compound of  claim 2 , wherein the compound is
 3H-(4′s)-1′-azaspiro[benzofuran-2,4′]tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′s)-1′-azaspiro[5-bromobenzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′s)-1′-azaspiro[5-phenylbenzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′s)-1′-azaspiro[5-(indol-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′s)-1′-azaspiro[5-(indol-6-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′s)-1′-azaspiro[5-(indol-4-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1″]decane;   3H-(4′r)-1′-azaspiro[benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-bromobenzofuran-2,4′]tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-phenylbenzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(indol-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(benzo[b]thiophen-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(indol-4-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(2-oxo-indolin-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(thiophen-3-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane;   3H-(4′r)-1′-azaspiro[5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane; or   3H-(4′r)-1′-azaspiro[5-(thieno[2,3-b]pyridin-5-yl)-benzofuran-2,4′]-tricyclo[3.3.1.1 3,7 ]decane.   
     
     
         13 . A method for treating or preventing conditions, disorders, or deficits modulated by an α7 nicotinic acetylcholine receptor, an α4β2 nicotinic acetylcholine receptor or both α7 and α4β2 nicotinic acetylcholine receptor wherein the condition, disorder or deficit is selected from memory disorder, cognitive disorder, neurodegeneration, and neurodevelopmental disorder, or a combination thereof, comprising administration of a therapeutically suitable amount of a compound of formula (I). 
     
     
         14 . The method according to  claim 13 , wherein the condition, disorder, or deficit is selected from attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, schizophrenia, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, smoking cessation, schizoaffective disorder, bipolar and manic disorders, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, or a combination thereof. 
     
     
         15 . The method according to  claim 13 , wherein the condition, disorder, or deficit is cognitive deficits associated with attention deficit disorder, hyperactivity disorder, schizophrenia, Alzheimer's disease, mild cognitive impairment, age-associated memory impairment, or a combination thereof. 
     
     
         16 . The method according to  claim 13 , further comprising administering a compound of formula (I) in combination with an atypical antipsychotic. 
     
     
         17 . The method according to  claim 13 , wherein progression of the condition, disorder, or deficit is improved by altering disease modifying processes implicated in neurodegenerative diseases. 
     
     
         18 . The method according to  claim 13 , wherein the condition, disorder, or deficit is selected from infertility, lack of circulation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, ischemia, inflammation, arthritis and related disorders, wound healing, and complications associated with diabetes.