Adenosine receptor antagonists and methods of making and using the same

Abstract

The invention is based on the discovery that compounds of Formula I are unexpectedly highly potent and selective inhibitors of the adenosine A 1 receptor. Adenosine A 1 antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. In one embodiment, the invention features a compound of formula I:

1 - 42 . (canceled) 
   
   
       43 . A method of making 8-substituted xanthines comprising the steps of: a) obtaining a N7,C8-dihydroxanthine; b) protecting the N7 position of the xanthine; c) deprotonating the C8 position with strong base to generate an anion; d) trapping the anion with a carboxyl, carbonyl, aldehyde, or ketone compound; and e) deprotecting the protected N7 position to obtain an 8-substituted xanthine. 
   
   
       44 . The method of  claim 43 , wherein N7 is protected with THP or BOM. 
   
   
       45 . The method of  claim 43 , wherein the C8 is deprotonated with n-BuLi or LDA. 
   
   
       46 . The method of  claim 43 , wherein the N7,C8-dihydroxanthine is obtained by treating a 1,3-disubstituted-5,6-diaminouracil with HC(OEt) 3 . 
   
   
       47 . A compound of formula (IV) 
     
       
         
         
             
             
         
       
       wherein R a  is selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy. 
     
   
   
       48 . A compound of formula (V) 
     
       
         
         
             
             
         
       
       wherein R a  is selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy. 
     
   
   
       49 . A method of making a compound of formula (J), the method comprising;
 coupling a compound of formula (VI)   
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of: 
       a) hydrogen; 
       b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and 
       c) aryl or substituted aryl; 
       with HOOC-Z-R 3 —COOR a  to form a compound of formula (H) 
       wherein R 3  is a bicyclic, tricyclic or pentacyclic group selected from the group consisting of: 
     
     
       
         
         
             
             
         
       
       wherein the bicyclic or tricyclic group is either unsubstituted or substituted with one or more substituents selected from the group consisting of: 
       (a) alkyl, alkenyl, and alkynyl; wherein each alkyl, alkenyl, or alkynyl group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of (amino)(R 5 )acylhydrazinylcarbonyl, (amino)(R 5 )acyloxycarboxy, (hydroxy)(carboalkoxy)alkylcarbamoyl, acyloxy, aldehydro, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylaminoalkylamino, alkylphosphono, alkylsulfonylamino, carbamoyl, R 5 , R 5 -alkoxy, cyano, cyanoalkylcarbamoyl, cycloalkylamino, dialkylamino, dialkylaminoalkylamino, dialkylphosphono, haloalkylsulfonylamino, (heterocyclylalkyl)amino, heterocyclylcarbamoyl, hydroxy, hydroxyalkylsulfonylamino, oximino, phosphono, substituted aralkylamino, substituted arylcarboxyalkoxycarbonyl, substituted heteroarylsulfonylamino, substituted heterocyclyl, thiocarbamoyl, and trifluoromethyl; and 
       (b) (alkoxycarbonyl)aralkylcarbamoyl, aldehydro, alkenoxy, alkenylsulfonylamino, alkoxy, alkoxycarbonyl, alkylcarbamoyl, alkoxycarbonylamino, alkylsulfonylamino, alkylsulfonyloxy, amino, aminoalkylaralkylcarbamoyl, aminoalkylcarbamoyl, aminoalkylheterocyclylalkylcarbamoyl, aminocycloalkylalkylcycloalkylcarbamoyl, aminocycloalkylcarbamoyl, aralkoxycarbonylamino, arylheterocyclyl, aryloxy, arylsulfonylamino, arylsulfonyloxy, carbamoyl, -R 5 , R 5 -alkoxy, R 5 -alkyl(alkyl)amino, R 5 -alkylalkylcarbamoyl, R 5 -alkylcarbamoyl, R 5 -alkylsulfonyl, R 5 -alkylsulfonylamino, R 5 -alkylthio, R 5 -heterocyclylcarbonyl, cyano, cycloalkylamino, dialkylaminoalkylcarbamoyl, halogen, heterocyclyl, (heterocyclylalkyl)amino, hydroxy, oximino, substituted aralkylamino, substituted heterocyclyl, substituted heterocyclylsulfonylamino, sulfoxyacylamino, and thiocarbamoyl; 
       R 4  is selected from the group consisting of hydrogen, C 1-4 -alkyl, C 1-4 -alkyl-CO 2 H, and phenyl, wherein the C 1-4 -alkyl, C 1-4 -alkyl-CO 2 H, and phenyl groups are either unsubstituted or substituted with one to three substituents selected from the group consisting of halogen, —OH, —OMe, —NH 2 , NO 2 , benzyl, and benzyl substituted with one to three substituents selected from the group consisting of halogen, —OH, —OMe, —NH 2 , and —NO 2 ; 
       R 5  is selected from the group consisting of —CH 2 COOH, —C(CF 3 ) 2 OH, —CONHNHSO 2 CF 3 , —CONHOR 4 , —CONHSO 2 R 4 , —CONHSO 2 NHR 4 , —C(OH)R 4 PO 3 H 2 , —NHCOCF 3 , —NHCONHSO 2 R 4 , —NHPO 3 H 2 , —NHSO 2 R 4 , —NHSO 2 NHCOR 4 , —OPO 3 H 2 , —OSO 3 H, —PO(OH)R 4 , —PO 3 H 2 , —SO 3 H, —SO 2 NHR 4 , and the following: 
     
     
       
         
         
             
             
         
       
       Z is selected from the group consisting of a single bond, —O—, —(CH 2 ) 1-3 —, —O(CH 2 ) 1-2 —, —CH 2 OCH 2 —, —(CH 2 ) 1-2 O—, —CH═CHCH 2 —, —CH═CH—, and —CH 2 CH═CH—; 
     
     
       
         
         
             
             
         
       
       wherein R a  is selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy; and 
       subjecting the compound of formula (H) to conditions sufficient to effect a ring closure, producing a compound of formula (J) 
     
     
       
         
         
             
             
         
       
     
   
   
       50 . The method of  claim 49 , wherein the coupling of the compound of formula (VI) is effected using a coupling reagent selected from the group consisting of benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP), O-benzo-triazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU). 
   
   
       51 . The method of  claim 49 , wherein the conditions sufficient to effect a ring closure are basic conditions. 
   
   
       52 . The method of  claim 49 , further comprising converting —COOR a  of formula (J) into an acrylic acid derivative. 
   
   
       53 . The method of  claim 49 , wherein the —COOR a  of formula (J) into an acrylic acid derivative comprising the following steps:
 i) when R a  is other than H, hydrolyzing COOR a  into the corresponding carboxylic acid;   ii) reducing the carbozylic acid to the corresponding alcohol;   iii) oxidizing the alcohol to the corresponding aldehyde, and   iv) performing a Wadsworth-Horner-Emmons or Wittig reaction to form the corresponding acrylic acid derivative.   
   
   
       54 . The method of  claim 49 , wherein Z is a bond. 
   
   
       55 . The method of  claim 49 , wherein R 3  is 
     
       
         
         
             
             
         
       
     
   
   
       56 . A method of making a compound of formula (III) 
     
       
         
         
             
             
         
       
       wherein R a  are R b  are each independently selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy; 
       the method comprising; 
       reacting a compound of formula (I) 
     
     
       
         
         
             
             
         
       
       with a chloroethane containing compound to make a compound of formula (II) 
     
     
       
         
         
             
             
         
       
       subjecting the compound of formula (II) to conditions to effect a ring closure, to form a compound of formula (III). 
     
   
   
       57 . The method of  claim 56 , wherein when R b  is other than H, further comprising converting the compound of formula (III) to a compound of formula (IV) 
     
       
         
         
             
             
         
       
     
   
   
       58 . The method of  claim 56  wherein the compound of formula (III) comprises an ester —COOR b , and the ester is hydrolyzed to an acid. 
   
   
       59 . The method of  claim 56  wherein the chloroethane containing compound is bromochloroethane. 
   
   
       60 . A compound of formula (XXI) 
     
       
         
         
             
             
         
       
       wherein R c  and R d  are each selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy. 
     
   
   
       61 . A compound of formula (XXII) 
     
       
         
         
             
             
         
       
       R d  is selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy. 
     
   
   
       62 . A method of making a compound of formula (XXI) 
     
       
         
         
             
             
         
       
       wherein R c  and R d  are each selected from the group consisting of H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy 
       the method comprising; 
       reducing a compound of formula (IV) to provide a compound of formula (XVI) 
     
     
       
         
         
             
             
         
       
       wherein R a  is H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy and, when R a  is not H, hydrolyising the —COOR a  ester to provide the corresponding carboxylic acid of formula (XVII) 
     
     
       
         
         
             
             
         
       
       protecting the resulting carboxylic acid of formula (XVII) to provide the resulting compound of formula (XVIII) 
     
     
       
         
         
             
             
         
       
       oxidizing the primary —OH of formula (XVIII) to provide the aldehyde of formula (XIX) 
     
     
       
         
         
             
             
         
       
       performing a Wadsworth-Horner-Emmons or Wittig reaction to form an acrylic acid derivative of formula (XX) 
     
     
       
         
         
             
             
         
       
       reducing the compound of formula (XX) to provide the compound of formula (XXI). 
     
   
   
       63 . The method of  claim 62 , wherein the compound of formula (IV) is reduced with sodium borohydride. 
   
   
       64 . The method of  claim 62 , wherein the compound of formula (XVI) is hydrolyzed under basic conditions. 
   
   
       65 . The method of  claim 62 , wherein R c  is benzyl. 
   
   
       66 . The method of  claim 62 , wherein the compound of formula (XVIII) is oxidized using a vilsmier reaction. 
   
   
       67 . A method of making a compound of formula (XIV), the method comprising coupling a compound of formula (VI) 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently selected from the group consisting of: 
       a) hydrogen; 
       b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and 
       c) aryl or substituted aryl; 
       with a compound of formula (XXII) 
     
     
       
         
         
             
             
         
       
       wherein R d  is H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy; 
       to form a compound of formula (XXIII) 
     
     
       
         
         
             
             
         
       
       subjecting the compound of formula (XXIII) to conditions sufficient to effect a ring closure, producing a compound of formula (XIV) 
     
     
       
         
         
             
             
         
       
     
   
   
       68 . The method of  claim 67 , wherein when R d  is not H, further comprising hydrolyzing the compound of formula (XIV) to produce the corresponding carboxylic acid. 
   
   
       69 . The method of  claim 67 , wherein the conditions sufficient to effect a ring closure are basic conditions. 
   
   
       70 . A compound of formula (XXXI) 
     
       
         
         
             
             
         
       
       wherein R a  is H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy. 
     
   
   
       71 . A method of making a compound of formula (XXXI) 
     
       
         
         
             
             
         
       
       formula (XXXI), the method comprising 
       effecting a ring closure of formula (XXXI) 
     
     
       
         
         
             
             
         
       
     
     to provide a compound of formula (XXX) 
     
       
         
         
             
             
         
       
       reducing the compound of formula (XXX) to provide a compound of formula (XXXI). 
     
   
   
       72 . A method of making compound of formula (XXXV), 
     
       
         
         
             
             
         
       
       wherein R a  is H, C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy R 1  and R 2  are independently selected from the group consisting of: 
       a) hydrogen; 
       b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and 
       c) aryl or substituted aryl; 
       X 1  and X 2  are independently selected from the group consisting of O and S; and 
       R 6  is selected from the group consisting of hydrogen, alkyl, acyl, alkylsulfonyl, aralkyl, substituted aralkyl, substituted alkyl, and heterocycly; 
       the method comprising converting the compound of formula (X) into a compound of formula (XL), by converting the —OH of formula (X) into a leaving group (LG) 
     
     
       
         
         
             
             
         
       
       displacing the leaving group LG with an ester to provide a compound of formula (XLI) 
     
     
       
         
         
             
             
         
       
       and converting the compound of formula (XLI) into the compound of formula (XXXV) by decarboxylating the compound of formula (XLI). 
     
   
   
       73 . The method of  claim 72 , wherein the leaving group LG is selected from the group consisting of halo, mesylate, nosylate, tosylate. and trifluoromethanesulfonate. 
   
   
       74 . The method of  claim 72 , wherein the LG is displaced with a malonic ester. 
   
   
       75 . A method of making a compound of formula (XXI) 
     
       
         
         
             
             
         
       
     
     wherein R c  and R d  are each independently selected from the group consisting of H or C 1-5  alkyl the method comprising; 
     performing a Wadsworth-Horner-Emmons or Wittig reaction on a compound of Formula (XIX) to form an acrylic acid derivative of formula (XX) 
     
       
         
         
             
             
         
       
     
     reducing the compound of formula (XX) to provide the compound of formula (XXI). 
   
   
       76 . The method of  claim 75 , wherein R c  is hydrogen. 
   
   
       77 . The method of  claim 69 , wherein potassium hydroxide is used as the base. 
   
   
       78 . A method of making a compound of Formula (XIV) 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are selected from the group consisting of
 a) hydrogen; 
 b) alkyl, alkenyl of not less than 3 carbons, or alkynyl of not less than 3 carbons; wherein said alkyl, alkenyl, or alkynyl is either unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and 
 c) aryl or substituted aryl; 
 
     the method comprising; 
     performing a Wadsworth-Horner-Emmons or Wittig reaction on a compound of Formula (XIX) to produce a compound of Formula (XX) 
     
       
         
         
             
             
         
       
     
     wherein R 1  is hydrogen, and R d  is selected from the group consisting of C 1-5  alkyl, or benzyl, the phenyl ring being optionally substituted with 1-3 substituents selected from the group consisting of halo, hydroxyl, or C 1-3  alkoxy; 
     reducing a compound of Formula (XX) to a compound of Formula (XXI) 
     
       
         
         
             
             
         
       
     
     converting a compound of Formula (XXI) to a compound of Formula (XXII) 
     
       
         
         
             
             
         
       
     
     reacting a compound of Formula (XXII) with a compound of Formula (VI) 
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are defined as above, to make a compound of Formula (XXIII) 
     
       
         
         
             
             
         
       
     
     converting a compound of Formula (XXIII) to a compound of Formula (XXIV), and then to a compound of Formula (XIV) in a “one pot” procedure 
     
       
         
         
             
             
         
       
     
   
   
       79 . The method of  claim 78 , wherein R 1  and R 2  are both n-propyl. 
   
   
       80 . The method of  claim 79 , wherein R d  is C 1-5  alkyl. 
   
   
       81 . The method of  claim 78 , wherein the reduction step is performed using hydrogen gas and a palladium catalyst. 
   
   
       82 . The method of  claim 78 , wherein the “one pot” procedure is performed using potassium hydroxide as a base and a hydrolyzing agent.