Novel Benzothiazolone Derivatives

Abstract

The present invention provides compounds of formula (I) wherein e, R 1 , R 2 , R 3 , R 4 , R 5 , R 4 , R 5 , R 6 , R 7 , R 7a , R 7b , A, D, m and n are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula 
     
       
         
         
             
             
         
       
       wherein 
       R 1  represents hydrogen; 
       each of R 2 , R 3 , R 4 , R 5 , R 4′  and R 5′  independently represents hydrogen or C 1 -C 6  alkyl; 
       e is 0; 
       A represents C(O); 
       D represents oxygen, sulphur or NR 8 ; 
       m is 1; 
       n is 1; 
       R 6  is (CH 2 )R 10a , wherein q is 0, 1, 2 or 3; R 10a  is phenyl, pyridyl, NR 9a R 9b  or piperidinyl, said piperidinyl being optionally N-substituted by C(O)O(C 1-6  alkyl); and R 9a  and R 9b  are, independently, C 1-4  alkyl; 
       R 7a  and R 7b  are, independently, hydrogen or C 1 -C 6  alkyl; 
       R 8  represents hydrogen or C 1 -C 6  alkyl; 
       R 7  represents a 5- to 14-membered aromatic or heteroaromatic ring system which is optionally substituted by halogen, trifluoromethyl, hydroxyl, carboxyl, C 1 -C 6  alkyl (optionally substituted by —NR 24 R 25 ), C 1 -C 6  alkoxy (optionally substituted by —NR 26 R 27 ), C 1 -C 6  alkoxycarbonyl, —NR 28 R 29 , C 1 -C 6  alkylcarbonylamino, C 1 -C 6  alkylsulphonylamino, phenylsulphonylamino, —C(O)NHR 30 , —SO 2 NHR 33 , C 0 -C 6  alkyl-R 34 , or a phenyl or 5- or 6-membered heteroaromatic ring (each of which is optionally substituted by halogen, trifluoromethyl, hydroxyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy or —NR 35 R 36 ); 
       R 24 , R 25 , R 26 , R 27 , R 28  and R 29  each independently represent hydrogen or C 1 -C 6  alkyl; 
       R 30  represents hydrogen, C 1 -C 6  alkyl, phenyl-C 0 -C 6  alkyl or C 2 -C 6  alkylene-NR 31 R 32 ; 
       either R 31  and R 32  each independently represent hydrogen or C 1 -C 6  alkyl, or R 31  and R 32  together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally comprising a further ring heteroatom selected from nitrogen and oxygen; 
       R 33  represents hydrogen, C 1 -C 6  alkyl, phenyl-C 0 -C 6  alkyl or C 2 -C 6  alkylene-NR 37 R 38 ; 
       R 34  represents a saturated, 5- or 6-membered nitrogen-containing ring; 
       R 35  and R 36  each independently represent hydrogen or C 1 -C 6  alkyl; and 
       either R 37  and R 38  each independently represent hydrogen or C 1 -C 6  alkyl, or R 37  and R 38  together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring optionally comprising a further ring heteroatom selected from nitrogen and oxygen; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . A compound as claimed in  claim 1  wherein each of R 2 , R 3 , R 4 , and R 5  is hydrogen. 
   
   
       3 - 5 . (canceled) 
   
   
       6 . A compound as claimed in  claim 1  wherein D is oxygen. 
   
   
       7 - 17 . (canceled) 
   
   
       18 . A compound as claimed in  claim 1  wherein R 7a  and R 7b  are, independently, hydrogen, methyl or ethyl. 
   
   
       19 . A compound as claimed in  claim 1  wherein R 7  is a 5- to 10-membered aromatic or heteroaromatic ring system optionally substituted by none, one or more substituents independently selected from halogen, trifluoromethyl, hydroxyl, carboxyl, C 1 -C 4  alkyl (optionally substituted by —NR 24 R 25 ), C 1 -C 4  alkoxy (optionally substituted by —NR 26 R 27 ), C 1 -C 4  alkoxycarbonyl, —NR 28 R 29 , C 1 -C 4  alkylcarbonylamino, C 1 -C 4  alkylsulphonylamino, phenylsulphonylamino, —C(O)NHR 30 , —SO 2 NHR 33 , C 0 -C 4  alkyl-R 34 , phenyl and a 5- to 6-membered heteroaromatic ring; wherein R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30  and R 33  are, independently, hydrogen or C 1 -C 6  alkyl; and R 34  is a saturated, 5- or 6-membered nitrogen containing ring. 
   
