Guanidinylamino heterocycle compounds useful as alpha-2 adrenoceptor agonists

Abstract

This invention involves compounds having the following structure: as described in the Claims; and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters thereof, as well as pharmaceutical compositions comprising such novel compounds. The invention also relates to the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.

What is claimed is:  
     
         1 . A compound of formula;  
       
         
           
           
               
               
           
         
       
       wherein; 
 a) R 1  is hydrogen; or alkyl or nil; where R 1  is nil, bond (a) is a double bond;  
 b) D is CR 2  where R 2  is selected from hydrogen; unsubstituted C 1 -C 3  alkanyl; amino, hydroxy, mercapto; C 1 -C 3  alkylthio or alkoxy; C 1 -C 3  alkylamino or C 1 -C 3  dialkylamino and halo; or when B is CR 3 , D may be N;  
 c) B is NR 9 , CR 3 ═CR 8 , CR 3 ═N, CR 3 , S, O, SO or SO 2 ; wherein R 9  is selected from hydrogen; and unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; and wherein R 3  and R 8  are each independently selected from hydrogen; unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3  alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C 1  -C 3  alkylamino or C 1 -C 3  dialkylamino and halo;  
 d) R 4 , R 5  and R 6  are each independently selected from hydrogen; unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3  alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C 1 -C 3  alkylamino or C 1 -C 3  dialkylamino; halo; and NH—NH—C(═NR 10 )NHR 11  (guanidinylamino); wherein R 10  and R 11  are independently selected from hydrogen; methyl; and ethyl; and wherein one and only one of R 4 , R 5  and R 6  is guanidinylamino;  
 e) R 7  is selected from hydrogen; unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C 1 -C 3  alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C 1 -C 3  alkylamino or C 1 -C 3  dialkylamino and halo;  
 and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters, and pharmaceutical compositions containing such novel compounds, and the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.  
 
     
     
         2 . A compound according to  claim 1  wherein R 6  is guanidinylamino and R 11  is hydrogen.  
     
     
         3 . A compound according to  claim 2  wherein B is CR 3 ═CR 8 , R 1  is nil and D is CR 2 .  
     
     
         4 . A compound according to  claim 3  wherein: 
 R 2 , R 3 , and R 8  are hydrogen.  
 R 4  is selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano;  
 R 5  is hydrogen;  
 R 7  is selected from methyl, chloro, and bromo; and  
 R 10  is selected from hydrogen, and methyl.  
 
     
     
         5 . A compound according to  claim 2  wherein B is NR 9  and D is CR 2 .  
     
     
         6 . A compound according to  claim 5  wherein 
 R 2 , R 9  and R 10  are each independently chosen from hydrogen and methyl;  
 R 4  is selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano;  
 R 5  is hydrogen; and  
 R 7  is selected from methyl, chloro, and bromo.  
 
     
     
         7 . A compound according to  claim 2  wherein B is S and D is CR 2 , and R 1  is nil.  
     
     
         8 . A compound according to  claim 7  wherein 
 R 2  and R 10  are each independently chosen from hydrogen and methyl; R 4  is selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano;  
 R 5  is hydrogen; and  
 R 7  is selected from hydrogen, methyl, chloro, and bromo.  
 
     
     
         9 . The compound according to  claim 2 , wherein: 
 R 4  is selected from hydrogen; unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; unsubstituted C 1 -C 3  alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; and C 1 -C 2  alkylamino or C 1 -C 2  dialkylamino and halo;    R 5  is hydrogen; and    R 7  is selected from hydrogen; unsubstituted C 1 -C 3  alkanyl, alkenyl or alkynyl; unsubstituted C 1 -C 3  alkylthio or alkoxy; and C 1 -C 2  alkylamino or C 1 -C 2  dialkylamino; and halo.    
     
     
         10 . The compound according to  claim 1 , wherein R 5  is guanidinylamino and R 11  is hydrogen.  
     
     
         11 . A compound according to  claim 10  wherein B is CR 3 ═CR 8 , R 1  is nil and D is CR 2 .  
     
     
         12 . A compound according to  claim 11  wherein: 
 R 2  is hydrogen;  
 R 3  is selected from methyl, bromo, fluoro or hydrogen;  
 R 4  is selected from methyl, chloro and bromo;  
 R 7  is selected from methyl, chloro, bromo, cyano, and methoxy;  
 R 8  is selected from methyl, bromo, chloro, fluoro, cyano, methoxy or hydrogen; and  
 R 10  is selected from hydrogen and methyl.  
 
     
     
         13 . A compound according to  claim 10  wherein B is S and D is CR 2  and R 1  is nil.  
     
