Novel anti-inflammatory agents

Abstract

Disclosed are methods of regulating interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1) and methods of treating and/or preventing cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s) by administering a naturally occurring or synthetic quinazolone derivative. The invention provides novel synthetic quinazolone compounds, as well as pharmaceutical compositions comprising those compounds.

1 - 46 . (canceled) 
     
     
         47 . A method of treating infectious disease or cancer mediated by IL-6 in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
 Q is N or CRa 3 ; 
 V is N or CRa 4 ; 
 W is N or CH; 
 U is C═O, C═S, SO 2 , or S═O; 
 X is OH, SH, NH 2 , S(O)H, S(O) 2 H, S(O) 2 NH 2 , S(O)NH 2 , NHAc, or NHSO 2 Me; 
 Ra 1 , Ra 3 , and Ra 4  are independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or halogen; 
 Ra 2  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, amino, amide, or halogen; 
 Rb 2  and Rb 6  are independently hydrogen, methyl or fluorine; 
 Rb 3  and Rb 5  are independently hydrogen, halogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or C 1 -C 6  alkoxy; and 
 Rb 2  and Rb 3  and/or Rb 5  and Rb 6  may be connected to form a cycloalkyl or a heterocycle, 
 provided that at least one of Ra 1 , Ra 2 , Ra 3 , and Ra 4  is not hydrogen. 
 
     
     
         48 . The method according to  claim 47 , wherein:
 U is C═O;   Q is CRa 3 ;   X is OH, NH 2 , S(O) 2 NH 2 , NHAc, or NHSO 2 Me;   Ra 1  is hydrogen or C 1 -C 6  alkoxy;   Ra 2  is hydrogen, C 1 -C 6  alkoxy, amino, amide, or C 1 -C 6  alkyl;   Ra 3  and Ra 4  are independently hydrogen or C 1 -C 6  alkoxy;   Rb 2  and Rb 6  are both hydrogen; and   Rb 3  and Rb 5  are independently C 1 -C 6  alkyl or halogen.   
     
     
         49 . The method according to  claim 48 , wherein:
 Ra 3  is hydrogen, methoxy,   
       
         
           
           
               
               
           
         
       
       wherein
 n is 1, 2, or 3; 
 R 1 , R 1 ′, R 2 , and R 2 ′ are independently hydrogen, C 1 -C 3  alkyl, cyclopropyl, or halogen wherein if n is 1, then R 2  and R 2 ′, R 1  and R 1 ′, R 1  and R 2 ′, or R 2  and R 1 ′ may form a double bond, wherein said double bond can be cis, trans, or a mixture thereof; 
 Rx is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or aryl; and 
 Rn 1  and Rn 2  are independently C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or aryl. 
 
     
     
         50 . The method according to  claim 48 , wherein:
 Ra 3  is hydrogen, methoxy,   
       
         
           
           
               
               
           
         
       
       wherein
 n is 1, 2, or 3; 
 R 5  is C 1 -C 6  alkyl substituted with one or more groups which is methyl, phenyl, or pyridinyl; and 
 R 6  and R 7  are independently unsubstituted C 1 -C 6  alkyl. 
 
     
     
         51 . The method according to  claim 50 , wherein Ra 3  is hydrogen, methoxy, 2-methoxy-ethoxy, 2-dimethylamino-ethoxy, 2-benzyloxy-ethoxy, or 2-(pyridin-3-ylmethoxy)ethoxy. 
     
     
         52 . The method according to  claim 48 , wherein Ra 4  is hydrogen or unsubstituted C 1 -C 6  alkoxy. 
     
     
         53 . The method according to  claim 52 , wherein Ra 4  is hydrogen or methoxy. 
     
     
         54 . The method according to  claim 48 , wherein X is OH. 
     
     
         55 . The method according to  claim 48 , wherein:
 Ra 1  is hydrogen, methoxy,   
       
         
           
           
               
               
           
         
       
       wherein
 n is 0, 1, or 3; 
 R 1 , R 1 ′, R 2 , and R 2 ′ are independently hydrogen, C 1 -C 3  alkyl, cyclopropyl, or halogen wherein if n is 1, then R 2  and R 2 ′, R 1  and R 1 ′, R 1  and R 2 ′, or R 2  and R 1 ′ may form a double bond, wherein said double bond can be cis, trans, or a mixture thereof; 
 Rx is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or aryl; and 
 Rn 1  and Rn 2  are independently C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or aryl. 
 
     
     
         56 . The method according to  claim 48 , wherein:
 Ra 1  is hydrogen, methoxy,   
       
         
           
           
               
               
           
         
         n is 1, 2, or 3; and 
         R 5 , R 6  and R 7  are independently unsubstituted C 1 -C 6  alkyl. 
       
     
     
         57 . The method according to  claim 56 , wherein Ra 1  is hydrogen, methoxy, 2-methoxy-ethoxy, or 2-dimethylamino-ethoxy. 
     
     
         58 . The method according to  claim 48 , wherein:
 Ra 2  is hydrogen, unsubstituted C 1 -C 6  alkoxy, NHR 9 , or C 1 -C 6  alkyl substituted with heterocycle or amino; and   R 9  is acyl or heteroaryl.   
     
     
         59 . The method according to  claim 58 , wherein Ra 2  is hydrogen, methoxy, acetamido, morpholin-4-ylmethyl, pyridin-2-ylamino, (4-methylpiperazin-1-yl)methyl, or methanesulfonamido. 
     
     
         60 . The method according to  claim 48 , wherein Rb 3  and Rb 5  are independently unsubstituted C 1 -C 6  alkyl or halogen. 
     
     
         61 . The method according to  claim 60 , wherein Rb 3  and Rb 5  are independently methyl, tert-butyl, fluorine, or chlorine. 
     
     
         62 . A method of treating infectious disease or cancer mediated by IL-6 in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I, wherein the compound of Formula I is:
 3-(3-fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1 (2H)-one;   3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1 (2H)-one;   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;   7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;   2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;   2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;   2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;   N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;   2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;   2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one;   5-(2-dimethylamino-ethoxy)-2(4-hydroxy-3,5-dimethylphenyl)-7-methoxy-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethyl-phenyl)-7-methoxy-5-(2-methoxy-ethoxy)-3H-quinazolin-4-one;   7-(2-amino-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-7-(2-methoxy-ethoxy)-3H-quinazolin-4-one;   7-(2-benzyloxy-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-7-[2-(pyridin-3-ylmethoxy)ethoxy]-3H-quinazolin-4-one;   7-(2-dimethylamino-ethoxy)-2-(4-hydroxy-3,5-dimethylphenyl)-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-4-ylamino)-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethyl-phenyl)-6-(pyridin-2-ylamino)-3H-quinazolin-4-one;   2-(4-hydroxy-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one; or   N-((2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)methanesulfonamide, or a   
       tatutomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof. 
     
     
         63 . The method according to  claim 47 , wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma. 
     
     
         64 . The method according to  claim 62 , wherein the cancer is selected from multiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladder cancers, cardiac myxoma, tumor-induced cachexia, cerebral edema secondary to brain tumors, hormone-independent prostate cancer, B cell lymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.