Azacyclosteroid histamine-3 receptor ligands

Abstract

Azacyclosteroid histamine-3 receptor ligands, pharmaceutical compositions comprising such compounds, and methods for using such compounds and compositions are described herein.

1 . A method of treating a condition modulated by the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein 
 R 1  is selected from the group consisting of hydrogen, acetyl, alkyl, fluoroalkyl, and cycloalkyl;  
 R 2  and R 3  are each independently selected from the group consisting of hydrogen and alkyl, or R 2  and R 3  taken together form a 3- to 6-membered ring;  
 Ring A of the formula:  
                     
 is selected from the following:  
                     
 wherein:  
 the dotted line represents an optional bond;  
 R 4  and R 5  are each independently selected from the group consisting of hydrogen and fluorine, provided that R 5  is present only when the bond represented by the dotted line is absent;  
 R 6  is selected from the group consisting of hydrogen, alkyl, and fluorine;  
 one of R 7  and R 8  is hydrogen; and the other of R 7  and R 8  is selected from the group consisting of:  
 a) NR 18 R 19 ;  
 b) OR 20 , SR 20 , O(C═O)OR 20 , O(C═O)N(R 20 )(R 21 ), O(C═O)C(R 23 )(R 24 )(R 24b ), or O(C═O)CH(NR 28 R 29 )R 25 ; and  
 c) NR 22 (C═O)R 25 , NR 22 (C═O)NR 26 R 27 , NR 22 (C═O)CH(NR 28 R 29 )R 30 , N(R 22 )(C═O)OR 20 , or NR 22 (C═O)C(OR 23 )R 3 OR 30b ; and  
 d) NR 22 SO 2 R 31  or NR 22 SO 2 N(R 22 )(R 23 );  
 or R 7  and R 8  taken together with the carbon atom to which each is attached forms a group of the formula —C═C(R a )(R b ), wherein R a  and R b  are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl;  
 R 9  and R 10  are each independently selected from the group consisting of hydrogen, halogen, alkyl, and cyano;  
 R 11  and R 12  are each independently selected from the group consisting of hydrogen, heteroaryl, heterocycle, aryl, arylalkyl, aryloxy, arylcarbonyl, arylcarbonyloxy, arylalkoxy, alkylsulfonyl, arylsulfonyl, and trifluoromethylsulfonyl; or one of R 10  and R 11  or R 11  and R 12  taken together with the atoms to which each is attached form a 5- to 6-membered aromatic or heteroaromatic ring;  
 R 13  is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl;  
 R 15  and R 16  taken together with the atom to which each is attached forms a 5- to 6-membered ring optionally substituted with an alkylamino group;  
 R 17  is selected from the group consisting of hydrogen, alkyl, and fluoro;  
 R 18  is hydrogen or C 1 -C 6  alkyl and R 19g  is selected from the group consisting of aryl and heteroaryl, or R 18  and R 19g  at each occurrence is taken together form a 3- to 8-membered heterocycle;  
 R 20  and R 21  at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkyl, aryl, aryloxy, arylalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, and heterocyclealkyl;  
 R 22  at each occurrence is selected from the group consisting of hydrogen and alkyl;  
 R 23  at each occurrence is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl;  
 R 24  and R 24b  are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, and cycloalkyl;  
 R 25  at each occurrence is independently selected from the group consisting of C 1 -C 6  alkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, and heterocyclealkyl;  
 R 26  and R 27  at each occurrence are each independently selected from the group consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or R 26  and R 27  taken together with the nitrogen atom to which each is attached forms an aromatic or non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms in the ring is substituted with a heteroatom selected from O, S, or NR 23 ;  
 R 28  and R 29  at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl, and heterocycle, or R 28  and R 29  taken together with the nitrogen atom to which each is attached forms an aromatic or non-aromatic 5- to 6-membered ring, wherein 0, 1, or 2 carbon atoms in the ring is substituted with a heteroatom selected from O, S, or NR 23 ;  
 R 30  at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, and heterocyclealkyl;  
 R 30b  is selected from the group consisting of hydrogen and alkyl, or when R 30  is alkyl and R 30b  is alkyl, the alkyl groups can be bonded together to form a C 3 -C 4  cycloalkyl group; and  
 R 31  is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl.  
 
     
     
         2 . The method according to  claim 1 , wherein the condition is related to a function in a mammal selected from the group consisting of memory and cognition processes, neurological processes, cardiovascular function, and regulation of blood sugar.  
     
     
         3 . The method according to  claim 1 , wherein the condition is related to memory and cognition processes.  
     
     
         4 . The method according to  claim 1 , wherein the condition is selected from the group consisting of acute myocardial infarction, Alzheimer's disease, asthma, attention-deficit hyperactivity disorder, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, deficits of memory, deficits of learning, dementia, cutaneous carcinoma, drug abuse, diabetes, type II diabetes, depression, epilepsy, gastrointestinal disorders, inflammation, insulin resistance syndrome, jet lag, medullary thyroid carcinoma, melanoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, migraine, mood and attention alteration, motion sickness, narcolepsy, neurogenic inflammation, obesity, obsessive compulsive disorder, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, seizures, septic shock, sleep disorders, Syndrome X, Tourette's syndrome, vertigo, and wakefulness.