Organic Compounds

Abstract

The present invention provides a compound of formula I: Said compound is inhibitor of aldosterone synthase and aromatase, and thus can be employed for the treatment of a disorder or disease mediated by aldosterone synthase or aromatase. Accordingly, the compound of formula I can be used in treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy. Finally, the present invention also provides a pharmaceutical composition.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 n is 1, or 2, or 3; 
 R is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, —C(O)O—R 10 , or —C(O)N(R 11 )(R 12 ), said —C(O)O—R 10 , or —C(O)N(R 11 )(R 12 ) optionally substituted by one to three substituents independently selected from hydroxyl, (C 1 -C 4 ) alkoxy, halo, —NH 2 , or (C 1 -C 4 ) dialkylamino; 
 wherein R 10 , R 11  and R 12  are independently hydrogen, (C 1 -C 4 ) alkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkyl-, (C 3 -C 8 ) cycloalkyl, or (C 2 -C 4 ) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C 1 -C 4 ) alkoxy; wherein R 11  and R 12  taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring; 
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected independently from the group consisting of hydrogen, halo, cyano, nitro, H 2 N—, (C 1 -C 4 ) dialkylamino, (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 6 -C 10 ) aryl, or (5-9)-membered heteroaryl, said (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl and (C 6 -C 10 ) aryl being optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, —NH 2 , cyano, nitro, (C 1 -C 4 ) alkoxy-(C 1 -C 4 ) alkyl-, or (C 1 -C 4 ) haloalkyl, with the proviso that no more than three of R 1 , R 2 , R 3 , R 4 , and R 5  are simultaneously hydrogen; 
 R and R 1  taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S; 
 R 6  and R 7  are independently hydrogen, hydroxyl, (C 1 -C 7 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 4 ) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkoxy; 
 when R 6  and R 7  are attached to the same carbon atom, they optionally form a moiety (A) represented by the following structure: 
 
       
         
           
           
               
               
           
         
         wherein R a  and R b  are independently hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkoxy, acyl, —COOR 15  or —COR 15 , said R 15  being hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) haloalkyl, aryl, or —NH 2 ; or 
         when R 6  and R 7  are attached to the same carbon atom, they taken together with said carbon atom optionally form a 3-8-membered ring; or 
         a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers. 
       
     
     
         2 . The compound of  claim 1 , wherein
 R and R 1  taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S; and   when R 6  and R 7  are attached to the same carbon atom, they optionally form said moiety (A) wherein R a  and R b  are independently hydrogen, or (C 1 -C 4 ) alkyl, or R 6  and R 7  taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.   
     
     
         3 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 R is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, —C(O)O—R 10 , or —C(O)N(R 11 )(R 12 ), said —C(O)O—R 10 , or —C(O)N(R 11 )(R 12 ) optionally substituted by one to three substituents independently selected from hydroxyl, (C 1 -C 4 ) alkoxy, halo, —NH 2 , or (C 1 -C 4 ) dialkylamino; 
 wherein R 10 , R 11  and R 12  are independently hydrogen, (C 1 -C 4 ) alkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkyl-, (C 3 -C 8 ) cycloalkyl, or (C 2 -C 4 ) alkenyl, each of which is optionally substituted by one to three substituents independently selected from halo, hydroxyl, or (C 1 -C 4 ) alkoxy; wherein R 11  and R 12  taken together with the nitrogen atom to which they are attached optionally form a 3-8-membered ring; 
 R 1 , R 2 , R 3 , R 4 , and R 5  are selected independently from the group consisting of hydrogen, halo, cyano, nitro, H 2 N—, (C 1 -C 4 ) dialkylamino, (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 6 -C 10 ) aryl, or (5-9)-membered heteroaryl, Said (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkyl and (C 6 -C 10 ) aryl being optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkyl, —NH 2 , cyano, nitro, (C 1 -C 4 ) alkoxy-(C 1 -C 4 ) alkyl-, or (C 1 -C 4 ) haloalkyl, with the proviso that no more than three of R 1 , R 2 , R 3 , R 4 , and R 5  are simultaneously hydrogen; 
 R and R 1  taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S; 
 R 6  and R 7  are independently hydrogen, hydroxyl, (C 1 -C 7 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 4 ) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) alkoxy; 
 when R 6  and R 7  are attached to the same carbon atom, they optionally form a moiety (A) represented by the following structure: 
 
       
         
           
           
               
               
           
         
         wherein R a  and R b  are independently hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) alkoxy, acyl, —COOR 15  or —COR 15 , said R 15  being hydrogen, (C 1 -C 7 ) alkyl, (C 1 -C 7 ) haloalkyl, aryl, or —NH 2 ; or 
         when R 6  and R 7  are attached to the same carbon atom, they taken together with said carbon atom optionally form a 3-8-membered ring, or 
         a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein R and R 1  taken together optionally form a 5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S; and when R 6  and R 7  are attached to the same carbon atom, they optionally form said moiety (A), wherein R a  and R b  are independently hydrogen, or (C 1 -C 4 ) alkyl, or R 6  and R 7  taken together with said carbon atom optionally form a 3-8-membered ring; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers. 
     
     
         5 . A method of treating a disorder or a disease wherein the disorder or the disease is selected from hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, chronic renal failure, restenosis, atherosclerosis, syndrome X, Obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, cardiac fibrosis, myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to  claim 1 . 
     
     
         6 . The method of claim  12 , the disorder or disease in a subject is characterized by an abnormal activity of aromatase. 
     
     
         7 . A method of treating a disorder or a disease wherein the disorder or disease is a estrogen-dependent disorder or disease selected from gynecomastia, Osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to  claim 1 . 
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and one or more pharmaceutically acceptable carriers.