Non-imidazole aryloxyalkylamines

Abstract

Substituted aryloxyalkylamines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

1 - 53 . (canceled) 
   
   
       54 . A method of treating dementia, mild cognitive impairment (pre-dementia), cognitive dysfunction, schizophrenia, depression manic disorders, bipolar disorders, and learning and memory disorders in a subject, comprising administering an effective amount of a compound of formula I to a subject in need of such treatment: 
     
       
         
         
             
             
         
       
       wherein R a  and R b  are independently C 1-8  alkyl, C 3-8  alkenyl, C 3-8  cycloakyl, (C 3-8  cycloalkyl) C 1-6  alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms; 
       n is 0-4; 
       one of R 1 , R 2  and R 3  is G, and the remaining two are hydrogen or halo; 
       G is a nitrogen-containing group selected from one of the following: 
       —OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 , 
     
     
       
         
         
             
             
         
       
       wherein: 
       L 1  is C 2-6  alkylene, C 3-8  cycloalkylene, C 4-6  alkenylene, C 4-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthyl)C 1-6  alkylene, (C 2-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, or (C 2-5  heteroaryoxy)C 1-6  alkylene; 
       L 2  is C 1-6  alkylene, C 3-8  cycloalkylene, C 3-6  alkenylene, C 3-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthylC 1-6  alkylene, (C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or (C 1-5  heteroarylthio)C 1-6  alkylene; 
       L 3  is C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, phenyl, naphthyl, (naphthl)C 1-6  alkylene, C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or C 2-5  heteroaryl; 
       L 4  is C 1-5  alkylene; 
       L 5 is C 1-5  alkylene; 
       L 6  is C 1-5  alkylene; 
       L 7  is C 1-5  alkylene or absent; 
       Q is —NR 8 R 9  or a non-aromatic C 2-15  heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring; 
       each of R 5  and R 6  is independently selected from hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, and (C 2-7  heterocyclyl)C 1-6  alkylene; 
       R 7  is H, hydroxyl halo, C 2-6  alkoxy or absent where the carbon linking L 6  and L 7  (or bonded to R 6 ) participates in a double bond; 
       each of R 8  and R 9  is independently selected from hydrogen, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, phenyl, (C 2-15  heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; 
       R 10  is H, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, (C 2-15  heterocyclyl)C 1-6  alkylene, or (phenyl) C 1-6  alkylene; 
       wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl cycloalkyl and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl and C 1-3  alkyl; 
       wherein substituents of Q can be further selected from carboxamide, C 2-6  alkyl, C 1-8  heterocyclyl, N(C 1-6  alkyl)(C 1-8  heterocyclyl), NH(C 1-8  heterocyclyl), (C 1-8  heterocyclyl) C 1-3  alkylene, O(C 1-8  heterocyclyl), C 1-6  alkoxy, (phenyl)C 3-6  cycloalkyl-O—, phenyl, (phenyl)C 1-3  alkylene, N(C 1-6  alkyl)[(phenyl)C 1-3  alkylene], and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3  alkyl; 
       or a pharmaceutically acceptable salt, ester, or amide thereof. 
     
   
   
       55 - 56 . (canceled) 
   
   
       57 . The method of  claim 54  comprising (a) administering to a subject a jointly effective amount of a histamine H 1  receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of  claim 54 , said method providing a jointly therapeutically effective amount of said compounds. 
   
   
       58 . The method of  claim 57  wherein the histamine H 1  receptor antagonist and the compound of  claim 54 , are present in the same dosage form. 
   
   
       59 . The method of  claim 54  comprising (a) administering to the subject a jointly effective amount of a histamine H 2  receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of  claim 54 , said method providing a jointly therapeutically effective amount of said compounds. 
   
   
       60 . The method of  claim 59  wherein the histamine H 2  receptor antagonist and the compound of  claim 54 , are present in the same dosage form. 
   
   
       61 - 65 . (canceled) 
   
   
       66 . The method of  claim 54 , wherein R a  and R b  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms. 
   
   
       67 . The method of  claim 54 , wherein R 1  is hydrogen or halo, and one of R 2  and R 3  is G and the other is hydrogen or halo. 
   
   
       68 . The method of  claim 67 , wherein R 2  is G. 
   
   
       69 . The method of  claim 67 , wherein R 3  is G. 
   
   
       70 . A method of treating schizophrenia in a subject, comprising administering an effective amount of a compound of formula I to a subject in need of such treatment: 
     
       
         
         
             
             
         
       
       wherein R a  and R b  are independently C 1-8  alkyl, C 3-8  alkenyl, C 3-8  cycloalkyl, (C 3-8  cycloalkyl) C 1-6  alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms; 
       n is 0-4; 
       one of R 1 , R 2 , and R 3  is G, and the remaining two are hydrogen or halo; 
       G is a nitrogen-containing group selected from one of the following: 
       —OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 , 
     
     
       
         
         
             
             
