Pyrido[3,4-b]indoles and methods of use

Abstract

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[3,4-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

1 - 24 . (canceled) 
     
     
         25 . A compound of formula (E): 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein:
 R 1  is hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, perhaloalkyl, acyloxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8  perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; 
 each R 2a  and R 2b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R 2a  and R 2b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino, cycloalkyl, acylamino or acyloxy or R 3a  and R 3b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; 
 each X 7 , X 8 , X 9  and X 10  is independently CR 4 ; 
 m and q are independently 0 or 1, provided that at least one of m and q is 1; 
 n is 1; 
 each R 4  is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8  perhaloalkyl, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8  perhaloalkoxy, C 1 -C 8  alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; 
 each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f)  and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f)  to form a bond, provided that when an R 8(a-f)  is taken together with a vicinal R 8  to form a bond, the geminal R 8(a-f)  is other than hydroxyl; 
 each R 10a  and R 10b  is independently H, halo, a substituted or unsubstituted C 1 -C 8  alkyl, hydroxyl, alkoxyl, cyano or nitro, or R 10a  and R 10b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; and 
 Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl, 
 provided that the compound is other than a compound selected from the group consisting of compounds: 2H-pyrido[3,4-b]indole-2-carboxamide, 1,3,4,9-tetrahydro-N-1H-indazol-3-yl-9-(2-methoxyethyl)-(Compound 295z), 9H-pyrido[3,4-b]indole-9-acetic acid, 1,2,3,4-tetrahydro-2-[[(3-methylphenyl)amino]carbonyl]-, 1,1-dimethylethyl ester (Compound 317z), (S)-2-((S)-4-amino-2-(16-((2S,3S)-1-(2-carbamoyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-3-methyl-1-oxopentan-2-ylamino)-16-oxohexadecanamido)-4-oxobutanamido)-3-phenylpropanoic acid (Compound 691z), 9H-pyrido[3,4-b]indole-9-acetic acid, 1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-, methyl ester (Compound 153x), 9H-pyrido[3,4-b]indole-9-acetamide, 1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-(Compound 309x), 1H-pyrido[3,4-b]indole, 9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6-methoxy-2-methyl-(Compound 320x), 9H-pyrido[3,4-b]indole-9-propanamine, 1,2,3,4-tetrahydro-N,N-dimethyl-2-[3-(4-pyridinyl)propyl]-(Compound 339x), 9H-pyrido[3,4-b]indole-9-propanamine, 1,2,3,4-tetrahydro-N,N-dimethyl-2-[3-(3-pyridinyl)propyl]-(Compound 569x), 1H-pyrido[3,4-b]indole, 2-benzyl-9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6-methoxy-(Compound 599x), 1H-pyrido[3,4-b]indole, 9-(2-dimethylaminoethyl)-2,3,4,9-tetrahydro-1,2-dimethyl-(Compound 601x), 9H-Pyrido[3,4-b]indole-9-acetamide, 1,2,3,4-tetrahydro-N,N-dimethyl-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-(Compound 793x), 1H-pyrido[3,4-b]indole-2,9-dipropanenitrile,3,4-dihydro-7-methoxy-1-methyl-(Compound 497z), and 9H-pyrido[3,4-b]indole-9-propanenitrile,2-(2,5-dioxo-1-phenyl-3-pyrrolidinyl)-1,2,3,4-tetrahydro-(Compound 732z); and salts thereof. 
 
       
     
     
         26 . The compound of  claim 25 , or a salt thereof, wherein R 1  is hydroxyl, nitro, cyano, halo, unsubstituted or substituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, perhaloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8  perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy,
 provided that (a) when R 1  is CH 3 , either (i) Q is other than —N(CH 3 ) 2 , or (ii) X 9  is CR 4 , wherein R 4  is other than OCH 3 , and R 3a  and R 3b  are both H; and   (b) when R 1  is substituted C 1 -C 8  alkyl, then Q is other than unsubstituted amino and —N(CH 3 ) 2 .   
     
     
         27 . The compound of  claim 25 , or a salt thereof, wherein Q is aminoacyl. 
     
     
         28 . The compound of  claim 27 , or a salt thereof, wherein Q is aminoacyl of the formula —NR a C(O)R b  where R a  is H or alkyl and R b  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. 
     
     
         29 . The compound of  claim 28 , or a salt thereof, wherein R a  is H. 
     
     
         30 . The compound of  claim 29 , or a salt thereof, wherein R b  is unsubstituted or substituted heteroaryl. 
     
     
         31 . The compound of  claim 25 , or a salt thereof, wherein q is 0, and m is 1. 
     
     
         32 . The compound of  claim 25 , or a salt thereof, wherein R 1  is substituted or unsubstituted C 1 -C 8  alkyl. 
     
     
         33 . The compound of  claim 32 , or a salt thereof, wherein R 1  is methyl. 
     
     
         34 . The compound of  claim 25 , or a salt thereof, wherein each R 4  is independently H, halo, substituted or unsubstituted C 1 -C 8  alkyl, or perhaloalkyl. 
     
     
         35 . The compound of  claim 25 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, or halo. 
     
     
         36 . The compound of  claim 35 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H. 
     
     
         37 . The compound of  claim 25 , or a salt thereof, wherein:
 each R 2a  and R 2b  is independently H, unsubstituted C 1 -C 8  alkyl, halo or R 2a  and R 2b  are taken together to form a carbonyl moiety; and   each R 3a  and R 3b  is independently H, unsubstituted C 1 -C 8  alkyl, halo.   
     
     
         38 . The compound of  claim 25 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, unsubstituted C 1 -C 4  alkyl, is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a carbonyl moiety or is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene. 
     
     
         39 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8a , R 8d , R 8e  and R 8f , where present, is hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety. 
     
     
         40 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f)  and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f)  to form a bond, provided that when an R 8(a-f)  is taken together with a vicinal R 8  to form a bond, the geminal R 8(a-f)  is other than hydroxyl. 
     
     
         41 . The compound of  claim 25 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is H. 
     
     
         42 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         43 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         44 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8e  and R 8f  is other than H. 
     
     
         45 . The compound of  claim 25 , or a salt thereof, wherein:
 R 1  is unsubstituted alkyl;   each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H; and   each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety.   
     
     
         46 . The compound of  claim 45 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is H. 
     
     
         47 . The compound of  claim 45 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         48 . The compound of  claim 45 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         49 . The compound of  claim 45 , or a salt thereof, wherein at least one of R 8e  and R 8f  is other than H. 
     
     
         50 . The compound of  claim 45 , wherein Q is aminoacyl. 
     
     
         51 . The compound of  claim 50 , or a salt thereof, wherein Q is aminoacyl of the formula —NR a C(O)R b  where R a  is H or alkyl and R b  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. 
     
     
         52 . The compound of  claim 51 , or a salt thereof, wherein R a  is H. 
     
     
         53 . The compound of  claim 52 , or a salt thereof, wherein R b  is unsubstituted or substituted heteroaryl. 
     
     
         54 . The compound of  claim 45 , or a salt thereof, wherein each R 4  is independently H, halo, substituted or unsubstituted C 1 -C 8  alkyl, or perhaloalkyl. 
     
     
         55 . A pharmaceutical composition comprising a compound according to  claim 25  or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         56 . A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to  claim 25  or a salt thereof. 
     
     
         57 . A kit comprising a compound according to  claim 25  or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder. 
     
     
         58 . A pharmaceutical composition comprising a compound according to  claim 45  or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         59 . A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to  claim 45  or a salt thereof. 
     
     
         60 . A kit comprising a compound according to  claim 45  or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.