Cyclopropyl amide derivatives

Abstract

Disclosed herein is at least one cyclopropyl amide derivative, at least one pharmaceutical composition comprising at least one cyclopropyl amide derivative disclosed herein, and at least one method of using at least one cyclopropyl amide derivative disclosed herein for treating at least one histamine H3 receptor associated condition therewith.

1 - 28 . (canceled) 
     
     
         29 . A method for treating a disorder selected from cognitive deficits in schizophrenia, Alzheimer's disease, obesity, narcolepsy, pain, and attention deficit hyperactivity disorder, in a warm-blooded animal, comprising administering to said animal in need of such treatment a therapeutically effective amount of at least one compound of formula I, or enantiomers or diastereomers thereof, or pharmaceutically acceptable salts of formula I or enantiomers or diastereomers thereof, or mixtures thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is aryl, heteroaryl, —C 1 -C 6 alkyl-C 1 -C 3 alkoxy, —C 1 -C 6 alkyl-hydroxy, —C 1 -C 6 alkyl-C(═O)—NR 11 R 12 , —S(═O) 2 NR 11 R 12 , heterocycle, cyano, haloalkyl, —C(═O)NR 11 R 12 , alkoxy, or halogen; 
 R 2  is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; 
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H and C 1 -C 3 alkyl; and 
 R 11  and R 12  are each independently selected from H, —C 1 -C 6 alkyl, —C 1 -C 3 alkyl-C 1 -C 3 alkoxy, 5-membered heterocycloalkyl containing at least one heteroatom selected from O and N, 6-membered heterocycloalkyl containing at least one heteroatom selected from O and N, —(C 1 -C 3 alkyl)-(5-membered heteroaryl containing at least one heteroatom selected from O and N), —(C 1 -C 3 alkyl)-(6-membered heteroaryl containing at least one heteroatom selected from O and N), haloalkyl, or R 11 , R 12  and the N to which they are attached come together to form a heterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, wherein said heterocycloalkyl is optionally substituted by at least one substituent selected from —C 1 -C 3 alkyl and —C 1 -C 6 alkyl-C 1 -C 3 alkoxy; and 
 provided:
 i) at least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is a C 1 -C 3 alkyl; 
 ii) formula I is not 
 
 
       
         
           
           
               
               
           
         
         
            when R 1  is a —C(═O)NR 11 R 12  group meta-attached to the phenyl, R 2  is isopropyl, and R 11  and R 12  are H; and 
           iii) formula I is not in the cis configuration at the cyclopropane. 
         
       
     
     
         30 . The method according to  claim 29 , wherein said disorder is pain. 
     
     
         31 . The method according to  claim 30 , wherein said pain is peripheral neuropathic pain. 
     
     
         32 . The method according to  claim 29 , wherein R 1  is —C(═O)NR 11 R 12 . 
     
     
         33 . The method according to  claim 32 , wherein R 11  and R 12  are H. 
     
     
         34 . The method according to  claim 29 , wherein R 2  is C 1 -C 3 alkyl. 
     
     
         35 . The method according to  claim 29 , wherein R 2  is C 3 -C 6 cycloalkyl. 
     
     
         36 . The method according to  claim 29 , wherein R 2  is isopropyl or cyclobutyl. 
     
     
         37 . The method according to  claim 29 , wherein R 3  is C 1 -C 3 alkyl and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         38 . The method according to  claim 37 , wherein R 3  is methyl. 
     
     
         39 . The method according to  claim 29 , wherein R 4  is C 1 -C 3 alkyl and R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         40 . The method according to  claim 39 , wherein R 4  is methyl. 
     
     
         41 . The method according to  claim 29 , wherein R 5  is C 1 -C 3 alkyl and R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         42 . The method according to  claim 41 , wherein R 5  is methyl or ethyl. 
     
     
         43 . The method according to  claim 29 , wherein R 6  is C 1 -C 3 alkyl and R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         44 . The method according to  claim 43 , wherein R 6  is methyl or ethyl. 
     
     
         45 . The method according to  claim 29 , wherein R 3  and R 4  are each independently selected from C 1 -C 3 alkyl and R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         46 . The method according to  claim 29 , wherein R 5  and R 6  are each independently selected from C 1 -C 3 alkyl and R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are each independently selected from H. 
     
     
         47 . The method according to  claim 29 , wherein said compound is selected from:
 4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((S)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   4-(trans-2-(4-cyclobutyl-2,2-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomeric mixture;   4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomeric mixture;   4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 1;   4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 2;   3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2;   3-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide; and   3-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture; and   pharmaceutically acceptable salts thereof or mixtures thereof.   
     
     
         48 . The method according to  claim 29 , wherein said compound is selected from the group consisting of:
 4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, diastereomeric mixture;   4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 1;   4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide, isomer 2; and   pharmaceutically acceptable salts thereof.   
     
     
         49 . The method according to  claim 29 , wherein said compound is 4-{(1S,2S)-2-[((R)-4-cyclobutyl-2-methylpiperazin-1-yl)carbonyl]cyclopropyl}-benzamide, which has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         50 . The method according to  claim 29 , wherein said compound is administered with a pharmaceutically acceptable carrier and/or diluent.