         
       
       wherein: 
       L 1  is C 2-6  alkylene, C 3-8  cycloalkylene, C 4-6  alkenylene, C 4-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthyl)C 1-6  alkylene, (C 2-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, or (C 2-5  heteroaryloxy)C 1-6  alkylene; 
       L 2  is C 1-6  alkylene, C 3-8  cycloalkylene, C 3-6  alkenylene, C 3-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthyl)C 1-6  alkylene, (C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or (C 1-5  heteroarylthio)C 1-6  alkylene; 
       L 3  is C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, phenyl, naphthyl, (naphthyl)C 1-6  alkylene, C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or C 2-5  heteroaryl; 
       L 4  is C 1-5  alkylene; 
       L 5  is C 1-5  alkylene; 
       L 6  is C 1-5  alkylene; 
       L 7  is C 1-5  alkylene or absent; 
       Q is —NR 8 R 9  or a non-aromatic C 2-15  heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring; 
       each of R 5  and R 6  is independently selected from hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, and (C 2-7  heterocyclyl)C 1-6  alkylene; 
       R 7  is H, hydroxyl, halo, C 2-6  alkoxy or absent where the carbon linking L 6  and L 7  (or bonded to R 6 ) participates in a double bond; 
       each of R 8  and R 9  is independently selected from hydrogen, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, phenyl, (C 2-15  heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; 
       R 10  is H, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, (C 2-15  heterocyclyl)C 1-6  alkylene, or (phenyl) C 1-6  alkylene; 
       wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3  alkyl; 
       wherein substituents of Q can be further selected from carboxamide, C 2-6  alkyl, C 1-8  heterocyclyl, N(C 1-6  alkyl)(C 1-8  heterocyclyl), NH(C 1-8  heterocyclyl), (C 1-8  heterocyclyl) C 1-3  alkylene, O(C 1-8  heterocyclyl), C 1-6  alkoxy, (phenyl)C 3-6  cycloalkyl-O—, phenyl, (phenyl) C 1-3  alkylene, N(C 1-6  alkyl)[(phenyl)C 1-3  alkylene], and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3  alkyl; 
       or a pharmaceutically acceptable salt, ester, or amide thereof. 
     
   
   
       71 . The method of  claim 70 , wherein R a  and R b  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms. 
   
   
       72 . The method of  claim 70 , wherein R 1  is hydrogen or halo, and one of R 2  and R 3  is G and the other is hydrogen or halo. 
   
   
       73 . The method of  claim 72 , wherein R 2  is G. 
   
   
       74 . The method of  claim 72 , wherein R 3  is G. 
   
   
       75 . A method of treating depression in a subject, comprising administering an effective amount of a compound of formula I to a subject in need of such treatment: 
     
       
         
         
             
             
         
       
       wherein R a  and R b  are independently C 1-8  alkyl, C 3-8  alkenyl, C 3-8  cycloalkyl, (C 3-8  cycloalkyl) C 1-6  alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms; 
       n is 0-4; 
       one of R 1 , R 2 , and R 3  is G, and the remaining two are hydrogen or halo; 
       G is a nitrogen-containing group selected from one of the following: 
       —OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 , 
     
     
       
         
         
             
             
         
       
       wherein: 
       L 1  is C 2-6  alkylene, C 3-8  cycloalkylene, C 4-6  alkenylene, C 4-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthyl)C 1-6  alkylene, (C 2-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, or (C 2-5  heteroaryloxy)C 1-6  alkylene; 
       L 2  is C 1-6  alkylene, C 3-8  cycloalkylene, C 3-6  alkenylene, C 3-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, (naphthyl)C 1-6  alkylene, (C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or (C 1-5  heteroarylthio)C 1-6  alkylene; 
       L 3  is C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, C 2-5  alkanoyl, (phenyl)C 1-6  alkylene, phenyl, naphthyl, (naphthyl)C 1-6  alkylene, C 1-5  heteroaryl)C 1-6  alkylene, (phenoxy)C 1-6  alkylene, (C 1-5  heteroaryloxy)C 1-6  alkylene, or C 2-5  heteroaryl; 
       L 4  is C 1-5  alkylene; 
       L 5  is C 1-5  alkylene; 
       L 6  is C 1-5  alkylene; 
       L 7  is C 1-5  alkylene or absent; 
       Q is —NR 8 R 9  or a non-aromatic C 2-15  heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring; 
       each of R 5  and R 6  is independently selected from hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, and (C 2-7  heterocyclyl)C 1-6  alkylene; 
       R 7  is H, hydroxyl, halo, C 2-6  alkoxy or absent where the carbon linking L 6  and L 7  (or bonded to R 6 ) participates in a double bond; 
       each of R 8  and R 9  is independently selected from hydrogen, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, C 2-15  heterocyclyl, phenyl, (C 2-15  heterocyclyl)C 1-6  alkylene, and (phenyl) C 1-6  alkylene; 
       R 10  is H, C 1-8  alkyl, C 3-8  alkenyl, C 3-7  cycloalkyl, (C 3-7  cycloalkyl)C 1-6  alkylene, (C 2-15  heterocyclyl)C 1-6  alkylene, or (phenyl) C 1-6  alkylene; 
       wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3  alkyl; 
       wherein substituents of Q can be further selected from carboxamide, C 2-6  alkyl, C 1-8  heterocyclyl, N(C 1-6  alkyl)(C 1-8  heterocyclyl), NH(C 1-8  heterocyclyl), (C 1-8  heterocyclyl) C 1-3  alkylene, O(C 1-8  heterocyclyl), C 1-6  alkoxy, (phenyl)C 3-6  cycloalkyl-O—, phenyl, (phenyl) C 1-3  alkylene, N(C 1-6  alkyl)[(phenyl)C 1-3  alkylene], and (phenyl)C 1-3  alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3  alkyl; 
       or a pharmaceutically acceptable salt, ester, or amide thereof. 
     
   
   
       76 . The method of  claim 75 , wherein R a  and R b  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms. 
   
   
       77 . The method of  claim 75 , wherein R 1  is hydrogen or halo, and one of R 2  and R 3  is G and the other is hydrogen or halo. 
   
   
       78 . The method of  claim 77 , wherein R 2  is G. 
   
   
       79 . The method of  claim 77 , wherein R 3  is G.