     
         14 . A compound according to  claim 13  wherein 
 R 2  and R 10  are each independently selected from hydrogen and methyl;  
 R 4  is selected from methyl, chloro, and bromo;  
 R 6  is hydrogen; and  
 R 7  is selected from hydrogen, methyl, methoxy, fluoro, chloro, bromo and cyano.  
 
     
     
         15 . The compound according to  claim 1 , wherein R 4  is guanidinylamino and R 11  is hydrogen.  
     
     
         16  The compound of  claim 15  wherein B is chosen from NR 9 , CR 3 ═CR 8  and S.  
     
     
         17 . The compound according to  claim 16 , wherein: 
 R 5 , R 6  and R 7  are each independently selected from hydrogen; methyl; ethyl; methoxy; methylthio; hydroxy; thio; cyano; amino and halo; and    R 2  is hydrogen.    
     
     
         18 . The compound according to  claim 1 , wherein the compound is: 
 [(8-Methylquinolin-7-yl)amino]guanidine; or    [(4-Methylbenzimidazol-5-yl)amino]guanidine.    
     
     
         19 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of any of claims  1 ,  2 ,  10 ,  15  or  18 ; and    (b) a pharmaceutically-acceptable carrier.    
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 1  and one or more actives chosen from the group consisting of an antihistamine, antitussive, mast cell stabilizer, leukotriene antagonist, expectorant/mucolytic, antioxidant or radical inhibitor, steroid, bronchodilator, antiviral, analgesic, antiinflammatory, gastrointestinal and ocular active.  
     
     
         21 . A pharmaceutical composition according to  claim 19  further comprising an antihistamine.  
     
     
         22 . A pharmaceutical composition according to  claim 19  further comprising an antiinflammatory.  
     
     
         23 . A method for preventing or treating a disorder modulated by alpha-2 adrenoceptors, by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoceptor agonist compound according to  claim 1 .  
     
     
         24 . A method for preventing or treating a disorder modulated by alpha-2 adrenoceptors, wherein the disorder is chosen from the groups comprising, nasal congestion, otitis media, sinusitis, asthma, pain, migraine, substance abuse and addiction, gastrointestinal disorder, ulcer, stomach hyperacidity, benign prostatic hypertrophy, by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoceptor agonist compound according to  claim 1 .  
     
     
         25 . A method of treating or preventing nasal congestion by administering to a mammal in need of such treatment a safe and effective amount of a compound according to  claim 1 .  
     
     
         26 . A method of treating or preventing nasal congestion by administering to a mammal in need of such treatment a safe and effective amount of a compound according to  claim 18 .  
     
     
         27 . The method of  claim 24 , wherein the disorder is otitis media.  
     
     
         28 . The method of  claim 24 , wherein the disorder is sinusitis.  
     
     
         29 . A method for preventing or treating a respiratory disorder, wherein the disorder is chosen from the group comprising cough, chronic obstructive pulmonary disease and asthma, by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to  claim 1 .  
     
     
         30 . A method for preventing or treating a respiratory disorder according to  claim 29 , wherein the disorder is asthma.  
     
     
         31 . A method for preventing or treating disorders mediated by sympathetic activity and modulated by alpha-2 adrenoceptors by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoceptor agonist compound according to  claim 1 .  
     
     
         32 . A method of treating a disorder according to  claim 31 , wherein the disorder is chosen from the group comprising benign prostatic hypertrophy, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.  
     
     
         33  The method of  claim 32 , wherein the disorder is heart failure.  
     
     
         34 . A method for preventing or treating an ocular disorder modulated by alpha-2 adrenoceptors, by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to  claim 1 .  
     
     
         35 . A method for preventing or treating an ocular disorder according to  claim 34  wherein the disorder is chosen from the group comprising ocular hypertension, glaucoma, hyperemia, conjunctivitis, and uveitis and glaucoma.  
     
     
         36 . A method for preventing or treating an ocular hypertensive disorder according to  claim 35  wherein the disorder is glaucoma.  
     
     
         37 . A method for preventing or treating a gastrointestinal disorder modulated by alpha-2 adrenoceptors by administering to a mammal in need of such treatment, a safe and effective amount of an alpha-2 adrenoceptor agonist compound according to  claim 1 .  
     
     
         38 . A method for preventing or treating a gastrointestinal disorder, according to  claim 37 , wherein the disorder is chosen from the group comprising diarrhea and irritable bowel syndrome.  
     
     
         39 . A method for preventing or treating a gastrointestinal disorder, according to  claim 38 , wherein the disorder is diarrhea.  
     
     
         40 . A method for preventing or treating migraine by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to  claim 1 .  
     
     
         41 . A method for preventing or treating pain by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to  claim 1 .  
     
     
         42 . A method for treating substance abuse by administering to a mammal in need of such treatment, a safe and effective amount of a compound according to  claim 1.