   
       20 . A compound as claimed in  claim 1  that is:
 tert-Butyl 4-({(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)[3-(2-phenyl ethoxy)propanoyl]amino}methyl)piperidine-1-carboxylate;   N-{2-[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-phenethyloxy-N-piperidin-4-ylmethyl-propionamide;   N-[2-[2-(4-Hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-N-phenethyl-3-phenethyloxy-propanamide;   N-Benzyl-N-[2-[2-(4-hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-3-phenethyloxy-propanamide;   N-[2-[2-(4-Hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-3-phenethyloxy-N-(3-pyridylmethyl)propanamide;   N-[2-[2-(4-Hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-3-phenethyloxy-N-phenyl-propanamide;   N-(3-{[2-(4-Hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}propyl)-3-(2-phenylethoxy)-N-(2-phenylethyl)propanamide;   3-[2-(4-Bromophenyl)ethoxy]-N-[2-[2-(4-hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-N-phenethyl-propanamide;   N-{2-[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-phenethyloxy-N-piperidin-4-yl propanamide;   N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-(2-phenylethoxy)propanamide;   N-[2-(Dimethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-(2-phenylethoxy)propanamide;   N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-{2-[2-(trifluoromethyl)phenyl]ethoxy}propanamide;   3-[2-(3-Chlorophenyl)ethoxy]-N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)propanamide;   N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(4-hydroxyphenyl)ethoxy]propanamide;   3-[2-(2,3-Dichlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)propanamide;   3-[2-(2-Bromo-5-methoxyphenyl)ethoxy]-N-[2-(diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)propanamide;   N-(2-Diethylaminoethyl)-3-[2-(3-fluorophenyl)ethoxy]-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}propanamide;   N-(2-Diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}-3-(2-methyl-2-phenylpropoxy)propanamide;   3-[2-(2,6-Dichlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}propanamide;   N-(2-Diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}-3-[2-(3-trifluoromethylphenyl)ethoxy]propanamide;   3-[2-(4-Chlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}propanamide;   3-[2-(3,4-Dichlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}propanamide;   N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(3-methylphenyl)ethoxy]propanamide;   N-(2-Diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}-3-[2-(3-hydroxyphenyl)ethoxy]propanamide;   N-(2-Diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}-3-[2-(3-methoxyphenyl)ethoxy]propanamide;   3-[2-(2-Chlorophenyl)ethoxy]-N-(2-diethylaminoethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethylamino]ethyl}propanamide; or,   N-[2-(Diethylamino)ethyl]-N-(2-{[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]amino}ethyl)-3-[2-(2-naphthyl)ethoxy]propanamide;   or a pharmaceutically acceptable salt thereof.   
   
   
       21 . A process for preparing a compound of formula (I) as claimed in  claim 1  the process comprising:
 (a) reacting a compound of formula (II):   
     
       
         
         
             
             
         
       
       wherein L 1  represents a leaving group and the other variables are as defined in formula (I), with a compound of formula (III) or a suitable salt thereof: 
     
     
       
         
         
             
             
         
       
       wherein R 1  is as defined in formula (I), in the presence of a base; 
       (b) when R 2  and R 3  each represent hydrogen, reacting a compound of formula (IV) 
     
     
       
         
         
             
             
         
       
       wherein e, R 4 , R 5 , R 4′ , R 5′ , R 6 , R 7 , A, D, m and n are as defined in formula (I), with a compound of formula (III) or a suitable salt thereof as defined in (a) above in the presence of a suitable reducing agent; 
       (c) when R 2  and R 3  each represent hydrogen, contacting a compound of formula (V) 
     
     
       
         
         
             
             
         
       
       wherein e, R 1 , R 4 , R 5 , R 4′ , R 5′ , R 6 , R 7 , A, D, m and n are as defined in formula (I) with a suitable reducing agent; 
       (d) when A is C(O), e is 0, and R 2 , R 3 , R 4  and R 5  are all hydrogen, deprotecting a compound of formula (XIX): 
     
     
       
         
         
             
             
         
       
       wherein R′ is alkyl or other suitable part of a protecting group; or, 
       (e) when A is C(O) and R 2  and R 3  are both alkyl, coupling a compound of formula (XI): 
     
     
       
         
         
             
             
         
       
       with a compound of formula (XXVI) 
     
     
       
         
         
             
             
         
       
       wherein L 2  is a leaving group under standard conditions; 
       and optionally after (a), (b), (c), (d), or (e) carrying out one or more of the following:
 converting the compound obtained to a further compound of formula (I) 
 forming a pharmaceutically acceptable salt of the compound. 
 
     
   
   
       22 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       23 . (canceled) 
   
   
       24 . (canceled) 
   
   
       25 . A method for treating adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 . 
   
   
       26 . A method of treating, or reducing the risk of, a disease or condition in which modulation of β2 adrenoreceptor activity is beneficial which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 . 
   
   
       27 . A method of treating, or reducing the risk of, an inflammatory disease or condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1 . 
   
   
       28 . (canceled) 
   
   
       29 . A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in  claim 1  and one or more agents selected from the list comprising:
 a non-steroidal glucocorticoid receptor (GR-receptor) agonist;   a PDE4 inhibitor;   a muscarinic receptor antagonist;   a modulator of chemokine receptor function; or,   an inhibitor of p38 kinase function.   
   
   
       30 . A compound as claimed in  claim 1 , wherein q is 2. 
   
   
       31 . A compound as claimed in  claim 1 , wherein R 9a  and R 9b  are, independently, methyl or ethyl.