Quinolinone derivatives and their pharmaceutical compositions

Abstract

Compounds of formula I in salt or solvate form, wherein W, Rx, Ry, R1, R2, R3, R4, R5, R6 and R7 and A have the meanings as indicated in the specification, are useful for treating diseases mediated by the β2-adrenoreceptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         in salt or solvate form, 
         where W is a group of formula 
       
       
         
           
           
               
               
           
         
         R x  and R y  are both —CH 2 — or —(CH 2 ) 2 —; 
         R 1  is hydrogen, hydroxy, or C 1 -C 10 -alkoxy; 
         R 2  and R 3  are each independently hydrogen or C 1 -C 10 -alkyl; 
         R 4 , R 5 , R 6  and R 7  are each independently hydrogen, halogen, cyano, hydroxy, C 1 -C 10 -alkoxy, 
         C 6 -C 10 -aryl, C 1 -C 10 -alkyl, C 1 -C 10 -alkyl substituted by one or more halogen atoms or one or more hydroxy or C 1 -C 10 -alkoxy groups, C 1 -C 10 -alkyl interrupted by one or more hetero atoms, C 2 -C 10 -alkenyl, trialkylsilyl, carboxy, C 1 -C 10 -alkoxycarbonyl, or —CONR 11 R 12  where R 11  and R 12  are each independently hydrogen or C 1 -C 10 -alkyl, 
         or R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  together with the carbon atoms to which they are attached denote a 5-, 6- or 7-membered carbocyclic ring or a 4- to 10-membered heterocyclic ring; 
         R 8 , R 9  and R 10  are each independently hydrogen or C 1 -C 4 -alkyl; and 
         A is selected from the group consisting of hydrogen succinate, fumarate, hippurate, mesylate, hydrogen sulphate, hydrogen tartrate, hydrogen chloride, hydrogen bromide, formate, esylate, tosylate, glycolate, acetate, xinafoate and hydrogen malonate. 
       
     
     
         2 . A compound according to  claim 1 , wherein
 R 8 , R 9  and R 10  are each H, R 1  is OH, R 2  and R 3  are each H and   (i) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each CH 3 O— and R 5  and R 6  are each H;   (ii) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  are each CH 3 CH 2 —;   (iii) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  are each CH 3 —;   (iv) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each CH 3 CH 2 — and R 5  and R 6  are each H;   (v) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  together denote —(CH 2 ) 4 —;   (vi) R x  and R y  are both —CH 2 -, and R 4  and R 7  are each H and R 5  and R 6  together denote —O(CH 2 ) 2 O —;   (vii) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  are each CH 3 (CH 2 ) 3 —;   (viii) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  are each CH 3 (CH 2 ) 2 —;   (ix) R x  and R y  are both —(CH 2 ) 2 —, R 4 , R 5 , R 6  and R 7  are each H; or   (x) R x  and R y  are both —CH 2 —, and R 4  and R 7  are each H and R 5  and R 6  are each CH 3 OCH 2 —.   
     
     
         3 . A compound according to  claim 1  or  2 , wherein A is selected from the group consisting of glycolate, acetate, xinafoate and hydrogen malonate. 
     
     
         4 . A compound according to  claim 1  or  2  that is selected from the group consisting of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen succinate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one fumarate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hippurate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one mesylate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen sulfate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen tartrate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen chloride, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen bromide, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one formate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one esylate, and (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one tosylate. 
     
     
         5 . A compound according to any one of  claims 1  to  3  that is selected from the group consisting of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one glycolate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate, and (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen malonate. 
     
     
         6 . A pharmaceutical composition comprising, as active ingredient, an effective amount of a compound of  claim 1 , optionally together with a pharmaceutically acceptable carrier. 
     
     
         7 . A pharmaceutical composition according to  claim 6 , wherein the active ingredient is selected from the group consisting of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen succinate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one fumarate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hippurate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one mesylate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen sulfate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen tartrate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen chloride, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen bromide, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one formate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one esylate and (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one tosylate. 
     
     
         8 . A pharmaceutical composition according to  claim 6 , wherein the active ingredient is selected from the group consisting of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one glycolate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate, and (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen malonate. 
     
     
         9 . A pharmaceutical composition according to  claim 6 , which is in inhalable form. 
     
     
         10 . A pharmaceutical composition according to  claim 6 , that further comprises as active ingredient one, two, three or more anti-inflammatory, bronchodilatory, antihistaminic/anti-allergic or anti-tussive drug substances. 
     
     
         11 . A pharmaceutical composition according to  claim 10 , that further comprises as active ingredient one or both of mometasone and glycopyrrolate. 
     
     
         12 . The use of a compound of formula I for the preparation of a medicament for the treatment of an inflammatory or obstructive airways disease. 
     
     
         13 . The use of a compound of formula I for the preparation of a medicament for the treatment of asthma or chronic obstructive pulmonary disease. 
     
     
         14 . The use according to  claim 12  or  13  wherein the compound of formula I is selected from the group consisting of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen succinate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one fumarate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hippurate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one mesylate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen sulfate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen tartrate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen chloride, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen bromide, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one formate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one esylate, or (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one tosylate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one glycolate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one acetate, (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate, and (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one hydrogen malonate. 
     
     
         15 . A process for preparing a compound of  claim 1  comprising:
 (i) for the preparation of compounds of formula I where A is hydrogen succinate, reacting the free base with succinic acid; 
 (ii) for the preparation of compounds of formula I where A is fumarate, reacting the free base with fumaric acid; 
 (iii) for the preparation of compounds of formula I where A is hippurate, reacting the free base with hippuric acid; 
 (iv) for the preparation of compounds of formula I where A is mesylate, reacting the free base with methanesulfonic acid; 
 (v) for the preparation of compounds of formula I where A is hydrogen sulphate, reacting the free base with sulfuric acid; 
 (vi) for the preparation of compounds of formula I where A is hydrogen tartrate, reacting the free base with (+)-L-tartaric; 
 (vii) for the preparation of compounds of formula I where A is hydrogen chloride, reacting the free base with hydrochloric acid; 
 (viii) for the preparation of compounds of formula I where A is hydrogen bromide, reacting the free base with hydrobromic acid; 
 (ix) for the preparation of compounds of formula I where A is formate, reacting the free base with formic acid; 
 (x) for the preparation of compounds of formula I where A is esylate, reacting the free base with ethansulfonic acid; 
 (xi) for the preparation of compounds of formula I where A is tosylate, reacting the free base with p-toluenesulfonic acid; 
 (xii) for the preparation of compounds of formula I where A is glycolate, reacting the free base with glycolic acid; 
 (xiii) for the preparation of compounds of formula I where A is acetate, reacting the free base with acetic acid; 
 (xiv) for the preparation of compounds of formula I where A is xinafoate, reacting the free base with 1-hydroxy-2-naphthoic acid; or (xv) for the preparation of compounds of formula I where A is, hydrogen malonate, reacting the free base with malonic acid.