Novel pharmaceutical compounds

Abstract

The instant invention provides compounds of Formula Ia which are leukotriene biosynthesis inhibitors. Compounds of Formula Ia are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.

1 - 7 . (canceled) 
   
   
       8 . A method of preventing the synthesis, the action, or the release of leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of structural Formula Ia 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts, esters and solvates thereof wherein:
    is selected from a single and a double bond; 
 “A” is selected from the group consisting of
 (a) a 5-membered aromatic ring containing (i) one or more carbon atoms, (ii) one heteroatom selected from oxygen and sulfur, and (iii) zero, one, two or three nitrogen atoms, 
 (b) a 5-membered aromatic ring containing one or more carbon atoms and from one to four nitrogen atoms, 
 (c) a 6-membered aromatic ring containing carbon atoms and one, two or three nitrogen atoms; 
 (d) a bicyclic aromatic ring system selected from benzothienyl, indolyl, quinolinyl and naphthalenyl; 
 (e) phenyl, and 
 (f) —CH 2 — phenyl; 
 
 
     and wherein A is optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of (i) —F (ii) —Cl, (iii) —C 1-3 alkyl optionally substituted with one or more of halo, (iv) —OC 1-3 alkyl optionally substituted with one or more of halo, (v) —OC 3-6 cycloalkyl, (vi) —CH 2 OH, (vii) —COOR 1 , (viii) —CN and (ix) —NR 10 R 11 ;
 X is selected from —O— and —S—; 
 Y is selected from:
 (a) —NR 6 —CHR 7  and —NR 8 —C(O)— wherein the nitrogen in Y is linked to the 5-membered heterocyclic moiety of Formula Ia and the carbon in Y is linked to the bicyclic heterocyclic moiety of Formula Ia; 
 (b) —S— and 
 (c) —O—; 
 
 R 1  is selected from the group consisting of —H, —C 1-6  alkyl and —C 3-6  cycloalkyl; 
 R 2  is selected from the group consisting of —H, —OH, —F, —C 1-3 alkyl, —OC 1-3 alkyl and —OC(O)—C 1-3 alkyl; 
 R 3  is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 9 , —C 2-6 alkenyl, —C 3-6 cycloalkyl, —C 5-7 cycloalkenyl and -Z; 
 R 4  is selected from the group consisting of —H, —C 1-6 alkyl, —C 1-6 alkyl substituted with one or more of fluoro, —C 1-6 alkyl substituted with R 9 , —C 2-6 alkenyl, —C 3-6 cycloalkyl, —C 5-7 cycloalkenyl and -Z; 
 or R 3  and R 4  together represent oxo; 
 or R 3  and R 4  are joined together with the carbon to which they are attached to form a ring selected from the group consisting of a —C 3-6 cycloalkyl ring and a —C 5-7 cycloalkenyl ring, provided that when R 3  and R 4  are joined together with the carbon to which they are attached to form a —C 5-7 cycloalkenyl ring, there is no double bond at the C-1 position in the ring; 
 or R 2 , R 3  and R 4  are joined together with the carbon to which they are attached to form a cycloalkenyl ring selected from: 
 
     
       
         
         
             
             
         
       
       R 5  is absent or is a substituent selected from the group consisting of —C 1-6  alkyl, —C 3-6  cycloalkyl and halo; 
       R 6  is selected from the group consisting of (a) —H, (b) —C 1-4  alkyl, (c) —C(O)C 1-4  alkyl, and (d) —C(O)phenyl optionally substituted with —C 1-4  alkyl; 
       R 7  is selected from the group consisting of (a) —H, (b) —C 1-4  alkyl, (c) —C 3-6 cycloalkyl, (d) phenyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of —C 1-4  alkyl, —F and —Cl, and (e) a 5-membered aromatic ring containing (i) one or more carbon atoms, (ii) one heteroatom selected from oxygen and sulfur, and (iii) zero, one, two or three nitrogen atoms; 
       R 8  is selected from the group consisting of —H and —C 1-4  alkyl; 
       R 9  is selected from the group consisting of —COOR 1 , —C(O)H, —CN, —CR 1 R 1 OH, —OR 1 , —S—C 1-6 alkyl and —S—C 3-6  cycloalkyl; 
       R 10  is selected from the group consisting of —H, —C 1-6  alkyl, —C 3-6  cycloalkyl and —COOR 1 ; 
       R 11  is selected from the group consisting of —H, —C 1-6  alkyl and —C 3-6  cycloalkyl; and 
       Z is selected from the group consisting of
 (a) a 5-membered aromatic ring containing (i) one or more carbon atoms, (ii) one heteroatom selected from oxygen and sulfur, and (iii) zero, one, two or three nitrogen atoms, 
 (b) a 5-membered aromatic ring containing one or more carbon atoms and from one to four nitrogen atoms, 
 (c) a 6-membered aromatic ring containing carbon atoms and one, two or three nitrogen atoms; 
 
       (d) phenyl, and
 (e) —CH 2 -phenyl and —CH 2 -dioxolanyl, 
 
     
     and wherein Z is optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of (i) —F, (ii) —Cl, (iii) —C 1-3 alkyl optionally substituted with one or more of halo, (iv) —OC 1-3 alkyl optionally substituted with one or more of halo, (v) —OC 3-6 cycloalkyl, (vi) —CH 2 OH, (vii) —COOR 1 , (viii) —CN and (ix) —NR 10 R 11 . 
   
   
       9 . The method of  claim 8  wherein the mammal is a human. 
   
   
       10 - 18 . (canceled) 
   
   
       19 . A method for the prevention or treatment of asthma comprising administering a therapeutically effective amount of a compound of Formula Ia to a patient in need of such treatment. 
   
   
       20 . A method for treating allergic rhinitis comprising administering a therapeutically effective amount of a compound of Formula Ia to a patient in need of such treatment. 
   
   
       21 . A method for treating chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of Formula Ia to a patient in need of such treatment.