Amine Derivatives

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

1 . A compound of formula (1), 
     
       
         
         
             
             
         
       
     
     wherein A is selected from: 
     
       
         
         
             
             
         
       
     
     wherein * is the attachment point of A to the carbon bearing the hydroxy; and B is selected from:
 1) **—(CH 2 ) 2 —(CH 2 ) m —X 1 —(CH 2 ) n —*** wherein X 1  is O or S, m is an integer from 0 to 9, n is an integer from 0 to 9 and n+m is 4 to 9 inclusive; 
 2) C 6 -C 12  alkylene optionally substituted with one or two C 1 -C 4  alkyl; 
 3) a group of formula 
 
     
       
         
         
             
             
         
       
     
     wherein X 2  is O or S, r is an integer from 2 to 7, s is an integer from 0 to 6, t is an integer from 0 to 6, s+t is 1 to 6 inclusive and r+s+t is 3 to 8 inclusive; and
 4) a group of formula: 
 
     
       
         
         
             
             
         
       
       ** is the attachment point of B to the adjacent NH group and *** is the attachment point of B to the adjacent phenyl group; or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
     
   
   
       2 . A compound according to  claim 1  wherein B is C 6 -C 12  alkylene; or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       3 . A compound according to  claim 2  wherein B is (CH 2 ) 8 , (CH 2 ) 9  or (CH 2 ) 10 ; or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       4 . A compound according to  claim 1  wherein B is (CH 2 ) 2 —(CH 2 ) m —X 1 —(CH 2 ) n ; or a tautomer thereof; or a Pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       5 . A compound according to  claim 4  wherein X 1  is O; or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       6 . A compound according to  claim 5  wherein B is selected from (CH 2 ) 6 —O—(CH 2 ) 3 , (CH 2 ) 6 —O—(CH 2 ) 4 , and (CH 2 ) 7 —O—; or a tautomer thereof; or a Pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       7 . A compound according to  claim 1  wherein B is a group of formula 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       8 . A compound according to  claim 7  wherein X 2  is O; or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       9 . A compound according to  claim 8  wherein B is 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       10 . A compound according to  claim 9  where B is 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a Pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       11 . A compound according to  claim 1  wherein B is of formula: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       12 . A compound according to  claim 11  wherein B is of formula: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       13 . A compound according to  claim 1  to wherein A is of formula: 
     
       
         
         
             
             
         
       
     
     or a tautomer thereof; or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       14 . A compound according to  claim 1  selected from the group consisting of: 
     N-(5-{(1R) 2 -[(10-(3-[(1R-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}decyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)methanesulfonamide; 
     N-(5-[(1R)-2-({2-[4-(3-{3-[(1R)-3-(diisopropylamino-1-phenylpropyl]-4-hydroxyphenyl}propoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}methane sulfonamide; 
     N-(5-[(1R)-2-({2-[4(4-{3-[(1R-3-(Diisopropylamino)-1-phenylpropyl]-4-hydroxyphenylbutoxy)phenyl]ethyl{amino)-1-hydroxyethyl]-2-hydroxypheny}methanesulfonamide; 
     N-(5-[(1R)-2-[(7-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenoxy}heptyl)amino]-1-hydroxyethyl)-2-hydroxyphenyl)methanesulfonamide; 
     N-{5-[(1R)-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide; 
     N-{5-[(1R)-2-{[6-(4-{3-[(1R)-3-(Diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy) hexyl]amino}-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide; 
     N{5-[(1R)-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)pheny]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}formamide; 
     5-[(1R)-2-({2-[4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one; 
     5-[(1R)-1-{[hydroxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]benzene-1,3-diol; 
     N-{5-[(1R)-2-({2-[3-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl)amino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide; 
     2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(2-{3-[2-({(2R-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethyl)phenol; 
     5-[(1R)-2-({2-[4-(2-{3-[(1R-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]benzene-1,3-diol; 
     N-{5-[(1R)-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy) phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}formamide; 
     5-[(1R-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one; 
     2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(2-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}ethyl)phenol; 
     N-(5-{(1R)-2-[(8-(3-(1R)-3-(diisopropylamino)-1-phenylpropyl-]-4-hydroxyphenyl}octyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)methanesulfonamide; 
     N-(5-(1R)-2-[(2-{4-[(5-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}pentyl)oxy]phenyl]ethyl)amino]-1-hydroxyethyl]-2-hydroxyphenyl)methanesulfonamide; 
     2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(4-{4-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenoxy}butyl)phenol; 
     N-{5-[(1R)-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide succinate salt; and 
     5-[(1R)-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]-11-dimethylethyl}amino)-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one; or 
     a tautomer thereof or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer. 
   
   
       15 .- 16 . (canceled) 
   
   
       17 . A pharmaceutical composition comprising at least an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or additive. 
   
   
       18 .- 23 . (canceled) 
   
   
       24 . A method of treating a disease, disorder or condition in a mammal said method comprising administering to said mammal in need thereof a therapeutically effective amount of a compound of  claim 1 , a tautomer thereof, or a pharmaceutically acceptable salt or pharmaceutically acceptable quaternary ammonium salt of said compound or tautomer, wherein said disease, disorder or condition is selected from the group consisting of asthma, chronic or acute bronchoconstriction, bronchitis, small airways obstruction, emphysema, obstructive or inflammatory airways disease, acute lung injury or bronchiectasis. 
   
   
       25 . A method according to  claim 24  wherein said asthma is selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atomic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral Infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolitis. 
   
   
       26 - 27 . (canceled) 
   
   
       28 . A method according to  claim 24  wherein said obstructive or inflammatory airways disease is selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension. 
   
   
       29 . A method according to  claim 24  wherein said bronchitis is selected from the group consisting of chronic bronchitis, acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus bronchitis, streptococcal bronchitis and vesicular bronchitis. 
   
   
       30 . A method according to  claim 24  wherein said bronchiectasis is selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchlectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis. 
   
   
       31 . The method according to  claim 24  wherein said disease, disorder or condition is asthma or chronic obstructive pulmonary disease (COPD). 
   
   
       32 . N-{5-[(1R-2-({2-[4(2-{3-[(1R-3-(diisopropylamino 1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide.