Pyrrolo[2,3d]pyrimidine compositions and their use

Abstract

This invention pertains to compounds having the structure: wherein R 1 and R 2 together form a substituted or unsubstituted heterocyclic ring; R 3 is a substituted or unsubstituted aryl moiety; R 4 is a hydrogen atom, an unsubstituted alkyl, or a substituted or unsubstituted aryl moiety; and R 5 and R 6 are each independently a halogen atom, a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety, or a pharmaceutically acceptable salt thereof, and the use of these compounds to treat a disease associated with increased levels of adenosine in a subject.

1 - 62 . (canceled) 
   
   
       63 . A deazapurine having the formula II: 
     
       
         
         
             
             
         
       
       wherein
 X is N or CR 6 ; 
 R 1  and R 2  are each independently hydrogen, or substituted or unsubstituted alkoxy, aminoalkyl, alkyl, aryl, or alkylaryl, or together form a substituted or unsubstituted heterocyclic ring, provided that both R 1  and R 2  are both not hydrogen; 
 
       R 3  is substituted or unsubstituted arylalkyl, or aryl; 
       R 4  is hydrogen or substituted or unsubstituted C 1 -C 6  alkyl; 
       L is hydrogen, substituted or unsubstituted alkyl, or R 4  and L together form a substituted or unsubstituted heterocyclic or carbocyclic ring; 
       R 6  is hydrogen, substituted or unsubstituted alkyl, or halogen; 
       Q is CH 2 , O, S, or NR 7 , wherein R 7  is hydrogen or substituted or unsubstituted C 1 -C 6  alkyl; and 
       W is unsubstituted or substituted alkyl, cycloalkyl, alkynyl, aryl, arylalkyl, biaryl, heteroaryl, substituted carbonyl, substituted thiocarbonyl, or substituted sulfonyl; 
       provided that if R 3  is pyrrolidino, then R 4  is not methyl, 
     
     or a pharmaceutical acceptable salt thereof. 
   
   
       64 . The deazapurine of  claim 63  having the formula III: 
     
       
         
         
             
             
         
       
       wherein Q is CH 2 , O, S, or NH. 
     
   
   
       65 . The deazapurine of  claim 64 , wherein R 4  is hydrogen, L is hydrogen or methyl and R 3  is unsubstituted or substituted aryl. 
   
   
       66 . The deazapurine of  claim 65 , wherein
 W is substituted or unsubstituted aryl, 5- or 6-member heteroaryl, or biaryl; or   W is substituted or unsubstituted alkyl, cycloalkyl, alkynyl or arylalkyl;   or   W is —(CH 2 ) a —C(═O)Y or —(CH 2 ) a —C(═S)Y, wherein a is 0, 1, 2 or 3, Y is aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, NHR 11 R 12 , or, provided that Q is NH, OR 13 , and wherein R 11 , R 12  and R 13  are each independently hydrogen, or unsubstituted or substituted alkyl, aryl, arylalkyl, or cycloalkyl;   or   W is —(CH 2 ) b —S(═O) j Y, wherein j is 1 or 2, b is 0, 1, 2 or 3,   Y is aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, NHR 14 R 15 , or, provided that Q is NH, OR 16 , and wherein R 14 , R 15  and R 16  are each independently hydrogen, or unsubstituted or substituted alkyl, aryl, arylalkyl, or cycloalkyl.   
   
   
       67 - 70 . (canceled) 
   
   
       71 . The deazapurine of  claim 66 , wherein W is selected from the group consisting of pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, triazolyl, thioazolyl, oxazolyl, oxadiazolyl, pyrazolyl, furanyl, and thiophenyl. 
   
   
       72 - 84 . (canceled) 
   
   
       85 . The deazapurine of  claim 64 , wherein R 3  is selected from the group consisting of substituted and unsubstituted phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, triazolyl, thioazolyl, oxazolyl, oxadiazolyl, pyrazolyl, furanyl, methylenedioxyphenyl, and thiophenyl. 
   
   
       86 - 97 . (canceled) 
   
   
       98 . The deazapurine of  claim 64 , wherein R 6  is hydrogen or C 1 -C 3  alkyl. 
   
   
       99 . (canceled) 
   
   
       100 . The deazapurine of  claim 64 , wherein R 1  is hydrogen, and R 2  is substituted or unsubstituted alkyl or alkoxy, substituted or unsubstituted alkylamine, arylamine, or
 alkylarylamine, substituted or unsubstituted aminoalkyl, amino aryl, or aminoalkylaryl, substituted or unsubstituted alkylamide, arylamide or alkylarylamide, substituted or unsubstituted alkylsulfonamide, arylsulfonamide or alkylarylsulfonamide, substituted or unsubstituted alkylurea, arylurea or alkylarylurea, substituted or unsubstituted alkylcarbamate, arylcarbamate or alkylarylcarbamate, or substituted or unsubstituted alkylcarboxylic acid, arylcarboxylic acid or alkylarylcarboxylic acid.   
   
   
       101 - 105 . (canceled) 
   
   
       106 . The deazapurine of  claim 98 , wherein R 2  is 
     
       
         
         
             
             
         
       
       wherein
 A is C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, a chain of one to seven atoms, or a ring of three to seven atoms, optionally substituted with C 1 -C 6  alkyl, halogens, hydroxyl, carboxyl, thiol, or amino groups; 
 
       B is methyl, N(Me) 2 , N(Et) 2 , NHMe, NHEt, (CH 2 ) r NH 3   + , NH(CH 2 ) r CH 3 , (CH 2 ) r NH 2 , (CH 2 ) r CHCH 3 NH 2 , (CH 2 ) r NHMe, (CH 2 ) r OH, CH 2 CN, (CH 2 ) m CO 2 H, CHR 18 R 19 , or CHMeOH, wherein r is an integer from 0 to 2, m is 1 or 2, R 18  is alkyl, R 19  is NH 3 + or CO 2 H or R 18  and R 19  together are: 
     
     
       
         
         
             
             
         
       
       wherein p is 2 or 3; and R 17  is C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, a chain of one to seven atoms, or a ring of three to seven atoms, optionally substituted with C 1 -C 6  alkyl, halogens, hydroxyl, carboxyl, thiol, or amino groups. 
     
   
   
       107 . The deazapurine of  claim 106 , wherein A is unsubstituted or substituted C 1 -C 6  alkyl,
 and B is unsubstituted or unsubstituted C 1 -C 6  alkyl.   
   
   
       108 . (canceled) 
   
   
       109 . The deazapurine of  claim 106 , wherein R 2  is -A-NHC(═O)B, wherein A is —CH 2 CH 2 — and B is methyl. 
   
   
       110 - 114 . (canceled) 
   
   
       115 . The deazapurine of  claim 64 , wherein R 1  and R 2  together are: 
     
       
         
         
             
             
         
       
       wherein n is 1 or 2, and wherein the ring may be optionally substituted with one or more hydroxyl, amino, amino carbonyl, thiol, carboxyl, halogen, CH 2 OH, CH 2 NHC(═O)alkyl, or CH 2 NHC(═O)NHalkyl groups. 
     
   
   
       116 . The deazapurine of  claim 115 , wherein n is 1 or 2 and said ring is substituted with —NHC(═O)alkyl. 
   
   
       117 . The deazapurine of  claim 64 , wherein R 1  is hydrogen, R 2  is substituted or unsubstituted C 1 -C 6  alkyl, R 3  is substituted or unsubstituted phenyl, R 4  is hydrogen, L is hydrogen or substituted or unsubstituted C 1 -C 6  alkyl, Q is O, S or NR 7 , wherein R 7  is hydrogen or substituted or unsubstituted C 1 -C 6  alkyl, and W is substituted or unsubstituted aryl. 
   
   
       118 . The deazapurine of  claim 117 , wherein R 2  is -A-NHC(═O)B, wherein A and B are each independently unsubstituted C 1 -C 4  alkyl and R 3  is unsubstituted phenyl. 
   
   
       119 - 140 . (canceled) 
   
   
       141 . The deazapurine of  claim 117 , wherein said deazapurine is selected from the group consisting of: 
     4-(2-acetylaminoethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-fluorophenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-chlorophenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-methoxyphenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(2-pyridyloxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(N-phenylamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(N-methyl-N-phenylamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; and 
     4-(2-N′-methylureaethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. 
   
   
       142 - 148 . (canceled) 
   
   
       149 . A method for inhibiting the activity
 of an adenosine receptor in a cell, which comprises contacting said cell with a deazapurine of  claim 63  or  65 .   
   
   
       150 . The method of  claim 149 , wherein said deazapurine is selected from the group consisting of: 
     4-(2-acetylaminoethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-fluorophenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-chlorophenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(4-methoxyphenoxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(2-pyridyloxy)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(N-phenylamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; 
     4-(2-acetylaminoethyl)amino-6-(N-methyl-N-phenylamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine; and 
     4-(2-N′-methylureaethyl)amino-6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. 
   
   
       151 - 184 . (canceled) 
   
   
       185 . A method for the preparation of 
     
       
         
         
             
             
         
       
       comprising the steps of: 
       a) reacting 
     
     
       
         
         
             
             
         
       
     
     to provide 
     
       
         
         
             
             
         
       
     
     wherein P is a lower alkyl or a protecting group;
 b) cyclizing the product of step a) to provide 
 
     
       
         
         
             
             
         
       
       c) chlorinating the product of step b) to provide 
     
     
       
         
         
             
             
         
       
       
         and 
       
       d) treating the product of step c) with an amine, thereby providing 
     
     
       
         
         
             
             
         
       
     
     wherein
 R 1  and R 2  are each independently hydrogen, or substituted or unsubstituted alkoxy, aminoalkyl, alkyl, aryl, or alkylaryl, or together form a substituted or unsubstituted heterocyclic ring, provided that both R 1  and R 2  are both not hydrogen; 
 R 3  is substituted or unsubstituted arylalkyl, or aryl; 
 L is hydrogen, substituted or unsubstituted alkyl; 
 Q is CH 2 , O, S, or NR 7 , wherein R 7  is hydrogen or substituted or unsubstituted C 1 -C 6  alkyl; and 
 W is unsubstituted or substituted alkyl, cycloalkyl, alkynyl, aryl, arylalkyl, biaryl, heteroaryl, substituted carbonyl, substituted thiocarbonyl, or substituted sulfonyl. 
 
   
   
       186 . (canceled)